Archive for May, 2020

Summary

It turns out that finding driver mutations may be more complicated than previously thought: Nearly a quarter of all tumors have two different mutations in the same gene.

A major effort in cancer research is the search for driver mutations in tumors. These mutations are changes in a genes DNA that play a direct role in the growth of cancer. They are different from passenger mutations, which are genetic changes found in tumors that dont have anything to do with the cancer: Those are just along for the ride.

Figuring out which tumor mutations are drivers is important because they help provide an understanding of how and why tumors grow. Identifying driver mutations also helps researchers design treatments and helps doctors predict how a persons cancer is likely to behave.

But according to a studypublished by Memorial Sloan Kettering researchers in Nature on May 27, the strategy of focusing on driver mutations may be more complicated than previously thought. It turns out that nearly a quarter of all tumors have two different mutations in the same gene that are contributing to the formation of an individual cancer.

Weve seen this phenomenon here and there before, but until now we had no idea how common it was, says MSK computational oncologist Barry Taylor, one of the studys two senior authors. The harder we looked, the more clearly we saw it.

MSK-IMPACT: A Targeted Test for Mutations in Both Rare and Common Cancers

MSK-IMPACT stands for integrated mutation profiling of actionable cancer targets. It is a targeted tumor-sequencing test available to MSK patients.

In every cell of our bodies, we have two copies of each gene. One comes from our mother and the other from our father. When one copy of a gene develops a mutation either by chance or due to exposure to something harmful like UV light, radiation, or tobacco smoke the other copy is there to potentially make up for the loss. If there is a mutation in the second copy, thats when trouble can start: If both copies of a gene are mutated, it can send the cell down the road toward becoming cancerous. These multiple mutations, also called composite mutations,were known to occur with a class of genes called tumor suppressors, where the double mutation effectively cripples the function of both copies of a gene and can lead to cancer.

But it turns out that another type of composite mutation that hasnt been well understood is much more common than expected: It occurs when two different mutations affect the same copy of a gene. Here, the two mutations work together to produce a mutant protein with new, unexpected functions. This situation can lead to the formation of oncogenic proteins those that drive cancer growth.

[MSK-IMPACT data is] well suited to doing this kind of detailed analysis.

In a way, were looking at a phenomenon thats been staring people in the face for a long time, says MSK computational oncologist Ed Reznik, the papers other senior author. I credit graduate student Alex Gorelick, who was working in both my and Barrys labs, with coming up with the idea to look at how common composite mutations are and what they may mean. Mr. Gorelick is first author on the Nature paper.

The team was able to make this discovery thanks to data from MSK-IMPACT, a diagnostic test that helps match people with cancer to the best treatment based on the genetic changes in their tumors. This test, which has been used since 2014, has now analyzed more than 50,000 tumors, giving researchers a lot of data to work with.

One special thing about MSK-IMPACT data is that its very deep and contains a lot more information than other sequencing platforms, Dr. Reznik says. That makes it well suited to doing this kind of detailed analysis.

Now that the researchers know about composite mutations, the next step is to determine what they might mean for individual cancers. One study that came out last year in Science, published by MSK cancer biologist Maurizio Scaltriti and colleagues, found that breast cancers with composite mutations in the gene PIK3CA may respond better to targeted therapy than breast cancers in which only one PIK3CA mutation is present.

However, with other cancers and other mutations, its possible that composite mutations may make them harder to treat.

This gives us a tremendous opportunity to look at the function of these mutations in a different way.

Theres still so much we dont understand about composite mutations. Rather than creating frustration, knowing of their existence leads to new opportunities, concludes Dr. Taylor, who is an Associate Director of the Marie-Jose & Henry R. Kravis Center for Molecular Oncology. This gives us a tremendous opportunity to look at the function of these mutations in a different way and learn something fundamental about cancer genes that we may not have appreciated before.

Read the rest here:
Double Trouble: Researchers Find Many Cancers Carry Two Mutations in the Same Gene - On Cancer - Memorial Sloan Kettering

Text size

Sanofi is about to have $11.7 billion burning a hole in its pocket. What might it buy?

Days after the French drug giant announced that it would sell its stake in the biotech company Regeneron Pharmaceuticals (ticker: REGN), speculation is growing on whether the company might pursue an acquisition or two in the coming months.

Sanofi (SNY) has not said what it plans to do with the proceeds of its sale of 21.6 million shares of Regeneron. In a statement, the company said it would use the proceeds to further execute on its strategy to drive innovation and growth.

Still, Sanofis new CEO, Paul Hudson, said in December that the company would consider future deals: We are open-minded and interested, he said at the time. In January, Sanofi completed the acquisition of the cancer drug developer Synthorx for $2.5 billion.

