Archive for the ‘Cardiac Stem Cells’ Category

Global Stem Cell Reconstructive Marketwas valued US$ XX Mn in 2019 and is expected to reach US$ XX Mn by 2027, at a CAGR of 24.5% during a forecast period.

Market Dynamics

The Research Report gives an in-depth account of the drivers and restraints in the stem cell reconstructive market. Stem cell reconstructive surgery includes the treatment of injured or dented part of body. Stem cells are undifferentiated biological cells, which divide to produce more stem cells. Growing reconstructive surgeries led by the rising number of limbs elimination and implants and accidents are boosting the growth in the stem cell reconstructive market. Additionally, rising number of aged population, number of patients suffering from chronic diseases, and unceasing development in the technology, these are factors which promoting the growth of the stem cell reconstructive market. Stem cell reconstructive is a procedure containing the use of a patients own adipose tissue to rise the fat volume in the area of reconstruction and therefore helping 3Dimentional reconstruction in patients who have experienced a trauma or in a post-surgical event such as a mastectomy or lumpectomy, brain surgery, or reconstructive surgery as a result of an accident or injury. Stem cell reconstructive surgeries are also used in plastic or cosmetic surgeries as well. Stem cell and regenerative therapies gives many opportunities for development in the practice of medicine and the possibility of an array of novel treatment options for patients experiencing a variety of symptoms and conditions. Stem cell therapy, also recognised as regenerative medicine, promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives.

The common guarantee of all the undifferentiated embryonic stem cells (ESCs), foetal, amniotic, UCB, and adult stem cell types is their indefinite self-renewal capacity and high multilineage differentiation potential that confer them a primitive and dynamic role throughout the developmental process and the lifespan in adult mammal.However, the high expenditure of stem cell reconstructive surgeries and strict regulatory approvals are restraining the market growth.

The report study has analyzed revenue impact of covid-19 pandemic on the sales revenue of market leaders, market followers and disrupters in the report and same is reflected in our analysis.

Global Stem Cell Reconstructive Market Segment analysis

Based on Cell Type, the embryonic stem cells segment is expected to grow at a CAGR of XX% during the forecast period. Embryonic stem cells (ESCs), derived from the blastocyst stage of early mammalian embryos, are distinguished by their capability to distinguish into any embryonic cell type and by their ability to self-renew. Owing to their plasticity and potentially limitless capacity for self-renewal, embryonic stem cell therapies have been suggested for regenerative medicine and tissue replacement after injury or disease. Additionally, their potential in regenerative medicine, embryonic stem cells provide a possible another source of tissue/organs which serves as a possible solution to the donor shortage dilemma. Researchers have differentiated ESCs into dopamine-producing cells with the hope that these neurons could be used in the treatment of Parkinsons disease. Upsurge occurrence of cardiac and malignant diseases is promoting the segment growth. Rapid developments in this vertical contain protocols for directed differentiation, defined culture systems, demonstration of applications in drug screening, establishment of several disease models, and evaluation of therapeutic potential in treating incurable diseases.

Global Stem Cell Reconstructive Market Regional analysis

The North American region has dominated the market with US$ XX Mn. America accounts for the largest and fastest-growing market of stem cell reconstructive because of the huge patient population and well-built healthcare sector. Americas stem cell reconstructive market is segmented into two major regions such as North America and South America. More than 80% of the market is shared by North America due to the presence of the US and Canada.

Europe accounts for the second-largest market which is followed by the Asia Pacific. Germany and UK account for the major share in the European market due to government support for research and development, well-developed technology and high healthcare expenditure have fuelled the growth of the market. This growing occurrence of cancer and diabetes in America is the main boosting factor for the growth of this market.

The objective of the report is to present a comprehensive analysis of the Global Stem Cell Reconstructive Market including all the stakeholders of the industry. The past and current status of the industry with forecasted market size and trends are presented in the report with the analysis of complicated data in simple language. The report covers all the aspects of the industry with a dedicated study of key players that includes market leaders, followers and new entrants. PORTER, SVOR, PESTEL analysis with the potential impact of micro-economic factors of the market has been presented in the report. External as well as internal factors that are supposed to affect the business positively or negatively have been analysed, which will give a clear futuristic view of the industry to the decision-makers.

The report also helps in understanding Global Stem Cell Reconstructive Market dynamics, structure by analysing the market segments and projects the Global Stem Cell Reconstructive Market size. Clear representation of competitive analysis of key players by Application, price, financial position, Product portfolio, growth strategies, and regional presence in the Global Stem Cell Reconstructive Market make the report investors guide.Scope of the Global Stem Cell Reconstructive Market

Global Stem Cell Reconstructive Market, By Sources

Allogeneic Autologouso Bone Marrowo Adipose Tissueo Blood Syngeneic OtherGlobal Stem Cell Reconstructive Market, By Cell Type

Embryonic Stem Cell Adult Stem CellGlobal Stem Cell Reconstructive Market, By Application

Cancer Diabetes Traumatic Skin Defect Severe Burn OtherGlobal Stem Cell Reconstructive Market, By End-User

Hospitals Research Institute OthersGlobal Stem Cell Reconstructive Market, By Regions

North America Europe Asia-Pacific South America Middle East and Africa (MEA)Key Players operating the Global Stem Cell Reconstructive Market

Osiris Therapeutics NuVasives Cytori Therapeutics Takeda (TiGenix) Cynata Celyad Medi-post Anterogen Molmed Baxter Eleveflow Mesoblast Ltd. Micronit Microfluidics TAKARA BIO INC. Tigenix Capricor Therapeutics Astellas Pharma US, Inc. Pfizer Inc. STEMCELL Technologies Inc.

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Best hair transplant clinics in the world

Hair restoration is a surgical performance which entails the removal of hair from an area known as the donor site to an area facing balding which is called the receiving site. This method is primarily used to counter alopecia in males as it is a less invasive technique which uses grafts containing grafts which have hair follicles that are genetically resistant to balding. These grafts are most often harvested from the back of the head. The harvested hair is then transplanted to the patchy region. Hair restoration can also be used to restore eyebrows, eyelashes, beard hair, pubic hair, and chest hair. Hair restoration is also possible in areas that have experienced hair loss as a result of scars from accidents or surgery, such as previous hair transplant surgery. There are two conventional methods for hair restoration hair transplanting and skin grafting. In a skin grafting procedure, the grafts harbour nearly all the dermis and epidermis neighbouring the hair follicles. A hair transplant involves numerous little grafts which are replaced instead of a distinct strip of skin.

Hair restoration is not a new pursuit. For instance, dating back to the 19th century is the use of scalp blinkers, such that a band of tissue containing the unique blood resource is allocated to another bald area. Back in 1897, Menahem Hodara successfully transplanted hair that was sourced from the unaffected regions of the scalp to the scars that were left bare by favus. The use of modern transplant methods started back in the 1930s, when the surgical team made use of small grafts and follicular unit grafts to substitute the impaired regions of the eyelashes and the eyebrows. Still, the method was not used to treat baldness. The surgeons continuous efforts did not receive any attention, and the traumas caused by World War II kept their discoveries unknown for the subsequent two decades.

The current age of hair restoration in the western world began in the late 1950s when the then New York-based Norman Orentreich started experimentation using free donor grafts to zones that had been faced by alopecia in patients experiencing male-related baldness. Earlier on, it was supposed that the restored hair would not flourish just like the unique hair in the receiving region.

Follicular Unit Extraction (FUE) is the favoured method for hair restoration. Dr. Asim Shahmalak, MD, hair transplant surgeon, broadcaster and founder of the Crown Clinic in Manchester, says 70% of his clients opt for the FUE method. The procedure takes about six to seven hours, with many clients going home the same day. Dr. Shahmalak explains: With FUE, specific follicles are detached from the back and side of the scalp and then transferred by a surgeon to the balding regions, which are mainly the top of the scalp. The benefit of this technique is that there is minimal scarring. The patients who opt for this method usually tend to heal after two weeks. FUE is predominantly appropriate for clients who like their hair short or shaved, as the scars are hardly noticeable. During the process, the giver part, which is usually the back of the scalp, is numbed with an anaesthetic. Then the donor follicles are detached separately, leaving behind minor scars where the hair is attached.

In the last few years, FUE has increased in popularity relative to Follicular Unit Transplantation (FUT). This can, in part, be attributed to the growing number of celebrities who have chosen FUE. FUE is also recommended for men who want to shave their heads or wear their hair short. The FUE technique is also faster, with an average of five hours to complete a procedure. This is because the extraction of hair from the hair follicles is quicker. FUE will also deliver a faster healing process than FUT, as in FUT a strip of skin is detached from a patient so as to get the donor hair rather than the separate follicles.

Best hair transplant clinics

CapilClinic, the largest private hospital group in Istanbul, specialises in hair transplantation. They are the leader in the field of hair transplants and the primary referral hospital recognised as the international model for the best service and results. CapilClinic began operations in 2015. The facility is known for its world-renowned medical staff, many of them with more than ten years of experience in hair transplantation procedures and patients from all over the world. The facility outshines the others as a result of its renowned specialists, top-notch facilities, state-of-the-art equipment, machinery and tools.

Dr Ouz Kayiran is a plastic surgeon, aesthetic surgeon and medical director at CapilClinic. As a plastic surgeon, he has over nine years experience in the industry, regularly takes part in cutting edge scientific research, and is featured in international publications.

The clinic has a luxury hotel used to accommodate its clients from abroad before they jet back to their home country. The hotel is located in the Kadky area of Istanbul, a large, populous and cosmopolitan district that boasts colourful murals, indie boutiques, hip cafes and Anatolian eateries. The hotel provides wireless internet in the rooms, business centre, meeting areas, and public areas.

As an added benefit to your luxury experience at CapilClinic, the hospital provides concierge airport transfers for its patients. CapilClinic will have a staff member at the airport waiting to receive you on arrival and then transfer you to the hotel. It is not uncommon on arrival in Istanbul for travellers to complain about long waits or delays at the airport. CapilClinic has removed that obstacle for its patients. Simply identify yourself to the waiting driver and enjoy a quick transfer to the hotel.

https://www.capilclinic.uk

Dr. Thomas Frist started the Hospital Corporation of America (HCA) in 1968. He had a dream to generate a healthcare institution with scope, expertise, and resources to provide the highest global standards of client care. HCA now has over 300 branches in the US and the UK and boasts 37,000 doctors, 240,000 nurses and a total of 27 million patient visits each year. Experienced staff strive to provide a quality of service and excellence that they desire for themselves, family members and loved ones.

HCA opened in the UK in 1995. Since that time, the institution has put up a world-class chain of more than thirty clinics in London and Manchester, equipped with modern diagnostic and handling equipment. In 2017, they expanded their operations to include diagnostic and outpatient services in Elstree, Chelsea, Marylebone, and Chiswick, thereby conveying high-quality services to those communities.

Patient care is the priority at the Harley Street Clinic. The clinic provides a variety of compound care for patients, through its specialisation in areas such as neurosciences for adults, children and babies, cardiology, and oncology. From heart surgery of newborn infants to the leading procedures for combating cancer, the technicians work in harmony to render exceptional service and treatments for their clients. The hospital also has one of the biggest private paediatric ICU units in Europe, with 12 beds. The paediatric ICU facilitates a variety of complicated treatments for babies and children, including thoracic and cardiac surgery, spinal surgery, and cancer care. The hospital is proud to be working with world-class experts who also have jobs in the UKs leading NHS teaching hospitals. Consultants, expert in their respective fields, have offices at the hospital; they look after their patients themselves throughout the entire treatment process.

Bernstein Medical is a renowned hair transplant clinic and also a referral centre devoted to the treatment of alopecia in both genders with the use of state-of-the-art technologies. It was founded by the worlds leading hair transplant developer, Dr. Robert M. Bernstein, back in the year 2005. The clinic is situated in midtown Manhattan, New York City. Hair restoration surgery at this clinic is conducted using the FUT and FUE methods, which were introduced by Dr. Bernstein. FUE technique is performed with the use of the mechanical hair transplant system. The clinic provides the best and highest level of care and treatment to the patients who visit them.

Dr. Bernstein is a pioneer of the current hair transplant surgery and founder of Bernstein Medical, which caters to all hair transplantation needs in New York City. Dr. Bernstein is globally recognised for having introduced the FUE and FUT to the medical community. These are the techniques that revolutionizsd the surgical hair restoration industry.

Bernstein Clinic offers the following services to its clients:

Located in Vancouver, Canada, the Hasson & Wong Clinic is proud of its results from hair transplant procedures. They feature their work on the company webpage with clear photos of real patients that have undergone hair restoration procedures at their clinic.

Hasson & Wong Clinic takes pride in the number of patients who, at their own initiative, have gone to the internet to document their positive experience and applaud the quality of their medical staff and facilities. The vast majority of their clients are pleased with the achieved results.

This clinic has acquired a global reputation for its consistency in offering excellent results. They welcome patients from all over the world, with approximately 50 per cent of the patients originating from Europe, Canada, the United States and Asia.

For hair restoration surgery, Hasson & Wong is one of the best hair restoration clinics to help patients achieve their desired goals.

Their team of professionals offer world-class service to the patients who visit the facility.

Dr. Jerry Wong graduated with a medical doctor degree from the University of Alberta. He then worked for many years as a GP at a hospital in Maple Ridge, Canada. In 1991, Dr. Dorman, a hair renewal surgeon based in Vancouver, ushered Dr. Wong into the field of hair restoration. Dr. Wong was excited about the microsurgical method of the technique. In 1992, he attended a hair transplant surgery school in Australia. On top of micro-mini grafting, he also obtained the necessary skills to perform lift and lap techniques and scalp reductions. Trained know-how in major scalp surgery is important for repair cases. Since then, the two doctors have remained to be great friends, taking part in conferences and occasionally sharing vacations.

Hasson & Wong Clinic is consistently able to work for long hours as a result of the experienced and dedicated team of surgeons. They have also been able to conduct massive mega sessions of hair restoration at their clinic with efficiency and safety, acquiring more than 5000 grafts over a single session. Their dedication to the development of hair restoration procedures is evidenced by the contribution they have made to the medical community.

Founded by Beverly Hills hair professionals Dr. George Abrahamian and Jacques Abrahamian, LA FUE Hair Clinic provide FUE hair renewal and FUE hair transplant services to patients who want a natural-looking final result. The clinic offers excellent services to its clients and prides itself on being the top choice for hair restoration needs. The doctors opened LA FUE Clinic after both having performed hair transplants for prominent people, including global celebrities, politicians, producers, musicians and successful businesspeople.

The LA FUE Hair Clinic offers a team of surgeons with over ten years of combined experience in the FUE hair transplant and FUE hair restoration field. As one of the few hair transplant clinics in Pasadena and the Los Angeles surrounding areas, the facility is proud to offer the best FUE Hair Transplant technique to help their clients get the look they desire.

The LA clinic offers the following services to its customers:

LA FUE Hair Clinic was founded with the mission of providing natural-looking hair renewal and restoration services to those suffering from alopecia. The clinic strives to be the first option for hair restoration services.

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Two and a half years ago, a study published in Science Advances detailed how the gene editing tool CRISPR/Cas-9 repaired genetic mutations related to Duchenne Muscular Dystrophy (DMD). The study was a proof of concept, and used induced pluripotent stem cells (iPSCs).

But now a similar treatment has not only been administered to real people, it has worked and made a difference in their quality of life and the progression of their disorder. Nine boys aged 6 to 12 who have been living with DMD since birth received a gene therapy treatment from pharmaceutical giant Pfizer, and a year later, 7 of the boys show significant improvement in muscle strength and function.

Though the treatments positive results are limited to a small group, theyre an important breakthrough for gene therapy, and encouraging not just for muscular dystrophy but for many other genetic diseases that could soon see similar treatments developed.

DMD is a genetic disorder that causes muscles to progressively degenerate and weaken. Its caused by mutations in the gene that makes dystrophin, a protein that serves to rebuild and strengthen muscle fibers in skeletal and cardiac muscles. As the gene is carried on the X chromosome, the disorder primarily affects boys. Many people with DMD end up in wheelchairs, on respirators, or both, and while advances in cardiac and respiratory care have increased life expectancy into the early 30s, theres no cure for the condition.

The gene therapy given to the nine boys by Pfizer was actually developed by a research team at the UNC Chapel Hill School of Medicineand it took over 30 years.

The team was led by Jude Samulski, a longtime gene therapy researcher and professor of pharmacology at UNC. As a grad student in 1984, Samulski was part of the first team to clone an adeno-associated virus, which ended up becoming a leading method of gene delivery and thus crucial to gene therapy.

Adeno-associated viruses (AAVs) are small viruses whose genome is made up of single-stranded DNA. Like other viruses, AAVs can break through cells outer membranesespecially eye and muscle cellsget inside, and infect them (and their human hosts). But AAVs are non-pathogenic, meaning they dont cause disease or harm; the bodies of most people treated with AAVs dont launch an immune response, because their systems detect that the virus is harmless.

Samulskis gene therapy treatment for DMD used an adeno-associated virus to carry a healthy copy of the dystrophin gene; the virus was injected into boys with DMD, broke into their muscle cells, and replaced their non-working gene.

Samulski said of the adeno-associated virus, Its a molecular FedEx truck. It carries a genetic payload and its delivering it to its target. The company Samulski founded sold the DMD treatment to Pfizer in 2016 so as to scale it and make it accessible to more boys suffering from the condition.

A year after receiving the gene therapy, seven of nine boys are showing positive results. As reported by NPR, the first boy to be treated, a nine-year old from Connecticut, saw results that were not only dramatic, but fast. Before treatment he couldnt walk up more than four stairs without needing to stop, but within three weeks of treatment he was able to run up the full flight of stairs. I can run faster. I stand better. And I can walk [] more than two miles and I couldnt do that before, he said.

The muscle cells already lost to DMD wont grow back, but the treatment appears to have restored normal function of the protein that fixes muscle fibers and helps them grow, meaning no further degeneration should take place.

Gene therapy trials are underway for several different genetic diseases, including sickle cell anemia, at least two different forms of inherited blindness, and Alzheimers, among others. Its even been used as part of cancer treatment.

Its only been a year, we dont yet know whether these treatments may have some sort of detrimental effect in the longer term, and the treatment itself can still be improved. But all of that considered, signs point to the DMD treatment being a big win for gene therapy.

Before it can be hailed as a resounding success, though, scientists feel that a more extensive trial of the therapy is needed, and are working to launch such a trial later this year.

Image Credit: pixelRaw from Pixabay

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A Year After Gene Therapy, Boys With Muscular Dystrophy Are Healthier and Stronger - Singularity Hub

A new intelligence report Autologous Stem Cell Based Therapies Market has been Lately Added into Adroit Market Research collection of top-line market research reports. Global Autologous Stem Cell Based Therapies Market report is a meticulous comprehensive analysis of this market that provides access to direct first-hand insights on the growth trail of market in near term and long term. On the basis of factual advice sourced from authentic industry pros and extensive main industry research, the report provides insights about the historical growth pattern of Autologous Stem Cell Based Therapies Market and current market situation. It then provides short- and long-term market development projections.

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Competitive companies And manufacturers in global market

segment by Type, the product can be split intoEmbryonic Stem CellResident Cardiac Stem CellsUmbilical Cord Blood Stem CellsMarket segment by Application, split intoNeurodegenerative DisordersAutoimmune DiseasesCardiovascular Diseases

Market segment by Regions/Countries, this report coversNorth AmericaEuropeChinaJapanSoutheast AsiaIndiaCentral & South America

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Autologous Stem Cell Based Therapies Market Consumption Sales By Type, Product Specifications, Market Research Methodology, Market Forecast To 2023 -...

The myocardial injury that has been documented in patients with COVID-19 may stem from active virus replicating in heart tissue, a German autopsy study suggests.

In the paper, published online July 27, 2020, in JAMA Cardiology, the researchers say it appears that the presence of SARS-CoV-2 in cardiac tissue does not necessarily cause an inflammatory reaction consistent with clinical myocarditis, and that the long-term consequences of this cardiac infection requires further investigation.

Speaking with TCTMD, Gregg C. Fonarow, MD (University of California, Los Angeles), said it is important to bear in mind that the autopsy reports from COVID-19 patients published to date, including this one, have all been relatively small and either single-center or pooled data in select, most elderly patients.

But on the other hand, they do give important insights for which there are clinical correlates, he added. Specifically, with this autopsy series, it's enlightening because from the very earliest reports coming out of China regarding COVID-19, there were elevations in cardiac troponins, and there was a lot of puzzlement as to what that actually meant.

Fonarow, who along with Clyde W. Yancy, MD (Northwestern University, Chicago, IL), wrote an editorial accompanying the study, said if anything, its reassuring that we're, at least in these cases, not seeing acute myocarditis with the frequency that some people speculated very early on when reports started to come in. But it also shows that there is more cardiac involvement than initially suspected, some of it clearly subclinical, he added.

Interstitial Cell Involvement

Hamburg, Germany, where the autopsies were performed, has mandated full-body postmortems for all COVID-19 deaths in the city, senior study author Dirk Westermann, MD (University Heart and Vascular Centre Hamburg), noted in an email. TCTMD has previously reported on a smaller series of autopsies from the Hamburg region that described lung weights that ranged from two- to fourfold higher than average.

In the new report, Westermann and colleagues led by Diana Lindner, PhD (University Heart and Vascular Centre, Hamburg, Germany), used reverse transcriptase-polymerase chain reaction testing to identify SARS-CoV-2 RNA in the myocardium of 24 of 39 patients (61.5%) who died in April 2020. All had tested positive for the virus prior to death, and none had clinically fulminant myocarditis. The median age was 85 years and the cause of death in 89% was pneumonia. The cardiac tissue included two specimens from the left ventricle.

