Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that targets motor neurons, gradually bereaving patients of their ability to control muscle movements. Scientists discovered more than 50 potential disease-causing genes and linked several cellular pathways to ALS, but the syndromes diverse clinical and genetic nature make it difficult to predict and interfere with disease progression.1

Researchers discovered a T cell population in mice that mirrors ALS-4 disease progression.

In a recent study published in Nature, Laura Campisi, Ivan Marazzi, and colleagues at Icahn School of Medicine at Mount Sinai discovered an immune cell signature in patients with early onset ALS (ALS-4) that mirrors disease progression and may contribute to neuronal death.2 These findings could have significant implications for ALS diagnostics, prognostics, and therapeutics.

Laura Campisi joined Marazzis laboratory wanting to better understand how the body mounts immune responses. She set out to molecularly profile activated immune cells and discovered several immunity regulators, including SENATAXIN (SETX). Because SETX mutations cause ALS-4, Campisi wondered if ALS might join the suite of other neurodegenerative diseases such as narcolepsy, Alzheimers disease, and Parkinsons disease that scientists recently connected to the immune system.3,4,5,6

To test whether the immune system plays a role in ALS-4 disease progression, Campisi turned to a mouse model that carries the most common human SETX mutation.7 She replaced their mutated hematopoietic stem cells (HSCs)progenitors that form immune cellswith wildtype ones and found that they protected against disease. In contrast, replacing healthy HSCs with SETXmutant ones in wildtype mice did not cause disease. This set of experiments showed that mutant HSCs and their progeny contribute to disease, but do not cause disease on their own. This is extremely strong preclinical evidence that forms a basis for pharmaceutically targeting these cells, said David Gate, an assistant professor of neurology at Northwestern University, who was not involved in this study.

Campisi and her colleagues next characterized the immune system in pre-symptomatic mice and discovered an ALS-specific immune cell signature: ALS-4 mice contained more CD8+ T cells in their blood and cerebrospinal fluid (CSF) prior to symptom onset, and this cell population continued to expand as the disease progressed. While Campisis team faced pandemic-related difficulties in recruiting enough ALS-4 patients to confirm these findings, they are now teaming up with clinicians to expand their preclinical trials. We want to follow this [T cell] population in patients to see if they express specific markers that can predict if and when the disease progresses, Campisi said.

My hypothesis is that the T cells are autoreactive, so they are reacting against a cellular antigen.Laura Campisi, Icahn School of Medicine at Mount Sinai

To find what these T cells responded to, Campisi sequenced them and found that nearly all cells expressed the same T cell receptor, suggesting they bind the same antigen. The problem is that it is very difficult to find the antigen. I dont think it is an infection because [the] mice live in a pathogen-free facility. My hypothesis is that the T cells we found are autoreactive, so they are reacting against a cellular antigen, Campisi said.

Given that ALS targets motor neurons, Campisi wondered if the ALS-4 T cells promoted disease progression because they react to and are activated by a protein in the brain. To test this hypothesis, Campisi injected ALS-4mice with brain cancer cells that express neuronal antigens to see if the T cell population would react and confer protection against the cancer type. It was pretty striking: the tumors became so big in wildtype mice that I had to stop the experiment, but the [mutant] mice that were in the same cage were completely fine, their tumor was not growing, Campisi said. In contrast, there was no protection against skin-related cancer cells that she injected as a control. The T cells that infiltrated the ALS-4 mices brain tumors expressed the same T cell receptor as cells found in their CSF. While Gate cautions that cancer cells typically express many newly created neoantigens, Campisis data suggests that the T cell population likely recognizes a brain cell-related antigen.

Campisis challenge now lies in identifying the actual antigen and therapeutically targeting these T cells to slow and restrict the disease course. In ALS, you probably have a defect that starts with neurons, triggering a cascade of events. So, even if you restore what is wrong in neurons, we have to [also] target the other players, Campisi said.

References

Excerpt from:
Mutant T Cells That Drive Amyotrophic Lateral Sclerosis (ALS) Progression May React To a Brain Antigen - The Scientist

Skin Stem Cells Comments Off on Mutant T Cells That Drive Amyotrophic Lateral Sclerosis (ALS) Progression May React To a Brain Antigen – The Scientist | August 10th, 2022

The procedure recommended by most doctors might not always be a good option, as it could turn a potentially benign situation into a malignant one.

Thomas Seyfried, Ph.D., professor in the biology department at Boston College, is a leading expert and researcher in the field of cancer metabolism and nutritional ketosis. His book, Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer is a foundational textbook on this topic, and in August 2016, he received the Mercola.com Game Changer Award for his work.

Here, we discuss the mechanisms of cancer and the influence of mitochondrial function, which plays a crucial role in the development and treatment of this disease. Hislandmark cancer theory is available as a free PDF.

Many of his views are now encapsulated in his most paper,1Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis, published online December 27, 2018. Hes also published a number of other papers2,3,4on the metabolic underpinnings of cancer.

The paper is a review and hypothesis paper identifying the missing link in Otto Warburgs central theory,Seyfried explains. [Warburg] defined the origin of cancer very accurately back in the 1920s, 30s, 40s and 50s in his work in Germany. Basically, he argued and provided data showing that all cancer cells, regardless of tissue origin, were fermenters. They fermented lactic acid from glucose as a substrate.

Even in the presence of oxygen, these cells were fermenting. This is clearly a defect in oxidative phosphorylation. The problem is that for decades, people said Warburg was wrong mainly because we see a lot of cancer cells take up oxygen and make adenosine triphosphate (ATP) from within the mitochondria People began to question, If cancer cells have normal respiration, why would they want to use glucose as a fermentable fuel?

The whole concept became distorted The cancer cells simply choose to ferment rather than respire. Now, of course, if you look under the electron microscope at majority of cancers, youll see that the mitochondria are defective in a number of different ways. Their structures are abnormal. The numbers are abnormal. There are many abnormalities of mitochondria seen directly under electron microscopy. Clearly, Warburg was not wrong.

Before we delve into the meat of how cancer actually occurs it would be good to review a diagnostic strategy that nearly all of us are offered when confronted with a cancer diagnosis. It is vital to understand that this may not be your best strategy and that for many it would be wise to avoid the biopsy.

Seyfried warns against doing biopsies, as this procedure may actually cause the cancer to spread. A tumor is basically a group of proliferating cells in a particular part of your body. For purposes of diagnosis, a small biopsy sample will often be taken to ascertain whether the tumor is benign or malignant.

The problem is that when you stab into the cancer microenvironment to remove a part of the tissue, it creates a wound in that microenvironment that in turn elicits the invasion by macrophages and other immune cells.

If you already have an acidic microenvironment, you run the risk of causing a fusion hybridization event in that microenvironment between your macrophages and cancer stem cells (as discussed below). This could turn a potentially benign situation into a malignant one, and if the tumor is malignant, stabbing into it could make a bad situation worse.

The question is, what is the value of doing a biopsy in the first place? We take biopsies of breast tissue to get a genomic readout of the different kinds of mutations that might be in the cells. Now, if cancer is not a genetic disease and the mutations are largely irrelevant, then it makes no sense to do that in the first place. If the tumor is benign, why would you want to stab it? If the tumor is malignant, why would you ever want to stab it?

I came to this view by reading so many articles in the literature based on brain cancer, breast cancer, colon cancer, liver cancer showing how needle biopsies have led to the dissemination of these tumor cells, putting these people at risk for metastatic cancer and death,Seyfried says.

In metabolic therapy you would not touch the tumor; you would not disturb the microenvironment. By leaving it alone, you allow the tumor to shrink and go away.

When you start to look at this as a biological problem, many of the things that we do in cancer make no sense. We have, in brain cancer, people say, You have a very low-grade tumor. Lets go in and get it out. What happens is you go in and get it out, and then the following year it turns into a glioblastoma.

How did that happen? Well, you disturbed the microenvironment. You allowed these cells that are marginally aggressive to become highly aggressive. Then you lead to the demise of the patient,Seyfried says.

That happens significantly because its called secondary glioblastoma arising from therapeutic attempt to manage a low-grade tumor. The same thing can happen with all these different organs. You stab breast tumors, you stab colon tumors, you run the risk of spreading the cells

My argument is the following: If the patient has a lump, whether its in the breast, in the colon, lung or wherever or a lesion of some sort, that should be the cue to do metabolic therapy.

Do metabolic therapy first. In all likelihood, it will shrink down and become less aggressive. Then the option becomes, Should we debulk completely rather than doing some sort of a biopsy? We want to reduce the risk, because if we can catch the whole tumor completely, then we dont run the risk of spreading it

In our procedure, you bring the body back into a very high state of metabolic balance, and then you strategically go and degrade the tumors slowly without harming the rest of the body.

Radiation, chemo and the strategies that were using today dont do this. Theyre based on the gene theory of cancer that genetic mutations are causing the cell cycle to grow out of control. Well, this is not the case. Again, a lot of these toxic procedures need to be rethought, reanalyzed in my mind.

In biology, structure determines function. This is an evolutionarily conserved concept. So, how can mitochondria be structurally abnormal in tissue, yet have normal respiration? As Seyfried notes, this doesnt make sense. Confusion has arisen in part because many study cancer in culture, and make profound statements and comments regarding what happens in culture, Seyfried says.

If you look at cancer cells in culture, many of them do take in oxygen and make ATP, but at the same time, theyre fermenting. This was the conundrum. They called it the Warburg Effect. Theyre fermenting, but many people at the same time thought their respiration was normal.

This was the main problem with Warburgs theory. But Warburg clearly said in his papers [that] its not the fact that they take in oxygen; its how much ATP they can generate from oxidative phosphorylation, which is the normal respiratory capacity of the mitochondria.

As explained by Seyfried, if you measure ATP and look at oxygen consumption in tumor cells, it appears theyre making ATP and taking in oxygen, therefore, their respiration is assumed to be normal. However, when you look at the tissues in cancer patients, the mitochondria are abnormal.

What I and Dr. Christos Chinopoulos from Semmelweis University in Budapest, Hungary, who is the world-leading expert on mitochondrial physiology and biochemistry realized [was] that the mitochondria of tumor cells are actually fermenting amino acids, glutamine in particular. Theyre not respiring. Theyre fermenting an alternative fuel, which is glutamine,Seyfried says.

With this understanding, Warburgs theory can be proven correct cancer arises from damage to the mitochondrias ability to produce energy through respiration in their electron transport chain.

The compensatory fermentation involves not only lactic acid fermentation, but also succinic acid fermentation using glutamine as a fermentable fuel. Its been known for decades that glutamine is a main fuel for many different kinds of cancers, but most people thought it was being respired, not fermented.

Seyfried and Chinopoulos discovery confirms that cancer cells in fact have damaged respiration, and to survive, the cancer cells must use fermentation. The two most available fermentable fuels in the cancer microenvironment are glucose and glutamine. Hence, targeting glucose and glutamine is a crucial component of cancer treatment.

Without glucose and glutamine, the cancer cells will starve, as they cannot use ketones. The simplest approach to cancer then is to bring patients into therapeutic ketosis, and then strategically target the availability of glucose and glutamine.

Basically, what were saying [is] that mitochondrial substrate-level phosphorylation is a non-oxidative metabolism mechanism inside the mitochondria that would generate significant amounts of energy without oxidative phosphorylation,Seyfried says.

According to Seyfried, mitochondrial dysfunction is at the heart of nearly every type of cancer. Unfortunately, few oncologists have this understanding and many still believe cancer is the result of genetic defects. However, nuclear transfer experiments clearly show cancer cannot be a genetic disease.

Theres been no rational scientific argument that I have seen, to discredit the multitude of evidence showing that the [genetic] mutations are not the drivers but the effects [of mitochondrial dysfunction],Seyfried says.

As a matter of fact, theres new information now where people are finding so-called genetic drivers of cancer expressed and present in normal cells, normal skin and also esophagus This is another [issue] how you get these so-called driver mutations in normal tissues. Were also finding some cancers that have no mutations, yet, theyre fermenting and growing out of control.

There are a number of new observations coming out that challenge the concept that cancer is a genetic disease. And once you realize that its not a genetic disease, then you have to seriously question the majority of therapies being used to manage the disease. This [helps] explain [why] we have 1,600 people a day dying from cancer in the United States.

Why do we have such an epidemic of suffering and death when we have been studying this disease for decades? Well, if you look at the massive amounts of scientific papers being written on cancer, youll often find that theyre structured around gene defects.

What Im saying is that if cancer is not a genetic disease and the mutations are downstream epiphenomena, why would the field continue to focus on things that are mostly irrelevant to the nature of the disease? What Im saying is very devastating, because Im telling the majority of the people in the field that theyre basically wasting their time

I think we can drop the death rate of this disease by about 50% in 10 years if cancer is treated as a mitochondrial metabolic disease, targeting fermentable fuels rather than using toxic therapies that are focused on downstream effects.

Radiation is designed to stop DNA replication. DNA replication requires energy. If you pull the plug on their fermentable fuels, theyre not going to be able to replicate anyway All of the things that were doing to treat cancer is basically approaching the disease from a misunderstanding of the biology

We know viruses can cause cancer. We know radiation causes cancer. We know carcinogens cause cancer. We know intermittent hypoxia causes cancer. We know systemic inflammation causes cancer. We know just getting older puts you at risk for more cancer.

We know there are inherited mutations in the genome that can cause cancer. But how are all these things linked through a common pathophysiological mechanism? The common pathophysiological mechanism is damaged through the structure and function of the mitochondria.

Every one of the issues including inherited mutations, damage the respiration of a particular population of cells in a tissue. You look at the breast cancer gene (BRCA 1), for example. People will say, Cancer must be a genetic disease because you inherit a mutation that causes the disease.

You only get the disease if that mutation disrupts the function of the mitochondria. Fifty percent of women who carry the mutation never get cancer or breast cancer because the mutation, for some reason, did not damage the mitochondria in that person.

So, to summarize, the true origin of cancer is damage to the respiratory function of the mitochondria, triggering compensatory fermentation, which is run by oncogenes. Oncogenes play a role by facilitating the entry of glucose and glutamine into the cell to replace oxidative phosphorylation.

Seyfried also has a very different view on the biology of metastasis (the spread of cancer). He explains:

Weve looked at cancer stem cells in a number of our preclinical models These guys grow like crazy in place. The tumor just keeps expanding, but it doesnt spread. It doesnt spread into the bloodstream or metastasize to various organs.

We discovered a very unusual cancer 20 years ago. It took us 10 to 15 years to figure out what it was. You can put a few of these cells anywhere in the mouses body and within three to four weeks, this mouse is full of metastatic cancer. It made the cover of the International Journal of Cancer, when we published this back in 2008, but we had worked on the problem for years.

We couldnt figure out what it was that made these cells so incredibly metastatic. We found out that once we identified the biology of the cell, it turned out [it has] many characteristics in common with the macrophage, which is one of the most powerful immune cells in our body.

We said, Wow. Is this unique only to this kind of cell or do metastatic cancers in humans also express characteristics of macrophages? We looked and we found that almost every major cancer that metastasizes has characteristics of macrophages. Then we said, Well, how could this possibly happen? Is it coming from the macrophage?

A number of scientists have all clearly shown that there is some fusion hybridization character going on. In other words, macrophages, our wound-healing cells, they come into a microenvironment where you might find many proliferating neoplastic stem cells, but they dont have the capacity to metastasize.

Its only when the macrophages fuse with these stem cells that you have a dysregulated energy metabolism coming in this hybrid cell. This hybrid cell now has characteristics of both stem cells and macrophages.

