Comparing the effects of e-cigarettes and regular smoking on the brain.

An ever accumulating volume of scientific and preclinical data shows new evidence of ways that e-cigarettes are dangerous. Understandably, most of the focus has been on the effects on the lungs, cardiovascular disease, and addiction. But recently, a growing body of scientific studies are starting to show the serious potential negative effects e-cigarette use may have on the brain.

Electronic-cigerettes (e-cigarettes), and more broadly electric vaporizers, have a history that goes back almost 100 years. The modern commercial version of the e-cigarette is usually attributed to the Chinese pharmacist Hon Lik, although numerous patents and related technologies developed by others were prevalent throughout the 1980s and 90s.

The immediate urgency in attempting to understand the health effects of e-cigarettes stems from their increasing rate of use, most concerning among young people. The challenge though is that they are simply too new, and not enough time has passed to understand and really appreciate their potential long term clinical effects due to sustained or chronic use.

Among high school students, the use of tobacco products had been on the decline until 1998, attributed to aggressive anti-smoking campaigns through the 90s. But this changed that year, with an increase in tobacco use due exclusively to the use of e-cigarettes. By 2014 e-cigarettes overtook all other tobacco products among this population. Even more concerning is the rate at which their use is increasing. According to the Centers for Disease Control and Prevention (CDC) e-cigarette use among high schoolers increased 77.8% in 2018 over 2017, with similar trends observed internationally.

And while it is possible to find e-cigarette pods and inserts that do not have nicotine, the vast majority do. Whats worse, the trend has been to increase the concentration of nicotine delivered by these products. In the case of the popular Juul brand, the average concentration of nicotine considerably exceeds the concentration in regular cigarettes.

To be fair, one potential positive use of these devices might be in helping long time smokers reduce the use of regular cigarettes. The CDC has stated that that while e-cigarettes are not safe for people that dont use tobacco, they are dohave potential to benefit adult smokers. By triturating the chemical composition and rate of nicotine delivery, it may offer a new tool to assist these individuals. Getting a long time smoker to reduce their dependency on combustible cigarettes is a meaningful thing.

And a National Academies report concluded, ecigarettes are not without risk, but compared to combustible tobacco cigarettes they contain fewer toxicants and are likely to be far less harmful than combustible tobacco cigarettes. The Federal Drug Administration (FDA) has stated that nicotine is what addicts and keeps people using tobacco products, but it is not what makes tobacco use so deadly. Yet, at the same time, even within the FDA and CDC, they state that they continue to investigate the distressing incidents of severe respiratory illness associated with use of vaping products. However, this does not necessarily imply that nicotine is responsible, but rather, that other additives and the delivery technologies themselves may be contributing to such clinical effects.

When it comes to the brain, the potential dangerous effects e-cigarettes may have on the brain and their long term consequences stem from the well established effects nicotine in general has on the brain and brain development, the degree and concentration of nicotine e-cigarettes are capable of delivering, and the chemistry associated with how these devices deliver it. The microvascuature of the brain - the collection of specialized blood vessels that feed the brain and spinal cord and regulate their chemical environment - as well as the cells that make up the brain itself (neurons and other cells), are all vulnerable to damage.

The microvascuature of the brain and spinal cord consists of a vast collection of capillaries that provide brain cells with oxygen and nutrients. It also shuttles away cellular waste products. The brains microvascuature is unique compared to the rest of the body. The endothelial cells that make up these tiny blood vessels form a regulated barrier between the blood on one side (the lumen side of the blood vessels) and the chemical environment the brain and spinal cord float in on the other side. This barrier is called the blood brain barrier.

The normal compliment of molecules and immune cells capable of moving between the blood and the cellular spaces in the other tissues of the body cannot freely do so with the brain and spinal cord - which collectively form the central nervous system. The unique chemical environment of the central nervous system formed by the blood brain barrier is the cerebral spinal fluid.

There is a strong correlation between long term smoking, cognitive decline in the later decades of life, and disruption of the blood brain barrier and microvasculature of the brain. In fact, cognitive decline and microvascular dysfunction are essentially universal consequences of long term smoking for everyone. The exact pathophysiological mechanisms involved are still not completely clear though, warranting continued research. But a recently published paper suggests how the negative physiological effects nicotine has on brain cells when delivered via e-cigarettes mirrors the effects observed with combustible cigarettes.

The endothelial cells that make up the microvasculature are particularly vulnerable. This means that the normal regulatory mechanisms responsible for maintaining the unique chemical environment of the cerebral spinal fluid via the blood brain barrier may slowly break down, contributing to cognitive decline.

And in at least one mouse model study, the authors suggest that e-cigarettes may also have short term disruptive effects on cognitive and memory functions. So there may be more immediate and acute concerns with e-cigarette use, in particular in younger populations where the brain is still developing.

In another study, scientists found that e-cigarettes produce a stress response in neural stem cells, which are populations of cells that eventually become neurons and other important cell types in the brain. Again, potential effects on the still developing brain of adolescents is of immediate concern.

On a positive note, a clinically significant exception to the above effects is the use of nicotine to potentially treat Parkinsons disease. Nicotine and chemically related drugs have been shown to be effective in protecting the parts of the brain that are affected and degenerate in Parkinsons, as well as in treating the symptoms of the disease. Its use has also been indicated in reducing the significant side effects of other Parkinsons drugs.

At the moment there are more questions than answers when it comes to understanding the physiological and cellular effects e-cigarettes - and in particular high concentration nicotine delivery via these devices - has on the brain. The inclusion of additional additives may further exacerbate microvasculature and cellular damage to the brain. These risks should of course be balanced against e-cigarettes ability to help people quit combustible tobacco products, which for that population is judged to be significantly more dangerous than e-cigarettes. The long term epidemiological and public health consequences of e-cigarettes - both good and bad - will not be fully appreciated for years to come. But the data at the moment seems to suggest potential significant pathophysiological effects on brain function.

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Accumulating Evidence Suggests E-Cigarettes Are Likely As Harmful To The Brain As Regular Smoking - Forbes

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Lymph nodes are small, bean-shaped glands that play a crucial role in the immune system. They filter lymphatic fluid, which helps rid the body of germs and remove waste products.

The body contains hundreds of lymph nodes. They form clusters around the body and are particularly prominent in areas such as the neck, armpit and groin and behind the ears.

The bodys cells and tissues dispose of waste products in lymphatic fluid, which lymph nodes then filter. During this process, they catch bacteria and viruses that could harm the rest of the body.

Lymph nodes are an essential part of the bodys immune system. Due to their function, they come into contact with toxins, which can cause them to swell. Although swollen lymph nodes are common, they may occasionally indicate lymph node cancer, or lymphoma.

Keep on reading to learn more about lymph nodes and their function within the immune system.

Lymph nodes are part of the lymphatic system, which is a complex network of nodes and vessels.

In certain areas of the body, such as the neck, armpit, and groin, lymph nodes sit close to the skin. This means a person may feel them swell when an infection develops.

Lymph nodes are also present in the stomach and between the lungs. However, there are no lymph nodes in the brain or spinal cord.

The name of a lymph node depends on its location in the body.

Lymph nodes form clusters throughout the body. Their main function is to filter out potentially harmful substances.

All tissues and cells in the body excrete lymphatic fluid, or lymph, in order to eliminate waste products. The lymph then travels through vessels in the lymphatic system and passes through lymph nodes for filtering.

Lymph nodes contain lymphocytes. These are a type of white blood cells that help destroy pathogens, such as bacteria, viruses, and fungi. When lymph nodes detect a pathogen in the lymph, they produce more lymphocytes, which causes them to swell.

Upon encountering bacteria or damaged cells, lymph nodes destroy them and turn them into a waste product.

When the lymph reenters the bloodstream, waste products travel to the kidneys and liver. The body then excretes waste products in the urine and feces.

Learn more about how the lymphatic system works here.

Swollen lymph nodes do not always indicate cancer. Below, we list some of many conditions that can cause lymph node swelling.

Lymphadenitis occurs when bacteria, viruses, or fungi in the lymph infect lymph nodes. When this happens, lymph nodes swell and are painful to the touch.

If multiple clusters of nodes become infected, a person may feel pain and swelling in both their neck and groin.

The most common type of lymphadenitis is localized lymphadenitis. This means the condition only affects a few nodes. If the infection occurs in several node clusters, a doctor will likely diagnose generalized lymphadenitis.

The condition usually results from an infection elsewhere in the body.

Symptoms of lymphadenitis include:

Lymphadenitis treatments include:

The type of treatment necessary will depend on a variety of factors, such as the severity of the disease and a persons underlying conditions and allergies. A doctor will help a person choose the most suitable treatment based on these factors.

Learn more about swollen lymph nodes in the neck here.

Swollen lymph nodes in the neck may be due to a viral or bacterial throat infection, such as strep throat.

Viral throat infections, such as colds, can present with swollen lymph nodes, a runny nose, and pinkeye.

These infections usually resolve on their own. However, a person can take over-the-counter pain relievers to alleviate pain they may experience when swallowing.

Strep throat is a bacterial infection that develops in the throat and tonsils due to group A streptococcus. People may contract strep throat if they come into contact with droplets containing the strep bacteria.

A person with strep throat may experience swollen lymph nodes on the neck, a sore throat, a fever, and red spots on the roof of the mouth.

Doctors treat strep throat with antibiotics.

Impetigo is an infection that develops due to group A streptococcus and may cause lymph nodes in the armpits and groin to swell.

A person can contract impetigo when the bacteria enter the body through a break in the skin. This can happen through sharing a towel, razor, or yoga mat.

Symptoms of impetigo include:

If a person has impetigo, they should seek medical attention to address their symptoms and prevent the condition from spreading to others.

Treatment will usually involve antibiotics.

Ringworm, or jock itch, is a fungal infection that can affect many areas of the body. If the fungus develops in the groin, a person may experience lymph node swelling in that area.

Typically, ringworm starts as a fungal lesion. The fungus often transmits when people share towels or razors.

Ringworm thrives in moist environments, and therefore a person should take care to dry thoroughly after a wash and try not to stay in damp clothes.

Common ringworm symptoms include:

A doctor will prescribe an antifungal treatment to address ringworm.

The best way to prevent ringworm is to wear breathable fabrics, avoid sharing towels and razors, and dry thoroughly after bathing.

Learn more about swollen lymph nodes in the groin here.

Lymphoma is a type of cancer that affects the lymphatic system. The two main types of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma.

Hodgkin lymphoma occurs when cancer cells spread from one cluster of lymph nodes to another. By contrast, in non-Hodgkin lymphoma, there is no order in how cancer cells spread throughout the lymphatic system.

