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Elephant – Wikipedia, the free encyclopedia

Elephants are large mammals of the family Elephantidae and the order Proboscidea. Two species are traditionally recognised, the African elephant (Loxodonta africana) and the Asian elephant (Elephas maximus), although some evidence suggests that African bush elephants and African forest elephants are separate species (L.africana and L.cyclotis respectively). Elephants are scattered throughout sub-Saharan Africa, South Asia, and Southeast Asia. Elephantidae is the only surviving family of the order Proboscidea; other, now extinct, members of the order include deinotheres, gomphotheres, mammoths, and mastodons. Male African elephants are the largest extant terrestrial animals and can reach a height of 4m (13ft) and weigh 7,000kg (15,000lb). All elephants have several distinctive features, the most notable of which is a long trunk or proboscis, used for many purposes, particularly breathing, lifting water and grasping objects. Their incisors grow into tusks, which can serve as weapons and as tools for moving objects and digging. Elephants’ large ear flaps help to control their body temperature. Their pillar-like legs can carry their great weight. African elephants have larger ears and concave backs while Asian elephants have smaller ears and convex or level backs.

Elephants are herbivorous and can be found in different habitats including savannahs, forests, deserts and marshes. They prefer to stay near water. They are considered to be keystone species due to their impact on their environments. Other animals tend to keep their distance where predators such as lions, tigers, hyenas, and wild dogs usually target only the young elephants (or “calves”). Females (“cows”) tend to live in family groups, which can consist of one female with her calves or several related females with offspring. The groups are led by an individual known as the matriarch, often the oldest cow. Elephants have a fissionfusion society in which multiple family groups come together to socialise. Males (“bulls”) leave their family groups when they reach puberty, and may live alone or with other males. Adult bulls mostly interact with family groups when looking for a mate and enter a state of increased testosterone and aggression known as musth, which helps them gain dominance and reproductive success. Calves are the centre of attention in their family groups and rely on their mothers for as long as three years. Elephants can live up to 70 years in the wild. They communicate by touch, sight, smell and sound; elephants use infrasound, and seismic communication over long distances. Elephant intelligence has been compared with that of primates and cetaceans. They appear to have self-awareness and show empathy for dying or dead individuals of their kind.

African elephants are listed as vulnerable by the International Union for Conservation of Nature (IUCN), while the Asian elephant is classed as endangered. One of the biggest threats to elephant populations is the ivory trade, as the animals are poached for their ivory tusks. Other threats to wild elephants include habitat destruction and conflicts with local people. Elephants are used as working animals in Asia. In the past they were used in war; today, they are often controversially put on display in zoos, or exploited for entertainment in circuses. Elephants are highly recognisable and have been featured in art, folklore, religion, literature and popular culture.

The word “elephant” is based on the Latin elephas (genitive elephantis) (“elephant”), which is the Latinised form of the Greek (elephas) (genitive (elephantos)),[1] probably from a non-Indo-European language, likely Phoenician.[2] It is attested in Mycenaean Greek as e-re-pa (genitive e-re-pa-to) in Linear B syllabic script.[3][4] As in Mycenaean Greek, Homer used the Greek word to mean ivory, but after the time of Herodotus, it also referred to the animal.[1] The word “elephant” appears in Middle English as olyfaunt (c.1300) and was borrowed from Old French oliphant (12th century).[2]Loxodonta, the generic name for the African elephants, is Greek for “oblique-sided tooth”.[5]

Elephants belong to the family Elephantidae, the sole remaining family within the order Proboscidea. Their closest extant relatives are the sirenians (dugongs and manatees) and the hyraxes, with which they share the clade Paenungulata within the superorder Afrotheria.[6] Elephants and sirenians are further grouped in the clade Tethytheria.[7] Traditionally, two species of elephants are recognised; the African elephant (Loxodonta africana) of sub-Saharan Africa, and the Asian elephant (Elephas maximus) of South and Southeast Asia. African elephants have larger ears, a concave back, more wrinkled skin, a sloping abdomen and two finger-like extensions at the tip of the trunk. Asian elephants have smaller ears, a convex or level back, smoother skin, a horizontal abdomen that occasionally sags in the middle and one extension at the tip of the trunk. The looped ridges on the molars are narrower in the Asian elephant while those of the African are more diamond-shaped. The Asian elephant also has dorsal bumps on its head and some patches of depigmentation on its skin.[8] In general, African elephants are larger than their Asian cousins.

Swedish zoologist Carl Linnaeus first described the genus Elephas and an elephant from Sri Lanka (then known as Ceylon) under the binomial Elephas maximus in 1758. In 1798, Georges Cuvier classified the Indian elephant under the binomial Elephas indicus. Dutch zoologist Coenraad Jacob Temminck described the Sumatran elephant in 1847 under the binomial Elephas sumatranus. English zoologist Frederick Nutter Chasen classified all three as subspecies of the Asian elephant in 1940.[9] Asian elephants vary geographically in their colour and amount of depigmentation. The Sri Lankan elephant (Elephas maximus maximus) inhabits Sri Lanka, the Indian elephant (E.m.indicus) is native to mainland Asia (on the Indian subcontinent and Indochina), and the Sumatran elephant (E.m.sumatranus) is found in Sumatra.[8] One disputed subspecies, the Borneo elephant, lives in northern Borneo and is smaller than all the other subspecies. It has larger ears, a longer tail, and straighter tusks than the typical elephant. Sri Lankan zoologist Paules Edward Pieris Deraniyagala described it in 1950 under the trinomial Elephas maximus borneensis, taking as his type an illustration in National Geographic.[10] It was subsequently subsumed under either E.m.indicus or E.m.sumatranus. Results of a 2003 genetic analysis indicate its ancestors separated from the mainland population about 300,000years ago.[11] A 2008 study found that Borneo elephants are not indigenous to the island but were brought there before 1521 by the Sultan of Sulu from Java, where elephants are now extinct.[10]

The African elephant was first named by German naturalist Johann Friedrich Blumenbach in 1797 as Elephas africana.[12] The genus Loxodonta was commonly believed to have been named by Georges Cuvier in 1825. Cuvier spelled it Loxodonte and an anonymous author romanised the spelling to Loxodonta; the International Code of Zoological Nomenclature recognises this as the proper authority.[13] In 1942, 18 subspecies of African elephant were recognised by Henry Fairfield Osborn, but further morphological data has reduced the number of classified subspecies,[14] and by the 1990s, only two were recognised, the savannah or bush elephant (L.a.africana) and the forest elephant (L.a.cyclotis);[15] the latter has smaller and more rounded ears and thinner and straighter tusks, and is limited to the forested areas of western and Central Africa.[16] A 2000 study argued for the elevation of the two forms into separate species (L.africana and L.cyclotis respectively) based on differences in skull morphology.[17] DNA studies published in 2001 and 2007 also suggested they were distinct species,[18][19] while studies in 2002 and 2005 concluded that they were the same species.[20][21] Further studies (2010, 2011, 2015) have supported African savannah and forest elephants’ status as separate species.[22][23][24] The two species are believed to have diverged 6 million years ago.[25] The third edition of Mammal Species of the World lists the two forms as full species[13] and does not list any subspecies in its entry for Loxodonta africana.[13] This approach is not taken by the United Nations Environment Programme’s World Conservation Monitoring Centre nor by the IUCN, both of which list L.cyclotis as a synonym of L.africana.[26][27] Some evidence suggests that elephants of western Africa are a separate species,[28] although this is disputed.[21][23] The pygmy elephants of the Congo Basin, which have been suggested to be a separate species (Loxodonta pumilio) are probably forest elephants whose small size and/or early maturity are due to environmental conditions.[29]

Over 161 extinct members and three major evolutionary radiations of the order Proboscidea have been recorded. The earliest proboscids, the African Eritherium and Phosphatherium of the late Paleocene, heralded the first radiation.[30] The Eocene included Numidotherium, Moeritherium and Barytherium from Africa. These animals were relatively small and aquatic. Later on, genera such as Phiomia and Palaeomastodon arose; the latter likely inhabited forests and open woodlands. Proboscidean diversity declined during the Oligocene.[31] One notable species of this epoch was Eritreum melakeghebrekristosi of the Horn of Africa, which may have been an ancestor to several later species.[32] The beginning of the Miocene saw the second diversification, with the appearance of the deinotheres and the mammutids. The former were related to Barytherium, lived in Africa and Eurasia,[33] while the latter may have descended from Eritreum[32] and spread to North America.[33]

The second radiation was represented by the emergence of the gomphotheres in the Miocene,[33] which likely evolved from Eritreum[32] and originated in Africa, spreading to every continent except Australia and Antarctica. Members of this group included Gomphotherium and Platybelodon.[33] The third radiation started in the late Miocene and led to the arrival of the elephantids, which descended from, and slowly replaced, the gomphotheres.[34] The African Primelephas gomphotheroides gave rise to Loxodonta, Mammuthus and Elephas. Loxodonta branched off earliest, around the Miocene and Pliocene boundary, while Mammuthus and Elephas diverged later during the early Pliocene. Loxodonta remained in Africa, while Mammuthus and Elephas spread to Eurasia, and the former reached North America. At the same time, the stegodontids, another proboscidean group descended from gomphotheres, spread throughout Asia, including the Indian subcontinent, China, southeast Asia and Japan. Mammutids continued to evolve into new species, such as the American mastodon.[35]

At the beginning of the Pleistocene, elephantids experienced a high rate of speciation. Loxodonta atlantica became the most common species in northern and southern Africa but was replaced by Elephas iolensis later in the Pleistocene. Only when Elephas disappeared from Africa did Loxodonta become dominant once again, this time in the form of the modern species. Elephas diversified into new species in Asia, such as E.hysudricus and E.platycephus;[36] the latter the likely ancestor of the modern Asian elephant.[37]Mammuthus evolved into several species, including the well-known woolly mammoth.[36] In the Late Pleistocene, most proboscidean species vanished during the Quaternary glaciation which killed off 50% of genera weighing over 5kg (11lb) worldwide.[38] The Pleistocene also saw the arrival of Palaeoloxodon namadicus, the largest terrestrial mammal of all time.[39]

Proboscideans experienced several evolutionary trends, such as an increase in size, which led to many giant species that stood up to 5m (16ft) tall.[39] As with other megaherbivores, including the extinct sauropod dinosaurs, the large size of elephants likely developed to allow them to survive on vegetation with low nutritional value.[40] Their limbs grew longer and the feet shorter and broader. Early proboscideans developed longer mandibles and smaller craniums, while more advanced ones developed shorter mandibles, which shifted the head’s centre of gravity. The skull grew larger, especially the cranium, while the neck shortened to provide better support for the skull. The increase in size led to the development and elongation of the mobile trunk to provide reach. The number of premolars, incisors and canines decreased.[41] The cheek teeth (molars and premolars) became larger and more specialized, especially after elephants started to switch from C3-plants to C4-grasses, which caused their teeth to undergo a three-fold increase in teeth height as well as substantial multiplication of lamellae after about five million years ago. Only in the last million year or so did they return to a diet mainly consisting of C3 trees and shrubs.[42][43] The upper second incisors grew into tusks, which varied in shape from straight, to curved (either upward or downward), to spiralled, depending on the species. Some proboscideans developed tusks from their lower incisors.[41] Elephants retain certain features from their aquatic ancestry such as their middle ear anatomy and the internal testes of the males.[44]

There has been some debate over the relationship of Mammuthus to Loxodonta or Elephas. Some DNA studies suggest Mammuthus is more closely related to the former,[45][46] while others point to the latter.[7] However, analysis of the complete mitochondrial genome profile of the woolly mammoth (sequenced in 2005) supports Mammuthus being more closely related to Elephas.[18][22][24][47]Morphological evidence supports Mammuthus and Elephas as sister taxa, while comparisons of protein albumin and collagen have concluded that all three genera are equally related to each other.[48] Some scientists believe a cloned mammoth embryo could one day be implanted in an Asian elephant’s womb.[49]

Several species of proboscideans lived on islands and experienced insular dwarfism. This occurred primarily during the Pleistocene, when some elephant populations became isolated by fluctuating sea levels, although dwarf elephants did exist earlier in the Pliocene. These elephants likely grew smaller on islands due to a lack of large or viable predator populations and limited resources. By contrast, small mammals such as rodents develop gigantism in these conditions. Dwarf proboscideans are known to have lived in Indonesia, the Channel Islands of California, and several islands of the Mediterranean.[50]

Elephas celebensis of Sulawesi is believed to have descended from Elephas planifrons. Elephas falconeri of Malta and Sicily was only 1m (3ft), and had probably evolved from the straight-tusked elephant. Other descendants of the straight-tusked elephant existed in Cyprus. Dwarf elephants of uncertain descent lived in Crete, Cyclades and Dodecanese, while dwarf mammoths are known to have lived in Sardinia.[50] The Columbian mammoth colonised the Channel Islands and evolved into the pygmy mammoth. This species reached a height of 1.21.8m (46ft) and weighed 2002,000kg (4404,410lb). A population of small woolly mammoths survived on Wrangel Island, now 140km (87mi) north of the Siberian coast, as recently as 4,000 years ago.[50] After their discovery in 1993, they were considered dwarf mammoths.[51] This classification has been re-evaluated and since the Second International Mammoth Conference in 1999, these animals are no longer considered to be true “dwarf mammoths”.[52]

Elephants are the largest living terrestrial animals. African elephants stand 34m (1013ft) and weigh 4,0007,000kg (8,80015,400lb) while Asian elephants stand 23.5m (711ft) and weigh 3,0005,000kg (6,60011,000lb).[8] In both cases, males are larger than females.[9][12] Among African elephants, the forest form is smaller than the savannah form.[16] The skeleton of the elephant is made up of 326351 bones.[53] The vertebrae are connected by tight joints, which limit the backbone’s flexibility. African elephants have 21 pairs of ribs, while Asian elephants have 19 or 20 pairs.[54]

An elephant’s skull is resilient enough to withstand the forces generated by the leverage of the tusks and head-to-head collisions. The back of the skull is flattened and spread out, creating arches that protect the brain in every direction.[55] The skull contains air cavities (sinuses) that reduce the weight of the skull while maintaining overall strength. These cavities give the inside of the skull a honeycomb-like appearance. The cranium is particularly large and provides enough room for the attachment of muscles to support the entire head. The lower jaw is solid and heavy.[53] Because of the size of the head, the neck is relatively short to provide better support.[41] Lacking a lacrimal apparatus, the eye relies on the harderian gland to keep it moist. A durable nictitating membrane protects the eye globe. The animal’s field of vision is compromised by the location and limited mobility of the eyes.[56] Elephants are considered dichromats[57] and they can see well in dim light but not in bright light.[58] The core body temperature averages 35.9C (97F), similar to a human. Like all mammals, an elephant can raise or lower its temperature a few degrees from the average in response to extreme environmental conditions.[59]

Elephant ears have thick bases with thin tips. The ear flaps, or pinnae, contain numerous blood vessels called capillaries. Warm blood flows into the capillaries, helping to release excess body heat into the environment. This occurs when the pinnae are still, and the animal can enhance the effect by flapping them. Larger ear surfaces contain more capillaries, and more heat can be released. Of all the elephants, African bush elephants live in the hottest climates, and have the largest ear flaps.[60] Elephants are capable of hearing at low frequencies and are most sensitive at 1 kHz.[61]

The trunk, or proboscis, is a fusion of the nose and upper lip, although in early fetal life, the upper lip and trunk are separated.[41] The trunk is elongated and specialised to become the elephant’s most important and versatile appendage. It contains up to 150,000 separate muscle fascicles, with no bone and little fat. These paired muscles consist of two major types: superficial (surface) and internal. The former are divided into dorsals, ventrals and laterals, while the latter are divided into transverse and radiating muscles. The muscles of the trunk connect to a bony opening in the skull. The nasal septum is composed of tiny muscle units that stretch horizontally between the nostrils. Cartilage divides the nostrils at the base.[62] As a muscular hydrostat, the trunk moves by precisely coordinated muscle contractions. The muscles work both with and against each other. A unique proboscis nerve formed by the maxillary and facial nerves runs along both sides of the trunk.[63]

Elephant trunks have multiple functions, including breathing, olfaction, touching, grasping, and sound production.[41] The animal’s sense of smell may be four times as sensitive as that of a bloodhound.[64] The trunk’s ability to make powerful twisting and coiling movements allows it to collect food, wrestle with conspecifics,[65] and lift up to 350kg (770lb).[41] It can be used for delicate tasks, such as wiping an eye and checking an orifice,[65] and is capable of cracking a peanut shell without breaking the seed.[41] With its trunk, an elephant can reach items at heights of up to 7m (23ft) and dig for water under mud or sand.[65] Individuals may show lateral preference when grasping with their trunks: some prefer to twist them to the left, others to the right.[63] Elephants can suck up water both to drink and to spray on their bodies.[41] An adult Asian elephant is capable of holding 8.5L (2.2USgal) of water in its trunk.[62] They will also spray dust or grass on themselves.[41] When underwater, the elephant uses its trunk as a snorkel.[44]

The African elephant has two finger-like extensions at the tip of the trunk that allow it to grasp and bring food to its mouth. The Asian elephant has only one, and relies more on wrapping around a food item and squeezing it into its mouth.[8] Asian elephants have more muscle coordination and can perform more complex tasks.[62] Losing the trunk would be detrimental to an elephant’s survival,[41] although in rare cases individuals have survived with shortened ones. One elephant has been observed to graze by kneeling on its front legs, raising on its hind legs and taking in grass with its lips.[62]Floppy trunk syndrome is a condition of trunk paralysis in African bush elephants caused by the degradation of the peripheral nerves and muscles beginning at the tip.[66]

Elephants usually have 26 teeth: the incisors, known as the tusks, 12 deciduous premolars, and 12 molars. Unlike most mammals, which grow baby teeth and then replace them with a single permanent set of adult teeth, elephants are polyphyodonts that have cycles of tooth rotation throughout their lives. The chewing teeth are replaced six times in a typical elephant’s lifetime. Teeth are not replaced by new ones emerging from the jaws vertically as in most mammals. Instead, new teeth grow in at the back of the mouth and move forward to push out the old ones. The first chewing tooth on each side of the jaw falls out when the elephant is two to three years old. The second set of chewing teeth falls out when the elephant is four to six years old. The third set is lost at 915 years of age, and set four lasts until 1828 years of age. The fifth set of teeth lasts until the elephant is in its early 40s. The sixth (and usually final) set must last the elephant the rest of its life. Elephant teeth have loop-shaped dental ridges, which are thicker and more diamond-shaped in African elephants.[67]

The tusks of an elephant are modified incisors in the upper jaw. They replace deciduous milk teeth when the animal reaches 612 months of age and grow continuously at about 17cm (7in) a year. A newly developed tusk has a smooth enamel cap that eventually wears off. The dentine is known as ivory and its cross-section consists of crisscrossing line patterns, known as “engine turning”, which create diamond-shaped areas. As a piece of living tissue, a tusk is relatively soft; it is as hard as the mineral calcite. Much of the incisor can be seen externally, while the rest is fastened to a socket in the skull. At least one-third of the tusk contains the pulp and some have nerves stretching to the tip. Thus it would be difficult to remove it without harming the animal. When removed, ivory begins to dry up and crack if not kept cool and moist. Tusks serve multiple purposes. They are used for digging for water, salt, and roots; debarking or marking trees; and for moving trees and branches when clearing a path. When fighting, they are used to attack and defend, and to protect the trunk.[68]

Like humans, who are typically right- or left-handed, elephants are usually right- or left-tusked. The dominant tusk, called the master tusk, is generally more worn down, as it is shorter with a rounder tip. For the African elephants, tusks are present in both males and females, and are around the same length in both sexes, reaching up to 3m (10ft),[68] but those of males tend to be thicker.[69] In earlier times elephant tusks weighing over 200 pounds (more than 90kg) were not uncommon, though it is rare today to see any over 100 pounds (45kg).[70]

In the Asian species, only the males have large tusks. Female Asians have very small ones, or none at all.[68] Tuskless males exist and are particularly common among Sri Lankan elephants.[71] Asian males can have tusks as long as Africans’, but they are usually slimmer and lighter; the largest recorded was 3.02m (10ft) long and weighed 39kg (86lb). Hunting for elephant ivory in Africa[72] and Asia[73] has led to natural selection for shorter tusks[74][75] and tusklessness.[76][77]

An elephant’s skin is generally very tough, at 2.5cm (1in) thick on the back and parts of the head. The skin around the mouth, anus and inside of the ear is considerably thinner. Elephants typically have grey skin, but African elephants look brown or reddish after wallowing in coloured mud. Asian elephants have some patches of depigmentation, particularly on the forehead and ears and the areas around them. Calves have brownish or reddish hair, especially on the head and back. As elephants mature, their hair darkens and becomes sparser, but dense concentrations of hair and bristles remain on the end of the tail as well as the chin, genitals and the areas around the eyes and ear openings. Normally the skin of an Asian elephant is covered with more hair than its African counterpart.[78]

An elephant uses mud as a sunscreen, protecting its skin from ultraviolet light. Although tough, an elephant’s skin is very sensitive. Without regular mud baths to protect it from burning, insect bites, and moisture loss, an elephant’s skin suffers serious damage. After bathing, the elephant will usually use its trunk to blow dust onto its body and this dries into a protective crust. Elephants have difficulty releasing heat through the skin because of their low surface-area-to-volume ratio, which is many times smaller than that of a human. They have even been observed lifting up their legs, presumably in an effort to expose their soles to the air.[78]

To support the animal’s weight, an elephant’s limbs are positioned more vertically under the body than in most other mammals. The long bones of the limbs have cancellous bone in place of medullary cavities. This strengthens the bones while still allowing haematopoiesis.[79] Both the front and hind limbs can support an elephant’s weight, although 60% is borne by the front.[80] Since the limb bones are placed on top of each other and under the body, an elephant can stand still for long periods of time without using much energy. Elephants are incapable of rotating their front legs, as the ulna and radius are fixed in pronation; the “palm” of the manus faces backward.[79] The pronator quadratus and the pronator teres are either reduced or absent.[81] The circular feet of an elephant have soft tissues or “cushion pads” beneath the manus or pes, which distribute the weight of the animal.[80] They appear to have a sesamoid, an extra “toe” similar in placement to a giant panda’s extra “thumb”, that also helps in weight distribution.[82] As many as five toenails can be found on both the front and hind feet.[8]

Elephants can move both forwards and backwards, but cannot trot, jump, or gallop. They use only two gaits when moving on land, the walk and a faster gait similar to running.[79] In walking, the legs act as pendulums, with the hips and shoulders rising and falling while the foot is planted on the ground. With no “aerial phase”, the fast gait does not meet all the criteria of running, although the elephant uses its legs much like other running animals, with the hips and shoulders falling and then rising while the feet are on the ground.[83] Fast-moving elephants appear to ‘run’ with their front legs, but ‘walk’ with their hind legs and can reach a top speed of 18km/h (11mph).[84] At this speed, most other quadrupeds are well into a gallop, even accounting for leg length. Spring-like kinetics could explain the difference between the motion of elephants and other animals.[85] During locomotion, the cushion pads expand and contract, and reduce both the pain and noise that would come from a very heavy animal moving.[80] Elephants are capable swimmers. They have been recorded swimming for up to six hours without touching the bottom, and have travelled as far as 48km (30mi) at a stretch and at speeds of up to 2.1km/h (1mph).[86]

The brain of an elephant weighs 4.55.5kg (1012lb) compared to 1.6kg (4lb) for a human brain. While the elephant brain is larger overall, it is proportionally smaller. At birth, an elephant’s brain already weighs 3040% of its adult weight. The cerebrum and cerebellum are well developed, and the temporal lobes are so large that they bulge out laterally.[59] The throat of an elephant appears to contain a pouch where it can store water for later use.[41]

The heart of an elephant weighs 1221kg (2646lb). It has a double-pointed apex, an unusual trait among mammals.[59] When standing, the elephant’s heart beats approximately 30 times per minute. Unlike many other animals, the heart rate speeds up by 8 to 10 beats per minute when the elephant is lying down.[87] The lungs are attached to the diaphragm, and breathing relies mainly on the diaphragm rather than the expansion of the ribcage.[59]Connective tissue exists in place of the pleural cavity. This may allow the animal to deal with the pressure differences when its body is underwater and its trunk is breaking the surface for air,[44] although this explanation has been questioned.[88] Another possible function for this adaptation is that it helps the animal suck up water through the trunk.[44] Elephants inhale mostly through the trunk, although some air goes through the mouth. They have a hindgut fermentation system, and their large and small intestines together reach 35m (115ft) in length. The majority of an elephant’s food intake goes undigested despite the process lasting up to a day.[59]

A male elephant’s testes are located internally near the kidneys. The elephant’s penis can reach a length of 100cm (39in) and a diameter of 16cm (6in) at the base. It is S-shaped when fully erect and has a Y-shaped orifice. The female has a well-developed clitoris at up to 40cm (16in). The vulva is located between the hind legs instead of near the tail as in most mammals. Determining pregnancy status can be difficult due to the animal’s large abdominal cavity. The female’s mammary glands occupy the space between the front legs, which puts the suckling calf within reach of the female’s trunk.[59] Elephants have a unique organ, the temporal gland, located in both sides of the head. This organ is associated with sexual behaviour, and males secrete a fluid from it when in musth.[89] Females have also been observed with secretions from the temporal glands.[64]

The African bush elephant can be found in habitats as diverse as dry savannahs, deserts, marshes, and lake shores, and in elevations from sea level to mountain areas above the snow line. Forest elephants mainly live in equatorial forests, but will enter gallery forests and ecotones between forests and savannahs.[16] Asian elephants prefer areas with a mix of grasses, low woody plants and trees, primarily inhabiting dry thorn-scrub forests in southern India and Sri Lanka and evergreen forests in Malaya.[9] Elephants are herbivorous and will eat leaves, twigs, fruit, bark, grass and roots.[16] They are born with sterile intestines, and require bacteria obtained from their mothers feces to digest vegetation.[90] African elephants are mostly browsers while Asian elephants are mainly grazers. They can consume as much as 150kg (330lb) of food and 40L (11USgal) of water in a day. Elephants tend to stay near water sources.[16] Major feeding bouts take place in the morning, afternoon and night. At midday, elephants rest under trees and may doze off while standing. Sleeping occurs at night while the animal is lying down.[79][91] Elephants average 34 hours of sleep per day.[92] Both males and family groups typically move 1020km (612mi) a day, but distances as far as 90180km (56112mi) have been recorded in the Etosha region of Namibia.[93] Elephants go on seasonal migrations in search of food, water and mates. At Chobe National Park, Botswana, herds travel 325km (202mi) to visit the river when the local waterholes dry up.[94]

Because of their large size, elephants have a huge impact on their environments and are considered keystone species. Their habit of uprooting trees and undergrowth can transform savannah into grasslands; when they dig for water during drought, they create waterholes that can be used by other animals. They can enlarge waterholes when they bathe and wallow in them. At Mount Elgon, elephants excavate caves that are used by ungulates, hyraxes, bats, birds and insects.[95] Elephants are important seed dispersers; African forest elephants ingest and defecate seeds, with either no effect or a positive effect on germination. The seeds are typically dispersed in large amounts over great distances.[96] In Asian forests, large seeds require giant herbivores like elephants and rhinoceros for transport and dispersal. This ecological niche cannot be filled by the next largest herbivore, the tapir.[97] Because most of the food elephants eat goes undigested, their dung can provide food for other animals, such as dung beetles and monkeys.[95] Elephants can have a negative impact on ecosystems. At Murchison Falls National Park in Uganda, the overabundance of elephants has threatened several species of small birds that depend on woodlands. Their weight can compact the soil, which causes the rain to run off, leading to erosion.[91]

Elephants typically coexist peacefully with other herbivores, which will usually stay out of their way. Some aggressive interactions between elephants and rhinoceros have been recorded. At Aberdare National Park, Kenya, a rhino attacked an elephant calf and was killed by the other elephants in the group.[91] At HluhluweUmfolozi Game Reserve, South Africa, introduced young orphan elephants went on a killing spree that claimed the lives of 36 rhinos during the 1990s, but ended with the introduction of older males.[98] The size of adult elephants makes them nearly invulnerable to predators,[9] though there are rare reports of adult elephants falling prey to tigers.[99] Calves may be preyed on by lions, spotted hyenas, and wild dogs in Africa[12] and tigers in Asia.[9] The lions of Savuti, Botswana, have adapted to hunting juvenile elephants during the dry season, and a pride of 30 lions has been recorded killing juvenile individuals between the ages of four and eleven years.[100] Elephants appear to distinguish between the growls of larger predators like tigers and smaller ones like leopards (which have not been recorded killing calves); the latter they react less fearfully and more aggressively to.[101] Elephants tend to have high numbers of parasites, particularly nematodes, compared to other herbivores. This is due to lower predation pressures that would otherwise kill off many of the individuals with significant parasite loads.[102]

Female elephants spend their entire lives in tight-knit matrilineal family groups, some of which are made up of more than ten members, including three pairs of mothers with offspring, and are led by the matriarch which is often the eldest female.[103] She remains leader of the group until death[12] or if she no longer has the energy for the role;[104] a study on zoo elephants showed that when the matriarch died, the levels of faecal corticosterone (‘stress hormone’) dramatically increased in the surviving elephants.[105] When her tenure is over, the matriarch’s eldest daughter takes her place; this occurs even if her sister is present.[12] The older matriarchs tend to be more effective decision-makers.[106]

The social circle of the female elephant does not necessarily end with the small family unit. In the case of elephants in Amboseli National Park, Kenya, a female’s life involves interaction with other families, clans, and subpopulations. Families may associate and bond with each other, forming what are known as bond groups. These are typically made of two family groups. During the dry season, elephant families may cluster together and form another level of social organisation known as the clan. Groups within these clans do not form strong bonds, but they defend their dry-season ranges against other clans. There are typically nine groups in a clan. The Amboseli elephant population is further divided into the “central” and “peripheral” subpopulations.[103]

Some elephant populations in India and Sri Lanka have similar basic social organisations. There appear to be cohesive family units and loose aggregations. They have been observed to have “nursing units” and “juvenile-care units”. In southern India, elephant populations may contain family groups, bond groups and possibly clans. Family groups tend to be small, consisting of one or two adult females and their offspring. A group containing more than two adult females plus offspring is known as a “joint family”. Malay elephant populations have even smaller family units, and do not have any social organisation higher than a family or bond group. Groups of African forest elephants typically consist of one adult female with one to three offspring. These groups appear to interact with each other, especially at forest clearings.[103]

The social life of the adult male is very different. As he matures, a male spends more time at the edge of his group and associates with outside males or even other families. At Amboseli, young males spend over 80% of their time away from their families when they are 1415. The adult females of the group start to show aggression towards the male, which encourages him to permanently leave. When males do leave, they either live alone or with other males. The former is typical of bulls in dense forests. Asian males are usually solitary, but occasionally form groups of two or more individuals; the largest consisted of seven bulls. Larger bull groups consisting of over 10 members occur only among African bush elephants, the largest of which numbered up to 144 individuals.[107] A dominance hierarchy exists among males, whether they range socially or solitarily. Dominance depends on the age, size and sexual condition.[107] Old bulls appear to control the aggression of younger ones and prevent them from forming “gangs”.[108] Adult males and females come together for reproduction. Bulls appear to associate with family groups if an oestrous cow is present.[107]

Adult males enter a state of increased testosterone known as musth. In a population in southern India, males first enter musth at the age of 15, but it is not very intense until they are older than 25. At Amboseli, bulls under 24 do not go into musth, while half of those aged 2535 and all those over 35 do. Young bulls appear to enter musth during the dry season (JanuaryMay), while older bulls go through it during the wet season (JuneDecember). The main characteristic of a bull’s musth is a fluid secreted from the temporal gland that runs down the side of his face. He may urinate with his penis still in his sheath, which causes the urine to spray on his hind legs. Behaviours associated with musth include walking with the head held high and swinging, picking at the ground with the tusks, marking, rumbling and waving only one ear at a time. This can last from a day to four months.[109]

Males become extremely aggressive during musth. Size is the determining factor in agonistic encounters when the individuals have the same condition. In contests between musth and non-musth individuals, musth bulls win the majority of the time, even when the non-musth bull is larger. A male may stop showing signs of musth when he encounters a musth male of higher rank. Those of equal rank tend to avoid each other. Agonistic encounters typically consist of threat displays, chases and minor sparring with the tusks. Serious fights are rare.[109]

Elephants are polygynous breeders,[110] and copulations are most frequent during the peak of the wet season.[111] A cow in oestrus releases chemical signals (pheromones) in her urine and vaginal secretions to signal her readiness to mate. A bull will follow a potential mate and assess her condition with the flehmen response, which requires the male to collect a chemical sample with his trunk and bring it to the vomeronasal organ.[112] The oestrous cycle of a cow lasts 1416 weeks with a 46-week follicular phase and an 810-week luteal phase. While most mammals have one surge of luteinizing hormone during the follicular phase, elephants have two. The first (or anovulatory) surge, could signal to males that the female is in oestrus by changing her scent, but ovulation does not occur until the second (or ovulatory) surge.[113] Fertility rates in cows decline around 4550 years of age.[104]

Bulls engage in a behaviour known as mate-guarding, where they follow oestrous females and defend them from other males. Most mate-guarding is done by musth males, and females actively seek to be guarded by them, particularly older ones.[114] Thus these bulls have more reproductive success.[107] Musth appears to signal to females the condition of the male, as weak or injured males do not have normal musths.[115] For young females, the approach of an older bull can be intimidating, so her relatives stay nearby to provide support and reassurance.[116] During copulation, the male lays his trunk over the female’s back.[117] The penis is very mobile, being able to move independently of the pelvis.[118] Prior to mounting, it curves forward and upward. Copulation lasts about 45 seconds and does not involve pelvic thrusting or ejaculatory pause.[119]

Homosexual behaviour is frequent in both sexes. As in heterosexual interactions, this involves mounting. Male elephants sometimes stimulate each other by playfighting and “championships” may form between old bulls and younger males. Female same-sex behaviours have been documented only in captivity where they are known to masturbate one another with their trunks.[120]

Gestation in elephants typically lasts around two years with interbirth intervals usually lasting four to five years. Births tend to take place during the wet season.[121] Calves are born 85cm (33in) tall and weigh around 120kg (260lb).[116] Typically, only a single young is born, but twins sometimes occur.[122][123] The relatively long pregnancy is maintained by five corpus luteums (as opposed to one in most mammals) and gives the foetus more time to develop, particularly the brain and trunk.[122] As such, newborn elephants are precocial and quickly stand and walk to follow their mother and family herd.[124] A new calf is usually the centre of attention for herd members. Adults and most of the other young will gather around the newborn, touching and caressing it with their trunks. For the first few days, the mother is intolerant of other herd members near her young. Alloparenting where a calf is cared for by someone other than its mother takes place in some family groups. Allomothers are typically two to twelve years old.[116] When a predator is near, the family group gathers together with the calves in the centre.[125]

For the first few days, the newborn is unsteady on its feet, and needs the support of its mother. It relies on touch, smell and hearing, as its eyesight is poor. It has little precise control over its trunk, which wiggles around and may cause it to trip. By its second week of life, the calf can walk more firmly and has more control over its trunk. After its first month, a calf can pick up, hold and put objects in its mouth, but cannot suck water through the trunk and must drink directly through the mouth. It is still dependent on its mother and keeps close to her.[124]

For its first three months, a calf relies entirely on milk from its mother for nutrition after which it begins to forage for vegetation and can use its trunk to collect water. At the same time, improvements in lip and leg coordination occur. Calves continue to suckle at the same rate as before until their sixth month, after which they become more independent when feeding. By nine months, mouth, trunk and foot coordination is perfected. After a year, a calf’s abilities to groom, drink, and feed itself are fully developed. It still needs its mother for nutrition and protection from predators for at least another year. Suckling bouts tend to last 24 min/hr for a calf younger than a year and it continues to suckle until it reaches three years of age or older. Suckling after two years may serve to maintain growth rate, body condition and reproductive ability.[124] Play behaviour in calves differs between the sexes; females run or chase each other, while males play-fight. The former are sexually mature by the age of nine years[116] while the latter become mature around 1415 years.[107] Adulthood starts at about 18 years of age in both sexes.[126][127] Elephants have long lifespans, reaching 6070 years of age.[67]Lin Wang, a captive male Asian elephant, lived for 86 years.[128]

Touching is an important form of communication among elephants. Individuals greet each other by stroking or wrapping their trunks; the latter also occurs during mild competition. Older elephants use trunk-slaps, kicks and shoves to discipline younger ones. Individuals of any age and sex will touch each other’s mouths, temporal glands and genitals, particularly during meetings or when excited. This allows individuals to pick up chemical cues. Touching is especially important for mothercalf communication. When moving, elephant mothers will touch their calves with their trunks or feet when side-by-side or with their tails if the calf is behind them. If a calf wants to rest, it will press against its mother’s front legs and when it wants to suckle, it will touch her breast or leg.[129]

Visual displays mostly occur in agonistic situations. Elephants will try to appear more threatening by raising their heads and spreading their ears. They may add to the display by shaking their heads and snapping their ears, as well as throwing dust and vegetation. They are usually bluffing when performing these actions. Excited elephants may raise their trunks. Submissive ones will lower their heads and trunks, as well as flatten their ears against their necks, while those that accept a challenge will position their ears in a V shape.[130]

Elephants produce several sounds, usually through the larynx, though some may be modified by the trunk. Perhaps the most well known is the trumpet, which is made during excitement, distress or aggression.[131] Fighting elephants may roar or squeal, and wounded ones may bellow.[132]Rumbles are produced during mild arousal[133] and some appear to be infrasonic.[134] Infrasonic calls are important, particularly for long-distance communication,[131] in both Asian and African elephants. For Asian elephants, these calls have a frequency of 1424Hz, with sound pressure levels of 8590dB and last 1015 seconds.[134] For African elephants, calls range from 1535Hz with sound pressure levels as high as 117dB, allowing communication for many kilometres, with a possible maximum range of around 10km (6mi).[135]

At Amboseli, several different infrasonic calls have been identified. A greeting rumble is emitted by members of a family group after having been separated for several hours. Contact calls are soft, unmodulated sounds made by individuals that have been separated from their group and may be responded to with a “contact answer” call that starts out loud, but becomes softer. A “let’s go” soft rumble is emitted by the matriarch to signal to the other herd members that it is time to move to another spot. Bulls in musth emit a distinctive, low-frequency pulsated rumble nicknamed the “motorcycle”. Musth rumbles may be answered by the “female chorus”, a low-frequency, modulated chorus produced by several cows. A loud postcopulatory call may be made by an oestrous cow after mating. When a cow has mated, her family may produce calls of excitement known as the “mating pandemonium”.[133]

Elephants are known to communicate with seismics, vibrations produced by impacts on the earth’s surface or acoustical waves that travel through it. They appear to rely on their leg and shoulder bones to transmit the signals to the middle ear. When detecting seismic signals, the animals lean forward and put more weight on their larger front feet; this is known as the “freezing behaviour”. Elephants possess several adaptations suited for seismic communication. The cushion pads of the feet contain cartilaginous nodes and have similarities to the acoustic fat found in marine mammals like toothed whales and sirenians. A unique sphincter-like muscle around the ear canal constricts the passageway, thereby dampening acoustic signals and allowing the animal to hear more seismic signals.[136] Elephants appear to use seismics for a number of purposes. An individual running or mock charging can create seismic signals that can be heard at great distances.[137] When detecting the seismics of an alarm call signalling danger from predators, elephants enter a defensive posture and family groups will pack together. Seismic waveforms produced by locomotion appear to travel distances of up to 32km (20mi) while those from vocalisations travel 16km (10mi).[138]

Elephants exhibit mirror self-recognition, an indication of self-awareness and cognition that has also been demonstrated in some apes and dolphins.[139] One study of a captive female Asian elephant suggested the animal was capable of learning and distinguishing between several visual and some acoustic discrimination pairs. This individual was even able to score a high accuracy rating when re-tested with the same visual pairs a year later.[140] Elephants are among the species known to use tools. An Asian elephant has been observed modifying branches and using them as flyswatters.[141] Tool modification by these animals is not as advanced as that of chimpanzees. Elephants are popularly thought of as having an excellent memory. This could have a factual basis; they possibly have cognitive maps to allow them to remember large-scale spaces over long periods of time. Individuals appear to be able to keep track of the current location of their family members.[58]

Scientists debate the extent to which elephants feel emotion. They appear to show interest in the bones of their own kind, regardless of whether they are related.[142] As with chimps and dolphins, a dying or dead elephant may elicit attention and aid from others, including those from other groups. This has been interpreted as expressing “concern”,[143] however, others would dispute such an interpretation as being anthropomorphic;[144][145] the Oxford Companion to Animal Behaviour (1987) advised that “one is well advised to study the behaviour rather than attempting to get at any underlying emotion”.[146]

Distribution of elephants

African elephants were listed as vulnerable by the International Union for Conservation of Nature (IUCN) in 2008, with no independent assessment of the conservation status of the two forms.[26] In 1979, Africa had an estimated minimum population of 1.3million elephants, with a possible upper limit of 3.0million. By 1989, the population was estimated to be 609,000; with 277,000 in Central Africa, 110,000 in eastern Africa, 204,000 in southern Africa, and 19,000 in western Africa. About 214,000 elephants were estimated to live in the rainforests, fewer than had previously been thought. From 1977 to 1989, elephant populations declined by 74% in East Africa. After 1987, losses in elephant numbers accelerated, and savannah populations from Cameroon to Somalia experienced a decline of 80%. African forest elephants had a total loss of 43%. Population trends in southern Africa were mixed, with anecdotal reports of losses in Zambia, Mozambique and Angola, while populations grew in Botswana and Zimbabwe and were stable in South Africa.[147] Conversely, studies in 2005 and 2007 found populations in eastern and southern Africa were increasing by an average annual rate of 4.0%.[26] Due to the vast areas involved, assessing the total African elephant population remains difficult and involves an element of guesswork. The IUCN estimates a total of around 440,000 individuals for 2012.[148]

African elephants receive at least some legal protection in every country where they are found, but 70% of their range exists outside protected areas. Successful conservation efforts in certain areas have led to high population densities. As of 2008, local numbers were controlled by contraception or translocation. Large-scale cullings ceased in 1988, when Zimbabwe abandoned the practice. In 1989, the African elephant was listed under Appendix I by the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES), making trade illegal. Appendix II status (which allows restricted trade) was given to elephants in Botswana, Namibia and Zimbabwe in 1997 and South Africa in 2000. In some countries, sport hunting of the animals is legal; Botswana, Cameroon, Gabon, Mozambique, Namibia, South Africa, Tanzania, Zambia, and Zimbabwe have CITES export quotas for elephant trophies.[26] In June 2016 the First Lady of Kenya, Margaret Kenyatta, helped launch the East Africa Grass-Root Elephant Education Campaign Walk, organised by elephant conservationist Jim Nyamu. The event was conducted to raise awareness of the value of elephants and rhinos, to help mitigate human-elephant conflicts, and to promote anti-poaching activities.[149][150]

In 2008, the IUCN listed the Asian elephant as endangered due to a 50% population decline over the past 6075 years,[151] while CITES lists the species under Appendix I.[151] Asian elephants once ranged from Syria and Iraq (the subspecies Elephas maximus asurus), to China (up to the Yellow River)[152] and Java. It is now extinct in these areas,[151] and the current range of Asian elephants is highly fragmented.[152] The total population of Asian elephants is estimated to be around 40,00050,000, although this may be a loose estimate. It is likely that around half of the population is in India. Although Asian elephants are declining in numbers overall, particularly in Southeast Asia, the population in the Western Ghats appears to be increasing.[151]

The poaching of elephants for their ivory, meat and hides has been one of the major threats to their existence.[151] Historically, numerous cultures made ornaments and other works of art from elephant ivory, and its use rivalled that of gold.[153] The ivory trade contributed to the African elephant population decline in the late 20th century.[26] This prompted international bans on ivory imports, starting with the United States in June 1989, and followed by bans in other North American countries, western European countries, and Japan.[153] Around the same time, Kenya destroyed all its ivory stocks.[154] CITES approved an international ban on ivory that went into effect in January 1990.[153] Following the bans, unemployment rose in India and China, where the ivory industry was important economically. By contrast, Japan and Hong Kong, which were also part of the industry, were able to adapt and were not badly affected.[153] Zimbabwe, Botswana, Namibia, Zambia, and Malawi wanted to continue the ivory trade and were allowed to, since their local elephant populations were healthy, but only if their supplies were from elephants that had been culled or died of natural causes.[154]

The ban allowed the elephant to recover in parts of Africa.[153] In January 2012, 650 elephants in Bouba Njida National Park, Cameroon, were killed by Chadian raiders.[155] This has been called “one of the worst concentrated killings” since the ivory ban.[154] Asian elephants are potentially less vulnerable to the ivory trade, as females usually lack tusks. Still, members of the species have been killed for their ivory in some areas, such as Periyar National Park in India.[151] China was the biggest market for poached ivory but announced they would phase out the legal domestic manufacture and sale of ivory products in May, 2015, and in September 2015 China and the United States “said they would enact a nearly complete ban on the import and export of ivory.”[156]

Other threats to elephants include habitat destruction and fragmentation.[26] The Asian elephant lives in areas with some of the highest human populations. Because they need larger amounts of land than other sympatric terrestrial mammals, they are the first to be affected by human encroachment. In extreme cases, elephants may be confined to small islands of forest among human-dominated landscapes. Elephants cannot coexist with humans in agricultural areas due to their size and food requirements. Elephants commonly trample and consume crops, which contributes to conflicts with humans, and both elephants and humans have died by the hundreds as a result. Mitigating these conflicts is important for conservation.[151] One proposed solution is the provision of urban corridors which allow the animals access to key areas.[157]

Elephants have been working animals since at least the Indus Valley Civilization[158] and continue to be used in modern times. There were 13,00016,500 working elephants employed in Asia as of 2000. These animals are typically captured from the wild when they are 1020 years old, when they can be trained quickly and easily, and will have a longer working life.[159] They were traditionally captured with traps and lassos, but since 1950, tranquillisers have been used.[160] Individuals of the Asian species are more commonly trained to be working animals, although the practice has also been attempted in Africa. The taming of African elephants in the Belgian Congo began by decree of Leopold II of Belgium during the 19th century and continues to the present with the Api Elephant Domestication Centre.[161]

Asian elephants perform tasks such as hauling loads into remote areas, moving logs into trucks, transporting tourists around national parks, pulling wagons and leading religious processions.[159] In northern Thailand, the animals are used to digest coffee beans for Black Ivory coffee.[162] They are valued over mechanised tools because they can work in relatively deep water, require relatively little maintenance, need only vegetation and water as fuel and can be trained to memorise specific tasks. Elephants can be trained to respond to over 30 commands.[159] Musth bulls can be difficult and dangerous to work with and are chained until the condition passes.[163] In India, many working elephants are alleged to have been subject to abuse. They and other captive elephants are thus protected under the The Prevention of Cruelty to Animals Act of 1960.[164]

In both Myanmar and Thailand, deforestation and other economic factors have resulted in sizable populations of unemployed elephants resulting in health problems for the elephants themselves as well as economic and safety problems for the people amongst whom they live.[165][166]

Historically, elephants were considered formidable instruments of war. They were equipped with armour to protect their sides, and their tusks were given sharp points of iron or brass if they were large enough. War elephants were trained to grasp an enemy soldier and toss him to the person riding on them or to pin the soldier to the ground and impale him.[167]

One of the earliest references to war elephants is in the Indian epic Mahabharata (written in the 4th century BCE, but said to describe events between the 11th and 8th centuries BCE). They were not used as much as horse-drawn chariots by either the Pandavas or Kauravas. During the Magadha Kingdom (which began in the 6th century BCE), elephants began to achieve greater cultural importance than horses, and later Indian kingdoms used war elephants extensively; 3,000 of them were used in the Nandas (5th and 4th centuries BCE) army, while 9,000 may have been used in the Mauryan army (between the 4th and 2nd centuries BCE). The Arthashastra (written around 300 BCE) advised the Mauryan government to reserve some forests for wild elephants for use in the army, and to execute anyone who killed them.[168] From South Asia, the use of elephants in warfare spread west to Persia[167] and east to Southeast Asia.[169] The Persians used them during the Achaemenid Empire (between the 6th and 4th centuries BCE),[167] while Southeast Asian states first used war elephants possibly as early as the 5th century BCE and continued to the 20th century.[169]

Alexander the Great trained his foot soldiers to injure the animals and cause them to panic during wars with both the Persians and Indians. Ptolemy, who was one of Alexander’s generals, used corps of Asian elephants during his reign as the ruler of Egypt (which began in 323 BCE). His son and successor Ptolemy II (who began his rule in 285 BCE) obtained his supply of elephants further south in Nubia. From then on, war elephants were employed in the Mediterranean and North Africa throughout the classical period. The Greek king Pyrrhus used elephants in his attempted invasion of Rome in 280 BCE. While they frightened the Roman horses, they were not decisive and Pyrrhus ultimately lost the battle. The Carthaginian general Hannibal took elephants across the Alps during his war with the Romans and reached the Po Valley in 217 BCE with all of them alive, but they later succumbed to disease.[167]

Elephants were historically kept for display in the menageries of Ancient Egypt, China, Greece and Rome. The Romans in particular pitted them against humans and other animals in gladiator events. In the modern era, elephants have traditionally been a major part of zoos and circuses around the world. In circuses, they are trained to perform tricks. The most famous circus elephant was probably Jumbo (1861 15 September 1885), who was a major attraction in the Barnum & Bailey Circus.[170] These animals do not reproduce well in captivity, due to the difficulty of handling musth bulls and limited understanding of female oestrous cycles. Asian elephants were always more common than their African counterparts in modern zoos and circuses. After CITES listed the Asian elephant under Appendix I in 1975, the number of African elephants in zoos increased in the 1980s, although the import of Asians continued. Subsequently, the US received many of its captive African elephants from Zimbabwe, which had an overabundance of the animals.[171] As of 2000, around 1,200 Asian and 700 African elephants were kept in zoos and circuses. The largest captive population is in North America, which has an estimated 370 Asian and 350 African elephants. About 380 Asians and 190 Africans are known to exist in Europe, and Japan has around 70 Asians and 67 Africans.[171]

Keeping elephants in zoos has met with some controversy. Proponents of zoos argue that they offer researchers easy access to the animals and provide money and expertise for preserving their natural habitats, as well as safekeeping for the species. Critics claim that the animals in zoos are under physical and mental stress.[172] Elephants have been recorded displaying stereotypical behaviours in the form of swaying back and forth, trunk swaying or route tracing. This has been observed in 54% of individuals in UK zoos.[173] Elephants in European zoos appear to have shorter lifespans than their wild counterparts at only 17 years, although other studies suggest that zoo elephants live as long those in the wild.[174]

The use of elephants in circuses has also been controversial; the Humane Society of the United States has accused circuses of mistreating and distressing their animals.[175] In testimony to a US federal court in 2009, Barnum & Bailey Circus CEO Kenneth Feld acknowledged that circus elephants are struck behind their ears, under their chins and on their legs with metal-tipped prods, called bull hooks or ankus. Feld stated that these practices are necessary to protect circus workers and acknowledged that an elephant trainer was reprimanded for using an electric shock device, known as a hot shot or electric prod, on an elephant. Despite this, he denied that any of these practices harm elephants.[176] Some trainers have tried to train elephants without the use of physical punishment. Ralph Helfer is known to have relied on gentleness and reward when training his animals, including elephants and lions.[177] In January 2016 Ringling Bros. and Barnum and Bailey circus announced it would retire its touring elephants in May 2016.[178]

Like many mammals, elephants can contract and transmit diseases to humans, one of which is tuberculosis. In 2012, two elephants in Tete dOr zoo, Lyon were diagnosed with the disease. Due to the threat of transmitting tuberculosis to other animals or visitors to the zoo, their euthanasia was initially ordered by city authorities but a court later overturned this decision.[179] At an elephant sanctuary in Tennessee, a 54-year-old African elephant was considered to be the source of tuberculosis infections among eight workers.[180]

As of 2015[update], tuberculosis appears to be widespread among captive elephants in the US. It is believed that the animals originally acquired the disease from humans, a process called reverse zoonosis. Because the disease can spread through the air to infect both humans and other animals, it is a public health concern affecting circuses and zoos.[181][182]

Elephants can exhibit bouts of aggressive behaviour and engage in destructive actions against humans.[183] In Africa, groups of adolescent elephants damaged homes in villages after cullings in the 1970s and 1980s. Because of the timing, these attacks have been interpreted as vindictive.[108][184] In India, male elephants regularly enter villages at night, destroying homes and killing people. Elephants killed around 300 people between 2000 and 2004 in Jharkhand, while in Assam 239 people were reportedly killed between 2001 and 2006.[183] Local people have reported their belief that some elephants were drunk during their attacks, although officials have disputed this explanation.[185][186] Purportedly drunk elephants attacked an Indian village a second time in December 2002, killing six people, which led to the killing of about 200 elephants by locals.[187]

Elephants have been represented in art since Paleolithic times. Africa in particular contains many rock paintings and engravings of the animals, especially in the Sahara and southern Africa.[188] In the Far East, the animals are depicted as motifs in Hindu and Buddhist shrines and temples.[189] Elephants were often difficult to portray by people with no first-hand experience with them.[190] The ancient Romans, who kept the animals in captivity, depicted anatomically accurate elephants on mosaics in Tunisia and Sicily. At the beginning of the Middle Ages, when Europeans had little to no access to the animals, elephants were portrayed more like fantasy creatures. They were often depicted with horse- or bovine-like bodies with trumpet-like trunks and tusks like a boar; some were even given hooves. Elephants were commonly featured in motifs by the stonemasons of the Gothic churches. As more elephants began to be sent to European kings as gifts during the 15th century, depictions of them became more accurate, including one made by Leonardo da Vinci. Despite this, some Europeans continued to portray them in a more stylised fashion.[191]Max Ernst’s 1921 surrealist painting The Elephant Celebes depicts an elephant as a silo with a trunk-like hose protruding from it.[192]

Elephants have been the subject of religious beliefs. The Mbuti people believe that the souls of their dead ancestors resided in elephants.[189] Similar ideas existed among other African tribes, who believed that their chiefs would be reincarnated as elephants. During the 10th century AD, the people of Igbo-Ukwu buried their leaders with elephant tusks.[193] The animals’ religious importance is only totemic in Africa[194] but is much more significant in Asia. In Sumatra, elephants have been associated with lightning. Likewise in Hinduism, they are linked with thunderstorms as Airavata, the father of all elephants, represents both lightning and rainbows.[189] One of the most important Hindu deities, the elephant-headed Ganesha, is ranked equal with the supreme gods Shiva, Vishnu, and Brahma.[195] Ganesha is associated with writers and merchants and it is believed that he can give people success as well as grant them their desires.[189] In Buddhism, Buddha is said to have been a white elephant reincarnated as a human.[196] In Islamic tradition, the year 570, when Muhammad was born, is known as the Year of the Elephant.[197] Elephants were thought to be religious themselves by the Romans, who believed that they worshipped the sun and stars.[189] The ‘Land of a Million Elephants’ was the name of the ancient kingdom of Lan Xang and later the Lan Chang Province and it is now a nickname for Laos.

Elephants are ubiquitous in Western popular culture as emblems of the exotic, especially since as with the giraffe, hippopotamus and rhinoceros there are no similar animals familiar to Western audiences.[198] The use of the elephant as a symbol of the US Republican Party began with an 1874 cartoon by Thomas Nast.[199] As characters, elephants are most common in children’s stories, in which they are generally cast as models of exemplary behaviour. They are typically surrogates for humans with ideal human values. Many stories tell of isolated young elephants returning to a close-knit community, such as “The Elephant’s Child” from Rudyard Kipling’s Just So Stories, Disney’s Dumbo and Kathryn and Byron Jackson’s The Saggy Baggy Elephant. Other elephant heroes given human qualities include Jean de Brunhoff’s Babar, David McKee’s Elmer and Dr. Seuss’s Horton.[198]

Several cultural references emphasise the elephant’s size and exotic uniqueness. For instance, a “white elephant” is a byword for something expensive, useless and bizarre.[198] The expression “elephant in the room” refers to an obvious truth that is ignored or otherwise unaddressed.[200] The story of the blind men and an elephant teaches that reality may be viewed by different perspectives.[201]

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Genetics of Breast and Gynecologic Cancers (PDQ)Health …

Executive Summary

This executive summary provides an overview of the genetics of breast and gynecologic cancer topics covered in this PDQ summary. Click on the hyperlinks within the executive summary to go to the section of the summary where the evidence surrounding each of these topics is covered in detail.

Breast and ovarian cancer are present in several autosomal dominant cancer syndromes, although they are most strongly associated with highly penetrant germline mutations in BRCA1 and BRCA2. Other genes, such as PALB2, TP53 (associated with Li-Fraumeni syndrome), PTEN (associated with Cowden syndrome), CDH1 (associated with diffuse gastric and lobular breast cancer syndrome), and STK11 (associated with Peutz-Jeghers syndrome), confer a risk to either or both of these cancers with relatively high penetrance.

Inherited endometrial cancer is most commonly associated with LS, a condition caused by inherited mutations in the highly penetrant mismatch repair genes MLH1, MSH2, MSH6, PMS2, and EPCAM. Colorectal cancer (and, to a lesser extent, ovarian cancer and stomach cancer) is also associated with LS.

Additional genes, such as CHEK2, BRIP1, RAD51, and ATM, are associated with breast and/or gynecologic cancers with moderate penetrance. Genome-wide searches are showing promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including breast and gynecologic cancers, but the clinical utility of these findings remains uncertain.

Breast cancer screening strategies, including breast magnetic resonance imaging and mammography, are commonly performed in BRCA mutation carriers and in individuals at increased risk of breast cancer. Initiation of screening is generally recommended at earlier ages and at more frequent intervals in individuals with an increased risk due to genetics and family history than in the general population. There is evidence to demonstrate that these strategies have utility in early detection of cancer. In contrast, there is currently no evidence to demonstrate that gynecologic cancer screening using cancer antigen 125 testing and transvaginal ultrasound leads to early detection of cancer.

Risk-reducing surgeries, including risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), have been shown to significantly reduce the risk of developing breast and/or ovarian cancer and improve overall survival in BRCA1 and BRCA2 mutation carriers. Chemoprevention strategies, including the use of tamoxifen and oral contraceptives, have also been examined in this population. Tamoxifen use has been shown to reduce the risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers after treatment for breast cancer, but there are limited data in the primary cancer prevention setting to suggest that it reduces the risk of breast cancer among healthy female BRCA2 mutation carriers. The use of oral contraceptives has been associated with a protective effect on the risk of developing ovarian cancer, including in BRCA1 and BRCA2 mutation carriers, with no association of increased risk of breast cancer when using formulations developed after 1975.

Psychosocial factors influence decisions about genetic testing for inherited cancer risk and risk-management strategies. Uptake of genetic testing varies widely across studies. Psychological factors that have been associated with testing uptake include cancer-specific distress and perceived risk of developing breast or ovarian cancer. Studies have shown low levels of distress after genetic testing for both carriers and noncarriers, particularly in the longer term. Uptake of RRM and RRSO also varies across studies, and may be influenced by factors such as cancer history, age, family history, recommendations of the health care provider, and pretreatment genetic education and counseling. Patients’ communication with their family members about an inherited risk of breast and gynecologic cancer is complex; gender, age, and the degree of relatedness are some elements that affect disclosure of this information. Research is ongoing to better understand and address psychosocial and behavioral issues in high-risk families.

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

Among women, breast cancer is the most commonly diagnosed cancer after nonmelanoma skin cancer, and it is the second leading cause of cancer deaths after lung cancer. In 2016, an estimated 249,260 new cases will be diagnosed, and 40,890 deaths from breast cancer will occur.[1] The incidence of breast cancer, particularly for estrogen receptorpositive cancers occurring after age 50 years, is declining and has declined at a faster rate since 2003; this may be temporally related to a decrease in hormone replacement therapy (HRT) after early reports from the Womens Health Initiative (WHI).[2] An estimated 22,280 new cases of ovarian cancer are expected in 2016, with an estimated 14,240 deaths. Ovarian cancer is the fifth most deadly cancer in women.[1] An estimated 60,050 new cases of endometrial cancer are expected in 2016, with an estimated 10,470 deaths.[1] (Refer to the PDQ summaries on Breast Cancer Treatment; Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment; and Endometrial Cancer Treatment for more information about breast, ovarian, and endometrial cancer rates, diagnosis, and management.)

A possible genetic contribution to both breast and ovarian cancer risk is indicated by the increased incidence of these cancers among women with a family history (refer to the Risk Factors for Breast Cancer, Risk Factors for Ovarian Cancer, and Risk Factors for Endometrial Cancer sections below for more information), and by the observation of some families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with an inheritance of autosomal dominant cancer susceptibility. Formal studies of families (linkage analysis) have subsequently proven the existence of autosomal dominant predispositions to breast and ovarian cancer and have led to the identification of several highly penetrant genes as the cause of inherited cancer risk in many families. (Refer to the PDQ summary Cancer Genetics Overview for more information about linkage analysis.) Mutations in these genes are rare in the general population and are estimated to account for no more than 5% to 10% of breast and ovarian cancer cases overall. It is likely that other genetic factors contribute to the etiology of some of these cancers.

Refer to the PDQ summary on Breast Cancer Prevention for information about risk factors for breast cancer in the general population.

