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Genetic Testing | MD Anderson Cancer Center

Between five and 10% of all cancers are hereditary, which means that changes (or mutations) in specific genes are passed from one blood relative to another. People who inherit one of these gene changes will have a higher risk of developing cancer at some point in their life. Genetic counseling can help people understand this risk.

Genetic counseling is not for everyone. In most cases, people who need genetic counseling fit into one of two groups.

Group one includes people who are cancer-free but, due to other medical conditions or family history, may have an increased risk for developing the disease. This includes people with:

Group two includes people who have a cancer diagnosis and want to learn if it is genetic. Not everyone with cancer needs genetic counseling, though. Instead, it is usually recommended for patients who have:

If you fit into one of these categories, it’s a good idea to meet with a genetic counselor.

The first step to understanding your genetic cancer risk is a genetic counseling session. There are several steps to these sessions.

The genetic counselor will take your medical history, as well as a cancer-focused family tree going back generations. Based on this information, the counselor will discuss how your familys cancer history may be hereditary and what that means for you.

Genetic testsuse a patients blood sample to look for genetic mutations that may lead to an increased risk for some cancers. After the medical and family history review, the counselor will discuss whether genetic testing is right for you. You will also cover the ethical and legal issues of genetic testing. If the counselor recommends genetic testing, you will be given information about the appropriate test or tests.

Based on your family history and/or genetic test results, you will discuss ways to reduce your cancer risk. This discussion may cover cancer screening strategies, chemoprevention or even preventative surgery. You also may be referred to a high-risk screening clinic for further discussion and long-term cancer screening and monitoring.

Patients are often given the chance to join clinical research trials and registries. These can improve cancer care in many ways. For example, they can help doctors understand cancer risk factors and learn what screening and prevention methods work best.

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Genetic Testing | MD Anderson Cancer Center

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Genetic Counseling | DNA Testing | Aurora Health Care

Aurora Hereditary Cancer Prevention and Management Center (HCPMC)

Have genetic counseling and DNA testing determined that you or your family members have a hereditary cancer syndrome? Families with hereditary cancer syndromes are at high risk for multiple types of cancer. Even families whose genetic testing results are normal may be at increased risk for multiple cancers if they have complex cancer histories.

If your family history of cancer has been determined to be hereditary, or if your complex family history cant be explained by genetic testing, you deserve comprehensive care from a multidisciplinary team of experts in a single, convenient location.

The Aurora Hereditary Cancer Prevention and Management Center (HCPMC) specializes in testing and monitoring individuals and families with complex or difficult hereditary cancer conditions.

Through the HCPMC, you can:

If youre at risk for multiple types of cancer, ask your doctor for a referral to the Aurora Hereditary Cancer Prevention and Management Center in Milwaukee or Green Bay.

The HCPMC in Milwaukee is located within the Vince Lombardi Cancer Clinic at St. Lukes Medical Center. The HCPMC in Green Bay is located within the Vince Lombardi Cancer Clinic at Aurora BayCare Medical Center.

Call 877-647-2502 for more information.

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Genetic Counseling | DNA Testing | Aurora Health Care

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Custom CRISPR Products | Sigma-Aldrich

Articles A CRISPR/Cas-GFP Vector for Rapid Expression Verification and Enrichment of Genome Edited Cells

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Custom CRISPR Products | Sigma-Aldrich

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Hypopituitarism Disease Reference Guide – Drugs.com

Medically reviewed on August 22, 2017

Hypopituitarism is a rare disorder in which your pituitary gland either fails to produce one or more of its hormones or doesn’t produce enough of them.

The pituitary gland is a small bean-shaped gland situated at the base of your brain, behind your nose and between your ears. Despite its size, this gland secretes hormones that influence nearly every part of your body.

In hypopituitarism, you have a short supply of one or more of these pituitary hormones. This deficiency can affect any number of your body’s routine functions, such as growth, blood pressure and reproduction.

You’ll likely need medications for the rest of your life to treat hypopituitarism, but your symptoms can be controlled.

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.

The pituitary gland and the hypothalamus are situated within the brain and control hormone production.

The endocrine system includes the pituitary gland, thyroid gland, parathyroid glands, adrenal glands, pancreas, ovaries (in females) and testicles (in males).

If your doctor suspects a pituitary disorder, he or she will likely order several tests to check levels of various hormones in your body. Your doctor may also want to check for hypopituitarism if you’ve had a recent head injury or radiation treatment that might have put you at risk of damage to your pituitary gland.

Tests your doctor may order include:

Successful treatment of the underlying condition causing hypopituitarism may lead to a complete or partial recovery of your body’s normal production of pituitary hormones. Treatment with the appropriate hormones is often the first step. These drugs are considered as “replacement,” rather than treatment, because the dosages are set to match the amounts that your body would normally manufacture if it didn’t have a pituitary problem. Treatment may be lifelong.

Treatment for pituitary tumors may involve surgery to remove the growth. In some instances, doctors also recommend radiation treatment.

Hormone replacement medications may include:

If you’ve become infertile, LH and FSH (gonadotropins) can be administered by injection to stimulate ovulation in women and sperm production in men.

A doctor who specializes in endocrine disorders (endocrinologist) may monitor the levels of these hormones in your blood to ensure you’re getting adequate but not excessive amounts.

Your doctor will advise you to adjust your dosage of corticosteroids if you become seriously ill or experience major physical stress. During these times, your body would ordinarily produce extra cortisol hormone. The same kind of fine-tuning of dosage may be necessary when you have the flu, experience diarrhea or vomiting, or have surgery or dental procedures. Adjustments in dosage may also be necessary during pregnancy or with marked changes in weight. You may need periodic CT or MRI scans as well to monitor a pituitary tumor or other diseases causing the hypopituitarism.

Wear a medical alert bracelet or pendant, and carry a special card, notifying others in emergency situations, for example that you’re taking corticosteroids and other medications.

You’re likely to start by seeing your family doctor or a general practitioner. However, in some cases, when you call to set up an appointment, you may be referred to a specialist called an endocrinologist.

Here’s some information to help you prepare for your appointment.

Create a list of questions before your appointment so that you can make the most of your time with your doctor. For hypopituitarism, some basic questions to ask your doctor include:

Don’t hesitate to ask any questions you have during your appointment.

Your doctor is likely to ask you some questions, such as:

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Hypopituitarism Disease Reference Guide – Drugs.com

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Hypopituitarism Treatment & Causes | Lurie Children’s

Hypopituitarism (an underactive pituitary gland) is rare in children. When a child has hypopituitarism, the pituitary gland has lost its ability to make one, some or all pituitary hormones. The condition is often permanent, but very treatable.

The pituitary gland in the middle of the head and brain is the bodys master gland. The table below describes what each hormone made by the pituitary gland does, what happens when each hormone is missing and medication that can replace each hormone.

In children, hypopituitarism is usually caused by something congenital (the child is born with the problem) or by a pituitary tumor. The tumor interferes with the gland. Sometimes, the cause cannot be determined.

Sometimes, the cause was present before the child was born. Often, we see that the pituitary gland is under-developed. A genetic error may be the reason the gland doesnt work well.

Children withsepto-optic dysplasia have varying degrees of hypopituitarism. Their vision is usually impaired because the optic nerves are under-developed. The eyes can move irregularly or wander. This disorder can affect the pituitary gland and other structures in the brain. Often, these children have diabetes insipidus and not enough growth hormone.

There are other forms of congenital hypopituitarism. Sometimes, the pituitary gland doesnt make enough growth hormone. Sometimes, the thyroid gland is underactive, or the adrenal gland doesnt work well. In Kallman syndrome, not enough of the hormones that stimulate the testes or ovaries are made, puberty is late or doesnt happen, and the sense of smell is affected.

A tumor can cause hypopituitarism. The tumor may grow in the pituitary gland or outside the gland, compressing the normal tissue. Parents worry that the tumor may be cancer, but thats unlikely.

Rarely, one of these conditions leads to this hormone problem:

Some hormone deficiencies cause complications over time. Our experienced doctors help you understand any long-term or serious effects of the missing hormones. For example:

Signs and symptoms vary, depending on which hormones are lacking and the childs age.

Common symptoms in newborns:

Commonsymptomsin older infants and children:

The symptoms you see may be due to other conditions and medical problems. Always talk to your childs doctor if you have a concern.

Our approach to diagnosing hypopituitarism is very thorough. We take one step at a time andminimizeinvasive procedures.

We can use other tests as needed. For example:

We know that the weeks of waiting for the full picture can be difficult. Our compassionate team and family-friendly environment support your family while we progress toward the answers and plan the right treatment. As soon as possible, youll receive a call from a doctor or nurse about what weve found and the next steps to take.

We treat the cause of the condition and replace the hormones the body isnt making.

Hormone replacement therapy mimics the bodys natural production. The medicines can be continued as long as needed, during childhood and adulthood. These medications are tolerated very well when the right amounts of hormones are replaced. The following are examples of hormone replacement therapy:

Some tumors respond to medicine that is swallowed. Other tumors need to be removed with surgery. Usually, the hormone deficiencies remain after a tumor is removed. Hormone therapy works for this.

To be effective, hormone replacement must be supported with ongoing care. Throughout childhood, we need to adjust the hormone doses to accommodate the growing childs needs and changes in symptoms. We evaluate the childs growth and development frequently and develop a working relationship with parent and child.

Our resources help bring the right specialists into your childs care to make sure the child gets the best treatment possible. Our endocrinologists and neurosurgeons co-manage patients in our hospital. Tools such as our electronic health record help nurses and doctors throughout the team work closely together.

We care for children with all forms of hypopituitarism. We treat each hormone deficiency to maintain the childs health and normal development. With the right care plan, children with hypopituitarism usually enjoy a normal life. We help the child to develop normally, interact with peers and feel well.

Learn more about pituitary disorders by visiting these physician-recommended websites:

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Hypopituitarism Treatment & Causes | Lurie Children’s

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All Things Stem Cell Visual Stem Cell Glossary

Stem cells: Cells that are able to (1) self-renew (can create more stem cells indefinitely) and (2) differentiate into (become) specialized, mature cell types.

Embryonic stem cells: Stem cells that are harvested from a blastocyst. These cells are pluripotent, meaning they can differentiate into cells from all three germ layers.

Embryonic stem cells are isolated from cells in a blastocyst, a very early stage embryo. Once isolated from the blastocyst, these cells form colonies in culture (closely packed groups of cells) and can become cells of the three germ layers, which later make up the adult body.

Adult stem cells (or Somatic Stem Cell): Stem cells that are harvested from tissues in an adult body. These cells are usually multipotent, meaning they can differentiate into cells from some, but not all, of the three germ layers. They are thought to act to repair and regenerate the tissue in which they are found in, but usually they can differentiate into cells of completely different tissue types.

Adult stem cells can be found in a wide variety of tissues throughout the body; shown here are only a few examples.

The Three Germ Layers: These are three different tissue types that exist during development in the embryo and that, together, will later make up the body. These layers include the mesoderm, endoderm, and ectoderm.

The three germ layers form during the gastrula stage of development. The layers are determined by their physical position in the gastrula. This stage follows the zygote and blastocyst stages; the gastrula forms when the embryo is approximately 14-16 days old in humans.

Endoderm: One of the three germ layers. Specifically, this is the inner layer of cells in the embryo and it will develop into lungs, digestive organs, the liver, the pancreas, and other organs.

Mesoderm: One of the three germ layers. Specifically, this is the middle layer of cells in the embryo and it will develop into muscle, bone, blood, kidneys, connective tissue, and related structures.

Ectoderm: One of the three germ layers. Specifically, this is the outer layer of cells in the embryo and it will develop into skin, the nervous system, sensory organs, tooth enamel, eye lens, and other structures.

Differentiation, Differentiated: The process by which a stem cell turns into a different, mature cell. When a stem cell has become the mature cell type, it is called differentiated and has lost the ability to turn into multiple different cell types; it is also no longer undifferentiated.

Directed differentiation: To tightly control a stem cell to become a specific mature cell type. This can be done by regulating the conditions the cell is exposed to (i.e. specific media supplemented with different factors can be used).

The differentiation of stem cells can be controlled by exposing the cells to specific conditions. This regulation can cause the cells to become a specific, desired mature cell type, such as neurons in this example.

Undifferentiated: A stem cell that has not become a specific mature cell type. The stem cell holds the potential to differentiate, to become different cell types.

Potential, potency: The number of different kinds of mature cells a given stem cell can become, or differentiate into.

Totipotent: The ability to turn into all the mature cell types of the body as well as embryonic components that are required for development but do not become tissues of the adult body (i.e. the placenta).

A totipotent cell has the ability to become all the cells in the adult body; such cells could theoretically create a complete embryo, such as is shown here in the early stages.

Pluripotent: The ability to turn into all the mature cell types of the body. This is shown by differentiating these stem cells into cell types of the three different germ layers.

Embryonic stem cells are pluripotent cells isolated from an early stage embryo, called the blastocyst. These isolated cells can turn into cells representative of the three germ layers, all the mature cell types of the body.

Multipotent: The ability to turn into more than one mature cell type of the body, usually a restricted and related group of different cell types.

Mesenchymal stem cells are an example of multipotent stem cells; these stem cells can become a wide variety, but related group, of mature cell types (bone, cartilage, connective tissue, adipose tissue, and others).

Unipotent: The ability to give rise to a single mature cell type of the body.

Tissue Type: A group of cells that are similar in morphology and function, and function together as a unit.

Mesenchyme Tissue: Connective tissue from all three germ layers in the embryo. This tissue can become cells that make up connective tissue, cartilage, adipose tissue, the lymphatic system, and bone in the adult body.

Mesenchyme tissue can come from all three of the germ layers (ectoderm, mesoderm, and endoderm) in the developing embryo, shown here at the gastrula stage. The mesenchyme can become bone, cartilage, connective tissue, adipose tissue, and other components of the adult body.

Hematopoietic Stem Cells: Stem cells that can create all the blood cells (red blood cells, white blood cells, and platelets). These stem cells reside within bone marrow in adults and different organs in the fetus.

Hematopoietic stem cells can become, or differentiate into, all the different blood cell types. This process is referred to as hematopoiesis.

Bone marrow: Tissue within the hollow inside of bones that contains hematopoietic stem cells and mesenchymal stem cells.

Development: The process by which a fertilized egg (from the union of a sperm and egg) becomes an adult organism.

Zygote: The single cell that results from a sperm and egg uniting during fertilization. The zygote undergoes several rounds of cell division before it becomes an embryo (after about four days in humans).

When an egg is fertilized by a sperm, the resultant single cell is referred to as a zygote.

Blastocyst: A very early embryo (containing approximately 150 cells) that has not yet implanted into the uterus. The blastocyst is a fluid-filled sphere that contains a group of cells inside it (called the inner cell mass) and is surrounded by an outer layer of cells (the trophoblast, which forms the placenta).

The blastocyst contains three primary components: the inner cell mass, which can become the adult organism, the trophoblast, which becomes the placenta, and the blastocoele, which is a fluid-filled space. The blastocyst develops into the gastrula, a later stage embryo.

Inner Cell Mass: A small group of cells that are attached inside the blastocyst. Human embryonic stem cells are created from these cells in blastocysts that are four or five days post-fertilization. The cells from the inner cell mass have the potential to develop into an embryo, then later the fetus, and eventually the entire body of the adult organism.

Cells taken from the inner cell mass of the blastocyst (a very early stage embryo) can become embryonic stem cells.

Embryo: The developing organism from the end of the zygote stage (after about four days in humans) until it becomes a fetus (until 7 to 8 weeks after conception in humans).

Models: A biological system that is easy to study and similar enough to another, more complex system of interest so that knowledge of the model system can be used to better understand the more complex system. Such systems can include cells and whole organisms.

Model organism: An organism that is easy to study and manipulate and is similar enough to another organism of interest so that by understanding the model organism, a greater understanding of the other organism may be gained. For example, rats and mice can be used as model organisms to better understand humans.

Shown are several different model organisms frequently used in laboratory studies.

Severe Combined Immune-Deficient (SCID) mouse: A mouse lacking a functional immune system, specifically lacking or abnormal T and B lymphocytes. This is due to inbreeding or genetic engineering. They are extensively used for tissue transplants, because they lack an immune system to reject foreign substances, and for studying an immunocompromised system.

Cellular models: A cell system that can be used to understand normal, or diseased, functions that the cell has within the body. By taking cells from the body and studying them outside of the body, in culture, different conditions can be manipulated and the results studied, whereas this can be much more difficult, or impossible, to do within the body.

Stem cells obtained from different tissues of the body can be used as models to study normal, or diseased, cells in these tissues.

Cell Types:

Somatic Cell: Any cell in the body, developing or adult, other than the germline cells (the gametes, or sperm and eggs).

Gametes: The cells in the body that carry the genetic information that will be passed to the offspring. In other words, these are the germline cells: an egg (for females) or sperm (for males) cell.

Other terms:

Regenerative Medicine: A field of research that investigates how to repair or replace damaged tissues, usually by using stem cells. In this manner, stem cells may be differentiated into, or made to become, the type of cell that is damaged and then used in transplants. Also see clinical trials.

Clinical trials: A controlled test of a new drug or treatment on human subjects, normally performed after successful trials with model organisms. ClinicalTrials.gov lists many stem cell clinical trials.

Stem cells have great potential to treat a wide variety of human diseases and medical conditions.

Cell Surface Marker proteins, or simply Cell Markers: A protein on the surface of a cell that identifies the cell as a certain cell type.

Somatic Cell Nuclear Transfer (SCNT): A technique that uses an egg and a somatic cell (a non-germline cell). The nucleus, which contains the genetic material, is removed from the egg and the nucleus from the somatic cell is removed and combined with the egg. The resultant cell contains the genetic material of the nucleus donor, and is turned into a totipotent state by the egg. This cell has the potential to develop into an organism, a clone of the nucleus donor.

Dolly the sheep was cloned through somatic cell nuclear transfer (SCNT). An adult cell from the mammary gland of a Finn-Dorset ewe acted as the nuclear donor; it was fused with an enucleated egg from a Scottish Blackface ewe, which acted as the cytoplasmic (or egg) donor. An electrical pulse acted to fuse the cells and activate the oocyte after injection into the surrogate mother ewe. A successfully implanted oocyte developed into the lamb Dolly, a clone of the nuclear donor, the Finn-Dorset ewe.

Clone: A genetic, identical copy of an individual organism through asexual methods. A clone can be created through somatic cell nuclear transfer.

Other stem cell glossaries:

Image creditsImages of Endoderm, Mesoderm, Ectoderm, Bone Marrow, Neurons, Cartilage, Hand Skeleton, Connective and Adipose Tissue, Gastrula, Clinical Trials, Mouse, Rat, Drosophila, C. Elegans, Arabidopsis, Sea Urchin, Xenopus, Somatic Cell Nuclear Transfer to Create Dolly and other images were taken from the Wikimedia Commons and redistributed and altered freely as they are all in the public domain. The image of Hematopoiesis was also taken from the Wikimedia Commons and redistributed according to the GNU Free Documentation License.

2009. Teisha Rowland. All rights reserved.

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All Things Stem Cell Visual Stem Cell Glossary

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Kotton Lab – Boston University Medical Campus | Boston …

The Kotton labs goal is advancing our understanding of lung disease and developmental biology with a focus on stem cell biology and gene therapy. We believe that novel treatments for many lung diseases can be realized based on a better understanding of how the lung develops as well as regenerates after lung injury.

We are particularly interested in understanding how lung cells decide and remember who they are. To this end, one focus of our group is defining the genomic and epigenomic programs that regulate lung cell fate. A longer term goal is the de novo generation of the full diversity of lung lineages and transplantable 3D lung tissues from pluripotent stem cells. Our Principal Investigator, Dr. Darrell Kotton, also serves as the founding Director of the Center for Regenerative Medicine (CReM). Take a full tour of the CReM by clicking on our logo above.

Click on the menu to learn more about our research areas and our team

Have forty five minutes for an overview of our last decade? Listen here to Darrells ATS Discovery Series Lecture, Lung Regeneration: An Achievable Mission.

Open Source Works! Click here to access our:iPS Cell Lines, Lentiviral Vectors, Bioinformatics Datasets, or Detailed Protocols!

or read more about our Open Source Biology Philosophyor a recent interview on Darrells approach to sharing our cells

More photos of lab life

See all our latest news on twitter:

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Kotton Lab – Boston University Medical Campus | Boston …

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Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ …

More than 55% of VHL-affected individuals develop only multiple renal cell cysts. The VHL-associated RCCs that occur are characteristically multifocal and bilateral and present as a combined cystic and solid mass.[66] Among individuals with VHL, the cumulative RCC risk has been reported as 24% to 45% overall. RCCs smaller than 3 cm in this disease tend to be low grade (Fuhrman nuclear grade 2) and minimally invasive,[67] and their rate of growth varies widely.[68] An investigation of 228 renal lesions in 28 patients who were followed up for at least 1 year showed that transition from a simple cyst to a solid lesion was infrequent.[66] Complex cystic and solid lesions contained neoplastic tissue that uniformly enlarged. These data may be used to help predict the progression of renal lesions in VHL. Figure 1 depicts bilateral renal tumors in a patient with VHL.

Enlarge Figure 1. von Hippel-Lindau diseaseassociated renal cell cancers are characteristically multifocal and bilateral and present as a combined cystic and solid mass. Red arrow indicates a lesion with a solid and cystic component, and white arrow indicates a predominantly solid lesion.

Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur.[68,69] RCCs often remain asymptomatic for long intervals.

Patients can also develop pancreatic cysts, cystadenomas, and pancreatic NETs.[2] Pancreatic cysts and cystadenomas are not malignant, but pancreatic NETs possess malignant characteristics and are typically resected if they are 3 cm or larger (2 cm if located in the head of the pancreas).[70] A review of the natural history of pancreatic NETs shows that these tumors may demonstrate nonlinear growth characteristics.[71]

Retinal manifestations, first reported more than a century ago, were one of the first recognized aspects of VHL. Retinal hemangioblastomas (also known as capillary retinal angiomas) are one of the most frequent manifestations of VHL and are present in more than 50% of patients.[72] Retinal involvement is one of the earliest manifestations of VHL, with a mean age at onset of 25 years.[1,2] These tumors are the first manifestation of VHL in nearly 80% of affected individuals and may occur in children as young as 1 year.[2,73,74]

Retinal hemangioblastomas occur most frequently in the periphery of the retina but can occur in other locations such as the optic nerve, a location much more difficult to treat. Retinal hemangioblastomas appear as a bright orange spherical tumor supplied by a tortuous vascular supply. Nearly 50% of patients have bilateral retinal hemangioblastomas.[72] The median number of lesions per affected eye is approximately six.[75] Other retinal lesions in VHL can include retinal vascular hamartomas, flat vascular tumors located in the superficial aspect of the retina.[76]

Longitudinal studies are important for the understanding of the natural history of these tumors. Left untreated, retinal hemangioblastomas can be a major source of morbidity in VHL, with approximately 8% of patients [72] having blindness caused by various mechanisms, including secondary maculopathy, contributing to retinal detachment, or possibly directly causing retinal neurodegeneration.[77] Patients with symptomatic lesions generally have larger and more numerous retinal hemangioblastomas. Long-term follow-up studies demonstrate that most lesions grow slowly and that new lesions do not develop frequently.[75,78]

Hemangioblastomas are the most common disease manifestation in patients with VHL, affecting more than 70% of individuals. A prospective study assessed the natural history of hemangioblastomas.[79] The mean age at onset of CNS hemangioblastomas is 29.1 years (range, 773 y).[80] After a mean follow-up of 7 years, 72% of the 225 patients studied developed new lesions.[81] Fifty-one percent of existing hemangioblastomas remained stable. The remaining lesions exhibited heterogeneous growth rates, with cerebellar and brainstem lesions growing faster than those in the spinal cord or cauda equina. Approximately 12% of hemangioblastomas developed either peritumoral or intratumoral cysts, and 6.4% were symptomatic and required treatment. Increased tumor burden or total tumor number detected was associated with male sex, longer follow-up, and genotype (all P

Enlarge Figure 2. Hemangioblastomas are the most common disease manifestation in patients with von Hippel-Lindau disease. The left panel shows a sagittal view of brainstem and cerebellar lesions. The middle panel shows an axial view of a brainstem lesion. The right panel shows a cerebellar lesion (red arrow) with a dominant cystic component (white arrow).