Typical symptoms of lymphoma include:

These are also common symptoms of viral infections, which can make lymphoma hard to diagnose. However, in people with lymphoma, symptoms tend to persist for longer periods of time.

It is of note that these symptoms do not clearly indicate cancer. If a person experiences any of these, they should contact a doctor to identify the cause of their symptoms.

Treatment options for lymphoma include:

A person should contact a healthcare professional if they are experiencing persistent swelling of lymph nodes.

Swelling usually indicates an infection, and therefore a person should not immediately worry about lymphoma.

After reaching a diagnosis, a doctor will recommend the appropriate course of treatment.

Lymph nodes are a part of the lymphatic system. They filter lymph, which contains pathogens and damaged cells, and send the dead cells to the kidneys and liver.

Lymph node swelling usually results from an infection. In rare cases, however, it may be due to lymphoma.

If a person is concerned about swelling and other symptoms they have, they should contact a doctor.

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Lymph nodes: Purpose, location, and disease warning signs - Medical News Today

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bluebird bios cerebral adrenoleukodystrophy (CALD) gene therapy Skysona has moved closer towards EU approval after gaining a positive opinion from the European Medicines Agencys Committee for Medicinal Products for Human Use (CHMP).

The CHMP has recommended marketing authorisation for Skysona (elivaldogene autotemcel, Lenti-D) for the early treatment of CALD in patients under 18 years old with an ABCD1 genetic mutations, and who do not have a matched sibling haematopoietic stem cell (HSC) donor.

bluebird bio's Skysona is a potential one-time gene therapy designed to add functional copies of the ABCD1 gene into a patients hematopoietic stem cells.

Once this functional gene is added to a CALD patients stem cells, the patient's body can produce the adrenoleukodystrophy protein (ALDP), which is believed to allow for the breakdown of very-long-chain fatty acids that build up to toxic levels in the brain.

CALD is a progressive and fatal neurodegenerative disease that overwhelmingly affects males. It involves the breakdown of myelin the protective sheath of nerve cells in the brain that is responsible for muscle control and thinking.

The condition is caused by mutations in the ABCD1 gene that affect the production of ALDP which eventually causes damage to the adrenal cortex and white matter of the brain and spinal cord.

Currently, the only treatment for the disease is a stem cell transplant, although this carries a significant risk from the high-dose chemotherapy used to prepare patients for the procedure.

Other complications include graft-versus-host (GvHD) disease, which occurs when the transplanted cells recognise the recipients cells as foreign and attack them.

In the phase 2/3 Starbeam study evaluating Skysona, 90% of CALD patients met the month 24 major functional disability- (MFD) free survival endpoint as of the last data cutoff date.

MFDs are the six severe disabilities commonly attributed to CALD, which have the most severe effect on a patients ability to function independently.

In addition, 26 out of 28 evaluable patients maintained a neurologic function score (NFS) less than or equal to one until month 24, with 24 of those patients having no change in their NFS.

The CHMPs positive opinion is now due to be reviewed by the European Commission, with a final decision for Skysona expected in mid-2021.

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bluebird bio's CALD gene therapy Skysona gains positive opinion from CHMP - PMLiVE

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NEARLY 10,000 has been raised in less than a week to help pay for a Dunfermline mum to have life-changing treatment in Russia.

Lynda Hogg was first diagnosed with Primary Progressive Multiple Sclerosis (PPMS) seven years ago and since then, she has seen her health deteriorate.

She has been forced to give up her job as a theatre nurse at Queen Margaret Hospital and faces a daily battle with pain from a condition for which there is no cure and no treatment on the NHS.

Lynda, 58, and her family are now pinning their hopes on travelling to Russia for Hematopoietic Stem Cell Transplantation which, it is hoped, will stop the progression of her MS.

Within a week of being set up, a GoFundMe page has already raised nearly a quarter of the required 45,000, something which Lynda said she was overwhelmed and humbled by.

It was my son who said how do you feel in 10 years time if you are wheelchair-bound knowing you had this opportunity and didnt take it? she explained.

We have considered selling the house if we have to.

Daughter Popsi is hopeful that the GoFundMe page will mean such a drastic step is not necessary.

Before the GoFundMe, these were all considerations, she said. Shall we sell the house, will my dad have to give up his job and become a carer?

After we found out about this treatment years ago, I dont think we ever really considered it a possibility. It has been quite tough. I have three brothers. Speaking on behalf of the younger ones, I want them to remember them as I remember her, full of life.

This treatment is kind of a possibility that it would not get any worse. It is a pipe dream. We never thought it could happen. The support and kindness of others has been so touching.

Multiple Sclerosis (MS) is a disabling disease of the brain and spinal cord which results in muscle and nerve damage, ongoing pain and fatigue.

Since her diagnosis, Lynda, who is married to Murray and has four children, Adam, 29, Popsi, 23, Mitchell, 18, and Charlie, 15, has seen her health go downhill with her mobility decreasing.

She has been shocked at the lack of available medication.

Basically, I get co-codamol, she said. Progressive Primary MS is the worst form of it. There is no treatment and there is really little in the way of emotional support. It is not a fault of the NHS. There is nothing and there needs to be something.

PPMS is 15 per cent of people diagnosed. It is horrible to think there is nothing out there for them.

Trials for the treatment which Lynda hopes to have in Russia have taken place in the UK but, to date, are not available on the NHS for patients like herself.

They give you medication to increase the quality of stem cells. They are harvested and then you are given chemo then the stem cells are reintroduced to you. They can stop MS in its tracks. It will stop the progression. It wont give you functions back.

Even just to stop it progressing; I can cope with the disabilities I have but I dont know if I can cope with them moving forward and getting worse.

Popsi and her siblings are planning to hold further fundraisers when coronavirus restrictions allow while also raising awareness of MS.

We have had to watch our mum struggle with the disease and battle with pain every day, she added. We feel that its time to give back to our mum, and everything that she has done for us over the years.

Anyone wanting to help can do so by visiting https://gofund.me/61401f6e.

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Dunfermline mum "overwhelmed" by fundraiser aiming to fund vital treatment in Russia - Dunfermline Press

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Animal cloning has come a long way from Dolly the sheep, but all through that time the ethical and scientific repercussions only continue to pile up.

One thing is getting clearer though: The cloning process has improved by leaps and bounds (though not yet on the levels shown in science-fiction). This has resulted in headways in a number of cloning-related endeavors, from the revival of endangered (and even extinct) species to replicating dead pets.

Still, both critics and proponents are still a bit out of touch with regards to how current cloning tech is being used to address these issues.

There is some truth to the hype that bringing back the woolly mammoth via cloning could be in the not-so-distant future.

On the other hand, many critics question the wisdom of bringing back prehistoric animals to habitats that have long changed from their disappearance. Still, this ignores the possibility of restoring more recently extinct species and how cloning could counteract such drastic environmental changes from their loss.

Another popular argument against cloning is the idea that its novelty and high costs could be redirected to more natural methods of conservation. But while that may be true for a majority of endangered species, it may not be so for those that have been officially declared extinct in the wild.

Cloning could be an important tool in ensuring the genetic diversity that allows populations in captivity to grow (and make reintroduction more feasible).

The idea of cloning animals that retain a set of desirable traits has raised considerable alarm (especially among more conservative groups). However, there are benefits to the practice that cannot be ignored.

Replicating the sharp noses of bomb sniffer (or even disease sniffer) dogs could make a difference in times of need. Likewise, cloning cattle with more consistent yields of milk and meat could have applications for more efficient livestock farming.

Also read: Trained Bees Can Identify COVID-19 Infection Through Sense of Smell Within Seconds!

Now, despite the advances, today's cloning technology is still decades away from producing perfect, one-for-one genetic copies of an original animal. Differences (even large ones) can still be found. There is also the fact that environment, behavior and upbringing could still drastically alter the genetic makeup of a cloned animal (as the study of epigenetics will gradually reveal).

Throwing a bit of caution to the wind will also be important if the increase of cloned designer animals could lead to other adverse effects on the global environment (especially in the feeding of quality livestock). The same applies to the use of clones to restore and reintroduce critically endangered species.

Overall, the bounds of the technology's research has expanded considerably (and so has the conversation). But at the same time, it is important to have a strong sense of moderation regarding its application. It has the potential of causing problems and incurring needless costs, but these should not discourage future research on cloning's potential.

Also read: Snakes Can Store Sperm for up to 5 Years Before Getting Pregnant

2021 NatureWorldNews.com All rights reserved. Do not reproduce without permission.

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Rise of Animal Cloning in 2021: Benefits, Risks, and Why It Matters - Nature World News

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Cell and gene therapies are overlapping fields of research and treatments. While both aim to treat and potentially cure diseases, they have slightly differing approaches and have different historical backgrounds. Due to growing interest surrounding this field, the general public still has much to learn and understand about each of these potentially life-saving therapies.

Below, we provide a general overview and brief historical context for each type of therapy.

Cell therapyis the process of replacing damaged or dysfunctional cells with new, healthy ones by transferring live cells into a patient. These can be autologous (also known as self-to-self, using cells from the patient receiving the treatment) or allogeneic (using cells from a donor for the treatment). While this field of treatment has recently begun to expand, some forms of cell therapy like the cancer-treating hematopoietic stem cell transplantation(HSCT) have been in practice for decades.

While many people have heard of bone marrow transplants, few realize that this procedure is a stem cell therapy. While stem cells can be derived from many sources, such as umbilical cord blood and mobilized peripheral blood, bone marrow derived stem cell therapy is the most commonly used today and has been for more than 50 years.

The first transfusion of human bone marrow was given to a patient with aplastic anemia in 1939. After World War II researchers diligently worked to restore bone marrow function in aplasia patients caused by exposure to radiation produced by the atomic bomb. After a decade of work they were able to show, in a mouse model, that aplasia could be overcome by bone marrow treatment.

The first allogeneic HSCT, which led the way to current protocols, was pioneered by E. Donnall Thomas and his team at the Fred Hutchinson Cancer Research Center and reported in the New England Journal of Medicine in 1957. In this study six patients were treated with radiation and chemotherapy and then received intravenous infusion of bone marrow rich stem cells from a normal donor to reestablish the damaged or defective cells. Since then the field has evolved and expanded worldwide. While almost half of HSCT are allogeneic, the majority of HSCT are autologous, the patient's own stem cells are used for treatment, which carries less risk to the patient.

