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DNA repair Wikipedia, the free encyclopedia IPS Cell …

DNA damage resulting in multiple broken chromosomes

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day.[1] Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cells ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cells genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages (interstrand crosslinks or ICLs).[2][3]

The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:

The DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal functionality of that organism. Many genes that were initially shown to influence life span have turned out to be involved in DNA damage repair and protection.[4]

The 2015 Nobel Prize in Chemistry was awarded to Tomas Lindahl, Paul Modrich, and Aziz Sancar for their work on the molecular mechanisms of DNA repair processes.[5][6]

DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 10,000 to 1,000,000 molecular lesions per cell per day.[1] While this constitutes only 0.000165% of the human genomes approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cells ability to carry out its function and appreciably increase the likelihood of tumor formation and contribute to tumour heterogeneity.

The vast majority of DNA damage affects the primary structure of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. Unlike proteins and RNA, DNA usually lacks tertiary structure and therefore damage or disturbance does not occur at that level. DNA is, however, supercoiled and wound around packaging proteins called histones (in eukaryotes), and both superstructures are vulnerable to the effects of DNA damage.

DNA damage can be subdivided into two main types:

The replication of damaged DNA before cell division can lead to the incorporation of wrong bases opposite damaged ones. Daughter cells that inherit these wrong bases carry mutations from which the original DNA sequence is unrecoverable (except in the rare case of a back mutation, for example, through gene conversion).

There are several types of damage to DNA due to endogenous cellular processes:

Damage caused by exogenous agents comes in many forms. Some examples are:

UV damage, alkylation/methylation, X-ray damage and oxidative damage are examples of induced damage. Spontaneous damage can include the loss of a base, deamination, sugar ring puckering and tautomeric shift.

In human cells, and eukaryotic cells in general, DNA is found in two cellular locations inside the nucleus and inside the mitochondria. Nuclear DNA (nDNA) exists as chromatin during non-replicative stages of the cell cycle and is condensed into aggregate structures known as chromosomes during cell division. In either state the DNA is highly compacted and wound up around bead-like proteins called histones. Whenever a cell needs to express the genetic information encoded in its nDNA the required chromosomal region is unravelled, genes located therein are expressed, and then the region is condensed back to its resting conformation. Mitochondrial DNA (mtDNA) is located inside mitochondria organelles, exists in multiple copies, and is also tightly associated with a number of proteins to form a complex known as the nucleoid. Inside mitochondria, reactive oxygen species (ROS), or free radicals, byproducts of the constant production of adenosine triphosphate (ATP) via oxidative phosphorylation, create a highly oxidative environment that is known to damage mtDNA. A critical enzyme in counteracting the toxicity of these species is superoxide dismutase, which is present in both the mitochondria and cytoplasm of eukaryotic cells.

Senescence, an irreversible process in which the cell no longer divides, is a protective response to the shortening of the chromosome ends. The telomeres are long regions of repetitive noncoding DNA that cap chromosomes and undergo partial degradation each time a cell undergoes division (see Hayflick limit).[10] In contrast, quiescence is a reversible state of cellular dormancy that is unrelated to genome damage (see cell cycle). Senescence in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell for spatial reasons is required by the organism,[11] which serves as a last resort mechanism to prevent a cell with damaged DNA from replicating inappropriately in the absence of pro-growth cellular signaling. Unregulated cell division can lead to the formation of a tumor (see cancer), which is potentially lethal to an organism. Therefore, the induction of senescence and apoptosis is considered to be part of a strategy of protection against cancer.[12]

It is important to distinguish between DNA damage and mutation, the two major types of error in DNA. DNA damages and mutation are fundamentally different. Damages are physical abnormalities in the DNA, such as single- and double-strand breaks, 8-hydroxydeoxyguanosine residues, and polycyclic aromatic hydrocarbon adducts. DNA damages can be recognized by enzymes, and, thus, they can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented, and, thus, translation into a protein will also be blocked. Replication may also be blocked or the cell may die.

In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and, thus, a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair; these errors are a major source of mutation.

Given these properties of DNA damage and mutation, it can be seen that DNA damages are a special problem in non-dividing or slowly dividing cells, where unrepaired damages will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damages that do not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cells survival. Thus, in a population of cells composing a tissue with replicating cells, mutant cells will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism, because such mutant cells can give rise to cancer. Thus, DNA damages in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer. In contrast, DNA damages in infrequently dividing cells are likely a prominent cause of aging.[13]

Single-strand and double-strand DNA damage

Cells cannot function if DNA damage corrupts the integrity and accessibility of essential information in the genome (but cells remain superficially functional when non-essential genes are missing or damaged). Depending on the type of damage inflicted on the DNAs double helical structure, a variety of repair strategies have evolved to restore lost information. If possible, cells use the unmodified complementary strand of the DNA or the sister chromatid as a template to recover the original information. Without access to a template, cells use an error-prone recovery mechanism known as translesion synthesis as a last resort.

Damage to DNA alters the spatial configuration of the helix, and such alterations can be detected by the cell. Once damage is localized, specific DNA repair molecules bind at or near the site of damage, inducing other molecules to bind and form a complex that enables the actual repair to take place.

Cells are known to eliminate three types of damage to their DNA by chemically reversing it. These mechanisms do not require a template, since the types of damage they counteract can occur in only one of the four bases. Such direct reversal mechanisms are specific to the type of damage incurred and do not involve breakage of the phosphodiester backbone. The formation of pyrimidine dimers upon irradiation with UV light results in an abnormal covalent bond between adjacent pyrimidine bases. The photoreactivation process directly reverses this damage by the action of the enzyme photolyase, whose activation is obligately dependent on energy absorbed from blue/UV light (300500nm wavelength) to promote catalysis.[14] Photolyase, an old enzyme present in bacteria, fungi, and most animals no longer functions in humans,[15] who instead use nucleotide excision repair to repair damage from UV irradiation. Another type of damage, methylation of guanine bases, is directly reversed by the protein methyl guanine methyl transferase (MGMT), the bacterial equivalent of which is called ogt. This is an expensive process because each MGMT molecule can be used only once; that is, the reaction is stoichiometric rather than catalytic.[16] A generalized response to methylating agents in bacteria is known as the adaptive response and confers a level of resistance to alkylating agents upon sustained exposure by upregulation of alkylation repair enzymes.[17] The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.

When only one of the two strands of a double helix has a defect, the other strand can be used as a template to guide the correction of the damaged strand. In order to repair damage to one of the two paired molecules of DNA, there exist a number of excision repair mechanisms that remove the damaged nucleotide and replace it with an undamaged nucleotide complementary to that found in the undamaged DNA strand.[16]

Double-strand breaks, in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements. Three mechanisms exist to repair double-strand breaks (DSBs): non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and homologous recombination.[16] PVN Acharya noted that double-strand breaks and a cross-linkage joining both strands at the same point is irreparable because neither strand can then serve as a template for repair. The cell will die in the next mitosis or in some rare instances, mutate.[2][3]

In NHEJ, DNA Ligase IV, a specialized DNA ligase that forms a complex with the cofactor XRCC4, directly joins the two ends.[21] To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate.[22][23][24][25] NHEJ can also introduce mutations during repair. Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms insertions or translocations. NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination. There are backup NHEJ pathways in higher eukaryotes.[26] Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during V(D)J recombination, the process that generates diversity in B-cell and T-cell receptors in the vertebrate immune system.[27]

MMEJ starts with short-range end resection by MRE11 nuclease on either side of a double-strand break to reveal microhomology regions.[28] In further steps,[29] PARP1 is required and may be an early step in MMEJ. There is pairing of microhomology regions followed by recruitment of flap structure-specific endonuclease 1 (FEN1) to remove overhanging flaps. This is followed by recruitment of XRCC1LIG3 to the site for ligating the DNA ends, leading to an intact DNA.

DNA double strand breaks in mammalian cells are primarily repaired by homologous recombination (HR) and non-homologous end joining (NHEJ).[30] In an in vitro system, MMEJ occurred in mammalian cells at the levels of 1020% of HR when both HR and NHEJ mechanisms were also available.[28] MMEJ is always accompanied by a deletion, so that MMEJ is a mutagenic pathway for DNA repair.[31]

Homologous recombination requires the presence of an identical or nearly identical sequence to be used as a template for repair of the break. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for chromosomal crossover during meiosis. This pathway allows a damaged chromosome to be repaired using a sister chromatid (available in G2 after DNA replication) or a homologous chromosome as a template. DSBs caused by the replication machinery attempting to synthesize across a single-strand break or unrepaired lesion cause collapse of the replication fork and are typically repaired by recombination.

Topoisomerases introduce both single- and double-strand breaks in the course of changing the DNAs state of supercoiling, which is especially common in regions near an open replication fork. Such breaks are not considered DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are immediately repaired by the enzymes that created them.

A team of French researchers bombarded Deinococcus radiodurans to study the mechanism of double-strand break DNA repair in that bacterium. At least two copies of the genome, with random DNA breaks, can form DNA fragments through annealing. Partially overlapping fragments are then used for synthesis of homologous regions through a moving D-loop that can continue extension until they find complementary partner strands. In the final step there is crossover by means of RecA-dependent homologous recombination.[32]

Translesion synthesis (TLS) is a DNA damage tolerance process that allows the DNA replication machinery to replicate past DNA lesions such as thymine dimers or AP sites.[33] It involves switching out regular DNA polymerases for specialized translesion polymerases (i.e. DNA polymerase IV or V, from the Y Polymerase family), often with larger active sites that can facilitate the insertion of bases opposite damaged nucleotides. The polymerase switching is thought to be mediated by, among other factors, the post-translational modification of the replication processivity factor PCNA. Translesion synthesis polymerases often have low fidelity (high propensity to insert wrong bases) on undamaged templates relative to regular polymerases. However, many are extremely efficient at inserting correct bases opposite specific types of damage. For example, Pol mediates error-free bypass of lesions induced by UV irradiation, whereas Pol introduces mutations at these sites. Pol is known to add the first adenine across the T^T photodimer using Watson-Crick base pairing and the second adenine will be added in its syn conformation using Hoogsteen base pairing. From a cellular perspective, risking the introduction of point mutations during translesion synthesis may be preferable to resorting to more drastic mechanisms of DNA repair, which may cause gross chromosomal aberrations or cell death. In short, the process involves specialized polymerases either bypassing or repairing lesions at locations of stalled DNA replication. For example, Human DNA polymerase eta can bypass complex DNA lesions like guanine-thymine intra-strand crosslink, G[8,5-Me]T, although can cause targeted and semi-targeted mutations.[34] Paromita Raychaudhury and Ashis Basu[35] studied the toxicity and mutagenesis of the same lesion in Escherichia coli by replicating a G[8,5-Me]T-modified plasmid in E. coli with specific DNA polymerase knockouts. Viability was very low in a strain lacking pol II, pol IV, and pol V, the three SOS-inducible DNA polymerases, indicating that translesion synthesis is conducted primarily by these specialized DNA polymerases. A bypass platform is provided to these polymerases by Proliferating cell nuclear antigen (PCNA). Under normal circumstances, PCNA bound to polymerases replicates the DNA. At a site of lesion, PCNA is ubiquitinated, or modified, by the RAD6/RAD18 proteins to provide a platform for the specialized polymerases to bypass the lesion and resume DNA replication.[36][37] After translesion synthesis, extension is required. This extension can be carried out by a replicative polymerase if the TLS is error-free, as in the case of Pol , yet if TLS results in a mismatch, a specialized polymerase is needed to extend it; Pol . Pol is unique in that it can extend terminal mismatches, whereas more processive polymerases cannot. So when a lesion is encountered, the replication fork will stall, PCNA will switch from a processive polymerase to a TLS polymerase such as Pol to fix the lesion, then PCNA may switch to Pol to extend the mismatch, and last PCNA will switch to the processive polymerase to continue replication.

Cells exposed to ionizing radiation, ultraviolet light or chemicals are prone to acquire multiple sites of bulky DNA lesions and double-strand breaks. Moreover, DNA damaging agents can damage other biomolecules such as proteins, carbohydrates, lipids, and RNA. The accumulation of damage, to be specific, double-strand breaks or adducts stalling the replication forks, are among known stimulation signals for a global response to DNA damage.[38] The global response to damage is an act directed toward the cells own preservation and triggers multiple pathways of macromolecular repair, lesion bypass, tolerance, or apoptosis. The common features of global response are induction of multiple genes, cell cycle arrest, and inhibition of cell division.

After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the G1/S and G2/M boundaries. An intra-S checkpoint also exists. Checkpoint activation is controlled by two master kinases, ATM and ATR. ATM responds to DNA double-strand breaks and disruptions in chromatin structure,[39] whereas ATR primarily responds to stalled replication forks. These kinases phosphorylate downstream targets in a signal transduction cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including BRCA1, MDC1, and 53BP1 has also been identified.[40] These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.

DNA damage checkpoint is a signal transduction pathway that blocks cell cycle progression in G1, G2 and metaphase and slows down the rate of S phase progression when DNA is damaged. It leads to a pause in cell cycle allowing the cell time to repair the damage before continuing to divide.

Checkpoint Proteins can be separated into four groups: phosphatidylinositol 3-kinase (PI3K)-like protein kinase, proliferating cell nuclear antigen (PCNA)-like group, two serine/threonine(S/T) kinases and their adaptors. Central to all DNA damage induced checkpoints responses is a pair of large protein kinases belonging to the first group of PI3K-like protein kinases-the ATM (Ataxia telangiectasia mutated) and ATR (Ataxia- and Rad-related) kinases, whose sequence and functions have been well conserved in evolution. All DNA damage response requires either ATM or ATR because they have the ability to bind to the chromosomes at the site of DNA damage, together with accessory proteins that are platforms on which DNA damage response components and DNA repair complexes can be assembled.

