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Archive for the ‘Death by Stem Cells’ Category

Storing Stem Cells For Life – Smart Cells

Monday, March 18th, 2019

One of the bravest moves in that direction has come from stem cell research and therapy. Stem cell therapy is currently being used to successfully treat more than 80 diseases, but the field is rapidly evolving backed by prestigious research and clinical trials.

Smart Cells is the first private UK stem cell storage company to have released stored stem cell units for use in the treatment of children with life-threatening illnesses. We have released the greatest number of samples for use in transplants from the UK.

We believe with the development of technology in the future we will be able to treat even more illnesses.

We believe our customers deserve the best service available and we run our state of the art facility with leading professionals in the field.

We believe that storing your childs stem cells at birth can be a crucial part of treating or curing an unexpected illness.

We believe that in the future this service should be available to every parent, child and family.

We are a company that is for life.

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Stem Cells – The ALS Association

Friday, March 8th, 2019

Overview

Stem cells have the ability to divide for indefinite periods in culture and give rise to multiple specialized cell types. They can develop into blood, neurons, bone, muscle, skin and other cell types. They have emerged as a major tool for research into the causes of ALS, and in the search of new treatments.

Types of Stem Cells:

The field of stem cell research is progressing rapidly, and The ALS Association is spearheading work on several critical fronts. The research portfolio supports innovative projects using IPSCs for drug development and disease modeling. The Association is supporting an IPSC core at Cedars-Sinai Medical Center providing access to lines for researchers globally. Several of the big data initiatives are collecting skin cells or blood for IPSC generation, such as Genomic Translation for ALS Clinical Care (GTAC), Project MinE, NeuroLINCS and Answer ALS. The ALS Association also sponsors pre-clinical studies and pilot clinical trials using stem cell transplant approaches to develop the necessary tools for stem cell transplant studies and to improve methods for safety and efficiency. We also support studies that involve isolating IPSCs to develop biomarkers for clinical trials through ALS ACT. In addition, the retigabine clinical trial that we sponsor uses iPSCs derived from participants in parallel with clinical data to help test whether the drug has the desired effect.

Stem cells are being used in many laboratories today for research into the causes of and treatments for ALS. Most commonly, researchers use iPSCs to make a unique source of motor neurons from individual ALS patients to try to understand why and how motor neurons die in ALS. Two types of motor neurons are affected in ALS are upper coriticospinal motor neurons, that when damaged, cause muscle spasticity (uncontrolled movement), and lower motor neurons, that when damaged, cause muscle weakness. Both types can be made from iPSCs to cover the range of pathology and symptoms found in ALS. Astrocytes, a type of support cell, called glia, of the central nervous system (CNS), are also being generated from iPSCs. It is well established that glia play a role in disease process and contribute to motor neuron death.

Motor neurons created from iPSCs have many uses. The availability of large numbers of identical neurons, made possible by iPSCs, has dramatically expanded the ability to search for new treatments. For example, they can also be used to screen for drugs that can alter the disease process. Motor neurons derived from iPSCs can be genetically modified to produce colored fluorescent markers that allow clear visualization under a microscope. The health of individual motor neurons can be tracked over time to understand if a test compound has a positive or negative effect.

Because iPSCs can be made from skin samples or blood of any person, researchers have begun to make cell lines derived from dozens of individuals with ALS. One advantage of iPSCs are that they capture a persons exact genetic material and provide an unlimited supply of cells that can be studied in a dish, which is like persons own avatar. Comparing the motor neurons derived from these cells lines allows them to ask what is common, and what is unique, about each case of ALS, leading to further understanding of the disease process. They are also used to correlate patients clinical parameters, such as site of onset and severity with any changes in the same patients motor neurons.

Stem cells may also have a role to play in treating the disease. The most likely application may be to use stem cells or cells derived from them to deliver growth factors or protective molecules to motor neurons in the spinal cord. Clinical trials of such stem cell transplants are in the early stages, but appear to be safe. In addition, transplantation of healthy astrocytes have the potential to be beneficial in supporting motor neurons in the brain and spinal cord.

While the idea of replacing dying motor neurons with new ones derived from stem cells is appealing, using stem cells as a delivery tool to provide trophic factors to motor neurons is a more realistic and feasible approach. The significant challenge to replacing dying motor neurons is making the appropriate connections between muscles and surrounding neurons.

Isolation of IPSCs from people with ALS in clinical trials is extremely valuable for the identification of unique signatures in the presence or absence of a specific treatment approach and as a read out to test whether a drug or test compound has an impact on the health of motor neurons and/or astrocytes. A positive result gives researchers confidence to move forward to more advanced clinical trials. For example, The ALS Association is currently funding a clinical trial to test the effects of retigabine on motor neurons, which use the enrolled patients individual iPSCs lines derived from collected skin samples and testing whether there is a change in the excitability of motor neurons in people with ALS. (see above).

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Apple Stem Cells – The Anti-Aging skin care ingredient …

Thursday, March 7th, 2019

What are Stem Cells?

Stem cells are super unique in that they have the ability to go through numerous cycles and cell divisions while maintaining the undifferentiated state. Primarily, stem cells are capable of self-renewal and can transform themselves into other cell types of the same tissue. Their crucial role is to replenish dying cells and regenerate damaged tissue. Stem cells have a limited life expectation due to environmental and intrinsic stress factors. Because their life is endangered by internal and external stresses, stem cells have to be protected and supported to delay preliminary aging. In aged bodies, the number and activity of stem cells in reduced.

Until several years ago, the tart, unappealing breed of the Swiss-grown Uttwiler Sptlauber apples, did not seem to offer anything of value. That was until Swiss scientists discovered the unusual longevity of the stem cells that kept these apples alive months after other apples shriveled and fell off their trees. In the rural region of Switzerland, home of these magical apples, it was discovered that when the unpicked apples or tree bark was punctured, Swiss Apple trees have the ability to heal themselves and last longer than other varieties. What was the secret to these apples prolonged lives?

Proven to Diminish the Signs of Aging

These scientists got to work to find out. What they revealed was that apple stem cells work just like human stem cells, they work to maintain and repair skin tissue. The main difference is that unlike apple stem cells, skin stem cells do not have a long lifespan, and once they begin depleting, the signs of aging start kicking in (in the forms of loose skin, wrinkles, the works). Time to harness these apple stem cells into anti aging skin care! Not so fast. As mentioned, Uttwiler Sptlauber apples are now very rare to the point that the extract can no longer be made in a traditional fashion. The great news is that scientists developed a plant cell culture technology, which involves breeding the apple stem cells in the laboratory.

Human stem cells on the skins epidermis are crucial to replenish the skin cells that are lost due to continual shedding. When epidermal stem cells are depleted, the number of lost or dying skin cells outpaces the production of new cells, threatening the skins health and appearance.

Like humans, plants also have stem cells. Enter the stem cells of the Uttwiler Sptlauber apple tree, whose fruit demonstrates an exceptionally long shelf-life. How can these promising stem cells help our skin?

Studies show that apple stem cells boosts production of human stem cells, protect the cell from stress, and decreases wrinkles. How does it work? The internal fluid of these plant cells contains components that help to protect and maintain human stem cells. Apple stem cells contain metabolites to ensure longevity as the tree is known for the fact that its fruit keep well over long periods of time.

When tested in vitro, the apple stem cell extract was applied to human stem cells from umbilical cords and was found to increase the number of the stem cells in culture. Furthermore, the addition of the ingredient to umbilical cord stem cells appeared to protect the cells from environmental stress such as UV light.

Apple stem cells do not have to be fed through the umbilical cord to benefit our skin! The extract derived from the plant cell culture technology is being harnessed as an active ingredient in anti aging skincare products. When delivered into the skin nanotechnology, the apple stem cells provide more dramatic results in decreasing lines, wrinkles, and environmental damage.

Currently referred to as The Fountain of Youth, intense research has proved that with just a concentration level of 0.1 % of the PhytoCellTec (apple stem cell extract) could proliferate a wealth of human stem cells by an astounding 80%! These wonder cells work super efficiently and are completely safe. Of the numerous benefits of apple stems cells, the most predominant include:

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Register to donate stem cells | Canadian Blood Services

Thursday, March 7th, 2019

The decision to begin a search for a suitable unrelated donor rests entirely with the transplant centre. Our mandate is to coordinate the search and subsequent donation of an unrelated volunteer donor. All volunteer donors must meet a variety of eligibility requirements and undergo a comprehensive health assessment to ensure that the donation process will be safe for them and anyone receiving their stem cells.

Within one business day of receiving the request, the stem cell network forwards a preliminary search report of possible matches to the transplant team. This report lists any potential Canadian and international donors who might be a match to a patient. These potential donors are contacted for further health assessment and to provide DNA samples for additional testing. It is important to remember that each patient not only needs a matched donor, but also a well-informed, committed and healthy donor. On average, it can take up to six months to complete the necessary testing and health assessment screening to confirm the best matched donor.

The search is repeated continuously, so that any newly added donors may be identified. The search process continues until a donor is found and makes a stem cell donation or until the transplant team makes a decision to cancel the search request. Please note that it is not the responsibility of you or your family to find your donor. Your transplant team, working with Canadian Blood Services, is responsible for locating a matched, committed donor for you.

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Can Stem Cells Stop Aging? – Medical News Bulletin …

Monday, February 18th, 2019

Aging is a natural process that is the cumulative effect of genetic and environmental damage to our bodies and DNA. Stem cells found within the body help to combat the effects of aging. Researchers in the US have summarized the research to date concerning how stem cells and anti-aging genes impact the process of aging.

Aging is the unavoidable consequence of living, which may bring a host of health problems. Loss of hearing, vision, muscle strength, bone mass, immunity, cognition, and metabolism are just a few of the issues aging causes. Cumulatively, these health issues impact the society, the economy, and the health care system. Although we cope with these issues through shared programs such as senior housing, retirement savings, and Medicare, they do not cure but merely treat the health problems associated with aging.

Aging is a natural progressive development that is controlled by genetic and environmental factors. These factors negatively or positively affect our bodies to increase or decrease the aging process within our bodies. The accumulation of these factors will ultimately affect the stem cells within our bodies, which can be considered the essential building blocks of our bodies. Stem cells do not typically do work in our bodies, unlike muscle cells that are used for running or neurons within our brain for thinking. Instead, stem cells have the special ability to create copies of themselves and transform into other types of cellssuch as muscle cells or neurons which is the basis of body regeneration.

Stem cells could be considered the key to regulating our aging. Since aging is the natural deterioration of our bodies, stem cells help regenerate our bodies by replacing old cells that are too deteriorated to work or damaged beyond self-help. This is seen most prominently within other animals such as those belonging to thePlanaria genus, which can regenerate their entire bodies in five days, and Hydra, which can also regenerate their entire bodies in seven to ten days. Salamanders can also regenerate their limbs within just a few days.

Although humans do not share the same extent of regeneration, we do have the capacity of regenerating over 2/3 of our livers as well as the entire tips of our fingers at a young age. However, our regeneration is more apparent in healing our bodies from the daily traumas we endure such as environmental pollutants, smoking, drinking, stress, social burden, and depression. A recent review in the journal Stem Cell Research and Therapy summarizes what we know so far about stem cells and aging.

In conjunction with stem cells, genetics play a pivotal role in determining how fast we age. Klotho, named after the Greek goddess which controls the thread of life, is one of the most well-studied anti-aging genes. In genetic studies, turning Klotho on increases the lifespan of mice, while turning Klotho off results in premature aging. Researchers have shown Klotho controls many elements of aging such tissue oxidation, insulin levels, and stem cell regeneration.

Telomere length has been shown to be highly associated with body age. Telomeres are the end-caps of DNA that protect them from being damaged. The longer your telomeres are, the younger your body is. Normally, we are all born with long telomeres, however, as we age our telomeres begin to shorten. Indeed, telomere shortening has been known to be a cause of stem cell senescence (deactivation) and subsequent death.

To combat telomere shortening, our bodies employ an enzyme called telomerase to maintain telomere length as we age. However, telomerase activity also diminishes with age which limits its anti-aging capabilities. Interestingly, calorie restriction has been shown increase telomerase activity and maintain telomere length. Lowering calorie intake by 30% increases lifespan by 30%. Calorie restriction in animal models have shown to have beneficial effects on counteracting oxidation, inflammation, detoxification, telomerase activity, and DNA repair. This phenomenon has been consistent across all animals tested of all complexity suggesting a fundamental link between diet and aging. For ethical reasons, this has never been proven in humans and is not condoned by physicians.