In 1988, scientists discovered that they could derive stem cells from human embryos and grow the cells in a laboratory. These newly derived stem cells, referred to as embryonic stem cells (hESCs), were found to be pluripotent, meaning they can give rise to virtually any other type of cell in the body. This versatility allows hESCs cells to potentially regenerate or repair diseased tissue and organs. Two decades after they were discovered, treatments based on hESCs have been slow in coming because of controversy over their source and concerns that they could turn into tumours once implanted. Only recently, testing has begun as a treatment for two major diseases: heart failure and type 1 diabetes.

In 2006, researchers made a groundbreaking discovery by identifying conditions that would allow some cells to be 'reprogrammed' genetically. This new type of stem cell became known as induced pluripotent stem cells (iPSCs). Since this discovery, the field has expanded tremendously in the past two decades. Stem cell therapies have expanded in use and have been used to treat diseases such as type 1 diabetes, Parkinson's and even spinal cord injuries.

There has also been a growing focus on using other immune cells to treat cancer. Therapies such as CAR T-cellare dependent upon a patient's T-cells, which play a critical role in managing the immune response and killing cells affected by harmful pathogens. These cells are then reengineered to target and kill certain cancerous cells. Several CAR T-cell therapies have been FDA approved, with the first approval being given in 2017 for Yescarta and Kymriah, to be used for the treatment of B-cell leukemia in children and young adults.

Gene therapyis a process that modifies the expression of a gene or alters the biological process of living cells for therapeutic use. This process can take the form of replacing a disease-causing gene with a new, healthy one, inactivating the mutated gene, or introducing a new gene to help the patient's body fight a disease.

While the use of gene therapy to treat humans is fairly new, the science behind it has been used in science for decades. Farmers and geneticists have collaborated for years on crop improvement using cross pollination, genetic engineering and microinjection techniques to create stronger, more resilient crops.

The first human patient to be treated with gene therapy was a four-year old girlsuffering from severe combined immunodeficiencyin 1990. She received treatment for a congenital disease called adenosine deaminase (ADA). Since then, gene therapies have been used to treat diseases such as cancer, cystic fibrosis and hemophilia.In 2017, the FDA gave its first approval of a gene therapy called Luxturna, which is used to treat patients with established genetic vision loss that may result in blindness. Gene therapies are still being studied and developed, with over 1,000 clinical trialscurrently underway.

ThermoGenesis Holdings Inc., is a pioneer and market leader in the development and commercialization of automated cell processing technologies for the cell and gene therapy fields. We market a full suite of solutions for automated clinical biobanking, point-of-care applications and large-scale cell processing and manufacturing with a special emphasis on the emerging CAR-T immunotherapy market. We are committed to making the world a healthier place by creating innovative solutions for those in need.

For more information on the CAR-TXpress multi-system platform, please contact our Sales team.

Disclaimer

Thermogenesis Holdings Inc. published this content on 13 April 2021 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 13 April 2021 07:10:03 UTC.

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LCol Laura Laycock on deployment.

LCol Laura Laycock

It was Oct. 7, 2019, and life was not just good, it was amazing.

My career in the Royal Canadian Air Force was going great. I loved my job and was getting promoted. Throughout my Canadian Armed Forces career of over 20years, I had represented Canada around the world with NORAD, NATO and the UN. I had married the most incredible man. We relocated to Ottawa, started to travel the world together, and were ready to start a family.

Then, on Oct. 8, 2019, everything changed.

I was diagnosed with Chronic Myeloid Leukemia(CML) after blood work for vertigo showed extremely elevated white blood cell counts. CML is a blood cancer where the bone marrow overproduces white blood cells, which eventually impairs the development of white and red blood cells and platelets. Its usually caused by a spontaneous mutation in DNA, which contains our genetic code.

LCol Laycock

Twenty years ago, researchers developed a new line of drugs that combat this overproduction of white blood cells. These targeted oral chemotherapy pills have been revolutionary in the fight against CML. Most people who take them do so for the rest of their lives and have good survival rates; however, a stem cell transplant remains the only actual cure. But its risky and not needed for most people.

Its now been about 17months since my diagnosis and my body has not tolerated this targeted chemotherapy. I fall into that small fraction of people who get debilitating or life-threatening side effects from this medication. My doctors are discussing other treatment options, one of which is a stem cell transplant, but my mixed ethnicity (European/Middle Eastern) has made it difficult to find a donor match.

My journey since my diagnosis has been to slow down and educate myself so that I can heal and advocate for my care; to appreciate every little moment of joy; and to do my best to overcome each challenge that arises. I have found strength in the extraordinary support Ive received from my family, my friends and my community, both old and new.

With the help of family and friends, I recently began a social media campaign to increase stem cell donor education and registration in Canada and around the world. Many people are unaware of the potentially lifesaving role they can play by registering to become stem cell donors. Stem cell transplants are vital treatment options for people with a range of medical conditions including spinal cord injuries, heart disease, diabetes, and some cancers.

The process to donate is simple. First, you register online with Canadian Blood Services or Hma-Qubec and do a mail-in cheek swab., and then you wait. It could be months or years before you are identified as a match. During this waiting period, you should update your contact information with the registry if it changes.

When you are matched, you will be contacted to continue with the donation process. This process is similar to giving blood, but it has its differences. The cells are usually collected intravenously from peripheral blood in a non-surgical procedure but, in rare cases, they are collected directly from the bone marrow in a surgical procedure. In either case, the risks associated with donating are minor.

In Canada, individuals aged17 to 35 can register to become stem cell donors (ages18 to 35 in Quebec). Both CBS and Hma-Qubec are part of an international network of donor registries from over 50countries. This network has a pool of over 38million donors but, unfortunately, matches are rare.

Your stem cells could potentially help others around the world, and throughout this process donor privacy is assured at all times.

LCol Laycock on her wedding day.

Stem cell matching relies on Human Leukocyte Antigen typing, which is highly influenced by ethnicity. This means that a patients best chance of finding a matching donor is from those who share similar ethnic backgrounds. Research conducted by Gragert et al.(2014) has shown that the likelihood of finding a match for certain ethnic groups can be as low as 16 percent and as high as 75 percent for others. This disparity highlights the need for more ethnically diverse stem cell donors in our registries.

Today, I am calling on my DND and CAF families to register as stem cell donors to help people, like me, who are fighting for our lives. If you arent able to register, please share this call with those who can. You, or someone you know, could be the match that saves a life a simple swab is all it takes to be a hero.

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Stem cell treatment needed to fight the good fight - Victoria Lookout

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Stem cell therapy, also known as regenerative medicine, has been around for decades, but in recent years, the use of and interest in stem cell therapy has increased exponentially. The dramatic utilization of stem cell therapy, and the increasing government spend related to these novel techniques, have now caught the eye of federal regulators and prosecutors. In this client alert, we profile some brief context of stem cell therapy, the governments regulations governing these techniques, and some of the best practices for those interested in this emerging space.

Stem cells are cells from which all other cells with specialized functions are generated (i.e., the bodys raw materials). Stem cells may duplicate themselves to create more stem cells or they may generate cells with a specific function like blood or brain cells.

Stem cell therapy is used to repair or replace damaged tissue or cells within the body. Many in the medical community are hopeful that stem cell therapy can be used to treat a wide array of conditions and diseases from multiple sclerosis to vision loss to traumatic spinal cord injuries to Lou Gehrigs disease just to name a few.

The Food and Drug Administration (FDA) oversees and regulates stem cell therapy treatments. While the FDA has acknowledged that stem cell therapy has the potential to treat diseases or conditions for which few treatments exist, there are still only a few treatments that have actually been approved by the FDA. Many treatments are still only in early investigatory stages.

The FDA has recognized the massive potential that stem cell therapy has in allowing patients treatments for various conditions. Consequently, in 2017, the FDA issued guidance indicating its intent to exercise enforcement discretion as a means to support and expedite the development of regenerative medicine products. This enforcement discretion period was to allow innovators time to determine whether to submit an Investigational New Drug (IND) or marketing application and, if such an application is needed, to prepare and submit the application as appropriate. The FDA, however, has made clear its enforcement discretion policy only applies to products that do not raise potential significant safety concerns. What the FDA considers significant is debatable, creating uncertainty and ambiguity for those who might be relying on the FDAs enforcement discretion period.

Initially, the FDA stated that its enforcement discretion period would last through November 2020. But in July 2020, the FDA extended its enforcement discretion period through May 2021 a fast-arriving date. It remains unclear whether the FDA intends to extend the time period of its enforcement discretion any further, but either way, stem cell therapy providers would be well-served by planning for and expecting enforcement efforts to ramp up in the near future.

In 2019, the FDA went to great lengths to warn consumers of the potential fraud that may arise from what it called stem cell therapy hype, and encouraged consumers to make sure any stem cell therapy treatments were either approved or being studied as an IND. The FDAs concerns have led to multiple enforcement actions, including one just last month. On February 1, 2021, for example, the government announced the indictment of Ashton Derges, a healthcare provider in Missouri, who marketed stem cell shots as a successful treatment for various conditions, including COVID-19. According to the indictment, Derges was paid nearly $200,000 by patients for the stem cell shots, none of which actually contained stem cells at all. While this alleged fraud was not particularly sophisticated, it nonetheless marked a significant development: the governments first criminal prosecution of those touting stem cell therapies.

But blatant fraud is not the only type of stem cell therapy case the government has expressed interest in investigating. A primary concern of the government is the marketing and use of unproven stem cell treatments as miracle cures. A good case study of the risks associated with aggressive marketing of stem cell therapy is a case out of Florida involving US Stem Cell Clinic Inc. The clinic was marketing stem cell therapy to treat conditions and diseases such as Parkinsons disease, stroke, and brain injuries none of which were approved by the FDA. And, much of the marketing that US Stem Cell Clinic used promised almost miraculous results. As a result, last year, the FDA successfully permanently enjoined the US Stem Cell Clinic from selling or providing those stem cell therapy treatments. Notably, this case was pursued by the FDA despite the FDA explicitly stating its intent to be lenient with emerging stem cell therapy treatments.

Stem cell therapy is a groundbreaking medical tool with great possibilities to treat a plethora of diseases and conditions. As the industry continues to expand, so will the governments interest. Our firm continues to see an uptick in cases involving stem cell therapy treatments. And we have successfully assisted clients in avoiding unnecessary scrutiny by the FDA and other government regulators.

If you are in the stem cell therapy industry or are considering offering stem cell therapy treatments, we recommend that you:

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The Governments Watchful Eye on Fraud Stemming from Stem Cell Therapy - JD Supra

Spinal Cord Stem Cells Comments Off on The Governments Watchful Eye on Fraud Stemming from Stem Cell Therapy – JD Supra | April 4th, 2021

Multiple sclerosis (MS) causes a wide range of symptoms involving the brain, optic nerves, and spinal cord. Research is only just beginning to reveal who is at risk and what causes the condition.

