MELBOURNE, Australia and BAAR, Switzerland, Nov. 29, 2020 (GLOBE NEWSWIRE) -- Telix Pharmaceuticals Limited (ASX: TLX, Telix, the Company) announces it has entered into an agreement with Scintec Diagnostics GmbH (Scintec) to acquire TheraPharm GmbH (TheraPharm), a Swiss-German biotechnology company developing innovative diagnostic and therapeutic solutions in the field of hematology.

The acquisition of TheraPharm provides Telix with access to a portfolio of patents, technologies, production systems, clinical data and know-how in relation to the use of Molecularly Targeted Radiation (MTR) in hematology and immunology. TheraPharm is developing antibody MTR technology against CD66, a cell surface target highly expressed by neutrophils (a type of white blood cell) and tumor-infiltrating lymphocytes. As such, the technology has potentially very broad applications in the diagnosis and treatment of hematologic diseases (e.g. blood cancers), lymphoproliferative disorders and immune-mediated diseases (e.g. lupus, and multiple sclerosis). Of particular interest is the demonstrated use of the technology to safely and effectively perform bone marrow conditioning (BMC) prior to bone marrow stem cell transplant.

Telix CEO, Dr. Christian Behrenbruch stated, Telix is committed to extending and improving the lives of patients with serious diseases. As such, the acquisition of TheraPharm and its MTR assets are uniquely aligned to Telixs mission and technical strengths in antibody engineering and radiochemistry. TheraPharms technology has a significant role to play in BMC and stem cell transplantation across a broad range of blood cancers and rare diseases. The current approach to BMC employs highly toxic drugs that have a poor morbidity and mortality profile, and for which many patients are ineligible. MTR offers an excellent safety profile that may greatly expand the number of patients able to undergo life prolonging stem cell transplantation while greatly reducing the hospitalisation burden and cost associated with such procedures.

TheraPharm co-founder and Managing Director, Dr. Klaus Bosslet added, Over the past 5 years, TheraPharm, in collaboration with Dr. Kim Orchard from the University of Southampton (UK), has made excellent progress developing 90Y-besilesomab for the treatment of hematologic cancers and several related conditions including multiple myeloma, leukemia and amyloidosis. This unique asset is a logical addition to Telixs portfolio, offering a potentially rapid development path to a first commercial indication for the treatment of patients with SALA, while at the same time having potentially broad applications for stem cell transplantation in patients with more common cancers of the blood, including multiple myeloma and leukemia. We look forward to joining the Telix team in order to expedite the development of products for this under-served field.

Full transaction details, including financial terms, can be found via the Telix website and ASX portal here.

About Hematopoietic Stem Cell Transplant (HSCT)

Bone marrow conditioning (BMC) followed by hematopoietic stem cell transplantation (HSCT) is presently performed to treat patients with hematologic malignancies (blood cancers), with the objective of extending patient survival or achieving cure. HSCT is also performed for a broad range of non-cancer conditions. HSCT is preferentially performed in countries of high income (Europe >30,000, Americas >20,000, worldwide >65,000 p.a., respectively) and is growing at around 5% annually.

About Systemic Amyloid Light-Chain Amyloidosis (SALA)

SALA is a rare, but serious protein deposition disease, caused by a protein known as amyloid that is produced by abnormal plasma cells residing in the bone marrow. As amyloid accumulates in the organs of the body, organ function will eventually deteriorate, ultimately causing organ failure. SALA has an estimated prevalence of 30,000 and 45,000 in United States and Europe, respectively and while a rare disease, SALA portends a very poor prognosis, with a median survival from diagnosis of ~11 months if untreated.

The current standard of care comprises of induction therapy (typically cyclophosphamide, bortezomib, dexamethasone) plus high dose melphalan BMC, followed by HSCT. This approach is typically only accessible to a small proportion of patients (<20%) who are able to tolerate induction therapy and melphalan BMC.

About Telix Pharmaceuticals Limited

Telix is a clinical-stage biopharmaceutical company focused on the development of diagnostic and therapeutic products using Molecularly Targeted Radiation (MTR). Telix is headquartered in Melbourne, Australia with international operations in Belgium, Japan and the United States. Telix is developing a portfolio of clinical-stage oncology products that address significant unmet medical needs in prostate, kidney and brain cancer. Telix is listed on the Australian Securities Exchange (ASX: TLX). For more information visit http://www.telixpharma.com.

AboutTheraPharm GmbH

TheraPharm is a biotechnology company specialised in the research, development and manufacturing of monoclonal antibodies for targeted radiation of hematopoietic malignant and non-malignant diseases, lymphoproliferative diseases, conditioning for allogeneic stem cells as well as in diagnostics of inflammatory diseases and bone marrow metastases.

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Telix Pharmaceuticals Limited Acquires TheraPharm GmbH, Broadening Reach to Hematologic Cancers and Transplant Medicine - BioSpace

Bone Marrow Stem Cells Comments Off on Telix Pharmaceuticals Limited Acquires TheraPharm GmbH, Broadening Reach to Hematologic Cancers and Transplant Medicine – BioSpace | November 30th, 2020

Scientists at Bay Area universities, laboratories, biotechnology companies and drug manufacturers are fashioning drug concoctions out of blood plasma, chimpanzee viruses and cells taken from bone marrow in the race to rid the world of COVID-19.

The microbial treasure hunt is not just to find a cure which may not be possible but to control the debilitating health problems caused by the coronavirus.

Major progress has been made this year. The antiviral drug remdesivir, produced in Foster City, has improved recovery times, and the steroid dexamethasone has cut the number of deaths in severely ill patients.

What follows is a list of some of the most promising medications and vaccines with ties to the Bay Area:

Antibodies

and Immunity

Mesenchymal stem cells / UCSF and UC Davis Medical Center:

UCSF Dr. Michael Matthay is leading a study of whether a kind of stem cell found in bone marrow can help critically ill patients with severe respiratory failure, known as ARDS. Matthay hopes the stem cells can help reduce the inflammation associated with some of ARDS most dire respiratory symptoms, and help patients lungs recover.

In all, 120 patients are being enrolled at UCSF Medical Center, Zuckerberg San Francisco General Hospital, the UC Davis Medical Center in Sacramento and hospitals in Oregon and Texas. He said the trial, which includes a small number of ARDS patients who dont have COVID-19, should have results by summer or fall 2021. So far, 28 patients are enrolled in San Francisco.

Lambda-interferon / Stanford University:

Lambda-interferon is a manufactured version of a naturally occurring protein that had been used to treat hepatitis, and researchers hoped it would help patients in the early stages of COVID-19.

Stanford researchers completed their trial of lambda-interferon and found that it did not boost the immune system response to coronavirus infections.

That trial did not find any difference in outcomes between the treatment and placebo, said Yvonne Maldonado, chief of pediatric infectious diseases at Lucile Packard Childrens Hospital at Stanford, where 120 patients were enrolled in the trial. It didnt work.

Antiviral drugs

Remdesivir / Gilead Sciences (Foster City):

Remdesivir, once conceived as a potential treatment for Ebola, was approved by the Food and Drug Administration in October for use on hospitalized COVID-19 patients.

Trademarked under the name Veklury, the drug interferes with the process through which the virus replicates itself. It was one of the drugs given to President Trump and has been used regularly in hospitals under what is known as an emergency use authorization.

It was approved after three clinical trials showed hospitalized coronavirus patients who received remdesivir recovered five days faster on average than those who received a placebo. Patients who required oxygen recovered seven days faster, according to the studies.

Gilead now plans to conduct clinical trials to see how remdesivir works on pediatric patients, from newborns to teenagers, with moderate to severe COVID-19 symptoms. Remdesivir is also being studied with steroids and other drugs to see if it works better as part of a medicinal cocktail. An inhalable form of the drug is also being developed.

Favipiravir / Fujifilm Toyama Chemical (Stanford University):

This antiviral drug, developed in 2014 by a subsidiary of the Japanese film company to treat influenza, is undergoing numerous clinical studies worldwide, including a trial involving 180 patients at Stanford University.

Stanford epidemiologists are testing favipiravir to see if it prevents the coronavirus from replicating in human cells, halts the shedding of the virus and reduces the severity of infection. Unlike remdesivir, it can be administered orally, so it can be used to treat patients early in the disease, before hospitalization is necessary.

The Stanford study has so far enrolled about 90 patients, who are given the drug within 72 hours of when they were first diagnosed with COVID-19. Half of them get a placebo. People can enroll by emailing treatcovid@stanford.edu.

Monoclonal antibodies

REGN-COV2 / Regeneron Pharmaceuticals / Stanford School of Medicine:

The REGN-COV2 cocktail is the same one Trump received, and Stanford is one of dozens of locations nationwide where clinical trials are being held. Two separate trials are under way at Stanford one for hospitalized patients, the other for outpatients. A third trial is about to begin for people who arent sick but are in contact with carriers of the virus.

Regeneron halted testing on severely ill patients requiring high-flow oxygen or mechanical ventilation after the independent Data and Safety Monitoring Board determined that the drug was unlikely to help them.

The drug is a combination of two monoclonal antibodies lab-made clones of the antibodies produced naturally in people who have recovered from COVID-19. The antibodies bind to the virus spike protein and block the virus ability to enter cells.

Dr. Aruna Subramanian, professor of infectious diseases at Stanford and lead investigator for the inpatient trial, said the 21 hospitalized patients in the study receive a high dose like Trump, a lower dose or a placebo. Subramanian plans to expand the inpatient trial to 45 patients. The outpatient study has enrolled a little more than 40 of the 60 patients researchers intend to sign up.

Theres enough promising evidence that it helps people early in the infection, Subramanian said. What we dont know is whether it helps people who are pretty sick but not critically ill.

Bamlanivimab / Eli Lilly / Stanford and UCSF:

Stanford and UCSF are testing the Eli Lilly monoclonal antibodies on outpatients after the pharmaceutical company halted trials on hospitalized COVID-19 patients because of adverse results.

Dr. Andra Blomkalns, chair of emergency medicine at Stanford and the lead in the Eli Lilly outpatient trial, said she is now enrolling older people with comorbidities like heart disease, chronic lung disease, a history of strokes and severe obesity shortly after they test positive.

The hypothesis is that the bamlanivimab monotherapy, which is very similar to the Regeneron monoclonals, might work best early in the infection. Although about 400 patients have been enrolled in the Lilly phase 3 trials nationwide, to date fewer than 10 have been enrolled at Stanford and UCSF.

Matthay, who headed up the Lilly monoclonal study with LY-CoV555 at UCSF, said the cancellation of this inpatient trial was disappointing, but just because this one did not work, doesnt mean another one wont work for hospitalized patients.

Blomkalns said the testing criteria has been changing. She expects the outpatient trial to open soon to adolescents ages 12 and up to determine whether the drug can be used as a preventive.

Designer monoclonal antibodies / Vir Biotechnology, San Francisco:

Scientists at Vir are studying several types of monoclonal antibodies, including a type engineered to activate T cells, which can search out and destroy cells infected with the coronavirus. A study published in the journal Nature in October found that monoclonals, modified to bind with certain receptors, stimulated T cells and improved the human immune response.

By observing and learning from our bodys powerful natural defenses, we have discovered how to maximize the capacity of antibodies through the amplification of key characteristics that may enable more effective treatments for viral diseases, said Herbert Virgin, the chief scientific officer at Vir and co-author of the study.

A similarly modified monoclonal antibody, leronlimab, is being studied in coronavirus clinical trials by its Washington state drugmaker, CytoDyn, which has developed drugs to treat HIV. The companys chief medical officer is in San Francisco, and the company that does laboratory tests of leronlimab is in San Carlos.

Anti-inflammatory drugs

Colchicine / UCSF (San Francisco and New York):

The anti-inflammatory drug commonly used to treat gout flare-ups is being studied by scientists at UCSF and New York University. The drug short-circuits inflammation by decreasing the bodys production of certain proteins, and researchers hope that it will reduce lung complications and prevent deaths from COVID-19.

Preliminary results from a clinical trial found that Colchicine can be effective in reducing systemic symptoms of COVID-19 by inhibiting inflammatory biomarkers.

Selinexor / Kaiser Permanente:

Kaiser hospitals in San Francisco, Oakland and Sacramento are studying selinexor, an anticancer drug that blocks a key protein in the cellular machinery for DNA processing. Preliminary findings during the trials indicated that low doses of selinexor helped hospitalized patients with severe COVID-19. The drug has both antiviral and anti-inflammatory properties, and its administered orally, according to Kaisers Dr. Jacek Skarbinski.

Vaccines

VXA-COV2-1 / Vaxart, South San Francisco:

The biotechnology company Vaxart is testing VXA-COV2-1, the only potential vaccine in pill form. It uses the genetic code of the coronavirus to trigger a defensive response in mucous membranes. The hope is that the newly fortified membranes will prevent the virus from entering the body.

Its the only vaccine (candidate) that activates the first line of defense, which is the mucosa, said Andrei Floroiu, Vaxarts chief executive. He said intravenous vaccines kill the virus after it is inside the body, but this one stops it beforehand.

The drug, which is effective against influenza and norovirus, induced both neutralizing antibodies and T cells during coronavirus drug trials, according to preliminary trial results published in September.

VaxiPatch / Verndari (Napa and UC Davis Medical Center):

A Napa company, Verndari, is studying vaccines for COVID-19 that can be delivered using an adhesive patch. Researchers at UC Davis Medical Center in Sacramento said the patch caused an immune response in preclinical tests.

An October report in the online journal ScienceDirect touted the system, saying it could serve as a shelter in place vaccination strategy, in which vulnerable populations receive delivery at home without needing to engage an already-overtaxed health care infrastructure.

If the vaccine is proven effective and safe, patients could receive it through the mail, according to Dr. Daniel Henderson, Verndaris chief executive officer.

ChAdOx1 / AstraZeneca (UCSF, San Francisco General Hospital, Bridge HIV):

Enrollment is under way at 80 sites in the United States, including three in the Bay Area, for the phase 3 trial of AstraZenecas vaccine, developed by Oxford University from an adenovirus, which typically causes colds in chimpanzees.

At least 1,000 of the 40,000 participants in the phase 3 AstraZeneca trial will be from the Bay Area, including 500 at Sutter Healths East Bay AIDS Center in Oakland, 250 at Zuckerberg San Francisco General Hospital and another 250 at Bridge HIV San Francisco.

An interim analysis of trials in Britain and Brazil showed the vaccine was 90% effective in preventing COVID-19 in 131 patients who got a half-dose of the vaccine by mistake. The vaccine was only 62% effective in people who got a full dose, leading to major questions about the results and how the trial was conducted.

Bay Area trial leaders Dr. Annie Luetkemeyer of UCSF and Dr. Susan Buchbinder, director of Bridge HIV and a UCSF professor of medicine and epidemiology, are hoping future trial results are more clear. Thats because AstraZenecas vaccine is cheaper than those made by its rivals Pfizer and Moderna, whose vaccines were 95% and 94.5% effective in preliminary tests.

The AstraZeneca candidate can also be stored at temperatures between 36 and 46 degrees Fahrenheit, which is orders of magnitude higher than the Pfizer and Moderna vaccines. The Pfizer and Moderna vaccines must be kept at 94 degrees below zero Fahrenheit, colder than many storage facilities can manage.

Johnson & Johnson (Stanford University)

The Johnson & Johnson clinical trials have enrolled 20,000 of the 60,000 volunteers worldwide that officials expect to have signed up by Christmas. That includes 70 people at Stanford.

The vaccine is, like the AstraZeneca version, a chimpanzee adenovirus that was genetically altered so that it carries the RNA of the coronavirus spike protein. The technique inspires the body to produce antibodies that block the protein without causing people to get sick.

Phase 2 studies show that it produces a good immune response and the early results of phase 3 show that its safe, said Dr. Philip Grant, assistant professor of infectious disease at Stanford and leader of the trial.

Grant, who is enrolling about 15 people a day for the trial, said he doesnt expect results on the vaccines effectiveness until sometime in March.

Peter Fimrite is a San Francisco Chronicle staff writer. Email: pfimrite@sfchronicle.com Twitter: @pfimrite

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Coronavirus treatments and vaccines. Here are the latest developments - San Francisco Chronicle

Bone Marrow Stem Cells Comments Off on Coronavirus treatments and vaccines. Here are the latest developments – San Francisco Chronicle | November 30th, 2020

A one-year-old boy has been diagnosed with a condition so rare only one in a million people suffer from it.

Max Gardner was diagnosed with aplastic anaemia - a condition that means the bone marrow and stem cells do not produce enough blood cells and is fatal if untreated.

He was diagnosed after his parents, Connor Gardner and Rachel Nicholson, who live in Hebburn, became alarmed by significant bruising and rashes all over his body.

The couple took him to South Tyneside District Hospital, where he was incorrectly diagnosed with immune thrombocytopenic purpura, a condition which a child will grow out of.

However, as Maxs condition worsened, he ended up at the Royal Victoria Infirmary in Newcastle, where doctors conducted tests which showed he had the much rarer aplastic anaemia.

Connor said: He looked like he was a child abuse victim; we were really worried about what people would think, as he was covered in bruises.

We took him to the RVI for further tests, and they realised that maybe the condition was worse. Initially, we thought he would be diagnosed with leukaemia, but the consultant told us that it was aplastic anaemia after a bone marrow biopsy, which was administered under anaesthetic.

They told us about the condition, and that the outcome could lead to death if Max was to catch any type of sickness bug, as his immune system was non-existent.

