The latest study of the Personalized Cell Therapy MarketStatistics2022Report providesan elaborative analysis of the market size, industry share, growth, development, and competitive landscape. The report also provides a comprehensive analysis of the sales volume, revenue, gross margin, and price growth in the Personalized Cell TherapyMarket. Many key points covered in the report, include recent development in the global market, such as mergers and acquisitions, SWOT analysis, competitive landscape, industry trends, and company profiles.

Leading Key Players Covered in the GlobalPersonalized Cell Therapy Market Research Report:

Novartis AG, Vericel Corporation, Bellicum Pharmaceuticals, MolMed SpA, Cytori Therapeutics Inc, Gilead Sciences, Inc, Celgene Corporation, Bluebird Bio, Aurora Biopharma Inc, Saneron CCEL TherapeuticsInc, Kuur Therapeutics, MediGene AG, Sangamo Therapeutics

Get a Sample PDF of the Report @ https://www.alexareports.com/report-sample/2856089

Market Segment by Types:

By Cell Type, Hematopoietic Stem Cell, Skeletal Muscle Stem Cell/Mesenchymal Stem Cells/Lymphocytes, By Technique, Platelet Transfusions/Bone Marrow Transplantation/Packed Red Cell Transfusions/Organ Transplantation

Market Segment by Applications:

Cardiovascular Diseases, Neurological Disorders, Inflammatory Diseases, Diabetes, Cancer

Market Segment by Regions:

Table of Contents

Section 1 Personalized Cell Therapy Market Overview

Section 2 Global Personalized Cell Therapy Market Key Players Share

Section 3 Key PlayersPersonalized Cell Therapy Business Introduction

Section 4 Global Personalized Cell Therapy Market Segmentation (By Region)

Section 5 Global Personalized Cell Therapy Market Segmentation (by Product Type)

Section 6 Global Personalized Cell Therapy Market Segmentation (by Application)

Section 7 Global Personalized Cell Therapy Market Segmentation (by Channel)

Section 8 Personalized Cell Therapy Market Forecast 2021-2026

Section 9 Personalized Cell Therapy Application and Client Analysis

Section 10 Personalized Cell Therapy Manufacturing Cost of Analysis

Section 11 Conclusion

Section 12 Methodology and Data Source

If any customization or requirements in the research study, please let us know Alexa Reportsoffer the report as you want.

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Alexa Reports is a globally celebrated premium market research service provider, with a strong legacy of empowering businesses with years of experience. We help our clients by implementing a decision support system through progressive statistical surveying, in-depth market analysis, and reliable forecast data.

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Personalized Cell Therapy Market Size by Applications, Company Profiles, Product Types, Revenue and Forecast to 2026 ChattTenn Sports - ChattTenn...

Bone Marrow Stem Cells Comments Off on Personalized Cell Therapy Market Size by Applications, Company Profiles, Product Types, Revenue and Forecast to 2026 ChattTenn Sports – ChattTenn… | April 3rd, 2022

One of the most important sacrifices a person can make is to offer the gift of life to another. Especially if they dont know whos receiving the gift, and they have to give up something they may need like the marrow in their bones.

Donating bone marrow to someone who is in distress, and may die without a transplant, is a selfless act. Blood diseases, such as leukemia, are horrific, causing tiredness, infections, and pain. A bone marrow transplant replaces damaged or diseased blood forming cells, also called stem cells, with healthy stem cells.

Those in need of a bone marrow transplant are put on a waiting list, because they need to be matched by a donor. Fortunately, there is a registry for those willing to donate their bone marrow.

Caitlin Stone-Webber of Port Austin was willing. She registered to be a donor while in college.

Back in 2011, I was a student at Central Michigan University, Stone-Webber said. There was a student who had a form of leukemia. They were doing a bone marrow drive, testing anyone who was willing to go on the registry, to see if there was a match on campus.

She was not compatible, but her name remained on the registry.

Its an international registry, Stone-Webber said. There are a lot of different groups that help build up this registry.

Five years ago, Stone-Webber received word she had matched. She went through a process of confirmation. Something happened on the recipients end, so the process wasnt completed. Two years later, the same thing happened. Earlier this year, she was contacted again. This time, the donation went through.

Upon receipt of the notification that shed matched, Stone-Webber was required to undergo a physical. The donation process is tiring, and the donor needs to be in good health.

The physical included checking her veins.

Even though its bone marrow, it no longer has to be hip surgery, Stone-Webber said. They can do whats called peripheral cell donation.

Peripheral blood stem celldonation is a method of collecting blood-forming cells for the transplant. The same blood-forming cells that are found in bone marrow are also found in the circulating (peripheral) blood. It is a procedure called apheresis.

They take your blood from one arm, Stone-Webber said. It goes through a machine, takes out your stem cells, and goes back in your other arm.

In addition to the physical, she also had to have injections that raised her stem cell count.

You do four days of injections, Stone-Webber said. And then the day of the procedure, you receive injections, as well.

The injections leading up to the procedure were given at her home.

Because of my size, I actually had to have two shots each day, one in each arm, Stone-Webber said. The nurse would come in, take my vitals, give the shots and then wait to make sure there was no reaction.

Although some people work throughout this stage, Stone-Webber took time off.

So I was able to just go to bed, she said. I was very tired, and my bones hurt. Thats where your bodys creating these extra stem cells ... in your bones. I was very aware of where every bone in my body was, but not at the same time. The first day it was in my legs. They hurt. The second day it was in my hips. One day it was in my toes. It was the strangest thing.

It was a normal part of the process.

They say to prepare for that, that your bones are going to hurt, Stone-Webber said.

She was told to take Tylenol for pain, as well as, oddly enough, Claritin, which relieves allergies.

They said they dont really know what part of the (Claritin) makes it work, but it works, Stone-Webber said.

The procedure took place at a hospital, although Stone-Webber isnt allowed to say where.

When you donate to someone, you stay anonymous until a year from the donation date, she said. I had to sign a confidentially document saying I could talk about the procedure I can talk about my experience. But I cant talk about where I donated.

Details on the identity of the recipient are unknown to her.

I know gender, Stone-Webber said. I know age. I know country. And, I know the type of leukemia. I didnt know what country they were in until post donation. Thats something I thought was real cool about being able to donate right now, is that with the world the way it is, to be able to help someone without knowing their political affiliation, or religion. None of that mattered. I was just helping another person.

Due to the fact that the bone marrow registry is international there are also national registries potential donors should be aware they may have to travel if they match. Stone-Webbers expenses, including travel, food, and lodging, were covered by the nonprofit organization the donation was set up through.

I was never billed for anything, Stone-Webber said.

All it cost her was time and a little discomfort.

The way I looked at it is, anyone can be sick for four or five days in order to save someones life, Stone-Webber said.

The actual donation took place in the course of one day. She was hooked up to a machine that recycled her blood. Due to her size her veins werent large enough for the procedure Stone-Webber required a catheter to be inserted in her jugular vein.

I could feel the catheter when I swallowed, she said. And when they pulled it out, I could feel a little bit of discomfort. For a couple days afterward, there were times I was a little uncomfortable.

Once the procedure started, Stone-Webber was confined to a hospital bed. She was given medication that allowed her to remain still, so the machine could recycle her blood.

It went in and out the same port, she said. I was hooked up to the machine for five hours, and it cycled my blood through the machine four and a half times. It was kind of cool to think someone has invented this machine that can cycle blood. Because of the injections, my body was still making stem cells, so that machine could continue to get out everything this recipient could need.

A bone marrow transplant is beneficial to those receiving the new stem cells. In some cases it may even provide a cure for their disease.

Its mostly for blood-related cancers, Stone-Webber said. There may be other blood-related disorders and diseases that it could help with. In some cases the donation is a treatment to kind of stall things. In others, its a cure. I was told the day of the donation, that my donation would be a cure that when the patient received my donated stem cells, it would cure their leukemia providing its a successful donation and their body accepts it.

The bone marrow registry can be accessed through a number of nonprofit organizations, including http://www.dkms.org and http://www.bethematch.org, which Stone-Webber worked with.

As of now, she knows her stem cells have been received by the recipient, but has no idea of the outcome. At the end of the year required by her confidentiality agreement, she would like to know whether or not they were affective. After all, her stem cells are now in someone else.

I think we now connect in a different way than most people would, Stone-Webber said. I think I would like the opportunity to know how theyre doing.

That connection is a bone marrow transplant, the gift of life. Stone-Webber would do it again.

For further information on bone marrow transplants and the bone marrow registry, email Stone-Webber at caitlinstone22@gmail.com or visit http://www.dkms.org or http://www.bethematch.org.

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Port Austin woman gives gift of life with marrow donation - Huron Daily Tribune

Bone Marrow Stem Cells Comments Off on Port Austin woman gives gift of life with marrow donation – Huron Daily Tribune | March 22nd, 2022

REDWOOD CITY, Calif., March 21, 2022 (GLOBE NEWSWIRE) --Jasper Therapeutics, Inc. (NASDAQ: JSPR), a biotechnology company focused on hematopoietic cell transplant therapies, today announced changes to its management team, including the promotions of Jeet Mahal to the newly created position of Chief Operating Officer, and of Wendy Pang, M.D., Ph.D., to Senior Vice President of Research and Translational Medicine. Both promotions are effective as of March 21, 2022. Jasper also announced that a new position of Chief Medical Officer has been created, for which an active search is underway. Judith Shizuru, M.D. PhD, co-founder, and Scientific Advisory Board Chairwoman will lead clinical development activities on an interim basis and Kevin Heller, M.D., EVP of Research and Development, will be transitioning to a consultant role.

Based on the recent progress with JSP191, our anti-CD117 monoclonal antibody, as a targeted non-toxic conditioning agent and our mRNA hematopoietic stem cell program we have decided to advance Jaspers organizational structure with the creation of the roles of Chief Operating Officer and Chief Medical Officer and by elevating our research and translational medicine team to report directly to the CEO, said Ronald Martell, CEO of Jasper Therapeutics. We also are pleased that Dr. Shizuru will lead clinical development activities on an interim basis, a role she served during the companys founding in 2019.

These changes will allow us to advance our upcoming pivotal trial of JSP191 in AML/ MDS and execute on our pipeline opportunities with a best-in-class organization, continued Mr. Martell. We also wish to thank Dr. Heller for his help advancing JSP191 through our initial AML/MDS transplant study.

In the two plus years since we founded Jasper and received our initial funding, the company has been able to advance JSP191 in two clinical studies, develop our mRNA stem cell graft platform and publicly list on NASDAQ, said Dr. Shizuru, co-founder and member of the Board of Directors of Jasper Therapeutics. These changes will strengthen the companys ability to advance the field of hematopoietic stem cell therapies and bring cures to patients with hematologic cancers, autoimmune diseases and debilitating genetic diseases."

Mr. Mahal joined Jasper in 2019 as Chief Finance and Business Officer and has led Finance, Business Development, Marketing and Facilities/ IT since the companys inception. Prior to joining Jasper, he was Vice President, Business Development and Vice President, Strategic Marketing at Portola Pharmaceuticals, where he led the successful execution of multiple business development partnerships for Andexxa, Bevyxxaand cerdulatinib. He also played a key role in the companys equity financings, including its initial public offering and multiple royalty transactions. Earlier in his career, Mr. Mahal was Director, Business and New Product Development, at Johnson & Johnson on the Xareltodevelopment and strategic marketing team. Mr. Mahal holds a BA in Molecular and Cell Biology from U.C. Berkeley, a Masters in Molecular and Cell Biology from the Illinois Institute of Technology, a Masters in Engineering from North Carolina State University and an MBA from Duke University.

Dr. Pang joined Jasper in 2020 and has led early research and development including leading creation of the companys mRNA stem cell graft platform and playing a pivotal role in advancing JSP191 across multiple clinical studies. Previously Dr. Pang was an Instructor in the Division of Blood and Marrow Transplantation at Stanford University and the lead scientist in the preclinical drug development of an anti-CD117 antibody program. She was the lead author on the proof-of-concept studies showing that an anti-CD117 antibody therapy targets disease-initiating human hematopoietic (blood cell-forming) stem cells in myelodysplastic syndrome (MDS). She has authored numerous publications on the characterization of hematopoietic stem and progenitor cell behavior in hematopoieticdiseases, as well as hematopoietic malignancies, including MDS and acute myeloid leukemia (AML), and in hematopoietic stem cell transplantation. Dr. Pang earned her AB and BM in Biology from Harvard University and her MD and PhD in cancer biology from Stanford University.

Dr. Shizuru is a Professor of Medicine (Blood and Marrow Transplantation) and Pediatrics (Stem Cell Transplantation) at StanfordUniversity.She is the clinician-scientist co-founder of Jasper Therapeutics. Dr. Shizuru is an internationally recognized expert on the basic biology of blood stem cell transplantation and the translation of this biology to clinical protocols.Dr Shizuruis a member of the Stanford Blood and Marrow Transplantation (BMT) faculty, the Stanford Immunology Program, and the Institute for Stem Cell Biology and Regenerative Medicine. Shehas been an attending clinicianattendedon the BMT clinical service since 1997.Currently, she oversees a research laboratory focused on understanding the cellular and molecular basis of resistance to engraftment of transplantedallogeneic bone marrow blood stemcells and the way in which bone marrow grafts modify immune responses.Dr. Shizuru earned her BA from Bennington College and her MD and PhD in immunology from Stanford University

About Jasper Therapeutics

Jasper Therapeutics is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The company is advancing two potentially groundbreaking programs. JSP191, an anti-CD117 monoclonal antibody, is in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow in patients undergoing a hematopoietic cell transplantation. It is designed to enable safer and more effective curative allogeneic hematopoietic cell transplants and gene therapies. Jasper is also advancing JSP191 as a potential therapeutic for patients with lower risk Myelodysplastic Syndrome (MDS). Jasper Therapeutics is also advancing its preclinical mRNA hematopoietic stem cell graft platform, which is designed to overcome key limitations of allogeneic and autologous gene-edited stem cell grafts. Both innovative programs have the potential to transform the field and expand hematopoietic stem cell therapy cures to a greater number of patients with life-threatening cancers, genetic diseases and autoimmune diseases than is possible today. For more information, please visit us at jaspertherapeutics.com.