MS is a chronic condition affecting 2.8 million people worldwide. While treatment options are currently limited, trials of several new approaches are underway.

Researchers believe that MS is an autoimmune disorder. This type of illness involves the immune system attacking healthy cells, much as it would attack viruses or bacteria.

In the case of MS, the immune system attacks the myelin sheath that surrounds nerve cells. The attack causes lesions to form, and over time, these cause scarring, which leads to nerve damage and reduced function.

As a result of this damage, a person with MS may experience numbness and tingling sensations, fatigue, muscle weakness, dizziness and vertigo, memory issues, and vision problems, among other symptoms.

There are four types of MS: clinically isolated syndrome (CIS), relapsing-remitting MS, primary progressive MS, and secondary progressive MS.

CIS is a single episode of MS-like symptoms that lasts for at least 24 hours. People with CIS do not necessarily have MS, but experiencing an episode can be the first sign of the condition.

Treating MS involves interdisciplinary care, including rehabilitation, disease-modifying drugs (DMARDs), and complementary and alternative therapies.

Scientists do not fully understand the risk factors for MS and the mechanisms of the condition. However, they are making new headway in the search for answers and improvements in treatment.

What does the latest research show about the risk factors, mechanisms, and treatments of MS? In this Special Feature, Medical News Today takes a closer look.

French neurologist Jean-Martin Charcot first described the features of MS in 1868. He noted the differences between this condition and the tremor of paralysis agitans, a symptom of the neurological condition later named Parkinsons disease.

The three symptoms associated with MS at the time were called Charcots triad. They included a characteristic tremor, involuntary eye movements, also known as nystagmus, and scanning speech, which some call staccato or explosive speech.

Decades later, the invention of MRI scans helped doctors diagnose MS. Treatment with steroids became commonplace, and doctors then began to use medications in a class of drugs called interferons. The Food and Drug Administration (FDA) first approved interferons for use in people with MS in 1993.

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Although scientists and healthcare professionals understand the defining features of MS, several aspects of the condition remain a mystery.

While researchers recognize that MS is an autoimmune condition, they do not understand why immune cells attack myelin.

Also, diagnosing MS is still an ambiguous process because its symptoms are similar to those of many other health conditions.

In addition, experts do not know why women are 23 times more likely to be diagnosed with MS than men.

Research suggests that risk factors of MS include a lack of vitamin D or sunlight, smoking, obesity, a history of infection with the Epstein-Barr virus, being female, and possibly having inherited specific genes, as well as environmental factors.

More recently, the gut microbiota has emerged as a possible risk modulator.

A recent overview of clinical research found that people with MS had larger populations of Pedobacteria, Flavobacterium, Pseudomonas, Mycoplana, Acinetobacter, Eggerthella, Dorea, Blautia, Streptococcus, and Akkermansia bacteria in their intestines than people without MS.

People with MS also had reduced populations of Prevotella, Bacteroides, Parabacteroides, Haemophilus, Sutterella, Adlercreutzia, Coprobacillus, Lactobacillus, Clostridium, Anaerostipes, and Faecalibacterium bacteria.

Researchers speculate that balancing out the populations of gut bacteria in people with MS may reduce inflammation and the overactivation of the immune system.

Research from the MS Society Edinburgh Centre for MS Research found that people with MS had reduced numbers of inhibitory neurons, compared with people who did not have the condition.

However, people with MS had as many stimulating neurons as those without the condition. This was true even for people who had received their MS diagnoses many years earlier.

These findings help reveal the types of neurons affected by MS, shedding more light on how the condition evolves within the body. The research may also offer insight into treatments that could protect the targeted neurons.

DMARDs that health authorities have recently approved as MS treatments include cladribine (Mavenclad) and siponimod (Mayzent) for relapsing-remitting and active secondary progressive forms of the condition.

Cladribine targets lymphocytes, white blood cells responsible for attacks on myelin. Siponimod harnesses specific white blood cells that attack myelin and prevents them from circulating in the body.

However, due to their interactions with the immune system, these drugs may lead to a reduction in lymphocytes, making a person vulnerable to infections.

The medicines actions may also contribute to reduced responses to vaccines in people who receive routine vaccinations. With the introduction of COVID-19 vaccines, scientists have investigated whether people with MS who take medications such as cladribine can have adequate responses to vaccines.

The latest research indicates that people taking cladribine do produce protective antibodies to other common vaccines, despite having decreased lymphocyte levels induced by the medication.

This result gives scientists and others in the medical community hope that people who take these drugs for MS will have similarly adequate responses to COVID-19 vaccines.

Some scientists are currently investigating the potential for stem cell therapy for MS. In a phase 1 study conducted at the Karolinska Institute, in Stockholm, Sweden, seven people with progressive MS received infusions of stem cells derived from each participants own bone marrow.

As early as 7 days after administration of the stem cell therapy, researchers found evidence of positive changes in the participants immune systems. At 12 weeks, five out of six participants had no new characteristic lesions on follow-up MRI brain scans.

As their understanding of the condition evolves, many scientists are investigating the root cause of MS.

An analysis of the current data has revealed a possible connection between gut health and the condition. Data revealing relationships between the gut microbiota and the brain continually emerge, and scientists are hopeful that diet modifications, probiotics, and certain drugs that balance the gut microbiome will play a role in MS treatment.

Also in development are remyelination and neuroprotection therapies. The latter aim to protect the axons and myelin from further damage, while the former could restore lost function for people with MS.

Meanwhile, immunotherapy drugs would protect the nerves from destruction and rebuild neurons that have already sustained damage.

Another potential treatment in phase 1 trials is a tumor necrosis factor-alpha (TNF-alpha) inhibitor called MYMD-1. TNF-alpha is a type of cytokine produced by white blood cells that regulates some aspects of the immune system.

Overproduction of this cytokine is associated with several autoimmune conditions, including MS. MYMD-1 is a new type of TNF-alpha blocker that shows promise as a treatment for MS and other conditions.

Trials for therapies involving the gut microbiome, stem cells, neuroprotective treatments, remyelination, and MYMD-1 are still in the earliest stages. However, the possibilities provide hope that ongoing research will lead to effective ways to prevent MS and better methods of treatment.

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Multiple sclerosis: Recent research on causes and treatments - Medical News Today

Spinal Cord Stem Cells Comments Off on Multiple sclerosis: Recent research on causes and treatments – Medical News Today | April 4th, 2021

Stem cells are found in all human beings, from the initial stages of human growth to the end of life. All stem cells are beneficial for medical research; however, each of the different kinds of stem cells has both limitations and promise. Embryonic stem cells that can be obtained from a very initial stage in human development have the prospect to develop all of the cell types in the human body. Adult stem cells are found in definite tissues in fully developed humans. Stem cells are basic cells of all multicellular animals having the ability to differentiate into a wide range of adult cells. Totipotency and self-renewal are characteristics of stem cells. However, totipotency is seen in very early embryonic stem cells. The adult stem cells owes multipotency and difference flexibility which can be exploited for next generation therapeutic options. Recently, scientists have also recognized stem cells in the placenta and umbilical cord blood that can give rise to several types of blood cells. Research for stem cells is being undertaken with the expectation of achieving major medical inventions. Scientists are attempting to develop therapies that replace or rebuild spoiled cells with the tissues generated from stem cells and offer hope to people suffering from diabetes, cancer, spinal-cord injuries, cardiovascular disease, and many other disorders.

The stem cell therapy market is segmented on the basis of type, therapeutic applications, cell source, and geography. On the basis of type, the stem cell therapy market is categorized into allogeneic stem cell therapy and autologous stem cell therapy. Allogeneic stem cell therapy includes transferring the stem cells from a healthy person (the donor) to the patients body through high-intensity radiation or chemotherapy. Allogeneic stem cell therapy is used to treat patients who do not respond fully to treatment, who have high risk of relapse, and relapse after prior successful treatment. Autologous stem cell therapy is a type of therapy that uses the persons own stem cells. These type of cells are collected earlier and returned in future. The use of stem cells is done to replace damaged cells by high doses of chemotherapy, and to treat the persons underlying disease. On the basis of therapeutic applications, the stem cell therapy market is segmented into cardiovascular diseases, wounds and injuries, musculoskeletal disorders, gastrointestinal diseases, surgeries, neurodegenerative disorders, and others. On the basis of cell source, stem cells therapy is segmented into bone marrow-derived mesenchyme stem cells, adipose tissue-derived mesenchyme stem cells, and cord blood or embryonic stem cells

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By geography, the market for stem cell therapy is segmented into North America, Europe, Asia Pacific, Latin America, and Middle East & Africa. North America leads the stem cell therapy market owing to rising awareness among people, early treatment adoption, and new product innovations. Europe is the second leading market for stem cell therapy due to development and expansion of more efficient and advanced technologies. The Asia Pacific stem cell therapy market is also anticipated to grow at an increasing rate owing to increasing healthcare spending, adoption of western lifestyles, and growth in research and development. Asia Pacific is the fastest growing region for stem cell therapy as several players have invested in the development of new stem cell technologies. These factors are expected to drive the growth of the stem cell therapy market globally during the forecast period.

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The major player in the stem cell therapy market are Regenexx, Takara Bio Company, Genea Biocells, PromoCell GmbH, CellGenix GmbH, Cellular Engineering Technologies, BIOTIME, INC., Astellas Pharma US, Inc., AlloSource, RTI Surgical, Inc., NuVasive, Inc., JCR Pharmaceuticals Co., Ltd., Holostem Terapie Avanzate S.r.l., PHARMICELL Co., Ltd, ANTEROGEN.CO., LTD., The Future of Biotechnology, and Osiris Therapeutics, Inc. Rising demand for advanced stem cell therapies will increase the competition between players in the stem cell therapy market.

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Stem Cell Therapy Market Research Reveals Enhanced Growth During The Forecast Period 2017 2025 FLA News - FLA News

Spinal Cord Stem Cells Comments Off on Stem Cell Therapy Market Research Reveals Enhanced Growth During The Forecast Period 2017 2025 FLA News – FLA News | March 8th, 2021

For baby Teera Kamat, who has been on the earth for a mere six months, every day has been a struggle for existence and a grim reminder to her parents about the fragile little being that needed a miracle to be saved. Mumbai-born Teera is suffering from Spinal Muscular Atrophy, a very rare medical condition that often does not let children live beyond 5 months of age and her condition requires a lot of money for the treatment.

