Professor Michael P Lisanti, Chair in Translational Medicine at the University of Salford, has been an active research scientist for more than 30 years and is an expert in the field of cellular senescence. In 2018 Lisanti, along with his wife and research partner Professor Federica Sotgia, co-authored a paper entitled Azithromycin and Roxithromycin define a new family of senolytic drugs that target senescent human fibroblasts, which identified the FDA-approved antibiotic azithromycin as a senolytic drug: a compound which can be used to treat the symptoms of ageing.

Their research was made possible through generous funding contributions from Lunella Biotech, Inc, a Canadian-based pharmaceutical developer which fosters medical innovation; the Foxpoint Foundation, also based in Canada; and the Healthy Life Foundation, a UK charity which funds research into ageing and age-related conditions. Lisanti speaks to HEQ about his work and the future of senescence studies.

We started out focusing on cancer, but the relationship between cancer and ageing led us to shift our focus towards senescence, the process by which cells chronologically age and go into cell cycle arrest. Senescence leads to chronic inflammation: the cells secrete a lot of inflammatory mediators, which allows the cells to become almost infectious; so then neighbouring normal cells become senescent it has a kind of cataclysmic effect. As you age especially as you approach around 50 you begin to accumulate more senescent cells, which are thought to be the root cause of ageing; this then leads to various ageing-associated diseases, such as heart disease, diabetes, dementia and cancer, the most life threatening conditions in the Western world.

The goal, therefore, would be to remove the senescent cells. It is possible to use a genetic trick to remove senescent cells from mice: this causes them to live longer by preventing ageing-associated diseases; but it is not possible to use the same genetic trick for humans. We would therefore need a drug that only kills or removes senescent cells; and that could then potentially lead to rejuvenation, thereby extending the patients healthy lifespan.

We set up a drug assay using normal, commercially available, human fibroblasts: MRC-5, which comes from the lungs, and BJ-1, which comes from the skin. The idea was to artificially induce ageing, which we did using a compound called BrdU. This compound is a nucleoside: it incorporates into the DNA and that leads to DNA damage; and the DNA damage in turn induces the senescence phenotype. The overarching concept was to create a population of cells artificially that were senescent; and then to compare primary cells that were normal with cells which were senescent, with the goal of identifying drugs which could only selectively kill the senescent cells and not harm the normal cells.

We had previously observed positive results in tests on the metabolic effects of antibiotics, so our drug screening identified two drugs called azithromycin and roxithromycin, which constitute a new family of senolytic drugs. Theyre both clinically approved drugs azithromycin has been around longer; and has a strong safety profile and we looked at other members of the same drug family such as erythromycin, which is the parent compound, but erythromycin has no senolytic activity. The characteristics we were looking for appeared to be relatively restricted to azithromycin, which in our observation was very efficiently killing the senescent cells. As we reported in the paper, it had an efficacy of approximately 97%, meaning that it was able to facilitate the growth of the normal cells, while concurrently selectively killing the senescent cells.

We tested the drug on normal and senescent cells which were otherwise identical. The senescent cells underwent apoptosis programmed cell death so that led us to the conclusion that the drug selectively kills the senescent cells, while at the same time the normal cells are able to continue to proliferate. That selective effect of removing exclusively the senescent cells is what we were searching for; because in this instance we would want a drug that could potentially be used in humans and which would only kill senescent cells.

Obviously, we would have to do clinical trials going forward, but the first step should be to identify the pharmaceutical application. Given that this drug appears to selectively kill and remove the senescent cells, it could be used potentially to prevent ageing-associated disease; and it could therefore potentially extend the human lifespan, especially in terms of reducing diseases and conditions like diabetes, heart disease, dementia and even cancer.

Cystic fibrosis is the most common genetic disease in humans; patients with cystic fibrosis are prone to bacterial lung infections. Researchers started to explore the possibility of using azithromycin preventatively in patients with cystic fibrosis; and they found that, while it didnt necessarily affect patients susceptibility to infection, it did prevent lung fibrosis where the lungs become stiff and the patient is unable to breathe and in doing so, extended the patients lifespan. These studies were focused on myofibroblasts, which at the time werent really seen as senescent; whereas the literature now acknowledges a general consensus that myofibroblasts are indeed senescent cells.

We havent specifically examined anything relating ageing to antimicrobial resistance; but azithromycin is an antibiotic, which is not ideal within the context of AMR. Potentially in the future, once researchers identify what it is about the azithromycin that is causing the senescent cells to die, they could develop future drugs azithromycin is a stepping stone in this context, but what it shows is proof of principle that a drug can be identified which selectively kills senescent cells. This indicates that senescent cells are clearly biochemically distinct from the normal cells, and that it is possible to find a drug that selectively kills them and that is relatively safe. It provides a starting point for further new drug discovery to identify other drugs which might also be selective.

Ideally, we would want a drug which is not an antibiotic; but that means further research will be necessary to find additional drugs or to refine the senolytic activity which weve discovered in this drug. We are in the early stages; the point is that it is experimentally feasible and this would then lend itself to doing new clinical trials in the future, because azithromycin is relatively safe and it probably wont need to be administered over a long period of time to remove senescent cells you might not need to use it for any longer than you would as an antibiotic.

This research has been supported by the Foxpoint Foundation (Canada), the Healthy Life Foundation (UK), and Lunella Biotech, Inc. (Canada).

Professor Michael P Lisanti is Chair of Translational Medicine at the University of Salford School of Science, Engineering & Environment, UK. His current research programme is focused on eradicating cancer stem cells (CSCs); and anti-ageing therapies, in the context of age-associated diseases, such as cancer and dementia.

Lisanti began his education at New York University, US, graduating magna cum laude in chemistry (1985); before completing an MD-PhD in cell biology and genetics at Cornell University Medical College, US (1992). In 1992, he moved to MIT, US, where he worked alongside Nobel laureate David Baltimore and renowned cell biologist Harvey Lodish as a Whitehead Institute fellow (1992-96).

His career has since taken him to the Albert Einstein College of Medicine, US (1997-2006), the Kimmel Cancer Center, US (2006-12), and the University of Manchester, UK (2012-16), where he served as the Muriel Edith Rickman chair of breast oncology, director of the Breakthrough Breast Cancer and the Breast Cancer Now Research Units, and founder and director of the Manchester Centre for Cellular Metabolism.

Lisanti has contributed to 564 publications in peer-reviewed journals and been cited more than 90,000 times. A list of his works can be found at: https://pubmed.ncbi.nlm.nih.gov/?term=lisanti+mp&sort=date

Professor Federica Sotgia currently serves as chair in cancer biology and ageing at the University of Salford School of Science, Engineering and Environment, UK, where she focuses on, inter alia, the role of the tumour microenvironment in cancer and the metabolic requirements of tumour-initiating cells.

Sotgia graduated magna cum laude with an MS in biological sciences (1996) from the University of Genova, Italy, where she later completed a PhD in medical genetics (2001). She moved to the Albert Einstein College of Medicine, US, in 1998, originally as a visiting student and then postdoctoral fellow, and she was appointed an instructor in 2002.

Sotgia has since worked as an assistant professor at the Kimmel Cancer Center, US (2006-12), a senior lecturer at the University of Manchester, UK (2012-16), and a Professor in biomedical science at the University of Salford (2016-present).

She has contributed to 206 publications in peer-reviewed journals and been cited upwards of 27,000 times.

A list of her works can be found at: https://pubmed.ncbi.nlm.nih.gov/?term=sotgia+f&sort=date

Professor Michael P Lisanti, MD-PhD, FRSA, FRSBChair in Translational MedicineSchool of Science, Engineering & EnvironmentUniversity of Salford+44 (0)1612 950 240M.P.Lisanti@salford.ac.uk

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Senolytic drugs: can this antibiotic treat symptoms of ageing? - Health Europa

(MENAFN - GetNews) Market Research Future (MRFR) collected data on several factors including implications of COVID 19 Impact on Regenerative Medicine Market and demographic challenges, showed how it could move forward in the coming years.

Regenerative Medicine Market Outlook

Global regenerative medicine market is growing continually, witnessing a massive uptake. Market growth primarily attributes to the increasing advancement in healthcare technology and the growing prevalence of chronic diseases. Besides, improvements in the field of regenerative medicine and stem cell technology drive the growth of the market excellently.

Moreover, the rising uptake of therapeutics such as stem cell biology, cellular therapy, tissue engineering in applications, including cord blood, oncology, urology, orthopedics, neurology, dermatology, and others accelerate the market growth. According to Market Research Future (MRFR), the global regenerative medicine market is poised to grow at 25.4% CAGR throughout the forecast period (2016 2022).

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Additionally, the rising uptake of stem cell & tissue engineering processes in the treatment of health issues ranging from orthopedics, musculoskeletal & spine, dental, and skin/integumentary to cancer, neurology, and cardiology substantiate the market growth. Furthermore, the increasing rate of road accidents, injuries, and trauma cases drive the market exponentially, driving the demand for transplants & surgical reconstruction procedures.

On the other hand, factors such as the lack of awareness, skilled professionals, and stringent regulatory policies are projected to act as significant impeders for market growth. Nevertheless, funding support for the development of regenerative medicines would support the growth of the market throughout the predicted period. Also, widening application areas of regenerative medicines in the field of stem cell reconstructive and skin grafting would increase the market growth.

Global Regenerative Medicine Market Segments

The analysis is segmented into four dynamics;

By Material : Synthetic Materials, Genetically Engineered Materials, Pharmaceuticals, and others.

By Therapy : Stem Cell Biology, Cellular Therapy, Tissue Engineering, and others.

By Application : Cord Blood, Oncology, Urology, Orthopedics, Neurology, Dermatology, and others.

By Regions : Americas, Europe, Asia Pacific, Middle East & Africa, and Rest-of-the-World.

Regenerative Medicine Market Regional Analysis

North America is projected to continue dominating the global regenerative medicine market throughout the forecast period. In 2015, North America accounted for more than 44% of the overall market share. This huge market growth attributes to the presence of a large number of major players and pharma & biotechnology companies. Moreover, huge investments made by public & private organizations drive the regenerative medicine industry in the region.

Besides, the rising prevalence of chronic diseases and orthopedic issues and increasing clinical trials to evaluate the therapeutic potential of products foster regional market growth. Also, the well-spread awareness towards the therapeutic potency of regenerative medicines impacts the market growth positively. The North American regenerative medicine market is expected to grow at a robust CAGR of 22.3% over the review period.

Europe stands second in the global regenerative medicine market. Factors such as the increasing per capita healthcare expenses and penetration of healthcare sectors in the region boost the market growth. Additionally, the rising government support and R & D funding in the life science developments substantiate the regional market growth. Markets in the UK, Germany, and France, contribute to the regional market majorly. The European regenerative medicine market is estimated to grow at 22.5% CAGR during the assessment period.

The Asia Pacific regenerative medicine market has emerged as a rapidly growing market. Factors such as the large advances in biotechnology and increasing government support for R & D are fostering the growth of the regional market. Regenerative medicine markets in highly populated countries such as China, India, and Japan support the regional market growth excellently, heading with huge technological advances. The APAC Regenerative Medicine market is predicted to demonstrate huge growth potential.

Global Regenerative Medicine Market - Competitive Analysis

The well-established regenerative medicine market appears to be highly competitive with the presence of several notable players. To gain a larger competitive advantage, market players incorporate strategic initiatives such as mergers & acquisitions, expansions, and product/technology launch. Also, they make substantial investments to drive R & D to develop their capabilities and to expand their global footprints. Simultaneously, R & D funding programs initiated by the governments to enhance regenerative medicine capabilities are offering high growth potential. This is further going to attract several new entrants to the market and intensify the market competition further.

Regenerative Medicine Market Major Players:

Players active in the global regenerative medicine market include Osiris Therapeutics, Cook Biotech, Organogenesis, Baxter International, Inc., Stryker and RTI surgical, LifeSciences, CryoLife, Advanced Cell Technology, Sanofi, BioMimetic Therapeutics, Medtronic, StemCellsInc, and LifeCell Kinetic Concepts, among others.

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Regenerative Medicine Industry/Innovations/Related News:

March 15, 2020 - Research team at the University of Sheffield published their study on stem cell mutations that could improve regenerative medicine in the magazine Stem Cell Reports.' Their study gives new insights into the cause of mutations in pluripotent stem cells and potential ways of stopping these mutations from occurring. It also suggests ways to reduce the likelihood of variations occurring in these cells when cultured.There is considerable interest in using Pluripotent stem cells to produce cells that can replace diseased or damaged tissues in applications referred to as regenerative medicine.

Pharmaceutical Industry Related Reports

Global Anti-viral drugs Market Information, by application (hepatitis, HIV/AIDS, herpes, influenza and others) and by mechanism of action (nucleotide polymerase inhibitors, reverse transcriptase inhibitors, protease inhibitors and others) - Forecast to 2022: https://www.marketresearchfuture.com/reports/anti-viral-drugs-market-2454

Drug allergy market information: by type (immunologic, nonimmunologic, and others), diagnosis (skin tests, blood tests, and others), by treatment (antihistamines, corticosteroids, and others), by end user- global forecast till 2023: https://www.marketresearchfuture.com/reports/drug-allergy-market-4033

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Impacts of COVID 19 on the Global Regenerative Medicine Market Size: Global Industry Analysis, Growth, Top Companies Revenue, MRFR Reveals Insights...

ORLANDO, Fla.--(BUSINESS WIRE)--Hesperos Inc., pioneers of the Human-on-a-Chip in vitro system, today announced the publication of a new peer-reviewed publication that describes how the companys technology can be used to investigate immune responses following treatment with biological therapeutics for multi-organ systemic diseases, including cancer, infectious diseases and inflammatory disorders. The study was part of a collaboration between Hesperos, Hoffman-La Roche Pharmaceuticals and the University of Central Florida. The manuscript, titled Differential Monocyte Actuation in a Three-Organ Functional Innate Immune System-on-a-Chip, was published today in the prestigious journal Advanced Science. Click here to view a multimedia version of the press release, including media-ready images, downloadable resources, and more.

The immune system plays an important role in coordinating with other organ systems to combat infection, eliminate damaged cells and repair tissue. However, modeling immune response following drug treatment in preclinical studies is challenging due to poor predictability, especially for the innate portion of the system. As the scientific community begins to turn more towards using multi-organ, human-on-a-chip systems as a cost-effective way to increase efficiency and lower toxicity, many of these models lack a systemic immune component.

Hesperos, in collaboration with Hoffmann-La Roche Pharmaceuticals, describe an in vitro, pumpless, three-organ system containing functional human cardiomyocytes, skeletal muscle and hepatocytes in a serum-free medium, along with recirculating human monocyte THP-1 immune cells. Monocytes are a vital immune system cells involved in wound healing, pathogen clearance and activation of the innate immune response, but are also responsible for the cytokine storm found in conditions such as sepsis.

One application where the immune-system-on-a-chip can be immediately useful is for uncovering how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly affects multi-organ systems by activating the cytokine storm from inflammatory macrophages and to support the rapid development of therapeutics. As the global pandemic of COVID-19 continues to grow, this system has the potential to quickly evaluate antiviral and repurposed drugs to help combat this devastating disease, said Michael L. Shuler, Ph.D., Chief Executive Officer of Hesperos.

In the study, the researchers evaluated two different innate immune responses: 1) targeted immune response following tissue-specific damage, which simulates indirect activation of THP-1 cells and, 2) pro-inflammatory immune response following direct activation of immune cells, mimicking acute inflammation and the cytokine storm. Though not reported in this study, Hesperos has also shown that peripheral blood mononuclear cells (PBMCs) and T-cells are sustainable in these multi-organs systems, which would allow some aspects of adaptive immunity to also be modeled.

In the targeted immune response experiments, the cardiotoxic compound amiodarone was used to selectively damage cardiac cells to evaluate how THP-1 immune cells affect the three-organ system. The presence of both amiodarone and THP-1 immune cells led to a more pronounced reduction in cardiac force, conduction velocity and beat frequency compared to amiodarone alone. THP-1 cells were also found to infiltrate the damaged cardiomyocytes and induce significantly increased cytokine IL-6 expression, indicating an M2 macrophage phenotype. No immune-activated damage was reported in the skeletal muscle or liver cells.

The most striking features of our immune-system-on-a-chip is that it emulates different immune reactions for direct tissue-damage and acute inflammation, as well as distinguishes between M1 vs. M2 macrophage phenotypes, said James Hickman, Ph.D., Chief Scientist at Hesperos and Professor at the University of Central Florida.

The study was initially funded by Roche Pharmaceuticals and completed under an NIH grant from National Center for Advancing Translational Sciences (NCATS) Small Business Innovation Research program, which supports studies to advance tissue chip technology toward commercialization.

Tissue chips are a promising technology for accelerating the preclinical timeline and getting treatments to patients more efficiently, said Danilo A. Tagle, Ph.D., associate director for special initiatives at NCATS. Finding improved ways to study immune responses has tremendous implications for drug discovery and the development of more effective personalized medicines in diseases that affect multiple organ systems.

In the pro-inflammatory response experiments, the three-organ system was exposed to lipopolysaccharide (LPS) and interferon gamma (IFN-) to stimulate acute inflammation/cytokine storm and provoke monocyte differentiation and activation. In the absence of THP-1 immune cells, LPS/IFN- treatment had no significant effect on function of the three-organ system. However, with the addition of THP-1 immune cells, LPS/IFN- treatment caused cellular damage to all three-organ components, including THP-1 cell infiltration in liver tissue, and led to significant alterations in cardiac force and beat frequency, as well as skeletal muscle force. Additionally, there was an upregulation of pro-inflammatory cytokines, including TNF-, IL-6 and IL-10, indicating an M1 macrophage phenotype, which is analogous to the cytokine storm found during certain reactions to biologic therapeutics and emulates what occurs during sepsis.