An important downstream target of ATM and ATR is p53, as it is required for inducing apoptosis following DNA damage.[41] The cyclin-dependent kinase inhibitor p21 is induced by both p53-dependent and p53-independent mechanisms and can arrest the cell cycle at the G1/S and G2/M checkpoints by deactivating cyclin/cyclin-dependent kinase complexes.[42]

The SOS response is the changes in gene expression in Escherichia coli and other bacteria in response to extensive DNA damage. The prokaryotic SOS system is regulated by two key proteins: LexA and RecA. The LexA homodimer is a transcriptional repressor that binds to operator sequences commonly referred to as SOS boxes. In Escherichia coli it is known that LexA regulates transcription of approximately 48 genes including the lexA and recA genes.[43] The SOS response is known to be widespread in the Bacteria domain, but it is mostly absent in some bacterial phyla, like the Spirochetes.[44] The most common cellular signals activating the SOS response are regions of single-stranded DNA (ssDNA), arising from stalled replication forks or double-strand breaks, which are processed by DNA helicase to separate the two DNA strands.[38] In the initiation step, RecA protein binds to ssDNA in an ATP hydrolysis driven reaction creating RecAssDNA filaments. RecAssDNA filaments activate LexA autoprotease activity, which ultimately leads to cleavage of LexA dimer and subsequent LexA degradation. The loss of LexA repressor induces transcription of the SOS genes and allows for further signal induction, inhibition of cell division and an increase in levels of proteins responsible for damage processing.

In Escherichia coli, SOS boxes are 20-nucleotide long sequences near promoters with palindromic structure and a high degree of sequence conservation. In other classes and phyla, the sequence of SOS boxes varies considerably, with different length and composition, but it is always highly conserved and one of the strongest short signals in the genome.[44] The high information content of SOS boxes permits differential binding of LexA to different promoters and allows for timing of the SOS response. The lesion repair genes are induced at the beginning of SOS response. The error-prone translesion polymerases, for example, UmuCD2 (also called DNA polymerase V), are induced later on as a last resort.[45] Once the DNA damage is repaired or bypassed using polymerases or through recombination, the amount of single-stranded DNA in cells is decreased, lowering the amounts of RecA filaments decreases cleavage activity of LexA homodimer, which then binds to the SOS boxes near promoters and restores normal gene expression.

Eukaryotic cells exposed to DNA damaging agents also activate important defensive pathways by inducing multiple proteins involved in DNA repair, cell cycle checkpoint control, protein trafficking and degradation. Such genome wide transcriptional response is very complex and tightly regulated, thus allowing coordinated global response to damage. Exposure of yeast Saccharomyces cerevisiae to DNA damaging agents results in overlapping but distinct transcriptional profiles. Similarities to environmental shock response indicates that a general global stress response pathway exist at the level of transcriptional activation. In contrast, different human cell types respond to damage differently indicating an absence of a common global response. The probable explanation for this difference between yeast and human cells may be in the heterogeneity of mammalian cells. In an animal different types of cells are distributed among different organs that have evolved different sensitivities to DNA damage.[46]

In general global response to DNA damage involves expression of multiple genes responsible for postreplication repair, homologous recombination, nucleotide excision repair, DNA damage checkpoint, global transcriptional activation, genes controlling mRNA decay, and many others. A large amount of damage to a cell leaves it with an important decision: undergo apoptosis and die, or survive at the cost of living with a modified genome. An increase in tolerance to damage can lead to an increased rate of survival that will allow a greater accumulation of mutations. Yeast Rev1 and human polymerase are members of [Y family translesion DNA polymerases present during global response to DNA damage and are responsible for enhanced mutagenesis during a global response to DNA damage in eukaryotes.[38]

DNA repair rate is an important determinant of cell pathology

Experimental animals with genetic deficiencies in DNA repair often show decreased life span and increased cancer incidence.[13] For example, mice deficient in the dominant NHEJ pathway and in telomere maintenance mechanisms get lymphoma and infections more often, and, as a consequence, have shorter lifespans than wild-type mice.[47] In similar manner, mice deficient in a key repair and transcription protein that unwinds DNA helices have premature onset of aging-related diseases and consequent shortening of lifespan.[48] However, not every DNA repair deficiency creates exactly the predicted effects; mice deficient in the NER pathway exhibited shortened life span without correspondingly higher rates of mutation.[49]

If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in early senescence, apoptosis, or cancer. Inherited diseases associated with faulty DNA repair functioning result in premature aging,[13] increased sensitivity to carcinogens, and correspondingly increased cancer risk (see below). On the other hand, organisms with enhanced DNA repair systems, such as Deinococcus radiodurans, the most radiation-resistant known organism, exhibit remarkable resistance to the double-strand break-inducing effects of radioactivity, likely due to enhanced efficiency of DNA repair and especially NHEJ.[50]

Most life span influencing genes affect the rate of DNA damage

A number of individual genes have been identified as influencing variations in life span within a population of organisms. The effects of these genes is strongly dependent on the environment, in particular, on the organisms diet. Caloric restriction reproducibly results in extended lifespan in a variety of organisms, likely via nutrient sensing pathways and decreased metabolic rate. The molecular mechanisms by which such restriction results in lengthened lifespan are as yet unclear (see[51] for some discussion); however, the behavior of many genes known to be involved in DNA repair is altered under conditions of caloric restriction.

For example, increasing the gene dosage of the gene SIR-2, which regulates DNA packaging in the nematode worm Caenorhabditis elegans, can significantly extend lifespan.[52] The mammalian homolog of SIR-2 is known to induce downstream DNA repair factors involved in NHEJ, an activity that is especially promoted under conditions of caloric restriction.[53] Caloric restriction has been closely linked to the rate of base excision repair in the nuclear DNA of rodents,[54] although similar effects have not been observed in mitochondrial DNA.[55]

It is interesting to note that the C. elegans gene AGE-1, an upstream effector of DNA repair pathways, confers dramatically extended life span under free-feeding conditions but leads to a decrease in reproductive fitness under conditions of caloric restriction.[56] This observation supports the pleiotropy theory of the biological origins of aging, which suggests that genes conferring a large survival advantage early in life will be selected for even if they carry a corresponding disadvantage late in life.

Defects in the NER mechanism are responsible for several genetic disorders, including:

Mental retardation often accompanies the latter two disorders, suggesting increased vulnerability of developmental neurons.

Other DNA repair disorders include:

All of the above diseases are often called segmental progerias (accelerated aging diseases) because their victims appear elderly and suffer from aging-related diseases at an abnormally young age, while not manifesting all the symptoms of old age.

Other diseases associated with reduced DNA repair function include Fanconi anemia, hereditary breast cancer and hereditary colon cancer.

Because of inherent limitations in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer.[57][58] There are at least 34 Inherited human DNA repair gene mutations that increase cancer risk. Many of these mutations cause DNA repair to be less effective than normal. In particular, Hereditary nonpolyposis colorectal cancer (HNPCC) is strongly associated with specific mutations in the DNA mismatch repair pathway. BRCA1 and BRCA2, two famous genes whose mutations confer a hugely increased risk of breast cancer on carriers, are both associated with a large number of DNA repair pathways, especially NHEJ and homologous recombination.

Cancer therapy procedures such as chemotherapy and radiotherapy work by overwhelming the capacity of the cell to repair DNA damage, resulting in cell death. Cells that are most rapidly dividing most typically cancer cells are preferentially affected. The side-effect is that other non-cancerous but rapidly dividing cells such as progenitor cells in the gut, skin, and hematopoietic system are also affected. Modern cancer treatments attempt to localize the DNA damage to cells and tissues only associated with cancer, either by physical means (concentrating the therapeutic agent in the region of the tumor) or by biochemical means (exploiting a feature unique to cancer cells in the body).

Classically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumour-suppressor genes and oncogenes, and chromosomal aberrations. However, it has become apparent that cancer is also driven by epigenetic alterations.[59]

Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are changes in DNA methylation (hypermethylation and hypomethylation) and histone modification,[60] changes in chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or HMGA1)[61] and changes caused by microRNAs. Each of these epigenetic alterations serves to regulate gene expression without altering the underlying DNA sequence. These changes usually remain through cell divisions, last for multiple cell generations, and can be considered to be epimutations (equivalent to mutations).

While large numbers of epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, appear to be particularly important. Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.[62][63][64][65]

Reduced expression of DNA repair genes causes deficient DNA repair. When DNA repair is deficient DNA damages remain in cells at a higher than usual level and these excess damages cause increased frequencies of mutation or epimutation. Mutation rates increase substantially in cells defective in DNA mismatch repair[66][67] or in homologous recombinational repair (HRR).[68] Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.[69]

Higher levels of DNA damage not only cause increased mutation, but also cause increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.[70][71]

Deficient expression of DNA repair proteins due to an inherited mutation can cause increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have an increased risk of cancer, with some defects causing up to a 100% lifetime chance of cancer (e.g. p53 mutations).[72] However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.[73]

Deficiencies in DNA repair enzymes are occasionally caused by a newly arising somatic mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. For example, when 113 colorectal cancers were examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).[74] Five different studies found that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.[75][76][77][78][79]

Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).[80] In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.[81]

In further examples (tabulated in Cancer epigenetics), epigenetic defects were found at frequencies of between 13%-100% for the DNA repair genes BRCA1, WRN, FANCB, FANCF, MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1 and ATM. These epigenetic defects occurred in various cancers (e.g. breast, ovarian, colorectal and head and neck). Two or three deficiencies in the expression of ERCC1, XPF or PMS2 occur simultaneously in the majority of the 49 colon cancers evaluated by Facista et al.[82]

The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes.[83] Of these, 83 are directly employed in the 5 types of DNA repair processes illustrated in the chart. The more well studied genes central to these repair processes are also shown in the chart. As indicated by the DNA repair genes shown in red, many of the genes in these repair pathways are regulated by epigenetic mechanisms, and these are frequently reduced or silent in various cancers (marked by an asterisk). Two review articles,[65][84] and two broad experimental survey articles[85][86] document most of these epigenetic DNA repair deficiencies.

It appears that epigenetic repression of DNA repair genes in accurate DNA repair pathways are central to carcinogenesis. However microhomology-mediated end joining (MMEJ) is an additional error-prone repair pathway for double-strand breaks. In MMEJ repair of a double-strand break, an homology of 5 25 complementary base pairs on both strands is identified and used as a basis to align the strands, but with mismatched ends. MMEJ removes extra nucleotides (flaps) where strands are joined, then ligates the strands to create an intact DNA double helix. MMEJ always involves at least a small deletion, so that it is a mutagenic pathway.[30]FEN1, the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast,[87] prostate,[88] stomach,[89][90] neuroblastomas,[91] pancreatic,[92] and lung.[93] Other genes in the MMEJ pathway are also over-expressed in a number of cancers (see MMEJ for summary), and are shown in cyan (blue) in the chart in this section.

The basic processes of DNA repair are highly conserved among both prokaryotes and eukaryotes and even among bacteriophage (viruses that infect bacteria); however, more complex organisms with more complex genomes have correspondingly more complex repair mechanisms.[94] The ability of a large number of protein structural motifs to catalyze relevant chemical reactions has played a significant role in the elaboration of repair mechanisms during evolution. For an extremely detailed review of hypotheses relating to the evolution of DNA repair, see.[95]

The fossil record indicates that single-cell life began to proliferate on the planet at some point during the Precambrian period, although exactly when recognizably modern life first emerged is unclear. Nucleic acids became the sole and universal means of encoding genetic information, requiring DNA repair mechanisms that in their basic form have been inherited by all extant life forms from their common ancestor. The emergence of Earths oxygen-rich atmosphere (known as the oxygen catastrophe) due to photosynthetic organisms, as well as the presence of potentially damaging free radicals in the cell due to oxidative phosphorylation, necessitated the evolution of DNA repair mechanisms that act specifically to counter the types of damage induced by oxidative stress.

On some occasions, DNA damage is not repaired, or is repaired by an error-prone mechanism that results in a change from the original sequence. When this occurs, mutations may propagate into the genomes of the cells progeny. Should such an event occur in a germ line cell that will eventually produce a gamete, the mutation has the potential to be passed on to the organisms offspring. The rate of evolution in a particular species (or, in a particular gene) is a function of the rate of mutation. As a consequence, the rate and accuracy of DNA repair mechanisms have an influence over the process of evolutionary change.[96] Since the normal adaptation of populations of organisms to changing circumstances (for instance the adaptation of the beaks of a population of finches to the changing presence of hard seeds or insects) proceeds by gene regulation and the recombination and selection of gene variations alleles and not by passing on irreparable DNA damages to the offspring,[97] DNA damage protection and repair does not influence the rate of adaptation by gene regulation and by recombination and selection of alleles. On the other hand, DNA damage repair and protection does influence the rate of accumulation of irreparable, advantageous, code expanding, inheritable mutations, and slows down the evolutionary mechanism for expansion of the genome of organisms with new functionalities. The tension between evolvability and mutation repair and protection needs further investigation.

A technology named clustered regularly interspaced short palindromic repeat shortened to CRISPR-Cas9 was discovered in 2012. The new technology allows anyone with molecular biology training to alter the genes of any species with precision.[98]

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Genetics and Inheritance – National Fragile X Foundation

What Are Chromosomes?

Our bodies are made up of about 60 trillion cells. Each one of those cells manufactures proteins. The kinds of proteins any given cell makes determine its particular characteristics, which in turn create the characteristics of the entire body.

The instructions for making these proteins are stored in chemicals or molecules called DNA, which is organized into chromosomes. Chromosomes are found in the center, or nucleus, of all of our cells, including the eggs and sperm.

Female Chromosomes

Male Chromosomes

Chromosomes are passed down from generation to generation through the egg and sperm. Typically, we all have 46 chromosomes in our cells, two of which are sex chromosomes. In females, these are two Xs; in males they are an X and a Y.

Genes are sections of DNA that are passed from generation to generation and perform one function. If we think of DNA as letters in the alphabet, the genes are words and the chromosome is a full sentence. All 46 chromosomes then make up the whole book.

There are many genes on each chromosome; we all have tens of thousands of genes that instruct our bodies on how to develop.

Genes are given names to identify them and the gene responsible for fragile X syndrome is called FMR1. The FMR1 Gene is on the X chromosome.

The FMR1 gene appears in four forms that are defined by the number of repeats of a pattern of DNA called CGG repeats.

Individuals with less than 45 CGG repeats have a normal FMR1 gene. Those with 45-54 CGG repeats have what is called an intermediate or grey zone allele, which does not cause any of the known fragile X associated disorders.

Individuals with 55-200 CGG repeats have a premutation, which means they carry an unstable mutation of the gene that can expand in future generations and thus cause fragile X syndrome in their children or grandchildren. Individuals with a premutation can also develop FXTAS or FXPOI themselves.

Individuals with over 200 CGG repeats have a full mutation of the FMR1 gene, which causes fragile X syndrome.

The full mutation causes the FMR1 gene to shut down or methylate in one region. Normally, the FMR1 gene produces an important protein called FMRP. When the gene is turned off, the individual does not make this protein. The lack of this specific protein is what causes fragile X syndrome.

