Abbie Young was 16 when she was given the devastating news that her body was suffering from severe Aplastic Anaemia.

With her bone marrow failing, medics at Newcastles Royal Victoria Infirmary Ward 3 were in a race against time to find a stem cell donor who could give her a fighting chance.

Abbie, now 18, is on the road to recovery thanks to the Anthony Nolan Trust.

To say thank you for saving her life, the Harton Academy pupil is aiming to help boost the charitys work by hosting a fundraising day at school on Friday, April 8.

Abbie, who hopes to become an Anthony Nolan youth ambassador, is aiming to encourage others to sign up as stem cell donors and help save lives.

She said: I just feel really grateful that someone out there took the time to sign up to the stem cell register and that one choice someone made, has saved my life.

I know some kids die waiting for a donor, so I will always be forever grateful for what my donors did and to the Anthony Nolan Trust.

The teenager discovered her bone marrow was failing her after her mum became concerned over the number of bruises her daughter had. Abbie was diagnosed in January 2020.

Mum Caroline, 49, said: We went to the doctors who sent Abbie to South Tyneside Hospital for blood tests.

Abbie was at the hospital on the Friday (January 10), then by Saturday morning we had a knock on the door and there was an ambulance outside, they had come for Abbie.

They took us to Sunderland hospital and her dad followed up in the car, where they did more tests, they thought she had leukaemia, so we were transferred straight to the RVI.

According to information from Great Ormond Street Hospital, severe Aplastic Anaemia only affects around 30 to 40 children in the UK each year.

After Abbies older siblings, brother Sam, 26, and sister Kate, 21, were found not to be matches, a donor from Germany was found with the charitys help.

Abbies first transplant was in May 2020, but with the country in Covid lockdown, the stem cells had to be frozen due to restrictions.

The first transplant failed, believed in part due to the stem cells having been frozen.

The Anthony Nolan Trust stepped in and a second donor was found, but the cells were not frozen this time at the request of the hospital.

Caroline added: It is so hard when it's your child's life is suddenly put into the hands of a stranger. You're waiting for someone you don't know to come forward and help save your child's life.

The teenager underwent her second transplant in July 2020 and following a number of blood transfusions, the treatment started to work.

But due to complexities, she needed to have a top-up from her second donor at a later date.

Throughout Abbies treatment, which also included several doses of chemotherapy, radiotherapy and the top-up donation dose, she needed to stay confined in a bubble with only Caroline, dad Karl and nursing staff for company.

Abbie, of Beacon Glade, told the Gazette she felt like shed lost her purpose while receiving treatment and that losing her hair felt like the worst day of my life.

She explained: I was in denial about the whole thing. I knew I was bruising easily, but I didn't want to do anything about it. I was in denial about everything.

"I knew people lost their hair with treatment but I thought I'd be the one who didn't. Then I did and I was devastated.

I just felt like I had lost my purpose. When I lost my hair, it felt like the worst day of my life, I had had also put on quite a bit of weight.

Following her treatment and a number of blood and platelet transfusions, Abbie was finally able to ring the bell on leaving Ward 3 in August 2020; but she still needed to shield to give her body the best chance of survival.

Now, shes studying Biology, Chemistry and Psychology at A-Level and focusing on supporting the life-saving charity with her fundraising mission.

At time of writing and with weeks to go until her fundraising day at school more than 1,500 has been donated to her JustGiving page.

On her page, she said: Without you there is no cure. For someone with blood cancer, a stem cell transplant could be their last chance of survival.

Mum Caroline added: The hospital, the staff on Ward 3, were brilliant and the nurses were amazing. They were more like friends than medical professionals.

"At the time, you couldn't mix with anyone, so they were a good support to us as a family and to Abbie.

Abbie's school has also been supportive. Sir Ken, who is the school's executive head teacher, would call every day and ask how she was.

When it happened, teachers would drop off books for Abbie and they were even talking about a teacher going into a bubble, so that they could invigilate her for her GCSE exams. But the exams never happened because of Covid.

"We will be forever grateful for everyone's support.

Abbie and her family would like to thank the following companies who have donated prizes to help raise funds through a raffle or have donated to her JustGiving page. They include:

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'Without you there is no cure' - Teenager's call for stem cell donors in mission to support Anthony Nolan Trust - Shields Gazette

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Hemolysis refers to the destruction of red blood cells (RBCs). Typically, RBCs can live for up to 120 days before the body naturally destroys them. However, certain conditions and medications may cause them to break down quicker than usual.

RBCs, or erythrocytes, are one of the main components of blood. They have the shape of a slightly indented, flattened disk and help transport oxygen to and from the lungs. The average life span of a healthy RBC is roughly 4 months.

Typically, the body will destroy old or damaged RBCs in the spleen or in other parts of the body through a process known as hemolysis.

Usually, the body is capable of quickly replacing RBCs, producing around 2 million blood cells every second. However, people may experience symptoms of anemia if the body has a low number of RBCs due to excessive hemolysis.

In this article, we discuss hemolysis in detail, including its potential causes and treatment options.

Hemolysis is the breakdown of RBCs. Some people may also refer to hemolysis by other names, such as hematolysis, erythrolysis, or erythrocytolysis.

Hemolysis is a natural bodily process that occurs when RBCs become too old. As RBCs age, they begin to lose certain properties and work less efficiently. For example, they may lose their deformability, which allows them to reversibly change shape to pass through blood vessels.

As RBCs begin to lose functionality, they accumulate signals that initiate erythrocyte turnover. The body typically performs hemolysis in the spleen. As blood filters through this organ, it is able to detect any old or damaged RBCs. Then, large white blood cells, or macrophages, break down these RBCs.

However, some conditions, medications, and toxins may cause RBCs to break down quicker than usual.

A doctor may measure a persons hematocrit levels. This refers to the percentage of RBCs in the body. A typical hematocrit level can vary depending on many factors, such as age and race. However, low levels may suggest a high turnover of RBCs.

There are many potential factors that may lead to hemolysis. The cause of hemolysis can be extrinsic, coming from an outside source, or intrinsic, which is when it comes from the RBC itself.

Extrinsic causes include certain conditions or outside factors that destroy RBC, such as:

Certain conditions may result in changes within the RBC itself, which can lead to hemolysis. This can include deformities in the cell structure and metabolism or in the hemoglobin structure.

These conditions may include:

Excessive hemolysis can lead to hemolytic anemia. This refers to a group of conditions that present with symptoms similar to those of other types of anemia, due to hemolysis occurring too fast or too often.

The condition can develop suddenly or slowly, and it can be mild or severe. Possible symptoms may include:

Symptoms of severe hemolytic anemia may include:

Hemolytic disease of the newborn, which health experts also call erythroblastosis fetalis, is a blood condition in which a rhesus (Rh) factor incompatibility occurs during pregnancy. This refers to a protein that may be present on the surface of RBCs.

If a person with Rh-negative blood becomes pregnant, and the fetus inherits Rh-positive blood from the persons partner, it can result in a harmful immune response. Around 13 in 1,000 people experience this reaction.

During pregnancy, blood from the fetus can cross the placenta and enter the parents blood. With Rh incompatibility, the parents immune system may recognize this blood as foreign material and produce antibodies against the Rh-positive blood.

This is more likely to occur after the first pregnancy, since the pregnant persons immune system will recognize the fetuss blood as foreign and have antibodies ready. If doctors detect this early, they can prevent this condition by giving the parent an Rh immunoglobulin (RHIg) to prevent their immune system from producing antibodies.

A person will receive RHIg as an injection at 28 weeks of pregnancy to prevent the production of antibodies, and within 72 hours of delivering the baby with Rh-positive blood to prevent the production of antibodies that could affect a future pregnancy.

AIHA is a rare condition in children, affecting 0.8 in 100,000 children under the age of 18 years. It can occur after a recent viral infection or after using certain drugs. It can also be due to some conditions.

The most common form of AIHA in children is due to warm-reactive antibodies. The term warm-reactive refers to the fact that optimal antigen binding occurs close to body temperature at 98.6F.

A 2021 study notes that a sudden presentation of AIHA is often life threatening and progresses quickly, requiring prompt diagnosis, treatment, and monitoring.

Initially, a doctor will review a persons symptoms and medical history and perform a physical examination.

If they suspect hemolytic anemia, they may request the following tests:

Treatment options will depend on the cause of hemolysis. Moreover, doctors will consider the following when creating a treatment plan:

Treatments may include:

The byproducts of RBC destruction can cause reactions that can damage multiple organs. Complications due to hemolytic anemia can include:

Arrhythmia, cardiomyopathy, heart failure, and iron deficiency are other possible complications.

It is advisable for a person to consult a doctor if they experience any of the following symptoms:

Hemolysis is a natural process where the body destroys older RBCs that no longer work efficiently. However, some conditions, medications, and toxins may cause RBCs to break down prematurely.

When this occurs, people may experience symptoms of anemia, such as fatigue, dizziness, and headaches. In other cases, symptoms can be more severe.

A person exhibiting early signs of anemia should consult a doctor for a prompt diagnosis and treatment.

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Hemolysis: Types, causes, and treatments - Medical News Today

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Emily Whitehead:

Emily Whitehead

Warriors come in all shapes and sizes. Take for example Emily Whitehead, as fresh-faced a 16-year-old as has ever graced the planet. Her eyes nearly sparkle with intellectual curiosity and dreams for a fulfilling future. But Emily is not a typical teen. She is the first pediatric patient in the world to receive CAR T-cell therapy for relapsed/refractory acute lymphoblastic leukemia (ALL). She is a singular figure in the annals of medicine. She is a soldier on the front lines of the war on cancer. And like the shot heard round the world, her personal medical assault sparked a revolution in cancer care that continues to power forward.

It has been 10 years since the only child of Thomas and Kari Whitehead of Philipsburg, PA, received an infusion of CAR T cells at the hands of a collaborative medical team from the Children's Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania. That team included, among others, luminary CAR T-cell therapy pioneer, Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine and Director of the Center for Cellular Immunotherapies at Penn's Perelman School of Medicine; as well as Stephan Grupp, MD, PhD, Professor of Pediatrics at the Perelman School of Medicine (at that time, Director of the Cancer Immunotherapy Program at CHOP) and now Section Chief for Cell Therapy and Transplant at the hospital. He had been working with June on cell therapies since 2000.

Tremendous progress has flowedgushedfrom the effort to save Emily Whitehead; many more lives have been saved around the globe since that fatefulyet nearly fatalundertaking. While all the progress that has come from this story must be our ultimate theme, it cannot be fully appreciated without knowing how it came to be.

In 2010, Emily, then 5 years old, went from a being a healthy youngster one day, to a child diagnosed with ALL. Chemotherapy typically works well in pediatric ALL patients; Emily was one of the exceptions. After 2 years of intermittent chemotherapy, she continued to relapse. And when a bone marrow transplant seemed the only hope left, her disease was out of control and the treatment just wasn't possible. The Whiteheads were told by her medical team in Hershey, PA, nothing more could be done. They were instructed to take Emily home where she could die peacefully, surrounded by family.

But peaceful surrender didn't interest the Whiteheads; they rejected any version of giving up. It ran contrary to Tom Whitehead's vision of her recovery, something he said was revealed to him in the whispers. He saw, in a prophetic whispering dream, that Emily would be treated in Philadelphia. More importantly, he saw she would survive. It is as if it happened yesterday, said Tom, remembering how unrelentingly he called doctors at CHOP and said, We're coming there, no matter what you can or cannot do. We're not letting it end like this.

Since we treated Emily, we have treated more than 420 patients with CAR T cells at CHOP. She launched a whole group to be treated with this therapy; thousands have been treated around the world.Stephan Grupp, MD, PhD

A combination of persistence and perfect timing provided the magic bullet. It was just the day before that CHOP received approval to treat their first pediatric relapsed/refractory ALL patient with CAR T cells in a trial. And standing right there, on the threshold of history, was that deathly sick little girl named Emily.

At that time, only a scant few terminal adult patients had ever received the treatment, which is now FDA-approved as tisagenlecleucel and developed in cooperation with CHOP and the University of Pennsylvania. When three adults were treated, two experienced quick and complete remission of their cancers. Could CAR T-cell therapy perform a miracle for Emily? A lot would ride on the answer.

On March 1, 2012, Emily was transferred to CHOP and a few days later an apheresis catheter was placed in her neck; her T cells were extracted and sent to a lab. Emily received more chemotherapy, which knocked out her existing immune system, and she was kept in isolation for 6 weeks. Waiting.

Finally, over 3 days in April, Emily's re-engineered T cells, weaponized with chimeric antigen receptors, were infused back into her weakening body. But Emily did not rise like a Phoenix from the ashes of ALL. Instead, she sunk into the feverish fire of cytokine release syndrome (CRS), and experienced a worse-than-anticipated reaction. The hope for a swift victory seemed to be disappearing.

I can still see Emily's blood pressure dropping down to 53/29, her fever going up to 105F, her body swelling beyond recognition, her struggle to breathe, said Tom, of the most nightmarish period of his life. Doctors induced a coma, and Emily was put on a ventilator. For 14 days, her death seemed imminent. Doctors told us Emily had a one in a thousand chance of surviving, said Tom. They said she could die at any moment. But she didn't.

Medical team members who fought alongside the young patient are unwavering heroes in Emily's story. But at the time of her massive struggle, they too were exhausted and battle-scarred, descending into the quicksand of what could have been a failing trial, grasping for some life-saving branch of stability. They knew if CRS could be overcome, the CAR T cells might work a miracle as they had done for those earlier adult patients. But the CRS was severe. There was no obvious antidote; time was running out.

I recall Dr. June saying he believed Emily was past the point where she could come back and recover, said her father. And he said if she didn't turn around, this whole immunotherapy revolution would be over.

The Whiteheads enjoy Penn State football games not far from their hometown. The family has often taken part in Penn State's THON, a 48-hour dance marathon that raises funds for childhood cancer.

June confirmed to Oncology Times that he and Grupp believed Emily would not survive the night. It was mentioned to the Whiteheads that perhaps they should just concentrate on comfort care measures and stop all the ICU interventions, he recalled. I believed she was going to die on the trial due to all the toxicity. I even drafted a letter to our provost to give a heads up.

When the first patient in a trial dies, that's called a Grade 5 toxicity, June noted. That closes the trial as well. It goes right into the trash bin and you have to start all over again. But fortunately, that letter never left my outbox. We decided to continue one more day, and an amazing event happened.

Grupp, offering context to the mysterious amazing event, said it was clear that Emily's extreme CRS was caused by the infusion of cells that he himself had placed in her fragile body. He said he felt an enormous sense of responsibility and incredible urgency as he watched the child struggle to live.

It was not until the CHOP/Penn team received results from a test profiling cytokines in Emily's body that a new flicker of hope sparked. Though Emily had many cytokine abnormalities, the one most strikingly abnormal, interleukin-6 (IL-6), caught the team's attention. It is not made by T cells, and should not have been part of the critical mix. Though there were very few cytokines that had drugs to target them individually, IL-6 was one that did. So the doctors decided to repurpose tocilizumab, an arthritis drug, as a last-ditch effort at saving their young patient.

We treated Emily with tocilizumab out of desperation, June admitted. Steve [Grupp] has told me that when he went to the ICU with tocilizumab as a rescue attempt for CRS, the ICU docs called him a cowboy. The ICU docs had given up hope for Emily. But she turned aroundunbelievably rapidly. Today, tocilizumab is the standard of care for CRS, and the only drug approved by the FDA for that complication. Emily's recovery was huge for the entire field.

Grupp reflected on the immensity of the moment. If things had gone differently, if Emily had experienced fatal toxicity, it would have been devastating to her family and to the medical team. And it might have ended the whole research endeavor. It would have set us back years and years. The impact that Emily and her family had on the field is nothing short of transformational, he declared.

Since we treated Emily, we have treated more than 420 patients with CAR T cells at CHOP. She launched a whole group to be treated with this therapy; thousands have been treated around the world, Grupp noted. And, if not for Emily, we wouldn't be in the position we are in todaywith five FDA-approved [CAR T-cell] products: four for adults and one for kids. And I think it also important to point out that the very first CAR-T approval, thanks to Emily, was in pediatric ALL.

June noted that between 2010 and the time of Emily's treatment in 2012, My work was running like a shoestring operation. I had to fire people because I couldn't get grants to support the infrastructure of the research. It was thought there was no way beyond an academic enterprise to actually make customized T cells, then mail and deliver them worldwide, he recalled.

But then everything changed. We experienced that initial success; it was totally exciting. It was a career-defining moment and the culmination of decades of research. It led to a lot of recognition, both for my contribution and for the team here at the University of Pennsylvania and at CHOP.

Today, hundreds of pharmaceutical and biotech companies are developing innovations. Hundreds of labs are making next-generation approaches to improve in this area, June noted. Today, I'm a kid in a candy shop because all kinds of things are happening. We have funding thanks to the amazing momentum from Emily. She literally changed the landscape of modern cancer therapy.

