Archive for the ‘Bone Marrow Stem Cells’ Category

This article was originally published here

J Vasc Interv Radiol. 2020 Nov 25:S1051-0443(20)30769-7. doi: 10.1016/j.jvir.2020.09.003. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate safety and efficacy of angiogenesis induced by intraarterial autologous bone marrow-derived stem cell (BMSC) injection in patients with severe peripheral arterial disease (PAD).

MATERIALS AND METHODS: Eighty-one patients with severe PAD (77 men), including 56 with critical limb ischemia (CLI) and 25 with severe claudication, were randomized to receive sham injection (group A) or intraarterial BMSC injection at the site of occlusion (group B). Primary endpoints included improvement in ankle-brachial index (ABI) of > 0.1 and transcutaneous pressure of oxygen (TcPO2) of > 15% at mid- and lower foot at 6 mo. Secondary endpoints included relief from rest pain, > 30% reduction in ulcer size, and reduction in major amputation in patients with CLI and > 50% improvement in pain-free walking distance in patients with severe claudication.

RESULTS: Technical success was achieved in all patients, without complications. At 6 mo, group B showed more improvements in ABI of > 0.1 (35 of 41 [85.37%] vs 13 of 40 [32.50%]; P < .0001) and TcPO2 of > 15% at the midfoot (35 of 41 [85.37%] vs 17 of 40 [42.50%]; P = .0001] and lower foot (37 of 41 [90.24%] vs 19 of 40 [47.50%]; P < .0001). No patients with CLI underwent major amputation in group B, compared with 4 in group A (P = .0390). No significant difference was observed in relief from rest pain or > 30% reduction in ulcer size among patients with CLI or in > 50% improvement in pain-free walking distance among patients with severe claudication.

CONCLUSIONS: Intraarterial delivery of autologous BMSCs is safe and effective in the management of severe PAD.

PMID:33248918 | DOI:10.1016/j.jvir.2020.09.003

Original post:
Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Safety and Therapeutic Efficacy of Angiogenesis Induced by Intraarterial Autologous...

There are 206 bones in the human body ranging in size from the tiniest, found in your ear, to the largest, in your thigh.

We have just one heart roughly the size of your fist in our chest and continuously pumping about eight pints of blood.

206 bones and only one heart. But how are the two connected? Does the quality of your bones affect your heart?

BHF-funded researcher Dr Zahra Raisi-Estabragh and her team at Queen Mary University of London recently discovered that poor bone quality is in fact linked to poor heart health.

In this study, they used the UK Biobank the world's largest biomedical database to study the link between osteoporosis and cardiovascular health. Osteoporosis affects over 3 million people in the UK and results in brittle and weak bones that are more likely to break.

We know that osteoporosis and heart disease share a number of risk factors such as increasing age, a sedentary lifestyle, and smoking but are these risk factors all they share? Is there something we havent uncovered yet? This is what Dr Raisi-Estabragh and the team of researchers set out to find.

They discovered that lower bone density (the amount of bone mineral in bone tissue) is linked to stiffer arteries (a sign of poor heart health). They also found that people with poor bone quality have a higher risk of dying from coronary heart disease when the arteries supplying the heart with blood get clogged up with fatty deposits.

With this wealth of information available, the next step will be to identify more of the factors that leave people at high risk of each disease and inform public health policy aimed at improving both bone and heart health.

At the University of Manchester, BHF-funded researcher Dr John Bowes is looking at why coronary heart disease is more common in people with rheumatoid arthritis. Rheumatoid arthritis is an autoimmune disease when your immune system (which usually fights infection) attacks the cells that line your joints by mistake, making the joints swollen, stiff and painful. Over time, this can damage the joints, cartilage and nearby bone.

We know that coronary heart disease causes around half of the early deaths of people with rheumatoid arthritis. Unfortunately, however, there is no effective method to measure the risk of heart disease in people with arthritis, because the risk factors are different in these people. In fact, screening tools based on the usual risk factors (such as high blood pressure, high cholesterol, smoking) are not reliable in predicting the risk of heart disease in people with arthritis.

In comes Dr John Bowes and his team their aim is to create a tool that does just that. First, they will use genetic data and statistical analyses to understand why these two diseases frequently occur together. Based on these results, an accurate tool to identify which people with rheumatoid arthritis are most at risk of coronary heart disease could then be developed.

Your heart is a remarkable organ. It beats about 60 to 100 times every minute, pumping blood and oxygen all around your body with each heartbeat. But theres more to it than that. Your heart also produces a small number of hormones chemical messengers released into the blood and carried to target organs.

BHF-funded researcher Professor Svetlana Reilly and her team at the University of Oxford have recently discovered a new heart hormone calcitonin previously thought to only be produced by the thyroid gland. Published in Nature, the research revealed that cells in the atria (the top chambers of the heart) produce more calcitonin than cells in the thyroid.

It has long been known that calcitonins role in our bodies is to help regulate bone density. However, the Oxford researchers found that calcitonin also plays an important role in reducing atrial scarring. Scarring disrupts the electrical impulses travelling through the atria, which in turn causes the heart to beat in an irregular manner this is known as atrial fibrillation(AF). People with AF may experience dizziness, palpitations, shortness of breath, and tiredness. They are also more at risk of having a stroke.

Around 1.4 million people in the UK have been diagnosed with AF. For most people, this is a shock and emotionally challenging but new research brings new hope. Professor Reilly and her team are making great strides in this area and are hopeful that this bone and heart hormone could lead to new therapies to control or prevent this potentially devastating condition.

Another extraordinary part of the human body is bone marrow the spongy tissue deep inside some of your bones, such as your hip and thigh bones. Bone marrow is essential in repairing tissue damage because it contains stem cells, which can turn into any type of cell in the body, including blood cells.

At the University of Bristol, BHF-funded researcher Professor Paolo Madeddu is studying how diabetescauses damage to bone marrow. We know that diabetes can gradually damage blood vessels, which increases the risk of heart and circulatory diseases. This blood vessel damage impairs blood flow to bone marrow, which in turn decreases the amount of stem cells produced by bone marrow and with it the bodys ability to repair itself.