We got our emotions out after we got the diagnosis we had a cry but we knew that we needed to be there for Max and help him get better.

The only way to cure aplastic anaemia fully is with a bone marrow transplant, and both Connor, 29, and Rachel, 27, were tested to see if they were matches.

Fortunately, Rachel was a near-perfect match, a very rare scenario.

Connor said: Usually they would use siblings for the transplant but Max does not have any. There is about a 25% chance that me or Rachel would be a match, and then there is about a 1% chance that it would be a 9/10 match.

The condition that Max has affects one in a million people, so it is very unfortunate for Max to have had this condition, but it is lucky that his mother has been a near-perfect match.

Chemotherapy is the next stage before you have the transplant, but that can lead to wiping out fertility, so we agreed to a new trial that would give Max the best chance of being able to have children of his own when he grows up.

They take a biopsy of one of his testicles and they store it for future; it is the best chance he has of having a child when he is older if he is infertile.

The family now have to shield for two weeks, before Max and his mother head back to hospital and onto the transplant ward, where he will spend the next two months.

Fortunately, Rachel can stay with Max during this time, but Connor can only see his son at specific visiting hours and has to isolate, so that the risk of spreading any illness is at a minimum.

He said: Max starts his chemotherapy on December 10, which takes place over five days, and during that time Rachel will be getting treatment so that the hospital can help harvest her bone marrow.

Then, when she goes to give the transplant, she will be there for four hours while the machine separates the bone marrow before it is given to Max.

Then he gets a bone marrow transplant, which is very similar to a normal blood transfusion."

Connor and Rachel have set up a fundraising page to help pay for the added costs of not working and to help them support them through this tough time.

He said: We have been overwhelmed with the support that people have given us and the GoFundMe page has been a great way for people to give us time.

I have been taken back by the generosity of total strangers.

Connor stressed the importance of raising awareness for bone marrow transplants, and had his fiance not been a very rare match, they would likely have had to wait for a match on the donor register.

I think it is important to raise awareness of the Anthony Nolan page. We have been lucky enough to get a donor for Max through his mam, but there are lots of people out there who have not been so lucky and are waiting for a donor.

We have met a little girl who is eight years old and she hasnt got a match yet, so we are just hoping that people will join the donor list as it may save someones life.

You can donate to the fundraising campaign by visiting here.

Continued here:
Family's heartache after Hebburn boy diagnosed with one in a million condition - Chronicle Live

Bone Marrow Stem Cells Comments Off on Family’s heartache after Hebburn boy diagnosed with one in a million condition – Chronicle Live | November 30th, 2020

Global Research Antibodies Market: Overview

The global research antibodies market is anticipated to rise at a notable pace over the forecast period. Antibodies display exceptional physiological properties that make them sought-after for cell research.

Antibodies display other properties too. As they have the ability to attach to specific molecules, this enables specific molecules to be isolated for research. Hence, this makes for a key factor for continual research to examine the physiology and anatomy of antibodies.

The report serves to identify prevailing growth trends based on which projections made. The report constitutes most relevant data pertaining to comprehend the growth dynamics of research antibodies market. Geographical distribution of the research antibodies market and an analysis of the competitive structure are highlights of the report.

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Global Research Antibodies Market: Key Trends

Currently, pharmaceutical and biopharmaceutical companies are undertaking extensive R&D activities to introduce novel products. These pursuits involve widespread use of antibodies because of their exceptional physiological properties. Therefore, research on antibodies receives a boost for their use in secondary cell research.

Pharmaceutical giants are also making hefty investments for advancement of antibodies research.

Increasing incidence of chronic diseases and life-threatening diseases such as cancer has led to extensive initiatives for advanced therapeutics. Pharmaceutical and biotechnology companies are making efforts in terms of upgrading their R&D capability and pumping money. These efforts are aimed to develop advanced therapeutics as well as personalized medicine for a gamut of chronic and fatal diseases. These factors collectively bode well for research antibodies market.

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At present, stem cell research is finding keen interest of researchers and geneticists. Several studies support the efficacy of stem cell for blood cancers, blood and bone marrow diseases, immune disorders. Lately, stem cells from the umbilical cord and stem cells from the blood stream have been used to treat rare blood related diseases. Due to the dependency an antibodies for stem cell research, researchers are involved to isolate different antibodies molecules. This is aiding growth of research antibodies market.

Lastly, novel use of antibodies that are receiving acceptance of accredited bodies is serving to boost the research antibodies market. For example, in a new development, FDA approved the clinical application of DNA-encoded monoclonal antibody therapy as a prevention against Zika virus.

Global Research Antibodies Market: Regional Analysis

The global research antibodies market is spread across North America, Asia Pacific, Europe, Latin America, and the Middle East & Africa. Among them, North America holds supremacy in the overall market. The region being home to large biotechnology and biopharmaceutical companies, along with immense government aid for research are key factors behind exceptional growth of North America antibodies market.

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Stringent regulations in place for manufacturers of antibodies and due adherence to these regulations accounts for high quality products from the region. This further pushes the North America research antibodies market.

On the other hand, Asia Pacific is emerging as a key region for research antibodies. Increasing R&D for antibodies and adoption of novel techniques for the production of antibodies is serving to fuel the region.

Global Research Antibodies Market: Competitive Outlook

Prominent players in the global research antibodies market include Abcam plc, Agilent Technologies, and Thermo Fisher Scientific Inc.

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Research Antibodies Market is Driven by Increasing Incidence of Chronic Diseases and Life-threatening Diseases - Cheshire Media

Bone Marrow Stem Cells Comments Off on Research Antibodies Market is Driven by Increasing Incidence of Chronic Diseases and Life-threatening Diseases – Cheshire Media | November 30th, 2020

Medical skin care products are used for beautifying or to address some other skin care problems. The cosmetic industry is booming and skin care forms a very huge part of this industry. The aesthetic appearance is so important that people spend a lot on skin care products and treatment. People being more technologically aware of the various new skin care products trending in the market. In addition to the aesthetic application, the medical skin care products are also used to address issues such as acne, pimples or scars.

Medical Skin Care Products Market: Drivers and Restraints

The medical skin care products is primarily driven by the need of natural based active ingredients products which are now trending in the market. Consumers demand medical skin care products which favor health and environment. Moreover, the consumers are updated with the trends so that various companies end up providing such products to satisfy the customers. For instance, a single product face mask has thousands of different variants. This offers consumers different options to select the product depending on the skin type. Moreover, the market players catering to the medical skin care products are offering products with advanced technologies. For instance, Santinov launched the CICABEL mask using stem cell material based on advanced technologies. The stem cells used in the skin care product helps to to protect and activate the cells and promote the proliferation of skin epidermal cells and the anagenesis of skin fibrosis.

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Medical Skin Care Products Market: Segmentation

On the basis of product type the medical skin care products market can be segmented as:

On the basis of application, the medical skin care products market can be segment as:

On the basis of distribution channel, the medical skin care products market can be segment as:

Medical Skin Care Products Market: Overview

Medical skin care products are used to address basic skin problems ranging from acne to scars. There are various advancements in the ingredients used to offer skin care products to the consumers. For instance, the use of hyaluronic acid and retinoids is the latest development in the industry. The anti-aging creams are at the forefront as the help treating issues such as wrinkles, scars, acne, and sun damage. Another, product in demand is the probiotic skincare which include lactobacillus and bifidobacterium.

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Medical Skin Care Products Market: Region-wise Outlook

In terms of geography, medical skin care products market has been divided into five regions including North- America, Asia- Pacific, Middle-East & Africa, Latin America and Europe. North America dominated the global medical skin care products market as international players are acquiring domestic companies to make their hold strong in the U.S. LOral is accelerating its U.S. market by signing a definitive agreement with Valeant Pharmaceuticals International Inc. to acquire CeraVe, AcneFree and Ambi skin-care brands for US$ 1.3 billion. The acquisition is expected LOreal to get hold of the brands in the price-accessible segment. Asia Pacific is expected to be the fastest growing region owing to the increasing disposable income and rising awareness towards the skin care products.

Medical Skin Care Products Market: Key Market Participants

Some of the medical skin care products market participants are Avon Products Inc., Beiersdorf AG, Colgate-Palmolive Company, Kao Corporation, LOral S.A., Procter & Gamble, Shiseido Company, The Estee Lauder Companies Inc., Unilever PLC, Revlon, Clinique Laboratories, llc., Murad, LLC., SkinCeuticals, RMS Beauty, J.R. Watkins and 100% PURE.

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The end-use Industries to Help the Medical Skin Care Products Market stand in a good stead between 2017 and 2025 - Cheshire Media

Skin Stem Cells Comments Off on The end-use Industries to Help the Medical Skin Care Products Market stand in a good stead between 2017 and 2025 – Cheshire Media | November 30th, 2020

By Mark Philips.

New York - November 30th, 2020 - To put it simply, it concerns nanotechnological research, its adaptation and then application in cosmetology. Nanoasia, under the management of Kira Sorokina, was one of the first international companies to work in this field when it started more than five years ago. Nanoasia is a brand of exclusive cosmetics for use in salons and at home, which was the first to test and bring airbrush non-injection anti-ageing products to the market.

The secret lies in tiny nano particles, each around 4 nanometers in length (and so therefore smaller than the diameter of even the driest skin pores). This means that the active components can penetrate deeper into the skin without needing to use an injection, mentioned Kira Sorokina. The product contains peptides, biosynthesized from plants, amino acids (proteins) and plant extracts of the highest quality. It is important to note that Nanoasias ingredients are all able to serve their complex individual function due to the balanced recipe, which ensures that every ingredient compliments and enhances the others. This is why just a handful of components can come together to provide an integrated product that solves all of the most common issues, she added. Despite Nanoasia being produced in South Korea, using their technologies, all of the formulas are adapted to the needs of European skin types. The device and cosmetic products, developed and produced by Nanoasia, are designed to work with the skin, skin cells and facial muscles.

Now lets take a closer look at Nanoasias innovative components and how they work!

Nanoasias serums (which are currently produced in three distinct varieties) represent the new generation of non-injection bio-revitalizers. These unique plant-based nanocomplexes contain a high concentration of nano-peptides, amino acids and plant extracts. They target all of a skins age-related changes, penetrating directly into the dermis and working instantly from the first application! They can correct the faces oval shape, tightening the cheeks and restoring their elasticity. They iron out any smile lines and baggy skin under the eyes, whilst also helping lose any facial fat (by improving blood circulation and lymphatic drainage). They nourish and rejuvenate the skin at a cellular level. They help to lighten up any pigment stains and bleaching. They help to prevent muscular spasms, preserving your natural facial expressions, reducing puffiness and dark circles under the eyes. They restore the cellular structure of collagen fibers, preventing the sebaceous glands from becoming overactive. They enhance cell regeneration, removing any pigment stains and rebuilding the structure of the dermis.

Nanoasia has developed a unique device to allow these special serums to penetrate deep into the skin. Simply put, it is a portable compressor, suitable for use at a salon or, indeed, at home. Thanks to the products low-molecular composition and the tiny dimensions of the particles, non-injection mesotherapy using Nanoasias serums easily gets into the deeper layers of the skin, helped by the compressed air brush. The procedure of applying the product to the skin with a strong jet of air is as painless as can be.

Besides the serums, Nanoasia also produces many incredible products which work on both the dermis and the facial muscles. Our mousse, enzyme exfoliating roll and the serum effectively clean and maintain the skin thanks to their Air Bubbles technology. This is the ideal base care for everyone - deep and delicate cleansing, intense moisturization, nourishment and stimulation to help the skin become rejuvenated and regenerated. This all comes from the high concentration of peptides, amino acids and plant extracts.

The product containing nanoneedles (cream + serum) has a comprehensive effect: it lifts and rejuvenates the skin, eliminating wrinkles and pigmentation, improving skin tone and elasticity. It provides nutrition and protection to the skin, thanks to the inclusion of plant extracts, amino acids and the self-soluble nanoneedles (compounds derived from seaweed which ensure that the nutritional components can penetrate as far as possible into the skin).

Nanoasias creams have a unique formula. The My Che duet (cream for the skin around your eyes and face), our EVA body cream and VS - our air-cushioning cream - are all the first of their kind in the world. They contain a high concentration of amino acids (the building blocks of our very organisms), peptides and plant stem cell extracts from a 100 year old ginseng plant and a 1000 year old yew tree. The formulas of these products guarantee rejuvenation, recovery and care from within, at a cellular level, giving you a powerful lifting effect, nourishment, protection and ironing out any wrinkles, pigments and much more. Air Cushion is also SPF 50+ and contains UV protection thanks to its intelligent fluid formula and nano-particle technologies. This ensures the ideal coverage for every day, without clogging or overwhelming the pores. It is a light foundation with an almost weightless texture and is compatible with any skin color when heated.

Their products pay special attention to your facial muscles. Their mask contains 45 active components including peptides, extracts from gem stones and plants. The mask stimulates isometric pressures within the skin. The muscles pulsate against this pressure with the uniform pressure acting like yoga for the face. The muscles then become toned and stronger. Facial and dermal muscles are smoothed out, skin elasticity is restored, the youthful oval shape of one's face returns and double chins are removed. Our Nanolifting system for Youthful Skin is a revolutionary lifting mask forone's facial muscles and dermis, containing powerful antioxidant and antiseptic components. The mask contains the highly-prized components of Astragalus root extract, Trehalose, 9 different peptides and 12 plant extracts which combine to achieve the following: they slow down the ageing process of cells; kickstart the extracellular matrix; regulate the tension of the vascular wall (Rosacea) and stimulate the restoration of the structural elements of the dermis - collagen, elastin, fibronectin and glycosaminoglycans.

Besides its exterior care potential, Nanoasia also looks after the skin from within. To achieve this they have developed unique products, including a bio-active additive (Nanodessert Nutritional) and a youthful elixir (Nanocell Youth Elixir).

Nanoasia holds three patents for cutting-edge research in cosmetology, as well as having a few further patents pending approval. The company has not only won praise in Russia, CIS countries and Europe, but also made it to Canada and Panama, and it is expected to open a branch in the United States soon expressed Kira; today, Nanoasia has 60 representatives in 28 cities and 8 countries. Our brands mission is to give every woman the opportunity to hold onto her natural beauty for as long as possible.

Media ContactCompany Name: Prysma MediaContact Person: Mark PhilippsEmail: Send EmailCountry: United StatesWebsite: https://nanoasia.ru/

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What exactly is the revolutionary Smart Beauty Technology, and how Kira Sorokina, the Founder of NanoAsia leads it - Press Release - Digital Journal

Skin Stem Cells Comments Off on What exactly is the revolutionary Smart Beauty Technology, and how Kira Sorokina, the Founder of NanoAsia leads it – Press Release – Digital Journal | November 30th, 2020

Myocardial Infarction Drug used to treat Heart Attack. Medicines and chemical substances that can cause myocardial infarction. Treatment ranges from lifestyle changes and cardiac rehabilitation to medication, stents, and bypass surgery.

Myocardial Infarction Drug Market is anticipated to grow at a CAGR of +6% during the forecast period 2020-2028.

A Global Myocardial Infarction Drug Market analysis and forecast is released based on a wide study of the market. Statistics about the approaching market trends as well as the current scenario of the market is a vital implement for existence and development in the constantly developing industry.

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Due to the pandemic, we have included a special section on the Impact of COVID 19 on the Myocardial Infarction Drug Market which would mention How the Covid-19 is affecting the Myocardial Infarction Drug Industry, Market Trends and Potential Opportunities in the COVID-19 Landscape, Covid-19 Impact on Key Regions and Proposal for Myocardial Infarction Drug Players to Combat Covid-19 Impact.

The Top Key Players of the global Myocardial Infarction Drug Market:

BioCardia, Inc., Laboratoires Pierre Fabre SA, Human Stem Cells Institute, CSL Limited, Capricor Therapeutics, Inc., Hemostemix Ltd, Compugen Ltd., Celyad SA, FibroGen, Inc., Lees Pharmaceutical Holdings Limited, Juventas Therapeutics, Inc., Cynata Therapeutics Limited, CellProthera, Biscayne Pharmaceuticals, Inc., HUYA Bioscience International, LLC, LegoChem Biosciences, Inc, Immune Pharmaceuticals Inc.

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The Global Myocardial Infarction Drug Market has demonstrated an increasing need to alter the policies that are being currently used by the players so as to exhibit commercial capacities of the manufacturers, distributors, and vendors. This helps the key players in developing a firm strategy that is flexible enough to keep up with future events in the market space.

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Global Myocardial Infarction Drug Market to have sustainable growth over the forecast period 2020-2028| Leading Players BioCardia, Inc., Laboratoires...

Cardiac Stem Cells Comments Off on Global Myocardial Infarction Drug Market to have sustainable growth over the forecast period 2020-2028| Leading Players BioCardia, Inc., Laboratoires… | November 30th, 2020

The researchers noted a weakening of possible repair mechanisms of blood vessels in patients who showed clinically significant vasoplegia

Vasoplegia, where vaso refers to blood vessels and plegia stands for paralysis, is a condition where the patient exhibits a low blood pressure, even in the presence of normal or increased output of blood from the heart. When this occurs as a complication of cardiopulmonary bypass surgery, there is a chance that it can lead to multiple organ failure and even death. Now, a diverse group of researchers including clinicians, computational biologists and biotechnologists have come together to study how this may be predicted early on based on clinical observations, so that effective treatment may be given.