The stem cell is not genetically equipped to enter and exit tissue. The macrophage, as a normal cell of your body, is genetically equipped to enter and exit tissue and live in the bloodstream. Theyre very strongly immunosuppressive. These are all characteristics of metastatic cancer.

According to Seyfried, metastatic cancer cells are essentially a hybrid, a mix of an immune system cell and a dysregulated stem cell, the latter of which could originate from a disorganized epithelial cell or something similar. In short, its a hybrid cell with macrophage characteristics.

Macrophages are essential for wound healing and part of our primary defense system against bacterial infections. They live both in the bloodstream and in tissues, and can go anywhere in the body. When an injury or infection occurs, they immediately move in to protect the tissue.

The metastatic cancer cell has many of those same properties,Seyfried explains,But the energy and the function of the cell is completely dysregulated, so it proliferates like crazy but has the capacity to move and spread through the body, so its a corrupted macrophage. We call it a rogue macrophage.

Like macrophages, metastatic cancer cells can also survive in hypoxic environments, which is why most angiogenic therapies are ineffective against metastatic cancer.

So, what do these metastatic hybrid cells need to survive? Both macrophages and immune cells are major glutamine consumers, and according to Seyfried, you can effectively kill metastatic cells by targeting glutamine.

However, it must be done in such a way so as to not harm the normal macrophages and the normal immune cells. In other words, it must be strategic. For this reason, Seyfried developed a press-pulse therapy for cancer, which allows the patient to maintain normal immune system function, while at the same time targeting the corrupted immune cells the macrophage fusion hybrid metastatic cells as well as inflammation.

The therapies we are using to attempt to kill these [metastatic] cells put us at risk for having the cells survive and kill us. You can control these cells for a short period of time, but they can hunker down and enter into some sort of a slightly dormant state, but they reappear.

People say, Oh, these tumor cells are so nifty and smart they can come back at you. The problem is youve never really challenged them on their very existence, which is they depend on fermentation to survive. If you dont target their fermentation, theyre going to continue to survive and come back at you.

Many of the therapies that we use radiation, chemo and some of these other procedures are not really going after the heart of the problem. That oftentimes puts you at risk for the recurrence of the disease. Your body is already seriously weakened by the toxic treatments. And in the battle, you lose. If you are fortunate enough to survive your body is still beat up.

You have now put your [body] at risk for other kinds of maladies Why are we using such toxic therapies to kill a cell when we know what its weaknesses are? These are the paradigm changes that will have to occur as we move into the new era of managing cancer in a logical way.

To properly address cancer, then, you need to clean up the microenvironment, because the microenvironment will strategically kill cells that are dependent on fermentation while enhancing cells that arent. At the same time, the microenvironment will also reduce inflammation.

You also have to be very careful not to kill your normal and healthy immune cells, because they need glutamine too,Seyfried says. What we find is that when we strategically attack the tumor this way, it turns out that our immune cells are paralyzed.

The cancer cells are killed, but the normal immune cells are paralyzed. Theyre not dying, theyre just not doing their job. What we do is we back off the therapy a little; allow the normal immune cells to regain their biological capacity, pick up dead corpses, heal the microenvironment, and then we go after the cancer cells again.

Its a graded response, knowing the biology of the normal cells and the abnormal biology of the tumor cells. This is a beautiful strategy. Once people know how you can play one group of cells off another, and how you can strategically kill one group of cells without harming the other cells, it really becomes a precision mechanism for eliminating tumor cells without harming the rest of the body.

You dont need to be poisoned and irradiated. You just have to know how to use these procedures to strategically kill the cells. Protecting normal macrophages is part of the strategic process. Killing the corrupted ones is part of the strategic process. Again, you have to put all of these together in a very logical path. Otherwise, youre not going to get the level of success that we should be getting.

This strategy is what Seyfried calls press-pulse treatment, and essentially involves restricting the fermentable fuels glucose and glutamine in a cyclical fashion to avoid causing damage to normal cells and tissues. Glucose is effectively restricted through a ketogenic diet. Restricting glutamine is slightly trickier.

The press-pulse strategy was developed from the concept of press-pulse in the field of the paleobiology. A press was some chronic stress on populations, killing off large numbers, but not everything, because some organisms can adapt to stress. The pulse refers to some catastrophic event.

The simultaneous occurrence of these two unlikely events led to the mass extinction of almost all organisms that existed on the planet. This was a cyclic event over many hundreds of millions of years. The geological records show evidence for this press-pulse extinction phenomenon.

What we simply did was take that concept and say, Lets chronically stress the tumor cells. They need glucose. You can probably kill a significant number of tumor cells by just stressing their glucose. Thats the press. The press is different ways to lower blood sugar. You put that chronic stress on top of the population either by restricted ketogenic diets [or] therapeutic fasting. There are a lot of ways that you can do this.

Also, emotional stress reduction. People are freaked out because they have cancer, therefore their corticoid steroids are elevated, which elevates blood sugar. Using various forms of stress management, moderate exercise all of these will lower blood sugar and contribute to a chronic press and stress on the cancer cells.

However, youre not going to kill all cancer cells if you just take away glucose. Because the other fuel thats keeping the beast alive is the glutamine. We have to pulse, because we cant use a press for glutamine targeting, because then youre going to kill your normal immune cells or impair them, and they are needed for the eventual resolution of the disease.

What were going to do is were going to pulse various drugs. We dont have a diet system that will target glutamine. Glutamine is everywhere. Its the most abundant amino acid in your body But you have to use [the drugs] very strategically; otherwise they can harm our normal immune system and then be counterproductive

I think that once we understand how we can target effectively glutamine without harming our normal immune cells this is the strategy that will make most of these other therapies obsolete Its cost-effective and non-toxic and it will work very well.

But were still at the very beginning of this. We need to continue to develop the doses, timing and scheduling of those drugs that are most effective in targeting glutamine that can be done without harming the rest of the cells in our body.

If you would like to support Dr. Seyfrieds research, please consider making a donation to the Foundation For Metabolic Cancer Therapies. The donation tag is on the top row of the of the foundationsite. This Foundation is dedicated to supporting Dr. Seyfrieds studies using metabolic therapy for cancer management with 100% of the donated funds going directly to research on metabolic therapy for cancer.

Originally published July 31, 2022 on Mercola.com

Views expressed in this article are the opinions of the author and do not necessarily reflect the views of The Epoch Times. Epoch Health welcomes professional discussion and friendly debate. To submit an opinion piece, please follow these guidelines and submit through our form here.

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Why Glucose Restrictions Are Essential in Treating Cancer - The Epoch Times

Skin Stem Cells Comments Off on Why Glucose Restrictions Are Essential in Treating Cancer – The Epoch Times | August 10th, 2022

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Heart failure in obesity: insights from proteomics in patients treated with or without weight-loss surgery | International Journal of Obesity -...

Cardiac Stem Cells Comments Off on Heart failure in obesity: insights from proteomics in patients treated with or without weight-loss surgery | International Journal of Obesity -… | August 10th, 2022

Research led by Muhammad Riaz, PhD, Jinkyu Park, PhD, and Lorenzo Sewanan, MD, PhD, from the Qyang and Campbell laboratories at Yale, provides a mechanism to identify abnormalities linked with a hereditary cardiac condition, hypertrophic cardiomyopathy (HCM), in which walls of the left ventricle become abnormally thick and often stiff. The findings appear in the journal Circulation.

Patients with familial HCM have an increased risk of sudden death, heart failure, and arrhythmias. HCM is the most common inherited cardiac disease, affecting one in 500 people. The disease is thought to be caused by mutations that regulate cardiac muscle contraction, compromising the hearts ability to pump blood. However, the mechanisms behind the disease are poorly understood.

For this multi-model study, the researchers used stem cell approaches to understand the mechanisms that drive inherited HCM. The technology, induced pluripotent stem cells (iPSCs), can accelerate insights into the genetic causes of disease and the development of new treatments using the patients own cells.

This is a humbling experience that a patients disease phenotypes teach researchers fundamental basic knowledge that sets the stage for innovative new therapies. Furthermore, our research has established a great model to assist many physicians at Yale School of Medicine and Yale New Haven Hospital to unravel mechanistic insights into disease progression using the patients own iPSCs and engineered tissues, said Yibing Qyang, PhD, associate professor of medicine (cardiology) and of pathology.

We wanted to understand the disease mechanism and find a new therapeutic strategy, Park said.

Probing the heart disorders mechanismThe concept originated with an 18-month-old patient who suffered from familial HCM. Through a collaboration with Daniel Jacoby, MD, adjunct associate professor of cardiovascular medicine and an expert on HCM, who provided medical care for this patient, Park and the team used stem cell technologies to address a fundamental question, the disease mechanisms behind HCM. They collected 10 cc of the patients blood and introduced stem cell factors into the blood cells to generate self-renewable iPSCs. By applying cardiac knowledge, they coaxed iPSCs into patients own cardiomyocytes (heart cells) for cardiac disease studies. We discovered a general mechanism which explains the disease progression, said Park.

Next, they engineered heart tissues that resembled the early-onset disease scenario of the young patient. The disease was a severe presentation at the age of 18 months, which suggested that the disease started at the fetal/neonatal stage.

The next phase of the study was to recreate a 3-D model that was used to mimic the progression of the disease, including mechanical properties such as contraction and force production of that muscle, to understand how much force is compromised if the mutation is present. This was performed in collaboration with Stuart Campbell, PhD, and Sewanan from Yales Department of Biomedical Engineering. Coupled with computational modeling for muscle contraction, the authors developed robust systems that allowed them to examine the biomechanical properties of the tissue at three-dimensional levels.

Finally, using advanced gene editing technologies, the research team modified these mutations. They discovered that after the mutations were corrected, the disease was reversed. These insights about sarcomeric protein mutations could lead to novel therapeutics for HCM and other diseases. The interaction between mutations could also suggest that the same biomechanical mechanism exists in other conditions such as ischemic heart disease.

Our research has established a great model to assist many physicians at Yale School of Medicine and Yale New Haven Hospital to unravel mechanistic insights into disease progression using the patients own iPSCs and engineered tissues.

Yibing Qyang, PhDWe can apply these findings to cardiac conditions associated with hypertension, diabetes, or aging, said Riaz.

Applying the findings to heart diseaseOne of the fundamental challenges was that we needed to generate iPSCs from the patients family, Riaz added. Using this technology, Park was able to recreate primary cells from the cells of a patient with HCM, a process which takes over a month. Riaz and Park used stem cells to identify the vital role of pathological tissue remodeling, which is caused by sarcomeric hypertrophic cardiomyopathy mutations.

We are hopeful that our findings will be replicated in the scientific community, said Riaz. This is an example of bed to bench research, where scientists extract materials from clinics and conduct the experiment in the laboratory and then discover new methods to treat patients.

The authors also noted that RNA sequencing could be used as a guide to characterize the disease at a molecular level. Scientists may be able to identify more targeted drugs by examining the biomechanical properties of the tissue. We can now screen multiple drugs to see whether any of those drugs are able to rescue the phenotype, they said.

Riaz, now an associate research scientist in the Qyang lab, began as a cancer researcher. He earned a PhD from the Erasmus University Medical Center, based in Rotterdam, Netherlands. He later studied genetic disorders in skeletal muscle disease before joining the lab in 2017.

Park, also from the Qyang lab, graduated from Seoul National University, South Korea in 2013. He completed postdoctoral research at the University of Missouri where he focused on vascular biology and emerging areas in stem cell technology.

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Yale University: Uncovering New Approaches to a Common Inherited Heart Disorder | India Education - India Education Diary

Cardiac Stem Cells Comments Off on Yale University: Uncovering New Approaches to a Common Inherited Heart Disorder | India Education – India Education Diary | August 10th, 2022

Raising the dead sounds like science fiction, but a team of medical scientists at Yale University have managed to achieve just thatat least on a cellular level. They successfully revived cells from pigs that were dead for an hour, as a Nature study published August 3 reports. While the study authors emphasize the technology is ages away from being used on people, the work could eventually help keep human tissues alive longer, increasing the supply of viable organs for transplants.

These cells are functioning hours after they should not be, said Nenad Sestan, a professor of neuroscience and comparative medicine at Yale and lead author of the study, in a news briefing per CNN. And what this tells us is that the demise of cells can be halted. And their functionality restored in multiple vital organs. Even one hour after death.

Sestan and his colleagues received 100 pigs from a local breeder. They placed the pigs on ventilators and shocked the animals hearts to induce cardiac arrest. An hour after confirmed death, the Yale scientists used two systems to pump blood back into the bodiesan ECMO machine removed carbon dioxide and added oxygenated blood to one group, while another device, called OrganEx, pumped artificial blood back into the other. That fluid entered the blood vessels of the dead pigs, where synthetic forms of hemoglobin and other molecules protected cells from degradation and stopped blood clots.

After six hours, the researchers recorded signs of oxygen recirculating into the pigs tissues. A heart scan confirmed signs of electrical activity in the heart of pigs on the OrganEx machine, though those organs did not fully restart. Elsewhere, there were signs of business as usual, too: The livers of the deceased pigs resumed production of a protein called albumin. Additionally, the cells of other vital organs were responsive to glucose, suggesting the pigs metabolic processes were working again.

The experiment is not the first time scientists have tried to redefine life and death. In the early 20th century, there were attempts to reboot the brains of deceased monkeys. And in 2019, neuroscientists reanimated the brains of decapitated pigs four hours after they died in a slaughterhouse.

Studies such as these raise questions about what it means to be dead. We presume death is a thing, it is a state of being, Nita Farahany, a Duke law professor who studies ethical, legal and social implications of emerging technologies, told The New York Times. Are there forms of death that are reversible? Or not?

The findings also call into question who is considered legally dead, especially as medicine adapts to make cardiac death one day reversible. People tend to focus on brain death, but theres not much consensus on when cardiac death occurs, Arthur Caplan, a bioethicist at New York University told Nature News. This paper brings that home in an important way.

Ethical challenges abound if technology such as this were applied to people. In 2016 Indias medical research council, citing ethical concerns, blocked a planned clinical trial that aimed to revive brain-dead people to a minimally conscious state using a mix of stem cells and other techniques.

While the current study showed no signs of brain activity in the pigs, the researchers observed the heads, necks, and torsos moved. If brain activity was restored, there is no telling how functional or conscious the pigs would be, making it one of a slew of ethical questions scientists will need to answer as they breach this murky area of science.

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Pigs died after heart attacks. Scientists brought their cells back to life. - Popular Science

Cardiac Stem Cells Comments Off on Pigs died after heart attacks. Scientists brought their cells back to life. – Popular Science | August 10th, 2022

Immediate cord clamping (ICC), within a few seconds after birth, became routine in the latter half of the 20th century, as part of a tranche of medical birth-related interventions that collectively, undoubtedly improved maternal and neonatal survival and outcomes [1]. The trend to ICC (within 15-20 seconds after birth) was partly driven by some early studies suggesting that the most benefit in terms of blood volume is achieved within this time frame [2], and that deferred cord clamping (DCC) increased rates of polycythemia and jaundice [1]. It may also have been partly driven by increased rates of operative deliveries and consequent pressure to minimize surgical times, as well as the increased availability and effectiveness of neonatal resuscitation. Furthermore, ICC was proposed as a means to reduce the risk of maternal exposure to fetal blood group antigens at a time (before RhD immunoprophylaxis) when hemolytic disease of the fetus and newborn was far more common than it is now.

Formal evidence that ICC was beneficial was never sought, and recent research summarized in systematic reviews [3-6] has suggested that it may be harmful when compared with DCC for various intervals from 30 seconds until when the cord stops pulsating (defined in some studies as physiological cord clamping). ICC before the onset of breathing exposes the newborn baby to a period of significantly restricted cardiac function, whereas DCC until after the onset of breathing (which often does not occur until late in the first minute after birth) may mean that the expanding pulmonary circulation is able to fill with blood from the placenta, rather than by reverse flow across the ductus arteriosus [7]. This may improve left ventricular preload and stabilize pressures and flows in major vessels [7].