Forward-Looking Statements

Certain statements included in this press release that are not historical facts are forward-looking statements for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements are sometimes accompanied by words such as believe, may, will, estimate, continue, anticipate, intend, expect, should, would,plan,predict,potential,seem,seek,future,outlookandsimilarexpressionsthat predict or indicate future events or trends or that are not statements of historical matters. These forward-looking statements include, but are not limited to, statements regarding the potentialof the Companys JSP191 and mRNA engineered stem cell graft programs. Thesestatementsarebasedonvariousassumptions,whetherornotidentifiedinthispressrelease, and on the current expectations of Jasper and are not predictions of actual performance. These forward-lookingstatementsareprovidedforillustrativepurposesonlyandarenotintendedtoserve as, and must not be relied on by an investor as, a guarantee, an assurance, a prediction or a definitivestatementoffactorprobability.Actualeventsandcircumstancesaredifficultorimpossible to predict and will differ from assumptions. Many actual events and circumstances are beyond the control of Jasper. These forward-looking statements are subject to a number of risks and uncertainties, including general economic, political and business conditions; the risk that the potential product candidates that Jasper develops may not progress through clinical development or receive required regulatory approvals within expected timelines or at all; risks relating to uncertainty regarding the regulatory pathway for Jaspers product candidates; the risk that prior study results may not be replicated; the risk that clinical trials may not confirm any safety, potency or other product characteristics described or assumed in this press release; the risk that Jasper will be unable to successfully market or gain market acceptance of its product candidates; the risk that Jaspers product candidates may not be beneficialtopatientsorsuccessfullycommercialized;patientswillingnesstotrynewtherapiesand the willingness of physicians to prescribe these therapies; the effects of competition on Jaspers business; the risk that third parties on which Jasper depends for laboratory, clinical development, manufacturing and other critical services will fail to perform satisfactorily; the risk thatJaspers business, operations, clinical development plans and timelines, and supply chain could be adversely affected by the effects of health epidemics, including the ongoing COVID-19 pandemic; the risk that Jasper will be unable to obtain and maintain sufficient intellectual property protection foritsinvestigationalproductsorwillinfringetheintellectualpropertyprotectionofothers;andother risks and uncertainties indicated from time to time in Jaspers filings with the SEC. If any of these risksmaterializeorJaspersassumptionsproveincorrect,actualresultscoulddiffermateriallyfrom the results implied by these forward-looking statements. While Jasper may elect to update these forward-lookingstatementsatsomepointinthefuture,Jasperspecificallydisclaimsanyobligation to do so. These forward-looking statements should not be relied upon as representing Jaspers assessmentsofanydatesubsequenttothedateofthispressrelease.Accordingly,unduereliance should not be placed upon the forward-lookingstatements.

Contacts:

John Mullaly (investors)LifeSci Advisors617-429-3548jmullaly@lifesciadvisors.com

Jeet Mahal (investors)Jasper Therapeutics650-549-1403jmahal@jaspertherapeutics.com

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Jasper Therapeutics Announces Management Changes to Strengthen Leadership Team - BioSpace

Bone Marrow Stem Cells Comments Off on Jasper Therapeutics Announces Management Changes to Strengthen Leadership Team – BioSpace | March 22nd, 2022

An article published in the journal Biomaterials shows that [emailprotected]2 nanoparticles (NPs) synthesized with a short bacteriophage-selected mesenchymal stem cell(MSC) targeting peptide allowed the MSCs to take up these NPs. NP-modified MSCs produced greatly improved therapy of Rheumatoid Arthritis(RA) using stem cells.

Study:Highly effective rheumatoid arthritis therapy by peptide-promoted nanomodification of mesenchymal stem cells. Image Credit:Emily frost/Shutterstock.com

RA, which is marked by progressive joint degeneration andsynovial inflammation, is one ofthe primary widespread inflammatory arthritis thataffectsaround 1 % of the global population, however, it currently lacks an effective treatment.

Glucocorticoids (GCs), disease-modifying anti-rheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs)are the three maintypes of medicationscurrently used in clinical practice.

GCs and NSAIDscan help with joint pain and stiffness, but they may cause side effects such asheart problems, osteoporosis, infections andgastric ulcers.

Standard DMARDs, like methotrexate (MTX), can lessen swelling by inhibiting the synthesis of pro-inflammatory cytokines and have little effect on cartilage degeneration. MTX, on the other hand, has a short plasma half-lifeand a poor concentration of the drug in the inflammatory region of the body.

Other side effects may also include liver and kidney damage, bone marrow depletion, and gastrointestinal problems. Biological DMARDs have been rapidly developed in recent years, thoughtheir action slows the progression of structural damage by reducing inflammation and have issues including drug resistance and the potential to cause significant infections and malignant tumors.

Multilineage differentiation, inflammatory site and immunomodulationhoming are all features of MSCs. These distinctivecharacteristicsallowMSCs to become apotential treatmentfora variety ofinflammatory and degenerativediseases, including the treatment of RA,through cell therapy. Unfortunately, over 50 % of patients do not react to MSC treatment, and the therapeutic benefit of MSCs is only temporary.

Firstly, MSCs are susceptible to the inflammatory milieu and so lose their functions of immune-regulationwhen disclosed in an inflamed joint. Reactive oxygen species (ROS) are thought to be engaged in the inflammation development of RA and hence damaging to MSCs, as seen by the gradualdecline in the quantity of MSCs in RA patients' synovial fluid.

Secondly, while the direct impacts of MSCs on tissue regeneration in RA are unknown, an evidentclinical experiment found that MSC injections increased hyaline cartilage regeneration in RA patients. Nevertheless, the unregulated distinction of MSCs can alsoresult in the development of tumors andthe inability of cartilage repair.

As a result, it is important for an optimal stem cell strategy to include MSCs that have the ability to preserve their bio functions and chondrogenically develop to regenerate cartilage under the oxidative stress caused by RA.

According to thisstudy, RA therapy could be enhanced byshort targeting peptide-promoted nanomodification of MSCs. To begin with, [emailprotected]2 NPs wereproduced due to some of theirelements' appealing features. Mn and Cu both are critical trace components in the human body, and they play a keyrole in the production of natural Mnsuperoxide dismutase (SOD) and Cu-ZnSOD, respectively.

Cu and Mn can also encourage stem cell chondrogenesis. The study further explains the modification of [emailprotected]2 NPs with MSC-targeting peptides to increase the passage of the nanoparticles into MSCs since transporting nanomaterials into modifications of MSCs is still a difficult task.

To make [emailprotected]2/MET NPs, [emailprotected]2 NPs were injected with metformin. Lastly, MSCs were allowedto take up these NPs and utilizethem to effectively limit synovial inflammation and maintain cartilage structure, alleviating arthritic symptoms greatly.

This study demonstrates that VCMM-MCSs werecreated by engineering MSCs with catalase (CAT) and superoxide dismutase (SOD)- like activity using dynamically MSC-targeting [emailprotected]2/MET NPs.

The biological features of these cells required in stem cell treatment, such as chondrogenesis, anti-inflammation, cell migration, and increased survival under oxidative stress, were improved by VCMM-MCSs.

Consequently, the VCMM-MSCs injections reduced cartilage damage andsynovial hyperplasiain adjuvant-induced arthritis (AIA) as well as collagen-induced arthritis (CIA) models, substantially reducing arthritic symptoms. Since oxidative stress is present in numerous degenerative and inflammatory disorders, this strategy of altering MSCs with NPs could be applied to treat a number of other disorders as well as to achieve faster tissue healing using stem cell therapy.

Lu, Y., Li, Z. et al. (2022). Highly effective rheumatoid arthritis therapy by peptide-promoted nanomodification of mesenchymal stem cells. Biomaterials. Available at: https://www.sciencedirect.com/science/article/pii/S0142961222001132?via%3Dihub

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

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Nano-Improvements to Rheumatoid Arthritis Stem Cell Therapy Show Success - AZoNano

Bone Marrow Stem Cells Comments Off on Nano-Improvements to Rheumatoid Arthritis Stem Cell Therapy Show Success – AZoNano | March 22nd, 2022

London-based leukaemia patient Yvette Chin, 41, has just months to live unless a stem cell donor is found. PROVIDED TOCHINA DAILY

The family of a Chinese leukaemia patient in the United Kingdom has launched an urgent appeal calling for the East Asian community around the world to become stem cell donors.

Yvette Chin, 41, from London has acute lymphoblastic leukaemia, a rare aggressive blood cancer, and has just months to live unless a donor can be found.

Her brother, Colin Chin, 48, and sister-in-law Serena Chin are urging more people in the Chinese and East Asian community to register as stem cell donors to increase the chances of saving her life.

According to charity Anthony Nolan, which works in the areas of leukaemia and hematopoietic stem cell transplantation, 75 percent of UK patients will not find a matching donor in their families.

Only 72 percent of patients from white Caucasian backgrounds can find the best possible match from a stranger. This drops to 37 percent for patients from a minority ethnic background.

Yvette, who was diagnosed with the disease in May 2021, needs to have a stem cell transplant with a 90 percent genetic match.

The family hopes more people in the East Asian community in the UK and internationally can sign up to a bone marrow register to help Yvette and others in a similar position.

"Our family has registered but it's not enough. I hope if more people from the community know how quick and easy it is to do, and that it's literally lifesaving, we can find a match," Colin said.

"Not just for Yvette, but also for others who don't have time to wait. I'm asking for everyone to sign up and share #SwabForYvette on social media to spread awareness that we all have the power to save lives with a simple mouth swab."

Yvette's sister-in-law Serena hopes their campaign will help more people in ethnic minority groups gain a better understanding of what being a stem cell donor involves.

"When we looked into it, we realize Yvette isn't the only one in the community who needed this and that others are waiting for a donor, waiting for that second chance of life," she said. "Of course, we hope we find a match for Yvette, but I hope also we help save other people's lives as well who are in the same situation."

Yvette, a keen explorer who has scaled Mount Kilimanjaro, has been in and out of hospital for chemotherapy since her diagnosis last year. She took part in an experimental trial but in February she was told the trial had failed.

"After the trial, the leukaemia came back with so much ferocity and we still don't have a match, my brother wasn't a match and that was the reality that it was going to be difficult," Yvette said. "It feels like the stars have to align so much with me being in remission and finding a match."

Reshna Radiven, head of communications and engagement at DKMS UK, an international nonprofit bone marrow donor center, said ethnic minority communities are massively under-represented, especially the Chinese, Pakistani, Bangladeshi, Black-African and Black-Caribbean communities.

"There is an element of hesitancy, for some of the communities we know they don't trust the health system or the system generally in the countries that they're resident in," Radiven said. "But there is also a fundamental lack of awareness of the need for stem cell donors and the impact a stem cell donation can have for a cancer patient."

She added more work needs to be done to communicate and encourage people to become donors.

"You're very likely to find a match from a donor who is from the same ethnic community as you, so it's really important for all people to be represented in the register," Radiven said. "We offer the family and the patient hope, which is really significant when you're in a very difficult situation.

"In a world where we're trying to bridge the gap of inequality, we just want to get the word out there to encourage more bone marrow donations and blood too," Yvette said.

"I feel like the East Asian community has trepidation about doing that, so if they don't do it for me, then do it for someone else and bridge that stark statistic between our white Caucasian counterparts and everybody else."

Link:
Family calls on East Asians to help by donating much-needed stem cells - China Daily

Bone Marrow Stem Cells Comments Off on Family calls on East Asians to help by donating much-needed stem cells – China Daily | March 22nd, 2022

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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Read more from the original source:
'Without you there is no cure' - Teenager's call for stem cell donors in mission to support Anthony Nolan Trust - Shields Gazette

Bone Marrow Stem Cells Comments Off on ‘Without you there is no cure’ – Teenager’s call for stem cell donors in mission to support Anthony Nolan Trust – Shields Gazette | March 22nd, 2022

Mixed-phenotype acute leukemia (MPAL) is a rare type of blood cancer. Typically, a doctor can classify the cancer as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), depending on the cells involved. However, MPAL presents with features of both AML and ALL.

Leukemia describes a cancer of the blood or bone marrow. There are many types of leukemia, and doctors typically classify them as either acute (sudden) or chronic (slow), depending on how quickly the cancer develops. They can then further classify these cancers depending on whether they affect myeloid or lymphocytic blood cells.

MPAL refers to a rare subtype of leukemia that displays no clear sign of origin and presents with features of both AML and ALL.

In this article, we will discuss MPAL leukemia, including the symptoms, diagnosis, treatment options, and outlook.

Mixed-phenotype acute leukemia (MPAL) is a rare type of acute leukemia where leukemia cells present with both myeloid and lymphocytic features. Some may also refer to this type of leukemia as acute leukemia of ambiguous lineage (ALAL), mixed-lineage leukemia, and acute undifferentiated leukemia.

In 2008, the World Health Organization (WHO) introduced the term MPAL to classify this group of blood cancers. Previously, the scientific community used other terms such as biphenotype acute leukemia to label these diseases.

A doctor may also further classify MPAL into bilineal or biphenotypic leukemia. The former refers to two separate populations of cells with myeloid and lymphoid origin, while the latter describes a single population of leukemia cells that express markers of both lymphoid and myeloid origin.

Some evidence suggests that the frequency of MPAL is 3%, while other research indicates that it accounts for roughly 25% of all acute leukemia diagnoses. MPAL can affect both children and adults.

As with other types of acute leukemia, the exact cause of MPAL is currently unknown. Some evidence suggests that MPAL may derive from alterations in blood stem cells that have the ability to undergo myeloid and lymphoid differentiation.

Research indicates that genetic alterations are associated with acute leukemias and may explain the abnormal development and maturation of white blood cells.

Certain genomic alterations may drive the biphenotypic expression in leukemia cells. Chromosome alterations that are often present in individuals with MPAL include Philadelphia chromosome and chromosome 11q23 abnormalities.

Potential risk factors for developing leukemia may include:

The symptoms of MPAL can occur suddenly and typically relate to problems with bone marrow. Symptoms can include:

Many of these symptoms are common to other conditions, including other types of leukemia. However, healthcare practitioners are aware of symptoms that may indicate MPAL leukemia and will request further testing if they think it is necessary.

Initially, doctors will likely use the same tools for diagnosing other forms of leukemia. These may include:

Due to the lack of consensus on the diagnostic criteria for MPAL, it can be difficult to diagnose the condition. The WHO diagnostic criteria provide a small list of specific lineage markers that can help diagnose MPAL.

Health experts use an immunophenotyping method, known as flow cytometry, on blood or bone marrow samples to identify these markers on leukemia cells.

This technique uses light to detect and measure the characteristics of cells. For an MPAL diagnosis, the sample will contain markers of both myeloid and lymphoid origin. This can also help guide if an AML or ALL treatment regimen will be more appropriate for a treatment plan.

If a doctor suspects an MPAL diagnosis, they will likely request genetic testing to identify the presence of genetic alterations, such as Philadelphia chromosome and chromosome 11q23 abnormalities. This is because a person with these alterations may require a more intensive treatment plan.

Treatment options for MPAL leukemia will vary depending on the diagnosis, age, and medical history. As MPAL leukemia is challenging to treat, the treatment plan is often intensive and usually starts quickly after diagnosis.

A 2018 systematic review and meta-analysis and a 2017 review both suggest that using a chemotherapy regimen for ALL or a combined ALL/AML regimen can result in a better outcome for people with MPAL leukemia than using chemotherapy that doctors use only for AML. A 2019 paper also suggests that ALL treatment may be preferable for treating MPAL.

A 2020 study notes that in cases of MPAL with a Philadelphia chromosome abnormality, the use of targeted therapy such as tyrosine kinase inhibitors can help to improve outcomes.

Doctors may consider other treatments if these options do not provide a satisfactory response. For example, they may use immunotherapies, which activate the immune system to detect and attack cancer cells. A doctor may also perform a stem cell transplant to eradicate any remaining leukemia cells in the bone marrow.

Historically, the outlook for individuals with MPAL has not been very positive. However, with more research and advances in treatment options, the outlook is improving. While it remains hard to predict the overall survival for those with MPAL, evidence suggests that factors that may predict a less positive outcome include:

A 2017 retrospective study suggested the three-year overall survival rate for MPAL was 56.3%, compared with the 5-year survival rate of 65% for leukemia in general. Like other acute leukemias, the quicker the diagnosis and treatment of MPAL, the higher the chance of recovery.

MPAL is a rare form of blood cancer that presents with clinical features of AML and ALL. As with other acute leukemias, the exact cause is unknown, but many cases are associated with genetic abnormalities. Due to its rarity and various diagnostic criteria, it can be a difficult condition to diagnose.

Treatment options vary depending on an individuals diagnosis, age, and medical history but may include chemotherapy, targeted therapy, immunotherapy, and stem cell transplants. While the outlook for MPAL is generally poorer than other leukemias, advances in research and treatments are improving outcomes.