Enlarge Figure 3. Hemangioblastomas are the most common disease manifestation in patients with von Hippel-Lindau disease. Multiple spinal cord hemangioblastomas are shown.

The rate of pheochromocytoma formation in the VHL patient population is 25% to 30%.[82,83] Of patients with VHL-associated pheochromocytomas, 44% developed disease in both adrenal glands.[84] The rate of malignant transformation is very low. Levels of plasma and urine normetanephrine are typically elevated in patients with VHL,[85] and approximately two-thirds will experience physical manifestations such as hypertension, tachycardia, and palpitations.[82] Patients with a partial loss of VHL function (Type 2 disease) are at higher risk of pheochromocytoma than are VHL patients with a complete loss of VHL function (Type 1 disease); the latter develop pheochromocytoma very rarely.[13,14,82,86] The rate of VHL germline pathogenic variants in nonsyndromic pheochromocytomas and paragangliomas was very low in a cohort of 182 patients, with only 1 of 182 patients ultimately diagnosed with VHL.[87]

Paragangliomas are rare in VHL patients but can occur in the head and neck or abdomen.[88] A review of VHL patients who developed pheochromocytomas and/or paragangliomas revealed that 90% of patients manifested pheochromocytomas and 19% presented with a paraganglioma.[84]

The mean age at diagnosis of VHL-related pheochromocytomas and paragangliomas is approximately 30 years,[83,89] and patients with multiple tumors were diagnosed more than a decade earlier than patients with solitary lesions in one series (19 vs. 34 y; P

VHL patients may develop multiple serous cystadenomas, pancreatic NETs, and simple pancreatic cysts.[1] VHL patients do not have an increased risk of pancreatic adenocarcinoma. Serous cystadenomas are benign tumors and warrant no intervention. Simple pancreatic cysts can be numerous and rarely cause symptomatic biliary duct obstruction. Endocrine function is nearly always maintained; occasionally, however, patients with extensive cystic disease requiring pancreatic surgery may ultimately require pancreatic exocrine supplementation.

Pancreatic NETs are usually nonfunctional but can metastasize (to lymph nodes and the liver). The risk of pancreatic NET metastasis was analyzed in a large cohort of patients, in which the mean age at diagnosis of a pancreatic NET was 38 years (range, 1668 y).[90] The risk of metastasis was lower in patients with small primary lesions (3 cm), in patients without an exon 3 pathogenic variant, and in patients whose tumor had a slow doubling time (>500 days). Nonfunctional pancreatic NETs can be followed by imaging surveillance with intervention when tumors reach 3 cm. Lesions in the head of the pancreas can be considered for surgery at a smaller size to limit operative complexity.

ELSTs are adenomatous tumors arising from the endolymphatic duct or sac within the posterior part of the petrous bone.[91] ELSTs are rare in the sporadic setting, but are apparent on imaging in 11% to 16% of patients with VHL. Although these tumors do not metastasize, they are locally invasive, eroding through the petrous bone and the inner ear structures.[91,92] Approximately 30% of VHL patients with ELSTs have bilateral lesions.[91,93]

ELSTs are an important cause of morbidity in VHL patients. ELSTs evident on imaging are associated with a variety of symptoms, including hearing loss (95% of patients), tinnitus (92%), vestibular symptoms (such as vertigo or disequilibrium) (62%), aural fullness (29%), and facial paresis (8%).[91,92] In approximately half of patients, symptoms (particularly hearing loss) can occur suddenly, probably as a result of acute intralabyrinthine hemorrhage.[92] Hearing loss or vestibular dysfunction in VHL patients can also present in the absence of radiologically evident ELSTs (approximately 60% of all symptomatic patients) and is believed to be a consequence of microscopic ELSTs.[91]

Hearing loss related to ELSTs is typically irreversible; serial imaging to enable early detection of ELSTs in asymptomatic patients and resection of radiologically evident lesions are important components in the management of VHL patients.[94,95] Surgical resection by retrolabyrinthine posterior petrosectomy is usually curative and can prevent onset or worsening of hearing loss and improve vestibular symptoms.[92,94]

Tumors of the broad ligament can occur in females with VHL and are known as papillary cystadenomas. These tumors are extremely rare, and fewer than 20 have been reported in the literature.[96] Papillary cystadenomas are histologically identical to epididymal cystadenomas commonly observed in males with VHL.[97] One important difference is that papillary cystadenomas are almost exclusively observed in patients with VHL, whereas epididymal cystadenomas in men can occur sporadically.[98] These tumors are frequently cystic, and although they become large, they generally have a fairly indolent behavior.

More than one-third of all cases of epididymal cystadenomas reported in the literature and most cases of bilateral cystadenomas have been reported in patients with VHL.[99] Among symptomatic patients, the most common presentation is a painless, slow-growing scrotal swelling. The differential diagnoses of epididymal tumors include adenomatoid tumor (which is the most common tumor in this site), metastatic ccRCC, and papillary mesothelioma.[100]

In a small series, histological analysis did not reveal features typically associated with malignancy, such as mitotic figures, nuclear pleomorphism, and necrosis. Lesions were strongly positive for CK7 and negative for RCC. Carbonic anhydrase IX (CAIX) was positive in all tumors. PAX8 was positive in most cases. These features were reminiscent of clear cell papillary RCC, a relatively benign form of RCC without known metastatic potential.[97]

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Nocturia or Frequent Urination at Night – National Sleep …

A frequent need to get up and go to the bathroom to urinate at night is called nocturia. It differs from enuresis, or bedwetting, in which the person does not arouse from sleep, but the bladder empties anyway. Nocturia is a common cause of sleep loss, especially among older adults.

Most people without nocturia can sleep for 6 to 8 hours without having to urinate. Some researchers believe that one event per night is within normal limits; two or more events per night may be associated with daytime tiredness. Patients with severe nocturia may get up five or six times during the night to go to the bathroom.

Nocturia is often a symptom of other medical conditions including urological infection, a tumor of the bladder or prostate, a condition called bladder prolapse, or disorders affecting sphincter control. It is also common in people with heart failure, liver failure, poorly controlled diabetes mellitus, or diabetes insipidus. Diabetes, pregnancy and diuretic medications are also associated with nocturia.

Until recently, nocturia was thought to be caused by a full bladder, but it is also a symptom of sleep apnea.

Nocturia becomes more common as we age. As we get older, our bodies produce less of an anti-diuretic hormone that enables us to retain fluid. With decreased concentrations of this hormone, we produce more urine at night. Another reason for nocturia among the elderly is that the bladder tends to lose holding capacity as we age. Finally, older people are more likely to suffer from medical problems that may have an effect on the bladder.

In fact, nearly two-thirds (65%) of those responding to NSF’s 2003 Sleep in America poll of adults between the ages of 55 and 84 reported this disturbance at least a few nights per week.

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Nocturia or Frequent Urination at Night – National Sleep …

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Adrenal gland – Wikipedia

The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol.[1][2] They are found above the kidneys. Each gland has an outer cortex which produces steroid hormones and an inner medulla. The adrenal cortex itself is divided into three zones: the zona glomerulosa, the zona fasciculata and the zona reticularis.[3]

The adrenal cortex produces three main types of steroid hormones: mineralocorticoids, glucocorticoids, and androgens. Mineralocorticoids (such as aldosterone) produced in the zona glomerulosa help in the regulation of blood pressure and electrolyte balance. The glucocorticoids cortisol and corticosterone are synthesized in the zona fasciculata; their functions include the regulation of metabolism and immune system suppression. The innermost layer of the cortex, the zona reticularis, produces androgens that are converted to fully functional sex hormones in the gonads and other target organs.[4] The production of steroid hormones is called steroidogenesis, and involves a number of reactions and processes that take place in cortical cells.[5] The medulla produces the catecholamines adrenaline and noradrenaline, which function to produce a rapid response throughout the body in stress situations.[4]

A number of endocrine diseases involve dysfunctions of the adrenal gland. Overproduction of cortisol leads to Cushing’s syndrome, whereas insufficient production is associated with Addison’s disease. Congenital adrenal hyperplasia is a genetic disease produced by dysregulation of endocrine control mechanisms.[4][6] A variety of tumors can arise from adrenal tissue and are commonly found in medical imaging when searching for other diseases.[7]

The adrenal glands are located on both sides of the body in the retroperitoneum, above and slightly medial to the kidneys. In humans, the right adrenal gland is pyramidal in shape, whereas the left is semilunar or crescent shaped and somewhat larger.[8] The adrenal glands measure approximately 3cm in width, 5.0cm in length, and up to 1.0cm in thickness.[9] Their combined weight in an adult human ranges from 7 to 10grams.[10] The glands are yellowish in colour.[8]

The adrenal glands are surrounded by a fatty capsule and lie within the renal fascia, which also surrounds the kidneys. A weak septum (wall) of connective tissue separates the glands from the kidneys.[11] The adrenal glands are directly below the diaphragm, and are attached to the crura of the diaphragm by the renal fascia.[11]

Each adrenal gland has two distinct parts, each with a unique function, the outer adrenal cortex and the inner medulla, both of which produce hormones.[12]

The adrenal cortex is the outermost layer of the adrenal gland. Within the cortex are three layers, called “zones”. When viewed under a microscope each layer has a distinct appearance, and each has a different function.[13] The adrenal cortex is devoted to production of hormones, namely aldosterone, cortisol, and androgens.[14]

The outermost zone of the adrenal cortex is the zona glomerulosa. It lies immediately under the fibrous capsule of the gland. Cells in this layer form oval groups, separated by thin strands of connective tissue from the fibrous capsule of the gland and carry wide capillaries.[15]

This layer is the main site for production of aldosterone, a mineralocorticoid, by the action of the enzyme aldosterone synthase.[16][17] Aldosterone plays an important role in the long-term regulation of blood pressure.[18]

The zona fasciculata is situated between the zona glomerulosa and zona reticularis. Cells in this layer are responsible for producing glucocorticoids such as cortisol.[19] It is the largest of the three layers, accounting for nearly 80% of the volume of the cortex.[3] In the zona fasciculata, cells are arranged in columns radially oriented towards the medulla. Cells contain numerous lipid droplets, abundant mitochondria and a complex smooth endoplasmic reticulum.[15]

The innermost cortical layer, the zona reticularis, lies directly adjacent to the medulla. It produces androgens, mainly dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and androstenedione (the precursor to testosterone) in humans.[19] Its small cells form irregular cords and clusters, separated by capillaries and connective tissue. The cells contain relatively small quantities of cytoplasm and lipid droplets, and sometimes display brown lipofuscin pigment.[15]

The adrenal medulla is at the centre of each adrenal gland, and is surrounded by the adrenal cortex. The chromaffin cells of the medulla are the body’s main source of the catecholamines adrenaline and noradrenaline, released by the medulla. Approximately 20% noradrenaline (norepinephrine) and 80% adrenaline (epinephrine) are secreted here.[19]

The adrenal medulla is driven by the sympathetic nervous system via preganglionic fibers originating in the thoracic spinal cord, from vertebrae T5T11.[20] Because it is innervated by preganglionic nerve fibers, the adrenal medulla can be considered as a specialized sympathetic ganglion.[20] Unlike other sympathetic ganglia, however, the adrenal medulla lacks distinct synapses and releases its secretions directly into the blood.

The adrenal glands have one of the greatest blood supply rates per gram of tissue of any organ: up to 60 small arteries may enter each gland.[21] Three arteries usually supply each adrenal gland:[8]

These blood vessels supply a network of small arteries within the capsule of the adrenal glands. Thin strands of the capsule enter the glands, carrying blood to them.[8]

Venous blood is drained from the glands by the suprarenal veins, usually one for each gland:[8]

The central adrenomedullary vein, in the adrenal medulla, is an unusual type of blood vessel. Its structure is different from the other veins in that the smooth muscle in its tunica media (the middle layer of the vessel) is arranged in conspicuous, longitudinally oriented bundles.[3]

The adrenal glands may not develop at all, or may be fused in the midline behind the aorta.[12] These are associated with other congenital abnormalities, such as failure of the kidneys to develop, or fused kidneys.[12] The gland may develop with a partial or complete absence of the cortex, or may develop in an unusual location.[12]

The adrenal gland secretes a number of different hormones which are metabolised by enzymes either within the gland or in other parts of the body. These hormones are involved in a number of essential biological functions.[23]

Corticosteroids are a group of steroid hormones produced from the cortex of the adrenal gland, from which they are named.[24] Corticosteroids are named according to their actions:

The adrenal gland produces aldosterone, a mineralocorticoid, which is important in the regulation of salt (“mineral”) balance and blood volume. In the kidneys, aldosterone acts on the distal convoluted tubules and the collecting ducts by increasing the reabsorption of sodium and the excretion of both potassium and hydrogen ions.[18] Aldosterone is responsible for the reabsorption of about 2% of filtered glomerular filtration rates.[27] Sodium retention is also a response of the distal colon and sweat glands to aldosterone receptor stimulation. Angiotensin II and extracellular potassium are the two main regulators of aldosterone production.[19] The amount of sodium present in the body affects the extracellular volume, which in turn influences blood pressure. Therefore, the effects of aldosterone in sodium retention are important for the regulation of blood pressure.[28]

Cortisol is the main glucocorticoid in humans. In species that do not create cortisol, this role is played by corticosterone instead. Glucocorticoids have many effects on metabolism. As their name suggests, they increase the circulating level of glucose. This is the result of an increase in the mobilization of amino acids from protein and the stimulation of synthesis of glucose from these amino acids in the liver. In addition, they increase the levels of free fatty acids, which cells can use as an alternative to glucose to obtain energy. Glucocorticoids also have effects unrelated to the regulation of blood sugar levels, including the suppression of the immune system and a potent anti-inflammatory effect. Cortisol reduces the capacity of osteoblasts to produce new bone tissue and decreases the absorption of calcium in the gastrointestinal tract.[28]

The adrenal gland secretes a basal level of cortisol but can also produce bursts of the hormone in response to adrenocorticotropic hormone (ACTH) from the anterior pituitary. Cortisol is not evenly released during the day its concentrations in the blood are highest in the early morning and lowest in the evening as a result of the circadian rhythm of ACTH secretion.[28] Cortisone is an inactive product of the action of the enzyme 11-HSD on cortisol. The reaction catalyzed by 11-HSD is reversible, which means that it can turn administered cortisone into cortisol, the biologically active hormone.[28]

All corticosteroid hormones share cholesterol as a common precursor. Therefore, the first step in steroidogenesis is cholesterol uptake or synthesis. Cells that produce steroid hormones can acquire cholesterol through two paths. The main source is through dietary cholesterol transported via the blood as cholesterol esters within low density lipoproteins (LDL). LDL enters the cells through receptor-mediated endocytosis. The other source of cholesterol is synthesis in the cell’s endoplasmic reticulum. Synthesis can compensate when LDL levels are abnormally low.[4] In the lysosome, cholesterol esters are converted to free cholesterol, which is then used for steroidogenesis or stored in the cell.[29]

The initial part of conversion of cholesterol into steroid hormones involves a number of enzymes of the cytochrome P450 family that are located in the inner membrane of mitochondria. Transport of cholesterol from the outer to the inner membrane is facilitated by steroidogenic acute regulatory protein and is the rate-limiting step of steroid synthesis.[29]

The layers of the adrenal gland differ by function, with each layer having distinct enzymes that produce different hormones from a common precursor.[4] The first enzymatic step in the production of all steroid hormones is cleavage of the cholesterol side chain, a reaction that forms pregnenolone as a product and is catalyzed by the enzyme P450scc, also known as cholesterol desmolase. After the production of pregnenolone, specific enzymes of each cortical layer further modify it. Enzymes involved in this process include both mitochondrial and microsomal P450s and hydroxysteroid dehydrogenases. Usually a number of intermediate steps in which pregnenolone is modified several times are required to form the functional hormones.[5] Enzymes that catalyze reactions in these metabolic pathways are involved in a number of endocrine diseases. For example, the most common form of congenital adrenal hyperplasia develops as a result of deficiency of 21-hydroxylase, an enzyme involved in an intermediate step of cortisol production.[30]

Glucocorticoids are under the regulatory influence of the hypothalamus-pituitary-adrenal (HPA) axis. Glucocorticoid synthesis is stimulated by adrenocorticotropic hormone (ACTH), a hormone released into the bloodstream by the anterior pituitary. In turn, production of ACTH is stimulated by the presence of corticotropin-releasing hormone (CRH), which is released by neurons of the hypothalamus. ACTH acts on the adrenal cells first by increasing the levels of StAR within the cells, and then of all steroidogenic P450 enzymes. The HPA axis is an example of a negative feedback system, in which cortisol itself acts as a direct inhibitor of both CRH and ACTH synthesis. The HPA axis also interacts with the immune system through increased secretion of ACTH at the presence of certain molecules of the inflammatory response.[4]

Mineralocorticoid secretion is regulated mainly by the reninangiotensinaldosterone system (RAAS), the concentration of potassium, and to a lesser extent the concentration of ACTH.[4] Sensors of blood pressure in the juxtaglomerular apparatus of the kidneys release the enzyme renin into the blood, which starts a cascade of reactions that lead to formation of angiotensin II. Angiotensin receptors in cells of the zona glomerulosa recognize the substance, and upon binding they stimulate the release of aldosterone.[31]

Primarily referred to in the United States as epinephrine and norepinephrine, adrenaline and noradrenaline are catecholamines, water-soluble compounds that have a structure made of a catechol group and an amine group. The adrenal glands are responsible for most of the adrenaline that circulates in the body, but only for a small amount of circulating noradrenaline.[23] These hormones are released by the adrenal medulla, which contains a dense network of blood vessels. Adrenaline and noradrenaline act at adrenoreceptors throughout the body, with effects that include an increase in blood pressure and heart rate.[23] actions of adrenaline and noradrenaline are responsible for the fight or flight response, characterised by a quickening of breathing and heart rate, an increase in blood pressure, and constriction of blood vessels in many parts of the body.[32]

Catecholamines are produced in chromaffin cells in the medulla of the adrenal gland, from tyrosine, a non-essential amino acid derived from food or produced from phenylalanine in the liver. The enzyme tyrosine hydroxylase converts tyrosine to L-DOPA in the first step of catecholamine synthesis. L-DOPA is then converted to dopamine before it can be turned into noradrenaline. In the cytosol, noradrenaline is converted to epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT) and stored in granules. Glucocorticoids produced in the adrenal cortex stimulate the synthesis of catecholamines by increasing the levels of tyrosine hydroxylase and PNMT.[4][13]

Catecholamine release is stimulated by the activation of the sympathetic nervous system. Splanchnic nerves of the sympathetic nervous system innervate the medulla of the adrenal gland. When activated, it evokes the release of catecholamines from the storage granules by stimulating the opening of calcium channels in the cell membrane.[33]

Cells in zona reticularis of the adrenal glands produce male sex hormones, or androgens, the most important of which is DHEA. In general, these hormones do not have an overall effect in the male body, and are converted to more potent androgens such as testosterone and DHT or to estrogens (female sex hormones) in the gonads, acting in this way as a metabolic intermediate.[34]

Thehuman genomeincludes approximately 20,000 protein coding genes and 70% of thesegenes are expressedin the normal, adult adrenal glands.[35][36]Only some 250 genes are more specifically expressed in the adrenal glands compared to other organs and tissues.The adrenal gland specific genes with highest level of expression include members of the cytochrome P450 superfamily of enzymes. Corresponding proteins are expressed in the different compartments of the adrenal gland, such as CYP11A1, HSD3B2 and FDX1 involved in steroid hormone synthesis and expressed in cortical cell layers, and PNMT and DBH involved in noradrenalin and adrenalin synthesis and expressed in the medulla.[37]

The adrenal glands are composed of two heterogenous types of tissue. In the center is the adrenal medulla, which produces adrenaline and noradrenaline and releases them into the bloodstream, as part of the sympathetic nervous system. Surrounding the medulla is the cortex, which produces a variety of steroid hormones. These tissues come from different embryological precursors and have distinct prenatal development paths. The cortex of the adrenal gland is derived from mesoderm, whereas the medulla is derived from the neural crest, which is of ectodermal origin.[12]

The adrenal glands in a newborn baby are much larger as a proportion of the body size than in an adult.[38] For example, at age three months the glands are four times the size of the kidneys. The size of the glands decreases relatively after birth, mainly because of shrinkage of the cortex. The cortex, which almost completely disappears by age 1, develops again from age 45. The glands weigh about 1 g at birth[12] and develop to an adult weight of about 4 grams each.[28] In a fetus the glands are first detectable after the sixth week of development.[12]

Adrenal cortex tissue is derived from the intermediate mesoderm. It first appears 33 days after fertilisation, shows steroid hormone production capabilities by the eighth week and undergoes rapid growth during the first trimester of pregnancy. The fetal adrenal cortex is different from its adult counterpart, as it is composed of two distinct zones: the inner “fetal” zone, which carries most of the hormone-producing activity, and the outer “definitive” zone, which is in a proliferative phase. The fetal zone produces large amounts of adrenal androgens (male sex hormones) that are used by the placenta for estrogen biosynthesis.[39] Cortical development of the adrenal gland is regulated mostly by ACTH, a hormone produced by the pituitary gland that stimulates cortisol synthesis.[40] During midgestation, the fetal zone occupies most of the cortical volume and produces 100200mg/day of DHEA-S, an androgen and precursor of both androgens and estrogens (female sex hormones).[41] Adrenal hormones, especially glucocorticoids such as cortisol, are essential for prenatal development of organs, particularly for the maturation of the lungs. The adrenal gland decreases in size after birth because of the rapid disappearance of the fetal zone, with a corresponding decrease in androgen secretion.[39]

During early childhood androgen synthesis and secretion remain low, but several years before puberty (from 68 years of age) changes occur in both anatomical and functional aspects of cortical androgen production that lead to increased secretion of the steroids DHEA and DHEA-S. These changes are part of a process called adrenarche, which has only been described in humans and some other primates. Adrenarche is independent of ACTH or gonadotropins and correlates with a progressive thickening of the zona reticularis layer of the cortex. Functionally, adrenarche provides a source of androgens for the development of axillary and pubic hair before the beginning of puberty.[42][43]

The adrenal medulla is derived from neural crest cells, which come from the ectoderm layer of the embryo. These cells migrate from their initial position and aggregate in the vicinity of the dorsal aorta, a primitive blood vessel, which activates the differentiation of these cells through the release of proteins known as BMPs. These cells then undergo a second migration from the dorsal aorta to form the adrenal medulla and other organs of the sympathetic nervous system.[44] Cells of the adrenal medulla are called chromaffin cells because they contain granules that stain with chromium salts, a characteristic not present in all sympathetic organs. Glucocorticoids produced in the adrenal cortex were once thought to be responsible for the differentiation of chromaffin cells. More recent research suggests that BMP-4 secreted in adrenal tissue is the main responsible for this, and that glucocorticoids only play a role in the subsequent development of the cells.[45]

The normal function of the adrenal gland may be impaired by conditions such as infections, tumors, genetic disorders and autoimmune diseases, or as a side effect of medical therapy. These disorders affect the gland either directly (as with infections or autoimmune diseases) or as a result of the dysregulation of hormone production (as in some types of Cushing’s syndrome) leading to an excess or insufficiency of adrenal hormones and the related symptoms.