Grupp said the continuing CAR T-cell program at CHOP offers evidence of success in a broad perspective. There are two things to look at, he offered. The first is how well patients do with their therapy in terms of getting into remission. A month after getting their cells, are they in remission or not? A study with just CHOP patients showed that more than 90 percent met that bar (N Engl J Med 2014; doi: 10.1056/NEJMoa1407222). Worldwide, the numbers appear to be in the 80 percent range (N Engl J Med 2018; doi: 10.1056/NEJMoa1709866). So, I would say it is a highly successful therapy.

We now have trials using different cell types, like natural killer cells, monocytes, and stem cells, noted Carl June, MD, at Penn's Perelman School of Medicine. An entirely new field has opened because of our initial success. This is going to continue for a long time, making more potent cells that cover all kinds of cancer.

The other big question, Grupp noted: How long does remission last? We are probably looking at about 50 percent of patients remaining in remission long-term, which is to say years after the infusion. The farther out we go, the fewer patients there are to look at because it just started with Emily in 2012, reminded Grupp. We have Emily now 10 years out, and other patients who are at 5, 6, 7, 8 years out, but most were treated more recently than that. We need to follow them longer.

June said registries of patients treated with CAR T-cell therapy are being kept worldwide by various groups, including the FDA. CAR T-cell therapy happened fastest in the U.S., but it's gained traction in Japan, Europe, Australia, and they all have databases. The U.S. database for CAR T cells will probably be the best that exists, because the FDA requires people treated continue follow-up for at least 15 years, he explained.

This will provide important information about any long-term complications, and the relapse rate. If patients do get cancer again, will it be a new one or related to the first one we treated? We will follow the outcomes, he noted. Clinicians are teaching us a lot about how to use the informationat what stage of the disease the therapy is best used, and which patients are most likely to respond. This can move us forward.

June mentioned that Grupp is collaborating with the Children's Oncology Group ALL Committee led by Mignon Loh, MD, at the University of California in San Francisco.

They are conducting a national trial to explore using CAR T cells as a frontline therapy in newly diagnosed patients, he detailed. Emily was treated when she had pounds and pounds of leukemia in her body; ideally we don't want to wait so long. There are a lot of reasons to believe it would work as a frontline therapy and spare patients all the complications of previous chemotherapy and/or radiation. The good news is that the clinical trial is under way, and I suspect we may know the answer within 2 years.

The only true measure of success in Emily's case is the state of her health. When asked if she is considered cured, June said, All we can do is a lot of prognostication. We know with other therapies in leukemia, the most similar being bone marrow transplants, if you go 5 years without relapsing, basically you are considered cured. We don't know with CAR T cells because Emily is the first one. We have no other history. But she's at a decade now, and in lab data we cannot find any leukemia in her. So by all of the evidence we haveand by looking in the magic eight ballI believe Emily is cured.

One might think that going through such a battle for life would be enough for any one person, any one family. But for Emily and her parents, her survival was just the beginning of a larger assault. All of them saw the experience as a way to provide interest in continuing research, education for patients as well as physicians, and an extension of hope to other patients about to succumb to a cancerous enemy.

Tom thought back to one particular occasion, all those years ago, when Emily finally slept peacefully through the night in her hospital bed. I should have felt nothing but relief, but I heard a mother crying in the hallway. Her child, who has been in the room next door, had died that morning, he recalled. I am constantly reminded of how fortunate we are. There are so many parents fighting for their children who do not have a good outcome.

As soon as Emily regained her strength and resumed normal childhood activities, the family began travelling with members of the medical team, joining in presentations at meetings and conferences throughout the world. They wanted to give a human face to the potential of CAR T-cell therapy, and as such they willingly became a powerful tool to raise understanding and essential research dollars. In 2016, the Whiteheads founded the Emily Whitehead Foundation (www.emilywhiteheadfoundation.org) ...to help fund research for new, less toxic pediatric treatments, and to give other families hope.

We decided to hold what we called the Believe Ball in 2017. We asked lots of companies to sponsor a child who had received CAR T-cell treatment to come with their family to the ball at no cost to them. Each company's representative would be seated with the child and family they sponsored, and would meet the doctors and scientists involved in the research, as well as members of industry and pharma, to see exactly where research dollars are going. We implored these companies to move the cancer revolution forward with sponsorship. When it all shook out, we had around 35 CAR T-cell families together for the first time, said Tom.

He noted proudly that since the foundation's debut, donations have been consistent and now have totaled an impressive $1.5 million.

When the Emily Whitehead Foundation had a virtual gala recently, it awarded a $50,000 grantthe Nicole Gularte Fight for Cures Ambassador Awardto a young researcher working to get another trial started. The award is named for a woman who found her way to CAR T-cell trials at Penn through the Whitehead Foundation. The treatment extended her life by 5 years during which time Gularte became an advocate for other cancer patients, travelled with the Whiteheads, and made personal appearances whenever she thought she could be of help or inspiration. Eventually, she would relapse and succumb, but she assured Tom Whitehead, These were 5 of the best years of my life. I think my time here on Earth was meant to help cancer research move forward.'

While raising funds for progress is important, the Whiteheads' work is not just about bringing in money. It's also about education.

We want to send a message to all oncologists; they need to be more informed about these emerging treatments when their patients ask for help, Tom noted. In the beginning of CAR T-cell therapy, a lot of doctors were against it. It's hard to believe, but some still are, though not as much. We need more education so that oncologists give patients a chance to get to big research hospitals for cutting-edge treatments before everything else has failed.

June said he regularly interacts with patients Tom or the foundation refer to him. Such unawareness happens with all new therapies, he noted. The people most familiar with them are at academic medical centers. But only about 10 percent of patients actually go to academic centers, the rest are in community centers where newer therapies take much longer to roll out, he explained.

So much of Emily's life has been chronicled through the eyes of observers. But since her watershed medical intervention, she has grown into a well-travelled, articulate young woman who talks easily about her life. I used to let my father do all the talking, but I am finding my own voice now, she said, having granted an interview to Oncology Times.

I'm currently 16 years old and I'm a junior at high school. Just like when I was younger, cows are my favorite animals, she offered with a laugh. I still love playing with our chihuahua, Luna. In school, I love my young adult literature class because I really like reading. Besides that, I like art and film. And I'm in really good health today.

She mentioned her health casually, almost as an afterthought. I really don't have any memory of my treatment at this point, she revealed, but, the experiences that I've had since then have really shaped who I am. Traveling is a huge part of my life now and something I look forward to. We've been to conferences at a lot of distant places. I'm so grateful that I get to travel with my family and make these memories that I will have forever, while still being able to advocate for less toxic treatment options and raising money for cancer research. All of that is really important to me.

Reminded that she has already obtained fame as pediatric patient No. 1 for CAR T-cell therapy, Emily considered her status for a moment then commented, I don't really like to base the progress of the therapy on my story and what I went through. Instead, I like to take my experience and use it to advocate for all patients so that what happened to me does not have to be repeated and endured by another family. My hope is that CAR T-cell therapy will become a frontline treatment option and be readily available, so pediatric patients can get back to a normal life as soon as possible. I want to tell people if conventional treatments do not work, other options do exist. Overall, I am grateful that I can encourage others to keep fighting. That's the main thing; I am grateful.

After a brief pause, Emily continued, I always tell oncologists and scientists that the work they are doing is truly saving children's lives. It allows these kids to grow up, be with their friends and families, take vacations, play with their dogs, and someday go to college, just like me. They are not only saving patients' lives, they are saving families. The work they do does not go unnoticed or unappreciated. Again, I am really so grateful.

Appreciation is a two-way street, and June said he and his team appreciate and draw inspiration from Emily on a daily basis. Her picture hangs on the wall of our manufacturing center, June stated. Some of the technicians who were in high school when Emily was infused are now manufacturing CAR T cells. They learned so much from Emily's experience; she continues to be a big motivator. She's helped my team galvanize and see that the work can really benefit people.

Grupp said the success that is embodied in Emily Whitehead has spurred additional successes, and new inroads in CAR T-cell therapy. There are more applications now, especially in other blood cancerslymphoma and myeloma, in addition to leukemia. We've seen a lot of expansion there.

He noted a national trial is under way for an FDA-approved therapy called idecabtagene vicleucel, which can benefit multiple myeloma patients. All other CAR Ts target the same target, CD19. But this goes after an entirely different target, BCMA. The fact that we now have approval in something that isn't aimed at CD19 is very exciting. And there are others coming right behind it.

The field also has seen further expansion ...into adults being treated safely, because initially there was concern that these drug therapies were too powerful for safe treatment in older adults, detailed Grupp. Now we know that is clearly not the case, and that is great news, particularly because multiple myeloma most often occurs in people over 60.

The use of CAR T cells in solid tumors continues to be challenging, although Grupp noted, We have certainly seen hints of patients with solid tumors having major responses and going into remission with CAR T cells. It is still a small handful of patients, so we haven't perfected the recipe for solid tumors yet. But I am absolutely confident we will have the answers in a very short numberperhaps 2-4of years.

June said, since Emily's infusion, CAR T cells have matured and gotten better. There are many ways that has happened, he informed. We have different kinds of CAR designs to improve and increase the response rates, to decrease the CRS, or to target other kinds of bone marrow cancers. One that is not curable with a lot of therapies is acute myeloid leukemia (AML), so we have a huge group at Penn and CHOP working on AML specifically. And there is the whole field of solid cancer; we have teams working on pancreatic, prostate, breast, brain, and lung cancer now.

In addition to targeting different types of cancer, June said contemporary research is also exploring the use of different types of cells. Our initial CAR T trial used T cells, and that is what all the FDA-approved CARs are. But we now have trials using different cell types, like natural killer cells, monocytes, and stem cells. An entirely new field has opened because of our initial success. This is going to continue for a long time, making more potent cells that cover all kinds of cancer, not just leukemia and lymphoma.

Is this the beginning of the end of cancer? Is this that Holy Grail called a cure to cancer? It's a question June has pondered.

Some people do think that, he answered. They believe the immune system is the solution. And that's a huge statement. President Biden has made a big investment in this work, with the Cancer Moonshot. He's accelerated this research at the federal level. But we just don't know how long it is going to take. Fortunately, a lot of good minds are working hard to make an end to cancer a reality.

As the battle grinds on, June said he applies something he's learned over time, with reinforcement from Tom and Kari Whitehead. They were bulldogs. When it came to getting treatment for Emily, they just wouldn't take no for an answer. They demonstrated the importance of never giving up. That's what happened; they would not surrender. I think that is why Emily is alive today.

Valerie Neff Newitt is a contributing writer.

The Emily Whitehead Foundation and the Whitehead family take extraordinary advantage of a variety of media to reach patients and physicians and optimize educational opportunities.

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The Incredible Story of Emily Whitehead & CAR T-Cell Therapy : Oncology Times - LWW Journals

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Theranostics. 2020; 10(8): 36223635.

Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673, Singapore

Competing Interests: The authors have declared that no competing interest exists.

Received 2019 Oct 4; Accepted 2019 Dec 20.

The transcriptional co-regulators YAP and TAZ pair primarily with the TEAD family of transcription factors to elicit a gene expression signature that plays a prominent role in cancer development, progression and metastasis. YAP and TAZ endow cells with various oncogenic traits such that they sustain proliferation, inhibit apoptosis, maintain stemness, respond to mechanical stimuli, engineer metabolism, promote angiogenesis, suppress immune response and develop resistance to therapies. Therefore, inhibiting YAP/TAZ- TEAD is an attractive and viable option for novel cancer therapy. It is exciting to know that many drugs already in the clinic restrict YAP/TAZ activities and several novel YAP/TAZ inhibitors are currently under development. We have classified YAP/TAZ-inhibiting drugs into three groups. Group I drugs act on the upstream regulators that are stimulators of YAP/TAZ activities. Many of the Group I drugs have the potential to be repurposed as YAP/TAZ indirect inhibitors to treat various solid cancers. Group II modalities act directly on YAP/TAZ or TEADs and disrupt their interaction; targeting TEADs has emerged as a novel option to inhibit YAP/TAZ, as TEADs are major mediators of their oncogenic programs. TEADs can also be leveraged on using small molecules to activate YAP/TAZ-dependent gene expression for use in regenerative medicine. Group III drugs focus on targeting one of the oncogenic downstream YAP/TAZ transcriptional target genes. With the right strategy and impetus, it is not far-fetched to expect a repurposed group I drug or a novel group II drug to combat YAP and TAZ in cancers in the near future.

Keywords: TEAD, YAP, TAZ, Hippo, cancer therapy

The transcriptional co-regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are key players that mediate various oncogenic processes and targeting their activities has emerged as an attractive option for potential cancer therapy. YAP, as the name suggests, was initially identified as a protein that associates with Yes, a src family kinase (SFK) 1. The exact function of YAP remained elusive until it was demonstrated to be a potent transcriptional activator 2. YAP's paralog TAZ, identified from a screen for 14-3-3 interacting proteins, is also a transcriptional co-activator 3 (Figure ).

The oncogenic milestones of the transcriptional co-regulators YAP and TAZ. Discovery of YAP/TAZ and TEAD functions predate the discovery of the Hippo pathway. Role of YAP/TAZ in the Hippo pathway and the discovery of their oncogenic abilities in cell and animal models are considered significant. The initial studies from the groups that linked YAP/TAZ to oncogenic signaling pathway, stemness, actin cytoskeleton, fusion genes, drug resistance, metabolism, angiogenesis and immune suppression are also listed.

YAP and TAZ do not have a DNA-binding domain and they need to associate with a transcription factor in order to access DNA. It has now emerged that YAP/TAZ use predominantly the TEAD (TEA domain) family of transcription factors 4 to elicit most of their biologically relevant gene expression programs. ChIP-Seq data unraveled a significant overlap in YAP/TAZ and TEAD peaks throughout the genome, and also showed that some YAP/TAZ-responsive genes are also synergistically regulated by AP-1 transcription factors 5, 6. In addition to its interaction with TEADs, YAP/TAZ also communicates with the mediator complex and chromatin modeling enzymes like the methyltransferase and SWI/SNF complex to elicit changes in gene expression 7-9. YAP/TAZ also suppress gene expression and should be regarded as co-regulators rather than co-activators 10.

YAP/TAZ are now considered as effectors of a physiologically and pathologically important signaling pathway - popularly called the Hippo pathway 11. The Hippo pathway was initially identified in a genetic mosaic screen in Drosophila but the pathway components are evolutionarily conserved. It is now known that the primary function of the Hippo pathway is to suppress the activity of Yorkie - the Drosophila homolog of YAP 12. The Hippo pathway in mammals also inhibits YAP/TAZ through phosphorylation by the large tumor suppressor (LATS) family of Hippo core kinases 13, which leads to cytoplasmic sequestration via interaction with 14-3-3 proteins and/or degradation via ubiquitin proteasome pathway 14, 15.

YAP and TAZ were first shown to transform mammary epithelial cells 16, 17. The oncogenic role of YAP became apparent when it was shown to be a driver gene in a mouse model of liver cancer 18 (Figure ). In a conditional transgenic mouse model, YAP overexpression dramatically increases liver size and the mouse eventually develops hepatocellular carcinoma 19, 20. In addition to causing primary tumor growth, YAP also helps in the metastatic dissemination of tumor cells 21.

Over a decade of research has revealed that YAP/TAZ integrates the inputs of various oncogenic signaling pathways, such as EGFR, TGF, Wnt, PI3K, GPCR and KRAS. Through expression of the ligand AREG, YAP was first shown to communicate with the EGFR pathway 22 (Figure ). The genes regulated by YAP/TAZ collectively coordinate various oncogenic processes, such as stemness, mechanotransduction, drug resistance, metabolic reprogramming, angiogenesis and immune suppression (Figure ), many of which are considered to be cancer hallmarks 23.

YAP and TAZ regulate the expression of crucial transcription factors like Sox2, Nanog and Oct4 and are able to maintain pluripotency or stemness in human embryonic stem cells (ESCs) and in induced pluripotent stem (iPS) cells 24, 25 (Figure ). More specifically, TAZ has been shown to confer self- renewal and tumorigenic capabilities to cancer stem cells 26. Within the microenvironmental landscape of tissues, YAP/TAZ are increasingly recognized as mechanosensors that respond to extrinsic and cell-intrinsic mechanical cues. To this end, mechanical signals related to extracellular matrix (ECM) stiffness, cell morphology and cytoskeletal tension rely on YAP/TAZ for a mechano-activated transcriptional program 27-29. YAP/TAZ target genes, CTGF and CYR61, cause resistance to chemotherapy drugs like Taxol 30 and YAP/TAZ has emerged as a widely used alternate survival pathway that is adopted by drug-resistant cancer cells 31. YAP/TAZ activity is regulated by glucose metabolism and is connected to the activity of the central metabolic sensor AMP-activated protein kinase (AMPK) 32-35. YAP/TAZ reprograms glucose, nucleotide and amino acid metabolism in order to increase the supply of energy and nutrients to fuel cancer cells 36. Through expression of proangiogenic factors like VEGF and angiopoetin-2 37, 38, YAP is able to stimulate blood vessel growth to support tumor angiogenesis 39. YAP is also shown to recruit myeloid-derived suppressor cells in prostate cancers in order to maintain an immune suppressive environment 40. Active YAP also recruits M2 macrophages to evade immune clearance 41.

