SUZHOU, China and SHANGHAI, May 29, 2020 /PRNewswire/ -- Gracell Biotechnologies Co., Ltd. ("Gracell"), a clinical-stage immune cell and gene therapy company, today announced that two presentations were accepted at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

Both presentations can be found in the Development Therapeutics Immunotherapy session, central on Gracell's TruUCAR GC027 in relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) patients and EnhancedCAR GC008t in patients with advanced mesothelin-positive solid tumors.

"We are delighted to report on both TruUCAR GC027 in T-ALL and EnhancedCAR GC008t in solid tumors" said Dr. Martina Sersch, CMO of Gracell. "and glad to share safety and preliminary efficacy data on two of our exciting new CAR-T platform therapies with the scientific community at the ASCO annual meeting." Dr. William CAO, CEO of Gracell, added "Thanks to our highly efficient gene editing capability, CAR-T cells with PD-1 gene edited are generated to have enhanced capability of tumor control in inhibitory tumor microenvironment. We believe this strategy will improve CAR-T/TCR-T's potency against solid tumors.Gracell carried out this strategy as early as 2017, upon our foundation. With two years' preclinical and clinical investigations, we are very glad to see it showing first encouraging results in an effort to enhance CAR-T cells to combat solid tumors".

Session type: poster discussionAbstract Title: Safety and efficacy results of GC027: The first-in-human, universal CAR-T cell therapy for adult relapsed/refractory T-cell acute lymphoblastic leukemia (r/r T-ALL)Abstract ID: 3013Link: https://meetinglibrary.asco.org/record/185068/poster

Session type: posterAbstract Title: Phase I study of CRISPR-engineered CAR-T cells with PD-1 inactivation in treating mesothelin-positive solid tumorsAbstract ID: 3038Link:https://meetinglibrary.asco.org/record/189057/poster

About TruUCAR

TruUCAR is Gracell's proprietary and patented platform technology, with selected genes being edited to avoid GvHD and immune rejection without using strong immunosuppressive drugs. In addition to T-ALL antigen, the platform technology can also be implemented for other targets of hematological malignancies.

About GC027

GC027is an investigational, off-the-shelf CAR-T cell therapy, redirected to CD7 for the treatment of T cell malignancies. GC027 was manufactured from T cells of human leukocyte antigen (HLA) unmatched healthy donors using TruUCAR technology, which is expected to improve efficacy and reduce production time, available for off-the-shelf use in a timely manner.

About EnhancedCAR

EnhancedCAR is Gracell's proprietary and patented platform technology, with selected genes edited to enhance immune cell performance in terms of killing efficiency, in vivo persistence, including selected PD-1 and TCR mediations. The technology can be implemented to many other targets with high editing precision and efficiency.

About GC008t

GC008t is an investigational, autologous CAR-T cell therapy, redirected to mesothelin with PD-1 disruption for the treatment of mesothelin-positive solid tumors. With PD-1 knocking out, GC008t is expected improve persistence and clinical efficacy.

About T-ALL

T - Lymphoblastic Leukemia (T-ALL) is an aggressive form of acute lymphoblastic leukemia, with a diffuse invasion of bone marrow and peripheral blood. In 2015, T-ALL affected around 876,000 people globally and resulted in 110,000 deaths worldwide. T-ALL compromises about 15%-20% of all children and adult acute lymphoblastic leukemia[1].Current standard of care therapies for T-ALL are chemotherapy and stem cell transplantation. 40-50% of patients will experience relapse within two years following front line therapy with limited treatment options available[2][3]. Treatment of relapsed and refractory T-ALL remains a high unmet medical need.

About Mesothelin-positive Solid Tumors

Mesothelin, a cell surface antigen, has high expression to a broad spectrum of solid tumors while express low levels on normal cells. Mesothelin is believed as a good target for multiple solid tumors. The GC008t study enrolled patients with advanced solid tumors, including pancreatic cancer, ovarian cancer, and colorectal cancer, of which clinical outcome of standard of care remains poor.

About Gracell

Gracell Biotechnologies Co., Ltd. ("Gracell") is a clinical-stage biotech company, committed to developing highly reliable and affordable cell gene therapies for cancer. Gracell is dedicated to resolving the remaining challenges in CAR-T, such as high production costs, lengthy manufacturing process, lack of off-the-shelf products, and inefficacy against solid tumors. Led by a group of world-class scientists, Gracell is advancing FasTCAR, TruUCAR (off-the-shelf CAR), DualCAR and EnhancedCAR-T cell therapies for leukemia, lymphoma, myeloma, and solid tumors.

[1]Pediatric hematologic Malignancies: T-cell acute lymphoblastic Leukemia, Hematology 2016

[2]Progress and innovations in the management JAMA Oncol 2018

[3]Defining the course and prognosis of adults with acute lymphoblastic leukemia, Cancer 2010

SOURCE Gracell

http://www.gracellbio.com

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Gracell Announces Two Presentations at the Annual Meeting of American Society of Clinical Oncology (ASCO) - PRNewswire

Bone Marrow Stem Cells Comments Off on Gracell Announces Two Presentations at the Annual Meeting of American Society of Clinical Oncology (ASCO) – PRNewswire | May 30th, 2020

Acute lung injury (ALI) is a devastating disease process involving pulmonary edema and atelectasis caused by capillary membrane injury [1]. The main clinical manifestation is the acute onset of hypoxic respiratory failure, which can subsequently trigger a cascade of serious complications and even death [2]. Thus, ALI causes a considerable financial burden for health care systems throughout the world. ALI can result from various causes, including multiple traumas, large-volume blood transfusions, and bacterial and viral infections [2, 3]. A variety of viruses, including influenza virus, coronavirus (CoV), adenovirus, cytomegalovirus (CMV), and respiratory syncytial virus (RSV), are associated with ALI [4]. Importantly, most viruses, whose hosts are various animal species, can cause severe and rapidly spreading human infections. In the early 2000s, several outbreaks of influenza virus and CoV emerged, causing human respiratory and intestinal diseases worldwide, including the more recent SARS-CoV-2 infection [5,6,7]. To date, SARS-CoV-2 has affected more than 80,000 people, causing nearly 3300 deaths in China and more than 1,800,000 people, causing nearly 110,000 deaths all over the world (http://2019ncov.chinacdc.cn/2019-nCoV/).

Infectious respiratory diseases caused by different viruses are associated with similar respiratory symptoms ranging from the common cold to severe acute respiratory syndrome [8]. This makes the clinical distinction between different agents involved in infection very difficult [8, 9]. Currently, the clinical experience mainly includes antibacterial and antiviral drug treatment derived from handling several outbreaks of influenza virus and human CoVs. Numerous agents have been identified to inhibit the entry and/or replication of these viruses in cell culture or animal models [10]. Although these antiviral drugs can effectively prevent and eliminate the virus, the full recovery from pneumonia and ALI depends on the resistance of the patient. Recently, stem cell-based therapy has become a potential approved tool for the treatment of virus-induced lung injury [11,12,13]. Here, we will give a brief overview of influenza virus and CoVs and then present the cell-based therapeutic options for lung injury caused by different kinds of viruses.

Influenza virus and human CoV are the two most threatening viruses for infectious lung injury [14]. These pathogens can be transmitted through direct or indirect physical contact, droplets, or aerosols, with increasing evidence suggesting that airborne transmission, including via droplets or aerosols, enhances the efficiency of viral transmission among humans and causes uncontrolled infectious disease [15]. Throughout human history, outbreaks and occasional pandemics caused by influenza virus and CoV have led to approximately hundreds of millions of deaths worldwide [16].

Influenza virus is a well-known human pathogen that has a negative-sense RNA genome [17]. According to its distinct antigenic properties, the influenza virus can be divided into 4 subtypes, types A, B, C, and D. Influenza A virus (IAV) lineages in animal populations cause economically important respiratory disease. Little is known about the other human influenza virus types B, C, and D [18]. Further subtypes are characterized by the genetic and antigenic properties of the hemagglutinin (HA) and neuraminidase (NA) glycoproteins [19]. Sporadic and seasonal infections in swine with avian influenza viruses of various subtypes have been reported. The most recent human pandemic virusesH1N1 from swine and H5N1 from aviancause severe respiratory tract disease and lung injury in humans [20, 21].

CoVs, a large family of single-stranded RNA viruses, typically affect the respiratory tract of mammals, including humans. CoVs are further divided into four genera: alpha-, beta-, gamma-, and delta-CoVs. Alpha- and beta-CoVs can infect mammals, and gamma- and delta-CoVs tend to infect birds, but some of these viruses can also be transmitted to mammals [22]. Human CoVs were considered relatively harmless respiratory pathogens in the past. Infections with the human CoV strains 229E, OC43, NL63, and HKU1 usually result in mild respiratory illness, such as the common cold [23]. In contrast, the CoV responsible for the 2002 severe acute respiratory syndrome (SARS-CoV), the 2012 Middle East respiratory syndrome CoV (MERS-CoV), and, more recently, the SARS-CoV-2 have received global attention owing to their genetic variation and rapid spread in human populations [5,6,7].

Usually, the influenza virus can enter the columnar epithelial cells of the respiratory tract, such as the trachea, bronchi, and bronchioles. Subsequently, the influenza virus begins to replicate for an asymptomatic period of time and then migrate to the lung tissue to cause acute lung and respiratory injury [24]. Similar to those with influenza virus infection, patients with SARS, MERS, or SARS-CoV-2 present with various clinical features, ranging from asymptomatic or mild respiratory illness to severe ALI, even with multiple organ failure [5,6,7]. The pathogenesis of ALI caused by influenza virus and human CoV is often associated with rapid viral replication, marked inflammatory cell infiltration, and elevated proinflammatory cytokine/chemokine responses [25]. Interestingly, in IAV- and human CoV-infected individuals, the pulmonary pathology always involves diffuse alveolar damage, but viral RNA is present in only a subset of patients [26]. Some studies suggest that an overly exaggerated immune response, rather than uncontrolled viral spread, is the primary cause in fatal cases caused by virus infection [27]. Several immune cell types have been found to contribute to damaging host responses, providing novel approaches for therapeutic intervention [28].

IAV infection, the most common cause of viral pneumonia, causes substantial seasonal and pandemic morbidity and mortality [29]. Currently, antiviral drugs are the primary treatment strategy for influenza-induced pneumonia. However, antiviral drugs cannot repair damaged lung cells. Here, we summarize the present studies of stem cell therapy for influenza virus-induced lung injury.

Mesenchymal stem/stromal cells (MSCs) constitute a heterogeneous subset of stromal regenerative cells that can be harvested from several adult tissue types, including bone marrow, umbilical cord, adipose, and endometrium [30]. They retain the expression of the markers CD29, CD73, CD90, and CD105 and have a rapid proliferation rate, low immunogenicity, and low tumorigenicity [30]. MSCs also have self-renewal and multidifferentiation capabilities and exert immunomodulatory and tissue repair effects by secreting trophic factors, cytokines, and chemokines [31]. Due to these beneficial biological properties, MSCs and their derivatives are attractive as cellular therapies for various inflammatory diseases, including virus-induced lung injury.