In 16 cases, a viral load above 1,000 copies per g RNA was noted. Those patients also had increased proinflammatory genes. Virus replication in the myocardium was documented in five patients with the highest virus load.

Lindner and colleagues also conducted in situ hybridization of SARS-CoV-2 RNA and found virus present in interstitial cells or macrophages within the cardiac tissue rather than in myocardiocytes.

Importantly, fulminant myocarditis was not associated with SARS-CoV-2 infection in this study with no significant change in transendothelial migration of inflammatory cells in the myocardium in patients with high virus load vs no virus, they write. In the published cases in which myocardial inflammation was present, there was also evidence of clinical myocarditis, and therefore the current cases underlie a different pathophysiology.

While the findings provide important new clues as to the possible mechanism of myocardial injury in COVID-19 infected patients, Lindner and colleagues say the clues provided by the autopsies are limited and that future studies are needed to reveal whether cytokine expression correlates with cardiac dysfunction during the disease and its aftermath. They also question whether myocardial biomarkers might be upregulated due to the SARS-CoV-2 infection.

Indeed, the literature to date has been mixed on the extent to which this virus is infiltrating the heart, with another recent autopsy analysis reported by TCTMD making the case that not all patients with cardiac manifestations of COVID-19 show signs of direct viral infiltration. Indeed, 15 of the patients in the current autopsy analysis showed no SARS-CoV-2 RNA in the myocardium.

According to Fonarow, many avenues for additional research can grow out of these sorts of clues, especially in the current environment where there is still so much left to learn about COVID-19, its management, and any lasting impact on the heart.

It would be really interesting with therapies like dexamethasone, for example, to look at . . . whether we see a corresponding decline in troponin levels in those who respond that parallel that time course, he said. Further insight from autopsy studies showing how COVID-19 impacts the heart also may help lead to the creation of strategies involving cardioprotective medications. Thats an idea also put forward by the authors of another article out this week in JAMA Cardiology that found evidence of myocardial inflammation on MRI in recovered COVID-19 patients more than 2 months after their initial positive COVID-19 test, even those who never experienced severe illness.

Even in that period where clinically patients are recovering, theres still evidence of myocardial inflammation, reflecting this injury, he noted. Those findings also need to be replicated to see how generalizable they are and [if] we see that same frequency of involvement of the heart through cardiac MRI.

Read more from the original source:
COVID-19 Autopsies Hint at Direct Viral Infection of the Heart - TCTMD

Cardiac Pacemakers Market AnalysisReport gives the clear picture of current scenario which includes historical and projected Cardiac Pacemakers Market size, Share, industry growth, trends in terms of value and volume, technological advancement, macro economical and governing factors in the market. The report also gives a broad study of the different market segments and regions.

Cardiac Pacemakers Market report 2020 covers key business segments and wide scope geographies to get deep dive analyzed industry data. The company profiles of top Market players will provide financial analysis listing the company revenue, and market share. The past and present revenue of top players will offer forecast revenue estimates and growth rates. Cardiac Pacemakers Market Research Report provide the details about Industry Overview and analysis about Manufacturing Cost Structure, Revenue, Gross Margin, Consumption Value and Sale Price, Major Manufacturers, Distributors with Development Trends and Forecast 2026.

An Overview of the Impact of COVID-19 on Cardiac Pacemakers Market:

The emergence of COVID-19 has brought the world to a standstill. We understand that this health crisis has brought an unprecedented impact on businesses across industries. However, this too shall pass. Rising support from governments and several companies can help in the fight against this highly contagious disease. There are some industries that are struggling and some are thriving. Overall, almost every sector is anticipated to be impacted by the pandemic.

We are taking continuous efforts to help your business sustain and grow during COVID-19 pandemics. Based on our experience and expertise, we will offer you an impact analysis of coronavirus outbreak across industries to help you prepare for the future.

The report offers insights into the ongoing Cardiac Pacemakers market trends. The report provides forecast values for the market for the period of 2019-2026. It highlights leading companies in the market and discusses the strategies that these companies have adopted in recent years. The competitive landscape scenario has been discussed in detail. Factual figures have been evaluated through trusted sources. Other forecast values have been gathered through interviews and opinions of experienced market research professionals.

The report also focuses on global major leading industry players of Global Cardiac Pacemakers market providing information such as company profiles, product picture and specification, capacity, production, price, cost, revenue and contact information. Upstream raw materials and equipment and downstream demand analysis is also carried out. The Global Cardiac Pacemakers market development trends and marketing channels are analyzed. Finally, the feasibility of new investment projects is assessed and overall research conclusions offered.

Intended Audience:

Cardiac Pacemakers Key Players

Cardiac Pacemakers Suppliers

Research and Development (RandD) Companies

Distributer and Supplier companies

End Users

Consultants and Investment bankers

Government as well as Independent Regulatory Authorities

Report Highlights:

In-depth information about the latest Cardiac Pacemakers Industry trends, opportunities, and challenges.

Extensive analysis of the growth drivers And barriers.

Competitive landscape consisting of investments, agreements, contracts, novel product launches, strategic collaborations, and mergers and acquisitions.

List of the segments and the niche areas.

Comprehensive details about the strategies that are being adopted by key players.

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Table Of Content:

Introduction

1.1. Research Scope

1.2. Market Segmentation

1.3. Research Methodology

1.4. Definitions and Assumptions

Executive Summary

Market Dynamics

3.1. Market Drivers

3.2. Market Restraints

3.3. Market Opportunities

Key Insights

Continued

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Cardiac Pacemakers Market Analysis By COVID-19 Impact 2020-2026 - The Midland Weekly

Rasmussens fascination with viruses began in the fifth grade, when she contracted pneumonia and was left with chronic asthma. I was very interested in how these tiny things that you cant even see cause such severe disease, she says. How can something invisible make you so sick and cause you long-lasting problems?

Rasmussens research explores how a host responds to a virus. Given that all viruses have to infect a host, viruses are obligate parasites, she says. Its always relevant to know how the host is responding as well as how the virus itself workswhat kinds of host responses and what kind of genes are expressed in response to infection over time.

As an expert, Rasmussen, who is currently an associate research scientist at Columbia Universitys Mailman School of Public Health, advocates for all the common sense and scientifically based practices for combating a pandemic, including social distancing and wearing masks. Here she talks about some of the things weve learned about COVID-19 since it emerged, her concerns about rushing a vaccine and how the pandemic has brought to light issues of equity.

Virology 101Viruses cant exist on their own; they have to have a host. Thats why theres a big philosophical debate about whether viruses are alive or not. They cant replicate independently. They cant reproduce themselves without infecting a host cell. I think of viruses more as machines. People have a real tendency to anthropomorphize them, talk about what a virus wants to do or what a virus thinks. Viruses are really just a set of instructions to make more viruses. Its sort of incidental whether or not they actually cause disease. Since a virus is under evolutionary pressure to reproduce itself, a really effective virus would be one that doesnt affect its host at all, so it can fly under the radar and just replicate efficiently.

Viruses Are Here to StayI dont think viruses are going anywhere. And they are an important part of the ecosystem, too. Viruses drive evolution of their host. They may not even be infectious anymore, capable of producing viruses or causing disease, but they can drive the way that we evolve, and they have driven evolution across millennia.

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Unexpected Effects of SARS-CoV-2 and COVID-19One of the things that I think is surprising to a lot of people is this virus doesnt just cause pneumonia; it doesnt just cause respiratory disease. There are indications that it affects other parts of the body. There have been reports of kidney and liver disease. It may damage the beta islet cells of the pancreas that produce insulin and may predispose people to diabetes, which may explain why people with diabetes have a different risk factor for severe COVID-19. There are reports of weird clotting abnormalities and cardiac effects and neurological things like the loss of sense of smell or taste.

Current Treatment Protocol: Everything and the Kitchen SinkPeople are screening compounds that are not approved drugs, or havent been used for anything, to see if we can find new compounds that might be effective, mostly as antivirals. There are other drugs being studied that treat the patients immune and inflammatory responses that are out of control, which is associated with the most severe cases. Some of those are also in trials right now to see if they can help patients with the most severe disease. In many cases, if doctors have a patient whos on a vent, they throw the kitchen sink at them. They treat them with everything they can think of that might be safe. So, I think were going to see a lot of observational data like that: We used this to treat X number of patients, and they got better. From there, people will start doing randomized, controlled clinical trials.

The Potential Consequences of Rushing a VaccineMy biggest concerns are that we might approve a vaccine thats not effective. Theres only so much you can do to hurry the process along. People have talked about ways to speed this up, like doing human challenge trials, which I dont think is a very good idea because this is a deadly virus and we dont know what the long-term sequelae of being infected are. So, I think it would be almost impossible for people to actually give informed consent to participate in a human challenge trial like that. The other thing is that you wouldnt be getting data about how the vaccine works in the most vulnerable people. Older people or people with preexisting conditions that we know are risk factors would be excluded from a human challenge trial like that, so we wouldnt know if, say, the vaccine is less effective in those people.

The Socio-Political Fallout of COVID-19What I hope comes out of all of this is increased equitygender equity, equity for LGBTQ+ people, racial equity and religious equity. Thats easier said than done. This pandemic has made clear, at least as far as gender is concerned, that there are still very gendered responsibilities in our society. Many people are working from home, for example. Women tend to take on more of the housework and responsibilities for caring for others in their household. As a result, women have been disproportionately affected by that. In science, weve seen that women are submitting fewer papers. Theyre submitting fewer grant applications. To my knowledge, there isnt really a policy level plan to address this. One thing that Ive experienced both in my work and on the National Institutes of Health advisory committee to the Working Group on Changing the Culture to End Sexual Harassment is that its a challenge to even convince people theres a problem. Many menand some womenwill say, Im for equity. Im not racist. Im not sexist, but that doesnt change the fact that they arent actively doing anything against it. Thats what the Shut Down STEM movement and the Black Lives Matter protests have really drawn to peoples attentionthat its not enough to just not be racist or not be sexist or not be homophobic or transphobic. You have to actively be against those things.

See more here:
Angela Rasmussen '00: Getting to the Heart of COVID-19 - Smith College Grcourt Gate

Onconova is developing a late-stage clinical asset and has run up 108% over the last month. With the run up completed, Onconova represents a more risky bet with an upcoming binary event. In the meantime, a recently published debate on Onconova's primary asset, Rigosertib, raises questions about the drug's MOA.

Back in June, and what seems like a lifetime ago by 2020 standards, I was going through my watch list of approximately 300 companies in the biotech space and finishing my quarterly review of quarterly earnings reports. An unlikely candidate rose up to the surface after being left to the outer darkness of my extended watch list for several years. Onconova, a development stage Phase 3 biotech with an upcoming catalyst in MDS and an attractive valuation (which at the time fully diluted was around $90M with an enterprise value of around $60M). That valuation felt low given the point at which they were at in their lifecycle.

I was familiar with this company from its original IPO. When it debuted, I was drawn in because it fell squarely in my zone of interest with its development of Rigosertib. At the time, the MOA was described as an inhibitor of PI3 kinase, which should function to slow cellular proliferation in various cancer indications. At the time, I was very interested in the potential of coupling genomic analysis with targeted cancer therapeutics, so Rigosertib fit nicely into the toolbox that I envisioned being utilized in individualized cancer therapies. The molecule had been first characterized by Dr. Premkumar Reddy, a highly accomplished cancer researcher, who also happens to be the original founder of Onconova. Dr. Reddy continues to be involved with the company as a member of their board of directors.

As of their last quarterly report, Onconova had a cash position of $31 Million. They have guided that they will not need to raise additional capital before the readout of INSPIRE. Additionally, since their financing activities in November of 2019, $10.6 Million in additional capital has come into the coffers via the exercising of outstanding warrants. The company indicated that there are approximately 29 million warrants outstanding at the end of March 2020, and 80% of them were in-the-money as of May 13th. They guide that they have sufficient cash to fund operations through 3Q2021. This was an attractive feature in my evaluation of the company that there would likely be no capital raise before the release of pivotal clinical results. Onconova appeared ripe for a run up.

Before I get started on all of the background on the history of Rigosertib I need to give enormous credit to Jonathan Weissman at University of California San Francisco, who published work on this subject that was incredibly informative on the various efforts in elucidating the MOA of Rigosertib. I have not interviewed Dr. Weissman, but his published work was a great resource for the background in this article. Prior to finding his work, we took a significant position in the company at a cost average of $0.45 per share. But recently, after reviewing his work published on July 2, 2020, and performing a retrospective and comprehensive analysis of the work of others in this space, we have closed the entirety of our position.

Early studies with Rigosertib revealed its promise as a potent anticancer agent. Initially, it was hypothesized by Reddy et al that the drug worked on polo-like kinase1 (Plk1) and arrested cells during mitosis and induced apoptosis. Mitotic spindle abnormalities were identified in these early studies which were deemed to be downstream from the compounds inhibition of Plk1. Binding affinity for Rigosertib to Plk1 was found by Reddy's group to be strong with an IC50 of 9-10nM.

Soon after this publication, others questioned the affinity of Rigosertib (referred to in early studies as ON01910). Steegmaier et al was testing the affinity of a different drug, BI 2536, against Plk1 and found no appreciable affinity of Rigosertib against Plk1 up to a concentration of 30,000nM. For those unfamiliar with binding studies, the IC50 represents the concentration at which 50% of the target would be inhibited, or bound. A lower IC50 means that the binding is more efficient. For a "good drug" we like to see low nano molar affinity for its target ligand, and no appreciable affinity for other "off-target" molecules.

Steegmaier's study found no appreciable direct binding of Plk1 at concentrations 3000 times higher than the IC50 that was determined by Reddy. Instead, Steegmaier claimed that "The cellular effects caused by ON01910 resembled the phenotype that is caused by treatment with low doses of microtubule depolymerizing agents rather than Plk1 RNAi. Supporting this notion, depolymerization of microtubules was clearly visible in interphase cells when these were treated with higher doses of ON01910".

I have not seen data where Reddy or Onconova retracted the Plk1 claim, but eventually additional studies were carried out by Reddy's group and it was proposed that Rigosertib targeted PI3 kinase signaling. However, here again, independent groups were unable to confirm this and similar to Steegmaier, Maki-Jouppilia et al implied that the effects of Rigosertib were targeted at the mitotic process rather than a modulator of signal transduction.

After Onconova's IPO I was drawn to the company because of the indication being tested. And although the trial was with IV Rigosertib, I liked that the drug was orally bioavailable and that the side effect profile looked pretty good. At the time of their IPO, they were conducting a Phase 3 trial dubbed "ONTIME" for Myelodysplastic Syndrome. For patients who are not good candidates for a stem cell transplant, MDS was essentially a death sentence with limited treatment options and it represented a largely untapped field for an effective new agent. At the time of their IPO, the only approved therapies were the hypomethylating agents, Azacitidine and Decitabine.

Since then, of course, three new agents have been approved in MDS. These are Lenalidomide for transfusion dependent del(5q) MDS, Luspatercept-aamt, and Inqovi (an oral combination of decitabine and cedazurine for intermediate and high risk MDS). Still, MDS patients have a poor prognosis, so Onconova represented precisely the type of drug and company that I feel good investing in. The ONTIME trial enrolled 299 MDS patients that were treated 2:1 in the Rigo arm. However, despite demonstrating signs of efficacy, the results failed to reach statistical significance. Median overall survival was 8.2 months in the Rigo group and 5.9 months in the best supportive care group, but the P value was 0.33. I'll come back to this data later in this article. But the bottom line is that ONTIME failed.

In the aftermath of the trial's failure, they were able to identify a sub-group of patients for whom the drug looked more promising. In the 184 patients who had progressed on or failed previous treatment with HMAs, the median survival was 8.5 months vs. 4.7 months (p=0.022). And the study was able to build on the SAE profile for Rigosertib with Grade 3/4 hematologic and non-hematologic AE's in less than 7% and 3% of patients, respectively. Not bad when you consider that the overall health of this patient group was pretty fragile.

So with this promising subgroup analysis, the company vowed to redo a Phase 3 trial looking at patients who matched the subgroup. That was right about when I lost track of them. The share price languished, resulting in two reverse splits and compromised capital raises involving warrants. I'm never a fan of warrants, but they have a place and time in attracting investment when the potential reward may be a way off.

It would cost Onconova a great deal of capital and an indeterminable period of time to bring the trial to fruition. In the meantime, additional pre-clinical data were generated by the company around Rigosertib's MOA.

A few words about subgroups before I continue. When we conduct clinical trials, we are simply conducting an experiment in which we seek to answer a question. Easy enough, right? In the land of biostatistics, when we design a clinical trial to answer one question, we utilize assumptions in our hypothesis to power the trial with the appropriate number of patients to answer the question...that question, and only that question. Very often, when a trial is completed, we generate lots of other data and within this data we almost always find other bits of interesting information. Sometimes this information can guide new experiments that will answer new questions. However, it is a bad idea to take this ancillary information as gospel. I was down at FDA some time ago to hear deputy director and FDA legend Robert Temple speak on this topic. He recanted a few fascinating examples.

One of the most referenced examples of subgroup analysis gone awry was in the Anturane Reinfarction Trial in which FDA rejected sulfinpyrazone for the prevention of sudden death following heart attack. This study looked at 1600 patients with a recent MI and followed them for two years. There was identified in the study a 74% reduction in sudden death in a subgroup of the treatment arm and multiple groups for which the p values were well under 0.05. However, the data excluded some patients and when the pooled group was analyzed as originally designed, the treatment failed to meet the threshold of statistical significance. Such was the data manipulation with Anturane that FDA published their rationale in NEJM as an example for the industry in 1980 and as I listened to Dr. Temple speak about this example literally 40 years after the original FDA decision, I was reminded about how timeless some clinical failures are in instructing the future. Another useful retrospective analysis of the trial can be found here. Ultimately, sulfinpyrazone was not found to be efficacious in preventing cardiac arrest or secondary MI in post infarction patients.

Expressed another way, subgroup analysis is kind of like shooting at a barn and then drawing a bullseye around the bullet hole. You would be correct in concluding after-the-fact that you hit the bullseye, but if you shoot at the barn a second time, you'll probably hit the barn again, but not the bullseye. Statistical significance is customarily accepted as a P value equal to or less than 0.05 or a less than 5% probability of happening by chance. When you allow multiplicity to occur with multiple subgroups, the probability of identifying a false positive is directly in proportion to the number of subgroups analyzed. For example, if you look at 20 different subgroups, you have nearly a 100% chance of identifying a false positive. Generally, companies present a subgroup finding not as a false positive, but as a potentially promising finding (but they generally neglect to mention that they cut up the data forwards, backwards and sideways to come to the finding). Here's another great article on the topic for those that want further reading.

Getting back to Onconova and Rigosertib, the new Phase 3 trial of Rigosertib in MDS was named "INSPIRE" and began enrolling patients in December of 2015. This trial would initially enroll 225 patients, again 2:1 Rigo vs. "Physician's choice". The primary endpoint would be overall survival as it had been in ONTIME, but also look at the International Prognostic Scoring System - Revised (IPSS-R) in the Very High-Risk (VHR) Subgroup. After an interim analysis by the Independent Data Monitoring Committee in early 2018, the trial was expanded to 360 patients on a pre-planned sample size re-estimation.

In the meantime, additional pre-clinical data were generated by Reddy et al., this time identifying Rigosertib as a RAS mimetic. A key journal publication in 2016 co-authored by Reddy, laid out compelling evidence that Rigosertib exerted its anticancer effects by binding the RAS binding domain (RBD) of RAS effectors, like RAF. Binding studies were reported with a sub-1nM Kd for both b-RAF and c-RAF. This new proposed MOA would represent a significant discovery because mutations in various RAS effector genes are implicated in 20-30% of cancers. If you follow the sector, you probably know that the RAS-pathway has been a prime, yet elusive target for cancer therapeutics. Several companies have pursued K-RAS and other RAS candidates (Amgen and Mirati, in particular), but the failures and only partial successes over the years have caused some to call RAS an "undruggable" target.

Unfortunately, as it was with Plk1 and PI3k, the controversy around Rigo's MOA didn't stop there. Although the company still regularly references the 2016 article, shortly after the article's publication, a different group, Ritt et al., conducted experiments in which they found Rigosertib did not block interaction of RAF with RAS, again at concentrations far higher than those looked at by Reddy's group. They did find signs of JNK signaling, but they could not conclude with the experiments conducted if the effect was direct or indirect, but since binding of RAS was unaffected, they concluded that any effects observed on RAS signaling would be indirect and downstream from Rigosertib's actual MOA. The only reason I can speculate as to the stark difference in binding between the two groups is that Reddy's group tested Rigo binding against a shortened version of the RAS Binding Domain of b-RAF and c-RAF in a recombinant construct rather than the whole protein.

Meanwhile, Anang Shelat's research group at St. Judes published work in 2016 applying phenotypic grouping to 154 molecules, including Rigosertib. The study was conceived as a methodology in high throughput screening for novel drug candidates. As they ran the exercise, 78% of the molecules correctly matched to the phenotypic class previously identified for them. One of the notable failures from the study was Rigosertib which classified in the study as a microtubule disruptor rather than an inhibitor of intracellular signaling with Plk1. The study also referenced a structural analysis of another compound in the study, TL-77, which was a close analog of Rigosertib. It's MOA? Strong direct inhibition of tubulin polymerization, and no interaction with Plk1 or PI3k signaling pathways.