A TAZ fusion gene (TAZ-CAMTA1) alone, in the absence of any other chromosomal alteration or mutation, is sufficient to drive epithelioid hemangioendothelioma (EHE), a vascular sarcoma 42, 43. Furthermore, comprehensive analysis of human tumors across multiple cancer types from the TCGA database unraveled that YAP and TAZ are frequently amplified in squamous cell cancers in a mutually exclusive manner 44. In human cancers, there is also a good correlation between YAP/TAZ target gene signature and poor prognosis. To date, a proportion of every solid tumor type has been shown to possess aberrant YAP/TAZ activity. Further, many of the upstream Hippo components that negatively regulate YAP/TAZ are found inactivated across many cancer types 45. Thus, all of this paint a clear picture of the prominent role played by YAP and TAZ at the roots of cancers 46, 47.

There are more than fifty drugs that have been shown to inhibit YAP/TAZ activity 48, however, with the exception of verteporfin; none act directly on YAP/TAZ. The unstructured nature of YAP and TAZ renders them difficult to target using small molecules. Therefore, YAP/TAZ inhibition is achieved indirectly through targeting their stimulators or partners. In this review, we focus on small molecules, antibody and peptide-based drugs, as the majority of the drugs in the clinic belong to this class. Less attention is given to nucleotide-based molecules and to small molecule YAP/TAZ inhibitors whose targets are unknown. We classify the YAP/TAZ-inhibiting drugs into three groups with each group having its own combating strategy to counter YAP/TAZ activity (Figure ). Group I drugs target the upstream YAP/TAZ stimulators and enhance the LATS-dependent inhibitory phosphorylation of YAP/TAZ in order to restrain their transcriptional output. Group II drugs/candidates act directly on YAP/TAZ or TEAD and may either interfere with the formation of the YAP/TAZ-TEAD complex or inhibit TEADs directly and hence affect YAP/TAZ-TEAD transcriptional outcomes. Group III drugs' combat strategy is to target the oncogenic proteins that are transcriptionally upregulated by YAP and TAZ.

Classification ofYAP/TAZ-TEAD inhibiting drugs into three groups. Group I drugs (red font) act upstream and prevent the nuclear entry of YAP and TAZ, group I drug targets for potential pharmacological exploitation in order to generate repurposed YAP/TAZ-inhibiting drugs are circled. Group II drugs (green font) disrupt the formation of the YAP/TAZ-TEAD complex and they primarily bind to the TEAD family of transcription factors. Group Ill drugs (blue font) act on the downstream transcriptional targets in order to prevent YAP/TAZ-mediated oncogenicity.

Group I drugs target the upstream proteins (Figure ), inhibition of which culminates in the enhancement of the LATS-dependent inhibitory phosphorylation of YAP/TAZ 49, 50. However, some group I targets like SFKs 51-53, AMPK 33, 34 and phosphatases 54-56 act directly on YAP and TAZ and activate them. Majority of group I drugs are kinase inhibitors, in addition to restricting YAP/TAZ nuclear entry; they intriguingly promote TAZ, but not YAP degradation. A possible explanation for this is the presence of two phosphodegrons that render TAZ more prone to degradation 15. Some group I drugs, such as MEK/MAPK inhibitors 57, 58 and -secretase inhibitors (GSIs) 59 have the ability to actively reduce both YAP and TAZ levels. HDAC inhibitors however, reduce YAP, but not TAZ levels 60. Here, we have classified the group I drugs based on the nature of the drug target.

Drugs targeting the EGFR, GPCR, Integrin, VEGFR and adenylyl cyclase families as well as those targeting receptors like the -secretase complex and Agrin are shown to inhibit YAP/TAZ activity 51, 61-64.

YAP/TAZ exploits the transformative abilities of the ErbB receptors (EGFR family) to drive cell proliferation. By transcribing ErbB ligands, such as AREG 22, 65, TGF- 66, NRG1 67 as well as the ErbB receptors EGFR and ErbB3 67, YAP is able to activate ErbB signaling and promote tumorigenesis. Sustained EGFR signaling also disassembles the Hippo core complexes leading to an increased active pool of YAP/TAZ 68 that is ready to transcribe more ErbB ligands/receptors. Under these conditions, EGFR inhibitors like Erlotinib 22 and AG-1478 66 (Figure ) are able to act as YAP/TAZ inhibitors and may be used for EGFR-driven cancers requiring YAP/TAZ transcription.

Signaling from G-protein coupled receptors (GPCRs), transduced by the associated G subunit or by the G subunits, modulates YAP/TAZ activities 69. Inhibiting Gq/11 sub-type signaling, using losartan 70, or stimulating Gs sub-type, using dihydrexidine, has been shown to stimulate YAP inhibitory phosphorylation 69. Agonism of Gs has been recently exploited to facilitate YAP/TAZ inhibition that reverses fibrosis in mice 71. G inhibition using gallein has also been shown to restrict YAP/TAZ 72. Activating mutations in the Gq/11 types of GPCRs present in approximately 80% of the uveal melanoma patients generate an active pool of YAP 73, 74 but the signal transduction occurs via Trio-Rho/Rac signaling and not through the canonical Hippo pathway 74.

Integrin signaling negatively regulates the Hippo pathway complexes to drive YAP/TAZ activity 75, 76. Although blocking integrin activity using RGD peptides 63, cilengitide (cyclic RGD peptide) 77, function-blocking antibodies - BHA 2.1 76 and clone AIIB2 78 has been shown to increase YAP/ TAZ's inhibitory phosphorylation, disappointingly, the efficacy of integrin- blocking drugs against cancers has not been clinically proven 79. Interestingly, a function-blocking antibody against Agrin, an extrinsic stimulator of integrin signaling, abrogates YAP-dependent proliferation in mouse models 63, 80.

Among the kinase inhibitors tested in a biosensor screen for LATS activity, the VEGFR inhibitors are shown to potently activate LATS and thereby inhibit YAP and TAZ activity 81. Further, VEGFR2 signaling is also shown to induce actin cytoskeletal changes and promote YAP/TAZ activation 82. Therefore, VEGFR inhibitors like SU4312, Apatinib, Axitinib and pazopanib are able to inhibit the expression of YAP/TAZ-responsive genes in endothelial cells. But whether these drugs work as YAP/TAZ inhibitors in cancer cells remains to be seen.

Enhancing cyclic AMP (cAMP) levels using the adenylyl cyclase activator forskolin activates the LATS kinases through Protein kinase A (PKA) and Rho 69, therefore forskolin is also a YAP/TAZ inhibitor. cAMP is degraded by the cyclic nucleotide phosphodiesterases (PDE), the use of PDE inhibitors like theophylline, IBMX, ibudilast and rolipram also promotes YAP/TAZ-inhibitory phosphorylation 83, 84.

Notch and YAP/TAZ signaling are also closely linked, inhibiting notch activity by targeting the -secretase complex, either using DAPT or dibenzazepine has been shown to decrease YAP/TAZ expression levels in mouse livers and also reduce YAP activation and YAP-induced dysplasia in the intestine 20, 51, 59.

Integrin signaling activates focal adhesion kinase (FAK), SFK and integrin- linked kinase (ILK). Growth factor and GPCR signaling occurs through mitogen-activated protein kinase (MAPK) and phosphoinositide 3-OH kinase (PI3K) signaling. There is also significant crosstalk in the signaling from these membrane receptors. Given the availability of potent small molecule drugs targeting the downstream kinases, they are leveraged on to inhibit YAP or TAZ activities.

Members of downstream integrin signaling pathway including FAK, its counterpart PYK2, and ILK have emerged as negative regulators of the core Hippo pathway and thus activate YAP/TAZ. Membrane receptors, such as ErbB and GPCRs are unable to activate YAP upon genetic deletion of ILK. Therefore, pharmacological inhibition of ILK using a specific ILK inhibitor, QLT0267 potently inhibits YAP-dependent tumor growth in xenograft models 85. The FAK inhibitors PF-562271 and PF-573228 have also been shown to enhance the LATS-mediated inhibitory phosphorylation of YAP 63, 75. A multi-kinase inhibitor CT-707 that predominantly inhibits FAK, anaplastic lymphoma kinase (ALK) and PYK2 is able to render cancer cells vulnerable to hypoxia through YAP inhibition 86. Inhibiting PYK2 activity using the dual PYK2/FAK inhibitor PF431396 destabilizes TAZ and also inhibits YAP/TAZ activity in triple negative breast cancer cells 87.

The SFK member Src prevents the activation of LATS 75, 88, thereby relieves YAP/TAZ inhibition by LATS. Interestingly, SFKs, Src and YES are also shown to activate YAP through direct tyrosine phosphorylation 51-53. Treating cells with SFK inhibitors, such as Dasatinib, PP2, SU6656, AZD0530 and SKI-1 inactivates YAP 51-53, 75, 88. In -catenin-driven cancers, YES facilitates the formation of a tripartite complex comprising -catenin, YAP and TBX5 that drives cell survival and tumor growth 53, 89. The SFK inhibitor dasatinib also serves as YAP inhibitor in these cancers 53. Dasatinib, in addition to inhibiting SFKs may also potently inhibit PDGFR and Ephrin receptors, both of which are known to activate YAP/TAZ 90, 91. However, FAK and SFK inhibitors have shown very limited efficacy against solid tumors in clinical trials therefore their utility in YAP-driven cancers remains to be seen.

MEK (MAP kinase kinase) and YAP interact with each other and maintain transformed phenotypes in liver cancer cells 57. MEK inhibitors PD98059, U0126 and trametinib or MAPK inhibitors CAY10561 and {"type":"entrez-nucleotide","attrs":{"text":"FR180204","term_id":"258307209","term_text":"FR180204"}}FR180204 are able to trigger degradation of YAP in a Hippo-independent manner 57, 58. The finding that MEK inhibition causes YAP degradation is, however, difficult to reconcile if YAP and TAZ are shown to mediate resistance to the MEK inhibitor trametinib 92. The efficacy of trametinib is also being evaluated in EHE, a cancer that is caused by the TAZ-CAMTA1 fusion gene ({"type":"clinical-trial","attrs":{"text":"NCT03148275","term_id":"NCT03148275"}}NCT03148275).

PI3K inhibitors Wortmannin/LY294002 as well as the drug BX795, an inhibitor of its effector 3'-phosphoinositide-dependent kinase-1 (PDK1) prevents nuclear entry of YAP 68. PI3K is closely linked to the mammalian target of rapamycin (mTOR) pathway. mTOR inhibitors temsirolimus and MLN0128 have been shown to inhibit YAP activity in patients with idiopathic pulmonary fibrosis and in a mouse model of cholangiocarcinoma, respectively 93, 94. YAP levels in TSC1 mutant mouse could also be reduced by blocking mTOR using torin1 treatment that induces the autophagy-lysosomal pathway 95.

YAP/TAZ inhibition is an additional unexpected activity possessed by the few kinase inhibitors mentioned above. However, apart from YAP/TAZ inhibition, all other signaling events initiated by the target kinase are also shut down due to inhibitor treatment. If these signaling events are critical for cellular homeostasis, then, toxic side effects will outweigh clinical benefits and this cannot be uncoupled from YAP/TAZ inhibition. Therefore, kinase inhibitors that failed in the trials due to unacceptable toxcity or poor pharmacokinetics may not be repurposed as YAP/TAZ inhibitors in the clinic. Focus should be on the kinase inhibitors that are already in the clinic like EGFR, VEGFR, MEK, PI3K or mTOR inhibitors but efficacy needs to be proven in order to repurpose them as YAP/TAZ inhibitors. The kinase targeted by the inhibitor must activate YAP/TAZ in tumors, for the treatment to be efficacious and this restricts the use of kinase inhibitors to selective tumor types. Intriguingly, YAP/TAZ activation has emerged as a prominent survival strategy adapted by cancers that cause drug resistance to EGFR and its downstream MEK/MAPK inhibitors 31. In such scenarios, coupling a group II YAP/TAZ inhibitor with a EGFR pathway inhibitor might offer the intended treatment benefits.

The mevalonate pathway is essential for the biosynthesis of isoprenoids, cholesterol and steroid hormones. Statins as well as other mevalonate pathway inhibitors like zoledronic acid and GGTI-298 that target farnesyl pyrophosphate synthase and geranylgeranyltransferase, respectively are identified as drugs that restrict the nuclear entry of YAP and TAZ 96, 97. Studies have also shown that combining statins like simvastatin with the EGFR inhibitor gefitinib provides stronger anti-neoplastic effects 98. Atorvastatin and zoledronic acid have entered Phase II clinical trials in triple negative breast cancer to test if they improve the pathological complete response rates ({"type":"clinical-trial","attrs":{"text":"NCT03358017","term_id":"NCT03358017"}}NCT03358017).

Actin polymerization promotes YAP/TAZ nuclear localization and therefore, polymerization inhibitors like latrunculin A 27 and cytochalasin D 28, 29 inhibit YAP/TAZ. Myosin or myosin light-chain kinase inhibitors like blebbistatin and ML-7, respectively have a similar effect 27, 29. Interfering with the actomyosin cytoskeleton through other means, such as Rho inhibition (toxin C3 treatment), or by using Rho kinase inhibitors like Y27632 has also been shown to have an inhibitory effect on YAP/TAZ 27, 29. p21 activated kinase (PAK) family kinases are cytoskeletal regulators as well as Hippo inhibitors. The PAK allosteric inhibitor IPA3 prevents YAP's nuclear entry 63, 99, further, the PAK4 inhibitor PF-03758309 is also shown to reduce YAP levels 77.

YAP/TAZ inhibitory phosphorylation is dynamic and the protein phosphatases PP1 and PP2A are shown to associate with YAP/TAZ and aid in their dephosphorylation and activation. Inhibiting these phosphatases using okadaic acid or calyculin A increases YAP/TAZ phosphorylation and shifts YAP/TAZ to the cytoplasm 54-56. Some of the oncogenic functions of YAP/TAZ are also mediated by the protein-tyrosine phosphatase SHP2 100, therefore SHP2 inhibitors have also been shown to attenuate YAP/TAZ activity 101.

Cellular energy stress is closely linked with attenuation of YAP/TAZ activities 32. Drugs that enhance energy stress like the mitochondrial complex I inhibitors metformin and phenformin, enhance YAP/TAZ inhibitory phosphorylation, cytoplasmic localization and suppression of YAP/TAZ- mediated transcription 32. The energy stress induced by these drugs activates AMPK, which is shown to phosphorylate and stabilize AMOTL1 - a YAP/TAZ negative regulator 32. AMPK is also shown to directly phosphorylate and inactivate YAP by disrupting its interaction with TEADs 33, 34. Therefore, AMPK activators A769662 and AICAR (an AMP-mimetic) are YAP inhibitors 32-34.

Histone deacetylases (HDACs) are uniquely positioned to alter the transcription of target genes. Interestingly, HDAC inhibitors panobinostat, quisinostat, dacinostat, vorinostat and Trichostatin A transcriptionally repress the expression of YAP but not TAZ, and thereby reduce YAP-addicted tumorigenicity 60. Treatment of cholangiocarinoma cells with the HDAC inhibitor {"type":"entrez-nucleotide","attrs":{"text":"CG200745","term_id":"34091806","term_text":"CG200745"}}CG200745 is also shown to decrease YAP levels 102. Although HDAC inhibitors are used to treat hematological malignancies their efficacy in solid cancers is questionable, however, combining HDAC inhibitor panobinostat with BET (bromodomain and extra-terminal) inhibitor I-BET151 achieves more effective YAP inhibition 103. There is also a clinical trial designed to evaluate the efficacy of HDAC/BET inhibitor combination in solid tumors and determination of YAP expression level after drug treatment is used as one of the objectives ({"type":"clinical-trial","attrs":{"text":"NCT03925428","term_id":"NCT03925428"}}NCT03925428). The BET family protein BRD4 is a part of the YAP/TAZ-TEAD transcriptional complex and inhibiting BRD4 using BET inhibitor JQ1 inhibits YAP upregulation and YAP-mediated transcription in KRAS mutant cells 104.

Many group I drugs can potentially be repurposed to treat YAP/TAZ- driven cancers 105. Among the group I drugs, only statins, trametinib and HDAC/BET inhibitors are being evaluated in clinical trials to test if they act against YAP/TAZ. Our prediction is that group I drugs that facilitate YAP/ TAZ inhibitory phosphorylation as well as degradation will have greater success in combating YAP/TAZ in cancers as YAP/TAZ degradation prevents their reactivation through other mechanisms. Importantly, the repurposing of group I drugs would also allow YAP/TAZ and its target gene(s) expression-based stratification amongst cancer patients.