Sanofi appears to be taking advantage of the strong liquidity in biotech equity markets, and in REGN in particular, to accelerate the implementation of their strategy, and we do not expect them to sit on their new capital, SVB Leerink analyst Geoffrey Porges wrote in a note on Tuesday.

Porges suggested that the company could be looking for a gene therapy company to acquire.

We certainly expect a M&A deal of decent size ($5bn) in the coming months for Sanofi, he wrote.

In another note Tuesday, Citi Research analyst Mohit Bansal wrote that the gene therapy company BioMarin Pharmaceutical (BMRN) was an unlikely target for Sanofi. Bansal said that BioMarin does not fit with previous comments from Sanofi about their acquisition interests, noting that the company has indicated a preference toward smaller companies, and away from the crowded hemophilia gene therapy race in which BioMarin is a lead contender. BioMarins market value is $18.8 billion.

Gene therapy companies with market value closer to the $5 billion range include bluebird bio (BLUE), which has a market value of $3.6 billion, and Ultragenyx Pharmaceutical (RARE), which has a market value of $4.4 billion.

Sanofi had some $10.3 billion in cash and cash equivalents on hand as of the end of 2019. The company did not immediately respond to a request for comment.

Shares of Sanofi are down 6.8% so far this year, and on Wednesday morning were trading down 1%. The stock trades at 13.4 times earnings projected over the next 12 months, close to its five-year average of 13.5 times earnings.

Write to Josh Nathan-Kazis at josh.nathan-kazis@barrons.com

Read the rest here:
What Sanofi Might Buy With Its Regeneron Windfall - Barron's

Gene therapy does more than treat genetic diseases it can cure them. A one-time dose of a non-replicative viral vector, such as commonly used recombinant adeno-associated virus (AAV), delivers a functional gene to replace or compensate for a dysfunctional version that is causing a patients disease (Figure 1). As a cutting-edge biopharmaceutical technology, there are multiple gene therapies now FDA approved; with hundreds more in clinical trials, were likely to see many more of these therapies on the market soon.1 However, to keep up with the rapid pace of clinical research, developers are working to streamline the manufacturing and quality control process to improve quality and lower the cost of bringing these important drugs to market.Developers use a multitude of analytical tests to develop gene therapies and optimize their manufacturing process. When developers get aberrant test results, they must be able to interpret where the problem lies. Did the manufacturing process produce an undesirable product, or is the analytical testing method unreliable? Analytical testing companies that have the infrastructure, personnel, and experience often partner with developers to tighten up analytical variability so that results of tests clearly indicate where there are opportunities to increase efficiency and product quality.

Figure 1. Gene delivery by recombinant viral vector.During gene therapy, viral capsids containing the therapeutic gene are taken up by the patients cells and the genetic material is delivered to the nucleus. There, the gene gets expressed as a protein necessary for the patients health. Credit: Avomeen.

Figure 2. A full AAV capsid and associated capsid impurities. Complete viral capsids have AAV are assembled from 60 capsid proteins, with a defined stoichiometry and shape and contain a therapeutic gene. AAV vector impurities include capsids that contain too many copies of the gene (overfilled), those that contain lower copy numbers or truncations of the gene (partially full), or empty capsids that contain no genetic material. Credit:Avomeen.

There are several ways to measure the empty/full capsid ratio, and as developers are establishing their chemistry, manufacturing and control (CMC) protocol, it is important that they choose an optimized method, as they must use that method for effective quality control from early process development to lot release and stability.3 Gene therapy developers may choose analytical ultracentrifugation to evaluate capsids, but while highly effective, this method is not as quantitative, robust or efficient as some newer methods. High-performance liquid chromatography (HPLC) using AAV full/empty analytical columns have been demonstrated to be highly effective at separating full, empty, and improperly filled capsids for robust quantification. Additionally, this method is higher throughput than ultracentrifugation, and requires less precious AAV sample to run.

Cellular potency is evaluated by transducing cells with the AAV product and then measuring a phenotypic or functional outcome due to the transduction. Developing these tests can be challenging because there is no one-size-fits-all test that will give developers the answers they need. Developers often draw on the experience of analytical labs to determine how to best evaluate their AAV products transduction efficiency.A gene therapy in development must also be tested to ensure that it is free of residual, process-related impurities such as polyethylenimine, iodixanol, poloxamer, and other excipients that must be removed in the final product to ensure safety. Few research and manufacturing facilities have the equipment and expertise necessary to perform this kind of testing, and it is advisable to find one that has experience testing polymers, extractables and leachables to examine if components of the manufacturing equipment or drugs packaging are not contaminating the final product.