All of the controversy caught the eye of Jonathan Weissman, who was using a CRISPR-mediated chemical-genetic strategy for identifying molecular targets. Applying his method to Rigosertib pointed to a MOA as a microtubule-destabilizing agent, but then he went further to demonstrate direct tubulin binding in several cell lines, and also by showing Rigosertib's ability to inhibit microtubule growth in vitro in a concentration specific manner. He went on to identify the colchicine site of tubulin as the Rigosertib binding site by isolating and analyzing crystal structures of the complex formed by alpha and beta tubulin. Finally, he identified a beta tubulin mutant with modifications in the colchicine binding site that conferred resistance to Rigosertib. In my view, Weissman's work was pretty comprehensive.

Brief side note: Colchicine was originally derived from the autumn crocus in the 1800s and is still used for the treatment of gout. If you're an adept botanist, be careful, because too much is deadly because of its anti-mitotic effects. Many early therapies have their origins in flower extracts, as was the case with the Madagascar periwinkle. In the 1950s, researchers from Eli Lilly noticed that the flower extract significantly decreased the level of white blood cells in mice, which lead to the discovery of two mitotic disrupting molecules, Vincristine and Vinblastine, which are still widely used today globally.

The disagreement between Reddy and Weissman culminated in the journal Molecular Cell on July 2, 2020, with dual publications on the matter. Reddy's group published data that a contaminant impurity in commercially available Rigosertib, ON01500, was responsible for the tubulin binding rather than Rigosertib itself, and that in Pharmaceutical grade Rigosertib, the impurity is absent and therefore, does not bind Tubulin. However, in response to this study, Weissman's group repeated the analysis on Pharmaceutical grade Rigosertib and was able to repeat their previous results.

Not only did Weissman repeat the results of microtubule inhibition with pharmaceutical grade Rigosertib, but they also went on to refute Reddy's rebuttal to Weissman's original study nearly point by point. Rather than go through the rebuttal section by section, you should read the paper, and especially the discussion section for yourself here. While they don't specifically accuse Reddy or Onconova of fabricating data, they write, "We find it impossible to reconstruct what may have led to these conflicting results and thus choose not to speculate about the origins."

Whenever I invest in a drug-in-development, I always feel better when I can find independent research saying similar things about the drug and/or target. That was actually how I ran into the conflicting research because I was digging into the MOA so that I could learn more and write an article in support of the company (we were long at the time). But that's science, it doesn't always give you the answers you want. When you can couple unbiased and independent scientific literature to rationalize claims put out by companies on the FDA development path, you will always have a stronger probability of success. That just wasn't the case with Onconova, unfortunately, and I adjusted accordingly.

With Rigosertib, you essentially have the company and the founder behind the company saying one thing, and then the scientific community at large saying something else. That said, I'm certain Reddy and Onconova utilize collaborators and/or contractors that may have independently verified some or all of their data, but the truth remains that I cannot find any truly independent research published that agrees with the company's findings. Their publications and the science behind them appear to be well thought out. Unlike the independently published literature, the company, and presumably Reddy, have a financial interest in the success of Rigosertib. So it begs the question why the company is seemingly in denial of what I would characterize as comprehensive and compelling evidence from multiple research groups over nearly 15 years that Rigosertib is functioning as a microtubule-destabilizing agent.

I don't think this really changes the current INSPIRE trial. Obviously, that trial is now on autopilot until it reads out later in the year. But for everything else in the hopper for Rigosertib, and in particular, its recently announced investigation into K-RAS mutated lung adenocarcinoma, this changes everything. The rationale for the trial is that Rigosertib exerts a direct effect on RAS signaling, but the external evidence suggests that any effect on RAS is indirect and secondary to its primary MOA on tubulin. In other words, the rationale for this trial is likely misguided. In my view, the company needs to take a harder look at the external data generated about Rigo's MOA and potentially retool their entire clinical strategy if they can change their view at some point. This includes their hints of Rigosertib's potential utility in COVID-19, based on this. I don't think you could argue that Vincristine with its MOA in mitotic arrest would be a logical approach for COVID-19, a similar rationale would probably follow for Rigosertib.

It's worth remembering that subgroup analyses often result in false positives that are likely to fail when retested. On that basis, INSPIRE is more than likely going to fail. However, I think INSPIRE has a chance of reading out with a nominal survival benefit in MDS. Here is my rationale. In the ONTIME trial, there appeared to be a survival benefit that failed to achieve statistical significance. Recall overall survival was 8.2 months in the treatment group and 5.9 months in the BSC group. In the treatment experienced subgroup, the survival in the BSC group was lower and Rigo arm was slightly higher, and this pushed the subgroup P value below the threshold of 0.05. So without seeing the totality of the data, I think that the study didn't have so much of an efficacy problem, but rather a standard deviation problem where this original study included both treatment naive and treatment experienced patients. I suspect that this variety in the disease timeline for patients enrolled in ONTIME resulted in a greater standard deviation in the survival and that if they had picked a more specific group, they may have pulled off a win the first time around.

That said, 2.3 months, or even the 3.8 months in the subgroup, isn't a huge survival benefit, but it is possible that with a more refined patient population as they've built into the INSPIRE trial, that the deviation will be lower and they will achieve the P value needed to deem it successful. Plus, they have two shots on goal with the trial design looking at the total study population, but also the Very High Risk (VHR) sub-population. In summary, I estimate INSPIRE has a 40% chance of success. Not great, but not terrible odds if you're the gambling type. However, if you are invested thinking that this is a slam dunk, you should probably adjust accordingly.

If INSPIRE fails, I think Onconova has a difficult decision to make in terms of continuing to throw money at a drug that has failed two Phase 3's. In other words, if INSPIRE fails, I think they go to zero. If INSPIRE succeeds, the company will have lots of work to complete for an NDA. The share price will spike, however, if I worked for FDA, I can already imagine lots of additional questions I would want answered about Rigosertib. Their recent denial of the published literature may work for regaining Nasdaq compliance, but it's not going to work on the mother ship.

For me, the more concerning thing is the company's reluctance to embrace the external science that points to a MOA that differs from the company's public pronouncement that Rigosertib acts on the RAS pathway. After my review of the literature on this matter, I emailed Investor Relations at Onconova on July 22. My question was simple, does Onconova acknowledge or refute the Weissman study that was published alongside the company's study on July 2, 2020. The next day I received an email back that the company had put out a PR that essentially restated their position on the matter and addressed NONE of the criticism of their own study. I found their response lacking given the strong and cogent data presented by Weissman. A Latin legal principle comes to mind, "Falsus in uno, falsus in omnibus".

Like many these days, I enjoy reading the conversations and comments on StockTwits and Twitter (mostly as a quiet observer) for the various equities I follow. If nothing else, they're entertaining. When you look at Onconova specifically you'll find a population of 30,000+ investors that are "in the room". Many posters claim to have completed significant due diligence on the company, yet none of them have challenged the company on the vast body of published data questioning the assertions of the company regarding the MOA of Rigosertib. Moreover, I witnessed many investors claim that the July 23rd PR stimulated by my innocent question to Investor Relations was "Great news".

With professional sports on a seemingly indefinite pause, many retail investors who have never made direct investments in equities are throwing money in the ring. Call it a combination of boredom and nowhere else to spend your stimulus checks, I suppose. If you're looking for big gains, biotech can indeed be a point of differentiation in your portfolio, and nowhere are these gains (and losses) bigger than with the small caps. However, credible investors in the biotech space need to question everything and not simply rely on the claims of the company and/or other investors to decide where to put their money. We are in interesting times, folks, and the technical and momentum traders treat any shred of PR like free press, even if they don't understand the reason behind it. The Sheriff of Nottingham will take your gold soon enough if you fail to do your homework.

In summary, Onconova has enjoyed a significant appreciation in share value, but investors should tread carefully into the readout of INSPIRE and consider how the conflicting data around Rigosertib's MOA could potentially impact the overall value and potential of this drug.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.

Read more:
Onconova And The Conflict Lurking Beneath The Hype - Seeking Alpha

The FDA has put a phase 1 trial of Cellectis off-the-shelf CAR-T therapy UCARTCS1A on clinical hold after learning of a death in the study. Cellectis said the multiple myeloma patient suffered a cardiac arrest after receiving the highest dose of the anti-CS1 allogeneic CAR-T.

Before joining the Cellectis trial, the patient underwent multiple prior lines of treatment, including with autologous CAR-T cells, without success. In the Cellectis trial, the patient was the first person to receive the higher, 3 million cells per kilogram dose of UCARTCS1A. The patient experienced cytokine release syndrome of undisclosed severity and died of a cardiac arrest 25 days after treatment.

The FDA has placed the trial on clinical hold while Cellectis evaluates the case. According to Cellectis, plans were already afoot to expand the lower, 1 million cells per kilogram dose cohort before the patient death. Preliminary data suggest 1 million cells per kilogram may be the phase 2 dose.

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There are signs the lower dose also has some safety issues. Analysts at Jefferies think investigators gave one or more of the three low-dose patients rituximab to activate the CAR-T safety switch. Work is underway to update the phase 1 protocol to mitigate the potential risks posed by UCARTCS1A.

The modifications may include increased monitoring of parameters related to cytokines. The Jefferies analysts think Cellectis should exclude patients previously treated with anti-BCMA CAR-Ts, such as Johnson & Johnsons JNJ-4528, due to risks related to back-to-back rounds of lymphodepletion, but note that management at the biotech think it is important to enroll that pre-treated population.

In a follow-up note, the analysts identified the use of cyclophosphamide, a chemotherapy drug, in the lymphodepletion regimen as a potential cause of the cardiac arrest. The argument is based on a 2017 paper that describes the case of a patient who died of acute heart failure after receiving a high dose of cyclophosphamide as part of an autologous stem cell transplantation treatment.

Many patients receive cyclophosphamide without suffering cardiac complications, but the analysts see reasons to think the subject enrolled in the Cellectis trial may have been at higher risk. Notably, prior exposure may increase risk, according to the analysts, suggesting the patients previous round of lymphodepletion may have been a factor.

Even if cyclophosphamide is at the heart of the problem, the analysts still think the UCARTCS1A dose is a contributing factor. With patients in the low-dose cohort also experiencing adverse events, the analysts see dosing at below 1 million cells per kilogram as one possible outcome of the situation.

Shares in Cellectis fell 13% in after-hours trading following news of the clinical hold. The value of Allogene Therapeutics, which licensed CAR-T assets that originated at Cellectis, held steady, likely reflecting a belief that the safety issue is limited to UCARTCS1A.

The Jefferies analysts see little or no read-through to other allogeneic programs, noting that the UCARTCS1A trial started at a higher dose than Cellectis two other clinical programs and that Allogene is testing several lymphodepletion regimens. The FDA placed a clinical trial of another Cellectis CAR-T, UCART123, on hold in 2017 after a patient died, but cleared it to resume months later.

Originally posted here:
Death in Cellectis off-the-shelf CAR-T trial triggers FDA hold - FierceBiotech

Embryonic stem cells. The ethical issues associated with stem cell research could be resolved through the use of induced pluripotent stem cells, which are derived from fully committed and differentiated cells of the adult body

The almost miraculous benefits that stem cells may one day deliver have long been speculated on. Capable of becoming different types of cells, they offer huge promise in terms of transplant and regenerative medicine. It is, however, also a medical field that urges caution one that must constantly battle exaggeration. If stem cells do in fact hold the potential to reverse the ageing process, for example, then such breakthroughs remain many years away.

Recently, though, the field has had cause for excitement. In 2006, Japanese researcher Shinya Yamanaka discovered that mature cells could be reprogrammed to become pluripotent, meaning they can give rise to any cell type of the body. In 2012, the discovery of these induced pluripotent stem cells (iPSCs) saw Yamanaka and British biologist John Gurdon awarded the Nobel Prize in Physiology or Medicine. Since then, there has been much talk regarding the potential iPSCs possess, not only for the world of medicine, but for society more generally, too.

A big stepHistorically, one of the major hurdles preventing further research into stem cells has been an ethical one. Until the discovery of iPSCs, embryonic stem cells (ESCs) represented the predominant area of research, with cells being taken from preimplantation human embryos. This process, however, involves the destruction of the embryo and, therefore, prevents the development of human life. Due to differences in opinion over when life is said to begin during embryonic development, stem cell researchers face an ethical quandary.

The promise of significant health benefits and new revenue streams has led some clinics to offer unproven stem cell treatments to individuals

With iPSCs, though, no such dilemmas exist. IPSCs are almost identical to ESCs but are derived from fully committed and differentiated cells of the adult body, such as a skin cell. Like ESCs, iPSCs are pluripotent and, as they are stem cells, can self-renew and differentiate, remaining indefinitely propagated and retaining the ability to give rise to any human cell type over time.

One important distinction to make is that both ESCs and iPSCs do not exist in nature, Vittorio Sebastiano, Assistant Professor (Research) of Obstetrics and Gynaecology (Reproductive and Stem Cell Biology) at Stanford Universitys Institute for Stem Cell Biology and Regenerative Medicine, told The New Economy. They are both beautiful laboratory artefacts. This means that at any stage of development, you cannot find ESCs or iPSCs in the developing embryo, foetus or even in the postnatal or adult body. Both ESCs and iPSCs can only be established and propagated in the test tube.

The reason neither ESCs nor iPSCs can be found in the body is that they harbour the potential to be very dangerous. As Sebastiano explained, these cells could spontaneously differentiate into tumorigenic masses because of their intrinsic ability to give rise to any cell type of the body. Over many years of research, scientists have learned how to isolate parts of the embryo (in the case of ESCs) and apply certain culture conditions that can lock cells in their proliferative and stem conditions. The same is true for iPSCs.

To create iPSCs, scientists take adult cells and exogenously provide a cocktail of embryonic factors, known as Yamanaka factors, for a period of two to three weeks. If the expression of such factors is sustained for long enough, they can reset the programme of the adult cells and establish an embryonic-like programme.

Turning back the clockThere is already a significant body of research dedicated to how stem cells can be used to treat disease. For example, mesenchymal stem cells (usually taken from adult bone marrow) have been deployed to treat bone fractures or as treatments for autoimmune diseases. It is hoped that iPSCs could hold the key for many more treatments.

Global stem cell market:25.5%Expected compound annual growth rate (2018-24)$467bnExpected market value (2024)

IPSCs are currently utilised to model diseases in vitro for drug screening and to develop therapies that one day will be implemented in people, Sebastiano explained. Given their ability to differentiate into any cell type, iPSCs can be used to differentiate into, for example, neurons or cardiac cells, and study specific diseases. In addition, once differentiated they can be used to test drugs on the relevant cell type. Some groups and companies are developing platforms for cell therapy, and I am personally involved in two projects that will soon reach the clinical stage.

Perhaps the most exciting prospects draw on iPSCs regenerative properties. Over time, cells age for a variety of reasons namely, increased oxidative stress, inflammation and exposure to pollutants or sunlight, among others. All these inputs lead to an accumulation of epigenetic mistakes those that relate to gene expression rather than an alteration of the genetic code itself in the cells, which, over time, results in the aberrant expression of genes, dysfunctionality at different levels, reduced mitochondrial activity, senescence and more besides. Although the epigenetic changes that occur with time may not be the primary cause of ageing, the epigenetic landscape ultimately affects and controls cell functionality.

What we have shown is that, if instead of being expressed for two weeks we express the reprogramming factors for a very short time, then we see that the cells rejuvenate without changing their identity, Sebastiano said. In other words, if you take a skin cell and express the reprogramming genes for two to four days, what you get is a younger skin cell.

By reprogramming a cell into an iPSC, you end up with an embryonic-like cell the reprogramming erases any epigenetic errors. If expressed long enough, it erases the epigenetic information of cell identity, leaving embryonic-like cells that are also young.

Slow and steadyAs with any scientific advancement, financial matters are key. According to Market Research Engine, the global stem cell market is expected to grow at a compound annual growth rate of 25.5 percent between 2018 and 2024, eventually reaching a market value of $467bn. The emergence of iPSCs has played a significant role in shaping these predictions, with major bioscience players, such as Australias Mesoblast and the US Celgene, working on treatments involving this particular type of stem cell.

The business potential around stem cell research is huge, Sebastiano told The New Economy. [Particularly] when it comes to developing cell banks for which we have detailed genetic information and, for example, studying how different drugs are toxic or not on certain genetic backgrounds, or when specific susceptibility mutations are present.

Unfortunately, even as the business cases for iPSC treatments increase, a certain degree of caution must be maintained. The promise of significant health benefits and new revenue streams has led some clinics to offer unproven stem cell treatments to individuals. There have been numerous reports of complications emerging, including the formation of a tumour following experimental stem cell treatment in one particular patient, as recorded in the Canadian Medical Association Journal last year. Such failures risk setting the field back years.

The challenge for researchers now will be one of balance. The potential of iPSCs is huge both in terms of medical progress and business development but can easily be undermined by misuse. Medical advancements, particularly ones as profound as those associated with iPSCs, simply cannot be rushed.

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Could induced pluripotent stem cells be the breakthrough genetics has been waiting for? - The New Economy

Stem cells have been holding great promise for regenerative medicine for ages. In the last decade, many studies have revealed this form of cell, which in Spanish is calledmother cell due to its ability to contribute to various different cell types, may be applied in regenerative medicine to diseases such as muscle and nervous system disorders, among others.

Scientists and stem cell leaders Sir John B. Gurdon and Shinya Yamanaka received the Nobel Prize in Physiology and Medicine in 2012 for this idea.

However, one of the key constraints in the application of these herbal remedies is the caliber of the stem cells that may be made in the lab, which impedes their use for curative purposes.

Currently, a team in the Cell Division and Cancer Group of the Spanish National Cancer Research Centre (CNIO), headed by researcher Marcos Malumbres, has recently developed a fresh, easy and fast technology that enhances in vitro and in vivo the possibility of stem cells to differentiate into adult cells. The study results will be released this week in The EMBO Journal.

In recent years, several protocols have been proposed to obtain reprogrammed stem cells in the laboratory from adult cells, but very few to improve the cells we already have.The method we developed is able to significantly increase the quality of stem cells obtained by any other protocol, thus favouring the efficiency of the production of specialised cell types.Mara Salazar-Roa, Study First Author and Researcher, Centro Nacional de Investigaciones Oncolgicas

Roa is likewise the co-corresponding author of this analysis.

Within this study, the researchers identified an RNA sequence, called microRNA 203, that can be found at the earliest embryonic stages before the embryo implants in the uterus and when stem cells have their highest ability to generate all the different cells.When they added this molecule to stem cells from the laboratory, they discovered that the cells ability to convert into other cell types improved appreciably.

To corroborate them, they used stem cells of both human and murine origin, and of genetically altered mice. The results were so spectacular, both in mouse cells and in human cells

Application of the microRNA for just 5 days boosts the potential of stem cells in most situations we tested and improves their ability to become other specialised cells, even months after being connected with the microRNA. Says Salazar-Roa.

According to the research, cells modified by this new protocol are more efficient in generating functional cardiac cells, opening the doorway to a better generation of different cell types essential for the cure of degenerative disorders.

Malumbres, mind of the CNIO Cell and Cancer Division Group, states:To deliver this asset to the clinic, cooperation with labs or companies that are looking to exploit that technology is now essential in each particular case.

In this circumstance, Salazar-Roa recently participated, in close collaboration with all the CNIOs Innovation group, in prestigious creation programs like IDEA2 International of the Massachusetts Institute of Technology (MIT) and also CaixaImpulse of thisLa Caixa Foundation, where they also obtained funding to start the maturation of the technology.

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New technology May Raise the quality of stem cells Found in regenerative medicine - Microbioz India

NEW YORK, July 06, 2020 (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq:MESO; ASX:MSB) today announced that an expanded access protocol (EAP) has been initiated in the United States for compassionate use of its allogeneic mesenchymal stem cell (MSC) product candidate remestemcel-L in the treatment of COVID-19 infected children with cardiovascular and other complications of multisystem inflammatory syndrome (MIS-C). Patients aged between two months and 17 years may receive one or two doses of remestemcel-L within five days of referral under the EAP.

The protocol was filed with the United States Food and Drug Administration (FDA) and provides physicians with access to remestemcel-L for an intermediate-size patient population1 under Mesoblast’s existing Investigational New Drug (IND) application. According to the FDA, expanded access is a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available.

MIS-C is a life-threatening complication of COVID-19 in otherwise healthy children and adolescents that includes massive simultaneous inflammation of multiple critical organs and their vasculature. In approximately 50% of cases this inflammation is associated with significant cardiovascular complications that directly involve heart muscle and may result in decreased cardiac function. In addition, the virus can result in dilation of coronary arteries with unknown future consequences. Recent articles from Europe and the United States have described this disease in detail.2-5

Mesoblast Chief Medical Officer Dr Fred Grossman said: The extensive body of safety and efficacy data generated to date using remestemcel-L in children with graft versus host disease suggest that our cellular therapy could provide a clinically important therapeutic benefit in MIS-C patients, especially if the heart is involved as a target organ for inflammation. Use of remestemcel-L in children with COVID-19 builds on and extends the potential application of this cell therapy in COVID-19 cytokine storm beyond the most severe adults with acute respiratory distress syndrome.”