In cross-sectional studies of adult populations, 5% to 10% of women have a mother or sister with breast cancer, and about twice as many have either a first-degree relative (FDR) or a second-degree relative with breast cancer.[3-6] The risk conferred by a family history of breast cancer has been assessed in case-control and cohort studies, using volunteer and population-based samples, with generally consistent results.[7] In a pooled analysis of 38 studies, the relative risk (RR) of breast cancer conferred by an FDR with breast cancer was 2.1 (95% confidence interval [CI], 2.02.2).[7] Risk increases with the number of affected relatives, age at diagnosis, the occurrence of bilateral or multiple ipsilateral breast cancers in a family member, and the number of affected male relatives.[4,5,7-9] A large population-based study from the Swedish Family Cancer Database confirmed the finding of a significantly increased risk of breast cancer in women who had a mother or a sister with breast cancer. The hazard ratio (HR) for women with a single breast cancer in the family was 1.8 (95% CI, 1.81.9) and was 2.7 (95% CI, 2.62.9) for women with a family history of multiple breast cancers. For women who had multiple breast cancers in the family, with one occurring before age 40 years, the HR was 3.8 (95% CI, 3.14.8). However, the study also found a significant increase in breast cancer risk if the relative was aged 60 years or older, suggesting that breast cancer at any age in the family carries some increase in risk.[9] (Refer to the Penetrance of BRCA mutations section of this summary for a discussion of familial risk in women from families with BRCA1/BRCA2 mutations who themselves test negative for the family mutation.)

Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years.[10] In women with a genetic susceptibility, breast cancer, and to a lesser degree, ovarian cancer, tends to occur at an earlier age than in sporadic cases.

In general, breast cancer risk increases with early menarche and late menopause and is reduced by early first full-term pregnancy. There may be an increased risk of breast cancer in BRCA1 and BRCA2 mutation carriers with pregnancy at a younger age (before age 30 years), with a more significant effect seen for BRCA1 mutation carriers.[11-13] Likewise, breast feeding can reduce breast cancer risk in BRCA1 (but not BRCA2) mutation carriers.[14] Regarding the effect of pregnancy on breast cancer outcomes, neither diagnosis of breast cancer during pregnancy nor pregnancy after breast cancer seems to be associated with adverse survival outcomes in women who carry a BRCA1 or BRCA2 mutation.[15] Parity appears to be protective for BRCA1 and BRCA2 mutation carriers, with an additional protective effect for live birth before age 40 years.[16]

Reproductive history can also affect the risk of ovarian cancer and endometrial cancer. (Refer to the Reproductive History sections in the Risk Factors for Ovarian Cancer and Risk Factors for Endometrial Cancer sections of this summary for more information.)

Oral contraceptives (OCs) may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of data from 54 studies, the risk of breast cancer associated with OC use did not vary in relationship to a family history of breast cancer.[17]

OCs are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers. (Refer to the Oral Contraceptives section in the Risk Factors for Ovarian Cancer section of this summary for more information.) Although the data are not entirely consistent, a meta-analysis concluded that there was no significant increased risk of breast cancer with OC use in BRCA1/BRCA2 mutation carriers.[18] However, use of OCs formulated before 1975 was associated with an increased risk of breast cancer (summary relative risk [SRR], 1.47; 95% CI, 1.062.04).[18] (Refer to the Reproductive factors section in the Clinical Management of BRCA Mutation Carriers section of this summary for more information.)

Data exist from both observational and randomized clinical trials regarding the association between postmenopausal HRT and breast cancer. A meta-analysis of data from 51 observational studies indicated a RR of breast cancer of 1.35 (95% CI, 1.211.49) for women who had used HRT for 5 or more years after menopause.[19] The WHI (NCT00000611), a randomized controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, in which more than 16,000 women were randomly assigned to receive combined HRT or placebo, was halted early because health risks exceeded benefits.[20,21] Adverse outcomes prompting closure included significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150 cases) breast cancers (RR, 1.24; 95% CI, 1.021.5, P

The association between HRT and breast cancer risk among women with a family history of breast cancer has not been consistent; some studies suggest risk is particularly elevated among women with a family history, while others have not found evidence for an interaction between these factors.[24-28,19] The increased risk of breast cancer associated with HRT use in the large meta-analysis did not differ significantly between subjects with and without a family history.[28] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/BRCA2 mutations.[21] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.[19,29] The effect of HRT on breast cancer risk among carriers of BRCA1 or BRCA2 mutations has been studied only in the context of bilateral risk-reducing oophorectomy, in which short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk.[30] (Refer to the Hormone replacement therapy in BRCA1/BRCA2 mutation carriers section of this summary for more information.)

Hormone use can also affect the risk of developing endometrial cancer. (Refer to the Hormones section in the Risk Factors for Endometrial Cancer section of this summary for more information.)

Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received therapeutic radiation treatments to the chest and upper body document increased breast cancer risk as a result of radiation exposure. The significance of this risk factor in women with a genetic susceptibility to breast cancer is unclear.

Preliminary data suggest that increased sensitivity to radiation could be a cause of cancer susceptibility in carriers of BRCA1 or BRCA2 mutations,[31-34] and in association with germline ATM and TP53 mutations.[35,36]

The possibility that genetic susceptibility to breast cancer occurs via a mechanism of radiation sensitivity raises questions about radiation exposure. It is possible that diagnostic radiation exposure, including mammography, poses more risk in genetically susceptible women than in women of average risk. Therapeutic radiation could also pose carcinogenic risk. A cohort study of BRCA1 and BRCA2 mutation carriers treated with breast-conserving therapy, however, showed no evidence of increased radiation sensitivity or sequelae in the breast, lung, or bone marrow of mutation carriers.[37] Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Studies examining the impact of radiation exposure, including, but not limited to, mammography, in BRCA1 and BRCA2 mutation carriers have had conflicting results.[38-43] A large European study showed a dose-response relationship of increased risk with total radiation exposure, but this was primarily driven by nonmammographic radiation exposure before age 20 years.[42] Subsequently, no significant association was observed between prior mammography exposure and breast cancer risk in a prospective study of 1,844 BRCA1 carriers and 502 BRCA2 carriers without a breast cancer diagnosis at time of study entry; average follow-up time was 5.3 years.[43] (Refer to the Mammography section in the Clinical Management of BRCA Mutation Carriers section of this summary for more information about radiation.)

The risk of breast cancer increases by approximately 10% for each 10 g of daily alcohol intake (approximately one drink or less) in the general population.[44,45] Prior studies of BRCA1/BRCA2 mutation carriers have found no increased risk associated with alcohol consumption.[46,47]

Weight gain and being overweight are commonly recognized risk factors for breast cancer. In general, overweight women are most commonly observed to be at increased risk of postmenopausal breast cancer and at reduced risk of premenopausal breast cancer. Sedentary lifestyle may also be a risk factor.[48] These factors have not been systematically evaluated in women with a positive family history of breast cancer or in carriers of cancer-predisposing mutations, but one study suggested a reduced risk of cancer associated with exercise among BRCA1 and BRCA2 mutation carriers.[49]

Benign breast disease (BBD) is a risk factor for breast cancer, independent of the effects of other major risk factors for breast cancer (age, age at menarche, age at first live birth, and family history of breast cancer).[50] There may also be an association between BBD and family history of breast cancer.[51]

An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram,[50,52,53] and breast density is likely to have a genetic component in its etiology.[54-56]

Other risk factors, including those that are only weakly associated with breast cancer and those that have been inconsistently associated with the disease in epidemiologic studies (e.g., cigarette smoking), may be important in women who are in specific genotypically defined subgroups. One study [57] found a reduced risk of breast cancer among BRCA1/BRCA2 mutation carriers who smoked, but an expanded follow-up study failed to find an association.[58]

Refer to the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention for information about risk factors for ovarian cancer in the general population.

Although reproductive, demographic, and lifestyle factors affect risk of ovarian cancer, the single greatest ovarian cancer risk factor is a family history of the disease. A large meta-analysis of 15 published studies estimated an odds ratio of 3.1 for the risk of ovarian cancer associated with at least one FDR with ovarian cancer.[59]

Ovarian cancer incidence rises in a linear fashion from age 30 years to age 50 years and continues to increase, though at a slower rate, thereafter. Before age 30 years, the risk of developing epithelial ovarian cancer is remote, even in hereditary cancer families.[60]

Nulliparity is consistently associated with an increased risk of ovarian cancer, including among BRCA1/BRCA2 mutation carriers, yet a meta-analysis could only identify risk-reduction in women with four or more live births.[13] Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid.[61,62] Several studies have reported a risk reduction in ovarian cancer after OC pill use in BRCA1/BRCA2 mutation carriers;[63-65] a risk reduction has also been shown after tubal ligation in BRCA1 carriers, with a statistically significant decreased risk of 22% to 80% after the procedure.[65,66] On the other hand, evidence is growing that the use of menopausal HRT is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-progesterone schedules.[67-70]

Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk,[61,71,72] including in BRCA1/BRCA2 mutation carriers.[73] Ovarian cancer risk is reduced more than 90% in women with documented BRCA1 or BRCA2 mutations who chose risk-reducing salpingo-oophorectomy. In this same population, risk-reducing oophorectomy also resulted in a nearly 50% reduction in the risk of subsequent breast cancer.[74,75] (Refer to the Risk-reducing salpingo-oophorectomy section of this summary for more information about these studies.)

Use of OCs for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population.[61,76] A majority of, but not all, studies also support OCs being protective among BRCA1/ BRCA2 mutation carriers.[66,77-80] A meta-analysis of 18 studies including 13,627 BRCA mutation carriers reported a significantly reduced risk of ovarian cancer (SRR, 0.50; 95% CI, 0.330.75) associated with OC use.[18] (Refer to the Oral contraceptives section in the Chemoprevention section of this summary for more information.)

Refer to the PDQ summary on Endometrial Cancer Prevention for information about risk factors for endometrial cancer in the general population.

Although the hyperestrogenic state is the most common predisposing factor for endometrial cancer, family history also plays a significant role in a womans risk for disease. Approximately 3% to 5% of uterine cancer cases are attributable to a hereditary cause,[81] with the main hereditary endometrial cancer syndrome being Lynch syndrome (LS), an autosomal dominant genetic condition with a population prevalence of 1 in 300 to 1 in 1,000 individuals.[82,83] (Refer to the LS section in the PDQ summary on Genetics of Colorectal Cancer for more information.)

Age is an important risk factor for endometrial cancer. Most women with endometrial cancer are diagnosed after menopause. Only 15% of women are diagnosed with endometrial cancer before age 50 years, and fewer than 5% are diagnosed before age 40 years.[84] Women with LS tend to develop endometrial cancer at an earlier age, with the median age at diagnosis of 48 years.[85]

Reproductive factors such as multiparity, late menarche, and early menopause decrease the risk of endometrial cancer because of the lower cumulative exposure to estrogen and the higher relative exposure to progesterone.[86,87]

Hormonal factors that increase the risk of type I endometrial cancer are better understood. All endometrial cancers share a predominance of estrogen relative to progesterone. Prolonged exposure to estrogen or unopposed estrogen increases the risk of endometrial cancer. Endogenous exposure to estrogen can result from obesity, polycystic ovary syndrome (PCOS), and nulliparity, while exogenous estrogen can result from taking unopposed estrogen or tamoxifen. Unopposed estrogen increases the risk of developing endometrial cancer by twofold to twentyfold, proportional to the duration of use.[88,89] Tamoxifen, a selective estrogen receptor modulator, acts as an estrogen agonist on the endometrium while acting as an estrogen antagonist in breast tissue, and increases the risk of endometrial cancer.[90] In contrast, oral contraceptives, the levonorgestrel-releasing intrauterine system, and combination estrogen-progesterone hormone replacement therapy all reduce the risk of endometrial cancer through the antiproliferative effect of progesterone acting on the endometrium.[91-94]

Autosomal dominant inheritance of breast and gynecologic cancers is characterized by transmission of cancer predisposition from generation to generation, through either the mothers or the fathers side of the family, with the following characteristics:

Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are the BRCA1 or BRCA2 mutation syndromes. Breast cancer is also a common feature of Li-Fraumeni syndrome due to TP53 mutations and of Cowden syndrome due to PTEN mutations.[95] Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia gene and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with LS, basal cell nevus (Gorlin) syndrome (OMIM), and multiple endocrine neoplasia type 1 (OMIM).[95] LS is mainly associated with colorectal cancer and endometrial cancer, although several studies have demonstrated that patients with LS are also at risk of developing transitional cell carcinoma of the ureters and renal pelvis; cancers of the stomach, small intestine, liver and biliary tract, brain, breast, prostate, and adrenal cortex; and sebaceous skin tumors (Muir-Torre syndrome).[96-102]

Germline mutations in the genes responsible for these autosomal dominant cancer syndromes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.

The family characteristics that suggest hereditary cancer predisposition include the following:

Figure 1 and Figure 2 depict some of the classic inheritance features of a deleterious BRCA1 and BRCA2 mutation, respectively. Figure 3 depicts a classic family with LS. (Refer to the Standard Pedigree Nomenclature figure in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for definitions of the standard symbols used in these pedigrees.)

Figure 1. BRCA1 pedigree. This pedigree shows some of the classic features of a family with a deleterious BRCA1 mutation across three generations, including affected family members with breast cancer or ovarian cancer and a young age at onset. BRCA1 families may exhibit some or all of these features. As an autosomal dominant syndrome, a deleterious BRCA1 mutation can be transmitted through maternal or paternal lineages, as depicted in the figure.

Figure 2. BRCA2 pedigree. This pedigree shows some of the classic features of a family with a deleterious BRCA2 mutation across three generations, including affected family members with breast (including male breast cancer), ovarian, pancreatic, or prostate cancers and a relatively young age at onset. BRCA2 families may exhibit some or all of these features. As an autosomal dominant syndrome, a deleterious BRCA2 mutation can be transmitted through maternal or paternal lineages, as depicted in the figure.

Figure 3. Lynch syndrome pedigree. This pedigree shows some of the classic features of a family with Lynch syndrome, including affected family members with colon cancer or endometrial cancer and a younger age at onset in some individuals. Lynch syndrome families may exhibit some or all of these features. Lynch syndrome families may also include individuals with other gastrointestinal, gynecologic, and genitourinary cancers, or other extracolonic cancers. As an autosomal dominant syndrome, Lynch syndrome can be transmitted through maternal or paternal lineages, as depicted in the figure.

There are no pathognomonic features distinguishing breast and ovarian cancers occurring in BRCA1 or BRCA2 mutation carriers from those occurring in noncarriers. Breast cancers occurring in BRCA1 mutation carriers are more likely to be ER-negative, progesterone receptornegative, HER2/neu receptornegative (i.e., triple-negative breast cancers), and have a basal phenotype. BRCA1-associated ovarian cancers are more likely to be high-grade and of serous histopathology. (Refer to the Pathology of breast cancer and Pathology of ovarian cancer sections of this summary for more information.)

Some pathologic features distinguish LS mutation carriers from noncarriers. The hallmark feature of endometrial cancers occurring in LS is mismatch repair (MMR) defects, including the presence of microsatellite instability (MSI), and the absence of specific MMR proteins. In addition to these molecular changes, there are also histologic changes including tumor-infiltrating lymphocytes, peritumoral lymphocytes, undifferentiated tumor histology, lower uterine segment origin, and synchronous tumors.

The accuracy and completeness of family histories must be taken into account when they are used to assess risk. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than does breast or ovarian cancer on the maternal side, so information may be more difficult to obtain. When self-reported information is compared with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.[103,104] Additional limitations of relying on family histories include adoption; families with a small number of women; limited access to family history information; and incidental removal of the uterus, ovaries, and/or fallopian tubes for noncancer indications. Family histories will evolve, therefore it is important to update family histories from both parents over time. (Refer to the Accuracy of the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

Models to predict an individuals lifetime risk of developing breast and/or gynecologic cancer are available.[105-108] In addition, models exist to predict an individuals likelihood of having a mutation in BRCA1, BRCA2, or one of the MMR genes associated with LS. (Refer to the Models for prediction of the likelihood of a BRCA1 or BRCA2 mutation section of this summary for more information about some of these models.) Not all models can be appropriately applied to all patients. Each model is appropriate only when the patients characteristics and family history are similar to those of the study population on which the model was based. Different models may provide widely varying risk estimates for the same clinical scenario, and the validation of these estimates has not been performed for many models.[106,109,110]

In general, breast cancer risk assessment models are designed for two types of populations: 1) women without a predisposing mutation or strong family history of breast or ovarian cancer; and 2) women at higher risk because of a personal or family history of breast cancer or ovarian cancer.[110] Models designed for women of the first type (e.g., the Gail model, which is the basis for the Breast Cancer Risk Assessment Tool [BCRAT]) [111], and the Colditz and Rosner model [112]) require only limited information about family history (e.g., number of first-degree relatives with breast cancer). Models designed for women at higher risk require more detailed information about personal and family cancer history of breast and ovarian cancers, including ages at onset of cancer and/or carrier status of specific breast cancer-susceptibility alleles. The genetic factors used by the latter models differ, with some assuming one risk locus (e.g., the Claus model [113]), others assuming two loci (e.g., the International Breast Cancer Intervention Study [IBIS] model [114] and the BRCAPRO model [115]), and still others assuming an additional polygenic component in addition to multiple loci (e.g., the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA] model [116-118]). The models also differ in whether they include information about nongenetic risk factors. Three models (Gail/BCRAT, Pfeiffer,[108] and IBIS) include nongenetic risk factors but differ in the risk factors they include (e.g., the Pfeiffer model includes alcohol consumption, whereas the Gail/BCRAT does not). These models have limited ability to discriminate between individuals who are affected and those who are unaffected with cancer; a model with high discrimination would be close to 1, and a model with little discrimination would be close to 0.5; the discrimination of the models currently ranges between 0.56 and 0.63).[119] The existing models generally are more accurate in prospective studies that have assessed how well they predict future cancers.[110,120-122]

In the United States, BRCAPRO, the Claus model,[113,123] and the Gail/BCRAT [111] are widely used in clinical counseling. Risk estimates derived from the models differ for an individual patient. Several other models that include more detailed family history information are also in use and are discussed below.

The Gail model is the basis for the BCRAT, a computer program available from the National Cancer Institute (NCI) by calling the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). This version of the Gail model estimates only the risk of invasive breast cancer. The Gail/BCRAT model has been found to be reasonably accurate at predicting breast cancer risk in large groups of white women who undergo annual screening mammography; however, reliability varies depending on the cohort studied.[124-129] Risk can be overestimated in the following populations:

The Gail/BCRAT model is valid for women aged 35 years and older. The model was primarily developed for white women.[128] Extensions of the Gail model for African American women have been subsequently developed to calibrate risk estimates using data from more than 1,600 African American women with invasive breast cancer and more than 1,600 controls.[130] Additionally, extensions of the Gail model have incorporated high-risk single nucleotide polymorphisms and mutations; however, no software exists to calculate risk in these extended models.[131,132] Other risk assessment models incorporating breast density have been developed but are not ready for clinical use.[133,134]

Generally, the Gail/BCRAT model should not be the sole model used for families with one or more of the following characteristics:

Commonly used models that incorporate family history include the IBIS, BOADICEA, and BRCAPRO models. The IBIS/Tyrer-Cuzick model incorporates both genetic and nongenetic factors.[114] A three-generation pedigree is used to estimate the likelihood that an individual carries either a BRCA1/BRCA2 mutation or a hypothetical low-penetrance gene. In addition, the model incorporates personal risk factors such as parity, body mass index (BMI); height; and age at menarche, first live birth, menopause, and HRT use. Both genetic and nongenetic factors are combined to develop a risk estimate. The BOADICEA model examines family history to estimate breast cancer risk and also incorporates both BRCA1/BRCA2 and non-BRCA1/BRCA2 genetic risk factors.[117] The most important difference between BOADICEA and the other models using information on BRCA1/BRCA2 is that BOADICEA assumes an additional polygenic component in addition to multiple loci,[116-118] which is more in line with what is known about the underlying genetics of breast cancer. However, the discrimination and calibration for these models differ significantly when compared in independent samples;[120] the IBIS and BOADICEA models are more comparable when estimating risk over a shorter fixed time horizon (e.g., 10 years),[120] than when estimating remaining lifetime risk. As all risk assessment models for cancers are typically validated over a shorter time horizon (e.g., 5 or 10 years), fixed time horizon estimates rather than remaining lifetime risk may be more accurate and useful measures to convey in a clinical setting.

In addition, readily available models that provide information about an individual womans risk in relation to the population-level risk depending on her risk factors may be useful in a clinical setting (e.g., Your Disease Risk). Although this tool was developed using information about average-risk women and does not calculate absolute risk estimates, it still may be useful when counseling women about prevention. Risk assessment models are being developed and validated in large cohorts to integrate genetic and nongenetic data, breast density, and other biomarkers.

Two risk predictions models have been developed for ovarian cancer.[107,108] The Rosner model [107] included age at menopause, age at menarche, oral contraception use, and tubal ligation; the concordance statistic was 0.60 (0.570.62). The Pfeiffer model [108] included oral contraceptive use, menopausal hormone therapy use, and family history of breast cancer or ovarian cancer, with a similar discriminatory power of 0.59 (0.560.62). Although both models were well calibrated, their modest discriminatory power limited their screening potential.

The Pfeiffer model has been used to predict endometrial cancer risk in the general population.[108] For endometrial cancer, the relative risk model included BMI, menopausal hormone therapy use, menopausal status, age at menopause, smoking status, and oral contraceptive pill use. The discriminatory power of the model was 0.68 (0.660.70); it overestimated observed endometrial cancers in most subgroups but underestimated disease in women with the highest BMI category, in premenopausal women, and in women taking menopausal hormone therapy for 10 years or more.

In contrast, MMRpredict, PREMM1,2,6, and MMRpro are three quantitative predictive models used to identify individuals who may potentially have LS.[135-137] MMRpredict incorporates only colorectal cancer patients but does include MSI and immunohistochemistry (IHC) tumor testing results. PREMM1,2,6 accounts for other LS-associated tumors but does not include tumor testing results. MMRpro incorporates tumor testing and germline testing results, but is more time intensive because it includes affected and unaffected individuals in the risk-quantification process. All three predictive models are comparable to the traditional Amsterdam and Bethesda criteria in identifying individuals with colorectal cancer who carry MMR mutations.[138] However, because these models were developed and validated in colorectal cancer patients, the discriminative abilities of these models to identify LS are lower among individuals with endometrial cancer than among those with colon cancer.[139] In fact, the sensitivity and specificity of MSI and IHC in identifying mutation carriers are considerably higher than the prediction models and support the use of molecular tumor testing to screen for LS in women with endometrial cancer.

Table 1 summarizes salient aspects of breast and gynecologic cancer risk assessment models that are commonly used in the clinical setting. These models differ by the extent of family history included, whether nongenetic risk factors are included, and whether carrier status and polygenic risk are included (inputs to the models). The models also differ in the type of risk estimates that are generated (outputs of the models). These factors may be relevant in choosing the model that best applies to a particular individual.

The proportion of individuals carrying a mutation who will manifest a certain disease is referred to as penetrance. In general, common genetic variants that are associated with cancer susceptibility have a lower penetrance than rare genetic variants. This is depicted in Figure 4. For adult-onset diseases, penetrance is usually described by the individual carrier’s age, sex, and organ site. For example, the penetrance for breast cancer in female BRCA1 mutation carriers is often quoted by age 50 years and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual mutation carrier’s risk of cancer involves some level of imprecision.

Figure 4. Genetic architecture of cancer risk. This graph depicts the general finding of a low relative risk associated with common, low-penetrance genetic variants, such as single-nucleotide polymorphisms identified in genome-wide association studies, and a higher relative risk associated with rare, high-penetrance genetic variants, such as mutations in the BRCA1/BRCA2 genes associated with hereditary breast and ovarian cancer and the mismatch repair genes associated with Lynch syndrome.

Throughout this summary, we discuss studies that report on relative and absolute risks. These are two important but different concepts. Relative risk (RR) refers to an estimate of risk relative to another group (e.g., risk of an outcome like breast cancer for women who are exposed to a risk factor RELATIVE to the risk of breast cancer for women who are unexposed to the same risk factor). RR measures that are greater than 1 mean that the risk for those captured in the numerator (i.e., the exposed) is higher than the risk for those captured in the denominator (i.e., the unexposed). RR measures that are less than 1 mean that the risk for those captured in the numerator (i.e., the exposed) is lower than the risk for those captured in the denominator (i.e., the unexposed). Measures with similar relative interpretations include the odds ratio (OR), hazard ratio (HR), and risk ratio.

Absolute risk measures take into account the number of people who have a particular outcome, the number of people in a population who could have the outcome, and person-time (the period of time during which an individual was at risk of having the outcome), and reflect the absolute burden of an outcome in a population. Absolute measures include risks and rates and can be expressed over a specific time frame (e.g., 1 year, 5 years) or overall lifetime. Cumulative risk is a measure of risk that occurs over a defined time period. For example, overall lifetime risk is a type of cumulative risk that is usually calculated on the basis of a given life expectancy (e.g., 80 or 90 years). Cumulative risk can also be presented over other time frames (e.g., up to age 50 years).

Large relative risk measures do not mean that there will be large effects in the actual number of individuals at a population level because the disease outcome may be quite rare. For example, the relative risk for smoking is much higher for lung cancer than for heart disease, but the absolute difference between smokers and nonsmokers is greater for heart disease, the more-common outcome, than for lung cancer, the more-rare outcome.

Therefore, in evaluating the effect of exposures and biological markers on disease prevention across the continuum, it is important to recognize the differences between relative and absolute effects in weighing the overall impact of a given risk factor. For example, the magnitude is in the range of 30% (e.g., ORs or RRs of 1.3) for many breast cancer risk factors, which means that women with a risk factor (e.g., alcohol consumption, late age at first birth, oral contraceptive use, postmenopausal body size) have a 30% relative increase in breast cancer in comparison with what they would have if they did not have that risk factor. But the absolute increase in risk is based on the underlying absolute risk of disease. Figure 5 and Table 2 show the impact of a relative risk factor in the range of 1.3 on absolute risk. (Refer to the Standard Pedigree Nomenclature figure in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for definitions of the standard symbols used in these pedigrees.) As shown, women with a family history of breast cancer have a much higher benefit from risk factor reduction on an absolute scale.[1]

Figure 5. These five pedigrees depict probands with varying degrees of family history. Table 2 accompanies this figure.

Since the availability of next-generation sequencing and the Supreme Court of the United States ruling that human genes cannot be patented, several clinical laboratories now offer genetic testing through multigene panels at a cost comparable to single-gene testing. Even testing for BRCA1 and BRCA2 is a limited panel test of two genes. Looking beyond BRCA1 and BRCA2, some authors have suggested that one-quarter of heritable ovarian/tubal/peritoneal cancers may be attributed to other genes, many associated with the Fanconi anemia pathway or otherwise involved with homologous recombination.[1] In a population of patients who test negative for BRCA1 and BRCA2 mutations, multigene panel testing can reveal actionable pathologic mutations.[2,3] A caveat is the possible finding of a variant of uncertain significance, where the clinical significance remains unknown. Many centers now offer a multigene panel test instead of just BRCA1 and BRCA2 testing if there is a concerning family history of syndromes other than hereditary breast and ovarian cancer, or more importantly, to gain as much genetic information as possible with one test, particularly if there may be insurance limitations.

(Refer to the Multigene [panel] testing section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about multigene testing, including genetic education and counseling considerations and research examining the use of multigene testing.)

Epidemiologic studies have clearly established the role of family history as an important risk factor for both breast and ovarian cancer. After gender and age, a positive family history is the strongest known predictive risk factor for breast cancer. However, it has long been recognized that in some families, there is hereditary breast cancer, which is characterized by an early age of onset, bilaterality, and the presence of breast cancer in multiple generations in an apparent autosomal dominant pattern of transmission (through either the maternal or the paternal lineage), sometimes including tumors of other organs, particularly the ovary and prostate gland.[1,2] It is now known that some of these cancer families can be explained by specific mutations in single cancer susceptibility genes. The isolation of several of these genes, which when mutated are associated with a significantly increased risk of breast/ovarian cancer, makes it possible to identify individuals at risk. Although such cancer susceptibility genes are very important, highly penetrant germline mutations are estimated to account for only 5% to 10% of breast cancers overall.

A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families.[3] The search for genes associated with hereditary susceptibility to breast cancer has been facilitated by studies of large kindreds with multiple affected individuals and has led to the identification of several susceptibility genes, including BRCA1, BRCA2, TP53, PTEN/MMAC1, and STK11. Other genes, such as the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, have been associated with an increased risk of ovarian cancer, but have not been consistently associated with breast cancer.

In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q12-21.[4] The linkage between breast cancer and genetic markers on chromosome 17q was soon confirmed by others, and evidence for the coincident transmission of both breast and ovarian cancer susceptibility in linked families was observed.[5] The BRCA1 gene (OMIM) was subsequently identified by positional cloning methods and has been found to contain 24 exons that encode a protein of 1,863 amino acids. Germline mutations in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance of BRCA mutations section of this summary for more information.) Male breast cancer, pancreatic cancer, testicular cancer, and early-onset prostate cancer may also be associated with mutations in BRCA1;[6-9] however, male breast cancer, pancreatic cancer, and prostate cancer are more strongly associated with mutations in BRCA2.

A second breast cancer susceptibility gene, BRCA2, was localized to the long arm of chromosome 13 through linkage studies of 15 families with multiple cases of breast cancer that were not linked to BRCA1. Mutations in BRCA2 (OMIM) are associated with multiple cases of breast cancer in families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, melanoma, and pancreatic cancer.[8-14] (Refer to the Penetrance of BRCA mutations section of this summary for more information.) BRCA2 is a large gene with 27 exons that encode a protein of 3,418 amino acids.[15] While not homologous genes, both BRCA1 and BRCA2 have an unusually large exon 11 and translational start sites in exon 2. Like BRCA1, BRCA2 appears to behave like a tumor suppressor gene. In tumors associated with both BRCA1 and BRCA2 mutations, there is often loss of the wild-type (nonmutated) allele.

Mutations in BRCA1 and BRCA2 appear to be responsible for disease in 45% of families with multiple cases of breast cancer only and in up to 90% of families with both breast and ovarian cancer.[16]

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function, although some missense mutations cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on one copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. In most breast and ovarian cancers that have been studied from mutation carriers, deletion of the normal allele results in loss of all function, leading to the classification of BRCA1 and BRCA2 as tumor suppressor genes. In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in myriad functions within cells, including homologous DNA repair, genomic stability, transcriptional regulation, protein ubiquitination, chromatin remodeling, and cell cycle control.[17,18]

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.[19] Approximately 1 in 400 to 800 individuals in the general population may carry a pathogenic germline mutation in BRCA1 or BRCA2.[20,21] The mutations that have been associated with increased risk of cancer result in missing or nonfunctional proteins, supporting the hypothesis that BRCA1 and BRCA2 are tumor suppressor genes. While a small number of these mutations have been found repeatedly in unrelated families, most have not been reported in more than a few families.

Mutation-screening methods vary in their sensitivity. Methods widely used in research laboratories, such as single-stranded conformational polymorphism analysis and conformation-sensitive gel electrophoresis, miss nearly a third of the mutations that are detected by DNA sequencing.[22] In addition, large genomic alterations such as translocations, inversions, or large deletions or insertions are missed by most of the techniques, including direct DNA sequencing, but testing for these is commercially available. Such rearrangements are believed to be responsible for 12% to 18% of BRCA1 inactivating mutations but are less frequently seen in BRCA2 and in individuals of Ashkenazi Jewish (AJ) descent.[23-29] Furthermore, studies have suggested that these rearrangements may be more frequently seen in Hispanic and Caribbean populations.[27,29,30]

Germline deleterious mutations in the BRCA1/BRCA2 genes are associated with an approximately 60% lifetime risk of breast cancer and a 15% to 40% lifetime risk of ovarian cancer. There are no definitive functional tests for BRCA1 or BRCA2; therefore, the classification of nucleotide changes to predict their functional impact as deleterious or benign relies on imperfect data. The majority of accepted deleterious mutations result in protein truncation and/or loss of important functional domains. However, 10% to 15% of all individuals undergoing genetic testing with full sequencing of BRCA1 and BRCA2 will not have a clearly deleterious mutation detected but will have a variant of uncertain (or unknown) significance (VUS). VUS may cause substantial challenges in counseling, particularly in terms of cancer risk estimates and risk management. Clinical management of such patients needs to be highly individualized and must take into consideration factors such as the patients personal and family cancer history, in addition to sources of information to help characterize the VUS as benign or deleterious. Thus an improved classification and reporting system may be of clinical utility.[31]

A comprehensive analysis of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratories, Inc., described the frequency of VUS over a 3-year period.[32] Among subjects who had no clearly deleterious mutation, 13% had VUS defined as missense mutations and mutations that occur in analyzed intronic regions whose clinical significance has not yet been determined, chain-terminating mutations that truncate BRCA1 and BRCA2 distal to amino acid positions 1853 and 3308, respectively, and mutations that eliminate the normal stop codons for these proteins. The classification of a sequence variant as a VUS is a moving target. An additional 6.8% of subjects with no clear deleterious mutations had sequence alterations that were once considered VUS but were reclassified as a polymorphism, or occasionally as a deleterious mutation.

The frequency of VUS varies by ethnicity within the U.S. population. African Americans appear to have the highest rate of VUS.[33] In a 2009 study of data from Myriad, 16.5% of individuals of African ancestry had VUS, the highest rate among all ethnicities. The frequency of VUS in Asian, Middle Eastern, and Hispanic populations clusters between 10% and 14%, although these numbers are based on limited sample sizes. Over time, the rate of changes classified as VUS has decreased in all ethnicities, largely the result of improved mutation classification algorithms.[34] VUS continue to be reclassified as additional information is curated and interpreted.[35,36] Such information may impact the continuing care of affected individuals.

A number of methods for discriminating deleterious from neutral VUS exist and others are in development [37-40] including integrated methods (see below).[41] Interpretation of VUS is greatly aided by efforts to track VUS in the family to determine if there is cosegregation of the VUS with the cancer in the family. In general, a VUS observed in individuals who also have a deleterious mutation, especially when the same VUS has been identified in conjunction with different deleterious mutations, is less likely to be in itself deleterious, although there are rare exceptions. As an adjunct to the clinical information, models to interpret VUS have been developed, based on sequence conservation, biochemical properties of amino acid changes,[37,42-46] incorporation of information on pathologic characteristics of BRCA1- and BRCA2-related tumors (e.g., BRCA1-related breast cancers are usually estrogen receptor [ER]negative),[47] and functional studies to measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 proteins.[48,49] When attempting to interpret a VUS, all available information should be examined.

Statistics regarding the percentage of individuals found to be BRCA mutation carriers among samples of women and men with a variety of personal cancer histories regardless of family history are provided below. These data can help determine who might best benefit from a referral for cancer genetic counseling and consideration of genetic testing but cannot replace a personalized risk assessment, which might indicate a higher or lower mutation likelihood based on additional personal and family history characteristics.

In some cases, the same mutation has been found in multiple apparently unrelated families. This observation is consistent with a founder effect, wherein a mutation identified in a contemporary population can be traced to a small group of founders isolated by geographic, cultural, or other factors. Most notably, two specific BRCA1 mutations (185delAG and 5382insC) and a BRCA2 mutation (6174delT) have been reported to be common in AJs. However, other founder mutations have been identified in African Americans and Hispanics.[30,50,51] The presence of these founder mutations has practical implications for genetic testing. Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without limitations. For example, it is estimated that up to 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.[32]

Among the general population, the likelihood of having any BRCA mutation is as follows:

Among AJ individuals, the likelihood of having any BRCA mutation is as follows:

Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1 [55,70] and BRCA2 [55] mutations in various ethnic groups. The prevalence of BRCA1 mutations in breast cancer patients by ethnic group was 3.5% in Hispanics, 1.3% to 1.4% in African Americans, 0.5% in Asian Americans, 2.2% to 2.9% in non-Ashkenazi whites, and 8.3% to 10.2% in Ashkenazi Jewish individuals.[55,70] The prevalence of BRCA2 mutations by ethnic group was 2.6% in African Americans and 2.1% in whites.[55]

A study of Hispanic patients with a personal or family history of breast cancer and/or ovarian cancer, who were enrolled through multiple clinics in the southwestern United States, examined the prevalence of BRCA1 and BRCA2 mutations. Deleterious BRCA mutations were identified in 189 of 746 patients (25%) (124 BRCA1, 65 BRCA2);[71] 21 of the 189 (11%) deleterious BRCA mutations identified were large rearrangements, of which 13 (62%) were the BRCA1 exon 912 deletion. An unselected cohort of 810 women of Mexican ancestry with breast cancer were tested; 4.3% had a BRCA mutation. Eight of the 35 mutations identified also were the BRCA1 exon 912 deletion.[72] In another population-based cohort of 492 Hispanic women with breast cancer, the BRCA1 exon 912 deletion was found in three patients, suggesting that this mutation may be a Mexican founder mutation and may represent 10% to 12% of all BRCA1 mutations in similar clinic- and population-based cohorts in the United States. Within the clinic-based cohort, there were nine recurrent mutations, which accounted for 53% of all mutations observed in this cohort, suggesting the existence of additional founder mutations in this population.

A retrospective review of 29 AJ patients with primary fallopian tube tumors identified germline BRCA mutations in 17%.[69] Another study of 108 women with fallopian tube cancer identified mutations in 55.6% of the Jewish women and 26.4% of non-Jewish women (30.6% overall).[73] Estimates of the frequency of fallopian tube cancer in BRCA mutation carriers are limited by the lack of precision in the assignment of site of origin for high-grade, metastatic, serous carcinomas at initial presentation.[6,69,73,74]

Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer.[55,56,70,75-83] Personal characteristics associated with an increased likelihood of a BRCA1 and/or BRCA2 mutation include the following:

Family history characteristics associated with an increased likelihood of carrying a BRCA1 and/or BRCA2 mutation include the following:

Several professional organizations and expert panels, including the American Society of Clinical Oncology,[88] the National Comprehensive Cancer Network (NCCN),[89] the American Society of Human Genetics,[90] the American College of Medical Genetics and Genomics,[91] the National Society of Genetic Counselors,[91] the U.S. Preventive Services Task Force,[92] and the Society of Gynecologic Oncologists,[93] have developed clinical criteria and practice guidelines that can be helpful to health care providers in identifying individuals who may have a BRCA1 or BRCA2 mutation.

Many models have been developed to predict the probability of identifying germline BRCA1/BRCA2 mutations in individuals or families. These models include those using logistic regression,[32,75,76,78,81,94,95] genetic models using Bayesian analysis (BRCAPRO and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA]),[81,96] and empiric observations,[52,55,58,97-99] including the Myriad prevalence tables.

In addition to BOADICEA, BRCAPRO is commonly used for genetic counseling in the clinical setting. BRCAPRO and BOADICEA predict the probability of being a carrier and produce estimates of breast cancer risk (see Table 3). The discrimination and accuracy (factors used to evaluate the performance of prediction models) of these models are much higher for these models’ ability to report on carrier status than for their ability to predict fixed or remaining lifetime risk.

More recently, a polygenetic model (BOADICEA) using complex segregation analysis to examine both breast cancer risk and the probability of having a BRCA1 or BRCA2 mutation has been published.[96] Even among experienced providers, the use of prediction models has been shown to increase the power to discriminate which patients are most likely to be BRCA1/BRCA2 mutation carriers.[100,101] Most models do not include other cancers seen in the BRCA1 and BRCA2 spectrum, such as pancreatic cancer and prostate cancer. Interventions that decrease the likelihood that an individual will develop cancer (such as oophorectomy and mastectomy) may influence the ability to predict BRCA1 and BRCA2 mutation status.[102] One study has shown that the prediction models for genetic risk are sensitive to the amount of family history data available and do not perform as well with limited family information.[103]

The performance of the models can vary in specific ethnic groups. The BRCAPRO model appeared to best fit a series of French Canadian families.[104] There have been variable results in the performance of the BRCAPRO model among Hispanics,[105,106] and both the BRCAPRO model and Myriad tables underestimated the proportion of mutation carriers in an Asian American population.[107] BOADICEA was developed and validated in British women. Thus, the major models used for both overall risk (Table 1) and genetic risk (Table 3) have not been developed or validated in large populations of racially and ethnically diverse women. Of the commonly used clinical models for assessing genetic risk, only the Tyrer-Cuzick model contains nongenetic risk factors.

The power of several of the models has been compared in different studies.[108-111] Four breast cancer genetic-risk models, BOADICEA, BRCAPRO, IBIS, and eCLAUS, were evaluated for their diagnostic accuracy in predicting BRCA1/2 mutations in a cohort of 7,352 German families.[112] The family member with the highest likelihood of carrying a mutation from each family was screened for BRCA1/2 mutations. Carrier probabilities from each model were calculated and compared with the actual mutations detected. BRCAPRO and BOADICEA had significantly higher diagnostic accuracy than IBIS or eCLAUS. Accuracy for the BOADICEA model was further improved when information on the tumor markers ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) were included in the model. The inclusion of these biomarkers has been shown to improve the performance of BRCAPRO.[113,114]

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Man vs. Estrogen: It’s Not Just A Woman Thing! | Seasons …

Posted by Dr. Nathan Goodyear on June 5, 2012 45 Comments

Nathan Goodyear, M.D.

Testosterone is the defining hormone of a man.Estrogen is the defining hormone of a woman.

So when we talk about estrogen, its that word men whisper in secret when the women in their lives seem a little hormonal, right? When people find out that my wife and I have 3 daughters, the resulting comment is usually, Wow, thats a lot of estrogen in your household! (Thankfully, I have a son, too, who helps balance the estrogen to testosterone ratio at our house!)

Im sorry to burst your bubble, guys, but estrogen is not exclusive to women. We make estrogen, too.In fact, some of us make aLOTof estrogen. Too much, in fact. And it creates some serious problems.

But before we talk about estrogen, we need to talk about testosterone.Testosterone levels in American men are at an all-time low! There are four major reasons for that: stress, weight, endogenous estrogens, and xenoestrogens. In this post, Ill address three of those stress, weight, and endogenous estrogen.

So lets get started learning four important facts about testosterone, estrogen, and men!

What problems do high estrogen levels create in men?

1. High estrogen = low testosterone.One of the primary causes of low testosterone is a high estrogen level.Estrogens can be endogenous (produced by your body) or exogenous (from the environment, also known as xenoestrogens).Estradiol and Estrone (two of the three kinds of estrogen produced by your body) feed back to the hypothalamus and pituitary and shut off testosterone production.

2. High estrogen = inflammation.Not only do high estrogen levels decrease testosterone in men, they also increaseinflammation. And this is VERY significant.Inflammation, just like stress, is a biochemical process.

Inflammation is the natural result of the immune system.Remember the last time you got a paper cut? It was incredibly painful, probably red, warm and swollen, allcardinal symptoms of inflammation.Inflammation, in the right setting, is actually the body protecting itself. However, when the immune system becomesimbalancedorchronically activated, the immune system causes damage through inflammation. For example, chronically activated immune cells in the brain (glial cells) play a pivotal role in the development of Alzheimers, Parkinsons, and Multiple Sclerosis.

Inflammation is a SERIOUS issue.Chronic inflammation has been linked to many of the chronic diseases of aging: Type II Diabetes, obesity, hypertension, and cancer.In fact, a new term has been coined to describe inflammation arising from the gut which results in many of the above listed disease states metabolic endotoxemia.

Weve established that high estrogen levels are bad for men, shutting down testosterone production and causing chronic inflammation leading to disease.

What causes high estrogen levels in men?

1. High aromatase activity = high estrogen.First, high endogenous estrogen levels in men come fromhigh aromatase activity.Aromataseis the enzyme that converts androstenedione and testosterone into estrone and estradiol respectively. Aromatase is present in many different tissues. But in men aromatase is highly concentrated in thatmid-life bulge.

Unfortunately, aromatase activity in menincreasesas we age due to stress, weight gain, and inflammation. None of us are going to get away from aging (its right there with death and taxes). And who do you know that has NO stress? (Remember, it is estimated that 90% of doctor visits are stress-related.) Typically, as we age we gain weight and have more inflammation.

That age-related tire around the mid-section is more than just unsightly. It is a hormone and inflammation-producing organ.Remember metabolic endotoxemia, the disease-producing state I mentioned earlier? Metabolic endotoxemia is inflammation arising from the GI system whichcausesobesity and then turns right around andproducesinflammation. Its a vicious cycle! And guess what is concentrated in fat? If you guessed aromatase activity, then you are absolutely correct. Aromatase activity in men accounts for80%of estrogen production.

Hormones are not just about numbers, but balance and metabolism as well (readmy recent post on the topic).

2. Overdosage of testosterone = high estrogen.As mentioned earlier, testosterone levels in men are at an all-time low. And the mass solution for this problem with most physicians is to increase testosterone without evaluating or treating the underlying causes for low testosterone. Unfortunately, this complicates the entire low testosterone problem. Overdosage of testosterone increases estrogen production.

What? You mean you can dose too high on testosterone? Yes, andmost of the patients I see who are being treated with testosterone have been, in fact,overdosed.

In fact, at Seasons Wellness Clinic and Seasons of Farragut, we have seen many men must donate blood due to excess production of hemoglobin and hematocrit, a by-product of testosterone overdosage. A 20-22 year old male normally produces5-10 mgdaily of testosterone. It is during this age range that men are at their physical peak of testosterone production. For me, this was during my college football years.

Does it make sense for 40-and-up men currently taking testosterone, that they didnotneed to donate blood monthly during their peak years of natural testosterone production, but are currently required to donate blood regularly with their current regimen of testosterone? Of course not. So, if you didnt have to donate blood with your peak testosterone production in your 20s, you shouldnt have to donate with testosterone therapy in your 40s and beyond either. Something is wrong here, right?

Thestartingdosage for one of the most highly-prescribed androgen gels is1 gram daily.Men, we didnt need 1 gram of testosterone in our early 20s, and we dont need it in our 30s and beyond.

80% of a mans Estrogen production occurs from aromatase activity, and aromatase activity increases as we age. So high doses of testosterone dont make sense. Doctors are just throwing fuel on the fire with these massive doses. More is not better if its too much, even when it is something your body needs.

Then, there is the delivery of testosterone therapy. The bodys natural testosterone secretion follows a normal diurnal rhythm. Testosterone is known to be greatest in early morning and lowest in the evening. But with many prescribing testosterone therapy today, it is very common to get weekly testosterone shots or testosterone pellets. This method of delivery does NOT follow the bodys natural rhythm. The shots and pellets delivery method of testosterone produce supra physiologic (abnormal) peaks. If the purpose of hormone therapy is to return the body to normal levels, then that objective can never be reached with this type of testosterone therapy.

The effects of Testosterone to estrogen conversion in men and women are different. Thats certainly no surprise. In men, high aromatase activity and conversion of testosterone to estrogen has been linked to elevatedCRP,fibrinogen, andIL-6.

Are these important?CRPis one of the best indicators of future cardiovascular disease/events (heart attacks and strokes), and is associated with metabolic syndrome. And yes, it is more predictive than even a high cholesterol level. Fibrinogen is another marker of inflammation that has been associated with cardiovascular disease and systemic inflammation. IL-6 is an inflammatory cytokine (immune signal) that has been implicated in increased aromatase activity (conversion of testosterone to estrogen) and at the same time is the result of increased testosterone to estrogen activity.

So, whats the big deal?The studies are not 100% conclusive, but it is clear thatinflammation increases the testosterone to estrogen conversionthrough increasedaromataseactivity. And the increased estrogen conversion is associated with increased inflammation in men. Itsa vicious cycle that will lead to disease states such asinsulin resistance, hypertension, prostatitis, cardiovascular disease, autoimmune disease,andcancer,to name a few.

You may be thinking, Is the testosterone I need leading me to disease?

The answer is, Yes, it sure can.If your testosterone therapy includes prescription of supra physiologic levels of testosterone, lack of follow-up on hormone levels, and no effort to balance hormones and metabolism, then yes, it sure can.

Is there a safe and effective way to balance hormones, lower estrogen and increase testosterone for men?

Effectively administering hormone therapy requires the following:

At Seasons of Farragut, Nan Sprouse and I are fellowship-trained (or completing fellowship training) specifically in the areas of hormone therapy and wellness-based medicine.

Our patient experience begins with an initial consultation to evaluate symptoms and develop an evaluation plan.

The next step is testing.In the case of hormone imbalance, we evaluate hormones withstate-of-the-arthormone testing via saliva, not just blood. As stated in a 2006 article, plasma levels of estradiol do not necessarily reflect tissue-level activity. Saliva has been shown to reveal the active hormone inside the cell at the site of action.

After initial testing and a therapy program, hormone levels are re-evaluated to ensure the progression of treatment and necessary changes are made to the treatment program. Testing and follow-up are key to proper balance of hormones (read myrecent post). At Seasons of Farragut, our approach to treatment and therapy is fully supported in the scientific research literature, and were happy to share that research with you if youd like to educate yourself.

The way estrogens aremetabolizedplays an equally pivotol role in hormone risk and effect. At Seasons of Farragut, our system of testing, evaluating, and monitoring is the only way to ensure that testosterone therapy for men is raising the testosterone and DHT levels instead of all being converted to estrogen. Hormone therapy is safe, but for it to work effectively, it must be properly evaluated, dosed, followed, and re-evaluated.

If you have questions or comments, please post them below and Ill respond as soon as possible. What is your experience with testosterone therapy? How has your physician tested and re-evaluated your therapy program?

For more information about the Seasons approach to wellness or to schedule an appointment, please contact our office at (865) 675-WELL (9355).

Filed under Bioidentical Hormone Replacement Therapy, Bioidentical Hormone Replacement Therapy, Cancer, Etcetera, From The Doctor’s Desk, Heart Health, Hormone Balance, Hormone Balance, Hormone Symphony, Hormone Symphony, Men’s Health, Mind Tagged with BHRT, bioidentical hormones, Conditions and Diseases, DHEA, Diabetes, Diabetes Mellitus Type 2, estrogen, Heart disease, Hormone, Hormone Balance, Hormone Imbalance, stress, Symptom

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Man vs. Estrogen: It’s Not Just A Woman Thing! | Seasons …

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Bone Marrow (Hematopoietic) Stem Cells | stemcells.nih.gov

by Jos Domen*, Amy Wagers** and Irving L. Weissman***

Blood and the system that forms it, known as the hematopoietic system, consist of many cell types with specialized functions (see Figure 2.1). Red blood cells (erythrocytes) carry oxygen to the tissues. Platelets (derived from megakaryocytes) help prevent bleeding. Granulocytes (neutrophils, basophils and eosinophils) and macrophages (collectively known as myeloid cells) fight infections from bacteria, fungi, and other parasites such as nematodes (ubiquitous small worms). Some of these cells are also involved in tissue and bone remodeling and removal of dead cells. B-lymphocytes produce antibodies, while T-lymphocytes can directly kill or isolate by inflammation cells recognized as foreign to the body, including many virus-infected cells and cancer cells. Many blood cells are short-lived and need to be replenished continuously; the average human requires approximately one hundred billion new hematopoietic cells each day. The continued production of these cells depends directly on the presence of Hematopoietic Stem Cells (HSCs), the ultimate, and only, source of all these cells.

Figure 2.1. Hematopoietic and stromal cell differentiation.

2001 Terese Winslow (assisted by Lydia Kibiuk)

The search for stem cells began in the aftermath of the bombings in Hiroshima and Nagasaki in 1945. Those who died over a prolonged period from lower doses of radiation had compromised hematopoietic systems that could not regenerate either sufficient white blood cells to protect against otherwise nonpathogenic infections or enough platelets to clot their blood. Higher doses of radiation also killed the stem cells of the intestinal tract, resulting in more rapid death. Later, it was demonstrated that mice that were given doses of whole body X-irradiation developed the same radiation syndromes; at the minimal lethal dose, the mice died from hematopoietic failure approximately two weeks after radiation exposure.1 Significantly, however, shielding a single bone or the spleen from radiation prevented this irradiation syndrome. Soon thereafter, using inbred strains of mice, scientists showed that whole-body-irradiated mice could be rescued from otherwise fatal hematopoietic failure by injection of suspensions of cells from blood-forming organs such as the bone marrow.2 In 1956, three laboratories demonstrated that the injected bone marrow cells directly regenerated the blood-forming system, rather than releasing factors that caused the recipients’ cells to repair irradiation damage.35 To date, the only known treatment for hematopoietic failure following whole body irradiation is transplantation of bone marrow cells or HSCs to regenerate the blood-forming system in the host organisms.6,7

The hematopoietic system is not only destroyed by the lowest doses of lethal X-irradiation (it is the most sensitive of the affected vital organs), but also by chemotherapeutic agents that kill dividing cells. By the 1960s, physicians who sought to treat cancer that had spread (metastasized) beyond the primary cancer site attempted to take advantage of the fact that a large fraction of cancer cells are undergoing cell division at any given point in time. They began using agents (e.g., chemical and X-irradiation) that kill dividing cells to attempt to kill the cancer cells. This required the development of a quantitative assessment of damage to the cancer cells compared that inflicted on normal cells. Till and McCulloch began to assess quantitatively the radiation sensitivity of one normal cell type, the bone marrow cells used in transplantation, as it exists in the body. They found that, at sub-radioprotective doses of bone marrow cells, mice that died 1015 days after irradiation developed colonies of myeloid and erythroid cells (see Figure 2.1 for an example) in their spleens. These colonies correlated directly in number with the number of bone marrow cells originally injected (approximately 1 colony per 7,000 bone marrow cells injected).8 To test whether these colonies of blood cells derived from single precursor cells, they pre-irradiated the bone marrow donors with low doses of irradiation that would induce unique chromosome breaks in most hematopoietic cells but allow some cells to survive. Surviving cells displayed radiation-induced and repaired chromosomal breaks that marked each clonogenic (colony-initiating) hematopoietic cell.9 The researchers discovered that all dividing cells within a single spleen colony, which contained different types of blood cells, contained the same unique chromosomal marker. Each colony displayed its own unique chromosomal marker, seen in its dividing cells.9 Furthermore, when cells from a single spleen colony were re-injected into a second set of lethally-irradiated mice, donor-derived spleen colonies that contained the same unique chromosomal marker were often observed, indicating that these colonies had been regenerated from the same, single cell that had generated the first colony. Rarely, these colonies contained sufficient numbers of regenerative cells both to radioprotect secondary recipients (e.g., to prevent their deaths from radiation-induced blood cell loss) and to give rise to lymphocytes and myeloerythroid cells that bore markers of the donor-injected cells.10,11 These genetic marking experiments established the fact that cells that can both self-renew and generate most (if not all) of the cell populations in the blood must exist in bone marrow. At the time, such cells were called pluripotent HSCs, a term later modified to multipotent HSCs.12,13 However, identifying stem cells in retrospect by analysis of randomly chromosome-marked cells is not the same as being able to isolate pure populations of HSCs for study or clinical use.

Achieving this goal requires markers that uniquely define HSCs. Interestingly, the development of these markers, discussed below, has revealed that most of the early spleen colonies visible 8 to 10 days after injection, as well as many of the later colonies, visible at least 12 days after injection, are actually derived from progenitors rather than from HSCs. Spleen colonies formed by HSCs are relatively rare and tend to be present among the later colonies.14,15 However, these findings do not detract from Till and McCulloch’s seminal experiments to identify HSCs and define these unique cells by their capacities for self-renewal and multilineage differentiation.

While much of the original work was, and continues to be, performed in murine model systems, strides have been made to develop assays to study human HSCs. The development of Fluorescence Activated Cell Sorting (FACS) has been crucial for this field (see Figure 2.2). This technique enables the recognition and quantification of small numbers of cells in large mixed populations. More importantly, FACS-based cell sorting allows these rare cells (1 in 2000 to less than 1 in 10,000) to be purified, resulting in preparations of near 100% purity. This capability enables the testing of these cells in various assays.

Figure 2.2. Enrichment and purification methods for hematopoietic stem cells. Upper panels illustrate column-based magnetic enrichment. In this method, the cells of interest are labeled with very small iron particles (A). These particles are bound to antibodies that only recognize specific cells. The cell suspension is then passed over a column through a strong magnetic field which retains the cells with the iron particles (B). Other cells flow through and are collected as the depleted negative fraction. The magnet is removed, and the retained cells are collected in a separate tube as the positive or enriched fraction (C). Magnetic enrichment devices exist both as small research instruments and large closed-system clinical instruments.

Lower panels illustrate Fluorescence Activated Cell Sorting (FACS). In this setting, the cell mixture is labeled with fluorescent markers that emit light of different colors after being activated by light from a laser. Each of these fluorescent markers is attached to a different monoclonal antibody that recognizes specific sets of cells (D). The cells are then passed one by one in a very tight stream through a laser beam (blue in the figure) in front of detectors (E) that determine which colors fluoresce in response to the laser. The results can be displayed in a FACS-plot (F). FACS-plots (see figures 3 and 4 for examples) typically show fluorescence levels per cell as dots or probability fields. In the example, four groups can be distinguished: Unstained, red-only, green-only, and red-green double labeling. Each of these groups, e.g., green fluorescence-only, can be sorted to very high purity. The actual sorting happens by breaking the stream shown in (E) into tiny droplets, each containing 1 cell, that then can be sorted using electric charges to move the drops. Modern FACS machines use three different lasers (that can activate different set of fluorochromes), to distinguish up to 8 to 12 different fluorescence colors and sort 4 separate populations, all simultaneously.

Magnetic enrichment can process very large samples (billions of cells) in one run, but the resulting cell preparation is enriched for only one parameter (e.g., CD34) and is not pure. Significant levels of contaminants (such as T-cells or tumor cells) remain present. FACS results in very pure cell populations that can be selected for several parameters simultaneously (e.g., Linneg, CD34pos, CD90pos), but it is more time consuming (10,000 to 50,000 cells can be sorted per second) and requires expensive instrumentation.

2001 Terese Winslow (assisted by Lydia Kibiuk)

Assays have been developed to characterize hematopoietic stem and progenitor cells in vitro and in vivo (Figure 2.3).16,17In vivo assays that are used to study HSCs include Till and McCulloch’s classical spleen colony forming (CFU-S) assay,8 which measures the ability of HSC (as well as blood-forming progenitor cells) to form large colonies in the spleens of lethally irradiated mice. Its main advantage (and limitation) is the short-term nature of the assay (now typically 12 days). However, the assays that truly define HSCs are reconstitution assays.16,18 Mice that have been quot;preconditionedquot; by lethal irradiation to accept new HSCs are injected with purified HSCs or mixed populations containing HSCs, which will repopulate the hematopoietic systems of the host mice for the life of the animal. These assays typically use different types of markers to distinguish host and donor-derived cells.

For example, allelic assays distinguish different versions of a particular gene, either by direct analysis of dna or of the proteins expressed by these alleles. These proteins may be cell-surface proteins that are recognized by specific monoclonal antibodies that can distinguish between the variants (e.g., CD45 in Figure 2.3) or cellular proteins that may be recognized through methods such as gel-based analysis. Other assays take advantage of the fact that male cells can be detected in a female host by detecting the male-cell-specific Y-chromosome by molecular assays (e.g., polymerase chain reaction, or PCR).

Figure 2.3. Assays used to detect hematopoietic stem cells. The tissue culture assays, which are used frequently to test human cells, include the ability of the cells to be tested to grow as quot;cobblestonesquot; (the dark cells in the picture) for 5 to 7 weeks in culture. The Long Term Culture-Initiating Cell assay measures whether hematopoietic progenitor cells (capable of forming colonies in secondary assays, as shown in the picture) are still present after 5 to 7 weeks of culture.

In vivo assays in mice include the CFU-S assay, the original stem cell assay discussed in the introduction. The most stringent hematopoietic stem cell assay involves looking for the long-term presence of donor-derived cells in a reconstituted host. The example shows host-donor recognition by antibodies that recognize two different mouse alleles of CD45, a marker present on nearly all blood cells. CD45 is also a good marker for distinguishing human blood cells from mouse blood cells when testing human cells in immunocompromised mice such as NOD/SCID. Other methods such as pcr-markers, chromosomal markers, and enzyme markers can also be used to distinguish host and donor cells.

Small numbers of HSCs (as few as one cell in mouse experiments) can be assayed using competitive reconstitutions, in which a small amount of host-type bone marrow cells (enough to radioprotect the host and thus ensure survival) is mixed in with the donor-HSC population. To establish long-term reconstitutions in mouse models, the mice are followed for at least 4 months after receiving the HSCs. Serial reconstitution, in which the bone marrow from a previously-irradiated and reconstituted mouse becomes the HSC source for a second irradiated mouse, extends the potential of this assay to test lifespan and expansion limits of HSCs. Unfortunately, the serial transfer assay measures both the lifespan and the transplantability of the stem cells. The transplantability may be altered under various conditions, so this assay is not the sine qua non of HSC function. Testing the in vivo activity of human cells is obviously more problematic.

Several experimental models have been developed that allow the testing of human cells in mice. These assays employ immunologically-incompetent mice (mutant mice that cannot mount an immune response against foreign cells) such as SCID1921 or NOD-SCID mice.22,23 Reconstitution can be performed in either the presence or absence of human fetal bone or thymus implants to provide a more natural environment in which the human cells can grow in the mice. Recently NOD/SCID/c-/- mice have been used as improved recipients for human HSCs, capable of complete reconstitution with human lymphocytes, even in the absence of additional human tissues.24 Even more promising has been the use of newborn mice with an impaired immune system (Rag-2-/-C-/-), which results in reproducible production of human B- and T-lymphoid and myeloerythroid cells.25 These assays are clearly more stringent, and thus more informative, but also more difficult than the in vitro HSC assays discussed below. However, they can only assay a fraction of the lifespan under which the cells would usually have to function. Information on the long-term functioning of cells can only be derived from clinical HSC transplantations.