The goal of many current anti-aging treatments is to increase the health and population of stem cells within the body to better counteract the effects of aging through regeneration. One type of stem cell that is of keen interest to researchers and pharmaceutical companies are mesenchymal stem cells (MSC). These stem cells have been shown to be a core factor in skin, muscle, cartilage, and bone regeneration. Normally, MSC is found in the bone marrow. When the body is injured (e.g. skin cut), cytokines, which are chemical signals used by the body to communicate, are released to activate MSC and travel to the injured area for repair.

However, as we age the number of mesenchymal stem cells within our bone marrow will deplete which slows down our regeneration causing us to age. This is most apparent within our skin which deteriorates over time causing loss of elasticity, sagging, and wrinkling. Pharmaceutical companies are interested in harvesting certain growth factors, which are found naturally within our body, to supplement into skin care products. This will hopefully cause the mesenchymal stem cell population within the skin to multiply which will increase our bodys natural skin regeneration.

Aging is a natural process that is the cumulative effect of genetic and environmental damage to our bodys and DNA. Stem cells found naturally within our body help to combat the effects of aging, but degrade over time due to factors such as telomerase decline. Though researchers and pharmaceuticals have shown ways to extend lifespans through genetic and diet alterations, the goal of halting aging altogether seems distant. However, a new wave of anti-aging products, medical advancements, and a better understanding of diet may be able to slow down the aging process and give us more exciting and youthful years.

Written byAaron Kwong, MSc

References:

(1) Ullah, M. & Sun, Z. Stem cells and anti-aging genes: double-edged sworddo the same job of life extension. Stem Cell Res. Ther.9, 3 (2018).(2) Shieh, S.-J. & Cheng, T.-C. Regeneration and repair of human digits and limbs: fact and fiction. Regen. (Oxford, England)2, 14968 (2015).(3) Ogoke, O., Oluwole, J. & Parashurama, N. Bioengineering considerations in liver regenerative medicine. J. Biol. Eng.11, 46 (2017).(4) Heilbronn, L. K. & Ravussin, E. Calorie restriction and aging: review of the literature and implications for studies in humans 1 3. (2003).

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Olivia Colman’s heartfelt appeal for stem cell donors …

Monday, February 18th, 2019

BAFTA winner Olivia Colman has made a heartfelt appeal for people to donate stem cells after losing her school friend to blood cancer.

The Favourite actress revealed how a transplant gave classmate Pip hope in the darkness.

In a video for the charity Anthony Nolan, the star describes how her friend, who was diagnosed with leukaemia at the age of 31, didnt make it.

Colman urges the public to sign up to the charitys stem cell register, which she and husband Ed Sinclair joined in 2008, so that others have a chance of living. In the film, she says: Sadly my friend Pip didnt make it, but together we can make sure more people like Pip do make it. We want more people on the register. Its just a little swab of the mouth Without you there is no cure.

Pips only chance of survival had been a donor who could provide a perfect match, according to Colman. Soon a donor was found in Australia. Anthony Nolan did an amazing thing, Colman said. She became patron of Anthony Nolan in July last year.

About 2,000 people in the UK need a stem cell transplant every year. Donations from young men and people with black, Asian and ethnic minority backgrounds are needed in particular.

Anthony Nolans chief executive Henny Braund said: It is wonderful to have Olivias support and I am grateful to her for sharing this heartfelt story. This will help us continue to give hope to thousands of people every year.

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Neurogenesis – Wikipedia

Tuesday, February 12th, 2019

Neurogenesis is the process by which nervous system cells, known as neurons, are produced by neural stem cells (NSC)s, and it occurs in all species of animals except the porifera (sponges) and placozoans.[1] Types of NSCs include neuroepithelial cells (NECs), radial glial cells (RGCs), basal progenitors (BPs), intermediate neuronal precursors (INP)s, subventricular zone astrocytes, and subgranular zone radial astrocytes, among others.[2] Neurogenesis is most active during embryonic development, and is responsible for producing all the various types of neurons of the organism, but continues throughout adult life in a variety of organisms.[3] Once born, neurons do not divide (see mitosis), and many will live the lifetime of the animal.[4]

During embryonic development, the mammalian central nervous system (CNS; brain and spinal cord) is derived from the neural tube, which contains NSCs that will later generate neurons.[5] However, neurogenesis doesn't begin until a sufficient population of NSCs has been achieved. These early stem cells are called neuroepithelial cells (NEC)s, but soon take on a highly elongated radial morphology and are then known as radial glial cells (RGC)s.[6] RGCs are the primary stem cells of the mammalian CNS, and reside in the embryonic ventricular zone, which lies adjacent to the central fluid-filled cavity (ventricular system) of the neural tube.[7][8] Following RGC proliferation, neurogenesis involves a final cell division of the parent RGC, which produces one of two possible outcomes. First, this may generate a subclass of neuronal progenitors called intermediate neuronal precursors (INP)s, which will divide one or more additional times to produce neurons. Alternatively, daughter neurons may be produced directly. Neurons do not immediately form neural circuits through the growth of axons and dendrites. Instead, newborn neurons must first migrate long distances to their final destinations, maturing and finally generating neural circuitry. For example, neurons born in the ventricular zone migrate radially to the cortical plate, which is where neurons accumulate to form the cerebral cortex.[9][10] Thus, the generation of neurons occurs in a specific tissue compartment or 'neurogenic niche' occupied by their parent stem cells.

The rate of neurogenesis and the type of neuron generated (broadly, excitatory or inhibitory) are principally determined by molecular and genetic factors. These factors notably include the Notch signaling pathway, and many genes have been linked to Notch pathway regulation.[11][12] The genes and mechanisms involved in regulating neurogenesis are the subject of intensive research in academic, pharmaceutical, and government settings worldwide.

The amount of time required to generate all the neurons of the CNS varies widely across mammals, and brain neurogenesis is not always complete by the time of birth.[13] For example, mice undergo cortical neurogenesis from about embryonic day (post-conceptional day) (E)11 to E17, and are born at about E19.5.[14] Ferrets are born at E42, although their period of cortical neurogenesis does not end until a few days after birth.[15] In contrast, neurogenesis in humans generally begins around gestational week (GW) 10 and ends around GW 25 with birth about GW 38-40.[16]

Adult neurogenesis has been shown to occur at low levels compared with development, and in only two regions of the brain: the adult subventricular zone (SVZ) of the lateral ventricles, and the dentate gyrus of the hippocampus.[17][18][19]

In many mammals, including for example rodents, the olfactory bulb is a brain region containing cells that detect smell, featuring integration of adult-born neurons, which migrate from the SVZ of the striatum to the olfactory bulb through the rostral migratory stream (RMS).[20][21] The migrating neuroblasts in the olfactory bulb become interneurons that help the brain communicate with these sensory cells. The majority of those interneurons are inhibitory granule cells, but a small number are periglomerular cells. In the adult SVZ, the primary neural stem cells are SVZ astrocytes rather than RGCs. Most of these adult neural stem cells lie dormant in the adult, but in response to certain signals, these dormant cells, or B cells, go through a series of stages, first producing proliferating cells, or C cells. The C cells then produce neuroblasts, or A cells, that will become neurons.[22]

Significant neurogenesis also occurs during adulthood in the hippocampus of many mammals, from rodents to some primates, although its existence in adult humans is debated.[23][24] The hippocampus plays a crucial role in the formation of new declarative memories, and it has been theorized that the reason human infants cannot form declarative memories is because they are still undergoing extensive neurogenesis in the hippocampus and their memory-generating circuits are immature.[25] Many environmental factors, such as exercise, stress, and antidepressants have been reported to change the rate of neurogenesis within the hippocampus of rodents.[26][27] Some evidence indicates postnatal neurogenesis in the human hippocampus decreases sharply in newborns for the first year or two after birth, dropping to "undetectable levels in adults."[28]

Neurogenesis has been best characterized in the fruit fly, Drosophila melanogaster.[29] In Drosophila, Notch signaling was first described, controlling a cell-to-cell signaling process called lateral inhibition, in which neurons are selectively generated from epithelial cells.[30][31] In some vertebrates, regenerative neurogenesis has also been shown to occur.[32]

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Brain Death Reversed with Stem Cells – Live Trading News

Thursday, December 6th, 2018

Brain Death Reversed With Stem Cells

Stem cells have the potential to be used to treat and better understand some of the worlds most deadly and disabling diseases.

The Big Q: Who is not interested in new ways to apply stem cell therapy?

The Big A: We are and have opened our Tatget 150 clinic in Bangkok, Thailand to apply this growing, life extending science.

We have recently heard about scientists in Philadelphia, PA, USA who have been injecting stem cells directly into the spinal cords of medically brain-dead people in order to revive them.

The idea of bringing people back from the dead is a little too much for some critics to manage.

In March 2017, researchers at the biotech company,Bioquark,got approval to begin a clinical trial with 20 test patients to see if neural brain damage could be reversed.

TheBioquarkwebsite says the research and development organization is a life sciences company developing proprietary combinatorial biologic products for both the regeneration and repair of human organs and tissues, as well as the reversion of a range of chronic degenerative diseases.

Integrating regenerative biology, evolutionary genomics, and bio-cybernetics, the futurists are offering death-resisting treatments: a set of novel bio-products capable of directly remodeling diseased, damaged, or aged tissues.

These achievements alone sound compelling, Yes?

But, then when adding the potential of restoring brain function to a lifeless mind and the appeal goes up, way up.

Bioquarkgot the federal nod t go ahead with their Non-randomized, Open-labeled, Interventional, Single Group, Proof of Concept Study With Multi-modality Approach in Cases of Brain Death Due to Traumatic Brain Injury Having Diffuse Axonal Injury study, slated to begin in July 2018. Youll note theres no mention of raising the dead at this point.

The study participants will not be injected with stem cells. that is just the 1st step of this experimental treatment. Next, a peptide formula will be injected into the spinal cord. This is supposed to help new neurons grow. Finally, a 15-day course of nerve stimulation and laser therapy will be administered, to stimulate neurons to form connections.

The main diagnostic tool is the electroencephalogram (EEG) which measures brainwaves and records them for future review. EEG results will be used to determine if the therapy is working or not.

Diffuse axonal injury (DAI) is a type of traumatic brain injury. It happens when the brain suddenly and swiftly shifts inside the skull while an injury is happening. The axons (long connecting fibers) in the brain are sheared when the brain smacks against the skull and bounces back, accelerating and decelerating rapidly.

DAI commonly damages many parts of the brain, to the extent that DAI patients are typically in a coma state. The main symptom is loss of consciousness, which usually lasts no more than six hours or so. But even if a person comes out of a comatose state, there may be signs of brain damage such as:

This multi-pronged treatment that combines injections of stem cells and chemical formulas with nerve stimulation is brand new and already attracting controversy.

Some of the debate has nothing to do with morality or ethics, but talk about the way to sign up a study participant who has been pronounced legally dead.

Most US state laws define death as the irreversible loss of heart and lung or brain function.

The Big Qs 2&3: If the researchers are successful in restoring brainwaves to an inactive mind, will the patients personality and memories be restored intact? Will the individual be in a mental condition comparable to what the person had before the traumatic brain injury?

The Big As 2&3:

Dr. Ed Cooper, an orthopedic surgeon involved in the study, gave Zero odds for success because the procedure must act on a functional brain stem which connects most of the motor neurons to the cerebral cortex.

But Ira Pastor, Bioquarks CEO, agreed with his colleague, Dr. Cooper in principle but gave hope for a positive outcome because there is a small nest of cells that continue to operate in brain-dead patients.

Dr. Pastor is an optimist about restoring brain activity in comatose or brain-damaged patients. I just think its a matter of putting it all together and getting the right people and the right minds on it, he said.

Dr. Charles Cox, a pediatric surgeon at the University of Texas Health Science Center at Houston who has researched the kind of stem cells used in the Bioquark trial, echoed Dr. Coopers reservations: I think reviving someone would technically be a miracle. I think the Pope would technically call that a miracle.

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Brain Death Reversed with Stem Cells - Live Trading News

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Reverse Brain Death with Stem Cells | The Health Edge

Thursday, December 6th, 2018

Who isnt interested in new ways to apply stem cell therapy these days?

Speaking of, have you heard about the scientists in Philadelphia, PA, who have been injecting stem cells directly into the spinal cords of medically brain-dead people in order to revive them?

In a page taken from Mary Shelleys Frankenstein, the idea of bringing people back from the dead is a little too much like playing God for some critics to appreciate.

In March 2017, researchers at the biotech company, Bioquark, got approval to begin a clinical trial with 20 test patients to see if neural brain damage could be reversed.

The Bioquark website says the research and development organization is a life sciences company developing proprietary combinatorial biologic products for both the regeneration and repair of human organs and tissues, as well as the reversion of a range of chronic degenerative diseases.