Remestemcel-L Remestemcel-L is an investigational therapy comprising culture-expanded mesenchymal stem cells derived from the bone marrow of an unrelated donor and is administered in a series of intravenous infusions. Remestemcel-L is believed to have immunomodulatory properties to counteract the inflammatory processes that are implicated in several diseases by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

1.www.clinicaltrials.gov; NCT04456439 2.Lancet2020; May 7. DOI: https://doi.org/10.1016/S0140-6736(20)31094-1 3.Lancet. 2020; (May 13) https://doi.org/10.1016/S0140-6736(20)31103-X 4.https://www.nejm.org/doi/full/10.1056/NEJMoa2021756 5.https://www.nejm.org/doi/full/10.1056/NEJMoa2021680

About Mesoblast Mesoblast Limited (Nasdaq:MESO; ASX:MSB) is a world leader in developing allogeneic (off-the-shelf) cellular medicines. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of commercial products and late-stage product candidates. Mesoblast has a strong and extensive global intellectual property (IP) portfolio with protection extending through to at least 2040 in all major markets. The Company’s proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

Mesoblast’s Biologics License Application to seek approval of its product candidate RYONCIL (remestemcel-L) for pediatric steroid-refractory acute graft versus host disease (acute GVHD) has been accepted for priority review by the United States Food and Drug Administration (FDA), and if approved, product launch in the United States is expected in 2020. Remestemcel-L is also being developed for other inflammatory diseases in children and adults including moderate to severe acute respiratory distress syndrome. Mesoblast is completing Phase 3 trials for its product candidates for advanced heart failure and chronic low back pain. Two products have been commercialized in Japan and Europe by Mesoblast’s licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets.

Mesoblast has locations in Australia, the United States and Singapore and is listed on the Australian Securities Exchange (MSB) and on the Nasdaq (MESO). For more information, please see http://www.mesoblast.com, LinkedIn: Mesoblast Limited and Twitter: @Mesoblast

Forward-Looking Statements This announcement includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements should not be read as a guarantee of future performance or results, and actual results may differ from the results anticipated in these forward-looking statements, and the differences may be material and adverse. Forward- looking statements include, but are not limited to, statements about: the timing, progress and results of Mesoblast’s preclinical and clinical studies; Mesoblast’s ability to advance product candidates into, enroll and successfully complete, clinical studies; the timing or likelihood of regulatory filings and approvals; and the pricing and reimbursement of Mesoblast’s product candidates, if approved; Mesoblast’s ability to establish and maintain intellectual property on its product candidates and Mesoblast’s ability to successfully defend these in cases of alleged infringement. You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblast’s actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise.

Release authorized by the Chief Executive.

For further information, please contact:

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Expanded Access Protocol Initiated for Compassionate Use of Remestemcel-L in Children With Multisystem Inflammatory Syndrome Associated With COVID-19...

LOS ANGELES As medical experts learn about the novel coronavirus, which continues to exhibit an array of ever-evolving symptoms and long-term effects, researchers have found that the deadly illness can have deleterious impacts on the heart and brain.

A recent study published on June 25 in the journalCell Reports Medicine, found that while COVID-19 is commonly known as a respiratory illness, the disease has also been known to instigate inflammatory responses in the body which can negatively affect the function of ones heart and brain.

According to the study, researchers observed SARS-CoV-2 infecting human heart cells that were grown from stem cells in a lab. Within 72 hours of infection, the virus managed to spread and replicate, killing the heart cells.

The researchers brought up the particularly alarming possibility that if COVID-19 can infect the heart cells in a laboratory setting, it could possibly infect those specific organs, prompting the need for a cardiac-specific antiviral drug screen program.

And those concerns are not unwarranted, according to doctors and other researchers who have been observing and studying the wide range of health problems and negative outcomes that appear to come with the not-yet-fully-known territory of the novel virus.

The most common coronavirus symptoms are fever, a dry cough and shortness of breath and some people are contagious despite never experiencing symptoms. But as the virus continues to spread, less common symptoms are being reported, including loss of smell, vomiting and diarrhea, along with a variety of skin problems and harmful neurological effects.

A recentreportfromDr. Robert Stevens, M.D., the associate director of the Johns Hopkins Precision Medicine Center of Excellence for Neurocritical Care, said that coronavirus patients are continuously experiencing a wide range of disconcerting effects on the brain.

Some of the neural symptoms, according to Johns Hopkins, include:

Patients are also having peripheral nerve issues, such as Guillain-Barr syndrome, which can lead to paralysis and respiratory failure, wrote Stevens. I estimate that at least half of the patients Im seeing in the COVID-19 units have neurological symptoms.

While medical experts have continuously repeated that more is still being discovered about the virus, Stevens listed some possibilities on how COVID-19, a respiratory illness, is making its way to the brain.

The first possible way is that the virus may have the capacity to enter the brain and cause a severe and sudden infection. Cases reported in China and Japan found the viruss genetic material in spinal fluid, and a case in Florida found viral particles in brain cells, Stevens wrote.

He added that viral particles in the brain and spine may occur when the virus enters the body through a patients bloodstream or nerve endings.

The second possibility is that the bodys immune system has an overreaction to the virus, causing severe inflammatory responses that cause organ and tissue damage.

The third theory is the erratic physiological changes the disease causes in the body, which involve extremely high fever and low oxygen levels in the blood, result in harmful effects to the brain.

Stevens added that there has been an abnormal observance of blood clotting that has caused some coronavirus patients to suffer strokes. A stroke could occur if a blood clot were to block or narrow arteries leading to the brain, he said.

Another illness that has been known to impact the brain in patients with COVID-19 is currently being studied by Dr. Mady Hornig, an immunologist and professor of epidemiology at Columbia University.

Hornig said that Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness that has been found in patients who have recovered from coronaviruses such as SARS.

TheCenters for Disease Control and Preventioncites a 2015 report from the nations top medical advisory body, the Institute of Medicine, which says that an estimated 836,000 to 2.5 million Americans suffer from ME/CFS.

The CDC says that people with ME/CFS experience severe fatigue, sleep problems, as well as difficulty with thinking and concentrating while experiencing pain and dizziness.

Hornig said SARS-CoV-1 and MERS have been associated with longer-term difficulties, in which many people appeared to have symptoms of ME/CFS.

Hornig is currently researching the long-term effects of COVID-19, and has been confronted with an array of concerning symptoms that have persisted in patients, as well as herself.

She can personally attest to the variety of symptoms that have been reported in coronavirus patients, ever since she began to experience her own COVID-19 symptoms in April that have continued to impact her daily life for the past few months.

She has also experienced cardiac complications while dealing with the illness.

Since getting sick, Hornig said shes had to carry a pulse oximeter with her, a device which registers her pulse since she began to have tachycardia episodes when her fever began to decline. Tachycardia is a condition that can make a persons heart beat abnormally fast, reducing blood flow to the rest of the body,according to the Mayo Clinic.

Hornigs most recent episode was on June 22. Her pulse registered at 135 beats per minute, which she said occurred just from her sitting at her computer. She said a normal pulse for someone her age would be around 60-70 beats per minute.

The findings on the novel virus potential effects on the heart and brain come as the CDC continues to update itslistof coronavirus symptoms and high-risk conditions for COVID-19 complications.

Notably, the CDC also removed the specific age threshold from the older adult classification. CDC now warns that among adults, risk increases steadily as you age, and its not just those over the age of 65 who are at increased risk for severe illness, the agency wrote.

Johns Hopkins has noted that younger patients in their 30s and 40s are reportedly having strokes as a result of COVID-19.

It may have something to do with the hyperactive blood-clotting system in these patients, Stevens said. Another system that is hyper-activated in patients with COVID-19 is the endothelial system, which consists of the cells that form the barrier between blood vessels and body tissue. This system is more biologically active in younger patients, and the combination of hyperactive endothelial and blood-clotting systems puts these patients at a major risk for developing blood clots.

But Stevens cautioned that more conclusive data is needed before the medical community can say with assurance that younger people are particularly susceptible to strokes caused by the novel coronavirus.

It is also plausible that theres an increase in stroke in COVID-19 patients of all ages, Stevens said.

34.052234-118.243685

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Its not just the lungs: COVID-19 can affect the brain and heart of those infected, researchers say - WITI FOX 6 Milwaukee

Stem cells have been holding great promise for regenerative medicine for years. In the last decade, several studies have shown that this type of cell, which in Spanish is called mother cell because of its ability to give rise to a variety of different cell types, can be applied in regenerative medicine for diseases such as muscular and nervous system disorders, among others. Researchers and stem cell pioneers Sir John B. Gurdon and Shinya Yamanaka received the Nobel Prize in Physiology and Medicine in 2012 for this idea. However, one of the main limitations in the application of these cell therapies is the quality of the stem cells that can be generated in the laboratory, which impedes their use for therapeutic purposes.Now, a team from the Cell Division and Cancer Group of the Spanish National Cancer Research Centre (CNIO), led by researcher Marcos Malumbres, has developed a new, simple and fast technology that enhances in vitro and in vivo the potential of stem cells to differentiate into adult cells. The research results are published in The EMBO Journal.

In recent years, several protocols have been proposed to obtain reprogrammed stem cells in the laboratory from adult cells, but very few to improve the cells we already have. The method we developed is able to significantly increase the quality of stem cells obtained by any other protocol, thus favouring the efficiency of the production of specialised cell types, says Mara Salazar-Roa, researcher at the CNIO, first author of the article and co-corresponding author.

In this study, the researchers identified an RNA sequence, called microRNA 203, which is found in the earliest embryonic stages before the embryo implants in the womb and when stem cells still have their maximum capacity to generate all the different tissues. When they added this molecule to stem cells in the laboratory, they discovered that the cells ability to convert to other cell types improved significantly.

To corroborate this, they used stem cells of human and murine origin, and of genetically modified mice. The results were spectacular, both in mouse cells and in human cells. Application of this microRNA for just 5 days boosts the potential of stem cells in all scenarios we tested and improves their ability to become other specialised cells, even months after having been in contact with the microRNA, says Salazar-Roa.

According to the study, cells modified by this new protocol are more efficient in generating functional cardiac cells, opening the door to an improved generation of different cell types necessary for the treatment of degenerative diseases.

Malumbres, head of the CNIO Cell and Cancer Division Group, says: To bring this asset to the clinic, collaboration with laboratories or companies that want to exploit this technology is now necessary in each specific case. In this context, Salazar-Roa recently participated, in close collaboration with the CNIOs Innovation team, in prestigious innovation programs such as IDEA2 Global of the Massachusetts Institute of Technology (MIT) and CaixaImpulse of the la Caixa Foundation, from which they also obtained funding to start the development of this technology.

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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Quick and Simple Technology Enhances the Potential of Stem Cells To Differentiate Into Adult Cells - Technology Networks

Transparency Market Research (TMR) has published a new report on the globalcell separation technology marketfor the forecast period of 20192027. According to the report, the global cell separation technology market was valued at ~ US$ 5 Bn in 2018, and is projected to expand at a double-digit CAGR during the forecast period.

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Cell separation, also known as cell sorting or cell isolation, is the process of removing cells from biological samples such as tissue or whole blood. Cell separation is a powerful technology that assists biological research. Rising incidences of chronic illnesses across the globe are likely to boost the development of regenerative medicines or tissue engineering, which further boosts the adoption of cell separation technologies by researchers.

Expansion of the global cell separation technology market is attributed to an increase in technological advancements and surge in investments in research & development, such asstem cellresearch and cancer research. The rising geriatric population is another factor boosting the need for cell separation technologies Moreover, the geriatric population, globally, is more prone to long-term neurological and other chronic illnesses, which, in turn, is driving research to develop treatment for chronic illnesses. Furthermore, increase in the awareness about innovative technologies, such as microfluidics, fluorescent-activated cells sorting, and magnetic activated cells sorting is expected to propel the global cell separation technology market.

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North America dominated the global cell separation technology market in 2018, and the trend is anticipated to continue during the forecast period. This is attributed to technological advancements in offering cell separation solutions, presence of key players, and increased initiatives by governments for advancing the cell separation process. However, insufficient funding for the development of cell separation technologies is likely to hamper the global cell separation technology market during the forecast period. Asia Pacific is expected to be a highly lucrative market for cell separation technology during the forecast period, owing to improving healthcare infrastructure along with rising investments in research & development in the region.

Rising Incidences of Chronic Diseases, Worldwide, Boosting the Demand for Cell Therapy

Incidences of chronic diseases such as diabetes, obesity, arthritis, cardiac diseases, and cancer are increasing due to sedentary lifestyles, aging population, and increased alcohol consumption and cigarette smoking. According to the World Health Organization (WHO), by 2020, the mortality rate from chronic diseases is expected to reach73%, and in developing counties,70%deaths are estimated to be caused by chronic diseases. Southeast Asia, Eastern Mediterranean, and Africa are expected to be greatly affected by chronic diseases. Thus, the increasing burden of chronic diseases around the world is fuelling the demand for cellular therapies to treat chronic diseases. This, in turn, is driving focus and investments on research to develop effective treatments. Thus, increase in cellular research activities is boosting the global cell separation technology market.

Increase in Geriatric Population Boosting the Demand for Surgeries

The geriatric population is likely to suffer from chronic diseases such as cancer and neurological disorders more than the younger population. Moreover, the geriatric population is increasing at a rapid pace as compared to that of the younger population. Increase in the geriatric population aged above 65 years is projected to drive the incidences of Alzheimers, dementia, cancer, and immune diseases, which, in turn, is anticipated to boost the need for corrective treatment of these disorders. This is estimated to further drive the demand for clinical trials and research that require cell separation products. These factors are likely to boost the global cell separation technology market.

According to the United Nations, the geriatric population aged above 60 is expected to double by 2050 and triple by 2100, an increase from962 millionin 2017 to2.1 billionin 2050 and3.1 billionby 2100.

Productive Partnerships in Microfluidics Likely to Boost the Cell Separation Technology Market

Technological advancements are prompting companies to innovate in microfluidics cell separation technology. Strategic partnerships and collaborations is an ongoing trend, which is boosting the innovation and development of microfluidics-based products. Governments and stakeholders look upon the potential in single cell separation technology and its analysis, which drives them to invest in the development ofmicrofluidics. Companies are striving to build a platform by utilizing their expertise and experience to further offer enhanced solutions to end users.

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Stem Cell Research to Account for a Prominent Share

Stem cell is a prominent cell therapy utilized in the development of regenerative medicine, which is employed in the replacement of tissues or organs, rather than treating them. Thus, stem cell accounted for a prominent share of the global market. The geriatric population is likely to increase at a rapid pace as compared to the adult population, by 2030, which is likely to attract the use of stem cell therapy for treatment. Stem cells require considerably higher number of clinical trials, which is likely to drive the demand for cell separation technology, globally. Rising stem cell research is likely to attract government and private funding, which, in turn, is estimated to offer significant opportunity for stem cell therapies.

Biotechnology & Pharmaceuticals Companies to Dominate the Market

The number of biotechnology companies operating across the globe is rising, especially in developing countries. Pharmaceutical companies are likely to use cells separation techniques to develop drugs and continue contributing through innovation. Growing research in stem cell has prompted companies to own large separate units to boost the same. Thus, advancements in developing drugs and treatments, such as CAR-T through cell separation technologies, are likely to drive the segment.

As per research, 449 public biotech companies operate in the U.S., which is expected to boost the biotechnology & pharmaceutical companies segment. In developing countries such as China, China Food and Drug Administration (CFDA) reforms pave the way for innovation to further boost biotechnology & pharmaceutical companies in the country.

Global Cell Separation Technology Market: Prominent Regions

North America to Dominate Global Market, While Asia Pacific to Offer Significant Opportunity

In terms of region, the global cell separation technology market has been segmented into five major regions: North America, Europe, Asia Pacific, Latin America, and the Middle East & Africa. North America dominated the global market in 2018, followed by Europe. North America accounted for a major share of the global cell separation technology market in 2018, owing to the development of cell separation advanced technologies, well-defined regulatory framework, and initiatives by governments in the region to further encourage the research industry. The U.S. is a major investor in stem cell research, which accelerates the development of regenerative medicines for the treatment of various long-term illnesses.

The cell separation technology market in Asia Pacific is projected to expand at a high CAGR from 2019 to 2027. This can be attributed to an increase in healthcare expenditure and large patient population, especially in countries such as India and China. Rising medical tourism in the region and technological advancements are likely to drive the cell separation technology market in the region.

Launching Innovative Products, and Acquisitions & Collaborations by Key Players Driving Global Cell Separation Technology Market

The global cell separation technology market is highly competitive in terms of number of players. Key players operating in the global cell separation technology market include Akadeum Life Sciences, STEMCELL Technologies, Inc., BD, Bio-Rad Laboratories, Inc., Miltenyi Biotech, 10X Genomics, Thermo Fisher Scientific, Inc., Zeiss, GE Healthcare Life Sciences, PerkinElmer, Inc., and QIAGEN.

These players have adopted various strategies such as expanding their product portfolios by launching new cell separation kits and devices, and participation in acquisitions, establishing strong distribution networks. Companies are expanding their geographic presence in order sustain in the global cell separation technology market. For instance, in May 2019, Akadeum Life Sciences launched seven new microbubble-based products at a conference. In July 2017, BD received the U.S. FDAs clearance for its BD FACS Lyric flow cytometer system, which is used in the diagnosis of immunological disorders.

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Cell Separation Technology Market by Leading Manufacturers, Demand and Growth Overview 2019 to 2027 - Jewish Life News

SAN FRANCISCO, June 29, 2020 /PRNewswire/ --Entitled "Randomized, Double Blind, Placebo-Controlled, Safety and Efficacy Study of Dutogliptin in Combination with Filgrastim in Early Recovery Post-Myocardial Infarction: rationale, design and first interim analysis", the presentation provides an initial insight into patient outcomes of the trial that is currently ongoing in multiple centers. Patients included in this trial experienced a severe form of Myocardial Infarction known as STEMI. Soon after the initial intervention to re-establish adequate blood flow to the coronary arteries, patients begin a two-week treatment with Recardio's dutogliptin, a small molecule that enables sustained homing of mobilised stem cells to the site of cardiac injury. By releasing paracrine factors, stem cells have been shown to have significant repair and regenerative effects that improve healing and recovery of cardiac function after the infarction.

More information about the clinical program is available by visiting the "clinicaltrials.gov" website at the following link:https://clinicaltrials.gov/ct2/show/NCT03486080

About Recardio

Recardio Inc. is a clinical-stage life science company focusing ontherapies for cardiovascular, oncology and infectious diseases. The company is located in San Francisco, California, and hasoperations in the USA and Europe.The company's lead drug candidate, dutogliptin, is a DPP-IV inhibitor that has demonstrated significant effects in activating various chemokines like SDF-1, a protein that is critical for cardiac regeneration. In addition to its current Phase 2 cardiovascular clinical program, Recardio will fully develop the therapeutic platform as a regenerative medication for patients with various cardiovascular diseases including acute myocardial infarction and chronic heart failure, with the potential of improving heart function, quality of life and survival.

For more information, visit:http://www.recardio.eu/or contact[emailprotected]

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Interim Analysis of Recardio's Phase II Clinical Trial to Be Presented at the 2020 Congress of the European Society of Cardiology - PRNewswire

Pune, Maharashtra, India, June 29 2020 (Wiredrelease) Data Bridge Market Research A New Business Intelligence Report released by Data Bridge Market Research with title Global Exosome Therapeutic Market size, share, growth, Industry Trends and Forecast 2027 has abilities to raise as the most significant market worldwide as it has remained playing a remarkable role in establishing progressive impacts on the universal economy. The Global Exosome Therapeutic Market Report offers energetic visions to conclude and study the market size, market hopes, and competitive surroundings. The research is derived through primary and secondary statistics sources and it comprises both qualitative and quantitative detailing. This report has been crafted as the result of persistent efforts lead by knowledgeable forecasters, innovative analysts and brilliant researchers who indulge in detailed and diligent research on different markets, trends and emerging opportunities in the successive direction for the business needs.

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DBMR Analyses that the Exosome Therapeutic Market is growing with a CAGR of 21.9% in the forecast period of 2019 to 2026 and expected to reach USD 31,691.52 million by 2026 from USD 6,500.00 million in 2018. Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

Increased number of exosome therapeutics as compared to the past few years will accelerate market growth. Companies are receiving funding for exosome therapeutic research and clinical trials. For instance, In September 2018, EXOCOBIO has raised USD 27 million in its series B funding. The company has raised USD 46 million as series a funding in April 2017. The series B funding will help the company to set up GMP-compliant exosome industrial facilities to enhance production of exosomes to commercialize in cosmetics and pharmaceutical industry.

KNOW YOUR OPTIONS IN THE FIGHT AGAINST COVID-19

The COVID-19 Pandemic has created bottlenecks across industry pipelines, sales funnels, and supply chain activities. This has created unprecedented budget pressure on company spending for industry leaders. This has increased requirement for opportunity analysis, price trend knowledge and competitive outcomes. Use the DBMR team to create new sales channels and capture new markets previously unknown. DBMR helps its clients to grow in these uncertain markets.

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The Global Exosome Therapeutic market 2020 research provides a basic overview of the industry including definitions, classifications, applications and industry chain structure. The Global Exosome Therapeutic Market Share analysis is provided for the international markets including development trends, competitive landscape analysis, and key regions development status. Development policies and plans are discussed as well as manufacturing processes and cost structures are also analyzed. This report also states import/export consumption, supply and demand Figures, cost, price, revenue and gross margins. For each manufacturer covered, this report analyzes their Exosome Therapeutic manufacturing sites, capacity, production, ex-factory price, revenue and market share in global market.

Major Players in Global Exosome Therapeutic Market Include

evox THERAPEUTICSEXOCOBIOExopharmAEGLE TherapeuticsUnited Therapeutics CorporationCodiak BioSciencesJazz Pharmaceuticals, Inc.Boehringer Ingelheim International GmbHReNeuron Group plcCapricor TherapeuticsAvalon Globocare Corp.CREATIVE MEDICAL TECHNOLOGY HOLDINGS INC.Stem Cells Group..