To read the full manuscript, please visit https://doi.org/10.1002/advs.202000323.

About Hesperos

Hesperos, Inc. is a leader in efforts to characterize an individuals biology with Human-on-a-Chip microfluidic systems. Founders Michael L. Shuler and James J. Hickman have been at the forefront of every major scientific discovery in this realm, from individual organ-on-a-chip constructs to fully functional, interconnected multi-organ systems. With a mission to revolutionize toxicology testing as well as efficacy evaluation for drug discovery, the company has created pumpless platforms with serum-free cellular mediums that allow multi-organ system communication and integrated computational PKPD modeling of live physiological responses utilizing functional readouts from neurons, cardiac, muscle, barrier tissues and neuromuscular junctions as well as responses from liver, pancreas and barrier tissues. Created from human stem cells, the fully human systems are the first in vitro solutions that accurately utilize these platforms to predict in vivo functions without the use of animal models, as featured in Science. More information is available at https://hesperosinc.com

Hesperos and Human-on-a-Chip are trademarks of Hesperos Inc. All other brands may be trademarks of their respective holders.

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Hesperos demonstrates innovative Human-on-a-Chip approach to modeling innate immune system response following tissue damage and acute inflammation -...

Stem Cell Assay Market: Snapshot

Stem cell assay refers to the procedure of measuring the potency of antineoplastic drugs, on the basis of their capability of retarding the growth of human tumor cells. The assay consists of qualitative or quantitative analysis or testing of affected tissues andtumors, wherein their toxicity, impurity, and other aspects are studied.

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With the growing number of successfulstem cell therapytreatment cases, the global market for stem cell assays will gain substantial momentum. A number of research and development projects are lending a hand to the growth of the market. For instance, the University of Washingtons Institute for Stem Cell and Regenerative Medicine (ISCRM) has attempted to manipulate stem cells to heal eye, kidney, and heart injuries. A number of diseases such as Alzheimers, spinal cord injury, Parkinsons, diabetes, stroke, retinal disease, cancer, rheumatoid arthritis, and neurological diseases can be successfully treated via stem cell therapy. Therefore, stem cell assays will exhibit growing demand.

Another key development in the stem cell assay market is the development of innovative stem cell therapies. In April 2017, for instance, the first participant in an innovative clinical trial at the University of Wisconsin School of Medicine and Public Health was successfully treated with stem cell therapy. CardiAMP, the investigational therapy, has been designed to direct a large dose of the patients own bone-marrow cells to the point of cardiac injury, stimulating the natural healing response of the body.

Newer areas of application in medicine are being explored constantly. Consequently, stem cell assays are likely to play a key role in the formulation of treatments of a number of diseases.

Global Stem Cell Assay Market: Overview

The increasing investment in research and development of novel therapeutics owing to the rising incidence of chronic diseases has led to immense growth in the global stem cell assay market. In the next couple of years, the market is expected to spawn into a multi-billion dollar industry as healthcare sector and governments around the world increase their research spending.

The report analyzes the prevalent opportunities for the markets growth and those that companies should capitalize in the near future to strengthen their position in the market. It presents insights into the growth drivers and lists down the major restraints. Additionally, the report gauges the effect of Porters five forces on the overall stem cell assay market.

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Global Stem Cell Assay Market: Key Market Segments

For the purpose of the study, the report segments the global stem cell assay market based on various parameters. For instance, in terms of assay type, the market can be segmented into isolation and purification, viability, cell identification, differentiation, proliferation, apoptosis, and function. By kit, the market can be bifurcated into human embryonic stem cell kits and adult stem cell kits. Based on instruments, flow cytometer, cell imaging systems, automated cell counter, and micro electrode arrays could be the key market segments.

In terms of application, the market can be segmented into drug discovery and development, clinical research, and regenerative medicine and therapy. The growth witnessed across the aforementioned application segments will be influenced by the increasing incidence of chronic ailments which will translate into the rising demand for regenerative medicines. Finally, based on end users, research institutes and industry research constitute the key market segments.

The report includes a detailed assessment of the various factors influencing the markets expansion across its key segments. The ones holding the most lucrative prospects are analyzed, and the factors restraining its trajectory across key segments are also discussed at length.

Global Stem Cell Assay Market: Regional Analysis

Regionally, the market is expected to witness heightened demand in the developed countries across Europe and North America. The increasing incidence of chronic ailments and the subsequently expanding patient population are the chief drivers of the stem cell assay market in North America. Besides this, the market is also expected to witness lucrative opportunities in Asia Pacific and Rest of the World.

Global Stem Cell Assay Market: Vendor Landscape

A major inclusion in the report is the detailed assessment of the markets vendor landscape. For the purpose of the study the report therefore profiles some of the leading players having influence on the overall market dynamics. It also conducts SWOT analysis to study the strengths and weaknesses of the companies profiled and identify threats and opportunities that these enterprises are forecast to witness over the course of the reports forecast period.

Some of the most prominent enterprises operating in the global stem cell assay market are Bio-Rad Laboratories, Inc (U.S.), Thermo Fisher Scientific Inc. (U.S.), GE Healthcare (U.K.), Hemogenix Inc. (U.S.), Promega Corporation (U.S.), Bio-Techne Corporation (U.S.), Merck KGaA (Germany), STEMCELL Technologies Inc. (CA), Cell Biolabs, Inc. (U.S.), and Cellular Dynamics International, Inc. (U.S.).

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TMR Research is a premier provider of customized market research and consulting services to business entities keen on succeeding in todays supercharged economic climate. Armed with an experienced, dedicated, and dynamic team of analysts, we are redefining the way our clients conduct business by providing them with authoritative and trusted research studies in tune with the latest methodologies and market trends.

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Stem Cell Assay Market to Witness Growth Acceleration During 2017-2025 - Cole of Duty

The art (and existing science) of regenerative medicine in equine practice, and whats to come

Regenerative therapy is an umbrellaterm encompassing any method that encourages the body to self- heal. Because it is drawing onits own properties, healing tissue more closely resembles native tissue than weak, disorganized scar tissue typically seen post-injury.

The goal is to allow restoration of normal function and structure of the injured tissue to allow horses to perform at their previous level, whatever that might be, with a reduced risk of reinjury, says Kyla Ortved, DVM, PhD, Dipl. ACVS, ACVSMR, assistant professor of large animal surgery at the University of Pennsylvanias New Bolton Center, in Kennett Square.

She says the three main components of regenerative medicine that help tissues self-heal include:

A specific therapy may incorporate some or all three of these components, says Ortved.

Due to the regenerative therapy industrys popularity and continued growth, many articles weve published review recent laboratory studies about stem cell production and data on efficacy andsafety (you can find them at TheHorse.com/topics/regenerative-medicine). Here, well review the basics of three regenerative modalities commonly used in equine medicine and when veterinarians and horse owners might consider each.

With this approach the practitioner collects blood from a horse and processes it using a commercial system that concentrates the platelets. When he or she injects that concentrated platelet product back into the horse, granules within the platelets release an array of growth factors that aim to facilitate and modulate the healing process. Specifically, granule-derived growth factors encourage target tissue cells at the injury site to migrate and proliferate, improve extracellular matrix synthesis, and stimulate blood vessel development.

Recently, leukocyte-reduced PRP hasbecome many equine veterinarians PRP product of choice. These preparations contain fewer white blood cells (leukocytes) and, reportedly, inflammatory mediators than normal PRP products do. These mediators break tissues down, effectively counteracting the anabolic (tissue-building) effects of the platelets and their granules.

Veterinarians can easily prepare ACS by collecting a blood sample from the patient, then incubating it with special commercially available glass beads to stimulate interleukin-1 receptor antago- nist protein (IRAP) production. Theythen inject the resultant IRAP-rich serumsample back into the patient at the target location or injury site. This protein blocks the action of interleukin-1, a powerful and damaging pro-inflammatory mediator. Additionally, glass bead incubation stimulates the production of anti-inflammatory mediators and growth factors similar to those found in PRP.

Ortved says its important to remember that all biologics, including PRP and IRAP, contain various concentrations of growth factors and bioactive protein.

Remember, they are made from your horses blood and, therefore, containall of the components in blood, just in varying concentrations, she says.

Regenerative therapies that contain highconcentrations of IRAP include IRAP II, autologous protein solution (APS), and bone marrow aspirate concentrate (BMAC).

In certain tissues, such as adipose (fat) and bone marrow, we can find specific cells that have the ability to self-renew and grow more than 200 types of body cells. Veterinarians can isolate these cells, called stem cells or progenitor cells, and either:

Perhaps more important than theirability to differentiate into other celltypes, stem cells have powerful anti-inflammatoryproperties and play acentral role in coordinating healing in alltypes of tissues through cell-to-cell signaling,Ortved says.

Which of these three modality typeswill provide the most benefit to yourhorse depends on a variety of factors thatyou and your veterinarian will consider.

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Regenerative Therapies: Helping Horses Self-Heal The Horse - TheHorse.com

KENILWORTH, N.J. & WOODCLIFF LAKE, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced new data from analyses of two trials evaluating KEYTRUDA, Mercks anti-PD-1 therapy, plus LENVIMA, an orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai. In the KEYNOTE-524/Study 116 and KEYNOTE-146/Study 111 trials, the KEYTRUDA plus LENVIMA combination demonstrated clinically meaningful objective response rates (ORR) in patients with unresectable hepatocellular carcinoma (HCC) with no prior systemic therapy and in patients with metastatic clear cell renal cell carcinoma (ccRCC) who progressed following immune checkpoint inhibitor therapy, respectively.

The tumor response rates demonstrated with KEYTRUDA plus LENVIMA in these studies underscore the potential of this combination regimen in certain types of hepatocellular and renal cell carcinoma, said Dr. Jonathan Cheng, Vice President, Oncology Clinical Research, Merck Research Laboratories. KEYTRUDA plus LENVIMA is an important pillar of our broad oncology research program, and we continue to advance the study of the combination across multiple types of cancers and stages of disease.

As data from our combination trials continue to read out, our enthusiasm for and belief in the potential of KEYTRUDA plus LENVIMA are strengthened by the growing body of evidence observed in multiple advanced cancers, said Dr. Takashi Owa, Chief Medicine Creation and Chief Discovery Officer, Oncology Business Group at Eisai. Our ongoing clinical study efforts on this combination exemplify our commitment to following the science and exploring possible solutions for patients affected by difficult-to-treat cancers.

Results from KEYNOTE-524/Study 116 (Abstract #4519) are being presented in a poster discussion session, and results from KEYNOTE-146/Study 111 (Abstract #5008) are being presented in an oral abstract session of the Virtual Scientific Program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting.

KEYNOTE-524/Study 116 Trial Design and Data (Abstract #4519)

KEYNOTE-524/Study 116 (ClinicalTrials.gov, NCT03006926) is a Phase 1b, open-label, single-arm trial evaluating the KEYTRUDA plus LENVIMA combination in 100 patients with unresectable HCC with no prior systemic therapy. Patients were treated with KEYTRUDA 200 mg intravenously every three weeks in combination with LENVIMA 8 or 12 mg (based on baseline body weight 60 kilograms or 60 kilograms, respectively) orally once daily. The primary endpoints are ORR and duration of response (DOR) by modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST v1.1 per independent imaging review (IIR). Secondary endpoints include progression-free survival (PFS), time to progression (TTP) and overall survival (OS). At data cutoff (Oct. 31, 2019) and a median duration of follow-up of 10.6 months (95% CI: 9.2-11.5), 37 patients were still on study treatment (KEYTRUDA plus LENVIMA: n=34; LENVIMA only: n=3), and median duration of treatment exposure to the KEYTRUDA plus LENVIMA combination was 7.9 months (range: 0.2-31.1).

The final analysis of the studys primary endpoints showed the KEYTRUDA plus LENVIMA combination demonstrated an ORR of 36% (n=36) (95% CI: 26.6-46.2), with a complete response rate of 1% (n=1) and a partial response rate of 35% (n=35), and a median DOR of 12.6 months (95% CI: 6.9-not estimable [NE]), using RECIST v1.1 criteria per IIR. As assessed using mRECIST criteria per IIR, the KEYTRUDA plus LENVIMA combination demonstrated an ORR of 46% (n=46) (95% CI: 36.0-56.3), with a complete response rate of 11% (n=11) and a partial response rate of 35% (n=35), and a median DOR of 8.6 months (95% CI: 6.9-NE).

Treatment-related adverse events (TRAEs) led to discontinuation of KEYTRUDA and LENVIMA in 6% of patients, discontinuation of KEYTRUDA in 10% of patients, and discontinuation of LENVIMA in 14% of patients. Grade 3 TRAEs occurred in 67% of patients (Grade 3: 63%; Grade 4: 1%; Grade 5: 3%). There was one Grade 4 TRAE (leukopenia/neutropenia), and there were three Grade 5 treatment-related deaths (acute respiratory failure/acute respiratory distress syndrome, intestinal perforation and abnormal hepatic function; n=1 for each). The most common TRAEs of any grade (20%) were hypertension (36%), diarrhea (35%), fatigue (30%), decreased appetite (28%), hypothyroidism (25%), palmar-plantar erythrodysesthesia syndrome (23%), decreased weight (22%), dysphonia (21%), increased aspartate aminotransferase (20%) and proteinuria (20%).

KEYNOTE-146/Study 111 Trial Design and Data from the RCC Cohort (Abstract #5008)

KEYNOTE-146/Study 111 (ClinicalTrials.gov, NCT02501096) is a Phase 1b/2, open-label, single-arm trial evaluating the KEYTRUDA plus LENVIMA combination in patients with selected solid tumors. Results from the RCC cohort of the Phase 2 part of the study are based on 104 patients with metastatic ccRCC with disease progression following PD-1/PD-L1 immune checkpoint inhibitor therapy using RECIST v1.1 criteria. Patients were treated with KEYTRUDA 200 mg intravenously every three weeks in combination with LENVIMA 20 mg orally once daily until unacceptable toxicity or disease progression. The primary endpoint is ORR at week 24 by immune-related RECIST (irRECIST) per investigator review. Secondary endpoints include ORR, PFS, OS, safety and tolerability for a maximum of 35 cycles/treatments (approximately two years).

At data cutoff (Apr. 9, 2020), results from the Phase 2 part of the study showed the KEYTRUDA plus LENVIMA combination demonstrated an ORR at week 24 of 51% (95% CI: 41-61) by irRECIST per investigator review. As assessed by irRECIST per investigator review, ORR was 55% (95% CI: 45-65), with a partial response rate of 55%, a stable disease rate of 36% and a progressive disease rate of 5% (5% were not evaluable). Median DOR was 12 months (95% CI: 9-18). Median PFS was 11.7 months (95% CI: 9.4-17.7), and the 12-month PFS rate was 45% (95% CI: 32-57). Median OS was not reached (NR) (95% CI:16.7-NR), and the 12-month OS rate was 77% (95% CI: 67-85).

As assessed by RECIST v1.1 per investigator review, ORR was 52% (95% CI: 42-62), with a partial response rate of 52%, a stable disease rate of 38% and a progressive disease rate of 6% (5% were not evaluable). Median DOR was 12 months (95% CI: 9-18). Median PFS was 11.3 months (95% CI: 7.6-17.7), and the 12-month PFS rate was 44% (95% CI: 31-55).

TRAEs led to discontinuation of KEYTRUDA and LENVIMA in 15% of patients, discontinuation of KEYTRUDA in 12% of patients, and discontinuation of LENVIMA in 12% of patients (2% due to proteinuria). The most common TRAEs that led to dose reduction of LENVIMA were fatigue (14%), diarrhea (10%) and proteinuria (9%). Grade 4 TRAEs included lipase increased, diverticulitis, large intestine perforation and myocardial infarction, and there were two Grade 5 treatment-related deaths of upper gastrointestinal hemorrhage and sudden death. The most common TRAEs of any grade (20%) were fatigue (53%), diarrhea (46%), proteinuria (39%), dysphonia (35%), hypertension (34%), nausea (32%), stomatitis (32%), arthralgia (29%), decreased appetite (28%), palmar-plantar erythrodysesthesia syndrome (25%), hypothyroidism (23%) and headache (22%).

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).

Endometrial Carcinoma

KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. 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 trial.

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%).

Originally posted here:
KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) Combination Demonstrated Clinically Meaningful Tumor Response Rates in Unresectable Hepatocellular...

BAR HARBOR Research by scientists at the MDI Biological Laboratoryis opening up new approaches to promoting tissue regeneration in organs damaged by disease or injury.

In recent years, research in regenerative biology has focused on stem cell therapies that reprogram the bodys own cells to replace damaged tissue, which is a complicated process because it involves turning genes in the cells nucleus on and off.

A recent paper in the journal Genetics by MDI Biological Laboratory scientist Elisabeth Marnik, Ph.D., a postdoctoral fellow in the laboratory of Dustin Updike, Ph.D., offers insight into an alternate pathway to regeneration: by recreating the properties of germ cells.

Germ cells, which are the precursors to the sperm and egg, are considered immortal because they are the only cells in the body with the potential to create an entirely new organism. The stem cell-like ability of germ cells to turn into any type of cell is called totipotency.

By getting a handle on what makes germ cells totipotent, we can promote regeneration by unlocking the stem cell-like properties of other cell types, said Updike. Our research shows that such cells can be reprogrammed by manipulating their cytoplasmic composition and chemistry, which would seem to be safer and easier than changing the DNA within a cells nucleus.