Several studies on IAV-infected animal models have shown the beneficial effects of the administration of different tissue-derived MSCs [32,33,34,35]. H5N1 virus infection reduces alveolar fluid clearance (AFC) and enhances alveolar protein permeability (APP) in human alveolar epithelial cells, which can be inhibited by coculture with human bone marrow-derived MSCs (BMSCs) [32]. Mechanistically, this process can be mediated by human BMSC secreted angiopoietin-1 (Ang1) and keratinocyte growth factor (KGF) [32]. Moreover, in vivo experiments have shown that human BMSCs have a significant anti-inflammatory effect by increasing the number of M2 macrophages and releasing various cytokines and chemokines, such as interleukin (IL)-1, IL-4, IL-6, IL-8, and IL-17 [32]. Similar anti-inflammatory effects have been achieved in another virus-induced lung injury model. The intravenous injection of mouse BMSCs into H9N2 virus-infected mice significantly attenuates H9N2 virus-induced pulmonary inflammation by reducing chemokine (GM-CSF, MCP-1, KC, MIP-1, and MIG) and proinflammatory cytokine (IL-1, IL-6, TNF-, and IFN-) levels, as well as reducing inflammatory cell recruitment into the lungs [33]. Another study on human BMSCs cocultured with CD8+ T cells showed that MSCs inhibit the proliferation of virus-specific CD8+ T cells and the release of IFN- by specific CD8+ T cells [36].

In addition, human umbilical cord-derived MSCs (UC-MSCs) were found to have a similar effect as BMSCs on AFC, APP, and inflammation by secreting growth factors, including Ang1 and hepatocyte growth factor (HGF), in an in vitro lung injury model induced by H5N1 virus [34]. UC-MSCs also promote lung injury mouse survival, increase the body weight, and decreased the APP levels and inflammation in vivo [34]. Unlike Ang1, KGF, and HGF mentioned above, basic fibroblast growth factor 2 (FGF2) plays an important role in lung injury therapy via immunoregulation. The administration of the recombinant FGF2 protein improves H1N1-induced mouse lung injury and promotes the survival of infected mice by recruiting and activating neutrophils via the FGFR2-PI3K-AKT-NFB signaling pathway [37]. FGF2-overexpressing MSCs have an enhanced therapeutic effect on lipopolysaccharide-induced ALI, as assessed by the proinflammatory factor level, neutrophil quantity, and histopathological index of the lung [38].

MSCs secrete various soluble factors and extracellular vesicles (EVs), which carry lipids, proteins, DNA, mRNA, microRNAs, small RNAs, and organelles. These biologically active components can be transferred to recipient cells to exert anti-inflammatory, antiapoptotic, and tissue regeneration functions [39]. EVs isolated from conditioned medium of pig BMSCs have been demonstrated to have anti-apoptosis, anti-inflammation, and antiviral replication functions in H1N1-affected lung epithelial cells and alleviate H1N1-induced lung injury in pigs [35]. Moreover, the preincubation of EVs with RNase abrogates their anti-influenza activity, suggesting that the anti-influenza activity of EVs is due to the transfer of RNAs from EVs to epithelial cells [35]. Exosomes are a subset of EVs that are 50200nm in diameter and positive for CD63 and CD81 [40]. Exosomes isolated from the conditioned medium of UC-MSCs restore the impaired AFC and decreased APP in alveolar epithelial cells affected by H5N1 virus [34]. In addition, the ability of UC-MSCs to increase AFC is superior to that of exosomes, which indicates that other components secreted by UC-MSCs have synergistic effects with exosomes [34].

Despite accumulating evidence demonstrating the therapeutic effects of MSC administration in various preclinical models of lung injury, some studies have shown contrasting results. Darwish and colleagues proved that neither the prophylactic nor therapeutic administration of murine or human BMSCs could decrease pulmonary inflammation or prevent the progression of ALI in H1N1 virus-infected mice [41]. In addition, combining MSC administration with the antiviral agent oseltamivir was also found to be ineffective [41]. Similar negative results were obtained in another preclinical study. Murine or human BMSCs were administered intravenously to H1N1-induced ARDS mice [42]. Although murine BMSCs prevented influenza-induced thrombocytosis and caused a modest reduction in lung viral load, murine or human BMSCs failed to improve influenza-mediated lung injury as assessed by weight loss, the lung water content, and bronchoalveolar lavage inflammation and histology, which is consistent with Darwishs findings [42]. However, the mild reduction in viral load observed in response to murine BMSC treatment suggests that, on balance, MSCs are mildly immunostimulatory in this model [42]. Although there are some controversial incidents in preclinical research, the transplant of menstrual-blood-derived MSCs into patients with H7N9-induced ARDS was conducted at a single center through an open-label clinical trial (http://www.chictr.org.cn/). MSC transplantation significantly lowered the mortality and did not result in harmful effects in the bodies of the patients [43]. This clinic study suggests that MSCs significantly improve the survival rate of influenza virus-induced lung injury.

The effects of exogenous MSCs are exerted through their isolation and injection into test animals. There are also some stem/progenitor cells that can be activated to proliferate when various tissues are injured. Basal cells (BCs), distributed throughout the pseudostratified epithelium from the trachea to the bronchioles, are a class of multipotent tissue-specific stem cells from various organs, including the skin, esophagus, and olfactory and airway epithelia [44, 45]. Previously, TPR63+/KRT5+ BCs were shown to self-renew and divide into club cells and ciliated cells to maintain the pseudostratified epithelium of proximal airways [46]. Several studies have shown that TPR63+/KRT5+ BCs play a key role in lung repair and regeneration after influenza virus infection. When animals typically recover from H1N1 influenza infection, TPR63+/KRT5+ BCs accumulate robustly in the lung parenchyma and initiate an injury repair process to maintain normal lung function by differentiating into mature epithelium [47]. Lineage-negative epithelial stem/progenitor (LNEP) cells, present in the normal distal lung, can activate a TPR63+/KRT5+ remodeling program through Notch signaling after H1N1 influenza infection [48]. Moreover, a population of SOX2+/SCGB1A/KRT5 progenitor cells can generate nascent KRT5+ cells as an early response to airway injury upon H1N1 influenza virus infection [49]. In addition, a rare p63+Krt5 progenitor cell population also responds to H1N1 virus-induced severe injury [50]. This evidence suggests that these endogenous lung stem/progenitor cells (LSCs) play a critical role in the repopulation of damaged lung tissue following severe influenza virus infection (Table2).

Taken together, the present in vitro (Table1) and in vivo (Table2) results show that MSCs and LSCs are potential cell sources to treat influenza virus-induced lung injury.

Lung injury caused by SARS, MERS, or SARS-CoV-2 poses major clinical management challenges because there is no specific treatment that has been proven to be effective for each infection. Currently, virus- and host-based therapies are the main methods of treatment for spreading CoV infections. Virus- and host-based therapies include monoclonal antibodies and antiviral drugs that target the key proteins and pathways that mediate viral entry and replication [51].The major challenges in the clinical development of novel drugs include a limited number of suitable animal models for SARS-CoV, MERS-CoV, and SARS-CoV-2 infections and the current absence of new SARS and MERS cases [51]. Although the number of cases of SARS-CoV-2-induced pneumonia patients is continuously increasing, antibiotic and antiviral drugs are the primary methods to treat SARS-CoV-2-infected patients. Similar to that of IAV, human CoV-mediated damage to the respiratory epithelium results from both intrinsic viral pathogenicity and a robust host immune response. The excessive immune response contributes to viral clearance and can also worsen the severity of lung injury, including the demise of lung cells [52]. However, the present treatment approaches have a limited effect on lung inflammation and regeneration.

Stem cell therapy for influenza virus-induced lung injury shows promise in preclinical models. Although it is difficult to establish preclinical models of CoV-induced lung injury, we consider stem cell therapies to be effective approaches to improve human CoV-induced lung injury. Acute inflammatory responses are one of the major underlying mechanisms for virus-induced lung injury. Innate immune cells, including neutrophils and inflammatory monocytes-macrophages (IMMs), are major innate leukocyte subsets that protect against viral lung infections [53]. Both neutrophils and IMMs are rapidly recruited to the site of infection and play crucial roles in the host defense against viruses. Neutrophils and IMMs can activate Toll-like receptors (TLRs) and produce interferons (IFNs) and other cytokines/chemokines [54]. There are two functional effects produced by the recruitment of neutrophils and IMMs: the orchestration of effective adaptive T cell responses and the secretion of inflammatory cytokines/chemokines [55]. However, excessive inflammatory cytokine and chemokine secretion impairs antiviral T cell responses, leading to ineffective viral clearance and reduced survival [56].

MSCs are known to suppress both innate and adaptive immune responses. MSCs have been suggested to inhibit many kinds of immune cells, including T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells in vitro and in vivo [57] (Fig.1). Several molecules, including IL-1, TNF-, and INF-, most of which are produced by inflammatory cells, are reported to be involved in MSC-mediated immunosuppression [58]. Furthermore, MSCs can produce numerous immunosuppressive molecules, such as IL-6, PGE2, IDO, and IL-10, in response to inflammatory stimuli. PGE2 has been reported to mediate the MSC-mediated suppression of T cells, NK cells, and macrophages. Moreover, PGE2 has been found to act with IDO to alter the proliferation of T cells and NK cells [59]. In contrast, MSCs have come to be recognized as one type of adult stem cell actively participating in tissue repair by closely interacting with inflammatory cells and various other cell types [60]. Numerous reports have demonstrated that MSCs can release an array of growth and inhibitory factors, such as EGF, FGF, PDGF, and VEGF, and express several leukocyte chemokines, such as CXCL9, CCL2, CXCL10, and CXCL11. These factors provide an important microenvironment to activate adaptive immunity for lung repair [61]. Thus, the dual functions of MSCs may improve lung recovery after human CoV-induced ALI. Recently, MSCs was transplanted intravenously to enrolled patients with COVID-19 pneumonia. After treatment, the pulmonary function and symptoms of these patients were significantly improved. Meanwhile, the peripheral lymphocytes were increased, the C-reactive protein decreased, the level of TNF- was significantly decreased, and the overactivated cytokine-secreting immune cells disappeared. In addition, a group of regulatory DC cell population dramatically increased. Thus, the intravenous transplantation of MSCs was effective for treatment in patients with COVID-19 pneumonia [62, 63].

Stem cell therapies for treatment of influenza virus and coronavirus-induced lung injury. CoVs, coronavirus; MSCs, mesenchymal stem/stromal cells; LSCs, lung stem/progenitor cells; NK cells, natural killer cells; DC cells, dendritic cells

In addition, endogenous LSCs also play an important role in lung cell reconstitution after virus-induced ALI. In particular, TPR63+/KRT5+ airway BCs comprise approximately equal numbers of stem cells and committed precursors and give rise to differentiated luminal cells during steady state and epithelial repair after lung injury [44, 64]. Research has shown that KRT5+ cells repopulate damaged alveolar parenchyma following influenza virus infection [47]. However, there is still little evidence for the role of altered TPR63+/KRT5+ stem cells during lung injury repair caused by human CoVs.