Also Read | Mumbais first robot-assisted cardiac surgery

In a pilot study involving 19 patients who underwent elective cardiac surgery, the researchers measured the circulating counts of endothelial progenitor cells and hematopoietic stem cells at different points in time starting from when the patient was being anaesthetised to until 24 hours after the surgery. They find that in a statistically significant number of people in the group that showed clinically significant vasoplegia, there was a blunting of the endothelial progenitor cell response. Also, in the group that did not show clinically significant vasoplegia, they observed that there was no such blunting.

We can say there appears to be a pattern, which is well worth exploring in a larger cohort of patients and further delineating this particular response as a biomarker in predicting a potentially devastating complication following cardiac surgeries, says Dr. Paul Ramesh Thangaraj, from the department of cardiothoracic surgery, Apollo Hospitals, Chennai, who is one of the PIs of the study. This research is published in the journal PLOS ONE.

Hematopoietic and endothelial progenitor cells play an important role in repair of damaged tissues and inner lining of the blood vessels called the endothelium, respectively. Usually, these cells reside in the bone marrow; however, in response to injury to a tissue or a blood vessel, they come out into the circulation from the bone marrow and home into the site of injury for tissue repair, says Madhulika Dixit from the Department of Biotechnology, Indian Institute of Technology Madras, in an email to The Hindu.

Prof Dixit describes using flow cytometry to measure the counts during the surgery and afterwards. The cells were identified by means of expression of specialised cell surface receptors. For this, at regular intervals the blood withdrawn from the patient was subjected to flow cytometry. We checked for time-dependent changes in circulating counts of progenitor cells during the course of cardiopulmonary bypass in patients.

Also Read | Minimally invasive cardiac surgery the best bet

One of the key challenges was to get significant patterns in this small dataset, according to Rahul Siddharthan, from The Institute of Mathematical Sciences, Chennai, who was one of the people involved in formal analysis. In this case, we have two data sets, with two-valued outcomes [non-vasoplegic or vasoplegic], and the goal is to see how other measured parameters can predict them, he says. There are very sophisticated machine-learning algorithms available these days for such tasks. In this case the most basic algorithm, logistic regression, is good enough, says Prof. Siddharthan.

As he explains, in both cases, the idea is to look at a single value (change in circulating progenitor cells at two timepoints) and in seeing its predictive power for the output. The trend is clear, that for non-vasoplegic patients, the level of circulating progenitor cells increases, while for vasoplegic patients, it stays flat or decreases. There are exceptions but the finding is statistically significant even on this small study, says Prof. Siddharthan.

With a larger study, Dr.. Paul Ramesh envisages even developing a risk score for predicting vasoplegia as a complication following surgery.

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Pilot study finds potential signal indicative of loss of tone in blood vessels after cardiac surgery - The Hindu

Cardiac Stem Cells Comments Off on Pilot study finds potential signal indicative of loss of tone in blood vessels after cardiac surgery – The Hindu | November 30th, 2020

The U.S. Food and Drug Administration (FDA) has approved naxitamab* (naxitamab-gqgk; Danyelza; Y-mAbs Therapeutics), a humanized form of the mouse antibody 3F8, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response (PR), minor response (mR), or stable disease (SD) to prior therapy.[1]

A rare diseaseNeuroblastoma is a heterogeneous pediatric neoplasm that arises in the sympathetic nervous system. The disease is the most common extra-cranial solid tumor in infants and children, representing between 8%-10% of all childhood tumors. Overall, neuroblastoma accounts for approximately 15% of all cancer-related deaths in children. [1]

The clinical behavior of neuroblastoma is highly variable, with some tumors being easily treatable, resulting in near-uniform survival. The majority of tumors are, however, very aggressive, with a high risk of death. [2] Age, stage, and amplification of the MYCN oncogene are the most validated prognostic markers.[2]

The incidence of neuroblastoma is 10.2 cases per million children under 15 years of age. [3] In the United States, nearly 700 new cases are reported each year. While 90% of cases are diagnosed before the age of 5, approximately 30% of patients are diagnosed within the first year. The median age of diagnosis is 22 months. [4]

Neuroblastoma develops in very early forms of nerve cells that are usually found in a developing baby, which explains why children as young as newborns can develop this cancer.

The disease rarely presents in adolescence and adulthood, but outcomes are much poorer in this age group. There does not appear to be an increased prevalence among races, but there is a slight predilection for males (1.2:1).[4]

Neuroblastoma develops in a part of the peripheral nervous system called the sympathetic nervous system. Since some of the sympathetic nervous system cells are concentrated in the adrenal glands, which sit above the kidneys, neuroblastoma often starts growing there. Tumors typically begin in the belly, neck, chest, pelvis, or adrenal glands and can spread to other parts of the body, including the bones.

All patients are staged based on the International Neuroblastoma Staging System Committee (INSS) system, ranging from stage 1 through stage 4S. Based on this staging system, patients with stage 4 disease diagnosed after one year of age are classified in the high-risk category, where the neuroblastoma tumor cells have already metastasized to other sites in the body, such as the bone or bone marrow.

Essentially all patients who have tumors with many copies, or amplification, of the MYCN oncogene also have high-risk disease, even if they do not have evidence of the tumor having spread.

Although children with a family history of neuroblastoma may have a higher risk for developing this disease, this factor accounts for only 1-2 % of all cases of neuroblastoma. The vast majority of children who develop the tumor, do not have a family history of the same.

Mechanism of actionIn simple terms, naxitamab, conceived and developed by physician-scientist Nai-Kong Cheung, M.D., Ph.D., a medical oncologist at Memorial Sloan Kettering ** who heads the organizations neuroblastoma program, detects neuroblastoma cells that have survived chemo- or radiation therapy by attaching to GD2, a ganglioside that is ubiquitously expressed in the plasma membrane of neuroblastoma and is shed into the circulation, after which the patients own immune system, especially white blood cells, can destroy the malignant neuroblastoma cells. [5]

In the late 1980s, investigators at Memorial Sloan Kettering started using 3F8 in combination with surgery and chemotherapy to treat patients diagnosed with neuroblastoma. The investigational treatment significantly improved cure rates for pediatric patients with high-risk disease.

Later, in 2007, Cheung and colleagues began developing a humanized form of 3F8 called Hu3F8. In August 2011 the researchers started a phase I study of Hu3F8 (NCT01419834). The study was designed to investigate the best and safest dose to give to patients.

Accelerated approval The new indication of naxitamab + GM-CSF is approved under accelerated approval regulation based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefits in a confirmatory trial.

Naxitamab is a humanized, monoclonal antibody that targets the ganglioside GD2, which is highly expressed in various neuroectoderm-derived tumors and sarcomas. The drug is administered to patients three times per week in an outpatient setting and the treatment is repeated every four weeks. The product has received Priority Review, Orphan Drug, Breakthrough Therapy, and Rare Pediatric Disease designations from the FDA.

Much needed treatmentOver the last decades, the development of novel treatments for pediatric cancers has been successful. For example, the five-year survival rates for children diagnosed with cancer in the late 1980s approaches 70%. For some types of localized embryonal tumors, including retinoblastoma and Wilms tumor, the cure rates approach or exceed 90%.

However, for every two children who survive today, one child still succumbs to their disease. And for some childhood cancers, such as neuroblastoma and certain types of brain cancer, the prognosis remains poor. Hence, despite the observed successes, there remained a major unmet medical need remains patients diagnosed with neuroblastoma. The development and subsequent approval of naxitamab may be one much-needed treatment options for these patients. [6]

[The approval represents a major milestone] for children living with refractory/relapsed high-risk neuroblastoma, noted Thomas Gad, founder, Chairman, and President of Y-mAbs Therapeutics, whose own daughters neuroblastoma was successfully treated with 3F8 at Memorial Sloan Kettering more than a decade ago.

In 2015, Memorial Sloan Kettering licensed Hu3F8 to Y-mAbs Therapeutics tpo expand the clinical trial and development program and manufacturing of naxitamab.

Its very exciting to see this treatment go from being an experimental therapy used at my daughters bedside to now being FDA approved, Gad added.

We believe that naxitamab in combination with GM-CSF is a much-needed treatment for patients with relapsed/refractory high-risk neuroblastoma in the bone or bone marrow who have historically not had approved treatments available. This approval of Y-mAbs first BLA represents a key step in working towards our mission of becoming a world leader in developing better and safer antibody-based oncology products addressing unmet pediatric and adult medical needs, said Claus Moller, Y-mAbs Therapeutics Chief Executive Officer.

Clinical trialsThe FDA approval of naxitamab is supported by clinical evidence from two pivotal studies in patients with high-risk neuroblastoma with refractory or relapsed disease.

In these clinical studies, naxitamab appears to be well tolerated with few discontinuations of treatment. The observed treatment-related adverse events were clinically manageable.

The efficacy of naxitamab in combination with GM-CSF was evaluated in two open-label, single-arm trials in patients with high-risk neuroblastoma with refractory or relapsed disease in the bone or bone marrow.

Both trials included patients with relapsed or refractory neuroblastoma in the bone marrow or bone. Participating patients received a 3 mg/kg of naxitamab intravenously on days one, three, and five of each four-week cycle, in addition to GM-CSF subcutaneously, or under the skin, at varying doses throughout the cycle. Patients were allowed to receive preplanned radiation in specific areas based on which trial they were enrolled in.

Efficacy outcomes included overall response rate (ORR) according to the revised International Neuroblastoma Response Criteria (INRC), as determined by independent pathology and imaging review and confirmed by at least one subsequent assessment. An additional efficacy outcome measure was the duration of response (DOR).

Study 201In the first study (Study 201; NCT03363373), a multicenter open-label, single-arm trial. researchers evaluated the combination of naxitamab in combination with GM-CSF in a subpopulation of patients who had refractory or relapsed high-risk neuroblastoma in the bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded.

Of the 22 patients included in the efficacy analysis, 64% had refractory disease and 36% had relapsed disease. The median age was 5 years (range 3 to 10 years), 59% were male; 45% were White, 50% were Asian and 5% were Black.

MYCN amplification was present in 14% of patients and 86% of patients were International Neuroblastoma Staging System (INSS) stage 4 at the time of diagnosis. Disease sites included 59% in the bone only, 9% in bone marrow only, and 32% in both. Prior therapies included surgery (91%), chemotherapy (95%), radiation (36%), autologous stem cell transplant (ASCT) (18%), and anti-GD2 antibody treatment (18%).

Study 12-230The second study (Study 12-230; NCT01757626), a single-center, open-label, single-arm clinical trial, included a subpopulation of patients who had relapsed or refractory high-risk neuroblastoma in bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. In this study patients with progressive disease were excluded.

Participating patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. They were required to have received at least one dose of naxitamab at a dose of 3 mg/kg or greater per infusion and have evaluable disease at baseline according to independent review per the revised INRC. Radiation to non-target bony lesions and soft tissue lesions was permitted at the investigators discretion (assessment of response excluded sites that received radiation).

Of the 38 patients included in the efficacy analysis, 55% had relapsed neuroblastoma and 45% had refractory disease; 50% were male, the median age was 5 years (range 2 to 23 years), 74% were White, 8% Asian and 5% were Black, 5% Native American/American Indian/Alaska Native, 3% other races and 5% was not available. MYCN-amplification was present in 16% of patients and most patients were International Neuroblastoma Staging System (INSS) stage 4 (95%).

Fifty percent (50%) of patients had disease involvement in the bone only, 11% only in bone marrow, and 39% in both. Prior therapies included surgery (100%), chemotherapy (100%), radiation (47%), autologous stem cell transplant (ASCT) (42%), and anti-GD2 antibody treatment (58%)

Adverse eventsThe most common adverse reactions (incidence 25% in either trial) in patients receiving naxitamab were infusion-related reactions, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability.

The most common Grade 3 or 4 laboratory abnormalities (5% in either trial) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium, and decreased phosphate.

Boxed warningThe prescribing information for naxitamab contains a Boxed Warning which states that the drug can cause serious infusion-related reactions and neurotoxicity, including severe neuropathic pain, transverse myelitis, and reversible posterior leukoencephalopathy syndrome (RPLS). Hence, to mitigate these risks, patients should receive premedication prior to each naxitamab infusion and be closely monitored during and for at least two hours following completion of each infusion.

Note* Also known as humanized 3F8 or Hu3F8,** Researchers at Memorial Sloan Kettering Cancer Center (MSK) developed naxitamab, which is exclusively licensed by MSK to Y-mAbs. As a result of this licensing arrangement, MSK has institutional financial interests related to the compound and Y-mAbs.

Clinical trialsHumanized 3F8 Monoclonal Antibody (Hu3F8) in Patients With High-Risk Neuroblastoma and GD2-Positive Tumors NCT01419834Humanized 3F8 Monoclonal Antibody (Hu3F8) When Combined With Interleukin-2 in Patients With High-Risk Neuroblastoma and GD2-positive Solid Tumors NCT01662804Humanized Anti-GD2 Antibody Hu3F8 and Allogeneic Natural Killer Cells for High-Risk Neuroblastoma NCT02650648Study of the Safety and Efficacy of Humanized 3F8 Bispecific Antibody (Hu3F8-BsAb) in Patients With Relapsed/Refractory Neuroblastoma, Osteosarcoma and Other Solid Tumor Cancers NCT03860207Combination Therapy of Antibody Hu3F8 With Granulocyte- Macrophage Colony Stimulating Factor (GM-CSF) in Patients With Relapsed/Refractory High-Risk Neuroblastoma NCT01757626Naxitamab for High-Risk Neuroblastoma Patients With Primary Refractory Disease or Incomplete Response to Salvage Treatment in Bone and/or Bone Marrow NCT03363373

Highlights of prescription informationNaxitamab (naxitamab-gqgk; Danyelza; Y-mAbs Therapeutics) [Prescribing Information]

Reference[1] Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Hematol Oncol Clin North Am. 2010 Feb;24(1):65-86. doi: 10.1016/j.hoc.2009.11.011. PMID: 20113896.[2] Modak S, Cheung NK. Neuroblastoma: Therapeutic strategies for a clinical enigma. Cancer Treat Rev. 2010 Jun;36(4):307-17. doi: 10.1016/j.ctrv.2010.02.006. Epub 2010 Mar 12. PMID: 20227189.[3] Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010 Jun 10;362(23):2202-11. doi: 10.1056/NEJMra0804577. PMID: 20558371; PMCID: PMC3306838.[4] Esiashvili N, Anderson C, Katzenstein HM. Neuroblastoma. Curr Probl Cancer. 2009 Nov-Dec;33(6):333-60. doi: 10.1016/j.currproblcancer.2009.12.001. PMID: 20172369.[5] Balis FM, Busch CM, Desai AV, Hibbitts E, Naranjo A, Bagatell R, Irwin M, Fox E. The ganglioside GD2 as a circulating tumor biomarker for neuroblastoma. Pediatr Blood Cancer. 2020 Jan;67(1):e28031. doi: 10.1002/pbc.28031. Epub 2019 Oct 14. PMID: 31612589.[6] Balis FM. The Challenge of Developing New Therapies for Childhood Cancers. Oncologist. 1997;2(1):I-II. PMID: 10388032.

Featured image: A close up of a newborn babys foot in the neonatal unit in a hospital. Photo courtesy: 2016 2020 Fotolia/Adobe. Used with permission

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US FDA Approves Naxitamab for the Treatment of Neuroblastoma - OncoZine

Bone Marrow Stem Cells Comments Off on US FDA Approves Naxitamab for the Treatment of Neuroblastoma – OncoZine | November 28th, 2020

Since the discovery of induced pluripotent stem cells (iPSCs) in 2006, a large and thriving research products market has emerged, largely because the cells are non-controversial and can be generated directly from adult cells. It is clear that iPSCs represent a lucrative market segment, because methods for commercializing this cell type are expanding every year and clinical studies investigating iPSCs are swelling in number.

Therapeutic applications of iPSCs are also emerging. In 2013, RIKEN launched the worlds first study of an iPSC-derived cell therapy product, treating the first patient in 2014 with iPS cell-derived retinal sheets.Numerous studies with iPSCs have also been undertaken in Japan, with iPSC-derived treatments being used for the treatment of Parkinsons disease, heart disease, spinal cord injury, and platelet production.

In a world-first achieved in 2016, Cynata Therapeutics received approval to launch the worlds first formal trial of an allogeneic iPSC-derived cell product (CYP-001) for the treatment of GvHD. Riding the momentum within the CAR-T field, Fate Therapeutics is developing FT819, its off-the-shelf iPSC-derived CAR-T cell product candidate.

While the therapeutic progress is exciting, other methods of commercializing iPS cells have also expanded exponentially.

Since the discovery of iPSC technology nearly 15 years ago, exponential progress has been made in stem cell biology and regenerative medicine.

New pathological mechanisms have been identified and explained, new drugs identified by iPSC screens are in the pipeline, and the first clinical trials employing human iPSC-derived cell types have been initiated.

What do you think the next 15 years will hold? Let us know in the comments below.

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Induced Pluripotent Stem Cell (iPS Cell) Applications in 2020

IPS Cell Therapy Comments Off on Induced Pluripotent Stem Cell (iPS Cell) Applications in 2020 | November 28th, 2020

Introduction

An increasing number of patients with end-stage renal failure are undergoing dialysis therapy worldwide. It causes both medical and medicoeconomic problems. Renal transplantation has proven a successful therapy for most patients with end-stage renal failure, as the therapy results in a significant improvement in the patients quality of life, prolongs survival and is considered cost-effective [1]. However, the annual increase in the number of new patients with end-stage renal disease who need a renal transplant, and the widening gap between the demand for and the supply of donor kidneys have led to a progressive shortage of donor organs for transplant. This has become a serious issue and is worsened by the problem of limited graft survival due to immune rejection [1].