Integrating regenerative biology, evolutionary genomics, and bio-cybernetics, the futurists are offering death-resisting treatments: a set of novel bio-products capable of directly remodeling diseased, damaged, or aged tissues.

These achievements alone sound pretty compelling. But toss in restoring brain function to a lifeless mind and the appeal goes way up.

Bioquark got the federal nod t go ahead with their Non-randomized, Open-labeled, Interventional, Single Group, Proof of Concept Study With Multi-modality Approach in Cases of Brain Death Due to Traumatic Brain Injury Having Diffuse Axonal Injury study, slated to begin in July 2018. Youll note theres no mention of raising the dead at this point.

The study participants will not be injected with stem cells thats just the first step of this experimental treatment. Next, a peptide formula will be injected into the spinal cord. This is supposed to help new neurons grow. Finally, a 15-day course of nerve stimulation and laser therapy will be administered, to stimulate neurons to form connections.

The main diagnostic tool is the electroencephalogram (EEG) which measures brainwaves and records them for future review. EEG results will be used to determine if the therapy is working or not.

Diffuse axonal injury (DAI) is a type of traumatic brain injury. It happens when the brain suddenly and swiftly shifts inside the skull while an injury is happening. The axons (long connecting fibers) in the brain are sheared when the brain smacks against the skull and bounces back, accelerating and decelerating rapidly.

DAI commonly damages many parts of the brain, to the extent that DAI patients are typically in a coma state. The main symptom is loss of consciousness, which usually lasts no more than six hours or so. But even if a person comes out of a comatose state, there may be signs of brain damage such as:

This multi-pronged treatment that combines injections of stem cells and chemical formulas with nerve stimulation is brand new and already attracting controversy. Some of the debate has nothing to do with morality or ethics. One question raised was: How do you sign up a study participant who has been pronounced legally dead? (Most U.S. state laws define death as the irreversible loss of heart and lung or brain function.)

If the researchers are successful in restoring brainwaves to an inactive mind, will the patients personality and memories be restored intact? Will the individual be in a mental condition comparable to what s/he had before the traumatic brain injury?

Dr. Ed Cooper, an orthopedic surgeon involved in the study, gave zero odds for success because the procedure must act on a functional brain stem which connects most of the motor neurons to the cerebral cortex.

But Ira Pastor, Bioquarks CEO, agreed with his colleague Cooper in principle but gave hope for a positive outcome because there is a small nest of cells that continue to operate in brain-dead patients.

Pastor is nothing but an optimist about restoring brain activity in comatose or brain-damaged patients. I just think its a matter of putting it all together and getting the right people and the right minds on it, he said.

Dr. Charles Cox, a pediatric surgeon at the University of Texas Health Science Center at Houston who has researched the kind of stem cells used in the Bioquark trial, echoed Dr. Coopers reservations:

I think [reviving someone] would technically be a miracle. I think the pope would technically call that a miracle.

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Reverse Brain Death with Stem Cells | The Health Edge

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Brain Death Reversed with Stem Cells – Emex Investment

Thursday, December 6th, 2018

Brain Death Reversed With Stem Cells

Stem cells have the potentialto be used to treat and better understand some of the worldsmost deadly and disabling diseases.

The Big Q: Who is not interested in new ways to apply stem celltherapy?

The Big A:We are and have opened our Tatget 150 clinic in Bangkok,Thailand to apply this growing, life extending science.

We have recently heard about scientists in Philadelphia, PA,USA who have been injecting stem cells directly into the spinalcords of medically brain-dead people in order to revive them.

The idea of bringing people back from the dead is alittle too much for some critics to manage.

In March 2017, researchers at the biotechcompany,Bioquark,gotapproval to begin a clinical trial with 20 test patients to seeif neural brain damage could be reversed.

TheBioquarkwebsitesays the research and development organization is a lifesciences company developing proprietary combinatorial biologicproducts for both the regeneration and repair of human organsand tissues, as well as the reversion of a range of chronicdegenerative diseases.

Integrating regenerative biology, evolutionary genomics, andbio-cybernetics, the futurists are offering death-resistingtreatments: a set of novel bio-products capable of directlyremodeling diseased, damaged, or aged tissues.

These achievements alone sound compelling, Yes?

But, then when adding the potential of restoring brain functionto a lifeless mind and the appeal goes up, way up.

Bioquarkgotthe federal nod t go ahead with their Non-randomized,Open-labeled, Interventional, Single Group, Proof of ConceptStudy With Multi-modality Approach in Cases of Brain Death Dueto Traumatic Brain Injury Having Diffuse Axonal Injury study,slated to begin in July 2018. Youll note theres no mention ofraising the dead at this point.

The study participants will not be injected with stem cells.that is just the 1st step of this experimental treatment. Next,a peptide formula will be injected into the spinal cord. Thisis supposed to help new neurons grow. Finally, a 15-day courseof nerve stimulation and laser therapy will be administered, tostimulate neurons to form connections.

The main diagnostic tool is the electroencephalogram (EEG)which measures brainwaves and records them for future review.EEG results will be used to determine if the therapy is workingor not.

Diffuse axonal injury (DAI) is a type of traumatic braininjury. It happens when the brain suddenly and swiftly shiftsinside the skull while an injury is happening. The axons (longconnecting fibers) in the brain are sheared when the brainsmacks against the skull and bounces back, accelerating anddecelerating rapidly.

DAI commonly damages many parts of the brain, to the extentthat DAI patients are typically in a coma state. The mainsymptom is loss of consciousness, which usually lasts no morethan six hours or so. But even if a person comes out of acomatose state, there may be signs of brain damage such as:

This multi-pronged treatment that combines injections of stemcells and chemical formulas with nerve stimulation is brand newand already attracting controversy.

Some of the debate has nothing to do with morality or ethics,but talk about the way to sign up a study participant who hasbeen pronounced legally dead.

Most US state laws define death as the irreversible loss ofheart and lung or brain function.

The Big Qs 2&3: If the researchers are successful inrestoring brainwaves to an inactive mind, will the patientspersonality and memories be restored intact? Will theindividual be in a mental condition comparable to what theperson had before the traumatic brain injury?

The Big As 2&3:

Dr. Ed Cooper, an orthopedic surgeon involved in the study,gave Zero odds for success because the procedure must act on afunctional brain stem which connects most of the motor neuronsto the cerebral cortex.

But Ira Pastor, Bioquarks CEO, agreed with his colleague, Dr.Cooper in principle but gave hope for a positive outcomebecause there is a small nest of cells that continue tooperate in brain-dead patients.

Dr. Pastor is an optimist about restoring brain activity incomatose or brain-damaged patients. I just think its a matterof putting it all together and getting the right people and theright minds on it, he said.

Dr. Charles Cox, a pediatric surgeon at the University of TexasHealth Science Center atHouston who has researched the kind of stem cells used in theBioquark trial, echoed Dr. Coopers reservations: I thinkreviving someone would technically be a miracle. I think thePope would technically call that a miracle.

Eat healthy, Be healthy, Live lively

brain, cells, dead,injury, loss,miracle, neurons, patients, Pope,restoring, reversed, stem,study

Paul A. Ebeling, polymath, excels in diverse fields ofknowledge. Pattern Recognition Analyst in Equities,Commodities and Foreign Exchange and author of The RedRoadmasters Technical Report on the US Major MarketIndices, a highly regarded, weekly financial marketletter, he is also a philosopher, issuing insights on awide range of subjects to a following of over 250,000cohorts. An international audience of opinion makers,business leaders, and global organizations recognizesEbeling as an expert.

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The ARTS of life and death in the intestinal stem cells

Wednesday, November 21st, 2018

After passing through thestomach, the next stage of the digestive system occurs in the small intestine,where nutrients and minerals are absorbed. With a host of digestive enzymes, inaddition to a diverse microbiome present, the lining of the small intestine isexposed to quite the chemical soup that causes the cells much wear and tear. Betweenthe villi of the small intestine, that increase the surface area available toabsorb nutrients, are crypts, at the bottom of which reside stem cells. Thesestem cells are the source for new cells to replace the ones lost at the epitheliallining maintaining the balance of life and death. However, not all the stemcells stay as stem cells. This is important to prevent overgrowth of theintestine which could lead to cancer. The exact molecular mechanisms thatunderpin this critical balance between stem cell life and death is stillincomplete. However, a new paper published in Nature 1 by Koren et al. provides new light on the role of ARTS inthis process.

Making the intestine pretty

Goblet cells may not soundvery pretty, but they make up one of the six different differentiated celltypes in the intestine epithelium. Along with enterocytes covered inmicrovilli, the goblet cells make up the villus lining. At the other end, atthe bottom of the crypt, are the Paneth cells, the crypt-base columnar cells(CBCs) and the +4 cells, so named for their position from the base of the crypt(Figure 1).

Figure 1 cells in the smallintestine crypt

Of these cells, the CBCs arethought to be the true stem cells of the small intestine, replicating toproduce more stem cells or cells that will later differentiate to become theother cell types. Since some stem cells will divide to produce more stem cellswhilst others divide and differentiate, over time the small intestine crypt becomesdominated by cells originating from one stem cell clone it becomes monoclonal.A previous study beautifully illustrated this phenomenon using differentcoloured fluorescent markers as can be seen in Figure 2.

Figure 2 taken from ref(2),the crypt shows that differentiated cells originate from stem cells at thebottom of the crypt

These results clearly showed howthe regeneration of the small intestine occurs through a conveyor beltmechanism 2 . It also confirmed known ideas that the stemcells resided near the bottom of crypts. But how are the stem cells eliminated?

Apoptosis a type of celldeath

There are many ways thatcells can die they can get damaged and release all of their contents, cellscan get infected by bacteria or viruses, or cells can trigger their own death.The last case is best known as apoptosis. There are proteins in a cell that promote apoptosis. So, to prevent cells from killing themselves all the time, there are also proteins that prevent cell death. The proteins are referred to as pro-apoptotic or anti-apoptotic respectively. One family of the anti-apoptotic proteins are literally called IAP, for inhibitor of apoptosis. However, these inhibitors can also get inhibited. For example, one IAP, xIAP, can be inhibited by ARTS. ARTS is therefore a pro-apoptotic protein. Its like how the enemy of an enemy is your friend xIAP is an enemy of ARTS and apoptosis is an enemy of IAP so ARTS and apoptosis are friends Well, I reckon that would be an interesting friendship, but by antagonising xIAP, the inhibitor of apoptosis can no longer inhibit apoptosis.

Where ARTS thou?

By using a tagged antibodythat specifically recognises ARTS, the authors were able to stain and locateARTS within the crypt of the small intestine. ARTS was mainly found both in thestem cells and the neighbouring Paneth cells. When they deleted the ARTS genefrom the cells they saw that the crypt increased in size and cell number. Thisis somewhat expected given ARTS role as a pro-cell-death factor and thephenotype was reversed when xIAP was also genetically removed. By using astem-cell specific reporter, it became clear that part of this increased cellsnumber was due to an increase in stem cell number. Paneth cells also increasedin number.

But is this cell expansiondue to less death or more proliferation?

To determine this, the teamtreated the crypt cells with staurosporine, a chemical that induces apoptosis.Compared to a wild type control, the crypts lacking ARTS showed less expressionof a pro-apoptotic protein, cleaved-caspase 3.

But could proliferation alsobe increased?

The Paneth cells, neighbouringthe stem cells, promote stem cell proliferation by providing growth factors. Themain growth pathway activated in the stem cells is the Wnt/-catenin. When cells lacked ARTS, the authors saw not onlyincreased levels of a proliferation marker but also increased -catenin levels in the nucleus a good indication that the growthpathway has been activated. However, preventing Wnt signalling does not preventthe apoptosis resistance seen without ARTS.

The function of ARTS in theintestine

Korens teams work is one ofthe first to examine the death of stem cells, an important mechanism as leftunregulated could result in uncontrollable tissue growth. Since uncontrollablegrowth is one of the hallmarks of cancer, including colorectal cancer, and thatloss of ARTS promotes crypt cell growth, this work provides new theory forrational drug development.

Further reading

1. Koren, E. et al. ARTSmediates apoptosis and regeneration of the intestinal stem cell niche. Nat.Commun. 117 doi:10.1038/s41467-018-06941-4

2. Snippert, H. J. et al.Intestinal crypt homeostasis results from neutral competition betweensymmetrically dividing Lgr5 stem cells. Cell 143, 134144 (2010).

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Necrosis – Wikipedia

Friday, September 28th, 2018

Necrosis (from the Greek "death, the stage of dying, the act of killing" from "dead") is a form of cell injury which results in the premature death of cells in living tissue by autolysis.[1]

Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma which result in the unregulated digestion of cell components.

In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death.

While apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal.[2]

Cellular death due to necrosis does not follow the apoptotic signal transduction pathway, but rather various receptors are activated, and result in the loss of cell membrane integrity and an uncontrolled release of products of cell death into the extracellular space.[1]

This initiates in the surrounding tissue an inflammatory response which attracts leukocytes and nearby phagocytes which eliminate the dead cells by phagocytosis. However, microbial damaging substances released by leukocytes would create collateral damage to surrounding tissues.[3] This excess collateral damage inhibits the healing process. Thus, untreated necrosis results in a build-up of decomposing dead tissue and cell debris at or near the site of the cell death. A classic example is gangrene. For this reason, it is often necessary to remove necrotic tissue surgically, a procedure known as debridement.

Structural signs that indicate irreversible cell injury and the progression of necrosis include dense clumping and progressive disruption of genetic material, and disruption to membranes of cells and organelles.[4]

There are six distinctive morphological patterns of necrosis:[5]

Necrosis may occur due to external or internal factors.

External factors may involve mechanical trauma (physical damage to the body which causes cellular breakdown), damage to blood vessels (which may disrupt blood supply to associated tissue), and ischemia.[11] Thermal effects (extremely high or low temperature) can result in necrosis due to the disruption of cells.

In frostbite, crystals form, increasing the pressure of remaining tissue and fluid causing the cells to burst.[11] Under extreme conditions tissues and cells die through an unregulated process of destruction of membranes and cytosol.[12]

Internal factors causing necrosis include: trophoneurotic disorders; injury and paralysis of nerve cells. Pancreatic enzymes (lipases) are the major cause of fat necrosis.[11]

Necrosis can be activated by components of the immune system, such as the complement system; bacterial toxins; activated natural killer cells; and peritoneal macrophages.[1] Pathogen-induced necrosis programs in cells with immunological barriers (intestinal mucosa) may alleviate invasion of pathogens through surfaces affected by inflammation.[1] Toxins and pathogens may cause necrosis; toxins such as snake venoms may inhibit enzymes and cause cell death.[11] Necrotic wounds have also resulted from the stings of Vespa mandarinia.[13]

Pathological conditions are characterized by inadequate secretion of cytokines. Nitric oxide (NO) and reactive oxygen species (ROS) are also accompanied by intense necrotic death of cells.[11] A classic example of a necrotic condition is ischemia which leads to a drastic depletion of oxygen, glucose, and other trophic factors and induces massive necrotic death of endothelial cells and non-proliferating cells of surrounding tissues (neurons, cardiomyocytes, renal cells, etc.).[1] Recent cytological data indicates that necrotic death occurs not only during pathological events but it is also a component of some physiological process.[11]

Activation-induced death of primary T-lymphocytes and other important constituents of the immune response are caspase-independent and necrotic by morphology; hence, current researchers have demonstrated that the occurrence of necrotic cell death can not only occur during pathological processes but also during normal processes such as tissue renewal, embryogenesis, and immune response.[11]

Until recently, necrosis was thought to be an unregulated process.[14] There are two broad pathways in which necrosis may occur in an organism.[14]

The first of these two pathways initially involves oncosis, where swelling of the cells occur.[14] The cell then proceeds to blebbing, and this is followed by pyknosis, in which nuclear shrinkage transpires.[14] In the final step of this pathway the nucleus is dissolved into the cytoplasm, which is referred to as karyolysis.[14]

The second pathway is a secondary form of necrosis that is shown to occur after apoptosis and budding.[14] Cellular changes of necrosis occur in this secondary form of apoptosis, where the nucleus breaks into fragments, which is known as karyorrhexis.[14]

The nucleus changes in necrosis, and characteristics of this change are determined by manner in which its DNA breaks down:

Plasma alterations are also seen in necrosis. Plasma membranes appear discontinuous when viewed with an electron microscope. This discontinuous membrane is caused by cell blebbing and the loss of microvilli.[5]

There are many causes of necrosis, and as such treatment is based upon how the necrosis came about. Treatment of necrosis typically involves two distinct processes: Usually, the underlying cause of the necrosis must be treated before the dead tissue itself can be dealt with.

Even after the initial cause of the necrosis has been halted, the necrotic tissue will remain in the body. The body's immune response to apoptosis, which involves the automatic breaking down and recycling of cellular material, is not triggered by necrotic cell death due to the apoptotic pathway being disabled.[20]

If calcium is deficient, pectin cannot be synthesized, and therefore the cell walls cannot be bonded and thus an impediment of the meristems. This will lead to necrosis of stem and root tips and leaf edges.[21] For example, necrosis of tissue can occur in Arabidopsis thaliana due to plant pathogens.

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Skin & Human Stem Cells : An Introduction | BareFacedTruth.com

Friday, August 3rd, 2018

We have a lot of knowledge to share with you about stem cells and their value in skin care. We thought we would start with a current review of ongoing work in human stem cell science to give you some context. In the next few days we will be getting a lot more specific about wound healing, anti-aging, and related applications.

Human Stem Cells: Introduction

Future advances in many medical fields are thought to be dependent on continued progress in stem cell research. In this section, BTF briefly looks at the future of stem cell based therapies in the treatment of traumatic injury, degenerative diseases, and other ailments, and concludes with a review of current cell based therapies (stem cell and non-stem cell) in the field of skin care.

While the possible indications for stem cell based therapies are numerous,the field of stem cell science is young and years (or decades) may pass before todays promising laboratory results translate into useful clinical treatments. Only time will tell whether successes evolve or remain frustratingly elusive. We do know that success is possible.

The first stem cell therapy was bone marrow transplantation, originally accomplished in the mid 1960s. Last year, there were more than 50,000 such transplants worldwide. In earlier years, infusion of filtered bone marrow cells was performed with stem cells comprising but a very small part of the volume. Newer techniques have made it possible to separate cellular types to enable use of much higher concentrations of stem cells.

Much progress has been made in characterizing stem cells and understanding how they function. There is much more to the story than differentiation into tissue specific cells. Recent research shows that perhaps even more important is the fact that stem cells, especially certain types of stem cells, communicate with the cells around them by producing cellular signals called cytokines, of which there are hundreds.

Cytokines trigger specific receptors on cell membranes that result in precise responses. This phenomenon is considered an essential element in the healing response of all tissues. Identifying and characterizing the large number of cytokines is an important part of stem cell research.

Not every induced response is necessarily beneficial. It is the symphony of responses that is important. How to promote helpful responses while inhibiting non-beneficial ones is a continuing focus of cellular biochemical research as well as the basis upon which drug companies spend huge resources developing drugs to either trigger or block particular cytokine receptors. Good examples in the field of dermatology are EGFR (epidermal growth factor receptor) blocking compounds for use in treating susceptible cells, most notably cancers stimulated by EGF.

Potential Treatments

Stem cell therapies hold potential to treat many conditions and diseases that affect millions of people in the U.S.

From the Laboratory to the Bedside

Going from the research laboratory to the bedside takes time. Only one month ago, the FDA granted marketing approval for the first licensed stem cell product. Derived from donated umbilical cord blood, the product contains stem cells that can restore a recipients blood cell levels and function. In the chart below, the type of cells recovered from umbilical cord blood are those designated as HSC cell. They are the exact cells responsible for the success of bone marrow transplantation.

Of particular note are the cells designated in the chart as MSC or mesenchymal stem cells. MSC cells are the focus of intense research in the treatment of a number of conditions because this type of stem cell can differentiate into a variety of cell types including bone, cartilage, muscles, nerve, and skin (fibroblast.)

Recent announcements about stem cells being used to fabricate replacement parts (bone, cartilage, heart muscle) are based on MSC research. They truly are the duct tape of the bodys repair tool box; a phrase coined because of their importance in the healing of injuries.

Research has shown MSC cells reside in a number of tissues, including the bone marrow. Through precise chemical signaling that originate from sites of injury, MSC cells have the ability to become mobile, enter the blood stream and travel through the circulation to the injury. Upon arrival, MSCs orchestrate the healing response. Local resident stem cells are also called into action, to produce more stem cells or to produce needed tissue specific cells. In large part, MSCs accomplish their tasks bio-chemically.

Secreted cytokines have been identified as themajormechanism by which MSCs perform their important reparative functions. There are hundreds of cytokines identified thus far. The healing response is an intricate and balanced process in which many cytokines participate.

Despite their inherent ability to differentiate into essentially any type of cell, embryonic stem cells are unlikely to be a major research focus in the foreseeable future. Ethical and political considerations limit the acceptability of their use. Federal regulations permit research only on existing cell lines which are few in number. It is difficult to see how this prohibition will end any time soon.

Getting Closer butNot There Yet

MSC (mesenchymal stem cell) therapies include use ofcellsanduse of MSC factors, the cytokines or chemical messengers mentioned above. Methods of administration will likely include intravenous infusion, injections into tissues or body spaces, or development of drugs that activate or block certain cytokine effects. Drugs already in development include epidermal growth factor receptor (EGFR) blockers for use in cancer treatment.

Stem Cells and Skin Health

From fetal life to death, the numbers and activity of stem cells diminish. The chart at left shows how the population of mesenchymal stem cells in the bone marrow dwindles with age.

Knowing that stem cells are important in producing differentiated daughter cells (such as fibroblasts within the dermis) and are instrumental in orchestrating the bodys response to injury, it is easy to understand how skin damage from sun exposure, gravity, smoking, trauma, toxins, even repetitive facial movement, accumulates over time.

This is one line of evidence (we will look at others) that mesenchymal stem cells (or more specifically the relative lack of same) has a lot to do with aging. Skin aging included.

Products Claiming to Activate Skin Stem Cells

The number of skin products claiming to activate human skin stem cells is large and growing. As discussed previously on BFT, a whole slew of plant derived stem cell products are being marketing, NONE of which can actually or theoretically activate anything, especially not a human stem cell.

Other products claim to have essential nutrients or antioxidants or some other magical ingredient that will suddenly make stem cells take notice and unleash their regenerative power. It is highly unlikely, except in the most extreme case of malnourishment, that any nutrient or antioxidant is deficient enough to cause a cell not to function.

These and the botanical stem cell products are marketing ploys. Human stem cells deep within the dermis will never know whether or not these substances are applied. Moisturizers and other recognized ingredients in these products can be beneficial to skin appearancebut not because a stem cell is involved.

This is worse than junk science. This is scamming.

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Scientists edit heart muscle gene in stem cells, may be …

Sunday, July 22nd, 2018

Story highlights

In other words, the impact certain variants could have on your health remains a guessing game.

"Patients often ask us what do these variants of uncertain significance mean. But in reality, we don't know most of the time ourselves. So we end up having to follow the patients for the next five, 10, 20, or 30 years to see if the patient manifests the disease or not," Wu said.

"Here, we now have a way to shorten that time because we can generate patients' induced pluripotent stem cells from blood."

How do those stem cells then help predict if a variant is harmful or not? They can be differentiated into heart cells.

If the heart cells look abnormal, that probably means the variant of uncertain significance is pathogenic, meaning it's capable of causing disease.

If the heart cells look normal, that probably means the variant of uncertain significance is actually benign.

"This is one of the very first proof of principles to show that concept," Wu said.

'An important step towards precision medicine'

The researchers found 592 genetic variants across the 54 people. While 78% of the variants were categorized as benign, there were 17 people who each carried a variant categorized as "likely pathogenic." For four of those people, their variant was hypertrophic cardiomyopathy-related.

So the researchers then took that knowledge and used CRISPR to turn the patient's stem cells with this MYL3 genetic variant from being heterozygous, meaning they have one normal and one recessive form of the variant, to being homozygous, so that they have two recessive forms of the variant.

Specifically, the researchers took the one study participant's blood cells, turned them into induced pluripotent stem cells, and then used CRISPR to edit those cells in a petri dish. The researchers then differentiated the edited stem cells so they would become heart muscle cells, and performed a comprehensive analysis to evaluate the variant, determining exactly how harmful the variant was or whether it was benign.

In this case, the study participant's variant was predicted to be benign.

A risk with using CRISPR is that it could introduce some unintended changes, but no off-target mutations were detected in the gene-edited cells, the researchers reported in their study.

"Much work remains to further develop stepping stones between editing cells in a dish and genome editing therapeutics that can treat patients, but studies such as this one help identify variants that are promising targets for therapeutic editing," said David Liu, core institute member of the Broad Institute and professor of chemistry and chemical biology at Harvard University, who was not involved in the study.

This gene-editing approach was found to be feasible in this one patient, but more research is needed to determine whether similar results would emerge among more patients.

"While it's very elegant, the major limitation of this work is that it took years of expensive work by a team of very talented scientists to do this for just one patient," said Dr. Kiran Musunuru, an associate professor of cardiovascular medicine at the University of Pennsylvania's Perelman School of Medicine, who was not involved in the new study but has conducted separate research involving CRISPR.