Cushing’s syndrome is the manifestation of glucocorticoid excess. It can be the result of a prolonged treatment with glucocorticoids or be caused by an underlying disease which produces alterations in the HPA axis or the production of cortisol. Causes can be further classified into ACTH-dependent or ACTH-independent. The most common cause of endogenous Cushing’s syndrome is a pituitary adenoma which causes an excessive production of ACTH. The disease produces a wide variety of signs and symptoms which include obesity, diabetes, increased blood pressure, excessive body hair (hirsutism), osteoporosis, depression, and most distinctively, stretch marks in the skin, caused by its progressive thinning.[4][6]

When the zona glomerulosa produces excess aldosterone, the result is primary aldosteronism. Causes for this condition are bilateral hyperplasia (excessive tissue growth) of the glands, or aldosterone-producing adenomas (a condition called Conn’s syndrome). Primary aldosteronism produces hypertension and electrolyte imbalance, increasing potassium depletion and sodium retention.[6]

Adrenal insufficiency (the deficiency of glucocorticoids) occurs in about 5 in 10,000 in the general population.[6] Diseases classified as primary adrenal insufficiency (including Addison’s disease and genetic causes) directly affect the adrenal cortex. If a problem that affects the hypothalamic-pituitary-adrenal axis arises outside the gland, it is a secondary adrenal insufficiency.

Addison’s disease refers to primary hypoadrenalism, which is a deficiency in glucocorticoid and mineralocorticoid production by the adrenal gland. In the Western world, Addison’s disease is most commonly an autoimmune condition, in which the body produces antibodies against cells of the adrenal cortex. Worldwide, the disease is more frequently caused by infection, especially from tuberculosis. A distinctive feature of Addison’s disease is hyperpigmentation of the skin, which presents with other nonspecific symptoms such as fatigue.[4]

A complication seen in untreated Addison’s disease and other types of primary adrenal insufficiency is the adrenal crisis, a medical emergency in which low glucocorticoid and mineralocorticoid levels result in hypovolemic shock and symptoms such as vomiting and fever. An adrenal crisis can progressively lead to stupor and coma.[4] The management of adrenal crises includes the application of hydrocortisone injections.[46]

In secondary adrenal insufficiency, a dysfunction of the hypothalamic-pituitary-adrenal axis leads to decreased stimulation of the adrenal cortex. Apart from suppression of the axis by glucocorticoid therapy, the most common cause of secondary adrenal insufficiency are tumors that affect the production of adrenocorticotropic hormone (ACTH) by the pituitary gland.[6] This type of adrenal insufficiency usually does not affect the production of mineralocorticoids, which are under regulation of the reninangiotensin system instead.[4]

Congenital adrenal hyperplasia is a congenital disease in which mutations of enzymes that produce steroid hormones result in a glucocorticoid deficiency and malfunction of the negative feedback loop of the HPA axis. In the HPA axis, cortisol (a glucocorticoid) inhibits the release of CRH and ACTH, hormones that in turn stimulate corticosteroid synthesis. As cortisol cannot be synthesized, these hormones are released in high quantities and stimulate production of other adrenal steroids instead. The most common form of congenital adrenal hyperplasia is due to 21-hydroxylase deficiency. 21-hydroxylase is necessary for production of both mineralocorticoids and glucocorticoids, but not androgens. Therefore, ACTH stimulation of the adrenal cortex induces the release of excessive amounts of adrenal androgens, which can lead to the development of ambiguous genitalia and secondary sex characteristics.[30]

Adrenal tumors are commonly found as incidentalomas, unexpected asymptomatic tumors found during medical imaging. They are seen in around 3.4% of CT scans,[7] and in most cases they are benign adenomas.[47] Adrenal carcinomas are very rare, with an incidence of 1 case per million per year.[4]

Pheochromocytomas are tumors of the adrenal medulla that arise from chromaffin cells. They can produce a variety of nonspecific symptoms, which include headaches, sweating, anxiety and palpitations. Common signs include hypertension and tachycardia. Surgery, especially adrenal laparoscopy, is the most common treatment for small pheochromocytomas.[48]

Bartolomeo Eustachi, an Italian anatomist, is credited with the first description of the adrenal glands in 1563-4.[49][50] However, these publications were part of the papal library and did not receive public attention, which was first received with Caspar Bartholin the Elder’s illustrations in 1611.[50]

The adrenal glands are named for their location relative to the kidneys. The term “adrenal” comes from ad- (Latin, “near”) and renes (Latin, “kidney”).[51] Similarly, “suprarenal”, as termed by Jean Riolan the Younger in 1629, is derived from the Latin supra (Latin: “above”) and renes (Latin: kidney). The suprarenal nature of the glands was not truly accepted until the 19th century, as anatomists clarified the ductless nature of the glands and their likely secretory role prior to this, there was some debate as to whether the glands were indeed suprarenal or part of the kidney.[50]

One of the most recognized works on the adrenal glands came in 1855 with the publication of On the Constitutional and Local Effects of Disease of the Suprarenal Capsule, by the English physician Thomas Addison. In his monography, Addison described what the French physician George Trousseau would later name Addison’s disease, an eponym still used today for a condition of adrenal insufficiency and its related clinical manifestations.[52] In 1894, English physiologists George Oliver and Edward Schafer studied the action of adrenal extracts and observed their pressor effects. In the following decades several physicians experimented with extracts from the adrenal cortex to treat Addison’s disease.[49] Edward Calvin Kendall, Philip Hench and Tadeusz Reichstein were then awarded the 1950 Nobel Prize in Physiology or Medicine for their discoveries on the structure and effects of the adrenal hormones.[53]

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Get Paid to be an Apartment Mystery Shopper – Ellis Partners

Get Paid to be an Apartment Mystery Shopper

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Ellis contracts with individuals to conduct over 8,000 apartment mystery shops monthly. Were fair to our shoppers, and our staff is available to answer questions and help with challenges.

Become an Ellis apartment mystery shop contractor today.

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BEWARE of Email Shopping ScamsEllis has been made aware of an email scam regarding shop contracts for our company. Please be advised you can verify the legitimacy of ALL Ellis shop contracts that are available by logging into your Ellis shopper account or contacting us by email or phone. Ellis does not offer apartment shop contract opportunities by mail. If you have reason to believe you have received a fraudulent email or other type of communication involving Ellis shop contract opportunities (especially for any type of assignment other than a multifamily housing mystery shop), please notify us immediately so we can take proper action.

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Gene Therapy Manufacturing – The Bioprocessing Summit

Cambridge Healthtech Institute s 3rd AnnualAugust 16-17, 2018

It is an exciting time for gene therapy therapies on the market, encouraging clinical data and a long list of pharma collaborations. Pricing and reimbursement takes a majority of the headlines but equally important is producing these therapies in a scalable, cost-effective and robust way, all the while developing a clear CMC and characterization profile that satisfies the regulators.

Cambridge Healthtech Institutes Gene Therapy Manufacturing meeting takes a practical, case study driven approach to the process development, scale-up and production of gene therapies, tackling key topics such as AAV, lentivirus and retrovirus process development and scale-up, CMO management from early to late-stage development.

Final Agenda

Day 1 | Day 2 | Speaker Biographies

Thursday, August 16

11:30 am Registration Open (Grand Ballroom Foyer)

12:15 pm Enjoy Lunch on Your Own

1:15 10th Anniversary Cake Break in the Exhibit Hall with Last Chance for Poster Viewing (Grand Ballroom)

1:55 Chairpersons Remarks

John Pieracci, PhD, Director, Purification, Biogen

2:00 KEYNOTE PRESENTATION: Challenges and Strategies for the Development of a Robust, Scalable, Cost-Effective Biomanufacturing Process

Sadettin Ozturk, PhD, Senior Vice President, Process and Analytical Development, MassBiologics

The use of viral vectors has increased in recent years, both as gene therapies and as vectors for ex vivo cell therapy products. Industrialization of viral vector manufacturing is maturing as companies tackle problems in process control, scale-up, facility design, characterization and quality, and regulatory considerations. This presentation will examine the current state of the art, emerging technologies and challenges.

2:45 Enabling Industrial Scale Production of Lentiviral Vectors for Gene Therapy

Kelly Kral, PhD, Associate Director, Vector Process Development and Manufacturing, bluebird bio

Lentiviral vectors are an ideal platform for indications requiring long-term, stable expression, but the production processes have historically been limited by scale. As the field has now entered commercialization, there is demand for larger quantities of vector, driving the need for more scalable processes. This presentation will review the development, scale-up, and tech transfer of our suspension-based lentiviral vector process.

3:15 Strategies to Deliver Scalable and Reliable Lentiviral Vector Biomanufacturing

Jeffrey Bartlett, PhD, CSO, Calimmune, Inc.

Large-scale clinical production of lentiviral vectors (LV) using current good manufacturing practice (cGMP) methods comes with significant challenges. We have established the Cytegrity stable cell line system for LV bioproduction and have defined key process, quality and regulatory parameters needed to achieve desired productivity and quality across multiples scales and different bioproduction systems. This approach has allowed the production of LV required for Phase I and II clinical trials, while paving the way for future commercialization.

3:45Evolving Process-Centric Facility Design

Mike Sheehan, MSc, MBA, PMP, Senior Project Manager, DPS Group

Increasingly gene therapy products transitioning from clinical phase to commercial manufacture is driving demand for companies to provide additional capacity. Bringing products to market requires exploring opportunities for leading edge facility design, implementing new & evolving technologies, responding to scalability, speed to market and financial considerations.

4:00 Refreshment Break (Foyer)

4:15 Scalable Lentiviral Vector Production Using HEK293 Suspension Cells

Parminder S Chahal, Research Officer, Human Health Therapeutics Research Centre, National Research Council Canada

We have developed expertise in the production of lentiviral vectors (LV) using packaging cell lines and stable producers. Both grow in suspension and in serum-free conditions. Using a stable producer cell line that produces LV expressing GFP, we have compared different modes of operation in bench-scale bioreactors (batch, fed-batch and perfusion). Next, a battery of filters and supplements were evaluated for clarification. A maximal recovery of 78% was obtained.

4:45 Development and Characterization of Novel Micro-RNA Attenuated Oncolytic Herpes Simplex Viruses

Jonathan Platt, PhD., Senior Research Scientist, CMC Operations, Oncorus

Oncorus is developing next generation HSV-based oncolytic virus with enhanced potency for tumor cell killing and recruitment of the immune system. Our innovative miR-attenuation strategy enables robust viral replication in tumor cells, while preventing replication in healthy tissue. The development and characterization of therapeutic oHSV requires thorough product understanding gained through process characterization. Strategies for development and characterization of manufacturing processes centered around a strong organizational infrastructure will be presented.

5:15 End of Day

Day 1 | Day 2 | Speaker Biographies

FRIDAY, AUGUST 17

8:00 am Registration Open and Morning Coffee (Grand Ballroom Foyer)

8:25 Chairpersons Remarks

Nathalie Clment, PhD, Associate Director and Associate Professor, Powell Gene Therapy Center, Pediatrics, University of Florida

8:30 FEATURED PRESENTATION: rAAV Vector Design, Capsid Directed Evolution and Scale Up Activities Using the BEVS System

Jacek Lubelski, PhD., VP, Global Pharmaceutical Development, uniQure

9:00 Towards a Pivotal Process for AAV Manufacture with HSV

David Knop, PhD, Executive Director, Process Development, AGTC

9:30 Large-Scale Manufacturing of Clinical Grade AAV in the Academic Setting

Nathalie Clment, PhD, Associate Director and Associate Professor, Powell Gene Therapy Center, Pediatrics, University of Florida

The talk will present our current methods for the production of research and clinical-grade rAAV with a special emphasis on the HSV-based suspension method capable of generating high titers of improved rAAV quality. Up-to-date in vitro, in vivo, and clinical data will be shown, and pros and cons of the method will be discussed in comparison to the two other most common methods, transfection and the baculovirus system.

10:00 Networking Coffee Break (Foyer)

10:30 Scale-Up Approach to AAV Manufacturing

Johannes C.M. van der Loo, PhD, Director, Clinical Vector Core, The Raymond G. Perelman Center for Molecular and Cellular Therapies, Childrens Hospital of Philadelphia

The Clinical Vector Core at the Childrens Hospital of Philadelphia manufactures preclinical- and clinical-grade AAV for academia and industry-sponsored clinical trials. With the field of gene therapy maturing, there is a growing need for larger scale products. We will discuss a strategy for scale-up that builds on our existing mammalian adherent cell-based manufacturing platform.

11:00 Virus-Like Particles and Other Extracellular Particles from Insect and Mammalian Cells

Alois Jungbauer, PhD, Professor, Institute of Biotechnology, University of Natural Resources and Life Sciences (BOKU)

Virus-like particles and other extra cellular particles are a next generation of biopharmaceuticals. They can be produced by a wide variety of host cells. The challenge is the production of high titers and downstream processing. The particle of interest are contaminated with other particles with similar biophysical properties and therefore difficult to separate. Examples will be given for 3 different cell types.

11:30 Considerations for the Purification Process Characterization of an AAV from Recovery to Drug Substance

Ratish Krishnan, PhD, Scientist, Bioprocessing Research & Development, Pfizer

Smart and efficient approaches for lab-scale characterization are required to ensure a robust adeno-associated manufacturing process. Specific challenges related to the uniqueness of characterizing an AAV manufacturing process will be discussed. Focus will be given to working with limited quantities of material and employing assays that are still being defined.

12:00 pm Next Generation AAV Viral Vector Manufacturing: Proven Technologies with a Modern Twist

Sandhya Buchanan, Director, Upstream Process Development, FUJIFILM Diosynth Biotechnologies

Current approaches to commercial-scale manufacture of viral vectors have been successful for many early phase trials and some late phase trials. Unique challenges/limitations arising for AAV manufacturing include quantities sufficient for patient needs and consumables for manufacturing. We discuss proven technologies blended with modern advancements to meet the needs of the advancing field of gene therapy.

12:30 Enjoy Lunch on Your Own

1:25 Chairpersons Remarks

Chia Chu, Senior Principal Scientist, Bioprocess Research & Development, Pfizer

1:30 FEATURED PRESENTATION: Separation of Full and Empty AAV Particles Using Scalable Isocratic Elution Chromatography

Meisam Bakhshayeshi, PhD, Head, Purification Development, Gene Therapy, Biogen

Robust and efficient removal of AAV empty particles is a critical part of the AAV manufacturing process. In this study, we present a scalable ion exchange chromatography process with isocratic wash and elution to separate full and empty particles. A combination of mono- and di-valent salts were used as eluents to achieve the high degree of resolution required for this separation. High product purity and recovery was achieved from this process.

2:00 Lyophilisation of AAV Gene Therapy Product

Tanvir Tabish, PhD, Head, Drug Product Development for Gene Therapy, Device and Combination Products, Shire

The gene therapy adeno-associated virus (AAV) subtype 8 containing Factor IX (FIX)(BAX335) was formulated in a new proprietary buffer and lyophilized. A stability study was established with the lyophilized material to determine its stability profile at the accelerated temperature of +5C over a 10 month period. The freeze-dried product displayed an improved stability profile when stored at a temperature of +5C. We demonstrated the feasibility of lyophilisation of the AAV viral drug product in the formulation buffer.

2:30 AAV Manufacturing at 2,000L Scale

Alex Fotopoulos, PhD., Senior Vice President, Technical Operations, Ultragenyx.

Changing the manufacturing site (tech transfer) should always include an assessment of comparability, however the ability to demonstrate this varies between early and late development. This talk will discuss common pitfalls and mistakes and highlight key aspects of the comparability exercise.

3:00 CMO Selection for Cell & Gene Therapy

Chad Green, PhD, Principal & Senior Consultant, Dark Horse

As the diversity of CMOs available for cell and gene therapies continues to grow worldwide, identifying the most suitable to engage is becoming an increasingly complex challenge. This presentation will address fundamental questions, such as whether a CMO is even the best choice for manufacturing before progressing to provide concrete guidance on the critical questions to ask prospective CMOs (and yourself), how to ask them and how to analyze the answers and make an optimal, rational choice.

3:30 Close of Conference

Day 1 | Day 2 | Speaker Biographies

Continue reading here:
Gene Therapy Manufacturing – The Bioprocessing Summit

Recommendation and review posted by Jack Burke

Oncotype DX: Genomic Test to Inform Breast Cancer Treatment

The Oncotype DX test is a genomic test that analyzes the activity of a group of genes that can affect how a cancer is likely to behave and respond to treatment. The Oncotype DX is used in two ways:

Of all the breast cancer genomic tests, the Oncotype DX test hasthe strongest research behind it.

The results of the Oncotype DX test, combined with other features of the cancer, can help you make a more informed decision about whether or not to have chemotherapy to treat early-stage, hormone-receptor-positive breast cancer or radiation therapy to treat DCIS.

Genomic tests analyze a sample of a cancer tumor to see how active certain genes are. The activity level of these genes affects the behavior of the cancer, including how likely it is to grow and spread. Genomic tests are used to help make decisions about whether more treatments after surgery would be beneficial.

While their names sound similar, genomic testing and genetic testing are very different.

Genetic testing is done on a sample of your blood, saliva, or other tissue and can tell if you have an abnormal change (also called a mutation) in a gene that is linked to a higher risk of breast cancer. See the Genetic Testing pages for more information.

You may be a candidate for the Oncotype DX test if:

Most early-stage (stage I or II), estrogen-receptor-positive breast cancers that havent spread to the lymph nodes are considered to be at low risk for recurrence. After surgery, hormonal therapies such as an aromatase inhibitor or tamoxifen are prescribed to reduce the risk that the cancer will come back in the future. Whether or not chemotherapy is also necessary has been an area of uncertainty for patients and their doctors.

If youve been diagnosed with early-stage, estrogen-receptor-positive breast cancer, the Oncotype DX test can help you and your doctor make a more informed decision about whether or not you need chemotherapy. (Some research also suggests the test may help postmenopausal women with estrogen-receptor-positive breast cancer that has spread to the lymph nodes make chemotherapy decisions. Talk to your doctor if you are in this group.)

You also may be a candidate for the Oncotype DX test if:

DCIS is the most common form of non-invasive breast cancer. DCIS usually is treated by surgically removing the cancer (lumpectomy in most cases). After surgery, hormonal therapy may be recommended if the DCIS is hormone-receptor-positive. Radiation therapy may be recommended for some women. Doctors arent always sure which women will benefit from radiation therapy.

If youve been diagnosed with DCIS, the Oncotype DX test can help you and your doctor make a more informed decision about whether or not you need radiation therapy.

The Oncotype DX genomic test analyzes the activity of 21 genes that can influence how likely a cancer is to grow and respond to treatment.

Looking at these 21 genes can provide specific information on:

So, the Oncotype DX test is both a prognostic test, since it provides more information about how likely (or unlikely) the breast cancer is to come back, and a predictive test, since it predicts the likelihood of benefit from chemotherapy or radiation therapy treatment. Studies have shown that Oncotype DX is useful for both purposes.

Oncotype DX test results assign a Recurrence Score a number between 0 and 100 to the early-stage breast cancer or DCIS. You and your doctor can use the following ranges to interpret your results for early-stage invasive cancer:

The Oncotype DX DCIS score analyzes the activity of 12 genes. You and your doctor can use the following ranges to interpret your results for DCIS:

You and your doctor will consider the Recurrence Score in combination with other factors, such as the size and grade of the cancer, the number of hormone receptors the cancer cells have (many versus few), and your age. Together, you can make a decision about whether or not you should have chemotherapy or radiation therapy.

The Medicare program and several other major insurance companies have agreed to cover the Oncotype DX test. According to Genomic Health, about 90% of insured people in the U.S. are members of a plan that covers the test. If you discover that your plan does not cover the Oncotype DX test, talk to your doctor: he or she may be able to work with your insurance company to get coverage. If you have a low Recurrence Score and you and your doctor decide you do not need to have chemotherapy or radiation, your insurance company can save much more than the cost of the test.

Genomic Health also has started the Genomic Access Program to assist you with verifying insurance coverage and obtaining reimbursement. If you do not have or cannot secure insurance coverage, the Genomic Access Program still may be able to help. Various forms of financial assistance and payment plans are available for people facing financial hardships or those who are uninsured or underinsured. The Oncotype DX test costs about $4,000. For insurance- and payment-related questions, call 1-866-ONCOTYPE (1-866-662-6897) or by email at customerservice@genomichealth.com.

There are other genomics tests used to analyze breast cancer tumors. To learn more, click on the links below.

More here:
Oncotype DX: Genomic Test to Inform Breast Cancer Treatment

Recommendation and review posted by simmons

London Underground train life extension Rail Engineer

As is often seen on heritage railways, it is possible to keep old rail vehicles in service virtually indefinitely, although to do so often involves extensive repair and restoration work. Sometimes, circumstances are such that it is necessary for trains in front line operation to undergo similar extensive work.

It was with this thought in mind that Rail Engineer recently visited London Undergrounds project team to view some of the work taking place on the forty-year-old Bakerloo line trains to keep them in service for at least another 10 years.

Background

The Bakerloo line (Baker Street to Waterloo Railway) opened just over 110 years ago in 1906. Since then, it has been extended, had a branch opened, been truncated and eventually settled on its current route from Elephant and Castle in south east London to Harrow and Wealdstone in north east London. From Queens Park to Harrow and Wealdstone, it runs over Network Rails tracks, shared with London Overgrounds Class 378 trains.

Stabling sidings are provided at London Road, Lambeth, and at Queens Park. The main depot at Stonebridge Park is unique in that it is connected to Network Rails track and not to London Undergrounds.

The Bakerloo line is operated by a fleet of 36, seven-car, 1972 tube stock trains originally delivered in 1973/74. These trains are made up of a four-car unit and a three-car unit coupled together. They were designed for a nominal life of 36 years.

At 42 years, the Bakerloo trains are the oldest on the Underground, and amongst the oldest operating anywhere in the UK (other than heritage railways). Their design was based on the original Victoria line fleet, and has an aluminium-framed body with aluminium cladding mounted on a steel underframe.

They have four motor cars, each with four DC motors controlled by a camshaft-operated resistance controller and fitted with rheostatic braking. In addition, the entire train has electro-pneumatic brakes with a Westinghouse emergency brake, and there are electro-pneumatic sliding doors, and train protection is provided by tripcocks.

The fleet of 36 trains is made up of 33 Mk II and three Mk I units. The differences are superficial, and have mostly been eradicated over the years, but there are still some left to catch out anyone thinking they are all the same. They last had major work in the mid-1990s when they were refurbished an extensive visual modernisation whilst eliminating materials that were a fire hazard. For this work they were hauled over the National Rail network to the dockyard at Rosyth, which included travelling over the historic Forth Bridge.

The trains were originally planned for replacement by 2019 as part of the former PPP contracts, and then as the first use of the New Tube for London project. However, in 2013, London Underground decided to extend the life of the Bakerloo line trains to at least 2026.

Current projects

It was to understand more about what it takes to extend the life of a Tube train that Rail Engineer visited London Underground to talk to the project team and see the works over two days in May 2016.

The life extension project is just one of many projects that LU is carrying out on its older trains. LU has set up a Rolling Stock Renewals programme team to manage them all. The teams head, David Caulfield, outlined the various projects being carried out by his team. These include significant modifications to the Central line trains, upgrading 1960s and 1970s battery locomotives, and creating a Rail Adhesion Train (RAT) from some old District line cars to apply Sandite during the autumn leaf fall season.

The aim with all these projects is to keep older trains going to help Keep London Moving (from the Mayors Transport Strategy). David explained how LU is approaching these works.