In summary, exogenous MSCs may modulate human CoV-induced lung injury repair and regeneration through their immunoregulatory properties. These cells are capable of interacting with various types of immune cell, including neutrophils, macrophages, T cells, B cells, NK cells, and DCs. Furthermore, viral infections can activate endogenous LSCs to produce new lung cells and maintain lung function (Fig.1). Thus, we propose that MSCs and LSCs are two potential cell sources for treating human CoV-induced lung injury.

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Skin Stem Cells Comments Off on Stem cell therapy: a potential approach for treatment of influenza virus and coronavirus-induced acute lung injury – BMC Blogs Network | May 30th, 2020

Introducing the best in mens grooming for the year. The fourth and final segment in this series is a compilation of trusted head-to-toe treatment services every gentleman should indulge in to look and feel your best.Sometimes its better to leave things to an experts hands.

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Treatment: The Ultimate Shave Experience, Truefitt + Hill

We found out why people say its better to leave things to the experts. At this salon, the barber put us through an aromatic hot towel treatment to both soften our facial hair and help us relax. Swift and gentle strokes of the straight razor gave us a close shave, leaving our skin baby smooth and looking dapper fresh. We also appreciate the massage, which made us forget our worries and feel good to be alive.Available at Truefitt + Hill for $80

Treatment: Miracle Stem Cell Treatment, PHS Hairscience

This may not be as effective as a hair transplant, but it is a much less painful alternative to revive dormant hair follicles. The treatment uses the brands potent Miracle Stem Cell Solution, which contains a blend of growth factors, botanical stem cells and nutrients that nourish the scalp and encourage hair growth. DHT blockers neutralise the effects of androgen, the hormonal culprit behind hair loss.Available at PHS Hairscience for $297

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Whether you pick the 60- or 90- minute option, this massage provides soothing relief from the tensions that city life inflicts. Swedish techniques were used to loosen tight knots, and this release of built-up tension left us feeling calmer and more in touch with our senses. The luxurious oils used in the treatment also left our skin feeling moisturised and nourished. Make time to use the baths to reap fuller relaxation benefits.Available at Raffles Hotel from $245

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AUGUSTMAN Grooming Awards 2020 Part IV: Best Head-To-Toe Treatment Services For Gentlemen - AUGUSTMAN

Skin Stem Cells Comments Off on AUGUSTMAN Grooming Awards 2020 Part IV: Best Head-To-Toe Treatment Services For Gentlemen – AUGUSTMAN | May 30th, 2020

According to the latest research report by Global Market Insights, Inc., minoxidil market size is projected to surpass US$ 1 billion by 2024.

Frontrunners in the Minoxidil industry:

Nanz Med Science Pharma Private Limited, Bakul Group of companies, Kumar Organic Products Limited, Changzhou Tianhua Pharmaceutical Co. Ltd., Par Pharmaceuticals, Provizer Pharma, Metapharmaceutical Ind. S.L., Pharhome International Limited, LOY Pharma Lab, Inc., Maruti Futuristic Pharma Pvt. Ltd., Dr. R. Pfleger Chemical Factory GmbH, Renata Limited, McNeil Consumer Healthcare

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2% product segment is likely to provide a positive impetus to the industry forecast as it is believed to bolster effectiveness and enhance quality of hair growth. Apparently, 2% formulation triggers the hair growth via dermal papilla and epithelial cells. Given it seemingly has minimal side effects to the skin, the product is said to be apt for patients with sensitive skin.

2% solution tends to reduce baldness at the receding hairline and at the front as the product offsets hair thinning and boosts hair growth. Prominently, soaring adoption of topical supplementation to improve hair density is expected to spur demand for 2% solution.

5% product is also expected to impel minoxidil market size as demand for high dosage medicines with minimal side effects continues to rise unabated. 5% solution is said to be highly efficacious in hair growth, thereby spurring growth of adipose-derived stem cells (ASCs) and reducing hair thinning. Stakeholders are increasingly being involved in product development to negate irritation and burning sensation.

According to the American Hair Loss Association, more than 80% of men suffer from hair loss by the age of 50. Strikingly, 40% of the 21 million women who are inflicted with hair loss problems opt for active treatments. As it pans out, North America minoxidil market size is expected to expand substantially. Prevalence of oral medication and skepticism towards surgical procedures are anticipated to bolster North America minoxidil market share.

Growth Drivers:

Pitfalls & Challenges:

Make an inquiry for purchasing this report @ https://www.gminsights.com/inquiry-before-buying/750

Geographies covered:

U.S., Canada, Germany, UK, France, Italy, Spain, Russia, Poland, China, India, Japan, South Korea, Indonesia, Thailand, Malaysia, Australia, Brazil, Mexico, Argentina, Saudi Arabia, UAE, South Africa

Stakeholders will continue to invest in APAC minoxidil market as number of people with thin hair line problem has soared drastically in the region. According to reports from United Nations Economic & Social Commission for Asia and the Pacific (ESCAP) in North & Central Asia, population ratio aged 60 or above will rise to 24% by 2050up 8% from 2016. As regions such as APAC and Europe witness an uptick in middle-age population, minoxidil market value will rise significantly in the next half a decade.

New product roll outs and mergers & acquisitions are expected to grab headlines among leading companies such as Renata Ltd., Kumar Organic Products, McNeil PPC, Par Pharmaceuticals, and Dr. R.P Fletcher Chemical Factory, among others. For instance, Kumar Organic Products Ltd. inaugurated a new office in Switzerland in February 2018 to expand market footprints.

Browse Related News, May You Also Like:

https://www.openpr.com/news/2008806/what-s-driving-the-bitumen-market-size-leading-players-exxon

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Minoxidil Market will witness over 100 million units demand by 2024 - Cole of Duty

Skin Stem Cells Comments Off on Minoxidil Market will witness over 100 million units demand by 2024 – Cole of Duty | May 30th, 2020

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...

Skin Stem Cells Comments Off on KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) Combination Demonstrated Clinically Meaningful Tumor Response Rates in Unresectable Hepatocellular… | May 30th, 2020

For many years, the standard of care for the first-line treatment of patients with MSI-H colorectal cancer has been the combination of mFOLFOX6 plus bevacizumab. This is the first time a single-agent, anti-PD-1 therapy demonstrated a superior, statistically significant and clinically meaningful improvement in progression-free survival compared to chemotherapy for these patients, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. There is an unmet need for new treatment options in the first-line setting that may provide sustained, long-term improvements in outcomes for patients with MSI-H colorectal cancer. We are grateful to have the opportunity to present these practice-changing findings at the plenary session of this years ASCO.

KEYTRUDA monotherapy significantly reduced the risk of disease progression or death by 40% versus standard of care chemotherapy, with fewer treatment-related adverse events observed, in patients with MSI-H metastatic colorectal cancer. KEYTRUDA also demonstrated a long-term, durable response that lasted over two years for those who responded to treatment, said Thierry Andre, MD, professor of medical oncology, Sorbonne University, and Head of the Medical Oncology Department in St. Antoine Hospital, Assistance Publique Hpitaux de Paris. Data from KEYNOTE-177 show that KEYTRUDA monotherapy has the potential to become the new standard of care for first-line treatment of patients with MSI-H metastatic colorectal cancer.

In May 2017, KEYTRUDA became the first cancer therapy approved by the U.S. Food and Drug Administration for use based on a biomarker, regardless of tumor type, in previously treated patients with MSI-H or dMMR solid tumors.

As announced, more than 80 abstracts in nearly 20 types of solid tumors and blood cancers will be presented from Mercks broad oncology portfolio and investigational pipeline at ASCO. A compendium of presentations and posters of Merck-led studies will be posted by Merck on Friday, May 29 at 8 a.m. ET. Follow Merck on Twitter via @Merck and keep up to date with ASCO news and updates by using the hashtag #ASCO20.

KEYNOTE-177 Study Design and Additional Data (Abstract #LBA4)

KEYNOTE-177 is a randomized, open-label, Phase 3 trial evaluating KEYTRUDA monotherapy versus standard of care chemotherapy for the first-line treatment of patients with MSI-H or dMMR metastatic colorectal cancer (ClinicalTrials.gov, NCT02563002). The dual primary endpoints are PFS and OS. The study enrolled 307 patients, who were randomized to receive either KEYTRUDA (200 mg intravenously on Day 1 of each three-week cycle for up to 35 cycles) or investigators choice of one of the following chemotherapy-based regimens: mFOLFOX6; mFOLFOX6 plus bevacizumab (5 mg/kg IV on Day 1 of each two-week cycle); mFOLFOX6 plus cetuximab (400 mg/m2 IV, then 250 mg/m2 weekly in each two-week cycle); FOLFIRI; FOLFIRI plus bevacizumab (5 mg/kg IV on Day 1 of each two-week cycle); or FOLFIRI plus cetuximab (400 mg/m2 IV, then 250 mg/m2 weekly in each two-week cycle).

In this study, KEYTRUDA demonstrated a statistically significant and clinically meaningful improvement in PFS (HR=0.60 [95% CI, 0.45-0.80; p=0.0002]) and showed a median PFS of 16.5 months compared with 8.2 months for patients treated with chemotherapy. The two-year PFS rate was 48% with KEYTRUDA versus 19% with chemotherapy. The ORR was 43.8% with KEYTRUDA versus 33.1% with chemotherapy, with a complete response observed in 11.1% and 3.9% of patients, respectively; partial responses were observed in 32.7% and 29.2% of patients, respectively. Median duration of response was not reached with KEYTRUDA (range, 2.3+ to 41.4+) versus 10.6 months with chemotherapy (range, 2.8 to 37.5+). Additionally, 83% of patients had durable responses lasting at least two years with KEYTRUDA versus 35% with chemotherapy. In the study, 59% of patients in the intent-to-treat population received subsequent anti-PD-1/PD-L1 therapy after discontinuing study treatment in the chemotherapy arm.

The safety profile of KEYTRUDA demonstrated a lower incidence of Grade 3 treatment-related adverse events (AEs) versus chemotherapy (22% versus 66%, respectively), and no new toxicities were observed. Immune-mediated AEs and infusion reactions occurred in 31% of patients receiving KEYTRUDA and 13% of patients receiving chemotherapy. The most commonly reported immune-mediated AEswere hypothyroidism (12%) and colitis (7%) with KEYTRUDA, and infusion reactions (8%) with chemotherapy.

Merck Investor Event

Merck will hold a virtual investor event in conjunction with the ASCO Annual Meeting on Tuesday, June 2 at 2 p.m. ET. Details will be provided at a date closer to the event at http://investors.merck.com/home/default.aspx.

About Microsatellite Instability High (MSI-H)

Microsatellite instability (or MSI) is defined by the National Cancer Institute as a change that occurs in the DNA of certain cells (such as tumor cells) in which the number of repeats of microsatellites (short, repeated sequences of DNA) is different from the number of repeats that was in the DNA when it was inherited. The cause of MSI may be a defect in the ability to repair mistakes made when DNA is copied in the cell. This defect is also referred to as mismatch repair deficiency (dMMR). It is estimated that approximately 5-15% of colorectal cancer patients have tumors that score as either MSI-H or dMMR when testing is performed.