Fragile X-associated Disorders are a group of conditions called trinucleotide repeat disorders. A common feature of these conditions is that the gene can change sizes over generations, becoming more unstable, and thus the conditions may occur more frequently or severely in subsequent generations. These conditions are often caused by a gene change that begins with a premutation and then expands to a full mutation in subsequent generations.

Approximately 1 in 151 females and 1 in 468 males carry the FMR1 premutation. They are thus carriers of the premutation.

Premutations are defined as having 55-200 CGG repeats and can occur in both males and females. When a father passes the premutation on to his daughters, it usually does not expand to a full mutation. A man never passes the fragile X gene to his sons, since he passes only his Y chromosome to them, which does not contain a fragile X gene.

A female with the FMR1 premutation will often pass on a larger version of the mutation to her children (more on this point below). She also has a 50 percent chance of passing on her normal X chromosome in each pregnancy, since usually only one of her X chromosomes has the FMR1 mutation.

The chance of the premutation expanding to a full mutation is related to the size of the mothers premutation. The larger the mothers CGG repeat number, the higher the chance that it will expand to a full mutation if it is passed on.

Typically, the premutation has no immediate and observable impact on a persons appearance or health. However, some females with a premutation will experience fragile X-associated primary ovarian insufficiency (FXPOI), which causes infertility, irregular or missed menstrual cycles, and/or early menopause.

Additionally, some older adults with a premutation may develop a neurological condition called FXTAS, (fragile X-associated tremor/ataxia syndrome), an adult onset neurodegenerative disorder.

FXTAS and FXPOI are part of the family of conditions called Fragile X-associated Disorders.

A full mutation is defined as having over 200 CGG repeats and causes that indicate the presence of fragile X syndrome in males and some females. Most full mutation expansions have some degree of Methylation (the process which turns off the gene). Males with a full mutation will have Fragile X Syndrome, though with varying degrees of severity

About 65-70 percent of females with a full mutation exhibit some difficulties with cognitive, learning, behavioral, or social functioning, and may also have some of the physical features of FXS (such as large ears or a long face). The remaining 30-35 percent are at risk to develop mental health issues such as anxiety or depression, or they may have no observable effects of the full mutation.

Fragile X in an X-linked condition, which means that the gene is on the X chromosome.

Since a woman has two X chromosomes a woman with a premutation or full mutation has a 50% chance of passing on the X with the mutation in each pregnancy, and a 50% chance of passing on her normal X.

If she has a premutation, and it is passed on (to either males or females), it can remain a premutation or it can expand to a full mutation. If she has a full mutation and it is passed on (to either males or females), it will remain a full mutation.

Because males have only one X chromosome, fathers who carry the premutation will pass it on to all their daughters and none of their sons (they pass their Y chromosome on to their sons). There have been no reports of premutations that are passed from a father to his daughter expanding to a full mutation. This appears to only occur when passed from a mother to her children.

In many X-linked conditions only males who inherit the abnormal gene are affected. Fragile X syndrome is one of the X-linked conditions that can also affect females.

Additionally, in other X-linked conditions all males who carry the abnormal form of the gene are affected. In fragile X syndrome, unaffected males can carry the gene in the premutation form while themselves having no symptoms of the condition.

Follow this link:
Genetics and Inheritance – National Fragile X Foundation

Recommendation and review posted by Bethany Smith

Hypopituitarism –

Hypopituitarism: Introduction

Hypopituitarism: A condition characterized by diminished hormonal section by the pituitary gland. See detailed information below for a list of 22 causes of Hypopituitarism, Symptom Checker, including diseases and drug side effect causes.

Review Causes of Hypopituitarism: Causes | Symptom Checker

Home medical tests possibly related to Hypopituitarism:

Listed below are some combinations of symptoms associated with Hypopituitarism, as listed in our database. Visit the Symptom Checker, to add and remove symptoms and research your condition.

See full list of 501 Symptom Checkers for Hypopituitarism

Review further information on Hypopituitarism Treatments.

Real-life user stories relating to Hypopituitarism:

Some of the comorbid or associated medical symptoms for Hypopituitarism may include these symptoms:

See all associated comorbid symptoms for Hypopituitarism

Research the causes of these more general types of symptom:

Research the causes of these symptoms that are similar to, or related to, the symptom Hypopituitarism:

Read more about causes and Hypopituitarism deaths.

Pituitary conditions often undiagnosed cause of symptoms: There are a variety of symptoms that can be caused by a pituitary disorder (see symptoms of pituitary disorders). For example, fatigue, headache, weight…read more

Read more about Misdiagnosis and Hypopituitarism

Other medical conditions listed in the Disease Database as possible causes of Hypopituitarism as a symptom include:

See full list of 22 causes of Hypopituitarism – (Source – Diseases Database)

Diminution or cessation of secretion of one or more hormones from the anterior pituitary gland (including LH; FOLLICLE STIMULATING HORMONE; SOMATOTROPIN; and CORTICOTROPIN). This may result from surgical or radiation ablation, non-secretory PITUITARY NEOPLASMS, metastatic tumors, infarction, PITUITARY APOPLEXY, infiltrative or granulomatous processes, and other conditions. – (Source – Diseases Database)

Diminution or cessation of secretion of one or more hormones from the anterior pituitary gland (including luteinizing hormone, follicle stimulating hormone, somatotropin; and corticotropin); may result from surgical or radiation ablation, non-secretory pituitary neoplasms, metastatic tumors, infarction, pituitary apoplexy, infiltrative or granulomatous processes, and other conditions. – (Source – CRISP)

Hypopituitarism is listed as a “rare disease” by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH). This means that Hypopituitarism, or a subtype of Hypopituitarism, affects less than 200,000 people in the US population. – (Source – National Institute of Health)

The list below shows some of the causes of Hypopituitarism mentioned in various sources:

See full list of 22 causes of Hypopituitarism

This information refers to the general prevalence and incidence of these diseases, not to how likely they are to be the actual cause of Hypopituitarism. Of the 22 causes of Hypopituitarism that we have listed, we have the following prevalence/incidence information:

See the analysis of the prevalence of 22 causes of Hypopituitarism

The following list of conditions have ‘Hypopituitarism’ or similar listed as a symptom in our database. This computer-generated list may be inaccurate or incomplete. Always seek prompt professional medical advice about the cause of any symptom.

Select from the following alphabetical view of conditions which include a symptom of Hypopituitarism or choose View All.

The following list of medical conditions have Hypopituitarism or similar listed as a medical complication in our database. The distinction between a symptom and complication is not always clear, and conditions mentioning this symptom as a complication may also be relevant. This computer-generated list may be inaccurate or incomplete. Always seek prompt professional medical advice about the cause of any symptom.

Ask or answer a question about symptoms or diseases at one of our free interactive user forums.

Medical story forums: If you have a medical story then we want to hear it.

See a list of all the medical forums

Adenohypophyseal hyposecretion, Pituitary failure – (Source – Diseases Database)

Medical Conditions associated with Hypopituitarism:

Pituitary symptoms (18 causes), Endocrine symptoms (217 causes)

Symptoms related to Hypopituitarism:

Pituitary symptoms (18 causes), Pituitary disorders, Arthrogryposis (47 causes), Distal, With hypopituitarism, Mental retardation (2098 causes), Facial anomalies (72 causes), Combined pituitary hormone deficiency (PROP1 gene), Craniopharyngioma, Angelmann’s syndrome, Froehlich syndrome

Doctor-patient articles related to symptoms and diagnosis:

These general medical articles may be of interest:

See full list of premium articles on symptoms and diagnosis

Tools & Services:

Medical Articles:

Original post:
Hypopituitarism –

Recommendation and review posted by sam

Mesenchymal and haematopoietic stem cells form a unique …

ai, In vivo self-renewal of adult bone marrow CD45Nes-GFP+ cells in secondary transplants. a, Scheme showing the experimental paradigm. be, Primary ossicles showing numerous -galactosidase+ osteoblasts derived from CD45Nes-GFP+ cells (b, blue; d, e, dark deposits, arrowheads) but none from CD45Nes-GFP cells (c); haematopoietic areas (b, e; circled by dashed line) were detected only in the former group and frequently associated with GFP+ cells (e, green). f, Secondary ossicle showing numerous -galactosidase+ osteoblasts derived from CD45Nes-GFP+ cells (blue) and also haematopoietic areas (circled by dashed line). g, CD45+ haematopoietic cells (red) localized near Nes-GFP+ (green) cells in the ossicles; cell nuclei have been stained with DAPI (blue); grid, 50 m per square. h, i, Secondary ossicles yielded 8,557 537 GFP+ spheres (h) that generated Col2.3+ osteoblasts (i; blue precipitates). jm, Adult nestin+ MSCs contribute to endochondral lineages. jl, Femoral sections from 11-month-old Nes-creERT2/RCE:loxP double-transgenic mice 8 months after tamoxifen treatment showing the contribution of adult nestin+ cells to bone-lining osteoblasts (j), osteocytes (k; asterisks indicate GFP+ cells, arrowheads indicate GFP osteocytes) and collagen 1 type 2+ (red) chondrocytes (l). m, GFP+ (green) perivascular cells (asterisk) identical in frequency, morphology and distribution to Nes-GFP+ cells and osteoblasts (arrowhead) co-stained with anti-GFP antibodies (red). n, o, Bone marrow section of Nes-Gfp/Col2.3-cre/R26R triple-transgenic mouse showing X-gal+ osteoblasts (dark precipitates), GFP+ (green) and CD31+ vascular endothelial cells (red); Col2.3+ osteoblasts localized near Nes-GFP+ perivascular cells are indicated with arrowheads. p, q, Immunostaining for osterix (red) in trabecular bone section of a 5-week-old Nes-Gfp (green) mouse. g, jm, oq, Nuclei have been stained with DAPI (blue). j, l,m, p, q, Bone (b) margins are indicated with dashed lines. b, c, f, i, n, Bright field; g, j, k, p, q, fluorescence; d, e, h, l, m, o, overlapped fluorescence and bright field. Scale bars: 100 m (cf, h, i); 20 m (jq).

Read this article:
Mesenchymal and haematopoietic stem cells form a unique …

Recommendation and review posted by sam

Male Infertility – Genetics & IVF Institute

Among infertile couples, either partner may contribute to the failure to conceive. It is estimated that 30-40% of infertility is due to male abnormalities, another 20% to a combination of various factors, and about 30-40% to problems with the female partner.

The Genetics & IVF Institute offers expert diagnosis and treatment of male infertility. Our male infertility treatment offers the following benefits:

If donor sperm is needed, our on-site sperm bank, Fairfax Cryobank, provides a large selection of high quality, fully screened donor sperm. In fact, GIVF patients who choose donor sperm from Fairfax Cryobank can enjoy free shipping and handling, as well as same day delivery. Click here to learn more about Fairfax Cryobank.

An important component in the treatment of men with infertility is establishing the correct diagnosis. Our medical specialists conduct a thorough clinical evaluation of each couple. State of the art semen analysis and specialized sperm function testing are available, including measurement of sperm capacitation and acrosome reaction, computer assisted sperm motion analysis (CASA), sperm antibody, and leukocyte quantitation. An appropriate individualized treatment is then recommended.

Intracytoplasmic sperm injection (ICSI), is the direct injection of sperm into eggs obtained for in vitro fertilization (IVF). GIVF has extensive experience with ICSI and have established thousands of pregnancies using this technique. ICSI frequently permits the establishment of pregnancy in even the most difficult types of male infertility, including men who have fewer than 100 sperm in their semen. For men with no sperm at all in their semen, sperm can be obtained directly from the testis with non-surgical sperm aspiration (NSA). Testicular sperm can fertilize when injected directly into eggs using ICSI.

The ICSI Process:

ICSI has been widely used for over ten years. GIVF performed the first ICSI pregnancy in the US and since then the procedure has become the standard of care for male factor infertility. The American Society for Reproductive Medicine (ASRM) considers it a safe, effective procedure that has helped thousands of men becomes fathers. If you have questions or concerns about ICSI, please let your doctor or nurse know so that we can discuss it with you.

The difference between IVF and ICSI is in how the sperm meets the egg. With traditional IVF, the sperm is poured on the egg. That is to say that the sperm is put into the petri dish that the eggs are in and fertilization takes place in the dish the same way it would in the fallopian tubes. Millions of sperm compete to fertilize each egg.

With ICSI, an individual sperm is injected into a single egg. ICSI is used when there is a problem with the sperm; thereby the likelihood of fertilization is increased if we inject the sperm directly into the egg. ICSI does not guarantee that fertilization takes place, but it does ensure that sperm meets egg. With traditional IVF, the sperm may never pass through the outer zona of the egg. Your doctor will advise you if ICSI is recommended for you based on the results of the semen testing and a few other risk factors.

Non-surgical sperm aspiration (NSA) is a quick and painless procedure performed in our clinic under sedation. A tiny needle is used to extract sperm directly from the testis. While the ejaculate normally contains 100 million to 300 million sperm, aspiration of as few as 100-200 sperm by NSA have been enough to achieve pregnancy when it is combined with ICSI.

NSA may be recommended for men who:

It is possible to reverse a vasectomy by having bypass surgery, but the operation is frequently unsuccessful, especially for men with long-standing vasectomies. Additionally, sperm quality after vasectomy reversal is often reduced and ICSI is required even if sperm appear in the ejaculate. For many men, NSA eliminates the need for vasectomy reversal surgery.

Prior to the development of NSA, men with no sperm in their ejaculate had to undergo surgery to remove sperm either from their testes or from tubes connected to the testis. The operation required a costly hospital stay and a lengthy recuperation. NSA is a quick and painless procedure performed at GIVF, does not require hospitalization, and recovery is virtually immediate. It should be noted that for some men, a single NSA procedure may yield enough sperm to permit sperm freezing for several subsequent ICSI attempts.

NSA must be done with ICSI because testicular sperm cannot enter eggs by themselves. In order to accomplish this, the female partner receives a series of medications to increase the number of eggs created by the ovary as in a conventional IVF cycle. When the eggs grow to adequate size, they are extracted non-surgically at GIVF under sedation, and NSA is scheduled the same day. After egg retrieval and sperm aspiration, our embryologists inject each egg with a single sperm. Two days after the procedures, definite information regarding fertilization of the eggs, and the number of embryos are available. Embryos are transferred back to the uterus two or three days following fertilization; additional embryos may be cryopreserved (frozen), as requested.