A number of assays have been developed to recognize HSCs in vitro (e.g., in tissue culture). These are especially important when assaying human cells. Since transplantation assays for human cells are limited, cell culture assays often represent the only viable option. In vitro assays for HSCs include Long-Term Culture-Initializing Cell (LTC-IC) assays2628 and Cobble-stone Area Forming Cell (CAFC) assays.29 LTC-IC assays are based on the ability of HSCs, but not more mature progenitor cells, to maintain progenitor cells with clonogenic potential over at least a five-week culture period. CAFC assays measure the ability of HSCs to maintain a specific and easily recognizable way of growing under stromal cells for five to seven weeks after the initial plating. Progenitor cells can only grow in culture in this manner for shorter periods of time.

While initial experiments studied HSC activity in mixed populations, much progress has been made in specifically describing the cells that have HSC activity. A variety of markers have been discovered to help recognize and isolate HSCs. Initial marker efforts focused on cell size, density, and recognition by lectins (carbohydrate-binding proteins derived largely from plants),30 but more recent efforts have focused mainly on cell surface protein markers, as defined by monoclonal antibodies. For mouse HSCs, these markers include panels of 8 to 14 different monoclonal antibodies that recognize cell surface proteins present on differentiated hematopoietic lineages, such as the red blood cell and macrophage lineages (thus, these markers are collectively referred to as quot;Linquot;),13,31 as well as the proteins Sca-1,13,31 CD27,32 CD34,33 CD38,34 CD43,35 CD90.1(Thy-1.1),13,31 CD117(c-Kit),36 AA4.1,37 and MHC class I,30 and CD150.38 Human HSCs have been defined with respect to staining for Lin,39 CD34,40 CD38,41 CD43,35 CD45RO,42 CD45RA,42 CD59,43 CD90,39 CD109,44 CD117,45 CD133,46,47CD166,48 and HLA DR(human).49,50 In addition, metabolic markers/dyes such as rhodamine123 (which stains mitochondria),51 Hoechst33342 (which identifies MDR-type drug efflux activity),52 Pyronin-Y (which stains RNA),53 and BAAA (indicative of aldehyde dehydrogenase enzyme activity)54 have been described. While none of these markers recognizes functional stem cell activity, combinations (typically with 3 to 5 different markers, see examples below) allow for the purification of near-homogenous populations of HSCs. The ability to obtain pure preparations of HSCs, albeit in limited numbers, has greatly facilitated the functional and biochemical characterization of these important cells. However, to date there has been limited impact of these discoveries on clinical practice, as highly purified HSCs have only rarely been used to treat patients (discussed below). The undeniable advantages of using purified cells (e.g., the absence of contaminating tumor cells in autologous transplantations) have been offset by practical difficulties and increased purification costs.

Figure 2.4. Examples of Hematopoietic Stem Cell staining patterns in mouse bone marrow (top) and human mobilized peripheral blood (bottom). The plots on the right show only the cells present in the left blue box. The cells in the right blue box represent HSCs. Stem cells form a rare fraction of the cells present in both cases.

HSC assays, when combined with the ability to purify HSCs, have provided increasingly detailed insight into the cells and the early steps involved in the differentiation process. Several marker combinations have been developed that describe murine HSCs, including [CD117high, CD90.1low, Linneg/low, Sca-1pos],15 [CD90.1low, Linneg, Sca-1pos Rhodamine123low],55 [CD34neg/low, CD117pos, Sca-1pos, Linneg],33 [CD150 pos, CD48neg, CD244neg],38 and quot;side-populationquot; cells using Hoechst-dye.52 Each of these combinations allows purification of HSCs to near-homogeneity. Figure 2.4 shows an example of an antibody combination that can recognize mouse HSCs. Similar strategies have been developed to purify human HSCs, employing markers such as CD34, CD38, Lin, CD90, CD133 and fluorescent substrates for the enzyme, aldehyde dehydrogenase. The use of highly purified human HSCs has been mainly experimental, and clinical use typically employs enrichment for one marker, usually CD34. CD34 enrichment yields a population of cells enriched for HSC and blood progenitor cells but still contains many other cell types. However, limited trials in which highly FACS-purified CD34pos CD90pos HSCs (see Figure 2.4) were used as a source of reconstituting cells have demonstrated that rapid reconstitution of the blood system can reliably be obtained using only HSCs.5658

The purification strategies described above recognize a rare subset of cells. Exact numbers depend on the assay used as well as on the genetic background studied.16 In mouse bone marrow, 1 in 10,000 cells is a hematopoietic stem cell with the ability to support long-term hematopoiesis following transplantation into a suitable host. When short-term stem cells, which have a limited self-renewal capacity, are included in the estimation, the frequency of stem cells in bone marrow increases to 1 in 1,000 to 1 in 2,000 cells in humans and mice. The numbers present in normal blood are at least ten-fold lower than in marrow.

None of the HSC markers currently used is directly linked to an essential HSC function, and consequently, even within a species, markers can differ depending on genetic alleles,59 mouse strains,60 developmental stages,61 and cell activation stages.62,63 Despite this, there is a clear correlation in HSC markers between divergent species such as humans and mice. However, unless the ongoing attempts at defining the complete HSC gene expression patterns will yield usable markers that are linked to essential functions for maintaining the quot;stemnessquot; of the cells,64,65 functional assays will remain necessary to identify HSCs unequivocally.16

More recently, efforts at defining hematopoietic populations by cell surface or other FACS-based markers have been extended to several of the progenitor populations that are derived from HSCs (see Figure 2.5). Progenitors differ from stem cells in that they have a reduced differentiation capacity (they can generate only a subset of the possible lineages) but even more importantly, progenitors lack the ability to self-renew. Thus, they have to be constantly regenerated from the HSC population. However, progenitors do have extensive proliferative potential and can typically generate large numbers of mature cells. Among the progenitors defined in mice and humans are the Common Lymphoid Progenitor (CLP),66,67 which in adults has the potential to generate all of the lymphoid but not myeloerythroid cells, and a Common Myeloid Progenitor (CMP), which has the potential to generate all of the mature myeloerythroid, but not lymphoid, cells.68,69 While beyond the scope of this overview, hematopoietic progenitors have clinical potential and will likely see clinical use.70,71

Figure 2.5. Relationship between several of the characterized hematopoietic stem cells and early progenitor cells. Differentiation is indicated by colors; the more intense the color, the more mature the cells. Surface marker distinctions are subtle between these early cell populations, yet they have clearly distinct potentials. Stem cells can choose between self-renewal and differentiation. Progenitors can expand temporarily but always continue to differentiate (other than in certain leukemias). The mature lymphoid (T-cells, B-cells, and Natural Killer cells) and myeloerythroid cells (granulocytes, macrophages, red blood cells, and platelets) that are produced by these stem and progenitor cells are shown in more detail in Figure 2.1.

HSCs have a number of unique properties, the combination of which defines them as such.16 Among the core properties are the ability to choose between self-renewal (remain a stem cell after cell division) or differentiation (start the path towards becoming a mature hematopoietic cell). In addition, HSCs migrate in regulated fashion and are subject to regulation by apoptosis (programmed cell death). The balance between these activities determines the number of stem cells that are present in the body.

One essential feature of HSCs is the ability to self-renew, that is, to make copies with the same or very similar potential. This is an essential property because more differentiated cells, such as hematopoietic progenitors, cannot do this, even though most progenitors can expand significantly during a limited period of time after being generated. However, for continued production of the many (and often short-lived) mature blood cells, the continued presence of stem cells is essential. While it has not been established that adult HSCs can self-renew indefinitely (this would be difficult to prove experimentally), it is clear from serial transplantation experiments that they can produce enough cells to last several (at least four to five) lifetimes in mice. It is still unclear which key signals allow self-renewal. One link that has been noted is telomerase, the enzyme necessary for maintaining telomeres, the DNA regions at the end of chromosomes that protect them from accumulating damage due to DNA replication. Expression of telomerase is associated with self-renewal activity.72 However, while absence of telomerase reduces the self-renewal capacity of mouse HSCs, forced expression is not sufficient to enable HSCs to be transplanted indefinitely; other barriers must exist.73,74

It has proven surprisingly difficult to grow HSCs in culture despite their ability to self-renew. Expansion in culture is routine with many other cells, including neural stem cells and ES cells. The lack of this capacity for HSCs severely limits their application, because the number of HSCs that can be isolated from mobilized blood, umbilical cord blood, or bone marrow restricts the full application of HSC transplantation in man (whether in the treatment of nuclear radiation exposure or transplantation in the treatment of blood cell cancers or genetic diseases of the blood or blood-forming system). Engraftment periods of 50 days or more were standard when limited numbers of bone marrow or umbilical cord blood cells were used in a transplant setting, reflecting the low level of HSCs found in these native tissues. Attempts to expand HSCs in tissue culture with known stem-cell stimulators, such as the cytokines stem cell factor/steel factor (KitL), thrombopoietin (TPO), interleukins 1, 3, 6, 11, plus or minus the myeloerythroid cytokines GM-CSF, G-CSF, M-CSF, and erythropoietin have never resulted in a significant expansion of HSCs.16,75 Rather, these compounds induce many HSCs into cell divisions that are always accompanied by cellular differentiation.76 Yet many experiments demonstrate that the transplantation of a single or a few HSCs into an animal results in a 100,000-fold or greater expansion in the number of HSCs at the steady state while simultaneously generating daughter cells that permitted the regeneration of the full blood-forming system.7780 Thus, we do not know the factors necessary to regenerate HSCs by self-renewing cell divisions. By investigating genes transcribed in purified mouse LT-HSCs, investigators have found that these cells contain expressed elements of the Wnt/fzd/beta-catenin signaling pathway, which enables mouse HSCs to undergo self-renewing cell divisions.81,82 Overexpression of several other proteins, including HoxB48386 and HoxA987 has also been reported to achieve this. Other signaling pathways that are under investigation include Notch and Sonic hedgehog.75 Among the intracellular proteins thought to be essential for maintaining the quot;stem cellquot; state are Polycomb group genes, including Bmi-1.88 Other genes, such as c-Myc and JunB have also been shown to play a role in this process.89,90Much remains to be discovered, including the identity of the stimuli that govern self-renewal in vivo, as well as the composition of the environment (the stem cell quot;nichequot;) that provides these stimuli.91 The recent identification of osteoblasts, a cell type known to be involved in bone formation, as a critical component of this environment92,93 will help to focus this search. For instance, signaling by Angiopoietin-1 on osteoblasts to Tie-2 receptors on HSCs has recently been suggested to regulate stem cell quiescence (the lack of cell division).94 It is critical to discover which pathways operate in the expansion of human HSCs to take advantage of these pathways to improve hematopoietic transplantation.

Differentiation into progenitors and mature cells that fulfill the functions performed by the hematopoietic system is not a unique HSC property, but, together with the option to self-renew, defines the core function of HSCs. Differentiation is driven and guided by an intricate network of growth factors and cytokines. As discussed earlier, differentiation, rather than self-renewal, seems to be the default outcome for HSCs when stimulated by many of the factors to which they have been shown to respond. It appears that, once they commit to differentiation, HSCs cannot revert to a self-renewing state. Thus, specific signals, provided by specific factors, seem to be needed to maintain HSCs. This strict regulation may reflect the proliferative potential present in HSCs, deregulation of which could easily result in malignant diseases such as leukemia or lymphoma.

Migration of HSCs occurs at specific times during development (i.e., seeding of fetal liver, spleen and eventually, bone marrow) and under certain conditions (e.g., cytokine-induced mobilization) later in life. The latter has proven clinically useful as a strategy to enhance normal HSC proliferation and migration, and the optimal mobilization regimen for HSCs currently used in the clinic is to treat the stem cell donor with a drug such as cytoxan, which kills most of his or her dividing cells. Normally, only about 8% of LT-HSCs enter the cell cycle per day,95,96 so HSCs are not significantly affected by a short treatment with cytoxan. However, most of the downstream blood progenitors are actively dividing,66,68 and their numbers are therefore greatly depleted by this dose, creating a demand for a regenerated blood-forming system. Empirically, cytokines or growth factors such as G-CSF and KitL can increase the number of HSCs in the blood, especially if administered for several days following a cytoxan pulse. The optimized protocol of cytoxan plus G-CSF results in several self-renewing cell divisions for each resident LT-HSC in mouse bone marrow, expanding the number of HSCs 12- to 15-fold within two to three days.97 Then, up to one-half of the daughter cells of self-renewing dividing LT-HSCs (estimated to be up to 105 per mouse per day98) leave the bone marrow, enter the blood, and within minutes engraft other hematopoietic sites, including bone marrow, spleen, and liver.98 These migrating cells can and do enter empty hematopoietic niches elsewhere in the bone marrow and provide sustained hematopoietic stem cell self-renewal and hematopoiesis.98,99 It is assumed that this property of mobilization of HSCs is highly conserved in evolution (it has been shown in mouse, dog and humans) and presumably results from contact with natural cell-killing agents in the environment, after which regeneration of hematopoiesis requires restoring empty HSC niches. This means that functional, transplantable HSCs course through every tissue of the body in large numbers every day in normal individuals.

Apoptosis, or programmed cell death, is a mechanism that results in cells actively self-destructing without causing inflammation. Apoptosis is an essential feature in multicellular organisms, necessary during development and normal maintenance of tissues. Apoptosis can be triggered by specific signals, by cells failing to receive the required signals to avoid apoptosis, and by exposure to infectious agents such as viruses. HSCs are not exempt; apoptosis is one mechanism to regulate their numbers. This was demonstrated in transgenic mouse experiments in which HSC numbers doubled when the apoptosis threshold was increased.76 This study also showed that HSCs are particularly sensitive and require two signals to avoid undergoing apoptosis.

The best-known location for HSCs is bone marrow, and bone marrow transplantation has become synonymous with hematopoietic cell transplantation, even though bone marrow itself is increasingly infrequently used as a source due to an invasive harvesting procedure that requires general anesthesia. In adults, under steady-state conditions, the majority of HSCs reside in bone marrow. However, cytokine mobilization can result in the release of large numbers of HSCs into the blood. As a clinical source of HSCs, mobilized peripheral blood (MPB) is now replacing bone marrow, as harvesting peripheral blood is easier for the donors than harvesting bone marrow. As with bone marrow, mobilized peripheral blood contains a mixture of hematopoietic stem and progenitor cells. MPB is normally passed through a device that enriches cells that express CD34, a marker on both stem and progenitor cells. Consequently, the resulting cell preparation that is infused back into patients is not a pure HSC preparation, but a mixture of HSCs, hematopoietic progenitors (the major component), and various contaminants, including T cells and, in the case of autologous grafts from cancer patients, quite possibly tumor cells. It is important to distinguish these kinds of grafts, which are the grafts routinely given, from highly purified HSC preparations, which essentially lack other cell types.

In the late 1980s, umbilical cord blood (UCB) was recognized as an important clinical source of HSCs.100,101 Blood from the placenta and umbilical cord is a rich source of hematopoietic stem cells, and these cells are typically discarded with the afterbirth. Increasingly, UCB is harvested, frozen, and stored in cord blood banks, as an individual resource (donor-specific source) or as a general resource, directly available when needed. Cord blood has been used successfully to transplant children and (far less frequently) adults. Specific limitations of UCB include the limited number of cells that can be harvested and the delayed immune reconstitution observed following UCB transplant, which leaves patients vulnerable to infections for a longer period of time. Advantages of cord blood include its availability, ease of harvest, and the reduced risk of graft-versus-host-disease (GVHD). In addition, cord blood HSCs have been noted to have a greater proliferative capacity than adult HSCs. Several approaches have been tested to overcome the cell dose issue, including, with some success, pooling of cord blood samples.101,102 Ex vivo expansion in tissue culture, to which cord blood cells are more amenable than adult cells, is another approach under active investigation.103

The use of cord blood has opened a controversial treatment strategyembryo selection to create a related UCB donor.104 In this procedure, embryos are conceived by in vitro fertilization. The embryos are tested by pre-implantation genetic diagnosis, and embryos with transplantation antigens matching those of the affected sibling are implanted. Cord blood from the resulting newborn is then used to treat this sibling. This approach, successfully pioneered at the University of Minnesota, can in principle be applied to a wide variety of hematopoietic disorders. However, the ethical questions involved argue for clear regulatory guidelines.105

Embryonic stem (ES) cells form a potential future source of HSCs. Both mouse and human ES cells have yielded hematopoietic cells in tissue culture, and they do so relatively readily.106 However, recognizing the actual HSCs in these cultures has proven problematic, which may reflect the variability in HSC markers or the altered reconstitution behavior of these HSCs, which are expected to mimic fetal HSC. This, combined with the potential risks of including undifferentiated cells in an ES-cell-derived graft means that, based on the current science, clinical use of ES cell-derived HSCs remains only a theoretical possibility for now.

An ongoing set of investigations has led to claims that HSCs, as well as other stem cells, have the capacity to differentiate into a much wider range of tissues than previously thought possible. It has been claimed that, following reconstitution, bone marrow cells can differentiate not only into blood cells but also muscle cells (both skeletal myocytes and cardiomyocytes),107111 brain cells,112,113 liver cells,114,115 skin cells, lung cells, kidney cells, intestinal cells,116 and pancreatic cells.117 Bone marrow is a complex mixture that contains numerous cell types. In addition to HSCs, at least one other type of stem cell, the mesenchymal stem cell (MSC), is present in bone marrow. MSCs, which have become the subject of increasingly intense investigation, seem to retain a wide range of differentiation capabilities in vitro that is not restricted to mesodermal tissues, but includes tissues normally derived from other embryonic germ layers (e.g., neurons).118120MSCs are discussed in detail in Dr. Catherine Verfaillie’s testimony to the President’s Council on Bioethics at this website: refer to Appendix J (page 295) and will not be discussed further here. However, similar claims of differentiation into multiple diverse cell types, including muscle,111 liver,114 and different types of epithelium116 have been made in experiments that assayed partially- or fully-purified HSCs. These experiments have spawned the idea that HSCs may not be entirely or irreversibly committed to forming the blood, but under the proper circumstances, HSCs may also function in the regeneration or repair of non-blood tissues. This concept has in turn given rise to the hypothesis that the fate of stem cells is quot;plastic,quot; or changeable, allowing these cells to adopt alternate fates if needed in response to tissue-derived regenerative signals (a phenomenon sometimes referred to as quot;transdifferentiationquot;). This in turn seems to bolster the argument that the full clinical potential of stem cells can be realized by studying only adult stem cells, foregoing research into defining the conditions necessary for the clinical use of the extensive differentiation potential of embryonic stem cells. However, as discussed below, such quot;transdifferentiationquot; claims for specialized adult stem cells are controversial, and alternative explanations for these observations remain possible, and, in several cases, have been documented directly.

While a full discussion of this issue is beyond the scope of this overview, several investigators have formulated criteria that must be fulfilled to demonstrate stem cell plasticity.121,122 These include (i) clonal analysis, which requires the transfer and analysis of single, highly-purified cells or individually marked cells and the subsequent demonstration of both quot;normalquot; and quot;plasticquot; differentiation outcomes, (ii) robust levels of quot;plasticquot; differentiation outcome, as extremely rare events are difficult to analyze and may be induced by artefact, and (iii) demonstration of tissue-specific function of the quot;transdifferentiatedquot; cell type. Few of the current reports fulfill these criteria, and careful analysis of individually transplanted KTLS HSCs has failed to show significant levels of non-hematopoietic engraftment.123,124In addition, several reported trans-differentiation events that employed highly purified HSCs, and in some cases a very strong selection pressure for trans-differentiation, now have been shown to result from fusion of a blood cell with a non-blood cell, rather than from a change in fate of blood stem cells.125127 Finally, in the vast majority of cases, reported contributions of adult stem cells to cell types outside their tissue of origin are exceedingly rare, far too rare to be considered therapeutically useful. These findings have raised significant doubts about the biological importance and immediate clinical utility of adult hematopoietic stem cell plasticity. Instead, these results suggest that normal tissue regeneration relies predominantly on the function of cell type-specific stem or progenitor cells, and that the identification, isolation, and characterization of these cells may be more useful in designing novel approaches to regenerative medicine. Nonetheless, it is possible that a rigorous and concerted effort to identify, purify, and potentially expand the appropriate cell populations responsible for apparent quot;plasticityquot; events, characterize the tissue-specific and injury-related signals that recruit, stimulate, or regulate plasticity, and determine the mechanism(s) underlying cell fusion or transdifferentiation, may eventually enhance tissue regeneration via this mechanism to clinically useful levels.

Recent progress in genomic sequencing and genome-wide expression analysis at the RNA and protein levels has greatly increased our ability to study cells such as HSCs as quot;systems,quot; that is, as combinations of defined components with defined interactions. This goal has yet to be realized fully, as computational biology and system-wide protein biochemistry and proteomics still must catch up with the wealth of data currently generated at the genomic and transcriptional levels. Recent landmark events have included the sequencing of the human and mouse genomes and the development of techniques such as array-based analysis. Several research groups have combined cDNA cloning and sequencing with array-based analysis to begin to define the full transcriptional profile of HSCs from different species and developmental stages and compare these to other stem cells.64,65,128131 Many of the data are available in online databases, such as the NIH/NIDDK Stem Cell Genome Anatomy Projects. While transcriptional profiling is clearly a work in progress, comparisons among various types of stem cells may eventually identify sets of genes that are involved in defining the general quot;stemnessquot; of a cell, as well as sets of genes that define their exit from the stem cell pool (e.g., the beginning of their path toward becoming mature differentiated cells, also referred to as commitment). In addition, these datasets will reveal sets of genes that are associated with specific stem cell populations, such as HSCs and MSCs, and thus define their unique properties. Assembly of these datasets into pathways will greatly help to understand and to predict the responses of HSCs (and other stem cells) to various stimuli.

The clinical use of stem cells holds great promise, although the application of most classes of adult stem cells is either currently untested or is in the earliest phases of clinical testing.132,133 The only exception is HSCs, which have been used clinically since 1959 and are used increasingly routinely for transplantations, albeit almost exclusively in a non-pure form. By 1995, more than 40,000 transplants were performed annually world-wide.134,135 Currently the main indications for bone marrow transplantation are either hematopoietic cancers (leukemias and lymphomas), or the use of high-dose chemotherapy for non-hematopoietic malignancies (cancers in other organs). Other indications include diseases that involve genetic or acquired bone marrow failure, such as aplastic anemia, thalassemia sickle cell anemia, and increasingly, autoimmune diseases.

Transplantation of bone marrow and HSCs are carried out in two rather different settings, autologous and allogeneic. Autologous transplantations employ a patient’s own bone marrow tissue and thus present no tissue incompatibility between the donor and the host. Allogeneic transplantations occur between two individuals who are not genetically identical (with the rare exceptions of transplantations between identical twins, often referred to as syngeneic transplantations). Non-identical individuals differ in their human leukocyte antigens (HLAs), proteins that are expressed by their white blood cells. The immune system uses these HLAs to distinguish between quot;selfquot; and quot;nonself.quot; For successful transplantation, allogeneic grafts must match most, if not all, of the six to ten major HLA antigens between host and donor. Even if they do, however, enough differences remain in mostly uncharacterized minor antigens to enable immune cells from the donor and the host to recognize the other as quot;nonself.quot; This is an important issue, as virtually all HSC transplants are carried out with either non-purified, mixed cell populations (mobilized peripheral blood, cord blood, or bone marrow) or cell populations that have been enriched for HSCs (e.g., by column selection for CD34+ cells) but have not been fully purified. These mixed population grafts contain sufficient lymphoid cells to mount an immune response against host cells if they are recognized as quot;non-self.quot; The clinical syndrome that results from this quot;non-selfquot; response is known as graft-versus-host disease (GVHD).136

In contrast, autologous grafts use cells harvested from the patient and offer the advantage of not causing GVHD. The main disadvantage of an autologous graft in the treatment of cancer is the absence of a graft-versusleukemia (GVL) or graft-versus-tumor (GVT) response, the specific immunological recognition of host tumor cells by donor-immune effector cells present in the transplant. Moreover, the possibility exists for contamination with cancerous or pre-cancerous cells.

Allogeneic grafts also have disadvantages. They are limited by the availability of immunologically-matched donors and the possibility of developing potentially lethal GVHD. The main advantage of allogeneic grafts is the potential for a GVL response, which can be an important contribution to achieving and maintaining complete remission.137,138

Today, most grafts used in the treatment of patients consist of either whole or CD34+-enriched bone marrow or, more likely, mobilized peripheral blood. The use of highly purified hematopoietic stem cells as grafts is rare.5658 However, the latter have the advantage of containing no detectable contaminating tumor cells in the case of autologous grafts, therefore not inducing GVHD, or presumably GVL,139141in allogeneic grafts. While they do so less efficiently than lymphocyte-containing cell mixtures, HSCs alone can engraft across full allogeneic barriers (i.e., when transplanted from a donor who is a complete mismatch for both major and minor transplantation antigens).139141The use of donor lymphocyte infusions (DLI) in the context of HSC transplantation allows for the controlled addition of lymphocytes, if necessary, to obtain or maintain high levels of donor cells and/or to induce a potentially curative GVL-response.142,143 The main problems associated with clinical use of highly purified HSCs are the additional labor and costs144 involved in obtaining highly purified cells in sufficient quantities.

While the possibilities of GVL and other immune responses to malignancies remain the focus of intense interest, it is also clear that in many cases, less-directed approaches such as chemotherapy or irradiation offer promise. However, while high-dose chemotherapy combined with autologous bone marrow transplantation has been reported to improve outcome (usually measured as the increase in time to progression, or increase in survival time),145154 this has not been observed by other researchers and remains controversial.155161 The tumor cells present in autologous grafts may be an important limitation in achieving long-term disease-free survival. Only further purification/ purging of the grafts, with rigorous separation of HSCs from cancer cells, can overcome this limitation. Initial small scale trials with HSCs purified by flow cytometry suggest that this is both possible and beneficial to the clinical outcome.56 In summary, purification of HSCs from cancer/lymphoma/leukemia patients offers the only possibility of using these cells post-chemotherapy to regenerate the host with cancer-free grafts. Purification of HSCs in allotransplantation allows transplantation with cells that regenerate the blood-forming system but cannot induce GVHD.

An important recent advance in the clinical use of HSCs is the development of non-myeloablative preconditioning regimens, sometimes referred to as quot;mini transplants.quot;162164 Traditionally, bone marrow or stem cell transplantation has been preceded by a preconditioning regimen consisting of chemotherapeutic agents, often combined with irradiation, that completely destroys host blood and bone marrow tissues (a process called myeloablation). This creates quot;spacequot; for the incoming cells by freeing stem cell niches and prevents an undesired immune response of the host cells against the graft cells, which could result in graft failure. However, myeloablation immunocompromises the patient severely and necessitates a prolonged hospital stay under sterile conditions. Many protocols have been developed that use a more limited and targeted approach to preconditioning. These nonmyeloablative preconditioning protocols, which combine excellent engraftment results with the ability to perform hematopoietic cell transplantation on an outpatient basis, have greatly changed the clinical practice of bone marrow transplantation.

FACS purification of HSCs in mouse and man completely eliminates contaminating T cells, and thus GVHD (which is caused by T-lymphocytes) in allogeneic transplants. Many HSC transplants have been carried out in different combinations of mouse strains. Some of these were matched at the major transplantation antigens but otherwise different (Matched Unrelated Donors or MUD); in others, no match at the major or minor transplantation antigens was expected. To achieve rapid and sustained engraftment, higher doses of HSCs were required in these mismatched allogeneic transplants than in syngeneic transplants.139141,165167 In these experiments, hosts whose immune and blood-forming systems were generated from genetically distinct donors were permanently capable of accepting organ transplants (such as the heart) from either donor or host, but not from mice unrelated to the donor or host. This phenomenon is known as transplant-induced tolerance and was observed whether the organ transplants were given the same day as the HSCs or up to one year later.139,166Hematopoietic cell transplant-related complications have limited the clinical application of such tolerance induction for solid organ grafts, but the use of non-myeloablative regimens to prepare the host, as discussed above, should significantly reduce the risk associated with combined HSC and organ transplants. Translation of these findings to human patients should enable a switch from chronic immunosuppression to prevent rejection to protocols wherein a single conditioning dose allows permanent engraftment of both the transplanted blood system and solid organ(s) or other tissue stem cells from the same donor. This should eliminate both GVHD and chronic host transplant immunosuppression, which lead to many complications, including life-threatening opportunistic infections and the development of malignant neoplasms.

We now know that several autoimmune diseasesdiseases in which immune cells attack normal body tissuesinvolve the inheritance of high risk-factor genes.168 Many of these genes are expressed only in blood cells. Researchers have recently tested whether HSCs could be used in mice with autoimmune disease (e.g., type 1 diabetes) to replace an autoimmune blood system with one that lacks the autoimmune risk genes. The HSC transplants cured mice that were in the process of disease development when nonmyeloablative conditioning was used for transplant.169 It has been observed that transplant-induced tolerance allows co-transplantation of pancreatic islet cells to replace destroyed islets.170 If these results using nonmyeloablative conditioning can be translated to humans, type 1 diabetes and several other autoimmune diseases may be treatable with pure HSC grafts. However, the reader should be cautioned that the translation of treatments from mice to humans is often complicated and time-consuming.

Banking is currently a routine procedure for UCB samples. If expansion of fully functional HSCs in tissue culture becomes a reality, HSC transplants may be possible by starting with small collections of HSCs rather than massive numbers acquired through mobilization and apheresis. With such a capability, collections of HSCs from volunteer donors or umbilical cords could be theoretically converted into storable, expandable stem cell banks useful on demand for clinical transplantation and/or for protection against radiation accidents. In mice, successful HSC transplants that regenerate fully normal immune and blood-forming systems can be accomplished when there is only a partial transplantation antigen match. Thus, the establishment of useful human HSC banks may require a match between as few as three out of six transplantation antigens (HLA). This might be accomplished with stem cell banks of as few as 4,00010,000 independent samples.

Leukemias are proliferative diseases of the hematopoietic system that fail to obey normal regulatory signals. They derive from stem cells or progenitors of the hematopoietic system and almost certainly include several stages of progression. During this progression, genetic and/or epigenetic changes occur, either in the DNA sequence itself (genetic) or other heritable modifications that affect the genome (epigenetic). These (epi)genetic changes alter cells from the normal hematopoietic system into cells capable of robust leukemic growth. There are a variety of leukemias, usually classified by the predominant pathologic cell types and/or the clinical course of the disease. It has been proposed that these are diseases in which self-renewing but poorly regulated cells, so-called “leukemia stem cells” (LSCs), are the populations that harbor all the genetic and epigenetic changes that allow leukemic progression.171176 While their progeny may be the characteristic cells observed with the leukemia, these progeny cells are not the self-renewing “malignant” cells of the disease. In this view, the events contributing to tumorigenic transformation, such as interrupted or decreased expression of “tumor suppressor” genes, loss of programmed death pathways, evasion of immune cells and macrophage surveillance mechanisms, retention of telomeres, and activation or amplification of self-renewal pathways, occur as single, rare events in the clonal progression to blast-crisis leukemia. As LT HSCs are the only selfrenewing cells in the myeloid pathway, it has been proposed that most, if not all, progression events occur at this level of differentiation, creating clonal cohorts of HSCs with increasing malignancy (see Figure 2.6). In this disease model, the final event, explosive selfrenewal, could occur at the level of HSC or at any of the known progenitors (see Figures 2.5 and 2.6). Activation of the -catenin/lef-tcf signal transduction and transcription pathway has been implicated in leukemic stem cell self-renewal in mouse AML and human CML.177 In both cases, the granulocyte-macrophage progenitors, not the HSCs or progeny blast cells, are the malignant self-renewing entities. In other models, such as the JunB-deficient tumors in mice and in chronic-phase CML in humans, the leukemic stem cell is the HSC itself.90,177 However, these HSCs still respond to regulatory signals, thus representing steps in the clonal progression toward blast crisis (see Figure 2.6).

Figure 2.6. Leukemic progression at the hematopoietic stem cell level. Self-renewing HSCs are the cells present long enough to accumulate the many activating events necessary for full transformation into tumorigenic cells. Under normal conditions, half of the offspring of HSC cell divisions would be expected to undergo differentiation, leaving the HSC pool stable in size. (A) (Pre) leukemic progression results in cohorts of HSCs with increasing malignant potential. The cells with the additional event (two events are illustrated, although more would be expected to occur) can outcompete less-transformed cells in the HSC pool if they divide faster (as suggested in the figure) or are more resistant to differentiation or apoptosis (cell death), two major exit routes from the HSC pool. (B) Normal HSCs differentiate into progenitors and mature cells; this is linked with limited proliferation (left). Partially transformed HSCs can still differentiate into progenitors and mature cells, but more cells are produced. Also, the types of mature cells that are produced may be skewed from the normal ratio. Fully transformed cells may be completely blocked in terminal differentiation, and large numbers of primitive blast cells, representing either HSCs or self-renewing, transformed progenitor cells, can be produced. While this sequence of events is true for some leukemias (e.g., AML), not all of the events occur in every leukemia. As with non-transformed cells, most leukemia cells (other than the leukemia stem cells) can retain the potential for (limited) differentiation.

Many methods have revealed contributing protooncogenes and lost tumor suppressors in myeloid leukemias. Now that LSCs can be isolated, researchers should eventually be able to assess the full sequence of events in HSC clones undergoing leukemic transformation. For example, early events, such as the AML/ETO translocation in AML or the BCR/ABL translocation in CML can remain present in normal HSCs in patients who are in remission (e.g., without detectable cancer).177,178 The isolation of LSCs should enable a much more focused attack on these cells, drawing on their known gene expression patterns, the mutant genes they possess, and the proteomic analysis of the pathways altered by the proto-oncogenic events.173,176,179 Thus, immune therapies for leukemia would become more realistic, and approaches to classify and isolate LSCs in blood could be applied to search for cancer stem cells in other tissues.180

After more than 50 years of research and clinical use, hematopoietic stem cells have become the best-studied stem cells and, more importantly, hematopoietic stem cells have seen widespread clinical use. Yet the study of HSCs remains active and continues to advance very rapidly. Fueled by new basic research and clinical discoveries, HSCs hold promise for such indications as treating autoimmunity, generating tolerance for solid organ transplants, and directing cancer therapy. However, many challenges remain. The availability of (matched) HSCs for all of the potential applications continues to be a major hurdle. Efficient expansion of HSCs in culture remains one of the major research goals. Future developments in genomics and proteomics, as well as in gene therapy, have the potential to widen the horizon for clinical application of hematopoietic stem cells even further.

Notes:

* Cellerant Therapeutics, 1531 Industrial Road, San Carlos, CA 94070. Current address: Department of Surgery, Arizona Health Sciences Center, 1501 N. Campbell Avenue, P.O. Box 245071, Tucson, AZ 857245071,e-mail: jdomen@surgery.arizona.edu.

** Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, E-mail: Amy_Wagers@harvard.edu

*** Director, Institute for Cancer/Stem Cell Biology and Medicine, Professor of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, Irv@stanford.edu.

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The Physician Assistant Life – Essay

by Stephen Pasquini PA-C

After reading a number of questions about acceptance into PA programs a prevailing theme has emerged.

Many international physicians stated that their interest in becoming PAs stems from dissatisfaction with the hours or volume of patients they are seeing in their own practices in their native countries.

So, what is my advice?

That you make an honest, soul-searching assessment of what it is you are seeking.

If you have a prevailing feeling that your MD is a superior credential and that you will be functioning as an “MD Surrogate” in the US, then perhaps you don’t fully understand the concept of a PA/supervising MD team.

Every good PA knows very well our limits in scope of practice which have served us and our physician mentors very well for over 40 years.

We aren’t, and never will be physicians!

Nor will you, if you practice as a PA within your scope of practice.

You may also want to investigate why you believe that coming to the United States to become a PA will ensure that your hours will be regular, predictable and better than what you have now.

Your hours will depend completely on the medical practice or hospital which hires you.

Expecting that as a PA you will have it easier than you have it as an MD may be a false assumption.

Many PAs work very long, grueling hours in emergency rooms, critical care, hospitals, public health facilities, family health care, community clinics and countless other fields in addition to volunteer work on their own time.

The person who inquired about coming to a US PA program because PAs in Canada are still new and not well respected might do well to step back for perspective.

PAs in the US are the single most serially tested group of medical providers in the world.

We are currently changing a decades-old requirement for national board certification exams every six years to maintain our treasured “C” on our credential, indicating board certification.

But if you look closely at the environment which mandated our test schedule it reveals that we have been regularly asked to “prove” our knowledge, skills, and trustworthiness for those same decades.

Each of us went through some version of facing the “newness” question about what is a PA and scrutiny and occasional rejection by physicians, nurses, and patients.

And most of us will tell you the struggle to prove ourselves is hard.

And at one time it may have been necessary.

But now, for most situations, when you join a medical practice, your patients already know what a PA is and how we function with their physicians.

In Canada, your PA profession, though in comparative infancy to the US, needs great people to choose it, build its competence and support its growth rather than abandon it and go to already proven territory.

If you believe in rigorous academic and clinical training then wouldn’t you want to be in the vanguard in Canada demanding that rigor?

I treasure my life and work as a PA in California and Florida.

Anyone fortunate enough to come here as an immigrant looking for anopportunity to serve in the medical corps is warmly welcomed and will be honored by our ranks.

But when you choose this path to PA make sure you are seeing the good with the challengingand accepting that part of being in medical care.

Every place in the world demands a near total commitment of time and the humility to be comfortable caring for impoverished people, people of every cultural and ethnic background, just as you are doing wherever you currently live.

Your challenges are the same as ours in that regard.

The United States PA programs are unparalleled in preparing a workforce to address the overwhelming problem of inadequate access to health care.

But we may not be a panacea for overworked, over-scheduled and feeling unappreciated, at times.

Sincerely, and with good wishes for your success,

– Martie Lynch BS, PA-C

Today’s post comes to us via the comments section and was written by physician assistant Margie Lynch, PA-C .

I receive many comments and emails from internationally trained doctors looking for career options here in the United States.

In fact, as an undergraduate, while working in the campus health clinic, I had the privilege of being trained by a foreign medical doctor from India who had transitioned to a laboratory tech in the United States.

The truth is, in many instances, a foreign medical degree is non-transferable and the barriers to practice prevent many highly skilled, well-intentioned international providers from coming to the United States. And like the MD I worked with, their skills and training may go to waste. This is a shame sad there are many clinics and hospitals in the US that would benefit from culturally competent bilingual practitioners.

And like the MD I worked with, their skills and training may go to waste. This is a shame sad there are many clinics and hospitals in the US that would benefit from culturally competent bilingual practitioners.

This is a shame as there are many clinics and hospitals in the US that would benefit from culturally competent, highly skilled, bilingual practitioners.

According to this NY Times Article, the United States already faces a shortage of physicians in many parts of the country, especially in specialties where foreign-trained physicians are most likely to practice, like primary care. And that shortage has gotten exponentially worse since the passage of the affordable healthcare act in 2014.

For years the United States has been training too few doctors to meet its own needs, in part because of industry-set limits on the number of medical school slots available. Today about one in four physicians practicing in the United States were trained abroad, a figure that includes a substantial number of American citizens who could not get into medical school at home and studied in places like the Caribbean.

But immigrant doctors, no matter how experienced and well trained, must run a long, costly and confusing gantlet before they can actually practice here.

The process usually starts with an application to a private nonprofit organization that verifies medical school transcripts and diplomas. Among other requirements, foreign doctors must prove they speak English; pass three separate steps of the United States Medical Licensing Examination; get American recommendation letters, usually obtained after volunteering or working in a hospital, clinic or research organization; and be permanent residents or receive a work visa (which often requires them to return to their home country after their training).

The biggest challenge is that an immigrant physician must win one of the coveted slots in Americas medical residency system, the step that seems to be the tightest bottleneck.

That residency, which typically involves grueling 80-hour workweeks, is required even if a doctor previously did a residency in a country with an advanced medical system, like Britain or Japan. The only exception is for doctors who did their residencies in Canada.

The whole process can consume upward of a decade for those lucky few who make it through.

The counterargument for making it easier for foreign physicians to practice in the United States aside from concerns about quality controls is that doing so will draw more physicians from poor countries. These places often have paid for their doctors medical training with public funds, on the assumption that those doctors will stay.

According to one study, about one in 10 doctors trained in India have left that country, and the figure is close to one in three for Ghana. (Many of those moved to Europe or other developed nations other than the United States.)

No one knows exactly how many immigrant doctors are in the United States and not practicing, but some other data points provide a clue. Each year the Educational Commission for Foreign Medical Graduates, a private nonprofit, clears about 8,000 immigrant doctors (not including the American citizens who go to medical school abroad) to apply for the national residency match system. Normally about 3,000 of them successfully match to a residency slot, mostly filling less desired residencies in community hospitals, unpopular locations and in less lucrative specialties like primary care.

In the United States, some foreign doctors work as waiters or taxi drivers while they try to work through the licensing process.

Is PA a reasonable alternative to foreign trained medical providers whose skills we desperately need here in the United States?

And just how many PA schools are eagerly opening their doors to these practitioners?

This, my friends, is a topic for another blog post.

Feel free to share your thoughts in the comments section down below.

Warmly,

-Stephen Pasquini PA-C

Are you or someone you know a foreign trained doctor or medical provider looking to practice as a PA in the US? Here are some useful resources from the internets:

by Stephen Pasquini PA-C

Welcome to episode 41of the FREE Audio PANCE and PANRE Physician Assistant Board Review Podcast.

Join me as Icover 10 PANCE and PANRE board review questions from the Academy course content following the NCCPA content blueprint.

This week we will be taking a break from topic specific board review and covering 10 generalboard review questions.

Below you will find an interactive exam to complement the podcast.

I hope you enjoy this free audio component to the examination portion of this site. The full genitourinary boardreview includes over 72 GUspecific questions andis available to all members of the PANCE and PANRE Academy.

If you can’t see the audio player click here to listen to the full episode.

1. A mother brings her 6-year-old boy for evaluation of school behavior problems. She says the teacher told her that the boy does not pay attention in class, that he gets up and runs around the room when the rest of the children are listening to a story, and that he seems to be easily distracted by events outside or in the hall. He refuses to remain in his seat during class, and occasionally sits under his desk or crawls around under a table. The teacher told the mother this behavior is interfering with the child’s ability to function in the classroom and to learn. The mother states that she has noticed some of these behaviors at home, including his inability to watch his favorite cartoon program all the way through. Which of the following is the most likely diagnosis?

Click here to see the answer

Answer: D. Attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder is characterized by inattention, including increased distractibility and difficulty sustaining attention; poor impulse control and decreased self-inhibitory capacity; and motor over activity and motor restlessness, which are pervasive and interfere with the individual’s ability to function under normal circumstances.

Explanations

2. Which of the following is the treatment of choice for a torus (buckle) fracture involving the distal radius?

A. Open reduction and internal fixation B. Ace wrap or anterior splinting C. Closed reduction and casting D. Corticosteroid injection followed by splinting

Click here to see the answer

Answer:B. Ace wrap or anterior splinting

Atorus or buckle fracture occurs after a minor fall on the hand. These fractures are very stable and are not as painful as unstable fractures. They heal uneventfully in 3-4 weeks.

3. Which of the following can be used to treat chronic bacterial prostatitis?

A. Penicillin B. Cephalexin (Keflex) C. Nitrofurantoin (Macrobid) D. Levofloxacin (Levaquin)

Click here to see the answer

Chronic bacterial prostatitis (Type II prostatitis) can be difficult to treat and requires the use of fluoroquinolones or trimethoprim-sulfamethoxazole, both of which penetrate the prostate.

4. A 25 year-old male with history of syncope presents for evaluation. The patient admits to intermittent episodes ofrapid heart beating that resolve spontaneously. 12 Lead EKG shows delta waves and a short PR interval. Which ofthe following is the treatment of choice in this patient?

A. Radiofrequency catheter ablation B. Verapamil (Calan) C. Percutaneous coronary intervention D. Digoxin (Lanoxin)

Click here to see the answer

Answer:A. Radiofrequency catheter ablation

Radiofrequency catheter ablation is the treatment of choice on patients with accessory pathways, such as Wolff-Parkinson-White Syndrome.

Explanations

5. Which of the following pathophysiological processes is associated with chronic bronchitis?

A. Destruction of the lung parenchyma B. Mucous gland enlargement and goblet cell hyperplasia C. Smooth muscle hypertrophy in the large airways D. Increased mucus adhesion secondary to reduction in the salt and water content of the mucus

Click here to see the answer

Chronic bronchitis results from the enlargement of mucous glands and goblet cell hypertrophy in the large airways.

Explanations

6. Which of the following dietary substances interact with monoamine oxidase-inhibitor antidepressant drugs?

A. Lysine B. Glycine C. Tyramine D. Phenylalanine

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Answer:C. Tyramine

Monoamine oxidase inhibitors are associated with serious food/drug and drug/drug interactions. Patient must restrict intake of foods having a high tyramine content to avoid serious reactions. Tyramine is a precursor to norepinephrine.

Explanations

Lysine, glycine, and phenylalanine are not known to interact with MAO inhibitors.

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The Physician Assistant Life – Essay

Recommendation and review posted by sam

Melatonin – Wikipedia, the free encyclopedia

Melatonin, chemically N-acetyl-5-methoxy tryptamine,[1] is a substance found in animals, plants, fungi, and bacteria. In animals, it is a hormone that anticipates the daily onset of darkness;[2] however in other organisms, it may have different functions. Likewise, the synthesis of melatonin in animals differs from that in other organisms.

In animals, melatonin is involved in the entrainment (synchronization) of the circadian rhythms of physiological functions including sleep timing, blood pressure regulation, seasonal reproduction, and many others.[3] Many of melatonin’s biological effects in animals are produced through activation of melatonin receptors,[4] while others are due to its role as a pervasive and powerful antioxidant,[5] with a particular role in the protection of nuclear and mitochondrial DNA.[6]

It is used as a medication for insomnia, however, scientific evidence is insufficient to demonstrate a benefit in this area.[7] Melatonin is sold over-the-counter in the United States and Canada. In other countries, it may require a prescription or it may be unavailable.

Melatonin has shown promise in treating sleep-wake cycle disorders in children with underlying neurodevelopment difficulties.[8][9] As add-on to antihypertensive therapy, prolonged-release melatonin has improved blood pressure control in people with nocturnal hypertension.[10]

People with circadian rhythm sleep disorders may use oral melatonin to help entrain (biologically synchronize in the correct phase) to the environmental light-dark cycle. Melatonin reduces sleep onset latency to a greater extent in people with delayed sleep phase disorder than in people with insomnia.[11]

Melatonin has been studied for insomnia in the elderly.[12][13][14] Prolonged-release melatonin has shown good results in treating insomnia in older adults.[15] Short-term treatment (up to three months) of prolonged-release melatonin was found to be effective and safe in improving sleep latency, sleep quality, and daytime alertness.[16]

Evidence for use of melatonin as a treatment for insomnia is, as of 2015, insufficient;[7] low-quality evidence indicates it may speed the onset of sleep by 6 minutes.[7] A 2004 review found “no evidence that melatonin had an effect on sleep onset latency or sleep efficiency” in shift work or jet lag, while it did decrease sleep onset latency in people with a primary sleep disorder and it increased sleep efficiency in people with a secondary sleep disorder.[11] A later review[17] found minimal evidence for efficacy in shift work.

Melatonin is known to aid in reducing the effects of jet lag, especially in eastward travel, by promoting the necessary reset of the body’s sleep-wake phase. If the timing is not correct, however, it can instead delay adaption.[18]

Melatonin appears also to have limited use against the sleep problems of people who work rotating or night shifts.[17]

Tentative evidence shows melatonin may help reduce some types of headaches including cluster headaches.[19]

A 2013 review by the National Cancer Institutes found evidence for use to be inconclusive.[20] A 2005 review of unblinded clinical trials found a reduced rate of death, but that blinded and independently conducted randomized controlled trials are needed.[21]

Melatonin presence in the gallbladder has many protective properties, such as converting cholesterol to bile, preventing oxidative stress, and increasing the mobility of gallstones from the gallbladder.[22]

Both animal[23] and human[24][25] studies have shown melatonin to protect against radiation-induced cellular damage. Melatonin and its metabolites protect organisms from oxidative stress by scavenging reactive oxygen species which are generated during exposure.[26] Nearly 70% of biological damage caused by ionizing radiation is estimated to be attributable to the creation of free radicals, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. Melatonin has been described as a broadly protective, readily available, and orally self-administered antioxidant that is without major known side effects.[27]

Tentative evidence of benefit exists for treating tinnitus.[28]

Melatonin might improve sleep in autistic people.[29] Children with autism have abnormal melatonin pathways and below-average physiological levels of melatonin.[30][31] Melatonin supplementation has been shown to improve sleep duration, sleep onset latency, and night-time awakenings.[30][32][33] However, many studies on melatonin and autism rely on self-reported levels of improvement and more rigorous research is needed.

While the packaging of melatonin often warns against use in people under 18 years of age, available studies suggest that melatonin is an efficacious and safe treatment for insomnia in people with ADHD. However, larger and longer studies are needed to establish long-term safety and optimal dosing.[34]

Melatonin in comparison to placebo is effective for reducing preoperative anxiety in adults when given as premedication. It may be just as effective as standard treatment with midazolam in reducing preoperative anxiety. Melatonin may also reduce postoperative anxiety (measured 6 hours after surgery) when compared to placebo.[35]

Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin increased REM sleep time and dream activity in people both with and without narcolepsy.[36]

Melatonin appears to cause very few side effects as tested in the short term, up to three months, at low doses. Two systematic reviews found no adverse effects of exogenous melatonin in several clinical trials and comparative trials found the adverse effects headaches, dizziness, nausea, and drowsiness were reported about equally for both melatonin and placebo.[37][38] Prolonged-release melatonin is safe with long-term use of up to 12 months.[39]

Melatonin can cause nausea, next-day grogginess, and irritability.[40] In the elderly, it can cause reduced blood flow and hypothermia.[41] In autoimmune disorders, evidence is conflicting whether melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation.[42][43]

Melatonin can lower follicle-stimulating hormone levels.[44] Effects of melatonin on human reproduction remain unclear,[45] although it was with some effect tried as a contraceptive in the 1990s.[46]

Anticoagulants and other substances are known to interact with melatonin.[47]

In animals, the primary function is regulation of day-night cycles. Human infants’ melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 8:00 am.[48] Human melatonin production decreases as a person ages.[49] Also, as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.[50]

Besides its function as synchronizer of the biological clock, melatonin is a powerful free-radical scavenger and wide-spectrum antioxidant as discovered in 1993.[51] In many less-complex life forms, this is its only known function.[26] Melatonin is an antioxidant that can easily cross cell membranes[52] and the bloodbrain barrier.[5][53] This antioxidant is a direct scavenger of radical oxygen and nitrogen species including OH, O2, and NO.[54][55] Melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant.[55] Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant.[56] An important characteristic of melatonin that distinguishes it from other classic radical scavengers is that its metabolites are also scavengers in what is referred to as the cascade reaction.[26] Also different from other classic antioxidants, such as vitamin C and vitamin E, melatonin has amphiphilic properties. When compared to synthetic, mitochondrial-targeted antioxidants (MitoQ and MitoE), melatonin proved to be a comparable protector against mitochondrial oxidative stress.[57]

While it is known that melatonin interacts with the immune system,[58][59] the details of those interactions are unclear. Antiinflammatory effect seems to be the most relevant and most documented in the literature.[60] There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete clinical trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production,[61] and by doing this, counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease[62] including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.

In rheumatoid arthritis patients, melatonin production has been found increased when compared to age-matched healthy controls.[63][relevant? discuss]

In vitro, melatonin can form complexes with cadmium and other metals.[64]

Biosynthesis of melatonin occurs through hydroxylation, decarboxylation, acetylation and a methylation starting with L-tryptophan. [65] L-tryptophan is produced in the shikimate pathway from chorismate or is acquired from protein catabolism. First L-tryptophan is hydroxylated on the indole ring by tryptophan hydroxylase. The intermediate is decarboxylated by PLP and 5-hydroxy-L-tryptophan to produce serotonin also known as 5-hydroxytryptamine. Serotonin acts as a neurotransmitter on its own, but is also converted into N-acetyl-serotonin by serotonin N-acetyl transferase and acetyl-CoA. Hydroxyindole O-methyl transferase and SAM convert N-acetyl-serotonin into melatonin through methylation of the hydroxyl group.

In bacteria, protists, fungi, and plants, melatonin is synthesized indirectly with tryptophan as an intermediate product of the shikimic acid pathway. In these cells, synthesis starts with d-erythrose-4-phosphate and phosphoenolpyruvate, and in photosynthetic cells with carbon dioxide. The rest of the reactions are similar, but with slight variations in the last two enzymes.[66][67]

In order to hydroxylate L-tryptophan, the cofactor tetrahydrobiopterin must first react with oxygen and the active site iron of tryptophan hydroxylase. This mechanism is not well understood, but two mechanisms have been proposed:

1. A slow transfer of one electron from the pterin to O2 could produce a superoxide which could recombine with the pterin radical to give 4a-peroxypterin. 4a-peroxypterin could then react with the active site iron (II) to form an iron-peroxypterin intermediate or directly transfer an oxygen atom to the iron.

2. O2 could react with the active site iron (II) first, producing iron (III) superoxide which could then react with the pterin to form an iron-peroxypterin intermediate.

Iron (IV) oxide from the iron-peroxypterin intermediate is selectively attacked by a double bond to give a carbocation at the C5 position of the indole ring. A 1,2-shift of the hydrogen and then a loss of one of the two hydrogen atoms on C5 reestablishes aromaticity to furnish 5-hydroxy-L-tryptophan. [68]

A decarboxylase with cofactor pyridoxal phosphate (PLP) removes CO2 from 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine. [69] PLP forms an imine with the amino acid derivative. The amine on the pyridine is protonated and acts as an electron sink, breaking the C-C bond and releasing CO2. Protonation of the amine from tryptophan restores the aromaticity of the pyridine ring and then imine is hydrolyzed to produce 5-hydroxytryptamine and PLP. [70]

It has been proposed that His122 of serotonin N-acetyl transferase is the catalytic residue that deprotonates the primary amine of 5-hydroxytryptamine, which allows the lone pair on the amine to attack acetyl-CoA, forming a tetraherdral intermediate. The thiol from coenzyme A serves as a good leaving group when attacked by a general base to give N-acetyl-serotonin.[71]

N-acetyl-serotonin is methylated at the hydroxyl position by S-adenosyl methionine (SAM) to produce S-adenosyl homocysteine (SAH) and melatonin.[72][73]

In vertebrates, melatonin secretion is regulated by norepinephrine. Norepinephrine elevates the intracellular cAMP concentration via beta-adrenergic receptors and activates the cAMP-dependent protein kinase A (PKA). PKA phosphorylates the penultimate enzyme, the arylalkylamine N-acetyltransferase (AANAT). On exposure to (day)light, noradrenergic stimulation stops and the protein is immediately destroyed by proteasomal proteolysis.[74] Production of melatonin is again started in the evening at the point called the dim-light melatonin onset.

Blue light, principally around 460 to 480nm, suppresses melatonin,[75] proportional to the light intensity and length of exposure. Until recent history, humans in temperate climates were exposed to few hours of (blue) daylight in the winter; their fires gave predominantly yellow light.[citation needed] The incandescent light bulb widely used in the 20th century produced relatively little blue light.[76] Light containing only wavelengths greater than 530nm does not suppress melatonin in bright-light conditions.[77] Wearing glasses that block blue light in the hours before bedtime may decrease melatonin loss. Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.[78]

When used several hours before sleep according to the phase response curve for melatonin in humans, small amounts (0.3mg[79]) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.[80] In humans, 90% of orally administered exogenous melatonin is cleared in a single passage through the liver, a small amount is excreted in urine, and a small amount is found in saliva.[11]

In vertebrates, melatonin is produced in darkness, thus usually at night, by the pineal gland, a small endocrine gland[81] located in the center of the brain but outside the bloodbrain barrier. Light/dark information reaches the suprachiasmatic nuclei from retinal photosensitive ganglion cells of the eyes[82][83] rather than the melatonin signal (as was once postulated). Known as “the hormone of darkness”, the onset of melatonin at dusk promotes activity in nocturnal (night-active) animals and sleep in diurnal ones including humans.

Many animals use the variation in duration of melatonin production each day as a seasonal clock.[84] In animals including humans,[85] the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organization of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behavior, coat growth, and camouflage coloring in seasonal animals.[85] In seasonal breeders that do not have long gestation periods and that mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds[86] and hamsters.[87] Melatonin can suppress libido by inhibiting secretion of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin.

During the night, melatonin regulates leptin, lowering its levels.

Until its identification in plants in 1987, melatonin was for decades thought to be primarily an animal neurohormone. When melatonin was identified in coffee extracts in the 1970s, it was believed to be a byproduct of the extraction process. Subsequently, however, melatonin has been found in all plants that have been investigated. It is present in all the different parts of plants, including leaves, stems, roots, fruits, and seeds in varying proportions.[88][89] Melatonin concentrations differ not only among plant species, but also between varieties of the same species depending on the agronomic growing conditions, varying from picograms to several micrograms per gram.[90][67] Notably high melatonin concentrations have been measured in popular beverages such as coffee, tea, wine, and beer, and crops including corn, rice, wheat, barley, and oats.[89] Melatonin is a poor direct antioxidant, it is, however, a highly efficient direct free radical scavenger and indirect antioxidant due to its ability to stimulate antioxidant enzymes.[91][92][93] Thus, melatonin in the human diet is believed to confer a number of beneficial health-related effects.[89][90][94] In some common foods and beverages, including coffee[89] and walnuts,[95] the concentration of melatonin has been estimated or measured to be sufficiently high to raise the blood level of melatonin above daytime baseline values.

Although a role for melatonin as a plant hormone has not been clearly established, its involvement in processes such as growth and photosynthesis is well established. Only limited evidence of endogenous circadian rhythms in melatonin levels has been demonstrated in some plant species and no membrane-bound receptors analogous to those known in animals have been described. Rather, melatonin performs important roles in plants as a growth regulator, as well as environmental stress protector. It is synthesized in plants when they are exposed to both biological stresses, for example, fungal infection, and nonbiological stresses such as extremes of temperature, toxins, increased soil salinity, drought, etc.[67][93][96]

Melatonin is categorized by the US Food and Drug Administration (FDA) as a dietary supplement, and is sold over-the-counter in both the US and Canada.[97] The FDA regulations applying to medications are not applicable to melatonin.[3] However, new FDA rules required that by June 2010, all production of dietary supplements must comply with “current good manufacturing practices” (cGMP) and be manufactured with “controls that result in a consistent product free of contamination, with accurate labeling.”[98] The industry has also been required to report to the FDA “all serious dietary supplement related adverse events”, and the FDA has (within the cGMP guidelines) begun enforcement of that requirement.[99]

As melatonin may cause harm in combination with certain medications or in the case of certain disorders, a doctor or pharmacist should be consulted before making a decision to take melatonin.[18]

In many countries, melatonin is recognized as a neurohormone and it cannot be sold over-the-counter.[100]

Melatonin has been reported in foods including cherries to about 0.1713.46ng/g,[101] bananas and grapes, rice and cereals, herbs, plums,[102] olive oil, wine[103] and beer. When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.[104] When humans consume foods rich in melatonin such as banana, pineapple and orange, the blood levels of melatonin increase significantly.[105]

As reported in the New York Times in May 2011,[106] beverages and snacks containing melatonin are sold in grocery stores, convenience stores, and clubs. The FDA is considering whether these food products can continue to be sold with the label “dietary supplements”. On 13 January 2010, it issued a warning letter to Innovative Beverage, creators of several beverages marketed as drinks, stating that melatonin is not approved as a food additive because it is not generally recognized as safe.[107]

Melatonin was first discovered in connection to the mechanism by which some amphibians and reptiles change the color of their skin.[108][109] As early as 1917, Carey Pratt McCord and Floyd P. Allen discovered that feeding extract of the pineal glands of cows lightened tadpole skin by contracting the dark epidermal melanophores.[110][111]

In 1958, dermatology professor Aaron B. Lerner and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated the hormone from bovine pineal gland extracts and named it melatonin.[112] In the mid-70s Lynch et al. demonstrated[113] that the production of melatonin exhibits a circadian rhythm in human pineal glands.

The discovery that melatonin is an antioxidant was made in 1993.[114] The first patent for its use as a low-dose sleep aid was granted to Richard Wurtman at MIT in 1995.[115] Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.[116]The New England Journal of Medicine editorialized in 2000: “With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear.”[117]

Immediate-release melatonin is not tightly regulated in countries where it is available as an over-the-counter medication. It is available in doses from less than half a milligram to 5mg or more. Immediate-release formulations cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, tablets, or liquids. It is also available for use sublingually, or as transdermal patches.

Formerly, melatonin was derived from animal pineal tissue, such as bovine. It is now synthetic and does not carry a risk of contamination or the means of transmitting infectious material.[3][118]

Melatonin is available as a prolonged-release prescription drug. It releases melatonin gradually over 810 hours, intended to mimic the body’s internal secretion profile.

In June 2007, the European Medicines Agency approved UK-based Neurim Pharmaceuticals’ prolonged-release melatonin medication Circadin for marketing throughout the EU.[119] The drug is a prolonged-release melatonin, 2mg, for patients aged 55 and older, as monotherapy for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor quality of sleep.[120][121]

Other countries’ agencies that subsequently approved the drug include:

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Melatonin – Wikipedia, the free encyclopedia

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Stem Cell Basics IV. | stemcells.nih.gov

An adult stem cell is thought to be an undifferentiated cell, found among differentiated cells in a tissue or organ. The adult stem cell can renew itself and can differentiate to yield some or all of the major specialized cell types of the tissue or organ. The primary roles of adult stem cells in a living organism are to maintain and repair the tissue in which they are found. Scientists also use the term somatic stem cell instead of adult stem cell, where somatic refers to cells of the body (not the germ cells, sperm or eggs). Unlike embryonic stem cells, which are defined by their origin (cells from the preimplantation-stage embryo), the origin of adult stem cells in some mature tissues is still under investigation.