Using the tiny, soil-dwelling nematode worm, C. elegans, as a model, the Updike lab studies organelles called germ granules that reside in the cytoplasm (the contents of the cell outside of the nucleus) of germ cells. These organelles, which are conserved from nematodes to humans, are one of the keys to the remarkable attributes of germ cells, including the ability to differentiate into other types of cells.

In their recent paper entitled Germline Maintenance Through the Multifaceted Activities of GLH/Vasa in Caenorhabditis elegans P Granules, Updike and his team describe the intriguing and elusive role of Vasa proteins within germ granules in determining whether a cell is destined to become a germ cell with totipotent capabilities or a specific type of cell, like those that comprise muscle, nerves or skin.

Because of the role of Vasa proteins in preserving totipotency, an increased understanding of how such proteins work could lead to unprecedented approaches to de-differentiating cell types to promote regeneration; or alternatively, to new methods to turn off totipotency when it is no longer desirable, as in the case of cancer.

The increase in chronic and degenerative diseases caused by the aging of the population is driving demand for new therapies, said MDI Biological Laboratory President Hermann Haller, M.D. Dustins research on germ granules offers another route to repairing damaged tissues and organs in cases where therapeutic options are limited or non-existent, as well as an increased understanding of cancer.

Because of the complexity of the cellular chemistry, research on Vasa and other proteins found in germ granules is often overlooked, but that is rapidly changing especially among pharmaceutical companies as more scientists realize the impact and potential of such research, not only for regenerative medicine but also for an understanding of tumorigenesis, or cancer development, Updike said.

Recent research has found that some cancers are accompanied by the mis-expression of germ granule proteins, which are normally found only in germ cells. The mis-expression of these germ-granule proteins seems to promote the immortal properties of germ cells, and consequently tumorigenesis, with some germ-granule proteins now serving as prognosis markers for different types of cancer, Updike said.

Updike is a former postdoctoral researcher in the laboratory of Susan Strome, Ph.D., at University of California, Santa Cruz. Strome, who was inducted into the National Academy of Sciences last year, first discovered P granules more than 30 years ago. She credits Updike, who has published several seminal papers on the subject, with great imagination, determination and excellent technical skill in the pursuit of his goal of elucidating the function and biochemistry of these tiny organelles.

The lead author of the new study from the Updike laboratory, Elisabeth A. Marnik, Ph.D., will be launching her own laboratory at Husson University in Bangor, Maine, this fall. Other contributors include J. Heath Fuqua, Catherine S. Sharp, Jesse D. Rochester, Emily L. Xu and Sarah E. Holbrook. Their research was conducted at the Kathryn W. Davis Center for Regenerative Biology and Medicine at the MDI Biological Laboratory.

Updikes research is supported by a grant (R01 GM-113933) from the National Institute of General Medical Sciences (NIGMS), an institute of the National Institutes of Health (NIH). The equipment and cores used for part of the study were supported by NIGMS-NIH Centers of Biomedical Research Excellence and IDeA Networks of Biomedical Research Excellence grants P20 GM-104318 and P20 GM-203423, respectively.

We aim to improve human health and healthspan by uncovering basic mechanisms of tissue repair, aging and regeneration, translating our discoveries for the benefit of society and developing the next generation of scientific leaders. For more information, please visitmdibl.org.

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Trusted Business Insights answers what are the scenarios for growth and recovery and whether there will be any lasting structural impact from the unfolding crisis for the Cell Therapy market.

Trusted Business Insights presents an updated and Latest Study on Cell Therapy Market 2019-2026. The report contains market predictions related to market size, revenue, production, CAGR, Consumption, gross margin, price, and other substantial factors. While emphasizing the key driving and restraining forces for this market, the report also offers a complete study of the future trends and developments of the market.The report further elaborates on the micro and macroeconomic aspects including the socio-political landscape that is anticipated to shape the demand of the Cell Therapy market during the forecast period (2019-2029).It also examines the role of the leading market players involved in the industry including their corporate overview, financial summary, and SWOT analysis.

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Industry Insights, Market Size, CAGR, High-Level Analysis: Cell Therapy Market

The global cell therapy market size was valued at USD 5.8 billion in 2019 and is projected to witness a CAGR of 5.4% during the forecast period. The development of precision medicine and advancements in Advanced Therapies Medicinal Products (ATMPS) in context to their efficiency and manufacturing are expected to be the major drivers for the market. In addition, automation in adult stem cell and cord blood processing and storage are the key technological advancements that have supported the growth of the market for cell therapy.The investment in technological advancements for decentralizing manufacturing of this therapy is anticipated to significantly benefit the market. Miltenyi Biotec is one of the companies that has contributed to the decentralization in manufacturing through its CliniMACS Prodigy device. The device is an all-in-one automated manufacturing system that exhibits the capability of manufacturing various cell types.

An increase in financing and investments in the space to support the launch of new companies is expected to boost the organic revenue growth in the market for cell therapy. For instance, in July 2019, Bayer invested USD 215 million for the launch of Century Therapeutics, a U.S.-based biotechnology startup that aimed at developing therapies for solid tumors and blood cancer. Funding was further increased to USD 250 billion by a USD 35 million contribution from Versant Ventures and Fujifilm Cellular Dynamics.The biomanufacturing companies are working in collaboration with customers and other stakeholders to enhance the clinical development and commercial manufacturing of these therapies. Biomanufacturers and OEMs such as GE healthcare are providing end-to-end flexible technology solutions to accelerate the rapid launch of therapies in the market for cell therapy.The expanding stem cells arena has also triggered the entry of new players in the market for cell therapy. Celularity, Century Therapeutics, Rubius Therapeutics, ViaCyte, Fate Therapeutics, ReNeuron, Magenta Therapeutics, Frequency Therapeutics, Promethera Biosciences, and Cellular Dynamics are some startups that have begun their business in this arena lately.Use-type InsightsThe clinical-use segment is expected to grow lucratively during the forecast period owing to the expanding pipeline for therapies. The number of cancer cellular therapies in the pipeline rose from 753 in 2018 to 1,011 in 2019, as per Cancer Research Institute (CRI). The major application of stem cell treatment is hematopoietic stem cell transplantation for the treatment of the immune system and blood disorders for cancer patients.In Europe, blood stem cells are used for the treatment of more than 26,000 patients each year. These factors have driven the revenue for malignancies and autoimmune disorders segment. Currently, most of the stem cells used are derived from bone marrow, blood, and umbilical cord resulting in the larger revenue share in this segment.On the other hand, cell lines, such as Induced Pluripotent Stem Cells (iPSC) and human Embryonic Stem Cells (hESC) are recognized to possess high growth potential. As a result, a several research entities and companies are making significant investments in R&D pertaining to iPSC- and hESC-derived products.TherapyType Insights of Cell Therapy Market

An inclination of physicians towards therapeutic use of autologous and allogeneic cord blood coupled with rising awareness about the use of cord cells and tissues across various therapeutic areas is driving revenue generation. Currently, the allogeneic therapies segment accounted for the largest share in 2019 in the cell therapy market. The presence of a substantial number of approved products for clinical use has led to the large revenue share of this segment.

Furthermore, the practice of autologous tissue transplantation is restricted by the limited availability of healthy tissue in the patient. Moreover, this type of tissue transplantation is not recommended for young patients wherein tissues are in the growth and development phase. Allogeneic tissue transplantation has effectively addressed the above-mentioned challenges associated with the use of autologous transplantation.However, autologous therapies are growing at the fastest growth rate owing to various advantages over allogeneic therapies, which are expected to boost adoption in this segment. Various advantages include easy availability, no need for HLA-matched donor identification, lower risk of life-threatening complications, a rare occurrence of graft failure, and low mortality rate.

Regional Insights of Cell Therapy Market

The presence of leading universities such as the Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, and Yale Stem Cell Center that support research activities in U.S. is one of the key factor driving the market for cell therapy in North America. Moreover, strong regulatory and financing support from the federal bodies for expansion of this arena in U.S. as well as Canada is driving the market.In Asia Pacific, the market is anticipated to emerge as a lucrative source of revenue owing to the availability of therapies at lower prices coupled with growing awareness among the healthcare entities and patients pertaining the potential of these therapies in chronic disease management. Japan is leading the Asian market for cell therapy, which can be attributed to its fast growth as a hub for research on regenerative medicine.Moreover, the Japan government has recognized regenerative medicine and cell therapy as a key contributor to the countrys economic growth. This has positively influenced the attention of global players towards the Asian market, thereby driving marketing operations in the region.

Market Share Insights of Cell Therapy Market

Some key companies operating in this market for cell therapy are Fibrocell Science, Inc.; JCR Pharmaceuticals Co. Ltd.; Kolon TissueGene, Inc.; PHARMICELL Co., Ltd.; Osiris Therapeutics, Inc.; MEDIPOST; Cells for Cells; NuVasive, Inc.; Stemedica Cell Technologies, Inc.; Vericel Corporation; and ANTEROGEN.CO.,LTD. These companies are collaborating with the blood centers and plasma collection centers in order to obtain cells for use in therapeutics development.Several companies have marked their presence in the market by acquiring small and emerging therapy developers. For instance, in August 2019, Bayer acquired BlueRock Therapeutics to establish its position in the market for cell therapy. BlueRock Therapeutics is a U.S. company that relies on a proprietary induced pluripotent stem cell (iPSC) platform for cell therapy development.Several companies are making an entry in the space through the Contract Development and Manufacturing Organization (CDMO) business model. For example, in April 2019, Hitachi Chemical Co. Ltd. acquired apceth Biopharma GmbH to expand its global footprint in the CDMO market for cell and gene therapy manufacturing.

Segmentations, Sub Segmentations, CAGR, & High-Level Analysis overview of Cell Therapy Market Research ReportThis report forecasts revenue growth at global, regional, and country levels and provides an analysis of the latest industry trends in each of the sub-segments from 2019 to 2030. For the purpose of this study, this market research report has segmented the global cell therapy market on the basis of use-type, therapy-type, and region:

Use-Type Outlook (Revenue, USD Million, 2019 2030)

Clinical-use

By Therapeutic Area

Malignancies

Musculoskeletal Disorders

Autoimmune Disorders

Dermatology

Others

By Cell Type

Stem Cell Therapies

BM, Blood, & Umbilical Cord-derived Stem Cells

Adipose derived cells

Others

Non-stem Cell Therapies

Research-use

Therapy Type Outlook (Revenue, USD Million, 2019 2030)

Allogeneic Therapies

Autologous Therapies

Quick Read Table of Contents of this Report @ Cell Therapy Market Size, Share, Market Research and Industry Forecast Report, 2020-2027 (Includes Business Impact of COVID-19)

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Cell Therapy Market Analysis Of Global Trends, Demand And Competition 2020-2028 - Jewish Life News

INTRODUCTION

Embryonic development is characterized by the temporal and spatial regulation of cell proliferation, migration, differentiation, and tissue formation. Although these processes are genetically determined, several signaling mechanisms including Wnt have been recognized as essential in regulating cell lineage specification and organogenesis (13).

The Na/Kadenosine triphosphatase (ATPase) (NKA), discovered in crab nerve fibers by Skou (4), belongs to the P-type ATPase superfamily. It has an enzymatic function that couples adenosine 5-triphosphate (ATP) hydrolysis to the transmembrane movement of Na+ and K+ in a cell lineagedependent manner. For example, while the NKA is involved in the formation of action potentials in excitable cells, its polarized distribution is key to the functionality of the epithelium.

In addition to its canonical enzymatic function, we and others have shown that the NKA has an enzymatic activityindependent signaling function through its interactions with membrane cholesterol and proteins such as Src, epidermal growth factor (EGF) receptor, and caveolin-1 (58). We use the term signaling with liberty here, referring to the ability of NKA to work as a receptor, a scaffold, and a signal integrator by regulating the functions of its interacting proteins. This newly appreciated signaling function of the NKA has been implicated in several cellular processes (912). However, direct genetic evidence supporting a role for NKA signaling in animal physiology and disease progression is still lacking. This is due, in part, to the technical difficulties in studying its signaling separately from its ATPase-mediated pumping function because the latter is required for the survival of animal cells (13). Fundamentally, it is unknown whether the signaling function is an intrinsic property of the protein NKA, as its Na+- and K+-driven enzymatic activity has been recognized as. Therefore, we were prompted to address two important questions: (i) Were the signaling and Na+/K+ transport functions of the NKA coevolved? (ii) If so, does the signaling function of NKA represent a primordial yet common mechanism for the regulation of a fundamental process in animal biology?

Structurally, the NKA is composed of both and subunits. The subunit contains the binding sites for Na+/K+ as well as ouabain, which are distinct from that of other P-type ATPases (14). It also has an N-terminal caveolin binding motif (CBM) proximal to the first transmembrane helix (fig. S1A). To assess the functionality of this motif, we made F97A and F100A mutations that map to the rat 1 NKA sequence. This strategy has been used by others to study the function of CBM in proteins other than the NKA (15). We used a knockdown and rescue protocol to generate a stable cell line (LW-mCBM) that essentially expresses just the CBM mutant 1, which was confirmed using [3H]ouabain binding assays (fig. S1B). Western blot and confocal imaging analyses showed that the expression of mutant 1 NKA in LW-mCBM was comparable to that in the control cell line, named AAC-19 cells (fig. S1, B and C). The expression of CBM mutant 1 was sufficient to restore the expression of the 1 subunit of the NKA, allowing normal plasma membrane targeting of the CBM mutant NKA in LW-mCBM cells (fig. S1, C and D). The successful generation of a stable CBM mutant 1 cell line suggests that the CBM is not essential for the enzymatic activity of the NKA because the ion-transporting function is necessary for animal cell survival (13). In further support, we conducted kinetic studies of the CBM mutant NKA. As shown in Fig. 1A, the overall enzymatic activity per unit of 1 NKA expression was identical between the control AAC-19 and LW-mCBM cells. The Km values of Na+, K+, and ouabain were comparable between the CBM mutant NKA and control (Fig. 1, B to D) (16). Together, these data indicate that the N-terminal CBM is not directly involved in the regulation of the enzymatic properties of the NKA.

(A) Crude membrane preparations were made from AAC-19 and LW-mCBM cells and measured for ouabain-sensitive ATPase activity as described in Material and Methods. (B) Ouabain concentration curve. Crude membrane from LW-mCBM cells was prepared and measured for ATPase activity in the presence of different concentrations of ouabain. Data are shown as percentage of control, and each point represents three independent experiments. Curve fit analysis and IC50 (median inhibitory concentration) were calculated by GraphPad. (C and D) Measurements of Na+ and K+ Km. Assays were done as in (B). The combined data were collected from at least three repeats, and Km value (means SEM) was calculated using GraphPad.

On the basis of the above, we next turned our attention to determining the effects of the CBM mutation on signaling capabilities of the 1 NKA. Specifically, we first conducted immunoprecipitation experiments. As we reported previously in many types of cells (8), immunoprecipitation of caveolin-1 coprecipitated 1 in AAC-19 cells. In contrast, mutation of the CBM resulted in an over 80% decrease in coprecipitated 1 in LW-mCBM cells (Fig. 2A).

(A) Cell lysates from AAC-19 and LW-mCBM were immunoprecipitated (IP) with polyclonal anticaveolin-1 antibody. Immunoprecipitated complex was analyzed by Western blot for 1 and caveolin-1 (n = 4). **P < 0.01 compared to AAC-19. (B) Cell lysates from AAC-19 and LW-mCBM cells were subjected to sucrose gradient fractionation as described in Materials and Methods. A representative Western blot of three independent experiments was shown. **P < 0.01 in comparison to AAC-19. (C) AAC-19 and LW-mCBM cells were treated with different concentrations of ouabain for 10 min and analyzed by Western blot. A representative Western blot was shown (n = 4). *P < 0.05 versus 0 mM ouabain. (D) Cell growth curves of AAC-19 and LW-mCBM. *P < 0.05 versus AAC-19 cells. (E) BrdU assay of AAC-19 and LW-mCBM. The values are means SEM from at least three independent experiments. Photo credit: Xiaoliang Wang, Marshall Institute for Interdisciplinary Research at Marshall University.

To substantiate these observations, we next conducted a detergent-free and carbonate-based density gradient fractionation procedure and found that 1 NKA and its main signaling partners (Src and caveolin-1) were co-enriched in the low-density caveolar fractions, as previously reported in epithelial cells (8, 17). In sharp contrast, the expression of the CBM mutant 1 caused the redistribution of these proteins from low-density to high-density fractions (Fig. 2B). Quantitatively, when the ratios of fraction 4/5 of each protein versus total were calculated, we found that the low-density fraction 4/5 prepared from the control AAC-19 cells contained ~60, ~70, and 80% of caveolin-1, Src, and 1 NKA, respectively. However, in LW-mCBM cells, only ~20% of caveolin-1, Src, and 1 NKA were detected in fraction 4/5 (Fig. 2B).

To address the functional consequences of the dissociation of the 1 NKA from its signaling partners in LW-mCBM cells, we exposed these cells to ouabain, a specific agonist of the receptor NKA/Src complex. As shown in Fig. 2C, while ouabain stimulated phosphorylation of extracellular signalregulated kinase (ERK), a downstream effector of the NKA/Src signaling pathway in AAC-19 cells (5, 8), it failed to do so in LW-mCBM cells.

We have previously shown that 1 NKA signaling is key to the dynamic regulation of cell growth (16, 18). As shown in Fig. 2D, LW-mCBM cells grew much slower than AAC-19 cells. 5-Bromo-2-deoxyuridine (BrdU) incorporation assays further verified that the expression of CBM mutant 1 resulted in an inhibition of cellular proliferation (Fig. 2E). In short, the above in vitro experiments indicate that the gain of CBM enables the NKA to perform the enzymatic activityindependent signaling functions.