In addition, when cord clamping is deferred, babies may receive a transfusion of blood from the umbilical cord and placenta. A recent systematic review demonstrated that DCC in preterm babies improves peak hematocrit in the first week by 2.7% (95% confidence intervals (CI) 1.88-3.52) and reduced the proportion of babies receiving any subsequent blood transfusion (RD: -0.07, 95%CI -0.11 to -0.04) [6]. Some studies have found a weight increase in the first two minutes after birth when the cord is not clamped, supporting the hypothesis of placental transfusion [8]. Yet, recent evidence shows that placental transfusion may not always occur (Conference abstract: Vijayaselvi R, Abraham A, Kumar M, Kuruvilla A, Mathews J, Duley L. Measuring Umbilical Flow and Placental Transfusion for Preterm Births: Weighing Babies at 33-36 Weeks Gestation with Cord Intact. 1st Congress of Joint European Neonatal Societies; 2015).

The relative roles of cardiovascular stabilization at birth versus placental transfusion in improving outcomes have not been established. Understanding the contributions of these two mechanisms has significant implications for research and practice: for example, if the size of placental transfusion is more important, then prescribing a top-up transfusion soon after birth for babies with lower than average hemoglobin (who are known to be at higher risk of various adverse outcomes) [9] may be justified, especially for the babies for whom DCC has been precluded by maternal or fetal conditions. These include significant maternal bleeding, and monochorionic twins, where deferred cord clamping in the first twin could lead to one twin losing blood to the other. However, if it is the effects on improving cardiovascular stability in the first minutes (with consequential benefits for cardiorespiratory function and reducing severity of illness during the subsequent neonatal intensive care unit (NICU) stay), regardless of the magnitude of transfusion, then early top-up transfusion is unlikely to be helpful.

Observational studies suggest that exposure to blood transfusion itself is harmful to preterm babies, increasing the risk of adverse outcomes [10]. However, this suggestion has not been supported by the small number (to date) of randomized controlled trials of blood (red cell) transfusion thresholds [11-14]. It is unlikely to be the means by which DCC reduced deaths in the largest trial to date of deferred cord clamping in preterm babies, the Australian Placental Transfusion Study (APTS), and in the most recent systematic review on this, because neither showed a difference in rates of other adverse outcomes [6,15].

Another possibility is that it is the umbilical cord blood stem cells received by the baby are the main reason for the observed benefits to both survival and reduced requirement for later blood transfusion [16]. Umbilical cord blood has been demonstrated to be such a good contributor to hematopoiesis that it is a recognized stem cell resource for pediatric and adult hematopoietic stem cell transplant [17]. In addition, umbilical cord blood is a potential regenerative and immunomodulatory agent for a variety of clinical conditions [18], so in this case, the extent of placental transfusion would be critical to the improvement of outcomes, and transfusion with adult red cells would not suffice. There are no established methods to quantify the contribution of umbilical cord stem cells to placental transfusion. However, a larger volume of placental transfusion results in the baby receiving more nucleated cells [19], including more umbilical cord stem cells.

Discerning whether these effects (initial enhanced cardiovascular stability leading to early and sustained reduction in severity of illness or volume of placental transfusion) appear to be the main driver of improved outcomes is likely to contribute to practice change, as well as to informing the design of future research studies into methods to improve outcomes of high-risk newborn babies and reduce their transfusion dependence.

The causal mechanisms of reduced transfusion requirements found in DCC relative to ICC are yet to be resolved. The aim of the study is to address the question; In preterm infants (P) does DCC (I) compared to ICC (C) reduce dependence on red cell transfusion via enhanced cardiovascular stability (mediator 1, M1) or via an increased volume of placental transfusion (M2).

The study is a nested retrospective study, called the Transfusions in the APTS Newborns Study (TITANS) (study registration: ACTRN12620000195954), of the cohort of babies who were enrolled and randomly assigned to ICC or DCC in the Australian and New Zealand (NZ) sites for APTS (study registration: ACTRN12610000633088). This design has been developed to take advantage of the comprehensive dataset already collected for APTS, and because there is currently no suitable prospective study that could address the same research questions in such a large group of participants.

Babies had been considered eligible for APTS if obstetricians or maternal-fetal medicine specialists anticipated that delivery would occur before 30 weeks of gestation. Exclusion criteria included fetal hemolytic disease, hydrops fetalis, twin-twin transfusion, genetic syndromes, and potentially lethal malformations. Further details are available in the original APTS publication [15]. In the present TITANS analysis, we will also exclude any baby with a diagnosis of hemolytic anemia or aplastic/hypoplastic anemia.

There were 1401 babies enrolled for APTS from the 13 Australian and 5 NZ hospital sites [15]. APTS data was provided to the TITANS team on 31 July, 2020. It is planned to collect additional data from Australian and NZ APTS sites using a customised, secure web-based database application (REDCap) [20], which is maintained by the University of Sydney, Sydney, Australia. Data will be obtained from source documents (patient hospital records and laboratory reports) using the electronic data collection application from each study site. The individual participant data collected will correspond to the minimum data required to answer the research questions. Baby identification (ID) and other babies details from APTS will be used to re-identify participants and link them to hospital records. Identified data will be collected, in order to allow linkage between the data newly collected from patient records and hospital laboratories and the existing APTS dataset. The data will be checked with respect to range, internal consistency, consistency with published reports and missing items. After data cleaning and analysis, data will be stored in re-identifiable form, with each participants data being identified with the same study numbering system as used for the APTS study.

We will combine the data already extracted, stored and cleaned from APTS with the additional data obtained from study sites for each participating baby, to determine which factors are most influential in reducing transfusion requirements. The specific objectives are, after adjustment for prior risk factors (listed below), to determine:

1.Whether the effect of the intervention (cord clamping) on the outcome (blood transfusions) is mediated by placental transfusion (measured by hematocrit (Hct)) as seen in Figure 1 (a, c) following the causal path X M1 Y, where X is the intervention, ICC or DCC, Y is the outcome, mediator M1 is placental transfusion, and M2 is initial severity of illness stability

2.Whether the effect of the intervention (cord clamping) on the outcome (blood transfusions) is mediated by initial severity of illness (respiratory support, sampling line yes/no and total duration number, blood pressure, cumulative blood sample volume) as seen in Figure 1 (b, c) following the causal path X M2 Y

3.Whether the effect of cord clamping intervention on the outcome (blood transfusions) is driven by multiple mediators (placental transfusion and initial severity of illness) as seen in Figure 1 (c)

4.Whether cording clamping intervention (ICC or DCC) has a direct effect on the outcome after accounting for the mediators as seen in all panels of Figure 1: X Y.

The protocol was approved by the Northern Sydney Local Health District Human Research Ethics Committee in November 2019 (Version 3.0, Reference 2019/ETH12819), the Mater Misericordiae Ltd Human Research Ethics Committee (Version 1.0, Reference HREC/MML/56247), the Mercy Health Human Research Ethics Committee (Version 2.0, Reference 2020-078), and the Southern Health and Disability Ethics Committee (Version 1.0, Reference 19/STH/195). The ethics committees have granted a waiver of consent. The study is conducted in accordance with the National Health and Medical Research Council Statement on Ethical Conduct in Research Involving Humans.

Intervention

The intervention consisted of either immediate or delayed cord clamping (as assigned in APTS). Immediate clamping was defined as clamping the cord within 10 seconds of delivery. Delayed clamping was defined as clamping the cord at least 60 seconds after delivery, with the infant held as low as possible, below the introitus or placenta, and with no palpation of the cord. Variations in the protocol were allowed if they would aid the mother, baby, or both. If the baby was non-vigorous (heart rate <100 beats per minute, low muscle tone, or lack of breathing, or crying), clinicians were allowed to break protocol using their discretion. Cord milking was not part of the protocol for either intervention. Further details may be sourced from the original APTS publication [15].

Outcomes

The primary outcome is the proportion of babies receiving red cell transfusion (for restoration of hemoglobin or blood volume). The secondary outcomes are number of transfusions per baby, cumulative transfusion volume (mL/kg) per baby, and primary reasons for each transfusion.

Putative Mediators

M1: Indicators of placental transfusion to be assessed will be hematocrit (on admission, highest on the first day, highest in the first week collected before any postnatal transfusion).

M2: Indicators of initial severity of illness to be assessed will be cumulative blood sample volume collected throughout hospital stay (number of blood tests multiplied by hospitals usual sample volume for each type of test), sampling line (umbilical arterial line or peripheral arterial line) - yes/no and total duration, mechanical ventilation or inspired O2, and blood pressure.

Sensitivity Analyses (For the Primary Outcome Analysis Only)

Sensitivity analyses will adjust for the following variables: gender, birth <27 weeks vs. 27 weeks, method of delivery (vaginal versus cesarean), intraventricular hemorrhage (IVH) (yes/no and grade III/IV yes/no), surgery for patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), and sodium in the first 24 hours of life. We will also test model assumptions relating to sequential ignorability and post-randomization confounding (discussed further in the data analysis plan).

Potential Confounders (Covariates)

The following covariates may be used for adjustment in the analysis: gestational age at randomization before birth and any oral iron supplement pre-transfusion.

Timing of Assessments

Putative mediating variables will only be analyzed if they have been measured before the outcome and will be excluded if there is not adequate time and date information available. If the multiple mediator model is applied, careful consideration of timing information will be evaluated. If there is insufficient empirical information to conclude the causal ordering of mediators (M1 causes M2), we will adjust our analytic approach (as discussed in the analysis plan) and discuss any limitations.

Data Analysis Plan

The analysis will include all babies who were initially randomized in the APTS trial for whom we were able to obtain the relevant data and be based on intention-to-treat. All statistical analyses will be conducted in R version 4.1.3 (2022-03-10; R Foundation for Statistical Computing, Vienna, Austria). Descriptive characteristics for continuous data will be presented as means or medians, as appropriate, and categorical data will be presented as frequencies and percentages.

A model-based inference approach will be applied to estimate the average causal mediation effect (ACME), average direct effect (ADE), and the average total effect as recommended [23-25]. This approach will be applied with the R mediation package [26]. We will initially fit two models, one model with mediation as the dependent variable and intervention as the independent variable (mediator model), and a second model with the outcome as the dependent variable, and both mediation and intervention as independent variables (outcome model). To account for the clustering of multiples, estimates will be calculated with generalized estimating equations with a compound symmetric correlation structure to account for within subject correlations. Depending on the outcome (binary, count, skew) these will be modelled with the appropriate family and link functions.

A counterfactual framework will be applied to the mediator and outcome models to simulate the values of the mediator and outcome to estimate the potential values of the mediator. This process is used to estimate the ACME, ADE, and average total effects; 95%CI will be estimated with 1000 bootstrap simulations.

We will apply single mediator models on both placental transfusion variables and initial severity of illness variables if mediators are statistically independent, as seen in Table 1. Independence will be tested using linear regression and any appropriate link functions. If both mediators are not statistically independent, we will investigate the possibility of multiple mediator models, which require an expanded framework for analysis [21]. Here we assume that initial severity of illness is causally related to placental transfusion. For this process, we will use the method developed by Imai and Yamamoto [21] to estimate the ACME and ADE. Following this, 95%CI will be estimated with 1000 bootstrap simulations. If theoretical and empirical timing data and sensitivity analyses suggest that M1 and M2 have non-causal correlation and may be affected by an unmeasured latent mediator, we will adjust our approach to estimate interventional direct and path-specific indirect effects [27,28].

Sensitivity analyses have been limited to a set of biologically plausible and clinically meaningful groups that will be explored by including them for adjustment with covariates, and with the introduction of interaction terms if appropriate. Missing data will be described, reasons for missing data will be explored, and the impact of missing data on conclusions about the treatment effect on the primary outcome will also be explored where possible (e.g., using sensitivity analyses and multiple imputation techniques).

Methodological Assumptions

The causal mediation approach assumes sequential ignorability: that the treatment effect on the outcome is not confounding and that the mediator effect on the outcome is not confounded. As treatment was randomly allocated to neonates, we will assume that the treatment-mediator relationship is not confounded. However, the mediator itself has not been randomized. Thus, unknown confounders may be driving a spurious effect in the mediator-outcome relationship. We will employ additional sensitivity analyses to estimate whether any mediation effects are sensitive to the violation of the assumption of sequential ignorability. To test the possibility of unmeasured confounders we will examine the correlation between residuals in the mediator model and the outcome model. If there is no correlation this would suggest there is no unmeasured confounding, if there is correlation between the residuals, an unmeasured mediator may be affecting both the measured mediator and the outcome. We will apply the method developed by Imai et al. andTingley et al. [23,26] that uses sensitivity analyses to evaluate if the ACME estimate is sensitive to unmeasured confounding.

Post-randomization confounders are dependent on the treatment allocated, affect both mediator and outcome, and can corrupt the mediation estimate. In the context of the present trial, it is possible that non-adherence to the intervention is a post-randomization confounder. We are analyzing our data based on intention to treat principles; however, a sensitivity analysis based on the actual time of cord clamping to assess the influence of non-adherence with the treatment protocol on our estimates may be performed.

Blood transfusions of neonates have been associated with a number of serious adverse outcomes [29]. Nevertheless, there are few evidence-based methods to reduce transfusion exposure [30]. The APTS study found that DCC was associated with a statistically significant reduced need for red cell transfusions by about 10% compared to ICC [15]. However, the mechanism remains unclear.

The study will, at a minimum, provide further information that should increase clinicians understanding of the pathways by which DCC (or other methods to accomplish placental transfusion) results in beneficial patient outcomes. Since one of the main barriers to implementation is lack of understanding about the mechanisms by which such a simple practice change should have such dramatic effects, this should improve adherence to recommendations to defer cord clamping for most babies, thereby reducing mortality and transfusion incidence.

By elaborating on the mechanisms, it may also provide good evidence for how other routine neonatal intensive care practices and interventions affect likelihood of needing to transfuse. Better understanding of these effects may lead to other testable hypotheses or improvements in other aspects of practice, further reducing transfusion exposure and improving other outcomes.

Potential limitations of the study include the dependence on some routinely collected clinical data, which were not collected at the time by the original study according to predefined research definitions. However, we have no reason to think that potential problems of data quality would have been influenced by study group allocation and so do not anticipate that this will be a source of bias.

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Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort - Cureus

Cardiac Stem Cells Comments Off on Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort – Cureus | August 10th, 2022

Abstract: The olfactory ecto-mesenchymal stem cell (OE-MSC) are mesenchymal stem cells originating from the lamina propria of the nasal mucosa. They have neurogenic and immune-modulatory properties and showed therapeutic potential in animal models of spinal cord trauma, hearing loss, Parkinsons disease, amnesia, and peripheral nerve injury. In this paper we designed a protocol that meet the requirements set by human health agencies to manufacture these stem cells for clinical applications. Once purified, OE-MSCs can be used per se or expanded in order to get the extracellular vesicles (EV) they secrete. A protocol for the extraction of these vesicles was validated and the EV from the OE-MSC were functionally tested on an in vitro model. Nasal mucosa biopsies from three donors were used to validate the manufacturing process of clinical grade OE-MSC. All stages were performed by expert staff of the cell therapy laboratory according to aseptic handling manipulations, requiring grade A laminar airflow. Enzymatic digestion provides more rapidly a high number of cells and is less likely to be contaminated. Foetal calf serum was replaced with human platelet lysate and allowed stronger cell proliferation, with the optimal percentage of platelet lysate being 10%. Cultivated OE-MSCs are sterile, highly proliferative (percentage of CFU-F progenitors was 15,5%) and their maintenance does not induce chromosomal rearrangement (karyotyping and chromosomal microarray analysis were normal). These cells express the usual phenotypic markers of OE-MSC. Purification of the EVs was performed with ultracentrifugation and size exclusion chromatography. Purified vesicles expressed the recognized markers of EVs (Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines) and promoted cell differentiation and neurite elongation in a model of neuroblastoma Neuro2a cell line. We developed a safer and more efficient manufacturing process for clinical-grade olfactory stem cells, these cells can now be used in humans. A phase I clinical trial will begin soon. An efficient protocol for the purification of the OE-MSC EVs have been validated. These EVs exert neurogenic properties in vitro. More studies are needed to understand the exact mechanisms of action of these EVs and prove their efficacy and safety in animal models.