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MPAL leukemia: Symptoms, diagnosis, and treatments - Medical News Today

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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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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...

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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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Bone marrow-derivedstem cells(BMSCS) market is expected to gain market growth in the forecast period of 2020 to 2027. Data Bridge Market Research analyses the market to growing at a CAGR of 10.4% in the above-mentioned forecast period. Increasing awareness regarding the benefits associates with the preservation of bone marrow derived stem cells will boost the growth of the market.

Later on, the report assesses gross sales (volume & value), market share, market size, market growth rate based variety of applications.The Bone Marrow-Derived Stem Cells (BMSCS) report also focuses on regional and provincial markets to analyze manufacturers, niche market segments, industry environment, raw material resources, and rivalry of the specific marketplace.

Key Players in Bone Marrow-Derived Stem Cells (BMSCS) Marketcovers the complete in-depth information, which in brief coversthere:

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Prominent Key Players Covered in the report:

CBR Systems, Inc, Cordlife Sciences India Pvt. Ltd., Cryo-Cell International, Inc.ESPERITE N.V., LifeCell International Pvt. Ltd., StemCyte India Therapeutics Pvt. Ltd, PerkinElmer Inc, Global Cord Blood Corporation., Smart Cells International Ltd., Vita 34 among other domestic and global players. (Customization Available)

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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

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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

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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

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Introduction

Given the multi-lineage differentiation abilities of mesenchymal stem cells (MSCs) isolated from different tissues and organs, MSCs have been widely used in various medical fields, particularly regenerative medicine.13 The representative sources of MSCs are bone marrow, adipose, periodontal, muscle, and umbilical cord blood.410 Interestingly, slight differences have been reported in the characteristics of MSCs depending on the different sources, including their population in source tissues, immunosuppressive activities, proliferation, and resistance to cellular aging.11 Bone marrow-derived MSCs (BM-MSCs) are the most intensively studied and show clinically promising results for cartilage and bone regeneration.11 However, the isolation procedures for BM-MSCs are complicated because bone marrow contains a relatively small fraction of MSCs (0.0010.01% of the cells in bone marrow).12 Furthermore, bone marrow aspiration to harvest MSCs in human bones is a painful procedure and the slower proliferation rate of BM-MSCs is a clinical limitation.13 In comparison with BM-MSCs, adipose-derived MSCs (AD-MSCs) are relatively easy to collect and can produce up to 500 times the cell population of BM-MSCs.14 AD-MSCs showed a greater ability to regenerate damaged cartilage and bone tissues with increased immunosuppressive ability.14,15 Umbilical cord blood-derived MSCs (UC-MSCs) proliferate faster than BM-MSCs and are resistant to significant cellular aging.11

MSCs have been investigated and gained worldwide attention as potential therapeutic candidates for incurable diseases such as arthritis, spinal cord injury, and cardiac disease.3,1623 In particular, the inherent tropism of MSCs to inflammatory sites has been thoroughly studied.24 This inherent tropism, also known as homing ability, originates from the recognition of various chemokine sources in inflamed tissues, where profiled chemokines are continuously secreted and the MSCs migrate to the chemokines in a concentration-dependent manner.24 Rheumatoid arthritis (RA) is a representative inflammatory disease that primarily causes inflammation in the joints, and this long-term autoimmune disorder causes worsening pain and stiffness following rest. RA affects approximately 24.5 million people as of 2015, but only symptomatic treatments such as pain medications, steroids, and nonsteroidal anti-inflammatory drugs (NSAIDs), or slow-acting drugs that inhibit the rapid progression of RA, such as disease-modifying antirheumatic drugs (DMARDs) are currently available. However, RA drugs have adverse side effects, including hepatitis, osteoporosis, skeletal fracture, steroid-induced arthroplasty, Cushings syndrome, gastrointestinal (GI) intolerance, and bleeding.2527 Thus, MSCs are rapidly emerging as the next generation of arthritis treatment because they not only recognize and migrate toward chemokines secreted in the inflamed joints but also regulate inflammatory progress and repair damaged cells.28

However, MSCs are associated with many challenges that need to be overcome before they can be used in clinical settings.2931 One of the main challenges is the selective accumulation of systemically administered MSCs in the lungs and liver when they are administered intravenously, leading to insufficient concentrations of MSCs in the target tissues.32,33 In addition, most of the administered MSCs are typically initially captured by macrophages in the lungs, liver, and spleen.3234 Importantly, the viability and migration ability of MSCs injected in vivo differed from results previously reported as favorable therapeutic effects and migration efficiency in vitro.35

To improve the delivery of MSCs, researchers have focused on chemokines, which are responsible for MSCs ability to move.36 The chemokine receptors are the key proteins on MSCs that recognize chemokines, and genetic engineering of MSCs to overexpress the chemokine receptor can improve the homing ability, thus enhancing their therapeutic efficacy.37 Genetic engineering is a convenient tool for modifying native or non-native genes, and several technologies for genetic engineering exist, including genome editing, gene knockdown, and replacement with various vectors.38,39 However, safety issues that prevent clinical use persist, for example, genome integration, off-target effects, and induction of immune response.40 In this regard, MSC mimicking nanoencapsulations can be an alternative strategy for maintaining the homing ability of MSCs and overcoming the current safety issues.4143 Nanoencapsulation involves entrapping the core nanoparticles of solids or liquids within nanometer-sized capsules of secondary materials.44

MSC mimicking nanoencapsulation uses the MSC membrane fraction as the capsule and targeting molecules, that is chemokine receptors, with several types of nanoparticles, as the core.45,46 MSC mimicking nanoencapsulation consists of MSC membrane-coated nanoparticles, MSC-derived artificial ectosomes, and MSC membrane-fused liposomes. Nano drug delivery is an emerging field that has attracted significant interest due to its unique characteristics and paved the way for several unique applications that might solve many problems in medicine. In particular, the nanoscale size of nanoparticles (NPs) enhances cellular uptake and can optimize intracellular pathways due to their intrinsic physicochemical properties, and can therefore increase drug delivery to target tissues.47,48 However, the inherent targeting ability resulting from the physicochemical properties of NPs is not enough to target specific tissues or damaged tissues, and additional studies on additional ligands that can bind to surface receptors on target cells or tissues have been performed to improve the targeting ability of NPs.49 Likewise, nanoencapsulation with cell membranes with targeting molecules and encapsulation of the core NPs with cell membranes confer the targeting ability of the source cell to the NPs.50,51 Thus, MSC mimicking nanoencapsulation can mimic the superior targeting ability of MSCs and confer the advantages of each core NP. In addition, MSC mimicking nanoencapsulations have improved circulation time and camouflaging from phagocytes.52

This review discusses the mechanism of MSC migration to inflammatory sites, addresses the potential strategy for improving the tropism of MSCs using genetic engineering, and discusses the promising therapeutic agent, MSC mimicking nanoencapsulations.

The MSC migration mechanism can be exploited for diverse clinical applications.53 The MSC migration mechanism can be divided into five stages: rolling by selectin, activation of MSCs by chemokines, stopping cell rolling by integrin, transcellular migration, and migration to the damaged site (Figure 1).54,55 Chemokines are secreted naturally by various cells such as tumor cells, stromal cells, and inflammatory cells, maintaining high chemokine concentrations in target cells at the target tissue and inducing signal cascades.5658 Likewise, MSCs express a variety of chemokine receptors, allowing them to migrate and be used as new targeting vectors.5961 MSC migration accelerates depending on the concentration of chemokines, which are the most important factors in the stem cell homing mechanism.62,63 Chemokines consist of various cytokine subfamilies that are closely associated with the migration of immune cells. Chemokines are divided into four classes based on the locations of the two cysteine (C) residues: CC-chemokines, CXC-chemokine, C-chemokine, and CX3 Chemokine.64,65 Each chemokine binds to various MSC receptors and the binding induces a chemokine signaling cascade (Table 1).56,66

Table 1 Chemokine and Chemokine Receptors for Different Chemokine Families

Figure 1 Representation of stem cell homing mechanism.

The mechanisms underlying MSC and leukocyte migration are similar in terms of their migratory dynamics.55 P-selectin glycoprotein ligand-1 (PSGL-1) and E-selectin ligand-1 (ESL-1) are major proteins involved in leukocyte migration that interact with P-selectin and E-selectin present in vascular endothelial cells. However, these promoters are not present in MSCs (Figure 2).53,67

Figure 2 Differences in adhesion protein molecules between leukocytes and mesenchymal stem cells during rolling stages and rolling arrest stage of MSC. (A) The rolling stage of leukocytes starts with adhesion to endothelium with ESL-1 and PSGL-1 on leukocytes. (B) The rolling stage of MSC starts with the adhesion to endothelium with Galectin-1 and CD24 on MSC, and the rolling arrest stage was caused by chemokines that were encountered in the rolling stage and VLA-4 with a high affinity for VACM present in endothelial cells.

Abbreviations: ESL-1, E-selectin ligand-1; PSGL-1, P-selectin glycoprotein ligand-1 VLA-4, very late antigen-4; VCAM, vascular cell adhesion molecule-1.

The initial rolling is facilitated by selectins expressed on the surface of endothelial cells. Various glycoproteins on the surface of MSCs can bind to the selectins and continue the rolling process.68 However, the mechanism of binding of the glycoprotein on MSCs to the selectins is still unclear.69,70 P-selectins and E-selectins, major cell-cell adhesion molecules expressed by endothelial cells, adhere to migrated cells adjacent to endothelial cells and can trigger the rolling process.71 For leukocyte migration, P-selectin glycoprotein ligand-1 (PSGL-1) and E-selectin ligand-1 (ESL-1) expressed on the membranes of leukocytes interact with P-selectins and E-selectins on the endothelial cells, initiating the process.72,73 As already mentioned, MSCs express neither PSGL-1 nor ESL-1. Instead, they express galectin-1 and CD24 on their surfaces, and these bind to E-selectin or P-selectin (Figure 2).7476

In the migratory activation step, MSC receptors are activated in response to inflammatory cytokines, including CXCL12, CXCL8, CXCL4, CCL2, and CCL7.77 The corresponding activation of chemokine receptors of MSCs in response to inflammatory cytokines results in an accumulation of MSCs.58,78 For example, inflamed tissues release inflammatory cytokines,79 and specifically, fibroblasts release CXCL12, which further induces the accumulation of MSCs through ligandreceptor interaction after exposure to hypoxia and cytokine-rich environments in the rat model of inflammation.7982 Previous studies have reported that overexpressing CXCR4, which is a receptor to recognize CXCL12, in MSCs improves the homing ability of MSCs toward inflamed sites.83,84 In short, cytokines are significantly involved in the homing mechanism of MSCs.53

The rolling arrest stage is facilitated by integrin 41 (VLA-4) on MSC.85 VLA-4 is expressed by MSCs which are first activated by CXCL-12 and TNF- chemokines, and activated VLA-4 binds to VCAM-1 expressed on endothelial cells to stop the rotational movement (Figure 2).86,87

Karp et al categorized the migration of MSCs as either systemic homing or non-systemic homing. Systemic homing refers to the process of migration through blood vessels and then across the vascular endothelium near the inflamed site.67,88 The process of migration after passing through the vessels or local injection is called non-systemic homing. In non-systemic migration, stem cells migrate through a chemokine concentration gradient (Figure 3).89 MSCs secrete matrix metalloproteinases (MMPs) during migration. The mechanism underlying MSC migration is currently undefined but MSC migration can be advanced by remodeling the matrix through the secretion of various enzymes.9093 The migration of MSCs to the damaged area is induced by chemokines released from the injured site, such as IL-8, TNF-, insulin-like growth factor (IGF-1), and platelet-derived growth factors (PDGF).9496 MSCs migrate toward the damaged area following a chemokine concentration gradient.87

Figure 3 Differences between systemic and non-systemic homing mechanisms. Both systemic and non-systemic homing to the extracellular matrix and stem cells to their destination, MSCs secrete MMPs and remodel the extracellular matrix.

Abbreviation: MMP, matrix metalloproteinase.

RA is a chronic inflammatory autoimmune disease characterized by distinct painful stiff joints and movement disorders.97 RA affects approximately 1% of the worlds population.98 RA is primarily induced by macrophages, which are involved in the innate immune response and are also involved in adaptive immune responses, together with B cells and T cells.99 Inflammatory diseases are caused by high levels of inflammatory cytokines and a hypoxic low-pH environment in the joints.100,101 Fibroblast-like synoviocytes (FLSs) and accumulated macrophages and neutrophils in the synovium of inflamed joints also express various chemokines.102,103 Chemokines from inflammatory reactions can induce migration of white blood cells and stem cells, which are involved in angiogenesis around joints.101,104,105 More than 50 chemokines are present in the rheumatoid synovial membrane (Table 2). Of the chemokines in the synovium, CXCL12, MIP1-a, CXCL8, and PDGF are the main ones that attract MSCs.106 In the RA environment, CXCL12, a ligand for CXCR4 on MSCs, had 10.71 times higher levels of chemokines than in the normal synovial cell environment. MIP-1a, a chemokine that gathers inflammatory cells, is a ligand for CCR1, which is normally expressed on MSC.107,108 CXCL8 is a ligand for CXCR1 and CXCR2 on MSCs and induces the migration of neutrophils and macrophages, leading to ROS in synovial cells.59 PDGF is a regulatory peptide that is upregulated in the synovial tissue of RA patients.109 PDGF induces greater MSC migration than CXCL12.110 Importantly, stem cells not only have the homing ability to inflamed joints but also have potential as cell therapy with the anti-apoptotic, anti-catabolic, and anti-fibrotic effect of MSC.111 In preclinical trials, MSC treatment has been extensively investigated in collagen-induced arthritis (CIA), a common autoimmune animal model used to study RA. In the RA model, MSCs downregulated inflammatory cytokines such as IFN-, TNF-, IL-4, IL-12, and IL1, and antibodies against collagen, while anti-inflammatory cytokines, such as tumor necrosis factor-inducible gene 6 protein (TSG-6), prostaglandin E2 (PGE2), transforming growth factor-beta (TGF-), IL-10, and IL-6, were upregulated.112116

Table 2 Rheumatoid Arthritis (RA) Chemokines Present in the Pathological Environment and Chemokine Receptors Present in Mesenchymal Stem Cells

Genetic engineering can improve the therapeutic potential of MSCs, including long-term survival, angiogenesis, differentiation into specific lineages, anti- and pro-inflammatory activity, and migratory properties (Figure 4).117,118 Although MSCs already have an intrinsic homing ability, the targeting ability of MSCs and their derivatives, such as membrane vesicles, which are utilized to produce MSC mimicking nanoencapsulation, can be enhanced.118 The therapeutic potential of MSCs can be magnified by reprogramming MSCs via upregulation or downregulation of their native genes, resulting in controlled production of the target protein, or by introducing foreign genes that enable MSCs to express native or non-native products, for example, non-native soluble tumor necrosis factor (TNF) receptor 2 can inhibit TNF-alpha signaling in RA therapies.28

Figure 4 Genetic engineering of mesenchymal stem cells to enhance therapeutic efficacy.

Abbreviations: Sfrp2, secreted frizzled-related protein 2; IGF1, insulin-like growth factor 1; IL-2, interleukin-2; IL-12, interleukin-12; IFN-, interferon-beta; CX3CL1, C-X3-C motif chemokine ligand 1; VEGF, vascular endothelial growth factor; HGF, human growth factor; FGF, fibroblast growth factor; IL-10, interleukin-10; IL-4, interleukin-4; IL18BP, interleukin-18-binding protein; IFN-, interferon-alpha; SDF1, stromal cell-derived factor 1; CXCR4, C-X-C motif chemokine receptor 4; CCR1, C-C motif chemokine receptor 1; BMP2, bone morphogenetic protein 2; mHCN2, mouse hyperpolarization-activated cyclic nucleotide-gated.