With the preceding in vitro data suggesting that the CBM is critically important to the signaling function of the NKA, we next set forth to test the physiological significance of this finding. Thus, we generated a knock-in mouse line expressing the aforementioned CBM mutant 1. The CBM mutant (mCBM) mouse was generated using the Cre/LoxP gene targeting strategy (19), as depicted in fig. S2A. The chimeric offspring were crossed to C57BL6 females to yield mCBM heterozygous mice, and the desired F97A and F100A substitutions were verified (fig. S2B). mCBM heterozygous mice were born fertile and survived to adulthood. Our attempts to generate mCBM homozygous mice yielded no viable homozygous pups (Fig. 3A) in nearly 400 young mice genotyped by polymerase chain reaction (PCR). These results document for the first time that the CBM in the 1 subunit of the NKA represents a fundamental signaling mechanism essential for mouse embryonic development and survival.

(A) Early embryonic lethality of mCBM homozygous embryos. (B) Morphological comparison and body size of wild-type (WT) (top), heterozygous (middle), and homozygous (bottom) mCBM embryos at E9.5. Black bars, 0.3 mm. The arrows show the abnormal head morphology. Body size was measured from at least 12 embryos in different genotypes by ImageJ. Data are presented as means SEM. ***P < 0.01 versus the average of WT. (C) Sagittal sections of WT and homozygous (Homo) and heterozygous (Het) embryos at E9.5 with hematoxylin and eosin (H&E) staining. Homozygous embryos that had defective brain development indicated by open arrows. (D) Brain cross section of WT, homozygous, and heterozygous embryos at E9.5 with H&E staining. Homozygous embryos that had unclosed neural tube in forebrain, midbrain, and hindbrain were indicated by arrows; WT and heterozygous E9.5 embryos with closed neural tube were indicated by arrowhead. (E) Morphological comparison of WT and Na/K-ATPase 1 (+/) embryos at E9.5. White bars, 0.3 mm (n = 5 to 7). Photo credit: Xiaoliang Wang, Marshall Institute for Interdisciplinary Research at Marshall University.

There is evidence that endogenous ouabain is important in animal physiology because of its role in stimulating the signaling function of the NKA (10, 19, 20). Because the loss of the CBM abolishes ouabain-induced signal transduction in vitro, we tested whether administration of pNaKtide, a specific inhibitor of the receptor NKA/Src complex (21), would cause the same embryonic lethality as we observed in mCBM mice. As depicted in fig. S3, we observed no change in fetal survival after administration of pNaKtide to female mice before mating and continued until the end of pregnancy. It is important to mention that pNaKtide has been proven to be specific and effective in blocking the NKA/Src receptor signaling in vivo (2226), and our control experiments showed that pNaKtide could cross the placental barrier. Moreover, this lack of pNaKtide effect on mouse embryogenesis appears to be consistent with a previous report demonstrating that neutralization of endogenous ouabain by injection of an anti-ouabain antibody did affect the kidney development of neonatal mice but did not affect their overall survival (20). On the basis of these, we concluded that the NKA/Src receptor function in the CBM mutant embryo was not the direct cause of lethality and set out to identify a hitherto unrecognized NKA CBM-dependent yet NKA-Srcindependent underlying mechanism.

Embryo implantation within mice occurs around embryonic day 4.5 (E4.5) (27), followed by gastrulation around E5.5 to E7.5 (28), when the simple embryo develops into an organized and patterned structure with three germ layers (29). Subsequently, organogenesis takes place at E8.0 and onward; the patterned embryo starts to develop its organ systems including the brain, heart, limbs, and spinal cord.

To further analyze and explore the molecular mechanisms of the CBM mutation in the embryonic development of mice, we harvested the fertilized eggs at E1.5, and cultured them in vitro. It has previously been demonstrated that 1 knockout results in the failure of blastocyst formation (13). In contrast, we found that eggs from mCBM heterozygous parents developed into morphologically normal blastocysts. These findings indicate that loss of the CBM does not affect the molecular mechanisms necessary for blastocyst formation. Thus, a loss of functional 1 CBM and complete knockout of 1 NKA both result in embryonic lethality but differ by their specific mechanisms. Knockout of 1 NKA inevitably causes the loss of NKA enzymatic function, which is incompatible with life (13), and results in the failure of blastocyst formation in mice. In contrast, our in vitro data indicate that a loss of the CBM does not cause any notable alteration in NKA enzymatic activity, which is supported by the observation that mCBM mice are still capable of producing morphologically normal blastocysts. Consequently, CBM role in development appears to be critical at a developmental stage beyond blastocyst stage, and we further set out to identify this stage.

To this end, we collected and genotyped embryos or yolk sacs from mCBM heterozygous mice at different days of gestation. We first dissected 31 embryos at E12.5 from three different mice (Fig. 3A). Reabsorption and empty deciduae were observed in six implantation sites with only the mothers genotype detectable. At E9.5, we were able to dissect a total of 303 embryos. Sixty-four of them were mCBM homozygous (21%), 71 were wild-type (23%), and 168 were mCBM heterozygous (55%) (Fig. 3A).

To further analyze the embryonic developmental defects, we examined mCBM embryos at E7.5, E8.5, and E9.5. The embryos looked similar between wild-type and mCBM homozygous mice at E7.5 and E8.5 under dissection microscopy. However, we found several severe morphological defects in homozygous embryos at E9.5 (Fig. 3, C and D). First, the overall size of embryos was considerably reduced in mCBM homozygous embryos (about 35% the size of the wild-type embryos). In addition, the observed effect of the CBM mutant on embryonic size was gene dose dependent, as the mCBM heterozygous embryos were significantly smaller than those of wild-type embryos but much bigger than the homozygous embryos. Second, most homozygous embryos did not turn, a process normally initiated at E8.5, suggesting that the loss of a functional CBM was responsible for a developmental arrest at an early stage of organogenesis. Last, the most severe morphological defects were observed in the heads of the mCBM homozygous embryos. In addition to the reduced size (about 25% of the size of wild-type embryos), we observed that mCBM homozygous embryos failed to close their cephalic neural folds (anterior neuropore) as indicated by the arrow in Fig. 3B. This phenotype more closely resembled wild-type embryos at E8.0 to E8.5, suggesting again that the loss of CBM arrested organogenesis in its early stages. On the other hand, all heterozygous embryos, although smaller than wild-type embryos, showed normal head morphology (Fig. 3B).

To follow up on the above observations, we collected and made histological sections of wild-type, heterozygous, and homozygous embryos at E9.5 (Fig. 3, C and D). Normally, formation and closure of the anterior neuropore occurs at E9.5 (Fig. 3D). In sharp contrast, mCBM homozygous embryos developed defects in neural closure. Specifically, failure of neural tube closure at the level of forebrain, midbrain, and hindbrain was prominent in homozygous embryos (Fig. 3D).

To further explore the molecular mechanism by which the loss of the CBM led to defects in organogenesis, we next conducted RNA sequencing analyses (RNAseq) in wild-type and mCBM homozygous embryos. More than 17,000 genes were read out in either mCBM homozygous or wild-type samples. Data analyses indicated that 214 and 208 genes from mCBM homozygous embryos were significantly down- and up-regulated, respectively (fig. S4). Among them, the expression of a cluster of transcriptional factors important for neurogenesis was significantly reduced. As depicted in Fig. 4A, the expression of neurogenin 1 and 2 (Ngn1/2), two basic helix-loop-helix (bHLH) transcriptional factors (30), was significantly down-regulated in homozygous embryos. Ngn1/2 are considered to be determination factors for neurogenesis, while members of the NeuroD family of bHLH work downstream to promote neuronal differentiation (31). We found that the expression of NeuroD1/4 was further reduced in mCBM homozygous embryos. As expected from these findings, the marker of neural stem cells nestin (Nes) and other genes related to neurogenesis including huntington-associated protein 1 (Hap1), nuclear receptor subfamily 2 group E members 1 (Nr2e1), and adhesion G protein (heterotrimeric guanine nucleotidebinding protein)coupled receptor (Adgrb1) were all down-regulated in mCBM homozygous embryos (Fig. 4A). To verify these data, we performed reverse transcription quantitative PCR (RT-qPCR) analyses of both wild-type and mCBM homozygous embryos collected at E9.5. As depicted in Fig. 4 (B to D), the aforementioned transcriptional factors were all down-regulated in a cascade fashion. While a modest reduction was found with Ngn1/2, the expression of NeuroD1/4 was almost completely inhibited. To test whether the effects of the CBM mutation on the expression levels of these transcriptional factors were gene dose dependent, we also examined mRNA levels of Ngn1/2 and NeuroD1/4 in mCBM heterozygous embryos. As depicted in Fig. 4 (B and C), the expression of these genes followed the pattern found in homozygous embryos. The expression level in heterozygous embryos was significantly reduced compared to wild-type embryos but was much higher than that of mCBM homozygous embryos. These gene dosingdependent cascade effects suggest that the 1 NKA is an important upstream regulator but not a determinant of neurogenesis like Ngn1/2 (32) or a key receptor mechanism like Wnt is.

(A) RNAseq results of several neurogenesis and neural stem cell markers. Log2 ratio = 1 means twofold of change. *P < 0.05 compared to WT. (B and C) RT-qPCR analysis of selected gene expression in WT, heterozygous, and homozygous mCBM embryos at E9.5. (D) RT-qPCR analysis of neural stem cell marker gene expression in WT and homozygous mCBM E9.5 embryos. (E) RT-qPCR analysis of neurogenesis marker genes in WT and NKA 1+/ mouse E9.5 embryos. Quantitative data are presented as means SEM from at least six independent experiments. *P < 0.05, **P < 0.01 versus WT control.

As a control, we also assessed the expression of different isoforms of NKA and caveolin-1. As depicted in fig. S5, no changes were detected in the expression of the 1 isoform of the NKA. This is expected, as the mutations were only expressed on exon 4. Previous reports have demonstrated that, in addition to the 1 isoform, neurons also express the 3 isoform, while muscle and glial cells express the 2 isoform of the NKA (9). No difference was observed in the expression of 3, while the expression of 2 was too low to be measured. We were also unable to detect any change in the expression of caveolin-1.

The total amount of protein recognized by the anti-NKA 1 antibody is unchanged in mCBM heterozygous mouse tissues compared to that of the wild type, albeit with changes in distribution in caveolar versus noncaveolar fractions. This indicates that the CBM mutant protein is fully expressed, as observed in cells (fig. S1), and further demonstrates that a reduction of enzymatic activity is not responsible for the observed phenotype in mCBM homozygous embryos. However, because the expression of wild-type 1 in mCBM heterozygous animals is most likely reduced, the phenotypic changes we observed in these mice could be due to the reduction of wild-type 1 expression rather than the expression of CBM mutant 1. To address this important issue, we collected embryos from 1 NKA heterozygous (1+/) mice and their littermate controls (33). In contrast to mCBM heterozygotes, reduction of 1 expression alone did not change the size of embryos (Fig. 3D), head morphology, or the expression of neuronal transcriptional factors (Fig. 4E). Because NKA 1 haploinsufficiency did not phenocopy mCBM heterozygosity, it was concluded that the mCBM allele was responsible for the observed changes.

The CBM in NKA has a consensus sequence of FCxxxFGGF (fig. S6). To assess the generality of CBM-mediated regulation, we first turned to the conserveness of the CBM in animal NKA. A database search reveals that, like Wnt, the mature form of NKA (i.e., containing CBM, Na+/K+ binding sites, and subunit) is absent in unicellular organisms but present in all multicellular organisms within animal kingdom (fig. S6). Further analysis of published data confirms the coevolutionary nature of the CBM and the binding sites for Na+ and K+ in the NKA. The first indication is from the analysis of single-cell organisms. No mature form of NKA is found in these organisms (fig. S6A). However, Salpingoeca rosetta, a marine eukaryote belonging to the Choanoflagellates class, undergoes a very primitive level of cell differentiation and specialization in their life cycle and expresses a putative NKA with several conserved motifs involved in the binding of Na+/K+. On the other hand, it contains no CBM (fig. S6) and there is also no evidence that it expresses a subunit.

Second, as depicted in figs. S6 and S7, Caenorhabditis elegans, an example of a metazoan organism, expresses a mature form of NKA (eat-6) that contains binding sites for Na+ and K+ as well as the N-terminal CBM. It also expresses a couple of putative NKA such as catp-2 (34). However, they contain neither the CBM nor Na+ and K+ binding sites.

Third, although the X amino acids in the NKA CBM in invertebrates vary, only conserved substitutions occurred in this motif. This is in sharp contrast to many other membrane receptors/transducers such as Patched and G that also contain a consensus CBM (figs. S6 and S7). Within vertebrates, the CBM sequence FCRQLFGGF in NKA remains completely conserved across all species. Moreover, this sequence remains conserved in all isoforms of the subunit except for the 4 isoform, which is exclusively expressed in sperm. The 4 isoform in some species still adapts the CBM sequence found in invertebrates (fig. S6). Moreover, of a total of nine subunits found in zebrafish (35), five appear to be 1 homologs that, like the 4 isoform, contain both vertebrate and invertebrate CBM sequences.

Last, turning to the evolutionary aspect of the receptor NKA/Src complex, we found that the Src-binding NaKtide and Y260 sequences, in sharp contrast to the CBM, are only conserved in mammalian ATP1A1 (fig. S7). Therefore, the NKA/Src receptor may have evolved after the acquisition of the CBM, and hence is not a part of the fundamental regulation of animal organogenesis (fig. S3).

In short, the N-terminal CBM, like the binding sites for Na+ and K+, is conserved in all subunits of NKA in animals, even after taking into consideration gene duplications and the generation of different isoforms or homologs. Thus, we postulate that this CBM must be evolutionally conserved to enable the NKA, in parallel with its enzymatic function, to serve an important role in the origination of multicellular organisms within the animal kingdom.

Organogenesis represents a unique feature of multicellular organisms. In considering the preceding findings, we reasoned that the loss of NKA CBM would also affect embryonic development in invertebrates such as C. elegans. To test our hypothesis, we used CRISPR-Cas9 to knock in the equivalent CBM double mutations of F75A and F78A in C. elegans NKA gene eat-6 (named as syb575) (fig. S8). Similar to the impact of the expression of CBM mutant 1 NKA in mice, no homozygous worms were produced, whereas the heterozygous worms hatched normally. Moreover, by using the gene balancer nT1, we confirmed that the F75A and F78A double mutations induced embryonic lethality in syb575 homozygotes secondary to L1 arrest (Fig. 5A). Furthermore, the observed larval arrest due to the loss of the eat-6 CBM was rescued by a transgene expressing a wild-type eat-6 complementary DNA (cDNA) through an extrachromosomal array (Fig. 5B). The lethality phenotype in syb575 mutants was different from those of the eat-6 mutants defective in enzymatic (transport) activity, because while the eat-6 mutants had growth defects, they were able to grow past the L1 stage (36). An exception to this was a cold-sensitive eat-6 (ad792) mutant with severely reduced transport activity, which exhibited L1 arrest at lower temperatures similarly to the syb575 mutant worms (36). Overall, those data suggest that both CBM-mediated signaling and ion transport activity by the NKA are essential to full-scale organogenesis in C. elegans.

(A) Heterozygous CBM mutant (mCBM) worms syb575/nT1 have GFP signals in pharynx (pointed with the arrowhead), while mCBM homozygous worms are GFP negative and arrested at larval stage (pointed with an arrow). (B) Rescue with a WT eat-6 gene showing a mCBM homozygous worm with a transgenic marker sur-5::GFP. Arrow points the somatic GFP signals. (C) Mutation of CBM1 NKA (F97A; F100A) results in reduced colony formation in human iPSC (mCBM iPSC). (D) RT-qPCR analysis of stem cell markers and primary germ layer markers in WT and mCBM iPSC. *P < 0.05 compared to WT. n = 7. Photo credit: Liquan Cai, Marshall Institute for Interdisciplinary Research at Marshall University.

In short, our data indicate that loss of the NKA CBM results in defective organogenesis in both mice and C. elegans. This, together with our finding that the NKA CBM is conserved in all NKA regardless of isoform or homolog, indicates that the NKA was originally evolved as a dual functional protein in multicellular organisms, and that it represents a primordial and common mechanism for regulating stem cell differentiation and early stage of organogenesis in animals.

Turning now to even more general features of the CBM in organogenesis, we searched for the plant plasma membrane H-ATPase that functions equivalently to the animal NKA. Like the NKA, the plant plasma membrane H-ATPase also contains a sequence motif at the first transmembrane segment that is in accordance with the consensus CBM. This motif is completely conserved from blue algae to land plants but does not exist within yeast and bacteria (fig. S6).

To assess the human relevance of our findings, we used CRISPR-Cas9 gene editing to generate the same mutations in human induced pluripotent stem cells (iPSCs) (fig. S9). As depicted in Fig. 5C, the expression of mutant CBM 1 reduced the colony formation ability of human iPSCs. Concomitantly, this was accompanied by a significant reduction in the expression of stemness markers (both Nanog and Oct4), and transcriptional factors controlling germ layer differentiation (gene MIXL and T for mesoderm, OTX2 and SOX1 for ectoderm, and GATA4 and SOX17 for endoderm) (Fig. 5D). These findings confirm an essential role of the NKA CBM in the regulation of stem cell differentiation and suggest the potential utility of targeting the NKA for improving tissue regeneration.

The canonical Wnt pathway is made of multiple components localized in the plasma membrane and cytosol (2, 3). Functionally, this pathway is critically important in animal organogenesis (2, 37). For example, it plays an essential role in the establishment of neurogenic niches and regulates the differentiation of neural stem cells into neuroblasts during organogenesis by regulating the expression of transcriptional factors Ngn and NeuroD (37, 38). Thus, we were prompted by the observed neural defects in mice to test whether the expression of the CBM mutant 1 NKA affects Wnt/-catenin signaling.