About Colorectal Cancer

Colorectal cancer starts in the colon or the rectum, and these cancers are referred to as colon cancer and rectal cancer depending on where the cancer starts. Colorectal cancer often begins with growths on the inner lining of the colon or rectum called polyps, which can change into cancer over time. Colorectal cancer is the third most commonly diagnosed cancer and the second most common cause of cancer-related death worldwide. It is estimated there were nearly 850,000 new cases of colorectal cancer and more than 880,000 deaths from the disease globally in 2018. In the United States, it is estimated there will be nearly 105,000 new cases of colon cancer and more than 43,000 new cases of rectal cancer, resulting in more than 53,000 deaths from colorectal cancer in 2020. The five-year survival rates for advanced/metastatic colon cancer and rectal cancer (stage IV) are estimated to be 14% and 15%, respectively.

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).

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

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

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

Immune-Mediated Colitis

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

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

Immune-Mediated Hepatitis

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

Hepatotoxicity in Combination With Axitinib

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

Immune-Mediated Endocrinopathies

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

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

Immune-Mediated Nephritis and Renal Dysfunction

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

Immune-Mediated Skin Reactions

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

Other Immune-Mediated Adverse Reactions

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

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

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

Infusion-Related Reactions

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

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

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

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

Increased Mortality in Patients With Multiple Myeloma

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

Embryofetal Toxicity

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

Adverse Reactions

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

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

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

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

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

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

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

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

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

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

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

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

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

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Cardiac Stem Cells Comments Off on Merck’s KEYTRUDA (pembrolizumab) Superior to Standard of Care Chemotherapy in Patients with MSI-H Colorectal Cancer – BioSpace | May 30th, 2020

ORLANDO, Fla.--(BUSINESS WIRE)--Hesperos Inc., pioneers of the Human-on-a-Chip in vitro system, today announced a new peer-reviewed publication that describes how the companys functional Human-on-a-Chip system can be used as a drug discovery platform to identify therapeutic interventions targeting the preclinical stages of Alzheimers disease (AD) and mild cognitive impairment (MCI). The manuscript, titled A human induced pluripotent stem cell-derived cortical neuron human-on-a-chip system to study A42 and tau-induced pathophysiological effects on long-term potentiation, was published this week in Alzheimer's & Dementia: Translational Research & Clinical Interventions. The work was conducted in collaboration with the University of Central Florida and with David G. Morgan, Ph.D., Professor of Translational Neuroscience at Michigan State University, and expert in AD pathology.

To date, more than 100 potential therapeutics in development for AD have been abandoned or failed during clinical trials. These therapeutics relied on research conducted in preclinical animal studies, which often are unable to accurately capture the full spectrum of the human disease phenotype, including differences in drug metabolism and excretion between humans and animals. Therefore, there is a need for human models, especially those that accurately recapitulate the functional impairments during the preclinical phases of AD and MCI.

Hesperos offers a breakthrough technology that provides a human cell-based assay based on cognitive function metrics to evaluate drugs designed to restore cognition at early stages of the Alzheimers continuum, said Dr. Morgan. This system can serve as a novel drug discovery platform to identify compounds that rescue or alleviate the initial neuronal deficits caused by A1-42 and/or tau oligomers, which is a main focus of clinical trials.

In 2018, Hesperos received a Phase I Small Business Innovation Research (SBIR) grant from the National Institute on Aging (NIA) division within the US National Institutes of Health (NIH) to help create a new multi-organ human-on-a-chip model for testing AD drugs. Research conducted under this grant included a study to assess therapeutic interventions based on functional changes in neurons, not neuronal death.

In the recent Alzheimer's & Dementia publication, Hesperos describes its in vitro human induced pluripotent stem cell (iPSC)-derived cortical neuron human-on-a-chip system for the evaluation of neuron morphology and function after exposure to toxic A and tau oligomers as well as brain extracts from AD transgenic mouse models.

Researchers are now focusing on biomarker development and therapeutic intervention before symptoms arise in AD and MCI, said James Hickman, Ph.D., Chief Scientist at Hesperos and Professor at the University of Central Florida. By studying functional disruption without extensive cell loss, we now have a screening methodology for drugs that could potentially evaluate therapeutic efficacy even before the neurodegeneration in MCI and AD occurs.

The researchers found that compared to controls, treatment with toxic A and tau oligomers or brain extracts on the iPSC cortical neurons significantly impaired information processing as demonstrated by reduction in high-frequency stimulation-induced long-term potentiation (LTP), a process that is thought to underlie memory formation and learning. Additionally, oligomer and brain extract exposure led to dysfunction in iPSC cortical neuron electrophysiological activity, including decreases in ion current and action potential firing.

While exposure to the toxic oligomers and brain extracts caused morphological defects in the iPSC cortical neurons, there was no significant loss in cell viability.

Clinical success for AD therapies has been challenging since preclinical animal studies often do not translate to humans, said Michael L. Shuler, Ph.D., Chief Executive Officer of Hesperos. With our recent study, we are now one step closer in developing an AD multi-organ model to better evaluate drug metabolism in the liver, penetration through the blood-brain barrier and the effects on neuronal cells.

About Alzheimers Disease/Preclinical Stage AD

AD is a progressive disease that is characterized by memory loss and deterioration of cognitive function. Preclinical AD is the first stage of the disease, and it begins long before any symptoms become apparent. It is thought that symptoms do not manifest until there is a significant death of neuronal cells, which is caused by the aggregation of toxic amyloid beta (A) and tau oligomers, typically during the earliest stages of the disease. Unfortunately, treatment after the diagnosis of MCI may be too late to reverse or modify disease progression.

To read the full manuscript, please visit https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.12029.

About Hesperos

Hesperos, Inc. is a leading provider of Human-on-a-Chip microfluidic systems to characterize an individuals biology. 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 to accurately predict in vivo functions without the use of animal models. More information is available at http://www.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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Cardiac Stem Cells Comments Off on Hesperos Human-on-a-Chip System Used to Model Preclinical Stages of Alzheimer’s Disease and Mild Cognitive Impairment – Business Wire | May 30th, 2020

Due to the pandemic, we have included a special section on the Impact of COVID 19 on the progenitor cell productMarket which would mention How the Covid-19 is Affecting the Industry, Market Trends and Potential Opportunities in the COVID-19 Landscape, Key Regions and Proposal for progenitor cell product Market Players to battle Covid-19 Impact.

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progenitor cell product Market Latest trending report is booming globally by Top Leading Players NeuroNova AB, StemCells, ReNeuron Limited, Asterias...

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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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Research at MDI Biological Laboratory explores novel pathways of regeneration and tumorigenesis - Bangor Daily News

Skin Stem Cells Comments Off on Research at MDI Biological Laboratory explores novel pathways of regeneration and tumorigenesis – Bangor Daily News | May 28th, 2020

The bones of the skeletal system serve many important functions for the body, from giving your body support to allowing you to move. They also play an important role in blood cell production and fat storage.

Bone marrow is the spongy or viscous tissue that fills the inside of your bones. There are actually two types of bone marrow:

Read on to learn more about different functions of red and yellow bone marrow as well as the conditions that affect bone marrow.

Red bone marrow is involved in hematopoiesis. This is another name for blood cell production. Hematopoietic stem cells that are found in red bone marrow can develop into a variety of different blood cells, including:

Newly produced blood cells enter your bloodstream through vessels called sinusoids.

As you age, your red bone marrow is gradually replaced with yellow bone marrow. And by adulthood, red bone marrow can be found only in a handful of bones, including the:

Yellow bone marrow is involved in the storage of fats. The fats in yellow bone marrow are stored in cells called adipocytes. This fat can be used as an energy source as needed.

Yellow bone marrow also contains mesenchymal stem cells. These are cells that can develop into bone, fat, cartilage, or muscle cells.

Remember, over time, yellow bone marrow starts to replace red bone marrow. So, most bones in an adult body contain yellow bone marrow.

Bone marrow is crucial for producing blood cells. Therefore, a range of blood-related conditions involve issues with bone marrow.

Many of these conditions affect the numbers of blood cells produced in bone marrow. This causes them to share many common symptoms, including:

Heres a look at some specific conditions involving bone marrow issues.

Leukemia is a type of cancer that can affect both your bone marrow and lymphatic system.

It happens when blood cells get mutations in their DNA. This causes them to grow and divide more rapidly than healthy blood cells. Over time, these cells start to crowd out the healthy cells in your bone marrow.

Leukemia is classified as either acute or chronic, depending on how fast it progresses. Its further broken down by the type of white blood cells it involves.

Myelogenous leukemia involves red blood cells, white blood cells, and platelets. Lymphocytic leukemia involves lymphocytes, a specific type of white blood cell.

Some of the major types of leukemia include:

Theres no clear cause of leukemia, but certain things can increase your risk, including:

Aplastic anemia occurs when bone marrow doesnt produce enough new blood cells. It occurs from damage to the stem cells of bone marrow. This makes it harder from them to grow and develop into new blood cells.

This damage can be either:

Myeloproliferative disorders happen when the stem cells in bone marrow grow abnormally. This can lead to increased numbers of a specific type of blood cell.

There are several types of myeloproliferative disorders, including:

Bone marrow is found in the bones throughout your body. There are two types of bone marrow. Red bone marrow is involved in production of blood cells, while yellow marrow is important for fat storage. As you age, yellow bone marrow replaces red bone marrow.

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Function of Bone Marrow: What Is Bone Marrow, and What ...

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SHANGHAI, May27, 2020 /PRNewswire/ -- Shanghai Cell Therapy Group (SHCell) recently entered intoa six-year research collaborative project with Professor Qi-Long Ying from the University of Southern California (USC). Through the project, sponsored by $3.6 million from the Baize Plan Fund, the Ying laboratory aims to develop conditions for the long-term ex vivo expansion of mouse and human hematopoietic stem and progenitor cells.

"Hematopoietic stem cells, or HSCs, are found in the bone marrow of adults," said Professor Qijun Qian, CEO of Shanghai Cell Therapy Group. "HSCs have the ability for long-term self-renewal and differentiation into various types of mature blood cells, and for rebuilding normal hematopoiesis and immune function in patients. They also have enormous potential to treat diseases, including tumors, autoimmune diseases, severe infectious disease, and inherited blood diseases, and to combat the effects of aging."

This research project will be conducted and supervised by Professor Qi-Long Ying, a Professor of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC. Professor Ying's pioneering stem cell research has won international acclaim, including the 2016 McEwen Award for Innovation, the highest honor in the field.

"We'll develop and optimize culture conditions for the long-term ex vivo expansion of HSCs," said Professor Ying. "We'll also test combinations of basal media, small molecules, cytokines and growth factors, and characterize ex vivo expanded hematopoietic stem and progenitor cells. These cells will then be genetically modified and tested for their potential to treat different diseases, including blood disorders and cancers."