MSCs can be genetically engineered using different techniques, including by introducing particular genes into the nucleus of MSCs or editing the genome of MSCs (Figure 5).119 Foreign genes can be transferred into MSCs using liposomes (chemical method), electroporation (physical method), or viral delivery (biological method). Cationic liposomes, also known as lipoplexes, can stably compact negatively charged nucleic acids, leading to the formation of nanomeric vesicular structure.120 Cationic liposomes are commonly produced with a combination of a cationic lipid such as DOTAP, DOTMA, DOGS, DOSPA, and neutral lipids, such as DOPE and cholesterol.121 These liposomes are stable enough to protect their bound nucleic acids from degradation and are competent to enter cells via endocytosis.120 Electroporation briefly creates holes in the cell membrane using an electric field of 1020 kV/cm, and the holes are then rapidly closed by the cells membrane repair mechanism.122 Even though the electric shock induces irreversible cell damage and non-specific transport into the cytoplasm leads to cell death, electroporation ensures successful gene delivery regardless of the target cell or organism. Viral vectors, which are derived from adenovirus, adeno-associated virus (AAV), or lentivirus (LV), have been used to introduce specific genes into MSCs. Recombinant lentiviral vectors are the most widely used systems due to their high tropism to dividing and non-dividing cells, transduction efficiency, and stable expression of transgenes in MSCs, but the random genome integration of transgenes can be an obstacle in clinical applications.123 Adenovirus and AAV systems are appropriate alternative strategies because currently available strains do not have broad genome integration and a strong immune response, unlike LV, thus increasing success and safety in clinical trials.124 As a representative, the Oxford-AstraZeneca COVID-19 vaccine, which has been authorized in 71 countries as a vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spread globally and led to the current pandemic, transfers the spike protein gene using an adenovirus-based viral vector.125 Furthermore, there are two AAV-based gene therapies: Luxturna for rare inherited retinal dystrophy and Zolgensma for spinal muscular atrophy.126

Figure 5 Genetic engineering techniques used in the production of bioengineered mesenchymal stem cells.

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 were recently used for genome editing and modification because of their simpler design and higher efficiency for genome editing, however, there are safety issues such as off-target effects that induce mutations at sites other than the intended target site.127 The foreign gene is then commonly transferred into non-integrating forms such as plasmid DNA and messenger RNA (mRNA).128

The gene expression machinery can also be manipulated at the cytoplasmic level through RNA interference (RNAi) technology, inhibition of gene expression, or translation using neutralizing targeted mRNA molecules with sequence-specific small RNA molecules such as small interfering RNA (siRNA) or microRNA (miRNA).129 These small RNAs can form enzyme complexes that degrade mRNA molecules and thus decrease their activity by inhibiting translation. Moreover, the pre-transcriptional silencing mechanism of RNAi can induce DNA methylation at genomic positions complementary to siRNA or miRNA with enzyme complexes.

CXC chemokine receptor 4 (CXCR4) is one of the most potent chemokine receptors that is genetically engineered to enhance the migratory properties of MSCs.130 CXCR4 is a chemokine receptor specific for stromal-derived factor-1 (SDF-1), also known as CXC motif chemokine 12 (CXCL12), which is produced by damaged tissues, such as the area of inflammatory bone destruction.131 Several studies on engineering MSCs to increase the expression of the CXCR4 gene have reported a higher density of the CXCR4 receptor on their outer cell membrane and effectively increased the migration of MSCs toward SDF-1.83,132,133 CXC chemokine receptor 7 (CXCR7) also had a high affinity for SDF-1, thus the SDF-1/CXCR7 signaling axis was used to engineer the MSCs.134 CXCR7-overexpressing MSCs in a cerebral ischemia-reperfusion rat hippocampus model promoted migration based on an SDF-1 gradient, cooperating with the SDF-1/CXCR4 signaling axis (Figure 6).37

Figure 6 Engineered mesenchymal stem cells with enhanced migratory abilities.

Abbreviations: CXCR4, C-X-C motif chemokine receptor 4; CXCR7, C-X-C motif chemokine receptor 7; SDF1, stromal cell-derived factor 1; CXCR1, C-X-C motif chemokine receptor 1; IL-8, interleukin-8; Aqp1, aquaporin 1; FAK, focal adhesion kinase.

CXC chemokine receptor 1 (CXCR1) enhances MSC migratory properties.59 CXCR1 is a receptor for IL-8, which is the primary cytokine involved in the recruitment of neutrophils to the site of damage or infection.135 In particular, the IL-8/CXCR1 axis is a key factor for the migration of MSCs toward human glioma cell lines, such as U-87 MG, LN18, U138, and U251, and CXCR1-overexpressing MSCs showed a superior capacity to migrate toward glioma cells and tumors in mice bearing intracranial human gliomas.136

The migratory properties of MSCs were also controlled via aquaporin-1 (Aqp1), which is a water channel molecule that transports water across the cell membrane and regulates endothelial cell migration.137 Aqp1-overexpressing MSCs showed enhanced migration to fracture gap of a rat fracture model with upregulated focal adhesion kinase (FAK) and -catenin, which are important regulators of cell migration.138

Nur77, also known as nerve growth factor IB or NR4A1, and nuclear receptor-related 1 (Nurr1), can play a role in improving the migratory capabilities of MSCs.139,140 The migrating MSCs expressed higher levels of Nur77 and Nurr1 than the non-migrating MSCs, and overexpression of these two nuclear receptors functioning as transcription factors enhanced the migration of MSCs toward SDF-1. The migration of cells is closely related to the cell cycle, and normally, cells in the late S or G2/M phase do not migrate.141 The overexpression of Nur77 and Nurr1 increased the proportion of MSCs in the G0/G1-phase similar to the results of migrating MSCs had more cells in the G1-phase.

MSC mimicking nanoencapsulations are nanoparticles combined with MSC membrane vesicles and these NPs have the greatest advantages as drug delivery systems due to the sustained homing ability of MSCs as well as the advantages of NPs. Particles sized 10150 nm have great advantages in drug delivery systems because they can pass more freely through the cell membrane by the interaction with biomolecules, such as clathrin and caveolin, to facilitate uptake across the cell membrane compared with micron-sized materials.142,143 Various materials have been used to formulate NPs, including silica, polymers, metals, and lipids.144,145 NPs have an inherent ability, called passive targeting, to accumulate at specific sites based on their physicochemical properties such as size, surface charge, surface hydrophilicity, and geometry.146148 However, physicochemical properties are not enough to target specific tissues or damaged tissues, and thus active targeting is a clinically approved strategy involving the addition of ligands that can bind to surface receptors on target cells or tissues.149,150 MSC mimicking nanoencapsulation uses natural or genetically engineered MSC membranes to coat synthetic NPs, producing artificial ectosomes and fusing them with liposomes to increase their targeting ability (Figure 7).151 Especially, MSCs have been studied for targeting inflammation and regenerative drugs, and the mechanism and efficacy of migration toward inflamed tissues have been actively investigated.152 MSC mimicking nanoencapsulation can mimic the well-known migration ability of MSCs and can be equally utilized without safety issues from the direct application of using MSCs. Furthermore, cell membrane encapsulations have a wide range of functions, including prolonged blood circulation time and increased active targeting efficacy from the source cells.153,154 MSC mimicking encapsulations enter recipient cells using multiple pathways.155 MSC mimicking encapsulations can fuse directly with the plasma membrane and can also be taken up through phagocytosis, micropinocytosis, and endocytosis mediated by caveolin or clathrin.156 MSC mimicking encapsulations can be internalized in a highly cell type-specific manner that depends on the recognition of membrane surface molecules by the cell or tissue.157 For example, endothelial colony-forming cell (ECFC)-derived exosomes were shown CXCR4/SDF-1 interaction and enhanced delivery toward the ischemic kidney, and Tspan8-alpha4 complex on lymph node stroma derived extracellular vesicles induced selective uptake by endothelial cells or pancreatic cells with CD54, serving as a major ligand.158,159 Therefore, different source cells may contain protein signals that serve as ligands for other cells, and these receptorligand interactions maximized targeted delivery of NPs.160 This natural mechanism inspired the application of MSC membranes to confer active targeting to NPs.

Figure 7 Mesenchymal stem cell mimicking nanoencapsulation.

Cell membrane-coated NPs (CMCNPs) are biomimetic strategies developed to mimic the properties of cell membranes derived from natural cells such as erythrocytes, white blood cells, cancer cells, stem cells, platelets, or bacterial cells with an NP core.161 Core NPs made of polymer, silica, and metal have been evaluated in attempts to overcome the limitations of conventional drug delivery systems but there are also issues of toxicity and reduced biocompatibility associated with the surface properties of NPs.162,163 Therefore, only a small number of NPs have been approved for medical application by the FDA.164 Coating with cell membrane can enhance the biocompatibility of NPs by improving immune evasion, enhancing circulation time, reducing RES clearance, preventing serum protein adsorption by mimicking cell glycocalyx, which are chemical determinants of self at the surfaces of cells.151,165 Furthermore, the migratory properties of MSCs can also be transferred to NPs by coating them with the cell membrane.45 Coating NPs with MSC membranes not only enhances biocompatibility but also maximizes the therapeutic effect of NPs by mimicking the targeting ability of MSCs.166 Cell membrane-coated NPs are prepared in three steps: extraction of cell membrane vesicles from the source cells, synthesis of the core NPs, and fusion of the membrane vesicles and core NPs to produce cell membrane-coated NPs (Figure 8).167 Cell membrane vesicles, including extracellular vesicles (EVs), can be harvested through cell lysis, mechanical disruption, and centrifugation to isolate, purify the cell membrane vesicles, and remove intracellular components.168 All the processes must be conducted under cold conditions, with protease inhibitors to minimize the denaturation of integral membrane proteins. Cell lysis, which is classically performed using mechanical lysis, including homogenization, sonication, or extrusion followed by differential velocity centrifugation, is necessary to remove intracellular components. Cytochalasin B (CB), a drug that affects cytoskeletonmembrane interactions, induces secretion of membrane vesicles from source cells and has been used to extract the cell membrane.169 The membrane functions of the source cells are preserved in CB-induced vesicles, forming biologically active surface receptors and ion pumps.170 Furthermore, CB-induced vesicles can encapsulate drugs and NPs successfully, and the vesicles can be harvested by centrifugation without a purification step to remove nuclei and cytoplasm.171 Clinically translatable membrane vesicles require scalable production of high volumes of homogeneous vesicles within a short period. Although mechanical methods (eg, shear stress, ultrasonication, or extrusion) are utilized, CB-induced vesicles have shown potential for generating membrane encapsulation for nano-vectors.168 The advantages of CB-induced vesicles versus other methods are compared in Table 3.

Table 3 Comparison of Membrane Vesicle Production Methods

Figure 8 MSC membrane-coated nanoparticles.

Abbreviations: EVs, extracellular vesicles; NPs, nanoparticles.

After extracting cell membrane vesicles, synthesized core NPs are coated with cell membranes, including surface proteins.172 Polymer NPs and inorganic NPs are adopted as materials for the core NPs of CMCNPs, and generally, polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), chitosan, and gelatin are used. PLGA has been approved by FDA is the most common polymer of NPs.173 Biodegradable polymer NPs have gained considerable attention in nanomedicine due to their biocompatibility, nontoxic properties, and the ability to modify their surface as a drug carrier.174 Inorganic NPs are composed of gold, iron, copper, and silicon, which have hydrophilic, biocompatible, and highly stable properties compared with organic materials.175 Furthermore, some photosensitive inorganic NPs have the potential for use in photothermal therapy (PTT) and photodynamic therapy (PDT).176 The fusion of cell membrane vesicles and core NPs is primarily achieved via extrusion or sonication.165 Cell membrane coating of NPs using mechanical extrusion is based on a different-sized porous membrane where core NPs and vesicles are forced to generate vesicle-particle fusion.177 Ultrasonic waves are applied to induce the fusion of vesicles and NPs. However, ultrasonic frequencies need to be optimized to improve fusion efficiency and minimize drug loss and protein degradation.178

CMCNPs have extensively employed to target and treat cancer using the membranes obtained from red blood cell (RBC), platelet and cancer cell.165 In addition, membrane from MSC also utilized to target tumor and ischemia with various types of core NPs, such as MSC membrane coated PLGA NPs targeting liver tumors, MSC membrane coated gelatin nanogels targeting HeLa cell, MSC membrane coated silica NPs targeting HeLa cell, MSC membrane coated PLGA NPs targeting hindlimb ischemia, and MSC membrane coated iron oxide NPs for targeting the ischemic brain.179183 However, there are few studies on CMCNPs using stem cells for the treatment of arthritis. Increased targeting ability to arthritis was introduced using MSC-derived EVs and NPs.184,185 MSC membrane-coated NPs are proming strategy for clearing raised concerns from direct use of MSC (with or without NPs) in terms of toxicity, reduced biocompatibility, and poor targeting ability of NPs for the treatment of arthritis.

Exosomes are natural NPs that range in size from 40 nm to 120 nm and are derived from the multivesicular body (MVB), which is an endosome defined by intraluminal vesicles (ILVs) that bud inward into the endosomal lumen, fuse with the cell surface, and are then released as exosomes.186 Because of their ability to express receptors on their surfaces, MSC-derived exosomes are also considered potential candidates for targeting.187 Exosomes are commonly referred to as intracellular communication molecules that transfer various compounds through physiological mechanisms such as immune response, neural communication, and antigen presentation in diseases such as cancer, cardiovascular disease, diabetes, and inflammation.188

However, there are several limitations to the application of exosomes as targeted therapeutic carriers. First, the limited reproducibility of exosomes is a major challenge. In this field, the standardized techniques for isolation and purification of exosomes are lacking, and conventional methods containing multi-step ultracentrifugation often lead to contamination of other types of EVs. Furthermore, exosomes extracted from cell cultures can vary and display inconsistent properties even when the same type of donor cells were used.189 Second, precise characterization studies of exosomes are needed. Unknown properties of exosomes can hinder therapeutic efficiencies, for example, when using exosomes as cancer therapeutics, the use of cancer cell-derived exosomes should be avoided because cancer cell-derived exosomes may contain oncogenic factors that may contribute to cancer progression.190 Finally, cost-effective methods for the large-scale production of exosomes are needed for clinical application. The yield of exosomes is much lower than EVs. Depending on the exosome secretion capacity of donor cells, the yield of exosomes is restricted, and large-scale cell culture technology for the production of exosomes is high difficulty and costly and isolation of exosomes is the time-consuming and low-efficient method.156

Ectosome is an EV generated by outward budding from the plasma membrane followed by pinching off and release to the extracellular parts. Recently, artificially produced ectosome utilized as an alternative to exosomes in targeted therapeutics due to stable productivity regardless of cell type compared with conventional exosome. Artificial ectosomes, containing modified cargo and targeting molecules have recently been introduced for specific purposes (Figure 9).191,192 Artificial ectosomes are typically prepared by breaking bigger cells or cell membrane fractions into smaller ectosomes, similar size to natural exosomes, containing modified cargo such as RNA molecules, which control specific genes, and chemical drugs such as anticancer drugs.193 Naturally secreted exosomes in conditioned media from modified source cells can be harvested by differential ultracentrifugation, density gradients, precipitation, filtration, and size exclusion chromatography for exosome separation.194 Even though there are several commercial kits for isolating exosomes simply and easily, challenges in compliant scalable production on a large scale, including purity, homogeneity, and reproducibility, have made it difficult to use naturally secreted exosomes in clinical settings.195 Therefore, artificially produced ectosomes are appropriate for use in clinical applications, with novel production methods that can meet clinical production criteria. Production of artificially produced ectosomes begins by breaking the cell membrane fraction of cultured cells and then using them to produce cell membrane vesicles to form ectosomes. As mentioned above, cell membrane vesicles are extracted from source cells in several ways, and cell membrane vesicles are extracted through polycarbonate membrane filters to reduce the mean size to a size similar to that of natural exosomes.196 Furthermore, specific microfluidic devices mounted on microblades (fabricated in silicon nitride) enable direct slicing of living cells as they flow through the hydrophilic microchannels of the device.197 The sliced cell fraction reassembles and forms ectosomes. There are several strategies for loading exogenous therapeutic cargos such as drugs, DNA, RNA, lipids, metabolites, and proteins, into exosomes or artificial ectosomes in vitro: electroporation, incubation for passive loading of cargo or active loading with membrane permeabilizer, freeze and thaw cycles, sonication, and extrusion.198 In addition, protein or RNA molecules can be loaded by co-expressing them in source cells via bio-engineering, and proteins designed to interact with the protein inside the cell membrane can be loaded actively into exosomes or artificial ectosomes.157 Targeting molecules at the surface of exosomes or artificial ectosomes can also be engineered in a manner similar to the genetic engineering of MSCs.