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Culture of human nasal olfactory stem cells and their extracellular vesicles as advanced therapy medicinal products - Newswise

Spinal Cord Stem Cells Comments Off on Culture of human nasal olfactory stem cells and their extracellular vesicles as advanced therapy medicinal products – Newswise | August 10th, 2022

What is inside teeth? Nicholas, age 5, Australian Capital Territory

Great question, Nicholas. It is important for us to know whats inside teeth as they help us eat, and eating gives us the energy to do our daily activities.

Our teeth are not just for chewing, though. We also need teeth for speaking, because different teeth contribute to different sounds. For example, we need upper front teeth to speak words starting with f or v sounds.

The teeth in the upper jaw are called as maxillary or upper teeth, and those on the lower jaw are called as mandibular or lower teeth. Then each jaw has two side-to-side halves. All up, thats four quadrants of teeth.

We have two sets of teeth. There are 20 teeth in the first set. We commonly call these milk teeth or primary teeth. They start forming while we are in the womb, even before we are born! The first one starts coming out of the gums when we are six months old, and most people have all their milk teeth by the age of three.

We keep our milk teeth until we are six years old, when we start losing them and the adult teeth or permanent teeth start coming in. By 14 or 15 years of age, most of us will have all our adult teeth except the last tooth in each side of the jaws. Some people call these wisdom teeth. There are 32 teeth in an entire adult set, with an equal number of teeth on each side.

We have four different types of teeth:

Read more: Curious Kids: what is brain freeze?

Each tooth can be divided into two parts. The crown is the part of the tooth we can see in the mouth, while the root sits within the gum and bone of the jaw. Some teeth have more than one root.

And each tooth has two layers: enamel and dentine, with pulp at the centre which has nerves and blood. Roots do not have enamel but another layer called cementum.

Enamel is the hardest substance in the body and protects the dentine and pulp, just like a helmet protects your head.

Dentine is the second layer and makes up most of the tooth.

We feel pain in the tooth when the innermost part, pulp, is involved.

Scientists have been working hard to find how special cells called stem cells in pulp could be used to repair other parts of the teeth, gums and even other body parts such as the spinal cord, brain and heart.

Read more: Curious kids: why dont whales have teeth like we do?

Hopefully youve already got into the habit of brushing twice every day with a fluoridated toothpaste for at least two minutes.

Tooth decay is caused by germs that love to feast on sugary or treat food in our mouth. We can stop that happening by saving lollies and sweets for special occasions and cleaning every tooth really well.

When teeth are not well cared for, they can develop tooth decay, which could cause pain when it involves that pulp deep inside your teeth. Its important to visit an oral health professional (such as your family dentist or hygienist) regularly. They can tell you how to take good care of your teeth and treat damaged teeth when required.

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Curious kids: what is inside teeth? - The Conversation

Spinal Cord Stem Cells Comments Off on Curious kids: what is inside teeth? – The Conversation | August 10th, 2022

Tracing features in a large 3D electron microscopy dataset reveals a zebrafish blood stem cell (in green) and its surrounding niche support cells, a group photo method that will help researchers understand factors that contribute to blood stem cell health which could in turn help develop therapies for blood diseases and cancers. Image by Keunyoung Kim.

MADISON For the first time, researchers can get a high-resolution view of single blood stem cells thanks to a little help from microscopy and zebrafish.

Researchers at the University of WisconsinMadison and the University of California San Diego have developed a method for scientists to track a single blood stem cell in a live organism and then describe the ultrastructure, or architecture, of that same cell using electron microscopy. This new technique will aid researchers as they develop therapies for blood diseases and cancers.

Currently, we look at stem cells in tissues with a limited number of markers and at low resolution, but we are missing so much information, says Owen Tamplin, an assistant professor in UWMadisons Department of Cell & Regenerative Biology, a member of the Stem Cell & Regenerative Medicine Center, and a co-author on the new study, which was published Aug. 9 in eLife. Using our new techniques, we can now see not only the stem cell, but also all the surrounding niche cells that are in contact.

The niche is a microenvironment found within tissues like the bone marrow that contain the blood stem cells that support the blood system. The niche is where specialized interactions between blood stem cells and their neighboring cells occur every second, but these interactions are hard to track and not clearly understood.

As a part of the new study, Tamplin and his co-lead author, Mark Ellisman, a professor of neuroscience at UC San Diego, identified a way to integrate multiple types of microscopic imaging to investigate a cells niche. With the newly developed technique that uses confocal microscopy, X-ray microscopy, and serial block-face scanningelectron microscopy, researchers will now be able to track the once elusive cell-cell interactions occurring in this space.

This has allowed us to identify cell types in the microenvironment that we didnt even know interacted with stem cells, which is opening new research directions, Tamplin says.

As a part of this study, Tamplin, and his colleagues, including co-first authors Sobhika Agarwala and Keunyoung Kim, identified dopamine beta-hydroxylase positive ganglia cells, which were previously an uncharacterized cell type in the blood stem cell niche. This is crucial, as understanding the role of neurotransmitters like dopamine in regulating blood stem cells could lead to improved therapeutics.

Transplanted blood stem cells are used as a curative therapy for many blood diseases and cancers, but blood stem cells are very rare and difficult to locate in a living organism, Tamplin says. That makes it very challenging to characterize them and understand how they interact and connect with neighboring cells.

While blood stem cells are difficult to locate in most living organisms, the zebrafish larva, which is transparent, offers researchers a unique opportunity to view the inner workings of the blood stem cell niche more easily.

Thats the really nice thing about the zebrafish and being able to image the cells, Tamplin says of animals transparent quality. In mammals, blood stem cells develop in utero in the bone marrow, which makes it basically impossible to see those events happening in real time. But, with zebrafish you can actually watch the stem cell arrive through circulation, find the niche, attach to it, and then go in and lodge there.

While the zebrafish larva makes it easier to see blood stem cell development, specialized imaging is needed to find such small cells and then detail their ultrastructure. Tamplin and his colleagues spent over six years perfecting these imaging techniques. This allowed them to see and track the real-time development of a blood stem cell in the microenvironment of a live organism, then zoom in even further on the same cell using electron microscopy.

First, we identified single fluorescently labeledstem cells bylight sheet or confocal microscopy, Tamplin says. Next, we processed the same sample forserial block-face scanningelectron microscopy. We then aligned the 3D light and electron microscopy datasets. Byintersecting these different imaging techniques,we could see the ultrastructure of single rare cells deep inside a tissue. This also allowed us to find all the surrounding niche cellsthat contact a blood stem cell. We believe our approach will be broadly applicable for correlative light and electron microscopy in many systems.

Tamplin hopes that this approach can be used for many other types of stem cells, such as those in the gut, lung, and the tumor microenvironment, where rare cells need to be characterized at nanometer resolution. But, as a developmental biologist, Tamplin is especially excited to see how this work can improve researchers understanding of how the blood stem cell microenvironment forms.

I think this is really exciting because we generate all of our blood stem cells during embryonic development, and depending on what organism you are, a few hundred or maybe a few thousand of these stem cells will end up producing hundreds of billions of new blood cells every day throughout your life, Tamplin says. But we really dont know much about how stem cells first find their home in the niche where theyre going to be for the rest of the life of the organism. This research will really help us to understand how stem cells behave and function. A better understanding of stem cell behavior, and regulation by surrounding niche cells, could lead to improved stem cell-based therapies.

This research was supported by grants from the National Institutes of Health (R01HL142998, K01DK103908, 1U24NS120055-01, R24 GM137200) and the American Heart Association (19POST34380221).

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See-through zebrafish, new imaging method put blood stem cells in high-resolution spotlight - University of Wisconsin-Madison

Bone Marrow Stem Cells Comments Off on See-through zebrafish, new imaging method put blood stem cells in high-resolution spotlight – University of Wisconsin-Madison | August 10th, 2022

A bone marrow transplant is a medical procedure that replacesthe bone marrow with healthy cells. Replacement cells might come from either ones own body or from a donor. A stem cell transplant, or more specifically, a hematopoietic stem cell transplant, is another name for a bone marrow transplant. Transplantation can be used to treat leukemia, myeloma, and lymphoma, as well as other blood and immune system illnesses that impact the bone marrow. Cancer and cancer treatment can damage the hematopoietic stem cells. Hematopoietic stem cells are blood-forming stem cells. Hematopoietic stem cells that are damaged may not develop into red blood cells, white blood cells, or platelets. These blood cells are vital, and each one serves a specific purpose. A bone marrow transplant can help the body regenerate the red blood cells, white blood cells, and platelets it requires.

The global Bone Marrow Transplant market is estimated to be valued at $10,356.1 Mn Mn in 2021 and is expected to exhibit a CAGR of 4.0% over the forecast period (2022-2028).

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The study provides data on the most exact revenue estimates for the complete market and its segments to aid industry leaders and new participants in this market. The purpose of this study is to help stakeholders better understand the competitive landscape and design suitable go-to-market strategies. The market size, features, and growth of theBone Marrow Transplantindustry are segmented by type, application, and consumption area in this study. Furthermore, key sections of the GlobalBone Marrow Transplantmarket are evaluated based on their performance, such as cost of production, dispatch, application, volume of usage, and arrangement.

Competitive Analysis: Global Bone Marrow Transplant Market

Detailed Segmentation:

By Type:

By Treatment Type:

:

: United States, Canada, and Mexico & : Argentina, Chile, Brazil and Others & : Saudi Arabia, UAE, Israel, Turkey, Egypt, South Africa & Rest of MEA. : UK, France, Italy, Germany, Spain, BeNeLux, Russia, NORDIC Nations and Rest of Europe. -: India, China, Japan, South Korea, Indonesia, Thailand, Singapore, Australia and Rest of APAC.

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This report has looked at high-impact rendering elements and causes to help readers comprehend the overall trend. Furthermore, the report contains constraints and obstacles that may operate as roadblocks for the players. This will enable people to pay attention and make well-informed business judgments. Specialists have also focused on future business opportunities.

Competitive Outlook:

Company profiles, revenue sharing, and SWOT analyses of the major players in theBone Marrow TransplantMarket are also included in the research. TheBone Marrow Transplantindustry research offers a thorough examination of the key aspects that are changing, allowing you to stay ahead of the competition. These market measuring methods assist in the identification of market drivers, constraints, weaknesses, opportunities, and threats in the global market.

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Use of current statistics gathered by our own researchers. These provide you historical and projected data that is evaluated to inform you why theBone Marrow TransplantMarket is changing this allows you to anticipate market changes and stay ahead of your competition.

Youll be able to quickly pinpoint the information you need thanks to the concise analysis, clear graph, and table style.

Denotes the area and market segment that is likely to expand the fastest and dominate the market.

A geographical analysis showing the consumption of the product/service in each region as well as the variables impacting the market within each region

Comprehensive company profiles for the major market players, including company overviews, company insights, product benchmarking, and SWOT analysis for the major market players, as well as new service/product launches, partnerships, business expansions, and acquisitions in the last five years of companies profiled.

The industrys present and future market outlook, including recent changes such as growth possibilities and drivers, as well as challenges and restraints in both emerging and developed markets.

Porters five forces analysis is used to provide an in-depth examination of the market from numerous angles.

Provides industry understanding via Value Chain Market Dynamics scenario, as well as market development potential in the next years

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Increasing efforts to set up centers for Bone Marrow Transplant is expected to Boost the growth of the market, Top Key players | Lonza, Merck KgaA,...

Bone Marrow Stem Cells Comments Off on Increasing efforts to set up centers for Bone Marrow Transplant is expected to Boost the growth of the market, Top Key players | Lonza, Merck KgaA,… | August 10th, 2022

Cell membrane-coated nanoparticles, applied in targeted drug delivery strategies, combine the intrinsic advantages of synthetic nanoparticles and cell membranes. Although stem cell-based delivery systems were highlighted for their targeting capability in tumor therapy, inappropriate stem cells may promote tumor growth.

Study:Stem cell membrane-camouflaged targeted delivery system in tumor. Image Credit:pinkeyes/Shutterstock.com

A review published in the journalMaterials Today Biosummarized the role of stem cell membrane-camouflaged targeted delivery system in tumor therapy and focused on the underlying mechanisms of stem cell homing toward target tumors. Nanoparticle-coated stem cell membranes have enhanced targetability, biocompatibility, and drug loading capacity.

Furthermore, the clinical applications of induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) were investigated as membrane-camouflaged targeted delivery systems for their anti-tumor therapies. In concurrence, the stem cell membrane-coated nanoparticles have immense prospects in tumor therapy.

Cell-based targeted delivery systems have low immunogenicity and toxicity, innate targeting capability, ability to integrate receptors, and long circulation time. Cells such as red blood cells, platelets, stem cells, tumor cells, immune cells, and even viral/bacterial cells can serve as effective natural vesicles.

MSCs derived from the umbilical cord (UC-MSCs), bone marrow (BM-MSCs), and adipose tissue (ATMSCs) are utilized in clinical applications. However, iPSCs are preferable over MSCs in clinical applications due to their easy fetch by transcription factor-based reprogramming of differentiation of somatic cells.

Stem cells (MSCs/ iPSCs) can be easily isolated and used as drug delivery systems for tumor therapy. Stem cell-based delivery systems have inflammation or tumor lesions targeting capacity. However, stem cells are often entrapped in the lung due to their size, resulting in microembolism.

Cell membrane-coated nanoparticles are applied in targeted delivery strategies. To this end, stem cell membrane-coated nanoparticles have tremendous prospects in biomedical applications. Although previous reports mentioned the role of cell membrane-coated nanocarriers in tumor therapy, delivery systems based on stem cell membranes have not been explored extensively.

Stem cell membrane-coated nanoparticles obtained from stem cells have complex functioning and can achieve biological interfacing. Consequently, stem cell membrane-coated nanoparticles served as novel drug delivery systems that could effectively target the tumor.

Previous reports mentioned the preparation of doxorubicin (DOX) loaded, poly (lactic-co-glycolic acid) (PLGA) coated MSC membrane-based nanovesicles, which showed higher cellular uptake than their PLGA uncoated counterparts. Similarly, the DOX-loaded MSC membrane-coated gelatin nanogels showed enhanced storage stability and sustained drug release.

Thus, the stem cell membrane-coated nanoparticles served as novel carriers for stem cells and facilitated the targeted delivery of the drugs at the tumor site. Since the stem cell membrane-coated nanoparticles had good targeting and penetration abilities, they enhanced the efficiency of chemotherapeutic agents in tumor therapy and minimized the side effects.

Reactive oxygen species (ROS) based photodynamic therapy (PDT) is mediated by photosensitizers with laser irradiations. Previous reports mentioned the development of MSC membrane-based mesoporous silica up-conversion ([emailprotected]2) nanoparticles that efficiently targeted the tumor due to their high affinity after being coated with MSC membrane.