Modalities that target either the TEAD family of transcription factors or YAP/TAZ are classified under this group (Figure ). The majority of the modalities, with the exception of verteporfin 106, target TEADs and are therefore predicted to act in the nucleus. By pairing with the TEAD family of transcription factors, YAP and TAZ upregulate the expression of many oncoproteins. The C-terminus of all TEADs possesses the YAP/TAZ-binding domain. The partnership between YAP/TAZ and TEAD is essential for the initiation of transcriptional program to drive oncogenesis. YAP is no longer oncogenic when sequestered by a dominant negative TEAD that lacks the DNA-binding domain 106. Similarly, a naturally occurring DNA-binding deficient TEAD isoform is also able to inhibit YAP/TAZ-mediated oncogenicity 107. Therefore, directly inhibiting TEAD or preventing YAP/TAZ-TEAD interaction is a promising and most direct strategy that warrants special attention 108.

Disruptors, stabilizers and destabilizers/degraders. A preformed YAP/TAZ-TEAD complex prevents access to drugs that occupy either the TEADs' surface or the palmitate-binding pocket (PBP), however, unassembled TEADs are accessible to drugs. Majority of the known YAP/TEAD-binding compounds are disruptors as they prevent the formation of the YAP/TAZ-TEAD complex. Two other classes of TEAD-binding compounds are stabilizers and destabilizers/degraders. Stabilizers either stabilize TEAD expression levels or enhance the formation of the YAP/TAZ-TEAD complex. Destabilizers bind to TEADs' surface or PBP and reduce TEAD expression levels through in situ denaturation, degraders on the other hand direct TEADs for proteasomal degradation.

Group I drugs target the upstream YAP/TAZ-activating proteins like the EGFR, GPCR, Src, or Integrins. As there are so many upstream YAP/TAZ activators, group I drugs are vulnerable to oncogenic bypass where inhibition of one group I YAP/TAZ activator leads to selection of cancer cells that activate YAP/TAZ via another group I activator. Strategically, Group II drugs may address this issue by directly targeting YAP/TAZ or TEAD, the converging points for various pathways and also the effectors for oncogenic transcription. However, Group II targeting modalities are still at the exploratory stage and it remains to be seen whether it is feasible to develop a Group II modality that works in clinic. We also need to be mindful of the possible associated toxicities due to YAP/TAZ-TEAD inhibition 109.

Most of the reported Group II modalities are disruptors; they target YAP/TAZ or TEAD and prevent their binary interaction. However, in addition to disruptors, in the future, we predict the emergence two other classes of group II compounds that would act as TEAD stabilizers and destabilizers/degraders (Figure ).

A small molecule benzoporphyrin drug named Verteporfin (VP) was shown to have the ability to bind to YAP and disrupt the YAP-TEAD interaction 106. VP is also able to inhibit YAP-induced excessive cell proliferation in YAP- inducible transgenic mice and in NF2 (upstream Hippo pathway component) liver-specific knockout mouse models 106. Although we do not understand the molecular details of VP binding to YAP, it is still undoubtedly the most popular YAP inhibitor within the scientific community. However, we need to be cautious as some of the tumor-inhibitory effects of VP are reported to be YAP- independent 110, 111. VP is photosensitive and proteotoxic and there is a need for better derivatives. A VP derivative, a symmetric divinyldipyrrine was shown to inhibit YAP/TAZ-dependent transcription but it is not clear if the compound specifically binds to YAP 112.

YAP and TAZ bind on the TEADs' surface; Inventiva Pharma has identified several compounds with benzisothiazole-dioxide scaffold that bind to the TEADs' surface and disrupt the YAP/TAZ-TEAD interaction. These compounds are currently in the lead optimization stage and have the potential to treat malignant pleural mesothelioma as well as lung and breast cancers that are driven by YAP/TAZ 113.

YAP cyclic peptide (peptide 17) and cystine-dense peptide (TB1G1) are also disruptors of YAP/TAZ-TEAD interaction in vitro but they have poor cell-penetrating abilities 114, 115. Interestingly, a peptide derived from the co-regulator Vgll4 appears to have remarkable cell-penetrating abilities and inhibits YAP-mediated tumorigenesis in animal models 116. Vgll proteins, named Vgll1-4 in mammals, belong to another class of co-regulators that pair with TEADs in a structurally similar, and therefore, in a mutually exclusive manner with YAP and TAZ 117, 118.

We identified a novel druggable pocket in the center of the TEADs' YAP/TAZ- binding domain 119 that could be occupied by fenamate drugs. Palmitate was subsequently shown to occupy this pocket, hereafter referred to as the palmitate-binding pocket (PBP). TEAD palmitoylation is shown to be important for stability and for the interaction with YAP 120, 121. Although the fenamate drug flufenamic acid competes with palmitate for binding to TEAD, higher concentrations are needed for it to be effective and it is not a disruptor of the interaction between YAP/TAZ with TEADs 122. However, covalently linking the fenamate to TEAD, using a chloromethyl ketone substitution, enables it to disrupt the YAP-TEAD interaction 123. The non-fused tricyclic compounds identified by Vivace Therapeutics could also be considered as fenamate analogs but it remains to be seen if they function as disruptors 124. Through structure-based virtual screen, vinylsulfonamide derivatives were identified as compounds that bind to PBP 125. Optimization of these derivatives yielded DC-TEADin02 a covalent TEAD autopalmitoylation inhibitor with an IC50 value of 200 nM. Interestingly, DC-TEADin02 is able to inhibit TEAD activity without disrupting the YAP-TEAD interaction.

Palmitate, by occupying the PBP, allosterically modulates YAP's interaction with TEAD 121, therefore it is conceivable that there might be small molecules that occupy the PBP and allosterically disrupt YAP/TAZ's interaction with TEADs. To this end, Xu Wu's group has identified and patented several potent compounds with alkylthio-triazole scaffold as PBP- occupying compounds that prevent YAP-TEAD interaction in cells 126. Another potent TEAD inhibitor that occupies the PBP is the small molecule K-975 127. K-975 also disrupts the YAP-TAZ-TEAD interaction and displayed anti-tumorigenic properties in malignant pleural mesothelioma cell lines much akin to the loss of YAP. Although palmitate is covalently attached to TEAD, it is a reversible modification and addition of PBP-occupying small molecules reduce the cellular palmitoylation status of TEADs 126. Moreover, the palmitoyl group is also removed from TEADs by depalmitoylases 128.

Being predominantly unstructured, YAP and TAZ are difficult to target directly. However, TEADs offer two attractive ways for targeting, one is to directly block the YAP/TAZ-binding pocket on the TEADs' surface with small molecules or peptides, whilst the other is to leverage on the PBP and allosterically disrupt YAP/TAZ interaction or inhibit TEADs (Figure ). However, the molecular determinants that confer YAP/TAZ disrupting ability to PBP-occupying small molecules are not clear. We do not know why flufenamate and DC-TEADin02 are unable to disrupt YAP/TAZ-TEAD interaction, like chloromethyl fenamate, K-975 and compounds with alkylthio-triazole scaffold.

The PBP could also be leveraged to allosterically enhance YAP/TAZ-TEAD stability or interaction. This prediction is subject to the identification of small molecules that functionally mimic the ligand palmitate (Figure ). Compounds with such an ability will enhance TEAD-dependent transcription and may have therapeutic value for regenerative medicine where enhancement of YAP/TAZ- TEAD activity is needed to repair damaged tissues 129. We recently identified that quinolinols occupy the PBP, stabilize YAP/TAZ levels and upregulate TEAD-dependent transcription 130. Enhanced YAP/TAZ levels increase the pool of assembled YAP/TAZ complex and therefore quinolinols could be considered as stabilizers (Figure ).

We identified a few chemical scaffolds that have the ability to occupy the PBP and destabilize TEAD (unpublished results). Addition of these compounds unfolds the TEADs' YAP/TAZ-binding domain and we call these compounds destabilizers (Figure ). Degraders could be generated when potent and selective TEAD surface or PBP-occupying compounds are coupled to proteolysis targeting chimera (PROTAC) 131 to direct TEAD proteasomal degradation. Therefore, destabilizers aim to reduce the cellular concentration of TEADs through in situ unfolding and degraders reduce TEAD levels through proteasomal degradation. Reducing the levels of their interacting partners deprives YAP/TAZ of their ability to activate transcription.

Any TEAD-binding compounds (disruptors, stabilizers or destabilizers/degraders) can only access unbound TEADs, as binding of YAP and TAZ blocks both the surface and the palmitate-binding pockets (Figure ). After accessing unbound TEADs, the disruptors and destabilizers/degraders reduce, whereas the stabilizers enhance, the formation of the YAP/TAZ-TEAD complex.

YAP/TAZ-mediated tumor development is due to the collective action of the repertoire of proteins that are expressed under their influence. However, some proteins are able to drive oncogenesis much better than others and they vary depending on the solid tumor and context. Therefore, drugs against these downstream YAP/TAZ targets including metabolic enzymes, kinases, ligands and proteins, such as BCL-xL, FOXM1 and TG2 are also used to combat YAP/TAZ-mediated oncogenicity (Figure ).

TAZ-dependent expression of ALDH1A1 (aldehyde dehydrogenase) is shown to impart stemness and tumorigenic ability; inhibition of ALDH1A1 using A37 reverses this transformation 132. GOT1 - the aspartate transaminase induced by YAP/TAZ, confers glutamine dependency to breast cancer cells and targeting this metabolic vulnerability using aminooxyacetate (AOA) represses breast cancer cell proliferation 133. Targeting the YAP/TAZ transcriptional target cyclooxygenase 2 (COX-2) using celecoxib inhibits cell proliferation and tumorigenesis in NF2 mutant cells 134. Interestingly, a positive feedback is seen in hepatocellular carcinoma cell lines where COX-2 is also shown to increase the expression of YAP 135. Inhibiting COX-2 using NS398 stimulates LATS-dependent phosphorylation of TAZ 136.

In hepatocellular carcinoma, Axl kinase has been shown to be crucial for mediating several YAP-driven oncogenic functions like cell proliferation and invasion 137. Similarly, YAP-driven Axl expression has been implicated in the development of resistance against EGFR inhibitors in lung cancer and sensitivity could be restored through Axl inhibition using TP-0903 138. YAP is shown to upregulate the expression of the kinase NUAK2 139 that, in turn activates YAP/TAZ by inhibiting LATS. Specific pharmacological inhibition of NUAK2 using WZ400 shifts YAP/TAZ to the cytoplasm and reduces cancer cell proliferation 140.

In a mouse model of prostate adenocarcinoma, the YAP-TEAD complex promotes the expression of the chemokine ligand CXCL5 that facilitates myeloid-derived suppressor cells (MDSC) infiltration and adenocarcinoma progression. Administering CXCL5 neutralizing antibody, or blocking CXCL5 receptor using the inhibitor SB255002, inhibits MDSC migration and tumor burden 40. The notch ligand Jagged-1 that is upregulated by YAP/TAZ is crucial for liver tumorigenesis 59, 141. Treating liver tumor cells with Jagged-1 neutralizing antibody greatly reduces oncogenic traits. The levels of integrin ligands CTGF and CYR61 that are also YAP target genes, could be reduced using the cyclopeptide RA-V (deoxybouvardin) leading to a reduction of YAP- mediated tumorigenesis in mst1/2 (Hippo homolog) knockout mouse model 142. Although neutralizing CTGF (FG-3019/pamrevlumab) and CYR61 (093G9) antibodies are available, they have not been effectively used against YAP/TAZ-driven cancers.

YAP mediates drug resistance to RAF- and MEK-targeted therapies in BRAF V600E cells, in part through the expression of the anti-apoptotic protein BCL- xL. BCL-xL inhibition using navitoclax sensitizes these cells to targeted therapies 92.

YAP-mediated proliferation through its target gene FOXM1 could be prevented in sarcoma cell lines and mouse models through the administration of thiostrepton that reduces FOXM1 levels 143.

Transglutaminase 2 (TG2) - the multifunctional transamidase is a YAP/TAZ target gene that is important for cancer stem cell survival and for maintaining integrin expression. TG2 inhibition using NC9 dramatically reduces tumorigenicity 144, 145.

We are aware that many of these target proteins also act upstream and stimulate YAP/TAZ by forming a positive feedback but we would nevertheless consider them in this group and not as group I as their expression is influenced by the TEAD-binding motif and YAP/TAZ.

Although attractive, toxicity issues and the identification of responsive patient population could be challenges in the successful implementation of the YAP/TAZ inhibitors in the clinic. YAP/TAZ inhibition might elicit toxicity 146; homozygous disruption of YAP in mice causes embryonic lethality, whereas TAZ knockouts are viable 147-150. Tissue-specific deletions of YAP in the heart 151, lung 152 or kidney 153 cause hypoplasia, whereas YAP/TAZ deletion in the liver cause hepatomegaly and liver injury 154. Surprisingly, YAP/TAZ knockouts in the intestine are well tolerated with no apparent tissue defects 155. All of these suggest that YAP and TAZ are crucial for development. However, they appear to be dispensable for adult tissue homeostasis. In most adult tissues, under normal homeostasis, YAP/TAZ are found restricted to the cytoplasm and are activated primarily in response to injury to initiate tissue regeneration. Therefore, it is predictable that administration of a YAP/TAZ inhibitor may not elicit severe toxicity. However, given the dynamic shuttling of YAP/TAZ/Yorkie between nucleus and cytoplasm 156-158, it is feasible that they still have a role in normal tissue homeostasis. Fittingly, YAP has been identified to be important for podocyte homeostasis and its functional inactivation compromises the glomerular filtration barrier and cause renal disease 109. Along similar lines, renal toxicity was observed in mice administered with K-975 - a YAP/TAZ-TEAD inhibitor 127. Renal toxicity in targeted therapy is very common and is seen in most of the kinase inhibitors used in oncology 159. Yet these kinase inhibitors are in the clinic as there is a therapeutic window, where the drug could be dosed to improve patient survival without causing much toxicity. The same could be envisaged for YAP/TAZ-inhibiting drugs.

Several drugs that act as YAP/TAZ inhibitors target multiple signaling pathways. Targeting multiple pathways could be a boon or a bane. Drug resistance is minimized in a multi-targeted approach as potential bypass mechanisms are also targeted. However, toxicity becomes an issue when the drug targets multiple important signaling pathways. For instance, raising cAMP through the use of PDE inhibitors activates a multitude of proteins like PKA, EPACs, ion channels and small GTPases. Similarly, GPCR modulators influence multiple pathways through signaling via G proteins, arrestins or GPCR kinases. To reduce toxic side effects, there are options available like selective targeting or biased signaling. Instead of hitting all the PDEs, the PDE enzyme that is the most potent activator of YAP/TAZ should be selectively targeted. Nonspecific PDE inhibitors cause more severe side effects than sub-type selective PDE inhibitors 160. Similarly, through stabilizing a particular GPCR conformation, certain small molecule GPCR modulators are able to effect signaling bias where one GPCR effector is preferentially activated over others, say G proteins over -arrestins, this way only a subset of signaling pathways get activated 161.

Another major challenge is the identification of patients responding to a YAP/TAZ inhibitor. YAP/TAZ expression is low in normal tissues and their levels are significantly elevated in cancers. Is YAP or TAZ positivity in tumors sufficient criteria to administer a YAP/TAZ inhibitor? YAP and TAZ might not be transcriptionally active or drivers in all tumors. Further, they could be expressing target genes that negatively regulate their activity 162, 163. There are also tumor types where YAP/TAZ or TEAD levels have no prognostic significance 46. These YAP/TAZ positive tumors are unlikely to respond to a YAP/TAZ inhibitor. Barring a few such scenarios, in many solid tumors, YAP or TAZ expression levels correlate well with higher-grade cancers or poor prognosis. Tumors with nuclear YAP or TAZ that are also positive for the downstream oncogenic YAP/TAZ target genes are likely to respond to a YAP/TAZ inhibitor and this should be used as criteria for patient stratification. As many of the YAP/TAZ-TEAD target genes are secreted proteins, the expression levels of these in the serum could also be estimated in addition to assessing their levels through immunohistochemistry.