Complete Report is Available (Including Full TOC, List of Tables & Figures, Graphs, and Chart)@https://www.databridgemarketresearch.com/toc/?dbmr=global-exosome-therapeutic-market

New Exosome Therapeutic Market Developments in 2019

In January 2019, Codiak BioSciences has collaborated with Jazz Pharmaceuticals, Inc. to develop and commercialize exosome therapeutics to treat cancer. The collaboration will help the company to address issues which have been often implicated in solid tumors and hematological malignancies.

In October 2018, Avalon GloboCare Corp. has collaborated with Weill Cornell Medicine to form standards in cGMP-grade for human endothelial cells sourced exosome which is significant for organ regeneration and vascular health and isolation and identification of exosomes sourced from tissue for liquid biopsy and clinical use. The collaboration will help the company to lead market as exosome isolation system as will be first in the world for standardization processing of cGMP-grade exosomes for clinical studies.

In July 2018, Capricor Therapeutics has formed collaboration with the U.S. Army Institute of Surgical Research (USAISR) to discover potential for CAP-2003 (exosomes) in order to address trauma-related conditions and injuries. The collaboration will help to test CAP-2003 as a tool for preservation of life.

This research is categorized differently considering the various aspects of this market. It also evaluates the current situation and the future of the market by using the forecast horizon. The forecast is analyzed based on the volume and revenue of this market. The tools used for analyzing the Global Exosome Therapeutic Market research report include SWOT analysis.

The Global Exosome Therapeutic segments and Market Data Break Down are illuminated below:

By Type (Natural Exosomes, Hybrid Exosomes

By Source (Dendritic Cells, Mesenchymal Stem Cells, Blood, Milk, Body Fluids, Saliva, Urine Others)

By Therapy (Immunotherapy, Gene Therapy, Chemotherapy)

By Transporting Capacity (Bio Macromolecules, Small Molecules

By Application (Oncology, Neurology, Metabolic Disorders, Cardiac Disorders, Blood Disorders, Inflammatory Disorders, Gynecology Disorders, Organ Transplantation, Others)

By Route of administration (Oral, Parenteral)

By End User (Hospitals, Diagnostic Centers, Research & Academic Institutes)

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The Global Exosome Therapeutic Market in terms of investment potential in various segments of the market and illustrate the feasibility of explaining the feasibility of a new project to be successful in the near future. The core segmentation of the global market is based on product types, SMEs and large corporations. The report also collects data for each major player in the market based on current company profiles, gross margins, sales prices, sales revenue, sales volume, photos, product specifications and up-to-date contact information.

What are the strengths and weaknesses of the key vendors?

Definitively, this report will give you an unmistakable perspective on every single reality of the market without a need to allude to some other research report or an information source. Our report will give all of you the realities about the past, present, and eventual fate of the concerned Market.

Scope of the Exosome Therapeutic Market

The global exosome therapeutic market is segmented on the basis of countries into U.S., Mexico, Turkey, Hong Kong, Australia, South Korea, Argentina, Colombia, Peru, Chile, Ecuador, Venezuela, Panama, Dominican Republic, El Salvador, Paraguay, Costa Rica, Puerto Rico, Nicaragua and Uruguay.

All country based analysis of the exosome therapeutic market is further analyzed based on maximum granularity into further segmentation. On the basis of type, the market is segmented into natural exosomes and hybrid exosomes. Based on source, the market is segmented into dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, urine and others. On the basis of therapy, the market is segmented into immunotherapy, gene therapy and chemotherapy. On the basis of transporting capacity, the market is segmented into bio macromolecules and small molecules. On the basis of application, the market is segmented into oncology, neurology, metabolic disorders, cardiac disorders, blood disorders, inflammatory disorders, gynecology disorders, organ transplantation and others. On the basis of route of administration, the market is segmented into pa oral and parenteral. On the basis of end user, the market is segmented into hospitals, diagnostic centers and research & academic institutes and others.

Some Points from Table of Content:

1 Report Overview1.1 Study Scope1.2 Key Market Segments1.3 Regulatory Scenario by Region/Country1.4 Market Investment Scenario Strategic1.5 Market Analysis by Type1.5.1 Global Exosome Therapeutic Market Share by Type (2020-2027)1.5.2 Type 11.5.3 Type 21.5.4 Other1.6 Market by Application1.6.1 Global Exosome Therapeutic Market Share by Application (2020-2027)1.6.2 Application 11.6.3 Application 21.6.4 Other1.7 Exosome Therapeutic Industry Development Trends under COVID-19 Outbreak1.7.1 Region COVID-19 Status Overview1.7.2 Influence of COVID-19 Outbreak on Exosome Therapeutic Industry Development

Global Market Growth Trends2.1 Industry Trends2.1.1 SWOT Analysis2.1.2 Porters Five Forces Analysis2.2 Potential Market and Growth Potential Analysis2.3 Industry News and Policies by Regions2.3.1 Industry News2.3.2 Industry Policies3 Value Chain of Exosome Therapeutic Market3.1 Value Chain Status3.2 Exosome Therapeutic Manufacturing Cost Structure Analysis3.2.1 Production Process Analysis3.2.2 Manufacturing Cost Structure of Exosome Therapeutic3.2.3 Labor Cost of Exosome Therapeutic3.3 Sales and Marketing Model Analysis3.4 Downstream Major Customer Analysis (by Region)

4 Players Profiles4.1 Player 14.1.1 Player 1 Basic Information4.1.2 Exosome Therapeutic Product Profiles, Application and Specification4.1.3 Player 1 Exosome Therapeutic Market Performance (2015-2020)4.1.4 Player 1 Business Overview4.2 Player 24.2.1 Player 2 Basic Information4.2.2 Exosome Therapeutic Product Profiles, Application and Specification4.2.3 Player 2 Exosome Therapeutic Market Performance (2015-2020)4.2.4 Player 2 Business Overview4.3 Player 34.3.1 Player 3 Basic Information4.3.2 Exosome Therapeutic Product Profiles, Application and Specification4.3.3 Player 3 Exosome Therapeutic Market Performance (2015-2020)4.3.4 Player 3 Business Overview4.4 Player 44.4.1 Player 4 Basic Information4.4.2 Exosome Therapeutic Product Profiles, Application and Specification4.4.3 Player 4 Exosome Therapeutic Market Performance (2015-2020)4.4.4 Player 4 Business Overview4.5 Player 54.5.1 Player 5 Basic Information4.5.2 Exosome Therapeutic Product Profiles, Application and Specification4.5.3 Player 5 Exosome Therapeutic Market Performance (2015-2020)

4.5.4 Player 5 Business Overview5 Global Exosome Therapeutic Market Analysis by Regions5.1 Global Exosome Therapeutic Sales, Revenue and Market Share by Regions5.1.1 Global Exosome Therapeutic Sales by Regions (2015-2020)5.1.2 Global Exosome Therapeutic Revenue by Regions (2015-2020)5.2 North America Exosome Therapeutic Sales and Growth Rate (2015-2020)5.3 Europe Exosome Therapeutic Sales and Growth Rate (2015-2020)5.4 Asia-Pacific Exosome Therapeutic Sales and Growth Rate (2015-2020)5.5 Middle East and Africa Exosome Therapeutic Sales and Growth Rate (2015-2020)5.6 South America Exosome Therapeutic Sales and Growth Rate (2015-2020)

11 Global Exosome Therapeutic Market Segment byTypes12 Global Exosome Therapeutic Market Segment by Applications13 Exosome Therapeutic Market Forecast by Regions (2020-2027)ContinuedComplete Report Is Available| Get Free TOC @https://www.databridgemarketresearch.com/toc/?dbmr=global-exosome-therapeutic-market

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Exosome Therapeutic Market Size, 2020-New Technological Change Helping Market, Application, Driver, - PharmiWeb.com

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Mercks anti-PD-1 therapy, as monotherapy for the first-line treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. The approval is based on results from the Phase 3 KEYNOTE-177 trial, in which KEYTRUDA significantly reduced the risk of disease progression or death by 40% (HR=0.60 [95% CI, 0.45-0.80; p=0.0004]) compared with chemotherapy, the current standard of care. In the study, treatment with KEYTRUDA also more than doubled median progression-free survival (PFS) compared with chemotherapy (16.5 months [95% CI, 5.4-32.4] versus 8.2 months [95% CI, 6.1-10.2]).

Todays approval has the potential to change the treatment paradigm for the first-line treatment of patients with MSI-H colorectal cancer, based on the important findings from KEYNOTE-177 that showed KEYTRUDA monotherapy demonstrated superior progression-free survival compared to standard of care chemotherapy, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. Our commitment to pursuing biomarker research continues to help us bring new treatments to patients, particularly for those who have few available options.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see Selected Important Safety Information below.

This approval was granted less than one month following the submission of a new supplemental Biologics License Application (sBLA), which was reviewed under the FDAs Real-Time Oncology Review (RTOR) pilot program. This review also was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among its international partners. For this application, a modified Project Orbis was undertaken, and the FDA is collaborating with the Australian Therapeutic Goods Administration, Health Canada and Swissmedic on their ongoing review of the application.

Patients with unresectable or metastatic MSI-H colorectal cancer have historically faced poor outcomes, and until today, chemotherapy-containing regimens were the only FDA-approved first-line treatment options, said Luis A. Diaz, M.D., head of the division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center. In patients who were treated with KEYTRUDA and responded (n=67) in the KEYNOTE-177 trial, 43% of patients experienced a duration of response lasting two years or longer. This approval helps address the unmet need to provide a new monotherapy treatment option for patients.

Data Supporting the Approval

The approval was based on data from KEYNOTE-177 (NCT02563002), a multi-center, randomized, open-label, active-controlled trial that enrolled 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR colorectal cancer. Microsatellite instability (MSI) or mismatch repair (MMR) tumor status was determined locally using polymerase chain reaction or immunohistochemistry, respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

Patients were randomized 1:1 to receive KEYTRUDA 200 mg intravenously every three weeks or investigators choice of the following chemotherapy regimens given intravenously every two weeks:

Treatment with KEYTRUDA or chemotherapy continued until Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every nine weeks. Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression. The main efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR) according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ, and overall survival (OS). Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DOR).

Patients were enrolled and randomized to KEYTRUDA (n=153) or chemotherapy (n=154). The baseline characteristics of these 307 patients were: median age of 63 years (range, 24 to 93), 47% age 65 or older; 50% male; 75% White and 16% Asian; 52% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, and 48% had an ECOG PS of 1; and 27% received prior adjuvant or neoadjuvant chemotherapy. Among the 154 patients randomized to receive chemotherapy, 143 received chemotherapy per the protocol. Of these 143 patients, 56% received mFOLFOX6, 44% received FOLFIRI, 70% received bevacizumab plus mFOLFOX6 or FOLFIRI, and 11% received cetuximab plus mFOLFOX6 or FOLFIRI. The median follow-up time was 27.6 months (range, 0.2 to 48.3 months).

In this study, KEYTRUDA monotherapy significantly reduced the risk of disease progression or death by 40% (HR=0.60 [95% CI, 0.45-0.80; p=0.0004]) and showed a median PFS of 16.5 months (95% CI, 5.4-32.4) compared with 8.2 months (95% CI, 6.1-10.2) for patients treated with chemotherapy. For PFS, in the KEYTRUDA arm, there were 82 patients (54%) with an event versus 113 patients (73%) in the chemotherapy arm. At the time of the PFS analysis, the OS data were not mature (66% of the required number of events for the OS final analysis). For patients treated with KEYTRUDA, the ORR was 44% (95% CI, 35.8-52.0), with a complete response rate of 11% and a partial response rate of 33%, and for patients treated with chemotherapy, the ORR was 33% (95% CI, 25.8-41.1), with a complete response rate of 4% and a partial response rate of 29%. Median DOR was not reached (range, 2.3+ to 41.4+) with KEYTRUDA versus 10.6 months (range, 2.8 to 37.5+) with chemotherapy. Based on 67 patients with a response in the KEYTRUDA arm and 51 patients with a response in the chemotherapy arm, 75% in the KEYTRUDA arm had a duration of response greater than or equal to 12 months versus 37% in the chemotherapy arm, and 43% in the KEYTRUDA arm had a duration of response greater than or equal to 24 months versus 18% in the chemotherapy arm.

Among the 153 patients with MSI-H or dMMR colorectal cancer treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 11.1 months (range, 1 day to 30.6 months). Adverse reactions occurring in patients with MSI-H or dMMR colorectal cancer were similar to those occurring in 2,799 patients with melanoma or non-small cell lung cancer treated with KEYTRUDA as a single agent.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) 10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High (TMB-H)

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

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FDA Approves Merck's KEYTRUDA (pembrolizumab) for First-Line Treatment of Patients With Unresectable or Metastatic MSI-H or dMMR Colorectal Cancer -...

New York, July 1 : A team of US scientists, led by an Indian-origin researcher revealed that SARS-CoV-2 (coronavirus), the virus behind Covid-19, can infect heart cells in a lab dish.

This suggests it may be possible for heart cells in Covid-19 patients to be directly infected by the virus.

The discovery, published today in the journal Cell Reports Medicine, was made using heart muscle cells that were produced by stem cell technology.

We not only uncovered that these stem cell-derived heart cells are susceptible to infection by a novel coronavirus, but that the virus can also quickly divide within the heart muscle cells, said study researcher Arun Sharma from the Cedars-Sinai Board of Governors Regenerative Medicine Institute in the US.

Even more significant, the infected heart cells showed changes in their ability to beat after 72 hours of infection, Sharma added.Although many COVID-19 patients experience heart problems, the reasons remain unclear. Pre-existing cardiac conditions or inflammation and oxygen deprivation resulting from the infection have all been implicated.

But there has until now been only limited evidence the SARS-CoV-2 virus directly infects the individual muscle cells of the heart.The study also demonstrated human stem cell-derived heart cells infected by SARS-CoV-2 change their gene expression profile.This offers further confirmation the cells can be actively infected by the virus and activate innate cellular defence mechanisms in an effort to help clear-out the virus.

This viral pandemic is predominately defined by respiratory symptoms, but there are also cardiac complications, including arrhythmia, heart failure and viral myocarditis, said study co-author Clive Svendsen.

While this could be the result of massive inflammation in response to the virus, our data suggest that the heart could also be directly affected by the virus in Covid-19, Svendsen added.

Researchers also found that treatment with an ACE2 antibody was able to blunt viral replication on stem cell-derived heart cells, suggesting that the ACE2 receptor could be used by SARS-CoV-2 to enter human heart muscle cells.

By blocking the ACE2 protein with an antibody, the virus is not as easily able to bind to the ACE2 protein, and thus cannot easily enter the cell, said Sharma. This not only helps us understand the mechanisms of how this virus functions, but also suggests therapeutic approaches that could be used as a potential treatment for SARS-CoV-2 infection, he explained.

The study used human induced pluripotent stem cells (iPSCs), a type of stem cell that is created in the lab from a persons blood or skin cells. IPSCs can make any cell type found in the body, each one carrying the DNA of the individual. This work illustrates the power of being able to study human tissue in a dish, the authors wrote.

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Autologous Stem Cell Based Therapies Market 2020-2026 research report is an in-depth analysis of the latest trends, market size, status, upcoming technologies, industry drivers, challenges opportunity with key company profiles and strategies of players.The Autologous Stem Cell Based Therapies Market report also provides the market impact and new opportunities created due to the COVID19 catastrophe.

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Autologous Stem Cell Based Therapies Market 2020-2025: Segmentation

Autologous Stem Cell Based Therapies Market is segmented as below:

Breakup Product Type:Embryonic Stem Cell, Resident Cardiac Stem Cells, Umbilical Cord Blood Stem Cells

Breakup by Application:Neurodegenerative Disorders, Autoimmune Diseases, Cardiovascular Diseases

Geographic segmentation

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INTRODUCTION

Cardiovascular disease associated with myocardial infarction (MI) is a major cause of morbidity and mortality worldwide (1, 2). The heart is composed of dynamic and multicellular tissues that exhibit highly specific structural and functional characteristics. Adult cardiac muscle is thought to lack the ability to self-repair and regenerate after MI. Traditional cardiac patches serve as temporary mechanical supporting systems to prevent the progression of postinfarction left ventricular (LV) remodeling (2). However, the damaged myocardium is still unable to self-restore, and the subsequent maladaptive remodeling is typically irreversible (2). Because of the shortage of organ donors and the limited retention of cellular therapies, the field of cardiac engineering has emerged to generate functional cardiac tissues to provide a promising alternative means to repair damaged heart tissue (3, 4). In addition to playing a role in providing mechanical support, cellularized cardiac patches and scaffolds have also been investigated to restore the functionality of the damaged myocardium (5, 6). Compared to synthetic materials, hydrogel-based materials derived from, or partially derived from, natural sources can mimic the specific aspects of the tissue microenvironment and can support both cell adhesion and growth (7). Hence, these hydrogel-based materials can provide a more favorable matrix for the growth and differentiation of cardiomyocytes (7, 8). However, limitations of structural design and manufacturing techniques, as well as the low mechanical strength and weak processability of hydrogel-based patches, still make their clinical application challenging (3, 7, 8).

Because of the limited expansion and regeneration capacity of primary cardiomyocytes, the use of human induced pluripotent stem cellderived cardiomyocytes (hiPSC-CMs) provides a continuous cell source by which to produce terminally differentiated cells and avoid controversial ethical issues in biomedical research (9, 10). Although several studies have been performed with hiPSC-CMs to generate functional cardiac tissue constructs (11, 12), more studies are required to explore the interaction between hiPSC-CMs and the matrix microenvironment (i.e., scaffolds and other cells) for therapeutic improvement. Hence, further studies should focus on exploring material bioactivity, architectural design and manufacturing, the biomechanical properties of tissue constructs, and the long-term in vivo development of these tissue constructs, which will ultimately affect three-dimensional (3D) cell assembly and neotissue remodeling for clinical research purposes (2, 10, 13).

In this study, a 4D hydrogel-based cardiac patch was developed with a specific smart design for physiological adaptability (or tunability) using a beam-scanning stereolithography (SL) printing technique. Beam-scanning SL printing offers an effective methodology for creating microfabricated tissue constructs with photocurable hydrogels, which are able to achieve many essential requirements in manufacturing tissue micropatterns and macroarchitectures (14). The printing speed and laser intensity are able to be varied as required, which provides the ability to tailor the cross-linking degree of the inks and, therefore, affects the physicochemical properties of hydrogels. Moreover, it was observed that a light-induced graded internal stress, followed by a solvent-induced relaxation of material, drove an autonomous 4D morphing of the objects after printing (15, 16). It was found that this self-morphing process was able to achieve conformations that were nearly identical to the surface curvature of the heart. Moreover, taking the physiological features of the cardiac tissue and the physical properties of the hydrogel into account, a highly stretchable microstructure was created to allow for an easy switch of fiber arrangement from a wavy pattern to a mesh pattern, in accordance with the diastole and systole in the cardiac cycle. The specific design was expected to increase the mechanical tolerance of the printed hydrogel and to decrease the unfavorable effect of hiPSC-CM residence on the printed patches when exposed to the dynamic mechanics. By triculturing cardiomyocytes, mesenchymal stromal cells, and endothelial cells, the printed microfibers with specific nonlinear microstructures could reproduce the anisotropy of elastic epicardial fibers and vascular networks, which plays a crucial role in supporting the effective exchange of nutrients and metabolites, as well as guiding contracting cells for engineered cardiac tissue.

The cardiac muscle fibers mainly consist of longitudinally bundled myofibrils (cardiomyocytes and collagen sheaths), which are surrounded by high-density capillaries (17, 18). This anisotropic (directionally dependent) muscular architecture results in the coordinated electromechanical activity of the ventricles, which involves the directionally dependent myocardial contraction and the propagation of the excitation wave (19, 20). As can be observed by diffusion tensor imaging (DTI) (21, 22), a helical network of myofibers in the LV is organized to form a sheet structure, and the orientation of the fiber angles varies from approximately +60 to 60 across the ventricular wall (Fig. 1A). The visualization of the fiber structure illustrates the left-handed to the right-handed rotation of the fibers going from the epicardium to the endocardium in the LV (21). Computer-aided design (CAD)driven 3D printing offers a promising technique by which to transform the anatomical detail of cardiac fiber maps into a highly complex arrangement of fibers within an engineered cardiac tissue (23). Figure 1B shows that the spiral arrangement of 3D myocardial fibers crosses the ventricular wall (a left-handed to right-handed spiral of the fibers going from the epicardium to the endocardium) and their 2D mesh pattern projections at different angles.

(A) Photograph of the anatomical heart and the fiber structure of the LV visualized by DTI data. (B) Schematic illustration of a short-sectioned LV that illustrates the variation of fiber angle from the epicardium to the endocardium. The orientation (2D mesh pattern projection) of the fiber angles varies continuously with the position across the wall and distribution changes from the apical region to the basal region. (C) Curvature change of cardiac tissue at two different phases (diastole and systole) of the cardiac cycle, which occurs as the heartbeat and pumping blood. (D) CAD design of 3D stretchable architecture on the heart. It provides dynamic stretchability without material deformation or failure when the heart repeatedly contracts and relaxes. (E) Representation of a simplified geometric model of the fibers in the printed object. In the selected region, the angle (), the length of fiber (L), spatial displacement (D) and the ventricular curvature () are defined with systole (1) and diastole (2) states. (F) Mechanism of the internal stress-induced morphing process. Uneven cross-linking density results in different volume shrinkage after stress relaxation. Photo credit: Haitao Cui, The George Washington University (GWU).