Research on adult stem cells has generated a great deal of excitement. Scientists have found adult stem cells in many more tissues than they once thought possible. This finding has led researchers and clinicians to ask whether adult stem cells could be used for transplants. In fact, adult hematopoietic, or blood-forming, stem cells from bone marrow have been used in transplants for more than 40 years. Scientists now have evidence that stem cells exist in the brain and the heart, two locations where adult stem cells were not at firstexpected to reside. If the differentiation of adult stem cells can be controlled in the laboratory, these cells may become the basis of transplantation-based therapies.

The history of research on adult stem cells began more than 60 years ago. In the 1950s, researchers discovered that the bone marrow contains at least two kinds of stem cells. One population, called hematopoietic stem cells, forms all the types of blood cells in the body. A second population, called bone marrow stromal stem cells (also called mesenchymal stem cells, or skeletal stem cells by some), were discovered a few years later. These non-hematopoietic stem cells make up a small proportion of the stromal cell population in the bone marrow and can generate bone, cartilage, and fat cells that support the formation of blood and fibrous connective tissue.

In the 1960s, scientists who were studying rats discovered two regions of the brain that contained dividing cells that ultimately become nerve cells. Despite these reports, most scientists believed that the adult brain could not generate new nerve cells. It was not until the 1990s that scientists agreed that the adult brain does contain stem cells that are able to generate the brain’s three major cell typesastrocytes and oligodendrocytes, which are non-neuronal cells, and neurons, or nerve cells.

Adult stem cells have been identified in many organs and tissues, including brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis. They are thought to reside in a specific area of each tissue (called a “stem cell niche”). In many tissues, current evidence suggests that some types of stem cells are pericytes, cells that compose the outermost layer of small blood vessels. Stem cells may remain quiescent (non-dividing) for long periods of time until they are activated by a normal need for more cells to maintain tissues, or by disease or tissue injury.

Typically, there is a very small number of stem cells in each tissue and, once removed from the body, their capacity to divide is limited, making generation of large quantities of stem cells difficult. Scientists in many laboratories are trying to find better ways to grow large quantities of adult stem cells in cell culture and to manipulate them to generate specific cell types so they can be used to treat injury or disease. Some examples of potential treatments include regenerating bone using cells derived from bone marrow stroma, developing insulin-producing cells for type1 diabetes, and repairing damaged heart muscle following a heart attack with cardiac muscle cells.

Scientists often use one or more of the following methods to identify adult stem cells: (1) label the cells in a living tissue with molecular markers and then determine the specialized cell types they generate; (2) remove the cells from a living animal, label them in cell culture, and transplant them back into another animal to determine whether the cells replace (or “repopulate”) their tissue of origin.

Importantly, scientists must demonstrate that a single adult stem cell can generate a line of genetically identical cells that then gives rise to all the appropriate differentiated cell types of the tissue. To confirm experimentally that a putative adult stem cell is indeed a stem cell, scientists tend to show either that the cell can give rise to these genetically identical cells in culture, and/or that a purified population of these candidate stem cells can repopulate or reform the tissue after transplant into an animal.

As indicated above, scientists have reported that adult stem cells occur in many tissues and that they enter normal differentiation pathways to form the specialized cell types of the tissue in which they reside.

Normal differentiation pathways of adult stem cells. In a living animal, adult stem cells are available to divide for a long period, when needed, and can give rise to mature cell types that have characteristic shapes and specialized structures and functions of a particular tissue. The following are examples of differentiation pathways of adult stem cells (Figure 2) that have been demonstrated in vitro or in vivo.

Figure 2. Hematopoietic and stromal stem cell differentiation. Click here for larger image. ( 2008 Terese Winslow)

Transdifferentiation. A number of experiments have reported that certain adult stem cell types can differentiate into cell types seen in organs or tissues other than those expected from the cells’ predicted lineage (i.e., brain stem cells that differentiate into blood cells or blood-forming cells that differentiate into cardiac muscle cells, and so forth). This reported phenomenon is called transdifferentiation.

Although isolated instances of transdifferentiation have been observed in some vertebrate species, whether this phenomenon actually occurs in humans is under debate by the scientific community. Instead of transdifferentiation, the observed instances may involve fusion of a donor cell with a recipient cell. Another possibility is that transplanted stem cells are secreting factors that encourage the recipient’s own stem cells to begin the repair process. Even when transdifferentiation has been detected, only a very small percentage of cells undergo the process.

In a variation of transdifferentiation experiments, scientists have recently demonstrated that certain adult cell types can be “reprogrammed” into other cell types in vivo using a well-controlled process of genetic modification (see Section VI for a discussion of the principles of reprogramming). This strategy may offer a way to reprogram available cells into other cell types that have been lost or damaged due to disease. For example, one recent experiment shows how pancreatic beta cells, the insulin-producing cells that are lost or damaged in diabetes, could possibly be created by reprogramming other pancreatic cells. By “re-starting” expression of three critical beta cell genes in differentiated adult pancreatic exocrine cells, researchers were able to create beta cell-like cells that can secrete insulin. The reprogrammed cells were similar to beta cells in appearance, size, and shape; expressed genes characteristic of beta cells; and were able to partially restore blood sugar regulation in mice whose own beta cells had been chemically destroyed. While not transdifferentiation by definition, this method for reprogramming adult cells may be used as a model for directly reprogramming other adult cell types.

In addition to reprogramming cells to become a specific cell type, it is now possible to reprogram adult somatic cells to become like embryonic stem cells (induced pluripotent stem cells, iPSCs) through the introduction of embryonic genes. Thus, a source of cells can be generated that are specific to the donor, thereby increasing the chance of compatibility if such cells were to be used for tissue regeneration. However, like embryonic stem cells, determination of the methods by which iPSCs can be completely and reproducibly committed to appropriate cell lineages is still under investigation.

Many important questions about adult stem cells remain to be answered. They include:

Previous|IV. What are adult stem cells?|Next

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Stem Cell Basics IV. | stemcells.nih.gov

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Science & Health, Colleges Around Cincinnati, University …

The mission of the Department of Science and Health Department at UC Clermont is to provide outstanding, comprehensive undergraduate programs for careers in the biological and chemical sciences and in allied health professions. We strive to nurture a classroom environment which demonstrates and inculcates in our students the understanding and ability to acquire and critically interpret knowledge of basic facts and theories of the basic and clinical sciences, strive to add to the body of scientific knowledge through research, and encourage our students to communicate their understanding to others.We use every opportunity in our classrooms to encourage curiosity, propose hypotheses, construct scientifically valid tests for hypotheses, and nurture critical thinking skills. We teach our students the tools needed to create hypothetical answers to new questions, to make an educated guess.

Our laboratories emphasize hands-on experiments or manipulations which demonstrate principles presented in lecture. Each student will be taught the use of specialized scientific or clinical equipment and the performance of important lab or clinical techniques.

We provide a classroom environment which favors the learning process through small class size and lively classroom discussions. We test in a manner which enhances student improvement to more effectively engage them in their learning process. We believe that all of the material we teach should relate directly or indirectly to a students life or professional interests. Our curriculum is organized around these shared values.

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Science & Health, Colleges Around Cincinnati, University …

Recommendation and review posted by Bethany Smith

Muscle – Wikipedia, the free encyclopedia

Muscle is a soft tissue found in most animals. Muscle cells contain protein filaments of actin and myosin that slide past one another, producing a contraction that changes both the length and the shape of the cell. Muscles function to produce force and motion. They are primarily responsible for maintaining and changing posture, locomotion, as well as movement of internal organs, such as the contraction of the heart and the movement of food through the digestive system via peristalsis.

Muscle tissues are derived from the mesodermal layer of embryonic germ cells in a process known as myogenesis. There are three types of muscle, skeletal or striated, cardiac, and smooth. Muscle action can be classified as being either voluntary or involuntary. Cardiac and smooth muscles contract without conscious thought and are termed involuntary, whereas the skeletal muscles contract upon command.[1] Skeletal muscles in turn can be divided into fast and slow twitch fibers.

Muscles are predominantly powered by the oxidation of fats and carbohydrates, but anaerobic chemical reactions are also used, particularly by fast twitch fibers. These chemical reactions produce adenosine triphosphate (ATP) molecules that are used to power the movement of the myosin heads.[2]

The term muscle is derived from the Latin musculus meaning “little mouse” perhaps because of the shape of certain muscles or because contracting muscles look like mice moving under the skin.[3][4]

The anatomy of muscles includes gross anatomy, which comprises all the muscles of an organism, and microanatomy, which comprises the structures of a single muscle.

Muscle tissue is a soft tissue, and is one of the four fundamental types of tissue present in animals. There are three types of muscle tissue recognized in vertebrates:

Cardiac and skeletal muscles are “striated” in that they contain sarcomeres that are packed into highly regular arrangements of bundles; the myofibrils of smooth muscle cells are not arranged in sarcomeres and so are not striated. While the sarcomeres in skeletal muscles are arranged in regular, parallel bundles, cardiac muscle sarcomeres connect at branching, irregular angles (called intercalated discs). Striated muscle contracts and relaxes in short, intense bursts, whereas smooth muscle sustains longer or even near-permanent contractions.

Skeletal (voluntary) muscle is further divided into two broad types: slow twitch and fast twitch:

The density of mammalian skeletal muscle tissue is about 1.06kg/liter.[8] This can be contrasted with the density of adipose tissue (fat), which is 0.9196kg/liter.[9] This makes muscle tissue approximately 15% denser than fat tissue.

All muscles are derived from paraxial mesoderm. The paraxial mesoderm is divided along the embryo’s length into somites, corresponding to the segmentation of the body (most obviously seen in the vertebral column.[10] Each somite has 3 divisions, sclerotome (which forms vertebrae), dermatome (which forms skin), and myotome (which forms muscle). The myotome is divided into two sections, the epimere and hypomere, which form epaxial and hypaxial muscles, respectively. The only epaxial muscles in humans are the erector spinae and small intervertebral muscles, and are innervated by the dorsal rami of the spinal nerves. All other muscles, including those of the limbs are hypaxial, and inervated by the ventral rami of the spinal nerves.[10]

During development, myoblasts (muscle progenitor cells) either remain in the somite to form muscles associated with the vertebral column or migrate out into the body to form all other muscles. Myoblast migration is preceded by the formation of connective tissue frameworks, usually formed from the somatic lateral plate mesoderm. Myoblasts follow chemical signals to the appropriate locations, where they fuse into elongate skeletal muscle cells.[10]

Skeletal muscles are sheathed by a tough layer of connective tissue called the epimysium. The epimysium anchors muscle tissue to tendons at each end, where the epimysium becomes thicker and collagenous. It also protects muscles from friction against other muscles and bones. Within the epimysium are multiple bundles called fascicles, each of which contains 10 to 100 or more muscle fibers collectively sheathed by a perimysium. Besides surrounding each fascicle, the perimysium is a pathway for nerves and the flow of blood within the muscle. The threadlike muscle fibers are the individual muscle cells (myocytes), and each cell is encased within its own endomysium of collagen fibers. Thus, the overall muscle consists of fibers (cells) that are bundled into fascicles, which are themselves grouped together to form muscles. At each level of bundling, a collagenous membrane surrounds the bundle, and these membranes support muscle function both by resisting passive stretching of the tissue and by distributing forces applied to the muscle.[11] Scattered throughout the muscles are muscle spindles that provide sensory feedback information to the central nervous system. (This grouping structure is analogous to the organization of nerves which uses epineurium, perineurium, and endoneurium).

This same bundles-within-bundles structure is replicated within the muscle cells. Within the cells of the muscle are myofibrils, which themselves are bundles of protein filaments. The term “myofibril” should not be confused with “myofiber”, which is a simply another name for a muscle cell. Myofibrils are complex strands of several kinds of protein filaments organized together into repeating units called sarcomeres. The striated appearance of both skeletal and cardiac muscle results from the regular pattern of sarcomeres within their cells. Although both of these types of muscle contain sarcomeres, the fibers in cardiac muscle are typically branched to form a network. Cardiac muscle fibers are interconnected by intercalated discs,[12] giving that tissue the appearance of a syncytium.

The filaments in a sarcomere are composed of actin and myosin.

The gross anatomy of a muscle is the most important indicator of its role in the body. There is an important distinction seen between pennate muscles and other muscles. In most muscles, all the fibers are oriented in the same direction, running in a line from the origin to the insertion. However, In pennate muscles, the individual fibers are oriented at an angle relative to the line of action, attaching to the origin and insertion tendons at each end. Because the contracting fibers are pulling at an angle to the overall action of the muscle, the change in length is smaller, but this same orientation allows for more fibers (thus more force) in a muscle of a given size. Pennate muscles are usually found where their length change is less important than maximum force, such as the rectus femoris.

Skeletal muscle is arranged in discrete muscles, an example of which is the biceps brachii (biceps). The tough, fibrous epimysium of skeletal muscle is both connected to and continuous with the tendons. In turn, the tendons connect to the periosteum layer surrounding the bones, permitting the transfer of force from the muscles to the skeleton. Together, these fibrous layers, along with tendons and ligaments, constitute the deep fascia of the body.

The muscular system consists of all the muscles present in a single body. There are approximately 650 skeletal muscles in the human body,[13] but an exact number is difficult to define. The difficulty lies partly in the fact that different sources group the muscles differently and partly in that some muscles, such as palmaris longus, are not always present.

A muscular slip is a narrow length of muscle that acts to augment a larger muscle or muscles.

The muscular system is one component of the musculoskeletal system, which includes not only the muscles but also the bones, joints, tendons, and other structures that permit movement.

The three types of muscle (skeletal, cardiac and smooth) have significant differences. However, all three use the movement of actin against myosin to create contraction. In skeletal muscle, contraction is stimulated by electrical impulses transmitted by the nerves, the motoneurons (motor nerves) in particular. Cardiac and smooth muscle contractions are stimulated by internal pacemaker cells which regularly contract, and propagate contractions to other muscle cells they are in contact with. All skeletal muscle and many smooth muscle contractions are facilitated by the neurotransmitter acetylcholine.

The action a muscle generates is determined by the origin and insertion locations. The cross-sectional area of a muscle (rather than volume or length) determines the amount of force it can generate by defining the number of sarcomeres which can operate in parallel.[citation needed] The amount of force applied to the external environment is determined by lever mechanics, specifically the ratio of in-lever to out-lever. For example, moving the insertion point of the biceps more distally on the radius (farther from the joint of rotation) would increase the force generated during flexion (and, as a result, the maximum weight lifted in this movement), but decrease the maximum speed of flexion. Moving the insertion point proximally (closer to the joint of rotation) would result in decreased force but increased velocity. This can be most easily seen by comparing the limb of a mole to a horse – in the former, the insertion point is positioned to maximize force (for digging), while in the latter, the insertion point is positioned to maximize speed (for running).

Muscular activity accounts for much of the body’s energy consumption. All muscle cells produce adenosine triphosphate (ATP) molecules which are used to power the movement of the myosin heads. Muscles have a short-term store of energy in the form of creatine phosphate which is generated from ATP and can regenerate ATP when needed with creatine kinase. Muscles also keep a storage form of glucose in the form of glycogen. Glycogen can be rapidly converted to glucose when energy is required for sustained, powerful contractions. Within the voluntary skeletal muscles, the glucose molecule can be metabolized anaerobically in a process called glycolysis which produces two ATP and two lactic acid molecules in the process (note that in aerobic conditions, lactate is not formed; instead pyruvate is formed and transmitted through the citric acid cycle). Muscle cells also contain globules of fat, which are used for energy during aerobic exercise. The aerobic energy systems take longer to produce the ATP and reach peak efficiency, and requires many more biochemical steps, but produces significantly more ATP than anaerobic glycolysis. Cardiac muscle on the other hand, can readily consume any of the three macronutrients (protein, glucose and fat) aerobically without a ‘warm up’ period and always extracts the maximum ATP yield from any molecule involved. The heart, liver and red blood cells will also consume lactic acid produced and excreted by skeletal muscles during exercise.

At rest, skeletal muscle consumes 54.4 kJ/kg(13.0kcal/kg) per day. This is larger than adipose tissue (fat) at 18.8kJ/kg (4.5kcal/kg), and bone at 9.6kJ/kg (2.3kcal/kg).[14]

The efferent leg of the peripheral nervous system is responsible for conveying commands to the muscles and glands, and is ultimately responsible for voluntary movement. Nerves move muscles in response to voluntary and autonomic (involuntary) signals from the brain. Deep muscles, superficial muscles, muscles of the face and internal muscles all correspond with dedicated regions in the primary motor cortex of the brain, directly anterior to the central sulcus that divides the frontal and parietal lobes.

In addition, muscles react to reflexive nerve stimuli that do not always send signals all the way to the brain. In this case, the signal from the afferent fiber does not reach the brain, but produces the reflexive movement by direct connections with the efferent nerves in the spine. However, the majority of muscle activity is volitional, and the result of complex interactions between various areas of the brain.

Nerves that control skeletal muscles in mammals correspond with neuron groups along the primary motor cortex of the brain’s cerebral cortex. Commands are routed though the basal ganglia and are modified by input from the cerebellum before being relayed through the pyramidal tract to the spinal cord and from there to the motor end plate at the muscles. Along the way, feedback, such as that of the extrapyramidal system contribute signals to influence muscle tone and response.

Deeper muscles such as those involved in posture often are controlled from nuclei in the brain stem and basal ganglia.

The afferent leg of the peripheral nervous system is responsible for conveying sensory information to the brain, primarily from the sense organs like the skin. In the muscles, the muscle spindles convey information about the degree of muscle length and stretch to the central nervous system to assist in maintaining posture and joint position. The sense of where our bodies are in space is called proprioception, the perception of body awareness. More easily demonstrated than explained, proprioception is the “unconscious” awareness of where the various regions of the body are located at any one time. This can be demonstrated by anyone closing their eyes and waving their hand around. Assuming proper proprioceptive function, at no time will the person lose awareness of where the hand actually is, even though it is not being detected by any of the other senses.

Several areas in the brain coordinate movement and position with the feedback information gained from proprioception. The cerebellum and red nucleus in particular continuously sample position against movement and make minor corrections to assure smooth motion.

The efficiency of human muscle has been measured (in the context of rowing and cycling) at 18% to 26%. The efficiency is defined as the ratio of mechanical work output to the total metabolic cost, as can be calculated from oxygen consumption. This low efficiency is the result of about 40% efficiency of generating ATP from food energy, losses in converting energy from ATP into mechanical work inside the muscle, and mechanical losses inside the body. The latter two losses are dependent on the type of exercise and the type of muscle fibers being used (fast-twitch or slow-twitch). For an overall efficiency of 20 percent, one watt of mechanical power is equivalent to 4.3 kcal per hour. For example, one manufacturer of rowing equipment calibrates its rowing ergometer to count burned calories as equal to four times the actual mechanical work, plus 300 kcal per hour,[15] this amounts to about 20 percent efficiency at 250 watts of mechanical output. The mechanical energy output of a cyclic contraction can depend upon many factors, including activation timing, muscle strain trajectory, and rates of force rise & decay. These can be synthesized experimentally using work loop analysis.

A display of “strength” (e.g. lifting a weight) is a result of three factors that overlap: physiological strength (muscle size, cross sectional area, available crossbridging, responses to training), neurological strength (how strong or weak is the signal that tells the muscle to contract), and mechanical strength (muscle’s force angle on the lever, moment arm length, joint capabilities).

Vertebrate muscle typically produces approximately 2533N (5.67.4lbf) of force per square centimeter of muscle cross-sectional area when isometric and at optimal length.[16] Some invertebrate muscles, such as in crab claws, have much longer sarcomeres than vertebrates, resulting in many more sites for actin and myosin to bind and thus much greater force per square centimeter at the cost of much slower speed. The force generated by a contraction can be measured non-invasively using either mechanomyography or phonomyography, be measured in vivo using tendon strain (if a prominent tendon is present), or be measured directly using more invasive methods.

The strength of any given muscle, in terms of force exerted on the skeleton, depends upon length, shortening speed, cross sectional area, pennation, sarcomere length, myosin isoforms, and neural activation of motor units. Significant reductions in muscle strength can indicate underlying pathology, with the chart at right used as a guide.

Since three factors affect muscular strength simultaneously and muscles never work individually, it is misleading to compare strength in individual muscles, and state that one is the “strongest”. But below are several muscles whose strength is noteworthy for different reasons.

Humans are genetically predisposed with a larger percentage of one type of muscle group over another. An individual born with a greater percentage of Type I muscle fibers would theoretically be more suited to endurance events, such as triathlons, distance running, and long cycling events, whereas a human born with a greater percentage of Type II muscle fibers would be more likely to excel at sprinting events such as 100 meter dash.[citation needed]

Exercise is often recommended as a means of improving motor skills, fitness, muscle and bone strength, and joint function. Exercise has several effects upon muscles, connective tissue, bone, and the nerves that stimulate the muscles. One such effect is muscle hypertrophy, an increase in size. This is used in bodybuilding.

Various exercises require a predominance of certain muscle fiber utilization over another. Aerobic exercise involves long, low levels of exertion in which the muscles are used at well below their maximal contraction strength for long periods of time (the most classic example being the marathon). Aerobic events, which rely primarily on the aerobic (with oxygen) system, use a higher percentage of Type I (or slow-twitch) muscle fibers, consume a mixture of fat, protein and carbohydrates for energy, consume large amounts of oxygen and produce little lactic acid. Anaerobic exercise involves short bursts of higher intensity contractions at a much greater percentage of their maximum contraction strength. Examples of anaerobic exercise include sprinting and weight lifting. The anaerobic energy delivery system uses predominantly Type II or fast-twitch muscle fibers, relies mainly on ATP or glucose for fuel, consumes relatively little oxygen, protein and fat, produces large amounts of lactic acid and can not be sustained for as long a period as aerobic exercise. Many exercises are partially aerobic and partially anaerobic; for example, soccer and rock climbing involve a combination of both.

The presence of lactic acid has an inhibitory effect on ATP generation within the muscle; though not producing fatigue, it can inhibit or even stop performance if the intracellular concentration becomes too high. However, long-term training causes neovascularization within the muscle, increasing the ability to move waste products out of the muscles and maintain contraction. Once moved out of muscles with high concentrations within the sarcomere, lactic acid can be used by other muscles or body tissues as a source of energy, or transported to the liver where it is converted back to pyruvate. In addition to increasing the level of lactic acid, strenuous exercise causes the loss of potassium ions in muscle and causing an increase in potassium ion concentrations close to the muscle fibres, in the interstitium. Acidification by lactic acid may allow recovery of force so that acidosis may protect against fatigue rather than being a cause of fatigue.[18]

Delayed onset muscle soreness is pain or discomfort that may be felt one to three days after exercising and generally subsides two to three days later. Once thought to be caused by lactic acid build-up, a more recent theory is that it is caused by tiny tears in the muscle fibers caused by eccentric contraction, or unaccustomed training levels. Since lactic acid disperses fairly rapidly, it could not explain pain experienced days after exercise.[19]

Independent of strength and performance measures, muscles can be induced to grow larger by a number of factors, including hormone signaling, developmental factors, strength training, and disease. Contrary to popular belief, the number of muscle fibres cannot be increased through exercise. Instead, muscles grow larger through a combination of muscle cell growth as new protein filaments are added along with additional mass provided by undifferentiated satellite cells alongside the existing muscle cells.[13]

Biological factors such as age and hormone levels can affect muscle hypertrophy. During puberty in males, hypertrophy occurs at an accelerated rate as the levels of growth-stimulating hormones produced by the body increase. Natural hypertrophy normally stops at full growth in the late teens. As testosterone is one of the body’s major growth hormones, on average, men find hypertrophy much easier to achieve than women. Taking additional testosterone or other anabolic steroids will increase muscular hypertrophy.

Muscular, spinal and neural factors all affect muscle building. Sometimes a person may notice an increase in strength in a given muscle even though only its opposite has been subject to exercise, such as when a bodybuilder finds her left biceps stronger after completing a regimen focusing only on the right biceps. This phenomenon is called cross education.[citation needed]

Inactivity and starvation in mammals lead to atrophy of skeletal muscle, a decrease in muscle mass that may be accompanied by a smaller number and size of the muscle cells as well as lower protein content.[20] Muscle atrophy may also result from the natural aging process or from disease.

In humans, prolonged periods of immobilization, as in the cases of bed rest or astronauts flying in space, are known to result in muscle weakening and atrophy. Atrophy is of particular interest to the manned spaceflight community, because the weightlessness experienced in spaceflight results is a loss of as much as 30% of mass in some muscles.[21][22] Such consequences are also noted in small hibernating mammals like the golden-mantled ground squirrels and brown bats.[23]

During aging, there is a gradual decrease in the ability to maintain skeletal muscle function and mass, known as sarcopenia. The exact cause of sarcopenia is unknown, but it may be due to a combination of the gradual failure in the “satellite cells” that help to regenerate skeletal muscle fibers, and a decrease in sensitivity to or the availability of critical secreted growth factors that are necessary to maintain muscle mass and satellite cell survival. Sarcopenia is a normal aspect of aging, and is not actually a disease state yet can be linked to many injuries in the elderly population as well as decreasing quality of life.[24]

There are also many diseases and conditions that cause muscle atrophy. Examples include cancer and AIDS, which induce a body wasting syndrome called cachexia. Other syndromes or conditions that can induce skeletal muscle atrophy are congestive heart disease and some diseases of the liver.

Neuromuscular diseases are those that affect the muscles and/or their nervous control. In general, problems with nervous control can cause spasticity or paralysis, depending on the location and nature of the problem. A large proportion of neurological disorders, ranging from cerebrovascular accident (stroke) and Parkinson’s disease to CreutzfeldtJakob disease, can lead to problems with movement or motor coordination.

Symptoms of muscle diseases may include weakness, spasticity, myoclonus and myalgia. Diagnostic procedures that may reveal muscular disorders include testing creatine kinase levels in the blood and electromyography (measuring electrical activity in muscles). In some cases, muscle biopsy may be done to identify a myopathy, as well as genetic testing to identify DNA abnormalities associated with specific myopathies and dystrophies.

A non-invasive elastography technique that measures muscle noise is undergoing experimentation to provide a way of monitoring neuromuscular disease. The sound produced by a muscle comes from the shortening of actomyosin filaments along the axis of the muscle. During contraction, the muscle shortens along its longitudinal axis and expands across the transverse axis, producing vibrations at the surface.[25]

The evolutionary origin of muscle cells in metazoans is a highly debated topic. In one line of thought scientists have believed that muscle cells evolved once and thus all animals with muscles cells have a single common ancestor. In the other line of thought, scientists believe muscles cells evolved more than once and any morphological or structural similarities are due to convergent evolution and genes that predate the evolution of muscle and even the mesoderm – the germ layer from which many scientists believe true muscle cells derive.

Schmid and Seipel argue that the origin of muscle cells is a monophyletic trait that occurred concurrently with the development of the digestive and nervous systems of all animals and that this origin can be traced to a single metazoan ancestor in which muscle cells are present. They argue that molecular and morphological similarities between the muscles cells in cnidaria and ctenophora are similar enough to those of bilaterians that there would be one ancestor in metazoans from which muscle cells derive. In this case, Schmid and Seipel argue that the last common ancestor of bilateria, ctenophora, and cnidaria was a triploblast or an organism with three germ layers and that diploblasty, meaning an organism with two germ layers, evolved secondarily due to their observation of the lack of mesoderm or muscle found in most cnidarians and ctenophores. By comparing the morphology of cnidarians and ctenophores to bilaterians, Schmid and Seipel were able to conclude that there were myoblast-like structures in the tentacles and gut of some species of cnidarians and in the tentacles of ctenophores. Since this is a structure unique to muscle cells, these scientists determined based on the data collected by their peers that this is a marker for striated muscles similar to that observed in bilaterians. The authors also remark that the muscle cells found in cnidarians and ctenophores are often contests due to the origin of these muscle cells being the ectoderm rather than the mesoderm or mesendoderm. The origin of true muscles cells is argued by others to be the endoderm portion of the mesoderm and the endoderm. However, Schmid and Seipel counter this skepticism about whether or not the muscle cells found in ctenophores and cnidarians are true muscle cells by considering that cnidarians develop through a medusa stage and polyp stage. They observe that in the hydrozoan medusa stage there is a layer of cells that separate from the distal side of the ectoderm to form the striated muscle cells in a way that seems similar to that of the mesoderm and call this third separated layer of cells the ectocodon. They also argue that not all muscle cells are derived from the mesendoderm in bilaterians with key examples being that in both the eye muscles of vertebrates and the muscles of spiralians these cells derive from the ectodermal mesoderm rather than the endodermal mesoderm. Furthermore, Schmid and Seipel argue that since myogenesis does occur in cnidarians with the help of molecular regulatory elements found in the specification of muscles cells in bilaterians that there is evidence for a single origin for striated muscle.[26]

In contrast to this argument for a single origin of muscle cells, Steinmetz et al. argue that molecular markers such as the myosin II protein used to determine this single origin of striated muscle actually predate the formation of muscle cells. This author uses an example of the contractile elements present in the porifera or sponges that do truly lack this striated muscle containing this protein. Furthermore, Steinmetz et al. present evidence for a polyphyletic origin of striated muscle cell development through their analysis of morphological and molecular markers that are present in bilaterians and absent in cnidarians, ctenophores, and bilaterians. Steimetz et al. showed that the traditional morphological and regulatory markers such as actin, the ability to couple myosin side chains phosphorylation to higher concentrations of the positive concentrations of calcium, and other MyHC elements are present in all metazoans not just the organisms that have been shown to have muscle cells. Thus, the usage of any of these structural or regulatory elements in determining whether or not the muscle cells of the cnidarians and ctenophores are similar enough to the muscle cells of the bilaterians to confirm a single lineage is questionable according to Steinmetz et al. Furthermore, Steinmetz et al. explain that the orthologues of the MyHc genes that have been used to hypothesize the origin of striated muscle occurred through a gene duplication event that predates the first true muscle cells (meaning striated muscle), and they show that the MyHc genes are present in the sponges that have contractile elements but no true muscle cells. Furthermore, Steinmetz et all showed that the localization of this duplicated set of genes that serve both the function of facilitating the formation of striated muscle genes and cell regulation and movement genes were already separated into striated myhc and non-muscle myhc. This separation of the duplicated set of genes is shown through the localization of the striated myhc to the contractile vacuole in sponges while the non-muscle myhc was more diffusely expressed during developmental cell shape and change. Steinmetz et al. found a similar pattern of localization in cnidarians with except with the cnidarian N. vectensis having this striated muscle marker present in the smooth muscle of the digestive track. Thus, Steinmetz et al. argue that the pleisiomorphic trait of the separated orthologues of myhc cannot be used to determine the monophylogeny of muscle, and additionally argue that the presence of a striated muscle marker in the smooth muscle of this cnidarian shows a fundamentally different mechanism of muscle cell development and structure in cnidarians.[27]

Steinmetz et al. continue to argue for multiple origins of striated muscle in the metazoans by explaining that a key set of genes used to form the troponin complex for muscle regulation and formation in bilaterians is missing from the cnidarians and ctenophores, and of 47 structural and regulatory proteins observed, Steinmetz et al. were not able to find even on unique striated muscle cell protein that was expressed in both cnidarians and bilaterians. Furthermore, the Z-disc seemed to have evolved differently even within bilaterians and there is a great deal diversity of proteins developed even between this clade, showing a large degree of radiation for muscle cells. Through this divergence of the Z-disc, Steimetz et al. argue that there are only four common protein components that were present in all bilaterians muscle ancestors and that of these for necessary Z-disc components only an actin protein that they have already argued is an uninformative marker through its pleisiomorphic state is present in cnidarians. Through further molecular marker testing, Steinmetz et al. observe that non-bilaterians lack many regulatory and structural components necessary for bilaterians muscle formation and do not find any unique set of proteins to both bilaterians and cnidarians and ctenophores that are not present in earlier, more primitive animals such as the sponges and amoebozoans. Through this analysis the authors conclude that due to the lack of elements that bilaterians muscles are dependent on for structure and usage, nonbilaterian muscles must be of a different origin with a different set regulatory and structural proteins.[27]

In another take on the argument, Andrikou and Arnone use the newly available data on gene regulatory networks to look at how the hierarchy of genes and morphogens and other mechanism of tissue specification diverge and are similar among early deuterostomes and protostomes. By understanding not only what genes are present in all bilaterians but also the time and place of deployment of these genes, Andrikou and Arnone discuss a deeper understanding of the evolution of myogenesis.[28]

In their paper Andrikou and Arnone argue that to truly understand the evolution of muscle cells the function of transcriptional regulators must be understood in the context of other external and internal interactions. Through their analysis, Andrikou and Arnone found that there were conserved orthologues of the gene regulatory network in both invertebrate bilaterians and in cnidarians. They argue that having this common, general regulatory circuit allowed for a high degree of divergence from a single well functioning network. Andrikou and Arnone found that the orthologues of genes found in vertebrates had been changed through different types of structural mutations in the invertebrate deuterostomes and protostomes, and they argue that these structural changes in the genes allowed for a large divergence of muscle function and muscle formation in these species. Andrikou and Arnone were able to recognize not only any difference due to mutation in the genes found in vertebrates and invertebrates but also the integration of species specific genes that could also cause divergence from the original gene regulatory network function. Thus, although a common muscle patterning system has been determined, they argue that this could be due to a more ancestral gene regulatory network being coopted several times across lineages with additional genes and mutations causing very divergent development of muscles. Thus it seems that myogenic patterning framework may be an ancestral trait. However, Andrikou and Arnone explain that the basic muscle patterning structure must also be considered in combination with the cis regulatory elements present at different times during development. In contrast with the high level of gene family apparatuses structure, Andrikou and Arnone found that the cis regulatory elements were not well conserved both in time and place in the network which could show a large degree of divergence in the formation of muscle cells. Through this analysis, it seems that the myogenic GRN is an ancestral GRN with actual changes in myogenic function and structure possibly being linked to later coopts of genes at different times and places.[28]

Evolutionarily, specialized forms of skeletal and cardiac muscles predated the divergence of the vertebrate/arthropod evolutionary line.[29][dead link] This indicates that these types of muscle developed in a common ancestor sometime before 700 million years ago (mya). Vertebrate smooth muscle was found to have evolved independently from the skeletal and cardiac muscle types.

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Breast Cancer Research | Home page

Dr. Lewis A. Chodosh is a physician-scientist who received a BS in Molecular Biophysics and Biochemistry from Yale University, and MD from Harvard Medical School, and a PhD. in Biochemistry from M.I.T. in the laboratory of Dr. Phillip Sharp.He performed his clinical training in Internal Medicine and Endocrinology at the Massachusetts General Hospital, after which he was a postdoctoral research fellow with Dr. Philip Leder at Harvard Medical School.Dr. Chodosh joined the faculty of the University of Pennsylvania in 1994, where he is currently a Professor in the Departments of Cancer Biology, Cell & Developmental Biology, and Medicine. He serves as Chairman of the Department of Cancer Biology, Associate Director for Basic Science of the Abramson Cancer Center, and Director of Cancer Genetics for the Abramson Family Cancer Research Institute at the University of Pennsylvania. Additionally, heis on the scientific advisory board for the Harvard Nurses’ Health Studies I and II.

Dr. Chodosh’s research focuses on genetic, genomic and molecular approaches to understanding breast cancer susceptibility and pathogenesis.

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Worlds Leading Biomarkers Congress | CPD Points …

Conference Series LLC Conferences invites all the participants across the globe to attend 8th International Conference on Biomarkers and Clinical Research during December 05-07, 2016 in Philadelphia, USA which includes prompt Keynote presentations, Oral talks, Poster presentations and Exhibitions.

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Conference Series LLC, the host of this conference is comprised of 3000+ Global Events with over 600+ Conferences, 1200+ Symposiums and 1200+Workshops on diverse Medical, Pharmaceutical, Clinical, Engineering, Science, Technology, Business and Management field is organizing conferences all over the globe.Biomarkers 2016 is the worlds largest multidisciplinarycancer meeting. Biomarkers and cancer conferencesinclude scientific keynote lectures, symposia, workshops, exhibitions with the support fromOncology SocietyandAmerican Oncology Society. Cancer conferences includeEuropean oncology conferences,surgical oncology global cancer conferenceandcancer conferences.

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Biomarkeris a characteristic diagnostic tool that is objectively measured and evaluated as an indicator of normalbiological processes, pathogenic processes or pharmacological responses to a therapeutic intervention. Biomarkers can be molecules, or genes, gene products, enzymes, or hormones referred asprotein biomarkers, analytical biomarkers, blood biomarkers, fluorescent biomarkers, circulating biomarkers and molecular biomarkers to quantify the degree of disease condition. Biomarkers are the measures used to perform a clinical assessment in case ofcancer biomarkers. They predict health states in individuals across populations so that appropriate therapeutic intervention can be planned. In the current scenario more than a thousand organizations and universities have contributed to the field of Biomarkers research especially molecular and cancer biomarkers, with its wings spreading across major organizations in USA, UK, Germany and China. The global biomarkers market is expected to grow from $29.3 billion in 2013 to $53.6 billion in 2018, a compound annual growth rate (CAGR) of 12.8%.Different types of biomarkers includeProtein biomarkers, Fluorescent biomarkers,Blood biomarkers, Cancer biomarkers, Analytical biomarkers andMolecular Biomarkers.

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Cancer biomarkers are used to detect the natural course of a tumour and are used to assess chances of developing cancer. Biomarkers in cancer screening play an important role in cancer detection and risk assessment to reduce cancer deaths. Tumour biomarkers are used to detect cancer development and progression. Uterine cervical cancer, endometrial cancer, trophoblastic neoplasms and ovarian cancer are gynaecologic malignancies for which tumour markers are in clinical use. Effective cancer biomarkers are used to reduce cancer mortality rates by facilitating diagnosis of cancers at early stages. Cancer biomarkers can also be used in diagnosis, risk assessment and recurrence of cancer.

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Track 3:Functional Genomics and Cytogenetic Biomarkers

The branch ofgenomicsthat determines the biological function and complex association of the genes and their products depicts thefunctional genomics. The measurable degree of these parameters through various processes and equipment inclusive of Next generation sequencing, Personalized genome sequencing and mi-RNA sequencing utilizing cellular entities to predict SNP biomarkers, immuno fluorescent biomarkers,oxidative stress biomarkers, si-RNA and mi-RNA will aid in better understanding of the disease outcome. Thecytogeneticbiomarkers are a feasible diagnostic tool to detect DNA and chromatin damage.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

MolecularBiomarkers Conference, September 15-17 2016 Berlin, Germany; Cervical Cancer Conference, September 22-23 2016, Vienna, Austria; Surgical Oncology Conference, October 23-25, 2017 Chicago, USA; 2nd Cervical Cancer Conference, October 29 -31, 2017 Brussels, Belgium; Cancer World Conventaion, November 26-28, 2017 Frankfurt, Germany; 89thAnnual Italian Society of Urology Congress, October 15-18, 2016 Venezia Italy; 62ndAnnual Meeting of Czech Urological Society, October 19-21, 2016 Czech Budejovice, Czech Republic; ESMO 2017 Congress, September 08-12, 2017 Madrid, Spain; International Cancer Education Conference, September 14-16, 2016 Bethesda, USA; 16th Biennial Meeting of the International Gynecologic Cancer Society, October 29-31 Lisbon, Portugal; World Cancer Congress , October 31 – November 3 Paris, France, Malaysia Urology Conference, November 24-28,2016 Kuala Lumpur, Malaysia; Annual AUA Meeting, May 12-16, 2017 Boston, USA.

Track 4: Functional Transcriptomics and Profiling Techniques

The newly emerged discipline in the field of cytogenetic andfunctional genomicsis Molecular imaging biomarkers, aids in better visualization of the cellular function and the follow-up of the molecular process in living organisms without penetrance. Roche Diagnostics, GlaxoSmithKline, Siemens Healthcare, GE Healthcare and Merck & Co are a few of the key players in this market as observed inbiomarkerscongress. The functional genomics and cytogenetic market is estimated to reach 150M$ by 2017.Functional genomicscovers various areas of biomarkers applications like Next gen sequencing, Personalized genome sequencing, Micro RNA sequencing and SNP biomarkers.Cytogenetic biomarkersinclude Immuno flouscent biomarkers, Molecular imaging biomarkers, Oxidative Stress Biomarkers and si-RNA and mi-RNA.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

12th Euro Global Summit onCancer Therapy, September 26-28 2016, London, UK; 13th GlobalOncologistsSummit, October 17-19 2016, Dubai, UAE; Global Summit onMelanoma, September 25-26, 2017 Rome, Italy; Multiple Myeloma Conference, October 15-17, 2017 Milan, Italy; Radiology Conference, October 23-25, 2017 Chicago, USA; 6thAnnual Asia-Pacific Prostate Society Conference, September 9 -10 Seoul, Korea; 68thAnnual German Society of Urology Congress, September 28-October 1, 2016 Leipzig, Germany; 72ndAnnual Canadian Urological Association Meeting, June 25-27, 2017 Toronto, Canada; 4th Annual Immuno-Oncology Summit, August 29-September 2, 2016 Boston, USA; 2nd Biomarkers, Diagnostics & Clinical Research Conference, September 19-20 Boston, USA; Biomarkers and Targeted Therapeutics in Sjgrens (BATTS) Conference, September 19-22, 2016 Oklahoma, USA; NCRI Cancer Conference, November 6-9, 2016 Liverpool, UK; 6th Munich Biomarker Conference, November 29-30, 2016 Munchen, Germany; Annual Meeting of American Association of Genitourinary Surgeons, April 27-30, 2017 Florida, USA.

Track 5:Biomarkers in Clinical Research and Development

TheBiomarkersfinds its valuable application in the field ofClinical researchand development by case study and data management as evident through Biomarker conferences. The Bioethics and intellectual property right establishes the norms and standard of conduct of hypothesis with respect to clinical validation of biomarkers. The incorporation of biomarker inclinical trialsfor various disease conditions will put forth a valid diagnostic and therapeutic approach utilizing even the medical devices to detectclinical biomarkers. Currently this is the booming industry. Most of the reputed organizations like Pfizer, Parexel and Quintiles are into clinical research and development. The companies, hospitals and clinical research organizations are the hot spots for conducting clinical research with its growth rate increasing exponentially by an estimated 75B$ by 2016.In clinical research and development, clinical biomarkers are used in case study anddata management, clinical trials and in medical devices.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

Oral Cancer Conference, August 18-20 2016, Portland, USA; Surgical Oncology Conference, August 29-31 2016, Sao Paulo, Brazil; Cancer Diagnostics Conference, May 8-10, 2017 Dubai, UAE; 3rd Prostate Cancer Conference, June 26-28, 2017 Baltimore, USA; Lymphoma Conference, July 24-26, 2017 Rome, Italy; 14thUrological Association of Asia Congress, July 20-24, 2016 Suntec, Singapore; 17thAsia-Pacific Prostate Cancer Conference, August 31- September 3, 2016 Melbourne, Australia; ASCO Genitourinary Cancers Symposium, February, 16-18, 2017 Orlando, USA; 2ndInternational Prostate Cancer Symposium, August 6 -7, 2016 Moscow, Russia, 13thMeeting of the EAU Robotic Urology Section, September 14-16, 2016 Milan Italy; 11thAnnual Congress of Russian Association of Oncological Urology, 05-07, 2016 Moscow, Russia; 36thInternational Urology Congress, October 20-23, 2016 Argentina, South America, 27thInternational Prostate Cancer Update, January 24-27, 2017 Colorado, USA.

Track 6:Omics Technologies in Biomarkers Discovery and Validation

Biomarkersplay a critical role in disease diagnosis and treatment, especially for the early detection of cancer, to enable screening of asymptomatic populations. Recent omics technologies, such as Transcriptomics,genomicsand proteomics approaches besides Metabolomics are accelerating the rate of biomarker discovery. The incorporation of techniques like microarray data analysis, computational biology, data mining methods, Transcriptomics and profiling techniques are playing a crucial role in the validation of biomarkers. Since theHuman Genome Projectwas completed in April 2003, genome-wide association studies (GWAS) have contributed toward a greater understanding of the genetic basis of complex diseases and advances in high-throughput technologies. This has enabled researchers to rapidly map the genome of vertebrates, invertebrates and pathogens through cost-effective methods. The applications ofBioinformaticstool in biomarker research is the current emerging field promoting better diagnosable parameters. The global omics market was valued at nearly $2.8 billion in 2011, nearly $3.2 billion in 2012, and is forecast to grow to nearly $7.5 billion by 2017 after increasing at a compound annual growth rate (CAGR) of 18.7%. The omics technology segment holds the largest share of ~75% of the biomarker discovery market, primarily due to the increase in adoption ofproteomicsand genomics technologies, globally. There are several approaches in biomarkers discovery and validation likegenomics and proteomicapproaches, Microarray data analysis, Data mining methods and Transcriptomics and profiling techniques by making use of Computational biology and Application of Bioinformatics in biomarker discovery.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

2ndInternational Conference onProstate Cancerand Treatment, August 22-23, 2016, USA, Experts Meeting onGynaecologic Oncology, May 19-21, 2016 , USACancer DiagnosticsConference and Expo, June 13-15, 2016, Italy, 11thAsia PacificOncologistsConference, July 11-13, 2016, Kualalumpur, Malaysia, Global Summit onMelanoma and Carcinoma, July 14-15, 2016, Australia, Controversies inBreast Cancer (CoBRA) October 22-24, 2015, Australia, 16th Biennial Meeting of the InternationalGynaecologic CancerSociety, 29-31stOctober 2016, Lisbon, WSMOS FallOncologyConference, 30thOctober 2015,Uk, Next NRGOncologySemiannual Meeting, Jan 21-24th ,2015, Atlanta, Progress and Controversies inGynaecologic OncologyConference, 16-17 January 2015, Spain; 12thCancer ConferencesEurope September 26-28, 2016 London, UK; 12thOncology ConferencesEurope September 26-28, 2016 London, UK; 12thCancer Science EventsEurope September 26-28, 2016 London, UK;Cancer Global ConferencesMiddle East November 21-23, 2016 Dubai, UAE;Oncology ConferencesNovember 21-23, 2016 Dubai, UAE;Worldwide Cancer EventsNovember 21-23, 2016 Dubai, UAE;Breast Cancer ConferencesOctober 03-05, 2016 London, UK;Womens Health ConferencesOctober 03-05, 2016 London, UK.

Track 7:Biomarkers of Exposure Response and Susceptibility

Biomarkersof exposure are important in toxicology, because they are an indicator of internal exposure and genetic susceptibility to drug, chemicals or the amount ofchemicalexposure that got accumulated in the body. Significant advances have been made in developing analytical methods that detect and quantify many natural or synthetic toxins or their breakdown products in thebiologicalmatrix. The ability to accurately measure biomarkers of exposure depends upon an adequate understanding of the chemistry and toxicology of the substance under consideration.Epigenetic biomarkersalso quantify the degree of exposure to toxic dynamic and pharmacodynamics parameters inpathologicaland biochemical changes occurring due to exposure to harmful agents, brought to light by toxic dynamics meetings andpharmacodynamicsworkshops. This emerging field of study is gaining importance in industry with an estimate of more than 7,287 personnel conducting study across the globe. While studying the response and susceptibility parameters like toxic dynamic and pharmacodynamic parameters are taken into consideration to measure the internal exposure and genetic susceptibility to drugs and chemicals.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

MolecularBiomarkers Conference, September 15-17 2016 Berlin, Germany; Cervical Cancer Conference, September 22-23 2016, Vienna, Austria; Surgical Oncology Conference, October 23-25, 2017 Chicago, USA; 2nd Cervical Cancer Conference, October 29 -31, 2017 Brussels, Belgium; Cancer World Conventaion, November 26-28, 2017 Frankfurt, Germany; 89thAnnual Italian Society of Urology Congress, October 15-18, 2016 Venezia Italy; 62ndAnnual Meeting of Czech Urological Society, October 19-21, 2016 Czech Budejovice, Czech Republic; ESMO 2017 Congress, September 08-12, 2017 Madrid, Spain; International Cancer Education Conference, September 14-16, 2016 Bethesda, USA; 16th Biennial Meeting of the International Gynecologic Cancer Society, October 29-31 Lisbon, Portugal; World Cancer Congress , October 31 – November 3 Paris, France, Malaysia Urology Conference, November 24-28,2016 Kuala Lumpur, Malaysia; Annual AUA Meeting, May 12-16, 2017 Boston, USA.

Track 8:Biomarkers for Disorders

Biomarkers are the characteristicbiological measurableindictors for the various disorders if occurring inabnormal levels. These are used as quantitative entities for neurological disorders, genetic disorders, metabolic disorders, cardiac disorders and inborn errors. The present era is focusing on the cancer research utilizing biomarkers as indictor of disease conditions. The lungcancer biomarkersand biomarkers for breast cancer are inclusive of genes, enzymes, proteins and cell surface entitles. Registering a compound annual growth rate of 14.60% from 2011 to 2018, the market foroncology biomarkerswas valued at $13.16 billion in 2011 and is expected to be worth $29.78 billion in 2018.Biomarkers are also used in diagnosing and treating various diseases and disorders likeNeurological disorders, Genetic disorders,Metabolic disorders, Cardiac disorders, Inborn errors, Lung cancer and Breast cancer.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

12th Euro Global Summit onCancer Therapy, September 26-28 2016, London, UK; 13th GlobalOncologistsSummit, October 17-19 2016, Dubai, UAE; Global Summit onMelanoma, September 25-26, 2017 Rome, Italy; Multiple Myeloma Conference, October 15-17, 2017 Milan, Italy; Radiology Conference, October 23-25, 2017 Chicago, USA; 6thAnnual Asia-Pacific Prostate Society Conference, September 9 -10 Seoul, Korea; 68thAnnual German Society of Urology Congress, September 28-October 1, 2016 Leipzig, Germany; 72ndAnnual Canadian Urological Association Meeting, June 25-27, 2017 Toronto, Canada; 4th Annual Immuno-Oncology Summit, August 29-September 2, 2016 Boston, USA; 2nd Biomarkers, Diagnostics & Clinical Research Conference, September 19-20 Boston, USA; Biomarkers and Targeted Therapeutics in Sjgrens (BATTS) Conference, September 19-22, 2016 Oklahoma, USA; NCRI Cancer Conference, November 6-9, 2016 Liverpool, UK; 6th Munich Biomarker Conference, November 29-30, 2016 Munchen, Germany; Annual Meeting of American Association of Genitourinary Surgeons, April 27-30, 2017 Florida, USA.

Track 9:Techniques to Maximize Biomarker Identification

Biomarkersare the existing bimolecular and integral indictors of disease condition of biological systems. The techniques used to identify and maximize the expression of biomarkers include RT-PCR genotyping, molecular imaging and dynamics,biochemicalassay and profiling,immunologicaltechniques and chromatographic techniques. A wider approach towards identification of biomarkers lies in theproteomicapproach besides utilizing biosensors as a compatible tool for evaluation of biomarker levels in the biological systems. Most of the companys focus is on generating cost effective durable profiling techniques and equipment to quantify biomarkers within a short span of time. Johnson & Johnson, GlaxoSmithKline Plc., GEHealthcare, Affymetrix Inc., Bio-Rad Laboratories Inc. are a few of the key players in this market. Partnerships, agreements,collaborations, & mergers and acquisitions are the key business strategies adopted by market participants to ensure their growth in the market.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

Oral Cancer Conference, August 18-20 2016, Portland, USA; Surgical Oncology Conference, August 29-31 2016, Sao Paulo, Brazil; Cancer Diagnostics Conference, May 8-10, 2017 Dubai, UAE; 3rd Prostate Cancer Conference, June 26-28, 2017 Baltimore, USA; Lymphoma Conference, July 24-26, 2017 Rome, Italy; 14thUrological Association of Asia Congress, July 20-24, 2016 Suntec, Singapore; 17thAsia-Pacific Prostate Cancer Conference, August 31- September 3, 2016 Melbourne, Australia; ASCO Genitourinary Cancers Symposium, February, 16-18, 2017 Orlando, USA; 2ndInternational Prostate Cancer Symposium, August 6 -7, 2016 Moscow, Russia, 13thMeeting of the EAU Robotic Urology Section, September 14-16, 2016 Milan Italy; 11thAnnual Congress of Russian Association of Oncological Urology, 05-07, 2016 Moscow, Russia; 36thInternational Urology Congress, October 20-23, 2016 Argentina, South America, 27thInternational Prostate Cancer Update, January 24-27, 2017 Colorado, USA.

Track 10:Biomarkers in Nano science

Nano science is the study of structures and materials on the scale of nanometres.Nanotechnologymay be able to create many new materials and devices with a vast range of applications in medicine, electronics, biomaterialsenergy production, and consumer products. Nanotechnology is evolving rapidly with nanoparticles events. An estimated 1 million workers in R&D and production are involved in the field of Nano science and nanomaterial generation. Interaction of biomarkers with nanoparticles aids in identification and validation throughbiologicaland biomedical applications. Current marketholds Nano devices and nanomaterial for identification, quantifying, calibrating and even in surgeries. The US leads the world in investing and in the number ofNanotech Companies. Global consumption ofnanomaterialis expected to grow in unit terms from nearly 225,060 metric tons in 2014 to nearly 584,984 metric tons in 2019, a compound annual growth rate (CAGR) of 21.1% for the period of 2014 to 2019.Nano science is another rapidly growing area where application ofnanotechnologytobiomarkersis used for biological and biomedical applications like Nano devices.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

MolecularBiomarkers Conference, September 15-17 2016 Berlin, Germany; Cervical Cancer Conference, September 22-23 2016, Vienna, Austria; Surgical Oncology Conference, October 23-25, 2017 Chicago, USA; 2nd Cervical Cancer Conference, October 29 -31, 2017 Brussels, Belgium; Cancer World Conventaion, November 26-28, 2017 Frankfurt, Germany; 89thAnnual Italian Society of Urology Congress, October 15-18, 2016 Venezia Italy; 62ndAnnual Meeting of Czech Urological Society, October 19-21, 2016 Czech Budejovice, Czech Republic; ESMO 2017 Congress, September 08-12, 2017 Madrid, Spain; International Cancer Education Conference, September 14-16, 2016 Bethesda, USA; 16th Biennial Meeting of the International Gynecologic Cancer Society, October 29-31 Lisbon, Portugal; World Cancer Congress , October 31 – November 3 Paris, France, Malaysia Urology Conference, November 24-28,2016 Kuala Lumpur, Malaysia; Annual AUA Meeting, May 12-16, 2017 Boston, USA.

Track 11: Biomarkers in Toxicology

Biomarkers are used for detecting kidney toxicity. Kidney toxicity is detected using biomarkers serum creatinine and blood urea nitrogen. Many qualified biomarkers are used to develop products to conquer the kidney toxicity problem. Latest research on biomarkers discovered new approaches to predicting and recognising toxic exposures of macromolecular adducts and their potential consequences.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

12th Euro Global Summit onCancer Therapy, September 26-28 2016, London, UK; 13th GlobalOncologistsSummit, October 17-19 2016, Dubai, UAE; Global Summit onMelanoma, September 25-26, 2017 Rome, Italy; Multiple Myeloma Conference, October 15-17, 2017 Milan, Italy; Radiology Conference, October 23-25, 2017 Chicago, USA; 6thAnnual Asia-Pacific Prostate Society Conference, September 9 -10 Seoul, Korea; 68thAnnual German Society of Urology Congress, September 28-October 1, 2016 Leipzig, Germany; 72ndAnnual Canadian Urological Association Meeting, June 25-27, 2017 Toronto, Canada; 4th Annual Immuno-Oncology Summit, August 29-September 2, 2016 Boston, USA; 2nd Biomarkers, Diagnostics & Clinical Research Conference, September 19-20 Boston, USA; Biomarkers and Targeted Therapeutics in Sjgrens (BATTS) Conference, September 19-22, 2016 Oklahoma, USA; NCRI Cancer Conference, November 6-9, 2016 Liverpool, UK; 6th Munich Biomarker Conference, November 29-30, 2016 Munchen, Germany; Annual Meeting of American Association of Genitourinary Surgeons, April 27-30, 2017 Florida, USA.

Track 12: Biomarkers in Microbial Infections

Biomarkers can be used for microbial infections and can be used for early diagnosis and prognosis of the disease. The diagnostic performance of biomarkers is usually measured in terms of sensitivity.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

Oral Cancer Conference, August 18-20 2016, Portland, USA; Surgical Oncology Conference, August 29-31 2016, Sao Paulo, Brazil; Cancer Diagnostics Conference, May 8-10, 2017 Dubai, UAE; 3rd Prostate Cancer Conference, June 26-28, 2017 Baltimore, USA; Lymphoma Conference, July 24-26, 2017 Rome, Italy; 14thUrological Association of Asia Congress, July 20-24, 2016 Suntec, Singapore; 17thAsia-Pacific Prostate Cancer Conference, August 31- September 3, 2016 Melbourne, Australia; ASCO Genitourinary Cancers Symposium, February, 16-18, 2017 Orlando, USA; 2ndInternational Prostate Cancer Symposium, August 6 -7, 2016 Moscow, Russia, 13thMeeting of the EAU Robotic Urology Section, September 14-16, 2016 Milan Italy; 11thAnnual Congress of Russian Association of Oncological Urology, 05-07, 2016 Moscow, Russia; 36thInternational Urology Congress, October 20-23, 2016 Argentina, South America, 27thInternational Prostate Cancer Update, January 24-27, 2017 Colorado, USA.

Track 13: Biomarkers in Drug Discovery

The role of Biomarkers in drug discovery and development is to understand the pathophysiology of disease. Biomarkers can be a clinical tool for drug discovery and development by confirming the efficacy and safety to the right patient. Biomarkers can be used in understanding the mechanism of drug.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

MolecularBiomarkers Conference, September 15-17 2016 Berlin, Germany; Cervical Cancer Conference, September 22-23 2016, Vienna, Austria; Surgical Oncology Conference, October 23-25, 2017 Chicago, USA; 2nd Cervical Cancer Conference, October 29 -31, 2017 Brussels, Belgium; Cancer World Conventaion, November 26-28, 2017 Frankfurt, Germany; 89thAnnual Italian Society of Urology Congress, October 15-18, 2016 Venezia Italy; 62ndAnnual Meeting of Czech Urological Society, October 19-21, 2016 Czech Budejovice, Czech Republic; ESMO 2017 Congress, September 08-12, 2017 Madrid, Spain; International Cancer Education Conference, September 14-16, 2016 Bethesda, USA; 16th Biennial Meeting of the International Gynecologic Cancer Society, October 29-31 Lisbon, Portugal; World Cancer Congress , October 31 – November 3 Paris, France, Malaysia Urology Conference, November 24-28,2016 Kuala Lumpur, Malaysia; Annual AUA Meeting, May 12-16, 2017 Boston, USA.

Track 14: Personalized Medicine and Data Analysis

Recently there has been enhanced and advanced biomedical technology such as high-throughput molecular imaging and microarrays to monitor SNPs, gene and protein expressions, to provide exhaustive situations for individuals. The biological and medical status from such data sets, which are viewed as biomarkers in a wide sense to help to do identification, association, and prediction studies for phenotypes such as cancer subtypes, prognosis, treatment responsiveness, and adverse reactions for personalized medicine.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

12th Euro Global Summit onCancer Therapy, September 26-28 2016, London, UK; 13th GlobalOncologistsSummit, October 17-19 2016, Dubai, UAE; Global Summit onMelanoma, September 25-26, 2017 Rome, Italy; Multiple Myeloma Conference, October 15-17, 2017 Milan, Italy; Radiology Conference, October 23-25, 2017 Chicago, USA; 6thAnnual Asia-Pacific Prostate Society Conference, September 9 -10 Seoul, Korea; 68thAnnual German Society of Urology Congress, September 28-October 1, 2016 Leipzig, Germany; 72ndAnnual Canadian Urological Association Meeting, June 25-27, 2017 Toronto, Canada; 4th Annual Immuno-Oncology Summit, August 29-September 2, 2016 Boston, USA; 2nd Biomarkers, Diagnostics & Clinical Research Conference, September 19-20 Boston, USA; Biomarkers and Targeted Therapeutics in Sjgrens (BATTS) Conference, September 19-22, 2016 Oklahoma, USA; NCRI Cancer Conference, November 6-9, 2016 Liverpool, UK; 6th Munich Biomarker Conference, November 29-30, 2016 Munchen, Germany; Annual Meeting of American Association of Genitourinary Surgeons, April 27-30, 2017 Florida, USA.

Track 15: Nutritional Biomarkers

A nutritional biomarker can be any biological specimen that is an indicator of nutritional status with respect to intake or metabolism of dietary constituents. It can be a biochemical, functional or clinical index of status of an essential nutrient or other dietary constituent. Nutritional biomarkers may be interpreted more broadly as a biologic consequence of dietary intake or dietary patterns.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

Oral Cancer Conference, August 18-20 2016, Portland, USA; Surgical Oncology Conference, August 29-31 2016, Sao Paulo, Brazil; Cancer Diagnostics Conference, May 8-10, 2017 Dubai, UAE; 3rd Prostate Cancer Conference, June 26-28, 2017 Baltimore, USA; Lymphoma Conference, July 24-26, 2017 Rome, Italy; 14thUrological Association of Asia Congress, July 20-24, 2016 Suntec, Singapore; 17thAsia-Pacific Prostate Cancer Conference, August 31- September 3, 2016 Melbourne, Australia; ASCO Genitourinary Cancers Symposium, February, 16-18, 2017 Orlando, USA; 2ndInternational Prostate Cancer Symposium, August 6 -7, 2016 Moscow, Russia, 13thMeeting of the EAU Robotic Urology Section, September 14-16, 2016 Milan Italy; 11thAnnual Congress of Russian Association of Oncological Urology, 05-07, 2016 Moscow, Russia; 36thInternational Urology Congress, October 20-23, 2016 Argentina, South America, 27thInternational Prostate Cancer Update, January 24-27, 2017 Colorado, USA.