Using powerful microscopes and scanning machines, the researchers are now investigating the blood circulatory system of bone marrow in around 150 people with diabetes. They hope to find new ways to protect cells in the bone marrow from the damage caused by diabetes.

Maintaining healthy blood vessels and normal bone marrow function is important for people with diabetes, as this could help prevent heart and circulatory diseases in these people diseases which still kill one in four in the UK, and still cause heartbreak in every family.

Help us power our life saving research

We can all agree that 2020 has been a year like no other, but the fact that there are researchers out there using a Nobel Prize-winning discovery to help us beat heartbreak forever to help us live in a world free from the fear of heart and circulatory diseases is exactly what we all needed to know right now.

Read more BHF research blogs

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How are bones and the heart connected? - British Heart Foundation

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

Report covers a detailed analysis of the Hematopoietic Stem Cell Transplantation (HSCT) Market in the estimated forecast period. It analyses and determines the effect of the external factors which are impacting the revenues and the growth of the market in the estimated forecast period. In addition, with the emergence of the global pandemic, the effect of COVID-19 is also analyzed in the report. Based on the type and applications, introduction of new products and research involved in the development of new products is one of the major aspects which is likely to have an impact on the Hematopoietic Stem Cell Transplantation (HSCT) Market. Similarly, the impact of the COVID-19 on the manufacturing and the effect of the demand for these products is also one of the major aspects which are likely to have an impact on the growth of the market in the estimated forecasts period.

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The comprehensive list ofKey Market Playersalong with their market overview, product protocol, key highlights, key financial issues, SWOT analysis, and business strategies:Regen Biopharma IncChina Cord Blood CorpCBR Systems IncEscape Therapeutics IncCryo-Save AGLonza Group LtdPluristem Therapeutics IncViaCord Inc

The following points are involved along with an in-depth study of each point for Hematopoietic Stem Cell Transplantation (HSCT) Market:

Manufacture Analysis Manufacture of the Hematopoietic Stem Cell Transplantation (HSCT) is analyzed with respect to different applications, types and regions.

Resource and Consumption In extension with sales, this segment studies Resource and consumption for the Hematopoietic Stem Cell Transplantation (HSCT) Market. Import export data is also provided by region if applicable.

Additionally, we provide customized report as per our clients requirement.

Historical year: 2015-2019Base year: 2019Forecast period: 2020-2027

Focus on segments and sub-section of the Market are illuminated below:

Geographical Analysis: United States, Europe, China, Japan, Southeast Asia & India, Rest of World etc.

Type Analysis:AllogeneicAutologous

Application Analysis:Peripheral Blood Stem Cells Transplant (PBSCT)Bone Marrow Transplant (BMT)Cord Blood Transplant (CBT)

Each and every segment has been detailed in the report with its market share, revenue, basic data, and highest growing segment globally.

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Global Hematopoietic Stem Cell Transplantation (HSCT) Competitive Analysis:

The key players are aiming innovation to increase efficiency and product life. The long-term growth opportunities available in the sector are captured by ensuring constant process improvements and economic flexibility to spend in the optimal schemes. Company profile section of top players includes its basic information like company legal name, website, headquarters, subsidiaries, its market position, history and 5 closest competitors by Market capitalization / revenue along with contact information.

Industrial Dynamics:

Hematopoietic Stem Cell Transplantation (HSCT) Market Report concentrates on market dynamics which give holistically view on driving factors mainly impacting on growth of Hematopoietic Stem Cell Transplantation (HSCT) market. It also includes restraints that have negative impact along with lucrative opportunities in near future so that readers get an idea about the profitability of market. It also gives complete information about the market scenario due to attack of corona virus. Thus, it also provides threats to the market.

This report is very useful for the new entrants as it offers them with the idea about the different approaches towards the market and the impact of COVID-19.

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Global Hematopoietic Stem Cell Transplantation (HSCT) Market 2020 Impact of COVID-19, Future Growth Analysis and Challenges | Regen Biopharma Inc,...

(TNS) - 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 don't 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 Children's Hospital at Stanford, where 120 patients were enrolled in the trial. "It didn't 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 aren't 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.

"There's enough promising evidence that it helps people early in the infection," Subramanian said. "What we don't 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, doesn't mean another one won't 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 body's 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 company's 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 body's 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 it's administered orally, according to Kaiser's 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.

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

See original here:
Coronavirus Updates: The Latest Treatments and Vaccines - GovTech

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The Report Segments for Hematopoietic Stem Cell Transplantation (HSCT) Market Analysis & Forecast 20192025 are as:Global Hematopoietic Stem Cell Transplantation (HSCT) Market, by ProductsAllogeneicAutologous

Global Hematopoietic Stem Cell Transplantation (HSCT) Market, by ApplicationsPeripheral Blood Stem Cells Transplant (PBSCT)Bone Marrow Transplant (BMT)Cord Blood Transplant (CBT)

The Major Players Reported in the Market Include:Regen Biopharma IncChina Cord Blood CorpCBR Systems IncEscape Therapeutics IncCryo-Save AGLonza Group LtdPluristem Therapeutics IncViaCord Inc

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Hematopoietic Stem Cell Transplantation (HSCT) Market To Witness Huge Growth By 2027 | Regen Biopharma Inc, China Cord Blood Corp, CBR Systems Inc,...

Bone marrow aspiration and trephine biopsy are usually performed on the back of the hipbone, or posterior iliac crest. An aspirate can also be obtained from the sternum (breastbone). For the sternal aspirate, the patient lies on their back, with a pillow under the shoulder to raise the chest. A trephine biopsy should never be performed on the sternum, due to the risk of injury to blood vessels, lungs or the heart.

The need to selectively isolate and concentrate selective cells, such as mononuclear cells, allogeneic cancer cells, T cells and others, is driving the market. Over 30,000 bone marrow transplants occur every year. The explosive growth of stem cells therapies represents the largest growth opportunity for bone marrow processing systems.

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Europe and North America spearheaded the market as of 2018, by contributing over 74.0% to the overall revenue. Majority of stem cell transplants are conducted in Europe, and it is one of the major factors contributing to the lucrative share in the cell harvesting system market.