On Wednesday, Prime Minister Narendra Modi, in a humanitarian move, decided to waive off Rs 6 crore as a GST amount against Rs 16 crore of imported medicines that are required to treat Teera. Baby Teera's parents Priyanka and Mihir Kamat have raised Rs 16 crore through crowdfunding for their daughter who needs a surgery to be cured. It also includes the cost of the medicine Zolgensma which has to be imported from the US. The tax exemption for baby's treatment amounts to at least Rs 6.5 crore and it includes 23 percent import duty and 12 percent Goods Services Tax.

The infant's parents had earlier appealed to PM Modi in October last year about Teeras medical condition and in January this year. The Leader of Opposition Devendra Fadnavis also wrote to the Prime Minister and Finance Minister Nirmala Sitaraman reiterating the request to exempt taxes on the medicine import.

It is a type of genetic disorder and a motor neuron disease that results in a person not having any control over movement of their muscles due because of the lack of nerve cells, in their spinal cord and/or brain stem.

Spinal muscular atrophy (SMA) results in muscle wasting and weakness. For someone suffering from SMA, it is very difficult to stand, walk and control their movements. Some intense forms of the SMA can also result in inability to breathe and swallow.

SMA can either occur at birth or even appear at stages of life and they can affect one's life expectancy depending upon the seriousness and the type of the SMA.

So far, there has been no cure of SMA, but certain medicines do help, such as nusinersen (Spinraza) and onasemnogene abeparvovec-xioi (Zolgensma), that help slow the disease's progress.

The types of SMA depend on when they start showing up in a patient and how the symptoms vary in them. There are basically four kinds of SMA, as National Institute of Neurological Disorders and Stroke list, which affects symptoms and life expectancy.

The first type of SMA, or Werdnig-Hoffmann disease appears before the infant is even 6 months of age. The child might be born with difficulty in breathing and the serious condition can turn fatal if there's no treatment.

Those with SMA type II will start showing symptoms of the disease usually when they are between 6 and 18 months of age. These children can sit but will not be able to walk or stand without helped and without treatment, they might just lose their power to sit as well.

Children with SMA type III or Kugelberg-Welander disease start showing symptoms after they are 18 months of age and can walk on their own. They however, experience difficultly in walking or running and other such physical exercises related to legs.

Those with SMA type IV usually develop the symptoms after they are over 21 years of age ad have minor muscle weakness and other issues. It doesn't affect one's life expectancy.

The USA Food and Drug Administration has approved the Zolgensma gene therapy for children who show the signs of the disease and are less than 2 years. Last year in August, the FDA also gave its nod to the orally-administered drug risdiplam (Evrysdi) for patients who are older than two months of age and are diagnosed with SMA.

Physical therapy, occupational therapy, and rehabilitation are some measures that can be taken to help improve posture, stop joint immobility and help in case of muscle weakness and atrophy.

You can find the link to the crowdfunding page for baby Teera here.

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PM Modi Waives off Rs 6 Crore Tax on Imported Medicine for 6-month-old Baby Girl from Mumbai - News18

Spinal Cord Stem Cells Comments Off on PM Modi Waives off Rs 6 Crore Tax on Imported Medicine for 6-month-old Baby Girl from Mumbai – News18 | February 11th, 2021

Endogenous activin A in ectopic bone formation

Heterotopic ossification (HO) is the formation of ectopic bone in soft tissues at sites of injury-induced inflammation. Similar to the development of normal endochondral bone, HO is initiated by a local mass of chondrocytes that progress through chondrogenesis, osteogenesis, and mineralization to form bone tissue. Using mouse models of both subcutaneous and intramuscular HO formation and single-cell RNA sequencing, Mundy et al. found that inflammatory cells and skeletal progenitor cells initially recruited to sites of HO formation expressed Inhba, which encodes the TGF- superfamily member activin A. Treating mice with an activin Aneutralizing antibody reduced the number of chondrogenic cells at HO sites and inhibited HO formation. These results demonstrate that this ligand plays an important role in the physiological progression in these mouse models of HO and suggest that interfering with activin A signaling may be effective in patients.

Heterotopic ossification (HO) is a common, potentially debilitating pathology that is instigated by inflammation caused by tissue damage or other insults, which is followed by chondrogenesis, osteogenesis, and extraskeletal bone accumulation. Current remedies are not very effective and have side effects, including the risk of triggering additional HO. The TGF- family member activin A is produced by activated macrophages and other inflammatory cells and stimulates the intracellular effectors SMAD2 and SMAD3 (SMAD2/3). Because HO starts with inflammation and because SMAD2/3 activation is chondrogenic, we tested whether activin A stimulated HO development. Using mouse models of acquired intramuscular and subdermal HO, we found that blockage of endogenous activin A by a systemically administered neutralizing antibody reduced HO development and bone accumulation. Single-cell RNA-seq analysis and developmental trajectories showed that the antibody treatment reduced the recruitment of Sox9+ skeletal progenitors, many of which also expressed the gene encoding activin A (Inhba), to HO sites. Gain-of-function assays showed that activin A enhanced the chondrogenic differentiation of progenitor cells through SMAD2/3 signaling, and inclusion of activin A in HO-inducing implants enhanced HO development in vivo. Together, our data reveal that activin A is a critical upstream signaling stimulator of acquired HO in mice and could represent an effective therapeutic target against forms of this pathology in patients.

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Activin A promotes the development of acquired heterotopic ossification and is an effective target for disease attenuation in mice - Science

Spinal Cord Stem Cells Comments Off on Activin A promotes the development of acquired heterotopic ossification and is an effective target for disease attenuation in mice – Science | February 10th, 2021

Three years ago, wading in the sun-warmed waters of the Florida Keys, I felt a sharp pinch and looked down at my feet in surprise. My friend Jen and I had driven down from Miami for a weekend full of strong Cuban coffee and Hemingways six-toed cats. Tempted by water so warm and aquamarine it was almost a cliche, we had stopped to swim at a roadside beach on Bahia Honda Key. I had eased in, careful to drag my feet slowly across the seafloor in a dance known to beachgoers as the stingray shuffle, hoping to alert any local sealife to my approach. But not careful enough.

My foot throbbing, I stumbled back to the beach toward Jen, who wondered if I might have stepped on some glass. But in the next half hour, as my ankle and foot ballooned and the pain ratcheted upfrom stinging to aching, from aching to bone breakingit became clear I must have been stung by something. Then my foot started to turn blue, and we drove to the hospital.

Bahia Honda? the nurse said. Youre the fourth person to come in with a stingray sting from there today.

The pain didnt subside until the next day, when my foot had returned to its normal color. That was the start of a six-week recovery, which also involved crutches, painkillers, heavy-duty antibiotics, and a horrible rash. I wouldnt wish the experiencewhich involves a level of discomfort that some have compared to a gunshot woundon anyone. But in retrospect, its an interesting one to consider. Because, it turns out, animal venoms like the one coursing through my veins on Bahia Honda Key are sought after for drug development, with seven FDA-approved drugs derived from venom toxins on the market so far. Harnessing their power to hurt opens up a world of possibilities for healing.

The Bahia Honda beach where the author had a run-in with a stingray. Image Credit: Giuseppe Milo, Flickr (CC BY 2.0)

Chemical biologist Mand Holford, who studies venom science at her lab at Hunter College, compares what was happening in my foot in the moment after the sting to a cluster bomb. The toxins in animal venom have been engineered by evolution over many millennia to incapacitate by affecting some component in the blood, brain, or cell membranes, she says. Youre getting invaded with 200 to 300 different toxins, all trying to figure out how to reach their target, moving through and rupturing cell membranes, doing all sorts of damage.

The nurse at the emergency room told me stingrays were migrating through the area, their path bringing them close to the cove where I went wading. Stingrays deliver their venom through one or more serrated barbs that lie along their tails. While at rest, a stingray keeps its barb tucked away, immunologist Carla Lima told me in an email. But when it feels threatenedsay, by the feet of a clueless human out for a swimit pushes its tail perpendicular to its body, puncturing that humans flesh with its venom-laden spine.

Lima studies toxins in venomous fish at the Butantan Institute in So Paolo, Brazil. Her research into stingray venom has shown that whats in that venom actually changes as a stingray matures. In the freshwater species she studieswhose venom properties are better explored than the marine stingray that got methe venom of young rays tends to contain toxins that cause pain to the target. Lima hypothesizes this may be to chase predators away. In contrast, the toxins in adult venom have a necrotizing effect, meaning they destroy tissue, which would be helpful for hunting.

Peptides, short chains of amino acids that play key roles in the biological functions of all kinds of organisms, make up a large part of most animal venomsand some are only found in those venoms. Lima and other researchers have identified the peptides porflan and orpotrin as two of the elements in the freshwater stingrays toxic cocktail, along with a number of different proteases, which are enzymes that break down peptides.

As I sat cradling my foot on the beach in Bahia Honda, similar proteases and related proteins worked to break down the structure of cells in my heel, helping the venom spread further, and to prompt an inflammatory reaction that led to the swelling I saw. The peptides, on the other hand, likely caused the arteries to constrict and blood to pool, creating more inflammation and blocking circulationperhaps the cause of my foot turning blue.

A southern stingray (Dasyatis americana) cruises the ocean floor off Grand Turk Island in the Caribbean. Image Credit: Nate Madden, Shutterstock

That a substance that causes so much pain and wreaks so much biological havoc can be used in medicine is what Holford calls the yin and yang of nature. And the fact that damage and healing are, at least in this case, two sides of the same coin forms the basis for the work she does in her lab, identifying new drug applications for various components of animal venom.

Venoms have great potential to contribute to drug development because they are both potent and highly targeted, Holford says, with peptides that fit physically into cell receptors and change how those cells function. Thanks to this dynamic, venom-based drugs can work almost instantaneously. And theyre not what people in the pharmaceutical business call leaky, meaning they tend to only act on the intended cell component and dont stop at other spots along the way causing side effects.

Most stingray venom research, like Limas, takes place in areas where stingrays pose a threat to people: tropical spots like Brazil and Australia. On a drug-development level, we still dont know much about it, Lima says. But we do know a lot about other venomsin particular those created by cone snails and snakes.

For one thing, not all venom toxins cause pain. Some peptides present in snake venom focus on manipulating proteins in the wound so blood flows freely, acting as natural anticoagulants. Other peptides in Gila monster venom promote insulin production, helpful for a hungry lizard that hasnt eaten for awhile. And yet other peptides in cone-snail venom do the opposite of what stingray venom does: paralyze and suppress pain, keeping the snails prey from going into fight-or-flight mode and slowing it down until the (also slow) snail can come nab it for a snack.