"It's an important step towards precision medicine, but going forward we will need to scale this up and be able to do this for dozens, hundreds, or even thousands of patients at a time, in a matter of weeks and much more cheaply," he said.

Time and cost are also limitations of this approach, Wu said.

"Cost-wise, it takes us probably about $10,000 and time-wise about six months," he said. Those six months would involve making the induced pluripotent stem cells, using CRISPR to edit the cells and then analyzing the differentiated heart cells.

Wu added, "but keep in mind that six months is actually still much better than the current alternative that we have, which is to tell patients that we don't know what the variant means."

The alternative would be following a patient with a variant for years, with the worrisome chance of a disease possibly developing or not developing. In either scenario, the patient as well as family members could have anxiety and stress.

Is this the future of gene editing?

"This addresses a major unmet need in patient care by helping determine whether your specific mutation is something to worry about," said Lagor, who was not involved in the study but has conducted separate research on CRISPR.

Then once a mutation has been identified as disease-causing, "this is an ideal platform for testing potential new drugs or gene therapy approaches in a patient-specific manner. This is truly personalized medicine," he said.

"The first therapeutic application of this technology would be to correct rare genetic diseases of the heart itself, where the potential benefit far outweighs the risk to the patient. Some of this technology already exists today, and it is now a matter of demonstrating that this can be done safely and effectively," he said.

"However, present-day forms of CRISPR technology do not work well enough in the actual heart muscle in a living being to correct a mutation for a disease like cardiomyopathy," he said. "It's possible that some future generation of gene-editing technology might be able to do the job of treating disease in the heart muscle, years or more likely decades in the future."

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Stem Cells in the Treatment of Heart Failure MyHeart

Tuesday, July 17th, 2018

The use of stem cells in the treatment of heart failure cases is currently being investigated. Cardiovascular disease is the #1 killer in the United States accounting forone third ofall deaths.Heart disease kills more people than cancer, HIV, diabetesor trauma. Many advances in medical and surgical treatment of heart disease have contributed to a growing number of patients in their 70s and 80s with congestive heart failure. An estimated 1% of the Western world has congestive heart failure, including over 5 million Americans with an additional 550,000 new cases each year. Patients with advanced heart failure who require hospitalization, have a 50% mortality within the first fiveyears.The patients with significant coronary artery disease can sometimes undergo coronary artery bypass surgery or percutaneous coronary intervention to open up blocked arteries. Below is an example of a patient evaluated for heart failure and was found to have severe coronary disease. He later underwent bypass surgery.In addition, current medical treatment of patients with congestive heart failure include proven beneficial medicine such as beta-blockers, ACE inhibitors, angiotensinIIreceptor blockers, angiotensin IIreceptor blocker Neprilysin inhibitors and diuretics. When appropriate, resynchronization of the right and left ventricles can be accomplished with special types of pacemaker and can be combined with a defibrillator (BiV-ICD). However, even after following all of these guideline proven therapies, some patients still run out of options and continue to have severe and debilitating congestive heart failure. Below is an example of a patient with severe heart failure symptoms despite having normal coronaries and a BiV-ICD.Heart transplant is a last resort for end stage heart disease.There is a very low number of donor hearts and transplant programs have very restricted eligibility criteria leaving a large number patients with very few options.There are reasons to believe that regenerative therapy could really help patients with congestive heart failure. Multi-potent cardiac stem cells exist in the heart and participate in the normal turnover of heart muscle cells and small blood vessels.A heart attack kills heart muscle which is made of millions of heart cells. The question is: Would regenerative therapy be able to replace those heart cells or cardiac myocytes?Thousands of patients have been enrolled in clinical trials to address this question. Regenerative or stem cell therapy has been shown to be safe. Modest benefits have been demonstrated but the mechanism has not been completely elucidated. So far, there is no evidence that cells regenerate from the transplanted stem cells. Animal studies have shown that only 1% of the stem cells injected into the heart tissue are detectable after 1 month. The clinical benefits observed appeared to be due to arelease of growth factors which triggers endogenous repair of the heart cells and inhibits cell death and fibrosis resulting in increased performance of the heart muscle.

An example of an abnormal echocardiogram.

Comments are purely for informational purposes and are not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Disclaimer

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Apoptosis – Wikipedia

Saturday, July 7th, 2018

Apoptosis (from Ancient Greek "falling off") is a process of programmed cell death that occurs in multicellular organisms.[2] Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global[vague] mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis.[a] For an average human child between the ages of 8 and 14, approximately 20 to 30 billion cells die a day.[4]

In contrast to necrosis, which is a form of traumatic cell death that results from acute cellular injury, apoptosis is a highly regulated and controlled process that confers advantages during an organism's lifecycle. For example, the separation of fingers and toes in a developing human embryo occurs because cells between the digits undergo apoptosis. Unlike necrosis, apoptosis produces cell fragments called apoptotic bodies that phagocytic cells are able to engulf and remove before the contents of the cell can spill out onto surrounding cells and cause damage to them.[5]

Because apoptosis cannot stop once it has begun, it is a highly regulated process. Apoptosis can be initiated through one of two pathways. In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells. Both pathways induce cell death by activating caspases, which are proteases, or enzymes that degrade proteins. The two pathways both activate initiator caspases, which then activate executioner caspases, which then kill the cell by degrading proteins indiscriminately.

Research on apoptosis has increased substantially since the early 1990s. In addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in a wide variety of diseases. Excessive apoptosis causes atrophy, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer.Some factors like Fas receptors and caspases promote apoptosis, while some members of the Bcl-2 family of proteins inhibit apoptosis.

German scientist Karl Vogt was first to describe the principle of apoptosis in 1842. In 1885, anatomist Walther Flemming delivered a more precise description of the process of programmed cell death. However, it was not until 1965 that the topic was resurrected. While studying tissues using electron microscopy, John Foxton Ross Kerr at the University of Queensland was able to distinguish apoptosis from traumatic cell death.[6] Following the publication of a paper describing the phenomenon, Kerr was invited to join Alastair R. Currie, as well as Andrew Wyllie, who was Currie's graduate student,[7] at University of Aberdeen. In 1972, the trio published a seminal article in the British Journal of Cancer.[8] Kerr had initially used the term programmed cell necrosis, but in the article, the process of natural cell death was called apoptosis. Kerr, Wyllie and Currie credited James Cormack, a professor of Greek language at University of Aberdeen, with suggesting the term apoptosis. Kerr received the Paul Ehrlich and Ludwig Darmstaedter Prize on March 14, 2000, for his description of apoptosis. He shared the prize with Boston biologist H. Robert Horvitz.[9]

For many years, neither "apoptosis" nor "programmed cell death" was a highly cited term. Two discoveries brought cell death from obscurity to a major field of research: identification of components of the cell death control and effector mechanisms, and linkage of abnormalities in cell death to human disease, in particular cancer.

The 2002 Nobel Prize in Medicine was awarded to Sydney Brenner, Horvitz and John E. Sulston for their work identifying genes that control apoptosis. The genes were identified by studies in the nematode C. elegans and homologues of these genes function in humans to regulate apoptosis.

In Greek, apoptosis translates to the "falling off" of leaves from a tree. Cormack, professor of Greek language, reintroduced the term for medical use as it had a medical meaning for the Greeks over two thousand years before. Hippocrates used the term to mean "the falling off of the bones". Galen extended its meaning to "the dropping of the scabs". Cormack was no doubt aware of this usage when he suggested the name. Debate continues over the correct pronunciation, with opinion divided between a pronunciation with the second p silent ( ap--TOH-sis[11][12]) and the second p pronounced (),[11][13] as in the original Greek.[citation needed] In English, the p of the Greek -pt- consonant cluster is typically silent at the beginning of a word (e.g. pterodactyl, Ptolemy), but articulated when used in combining forms preceded by a vowel, as in helicopter or the orders of insects: diptera, lepidoptera, etc.

In the original Kerr, Wyllie & Currie paper,[8] there is a footnote regarding the pronunciation:

"We are most grateful to Professor James Cormack of the Department of Greek, University of Aberdeen, for suggesting this term. The word "apoptosis" () is used in Greek to describe the "dropping off" or "falling off" of petals from flowers, or leaves from trees. To show the derivation clearly, we propose that the stress should be on the penultimate syllable, the second half of the word being pronounced like "ptosis" (with the "p" silent), which comes from the same root "to fall", and is already used to describe the drooping of the upper eyelid."

The initiation of apoptosis is tightly regulated by activation mechanisms, because once apoptosis has begun, it inevitably leads to the death of the cell. [15] The two best-understood activation mechanisms are the intrinsic pathway (also called the mitochondrial pathway) and the extrinsic pathway. The intrinsic pathway is activated by intracellular signals generated when cells are stressed and depends on the release of proteins from the intermembrane space of mitochondria. The extrinsic pathway is activated by extracellular ligands binding to cell-surface death receptors, which leads to the formation of the death-inducing signaling complex (DISC).

A cell initiates intracellular apoptotic signaling in response to a stress, which may bring about cell suicide. The binding of nuclear receptors by glucocorticoids,[19] heat,[19] radiation,[19] nutrient deprivation,[19] viral infection,[19] hypoxia[19] and increased intracellular calcium concentration,[20][21]for example, by damage to the membrane, can all trigger the release of intracellular apoptotic signals by a damaged cell. A number of cellular components, such as poly ADP ribose polymerase, may also help regulate apoptosis.[22]

Before the actual process of cell death is precipitated by enzymes, apoptotic signals must cause regulatory proteins to initiate the apoptosis pathway. This step allows those signals to cause cell death, or the process to be stopped, should the cell no longer need to die. Several proteins are involved, but two main methods of regulation have been identified: the targeting of mitochondria functionality,[23] or directly transducing the signal via adaptor proteins to the apoptotic mechanisms. An extrinsic pathway for initiation identified in several toxin studies is an increase in calcium concentration within a cell caused by drug activity, which also can cause apoptosis via a calcium binding protease calpain.

The mitochondria are essential to multicellular life. Without them, a cell ceases to respire aerobically and quickly dies. This fact forms the basis for some apoptotic pathways. Apoptotic proteins that target mitochondria affect them in different ways. They may cause mitochondrial swelling through the formation of membrane pores, or they may increase the permeability of the mitochondrial membrane and cause apoptotic effectors to leak out.[19][24] They are very closely related to intrinsic pathway, and tumors arise more frequently through intrinsic pathway than the extrinsic pathway because of sensitivity.[25] There is also a growing body of evidence indicating that nitric oxide is able to induce apoptosis by helping to dissipate the membrane potential of mitochondria and therefore make it more permeable.[26] Nitric oxide has been implicated in initiating and inhibiting apoptosis through its possible action as a signal molecule of subsequent pathways that activate apoptosis.[27][citation needed]

Mitochondrial proteins known as SMACs (second mitochondria-derived activator of caspases) are released into the cell's cytosol following the increase in permeability of the mitochondria membranes. SMAC binds to proteins that inhibit apoptosis (IAPs) thereby deactivating them, and preventing the IAPs from arresting the process and therefore allowing apoptosis to proceed. IAP also normally suppresses the activity of a group of cysteine proteases called caspases,[28] which carry out the degradation of the cell. Therefore, the actual degradation enzymes can be seen to be indirectly regulated by mitochondrial permeability.

Cytochrome c is also released from mitochondria due to formation of a channel, the mitochondrial apoptosis-induced channel (MAC), in the outer mitochondrial membrane,[29] and serves a regulatory function as it precedes morphological change associated with apoptosis.[19] Once cytochrome c is released it binds with Apoptotic protease activating factor 1 (Apaf-1) and ATP, which then bind to pro-caspase-9 to create a protein complex known as an apoptosome. The apoptosome cleaves the pro-caspase to its active form of caspase-9, which in turn activates the effector caspase-3.

MAC (not to be confused with the membrane attack complex formed by complement activation, also commonly denoted as MAC), also called "Mitochondrial Outer Membrane Permeabilization Pore" is regulated by various proteins, such as those encoded by the mammalian Bcl-2 family of anti-apoptopic genes, the homologs of the ced-9 gene found in C. elegans.[30][31] Bcl-2 proteins are able to promote or inhibit apoptosis by direct action on MAC/MOMPP. Bax and/or Bak form the pore, while Bcl-2, Bcl-xL or Mcl-1 inhibit its formation.

Overview of TNF (left) and Fas (right) signalling in apoptosis, an example of direct signal transduction.

Two theories of the direct initiation of apoptotic mechanisms in mammals have been suggested: the TNF-induced (tumor necrosis factor) model and the Fas-Fas ligand-mediated model, both involving receptors of the TNF receptor (TNFR) family[32] coupled to extrinsic signals.