Track 16: Current Research Concepts in Biomarkers

Current Research Concepts in Biomarkers include research in glucose disorders, Biomarkers in disease and health, technologies in biomarker discovery, translational biomarker research and the use of biomarkers in pre-clinical and clinical studies.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

MolecularBiomarkers Conference, September 15-17 2016 Berlin, Germany; Cervical Cancer Conference, September 22-23 2016, Vienna, Austria; Surgical Oncology Conference, October 23-25, 2017 Chicago, USA; 2nd Cervical Cancer Conference, October 29 -31, 2017 Brussels, Belgium; Cancer World Conventaion, November 26-28, 2017 Frankfurt, Germany; 89thAnnual Italian Society of Urology Congress, October 15-18, 2016 Venezia Italy; 62ndAnnual Meeting of Czech Urological Society, October 19-21, 2016 Czech Budejovice, Czech Republic; ESMO 2017 Congress, September 08-12, 2017 Madrid, Spain; International Cancer Education Conference, September 14-16, 2016 Bethesda, USA; 16th Biennial Meeting of the International Gynecologic Cancer Society, October 29-31 Lisbon, Portugal; World Cancer Congress , October 31 – November 3 Paris, France, Malaysia Urology Conference, November 24-28,2016 Kuala Lumpur, Malaysia; Annual AUA Meeting, May 12-16, 2017 Boston, USA

Track 17: Oncologists: Biomarkers

An oncologist is a doctor who specializes in treating people with cancer. The oncologists research into the causes, prevention, detection, and treatment of cancer is going on in many medical centres throughout the world.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

12th Euro Global Summit onCancer Therapy, September 26-28 2016, London, UK; 13th GlobalOncologistsSummit, October 17-19 2016, Dubai, UAE; Global Summit onMelanoma, September 25-26, 2017 Rome, Italy; Multiple Myeloma Conference, October 15-17, 2017 Milan, Italy; Radiology Conference, October 23-25, 2017 Chicago, USA; 6thAnnual Asia-Pacific Prostate Society Conference, September 9 -10 Seoul, Korea; 68thAnnual German Society of Urology Congress, September 28-October 1, 2016 Leipzig, Germany; 72ndAnnual Canadian Urological Association Meeting, June 25-27, 2017 Toronto, Canada; 4th Annual Immuno-Oncology Summit, August 29-September 2, 2016 Boston, USA; 2nd Biomarkers, Diagnostics & Clinical Research Conference, September 19-20 Boston, USA; Biomarkers and Targeted Therapeutics in Sjgrens (BATTS) Conference, September 19-22, 2016 Oklahoma, USA; NCRI Cancer Conference, November 6-9, 2016 Liverpool, UK; 6th Munich Biomarker Conference, November 29-30, 2016 Munchen, Germany; Annual Meeting of American Association of Genitourinary Surgeons, April 27-30, 2017 Florida, USA.

Track 18: Biomarkers in Market

With the emerging importance to quantify and validate various disease conditions, many organizations, companies, and universities have stepped forward to contribute to the field of biomarkers discovery and quantification for better prognosis of disease conditions. The Biomarkers is the second leading industry after clinical research and development. The Biomarkers in pharmaceutical industry, biomarkers in oncology & other diseases has attained utmost recognition due to global spread of cancer and other diseases. The Biomarkers validation and regulatory affairs and diagnostic biomarker are booming industry with an estimate of more than 270 companies involved across the globe in 2016.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

MolecularBiomarkers Conference, September 15-17 2016 Berlin, Germany; Cervical Cancer Conference, September 22-23 2016, Vienna, Austria; Surgical Oncology Conference, October 23-25, 2017 Chicago, USA; 2nd Cervical Cancer Conference, October 29 -31, 2017 Brussels, Belgium; Cancer World Conventaion, November 26-28, 2017 Frankfurt, Germany; 89thAnnual Italian Society of Urology Congress, October 15-18, 2016 Venezia Italy; 62ndAnnual Meeting of Czech Urological Society, October 19-21, 2016 Czech Budejovice, Czech Republic; ESMO 2017 Congress, September 08-12, 2017 Madrid, Spain; International Cancer Education Conference, September 14-16, 2016 Bethesda, USA; 16th Biennial Meeting of the International Gynecologic Cancer Society, October 29-31 Lisbon, Portugal; World Cancer Congress , October 31 – November 3 Paris, France, Malaysia Urology Conference, November 24-28,2016 Kuala Lumpur, Malaysia; Annual AUA Meeting, May 12-16, 2017 Boston, USA.

Track 19: Biomarkers Case Reports

Biomarkers case reports play a crucial role in moving new treatments to patients who need those most, securing data so regulatory approvals can be obtained and new drugs can move into widespread clinical practice.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

12th Euro Global Summit onCancer Therapy, September 26-28 2016, London, UK; 13th GlobalOncologistsSummit, October 17-19 2016, Dubai, UAE; Global Summit onMelanoma, September 25-26, 2017 Rome, Italy; Multiple Myeloma Conference, October 15-17, 2017 Milan, Italy; Radiology Conference, October 23-25, 2017 Chicago, USA; 6thAnnual Asia-Pacific Prostate Society Conference, September 9 -10 Seoul, Korea; 68thAnnual German Society of Urology Congress, September 28-October 1, 2016 Leipzig, Germany; 72ndAnnual Canadian Urological Association Meeting, June 25-27, 2017 Toronto, Canada; 4th Annual Immuno-Oncology Summit, August 29-September 2, 2016 Boston, USA; 2nd Biomarkers, Diagnostics & Clinical Research Conference, September 19-20 Boston, USA; Biomarkers and Targeted Therapeutics in Sjgrens (BATTS) Conference, September 19-22, 2016 Oklahoma, USA; NCRI Cancer Conference, November 6-9, 2016 Liverpool, UK; 6th Munich Biomarker Conference, November 29-30, 2016 Munchen, Germany; Annual Meeting of American Association of Genitourinary Surgeons, April 27-30, 2017 Florida, USA.

Track 20: Biomarkers: Entrepreneur Investments Meet

A key ingredient in successful entrepreneurship is self-knowledge. Biomarkers-2016 aims to bring together all existing and budding bio entrepreneurs to share experiences and present new innovations and challenges in cancer community. Each year, over a million companies are started in the world with about 510 of them classified as high technology companies. Turning ideas into business ventures is tricky and the opportunity-recognition step is critical in new venture creation. This gestalt in the entrepreneur’s perception of the relationship between the invention and final product is refined into a business model that describes how the venture will make money or provide an appropriate return to the potential investors. Cancer science is complex and rapidly changing and requires a specialized knowledge to understand the value of the innovation and its competitive position in the industry. This three day community-wide conference will be a highly interactive forum that will bring experts in areas ranging from Biomarkers to signalling pathways to novel therapeutic approaches to the scientific hub. In addition to our outstanding speakers, we will also showcase short talks and poster presentations from submitted abstracts .The speakers will discuss state-of-the-art treatments, current guidelines, clinical challenges, and review recent trial data and emerging therapeutic approaches with the potential to impact clinical practice. This session will include combined efforts of World-renowned speakers, the most recent techniques, developments, and the newest updates in Biomarkers.

Related Biomarkers Conferences | Cancer Conferences | Biomarkers Meetings

Oral Cancer Conference, August 18-20 2016, Portland, USA; Surgical Oncology Conference, August 29-31 2016, Sao Paulo, Brazil; Cancer Diagnostics Conference, May 8-10, 2017 Dubai, UAE; 3rd Prostate Cancer Conference, June 26-28, 2017 Baltimore, USA; Lymphoma Conference, July 24-26, 2017 Rome, Italy; 14thUrological Association of Asia Congress, July 20-24, 2016 Suntec, Singapore; 17thAsia-Pacific Prostate Cancer Conference, August 31- September 3, 2016 Melbourne, Australia; ASCO Genitourinary Cancers Symposium, February, 16-18, 2017 Orlando, USA; 2ndInternational Prostate Cancer Symposium, August 6 -7, 2016 Moscow, Russia, 13thMeeting of the EAU Robotic Urology Section, September 14-16, 2016 Milan Italy; 11thAnnual Congress of Russian Association of Oncological Urology, 05-07, 2016 Moscow, Russia; 36thInternational Urology Congress, October 20-23, 2016 Argentina, South America, 27thInternational Prostate Cancer Update, January 24-27, 2017 Colorado, USA.

OMICS International hosted the 6thInternational Conference on Biomarkers & Clinical Research (Biomarkers 2015) during August 31September 02 at Toronto Airport Marriott Hotel, Toronto, Canada. The scientific meeting has laid path for the designing and development of research methodologies with the theme impact of Lab to industry as bio-signatures to therapeutic discovery.

Biomarkers 2015 was fortunate to acquire support from association and societies – Clinical Research Association of Canada (CRAC), Hypertension Canada, International Society for Cellular Therapy (ISCT), The Egyptian Biophysical Society and media partners -Biomarkers Profile Corporation, Gate2Biotech, The Technology Networks, Council of European Bio-Region, Oncology Education and Edinburgh Science Triangle.

The highlights of the meeting were the eponymous lectures, delivered byDr. Claude Prigent, University of Rennes, France, Dr. Trevor G Marshall, Autoimmunity Research Foundation, USA, Dr. Alain Moreau, Sainte-Justine University Hospital, Canada, Dr. Sergey Suchkov, I. M. Sechenov First Moscow State Medical University, Russia, Dr. Alexander M Buko, Human Metabolome Technologies, USA, Dr. Chee Gee See, Proteome Sciences, UK, Dr. Biswendu B Goswami, FDA Center for Food Safety and Applied Nutrition, USA.

Biomarkers 2015 held pre-conference workshop on August 1, 2015 in Mumbai University, India under the supervision of Prof. K. P. Mishra, Founder President of Society of Radiation Research, India. The workshop gathered 650+ participants inclusive of students, faculty, societies and industrial personnel.

The conference held 2 workshops under the supervision of Prof. Sergey Suchkov, I. M. Sechenov First Moscow State Medical University, Russia; Dr. Trevor G Marshall, Autoimmunity Research Foundation, USA and their team from Czech Republic and Prof. Youhe Gao, Beijing Normal University, China.

Biomarkers-2014

The5thInternational Conference on Biomarkers & Clinical Research, the Biomarker-2014, was held during April 15-17, 2014 at Oxford, UK.

Biomarkers-2014 has taken up the scientific thoughts towards proving the importance of accurate diagnostics to be prevital towards the curing efficacy. The scientific meeting has laid path for the designing and development of research methodologies with the theme impact of Diagnostic significance of the therapeutic bio-clinical molecule.

The conference was greeted by the welcome message from Presidents desk at the European Association for Predictive, Preventive and Personalised Medicine (EPMA), Brussels, EU. The support was extended through the PPPM workshop being conducted with the PPPM representatives from Russia, USA, Czech Republic and Saudi Arabia. The conference has gathered support from Everest Biotech, EuroScienceCon, Biomarkers Profile Corporation, ArrayMold, BioNews, Edinburgh Science Triangle, Biowebspin, The Technology Networks, European Biotechnology Thematic Network Association, Visiongain and Current Partnering as the media partners. In addition SCIENION has participated at the conference as Exhibitor at this conference.

The program highlights of the meeting were the eponymous lectures, delivered byDr. Sergey Suchkovfrom I.M.Sechenov First Moscow State Medical University, Russia;Dr.Pavel Vodickafrom Institute of Experimental Medicine, Czech Republic;Dr.Ondrej Topolcan from Charles University in Prague, Czech Republic;Dr. Claudio Nicolinifrom University of Genova, Italy andDr. Claude Prigentfrom University of Rennes, France.

Biomarkers-2013

OMICS Grouporganized 4thInternational Conference on Biomarkers & Clinical Research, during July 15-17, 2013 at Philadelphia, USA under the theme of Impact of Biomarkers Development in Health Diagnostics and Clinical Research.

The conference was initiated with a series of invited lectures delivered by Dr. Jizu Yi from BD Diagnostics, USA; Dr. Yaping Tian from PLA General Hospital, China; Dr. Leticia Cano from Biomarker Profile Corporation, USA and Dr. Lawrence Greenfield from Affymetrix, USA.

Biomarkers-2012

The3rd International Conference on Biomarkers & Clinical Research, organized by theOMICS Groupwas held onJuly 2-4, 2012 at Embassy Suites Las Vegas, USA under the theme of “Commercialization of Biomarkers”. There were about 200 delegates representing 25 countries from different corners of the world who made this conference a big success in the field ofBiomarkers and Clinical Research.

The conference was initiated with a series of invited lectures delivered by both Honorable Guests and members of the Keynote forum. The list includesDr. Josip Blonder, Frederick National Laboratory for Cancer Research (NIH), USA;Dr. Marcel M. Daadi, Stanford University, USA;Dr. Ting-Chao Chou, Memorial Sloan-Kettering Cancer Center, USA;Dr. Jacob Kagan, National Cancer Institute, NIH, USA;Dr. Michael Sullivan, Worldwide Clinical Trials-Drug Development Solutions, USA;Dr. Hitoshi Sohma, Sapporo Medical University Center for Medical Education, Japan andDr. Da Zhi Liu, University of California at Devis, USA.All the above mentioned Honourable Guests and Keynote speakers gave their energetic and fruitful contributions atBiomarkers-2012. All accepted abstracts have been indexed in OMICS Group Journal of Molecular Biomarkers & Diagnosisas a special issue.

Biomarkers-2011

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Worlds Leading Biomarkers Congress | CPD Points …

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FAQ About Genetic Testing – National Human Genome Research …

Frequently Asked Questions About Genetic Testing What is genetic testing?

Genetic testing uses laboratory methods to look at your genes, which are the DNA instructions you inherit from your mother and your father. Genetic tests may be used to identify increased risks of health problems, to choose treatments, or to assess responses to treatments.

There are many different types of genetic tests. Genetic tests can help to:

Genetic test results can be hard to understand, however specialists like geneticists and genetic counselors can help explain what results might mean to you and your family. Because genetic testing tells you information about your DNA, which is shared with other family members, sometimes a genetic test result may have implications for blood relatives of the person who had testing.

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Diagnostic testing is used to precisely identify the disease that is making a person ill. The results of a diagnostic test may help you make choices about how to treat or manage your health.

Predictive and pre-symptomatic genetic tests are used to find gene changes that increase a person’s likelihood of developing diseases. The results of these tests provide you with information about your risk of developing a specific disease. Such information may be useful in decisions about your lifestyle and healthcare.

Carrier testing is used to find people who “carry” a change in a gene that is linked to disease. Carriers may show no signs of the disease; however, they have the ability to pass on the gene change to their children, who may develop the disease or become carriers themselves. Some diseases require a gene change to be inherited from both parents for the disease to occur. This type of testing usually is offered to people who have a family history of a specific inherited disease or who belong to certain ethnic groups that have a higher risk of specific inherited diseases.

Prenatal testing is offered during pregnancy to help identify fetuses that have certain diseases.

Newborn screening is used to test babies one or two days after birth to find out if they have certain diseases known to cause problems with health and development.

Pharmacogenomic testing gives information about how certain medicines are processed by an individual’s body. This type of testing can help your healthcare provider choose the medicines that work best with your genetic makeup.

Research genetic testing is used to learn more about the contributions of genes to health and to disease. Sometimes the results may not be directly helpful to participants, but they may benefit others by helping researchers expand their understanding of the human body, health, and disease.

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Benefits: Genetic testing may be beneficial whether the test identifies a mutation or not. For some people, test results serve as a relief, eliminating some of the uncertainty surrounding their health. These results may also help doctors make recommendations for treatment or monitoring, and give people more information for making decisions about their and their family’s health, allowing them to take steps to lower his/her chance of developing a disease. For example, as the result of such a finding, someone could be screened earlier and more frequently for the disease and/or could make changes to health habits like diet and exercise. Such a genetic test result can lower a person’s feelings of uncertainty, and this information can also help people to make informed choices about their future, such as whether to have a baby.

Drawbacks: Genetic testing has a generally low risk of negatively impacting your physical health. However, it can be difficult financially or emotionally to find out your results.

Emotional: Learning that you or someone in your family has or is at risk for a disease can be scary. Some people can also feel guilty, angry, anxious, or depressed when they find out their results.

Financial: Genetic testing can cost anywhere from less than $100 to more than $2,000. Health insurance companies may cover part or all of the cost of testing.

Many people are worried about discrimination based on their genetic test results. In 2008, Congress enacted the Genetic Information Nondiscrimination Act (GINA) to protect people from discrimination by their health insurance provider or employer. GINA does not apply to long-term care, disability, or life insurance providers. (For more information about genetic discrimination and GINA, see http://www.genome.gov/10002328/Genetic-Discrimination-Fact-Sheet).

Limitations of testing: Genetic testing cannot tell you everything about inherited diseases. For example, a positive result does not always mean you will develop a disease, and it is hard to predict how severe symptoms may be. Geneticists and genetic counselors can talk more specifically about what a particular test will or will not tell you, and can help you decide whether to undergo testing.

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There are many reasons that people might get genetic testing. Doctors might suggest a genetic test if patients or their families have certain patterns of disease. Genetic testing is voluntary and the decision about whether to have genetic testing is complex.

A geneticist or genetic counselor can help families think about the benefits and limitations of a particular genetic test. Genetic counselors help individuals and families understand the scientific, emotional, and ethical factors surrounding the decision to have genetic testing and how to deal with the results of those tests. (See: Frequently Asked Questions about Genetic Counseling)

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Talking Glossary of Genetic Terms

Genetic Testing From Genetics Home Reference: the benefits, costs, risks and limitations of genetic testing.

Genetic Testing Registry [ncbi.nlm.nih.gov] A publicly funded medical genetics information resource developed for physicians, other healthcare providers, and researchers.

Prenatal Screening [marchofdimes.com] Provides prenatal testing information, including ultrasound, amniocentesis and chorionic villus sampling (CVS).

National Newborn Screening & Genetics Resource Center [genes-r-us.uthscsa.edu] Provides information and resources in the area of newborn screening and genetics.

Genetic Alliance- Genes in Life [genesinlife.org] A guide from the Genetic Alliance with easy-to-read information about genetic testing.

Genetics and Cancer [cancer.gov] An information fact sheet from the National Cancer Institute about genetic testing for hereditary cancers.

Find a Genetic Counselor [nsgc.org] A search engine developed by the National Society of Genetic Counselors.

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Last Updated: August 27, 2015

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FAQ About Genetic Testing – National Human Genome Research …

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BRCA1 and BRCA2: Cancer Risk and Genetic Testing Fact Sheet …

What are BRCA1 and BRCA2?

BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged DNA and, therefore, play a role in ensuring the stability of the cells genetic material. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

Specific inherited mutations in BRCA1 and BRCA2 increase the risk of female breast and ovarian cancers, and they have been associated with increased risks of several additional types of cancer. Together, BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers (1) and about 5 to 10 percent of all breast cancers (2). In addition, mutations in BRCA1 and BRCA2 account for around 15 percent of ovarian cancers overall (3). Breast and ovarian cancers associated with BRCA1 and BRCA2 mutations tend to develop at younger ages than their nonhereditary counterparts.

A harmful BRCA1 or BRCA2 mutation can be inherited from a persons mother or father. Each child of a parent who carries a mutation in one of these genes has a 50 percent chance (or 1 chance in 2) of inheriting the mutation. The effects of mutations in BRCA1 and BRCA2 are seen even when a persons second copy of the gene is normal.

How much does having a BRCA1 or BRCA2 gene mutation increase a womans risk of breast and ovarian cancer?

A womans lifetime risk of developing breast and/or ovarian cancer is greatly increased if she inherits a harmful mutation in BRCA1 or BRCA2.

Breast cancer: About 12 percent of women in the general population will develop breast cancer sometime during their lives (4). By contrast, according to the most recent estimates, 55 to 65 percent of women who inherit a harmful BRCA1 mutation and around 45 percent of women who inherit a harmful BRCA2 mutation will develop breast cancer by age 70 years (5, 6).

Ovarian cancer: About 1.3 percent of women in the general population will develop ovarian cancer sometime during their lives (4). By contrast, according to the most recent estimates, 39 percent of women who inherit a harmful BRCA1 mutation (5, 6) and 11 to 17 percent of women who inherit a harmful BRCA2 mutation will develop ovarian cancer by age 70 years (5, 6).

It is important to note that these estimated percentages of lifetime risk are different from those available previously; the estimates have changed as more information has become available, and they may change again with additional research. No long-term general population studies have directly compared cancer risk in women who have and do not have a harmful BRCA1 or BRCA2 mutation.

It is also important to note that other characteristics of a particular woman can make her cancer risk higher or lower than the average risks. These characteristics include her family history ofbreast, ovarian, and, possibly, other cancers; the specific mutation(s) she has inherited; and other risk factors, suchas her reproductivehistory. However, at this time, based on current data, none of these other factors seems to be as strong as the effect of carrying a harmful BRCA1 or BRCA2 mutation.

What other cancers have been linked to mutations in BRCA1 and BRCA2?

Are mutations in BRCA1 and BRCA2 more common in certain racial/ethnic populations than others?

Yes. For example, people of Ashkenazi Jewish descent have a higher prevalence of harmful BRCA1 and BRCA2 mutations than people in the general U.S. population. Other ethnic and geographic populations around the world, such as the Norwegian, Dutch, and Icelandic peoples, also have a higher prevalence of specific harmful BRCA1 and BRCA2 mutations.

In addition, limited data indicate that the prevalence of specific harmful BRCA1 and BRCA2 mutations may vary among individual racial and ethnic groups in the United States, including African Americans, Hispanics, Asian Americans, and non-Hispanic whites (15, 16).

Are genetic tests available to detect BRCA1 and BRCA2 mutations?

Yes. Several different tests are available, including tests that look for a known mutation in one of the genes (i.e., a mutation that has already been identified in another family member) and tests that check for all possible mutations in both genes. DNA (from a blood or saliva sample) is needed for mutation testing. The sample is sent to a laboratory for analysis. It usually takes about a month to get the test results.

Who should consider genetic testing for BRCA1 and BRCA2 mutations?

Because harmful BRCA1 and BRCA2 gene mutations are relatively rare in the general population, most experts agree that mutation testing of individuals who do not have cancer should be performed only when the persons individual or family history suggests the possible presence of a harmful mutation in BRCA1 or BRCA2.

In December 2013, the United States Preventive Services Task Force recommended that women who have family members with breast, ovarian, fallopian tube, or peritoneal cancer be evaluated to see if they have a family history that is associated with an increased risk of a harmful mutation in one of these genes (17).

Several screening tools are now available to help health care providers with this evaluation (17). These tools assess family history factors that are associated with an increased likelihood of having a harmful mutation in BRCA1 or BRCA2, including:

When an individual has a family history that is suggestive of the presence of a BRCA1 or BRCA2 mutation, it may be most informative to first test a family member who has cancer if that person is still alive and willing to be tested. If that person is found to have a harmful BRCA1 or BRCA2 mutation, then other family members may want to consider genetic counseling to learn more about their potential risks and whether genetic testing for mutations in BRCA1 and BRCA2 might be appropriate for them.

If it is not possible to confirm the presence of a harmful BRCA1 or BRCA2 mutation in a family member who has cancer, it is appropriate for both men and women who do not have cancer but have a family medical history that suggests the presence of such a mutation to have genetic counseling for possible testing.

Some individualsfor example, those who were adopted at birthmay not know their family history. In cases where a woman with an unknown family history has an early-onset breast cancer or ovarian cancer or a man with an unknown family history is diagnosed with breast cancer, it may be reasonable for that individual to consider genetic testing for a BRCA1 or BRCA2 mutation. Individuals with an unknown family history who do not have an early-onset cancer or male breast cancer are at very low risk of having a harmful BRCA1 or BRCA2 mutation and are unlikely to benefit from routine genetic testing.

Professional societies do not recommend that children, even those with a family history suggestive of a harmful BRCA1 or BRCA2 mutation, undergo genetic testing for BRCA1 or BRCA2. This is because no risk-reduction strategies exist for children, and children’s risks of developing a cancer type associated with a BRCA1 or BRCA2 mutation are extremely low. After children with a family history suggestive of a harmful BRCA1 or BRCA2 mutation become adults, however, they may want to obtain genetic counseling about whether or not to undergoing genetic testing.

Should people considering genetic testing for BRCA1 and BRCA2 mutations talk with a genetic counselor?

Genetic counseling is generally recommended before and after any genetic test for an inherited cancer syndrome. This counseling should be performed by a health care professional who is experienced in cancer genetics. Genetic counseling usually covers many aspects of the testing process, including:

How much does BRCA1 and BRCA2 mutation testing cost?

The Affordable Care Act considers genetic counseling and BRCA1 and BRCA2 mutation testing for individuals at high risk a covered preventive service. People considering BRCA1 and BRCA2 mutation testing may want to confirm their insurance coverage for genetic tests before having the test.

Some of the genetic testing companies that offer testing for BRCA1 and BRCA2 mutations may offer testing at no charge to patients who lack insurance and meet specific financial and medical criteria.

What does a positive BRCA1 or BRCA2 genetic test result mean?

BRCA1 and BRCA2 gene mutation testing can give several possible results: a positive result, a negative result, or an ambiguous or uncertain result.

A positive test result indicates that a person has inherited a known harmful mutation in BRCA1 or BRCA2 and, therefore, has an increased risk of developing certain cancers. However, a positive test result cannot tell whether or when an individual will actually develop cancer. For example, some women who inherit a harmful BRCA1 or BRCA2 mutation will never develop breast or ovarian cancer.

A positive genetic test result may also have important health and social implications for family members, including future generations. Unlike most other medical tests, genetic tests can reveal information not only about the person being tested but also about that persons relatives:

What does a negative BRCA1 or BRCA2 test result mean?

A negative test result can be more difficult to understand than a positive result because what the result means depends in part on an individuals family history of cancer and whether a BRCA1 or BRCA2 mutation has been identified in a blood relative.

If a close (first- or second-degree) relative of the tested person is known to carry a harmful BRCA1 or BRCA2 mutation, a negative test result is clear: it means that person does not carry the harmful mutation that is responsible for the familial cancer, and thus cannot pass it on to their children. Such a test result is called a true negative. A person with such a test result is currently thought to have the same risk of cancer as someone in the general population.

If the tested person has a family history that suggests the possibility of having a harmful mutation in BRCA1 or BRCA2 but complete gene testing identifies no such mutation in the family, a negative result is less clear. The likelihood that genetic testing will miss a known harmful BRCA1 or BRCA2 mutation is very low, but it could happen. Moreover, scientists continue to discover new BRCA1 and BRCA2 mutations and have not yet identified all potentially harmful ones. Therefore, it is possible that a person in this scenario with a “negative” test result actually has an as-yet unknown harmful BRCA1 or BRCA2 mutation that has not been identified.

It is also possible for people to have a mutation in a gene other than BRCA1 or BRCA2 that increases their cancer risk but is not detectable by the test used. People considering genetic testing for BRCA1 and BRCA2 mutations may want to discuss these potential uncertainties with a genetic counselor before undergoing testing.

What does an ambiguous or uncertain BRCA1 or BRCA2 test result mean?

Sometimes, a genetic test finds a change in BRCA1 or BRCA2 that has not been previously associated with cancer. This type of test result may be described as ambiguous (often referred to as a genetic variant of uncertain significance) because it isnt known whether this specific gene change affects a persons risk of developing cancer. One study found that 10 percent of women who underwent BRCA1 and BRCA2 mutation testing had this type of ambiguous result (18).

As more research is conducted and more people are tested for BRCA1 and BRCA2 mutations, scientists will learn more about these changes and cancer risk. Genetic counseling can help a person understand what an ambiguous change in BRCA1 or BRCA2 may mean in terms of cancer risk. Over time, additional studies of variants of uncertain significance may result in a specific mutation being re-classified as either harmful or clearly not harmful.

How can a person who has a positive test result manage their risk of cancer?

Several options are available for managing cancer risk in individuals who have a known harmful BRCA1 or BRCA2 mutation. These include enhanced screening, prophylactic (risk-reducing) surgery, and chemoprevention.

Enhanced Screening. Some women who test positive for BRCA1 and BRCA2 mutations may choose to start cancer screening at younger ages than the general population or to have more frequent screening. For example, some experts recommend that women who carry a harmful BRCA1 or BRCA2 mutation undergo clinical breast examinations beginning at age 25 to 35 years (19). And some expert groups recommend that women who carry such a mutation have a mammogram every year, beginning at age 25 to 35 years.

Enhanced screening may increase the chance of detecting breast cancer at an early stage, when it may have a better chance of being treated successfully. Women who have a positive test result should ask their health care provider about the possible harms of diagnostic tests that involve radiation (mammograms or x-rays).

Recent studies have shown that MRI may be more sensitive than mammography for women at high risk of breast cancer (20, 21). However, mammography can also identify some breast cancers that are not identified by MRI (22), and MRI may be less specific (i.e., lead to more false-positive results) than mammography. Several organizations, such as the American Cancer Society and the National Comprehensive Cancer Network, now recommend annual screening with mammography and MRI for women who have a high risk of breast cancer.

No effective ovarian cancer screening methods currently exist. Some groups recommend transvaginal ultrasound, blood tests for the antigen CA-125, and clinical examinations for ovarian cancer screening in women with harmful BRCA1 or BRCA2 mutations, but none of these methods appears to detect ovarian tumors at an early enough stage to reduce the risk of dying from ovarian cancer (23). For a screening method to be considered effective, it must have demonstrated reduced mortality from the disease of interest. This standard has not yet been met for ovarian cancer screening.

The benefits of screening for breast and other cancers in men who carry harmful mutations in BRCA1 or BRCA2 is also not known, but some expert groups recommend that men who are known to carry a harmful mutation undergo regular mammography as well as testing for prostate cancer. The value of these screening strategies remains unproven at present.

Prophylactic (Risk-reducing) Surgery. Prophylactic surgery involves removing as much of the “at-risk” tissue as possible. Women may choose to have both breasts removed (bilateral prophylactic mastectomy) to reduce their risk of breast cancer. Surgery to remove a woman’s ovaries and fallopian tubes (bilateral prophylactic salpingo-oophorectomy) can help reduce her risk of ovarian cancer. Removing the ovaries also reduces the risk of breast cancer in premenopausal women by eliminating a source of hormones that can fuel the growth of some types of breast cancer.

No evidence is available regarding the effectiveness of bilateral prophylactic mastectomy in reducing breast cancer risk in men with a harmful BRCA1 or BRCA2 mutation or a family history of breast cancer. Therefore, bilateral prophylactic mastectomy for men at high risk of breast cancer is considered an experimental procedure, and insurance companies will not normally cover it.

Prophylactic surgery does not completely guarantee that cancer will not develop because not all at-risk tissue can be removed by these procedures. Some women have developed breast cancer, ovarian cancer, or primary peritoneal carcinomatosis (a type of cancer similar to ovarian cancer) even after prophylactic surgery. Nevertheless, the mortality reduction associated with this surgery is substantial: Research demonstrates that women who underwent bilateral prophylactic salpingo-oophorectomy had a nearly 80 percent reduction in risk of dying from ovarian cancer, a 56 percent reduction in risk of dying from breast cancer (24), and a 77 percent reduction in risk of dying from any cause (25).

Emerging evidence (25) suggests that the amount of protection that removing the ovaries and fallopian tubes provides against the development of breast and ovarian cancer may be similar for carriers of BRCA1 and BRCA2 mutations, in contrast to earlier studies (26).

Chemoprevention. Chemoprevention is the use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the recurrence of, cancer. Although two chemopreventive drugs (tamoxifen and raloxifene) have been approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of breast cancer in women at increased risk, the role of these drugs in women with harmful BRCA1 or BRCA2 mutations is not yet clear.

Data from three studies suggest that tamoxifen may be able to help lower the risk of breast cancer in BRCA1 and BRCA2 mutation carriers (27), including the risk of cancer in the opposite breast among women previously diagnosed with breast cancer (28, 29). Studies have not examined the effectiveness of raloxifene in BRCA1 and BRCA2 mutation carriers specifically.

Oral contraceptives (birth control pills) are thought to reduce the risk of ovarian cancer by about 50 percent both in the general population and in women with harmful BRCA1 or BRCA2 mutations (30).

What are some of the benefits of genetic testing for breast and ovarian cancer risk?

There can be benefits to genetic testing, regardless of whether a person receives a positive or a negative result.

The potential benefits of a true negative result include a sense of relief regarding the future risk of cancer, learning that one’s children are not at risk of inheriting the family’s cancer susceptibility, and the possibility that special checkups, tests, or preventive surgeries may not be needed.

A positive test result may bring relief by resolving uncertainty regarding future cancer risk and may allow people to make informed decisions about their future, including taking steps to reduce their cancer risk. In addition, people who have a positive test result may choose to participate in medical research that could, in the long run, help reduce deaths from hereditary breast and ovarian cancer.

What are some of the possible harms of genetic testing for breast and ovarian cancer risk?

The direct medical harms of genetic testing are minimal, but knowledge of test results may have harmful effects on a persons emotions, social relationships, finances, and medical choices.

People who receive a positive test result may feel anxious, depressed, or angry. They may have difficulty making choices about whether to have preventive surgery or about which surgery to have.

People who receive a negative test result may experience survivor guilt, caused by the knowledge that they likely do not have an increased risk of developing a disease that affects one or more loved ones.

Because genetic testing can reveal information about more than one family member, the emotions caused by test results can create tension within families. Test results can also affect personal life choices, such as decisions about career, marriage, and childbearing.

Violations of privacy and of the confidentiality of genetic test results are additional potential risks. However, the federal Health Insurance Portability and Accountability Act and various state laws protect the privacy of a persons genetic information. Moreover, the federal Genetic Information Nondiscrimination Act, along with many state laws, prohibits discrimination based on genetic information in relation to health insurance and employment, although it does not cover life insurance, disability insurance, or long-term care insurance.

Finally, there is a small chance that test results may not be accurate, leading people to make decisions based on incorrect information. Although inaccurate results are unlikely, people with these concerns should address them during genetic counseling.

What are the implications of having a harmful BRCA1 or BRCA2 mutation for breast and ovarian cancer prognosis and treatment?

A number of studies have investigated possible clinical differences between breast and ovarian cancers that are associated with harmful BRCA1 or BRCA2 mutations and cancers that are not associated with these mutations.

There is some evidence that, over the long term, women who carry these mutations are more likely to develop a second cancer in either the same (ipsilateral) breast or the opposite (contralateral) breast than women who do not carry these mutations. Thus, some women with a harmful BRCA1 or BRCA2 mutation who develop breast cancer in one breast opt for a bilateral mastectomy, even if they would otherwise be candidates for breast-conserving surgery. In fact, because of the increased risk of a second breast cancer among BRCA1 and BRCA2 mutation carriers, some doctors recommend that women with early-onset breast cancer and those whose family history is consistent with a mutation in one of these genes have genetic testing when breast cancer is diagnosed.

Breast cancers in women with a harmful BRCA1 mutation are also more likely to be “triple-negative cancers” (i.e., the breast cancer cells do not have estrogen receptors, progesterone receptors, or large amounts of HER2/neu protein), which generally have poorer prognosis than other breast cancers.

Because the products of the BRCA1 and BRCA2 genes are involved in DNA repair, some investigators have suggested that cancer cells with a harmful mutation in either of these genes may be more sensitive to anticancer agents that act by damaging DNA, such as cisplatin. In preclinical studies, drugs called PARP inhibitors, which block the repair of DNA damage, have been found to arrest the growth of cancer cells that have BRCA1 or BRCA2 mutations. These drugs have also shown some activity in cancer patients who carry BRCA1 or BRCA2 mutations, and researchers are continuing to develop and test these drugs.

What research is currently being done to help individuals with harmful BRCA1 or BRCA2 mutations?

Research studies are being conducted to find new and better ways of detecting, treating, and preventing cancer in people who carry mutations in BRCA1 and BRCA2. Additional studies are focused on improving genetic counseling methods and outcomes. Our knowledge in these areas is evolving rapidly.

Information about active clinical trials (research studies with people) for individuals with BRCA1 or BRCA2 mutations is available on NCIs website. The following links will retrieve lists of clinical trials open to individuals with BRCA1 or BRCA2 mutations.

NCIs Cancer Information Service (CIS) can also provide information about clinical trials and help with clinical trial searches.

Do inherited mutations in other genes increase the risk of breast and/or ovarian tumors?

Yes. Although harmful mutations in BRCA1 and BRCA2 are responsible for the disease in nearly half of families with multiple cases of breast cancer and up to 90 percent of families with both breast and ovarian cancer, mutations in a number of other genes have been associated with increased risks of breast and/or ovarian cancers (2, 31). These other genes include several that are associated with the inherited disorders Cowden syndrome, Peutz-Jeghers syndrome, Li-Fraumeni syndrome, and Fanconi anemia, which increase the risk of many cancer types.

Most mutations in these other genes are associated with smaller increases in breast cancer risk than are seen with mutations in BRCA1 and BRCA2. However, researchers recently reported that inherited mutations in the PALB2 gene are associated with a risk of breast cancer nearly as high as that associated with inherited BRCA1 and BRCA2 mutations (32). They estimated that 33 percent of women who inherit a harmful mutation in PALB2 will develop breast cancer by age 70 years. The estimated risk of breast cancer associated with a harmful PALB2 mutation is even higher for women who have a family history of breast cancer: 58 percent of those women will develop breast cancer by age 70 years.

PALB2, like BRCA1 and BRCA2, is a tumor suppressor gene. The PALB2 gene produces a protein that interacts with the proteins produced by the BRCA1 and BRCA2 genes to help repair breaks in DNA. Harmful mutations in PALB2 (also known as FANCN) are associated with increased risks of ovarian, pancreatic, and prostate cancers in addition to an increased risk of breast cancer (13, 33, 34). Mutations in PALB2, when inherited from each parent, can cause a Fanconi anemia subtype, FA-N, that is associated with childhood solid tumors (13, 33, 35).

Although genetic testing for PALB2 mutations is available, expert groups have not yet developed specific guidelines for who should be tested for, or the management of breast cancer risk in individuals with, PALB2 mutations.

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BRCA1 and BRCA2: Cancer Risk and Genetic Testing Fact Sheet …

Recommendation and review posted by Bethany Smith

Myriad Genetics | Patients & Families | Genetic Testing 101

Research has shown that up to 10 percent of cancers are due to factors that are passed from one generation to the next. These syndromes are known as hereditary cancers and there are genetic tests that can be used to determine an individuals risk for developing these cancers. If you suspect that you or someone you know may be at risk for cancer – such as a family history of cancer or membership in an at-risk ethnic population (such as people with Ashkenazi Jewish ancestry) – you may want to talk to your healthcare professional about genetic testing.

There are many benefits to getting tested, regardless of the eventual result. If one of your family members however distant had cancer, there is a chance that you inherited a gene mutation that not only increases your personal risk of cancer, but also could be passed to the next generation. Those who are carriers of hereditary cancer gene mutations, could be at risk of getting cancer earlier in life than the general population. The sooner genetic testing is done, the more likely it is that the risk can be managed appropriately.

Remember: Your healthcare professional is your most valuable source of information and advice about hereditary cancer screening.

Myriads Hereditary Cancer Quiz helps you to assess whether you might be a candidate for hereditary cancer genetic testing.

Click here to take the easy, 30-second Hereditary Cancer Quiz.

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Myriad Genetics | Patients & Families | Genetic Testing 101

Recommendation and review posted by simmons

Genetic testing – FSH Society

The FSH Society receives numerous inquiries about understanding genetic test results.

The following excerpts are from Deymeer F (ed): Neuromuscular Diseases: From Basic Mechanisms to Clinical Management. Clin Neurosci. Basel, Karger, 2000. vol 18. pp 44-60. The chapter title Facioscapulohumeral Muscular Dystrophy: Diagnostic and Molecular Aspects is by Peter Lunt, Ph.D., Clinical Genetics Unit, Bristol Royal Hospital for Sick Children, Bristol, UK.

Pages 48-49 have a section headed Molecular Testing: Confirmation of Diagnosis that states: In 90-95% of cases of FSHD, as defined by meeting the diagnostic criteria, the diagnosis can effectively be confirmed by showing the presence of a shortened (

Page 45 of the chapter defines the generally accepted correlation between clinical severity and D4Z4 repeat number calculation. It is found that the age at onset and severity of clinical presentation correlates broadly and inversely with the size of the residual DNA fragment at 4q35, and, by inference, therefore correlates directly with the number of repeat units deleted. Thus, the smallest residual fragment lengths at 10-17 kb (1-3 repeat copies) are usually associated with a severe infantile or childhood presentation, medium lengths (18 30 kb, or 4-7 repeat copies) are often found in the largest recognised dominant families, while the largest lengths (31-38 kb, or 8-10 repeat copies) have been associated with a milder predominantly scapulohumeral presentation and may well have reduced penetrance, particularly in females. New mutation cases are seen predominantly with the smallest residual fragment lengths, giving matching clinical severity, and may originate predominantly on the maternal copy of chromosome 4. Study of parental DNA suggests that around 20-30% of new mutations occur as somatic and germline events in one of the parents, this usually also being the mother.

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Genetic testing – FSH Society

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Genetics of Prostate Cancer (PDQ)Health Professional …

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The public health burden of prostate cancer is substantial. A total of 180,890 new cases of prostate cancer and 26,120 deaths from the disease are anticipated in the United States in 2016, making it the most frequent nondermatologic cancer among U.S. males.[1] A mans lifetime risk of prostate cancer is one in seven. Prostate cancer is the second leading cause of cancer death in men, exceeded only by lung cancer.[1]

Some men with prostate cancer remain asymptomatic and die from unrelated causes rather than as a result of the cancer itself. This may be due to the advanced age of many men at the time of diagnosis, slow tumor growth, or response to therapy.[2] The estimated number of men with latent prostate carcinoma (i.e., prostate cancer that is present in the prostate gland but never detected or diagnosed during a patients life) is greater than the number of men with clinically detected disease. A better understanding is needed of the genetic and biologic mechanisms that determine why some prostate carcinomas remain clinically silent, while others cause serious, even life-threatening illness.[2]

Prostate cancer exhibits tremendous differences in incidence among populations worldwide; the ratio of countries with high and low rates of prostate cancer ranges from 60-fold to 100-fold.[3] Asian men typically have a very low incidence of prostate cancer, with age-adjusted incidence rates ranging from 2 to 10 cases per 100,000 men. Higher incidence rates are generally observed in northern European countries. African American men, however, have the highest incidence of prostate cancer in the world; within the United States, African American men have a 60% higher incidence rate than white men.[4] African American men have been reported to have more than twice the rate of prostate cancerspecific death compared with non-Hispanic white men.[1] Differences in race-specific prostate cancer survival estimates may be narrowing over time.[5]

These differences may be due to the interplay of genetic, environmental, and social influences (such as access to health care), which may affect the development and progression of the disease.[6] Differences in screening practices have also had a substantial influence on prostate cancer incidence, by permitting prostate cancer to be diagnosed in some patients before symptoms develop or before abnormalities on physical examination are detectable. An analysis of population-based data from Sweden suggested that a diagnosis of prostate cancer in one brother leads to an early diagnosis in a second brother using prostate-specific antigen (PSA) screening.[7] This may account for an increase in prostate cancer diagnosed in younger men that was evident in nationwide incidence data. A genetic contribution to prostate cancer risk has been documented, and there is increasing knowledge of the molecular genetics of the disease, although much of what is known is not yet clinically actionable. Malignant transformation of prostate epithelial cells and progression of prostate carcinoma are likely to result from a complex series of initiation and promotional events under both genetic and environmental influences.[8]

The three most important recognized risk factors for prostate cancer in the United States are:

Age is an important risk factor for prostate cancer. Prostate cancer is rarely seen in men younger than 40 years; the incidence rises rapidly with each decade thereafter. For example, the probability of being diagnosed with prostate cancer is 1 in 325 for men 49 years or younger, 1 in 48 for men aged 50 through 59 years, 1 in 17 for men aged 60 through 69 years, and 1 in 10 for men aged 70 years and older, with an overall lifetime risk of developing prostate cancer of 1 in 7.[1]

Approximately 10% of prostate cancer cases are diagnosed in men younger than 56 years and represent early-onset prostate cancer. Data from the Surveillance, Epidemiology, and End Results (SEER) Program show that early-onset prostate cancer is increasing, and there is evidence that some cases may be more aggressive.[9] Because early-onset cancers may result from germline mutations, young men with prostate cancer are being extensively studied with the goal of identifying prostate cancer susceptibility genes.

The risk of developing and dying from prostate cancer is dramatically higher among blacks, is of intermediate levels among whites, and is lowest among native Japanese.[10,11] Conflicting data have been published regarding the etiology of these outcomes, but some evidence is available that access to health care may play a role in disease outcomes.[12]

Prostate cancer is highly heritable; the inherited risk of prostate cancer has been estimated to be as high as 60%.[13] As with breast and colon cancer, familial clustering of prostate cancer has been reported frequently.[14-18] From 5% to 10% of prostate cancer cases are believed to be primarily caused by high-risk inherited genetic factors or prostate cancer susceptibility genes. Results from several large case-control studies and cohort studies representing various populations suggest that family history is a major risk factor in prostate cancer.[15,19,20] A family history of a brother or father with prostate cancer increases the risk of prostate cancer, and the risk is inversely related to the age of the affected relative.[16-20] However, at least some familial aggregation is due to increased prostate cancer screening in families thought to be at high risk.[21]

Although some of the prostate cancer studies examining risks associated with family history have used hospital-based series, several studies described population-based series.[22-24] The latter are thought to provide information that is more generalizable. A meta-analysis of 33 epidemiologic case-control and cohort-based studies has provided more detailed information regarding risk ratios related to family history of prostate cancer. Risk appeared to be greater for men with affected brothers than for men with affected fathers in this meta-analysis. Although the reason for this difference in risk is unknown, possible hypotheses have included X-linked or recessive inheritance. In addition, risk increased with increasing numbers of affected close relatives. Risk also increased when a first-degree relative (FDR) was diagnosed with prostate cancer before age 65 years. (See Table 1 for a summary of the relative risks [RRs] related to a family history of prostate cancer.)[25]

Among the many data sources included in this meta-analysis, those from the Swedish population-based Family-Cancer Database warrant special comment. These data were derived from a resource that contained more than 11.8 million individuals, among whom there were 26,651 men with medically verified prostate cancer, of which 5,623 were familial cases.[26] The size of this data set, with its nearly complete ascertainment of the entire Swedish population and objective verification of cancer diagnoses, should yield risk estimates that are both accurate and free of bias. When the familial age-specific hazard ratios (HRs) for prostate cancer diagnosis and mortality were computed, as expected, the HR for prostate cancer diagnosis increased with more family history. Specifically, HRs for prostate cancer were 2.12 (95% CI, 2.052.20) with an affected father only, 2.96 (95% CI, 2.803.13) with an affected brother only, and 8.51 (95% CI, 6.1311.80) with a father and two brothers affected. The highest HR, 17.74 (95% CI, 12.2625.67), was seen in men with three brothers diagnosed with prostate cancer. The HRs were even higher when the affected relative was diagnosed with prostate cancer before age 55 years.

A separate analysis of this Swedish database reported that the cumulative (absolute) risks of prostate cancer among men in families with two or more affected cases were 5% by age 60 years, 15% by age 70 years, and 30% by age 80 years, compared with 0.45%, 3%, and 10%, respectively, by the same ages in the general population. The risks were even higher when the affected father was diagnosed before age 70 years.[27] The corresponding familial population attributable fractions (PAFs) were 8.9%, 1.8%, and 1.0% for the same three age groups, respectively, yielding a total PAF of 11.6% (i.e., approximately 11.6% of all prostate cancers in Sweden can be accounted for on the basis of familial history of the disease).

The risk of prostate cancer may also increase in men who have a family history of breast cancer. Approximately 9.6% of the Iowa cohort had a family history of breast and/or ovarian cancer in a mother or sister at baseline, and this was positively associated with prostate cancer risk (age-adjusted RR, 1.7; 95% CI, 1.03.0; multivariate RR, 1.7; 95% CI, 0.93.2). Men with a family history of both prostate and breast/ovarian cancer were also at increased risk of prostate cancer (RR, 5.8; 95% CI, 2.414.0).[22] Analysis of data from the Women’s Health Initiative also showed that a family history of prostate cancer was associated with an increase in the risk of postmenopausal breast cancer (adjusted HR, 1.14; 95% CI, 1.021.26).[28] Further analyses showed that breast cancer risk was associated with a family history of both breast and prostate cancers; the risk was higher in black women than in white women. Other studies, however, did not find an association between family history of female breast cancer and risk of prostate cancer.[22,29] A family history of prostate cancer also increases the risk of breast cancer among female relatives.[30] The association between prostate cancer and breast cancer in the same family may be explained, in part, by the increased risk of prostate cancer among men with BRCA1/BRCA2 mutations in the setting of hereditary breast/ovarian cancer or early-onset prostate cancer.[31-34] (Refer to the BRCA1 and BRCA2 section of this summary for more information.)

Prostate cancer clusters with particular intensity in some families. Highly penetrant genetic variants are thought to be associated with prostate cancer risk in these families. (Refer to the Linkage Analyses section of this summary for more information.) Members of such families may benefit from genetic counseling. Emerging recommendations and guidelines for genetic counseling referrals are based on prostate cancer age at diagnosis and specific family cancer history patterns.[35,36] Individuals meeting the following criteria may warrant referral for genetic consultation:[35-38]

Family history has been shown to be a risk factor for men of different races and ethnicities. In a population-based case-control study of prostate cancer among African Americans, whites, and Asian Americans in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Vancouver and Toronto),[39] 5% of controls and 13% of all cases reported a father, brother, or son with prostate cancer. These prevalence estimates were somewhat lower among Asian Americans than among African Americans or whites. A positive family history was associated with a twofold to threefold increase in RR in each of the three ethnic groups. The overall odds ratio associated with a family history of prostate cancer was 2.5 (95% CI, 1.93.3) with adjustment for age and ethnicity.[39]

Endogenous hormones, including both androgens and estrogens, likely influence prostate carcinogenesis. It has been widely reported that eunuchs and other individuals with castrate levels of testosterone before puberty do not develop prostate cancer.[40] Some investigators have considered the potential role of genetic variation in androgen biosynthesis and metabolism in prostate cancer risk,[41] including the potential role of the androgen receptor (AR) CAG repeat length in exon 1. This modulates AR activity, which may influence prostate cancer risk.[42] For example, a meta-analysis reported that AR CAG repeat length greater than or equal to 20 repeats conferred a protective effect for prostate cancer in subsets of men.[43]

(Refer to the PDQ summary on Prostate Cancer Prevention for more information about nongenetic modifiers of prostate cancer risk in the general population.)

The SEER Cancer Registries assessed the risk of developing a second primary cancer in 292,029 men diagnosed with prostate cancer between 1973 and 2000. Excluding subsequent prostate cancer and adjusting for the risk of death from other causes, the cumulative incidence of a second primary cancer among all patients was 15.2% at 25 years (95% CI, 5.015.4). There was a significant risk of new malignancies (all cancers combined) among men diagnosed before age 50 years, no excess or deficit in cancer risk in men aged 50 to 59 years, and a deficit in cancer risk in all older age groups. The authors suggested that this deficit may be attributable to decreased cancer surveillance in an elderly population. Excess risks of second primary cancers included cancers of the small intestine, soft tissue, bladder, thyroid, and thymus; and melanoma. Prostate cancer diagnosed in patients aged 50 years or younger was associated with an excess risk of pancreatic cancer.[44]

A review of more than 441,000 men diagnosed with prostate cancer between 1992 and 2010 demonstrated similar findings, with an overall reduction in the risk of being diagnosed with a second primary cancer. This study also examined the risk of second primary cancers in 44,310 men (10%) by treatment modality for localized cancer. The study suggested that men who received radiation therapy had increases in bladder (standardized incidence ratio [SIR], 1.42) and rectal cancer risk (SIR, 1.70) compared with those who did not receive radiation therapy (SIRbladder, 0.76; SIRrectal, 0.74).[45]

The underlying etiology of developing a second primary cancer after prostate cancer may be related to various factors, including treatment modality. More than 50% of the small intestine tumors were carcinoid malignancies, suggesting possible hormonal influences. The excess of pancreatic cancer may be due to mutations in BRCA2, which predisposes to both. The risk of melanoma was most pronounced in the first year of follow-up after diagnosis, raising the possibility that this is the result of increased screening and surveillance.[44]

One Swedish study using the nationwide Swedish Family Cancer Database assessed the role of family history in the risk of a second primary cancer after prostate cancer. Of 18,207 men with prostate cancer, 560 developed a second primary malignancy. Of those, the RR was increased for colorectal, kidney, bladder, and squamous cell skin cancers. Having a paternal family history of prostate cancer was associated with an increased risk of bladder cancer, myeloma, and squamous cell skin cancer. Among prostate cancer probands, those with a family history of colorectal cancer, bladder cancer, or chronic lymphoid leukemia were at increased risk of that specific cancer as a second primary cancer.[46]

Several reports have suggested an elevated risk of various other cancers among relatives within multiple-case prostate cancer families, but none of these associations have been established definitively.[47-49]

In a population-based Finnish study of 202 multiple-case prostate cancer families, no excess risk of all cancers combined (other than prostate cancer) was detected in 5,523 family members. Female family members had a marginal excess of gastric cancer (SIR, 1.9; 95% CI, 1.03.2). No difference in familial cancer risk was observed when families affected by clinically aggressive prostate cancers were compared with those having nonaggressive prostate cancer. These data suggest that familial prostate cancer is a cancer sitespecific disorder.[50]

Many types of epidemiologic studies (case-control, cohort, twin, family) strongly suggest that prostate cancer susceptibility genes exist in the population. Analysis of longer follow-up of the monozygotic (MZ) and dizygotic (DZ) twin pairs in Scandinavia concluded that 58% (95% CI, 5263) of prostate cancer risk may be accounted for by heritable factors.[13] Additionally, among affected MZ and DZ pairs, the time to diagnosis in the second twin was shortest in MZ twins (mean, 3.8 years in MZ twins vs. 6.5 years in DZ twins). This is in agreement with a previous U.S. study that showed a concordance of 7.1% between DZ twin pairs and a 27% concordance between MZ twin pairs.[51] The first segregation analysis was performed in 1992 using families from 740 consecutive probands who had radical prostatectomies between 1982 and 1989. The study results suggested that familial clustering of disease among men with early-onset prostate cancer was best explained by the presence of a rare (frequency of 0.003) autosomal dominant, highly penetrant allele(s).[15] Hereditary prostate cancer susceptibility genes were predicted to account for almost half of early-onset disease (age 55 years or younger). In addition, early-onset disease has been further supported to have a strong genetic component from the study of common variants associated with disease onset before age 55 years.[52]

Subsequent segregation analyses generally agreed with the conclusions but differed in the details regarding frequency, penetrance, and mode of inheritance.[53-55] A study of 4,288 men who underwent radical prostatectomy between 1966 and 1995 found that the best fitting genetic model of inheritance was the presence of a rare, autosomal dominant susceptibility gene (frequency of 0.06). In this study, the lifetime risk in carriers was estimated to be 89% by age 85 years and 3.9% for noncarriers.[51] This study also suggested the presence of genetic heterogeneity, as the model did not reliably predict prostate cancer risk in FDRs of probands who were diagnosed at age 70 years or older. More recent segregation analyses have concluded that there are multiple genes associated with prostate cancer [56-59] in a pattern similar to other adult-onset hereditary cancer syndromes, such as those involving the breast, ovary, colorectum, kidney, and melanoma. In addition, a segregation analysis of 1,546 families from Finland found evidence for Mendelian recessive inheritance. Results showed that individuals carrying the risk allele were diagnosed with prostate cancer at younger ages (

Various research methods have been employed to uncover the landscape of genetic variation associated with prostate cancer. Specific methodologies inform of unique phenotypes or inheritance patterns. The sections below describe prostate cancer research utilizing various methods to highlight their role in uncovering the genetic basis of prostate cancer. In an effort to identify disease susceptibility genes, linkage studies are typically performed on high-risk extended families in which multiple cases of a particular disease have occurred. Typically, gene mutations identified through linkage analyses are rare in the population, are moderately to highly penetrant in families, and have large (e.g., relative risk >2.0) effect sizes. The clinical role of mutations that are identified in linkage studies is a clearer one, establishing precedent for genetic testing for cancer with genes such as BRCA1 and BRCA2. (Refer to the BRCA1 and BRCA2 section in the Genes With Potential Clinical Relevance in Prostate Cancer Risk section of this summary for more information about these genes.) Genome-wide association studies (GWAS) are another methodology used to identify candidate loci associated with prostate cancer. Genetic variants identified from GWAS typically are common in the population and have low to modest effect sizes for prostate cancer risk. The clinical role of markers identified from GWAS is an active area of investigation. Case-control studies are useful in validating the findings of linkage studies and GWAS as well as for studying candidate gene alterations for association with prostate cancer risk, although the clinical role of findings from case-control studies needs to be further defined.

The recognition that prostate cancer clusters within families has led many investigators to collect multiple-case families with the goal of localizing prostate cancer susceptibility genes through linkage studies.

Linkage studies are typically performed on high-risk kindreds in whom multiple cases of a particular disease have occurred in an effort to identify disease susceptibility genes. Linkage analysis statistically compares the genotypes between affected and unaffected individuals and looks for evidence that known genetic markers are inherited along with the disease trait. If such evidence is found (linkage), it provides statistical data that the chromosomal region near the marker also harbors a disease susceptibility gene. Once a genomic region of interest has been identified through linkage analysis, additional studies are required to prove that there truly is a susceptibility gene at that position. Linkage analysis is affected by the following:

Furthermore, because a standard definition of hereditary prostate cancer has not been accepted, prostate cancer linkage studies have not used consistent criteria for enrollment.[1] One criterion that has been proposed is the Hopkins Criteria, which provides a working definition of hereditary prostate cancer families.[2] Using the Hopkins Criteria, kindreds with prostate cancer need to fulfill only one of following criteria to be considered to have hereditary prostate cancer:

Using these criteria, surgical series have reported that approximately 3% to 5% of men will be from a family with hereditary prostate cancer.[2,3]

An additional issue in linkage studies is the high background rate of sporadic prostate cancer in the context of family studies. Because a mans lifetime risk of prostate cancer is one in seven,[4] it is possible that families under study have men with both inherited and sporadic prostate cancer. Thus, men who do not inherit the prostate cancer susceptibility gene that is segregating in their family may still develop prostate cancer. There are no clinical or pathological features of prostate cancer that will allow differentiation between inherited and sporadic forms of the disease, although current advances in the understanding of molecular phenotypes of prostate cancer may be informative in identifying inherited prostate cancer. Similarly, there are limited data regarding the clinical phenotype or natural history of prostate cancer associated with specific candidate loci. Measurement of the serum prostate-specific antigen (PSA) has been used inconsistently in evaluating families used in linkage analysis studies of prostate cancer. In linkage studies, the definition of an affected man can be biased by the use of serum PSA screening as the rates of prostate cancer in families will differ between screened and unscreened families.

One way to address inconsistencies between linkage studies is to require inclusion criteria that define clinically significant disease (e.g., Gleason score 7, PSA 20 ng/mL) in an affected man.[5-7] This approach attempts to define a homogeneous set of cases/families to increase the likelihood of identifying a linkage signal. It also prevents the inclusion of cases that may be considered clinically insignificant that were identified by screening in families.

Investigators have also incorporated clinical parameters into linkage analyses with the goal of identifying genes that may influence disease severity.[8,9] This type of approach, however, has not yet led to the identification of consistent linkage signals across datasets.[10,11]

Table 2 summarizes the proposed prostate cancer susceptibility loci identified in families with multiple prostate canceraffected individuals. Conflicting evidence exists regarding the linkage to some of the loci described above. Data on the proposed phenotype associated with each locus are also limited, and the strength of repeated studies is needed to firmly establish these associations. Evidence suggests that many of these prostate cancer loci account for disease in a small subset of families, which is consistent with the concept that prostate cancer exhibits locus heterogeneity.

Genome-wide linkage studies of families with prostate cancer have identified several other loci that may harbor prostate cancer susceptibility genes, emphasizing the underlying complexity and genetic heterogeneity of this cancer. The following chromosomal regions have been found to be associated with prostate cancer in more than one study or clinical cohort with a statistically significant (2) logarithm of the odds (LOD) score, heterogeneity LOD (HLOD) score, or summary LOD score:

The chromosomal region 19q has also been found to be associated with prostate cancer, although specific LOD scores have not been described.[8,11,95]

Linkage studies have also been performed in specific populations or with specific clinical parameters to identify population-specific susceptibility genes or genes influencing disease phenotypes.

The African American Hereditary Prostate Cancer study conducted a genome-wide linkage study of 77 families with four or more affected men. Multipoint HLOD scores of 1.3 to less than 2.0 were observed using markers that map to 11q22, 17p11, and Xq21. Analysis of the 16 families with more than six men with prostate cancer provided evidence for two additional loci: 2p21 (multipoint HLOD score = 1.08) and 22q12 (multipoint HLOD score = 0.91).[92,99] A smaller linkage study that included 15 African American hereditary prostate cancer families from the southeastern and southcentral Louisiana region identified suggestive linkage for prostate cancer at 2p16 (HLOD = 1.97) and 12q24 (HLOD = 2.21) using a 6,000 single nucleotide polymorphism (SNP) platform.[111] Further study including a larger number of African American families is needed to confirm these findings.