If donor sperm is needed, our on-site sperm bank, Fairfax Cryobank, provides a large selection of high quality, fully screened donor sperm. In fact, GIVF patients who choose donor sperm from Fairfax Cryobank can enjoy free shipping and handling, as well as same day delivery. Click here to learn more about Fairfax Cryobank.

Click here or call 800.552.4363 or 703.698.7355 to schedule a fertility consultation at GIVF.

Read the original post:
Male Infertility – Genetics & IVF Institute

Recommendation and review posted by simmons

Molecular Genetics Laboratory of Female Reproductive Cancer

The long-term objectives of our research team are:

a. to understand the molecular etiology in the development of human cancer, and b. to identify and characterize cancer molecules for cancer detection, diagnosis, and therapy.

We use ovarian carcinoma as a disease model because it is one of the most aggressive neoplastic diseases in women. For the first research direction, we aim to identify and characterize the molecular alterations during initiation and progression of ovarian carcinomas. Previous genome-wide analyses from our team have identified molecular alterations in several new cancer-associated genes including Rsf-1, NAC-1, and Notch3 among several others. We have demonstrated the essential roles of these gene products in sustaining tumor growth and survival. Current projects are focusing on elucidating the mechanisms by which these genes function in cancer cells and delineating the cross-talks between those genes and other signaling pathways. Specifically, we are identifying their downstream targets and pathways, and are determining their roles in maintaining cancer stem cell-like features, invasion and drug resistance. The second research direction is a translation-based study. We are assessing the clinical significance of an array of new cancer-associated genes in predicting clinical outcome and in the developing potential target-based therapy in mouse preclinical models. We are also establishing innovative assays for cancer detection and diagnosis by identifying new tumor-associated genetic and protein biomarkers through serial analysis of gene expression, gene expression arrays, proteomics and methylation profiling. The purpose is to develop new tools in detecting human cancer using body fluid samples. In collaboration with several investigators, we are integrating new technologic platforms such as microfluidics, nanotechnology and systems biology in our studies.

In addition to ovarian cancer genetics, we are interested in the diagnostic pathology and basic research of gestational trophoblastic diseases. Please visit “Pathology of Trophoblastic Lesions” for details.

Click here for the Ovarian Cancer Prevention Website

Click here for the Ovarian Cancer Research Program

“What we observe is not nature itself, but nature exposed to our method of questioning.” — Werner Heisenberg, Physics and Philosophy, 1958

Tian-Li Wang, PhD

Professor Departments of Pathology, Oncology, and Gynecology & Obstetrics Faculty in Pathobiology Graduate Program Johns Hopkins Medical Institutions

National Taiwan University, BS Johns Hopkins University School of Medicine, PhD University of Pennsylvania, School of Medicine, Post-doc fellow (Neuroscience) Howard Hughes Medical Institutions, Associate (Cancer Genetics)

Ie-Ming Shih, MD, PhD Co-director, Breast & Ovarian Cancer Program Sidney Kimmel Comprehensive Cancer Center

Richard W. TeLinde Professor Department of Gynecology & Obstetrics Departments of Pathology and Oncology Faculty in Pathobiology Graduate Program Johns Hopkins University School of Medicine

Taipei Medical University, MD University of Pennsylvania, PhD Johns Hopkins University, Residency (Pathology) Johns Hopkins University, Fellowships (Gynecologic Pathology and Cancer Genetics)

See more here:
Molecular Genetics Laboratory of Female Reproductive Cancer

Recommendation and review posted by sam

Isoproterenol directs hair follicle-associated pluripotent …

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Isoproterenol directs hair follicle-associated pluripotent …

Recommendation and review posted by Bethany Smith

The Bone Marrow Niche for Haematopoietic Stem Cells

a. HSCs are found mainly adjacent to sinusoids throughout the bone marrow,,,, where endothelial cells and mesenchymal stromal cells promote HSC maintenance by producing SCF, CXCL12,,, and likely other factors. Similar cells may also promote HSC maintenance around other types of blood vessels, such as arterioles. The mesenchymal stromal cells can be identified based on their expression of Lepr-Cre, Prx1-Cre, Cxcl12-GFP, or Nestin-GFP transgene in mice and similar cells are likely to be identified by CD146 expression in humans. These perivascular stromal cells, which likely include Cxcl12-abundant Reticular (CAR) cells, are fated to form bone in vivo, express Mx-1-Cre and overlap with CD45/Ter119PDGFR +Sca-1+ stromal cells that are highly enriched for MSCs in culture. b. It is likely that other cells also contribute to this niche, likely including cells near bone surfaces in trabecular rich areas. Other cell types that regulate HSC niches include sympathetic nerves,, non-myelinating Schwann cells (which are also Nestin+), macrophages, osteoclasts, extracellular matrix ,, and calcium. Osteoblasts do not directly promote HSC maintenance but do promote the maintenance and perhaps the differentiation of certain lymphoid progenitors by secreting Cxcl12 and likely other factors,,,. Early lineage committed progenitors thus reside in an endosteal niche that is spatially and cellularly distinct from HSCs.

See the article here:
The Bone Marrow Niche for Haematopoietic Stem Cells

Recommendation and review posted by sam

Gene Therapy News — ScienceDaily

Validation of Screening Tool for ROS1 Gene Rearrangements May 11, 2016 Immunohistochemistry (IHC) is an effective tool that can be used for identifying proto-oncogene 1 receptor tyrosine kinase (ROS1) gene rearrangements and screening patients for the administration of … read more New Study Shows Children Benefited Most from Gene Therapy for LCA, a Rare Eye Disease Apr. 15, 2016 Scientists have completed a two-year Phase I clinical trial which showed that children showed the greatest benefit from gene therapy for treatment of Leber congenital amaurosis or severe early … read more Novel Mechanism of Crizotinib Resistance in a ROS1+ NSCLC Patient Apr. 11, 2016 Molecular analysis of a tumor biopsy from a proto-oncogene 1 receptor tyrosine kinase positive (ROS1+) patient with acquired crizotinib resistance revealed a novel mutation in the v-kit Hardy … read more Mar. 24, 2016 Two new gene modification methods have been developed: lsODN (long single-stranded oligodeoxynucleotide) and 2H2OP (two-hit two-oligo with plasmid).These methods use CRISPR (Clustered Regularly … read more Mar. 10, 2016 Neurons in the brain that have been supplemented with a synthetic gene can be remotely manipulated by a magnetic field, scientists have shown. The finding has implications for possible future … read more Modified Form of CRISPR Acts as a Toggle Switch to Control Gene Expression in Stem Cells Mar. 10, 2016 Combining the two most powerful biological tools of the 21st century, scientists have modified how the genome of induced pluripotent stem cells (iPSCs) is read for the first time using a variation of … read more Scientists Use Synthetic Gene and Magnets to Alter Behavior of Mice, Fish Mar. 7, 2016 Scientists have demonstrated that neurons in the brain that have been supplemented with a synthetic gene can be remotely manipulated by a magnetic field. This has implications for future treatment of … read more Rare Respiratory Disease Gene Carriers Actually Have Increased Lung Function Mar. 4, 2016 New research has revealed the healthy carriers of a gene that causes a rare respiratory disease are taller and larger than average, with greater respiratory capacity. The disease, alpha1-antitrypsin … read more Normal Stem Cells Linked to Aggressive Prostate Cancer Feb. 29, 2016 A study that revealed new findings about prostate cells may point to future strategies for treating aggressive and therapy-resistant forms of prostate cancer, report … read more Feb. 24, 2016 A new treatment for aplastic anemia is based on the transport of the telomerase gene to the bone marrow cells using gene therapy, a completely new strategy in the treatment of aplastic … read more Potential Treatment for Friedreich’s Ataxia Identified Feb. 16, 2016 Researchers have identified synthetic RNA and DNA that reverses the protein deficiency causing Friedreichs ataxia, a neurological disease for which there is currently no … read more Researchers Identify Way Radiation May Fight Cancer Cells Escaping Immune System Feb. 1, 2016 A team of researchers is fighting cancers using a combination of therapies and recently found ways that radiation could maximize responses to novel immune-based therapeutic approaches to fight … read more In Lung Cancer, Not All HER2 Alterations Are Created Equal Jan. 28, 2016 Study shows two distinct causes of HER2 activation in lung cancer: mutation of the gene and amplification of the gene. In patient samples of lung adenocarcinoma, 3 percent were found to have HER2 … read more Gene Therapy for Rare Bleeding Disorder Achieves Proof-of-Concept Jan. 20, 2016 Hematology researchers have used a single injection of gene therapy to correct a rare bleeding disorder, factor VII deficiency, in dogs. This success in large animals holds considerable potential for … read more Common Gene Mutation Bad for Liver Values, Good for Blood Lipids in Children Jan. 13, 2016 A common mutation in one gene raises liver values but at the same time improves blood lipid values in healthy children, according to a recent study. Children who carry the gene mutation had higher … read more Novel RNA Delivery System May Treat Incurable Blood Cancers Jan. 5, 2016 Mantle Cell Lymphoma is considered the most aggressive known blood cancer, and available therapies are scarce. A new study offers tangible hope of curing the currently incurable cancer — and others … read more Three Hits to Fight Lung Cancer Jan. 4, 2016 Cancers with KRAS-related gene mutations might benefit from a triple therapy with two experimental drugs plus radiation therapy, a new study in mice has … read more Dec. 16, 2015 Proteins are like bricks that form our cells and they are built by the orders given by our genetic material, DNA. In human diseases, eventually DNA alterations modify proteins and they don’t do … read more Dec. 12, 2015 Results from a long-term clinical trial conducted by cancer researchers show that combining radiation treatment with ‘suicide gene therapy’ provides a safe and effective one-two punch … read more Gene Therapy Used to Extend Estrogen’s Protective Effects on Memory Dec. 8, 2015 The hormone estrogen helps protect memory and promote a healthy brain, but this effect wanes as women age, and even estrogen replacement therapy stops working in humans after age 65. Now researchers … read more

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The rest is here:
Gene Therapy News — ScienceDaily

Recommendation and review posted by sam

Genetic Testing | Issue List

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Genetic Testing | Issue List

Recommendation and review posted by simmons

Genetic Testing: Best Defense Against Breast Cancer?

The Angelina Jolie effect. Health experts have coined the phrase to describe how the actresss public disclosure about her struggle with breast cancer has increased awareness of the benefits of genetic testing as a way to speed treatment for the disease, which kills more than 40,000 American women annually.

In 2013, Jolie had both breasts surgically removed after genetic tests revealed she carries a genetic mutation in her so-called BRCA1 gene that dramatically increases the chance of being diagnosed with potentially fatal breast cancer. The gene defect left the mother of six with an 87 percent greater risk of developing breast cancer and 50 percent risk of ovarian cancer.

Dr. Marisa C. Weiss chief medical officer of the advocacy group tells Newsmax Health the actress’s decision to go public with details of her double mastectomy and reconstructive surgery was enormously helpful in improving the public’s understanding of breast cancer treatment options and the benefits of genetic testing.

Her bravery and willingness to share her story has given a lot of women the courage to step forward and explore their own family history, start a conversation with their doctors about risk, and seek appropriate genetic testing, says Weiss, a breast oncologist in practice at Philadelphias Lankenau Medical Center and the author of five books on the topic.

In an interview with Newsmax Health, Weiss says major advances in genetic research over the past decade now offer women, and men predisposed to developing breast cancer unprecedented opportunities to find out if they are at risk and take appropriate actions that can save their lives.

Excerpts from Wessss interview follow.

Q: What do most women need to know about gene testing?

A: Only 10 percent of breast cancers are mostly due to an inherited genetic mutation, like what Angelina had, BRCA 1. Most women who get breast cancer do not have a family history or an inherited genetic mutation. Most breast cancers occur from the wear and tear of living including a list of modifiable lifestyle, reproductive, and environmental exposures.

All that said, genetic testing is underutilized. Breast cancer is the most common cancer to affect women and even 10 percent of cases adds up to many precious lives. These genetic mutations are associated with a very high level of risk. Finding out if you have an inherited high risk mutation, gives you more options to protect and save your life.

Q: What can you do if you find out you have a genetic mutation?

A: For prevention, finding out about an inherited abnormal breast cancer gene gives you the chance to take steps to prevent cancer before it has the chance to start, with options like risk-reducing medications and prophylactic surgeries.

In addition, there is important family planning, other reproductive choices, and everyday lifestyle choices that can also help. It’s also important to take steps to reduce the risk of other cancers which go along with the same genetic mutation, like ovarian cancer. For women diagnosed with breast cancer, finding out if you have an inherited genetic mutation, can have a big impact on selecting your most effective treatment options.

Specific chemotherapies can be extra effective in women with a BRCA1 (and BRCA2) cancer, like Cisplatin. A therapeutic mastectomy might be selected for the treatment of the breast affected by the cancer and a prophylactic mastectomy might be chosen for the other side, to help both reduce the risk of recurrence or the development of a new cancer.

Q: What factors should go into a womans decision about whether to undergo testing?

A: Genetic testing is recommended for women usually 25 or older who are most likely to carry the genetic mutation, like:

Q: What tests are available?

A: Many new tests are available to test for significant inherited mutations. Focused testing on just the three main “founder mutations” on the breast cancer genes, BRCA1 and 2, can be done. Or if a broader range of genes need to be checked out, then “panel testing” may be recommended.

Q: Does a positive test mean a woman will definitely develop breast or ovarian cancer?

A: No. Inherited genetic mutations such as BRCA1 or 2 both convey a high level of life-long risk, ranging from 40-87 percent, depending on the group studied. It’s not 100 percent. But given the high risk these genetic mutations produce, it makes sense to find out if you have one, so that you can take the time-sensitive, powerful bold steps required to substantially reduce your high risk.

Q: Is double mastectomy the best solution?

A: Double mastectomy is the single most powerful step to reduce the high risk that is associated with a BRCA 1 or 2 genetic mutation. It can reduce your risk by 90-plus percent. Doing this surgery is not an emergency. But, the sooner this procedure is done, before a cancer has the chance to develop, the greater the chance to avoid getting cancer in the first place.

There are other ways to reduce the risk of breast cancer, like with anti-estrogen hormonal therapy (like tamoxifen), especially in women who carry the BRCA2 mutation that’s more likely to be associated with hormone receptor positive breast cancer (BRCA1 mutations are more likely to produce a “triple negative” breast cancer).