LU has always carried out modifications to trains and has generally determined the sourcing strategy for each project on a one-off basis. For the future, LU has carried out a strategic review and has decided that it will invest in facilities to manage and execute work in house, bringing in specialist design and implementation resources or using in-house labour as appropriate.

This approach delivers a number of benefits including not having to send trains off site, which can add a week to each trains time out of service. LU train fleets achieve high utilisation and few trains are available to be taken out of service for modifications. An extra week in transit could add a year or more to a programme for fleets the size of LUs.

Bakerloo line

Back to the 42-year old Bakerloo line trains. One of the reasons that life extension was considered was, perversely, because extensive work was already under way to repair cracks and corrosion on the underframe and body. One might imagine these problems would hasten their demise, but the work was essential simply to keep the trains in service until the earliest date that new trains could be delivered.

In designing repairs, it is usually easiest to restore the original strength of the structure. It would be harder, and almost certainly no cheaper, to try and design repairs that would last just, say, five years. Thus the repair works deliver bodies that are structurally as good as new. As such, the work will easily last for the additional time required. Anything else necessary in sub-systems and components can and will be dealt with during routine maintenance, following proper engineering assessment of those components not normally replaced but being required to last beyond their normal lifespan.

The main consequence of extending the life beyond 2020 is the need to carry out modifications to comply with the Rail Vehicle Accessibility Regulations (2010). This contains similar requirements to those in the Technical Specification for Interoperability for People of Reduced Mobility TSIs do not apply to LU.

The RVAR work was explained by Paul Summers, project sponsor from the Asset Strategy and Investment team, and Zoe Dobell, RVAR project engineer (yes, my daughter!). The RVAR requires a number of features that make it easier to use such as handholds, passenger information displays, priority seats and provision for wheelchairs. Compliance is mandatory by 2020.

However, the Regulations recognise that strict compliance may not be possible for older trains. LU has therefore carried out extensive feasibility studies on the RVAR elements. These studies were then discussed with the Department for Transport with the aim of maximising the degree of compliance whilstnot incurring excessive cost for minimal benefit; DfT has been really supportive.

The main elements that will be installed are the wheelchair spaces (which will be in the trailer car of the three car unit), and an audio/visual passenger information system. The biggest challenge of all is the gap between the train and the platform. LUs practice on other lines is to use a mixture of platform humps and manual boarding ramps depending on the curvature and other factors. For the Bakerloo, LU has agreed with the DfT that no boarding aids will be provided where there is no interchange and no foreseeable prospect of providing street to platform step free access.

With agreement on all these features, the scope of the works is now frozen and work will start in mid-2018 for completion early in 2020, based on having two trains out of service at a time. To provide the wheelchair positions involves removing the seats on one side of the middle seat bay of the designated trailer cars. In common with all LU tube gauge cars, there is equipment under the seats this will have to be relocated and new flooring fitted to match the new floors being fitted as part of the body repairs (see below). Installing the passenger information system will involve work on all cars, and, although mandated by RVAR, will be of benefit to all passengers.

Acton Works

It was with considerable nostalgia that I set off from Acton Town station towards the large Acton Works complex, having first made that journey nearly 47 years ago.

The purpose was to see some of the repair works under way, a programme that will cost LU some 60 million or just over 200,000 per car. I was met by the underframe and body repairs project engineer Rob Bonarski, who is charged, inter alia, with making sure there is an approved repair system for every structural fault found.

Rob took me to shop AC15, which old timers like me will recall as the Heavy Repair shop. On the way, we visited some of the other workshops in which we saw Central line bogies being overhauled, Bakerloo line bogies being repaired, some battery locomotives being refurbished, D stock cars being converted for the new RAT and some 1938 tube stock cars being overhauled for the London Transport Museum.

Since I was last at Acton, AC15 shop has had extensive work carried out to prepare it for the Bakerloo line repairs. In former times, cars would have been lifted in Actons lifting shop and moved by traverser to the relevant workshop. This is no longer possible because the lifting shop was demolished many years ago to make way for LUs Railway Equipment overhaul Workshop (REW). The old wood block floor has been replaced with reinforced concrete to support the Mechan jacks that LU bought to lift the cars (four sets of 4 x 10 tonne jacks for passenger vehicles and one set of 4 x 20 tonne jacks that can also lift battery locomotives). There are nine roads, most of which can accommodate two cars. There has also been extensive work to improve lighting, and provide services for electric and pneumatic power tools.

Incompatible Train Movements

Bakerloo line trains start their journey for repairs at Stonebridge Park Depot in northwest London. From here, they make an overnight journey to Acton via Baker Street, Elephant and Castle, back to Baker Street, onto the Jubilee line to Wembley Park, onto the Metropolitan line to Rayners Lane, where they reverse and then travel via the Piccadilly line to Acton Town (see map right).

They travel overnight because there is no signalling nor train protection on the Jubilee line for Bakerloo line trains (Jubilee line trains use in-cab signalling with ATO and ATP). They travel over the Jubilee line section under special rules called an Incompatible Train Movement Plan.

On arrival at Acton Works, the cars are uncoupled on the reception road next to AC15 and moved via a traverser into AC15 where they are lifted. Here the real work starts.

Swan necks, floor traps and fasteners

Rob explained the voyage of discovery on the first few trains as they discovered the true extent of repairs required and the differences between apparently identical cars. Even he had been surprised by the extent of the work required, despite being involved since the beginning of the job. It soon became clear that what had to be done could only be confirmed, individually on each car, once they were stripped. During myvisit, they were working on train five, and Rob was confident that most of the problems had been discovered. Underframe swan neck repairs: Sole bars are straight, but the underframe also has two steel girders, approximately 300mm deep and 12mm thick, running the length of the car. In the main, as one would expect, the girders are under the floor but, over the bogies, this structure is above floor level and forms the seat risers for the longitudinal seats. The joint that connects the underfloor frame to the above floor frame is known as the swan neck. They are all cracked along the welds. The metal forming the joint is being cut out and replaced by a steel bracket of exactly the right shape machined from solid by WECS Precision of Epsom.

This allows welding to be carried out in locations where stresses are somewhat lower than they were in the original weld locations. The photo of the cut out section shows the cracks; anyone used to welding will not be surprised that they cracked.

Body pillars: Despite coatings applied during manufacture to protect against electrolytic corrosion between aluminium panels and the steel frame and underframes, the accumulation of moisture and cleaning fluids over 40 years has led to corrosion and cracks. These are being cut out and repaired. One of the challenges has been finding fittings that can be used in place of the hot rivets used on the original construction, especially where access is only available on one side. Fortunately, Alcoa Huck BOM fittings (rather like giant pop rivets) came to the rescue.

Body ends: Some of the body end brackets connecting the body end to the underframe have cracked. Investigations showed that many of the underframes were slightly distorted as a result of welding during manufacture and the brackets were adjusted to fit. They have cracked at the point of the adjustment. Rob explained that the replacements are being refitted with a metal putty being used to level the headstock plate.

Floors: The floor fitted during the 1990s refurbishment is a composite of polymer cladding and fire retardant ply on top of stainless steel in doorways and mild steel in seating bays. When the vehicles were stripped, it was found that the cladding was hiding a multitude of sins. The covering and ply is all stripped and the mild steel floor plates in the end seat bays are being replaced. From here, the entire floor is rebuilt with new fire retardant ply and a covering of Tiflex Treadmaster TM7 (see below). A feature of this era of tube train is trapdoors in the floor to access equipment on the underframe. One of the improvements made has been to rationalise the different designs of trapdoors used from 21 to seven.

Roofs: Over 40 years, some of the roof fasteners have become loose and these are being replaced by heavy duty blind fixings and fire retardant Terostat sealant (formerly Sikaflex).

Asbestos: Most of the materials containing asbestos are being replaced. Heat-barrier material is being replaced by Promat DURASTEEL, and the saloon heaters are being replaced by AmTecs low voltage heaters connected in series across the 600V traction supply.

Compressors: The three Mk I trains use a different, less reliable compressor than the remainder of the fleet, and the opportunity is being taken to replace them with compressors recovered from D stock trains (which are being replaced by S stock). This involves welding new mounts onto the underframe.

Drawings: As-built drawings lacked most of the detail necessary to source new parts and, as a result, over 600 new drawings have been produced.

The next challenge is to replace all the removed equipment, including the doors. The doors are a particular issue. Despite putting each door back in the same position from which it was removed, the scale of works on the vehicle has introduced small distortions that necessitate adjustments to each door so that it runs freely without binding.

From here its a case of testing each car, reassembling the vehicles into trains (in the right order!), testing as a train, and returning the trainto Stonebridge Park, from which it can enter service more or less immediately.

Rob told me that the plan is to increase the number of trains in work from one to two. This will have a great benefit in terms of both getting the work done more quickly and in terms of utilisation of the specialist teams who work on the trains. The repair work is due to be completed in 2018.

It was evident that the very high quality work being carried out will, in all probability, provide a structure that is stronger than new. The Bakerloo line structural repairs team are to be congratulated on what they have achieved.

Interior refresh

In parallel with the repair works, the interiors of the Bakerloo trains are being refreshed at Stonebridge Park Depot. Even things as apparently simple as new seat and floor coverings needed significant engineering input from the engineering team based in the LU operations department.

The seats, supplied by Pro Style, Coventry, had both to comply with modern fire standards and be comfortable. The floor had to be cleanable and slip resistant, and there is also a requirement to have a colour contrast between doorways and seating areas, to comply with the RVAR. Conventional wisdom was that the doorways had a higher footfall, would be more prone to dirt and so should be darker than seating areas.

In practice, cleaning around nooks and crannies in seating areas meant that the seated areas were not as clean as they ought to be, so following a trial, the lighter floor was specified for the doorway areas. In addition, to improve slip resistance, a new groove pattern was specified which also contributes to draining water from the floor to the outside.

On a final point, the observant reader might be wondering why the RVAR works were not merged with the weld repairs. It is simply a matter of urgency and timing. The structural repairs were urgent, couldnt be delayed and were under way before the decision was made to extend the life. In contrast, the RVAR works only became necessary as a result of the life-extension decision and a lot of feasibility work had to be completed before the scope could be decided and the works authorised. The teams are making every effort to make these two works streams as integrated as possible.

Thanks to LUs David Caulfield and his team, especially Guy Harris and Rob Bonarski, to Paul Summers from the Asset Strategy and Investment team, and to Sean Long from Operations LU Engineering for their assistance in preparing this article.

Written by Malcolm Dobell

See more here:
London Underground train life extension Rail Engineer

Recommendation and review posted by Jack Burke

The Ethics of Life Extension | TalkDeath

Be it through literature, film, or television, the idea of life extension has been nothing short of prolific. The concept has become so ingrained in our cultural psyche that most give its presence little thought. In North America, the average life expectancy today is 78 years of age. Even though our current life expectancy is much higher in the West than in other parts of the world, we nonetheless continue to be fascinated, and in some cases, obsessed with the idea of extending our lives beyond what is currently possible. Today when we hear of someone living to 100, it is considered almost miraculous. But as scientific developments continue to progress, the idea of life extension well beyond 100 may become a reality.

The average age a person could live until would increase to roughly 115 years old.

Scientific studies and technology have since developed even further, and brought hope to those seeking a way to extend human life. That being said, there a lot of questions that are raised when we think about life extension. Will everyone have an equal opportunity to benefit from these scientific discoveries? How will this affect the planet? Or society? Because of these questions, the pursuit of life extension is a highly controversial debate that will only become more important with the growth of technological advancements.

via http://www.viralnovelty.net

One of the underlying sentiments behindlife extension is the idea the life isgoodanddeath isbad. For those who are pro-life extension (life extensionists), this perspective is a response to our current experiences and expectations given our limited maximum lifespans. From their perspective, if we were able to live longer lives (and perhaps have better health throughout), this would change how, and if, we perceive deaths as tragic. If we couldlive to 150, woulddying at 90 make us feel the same sadness as it does today?

Another argument amongst life extensionists is thatdeath is a waste sincewe loseaccumulated knowledge, experiences, and memories. Scientist Victoria Stevenswas quoted as saying, “I think the prospect of death it just seems like an awful waste after people spend their lives learning and progressing” (source). For some life extensionists, prolonging human life allows us topreserve the memories and accomplishments of humankind, resulting in positive social consequences. For instance, people may feel a greater sense ofpersonal responsibility and accountabilityfor their actions if they lived longer. If we think about the current state of the environment, this point definitely strikes a chord. If we expect to live longer, we may be more likely to care about how our actions and behaviours influence others, ourselves, and the planet (no more of that, “let the next generation figure it out” mentality).

via http://www.img.rt.com

Not only wouldonly certainpeople in society be able to afford life extension, but certain societieswill be unable to afford itat all.

If humans were to somehow have indefinite life spans, the question of life’s meaning may become even more complex and confoundingthan it already is. And what would we do with the time that we have? Though it may seem to open us up to endless possibilities, the reality is that our lives would be similar to how they are now – just longer. We would have the same joys, but also the same struggles.

via http://www.iacpublishinglabs.com

There is also the argument that life extension technologies and treatments will createsocial problemsdue to the likely cost of these services. At first, they will undoubtedly be very expensive, essentially meaning that they wouldonly beaccessible to higher-incomeindividuals.This presents society with a wholemyriad of issues, as only certainpeople in society would be able to afford life extension, and certain societies (such as third worldcountries, for instance) would be unable to afford itat all. This couldcause greater social inequality, and greater social unrest. Disparities between rich and poor individuals, communities, and countries wouldgrow – the implications of which we cannot possibly know or predict. But it’s likely safe to say that whatever these implications would be, they would not be positive.

There are alsoenvironmentalconcerns to consider. Our planet is suffering greatly from climate change. Earth is over-populated, and does not have enough natural resources to continue to support the current population (that is growing exponentially each year!) So, if life extension is thrown into the mix, what does this mean? If everyone is able to live longer lives, there would have to be entire generations of human beings that were unable to reproduce in order to avoid further overcrowding our world. We would also have to reevaluate how our resources are distributed and preserved. Needless to say, there would have to be a great deal of thinking and rethinking regarding our planet’s population and use of resources in order for life extension to be at all a reasonable pursuit.

via lamcraft.wordpress.com

According to scholar Shai Lavi, one of the biggest changes in the 20th century was the way that death came to be seen as a failure, while medicine and science offered an intelligible hope in the face of a hopeless existence. While life extensionists want to showcase a highly optimistic future, the arguments against extending life are worthy of serious consideration. Our new will to master death goes hand-in-hand with the ways in which we avoid death. But as those in the Death Positive movement have tried to argue, death acceptance can bring us a long way towards fulfillment in life, and even hope in death (to say nothing of the role of religion in this respect).

A shift in our values and ethics will be unavoidable in the face of such a dramatic change in the way we live. Additionally, even if we live until 178 instead of 78, human beings are still just that: humans. Radical life-extensionist Aubrey de Grey acknowledges that humans will always be subject to violence, war, suicide, and accidents (Source). Life extension is not the same as invincibility. The extension of our human lives may makeus feel more than human, but that is what we will remain all the same.

With these arguments in mind, and regardless of which side of the debate you are on, it is important to consider how life extension will affect how human beings think about themselves and each other.

Originally posted here:
The Ethics of Life Extension | TalkDeath

Recommendation and review posted by simmons

The Gene Therapy Plan: Taking Control of Your Genetic …

Praise for The Gene Therapy PlanA guide to harnessing the power hidden in food to subvert a genetic predisposition for disease. . . . Gaynors informative tome is worth reading. Publishers Weekly

The Gene Therapy Plan identifies how the lives we lead, and in particular, the foods and nutritional supplements we ingest, are a key determining factor in whether latent disease (which most people have to some degree) materialize or stay dormant. By identifying researched nutritional protocols that target specific conditions, and by providing a range of rich case studies from his practice as a leading oncologist and internist, Dr. Gaynor provides insight and an action plan into how the body operates that will benefit medical practitioners and patients alike. Deepak Chopra, M.D.The Human Genome Project promised to create a new era of genetic medicine, new drugs, and therapies to advance human health. But the real awakening has been the understanding of foodreal whole foods, herbs, phytonutrientsas medicine and how it can literally upgrade your biologic software by improving the expression of your genes.In The Gene Therapy Plan Dr. Gaynor makes the healthcare of the future available to you today. If you want to learn how to use food and nutrients to prevent and even reverse most chronic disease, read this book! Mark Hyman, M.D., Director of the Cleveland Clinic Center for Functional Medicine and author of the #1 New York Times bestseller The Blood Sugar SolutionThe Gene Therapy Plan is a comprehensive and practical approach to the science of epigeneticsand how to apply it to your life right now. This book is a godsend that could save your life. Christiane Northrup, M.D., author of the New York Times bestseller Womens Bodies, Womens WisdomA brilliant and important piece of work from one of our most distinguished and creative medical thinkers. Do yourself and your family a huge favor: Read this phenomenally important book and learn why and how you can live a healthier life. Devra Davis, Ph.D., M.P.H., founder and president of the Environmental Health Trust, author of The Secret History of the War on CancerDr. Gaynor is a visionary healer. This is a comprehensive, coherent, practical, and easily digestible resource for all who wish to tip the balance away from disease toward health and wellness. Sheldon Marc Feldman, M.D., Vivian L. Milstein Associate Professor of Clinical Surgery, Columbia University College of Physicians and SurgeonsDr. Gaynor presents a comprehensive strategy for readers to re-orient their diet and lifestyle using everyday activities that can help one live longer, and live better. With The Gene Therapy Plan, Dr. Gaynor brings his own integrative philosophy and practice to readers in an engaging and actionable way. William Li, M.D., president and medical director of The Angiogenesis FoundationDr. Gaynor has and always will be at the forefront of integrative medicine. The Gene Therapy Plan empowers you to take control of your health and life. Mimi Guarneri, M.D., president of the Academy of Integrative Health and Medicine

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The Gene Therapy Plan: Taking Control of Your Genetic …

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GeoGene: Gene Therapy, What it is, The process and Vectors …

What is Gene Therapy?

Certain diseases are caused byfaulty genes which produce defective proteins. The symptoms of genetic disease are the result of subsequent disrupted vital cell processes caused by missing or defective proteins. In theBio Building Blockssection of this web-site, protein synthesisis outlined as the process whereby,genesultimately give rise toproteinswhich are responsible for important cell processes. If a particular gene is defective, its protein product may not be made at all, may work poorly or may behave too aggressively.

For example:Cystic Fibrosis(CF) is caused by amissing or mutated genethat results in adefective cell membrane transport protein. This ultimately results in a build-up of thick mucus in the lungs and the body’s airways.As another example,cancersare caused by cells that divide and grow uncontrollably.Particular genes can cause such cell growth to occur if they are defective. Such defective genes are calledoncogenes.

Are we treating the symptom or treating the cause? Historically, genetic disorders have been treated byaddressing the biological eventsthat result from the genetic mutation, as opposed tofixing a defective gene(or genes) the ultimate source of the problem.For example, the treatment of diabetes has historically involved the administration of insulin (a protein), instead of fixing the defective genes in pancreatic cells that actually prevent these cells from producing insulin in the proper amounts, on their own.

Gene therapy is an alternative approach whereby a genetic disorder is treated by inserting or integrating new genes into human cells. Many attempts at gene therapy aim to add a useful gene into a selected cell type to compensate for a missing or defective version. Other efforts aim to instill new properties in the target cell. This latter method is often employed in the treatment of cancer, where toxic genes are added to cancer cells in an effort to eliminate them.For an overview of how a specific gene is located and isolated from its source (so that it can be introduced into the patient) see ourGenetic Engineeringsection.

It should be noted that even the most advanced somatic cell therapy techniques are still in clinical trials, and are not yet approved for general application. Much more research is required to develop safe, reliable gene therapy techniques.

Depending on the cell types affected, gene therapy can be classified into two broad categories: germ-line gene therapy and somatic cell gene therapy.Germ-line therapyoccurs when germ cells (reproductive cells) are altered, meaning that the resultinggenetic changes will be passed on to the patient’s offspring. Alternatively,somatic cell gene therapyinvolves the alteration of somatic cells (non-reproductive body cells, like skin, brain or muscle cells). This genetic manipulation willonly affect the individualto which the changes were made. Somatic cell gene therapy is the only type presently being considered in humans.

Suppose a patient is afflicted with a genetic disorder that affected only certain cells in her or his brain. How could she or he be treated using gene therapy so that the therapeutic gene targets only those cells affected by the disorder? One solution is through the use of avector. A vector is simply a “transporter” for the genetic material that allows it to enter the target cell and, depending on the vector type, can cause new genes to be integrated into the host cell genome. Vectors must be administered totarget specific cell types.

There are three principal ways in which vectors can be administered to carry new genes into target cells. The first is calledex vivosomatic gene therapy, wherethe target cells are removed from the body, cultured in the laboratory with a vector, and re-inserted into the body. This process is usually carried out using blood cells because they are the easiest to remove and return.

The second option,in situsomatic gene therapy, occurs when thevector is placed directly into the affected tissue. This process is being developed for the treatment of cystic fibrosis (by direct infusion of the vector into the bronchi of the lungs), to destroy tumours (eg: brain cancer), and for the treatment of muscular dystrophy.

The third option isin vivosomatic gene therapy, where thevector is injected into the bloodstream, and is able to find and insert new genes only into the cells for which it was specifically designed. Although there are presently noin vivotreatments available, a breakthrough in this area will make gene therapy a very attractive option for treatment.In this case the vector designed to treat our hypothetical patient could be injected into a blood vessel in her or his arm and would find its way to the affected brain cells!

Vectors used in gene therapy can be classified as eitherviralornon-viral.

BothDNAandRNAviruses are being developed as vectors for use in gene therapy. Viruses are an excellent choice for use as vectors, because they have gained, through long periods of evolution, the ability to avoid destruction by the human immune system, and the capacity to get their own genetic material inside human cells. As discussed in theBio Building Blockssection, viruses consist of genetic material (DNA or RNA) surrounded by a protective coat made of proteins and occasionally other molecule types as well.

Normally, a virus infects a cell when its genetic material enters it. Once the viral genetic material is inside, it “hijacks” the cell’s DNA- and protein-making machinery, causing it to produce new viruses. Some viruses are even capable of integrating their own genetic material into the host cell’s genome.

It is the outer protective viral coat that allows the inner genetic material to penetrate the cell. This outer coat also determines the type of cell that a given virus will infect. Once inside, it is the harmful viral genes that actually hijack the cell and eventually cause it to die.

To trick the virus, scientists retain the outer viral coat, but modify the inner genetic material. They remove the harmful genes and replace them with therapeutic ones. Now the virus ispathogenically disabled(it is no longer harmful to the cell it infects) and incapable of reproducing itself. However, it retains its capability to transfer its genetic material to the cells for which its outer coat was designed.The transfer of genetic material by way of a viral vector is calledtransduction.

The structure and mode of infection of retroviruses is discussed in theBio Building Blockssection. Briefly, retroviruses have RNA as their genetic material. These viruses also carry a specialenzymethat, once inside a cell, makes double-stranded DNA from the virus’ RNA template. The new DNA becomes incorporated into the host cell’s genome. When the “new” chromosomal genes are transcribed, new virus particles are made, which will leave the cell to infect other cells.

Most types of retroviruses are not very harmful to the cell. Even though allviruses to be used as vectors are deactivated,’ meaning that their harmful genes are removed, the fact that the types of retroviruses presently being used as vectors are not very harmful in their natural forms means that their use poses less risk than the use of some other viruses. Even if something goes wrong and some of the original retrovirus particles are administered to the patient, they will not cause serious problems.