In an effort to identify loci contributing to prostate cancer aggressiveness, linkage analysis was performed in families with one or more of the following: Gleason grade 7 or higher, PSA of 20 ng/mL or higher, regional or distant cancer stage at diagnosis, or death from metastatic prostate cancer before age 65 years. One hundred twenty-three families with two or more affected family members with aggressive prostate cancer were studied. Suggestive linkage was found at chromosome 22q11 (HLOD score = 2.18) and 22q12.3-q13.1 (HLOD score = 1.90).[5] These findings suggest that using a clinically defined phenotype may facilitate finding prostate cancer susceptibility genes. A fine-mapping study of 14 extended high-risk prostate cancer families has subsequently narrowed the genomic region of interest to an 880-kb region at 22q12.3.[107] An analysis of high-risk pedigrees from Utah provides an overview of this strategy.[112] A linkage analysis utilizing a higher resolution marker set of 6,000 SNPs was performed among 348 families from the International Consortium for Prostate Cancer Genetics with aggressive prostate cancer.[44] Aggressive disease was defined as Gleason score 7 or higher, invasion into seminal vesicles or extracapsular extension, pretreatment PSA level of 20 ng/mL or higher, or death from prostate cancer. The region with strongest evidence of linkage among aggressive prostate cancer families was 8q24 with LOD scores of 3.093.17. Additional regions of linkage included with LOD scores of 2 or higher included 1q43, 2q35, and 12q24.31. No candidate genes have been identified.

In light of the multiple prostate cancer susceptibility loci and disease heterogeneity, another approach has been to stratify families based on other cancers, given that many cancer susceptibility genes are pleiotropic.[113] A genome-wide linkage study was conducted to identify a susceptibility locus that may account for both prostate cancer and kidney cancer in families. Analysis of 15 families with evidence of hereditary prostate cancer and one or more cases of kidney cancer (pathologically confirmed) in a man with prostate cancer or in a first-degree relative of a man with prostate cancer revealed suggestive linkage with markers that mapped to an 8 cM region of chromosome 11p11.2-q12.2.[114] This observation awaits confirmation. Another genome-wide linkage study was conducted in 96 hereditary prostate cancer families with one or more first-degree relatives with colon cancer. Evidence for linkage in all families was found in several regions, including 11q25, 15q14, and 18q21. In families with two or more cases of colon cancer, linkage was also observed at 1q31, 11q14, and 15q11-14.[113]

Linkage to chromosome 17q21-22 and subsequent fine-mapping and targeted sequencing have identified recurrent mutations in the HOXB13 gene that account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. Multiple studies have confirmed the association between the G84E mutation in HOXB13 and prostate cancer risk. (Refer to the HOXB13 section of this summary for more information.) The clinical utility of testing for HOXB13 mutations has not yet been defined, but studies are ongoing to define the clinical role. For example, a study evaluated 948 unselected men scheduled for prostate biopsy. The G84E mutation was found in three men (0.3%) who had prostate cancer detected on biopsy, although none of the 301 men who had a family history of prostate cancer carried the mutation.[115] Furthermore, many linkage studies have mapped several prostate cancer susceptibility loci (Table 2), although the genetic alterations contributing to hereditary prostate cancer from these loci have not been consistently reproduced. With the evolution of high-throughput sequencing technologies, there will likely be additional moderately to highly penetrant genetic mutations identified to account for subsets of hereditary prostate cancer families.[116]

A case-control study involves evaluating factors of interest for association to a condition. The design involves investigation of cases with a condition of interest, such as a specific disease or gene mutation, compared with a control sample without that condition, but often with other similar characteristics (i.e., age, gender, and ethnicity). Limitations of case-control design with regard to identifying genetic factors include the following:[117,118]

Additionally, identified associations may not always be valid, but they could represent a random association and, therefore, warrant validation studies.[117,118]

Androgen receptor (AR) gene variants have been examined in relation to both prostate cancer risk and disease progression. The AR is expressed during all stages of prostate carcinogenesis.[120] One study demonstrated that men with hereditary prostate cancer who underwent radical prostatectomy had a higher percentage of prostate cancer cells exhibiting expression of the AR and a lower percentage of cancer cells expressing estrogen receptor alpha than did men with sporadic prostate cancer. The authors suggest that a specific pattern of hormone receptor expression may be associated with hereditary predisposition to prostate cancer.[121]

Altered activity of the AR caused by inherited variants of the AR gene may influence risk of prostate cancer. The length of the polymorphic trinucleotide CAG and GGN microsatellite repeats in exon 1 of the AR gene (located on the X chromosome) have been associated with the risk of prostate cancer.[122,123] Some studies have suggested an inverse association between CAG repeat length and prostate cancer risk, and a direct association between GGN repeat length and risk of prostate cancer; however, the evidence is inconsistent.[120,122-132] A meta-analysis of 19 case-control studies demonstrated a statistically significant association between both short CAG length (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.11.3) and short GGN length (OR, 1.3; 95% CI, 1.11.6) and prostate cancer; however, the absolute difference in number of repeats between cases and controls is less than one, leading the investigators to question whether these small, statistically significant differences are biologically meaningful.[133] Subsequently, the large multiethnic cohort study of 2,036 incident prostate cancer cases and 2,160 ethnically matched controls failed to confirm a statistically significant association (OR, 1.02; P = .11) between CAG repeat size and prostate cancer.[134] A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between AR alleles, with more than 22 CAG repeats and prostate cancer (OR, 1.35; 95% CI, 1.081.69; P = .03).[135]

An analysis of AR gene CAG and CGN repeat length polymorphisms targeted African American men from the Flint Mens Health Study in an effort to identify a genetic modifier that might help explain the increased risk of prostate cancer in black versus white males in the United States.[136] This population-based study of 131 African American prostate cancer patients and 340 screened-negative African American controls showed no evidence of an association between shorter AR repeat length and prostate cancer risk. These results, together with data from three prior, smaller studies,[134,137,138] indicate that short AR repeat variants do not contribute significantly to the risk of prostate cancer in African American men.

Germline mutations in the AR gene (located on the X chromosome) have been rarely reported. The R726L mutation has been identified as a possible contributor to about 2% of both sporadic and familial prostate cancer in Finland.[139] This mutation, which alters the transactivational specificity of the AR protein, was found in 8 of 418 (1.91%) consecutive sporadic prostate cancer cases, 2 of 106 (1.89%) familial cases, and 3 of 900 (0.33%) normal blood donors, yielding a significantly increased prostate cancer OR of 5.8 for both case groups. A subsequent Finnish study of 38 early-onset prostate cancer cases and 36 multiple-case prostate cancer families with no evidence of male-to-male transmission revealed one additional R726L mutation in one of the familial cases and no new germline mutations in the AR gene.[140] These investigators concluded that germline AR mutations explain only a small fraction of familial and early-onset cases in Finland.

A study of genomic DNA from 60 multiple-case African American (n = 30) and white (n = 30) families identified a novel missense germline AR mutation, T559S, in three affected members of a black sibship and none in the white families. No functional data were presented to indicate that this mutation was clearly deleterious. This was reported as a suggestive finding, in need of additional data.[141]

Molecular epidemiology studies have also examined genetic polymorphisms of the steroid 5-alpha-reductase 2 gene, which is also involved in the androgen metabolism cascade. Two isozymes of 5-alpha-reductase exist. The gene that codes for 5-alpha-reductase type II (SRD5A2) is located on chromosome 2. It is expressed in the prostate, where testosterone is converted irreversibly to dihydrotestosterone (DHT) by 5-alpha-reductase type II.[142] Evidence suggests that 5-alpha-reductase type II activity is reduced in populations at lower risk of prostate cancer, including Chinese and Japanese men.[143,144]

A polymorphism in the untranslated region of the SRD5A2 gene may also be associated with prostate cancer risk.[145] Ten alleles fall into three families that differ in the number of TA dinucleotide repeats.[142,146] Although no clinical significance for these polymorphisms has yet been determined, some TA repeat alleles may promote an elevation of enzyme activity, which may in turn increase the level of DHT in the prostate.[120,142] A subsequent meta-analysis failed to detect a statistically significant association between prostate cancer risk and the TA repeat polymorphism, although a relationship could not be definitively excluded.[147] This meta-analysis also examined the potential roles of two coding variants: A49T and V89L. An association with V89L was excluded, and the role for A49T was found to have at most a modest effect on prostate cancer susceptibility. Bias or chance could account for the latter observation. A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between two variants in SRD5A2 and prostate cancer risk (OR, 1.45; 95% CI, 1.012.08; OR, 1.49; 95% CI, 1.032.15).[135] Another meta-analysis of 25 case-control studies, including 8,615 cases and 9,089 controls, found no overall association between the V89L polymorphism and prostate cancer risk. In a subgroup analysis, men younger than 65 years (323 cases and 677 controls) who carried the LL genotype had a modest association with prostate cancer (LL vs. VV, OR, 1.70; 95% CI, 1.092.66 and LL vs. VV+VL, OR, 1.75; 95% CI, 1.142.68).[148] A subsequent systematic review and meta-analysis including 27 nonfamilial case-control studies found no statistically significant association between either the V89L or A49T polymorphisms and prostate cancer risk.[149]

Polymorphisms in several genes involved in the biosynthesis, activation, metabolism, and degradation of androgens (CYP17, CYP3A4, CYP19A1, and SRD5A2) and the stimulation of mitogenic and antiapoptotic activities (IGF-1 and IGFBP-3) of normal prostate cells were examined for association with prostate cancer in 131 African American cases and 342 controls. While allele frequencies did not differ between cases and controls regarding three SNPs in the CYP17 gene (rs6163, rs6162, and rs743572), heterozygous genotypes of these SNPs were found to be associated with a reduced risk (OR, 0.56; 95% CI, 0.350.88; OR, 0.57; 95% CI, 0.360.90; OR, 0.55; 95% CI, 0.350.88, respectively). Evidence suggestive of an association between SNP rs5742657 in intron 2 of IGF-1 was also found (OR, 1.57; 95% CI, 0.942.63).[150] Additional studies are needed to confirm these findings.

Other investigators have explored the potential contribution of the variation in genes involved in the estrogen pathway. A Swedish population study of 1,415 prostate cancer cases and 801 age-matched controls examined the association of SNPs in the estrogen receptor-beta (ER-beta) gene and prostate cancer. One SNP in the promoter region of ER-beta, rs2987983, was associated with an overall prostate cancer risk of 1.23 and 1.35 for localized disease.[151] This study awaits replication.

Germline mutations in the tumor suppressor gene E-cadherin (also called CDH1) cause a hereditary form of gastric carcinoma. A SNP designated -160A, located in the promoter region of E-cadherin, has been found to alter the transcriptional activity of this gene.[152] Because somatic mutations in E-cadherin have been implicated in the development of invasive malignancies in a number of different cancers,[153] investigators have searched for evidence that this functionally significant promoter might be a modifier of cancer risk. A meta-analysis of 47 case-control studies in 16 cancer types included ten prostate cancer cohorts (3,570 cases and 3,304 controls). The OR of developing prostate cancer among risk allele carriers was 1.33 (95% CI, 1.111.60). However, the authors of the study noted that there are sources of bias in the dataset, stemming mostly from the small sample sizes of individual cohorts.[154] Additional studies are required to determine whether this finding is reproducible and biologically and clinically important.

There is a great deal of interest in the possibility that chronic inflammation may represent an important risk factor in prostate carcinogenesis.[155] The family of toll-like receptors has been recognized as a critical component of the intrinsic immune system,[156] one which recognizes ligands from exogenous microbes and a variety of endogenous substrates. This family of genes has been studied most extensively in the context of autoimmune disease, but there also have been a series of studies that have analyzed genetic variants in various members of this pathway as potential prostate cancer risk modifiers.[157-161] The results have been inconsistent, ranging from decreased risk, to null association, to increased risk.

One study was based upon 1,414 incident prostate cancer cases and 1,414 age-matched controls from the American Cancer Society Cancer Prevention Study II Nutrition Cohort.[162] These investigators genotyped 28 SNPs in a region on chromosome 4p14 that includes TLR-10, TLR-1, and TLR-6, three members of the toll-like receptor gene cluster. Two TLR-10 SNPs and four TLR-1 SNPs were associated with significant reductions in prostate cancer risk, ranging from 29% to 38% for the homozygous variant genotype. A more detailed analysis demonstrated these six SNPs were not independent in their effect, but rather represented a single strong association with reduced risk (OR, 0.55; 95% CI, 0.330.90). There were no significant differences in this association when covariates such as Gleason score, history of benign prostatic hypertrophy, use of nonsteroidal anti-inflammatory drugs, and body mass index were taken into account. This is the largest study undertaken to date and included the most comprehensive panel of SNPs evaluated in the 4p14 region. While these observations provide a basis for further investigation of the toll-like receptor genes in prostate cancer etiology, inconsistencies with the prior studies and lack of information regarding what the biological basis of these associations might be warrant caution in interpreting the findings.

SNPs in genes involved in the steroid hormone pathway have previously been studied in sporadic and familial prostate cancer using a sample of individuals with primarily Caucasian ancestry.[163] Another study evaluated 116 tagging SNPs located in 12 genes in the steroid hormone pathway for risk of prostate cancer in 886 cases and 1,566 controls encompassing non-Hispanic white men, Hispanic white men, and African American men.[164] The genes included CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1. Several SNPs in CYP19 were associated with prostate cancer risk in all three populations. Analysis of SNP-SNP interactions involving SNPs in multiple genes revealed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic whites (P = .001). In non-Hispanic whites, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P

A meta-analysis of the relationship between eight polymorphisms in six genes (MTHFR, MTR, MTHFD1, SLC19A1, SHMT1, and FOLH1) from the folate pathway was conducted by pooling data from eight case-control studies, four GWAS, and a nested case-control study named Prostate Testing for Cancer and Treatment in the United Kingdom. Numbers of tested subjects varied among these polymorphisms, with up to 10,743 cases and 35,821 controls analyzed. The report concluded that known common folate-pathway SNPs do not have significant effects on prostate cancer susceptibility in white men.[165]

Four SNPs in the p53 pathway (three in genes regulating p53 function including MDM2, MDM4, and HAUSP and one in p53) were evaluated for association with aggressive prostate cancer in a hospital-based prostate cancer cohort of men with Caucasian ethnicity (N = 4,073).[166] However, a subsequent meta-analysis of case-control studies that focused on MDM2 (T309G) and prostate cancer risk revealed no association.[167] Therefore, the biologic basis of the various associations identified requires further study.

Table 3 summarizes additional case-control studies that have assessed genes that are potentially associated with prostate cancer susceptibility.

Case-control studies assessed site-specific prostate cancer susceptibility in the following genes: EMSY, KLF6, AMACR, NBS1, CHEK2, AR, SRD5A2, ER-beta, E-cadherin, and the toll-like receptor genes. These studies have been complicated by the later-onset nature of the disease and the high background rate of prostate cancer in the general population. In addition, there is likely to be real, extensive locus heterogeneity for hereditary prostate cancer, as suggested by both segregation and linkage studies. In this respect, hereditary prostate cancer resembles a number of the other major adult-onset hereditary cancer syndromes, in which more than one gene can produce the same or very similar clinical phenotype (e.g., hereditary breast/ovarian cancer, Lynch syndrome, hereditary melanoma, and hereditary renal cancer). The clinical validity and utility of genetic testing for any of these genes based solely on evidence for hereditary prostate cancer susceptibility has not been established.

Admixture mapping is a method used to identify genetic variants associated with traits and/or diseases in individuals with mixed ancestry.[178] This approach is most effective when applied to individuals whose admixture was recent and consists of two populations who had previously been separated for thousands of years. The genomes of such individuals are a mosaic, comprised of large blocks from each ancestral locale. The technique takes advantage of a difference in disease incidence in one ancestral group compared with another. Genetic risk loci are presumed to reside in regions enriched for the ancestral group with higher incidence. Successful mapping depends on the availability of population-specific genetic markers associated with ancestry, and on the number of generations since admixture.[179,180]

Admixture mapping is a particularly attractive method for identifying genetic loci associated with increased prostate cancer risk among African Americans. African American men are at higher risk of developing prostate cancer than are men of European ancestry, and the genomes of African American men are mosaics of regions from Africa and regions from Europe. It is therefore hypothesized that inherited variants accounting for the difference in incidence between the two groups must reside in regions enriched for African ancestry. In prostate cancer admixture studies, genetic markers for ancestry were genotyped genome-wide in African American cases and controls in a search for areas enriched for African ancestry in the men with prostate cancer. Admixture studies have identified the following chromosomal regions associated with prostate cancer:

An advantage of this approach is that recent admixtures result in long stretches of linkage disequilibrium (up to hundreds of thousands of base pairs) of one particular ancestry.[182] As a result, fewer markers are needed to search for genetic variants associated with specific diseases, such as prostate cancer, than the number of markers needed for successful GWAS.[179] (Refer to the GWAS section of this summary for more information.)

Genome-wide searches have successfully identified susceptibility alleles for many complex diseases,[183] including prostate cancer. This approach can be contrasted with linkage analysis, which searches for genetic risk variants co-segregating within families that have a high prevalence of disease. Linkage analyses are designed to uncover rare, highly penetrant variants that segregate in predictable heritance patterns (e.g., autosomal dominant, autosomal recessive, X-linked, and mitochondrial). GWAS, on the other hand, are best suited to identify multiple, common, low-penetrance genetic polymorphisms. GWAS are conducted under the assumption that the genetic underpinnings of complex phenotypes, such as prostate cancer, are governed by many alleles, each conferring modest risk. Most genetic polymorphisms genotyped in GWAS are common, with minor allele frequencies greater than 1% to 5% within a given ancestral population (e.g., men of European ancestry). GWAS survey all common inherited variants across the genome, searching for alleles that are associated with incidence of a given disease or phenotype.[184,185] The strong correlation between many alleles located close to one another on a given chromosome (called linkage disequilibrium) allows one to scan the genome without having to test all tens of millions of known SNPs. GWAS can test approximately 1 million to 5 million SNPs and ascertain almost all common inherited variants in the genome.

In a GWAS, allele frequency is compared for each SNP between cases and controls. Promising signalsin which allele frequencies deviate significantly in case compared to control populationsare validated in replication cohorts. In order to have adequate statistical power to identify variants associated with a phenotype, large numbers of cases and controls, typically thousands of each, are studied. Because 1 million SNPs are typically evaluated in a GWAS, false-positive findings are expected to occur frequently when standard statistical thresholds are used. Therefore, stringent statistical rules are used to declare a positive finding, usually using a threshold of P

To date, approximately 100 variants associated with prostate cancer have been identified by well-powered GWAS and validated in independent cohorts (see Table 4).[189] These studies have revealed convincing associations between specific inherited variants and prostate cancer risk. However, the findings should be qualified with a few important considerations:

The implications of these points are discussed in greater detail below. Additional detail can be found elsewhere.[192]

In 2006, two genome-wide studies seeking associations with prostate cancer risk converged on the same chromosomal locus, 8q24. Using a technique called admixture mapping, a 3.8 megabase (Mb) region emerged as significantly involved with risk in African American men.[69] In another study, linkage analysis of 323 Icelandic prostate cancer cases also revealed an 8q24 risk locus.[68] Detailed genotyping of this region and an association study for prostate cancer risk in three case-control populations in Sweden, Iceland, and the United States revealed specific 8q24 risk markers: a SNP, rs1447295, and a microsatellite polymorphism, allele-8 at marker DG8S737.[68] The population-attributable risk of prostate cancer from these alleles was 8%. The results were replicated in an African American case-control population, and the population attributable risk was 16%.[68] These results were confirmed in several large, independent cohorts.[70-73,80-83,193] Subsequent GWAS independently converged on another risk variant at 8q24, rs6983267.[73-75] Fine mapping, genotyping a large number of variants densely packed within a region of interest in many cases and controls, was performed across 8q24 targeting the variants most significantly associated with prostate cancer risk. Across multiple ethnic populations, three distinct 8q24 risk loci were described: region 1 (containing rs1447295) at 128.54128.62 Mb, region 2 at 128.14128.28 Mb, and region 3 (containing rs6983267) at 128.47128.54 Mb.[75] Variants within each of these three regions independently confer disease risk with ORs ranging from 1.11 to 1.66. In 2009, two separate GWAS uncovered two additional risk regions at 8q24. In all, approximately nine genetic polymorphisms, all independently associated with disease, reside within five distinct 8q24 risk regions.[86,87]

Since the discovery of prostate cancer risk loci at 8q24, other chromosomal risk loci similarly have been identified by multistage GWAS comprised of thousands of cases and controls and validated in independent cohorts. The most convincing associations reported to date for men of European ancestry are included in Table 4. The association between risk and allele status for each variant listed in Table 4 reached genome-wide statistical significance in more than one independent cohort.

Most prostate cancer GWAS data generated to date have been derived from populations of European descent. This shortcoming is profound, considering that linkage disequilibrium structure, SNP frequencies, and incidence of disease differ across ancestral groups. To provide meaningful genetic data to all patients, well-designed, adequately powered GWAS must be aimed at specific ethnic groups.[206] Most work in this regard has focused on African American, Chinese, and Japanese men. The most convincing associations reported to date for men of non-European ancestry are included in Table 5. The association between risk and allele status for each variant listed in Table 5 reached genome-wide statistical significance in more than one independent cohort.

The African American population is of particular interest because American men with African ancestry are at higher risk of prostate cancer than any other group. In addition, inherited variation at the 8q24 risk locus appears to contribute to differences in African American and European American incidence of disease.[69] A handful of studies have sought to determine whether GWAS findings in men of European ancestry are applicable to men of African ancestry. One study interrogated 28 known prostate cancer risk loci via fine mapping in 3,425 African American cases and 3,290 African American controls.[208] On average, risk allele frequencies were 0.05 greater in African Americans than in European Americans. Of the 37 known risk SNPs analyzed, 18 replicated in the African American population were significantly associated with prostate cancer at P .05 (the study was underpowered to properly assess nine of the remaining 19 SNPs). For seven risk regions (2p24, 2p15, 3q21, 6q22, 8q21, 11q13, and 19q13), fine mapping identified SNPs in the African American population more strongly associated with risk than the index SNPs reported in the original European-based GWAS. Fine mapping of the 8q24 region revealed four SNPs associated with disease that are substantially more common in African Americans. The SNP most strongly correlated with disease among African Americans (rs6987409) is not strongly correlated with a European risk allele and may account for a portion of increased risk in the African American population. In all, the risk SNPs identified in this study are estimated to represent 11% of total inherited risk.

Some of the risk variants identified in Table 5 have also been found to confer risk in men of European ancestry. These include rs16901979, rs6983267, and rs1447295 at 8q24 in African Americans and rs13254738 in Japanese populations. Additionally, the Japanese rs4430796 at 17q12 and rs2660753 at 3p12 have also been observed in men of European ancestry. However, the vast majority of the variants identified in these studies reveal novel variants that are unique to that specific ethnic population. These results confirm the importance of evaluating SNP associations in different ethnic populations. Considerable effort is still needed to fully annotate genetic risk in these and other populations.

Because the variants discovered by GWAS are markers of risk, there has been great interest in using genotype as a screening tool to predict the development of prostate cancer. In an attempt to determine the potential clinical value of risk SNP genotype, cases of prostate cancer (n = 2,893) were identified from four cancer registries in Sweden. Controls (n = 1,781) were randomly selected from the Swedish Population Registry and were matched to cases by age and geographic region.[78] Known risk SNPs from 8q24, 17q12, and 17q24.3 were analyzed (rs4430796 at 17q12, rs1859962 at 17q24.3, rs16901979 at 8q24 [region 2], rs6983267 at 8q24 [region 3], and rs1447295 at 8q24 [region 1]). ORs for prostate cancer for men carrying any combination of one, two, three, or four or more genotypes associated with prostate cancer were estimated by comparing them with men carrying none of the associated genotypes using logistic regression analysis. Men who carried one to five risk alleles had an increasing likelihood of having prostate cancer compared with men carrying none of the alleles (P = 6.75 10-27). After controlling for age, geographic location, and family history of prostate cancer, men carrying four or more of these alleles had a significant elevation in risk of prostate cancer (OR, 4.47; 95% CI, 2.936.80; P = 1.20 10-13). When family history was added as a risk factor, men with five or more factors (five SNPs plus family history) had an even stronger risk of prostate cancer (OR, 9.46; 95% CI, 3.6224.72; P = 1.29 10-8). The population-attributable risks (PARs) for these five SNPs were estimated to account for 4% to 21% of prostate cancer cases in Sweden, and the joint PAR for prostate cancer of the five SNPs plus family history was 46%.

A second study assessed prostate cancer risk associated with a family history of prostate cancer in combination with various numbers of 27 risk alleles identified through four prior GWAS. Two case-control populations were studied, the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) in the United States (1,172 cases and 1,157 controls) and the Cancer of the Prostate in Sweden (CAPS) study (2,899 cases and 1,722 controls). The highest risk of prostate cancer from the CAPS population was observed in men with a positive family history and greater than 14 risk alleles (OR, 4.92; 95% CI, 3.646.64). Repeating this analysis in the PLCO population revealed similar findings (OR, 3.88; 95% CI, 2.835.33).[214]

However, the proportion of men carrying large numbers of the risk alleles was low. While ORs were impressively high for this subset, they do not reflect the utility of genotyping the overall population. Receiver operating characteristic curves were constructed in these studies to measure the sensitivity and specificity of certain risk profiles. The area under the curve (AUC) was 0.61 when age, geographic region, and family history were used to assess risk. When genotype of the five risk SNPs at chromosomes 8 and 17 were introduced, a very modest AUC improvement to 0.63 was detected.[78] The addition of more recently discovered SNPs to the model has not appreciably improved these results.[215] While genotype may inform risk status for the small minority of men carrying multiple risk alleles, testing of the known panel of prostate cancer SNPs is currently of questionable clinical utility.[216]

Another study incorporated 10,501 prostate cancer cases and 10,831 controls from multiple cohorts (including PLCO) and genotyped each individual for 25 prostate cancer risk SNPs. Age and family history data were available for all subjects. Genotype data helped discriminate those who developed prostate cancer from those who did not. However, similar to the series above, discriminative ability was modest and only compelling at the extremes of risk allele distribution in a relatively small subset population; younger subjects (men aged 50 to 59 years) with a family history of disease who were in 90th percentile for risk allele status had an absolute 10-year risk of 6.7% compared with an absolute 10-year risk of 1.6% in men in the 10th percentile for risk allele status.[217]

In another study, 49 risk SNPs were genotyped in 2,696 Swedish men, and a polygenic risk score was calculated. On the basis of their genetic risk scores, 172 men aged 50 to 69 years with PSA levels of 1 to 3 ng/mL underwent biopsy. Prostate cancer was diagnosed in 27% of these individuals, and 6% had Gleason 7 or higher disease.[218] The utility of this strategy for identifying who should undergo prostate biopsy is yet to be determined.

In July 2012, the Agency for Healthcare Research and Quality (AHRQ) published a report that sought to address the clinical utility of germline genotyping of prostate cancer risk markers discovered by GWAS.[216] Largely on the basis of the evidence from the studies described above, AHRQ concluded that established prostate cancer risk SNPs have poor discriminative ability to identify individuals at risk of developing the disease. Similarly, the authors of another study estimated that the contribution of GWAS polymorphisms in determining the risk of developing prostate cancer will be modest, even as meta-analyses or larger studies uncover additional common risk alleles (alleles carried by >1%5% of individuals within the population).[219]

GWAS findings to date account for only a fraction of heritable risk of disease. Research is ongoing to uncover the remaining portion of genetic risk. This includes the discovery of rarer alleles with higher ORs for risk. For example, a consortium led by deCODE genetics in Iceland performed whole-genome sequencing of 2,500 Icelanders and identified approximately 32.5 million variants, including millions of rare variants (carried by

In addition, other genetic polymorphisms, such as copy number variants, are becoming increasingly amenable to testing. As the full picture of inherited prostate cancer risk becomes more complete, it is hoped that germline information will become clinically useful.

Notably, almost all reported prostate cancer risk alleles reside in nonprotein coding regions of the genome, and the underlying biological mechanism of disease susceptibility remains unclear. Hypotheses explaining the mechanism of inherited risk include the following:

The 8q24 risk locus, which contains multiple prostate cancer risk alleles and risk alleles for other cancers, has been the focus of intense study. c-MYC, a known oncogene, is the closest known gene to the 8q24 risk regions, although it is located hundreds of kb away. Given this significant distance, SNPs within c-MYC are not in linkage disequilibrium with the 8q24 prostate cancer risk variants. One study examined whether 8q24 prostate cancer risk SNPs are in fact located in areas of previously unannotated transcription, and no transcriptional activity was uncovered at the risk loci.[222] Attention turned to the idea of distal gene regulation. Interrogation of the epigenetic landscape at the 8q24 risk loci revealed that the risk variants are located in areas that bear the marks of genetic enhancers, elements that influence gene activity from a distance.[223-225] To identify a prostate cancer risk gene, germline DNA from 280 men undergoing prostatectomy for prostate cancer was genotyped for all known 8q24 risk SNPs. Genotypes were tested for association with the normal prostate and prostate tumor RNA expression levels of genes located within one Mb of the risk SNPs. No association was detected between expression of any of the genes, including c-MYC, and risk allele status in either normal epithelium or tumor tissue. Another study, using normal prostate tissue from 59 patients, detected an association between an 8q24 risk allele and the gene PVT1, downstream from c-MYC.[226] Nonetheless, c-MYC, with its substantial involvement in many cancers, remains a prime candidate. A series of experiments in prostate cancer cell lines demonstrated that chromatin is configured in such a way that the 8q24 risk variants lie in close proximity to c-MYC, even though they are quite distant in linear space. These data implicate c-MYC despite the absence of expression data.[224,226] Further work at 8q24 and similar analyses at other prostate cancer risk loci are ongoing.

Additional insights are emerging regarding the potential interaction between SNPs identified from GWAS and prostate cancer susceptibility gene regulation. One study found that a SNP at 6q22 lies within a binding region for HOXB13. Through multiple functional approaches, the T allele of this SNP (rs339331) was found to enhance binding of HOXB13, leading to allele-specific upregulation of RFX6, which correlates with prostate cancer progression and severity.[227] Thus, this study supports the hypothesis that risk alleles identified from GWAS may play a role in regulating or modifying gene expression and therefore impact prostate cancer risk.

A 2012 study used a novel approach to identify polymorphisms associated with risk.[228] On the basis of the well-established principle that the AR plays a prominent role in prostate tumorigenesis, the investigators targeted SNPs that reside at sites where the AR binds to DNA. They leveraged data from previous studies that mapped thousands of AR binding sites genome-wide in prostate cancer cell lines to select SNPs to genotype in the Johns Hopkins Hospital cohort of 1,964 cases and 3,172 controls and the Cancer Genetic Markers of Susceptibility cohort of 1,172 cases and 1,157 controls. This modified GWAS revealed a SNP (rs4919743) located at the KRT8 locus at 12q13.13a locus previously implicated in cancer developmentassociated with prostate cancer risk, with an OR of 1.22 (95% CI, 1.131.32). The study is notable for its use of a reasonable hypothesis and prior data to guide a genome-wide search for risk variants.

Although the statistical evidence for an association between genetic variation at these loci and prostate cancer risk is overwhelming, the clinical relevance of the variants and the mechanism(s) by which they lead to increased risk are unclear and will require further characterization. Additionally, these loci are associated with very modest risk estimates and explain only a fraction of overall inherited risk. Further work will include genome-wide analysis of rarer alleles catalogued via sequencing efforts, such as the 1000 Genomes Project.[229] Disease-associated alleles with frequencies of less than 1% in the population may prove to be more highly penetrant and clinically useful. In addition, further work is needed to describe the landscape of genetic risk in non-European populations. Finally, until the individual and collective influences of genetic risk alleles are evaluated prospectively, their clinical utility will remain difficult to fully assess.

Prostate cancer is clinically heterogeneous. Many cases are indolent and are successfully managed with observation alone. Other cases are quite aggressive and prove deadly. Several variables are used to determine prostate cancer aggressiveness at the time of diagnosis, such as Gleason score and PSA, but these are imperfect. Additional markers are needed, as sound treatment decisions depend on accurate prognostic information. Germline genetic variants are attractive markers since they are present, easily detectable, and static throughout life. Several studies have interrogated inherited variants that may distinguish indolent and aggressive prostate cancer. Several of these studies identified polymorphisms associated with aggressiveness, after adjusting for commonly used clinical variables, and are reviewed in the Table 6.

Findings to date regarding inherited risk of aggressive disease are considered preliminary. Further work is needed to validate findings and assess prospectively.

Like studies of the genetics of prostate cancer risk, initial studies of inherited risk of aggressive prostate cancer focused on polymorphisms in candidate genes. Next, as GWAS revealed prostate cancer risk SNPs, several research teams sought to determine whether certain risk SNPs were also associated with aggressiveness (see table below). There has been great interest in launching more unbiased, genome-wide searches for inherited variants associated with indolent versus aggressive prostate cancer. While GWAS designed explicitly for disease aggressiveness have been initiated, most genome-wide analyses to date have relied on datasets previously generated to evaluate prostate cancer risk. The cases from these case-control cohorts were divided into aggressive and nonaggressive subgroups then compared with each other and/or with the control (nonprostate cancer) subjects. Several associations between germline markers and prostate cancer aggressiveness have been reported. However, there remains no accepted set of germline markers that clearly provides prognostic information beyond that provided by more traditional variables at the time of diagnosis.

In independent retrospective series (see Table 6) the prostate cancer risk allele at rs2735839 (G) was associated with less aggressive disease. This risk allele has also been associated with higher PSA levels.[198,238] A hypothesis explaining the association between the nonrisk allele (A) and more aggressive disease is that those carrying the A allele generally have lower PSA levels and are sent for prostate biopsy less often. They subsequently may be diagnosed later in the natural history of the disease, resulting in poorer outcomes.

To definitively identify the inherited variants associated with prostate cancer aggressiveness, GWAS focusing on prostate cancer subjects with poor disease-related outcomes are needed. Notably, in a genome-wide analysis in which two of the largest international prostate cancer genotyped cohorts were combined for analysis (24,023 prostate cancer cases, including 3,513 disease-specific deaths), no SNP was associated with prostate cancerspecific survival.[239] The authors concluded that any SNP associated with prostate cancer outcome must be fairly rare in the general population (minor allele frequency below 1%). As more data regarding rarer variants are generated and validated, the value of inherited variants for therapeutic decision making may be determined.

While genetic testing for prostate cancer is not yet standard clinical practice, research from selected cohorts has reported that prostate cancer risk is elevated in men with mutations in BRCA1, BRCA2, and on a smaller scale, in mismatch repair (MMR) genes. Since clinical genetic testing is available for these genes, information about risk of prostate cancer based on alterations in these genes is included in this section. In addition, mutations in HOXB13 were reported to account for a proportion of hereditary prostate cancer. Although clinical testing is not yet available for HOXB13 alterations, it is expected that this gene will have clinical relevance in the future and therefore it is also included in this section. The genetic alterations described in this section require further study and are not to be used in routine clinical practice at this time.

Studies of male BRCA1 [1] and BRCA2 mutation carriers demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[2] Prostate cancer in particular has been observed at higher rates in male BRCA2 mutations carriers than in the general population.[3]

The risk of prostate cancer in BRCA mutation carriers has been studied in various settings.

In an effort to clarify the relationship between BRCA mutations and prostate cancer risk, findings from several case series are summarized in Table 7.

Estimates derived from the Breast Cancer Linkage Consortium may be overestimated because these data are generated from a highly select population of families ascertained for significant evidence of risk of breast cancer and ovarian cancer and suitability for linkage analysis. However, a review of the relationship between germline mutations in BRCA2 and prostate cancer risk supports the view that this gene confers a significant increase in risk among male members of hereditary breast and ovarian cancer families but that it likely plays only a small role, if any, in site-specific, multiple-case prostate cancer families.[6] In addition, the clinical validity and utility of BRCA testing solely on the basis of evidence for hereditary prostate cancer susceptibility has not been established.

Several studies in Israel and in North America have analyzed the frequency of BRCA founder mutations among Ashkenazi Jewish (AJ) men with prostate cancer.[7-9] Two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) are common in individuals of AJ ancestry. Carrier frequencies for these mutations in the general Jewish population are 0.9% (95% CI, 0.71.1) for the 185delAG mutation, 0.3% (95% confidence interval [CI], 0.20.4) for the 5382insC mutation, and 1.3% (95% CI, 1.01.5) for the BRCA2 6174delT mutation.[10-13] (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about BRCA1 and BRCA2 genes.) In these studies, the relative risks (RRs) were commonly greater than 1, but only a few have been statistically significant. Many of these studies were not sufficiently powered to rule out a lower, but clinically significant, risk of prostate cancer in carriers of Ashkenazi BRCA founder mutations.

In the Washington Ashkenazi Study (WAS), a kin-cohort analytic approach was used to estimate the cumulative risk of prostate cancer among more than 5,000 American AJ male volunteers from the Washington, District of Columbia, area who carried one of the BRCA Ashkenazi founder mutations. The cumulative risk to age 70 years was estimated to be 16% (95% CI, 430) among carriers and 3.8% among noncarriers (95% CI, 3.34.4).[13] This fourfold increase in prostate cancer risk was equal (in absolute terms) to the cumulative risk of ovarian cancer among female mutation carriers at the same age (16% by age 70 years; 95% CI, 628). The risk of prostate cancer in male mutation carriers in the WAS cohort was elevated by age 50 years, was statistically significantly elevated by age 67 years, and increased thereafter with age, suggesting both an overall excess in prostate cancer risk and an earlier age at diagnosis among carriers of Ashkenazi founder mutations. Prostate cancer risk differed depending on the gene, with BRCA1 mutations associated with increasing risk after age 55 to 60 years, reaching 25% by age 70 years and 41% by age 80 years. In contrast, prostate cancer risk associated with the BRCA2 mutation began to rise at later ages, reaching 5% by age 70 years and 36% by age 80 years (numeric values were provided by the author [written communication, April 2005]).

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Genetics of Skin Cancer (PDQ)Health Professional Version

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The genetics of skin cancer is an extremely broad topic. There are more than 100 types of tumors that are clinically apparent on the skin; many of these are known to have familial components, either in isolation or as part of a syndrome with other features. This is, in part, because the skin itself is a complex organ made up of multiple cell types. Furthermore, many of these cell types can undergo malignant transformation at various points in their differentiation, leading to tumors with distinct histology and dramatically different biological behaviors, such as squamous cell carcinoma (SCC) and basal cell cancer (BCC). These have been called nonmelanoma skin cancers or keratinocyte cancers.

Figure 1 is a simple diagram of normal skin structure. It also indicates the major cell types that are normally found in each compartment. Broadly speaking, there are two large compartmentsthe avascular epidermis and the vascular dermiswith many cell types distributed in a largely acellular matrix.[1]

Figure 1. Schematic representation of normal skin. The relatively avascular epidermis houses basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for BCC and SCC, respectively. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

The outer layer or epidermis is made primarily of keratinocytes but has several other minor cell populations. The bottom layer is formed of basal keratinocytes abutting the basement membrane. The basement membrane is formed from products of keratinocytes and dermal fibroblasts, such as collagen and laminin, and is an important anatomical and functional structure. Basal keratinocytes lose contact with the basement membrane as they divide. As basal keratinocytes migrate toward the skin surface, they progressively differentiate to form the spinous cell layer; the granular cell layer; and the keratinized outer layer, or stratum corneum.

The true cytologic origin of BCC remains in question. BCC and basal cell keratinocytes share many histologic similarities, as is reflected in the name. Alternatively, the outer root sheath cells of the hair follicle have also been proposed as the cell of origin for BCC.[2] This is suggested by the fact that BCCs occur predominantly on hair-bearing skin. BCCs rarely metastasize but can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name “rodent ulcer.”[3]

Some debate remains about the origin of SCC; however, these cancers are likely derived from epidermal stem cells associated with the hair follicle.[4] A variety of tissues, such as lung and uterine cervix, can give rise to SCC, and this cancer has somewhat differing behavior depending on its source. Even in cancer derived from the skin, SCC from different anatomic locations can have moderately differing aggressiveness; for example, SCC from glabrous (smooth, hairless) skin has a lower metastatic rate than SCC arising from the vermillion border of the lip or from scars.[3]

Additionally, in the epidermal compartment, melanocytes distribute singly along the basement membrane and can undergo malignant transformation into melanoma. Melanocytes are derived from neural crest cells and migrate to the epidermal compartment near the eighth week of gestational age. Langerhans cells, or dendritic cells, are another cell type in the epidermis and have a primary function of antigen presentation. These cells reside in the skin for an extended time and respond to different stimuli, such as ultraviolet radiation or topical steroids, which cause them to migrate out of the skin.[5]

The dermis is largely composed of an extracellular matrix. Prominent cell types in this compartment are fibroblasts, endothelial cells, and transient immune system cells. When transformed, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma, and other vascular tumors. There are a number of immune cell types that move in and out of the skin to blood vessels and lymphatics; these include mast cells, lymphocytes, mononuclear cells, histiocytes, and granulocytes. These cells can increase in number in inflammatory diseases and can form tumors within the skin. For example, urticaria pigmentosa is a condition that arises from mast cells and is occasionally associated with mast cell leukemia; cutaneous T-cell lymphoma is often confined to the skin throughout its course. Overall, 10% of leukemias and lymphomas have prominent expression in the skin.[6]

Epidermal appendages are also found in the dermal compartment. These are derivatives of the epidermal keratinocytes, such as hair follicles, sweat glands, and the sebaceous glands associated with the hair follicles. These structures are generally formed in the first and second trimesters of fetal development. These can form a large variety of benign or malignant tumors with diverse biological behaviors. Several of these tumors are associated with familial syndromes. Overall, there are dozens of different histological subtypes of these tumors associated with individual components of the adnexal structures.[7]

Finally, the subcutis is a layer that extends below the dermis with varying depth, depending on the anatomic location. This deeper boundary can include muscle, fascia, bone, or cartilage. The subcutis can be affected by inflammatory conditions such as panniculitis and malignancies such as liposarcoma.[8]

These compartments give rise to their own malignancies but are also the region of immediate adjacent spread of localized skin cancers from other compartments. The boundaries of each skin compartment are used to define the staging of skin cancers. For example, an in situ melanoma is confined to the epidermis. Once the cancer crosses the basement membrane into the dermis, it is invasive. Internal malignancies also commonly metastasize to the skin. The dermis and subcutis are the most common locations, but the epidermis can also be involved in conditions such as Pagetoid breast cancer.

The skin has a wide variety of functions. First, the skin is an important barrier preventing extensive water and temperature loss and providing protection against minor abrasions. These functions can be aberrantly regulated in cancer. For example, in the erythroderma (reddening of the skin) associated with advanced cutaneous T-cell lymphoma, alterations in the regulations of body temperature can result in profound heat loss. Second, the skin has important adaptive and innate immunity functions. In adaptive immunity, antigen-presenting cells engender T-cell responses consisting of increased levels of TH1, TH2, or TH17 cells.[9] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Consequently, even small breaks in the skin can lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system. It may also be important in immune surveillance against cancer. Immunosuppression, which occurs during organ transplant, is a significant risk factor for skin cancer. The skin is significant for communication through facial expression and hand movements. Unfortunately, areas of specialized function, such as the area around the eyes and ears, are common places for cancer to occur. Even small cancers in these areas can lead to reconstructive challenges and have significant cosmetic and social ramifications.[1]

While the appearance of any one skin cancer can vary, there are general physical presentations that can be used in screening. BCCs most commonly have a pearly rim or can appear somewhat eczematous (see Figure 2 and Figure 3). They often ulcerate (see Figure 2). SCCs frequently have a thick keratin top layer (see Figure 4). Both BCCs and SCCs are associated with a history of sun-damaged skin. Melanomas are characterized by asymmetry, border irregularity, color variation, a diameter of more than 6 mm, and evolution (ABCDE criteria). (Refer to What Does Melanoma Look Like? on NCI’s website for more information about the ABCDE criteria.) Photographs representing typical clinical presentations of these cancers are shown below.

Enlarge

Figure 2. Ulcerated basal cell carcinoma (left panel) and ulcerated basal cell carcinoma with characteristic pearly rim (right panel).

Figure 3. Superficial basal cell carcinoma (left panel) and nodular basal cell carcinoma (right panel).

Enlarge

Figure 4. Squamous cell carcinoma on the face with thick keratin top layer (left panel) and squamous cell carcinoma on the leg (right panel).

Enlarge

Figure 5. Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.

Basal cell carcinoma (BCC) is the most common malignancy in people of European descent, with an associated lifetime risk of 30%.[1] While exposure to ultraviolet (UV) radiation is the risk factor most closely linked to the development of BCC, other environmental factors (such as ionizing radiation, chronic arsenic ingestion, and immunosuppression) and genetic factors (such as family history, skin type, and genetic syndromes) also potentially contribute to carcinogenesis. In contrast to melanoma, metastatic spread of BCC is very rare and typically arises from large tumors that have evaded medical treatment for extended periods of time. BCCs can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name “rodent ulcer.” With early detection, the prognosis for BCC is excellent.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types. There are different patterns of sun exposure associated with each major type of skin cancer (BCC, squamous cell carcinoma [SCC], and melanoma). (Refer to the PDQ summary on Skin Cancer Prevention for more information about risk factors for skin cancer in the general population.)

The high-risk phenotype consists of individuals with the following physical characteristics:

Specifically, people with more highly pigmented skin demonstrate lower incidence of BCC than do people with lighter pigmented skin. Individuals with Fitzpatrick Type I or II skin were shown to have a twofold increased risk of BCC in a small case-control study.[2] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) Blond or red hair color was associated with increased risk of BCC in two large cohorts: the Nurses Health Study and the Health Professionals Follow-Up Study.[3]

Individuals with BCCs and/or SCCs report a higher frequency of these cancers in their family members than do controls. The importance of this finding is unclear. Apart from defined genetic disorders with an increased risk of BCC, a positive family history of any skin cancer is a strong predictor of the development of BCC.

A study on the heritability of cancer among 80,309 monozygotic and 123,382 dizygotic twins showed that nonmelanoma skin cancers (NMSCs) have a heritability of 43% (95% confidence interval [CI], 26%59%), suggesting that almost half of the risk of NMSC is caused by inherited factors.[4] Additionally, the cumulative risk of NMSC was 1.9-fold higher for monozygotic than for dizygotic twins (95% CI, 1.82.0).[4]

A personal history of BCC or SCC is strongly associated with subsequent BCC or SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these NMSCs is the mid-60s.[5-10] In addition, several studies have found that individuals with a history of skin cancer have an increased risk of a subsequent diagnosis of a noncutaneous cancer;[11-14] however, other studies have contradicted this finding.[15-18] In the absence of other risk factors or evidence of a defined cancer susceptibility syndrome, as discussed below, skin cancer patients are encouraged to follow screening recommendations for the general population for sites other than the skin.

Mutations in the gene coding for the transmembrane receptor protein PTCH1, or PTCH, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. (Refer to the BCNS section of this summary for more information.) PTCH1, the human homolog of the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway, which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation) and regulatory (maintenance of stem cells) roles.

In the resting state, the transmembrane receptor protein PTCH1 acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction.[19] Binding of the hedgehog ligand to PTCH1 releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[20,21] Thus, the balance of PTCH1 (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH1 or gain-of-function mutations of Smo tip this balance toward activation, a key event in potential neoplastic transformation.

Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[22,23] Further investigation identified a mutation in PTCH1 that localized to the area of allelic loss.[24] Up to 30% of sporadic BCCs demonstrate PTCH1 mutations.[25] In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other tumors, have been associated with PTCH1 mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH1 mutations, predominantly truncation in type.[26]

Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, have been demonstrated in both BCC and medulloblastoma.[27,28] PTCH2 displays 57% homology to PTCH1.[29] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[27,30]

BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid BCC syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals.[31] The syndrome is notable for complete penetrance and high levels of variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[26,32] The clinical features of BCNS differ more among families than within families.[33] BCNS is primarily associated with germline mutations in PTCH1, but families with this phenotype have also been associated with alterations in PTCH2 and SUFU.[34-36]

As detailed above, PTCH1 provides both developmental and regulatory guidance; spontaneous or inherited germline mutations of PTCH1 in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS mutation has been localized to chromosome 9q22.3-q31, with a maximum logarithm of the odd (LOD) score of 3.597 and 6.457 at markers D9S12 and D9S53.[31] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH1.[37] The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH1 mutation as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[38-42] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[43]

The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (refer to Table 1 for a comparison of these criteria).[44-47] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying mutation carriers. The BCNS Colloquium Group proposed criteria in 2011 that required 1 major criterion with molecular diagnosis, two major criteria without molecular diagnosis, or one major and two minor criteria without molecular diagnosis.[47] PTCH1 mutations are found in 60% to 85% of patients who meet clinical criteria.[48,49] Most notably, BCNS is associated with the formation of both benign and malignant neoplasms. The strongest benign neoplasm association is with ovarian fibromas, diagnosed in 14% to 24% of females affected by BCNS.[41,45,50] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[51] Ameloblastomas, aggressive tumors of the odontogenic epithelium, have also been proposed as a diagnostic criterion for BCNS, but most groups do not include it at this time.[52]

Other associated benign neoplasms include gastric hamartomatous polyps,[53] congenital pulmonary cysts,[54] cardiac fibromas,[55] meningiomas,[56-58] craniopharyngiomas,[59] fetal rhabdomyomas,[60] leiomyomas,[61] mesenchymomas,[62] and nasal dermoid tumors. Development of meningiomas and ependymomas occurring postradiation therapy has been documented in the general pediatric population; radiation therapy for syndrome-associated intracranial processes may be partially responsible for a subset of these benign tumors in individuals with BCNS.[63-65] In addition, radiation therapy of malignant medulloblastomas in the BCNS population may result in many cutaneous BCCs in the radiation ports. Similarly, treatment of BCC of the skin with radiation therapy may result in induction of large numbers of additional BCCs.[40,41,61]

The diagnostic criteria for BCNS are described in Table 1 below.

Of greatest concern with BCNS are associated malignant neoplasms, the most common of which is BCC. BCC in individuals with BCNS may appear during childhood as small acrochordon -like lesions, while larger lesions demonstrate more classic cutaneous features.[66] Nonpigmented BCCs are more common than pigmented lesions.[67] The age at first BCC diagnosis associated with BCNS ranges from 3 to 53 years, with a mean age of 21.4 years; the vast majority of individuals are diagnosed with their first BCC before age 20 years.[45,50] Most BCCs are located on sun-exposed sites, but individuals with greater than 100 BCCs have a more uniform distribution of BCCs over the body.[67] Case series have suggested that up to 1 in 200 individuals with BCC demonstrate findings supportive of a diagnosis of BCNS.[31] BCNS has rarely been reported in individuals with darker skin pigmentation; however, significantly fewer BCCs are found in individuals of African or Mediterranean ancestry.[45,68,69] Despite the rarity of BCC in this population, reported cases document full expression of the noncutaneous manifestations of BCNS.[69] However, in individuals of African ancestry who have received radiation therapy, significant basal cell tumor burden has been reported within the radiation port distribution.[45,61] Thus, cutaneous pigmentation may protect against the mutagenic effects of UV but not against ionizing radiation.

Variants associated with an increased risk of BCC in the general population appear to modify the age of BCC onset in individuals with BCNS. A study of 125 individuals with BCNS found that a variant in MC1R (Arg151Cys) was associated with an early median age of onset of 27 years (95% CI, 2034), compared with individuals who did not carry the risk allele and had a median age of BCC of 34 years (95% CI, 3040) (hazard ratio [HR], 1.64; 95% CI, 1.042.58, P = .034). A variant in the TERT-CLPTM1L gene showed a similar effect, with individuals with the risk allele having a median age of BCC of 31 years (95% CI, 2837) relative to a median onset of 41 years (95% CI, 3248) in individuals who did not carry a risk allele (HR, 1.44; 95% CI, 1.081.93, P = .014).[70]

Many other malignancies have been associated with BCNS. Medulloblastoma carries the strongest association with BCNS and is diagnosed in 1% to 5% of BCNS cases. While BCNS-associated medulloblastoma is typically diagnosed between ages 2 and 3 years, sporadic medulloblastoma is usually diagnosed later in childhood, between the ages of 6 and 10 years.[41,45,50,71] A desmoplastic phenotype occurring around age 2 years is very strongly associated with BCNS and carries a more favorable prognosis than sporadic classic medulloblastoma.[72,73] Up to three times more males than females with BCNS are diagnosed with medulloblastoma.[74] As with other malignancies, treatment of medulloblastoma with ionizing radiation has resulted in numerous BCCs within the radiation field.[41,56] Other reported malignancies include ovarian carcinoma,[75] ovarian fibrosarcoma,[76,77] astrocytoma,[78] melanoma,[79] Hodgkin disease,[80,81] rhabdomyosarcoma,[82] and undifferentiated sinonasal carcinoma.[83]

Odontogenic keratocystsor keratocystic odontogenic tumors (KCOTs), as renamed by the World Health Organization working groupare one of the major features of BCNS.[84] Demonstration of clonal loss of heterozygosity (LOH) of common tumor suppressor genes, including PTCH1, supports the transition of terminology to reflect a neoplastic process.[37] Less than one-half of KCOTs from individuals with BCNS show LOH of PTCH1.[43,85] The tumors are lined with a thin squamous epithelium and a thin corrugated layer of parakeratin. Increased mitotic activity in the tumor epithelium and potential budding of the basal layer with formation of daughter cysts within the tumor wall may be responsible for the high rates of recurrence post simple enucleation.[84,86] In a recent case series of 183 consecutively excised KCOTs, 6% of individuals demonstrated an association with BCNS.[84] A study that analyzed the rate of PTCH1 mutations in BCNS-associated KCOTs found that 11 of 17 individuals carried a germline PTCH1 mutation and an additional 3 individuals had somatic mutations in this gene.[87] Individuals with germline PTCH1 mutations had an early age of KCOT presentation. KCOTs occur in 65% to 100% of individuals with BCNS,[45,88] with higher rates of occurrence in young females.[89]

Palmoplantar pits are another major finding in BCC and occur in 70% to 80% of individuals with BCNS.[50] When these pits occur together with early-onset BCC and/or KCOTs, they are considered diagnostic for BCNS.[90]

Several characteristic radiologic findings have been associated with BCNS, including lamellar calcification of falx cerebri;[91,92] fused, splayed or bifid ribs;[93] and flame-shaped lucencies or pseudocystic bone lesions of the phalanges, carpal, tarsal, long bones, pelvis, and calvaria.[49] Imaging for rib abnormalities may be useful in establishing the diagnosis in younger children, who may have not yet fully manifested a diagnostic array on physical examination.

Table 2 summarizes the frequency and median age of onset of nonmalignant findings associated with BCNS.

Individuals with PTCH2 mutations may have a milder phenotype of BCNS than those with PTCH1 mutations. Characteristic features such as palmar/plantar pits, macrocephaly, falx calcification, hypertelorism, and coarse face may be absent in these individuals.[94]

A 9p22.3 microdeletion syndrome that includes the PTCH1 locus has been described in ten children.[95] All patients had facial features typical of BCNS, including a broad forehead, but they had other features variably including craniosynostosis, hydrocephalus, macrosomia, and developmental delay. At the time of the report, none had basal cell skin cancer. On the basis of their hemizygosity of the PTCH1 gene, these patients are presumably at an increased risk of basal cell skin cancer.

Germline mutations in SUFU, a major negative regulator of the hedgehog pathway, have been identified in a small number of individuals with a clinical phenotype resembling that of BCNS.[35,36] These mutations were first identified in individuals with childhood medulloblastoma,[96] and the incidence of medulloblastoma appears to be much higher in individuals with BCNS associated with SUFU mutations than in those with PTCH1 mutations.[35] SUFU mutations may also be associated with an increased predisposition to meningioma.[58,97] Conversely, odontogenic jaw keratocysts appear less frequently in this population. Some clinical laboratories offer genetic testing for SUFU mutations for individuals with BCNS who do not have an identifiable PTCH1 mutation.

Rombo syndrome, a very rare probably autosomal dominant genetic disorder associated with BCC, has been outlined in three case series in the literature.[98-100] The cutaneous examination is within normal limits until age 7 to 10 years, with the development of distinctive cyanotic erythema of the lips, hands, and feet and early atrophoderma vermiculatum of the cheeks, with variable involvement of the elbows and dorsal hands and feet.[98] Development of BCC occurs in the fourth decade.[98] A distinctive grainy texture to the skin, secondary to interspersed small, yellowish, follicular-based papules and follicular atrophy, has been described.[98,100] Missing, irregularly distributed and/or misdirected eyelashes and eyebrows are another associated finding.[98,99] The genetic basis of Rombo syndrome is not known.

Bazex-Dupr-Christol syndrome, another rare genodermatosis associated with development of BCC, has more thorough documentation in the literature than Rombo syndrome. Inheritance is accomplished in an X-linked dominant fashion, with no reported male-to-male transmission.[101-103] Regional assignment of the locus of interest to chromosome Xq24-q27 is associated with a maximum LOD score of 5.26 with the DXS1192 locus.[104] Further work has narrowed the potential location to an 11.4-Mb interval on chromosome Xq25-27; however, the causative gene remains unknown.[105]

Characteristic physical findings include hypotrichosis, hypohidrosis, milia, follicular atrophoderma of the cheeks, and multiple BCC, which manifest in the late second decade to early third decade.[101] Documented hair changes with Bazex-Dupr-Christol syndrome include reduced density of scalp and body hair, decreased melanization,[106] a twisted/flattened appearance of the hair shaft on electron microscopy,[107] and increased hair shaft diameter on polarizing light microscopy.[103] The milia, which may be quite distinctive in childhood, have been reported to regress or diminish substantially at puberty.[103] Other reported findings in association with this syndrome include trichoepitheliomas; hidradenitis suppurativa; hypoplastic alae; and a prominent columella, the fleshy terminal portion of the nasal septum.[108,109]

A rare subtype of epidermolysis bullosa simplex (EBS), Dowling-Meara (EBS-DM), is primarily inherited in an autosomal dominant fashion and is associated with mutations in either keratin-5 (KRT5) or keratin-14 (KRT14).[110] EBS-DM is one of the most severe types of EBS and occasionally results in mortality in early childhood.[111] One report cites an incidence of BCC of 44% by age 55 years in this population.[112] Individuals who inherit two EBS mutations may present with a more severe phenotype.[113] Other less phenotypically severe subtypes of EBS can also be caused by mutations in either KRT5 or KRT14.[110] Approximately 75% of individuals with a clinical diagnosis of EBS (regardless of subtype) have KRT5 or KRT14 mutations.[114]

Characteristics of hereditary syndromes associated with a predisposition to BCC are described in Table 3 below.

(Refer to the Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis section in the Rare Skin Cancer Syndromes section of this summary for more information about Brooke-Spiegler syndrome.)

As detailed further below, the U.S. Preventive Services Task Force does not recommend regular screening for the early detection of any cutaneous malignancies, including BCC. However, once BCC is detected, the National Comprehensive Cancer Network guidelines of care for NMSCs recommends complete skin examinations every 6 to 12 months for life.[125]

The BCNS Colloquium Group has proposed guidelines for the surveillance of individuals with BCNS (see Table 4).

Level of evidence: 5

Avoidance of excessive cumulative and sporadic sun exposure is important in reducing the risk of BCC, along with other cutaneous malignancies. Scheduling activities outside of the peak hours of UV radiation, utilizing sun-protective clothing and hats, using sunscreen liberally, and strictly avoiding tanning beds are all reasonable steps towards minimizing future risk of skin cancer.[126] For patients with particular genetic susceptibility (such as BCNS), avoidance or minimization of ionizing radiation is essential to reducing future tumor burden.

Level of evidence: 2aii

The role of various systemic retinoids, including isotretinoin and acitretin, has been explored in the chemoprevention and treatment of multiple BCCs, particularly in BCNS patients. In one study of isotretinoin use in 12 patients with multiple BCCs, including 5 patients with BCNS, tumor regression was noted, with decreasing efficacy as the tumor diameter increased.[127] However, the results were insufficient to recommend use of systemic retinoids for treatment of BCC. Three additional patients, including one with BCNS, were followed long-term for evaluation of chemoprevention with isotretinoin, demonstrating significant decrease in the number of tumors per year during treatment.[127] Although the rate of tumor development tends to increase sharply upon discontinuation of systemic retinoid therapy, in some patients the rate remains lower than their pretreatment rate, allowing better management and control of their cutaneous malignancies.[127-129] In summary, the use of systemic retinoids for chemoprevention of BCC is reasonable in high-risk patients, including patients with xeroderma pigmentosum, as discussed in the Squamous Cell Carcinoma section of this summary.

A patients cumulative and evolving tumor load should be evaluated carefully in light of the potential long-term use of a medication class with cumulative and idiosyncratic side effects. Given the possible side-effect profile, systemic retinoid use is best managed by a practitioner with particular expertise and comfort with the medication class. However, for all potentially childbearing women, strict avoidance of pregnancy during the systemic retinoid courseand for 1 month after completion of isotretinoin and 3 years after completion of acitretinis essential to avoid potentially fatal and devastating fetal malformations.

Level of evidence (retinoids): 2aii

In a phase II study of 41 patients with BCNS, vismodegib (an inhibitor of the hedgehog pathway) has been shown to reduce the per-patient annual rate of new BCCs requiring surgery.[130] Existing BCCs also regressed for these patients during daily treatment with 150 mg of oral vismodegib. While patients treated had visible regression of their tumors, biopsy demonstrated residual microscopic malignancies at the site, and tumors progressed after the discontinuation of the therapy. Adverse effects included taste disturbance, muscle cramps, hair loss, and weight loss and led to discontinuation of the medication in 54% of subjects. Based on the side-effect profile and rate of disease recurrence after discontinuation of the medication, additional study regarding optimal dosing of vismodegib is ongoing.