These cell membrane-coated nanoparticles showed high cytocompatibility (with hepatocyte cells) and hemocompatibility (with blood). Moreover, the [emailprotected]2 nanoparticles-based PDT therapy under 980-nanometer laser irradiations could inhibit the tumors in vivo and in vitro. Consequently, the stem cell membrane-coated nanoparticles had circulation for an extended time and escaped the immune system, thereby increasing their accumulation at the tumor site.

Stem cell membrane-coated nanoparticles were also applied to deliver small interfering RNA (siRNA) via magnetic hyperthermia therapy and imaging. Previous reports mentioned the preparation of superparamagnetic iron oxide (SPIO) nanoparticles using an MSC membrane that reduced the immune response.

Additionally, the CD44 adhesion receptors were preserved on the surface of the MSC membrane during preparation. These prepared nanovesicles were unrecognized by macrophages, which enabled their stability in blood circulation. The nanosize and tumor homing capacity of MSCs helped the nanovesicles generate a dark contrast in T2-weight magnetic resonance imaging (MRI).

Cell membrane-coated nanoparticles helped fabricate various targeted delivery strategies. Especially, stem cell membrane-coated nanoparticles have the following advantages: stem cells are easy to isolate and expand in vitro. Thus, multilineage potential and phenotypes could be preserved for more than 50 population doublings in vitro.

Stem cell membrane-coated nanoparticles also have an intrinsic capacity to target inflammation or tumor lesions. Hence, these nanoparticles were established for tumor therapy, building a strong foundation for stem cell membrane-mediated delivery systems.

On the other hand, stem cell membrane-coated nanoparticles have the following drawbacks: Despite various sources for collecting MSCs (UC-MSCs/BM-MSCs/ATMSCs), the number of cells obtained is limited, although iPSCs are relatively easy to fetch by reprogramming differentiated somatic cells, the reprogramming is a high-cost step, restricting the clinical applications of iPSCs.

Zhang, W., Huang, X. (2022). Stem cell membrane-camouflaged targeted delivery system in tumor. Materials Today Bio.https://www.sciencedirect.com/science/article/pii/S2590006422001752

Disclaimer: The views expressed here are those of the author expressed in their private capacity and do not necessarily represent the views of AZoM.com Limited T/A AZoNetwork the owner and operator of this website. This disclaimer forms part of the Terms and conditions of use of this website.

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Stem Cell Membrane-Coated Nanoparticles in Tumor Therapy - AZoNano

Bone Marrow Stem Cells Comments Off on Stem Cell Membrane-Coated Nanoparticles in Tumor Therapy – AZoNano | August 10th, 2022

HAEMOGLOBIN IS a protein in your red blood cells. Your red blood cells carry oxygen throughout your body. If you have a condition that affects your bodys ability to make red blood cells, your haemoglobin levels may drop. Low haemoglobin levels may be a symptom of several conditions, including different kinds of anaemia and cancer.

If a disease or condition affects your bodys ability to produce red blood cells, your haemoglobin levels may drop. When your haemoglobin level is low, it means your body is not getting enough oxygen, making you feel very tired and weak.

Normal haemoglobin levels are different for men and women. For men, a normal level ranges between 14.0 grams per decilitre (gm/dL) and 17.5 gm/dL. For women, a normal level ranges between 12.3 gm/dL and 15.3 gm/dL. A severe low-haemoglobin level for men is 13.5 gm/dL or lower. For women, a severe low haemoglobin level is 12 gm/dL.

Your doctor diagnoses low haemoglobin by taking samples of your blood and measuring the amount of haemoglobin in it. This is a haemoglobin test. They may also analyse different types of haemoglobin in your red blood cells, or haemoglobin electrophoresis.

Several factors affect haemoglobin levels and the following situations may be among them:

Your body produces red blood cells and white blood cells in your bone marrow. Sometimes, conditions and diseases affect your bone marrows ability to produce or support enough red blood cells.

Your body produces enough red blood cells, but the cells are dying faster than your body can replace them.

You are losing blood from injury or illness. You lose iron any time you lose blood. Sometimes, women have low haemoglobin levels when they have their periods. You may also lose blood if you have internal bleeding, such as a bleeding ulcer.

Your body cannot absorb iron, which affects your bodys ability to develop red blood cells.

You are not getting enough essential nutrients like iron and vitamins B12 and B9.

Your bone marrow produces red blood cells. Diseases, conditions and other factors that affect red blood cell production include:

Lymphoma: This is a term for cancers in your lymphatic system. If you have lymphoma cells in your bone marrow, those cells can crowd out red blood cells, reducing the number of red blood cells.

Leukaemia: This is cancer of your blood and bone marrow. Leukaemia cells in your bone marrow can limit the number of red blood cells your bone marrow produces.

Anaemia: There are many kinds of anaemias involving low-haemoglobin levels. For example, if you have aplastic anaemia, the stem cells in your bone marrow dont create enough blood cells. In pernicious anaemia, an autoimmune disorder keeps your body from absorbing vitamin B12. Without enough B12, your body produces fewer red blood cells.

Multiple Myeloma: This causes your body to develop abnormal plasma cells that may displace red blood cells.

Chronic Kidney Disease: Your kidneys dont produce the hormone that signals to your bone marrow to make red blood cells. Chronic kidney disease affects this process.

Antiretroviral medications: These medications treat certain viruses. Sometimes these medications damage your bone marrow, affecting its ability to make enough red blood cells.

Chemotherapy: Chemotherapy may affect bone marrow cells, reducing the number of red blood cells your bone marrow produces.

Doctors treat low haemoglobin by diagnosing the underlying cause. For example, if your haemoglobin levels are low, your healthcare provider may do tests that reveal you have iron-deficiency anaemia. If that is your situation, they will treat your anaemia with supplements. They may recommend that you try to follow an iron-rich diet. In most cases, treating the underlying cause of anaemia will bring the haemoglobin level up.

Many things can cause low haemoglobin, and most of the time you cannot manage low haemoglobin on your own. But eating a vitamin-rich diet can help maintain your red blood cells. Generally, a balanced diet with a focus on important nutrients is the best way to maintain healthy red blood cells and haemoglobin.

keisha.hill@gleanerjm.comSOURCE: Centres for Disease Control and Prevention

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Factors that affect haemoglobin levels and how to detect when it's low - Jamaica Gleaner

Bone Marrow Stem Cells Comments Off on Factors that affect haemoglobin levels and how to detect when it’s low – Jamaica Gleaner | August 10th, 2022

TCR-CAR+ iPSC-derived CD8 T Cells Induced Complete and Durable Responses In Vivo in Systemic Leukemia Model

Cell-surface Markers, Gene Transcription Profile, and In Vivo Anti-tumor Activity of TCR-CAR+ iPSC-derived CD8 T Cells Compared Favorably with Healthy-donor Peripheral Blood CAR T Cells

Phase 1 Study Ongoing of First-ever iPSC-derived T-cell Product Candidate FT819 for Off-the-shelf Treatment of Patients with Relapsed / Refractory B-cell Malignancies

SAN DIEGO, Aug. 09, 2022 (GLOBE NEWSWIRE) -- Fate Therapeutics, Inc. ( FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for patients with cancer, today announced the publication of preclinical study results demonstrating the successful generation, durable anti-tumor response, and functional persistence of TCR-CAR+ iPSC-derived CD8 T cells from induced pluripotent stem cells (iPSCs). The CD8 T cells were derived from a single engineered iPSC integrating a novel chimeric antigen receptor (CAR) transgene into the T-cell receptor alpha constant (TRAC) locus, ensuring complete bi-allelic disruption of T-cell receptor (TCR) expression and promoting uniform CAR expression. The discoveries were made under a multi-year research collaboration between the Company and Memorial Sloan Kettering Cancer Center (MSK) led by Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering and Head, Gene Expression and Gene Transfer Laboratory, and were published this week in Nature Biomedical Engineering.

Scientists have previously differentiated induced pluripotent stem cells to form CAR T cells, however, it was observed that premature TCR or constitutive CAR expression resulted in the derivation of innate-like T cells that do not acquire the phenotype nor exhibit the function of conventional CD8 T cells, said Dr. Sadelain. Our published findings are the first to show the generation of iPSC-derived CD8 CAR T cells lacking a TCR, where timed and calibrated expression of the CAR in place of the TCR successfully drove T-cell maturation and promoted the acquisition of a transcriptional and functional profile more closely resembling that of natural CD8 T cells.

The mass production of TCR-CAR+ CD8 T cells from master engineered iPSC lines is a promising approach for development of off-the-shelf, cell-based cancer immunotherapies. Through a systematic assessment of factors that affect T-cell lineage commitment and induce adaptive T-cell formation, the researchers discovered that integrating the CAR construct into the TRAC locus delayed its expression and drove T-cell lineage commitment, and that regulation of CAR signaling strength promoted the generation of CD4+CD8+ double-positive cells mimicking thymic development in the absence of a TCR. Subsequent stimulation of the CAR matured the double-positive population into single-positive CD8 T cells with a phenotype highly correlated with peripheral blood CD8 effector T cells and distinct from T cells and natural killer cells. Preclinical studies showed that iPSC-derived TCR-CAR+ CD8 T cells were able to repeatedly lyse tumor cells in vitro and durably control leukemia in vivo, with persistence in the bone marrow, spleen, and blood, in a systemic NALM6 leukemia model.

These published findings continue to support our unique ability to generate TCR-CAR+ CD8 T cells from master engineered iPSC lines that exhibit a phenotypic profile and anti-tumor activity comparable to healthy donor-derived peripheral blood CAR T cells in preclinical model systems, said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. We believe our off-the-shelf, iPSC-derived CAR T cell programs overcome the numerous challenges associated with the manufacture, consistency, and reach of autologous and allogeneic CAR T cells, and we look forward to sharing initial clinical data from our landmark Phase 1 study of FT819 later this year.

The Company is conducting a multicenter Phase 1 study of FT819, the first T-cell therapy manufactured from a clonal master iPSC line to undergo clinical investigation. The product candidates clonal engineered master iPSC line is created from a single iPSC that has a novel CD19-targeted 1XX CAR construct integrated into the TRAC locus, ensuring complete bi-allelic disruption of TCR expression to prevent graft-versus-host disease and promoting uniform CAR expression for enhanced anti-tumor activity. Dose escalation is currently ongoing in single-dose and multi-dose escalation cohorts for relapsed / refractory B-cell malignancies.

Pursuant to a license agreement with MSK, Fate Therapeutics has an exclusive license for all human therapeutic use to U.S. Patent No. 10,370,452, which covers compositions and uses of effector T cells expressing a CAR, where such T cells are derived from a pluripotent stem cell including an iPSC. In addition to the patent rights licensed from MSK, the Company owns an extensive intellectual property portfolio that broadly covers compositions and methods for the genome editing of iPSCs using CRISPR and other nucleases, including the use of CRISPR to insert a CAR in the TRAC locus for endogenous transcriptional control.

Fate Therapeutics has licensed intellectual property from MSK on which Dr. Sadelain is an inventor. As a result of the licensing arrangement, MSK has financial interests related to Fate Therapeutics.

About Fate Therapeutics iPSC Product PlatformThe Companys proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that are designed to be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Companys first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Companys platform is uniquely designed to overcome numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics iPSC product platform is supported by an intellectual property portfolio of over 350 issued patents and 150 pending patent applications.

About FT819FT819 is an investigational, universal, off-the-shelf, T-cell receptor (TCR)-less CD19 chimeric antigen receptor (CAR) T-cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line, which is engineered with the following features designed to improve the safety and efficacy of CAR19 T-cell therapy: a novel 1XX CAR signaling domain, which has been shown to extend T-cell effector function without eliciting exhaustion; integration of the CAR19 transgene directly into the T-cell receptor alpha constant (TRAC) locus, which has been shown to promote uniform CAR19 expression and enhanced T-cell potency; and complete bi-allelic disruption of TCR expression for the prevention of graft-versus-host disease. FT819 demonstrated antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines comparable to that of primary CAR T cells, and persisted and maintained tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia. FT819 is being investigated in a multicenter Phase 1 clinical trial for the treatment of relapsed / refractory B-cell malignancies, including B-cell lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia (NCT04629729).

About Fate Therapeutics, Inc.Fate Therapeutics is a clinical-stage biopharmaceutical company dedicated to the development of first-in-class cellular immunotherapies for patients with cancer. The Company has established a leadership position in the clinical development and manufacture of universal, off-the-shelf cell products using its proprietary induced pluripotent stem cell (iPSC) product platform. The Companys immuno-oncology pipeline includes off-the-shelf, iPSC-derived natural killer (NK) cell and T-cell product candidates, which are designed to synergize with well-established cancer therapies, including immune checkpoint inhibitors and monoclonal antibodies, and to target tumor-associated antigens using chimeric antigen receptors (CARs). Fate Therapeutics is headquartered in San Diego, CA. For more information, please visit http://www.fatetherapeutics.com.

Forward-Looking StatementsThis release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 including statements regarding the advancement of and plans related to the Company's product candidates, clinical studies and preclinical research and development programs, the Companys progress, plans and timelines for the manufacture and clinical investigation of its product candidates, the Companys initiation and continuation of enrollment in its clinical trials including additional dose cohorts in ongoing clinical trials of its product candidates, the therapeutic and market potential of the Companys product candidates, and the Companys clinical development strategy, including for its product candidate FT819. These and any other forward-looking statements in this release are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that the Companys product candidates may not demonstrate the requisite safety or efficacy to warrant further development or to achieve regulatory approval, the risk that results observed in prior studies of the Companys product candidates, including preclinical studies and clinical trials, will not be observed in ongoing or future studies involving these product candidates, the risk of a delay or difficulties in the manufacturing of the Companys product candidates or in the initiation and conduct of, or enrollment of patients in, any clinical trials, the risk that the Company may cease or delay preclinical or clinical development of any of its product candidates for a variety of reasons (including requirements that may be imposed by regulatory authorities on the initiation or conduct of clinical trials, changes in the therapeutic, regulatory, or competitive landscape for which the Companys product candidates are being developed, the amount and type of data to be generated or otherwise to support regulatory approval, difficulties or delays in patient enrollment and continuation in the Companys ongoing and planned clinical trials, difficulties in manufacturing or supplying the Companys product candidates for clinical testing, and any adverse events or other negative results that may be observed during preclinical or clinical development), the risk that results observed in preclinical studies of FT819 may not be replicated in ongoing or future clinical trials, and the risk that FT819 may not produce therapeutic benefits or may cause other unanticipated adverse effects. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Companys actual results to differ from those contained in the forward-looking statements, see the risks and uncertainties detailed in the Companys periodic filings with the Securities and Exchange Commission, including but not limited to the Companys most recently filed periodic report, and from time to time in the Companys press releases and other investor communications. Fate Therapeutics is providing the information in this release as of this date and does not undertake any obligation to update any forward-looking statements contained in this release as a result of new information, future events or otherwise.

Contact:Christina TartagliaStern Investor Relations, Inc.212.362.1200[emailprotected]

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Fate Therapeutics Announces Preclinical Publication Highlighting Derivation of CD8 T Cells from TCR-CAR+ Induced Pluripotent Stem Cells -...

Bone Marrow Stem Cells Comments Off on Fate Therapeutics Announces Preclinical Publication Highlighting Derivation of CD8 T Cells from TCR-CAR+ Induced Pluripotent Stem Cells -… | August 10th, 2022

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BUDDY SCOTT: Love stems from the Father | Brazos Living | thefacts.com - Brazosport Facts

Bone Marrow Stem Cells Comments Off on BUDDY SCOTT: Love stems from the Father | Brazos Living | thefacts.com – Brazosport Facts | August 10th, 2022

The media continues the one-handed count of patients that seem to be cured of HIV as a man who has lived with the disease since the 1980s has been in remission for 17 months.