Among the strategies to overcome these problems is kidney regeneration using stem cells. Stem cells may be divided into two large categories: organ-specific or somatic stem cells and pluripotent stem cells. In contrast to organ-specific stem cells that generally have a limited potential for growth and differentiation, pluripotent stem cells, such as embryonic stem cells (ESCs) [24] and induced pluripotent stem (iPS) cells [57], have a virtually unlimited replicative capacity on culture dishes and are theoretically able to give rise to any cell type in the body. Stem cells have increasingly been used as a model system for understanding developmental mechanisms. In addition, in vitro culture and differentiation of stem cells offer unique opportunities for disease modeling, drug discovery, toxicology and cell replacement therapy [8]. The generation of specific functional cell types from ESCs has been demonstrated, including neural cells (several kinds of neuron and glia), vascular endothelia and smooth muscle, cardiomyocytes, hematopoietic cells, pancreatic insulin-producing cells and hepatocyte-like cells [8]. However, the protocol for in vitro differentiation of pluripotent stem cells into renal lineage cells has not been fully established.

Other approaches to regenerate kidney have also been investigated using organ-specific local stem cells within the kidney and bone marrow-derived hematopoietic stem cells [9]. Kidney regeneration using mesenchymal stem cells localized in bone marrow has also been examined [10]. However, the approaches are still being developed and the role of these stem cells in kidney regeneration remains to be well defined.

Therapeutic approaches using human ESCs face two major problems. One is the ethical issue derived from the use of human fertilized eggs, and the other is immune rejection in any cell or tissue transplantation due to histocompatibility antigenic differences between ESCs and patients. These problems have been overcome by a breakthrough experiment by Takahashi and Yamanaka. They identified four factors normally found in ESCs, Oct3/4, Sox2, c-Myc and Klf4, that were sufficient to reprogram both mouse and human somatic cells to closely resemble mouse and human ESCs [57]. They named these iPS cells. Since iPS cells can be generated from somatic cells of patients, clinical approaches using iPS cells are not associated with the two above problems (use of human fertilized egg and immune rejection). In the next natural step after iPS cell creation, significant progress has been made in redifferentiating iPS cells into somatic cells. As is the case with ESCs, iPS cells have been redifferentiated into several somatic tissues, including active motor neurons [11], insulin-secreting islet-like clusters [12], hepatocyte-like cells [13,14] and a number of cardiovascular cells (arterial endothelium, venous endothelium, lymphatic endothelium, cardiomyocytes), but not kidney [15,16].

This chapter first summarizes the mechanisms of kidney development and the research on the directed differentiation of ESCs into renal lineages based on the knowledge of kidney development. In vitro generation of kidney using the undifferentiated cell mass in amphibian eggs, similar to mammalian pluripotent stem cells in that the cell mass can differentiate into various organs in vitro, is also described as a reference to kidney regeneration in mammals. Recent advances in the iPS cell research and technology are then reviewed, and finally the future direction of iPS cells in the field of regenerative nephrology is described.

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Induced Pluripotent Stem Cell - an overview ...

IPS Cell Therapy Comments Off on Induced Pluripotent Stem Cell – an overview … | November 28th, 2020

Stem cell-derived cells are ready-made human induced pluripotent stem cells (iPS) and iPS-derived cell lines that are extracted ethically and have been characterized as per highest industry standards. Stem cell-derived cells iPS cells are derived from the skin fibroblasts from variety of healthy human donors of varying age and gender. These stem cell-derived cells are then commercialized for use with the consent obtained from cell donors. These stem cell-derived cells are then developed using a complete culture system that is an easy-to-use system used for defined iPS-derived cell expansion. Majority of the key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

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The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

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North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

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The Stem Cell-Derived Cells market to Scale new heights in the next decade - Khabar South Asia

IPS Cell Therapy Comments Off on The Stem Cell-Derived Cells market to Scale new heights in the next decade – Khabar South Asia | November 28th, 2020

Share This Article:A stem cell research center at UC Davis. Courtesy California Institute for Regenerative MedicineBy Barbara Feder Ostrov | CalMatters

Californias stem cell research agency was supposed to be winding down its operations right about now, after a 16-year run and hundreds of millions in grants to scientists researching cutting-edge treatments for diabetes, cancer, Alzheimers and other diseases.

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Instead, the taxpayer-supported California Institute for Regenerative Medicine will get a $5.5 billion reboot after voters earlier this month narrowly passed the Proposition 14bond measure. The overall cost of the bonds with interest will total about $7.8 billion.

Were thrilled that California voters saw fit to continue the work weve done, said Jonathan Thomas, chair of the agencys governing board. California has always had a frontier mentality and a love for the cutting edge, and the work that CIRM has done has put it on the very forefront of regenerative medicine.

Even with Californias economy in a coronavirus-induced tailspin and somescientists arguingthat stem cell research no longer needs taxpayer support,Prop. 14passed with 51 percent of the vote after well-financed supporters pourednearly $21 millioninto the Yes on 14 campaign. The measure was essentially a rerun of Proposition 71, which California voters approved in 2004 after a since-revoked federal ban on embryonic stem cell research.

The cash infusion is expected to keep the institute running for another 10 to 15 years, although the agency will see some significant changes under Prop. 14.

The institute also must contend with longstanding concerns over conflicts of interest that have dogged it since its inception, observers say. About 80% of the money distributed has gone to universities and companies tied to agency board members, according to an analysisby longtime agency watchdog David Jensen, a former Sacramento Bee journalist who runs theCalifornia Stem Cell Reportblog and wrote abookon the institute.

Prop. 14 allows the agency to fund a wider array of research projects even some that dont involve stem cells, but instead are related to genetics, personalized medicine and aging.

Thats necessary because the field has evolved, said Paul Knoepfler, a UC Davis professor of cell biology who studies the role of stem cells in cancer and writes a stem cell blog. He received a 2009 grant from the institute.

Stem cells are interesting and important, but there are going to be a lot of new therapies in the next 10 years that are not stem-cell centric, Knoepfler said.

Other changes for the agency include:

Ysabel Duron, who joined the institutes board late last year, said she sees her role as promoting equity in opportunities for both researchers and patients and ensuring that treatments resulting from the research can benefit all Californians.

Researchers in particular need to boost the diversity of patients in their clinical trials and do a better job communicating the value of their work to the public, Duron said, noting that nearly 40% of Californians are Latino.

We need to keep researchers feet to the fire, said Duron, a former television journalist and founder of the Latino Cancer Institute. They need to show us a plan and we need to reward them.

To date, the agency has funded 64 clinical trials of treatments for many types of cancer, sickle cell disease, spinal cord injuries, diabetes, kidney disease and amyotrophic lateral sclerosis, commonlyknown as Lou Gehrigs disease.But the most advanced trials involve therapies for relatively rare conditions, such asSevere Combined Immunodeficiency known as the bubble baby disease, Jensen noted. That therapy is being reviewed by the FDA but has not yet been approved.

Cancer, heart disease these are the big killers. Thats what most people are interested in, Jensen said. You can fund something for a rare disease, but that doesnt affect the majority of Californians.

And, Jensen asks, what will happen after the agency runs out of money again? Will taxpayers once again be asked to refill its coffers? There was hope when the agency began that revenues from successful treatments would sustain its grant-making in the years to come, but the institute has only received a few hundred thousand dollars, not nearly enough to become self-sustaining without taxpayer support, according to theLegislative Analysts Office.

The sustainability issue is important and its hard to address, Jensen said. The money doesnt last forever.

Stem Cell Medical Research to Expand in California Following Passage of Prop. 14 was last modified: November 27th, 2020 by Editor

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Stem Cell Medical Research to Expand in California Following Passage of Prop. 14 - Times of San Diego

Spinal Cord Stem Cells Comments Off on Stem Cell Medical Research to Expand in California Following Passage of Prop. 14 – Times of San Diego | November 28th, 2020

Researchers at Stanford Burnham Prebys Medical Discovery Institute recently developed a drug that can lure stem cells to impaired tissue and enhance the efficacy of treatment.

This is considered a "scientific first," not to mention a major advance for the field of regenerative drugs. Such a discovery, which theProceedings of the National Academy of Sciences or PNASpublished could enhance the present stem cell treatments developed to cure such neurological disorders like stroke, spinal cord injury, ALS or other amyotrophic lateral sclerosis, as well as other neurodegenerative diseases -- and have their use expanded to new conditions such as arthritis or heart disease.

In the study, toxic or green cells disappeared when mice with a neurodegenerative condition were given both therapeutic or red cells and the drug SDV1a, which matched with delayed onset of symptoms and longer lives.

(Photo : Stem Cell Research via Getty Images)In this undated handout photo released by the Institute for Stem Cell Research in 2005, neurons (red) and astrocytes (green), which can be made from neural stem cells, are seen.

Results Suggesting Efficacy of the Drug

The study results proposed that SDV1a can be used to enhance the stem cell treatments' efficacy. According to Evan Snyder, MD, PhD, theCenter for Stem Cells & Regenerative Medicine at Stanford Burnham Prebysprofessor and director, "the ability to instruct a stem cell where to go in the body, or to a particular region of a given organ is the 'Holy Grail' for regenerative medicine.

Snyder, who's also the senior author of the study, added, now, for the first time, stem cells can be directed to a desired area and focus its therapeutic effect.

Almost a decade-and-a-half back, the senior author, together with his team, found that stem cells are drawn to infection, a biological 'fire alarm' indicating that damage has taken place.

Nevertheless, using inflammation as a healing appeal is not possible since an inflammation environment can be dangerous to the body. Hence, researchers have been searching for mechanisms to help in the migration of stem cells or 'home' to the body's desired areas.

Such a mechanism or tool, according to reports on this new finding, would be a great contributor for disorders in which preliminary inflammatory indicators disappear over time, like chronic spinal cord injury or stroke, and conditions where the inflammation's role is not clearly understood, like heart disease, for one.

Fortunately, after decades of investing in stem cell science, scientists are now making "tremendous progress," saidCalifornia Institute for Regenerative Medicine or CIRMpresident and CEO Maria Millan, MD said, in their understanding of the manner such cells work and the manner they can be attached to help reverse disease or an injury.

The CIRM partially funded this new study. Millan also said, Snyder's group has identified a medicine that could enhance "the ability of neural stem cells to home to sites of injury and initiate repair."

More so, the president and CEO also explained, the drug candidate could help fast-track the stem cell treatments' development, specifically for conditions including Alzheimer's disease and spinal cord injury.

In the research, study investigators modified an inflammatory molecule called CXCL12, which the Snyder's group discovered previously, could guide healing stem cells to areas that need repair to develop the SDV1a.

As such, this new medicine works by improving stem cell binding and minimizing inflammatory indicating and can be injected anywhere to attract stem cells to a particular site without causing any inflammation.

Since such inflammation can be dangerous, Snyder explained, they modified CXL12 by "tripping away the risky beat and maximizing the good bit."

Now, he added, they have a drug, drawing stem cells to an area of pathology, but not creating or worsening the unwanted infection.

"Now, we have a drug that draws stem cells to a region of pathology, but without creating or worsening unwanted inflammation."

Furthermore, to present that the new medication can improve the effectiveness of stem cell therapy, the scientists implanted SDV1a and human neural stem cells into the brains of mice thatSandhoff disease, a neurodegenerative disease.

The scientists have already started testing the ability of SDV1a to enhance stem cell therapy in a mouse model of Lou Gehrig's disease, also known as ALS, which results from progressive loss of motor neurons in the brain.

Snyder said they are optimistic that the mechanism of action of this new drug may potentially benefit various neurodegenerative disorders and non-neurological conditions like arthritis, heart disease, and even brain cancer.

Interestingly, he also explained, since CXL12 and its receptor is said to be implicated in cytokine storm that exemplifies severeCOVID-19, some of their understandings of how to constrain infection without controlling other normal procedures selectively may be helpful in that field, as well.

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Scientists Reveal a New Drug That Directs Stem Cells To Desired Sites - Science Times

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INTRODUCTION

The myeloproliferative neoplasms are a family of clonal blood disorders characterized by overproduction of platelets [essential thrombocythemia (ET)], overproduction of red blood cells [polycythemia vera (PV)], or bone marrow fibrosis [myelofibrosis (MF)]. The genetic bases for these diseases have largely been described: Mutations in JAK2 are found in 99% of PV and 50 to 60% of ET and MF cases, while frameshift mutations in CALR are responsible for 25 to 40% of cases of ET and MF (13). Frameshift mutants of calreticulin (CALR) have a novel C terminus that acts as a rogue ligand for the thrombopoietin receptor, MPL, and activates Janus kinasesignal transducer and activator of transcription (JAK-STAT) signaling (4, 5). We recently described the generation of a mouse model of mutant CALR-driven ET that faithfully recapitulates the key phenotypes of the human disease, namely, increased numbers of cells throughout the megakaryocytic (MK) lineage, particularly platelets (6).

Hematopoiesis is classically modeled as a stepwise process beginning with a multipotent hematopoietic stem cell (HSC), which is functionally defined by its capability to reconstitute multilineage hematopoiesis when transplanted into a myeloablated recipient (7). This HSC then transits through a series of intermediate stages with increasing lineage restriction to terminally differentiated blood cells (8, 9). However, newly popularized single-cell technologies such as single-cell RNA sequencing (scRNAseq) have reshaped our understanding of hematopoiesis and suggest that cells travel through a continuum of differentiation rather than a series of rigidly defined stages (10, 11). In a recent demonstration of the power of scRNAseq to untangle complex differentiation processes, it was used to interrogate the transcriptomes of hematopoietic stem and progenitor cells (HSPCs) to identify novel intermediate populations within erythropoiesis, which could then be isolated and characterized via fluorescence-activated cell sorting (FACS) strategies (12).

While HSCs are traditionally defined to be capable of reconstituting all blood lineages in transplantation experiments, there is an increasing body of evidence that some cells within the immunophenotypic HSC compartment already exhibit some lineage bias or restriction (1315). Studies in mice have shown that MK and erythroid lineages may branch off before other myeloid and lymphoid lineages (1618), and lineage tracing studies have shown the MK lineage to be the earliest generated from HSCs (1923). A transposon-based lineage tracing strategy showed some tags to be shared between long-term HSCs (LT-HSCs) and megakaryocyte progenitors (MkPs) but not multipotent progenitors (MPPs), indicative of a direct pathway linking HSCs and MK bypassing MPP (19). We therefore asked whether our mouse model of mutant CALR-driven ET could allow us to interrogate the differences in the hematopoietic landscapes between wild-type (WT) and disease model mice, with a particular focus on MK trajectories.

We generated scRNAseq data from FACS-sorted HSPCs [Lin Sca1+ cKit+ (LSK) and Lin Sca1 cKit+ (LK) populations] from a pair of WT and CALR DEL (knock-in of del52 allele) homozygous (HOM) littermate mice. After quality control, we retained 11,098 WT (5959 LSK and 5139 LK) and 15,547 HOM (7732 LSK and 7815 LK) cells for downstream analysis. We began by defining highly variable genes, which we used to perform principal component analysis (PCA) and generate a k = 7 nearest-neighbor graph. Cells were then assigned to clusters by mapping onto a previously published dataset of 44,082 LK cells (24), with manual annotation of clusters (fig. S1A). Cells from all major blood lineages can be seen and separate into distinct trajectories. To determine which cells were over- or underrepresented in the CALR DEL HOM mouse, we compared relative numbers of cells from each genotype. The most notable changes in relative cell abundance were increased numbers of cells in the HSC and MK clusters (fig. S1B), consistent with the increased platelet phenotype of our ET mouse model (6). We repeated the analysis on a second pair of WT and CALR DEL HOM littermate mice, in this case retaining 3451 WT (972 LSK and 2479 LK) and 12,372 HOM (4548 LSK and 7824 LK) cells for downstream analysis after quality control, and again observed an increase in cells in the HSC and MK clusters (fig. S1C).

To better understand the subgroups of cells within stem/progenitor cells, we chose to use partition-based graph abstraction (PAGA) (25) to visualize our data. This method generates a graph in which each node represents a group of closely related cells and edge weights correspond to the strength of connection between two nodes. We again compared relative abundances between WT and CALR DEL HOM mice and colored the nodes so red nodes are enriched in CALR mice, while blue nodes are underrepresented. We observed that the fine cluster that was most overrepresented in CALR DEL HOM mice (marked with an arrow) fell between the HSC and MK clusters in both repeats (Fig. 1A and fig. S1D). We plotted the expression of the MK markers Cd9, Itga2b (CD41), Mpl, Pf4, and VWF in our PAGA and hypothesized two MK trajectories, as indicated by the green and blue arrows (fig. S1E). As the fine cluster most overrepresented in CALR DEL HOM mice would be an intermediate on one of these trajectories (green arrow), we further hypothesized that these cells would be of particular relevance in the disease setting of mutant CALR-driven ET and thus aimed to further study them.