TNF path

TNF-alpha is a cytokine produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF-alpha: TNFR1 and TNFR2. The binding of TNF-alpha to TNFR1 has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain (TRADD) and Fas-associated death domain protein (FADD). cIAP1/2 can inhibit TNF- signaling by binding to TRAF2. FLIP inhibits the activation of caspase-8.[33] Binding of this receptor can also indirectly lead to the activation of transcription factors involved in cell survival and inflammatory responses.[34] However, signalling through TNFR1 might also induce apoptosis in a caspase-independent manner.[35] The link between TNF-alpha and apoptosis shows why an abnormal production of TNF-alpha plays a fundamental role in several human diseases, especially in autoimmune diseases.

Fas path

The fas receptor (First apoptosis signal) (also known as Apo-1 or CD95) is a transmembrane protein of the TNF family which binds the Fas ligand (FasL).[32] The interaction between Fas and FasL results in the formation of the death-inducing signaling complex (DISC), which contains the FADD, caspase-8 and caspase-10. In some types of cells (type I), processed caspase-8 directly activates other members of the caspase family, and triggers the execution of apoptosis of the cell. In other types of cells (type II), the Fas-DISC starts a feedback loop that spirals into increasing release of proapoptotic factors from mitochondria and the amplified activation of caspase-8.[36]

Common components

Following TNF-R1 and Fas activation in mammalian cells a balance between proapoptotic (BAX,[37] BID, BAK, or BAD) and anti-apoptotic (Bcl-Xl and Bcl-2) members of the Bcl-2 family are established. This balance is the proportion of proapoptotic homodimers that form in the outer-membrane of the mitochondrion. The proapoptotic homodimers are required to make the mitochondrial membrane permeable for the release of caspase activators such as cytochrome c and SMAC. Control of proapoptotic proteins under normal cell conditions of nonapoptotic cells is incompletely understood, but in general, Bax or Bak are activated by the activation of BH3-only proteins, part of the Bcl-2 family.

CaspasesCaspases play the central role in the transduction of ER apoptotic signals. Caspases are proteins that are highly conserved, cysteine-dependent aspartate-specific proteases. There are two types of caspases: initiator caspases, caspase 2,8,9,10,11,12, and effector caspases, caspase 3,6,7. The activation of initiator caspases requires binding to specific oligomeric activator protein. Effector caspases are then activated by these active initiator caspases through proteolytic cleavage. The active effector caspases then proteolytically degrade a host of intracellular proteins to carry out the cell death program.

Caspase-independent apoptotic pathwayThere also exists a caspase-independent apoptotic pathway that is mediated by AIF (apoptosis-inducing factor).[38]

Amphibian frog Xenopus laevis serves as an ideal model system for the study of the mechanisms of apoptosis. In fact, iodine and thyroxine also stimulate the spectacular apoptosis of the cells of the larval gills, tail and fins in amphibians metamorphosis, and stimulate the evolution of their nervous system transforming the aquatic, vegetarian tadpole into the terrestrial, carnivorous frog.[39][40][41][42]

Negative regulation of apoptosis inhibits cell death signaling pathways, helping tumors to evade cell death and developing drug resistance. Many families of proteins act as negative regulators categorized into either antiapoptotic factors, such as IAPs and Bcl-2 proteins or prosurvival factors like cFLIP, BNIP3, FADD, Akt, and NF-B [43].

Many pathways and signals lead to apoptosis, but these converge on a single mechanism that actually causes the death of the cell. After a cell receives stimulus, it undergoes organized degradation of cellular organelles by activated proteolytic caspases. In addition to the destruction of cellular organelles, mRNA is rapidly and globally degraded by a mechanism that is not yet fully characterized.[44] mRNA decay is triggered very early in apoptosis.

A cell undergoing apoptosis shows a series of characteristic morphological changes. Early alterations include:

Apoptosis progresses quickly and its products are quickly removed, making it difficult to detect or visualize on classical histology sections. During karyorrhexis, endonuclease activation leaves short DNA fragments, regularly spaced in size. These give a characteristic "laddered" appearance on agar gel after electrophoresis.[49] Tests for DNA laddering differentiate apoptosis from ischemic or toxic cell death.[50]

Before the apoptotic cell is disposed of, there is a process of disassembly. There are three recognized steps in apoptotic cell disassembly:[52]

The removal of dead cells by neighboring phagocytic cells has been termed efferocytosis.[58]Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as phosphatidylserine, on their cell surface.[59] Phosphatidylserine is normally found on the inner leaflet surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a protein known as scramblase.[60] These molecules mark the cell for phagocytosis by cells possessing the appropriate receptors, such as macrophages.[61] The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response.[62] During apoptosis cellular RNA and DNA are separated from each other and sorted to different apoptotic bodies; separation of RNA is initiated as nucleolar segregation.[63]

Many knock-outs have been made in the apoptosis pathways to test the function of each of the proteins. Several caspases, in addition to APAF1 and FADD, have been mutated to determine the new phenotype. In order to create a tumor necrosis factor (TNF) knockout, an exon containing the nucleotides 37045364 was removed from the gene. This exon encodes a portion of the mature TNF domain, as well as the leader sequence, which is a highly conserved region necessary for proper intracellular processing. TNF-/- mice develop normally and have no gross structural or morphological abnormalities. However, upon immunization with SRBC (sheep red blood cells), these mice demonstrated a deficiency in the maturation of an antibody response; they were able to generate normal levels of IgM, but could not develop specific IgG levels. Apaf-1 is the protein that turns on caspase 9 by cleavage to begin the caspase cascade that leads to apoptosis. Since a -/- mutation in the APAF-1 gene is embryonic lethal, a gene trap strategy was used in order to generate an APAF-1 -/- mouse. This assay is used to disrupt gene function by creating an intragenic gene fusion. When an APAF-1 gene trap is introduced into cells, many morphological changes occur, such as spina bifida, the persistence of interdigital webs, and open brain. In addition, after embryonic day 12.5, the brain of the embryos showed several structural changes. APAF-1 cells are protected from apoptosis stimuli such as irradiation. A BAX-1 knock-out mouse exhibits normal forebrain formation and a decreased programmed cell death in some neuronal populations and in the spinal cord, leading to an increase in motor neurons.

The caspase proteins are integral parts of the apoptosis pathway, so it follows that knock-outs made have varying damaging results. A caspase 9 knock-out leads to a severe brain malformation. A caspase 8 knock-out leads to cardiac failure and thus embryonic lethality. However, with the use of cre-lox technology, a caspase 8 knock-out has been created that exhibits an increase in peripheral T cells, an impaired T cell response, and a defect in neural tube closure. These mice were found to be resistant to apoptosis mediated by CD95, TNFR, etc. but not resistant to apoptosis caused by UV irradiation, chemotherapeutic drugs, and other stimuli. Finally, a caspase 3 knock-out was characterized by ectopic cell masses in the brain and abnormal apoptotic features such as membrane blebbing or nuclear fragmentation. A remarkable feature of these KO mice is that they have a very restricted phenotype: Casp3, 9, APAF-1 KO mice have deformations of neural tissue and FADD and Casp 8 KO showed defective heart development, however in both types of KO other organs developed normally and some cell types were still sensitive to apoptotic stimuli suggesting that unknown proapoptotic pathways exist.

In order to perform analysis of apoptotic versus necrotic (necroptotic) cells, one can do analysis of morphology by time-lapse microscopy, flow fluorocytometry, and transmission electron microscopy. There are also various biochemical techniques for analysis of cell surface markers (phosphatidylserine exposure versus cell permeability by flow cytometry), cellular markers such as DNA fragmentation[64] (flow cytometry),[65] caspase activation, Bid cleavage, and cytochrome c release (Western blotting). It is important to know how primary and secondary necrotic cells can be distinguished by analysis of supernatant for caspases, HMGB1, and release of cytokeratin 18. However, no distinct surface or biochemical markers of necrotic cell death have been identified yet, and only negative markers are available. These include absence of apoptotic markers (caspase activation, cytochrome c release, and oligonucleosomal DNA fragmentation) and differential kinetics of cell death markers (phosphatidylserine exposure and cell membrane permeabilization). A selection of techniques that can be used to distinguish apoptosis from necroptotic cells could be found in these references.[66][67][68][69]

The many different types of apoptotic pathways contain a multitude of different biochemical components, many of them not yet understood.[70] As a pathway is more or less sequential in nature, removing or modifying one component leads to an effect in another. In a living organism, this can have disastrous effects, often in the form of disease or disorder. A discussion of every disease caused by modification of the various apoptotic pathways would be impractical, but the concept overlying each one is the same: The normal functioning of the pathway has been disrupted in such a way as to impair the ability of the cell to undergo normal apoptosis. This results in a cell that lives past its "use-by-date" and is able to replicate and pass on any faulty machinery to its progeny, increasing the likelihood of the cell's becoming cancerous or diseased.

A recently described example of this concept in action can be seen in the development of a lung cancer called NCI-H460.[71] The X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in cells of the H460 cell line. XIAPs bind to the processed form of caspase-9, and suppress the activity of apoptotic activator cytochrome c, therefore overexpression leads to a decrease in the amount of proapoptotic agonists. As a consequence, the balance of anti-apoptotic and proapoptotic effectors is upset in favour of the former, and the damaged cells continue to replicate despite being directed to die. Defects in regulation of apoptosis in cancer cells occur often at the level of control of transcription factors. As a particular example, defects in molecules that control transcription factor NF-B in cancer change the mode of transcriptional regulation and the response to apoptotic signals, to curtail dependence on the tissue that the cell belongs. This degree of independence from external survival signals, can enable cancer metastasis.[72]

The tumor-suppressor protein p53 accumulates when DNA is damaged due to a chain of biochemical factors. Part of this pathway includes alpha-interferon and beta-interferon, which induce transcription of the p53 gene, resulting in the increase of p53 protein level and enhancement of cancer cell-apoptosis.[73] p53 prevents the cell from replicating by stopping the cell cycle at G1, or interphase, to give the cell time to repair, however it will induce apoptosis if damage is extensive and repair efforts fail.[74] Any disruption to the regulation of the p53 or interferon genes will result in impaired apoptosis and the possible formation of tumors.

Inhibition of apoptosis can result in a number of cancers, autoimmune diseases, inflammatory diseases, and viral infections. It was originally believed that the associated accumulation of cells was due to an increase in cellular proliferation, but it is now known that it is also due to a decrease in cell death. The most common of these diseases is cancer, the disease of excessive cellular proliferation, which is often characterized by an overexpression of IAP family members. As a result, the malignant cells experience an abnormal response to apoptosis induction: Cycle-regulating genes (such as p53, ras or c-myc) are mutated or inactivated in diseased cells, and further genes (such as bcl-2) also modify their expression in tumors. Some apoptotic factors are vital during mitochondrial respiration e.g. cytochrome C.[75] Pathological inactivation of apoptosis in cancer cells is correlated with frequent respiratory metabolic shifts toward glycolysis (an observation known as the Warburg hypothesis [76]).

Apoptosis in HeLa[b] cells is inhibited by proteins produced by the cell; these inhibitory proteins target retinoblastoma tumor-suppressing proteins.[77] These tumor-suppressing proteins regulate the cell cycle, but are rendered inactive when bound to an inhibitory protein.[77] HPV E6 and E7 are inhibitory proteins expressed by the human papillomavirus, HPV being responsible for the formation of the cervical tumor from which HeLa cells are derived.[78] HPV E6 causes p53, which regulates the cell cycle, to become inactive.[79] HPV E7 binds to retinoblastoma tumor suppressing proteins and limits its ability to control cell division.[79] These two inhibitory proteins are partially responsible for HeLa cells' immortality by inhibiting apoptosis to occur.[80] CDV (Canine Distemper Virus) is able to induce apoptosis despite the presence of these inhibitory proteins. This is an important oncolytic property of CDV: this virus is capable of killing canine lymphoma cells. Oncoproteins E6 and E7 still leave p53 inactive, but they are not able to avoid the activation of caspases induced from the stress of viral infection. These oncolytic properties provided a promising link between CDV and lymphoma apoptosis, which can lead to development of alternative treatment methods for both canine lymphoma and human non-Hodgkin lymphoma. Defects in the cell cycle are thought to be responsible for the resistance to chemotherapy or radiation by certain tumor cells, so a virus that can induce apoptosis despite defects in the cell cycle is useful for cancer treatment.[80]

The main method of treatment for death from signaling-related diseases involves either increasing or decreasing the susceptibility of apoptosis in diseased cells, depending on whether the disease is caused by either the inhibition of or excess apoptosis. For instance, treatments aim to restore apoptosis to treat diseases with deficient cell death, and to increase the apoptotic threshold to treat diseases involved with excessive cell death. To stimulate apoptosis, one can increase the number of death receptor ligands (such as TNF or TRAIL), antagonize the anti-apoptotic Bcl-2 pathway, or introduce Smac mimetics to inhibit the inhibitor (IAPs). The addition of agents such as Herceptin, Iressa, or Gleevec works to stop cells from cycling and causes apoptosis activation by blocking growth and survival signaling further upstream. Finally, adding p53-MDM2 complexes displaces p53 and activates the p53 pathway, leading to cell cycle arrest and apoptosis. Many different methods can be used either to stimulate or to inhibit apoptosis in various places along the death signaling pathway.[81]

Apoptosis is a multi-step, multi-pathway cell-death programme that is inherent in every cell of the body. In cancer, the apoptosis cell-division ratio is altered. Cancer treatment by chemotherapy and irradiation kills target cells primarily by inducing apoptosis.