In the first set of studies, we examined the cellular distribution of -catenin in LW-mCBM cells. As depicted in Fig. 6A, confocal imaging analysis showed that -catenin was distributed away from the plasma membrane in a vesicle-like form in LW-mCBM cells. To verify this finding, we fractionated the cell lysates as performed in Fig. 3B and observed that -catenin, like Src and caveolin-1, moved from the low-density fractions to high-density fractions when compared to control cells (Fig. 6B). Control experiments showed no changes in the expression of E-cadherin, glycogen synthase kinase3 (GSK-3), LRP5/6 (Low-density lipoprotein receptor-related protein 5 and 6), and -catenin in LW-mCBM cells (Fig. 6C).

(A) -Catenin staining of AAC-19 and LW-mCBM at basal level (n = 5). Blue arrow indicated -catenin signal in the cytoplasm of cells. (B) Sucrose gradient fractionation of -catenin in AAC-19 and LW-mCBM cells (n = 3). **P < 0.01. (C) Western blot analysis of Wnt/-catenin signaling proteins in AAC-19, LX-2, and LW-mCBM cells from at least six independent experiments. Two samples from each cell lines are presented. (D) Wnt3a induced TOPFlash luciferase report assay in AAC-19 and LW-mCBM (n = 8). ***P < 0.01. (E) Wnt3a induced expression of Wnt/-catenin targeting genes (n = 8). **P < 0.01. (F) Wnt3a induced TOPFlash luciferase report assay in AAC-19, LX-2, and LW-mCBM cells (n = 4). ***P < 0.01.

To test whether these changes in -catenin distribution alter the function of canonical Wnt signaling, we conducted a TOPFlash luciferase activity assay (39). Cells were transiently transfected with the reporter plasmid, exposed to Wnt3a conditional medium, and then subjected to TOPFlash luciferase assays. As shown in Fig. 6D, while Wnt3a induced a greater than 35-fold increase in luciferase activity in AAC-19 cells, it only produced a fourfold increase in LW-mCBM cells, which equates to an approximate 90% reduction in the dynamics of Wnt activation. To further test the impact of the CBM mutation on Wnt signaling, we examined the effects of Wnt3a on the expression of Wnt target genes. Cells were exposed to Wnt3a for 6 hours and subjected to RT-qPCR analysis. As depicted in Fig. 6E, while Wnt3a increased the expression of c-Myc, Lef, and NKD1 expression in AAC-19 cells, it failed to do so in LW-mCBM cells.

On the basis of the above observations, we reasoned that the NKA CBM might play an essential role in the dynamic regulation of Wnt signaling. We therefore analyzed Wnt signaling in our LX-2 cell line. This cell line was made by the same strategy used for the generation of LW-mCBM cells, and it expresses essentially just the 2 isoform (40). We have observed that 2 NKA, like CBM mutant 1, maintains cellular pumping capacity but is unable to signal via Src like a wild-type 1 NKA (40). However, unlike CBM mutant 1, 2 does contain the same CBM at the N terminus (fig. S6). As depicted in Fig. 6F, expression of the 2 isoform produced a rescue of Wnt signaling dynamics when compared to that in LW-mCBM cells, which reinforces the idea that the NKA CBM is key to the dynamics of Wnt signaling. Like in LW-mCBM cells, no change in -catenin expression was noted in LX-2 cells. However, compared to LW-mCBM cells, caveolin-1 expression was decreased in LX-2 cells, while ERK activity was increased (Fig. 6C). Together, these findings suggest that the conserved NKA CBM is essential for regulating Wnt signaling, which is independent of the pumping or CTS (ardiotonic steroid)activated Src-dependent signaling transduction.

To see whether there is evidence of Wnt signaling defects in mCBM homozygous embryos, we examined the RNAseq data using a tool kit of pathway analysis. As depicted in fig. S10, Wnt signaling appears to be defective at the transcriptional level. First, the expression of one of the Wnt receptors [Frizzled homolog 5 (Fzd5)] and one of the Wnt ligands (Wnt7b) was down-regulated (fig. S10A). Second, the Wnt/-catenin signaling inhibitor, secreted frizzled-related protein 5 (Sfrp5), was up-regulated in mCBM homozygous embryos. Third, the -catenin destruction complex component adenomatosis polyposis coli (APC) was down-regulated in mCBM homozygous embryos. All these defects in Wnt signaling were confirmed by RT-qPCR analysis of both wild-type and mCBM homozygous embryos at E9.5 (fig. S10B). In addition, APC down-regulation was also observed at the protein level in mCBM iPSCs (fig. S10C). Last, the defect in Wnt signaling was further substantiated by the altered expression of Wnt downstream target genes. As shown in fig. S10B, the expression of Lef and NKD1 was significantly reduced in mCBM homozygous embryos. The expression of c-Myc was too low to be detected.

Together, these data provide strong support to the notion that the CBM is a key to the regulation of Wnt by the NKA. We hypothesize that this critical function of the NKA CBM may explain why the CBM is conserved in all four subunit isoforms of the NKA. It is important to mention that the specific molecular defects in Wnt signaling that we have identified were tested in epithelial cells, a model we have previously used to characterize 1-specific signaling functions (16, 41). In view of the cell/tissue specificity of both NKA expression and subunit assemble (42) and Wnt signaling (13, 37), it is likely that this mechanism does not fully explain the Wnt signalingrelated defects in embryogenesis.

The enzymatic function of NKA coordinates the transmembrane movement of Na+/K+, which is essential for the survival of individual animal cells. At the tissue/organ level, the ATP-powered transport of Na+/K+ by the NKA is required for neuronal firing, muscle contraction, and the formation and functionality of epithelia and endothelia. The NKA was found to be essential for forming septate junction in Drosophila melanogaster (43, 44) via a regulatory mechanism independent of its ion-pumping activity. Here, we reveal an additional fundamentally important role of NKA in the regulation of signal transduction through a separate functional domain (CBM) unrelated to its enzymatic activity.

Our findings raise the question of why NKA acquired the CBM in addition to its binding sites for Na+ and K+. One possible explanation for this is that the additional functionality in NKA (fulfilled by the CBM) evolved for the purpose of regulating stem cell differentiation and organogenesis in multicellular organisms. Two observations support this hypothesis. First, both Wnt and NKA are present in the first multicellular organisms within the animal kingdom and are evolutionally conserved ever since. Thus, it is likely that the NKA and Wnt work in concert to enable stem cell differentiation and organogenesis in animals. Second, while Wnt is key to the cellular programs of stemness and cell lineage specification (2), it does not directly participate in cell lineagespecific activities of newly differentiated cells. Instead, this particular function might be fulfilled by the NKA. Conceivably, the NKA could have been evolved, as exemplified by the mitochondrial cytochrome c in ATP generation, to bring together two seemingly unrelated processes (i.e., Wnt signaling regulation via the CBM and ion transport through Na+ and K+ binding) into one signaling circuitry, which is critical to the dynamic regulation of transcriptional factors that are required for organogenesis in a temporally and spatially organized manner. Needless to say, this hypothesis remains to be tested. In addition, other important signaling pathways such as Notch and Sonic Hedgehog may also be regulated by NKA.

It is also of interest to note the evolutionary conserveness of the CBM in the plant plasma membrane H-ATPase. Like its counterpart within the animal kingdom, the plasma membrane H-ATPase is essential for plant organogenesis (45). Unlike the NKA, the plasma membrane H-ATPase exists in single-celled organisms such as yeast, and their ion-pumping function is regulated by similar mechanisms (46). However, yeast, with no use for cellular machinery needed for organogenesis, does not contain the H-ATPase with conserved CBM. Moreover, we also observed that no CBM exists in the plasma membrane Ca-ATPase (fig. S6), both of which belong to the same type II P-type ATPase family as the NKA. While the Ca-ATPase is a more ancient protein than the NKA, as its expression can be found in unicellular organisms, the H/K-ATPase appeared later than the NKA, at some point during the development of vertebrates. Thus, we suggest that the NKA may have evolved from a P-ATPase of unicellular organisms via the gain of both the CBM and Na+/K+ binding sites. In contrast, the H/K-ATPase may have evolved from the NKA, losing not only the Na+ binding site but also the CBM.

We have shown a direct interaction between the NKA and caveolin-1 (8, 17), which has been independently confirmed (47). The loss of the CBM significantly reduced the interaction between NKA and caveolin-1 as revealed by multiple assays. In addition to caveolin-1, we and others have reported several signal transductionrelated interactions (48). Of these, the potential interaction between 1 NKA and Src has attracted the most attention, especially in the past 10 years (7). While most studies indicated an important role of Src in CTS-activated signal transduction via 1 NKA, several publications have questioned whether 1 NKA interacts with Src directly to regulate Src functionality (49, 50). While this important difference remains to be experimentally addressed, we would like to point out the following facts. First, while we recognize the merit of using purified protein preparation to study protein interaction, it is important to recognize the limitation of using purified Src from bacterial expression system because they are heterogeneously phosphorylated. Second, we have reported multiple lines of evidence that support a direct interaction between 1 NKA and Src, including the identification of isoform-specific Src interaction, the mapping of potential Src-interacting sites in the 1 isoform, and the development of pNaKtide as Src inhibitor and receptor antagonist. These findings have substantially increased our understanding of 1 NKA/Src interaction in cell biology and animal physiology. It is important to mention that several groups not associated with us have successfully used pNaKtide to block ouabain and NKA signaling in vitro and in vivo (2326, 51). While our group and others continue to characterize the molecular basis and biological function of the NKA/Src receptor complex, we propound that the question of NKA/caveolin-1 interaction is a more pressing one in the context of this study. The role of CBM in caveolin-protein interaction and caveolae-related signaling is still debated (41, 52, 53).

Last, we conclude from these interesting findings that the NKA is not just an ion pump or a CBM-directed regulator but a critical multifunctional protein. This whole functionality underlies a hitherto unrecognized common mechanism essential for stem cell differentiation and organogenesis in multicellular organisms within the animal kingdom. Moreover, many recent studies also support the concept that the 1 NKA has acquired more functional motifs (e.g., Src-binding sites for the formation of NKA/Src receptor complex) during evolution. In addition, we have demonstrated that either knockdown of 1 NKA or the expression of an N-terminal fragment containing the CBM of the 1 subunit was sufficient to attenuate purinergic calcium signaling in renal epithelial cells (54). The 1 NKA is also found to be essential for CD36 and CD40 signaling in macrophages and renal epithelial cells (55, 56). Aside from the profound biological and fundamental implications, the previously unidentified NKA-mediated regulation of Wnt signaling through its N-terminal CBM may have substantial implications in our understanding of disease progression. The rapidly increasing appreciation of Wnt signaling in the pathogenesis of cancer and cardiovascular diseases (2, 3, 38) underlies the potential utility of NKA as a multidrug target (12, 22, 57, 58).

Acknowledgments: Funding: This work was supported by grants from: National Institutes of Health (NIH) Research Enhancement Award (R15) (R15 HL 145666); American Heart Association (AHA) Scientist Development Grant (#17SDG33661117); Brickstreet Foundation and the Huntington Foundation, which provide discretionary funds to the Joan C. Edwards School of Medicine. (These funds are both in the form of endowments that are held by Marshall University). Author contributions: Conceptualization: Z.X., X.W., J.X.X., L.C., G.-Z.Z., S.V.P., and J.I.S.; methodology: X.W., L.C., I.L., D.W., and G.-Z.Z.; investigation: X.W., L.C., X.C., J.W., Y.C., and J.Z.; writing (original draft): X.W., J.X.X., and Z.X.; writing (review and editing): Z.X., J.X.X., L.C., J.I.S., S.V.P., D.W., G.-Z.Z., and X.W.; funding acquisition: Z.X.; visualization: X.W. and Z.X. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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A caveolin binding motif in Na/K-ATPase is required for stem cell differentiation and organogenesis in mammals and C. elegans - Science Advances

Regenerative Medicine Market: Snapshot

Regenerative medicine is a part of translational research in the fields of molecular biology and tissue engineering. This type of medicine involves replacing and regenerating human cells, organs, and tissues with the help of specific processes. Doing this may involve a partial or complete reengineering of human cells so that they start to function normally.

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Regenerative medicine also involves the attempts to grow tissues and organs in a laboratory environment, wherein they can be put in a body that cannot heal a particular part. Such implants are mainly preferred to be derived from the patients own tissues and cells, particularly stem cells. Looking at the promising nature of stem cells to heal and regenerative various parts of the body, this field is certainly expected to see a bright future. Doing this can help avoid opting for organ donation, thus saving costs. Some healthcare centers might showcase a shortage of organ donations, and this is where tissues regenerated using patients own cells are highly helpful.

There are several source materials from which regeneration can be facilitated. Extracellular matrix materials are commonly used source substances all over the globe. They are mainly used for reconstructive surgery, chronic wound healing, and orthopedic surgeries. In recent times, these materials have also been used in heart surgeries, specifically aimed at repairing damaged portions.

Cells derived from the umbilical cord also have the potential to be used as source material for bringing about regeneration in a patient. A vast research has also been conducted in this context. Treatment of diabetes, organ failure, and other chronic diseases is highly possible by using cord blood cells. Apart from these cells, Whartons jelly and cord lining have also been shortlisted as possible sources for mesenchymal stem cells. Extensive research has conducted to study how these cells can be used to treat lung diseases, lung injury, leukemia, liver diseases, diabetes, and immunity-based disorders, among others.

Global Regenerative Medicine Market: Overview

The global market for regenerative medicine market is expected to grow at a significant pace throughout the forecast period. The rising preference of patients for personalized medicines and the advancements in technology are estimated to accelerate the growth of the global regenerative medicine market in the next few years. As a result, this market is likely to witness a healthy growth and attract a large number of players in the next few years. The development of novel regenerative medicine is estimated to benefit the key players and supplement the markets growth in the near future.

Global Regenerative Medicine Market: Key Trends

The rising prevalence of chronic diseases and the rising focus on cell therapy products are the key factors that are estimated to fuel the growth of the global regenerative medicine market in the next few years. In addition, the increasing funding by government bodies and development of new and innovative products are anticipated to supplement the growth of the overall market in the next few years.

On the flip side, the ethical challenges in the stem cell research are likely to restrict the growth of the global regenerative medicine market throughout the forecast period. In addition, the stringent regulatory rules and regulations are predicted to impact the approvals of new products, thus hampering the growth of the overall market in the near future.

Global Regenerative Medicine Market: Market Potential

The growing demand for organ transplantation across the globe is anticipated to boost the demand for regenerative medicines in the next few years. In addition, the rapid growth in the geriatric population and the significant rise in the global healthcare expenditure is predicted to encourage the growth of the market. The presence of a strong pipeline is likely to contribute towards the markets growth in the near future.

Global Regenerative Medicine Market: Regional Outlook

In the past few years, North America led the global regenerative medicine market and is likely to remain in the topmost position throughout the forecast period. This region is expected to account for a massive share of the global market, owing to the rising prevalence of cancer, cardiac diseases, and autoimmunity. In addition, the rising demand for regenerative medicines from the U.S. and the rising government funding are some of the other key aspects that are likely to fuel the growth of the North America market in the near future.

Furthermore, Asia Pacific is expected to register a substantial growth rate in the next few years. The high growth of this region can be attributed to the availability of funding for research and the development of research centers. In addition, the increasing contribution from India, China, and Japan is likely to supplement the growth of the market in the near future.

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Global Regenerative Medicine Market: Competitive Analysis

The global market for regenerative medicines is extremely fragmented and competitive in nature, thanks to the presence of a large number of players operating in it. In order to gain a competitive edge in the global market, the key players in the market are focusing on technological developments and research and development activities. In addition, the rising number of mergers and acquisitions and collaborations is likely to benefit the prominent players in the market and encourage the overall growth in the next few years.

Some of the key players operating in the regenerative medicine market across the globe areVericel Corporation, Japan Tissue Engineering Co., Ltd., Stryker Corporation, Acelity L.P. Inc. (KCI Licensing), Organogenesis Inc., Medtronic PLC, Cook Biotech Incorporated, Osiris Therapeutics, Inc., Integra Lifesciences Corporation, and Nuvasive, Inc.A large number of players are anticipated to enter the global market throughout the forecast period.