Level of evidence (vismodegib): 1aii

A phase III, double-blind, placebo-controlled clinical trial evaluated the effects of oral nicotinamide (vitamin B3) in 386 individuals with a history of at least two NMSCs within 5 years before study enrollment.[131] After 12 months of treatment, those taking nicotinamide 500 mg twice daily had a 20% reduction in the incidence of new BCCs (95% CI, 6%39%; P = .12). The rate of new NMSCs was 23% lower in the nicotinamide group (95% CI, 438; P =.02) than in the placebo group. No clinically significant differences in adverse events were observed between the two groups, and there was no evidence of benefit after discontinuation of nicotinamide. Of note, this study was not conducted in a population with an identified genetic predisposition to BCC.

Level of evidence (nicotinamide): 1aii

Treatment of individual BCCs in BCNS is generally the same as for sporadic basal cell cancers. Due to the large number of lesions on some patients, this can present a surgical challenge. Field therapy with imiquimod or photodynamic therapy are attractive options, as they can treat multiple tumors simultaneously.[132,133] However, given the radiosensitivity of patients with BCNS, radiation as a therapeutic option for large tumors should be avoided.[45] There are no randomized trials, but the isolated case reports suggest that field therapy has similar results as in sporadic basal cell cancer, with higher success rates for superficial cancers than for nodular cancers.[132,133]

Consensus guidelines for the use of methylaminolevulinate photodynamic therapy in BCNS recommend that this modality may best be used for superficial BCC of all sizes and for nodular BCC less than 2 mm thick.[134] Monthly therapy with photodynamic therapy may be considered for these patients as clinically indicated.

Level of evidence (imiquimod and photodynamic therapy): 4

Topical treatment with LDE225, a Smoothened agonist, has also been investigated for the treatment of BCC in a small number of patients with BCNS with promising results;[135] however, this medication is not approved in this formulation by the U.S. Food and Drug Administration.

Level of evidence (LDE225): 1

In addition to its effects on the prevention of BCCs in patients with BCNS, vismodegib may also have a palliative effect on KCOTs found in this population. An initial report indicated that the use of GDC-0449, the hedgehog pathway inhibitor now known as vismodegib, resulted in resolution of KCOTs in one patient with BCNS.[136] Another small study found that four of six patients who took 150 mg of vismodegib daily had a reduction in the size of KCOTs.[137] None of the six patients in this study had new KCOTs or an increase in the size of existing KCOTs while being treated, and one patient had a sustained response that lasted 9 months after treatment was discontinued.

Level of evidence (vismodegib): 3diii

Squamous cell carcinoma (SCC) is the second most common type of skin cancer and accounts for approximately 20% of cutaneous malignancies. Although most cancer registries do not include information on the incidence of nonmelanoma skin cancer (NMSC), annual incidence estimates range from 1 million to 5.4 million cases in the United States.[1,2]

Mortality is rare from this cancer; however, the morbidity and costs associated with its treatment are considerable.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types; however, different patterns of sun exposure are associated with each major type of skin cancer.

Unlike basal cell carcinoma (BCC), SCC is associated with chronic exposure, rather than intermittent intense exposure to ultraviolet (UV) radiation. Occupational exposure is the characteristic pattern of sun exposure linked with SCC.[3] A case-control study in southern Europe showed increased risk of SCC when lifetime sun exposure exceeded 70,000 hours. People whose lifetime sun exposure equaled or exceeded 200,000 hours had an odds ratio (OR) 8 to 9 times that of the reference group.[4] A Canadian case-control study did not find an association between cumulative lifetime sun exposure and SCC; however, sun exposure in the 10 years before diagnosis and occupational exposure were found to be risk factors.[5]

In addition to environmental radiation, exposure to therapeutic radiation is another risk factor for SCC. Individuals with skin disorders treated with psoralen and ultraviolet-A radiation (PUVA) had a threefold to sixfold increase in SCC.[6] This effect appears to be dose-dependent, as only 7% of individuals who underwent fewer than 200 treatments had SCC, compared with more than 50% of those who underwent more than 400 treatments.[7] Therapeutic use of ultraviolet-B (UVB) radiation has also been shown to cause a mild increase in SCC (adjusted incidence rate ratio, 1.37).[8] Devices such as tanning beds also emit UV radiation and have been associated with increased SCC risk, with a reported OR of 2.5 (95% confidence interval [CI], 1.73.8).[9]

Investigation into the effect of ionizing radiation on SCC carcinogenesis has yielded conflicting results. One population-based case-control study found that patients who had undergone therapeutic radiation therapy had an increased risk of SCC at the site of previous radiation (OR, 2.94), compared with individuals who had not undergone radiation treatments.[10] Cohort studies of radiology technicians, atomic-bomb survivors, and survivors of childhood cancers have not shown an increased risk of SCC, although the incidence of BCC was increased in all of these populations.[11-13] For those who develop SCC at previously radiated sites that are not sun-exposed, the latent period appears to be quite long; these cancers may be diagnosed years or even decades after the radiation exposure.[14]

The effect of other types of radiation, such as cosmic radiation, is also controversial. Pilots and flight attendants have a reported incidence of SCC that ranges between 2.1 and 9.9 times what would be expected; however, the overall cancer incidence is not consistently elevated. Some attribute the high rate of NMSCs in airline flight personnel to cosmic radiation, while others suspect lifestyle factors.[15-20]

Like BCCs, SCCs appear to be associated with exposure to arsenic in drinking water and combustion products.[21,22] However, this association may hold true only for the highest levels of arsenic exposure. Individuals who had toenail concentrations of arsenic above the 97th percentile were found to have an approximately twofold increase in SCC risk.[23] For arsenic, the latency period can be lengthy; invasive SCC has been found to develop at an average of 20 years after exposure.[24]

Current or previous cigarette smoking has been associated with a 1.5-fold to 2-fold increase in SCC risk,[25-27] although one large study showed no change in risk.[28] Available evidence suggests that the effect of smoking on cancer risk seems to be greater for SCC than for BCC.

Additional reports have suggested weak associations between SCC and exposure to insecticides, herbicides, or fungicides.[29]

Like melanoma and BCC, SCC occurs more frequently in individuals with lighter skin than in those with darker skin.[3,30] A case-control study of 415 cases and 415 controls showed similar findings; relative to Fitzpatrick Type I skin, individuals with increasingly darker skin had decreased risks of skin cancer (ORs, 0.6, 0.3, and 0.1, for Fitzpatrick Types II, III, and IV, respectively).[31] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) The same study found that blue eyes and blond/red hair were also associated with increased risks of SCC, with crude ORs of 1.7 (95% CI, 1.22.3) for blue eyes, 1.5 (95% CI, 1.12.1) for blond hair, and 2.2 (95% CI, 1.53.3) for red hair.

However, SCC can also occur in individuals with darker skin. An Asian registry based in Singapore reported an increase in skin cancer in that geographic area, with an incidence rate of 8.9 per 100,000 person-years. Incidence of SCC, however, was shown to be on the decline.[30] SCC is the most common form of skin cancer in black individuals in the United States and in certain parts of Africa; the mortality rate for this disease is relatively high in these populations.[32,33] Epidemiologic characteristics of, and prevention strategies for, SCC in those individuals with darker skin remain areas of investigation.

Freckling of the skin and reaction of the skin to sun exposure have been identified as other risk factors for SCC.[34] Individuals with heavy freckling on the forearm were found to have a 14-fold increase in SCC risk if freckling was present in adulthood, and an almost threefold risk if freckling was present in childhood.[34,35] The degree of SCC risk corresponded to the amount of freckling. In this study, the inability of the skin to tan and its propensity to burn were also significantly associated with risk of SCC (OR of 2.9 for severe burn and 3.5 for no tan).

The presence of scars on the skin can also increase the risk of SCC, although the process of carcinogenesis in this setting may take years or even decades. SCCs arising in chronic wounds are referred to as Marjolins ulcers. The mean time for development of carcinoma in these wounds is estimated at 26 years.[36] One case report documents the occurrence of cancer in a wound that was incurred 59 years earlier.[37]

Immunosuppression also contributes to the formation of NMSCs. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than that observed in the general population, although the risks vary with transplant type.[38-41] NMSCs in high-risk patients (solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age, are more common and more aggressive, and have a higher risk of recurrence and metastatic spread than these cancers do in the general population.[42,43] Additionally, there is a high risk of second SCCs.[44,45] In one study, over 65% of kidney transplant recipients developed subsequent SCCs after their first diagnosis.[44] Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

This increased risk has been linked to an interaction between the level of immunosuppression and UV radiation exposure. As the duration and dosage of immunosuppressive agents increase, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[38,46,47] The risk appears to be highest in geographic areas with high UV exposure.[47] When comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC.[48] This finding underlines the importance of rigorous sun avoidance, particularly among high-risk immunosuppressed individuals.

Certain immunosuppressive agents have been associated with increased risk of SCC. Kidney transplant patients who received cyclosporine in addition to azathioprine and prednisolone had a 2.8-fold increase in risk of SCC over those kidney transplant patients on azathioprine and prednisolone alone.[38] In cardiac transplant patients, increased incidence of SCC was seen in individuals who had received OKT3 (muromonab-CD3), a murine monoclonal antibody against the CD3 receptor.[49]

A personal history of BCC or SCC is strongly associated with subsequent SCC. A study from Ireland showed that individuals with a history of BCC had a 14% higher incidence of subsequent SCC; for men with a history of BCC, the subsequent SCC risk was 27% higher.[50] In the same report, individuals with melanoma were also 2.5 times more likely to report a subsequent SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these NMSCs is the middle of the sixth decade of life.[26,51-55]

A Swedish study of 224 melanoma index cases and 944 of their first-degree relatives (FDRs) from 154 CDKN2A wild-type families and 11,680 matched controls showed that personal and family histories of melanoma increased the risk of SCC, with relative risks (RRs) of 9.1 (95% CI, 6.013.7) for personal history and 3.4 (95% CI, 2.25.2) for family history.[56]

Although the literature is scant on this subject, a family history of SCC may increase the risk of SCC in FDRs. In an independent survey-based study of 415 SCC cases and 415 controls, SCC risk was increased in individuals with a family history of SCC (adjusted OR, 3.4; 95% CI, 1.011.6), even after adjustment for skin type, hair color, and eye color.[31] This risk was elevated to an OR of 5.6 in those with a family history of melanoma (95% CI, 1.619.7), 9.8 in those with a family history of BCC (95% CI, 2.636.8), and 10.5 in those with a family history of multiple types of skin cancer (95% CI, 2.729.6). Review of the Swedish Family Center Database showed that individuals with at least one sibling or parent affected with SCC, in situ SCC (Bowen disease), or actinic keratosis had a twofold to threefold increased risk of invasive and in situ SCC relative to the general population.[57,58] Increased number of tumors in parents was associated with increased risk to the offspring. Of note, diagnosis of the proband at an earlier age was not consistently associated with a trend of increased incidence of SCC in the FDR, as would be expected in most hereditary syndromes because of germline mutations. Further analysis of the Swedish population-based data estimates genetic risk effects of 8% and familial shared-environmental effects of 18%.[59] Thus, shared environmental and behavioral factors likely account for some of the observed familial clustering of SCC.

A study on the heritability of cancer among 80,309 monozygotic and 123,382 dizygotic twins showed that NMSCs have a heritability of 43% (95% CI, 26%59%), suggesting that almost half of the risk of NMSC is caused by inherited factors.[60] Additionally, the cumulative risk of NMSC was 1.9-fold higher for monozygotic than for dizygotic twins (95% CI, 1.82.0).[60]

Major genes have been defined elsewhere in this summary as genes that are necessary and sufficient for disease, with important mutations of the gene as causal. The disorders resulting from single-gene mutations within families lead to a very high risk of disease and are relatively rare. The influence of the environment on the development of disease in individuals with these single-gene disorders is often very difficult to determine because of the rarity of the genetic mutation.

Identification of a strong environmental risk factorchronic exposure to UV radiationmakes it difficult to apply genetic causation for SCC of the skin. Although the risk of UV exposure is well known, quantifying its attributable risk to cancer development has proven challenging. In addition, ascertainment of cases of SCC of the skin is not always straightforward. Many registries and other epidemiologic studies do not fully assess the incidence of SCC of the skin owing to: (1) the common practice of treating lesions suspicious for SCC without a diagnostic biopsy, and (2) the relatively low potential for metastasis. Moreover, NMSC is routinely excluded from the major cancer registries such as the Surveillance, Epidemiology, and End Results registry.

With these considerations in mind, the discussion below will address genes associated with disorders that have an increased incidence of skin cancer.

Characteristics of the major hereditary syndromes associated with a predisposition to SCC are described in Table 5 below.

Xeroderma pigmentosum (XP) is a hereditary disorder of nucleotide excision repair that results in cutaneous malignancies in the first decade of life. Affected individuals have an increased sensitivity to sunlight, resulting in a markedly increased risk of SCCs, BCCs, and melanomas. One report found that NMSC was increased 150-fold in individuals with XP; for those younger than 20 years, the prevalence was almost 5,000 times what would be expected in the general population.[61]

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Regenerative Medicine Conferences | Tissue Engineering …

The 5th International Conference on Tissue Engineering & Regenerative Medicine which is going to be held during September 12-14, 2016 at Berlin, Germany will bring together world-class personalities working on stem cells, tissue engineering and regenerative medicine to discuss materials-related strategies for disease remediation and tissue repair.

Tissue Regeneration

In the field of biology, regeneration is the progression of renewal, regeneration and growth that makes it possible for genomes, cells, organ regeneration to natural changes or events that cause damage or disturbance.This study is carried out as craniofacial tissue engineering, in-situtissue regeneration, adipose-derived stem cells for regenerative medicine which is also a breakthrough in cell culture technology. The study is not stopped with the regeneration of tissue where it is further carried out in relation with cell signaling, morphogenetic proteins. Most of the neurological disorders occurred accidental having a scope of recovery by replacement or repair of intervertebral discs repair, spinal fusion and many more advancements. The global market for tissue engineering and regeneration products such as scaffolds, tissueimplants, biomimetic materials reached $55.9 billion in 2010 and it is expected to reach $89.7 billion by 2016 at a compounded annual growth rate (CAGR) of 8.4%. It grows to $135 billion by 2024.

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5th InternationalConference on Tissue Engineering and Regenerative Medicine September 12-14, 2016 Berlin, Germany; 5th International Conference onCell and Gene Therapy May 19-21, 2016 San Antonio, USA; InternationalConference on Cancer Immunologyand ImmunotherapyJuly 28-30, 2016 Melbourne, Australia; InternationalConference on Molecular BiologyOctober 13-15, 2016 Dubai, UAE; Tissue Niches and Resident Stem Cells in Adult Epithelia Gordon Research Conference, Regulation of Tissue Homeostasis by Signalling in the Stem Cell Niche August 7-12, Hong Kong, China; 10 Years of IPSCs, Cell Symposia, September 25-27, 2016 Berkeley, CA, USA; World Stem Cells and Regenerative Medicine Congress May 18-20, 2016 London, UK; Notch Signaling in Development, Regeneration and Disease Gordon Research Conference, July 31-August 5, 2016 Lewiston, ME, USA

Designs for Tissue Engineering

The developing field of tissue engineering aims to regenerate damaged tissues by combining cells from the body withbioresorbablematerials, biodegradable hydrogel, biomimetic materials, nanostructures andnanomaterials, biomaterials and tissue implants which act as templates for tissue regeneration, to guide the growth of new tissue by using with the technologies. The global market for biomaterials, nanostructures and bioresorbable materials are estimated to reach $88.4 billion by 2017 from $44.0 billion in 2012 growing at a CAGR of 15%. Further the biomaterials market estimated to be worth more than 300 billion US Dollars and to be increasing 20% per year.

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Organ Engineering

This interdisciplinary engineering has attracted much attention as a new therapeutic means that may overcome the drawbacks involved in the current artificial organs and organtransplantationthat have been also aiming at replacing lost or severely damaged tissues or organs. Tissue engineering and regenerative medicine is an exciting research area that aims at regenerative alternatives to harvested tissues for organ transplantation with soft tissues. Although significant progress has been made in thetissue engineeringfield, many challenges remain and further development in this area will require ongoing interactions and collaborations among the scientists from multiple disciplines, and in partnership with the regulatory and the funding agencies. As a result of the medical and market potential, there is significant academic and corporate interest in this technology.

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International Conference on Restorative Medicine October 24-26, 2016 Chicago, USA; 5th InternationalConference on Cell and Gene Therapy May 19-21, 2016 San Antonio, USA; 5th International Conference on Regenerative Medicine September 12-14, 2016 Berlin, Germany; 2nd International Conference on Tissue preservation August 18-19, 2016 Portland, USA;Cell and Gene TherapyJanuary 25-27, 2016 Washington D.C., USA; ISSCR Stem Cell Models of Neural Degeneration and Disease February 1-3, 2016 Dresden, Germany; Craniofacial Morphogenesis and Tissue Regeneration March 12-18, 2016 California, USA; Keystone Stem Cells and Cancer (C1) March 6-10, Colorado, USA; Keystone Stem Cells and Regeneration in the Digestive Organs (X6) March 13 17 Colorado, USA

Cancer Stem Cells

The characterization of cancer stem cell is done by identifying the cell within a tumor that possesses the capacity to self-renew and to cause theheterogeneous lineagesof cancer cells that comprise the tumor. This stem cell which acts as precursor for the cancer acts as a tool against it indulging the reconstruction of cancer stem cells, implies as the therapeutic implications and challenging the gaps globally. The global stem cell market will grow from about $5.6 billion in 2013 to nearly $10.6 billion in 2018, registering a compound annual growth rate (CAGR) of 3.6% from 2013 through 2018. The Americas is the largest region of globalstem cellmarket, with a market share of about $2.0 billion in 2013. The region is projected to increase to nearly $3.9 billion by 2018, with a CAGR of 13.9% for the period of 2013 to 2018. Europe is the second largest segment of the global stem cell market and is expected to grow at a CAGR of 13.4% reaching about $2.4 billion by 2018 from nearly $1.4 billion in 2013.

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5th InternationalConference Cell and Gene Therapy May 19-21, 2016 San Antonio, USA; International Conference on Molecular Biology October 13-15, 2016 Dubai, UAE; 5th International Conference on Tissue EngineeringSeptember 12-14, 2016 Berlin, Germany; 2nd International Conference on Tissue preservationAugust 18-19, 2016 Portland, USA; Molecular and Cellular Basis of Growth and Regeneration (A3) January 10 14, 2016 Colorado, USA; Cell and Gene TherapyJanuary 25-27, 2016 Washington D.C., USA; ISSCR Stem Cell Models of Neural Degeneration and Disease March 13 17, 2016 Dresden, Germany; Craniofacial Morphogenesis and Tissue Regeneration March 12-18, 2016 California, USA; World Stem Cells Congress May 18-20, 2016 London, UK

Bone Tissue Engineering

Tissue engineering ofmusculoskeletal tissues, particularly bone and cartilage, is a rapidly advancing field. In bone, technology has centered on bone graft substitute materials and the development of biodegradable scaffolds. Recently, tissue engineering strategies have included cell and gene therapy. The availability of growth factors and the expanding knowledge base concerning the bone regeneration with modern techniques like recombinant signaling molecules, solid free form fabrication of scaffolds, synthetic cartilage, Electrochemical deposition,spinal fusionand ossification are new generated techniques for tissue-engineering applications. The worldwide market for bone and cartilage repairs strategies is estimated about $300 million. During the last 10/15 years, the scientific community witnessed and reported the appearance of several sources of stem cells with both osteo and chondrogenic potential.

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5th International Conference on Tissue Engineering and Regenerative Medicine September 12-14, 2016 Berlin, Germany; 3rd 2nd International Conference on Tissue preservation and Bio-banking August 18-19, 2016 Portland, USA; 5th International Conference on Cell and Gene Therapy May 19-21, 2016 San Antonio, USA; International Conference on Restorative Medicine October 24-26, 2016 Chicago, USA; 10th World Biomaterials Congress May 17-22, 2016 Quebec, Canada; 2016 TERMIS-EU Conference June 28- July1, 2016 Uppsala, Sweden; 2016 TERMIS-AP Conference Tamsui Town of New Taipei City May 23-28, 2016; 2016 TERMIS-AM Conference September 3-6, 2016, San Diego, USA; Pluripotency: From basic science to therapeutic applications 22-24 March 2016 Kyoto, Japan

Scaffolds

Scaffolds are one of the three most important elements constituting the basic concept of regenerative medicine, and are included in the core technology of regenerative medicine. Every day thousands of surgical procedures are performed to replace or repair tissue that has been damaged through disease or trauma. The developing field of tissue engineering (TE) aims to regeneratedamaged tissuesby combining cells from the body with highly porous scaffold biomaterials, which act as templates for tissue regeneration, to guide the growth of new tissue. Scaffolds has a prominent role in tissue regeneration the designs, fabrication, 3D models, surface ligands and molecular architecture, nanoparticle-cell interactions and porous of thescaffoldsare been used in the field in attempts to regenerate different tissues and organs in the body. The world stem cell market was approximately 2.715 billion dollars in 2010, and with a growth rate of 16.8% annually, a market of 6.877 billion dollars will be formed in 2016. From 2017, the expected annual growth rate is 10.6%, which would expand the market to 11.38 billion dollars by 2021.

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InternationalConference on Restorative MedicineOctober 24-26, 2016 Chicago, USA; 5th InternationalConference onCell and Gene TherapyMay 19-21, 2016 San Antonio, USA; 5th InternationalConference on Regenerative MedicineSeptember 12-14, 2016 Berlin, Germany; 2ndInternational Conference on Tissue preservationAugust 18-19, 2016 Portland, USA;Cell and Gene TherapyJanuary 25-27, 2016 Washington D.C., USA; ISSCRStem Cell Modelsof Neural Degeneration and Disease February 1-3, 2016 Dresden, Germany; Craniofacial Morphogenesis andTissue RegenerationMarch 12-18, 2016 California, USA; KeystoneStem Cells and Cancer(C1) March 6-10, Colorado, USA; KeystoneStem Cells and Regenerationin the Digestive Organs (X6) March 13 17 Colorado, USA

Tissue Regeneration Technologies

Guided tissue regeneration is defined as procedures attempting to regenerate lost periodontal structures through differential tissue responses. Guidedbone regenerationtypically refers to ridge augmentation or bone regenerative procedures it typically refers to regeneration of periodontal therapy. The recent advancements and innovations in biomedical and regenerative tissue engineering techniques include the novel approach of guided tissue regeneration and combination ofnanotechnologyand regenerative medicine.

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Regeneration and Therapeutics

Regenerative medicinecan be defined as a therapeutic intervention which replaces or regenerates human cells, tissues or organs, to restore or establish normal function and deploys small molecule drugs, biologics, medical devices and cell-based therapies. It deals with the different therapeutic uses like stem cells for tissue repair, tissue injury and healing process, cardiacstem cell therapyfor regeneration, functional regenerative recovery, effects of aging on tissuerepair/regeneration, corneal regeneration & degeneration. The global market is expected to reach $25.5 billion by 2011 and will further grow to $36.1 billion by 2016 at a CAGR of 7.2%. It is expected to reach $65 billion mark by 2024.

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Regenerative medicine

Regenerative medicine is a branch oftranslational researchin tissue engineering and molecular biology which deals with the process of replacing, engineering or regenerating human cells, tissues or organs to restore or establish normal function. The latest developments involve advances in cell and gene therapy and stem cell research, molecular therapy, dental and craniofacial regeneration.Regenerative medicineshave the unique ability to repair, replace and regenerate tissues and organs, affected due to some injury, disease or due to natural aging process. These medicines are capable of restoring the functionality of cells and tissues. The global regenerative medicine market will reach $ 67.6 billion by 2020 from $16.4 billion in 2013, registering a CAGR of 23.2% during forecast period (2014 – 2020). Small molecules and biologics segment holds prominent market share in the overall regenerative medicine technology market and is anticipated to grow at a CAGR of 18.9% during the forecast period.

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Applications of Tissue Engineering

The applications of tissue engineering and regenerative medicine are innumerable as they mark the replacement of medication andorgan replacement. The applications involve cell tracking andtissue imaging, cell therapy and regenerative medicine, organ harvesting, transport and transplant, the application of nanotechnology in tissue engineering and regenerative medicine and bio banking. Globally the research statistics are increasing at a vast scale and many universities and companies are conducting events on the subject regenerative medicine conference like tissue implants workshops, endodontics meetings, tissue biomarkers events, tissue repair meetings, regenerative medicine conferences, tissue engineering conference, regenerative medicine workshop, veterinary regenerative medicine, regenerative medicine symposiums, tissue regeneration conferences, regenerative medicine congress.

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Regenerative Medicine Market

There are strong pricing pressures from public healthcare payers globally as Governments try to reduce budget deficits. Regenerative medicine could potentially save public health bodies money by reducing the need for long-term care and reducing associated disorders, with potential benefits for the world economy as a whole.The global market fortissue engineeringand regeneration products reached $55.9 billion in 2010, is expected to reach $59.8 billion by 2011, and will further grow to $89.7 billion by 2016 at a compounded annual growth rate (CAGR) of 8.4%. It grows to $135 billion to 2024. The contribution of the European region was 43.3% of the market in 2010, a value of $24.2 billion. Themarketis expected to reach $25.5 billion by 2011 and will further grow to $36.1 billion by 2016 at a CAGR of 7.2%. It grows to $65 billion to 2024.

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Regenerative Medicine Europe

Leading EU nations with strong biotech sectors such as the UK and Germany are investing heavily in regenerative medicine, seeking competitive advantage in this emerging sector. The commercial regenerative medicine sector faces governance challenges that include a lack of proven business models, an immature science base and ethical controversy surrounding hESC research. The recent global downturn has exacerbated these difficulties: private finance has all but disappeared; leading companies are close to bankruptcy, and start-ups are struggling to raise funds. In the UK the government has responded by announcing 21.5M funding for the regenerative medicine industry and partners. But the present crisis extends considerably beyond regenerative medicine alone, affecting much of the European biotech sector. A 2009 European Commission (EC) report showed the extent to which the global recession has impacted on access to VC finance in Europe: 75% of biopharma companies in Europe need capital within the next two years if they are to continue their current range of activities.

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Embryonic Stem Cell

Embryonic stem cells are pluripotent, meaning they are able to grow (i.e. differentiate) into all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body as long as they are specified to do so. Embryonic stem cells are distinguished by two distinctive properties: their pluripotency, and their ability to replicate indefinitely. ES cells are pluripotent, that is, they are able to differentiate into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm. These include each of the more than 220 cell types in the adult body. Pluripotency distinguishes embryonic stem cells from adult stem cells found in adults; while embryonic stem cells can generate all cell types in the body, adult stem cells are multipotent and can produce only a limited number of cell types. Additionally, under defined conditions, embryonic stem cells are capable of propagating themselves indefinitely. This allows embryonic stem cells to be employed as useful tools for both research and regenerative medicine, because they can produce limitless numbers of themselves for continued research or clinical use.

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Stem Cell Transplant

Stem cell transplantation is a procedure that is most often recommended as a treatment option for people with leukemia, multiple myeloma, and some types of lymphoma. It may also be used to treat some genetic diseases that involve the blood. During a stem cell transplant diseased bone marrow (the spongy, fatty tissue found inside larger bones) is destroyed with chemotherapy and/or radiation therapy and then replaced with highly specialized stem cells that develop into healthy bone marrow. Although this procedure used to be referred to as a bone marrow transplant, today it is more commonly called a stem cell transplant because it is stem cells in the blood that are typically being transplanted, not the actual bone marrow tissue.

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Market Analysis Report:

Tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ. Regenerative medicine is not one discipline. It can be defined as a therapeutic intervention which replaces or regenerates human cells, tissues or organs, to restore or establish normal function and deploys small molecule drugs, biologics, medical devices and cell-based therapies

Currently it has emerged as a rapidly diversifying field with the potential to address the worldwide organ shortage issue and comprises of tissue regeneration and organ replacement. Regenerative medicine could potentially save public health bodies money by reducing the need for long-term care and reducing associated disorders, with potential benefits for the world economy as a whole.The global tissue engineering and regeneration market reached $17 billion in 2013. This market is expected to grow to nearly $20.8 billion in 2014 and $56.9 billion in 2019, a compound annual growth rate (CAGR) of 22.3%. On the basis of geography, Europe holds the second place in the global market in the field of regenerative medicine & tissue engineering. In Europe countries like UK, France and Germany are possessing good market shares in the field of regenerative medicine and tissue engineering. Spain and Italy are the emerging market trends for tissue engineering in Europe.

Tissue engineering is “an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ. Currently it has emerged as a rapidly diversifying field with the potential to address the worldwide organ shortage issue and comprises of tissue regeneration and organ replacement. A novel set of tissue replacement parts and implementation strategies had shown a great revolution in this field. Cells placed on or within the tissue constructs is the most common methodology in tissue engineering.

Regenerative medicine is not one discipline. It can be defined as a therapeutic intervention which replaces or regenerates human cells, tissues or organs, to restore or establish normal function and deploys small molecule drugs, biologics, medical devices and cell-based therapies

This field continues to evolve. In addition to medical applications, non-therapeutic applications include using tissues as biosensors to detect biological or chemical threat agents, and tissue chips that can be used to test the toxicity of an experimental medication. Tissue Engineering and Regenerative Medicine is the major field in Medicine, which is still under research and the advancements are maximizing day to day.

Regenerative Medicine-2015 is an engrossed a vicinity of cognizant discussions on novel subjects like Tissue Regeneration, Materials & Designs for Tissue Engineering, Stem CellTools to Battle Cancer, Bioreactors in Tissue Engineering, Regeneration & Therapeutics, Cord Blood & Regenerative Medicine and Clinical Medicine, to mention a few. The three days event implants a firm relation of upcoming strategies in the field of Tissue Science & Regenerative Medicine with the scientific community. The conceptual and applicable knowledge shared, will also foster organizational collaborations to nurture scientific accelerations.We bring together business, creative, and technology leaders from the tissue engineering, marketing, and research industry for the most current and relevant.

Berlin is one of the largest and most diverse science regions in Europe. Roughly 200,000 people from around the world teach, research, work and study here. Approximately 17 percent of all students come from abroad, most of them from China, Russia and the USA. Many cooperative programs link Berlins institutes of higher education with partner institutes around the world. Berlin is a city of science at the heart of Europe a city whose history of scientific excellence stems from its many important research institutions and its long track record of scientific breakthroughs. Berlin has numerous modern Technology Centers. Their science-oriented infrastructure makes them attractive locations for young, technology-oriented companies.

Germany places great emphasis on globally networked research cooperation. Many organizations support international researchers and academics: Today more than 32,000 are being supported with scholarships. Besides this, research funding in Germany has the goal of financing the development of new ideas and technologies. The range covers everything from basic research in natural sciences, new technologies to structural research funding at institutions of higher education. On the basis of geography, the regenerative medicine bone and joint market Europe hold the second place in the global market in the field of regenerative medicine & tissue engineering. The market growth is expected to reach $65 billion by 2024 in Europe. In Europe countries like UK, France, and Germany are possessing good market share in the field of regenerative medicine and tissue engineering. Spain and Italy are the emerging market trends for tissue engineering in Europe. As per the scope and emerging market for tissue engineering and regenerative medicine Berlin has been selected as Venue for the 5th International Conference on Tissue Science and Regenerative Medicine.

Meet Your Target MarketWith members from around the world focused on learning about Advertising and marketing, this is the single best opportunity to reach the largest assemblage of participants from the tissue engineering and regenerative medicine community. The meeting engrossed a vicinity of cognizant discussions on novel subjects like Tissue Regeneration, Materials & Designs for Tissue Engineering, Stem CellTools to Battle Cancer, Bioreactors in Tissue Engineering, Regeneration & Therapeutics, Cord Blood & Regenerative Medicine and Clinical Medicine, to mention a few. The three days event implants a firm relation of upcoming strategies in the field of Tissue Engineering & Regenerative Medicine with the scientific community. The conceptual and applicable knowledge shared, will also foster organizational collaborations to nurture scientific accelerations.Conduct demonstrations, distribute information, meet with current and potential customers, make a splash with a new product line, and receive name recognition.

International Stem Cell Forum (ISCF)

International Society for Stem Cell Research (ISSCR)

UK Medical Research Council (MRC)

Australian Stem Cell Center

Canadian Institutes of Health Research (CIHR)

Euro Stem Cell (ACR)

Center for Stem Cell Biology

Stem Cell Research Singapore

UK National Stem Cell Network

Spain Mobile Marketing Association

European Marketing Confederation (EMC)

European Letterbox Marketing Association(ELMA)

European Sales & Marketing Association (ESMA)

The Incentive Marketing Association (IMA Europe)

European Marketing Academy

Figure 1: Statistical Analysis of Societies and Associations

Source: Reference7

Presidents or Vice Presidents/ Directors of Associations and Societies, CEOs of the companies associated with regenerative medicine and tissue engineering Consumer Products. Retailers, Marketing, Advertising and Promotion Agency Executives, Solution Providers (digital and mobile technology, P-O-P design, retail design, and retail execution), Professors and Students from Academia in the study of Marketing and Advertising filed.

Industry 40%

Academia 50%

Others 10%

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Regenerative Medicine Conferences | Tissue Engineering …

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How Your Heart Works | HowStuffWorks

Everyone knows that the heart is a vital organ. We cannot live without our heart. However, when you get right down to it, the heart is just a pump. A complex and important one, yes, but still just a pump. As with all other pumps it can become clogged, break down and need repair. This is why it is critical that we know how the heart works. With a little knowledge about your heart and what is good or bad for it, you can significantly reduce your risk for heart disease.

Heart disease is the leading cause of death in the United States. Almost 2,000 Americans die of heart disease each day. That is one death every 44 seconds. The good news is that the death rate from heart disease has been steadily decreasing. Unfortunately, heart disease still causes sudden death and many people die before even reaching the hospital.

The heart holds a special place in our collective psyche as well. Of course the heart is synonymous with love. It has many other associations, too. Here are just a few examples:

Certainly no other bodily organ elicits this kind of response. When was the last time you had a heavy pancreas?

In this article, we will look at this important organ so that you can understand exactly what makes your heart tick.

Excerpt from:
How Your Heart Works | HowStuffWorks

Recommendation and review posted by sam

Homosexuality – Conservapedia

Homosexuality is the condition of “sexual desire or behavior directed toward a person or persons of one’s own sex.”[1]

Homosexuality has a number of causal factors that influence its ultimate origination in individuals; these factors will be addressed shortly. In addition, homosexuality has a variety of effects on individuals and society. Next, some of the historical events, religious matters, and legal matters relating to homosexuality will be covered. Finally, the latter part of the 20th century has seen a large body of research on the causes and effects of homosexuality.

For more information please see: Homosexuality and biblical interpretation and Homosexuality and the Bible and Atheism and homosexuality and Atheism and the persecution of homosexuals

Below are several Bible verses that condemn homosexuality:

In addition, there are numerous other references that also condemn the lifestyle, such as 1 Kings 22:46 (NASB): “The remnant of the sodomites who remained in the days of his father Asa, he expelled from the land.”

For more information please see: Causes of Homosexuality

Homosexuality is sometimes also defined in terms of an attraction, preference, orientation, or identity. The term “orientation” is particularly favored by those who are promoting public acceptance of homosexuality.[2]

For more information please see: Homosexuality and Genetics

A common argument is that an inclination to homosexuality is inborn and immutable. It is widely believed that the public will become more accepting of homosexuality if they are convinced that it is inborn and immutable. For example, neuroscientist and homosexual Simon Levay stated: “…people who think that gays and lesbians are born that way are also more likely to support gay rights.”[3]

Eight major studies of identical twins in the United States, Australia and Scandinavia during the last two decades indicate that homosexuals were not born that way.[4]Research into the issue of the origins of homosexuality suggests that adoptive brothers are more likely to both be homosexuals than the biological brothers, who share half their genes which suggests that homosexuality is not genetically caused. [5][6] This data prompted the journal Science to report “this . . . suggests that there is no genetic component, but rather an environmental component shared in families”.[7][8] However, in regards to psychosocial and biological theories in regards to the origin of homosexuality, Columbia University psychiatry professors Drs. William Byrne and Bruce Parsons stated in 1994: “There is no evidence that at present to substantiate a biological theory. [T]he appeal of current biological explanations for sexual orientation may derive more from dissatisfaction with the present status of psychosocial explanations than from a substantiating body of experimental data”.[9]

Dr. Tahir I. Jaz, M.D., Winnipeg, Canada states: “The increasing claims of being “born that way” parallels the rising political activism of homosexual organizations, who politicize the issue of homosexual origins. In the 1970s, approximately ten percent of homosexuals claimed to be “born homosexual” according to a large scale survey….However, in a survey in the 1980s, with the homosexual rights movement increasingly becoming active, thirty-five percent claimed to be born that way.[10]

For more information please see: Religious Upbringing and Culture Affects Rates of Homosexuality

Dr. Neil Whitehead is a research scientist and biochemist from New Zealand and his wife Briar Whitehead is a writer.[11] Dr. Whitehead coauthored a book with with his wife entitled My Genes Made Me Do it – a scientific look at sexual orientation which argues that there is no genetic determinism in regards to homosexuality (homosexuals are “not born that way”) and that there is abundant documentation that individuals are able to leave homosexuality and become heterosexuals.[12]

Dr. Whitehead and Briar Whitehead declared:

This evidence comes from missionaries who commonly spend 25 years of their lives living in one culture, far more than almost any anthropologist….Overall they can be considered as reliable witnesses. For example, in contrast to groups like the Sambia in the New Guinea highlands, where homosexuality was compulsory, only about 2-3 percent of Western Dani (also in the New Guinea highlands) practiced it. However, in another group of Dani who were genetically related, homosexuality was totally unknown. Missionaries report that when they were translating the Bible into Dani for this group, their tribal assistants, who knew their own culture intimately, were nonplused by references to homosexuality in Romans 1; they did not understand the concept. Another missionary, with the same group for 25 years, overheard many jests and sexually ribald exchanges among the men, but never a single mention of homosexuality in all that time. When Dani went to help with missionary work among the Sambia, they were astounded at some of the homosexual practices they saw for the first time. Although it is always difficult for a foreigner to be completely sure whether a rare and stigmatized behavior exists, it is certainly true that if three such different experiences of homosexuality can occur in groups of people so closely related genetically, genetically enforced homosexuality is an impossibility.[13]

The religious leader and civil rights leader Martin Luther King (MLK) never championed the homosexual agenda. In fact, MLK saw homosexuality as probably a culturally induced “problem” and he believed that homosexuals could become ex-homosexuals. (see: Overcoming homosexuality).[14]

King wrote in a 1958 column: The type of feeling that you have toward boys is probably not an innate tendency, but something that has been culturally acquired, . You are already on the right road toward a solution, since you honestly recognize the problem and have a desire to solve it.[15]

In 1994, the book Sex in America: A definitive survey by Robert T. Michael, John H. Gagnon, Edward O. Laumann, and Gina Kolata stated the following:

The aforementioned authors Dr. Whitehead and Briar Whitehead similarly wrote:

For more information please see: Failure of Experiments to Show Genetic Determinism For Homosexuality

Dr. Dean Hamer is a researcher often cited to show that there is empirical data supporting the notion of genetic determinism in regards to homosexuality. News organizations like National Public Radio and Newsweek have done news stories regarding his work.[18] In respect to the press trumpeting various findings genetics-of-behavior research uncritically the science journal Science stated the following in 1994:

The Gallup Organization reported: “The Family Research Report says ‘around 2-3% of men, and 2% of women, are homosexual or bisexual.'”[20] The U.S Department of Health and Human Services reported: “While the percentage of women and men aged 18-44 years who reported they were either heterosexual or homosexual was similar (94% of women and 96% of men said they were heterosexual while 1.1% of women and 1.7% of men said they were homosexual or gay), the percentage of women who reported they were bisexual was more than 3 times as high as men (3.5% of women vs. 1.1% of men).”[21][22]

In regards to the issue of homosexuality and choice, given the existence of ex-homosexuals and given the existence of human cultures where homosexuality has apparently not existed, the position that homosexuality is ultimately a choice in individuals or at the very least can be a choice in individuals has strong evidential support. In short, there is a strong argument that one can leave homosexuality.

Also, in 2012 ABC News reported concerning actress Cynthia Nixon: “Cynthia Nixon stands by her statement that she is gay by choice, despite the backlash shes received from members of the gay community.”[23] In addition, given that the homosexual population has significantly higher rates of many diseases and the homosexual population also has significantly lower rates of various measures of mental health it can be strongly argued that engaging in homosexual acts is a bad choice for individuals. Another other factor that makes engaging in homosexual acts a bad choice for individuals is the significantly higher rates of domestic violence in homosexual couples. In addition, according to experts homosexual murders are relatively or quite common and often homosexual murders are very brutal. Also, the homosexual population has a greater propensity to engage in illegal drug use.

A 2003 poll done by Ellison Research of Phoenix, Arizona stated that 82% of all American Protestant ministers agreed with the statement homosexuality is a choice people make”.[24]

Immutability is the inability of a thing to be changed. For example, it is impossible to change a dog into a cat. Likewise, it is impossible to change one’s race, although with makeup or plastic surgery has made it possible to alter one’s racial appearance. The immutability of membership in a group is an important consideration in determining the level of scrutiny given to a law against that group under the Equal Protection Clause.

There has been much debate over whether homosexuality is immutable despite the existence of ex-homosexuals. Often the argument is made that it’s either genetically determined (and thus immutable), or that it is entirely a matter of choice. Given this dichotomy, the premise that “I didn’t choose to be gay” yields the conclusion that it must be genetically determined. However, the search for a “gay gene” has proved elusive. Many others, including most scientists, have a much less ‘black and white’ view. They propose that it is determined by a complex interaction of many factors, some of which could be genetic, but probably also include psychological, environmental and cognitive factors, and is shaped at a very early age.

Simon LeVay wrote: “It’s important to stress what I didn’t find. I did not prove that homosexuality is genetic, or find a genetic cause for being gay. I didn’t show that gay men are born that way, the most common mistake people make in interpreting my work. Nor did I locate a gay center in the brain. … Since I look at adult brains, we don’t know if the differences I found were there at birth or if they appeared later.”[25]

See also: Homosexuality and frontal lobe injury and Religiosity and larger frontal lobes and Atheism and brain function

The frontal lobe plays a role in controlling sexual behavior.[28][29]

According to the 2007 medical journal article (and its abstract) entitled Neurological control of human sexual behaviour: insights from lesion studies which was published in the Journal of Neurology, Neurosurgery, and Psychiatry:

Disinhibited sexual behaviour has been reported following damage to the frontal lobes, particularly the orbitofrontal region of the limbic system.

Kolarsky and colleagues54 examined the relationships between sexual deviation, age of lesion onset and localisation of lesion (temporal vs extratemporal). The authors defined two diagnostic categories: (1) sexual deviation, involving a deviation of sexual object (for example, paedophilia). Homosexuality was included in this category, which would now be considered inappropriate, and (2) sexual disturbances other than deviations, including orgasm in response to stimuli unrelated to the subject’s sexual preference, hypersexuality and hyposexuality…

An association between temporal lobe abnormalities and paedophilia has been reported by Mendez and colleagues.[30]

For more information please see: Ex-Homosexuals and Overcoming Homosexuality and Resources on becoming a Christian

In regards to the question of whether or not homosexuality is a permanent condition, one of the earliest historical records regarding of the existence of ex-homosexuals is a letter of the Apostle Paul to the Corinthian Christian church.

The Apostle Paul taught that homosexuality is a sin when he wrote the following:

Today people still report leaving homosexuality and becoming heterosexual through their Christian faith.[31]

Peter LaBarbera is the President of Americans for Truth which is a organization which counters the homosexual agenda. Peter LaBarbera stated the following regarding Christian ex-homosexuals who reported being transformed by the power of God:

In respect to Peter LaBarbera’s statement above regarding homosexuals overcoming homosexuality through the power of God, in 1980 a study was published in the American Journal of Psychiatry and eleven men participated in this study. The aforementioned study in the American Journal of Psychiatry stated that eleven homosexual men became heterosexuals “without explicit treatment and/or long-term psychotherapy” through their participation in a Pentecostal church.[33] The Apostle Paul in a letter to the church of Corinth indicated that Christians were able to overcome being drunkards through the power of Jesus Christ (I Corinthians 6:9-11).

Dr. Whitehead and Briar Whitehead state in their aforementioned book the following regarding ex-homosexuals overcoming homosexuality:

West mentions one man who was exclusively homosexual for eight years, then became heterosexual…

Another well known author in the field, Hatterer, who believes in sexual orientation change, said, Ive heard of hundreds of … men who went from a homosexual to a heterosexual adjustment on their own.[34]

See: Hate Crime Law Misapplied to Ex-homosexual

See also: Denials that ex-homosexuals exist

Commonly homosexual activists fallaciously argue that ex-homosexuals must never have been really gay at all (see: No true Scotsman fallacy) or is just deluding himself. [35] For example, when the alleged homosexual, male penguin “Harry” mated with a female penguin (see: Homosexuality in animals myth), the homosexual activist Wayne Besen angrily exclaimed “There is no ex-gay sexual orientation. Harry is simply in denial. Hes living what I call the big lie.[36] In Madison, Wisconsin an ex-homosexual was forced to do 50 hours of community service and undergo “tolerance training” (or face jail time and fines) due to a discussion he had with a homosexual (see: Hate Crime Law Misapplied to Ex-homosexual).

The denial that homosexuality is a choice by homosexual activists and liberals is similar to the behavior of fat acceptance movement activists who insist that being overweight is never a choice and ostracize ex-overweight people (see: fat acceptance movement for details).

Two of the more popular anti-homosexuality blogs are Americans For Truth and Gay Christian Movement Watch. The blog Americans For Truth is run by Peter LaBarbera and the blog Gay Christian Movement Watch is run by Pastor D.L. Foster.

A 2006 survey finds homosexual men seek to leave homosexual lifestyle to heal emotional pain and for spiritual reasons rather than outside pressure. In addition, there is other data that supports the above 2006 survey findings.

For additional information please see: Homosexuality and biblical interpretation and Homosexuality and the Bible and Atheism and homosexuality

In respect to homosexuality and the Bible, sound Bible exegesis and Bible exposition demonstrates that the Bible condemns homosexuality.[38][39][40][41] In addition, Christian apologist JP Holding refutes various arguments that assert that the Bible does not condemn homosexuality.[42][43][44][45][46] In his essay which examines the biblical passages regarding homosexuality, Pastor and Associate Professor of Pastoral Ministries at The Master’s Seminary Dr. Alex D. Montoya states that “The Christian needs to befriend and witness to the homosexual with such love, compassion, and wisdom that such will respond to the saving grace of God.”[47]

The Bible clearly associates the city of Sodom with homosexuality (Genesis 19:4-9), although the Bible associates with Sodom other sins as well. Claims that the primary reason for Sodom’s judgment was inhospitality are not supported by sound Bible exegesis.[48][49]

The Bible states regarding Sodom:

…the LORD rained on Sodom and Gomorrah brimstone and fire from the LORD out of heaven, and He overthrew those cities, and all the valley, and all the inhabitants of the cities, and what grew on the ground. Genesis 19:24-25

The following was reported in respect to Dr. Bryant Wood’s archaeological work in relating to the biblical city of Sodom:

Dr. Bryant Wood, in describing these charnel houses, stated that a fire began on the roofs of these buildings. Eventually the burning roof collapsed into the interior and spread inside the building. This was the case in every house they excavated. Such a massive fiery destruction would match the biblical account that the city was destroyed by fire that rained down from heaven. Wood states, “The evidence would suggest that this site of Bab edh-Drha is the biblical city of Sodom.”[50]

Dr. Wood provides some additional material in relation to the find being the biblical city of Sodom.[51][52]

For related information see: Homosexuality and promiscuity and Homosexuality Statistics

A 2004 article by Michael Foust states:

According to the researchers, 42.9 percent of homosexual men in Chicago’s Shoreland area have had more than 60 sexual partners, while an additional 18.4 percent have had between 31 and 60 partners. All total, 61.3 percent of the area’s homosexual men have had more than 30 partners, and 87.8 percent have had more than 15, the research found.

As a result, 55.1 percent of homosexual males in Shoreland — known as Chicago’s “gay center” — have at least one sexually transmitted disease, researchers said.

The three-year study on the sexual habits of Chicago’s citizens will appear in the upcoming book, “The Sexual Organization of The City” (University of Chicago Press), due out this spring.[53][54]

For more information please see: Homosexual Couples and Domestic Violence and Gay bashing

Studies report that homosexual couples have significantly higher incidences of violent behavior. For example, a recent study by the Canadian government states that “violence was twice as common among homosexual couples compared with heterosexual couples”.[55] According the American College of Pediatricians who cite several studies, “Violence among homosexual partners is two to three times more common than among married heterosexual couples.”[56] In addition, the American College of Pediatricians states the following: “Homosexual partnerships are significantly more prone to dissolution than heterosexual marriages with the average homosexual relationship lasting only two to three years.”[57]

In June of 2004, the journal Nursing Clinics of North America reported the following regarding homosexuality and domestic violence:

Male-on-male same-sex domestic violence also has been reported in couples where one or both persons are HIV-positive. Intimate partner abuse and violence include humilation, threatening to disclose HIV status, withholding HIV therapy, and harming family members or pets.[58]

For more information please see: Homosexuality and Murders

Vernon J. Geberth, M.S., M.P.S. who is a former commander of Bronx homicide for the New York City Police Department stated in 1995 concerning homosexuality and murders that homosexual murders are relatively common and these murders may involve male victims murdered by other males or may involve female victims who are in some type of lesbian relationship and they are murdered by another female.[59] In 2005, Dr. Harnam Singh, Dr. Luv Sharma, and Dr. Dhattarwal reported in the Journal of Indian Academy of Forensic Medicine in respect to homosexuality and murders that homosexual murders are quite common and that these murders may involve both sexes either as victims or as assailants.[60]

There have been a number of forensic journal articles on the issue of homosexual homicides and overkill.[61][62][63][64][65] In 1996, the forensic journal The American Journal of Forensic Medicine and Pathology published an article entitled Homicide in homosexual victims: a study of 67 cases from the Broward County, Florida, Medical Examiner’s office (1982-1992), with special emphasis on “overkill”. The abstract for the journal article states:

According to the New York Times, Dr. William Eckert was a world-renowned authority in the field of pathology and he worked on major murder cases including the assassination of Senator Robert F. Kennedy and the Charles Manson murders.[67] Dr. Eckert founded the American Journal of Forensic Medicine and Pathology.[68][69] According to Time magazine, Dr. Eckert was a pioneer who encouraged collaborative effort between law-enforcement and forensics teams.[70]

Dr. Eckert wrote concerning homosexual murders:

The Encyclopedia of Serial Killers by Michael Newton reports:

The previously cited pathology textbook by Knight and Saukko stated the following: “In addition, quite a number of fatal altercations arise because a heterosexual man becomes violent when importuned by a homosexual.”[74]

Women who engage in homosexuality are called lesbians (after the ancient Greek island of Lesbos). Recently, the former lesbian activist Charlene Cothran left homosexuality and converted her pro-homosexuality magazine to one that helps homosexuals find freedom and deliverance through faith in Jesus Christ.[75][76] Lesbian activist Yvette Cantu Schneider also became a Christian and left homosexuality.[77][78]

In 2007, WorldNetDaily published the following regarding a lesbian woman:

For more information please see: Homosexuality and health and Gay bathhouses

A review of the history of homosexuality and AIDS, indicates the original spread of AIDS is generally attributed to the aforementioned promiscuity of homosexual men. Originally the syndrome was called the “gay disease” because the overwhelming majority of patients were homosexual men.

In September of 2010, Reuters reported: “Nearly one in five gay and bisexual men in 21 major U.S. cities are infected with HIV, and nearly half of them do not know it”.[80] A September 2010 report of the Centers for Disease Control and Prevention (CDC) reported: “Gay, bisexual, and other men who have sex with men (MSM) represent approximately 2% of the US population, yet are the population most severely affected by HIV and are the only risk group in which new HIV infections have been increasing steadily since the early 1990s. In 2006, MSM accounted for more than half (53%) of all new HIV infections in the United States…”[81]

In August of 2009, LifeSiteNews reported: “An official with the Centers for Disease Control and Prevention (CDC) announced the CDC’s estimate Monday that in the United States AIDS is fifty times more prevalent among men who have sex with men (‘MSM’) than the rest of the population.”[82] This is a dramatic recent increase. In June of 2004, the journal Nursing Clinics of North America reported that homosexual men and men who have sex with men “are nine times more likely to become infected with HIV than their heterosexual counterparts”.[83] Of newly diagnosed HIV infections in the United States during the year 2003, the Centers for Disease Control and Prevention (CDC) estimated that about 63% were among men who were infected through sexual contact with other men.[84] As of 1998, fifty-four percent of all AIDS cases in the United States were homosexual men, and the CDC stated that nearly ninety percent of these men acquired HIV through sexual activity with other men.[85]

In 2004, Jeffrey D. Klausner, Robert Kohn, and Charlotte Kent reported in the journal Clinical Infectious Diseases the following: “Proctitis, or inflammation of the rectum, is a condition that is not uncommon among men who have sex with men (MSM), and, in HIV-negative men, greatly increases the risk of acquiring HIV infection. With the recent increases in bacterial sexually transmitted diseases (STDs) among MSM in the United States and Europe, there has been a concomitant increase in the number of cases of clinical proctitis.”[86] On March 15, 2004 Medscape published an article by John G. Bartlett, M.D. entitled New Look at “Gay Bowel Syndrome” in which they commented on the aforementioned 2004 journal article Etiology of clinical proctitis among men who have sex with men published by JD Klausner and C. Kent in the journal Clinical Infectious Diseases. The article in Medscape stated the following:

Johns Hopkins HIV Guide website has a duplicate of the aforementioned article by John G. Bartlett, M.D. at Medscape which was entitled New Look at “Gay Bowel Syndrome”.[88][89]

In 2004, the prominent medical website, WebMD, stated the following: “Men who have sex with men and women are a “significant bridge for HIV to women,” the CDC’s new data suggest.”[90]

See: Teenage homosexuality and Teenage AIDS

In relation to homosexuality and MRSA, on January 15, 2008 the newspaper San Francisco Chronicle had a news article entitled San Francisco gay community an epicenter for new strain of virulent staph.[91] The San Francisco Chronicle news article stated the following in regards to homosexuality and MRSA:

On February 19, 2008 the Annals of Internal Medicine published a study regarding antiobiotic resistant staph infection in relation to men who have sex with men and the abstract for the article states the following in relation to homosexuality and MRSA:

Syphilis is an infection caused by the bacteria Treponema pallidum. An early publication to propose the link between homosexuality contributing to the spread of sexually transmitted disease was the English publication Proceedings of the Royal Society of Medicine in 1962.[94] The Proceedings of the Royal Society of Medicine made the following statement: “The importance of homosexual practices in the spread of venereal diseases has attracted particular attention recently. It almost seems that these practices are keeping syphilis alive in this country.” [95]

The news organization Cybercast News Service reported the following about homosexuality and syphilis:

In a report on sexually transmitted diseases (STDs) issued Tuesday, the government said syphilis, a disease that was almost eliminated as a public health threat less than 10 years ago, is on the rise — with cases increasing each year since 2000.[96]

In relation to homosexuality and gonorrhea, in 2006, the American Association of Family Physicians reported: “Men who have sex with men (MSM) have high rates of gonococcal infection. In San Francisco, more than one half of these infections occur in MSM, and previous cross-sectional studies have reported a prevalence of up to 15.3 percent in this group.”[97]

In 2007, the medical journal Sexually Transmitted Diseases published an article entitled Sexually Transmitted Infections in Western Europe Among HIV-Positive Men Who Have Sex With Men which stated the following regarding homosexuality and gonorrhea:

In Denmark (19941999), gonorrhea incidence was 6 times higher among known HIV-positive MSM [men who have sex with men]… A study in a Parisian clinic showed that at least one-third (30/92) of MSM diagnosed with gonorrhea between January 1999 and May 2001 were HIV-positive… In Sweden, 5.4% (4/74) of gonorrhea cases were in HIV-positive MSM in 2000. By comparison, at sentinel sites in England and Wales, 32% (123/381) of MSM with gonorrhea were HIV-positive in 2004.[98]

Lymphogranuloma venereum is a sexually transmitted disease that mainly infects the lymphatics.[99] According to the recent medical literature, there have been recent outbreaks of lymphogranuloma venereum in Europe and North America and the outbreaks have been limited to the homosexual community.

In 2006, the The Medical Journal of Australia reported the following:

Amoebiasis has become endemic in MSM in Japan and causes significant morbidity and mortality; complications such as colitis and liver abscesses occur more frequently in homosexual and bisexual men than in heterosexual men. Similar findings on amoebiasis are reported from Taiwan, with MSM at increased risk for invasive amoebiasis and intestinal colonisation with E. histolytica.[101]

In 2001, The journal Internal Medicine (Tokyo, Japan) published an article entitled Amebiasis in acquired immunodeficiency syndrome in which they stated the following the following:

Sexually transmitted diseases that cause proctitis include syphilis, gonorrhea, lymphogranuloma venereum, and amebiasis and as noted earlier the homosexual community has significant problems in regards to these illnesses.[104] In addition, as mentioned earlier proctitis significant risk factor in respect to HIV infection.[105][106] According to the Mayo Clinic, “proctitis in general mainly affects adult males”.[107]Proctitis, syphilis, gonorrhea, lymphogranuloma venereum, and amebiasis are all maladies that are associated with gay bowel syndrome which why John G. Bartlett, M.D. stated at the Johns Hopkins HIV Guide website and at Medscape that gay bowel syndrome is still currently an issue.[108][109]

For more information please see: Homosexuality and Hepatitis

In relation to homosexuality and hepatitis, according to the Centers for Disease Control and Prevention (CDC) both Hepatitis A and Hepatitis B disproportionately affects men who have sex with men (MSM).[110][111]

In a 2007 article entitled Advances in the Management of Viral Hepatitis B and Hepatitis C Infection in HIV-Coinfected Patients Vincent V. Soriano, MD, PhD reported in Medscape the following regarding homosexuality and Hepatitis C viral infections:

Viral hepatitis is one of the illnesses of gay bowel syndrome.

Go here to read the rest:
Homosexuality – Conservapedia

Recommendation and review posted by simmons

Ageing – Wikipedia, the free encyclopedia

Ageing, also spelled aging, is the process of becoming older. The term refers especially to human beings, many animals, and fungi, whereas for example bacteria, perennial plants and some simple animals are potentially immortal. In the broader sense, ageing can refer to single cells within an organism which have ceased dividing (cellular senescence) or to the population of a species (population ageing).

In humans, ageing represents the accumulation of changes in a human being over time,[1] encompassing physical, psychological, and social change. Reaction time, for example, may slow with age, while knowledge of world events and wisdom may expand. Ageing is among the greatest known risk factors for most human diseases:[2] of the roughly 150,000 people who die each day across the globe, about two thirds die from age-related causes.

The causes of ageing are unknown; current theories are assigned to the damage concept, whereby the accumulation of damage (such as DNA breaks or oxidised DNA) may cause biological systems to fail, or to the programmed ageing concept, whereby internal processes (such as DNA telomere shortening) may cause ageing. Programmed ageing should not be confused with programmed cell death (apoptosis).

The discovery, in 1934, that calorie restriction can extend lifespan by 50% in rats has motivated research into delaying and preventing ageing.

Human beings and members of other species, especially animals, necessarily experience ageing and mortality. Fungi, too, can age.[3] In contrast, many species can be considered immortal: for example, bacteria fission to produce daughter cells, strawberry plants grow runners to produce clones of themselves, and animals in the genus Hydra have a regenerative ability with which they avoid dying of old age.

Early life forms on Earth, starting at least 3.7 billion years ago,[4] were single-celled organisms. Such single-celled organisms (prokaryotes, protozoans, algae) multiply by fissioning into daughter cells, thus do not age and are innately immortal.[5][6]

Ageing and mortality of the individual organism became possible with the evolution of sexual reproduction,[7] which occurred with the emergence of the fungal/animal kingdoms approximately a billion years ago, and with the evolution of flowering plants 160 million years ago. The sexual organism could henceforth pass on some of its genetic material to produce new individuals and itself could become disposable with regards to the survival of its species.[7] This classic biological idea has however been perturbed recently by the discovery that the bacterium E. coli may split into distinguishable daughter cells, which opens the theoretical possibility of “age classes” among bacteria.[8]

Even within humans and other mortal species, there are cells with the potential for immortality: cancer cells which have lost the ability to die when maintained in cell culture such as the HeLa cell line,[9] and specific stem cells such as germ cells (producing ova and spermatozoa).[10] In artificial cloning, adult cells can be rejuvenated back to embryonic status and then used to grow a new tissue or animal without ageing.[11] Normal human cells however die after about 50 cell divisions in laboratory culture (the Hayflick Limit, discovered by Leonard Hayflick in 1961).[9]

A number of characteristic ageing symptoms are experienced by a majority or by a significant proportion of humans during their lifetimes.