As YAP and TAZ contribute to the acquisition of many hallmarks of cancer traits, targeting them is predicted to be more relevant for the management of several cancer types. It is still early to expect a newly developed drug against YAP/TAZ but it is nevertheless disconcerting to see that there are hardly any clinical trials that evaluate if known drugs could be repurposed as YAP/TAZ- inhibitors. Group I drugs are well suited to repurpose 105 but only statins ({"type":"clinical-trial","attrs":{"text":"NCT03358017","term_id":"NCT03358017"}}NCT03358017); trametinib ({"type":"clinical-trial","attrs":{"text":"NCT03148275","term_id":"NCT03148275"}}NCT03148275) and epigenetic modulators ({"type":"clinical-trial","attrs":{"text":"NCT03925428","term_id":"NCT03925428"}}NCT03925428) are being evaluated in clinical trials, assessment of the expression levels of YAP/TAZ after drug treatment is used as one of the clinical trial objectives. It is essential that we bolster our pharmacological arsenal so that we are prepared to combat YAP and TAZ. Group I drugs that failed in oncology trials are not expected to fare any better against YAP/TAZ. However, drugs that are already in the clinic like the kinase inhibitors targeting the EGFR or MEK, PDE inhibitors as well as GPCR modulators could be repurposed to combat YAP/TAZ. The cancer types need to be carefully stratified to ensure they are driven by YAP/TAZ through the upstream stimulator targeted by the drug. To overcome potential bypass mechanism or drug resistance, combinatory use of group I and II drugs could also serve as an avenue for cancer treatment. For the group III drugs, the situation may not be as promising, as they target only one of the many possible oncogenic proteins regulated by YAP/TAZ. Again, combinatory inhibition of few downstream target genes could be considered if they are collectively essential for oncogenic manifestation of YAP/TAZ-driven transcription. As they are new and untested, there is much excitement and progress in the development of novel group II compounds as drugs against YAP/TAZ. We are at an exciting juncture in the Hippo field where we could potentially see a novel group II drug or a repurposed group I drug to combat YAP/TAZ in the near future.

A.V. Pobbati and W. Hong are supported by the Agency for Science, Technology, and Research (A*STAR), Singapore. We thank Sayan Chakraborty, Gandhi T.K.B. and John Hellicar for critical reading of this review. We apologize to all authors whose work was not cited due to space constraints.

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A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy

IPS Cell Therapy Comments Off on A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy | March 22nd, 2022

Despite progress involving the use of induced pluripotent stem cells (iPSCs) within disease modeling and drug discovery applications, it will be a long path to achieve the broad-scale use of iPSC-derived cell types in human patients.

Within a preclinical context, cell types differentiated from iPSCs are tested for their therapeutic response. Then, clinical trials are conducted to assure that essential parameters, such as tumorigenicity, dose toxicity, and immunogenicity, are assessed before authorizing the product for use in human patients. iPSC-derived cells have the potential to be used as therapies for treating cardiovascular, neurological, and metabolic diseases, as well as repairing damaged cartilage, spinal, motor neuron and eye tissues resulting from genetic defects or injuries.

In general, the targets for iPSC-derived therapies include any diseases or disorders for which there are no other viable treatments and where there is a need to repair or replace dysfunctional tissue.

Today, the following companies and organizations are forging the path toward iPSC-derived cell therapeutics.

While the groups above are involved with the development of iPSC-based cell therapeutics, not all of them have reached clinical-stage. Companies and organizations developing clinical-stage iPSC-derived therapeutics are described below.

In 2016, Cynata Therapeutics received a landmark approval to launch the worlds first formal clinical trial of an allogeneic iPSC-derived cell product (CYP-001) for the treatment of GvHD. In collaboration with Fujifilm, Cynata Therapeutics completed this Phase I trial in December 2018, reporting positive results.

Cynata Therapeutics is now testing its product candidate CYP-004 in a Phase 3 clinical trial enrolling up to 440 patients. CYP-004 is an allogeneic, iPSC-derived mesenchymal stem cell (MSC) product derived using Cynatas proprietary Cymerus technology. Led by the University of Sydney and funded by the Australian Government National Health and Medical Research Council (NHMRC), the trial will assess whether the cells can improve patient outcomes in osteoarthritis (OA).

It will be the worlds first clinical trial involving an iPSC-derived cell therapeutic to enter Phase 3 and the largest one ever completed.

In December 2019, the National Institutes of Health (NIH) announced it would be undertaking the first U.S. clinical trial of an iPSC-derived therapeutic. The goal of this trial is to restore dying cells of the retina. The Phase I/IIa clinical trial involves 12 patients with advanced-stage geographic atrophy who received an iPSC-derived retinal pigment epithelial (RPE) implant into a single eye. This trial is supported by the Ocular and Stem Cell Translational Research Section of the National Eye Institute (NEI). The NEI is part of the NIH.

In February 2019, allogeneic iPSC-derived NK cells produced by scientists from the University of Minnesota in collaboration with Fate Therapeutics were granted approval by FDA for a clinical trial. Specifically, Fate Therapeutics is exploring the clinical use of FT516 and FT500, which are its off-the-shelf, iPSC-derived natural killer (NK) cell product candidates. In December 2019, the company released promising clinical data from its Phase 1 studies.

In July 2020, Fate Therapeutics subsequently announced FDA clearance of its IND application for the worlds first iPSC-derived CAR T-cell therapy, FT819.FT819 is an off-the-shelf allogeneic chimeric antigen receptor (CAR) T-cell therapy targeting CD19+ malignancies. Notably, the use of a clonal master iPSC line as the starting cell source will position Fate to mass produce CAR T-cells to be delivered off-the-shelf to patients.

The Japanese company Healios K.K. is preparing, in collaboration with Sumitomo Dainippon Pharma, for a clinical trial using allogeneic iPSC-derived retinal cells to treat age-related macular degeneration (AMD).

Of course, there are also numerous physician-led studies underway in Japan investigating the use of iPSC-derived cellular products inhuman patients. These clinical trials are for diseases such as macular degeneration, ischemic cardiomyopathy, Parkinsons disease, solid tumors, spinal cord injury (SCI) and platelet production.

Details on each of these Japanese trials are provided below:

Significant progress has been made for retinal degeneration diseases, particularly for age-related macular degeneration (AMD). In 2009, preclinical data showed for the first time the recovery of visual function in patients injected with retinal pigment epithelium (RPE) differentiated from iPSCs in a rat models retina. A major breakthrough was made when the group led by Masayo Takahashi at the Riken Centre for Developmental Biology in Japan produced iPSC-RPE cell sheets in 2014.

The above-mentioned successes led to the initiation of the first iPSCs clinical trial in 2014 itself. Scientists at the RIKEN Centre in Japan transplanted an autologous iPSC-RPE cell sheet just below the affected retina, without immunosuppression, in a 77-year-old woman with AMD. One year after the transplantation, the progression of the degeneration simply halted, an area with photoreceptors recovery was observed, and the patients vision remained stable. There were no symptoms of immune rejection or tumor development.

In March 2017, Japanese scientists announced that a 60-year-old man was the first patient to receive iPSC-RPE cells derived from another person (an allogeneic source). A clinical-grade iPSC bank for collecting and storing healthy HLA homozygous donors is now being established at the Centre for iPS Cell Research and Application (CiRA) in Kyoto (Japan).

Also in 2017, iPSC-derived cardiomyocytes were grafted on to a porcine model of ischemic cardiomyopathy by Kawamura, et al., using a cell-sheet technique. Cardiac function was significantly improved, and neovasculogenesis was observed. Recently, scientists from Osaka University were granted approval for a clinical trial to transplant allogeneic sheets of tissue derived from iPSCs onto the diseased hearts of three human patients.

Several preclinical studies in spinal cord injuries using iPSC-derived neural progenitor cells in animal models have provided evidence for remyelination and locomotor function recovery. In February 2018, the Japanese government gave an approval to Professor Hideyuki Okano for a clinical trial that will involve the treatment of patients with spinal cord injuries at Keio University.

In September 2018, group of scientists from Kyoto University were granted approval to begin a transfusion trial using platelets derived from iPSCs into an individual with aplastic anemia. The hope is that iPSC-derived platelets could replace transfusions of donated blood.

As early as 2008, it was confirmed that iPSC-derived dopaminergic neurons improved the symptoms and dopaminergic function of a rat model of Parkinsons disease. Approximately a decade later, in October 2018, dopamine precursor cells were created from allogeneic iPSCs produced by Jun Takahashis research group at Kyoto University. Physicians at Kyoto University Hospital then transplanted these cells into subjects with Parkinsons disease. A total of seven patients were involved.

In July 2019, scientists at Osaka University started a clinical trial for limbal stem cell deficiency, a condition in which corneal stem cells are lost. The scientists grafted a sheet of iPSC-derived corneal cells onto the cornea of a patient. Within one month, her vision seemed to have improved.

What questions do you have about the development of iPSC-derived cell therapeutics? Ask them in the comments below.

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Disease in a dish: What mini-hearts and other organs reveal about long COVID - telegraphherald.com

Skin Stem Cells Comments Off on Disease in a dish: What mini-hearts and other organs reveal about long COVID – telegraphherald.com | March 22nd, 2022

Chemotherapy is a standard treatment for many different types of cancer.

Chemicals in chemotherapy drugs stop cancer cells from growing and spreading. These chemicals can also damage healthy cells, especially ones that divide quickly. This includes cells in your skin, digestive tracts, and bone marrow.

Damage to these cells can cause side effects. One common side effect is chemotherapy-induced anemia.

Anemia means you dont have enough red blood cells to properly carry oxygen around your body. This condition develops when chemotherapy drugs damage the cells in your bone marrow that create red blood cells.

Anemia usually goes away once chemotherapy stops but can lead to potentially serious complications when it develops. In this article, we break down causes of chemotherapy-induced anemia, signs and symptoms, and potential complications.

More than 100 types of medications have been developed to treat cancer, according to the University of Iowa Hospitals and Clinics. Different medications disrupt cancer growth in different ways, and all have potential side effects.

The chemicals in chemotherapy drugs mainly target cells that replicate quickly. Along with cancer cells, these drugs can damage healthy cells. A low red blood cell count caused by these medications is called chemotherapy-induced anemia.

The erythroid progenitor cell is particularly vulnerable to chemotherapy, according to 2018 research. These cells are found in your bone marrow and become red blood cells. If many of these cells are damaged, you can develop a low red blood cell count.

A low red blood cell count means your blood has less hemoglobin than average. Hemoglobin is the protein in red blood cells that carries oxygen to all your bodily tissues.

Its estimated that 70 percent of people who receive chemotherapy develop anemia. Its most common in people with:

At least 50 to 60 percent of people with these cancers require at least one blood transfusion. A transfusion is a procedure where youre given donated blood through an IV.

Chemotherapy-induced anemia is also common in people with low hemoglobin levels prior to treatment and people receiving platinum-based chemotherapy medications, according to the American Cancer Society. These medications include:

According to 2019 research, signs and symptoms of chemotherapy-induced anemia can overlap with cancer symptoms. These symptoms often include:

Other signs and symptoms may include:

Research from 2020 suggests anemia can negatively affect the survival rate of people receiving treatment for cancer. Severe anemia may delay or reduce part of your chemotherapy treatment, which can lead to worsened results.

Treatment for anemia may include:

A blood transfusion involves receiving blood from a donor through an IV. Donated blood needs to match your blood type or your immune system may attack the foreign blood cells. Transfusions can help quickly reduce your symptoms by increasing the circulation of oxygen to your organs and tissues.

Transfusions are commonly performed when hemoglobin levels drop below 8.0 grams per deciliter (g/dL) of blood.

A medical professional can administer erythropoietin-stimulating agents as a shot under your skin. Theyre synthetic versions of the hormone erythropoietin produced by your kidneys. This hormone stimulates the production of red blood cells.

It usually takes 4 to 6 weeks for these drugs to have a significant effect, and about a third of people dont respond at all. Healthcare professionals usually only recommend them for people receiving palliative treatment to ease symptoms of anemia when cancer isnt considered curable, according to 2019 research.

Erythropoietin-stimulating agents can help increase your hemoglobin levels and reduce the need for blood transfusions, but theyre associated with serious health complications and an increased risk of death, according to 2009 research.

About 65 percent of your bodys iron is found in hemoglobin, a protein in your blood that carries oxygen to your bodys organs and tissues. Without enough iron, blood cells cant carry oxygen to cells throughout your body. Low iron levels can also lead to anemia.

Your doctor may give you a prescription for an iron supplement or tell you to eat more high iron foods, like:

Researchers are still investigating the potential benefits of iron supplementation for people receiving erythropoietin-stimulating agents. Research from 2017 suggests that it may help reduce the need for blood transfusions.

Your doctor may also give you a prescription for folic acid (vitamin B9) or vitamin B12. These vitamins are also necessary to produce red blood cells.

Chemotherapy-induced anemia often goes away once treatment ends and your body has time to repair itself. According to the Canadian Cancer Society, low blood cell counts typically begin to recover 2 to 4 weeks after chemotherapy ends.

In the meantime, you can do the following to manage your symptoms:

According to the American Cancer Society, anemia has been found to shorten the lifespan of people with cancer. It may delay cancer treatment, and sometimes the lack of oxygen to your cells can be life threatening.

If your tissues arent getting enough oxygen, your heart has to work harder to move blood through your body. According to the National Heart, Lung, and Blood Institute, increased stress on your heart can worsen already present heart problems or lead to conditions such as:

Breathing problems from anemia can make everyday tasks, like walking, difficult and impact your quality of life.

Anemia is a common side effect of chemotherapy. The chemicals in chemotherapy medications that destroy cancer cells can also damage healthy cells in your body. Anemia usually passes once chemotherapy stops.

Your cancer team can help you manage symptoms of anemia through medications, blood transfusions, and prescribing vitamins and minerals. Its important to communicate with your team about any new symptoms you develop so you can build the best treatment plan possible.

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Chemotherapy-induced Anemia: Symptoms, Treatment & More - Healthline

Skin Stem Cells Comments Off on Chemotherapy-induced Anemia: Symptoms, Treatment & More – Healthline | March 22nd, 2022

HuffPosts Small Business Spotlight is a series aimed at highlighting the small businesses that are making a positive difference while forging new and significant futures in commerce.

Your scalp is really just an extension of the skin on your face, so why dont we care for it in the same way? Studies have shown that theres a direct correlation between scalp health and hair health and retention.

Helen Reavey, a hair stylist and trichologist, set out to solve that problem and found a solution in creating Act+Acre, a sustainable hair care line that focuses on improving the condition of the scalp first so that healthy hair can follow.

Throughout her 20-year career in the hair industry, Reavey worked in salons and at fashion weeks across the globe, and began to notice a pattern in the hair she saw and styled. Scalps were red and raw from overstyling and product buildup on the scalp, accompanied by dead and damaged hair.

I said to myself that I wished I had something to send these girls home with to dissolve the product, calm down inflammation and just really deliver nutrients to the scalp, the skin and the hair follicle, Reavey told HuffPost.

Now, products like Act+Acres Scalp Detox and Scalp Renew do just that by breaking down excess sebum, dead skin cells and product buildup, making the way for more abundant and healthier hair growth. Among other treatments, theres also a Stem Cell Serum that nourishes the hair follicle and helps to extend the growth phase.

Reavey said that the connection between scalp health and hair health seemed to be widely overlooked within the beauty industry, noting that caring for the scalp really goes beyond just the immediate improvements you may see once you start to address some of the most common concerns like itching, flaking and lack of hair volume.

Its really about from five to seven years from now that the hair in that cycle will really start to show what you were doing to it five, seven years ago. Its like when we work to prevent lines, wrinkles or sun damage now because we dont want them to appear in another five to 10 years, she said.

For Reavey, the conception and subsequent launch of Act+Acre in 2019 was also about challenging the norms and processes of the larger corporations that came before her their systems of transparency (or lack thereof) with their consumers, their wasteful approach to production and product development, and the kinds of ingredients being used.

Act+Acre uses a cold process method to create all of their products, a patented system that involves a hyperbaric chamber, cold air and pressure to extract the most from ingredients at their highest concentrations, which is possible because they arent evaporated off in the process. It also uses 90% less energy than traditional and cheaper methods with heat.

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This Hair Care Line Gives You Luscious Locks By Improving Your Scalp Health - HuffPost

Skin Stem Cells Comments Off on This Hair Care Line Gives You Luscious Locks By Improving Your Scalp Health – HuffPost | March 22nd, 2022

Spinal cord injuries can be devastating and there are currentlyfew options to reverse the effects, which can include paralysis, chronic pain and loss of bladder control.

But an international team of researchers, including the University of Torontos Molly Shoichet,hopes to change that.

Over the past few years, weve made a lot of progress in tissue engineering, drug delivery and regenerative medicine, says Shoichet, a University Professor in the department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering, the Institute of Biomedical Engineering and the Donnelly Centre for Cellular and Biomolecular Research.

With this ambitious project, we bring world leading experts together to try to do something that no one else has been able to do: promote repair and regeneration in the injured spinal cord.

Shoichet is a co-principal investigator withMend the Gap, an international collaboration of more than 30 researchers, engineers, scientists, surgeons and social scientists from Canada, the United States, Europe and Australia. The collaboration this week received $24 million from Canadas New Frontiers in Research Fund to advance their work.