The story is always the samethey seem to be cured, and they get a cool nicknamein this case the City of Hope Patient, after Duarte, California, where he was treated.

The difference in this case was the treatmenta bone marrow transplant to treat blood cancer leukemia from a donor who was naturally resistant to the virus.

The most remarkable difference however, is that he is only patient cured of HIV by coincidence.

The man had developed leukemia, and took the bone marrow transplant for that reason. As it happened, the donor was resistant to HIV, and taught the mans body to create an immune response against the virus.

RELATED: Worlds Second Person Cured of HIV: 40-Year-old Man is Confirmed to Be 30 Months Virus-Free

This is also the first one who got it during the epidemic of HIV/AIDS that took so many lives.

When I was diagnosed with HIV in 1988, like many others, I thought it was a death sentence, said the City of Hope Patient. I never thought I would live to see the day that I no longer have HIV.

SIMILAR: Two Patients Make History After Essentially Being Cured of HIV Using Stem Cell Transplant

So far, only three people have been seemingly cured of human immunodeficiency virus (HIV) which weakens the bodys immune system and leads to the more severe AIDS (autoimmune deficiency syndrome) which can be lethal.

The man no longer takes antiretroviral drugs, the only treatment for HIV. A bone marrow transplant is not a likely future cure, do to it being a tricky and side-effectual procedure.

Nevertheless, all cure cases have been those where a patient is given a transplant of some kind, mostly stem cells, that contain the very rarely occurring natural immunity to the virus.

The case was reported at the AIDS 2022 conference in Montreal, Canada.

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Fourth Patient Seemingly Cured of HIV Through Wild Coincidence - Good News Network

Bone Marrow Stem Cells Comments Off on Fourth Patient Seemingly Cured of HIV Through Wild Coincidence – Good News Network | August 10th, 2022

MANY people suffer with back pain, whether that's from poor posture or a sporting injury.

Teenager Daniel Greer had been struggling with this - as well as neck pain.

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But rather than an injury or pull - a blood test confirmed a shocking diagnosis.

The 14-year-old from Northern Ireland was told he had acute myeloid leukaemia two months ago.

Now his family are racing to find a stem cell donor - as this is his only chance of survival.

Since his diagnosis, the music fanatic has been staying at the Royal Belfast Hospital for Sick Children and is being treated with aggressive chemotherapy.

Doctors say that a stem cell transplant will help repair his immune system - but only one in four people will find a match within their own family.

His older brother James, sadly isn't a match so Daniel will need a transplant from an unrelated donor.

Mum, Anne, is now speaking out in the hopes of getting more people to sign up to the stem cell register - with the possibility of finding her son a donor.

She said: "Daniel is an amazing, bright young man who lights up any room he walks into.

"His wicked sense of humour keeps our spirits up, even now while hes in hospital receiving chemotherapy.

"I know hes really proud that his story is inspiring people to sign up to the stem cell register.

"Those people will potentially help him, as well as many other people around the world who desperately need a stem cell transplant like Daniel."

When it comes to the stem cell register, young men make up just 18 per cent of those on it, blood cancer charity Anthony Nolan states.

However, this demographic also makes up more than half of all stem cell transplants for blood cancer and blood disorder patients.

Now the charity is helping with an international appeal to get Daniel a donor, dubbed the DoItForDaniel campaign.

Daniel, lives in Newry and so far local pharmacies have got behind the campaign - urging people to sign up to help save the lives of others.

What is leukaemia?

Leukaemia is a type of blood cancer that affects cells in bone marrow and attacks the immune system.

In most cases of leukaemia, there is no obvious cause. Little Azaylia had been diagnosed with Acute Myeloid Leukaemia (AML) , which is a rapidly progressive form of the illness.

Leukaemia is a cancer that leads to the body making too many abnormal white blood cells and means the body is less likely to be able to defend itself against infection.

These blood cells are not fully developed and are called leukaemia cells.

The disease is often classified as the type of cell affected (myeloid or lymphatic) and how it progresses (acute or chronic).

There are four main types of leukaemia.

Acute Lymphocytic Leukaemia (ALL)-A rapidly progressing form of the disease.More common in children.

Acute Myeloid Leukaemia (AML) -Rapidly progressive. More common in adults.

Chronic Lymphocytic Leukaemia (CLL) -Slowly progressing form and more common in adults.

Chronic Myeloid Leukaemia (CML) -Progresses slowly and is more common in adults

There has also been an awareness-raising drive about stem cell donation at Belfast International Airport.

It's hoped that the drive will allow the keen mountain biker and rugby player to continue to do the things he enjoys most.

Anthony Nolan chief executive Henny Braund said that finding a matching donor would mean everything to Daniel and his family.

"We are committed to supporting Daniel as he waits for news of the donor who could save his life.

Last year over 1,300 people around the world with blood cancer or a blood disorder were given a second chance of life because of the wonderful people that are signed up to the Anthony Nolan register.

But too many people, like Daniel, are told there is no matching donor for them.

Signing up to the register is quick and simple, and we urge anyone who is in good general health, especially young men aged 16-30, to come forward and potentially save the life of someone like Daniel.

Anyone aged 16-30 can sign up online through the Anthony Nolan website.

DONATING STEM CELLS & SIGNING THE REGISTER

When you join a stem cell registry you are on standby to be matched and potentially save a life although many people are never called up.

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My little boy is fighting for his life after complaining of back pain you could save him... - The Sun

Bone Marrow Stem Cells Comments Off on My little boy is fighting for his life after complaining of back pain you could save him… – The Sun | August 10th, 2022

Type 1 diabetes (T1D) is a chronic immune-mediated disease characterized by the destruction of pancreatic -cells, resulting in absolute insulin deficiency and hyperglycemia. It is primarily a disease of youth, accounting for approximately 85% of cases in people under the age of 20 and 5% to 10% of all diagnosed cases of diabetes [1,2]. Although the exact mechanisms are unknown, T1D is thought to develop through immune system activation against -cell antigens and the initiation of proinflammatory cytokine responses. Environmental factors, obesity, viral infections, and nutritional factors were found to play a role in the pathophysiology as well [3]. T1D predisposes to a number of comorbidities, such as obesity, chronic kidney disease, metabolic syndrome, coronary artery disease, and hypertension. Such predispositions may account for higher mortality rates, affecting up to one in 10 adult patients within a year of diagnosis [4]. In fact, diabetic nephropathy (DN) is said to account for up to 40% of end-stage renal disease (ESRD) cases worldwide. Cardiovascular events account for up to 70% of T1D deaths and are 10 times more common in diabetics than in non-diabetics [5]. Therefore, it is critical to focus on novel therapies that aim to reduce the risks of acute complications such as hypoglycemia and diabetic ketoacidosis (DKA) while avoiding long-term complications such as DN, neuropathy, and retinopathy [5].

Exogenous insulin is currently the most prevalent treatment for T1D. Although exogenous insulin administration may be life-saving, it is not a cure for the disease. If patients are unable to maintain tight glycemic control by strictly adhering to their insulin regimen, they will invariably develop severe secondary complications that may shorten their life span [6]. Exogenous insulin is not a viable substitute for normal pancreatic islet function, mainly due to the absence of accurate temporal glucose control over time [7]. The administration of insulin can also result in hypoglycemic episodes [6]. A cross-sectional study conducted in Mexico revealed that patients' fear of hypoglycemic episodes prevented them from complying with their insulin treatment plan [8].

Replacement of the defective insulin-producing cells (IPC) is yet another potential therapy for T1D. This is possible through transplantation of the pancreas. Since the first pancreatic transplant took place in 1966, over 50,000 such transplants have been performed worldwide. Patients with T1D who receive a pancreatic transplant were found to have a reduced risk of subsequent complications and a longer life expectancy [9]. However, since transplantation is a major surgical procedure, patients must be fit for surgery [6]. Transplants necessitate permanent immunosuppression, which may put patients at risk for a variety of infections. In addition, they are associated with a number of postoperative complications, such as pancreatitis, due to low tolerance to cold ischemia, bleeding, thrombosis, and anastomotic leakage, which may require relaparotomy and graft pancreatectomy in recipients [9].

An alternative to pancreatic transplantation that is both safe and effective is islet cell transplantation. Scharp et al. published the first case of allogeneic intraportal islet transplantation for T1D in 1990, which led to short-term insulin independence and paved the way for clinical islet transplantation [10]. Despite the fact that the immunosuppressive regimen reported from Edmonton, Canada, also known as the Edmonton protocol (the Edmonton protocol introduced significant adjustments to the transplantation procedure, including the use of an immunosuppressive regimen free of steroids and the transplanting of an average islet mass of 11,000 islet equivalents per kilogram) has achieved unprecedented success in islet transplantation in terms of insulin independence, a number of factors continue to influence the outcome of this minimally invasive procedure [11]. Islet cell transplantation can induce a rapid inflammatory reaction in the circulation, leading to the loss of the vast majority of transplanted islets. The use of large doses of immunosuppressants during transplantation compromises the long-term viability and function of the graft, and the need for long-term immunosuppressive medications after the transplant poses a risk of organ damage, malignancies, new infections, and new-onset T1D in patients [12]. The high cost of islet transplantation and the paucity of human cadaveric islets highlight the urgent need for innovative pancreatic islet transplantation procedures [7]. This is where stem cells (SCs) pose an important role.

SCs are a highly promising novel treatment for T1D due to their ability to differentiate into several cell types and their regenerative potential. SCs can be categorized into four basic groups based on their origin as shown in Figure 1.

Mesenchymal stem cells (MSCs), also called mesenchymal stromal cells, are non-hematopoietic, multipotent SCs. They can be extracted from a variety of sources, including bone marrow, liver, kidney, adipose tissue, urine, umbilical cord blood, umbilical tissue, Wharton's jelly, placenta, and even endometrial tissue (menstrual blood-derived endometrial stem cells - MenSC). Several surface markers, including CD73, CD90, and CD105, can be utilized to identify MSCs. Due to their ability to differentiate into numerous cell types, they can be used to repopulate damaged tissues [13,14]. MSCs have gained enormous popularity in the treatment of T1D because of their ability to regulate fibrosis and tissue regeneration, as well as their ability to modulate immunological function. In addition, they produce a variety of secretory molecules, such as cytokines and exosomes, which play an essential role in the treatment of T1D [15]. Studies on animals treated with MSCs have shown a significant reduction in hyperglycemia, as evaluated by a decrease in serum glucose and an increase in insulin and C-peptide levels. In addition, they were able to restore normal levels of lipid fractions. Using MSCs lowered the serum levels of both liver and kidney function markers in diabetic rats, demonstrating their hepato-renal protective benefits in T1D [16].

Several mechanisms have been discovered to play a role in the management of T1D by MSCs (Figure 2).

MSCs, such as bone marrow stromal cells, promote angiogenesis through the secretion of cytokines such as basic fibroblast growth factor and vascular endothelial growth factor (VEGF) [17]. In addition, they play a crucial role in immunomodulation by moving to areas of inflammation and modifying the phenotype of dendritic cells (DC), T cells, B cells, and natural killer cells. They downregulate proinflammatory cytokines and escape CD8+ T cell-mediated apoptosis, inhibit maturation of DC, while reducing T-lymphocyte proliferation via transforming growth factor-beta 1 (TGF-1), hepatocyte growth factor, and nitric oxide. By stimulating the production of regulatory T cells, TGF-1 plays a significant role in the immunomodulation of MSCs. MSCs have also been found to improve the function, survival, and graft outcome of neonatal porcine islets by increasing the expression of genes involved in the formation of endocrine cells, insulin, and platelet-derived growth factor alpha (PDGFR-). PDGFR- suppresses Notch 1 signaling (Notch 1 downregulates transcription factors involved in the formation of endocrine cells and insulin), resulting in the maturation and development of islet cells [18]. Zhou et al. discovered that wild-type p53-induced phosphatase 1 (a serine/threonine phosphatase) regulates the immunomodulatory properties of MSCs via the expression of interferon-alpha and bone marrow stromal cell antigen 2, consequently playing an important role in the therapeutic effects of MSCs in T1D [19].

Even though studies have shown that MSCs are capable of reconfiguring the immune system, they must be rescued to some extent from immune-mediated destruction, indicating that immunomodulation will be necessary even if a viable MSCs therapy for T1D is produced [20]. When using -cells from an allogeneic stem cell source, an alloreactive response to donor antigens will be generated unless we obtain SCs from the patient's own cells. To circumvent this, researchers have investigated encapsulation strategies employing semipermeable immune barriers to provide immune shielding and prevent graft rejection [21]. Some studies have also demonstrated that the use of suicide genes together with stem cell transplants promotes functional immune reconstitution and thereby prevents graft-versus-host disease in patients [22].

It has been demonstrated that MSCs undergo apoptosis in the circulation of the host or in engrafted tissues following delivery to the patient's body, which plays a significant part in their therapeutic role in T1D. During the execution of apoptosis, apoptotic extracellular vesicles (apoEVs), formerly known as apoptotic bodies, have emerged as regulators of numerous biological processes, as opposed to being only debris. Specifically, apoEVs have been shown to regulate T cell and macrophage immunological function as well as stimulate tissue repair, including skin regeneration and vascular protection [23].

This game-changing discovery of MSCs in the treatment of T1D has propelled biological sciences to a new level of sophistication, allowing for the manipulation of cell fate and the cultivation of higher-order cellular structures. However, there is still a huge gap regarding its application in actual clinical practice.

We were only able to find 12 clinical trials on PubMed that evaluated the use of MSCs in the treatment of T1D. Ten of the 12 studies were undertaken in Asia, primarily in China and India. To date, the exact pathogenesis of T1D is not fully understood. Genetic factors have been found to play a role in the development of T1D, which may have affected the outcomes of previous clinical trials. Therefore, conducting multiple different studies worldwide would not only enable us to identify the effects of ethnicity and genetics on the response to MSC therapy in T1D patientsbut also help us to generalize the efficacy of MSCs to the entire population. In order to achieve the best outcomes while using medications to treat T1D, it is also crucial to perform additional research to more clearly identify the pathophysiology of T1D.

In the course of studying the patient selection criteria utilized in clinical trials, we made a fascinating discovery. We found that every clinical study had excluded patients with immunosuppression, viral illnesses such as hepatitis B and C, comorbidities including hematologic diseases, rheumatologic diseases, and kidney diseases, and pregnant patients, all of which could have influenced the results of the studies. Our present understanding of the action of apoEVs, as described by Fu et al., leads us to believe that in order for MSCs to undergo apoptosis, their recipients must be able to initiate apoptotic activity [23]. In order for this to occur, patients must have a particular number of cytotoxic T cells or natural killer cells; hence, patients who do not meet this criterion are unlikely to benefit from MSC delivery. To further elucidate the mechanisms of action of MSCs, it is essential to undertake additional studies with immunosuppressed patients in order to identify the optimal cohort of T1D patients for MSC therapy. In addition, further clinical research should be conducted to uncover the apoptotic signals that stimulate tissue regeneration and angiogenesis, as recognizing these signals would allow us to utilize a channel in parenchymal tissue to increase its regeneration capacity.

We also observed that the majority of trials exclusively enrolled patients with recent-onset T1D. A study conducted in Iran revealed that early transplantation of MSCs resulted in superior outcomes for T1D patients compared to late transplantation. This may be due to the honeymoon phase of diabetes, which may have obscured the effects of MSCs in these studies [24]. The honeymoon phase is the period during which a person with T1D appears to improve and may only require minimal amounts of insulin or experience normal or near-normal blood sugar levels without insulin. To extrapolate the results to a larger population and unmask the effects of the honeymoon period, it is necessary to conduct trials on patients with late-onset T1D.