Moreover, another specific feature of the cardiac tissue is the diastole and systole in the cardiac cycle induced by the contraction of cardiac muscle, which generates the force for blood circulation (8, 24). When taking the volume change of the heart into account, the arrangement of fibers is dynamically stretched in a selected region (Fig. 1C). Hence, the mesh pattern was changed to hexagon or wavy pattern in the 2D plane to adapt the change of ventricular curvature (Fig. 1D). It was able to create a highly stretchable structure with very limited deformability, which is expected to decrease the negative effect on the attached, susceptible cardiomyocytes. To mathematically characterize this design, we simplified the solid geometric model with a plane curve prototype to elaborate on the relationship between the redundant length of the stretchable structure (L) and the ventricular curvature () in the systole state (Fig. 1E). By the calculation, it can be estimated asL=cos1(1D22/2)D(1)where L is the redundant length of the stretchable structure from straight to curve, is the ventricular curvature in the systole state, and D is the approximate length of fiber in the diastole state (here, D = 400 m from our study). In the previous study, a light-induced 4D morphing phenomenon was demonstrated when using our customized beam-scanning SL printer (15, 16). The laser-induced graded internal stress, introduced through the printing process, is a major driving force of this 4D dynamic morphing (15, 16, 25). The uneven cross-linking density of photocrosslinkable inks generates the difference of modulus between the upper and lower surfaces of thin objects due to laser energy attenuation, leading to different volume shrinkage after stress relaxation (15). However, when multilayers were printed, the beam-scanning SL printing resulted in the repeated cross-linking of previous layers. The bottom layers had a higher cross-linking density. In this case, the bottom layer, which was cured the earliest, adhered to the substrate and could not shrink freely, while the top layer during printing could gradually and spontaneously shrink because of the release of internal stress. Thus, the printed objects have a tendency to bend toward the newly cured layer. We also found the humidity-responsive, reversible 4D phenomenon, which is swelling-induced stretching and dehydration-induced bending (15). After printing, the printed patch can transform from a 3D flat pattern to the 4D curved architecture when appropriate printing parameters are selected (Fig. 1F), which will be elaborated upon in the next section. It was hypothesized that by integrating a unique 4D self-morphing ability within the construct, the structural expandability of the design would improve the physiological adaptability of the engineered cardiac patch to the heart for in vivo cardiac regeneration.

A gelatin-based printable ink consisting of gelatin methacrylate (GelMA) and polyethylene glycol diacrylate (PEGDA) was used to create the anisotropic cardiac patch with myocardial fiber orientation. As a chemical derivative of gelatin [gelatin is derived from the hydrolysis of collagen, which is a major component of the extracellular matrix (ECM)], GelMA is a photocurable biomaterial with many arginine-glycine-aspartic acids and other peptide sequences that can significantly promote cell attachment and proliferation (14). The PEGDA solution was mixed with GelMA to decrease the swelling volume and to increase the mechanical modulus and structural stability of the printed hydrogels. The structural characteristics and mechanical properties of the printed hydrogels were determined by fiber design, printing parameters, the ink concentration, and mixing ratio of GelMA and PEGDA. To optimize the fiber design, stacked wavy architectures were generated with fiber width of 100, 200, and 400 m, fill density of 20, 40, and 60%, and fiber angles () of 30, 45, and 60 between each layer with two, four, and eight layers, respectively, using 10% GelMA and 10% PEGDA. The laser intensity, working distance, ink volume, and temperature were set to the same conditions as our previous studies (15, 26, 27) to eliminate the effect of the printing parameters. In this situation, the printing speed of the laser-based SL printing affects the photocuring performance, the structural accuracy (fineness), and the curvature of the 4D self-morphing. To ensure the complete solidification of the inks, a printing speed of 10 mm/s was set on the basis of our previous trials. By varying the printing speed (cross-linking density), a series of 4D self-morphing patches (wave pattern) were obtained with different curvatures. The mesh-patterned patches also exhibited a similar 4D morphing behavior. In all 4D self-morphing structures, the degree of deformation largely depends on the swelling, water content, and ionic strength. After 4D morphing, the wave-patterned patches maintained their wavy structure with a slight deformation. In our study, the bending of macrostructure does not significantly affect the microstructure. Figure 2A shows the curvature change of 4D morphing with increasing printing speed. Similar to the 4D morphing mathematical model by stress relaxation in the previous study (15), the relationship between the 4D curvature and printing speed can be modeled with the materials and printing parameters using the following equation1/r=4.7802.53lnv[mm1](2)where r is the radius of the object curvature after 4D morphing, is the printing speed (millimeters per second), and 0 is the shrinkage, which is dependent on both the material and the immersion medium. Here, 0 = 0.012 s1 in aqueous solution. The results demonstrated that the patches printed with a print speed (6 mm/s) had an appropriate curvature with the 4D morphing to obtain a sufficient integration with the LV surface of the mouse hearts.

(A) Curvature change of 4D morphing versus printing speed (means SD, n 6, *P < 0.05). (B) Printing accuracy of the hydrogel patches versus fiber width for different fill density (fd; means SD, n 6, *P < 0.05, **P < 0.01, and ***P < 0.001). (C) Color map of tensile moduli of the patches with varying GelMA and PEGDA concentrations. (D) Optical and 3D surface plot images of the patches. Scale bars, 200 m. (E) Average elasticity values of the wave-patterned patches in horizontal (x) and vertical (y) directions. Number sign (#) shows the statistical comparison between the horizontal and vertical directions (means SD, n 6, **P < 0.01 and ##P < 0.01). (F) Uniaxial tensile stress-strain curves of 5% GelMA and 15% PEGDA. Immunostaining of cell morphology (F-actin; red), sarcomeric structure (-actinin; green), gap junction [connexin 43 (Cx43); red], and contractile protein [cardiac troponin I (cTnI); red] on the patches on (G) day 1 and (H) day 7. Scale bars, 20 m. (I) Beating rate of hiPSC-CMs on the patch and well plate on day 3 and day 7 (means SD, n 6, *P < 0.05; n.s. no significant difference). BPM, beats per minute. Photo credit: Haitao Cui, GWU.

As is shown in Fig. 2B, the printing accuracy of different fiber width, fiber angle, layer number, and fill density of the fiber arrangement was investigated. The fiber pattern with a 100-m width showed significantly lower accuracy (50%) when compared to both fibers with 200-m (>70%) and 400-m (>90%) widths. In addition, the fiber pattern with a 60% fill density showed lower accuracy than the fiber pattern with 40% fill density. This implies that the fiber pattern with higher fill density or lower width is associated with more directional changes of the laser head per unit area, which is a function of the limitation of the printing resolution. In addition, there was no significant difference in the accuracy observed when increasing the number of stacked fibers (or fiber angles) due to the high reproducibility of the SL printing (fig. S1A). It was observed that smaller fiber widths or higher fill densities had a higher surface area per unit area, which was beneficial for the attachment of more cells, as the increased surface area better mimics the native myofibers. According to a previous study, the quantitative measurement of fiber angles showed that the dominant distribution of fiber angle was +45 to 45 from the epicardium to the endocardium (21). Therefore, a fiber pattern was printed with a 200-m width, 40% fill density, and a maximum angle of 45 for adjacent layers to optimize the mechanical properties of the hydrogel patches.

To test and measure the mechanical (both compression and tensile) modulus of the hydrogels, we varied the mixed weight ratio of GelMA and PEGDA from 5 to 20% (Fig. 2C and fig. S1, B and C). The results demonstrated that the mechanical moduli of the hydrogels fall within the range of the native myocardium modulus (101 to 102 kPa) in the physiological strain regime (28, 29). In addition, swelling testing showed that when GelMA was mixed with PEGDA, the printed hydrogels maintained excellent structural stability without notable swelling (fig. S1D). With consideration for the optimized ink viscosity and hydrogel elasticity, the inks used to fabricate our myofiber patches were formulated with concentrations of 5% GelMA and PEGDA (5, 10, and 15%) and were effectively printed on the basis of our design. Figure 2D shows the optical and 3D surface plot images of the patches printed by 5% GelMA and 15% PEGDA with a 200-m width, 40% fill density, and a 45 angle for adjacent layers. The fluorescent images of the 3D printed patches are also displayed (fig. S2A). The anisotropic behaviors of the wavy-patterned patches in the horizontal (x) and the vertical (y) direction demonstrated that uniaxial tension on the fiber pattern resulted in different deformation and stress generation in a directionally dependent manner (Fig. 2E). In particular, the stress-strain curve of the patch with 5% GelMA and 15% PEGDA was consistent with the tensile features of the native myocardium within the physiological strain regime (Fig. 2F) (19, 30). The fatigue was obvious along the y direction at the initial stage, which is attributed to the lower connectivity of fibers in the y direction and higher extendibility of the wavy-patterned fibers in the x direction. It is expected that this physiologically adaptable design would increase the stretchability and stability of the hydrogel patches, allowing them to absorb and release energy against the force of cardiac contraction (31, 32). Compared to the mesh design, the current architecture would allow for structural compliance of the hydrogel fibers without notable deformation. Moreover, the successfully printed patterns also well represent the microstructure of the native myocardial tissue, which is formed from collagen fibers and other ECM proteins, together with cardiomyocytes. However, the width of the myofibers within the myocardial tissue was much smaller (30 to 40 m) than the printed pattern (200 m), which is largely a limitation of the resolution of the currently available technology.

After the optimization of both the printing parameters and the ink formulation, the cardiac patches were manufactured with 5% GelMA and 15% PEGDA using a beam-scanning SL printing system. The wavy-patterned patches with a diameter of 8 mm and a thickness of 600 m were used to perform the in vitro studies, while the mesh-patterned patches of the same fiber volume fraction served as the control. By keeping the same surface area across the different construct patterns, we could ensure that there would be the same available cell number for each of the patches. Upon analysis, the redundant length (L) of the stretchable structure was determined to be around 140 m. Because of their capacity for restoring cardiac function in previous studies, hiPSC-CMs were cultured using the same protocol developed at the National Heart, Lung, and Blood Institute (NHLBI) (33). Before cell seeding, a thin layer of Matrigel was precoated on the well plate or patches surface to improve the hiPSC-CM adhesion. By day 7, spontaneous contractions of monolayer hiPSC-CMs were observed (fig. S2B and movie S1), and immunostaining results demonstrated that hiPSC-CMs displayed specific myocardial protein expression, including sarcomeric alpha-actinin (-actinin), connexin 43 (Cx43), and cardiac troponin I (cTnI). (fig. S2, C and D). The cell-laden ink was printed by mixing 1 106 per ml of hiPSC-CMs with 5% GelMA and 15% PEGDA. However, a decrease in the metabolic activity of the hiPSC-CMs was observed, and the distinct cardiac beating behavior was not evident (fig. S2, E and F). These observations were likely the result of the limited 3D space within the hydrogel. Hence, a postseeding approach was then applied to fabricate the cardiac patches. Compared to the cell-laden samples, the hiPSC-CMs seeded on the patches showed significantly higher proliferation and beating rate. The attached hiPSC-CMs exhibited spontaneous contractions along the fibers on day 3 (movie S2). Moreover, the immunostaining images revealed robust F-actin, -actinin, Cx43, and cTnI expression of hiPSC-CMs on the printed patches (Fig. 2G). After 7 days of culture, the hiPSC-CMs began to form aggregation structures atop the printed fibers and began to contract synchronously across the entire patches, indicating electrophysiological coupling of the cells (Fig. 2H). Moreover, the beating rate of the hiPSC-CMs on the printed patch was notably similar to that of the monolayer hiPSC-CMs on the seeded well plate (Fig. 2I).

According to previous studies, human mesenchymal stromal cells (hMSCs) have been widely used in coculture with cardiomyocytes and endothelial cells to improve cell viability, myogenesis, angiogenesis, cardiac contractility, and other functions due to their paracrine activity (34, 35). Hence, a triculture of hiPSC-CMs, human endothelial cells (hECs), and hMSCs was performed to fabricate the vascularized cardiac patches. The analysis of cell tracker staining was conducted to investigate the distribution of different cells in the triculture and to optimize the cell ratio in the triculture system based on the calculated fluorescent value. The results demonstrated that when the initial ratio of seeded cells was 4:2:1, the resultant cellular proportion of hiPSC-CMs, hECs, and hMSCs was ~ 30, ~40, and ~30%, respectively, at confluency, which falls within the range of the cellular composition [25 to 35% cardiomyocytes, 40 to 45% endothelial cells, and ~30% supporting cells (i.e., fibroblasts, smooth muscle cells, hematopoietic-derived cells, and others)] of the human heart (Fig. 3A) (36, 37). After 7 days of culture, the printed construct showed a uniform cell distribution and longitudinal alignment of the cells along the fiber direction (Fig. 3B and fig. S3). Autofluorescence images of green fluorescent proteintransfected (GFP+) hiPSC-CMs on day 7 indicated that the cardiomyocytes exhibited an increased proliferation rate on the patches, as compared to initial seeding on day 1, and were able to generate spontaneous contractions (Fig. 3C and fig. S4). After 7 days of culture, fluorescent image analysis of CD31 [platelet endothelial cell adhesion molecule-1 (PECAM-1)] stained patches revealed that the wave-patterned patch had a higher density of capillary-like hEC distribution along the fibers when compared to the mesh control (Fig. 3D). In our previous studies, we found that the beam-scanning laser is able to cure the ink for the macroarchitectural formation together with the aligned microstructure present on the printed fibers (16). Hence, the hECs were easily grown along the fiber direction. Moreover, the iPSC-CMs exhibited an excellent contraction-relaxation behavior along the fibers in the wave-patterned patches, potentially allowing for a local mechanical stimulation on the fiber resident cells, which can help to improve the growth and distribution of hECs. In addition, immunostaining analysis of the cTnI and the marker von Willebrand factor (vWf) indicated that our wave-patterned patches contained a dense network of vascular cells interwoven with hiPSC-CMs distributed over the printed fibers, and the ratio of hiPSC-CMs and hECs was largely retained with 45% hiPSC-CMs (Fig. 3, E and F). Furthermore, it has been well established that the electrical activity at the cardiomyocyte membrane is controlled by ion channels and G proteincoupled receptors, which are usually actuated by calcium transients (38). The electrophysiological profiles of the cardiac patches demonstrated the generation of typical calcium oscillation waveforms and synchronous beating along with the printed fibers across the entire patches after 3 days (Fig. 3G). Over the next 7 days of culture, the amplitudes of calcium transients gradually increased to a stable state, suggesting the establishment of excellent functional contraction-relaxation and electrophysiological behaviors (Fig. 3, H and I).

Cell distribution of tricultured hiPSC-CMs (green), hECs (red), and hMSCs (blue) on the cardiac patches using cell tracker staining after (A) 1 day of confluence and (B) 7 days of culture. Scale bars, 200 m. (C) Autofluorescence 3D images of GFP+ hiPSC-CMs on the wave-patterned patch on day 1 and day 7. Scale bars, 100 m. (D) Immunostaining of capillary-like hEC distribution (CD31; red) on the hydrogel patches. Scale bars, 200 m. Immunostaining (3D images) of cTnI (red) and vascular protein (vWf; green) on the (E) wave-patterned and (F) mesh-patterned patches. Scale bars, 200 m (3D image) and 20 m (2D inset). Calcium transients of hiPSC-CMs on the hydrogel patches recorded on (G) day 3 and (H) day 7. (I) Peak amplitude of the calcium transients of hiPSC-CMs on the mesh- and wave-patterned patches on day 3, day 7, and day 10 (means SD, n 30 cells, *P < 0.05).

To enhance the effectiveness of our design, a custom-made bioreactor consisting of a dynamic flow device and a mechanical loading device was constructed to provide a physiologically relevant environment, which could incorporate both mechanical strain and hydrodynamics (Fig. 4A) (39). The patches were compressed in the radial direction using positive pressure between the piston and stationary polydimethylsiloxane (PDMS) holder to yield a mechanical loading, which mimics the contractile behavior of the in vivo human heart (fig. S5A). During the dual mechanical stimulation (MS), the applied force was stored in the patch as strain energy, which was then responsible for returning the patch to its original shape. The out-of-plane loading (bending) determines the stretch and recovery of the fibers, while the fluid shear stress regulates cellular orientation (Fig. 4B). Both were applied to the patches and transferred onto the cells to improve the vascularization and myocardial maturation of the resident cells.

(A) Schematic illustration of a custom-made bioreactor to apply dual MS for the maturation of engineered cardiac tissue. PMMA, polymethylmethacrylate. (B) Both the out-of-plane loading and fluid shear stress applied to the patches. (C) Immunostaining of cTnI (red) and vWf (green) on the wave-patterned patch under MS condition (+MS) versus nonstimulated control (MS). Scale bars, 50 m. (D) Immunostaining of the -actinin (green) and Cx43 (red) on the wave-patterned patch under MS condition (+MS) versus nonstimulated control (MS). Scale bars, 20 m. (E) Cross-sectional immunostaining of the sarcomeric structure (Desmin; green) and vascular CD31 (red) on the patches under MS condition (+MS). Scale bars, 50 m. (F) The beating rate of hiPSC-CMs on the printed patches under MS condition (+MS) versus nonstimulated control (MS) on day 14 (means SD, n 6, *P < 0.05). BPM, beats per minute. Relative gene expression of (G) myocardial structure [myosin light chain 2 (MYL2)], (H) excitation-contraction coupling [ryanodine receptor 2 (RYR2)], and (I) angiogenesis (CD31) on the patches under MS condition (+MS) versus nonstimulated control (MS) on day 1, day 7, and day 14 (means SD, n 9, *P < 0.05, **P < 0.01, and ***P < 0.001).

After 2 weeks of dynamic culture, we observed a higher expression of mature cardiomyogenic cTnI and angiogenic vWf in MS samples and more longitudinally aligned vascular cells, when compared to the nonstimulated control (Fig. 4C and fig. S5, B and C). In addition, the patches exhibited enhanced sarcomere density and junctions, as identified by the -actinin and Cx43 expression of the hiPSC-CMs (Fig. 4D and fig. S5, D and E). Cross-sectional images illustrated that the high density of cell assemblies on the wave-patterned patches was evident under MS conditions and these assemblies exhibited a higher expression of desmin and CD31 markers compared to the mesh control (Fig. 4E). This suggests that the specific design of the cardiac patch was able to impede the mechanical force against material deformation in our dynamic system to support repeatable stretch cycles and decrease the negative effect on the cells. Moreover, the assembled hiPSC-CM fibers on the cardiac patch spontaneously and synchronously contracted along with the fiber direction (Fig. 4F and movie S3). However, the entire patch did not exhibit in-plane contraction or macroscopic movement itself due to the high mechanical resistance of the hydrogel material. In general, it was observed that the wave-patterned patch was capable of stretching to a physiologically relevant fiber pattern compared to the mesh design, which could improve cell guidance and elongation along the fiber direction.

Consistent with the immunostaining results, the expression of cardiac-related genes, including genes associated with sarcomeric structure, excitation-contraction coupling, and angiogenesis, was significantly increased on day 14 compared to day 7. These results suggest that there was an increase in maturation of the iPSC-CMs on the printed patches over time (Fig. 4, G to I, table S1, and fig. S6). After the application of the MS, the expression of the MYL2 (myosin light chain 2) and RYR2 (ryanodine receptor 2) genes were significantly increased in our wave-patterned patches on day 14, as compared to the mesh control. This demonstrates that our specific patch design can enhance iPSC-CM contractile and electrical function under MS. Moreover, the angiogenic CD31 gene was also considerably up-regulated on the wave-patterned patches with perfusion culture. In general, the gene expression on day 14 was up to 28-fold higher compared to day 1, and an average of 5.5-fold increase in the expression of maturation genes was observed with the MS condition as compared to the nonstimulated groups. This observation provides further evidence that significantly enhanced cardiac maturation is achievable on the printed patches when specific structural design and physiologically relevant culture conditions are combined.

Having used the dynamic culture system to enhance the maturation of hiPSC-CMs in vitro, we further investigated the vascularization and myogenic maturation of the printed cardiac patches in vivo. Ischemia-reperfusion (I/R) is a major contributor to the myocardial damage resulting from MI in humans (40). Murine models of I/R injury provide an effective means to simulate clinical acute or chronic heart disease for cardiovascular research (41, 42). Hence, a chronic MI model with I/R injury was created to assess the functional effects of cardiac patch implantation (43, 44). The cellularized and acellular patches were implanted onto the epicardium of immunodeficient nonobese diabetic severe combined immunodeficient gamma (NSG) mice and were assessed for long-term development 4 months after implantation. Compared to the classic MI model, our I/R injury model produced a shortened recovery time, less inflammation, and higher survival rates. The patches (4-mm diameter by 600-m thickness in size) were entirely positioned over the infarcted (ischemia) site of the mouse hearts (Fig. 5, A and B, and movie S4). To assess the direct interaction (structure and cells) between the patch and the host epicardium, we did not apply fibrin glue. After 3 weeks of implantation, optical images showed that the cellularized patches had a firm adhesion to the epicardium regardless of the contractile function of the heart (Fig. 5C). Hematoxylin and eosin (H&E) assessment confirmed the robust epicardial engraftment of the cell-laden patches, which contained high-density cell clusters after 3 weeks (Fig. 5D). Fluorescent images also showed that the GFP+ hiPSC-CMs (green) maintained higher viability after 3 weeks of implantation (Fig. 5E). The immunofluorescence analysis of cTnI and vWf illustrated the existence and development of hiPSC-CMs and hECs on the cellularized patches in the treated region with time. The image results showed that many vascular cells were found spanning the interface of the patch and myocardium and expanded within the myocardial patch (Fig. 5F).