This last type of venom is one of the focuses at Holfords lab. Many cone-snail venom peptides are rich in cysteine amino acids, whose structure she compares to Velcro. That makes it relatively easy for them to stick in the hourglass-shaped pores on the surface of cells that let important minerals like sodium, calcium, and potassium flow in and out. The free movement of those minerals is part of how cells talk to each other.

With those channels shut down, neurons cant communicate with one another to indicate pain. Thats what makes Prialt, the commercial version of the cone snails ziconotide peptide, an effective pain medication. Holford and her colleagues are also exploring the potential of other related cone-snail peptides to help dampen signals firing too fast in someone having a heart attack or an epileptic seizure.

She even sees possible applications here for cancer treatment. Current chemotherapy regimens dont discriminate between normal cells and tumor, she says. But because venom peptides work on specific receptorsreceptors that some tumors grow too many of as part of their developmentthey could help create a cancer drug that specifically starves cancer cells of essential minerals, stopping their growth.

The saw-scaled viper (Echis carinatus) is one of the deadliest snakes in India, and its venom is the basis of the blood-thinning drug Tirofiban. Image Credit: Sagar Khunte, Wikimedia Commons (CC BY-SA 4.0)

The venom that nearly ruined my Florida Keys vacation (though I still got to enjoy some beautiful sunsets, and the seafood was fantastic) was incredibly sophisticated, honed by evolution to inflict pain and physiological damage with laser precision. It was almost comforting to learn this in the weeks after, as I hobbled around on my crutches and watched with fascinated disgust as the wound developed a stingray-shaped blister. (My boyfriend said it was a sign I was developing superpowers, but sad to say none appeared.)

We know from nature that these peptides work, Holford says. What we dont know is massive: where they work, how they work, how effective they are. And thats a huge game of Wheres Waldo. Holford and her colleagues have come up with a protocol for finding new venom components that have potential in drug applications, then figuring out how to get them there. The first step is a practical look at the natural world: identifying which animal species are creating venom, especially venom that can be extracted manually. Next, the team uses new technologies that Holford refers to as the omics genomics, transcriptomics, proteomicsto identify the toxins within those venoms, by examining the instructions the animals' DNA and RNA contain and the proteins built by following those instructions.

From there, the team is able to use that genetic code to manufacture more of a chosen peptide in the lab, which is especially useful when it comes to studying venoms that are produced in small quantities in nature. They then test the synthetic toxin on the animals natural prey to make sure its effective and further tweak it to ensure its as specifically targeted as it can be for humans. And finally, they start to think about drug delivery. Does this drug need to cross the blood-brain barrier? Would it work if administered orally? These are essential questions, since potential drugs that cant be delivered effectively cant really be drugs at all.

Much like the experience of the sting itself, the possibilities for new drugs here are dizzying. Most venom-based drugs on the market are derived from a single peptide. But my stingrays venom (just like other naturally occurring venoms) featured hundreds of peptides. And with the advent of the omics, drug development with venom has become more efficient. Time- and resource-intensive experiments can now be run much more quickly using computer modeling, making the whole process more viable and opening up a whole world of drug prospects.

Lima and her colleagues in Brazil, for example, are continuing to explore the realm of fish venom. One synthetic peptide derived from the venom of a species of toadfish shows particular promise. A 2017 study suggested that peptide, known as TnP, has powerful anti-inflammatory and therapeutic effects in mice. Effects that could potentially help stem the autoimmune reactions that lead to spinal cord damage in patients with multiple sclerosis.

As Holford and her team navigate the new technological landscape, theyre also looking for ways to simplify their process. One innovation Holford is excited about is organoids, in this case, venom glands grown independently in a laboratory. Growing organoids would make acquiring venom samples much easier, she says, and would not require sacrificing an animal for the initial sample.

Thats especially important with climate change and habitat loss fueling a looming biodiversity collapse that could take with it undiscovered venoms with the capacity to heal. In 10 years were heading toward this major shift thats coming if we dont change our attitudes and lifestyle, she says. We could lose a lot of things on the planet that are potentially lifesaving.

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I got stung by a stingray, and all I got was this deeper understanding of venom medicine - NOVA Next

Spinal Cord Stem Cells Comments Off on I got stung by a stingray, and all I got was this deeper understanding of venom medicine – NOVA Next | February 6th, 2021

And for some families this wait is excruciating, he said at a Wednesday news conference.

Shandro said there is no specific budget or cap on how much the government will spend, but that it was working with drug manufacturer Novartis to provide access. Nearly 70 per cent of children with spinal muscular atrophy type 1 do not live past age two. The drug is typically only approved for children under two.

We just dont want kids to fall through the cracks, said Shandro.

Susi Vander Wyk, executive director of Cure SMA Canada, thanked the province for making a decision she said is saving lives.

Its a fairly new treatment, so we dont know the long-term future of it, but we sure know that it has an astounding impact on these babies, she said at the news conference.

The earlier they receive the treatment, the better their prognosis, Vander Wyk said.

Time is ticking for them.

For Lana Martin, whose two-year-old son Kaysen Martin received the Zolgensma treatment in December after fundraising and an anonymous $1.4 million donation, the news was a huge step towards more kids accessing the drug.

Its still early after Kaysens treatment, but hes already more confident in his movements and doesnt tire as easily, said Martin.

He can now officially completely roll from one side of the room to the other side of the room, and he was not able to do that before, she said.

Martin said it was difficult for her and her husband, normally private people, to advocate publicly for the drugs coverage, but shes glad they did.

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Alberta Health to cover $2.8-million gene therapy treatment on case-by-case basis - Edmonton Journal

Spinal Cord Stem Cells Comments Off on Alberta Health to cover $2.8-million gene therapy treatment on case-by-case basis – Edmonton Journal | January 29th, 2021

Cancer is an extremely complex disease. There are over 200 different types, some of which are considered common and others which are classified as rare cancers. But what exactly does it mean if a cancer is rare?

Usually, it means it only affects a small handful of people, but doctors might also call a cancer rare if it starts in an uncommon place in the body, or if the cancer is an unusual type and requires special treatment.

For secondary central nervous system (CNS) lymphoma, its an incredibly rare cancer for a combination of these reasons.

Secondary CNS lymphoma is a type of lymphoma thats spread to the brain and spinal cord nervous system after originating elsewhere in the body. And as well as being a rare cancer, secondary CNS lymphoma is an aggressive cancer, which has relatively low survival rates.

However, the latest results from the Stand Up To Cancer-funded MARIETTA clinical trial, which details a new potentially transforming treatment, has shed a glimmer of hope for patients and doctors alike.

We spoke to Dr Kate Cwynarski, who led the study in the UK, about what the latest results could mean for patients with secondary CNS lymphoma.

With a rare cancer such as secondary CNS lymphoma, finding a large enough group of patients can be a real challenge. And in cases like this, researchers have to think on a global scale.

Its a rare disease. So the reality of it is that you would not get this information if we just performed a trial in the UK, says Cwynarski. International collaboration is the only way to do it.

The MARIETTA trial is the largest study focused on patients with secondary CNS lymphoma, involving 24 centres across 4 countries and recruiting a total of 79 patients. It involved the International Extranodal Lymphoma Group (IELSG) lead by Professor Andres Ferreri in Italy and it built on the success of prior research with this group. In the UK, the trial was managed by CRUK Southampton CTU.

In particular, findings from a previous clinical trial partly funded by us, which tested treatments for primary CNS lymphoma, a lymphoma thats only found in the brain, helped inform the design of this clinical trial.

The IELSG-32 trial tested the benefits of an intensive chemotherapy regimen known as MATRIX, followed by either whole brain radiotherapy or a stem cell transplant using the patients own cells.

Cwynarski describes the IELSG-32 trial as practice changing, and its from these impressive results that the MARIETTA trial was developed. So we adapted a strategy that was successful in treating primary CNS lymphoma in the IELSG-32 trial and added another chemotherapy regimen, called R-ICE, to help treat the systemic disease on top of the secondary brain disease.

Cwynarski specialises in lymphoma, so she has treated SCNSL patients both on and off the trial. One of the big benefits of this trial, she describes, is that the inclusion criteria for the cohort more accurately reflected the patients she sees in her clinic and referral practice.

This trial included patients up to 70 years of age. And it wasnt just focused on fit, young people. So I have to say I think it was meaningful, because it included the kind of patients that we actually see.

The trial also included people regardless of when their secondary CNS lymphoma was diagnosed, whether that was when someone was originally diagnosed with lymphoma, during treatment, or after their cancer had come back.

And the results look promising. A total of 49 patients (65%) responded to the treatment in some way, with 37 people going on to have a stem cell transplant. 100% of the patients who had the stem cell transplant had not seen their cancer recur a year after registering onto the trial. We are optimistic many will be cured of this aggressive lymphoma.

But the trial also picked up differences between groups. While the regime was effective to an extent in every sub-group, the most significant results were seen in patients whose CNS disease was discovered at initial lymphoma diagnosis. Within this group, 71% of patients had lived for 2 years without their cancer growing.

A result which has never been seen before.

The results of the trial have completely transformed the teams optimism when meeting new patients. We really have identified a regimen which is intensive, but its potentially curative, concludes Cwynarski, and the word cure is not something weve really used before when talking about this disease.

Recently, Cwynarski has been busy filling out a cohort of her patients DVLA forms, confirming they are fit to drive again after being 2 years treatment free. So thats an amazing success and it was very symbolic as a reminder that these people have been alive and off all treatment for 2 years.

Moments like this are a reflection of the huge impact the MARIETTA trial has had for real people, like Maureen Brewster.

Maureen was diagnosed with lymphatic cancer of the liver in 2011 and was under the watchful eyes of a consultant during her treatment. But in the summer of 2016, I started to have very extreme headaches, says Maureen.

After getting an emergency appointment, she was taken to A&E and admitted to hospital straight away. I was transferred to the National Neurology hospital in Russell Square for a biopsy. They thought I might have had a stroke. But it wasnt. Instead, Maureen was diagnosed with a secondary cancer in her brain.

When Maureen was transferred to UCLH, she was told about the MARIETTA trial. I could have chosen not to go on the trial, but being part of it meant that I would get more examinations and monitoring. So it was more reassuring to be on the trial, she says.

Maureen during treatment.

Maureen went through 8 tough months of chemotherapy before having a stem cell transplant in the summer of 2017. During one round of chemo in the hospital I became ill with an infection and really thought I was going to die. The last chemo prior to me having stem cell transplant was so strong it really had an impact on me and I couldnt eat I felt very poorly for a few weeks.