(A) PAGA of scRNAseq data from WT and CALR DEL HOM mice. Red nodes represent those present at increased abundance in CALR DEL HOM mice, while blue nodes represent those at reduced abundance. The most highly enriched node is noted with an arrow. (B) RNA expression of the flow cytometry markers CD48, EPCR (Procr), and CD150 (Slamf1) plotted on PAGA graphs from (A). Cells within our node of interest (marked with an arrow) are CD48, EPCR, and CD150+. (C) Representative plots of SLAM cells from WT and CALR DEL HOM mice. CALR DEL HOM mice show higher numbers of both ESLAMs (Lin CD48 CD150+ CD45+ EPCR+) and pMKPs (Lin CD48 CD150+ CD45+ EPCR). FITC, fluorescein isothiocyanate; PE, phycoerythrin. (D) Quantification of bone marrow frequency of pMKPs in WT and CALR DEL HOM mice. The frequency of pMKPs within live bone marrow mononuclear cells (BMMNCs) is significantly increased in CALR DEL HOM mice (WT, n = 3, 0.00029 0.00008; HOM, n = 3, 0.0025 0.0008; *P = 0.042).

We examined the expression of a series of genes typically used to FACS isolate different hematopoietic populations and found this fine cluster to be CD48, EPCR (Procr), and CD150+ (Slamf1) (Fig. 1B). We designed an immunophenotypic scheme to identify and isolate cells from this fine cluster, defining them to be Lin, CD150+, CD48, EPCR, and CD45+. On the basis of our subsequent characterization of these cells, we eventually termed them proliferative MkPs or pMKPs. Consistent with our transcriptomic data, when comparing WT mice to CALR mutant mice, we found an increase in the frequency of pMKPs in CALR DEL HOM mice as assayed by flow cytometry (Fig. 1, C and D). We also found that pMKPs were expanded in CALR DEL HET mice, albeit to a lesser extent than observed in CALR DEL HOM mice (fig. S1F).

To characterize pMKPs, we FACS-sorted single ESLAM (EPCR+ SLAM) HSCs (Lin CD45+ CD48 CD150+ EPCR+) (26), pMKPs (Lin CD45+ CD48 CD150+ EPCR), and MkPs (Lin Sca1 cKit+ CD41+ CD150+) (27) (fig. S2A) from WT mice into individual wells of a 96-well plate and observed them every day for 4 days. We analyzed our sort data and observed that in pMKPs, markers traditionally used to define MkPs were Sca1/lo/mid, cKit+, and CD41mid/+ (fig. S2B). pMKPs were additionally CD9+ and MPL+ (fig. S2C). On each day, we classified each well with surviving cell(s) into one of four categories, using cell size as a proxy for megakaryopoiesis (2830): (i) exactly one large cell, presumed to be a megakaryocyte; (ii) multiple large cells; (iii) mixed expansion, with both large and small cells; and (iv) expansion with only small cells (Fig. 2A). To verify that larger cells represented MK cells, using cells from day 4 ESLAM, pMKP, and MkP colonies, we quantified average CD41 intensity via immunofluorescence and classified cells as small or large via bright-field microscopy, using a small/large dichotomy assessed via bright-field microscopy to match the classification scheme used in Fig. 2A. Here, we confirmed that large cells have significantly higher CD41 staining, supporting their identification as MK (fig. S2D). In some cases, particularly large cells within mixed colonies showed very high CD41 staining and membrane extensions that resembled proplatelets (representative picture is shown in fig. S2E). Furthermore, we sorted pMKPs from VWF (von Willebrand factor)green fluorescent proteinpositive (GFP+) mice and found that large cells had a very bright VWF-GFP signal, supporting their identification as MK. Smaller cells in these clones had a much dimmer VWF-GFP signal, suggesting that they likely represent more immature cells that have not progressed as far through megakaryopoiesis (fig. S2F).

(A) Representative pictures of in vitro culture output of single ESLAMs, pMKPs, and MkPs into four categories: 1 MK, >1 MK, mixed, or proliferation only. (B) Classification of in vitro culture output of single ESLAMs, pMKPs, and MkPs at day 4 after FACS isolation. ESLAMs almost exclusively proliferated without producing megakaryocytes, while MkPs almost exclusively produced MKs, usually producing only a single MK. pMKPs showed a strong MK bias but were more likely to proliferate than were MkPs. ESLAMs, n = 306 wells from five experiments; pMKPs, n = 291 wells from six experiments; MkPs, n = 235 wells from five experiments. Chi-square test, ****P < 0.0001. (C) Timing of megakaryopoiesis in ESLAMs, pMKPs, and MkPs. Individual cells were observed for 4 days after sort, and the first date on which cell(s) showed signs of megakaryopoiesis was noted. MkPs were faster to begin megakaryopoiesis than were pMKPs (at day 2, MkPs: 89.5 0.7%; pMKPs: 50 6%; *P = 0.02). ESLAMs, n = 5; pMKPs, n = 6; MkPs, n = 5. (D) Log2-transformed cell counts of megakaryocytes from pMKPs and MkPs after 4 days of culture. Each point represents the average value from one of four separate experiments. Average of four experiments: pMKP, 1.12; MkP, 0.412, *P = 0.0295. (E) Histogram of the minimum number of cell divisions for 103 pMKPs and 158 MkPs that produced only megakaryocytes after 4 days of culture across four experiments. Chi-square test, ***P = 0.0001.

The vast majority of ESLAMs showed expansion with only small cells at day 4, consistent with being highly primitive HSCs with considerable proliferative potential, but not yet producing megakaryocytes. Similarly, as predicted for MkPs, more than 95% of wells showed exclusively production of MKs at day 4, with the majority producing only one MK. This lack of in vitro proliferation for single MkPs is consistent with previously published results, where 75% of MkPs did not divide and none produced more than 10 MKs (31). pMKPs exhibited an intermediate phenotype: While approximately 90% of wells showed production of some MKs, they were much more likely to produce multiple MK than were MkPs. In particular, pMKPs frequently proliferated into mixed colonies with both large and small cells, a behavior that was rarely seen for either ESLAMs or MkPs (Fig. 2B). Kinetic analysis showed that MkPs were faster to begin megakaryopoiesis than were pMKPs (Fig. 2C), and when considering only wells that produced only MKs, pMKPs produced more MKs than did MkPs (Fig. 2, D and E). pMKPs maintained their MK bias even when incubated under pro-erythroid or pro-myeloid conditions (fig. S3A). Culturing cells with thrombopoietin (THPO) increased the proportion of pMKPs that formed colonies with multiple MKs while reducing the number of mixed colonies (fig. S3B). To verify that our observed MK bias is not simply due to culture conditions supporting only megakaryopoiesis, we cultured ESLAMs under the same conditions for 10 days followed by flow cytometric analysis and observed multilineage differentiation (fig. S3C).

To examine the extent of overlap between our pMKPs and traditionally defined MkPs, we stained bone marrow with a panel incorporating all necessary markers and index sorted single pMKPs and MkPs. On the basis of index sort values, 97% of MkPs were CD45+, 50% were EPCR, and only 2% were CD48; when taken together, fewer than 1% of immunophenotypic MkPs also fell within the pMKP gate (fig. S3D); thus, pMKPs and MkPs can be FACS-separated on the basis of CD48 and EPCR. In contrast, we found that an average of 51% of pMKPs were also immunophenotypically MkPs (CD41+ Sca1 cKit+) (fig. S3E). As we observed a partial overlap between pMKPs and MkPs, we used our index sort data to assign each pMKP an overlap score based on the levels of CD41, Sca1, and cKit: 1/3 if only one marker overlapped, 2/3 if two overlapped, and 3/3 for pMKPs that also fall within the MkP immunophenotypic gate. No pMKPs had an overlap score of 0/3. We used the same classification scheme as in Fig. 2B and found that lower overlap scores correlated to a more proliferative, less MK-restricted phenotype: The pMKPs that are least similar to MkPs are the most proliferative and the least restricted to the MK lineage, although they still display a strong preference for MK production (fig. S3F). pMKPs with the lowest overlap score took the longest to enter megakaryopoiesis (fig. S3G). Together, our data indicate that pMKPs represent a group of cells with an MK bias and an increased proliferative potential as compared to traditionally defined MkPs.

We next determined whether pMKPs were capable of producing platelets in vivo. We made use of CD45.2 VWF-GFP donor mice and cKit W41/W41 CD45.1 recipient mice, which allowed us to track platelets (via VWF-GFP) and nucleated cells (by CD45.1/CD45.2 staining) (Fig. 3A). We FACS-sorted ESLAMs, pMKPs, and MkPs from VWF-GFP donor mice and transplanted 30, 60, or 120 cells per recipient into sublethally irradiated W41 mice along with 250,000 spleen MNCs (mononuclear cells) (SPMNCs) as helper cells and assayed peripheral blood chimerism every week for 4 weeks and at 16 weeks. We did not sort on VWF-GFP+ at this stage, but flow cytometry analysis showed that ESLAMs, pMKPs, and MkPs were all highly enriched for VWF-GFP expression when compared to total bone marrow (fig. S4A). We also transplanted one mouse per cohort with 250,000 SPMNCs alone to serve as a negative control to help with gating to avoid false positives. Representative gating strategies are shown in fig. S4 (B and C). As expected, ESLAMs were able to generate relatively high levels of platelets at all three cell doses, starting with a very low level at week 1 and increasing over the course of 4 weeks and continuing up to 16 weeks (although one recipient of 30 ESLAMs was lost to follow-up before the 16-week time point). pMKPs and MkPs were only able to reconstitute platelets at a very low level (1/105 to 1/104), even at the highest cell dose (Fig. 3, B to D and summarized in E). Low levels of donor-derived platelets were detected in 10 of 12 pMKP recipients and 8 of 13 MkP recipients within the first 4 weeks; extended observation up to 16 weeks showed that few recipients continued to produce VWF-GFP+ platelets, although all 3 pMKP recipients at the highest dose still showed VWF-GFP+ platelets. ESLAMs successfully produced CD11b+ myeloid cells in 10 of 10 recipients across varying cell doses, while pMKPs and MkPs only produced CD11b+ cells at a low level in 3 of 12 and 2 of 10 recipients, respectively (fig. S4, D to F and summarized in G). Therefore, we concluded that while pMKPs and MkPs have limited capabilities in a transplantation experiment, they both show an MK bias, in agreement with their in vitro behaviors. These low levels of reconstitution suggest that pMKPs and MkPs do not divide considerably in vivo, again similar to in vitro data.

(A) Schematic of VWF-GFP+ transplantation strategy. ESLAMs, pMKPs, and MkPs were sorted from VWF-GFP+, CD45.2 donor mice and transplanted into sublethally irradiated cKit W41/W41 CD45.1 recipients. PB, peripheral blood. (B) Platelet reconstitution from 30 donor cells. (C) Platelet reconstitution from 60 donor cells. (D) Platelet reconstitution from 120 donor cells. (E) Table summarizing numbers of mice with successful platelet production from ESLAMs, pMKPs, and MkPs. Here, transplanted cells were defined to have produced platelets if platelets were observed at a level of at least 1 in 105 at one or more time points within the first 4 weeks after transplantation.

Our single-cell transcriptomic analysis showed pMKPs to be an intermediate stage on an MK trajectory maintaining CD48 negativity (Fig. 1B and green arrow in fig. S1E), which suggests that they bypass the traditional MPP2 pathway (blue arrow in fig. S1E). We therefore asked whether we could show production of pMKPs from HSCs in an MPP2-independent manner by making use of a mouse model allowing inducible depletion of HSPCs. In this model, Tal1-Cre/ERT mice are crossed with R26DTA mice, wherein treatment with tamoxifen leads to specific expression of diphtheria toxin in HSCs and primitive progenitors and hence suicidal depletion of these early populations (Fig. 4A) (32). Within 6 weeks after HSC depletion, very few LT-HSCs remain, but levels of MPPs, committed progenitors, and mature blood cells are only slightly lower than in control animals (32). We reasoned that if pMKPs arise directly from HSCs, they should be depleted to a similar extent as HSCs, while if they arise from an MPP pathway, they should be depleted to a similar extent as MPPs (i.e., to a lesser extent than HSCs).

(A) Schematic of DTA (diphtheria toxin fragment A) HSC depletion model experiment. Tal1-CreERT/R26DTA mice were treated with four doses of tamoxifen at 0.1 mg/g to induce suicidal depletion of HSCs and then euthanized after 6 weeks for bone marrow (BM) analysis. (B) Frequencies of stem and progenitor cells with or without stem cell depletion. Cell populations that were significantly diminished by suicidal depletion of HSCs include ESLAMs (Cre, 17.1 10.8/105 BMMNC; Cre+, 4.3 2.0/105 BMMNC; *P = 0.012), LTHSCs (LSK CD48 CD150+) (Cre, 15 12/105 BMMNC; Cre+, 3.6 1.7/105 BMMNC; *P = 0.031), pMKPs (Cre, 13.0 7.6/105 BMMNC; Cre+, 4.1/105 BMMNC; *P = 0.013), and MkPs (Cre, 44.2 26.4/105 BMMNC; Cre+, 21.4 6.1/105 BMMNC; *P = 0.046); Cre, n = 8 and Cre+, n = 10. MPP2 (Cre, 25.1 29.1/105 BMMNC; Cre+, 13.3 3.6/105 BMMNC; P = 0.48) and preMegE (Cre, 90.0 62.9/105 BMMNC; Cre+, 73.9 29.6/105 BMMNC; P = 0.66) populations were depleted to lesser extents that did not reach statistical significance; Cre n = 4 and Cre+ n = 6. ns, not significant.

We compared mice carrying either no Cre or Tal1-Cre/ERT after treatment with tamoxifen to induce specific depletion of HSCs. We observed a depletion of approximately 75% in the numbers of HSCs [whether using ESLAM markers or LT-HSC (LSK CD48 CD150+) markers] and a 68% reduction in the numbers of pMKPs in HSC-depleted mice. By contrast, there was no significant reduction in MPP2 or preMegE populations, while MkPs were reduced by approximately 51% (Fig. 4B). Consistent with previously published results, we observed no statistically significant reduction in other multipotent populations, including MPP3 and MPP4 (33), and committed progenitor populations, including CFU-E (erythroid colony-forming units), pCFU-E, pGM (pre-granulocyte/macrophage), and GMP (granulocyte/monocyte progenitors) (fig. S5) (27). We noted that one Cre mouse was an outlier, with noticeably higher frequencies of almost all progenitor populations, and tested removing this outlier to ensure our conclusions were not unduly relying on this mouse. With the outlier removed, we calculated reductions of 68% in ESLAMs (P = 0.0001), 60% in pMKPs (P = 1.5 105), and an increase of 24% in MPP2 (P = 0.50). Our analysis is therefore robust to the removal of this outlier and demonstrates that the reduction in pMKP levels correlates more closely to that of ESLAMs than that of MPP2. Together, these data support a model in which pMKPs are produced from HSCs in an MPP2-independent manner and MkPs can be generated from pMKPs or via MPP2, accounting for their intermediate level of reduction.

After characterizing the pMKP population in WT mice, we next asked whether there were qualitative differences between WT and CALR DEL HOM cells along the MK trajectory and not solely a quantitative difference. To do so, we sorted single ESLAMs, pMKPs, and MkPs from WT and CALR DEL HOM mice and monitored their in vitro behavior over 4 days. While very few WT ESLAMs showed any MKs within the first 4 days after sort, a higher proportion of CALR DEL HOM ESLAMs showed MKs within mixed colonies (Fig. 5A). CALR DEL HOM pMKPs showed similar proportions of wells in each category (Fig. 5B), while CALR DEL HOM MkPs were more likely to form multiple MKs and less likely to form a single MK (Fig. 5C). To assess the statistical significance of these differences, using a Fishers exact or chi-square test required consolidation of our data into fewer categories, as some categories contained values that were too low (for example, for day 4 ESLAMs, the categories 1 MK and >1 MK were 0 in both WT and HOM). We thus consolidated ESLAM data into two categoriesno MK and MK (Fig. 5D)and pMKP and MkP data into three categories1 MK, >1 MK, and mixed + prolif only (Fig. 5, E and F). This showed that CALR DEL HOM ESLAMs were significantly more likely to form MKs (Fig. 5D). CALR DEL HOM pMKPs showed no statistically significant difference, suggesting no change in their MK bias or proliferative behavior compared to WT pMKPs (Fig. 5E). CALR DEL HOM MkPs were significantly more proliferative than were WT MkPs (Fig. 5F). We also extended our observation of ESLAM clones to day 7 and observed an even stronger increase in the production of megakaryocytes from CALR DEL HOM ESLAMs, an increase noted both in wells producing mixed clones and in those producing MK-only clones (Fig. 5, G and H).

(A) Classification of in vitro culture output of single ESLAMs from WT and CALR DEL HOM mice at day 4, using the classification scheme as in Fig. 2A. WT, n = 223; HOM, n = 225. (B) Classification of in vitro culture output of single pMKPs from WT and CALR DEL HOM mice at day 4; WT, n = 117; HOM, n = 161. Chi-square test P = 0.9201. (C) Classification of in vitro culture output of single MkPs from WT and CALR DEL HOM mice at day 4; WT, n = 136; HOM, n = 152. (D) Reclassification of data from (A) into two categories (MK or no MK) for a Fishers exact test, *P = 0.0191. (E) Reclassification of data from (B) into three categories (1 MK, >1 MK, and mixed + prolif only) for a chi-square test, P = 0.8183. (F) Reclassification of data from (C) into three categories (1 MK, >1 MK, and mixed + prolif only) for a chi-square test, **P = 0.0069. (G) Classification of in vitro culture output of single ESLAMs at day 7; WT, n = 136; HOM, n = 152. (H) Reclassification of data from (G) into two categories (MK or no MK) for a Fishers exact test, **P = 0.0014. (I) pMKPs as a proportion of live cells generated from in vitro culture of WT and CALR DEL HOM ESLAMs, assessed at day 3. WT, 0.062 0.015; HOM, 0.193 0.036, *P = 0.0135, n = 3 independent mice.