To date, the exact mechanism by which MSCs contribute to the remission of T1D has not been identified; therefore, further research is required to get a better knowledge of mechanisms such as immunomodulation, homing, and paracrine signaling of MSCs. It is also vital to undertake studies to discover the appropriate number of MSCs, injection frequency, and optimal infusion route in order to maximize results. Cai et al. concluded that pancreatic arterial transfusion would assist in avoiding the first pass pulmonary effect of MSCs, hence lowering the sequestration of MSCs in the lungs and allowing for optimal results [25].

A few studies have used 3D microspheres to increase the proliferation capacity of MSCs with positive results. However, there is insufficient information available regarding the proliferation capacity, revascularization, efficiency of differentiation, and survival time of MSCs. Therefore, conducting studies to elucidate these aspects of MSC therapy is an urgent necessity. We would also be able to learn more about the graft's survival time and tumorigenic potential if we followed the patients for a longer period of time.

Patient-specific variables such as age, body mass index, lifestyle, socioeconomic status, level of activity, diet, autoimmune status, and drug interactions must be taken into consideration while conducting studies and analyzing data. In order to identify the ideal conditions necessary to create the desired quantities of MSCs to achieve remission of T1D, future research must also incorporate in-depth information regarding external factors that affect the viability of MSCs, such as storage conditions, plating density, and culture media.

In this article, we aim to discuss the role of MSCsderived from various tissues in the treatment of T1D, as well as their feasibility and limitations.

We present a summary of the extraction methods, advantages, limitations, and outcomes from several studies of MSCs derived from various types of tissues.

The majority of umbilical cord tissue-derived stem cells (UC-MSCs) are found in the subcortical endothelium of the umbilical cord, the perivascular area, and Wharton's jelly [26]. According to studies, roughly1 106UC-MSC can be extracted from a 20 cm human umbilical cord [27]. MSCs isolated from Wharton's jelly have been grown for over 80 population doublings without showing any signs of senescence, morphological alterations, an increase in growth rate, or a change in their ability to develop into neurons. Recent research has demonstrated that xenotransplantation of post-differentiated human UC-MSC without immunosuppressive therapy does not result in rejection [28]. This lack of immunogenicity may be attributable to the absence of major histocompatibility II and co-stimulatory molecules such as CD80 (B7-1), CD86 (B7-2), and CD40 [29]. Chao et al. successfully differentiated human UC-MSC into clusters of mature islet-like cells with insulin-producing capacity. In the islet cells, they detected an increase in insulin and other -cell-related genes, including Pdx1, Hlxb9, Nkx2.2, Nkx6.1, and Glut-2. Moreover, they discovered that hyperglycemia in diabetic rats was greatly under control after xenotransplantation of human pancreatic islet-like cell clusters [28]. Patients with newly diagnosed T1D who received repeated intravenous doses of allogeneic UC-MSC showed improved islet cell preservation and a significant rise in postprandial C-peptide levels. However, C-peptide levels did not alter significantly in patients with juvenile-onset T1D. The number of UC-MSC contributed more than other indicators to the prediction of clinical remission, bolstering the evidence of dose-dependent therapeutic efficacy. Therefore, appropriate doses and courses of MSC transplantation should be granted importance in future research [30].

UC-MSC can also be used to treat chronic complications of T1D, such as neuropathy, DN, and retinopathy [31]. Studies have shown that intraperitoneal injection of human UC-MSC can ameliorate renal injury in streptozotocin-induced diabetic mice.[32]. A mice study conducted in China demonstrated that the combination of human UC-MSC and resveratrol can better protect renal podocyte function and the resulting reduction in blood glucose levels and renal damage is superior to those obtained with insulin administration [33]. This suggests that the combination of resveratrol and human UC-MSC may be an innovative technique for treating T1D; however, additional research on humans is necessary to determine the effects of this combination treatment on the management of DN.Another investigation involving mice revealed that UC-MSC therapy restored erectile function by suppressing toll-like receptor 4, alleviating corpora cavernosa fibrosis, and boosting the production of VEGF and endothelial nitric oxide synthase [34]. Nonetheless, a significant advantage of UC-MSC is that they are a rich source of many SCs that can be easily manipulated [27]. They are collected at delivery by clamping and severing the umbilical cord. There are no ethical concerns regarding the use of UC-MSC because the collecting process is non-invasive and retains material that would otherwise be discarded as waste.

Adipose tissue-derived mesenchymal stem cells (ADSCs) are a group of cells that arise from the mesoderm during embryonic development. Amongst several types, subcutaneous adipose tissue seems to be the most clinically relevant source, being available in abundance for harvest, and its isolation only slightly invasive [35,36].

While two major kinds of adipose tissue (white and brown) have been isolated and studied, we focus on white adipose, which produces ADSCs, as brown adipocytes have not yet demonstrated an association with insulin resistance. White adipose tissue expressing uncoupling protein 2 (an isoform of uncoupling protein 1in brown adipose) acts as a storage of excess energy in the form of triglycerides and is thus prone to causing obesity and abnormalities in metabolic pathways such as insulin resistance during hyperplasia [37].

The extracted cell group of interest consists of a putative stem cell population of fibroblast-like cells known as processed lipoaspirate (PLA), found within the stromal compartments of adipose tissue [38]. Obtaining the sample requires lipoaspiration, and although the technique does not negatively affect the function of ADSCs, the vacuum process involved can cause damage to mature adipocytes [37]. Studies have shown that successfully extracted PLA can then differentiate in vitro into multiple cell lineages (including adipogenic, myogenic, chondrogenic, and osteogenic cells), thus providing another source of SCs with multi-germ-line potential instead of the traditional bone marrow-derived MSCs [38-41]. The discovery of the ability of ADSCs to efficiently differentiate into IPC has shed new light on the approach to T1D management [41].

ADSCs utilization can help avoid ethical barriers and tumorigenic complications that are increasingly encountered during stem cell isolation from embryos and induced pluripotent SCs [36]. Yet another advantage of ADSCs for their therapeutic application happens to be the relatively painless procedure and high yields in harvested cell numbers compared to bone marrow procurement [40]. These cells are devoid of human leukocyte antigen-DR expression and therefore have been successfully transplanted via intravenous, intraperitoneal, and renal capsule administration in mice without the need for immunosuppression [36,42].

Insulin replacement therapy with the help of co-transplantation of insulin-secreting ADSCs has been studied as an alternative to lifelong insulin therapy. As with multiple studies, no adverse effects were observed with ADSCs infusion, and in fact, an impressive absence of DKA episodes in all participants was seen [43]. A prospective study conducted in 2015 on 20 patients with T1D found better diabetic control (hemoglobin A1c levels) and sustained improvements in fasting blood sugar, postprandial blood sugar, hemoglobin A1c, and C-peptide levels with the transplantation of autologous insulin-secreting ADSCs [44]. Dantas et al. concluded that combination therapy with ADSCs and Vitamin D (daily cholecalciferol for six months) without immunosuppression was safe, demonstrated immunomodulatory effects, and may play a role in -cell preservation in patients with newly diagnosed T1D [45]. The significant functional and morphological improvements in islet cells as early as two months after transplantation of IPC clusters derived from ADSCs point to the promising nature of this therapeutic approach for achieving target normoglycemia [46,47]. A recent study conducted in 2022 discovered that systemic administration of ADSCs protects male non-obese diabetic (NOD) mice against diabetes induced by programmed death-1 and programmed death-ligand 1 (PD-1/PD-L1) inhibition. Multiple injections of neutralizing antibodies against mouse PD-L1 induce a significant infiltration of immune cells in the islets and a decrease in the -cell area and insulin content of the pancreas. Despite this, systemic ADSCinjection partially protected the pancreas from -cell loss and preserved insulin content, indicating therapeutic potential in T1D [15].

Apart from the therapeutic uses in T1D, the ADSCtherapy has also been shown to reduce adverse effects brought about by complications such as DN and ESRD [48,49]. Inactivation of nuclear factor kappa B pathways and downregulation of VEGF-A, amongst others, are the major mechanisms involved in ameliorating the pathological manifestations of mice with DN [50].

The problem remaining, however, is the inability to become totally free of exogenous insulin. Research suggests that a much larger dose of IPC may be required for a sustained cure of T1D using ADSCs [51]. Therefore, the need of the hour is to conduct further research, placing emphasis on ways to either enhance the production of insulin in IPC derived from ADSCs or alter cell signaling pathways to obtain a greater number of IPC from ADSCs.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are a type of adult stem cell that is abundant in bone marrow and has low immunogenicity [52]. Bone marrow stem cells are broadly categorized into hematopoietic stem cells and MSCs. These cells are sourced from the same individual, potentially minimizing rejection problems and making it a form of therapy for T1D [53]. BM-MSCs can differentiate into functionally competent -cells in vivo, and NOD mouse studies have shown the formation of normal T cell and B cell function, implying that allogeneic bone marrow transplant could prevent islet destruction and restore self-tolerance [54,55]. Because of their well-documented hypoimmunogenic and immunomodulatory properties, BM-MSCs are an appealing therapeutic option for T1D [56].

One study looked at T1D patients with DKA and found BM-MSCs to preserve -cell function in T1D patients, reducing levels of fasting and post-prandial C-peptide levels, with one patient achieving insulin independence for a period of three months [57].

BM-MSCs have been demonstrated to mitigate the effects of metabolic and hepato-renal abnormalities, enhance lipid profiles, and improve carbohydrate and glycemic management. Following an eight-week period of injections with BM-MSCs in diabetic rats, an improvement was observed in their lipid profiles compared to diabetic rats that were not treated with BM-MSCs [16]. In addition, BM-MSCs therapy has been demonstrated to ameliorate diabetes-related liver damage by boosting endogenous hepatocyte regenerative mechanisms and enhancing liver function [58].

BM-MSCs have also been shown to effectively treat comorbidities of T1D, such as DN, poor wound healing, and erectile dysfunction (ED). Nagaishi et al. investigated a novel approach of mixing BM-MSCs with umbilical cord extracts in Wharton's Jelly to enhance the therapeutic effect of ameliorating renal injury in T1D patients with DN. The study demonstrated morphological and functional improvements of diabetes-derived BM-MSC in vitro and a therapeutic impact on DN in vivo, suggesting that this may be beneficial not only for patients with DN but also for patients with other diabetic complications [59]. One study looked to address the problem of impaired epithelial wound healing in T1D patients and found that BM-MSCs promote corneal epithelial wound healing via tumor necrosis factor-inducible gene 6-dependent stem cell activation [60]. Another promising phase I pilot clinical trial found that treating ED in T1D patients with two consecutive intracavernous injections of autologous BM-MSC was safe and effective [61].

Currently, several potential therapeutic approaches are being postulated to approach this issue of T1D from a new viewpoint. Suicide gene therapy is a strategy with potential. This method involves the introduction of suicide-inducing transgenes into the body via BM-MSC. As a result, several processes will be induced, including the suppression of gene expression, the production of intracellular antibodies that block the essential pathways of cells, and the transgenic expression of caspases and deoxyribonucleases. Current clinical trials are examining strategies to restore damaged organs with the use of stem cells as the delivery mechanism [62].

The idea of transplanting BM-MSCs provides patients with hope. Particularly significant are autologous BM-MSC (which are easy to obtain and avoid graft rejection after transplantation) in contrast to allogeneic BM-MSC transplantations, which may result in graft rejection and be accompanied by complications [52]. For stem cell therapy to be most beneficial, early delivery of stem cells following a diagnosis of T1D is necessary compared to intervention at later stages [63].

Table 1compares the properties of MSCs derived from the bone marrow, umbilical cord, and adipose tissue.

Recent research has demonstrated that menstrual blood-derived endometrial stem cells (MenSCs) have therapeutic promise for the treatment of T1D due to their exceptionally high rates of proliferation, noninvasive collection method, and significant immunomodulatory activity. In T1D model mice, MenSC and UC-MSC transplantation resulted in a significant decrease in blood glucose and insulin levels, as well as an improvement in the morphology and function of the liver, kidneys, and spleen [14]. A 2021 study found that MenSCs expressed pancreatic -cell genes such as INSULIN, GLUT-2, and NGN-3 and had a greater capacity to develop into pancreatic cells [64].

Dental pulp-derived mesenchymal stem cells (DP-MSCs) are one of the unique MSCs proposed for the treatment of T1D. DP-MSCs are derived from exfoliated human deciduous teeth and have the properties of being easy to obtain with minimal donor injury. In a study by Mo et al. DP-MSCs revealed the ability to differentiate into pancreatic -cells; nevertheless, before proceeding with larger-scale investigations to firmly establish this approach, it is necessary to devise procedures for optimal -cell differentiation in-vivo [65].

An in-vivo study revealed that conjunctiva-derived mesenchymal stem cells (C-MSCs) efficiently differentiated into pancreatic islet stem cells in 2D cultures and 3D scaffolds under optimal induction conditions. C-MSCs have a strong proliferative capacity, a spindle shape, a high potential for clonogenic differentiation, and are widely available. However, larger in vitro studies are necessary before C-MSCs can be deemed an established treatment for T1D [64].

Table 2 lists all clinical trials that have utilized MSCs in the treatment of T1D and complications related to T1D (Table 2).

Our article relies on a survey of free full-text research journals over the past decade; consequently, it is possible that we have omitted pertinent information from paid full-text as well as research articles published prior to 2010.In addition, the scope of this study is confined to studies in the English language, so we may have overlooked papers published in other languages.

MSCs are postulated to act in T1D and numerous other disorders through diverse mechanisms. Among these are homing and immunomodulation. Our review revealed that MSCs not only effectively reduce fasting blood sugar, C-peptide, and hemoglobin A1c levels but are also capable of treating microvascular complications associated with T1D. However, the specific pathophysiology of T1D diabetes is still unknown, making it difficult to develop novel treatments. To achieve remission of T1D, we must also consider the effects of additional factors on the efficacy of MSCs, including patient-specific variables such as age, body mass index, lifestyle, socioeconomic status, level of activity, diet, autoimmune status, and drug interactions, as well as external factors such as storage conditions, plating density, and culture media. Therefore, it is urgent to conduct larger-scale studies.

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The Role of Mesenchymal Stem Cells in the Treatment of Type 1 Diabetes - Cureus

Bone Marrow Stem Cells Comments Off on The Role of Mesenchymal Stem Cells in the Treatment of Type 1 Diabetes – Cureus | August 2nd, 2022

CASE SUMMARY

A 54-year-oldwoman presented with Revised International Staging System stage II multiple myeloma, based on evaluations that showed a hemoglobin level of 7.0 g/dL, 2-microglobulin of 6 mg/dl, albumin 3.2 g/dL, calcium 11.3 mg/dL, lactate dehydrogenase of 200 U/L, and creatinine clearance of 45 mL/min. Bone marrow showed 22% clonal plasma cells. Serum kappa free light chains were 24 mg/dL. She had no cytogenetic abnormalities and an ECOG performance score of 1. A PET/CT scan showed multiple bone lesions in the vertebrae. She had no extramedullary disease. She was diagnosed with IgG-kappa myeloma and was considered transplant eligible.

Daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Dara-VRd) induction therapy was initiated. She achieved a very good partial response (VGPR) post induction therapy. She underwent stem cell mobilization and 2 months later underwent autologous stem cell transplant (ASCT). Her post-ASCT response was a VGPR.