Very close surveillance is necessary for women with a BRCA1/2 genetic mutation. For breast surveillance, digital mammography alternating with MRI is recommended every 6 months (e.g. a mammogram in January, MRI in June). An expert clinical breast exam is also important. It is also critical to be followed closely by an ob-gyn expert, to help reduce and watch for the high risk of ovarian, fallopian tubes, and peritoneal cancers (the inside lining of the pelvic and abdominal cavities).

Q: Should men consider a test?

A: Any man with breast cancer should have genetic testing. Women seeking genetic testing who have a family history of breast and related cancers on the father’s side may ask their father to obtain genetic testing, to help identify and define the impact of inherited genes in the members of their family.

Most people don’t know that genetic risk is equally inherited from your mother and your father.

2016 NewsmaxHealth. All rights reserved.

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Genetic Testing: Best Defense Against Breast Cancer?

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genetic testing |

Genetic testing, any of a group of procedures used to identify gene variations associated with health, disease, and ancestry and to diagnose inherited diseases and disorders. A genetic test is typically issued only after a medical history, a physical examination, and the construction of a family pedigree documenting the genetic diseases present in the past three generations have been considered. The pedigree is especially important, since it aids in determining whether a disease or disorder is inherited and likely to be passed on to subsequent generations. Genetic testing is increasingly being used in genealogy, the study of family origins and history.

A genetic disorder can occur in a child with parents who are not affected by the disorder. This situation arises when a gene mutation occurs in the egg or sperm (germinal mutation) or following conception, when chromosomes from the egg and sperm combine. Mutations can occur spontaneously or be stimulated by environmental factors, such as radiation or carcinogens (cancer-causing agents). Mutations occur with increasing frequency as people age. In men this may result from errors that occur throughout a lifetime as DNA (deoxyribonucleic acid) replicates to produce sperm. In women nondisjunction of chromosomes becomes more common later in life, increasing the risk of aneuploidy (too many or too few chromosomes). Long-term exposure to ambient ionizing radiation may cause genetic mutations in either gender. In addition to these exposure mutations, there also exist two broad classes of genes that are prone to mutations that give rise to cancer. These classes include oncogenes, which promote tumour growth, and tumour-suppressor genes, which suppress tumour growth.

Chemical, radiological, histopathologic, and electrodiagnostic procedures can diagnose basic defects in patients suspected of genetic disease. Genetic tests may involve cytogenetic analyses to investigate chromosomes, molecular assays to investigate genes and DNA, or biochemical assays to investigate enzymes, hormones, or amino acids. Tests such as amino acid chromatography of blood and urine, in which the amino acids present in these fluids are separated on the basis of certain chemical affinities, can be used to identify specific hereditary or acquired gene defects. There also exist numerous genetic tests for blood and blood typing and antibody determination. These tests are used to isolate blood or antibody abnormalities that can be traced to genes involved in the generation of these substances. Various electrodiagnostic procedures such as electromyography are useful for identifying defects in muscle and nerve function, which often result from inherited gene mutations.

Prenatal screening is performed if there is a family history of inherited disease, the mother is at an advanced age, a previous child had a chromosomal abnormality, or there is an ethnic indication of risk. Parents can be tested before or after conception to determine whether they are carriers.

A common prenatal test involves screening for alpha-fetoprotein (AFP) in maternal serum. Elevated levels of AFP are associated with neural tube defects in the fetus, including spina bifida (defective closure of the spine) and anencephaly (absence of brain tissue). When AFP levels are elevated, a more specific diagnosis is attempted, using ultrasound and amniocentesis to analyze the amniotic fluid for the presence of AFP. Fetal cells contained in the amniotic fluid also can be cultured and the karyotype (chromosome morphology) determined to identify chromosomal abnormality. Cells for chromosome analysis also can be obtained by chorionic villus sampling, the direct needle aspiration of cells from the chorionic villus (future placenta).

Women who have had repeated in vitro fertilization failures may undergo preimplantation genetic diagnosis (PGD). PGD is used to detect the presence of embryonic genetic abnormalities that have a high likelihood of causing implantation failure or miscarriage. In PGD a single cell is extracted from the embryo and is analyzed by fluorescence in situ hybridization (FISH), a technique used to identify structural abnormalities in chromosomes that standard tests such as karyotyping cannot detect. In some cases DNA is isolated from the cell and analyzed by polymerase chain reaction (PCR) for the detection of gene mutations that can give rise to certain disorders such as Tay-Sachs disease. Another technique, known as comparative genomic hybridization (CGH), may be used alongside PGD to identify chromosomal abnormalities.

Advances in DNA sequencing technologies have enabled scientists to reconstruct the human fetal genome from genetic material found in maternal blood and paternal saliva. This in turn has raised the possibility for development of prenatal diagnostic tests that are noninvasive to the fetus but capable of accurately detecting genetic defects in fetal DNA. Such tests are desirable because they would significantly reduce the risk of miscarriage that is associated with procedures requiring cell sampling from the fetus or chorionic villus.

Chromosomal karyotyping, in which chromosomes are arranged according to a standard classification scheme, is one of the most commonly used genetic tests. To obtain a persons karyotype, laboratory technicians grow human cells in tissue culture media. After being stained and sorted, the chromosomes are counted and displayed. The cells are obtained from the blood, skin, or bone marrow or by amniocentesis or chorionic villus sampling, as noted above. The standard karyotype has approximately 400 visible bands, and each band contains up to several hundred genes.

When a chromosomal aberration is identified, it allows for a more accurate prediction of the risk of its recurrence in future offspring. Karyotyping can be used not only to diagnose aneuploidy, which is responsible for Down syndrome, Turner syndrome, and Klinefelter syndrome, but also to identify the chromosomal aberrations associated with solid tumours such as nephroblastoma, meningioma, neuroblastoma, retinoblastoma, renal-cell carcinoma, small-cell lung cancer, and certain leukemias and lymphomas.

Karyotyping requires a great deal of time and effort and may not always provide conclusive information. It is most useful in identifying very large defects involving hundreds or even thousands of genes.

Techniques such as FISH, CGH, and PCR have high rates of sensitivity and specificity. These procedures provide results more quickly than traditional karyotyping because no cell culture is required. FISH can detect genetic deletions involving one to five genes. It is also useful in detecting moderate-sized deletions, such as those causing Prader-Willi syndrome. CGH is more sensitive than FISH and is capable of detecting a variety of small chromosomal rearrangements, deletions, and duplications. The analysis of individual genes also has been greatly enhanced by the development of PCR and recombinant DNA technology. In recombinant DNA technology, small DNA fragments are isolated and copied, thereby producing unlimited amounts of cloned material. Once cloned, the various genes and gene products can be used to study gene function both in healthy individuals and those with disease. Recombinant DNA and PCR methods can detect any change in DNA, down to a one-base-pair change, such as a point mutation or a single nucleotide polymorphism, out of the three billion base pairs in the human genome. The detection of these changes is facilitated by DNA probes that are labeled with radioactive isotopes or fluorescent dyes. Such methods can be used to identify persons who are carriers for inherited conditions, such as hemophilia A, polycystic kidney disease, sickle cell anemia, Huntington disease, cystic fibrosis, and hemochromatosis.

Biochemical tests primarily detect enzymatic defects such as phenylketonuria, porphyria, and glycogen-storage disease. Although testing of newborns for all these abnormalities is possible, it is not cost-effective, because some of these conditions are quite rare. Screening requirements for these disorders vary and depend on whether the disease is sufficiently common, has severe consequences, and can be treated or prevented if diagnosed early and whether the test can be applied to the entire population at risk.

Once the domain of oral traditions and written pedigrees, genealogy in the modern era has become grounded in the science of genetics. Increased rigour in the field has been made possible by the development and ongoing refinement of methods to accurately trace genes and genetic variations through generations. Genetic tests used in genealogy are mainly intended to identify similarities and differences in DNA between living humans and their ancestors. In some instances, however, in the process of tracing genetic lineages, gene variations associated with disease may be detected.

Methods used in genealogical genetics analysis include Y chromosome testing, mitochondrial DNA (mtDNA) testing, and detection of ancestry-associated genetic variants that occur as single nucleotide polymorphisms (SNPs) in the human genome. Y chromosome testing is based on genetic comparison of Y chromosomes, from males. Because males with a common male ancestor have matching Y chromosomes, scientists are able to trace paternal lineages and thereby determine distant relationships between males. Such analyses allow genealogists to confirm whether males with the same surname are related. Likewise, maternal lineages can be traced genetically through mtDNA testing, since the mitochondrial genome is inherited only from the mother. Maternal lineage tests typically involve analysis of a segment in mtDNA known as hypervariable region 1; comparison of this segment against reference mtDNA sequences (e.g., Cambridge Reference Sequence) enables scientists to reconstruct an individuals maternal genetic lineage.

Following the completion of the Human Genome Project in 2003, it became possible to more efficiently scan the human genome for SNPs and to compare SNPs occurring in the genomes of human populations in different geographical regions of the world. The analysis of this information for genetic testing and genealogical purposes forms the basis of biogeographical ancestry testing. These tests typically make use of panels of ancestry informative markers (AIMs), which are SNPs specific to human populations and their geographical areas that can be used to infer ancestry. In 2010 a study using genome-wide SNP analysis incorporating ancestral information successfully traced persons in Europe to the villages in which their grandparents lived. The technique was expected to advance genetic testing intended to map an individuals geographical ancestry.

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Genetic Testing and Molecular Biomarkers

Editor-in-Chief: Garth D. Ehrlich, PhD, FAAAS

Latest Impact Factor* is 1.464 *2014 Journal Citation Reports published by Thomson Reuters, 2015

Genetic Testing and Molecular Biomarkers is the leading peer-reviewed journal covering all aspects of human genetic testing including molecular biomarkers. The Journal provides a forum for the development of new technology; the application of testing to decision making in an increasingly varied set of clinical situations; ethical, legal, social, and economic aspects of genetic testing; and issues concerning effective genetic counseling. This is the definitive resource for researchers, clinicians, and scientists who develop, perform, and interpret genetic tests and their results.

Genetic Testing and Molecular Biomarkers is under the editorial leadership of Editor-in-Chief Garth D. Ehrlich, PhD, FAAAS,Drexel College of Medicine and other leading investigators. View the entire editorial board.

Audience: Researchers, clinicians, and scientists involved in genetic testing, medical geneticists, and genetic counselors, among others.

The Official Journal of Genetic Alliance

The views, opinions, findings, conclusions and recommendations set forth in any Journal article are solely those of the authors of those articles and do not necessarily reflect the views, policy or position of the Journal, its Publisher, its editorial staff or any affiliated Societies and should not be attributed to any of them.

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Genetic Testing and Molecular Biomarkers

Recommendation and review posted by Bethany Smith

Genetic Testing | Gluten-Free Society

You cannot control what genes you are born with, but you can identify them and change your diet and lifestyle to accommodate them. Fortunately gluten sensitivity and celiac disease can be evaluated with genetic testing.

Traditional diagnostic testing has focused on blood antibody tests and or intestinal biopsies.

Why?They only measure a fraction of how a persons immune system can react to gluten. Add to the problem that different grains contain different types of gluten. Blood tests only measure the gluten found in wheat (gliadin). The other problem is that people react to gluten in different ways. Some people have immune reactions, some have intestinal problems, some develop psychological problems, some suffer with migraine headaches, psoriasis, osteoporosis, fibromyalgia, chronic fatigue, multiple sclerosis The list is over 200 diseases long. I cant even begin to tell you how many patients have come to my office after they were already biopsied or blood tested and told that they did not have gluten intolerance only to find out that their gene DNA tests were positive.

Why?Most of the research regarding gluten is directly linked to celiac disease, and most of the research on celiac disease focuses only on 3 grains (wheat, barley, rye) and sometimes a fourth (oats). There are a number of studies that have linked the gluten in corn to adverse reactions! But wait, there is more Almost half of the people diagnosed with celiac disease do not get better on a traditionally defined gluten free diet! So the big question isWhy?!The answer The traditionally definedGluten Free Dietis not really gluten free.

Those directly related to someone who has already been diagnosed with gluten intolerance or celiac disease should always be tested, but those suffering with any of the following list of diseases should also get tested:

Because of recent media exposure on The View, Larry King and Fox News, gluten sensitivity is becoming more and more of a house hold word. Watch the video below to see a recent report by Fox News featuring Dr. Peter Osborne as an expert in gluten sensitivity. Pay particular attention to the symptoms and diseases that the woman had before finding out that she was gluten intolerant (hint they were the opposite of celiac disease symptoms!)

Read our FAQ below

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Genetic Testing | Gluten-Free Society

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Genetic testing – Canadian Cancer Society

Genetic testing uses special tests to identify people with an increased risk for cancer. Genetic testing may be considered if your healthcare team suspects you may have a genetic risk for cancer based on your personal history or family history.

Genetic tests find changes (mutations) to a gene, or a number of genes on a chromosome, that are associated with some inherited disorders or cancers. Genetic tests are available for people who may have an increased risk of certain cancers, such as breast, ovarian and colon cancer. These cancers occur more often in some families than in others. Genetic testing only provides a piece of information about a persons health. Other genetic and environmental factors and lifestyle choices affect a persons risk of developing cancer.

Genetic education and counselling is done before genetic testing. These resources help you make informed decisions and adapt to and manage possible risks.

Genetic tests have potential benefits, whether the results are positive or negative.

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Genetic testing has some limits.

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Not everyone qualifies for genetic testing. A person may not be offered genetic testing for several reasons. These reasons are discussed at the genetic counselling session.

Some people decide not to have genetic testing when they understand the implications of testing. It is their right to choose whether or not they go ahead with testing.

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Genetic testing involves examining a persons DNA. A sample of blood, skin or tissue is usually taken from a family member who has had cancer. The test searches for the defect or mutation known to be associated with the type of hereditary cancer in question. If the mutation is found, other family members can be tested, usually by doing a blood test.

Sometimes the healthcare team will do a physical examination to check if you have physical signs that suggest a hereditary cancer syndrome or to rule out an existing cancer.

If there is no close, living, affected relative who can be tested, testing can sometimes be done on stored tissue or DNA of a deceased relative. Testing stored tissue is technically difficult and may not give a conclusive result. If a living affected relative declines testing, other options may be discussed and an unaffected person may be tested. In these cases, the result is often uninformative because a negative result does not rule out the presence of a cancer susceptibility gene in the family or the person being tested.