Themurine leukaemia virus(MuLV) is one of the more popular retroviruses used as a retroviral vector. The reproductive genes in the retrovirus are replaced with the therapeutic gene. When the virus infects the cell,the therapeutic gene gets incorporated into the cell chromosomes. The new gene causes a protein to be produced which is hoped to have some positive therapeutic effects, either providing an otherwise missing protein, or causing the destruction of harmful cells.

There are several challenges that scientists must overcome for effectivein vivotreatment of disease using retroviral vectors. For example, theviruses must be capable of targeting only those cells affected by the disorder. If this were the case, they could be injected directly into the bloodstream (in vivogene therapy) where they would become dispersed throughout the body, but would only transduce those cells for which they were designed. Presently, retroviral vectors are not terribly specific, meaning that many cells not intended for the transfer of the gene are transduced by the virus, which reduces the transfer to the targeted cell population.

To understand how viruses can be made to be more specific, we should considerhow viruses “choose” the cells they infect. A virus must bind to specific surface receptor molecules to gain entry into a cell. To this end, retroviruses have outer envelope proteins that fit perfectly into certain receptors on specific cells. The MuLV virus binds to cells containing a receptor called theamphotropic receptor. The problem is that a broad range of cell types possess the amphotropic receptor. This means that the MuLV virus, in its natural form, can infect all of these cell types, most of which are likely not the target of the therapy!

To make retroviral vectors more specific about the cells they invade, scientists are experimenting with ways ofreplacing or modifying the outer viral proteins, so that they fit into more rare receptors that appear only on specific cell types being targeted for therapy.Another approach has been toadd new proteinsto the outer viral envelope which either better recognize the target cell, or better recognize the region of the body where the target cells are located.

Another challenge is toengineer retroviral vectors to transducenon-dividingcells. Most retroviruses target actively dividing cells, which makes them ideal for the treatment of rapidly dividing tumour cells, but not in situations where a therapeutic gene is to be introduced into a non-dividing cell, like in the treatment of cystic fibrosis mentioned above. Those few retroviruses that have the ability to infect non-dividing cells are the harmful ones (HIV, the virus that results in AIDS, is one of them). HIV viruses (with their harmful genes removed) cannot be used as vectors, because even with the removal of these genes, there is still a possibility that the virus might become harmful again through a process called recombination. To virtually eliminate the possibility that harmful viruses are produced in this way, while still harnessing the capability of HIV to transduce non-dividing cells, scientists are experimenting with the development of hybrid vectors, made up mostly of other retroviruses and which contain very small and harmless parts of the HIV virus.

As of April, 1998, there was only one vector-based therapeutic technique in the final clinical trial stage(called Phase III). This technique employs a retroviral vector called G1TkSvNa for the treatment ofglioblastoma multiforma, a malignant brain tumour. The treatment is an in situ therapeutic technique, where mouse cells capable of producing and secreting the vector are injected into the tumour.The secreted vectors infect only those cells that are rapidly dividing, meaning only the tumour cells and the vessels supplying blood to the tumour are transduced. The gene transduced into the tumour cells gives rise to a protein (calledHerpes Simplex Thymidine Kinaseor HSTk).Fourteen days later, a drug called ganciclovir is injected into the patient, which is toxic to any cell that incorporates it into its DNA. Only the cells containing HSTk (the tumour cells) are capable of incorporating ganciclovir into their DNA and these cells are therefore selectively killed off.

Adenoviruses are DNA viruses that are able to transduce a large number of cell types, including non-dividing cells. Adenoviruses also have the capacity to carry long segments of added genetic information. In addition, it is fairly easy to produce large amounts of adenoviruses in culture. Adenoviruses, in their natural form, are not very harmful, typically causing nothing more serious than a chest cold in otherwise healthy people. This means that their use as vectors is quite safe. For all these reasons, adenoviruses are currently the most widely used DNA vectors for experiments inin situgene therapy.Research is currently under way using adenoviral vectors for the treatment of several cancers and cystic fibrosis.

The size of the adenovirus protein coat is just large enough to fit the original viral DNA inside. As a result, for every new therapeutic gene to be inserted into the viral genome, a corresponding piece of the old viral DNA must be removed.To make room for the new therapeutic DNA, a region of the old viral DNA called E3 is sometimes removed. However, removing the E3 region has drawbacks, because it codes for a protein that suppresses the human immune response against the vector. Without the E3 region, the virus is more susceptible to the immune system and is more likely to be destroyed before it has served its purpose.

Adenoviral vectors send their DNA to the nucleus, butthe DNA does not get incorporated into the host cell’s chromosomes. For this reason, the viral DNA has a finite lifetime within the cell before it is degraded, meaning that the added genes are effective only temporarily. Treatments for chronic conditions like cystic fibrosis, therefore, would need to be repeated periodically, perhaps on a monthly or yearly basis. On the other hand, the transient nature of therapeutic gene expression is useful when the added genes are needed temporarily to induce an immune response to a cancer or pathogen.

Among the other virus types being explored as vectors are theadeno-associated virus(AAV) and theherpes simplex virus(HSV). Both are DNA-based viruses. AAV integrates its genetic material into a host chromosome and cause no diseases in humans. However, because AAV are small, they cannot accommodate large genes. HSV vectors do not integrate their genes into the host genome. They tend to target neurons and thus have the potential for use in the treatment of neurological disorders.

The use of non-viral vectors can involve a direct injection ofplasmid DNAor mixing plasmid DNA with compounds that allow it to cross the cell membrane and protect the DNA from degradation. These methods are currently less efficient than the use of viral vectors. However, unlike disabled viruses which have the possibility of changing spontaneously and causing disease, non-viral vectors possess no viral genes and therefore cannot cause disease.

Liposomes are small, hollow spheres of fatty molecules that are capable of carrying DNA inside of them.A liposome can fuse with the cell membrane, releasing its contents into the cell interior.

Plasmid DNA containing the therapeutic gene is incubated with the empty liposomes under specific conditions. The negatively charged DNA binds to the positively charged (calledcationic) liposomes and the plasmids are absorbed. Liposomes containing plasmid DNA are calledlipoplexes.The lipoplexes can subsequently enter the cells of interest, and thus introduce the therapeutic DNA into the cells.

Experiments have been carried out where lipoplexes have been injected into tumours. The lipolexes contained a gene that gives rise to a protein that is recognized by the human immune system. Theoretically, thesegenes should cause the tumour cells to express the recognizable protein on their surface, which will mark the cells for destructionby the immune system.

The use of lipoplexes for the treatment of cystic fibrosis is currently being studied as well. The cause of the illness is a defective gene which causes a particular protein in the patient’s lung cells to be defective. The lipoplexes that are administered using an aerosol spray into the patient’s lungs, contain the gene for a functional version of the protein.

Lipoplexes are not as efficient as viral vectors in introducing genes into cells. To improve their efficiency, scientists are attempting to incorporate some viral proteins into the outer surfaces of lipoplexes. In particular, the viral proteins that recognize and bind to specific molecules on the host cell’s surface, are being incorporated.

Muscle cells have been shown to be capable of taking up and expressing plasmid DNA. This raises the possibility that plasmid DNA injected into muscles could stimulate the production by muscle cells of a therapeutic protein. This protein could then be secreted into the bloodstream and to the rest of the body. For example, the gene coding for erythropoietin (a protein which helps stimulate the production of red blood cells) has been experimentally injected into animal muscles with some success. Such a treatment would be useful to patients after chemotherapy or radiation therapy.

In addition,plasmid DNA shows promise for use in vaccines, stimulating protective immune responses against diseases like herpes, AIDS or malaria. When the plasmid DNA is injected into muscles, it enters muscle cells and as a result, causes the cells to produce the proteins that correspond to the genes the plasmids contain. The immune system will then learn to recognize the new proteins and will destroy them if they are encountered in the future. Experiments are currently under way where plasmids containing genes for viral coat proteins are injected, in attempt to make the immune system recognize these viruses, so that it will attack and destroy them if they are ever encountered.

As discussed in theBio Building Blockssection, viruses hijack cellular machinery to produce their own proteins and to replicate their genetic material, which results in the production of new viruses.One of the potential uses of antisense technology is to prevent viruses that infect a host cell from producing their own proteins. This would, in turn, prevent their replication.

Recall that proteins are constructed through atwo step process. In the first step,DNA is transcribed to produce messenger RNA(mRNA). The second step involves thetranslation of the mRNA to make a protein. Antisense drugs interact with mRNA, preventing them from being translated into their corresponding protein.

An mRNA molecule is a chain of nucleotides, that gets “read” by a ribosome in the synthesis of a protein. An antisense drug is anoligonucleotide(a relatively small, single stranded chain of nucleotides) that iscomplementaryto a small segment of a target mRNA molecule. When the drug comes into contact with its complementary mRNA, it binds to the mRNA in the same way as the two strands of a DNA molecule bind together.This makes the mRNA “unreadable” by the ribosome, and so no protein is produced.

Because an antisense drug is designed to be complementary to a particular mRNA sequence that is specific to a particular virus’ mRNA, it will not interfere with any of the host cell’s naturally produced mRNA, meaning that the side effects of the drug are minimal.

At the end of August, 1998, the US Food and Drug Administration (FDA) approved a drug calledformivirsenfor the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS.This makes formivirsen the first antisense drug on the market.Formivirsen blocks the replication ofcytomegalovirus(CMV) which causesretinitis, an eye infection leading to blindness that mainly affects AIDS patients. The drug is periodically injected into the patient’s eye, and is claimed to cause only mild side-effects as compared to some other antiviral drugs.

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GeoGene: Gene Therapy, What it is, The process and Vectors …

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Bone marrow suppression – Wikipedia

Bone marrow suppressionSynonymMyelotoxicity, myelosuppression

Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (thrombocytes).[1] Bone marrow suppression is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine.[2] The risk is especially high in cytotoxic chemotherapy for leukemia.

Nonsteroidal anti-inflammatory drugs (NSAIDs), in some rare instances, may also cause bone marrow suppression. The decrease in blood cell counts does not occur right at the start of chemotherapy because the drugs do not destroy the cells already in the bloodstream (these are not dividing rapidly). Instead, the drugs affect new blood cells that are being made by the bone marrow.[3] When myelosuppression is severe, it is called myeloablation.[4]

Many other drugs including common antibiotics may cause bone marrow suppression. Unlike chemotherapy the affects may not be due to direct destruction of stem cells but the results may be equally serious. The treatment may mirror that of chemotherapy-induced myelosuppression or may be to change to an alternate drug or to temporarily suspend treatment.

Because the bone marrow is the manufacturing center of blood cells, the suppression of bone marrow activity causes a deficiency of blood cells. This condition can rapidly lead to life-threatening infection, as the body cannot produce leukocytes in response to invading bacteria and viruses, as well as leading to anaemia due to a lack of red blood cells and spontaneous severe bleeding due to deficiency of platelets.

Parvovirus B19 inhibits erythropoiesis by lytically infecting RBC precursors in the bone marrow and is associated with a number of different diseases ranging from benign to severe. In immunocompromised patients, B19 infection may persist for months, leading to chronic anemia with B19 viremia due to chronic marrow suppression.[5]

Bone marrow suppression due to azathioprine can be treated by changing to another medication such as mycophenolate mofetil (for organ transplants) or other disease-modifying drugs in rheumatoid arthritis or Crohn’s disease.

Bone marrow suppression due to anti-cancer chemotherapy is much harder to treat and often involves hospital admission, strict infection control, and aggressive use of intravenous antibiotics at the first sign of infection.[citation needed]

G-CSF is used clinically (see Neutropenia) but tests in mice suggest it may lead to bone loss.[6][7]

GM-CSF has been compared to G-CSF as a treatment of chemotherapy-induced myelosuppression/Neutropenia.[8]

In developing new chemotherapeutics, the efficacy of the drug against the disease is often balanced against the likely level of myelotoxicity the drug will cause. In-vitro colony forming cell (CFC) assays using normal human bone marrow grown in appropriate semi-solid media such as ColonyGEL have been shown to be useful in predicting the level of clinical myelotoxicity a certain compound might cause if administered to humans.[9] These predictive in-vitro assays reveal effects the administered compounds have on the bone marrow progenitor cells that produce the various mature cells in the blood and can be used to test the effects of single drugs or the effects of drugs administered in combination with others.

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Bone marrow suppression – Wikipedia

Recommendation and review posted by sam

What Is CRISPR? – CB Insights

CRISPR. What is it? And why is the scientific community so fascinated by its potential applications? Starting with its definition, we explain how this technology harnesses an ancient bacteria-based defense system and how it will impact the world around us today.

Imagine a future where parents can create bespoke babies, selecting the height and eye color of their yet unborn children.In fact, all traits can be customized to ones preferences: the size of domestic pets, the longevity of plants, etc.

It soundslike the backdrop of a dystopian science fiction novel. Yet some of this isalready happening.

Since its initial discovery in 2012, scientists have marveled at the applications of CRISPR (also known as Cas9 orCRISPR-Cas9).

And with a Jennifer Lopez-produced bio-terror TV drama called C.R.I.S.P.R. on the horizon, CRISPR has reached a new peak in interest from outside the scientific community.

CRISPR may revolutionize howwe tackle some of the worlds biggest problems, like cancer, food shortages, and organ transplant needs.Recent reports even examineits useasa highly efficient disease diagnostics tool. But, as with any new technology, it may also cause new unintended problems.

Changing DNA the code of life will inevitably come with a host ofimportant consequences. But society and industry cant have this conversation without understanding the basics of CRISPR.

In this explainer, we dive into CRISPR, from a simple explanation of what exactly it is to its applications and limitations.

CRISPR is adefining feature of the bacterial genetic code andits immune system,functioningas a defense system that bacteria use to protect themselves against attacks from viruses. Its also used by organisms in the Archaea kingdom (single-celled microorganisms).

The acronym CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. Essentially, it is a series ofshort repeating DNA sequences withspacers sitting in between them.

In short,bacteria usethese geneticsequences to remember each specific virus that attacks them.

They do this byincorporatingthe virus DNA into their own bacterial genome. Thisviral DNA ends up as the spacers in the CRISPR sequence.This method then gives thebacteria protection or immunity when a specific virus tries to attack again.

Accompanying CRISPR are genes that are always located nearby, called Cas (CRISPR-associated) genes.

Once activated, these genes make special proteins known as enzymes that seem to have co-evolved with CRISPR. The significance of these Cas enzymes is their ability to act as molecular scissors that can cut into DNA.

To recap: in nature,when a virus invades bacteria, its unique DNA is integrated into a CRISPR sequence in the bacterial genome. This means that the next time the virus attacks, the bacteria will remember it and sendRNA and Cas to locate and destroy the virus.

While there are other Cas enzymes derived from bacteria that cut out viruses when they attack bacteria, Cas9 is the best enzyme at doing this in animals. The widely-known term CRISPR-Cas9 refers to a Cas variety beingused to cut animal (and human) DNA.

Inharnessing this technology, researchers have added a new step: after DNA is cut by CRISPR-Cas9, a new DNA sequence carrying a fixed version of a gene can nestle into the new space. Alternatively, the cut can altogether knock out ofa particular unwanted gene for example, a gene that causes diseases.

Oneway to think about CRISPR-Cas9 isto compare it to theFind & Replace function in Word: itfinds thegenetic data (or word)you want to correct and replaces it with new material. Or, as CRISPR pioneer Jennifer Doudna puts it in her book A Crack In Creation: Gene Editing and the Unthinkable Power to Control Evolution, CRISPR is likea Swiss army knife, with different functions depending on how we want to use it.

CRISPR research has moved so fast that its already gone beyond basic DNA editing. In December 2017, the Salk Institute designed a handicapped version of the CRISPR-Cas9 system, capable of turninga targeted gene on or off without editing the genome at all. Going forward, this kind of process could ease the concerns surrounding the permanent nature of gene editing.

These are the 3 key players that help theCRISPR-Cas9 tech do its work:

Below, we illustrate how these parts come together to create a potential therapy.

Please click to enlarge.

The guide RNAserves as the GPS coordinates for finding the piece of DNA you want toedit and zeroes in on the targeted part of the gene. Once located, Cas9, the scissors, makes a double stranded break in the DNA, and the DNAyou want to insert takes its place.

The implications for this are vast.

Yes, this technology will disrupt medical treatment. But beyond that, it could also transform everything from the food we eat to the chemicals we use as fuel, since these may be engineered through gene technology as well.

Feng Zhang, PhD, from the Broad Institute of MIT and Harvard, describedCRISPR using a helpful nursery rhyme. We can imagine a certainDNA sequence that is fixed in this way:

Twinkle Twinkle Big Star Twinkle Twinkle Little Star

In this process:

The CRISPR sequence was first discovered in 1987. But its function would not be discovered until 2012.

Keypeople involved in the initial discovery of the bacterial CRISPR-Cas9 systems function include Jennifer Doudna, PhD at University of California, Berkeley, and French scientist Emmanuelle Charpentier, PhD. Through their strategic collaboration, they ushered in a new era of biotechnology.

Another important figure is Feng Zhang, PhD, who was instrumental in figuring out CRISPRs therapeutic applications using mice and human cells in 2013.Harvard geneticist George Church, PhDalso contributed to early CRISPR research with Zhang.

All four researchers went on to play crucial roles in setting up someof the most well-funded CRISPR therapeutic startups, includingEditas Medicine, CRISPR Therapeutics, and Intellia Therapeutics.All 3 of these companiesIPOed in 2016 and are in the drug discovery/pre-clinical stage of testing their respective CRISPR therapeutic candidates for various human diseases.

Before CRISPR was heralded asthegene editing method, two other gene-editing techniques dominated the field: Zinc Finger Nucleases (ZFNs) and Transcription Activator-Like Effector Nucleases (TALENs). Research efforts using these tools are still ongoing.

Like CRISPR, these toolscan each cut DNA. Thought they are generally more difficult to make and use, these tools do offer their own advantages:

Each also has vital therapeutic applications.

Biotech companyCellectis uses the TALEN gene editing technology to make CAR-T therapies for leukemia, whileSangamo BioSciencesmakes ZFNs that can disable a gene known to be key in HIV infection.Notably, each of these companies hold key IP rights to these specific gene-editing methods, which could make it difficult for other biotech companiesto use these tools.

Meanwhile, CRISPR has certainly stolen the spotlight as of late, due to its efficiency, flexibility, and cheap price tag. Itsplausible that CRISPR could face similar IP issues and there are already some IP controversies going on but with such vast applications for this system, research on multiple fronts seems to be moving forward fast.

Every industry can harnessCRISPR as a tool: itcan create new drug therapies for human diseases, help farmers grow pathogen-resistant crops, create new species of plants and animals and maybe even bring back old ones.

Since the initial discovery of CRISPR as a gene-editing mechanism, the list of applications has grown rapidly. Though still in early stages, animal models (i.e. lab animals) have provided key insights into how we may be able to manipulate CRISPR.

Mice have been especially telling when it comes to CRISPRs therapeutic potential. As mammals sharing more than 90% of our human genes, mice have been used as ideal test subjects.

Experiments on mice haveshown that CRISPR can disable a defective gene associated with Duchenne muscular dystrophy (DMD), inhibit the formation of deadly proteins involved in Huntingtons disease, and eliminate HIV infection.

In 2015, Chinese scientists created two super muscular beagles by disabling the myostatin gene, which directs normal muscle development. In the absence of thegene, the beagles displayed muscular hypertrophy, creating dogs which were visibly much more muscular than non-genetically modified ones.

Other CRISPR animal trials haveranged from genetically engineering long-haired goats for higher production of cashmere to breeding hornless cows to avoid the painful process of shearing horns off.

Compared to research involving animals, CRISPR trialsthat edit human DNA have movedmore slowly, largely due to the ethical and regulatory issues at play.

Given the permanent nature of altering a humans genome, the FDA is approaching CRISPR cautiously. Some scientists have even proposed a moratorium on CRISPR trials untilwe have more information on the potentialimpact on humans.

In the US and Europe, 2018 will be the year for CRISPR human trials.

Currently (as of 2/13/18),the University of Pennsylvania is awaiting the FDAs final approval to start a study that would evaluate the safety of using CRISPR for patients with multiple myeloma, melanoma, and sarcoma.

Europe may also see its first human CRISPR study in 2018 withCRISPR Therapeutics study focused on a blood disorder known as beta-thalassemia,which results in abnormal red blood cell production.

While clinical trials involving patient participation are still awaiting regulatory approval, CRISPR has already been applied to both viable and non-viable human embryos.

For example, in August 2017, a team lead by reproductive biologist Shoukhrat Mitalipov of Oregon Health and Science University received private funding to use CRISPR-Cas9 to target a mutation in viable human embryos that causes the thickening of heart muscles. The altered embryos came back 72% mutation-free in the lab (higher than theusual 50% chance of inheritance).

Some critics say the gene editing of embryos is unethical, even if the edited embryos are not destined for transfer and implantation. This type of testing currently does not receive federal funding, but instead relies on private donor funding.

On the other side of the world, Chinese researchersoperate under a different regulatory framework. Some hospital ethics committees can approve studies in as little as one day, with no need to seek approval from a federal agency.

Since 2015, China has been conductinghuman trials using CRISPRto combat various cancers, HIV, and HPV. It is the only country in the world toconduct human trials thus far.

According to ClinicalTrials.Gov, there are 10 active or upcoming CRISPR therapy trials in China, targeting advanced cancers like stage 4 gastric and nasopharyngeal carcinomas. So far results are only anecdotal, and while some participants tumors shrank, no formal results have been made available.

Although possible long-term side effectsarent fully understood,CRISPR is already an option for some patients in China who have exhausted all of the conventional treatments.

Potential high impact industries for CRISPR include medicine, food, agriculture, and the industrial biotech space. BecausetheCRISPR-Cas9 gene-editing system issoeasy to make and use, researchers from a range of scientific disciplines can access it to genetically engineer the organism of their choice.

The future of medicine will be written with CRISPR.

The current drug discovery process is long, given the need to ensure patientsafety and gain a thorough understanding of unintended effects.Moreover, current US regulatory policies often result in a decades-long development process.

However, teamsusing CRISPR can bringcustomized therapies to market more quickly than was previously dreamed, speeding upthe traditional drug discovery process.

Timeline of drug development. Credit: PhRMA

CRISPRscheap price tag and flexibilityallows accurate and fast identification of potential gene targets for efficient pre-clinical testing. Because itcan be used to knock out different genes, CRISPR givesresearchers a faster and more affordableway to study hundreds of thousands of genes to see which ones are affected by a particular disease.

Of course, alongwith providing a more streamlined drug development process, CRISPR offers the possibility of new ways to treat patients.

For example,monogenic diseasesdiseases caused by a mutation ina single gene present an attractive starting point for CRISPR trials. The nature of these illnesses provides an exact target for the treatment: the problematic mutation on a single gene.

Blood-based, single-gene diseases like beta-thalassemia or sickle cell are alsogreat candidates for CRISPR therapy, because of their ability to be treated outside of the body (known as ex-vivo therapy). A patients blood cells can be taken out, treated with the CRISPR system, then put back into the body.

An earlyapplication of CRISPR was pioneered by yogurt company Danisco in the 2000s, when scientists used an early version of CRISPR to combat a key bacterium found inmilk and yogurt cultures (streptococcus thermophilus) that kept getting infected by viruses. At that point, the ins and outs of CRISPRwere still unclear.

Fast forward to today, when climate change will further increasethe need to use CRISPR to protect the food and agriculture industries against new bacteria.For example, cacao is becoming difficult to farm as growing regions get hotter and drier. This environmental change will further exacerbate the damage done by pathogens.

If youve eaten yogurt or cheese, chances are youve eaten CRISPR-ized cells.