Professor Andrew P. McMahon, Director of Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research of USC, added: "Stem cell biology represents an exciting area in medicine with great therapeutic potential. I am delighted SHCell is supporting Professor Ying. A breakthrough in the ability to propagate and manipulate HSCs will have lasting clinical significance."

The project also plans to build animal models of different blood diseases and cancers and test the safety and effectiveness of genetically modified hematopoietic stem and progenitor cells before clinical translation. SHCell will actively explore clinical applications of hematopoietic stem and progenitor cells in the treatment of cancers or blood diseases.

As SHCell's first overseas collaboration, this project aims to advance the goals of the Baize Plan: to provide first-class cell treatments and cell therapies at an affordable price to cure cancer and increase life expectancy. SHCell hopes that this project will also accelerate original scientific breakthroughs in the stem cell field.

Shanghai Cell Therapy Group

Founded in 2013, Shanghai Cell Therapeutics Group Co., Ltd is located at the Shanghai Municipal Engineering and Technology Research Center, which was established by the Shanghai Science and Technology Commission. With a mission of "changing the length and abundance of life with cell therapy", SHCell has created a closed-loop industrial chain and an integrated platform for cell treatment and cell therapy. It comprises cell storage, cell drug research and cell clinical transformation with cell therapy as its core business.

The Baize Plan was proposed in 2016 by Wu Mengchao, an Academician of the Chinese Academy of Sciences (CAS) and initiated by Professor Qian, aiming to provide first-class cell treatments and cell therapies at an affordable price with the goal of curing cancers and increasing life expectancy. The Baize Plan Fund was created by the Shanghai Cell Therapy Group to realize the vision of the Baize Plan.

University of Southern California (USC)

Founded in 1880, the University of Southern California is one of the world's leading educational and research institutions, and also the oldest private research university in California. Located in the heart of Los Angeles, the University of Southern California comprises 23 schools and units, and students are encouraged to explore different fields of study. The University of Southern California ranked #22 in National Universities in the 2020 edition of Best Colleges, published by U.S. News & World Report.

For more information, visit http://www.shcell.com/

SOURCE Shanghai Cell Therapy Group

http://www.shcell.com

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Shanghai Cell Therapy Group Launches Collaboration with USC researcher to Improve the ex vivo Expansion of Hematopoietic Stem Cells for Clinical...

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She just wanted to be somewhere safe, somewhere familiar, where people looked and spoke like her and she could stand to eat the food. Midnight Robber by Nalo Hopkinson

Midnight Robber (2000) is about a woman, divided. Raised on the high-tech utopian planet of Touissant, Tan-Tan grows up on a planet populated by the descendants of a Caribbean diaspora, where all labor is performed by an all-seeing AI. But when she is exiled to Touissants parallel universe twin planet, the no-tech New Half-Way Tree, with her sexually abusive father, she becomes divided between good and evil Tan-Tans. To make herself and New Half-Way Tree whole, she adopts the persona of the legendary Robber Queen and becomes a legend herself. It is a wondrous blend of science fictional tropes and Caribbean mythology written in a Caribbean vernacular which vividly recalls the history of slavery and imperialism that shaped Touissant and its people, published at a time when diverse voices and perspectives within science fiction were blossoming.

Science fiction has long been dominated by white, Western perspectives. Vernes tech-forward adventures and Wells sociological allegories established two distinctive styles, but still centered on white imperialism and class struggle. Subsequent futures depicted in Verne-like pulp and Golden Age stories, where lone white heroes conquered evil powers or alien planets, mirrored colonialist history and the subjugation of non-white races. The civil rights era saw the incorporation of more Wellsian sociological concerns, and an increase in the number of non-white faces in the future, but they were often tokensparts of a dominant white monoculture. Important figures that presaged modern diversity included Star Treks Lieutenant Uhura, played by Nichelle Nichols. Nichols was the first black woman to play a non-servant character on TV; though her glorified secretary role frustrated Nichols, her presence was a political act, showing there was space for black people in the future.

Another key figure was the musician and poet Sun Ra, who laid the aesthetic foundation for what would become known as the Afrofuturist movement (the term coined by Mark Dery in a 1994 essay), which showed pride in black history and imagined the future through a black cultural lens. Within science fiction, the foundational work of Samuel Delany and Octavia Butler painted realistic futures in which the histories and cultural differences of people of color had a place. Finally, an important modern figure in the decentralization of the dominant Western perspective is Nalo Hopkinson.

A similarly long-standing paradigm lies at the heart of biology, extending back to Darwins theoretical and Mendels practical frameworks for the evolution of genetic traits via natural selection. Our natures werent determined by experience, as Lamarck posited, but by genes. Therefore, genes determine our reproductive fitness, and if we can understand genes, we might take our futures into our own hands to better treat disease and ease human suffering. This theory was tragically over-applied, even by Darwin, who in Descent of Man (1871) conflated culture with biology, assuming the Wests conquest of indigenous cultures meant white people were genetically superior. After the Nazis committed genocide in the name of an all-white future, ideas and practices based in eugenics declined, as biological understanding of genes matured. The Central Dogma of the 60s maintained the idea of a mechanistic meaning of life, as advances in genetic engineering and the age of genomics enabled our greatest understanding yet of how genes and disease work. The last major barrier between us and our transhumanist future therefore involved understanding how genes determine cellular identity, and as well see, key figures in answering that question are stem cells.

***

Hopkinson was born December 20, 1960 in Kingston, Jamaica. Her mother was a library technician and her father wrote, taught, and acted. Growing up, Hopkinson was immersed in the Caribbean literary scene, fed on a steady diet of theater, dance, readings, and visual arts exhibitions. She loved to readfrom folklore, to classical literature, to Kurt Vonnegutand loved science fiction, from Spock and Uhura on Star Trek, to Le Guin, James Tiptree Jr., and Delany. Despite being surrounded by a vibrant writing community, it didnt occur to her to become a writer herself. What they were writing was poetry and mimetic fiction, Hopkinson said, whereas I was reading science fiction and fantasy. It wasnt until I was 16 and stumbled upon an anthology of stories written at the Clarion Science Fiction Workshop that I realized there were places where you could be taught how to write fiction. Growing up, her family moved often, from Jamaica to Guyana to Trinidad and back, but in 1977, they moved to Toronto to get treatment for her fathers chronic kidney disease, and Hopkinson suddenly became a minority, thousands of miles from home.

Development can be described as an orderly alienation. In mammals, zygotes divide and subsets of cells become functionally specialized into, say, neurons or liver cells. Following the discovery of DNA as the genetic material in the 1950s, a question arose: did dividing cells retain all genes from the zygote, or were genes lost as it specialized? British embryologist John Gurdon addressed this question in a series of experiments in the 60s using frogs. Gurdon transplanted nuclei from varyingly differentiated cells into oocytes stripped of their genetic material to see if a new frog was made. He found the more differentiated a cell was, the lower the chance of success, but the successes confirmed that no genetic material was lost. Meanwhile, Canadian biologists Ernest McCulloch and James Till were transplanting bone marrow to treat irradiated mice when they noticed it caused lumps in the mices spleens, and the number of lumps correlated with the cellular dosage. Their lab subsequently demonstrated that each lump was a clonal colony from a single donor cell, and a subset of those cells was self-renewing and could form further colonies of any blood cell type. They had discovered hematopoietic stem cells. In 1981 the first embryonic stem cells (ESCs) from mice were successfully propagated in culture by British biologist Martin Evans, winning him the Nobel Prize in 2007. This breakthrough allowed biologists to alter genes in ESCs, then use Gurdons technique to create transgenic mice with that alteration in every cellcreating the first animal models of disease.

In 1982, one year after Evans discovery, Hopkinson graduated with honors from York University. She worked in the arts, as a library clerk, government culture research officer, and grants officer for the Toronto Arts Council, but wouldnt begin publishing her own fiction until she was 34. [I had been] politicized by feminist and Caribbean literature into valuing writing that spoke of particular cultural experiences of living under colonialism/patriarchy, and also of writing in ones own vernacular speech, Hopkinson said. In other words, I had models for strong fiction, and I knew intimately the body of work to which I would be responding. Then I discovered that Delany was a black man, which opened up a space for me in SF/F that I hadnt known I needed. She sought out more science fiction by black authors and found Butler, Charles Saunders, and Steven Barnes. Then the famous feminist science fiction author and editor Judy Merril offered an evening course in writing science fiction through a Toronto college, Hopkinson said. The course never ran, but it prompted me to write my first adult attempt at a science fiction story. Judy met once with the handful of us she would have accepted into the course and showed us how to run our own writing workshop without her. Hopkinsons dream of attending Clarion came true in 1995, with Delany as an instructor. Her early short stories channeled her love of myth and folklore, and her first book, written in Caribbean dialect, married Caribbean myth to the science fictional trappings of black market organ harvesting. Brown Girl in the Ring (1998) follows a young single mother as shes torn between her ancestral culture and modern life in a post-economic collapse Toronto. It won the Aspect and Locus Awards for Best First Novel, and Hopkinson was awarded the John W. Campbell Award for Best New Writer.

In 1996, Dolly the Sheep was created using Gurdons technique to determine if mammalian cells also could revert to more a more primitive, pluripotent state. Widespread animal cloning attempts soon followed, (something Hopkinson used as a science fictional element in Brown Girl) but it was inefficient, and often produced abnormal animals. Ideas of human cloning captured the public imagination as stem cell research exploded onto the scene. One ready source for human ESC (hESC) materials was from embryos which would otherwise be destroyed following in vitro fertilization (IVF) but the U.S. passed the Dickey-Wicker Amendment prohibited federal funding of research that destroyed such embryos. Nevertheless, in 1998 Wisconsin researcher James Thomson, using private funding, successfully isolated and cultured hESCs. Soon after, researchers around the world figured out how to nudge cells down different lineages, with ideas that transplant rejection and genetic disease would soon become things of the past, sliding neatly into the hole that the failure of genetic engineering techniques had left behind. But another blow to the stem cell research community came in 2001, when President Bushs stem cell ban limited research in the U.S. to nineteen existing cell lines.

In the late 1990s, another piece of technology capturing the public imagination was the internet, which promised to bring the world together in unprecedented ways. One such way was through private listservs, the kind used by writer and academic Alondra Nelson to create a space for students and artists to explore Afrofuturist ideas about technology, space, freedom, culture and art with science fiction at the center. It was wonderful, Hopkinson said. It gave me a place to talk and debate with like-minded people about the conjunction of blackness and science fiction without being shouted down by white men or having to teach Racism 101. Connections create communities, which in turn create movements, and in 1999, Delanys essay, Racism and Science Fiction, prompted a call for more meaningful discussions around race in the SF community. In response, Hopkinson became a co-founder of the Carl Brandon society, which works to increase awareness and representation of people of color in the community.