Figure 9 Mesenchymal stem cell-derived exosomes and artificial ectosomes. (A) Wound healing effect of MSC-derived exosomes and artificial ectosomes,231 (B) treatment of organ injuries by MSC-derived exosomes and artificial ectosomes,42,232234 (C) anti-cancer activity of MSC-derived exosomes and artificial ectosomes.200,202,235

Most of the exosomes derived from MSCs for drug delivery have employed miRNAs or siRNAs, inhibiting translation of specific mRNA, with anticancer activity, for example, miR-146b, miR-122, and miR-379, which are used for cancer targeting by membrane surface molecules on MSC-derived exosomes.199201 Drugs such as doxorubicin, paclitaxel, and curcumin were also loaded into MSC-derived exosomes to target cancer.202204 However, artificial ectosomes derived from MSCs as arthritis therapeutics remains largely unexplored area, while EVs, mixtures of natural ectosomes and exosomes, derived from MSCs have studied in the treatment of arthritis.184 Artificial ectosomes with intrinsic tropism from MSCs plus additional targeting ability with engineering increase the chances of ectosomes reaching target tissues with ligandreceptor interactions before being taken up by macrophages.205 Eventually, this will decrease off-target binding and side effects, leading to lower therapeutic dosages while maintaining therapeutic efficacy.206,207

Liposomes are spherical vesicles that are artificially synthesized through the hydration of dry phospholipids.208 The clinically available liposome is a lipid bilayer surrounding a hollow core with a diameter of 50150 nm. Therapeutic molecules, such as anticancer drugs (doxorubicin and daunorubicin citrate) or nucleic acids, can be loaded into this hollow core for delivery.209 Due to their amphipathic nature, liposomes can load both hydrophilic (polar) molecules in an aqueous interior and hydrophobic (nonpolar) molecules in the lipid membrane. They are well-established biomedical applications and are the most common nanostructures used in advanced drug delivery.210 Furthermore, liposomes have several advantages, including versatile structure, biocompatibility, low toxicity, non-immunogenicity, biodegradability, and synergy with drugs: targeted drug delivery, reduction of the toxic effect of drugs, protection against drug degradation, and enhanced circulation half-life.211 Moreover, surfaces can be modified by either coating them with a functionalized polymer or PEG chains to improve targeted delivery and increase their circulation time in biological systems.212 Liposomes have been investigated for use in a wide variety of therapeutic applications, including cancer diagnostics and therapy, vaccines, brain-targeted drug delivery, and anti-microbial therapy. A new approach was recently proposed for providing targeting features to liposomes by fusing them with cell membrane vesicles, generating molecules called membrane-fused liposomes (Figure 10).213 Cell membrane vesicles retain the surface membrane molecules from source cells, which are responsible for efficient tissue targeting and cellular uptake by target cells.214 However, the immunogenicity of cell membrane vesicles leads to their rapid clearance by macrophages in the body and their low drug loading efficiencies present challenges for their use as drug delivery systems.156 However, membrane-fused liposomes have advantages of stability, long half-life in circulation, and low immunogenicity due to the liposome, and the targeting feature of cell membrane vesicles is completely transferred to the liposome.215 Furthermore, the encapsulation efficiencies of doxorubicin were similar when liposomes and membrane-fused liposomes were used, indicating that the relatively high drug encapsulation capacity of liposomes was maintained during the fusion process.216 Combining membrane-fused liposomes with macrophage-derived membrane vesicles showed differential targeting and cytotoxicity against normal and cancerous cells.217 Although only a few studies have been conducted, these results corroborate that membrane-fused liposomes are a potentially promising future drug delivery system with increased targeting ability. MSCs show intrinsic tropism toward arthritis, and further engineering and modification to enhance their targeting ability make them attractive candidates for the development of drug delivery systems. Fusing MSC exosomes with liposomes, taking advantage of both membrane vesicles and liposomes, is a promising technique for future drug delivery systems.

Figure 10 Mesenchymal stem cell membrane-fused liposomes.

MSCs have great potential as targeted therapies due to their greater ability to home to targeted pathophysiological sites. The intrinsic ability to home to wounds or to the tumor microenvironment secreting inflammatory mediators make MSCs and their derivatives targeting strategies for cancer and inflammatory disease.218,219 Contrary to the well-known homing mechanisms of various blood cells, it is still not clear how homing occurs in MSCs. So far, the mechanism of MSC tethering, which connects long, thin cell membrane cylinders called tethers to the adherent area for migration, has not been clarified. Recent studies have shown that galectin-1, VCAM-1, and ICAM are associated with MSC tethering,53,220 but more research is needed to accurately elucidate the tethering mechanism of MSCs. MSC chemotaxis is well defined and there is strong evidence relating it to the homing ability of MSCs.53 Chemotaxis involves recognizing chemokines through chemokine receptors on MSCs and migrating to chemokines in a gradient-dependent manner.221 RA, a representative inflammatory disease, is associated with well-profiled chemokines such as CXCR1, CXCR4, and CXCR7, which are recognized by chemokine receptors on MSCs. In addition, damaged joints in RA continuously secrete cytokines until they are treated, giving MSCs an advantage as future therapeutic agents for RA.222 However, there are several obstacles to utilizing MSCs as RA therapeutics. In clinical settings, the functional capability of MSCs is significantly affected by the health status of the donor patient.223 MSC yield is significantly reduced in patients undergoing steroid-based treatment and the quality of MSCs is dependent on the donors age and environment.35 In addition, when MSCs are used clinically, cryopreservation and defrosting are necessary, but these procedures shorten the life span of MSCs.224 Therefore, NPs mimicking MSCs are an alternative strategy for overcoming the limitations of MSCs. Additionally, further engineering and modification of MSCs can enhance the therapeutic effect by changing the targeting molecules and loaded drugs. In particular, upregulation of receptors associated with chemotaxis through genetic engineering can confer the additional ability of MSCs to home to specific sites, while the increase in engraftment maximizes the therapeutic effect of MSCs.36,225

Furthermore, there are several methods that can be used to exploit the targeting ability of MSCs as drug delivery systems. MSCs mimicking nanoencapsulation, which consists of MSC membrane-coated NPs, MSC-derived artificial ectosomes, and MSC membrane-fused liposomes, can mimic the targeting ability of MSCs while retaining the advantages of NPs. MSC-membrane-coated NPs are synthesized using inorganic or polymer NPs and membranes from MSCs to coat inner nanosized structures. Because they mimic the biological characteristics of MSC membranes, MSC-membrane-coated NPs can not only escape from immune surveillance but also effectively improve targeting ability, with combined functions of the unique properties of core NPs and MSC membranes.226 Exosomes are also an appropriate candidate for use in MSC membranes, utilizing these targeting abilities. However, natural exosomes lack reproducibility and stable productivity, thus artificial ectosomes with targeting ability produced via synthetic routes can increase the local concentration of ectosomes at the targeted site, thereby reducing toxicity and side effects and maximizing therapeutic efficacy.156 MSC membrane-fused liposomes, a novel system, can also transfer the targeting molecules on the surface of MSCs to liposomes; thus, the advantages of liposomes are retained, but with targeting ability. With advancements in nanotechnology of drug delivery systems, the research in cell-mimicking nanoencapsulation will be very useful. Efficient drug delivery systems fundamentally improve the quality of life of patients with a low dose of medication, low side effects, and subsequent treatment of diseases.227 However, research on cell-mimicking nanoencapsulation is at an early stage, and several problems need to be addressed. To predict the nanotoxicity of artificially synthesized MSC mimicking nanoencapsulations, interactions between lipids and drugs, drug release mechanisms near the targeted site, in vivo compatibility, and immunological physiological studies must be conducted before clinical application.

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF-2019M3A9H1103690), by the Gachon University Gil Medical Center (FRD2021-03), and by the Gachon University research fund of 2020 (GGU-202008430004).

The authors report no conflicts of interest in this work.

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19. Liau LL, Looi QH, Chia WC, Subramaniam T, Ng MH, Law JX. Treatment of spinal cord injury with mesenchymal stem cells. Cell Biosci. 2020;10:112. doi:10.1186/s13578-020-00475-3

20. Williams AR, Hare JM, Dimmeler S, Losordo D. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res. 2011;109(8):923940. doi:10.1161/CIRCRESAHA.111.243147

21. Karantalis V, Hare JM. Use of mesenchymal stem cells for therapy of cardiac disease. Circ Res. 2015;116(8):14131430. doi:10.1161/CIRCRESAHA.116.303614

22. Bernstein HS, Srivastava D. Stem cell therapy for cardiac disease. Pediatr Res. 2012;71(4 Pt 2):491499. doi:10.1038/pr.2011.61

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24. Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther. 2008;15(10):730738. doi:10.1038/gt.2008.39

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27. Majithia V, Geraci SA. Rheumatoid arthritis: diagnosis and management. Am J Med. 2007;120(11):936939. doi:10.1016/j.amjmed.2007.04.005

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31. Kabat M, Bobkov I, Kumar S, Grumet M. Trends in mesenchymal stem cell clinical trials 20042018: is efficacy optimal in a narrow dose range? Stem Cells Transl Med. 2020;9(1):1727. doi:10.1002/sctm.19-0202

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34. Gholamrezanezhad A, Mirpour S, Bagheri M, et al. In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Nucl Med Biol. 2011;38(7):961967. doi:10.1016/j.nucmedbio.2011.03.008

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Stem Cell Mimicking Nanoencapsulation for Targeting Arthrit | IJN - Dove Medical Press

Bone Marrow Stem Cells Comments Off on Stem Cell Mimicking Nanoencapsulation for Targeting Arthrit | IJN – Dove Medical Press | January 3rd, 2022

1Regenerative Medicine Centre, Arabian Gulf University, Manama, Bahrain; 2Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain

Introduction: Stroke is a leading cause of death and disability worldwide. The disease is caused by reduced blood flow into the brain resulting in the sudden death of neurons. Limited spontaneous recovery might occur after stroke or brain injury, stem cell-based therapies have been used to promote these processes as there are no drugs currently on the market to promote brain recovery or neurogenesis. Adult stem cells (ASCs) have shown the ability of differentiation and regeneration and are well studied in literature. ASCs have also demonstrated safety in clinical application and, therefore, are currently being investigated as a promising alternative intervention for the treatment of stroke.Methods: Eleven studies have been systematically selected and reviewed to determine if autologous adult stem cells are effective in the treatment of stroke. Collectively, 368 patients were enrolled across the 11 trials, out of which 195 received stem cell transplantation and 173 served as control. Using data collected from the clinical outcomes, a broad comparison and a meta-analysis were conducted by comparing studies that followed a similar study design.Results: Improvement in patients clinical outcomes was observed. However, the overall results showed no clinical significance in patients transplanted with stem cells than the control population.Conclusion: Most of the trials were early phase studies that focused on safety rather than efficacy. Stem cells have demonstrated breakthrough results in the field of regenerative medicine. Therefore, study design could be improved in the future by enrolling a larger patient population and focusing more on localized delivery rather than intravenous transplantation. Trials should also introduce a more standardized method of analyzing and reporting clinical outcomes to achieve a better comparable outcome and possibly recognize the full potential that these cells have to offer.

Keywords: adult stem cells, autologous, neurogenesis, inflammation, clinical application, stroke, stroke recovery, systematic review, meta-analysis

Stroke is the second leading cause of death worldwide and one of the leading causes of disability.1 The blockade or the rupture of a blood vessel to the brain leads to either ischemic or hemorrhagic stroke, respectively.2,3 The extent and the location of the damaged brain tissue may be associated with irreversible cognitive impairment or decline in speech, comprehension, memory, and partial or total physical paralysis.4

Four chronological phases, namely hyperacute, acute, subacute, and chronic, describe the strokes cellular manifestations.5 The hyperacute phase is immediate and associated with glutamate-mediated excitotoxicity and a progressive neuronal death that can last a few hours.6 The glutamate, a potent excitatory neurotransmitter, is also an inducer of neurodegeneration following stroke.7 The acute phase, which could last over a week after the stroke, is associated with the delayed and progressive neuronal death and the infiltration of immune cells.5 The following subacute phase can extend up to three months after the stroke and is mainly associated with reduced inflammation and increased plasticity of neurons, astrocytes, microglia, and endothelial cells, allowing spontaneous recovery.8 In the chronic phase that follows, the plasticity of cells is reduced and only permits rehabilitation-induced recovery.5

The immediate treatments differ for ischemic and hemorrhagic strokes. Immediate intervention is required to restore the blood flow to the brain following an ischemic stroke. Thrombolytic agents, such as activase (Alteplase), a recombinant tissue plasminogen activator (tPA), are commonly given intravenously to dissolve the blood clots. Other more invasive approaches, such as a thrombectomy, use stents or catheters to remove the blood clot.9 Antiplatelet agents like Aspirin, anticoagulants, blood pressure medicines, or statins are generally given to reduce the risk of recurrence. Some ischemic strokes are caused by the narrowing of the carotid artery due to the accumulation of fatty plaques; a carotid endarterectomy is performed to correct the constriction.

The treatment of a hemorrhagic stroke requires a different approach. An emergency craniotomy is usually performed to remove the blood accumulating in the brain and repair the damaged blood vessels. Accumulation of cerebrospinal fluid in brain ventricles (hydrocephalus) is also a frequent complication following a hemorrhagic stroke, which requires surgery to drain the fluid. Medications to lower blood pressure are given before surgery and to prevent further seizures.10

These immediate treatments are critical to minimize the long-term consequence of the stroke but do not address the post-stroke symptoms caused by neurodegeneration. New therapeutic approaches adapted to the physiology of each phase of the stroke are currently developed. A promising therapy has been the use of stem cells.11 In this review, different clinical trials involving the use of various stem cells for the treatment of stroke are presented and compared using a meta-analysis of the published results.