Rodolphe Barrangou, former Daniscoscientist & Editor-in-Chief of The CRISPR Journal

To combat this issue, the Innovative Genomics Institute (IGI) at UC Berkeley is applying CRISPR to create disease-resistant cacao. Leading chocolate supplier MARS Inc. is supporting this effort.Gene editing can make farming more efficient. It can curb global food shortages for staple crops like potatoes and tomatoes. And it can create resilient crops, impervious to droughts and other environmental impacts.Regulators have shown little resistanceto gene-edited crops, and the United States Department of Agriculture (USDA) in particular is not regulating the space. This is largely because when CRISPR is applied to crops, theres no foreign DNA being added: CRISPR is simply used to edit a crops own genetics to select for desirable traits.In 2016, the white button mushroom, modified to beresistant to browning, became the first CRISPR-edited organism to bypass USDA. In October 2017, it was announced that agriculture company DuPont Pioneer and the Broad Institute would collaborate for agriculture researchusing their CRISPR-Cas9 intellectual property.

InSeptember 2017, biotech company Yield10 Bioscience got approval for its CRISPR-edited plantCamelina sativa (false flax), which hasenhanced omega-3 oil and is used to make vegetable oil and animal feed.

These are indicationsthat newbreeds of crops could reachmarketsmuch faster than previously thought. Without USDA oversight, these items and other food products could go into production relatively quickly.

This will impact the food we eat, as food items are edited tocarry more nutrients or to last longer on grocery shelves.

Another area currently generating buzz isthe production of leaner livestock.

In October 2017, scientists at the Chinese Academy of Sciences in Beijing used CRISPR to genetically engineer pig meat that had 24% less body fat.

Researchersdid this by inserting a mouse gene into pig cellsin order tobetter regulate body temperature.Although this example technically makes the result a GMO product, it may not be too long before pigs genes are used for the same purpose.

Future versionsof this technology applied to human nutrition will be one area to look out for.

Another key, but less obvious, use of CRISPR lies is in the industrial biotech space. By re-engineering microbes using CRISPR,researcher can create new materials.

How is this relevant to society at large?

From an industrial standpoint, this is big for modifying and creating new chemical products. We can alter microbes to increase diversity, create new bio-based materials, and make more efficient biofuels.From active chemicals in fragrances to those involved in industrial cleaning, CRISPR could have agreat impact here by creating new and more efficientbiological materials.

Jennifer Doudnas first CRISPR startup, Caribou Biosciences, was founded in 2011 for non-therapeutic research purposes across industries. It is one of the key companies providing various industries with the tools to use CRISPR fora range of purposes.

CRISPRs list of potential benefits is a long one. But the technology also brings with it a number of limitations.

Possible unintended effects and all the unknown variables are some of the drawbacks to this newtechnology, while newethicalquestions and controversies are also emerging as human trials near.

When using CRISPRfor human therapies, safety is the biggest issue. As with any new form of technology, researchers are unsure of the entire range of CRISPRs effects.Off-target activity is the main concern here. A single gene editcould cause unintended activity somewhere else in the genome. A possible consequence of this is abnormal growth of tissues, leading to cancer. As more research uncovers new details, this could result in more refined, precise gene targeting.

Another issue is the possibility of mosaic generation.After a CRISPR treatment, a patient could have a mix of both edited and unedited cells a mosaic. As cells continue to divide and replicate, some cells may get repaired, while others wont.

Finally, immune systemcomplications mean that these interventions and therapies may trigger an undesired response froma patients immune system.Early research shows theimmune system may dispose of Cas enzymes before they achieve their purpose, or may have an averse reaction resulting in side effects like inflammation. (In 1999, a patient in the US died of a severe immune reaction, instilling more caution in researchers when it comes to CRISPR trials.)

However, all three of these limitations have some possible solutions.

Different enzymes (molecular scissors) or more precise delivery vehicles can reduce off-target activity. If modified stem cells in egg or sperm (i.e. cells that can become every cell in the human body) are edited, mosaics can be avoided.

With the immune system issue, researchers can isolate different Cas proteins from more obscure bacterial strains that humans dont already have an adaptive immunity to in order to circumvent an unwanted immune response. Meanwhile, ex-vivo therapies, wherescientists take a patients blood cells out of the body and treat them before infusing them back in, can also helpbypass the immune system.

One potential big limitation for CRISPR isthat CRISPR-Cas9 system lacks surgical precision. The Cas enzyme cuts both strands of the DNA double helix, and this double-stranded breakcreates worries over the precision of the cut.

Repairing a defective gene would be like finding a needle in a haystack and then removing that needle without disturbing a single strand of hay in the process.-Jennifer Doudna

While currently the Cas9 enzyme gets the most attentionas the enzyme doing the cutting, scientists are actively pursuing alternatives to find better candidates.

Alternative options include asmaller version of Cas9, or a different enzyme entirely: Cpf1, whichhas become popular due to its easy transport to the targeted DNA location.

Besides using other Cas enzymes, alternate delivery vehiclesfor therapeutic genes are another option. Harmless engineered viruses can carry therapeutic genes to the site of mutation, while lipid nanoparticles can avoid immune system detection, avoiding an immune reaction. Both options present promising avenues of research.

Whentechnology can alter the code of life, its implications are far-reaching as are its controversies. Here we outlinea few of the main controversies surroundingCRISPR.

Originally posted here:
What Is CRISPR? – CB Insights

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What is genetic testing? – Genetics Home Reference – NIH

Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a persons chance of developing or passing on a genetic disorder. More than 1,000 genetic tests are currently in use, and more are being developed.

Several methods can be used for genetic testing:

Chromosomal genetic tests analyze whole chromosomes or long lengths of DNA to see if there are large genetic changes, such as an extra copy of a chromosome, that cause a genetic condition.

Genetic testing is voluntary. Because testing has benefits as well as limitations and risks, the decision about whether to be tested is a personal and complex one. A geneticist or genetic counselor can help by providing information about the pros and cons of the test and discussing the social and emotional aspects of testing.

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What is genetic testing? – Genetics Home Reference – NIH

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Homosexual behavior in animals – Wikipedia

Homosexual behavior in animals is sexual behavior among non-human species that is interpreted as homosexual or bisexual. This may include same-sex sexual activity, courtship, affection, pair bonding, and parenting among same-sex animal pairs.[1][2][3][4] Research indicates that various forms of this are found in every major geographic region and every major animal group. The sexual behavior of non-human animals takes many different forms, even within the same species, though homosexual behavior is best known from social species.

Scientists perceive homosexual behavior in animals to different degrees. The motivations for and implications of these behaviors have yet to be fully understood, since most species have yet to be fully studied.[5] According to Bruce Bagemihl, the animal kingdom engages in homosexual behavior “with much greater sexual diversity including homosexual, bisexual and nonreproductive sex than the scientific community and society at large have previously been willing to accept.”[6] Bagemihl adds, however, that this is “necessarily an account of human interpretations of these phenomena”.[7] Simon LeVay introduced caveat that “[a]lthough homosexual behavior is very common in the animal world, it seems to be very uncommon that individual animals have a long-lasting predisposition to engage in such behavior to the exclusion of heterosexual activities. Thus, a homosexual orientation, if one can speak of such thing in animals, seems to be a rarity.”[8] One species in which exclusive homosexual orientation occurs, however, is that of domesticated sheep (Ovis aries).[9][10] “About 10% of rams (males), refuse to mate with ewes (females) but do readily mate with other rams.”[10]

According to Bagemihl (1999), same-sex behavior (comprising courtship, sexual, pair-bonding, and parental activities) has been documented in over 450 species of animals worldwide.[11]

The term homosexual was coined by Karl-Maria Kertbeny in 1868 to describe same-sex sexual attraction and sexual behavior in humans.[12] Its use in animal studies has been controversial for two main reasons: animal sexuality and motivating factors have been and remain poorly understood, and the term has strong cultural implications in western society that are irrelevant for species other than humans.[13] Thus homosexual behavior has been given a number of terms over the years. According to Bruce Bagemihl, when describing animals, the term homosexual is preferred over gay, lesbian, and other terms currently in use, as these are seen as even more bound to human homosexuality.[14]

Bailey et al. says: “Homosexual: in animals, this has been used to refer to same-sex behavior that is not sexual in character (e.g. homosexual tandem running in termites), same-sex courtship or copulatory behavior occurring over a short period of time (e.g. homosexual mounting in cockroaches and rams) or long-term pair bonds between same-sex partners that might involve any combination of courting, copulating, parenting and affectional behaviors (e.g. homosexual pair bonds in gulls). In humans, the term is used to describe individual sexual behaviors as well as long-term relationships, but in some usages connotes a gay or lesbian social identity. Scientific writing would benefit from reserving this anthropomorphic term for humans and not using it to describe behavior in other animals, because of its deeply rooted context in human society”.[15]

Animal preference and motivation is always inferred from behavior. In wild animals, researchers will as a rule not be able to map the entire life of an individual, and must infer from frequency of single observations of behavior. The correct usage of the term homosexual is that an animal exhibits homosexual behavior or even same-sex sexual behavior; however, this article conforms to the usage by modern research,[14][16][17][18][pageneeded][19]applying the term homosexuality to all sexual behavior (copulation, genital stimulation, mating games and sexual display behavior) between animals of the same sex. In most instances, it is presumed that the homosexual behavior is but part of the animal’s overall sexual behavioral repertoire, making the animal “bisexual” rather than “homosexual” as the terms are commonly understood in humans.[18][pageneeded], but cases of homosexual preference and exclusive homosexual pairs are known.[20]

The observation of homosexual behavior in animals can be seen as both an argument for and against the acceptance of homosexuality in humans, and has been used especially against the claim that it is a peccatum contra naturam (“sin against nature”). For instance, homosexuality in animals was cited by the American Psychiatric Association and other groups in their amici curiae brief to the United States Supreme Court in Lawrence v. Texas, which ultimately struck down the sodomy laws of 14 states.[21][22]

A majority of the research available concerning homosexual behavior in animals lacks specification between animals that exclusively exhibit same-sex tendencies and those that participate in heterosexual and homosexual mating activities interchangeably. This lack of distinction has led to differing opinions and conflicting interpretations of collected data amongst scientists and researchers. For instance, Bruce Bagemihl, author of the book Biological Exuberence: Animal Homosexuality and Natural Diversity, emphasizes that there are no anatomical or endocrinological differences between exclusively homosexual and exclusively heterosexual animal pairs.[23][pageneeded] However, if the definition of “homosexual behavior” is made to include animals that participate in both same-sex and opposite-sex mating activities, hormonal differences have been documented among key sex hormones, such as testosterone and estradiol, when compared to those who participate solely in heterosexual mating.[24]

Many of the animals used in laboratory-based studies of homosexuality do not appear to spontaneously exhibit these tendencies often in the wild. Such behavior is often elicited and exaggerated by the researcher during experimentation through the destruction of a portion of brain tissue, or by exposing the animal to high levels of steroid hormones prenatally.[25][pageneeded] Information gathered from these studies is limited when applied to spontaneously occurring same-sex behavior in animals outside of the laboratory.[25]

Homosexual behaviour in animals has been discussed since classical antiquity. The earliest written mention of animal homosexuality appears to date back to 2,300 years ago, when Aristotle (384322 BC) described copulation between pigeons, partridges and quails of the same sex.[26] The Hieroglyphics of Horapollo, written in the 4th century AD by the Egyptian writer Horapollo, mentions “hermaphroditism” in hyenas and homosexuality in partridges.[26] The first review of animal homosexuality was written by the zoologist Ferdinand Karsch-Haack in 1900.[26]

Until recent times, the presence of same-sex sexual behavior was not “officially” observed on a large scale, possibly due to observer bias caused by social attitudes to same-sex sexual behavior,[27] innocent confusion, lack of interest, distaste, scientists fearing loss of their grants or even from a fear of “being ridiculed by their colleagues”.[28][29] Georgetown University biologist Janet Mann states “Scientists who study the topic are often accused of trying to forward an agenda, and their work can come under greater scrutiny than that of their colleagues who study other topics.”[30] They also noted “Not every sexual act has a reproductive function … that’s true of humans and non-humans.”[30] It appears to be widespread amongst social birds and mammals, particularly the sea mammals and the primates. The true extent of homosexuality in animals is not known. While studies have demonstrated homosexual behavior in a number of species, Petter Bckman, the scientific advisor of the exhibition Against Nature? in 2007, speculated that the true extent of the phenomenon may be much larger than was then recognized:

No species has been found in which homosexual behaviour has not been shown to exist, with the exception of species that never have sex at all, such as sea urchins and aphis. Moreover, a part of the animal kingdom is hermaphroditic, truly bisexual. For them, homosexuality is not an issue.[28]

An example of overlooking homosexual behavior is noted by Bagemihl describing mating giraffes where nine out of ten pairings occur between males:

Every male that sniffed a female was reported as sex, while anal intercourse with orgasm between males was only “revolving around” dominance, competition or greetings.[31]

Some researchers believe this behavior to have its origin in male social organization and social dominance, similar to the dominance traits shown in prison sexuality. Others, particularly Bagemihl, Joan Roughgarden, Thierry Lod[32] and Paul Vasey suggest the social function of sex (both homosexual and heterosexual) is not necessarily connected to dominance, but serves to strengthen alliances and social ties within a flock. Others have argued that social organization theory is inadequate because it cannot account for some homosexual behaviors, for example, penguin species where male individuals mate for life and refuse to pair with females when given the chance.[33][34] While reports on many such mating scenarios are still only anecdotal, a growing body of scientific work confirms that permanent homosexuality occurs not only in species with permanent pair bonds,[19] but also in non-monogamous species like sheep.

One report on sheep cited below states:

Approximately 8% of rams exhibit sexual preferences [that is, even when given a choice] for male partners (male-oriented rams) in contrast to most rams, which prefer female partners (female-oriented rams). We identified a cell group within the medial preoptic area/anterior hypothalamus of age-matched adult sheep that was significantly larger in adult rams than in ewes…[35]

In fact, apparent homosexual individuals are known from all of the traditional domestic species, from sheep, cattle and horses to cats, dogs and budgerigars.[36][pageneeded]

A definite physiological explanation or reason for homosexual activity in animal species has not been agreed upon by researchers in the field. Numerous scholars are of the opinion that varying levels (either higher or lower) of the sex hormones in the animal,[37] in addition to the size of the animal’s gonads,[24] play a direct role in the sexual behavior and preference exhibited by that animal. Others firmly argue no evidence to support these claims exists when comparing animals of a specific species exhibiting homosexual behavior exclusively and those that do not. Ultimately, empirical support from comprehensive endocrinological studies exist for both interpretations.[37][38] Researchers found no evidence of differences in the measurements of the gonads, or the levels of the sex hormones of exclusively homosexual western gulls and ring-billed gulls.[39] However, when analyzing these differences in bisexual rams, males were found to have lower levels of testosterone and estradiol in their blood, as well as smaller gonads than their heterosexual counterpart.[citation needed]

Additional studies pertaining to hormone involvement in homosexual behavior indicate that when administering treatments of testosterone and estradiol to female heterosexual animals, the elevated hormone levels increase the likelihood of homosexual behavior. Additionally, boosting the levels of sex hormones during an animal’s pregnancy appears to increase the likelihood of it birthing a homosexual offspring.[37]

Researchers found that disabling the fucose mutarotase (FucM) gene in laboratory mice which influences the levels of estrogen to which the brain is exposed caused the female mice to behave as if they were male as they grew up. “The mutant female mouse underwent a slightly altered developmental programme in the brain to resemble the male brain in terms of sexual preference” said Professor Chankyu Park of the Korea Advanced Institute of Science and Technology in Daejon, South Korea, who led the research. His most recent findings have been published in the BMC Genetics journal on July 7, 2010.[40][41] Another study found that by manipulating a gene in fruit flies (Drosophila), homosexual behavior appeared to have been induced. However, in addition to homosexual behavior, several abnormal behaviors were also exhibited apparently due to this mutation.[42]

In March 2011, research showed that serotonin is involved in the mechanism of sexual orientation of mice.[43][44] A study conducted on fruit flies found that inhibiting the dopamine neurotransmitter inhibited lab-induced homosexual behavior.[45]

An estimated one-quarter of all black swans pairings are of males. They steal nests, or form temporary threesomes with females to obtain eggs, driving away the female after she lays the eggs. The males spent time in each other’s society, guarded the common territory, performed greeting ceremonies before each other, and (in the reproductive period) pre-marital rituals, and if one of the birds tried to sit on the other, an intense fight began.[1][2] More of their cygnets survive to adulthood than those of different-sex pairs, possibly due to their superior ability to defend large portions of land. The same reasoning has been applied to male flamingo pairs raising chicks.[46][47]

Female albatross, on the north-western tip of the island of Oahu, Hawaii, form pairs for co-growing offspring. On the observed island, the number of females considerably exceeds the number of males (59% N=102/172), so 31% of females, after mating with males, create partnerships for hatching and feeding chicks. Compared to male-female couples female partnerships have a lower hatching rate (41% vs 87%) and lower overall reproductive success (31% vs. 67%).[48]

Research has shown that the environmental pollutant methylmercury can increase the prevalence of homosexual behavior in male American white ibis. The study involved exposing chicks in varying dosages to the chemical and measuring the degree of homosexual behavior in adulthood. The results discovered was that as the dosage was increased the likelihood of homosexual behavior also increased. The endocrine blocking feature of mercury has been suggested as a possible cause of sexual disruption in other bird species.[49][50]

Mallards form male-female pairs only until the female lays eggs, at which time the male leaves the female. Mallards have rates of male-male sexual activity that are unusually high for birds, in some cases, as high as 19% of all pairs in a population.[36][pageneeded] Kees Moeliker of the Natural History Museum Rotterdam has observed one male mallard engage in homosexual necrophilia.[51]

Penguins have been observed to engage in homosexual behaviour since at least as early as 1911. George Murray Levick, who documented this behaviour in Adlie penguins at Cape Adare, described it as “depraved”. The report was considered too shocking for public release at the time, and was suppressed. The only copies that were made available privately to researchers were translated into Greek, to prevent this knowledge becoming more widely known. The report was unearthed only a century later, and published in Polar Record in June 2012.[52]

In early February 2004 the New York Times reported that Roy and Silo, a male pair of chinstrap penguins in the Central Park Zoo in New York City had successfully hatched and fostered a female chick from a fertile egg they had been given to incubate.[21] Other penguins in New York zoos have also been reported to have formed same-sex pairs.[53][54]

In Odense Zoo in Denmark, a pair of male king penguins adopted an egg that had been abandoned by a female, proceeding to incubate it and raise the chick.[55][56]Zoos in Japan and Germany have also documented homosexual male penguin couples.[33][34] The couples have been shown to build nests together and use a stone as a substitute for an egg. Researchers at Rikkyo University in Tokyo found 20 homosexual pairs at 16 major aquariums and zoos in Japan.

The Bremerhaven Zoo in Germany attempted to encourage reproduction of endangered Humboldt penguins by importing females from Sweden and separating three male pairs, but this was unsuccessful. The zoo’s director said that the relationships were “too strong” between the homosexual pairs.[57] German gay groups protested at this attempt to break up the male-male pairs[58] but the zoo’s director was reported as saying “We don’t know whether the three male pairs are really homosexual or whether they have just bonded because of a shortage of females … nobody here wants to forcibly separate homosexual couples.”[59]

A pair of male Magellanic penguins who had shared a burrow for six years at the San Francisco Zoo and raised a surrogate chick, split when the male of a pair in the next burrow died and the female sought a new mate.[60]

Buddy and Pedro, a pair of male African penguins, were separated by the Toronto Zoo to mate with female penguins.[61][62] Buddy has since paired off with a female.[62]

Suki and Chupchikoni are two female African penguins that pair bonded at the Ramat Gan Safari in Israel. Chupchikoni was assumed to be male until her blood was tested.[63]

In 2014 Jumbs and Hurricane, two Humboldt penguins at Wingham Wildlife Park became the center of international media attention as two male penguins who had pair bonded a number of years earlier and then successfully hatched and reared an egg given to them as surrogate parents after the mother abandoned it halfway through incubation.[64]

In 1998 two male griffon vultures named Dashik and Yehuda, at the Jerusalem Biblical Zoo, engaged in “open and energetic sex” and built a nest. The keepers provided the couple with an artificial egg, which the two parents took turns incubating; and 45 days later, the zoo replaced the egg with a baby vulture. The two male vultures raised the chick together.[65] A few years later, however, Yehuda became interested in a female vulture that was brought into the aviary. Dashik became depressed, and was eventually moved to the zoological research garden at Tel Aviv University where he too set up a nest with a female vulture.[66]

Two male vultures at the Allwetter Zoo in Muenster built a nest together, although they were picked on and their nest materials were often stolen by other vultures. They were eventually separated to try to promote breeding by placing one of them with female vultures, despite the protests of German homosexual groups.[67]

Both male and female pigeons sometimes exhibit homosexual behavior. In addition to sexual behavior, same-sex pigeon pairs will build nests, and hens will lay (infertile) eggs and attempt to incubate them.[citation needed]

The Amazon river dolphin or boto has been reported to form up in bands of 35 individuals engaging in sexual activity. The groups usually comprise young males and sometimes one or two females. Sex is often performed in non-reproductive ways, using snout, flippers and genital rubbing, without regard to gender.[68] In captivity, they have been observed to sometimes perform homosexual and heterosexual penetration of the blowhole, a hole homologous with the nostril of other mammals, making this the only known example of nasal sex in the animal kingdom.[68][69] The males will sometimes also perform sex with males from the tucuxi species, a type of small porpoise.[68]

Courtship, mounting, and full anal penetration between bulls has been noted to occur among American bison. The Mandan nation Okipa festival concludes with a ceremonial enactment of this behavior, to “ensure the return of the buffalo in the coming season”.[70] Also, mounting of one female by another (known as “bulling”) is extremely common among cattle. The behaviour is hormone driven and synchronizes with the emergence of estrus (heat), particularly in the presence of a bull.