Hopkinsons second novel, Robber, was a breakthrough success and was nominated for Hugo, Nebula, and Tiptree Awards. She would also release Skin Folk (2001), a collection of stories in which mythical figures of West African and Afro-Caribbean culture walk among us, which would win the World Fantasy Award and was selected as one ofThe New York Times Best Books of the Year. Hopkinson also obtained masters degree in fiction writing (which helped alleviate U.S. border hassles when traveling for speaking engagements) during which she wrote The Salt Roads (2003). I knew it would take a level of research, focus and concentration I was struggling to maintain, Hopkinson said. I figured it would help to have a mentor to coach me through it. That turned out to be James Morrow, and he did so admirably. Roads is a masterful work of slipstream literary fantasy that follows the lives of women scattered through time, bound together by the salt uniting all black life. It was nominated for a Nebula and won the Gaylactic Spectrum Award. Hopkinson also edited anthologies centering around different cultures and perspectives, including Whispers from the Cotton Tree Root: Caribbean Fabulist Fiction (2000), Mojo: Conjure Stories (2003), and So Long, Been Dreaming: Postcolonial Science Fiction & Fantasy (2004). She also came out with the award-winning novelThe New Moons Arms in 2007, in which a peri-menopausal woman in a fictional Caribbean town is confronted by her past and the changes she must make to keep her family in her life.

While the stem cell ban hamstrung hESC work, Gurdons research facilitated yet another scientific breakthrough. Researchers began untangling how gene expression changed as stem cells differentiated, and in 2006, Shinya Yamanaka of Kyoto University reported the successful creation of mouse stem cells from differentiated cells. Using a list of 24 pluripotency-associated genes, Yamanaka systematically tested different gene combinations on terminally differentiated cells. He found four genesthereafter known as Yamanaka factorsthat could turn them into induced-pluripotent stem cells (iPSCs), and he and Gurdon would share a 2012 Nobel prize. In 2009, President Obama lifted restrictions on hESC research, and the first clinical trial involving products made using stem cells happened that year. The first human trials using hESCs to treat spinal injuries happened in 2014, and the first iPSC clinical trials for blindness began this past December.

Hopkinson, too, encountered complications and delays at points in her career. For years, Hopkinson suffered escalating symptoms from fibromyalgia, a chronic disease that runs in her family, which interfered with her writing, causing Hopkinson and her partner to struggle with poverty and homelessness. But in 2011, Hopkinson applied to become a professor of Creative Writing at the University of California, Riverside. It seemed in many ways tailor-made for me, Hopkinson said. They specifically wanted a science fiction writer (unheard of in North American Creative Writing departments); they wanted someone with expertise working with a diverse range of people; they were willing to hire someone without a PhD, if their publications were sufficient; they were offering the security of tenure. She got the job, and thanks to a steady paycheck and the benefits of the mild California climate, she got back to writing. Her YA novel, The Chaos (2012), coming-of-age novelSister Mine (2013), and another short story collection, Falling in Love with Hominids (2015) soon followed. Her recent work includes House of Whispers (2018-present), a series in DC Comics Sandman Universe, the final collected volume of which is due out this June. Hopkinson also received an honorary doctorate in 2016 from Anglia Ruskin University in the U.K., and was Guest of Honor at 2017 Worldcon, a year in which women and people of color dominated the historically white, male ballot.

While the Yamanaka factors meant that iPSCs became a standard lab technique, iPSCs are not identical to hESCs. Fascinatingly, two of these factors act together to maintain the silencing of large swaths of DNA. Back in the 1980s, researchers discovered that some regions of DNA are modified by small methyl groups, which can be passed down through cell division. Different cell types have different DNA methylation patterns, and their distribution is far from random; they accumulate in the promoter regions just upstream of genes where their on/off switches are, and the greater the number of methyl groups, the lesser the genes expression. Furthermore, epigenetic modifications, like methylation, can be laid down by our environments (via diet, or stress) which can also be passed down through generations. Even some diseases, like fibromyalgia, have recently been implicated as such an epigenetic disease. Turns out that the long-standing biological paradigm that rejected Lamarck also missed the bigger picture: Nature is, in fact, intimately informed by nurture and environment.

In the past 150 years, we have seen ideas of community grow and expand as the world became more connected, so that they now encompass the globe. The histories of science fiction and biology are full of stories of pioneers opening new doorsbe they doors of greater representation or greater understanding, or bothand others following. If evolution has taught us anything, its that nature abhors a monoculture, and the universe tends towards diversification; healthy communities are ones which understand that we are not apart from the world, but of it, and that diversity of types, be they cells or perspectives, is a strength.

Kelly Lagor is a scientist by day and a science fiction writer by night. Her work has appeared at Tor.com and other places, and you can find her tweeting about all kinds of nonsense @klagor

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On the Origins of Modern Biology and the Fantastic: Part 19 Nalo Hopkinson and Stem Cell Research - tor.com

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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.

Get Sample Copy of this Report @ Cell Therapy Market Size, Share, Market Research and Industry Forecast Report, 2020-2027 (Includes Business Impact of COVID-19)

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)

Trusted Business InsightsShelly ArnoldMedia & Marketing ExecutiveEmail Me For Any ClarificationsConnect on LinkedInClick to follow Trusted Business Insights LinkedIn for Market Data and Updates.US: +1 646 568 9797UK: +44 330 808 0580

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

Bone Marrow Stem Cells Comments Off on Cell Therapy Market Analysis Of Global Trends, Demand And Competition 2020-2028 – Jewish Life News | May 28th, 2020

Bloodcanceris one of the most common types of cancer that generally affects people of all age groups. According to a report published by WHOs International Agency for Research on Cancer, India has the third-highest number of haematologicalcancers,popularly known as blood cancer. There was a time when cancer was considered an incurable disease, but over the recent years, the situations have changed drastically with the evolution in medical technology. This has made cancer treatments possible with up to 90 per cent survival chances. The World Blood Cancer Day is observed every year on May 28th around the world to show support for blood cancer patients. According to experts, early diagnosis in cancer, especially blood cancer, increases the chance of survival, thanks to evolved treatment modalities of the modern times. Also Read - World Blood Cancer Day 2020: Understanding the types and symptoms

Mostly, heamatological cancers originate in bone marrow, where blood is produced. This condition occurs when faulty blood cells affect the function of the normal ones that fend off infections and generate new cells. There are three types of blood cancers leukaemia, lymphoma and myeloma. In leukaemia, your body develops too many abnormal white blood cells (leukocytes) and makes it tough for your bone marrow to produce red blood cells. Lymphoma occurs when in the lymphocites while myeloma has its origin in the plasma cells of the blood. These are white blood cells produced in your bone marrow. Also Read - Researchers discover role of mutation in blood cancers

The prominent symptoms of blood cancer include chills, fatigue and weakness, night sweats, pain in the bones and joints, and swollen lymph nodes. It takes a toll on your immunity, making you susceptible to various infections and other conditions. Cancer also affects the rate at which your blood clots. So, small cuts or injuries may tend to bleed for a longer period of time. You may also experience unusual bruising, bleeding of the gums, and blood in stool. Women may go through heavy bleeding during their periods. Also Read - Today health tips: 6 lifestyle modifications to bring down your breast cancer risk

Experts are of the opinion that lymphoma in adults is 80-90 per cent curable and acute leukaemia in adults can be 40-50 per cent curable. However, many of the myeloma cases are incurable. The treatment for blood cancer mostly depends on the type of cancer, age of the patient and the severity of the cancer. On the basis of these factors, doctors may suggest chemotherapy, supportive care, stem cell transplantation, etc.

According to the guidelines of the American Oncology Institute, one can decrease the risk of blood can by following certain lifestyle measures. They include exercising regularly, eating healthy, avoiding exposure to herbicides, insecticides and radiations. Here are some simple dietary tips to bring down your chance of falling prey to this condition.

Eat generous amounts of vegetables and fruits, salads, beans and cereals in your diet. This will try increase your immunity.

These acids have anti-cancer properties. The best food sources could be fish, walnuts, soya bean, so on and so forth. You can also opt for fish oil supplements.

An antioxidant known as lycopene is present in tomatoes. It comes with cancer fighting properties. The best way to get lycopene from tomatoes is to heat them well. So, tomato soup can be a good option. You can also have it with other anti-oxidant rich veggies in the form of a salad.

Several studies have associated high intake of olive oil with cancer risk reduction. You can have this oil in your salads or sprinkle it on cooked veggies too. Also, try using olive oil while marinating your meat, fish or poultry.

Published : May 28, 2020 12:30 pm | Updated:May 28, 2020 1:17 pm

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World Blood Cancer Day 2020: Bring down your risk of this condition with easy diet tips - TheHealthSite

Bone Marrow Stem Cells Comments Off on World Blood Cancer Day 2020: Bring down your risk of this condition with easy diet tips – TheHealthSite | May 28th, 2020

United States, California, Irvine 05-27-2020 (PRDistribution.com) Latest Patent Further Strengthens Intellectual Property Portfolio Covering Novel Platform for Precisely ControllingRegenerative Protein Expressions Including Stem Cell Homing and Differentiation Control