We also considered log2-transformed cell counts from those wells with exclusively megakaryocytes (i.e., 1 MK and >1 MK). In some cases, we observed the death of a cell or cells over our 4-day observation period; to account for cell death, we used the maximum number of cells observed over these 4 days. Mann-Whitney U tests showed no significant difference for pMKPs but a significant increase in MK production from CALR DEL HOM MkPs (fig. S6, A and B). Similarly, calculations of the minimum number of divisions required to produce the observed number of MKs found no difference for pMKPs but a significant shift to more divisions from CALR DEL HOM MkPs (fig. S6, C and D). We also cultured ESLAMs in vitro and assayed for the production of pMKPs, finding that CALR DEL HOM ESLAMs gave rise to significantly more pMKPs than did their WT counterparts (Fig. 5I). Together, we conclude that CALR DEL is acting at multiple stages of megakaryopoiesis, promoting an MK bias from the earliest HSC compartments and increased proliferation at both HSC and MkP levels. While pMKPs are increased in number in CALR DEL HOM mice, these cells do not show altered proliferation or MK bias in vitro.

Last, we made use of our scRNAseq data to compare gene expression between WT and CALR DEL HOM cells along the MK trajectory. We considered cells within 2 of the 13 clusters defined by our transcriptomic data (HSC and MK; fig. S1A) and 1 fine cluster (pMKP; arrow in Fig. 1A) (Fig. 6, A to C). As the pMKP fine cluster had fewer cells (24 in WT and 247 in CALR DEL HOM) than the larger HSC and MK clusters, we were only able to confidently call a small number of differentially expressed genes (DEGs) within this cluster. We performed Ingenuity Pathway Analysis (IPA) to determine which biological pathways and upstream regulators were most affected in the HSC and MK clusters; the small numbers of DEGs in pMKPs resulted in no statistically significant hits via IPA. The most affected canonical pathways fell into three broad groups: cell cycle (in blue), unfolded protein response (gold), and cholesterol biosynthesis (green) (Fig. 6, D and E). Full lists of canonical pathways, P values, and z scores are available in tables S1 (HSC) and S2 (MK). Genes contributing to these three pathways are highlighted in the same colors in Fig. 6, A to C; we note that pMKPs also show up-regulation of several UPR (unfolded protein response)associated genessuch as Hspa5, Pdia3, and Pdia6in addition to two known STAT targets (Ifitm2 and Socs2).

(A to C) Volcano plots showing DEGs between WT and CALR DEL HOM cluster 3 (HSC) (A), pMKP fine cluster (B), and cluster 11 (MK) (C). Genes within certain representative Gene Ontology (GO) terms are colored: regulation of cholesterol biosynthetic process (GO:0045540) (green), response to ER stress (GO:0034976) (gold), and regulation of mitotic cell cycle (GO:0007346) (blue). Other DEGs are colored in red. (D and E) Bar graphs showing z scores for up-regulated canonical pathways in cluster 3 (HSC) (C) and cluster 11 (MK) (D), filtered by P < 0.01 and z score of >1 or <1. Bars are highlighted in green for cholesterol biosynthesis, gold for ER stress/unfolded protein response, or blue for cell cycle. (F) Upstream regulator analysis. Hits were filtered by P < 0.01. Bar graph showing the 10 most up-regulated and 10 most down-regulated predicted upstream regulators, when comparing WT and CALR DEL HOM cluster 3 (HSC) (blue) and cluster 11 (MK) (red), as measured by combining the z scores from WT and MK analyses.

While cell cycle and UPR have previously been described as up-regulated in human CD34+ cells with CALR mutation (34), the discovery of cholesterol biosynthesis was somewhat unexpected. However, this aligned with the predicted significant activation of the lipid and cholesterol biosynthetic transcriptional machinery controlled by the sterol regulatory elementbinding proteins (SREBPs; SREBF1 and SREBF2) and the SREBF chaperone (SCAP) and their inhibitor insulin-induced gene 1 (INSIG1) (Fig. 6F). Moreover, as discussed further below, a role for cholesterol biosynthesis in a proliferative, platelet-biased blood disorder is biologically plausible. Upstream regulator analysis also pointed to activation of ERN1 (Ire1) and Xbp1, two constituents of UPR, as well as STAT5 (table S3), which is consistent with previous demonstrations that mutant CALR acts via STAT signaling (4, 3537). We additionally observed other previously undescribed signaling processes to be predicted to be activated, including drivers of proliferation such as CSF2 [granulocyte-macrophage colony-stimulating factor (GM-CSF)] and hepatocyte growth factor (HGF), or repressed, like the known tumor suppressors TP53 and let-7.

Single-cell transcriptomic approaches have allowed detailed examinations of differentiation landscapes in both normal and perturbed hematopoiesis without a requirement to initially define populations based on a set of cell surface markers. We therefore used single-cell transcriptomics to investigate our recently generated mutant CALR-driven mouse model of ET and found an expected increase in both HSCs and MK lineage cells. We also found an increase in a previously unknown group of cells, here termed pMKPs, linking HSCs with the MK lineage. In vitro, pMKPs displayed behaviors intermediate to those of HSCs and MkPs: Similarly to HSCs, they had some proliferative potential, but similarly to MkPs, they were almost exclusively restricted to the MK lineage. In transplantations, pMKPs and MkPs showed similar behavior: They both transiently produced platelets at a low level. We hypothesize that while pMKPs are more proliferative than MkPs in vitro, neither population is capable of sufficient proliferation to significantly contribute to platelet production in the transplant setting. While this manuscript was in preparation, another group described separating SLAM (Lin CD48 CD150+) cells based on EPCR and CD34, finding that EPCR SLAM cells performed poorly in transplants and showed gene expression profiles (high Gata1, Vwf, and Itga2b) indicative of MK bias (38), results that are broadly consistent with our own.

Our characterization of pMKPs accords well with an increasing understanding that at least a portion of megakaryopoiesis occurs via an early branch point directly from HSCs. While the standard model of hematopoiesis shows megakaryocytes subsequent to MPP2, lineage tracing experiments have shown that some MkPs are generated in an MPP2-independent way (19). Furthermore, in vivo labeling of the most primitive HSCs showed that within 1 week of label induction in LT-HSCs, label can be seen in MK lineages but no other, indicating that the HSC-to-MK pathway can be noticeably faster than pathways producing other lineages (22). Our results suggest that pMKPs are likely to arise independently of the MPP2 stage, as suicidal depletion of the earliest HSPCs reduces pMKPs to a much greater extent than MPP2s. It is therefore tempting to speculate that our pMKP sort scheme may isolate intermediate cells on this shorter, faster bypass trajectory. A recent study of JAK2 V617F-driven MF in humans attributed increased megakaryopoiesis to the expansion of both traditional MkPs and a novel MkP-like population, suggesting that cells that may be analogous to our pMKPs are relevant in human disease (30).

We also investigated an outstanding question about at which stages mutant CALR acts to drive a platelet phenotype. Mutant CALR has been demonstrated to increase the number of immunophenotypic HSCs and MkPs (6), and we also saw an expansion in the number of pMKPs. When considering the behavior of cells individually, it is clear that mutant CALR acts from the stem cell compartment: CALR DEL HOM HSCs were more proliferative and faster to produce megakaryocytes than were their WT counterparts. Mutant CALR did not show a strong effect on the proliferation or MK bias of pMKPs at the level of a single cell but drove an increase in proliferation of MkPs and thus the number of megakaryocytes produced. We therefore concluded that mutant CALR drives platelet bias and proliferation at multiple stages of megakaryopoiesis, although this effect is strongest within HSCs.

Last, we used our single-cell transcriptomic data to ask which biological pathways were most differentially regulated in our CALR DEL HOM mice. Mutant CALR was associated with an up-regulation of the unfolded protein response, as would be expected for cells with impaired chaperone activity and as has been seen in human patient cells (34). In addition, mutant CALR cells showed an increase in cell cycle genes, again consistent with observations from human patient cells (34) and in agreement with our in vitro data, which showed that mutant CALR HSCs and MkPs were more proliferative. We also found up-regulation of cholesterol biosynthesis pathway genes in mutant CALR hematopoietic cells. While cholesterol biosynthesis is broadly increased across numerous cancers (39), including hematological cancers (40), CALR has also been directly linked to cholesterol biosynthesis. CALR/ mouse embryonic fibroblasts show impaired endoplasmic reticulum (ER) Ca2+ levels, leading to overactivation of SREBPs, which then up-regulate cholesterol and triacylglycerol biosynthesis genes (41). As mutant CALR lacks its Ca2+-binding domain, it is possible that CALR DEL HOM cells phenocopy knockout cells with respect to ER Ca2+ stores, thus leading to the observed overactive transcription of cholesterol biosynthesis genes. While megakaryocytes derived from human patient samples have been shown to have increased store-operated Ca2+ entry due to the perturbation of a complex between STIM1, ERp57, and CALR (42), none of our differentially activated pathways from IPA pointed to altered cytoplasmic Ca2+ signaling in the stem and progenitor populations tested. This may reflect differences between progenitor and mature cells. Mice with impaired cholesterol efflux have more proliferative HSCs (43) and an increase in MkP proliferation and an ET-like phenotype (44), suggesting that there may be a previously unknown link between the CALR DEL mutation, cholesterol metabolism, proliferation of MkPs, and thus the overproduction of platelets. While cholesterol biosynthesis was the most prominent novel target found in our transcriptomic analysis, it was by no means alone. IPA upstream regulator analysis predicted an up-regulation of interleukin-5 (IL-5), GM-CSF, and HGFall with known roles in hematopoiesisin addition to several unexpected results, such as TBX2, a transcription factor that has not been studied in hematopoiesis. Upstream regulators predicted to be decreased include the tumor suppressor TP53; let-7, a microRNA with a role in the self-renewal of fetal HSCs (45); and KDM5B (Jarid1b), a histone methylase required for HSC self-renewal (46).

Overall, our study has characterized a previously undescribed MK trajectory implicated in the progression of ET. We find that pMKPs are an intermediate stage within one pathway of megakaryopoiesis and hypothesize that they may be situated within the MPP2-independent MK shortcut. Last, our analysis confirmed that JAK-STAT signaling, unfolded protein response, and cell cycle are all increased by the presence of mutant CALR and found up-regulation of cholesterol biosynthesis, in addition to numerous other potential upstream regulators. Functional validation of these biological pathways and upstream regulators may represent promising avenues of future research to better understand mutant CALR-driven disease and in the development of therapeutic strategies.

The objectives of the study were to generate transcriptomic data from our CALR mouse model of ET and to use these data to determine how the hematopoietic landscape is affected by the CALR DEL mutation. All mouse procedures were performed in strict accordance with the U.K. Home Office regulations for animal research under project license 70/8406.

Bone marrow cells were harvested from the femurs, tibia, and iliac crests of mice. Bones were crushed in a mortar and pestle in phosphate-buffered saline (PBS) and 2% fetal bovine serum (FBS) and 5 mM EDTA and then filtered through a 70-m filter to obtain a suspension of bone marrow cells. The suspension was incubated with an equal volume of ammonium chloride solution (STEMCELL Technologies, Vancouver, Canada) for 10 min on ice to lyse erythrocytes, followed by centrifugation for 5 min at 350g. The cell pellet was resuspended in PBS and 2% FBS and 5 mM EDTA, filtered again through a 70-m filter, and centrifuged again for 5 min at 350g. For cell sorting experiments, bone marrow mononuclear cell suspensions were immunomagnetically depleted of lineage (Lin)positive cells (EasySep Mouse Hematopoietic Progenitor Cell Isolation Kit, catalog no. 19856, STEMCELL Technologies). For staining, cells were incubated with the indicated antibodies for 40 min on ice; see attached tables for catalog information and concentrations used (table S4). Flow cytometry was performed on BD LSRFortessa analyzers, and flow cytometric sorting was performed on BD Influx 4 and 5 cell sorters (BD Biosciences, San Jose, USA). Flow data were analyzed using FlowJo software (Tree Star, Ashland, USA).

For 10x Chromium (10x Genomics, Pleasanton, CA) experiments, Lin c-Kit+ (LK) and Lin Sca1+ cKit+ (LSK) cells were sort purified as described above and processed according to the manufacturers protocol. Sample demultiplexing, barcodes processing, and gene counting were performed using the count commands from the Cell Ranger v1.3 pipeline (https://support.10xgenomics.com/single-cell-gene-expression/software/overview/welcome). After Cell Ranger processing, each sample (LK and LSK for WT and CALR HOM DEL) was filtered for potential doublets by simulating synthetic doublets from pairs of scRNAseq profiles and assigning scores based on a k nearest-neighbor classifier on PCA-transformed data. The 1 and 4.5% of cells with the highest doublets scores from each LSK or LK sample were removed from further analysis, respectively. Cells with >10% of unique molecular identifier (UMI) counts mapping to mitochondrial genes, expressing fewer than 500 genes, or with a total number of UMI counts further than 3 SDs from the mean were excluded. After quality control, 11,098 WT (5139 LK and 5959 LSK) and 15,547 HOM (7815 LK and 7732 LSK) cells were retained for downstream analysis from our first repeat. For our second repeat, 3451 WT (2479 LK and 972 LSK) and 12,372 HOM (7824 LK and 4548 LSK) cells were retained for downstream analysis. These cells were then normalized to the same total count. All scRNAseq data were analyzed using the Scanpy Python Module (47).

To assign cell type identities to WT and CALR samples, a previously published landscape of 45,000 WT LK and LSK hematopoietic progenitors (24) was used as a reference for cell type annotation. This reference was clustered using Louvain clustering, resulting in 13 clusters. LK + LSK samples were joined for each genotype (WT and CALR DEL HOM) and projected into the PCA space of this reference dataset. Nearest neighbors were calculated between the two datasets based on Euclidean distance in the top 50 PCA components. Cells were assigned to the same cluster to which the majority of their 15 nearest neighbors in the reference belonged.

A force-directed graph visualization of the 45,000 cell reference dataset was calculated by first constructing a k = 7 nearest-neighbor graph from the data, which was then used as input for the ForceAtlas2 algorithm as implemented in Gephi 0.9.1 (https://gephi.org). In the ForceAtlas2 algorithm, all cells are pushed away from each other, with the nearest-neighbor connections pulling them back together to segregate separate trajectories.

A fine-resolution clustering of the reference dataset was calculated using the Louvain algorithm, resulting in 63 clusters. These were used as input for a PAGA analysis of the reference dataset using the Scanpy Python Module with default parameters. The results of the PAGA analysis were visualized by using the nodes and their edge weights as input into the ForceAtlas2 algorithm for calculating force-directed graphs as implemented in Gephi 0.9.1. For visualization, only connections with edge weights of >0.3 were shown.

To visualize gene expression of the PAGA graph, the mean normalized expression of all cells belonging to each node was calculated and displayed on a per-node basis.

To calculate differential abundances, votes were given out from each WT LK and CALR LK cell to their k-nearest neighbors in the reference dataset, with k chosen such that the total number of votes given out by each sample was the same. For each cell in the reference dataset, the difference between the number of votes received from the WT and CALR HOM samples was calculated. This difference acts as a proxy for the differential abundance of WT and CALR HOM cells for the region of the LK landscape in which the reference cell is located. This differential abundance proxy could then be visualized either on the reference landscape itself or on the PAGA graph calculated using the reference landscape. In the latter case, each node of the PAGA graph was colored by the mean differential abundance of all cells belonging to that node.

After flow sorting, cells were cultured in StemSpan SFEM (serum-free expansion medium) (STEMCELL Technologies) supplemented with 10% FBS (STEMCELL Technologies), 1% penicillin/streptomycin (Sigma-Aldrich), 1% l-glutamine (Sigma-Aldrich), stem cell factor (SCF; 250 ng/ml), IL-3 (10 ng/ml), and IL-6 (10 ng/ml; STEMCELL Technologies), with or without thrombopoietin (100 ng/ml; STEMCELL Technologies), in round-bottom 96-well plates (Corning, Corning, USA). For pro-erythroid conditions, cells were cultured as above but with the following cytokines: SCF (250 ng/ml), THPO (thrombopoietin) (50 ng/ml), EPO (erythropoietin) (5 U/ml), IL-3 (20 ng/ml), and Flt3L (50 ng/ml). For pro-myeloid conditions, cells were cultured as above but with the following cytokines: SCF (250 ng/ml), THPO (50 ng/ml), granulocyte colony-stimulating factor (50 ng/ml), IL-3 (20 ng/ml), Flt3L (50 ng/ml), and GM-CSF (50 ng/ml).

At 1, 2, 3, 4, and, in some cases, 7 days after flow sorting, single cellderived clones were visually inspected. Wells with surviving cells were classified into one of four categories: (i) exactly one enlarged cell, presumed to be a megakaryocyte; (ii) multiple enlarged cells; (iii) mixed expansion, with both small and enlarged cells; and (iv) expansion with only small cells. In some cases, the experimenter was blinded to the identity of the cell population initially sorted into the well he/she was inspecting and the genotype of the mouse.