More than 20 species of bat have been documented to engage in homosexual behavior.[26][71] Bat species that have been observed engaging in homosexual behavior in the wild include:[26]

Bat species that have been observed engaging in homosexual behavior in captivity include the Comoro flying fox (Pteropus livingstonii), the Rodrigues flying fox (Pteropus rodricensis) and the common vampire bat (Desmodus rotundus).[26]

Homosexual behavior in bats has been categorized into 6 groups: mutual homosexual grooming and licking, homosexual masturbation, homosexual play, homosexual mounting, coercive sex, and cross-species homosexual sex.[26][71]

In the wild, the grey-headed flying fox (Pteropus poliocephalus) engages in allogrooming wherein one partner licks and gently bites the chest and wing membrane of the other partner. Both sexes display this form of mutual homosexual grooming and it is more common in males. Males often have erect penises while they are mutually grooming each other. Like opposite-sex grooming partners, same-sex grooming partners continuously utter a pre-copulation call, which is described as a “pulsed grating call,” while engaged in this activity.[26][71]

In wild Bonin flying foxes (Pteropus pselaphon), males perform fellatio or ‘male-male genital licking’ on other males. Malemale genital licking events occur repeatedly several times in the same pair, and reciprocal genital licking also occurs. The male-male genital licking in these bats is considered a sexual behavior. Allogrooming in Bonin flying foxes has never been observed, hence the male-male genital licking in this species does not seem to be a by-product of allogrooming, but rather a behavior of directly licking the male genital area, independent of allogrooming.[71] In captivity, same-sex genital licking has been observed among males of the Comoro flying fox (Pteropus livingstonii) as well as among males of the common vampire bat (Desmodus rotundus).[26][71]

In wild Indian flying foxes (Pteropus giganteus), males often mount one another, with erections and thrusting, while play-wrestling.[26] Males of the long-fingered bat (Myotis capaccinii) have been observed in the same position of male-female mounting, with one gripping the back of the others fur. A similar behavior was also observed in the common bent-wing bat (Miniopterus schreibersii).[26]

In wild little brown bats (Myotis lucifugus), males often mount other males (and females) during late autumn and winter, when many of the mounted individuals are torpid.[26] 35% of matings during this period are homosexual.[72] These coercive copulations usually include ejaculation and the mounted bat often makes a typical copulation call consisting of a long squawk.[26] Similarly, in hibernacula of the common noctule (Nyctalus noctula), active males were observed to wake up from lethargy on a warm day and engage in mating with lethargic males and (active or lethargic) females. The lethargic males, like females, called out loudly and presented their buccal glands with opened mouth during copulation.[26]

Vesey-Fitzgerald (1949) observed homosexual behaviours in all 12 British bat species known at the time: Homosexuality is common in the spring in all species, and, since the males are in full possession of their powers, I suspect throughout the summer…I have even seen homosexuality between Natterer’s and Daubenton’s bats (Myotis nattereri and M. daubentonii).”[26]

Dolphins of several species engage in homosexual acts, though it is best studied in the bottlenose dolphins.[36][pageneeded] Sexual encounters between females take the shape of “beak-genital propulsion”, where one female inserts her beak in the genital opening of the other while swimming gently forward.[73] Between males, homosexual behaviour includes rubbing of genitals against each other, which sometimes leads to the males swimming belly to belly, inserting the penis in the others genital slit and sometimes anus.[74]

Janet Mann, Georgetown University professor of biology and psychology, argues that the strong personal behavior among male dolphin calves is about bond formation and benefits the species in an evolutionary context.[75] She cites studies showing that these dolphins later in life as adults are in a sense bisexual, and the male bonds forged earlier in life work together for protection as well as locating females to reproduce with. Confrontations between flocks of bottlenose dolphins and the related species Atlantic spotted dolphin will sometimes lead to cross-species homosexual behaviour between the males rather than combat.[76]

African and Asian males will engage in same-sex bonding and mounting. Such encounters are often associated with affectionate interactions, such as kissing, trunk intertwining, and placing trunks in each other’s mouths. Male elephants, who often live apart from the general herd, often form “companionships”, consisting of an older individual and one or sometimes two younger males with sexual behavior being an important part of the social dynamic. Unlike heterosexual relations, which are always of a fleeting nature, the relationships between males may last for years. The encounters are analogous to heterosexual bouts, one male often extending his trunk along the other’s back and pushing forward with his tusks to signify his intention to mount. Same-sex relations are common and frequent in both sexes, with Asiatic elephants in captivity devoting roughly 45% of sexual encounters to same-sex activity.[77]

Male giraffes have been observed to engage in remarkably high frequencies of homosexual behavior. After aggressive “necking”, it is common for two male giraffes to caress and court each other, leading up to mounting and climax. Such interactions between males have been found to be more frequent than heterosexual coupling.[78] In one study, up to 94% of observed mounting incidents took place between two males. The proportion of same sex activities varied between 30 and 75%, and at any given time one in twenty males were engaged in non-combative necking behavior with another male. Only 1% of same-sex mounting incidents occurred between females.[79]

Olympic marmot (left) and Hoary marmot (right).

Homosexual behavior is quite common in wild marmots.[80] In Olympic marmots (Marmota olympus) and Hoary Marmots (Marmota caligata), females often mount other females as well as engage in other affectionate and sexual behaviors with females of the same species.[80] They display a high frequency of these behaviors especially when they are in heat.[80][81] A homosexual encounter often begins with a greeting interaction in which one female nuzzles her nose on the other females cheek or mouth, or both females touch noses or mouths. Additionally, a female may gently chew on the ear or neck of her partner, who responds by raising her tail. The first female may sniff the other’s genital region or nuzzle that region with her mouth. She may then proceed to mount the other female, during which the mounting female gently grasps the mounted female’s dorsal neck fur in her jaws while thrusting. The mounted female arches her back and holds her tail to one side to facilitate their sexual interaction.[80][82]

Both male and female lions have been seen to interact homosexually.[83][84] Male lions pair-bond for a number of days and initiate homosexual activity with affectionate nuzzling and caressing, leading to mounting and thrusting. About 8% of mountings have been observed to occur with other males. Pairings between females are held to be fairly common in captivity but have not been observed in the wild.

European polecats Mustela putorius were found to engage homosexually with non-sibling animals. Exclusive homosexuality with mounting and anal penetration in this solitary species serves no apparent adaptive function.[85][pageneeded]

Bonobos, which have a matriarchal society, unusual among apes, are a fully bisexual speciesboth males and females engage in heterosexual and homosexual behavior, being noted for femalefemale homosexuality in particular, including[86] between juveniles and adults. Roughly 60% of all bonobo sexual activity occurs between two or more females. While the homosexual bonding system in bonobos represents the highest frequency of homosexuality known in any primate species, homosexuality has been reported for all great apes (a group which includes humans), as well as a number of other primate species.[87][88][89][pageneeded][90][86][91][92][93][94]

Dutch primatologist Frans de Waal on observing and filming bonobos noted that there were two reasons to believe sexual activity is the bonobo’s answer to avoiding conflict. Anything that arouses the interest of more than one bonobo at a time, not just food, tends to result in sexual contact. If two bonobos approach a cardboard box thrown into their enclosure, they will briefly mount each other before playing with the box. Such situations lead to squabbles in most other species. But bonobos are quite tolerant, perhaps because they use sex to divert attention and to defuse tension.

Bonobo sex often occurs in aggressive contexts totally unrelated to food. A jealous male might chase another away from a female, after which the two males reunite and engage in scrotal rubbing. Or after a female hits a juvenile, the latter’s mother may lunge at the aggressor, an action that is immediately followed by genital rubbing between the two adults.[95]

With the Japanese macaque, also known as the “snow monkey”, same-sex relations are frequent, though rates vary between troops. Females will form “consortships” characterized by affectionate social and sexual activities. In some troops up to one quarter of the females form such bonds, which vary in duration from a few days to a few weeks. Often, strong and lasting friendships result from such pairings. Males also have same-sex relations, typically with multiple partners of the same age. Affectionate and playful activities are associated with such relations.[96]

Homosexual behavior forms part of the natural repertoire of sexual or sociosexual behavior of orangutans. Male homosexual behavior occurs both in the wild and in captivity, and it occurs in both adolescent and mature individuals. Homosexual behavior in orangutans is not an artifact of captivity or contact with humans.[97]

Among monkeys[clarification needed], Lionel Tiger and Robin Fox conducted a study on how Depo-Provera contraceptives lead to decreased male attraction to females.[98]

Ovis aries has attracted much attention due to the fact that around 810% of rams have an exclusive homosexual orientation.[9][99][100][101][102] Furthermore, around 1822% of rams are bisexual.[100]

An October 2003 study by Dr. Charles E. Roselli et al. (Oregon Health and Science University) states that homosexuality in male sheep (found in 8% of rams) is associated with a region in the rams’ brains which the authors call the “ovine Sexually Dimorphic Nucleus” (oSDN) which is half the size of the corresponding region in heterosexual male sheep.[35] Scientists found that, “The oSDN in rams that preferred females was significantly larger and contained more neurons than in male-oriented rams and ewes. In addition, the oSDN of the female-oriented rams expressed higher levels of aromatase, a substance that converts testosterone to estradiol, a form of estrogen which is believed to facilitate typical male sexual behaviors. Aromatase expression was no different between male-oriented rams and ewes.”

“The dense cluster of neurons that comprise the oSDN express cytochrome P450 aromatase. Aromatase mRNA levels in the oSDN were significantly greater in female-oriented rams than in ewes, whereas male-oriented rams exhibited intermediate levels of expression.” These results suggest that “… naturally occurring variations in sexual partner preferences may be related to differences in brain anatomy and its capacity for estrogen synthesis.”[35] As noted before, given the potential unagressiveness of the male population in question, the differing aromatase levels may also have been evidence of aggression levels, not sexuality. It should also be noted that the results of this study have not been confirmed by other studies.

The Merck Manual of Veterinary Medicine appears to consider homosexuality among sheep as a routine occurrence and an issue to be dealt with as a problem of animal husbandry.[103]

Homosexual courtship and sexual activity routinely occur among rams of wild sheep species, such as Bighorn sheep (Ovis canadensis), Thinhorn sheep (Ovis dalli), mouflons and urials (Ovis orientalis).[104] Usually a higher ranking older male courts a younger male using a sequence of stylized movements. To initiate homosexual courtship, a courting male approaches the other male with his head and neck lowered and extended far forward in what is called the ‘low-stretch’ posture. He may combine this with the ‘twist,’ in which the courting male sharply rotates his head and points his muzzle toward the other male, often while flicking his tongue and making grumbling sounds. The courting male also often performs a ‘foreleg kick,’ in which he snaps his front leg up against the other males belly or between his hind legs. He also occasionally sniffs and nuzzles the other males genital area and may perform the flehmen response. Thinhorn rams additionally lick the penis of the male they are courting. In response, the male being courted may rub his cheeks and forehead on the courting males face, nibble and lick him, rub his horns on the courting males neck, chest, or shoulders, and develop an erection. Males of another wild sheep species, the Asiatic Mouflons, perform similar courtship behaviors towards fellow males.[104]

Sexual activity between wild males typically involves mounting and anal intercourse. In Thinhorn sheep, genital licking also occurs. During mounting, the larger male usually mounts the smaller male by rearing up on his hind legs and placing his front legs on his partners flanks. The mounting male usually has an erect penis and accomplishes full anal penetration while performing pelvic thrusts that may lead to ejaculation. The mounted male arches his back to facilitate the copulation. Homosexual courtship and sexual activity can also take place in groups composed of three to ten wild rams clustered together in a circle. These non-aggressive groups are called ‘huddles’ and involve rams rubbing, licking, nuzzling, horning, and mounting each other. Female Mountain sheep also engage in occasional courtship activities with one another and in sexual activities such as licking each others genitals and mounting.[104]

The family structure of the spotted hyena is matriarchal, and dominance relationships with strong sexual elements are routinely observed between related females. Due largely to the female spotted hyena’s unique urogenital system, which looks more like a penis rather than a vagina, early naturalists thought hyenas were hermaphroditic males who commonly practiced homosexuality.[105][not in citation given] Early writings such as Ovid’s Metamorphoses and the Physiologus suggested that the hyena continually changed its sex and nature from male to female and back again. In Paedagogus, Clement of Alexandria noted that the hyena (along with the hare) was “quite obsessed with sexual intercourse”. Many Europeans associated the hyena with sexual deformity, prostitution, deviant sexual behavior, and even witchcraft.

The reality behind the confusing reports is the sexually aggressive behavior between the females, including mounting between females. Research has shown that “in contrast to most other female mammals, female Crocuta are male-like in appearance, larger than males, and substantially more aggressive,”[106] and they have “been masculinized without being defeminized”.[105][not in citation given]

Study of this unique genitalia and aggressive behavior in the female hyena has led to the understanding that more aggressive females are better able to compete for resources, including food and mating partners.[105][107] Research has shown that “elevated levels of testosterone in utero”[108] contribute to extra aggressiveness; both males and females mount members of both the same and opposite sex,[108][109] who in turn are possibly acting more submissive because of lower levels of testosterone in utero.[106]

Parthenogenesis. Several species of whiptail lizard (especially in the genus Aspidoscelis) consist only of females that have the ability to reproduce through parthenogenesis.[110] Females engage in sexual behavior to stimulate ovulation, with their behavior following their hormonal cycles; during low levels of estrogen, these (female) lizards engage in “masculine” sexual roles. Those animals with currently high estrogen levels assume “feminine” sexual roles. Some parthenogenetic lizards that perform the courtship ritual have greater fertility than those kept in isolation due to an increase in hormones triggered by the sexual behaviors. So, even though asexual whiptail lizards populations lack males, sexual stimuli still increase reproductive success. From an evolutionary standpoint, these females are passing their full genetic code to all of their offspring (rather than the 50% of genes that would be passed in sexual reproduction). Certain species of gecko also reproduce by parthenogenesis.[111]

“True” homosexuality in lizards. Some species of sexually reproducing geckos have been found to display homosexual behavior, e.g the day geckos Phelsuma laticauda and Phelsuma cepediana.[112]

Jonathan, the world’s oldest tortoise (an Aldabra giant tortoise), had been mating with another tortoise named Frederica since 1991. In 2017, it was discovered that Frederica was actually probably male all along, and was renamed Frederic.[113]

There is evidence of same-sex sexual behavior in at least 110 species of insects and arachnids.[114] Scharf et al. says: “Males are more frequently involved in same-sex sexual (SSS) behavior in the laboratory than in the field, and isolation, high density, and exposure to female pheromones increase its prevalence. SSS behavior is often shorter than the equivalent heterosexual behavior. Most cases can be explained via mistaken identification by the active (courting/mounting) male. Passive males often resist courting/mating attempts”.[114]

Scharf et al. continues: “SSS behavior has been reported in most insect orders, and Bagemihl (1999) provides a list of ~100 species of insects demonstrating such behavior. Yet, this list lacks detailed descriptions, and a more comprehensive summary of its prevalence in invertebrates, as well as ethology, causes, implications, and evolution of this behavior, remains lacking”.[114]

Male homosexuality has been inferred in several species of dragonflies (the order Odonata). The cloacal pinchers of male damselflies and dragonflies inflict characteristic head damage to females during sex. A survey of 11 species of damsel and dragonflies[115][116] has revealed such mating damages in 20 to 80% of the males too, indicating a fairly high occurrence of sexual coupling between males.

Male Drosophila melanogaster flies bearing two copies of a mutant allele in the fruitless gene court and attempt to mate exclusively with other males.[20] The genetic basis of animal homosexuality has been studied in the fly Drosophila melanogaster.[117] Here, multiple genes have been identified that can cause homosexual courtship and mating.[118] These genes are thought to control behavior through pheromones as well as altering the structure of the animal’s brains.[119][120] These studies have also investigated the influence of environment on the likelihood of flies displaying homosexual behavior.[121][122]

Male bed bugs (Cimex lectularius) are sexually attracted to any newly fed individual and this results in homosexual mounting. This occurs in heterosexual mounting by the traumatic insemination in which the male pierces the female abdomen with his needle-like penis. In homosexual mating this risks abdominal injuries as males lack the female counteradaptive spermalege structure. Males produce alarm pheromones to reduce such homosexual mating.

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Homosexual behavior in animals – Wikipedia

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Cardiac stem cells rejuvenate rats’ aging hearts … – CNN

The old rats appeared newly invigorated after receiving their injections. As hoped, the cardiac stem cells improved heart function yet also provided additional benefits. The rats’ fur fur, shaved for surgery, grew back more quickly than expected, and their chromosomal telomeres, which commonly shrink with age, lengthened.

The old rats receiving the cardiac stem cells also had increased stamina overall, exercising more than before the infusion.

“It’s extremely exciting,” said Dr. Eduardo Marbn, primary investigator on the research and director of the Cedars-Sinai Heart Institute. Witnessing “the systemic rejuvenating effects,” he said, “it’s kind of like an unexpected fountain of youth.”

“We’ve been studying new forms of cell therapy for the heart for some 12 years now,” Marbn said.

Some of this research has focused on cardiosphere-derived cells.

“They’re progenitor cells from the heart itself,” Marbn said. Progenitor cells are generated from stem cells and share some, but not all, of the same properties. For instance, they can differentiate into more than one kind of cell like stem cells, but unlike stem cells, progenitor cells cannot divide and reproduce indefinitely.

Since heart failure with preserved ejection fraction is similar to aging, Marbn decided to experiment on old rats, ones that suffered from a type of heart problem “that’s very typical of what we find in older human beings: The heart’s stiff, and it doesn’t relax right, and it causes fluid to back up some,” Marbn explained.

He and his team injected cardiosphere-derived cells from newborn rats into the hearts of 22-month-old rats — that’s elderly for a rat. Similar old rats received a placebo injection of saline solution. Then, Marbn and his team compared both groups to young rats that were 4 months old. After a month, they compared the rats again.

Even though the cells were injected into the heart, their effects were noticeable throughout the body, Marbn said

“The animals could exercise further than they could before by about 20%, and one of the most striking things, especially for me (because I’m kind of losing my hair) the animals … regrew their fur a lot better after they’d gotten cells” compared with the placebo rats, Marbn said.

The rats that received cardiosphere-derived cells also experienced improved heart function and showed longer heart cell telomeres.

Why did it work?

The working hypothesis is that the cells secrete exosomes, tiny vesicles that “contain a lot of nucleic acids, things like RNA, that can change patterns of the way the tissue responds to injury and the way genes are expressed in the tissue,” Marbn said.

It is the exosomes that act on the heart and make it better as well as mediating long-distance effects on exercise capacity and hair regrowth, he explained.

Looking to the future, Marbn said he’s begun to explore delivering the cardiac stem cells intravenously in a simple infusion — instead of injecting them directly into the heart, which would be a complex procedure for a human patient — and seeing whether the same beneficial effects occur.

Dr. Gary Gerstenblith, a professor of medicine in the cardiology division of Johns Hopkins Medicine, said the new study is “very comprehensive.”

“Striking benefits are demonstrated not only from a cardiac perspective but across multiple organ systems,” said Gerstenblith, who did not contribute to the new research. “The results suggest that stem cell therapies should be studied as an additional therapeutic option in the treatment of cardiac and other diseases common in the elderly.”

Todd Herron, director of the University of Michigan Frankel Cardiovascular Center’s Cardiovascular Regeneration Core Laboratory, said Marbn, with his previous work with cardiac stem cells, has “led the field in this area.”

“The novelty of this bit of work is, they started to look at more precise molecular mechanisms to explain the phenomenon they’ve seen in the past,” said Herron, who played no role in the new research.

One strength of the approach here is that the researchers have taken cells “from the organ that they want to rejuvenate, so that makes it likely that the cells stay there in that tissue,” Herron said.

He believes that more extensive study, beginning with larger animals and including long-term followup, is needed before this technique could be used in humans.

“We need to make sure there’s no harm being done,” Herron said, adding that extending the lifetime and improving quality of life amounts to “a tradeoff between the potential risk and the potential good that can be done.”

Capicor hasn’t announced any plans to do studies in aging, but the possibility exists.

After all, the cells have been proven “completely safe” in “over 100 human patients,” so it would be possible to fast-track them into the clinic, Marbn explained: “I can’t tell you that there are any plans to do that, but it could easily be done from a safety viewpoint.”

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Cardiac stem cells rejuvenate rats’ aging hearts … – CNN

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Market Players Developing iPS Cell Therapies – BioInformant

1. Cellular Dynamics International, Owned by FujiFilm Holdings

Founded in 2004 and listed on NASDAQ in July 2013, Cellular Dynamics International (CDI) is headquartered in Madison, Wisconsin. The company is known for its extremely robust patent portfolio containing more than 900 patents.

According to the company, CDI is the worlds largest producer of fully functional human cells derived from induced pluripotent stem (iPS) cells.[1] Their trademarked, iCell Cardiomyocytes, derived from iPSCs, are human cardiac cells used to aid drug discovery, improve the predictability of a drugs worth, and screen for toxicity. In addition, CDI provides: iCell Endothelial Cells for use in vascular-targeted drug discovery and tissue regeneration, iCell Hepatocytes, and iCell Neurons for pre-clinical drug discovery, toxicity testing, disease prediction, and cellular research.[2]

Induced pluripotent stem cells were first produced in 2006 from mouse cells and in 2007 from human cells, by Shinya Yamanaka at Kyoto University,[3] who also won the Nobel Prize in Medicine or Physiology for his work on iPSCs.[4] Yamanaka has ties to Cellular Dynamics International as a member of the scientific advisory board of iPS Academia Japan. IPS Academia Japan was originally established to manage the patents and technology of Yamanakas work, and is now the distributor of several of Cellular Dynamics products, including iCell Neurons, iCell Cardiomyocytes, and iCell Endothelial Cells.[5]

Importantly, in 2010 Cellular Dynamics became the first foreign company to be granted rights to use Yamanakas iPSC patent portfolio. Not only has CDI licensed rights to Yamanakas patents, but it also has a license to use Otsu, Japan-based Takara Bios RetroNectin product, which it uses as a tool to produce its iCell and MyCell products.[6]

Furthermore, in February 2015, Cellular Dynamics International announced it would be manufacturing cGMP HLA Superdonor stem cell lines that will support cellular therapy applications through genetic matching.[8] Currently, CDI has two HLA super donor cell lines that provide a partial HLA match to approximately 19% of the population within the U.S., and it aims to expand its master stem cell bank by collecting more donor cell lines that will cover 95% of the U.S. population.[9] The HLA super donor cell lines were manufactured using blood samples and used to produce pluripotent iPSC lines, giving the cells the capacity to differentiate into nearly any cell within the human body.

On March 30, 2015, Fujifilm Holdings Corporation announced that it was acquiring CDI for $307 million, allowing CDI to continue to run its operations in Madison, Wisconsin, and Novato, California as a consolidated subsidiary of Fujifilm.[14] A key benefit of the merger is that CDIs technology platform enables the production of high-quality fully functioning iPSCs (and other human cells) on an industrial scale, while Fujifilm has developed highly-biocompatible recombinant peptides that can be shaped into a variety of forms for use as a cellular scaffold in regenerative medicine when used in conjunction with CDIs products.[15]

Additionally, Fujifilm has been strengthening its presence in the regenerative medicine field over the past several years, including a recent A$4M equity stake in Cynata Therapeutics and an acquisition of Japan Tissue Engineering Co. Ltd. in December 2014. Most commonly called J-TEC, Japan Tissue Engineering Co. Ltd. successfully launched the first two regenerative medicine products in the country of Japan. According to Kaz Hirao, CEO of CDI, It is very important for CDI to get into the area of therapeutic products, and we can accelerate this by aligning it with strategic and technical resources present within J-TEC.

Kaz Hirao also states, For our Therapeutic businesses, we will aim to file investigational new drugs (INDs) with the U.S. FDA for the off-the-shelf iPSC-derived allogeneic therapeutic products. Currently, we are focusing on retinal diseases, heart disorders, Parkinsons disease, and cancers. For those four indicated areas, we would like to file several INDs within the next five years.

Finally, in September 2015, CDI again strengthened its iPS cell therapy capacity by setting up a new venture, Opsis Therapeutics. Opsis is focused on discovering and developing novel medicines to treat retinal diseases and is a partnership with Dr. David Gamm, the pioneer of iPS cell-derived retinal differentiation and transplantation.

In summary, several key events indicate CDIs commitment to developing iPS cell therapeutics, including:

Australian stem cell company Cynata Therapeutics (ASX:CYP) is taking a unique approach by creating allogeneic iPSC derived mesenchyal stem cell (MSCs) on a commercial scale. Cynatas Cymerus technology utilizes iPSCs provided by Cellular Dynamics International, a Fujifilm company, as the starting material for generating mesenchymoangioblasts (MCAs), and subsequently, for manufacturing clinical-grade MSCs. According to Cynatas Executive Chairman Stewart Washer who was interviewed by The Life Sciences Report, The Cymerus technology gets around the loss of potency with the unlimited iPS cellor induced pluripotent stem cellwhich is basically immortal.

On January 19, 2017, Fujifilm took an A$3.97 million (10%) strategic equity stake in Cynata, positioning the parties to collaborate on the further development and commercialization of Cynatas lead Cymerus therapeutic MSC product CYP-001 for graft-versus-host disease (GvHD). (CYP-001 is the product designation unique to the GVHD indication). The Fujifilm partnership also includes potential future upfront and milestone payments in excess of A$60 million and double-digit royalties on CYP-001 product net sales for Cynata Therapeutics, as well as a strategic relationship for the potential future manufacture of CYP-001 and certain rights to other Cynata technology.