On the other hand, loss of control of cell death (resulting in excess apoptosis) can lead to neurodegenerative diseases, hematologic diseases, and tissue damage. It is to note that neurons that rely on mitochondrial respiration undergo apoptosis in neurodegenerative diseases such as Alzheimers [82] and Parkinsons [83] (an observation known as the Inverse Warburg hypothesis [84][75] ).Moreover, there is an inverse epidemiological comorbidity between neurodegenerative diseases and cancer.[85] The progression of HIV is directly linked to excess, unregulated apoptosis. In a healthy individual, the number of CD4+ lymphocytes is in balance with the cells generated by the bone marrow; however, in HIV-positive patients, this balance is lost due to an inability of the bone marrow to regenerate CD4+ cells. In the case of HIV, CD4+ lymphocytes die at an accelerated rate through uncontrolled apoptosis, when stimulated.At the molecular level, hyperactive apoptosis can be caused by defects in signaling pathways that regulate the Bcl-2 family proteins. Increased expression of apoptotic proteins such as BIM, or their decreased proteolysis, leads to cell death, and can cause a number of pathologies, depending on the cells where excessive activity of BIM occurs. Cancer cells can escape apoptosis through mechanisms that suppress BIM expression or by increased proteolysis of BIM.[86]

Treatments aiming to inhibit works to block specific caspases. Finally, the Akt protein kinase promotes cell survival through two pathways. Akt phosphorylates and inhibits Bad (a Bcl-2 family member), causing Bad to interact with the 14-3-3 scaffold, resulting in Bcl dissociation and thus cell survival. Akt also activates IKK, which leads to NF-B activation and cell survival. Active NF-B induces the expression of anti-apoptotic genes such as Bcl-2, resulting in inhibition of apoptosis. NF-B has been found to play both an antiapoptotic role and a proapoptotic role depending on the stimuli utilized and the cell type.[87]

The progression of the human immunodeficiency virus infection into AIDS is due primarily to the depletion of CD4+ T-helper lymphocytes in a manner that is too rapid for the body's bone marrow to replenish the cells, leading to a compromised immune system. One of the mechanisms by which T-helper cells are depleted is apoptosis, which results from a series of biochemical pathways:[88]

Cells may also die as direct consequences of viral infections. HIV-1 expression induces tubular cell G2/M arrest and apoptosis.[89] The progression from HIV to AIDS is not immediate or even necessarily rapid; HIV's cytotoxic activity toward CD4+ lymphocytes is classified as AIDS once a given patient's CD4+ cell count falls below 200.[90]

Researchers from Kumamoto University in Japan have developed a new method to eradicate HIV in viral reservoir cells, named "Lock-in and apoptosis." Using the synthesized compound Heptanoylphosphatidyl L-Inositol Pentakisphophate (or L-Hippo) to bind strongly to the HIV protein PR55Gag, they were able to suppress viral budding. By suppressing viral budding, the researchers were able to trap the HIV virus in the cell and allow for the cell to undergo apoptosis (natural cell death). Associate Professor Mikako Fujita has stated that the approach is not yet available to HIV patients because the research team has to conduct further research on combining the drug therapy that currently exists with this "Lock-in and apoptosis" approach to lead to complete recovery from HIV.[91]

Viral induction of apoptosis occurs when one or several cells of a living organism are infected with a virus, leading to cell death. Cell death in organisms is necessary for the normal development of cells and the cell cycle maturation.[92] It is also important in maintaining the regular functions and activities of cells.

Viruses can trigger apoptosis of infected cells via a range of mechanisms including:

Canine distemper virus (CDV) is known to cause apoptosis in central nervous system and lymphoid tissue of infected dogs in vivo and in vitro.[94]Apoptosis caused by CDV is typically induced via the extrinsic pathway, which activates caspases that disrupt cellular function and eventually leads to the cells death.[77] In normal cells, CDV activates caspase-8 first, which works as the initiator protein followed by the executioner protein caspase-3.[77] However, apoptosis induced by CDV in HeLa cells does not involve the initiator protein caspase-8. HeLa cell apoptosis caused by CDV follows a different mechanism than that in vero cell lines.[77] This change in the caspase cascade suggests CDV induces apoptosis via the intrinsic pathway, excluding the need for the initiator caspase-8. The executioner protein is instead activated by the internal stimuli caused by viral infection not a caspase cascade.[77]

The Oropouche virus (OROV) is found in the family Bunyaviridae. The study of apoptosis brought on by Bunyaviridae was initiated in 1996, when it was observed that apoptosis was induced by the La Crosse virus into the kidney cells of baby hamsters and into the brains of baby mice.[95]

OROV is a disease that is transmitted between humans by the biting midge (Culicoides paraensis).[96] It is referred to as a zoonotic arbovirus and causes febrile illness, characterized by the onset of a sudden fever known as Oropouche fever.[97]

The Oropouche virus also causes disruption in cultured cells cells that are cultivated in distinct and specific conditions. An example of this can be seen in HeLa cells, whereby the cells begin to degenerate shortly after they are infected.[95]

With the use of gel electrophoresis, it can be observed that OROV causes DNA fragmentation in HeLa cells. It can be interpreted by counting, measuring, and analyzing the cells of the Sub/G1 cell population.[95] When HeLA cells are infected with OROV, the cytochrome C is released from the membrane of the mitochondria, into the cytosol of the cells. This type of interaction shows that apoptosis is activated via an intrinsic pathway.[92]

In order for apoptosis to occur within OROV, viral uncoating, viral internalization, along with the replication of cells is necessary. Apoptosis in some viruses is activated by extracellular stimuli. However, studies have demonstrated that the OROV infection causes apoptosis to be activated through intracellular stimuli and involves the mitochondria.[95]

Many viruses encode proteins that can inhibit apoptosis.[98] Several viruses encode viral homologs of Bcl-2. These homologs can inhibit proapoptotic proteins such as BAX and BAK, which are essential for the activation of apoptosis. Examples of viral Bcl-2 proteins include the Epstein-Barr virus BHRF1 protein and the adenovirus E1B 19K protein.[99] Some viruses express caspase inhibitors that inhibit caspase activity and an example is the CrmA protein of cowpox viruses. Whilst a number of viruses can block the effects of TNF and Fas. For example, the M-T2 protein of myxoma viruses can bind TNF preventing it from binding the TNF receptor and inducing a response.[100] Furthermore, many viruses express p53 inhibitors that can bind p53 and inhibit its transcriptional transactivation activity. As a consequence, p53 cannot induce apoptosis, since it cannot induce the expression of proapoptotic proteins. The adenovirus E1B-55K protein and the hepatitis B virus HBx protein are examples of viral proteins that can perform such a function.[101]

Viruses can remain intact from apoptosis in particular in the latter stages of infection. They can be exported in the apoptotic bodies that pinch off from the surface of the dying cell, and the fact that they are engulfed by phagocytes prevents the initiation of a host response. This favours the spread of the virus.[100]

Programmed cell death in plants has a number of molecular similarities to that of animal apoptosis, but it also has differences, notable ones being the presence of a cell wall and the lack of an immune system that removes the pieces of the dead cell. Instead of an immune response, the dying cell synthesizes substances to break itself down and places them in a vacuole that ruptures as the cell dies. Whether this whole process resembles animal apoptosis closely enough to warrant using the name apoptosis (as opposed to the more general programmed cell death) is unclear.[102]

The characterization of the caspases allowed the development of caspase inhibitors, which can be used to determine whether a cellular process involves active caspases. Using these inhibitors it was discovered that cells can die while displaying a morphology similar to apoptosis without caspase activation.[103] Later studies linked this phenomenon to the release of AIF (apoptosis-inducing factor) from the mitochondria and its translocation into the nucleus mediated by its NLS (nuclear localization signal). Inside the mitochondria, AIF is anchored to the inner membrane. In order to be released, the protein is cleaved by a calcium-dependent calpain protease.

In 2003, a method was developed for predicting subcellular location of apoptosis proteins.[104]Subsequent to this, various modes of Chou's pseudo amino acid composition were developed for improving the quality of predicting subcellular localization of apoptosis proteins based on their sequence information alone.[105][106][107][108]

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Cloning/Embryonic Stem Cells – National Human Genome …

Thursday, July 5th, 2018

Cloning/Embryonic Stem Cells

The term cloning is used by scientists to describe many different processes that involve making duplicates of biological material. In most cases, isolated genes or cells are duplicated for scientific study, and no new animal results. The experiment that led to the cloning of Dolly the sheep in 1997 was different: It used a cloning technique called somatic cell nuclear transfer and resulted in an animal that was a genetic twin -- although delayed in time -- of an adult sheep. This technique can also be used to produce an embryo from which cells called embryonic stem (ES) cells could be extracted to use in research into potential therapies for a wide variety of diseases.

Thus, in the past five years, much of the scientific and ethical debate about somatic cell nuclear transfer has focused on its two potential applications: 1) for reproductive purposes, i.e., to produce a child, or 2) for producing a source of ES cells for research.

The technique of transferring a nucleus from a somatic cell into an egg that produced Dolly was an extension of experiments that had been ongoing for over 40 years. In the simplest terms, the technique used to produce Dolly the sheep - somatic cell nuclear transplantation cloning - involves removing the nucleus of an egg and replacing it with the diploid nucleus of a somatic cell. Unlike sexual reproduction, during which a new organism is formed when the genetic material of the egg and sperm fuse, in nuclear transplantation cloning there is a single genetic "parent." This technique also differs from previous cloning techniques because it does not involve an existing embryo. Dolly is different because she is not genetically unique; when born she was genetically identical to an existing six-year-old ewe. Although the birth of Dolly was lauded as a success, in fact, the procedure has not been perfected and it is not yet clear whether Dolly will remain healthy or whether she is already experiencing subtle problems that might lead to serious diseases. Thus, the prospect of applying this technique in humans is troubling for scientific and safety reasons in addition to a variety of ethical reasons related to our ideas about the natural ordering of family and successive generations.

Several important concerns remain about the science and safety of nuclear transfer cloning using adult cells as the source of nuclei. To date, five mammalian species -- sheep, cattle, pigs, goats, and mice -- have been used extensively in reproductive cloning studies. Data from these experiments illustrate the problems involved. Typically, very few cloning attempts are successful. Many cloned animals die in utero, even at late stages or soon after birth, and those that survive frequently exhibit severe birth defects. In addition, female animals carrying cloned fetuses may face serious risks, including death from cloning-related complications.

An additional concern focuses on whether cellular aging will affect the ability of somatic cell nuclei to program normal development. As somatic cells divide they progressively age, and there is normally a defined number of cell divisions that can occur before senescence. Thus, the health effects for the resulting liveborn, having been created with an "aged" nucleus, are unknown. Recently it was reported that Dolly has arthritis, although it is not yet clear whether the five-and-a-half-year-old sheep is suffering from the condition as a result of the cloning process. And, scientists in Tokyo have shown that cloned mice die significantly earlier than those that are naturally conceived, raising an additional concern that the mutations that accumulate in somatic cells might affect nuclear transfer efficiency and lead to cancer and other diseases in offspring. Researchers working with clones of a Holstein cow say genetic programming errors may explain why so many cloned animals die, either as fetuses or newborns.

The announcement of Dolly sparked widespread speculation about a human child being created using somatic cell nuclear transfer. Much of the perceived fear that greeted this announcement centered on the misperception that a child or many children could be produced who would be identical to an already existing person. This fear is based on the idea of "genetic determinism" -- that genes alone determine all aspects of an individual -- and reflects the belief that a person's genes bear a simple relationship to the physical and psychological traits that compose that individual. Although genes play an essential role in the formation of physical and behavioral characteristics, each individual is, in fact, the result of a complex interaction between his or her genes and the environment within which he or she develops. Nonetheless, many of the concerns about cloning have focused on issues related to "playing God," interfering with the natural order of life, and somehow robbing a future individual of the right to a unique identity.