Genetic testing should always be done at a clinic that provides supportive counselling and education. However, some companies have started marketing direct-to-consumer (DTC) or at-home genetic testing services. With this service, the consumer usually buys the genetic test themselves instead of having to go through a healthcare professional. The consumer collects the DNA sample at home, often by swabbing the inside of the cheek (called a buccal sample), and sends it back to the laboratory. Sometimes the customer has to go to a laboratory to have blood taken. The consumer is notified of the results by mail or telephone. In some cases, a genetic counsellor or healthcare professional provides the results and answers questions. DTC gives a consumer access to genetic information without going through a doctor or insurance company. DTC genetic testing varies in price and can be very costly. DTC genetic tests have significant risks and limitations.

The medical community has many concerns about DTC genetic testing and about ensuring regulations are in place so that the consumer:

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There may be a fee for genetic testing. Provincial, territorial or personal health insurance plans may cover the fee if the test is ordered by a doctor. It may also be covered if it is part of a research study. Make sure you ask about fees before being tested. The cost for genetic testing varies depending on how complex the test is.

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Genetic testing is complex, so it is important to have a trained professional explain the results. It can also take several weeks or months to get the results of the test.

Genetic testing is usually done in a family member with cancer who has a family history that suggests a particular hereditary cancer syndrome. Testing in someone who already has cancer can have 3 possible results:

Predictive genetic testing looks for a known inherited cancer susceptibility mutation in a person who does not have cancer. This type of genetic testing helps identify whether a person is carrying a gene mutation that puts them at an increased risk of developing cancer. There are 2 possible results with predictive genetic testing:

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There are special considerations when doing genetic risk assessment and genetic testing for mutations in children. Genetic testing in children is very complex.

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Genetic testing – Canadian Cancer Society

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Myriad Genetics | Healthcare Professionals | About Genetic …

Advances in our understanding of DNA, RNA and protein biomarkers have led to the development of genetic tests, molecular diagnostics and companion diagnostics that are changing our understanding and treatment of disease. Genetic testing can be used to:

As a healthcare professional, you can use the knowledge gained from genetic testing to educate your patients and take action to potentially reduce their risk of disease, diagnose it earlier or provide more informed and personalized treatment.

More than 1.5 million patients have benefitted from Myriads BRACAnalysistest, which was the first full-length gene sequencing test for a major, common disease and the standard of care for identifying individuals with hereditary breast and ovarian cancer.

Patients and their healthcare professionals trust Myriad to deliver what no other company can:

At Myriad, we are committed to providing the highest-quality laboratory testing and delivering accurate, clinically actionable results to help you make better, more informed decisions. The Myriad myVision Variant Classification Program enables us to provide unmatched variant classification so that that your patients genetic testing results are as accurate as possible, reducing uncertainty for patients and their families, and increasing your confidence in providing treatment recommendations.

Learn more about our commitment to quality:

Download Myriads Quality Assurance White Paper.

Approximately five to 10 percent of all cancers are hereditary. Patients with a hereditary cancer syndrome are at a significant risk for developing an initial cancer and a second primary cancer. Hereditary cancer is more prevalent than might be expected. In fact, there are very likely patients in your practice who carry the genetic mutations responsible for increased cancer risk. Identifying these patients through appropriate testing can potentially lead to improved treatment options, more appropriate plans for risk management, and, ultimately, better outcomes.

On this site and, you will find comprehensive information on the most common hereditary cancer syndromes, and why inherited mutations in certain genes can lead to increased risk for breast, ovarian, colorectal, endometrial, gastric, prostate and pancreatic cancers and melanoma. You also will learn how to identify the familial patterns associated with hereditary cancer, and the appropriate processes for applying the powerful diagnostic tool of genetic testing.

*Based on internal validation data.

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Myriad Genetics | Healthcare Professionals | About Genetic …

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Genetic Testing – Benefits, costs, and risks of genetic testing

What is genetic testing?

Genetic testing is a means of determining if you are carrying a genetic mutation which has the potential to cause a medical condition. The testing detects changes in the genes, chromosomes and proteins that could result in a genetic condition. It is typically used to assess the risk of developing an inherited disorder and the presence of abnormalities. The test results can be used to determine the chances of an individual developing an inherited disorder and the risk of a parent passing on a disorder to their child.

There are hundreds of different genetic tests being used and new tests are becoming available all the time. Testing usually involves a blood sample being taken and analysed – the sample contains DNA and this is analysed to check for mutations.

Genetic testing is generally only useful if a condition is known to be caused by a specific genetic mutation or abnormality. For example, spinal muscular atrophy is caused by a specific mutation, so it is possible to determine the risk of an individual developing the condition by analysing their DNA.

The testing is done on a voluntary basis and the decision to have a test is down to the individual. There is help and advice available from genetic counsellors to help you decide whether or not to have a test. There are advantages and disadvantages of testing with support and advice available to help you make a decision.

Genetic testing can be beneficial regardless of the result. If the result is negative this can provide great relief and peace of mind, while a positive result can enable people to prepare and start making decisions based on information about the condition and advice from doctors and genetic counsellors.

The test result can also give you an idea of your prognosis and enable doctors to be more specific in terms of the information they can give you. The results can also allow treatment planning at an early stage, which can have a positive effect on quality of life and life expectancy.

Test results also have the potential to aid people in making choices about their future, especially in terms of having children. If there is a low risk of passing on a genetic condition, this may give people peace of mind if they are considering having children. While a positive test result may contribute to people deciding not to have children if there is a high risk of their offspring developing the condition.

Screening tests for newborn babies can help to identify conditions at a very early stage, which enables doctors to treat the condition where possible and gives parents time to accept the test result and start preparing for the future.

The major difference between research testing and clinical testing is the purpose of testing: research testing is designed to find out new information about genes and genetics, while clinical testing is intended to learn more about a specific disorder in terms of how it affects an individual or a family unit.

Research testing is important for clinical testing as the more information researchers can find out the better the understanding for doctors and patients. Research testing involves finding new genes, linking genes and genetic mutations to specific medical conditions, and finding out how genes work and affect individuals. The results of research tests are not commonly available for public consumption.

Clinical genetic testing aims to provide patients and families with more information about specific genetic conditions. The results of clinical genetic tests are used to inform people about their condition, so that they are able to make well-informed decisions about their future. Results are also used by doctors to draw-up suitable treatment plans.

It is essential for people to be aware of the difference between research and clinical genetics testing. Patients must consent to both types of testing and the benefits and risks should always be highlighted.

The price of genetic testing varies according to the tests involved and the provider of the test. For example, in the USA the price of testing can be anything from $100 to more than $2000. In the UK certain tests are available on the NHS and therefore free of charge. This includes newborn screening tests, cancer genetic testing and genetic testing for other inherited disorders. DNA tests to determine paternity are not currently available on the NHS and the price varies according to the clinic you choose.

Private testing carries a fee and this will increase if more than one family member is being tested. The cost will depend on a number of factors including the type of test and the clinic you visit. It is always beneficial to get a full written quote beforehand if you do choose a private clinic.

It can take several weeks for the results of the test to become available. Your genetic counsellor or doctor can give you an idea of the expected timeframe and they will be on hand to assist after the results are disclosed.

This is a term used to describe when an individual is discriminated against based on the fact that they have a genetic condition or a genetic mutation which increases their danger of developing a specific medical condition. Genetic discrimination can occur in the workplace and some people have suffered this at the hands of insurance providers.

The outcome of genetic testing is usually included in an individual’s medical history and will be visible to health insurance companies and potentially employers. This means that it is possible for people who have genetic conditions to experience genetic discrimination. Insurance providers look at medical records when people apply for medical and life insurance, and information about genetic testing may affect the price and type of insurance policy available to the client. Genetic testing is voluntary and people should be aware of the possible implications before they agree to go ahead.

Discrimination of any kind is illegal and if you think you are being discriminated against you should seek advice or talk to your employer.

Health insurance policies often cover the cost of genetic testing in instances when it is advised by a doctor. However, this is not always the case and it is best to check with your insurance provider beforehand.

Some people may prefer to cover the cost of genetic testing because the outcome may affect the cost of health insurance.

In the UK many people do not have health insurance because the NHS offers a comprehensive range of treatments and services. If a doctor recommends genetic testing the cost will be covered by the NHS and there are few exceptions.

It is often recommended by doctors and once an individual has decided to undergo testing the genetic counsellor or doctor will order the tests.

Genetic testing can be carried out on samples of blood, hair, skin or amniotic fluid which surrounds a foetus in the womb. Other types of tissue such as a swab used on the inside of the cheek can also be analysed. The sample will be delivered to a laboratory to be analysed under a microscope by highly trained technician. They look for the presence of specific genes or mutations and will then send a written report detailing the findings to the patient’s doctor or geneticist.

Screening tests for newborn babies are done by taking a small sample of the baby’s blood. The sample is collected by pricking the heel. If the result is positive further tests will usually be ordered. Unlike most other genetic tests parents are typically only given the result if it is positive.

Doctors and genetic counsellors have a responsibility to explain the testing process and answer any questions a patient has before they begin the process. It is also important to outline the advantages and disadvantages of testing. Patients must consent to testing and it is imperative that they have the relevant information to make an informed decision (informed consent).

The results of genetic testing are not simple and it can be complex to interpret and explain them. It is common for patients to have a lot of questions and they must be allowed to discuss the results with their doctor or genetic counsellor. It is vital for doctors and genetic counsellors to take factors such as the individual’s medical history and family history into account when they are interpreting the test results.

If the test result is positive this indicates that laboratory technicians detected a change in the chromosomes or genes or found an abnormality or genetic mutation. The test result can be used to rule out or confirm a diagnosis, determine the risk of an individual developing a certain medical condition and determine if the individual is a carrier of a condition, which can imply a risk of passing the disorder onto future generations.

Families have similar genetic information (DNA) and this means that a positive result can have implications for different members of the same family. If you have a relative whom receives a positive genetic test result you may be advised to undergo testing.

It is essential to be aware of genetic testing limitations. In a predictive genetic test it is not usually possible to determine the precise risk of a person developing a medical condition. It is also not usually possible for doctors to use the result of the tests to determine the severity of the condition.

If the test result is negative this means that the technicians did not notice any abnormalities, mutations or changes in the chromosomes and genes. A negative result may indicate that an individual does not have a genetic condition, is not a carrier of a specific condition or they do not have an increased risk. However, a negative result is not always conclusive as it is not possible for tests to identify all genetic changes linked with a specific condition. For this reason additional testing may be necessary.

A negative result may not be useful and this is known as indeterminate, inconclusive, uninformative or ambiguous. Uninformative results may result from polymorphisms (small variations in the DNA) which affect everyone. It can be difficult to decipher a natural polymorphism and a mutation which causes a condition. Inconclusive results cannot rule out or confirm a diagnosis and testing other family members may be useful.

Physical risks of genetic testing are minimal, especially for tests that require a blood sample or a swab. Antenatal testing carries a small risk of miscarriage because the test involves taking a sample of the amniotic fluid surrounding the foetus. It is important for parents to be aware of the risks before they agree to have the test.

Additional risks linked to genetic testing include social, financial and emotional risks. The outcome of the test can have far-reaching implications for both the individual and their family members, and it is important that the individual is aware of all the risks associated with genetic testing, as to be prepared for the result.

Genetic testing is useful but it does have limitations. It is not possible for tests to provide all the necessary information about a person’s condition; for example, what symptoms they will experience or how severe the condition will be.

Doctors and geneticists will be able to explain the limitations and risks of genetic testing. It is important that people are well-informed before they make a decision on whether or not to undergo genetic testing.

There are many types of genetic tests, including:

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Genetic Testing – Benefits, costs, and risks of genetic testing

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Information on Thyroid Disorders | Hormone Health Network

The thyroid gland is located at the front of your neck. This gland secretes hormones that govern many of the functions in your body, such as the way the body uses energy, consumes oxygen and produces heat. Thyroid disorders typically occur when this gland releases too many or too few hormones. An overactive or underactive thyroid can lead to a wide range of health problems. (See the thyroid basics infographic for more.)

Hyperthyroidism is a thyroid disorder that occurs when the thyroid is overactive. It can cause several problems, including:

Several illnesses can cause hyperthyroidism, including Graves’ disease or a viral infection of the thyroid gland. Treatment for hyperthyroidism usually involves medication to reduce the amount of hormones produced by the thyroid.

Hypothyroidism is a thyroid disorder that occurs when the thyroid does not produce enough hormones, which is the opposite of hyperthyroidism. This can cause:

Hypothyroidism is often caused by Hashimoto’s disease, an autoimmune disease where the body’s immune system attacks the thyroid gland. This condition can be treated using a drug called T4. Most patients must stay on T4 for their entire lives, and must be closely monitored by physicians.

Thyroid disorders can also occur because of thyroid nodules, which are growths on the gland. These small growths are usually harmless and can go unnoticed for years. Doctors can sometimes feel these nodules during routine examination. At times, thyroid nodules can be cancerous. If you have these nodules, your doctor may want to perform the following tests:

If the nodules are not cancerous, they will not need treatment in most cases. Sometimes they need to be removed. Cancerous nodules always need to be removed, followed by treatment with radioactive iodine.

If you think that you may have thyroid problems, talk to your doctor to see what tests need to be performed.

Information on Thyroid Disorders | Hormone Health Network

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Symptoms and causes – Hypopituitarism – Mayo Clinic


Hypopituitarism is often progressive. Although the signs and symptoms can occur suddenly, they more often develop gradually. They are sometimes subtle and may be overlooked for months or even years.

Signs and symptoms of hypopituitarism vary, depending on which pituitary hormones are deficient and how severe the deficiency is. They may include:

See your doctor if you develop signs and symptoms associated with hypopituitarism.

Contact your doctor immediately if certain signs or symptoms of hypopituitarism develop suddenly or are associated with a severe headache, visual disturbances, confusion or a drop in blood pressure. Such signs and symptoms could represent sudden bleeding into the pituitary gland (pituitary apoplexy), which requires prompt medical attention.

Hypopituitarism may be the result of inherited disorders, but more often it’s acquired. Hypopituitarism frequently is triggered by a tumor of the pituitary gland. As a pituitary tumor increases in size, it can compress and damage pituitary tissue, interfering with hormone production. A tumor can also compress the optic nerves, causing visual disturbances.

The cause of hypopituitarism can also be other diseases and events that damage the pituitary, such as:

Diseases of the hypothalamus, a portion of the brain situated just above the pituitary, also can cause hypopituitarism. The hypothalamus produces hormones of its own that directly affect the activity of the pituitary.