One of the key inventors of Cynatas technology is Igor Slukvin, MD, Ph.D., Scientific Founder of Cellular Dynamics International (CDI) and Cynata Therapeutics. Dr. Slukvin has released more than 70 publications about stem cell topics, including the landmark article in Cell describing the now patented Cymerus technique. Dr. Slukvins co-inventor is Dr. James Thomson, the first person to isolate an embryonic stem cell (ESC) and one of the first people to create a human induced pluripotent stem cell (hiPSC). Dr. James Thompson was the Founder of CDI in 2004.

There are three strategic connections between Cellular Dynamics International (CDI) and Cynata Therapeutics, which include:

Recently, Cynata received advice from the UK Medicines and Healthcare products Regulatory Agency (MHRA) that its Phase I clinical trial application has been approved, titled An Open-Label Phase 1 Study to Investigate the Safety and Efficacy of CYP-001 for the Treatment of Adults With Steroid-Resistant Acute Graft Versus Host Disease. It will be the worlds first clinical trial involving a therapeutic product derived from allogeneic (unrelated to the patient) induced pluripotent stem cells (iPSCs).

Participants for Cynatas upcoming Phase I clinical trial will be adults who have undergone an allogeneic haematopoietic stem cell transplant (HSCT) to treat a hematological disorder and subsequently been diagnosed with steroid-resistant Grade II-IV GvHD. The primary objective of the trial is to assess safety and tolerability, while the secondary objective is to evaluate the efficacy of two infusions of CYP-001 in adults with steroid-resistant GvHD.

Using Professor Yamanakas Nobel Prize-winning achievement of ethically uncontentious iPSCs and CDIs high-quality iPSCs as source material, Cynata has achieved two world firsts:

Cynata has also released promising pre-clinical data in Asthma, Myocardial Infarction (Heart Attack), and Critical Limb Ischemia.

There are four key advantages of Cynatas proprietary Cymerus MSC manufacturing platform. Because the proprietary Cymerus technology allows nearly unlimited production of MSCs from a single iPSC donor, there is batch-to-batch uniformity. Utilizing a consistent starting material allows for a standardized cell manufacturing process and a consistent cell therapy product. Unlike other companies involved with MSC manufacturing, Cynata does not require a constant stream of new donors in order to source fresh stem cells for its cell manufacturing process, nor does it require the massive expansion of MSCs necessitated by reliance on freshly isolated donations.

Finally, Cynata has achieved a cost-savings advantage through its unique approach to MSC manufacturing. Its proprietary Cymerus technology addresses a critical shortcoming in existing methods of production of MSCs for therapeutic use, which is the ability to achieve economic manufacture at commercial scale.

On June 22, 2016, RIKEN announced that it is resuming its retinal induced pluripotent stem cell (iPSC) study in partnership with Kyoto University.

2013 was the first time in which clinical research involving transplant of iPSCs into humans was initiated, led by Masayo Takahashi of the RIKEN Center for Developmental Biology (CDB) in Kobe, Japan. Dr. Takahashi and her team were investigating the safety of iPSC-derived cell sheets in patients with wet-type age-related macular degeneration. Although the trial was initiated in 2013 and production of iPSCs from patients began at that time, it was not until August of 2014 that the first patient, a Japanese woman, was implanted with retinal tissue generated using iPSCs derived from her own skin cells.

A team of three eye specialists, led by Yasuo Kurimoto of the Kobe City Medical Center General Hospital, implanted a 1.3 by 3.0mm sheet of iPSC-derived retinal pigment epithelium cells into the patients retina.[196] Unfortunately, the study was suspended in 2015 due to safety concerns. As the lab prepared to treat the second trial participant, Yamanakas team identified two small genetic changes in the patients iPSCs and the retinal pigment epithelium (RPE) cells derived from them. Therefore, it is major news that the RIKEN Institute will now be resuming the worlds first clinical study involving the use of iPSC-derived cells in humans.

According to the Japan Times, this attempt at the clinical study will involve allogeneic rather than autologous iPSC-derived cells for purposes of cost and time efficiency. Specifically, the researchers will be developing retinal tissues from iPS cells supplied by Kyoto Universitys Center for iPS Cell Research and Application, an institution headed by Nobel prize winner Shinya Yamanaka. To learn about this announcement, view this article from Asahi Shimbun, a Tokyo- based newspaper.

In November 2015 Astellas Pharma announced it was acquiring Ocata Therapeutics for $379M. Ocata Therapeutics is a biotechnology company that specializes in the development of cellular therapies, using both adult and human embryonic stem cells to develop patient-specific therapies. The companys main laboratory and GMP facility are in Marlborough, Massachusetts, and its corporate offices are in Santa Monica, California.

When a number of private companies began to explore the possibility of using artificially re-manufactured iPSCs for therapeutic purposes, one such company that was ready to capitalize on the breakthrough technology was Ocata Therapeutics, at the time called Advanced Cell Technology. In 2010, the company announced that it had discovered several problematic issues while conducting experiments for the purpose of applying for U.S. Food and Drug Administration approval to use iPSCs in therapeutic applications. Concerns such as premature cell death, mutation into cancer cells, and low proliferation rates were some of the problems that surfaced. [17]

As a result, the company shifted its induced pluripotent stem cell approach to producing iPS cell-derived human platelets, as one of the benefits of a platelet-based product is that platelets do not contain nuclei, and therefore, cannot divide or carry genetic information. While the companys Induced Pluripotent Stem Cell-Derived Human Platelet Program received a great deal of media coverage in late 2012, including being awarded the December 2012 honor of being named one of the 10 Ideas that Will Shape the Year by New Scientist Magazine,[178]. Unfortunately, the company did not succeed in moving the concept through to clinical testing in 2013.

Nonetheless, Astellas is clearly continuing to develop Ocatas pluripotent stem cell technologies involving embryonic stem cells (ESCs) and induced pluripotent stem cells (iPS cells). In a November 2015 presentation by Astellas President and CEO, Yoshihiko Hatanaka, he indicated that the company will aim to develop an Ophthalmic Disease Cell Therapy Franchise based around its embryonic stem cell (ESC) and induced pluripotent stem cell (iPS cell) technology. [19]

What other companies are developing iPSC derived therapeutics and products? Share your thoughts in the comments below.

BioInformant is the first and only market research firm to specialize in the stem cell industry. BioInformant research has been cited by major news outlets that include the Wall Street Journal, Nature Biotechnology, Xconomy, and Vogue Magazine. Serving Fortune 500 leaders that include GE Healthcare, Pfizer, and Goldman Sachs. BioInformant is your global leader in stem cell industry data.

Footnotes[1] CellularDynamics.com (2014). About CDI. Available at: http://www.cellulardynamics.com/about/index.html. Web. 1 Apr. 2015.[2] Ibid.[3] Takahashi K, Yamanaka S (August 2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126 (4): 66376.[4] 2012 Nobel Prize in Physiology or Medicine Press Release. Nobelprize.org. Nobel Media AB 2013. Web. 7 Feb 2014. Available at: http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/press.html. Web. 1 Apr. 2015.[5] Striklin, D (Jan 13, 2014). Three Companies Banking on Regenerative Medicine. Wall Street Cheat Sheet. Retrieved Feb 1, 2014 from, http://wallstcheatsheet.com/stocks/3-companies-banking-on-regenerative-medicine.html/?a=viewall.%5B6%5D Striklin, D (2014). Three Companies Banking on Regenerative Medicine. Wall Street Cheat Sheet [Online]. Available at: http://wallstcheatsheet.com/stocks/3-companies-banking-on-regenerative-medicine.html/?a=viewall. Web. 1 Apr. 2015.[7] Cellular Dynamics International (July 30, 2013). Cellular Dynamics International Announces Closing of Initial Public Offering [Press Release]. Retrieved from http://www.cellulardynamics.com/news/pr/2013_07_30.html.%5B8%5D Investors.cellulardynamics.com,. Cellular Dynamics Manufactures Cgmp HLA Superdonor Stem Cell Lines To Enable Cell Therapy With Genetic Matching (NASDAQ:ICEL). N.p., 2015. Web. 7 Mar. 2015.[9] Ibid.[10] Cellulardynamics.com,. Cellular Dynamics | Mycell Products. N.p., 2015. Web. 7 Mar. 2015.[11]Sirenko, O. et al. Multiparameter In Vitro Assessment Of Compound Effects On Cardiomyocyte Physiology Using Ipsc Cells.Journal of Biomolecular Screening 18.1 (2012): 39-53. Web. 7 Mar. 2015.[12] Sciencedirect.com,. Prevention Of -Amyloid Induced Toxicity In Human Ips Cell-Derived Neurons By Inhibition Of Cyclin-Dependent Kinases And Associated Cell Cycle Events. N.p., 2015. Web. 7 Mar. 2015.[13] Sciencedirect.com,. HER2-Targeted Liposomal Doxorubicin Displays Enhanced Anti-Tumorigenic Effects Without Associated Cardiotoxicity. N.p., 2015. Web. 7 Mar. 2015.[14] Cellular Dynamics International, Inc. Fujifilm Holdings To Acquire Cellular Dynamics International, Inc.. GlobeNewswire News Room. N.p., 2015. Web. 7 Apr. 2015.[15] Ibid.[16] Cyranoski, David. Japanese Woman Is First Recipient Of Next-Generation Stem Cells. Nature (2014): n. pag. Web. 6 Mar. 2015.[17] Advanced Cell Technologies (Feb 11, 2011). Advanced Cell and Colleagues Report Therapeutic Cells Derived From iPS Cells Display Early Aging [Press Release]. Available at: http://www.advancedcell.com/news-and-media/press-releases/advanced-cell-and-colleagues-report-therapeutic-cells-derived-from-ips-cells-display-early-aging/.%5B18%5D Advanced Cell Technology (Dec 20, 2012). New Scientist Magazine Selects ACTs Induced Pluripotent Stem (iPS) Cell-Derived Human Platelet Program As One of 10 Ideas That Will Shape The Year [Press Release]. Available at: http://articles.latimes.com/2009/mar/06/science/sci-stemcell6. Web. 9 Apr. 2015.[19] Astellas Pharma (2015). Acquisition of Ocata Therapeutics New Step Forward in Ophthalmology with Cell Therapy Approach. Available at: https://www.astellas.com/en/corporate/news/pdf/151110_2_Eg.pdf. Web. 29 Jan. 2017.

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Market Players Developing iPS Cell Therapies – BioInformant

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Stem Cells – MedicineNet

Stem cell facts

What are stem cells?

Stem cells are cells that have the potential to develop into many different or specialized cell types. Stem cells can be thought of as primitive, “unspecialized” cells that are able to divide and become specialized cells of the body such as liver cells, muscle cells, blood cells, and other cells with specific functions. Stem cells are referred to as “undifferentiated” cells because they have not yet committed to a developmental path that will form a specific tissue or organ. The process of changing into a specific cell type is known as differentiation. In some areas of the body, stem cells divide regularly to renew and repair the existing tissue. The bone marrow and gastrointestinal tract are examples of areas in which stem cells function to renew and repair tissue.

The best and most readily understood example of a stem cell in humans is that of the fertilized egg, or zygote. A zygote is a single cell that is formed by the union of a sperm and ovum. The sperm and the ovum each carry half of the genetic material required to form a new individual. Once that single cell or zygote starts dividing, it is known as an embryo. One cell becomes two, two become four, four become eight, eight become sixteen, and so on, doubling rapidly until it ultimately grows into an entire sophisticated organism composed of many different kinds of specialized cells. That organism, a person, is an immensely complicated structure consisting of many, many, billions of cells with functions as diverse as those of your eyes, your heart, your immune system, the color of your skin, your brain, etc. All of the specialized cells that make up these body systems are descendants of the original zygote, a stem cell with the potential to ultimately develop into all kinds of body cells. The cells of a zygote are totipotent, meaning that they have the capacity to develop into any type of cell in the body.

The process by which stem cells commit to become differentiated, or specialized, cells is complex and involves the regulation of gene expression. Research is ongoing to further understand the molecular events and controls necessary for stem cells to become specialized cell types.

Stem Cells:One of the human body’s master cells, with the ability to grow into any one of the body’s more than 200 cell types.

All stem cells are unspecialized (undifferentiated) cells that are characteristically of the same family type (lineage). They retain the ability to divide throughout life and give rise to cells that can become highly specialized and take the place of cells that die or are lost.

Stem cells contribute to the body’s ability to renew and repair its tissues. Unlike mature cells, which are permanently committed to their fate, stem cells can both renew themselves as well as create new cells of whatever tissue they belong to (and other tissues).

Why are stem cells important?

Stem cells represent an exciting area in medicine because of their potential to regenerate and repair damaged tissue. Some current therapies, such as bone marrow transplantation, already make use of stem cells and their potential for regeneration of damaged tissues. Other therapies that are under investigation involve transplanting stem cells into a damaged body part and directing them to grow and differentiate into healthy tissue.

Embryonic stem cells

During the early stages of embryonic development the cells remain relatively undifferentiated (immature) and appear to possess the ability to become, or differentiate, into almost any tissue within the body. For example, cells taken from one section of an embryo that might have become part of the eye can be transferred into another section of the embryo and could develop into blood, muscle, nerve, or liver cells.

Cells in the early embryonic stage are totipotent (see above) and can differentiate to become any type of body cell. After about seven days, the zygote forms a structure known as a blastocyst, which contains a mass of cells that eventually become the fetus, as well as trophoblastic tissue that eventually becomes the placenta. If cells are taken from the blastocyst at this stage, they are known as pluripotent, meaning that they have the capacity to become many different types of human cells. Cells at this stage are often referred to as blastocyst embryonic stem cells. When any type of embryonic stem cells is grown in culture in the laboratory, they can divide and grow indefinitely. These cells are then known as embryonic stem cell lines.

Fetal stem cells

The embryo is referred to as a fetus after the eighth week of development. The fetus contains stem cells that are pluripotent and eventually develop into the different body tissues in the fetus.

Adult stem cells

Adult stem cells are present in all humans in small numbers. The adult stem cell is one of the class of cells that we have been able to manipulate quite effectively in the bone marrow transplant arena over the past 30 years. These are stem cells that are largely tissue-specific in their location. Rather than typically giving rise to all of the cells of the body, these cells are capable of giving rise only to a few types of cells that develop into a specific tissue or organ. They are therefore known as multipotent stem cells. Adult stem cells are sometimes referred to as somatic stem cells.

The best characterized example of an adult stem cell is the blood stem cell (the hematopoietic stem cell). When we refer to a bone marrow transplant, a stem cell transplant, or a blood transplant, the cell being transplanted is the hematopoietic stem cell, or blood stem cell. This cell is a very rare cell that is found primarily within the bone marrow of the adult.

One of the exciting discoveries of the last years has been the overturning of a long-held scientific belief that an adult stem cell was a completely committed stem cell. It was previously believed that a hematopoietic, or blood-forming stem cell, could only create other blood cells and could never become another type of stem cell. There is now evidence that some of these apparently committed adult stem cells are able to change direction to become a stem cell in a different organ. For example, there are some models of bone marrow transplantation in rats with damaged livers in which the liver partially re-grows with cells that are derived from transplanted bone marrow. Similar studies can be done showing that many different cell types can be derived from each other. It appears that heart cells can be grown from bone marrow stem cells, that bone marrow cells can be grown from stem cells derived from muscle, and that brain stem cells can turn into many types of cells.

Peripheral blood stem cells

Most blood stem cells are present in the bone marrow, but a few are present in the bloodstream. This means that these so-called peripheral blood stem cells (PBSCs) can be isolated from a drawn blood sample. The blood stem cell is capable of giving rise to a very large number of very different cells that make up the blood and immune system, including red blood cells, platelets, granulocytes, and lymphocytes.

All of these very different cells with very different functions are derived from a common, ancestral, committed blood-forming (hematopoietic), stem cell.

Umbilical cord stem cells

Blood from the umbilical cord contains some stem cells that are genetically identical to the newborn. Like adult stem cells, these are multipotent stem cells that are able to differentiate into certain, but not all, cell types. For this reason, umbilical cord blood is often banked, or stored, for possible future use should the individual require stem cell therapy.

Induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) were first created from human cells in 2007. These are adult cells that have been genetically converted to an embryonic stem celllike state. In animal studies, iPSCs have been shown to possess characteristics of pluripotent stem cells. Human iPSCs can differentiate and become multiple different fetal cell types. iPSCs are valuable aids in the study of disease development and drug treatment, and they may have future uses in transplantation medicine. Further research is needed regarding the development and use of these cells.

Why is there controversy surrounding the use of stem cells?

Embryonic stem cells and embryonic stem cell lines have received much public attention concerning the ethics of their use or non-use. Clearly, there is hope that a large number of treatment advances could occur as a result of growing and differentiating these embryonic stem cells in the laboratory. It is equally clear that each embryonic stem cell line has been derived from a human embryo created through in-vitro fertilization (IVF) or through cloning technologies, with all the attendant ethical, religious, and philosophical problems, depending upon one’s perspective.

What are some stem cell therapies that are currently available?

Routine use of stem cells in therapy has been limited to blood-forming stem cells (hematopoietic stem cells) derived from bone marrow, peripheral blood, or umbilical cord blood. Bone marrow transplantation is the most familiar form of stem cell therapy and the only instance of stem cell therapy in common use. It is used to treat cancers of the blood cells (leukemias) and other disorders of the blood and bone marrow.

In bone marrow transplantation, the patient’s existing white blood cells and bone marrow are destroyed using chemotherapy and radiation therapy. Then, a sample of bone marrow (containing stem cells) from a healthy, immunologically matched donor is injected into the patient. The transplanted stem cells populate the recipient’s bone marrow and begin producing new, healthy blood cells.

Umbilical cord blood stem cells and peripheral blood stem cells can also be used instead of bone marrow samples to repopulate the bone marrow in the process of bone marrow transplantation.

In 2009, the California-based company Geron received clearance from the U. S. Food and Drug Administration (FDA) to begin the first human clinical trial of cells derived from human embryonic stem cells in the treatment of patients with acute spinal cord injury.

What are experimental treatments using stem cells and possible future directions for stem cell therapy?

Stem cell therapy is an exciting and active field of biomedical research. Scientists and physicians are investigating the use of stem cells in therapies to treat a wide variety of diseases and injuries. For a stem cell therapy to be successful, a number of factors must be considered. The appropriate type of stem cell must be chosen, and the stem cells must be matched to the recipient so that they are not destroyed by the recipient’s immune system. It is also critical to develop a system for effective delivery of the stem cells to the desired location in the body. Finally, devising methods to “switch on” and control the differentiation of stem cells and ensure that they develop into the desired tissue type is critical for the success of any stem cell therapy.

Researchers are currently examining the use of stem cells to regenerate damaged or diseased tissue in many conditions, including those listed below.

References

REFERENCE:

“Stem Cell Information.” National Institutes of Health.

Originally posted here:
Stem Cells – MedicineNet

Recommendation and review posted by Rebecca Evans

Crisprs Epic Patent Fight Changed the Course of Biology | WIRED

After three bitter years and tens of millions of dollars in legal fees, the epic battle over who owns one of the most common methods for editing the DNA in any living thing is finally drawing to a close. On Monday, the US Court of Appeals for the Federal Circuit issued a decisive ruling on the rights to Crispr-Cas9 gene editingawarding crucial intellectual property spoils to scientists at the Broad Institute of Cambridge, Massachusetts.

The fight for Crispr-Cas9which divided the research community and triggered an uncomfortable discussion about science for personal profit versus public goodhas dramatically shaped how biology research turns into real-world products. But its long-term legacy is not what happened in the courtroom, but what took place in the labs: A wealth of innovation that is now threatening to make Cas9 obsolete.

This latest legal decision, which upholds a 2017 ruling by the US Patent and Trademark Office, was an expected one, given how rarely such rulings are overturned. And it more or less seals defeat for researchers at the University of California Berkeley, who also have claims to invention of the world-remaking technology.

The Broad celebrated the win while calling for a cease-fire, saying it was time to work together to ensure wide, open access to this transformative technology. UCs general counsel, Charles F. Robinson, struck a less conciliatory note, saying in a statement that the university was evaluating further litigation options. Those could include a rehearing from the same court or appeal to the Supreme Court.

But legal experts say the chances of either happening are vanishingly slim. It is very possible that there is no path forward for Berkeley in regards to broad patents covering Crispr-Cas9 at this point , says Jacob Sherkow a scholar of patent law at New York Law School who has closely followed the case. In addition to the Broad Institutes claims, UC-Berkeley also has to contend with another foundational patent for Crispr-Cas9 gene editing filed before anyone else in March 2012, by Virginijus iknys, a Lithuanian scientist who shares the prestigious Kavli Prize with Berkeleys Jennifer Doudna and The University of Viennas Emmanuelle Charpentier for their early work on Crispr. The USPTO has since granted his patent. UC didnt know about it at the time of its own filing because of an 18-month secrecy statute surrounding new applications. If this was a choose-your-own-adventure book, they just turned all the wrong pages, says Sherkow.

The University of California isnt the only loser here; the companies that already placed bets on it being the patent victor must now tread a difficult though not impassable IP landscape. That includes Intellia and Crispr Therapeuticscompanies cofounded by Doudna and Charpentier respectivelywhich are both developing Crispr treatments for human disease. The two firms released a joint statement Monday afternoon underscoring their faith in the strength and scope of UCs foundational IP. A spokesperson for Intellia also said in an email that the Federal Circuit decision will not impact the companys freedom to operate going forward.

For all the ferocity that fueled the fight from its outset, Mondays decision was met with muted interest from inside the halls of science to the crowded trading floors of Wall Street. Thats because a lot has changed since the first gene editing pioneers filed the original Crispr-Cas9 patents. In 2012, Cas9 was the entire Crispr universe. That little enzyme powered all the promise of Crispr gene editing, and the stakes for owning it couldnt have been higher. Scientists didnt yet know that biology would prove to be more creative than patent lawyers. They still had no notion of the vast constellations of constructs and enzymes that could be engineered, evolved in a lab, or harvested from the wild to replace Cas9.

Since then though, the fast-moving field of Crispr biology has yielded more than just alternative pairs of molecular scissors. Researchers have updated the Crispr system to manipulate the code of life in myriad novel waysfrom swapping out individual DNA letters to temporarily flipping genes on and off to detecting dangerous infections. And theyve unearthed dozens of Crispr enzymes of still unknown functions that might one day solve problems scientists havent even thought of yet.

The rush of discoveries and inventions has led to a full-blown patent race, says Sherkow, with anyone who found any new variation racing to file IP protections. The irony is that as the universe of Crispr expands, owning a part of it becomes less and less valuable. Twenty years from now, when the umpteenth drug gets approved using Crispr and some nuclease named Cas132013, people are going to look back on this patent battle and think, what a godawful waste of money, says Sherkow.

He expects that the field will eventually reach a point where the value of each new Crispr patent is so low that researchers dont bother going through all the paperwork and spending the thousands of dollars necessary to file an application. Already, biotechnologists are beginning to learn this lesson in adjacent fields; a land grab for patents is not the only way to go.

The Biobricks Foundation is a nonprofit dedicated to supporting the development of an open-source biotechnology commons. In 2015, it created a legal framework for scientists to put their discoveries in the public domain, safeguarding them from being patented elsewhere, and ensuring that anyone can access them. So far, the organization has begun to stockpile gene sequences for useful tools like fluorescent proteins. Linda Kahl, Biobricks senior counsel and a director there, says theyre still waiting for a group to design an open-source Crispr system. Thats a gauntlet thats in front of researchers, she says. With the ashes of the patent fight still glowing, it might be too soon to expect anyone to give a Crispr tool away for free just yet. But it probably wont take long.

Read the original here:
Crisprs Epic Patent Fight Changed the Course of Biology | WIRED

Recommendation and review posted by Bethany Smith


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