The team takes its name from the fact that only a small gap, just a few centimetres long, is responsible for blocking the nerve impulses that normally flow through the spinal cord. Bridging that gap requires collaboration from some of the worlds top experts in a wide range of fields.

Shoichet is known internationally for her work on hydrogels biocompatible materials that can help facilitate tissue repair. Hydrogels can function as scaffolds, enhancing or augmenting natural processes that serve to repair damaged tissue.

Hydrogels can also serve as controlled-release mechanisms for drugs that aid healing, or to protect stem cells that are being injected into the body bykeeping them alive and healthy while they integrate into damaged tissues.

Another important line of research involves dealing with the glial scar that forms in the wake of a spinal cord injury. In the short term, this protective shield of cells and biochemicals prevents further injury in the damaged nerve, but in the long termit can serve as a barrier to nerve repair.

Shoichet and her team bring their expertise in hydrogels and local delivery strategies to deliver innovative biomolecules locally and directly to the injured spinal cord. For example, shere-engineered an enzymeto selectively degrade some of the biomolecules that make up the glial scar. This redesigned enzyme is both more stable and more active than the wild type.

By breaking through the glial scar with this new delivery strategy, the enzyme can enable other therapies from advanced drugs to stem cells to further promote tissue regeneration and repair.

The environment in the injured spinal cord is a very complicated place, says Shoichet. There are a whole range of natural processes at work some of which we want to enhance, others of which we need to find ways to circumvent. I am very excited to be part of this multidisciplinary team, which has the breadth and depth of expertise that we need to make a real difference when it comes to treating spinal cord injury.

Shoichet is the only person to be elected a fellow of all three of Canadas national academiesand is a foreign member of the U.S. National Academy of Engineering and a fellow of the Royal Society of London. She was the 2020 recipient of the Gerhard Herzberg Canada Gold Medal, Canadas highest honour for science and engineering research. She is also a member of the Order of Ontario and an Officer of the Order of Canada.

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Mending the gap: U of T's Molly Shoichet joins team developing new treatments for spinal cord injuries - News@UofT

Spinal Cord Stem Cells Comments Off on Mending the gap: U of T’s Molly Shoichet joins team developing new treatments for spinal cord injuries – News@UofT | January 18th, 2022

A mum who has lived with multiple sclerosis for over a decade says a 50,000 treatment unavailable on the NHS could be her last shot at living a life largely unhindered by the disease.

Jodie McQuillian, 32, was formally diagnosed with the chronic condition in 2015, a few years after the first signs appeared when she temporarily lost vision in her left eye.

Since then, she has undergone multiple treatments and bouts of physiotherapy in order to stave off relapses of the condition.

But the mum of one faces life in a wheelchair if she can't put a halt to the rampant flare-ups.

Multiple sclerosis, often known as MS, is a condition where the immune system mistakenly attacks nerves around the brain and spinal cord, affecting the body's ability to transmit signals properly.

Each time Jodie "relapses" - when her body launches a new attack on itself - she finds herself sapped of energy and often experiences issues with her sight and mobility.

It takes her months to recover from each flare-up, affecting the time she can spend with son Ethan, five, and her family.

And every time there's a relapse, a little bit of her doesn't come back.

Jodie, from Alloa, told the Record: "I've just had another relapse and everything I'm trying isn't really effective enough.

"Since I started my newest treatment my walking has gotten a lot worse.

"Every time you relapse you recover but it takes months and you get put on a high dose of steroids and that drains you of all your muscle.

"I'm always left a wee bit damaged from a relapse - and when I feel like I've sort of recovered they flare up again."

After experiencing a major flare-up when she gave birth to Ethan, Jodie began undergoing treatment for MS, trying every drug available on the NHS in a bid to reduce the risk of relapsing.

Despite trying Copaxone injections, Tecfidera tablets and Ocrevus infusions through a drip in her arm over the course of five years, the setbacks have continued and Jodie's outlook is bleak.

There is currently no cure for MS and while her condition is currently recurring intermittently, it is likely to become progressive later in life with little hope of recovery.

However, her last hope may lie in a new treatment known as haematopoietic stem cell transplantation, or HSCT.

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Backed by the MS Society, it is an intense chemotherapy procedure that aims to "reset" Jodie's immune system and stop it from attacking her brain and spinal cord using stem cells found in bone marrow.

The treatment was approved for use on the NHS in Scotland in 2019 but the criteria is so tight that even Jodie, with her frequent relapses, doesn't qualify for it.

Her only option has been to go private abroad - at a cost of 50,000 - and her sister Tricia has launched a GoFundMe page to crowdfund the costs of the operation.

Since publishing the page last week, over 13,000 has been donated by well-wishers, giving Jodie hope she can put a halt to her body's war against itself.

HSCT won't fix the damage done to nerves nerves in the last decade, and is not without its risks, with side-effects such as increased risk of developing cancer.

However, it should put a stop to further degeneration - and serves as Jodie's last hope to live a life relatively free of MS.

"Every relapse is like setting my body up from scratch, and it happens again and again," she added.

"If my MS becomes progressive there's not a lot of treatment available for that all.

"I know from my own research it's beneficial doing the treatment sooner rather than later - and I'm too young not to try it now.

"My next relapse will probably put me in a wheelchair. But you wouldn't look at me 90% of the time and think there's anything wrong.

"To be honest, I feel like this is the last hope. This is the most extreme treatment you can get - it's chemotherapy.

"There's not much else I can do after this but it can't wait.

"It won't be an easy fix, it's not a bounce back - but it will stop the progression, and that's the goal.

"I want to be able to live my life - that's all I ask."

Jodie's sister Tricia Moran, who spearheaded the fundraising appeal, said: "Watching Jodie go through that first episode...it was quite heartbreaking as a family to watch.

"We didn't get any answers for a long time and it really impacted on her confidence - we couldn't reassure her and felt quite helpless.

"As a family we've seen her struggle so much with her relapses and she's so aware of what she's lost.

"She can't just take Ethan to the toy shop on a whim - everything has to be planned.

"It's an understatement to say how overwhelmed we have been by the kindness of friends, family and complete strangers."

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Scots mum with MS says 50k treatment abroad is 'last hope' of halting disease - Daily Record

Spinal Cord Stem Cells Comments Off on Scots mum with MS says 50k treatment abroad is ‘last hope’ of halting disease – Daily Record | January 18th, 2022

Cytokines TNF and IL-6 can cause severely damaging inflammatory effects as a result of stem cells attacking host cells of blood cancer patients

By BRANDON NGUYEN science@theaggie.org

Researchers at the UC Davis Medical Center recently discovered a novel treatment against graft-versus-host disease (GVHD), a potentially lethal inflammatory condition that can arise following stem cell transplantation, which treats blood cancers and disorders. Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) to treat some blood cancers and disorders involves injecting a donors bone marrow stem cells, also known as graft, into blood cancer patients undergoing chemotherapy and radiation therapy.

Dr. William Murphy, a professor at the UC Davis School of Medicine under the Department of Dermatology and Internal Medicine and senior author of the study, further explained what GVHD is under the context of blood cancers.

If we take stem cells from another source, usually trying to match as much as we can from a related source such as a sibling, there seems to be an anti-tumor effect, Murphy said. This desired, beneficial effect from stem cell transplantation is called the graft-versus-tumor (GVT) effect. But the graft-versus-host disease means those immune cells can also attack not just the cancer, but the recipient or patient, which occurs pretty often.

The medical dilemma Murphy and his team of researchers faced involved maximizing GVT effects while minimizing GVHD during stem cell treatment to help the patient effectively fight off the tumor. Logan Vick, a graduate student under Murphys lab at the UC Davis Medical Center and a co-author of the study, talked about the major findings that help minimize GVHD in allo-HSCT patients.

In graft-versus-host disease, something that can be picked up as a symptom is this release of cytokines, which are inflammatory proteins, Vick said. TNF and IL-6, which are two inflammatory cytokines, are often used as tools of the immune system to combat either viruses or different pathogens, but prolonged inflammation can have consequences. So by blocking these two cytokines, what we call a dual cytokine blockade, can help ameliorate GVHD.

The cytokines, TNF and IL-6, that Vick focuses on can cause a cytokine storm, which can occur during GVHD when donor immune stem cells attack the hosts healthy cells instead of the tumor and induce inflammation caused by cytokines. GVHD and the dangerous cytokine storm effect has been a problem for stem cell transplantation treatments, but Murphys team of researchers have just found a potential cure to GVHD while still maintaining the efficacy of the treatment.

Lam T. Khuat, a postdoctoral researcher at Murphys lab and the first author of the study, summarized the beneficial results from dual cytokine blockage.

Many treatments for GVHD involve suppressing the bodys immunity, which can inhibit beneficial GVT effects, Khuat said via email. For this reason, it was important to determine if blocking these cytokines impacted the GVT response. Fortunately, anti-tumor effects remained after the transplant and with the combined intervention.

Clinical methods have often employed single cytokine blockades; however, with the novel finding that dual cytokine blockades can minimize the proinflammatory responses induced by GVHD, the treatment can also be applied in other health conditions that require stem cell transplantation or reducing inflammatory side effects.

Normally, when you have an overactive immune system, whether its autoimmune disorders or GVHD or even in viral infections, the treatments sometimes blanket immunosuppression with steroids, Murphy said. Well, that works because they turn off the immune system, but in the case of cancer and viral infections, you want a working immune system. The beauty of using this double block, which can be applied in other clinical settings, is it doesnt suppress the immune system while preventing the inflammation and the damage.

Written by: Brandon Nguyen science@theaggie.org

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UC Davis researchers find dual cytokine blockage as a novel treatment against graft-versus-host disease in blood stem cell transplantations - The...

Bone Marrow Stem Cells Comments Off on UC Davis researchers find dual cytokine blockage as a novel treatment against graft-versus-host disease in blood stem cell transplantations – The… | January 18th, 2022

Bone Marrow-Derived Stem Cells (BMSCS) Marketanalysis report gives a clear idea on various segments that are relied upon to observe the quickest business development amid the estimated forecast frame. This report indicates a professional and all-inclusive study of the market which concentrates on primary and secondary drivers, market share, competitor analysis, leading segments and geographical analysis. With the particular base year and the historic year, definite estimations and calculations are carried out in this business report. The globalBone Marrow-Derived Stem Cells (BMSCS) Marketreport displays a comprehensive study on production capacity, consumption, import, and export for all the major regions across the globe.

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Table of Content:

Chapter 1: Bone Marrow-Derived Stem Cells (BMSCS) Overview, Product Overview, Market Segmentation, Market Overview of Regions, Market Dynamics, Limitations, Opportunities and Industry News and Policies.

Chapter 2: PEST (Political, Economic, Social and Technological) Analysis of Bone Marrow-Derived Stem Cells (BMSCS) Market.

Chapter 3: Value Analysis, Production, Growth Rate and Price Analysis by Type of Bone Marrow-Derived Stem Cells (BMSCS).

Chapter 4: Downstream Characteristics, Consumption and Market Share by Application of Bone Marrow-Derived Stem Cells (BMSCS).

Chapter 5: Production Volume, Price, Gross Margin, and Revenue ($) of Bone Marrow-Derived Stem Cells (BMSCS) by Regions.

Chapter 6: Bone Marrow-Derived Stem Cells (BMSCS) Production, Consumption, Export, Market Trends and Competitive Landscape.

Chapter 7: Bone Marrow-Derived Stem Cells (BMSCS) Market Status and SWOT Analysis by Regions.

Chapter 8: Competitive Landscape, Product Introduction, Company Profiles, Market Distribution Status by Players of Bone Marrow-Derived Stem Cells (BMSCS).

Chapter 9: Bone Marrow-Derived Stem Cells (BMSCS) Market Analysis and Forecast by Type and Application.

Chapter 10: Market Analysis and Forecast by Regions.

Chapter 11: Industry Characteristics, Key Factors, New Entrants SWOT Analysis, Investment Feasibility Analysis.

Chapter 12: Market Conclusion.

Chapter 13: Appendix Such as Methodology and Data Resources of This Research.

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Bone Marrow-Derived Stem Cells (BMSCS) Market Size Is Expected To Generate Huge Revenue and Competitive Outlook Industrial IT - Industrial IT

Bone Marrow Stem Cells Comments Off on Bone Marrow-Derived Stem Cells (BMSCS) Market Size Is Expected To Generate Huge Revenue and Competitive Outlook Industrial IT – Industrial IT | January 18th, 2022

Over the past two years, the United States has seen more than 63 million Covid-19 cases, with some people infected more than once. More than 240 million people in the US have received at least one dose of a Covid-19 vaccine. More than 60 million have received three.

While Covid-19 infections are never a good thing, these numbers still add up to a glimmer of good news: A large majority of Americans now have some immunity against SARS-CoV-2, the virus that causes Covid-19. Thats a big step toward defanging the disease.

When the human body is infected by the virus or encounters a fragment of the pathogen in a vaccine, our immune systems change in subtle but important ways. Across a huge swath of the population, these changes could eventually help transform Covid-19 from a world-stopping catastrophe into a mild annoyance.

Antibodies, proteins that attach to the virus, are a critical part of the immune response and are often the center of discussions about protection from Covid-19. But they rise during infection and decline naturally over time. Fortunately, antibodies are not the whole story when it comes to the immune system.

Other, longer-lasting tools against infection are hiding inside our bones. The immune system draws on stem cells living in bone marrow to produce an array of components that we dont hear as much about. They form many kinds of white blood cells that jump into action right away when they encounter a virus for the first time, and that essentially take notes to start planning for the next infection.

Its this immune system memory thats key to long-term protection against Covid-19. Whats reassuring is that as white blood cells get more practice against SARS-CoV-2, they seem to get better at containing the virus even when it evolves into new variants. That appears to be happening in the omicron wave of Covid-19.

Omicron is the most transmissible variant of the coronavirus known to date. It also appears to be better at dodging immune protection from Covid-19 vaccines. Cases have reached record levels in many parts of the United States, and hospitals are once again straining under the burden.

But the fraction of cases leading to hospitalizations and deaths appears to be far smaller compared to other variants. While there are more reports of breakthrough infections and reinfections with omicron, many previously exposed people report mild, cold-like symptoms.

One reason is that the virus itself appears to have mutated in a way that leads to fewer dangerous complications. Yet its also clear that widespread immunity is absorbing some of the worst effects of the disease, a hopeful trend that is likely to continue in 2022 and beyond.

The world is full of so many things that can make us sick viruses, bacteria, parasites, fungi, even mutated versions of our own cells. The threats are varied and unrelenting, but so too is our immune system. Its an orchestra of cells, proteins, organs, and pathways that all harmonize to keep invaders at bay. In simplified form, heres how.

When a pathogen like the coronavirus enters the body for the first time, it confronts the innate immune system, which provides generalized protection against all pathogens, but isnt always enough to prevent illness on its own. After an infection takes root, the immune system launches a more targeted response with whats known as the adaptive immune system.

Neutralizing antibodies form the pillar of the adaptive immune system. The virus is studded with spike proteins (giving it its namesake corona, meaning crown in Latin), which attach to human cells to begin the infection process. Y-shaped antibodies can attach to the spikes on the virus and prevent it from entering cells, thereby neutralizing the pathogen. The parts of a virus that can trigger an immune response are known as antigens.

In general, neutralizing antibodies keep you from getting infected in the first place, said Lewis Lanier, chair of the microbiology and immunology department at the University of California San Francisco.

Neutralizing antibodies are picky about the parts of the virus they recognize, known as epitopes. If those attachment points on the virus change, as they do in many coronavirus variants, antibodies can become less effective. In the months following an infection or immunization, the amount of these neutralizing antibodies declines as well. Thats expected. Making antibodies takes a lot of energy, so the body makes fewer of them after an infection is gone.

That decline may sound worrisome, but the immune system has other powerful tools in its shed. To start, there are non-neutralizing antibodies. These dont directly interfere with how the virus functions, but they can help the immune system detect infected cells and mark them for destruction. This is a crucial task because viruses cant make copies of themselves on their own: They need to commandeer a host cell to reproduce. Once a virus enters a cell, its not accessible to neutralizing antibodies, but non-neutralizing antibodies that learned to recognize infected cells can still raise the alarm.

The task of eliminating infected cells falls to a group of white blood cells known as cytotoxic T cells, sometimes called killer T cells. They arise from stem cells in bone marrow and cause infected cells to self-destruct, without messing with normal cells.

T cells, they cannot prevent infection, said Lanier. The only way a T cell can recognize you have an infection is after a cell has been infected.

Helper T cells are another important white blood cell variety. They spur the production of antibodies by a different group of white blood cells called B cells. B cells form in bone marrow and then migrate to lymph nodes or the spleen.

After an infection or a vaccination, some B cells and T cells stick around, becoming memory B cells and T cells. They sit idle, sometimes for decades, waiting to see if a pathogen returns. If it does, they can quickly reactivate.