In some cases, the cause of hypopituitarism is unknown.

April 23, 2016

Symptoms and causes – Hypopituitarism – Mayo Clinic

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Fat vs. Bone Marrow Stem Cells: A Clinicians Perspective

This week I treated a patient with adipose SVF stem cells to augment a low stem cell yield from bone marrow. I dont do this often, as the quality of fat stem cells for orthopedic applications like arthritis is much less. We do use fat for an occasional structural graft in various procedures. Today I wanted to give you a clinicians eye view of the harvest procedures for both stem cell types that you wont see elsewhere, so let Fat vs Bone Marrow Stem Cells begin.

In summary, harvesting fat in a mini-liposuction is a violent affair, harvesting stem cells from a bone marrow aspirate is like an advanced blood draw. Let me explain.

In order to get fat through a mini-liposuction you need to first use a scalpel to open a small incision in the skin. This isnt at all required for a bone marrow aspiration as the needle is just inserted into the skin like any other needle. In the liposuction, the whole goal is disrupting large amounts of normal tissue. In fact, the stem cells live around the blood vessels, so you have to chew up as many blood vessels in the fat as possible to get a good stem cell yield. This involves placing a small wand like device under the skin and into the fat and moving it back and forth (through much resistance) to break apart large sections of tissue. The bone marrow aspiration simply involves directing the needle under the x-ray to the desired area of bone. The needle is then turned back and forth a few times to enter the bone (which is like hard plastic instead of cement). At this point in the liposuction the doctor must continue to break up large swaths of tissue with suction, sucking the broken tissue and blood vessels into a syringe. On the other hand, in the bone marrow aspiration the doctor simply draws the bone marrow aspirate (which looks like blood) into the syringe like a common blood draw.

The complication rates for these two procedures tell the rest of the story. Mini-liposuction procedures have surgical style complication rates of 3-10%, while bone marrow aspiration complication rates are so rare that only a handful occurred in more than 20,000 procedures in one U.K. registry. The upshot? It always makes me chuckle (in a bad way) when I hear fat stem cell advocates claim that a bone marrow aspiration procedure is so invasive. Youhavent seen invasive until youve seen a lipo-suction!

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Fat vs. Bone Marrow Stem Cells: A Clinicians Perspective

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iPS cell technologies: significance and applications to …

In 2006, we demonstrated that mature somatic cells can be reprogrammed to a pluripotent state by gene transfer, generating induced pluripotent stem (iPS) cells. Since that time, there has been an enormous increase in interest regarding the application of iPS cell technologies to medical science, in particular for regenerative medicine and human disease modeling. In this review article, we outline the current status of applications of iPS technology to cell therapies (particularly for spinal cord injury), as well as neurological disease-specific iPS cell research (particularly for Parkinsons disease and Alzheimers disease). Finally, future directions of iPS cell research are discussed including a) development of an accurate assay system for disease-associated phenotypes, b) demonstration of causative relationships between genotypes and phenotypes by genome editing, c) application to sporadic and common diseases, and d) application to preemptive medicine.

The 2012 Nobel Prize in Physiology or Medicine was awarded for The discovery that mature cells can be reprogrammed to become pluripotent. First, we would like to consider the significance of this research. The lives of mammals, including humans, begin with the fertilization of an egg by a sperm cell. In humans, a blastocyst composed of 70-100 cells forms by approximately 5.5 days after fertilization. The blastocyst is composed of the inner cell mass, the cell population that has the ability to differentiate into the various cells that constitute the body (pluripotency), and the trophoblast, the cells that develop into the placenta and extra-embryonic tissues and do not contribute cells to the body. In the embryonic stage, the pluripotent cells of the inner cell mass differentiate into the three germ layers, endoderm, mesoderm, and ectoderm, which will form specific organs and tissues containing somatic stem cells with limited differentiation potencies. These somatic stem cells continue to divide and differentiate, and, by adulthood, an individual composed of 60 trillion cells is produced. Somatic stem cells born in the fetal period actively divide, and are involved in the formation and growth of various organs. However, even in the adult, somatic stem cells persist in niches in every organ and tissue, and play an important role in maintaining organ and tissue homeostasis. When cells in the inner cell mass are removed at the blastocyst stage and cultured in vitro, pluripotent embryonic stem (ES) cells are obtained. Thus, in the normal process of development, cell differentiation of the three germ layers proceeds from the simple stages of the fertilized egg and blastocyst, and ultimately produces an individual consisting of a complex cellular society.

In 1893, August Weismann argued that only germ cells (eggs and spermatozoa) maintain a determinant, which was described as heritable information essential to decide on the functions and features of all somatic cells in the body [1]. In his germ plasm theory, the determinants are lost or irreversibly inactivated in differentiated somatic cells.

It took more than 50 years for researchers to rewrite this dogma. In 1962, Sir John Gurdon demonstrated the acquisition of pluripotency by reprogramming cells to their initial stage using a novel research technique, i.e., producing cloned individuals by transferring somatic cell nuclei into eggs [2]. However, for many years, that result was regarded as a special case limited to frogs alone. The production of Dolly the sheep by transferring the nucleus of a somatic cell (mammary gland epithelial cell) by Sir Ian Wilmut in the late 1990s [3] showed that cloning could also be applied to mammals.

These brilliant previous works led to our studies that culminated in the induction of pluripotency in mouse somatic cells in 2006, using retroviral vectors to introduce four genes that encode transcription factors i.e., Oct4, Sox2, Klf4, and c-Myc. We designated these cells as iPS cells [4]. In 2007, we succeeded in generating human iPS cells using genes encoding the same four transcription factors [1]. The results of this research showed that although the developmental process was thought to be irreversible, by introducing key genes into differentiated adult cells the cells could be reset to a state in the extremely early stage of development in which they possessed pluripotency. That is, the results demonstrated that the differentiation process was reversible. This startling discovery made it necessary to rewrite the embryology textbooks.

Three major lines of research led us to the production of iPS cells [

] (Figure

). The first, as described above, was nuclear reprogramming initiated by Sir John Gurdon in his research of cloning frogs by nuclear transfer in 1962 [

] and by Sir Ian Wilmut, who cloned a mammal for the first time in 1997 [

]. In addition, Takashi Tada showed that mouse ES cells contain factors that induce reprogramming in 2001 [

]. The second line of research was factor-mediated cell fate conversion, initiated by Harold Weintraub, who showed that fibroblasts can be converted into the muscle lineage by transduction with the

gene, which encodes a muscle lineage-specific basic helix-loop-helix transcription factor in 1987 [

]. The third line of research was the development of mouse ES cells, initiated by Sir Martin Evans and Gail Martin in 1981 [


]. Austin Smith established culture conditions for mouse ES cells and identified many factors essential for pluripotency including leukemia inhibitory factor (LIF) in 1988 [

]. Later, he developed the method to induce the ground state of mouse ES cell self-renewal using inhibitors for mitogen-activated protein kinase and glycogen synthase kinase 3 [

], which supports the establishment of fully reprogrammed mouse iPS cells. Furthermore, James Thomson generated human ES cells [

] and established their optimal culture conditions using fibroblast growth factor-2 (FGF-2). Without these previous studies, we could never have generated iPS cells. Interest rapidly escalated, and, in tandem with the birth of iPS cell technology, pluripotency leapt into the mainstream of life sciences research in the form of reprogramming technology [

]. However, there remain many unanswered questions regarding reprogramming technology. What are the reprogramming factors in the egg cytoplasm that are active in cloning technology? What do they have in common with the factors required to establish iPS cells and what are the differences? What kind of epigenetic changes occur in association with the reprogramming?

The history of investigations of cellular reprogramming that led to the development of iPS cells. Our generation of iPS cells in 2006 [4] became possible due to three scientific lines of investigation: 1) nuclear reprogramming, 2) factor-mediated cell fate conversion, and 3) ES cells. See the text for details (modified from Reference [5] with permission).

Apart from basic research in embryology, broad interest has been drawn to the following possible applications of iPS cell research: (1) regenerative medicine, including elucidating disease pathologies and drug discovery research using iPS cell disease models, and (2) medical treatments (Figure

). In this review, we describe these potential applications in the context of the results of our own research.

The application of iPS cell technologies to medical science. iPS cell technologies can be used for medical science including 1) cell therapies and 2) disease modeling or drug development. See the text for details.

iPS cells can be prepared from patients themselves and therefore great expectations have been placed on iPS cell technology because regenerative medicine can be implemented in the form of autografts presumably without any graft rejection reactions. Although there have been some controversies [

], the immunogenicity of terminally differentiated cells derived from iPS cells can be negligible [

]. Moreover, there has been substantial interest in the possibility of regenerative medicine without using the patients own cells; that is, using iPS cell stocks that have been established from donor somatic cells that are homozygous at the three major human leukocyte antigen (HLA) gene loci and match the patients HLA type [

]. The development of regenerative medicine using iPS cells is being pursued in Japan and the USA for the treatment of patients with retinal diseases, including age-related macular degeneration [

], spinal cord injuries [

], Parkinsons disease (PD) [


], corneal diseases [

], myocardial infarction [


], diseases that cause thrombocytopenia, including aplastic anemia and leukemia [


], as well as diseases such as multiple sclerosis (MS) and recessive dystrophic epidermolysis bullosa [

] (Table


Planned clinical trials of iPS cell-based therapies

Masayo Takahashi, (RIKEN)

Retinal Pigment Epithelium (sheet)

Age-related macular degeneration (wet type)

Alfred Lane, Anthony Oro, Marius Wernig (Stanford University)


Recessive dystrophic epidermolysis bullosa (RDEB)

Mahendra Rao (NIH)

DA neurons

Parkinsons disease

Koji Eto (Kyoto University)



Jun Takahashi (Kyoto University)

DA neurons

Parkinsons disease

Steve Goldman, (University of Rochester)

Oligodendrocyte precursor cell

Multiple Sclerosis

Hideyuki Okano, Masaya Nakamura (Keio University)

Neural stem/progenitor cells

Spinal Cord Injury

Shigeto Shimmura (Keio University)

Corneal endothelial cells

Corneal endothelial dysfunction

Koji Nishida (Osaka University)

Corneal epithelial cells (sheet)

Corneal epithelial dysfunction and trauma (e.g. StevensJohnson syndrome)

Yoshiki Sawa (Osaka University)

Cardiomyocytes (sheet)

Heart Failure

Keiichi Fukuda (Keio University)

Cardiomyocytes (sphere)

Heart Failure

Yoshiki Sasai and Masayo Takahashi (RIKEN)

Neuroretinal sheet including photoreceptor cells

Retinitis pigmentosa

Advanced Cell Technology


Refractory thrombocytopenia

In 1998, Hideyuki Okano, in collaboration with Steven Goldman, demonstrated for the first time the presence of neural stem/progenitor cells (NS/PCs) in the adult human brain using a neural stem cell marker, the ribonucleic acid (RNA)-binding protein Musashi1 [30, 31]. Research on nerve regeneration then commenced in earnest. That same year, we began regenerative medicine research on neural stem cell transplantation in a rat model of SCI, and have since made progress in developing NS/PC transplantation therapies in experiments on animal models of SCI. First, motor function was restored by transplanting rat fetal central nervous system (CNS)-derived NS/PCs into a rat SCI model [32]. The same study also showed that the sub-acute phase is the optimal time for NS/PC transplantation after SCI. In this study, at least part of the putative mechanism by which NS/PC transplantation restored function was identified in animal models of SCI. Both the cell autonomous effect (such as synaptogenesis between graft-derived neurons and host-derived neurons) and non-cell autonomous (trophic) effects mediated cytokines released from the graft-derived cells are likely contributing to tissue repair and functional recovery. Subsequently, a non-human primate SCI model was developed using the common marmoset, and motor function in that model was restored by transplanting human fetal CNS-derived stem cells [33]. In the same study, a behavioral assay for motor function associated with SCI was developed. Based on these studies, a preclinical research system for cell transplantation therapy was established in a non-human primate SCI model.

Given these findings, we began preparations for clinical studies of human fetal CNS-derived NS/PC transplantation to treat SCI patients. However, with the guidelines for clinical research on human stem cells of the Japanese Ministry of Health, Labor and Welfare that came into effect in 2006, human fetus-derived cells and ES cells became ineligible for use in regenerative medicine. Thus, we had no choice but to change our strategy (human ES cells became eligible for use in the 2013 guidelines). In 2006, one of our research groups (Yamanakas group) established iPS cells from adult mouse skin cells. Hypothesizing that it might be possible to induce NS/PCs from iPS cells, we (Okanos group) turned our attention to iPS cells as a means of obtaining NS/PCs without using fetal or ES cells. Based on conditions that were developed for experiments on mouse ES cells [34, 35], NS/PCs were induced from mouse iPS cells [36]. The following year, we succeeded in restoring motor function by transplanting these mouse iPS cell-derived NS/PCs into a mouse model of SCI, and reported that when good iPS cells -derived NS/PCs, which had been pre-evaluated as non-tumorigenic by the transplantation into the brains of immunocompromised mice, were used for transplantation, motor function was restored for a long period of time without tumors developing [37]. In 2011, we succeeded in restoring motor function by transplanting human iPS cell-derived stem cells into a mouse SCI model [38]. Moreover, in 2012, motor function was restored by transplanting human iPS (line 201B7) cell-derived NS/PCs into the marmoset SCI model, and long-term motor function was recovered without observable tumor formation [39]. This finding was of great significance in terms of preclinical research, and provided a proof of concept that could potentially lead to a treatment method.

Collectively, when mouse or human iPS cells were induced to form NS/PCs and were transplanted into mouse or non-human primate SCI models, long-term restoration of motor function was induced, without tumorigenicity, by selecting a suitable iPS cell line [17, 40]. Considering the sub-acute phase (2-4 weeks after the injury) as the optimal time for iPS cells-derived NS/PCs transplantation for SCI patients, there are following major difficulties with autograft-based cell therapy. First, it takes about a few months to establish iPS cells. Second, it also takes three months to induce them into NS/PCs in vitro. Third, one more year would be required for the quality control including their tumorigenesis.