For immunofluorescence, cells were allowed to adhere to the surface of poly-l-lysinecoated slides for 30 min at 37C (Poly-Prep Slides, Sigma-Aldrich). Cells were then fixed with 4% paraformaldehyde (Sigma-Aldrich) in PBS overnight at 4C, permeabilized with 0.25% Triton X-100 (Sigma-Aldrich) in PBS for 10 min at room temperature, and blocked with 1% bovine serum albumin (Sigma-Aldrich) for 1 hour at room temperature. Cells were stained with CD41 Alexa Fluor 488 (BioLegend, catalog no. 133908) overnight and mounted with 4,6-diamidino-2-phenylindole (DAPI) (VECTASHIELD Mounting Medium with DAPI, Vector Laboratories Inc., Burlingame, USA; catalog no. H-1500). Pictures were acquired on LSM-710 and LSM-780 confocal microscopes (Zeiss) and analyzed using ZEN software (Zeiss). For quantification of immunofluorescence, cells were cultured on CD44-coated glass-bottom plates for immobilization (48), followed by fixation and staining as above. Pictures were acquired on a Leica DMI4000 microscope (Leica), and CD41 intensity and cell size were quantified using Fiji software.

FACS-sorted cells from VWF-GFP+ donors were injected into the tail veins of W41/W41 (CD45.1) recipient that had been sublethally irradiated with 1 400 centigrays with 250,000 spleen cells as helpers. Peripheral blood was analyzed 1, 2, 3, 4, and 16 weeks after transplant for all cohorts.

Differential expression analysis was performed between WT (LK + LSK) and CALR DEL HOM (LK + LSK) clusters using the Wilcoxon rank sum test on all genes that passed initial quality control (typically approximately 15,000). A Benjamini-Hochberg correction was applied to correct for multiple testing. Genes with an adjusted P value of <0.05 and a fold change of >1.5 between genotypes were marked as differentially expressed. The original normalized counts were used in all cases.

DEGs were studied using IPA (Qiagen). We imputed the whole transcriptome in IPA and then filtered for analysis only statistically significant (adjusted P < 0.01) items with a log2FC > 0.3785 or log2FC < 0.3785. Pathways and upstream regulator networks showing relationships and interactions experimentally confirmed between DEGs and others that functionally interact with them were generated and ranked in terms of significance of participating genes (P < 0.05) and activation status (z score).

Data were analyzed, and graphs were generated in Microsoft Excel (Microsoft) and GraphPad PRISM (GraphPad, La Jolla, USA). Data are presented as means SD. Unless otherwise stated, statistical tests were unpaired Students t tests. P values are as follows: *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.

Acknowledgments: We would like to acknowledge J. Aungier, T. Hamilton, D. Pask, and R. Sneade for invaluable technical assistance; R. Schulte, C. Cossetti, and G. Grondys-Kotarba at the CIMR Flow Cytometry Core Facility for assistance with cell sorting; and S. Loughran, T. Klampfl, and E. Laurenti for valuable discussions. Funding: Work in the Gttgens laboratory is supported by the Medical Research Council (MR/M008975/1), Wellcome (206328/Z/17/Z), Blood Cancer UK (18002), and Cancer Research UK (RG83389, jointly with A.R.G.). Work in the Green laboratory is supported by Wellcome (RG74909), WBH Foundation (RG91681), and Cancer Research UK (RG83389, jointly with B.G.). Author contributions: D.P. and H.J.P. designed and conducted experiments with assistance from J.L. S.W. and H.P.B. performed bioinformatic analyses. M.V. performed IPA with supervision from A.V.-P. A.G. provided DTA mice. D.P. analyzed data and wrote the manuscript with input from H.J.P. and J.L. and supervision from B.G. and A.R.G. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. We have deposited scRNAseq data in the NCBI Gene Expression Omnibus (GEO) database with accession number GSE160466. Additional data related to this paper may be requested from the authors.

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The stem/progenitor landscape is reshaped in a mouse model of essential thrombocythemia and causes excess megakaryocyte production - Science Advances

Bone Marrow Stem Cells Comments Off on The stem/progenitor landscape is reshaped in a mouse model of essential thrombocythemia and causes excess megakaryocyte production – Science Advances | November 26th, 2020

Severe infections like malaria cause short and long-term damage to precursor blood cells in mice, but some damage could be reversed, find researchers.

A team led by researchers from Imperial College London and The Francis Crick Institute have discovered that severe infections caused by malaria disrupt the processes that form blood cells in mice. This potentially causes long-term damage that could mean people who have recovered from severe infections are vulnerable to new infections or to developing blood cancers.

The team also discovered that the damage could be reduced or partially reversed in mice with a hormone treatment that regulates bone calcium coupled with an antioxidant. The research could lead to new ways of preventing long-term damage from severe infections including malaria, TB and COVID-19.

First author Dr Myriam Haltalli, who completed the work while at the Department of Life Sciences at Imperial, said: "We discovered that malaria infection reprograms the process of blood cell production in mice and significantly affects the function of precursor blood cells. These changes could cause long-term alterations, but we also found a way to significantly reduce the amount of damage and potentially rescue the healthy production of blood cells."

Unexpectedly fast changes

Blood is made up of several different cell types, that all originate as haematopoietic stem cells (HSCs) in the bone marrow. During severe infection, the production of all blood cells ramps up to help the body fight the infection, depleting the HSCs.

Now, the team has shown how infections also damage the bone marrow environment that is crucial for healthy HSC production and function. They discovered this using advanced microscopy technologies at Imperial and the Crick, RNA analyses led by the Gottgens group at Cambridge University, and mathematical modelling led by Professor Ken Duffy at Maynooth University.

The mice developed malaria naturally, following bites from mosquitoes carrying Plasmodium parasites, provided by Dr Andrew Blagborough at Cambridge University. The researchers subsequently observed the changes in the bone marrow environment and the effect on HSC function.

Within days of infection, blood vessels became leaky and there was a dramatic loss in bone-forming cells called osteoblasts. These changes appear strongly linked to the decline in the pool of HSCs during infection.

Lead author Professor Cristina Lo Celso, from the Department of Life Sciences at Imperial, said: "We were surprised at the speed of the changes, which was completely unexpected. We may think of bone as an impenetrable fortress, but the bone marrow environment is incredibly dynamic and susceptible to damage."

Reducing the pool of HSCs can have several consequences. In the short-term, it appears to particularly affect the production of neutrophils - white blood cells that form an essential part of the immune system. This can leave patients vulnerable to further infections, with potentially long-term consequences for the functioning of the immune system.

In the long term, the pool of HSCs may remain below normal levels, which can increase the chances of the patient developing blood cancers like leukaemia.

Mitigating the impacts

After determining in detail how severe infection affects the bone marrow environment and HSC function, the team tested a way to prevent the damage. Before infecting the mice, they treated them with a hormone that regulates bone calcium and an antioxidant to counter cellular oxidative stress, and then again after infection.

This process led to a tenfold increase in HSC function following infection compared to mice that received no treatment (around 20-40 per cent function compared to two percent function, respectively). Although this is not a complete recovery, the vast increase in function is a positive sign.

The team note that the requirement to start the hormone treatment before infection, combined with its expense and need to be refrigerated, make it unviable as a solution, especially in many parts of the world where severe infections like malaria and TB are prevalent.

However, they hope that proof that the impact of severe infection on HSC function can be significantly lessened will lead to the development of new treatments that can be widely administered.

Professor Lo Celso said: "The long-term impacts of COVID-19 infection are just starting to be known. The impact on HSC function appears similar across multiple severe infections, suggesting our work on malaria could shed light on the possible long-term consequences of COVID-19, and how we might mitigate them."

Dr Haltalli concluded: "Protecting HSC function while still developing strong immune responses is key for healthy ageing."

Reference: Haltalli MLR, Watcham S, Wilson NK, et al. Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection. Nat. Cell Biol. 2020:1-12. doi:10.1038/s41556-020-00601-w

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Severe Infections Wreak Havoc on Mouse Blood Cell Production - Technology Networks

Bone Marrow Stem Cells Comments Off on Severe Infections Wreak Havoc on Mouse Blood Cell Production – Technology Networks | November 26th, 2020

Hematopoietic stem cells are young or immature blood cells found to be living in bone marrow. These blood cells on mature in bone marrow and only a small number of these cells get to enter blood stream. These cells that enter blood stream are called as peripheral blood stems cells. Hematopoietic stem cells transplantation is replacement of absent, diseased or damaged hematopoietic stem cells due to chemotherapy or radiation, with healthy hematopoietic stem cells. Over last 30 years hematopoietic stem cells transplantation market seen rapid expansion and constant expansion with lifesaving technological advances. Hematopoietic stem cells transplantation is also known blood and marrow transplantation which brings about reestablishment of the patients immune and medullary function while treating varied range of about 70 hematological and non-hematological disorders. In general hematopoietic stem cells transplantation is used in treatment of hereditary, oncological, immunological and malignant and non-malignant hematological diseases.

There are two types of peripheral blood stem cell transplants mainly autologous and allogeneic transplantation. In autologous transplants patients own hematopoietic stem cells are harvested or removed before the high-dose treatment that might destroy the patients hematopoietic stem cells. While in allogeneic transplants stem cells are obtained from a tissue type of matched or mismatched donor. Hematopoietic stem cells are harvested from blood or bone marrow and is then frozen to use later. Depending upon the source of hematopoietic stem cells, worldwide there are three types of hematopoietic stem cells transplants namely bone marrow transplant (BMT), peripheral blood stem cell transplant and cord blood transplant. Major drivers in the hematopoietic stem cells transplantation market are establishment of strong and well developed network of hematopoietic stem cells transplantation organizations having global reach and presence has recognized NGO named Worldwide Network for Blood and Marrow Transplantation Group (WBMT) in official relation with World Health Organization (WHO) and rapid increase in number of transplants. Major restraints in hematopoietic stem cells transplantation market is high cost of transplantation and lack of funding for WBMT and other organizations such as regional, national and donor.

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The global market for Hematopoietic stem cells transplantation market is segmented on basis of transplant type, application, disease indication, end user and geography:

Based on transplantation type, hematopoietic stem cells transplantation market is segmented into allogeneic and autologous. Hematopoietic stem cells transplantation market is also segmented by application type into bone marrow transplant (BMT), peripheral blood stem cell transplant and cord blood transplant. The market for hematopoietic stem cells transplantation is majorly driven by bone marrow transplant (BMT) segment. Based on end user hematopoietic stem cells transplantation market is segmented into hospitals and specialty centers. Peripheral blood stem cell transplant type holds the largest market for hematopoietic stem cells transplantation. Hematopoietic stem cells transplantation market is further segmented by disease indication into three main categories i.e. lymphoproliferative disorders, leukemia, and non-malignant disorders. Segment lymphoproliferative disorder holds largest share amongst the three in Hematopoietic stem cells transplantation market. On the basis of regional presence, global hematopoietic stem cells transplantation market is segmented into five key regions viz. North America, Latin America, Europe, Asia Pacific, and Middle East & Africa. Europe leads the global hematopoietic stem cells transplantation market followed by U.S. due to easy technological applications, funding and high income populations. Other reasons for rise in hematopoietic stem cells transplantation market is high prevalence of lymphoproliferative disorders and leukemia; demand for better treatment options; and easy accessibility and acceptance of population to new technological advances. Transplantation rates in high income countries are increasing at a greater extent but continued rise is also seen in low income countries and expected to rise more. Hematopoietic stem cells transplantation market will have its potential in near future as being a perfect alternative to traditional system in many congenital and acquired hematopoietic disorders management. While India, China and Japan will be emerging as potential markets. An excellent and long term alternative to relief by side effects of chemotherapy, radiotherapy and immune-sensitive malignancies is another driver for hematopoietic stem cells transplantation market. The key players in global hematopoietic stem cells transplantation market are Lonza, Escape Therapeutics, Cesca Therapeutics Inc., Regen BioPharma, Inc., Invitrx Inc, StemGenex, Lion Biotechnologies, Inc., CellGenix GmbH, Actinium Pharmaceuticals, Inc., Pluristem, Kite Pharma, Novartis AG.

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Revenue from the Sales of Hematopoietic Stem Cells Transplantation Market to Witness Relatively Significant Growth During 2017 2025 - Canaan Mountain...

Bone Marrow Stem Cells Comments Off on Revenue from the Sales of Hematopoietic Stem Cells Transplantation Market to Witness Relatively Significant Growth During 2017 2025 – Canaan Mountain… | November 26th, 2020

SHANGHAI and HONG KONG, Nov. 25, 2020 /PRNewswire/ -- Antengene Corporation Limited ("Antengene", HKSE stock code: 6996.HK), a leading innovative biopharmaceutical company dedicated to discovering, developing and commercializing global first-in-class and/or best-inclass therapeutics in hematology and oncology, announced that the National Medical Products Administration (NMPA) has approved the clinical trial of ATG-016 (eltanexor) in patients with intermediate and higher risk myelodysplastic syndrome (MDS) according to the Revised International Prognostic Scoring System (IPSS-R) after the failure of hypomethylating agents (HMA) based therapy. The trial is a Phase I/II, single-arm, open-label clinical study, aiming to evaluate the pharmacokinetics, safety and efficacy of ATG-016 (eltanexor) monotherapy.

MDS is a heterogeneous group of clonal disorders of the bone marrow hematopoietic stem cells (HPSCs), characterized by ineffective hematopoiesis with peripheral blood cytopenia and a higher risk for developing acute myeloid leukemia (AML). Patients with high-risk MDS refractory to hypomethylating agents have a median overall survival (OS) of only 4 to 6 months with limited options for follow-up treatment. Pre-clinical studies have demonstrated that selective inhibitor of nuclear export (SINE) compounds are able to block the nuclear export of many tumor suppressor proteins (e.g. p53, IkB, p21) leading to their accumulation and activation in the nucleus thereby exerting anti-tumor effects. In addition, SINE compounds can also reduce the nuclear export and translation of many oncogenic mRNA (c-Myc, Bcl-2, Bcl-6, cyclin D) which are bound to elF4E and result in selective apoptosis of tumor cells. ATG-016 is a member of the latest-generation of SINE compounds. Compared to the first-generation nuclear export inhibitor, ATG-016 demonstrates minimal blood-brain barrier permeability and a broader therapeutic window. It has shown preliminary anti-cancer activity in high-risk MDS patients.

Dr. Jay Mei, the Founder, Chairman and CEO of Antengene expressed, "The approval of the ATG-016 clinical trial demonstrates the efficient execution of the Antengene R&D team and is also the first clinical trial approval obtained by Antengene in mainland China after its listing." He also mentioned, "Selinexor, the first-generation selective inhibitor of nuclear export, has shown extensive activity against hematological malignancies and solid tumors, and has been approved by the FDA for relapsed/refractory multiple myeloma and diffuse large B-cell lymphoma. As a second-generation orally available SINE compound, ATG-016 can reduce the blood-brain barrier penetration, thereby representing a broader therapeutic window with potentially less adverse events and better drug tolerability."

About ATG-016

ATG-016 (eltanexor) is a second-generation selective inhibitor of nuclear export compound. Compared to the first-generation SINE compound, ATG-016 has lower blood-brain barrier penetration and broader therapeutic window which allows more frequent dosing and a longer period of exposure at higher levels with better tolerability. Therefore, ATG-016 may be used to target a wider range of indications. We plan to conduct phase I/II clinical studies for MDS in China, and plan to further develop ATG-016 for cancers with high prevalence in the Asia-Pacific region (such as KRAS-mutant solid tumors) and virus infection related malignancies (such as nasopharyngeal carcinoma).

About Antengene

Antengene Corporation Limited ("Antengene", SEHK: 6996.HK) is a leading clinical-stage Asia-Pacific biopharmaceutical company focused on innovative oncology medicines. Antengene aims to provide the most advanced anti-cancer drugs to patients in China, the Asia Pacific Region and around the world. Since its establishment, Antengene has built a pipeline of 12 clinical and pre-clinical stage assets, obtained 10 investigational new drug (IND) approvals and has 9 ongoing cross-regional clinical trials in Asia Pacific. At Antengene, we focus on developing drug candidates with novel mechanisms of action (MoAs) and first-in-class/best-in-class potential to address significant unmet medical needs. The vision of Antengene is to "Treat Patients Beyond Borders" through research, development and commercialization of first-in-class/best-in-class therapeutics.

Forward-looking statements

The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, we undertake no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development.

SOURCE Antengene Corporation Limited

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Approval of Phase I/II Clinical Trial of ATG-016 (Eltanexor), a Second Generation Selective Inhibitor of Nuclear Export (SINE), in Mainland China for...

Bone Marrow Stem Cells Comments Off on Approval of Phase I/II Clinical Trial of ATG-016 (Eltanexor), a Second Generation Selective Inhibitor of Nuclear Export (SINE), in Mainland China for… | November 26th, 2020

Orthopedic Regenerative Medicine Market

Coherent Market Insights, 26-11-2020: The research report on the Orthopedic Regenerative Medicine Market is a deep analysis of the market. This is a latest report, covering the current COVID-19 impact on the market. The pandemic of Coronavirus (COVID-19) has affected every aspect of life globally. This has brought along several changes in market conditions. The rapidly changing market scenario and initial and future assessment of the impact is covered in the report. Experts have studied the historical data and compared it with the changing market situations. The report covers all the necessary information required by new entrants as well as the existing players to gain deeper insight.

Furthermore, the statistical survey in the report focuses on product specifications, costs, production capacities, marketing channels, and market players. Upstream raw materials, downstream demand analysis, and a list of end-user industries have been studied systematically, along with the suppliers in this market. The product flow and distribution channel have also been presented in this research report.