This is why we a decline in neutralizing antibody counts isnt always a disaster. Even if concentrations of neutralizing antibodies dip so low that they can no longer prevent an infection, other parts of the immune system can spool up to make sure the virus doesnt do too much damage.

There is a window of time after virus gets into the body before it really starts manifesting disease in the person, said Deborah Fuller, a professor of microbiology at the University of Washington School of Medicine. That window of time enables the immune system that has been vaccinated and has memory immune responses to recall very quickly and shut down the virus before it actually causes disease.

Some health officials now say that Covid-19 is so rampant that most people are likely to become infected at some point. Its hard to process whats actually happening right now, which is most people are going to get Covid, Janet Woodcock, acting commissioner of the Food and Drug Administration told the Senate health committee on Tuesday. What we need to do is make sure the hospitals can still function, transportation, other essential services are not disrupted while this happens.

However, waves of infection can crest just as quickly as they form. Countries like the United Kingdom and South Africa experienced awful omicron spikes but subsequently saw precipitous drops in cases thereafter. Omicron cases also appear to be leveling off in some parts of the US, a sign that a decline may be ahead.

Whether these spikes in Covid-19 cases lead to severe health outcomes hinges on the teamwork of B cells, T cells, and antibodies, and how they hold up against any new mutations in the virus. Its an area of active research for scientists.

Vaccines and prior infection may not prevent you from being infected by the next waves of variants, but it may well keep you out of the hospital, Lanier said.

For the past two years, with recurring spikes in Covid-19 cases, neutralizing antibodies have taken center stage. Were really more concerned right now in the middle of the pandemic about the durability of that antibody because what were trying to do is prevent transmission, said Fuller. But that could change.

Neutralizing antibodies remain a key benchmark for vaccines: Scientists judge the success and timing of vaccines in part by measuring the number of antibodies they provoke in our blood, and how long the antibodies stick around. When the mRNA vaccines from Moderna and Pfizer/BioNTech were in development, they demonstrated that they could elicit a high level of neutralizing antibodies. Further clinical trials showed that this translated to more than 90 percent efficacy in preventing illness.

The next test is how well antibody production ramps back up if the same virus invades again. It can take up to two weeks to generate antibodies after being exposed to a virus for the first time, but production can ramp up much faster during a second infection.

At the same time, a virus is rarely the same when it comes back. Viruses mutate frequently as they reproduce, and RNA viruses like SARS-CoV-2 are especially prone to change. Versions of the virus with distinct groupings of mutations are categorized as variants, like omicron, delta, and alpha. Our immune systems are getting stronger and faster, but changes to the virus still have the potential to throw them for a loop.

Already, some companies are developing omicron-specific vaccines, but they may not hit the market for months. The reformulated shots may be too little, too late. In the meantime, we have to rely on the immunity we already have, including boosts to our antibody counts that come from booster doses of Covid-19 vaccines.

There is still much to learn about how all the elements of the immune system work together over time to hold off Covid-19, and some of the answers will only become evident with time. And the odd behavior of omicron is forcing researchers to rethink what theyve learned.

The good news is that many aspects of our immune system also appear to handle the latest variant well. From what Ive seen, the T cell responses are still working rather well against omicron, said Brianne Barker, a vaccine researcher at Drew University. I think that weve still got a bit of time in which immune protections will remain intact.

Immunity will continue building across the population and will blunt the sharp edges of the pandemic, even as the virus changes. Covid-19 is unlikely to go away entirely. As it circulates, it will continue to mutate and may cause sporadic outbreaks. But our immune systems are making progress.

As you expose the human body, even to the same antigen over and over again, our immune system evolves as well, Fuller said. What were starting to see in people with third immunizations is an antibody [response] that is broader.

Its a good sign that improvements in our immune system are likely to outpace changes in the virus. But the pandemic has also made it clear that there is nothing about its trajectory we can take for granted. While the cells within us may shield against infection, its still a good idea to limit transmission of the virus in any other way we can. The fewer people it infects, the fewer unpleasant surprises ahead.

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Covid-19 immunity: How antibodies, B cells, and T cells tackle omicron - Vox.com

Bone Marrow Stem Cells Comments Off on Covid-19 immunity: How antibodies, B cells, and T cells tackle omicron – Vox.com | January 18th, 2022

When Lily Whitmarsh was diagnosed with leukaemia in 2019, days after she turned 20, it came as a complete shock. My world came crashing down around me and I went into total meltdown, she says.

She had been a fit and healthy teenager, but in the run-up to her birthday began experiencing mysterious symptoms. I was constantly complaining that my legs ached and I was sometimes napping twice a day and still feeling exhausted, she recalls.

I looked extremely pale and was experiencing night sweats. I remember going out for a walk and having to stop halfway because I was so out of breath and felt dizzy.

Lily, now 21, from Gillingham in Dorset, noticed a slight pinprick rash on the bottoms of her legs and odd-looking bruises which she couldnt explain appearing randomly on her body. She went to her GP and was referred for blood tests.

Alarm bells rang when she was told her platelet count was extremely low and she was immediately sent to hospital.

After a bone marrow biopsy, Lily was diagnosed with acute lymphoblastic leukaemia. To make matters more complicated, she had a rarer subtype called Philadelphia positive, in which the leukaemia cells grow more rapidly.

She underwent chemotherapy treatment and went on to have a bone marrow transplant during the coronavirus pandemic. With no immune system, Lily knew she was extremely vulnerable and spent a lot of time shielding and avoiding people.

By the time the country went into lockdown and she left hospital after her transplant, she had already spent months in almost total isolation, only able to see close friends and family and with precautions to stay germ-free.

After having my bone marrow transplant in March 2020, my immune system was extremely weak and I had to be very careful not to pick up any bugs as my body would struggle to fight them.

When Lily went into hospital, she was only allowed visitors for about a week before the first coronavirus lockdown. Luckily, she had her mum, Lucy Shaw, by her side and says that she couldnt have coped without her support, or that of the Teenage Cancer Trust.

Every day, seven young people in the UK aged 13 to 24 hear the words you have cancer. Teenage Cancer Trust helps put them in the best possible place physically, mentally and emotionally for their cancer treatment and beyond through expert nurses and support teams.

Lily received support from the charitys youth support co-ordinator, Leonie, and says Leonie not only understood every aspect of a cancer diagnosis, but what it meant to be going through it as a young person.

Lily admits that being faced with a cancer diagnosis at such a young age, she had moments where she wondered: Why me? With so many young people being diagnosed with cancer every day now, I then had to think: why not me? I wasnt any different to anybody else before I got ill, so the denial soon wore off and I accepted my illness was a process and I just had to work through it.

Lily says that Leonie taught her to be strong and accept what was happening to her and feel more in control of her illness.

Lily says: The thing with cancer is, it literally doesnt care. It doesnt care about your gender, your age, your race; and in my case, it didnt care about my lifestyle either.

I just woke up one day with some dodgy cells and then, bam, youre told youve got it and it wont go away without gruelling treatment that puts your whole life on hold and makes you contemplate whether youre even going to survive.

A bone marrow donor was found for Lily using the Anthony Nolan bone marrow donor register. Three matches for her were found worldwide and all she knows about her donor is that he is a 39-year-old man from the UK.

After her transplant, the Covid-19 pandemic meant Lily had to isolate at home with her mother, sister and stepfather. She suffered severe exhaustion. I was like a newborn baby and was sleeping for 18 or 20 hours a day and my diet was bland, white food, she remembers. Having no immune system in a global pandemic isnt the ideal situation, but I felt safe knowing by not seeing people, I couldnt catch anything.

On 30 August, almost a year after her diagnosis, she celebrated her 21st birthday with an outdoor garden party and was finally able to see people, from a distance. It was a real milestone, she says.

However, in November 2020, just as Lily was making huge strides in her recovery, her mother received a diagnosis of breast cancer and had surgery that Christmas, followed by radiotherapy and chemotherapy in the new year.

My mum went through it all with me and then suddenly, our roles were reversed and I had to see her go through it all.

Between the two of us, we went through a lot that year, says Lily. But we got through it and came out the other side. My mum has finished all her treatment and is doing well.

The two women are now looking forward to a brighter 2022 and Lily says she is eternally grateful to the stranger who gave her her life back by donating his stem cells.

I count my lucky stars every day that my anonymous donor did what he did and donated his stem cells, says Lily.

Without him, I wouldnt have had another Christmas. What matters most now is spending time with my family and friends and to be able to finally start living again, not just surviving.

This random stranger did this wonderful and kind thing. He doesnt know me, but he has saved my life. Without him, I would be very poorly or not be here.

My treatment was harsh, it massively affected my life and will do for the next few years at least. But I have come so far and will forever be proud of myself for that.

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My mum helped me recover from leukaemia then she was diagnosed with breast cancer. This is how - iNews

Bone Marrow Stem Cells Comments Off on My mum helped me recover from leukaemia then she was diagnosed with breast cancer. This is how – iNews | January 18th, 2022

Stem cells are the bodys raw materials. They are unspecialized cells that have ability to renew themselves through mitotic cell division and differentiate into a diverse range of specialized cell types. They are critical for the development, growth, maintenance and repair of bones, muscles, blood, brain, nerves, skin and other organs. There are several sources of stem cells:

Embryonic Stem Cells: These stem cells come from embryos that are three to five days old. These are pluripotent stem cells and can be used to regenerate or repair diseased tissues and organsAdult Stem Cells: These stem cells are found in most adult tissues (bone marrow or fat) in small numbers. As compared to embryonic stem cells, they have more limited ability to give rise to various cells of the bodyInduced Pluripotent Stem Cells: Using genetic reprogramming, adult cells are transformed by scientists into stem cells that act similar to embryonic stem cellsPerinatal Stem Cells: These stem cells are found in amniotic fluid & umbilical cord blood. They have the ability to change into specialized cells

Factors Igniting Interest in Stem Cells

To Develop Understanding of How Diseases Occur: By observing how stem cells mature into cells in nerves, bones, heart muscles and other organs and tissues, researchers and healthcare professionals may better understand how diseases and conditions developHelp in Generating Healthy Cells to Replace Diseased Cells: Stem cells possess the potential to transform into specific cells that can be used to regenerate and repair diseased or damaged tissuesTo Test Safety and Effectiveness of New Drugs: Prior to using investigational drugs on people, researchers can use stem cells to test drugs for quality & safety

Transplantation of Blood Stem Cells Most Established Stem Cell Treatment

Currently, there are only limited stem cell therapies that have been thoroughly established as safe and effective treatment. The most well-established and widely used stem cell treatment is the transplantation of blood stem cells to treat diseases and conditions of the blood and immune system, or to restore the blood system after treatments for specific cancers.

Favorable investment environment, rising clinical trials for stem cell based-therapies, increasing demand for induced pluripotent stem cells (iPSCs) as an alternative to embryonic stem cells (ESCs) and the rising demand for cell & gene therapies are some of the key factors driving the growth of the Stem Cell Therapy Market.

Get Customized Report on Stem Cell Therapy Market @ https://meditechinsights.com/stem-cell-therapy-market/

Other areas/indications where stem cell therapies are being used are:

For the treatment of knee cartilage defects in patients with Osteoarthritis (OA)For the treatment of Crohns fistulaFor regeneration of subcutaneous adipose tissueFor the treatment of ALS (Amyotrophic Lateral Sclerosis)For the treatment of acute graft versus host disease (aGVHD) in children and adults, among others

Derivation of embryonic stem cells (ESCs) requires destruction of human embryos. Ethical concerns related to embryonic stem cells is one the of key factors that is likely to hamper the growth of the Stem Cell Therapy Market. Increasing number of clinics offering unproven stem cell-based treatments is another ethical issue faced in the field of stem cell-based therapies.

Stem cells have a bright future for the therapeutic world by promising stem cell therapy. We hope to see new horizon of therapeutics in the form of bone marrow transplant, skin replacement, organ development, and replacement of lost tissue such as hairs, tooth, retina and cochlear cells.

CEO, South Korea Based Stem Cell Therapy Provider

Future Outlook of Stem Cell Therapy Market

Stem cell therapy could be the medical innovation of the century. It has emerged as a promising new approach in almost every medicine specialty. Despite an enormous amount of research being undertaken, there are still limited safe and effective treatments available to patients. This is partially because complex diseases which are currently incurable require complex treatments and a personalized approach.

However, the future growth prospects of stem cell therapy market looks promising as there are several ongoing and completed clinical trials involving stem cells which are showcasing positive outcomes.

In clinical studies and treatment attempts, stem cell therapies have been tested with the following indications:

Macular DegenerationNeurological ConditionsDiabetesGraft-versus-host disease (GvHD)Cirrhosis of the Liver, among others

Stem cell therapies are increasingly being seen as the transformative step in treating conditions with unmet needs. This, coupled with growing investment in the sector and an increasing number of stem cell donors is expected to drive the global Stem Cell Therapy market forward in the coming years.

Sources: Medi-Tech Insights Analysis, Interviews, Company Websites

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Global Stem Cell Therapy Market valued at USD 200 million is set to witness a healthy growth of 17% in the upcoming years : Medi-Tech Insights -...

Skin Stem Cells Comments Off on Global Stem Cell Therapy Market valued at USD 200 million is set to witness a healthy growth of 17% in the upcoming years : Medi-Tech Insights -… | January 18th, 2022

News Release

Tuesday, January 11, 2022

Use of patient-derived stem cells will enable high-throughput drug screening for potential therapeutics.

Researchers at the National Eye Institute (NEI) have developed the first patient-derived stem cell model for studying eye conditions related to oculocutaneous albinism (OCA). The models development is described in the January issue of the journal Stem Cell Reports. NEI is part of the National Institutes of Health.

This disease-in-a-dish system will help us understand how the absence of pigment in albinism leads to abnormal development of the retina, optic nerve fibers, and other eye structures crucial for central vision, said Aman George, Ph.D., a staff scientist in the NEI Ophthalmic Genetics and Visual Function Branch, and the lead author of the report.

OCA is a set of genetic conditions that affects pigmentation in the eye, skin, and hair due to mutation in the genes crucial to melanin pigment production. In the eye, pigment is present in the retinal pigment epithelium (RPE), and aids vision by preventing the scattering of light. The RPE is located right next to the eyes light-sensing photoreceptors and provides them nourishment and support. People with OCA lack pigmented RPE and have an underdeveloped fovea, an area within the retina that is crucial for central vision. The optic nerve carries visual signals to the brain.

People with OCA have misrouted optic nerve fibers. Scientists think that RPE plays a role in forming these structures and want to understand how lack of pigment affects their development.

Animals used to study albinism are less than ideal because they lack foveae, said Brian P. Brooks, M.D., Ph.D., NEI clinical director and chief of the Ophthalmic Genetics and Visual Function Branch. A human stem cell model that mimics the disease is an important step forward in understanding albinism and testing potential therapies to treat it.

To make the model, researchers reprogrammed skin cells from individuals without OCA and people with the two most common types of OCA (OCA1A and OCA2) into pluripotent stem cells (iPSCs). The iPSCs were then differentiated to RPE cells. The RPE cells from OCA patients were identical to RPE cells from unaffected individuals but displayed significantly reduced pigmentation.

The researchers will use the model to study how lack of pigmentation affects RPE physiology and function. In theory, if fovea development is dependent on RPE pigmentation, and pigmentation can be somehow improved, vision defects associated with abnormal fovea development could be at least partially resolved, according to Brooks.

Treating albinism at a very young age, perhaps even prenatally, when the eyes structures are forming, would have the greatest chance of rescuing vision, said Brooks. In adults, benefits might be limited to improvements in photosensitivity, for example, but children may see more dramatic effects.

The team is now exploring how to use their model for high-throughput screening of potential OCA therapies.

NEI leads the federal governments research on the visual system and eye diseases. NEI supports basic and clinical science programs to develop sight-saving treatments and address special needs of people with vision loss. For more information, visit https://www.nei.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

Aman George, Ruchi Sharma, Tyler Pfister, Mones Abu-Asab, Nathan Hotaling, Devika Bose, Charles DeYoung, Justin Chang, David R. Adams, Tiziana Cogliati, Kapil Bharti, Brian P. Brooks. In Vitro Disease Modeling of Oculocutaneous Albinism Type I and II Using Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium (2022). doi: 10.1016/j.stemcr.2021.11.01.https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(21)00597-X.

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NIH researchers develop first stem cell model of albinism to study related eye conditions - National Institutes of Health

Skin Stem Cells Comments Off on NIH researchers develop first stem cell model of albinism to study related eye conditions – National Institutes of Health | January 18th, 2022

Genome Editing Market: Snapshot

Genome editing tools have come a long way from the mid-twentieth century. In 1970s and 1980s, gene targeting was done using largely homologous combination, but was only possible in mice. Since then, the expanding science of genetic analysis and manipulation extended to all types of cells and organisms. Advent of new tools helped scientists achieve targeted DNA double-strand break (DSB) in the chromosome, and is a key pivot on which revenue generation in the genome editing market prospered. New directions for programmable genome editing emerged in the decades of the twenty-first century, expanding the arena.