DISCUSSION QUESTIONS

CAITLIN COSTELLO, MD: This patient did get a quadruplet regimen with dara-VRd. She achieved a VGPR post-induction, had stem cells mobilized, underwent her transplant, and post-transplant her response is a VGPR. What would you do next?

THOMAS DEKKER, MD: Consolidation with CAR [chimeric antigen receptor] T-cell therapy.

COSTELLO: With CAR T cell, sure. Youre going for it; I like it. This patient is post-transplant, they have a VGPR. The GRIFFIN study [NCT02874742] would give these patients consolidation with dara-VRd.

PREETI CHAUDHARY, MD: I would not do CAR T-cell therapy.

COSTELLO: What would you do?

CHAUDHARY: In my opinion, in multiple myeloma, patients do a maximum of 11 months with CAR T-cell therapy. It has a good response, but I dont think thats sustainable.

COSTELLO: I appreciate throwing ideas out there. That is not something we have an option to do right now. Its an interesting option, and something we can talk about; but yes, I agree with you. I think for the meantime, short of trials that are looking at doing CAR T-cell therapyparticularly for those patients who have not had an adequate response to transplant or consolidation, or patients who relapse shortly after their transplantI think the standard of care as it stands now is doing consolidation or trying to find a maintenance regimen to get them to minimal residual disease [MRD] negativity.

With all that being said, what are we going to do now for these patients? Weve talked about what these transplant eligible patients are getting consolidation and maintenance; weve talked about maintenance approaches for these patients who get quadruplets, to put them on doublets. Seeing all those deep response rates, is anyone getting cold on transplants? If we are going to get 90% remission rates, does anyone reconsider the role of transplant here?

PAMELA MIEL, MD: I dont make that call, meaning I still send patients to the transplant doctors to see if theyre going to proceed with the transplant or not. But, if theyre transplant eligible, they get referred.

COSTELLO: As a transplanter, I thank you for that. We want to see these patients, make the decisions, have the discussion with the patients so we can look at their risk/benefit profile, and understand their responses to their current therapy. So, please still send them in their third cycle, if not earlier, so we can have those discussions and make plans.

There are a lot of maintenance regimens that are out there, and different things to choose from; a whole other conversation in and of itself. Lenalidomide is the mainstay where we have an overall survival benefit, where we dont have it in any other maintenance regimens.1 But it does allow for the option of continued doublets. I think we will soon see daratumumab and lenalidomide as a doublet get added on to that maintenance therapy once we have some of these randomized trials that are going on that show the continued benefit of patients to get daratumumab in the maintenance setting if they did not receive it in the up-front setting.

DISCUSSION QUESTION

How likely are you to change your practice with respect to management of transplant eligible newly diagnosed myeloma?

DEKKER: I already use quadruplet.

MILAN SHETH, MD: I feel that we still need a lot of long-term data to get a better sense of what it is that were achieving with the quadruplet therapy. Im still not convinced everybody needs quadruplet therapy. I think somebody else had already said that we know were going to get better responses because were using great drugs, but do we need to use everything up-front? I feel like theres still a lot of unanswered questions here.

MIEL: Ive been wanting to put patients on quadruplet treatment. I dont know if you know Nina Shah, MD, over at UC San Francisco, but Ive attended some of her talks, and shes pushing for the quadruplet treatment. The only thing that changed my mind was that when I spoke to the transplant doctor at UC San Diego, he said, If its not very high-risk disease, Id go with VRd [bortezomib, lenalidomide, and dexamethasone]. So, I put the patient on VRd. But I probably would want to put someone on dara-VRd, given the chance.

COSTELLO: Yes. I think that my takeaway from the data has been that we would, of course, love long-term data to come out, butwe have to wait a long time for it. While were waiting for some of these phase 3 studies to go on, which are happening now to look at real randomized data, to play out, I find that this is just too intriguing to not do quadruplets for everybody now.

Since [these data were presented at [the 2021 American Society of Hematology annual meeting], Ive transitioned just about everyone whos at least transplant eligible over to quadruplet regimens now.2 Any patients who are on the fence, where Im not sure if theyre going to be eligible for transplant, I still will try and give them the benefit of a quadruplet regimen, and very quickly drop the bortezomib if I get worried about them, and end up with dara-Vd [daratumumab, lenalidomide, dexamethasone]. But I think these MRD negativity rates are just too good, and if that is going to be the true surrogate end point that were all aiming for, dara-VRd has been my go-to for the last 6-plus months or so for these patients, until someone tells me otherwise.

References

1. Ho M, Zanwar S, Kapoor P, et al. The effect of duration of lenalidomide maintenance and outcomes of different salvage regimens in patients with multiple myeloma (MM).Blood Cancer J. 2021;11(9):158. doi:10.1038/s41408-021-00548-7

2. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Blood. 2021;138(Suppl_1):79. doi:10.1182/blood-2021-149024

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Treating Multiple Myeloma Following Quadruplet Induction Therapy and ASCT - Targeted Oncology

Bone Marrow Stem Cells Comments Off on Treating Multiple Myeloma Following Quadruplet Induction Therapy and ASCT – Targeted Oncology | August 2nd, 2022

Researchers have revealed the cellular mysteries behind aging.

A new explanation for aging has been developed by researchers who have shown that genetic abnormalities that develop gradually over a lifetime cause substantial alterations in how blood is generated beyond the age of 70.

According to recent research, the drastic reduction in blood production beyond the age of 70 is likely caused by genetic alterations that steadily accumulate in blood stem cells throughout life.

Researchers from the Wellcome Sanger Institute, the Wellcome-MRC Cambridge Stem Cell Institute, and others have published a study that offers a new theory of aging in the journal Nature.

Somatic mutations, or alterations to the genetic code, occur in all human cells during the course of a lifetime. Aging is most likely caused by the accumulation of numerous sorts of damage to our cells over time, with one hypothesis proposing that the accumulation of somatic mutations causes cells to gradually lose functional reserve. However, it is still unknown how such slow-building molecular damage may result in the rapid decline in organ performance around the age of 70.

The Wellcome Sanger Institute, the Cambridge Stem Cell Institute, and collaborators examined the production of blood cells from the bone marrow in 10 people ranging in age from newborns to the elderly in order to better understand how the body ages.

3,579 blood stem cells had their whole genomes sequenced, allowing researchers to determine every somatic mutation present in each cell. Using this information, the team was able to create family trees of each persons blood stem cells, providing for the first time an impartial perspective of the connections between blood cells and how these ties develop over the course of a persons lifetime.

After the age of 70 years, the researchers discovered that these family trees underwent significant change. In adults under the age of 65, 20,000 to 200,000 stem cells contributed roughly equal amounts to the creation of blood cells. In contrast, blood production was exceedingly uneven in those above the age of 70.

In every elderly person investigated, a small number of enlarged stem cell clonesas few as 10 to 20contributed as much as half of the total blood output. Because of an uncommon class of somatic mutations known as driver mutations, these highly active stem cells have gradually increased in number during that persons life.

These findings led the team to propose a model in which age-associated changes in blood production come from somatic mutations causing selfish stem cells to dominate the bone marrow in the elderly. This model, with the steady introduction of driver mutations that cause the growth of functionally altered clones over decades, explains the dramatic and inevitable shift to reduced diversity of blood cell populations after the age of 70. Which clones become dominant varies from person to person, and so the model also explains the variation seen in disease risk and other characteristics in older adults. A second study, also published in Nature, explores how different individual driver mutations affect cell growth rates over time.

Dr. Emily Mitchell, Haematology Registrar at Addenbrookes Hospital, a Ph.D. student at the Wellcome Sanger Institute, and lead researcher on the study, said: Our findings show that the diversity of blood stem cells is lost in older age due to positive selection of faster-growing clones with driver mutations.

These clones outcompete the slower-growing ones. In many cases this increased fitness at the stem cell level likely comes at a cost their ability to produce functional mature blood cells is impaired, so explaining the observed age-related loss of function in the blood system.

Dr. Elisa Laurenti, Assistant Professor and Wellcome Royal Society Sir Henry Dale Fellow at the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge, and joint senior researcher on this study, said: Factors such as chronic inflammation, smoking, infection, and chemotherapy cause earlier growth of clones with cancer-driving mutations. We predict that these factors also bring forward the decline in blood stem cell diversity associated with aging. It is possible that there are factors that might slow this process down, too. We now have the exciting task of figuring out how these newly discovered mutations affect blood function in the elderly, so we can learn how to minimize disease risk and promote healthy aging.

Dr. Peter Campbell, Head of the Cancer, Ageing and Somatic Mutation Programme at the Wellcome Sanger Institute, and senior researcher on the study said: Weve shown, for the first time, how steadily accumulating mutations throughout life lead to a catastrophic and inevitable change in blood cell populations after the age of 70. What is super exciting about this model is that it may well apply to other organ systems too. We see these selfish clones with driver mutations expanding with age in many other tissues of the body we know this can increase cancer risk, but it could also be contributing to other functional changes associated with aging.

References: Clonal dynamics of haematopoiesis across the human lifespan by Emily Mitchell, Michael Spencer Chapman, Nicholas Williams, Kevin J. Dawson, Nicole Mende, Emily F. Calderbank, Hyunchul Jung, Thomas Mitchell, Tim H. H. Coorens, David H. Spencer, Heather Machado, Henry Lee-Six, Megan Davies, Daniel Hayler, Margarete A. Fabre, Krishnaa Mahbubani, Federico Abascal, Alex Cagan, George S. Vassiliou, Joanna Baxter, Inigo Martincorena, Michael R. Stratton, David G. Kent, Krishna Chatterjee, Kourosh Saeb Parsy, Anthony R. Green, Jyoti Nangalia, Elisa Laurenti, and Peter J. Campbell, 1 June 2022, Nature.DOI: 10.1038/s41586-022-04786-y

The longitudinal dynamics and natural history of clonal haematopoiesis by Margarete A. Fabre, Jos Guilherme de Almeida, Edoardo Fiorillo, Emily Mitchell, Aristi Damaskou, Justyna Rak, Valeria Orr, Michele Marongiu, Michael Spencer Chapman, M. S. Vijayabaskar, Joanna Baxter, Claire Hardy, Federico Abascal, Nicholas Williams, Jyoti Nangalia, Iigo Martincorena, Peter J. Campbell, Eoin F. McKinney, Francesco Cucca, Moritz Gerstung, and George S. Vassiliou, 1 June 2022, Nature.DOI: 10.1038/s41586-022-04785-z

The study was funded by Wellcome and the William B Harrison Foundation.

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Scientists Unlock the Secrets of Cellular Aging: What Happens After You Turn 70? - SciTechDaily

Bone Marrow Stem Cells Comments Off on Scientists Unlock the Secrets of Cellular Aging: What Happens After You Turn 70? – SciTechDaily | August 2nd, 2022

For those with cancer, the threat of serious illness from COVID-19 is often a major concern. Cancer treatments can weaken your bodys immune system, increasing your risk of a serious infection.

Immunotherapy is a type of cancer treatment that boosts and supports your immune system in responding against cancer. If you or a loved one is receiving immunotherapy treatment for cancer, you may have concerns about how the COVID vaccine may affect your immune system and your treatment.

This article will answer some common questions about immunotherapy cancer treatment and the COVID vaccines.

People with a weakened immune system due to cancer are at an increased risk for poor outcomes from COVID-19. No matter where you are in your treatment plan, vaccination can reduce your risk of developing severe COVID. Vaccination is important even for those with a robust immune system.

The National Comprehensive Cancer Network (NCCN) and the American Cancer Society recommend that people with cancer, including those receiving treatment, get vaccinated as soon as possible. NCCN notes a few exceptions regarding immediacy:

Since they weaken the immune system, some cancer treatments reduce but dont eliminate vaccine effectiveness. Even if youre getting one or more of these treatments, you will gain some protection from the vaccine. Treatments include:

Vaccination combined with protective measures, such as wearing a mask and avoiding large crowds, provides you with more protection from COVID than you would have without them. For that reason, experts strongly recommend vaccination for people with cancer or a history of cancer.

But check with your oncologist first about when you should get vaccinated. If you are currently receiving treatment for cancer, it may be best to wait until your immune system recovers from treatment. This will give you the best chance of mounting a strong immune response.

Both the Pfizer BioNTech and the Moderna mRNA vaccines are appropriate for use in people who take immunotherapy drugs. Neither vaccine is known to be better than the other for this population.

A 2021 study found that the Moderna vaccine was safe for people with solid tumors receiving chemotherapy, immunotherapy, or both. Their response to the vaccine was similar to those who did not have cancer. The groups also saw similar rates of side effects.

A separate 2021 study noted that people with solid tumors who had the Pfizer vaccine had similar antibody levels to those without cancer 6 months after vaccination. In the subgroup of people on immunotherapy, about 87% still had antibodies, compared to about 84% of the control group.

If you cannot get or do not want either of these vaccines, you can also get the Johnson & Johnson (Janssen) vaccine.

Having cancer or taking immunotherapy drugs does not increase the possibility of serious side effects, such as allergic reactions or myocarditis.

Swelling in the lymph nodes under the arm on the same side as the injection site is a potential side effect of vaccination. While temporary, this can be concerning for people with breast cancer and other cancers.

Tenderness and swollen lymph nodes caused by vaccination should subside within a few days to a few weeks. Let a healthcare professional know if the swelling increases or does not go away within this timeframe.

To date, researchers do not know definitively if immunotherapy drugs affect the effectiveness of COVID-19 vaccines, either positively or negatively.

Scientific articles from 2021 and 2022 suggest that checkpoint inhibitors could theoretically boost your immune response to the COVID-19 vaccine. But both articles also state that no study has demonstrated such an effect.

Some immunotherapy drugs, such as CAR T-cells, may weaken the immune system temporarily. This may make the vaccine less effective. Other types of immunotherapy drugs, such as monoclonal antibodies, should not have this effect.

People with compromised immune systems may find it difficult to generate a robust response to the vaccine, no matter what type of cancer treatment they receive. This may be particularly true for people with blood cancers. For that reason, dosing protocols for people who are immunocompromised and have cancer differ from those used for the general public.

To date, no data indicate that the COVID vaccine reduces the effectiveness of immunotherapy medication. But there may be a 17% to 48% risk of side effects due to an overstimulated immune response, according to research.

A case report published in May 2021 suggests the potential for cytokine release syndrome after COVID vaccination in patients taking certain immunotherapy drugs. The study authors state that more data is needed and still favor vaccination for people with cancer.

A 2021 study involving 134 people found no adverse effects from immunotherapy drugs after receiving the Pfizer vaccine. The studys authors also stressed the need for larger studies and more data, but supported vaccination for people receiving immunotherapy.

However, the impact of certain immunotherapy treatments on your immune system makes the timing of vaccination important. Talk with your oncologist about when you should schedule your vaccine.

People taking immunotherapy drugs should receive an additional primary dose of the vaccine if they have active cancer or are immunocompromised. You may fall into one of these categories if any of the following situations apply:

Yes. Getting COVID does not ensure you will not get it again. In fact, with ever-changing variants continually emerging, contracting the virus more than once has become commonplace.

If youre on cancer treatments that cause you to be immunocompromised, it is vital to get vaccinated, even if youve already had COVID. Talk with your oncologist about when you should get vaccinated after having COVID-19.

If you have cancer, you may be more likely to experience serious complications from COVID-19. Cancer treatments, including certain immunotherapy drugs, may affect your scheduling for vaccination. Talk with your oncologist about when you should schedule your vaccines and how many doses you should get.

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Immunotherapy and COVID Vaccine: Your Questions Answered - Healthline

Bone Marrow Stem Cells Comments Off on Immunotherapy and COVID Vaccine: Your Questions Answered – Healthline | August 2nd, 2022