In 2018, North America dominated the research landscape as more than 54.0% of stem cell clinical trials were conducted in this region. The region also accounts for the second largest number of stem cell transplantation, which is further driving the demand for harvesting in the region.

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Asia Pacific is anticipated to witness lucrative growth over the forecast period, owing to rising incidence of chronic diseases and increasing demand for stem cell transplantation along with stem cell-based therapy. Japan and China are the biggest markets for harvesting systems in Asia Pacific. Emerging countries such as Mexico, South Korea, and South Africa are also expected to report lucrative growth over the forecast period. Growing investment by government bodies on stem cell-based research and increase in aging population can be attributed to the increasing demand for these therapies in these countries.

Major players operating in the global bone marrow processing systems market are ThermoGenesis (Cesca Therapeutics inc.), RegenMed Systems Inc., MK Alliance Inc., Fresenius Kabi AG, Harvest Technologies (Terumo BCT), Arthrex, Inc. and others.

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Bone Marrow Processing Systems Market Top Participant to Focus on Regional Expansion - Murphy's Hockey Law

Brilliant news as Keisha announces daughter Aurora is back in remission Photo Keisha Pile-Gray

Amazing news has been announced today (November 30) nine-year-old Aurora Pile-Gray from Westbrook is in remission.

Aurora was diagnosed with stage 4 Burkitts Lymphoma after becoming poorly towards the end of April.

The rare cancer affects blood and bone marrow. Aurora has been undergoing chemotherapy and her family were looking at CAR-T cell therapy and an allogeneic transplant.

Earlier this year, after 4 gruelling cycles of intensive chemo, Aurora had been given the news that she was in remission, however this was short lived.

In October the family were told the cancer had in fact spread to Auroras bones and that the youngster was in need of a bone marrow transplant. The situation was also complicated by Auroras mixed ethnicity, making it that much more difficult to find a match.

Aurora is currently being treated by Royal Marsden Hospital and Great Ormond Street Hospital.

But in brilliant news Auroras mum Keisha has today revealed her daughter is now in remission.

Posting to facebook Keisha said: Aurora is officially back in remission!!

Her bone marrow assessments show no cancer cells present, and no cancer cell regeneration on new cells in both the solid and liquid part of her biopsy.

We were aware about the liquid aspirate a week ago, but weve been anxiously waiting for news on the solid part up until today!

The transplant team have also sourced an 11/12 donor match which means that Aurora will have one more round of chemotherapy and will move forward with transplant in January!

We dont know much about her donor other than her stem cells will be coming from a 36 year old female, with 2 children. We arent sure if we are allowed to get in contact before two years but just know, if you read this and its you, or of you know who it could be, we owe our entire life to you and would give you the world.

Days like today make our heart burst with pride and love and just how strong she has been throughout this whole ordeal. We are forever in awe of how she has tackled this journey and we are absolutely overjoyed that things are starting to look up!

Theres still a long way to go, but shes already come this far, we are all so over the moon, and I can barely get my words out, so for now, we are celebrating that out little lion is fighting on.

Matching bone marrow donors is a much more complex process than matching blood type. It relies on matching individual tissue type, and genetic markers that are found on most cells in the body. These markers are used by the immune system as a way to distinguish what cells are supposed to be in the body, and which arent. The markers must be as closely matched as possible between host and guest, to prevent the body rejecting the new bone marrow. Everyones tissue type is inherited, so often bone marrow donations come directly from a donor with the same ethnic background.

Theres a lack of individuals from ethnic minorities on the register, and as a whole only 2% of the entire UK population is currently signed up to become a bone marrow donor despite having a 1 in 800 chance you would be a match for someone.

Keisha added: Auroras in remission but we still have to get her through transplant and theres a 90% chance it could return within a year. Were made up, but still very apprehensive.

This month Keisha and Aurora were announced as joint winners, alongside Westgates Wilfred Jenkins, after our call out for Thanet heroes of 2020.

And Keishas latest update here

Find out how to join the bone marrow register:

http://www.anthonynolan.org

http://www.dkms.org

A fundraising page has been set up to help the family in case treatment abroad is needed.

Related

Read more here:
Family 'over the moon' as nine-year-old Aurora confirmed as being back in remission - The Isle of Thanet News

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.

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

The elated family of a nine-year-old girl battling a rare cancer has revealed she is back in remission and a bone marrow donor has been found.

The odds had been stacked against Aurora Pile-Gray, from Westgate, who was diagnosed with stage 4 Burkitt Lymphoma in May, which affects the blood and bone marrow.

Not only did she need a bone marrow transplant, but in September her parents were told her cancer was more aggressive than ever, just two weeks after being given the all-clear.

But now, mum Keisha, who also has a baby son Oscar and two-year-old daughter Ada-Ireland, has announced the news they have all been desperately waiting for - that brave Aurora, who has undergone gruelling rounds of chemotherapy, is in remission.

A donor has also been found meaning she will have a transplant in the new year.

Writing on Facebook, Keisha said: "Her bone marrow assessments show no cancer cells present, and no cancer cell regeneration on new cells in both the solid and liquid part of her biopsy.

"We were aware about the liquid aspirate a week ago, but we've been anxiously waiting for news on the solid part up until today.

"The transplant team have also sourced an 11/12 donor match which means that Aurora will have one more round of chemotherapy and will move forward with transplant in January.

"We don't know much about her donor other than her stem cells will be coming from a 36-year-old female, with two children.

"We aren't sure if we are allowed to get in contact before two years but just know, if you read this and it's you, or if you know who it could be, we owe our entire life to you and would give you the world.

"Days like today make our heart burst with pride and love at just how strong she has been throughout this whole ordeal.

"We are forever in awe of how she has tackled this journey and we are absolutely overjoyed that things are starting to look up.

"There's still a long way to go, but she's already come this far, we are all so over the moon, and I can barely get my words out, so for now, we are celebrating that our little lion is fighting on."

The community has been rallying round to help the family raise money towards life-saving cell treatment abroad for the St Crispin's pupil.

For more on her journey see growingpainspaperplanes.wordpress.com.

Read more: All the latest news from Thanet

See the article here:
Family's joy as schoolgirl, 9, back in remission - Kent Online

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.