Maureens stem cell transplant went smoothly and prior to COVID-19, she was having regular check-ups and scans in hospital.

Prior to the first lockdown in March 2020, Maureen was able to do some volunteering and also go back to work, teaching a course on Project Management at a local adult college. In April 2019 I also secured a part-time job as a User Involvement Co-ordinator. It was great to get back to that level.

Dr Cwynarski emphasises that while the trial was a great success for some, it also exposed a group of patients who didnt do so well on the treatment.

The results threw up a real disparity and uncovered an unmet need in a particular group of patients. For the group of patients whose cancer had already failed to respond to a chemotherapy treatment, known as R-CHOP, at the follow up of 2 years, only 20% had not experienced their cancer progressing or getting worse.

We need to target this cohort of patients in a different way, says Cwynarski. So really the challenge is, can we identify experimental agents be it different biological agents or immunotherapies such as CAR T cell therapy in the patients who have relapsed, and maybe bringing these therapies into the frontline.

Lilly

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Transforming optimism: finding new ways to treat rare cancers - Cancer Research UK - Science Blog

Spinal Cord Stem Cells Comments Off on Transforming optimism: finding new ways to treat rare cancers – Cancer Research UK – Science Blog | January 29th, 2021

A study examining the damage caused to nerve cells by motor neuron disease (MND) has shown that by targeting these cells energy centers, called mitochondria, neuronal function can be restored.

The research, conducted by a team at the University of Edinburgh, has been published in the journal Acta Neuropathologica.1MND is a broad term for a group of rare, progressive and sometimes fatal neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP) and progressive muscular atrophy (PMA).

The research team, led by Dr Arpan Mehta, alongside Dr Bhuvaneish Selvaraj and Professor Siddharthan Chandran, all based at the University of Edinburghs Euan MacDonald Centre for MND Research, focused their work on the axon of human motor neurons. This is the region of a motor neuron that conducts electrical signals released by the brain and carries them to the body part they are intended for. In some human motor neurons, the axon can be over a meter long. These processes are energy-guzzling, and that power is provided by mitochondria, known to generations of long-suffering biology students as the powerhouses of the cell.

The scientists noted that the axons of MND-affected neurons were shorter than normal, and their mitochondria were not as easily able to move around the cell as they were in healthy neurons.

Using stem cells taken from people who have a mutation in a gene called C9orf72 that is known to play a causal role in both the MND subtype ALS and frontotemporal dementia, Mehta and colleagues created a stem cell model of MND, and sought to repair these stricken neurons.

In their stem cell models of MND, the team showed that by increasing the levels of a protein named PGC1 that regulates mitochondrial energy metabolism, the motor neurons function could be returned to healthy levels.

Dr Arpan Mehta (right), alongside Euan MacDonald MBE, co-founder of the Euan MacDonald Centre.

Our data provides hope that by restoring the cells energy source we can protect the axons and their connection to muscle from degeneration. Work is already underway to identify existing licensed drugs that can boost the mitochondria and repair the motor neurons. This will then pave the way to test them in clinical trials.

The team focused solely on the most common genetic form of ALS in their study and acknowledge that MNDs such as ALS are caused by a range of genetic and environmental factors. Nevertheless, they hope that their findings can be applied to other forms of the disease.

Reference:Mehta AR, Gregory JM, Dando O, et al. Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis. Acta Neuropathol. Published online January 4, 2021. doi:10.1007/s00401-020-02252-5

Correction: This article was updated on January 25, 2021 to amend a quote from Dr Mehta.

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Genetic Energy Boost Reverses Cellular Effects of Motor Neuron Disease - Technology Networks

Spinal Cord Stem Cells Comments Off on Genetic Energy Boost Reverses Cellular Effects of Motor Neuron Disease – Technology Networks | January 27th, 2021

Life for Miro, a 5-year-old German shepherd, has been what his owner describes as an emotional roller coaster over the past two years. Several peaks and valleys have dotted his metaphorical landscape as he has gone from premiere fitness to dealing with injuries and disease. But a clinical trial at the UC Davis veterinary hospital may have put him back on a positive track.

Working as a patrol dog with his handler/owner Martin Gilbertson, a ranger with California State Parks, Miro spent three years performing duties that required him to be at the top of his game. In early 2019, he was just that, having won the top dog award for his department.

By that summer, however, things started declining for Miro. He was diagnosed with lumbosacral intervertebral disc disease that caused spinal cord compression. UC Davis veterinary neurosurgeons performed a surgical decompression, and Miro eventually recovered after a lengthy recuperation period.

Miro with his handler Martin Gilbertson

Life was great, said Gilbertson. By early December 2019, Miro was cleared to return to work. I thought all the troubles were behind us.

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It only took a few weeks, though, until the roller coaster cleared a peak and started to descend.

In late December 2019, Miro collapsed for no apparent reason and started shaking in a way Gilbertson had never seen. So, the pair returned to UC Davis where Miro was diagnosed with myasthenia gravis, a disease in which there is a malfunction in the transmission of signals between the nerves and muscles. This causes muscle weakness, and an inability to walk or run properly, as well as potentially devastating neuromuscular disorders.

Gilbertson was devastated.

To go from the pinnacle of our profession to potentially being a couch potato at best for the rest of his life was a real gut check, he said.

But hope appeared a few weeks later when Neurology/Neurosurgery Service faculty members Drs. Pete Dickinson and Bev Sturges informed Gilbertson of a myasthenia gravis clinical trial they were beginning with the help of the schools Center for Companion Animal Health (CCAH) and the Veterinary Institute for Regenerative Cures.

I thought, What do we have to lose? stated Gilbertson. Dr. Dickinson told me that Miro would be the first dog to ever receive this new treatment. We were excited and grateful to be able to participate.

A computer program shows Miro's stride pattern on the Tekscan Strideway pressure walkway.

Over the next few months, Miro received three stem cell treatments, as well as traditional medications to treat myasthenia gravis. Additionally, part of Miros recovery involved examining his gait, which utilized a new piece of equipment aimed at better analyzing a dogs stride pattern. Thanks to CCAH funding, the school recently acquired a Tekscan Strideway pressure walkway that allows clinicians and researchers to better gauge a patients step pattern and make decisions about their optimal care and recovery. To fully understand a patients gait abnormalities associated with injuries or neuromuscular diseases, veterinarians and researchers rely on objective, quantitative ways to assess locomotor function. The Strideway system complements the force plates in the schools J.D. Wheat Veterinary Orthopedic Research Laboratory, which captures extensive information, but only for one gait step. The new pressure walkway expands the capabilities to quantify pressure, vertical force, and stride parameters (timing and spacing) on all limbs for several strides during walking, trotting or landing. Miros progress was able to be tracked with pinpoint accuracy throughout his recovery.

Before the trial, Miro could only walk about 10 steps before falling down. After the trial, he seemed fully recovered, and blood tests revealed no trace of antibodies to the disease. While the disease may not be completely gone from his system, the clinical trial seems to have repressed the disease to a point where it no longer inhibits Miro from his normal activities. Retired from his job, Miro now enjoys life as a family pet.

It is true that Miro is now in remission, but until more analysis of data is completed, it is still too early to determine if the stem cells were the driving force behind his recovery, since they were administered at the same time as standard-of-care medications. Miros results are being closely examined, along with the results of two other dogs that have completed the trial, to see if this stem cells treatment truly can be considered a cure for myasthenia gravis. Regardless of the final outcome of the study, Miros recovery, in one way or another, came from a novel combination of treatments pioneered at UC Davis.

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Novel Treatment Leads to Dog's Recovery - The Bark

Spinal Cord Stem Cells Comments Off on Novel Treatment Leads to Dog’s Recovery – The Bark | January 25th, 2021

Researchers at the National Institutes of Health have discovered a new genetic disorder characterized by developmental delays and malformations of the brain, heart and facial features. Named linkage-specific-deubiquitylation-deficiency-induced embryonic defects syndrome (LINKED), it is caused by a mutated version of the OTUD5 gene, which interferes with key molecular actions in embryo development.

The findings indicate that the newly identified pathway may be essential for human growth and may also underlie other disorders that are present at birth. The information will help scientists better understand such diseasesboth common and rareand enhance patient care. The results were reported Jan. 20, 2021 at Science Advances.

The project began when David B. Beck, M.D., Ph.D., a clinical fellow in the laboratory of Dan Kastner M.D., Ph.D., at the National Human Genome Research Institute (NHGRI) and co-first author, was asked to consult on a male baby who had been born with severe birth defects that included abnormalities of the brain, craniofacial skeleton, heart and urinary tract.

Our discovery of the dysregulated neurodevelopmental pathway that underlies LINKED syndrome was only possible through the teamwork of geneticists, developmental biologists and biochemists from NIH,. This collaboration provided the opportunity to pinpoint the likely genetic cause of disease, and then take it a step further to precisely define the sequence of cellular events that are disrupted to cause the disease.

Achim Werner, Ph.D., Investigator, National Institute of Dental and Craniofacial Research (NIDCR) and Lead Author

An in-depth examination of siblings and family members genomes, combined with hereditary bioinformatics analyses, revealed a mutation in the OTUD5 gene as the possible cause of the problem. Through outreach to other researchers working on similar problems, Beck found seven additional males ranging from 1 to 14 years of age who shared symptoms with the first patient and had varying mutations in the OTUD5 gene.

The gene comprises instructions for making the OTUD5 enzyme, which is involved in ubiquitylation, a process which molecularly alters a protein to change its purpose. Ubiquitylation plays a part in governing cell fate, where stem cells are taught to turn into specific cell types in the early stages of embryo development.

According to the genetic evidence, I was pretty sure OTUD5 mutations caused the disease, but I did not understand how this enzyme, when mutated, led to the symptoms seen in our patients, said Beck. For this reason we sought to work with Dr. Werners group, which specializes in using biochemistry to comprehend the functions of enzymes such as OTUD5.

To begin, the NIH team analyzed cells taken from patient samples, which were processed in the NIH Clinical Center. Usually, OTUD5 edits or eliminates molecular tags on particular proteins (substrates) to modulate their function. However, in cells from patients with OTUD5 mutations, this activity was diminished.

Using a method to reunite mature human cells into the stem cell-like state of embryo cells, the scientists discovered that OTUD5 mutations were linked to abnormalities in the development of neural crest cells, which give rise to tissues of the craniofacial skeleton, and of neural precursors, cells that eventually give rise to the brain and spinal cord.