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Regenerative Medicine Market to Witness a Pronounce Growth During 2017 to 2025 - 3rd Watch News

Juan-Hua Quan,1,* Fei Fei Gao,2,* Hassan Ahmed Hassan Ahmed Ismail,3,* Jae-Min Yuk,2 Guang-Ho Cha,2 Jia-Qi Chu,4 Young-Ha Lee2

1Department of Gastroenterology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524-001, Peoples Republic of China; 2Department of Infection Biology and Department of Medical Science, Chungnam National University College of Medicine, Daejeon 301-131, Korea; 3Communicable and Non-Communicable Diseases Control Directorate, Federal Ministry of Health, Khartoum, Sudan; 4Stem Cell Research and Cellular Therapy Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province 524-001, Peoples Republic of China

*These authors contributed equally to this work

Correspondence: Young-Ha LeeDepartment of Infection Biology and Department of Medical Science, Chungnam National University College of Medicine 6 Munhwa-Dong, Jung-Gu, Daejeon 35015, KoreaTel +82-42-580-8273Fax +82-42-583-8216Email yhalee@cnu.ac.kr

Purpose: External and internal stimuli easily affect the retina. Studies have shown that cells infected with Toxoplasma gondii are resistant to multiple inducers of apoptosis. Nanoparticles (NPs) have been widely used in biomedical fields; however, little is known about cytotoxicity caused by NPs in the retina and the modulators that inhibit nanotoxicity.Materials and Methods: ARPE-19 cells from human retinal pigment epithelium were treated with silver nanoparticles (AgNPs) alone or in combination with T. gondii. Then, the cellular toxicity, apoptosis, cell cycle analysis, autophagy, ROS generation, NOX4 expression, and MAPK/mTOR signaling pathways were investigated. To confirm the AgNP-induced cytotoxicity in ARPE-19 cells and its modulatory effects caused by T. gondii infection, the major experiments carried out in ARPE-19 cells were performed again using human foreskin fibroblast (HFF) cells and bone marrow-derived macrophages (BMDMs) from NOX4/ mice.Results: AgNPs dose-dependently induced cytotoxicity and cell death in ARPE-19 cells. Apoptosis, sub-G1 phase cell accumulation, autophagy, JNK phosphorylation, and mitochondrial apoptotic features, such as caspase-3 and PARP cleavages, mitochondrial membrane potential depolarization, and cytochrome c release into the cytosol were observed in AgNP-treated cells. AgNP treatment also increased the Bax, Bik, and Bim protein levels as well as NOX4-dependent ROS generation. However, T. gondii-infected ARPE-19 cells inhibited AgNP-induced apoptosis, JNK phosphorylation, sub-G1 phase cell accumulation, autophagy, NOX4-mediated ROS production, and mitochondrial apoptosis. Furthermore, mitochondrial apoptosis was found in AgNP-treated HFF cells and BMDMs, and AgNP-induced mitochondrial apoptosis inhibition via NOX4-dependent ROS suppression in T. gondii pre-infected HFF cells and BMDMs was also confirmed.Conclusion: AgNPs induced mitochondrial apoptosis in human RPE cells combined with cell cycle dysregulation and autophagy; however, these effects were significantly inhibited by T. gondii pre-infection by suppression of NOX4-mediated ROS production, suggesting that T. gondii is a strong inhibitory modulator of nanotoxicity in in vitro models.

Keywords: silver nanoparticles, Toxoplasma gondii, mitochondrial apoptosis, human retinal pigment epithelium, reactive oxygen species, NADPH oxidase 4

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Silver Nanoparticle-Induced Apoptosis in ARPE-19 Cells Is Inhibited by | IJN - Dove Medical Press

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NEW YORK, May 25, 2020 (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq:MESO; ASX:MSB), global leader in cellular medicines for inflammatory diseases, today announced that clinical outcomes of its allogeneic mesenchymal stem cell (MSC) medicine RYONCIL (remestemcel-L) in children and adults with steroid-refractory acute graft versus host disease (GVHD) have been published in three peer-reviewed articles and an accompanying editorial in the May issue of Biology of Blood and Marrow Transplantation, the official publication of the American Society for Transplantation and Cellular Therapy.

Mesoblast Chief Medical Officer Dr Fred Grossman said: Results from these three trials show a consistent pattern of safety and efficacy for RYONCIL (remestemcel-L) in patients with the greatest levels of inflammation and the most severe grades of acute GVHD. These clinical outcomes provide a compelling rationale for use of remestemcel-L in children and adults with other conditions associated with severe inflammation and cytokine release, including acute respiratory distress syndrome (ARDS) and systemic vascular manifestations of COVID-19 infection.

In the accompanying editorial, Dr Jacques Galipeau, Professor and Assistant Dean of Medicine at the Stem Cell & Regenerative Medicine Center at the University of WisconsinMadison and Chair of the International Society of Cell and Gene Therapy (ISCT) MSC Committee, concluded that after more than a decade of clinical study involving three distinct advanced trials, it appears that remestemcel-L might well have finally met the regulatory requirements for marketing approval in the United States for steroid refractory acute GVHD in children, and it is to be determined whether this industrial MSC product will find utility for adults afflicted by acute GVHD or other indications.

The trials highlighted in the three articles all evaluated the same treatment regimen of RYONCIL, with patients receiving twice weekly intravenous infusions of 2 million cells per kg body weight over a four-week period. RYONCIL was well-tolerated in all studies with no identified safety concerns. The three trials were:

1. Study 275: An Expanded Access Program in 241 children across 50 centers in eight countries where RYONCIL was used as salvage therapy for steroid-refractory acute GVHD in patients who failed to respond to steroid therapy as well as multiple other agents.

2. Study GVHD001/002: A Phase 3 single-arm trial in 55 children across 20 centers in the United States where RYONCIL was used as the first line of treatment for children who failed to respond to steroids for acute GVHD.

3. Study 280: A Phase 3 randomized placebo-controlled trial in 260 patients, including 28 children, across 72 centers in seven countries where RYONCIL or placebo were added to second line therapy in patients with steroid-refractory acute GVHD who failed to respond to steroid treatment.

About Acute Graft Versus Host Disease Acute GVHD occurs in approximately 50% of patients who receive an allogeneic bone marrow transplant (BMT). Over 30,000 patients worldwide undergo an allogeneic BMT annually, primarily during treatment for blood cancers, and these numbers are increasing.1 In patients with the most severe form of acute GVHD (Grade C/D or III/IV) mortality is as high as 90% despite optimal institutional standard of care.2,3 There are currently no FDA-approved treatments in the United States for children under 12 with steroid-refractory acute GVHD.

About RYONCILTM Mesoblasts lead product candidate, RYONCIL (remestemcel-L), is an investigational therapy comprising culture-expanded mesenchymal stem cells derived from the bone marrow of an unrelated donor. It is administered to patients in a series of intravenous infusions. RYONCIL is believed to have immunomodulatory properties to counteract the inflammatory processes that are implicated in SR-aGVHD 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.

References 1. Niederwieser D, Baldomero H, Szer J. Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey. Bone Marrow Transplant 2016; 51(6):778-85.2. Westin, J., Saliba, RM., Lima, M. (2011) Steroid-refractory acute GVHD: predictors and outcomes. Advances in Hematology 2011;2011:601953.3. Axt L, Naumann A, Toennies J (2019) Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation. Bone Marrow Transplantation 2019;54(11):1805-1814.

About MesoblastMesoblast 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. The Companys 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.

Mesoblasts 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 Mesoblasts licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets.

Mesoblast has a strong and extensive global intellectual property (IP) portfolio with protection extending through to at least 2040 in all major markets. This IP position is expected to provide the Company with substantial commercial advantages as it develops its product candidates for these conditions.

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 StatementsThis 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 include, but are not limited to, statements about the initiation, timing, progress and results of Mesoblast and its collaborators clinical studies; Mesoblast and its collaborators 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 Mesoblasts product candidates, if approved; the potential benefits of strategic collaboration agreements and Mesoblasts ability to maintain established strategic collaborations; Mesoblasts ability to establish and maintain intellectual property on its product candidates and Mesoblasts ability to successfully defend these in cases of alleged infringement; the scope of protection Mesoblast is able to establish and maintain for intellectual property rights covering its product candidates and technology. 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 Mesoblasts 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.

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Clinical Outcomes Using RYONCIL (remestemcel-L) in Children and Adults With Severe Inflammatory Graft Versus Host Disease Published in Three Articles...

The health focus today is squarely on the bodys natural defense system. Until there is a vaccination, preventative measures are all we can turn to. Ayurveda can help, experts believe, especially a technique thats been gaining popularity. It's called Photo Bio Modulation (PBM). Availableat Indus Valley AyurvedicCentre (IVAC) in Mysore, itsan emerging medical practicein which exposure to low-level laser light or light-emitting diodes stimulates cellular function. This results in beneficial clinical outcomes for various conditions and diseases, primarily low immunity, in addition to lung disorders, respiratory disorders, joint problems, skin issues, and stress.

How does it work?Also known as Low-Level Laser Therapy (LLLT), it increases the production of Adenosine Triphosphate (ATP) in the mitochondria of the cells, which scavenges the free radicals. By doing so, it stimulates stem cell proliferation, lymph nodes associated with respiratory tract, the immune system and stimulates local tissues to support lung function leading to protection from asthma, bronchitis, pneumonia and Chronic Obstructive Pulmonary Disease, says Dr Talavane Krishna, Founder,President, IVAC.

Nasal ApplicationWhile PBM is gaining prominence now, processes such as nasal application, part of Panchakarma (five actions) treatment, have been a standard Ayurvedic antidote to viruses for aeons. One has to apply different herbal powders, liquid extracts, medicated ghee or oil inside the nostrils. Medications like Anu Taila, sesame or coconut oil, Brahmi ghrutha etc are antimicrobial and act as a protective filter inside the nose and throatthe primary entry point for the viruses. This simple procedure could be a daily practice for both adults and children.

Oil pulling Likewise, oil pulling with sesame or coconut oil as a daily oral health practice is useful. It involves swishing a teaspoon of oil in the mouth for three-five minutes and then spitting the oil, followed by washing/brushing the mouth. This kills bacteria that may lead to tooth decay, bad breath, and gum disease.

Rasayana This is one of the eight major branches of Ayurveda. Popularly known as a form of rejuvenation therapy, not only does it focus on anti-aging, but also immunity. This is accomplished by taking certain Ayurvedic preparations, food based on body constitution, and following an Ayurvedic way of life. This increases Ojas, the very essence of the bodys immunity. Medicines include single herbs like Ashwagandha, Shatavari, Amrita, and formulations like Chyavanaprash, Triphala, Makaradhwaja, notto mention regular body-mind detoxifications like Panchakarma and Rejuvenation.

Balance is keyKeeping the body alignedwith its natural rhythms is a prerequisite to the success of your health. For this, Ayurvedic principles namely Dhincharya (daily regime) and Rithucharya (seasonal regime) are crucial. Dhinacharya looks at aspects such as oral hygiene, yoga, pranayama, meditation, diet, bowel movements and more. Ritucharya describes the various changes in our body during the different seasonsand its effect on health. Italso teaches us how to keepa good balance.

The importance of dietcannot be negated, therefore ensure you add ginger, garlic, pepper, turmeric, clove, cumin, fenugreek and cinnamon in your food as all these ingredients build the immunesystem and bring aboutperfect balance, says Gita Ramesh, Joint MD, Kairali Ayurvedic Group.Dont forget to take warm showers and apply sesame oil on the entire body before the morning bath. Allow nostrils to be lubricated by application of cow ghee or oil, and do warm turmeric water gargles regularly, says Dr Aruna Bhide, Senior Ayurveda Doctor and Consultant, Mercure Goa Devaaya Retreat. Breathing exerciseslike Anulom vilom pranayama (alternate breathing), Kapal bhati (forceful exhalation) and Nadi shuddhi pranayama are beneficial too. Keep in mind to exercise until you sweat as this is the best way to excrete toxins.

Potions for healing(Do consult an Ayurvedic doctor)

Indukantha Kashyam Prevents the recurrence of debilitating diseases and keeps the body healthyVilwadi GulikaA tablet used as a treatment for insect bites, rodent bites, gastroenteritis etc.

Chyawanprash High in Vitamin C, it aids in the production of haemoglobinand white blood cells

Kushmandarasayana Comes in a herbal jam form and is used in respiratory conditions

TriphalaGhritam Support bowel health and aids digestion. As an antioxidant, its also thought to detoxify the body and support immunity.

AshwagandhaIt has demonstrated excellent immune-boosting effects, and has also shown to encourage anti-inflammatory and disease-fighting immune cells, thatkeep illnesses at bay

Amrita Used as a blood purifierMakaradhwaja A mineral-based preparation used for its aphrodisiac characteristics, it enhances the effectiveness of several medicines

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COVID-19: The Prevention Prescription - The New Indian Express

Latest Patent Further Strengthens Intellectual Property Portfolio Covering Novel Platform for Precisely Controlling Core Cell Migration Mechanisms

Decelerator Technology Has Key Potential Applications in Treatment of Cancer and Fibrosis and Serves as Key Complement to Companys Cell Motility Accelerator Platform for Enhanced Tissue Repair

NEW YORK, May 20, 2020 (GLOBE NEWSWIRE) -- MicroCures, a biopharmaceutical company developing novel therapeutics that harness the bodys innate regenerative mechanisms to accelerate tissue repair, today announced the issuance of a new European patent providing broad protection for the companys first-of-its-kind cell movement decelerator technology, which has potential therapeutic applications in combating cancer metastases and fibrosis. The companys decelerator technology is being developed alongside MicroCures accelerator technology, which is designed to enhance repair of tissue, nerves, and organs following trauma. With the newly issued patent in the European Union (#3052117), the companys global patent estate now includes eight issued and 12 pending patents covering its underlying technology, as well as the therapeutic programs that have emerged from the platform.

Our proprietary platform technology represents a fundamentally new way of thinking about how to harness the bodys natural cell movement processes to drive therapeutic outcomes in response to a range of medical challenges. Whether it is removing the brakes from cells to accelerate their migration and drive tissue, nerve and organ repair, or putting the brakes on cell movement to combat tumor metastases and fibrosis, we are pioneering an entirely new treatment paradigm, said Derek Proudian, co-founder and chief executive officer of MicroCures. While we clearly recognize the importance of the development work we are undertaking in support of this platform, it is equally important to build a strong, wide-reaching intellectual property portfolio to protect it. This latest patent issuance provides us yet another key piece of intellectual property, bringing our total number of issued and pending patents to 20.

MicroCures technology is based on foundational scientific research at Albert Einstein College of Medicine regarding the fundamental role that cell movement plays as a driver of the bodys innate capacity to repair tissue, nerves, and organs. The company has shown that complex and dynamic networks of microtubules within cells crucially control cell migration, and that this cell movement can be reliably modulated to achieve a range of therapeutic benefits. Based on these findings, the company has established a first-of-its-kind proprietary platform to create siRNA-based therapeutics capable of precisely controlling the speed and direction of cell movement by selectively silencing microtubule regulatory proteins.

The company has developed a broad pipeline of therapeutic programs with an initial focus in the area of tissue, nerve and organ repair. Unlike regenerative medicine approaches that rely upon engineered materials or systemic growth factor/stem cell therapeutics, MicroCures technology directs and enhances the bodys inherent healing processes through local, temporary modulation of cell motility. Additionally, the company is developing a decelerator technology based on the same foundational science. Instead of accelerating cell movement for therapeutic repair and regeneration, this technology is designed to slow or halt the movement of cells, potentially offering a unique, natural approach to preventing cancer metastases and fibrosis.

About MicroCures

MicroCures develops biopharmaceuticals that harness innate cellular mechanisms within the body to accelerate and improve recovery after traumatic injury. MicroCures has developed a first-of-its-kind therapeutic platform that precisely controls the rate and direction of cell migration, offering the potential to deliver powerful therapeutic benefits for a variety of large and underserved medical applications.

MicroCures has developed a broad pipeline of novel therapeutic programs with an initial focus in the area of tissue, nerve and organ repair. The companys lead therapeutic candidate, siFi2, targets excisional wound healing, a multi-billion dollar market inadequately served by current treatments. Additional applications for the companys cell migration accelerator technology include dermal burn repair, corneal burn repair, cavernous nerve repair/regeneration, spinal cord repair/regeneration, and cardiac tissue repair. Cell migration decelerator applications include combatting cancer metastases and fibrosis. The company protects its unique platform and proprietary therapeutic programs with a robust intellectual property portfolio including eight issued patents, as well as 12 pending patent applications.

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For more information please visit: http://www.microcures.com

Contact:

MicroCuresinfo@microcures.com

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MicroCures Announces Issuance of New European Patent Providing Broad Protection for First-of-its-Kind Cell Movement Decelerator Technology - Yahoo...

MINNEAPOLIS & EL SEGUNDO, Calif.--(BUSINESS WIRE)--Be The Match BioTherapies, an organization offering solutions for companies developing and commercializing cell and gene therapies, and NantKwest (Nasdaq: NK), a next generation, clinical-stage immunotherapy company focused on harnessing the unique power of the immune system using natural killer (NK) cells to treat cancer and infectious diseases, today announced an agreement through which Be The Match BioTherapies is providing donor material for a NantKwest Phase 1b clinical trial to address acute respiratory distress syndrome (ARDS), one of the primary causes of COVID-19 deaths.

The agreement combines Be The Match BioTherapies ability to provide high-quality cellular source material from the worlds largest registry of volunteer donors with NantKwests capabilities in manufacturing off-the-shelf cell therapies. NantKwests allogeneic cell therapy is derived from human bone marrow and designed to treat the ARDS that results from severe COVID-19 cases. The therapy, called BM-Allo.MSC, uses mesenchymal stem cells (MSCs), multipotent progenitor cells known to have immunomodulatory properties, to reduce the lung inflammation associated with ARDS. Similar work in Europe with allogeneic MSC products in patients with COVID-19 and ARDS has demonstrated safety and efficacy in reducing inflammatory processes.

NantKwest recently announced FDA authorization of its investigational new drug (IND) application for BM-Allo.MSC and is moving rapidly to initiate a Phase 1b trial in patients with severe COVID-19. To expedite trial initiation, Be The Match BioTherapies is providing cryopreserved donor stem cell material from the Be The Match BioBank, a program of the National Marrow Donor Program/Be The Match. The accelerated access to material, combined with NantKwests scalable manufacturing processes, will allow for rapid distribution of BM-Allo.MSC to patients in need.

There is an immediate need for COVID-19 therapies across all stages of the disease, including for patients with ARDS, which is one of the most critical conditions caused by COVID-19, said Patrick Soon-Shiong, MD, Chairman and Chief Executive Officer of NantKwest. Thanks to the quality source material provided by Be The Match BioTherapies, we are prepared to rapidly scale manufacturing of this much-needed therapy, potentially saving numerous patients lives.