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The segments and sub-section of Orthopedic Regenerative Medicine market are shown below:

By Procedure Cell TherapyTissue EngineeringBy Cell TypeInduced Pluripotent Stem Cells (iPSCs)Adult Stem CellsTissue Specific Progenitor Stem Cells (TSPSCs),Mesenchymal Stem Cells (MSCs)Umbilical Cord Stem Cells (UCSCs)Bone Marrow Stem Cells (BMSCs)By SourceBone MarrowUmbilical Cord BloodAdipose TissueAllograftsAmniotic FluidBy ApplicationsTendons RepairCartilage RepairBone RepairLigament RepairSpine RepairOthers

Some of the key players/Manufacturers involved in the Orthopedic Regenerative Medicine Market are Curasan, Inc., Carmell Therapeutics Corporation, Anika Therapeutics, Inc., Conatus Pharmaceuticals Inc., Histogen Inc., Royal Biologics, Ortho Regenerative Technologies, Inc., Swiss Biomed Orthopaedics AG, Osiris Therapeutics, Inc., and Octane Medical Inc.

If opting for the Global version of Orthopedic Regenerative Medicine Market analysis is provided for major regions as follows:

North America (The US, Canada, and Mexico)

Europe (the UK, Germany, France, and Rest of Europe)

Asia Pacific (China, India, and Rest of Asia Pacific)

Latin America (Brazil and Rest of Latin America)

Middle East & Africa (Saudi Arabia, the UAE, South Africa, and Rest of Middle East & Africa)

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The Orthopedic Regenerative Medicine Market Report Consists of the Following Points:

The report consists of an overall prospect of the market that helps gain significant insights about the global market.

The market has been categorized based on types, applications, and regions. For an in-depth analysis and better understanding of the market, the key segments have been further categorized into sub-segments.

The factors responsible for the growth of the market have been mentioned. This data has been gathered from primary and secondary sources by industry professionals. This provides an in-depth understanding of key segments and their future prospects.

The report analyses the latest developments and the profiles of the leading competitors in the market.

The Orthopedic Regenerative Medicine Market research report offers an eight-year forecast.

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Impact of COVID 19 on Orthopedic Regenerative Medicine Market Detailed Research Study 2020-2027 | Curasan, Inc., Carmell Therapeutics Corporation,...

Bone Marrow Stem Cells Comments Off on Impact of COVID 19 on Orthopedic Regenerative Medicine Market Detailed Research Study 2020-2027 | Curasan, Inc., Carmell Therapeutics Corporation,… | November 26th, 2020

New York, Nov. 25, 2020 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Induced Pluripotent Stem Cell (iPSC) Industry" - https://www.reportlinker.com/p05798831/?utm_source=GNW 4 billion by the year 2027, trailing a post COVID-19 CAGR of 6.6%, over the analysis period 2020 through 2027. Stem cells are undifferentiated cells that hold the capability to divide, and differentiate into specialized cells in the body. Stem cells act as repair system and replenish adult tissues, maintaining the turnover of regenerative organs such as the blood and skin. In organs, such as the bone marrow, stem cells frequently form replacement cells to repair the worn out tissue. These cells can respond to signals from the body and transverse a particular developmental pathway to differentiate into one specific cell type. Due to their regenerative properties, stem cells are being researched for therapeutic applications in diabetes, cardiovascular disease, neurodegenerative disease, cancer, autoimmune diseases, spinal cord defects, among others. Stem Cell research is an exciting field where continuous discoveries are being made on new sources of stem cells and new methods of their acquisition and harvesting. Of late, adult stem cells have garnered a lions share of the stem cell space, purely based on the fact that they require less expensive clinical trials, need to comply with fewer regulatory norms and ethical issues compared to other stem cell variants such as embryonic stem cells.

Researchers around the world have been focusing research activities to develop adult stem cell therapies in order to combat a variety of diseases ranging from diabetes to heart disease. Factually, adult stem cells are the only stem cells that have been approved for use in transplants for the treatment of diseases such as cancer. Interestingly, with drug development based on embryonic stem cells being challenged amid growing debate over ethics and regulation of this research, iPSCS offers an alternate step forward in the commercialization of stem cell therapies and regenerative medicine. Embryonic stem cell research continues to remain embroiled in ethical, religious, and political controversies across various countries around the world. Induced Pluripotent Stem Cells (iPSs), which are reprogrammed to mimic embryonic stem cell-like state allowing expression of genes and human cells needed for therapeutic purposes, offers an attractive alternate way forwarding in furthering the goals of stem cell research. Pioneered in 2006 and developed in the following year, these cells are created by conversion of somatic cells into PSCs by introducing certain genes including Myc, Klf4, Oct3/4 and Sox2.

Pluripotent stem cells hold tremendous potential in the regenerative medicine arena. Based on their ability to proliferate indefinitely and develop into desirable cell type such as heart, liver, neuronal and pancreatic cells, iPSCs offer a source of new cells that can replace lost or damaged cells. For instance, iPSCs can be developed into beta islet cells, blood cells or neuronal cells for the treatment of diabetes, leukemia and neurological disorders, respectively. Parkinsons, Alzheimers & spinal cord injuries are key neurologic diseases expected to benefit from iPS research. Dramatic rise in cancer cases worldwide and the need for novel anti-cancer therapies will emerge as a key driver for the growth of iPSCs. Interest in cancer research soars high on new hopes of direct reprogramming of cancer cells with enforced expression of pluripotency factors and the resulting dedifferentiation of transformed cancer cells. The ongoing pandemic is also opening up new opportunities for Human induced pluripotent stem cells (hiPSCs) by offering a reliable model for researchers involved in studying how coronavirus indirectly or directly affects different cells in the human body. Made from a small sample of blood or skin cells, hiPSCs are robust stem cells that can be developed into any cell type and then infected with the coronavirus in order to analyse the disease prognosis and the resulting effects. By deploying hiPSCs, researchers have identified that stem cell-derived cardiomyocytes (heart muscle cells) and blood vessels remain directly exposed to COVID-19 infection. Scientists identified that a significant portion of stem cell-derived cardiomyocytes ceased beating and expired within 3 days after being infected by coronavirus. Researchers can leverage the infected cardiomyocytes to screen for potential drug candidates that can restore their function and improve their survival; and also for identifying new antiviral drugs that potentially curtail coronavirus replication in the heart, reduce cardiac injury and curb the disease prognosis. Researchers can also utilize the infected cardiomyocytes to analyze COVID-induced myocarditis through addition of immune cells to their lab experiments.

Competitors identified in this market include, among others,

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I. INTRODUCTION, METHODOLOGY & REPORT SCOPE I-1

II. EXECUTIVE SUMMARY II-1

1. MARKET OVERVIEW II-1 Impact of Covid-19 and a Looming Global Recession II-1 Induced Pluripotent Stem Cells (iPSCs) Market Gains from Increasing Use in Research for COVID-19 II-1 Studies Employing iPSCs in COVID-19 Research II-2 Stem Cells, Application Areas, and the Different Types: A Prelude II-3 Applications of Stem Cells II-4 Types of Stem Cells II-4 Induced Pluripotent Stem Cell (iPSC): An Introduction II-5 Production of iPSCs II-6 First & Second Generation Mouse iPSCs II-6 Human iPSCs II-7 Key Properties of iPSCs II-7 Transcription Factors Involved in Generation of iPSCs II-7 Noteworthy Research & Application Areas for iPSCs II-8 Induced Pluripotent Stem Cell ((iPSC) Market: Growth Prospects and Outlook II-9 Drug Development Application to Witness Considerable Growth II-11 Technical Breakthroughs, Advances & Clinical Trials to Spur Growth of iPSC Market II-11 North America Dominates Global iPSC Market II-12 Competition II-12 Recent Market Activity II-13 Select Innovation/Advancement II-16

2. FOCUS ON SELECT PLAYERS II-17 Axol Bioscience Ltd. (UK) II-17 Cynata Therapeutics Limited (Australia) II-17 Evotec SE (Germany) II-17 Fate Therapeutics, Inc. (USA) II-17 FUJIFILM Cellular Dynamics, Inc. (USA) II-18 Ncardia (Belgium) II-18 Pluricell Biotech (Brazil) II-18 REPROCELL USA, Inc. (USA) II-18 Sumitomo Dainippon Pharma Co., Ltd. (Japan) II-19 Takara Bio, Inc. (Japan) II-19 Thermo Fisher Scientific, Inc. (USA) II-20 ViaCyte, Inc. (USA) II-20

3. MARKET TRENDS & DRIVERS II-21 Effective Research Programs Hold Key in Roll Out of Advanced iPSC Treatments II-21 Induced Pluripotent Stem Cells: A Giant Leap in the Therapeutic Applications II-21 Research Trends in Induced Pluripotent Stem Cell Space II-22 Exhibit 1: Worldwide Publication of hESC and hiPSC Research Papers for the Period 2008-2010, 2011-2013 and 2014-2016 II-22 Exhibit 2: Number of Original Research Papers on hESC and iPSC Published Worldwide (2014-2016) II-23 Concerns Related to Embryonic Stem Cells Shift the Focus onto iPSCs II-23 Regenerative Medicine: A Promising Application of iPSCs II-24 Induced Pluripotent: A Potential Competitor to hESCs? II-25 Exhibit 3: Global Regenerative Medicine Market Size in US$ Billion for 2019, 2021, 2023 and 2025 II-27 Exhibit 4: Global Stem Cell & Regenerative Medicine Market by Product (in %) for the Year 2019 II-27 Exhibit 5: Global Regenerative Medicines Market by Category: Breakdown (in %) for Biomaterials, Stem Cell Therapies and Tissue Engineering for 2019 II-28 Pluripotent Stem Cells Hold Significance for Cardiovascular Regenerative Medicine II-28 Exhibit 6: Leading Causes of Mortality Worldwide: Number of Deaths in Millions & % Share of Deaths by Cause for 2017 II-30 Leading Causes of Mortality for Low-Income and High-Income Countries II-30 Growing Importance of iPSCs in Personalized Drug Discovery II-31 Persistent Advancements in Genetics Space and Subsequent Growth in Precision Medicine Augur Well for iPSCs Market II-33 Exhibit 7: Global Precision Medicine Market (In US$ Billion) for the Years 2018, 2021 & 2024 II-34 Increasing Prevalence of Chronic Disorders Supports Growth of iPSCs Market II-34 Exhibit 8: Worldwide Cancer Incidence: Number of New Cancer Cases Diagnosed for 2012, 2018 & 2040 II-35 Exhibit 9: Number of New Cancer Cases Reported (in Thousands) by Cancer Type: 2018 II-36 Exhibit 10: Fatalities by Heart Conditions: Estimated Percentage Breakdown for Cardiovascular Disease, Ischemic Heart Disease, Stroke, and Others II-37 Exhibit 11: Rising Diabetes Prevalence Presents Opportunity for iPSCs Market: Number of Adults (20-79) with Diabetes (in Millions) by Region for 2017 and 2045 II-38 Aging Demographics Add to the Global Burden of Chronic Diseases, Presenting Opportunities for iPSCs Market II-38 Exhibit 12: Expanding Elderly Population Worldwide: Breakdown of Number of People Aged 65+ Years in Million by Geographic Region for the Years 2019 and 2030 II-39 Growth in Number of Genomics Projects Propels Market Growth II-39 Genomic Initiatives in Select Countries II-40 Exhibit 13: New Gene-Editing Tools Spur Interest and Investments in Genetics, Driving Lucrative Growth Opportunities for iPSCs: Total VC Funding (In US$ Million) in Genetics for the Years 2014, 2015, 2016, 2017 and 2018 II-41 Launch of Numerous iPSCs-Related Clinical Trials Set to Benefit Market Growth II-41 Exhibit 14: Number of Induced Pluripotent Stem Cells based Studies by Select Condition: As on Oct 31, 2020 II-43 iPSCs-based Clinical Trial for Heart Diseases II-43 Induced Pluripotent Stem Cells for Stroke Treatment II-44 ?Off-the-shelf? Stem Cell Treatment for Cancer Enters Clinical Trial II-44 iPSCs for Hematological Disorders II-44 Market Benefits from Growing Funding for iPSCs-Related R&D Initiatives II-44 Exhibit 15: Stem Cell Research Funding in the US (in US$ Million) for the Years 2016 through 2021 II-46 Human iPSC Banks: A Review of Emerging Opportunities and Drawbacks II-46 Human iPSC Banks Worldwide: An Overview II-48 Cell Sources and Reprogramming Methods Used by Select iPSC Banks II-49 Innovations, Research Studies & Advancements in iPSCs II-50 Key iPSC Research Breakthroughs for Regenerative Medicine II-50 Researchers Develop Novel Oncogene-Free and Virus-Free iPSC Production Method II-51 Scientists Study Concerns of Genetic Mutations in iPSCs II-52 iPSCs Hold Tremendous Potential in Transforming Research Efforts II-52 Researchers Highlight Potential Use of iPSCs for Developing Novel Cancer Vaccines II-54 Scientists Use Machine Learning to Improve Reliability of iPSC Self-Organization II-54 STEMCELL Technologies Unveils mTeSR? Plus II-55 Challenges and Risks Related to Pluripotent Stem Cells II-56 A Glance at Issues Related to Reprogramming of Adult Cells to iPSCs II-57 A Note on Legal, Social and Ethical Considerations with iPSCs II-58

4. GLOBAL MARKET PERSPECTIVE II-59 Table 1: World Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-59

Table 2: World 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets for Years 2020 & 2027 II-60

Table 3: World Current & Future Analysis for Vascular Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-61

Table 4: World 7-Year Perspective for Vascular Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-62

Table 5: World Current & Future Analysis for Cardiac Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-63

Table 6: World 7-Year Perspective for Cardiac Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-64

Table 7: World Current & Future Analysis for Neuronal Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-65

Table 8: World 7-Year Perspective for Neuronal Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-66

Table 9: World Current & Future Analysis for Liver Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-67

Table 10: World 7-Year Perspective for Liver Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-68

Table 11: World Current & Future Analysis for Immune Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-69

Table 12: World 7-Year Perspective for Immune Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-70

Table 13: World Current & Future Analysis for Other Cell Types by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-71

Table 14: World 7-Year Perspective for Other Cell Types by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-72

Table 15: World Current & Future Analysis for Cellular Reprogramming by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-73

Table 16: World 7-Year Perspective for Cellular Reprogramming by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-74

Table 17: World Current & Future Analysis for Cell Culture by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-75

Table 18: World 7-Year Perspective for Cell Culture by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-76

Table 19: World Current & Future Analysis for Cell Differentiation by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-77

Table 20: World 7-Year Perspective for Cell Differentiation by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-78

Table 21: World Current & Future Analysis for Cell Analysis by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-79

Table 22: World 7-Year Perspective for Cell Analysis by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-80

Table 23: World Current & Future Analysis for Cellular Engineering by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-81

Table 24: World 7-Year Perspective for Cellular Engineering by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-82

Table 25: World Current & Future Analysis for Other Research Methods by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-83

Table 26: World 7-Year Perspective for Other Research Methods by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-84

Table 27: World Current & Future Analysis for Drug Development & Toxicology Testing by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-85

Table 28: World 7-Year Perspective for Drug Development & Toxicology Testing by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-86

Table 29: World Current & Future Analysis for Academic Research by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-87

Table 30: World 7-Year Perspective for Academic Research by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-88

Table 31: World Current & Future Analysis for Regenerative Medicine by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-89

Table 32: World 7-Year Perspective for Regenerative Medicine by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-90

Table 33: World Current & Future Analysis for Other Applications by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-91

Table 34: World 7-Year Perspective for Other Applications by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027 II-92

III. MARKET ANALYSIS III-1

GEOGRAPHIC MARKET ANALYSIS III-1

UNITED STATES III-1 Table 35: USA Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-1

Table 36: USA 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-2

Table 37: USA Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-3

Table 38: USA 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027 III-4

Table 39: USA Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-5

Table 40: USA 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027 III-6

CANADA III-7 Table 41: Canada Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-7

Table 42: Canada 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-8

Table 43: Canada Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-9

Table 44: Canada 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027 III-10

Table 45: Canada Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-11

Table 46: Canada 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027 III-12

JAPAN III-13 Table 47: Japan Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-13

Table 48: Japan 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-14

Table 49: Japan Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-15

Table 50: Japan 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027 III-16

Table 51: Japan Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-17

Table 52: Japan 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027 III-18

CHINA III-19 Table 53: China Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-19

Table 54: China 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-20

Table 55: China Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-21

Table 56: China 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027 III-22

Table 57: China Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-23

Table 58: China 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027 III-24

EUROPE III-25 Table 59: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - France, Germany, Italy, UK and Rest of Europe Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 III-25

Table 60: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - Percentage Breakdown of Value Sales for France, Germany, Italy, UK and Rest of Europe Markets for Years 2020 & 2027 III-26

Table 61: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-27

Table 62: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-28

Table 63: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-29

Table 64: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027 III-30

Table 65: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-31

Table 66: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027 III-32

FRANCE III-33 Table 67: France Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-33

Table 68: France 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-34

Table 69: France Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-35

Table 70: France 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027 III-36

Table 71: France Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-37

Table 72: France 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027 III-38

GERMANY III-39 Table 73: Germany Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-39

Table 74: Germany 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027 III-40

Table 75: Germany Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-41

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Growing Value of Stem Cells in Medicine to Create a US$2,4 Billion Opportunity for Induced Pluripotent Stem Cell ((iPSC) - GlobeNewswire

Cardiac Stem Cells Comments Off on Growing Value of Stem Cells in Medicine to Create a US$2,4 Billion Opportunity for Induced Pluripotent Stem Cell ((iPSC) – GlobeNewswire | November 26th, 2020