Considering these, our collaborative team (Okano and Yamanaka laboratories) are currently planning iPS-based cell therapy for SCI patients in the sub-acute phase using clinical-grade integration-free human iPS cell lines that will be generated by Kyoto Universitys Center for iPS Cell Research and Application (CiRA). We will establish a production method, as well as a storage and management system, for human iPS cell-derived NS/PCs for use in clinical research for spinal cord regeneration, build an iPS cell-derived NS/PC stock for regenerative medicine, establish safety screenings against post-transplantation neoplastic transformation, and commence clinical research (Phase IIIa) trials for the treatment of sub-acute phase SCI (Figure

). As these studies progress, the application of iPS cells to treat chronic phase SCI and stroke will be investigated. Significant therapeutic efficacy in the treatment of chronic phase SCI has not been achieved by cell transplantation alone [

]. However, clinical studies are planned using antagonists of axon growth inhibitors, such as Semaphorin3A inhibitors [

], followed by multidisciplinary rehabilitation combination therapies. We aim to perform a clinical trial based on the Pharmaceutical Affairs Act in collaboration with drug companies and to use iPS cell-derived NS/PC stocks for regenerative medicine to establish treatment methods for stroke, MS, and Huntingtons disease.

Strategies for the development of iPS cell-based cell therapy for SCI patients. Our collaborative team (Okanos group at Keio University and Yamanakas group at Kyoto University) have been developing an iPS cell-based cell therapy for SCI since 2006. Our previous preclinical studies have shown that long-term functional restoration can be obtained by transplantation of NS/PCs derived from appropriate iPS cells clones without observable tumor formation [10]. Currently, we aim to develop iPS cells-based cell therapy for SCI patients at sub-acute phase using the clinical grade iPS cell-derived NS/PCs (i.e., the role of Okanos group described in the blue box) which have been prepared from human iPS cell stock (i.e., the role of Yamanakas group described in the yellow box).

Lesion sites are difficult to access in patients with degenerative diseases of the nervous system. Therefore, in past studies, cell biological or biochemical analyses of their pathology centered on forced expression of the causative genes in non-nervous system cultured cell lines and on mice in which the causative gene was knocked out. However, in a few instances, the animal or cell models did not necessarily reflect the human pathology. Identifying cell biological or biochemical changes in the initial stages of the disease, before onset of symptoms, has been difficult given analyses conducted on postmortem brains. However, with the development of iPS cell technologies, it became possible to establish pluripotent stem cells from the somatic cells of anyone, irrespective of race, genetic background, or whether the person exhibits disease symptoms. Thus, it is no exaggeration to say that generation of disease-specific iPS cells using iPS cell technologies is the sole means of reproducing ex vivo phenomena that occur in patients in vivo, particularly for nervous system disorders. The result has been a tremendous desire by investigators who are conducting research on neurological diseases to become engaged in disease-specific iPS cell research [4345].

A variety of disease-specific iPS cells have been used to study nervous system diseases, including amyotrophic lateral sclerosis (ALS) [

], spinal muscular atrophy [

], spinobulbar muscular atrophy [

], Friedreichs ataxia [

], Alzheimers disease (AD) [

], PD [

], Huntingtons disease [


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iPS cell technologies: significance and applications to …

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Best Master’s Degrees in Biotechnology 2016

Biotechnology is a top-notch field of study that emerged into the scientific world as a result of revolutions in Biology, Chemistry, Informatics, and Engineering. It is considered to be an applied branch of Biology. Biotechnology helps out this old and respectable field of science keep up with the pace of time and remain competitive in the contemporary world.

With a Master in Biotechnology, students will study the use of living organisms and bioprocesses in technology, engineering, medicine, agriculture and results in all kinds of bioproducts, from genetically modified food to serious cutting-edge devices used to carry out gene therapy. Students in Master in Biotechnology programs may also explore bioinformatics, which is the application of statistics and computer science to the field of molecular biology. Bioinformatics is extremely important for contemporary biological and molecular researches because the data amount there grows by geometric progression and it is necessary to have adequate technology to process it. Bioinformatic methods are widely used for mapping and analyzing DNA and protein samples, as well as for the study of genetics and molecular modeling. Biotechnology and Bioinformatics do a great favour to traditional fields of study, refreshing them with new methods of research, which allows their drastic development, and you can make your contribution with a Master in Biotechnology degree.

Find out about various Master in Biotechnology programs by following the links below. Don’t hesitate to send the “Request free information” form to come in contact with the relevant person at the school and get even more information about the specific Master in Biotechnology program you are interested in.

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Best Master’s Degrees in Biotechnology 2016

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Current Opinion in Biotechnology – Journal – Elsevier

The Current Opinion journals were developed out of the recognition that it is increasingly difficult for specialists to keep up to date with the expanding volume of information published in their subject. In Current Opinion in Biotechnology, we help the reader by providing in a systematic manner: 1. The views of experts on current advances in biotechnology in a clear and readable form. 2. Evaluations of the most interesting papers, annotated by experts, from the great wealth of original publications.

Division of the subject into sections The subject of biotechnology is divided into themed sections, each of which is reviewed once a year. The amount of space devoted to each section is related to its importance.

Analytical biotechnology Plant biotechnology Food biotechnology Energy biotechnology Environmental biotechnology Systems biology Nanobiotechnology Tissue, cell and pathway engineering Chemical biotechnology Pharmaceutical biotechnology

Selection of topics to be reviewed Section Editors, who are major authorities in the field, are appointed by the Editors of the journal. They divide their section into a number of topics, ensuring that the field is comprehensively covered and that all issues of current importance are emphasised. Section Editors commission reviews from authorities on each topic that they have selected.

Reviews Authors write short review articles in which they present recent developments in their subject, emphasising the aspects that, in their opinion, are most important. In addition, they provide short annotations to the papers that they consider to be most interesting from all those published in their topic over the previous year.

Editorial Overview Section Editors write a short overview at the beginning of the section to introduce the reviews and to draw the reader’s attention to any particularly interesting developments. This successful format has made Current Opinion in Biotechnology one of the most highly regarded and highly cited review journals in the field (Impact factor = 8.035).

Ethics in Publishing: General Statement

The Editor(s) and Publisher of this Journal believe that there are fundamental principles underlying scholarly or professional publishing. While this may not amount to a formal ‘code of conduct’, these fundamental principles with respect to the authors’ paper are that the paper should: i) be the authors’ own original work, which has not been previously published elsewhere, ii) reflect the authors’ own research and analysis and do so in a truthful and complete manner, iii) properly credit the meaningful contributions of co-authors and co-researchers, iv) not be submitted to more than one journal for consideration, and v) be appropriately placed in the context of prior and existing research. Of equal importance are ethical guidelines dealing with research methods and research funding, including issues dealing with informed consent, research subject privacy rights, conflicts of interest, and sources of funding. While it may not be possible to draft a ‘code’ that applies adequately to all instances and circumstances, we believe it useful to outline our expectations of authors and procedures that the Journal will employ in the event of questions concerning author conduct. With respect to conflicts of interest, the Publisher now requires authors to declare any conflicts of interest that relate to papers accepted for publication in this Journal. A conflict of interest may exist when an author or the author’s institution has a financial or other relationship with other people or organizations that may inappropriately influence the author’s work. A conflict can be actual or potential and full disclosure to the Journal is the safest course. All submissions to the Journal must include disclosure of all relationships that could be viewed as presenting a potential conflict of interest. The Journal may use such information as a basis for editorial decisions and may publish such disclosures if they are believed to be important to readers in judging the manuscript. A decision may be made by the Journal not to publish on the basis of the declared conflict.

For more information, please refer to:

Hide full aims and scope

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Current Opinion in Biotechnology – Journal – Elsevier

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Biotechnology for Biofuels | Home page

Prof James du Preez is professor of microbiology and former chairperson (2002 2014) of the Department of Microbial, Biochemical & Food Biotechnology at the University of the Free State in Bloemfontein, South Africa. He obtained his PhD in microbiology from the above university in 1980 after completing a major part of his doctoral research at the Swiss Federal Institute of Technology, Zrich, which laid the foundation for his further work in the field of fermentation biotechnology. His special interests include continuous (chemostat) cultures, yeast physiology, the production of heterologous proteins and microbial metabolites, as well as bioethanol production from starchy and lignocellulosic feedstocks, including pentose fermentation by yeasts. The physiology of the yeast Saccharomyces cerevisiae is an ongoing interest.

James has authored close to 100 peer-reviewed articles as well as several other papers and book chapters. Involvement with the science community includes membership of the council of the South African Society for Microbiology and the International Commission for Yeasts. He was the American Society for Microbiologys ambassador to South Africa until 2014. He serves on the editorial board of FEMS Yeast Research and was a guest editor for a thematic issue of FEMS Yeast Research on yeast fermentations and other yeast bioprocesses. He was an associate editor for World Journal of Microbiology and Biotechnology until early 2015, currently is a joint editor-in-chief for Biotechnology for Biofuels and recently served on the Editors Advisory Group of BioMed Central. In 2014 he was appointed external expert on the Biological Production Systems panel of the Swedish Foundation for Strategic Research and in 2015 served for a second term on a grant evaluation panel of the European Research Council. Among honours received are election as member of the Academy of Science of South Africa, the award of a silver medal for exceptional achievement from the South African Society for Microbiology and awards from his home university for research excellence.

Dr Michael Himmel has 30 years of progressive experience in conducting, supervising, and planning research in protein biochemistry, recombinant technology, enzyme engineering, new microorganism discovery, and the physicochemistry of macromolecules. He has also supervised research that targets the application of site-directed-mutagenesis and rational protein design to the stabilization and improvement of important industrial enzymes, especially glycosyl hydrolases.

Dr Himmel has functioned as PI for the DOE EERE Office of the Biomass Program (OBP) since 1992, wherein his responsibilities have included managing research designed to improve cellulase performance, reduce biomass pretreatment costs, and improve yields of fermentable sugars. He has also developed new facilities at NREL for biomass conversion research, including a Cellulase Biochemistry Laboratory, a Biomass Surface Characterization Laboratory, a Protein Crystallography Laboratory, and a new Computational Science Team. Dr. Himmel also serves as the Principal Group Manger of the Biomolecular Sciences Group, where he has supervisory responsibly for 50 staff scientists.

Prof Debra Mohnen received her B.A. in biology from Lawrence University (Wisconsin) and her MS in botany and PhD in plant biology from the University of Illinois. Her PhD research was conducted at the Friedrich Miescher Institute in Basel, Switzerland. She held postdoctoral research associate positions at the USDA’s Richard Russell Research Center and at the Complex Carbohydrate Research Center (CCRC) in Athens, GA where she won an NIH National Research Service Award for her postdoctoral research. She was appointed to the CCRC faculty in September 1990 and is currently Professor in the Department of Biochemistry and Molecular Biology and also adjunct faculty member in the Department of Plant Biology and member of the Plant Center at UGA. Dr Mohnen has served on the Committee on the Status of Women in Plant Physiology of the American Society of Plant Physiologists, invited faculty sponsor for the UGA Association for Women in Science (AWIS), past member-at-large in the Cellulose and Renewable Materials Division of the American Chemical Society, and is currently a member of the Council for Chemical and Biochemical Sciences, Chemical Sciences, Geosciences, and Biosciences Division in the Office of Basic Energy Sciences, Office of Science, U.S. Department of Energy. As Co-PI on the NSF-funded Plant Cell Wall Biosynthesis Research Network Dr Mohnen established the originally NSF-funded service CarboSource Services, that provides rare substrates for plant wall polysaccharide synthesis to the research community. Her research centers on the biosynthesis, function and structure of plant cell wall polysaccharides is supported by funding from the USDA, NSF and DOE. Her emphasis is on pectin biosynthesis and pectin function in plants and human health, and on the improvement of plant cell wall structure so as to improve the efficiency of conversion of plant wall biomass to biofuels.

Prof Charles Wyman has devoted most of his career to leading advancement of technology for biological conversion of cellulosic biomass to ethanol and other products. In the fall of 2005, he joined the University of California at Riverside as a Professor of Chemical and Environmental Engineering and the Ford Motor Company Chair in Environmental Engineering with a research focus on pretreatment, enzymatic hydrolysis, and dehydration of cellulosic biomass to produce reactive intermediates for conversion to fuels and chemicals. Before joining UCR, he was the Paul E. and Joan H. Queneau Distinguished Professor in Environmental Engineering Design at the Thayer School of Engineering at Dartmouth College. Dr. Wyman recently founded Vertimass LLC that is devoted to commercialization of novel catalytic technology for simple one-step conversion of ethanol to fungible gasoline, diesel, and jet fuel blend stocks. Dr. Wyman is also cofounder and former Chief Development Officer and Chair of the Scientific Advisory Board for Mascoma Corporation, a startup focused on biomass conversion to ethanol and other products.

Before joining Dartmouth College in the fall of 1998, Dr. Wyman was Director of Technology for BC International and led process development for the first cellulosic ethanol plant planned for Jennings, Louisiana. Between 1978 and 1997, he served as Director of the Biotechnology Center for Fuels and Chemicals at the National Renewable Energy Laboratory (NREL) in Golden, Colorado; Director of the NREL Alternative Fuels Division; and Manager of the Biotechnology Research Branch. During that time, he held several other leadership positions at NREL, mostly focused on R&D for biological conversion of cellulosic biomass to fuels and chemicals. He has also been Manager of Process Development for Badger Engineers, an Assistant Professor of Chemical Engineering at the University of New Hampshire, and a Senior Chemical Engineer with Monsanto Company.

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What are stem cells and bone marrow? – Information and …

There are two different types of stem cell transplants:

To understand these treatments, it first helps to learn how the bone marrow and stem cells work.

Stem cells are blood cells at their earliest stage of development. All blood cells develop from stem cells. The full name for stem cells in the blood and bone marrow is haematopoietic stem cells, but in this booklet we call them stem cells.

Bone marrow is a spongy material inside the bones particularly the bones of the pelvis. The bone marrow is where stem cells are made.

Most of the time, almost all of your stem cells are in the bone marrow. There are usually only a very small number in the blood. Stem cells stay in the bone marrow while they develop into blood cells. Then, once they are fully mature, the blood cells are released into the bloodstream.

The three main types of blood cells are:

Illustration of bone marrow

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The levels of blood cells in your blood are measured in a blood test called a full blood count (FBC). Its often just called a blood count.

The figures below are a guide to the levels usually found in a healthy person.

These figures can vary from hospital to hospital. Your doctor or nurse can tell you what levels they use. They can also vary slightly between people from different ethnic groups.

The figures might look complicated when theyre written down, but in practice theyre used in a straightforward way. For example, youll hear doctors or nurses saying things like your haemoglobin is 140 or your neutrophils are 4.

Most people with cancer or leukaemia soon get used to these figures and what they mean. But you can always ask your medical team to explain if youre not sure.

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