Through our teams unparalleled ability to identify, source and deliver high-quality donor material we have the opportunity to support the advancement of a cell therapy with potential to change the world. We are proud to partner with NantKwest to support our mission to save lives through cellular therapy and continue to make a difference for critically ill patients around the globe, said Chris McClain, Senior Vice President, Sales and New Business Development at Be The Match BioTherapies.

About Be The Match BioTherapies

Be The Match BioTherapies is the only cell and gene therapy solutions provider with customizable services to support the end-to-end cell therapy supply chain. Backed by the industry-leading experience of the National Marrow Donor Program (NMDP)/Be The Match, and a research partnership with the CIBMTR (Center for International Blood and Marrow Transplant Research), the organization designs solutions that advance the development of cell and gene therapies across the globe.

Be The Match BioTherapies is dedicated to accelerating patient access to life-saving cell and gene therapies by providing high-quality cellular source material from the Be The Match Registry, the worlds largest and most diverse registry of more than 22 million potential blood stem cell donors. Through established relationships with apheresis, marrow collection and transplant centers worldwide, the organization develops, onboards, trains and manages expansive collection networks to advance cell therapies. Be The Match BioTherapies uses proven infrastructure consisting of regulatory compliance and managed logistics experts, as well as cell therapy supply chain case managers to successfully transport and deliver regulatory compliant life-saving therapies across the globe. Through the CIBMTR, Be The Match BioTherapies extends services beyond the cell therapy supply chain to include long-term follow-up tracking for the first two FDA-approved CAR-T therapies.

For more information, visit http://www.BeTheMatchBioTherapies.com or follow Be The Match BioTherapies on LinkedIn or Twitter at @BTMBioTherapies.

About NantKwest

NantKwest (Nasdaq: NK) is an innovative, clinical-stage immunotherapy company focused on harnessing the power of the innate immune system to treat cancer and virally-induced infectious diseases. NantKwest is the leading producer of clinical dose forms of off-the-shelf natural killer (NK) cell therapies. The activated NK cell platform is designed to destroy cancer and virally-infected cells. The safety of these optimized, activated NK cellsas well as their activity against a broad range of cancershas been tested in Phase I clinical trials in Canada and Europe, as well as in multiple Phase I and II clinical trials in the United States. By leveraging an integrated and extensive genomics and transcriptomics discovery and development engine, together with a pipeline of multiple, clinical-stage, immuno-oncology programs, NantKwests goal is to transform medicine by delivering living drugs-in-a-bag and bringing novel NK cell-based therapies to routine clinical care. NantKwest is a member of the NantWorks ecosystem of companies. For more information, please visit http://www.nantkwest.com.

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Be The Match BioTherapies and NantKwest Announce Collaboration to Accelerate Development of Cell Therapy to Prevent COVID-19 Deaths - Business Wire

DetailsCategory: DNA RNA and CellsPublished on Thursday, 14 May 2020 10:13Hits: 234

CAMBRIDGE, MA, USA I May 12, 2020 I Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology bothin vivoandex vivo,is presenting three oral presentations and two poster presentations at the 23rd Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT), taking place virtually from May 12-15, 2020. Intellia researchers are presenting new data in support of NTLA-5001, the companys engineered cell therapy candidate for the treatment of acute myeloid leukemia (AML). Intellia is also providing an update on NTLA-2002, its newest development candidate for the treatment of hereditary angioedema (HAE).

At Intellia, we are applying our CRISPR/Cas9 technology to develop new processes that can produce enhanced engineered cell therapies to treat severe cancers, such as AML, that traditional approaches cannot address. Our proprietary platform provides a powerful tool to generate more potent TCR-directed cells, that can treat blood cancers initially and potentially solid tumors. The data being presented today validate Intellias approach of reducing AML tumor cell blasts, and our plans to enter the clinic with NTLA-5001 next year, said Intellia President and CEO John Leonard, M.D. We are also pleased to present data that support our recently announced HAE development candidate, NTLA-2002, Intellias second systemic therapy employing our in vivo knockout approach and modular delivery platform.

Data Presentations on Intellias First Engineered Cell Therapy Development Candidate, NTLA-5001 for the Treatment of AML, and Proprietary Cell Engineering Process

NTLA-5001 is Intellias first engineered T cell receptor (TCR) T cell therapy development candidate, which targets the Wilms Tumor 1 (WT1) intracellular antigen for the treatment of AML. NTLA-5001 is being developed in collaboration with Chiara Boninis team at IRCCS Ospedale San Raffaele to treat AML patients regardless of the genetic subtype of a patients leukemia. AML is a cancer of the blood and bone marrow that is rapidly fatal without immediate treatment and is the most common type of acute leukemia in adults(Source:NIH SEER Cancer Stat Facts: Leukemia AML).

Intellias proprietary process is a significant improvement over standard engineering processes commonly used to introduce nucleic acids into cells. Intellias process enabled multiple gene edits using CRISPR/Cas9, while maintaining cell products with high expansion potential and minimal undesirable chromosomal translocations. CRISPR/Cas9 was used to insert a WT1-directed TCR in locus, while eliminating the expression of the endogenous TCRs, with the goal of producing homogeneous T cell therapies like NTLA-5001.

Intellias novel approach with NTLA-5001 can overcome the challenges of standard T cell therapy, including risks of reduced specificity associated with mixed expression and mispairing of endogenous and transgenic TCRs (tgTCRs); graph-versus-host disease (GvHD) risks, which could lead to an attack on the patients healthy cells; and reduced efficacy tied to lower tgTCR expression per T cell. Intellias unprecedented process is expected to streamline cell engineering and manufacturing, yielding a homogenous product comprising WT1-targeted T cells with high anti-tumor activity. Data highlights from todays presentation include the following:

Intellias cell engineering efforts are focused on its initial clinical investigation of NLTA-5001 on AML, while continuing preclinical studies exploring the potential for targeting WT1 in solid tumors. The company confirmed plans last week to submit an IND or IND-equivalent for NTLA-5001 for the treatment of AML in the first half of 2021.

The presentation titled, Enhanced tgTCR T Cell Product Attributes Through Process Improvement of CRISPR/Cas9 Engineering, will be made today by Aaron Prodeus, Ph.D., senior scientist, Cell Therapy, and can be found here, on the Scientific Publications & Presentations page of Intellias website. These data were a follow-on to the study presented at Keystone Symposias Engineering the Genome Conference from this past February.

In Vivo Data Supports Intellias Novel TCR Candidate

A second presentation on engineered cell therapy progress, in collaboration with IRCCS Ospedale San Raffaele, showed in vivo data demonstrating the potential of TCR-edited T cells to effectively target WT1 tumor cells in AML. In addition to the previously disclosed results of effective in vitro recognition of primary AML tumor cells by edited WT1-specific cytotoxic T cells (CD8 T cells), new data indicate that the selected TCR also enables T helper cells (CD4 T cells) to react to WT1-expressing tumor cells, providing cytokine support. This distinguishes Intellias TCR from other therapeutic TCR candidates, which either exclusively activate toxic CD8 T cells or require the co-transfection of CD8 into CD4 T cells to render them functional.

Using a mouse model carrying disseminated human primary AML, researchers observed a significant therapeutic effect, including decreased AML tumor burden. In addition, no signs of GvHD were observed in mice treated with the WT1-specific T cells. The data show that tgTCR-engineered cells have targeted anti-cancer activity in a challenging model of systemic AML, demonstrating the therapeutic potential of Intellias engineered TCR T cell approach.

The presentation titled, Exploiting CRISPR-Genome Editing and WT1-Specific T Cell Receptors to Redirect T Lymphocytes Against Acute Myeloid Leukemia, will be given today by Eliana Ruggiero, Ph.D., Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Italy. Notably, ASGCT meeting organizers selected this presentation as one of six to receive the ASGCT Excellence in Research Award this year.

Continued Progress on Intellias Second In Vivo Development Candidate, NTLA-2002 for the Treatment of HAE

Intellia is presenting development data updates on its potential HAE therapy, NTLA-2002, which utilizes the companys systemic in vivo knockout approach, including its proprietary lipid nanoparticle (LNP) system. HAE is a rare genetic disorder characterized by recurring and unpredictable severe swelling attacks in various parts of the body, and is significantly debilitating or even fatal in certain cases. NTLA-2002 aims to prevent unregulated production of bradykinin by knocking out the prekallikrein B1 (KLKB1) gene through a single course of treatment to ameliorate the frequency and intensity of these swelling attacks.

The KLKB1 gene knockout in an ongoing non-human primate (NHP) study resulted in a sustained 90% reduction in kallikrein activity, a level that translates to a therapeutically meaningful impact on HAE attack rates(Source: Banerji et al., NEJM, 2017). This kallikrein activity reduction was sustained for at least six months, demonstrating the same high level of efficacy and durability seen in earlier rodent studies.

The short talk titled, CRISPR/Cas9-Mediated Gene Knockout of KLKB1 to Treat Hereditary Angioedema, will be given by Jessica Seitzer, director, Genomics, Intellia on Fri., May 15, 2020, when it will be made available here, on the Scientific Publications & Presentations page of Intellias website. The presented data include results from ongoing collaborations with researchers at Regeneron, and the program is subject to an option by Regeneron to enter into a Co/Co agreement, in which Intellia would remain the lead party. Intellia expects to submit an IND or IND-equivalent to initiate a Phase 1 trial for NTLA-2002 in the second half of 2021.

About Intellia Therapeutics

Intellia Therapeuticsis a leading genome editing company focused on developing proprietary, curative therapeutics using the CRISPR/Cas9 system. Intellia believes the CRISPR/Cas9 technology has the potential to transform medicine by permanently editing disease-associated genes in the human body with a single treatment course, and through improved cell therapies that can treat cancer and immunological diseases, or can replace patients diseased cells. The combination of deep scientific, technical and clinical development experience, along with its leading intellectual property portfolio, puts Intellia in a unique position to unlock broad therapeutic applications of the CRISPR/Cas9 technology and create a new class of therapeutic products. Learn more aboutIntellia Therapeuticsand CRISPR/Cas9 atintelliatx.comand follow us on Twitter @intelliatweets.

SOURCE: Intellia Therapeutics

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Intellia Therapeutics Reports Progress on CRISPR/Cas9 AML Cancer Therapy Using Proprietary Cell Engineering Process at the 23rd Annual Meeting of the...

Presentation of new and updated results from ongoing Phase 1/2 HGB-206 study of LentiGlobin for sickle cell disease will include additional patients treated in the study

New and updated data, including analysis of healthy red blood cell production in patients with transfusion-dependent -thalassemia following treatment with betibeglogene autotemcel (LentiGlobin for -thalassemia) to be shared

CAMBRIDGE, Mass. bluebird bio, Inc. (Nasdaq: BLUE) announced today that data from its gene therapy programs for sickle cell disease (SCD), transfusion-dependent -thalassemia (TDT) and its cell therapy program for relapsed and refractory multiple myeloma (RRMM) will be presented during the Virtual Edition of the 25th European Hematology Association (EHA25) Annual Congress.

New data from the companys Phase 1/2 HGB-206 study of LentiGlobin gene therapy for SCD will be presented, including updated data from patients in Group C.

bluebird bio will also present data from its ongoing clinical studies of betibeglogene autotemcel (formerly LentiGlobin gene therapy for -thalassemia), including the Phase 3 Northstar-2 (HGB-207) study in patients who do not have a 0/0 genotype and the Phase 3 Northstar-3 (HGB-212) study in patients who have 0/0, 0/+IVS-I-110, or +IVS-I-110/+IVS-I-110 genotypes.

Data from studies of idecabtagene vicleucel (ide-cel; bb2121), the companys anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy in development with Bristol Myers Squibb, will be presented, including an encore presentation of results from the pivotal Phase 2 KarMMa study.

Sickle Cell Disease Data at EHA25

Oral Presentation: Outcomes in patients treated with LentiGlobin for sickle cell disease (SCD) gene therapy: Updated results from the Phase 1/2 HGB-206 group C study Presenting Author: Julie Kanter, M.D., University of Alabama at Birmingham, Birmingham, Ala.

Transfusion-Dependent -Thalassemia Data at EHA25

Oral Presentation: Improvement in erythropoiesis in patients with transfusion-dependent -thalassemia following treatment with betibeglogene autotemcel (LentiGlobin for -thalassemia) in the Phase 3 HGB-207 study Presenting Author: John B. Porter, MA, M.D., FRCP, FRCPath, University College London Hospital, London, UK

Poster: Betibeglogene autotemcel (LentiGlobin) in patients with transfusion-dependent -thalassemia and 0/0, +IVS-I-110/+IVS-I-110, or 0/+IVS-I-110 genotypes: Updated results from the HGB-212 study Presenting Author: Evangelia Yannaki, M.D., George Papanicolaou Hospital, Thessaloniki, Greece

Multiple Myeloma Data at EHA25

Oral Presentation:Phase II KarMMa study: Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T cell therapy, in patients with relapsed and refractory multiple myeloma Presenting Author: Jesus San-Miguel, M.D., Ph.D., Clinica Universidad de Navarra, Navarra, Spain

Poster: Quality of life in patients with relapsed and refractory multiple myeloma treated with the BCMA-targeted CAR T cell therapy Idecabtagene vicleucel (ide-cel; bb2121): results from the KarMMa Trial Presenting Author: Michel Delforge, M.D., Ph.D., Leuven University College, Brussels, Belgium

Poster: Matching-adjusted indirect comparisons of efficacy outcomes for idecabtagene vicleucel from the KarMMa study vs selinexor PLUS dexamethasone (STORM part 2) and belantamab mafodotin (DREAMM-2) Presenting Author: Paula Rodriguez-Otero, M.D., Clinica Universidad de Navarra, Navarra, Spain

Poster: Baseline and postinfusion pharmcodynamic biomarkers of safety and efficacy in patients treated with idecabtagene vicleucel (ide-cel; bb2121) in the KarMMa study Presenting Author: Justine DellAringa, Bristol Myers Squibb, Seattle, Wash.

Poster: Correlation of tumor BCMA expression with response and acquired resistance to idecabtagene vicleucel in the KarMMa study in relapsed and refractory multiple myeloma Presenting Author: Nathan Martin, Bristol Myers Squibb, Seattle, Wash.

Abstracts outlining bluebird bios accepted data at the EHA25 Virtual Congress have been made available on the EHA25 conference website. On Friday, June 12 at 8:30 AM CEST, the embargo will lift for poster and oral presentations accepted for EHA25.

About betibeglogene autotemcel The European Commission granted conditional marketing authorization (CMA) for betibeglogene autotemcel, marketed as ZYNTEGLO gene therapy, for patients 12 years and older with TDT who do not have a 0/0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen (HLA)-matched related HSC donor is not available. On April 28, 2020, the European Medicines Agency (EMA) renewed the CMA for ZYNTEGLO, supported by data from 32 patients treated with ZYNTEGLO including three patients with up to five years of follow-up.

TDT is a severe genetic disease caused by mutations in the -globin gene that result in reduced or significantly reduced hemoglobin (Hb). In order to survive, people with TDT maintain Hb levels through lifelong chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload.

Betibeglogene autotemcel adds functional copies of a modified form of the -globin gene (A-T87Q-globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once a patient has the A-T87Q-globin gene, they have the potential to produce HbAT87Q, which is gene therapy-derived hemoglobin, at levels that may eliminate or significantly reduce the need for transfusions.

Non-serious adverse events (AEs) observed during the clinical studies that were attributed to betibeglogene autotemcel were abdominal pain, thrombocytopenia, leukopenia, neutropenia, hot flush, dyspnoea, pain in extremity, and non-cardiac chest pain. One serious adverse event (SAE) of thrombocytopenia was considered possibly related to LentiGlobin for -thalassemia for TDT.

Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease.

The CMA for ZYNTEGLO is only valid in the 28 member states of the EU as well as Iceland, Liechtenstein and Norway. For details, please see the Summary of Product Characteristics (SmPC).

The U.S. Food and Drug Administration granted betibeglogene autotemcel Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT. Betibeglogene autotemcel is not approved in the United States.

Betibeglogene autotemcel continues to be evaluated in the ongoing Phase 3 Northstar-2 and Northstar-3 studies. For more information about the ongoing clinical studies, visit http://www.northstarclinicalstudies.com or clinicaltrials.gov and use identifier NCT02906202 for Northstar-2 (HGB-207), NCT03207009 for Northstar-3 (HGB-212).

About LentiGlobin for Sickle Cell Disease LentiGlobin for sickle cell disease is an investigational gene therapy being studied as a potential treatment for SCD. bluebird bios clinical development program for LentiGlobin for SCD includes the ongoing Phase 1/2 HGB-206 study and the ongoing Phase 3 HGB-210 study.

SCD is a serious, progressive and debilitating genetic disease caused by a mutation in the -globin gene that leads to the production of abnormal sickle hemoglobin (HbS), causing red blood cells (RBCs) to become sickled and fragile, resulting in chronic hemolytic anemia, vasculopathy and painful vaso-occlusive crises (VOCs). For adults and children living with SCD, this means unpredictable episodes of excruciating pain due to vaso-occlusion as well as other acute complicationssuch as acute chest syndrome (ACS), stroke, and infections, which can contribute to early mortality in these patients.

LentiGlobin for SCD received Orphan Medicinal Product designation from the European Commission for the treatment of SCD.

The U.S. Food and Drug Administration (FDA) granted Orphan Drug status and Regenerative Medicine Advanced Therapy designation for LentiGlobin for the treatment of SCD.

LentiGlobin for SCD is investigational and has not been approved by the European Medicines Agency (EMA) or FDA.

bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-303) for people who have participated in bluebird bio-sponsored clinical studies of betibeglogene autotemcel and LentiGlobin for SCD. For more information visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT02633943 for LTF-303.