(A) Optical image of surgical implantation of the patch. (B) Optical image of a heart I/R MI model after 4 months. (C) Optical image of the implanted cellularized patch at week 3, exhibiting a firm adhesion (inset). (D) H&E image of the cellularized patch at week 3, demonstrating the cell clusters with a high density (yellow arrowhead). Scale bar, 400 m. (E) Fluorescent image of (GFP+) iPSC-CMs on the patch at week 3, showing a high engraftment rate (yellow arrowhead). Scale bar, 100 m. (F) Immunostaining of cTnI (red) and vWf (green) on the cellularized patch at week 3. Scale bar, 100 m. (G) H&E images of mouse MI hearts without treatment (MI) and with cellularized patch (MI + patch) at week 10. Infarct area after MI (yellow circles). Scale bars, 800 m. (H) Cardiac magnetic resonance imaging (cMRI) images of a mouse heart with patch at week 10. Left (spin echo): the position of the heart and implanted patch. Right (cine): the blood (white color) perfusion from the heart to the patch. Photo credit: Haitao Cui, GWU.

After 10 weeks of implantation, H&E staining results showed that the infarct sizes of the patch groups (~3.8 0.7%) were smaller than the MI-only control (~8.4 1.1%), suggesting that the patch can provide mechanical support to effectively prevent LV remodeling (Fig. 5G and fig. S7A). The images and videos of the cardiac magnetic resonance imaging (cMRI) demonstrated that the implanted patch was able to contract and relax with the heartbeat of the mouse and also confirmed its excellent structural durability along with evident blood perfusion from the heart to the patch (Fig. 5H and movie S5). Fluorescent images also showed that the GFP+ hiPSC-CMs (green) maintained higher viability after 10 weeks of implantation (fig. S7B). hiPSC-CMs with cTnI+-expressing capillaries (vWf+) were observed in the patches, where the lumen structure of neovessels was also clearly visible (Fig. 6A). Together, these results indicated that epicardially implanted patches exhibited robust survival and vascularization in vivo. Moreover, a high density of capillaries identified by human-specific CD31 expression was observed within the cellularized patches, suggesting that the implanted hECs and hMSCs increased the vessel formation throughout the patch in vivo (Fig. 6B).

(A) Immunostaining of cTnI (red) and vWf (green) on the cellularized patch at week 10. Scale bar, 800 m. Border of the heart (white dashed line) and capillary lumen (white arrow). Scale bar (enlarged), 100 m. (B) Immunostaining of human-specific CD31 (red) on the cellularized patch at week 10, showing the generated capillaries by hECs. Scale bar, 800 m. Border of the heart (white dashed line). Scale bar (enlarged), 100 m. (C) Immunostaining of cTnI (red) and vWf (green) on the cellularized patch for 4 months, showing the increased density of the vessels. Scale bar, 800 m. Border of the heart (white dashed line) and capillary lumen (white arrow). Scale bar (enlarged), 100 m. (D) Quantification of capillaries with vWf staining data for 10 weeks and 4 months (means SD, n 6, *P < 0.05 and **P < 0.01). (E) Immunostaining of human-specific CD31 (red) on the cellularized patch for 4 months. Scale bar, 800 m. Border of the heart (white dashed line). Scale bar (enlarged), 100 m. (F) Immunostaining of -actinin (green) and human-specific CD31 (red) on the cellularized patch at month 4. Scale bars, 50 m.

By 4 months, H&E staining results showed a higher cell density and smaller infarct area (~5.6 1.5%) in the cellularized patch compared to the acellular patch and MI groups (~14.3 2.3%; fig. S7C). The GFP+ fluorescent results demonstrated that the hiPSC-CMs retained high engraftment rates (fig. S7D). Similar to what was observed at 10 weeks, the cellularized patch had a strong integration within the epicardium, whereas the cell-free patch had a weak adhesion by month 4. In addition, the cMRI images also illustrated that the implanted patch had an excellent connection with the mouse heart (fig. S7E). The positive expression of mature cTnI further indicated the presence of advanced structural maturation of the hiPSC-CMs in the treated region, and the capillaries were also substantially identified by the vWf staining in the cell-laden patch groups (Fig. 6C). The images also demonstrated more progressive implant vascularization with a 1.5-fold increase in blood vessel density after 4 months of implantation, when compared to cell-free controls (Fig. 6D). The data were counted by five randomly selected fields in each heart. However, the fraction of humanized vessels was not significantly increased, as identified by the human-specific CD31 staining (Fig. 6E). Therefore, the increased vascularization and vascular remodeling in vivo likely originated from the host vessel ingrowth as opposed to the implanted human vessels at the initial stage of implantation. However, differing from the in vitro results, the cross-sectional images of the implants did not exhibit substantial sarcomeric structure (identified by -actinin) when compared to the native cardiac tissue (Fig. 6F). It can be observed that the cell aggregation in the vertical direction showed a disordered assembly and 3D stacking behavior. Overall, these results demonstrated that the printed patches underwent progressive vascularization, largely remained on the epicardial surface of the LV over the 4-month implantation period, and effectively covered all of the infarcted area. Cardiac function was also evaluated at different time points after injury via cMRI assessments. The LV ejection fraction of all patch groups (~64.1 3.5%) was higher than the MI-only group (~56.1 1.5%); however, there was no difference observed between the cellularized patch group and the cellular group.

MI is a leading cause of morbidity and mortality worldwide. The hiPSC-CMs provide a potentially unlimited source for cardiac tissue regeneration, as they are able to recapitulate many of the physiological, structural, and genetic properties of human primary cardiomyocytes and heart tissue (13). Current methods for the treatment of MI largely involve injecting cardiomyocytes directly into the epicardial infarct zone; however, because of the limited engraftment capacity of the injected cardiomyocytes, injection therapies are not fully satisfactory in restoring cardiac functionality (13). Several studies have been performed with hiPSC-CMs to generate functional cardiac tissue constructs using tissue engineering techniques (7, 10). However, the physiological features of hiPSC-CMs are more sensitive to the physicochemical and bioactive properties of the scaffolds in which they reside. Compared to synthetic polymers, natural polymer-based hydrogels can provide a more favorable matrix for the growth and differentiation of cardiomyocytes (7). However, limitations of structural design and manufacturing techniques, as well as the low mechanical strength and weak processability of hydrogel-based patches, still make their clinical application challenging.

As a proof of concept, a physiologically adaptable 4D cardiac patch, which recapitulates the architectural and biological features of the native myocardial tissue, has been printed using a beam-scanning SL printing technique. The smart patches provided mechanical support, a physiologically tunable structure, and a suitable matrix environment (elasticity and bioactivity) for cell implantation. Successful vascularization of the patches allowed for the continued metabolic demand of hiPSC-CMs and permitted them to remain both viable and functional throughout the in vivo study. Robust engraftment and development of the implanted patches were further confirmed using a more clinically relevant and mechanically realistic environment. The study results showed that the anisotropic mechanical adaption of the printed patches improved the maturation of cardiomyocytes and vascularization in vitro under MS. After implantation into the murine MI model, the printed patches exhibited high levels of in vivo cell engraftment and vascularization.

In a previous study, an engineered auxetic design was developed to give a cardiac patch a negative Poissons ratio, providing it with the ability to conform to the demanding mechanics of the heart (31). Here, we further propose and develop a 4D physiologically adaptable design for a cardiac patch, which includes hierarchical macro- and microstructural transformations attuned to the mechanically dynamic process of the beating heart. Therein, a physiological adaptation is evident in the response of cells (or genes) to the microenvironmental change. Similarly, the adaptive responses of the resident cells on the scaffolds to replicate the native microenvironment are crucial for the in vivo integration of engineered tissue with and the host tissue after implantation. In addition, a highly biomimetic in vitro culture system was developed with dynamic perfusion and mechanical loading to enhance cardiac maturation. Overall, the current work has several unique features: (i) a greatly improved mechanical stretchability of the hydrogel patches; (ii) a triculture of hiPSC-CMs, hMSCs, and hECs, which is necessary to obtain a complex cardiac tissue; (iii) an application of in vitro dual MS by which to improve cardiac maturation; and (iv) in vivo long-term development of the printed patches in a murine chronic MI model to evaluate the potential therapeutic effect.

Although several studies have shown that cell transplantation can greatly improve cardiac function in the MI model, no substantial evidence supporting these improvements in cardiac function was found in the current study. In the MS culture studies, it was observed that the entire patch did not exhibit in-plane contraction. The high mechanical resistance of the hydrogel could be a reason as to why the patches did not significantly enhance cardiac function in vivo. Moreover, as is known, the implanted human cardiomyocytes exhibit different beating frequencies and other biological features within the host mouse heart (13, 45, 46). Hence, integrated functional repair was not observed in this study. Differing from the hypothesis of the functional enhancement, the in vivo results revealed that the enhanced cardiomyogenesis and neovascularization of humanized patches did not significantly improve the cardiac function of the MI mice. The patches provided cellularized niche conditions so that most of the implanted cardiomyocytes were alive, although they still exhibited immature 3D sarcomeric organization. Moreover, the neovascularization effects of the cell-laden patches at the infarct region were also confirmed, suggesting that paracrine effects appear to be a major contributing factor. Although there was a lack of functional integration between humanized patches with the hearts of the host mice, the printed patches exerted no adverse effects on the host cardiac function or vulnerability to arrhythmias. The cell transplantation improved the cellularized environment in the infarct area by, at least in part, promoting angiogenesis and increasing cell retention. The multiple cell transplantation with a high density of hiPSC-CMs retention in the murine MI model suggests that this goal may have been at least partially achieved. While applying humanized grafts to infarcted rodent hearts would likely confirm the paracrine effects, large animal studies are warranted to further evaluate the therapeutic efficacy toward a potential clinical use.

In the future, a physiologically relevant large animal study, such as a porcine or nonhuman primate MI model, will serve as a more realistic means to study cardiac patch engraftment (42, 46). Moreover, developments in advanced printing techniques will enable the development of thick, scale-up ready myocardial tissue, which will play a prominent role in the ultimate success of clinical cardiac engineering therapies. In general, the developed cardiac patch has a great potential to provide a desired therapeutic effect on the in vitro maturation and in vivo retention of hiPSC-CMs, based on the previously unidentified engineering design and manufacturing process.

These studies were designed to evaluate the concept of a 4D cell-laden cardiac patch with physiological adaptability as a potential method for the treatment of MI. To evaluate this technology, we tricultured hiPSC-CMs, hMSCs, and hECs to obtain a complex cardiac tissue and also applied in vitro dual MS to replicate the physiologically relevant conditions for the improvement of regenerated myocardial function. A 4-month in vivo study was conducted to assess the performance of our 4D cell-laden cardiac patches, where the animals were randomly assigned to different experimental groups before the experiments. The sample size and power calculation were determined on the basis of our experience with the experimental models and the anticipated biological variables. Typically, the power is 0.8, and the significance level is 0.05 when the effect size is determined by the minimum sample difference divided by the SD (GPower 3.1). All experiments were blinded and replicated. The sample sizes and replicates are shown in the figure legends.

Ten grams of gelatin (type A, Sigma-Aldrich) was dissolved in 100 ml of deionized water with stirring at 80C. Next, 5 ml of methacrylic anhydride was added dropwise into the gelatin solution. After reaction at 80C for 3 hours, the reactant was dialyzed in deionized water for 5 days at 40C to remove any excess methacrylic acid. The GelMA solid product was finally obtained through lyophilization. The ink solutions consisted of GelMA [with concentrations of 0, 5, 10, 15, or 20 weight % (wt %)], 1 wt % 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959, photoinitiator), and PEGDA (Mn = 700; Sigma-Aldrich; with concentration of 0, 5, 10, 15, and 20 wt %). Solutions were prepared using a 1 phosphate-buffered saline (PBS) solution.

Our 3D computational myocardium model was programmed on the basis of DTI results and was simplified to the basic geometry to replicate the fiber orientation of the native myocardium. The wave (or hexagonal) microstructure was configured with different diameter fibers and fiber angels between each layer, while the mesh microstructure served as a control. To optimize the fiber design, wave or mesh architectures with side lengths of 100, 200, and 400 m and internal angles () of 30, 45, and 60 between each layer were designed with two, four, and eight layers, respectively. All cardiac construct models were saved as .stl files, processed using the Slic3er software package, and were transferred to the 3D printer. Representative CAD models of the constructs were calculated and predicted for surface area, porosity, and other structural characteristics.

Printed cardiac patches were manufactured using our customized table-top beam-scanning SL printer, which is based on the existing Printrbot rapid prototyping platform. This system consists of a movable stage and a 110-m fiber optic-coupled solid-state ultraviolet (355 nm) laser mounted on an X-Y tool head for three-axis motion. The laser scans and solidifies the top layer of ink in a reservoir, and a movable platform lowers the construct further into the ink, covering it with the next material layer. For this study, the effective spot size of the emitted light was 150 50 m and had an energy output of ~20 uJ at 20 kHz. The ability to alter the frequency of the pulsed signal facilitates power control at the material surface ranging from 40 to 110 mW.

Different stacked architectures with fiber widths of 100, 200, and 400 m; fill densities of 20, 40, and 60%; and fiber angels of 30, 45, and 60 between each layer were manufactured with two, four, and eight layers, respectively. The printing accuracy of the patterns was quantified by the mean trajectory error (Et) compared to the designed shape. Et=1ni=0n(x(i)xt(i))2+(y(i)yt(i))2, where n 20 is the number of data points collected. Compressive and tensile mechanical properties were measured with an MTS criterion universal testing system equipped with a 100-N load cell (MTS Systems Corporation). For compressive testing, the printed patches (2 cm by 2 cm) having different microstructures were placed on the tester. The crosshead speed was set to 2 mm/min, and Youngs modulus was calculated from the linear region of the compressive stress-strain curves. For the tensile testing, the samples were mounted on to custom-made copper hooks affixed to the tester and were pulled at a rate of 1 mm/min to a maximum strain of 20%. Youngs modulus was calculated from the linear portion of the tensile stress-strain curve. In addition, the representative uniaxial tensile stress-strain plots for the latitudinal and longitudinal specimens of myocardial constructs were used to evaluate the anisotropic mechanical properties. The swelling behavior was evaluated by quantifying the weight gain after equilibrium swelling. The printed samples were immersed in PBS at 37C for 7 days. The swelling ratios of hydrogel matrices were calculated as equilibrium mass swelling ratio (SR). SR = (wt w0)/w0 100%, where w0 is the original weight of printed samples and wt is the equilibrium weight of samples after swelling.

hiPSC-CMs and GFP+ hiPSC-CMs were cultured in cardiomyocyte basic medium using the same protocol developed by our collaborators at the NHLBI (33). hECs (human umbilical vein endothelial cells; Thermo Fisher Scientific) were cultured in endothelial growth medium consisting of Medium 200 and low-serum growth supplement. hMSCs (harvested from normal human bone marrow, Texas A&M Health Science Center, Institute for Regenerative Medicine) were cultured in mesenchymal stem cell growth medium consisting of minimum essential medium, 20% fetal bovine serum, 1% l-glutamine, and 1% penicillin/streptomycin. All experiments were performed under standard cell culture conditions (in a humidified, 37C, 95% air/5% CO2 environment) with hECs and hMSCs of six cell passages or less.

After the patches were printed, iPSC-CMs, hECs, and hMSCs with different ratios were seeded on the patch constructs (the surface of the patch was precoated with a thin layer of Matrigel, Corning). The tricultured cardiac patches were maintained in the mixed medium at a 1:1:1 ratio for further characterization and in vitro cell study. hECs and hMSCs were prestained with CellTracker Orange CMRA Dye and CellTracker Blue CMAC Dye (Molecular Probes) and were then seeded onto the constructs. After 1, 3, and 7 days of coculture, cells were imaged using a Zeiss 710 confocal microscope. Cell proliferation on days 1, 3, and 7 were quantified using a cholecystokinin-8 solution [10% (v/v) in medium; Dojindo]. After 2 hours of incubation, the absorbance values were measured at 570 and 600 nm on a photometric plate reader (Thermo Fisher Scientific). The spreading morphology and arrangement of hMSCs and hECs were characterized using the double staining of F-actin (red, Texas Red; 1:200) and nuclei [blue, 4,6-diamidino-2-phenylindole dihydrochloride (DAPI), Thermo Fisher Scientific; 1:1000].

A customized bioreactor system consisting of a mechanical loading device and a dynamic flow device was used to culture our cell-laden constructs. The dynamic flow device is composed of four parts: a perfusion chamber, a flow controller, a nutrient controller, and a gas controller (5% CO2/95% air). The culture medium was perfused through the constructs using a digital peristaltic pump (Masterflex, Cole-Parmer) over the whole experimental period, which facilitated the efficient transfer of nutrients and oxygen. A shear stress was set at 10 dynes/cm2 (which is within the range of the shear stress observed in microcirculation), and a flow rate of 8.4 ml/min was selected (the viscosity of medium is ~7.8 104 Ns/m2) (47, 48). A PDMS holder was used to both firmly mount the patches within a polymethylmethacrylate chamber and to maintain the patch structure during cell culturing and MS to prevent undesired movement and damage. The patches were compressed at the speed of 60 times/min in the radial direction using positive pressure between the piston and the stationary holder to yield the mechanical force. The calculated (preload) contractile force per unit area was ~50 mN/mm2 along the fiber direction to match those in the native cardiac tissue. The cardiac constructs were placed in the bioreactor system and incubated at 37C for 7 and 14 days.

After 1 and 2 weeks of culture, cellular functions including cardiomyogenesis and angiogenesis were assessed using an immunofluorescence method. After the predetermined period, the cell-laden constructs were fixed with formalin for 20 min. The samples were permeabilized in 0.1% Triton X-100 for 15 min and were then incubated with a blocking solution [containing 1% bovine serum albumin, 0.1% Tween 20, and 0.3 M glycine in PBS] for 2 hours. The cells were then incubated with primary antibodies at 4C overnight. After incubation with primary antibodies, secondary antibodies were introduced to the samples in the dark for 2 hours at room temperature, followed by incubation with a DAPI (1:1000) solution for 5 min. All images were obtained using the confocal microscope, and protein quantifications were performed using ImageJ (49). In addition, the immunostaining analysis was performed with sliced fragments that were cut with a cryostat microtome. The primary antibodies that were used for our study were purchased from Abcam and included anti-actinin (1:500), antihuman-specific CD31 (human-specific PECAM-1; 1:500), anti-desmin (1:1000), anti-Cx43 (1:1000), anti-cTnI (1:500), and anti-vWf (1:1000). The secondary antibodies were purchased from Thermo Fisher Scientific and included anti-mouse Alexa Fluor 594 (1:1000) and goat anti-rabbit Alexa Fluor 488 (1:1000).

To evaluate the functional beating behavior, iPSC-CMs were observed and recorded using the inverted microscope and confocal microscopy. The Ca2+ that triggers contraction comes through the sarcolemma and plays an important role in excitation-contraction coupling of the heart beating. After the predetermined period, intracellular calcium transients were recorded under the fluorescent microscope at a wavelength of 494 nm over 30 to 120 s. Movies were analyzed with an ImageJ software to measure the fluorescence intensities for two to eight regions of interest (F) and for three to eight background regions (F0) per acquisition.

The cardiac tissue constructrelated gene expression was analyzed by a real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) assay. Specifically, myocardial structure [cTnI (TNNI3), cTnT (TNNI2), MYL2, MYL7, myosin heavy chain 6 (MYH6), MYH7, and -actinin 2 (ACTN2)], excitation-contraction coupling (calsequestrin 2, RYR2, phospholamban, sodium/calcium exchanger 1, and adenosine triphosphatase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2), and angiogenic genes (vWf and CD31) were studied to detect the cardiomyocyte and vascular maturation processes in the constructs. The primers that were used are shown in the Supplementary Materials (table S1). Briefly, the total RNA content was extracted using TRIzol reagent (Life Technologies). The total RNA purity and concentration were determined using a microplate reader [optical density at 260/280 nm within 1.8 to 2.0). The RNA samples were then reverse-transcribed to complementary DNA using the Prime Script RT Reagent Kit (Takara). RT-PCR was then performed on the CFX384 Real-Time System (Bio-Rad) using SYBR Premix Ex Taq according to the manufacturers protocol. The gene expression levels of the target genes were normalized against the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase. The relative gene expression was normalized against the control group to obtain the relative gene expression fold values, which were calculated via the 2Ct method.

The in vivo development of the printed cellularized constructs was evaluated using a xenograft model of transplantation into 6-week-old NSG mice. All the animal experiments were approved by the Institutional Animal Care and Use Committee of the NHLBI. A method of random and blinded group allocation was applied to our animal experiments. The murine model with chronic MI was created via an I/R procedure to analyze implanted cell development, remodeling, and infarction treatment for 4 months. The printed cellularized patches (4-mm diameter by 600-m thickness in size) were prepared in sterile conditions and were surgically implanted into the LV ischemic area of each NSG mouse through a limited left lateral thoracotomy. The acellular patch and MI-only groups served as controls. At different time points after implantation, cMRI was performed to visualize the beating heart and to evaluate the structural/functional parameters, which included the ejection fraction, end-systolic volume, end-diastolic volume, stroke volume, and cardiac output, among others. Last, animals were euthanized, and the specimens, along with the adjacent tissues, were collected for further examination.