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

By Adam Owens, WRAL anchor/reporter

A 74-year-old Raleigh man spends an average of two weeks a month traveling around the world delivering stem cells or bone marrow to patients as part of Be The Match, a volunteer-based donor program.

According to Troy "Davis" Moore, Be The Match uses a database of 135 countries to find life-saving bone marrow or stem cells for patients with leukemia and other blood diseases. The stem cells are delivered from donors to patients around the world by volunteers like Moore.

Moore said, when he retired 17 years ago, gardening and working around the house just wasn't enough. His friend, who was already a volunteer courier with Be The Match, told him about the opportunity.

To date, Moore has logged more than 5,000 hours as a volunteer courier. He has traveled as far as London, Barcelona, Croatia, Portugal, Singapore and Taiwan.

On Thanksgiving week, Moore will travel to South America to pick up blood stem cells and deliver them to a patient in the United States. He had to get a rapid COVID-19 test before his trip.

"It's been a lot more challenging during COVID-19 because the rules have changed so much in these countries," said Moore, explaining he recently ran into some trouble in Croatia when he hadn't had a coronavirus test in 72 hours.

Moore said, although he doesn't get to meet the families he helps due to confidentiality, the job is incredibly special. In an interview with WRAL's Adam Owens, Moore described a trip he made on Christmas Day, 10 years ago, to deliver bone marrow from the United Kingdom to a hospital in Columbus, Ohio.

Moore said a nurse was walking him through the hospital hallways when she tapped on his shoulder and pointed to a patient room. Inside, he saw the parents of a child waiting for a transplant. "I have children and I could only imagine," Moore said. "They were just pacing down the room, waiting for it."

Moore said he plans to keep traveling until he can't anymore. Volunteering works well for him, he said, especially now that his children are grown.

Some people might get caught up in the adventure of travel, Moore said, but he's usually only in another country for one day.

"At some point, you realize that's not what it's all about," he said. "It's about getting [a cure] to someone."

See the rest here:
Raleigh man delivers stem cells to patients around the world - WRAL.com

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

Bones make up the skeletal system and serve the important function of giving the body support to be able to move. Whats inside the bones also is essential to personal health.

Bone marrow can be found in the center of bones. According to the online wellness resource Healthline, this viscous or spongy tissue comes in two types: red or yellow bone marrow. Both have specific functions in the body.

Red bone marrow is essential for a process called hematopoiesis, or blood cell production. Hematopoietic stem cells in the red bone marrow can develop into key blood cells, including red blood cells, which carry oxygen-rich blood to the body; platelets, which help blood to clot; and white blood cells, which are involved in immune system responses.

Yellow bone marrow is involved with the storage of fats. These fats can be used as an energy source as needed. Yellow bone marrow also contains mesenchymal stem cells that can develop into bone, fat, muscle, or cartilage cells.

Over time, yellow bone marrow replaces red bone marrow in most of the bones in the adult body. Only a few bones, such as the pelvis, skull, vertebrae, and ribs, will contain red bone marrow into adulthood.

According to Medical News Today, bone marrow makes more than 200 billion new blood cells every day. Most blood cells in the body develop from bone marrow cells.

Issues with bone marrow can produce a host of side effects. Fatigue or weakness, fever, increased infections, easy bleeding and bruising, and specific conditions like leukemia and anemia can develop as a result of bone marrow-related problems. In some cases, a bone marrow transplant may be needed to replace diseased or nonfunctioning bone marrow. It also may help regenerate a new immune system that can fight leukemia or other cancers.

Bone marrow transplants also may involve replacing existing bone marrow with genetically healthy bone marrow to prevent future damage from certain genetic diseases, according to Medical News Today. Bone marrow transplants can come from ones own stem cells, a twin, a sibling, parent, or an unrelated donor. Marrow transplants also may come from stored umbilical cord blood.

Bone marrow is vital to the overall health and function of the human body. Bone marrow affects just about every other cell due to its unique relationship with blood production and immune function.

See the original post:
The roles bone marrow plays in the body - Therogersvillereview

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

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

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

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...

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...

Alex Vucish is a superhero. He has nearly one million Tik Tok views of him dancing as Iron Man, and a comic book artist painted a picture of him with Iron Man and titled it My Iron Boy.

What makes him a real hero, though, is that Alex, the son of Michael and Jessica Vucish of Hempfield Township, is not fighting off imaginary bad guys.

Since May, Alex has been fighting for his life.

Doctors at Childrens Hospital of Pittsburgh started him today on an intravenous drip of his own harvested stem cells. Thats part of the continuing battle against the neuroblastoma that invaded his stomach and impacted adjacent organs. He nearly died when side effects of one treatment landed him on life support.

There were many times that we werent sure if he was going to be with us, his mother said.

But after a series of surgeries, treatments, and chemotherapy, things are looking more promising for the boy who turned three in July.

Alex is the strongest person I know and we are going to fight this with everything we have. We will never give up until the day we can say All Done to cancer and we can all breathe again, Jessica Vucish wrote on his public Facebook page, Alex Strong 2020.

Her sons journey has been followed by people all over the world who send encouragement and prayers. The family credits that with holding them together through the toughest times that a child could ever experience.

His symptoms began earlier this year when he didnt want to eat and his sleep was interrupted with bouts of screaming. Several visits to his pediatrician did not bring any diagnosis nor relief.

Jessica Vucish gave birth to their second child, Dominic, on April 20, and soon after, Alexs condition worsened. He lost weight, his stomach was distended, and he was constantly crying. They finally took him to the emergency department at Excela Westmoreland Hospital on May 9.

They took one x-ray and immediately sent us to Childrens Hospital, said Jessica Vucish, who rode in the ambulance with him.

Because of COVID-19, only one parent was permitted in the hospital, so her husband and his mother, Lisa Jacobelli of Jeannette, stayed back to take care of the baby.

Alex was admitted for a night filled with testing.

I think they did four ultrasounds, blood work and a CT scan, his mom said. I woke up at 7 a.m. it was Mothers Day and one of the nurses told me that the doctors found a mass, and that it was huge. It was the worst day of our lives.

Alex had stage 3 neuroblastoma, a cancer that develops from immature nerve cells and most commonly strikes children under the age of 5. His had grown to about five by seven inches in his stomach.