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Cutting-edge platforms at various points in time continue to enrich genome editing market. Various classes of nucleases emerged, most notable of which is CRISPR-Cas. Research labs around the world have extensively used the platforms in making DSBs at any target of choice. Aside from this, agricultural sciences and medical sectors make substantial use of zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) in genome editing. Strides made in stem cell therapies, particularly in rectifying an aberrant mutation, have boosted the growth of the genome editing market. Genetic diseases such as muscular dystrophy and sickle cell disease present an incredible revenue prospect in the genome editing market. Ongoing research on novel vectors and non-vector approaches are expected to bolster the outlook of the market.

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Genomic editing refers to the strategies and techniques implemented for the modification of target genetic information of any living organism. Genome editing involves gene modification at specific areas through recombinant technology, which increases precision in insertion and decreases cell toxicity. Current advancement in genome editing is based on programmable nucleases. The genome editing market is presently witnessing significant growth due to increase in R&D expenditure, rise in government funding for genomic research, technological advancements, and growth in production of genetically modified crops. Companies have made significant investments in R&D in the past few years to develop cutting-edge technologies, such as, CRISPR and TALEN. For instance, Thermo Fisher Scientific is investing significantly in the development of its CRISPR technology for providing better efficiency and accuracy in research and also to fulfil the unmet demands in research and therapeutics. Cas9 protein and FokI protein have been combined to form a dimeric CRISPR/Cas9 RNA-guided FokI nucleases system, which is expected to have wide range of genome editing applications.

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The genome editing market is growing rapidly due to its application in a large number of areas, such as mutation, therapeutics, and agriculture biotechnology. Genome editing techniques offer large opportunities in crop improvement. However, the real potential of homologous recombination for crop improvement in targeted gene replacement therapy is yet to be realized. Homologous recombination is expected to be used as an effective methodology for crop improvement, which is not possible through transgene addition. Rise in the number of diseases and applications is likely to expand the scope of genome editing in the near future. It includes understanding the role of specific genes and processes of organ specific stem cells, such as, neural stem cells and spermatogonial stem cells. Genome editing has a significant scope to treat genetically affected cells, variety of cancers, and agents of infectious diseases such as viruses, bacteria, parasites, etc. However, genetic alteration of human germline for medicinal purpose has been debated for years. Ethical issues, comprising concern for animal welfare, can arise at all stages of generation and life span of genetically engineered animal.

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The global genome editing market can be segmented based on technology, application, end-user, and geography. In terms of technology, the genome editing market can be categorized into CRISPR, TALEN, ZFN, and other technologies. Bioinformatics has eased the process of data analysis through various technological applications. On the basis of application, the global genome editing market can be classified cell-line engineering, animal genome engineering, plant genome engineering, and others. Based on end-user, the genome editing market can be segmented into pharmaceutical and biotechnological companies and academic and clinical research organizations. In terms of region, the global genome editing market can be segmented into North America, Europe, Asia Pacific, Latin America, and Middle East & Africa. North America is projected to continue its dominance in the global genome editing market owing to high government funding for research on genetic modification in the region. Asia Pacific is a rapidly growing genome editing market due to rise in investments by key players in the region. Rise in drug discovery and development activities, coupled with increasing government initiatives toward funding small and start-up companies in the biotechnology and life sciences industry, is a major factor expected to drive the genome editing market in North America during the forecast period. Players should invest in the emerging economies and the countries of Asia-Pacific like China, South Korea, Australia, India and Singapore in which the genome editing market is expected to grow at rapid pace in future, due to growing funding in research.

Key players operating in the global genome editing market are CRISPR Therapeutics, Thermo Fisher Scientific, GenScript Corporation, Merck KgaA, Sangamo Therapeutics, Inc., Horizon Discovery Group, Integrated DNA Technologies, New England Biolabs, OriGene Technologies, Lonza Group, and Editas Medicine.

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The widespread diagnostic and serological testing is emerging as one of the key measures to mitigate the COVID-19 pandemic. The increased load on healthcare systems, social distancing, and convenience needs of individuals is anticipated to boost the growth of the North America direct-to-consumer laboratory testing market.

Topical Antibiotics Market :

Topical antibiotics have emerged as a popular drug class for the treatment and management of a range of medical conditions. Among different indications such as the skin, eye, and Bromhidrosis, the use of topical antibiotics to fight bacterial skin infection has witnessed consistent growth over the past few decades a trend that is expected to continue over the upcoming years. Research and development activities around the world are likely to fuel the growth of the global topical antibiotics market, as new topical antibiotics continue to enter the market. While the growing popularity of antiseptics could potentially hinder market growth, the growing awareness pertaining to the benefits of topical antibiotics is anticipated to boost the demand.

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Genome Editing Market: Rise in drug discovery and development activities to drive the market - BioSpace

Skin Stem Cells Comments Off on Genome Editing Market: Rise in drug discovery and development activities to drive the market – BioSpace | January 18th, 2022

This article was originally published here

Am J Transl Res. 2021 Dec 15;13(12):13261-13272. eCollection 2021.

ABSTRACT

Diabetic foot ulcers (DFUs) are a serious complication of diabetes and the main cause of nontraumatic lower limb amputations, resulting in a serious economic burden on society. The main causes of DFUs include peripheral neuropathy, foot deformity, chronic inflammation, and peripheral artery disease. There are many clinical approaches for the treatment of DFUs, but they are all aimed at addressing a single aetiological factor. Stem cells (SCs), which express many cytokines and a variety of nerve growth factors and modulate immunological function in the wound, may accelerate DFU healing by promoting angiogenesis, cell proliferation, and nerve growth and regulating the inflammatory response. However, the survival time of SCs without scaffold support in the wound is short. Multifunctional gel wound dressings play a critical role in skin wound healing due to their ability to maintain SC survival for a long time, provide moisture and prevent electrolyte and water loss in DFUs. Among the many methods for clinical treatment of DFUs, the most successful one is therapy with gel dressings loaded with SCs. To accelerate DFU healing, gel wound dressings loaded with SCs are needed to promote the survival and migration of SCs and increase wound contraction. This review summarizes the research advancements regarding multifunctional gel wound dressings and SCs in the treatment of DFU to demonstrate the effectiveness and safety of this combinational therapeutic strategy.

PMID:35035674 | PMC:PMC8748097

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The role of gel wound dressings loaded with stem cells in the treatment of diabetic foot ulcers - DocWire News

Skin Stem Cells Comments Off on The role of gel wound dressings loaded with stem cells in the treatment of diabetic foot ulcers – DocWire News | January 18th, 2022

In many ways, the human body is like any other machine in that it requires constant refueling and maintenance to keep functioning. Much of this happens without our intervention beyond us selecting what to eat that day. There are however times when due to an accident, physical illness or aging the automatic repair mechanisms of our body become overwhelmed, fail to do their task correctly, or outright fall short in repairing damage.

Most of us know that lizards can regrow tails, some starfish regenerate into as many new starfish as the pieces which they were chopped into, and axolotl can regenerate limbs and even parts of their brain. Yet humans too have an amazing regenerating ability, although for us it is mostly contained within the liver, which can regenerate even when three-quarters are removed.

In the field of regenerative medicine, the goal is to either induce regeneration in damaged tissues, or to replace damaged organs and tissues with externally grown ones, using the patients own genetic material. This could offer us a future in which replacement organs are always available at demand, and many types of injuries are no longer permanent, including paralysis.

Our level of understanding of human physiology and that of animals in general has massively expanded since the beginning of the 20th century when technology allowed us to examine the microscopic world in more detail than ever before. Although empirical medical science saw its beginnings as early as the Sumerian civilization of the 3rd millennium BCE, our generalized understanding of the processes and components that underlie the bodys functioning are significantly more recent.

DNA was first isolated in 1869 by Friedrich Miescher, but its structure was not described until 1953. This discovery laid the foundations for the field of molecular biology, which seeks to understand the molecular basis for biological activity. In a sense this moment can be seen as transformative as for example the transition from classical mechanics to quantum mechanics, in that it changed the focus from macroscopic observations to a more fundamental understanding of these observations.

This allowed us to massively increase our understanding of how exactly the body responds to damage, and the molecular basis for regenerative processes, as well as why humans are normally not able to regrow damaged limbs. Eventually in 1999 the term regenerative medicine was coined by William A. Haseltine, who wrote an article in 2001 on what he envisions the term to include. This would be the addressing of not only injuries and trauma from accidents and disease, but also aging-related conditions, which would address the looming demographic crisis as the average age of the worlds populations keeps increasing.

The state of the art in regenerative medicine back in 2015 was covered by Angelo S. Mao et al. (2015). This covers regenerative methods involving either externally grown tissues and organs, or the stimulating of innate regenerative capabilities. Their paper includes the biomedical discipline of tissue engineering due to the broad overlap with the field of regenerative medicine. Despite the very significant time and monetary requirement to bring a regenerative medicine product to market, Mao et al. list the FDA-approved products at that time:

While these were not miracle products by any stretch of the imagination, they do prove the effectiveness of these approaches, displaying similar or better effectiveness as existing products. While getting cells to the affected area where they can induce repair is part of the strategy, another essential part involves the extracellular matrix (ECM). These are essential structures of many tissues and organs in the body which provide not only support, but also play a role in growth and regeneration.

ECM is however non-cellular, and as such is seen as a medical device. They play a role in e.g. the healing of skin to prevent scar tissue formation, but also in the scaffolding of that other tantalizing aspect of regenerative medicine: growing entire replacement organs and body parts in- or outside of the patients body using their own cells. As an example, Mase Jr, et al. (2010) report on a 19-year old US Marine who had part of his right thigh muscle destroyed by an explosion. Four months after an ECM extracted from porcine (pig) intestinal submucossa was implanted in the area, gradual regrowth of muscle tissue was detected.

An important research area here is the development of synthetic ECM-like scaffolding, as this would make the process faster, easier and more versatile. Synthetic scaffolding makes the process of growing larger structures in vitro significantly easier as well, which is what is required to enable growing organs such as kidneys, hearts and so on. These organs would then ideally be grown from induced pluropotent stem cells (iPS), which are a patients own cells that are reverted back to an earlier state of specialization.

It should come as little surprise that as a field which brings together virtually every field that touches upon (human) biology in some fashion, regenerative medicine is not an easy one. While its one thing to study a working system, its a whole different level to get one to grow from scratch. This is why as great as it would be to have an essentially infinite supply of replacement organs by simply growing new ones from iPS cells, the complexity of a functional organ makes this currently beyond our reach.

Essentially the rule is that the less complicated the organ or tissue is, the easier it is to grow it in vitro. Ideally it would just consist out of a single type of cell, and happy develop in some growth medium without the need for an ECM. Attractive targets here are for example the cornea, where the number of people on a waiting list for a corneal transplant outnumber donor corneas significantly.

In a review by Mobaraki et al. (2019), the numerous currently approved corneal replacements as well as new methods being studied are considered. Even though artificial corneas have been in use for years, they suffer from a variety of issues, including biocompatibility issues and others that prevent long-term function. Use of donor corneas comes with shortages as the primary concern. Current regenerative research focuses on the stem cells found in the limbus zone (limbal stem cells, LSC). These seem promising for repairing ocular surface defects, which has been studied since 1977.

LSCs play a role in the regular regenerative abilities of the cornea, and provide a starting point for either growing a replacement cornea, or to repair a damaged cornea, along with the addition of an ECM as necessary. This can be done in combination with the inhibiting of the local immune response, which promotes natural wound healing. Even so, there is still a lot more research that needs to be performed before viable treatments for either repairing the cornea in situ, or growing a replacement in vitro can be approved the FDA or national equivalent.

A similar scenario can be seen with the development of artificial skin, where fortunately due to the large availability of skin on a patients body grafts (autografts) are usually possible. Even so, the application of engineered skin substitutes (ESS) would seem to be superior. This approach does not require the removal of skin (epidermis) elsewhere, and limits the amount of scar formation. It involves placing a collagen-based ECM on the wound, which is optionally seeded with keritanocytes (skin precursor cells), which accelerates wound closure.

Here the scaffolding proved to be essential in the regeneration of the skin, as reported by Tzeranis et al. (2015). This supports the evidence from other studies that show the cell adhesion to the ECM to be essential in cell regulation and development. With recent changes, it would seem that both the formation of hair follicles and nerve innervation may be solved problems.

It will likely still be a long time before we can have something like a replacement heart grown from a patients own iPS cells. Recent research has focused mostly on decellularization (leaving only the ECM) of an existing heart, and repopulating it with native cells (e.g. Glvez-Montn et al., 2012). By for example creating a synthetic scaffold and populating it with cells derived from a patients iPS cells, a viable treatment could be devised.

Possibly easier to translate into a standard treatment is the regrowth of nerves in the spinal cord after trauma, with a recent article by lvarez et al, (2021) (press release) covering recent advances in the use of artificial scaffolds that promotes nerve regeneration, reduces scarring and promotes blood vessel formation. This offers hope that one day spinal cord injures may be fully repairable.

If we were to return to the body as a machine comparison, then the human body is less of a car or piece of heavy machinery, and more of a glued-together gadget with complex circuitry and components inside. With this jump in complexity comes the need for a deeper level of understanding, and increasingly more advanced tools so that repairs can be made efficiently and with good outcomes.

Even so, regenerative medicine is already saving the lives of for example burn victims today, and improving the lives of countless others. As further advances in research continue to translate into treatments, we should see a gradual change from youll have to learn to live with that, to a more optimistic give it some time to grow back, as in the case of an injured veteran, or the victim of an accident.

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Regenerative Medicine: The Promise Of Undoing The Ravages Of Time - Hackaday

Skin Stem Cells Comments Off on Regenerative Medicine: The Promise Of Undoing The Ravages Of Time – Hackaday | January 18th, 2022

Editors note: This article has been updated to remove incorrect information provided by the University of Alberta.

Researchers at the University of Alberta say they have reached a milestone in the efforts to get people with diabetes off injected insulin for good.

A recent first-in-humans clinical trial is reporting early signs that pancreatic cells grown from stem cells can be safely implanted, and in some cases, begin to produce insulin.

The trial saw 17 adults with Type 1 diabetes at six centres in Canada, the United States and Europe receive implants of pluripotent stem cell-derived pancreatic endoderm cells.

Each patient received implants of several small permeable devices filled with millions of cells each. The cells were derived from stem cells then chemically transformed into stem cells programmed to become islet cells.

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Of the 17 patients who received implants, U of A researchers said 35 per cent showed signs in their blood of insulin production after meals within six months of the implant. On top of that, 63 per cent had evidence of insulin production inside the implant devices when they were removed after a year.

This is a very positive finding, said James Shapiro, professor of surgery, medicine and surgical oncology in the University of Albertas Faculty of Medicine & Dentistry.

Its not the endgame, but its a big milestone along the road to success, demonstrating that stem cell-derived islet therapies are safe and can begin to show some signal of efficacy in patients in the clinic.

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Shapiro also led the team that developed the Edmonton Protocol in the 1990s, which developed a way to transplant donated islet cells, reducing their need for insulin. However, the U of A says patients continue to need anti-rejection drugs which can have side effects such as an increased risk of cancer and kidney damage. The number of donated islet cells is also limited.

Shapiro said the main goal of this phase of the trial was to ensure safety, but added at least one patient who had 10 devices implanted was able to significantly reduce her insulin dose, which indicates the potential effectiveness of the treatment.

Were seeing some improvement in the patients blood sugar, but these cells are being transplanted right now in only very small quantities, so were not expecting big changes in insulin requirement, Shapiro said.

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But we can see in about 65 per cent of devices that we take out from under the skin that there are human insulin-producing cells surviving, and in about a third of patients they have measurable insulin levels in the bloodstream. So its a really good first start with this treatment, Im very excited about it.

The ultimate goal of the new research is to develop an unlimited supply of islet cells that can be safely transplanted without the need for anti-rejection drugs.

Weve seen a lot of advances in the last 100 years since the Canadian discovery of insulin, Shapiro said. The race isnt over yet, but were on our last laps and I really do believe that we can cross that ribbon.

Cell-based therapies have the promise to deliver something far better than insulin therapy.

Again, were not expecting to be curing diabetes in the first wave of this, were trying to do safety testing for first patients. And we see that really is helping mankind in the future of diabetes rather than any particular one patient at this point, but it will change as we move forward.

The next step will try to determine how many stem cell-derived pancreatic cells are needed for transplant to optimize insulin production in patients with both Type 1 and Type 2 diabetes.

2022 Global News, a division of Corus Entertainment Inc.

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University of Alberta study shows positive signs to get patients with diabetes off injected insulin - Global News

Skin Stem Cells Comments Off on University of Alberta study shows positive signs to get patients with diabetes off injected insulin – Global News | January 18th, 2022