Technology Has Key Potential Applications in Regeneration of Failing Heart, Brain, Kidney, Liver, Pancreas, Lungs, Aorta, Vision and Hearing as well as Transcutaneous Uses for Accelerated Wound Healing, Skin, Hair and Penile Function Regeneration (ED)Irvine, California, May 27th, 2020 Leonhardts Launchpads, an innovation and startup launch accelerator focused on developing novel therapeutics that harness the bodys innate mechanisms to regenerate failing organs and to heal tissues, today announced the issuance of a new U.S. patent providing broad protection for the companys first-of-its-kind combination bioelectrics and biologics technology platform, which has multiple potential therapeutic applications in organ regeneration and recovery. Previous stem cell therapies that delivered stem cells alone in a single application failed to regenerate organs fully. Electrical stimulation technologies to date have failed to zero in on and deliver the precise right bioelectric signaling sequences for controlling specific regenerative protein expressions when and where needed. This pioneering technology platform is the first to combine the powerful ability of bioelectric stimulation with repeat deliveries of not just stem cells but a whole host of support factors similar to an egg yolk designed to help cells survive, proliferate, engraft and differentiate with the intention of fully regenerating failing organs. stated primary inventor, Executive Chairman and CEO Howard J. Leonhardt. U.S. Patent 10,646,644 Issued May 12th, 2020 https://patents.justia.com/patent/10646644covers bioelectric stimulation controlled release of SDF1 and PDGF known stem cell homing and proliferation factors as well as use of a re-fillable micro infusion pump for slow infusion of a mixed composition of stem cells, exosomes, micro RNAs, nutrient hydrogel, growth factor cocktail, selected alkaloids and anti-inflammatory agents with the intention of regenerating organs and healing tissues. SDF1 and PDGF highlighted in these new patent claims also have strong capabilities in promoting arteriogenesis (mature blood vessel growth).The Leonhardt team has separately filed or acquired patent claims for bioelectric controlled expression of follistatin, klotho, tropoelastin, VEGF, IGF1, CXCL5, HIF1a, EGF, HGF, OPG, RANKL and COL17A1 all known to have a role in organ healing https://patents.justia.com/patent/20180064935. Separately the Leonhardts Launchpads startup CancerCell has 9 issued U.S. patents https://cancercellinc.com/list-of-the-issued-cancer-patents/ for bioelectric treatment of cancer and dozens of additional cancer treatment related claims pending https://patents.justia.com/patent/20190030330. The team has filed patent clams on the combination of bioelectric stimulation and PRF https://patents.justia.com/patent/20200000709. Other important patent filings have been submitted on bioelectric inflammation management https://patents.justia.com/patent/20190022389 and blood pressure management https://patents.justia.com/patent/20190022396The Leonhardts Launchpads technology platform is based on foundational scientific research that began in the late 1980s working with Dr. Race Kao and Dr. George Magovern Sr. in Pittsburgh when they injected satellite cells (myoblasts or muscle stem cells) to repair damaged heart tissue in dogs and published the results in The Physiologist in 1989. In 1995 Howard Leonhardt filed his first patent for a stem cell and biologics delivery system for organ repair ProCell https://patents.google.com/patent/US5693029A/en based on work that began in 1988. In 1998 the Leonhardt team began collaboration with Dr. Doris Taylor whom that year published a landmark paper in Nature Medicine https://www.nature.com/articles/nm0898-929 on repair of infarcted hearts with myoblast cells. Dr. Taylor currently still serves as co-chair of our Scientific Advisory Board today. In 1999 the Leonhardt team worked with Dr. Shinichi Kanno to publish in Circulation, the Journal of the American Heart Association, pioneering results with bioelectric stimulation driven VEGF protein expression for limb salvage via angiogenesis in animals https://www.ahajournals.org/doi/abs/10.1161/01.cir.99.20.2682 and filed a patent application for the same within a year. Since then the Leonhardt team and LeonhardtsLaunchpads and itsportfolio of startupshas had issued, pending,optioned orlicensed over 600patentclaims for organregeneration andrecovery. In 2001 Howard Leonhardt and Dr. Juan Chachques filed patents on bioelectric stimulation controlled myogenesis and dynamic cardiac support with an early less potent stem cell homing signal. That same year a Leonhardt led team working with Dr. Patrick Serruys completed the landmark first ever case of non-surgical cell based regeneration of a damaged human heart in The Netherlands. Howard Leonhardt began a collaboration at that time with Dr. Jorge Genovese co-inventor of this patent, and BioLeonhardts VP of Bioelectric Regeneration Research, that continues to this day. Over 200 dedicated talented people help Leonhardts Launchpads and its startups advance their developments almost every day see Team https://leonhardtventures.com/team/ and Scientific Advisory Board https://calxstars.com/scientific-advisory-board/.About Leonhardts Launchpads:Leonhardts Launchpads by Cal-X Stars Business Accelerator, Inc. in California, Leonhardts Launchpads Utah, Inc., Leonhardts Launchpads Australia PTY and Leonhardts Launchpads branches in Minneapolis, Pittsburgh and Brazil are the innovation and startup launch accelerator arms of Leonhardt Ventures (Leonhardt Vineyards LLC DBA Leonhardt Ventures). Leonhardt Ventures has been developing breakthrough medtech and biotech innovations since the 1980s. In the 1980s the team patented, developed and commercialized the PolyCath line of cardiovascular balloon catheters. In the 1990s they developed and completed the first non-surgical repair of an aortic aneurysm (Melbourne, Australia 1995) and patented what is still today the leading endovascular stent graft for aortic aneurysm repair. In that time period they also patented one of the first percutaneous heart valve systems. Since 2000 the team has been focused almost exclusively on stem cell, biologics and bioelectric based organ regeneration and healing. In May of 2001 the team completed the landmark first ever non-surgical case of cell therapy for heart damage recovery. In 2008 the team began exploring if what they had learned from research in regenerating hearts could be translated to other organs. The organization now has 30 related startups and organ specific innovations in its 2020 portfolio class https://leonhardtventures.com/development-pipeline/ in these groups (1) Heart & Cardiovascular, (2) Brain, (3) Cosmetic & Reproductive Health, (4) Major Organ Regeneration and (5) Cancer. The accelerator business model is to accelerate each organ specific innovation through first in human studies and then secure a strategic partner to advance the product through commercialization. Click on Leonhardt Ventures and Leonhardts Launchpads 2020 Annual Report for more information https://leonhardtventures.com/wp-content/uploads/2020/04/4_23_2020.pdfand our web site at http://www.leonhardtventures.comSee previous PDGF related press release https://www.biospace.com/article/releases/-b-leonhardt-b-and-b-genovese-b-file-patent-for-bioelectric-controlled-expression-of-pdgf-a-powerful-organ-regeneration-cytokine-/See previous KLOTHO anti-aging related press release https://www.biospace.com/article/leonhardt-s-launchpads-announces-filing-of-patent-for-bioelectric-stimulation-controlled-klotho-expression-powerful-anti-aging-and-regeneration-promoting-protein-/Contact See contact page on web site for contact information for all locations and phone numbers https://leonhardtventures.com/contact/Leonhardts Launchpads[emailprotected]Warning and Disclaimers: Product(s) are not yet proven safe or effective. Patents pending may not be issued. Patents licensed or optioned may not be maintained. Patents issued may be invalidated. Products are in early stage development. Forward looking statements may change without notice. As an investment these startups mentioned are in the highest risk category for total loss and only suitable for sophisticated experienced accredited investors. The company does not have on hand sufficient resources to bring these products through clinical studies and may not obtain these resources. The company is under staffed and under funded compared to most other participants in this space. Due to a small staff at the accelerator to maintain all web sites and other published materials they may not be fully up to date and there may be out date inaccurate information. If you have any questions on our products or our company please write us to ask.Leonhardts Launchpads by Cal-X Stars,18575 Jamboree Rd #6, Irvine, CA 92612Leonhardts Launchpads Utah, Inc.Research Lab @ 2500 S State St. #D249, Salt Lake City, UT 84115

Media Contacts:

Company Name: Leonhardts Launchpads by Cal-X Stars Business Accelerator, Inc.Full Name: Howard J. LeonhardtPhone: (424) 291-2133Email Address: Send EmailWebsite: http://www.leonhardtventures.com

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Leonhardts Launchpads Announces Issuance of New U.S. Patent for Bioelectric Plus Biologics Platform for Organ Regeneration and Healing - Life Pulse...

Cardiac Stem Cells Comments Off on Leonhardts Launchpads Announces Issuance of New U.S. Patent for Bioelectric Plus Biologics Platform for Organ Regeneration and Healing – Life Pulse… | May 28th, 2020

KENILWORTH, N.J.--(BUSINESS WIRE)--May 28, 2020--

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the first presentation of results from KEYNOTE-177, a Phase 3 trial evaluating KEYTRUDA, Mercks anti-PD-1 therapy, for the first-line treatment of patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic colorectal cancer. In this pivotal study, KEYTRUDA monotherapy significantly reduced the risk of disease progression or death by 40% (HR=0.60 [95% CI, 0.45-0.80; p=0.0002]) and showed a median progression-free survival (PFS) of 16.5 months compared with 8.2 months for patients treated with chemotherapy (investigators choice of mFOLFOX6 or FOLFIRI, with or without bevacizumab or cetuximab), a current standard of care in this patient population. As previously announced, the study will continue without changes to evaluate overall survival (OS), the other dual primary endpoint. These results were selected for presentation on Sunday, May 31, 2020 in the plenary session of the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #LBA4).

For many years, the standard of care for the first-line treatment of patients with MSI-H colorectal cancer has been the combination of mFOLFOX6 plus bevacizumab. This is the first time a single-agent, anti-PD-1 therapy demonstrated a superior, statistically significant and clinically meaningful improvement in progression-free survival compared to chemotherapy for these patients, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. There is an unmet need for new treatment options in the first-line setting that may provide sustained, long-term improvements in outcomes for patients with MSI-H colorectal cancer. We are grateful to have the opportunity to present these practice-changing findings at the plenary session of this years ASCO.

KEYTRUDA monotherapy significantly reduced the risk of disease progression or death by 40% versus standard of care chemotherapy, with fewer treatment-related adverse events observed, in patients with MSI-H metastatic colorectal cancer. KEYTRUDA also demonstrated a long-term, durable response that lasted over two years for those who responded to treatment, said Thierry Andre, MD, professor of medical oncology, Sorbonne University, and Head of the Medical Oncology Department in St. Antoine Hospital, Assistance Publique Hpitaux de Paris. Data from KEYNOTE-177 show that KEYTRUDA monotherapy has the potential to become the new standard of care for first-line treatment of patients with MSI-H metastatic colorectal cancer.

In May 2017, KEYTRUDA became the first cancer therapy approved by the U.S. Food and Drug Administration for use based on a biomarker, regardless of tumor type, in previously treated patients with MSI-H or dMMR solid tumors.

As announced, more than 80 abstracts in nearly 20 types of solid tumors and blood cancers will be presented from Mercks broad oncology portfolio and investigational pipeline at ASCO. A compendium of presentations and posters of Merck-led studies will be posted by Merck on Friday, May 29 at 8 a.m. ET. Follow Merck on Twitter via @Merck and keep up to date with ASCO news and updates by using the hashtag #ASCO20.

KEYNOTE-177 Study Design and Additional Data (Abstract #LBA4)

KEYNOTE-177 is a randomized, open-label, Phase 3 trial evaluating KEYTRUDA monotherapy versus standard of care chemotherapy for the first-line treatment of patients with MSI-H or dMMR metastatic colorectal cancer (ClinicalTrials.gov, NCT02563002 ). The dual primary endpoints are PFS and OS. The study enrolled 307 patients, who were randomized to receive either KEYTRUDA (200 mg intravenously on Day 1 of each three-week cycle for up to 35 cycles) or investigators choice of one of the following chemotherapy-based regimens: mFOLFOX6; mFOLFOX6 plus bevacizumab (5 mg/kg IV on Day 1 of each two-week cycle); mFOLFOX6 plus cetuximab (400 mg/m2 IV, then 250 mg/m2 weekly in each two-week cycle); FOLFIRI; FOLFIRI plus bevacizumab (5 mg/kg IV on Day 1 of each two-week cycle); or FOLFIRI plus cetuximab (400 mg/m2 IV, then 250 mg/m2 weekly in each two-week cycle).

In this study, KEYTRUDA demonstrated a statistically significant and clinically meaningful improvement in PFS (HR=0.60 [95% CI, 0.45-0.80; p=0.0002]) and showed a median PFS of 16.5 months compared with 8.2 months for patients treated with chemotherapy. The two-year PFS rate was 48% with KEYTRUDA versus 19% with chemotherapy. The ORR was 43.8% with KEYTRUDA versus 33.1% with chemotherapy, with a complete response observed in 11.1% and 3.9% of patients, respectively; partial responses were observed in 32.7% and 29.2% of patients, respectively. Median duration of response was not reached with KEYTRUDA (range, 2.3+ to 41.4+) versus 10.6 months with chemotherapy (range, 2.8 to 37.5+). Additionally, 83% of patients had durable responses lasting at least two years with KEYTRUDA versus 35% with chemotherapy. In the study, 59% of patients in the intent-to-treat population received subsequent anti-PD-1/PD-L1 therapy after discontinuing study treatment in the chemotherapy arm.