We were totally not prepared for this, Jessica Vucish said. The oncologist came up with a plan, that ok, were going to fight this. For the first two weeks we really mourned the cancer diagnosis and we mourned what he was going through. By the end of the second week, we were thinking, We can beat this.

Surgery confirmed the diagnosis, then chemotherapy started immediately to shrink the tumor. The parents signed papers acknowledging the possible side effects, including death.

We were taken aback by how severe everything ended up, his mom said. Alexs stomach became more distended after the first two days of treatment. The chemo sent him into a downward spiral. The tumor had soaked up Alexs blood and oozed it out into his abdomen. It was wrapped around his organs and that sent him into liver failure. His heart rate went up to 198 and he started foaming at the mouth.

He was rushed to the intensive care unit and put on life support. His organs were failing and the edema (doctors removed three liters of fluid) was almost collapsing his lungs. He was so sick that despite pandemic restrictions, both parents and his grandparents were called to his bedside to say goodbye.

We were prepared to lose him, Jessica Vucish said. I remember being told that we were lucky to have him for the time that we did, and that we had to let him go.

But Alex wasnt going anywhere. He was upgraded from the ICU two weeks later and soon resumed a total of six rounds of chemo. In all, he had three stem cell harvests, another stay in ICU, four visits to the emergency room, and the latest chemo to destroy his immunity in preparation for a bone marrow transplant. There also were seven surgeries, including a 16-hour operation to remove the tumor after round 4 of chemo. That left him with a triangle shaped scar similar to what Iron Man has on his chest from near fatal injuries.

Alex already loved Iron Man. His mother found the superhero costume for him to wear on Halloween and took a video of him dancing. When Tik Tok star Jennings Brower saw it, he got a video of a group of people dancing and posted it side by side with Alexs video.

When comic book inker Romeo Tanghal of New Jersey heard about Alex, he created a portrait of the boy with Iron Man and donated it to the family. Tanghal has an extensive rsum with DC Comics, Marvel Comics and others, including illustrating Batman, the Green Lantern, Star Trek and Wonder Woman.

The love and response from the community and from people we dont even know has been absolutely humbling, Jessica Vucish said.

That included a parade of emergency vehicles and other well-wishers that went by when he was home for his third birthday in July.

Alex will remain in isolation for weeks, possibly longer, to avoid infection, and his mother is staying with him for the first two weeks. Shes not permitted to leave the room. Shes a photographer and lost many sessions because of the pandemic, and that gives her time to spend with her son.

Her husband is involved in the family business, Stellar Precision Components in Jeannette, and is working from home. Hell spend the next block of time with Alex until his wife returns.

Vucish hopes that Alex wont remember the worst of the times all of the procedures that frightened him and that hell remember only that he survived. Hes now in the NED phase, which stands for No Evidence of Disease. But his parents know that the tumor can recur.

Everything thats happening is scary, his mom said. But you just have to do it one day at a time because the only other choice is to not do anything. We would much rather fight for his life.

Read this article:
Meet 'Iron Boy': Hempfield Twp. boy fighting cancer is real superhero - Gettysburg Times

We were discussing G1 Therapeutics (GTHX) in our TPT member chat yesterday. It has been a depressed stock for over a year now, and even today, despite having a PDUFA date in less than 3 months, the stock shows little sign of improvement. Lead drug candidate trilaciclib is a myelopreservation agent supporting chemo regimens that have shown enough data in phase 2 trials that the FDA has allowed GTHX to proceed to an NDA directly from there without requiring a phase 3 trial. Rintodestrant, their second asset, is in early stages of developing but targeting a larger opportunity in breast cancer and is going to announce a major update on December 9; and yet, the stock shows no sign of improvement.

Their current pipeline looks like this:

Source

I covered trilaciclib a year ago. There is not a lot to be added to that except that their NDA was accepted by the FDA on August 17 with a PDUFA date for February 15, 2021. The NDA was accepted under an accelerated review program, which is why PDUFA is occurring in 6 months instead of the regular 10. The Priority Review is based on positive data from three randomized clinical trials showing robust myelopreservation benefits for the drug.

There are currently no available therapies to protect patients from chemotherapy-induced toxicities before they occur, said Raj Malik, M.D., Chief Medical Officer and Senior Vice President, R&D. If approved, trilaciclib would be the first proactively administered myelopreservation therapy that is intended to make chemotherapy safer and reduce the need for rescue interventions, such as growth factor administrations and blood transfusions.

Trilaciclib also has a Breakthrough Therapy Designation - meaning preliminary clinical evidence for trilaciclib shows a clear advantage over available therapy. In the NDA acceptance letter, the FDA also stated that it is currently not planning to hold an advisory committee meeting for the drug.

While undergoing chemotherapy, many patients experience significant myelosuppression, become fatigued and susceptible to infection, and often require transfusions and growth factor administrations, said Jared Weiss, M.D., Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, NC. Preventing bone marrow damage proactively is an opportunity to improve the quality of life of patients receiving chemotherapy for small cell lung cancer and reduce costly rescue interventions.

Myelosuppression, caused by damage to bone marrow stem cells, occurs due to chemotherapy and can cause symptoms like anemia, neutropenia or thrombocytopenia. In clinical trials, trilaciclib has demonstrated strong reduction of chemotherapy-induced myelosuppression, and patients receiving trilaciclib experienced fewer dose delays/reductions, infections, hospitalizations, and need for rescue therapies compared to patients receiving chemotherapy alone.

Another important development is trilaciclibs expanded access program, which means the company is making the drug available to patients while it undergoes the approval process. The EAP usually means the drug is so beneficial that it is unethical to make patients wait even a few months to get it. This is an important development because it shows the value of trilaciclib.

In June, G1 Therapeutics entered into a 3-year US/Puerto Rico co-promotion agreement with Boehringer Engelheim, which has a lot of experience in oncology asset commercialization. GTHX will book revenue and retain full commercialization rights, and will pay Boehringer a promotional fee based on net sales. G1 will pay a promotion fee of a mid-twenties percentage of net sales in the first year of commercialization, which decreases to a low double-digit/high single-digit percentage in the second and third years of commercialization, respectively.