To narrow down the relevant literature, a search strategy focused on original literature and reporting the clinical application of stem cells in stroke was established. An NCBI PubMed word search for stroke, stem cells, and adult stem cells yielded 146 clinical studies between 2010 and 2021. Finally, 11 studies, using autologous adult stem cells in the treatment of stroke, were considered. A PRISMA flow diagram detailing an overview of the study selection procedure and the inclusion and exclusion of papers is included in Appendix I. The inclusion criteria comprise the injection of autologous adult stem cells at any stroke stages (hyperacute, acute, sub-acute, chronic), and clinical trials whose results have been published in the last 11 years. The exclusion criteria include studies published more than 11 years ago, studies not published in English, all preclinical studies, other diseases related to stroke (ex. cardiovascular diseases), embryonic or induced pluripotent stem cells, allogeneic stem cells, and other cell therapies. Two independent researchers reviewed and filtered the 146 studies by reading the titles and abstracts. All three authors approved the final selected studies.

Stem cells are undifferentiated and unspecialized cells characterized by their ability to self-renew and their potential to differentiate into specialized cell types.12 Ischemic stroke causes severe damage to the brain cells by destroying the heterogeneous cell population and neuronal connections along with vascular systems. The regenerative potential of several types of stem cells like embryonic stem cells, neural stem cells, adult stem cells (mesenchymal stem cells), and induced pluripotent stem cells have been assessed for treating stroke.

Adult stem cells exhibit multipotency and the ability to self-renew and differentiate into specialized cell types. They have been widely used in clinical trials and a safe option thus far in treating various diseases.12,13,14 The plasticity of these cells allow their differentiation across tissue lineages when exposed to defined cell culture conditions.15 There are multiple easily accessible sources of adult stem cells, mainly the bone marrow, blood, and adipose tissue. In clinical settings, both autologous and HLA-matched allogeneic cells have been transplanted and are deemed to be safe.

Adult stem cells can secrete a variety of bioactive substances into the injured brain following a stroke in the form of paracrine signals.1618 The paracrine signals include growth factors, trophic factors, and extracellular vesicles, which may be associated with enhanced neurogenesis, angiogenesis, and synaptogenesis (Figure 1). Also, mesenchymal stem cells (MSCs) are thought to contribute to the resolution of the stroke by attenuating inflammation,19 reducing scar thickness, enhancing autophagy, normalizing microenvironmental and metabolic profiles and possibly replacing damaged cells.20

Figure 1 Schematic depicting the clinical application of different cells in stroke patients. The cells were delivered in one of three ways, intravenously, intra-arterially, or via stereotactic injections. Once administered, the cells play a role in providing paracrine signals and growth factors to facilitate angiogenesis and cell regeneration, immunomodulatory effects that serve to protect the neurons from further damage caused by inflammation, and finally, trans-differentiation of stem cells. Data from Dabrowska S, Andrzejewska A, Lukomska B, Janowski M.19 Created with BioRender.com.

A few routes of administration have been used to deliver the stem cells to the patients. The most common is through intravenous injection. Intra-arterial delivery is also performed; but this mode can be extremely painful to patients compared to an intravenous transfusion. The third approach is via stereotactic injections. This is an invasive surgery that involves injecting the cells directly into the site of affected in the brain.

Also known as mesenchymal stromal cells or medicinal signaling cells, MSCs can be derived from different sources including bone marrow, peripheral blood, lungs, heart, skeletal muscle, adipose tissue, dental pulp, dermis, umbilical cord, placenta, amniotic fluid membrane and many more.21 MSCs are characterized by positive cell surface markers, including Stro-1, CD19, CD44, CD90, CD105, CD106, CD146, and CD166. The cells are also CD14, CD34, and CD45 negative.22,23 The cells are thought to provide a niche to stem cells in normal tissue and releases paracrine factors that promote neurogenesis (Figure 2).19,20,24 During the acute and subacute stage of stroke, MSCs may inhibit inflammation, thus, reducing the incidence of debilitating damage and symptoms that may occur post-stroke.

Figure 2 Schematic describing the role of mesenchymal stem cells in stroke. The cells release different growth factors, signals, and cytokines that serve to facilitate various functions. Through the release of cytokines, they can modulate inflammation and block apoptosis. The growth factors aid in promoting angiogenesis and neurogenesis. Data from Maleki M, Ghanbarvand F, Behvarz MR, Ejtemaei M, Ghadirkhomi E.23 Created with BioRender.com.

Derived from the bone marrow, mononuclear cells contain several types of stem cells, including mesenchymal stem cells and hematopoietic progenitor cells that give rise to hematopoietic stem cells and various other differentiated cells. They can produce and secrete multiple growth factors and cytokines. They are also attracted to the lesion or damage site where they can accelerate angiogenesis and promote repair endogenously through the proliferation of the hosts neural stem cells. Mononuclear cells have also demonstrated the ability to decrease neurodegeneration, modulate inflammation, and prevent apoptosis in animal models.25,26

Blood stem cells are a small number of bone marrow stem cells that have been mobilized into the blood by hematopoietic growth factors, which regulate the differentiation and proliferation of cells. They are increasingly used in cell therapies, most recently for the regeneration of non-hematopoietic tissue, including neurons. Recombinant human granulocyte colony-stimulating factor (G-CSF) has been used as a stimulator of hematopoiesis, which in turn amplifies the yield of peripheral blood stem cells.27

The literature review considered 11 clinical trials that satisfied the inclusion criteria. A total of 368 patients were enrolled including 179 patients treated with various types of adult stem cells. The clinical trial number 7 contained a historical control of 59 patients included in the data analysis (Figure 3). The analysis was done on the published clinical and functional outcomes of various tests such as mRS, and mBI. The analysis compared the patients clinical outcomes post stem cell therapy to the baseline clinical results. The variance in the patient population should be noted.

Figure 3 Schematic representing an overview of the total number of patients enrolled in all 11 clinical trials and the number of patients administered with each type of adult stem cell.

Abbreviations: MSC, mesenchymal stem cells; PBSC, peripheral blood stem cells; MNC, mononuclear stem cells; ADSVF, adipose derived stromal vascular fraction; ALD401, aldehyde dehydrogenase-bright stem cells.

Meta-analyses were conducted using modified Rankin scale (mRS) and Barthel Index (BI) scores. In the clinical trials, mRS and BI scores are commonly used scales to assess functional outcome in stroke patients. The BI score was developed to measures the patients performance in 10 activities of daily life from self-care to mobility. An mRS score follows a similar outcome but measures the patients independence in daily tasks rather than performance. OpenMeta[Analyst], an open-source meta-analysis software, was used to produce random-effects meta-analyses and create the forest plots. The number of patients, mean, and standard deviation (SD) of the scores were calculated to determine the study weights and create the forest plots.

All 11 clinical trials were compared based on their clinical and functional outcomes (Table 1; Figure 4). The data shows that stem cell therapy is relatively safe and viable in the treatment of stroke, indicating an improvement in patients overall health. However, when compared to the control, the improvement is not significant as patients in the control group also exhibited an improved clinical and functional outcome. Across trials that assigned a control group, the patients either received a placebo, or alternative form of treatment including physiotherapy. Variance in functional and clinical tests used to assess patients, and the number of patients enrolled in each trial results in a discrepancy in reporting. Most of the trials failed to report whether the patients suffered from an acute, subacute or chronic stroke which also affects the results of the treatments, with acute and subacute being the optimal periods to receive treatment due to cell plasticity and inhibiting unwarranted inflammation.39 The deaths in both the treatment and control population were attributed to the progression of the disease and are likely not the result of the treatment. Albeit, it has been noted down as they had occurred during the follow-up period.

Table 1 Overview of Selected Clinical Trials

Figure 4 Overview of clinical outcomes of the 11 clinical trials (N=368). (A) The chart shows the percentages of patients who have either improved, remained stable, deteriorated, or deceased. Some clinical trials are without a control arm. (B) The plot shows the overall percentage of patients that have improved after receiving either the stem cell treatment versus the standard of care. (C) The plot shows the overall percentage of patients that have remained stable and showed no clinical or functional improvement in the follow up period. (D) The plot shows the overall percentage of the patients whose condition has deteriorated in the follow up period.

A meta-analysis was conducted using modified Rankin scale (mRS) and Barthel Index (BI) scores. The results of the mRS scores were analyzed (Figure 5A; Table 2). In terms of study weights, CT6 is the highest (40.07%) as shown in Table 2. The combined results of the mRS functional test from CT1, CT5, CT6, and CT11 show a non-significant statistical heterogeneity in the studies (p-value 0.113). In conjunction, BI scores were analyzed and a meta-analysis was conducted using four comparable trials (Figure 5B; Table 3). In terms of study weights, CT3 is the highest (32.384%) as shown in Table 3. The combined results of BI scores from CT5, CT3, CT10, and CT11 show a statistical heterogeneity in the results of the studies (p-value 0.004) thus, precision of results is uncertain. More comparable studies are needed to have a better outcome. Therefore, standardized testing in trails should be considered in future trials.

Table 2 Clinical Outcomes of mRS Test

Table 3 Clinical Outcomes of BI Test

Figure 5 Meta-analysis conducted using three comparable trials. (A) Meta-analysis conducted using four comparable trials (CT1, CT5, CT6, CT11) for the mRS test. (B) Meta-analysis conducted using four comparable trials (CT3, CT5, CT10, and CT11) for the BI test.

Across all trials, patients injected with the MSCs, and other cell types did not trigger a degradation of the patient conditions demonstrating the safety of the procedures. However, the efficacy of the use of adult stem cells is less clear when compared to patients in the control group. This discrepancy could, however, exhibit improvement in patients receiving the treatment compared to the baseline clinical outcomes. However, when therapy results are compared to the patients in the control population that either received a placebo, physiotherapy, or prescribed medication, the efficacy of the use of adult stem cells is less clear.

Although multiple adult stem cell types have been used, mesenchymal stem cells have been widely used in many clinical trials. Albeit there is a consensus that the therapeutic and clinical outcomes of mesenchymal stem cell treatments are not yet significantly effective compared to the control treatment. Some trials have shown patient improvements, such as CT6 and CT8, where the investigators used PBSCs or BMMNSC, respectively. Although subjectively, the cells appear to be therapeutic, objectively, there are many limitations to the study designs included in this review. Not all the trials enrolled a control arm for a better comparison as some were only testing safety rather than efficacy. Therefore, we cannot conclude whether autologous adult stem cells are an effective therapeutic stroke treatment. Only autologous cells were included in this review as they are non-immunogenic.

Another factor to consider is the evident discrepancy in the number of patients enrolled in each trial. The trials included in this review are in Phase I and II trials, which primarily focus on safety rather than efficacy. Intravenous injection was the most used method of cell delivery due to its convenience and safety. However, it is commonly considered that this approach is not the most effective way of delivery, as the majority of the transplanted cells get absorbed by non-targeted organs, and the remaining cells find difficulty passing the blood-brain barrier. Due to this dilemma, the most obvious approach would be to inject the cells directly into the brain. However, a stereotactic procedure is invasive and will require general anesthesia, which may compromise patients health, especially ones suffering from acute ischemic stroke.40 Thus, an intra-arterial delivery seems feasible to accomplish the task as it is less invasive and might be more effective than an intravenous treatment such as the cases observed in CT3 and CT8. In CT11, the patients demonstrated a visible fmRI recovery as well as recovery of motor function in patients that have received a stem cell treatment. However, the analysis and test scores show no significance between the treatment group and the control group.

Only a few studies were comparable using a similar evaluation approach. Considering these factors, better study designs enrolling a higher number of patients in randomized clinical trial against the standard of care are needed. Moreover, a better grouping of the patients based on the type and stage of stroke may provide more relevant information for the safety and efficacy of adult stem cells for the recovery and prevention of recurrence of stroke patients.

ADSVF, Adipose-derived stromal vascular fraction; ASCs, Adult stem cells; ALD-401, Aldehyde dehydrogenase 401; BI, Barthel Index; BM-MNC, Bone marrow-derived mononuclear cells; FLAIR, Fluid attenuated inversion recovery; fMRI, Functional magnetic resonance imaging; G-CSF, Granulocyte colony-stimulating factor; MRI, Magnetic resonance imaging; MSCs, Mesenchymal stem cells; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; PBSC, Peripheral blood stem cells; SD, Standard deviation; tPA, tissue plasminogen activator.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

There is no funding to report.

We declare there is no conflict of interest.

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34. Taguchi A, Sakai C, Soma T, et al. Intravenous autologous bone marrow mononuclear cell transplantation for stroke: phase1/2a clinical trial in a homogeneous group of stroke patients. Stem Cells Dev. 2015;24(19):22072218. doi:10.1089/scd.2015.0160

35. Bhatia V, Gupta V, Khurana D, Sharma RR, Khandelwal N. Randomized assessment of the safety and efficacy of intra-arterial infusion of autologous stem cells in subacute ischemic stroke. Am J Neuroradiol. 2018;39(5):899904. doi:10.3174/ajnr.A5586

36. Duma C, Kopyov O, Kopyov A, et al. Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: results of a 3-year Phase 1 study of 113 injections in 31 patients. Mol Biol Rep. 2019;46(5):52575272. doi:10.1007/s11033-019-04983-5

37. Savitz SI, Yavagal D, Rappard G, et al. A phase 2 randomized, sham-controlled trial of internal carotid artery infusion of autologous bone marrow-derived ALD-401 cells in patients with recent stable ischemic stroke (RECOVER-stroke). Circulation. 2019;139(2):192205. doi:10.1161/CIRCULATIONAHA.117.030659

38. Jaillard A, Hommel M, Moisan A, et al. Autologous mesenchymal stem cells improve motor recovery in subacute ischemic stroke: a randomized clinical trial. Transl Stroke Res. 2020;11(5):910923. doi:10.1007/s12975-020-00787-z

39. Kwak K-A, Kwon H-B, Lee JW, Park Y-S. Current perspectives regarding stem cell-based therapy for ischemic stroke. Curr Pharm Des. 2018;24(28):33323340. doi:10.2174/1381612824666180604111806

40. Anastasian ZH. Anaesthetic management of the patient with acute ischaemic stroke. Br J Anaesth. 2014;113:ii9ii16. doi:10.1093/bja/aeu372

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Steven Fisher is a modern-day Spartan.59, 225 pounds of pure muscle, and hes constantly exercising.

In fact, his favorite hobby is touring the country, competing in Spartan Races with his wife. If youve never heard of a Spartan Race, its essentially running miles and miles, and youre rewarded for your efforts by completing physical tasks, like doing a billion pull-ups, or crawling through mud, at each mile.

For these obstacle and endurance races, youve got to be in pretty good shape.

However, as of late Fisher has had to take a break from said races. Not because hes tired, or anything like that. The mans a machine. His hiatus has stemmed from a life-long nagging injury thats been flaring up.

He said it all started during his young and dumb days. He and his friends were tobogganing down a hill. Fisher, who was 20 at the time, said he stood up on the toboggan to attempt a little surfing. He felt like a regular Kelly Slater before falling backwards.

Learn more:Orthopedics regenerative medicine at Sanford Health

My elbow hit into the ground and just caught. I broke my humerus into three pieces. Obviously, that was a lot of trauma in my shoulder as well, Fisher said.

Because of the impact, his doctor told him he was lucky his humerus didnt shoot through his shoulder.

Normally thats what they see with that kind of fall.

He went through rehabilitation, and other than some trouble resting his hands behind his head, he said he made a full recovery.

Fast forward a few decades, and hes lifting weights, running Spartan Races, and seemed to be doing well. One day, though, he noticed a sharp pain in the same shoulder he injured as a young adult.

He said he couldnt heal it the ways he normally would. So, he went to his doctor.