The safety profile of KEYTRUDA demonstrated a lower incidence of Grade 3 treatment-related adverse events (AEs) versus chemotherapy (22% versus 66%, respectively), and no new toxicities were observed. Immune-mediated AEs and infusion reactions occurred in 31% of patients receiving KEYTRUDA and 13% of patients receiving chemotherapy. The most commonly reported immune-mediated AEswere hypothyroidism (12%) and colitis (7%) with KEYTRUDA, and infusion reactions (8%) with chemotherapy.

Merck will hold a virtual investor event in conjunction with the ASCO Annual Meeting on Tuesday, June 2 at 2 p.m. ET. Details will be provided at a date closer to the event at http://investors.merck.com/home/default.aspx.

About Microsatellite Instability High (MSI-H)

Microsatellite instability (or MSI) is defined by the National Cancer Institute as a change that occurs in the DNA of certain cells (such as tumor cells) in which the number of repeats of microsatellites (short, repeated sequences of DNA) is different from the number of repeats that was in the DNA when it was inherited. The cause of MSI may be a defect in the ability to repair mistakes made when DNA is copied in the cell. This defect is also referred to as mismatch repair deficiency (dMMR). It is estimated that approximately 5-15% of colorectal cancer patients have tumors that score as either MSI-H or dMMR when testing is performed.

Colorectal cancer starts in the colon or the rectum, and these cancers are referred to as colon cancer and rectal cancer depending on where the cancer starts. Colorectal cancer often begins with growths on the inner lining of the colon or rectum called polyps, which can change into cancer over time. Colorectal cancer is the third most commonly diagnosed cancer and the second most common cause of cancer-related death worldwide. It is estimated there were nearly 850,000 new cases of colorectal cancer and more than 880,000 deaths from the disease globally in 2018. In the United States, it is estimated there will be nearly 105,000 new cases of colon cancer and more than 43,000 new cases of rectal cancer, resulting in more than 53,000 deaths from colorectal cancer in 2020. The five-year survival rates for advanced/metastatic colon cancer and rectal cancer (stage IV) are estimated to be 14% and 15%, respectively.

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

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those 2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those 2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those 2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with hepatocellular carcinoma (HCC) were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.

There is limited experience in pediatric patients. In a trial, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with various cancers, including unapproved usages, were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 117 doses), with 34 patients (85%) receiving 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions that occurred at a higher rate (15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), increased transaminases (28%), and hyponatremia (18%).

Mercks Focus on Cancer

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Merck's KEYTRUDA (pembrolizumab) Superior to Standard of Care Chemotherapy in Patients with MSI-H Colorectal Cancer - Maryville Daily Times

Cardiac Stem Cells Comments Off on Merck’s KEYTRUDA (pembrolizumab) Superior to Standard of Care Chemotherapy in Patients with MSI-H Colorectal Cancer – Maryville Daily Times | May 28th, 2020

Pune, May 27, 2020 (GLOBE NEWSWIRE) -- The global regenerative medicine market size is expected to reach USD 151,949.5 billion by 2026, exhibiting a CAGR of 26.1% during the forecast period. The growing R&D investment by key players for the development of innovative regenerative therapies can be a vital factor enabling the growth of the market during the forecast period, states Fortune Business Insights in a report, titled Regenerative Medicine Market Size, Share and Industry Analysis By Product (Cell Therapy, Gene Therapy, Tissue Engineering, Platelet Rich Plasma), By Application (Orthopaedics, Wound Care, Oncology), By Distribution Channel (Hospitals, Clinics) & Regional Forecast, 2019 2026 the market size stood at USD 23,841.5 Million in 2018. The growing organ transplantation surgeries will spur opportunities for the market during the forecast period.

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Market Driver:

Escalating Cases of Genetic Disorders to Augment Growth

The increasing prevalence of chronic disorders can be an essential factor enabling the growth of the market. Similarly, the growing incidence of genetic disorders will fuel demand for the market. The growing investment in R&D activities by major market players will have a positive impact on the regenerative medicine market growth during the forecast period. For instance, in March 2018, SanBio Group, a leader in regenerative medicine and therapies for neurological disorders announced that it has made a deal with Hitachi Chemical Advanced Therapeutics Solutions, LLC, a cell manufacturing company for the development and manufacturing of innovative regenerative medicines.

Furthermore, the rising cases of neurological disorders will influence the healthy growth of the market. The growing healthcare expenditure in developed and developing countries will boost the market in the forthcoming years. The ongoing clinical trials and robust pipeline products in stem cell andgene therapy will contribute tremendously to the growth of the market. The rising utilization of skin substitutes, grafts, bone matrix, and other tissue-engineered regenerative medicine in orthopedic and neurosurgical applications will augment the growth of the market.

An Overview of the Impact of COVID-19 on this Market:

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

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

To get the short-term and long-term impact of COVID-19 on this Market.

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Regional Analysis:

Development of Novel Therapies to Favor Growth in North America

The market in North America generated a revenue of USD 9,128.2 million in 2018 and is predicted to grow rapidly during the forecast period owing to the presence of major pharmaceutical companies. The growing launch of novel therapeutics and the availability of advanced technologies along with clinical trials will support growth in North America. Asia Pacific is expected to witness a high growth rate during the forecast period owing to the

developing healthcare infrastructure and facilities. The increasing stem cell research in developing countries such as India, Japan China will contribute positively to the growth of the market. For instance, In April 2013, the Japan Ministry of Health, Labor, and Welfare approved Regenerative Medicine law. The growing number of clinical developments of regenerative and cell-based therapies will drive the market in the region. The increasing government initiatives for human embryonic stem cell research and development will further encourage growth in the region. The surge in geriatric patients, the evolving lifestyle of people, and the growing need for novel therapies are factors likely to aid the expansion of the market in Asia Pacific.

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Key Development:

2018: Novartis announced that it has received EUs approval for one-time gene therapy Luxturna, to restore vision in people with rare and genetically-associated retinal disease.

List of the Key Companies Operating in the Regenerative Medicine Market are:

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Gene Therapy Market Size, Share and Global Trend By Disease Indication(Cancer, Genetic disorders, Cardiovascular diseases, Ophthalmology, Neurological conditions) By Type of Vectors (Viral vectors, Non-viral vectors), By Type of Cells(Somatic cells, Germline cells) and Geography Forecast till 2026

Induced Pluripotent Stem Cells Market Size, Share and Global Trend By Derived Cell Type (Amniotic cells, Fibroblasts, Keratinocytes, Hepatocytes, Others), By Application (Regenerative medicines, Drug development, Toxicity testing, Reprogramming technology, Academic research, Others), By End-user (Hospitals, Education & research institutes, Biotechnological companies) and Geography Forecast till 2026

Platelet Rich Plasma Market Size, Share And Global Trend By Origin (Allogeneic, Autologous, Homologous), By Type (Pure PRP, Leukocyte rich PRP, Leukocyte rich fibrin), By Application (Orthopaedic surgery, Cosmetic surgery, General surgery, Neurosurgery, Others), And Geography Forecast Till 2026

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Regenerative Medicine Market to Exhibit a CAGR of 26.1% by 2026; Rising Prevalence of Genetic Disorders to Fuel Demand, states Fortune Business...

Skin Stem Cells Comments Off on Regenerative Medicine Market to Exhibit a CAGR of 26.1% by 2026; Rising Prevalence of Genetic Disorders to Fuel Demand, states Fortune Business… | May 27th, 2020

The Faculty of Health and Medical Sciences at the University of Copenhagen recently discovered how a particular protein, Phosphoprotein phosphatase 2A (PP2A), inhibits tumor development in mice.

Proteins are complex molecules in cells that are necessary for the function, structure, and regulation of the body's organs and tissues. Proteins have five primary functions: antibodies, enzymes, messengers, structural components, and transport or storage of atoms or small molecules.

Professor Jakob Nilsson, from the Novo Nordisk Foundation Center for Protein Research, explained that PP2A is called a household protein as it can be commonly found in most places. Everything that lives with simple cells or complex cells contain PP2A.

The PP2A Protein is also being studied by pharmaceutical companies as it is known to show unique patterns of kinase opposition, or simply, it is a tumor suppressor. Protein kinases are enzymes that induce change, switching active proteins into an inactive form.

While there is still insufficient research on which specific types of proteins PP2A regulates to prevent cancer, results from the new data do gain more insight.

Other tumor suppressor proteins include the retinoblastoma protein (pRb) and the p53 gene. Both regulate the cycling behavior of cells in a process called cell proliferation and growth are known as cell cycle progression.

Rb has a vital part in regulation G1/S transition, which is the 'start' checkpoint which controls the production of starter kinase proteins. What follows is Rb's 'role in the functioning of normal andcancer stem cells,' as well as its effect on the 'energy metabolism of cancer cells.'

According to a study called Nanostructures for Cancer Therapy, P53 is a protein that can 'respond to hypoxia, DNA damage, and loss of normal cell contacts when activated,' as it mediates the growth and death of cells.

The same study notes, 'targeting p53-MDM2 interaction would be attractive in cancer therapy.'

Read Also: Metformin, a Drug for Diabetes, is Investigated for Cancer-Causing Contaminant

Associate Professor Marie Kveiborg from the Biotech Research and Innovation Centre notes that what is new about their study is that they can show how the specific PP2AB56 'selects the phosphate groups that shall be removed from other proteins,' while it turns off the enzyme ADAM17. ADAM17 being switched off resulted in 'inhibition of tumor growth in mice.'

A disintegrin and metalloprotease domain 17 (ADAM17) is a protein-coding gene associated with diseases including inflammatory skin (psoriasis), inflammatory bowel disease (Crohn's disease), and breast cancer. The test mice were all injected with three variations of ADAM17 cells.

On the day of injection, '4T1 A17wt, I762A, and LEE cells,' all ADAM17 variants, were given and the scientists monitored tumor growth through time.

When they began observing how PP2A-B56 interacted with ADAM17, 'none of the mice injected with ADAM17 LEE cells reached tumor endpoint criteria, as opposed to ADAM17 wt or I762A injected mice, which exhibited only 50% survival by the end of the experiment.'

The newly discovered data on cancer research will hopefully develop into studies with human tumors, expressed by the researchers. The scientists concluded, 'the B56 inhibitor displays excellent specificity toward the PP2AB56 holoenzyme family.' As a result, scientists also want to make additional research to determine if PP2A also can regulate other proteins with its tumor suppressor function.

Read Also:Will COVID-19 End Scientific Breakthroughs?

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BREAKTHROUGH! Scientists Discover Particular Protein that Could Block Cancer Growth - Science Times

Skin Stem Cells Comments Off on BREAKTHROUGH! Scientists Discover Particular Protein that Could Block Cancer Growth – Science Times | May 27th, 2020

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

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Rheumatoid Arthritis Stem Cell Therapy Market to Register Substantial Expansion by Fact.MR - The Cloud Tribune

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