As for the total addressable market or TAM, over 25,000 people in the U.S. and Puerto Rico are diagnosed with SCLC every year. Approximately 90% of SCLC patients receive first-line chemotherapy treatment, and approximately 60% of those patients receive subsequent second-line chemotherapy treatment. That means, there are 22,500 patients in the 1st line setting who will benefit from trilaciclib, and another 13,500 patients in the 2nd line setting. That is a total of 36,000 patients. From research available last year, cost of chemotherapy treatment for SCLC patients was around $60,000. If we assume a 10% cost for trilaciclib, then we have $6000 per patient. So, every year, they are looking at a TAM of $216mn in this one indication in the US. With Boehringers involvement, we can safely assume a 10% penetration within the first two years of approval, especially given the breakthrough designation. So, that is $22mn from the US; similar figure for Europe, and another such figure from the RoW will give us $60mn in about 3 years, with increasing penetration of the market.

This is a conservative estimate. As I wrote in my earlier coverage:

According to a 2027 estimate by Decision Resources Group, trilaciclib has the potential to benefit a significant number of patients beyond SCLC. There were approximately 1 million chemo treated patients including adjuvant/1L CRC, 1L NSCLC, and adjuvant/1L BC in the U.S., Europe, and Japan in 2018. Chemotherapy treated patients include:

68,000 - ES-SCLC (1st Line - 3rd Line)

68,000 - 1st Line BC

126,000 - 1st Line NSCLC

356,000 - Adjuvant & 1st Line CRC

354,000 - Adjuvant BC

This vast cohort of patients can benefit from trilaciclib in combination with chemotherapy. The company estimates the target market to be at $3bn.

Trilaciclib is a first-in-class drug and doesn't have real competition. It could replace current rescue growth factor support treatments, "including Neulasta (pegfigrastim), Neupogen (filgrastim), Procrit (epoeitin alpha), and Aranesp (darbepoetin alfa)."

Trilaciclib is also being evaluated in other cancers. From their press release:

In a randomized trial of women with metastatic triple-negative breast cancer, preliminary data showed that trilaciclib improved overall survival when administered in combination with chemotherapy compared with chemotherapy alone. The company plans to present final overall survival data from this trial in the fourth quarter of 2020.

On November 18, the company announced that final overall survival data from the mTNBC trial was consistent with the above preliminary findings announced last year, and showed that trilaciclib significantly improved median OS for patients treated with trilaciclib in combination with a chemotherapy regimen of gemcitabine/carboplatin.

They will initiate a pivotal trial in mTNBC in 2021 with OS as the primary endpoint.

Trilaciclib is being evaluated in neoadjuvant breast cancer as part of the I-SPY 2 TRIAL, and the company expects to initiate a Phase 3 trial in patients treated with chemotherapy for colorectal cancer in the fourth quarter of 2020.

In the same press release quoted above, GTHX also announced that it will provide an update on Rintodestrant at the 2020 San Antonio Breast Cancer Symposium (SABCS) to be held virtually on December 9, 2020. Specifically, they said The company will also present updated monotherapy findings from the Phase 1 portion of its ongoing clinical trial of rintodestrant, a potential best-in-class oral selective estrogen receptor degrader (SERD) in development for treatment of ER+, HER2- breast cancer.

It seems they will provide pk/pd and mtd (maximum tolerated dose) data, with probable comments on early signs of efficacy. Primary outcomes are dose limiting toxicity and phase 2 dose determination. secondary outcomes are about efficacy, specifically tumor response with RECIST, and pk/pd. Before competitor fulvestrant went generic last year, it had $541mn annual sales. This indicates the potential for Rintodestrant.

I am providing below the entire abstract on Rintodestrant - there will be three of these but this is the critical one.

Background: Rintodestrant (G1T48) is a potent oral selective estrogen receptor degrader (SERD) that competitively binds to the estrogen receptor (ER) and blocks ER signaling in tumors resistant to other endocrine therapies. Preliminary results from Part 1 dose escalation showed robust target engagement on 18F-fluoroestradiol positron emission tomography (FES-PET), a favorable safety profile, and encouraging antitumor activity in patients with heavily pretreated ER+/HER2- advanced breast cancer (ABC), including those with ESR1 mutations (Dees et al., ESMO 2019 [abstract #3587]). Here, we present updated results from dose escalation and expansion (Parts 1 and 2). Methods: This Phase 1, first-in-human, open-label study evaluated rintodestrant monotherapy in women with ER+/HER2- ABC after progression on endocrine therapy. Part 1 was a 3+3 dose escalation (200- 1000 mg once daily [QD]); Part 2 expanded 600 and 1000 mg QD; and Part 3 was added to assess rintodestrant with palbociclib in patients in earlier lines in the advanced setting. Primary objectives included dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and recommended Phase 2 dose. Secondary objectives included pharmacokinetics and antitumor activity (RECIST v1.1). Exploratory objectives included pharmacodynamic inhibition of ER target engagement (FES-PET), mutation profiling (cell-free DNA [cfDNA]), and change in ER expression from baseline to on-treatment tumor biopsies. Results: As of May 13, 2020, 67 patients (Part 1: n = 26; Part 2: n = 41) were treated, with a median age of 61 years (range 34-83) and ECOG PS of 0 (49%) or 1 (51%). Median number of prior lines in the advanced setting was 2 (range 0-9), including prior fulvestrant (64%), CDK4/6 inhibitor (69%), mTOR inhibitor (22%), and/or chemotherapy (46%). Median number of prior lines of endocrine therapy in the advanced setting was 2 (range 0-5), with 61% of patients having received 2 lines. Treatment-related adverse events (TRAEs) were reported in 70% of patients. The most common TRAEs in 10% of patients included hot flush (24%), fatigue (21%), nausea (19%), diarrhea (18%), and vomiting (10%), mostly grade 1 or 2. No DLTs were reported and MTD was not reached. Dose reduction due to TRAEs occurred in 1 patient (1%), with elevated transaminases (grade 3 ALT and grade 2 AST) at 600 mg. Serious TRAEs occurred in 2 patients at 1000 mg (grade 5 cerebral hemorrhage in the setting of low molecular weight heparin and grade 2 upper abdominal pain). Two patients (3%) discontinued treatment due to TRAEs. Overall, the frequency of patients with TRAEs at 800 mg was comparable with that at 600 mg (57% vs 63%) and less than that at 1000 mg (81%). Of 67 patients, 16 were on study treatment for 24 weeks and 3 (n = 1 at 600 mg; n = 2 at 1000 mg, including 1 with ESR1 mutation) had a confirmed partial response (clinical benefit rate [CBR]: 28%). FES-PET standard uptake values decreased at week 4 with a mean reduction of 87% (8%) at doses 600 mg. Of 59 patients tested for baseline cfDNA, 41% harbored 1 ESR1 mutation, with a similar CBR in both groups (33% in ESR1 mutant and 29% in ESR1 wild-type). Seven of 9 patients had a decrease in ER immunohistochemistry H-score at both 600 and 1000 mg (median [range]: -27.8% [-33.8%, - 3.4%]), irrespective of ESR1 mutation status. Based on safety, efficacy, and ER degradation, 800 mg was selected as the optimal dose for further study. Conclusions: Rintodestrant continues to demonstrate an excellent safety/tolerability profile across all doses, with promising antitumor activity in patients with heavily pretreated ER+/HER2- ABC, including those with tumors harboring ESR1 mutations. Part 3 of this study, evaluating rintodestrant 800 mg QD with palbociclib in a more endocrine-sensitive population, is ongoing (NCT03455270).