About idecabtagene vicleucel (ide-cel; bb2121) Ide-cel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T cell immunotherapy. The ide-cel CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for recognizing BCMA, attached to a human CD8 hinge and transmembrane domain fused to the T cell cytoplasmic signaling domains of CD137 4-1BB and CD3- chain, in tandem. Ide-cel recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

In addition to the pivotal KarMMa trial evaluating ide-cel in patients with relapsed and refractory multiple myeloma, bluebird bio and Bristol Myers Squibbs broad clinical development program for ide-cel includes clinical studies (KarMMa-2, KarMMa-3, KarMMa-4) in earlier lines of treatment for patients with multiple myeloma, including newly diagnosed multiple myeloma. For more information visit clinicaltrials.gov.

Ide-cel was granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) and PRIority Medicines (PRIME) designation, as well as Accelerated Assessment status, by the European Medicines Agency for relapsed and refractory multiple myeloma.

Ide-cel is being developed as part of a Co-Development, Co-Promotion and Profit Share Agreement between Bristol Myers Squibb and bluebird bio.

Ide-cel is not approved for any indication in any geography.

About KarMMa KarMMa (NCT03361748) is a pivotal, open-label, single-arm, multicenter, multinational, Phase 2 study evaluating the efficacy and safety of ide-cel in adults with relapsed and refractory multiple myeloma in North America and Europe. The primary endpoint of the study is overall response rate as assessed by an independent review committee (IRC) according to the International Myeloma Working Group (IMWG) criteria. Complete response rate is a key secondary endpoint. Other efficacy endpoints include time to response, duration of response, progression-free survival, overall survival, minimal residual disease evaluated by Next-Generation Sequencing (NGS) assay and safety. The study enrolled 140 patients, of whom 128 received ide-cel across the target dose levels of 150-450 x 10P6P CAR+ T cells after receiving lymphodepleting chemotherapy. All enrolled patients had received at least three prior treatment regimens, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody, and were refractory to their last regimen, defined as progression during or within 60 days of their last therapy.

About bluebird bio, Inc. bluebird bio is pioneering gene therapy with purpose. From our Cambridge, Mass., headquarters, were developing gene therapies for severe genetic diseases and cancer, with the goal that people facing potentially fatal conditions with limited treatment options can live their lives fully. Beyond our labs, were working to positively disrupt the healthcare system to create access, transparency and education so that gene therapy can become available to all those who can benefit.

bluebird bio is a human company powered by human stories. Were putting our care and expertise to work across a spectrum of disorders including cerebral adrenoleukodystrophy, sickle cell disease, -thalassemia and multiple myeloma, using three gene therapy technologies: gene addition, cell therapy and (megaTAL-enabled) gene editing.

bluebird bio has additional nests in Seattle, Wash.; Durham, N.C.; and Zug, Switzerland. For more information, visit bluebirdbio.com.

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ZYNTEGLO, LentiGlobin, and bluebird bio are trademarks of bluebird bio, Inc.

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bluebird bio to Present Data from Its Gene and Cell Therapy Programs During the Virtual Edition of the 25th European Hematology Association Annual...

This discovery may have clinical importance in management of heart failure.

This discovery may have clinical importance in management of heart failure.Many heart diseases are linked to oxidative stress, an overabundance of reactive oxygen species. The body reacts to reduce oxidative stress where the redox teeter-totter has gone too far up through production of endogenous antioxidants that reduce the reactive oxygen species. This balancing act is called redox homeostasis.

But what happens if the redox teeter-totter goes too far down, creating antioxidative stress, also known as reductive stress? Rajasekaran Namakkal-Soorappan, Ph.D., associate professor in the University of Alabama at Birmingham Department of Pathology, and colleagues have found that reductive stress, or RS/AS, is also pathological. This discovery, they say, may have clinical importance in management of heart failure.

They report that RS causes pathological heart enlargement and diastolic dysfunction in a mouse model. This study, published in the journal Antioxidants and Redox Signaling, was led by Namakkal-Soorappan and Pei Ping, Ph.D., David Geffen School of Medicine at the University of California-Los Angeles.

Antioxidant-based therapeutic approaches for human heart failure should consider a thorough evaluation of antioxidant levels before the treatment, they said. Our findings demonstrate that chronic RS is intolerable and adequate to induce heart failure.

The study used transgenic mice that had upregulated genes for antioxidants in the heart, which increased the amounts of antioxidant proteins and reduced glutathione, creating RS. One mouse line had low upregulation, and one had high upregulation, creating chronic low RS and chronic high RS, respectively, in the hearts of the mice.

The mice with high RS showed pathological heart changes called hypertrophic cardiomyopathy, and had an abnormally high heart ejection fraction and diastolic dysfunction at 6 months of age. Sixty percent of the high-RS mice died by 18 months of age.

The mice with low RS had normal survival rates, but they developed the heart changes at about 15 months of age, suggesting that even moderate RS can lead to irreversible damage in the heart over time.

Giving high-RS mice a chemical that blocked biosynthesis of glutathione, beginning at about 6 weeks of age, prevented RS and rescued the mice from pathological heart changes.

Gobinath Shanmugam, Ph.D., postdoctoral fellow in the UAB Department of Pathology, and Namakkal-Soorappan point out that a 2019 survey found about 77 percent of Americans are consuming dietary supplements every day, and within this group, about 58 percent are consuming antioxidants as multivitamins. Thus, a chronic consumption of antioxidant drugs by any individual without knowing their redox state might result in RS, which can induce pathology and slowly damage the heart.

In a related study, published in the journal Redox Biology, Namakkal-Soorappan looked at the impact of RS on myosatellite cells, which are also known as muscle stem cells. These cells, located near skeletal muscle fibers, are able to regenerate and differentiate into skeletal muscle after acute or chronic muscle injury. The regulation of myosatellite cells is of interest given the loss of skeletal muscle mass during aging or in chronic conditions like diabetes and AIDS.

Recently, Namakkal-Soorappan reported that tilting the redox teeter-totter to oxidative stress impaired regeneration of skeletal muscle. Now, in the Redox Biology paper, he has shown that tilting the redox to RS also causes significant inhibition of muscle satellite cell differentiation.

Rather than genetic manipulation to induce RS, as was done in the heart study, the researchers used the chemical sulforaphane or direct augmentation of intracellular glutathione to induce RS in cultured mouse myoblast cells. Both treatments inhibited myoblast differentiation. Finally, authors attempted to withdraw antioxidative stress by growing cells in medium without sulforaphane, which removes the RS and accelerates the differentiation. Namakkal-Soorappan and colleagues found that a pro-oxidative milieu, through a mild generation of reactive oxygen species, was required for myoblast differentiation.

The researchers also showed that genetic silencing of a negative regulator of the antioxidant genes also inhibited myoblast differentiation.

Co-authors with Namakkal-Soorappan and Ping, and first-author Shanmugam, in the Antioxidants and Redox Signaling study, Reductive stress causes pathological cardiac remodeling and diastolic dysfunction, are Silvio H. Litovsky and Rajesh Kumar Radhakrishnan, UAB Department of Pathology; Ding Wang, UCLA; Sellamuthu S. Gounder, Kevin Whitehead, Sarah Franklin and John R. Hoidal, University of Utah School of Medicine; Jolyn Fernandes and Dean P. Jones, Emory University, Atlanta, Georgia; Thomas W. Kensler, Fred Hutch Cancer Research Center, Seattle, Washington; Louis DellItalia, UAB Department of Medicine; Victor Darley-Usmar, UAB Department of Pathology; and E. Dale Abel, University of Iowa.

In the Redox Biology study, Reductive stress impairs myogenic differentiation, co-authors with Namakkal-Soorappan are Sandeep Balu Shelar, UAB Department of Pathology; Dean P. Jones, Emory University; and John R. Hoidal, University of Utah School of Medicine.

Support for both studies came from National Institutes of Health grants HL118067 and AG042860, American Heart Association grant BGIA 0865015F, the University of Utah, and UAB.

In the two studies, Namakkal-Soorappans name is listed as Namakkal S. Rajasekaran.

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Surplus antioxidants are pathogenic for hearts and skeletal muscle - The Mix

CRANFORD, N.J., May 13, 2020 /PRNewswire/ -- Citius Pharmaceuticals, Inc. ("Citius" or the "Company") (Nasdaq: CTXR), a specialty pharmaceutical company focused on developing and commercializing critical care drug products, today announced that data on NoveCite MSCs will be presented this week at the American Society of Gene and Cell therapy (ASGCT) annual meeting. NC-MSCs are made by Novellus, Inc. ("Novellus"), a Cambridge-based biotechnology company, using its patented mRNA-based cell-reprogramming process. Earlier this year, Citius signed an exclusive option agreement to in-license NC-MSCs for acute respiratory distress syndrome (ARDS), including in COVID-19 patients, from Novellus.

The data to be presented show that NC-MSCs secrete higher levels of anti-inflammatory proteins compared to MSCs derived from bone marrow. From the abstract: "Comparative secretome analysis showed overexpression of multiple neuroprotective and anti-inflammatory factors, including CXCL1, VEGF-A, and CXCL5." In addition, NC-MSCs showed therapeutic benefit in an experimental autoimmune encephalomyelitis (EAE) mouse model, delaying disease progression and improving the clinical score compared to the control group, while bone marrow-derived MSCs showed no difference from the control.

"We are pleased to present these data at the annual meeting of the ASGCT," said Matt Angel, PhD, co-founder and Chief Science Officer at Novellus. "While conventional MSCs have shown promise in the treatment of inflammatory lung disease, protein secretion and manufacturability remain challenges for these approaches. The data that will be presented this week show that iPSC-derived MSCs secrete higher levels of anti-inflammatory proteins, and exhibit greater expansion potential than bone marrow-derived MSCs. We believe that these properties make iPSC-derived MSCs especially well-suited for an allogeneic cell therapy for ARDS."

"Last month Citius signed an exclusive option agreement with Novellus for worldwide development and commercial rights related to the use of these uniquely derived MSCs for the treatment of ARDS. The pre-clinical data that is being presented at the ASGCT annual meeting adds to our confidence in the higher potency of these MSCs, which we expect will result in better outcomes for patients with COVID-19 and ARDS," stated Myron Holubiak, CEO of Citius Pharmaceuticals. "We intend to study these cells in the clinic later this year to determine safety, efficacy, and the optimal dose of these cells in moderate to severe ARDS patients with COVID-19."

Citius has submitted a pre-IND meeting request and supporting briefing documents to the Center for Biologics Evaluation and Research ("CBER") of the FDA under the Coronavirus Treatment Acceleration Program (CTAP) for use of these MSCs for patients with Acute Respiratory Distress Syndrome (ARDS) due to SARS-CoV-2 disease.

Presentation Information:Title:Mesenchymal Stem Cells (MSCs) Generated Using mRNA Reprogramming Show Enhanced Growth Potential, Secretome, and Therapeutic Efficacy in a Demyelinating Disease ModelPresenter:Harris, Jasmine, Novellus, Inc.Date and Time: Wednesday, May 13 | 5:30 PM - 6:30 PM

About Acute Respiratory Distress Syndrome (ARDS)ARDS is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. ARDS is a rapidly progressive disease that occurs in critically ill patients most notably now in those diagnosed with COVID-19. ARDS affects approximately 200,000 patients per year in the U.S., exclusive of the current COVID-19 pandemic, and has a 30% to 50% mortality rate. ARDS is sometimes initially diagnosed as pneumonia or pulmonary edema (fluid in the lungs from heart disease). Symptoms of ARDS include shortness of breath, rapid breathing and heart rate, chest pain (particularly while inhaling), and bluish skin coloration. Among those who survive ARDS, a decreased quality of life is relatively common.

About Coronavirus Treatment Acceleration Program (CTAP)In response to the pandemic, the FDA has created an emergency program called the Coronavirus Treatment Acceleration Program (CTAP) to accelerate the development of treatments for COVID-19. By redeploying staff, the FDA is responding to COVID-19-related requests and reviewing protocols within 24 hours of receipt. The FDA said CTAP "uses every available method to move new treatments to patients as quickly as possible, while at the same time finding out whether they are helpful or harmful." In practice, that means developers of potential treatments for COVID-19 will benefit from an unusually faster track at the FDA to shorten wait times at multiple steps of the process.

About Citius Pharmaceuticals, Inc.Citius is a late-stage specialty pharmaceutical company dedicated to the development and commercialization of critical care products, with a focus on anti-infectives and cancer care. For more information, please visit http://www.citiuspharma.com.

About Novellus, Inc.Novellus is a pre-clinical stage biotechnology company developing engineered cellular medicines using its non-immunogenic mRNA, nucleic-acid delivery, gene editing, and cell reprogramming technologies. Novellus is privately held and is headquartered in Cambridge, MA. For more information, please visit http://www.novellus-inc.com.

Safe HarborThis press release may contain "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Such statements are made based on our expectations and beliefs concerning future events impacting Citius. You can identify these statements by the fact that they use words such as "will," "anticipate," "estimate," "expect," "should," and "may" and other words and terms of similar meaning or use of future dates. Forward-looking statements are based on management's current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition, and stock price. Factors that could cause actual results to differ materially from those currently anticipated are: the risk of successfully negotiating a license agreement with Novellus within the option period; our need for substantial additional funds; the ability to access the FDA's CTAP program for the MARCO trial; the estimated markets for our product candidates, including those for ARDS, and the acceptance thereof by any market; risks associated with conducting trials for our product candidates, including those expected to be required for any treatment for ARDS and our Phase III trial for Mino-Lok; risks relating to the results of research and development activities; risks associated with developing our product candidates, including any licensed from Novellus, including that preclinical results may not be predictive of clinical results and our ability to file an IND for such candidates; uncertainties relating to preclinical and clinical testing; the early stage of products under development; risks related to our growth strategy; our ability to obtain, perform under, and maintain financing and strategic agreements and relationships; our ability to identify, acquire, close, and integrate product candidates and companies successfully and on a timely basis; our ability to attract, integrate, and retain key personnel; government regulation; patent and intellectual property matters; competition; as well as other risks described in our SEC filings. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions, or circumstances on which any such statement is based, except as required by law.

Contact:Andrew ScottVice President, Corporate Development(O) 908-967-6677 x105 [emailprotected]

SOURCE Citius Pharmaceuticals, Inc.

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Citius Announces Data on NoveCite Mesenchymal Stem Cells (NC-MSCs) to be Presented at the American Society of Gene and Cell Therapy (ASGCT) Annual...

A group of UB researchers have published a paper that clarifies certain cellular mechanisms that could lead to improved outcomes in patients with globoid cell leukodystrophy, commonly known as Krabbe disease.

The paper, titled Macrophages Expressing GALC Improve Peripheral Krabbe Disease by a Mechanism Independent of Cross-Correction, was published May 5 in the journal Neuron.

The research was led by Lawrence Wrabetz and M. Laura Feltri. Wrabetz and Feltri head the Hunter James Kelly Research Institute and both are professors in the departments of Biochemistry and Neurology in the Jacobs School of Medicine and Biomedical Sciences at UB.

The institute is named for the son of former Buffalo Bills quarterback Jim Kelly. Hunter Kelly died at age 8 in 2005 from complications of Krabbe disease.

Krabbe disease is a progressive and fatal neurologic disorder that usually affects newborns and causes death before a child reaches the age of 2 or 3.

Traditionally, hematopoietic stem cell transplantation, also known as a bone marrow transplant, has improved the long-term survival and quality of life of patients with Krabbe disease, but it is not a cure.

It has long been assumed that the bone marrow transplant works by a process calledcross-correction, in which an enzyme called GALC is transferred from healthy cells to sick cells.

Using a new Krabbe disease animal model and patient samples, the UB researchers determinedthatin reality cross-correctiondoes not occur. Rather, the bone marrow transplant helps patients through a different mechanism.

The researchers first determined which cells are involved in Krabbe disease and by which mechanism. They discovered that both myelin-forming cells, or Schwann cells, and macrophages require the GALC enzyme, which is missing in Krabbe patients due to genetic mutation.

Schwann cells require GALC to prevent the formation of a toxic lipid called psychosine, which causes myelin destruction and damage to neurons. Macrophages require GALC to aid with the degradation of myelin debris produced by the disease.

The research showed that hematopoietic stem cell transplantation does not work bycross-correction, but by providing healthy macrophages with GALC.

According to Feltri, the data reveal that improvingcross-correctionwould be a way to makebone marrow transplants and other experimental therapies such as gene therapy more effective.

Bone marrow transplantation and other treatments for lysosomal storage disorders, such as enzyme replacement therapy, have historically had encouraging but limited therapeutic benefit, says study first author Nadav I. Weinstock, an MD-PhD student in the Jacobs School. Our work defined the precise cellular and mechanistic benefit of bone marrow transplantation in Krabbe disease, while also shedding light on previously unrecognized limitations of this approach.

Future studies, using genetically engineered bone marrow transplantation or other novelapproaches,may one day build on our findings and eventually bridge the gap for effectively treating patients with lysosomal disease, he continues.

UB investigators included Daesung Shin, research assistant professor at the Hunter James Kelly Research Institute; Nicholas Silvestri, clinical associate professor of neurology, Jacobs School; Narayan Dhimal, PhD student; Chelsey B. Reed, MD-PhD student; and undergraduate student Oliver Sampson.

Also participating in the research were Eric E. Irons, MD-PhD student, and Joseph T.Y. Lau, a distinguished faculty member from the Department of Molecular and Cellular Biology at Roswell Park Comprehensive Cancer Center.

The research was funded by multiple grants from the National Institutes of Health awarded to Weinstock, Shin, Wrabetz and Feltri, and also supported by Hunters Hope.

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UB investigators uncover cellular mechanism involved in Krabbe disease - UB Now: News and views for UB faculty and staff - University at Buffalo...