Dementia becomes more common with age.[31] About 3% of people between the ages of 6574 have dementia, 19% between 75 and 84 and nearly half of those over 85 years of age.[32] The spectrum includes mild cognitive impairment and the neurodegenerative diseases of Alzheimer’s disease, cerebrovascular disease, Parkinson’s disease and Lou Gehrig’s disease. Furthermore, many types of memory may decline with ageing, but not semantic memory or general knowledge such as vocabulary definitions, which typically increases or remains steady until late adulthood[33] (see Ageing brain). Intelligence may decline with age, though the rate may vary depending on the type and may in fact remain steady throughout most of the lifespan, dropping suddenly only as people near the end of their lives. Individual variations in rate of cognitive decline may therefore be explained in terms of people having different lengths of life.[34] There might be changes to the brain: after 20 years of age there may be a 10% reduction each decade in the total length of the brain’s myelinated axons.[35][36]

Age can result in visual impairment, whereby non-verbal communication is reduced,[37] which can lead to isolation and possible depression. Macular degeneration causes vision loss and increases with age, affecting nearly 12% of those above the age of 80.[38] This degeneration is caused by systemic changes in the circulation of waste products and by growth of abnormal vessels around the retina.[39]

A distinction can be made between “proximal ageing” (age-based effects that come about because of factors in the recent past) and “distal ageing” (age-based differences that can be traced back to a cause early in person’s life, such as childhood poliomyelitis).[34]

Ageing is among the greatest known risk factors for most human diseases.[2] Of the roughly 150,000 people who die each day across the globe, about two thirds100,000 per daydie from age-related causes. In industrialised nations, the proportion is higher, reaching 90%.[40][41][42]

At present, researchers are only just beginning to understand the biological basis of ageing even in relatively simple and short-lived organisms such as yeast.[43] Less still is known about mammalian ageing, in part due to the much longer lives in even small mammals such as the mouse (around 3 years). A primary model organism for studying ageing is the nematode C. elegans, thanks to its short lifespan of 23 weeks, the ability to easily perform genetic manipulations or suppress gene activity with RNA interference, and other factors.[44] Most known mutations and RNA interference targets that extend lifespan were first discovered in C. elegans.[45]

Factors that are proposed to influence biological ageing[46] fall into two main categories, programmed and damage-related. Programmed factors follow a biological timetable, perhaps a continuation of the one that regulates childhood growth and development. This regulation would depend on changes in gene expression that affect the systems responsible for maintenance, repair and defence responses. Damage-related factors include internal and environmental assaults to living organisms that induce cumulative damage at various levels.[47]

There are three main metabolic pathways which can influence the rate of ageing:

It is likely that most of these pathways affect ageing separately, because targeting them simultaneously leads to additive increases in lifespan.[49]

The rate of ageing varies substantially across different species, and this, to a large extent, is genetically based. For example, numerous perennial plants ranging from strawberries and potatoes to willow trees typically produce clones of themselves by vegetative reproduction and are thus potentially immortal, while annual plants such as wheat and watermelons die each year and reproduce by sexual reproduction. In 2008 it was discovered that inactivation of only two genes in the annual plant Arabidopsis thaliana leads to its conversion into a potentially immortal perennial plant.[50]

Clonal immortality apart, there are certain species whose individual lifespans stand out among Earth’s life-forms, including the bristlecone pine at 5062 years[51] (however Hayflick states that the bristlecone pine has no cells older than 30 years), invertebrates like the hard clam (known as quahog in New England) at 508 years,[52] the Greenland shark at 400 years,[53] fish like the sturgeon and the rockfish, and the sea anemone[54] and lobster.[55][56] Such organisms are sometimes said to exhibit negligible senescence.[57] The genetic aspect has also been demonstrated in studies of human centenarians.

In laboratory settings, researchers have demonstrated that selected alterations in specific genes can extend lifespan quite substantially in yeast and roundworms, less so in fruit flies and less again in mice. Some of the targeted genes have homologues across species and in some cases have been associated with human longevity.[58]

Caloric restriction substantially affects lifespan in many animals, including the ability to delay or prevent many age-related diseases.[99] Typically, this involves caloric intake of 6070% of what an ad libitum animal would consume, while still maintaining proper nutrient intake.[99] In rodents, this has been shown to increase lifespan by up to 50%;[100] similar effects occur for yeast and Drosophila.[99] No lifespan data exist for humans on a calorie-restricted diet,[72] but several reports support protection from age-related diseases.[101][102] Two major ongoing studies on rhesus monkeys initially revealed disparate results; while one study, by the University of Wisconsin, showed that caloric restriction does extend lifespan,[103] the second study, by the National Institute on Ageing (NIA), found no effects of caloric restriction on longevity.[104] Both studies nevertheless showed improvement in a number of health parameters. Notwithstanding the similarly low calorie intake, the diet composition differed between the two studies (notably a high sucrose content in the Wisconsin study), and the monkeys have different origins (India, China), initially suggesting that genetics and dietary composition, not merely a decrease in calories, are factors in longevity.[72] However, in a comparative analysis in 2014, the Wisconsin researchers found that the allegedly non-starved NIA control monkeys in fact are moderately underweight when compared with other monkey populations, and argued this was due to the NIA’s apportioned feeding protocol in contrast to Wisconsin’s truly unrestricted ad libitum feeding protocol. [105] They conclude that moderate calorie restriction rather than extreme calorie restriction is sufficient to produce the observed health and longevity benefits in the studied rhesus monkeys.[106]

In his book How and Why We Age, Hayflick says that caloric restriction may not be effective in humans, citing data from the Baltimore Longitudinal Study of Aging which shows that being thin does not favour longevity.[need quotation to verify][107] Similarly, it is sometimes claimed that moderate obesity in later life may improve survival, but newer research has identified confounding factors such as weight loss due to terminal disease. Once these factors are accounted for, the optimal body weight above age 65 corresponds to a leaner body mass index of 23 to 27.[108]

Alternatively, the benefits of dietary restriction can also be found by changing the macro nutrient profile to reduce protein intake without any changes to calorie level, resulting in similar increases in longevity.[109][110] Dietary protein restriction not only inhibits mTOR activity but also IGF-1, two mechanisms implicated in ageing.[70] Specifically, reducing leucine intake is sufficient to inhibit mTOR activity, achievable through reducing animal food consumption.[111][112]

The Mediterranean diet is credited with lowering the risk of heart disease and early death.[113][114] The major contributors to mortality risk reduction appear to be a higher consumption of vegetables, fish, fruits, nuts and monounsaturated fatty acids, i.e., olive oil.[115]

The amount of sleep has an impact on mortality. People who live the longest report sleeping for six to seven hours each night.[116][117] Lack of sleep (9 hours) is associated with a doubling of the risk of death, though not primarily from cardiovascular disease.[118] Sleeping more than 7 to 8 hours per day has been consistently associated with increased mortality, though the cause is probably other factors such as depression and socioeconomic status, which would correlate statistically.[119] Sleep monitoring of hunter-gatherer tribes from Africa and from South America has shown similar sleep patterns across continents: their average sleeping duration is 6.4 hours (with a summer/winter difference of 1 hour), afternoon naps (siestas) are uncommon, and insomnia is very rare (tenfold less than in industrial societies).[120]

Physical exercise may increase life expectancy.[121] People who participate in moderate to high levels of physical exercise have a lower mortality rate compared to individuals who are not physically active.[122] Moderate levels of exercise have been correlated with preventing aging and improving quality of life by reducing inflammatory potential.[123] The majority of the benefits from exercise are achieved with around 3500 metabolic equivalent (MET) minutes per week.[124] For example, climbing stairs 10 minutes, vacuuming 15 minutes, gardening 20 minutes, running 20 minutes, and walking or bicycling for 25 minutes on a daily basis would together achieve about 3000 MET minutes a week.[124]

Avoidance of chronic stress (as opposed to acute stress) is associated with a slower loss of telomeres in most but not all studies,[125][126] and with decreased cortisol levels. A chronically high cortisol level compromises the immune system, causes cardiac damage/arterosclerosis and is associated with facial ageing, and the latter in turn is a marker for increased morbidity and mortality.[127][128] Stress can be countered by social connection, spirituality, and (for men more clearly than for women) married life, all of which are associated with longevity.[129][130][131]

The following drugs and interventions have been shown to retard or reverse the biological effects of ageing in animal models, but none has yet been proven to do so in humans.

Evidence in both animals and humans suggests that resveratrol may be a caloric restriction mimetic.[132]

As of 2015 metformin was under study for its potential effect on slowing ageing in the worm C.elegans and the cricket.[133] Its effect on otherwise healthy humans is unknown.[133]

Rapamycin was first shown to extend lifespan in eukaryotes in 2006 by Powers et al. who showed a dose-responsive effect of rapamycin on lifespan extension in yeast cells.[134] In a 2009 study, the lifespans of mice fed rapamycin were increased between 28 and 38% from the beginning of treatment, or 9 to 14% in total increased maximum lifespan. Of particular note, the treatment began in mice aged 20 months, the equivalent of 60 human years.[135] Rapamycin has subsequently been shown to extend mouse lifespan in several separate experiments,[136][137] and is now being tested for this purpose in nonhuman primates (the marmoset monkey).[138]

Cancer geneticist Ronald A. DePinho and his colleagues published research in mice where telomerase activity was first genetically removed. Then, after the mice had prematurely aged, they restored telomerase activity by reactivating the telomerase gene. As a result, the mice were rejuvenated: Shrivelled testes grew back to normal and the animals regained their fertility. Other organs, such as the spleen, liver, intestines and brain, recuperated from their degenerated state. “[The finding] offers the possibility that normal human ageing could be slowed by reawakening the enzyme in cells where it has stopped working” says Ronald DePinho. However, activating telomerase in humans could potentially encourage the growth of tumours.[139]

Most known genetic interventions in C. elegans increase lifespan by 1.5 to 2.5-fold. As of 2009[update], the record for lifespan extension in C. elegans is a single-gene mutation which increases adult survival by tenfold.[45] The strong conservation of some of the mechanisms of ageing discovered in model organisms imply that they may be useful in the enhancement of human survival. However, the benefits may not be proportional; longevity gains are typically greater in C. elegans than fruit flies, and greater in fruit flies than in mammals. One explanation for this is that mammals, being much longer-lived, already have many traits which promote lifespan.[45]

Some research effort is directed to slow ageing and extend healthy lifespan.[140][141][142]

The US National Institute on Aging currently funds an intervention testing programme, whereby investigators nominate compounds (based on specific molecular ageing theories) to have evaluated with respect to their effects on lifespan and age-related biomarkers in outbred mice.[143] Previous age-related testing in mammals has proved largely irreproducible, because of small numbers of animals and lax mouse husbandry conditions.[citation needed] The intervention testing programme aims to address this by conducting parallel experiments at three internationally recognised mouse ageing-centres, the Barshop Institute at UTHSCSA, the University of Michigan at Ann Arbor and the Jackson Laboratory.

Several companies and organisations, such as Google Calico, Human Longevity, Craig Venter, Gero,[144]SENS Research Foundation, and Science for Life Extension in Russia,[145] declared stopping or delaying ageing as their goal.

Prizes for extending lifespan and slowing ageing in mammals exist. The Methuselah Foundation offers the Mprize. Recently, the $1 Million Palo Alto Longevity Prize was launched. It is a research incentive prize to encourage teams from all over the world to compete in an all-out effort to “hack the code” that regulates our health and lifespan. It was founded by Joon Yun.[146][147][148][149][150]

Different cultures express age in different ways. The age of an adult human is commonly measured in whole years since the day of birth. Arbitrary divisions set to mark periods of life may include: juvenile (via infancy, childhood, preadolescence, adolescence), early adulthood, middle adulthood, and late adulthood. More casual terms may include “teenagers,” “tweens,” “twentysomething”, “thirtysomething”, etc. as well as “vicenarian”, “tricenarian”, “quadragenarian”, etc.

Most legal systems define a specific age for when an individual is allowed or obliged to do particular activities. These age specifications include voting age, drinking age, age of consent, age of majority, age of criminal responsibility, marriageable age, age of candidacy, and mandatory retirement age. Admission to a movie for instance, may depend on age according to a motion picture rating system. A bus fare might be discounted for the young or old. Each nation, government and non-governmental organisation has different ways of classifying age. In other words, chronological ageing may be distinguished from “social ageing” (cultural age-expectations of how people should act as they grow older) and “biological ageing” (an organism’s physical state as it ages).[151]

In a UNFPA report about ageing in the 21st century, it highlighted the need to “Develop a new rights-based culture of ageing and a change of mindset and societal attitudes towards ageing and older persons, from welfare recipients to active, contributing members of society.”[152] UNFPA said that this “requires, among others, working towards the development of international human rights instruments and their translation into national laws and regulations and affirmative measures that challenge age discrimination and recognise older people as autonomous subjects.”[152] Older persons make contributions to society including caregiving and volunteering. For example, “A study of Bolivian migrants who [had] moved to Spain found that 69% left their children at home, usually with grandparents. In rural China, grandparents care for 38% of children aged under five whose parents have gone to work in cities.”[152]

Population ageing is the increase in the number and proportion of older people in society. Population ageing has three possible causes: migration, longer life expectancy (decreased death rate) and decreased birth rate. Ageing has a significant impact on society. Young people tend to have fewer legal privileges (if they are below the age of majority), they are more likely to push for political and social change, to develop and adopt new technologies, and to need education. Older people have different requirements from society and government, and frequently have differing values as well, such as for property and pension rights.[153]

In the 21st century, one of the most significant population trends is ageing.[154] Currently, over 11% of the world’s current population are people aged 60 and older and the United Nations Population Fund (UNFPA) estimates that by 2050 that number will rise to approximately 22%.[152] Ageing has occurred due to development which has enabled better nutrition, sanitation, health care, education and economic well-being. Consequently, fertility rates have continued to decline and life expectancy have risen. Life expectancy at birth is over 80 now in 33 countries. Ageing is a “global phenomenon,” that is occurring fastest in developing countries, including those with large youth populations, and poses social and economic challenges to the work which can be overcome with “the right set of policies to equip individuals, families and societies to address these challenges and to reap its benefits.”[155]

As life expectancy rises and birth rates decline in developed countries, the median age rises accordingly. According to the United Nations, this process is taking place in nearly every country in the world.[156] A rising median age can have significant social and economic implications, as the workforce gets progressively older and the number of old workers and retirees grows relative to the number of young workers. Older people generally incur more health-related costs than do younger people in the workplace and can also cost more in worker’s compensation and pension liabilities.[157] In most developed countries an older workforce is somewhat inevitable. In the United States for instance, the Bureau of Labor Statistics estimates that one in four American workers will be 55 or older by 2020.[157]

Among the most urgent concerns of older persons worldwide is income security. This poses challenges for governments with ageing populations to ensure investments in pension systems continues in order to provide economic independence and reduce poverty in old age. These challenges vary for developing and developed countries. UNFPA stated that, “Sustainability of these systems is of particular concern, particularly in developed countries, while social protection and old-age pension coverage remain a challenge for developing countries, where a large proportion of the labour force is found in the informal sector.”[152]

The global economic crisis has increased financial pressure to ensure economic security and access to health care in old age. In order to elevate this pressure “social protection floors must be implemented in order to guarantee income security and access to essential health and social services for all older persons and provide a safety net that contributes to the postponement of disability and prevention of impoverishment in old age.”[152]

It has been argued that population ageing has undermined economic development.[158] Evidence suggests that pensions, while making a difference to the well-being of older persons, also benefit entire families especially in times of crisis when there may be a shortage or loss of employment within households. A study by the Australian Government in 2003 estimated that “women between the ages of 65 and 74 years contribute A$16 billion per year in unpaid caregiving and voluntary work. Similarly, men in the same age group contributed A$10 billion per year.”[152]

Due to increasing share of the elderly in the population, health care expenditures will continue to grow relative to the economy in coming decades. This has been considered as a negative phenomenon and effective strategies like labour productivity enhancement should be considered to deal with negative consequences of ageing.[159]

In the field of sociology and mental health, ageing is seen in five different views: ageing as maturity, ageing as decline, ageing as a life-cycle event, ageing as generation, and ageing as survival.[160] Positive correlates with ageing often include economics, employment, marriage, children, education, and sense of control, as well as many others. The social science of ageing includes disengagement theory, activity theory, selectivity theory, and continuity theory. Retirement, a common transition faced by the elderly, may have both positive and negative consequences.[161] As cyborgs currently are on the rise some theorists argue there is a need to develop new definitions of ageing and for instance a bio-techno-social definition of ageing has been suggested.[162]

With age inevitable biological changes occur that increase the risk of illness and disability. UNFPA states that,[155]

“A life-cycle approach to health care one that starts early, continues through the reproductive years and lasts into old age is essential for the physical and emotional well-being of older persons, and, indeed, all people. Public policies and programmes should additionally address the needs of older impoverished people who cannot afford health care.”

Many societies in Western Europe and Japan have ageing populations. While the effects on society are complex, there is a concern about the impact on health care demand. The large number of suggestions in the literature for specific interventions to cope with the expected increase in demand for long-term care in ageing societies can be organised under four headings: improve system performance; redesign service delivery; support informal caregivers; and shift demographic parameters.[163]

However, the annual growth in national health spending is not mainly due to increasing demand from ageing populations, but rather has been driven by rising incomes, costly new medical technology, a shortage of health care workers and informational asymmetries between providers and patients.[164] A number of health problems become more prevalent as people get older. These include mental health problems as well as physical health problems, especially dementia.

It has been estimated that population ageing only explains 0.2 percentage points of the annual growth rate in medical spending of 4.3% since 1970. In addition, certain reforms to the Medicare system in the United States decreased elderly spending on home health care by 12.5% per year between 1996 and 2000.[165]

Positive self-perception of health has been correlated with higher well-being and reduced mortality in the elderly.[166][167] Various reasons have been proposed for this association; people who are objectively healthy may naturally rate their health better than that of their ill counterparts, though this link has been observed even in studies which have controlled for socioeconomic status, psychological functioning and health status.[168] This finding is generally stronger for men than women,[167] though this relationship is not universal across all studies and may only be true in some circumstances.[168]

As people age, subjective health remains relatively stable, even though objective health worsens.[169] In fact, perceived health improves with age when objective health is controlled in the equation.[170] This phenomenon is known as the “paradox of ageing.” This may be a result of social comparison;[171] for instance, the older people get, the more they may consider themselves in better health than their same-aged peers.[172] Elderly people often associate their functional and physical decline with the normal ageing process.[173][174]

The concept of successful ageing can be traced back to the 1950s and was popularised in the 1980s. Traditional definitions of successful ageing have emphasised absence of physical and cognitive disabilities.[175] In their 1987 article, Rowe and Kahn characterised successful ageing as involving three components: a) freedom from disease and disability, b) high cognitive and physical functioning, and c) social and productive engagement.[176]

The ancient Greek dramatist Euripides (5th century BC) describes the multiply-headed mythological monster Hydra as having a regenerative capacity which makes it immortal, which is the historical background to the name of the biological genus Hydra. The Book of Job (c. 6th century BC) describes human lifespan as inherently limited and makes a comparison with the innate immortality that a felled tree may have when undergoing vegetative regeneration.[177]

Link:
Ageing – Wikipedia, the free encyclopedia

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Stem Cells Therapy IPS Cell Therapy IPS Cell Therapy

Editor-in-Chief Marek Malecki, MD PhD President Genetic and Biomolecular Engineering PBMEF, San Francisco, USA E-mail: [emailprotected]

Marek Malecki MD PhD is President of Phoenix Biomolecular Engineering Foundation, Chief Executive Officer of the Center for Molecular Medicine, and Visiting Professor at the University of Wisconsin. He earned MD degree at the Medical Academy, Poznan followed by Residency/Fellowship in Molecular Medicine in Rigshospitalet, Copenhagen. He earned PhD at the National Academy of Sciences, Warsaw followed by the postdoctoral fellowships in molecular biology at the Austrian Academy of Sciences, Karolinska Institutet, Stockholm, Salzburg and Vienna, ETH, Zurich, Utrecht University Medical School, Utrecht, Cancer Center, Vienna, Cancer Center, Amsterdam, Biozentrum, Basel. Dr Malecki developed a novel technology to identify and isolate single living pluripotent stem cells followed by their clonal expansion and molecular profiling including sequencing their proteomes, transcriptomes, and genomes. This technology serves also for reprogramming the stem cells for their use as the vectors in gene therapy of cancer. The technology, protected by the US and WIPO, is currently streamlined to clinical trials. He is the first author on the peer-reviewed articles. He is often an invited speaker and courses faculty at the international professional conferences. Dr Malecki is Editor in Chief of the Journal of Genetic Syndromes and Gene Therapy and Member of the Editorial Boards for many high-impact professional journals. He is the member of the American Medical Association, American Association of Human Genetics, American Antibody Society, Southern California Biotechnology Council, and Rho Chi Honor Society for Excellence in Teaching and as the Faculty Role Model.

cancers of ovaries, cancers of testes, cancer stem cells (CSC), circulating tumor cells (CTCs), genetic disorders, iatrogenic genetic mutations, gene therapy, targeted gene delivery, fertility sparing therapy, biobanking, in vitro fertilization.

Evan Yale Snyder, MD, PhD Professor Director, Program in Stem Cell & Regenerative Biology and Stem Cell Research Center Sanford-Burnham Medical Research Institute (SBMRI) California, USA

Evan Y. Snyder earned his M.D. and Ph.D. from the University of Pennsylvania. He completed residencies (including serving as Chief Resident) in pediatrics and neurology as well as a clinical fellowship in neonataology at Childrens Hospital-Boston, Harvard Medical School. He became a faculty physician in the Department of Pediatrics, Children & middots Hospital-Boston and while serving as a research fellow in the Department of Genetics, Harvard Medical School. He established a lab at Children & middots Hospital-Boston in 1992. In 2003, Dr. Snyder was recruited to the Burnham Institute for Medical Research as Professor and Director of the Program in Stem Cell & Regenerative Biology. He then inaugurated the Stem Cell Research Center and initiated the Southern California Stem Cell Consortium. He serves on multiple editorial boards, has published extensively in the stem cell literature, holds multiple patents in the stem cell space, has received numerous honors and lecturers widely internationally.

Fundamental stem cell biology Developmental neuroscience Neural transplantation Developmental biology Cellular (in vitro) and animal models of disease Differentiation of pluripotent and multipotent stem cells Neurodegenerative diseases Neural injury and repair Ethics and public policy Science education.

Fazlul Hoque Sarkar, PhD Distinguished Professor Departments of Pathology and Oncology Karmanos Cancer Institute Wayne State University School of Medicine Detroit, USA Read Interview session with Fazlul Hoque Sarkar

Fazlul H. Sarkar, Ph.D. is a Professor at Karmanos Cancer Center, Wayne State University with a track-record of cancer research for over 32 years. He received his Ph.D. degree in biochemistry and completed his post-doctoral training in molecular biology at Memorial Sloan Kettering Cancer Center in New York. His work has led to the discovery of the role of chemopreventive agents in sensitization of cancer cells (reversal of drug-resistance) to conventional therapeutics (chemo-radio-therapy). He has published over 400 original scientific articles in peer-reviewed journals, review articles and book chapters. He is currently a Senior Editor of the journal: Molecular Cancer Therapeutics and member of the editorial board of many scientific journals.

His research is focused on understanding the role of a master transcription factor, NF-B, and further directed toward elucidating the molecular mechanisms of action of natural agents and synthetic small molecules for cancer prevention and therapy.

LuZhe Sun, PhD Professor Department of Cellular & Structural Biology University of Texas Health Science Center San Antonio, USA

LuZhe Sun is Dielmann Endowed Chair in Oncology, Professor of Cellular & Structural Biology, University of Health Science Center at San Antonio. Associate Director for Translational Research, Cancer Treatment and Research Center, University of Health Science Center at San Antonio. He received Ph.D. in Physiology in 1990 from Rutgers State University of New Jersey and UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ. He is serving as an editorial board member of reputed journals and has reviewed manuscripts for more than twenty journals.

TGF-beta signaling Mammary stem cell function Cell cycle Tumor metastasis Breast cancer Prostate cancer

Laure Aurelian Professor Department of Pharmacology and Experimental Therapeutics The University of Maryland School of Medicine USA

1958-1962: Tel-Aviv University, Tel-Aviv, Israel. Awarded Master of Science Degree, June 1962. rn1962-1966: Graduate Work for the degree of Doctor of Philosophy. Department of Microbiology, The Johns Hopkins School of Medicine. rn1966: Degree of Doctor of Philosophy.

Oncology, Immunology and Genetic Vaccines.

Rita C. R. Perlingeiro Associate Professor Lillehei Heart Institute Department of Medicine University of Minnesota USA

Dr. Rita C. R. Perlingeiro received her Ph.D. at the University of Campinas (UNICAMP) in Campinas, Sao Paulo, Brazil. She completed her postdoctoral training in Stem Cell Biology at the Whitehead Institute, MIT, in Cambridge, MA. She started her own laboratory in the Department of Developmental Biology at the University of Texas Southwestern Medical Center in 2003. Currently, she is as an Associate Professor in the Department of Medicine, Cardiovascular Division, and a member of the Lillehei Heart Institute at the University of Minnesota, Twin Cities. She has authored over 30 research articles as well as a chapter, Regulation of Angiogenesis in Coronary Heart Disease: Clinical Pathological, Imaging and Molecular Profiles, to be in press by the end of this year. In 2008, Dr. Perlingeiro and colleagues published a seminal article, Functional skeletal muscle regeneration from differentiating embryonic stem cells (Nat. Med. 2008, 14:134-143). This was the first example of using embryonic stem cells to improve muscle function in muscular dystrophy. Such findings have extraordinary biological and therapeutic significance.

The main focus of the Perlingeiro laboratory is to understand the molecular mechanisms controlling lineage decision from early mesoderm towards skeletal muscle, blood, and endothelial cells, with the ultimate goal to generate specific cell types from ES and iPS cells for therapeutic applications.

Qing Ma Associate Professor of Cancer Medicine Department of Stem Cell Transplantation and Cellular Therapy University of Texas M.D. Anderson Cancer Center Houston, USA

Prof/Dr Qing Ma has received his PhD in Thomas Jefferson University during the period of 1990-1995. Currently, she is working as an Associate Professor of Cancer Medicine in the University of Texas M.D. Anderson Cancer Center. She has successfully completed his Administrative responsibilities as she is serving as an reviewer or editorial member of several reputed journals like Blood, Journal of Immunology, Biology of Blood and Marrow Transplantation, Journal of Biological Chemistry, Cancer Research, Journal of Leukocyte Biology, World Journal of Biological Chemistry , International Journal of Immunology Research. She has authored 23 research articles/books. She is a member of The American Association of Immunologists, The American Society of Hematology, American Society for Blood and Marrow Transplantation, The Society for Leukocyte Biology.She has honored as a Irvington Fellow and American Cancer Society Research Scholar.

Integrin, Chemokine, Stem cell transplantation, GVHD, GVL, Immunotherapy.

Min Du Associate Professor Department of Animal Science Developmental Biology Group, College of Agriculture University of Wyoming Laramie, USA

Min Du is the Leader of Development Biology Group, Department of Animal Science, Associate Professor in Muscle Biology, Associate Professor of Biomedical Program, Associate Professor of Molecular and Cellular Life Sciences, University of Wyoming. He has received a PhD in Muscle Biology from Iowa State University, Ames, IA in, 1998-2001. He has completed his M.S. in Muscle Biology in China Agricultural University, Beijing, China (1993). He has obtained his B.S. in Food Engineering in Zhejiang Agricultural University, Hangzhou, China (1990). He received Early Career Achievement Award, form American Society of Animal Science. He is serving as an associate editor for Journal of Animal Science, reviewer for more than 20 journals and several federal funding agencies. He has published more than 100 peer-reviewed papers in muscle biology.

Skeletal muscle development Mesenchymal stem cell differentiation Myogenesis Adipogenesis Fibrogenesis Cell signaling and gene expression Epigenetic modifications.

Elena Jones Associate Professor Academic Unit of Musculoskeletal Disease Leeds Institute of Molecular Medicine United Kingdom

Doctor Elena Jones is an Associate Professor in the Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), the University of Leeds. She graduated with a BSc in Immunology and obtained a PhD in Experimental Oncology from the All-Union Cancer Research Centre, Russian Academy of Medical Sciences, Moscow. In Moscow she has developed Russia-first antibodies to human hematopoietic stem cells and B cells applicable for leukaemia diagnosis. In 1993 she obtained a prestigious Royal Society Postdoctoral Research Fellowship and arrived in HMDS, Leeds, where she considerably advanced her experience in bone marrowphenotyping using flow cytometry. She subsequently obtained a post-doctoral research position in the Molecular Medicine Unit, where she gained first experience with marrow stromal cells/MSCs. Her post-doctoral studies were dedicated to gene therapy with MSCs. Since joining the Academic Unit of Musculoskeletal Disease, her research interests are focused on the study of human MSCs in health and disease and their use in Regenerative Medicine. In 2002 she described the phenotype of native/uncultured MSCs in bone marrow and in 2004 she discovered MSCs in synovial fluid. Her MSC isolation methodology based on the CD271 marker has been adopted by the Industry, initially as research methodology and subsequently as a clinical-grade process. She has subsequently developed novel ideas on large-scale extraction of MSCs from bone, soft tissues (synovium and joint fat) and from surgical by-products (reaming waste bags and fatty marrow). She is currently working towards the therapeutic use of minimally-manipulated uncultured MSCs in bone repair applications including novel scaffolds and quality-control assays for cell manufacture. In relation to cartilage tissue regeneration her major interest lies in the use of endogenous synovial MSCs in combination with biomimetic scaffolds in patients with early osteoarthritis. She continues to explore the biology of synovial fluid MSCs including their homeostatic trafficking and therapeutic targeting to injured areas.

She is currently working towards the therapeutic use of minimally-manipulated uncultured MSCs in bone repair applications including novel scaffolds and quality-control assays for cell manufacture. In relation to cartilage tissue regeneration her major interest lies in the use of endogenous synovial MSCs in combination with biomimetic scaffolds in patients with early osteoarthritis. She continues to explore the biology of synovial fluid MSCs including their homeostatic trafficking and therapeutic targeting to injured areas.

Thomas Lufkin Associate Professor Stem Cell and Developmental Biology National University of Singapore Singapore 138672 Tel. 65 6808 8167 Fax 65 6808 8307

Thomas Lufkin is a Senior Group Leader in Stem Cell & Developmental Biology, Genome Institute of Singapore. He is Associate Professor, Department of Biological Science, National University of Singapore, Associate Professor for the School of Biological Science, Nanyang Technological University. He completed postdoctoral training at the LGME, Strasbourg, France, in Molecular Embryology (with Pierre Chambon). He received his Ph.D. from Cornell University in Molecular Biology and Virology. He received his A.B. from the University of California, Berkeley in Cell Biology. He received the March of Dimes Basil OConner Jr. Faculty Award, was a Lucille B. Markey Scholar in Molecular Biology, received an Alfred P. Sloan Research Fellowship in Neuroscience, an American Cancer Society Postdoctoral Fellowship and a Morton J. Levy Predoctoral Fellowship. He is serving as an editorial board member of 3 reputed journals. He has 74 publications.

Embryonic Stem Cell Differentiation Embryogenesis Developmental Genomics Gene regulatory networks Systems Biology Regenerative Medicine Vertebrate Development.

Rosalinda Madonna, MD, PhD Assistant Professor Internal Medicine, Cardiology Division University of Texas Medical School Houston, USA

Rosalinda Madonna is Assistant Professor, Internal Medicine, Cardiology Division, University of Texas Medical School (UT) in Houston and Research Scientist, Texas Heart Institute (THI) in Houston. She received her MD in University of Chieti, Italy (1997) and PhD in Biotechnology at the same University (2003). She completed her post-doctoral research fellowship in Molecular Cardiology (2007, University of Louisville, KY) and Atherosclerosis and Heart Failure (2002 2006, UT and THI Houston). She completed her Residency and Clinical Fellowship in Cardiology in University of Chieti (2003-2007). She has a Master in Internal Echocardiography and Cardio-Respiratory Physiopathology and stress test (in Centro Cardiologico Monzino, Milan, Italy) She is recipient of several awards and research grants (2003: Award for best abstract by The International Society of Thrombosis and Haemostasis; 2003: Young Investigator award by The Italian Society of Thrombosis and Haemostasis; 2004: Travel grant by Alliance of Cardiovascular Researchers and The Brown Institute; 2004: Travel grant by The European Association Study of Diabetes (EASD); 2006: Scholarship by Italian Society of Cardiology (SIC); 2007, 2008 and 2009 Scholarship by The National Institute for Cardiovascular Research; 2008 Scholarship by SIC and Sanofi Aventis; 2010 Travel grant young scientist by European Society of Cardiology (ESC). Ongoing reviewer of Circulation Research, Expert Reviews, Cardiovascular Research, Atherosclerosis, Journal of Molecular and Cellular Cardiology, Thrombosis and Haemostasis, Journal of Internal and Emergency Medicine, International Journal of Cardiology, The Journal of Diabetes Complications. Member of several International Societies and Nucleus Member ESC Working Group on Cellular Biology of the Heart. Author and co-author of 42 journal papers, 7 book chapters, 100 abstracts.

Stem cells, iPS cells, Cardiac development, Gene cloning and gene therapy, Biomaterials, Physiopathology of atherosclerosis in diabetes.

Morayma Reyes Assistant Professor Department of Pathology Department of Laboratory Medicine University of Washington Seattle, USA

She is an Assistant Professor for the Department of Pathology and Laboratory Medicine, Member of Institute for Stem Cell and Regenerative Medicine, Member of Center for Cardiovascular Biology, University of Washington. She has received her MD/PhD degree from University of Minnesota, 1996-2003. She has completed her B.S. in biology and chemistry from the University of Puerto Rico, 1996. She is serving as an editorial board member of reputed journals and reviewer of 3 journals. She has been nominated and awarded for the Princeton Global Networks and the Madison Whos Who Member-Executives and Professionals. She received the Junior Faculty Awards: Perkins Coie Award and the Marian E. Smith award.

Adult stem cells Skeletal muscle and heart regeneration Stem cell therapy for muscular dystrophy Stem cell homing and migration Tissue regeneration/ Bioengineering/ artificial organs Mesenchymal stem cells Dental Pulp Stem Cells Vascular Biology Hemostasis/ thrombosis/ Coagulation Angiogenesis.

Ipsita Banerjee Assistant Professor Department of Chemical Engineering McGowan Institute for Regenerative Medicine University of Pittsburgh Pittsburgh, USA

Ipsita Banerjee is a faculty in Chemical Engineering department of University of Pittsburgh. Adjunct faculty of Bioengineering Department, University of Pittsburgh. Adjunct faculty of McGowan Institute for Regenerative Medicine. She has completed three years of post-doctoral training in Harvard Medical School, Boston, MA, (2005-2008). She received her PhD from Rutgers University, NJ (2000-2005). She received the NIH New Innovator Award and the Ralph Powe Faculty Enhancement Award. She currently has fourteen publications in reputed international journals. She is a reviewer for Tissue Engineering, Tissue Engineering and Regenerative Medicine, Journal of Biotechnology, Computers and Chemical Engineering, Journal of Integrative Biology, Cellular and Molecular Bioengineering. She serves on the review panel of National Science Foundation, Biomedical Engineering Division.

Embryonic stem cell differentiation iPS cell differentiation Diabetes Systems Biology Analysis of regulatory network of differentiating stem cells Optimization based algorithm for network identification Agent Based Modeling for differentiation patterning.

Porrata Luis F Assistant Professor and Assistant Deputy Director of the Blood and Marrow Program Mayo Clinic Transplant Center Rochester, USA

Luis F. Porrata is Assistant Deputy Director of the Blood and Marrow Program, Mayo Clinic. Assistant Professor, Division of Hematology, Department of Medicine, Mayo Clinic. He is serving as an editorial board member of reputed journals and reviewer of several journals including Blood, Bone Marrow Transplantation, and Biology of Blood and Marrow transplantation.

Autologous stem cell transplantation Lymphoma Immunotherapy.

Yoon-Young Jang Assistant Professor Stem Cell Biology Laboratory Johns Hopkins Medical Institutions Baltimore, USA

Yoon-Young Jang, MD, PhD is a Assistant Professor of Stem Cell Biology Laboratory, Oncology at Johns Hopkins University School of Medicine, Baltimore, Maryland. She has received MD, PhD from the Chung-Ang University, Seoul, Korea and has completed fellowpship in Johns Hopkins University. She been a faculty member at Johns Hopkins Oncology Center since 2005 and has awarded three stem cell grants from the Maryland State.

Stem cell biology (Pluripotent stem cells, Cancer stem cells, Hematopoietic stem cells) Hepatic differentiation of human stem cells Liver regeneration using animal models of liver diseases Disease modelling using iPS derived hepatocytes Stem cell niche biology

Yong Zhao Assistant Professor Section of Diabetes and Metabolism Department of Medicine University of Illinois Chicago, USA

Yong Zhao, MD, PhD, Assistant Professor, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago. He received his PhD (2000) in Immunology at Shanghai Second Military Medical University, Shanghai, China. He received his MD (1990) in Clinical Medicine at Weifang Medical College, Shandong, China. He received 2006 and 2008 Rachmiel Levine Scientific Achievement Award. He has 24 peer-reviewed publications. He owned 8 patents.

Umbilical cord blood stem cells Hematopoietic stem cells Immune modulation Type 1 diabetes Type 2 diabetes Pancreatic islet beta cell differentiation Humanized mice

Chia-Ying Lin Research Assistant Professor Director, Spine Research Laboratory University of Michigan Ann Arbor, USA

Chia-Ying Lin is a Research Assistant Professor, the Director of the Spine Research Laboratory at the Department of Neurosurgery in the University of Michigan. He has received his MS and PhD in Biomedical Engineering from the University of Michigan, Ann Arbor, MI, in 2002 and 2004, respectively. He has completed his B.A in Civil Engineering in National Taiwan University, Taipei, Taiwan in 1997. Dr. Lin is serving as an editorial board member of reputed journals and reviewer of 6 journals, including Biomacromolecules, Tissue Engineering, Journal of Biomedical Materials Research, Materials Letters, Cell Proliferation, and Journal of Orthopaedic Research. He has published over 20 articles to date in many journals specified in spine medicine, regenerative medicine, and cancer biology and therapy.

His research interests primarily focus on biological repair of degenerative intervertebral disc, spinal reconstruction with tissue engineering approaches, and inductive therapy for bone metastasis.

Tonya J. Roberts Webb Assistant Professor Department of Microbiology and Immunology Member of the Marlene and Stewart Greenebaum Cancer Center University of Maryland School of Medicine, USA

Tonya J. Roberts Webb completed Ph. D in 2003 and serving as Assistant Professor in Department of Microbiology and Immunology, University of Maryland School of Medicine.

Microbiology and Immunology.

Vincenzo Lionetti Assistant Professor of Physiology Sector of Medicine Scuola Superiore Sant Anna University Pisa, Italy Tel. 39-328-0078806 Read Interview session with Vincenzo Lionetti

Vincenzo Lionetti is Head of Unit of Molecular and Translational Medicine, National Institute of Biostructures and Biosystems, Bologna, Italy; Assistant Professor of Physiology, Sector of Medicine, Scuola Superiore SantAnna, Pisa, Itay; Adjunct Researcher, Institute of Clinical Physiology, National Council of Research, Pisa, Italy. Adjunct Researcher, Fondazione Regione Toscana Gabriele Monasterio, Pisa, Italy. He has received a PhD in Innovative Strategies in Biomedical Research from the Scuola Superiore SantAnna, Pisa, Italy, in 2007. He has specialized in Anesthesiology and Intensive Care Medicine at the University of Turin, Italy, in 2003. He received: Trainee Abstract Award from the Council on Basic Cardiovascular Sciences of the American Heart Association in 2002; Young Investigator Award from the National Institute of Cardiovascular Research in 2009. He is serving as a member of the Council on Cardiovascular Science of the American Heart Association and Study Group on Cellular and Molecular Biology of the Heart of the Italian Society of Cardiology. He is serving as peer reviewer for Cardiovascular Research, Ultrasound in Medicine and Biology, ECAM, Clinical Journal of the American Society of Nephrology, American Journal of Physiology-Heart and Circulatory Physiology. He has published 5 book chapters; 22 peer-reviewed articles in international journals including: Journal of Biological Chemistry, Cardiovascular Research, Journal of Cardiac Failure, American Journal of Physiology, Journal of Physiology (London), Journal of Molecular and Cellular Cardiology, FASEB Journal.

Physiology and physiopathology of regenerate myocardium Regional imaging of regenerate myocardium Physiopathology of heart failure Innovative acellular therapies to repair failing myocardium.

Rajasingh Johnson Assistant Professor Department of Medicine Cardiovascular Research Institute University of Kansas Medical Center, Kansas City, USA

Dr.Rajasingh Johnson has received his PhD in Vanderbilt University during the period of 2004-2007. Currently, he is working as Assistant Professor in University of Kansas Medical Center.

My research interests include the de-differentiation of somatic cells by chromatin modifying agents to generate induced pluripotent (iPS cells) or multipotent stem cells and its therapeutic potential in regenerative medicines; mechanisms of somatic cell reprogramming by histone deacetylation and DNA methylation inhibitors; differentiation of embryonic and adult stem cells in cardiovascular and lung vascular repair and regeneration.

Prasanna Krishnamurthy, DVM, PhD Assistant Professor Feinberg School of Medicine Cardiovascular Research Institute Northwestern University, Chicago, USA

Dr. Prasanna (Krish) Krishnamurthy received his PhD in Indian Veterinary Research Institute during the period of 2000-2003. Currently, he is working as Assistant Professor in Northwestern University.

My research interests include endothelial progenitor cell, myocardial ischemia, cell-based regenerative therapy for heart failure and bone marrow transplantation.

Atsushi Asakura Assistant Professor Department of Neurology University of Minnesota Medical School MN 55455, USA

Li Xiao Assistant Professor Department of Pharmacology The Nippon Dental University, Tokyo, Japan

Dr. Li Xiao has received her PhD in Prefectural University of Hiroshima in the year 2007. Currently, she is working as Asssistant Professor in The Nippon Dental University.

Research interests includes tissue engineering, antioxidant, radiation Biology, regenerative medicine and traditional Chinese medicine.

Raji Padmanabhan Research Scientist Laboratory of Cell Biology (LCB) Center for Cancer Research (CCR) National Cancer Institute(NCI) National Institutes of Health, (NIH)Bethesda Maryland 20892,USA Tel. (301) 496-3096 Read Interview session with Raji Padmanabhan

Richard Schaefer Department of Stem Cell and Regenerative Biology Harvard Stem Cell Institute Harvard University Cambridge, USA

Dr. Richard Schaefer, MD is the head of the Mesenchymal Stem Cell Laboratory, Institute of Clinical and Experimental Transfusion Medicine, University Hospital Tuebingen, Germany. Research Fellow at the Department of Stem Cell and Regenerative Biology Harvard University, Cambridge, USA. Specialist for Internal Medicine and Transfusion Medicine. After studying Medicine in Giessen, Germany and Mannheim/Heidelberg, Germany he has received his MD in 1997. He is serving as an editorial board member of reputed journals and reviewer of 12 journals. He is author of more than 20 articles published in international journals and co-editor of the Handbook of Stem Cell Based Tissue Repair Royal Society of Chemistry, Cambridge, U.K.

Stem Cell Biology Characterization, Differentiation, Immunomodulation Mesenchymal (Stem/Stromal) Cells Regenerative Medicine Labeling and Imaging of Stem Cells GMP production of cellular therapies.

Christian Drapeau, PhD StemTech HealthSciences, LLC 1011 Calle Amanecer San Clemente, California, USA

1991 Master degree in Neurology and Neurosurgery from McGill University, Montreal,Quebec, Canada. Work performed at the Montreal Neurological Institute.Thesis on epileptogenesis and the role of eicosanoids in long-term potentiation.1987 Bachelor degree in Honors Neurophysiology from McGill University, Montreal, Quebec, Canada. Program limited to 6 students.

Neurology and Neurophysiology.

Shi-Jiang Lu, PhD, MPH Senior Director for Research Advanced Cell Technology Marlborough, USA Read Interview session with Shi-Jiang Lu

Shi-Jiang Lu is currently a Senior Director of Stem Cell and Regenerative Medicine International, a joint venture between Advanced Cell Technology and CHA Biotech of Korea; Adjunct Professor, Department of Applied Bioscience, Cha University, Seoul, Korea, and Scientific Advisor, Advanced Cell Technology, Inc., Marlborough, MA. He was Senior Director, Director and Senior Scientist, Advanced Cell Technology, Inc., Marlborough, MA, and Director and Assistant Professor, Stem Cell Research Program, Department of Pediatrics, University of Illinois at Chicago, Chicago, IL. He received a PhD in Molecular Biology and Cancer from Department of Medical Biophysics, University of Toronto, Toronto, Canada (1992). He completed his MPH from School of Public Health, Columbia University in New York (1988) and MSc from Peking Union Medical College, Beijing, China (1985). He received a BS in Biochemistry from Wuhan University, Hubei, China (1982). He has more than 50 publications and Book Chapters.

Stem Cells: embryonic stem cells (ES), induced pluripotnet stem cells (iPS), and hematopoietic stem cells (HSC), cancer stem cells, ES and iPS cell lineage specific diffeentiation. Hematopoietic Cells: bone marrow transplantation, red blood cells, megakaryocytes and platelets.Stem Cell therapy: ischemic vessel lesions and stem cell treatment, diabetic retinopathy and stem cell treatment, cardiomyocyte infarction and stem cell treatment.

Alex F. Chen, MD, PhD, FAHA Director Department of Surgery University of Pittsburgh School of Medicine Pittsburgh, USA

Alex F. Chen is Director of VA Vascular Surgery Research, and an Associate Professor, Department of Surgery, University of Pittsburgh School of Medicine. He has received a MD from Hunan Medical University in 1985 and a PhD in Pharmacology from Southern Illinois University in 1995. He is serving as an editorial board member of several reputed journals.

Vascular and endothelial cell biology Endothelial progenitor cells Redox regulation of endothelial function in diabetes and hypertension.

Alastair Wilkins Senior Lecturer Neurology Consultant Neurologist University of Bristol Bristol, UK

Alastair Wilkins is Senior Lecturer in Neurology, University of Bristol and Head of Neurology, Frenchay Hospital, Bristol, UK. He received a PhD in Clinical Neuroscience from the University of Cambridge in 2003. He has completed his B.A in Medical Sciences and MB BChir from the University of Cambridge in 1993. He is a fellow of the Royal College of Physicians (UK). He has published more than 40 articles, including reviews and book chapters. His Current research projects includes role of the peroxisome in axonal degeneration and progressive MS, developing a model of secondary progressive MS (taiep rat), degenerative ataxias and the potential for stem cell neuroprotection, developing Growth factor therapies for progressive multiple sclerosis, analysis of VLCFAs in serum of patients with multiple sclerosis, analysis of Reactive Oxygen Species in Multiple Sclerosis cerebrospinal fluid, local investigator for the analysis of genetic factors in multiple sclerosis (PI: Prof Alastair Compston, University of Cambridge)

Multiple sclerosis Neurobiology of axon degeneration Applications of neuroreparative stem cell therapies.

James Adjaye Department of Vertebrate Genomics Molecular Embryology and Aging Group Max Planck Institute for Molecular Genetics Ihnestrasse 73, D-14195 Berlin, Germany

James Adjaye is a Group Leader at the Max-Planck Institute for Molecular Genetics (Molecular Embryology and Aging group).Adjunct Associate Professor for stem cell biology, College of Medicine Stem Cell Unit, King Saud University, Riyad, Saudi Arabia. He has received a PhD in biochemistry at Kings College London 1992. He has completed his BSc studies in biochemistry at University College Cardiff, Wales 1987. He is serving as an editorial board member of 4 reputed journals and reviewer of 17 journals.

Transcriptional and signal transduction mechanisms regulating self renewal and pluripotency in human embryonic stem cells, embryonal carcinoma cells and iPS cells (induced pluripotent stem cells). Reprogramming of somatic cells (healthy and diseased individuals- Alzheimers, Diabetic, Nijmegen breakage syndrome and Steatosis patients) into an ES-like state (iPS cells) and studying the underlying disease mechanisms. Systems biology of stem cell fate and cellular reprogramming.

Stefano Biressi Post-doctoral research associate Department of Neurology and Neurological Sciences Stanford University USA

He studied at the University of Milan, Italy. He received his PhD in Cellular and Molecular Biology from The Open University of London. He worked in the Telethon Institute for Gene Therapy (TIGeT) and in the Stem Cell Research Institute, Hospital San Raffaele, Milan, Italy. He is currently working in the Department of Neurology and Neurological Sciences at Stanford University, CA, USA.

Cellular and molecular mechanisms regulating skeletal muscle development, regeneration and muscle stem cells self-renewal and lineage progression in normal and pathological conditions.

Hosam A. Elbaz Department of Basic Pharmaceutical Sciences West Virginia University Morgantown, USA Read Interview session with Hosam A Elbaz

Dr Hosam A. Elbaz has received his PhD in West Virginia University during the period of 2007 2011. Currently, he is working as a postdoctoral fellow in Wayne State University School of Medicine. He is serving as an editorial member for several reputable journals like Journal of Bioengineering and Biomedical Sciences, Journal of Nanomedicine and Nanotechnology, Pharmaceutica Analytica Acta, and Biochemistry and Pharmacology. He is a member of American Society of Pharmacology and Experimental Therapeutics (ASPET), American Association of Pharmaceutical Scientists (AAPS), American Chemical Society (ACS), Egyptian General Syndicate of Pharmacists, and Golden Key International Honor Society.

Cancer Therapeutics,Carcinogenesis, Cell Cycle and Checkpoint Regulation, Apoptosis, Nanomedicine and Nanobiotechnology, Targeted Drug Delivery, Therapeutic Gene Delivery, Biochemical Pharmacology and Toxicology.

Amir Hamdi, MD Postdoctoral research fellow Department of Stem Cell Transplantation and Cellular Therapy The University of Texas MD Anderson Cancer Center Houston, Texas, USA

Dr. Amir Hamdi was born and raised in Iran. He received his M.D. degree from Tabriz University of Medical Sciences. He was a research scientist in Hematology, Oncology and Stem Cell Transplantation Research Center in Tehran and participated in several research projects. He is currently a postdoctoral research fellow in the Department of Stem Cell Transplantation and Cellular Therapy at The University of Texas MD Anderson Cancer Center.

Dr. Hamdis research interests include therapy of leukemias and lymphomas as well as development of investigational approach for the treatment of hematologic and neurologic disorders. He has published several papers related to neurology, hematology, oncology and stem cell transplantation; and serves as reviewer for various journals.

Haigang Gu Postdoctoral Fellow Vanderbilt University School of Medicine Nashville, USA Read Interview session with Haigang Gu

Haigang Gu, cuurently Postdoctoral researcher in Vanderbilt University School of Medicine, Nashville, USA. Haigang Gu has received his PhD in also in Emory University during the period of 2010-2011.

My current research is to understand how transcriptional factors affect neuronal differentiation and maturation and synaptic transmission and recycling in vitro and in vivo using stem cell-derived neurons, primary cultured neurons and brain slices by whole cell patch clamp recording and super-resolution live cell imaging. The underlying mechanisms could be extended to illustrate the functional recovery of neurological disease treated by drugs and stem cells. Recently, I have cloned most of neuronal transcriptional factors (15 genes) in lentiviral-based vector and packaged these vectors in lentivirus. We have developed some new protocols to induce stem cells, embryonic stem cells and neural stem cells to differentiate into neurons using defined chemicals and transcriptional factors related to neuronal differentiation and maintenance. Furthermore, we have made substantial progress on the synaptic transmission and recycling trafficking in cultured hippocampus, cortical and midbrain neurons. My research has been mainly focus on understanding (1) the mechanisms of proliferation and neuronal differentiation of embryonic stem cells and adult stem cells, such as neural stem cells and mesenchymal stem cells, (2) stem cell-based therapies for the treatment of such as Alzheimers disease and ischemic stroke, and (3) sustained release neurotrophic factors or neurotrophic factor genes for the treatment of neurodegenerative disease. I have strong background and extensive experience in molecular and cellular biology, stem cell culture and differentiation, whole cell patch clamp recording in cultured cells, live cell imaging as well as animal models, such as Parkinsons, Alzheimers disease and ischemic stroke.

Dhanajaya Nayak Department of Biochemistry University of Wisconsin-Madison USA

Dr. Dhanajaya Nayak (PhD) currently holds an Assistant Scientist position in the Department of Biochemistry at University of Wisconsin-Madison (2013-present). Previously, he has received a master of technology (M.Tech.) degree from the Indian Institute of Technology, Kharagpur, India, and a PhD degree in Biochemistry from the University of Texas Health Science Center at San Antonio (2004-2009), where he won the prestigious Armand J. Guarino Award for academic excellence in doctoral studies in Biochemistry. After his PhD, he joined the Department of Biochemistry at University of Wisconsin-Madison as a postdoctoral research associate (2009-2012). Dr. Nayak has more than 8 years of research experience in the field of transcription and gene regulation. He is a member of the American Association for the Advancement of Science (AAAS) and International Society for Cardiovascular Translational Research (ISCTR). At present, he is an active reviewer for several journals from the OMICS group: Journal of Stem Cell Research and Therapy, Journal of Enzyme Engineering, Journal of Molecular Biomarkers and Diagnosis, Journal of Chemical Engineering and Process Technology and Journal of Analytical and Bioanalytical Technique etc

Read more here:
Stem Cells Therapy IPS Cell Therapy IPS Cell Therapy

Recommendation and review posted by Bethany Smith

Home : Cleveland Clinic Journal of Medicine

2016 SEPTEMBER

4th Annual genetics and genomics: advances across the lifespan September 15 Cleveland, OH

Breakthroughs in cognitive neurological disorders September 16 Cleveland, OH

Fundamental to advanced echocardiography September 1618 Cleveland, OH

Cleveland Clinic Digestive Disease Institute boot camp for the GI boards September 1619 Las Vegas, NV

Heart rhythm care in the 21st century: allied professional regional conference September 17 Cleveland, OH

Cleveland Clinic Fairview Hospital epilepsy update September 17 Cleveland, OH

2016 Primary care women’s health: essentials and beyond September 22 Beachwood, OH

Women in healthcare forum: focus on resiliency September 23 Beachwood, OH, and Weston, FL

8th Annual practical management of acute stroke: fast and furious stroke care September 23 Independence, OH

Cleveland Clinic epilepsy update and review course September 2527 Cleveland, OH

11th Annual obesity summit September 2930 Cleveland, OH

Current management of prevalent cardiovascular diseases October 7 New York, NY

2016 Nephrology update October 2022 Cleveland, OH

18th Annual brain tumor update and 7th annual international symposium on long-term control of metastases to the brain and spineOctober 2223 Las Vegas, NV

3rd Annual multidisciplinary colorectal oncology course October 28 Cleveland, OH

5th Annual primary care evidence-based medicine update October 2829 Beachwood, OH

11th Annual Nemacolin international asthma conference October 2830 Farmington, PA

Exploring the functional medicine model: a case-based approach November 4 Cleveland, OH

52nd Annual gastroenterology update November 5 Warrensville Heights, OH

Advancing neurological therapeutics November 5 Las Vegas, NV

16th Annual multidisciplinary genitourinary oncology course November 10 Cleveland, OH

5th Annual comprehensive neurotoxin course for neurological conditions November 11 Cleveland, OH

2nd Cleveland Clinic beta cell therapy symposium: advances in management of diabetes November 1112 Cleveland, OH

Clinical management of MDS/MPN: a mountain of evidence for treatment selection in MDS/MPNDecember 2 San Diego, CA

Dr. Roizen’s preventive, integrative, and lifestyle medicine conference December 24 Las Vegas, NV

15th Annual liver update: a report from the American Association for the Study of Liver Disease annual meeting December 9 Beachwood, OH

Clinic seminars: dermatology December 9 Beachwood, OH

19th Annual pain management symposium February 48 Orlando, FL

Digestive Disease Institute week 2017 February 1419 Boca Raton, FL

6th Annual gastroenterology and hepatology symposium February 1618 Boca Raton, FL

5th Annual basic and clinical immunology for the busy clinician: an immunology boot camp February 1718 Las Vegas, NV

Breakthroughs in neuro-cognitive disorders February 25 Fort Lauderdale, FL

Valve disease and diastology summit March 46 Miami Beach, FL

2017 Multidisciplinary head and neck cancer update March 1011 Orlando, FL

Primary vasculitides: best practices and future advances April 5 Cleveland, OH

Biologic therapies VII summit: precision medicine in the biologic era April 68 Cleveland, OH

Cleveland breast cancer symposium 2017 May 11-12 Cleveland, OH

22nd Annual diabetes day May 12 Cleveland, OH

29th Annual intensive review of internal medicine June 49 Cleveland, OH

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Recommendation and review posted by simmons

Review of the Status of Aquaculture Genetics

Lakhaanantakun, A. 1992. The effects of triploidy on survival rate, growth rate and feed conversation ratio of walking catfish (Clarias macrocephalus Gunther). M.Sc. Thesis, Kasetsart University, Bangkok, 74 pp.

LaPatra, S.E., Lauda, K.A., Jones, G.R., Shewmaker, W.D., Groff, J.M. & Routledoe, D. 1996. Susceptibility and humoral response of brown trout x lake trout hybrids to infectious hematopoietic necrosis virus: a model for examining disease resistance mechanisms. Aquaculture, 146: 179-188.

LaPatra, S.E., Parsons, J.E., Jones, G.R. & McRoberts, W.O. 1993. Early life stage survival and susceptibility of brook trout, coho salmon, and rainbow trout x brook trout or coho salmon hybrids to IHN. J. Aquat. Anim. Health, 5: 270-264.

Lee, W.J. & Kocher, T.D. 1996. Microsatellite DNA markers for genetic mapping in Oreochromis niloticus. J. Fish Biol. 49: 169-171. Leeprasert, K. 1987. Genetic parameters of some quantitative traits in Pangasius sutchi Fowler. M.Sc. Thesis, Kasetsart University, Bangkok, 75 pp.

Lester, L.J., Lawson, K.S., Abella, T.A. & Palada, M.S. 1989. Estimated heritability of sex ratio and sexual dimorphism in tilapia. Aquacult. Fish. Manage. 20: 369-380.

Li, Y, Wilson, K.J., Byrne, K., Whan, V., Iglesis, D., Lehnert, S.A., Swan, J., Ballment, B., Fayazi, Z., Kenway, M., Benzie, J., Pongsomboon, S., Tassanakajon, A. & Moore, S.S. 2000. International collaboration on genetic maping of the black tiger shrimp, Penaeus monodon: progress update. Plant and Animal Genome VIII, p. 8. San Diego, January 9-12, 2000.

Lim, C., Leamaster, B. & Brock, J.A. 1993. Riboflavin requirement of fingerling red hybrid tilapia grown in seawater. J. World Aquacult. Soc. 24: 451-458.

Linhart, O., Flajshans, M., Gela, D., Duda, P., Slechta, V. & Slechtova, V. 1998. Breeding programme of common carp in the Czech Republic. XVIII-th Genetic Days, Ceske Budejovice.

Liu, Q., Goudi, C.A., Simco, B.A., Davis, K.B. & Morizot, D.C. 1992. Gene-centromere mapping of six enzyme loci in aynogenctic channel catfish. J. Hered. 83: 245-248.

Liu, Z.J. & Dunham, R.A. 1998. Genetic linkage and QTL mapping of ictalurid catfish. Alabama Agricultural Experiment Station Circ. Bull. 321: 1-19.

Liu, Z.J., Li, P., Argue, B. & Dunham, R.A.1998a. Inheritance of RAPD markers in channel catfish (Ictalurus punctatus), blue catfish (I. furcatus) and their Fl, F2 and backcross hybrids. Anim. Genet. 29: 58-62.

Liu, Z.J., Nichols, A., Li, P. & Dunham, R.A. 1998b. Inheritance and usefulness of AFLP markers in channel catfish (Ictalurus punctatus), blue catfish (I. furcatus) and their Fl, F2 and backcross hybrids. Mol. Gen. Genet. 258: 260-268.

Liu, Z.J., Li, P., Argue, B.P. & Dunham, R.A. 1999a. Random amplified polymorphic DNA markers: usefulness for gene mapping and analysis of genetic variation of catfish. Aquaculture, 174: 59-68.

Liu, Z.J., Li, P., Kucuktas, H., Nichols, A., Tan, G., Zheng, X., Argue, B.J., Yant, R. & Dunham, R.A. 1999b. Development of AFLP markers for genetic linkage mapping analysis using channel catfish and blue catfish interspecific hybrids. Trans. Am. Fish. Soc. 128: 317-327.

Liu, Z.J., Tan, G., Kucuktas, H., Li, P., Karsi, A., Yant, D.R. & Dunham, R.A. 1999c. High levels of conservation at microsatellite loci among ictalurid catfishes. J. Hered. 90: 307-312.

Liu, Z.J., Tan, G., Li, P. & Dunham, R.A. 1999d. Transcribed dinucleotide microsatellites and their associated genes from channel catfish, Ictalurus punctatus. Biochem. Biophys. Res. Comm. 259: 190-194.

Liu, Z.J., Karsi, A. & Dunham, R.A. (in press) Development of polymorphic EST markers suitable for genetic linkage mapping of catfish. Mar. Biotechnol.

Macaranas, J.M., Taniguchi, N., Pante, M.J.R., Capili, J.B. & Pullin, R.S.V. 1986. Electrophoretic evidence for extensive hybrid gene introgression into commercial Oreochromis niloticus (L.) stocks in the Philippines. Aquacult. Fish. Manage. 17: 249-258.

Mahapatra, K.D., Meher, P.K., Saha, J.N., Gjerde, B., Reddy, P.V.G.K., Jana, R.K., Sahoo, M. & Rye, M. 2000. Selection response of rohu, Labeo rohita, for two generations of selective breeding. The Fifth Indian Fisheries Forum, 17-20 January, 2000, Abstracts.

Mair, G.C., Abucay, J.S., Beardmore, J.A. & Skibinski, D.O.F. 1995. Growth performance trials of genetically male tilapia (GMT) derived from YY males in Oreochromis niloticus L.: on-station comparisons with mixed sex and sex reversed male populations. Aquaculture, 137: 313-322.

Mair, G.C., Scott, A.G., Penman, D.J., Skibinski, D.O.F. & Beardmore, J.A. 1991. Sex determination in Oreochromis. I. Gynogenesis, triploidy and sex reversal in Oreochromis niloticus. Theor. Appl. Genet. 82: 144-152.

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Review of the Status of Aquaculture Genetics

Recommendation and review posted by simmons


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