There is not a lot to comment here. 800 mg seems to be the optimal dose, and that one patient with grade 5 cerebral hemorrhaging may be an outlier, especially with heparin in the mix, but that is something to keep an eye out for. Effect on an endocrine-sensitive population is preliminary but encouraging, and although a partial response, at this late stage in the game, that is not a bad deal. A larger trial developing the ESR1 scenario more fully is going to be interesting to watch.

According to latest reports, the company has $200-205mn in cash and cash equivalents as of the latest quarter. Burn was around $90mn last year, so with the Boehringer deal, that is not going to increase substantially, putting them in a comfortable position with a 2-year cash runway. The company recently changed CEOs, which seems to be in anticipation of approval, and nothing else.

For whatever reasons I cannot fathom, the stock remains depressed. They have a major catalyst 3 months down the line, and if past performance in trials is anything to go by, theres considerable chance of approval. Post approval scenario, both in terms of revenue stream and label expansions/other indications, looks good. I think this is a good candidate to accumulate at this time.

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G1 Therapeutics: Depressed Price Before Catalyst, No Apparent Reason - Seeking Alpha

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.

Get a sample pages of this Report:https://www.coherentmarketinsights.com/insight/request-sample/3566

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,...

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

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

This article was originally published here

Stem Cells Dev. 2020 Nov 24. doi: 10.1089/scd.2020.0148. Online ahead of print.

ABSTRACT

Cytoreductive protocols are integral both as conditioning regimens for bone marrow transplantation and as part of therapies for malignancies, but their associated comorbidities represent a long-standing clinical problem. In particular, they cause myeloablation that debilitates the physiological role of mesenchymal stem and precursor cells (MSPCs) in sustaining hematopoiesis. This review addresses the damaging impact of cytoreductive regimens on MSPCs. Additionally, it discusses prospects for alleviating the resulting iatrogenic comorbidities. New insights into the structural and functional dynamics of hematopoietic stem cell (HSC) niches reveal the existence of empty niches and the ability of the donor-derived healthy HSCs to outcompete the defective HSCs in occupying these niches. These findings support the notion that conditioning regimens, conventionally used to ablate the recipient hematopoiesis to create space for engraftment of the donor-derived HSCs, may not be a necessity for allogeneic bone marrow transplantation. Additionally, the capacity of the MSPCs to cross-talk with hematopoietic stem cells, despite MHC disparity, and suppress graft versus host disease indicates the possibility for development of a conditioning-free, MSPCs-enhanced protocol for bone marrow transplantation. The clinical advantage of supplementing cytoreductive protocols with MSPCs to improve autologous hematopoiesis reconstitution and alleviate cytopenia associated with chemo and radiation therapies for cancer is also discussed.

PMID:33231142 | DOI:10.1089/scd.2020.0148

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New Insights on the Role of the Mesenchymal-Hematopoietic Stem Cell Axis in Autologous and Allogeneic Hematopoiesis - DocWire News

Newswise Princess Margaret scientists have revealed how stem cells are able to generate new blood cells throughout our life by looking at vast, uncharted regions of our genetic material that hold important clues to subtle biological changes in these cells.

The finding, obtained from studying normal blood, can be used to enhance methods for stem cell transplantation, and may also shed light into processes that occur in cancer cells that allow them to survive chemotherapy and relapse into cancer growth many years after treatment.

Using state-of-the art sequencing technology to perform genome-wide profiling of the epigenetic landscape of human stem cells, the research revealed important information about how genes are regulated through the three-dimensional folding of chromatin.

Chromatin is composed of DNA and proteins, the latter which package DNA into compact structures, and is found in the nucleus of cells. Changes in chromatin structure are linked to DNA replication, repair and gene expression (turning genes on or off).

The research by Princess Margaret Cancer Centre Senior Scientists Drs. Mathieu Lupien and John Dick is published in Cell Stem Cell, Wednesday, November 25, 2020.

We dont have a comprehensive view of what makes a stem cell function in a specific way or what makes it tick, says Dr. Dick, who is also a Professor in the Department of Molecular Genetics, University of Toronto.

Stem cells are normally dormant but they need to occasionally become activated to keep the blood system going. Understanding this transition into activation is key to be able to harness the power of stem cells for therapy, but also to understand how malignant cells change this balance.

Stem cells are powerful, potent and rare. But its a knifes edge as to whether they get activated to replenish new blood cells on demand, or go rogue to divide rapidly and develop mutations, or lie dormant quietly, in a pristine state.

Understanding what turns that knifes edge into these various stem cell states has perplexed scientists for decades. Now, with this research, we have a better understanding of what defines a stem cell and makes it function in a particular way.