Several groups have concluded that reproductive cloning of human beings creates ethical and scientific risks that society should not tolerate. In 1997, the National Bioethics Advisory Commission recommended that it was morally unacceptable to attempt to create a child using somatic cell nuclear transfer cloning and suggested that a moratorium be imposed until safety of this technique could be assessed. The commission also cautioned against preempting the use of cloning technology for purposes unrelated to producing a liveborn child.

Similarly, in 2001 the National Academy of Sciences issued a report stating that the United States should ban human reproductive cloning aimed at creating a child because experience with reproductive cloning in animals suggests that the process would be dangerous for the woman, the fetus, and the newborn, and would likely fail. The report recommended that the proposed ban on human cloning should be reviewed within five years, but that it should be reconsidered "only if a new scientific review indicates that the procedures are likely to be safe and effective, and if a broad national dialogue on societal, religious and ethical issues suggests that reconsideration is warranted." The panel concluded that the scientific and medical considerations that justify a ban on human reproductive cloning at this time do not apply to nuclear transplantation to produce stem cells. Several other scientific and medical groups also have stated their opposition to the use of cloning for the purpose of producing a child.

The cloning debate was reopened with a new twist late in 1998, when two scientific reports were published regarding the successful isolation of human stem cells. Stem cells are unique and essential cells found in animals that are capable of continually reproducing themselves and renewing tissue throughout an individual organism's life. ES cells are the most versatile of all stem cells because they are less differentiated, or committed, to a particular function than adult stem cells. These cells have offered hope of new cures to debilitating and even fatal illness. Recent studies in mice and other animals have shown that ES cells can reduce symptoms of Parkinson's disease in mouse models, and work in other animal models and disease areas seems promising.

In the 1998 reports, ES cells were derived from in vitro embryos six to seven days old destined to be discarded by couples undergoing infertility treatments, and embryonic germ (EG) cells were obtained from cadaveric fetal tissue following elective abortion. A third report, appearing in the New York Times, claimed that a Massachusetts biotechnology company had fused a human cell with an enucleated cow egg, creating a hybrid clone that failed to progress beyond an early stage of development. This announcement served as a reminder that ES cells also could be derived from embryos created through somatic cell nuclear transfer, or cloning. In fact, several scientists believed that deriving ES cells in this manner is the most promising approach to developing treatments because the condition of in vitro fertilization (IVF) embryos stored over time is questionable and this type of cloning could overcome graft-host responses if resulting therapies were developed from the recipient's own DNA.

For those who believe that the embryo has the moral status of a person from the moment of conception, research or any other activity that would destroy it is wrong. For those who believe the human embryo deserves some measure of respect, but disagree that the respect due should equal that given to a fully formed human, it could be considered immoral not to use embryos that would otherwise be destroyed to develop potential cures for disease affecting millions of people. An additional concern related to public policy is whether federal funds should be used for research that some Americans find unethical.

Since 1996, Congress has prohibited researchers from using federal funds for human embryo research. In 1999, DHHS announced that it intended to fund research on human ES cells derived from embryos remaining after infertility treatments. This decision was based on an interpretation "that human embryonic stem cells are not a human embryo within the statutory definition" because "the cells do not have the capacity to develop into a human being even if transferred to the uterus, thus their destruction in the course of research would not constitute the destruction of an embryo." DHHS did not intend to fund research using stem cells derived from embryos created through cloning, although such efforts would be legal in the private sector.

In July 2001, the House of Representatives voted 265 to 162 to make any human cloning a criminal offense, including cloning to create an embryo for derivation of stem cells rather than to produce a child. In August 2002, President Bush, contending with a DHHS decision made during the Clinton administration, stated in a prime-time television address that federal support would be provided for research using a limited number of stem cell colonies already in existence (derived from leftover IVF embryos). Current bills before Congress would ban all forms of cloning outright, prohibit cloning for reproductive purposes, and impose a moratorium on cloning to derive stem cells for research, or prohibit cloning for reproductive purposes while allowing cloning for therapeutic purposes to go forward. As of late June, the Senate has taken no action. President Bush's Bioethics Council is expected to recommend the prohibition of reproductive cloning and a moratorium on therapeutic cloning later this summer.

Prepared by Kathi E. Hanna, M.S., Ph.D., Science and Health Policy Consultant

Last Reviewed: April 2006

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Cloning/Embryonic Stem Cells - National Human Genome ...

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Recent Research on Stem Cells | Stem Cell Of America

Monday, June 18th, 2018

The following are recent research journals from US National Library of Medicine National Institutes of Health's pubmed.gov directory on the use of stem cells for various diseases and conditions:

Researchers said the treatment could be used for several conditions that include dementia.

By Stephen Feller | Oct. 15, 2015 at 4:30 PM

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motor neurons, characterized by progressive muscular atrophy and weakness which culminates in death within 2-5years...

J Clin Neurosci. 2013 Oct 19. pii: S0967-5868(13)00357-3. Author: Meamar R, Nasr-Esfahani MH, Mousavi SA, Basiri K.

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Alzheimer's disease (AD) is an irreversible neurodegenerative disease, still lacking proper clinical treatment. Therefore, many researchers have focused on the possibility of therapeutic use of stem cells for AD...

Neurodegener Dis. 2013 Oct 23. Author: Chang KA, Kim HJ, Joo Y, Ha S, Suh YH.

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Interleukin-6 (IL-6) is a pleiotropic cytokine with significant functions in the regulation of the immune system. As a potent pro-inflammatory cytokine, IL-6 plays a pivotal role in host defense against pathogens and acute stress...

Pharmacol Ther. 2013 Sep 27. pii: S0163-7258(13)00193-9. Author: Yao X, Huang J, Zhong H, Shen N, Faggioni R, Fung M, Yao Y.

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BACKGROUND AIMS: Pre-clinical evidence indicates that autologous bone marrow-derived mesenchymal stromal cell (BM-MSC) transplantation improves motor function in patients...

Cytotherapy. 2013 Oct 5. pii: S1465-3249(13)00561-6. Author: Wang X, Cheng H, Hua R, Yang J, Dai G, Zhang Z, Wang R, Qin C, An Y.

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Adult neural stem cells contribute to neurogenesis and plasticity of the brain which is essential for central regulation of systemic homeostasis. Damage to these homeostatic components...

Rev Endocr Metab Disord. 2013 Oct 25. Author:Purkayastha S, Cai D.

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Despite significant therapeutic advances, the prognosis of patients with heart failure (HF) remains poor, and current therapeutic approaches are palliative in the sense that they do not address the underlying problem...

Circ Res. 2013 Aug 30;113(6):810-34. Author: Sanganalmath SK, Bolli R.

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Recent evidence suggests that enhanced neutrophil extracellular trap (NET) formation activates plasmacytoid dendritic cells and serves as a source of autoantigens in SLE. We propose that aberrant NET formation...

J Clin Invest. 2013 Jul 1;123(7):2981-93. Author: Knight JS, Zhao W, Luo W, Subramanian V, O'Dell AA, Yalavarthi S, Hodgin JB, Eitzman DT, Thompson PR, Kaplan MJ.

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Diabetic retinopathy (DR) is the leading cause of visual loss in the developed world in those of working age, and its prevalence is predicted to double by 2025. The management of diabetic...

Clin Med. 2013 Aug;13(4):353-7. Author: Williams MA, Chakravarthy U.

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Interleukin (IL)-10 is an important immunoregulatory cytokine shown to impact inflammatory processes as manifested in patients with multiple sclerosis (MS) and in its animal model, experimental autoimmune...

Brain Behav Immun. 2013 May;30:103-14. Author: Payne NL, Sun G, McDonald C, Moussa L, Emerson-Webber A, Loisel-Meyer S, Medin JA, Siatskas C, Bernard CC.

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Stem cell transplantation is being tested as a potential therapy for a number of diseases. Stem cells isolated directly from tissue specimens or generated via reprogramming of differentiated cells require...

Hum Gene Ther. 2013 Oct 23. Author: Rozkalne A, Adkin C, Meng J, Lapan A, Morgan J, Gussoni E.

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IMPORTANCE Recent advances in stem cell technologies have rekindled an interest in the use of cell replacement strategies for patients with Parkinson disease...

JAMA Neurol. 2013 Nov 11. Author: Kefalopoulou Z, Politis M, Piccini P, Mencacci N, Bhatia K, Jahanshahi M, Widner H, Rehncrona S, Brundin P, Bjrklund A, Lindvall O, Limousin P, Quinn N, Foltynie T.

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Since several years, adult/perinatal mesenchymal and neural crest stem cells have been widely used to help experimental animal to recover from spinal cord injury. More interestingly...

Stem Cells. 2013 Oct 23. Author: Neirinckx V, Cantinieaux D, Coste C, Rogister B, Franzen R, Wislet-Gendebien S.

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Even after decades of intensive studies, therapeutic options for patients with stroke are rather limited. Thrombolytic drugs effectively treat the very acute stage of stroke, and several neuroprotectants...

Cell Transplant. 2013 Oct 22. Author: Yoo J, Seo JJ, Eom JH, Hwang DY.

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Although we have supplied the links above to research journals, we are not saying that any of these studies would relate to your particular disease or condition. Please note, stem cells are not a substitute for proper medical diagnosis and care.

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Recent Research on Stem Cells | Stem Cell Of America

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Cytokines, NK Cells, LAK Cells, Stem Cells Explained

Monday, June 18th, 2018

LAK Cells with Low Dose of Interleukin-2 in Patients with Solid Tumors

One of the procedures involves the separation of lymphocytes from the peripheral blood, culturing them in the patients own blood serum and expanding their numbers multifold before transfusing them back to the patient to yield maximum results.

The stem cell procedure that we administer consists of the stimulation of lymphocytes in vivo. During this stem cell procedure the sample is taken from the patients bone marrow of the head of the tibia bone and provides in addition to lymphocytes, stem cells, mature and immature leukocytes.

This combination renders the therapy even more powerful. As the stroma of bone marrow contains IL-7, which increases the effect of IL-2 by 5 times, we can decrease the dose of IL-2 while maintaining its potency.

Interleukin-2 stimulates the stem cells of the lymphocytes that then divide into T-Helper cells, such as THO, TH1 and TH2, which secrete lymphokines, various cytokines, such as interleukins and interferons.

TH1 secretes mainly IL-2, interferon gamma, GM-CSF, TNA-alpha, ligand CD40, which can activate macrophages. The LTC or cytotoxic CD8+ lymphocytes produce perforins, gamzymes, interferon gamma, TNF alpha and beta, and can in this way destroy circulating abnormal cells.

Stem cells are the human bodys master cells with the ability to renew themselves through cell division and grow into any one of its 200 cell types, except for cells of the placenta. They have the potential to multiply indefinitely, become highly specialized and replace cells that die or are lost.

Thus these specialized Stem Cells, aid in the repair of organs and tissue damaged by cancer progression, previous cancer treatments, or chronic degenerative conditions. They also maintain the normal turnover of regenerative organs, such as blood, skin, and intestinal tissues. Autologous Stem Cells from the patients own bone marrow do not have any adverse side effects.

Under normal conditions, we have less than 0.1% of stem cells in circulation, which is sometimes not sufficient for regenerative processes. The objective is, therefore, to increase the number of stem cells in circulation without the use of potent toxic drugs.

The immune-stimulatory effect of our therapy is sometimes quickly seen in the improvement of the overall condition of the patient, quality of life, reduction of pain, etc. Tumor shrinkage may take four weeks or longer. The procedure can be repeated after two months.

The protocols with autologous stem cells and low-dose Interleukin-2 that we administer do usually not cause any adverse effects.

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Cytokines, NK Cells, LAK Cells, Stem Cells Explained

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Susan Solomon: The promise of research with stem cells …

Monday, June 18th, 2018

There was a very sad example of this in the last decade.There's a wonderful drug, and a class of drugs actually,but the particular drug was Vioxx, andfor people who were suffering from severe arthritis pain,the drug was an absolute lifesaver,but unfortunately, for another subset of those people,they suffered pretty severe heart side effects,and for a subset of those people, the side effects wereso severe, the cardiac side effects, that they were fatal.But imagine a different scenario,where we could have had an array, a genetically diverse array,of cardiac cells, and we could have actually testedthat drug, Vioxx, in petri dishes, and figured out,well, okay, people with this genetic type are going to havecardiac side effects, people with these genetic subgroupsor genetic shoes sizes, about 25,000 of them,are not going to have any problems.The people for whom it was a lifesavercould have still taken their medicine.The people for whom it was a disaster, or fatal,would never have been given it, andyou can imagine a very different outcome for the company,who had to withdraw the drug.

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Susan Solomon: The promise of research with stem cells ...

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