Histology was used to qualitatively examine the samples at different time points and included the examination of cellular cytoplasm, red blood cells, and cell distributions. The samples were fixed in formalin, processed, and were embedded in optimal cutting temperature compound for cryosection histology. The samples were cut into 5- to 10-m slides. The mean infarct size was also calculated through the histologic studies. The infarct size was expressed as the percentage of the affected myocardial area (necrosis + inflammatory tissue) in all myocardial areas analyzed, with infarct area % = infarct area 100/total myocardial area. Immunostaining was used to evaluate the in vivo cardiomyogenesis and angiogenesis of the implants. The antibodies were used in a manner similar to the in vitro study. The number of neovessels, including sprouted capillaries, was counted per section, and a total of five sections per sample were analyzed. All of the slide analyses were performed using the ImageJ software.

All data are presented as the means SD. A one-way analysis of variance (ANOVA) with Tukeys test was used to verify statistically significant differences among groups via Origin Pro 8.5, with P < 0.05 being statistically significant (#, *P < 0.05; ##, **P < 0.01; ###, ***P < 0.001).

Acknowledgments: We would like to thank J. Zou and Y. Lin (IPSC core, NHLBI) for providing hiPSC-CMs and S. Anderson (Animal MRI core, NHLBI) for carrying out the MRI analysis. Funding: We also thank American Heart Association Transformative Project Award, NSF EBMS program grant #1856321, and NIH Directors New Innovator Award 1DP2EB020549-01 for financial support. Author contributions: H.C., C.L., Y.H., and L.G.Z. conceived the ideas and designed the experiments. H.C., X.Z., and S.-j.L. conducted the in vitro experiments. H.C., Y.H., C.L., Z.-x.Y., and H.S. carried out animal experiments. H.C., C.L., T.E., Y.H., Z.-x.Y., S.Y.H., M.B., M.M., J.P.F., and L.G.Z. performed data analysis and prepared the manuscript. Competing interests: A patent application describing the approach presented here was filed by H.C., L.G.Z., and Y.H. (US 62/571,684; PCT/US20 18/055707). The authors declare that they have no other 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. Additional information related to this paper may be requested from the authors.

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4D physiologically adaptable cardiac patch: A 4-month in vivo study for the treatment of myocardial infarction - Science Advances

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Mercks anti-PD-1 therapy, as monotherapy for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation. This approval is based on data from the Phase 2 KEYNOTE-629 trial, in which KEYTRUDA demonstrated meaningful efficacy and durability of response, with an objective response rate (ORR) of 34% (95% CI, 25-44), including a complete response rate of 4% and a partial response rate of 31%. Among responding patients, 69% had ongoing responses of six months or longer. After a median follow-up time of 9.5 months, the median duration of response (DOR) had not been reached (range, 2.7 to 13.1+ months).

Cutaneous squamous cell carcinoma is the second most common form of skin cancer, said Dr. Jonathan Cheng, vice president, clinical research, Merck Research Laboratories. In KEYNOTE-629, treatment with KEYTRUDA resulted in clinically meaningful and durable responses. Todays approval is great news for patients with cSCC and further demonstrates our commitment to bringing new treatment options to patients with advanced, difficult-to-treat cancers.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see Selected Important Safety Information below.

Data Supporting Approval

The efficacy of KEYTRUDA was investigated in patients with recurrent or metastatic cSCC enrolled in KEYNOTE-629 (NCT03284424), a multi-center, multi-cohort, non-randomized, open-label trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. The major efficacy outcome measures were ORR and DOR as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

Among the 105 patients treated, 87% received one or more prior lines of therapy and 74% received prior radiation therapy. Forty-five percent of patients had locally recurrent only cSCC, 24% had metastatic only cSCC and 31% had both locally recurrent and metastatic cSCC. The study population characteristics were: median age of 72 years (range, 29 to 95); 71% age 65 or older; 76% male; 71% White; 25% race unknown; 34% Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 and 66% ECOG PS of 1.

KEYTRUDA demonstrated an ORR of 34% (95% CI, 25-44) with a complete response rate of 4% and a partial response rate of 31%. Among the 36 responding patients, 69% had ongoing responses of six months or longer. After a median follow-up time of 9.5 months, the median DOR had not been reached (range, 2.7 to 13.1+ months).

Patients received KEYTRUDA 200 mg intravenously every three weeks until documented disease progression, unacceptable toxicity or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of KEYTRUDA during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Assessment of tumor status was performed every six weeks during the first year and every nine weeks during the second year.

Among the 105 patients with cSCC enrolled in KEYNOTE-629, the median duration of exposure to KEYTRUDA was 5.8 months (range, 1 day to 16.1 months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with cSCC were similar to those occurring in 2,799 patients with melanoma or non-small cell lung cancer (NSCLC) treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (11%).

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) 10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those 1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

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FDA Approves Merck's KEYTRUDA (pembrolizumab) for the Treatment of Patients with Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma (cSCC) that...

The Maryland Stem Cell Research Commission (The Commission) recently announced over $7M in Maryland Stem Cell Fund (MSCF) grant awards for its second round of 2020 MSCF fund recipients. The MSCF, which is a program of the Maryland Technology Development Corporation (TEDCO), has awarded $157M in funding to BioHealth Capital Region (BHCR) companies seeking to accelerate stem cell research, therapies and commercialization of products since 2007.

The $7M in new funding follows MSCFs announcement in September 2019 of over $1.3M in grants for the first cohort of 2020 recipients, bringing the total 2020 MSCF award tally to approximately $8.3M for the year. The financial awards are delivered across a wide range of areas, including clinical, commercialization, validation, launch, discovery, and post-doctoral fellowships. The first cohort of funding included three commercialization and two validation awards; the second, larger recipient pool included one clinical, one commercialization, one validation, four launches, 11 discovery, and five post-doctoral awards.

Notable BHCR MSCF recipients included:

Dr. Luis Garza of Johns Hopkins University (JHU) received a clinical grant to support clinical trials for his autologous volar fibroblast injection into the stump site of amputees. The trials are exploring ways to make the skin where a prosthetic limb meets the stump site tougher and less irritable to the wearer. Skin irritation is a major issue for those with prosthetic limbs and is often a cause for individuals to stop wearing their prosthesis.

Vita Therapeutics, a company that spun out of JHU, was awarded a 300K MSCF grant to support the commercialization of the companys satellite stem cell therapy for limb-girdle Muscular Dystrophy. According to the National Organization for Rare Disorders (NORD), Limb-girdle muscular dystrophies (LGMD) are a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Vita Therapeutics is led by CEO Douglass Falk, who is a JHU alum.

Jamie Niland, VP of Baltimore, Marylands Neoprogen Inc. received part of $892,080K in funding that was part of MSCFs first 2020 grant round. Jamie is the son of Bill Niland, Neoprogens current CEO and the former leader of Baltimore, Maryland life science community anchor Harpoon Medical, which was acquired by Edwards Scientific in 2017. The award was for Neoprogens neonatal cardiac stem cells for the heart tissue regeneration program.

Dr. Brian Pollok of Rockville, Marylands Propagenix, Inc., was also the recipient of a commercialization award for his Apical Surface-Outward (ASO) airway organoids, which is a potential novel cell system for drug discovery and personalized medicine. Propagenix develops innovative new technologies that address unmet needs in epithelial cell biologyfor applications in life science research as well as in precision diagnostics, and next-generation therapeutics such as immune-oncology, tissue engineering, and regenerative medicine, according to the companys website.

In addition, Dr. Ines Silva, R&D Manager of REPROCELL, USA received an MSCF commercialization grant for its work on building a commercial neural cell bank from patient-derived induced pluripotent stem cells. REPROCELL was founded in Japan in 2003 and acquired BioServe in Beltsville, Maryland in 2014.

Dr. Sashank Reddy, the founder of JHU startup LifeSprout and Medical Director, Johns Hopkins Technology Ventures Johns Hopkins University, received a portion of the $1,334,462 distributed for launch grants in 2020. The grant will go to support the launch of regenerative cell therapies for soft tissue restoration. LifeSprout recently closed a $28.5M seed round.

Past MSCF grant recipients include Frederick, Marylands RoosterBio, Inc. and Theradaptive, Inc., and Baltimore, Marylands Gemstone Biotherapeutics and Domicell, Inc., among others.

TEDCOs MSRF program continues to lend its deep support and ample funding to build and grow Marylands burgeoning and exciting regenerative medicine industry. Well be keeping a close eye on these companies as they grow and make future contributions to the thriving BHCR biocluster.

Steve has over 20 years experience in copywriting, developing brand messaging and creating marketing strategies across a wide range of industries, including the biopharmaceutical, senior living, commercial real estate, IT and renewable energy sectors, among others. He is currently the Principal/Owner of StoryCore, a Frederick, Maryland-based content creation and execution consultancy focused on telling the unique stories of Maryland organizations.

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Over $8M in 2020 Stem Cell Funding Awards Continue to Fuel Marylands Leading Cell Therapy Industry - BioBuzz

The Autologous Stem Cell Based Therapies Market globally is a standout amongst the most emergent and astoundingly approved sectors. This worldwide market has been developing at a higher pace with the development of imaginative frameworks and a developing end-client tendency.

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The worldwide Autologous Stem Cell Based Therapies market is an enlarging field for top market players,

The key players covered in this studyRegeneusMesoblastPluristem Therapeutics IncU.S. STEM CELL, INC.Brainstorm Cell TherapeuticsTigenixMed cell Europe

Market segment by Type, the product can be split intoEmbryonic Stem CellResident Cardiac Stem CellsUmbilical Cord Blood Stem Cells

Market segment by Application, split intoNeurodegenerative DisordersAutoimmune DiseasesCardiovascular Diseases

Market segment by Regions/Countries, this report coversUnited StatesEuropeChinaJapanSoutheast AsiaIndiaCentral & South America

The study objectives of this report are:To analyze global Autologous Stem Cell Based Therapies status, future forecast, growth opportunity, key market and key players.To present the Autologous Stem Cell Based Therapies development in United States, Europe and China.To strategically profile the key players and comprehensively analyze their development plan and strategies.To define, describe and forecast the market by product type, market and key regions.

In this study, the years considered to estimate the market size of Autologous Stem Cell Based Therapies are as follows:History Year: 2014-2018Base Year: 2018Estimated Year: 2019Forecast Year 2019 to 2025For the data information by region, company, type and application, 2018 is considered as the base year. Whenever data information was unavailable for the base year, the prior year has been considered.

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This Autologous Stem Cell Based Therapies report begins with a basic overview of the market. The analysis highlights the opportunity and Autologous Stem Cell Based Therapies industry trends that are impacted the market that is global. Players around various regions and analysis of each industry dimensions are covered under this report. The analysis also contains a crucial Autologous Stem Cell Based Therapies insight regarding the things which are driving and affecting the earnings of the market. The Autologous Stem Cell Based Therapies report comprises sections together side landscape which clarifies actions such as venture and acquisitions and mergers.

The Report offers SWOT examination and venture return investigation, and other aspects such as the principle locale, economic situations with benefit, generation, request, limit, supply, and market development rate and figure.

Quantifiable data:-

Geographically, this report studies the top producers and consumers, focuses on product capacity, production, value, consumption, market share and growth opportunity in these key regions, covering North America, Europe, China, Japan, Southeast Asia, India

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Finally, the global Autologous Stem Cell Based Therapies market provides a total research decision and also sector feasibility of investment in new projects will be assessed. Autologous Stem Cell Based Therapies industry is a source of means and guidance for organizations and individuals interested in their market earnings.

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Insight on the Growth of Autologous Stem Cell Based Therapies Market Growth with Challenges, Standardization, Competitive Market Share and Top Players...

LOS ANGELES, United States: QY Research has recently published a report, titled Global Autologous Stem Cell Based Therapies Market Size, Status and Forecast 2020-2026. The market research report is a brilliant, complete, and much-needed resource for companies, stakeholders, and investors interested in the global Autologous Stem Cell Based Therapies market. It informs readers about key trends and opportunities in the global Autologous Stem Cell Based Therapies market along with critical market dynamics expected to impact the global market growth. It offers a range of market analysis studies, including production and consumption, sales, industry value chain, competitive landscape, regional growth, and price. On the whole, it comes out as an intelligent resource that companies can use to gain a competitive advantage in the global Autologous Stem Cell Based Therapies market.

Key companies operating in the global Autologous Stem Cell Based Therapies market include , Regeneus, Mesoblast, Pluristem Therapeutics Inc, US STEM CELL, INC., Brainstorm Cell Therapeutics, Tigenix, Med cell Europe, Autologous Stem Cell Based Therapies

Get PDF Sample Copy of the Report to understand the structure of the complete report: (Including Full TOC, List of Tables & Figures, Chart) :

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Segmental Analysis

Both developed and emerging regions are deeply studied by the authors of the report. The regional analysis section of the report offers a comprehensive analysis of the global Autologous Stem Cell Based Therapies market on the basis of region. Each region is exhaustively researched about so that players can use the analysis to tap into unexplored markets and plan powerful strategies to gain a foothold in lucrative markets.

Global Autologous Stem Cell Based Therapies Market Segment By Type:

, Embryonic Stem Cell, Resident Cardiac Stem Cells, Umbilical Cord Blood Stem Cells Autologous Stem Cell Based Therapies

Global Autologous Stem Cell Based Therapies Market Segment By Application:

, Neurodegenerative Disorders, Autoimmune Diseases, Cardiovascular Diseases

Competitive Landscape

Competitor analysis is one of the best sections of the report that compares the progress of leading players based on crucial parameters, including market share, new developments, global reach, local competition, price, and production. From the nature of competition to future changes in the vendor landscape, the report provides in-depth analysis of the competition in the global Autologous Stem Cell Based Therapies market.

Key companies operating in the global Autologous Stem Cell Based Therapies market include , Regeneus, Mesoblast, Pluristem Therapeutics Inc, US STEM CELL, INC., Brainstorm Cell Therapeutics, Tigenix, Med cell Europe, Autologous Stem Cell Based Therapies

Key questions answered in the report:

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TOC

1 Report Overview1.1 Study Scope1.2 Key Market Segments1.3 Players Covered: Ranking by Autologous Stem Cell Based Therapies Revenue1.4 Market by Type1.4.1 Global Autologous Stem Cell Based Therapies Market Size Growth Rate by Type: 2020 VS 20261.4.2 Embryonic Stem Cell1.4.3 Resident Cardiac Stem Cells1.4.4 Umbilical Cord Blood Stem Cells1.5 Market by Application1.5.1 Global Autologous Stem Cell Based Therapies Market Share by Application: 2020 VS 20261.5.2 Neurodegenerative Disorders1.5.3 Autoimmune Diseases1.5.4 Cardiovascular Diseases1.6 Study Objectives1.7 Years Considered 2 Global Growth Trends2.1 Global Autologous Stem Cell Based Therapies Market Perspective (2015-2026)2.2 Global Autologous Stem Cell Based Therapies Growth Trends by Regions2.2.1 Autologous Stem Cell Based Therapies Market Size by Regions: 2015 VS 2020 VS 20262.2.2 Autologous Stem Cell Based Therapies Historic Market Share by Regions (2015-2020)2.2.3 Autologous Stem Cell Based Therapies Forecasted Market Size by Regions (2021-2026)2.3 Industry Trends and Growth Strategy2.3.1 Market Top Trends2.3.2 Market Drivers2.3.3 Market Challenges2.3.4 Porters Five Forces Analysis2.3.5 Autologous Stem Cell Based Therapies Market Growth Strategy2.3.6 Primary Interviews with Key Autologous Stem Cell Based Therapies Players (Opinion Leaders) 3 Competition Landscape by Key Players3.1 Global Top Autologous Stem Cell Based Therapies Players by Market Size3.1.1 Global Top Autologous Stem Cell Based Therapies Players by Revenue (2015-2020)3.1.2 Global Autologous Stem Cell Based Therapies Revenue Market Share by Players (2015-2020)3.1.3 Global Autologous Stem Cell Based Therapies Market Share by Company Type (Tier 1, Tier 2 and Tier 3)3.2 Global Autologous Stem Cell Based Therapies Market Concentration Ratio3.2.1 Global Autologous Stem Cell Based Therapies Market Concentration Ratio (CR5 and HHI)3.2.2 Global Top 10 and Top 5 Companies by Autologous Stem Cell Based Therapies Revenue in 20193.3 Autologous Stem Cell Based Therapies Key Players Head office and Area Served3.4 Key Players Autologous Stem Cell Based Therapies Product Solution and Service3.5 Date of Enter into Autologous Stem Cell Based Therapies Market3.6 Mergers & Acquisitions, Expansion Plans 4 Market Size by Type (2015-2026)4.1 Global Autologous Stem Cell Based Therapies Historic Market Size by Type (2015-2020)4.2 Global Autologous Stem Cell Based Therapies Forecasted Market Size by Type (2021-2026) 5 Market Size by Application (2015-2026)5.1 Global Autologous Stem Cell Based Therapies Market Size by Application (2015-2020)5.2 Global Autologous Stem Cell Based Therapies Forecasted Market Size by Application (2021-2026) 6 North America6.1 North America Autologous Stem Cell Based Therapies Market Size (2015-2020)6.2 Autologous Stem Cell Based Therapies Key Players in North America (2019-2020)6.3 North America Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)6.4 North America Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 7 Europe7.1 Europe Autologous Stem Cell Based Therapies Market Size (2015-2020)7.2 Autologous Stem Cell Based Therapies Key Players in Europe (2019-2020)7.3 Europe Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)7.4 Europe Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 8 China8.1 China Autologous Stem Cell Based Therapies Market Size (2015-2020)8.2 Autologous Stem Cell Based Therapies Key Players in China (2019-2020)8.3 China Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)8.4 China Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 9 Japan9.1 Japan Autologous Stem Cell Based Therapies Market Size (2015-2020)9.2 Autologous Stem Cell Based Therapies Key Players in Japan (2019-2020)9.3 Japan Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)9.4 Japan Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 10 Southeast Asia10.1 Southeast Asia Autologous Stem Cell Based Therapies Market Size (2015-2020)10.2 Autologous Stem Cell Based Therapies Key Players in Southeast Asia (2019-2020)10.3 Southeast Asia Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)10.4 Southeast Asia Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 11 India11.1 India Autologous Stem Cell Based Therapies Market Size (2015-2020)11.2 Autologous Stem Cell Based Therapies Key Players in India (2019-2020)11.3 India Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)11.4 India Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 12 Central & South America12.1 Central & South America Autologous Stem Cell Based Therapies Market Size (2015-2020)12.2 Autologous Stem Cell Based Therapies Key Players in Central & South America (2019-2020)12.3 Central & South America Autologous Stem Cell Based Therapies Market Size by Type (2015-2020)12.4 Central & South America Autologous Stem Cell Based Therapies Market Size by Application (2015-2020) 13 Key Players Profiles13.1 Regeneus13.1.1 Regeneus Company Details13.1.2 Regeneus Business Overview13.1.3 Regeneus Autologous Stem Cell Based Therapies Introduction13.1.4 Regeneus Revenue in Autologous Stem Cell Based Therapies Business (2015-2020))13.1.5 Regeneus Recent Development13.2 Mesoblast13.2.1 Mesoblast Company Details13.2.2 Mesoblast Business Overview13.2.3 Mesoblast Autologous Stem Cell Based Therapies Introduction13.2.4 Mesoblast Revenue in Autologous Stem Cell Based Therapies Business (2015-2020)13.2.5 Mesoblast Recent Development13.3 Pluristem Therapeutics Inc13.3.1 Pluristem Therapeutics Inc Company Details13.3.2 Pluristem Therapeutics Inc Business Overview13.3.3 Pluristem Therapeutics Inc Autologous Stem Cell Based Therapies Introduction13.3.4 Pluristem Therapeutics Inc Revenue in Autologous Stem Cell Based Therapies Business (2015-2020)13.3.5 Pluristem Therapeutics Inc Recent Development13.4 US STEM CELL, INC.13.4.1 US STEM CELL, INC. Company Details13.4.2 US STEM CELL, INC. Business Overview13.4.3 US STEM CELL, INC. Autologous Stem Cell Based Therapies Introduction13.4.4 US STEM CELL, INC. Revenue in Autologous Stem Cell Based Therapies Business (2015-2020)13.4.5 US STEM CELL, INC. Recent Development13.5 Brainstorm Cell Therapeutics13.5.1 Brainstorm Cell Therapeutics Company Details13.5.2 Brainstorm Cell Therapeutics Business Overview13.5.3 Brainstorm Cell Therapeutics Autologous Stem Cell Based Therapies Introduction13.5.4 Brainstorm Cell Therapeutics Revenue in Autologous Stem Cell Based Therapies Business (2015-2020)13.5.5 Brainstorm Cell Therapeutics Recent Development13.6 Tigenix13.6.1 Tigenix Company Details13.6.2 Tigenix Business Overview13.6.3 Tigenix Autologous Stem Cell Based Therapies Introduction13.6.4 Tigenix Revenue in Autologous Stem Cell Based Therapies Business (2015-2020)13.6.5 Tigenix Recent Development13.7 Med cell Europe13.7.1 Med cell Europe Company Details13.7.2 Med cell Europe Business Overview13.7.3 Med cell Europe Autologous Stem Cell Based Therapies Introduction13.7.4 Med cell Europe Revenue in Autologous Stem Cell Based Therapies Business (2015-2020)13.7.5 Med cell Europe Recent Development 14 Analysts Viewpoints/Conclusions 15 Appendix15.1 Research Methodology15.1.1 Methodology/Research Approach15.1.2 Data Source15.2 Disclaimer15.3 Author Details

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