He said I had arthritis. At the age of 43. He said if I was older, wed be talking about replacing my shoulder, he said.

Fisher got aPRP, or platelet rich plasma, injection. He noticed some relief for eight months, before the pain returned.

Basically at that point it was a labrum tear, and Id been re-tearing it quite a bit, Fisher said. He got another PRP shot but started to look more into stem cells and regenerative medicine. He lives in West Virgina and found a few doctors who offer stem cell therapy.

But you cant find a lot of information on how they do it, like what their method is. They dont even say if its from bone marrow or from fat. They also dont tell you how theyre extracting the stem cells, like if its mechanical or theyre doing something else. Theyre not going to tell you that stuff, he said.

He wanted to continue to explore this form of treatment, but only if it was done the right way. He talked with multiple providers on the East Coast, but it just didnt feel right.

Then, he stumbled onto Sanford.

He said he started talking with Tiffany Facile, the clinical director of regenerative medicine at Sanford Health. She explained to him that the stem cell treatment, and ENDURE clinical trial,Sanford Healthcan offer might be a great fit for Fisher.

We talked about different studies, and we talked about what Sanford is doing. Shes obviously really excited about it and there were some previous studies (Sanford has) done. I read up on the previous studies, and the results on the previous studies. For example, with a rotator cuff, they had done the same process and got great results with it, Fisher explained.

He also said he truly felt like he was heard and understood at Sanford Health. Some of the other places felt like more of a shop, so to speak, he said.

Everybody, from the top down to even the front desk, they were gracious. Everybody Ive worked with, theyre all passionate about this. I never felt like I was just getting pulled along, and I didnt have a say in my care or anything like that. I felt I was more part of the process itself and like I was walking with them, he said.

Fisher received adipose-derived stem cell treatment from Sanford. He said the way Sanford Health delivered the treatment differs from other health care providers. He explained some providers use a mechanical method to extract the stem cells, but Sanford uses a more concentrated enzyme-derived method.

There is an estimated range on the amount of stem cells that get extracted, like from an enzyme approach versus mechanical, and it can be on the order of like a thousand times more cells going to be extracted, versus the mechanical, he said.

Hes still on the sidelines for Spartan Races, but hes hoping to get back on the course soon. He has a check-up in January, but he says he feels both physically and mentally better after receiving care from Sanford.

Posted In Orthopedics, Research, Sports Medicine

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Cell therapy helps Sanford patient get back to racecourse - Sanford Health News

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By Stephanie Banat

17-year-old Samantha Horowitz is teaching the world about the healing powers of music.

A lifelong Merrick resident, Horowitz is a senior at Calhoun High School who for the past three years has been the sole vocalist in the production of a musical documentary, Second Chance, based on her mother, Tara Notricas, long battle with mast cell disease.

Some of the songs were written from my perspective, and some were written from my moms perspective, Horowitz explained. Music has given us the freedom to express things that we couldnt put into words and I truly believe its a huge part of the reason that my mom is here with us today.

In honor of her creative, healing effort, the Herald is proud to name Horowitz its 2021 Person of the Year.

Since Notricas early 20s, she had suffered from a number of physical maladies of unknown causes, including episodes of anaphylactic shock, hair loss and other issues.

It wasnt until April 2011, after consultations with scores of specialists, that Notrica was finally diagnosed with mast cell activation syndrome, a rare disorder caused by abnormal or overly active mast cells that affects multiple organ systems, including the gastrointestinal, neurological, endocrine, cardiac and respiratory systems.

It took a huge toll on me and my family, Horowitz said. I was 5 at the time, and I didnt understand what was going on. I just knew that my mom was sick, and that she couldnt be the mom she wanted to be for my brother, Jared, and I.

In 2018, Notrica endured a stem cell transplant, which was unsuccessful. Next, that June, her doctors offered her the option of receiving a bone marrow transplant, which, they said, she had a 50-50 chance of surviving. Nonetheless, Notrica decided to go forward with the procedure.

At this time, the whole music process really started picking up, her daughter said, because there were now a lot more emotions we were experiencing to write about because there were some days that my mom woke up and really didnt think she was going to make it.

Just two weeks before the bone marrow transplant, the family began filming a documentary, directed by Rochester-based filmmakers Matthew White and Brian Gerlach. The film documents Notricas health journey, and focuses on the weeks leading up to the transplant. Its title, Second Chance, comes from one of its songs, which is about Notrica getting a second chance at life, and getting to experience everything she had missed out on because of her illness.

Since 2017, Horowitz has written and recorded 11 original songs for the film. Her music career, however, started long before the documentary.

Ive had a passion for singing since I was around 3 or 4 years old, she said. In elementary school I did musical theater, and then in middle school I began writing my own original songs.

In 2017, at age 13, she wrote her first song for the documentary, alongside her mother and her vocal coach, former American Idol contestant and Merrick native Robbie Rosen. The ballad, called Brave the Storm, was written to show Notrica that she wasnt facing her illness alone, her daughter said.

Another one of her favorite songs from the documentary, Horowitz said, is called Carry On, which she wrote from her mothers perspective. This song is basically my mom saying that if it came down to it and she didnt make it, she wants my family to carry on without her, Samantha said, because shed always be a part of us and would always be watching over us.

Now, nearly three years after the transplant, and after facing a multitude of complications from it, Notrica is still under medical care at home.

The biggest thing, Horowitz said, is throughout this whole process of my mom being sick, whats always brought her a sense of comfort is music. Not just her favorite artists on the radio, but really the fact that I could sing to her and bring her joy and show her that there are things in life that are certainly worth fighting for not just her family, but also things like music.

Aside from her music, Horowitz has earned academic accolades throughout her high school career, and is a member of Calhouns national, math, science, English, social studies and world language honor societies. She is also a peer tutor for other students.

Rosen, who has gotten to know Horowitz well over the past four years, spoke about her dedication to the film and her ability to balance her various responsibilities despite the hardships shes faced. Shes been through so much since her childhood, Rosen said, so I think that her ability to keep it together, get the grades that she does, focus on music the way she does, and persevere through everything is a testament to who she is, her strength and her talent.

Calhoun Principal Nicole Hollings also noted Horowitzs many strengths, and the reasons that she is an ideal role model for others. Aside from being an outstanding student who has taken rigorous courses throughout high school, Hollings said, Samantha has been involved in many community service opportunities, and has always given her time and help to others who need it. She is truly a role model to others, showing how to be strong, caring, and how to live life in the moment, making every moment count, no matter how difficult it might be to do that.

Horowitz said that her mothers health journey has inspired her to major in biology when she starts college next year, and that she plans to go into the medical field. Im really interested in studying the correlation between music and someone healing, she said, Although this journey has caused me a lot of suffering, its made me extremely passionate about what I want to do with my future, and honestly, it has made me into who I am today.

Aside from sharing the familys ordeal, the documentary raises awareness of rare diseases, educates about bone marrow transplants, encourages people to become bone marrow donors and promotes State Senate Bill S1377, which would require school districts to establish medical hardship waiver policies.

But Horowitz said that her overall goal in creating the documentary is to help others who may be going through similar struggles. The main purpose isnt just to share my moms story or to get our music out there, she said, but really, its for people who are going through similar situations to see that they arent alone because its not easy for everyone to talk about their condition the way my mom does, and not everyone has a family member that can make songs about their journey to comfort them but I believe this film has the power to change peoples perspectives on life and to show them that music truly is a coping mechanism.

She added that she hoped the film would teach people not to take life for granted, and to make the best of every negative situation.

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Find out who can be a stem cell or bone marrow donor, and how to register.

A stem cell or bone marrow transplant is an important treatment for some people with types of blood cancer such as leukaemia, lymphoma and myeloma.

A transplant allows you to have high doses of chemotherapy and other treatments. The stem cellsare collected from the bloodstream or the bone marrow.Peoplehave a transplant either:

To be a donor you need to have stem cells that match the person you are donating to. To find this out, you have a blood test to look at HLA typing or tissue typing.

Staff in the laboratory look at the surface of your blood cells. They compare them to the surface of the blood cells of the person needing a transplant.

Everyone has their own set of proteins on the surface of their blood cells. The laboratory staff look for proteins called HLA markers and histocompatibility antigens. They check for 10 HLA markers. The result of this test shows how good the HLA match is between you and the person who needs the cells.

Abrother or sisteris most likely to be a match. There is a 1 in 4 chance of your cells matching.This is called a matched related donor (MRD) transplant.Anyone else in the family is unlikely to match. This can be very frustrating for relatives who are keen to help.

Sometimes if your cells are a half (50%) match, you might still be able to donate stem cells or bone marrow to a relative. This is called a haploidentical transplant.

You can't donate stem cells or bone marrow to your relative if you're not a match.

It's sometimes possible to get a match from someoneoutside of the family. This is calleda matched unrelated donor. To find a matched unrelated donor, it'susually necessary to search large numbers of people whose tissue type has been tested. So doctorssearch national and international registers to try to find a match for your relative.

Even if you can't donate to your relative, you might be ableto become a donor for someone else. You can do this by contacting one of the UK registers.

There are different donor registersin the UK.These work with each otherand with international registersto match donors with people who need stem cells. This helps doctors find donors for their patients as quickly as possiblefrom anywhere in the world.

Each registry has specific health criteriaand listmedical conditions that mightpreventyou from donating. Check their websitefor this information. Once registered, the organisation will contactyou if you are a match for someone who needs stem cells or bone marrow.

British Bone Marrow Registry (BBMR)

To register with the BBMR, you mustbe a blood donor. BBMR would like toregister those groups they are particularly short of ontheir register.This includes men between the ages of 17 and 40. And womenaged between 17 and 40 who are from Black, Asian, and minority ethnicities and mixed ethnicity backgrounds.

You have a blood test for tissue typing. Your details are kept on file until you are 60.

Anthony Nolan

You must be aged between 16 and 30 to register with Anthony Nolan. You have a cheek swab to test fortissue typing. Your details are kept on the register until you are 60.

Welsh Bone Marrow Donor Registry

You must be aged between 17 and 30 and your details are kept on the register until you are 60. You have a blood test for tissue typing.

DKMS

To register you must be aged between 17 and 55. You havea cheek swab for tissue typing. Your details stay on the register until your61st birthday.

This page is due for review. We will update this as soon as possible.

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Bone marrow is the spongy tissue inside some of the bones in the body, including the hip and thigh bones. Bone marrow contains immature cells called stem cells.

Many people with blood cancers, such as leukemia and lymphoma, sickle cell anemia, and other life threatening conditions rely on bone marrow or cord blood transplants to survive.

People need healthy bone marrow and blood cells to live. When a condition or disease affects bone marrow so that it can no longer function effectively, a marrow or cord blood transplant could be the best treatment option. For some people, it may be the only option.

This article looks at everything there is to know about bone marrow.

Bone marrow is soft, gelatinous tissue that fills the medullary cavities, or the centers of bones. The two types of bone marrow are red bone marrow, known as myeloid tissue, and yellow bone marrow, known as fatty tissue.

Both types of bone marrow are enriched with blood vessels and capillaries.

Bone marrow makes more than 220 billion new blood cells every day. Most blood cells in the body develop from cells in the bone marrow.

Bone marrow contains two types of stem cells: mesenchymal and hematopoietic.

Red bone marrow consists of a delicate, highly vascular fibrous tissue containing hematopoietic stem cells. These are blood-forming stem cells.

Yellow bone marrow contains mesenchymal stem cells, or marrow stromal cells. These produce fat, cartilage, and bone.

Stem cells are immature cells that can turn into a number of different types of cells.

Hematopoietic stem cells in the bone marrow give rise to two main types of cells: myeloid and lymphoid lineages. These include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, dendritic cells, and megakaryocytes, or platelets, as well as T cells, B cells, and natural killer (NK) cells.

The different types of hematopoietic stem cells vary in their regenerative capacity and potency. They can be multipotent, oligopotent, or unipotent, depending on how many types of cells they can create.

Pluripotent hematopoietic stem cells have renewal and differentiation properties. They can reproduce another cell identical to themselves, and they can generate one or more subsets of more mature cells.

The process of developing different blood cells from these pluripotent stem cells is known as hematopoiesis. It is these stem cells that are needed in bone marrow transplants.

Stem cells constantly divide and produce new cells. Some new cells remain as stem cells, while others go through a series of maturing stages, as precursor or blast cells, before becoming formed, or mature, blood cells. Stem cells rapidly multiply to make millions of blood cells each day.

Blood cells have a limited life span. This is around 120 days for red blood cells. The body is constantly replacing them. The production of healthy stem cells is vital.

The blood vessels act as a barrier to prevent immature blood cells from leaving bone marrow.

Only mature blood cells contain the membrane proteins required to attach to and pass through the blood vessel endothelium. Hematopoietic stem cells can cross the bone marrow barrier, however. Healthcare professionals may harvest these from peripheral, or circulating, blood.

The blood-forming stem cells in red bone marrow can multiply and mature into three significant types of blood cells, each with its own job:

Once mature, these blood cells move from bone marrow into the bloodstream, where they perform important functions that keep the body alive and healthy.

Mesenchymal stem cells are present in the bone marrow cavity. They can differentiate into a number of stromal lineages, such as:

Red bone marrow produces all red blood cells and platelets and around 6070% of lymphocytes in human adults. Other lymphocytes begin life in red bone marrow and become fully formed in the lymphatic tissues, including the thymus, spleen, and lymph nodes.

Together with the liver and spleen, red bone marrow also plays a role in getting rid of old red blood cells.

Yellow bone marrow mainly acts as a store for fats. It helps provide sustenance and maintain the correct environment for the bone to function. However, under particular conditions such as with severe blood loss or during a fever yellow bone marrow may revert to red bone marrow.

Yellow bone marrow tends to be located in the central cavities of long bones and is generally surrounded by a layer of red bone marrow with long trabeculae (beam-like structures) within a sponge-like reticular framework.

Before birth but toward the end of fetal development, bone marrow first develops in the clavicle. It becomes active about 3 weeks later. Bone marrow takes over from the liver as the major hematopoietic organ at 3236 weeks gestation.

Bone marrow remains red until around the age of 7 years, as the need for new continuous blood formation is high. As the body ages, it gradually replaces the red bone marrow with yellow fat tissue. Adults have an average of about 2.6 kilograms (kg) (5.7 pounds) of bone marrow, about half of which is red.

In adults, the highest concentration of red bone marrow is in the bones of the vertebrae, hips (ilium), breastbone (sternum), ribs, and skull, as well as at the metaphyseal and epiphyseal ends of the long bones of the arm (humerus) and leg (femur and tibia).

All other cancellous, or spongy, bones and central cavities of the long bones are filled with yellow bone marrow.

Most red blood cells, platelets, and most white blood cells form in the red bone marrow. Yellow bone marrow produces fat, cartilage, and bone.

White blood cells survive from a few hours to a few days, platelets for about 10 days, and red blood cells for about 120 days. Bone marrow needs to replace these cells constantly, as each blood cell has a set life expectancy.

Certain conditions may trigger additional production of blood cells. This may happen when the oxygen content of body tissues is low, if there is loss of blood or anemia, or if the number of red blood cells decreases. If these things happen, the kidneys produce and release erythropoietin, which is a hormone that stimulates bone marrow to produce more red blood cells.

Bone marrow also produces and releases more white blood cells in response to infections and more platelets in response to bleeding. If a person experiences serious blood loss, yellow bone marrow can activate and transform into red bone marrow.

Healthy bone marrow is important for a range of systems and activities.