In additional experiments, the team discovered that the OTUD5 enzyme acts on a few protein substrates called chromatin remodelers. This class of proteins alters the closely packed strands of DNA in a cells nucleus to make sure genes accessible for being turned on, or expressed.

With help from collaborators led by Pedro Rocha Ph.D., an investigator in the National Institute of Child Health and Human Development (NICHD), the group found that chromatin remodelers targeted by OTUD5 help enhance expression of genes that control the cell fate of neural precursors during embryo development.

Taken together, the investigators reasoned, OTUD5 normally keeps these chromatin remodelers from being tagged for destruction. However, while OTUD5 is mutated, its protective function is lost and the chromatin remodelers are destroyed, leading to abnormal development of neural precursors and neural crest cells. Ultimately, these changes can lead to some of the birth defects seen in LINKED patients.

This implies that the mechanism we discovered is a portion of a common developmental pathway that, when mutated at different points, will result in a spectrum of disease.

We were amazed to discover that OTUD5 elicits its effects via multiple, functionally related substrates, which shows a new principle of cellular signaling during early embryonic development, said Mohammed A. Basar, Ph.D., a postdoctoral fellow in Werners lab and co-first author of this study. These findings lead us to believe that OTUD5 may have far-reaching effects beyond those identified in LINKED patients.

In future work, Werners team plans to fully investigate the role which OTUD5 and similar enzymes play in development. The researchers hope the study can serve as a guiding framework for unraveling the causes of other undiagnosed diseases, ultimately helping clinicians better evaluate and care for patients.

Were finally able to provide families with a diagnosis, bringing an end to what is often a long and exhausting search for answers, said Beck.

Source:

Journal reference:

Beck, D.B.,et al.(2021) Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.Science Advances.doi.org/10.1126/sciadv.abe2116.

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Scientists find uncommon hereditary disorder that influences the brain, heart and facial highlights - Microbioz India

Spinal Cord Stem Cells Comments Off on Scientists find uncommon hereditary disorder that influences the brain, heart and facial highlights – Microbioz India | January 25th, 2021

Researchers at the National Institutes of Health have discovered a new genetic disorder characterized by developmental delays and malformations of the brain, heart and facial features.

Named linkage-specific-deubiquitylation-deficiency-induced embryonic defects syndrome (LINKED), it is caused by a mutated version of theOTUD5gene, which interferes with key molecular steps in embryo development. The findings indicate that the newly identified pathway may be essential for human development and may also underlie other disorders that are present at birth. The information will help scientists better understand such diseases both common and rare and improve patient care. The results were reported Jan. 20, 2021 inScience Advances.

Our discovery of the dysregulated neurodevelopmental pathway that underlies LINKED syndrome was only possible through the teamwork of geneticists, developmental biologists and biochemists from NIH, said Achim Werner, Ph.D., an investigator at the National Institute of Dental and Craniofacial Research (NIDCR) and lead author. This collaboration provided the opportunity to pinpoint the likely genetic cause of disease, and then take it a step further to precisely define the sequence of cellular events that are disrupted to cause the disease.

The project began when David B. Beck, M.D., Ph.D., a clinical fellow in the laboratory of Dan Kastner M.D., Ph.D., at the National Human Genome Research Institute (NHGRI) and co-first author, was asked to consult on a male infant who had been born with severe birth defects that included abnormalities of the brain, craniofacial skeleton, heart and urinary tract. An in-depth examination of siblings and family members genomes, combined with genetic bioinformatics analyses, revealed a mutation in theOTUD5gene as the likely cause of the condition. Through outreach to other researchers working on similar problems, Beck found seven additional males ranging from 1 to 14 years of age who shared symptoms with the first patient and had varying mutations in theOTUD5gene.

The gene contains instructions for making the OTUD5 enzyme, which is involved in ubiquitylation, a process that molecularly alters a protein to change its function. Ubiquitylation plays a role in governing cell fate, where stem cells are instructed to become specific cell types in the early stages of embryo development.

Based on the genetic evidence, I was pretty sureOTUD5mutations caused the disease, but I didnt understand how this enzyme, when mutated, led to the symptoms seen in our patients, said Beck. For this reason we sought to work with Dr. Werners group, which specializes in using biochemistry to understand the functions of enzymes like OTUD5.

To start, the NIH team examined cells taken from patient samples, which were processed at the NIH Clinical Center. Normally, OTUD5 edits or removes molecular tags on certain proteins (substrates) to regulate their function. But in cells from patients withOTUD5mutations, this activity was impaired.

Using a method to return mature human cells to the stem cell-like state of embryo cells, the scientists found thatOTUD5mutations were linked to abnormalities in the development of neural crest cells, which give rise to tissues of the craniofacial skeleton, and of neural precursors, cells that eventually give rise to the brain and spinal cord.

In further experiments, the team discovered that the OTUD5 enzyme acts on a handful of protein substrates called chromatin remodelers. This class of proteins physically alters the tightly packed strands of DNA in a cells nucleus to make certain genes more accessible for being turned on, or expressed.

With help from collaborators led by Pedro Rocha Ph.D., an investigator at the National Institute of Child Health and Human Development (NICHD), the team found that chromatin remodelers targeted by OTUD5 help enhance expression of genes that control the cell fate of neural precursors during embryo development.

Taken together, the researchers concluded, OTUD5 normally keeps these chromatin remodelers from being tagged for destruction. But when OTUD5 is mutated, its protective function is lost and the chromatin remodelers are destroyed, leading to abnormal development of neural precursors and neural crest cells. Ultimately, these changes can lead to some of the birth defects seen in LINKED patients.

Several of the chromatin remodelers OTUD5 interacts with are mutated in Coffin Siris and Cornelia de Lange syndromes, which have clinically overlapping features with LINKED syndrome, said Werner. This suggests that the mechanism we discovered is part of a common developmental pathway that, when mutated at various points, will lead to a spectrum of disease.

We were surprised to find that OTUD5 elicits its effects through multiple, functionally related substrates, which reveals a new principle of cellular signaling during early embryonic development, said Mohammed A. Basar, Ph.D., a postdoctoral fellow in Werners lab and co-first author of the study. These findings lead us to believe that OTUD5 may have far-reaching effects beyond those identified in LINKED patients.

In future work, Werners team plans to more fully investigate the role that OTUD5 and similar enzymes play in development. The researchers hope the study can serve as a guiding framework for unraveling the causes of other undiagnosed diseases, ultimately helping clinicians better assess and care for patients.

Were finally able to provide families with a diagnosis, bringing an end to what is often a long and exhausting search for answers, said Beck.

Reference: Beck DB, Basar MA, Asmar AJ, et al. Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation. Sci Adv. 2021;7(4):eabe2116. doi:10.1126/sciadv.abe2116.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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New Genetic Disorder Discovered That Affects Brain and Craniofacial Skeleton - Technology Networks

Spinal Cord Stem Cells Comments Off on New Genetic Disorder Discovered That Affects Brain and Craniofacial Skeleton – Technology Networks | January 23rd, 2021

Have researchers in Scotland truly found a way to reverse the damage done to nerve cells by motor neurone disease (MND)?

A new study suggests that it all comes down to boosting the energy output from the mitochondria, the cells power supply.

How can that be done? Possibly with drugs that already exist.

The researchers, from the University of Edinburgh, are already looking for existing drugs that boost mitochondrial function and may be able to be repurposed to treat MND.

Overall, this is a startling development, albeit one that has to be tempered with wait-and-see caution. There are thousands of people around the world, sufferers and their families, desperate for even a glimmer of good news.

People with MNDprogressively lose the use of their limbs and ability to speak, swallow and breathe, whilst their mind and senses usually remain intact.

The average life expectancy is two and a half years.

Motor neuron cells are nerve cells that control movement. An axon is the long part of the motor neuron cell that connects to the muscle and it can be up to a metre long.

The starting point in the study was examining axonal dysfunction a common problem in neurodegenerative disorders, including in amyotrophic lateral sclerosis (ALS), a form of MND.

For axons to function properly, they need a lot of energy. The scientists wondered if the production of energy in the cells is put out of whack by MND. And if that was true, could it be fixed and if so, could the axon be restored to full function?

The researchers from the Euan MacDonald Centre for MND Research at the University of Edinburgh used stem cells taken from people with the C9orf72 gene mutation that causes both MND and frontotemporal dementia.

They discovered that, in these human stem cell models of MND, the axon was shorter than in healthy cells.

The study then found the back-and-forth movement along the axon was impaired.

And then, bingo! Once the mitochondrial performance was boosted, the axon think of a stunted tree suddenly getting water and nourishment regained its healthy function. Back to normal.

This then allowed the mitochondria to travel freely along the axon.

The study also examined human post-mortem spinal cord tissue from people with MND. The tissue was obtained from the Medical Research Council Edinburgh Brain and Tissue Bank.

These examinations supported the findings from the stem cells.

The first film shows mitochondria travelling along an axon in a healthy motor neuron:

data-s="video/mp4">

This second film shows how the mitochondria becomes stalled as it attempts to travel along damaged motor neuron with the C9orf72 gene:

data-s="video/mp4">

In this third film we see a damaged motor neuron with the C9orf72 gene restored to function after boosting the mitochondria:

data-s="video/mp4">

Dr Arpan Mehta, the Lady Edith Wolfson Fellow and a PhD student at the University of Edinburgh, led the study. In a prepared statement he said:

The importance of the axon in motor nerve cells cannot be understated. Our data provides hope that by restoring the cells energy source we can protect the axons and their connection to muscle from degeneration.

Work is already underway to identify existing licensed drugs that can boost the mitochondria and repair the motor neurons. This will then pave the way to test them in clinical trials.

Although the research focused on the people with the commonest genetic cause of the ALS (amyotrophic lateral sclerosis) type of MND, researchers are hopeful that the results will also apply to other forms of the disease.

By the way: Frontotemporal dementia is a consequence of progressive damage to the frontal and/or temporal lobes of the brain.The right and left frontal lobes at the front of the brain are involved in mood, social behaviour, attention, judgement, planning and self-control.

Hence, damage can lead to reduced intellectual abilities and changes in personality, emotion and behaviour.

More than 2000 people have MND in Australia, of whom 60 per cent are male and 40 per cent female, according to figures from MND Australia.

The mean time from onset to confirmation of diagnosis is 10 to 18 months, and approximately 58 per cent of people with MND are under 65.

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Motor neurone disease: Researchers dare to hope existing drugs can reverse the deadly nerve damage - The New Daily

Spinal Cord Stem Cells Comments Off on Motor neurone disease: Researchers dare to hope existing drugs can reverse the deadly nerve damage – The New Daily | January 23rd, 2021