We are exploring uncharted territory, says Dr. Mathieu Lupien, who is also an Associate Professor in the Department of Medical Biophysics, University of Toronto. We had to look into the origami of the genome of cells to understand why some can self-renew throughout our life while others lose that ability. We had to look beyond what genetics alone can tell us.

In this research, scientists focused on the often overlooked noncoding regions of the genome: vast stretches of DNA that are free of genes (i.e. that do not code for proteins), but nonetheless harbour important regulatory elements that determine if genes are turned on or off.

Hidden amongst this noncoding DNA which comprise about 98% of the genome - are crucial elements that not only control the activity of thousands of genes, but also play a role in many diseases.

The researchers examined two distinct human hematopoietic stem cells or immature cells that go through several steps in order to develop into different types of blood cells, such as white or red blood cells, or platelets.

They looked at long-term hematopoietic stem cells (HSCs) and short-term HSCs found in the bone marrow of humans. The researchers wanted to map out the cellular machinery involved in the dormancy state of long-term cells, with their continuous self-renewing ability, as compared to the more primed, activated and ready-to-go short-term cells which can transition quickly into various blood cells.

The researchers found differences in the three-dimensional chromatin structures between the two stem cell types, which is significant since the ways in which chromatin is arranged or folded and looped impacts how genes and other parts of our genome are expressed and regulated.

Using state-of-the-art 3D mapping techniques, the scientists were able to analyze and link the long-term stem cell types with the activity of the chromatin folding protein CTCF and its ability to regulate the expression of 300 genes to control long-term, self-renewal.

Until now, we have not had a comprehensive view of what makes a stem cell function in a particular way, says Dr. Dick, adding that the 300 genes represent what scientists now think is the essence of a long-term stem cell.

He adds that long-term dormant cells are a protection against malignancy, because they can survive for long periods and evade treatment, potentially causing relapse many years later.

However, a short-term stem cell that is poised to become active, dividing and reproducing more quickly than a long-term one, can gather up many more mutations, and sometimes these can progress to blood cancers, he adds.

This research gives us insight into aspects of how cancer starts and how some cancer cells can retain stem-cell like properties that allow them to survive long-term, says Dr. Dick.

He adds that a deeper understanding of stem cells can also help with stem cells transplants for the treatment of blood cancers in the future, by potentially stimulating and growing these cells ex vivo (out of the body) for improved transplantation.

The research was supported by The Princess Margaret Cancer Foundation, Ontario Institute for Cancer Research, Canadian Institutes for Health Research (CIHR), Medicine by Design, University of Toronto, Canadian Cancer Society Research Institute, and the Terry Fox Research Institute.

Competing Interests

Dr. John Dick served on the SAB at Trillium Therapeutics, and has ownership interest (including patents) in Trillium Therapeutics. He also reports receiving a commercial research grant from Celgene.

About Princess Margaret Cancer Centre

Princess Margaret Cancer Centre has achieved an international reputation as a global leader in the fight against cancer and delivering personalized cancer medicine. The Princess Margaret, one of the top five international cancer research centres, is a member of the University Health Network, which also includes Toronto General Hospital, Toronto Western Hospital, Toronto Rehabilitation Institute and the Michener Institute for Education at UHN. All are research hospitals affiliated with the University of Toronto. For more information: http://www.theprincessmargaret.ca

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Mapping out the mystery of blood stem cells - Newswise

Novartis has licensed a new stem cell therapy from Mesoblast, just weeks after the FDA rejected the Australian biotechs pitch for an approval on a separate indication.

The Swiss pharma announced Thursday afternoon it is partnering with Mesoblast $MESO to develop remestemcel-L for the treatment of acute respiratory distress syndrome, including ARDS related to Covid-19. As part of the deal, Novartis will shell out $25 million in upfront cash and take a $25 million stake in the biotech, while offering up to $1.255 billion in potential milestone payments.

Mesoblast investors embraced the news, sending shares up 11% on the Australian stock exchange Friday. The companys stock was also up roughly 17% on the Nasdaq before Fridays opening bell.

The milestone payments are split as such, per Mesoblast: $505 million will be available pre-commercialization, with an additional $750 million set aside for hitting certain sales targets and double-digit royalties.

Remestemcel-L, or Ryoncil, acts as an anti-inflammatory and consists of culture-expanded mesenchymal stem cells derived from a bone marrow donor. Currently, the drug is being evaluated in a Phase III study for Covid-19-related ARDS with 300 patients, and the first cut of data is expected in early 2021.

Should that outcome prove successful, Novartis will launch a Phase III in non-Covid ARDS after the deal closes. The companies highlighted Novartis ability to rapidly scale up cell-based therapies from the clinic to the commercial phase as a motivator for the collaboration.

The drug had been examined in a small compassionate use program for Covid-19 ARDS back in March, which included 12 patients requiring ventilators. Remestemcel-L treatment demonstrated an 83% survival rate in that program and was the basis for the ongoing Phase III.

Thursdays deal comes less than two months after the FDA issued a CRL for remestemcel-L in Mesoblasts pediatric acute graft-versus-host disease program. The rejection, which denied the company an accelerated approval, came after an ODAC adcomm in August voted 9 to 1 in favor of approval as panel members struggled to envision what a pivotal trial might look like.

During both the adcomm and in their CRL, regulators took issue with Mesoblasts study design given that the company submitted its application on the basis of one, single-arm and open-label trial. In the study, Remestemcel-L demonstrated a statistically significant benefit in its primary endpoint against the historical control rate.

But because many parents and pediatricians are reluctant to risk putting children into the placebo arm of a randomized study, Mesoblast argued that key opinion leaders said an additional study was not feasible. The veto came despite the FDA approving a similar drug Incyte and Novartis Jakafi based on one single-arm trial, something for which ODAC members chastised the FDA.

Earlier this week, Mesoblast met with the agency for its Type A meeting, and the company reported in its third quarter earnings that it does not expect the FDA to reverse its decision for accelerated approval. Mesoblast is still waiting to receive final meeting minutes to know whether thats indeed the case. The CRL set back potential approval in GvHD from 2021 to 2024, per analysts.

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Novartis bags Mesoblast's stem cell therapy for ARDS, including in Covid-19, in a deal worth up to $1.2B+ - Endpoints News