The circulatory system touches every organ and system in the body. It involves a number of different cells with a variety of functions. Red blood cells transport oxygen to cells and tissues, platelets travel in the blood to help clotting after injury, and white blood cells travel to sites of infection or injury.

Hemoglobin is the protein in red blood cells that gives them their color. It collects oxygen in the lungs, transports it in the red blood cells, and releases oxygen to tissues such as the heart, muscles, and brain. Hemoglobin also removes carbon dioxide (CO2), which is a waste product of respiration, and sends it back to the lungs for exhalation.

Iron is an important nutrient for human physiology. It combines with protein to make the hemoglobin in red blood cells and is essential for producing red blood cells (erythropoiesis). The body stores iron in the liver, spleen, and bone marrow. Most of the iron a person needs each day for making hemoglobin comes from the recycling of old red blood cells.

The production of red blood cells is called erythropoiesis. It takes about 7 days for a committed stem cell to mature into a fully functional red blood cell. As red blood cells age, they become less active and more fragile.

White blood cells called macrophages remove aging red cells in a process known as phagocytosis. The contents of these cells are released into the blood. The iron released in this process travels either to bone marrow for the production of new red blood cells or to the liver or other tissues for storage.

Typically, the body replaces around 1% of its total red blood cell count every day. In a healthy person, this means that the body produces around 200 billion red blood cells each day.

Bone marrow produces many types of white blood cells. These are necessary for a healthy immune system. They prevent and fight infections.

The main types of white blood cells, or leukocytes, are as follows.

Lymphocytes are produced in bone marrow. They make natural antibodies to fight infection due to viruses that enter the body through the nose, mouth, or another mucous membrane or through cuts and grazes. Specific cells recognize the presence of invaders (antigens) that enter the body and send a signal to other cells to attack them.

The number of lymphocytes increases in response to these invasions. There are two major types of lymphocytes: B and T lymphocytes.

Monocytes are produced in bone marrow. Mature monocytes have a life expectancy in the blood of only 38 hours, but when they move into the tissues, they mature into larger cells called macrophages.

Macrophages can survive in the tissues for long periods of time, where they engulf and destroy bacteria, some fungi, dead cells, and other material that is foreign to the body.

Granulocytes is the collective name given to three types of white blood cells: neutrophils, eosinophils, and basophils. The development of a granulocyte may take 2 weeks, but this time reduces when there is an increased threat, such as a bacterial infection.

Bone marrow stores a large reserve of mature granulocytes. For every granulocyte circulating in the blood, there may be 50100 cells waiting in the bone marrow to be released into the bloodstream. As a result, half the granulocytes in the bloodstream can be available to actively fight an infection in the body within 7 hours of it detecting one.

Once a granulocyte has left the blood, it does not usually return. A granulocyte may survive in the tissues for up to 45 days, depending on the conditions, but it can only survive for a few hours in circulating blood.

Neutrophils are the most common type of granulocyte. They can attack and destroy bacteria and viruses.

Eosinophils are involved in the fight against many types of parasitic infections and against the larvae of parasitic worms and other organisms. They are also involved in some allergic reactions.

Basophils are the least common of the white blood cells. They respond to various allergens that cause the release of histamines, heparin, and other substances.

Heparin is an anticoagulant. It prevents blood from clotting. Histamines are vasodilators that cause irritation and inflammation. Releasing these substances makes a pathogen more permeable and allows for white blood cells and proteins to enter the tissues to engage the pathogen.

The irritation and inflammation in tissues that allergens affect are parts of the reaction associated with hay fever, some forms of asthma, hives, and, in its most serious form, anaphylactic shock.

Bone marrow produces platelets in a process known as thrombopoiesis. Platelets are necessary for blood to coagulate and for clots to form in order to stop bleeding.

Sudden blood loss triggers platelet activity at the site of an injury or wound. Here, the platelets clump together and combine with other substances to form fibrin. Fibrin has a thread-like structure and forms an external scab or clot.

Platelet deficiency causes the body to bruise and bleed more easily. Blood may not clot well at an open wound, and there may be a higher risk of internal bleeding if the platelet count is very low.

The lymphatic system consists of lymphatic organs such as bone marrow, the tonsils, the thymus, the spleen, and lymph nodes.

All lymphocytes develop in bone marrow from immature cells called stem cells. Lymphocytes that mature in the thymus gland (behind the breastbone) are called T cells. Those that mature in bone marrow or the lymphatic organs are called B cells.

The immune system protects the body from disease. It kills unwanted microorganisms such as bacteria and viruses that may invade the body.

Small glands called lymph nodes are located throughout the body. Once lymphocytes are made in bone marrow, they travel to the lymph nodes. The lymphocytes can then travel between each node through lymphatic channels that meet at large drainage ducts that empty into a blood vessel. Lymphocytes enter the blood through these ducts.

Three major types of lymphocytes play an important part in the immune system: B lymphocytes, T lymphocytes, and NK cells.

These cells originate from hematopoietic stem cells in bone marrow in mammals.

B cells express B cell receptors on their surface. These allow the cell to attach to an antigen on the surface of an invading microbe or another antigenic agent.

For this reason, B cells are known as antigen-presenting cells, as they alert other cells of the immune system to the presence of an invading microbe.

B cells also secrete antibodies that attach to the surface of infection-causing microbes. These antibodies are Y-shaped, and each one is akin to a specialized lock into which a matching antigen key fits. Because of this, each Y-shaped antibody reacts to a different microbe, triggering a larger immune system response to fight infection.

In some circumstances, B cells erroneously identify healthy cells as being antigens that require an immune system response. This is the mechanism behind the development of autoimmune conditions such as multiple sclerosis, scleroderma, and type 1 diabetes.

These cells are so-called because they mature in the thymus, which is a small organ in the upper chest, just behind the sternum. (Some T cells mature in the tonsils.)

There are many different types of T cells, and they perform a range of functions as part of adaptive cell-mediated immunity. T cells help B cells make antibodies against invading bacteria, viruses, or other microbes.

Unlike B cells, some T cells engulf and destroy pathogens directly after binding to the antigen on the surface of the microbe.

NK T cells, not to be confused with NK cells of the innate immune system, bridge the adaptive and innate immune systems. NK T cells recognize antigens presented in a different way from many other antigens, and they can perform the functions of T helper cells and cytotoxic T cells. They can also recognize and eliminate some tumor cells.

These are a type of lymphocyte that directly attack cells that a virus has infected.

A bone marrow transplant is useful for various reasons. For example:

Stem cells mainly occur in four places:

Stem cells for transplantation are obtainable from any of these except the fetus.

Hematopoietic stem cell transplantation (HSCT) involves the intravenous (IV) infusion of stem cells collected from bone marrow, peripheral blood, or umbilical cord blood.

This is useful for reestablishing hematopoietic function in people whose bone marrow or immune system is damaged or defective.

Worldwide, more than 50,000 first HSCT procedures, 28,000 autologous transplantation procedures, and 21,000 allogeneic transplantation procedures take place every year. This is according to a 2015 report by the Worldwide Network for Blood and Marrow Transplantation.

This number continues to increase by over 7% annually. Reductions in organ damage, infection, and severe, acute graft-versus-host disease (GVHD) seem to be contributing to improved outcomes.

In a study of 854 people who survived at least 2 years after autologous HSCT for hematologic malignancy, 68.8% were still alive 10 years after transplantation.

Bone marrow transplants are the leading treatment option for conditions that threaten bone marrows ability to function, such as leukemia.

A transplant can help rebuild the bodys capacity to produce blood cells and bring their numbers to acceptable levels. Conditions that may be treatable with a bone marrow transplant include both cancerous and noncancerous diseases.

Cancerous diseases may or may not specifically involve blood cells, but cancer treatment can destroy the bodys ability to manufacture new blood cells.

A person with cancer usually undergoes chemotherapy before transplantation. This eliminates the compromised marrow.

A healthcare professional then harvests the bone marrow of a matching donor which, in many cases, is a close family member and ready it for transplant.

Types of bone marrow transplant include:

A persons tissue type is defined as the type of HLA they have on the surface of most of the cells in their body. HLA is a protein, or marker, that the body uses to help it determine whether or not the cell belongs to the body.

To check if the tissue type is compatible, doctors assess how many proteins match on the surface of the donors and recipients blood cells. There are millions of different tissue types, but some are more common than others.

Tissue type is inherited, and types pass on from each parent. This means that a relative is more likely to have a matching tissue type.

However, if it is not possible to find a suitable bone marrow donor among family members, healthcare professionals try to find someone with a compatible tissue type on the bone marrow donor register.

Healthcare professionals perform several tests before a bone marrow transplant to identify any potential problems.

These tests include:

In addition, a person needs a complete dental exam before a bone marrow transplant to reduce the risk of infection. Other precautions to lower the risk of infection are also necessary before the transplant.

Bone marrow is obtainable for examination by bone marrow biopsy and bone marrow aspiration.

Bone marrow harvesting has become a relatively routine procedure. Healthcare professionals generally aspirate it from the posterior iliac crests while the donor is under either regional or general anesthesia.

Healthcare professionals can also take it from the sternum or from the upper tibia in children, as it still contains a substantial amount of red bone marrow.

To do so, they insert a needle into the bone, usually in the hip, and withdraw some bone marrow. They then freeze and store this bone marrow.

National Marrow Donor Program (NMDP) guidelines limit the volume of removable bone marrow to 20 milliliters (ml) per kg of donor weight. A dose of 1 x 103 and 2 x 108 marrow mononuclear cells per kg is necessary to establish engraftment in autologous and allogeneic marrow transplants, respectively.

Complications related to bone marrow harvesting are rare. When they do occur, they typically involve problems related to anesthetics, infection, and bleeding.

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Bone marrow: Function, diseases, transplants, and donation

Bone Marrow Stem Cells Comments Off on Bone marrow: Function, diseases, transplants, and donation | December 23rd, 2021

MELVILLE, N.Y., Dec. 20, 2021 (GLOBE NEWSWIRE) -- BioRestorative Therapies, Inc. (the Company" or BioRestorative) (NASDAQ:BRTX), a life sciences company focused on adult stem cell-based therapies, today released the following year-end message.

As we reach the end of 2021, we are inspired by the many healthcare workers and biopharmaceutical companies that have worked to combat the COVID-19 pandemic. This year has been environmentally difficult, but we have seen incredible advancements in our sector which have reinforced the importance of our mission to become a clinical stage company. Since our emergence from Chapter 11 in 2020, we have sought to take positive steps at BioRestorative Therapies with the goal of making it a preeminent cell therapy company. During 2021, we achieved important transformational milestones, which created meaningful intrinsic value and advanced us toward our stated strategic goals.

In November of this year, we closed on a $23 million capital raise and concurrently listed our securities on the Nasdaq Capital Market. This is a very significant development as we are now fully funded to complete our Phase 2 trial for our lead clinical candidate, BRTX-100, for the treatment of chronic lumbar disc disease (CLDD.) During this process, we have attracted many new institutional fundamental investors as well as some retail investors. With that accomplished, I would like to briefly discuss the status of our programs and the opportunities that lie ahead of us.

BRTX-100 is our lead program for the treatment of CLDD, one of the leading causes of lower back pain. Our solution is a one-time injection of 40 million mesenchymal stem cells derived from a patients own bone marrow and expanded ex vivo before re-injection. Two things make us optimistic about this program. First, in connection with our IND filing, we referred the FDA to prior human clinical studies from different institutions that demonstrated the safety/feasibility of using mesenchymal stem cells to treat disc orders. This data not only enabled us to accelerate our clinical program and initiate a Phase 2 trial, but we believe it substantially reduces risk in offering compelling guidance on the use of cell-based interventions to treat lower back pain. Second, our manufacturing of BRTX-100 involves the use of low oxygen conditions, which ensures that the cells have enhanced survivability after introduction into the harsh avascular environment of the injured disc which has little or no blood flow. The benefits of this process are significant and are illustrated well in our recent Journal of Translational Medicine publication. Our approach is akin to transplant medicine in which specific cell types are used to replace the ones which have been lost to disease. We believe that transplanting targeted cells can offer a more attractive safety profile and potentially an improved clinical outcome. We remain optimistic that we will see significant positive clinical outcomes as we proceed with our clinical trial.

The most significant milestones we achieved in 2021 include:

Our 2022 objectives include the initiation of enrollment for our BRTX-100 clinical trial, the development of our overall product profiles via manufacturing and delivery system improvements, and the entering into of technology validation and enabling partnerships to accelerate our clinical timelines.

Some of the events and milestones that we hope to accomplish in 2022 include:

This is an exciting time to be part of the BioRestorative family. As we enter 2022 with a well-capitalized balance sheet to fully fund our Phase 2 trial, we look to accelerate our research and development pipeline. We do not take for granted that our technologies give us an opportunity to make a profound impact on the everyday lives of many people. We are grateful for the opportunity to validate such technologies; it is what we do and what we believe is the center of our core competencies.

Visit our website at http://www.biorestorative.com for more information about BioRestorative.

Thank you to the BioRestorative family for your loyalty and ongoing support.

I wish you and all those near and dear to you a wonderful Holiday Season and the very best for 2022 and beyond.

Very truly yours,

Lance AlstodtPresident, CEO and Chairman of the Board

About BioRestorative Therapies, Inc.

BioRestorative Therapies, Inc. (www.biorestorative.com) develops therapeutic products using cell and tissue protocols, primarily involving adult stem cells. Our two core programs, as described below, relate to the treatment of disc/spine disease and metabolic disorders:

Disc/Spine Program (brtxDISC): Our lead cell therapy candidate, BRTX-100, is a product formulated from autologous (or a persons own) cultured mesenchymal stem cells collected from the patients bone marrow. We intend that the product will be used for the non-surgical treatment of painful lumbosacral disc disorders or as a complementary therapeutic to a surgical procedure. The BRTX-100 production process utilizes proprietary technology and involves collecting a patients bone marrow, isolating and culturing stem cells from the bone marrow and cryopreserving the cells. In an outpatient procedure, BRTX-100 is to be injected by a physician into the patients damaged disc. The treatment is intended for patients whose pain has not been alleviated by non-invasive procedures and who potentially face the prospect of surgery. We have received authorization from the Food and Drug Administration to commence a Phase 2 clinical trial using BRTX-100 to treat chronic lower back pain arising from degenerative disc disease.

Metabolic Program (ThermoStem): We are developing a cell-based therapy candidate to target obesity and metabolic disorders using brown adipose (fat) derived stem cells to generate brown adipose tissue (BAT). BAT is intended to mimic naturally occurring brown adipose depots that regulate metabolic homeostasis in humans. Initial preclinical research indicates that increased amounts of brown fat in animals may be responsible for additional caloric burning as well as reduced glucose and lipid levels. Researchers have found that people with higher levels of brown fat may have a reduced risk for obesity and diabetes.

FORWARD-LOOKING STATEMENTS

This letter contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events or results to differ materially from those projected in the forward-looking statements as a result of various factors and other risks, including, without limitation, those set forth in the Company's latest Form 10-K filed with the Securities and Exchange Commission (SEC) and other filings made with the SEC. You should consider these factors in evaluating the forward-looking statements included herein, and not place undue reliance on such statements. The forward-looking statements in this letter are made as of the date hereof and the Company undertakes no obligation to update such statements.

CONTACT:

Email: ir@biorestorative.com

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BioRestorative Therapies, Inc. Releases Year-End Message - BioSpace

Bone Marrow Stem Cells Comments Off on BioRestorative Therapies, Inc. Releases Year-End Message – BioSpace | December 23rd, 2021