As fast-paced as the gene therapy field is now, it stands to become a true race to the finish line to bring new gene therapies to market in the near future. Regulatory bodies are becoming more familiar with reviewing gene therapies, and the road to commercialization will move more quickly. There is no denying that gene therapies will bring incredible benefits to patients, but it will be crucial to improve manufacturing efficiency and lower costs to make gene therapies more accessible to the patients who need them.References

1. Colasante, W., Diesel, P., and Gerlovin, Lev. (2018). New Approaches To Market Access And Reimbursement For Gene And Cell Therapies. Cell & Gene. Retrieved from: https://www.cellandgene.com/doc/new-approaches-to-market-access-and-reimbursement-for-gene-and-cell-therapies-0001

2. Fraser Wright, J. (2014). Product-Related Impurities in Clinical-Grade Recombinant AAV Vectors: Characterization and Risk Assessment. Biomedicines, 2, 80-97; doi:10.3390/biomedicines2010080

3. U.S. Food & Drug Administration (2019). Guidance for Human Somatic Cell Therapy and Gene Therapy. Retrieved from: https://www.fda.gov/animal-veterinary/guidance-industry/chemistry-manufacturing-and-controls-cmc-guidances-industry-gfis

4. Stein, R. (2019). At $2.1 Million, New Gene Therapy Is The Most Expensive Drug Ever. NPR. Retrieved from: https://www.npr.org/sections/health-shots/2019/05/24/725404168/at-2-125-million-new-gene-therapy-is-the-most-expensive-drug-ever

5. Cohen, J.T, Chambers, J. D., Silver, M. C., Lin, P., Neumann, P.J. (2019). Putting The Costs And Benefits Of New Gene Therapies Into Perspective. Health Affairs. Retrieved from: https://www.healthaffairs.org/do/10.1377/hblog20190827.553404/full/

6. ATCC (accessed May, 2020) ATCC Virus Reference Materials. Retrieved from: https://www.atcc.org/en/Standards/Standards_Programs/ATCC_Virus_Reference_Materials.aspx#

7. U.S. FDA (2020). FDA Details Policies on Gene Therapies in Seven Guidances. Retrieved from: https://www.fdanews.com/articles/195767-fda-details-policies-on-gene-therapies-in-seven-guidances

See original here:
Troubleshooting the Development of New Gene Therapies - Technology Networks

May 27, 2020 |May featured exciting new, products, and partnerships from around the bio-IT community from innovating companies, organizations, and universities, including Benchling, BERG, Thermo Fisher Scientific, and more.

Benchlingannounced the launch ofBenchling Insights, a new solution that gives life sciences companies the ability to query, visualize and collaborate around high quality, structured data that resides on the platform. While the biotech industry continues to grow, companies are faced with increased competition, patent expirations and increased scrutiny over pricing and efficacy. Biotech companies are under immense pressure to deliver new products into clinical evaluation faster than ever, which requires disciplined execution, a high degree of collaboration and unfettered access to data across the R&D lifecycle, saidSaji Wickramasekara, CEO and Co-Founder of Benchling, in a press release. We launched Benchling Insights so that our customers can make intelligent decisions with a complete view of their experimental and operational data. Analyses and dashboards can be rapidly created and shared across programs, teams, and leadership so companies can reach breakthroughs faster. Benchling Insights extends the Benchling Life Sciences R&D Cloudwith an integrated solution for data querying, visualization, and collaboration. Scientists can tailor advanced queries to visualize scientific and operational metrics, and use these to quickly answer key questions about their programs. For example, they can assess which cell lines generate the best assay performance, or which process variants lead to optimal outputs. R&D leaders can use centralized data to track overall pipeline performance and remove operational bottlenecks, while IT leaders can track product utilization and compliance. Press release

BERGannounced a new collaboration with Boehringer Ingelheimaround understanding the multifaceted nature of the spectrum of inflammatory diseases and seeks to unravel the associated biological drivers. The pilot program with Boehringer Ingelheim will work to reveal novel insights into the complexities of various inflammatory diseases. The potential outcomes of this partnership could lead to a broader understanding of the etiology of potential candidate biomarkers. BERG has previously collaborated with multiple pharmaceutical companies and applied its Interrogative Biologyplatform to diverse datasets to address major clinical unmet needs. Were excited to partner with Boehringer Ingelheim, which will combine Boehringer Ingelheim's translational medicine and biomarker expertise with BERGs next generation AI-driven, patient-biology capability, Niven R. Narain, BERG Co-founder, President and Chief Executive Officer, said in a press release. Our intent is for BERGs Interrogative Biology platform to enable the discoveryofbiomarkersthat willrevolutionize how to diagnose and treat patients with inflammatory diseases. Press release

Thermo Fisher Scientificreleased the Thermo Scientific Helios 5 Laser PFIBsystem, an advanced focused ion beam scanning electron microscope (FIB-SEM) with a fully integrated femtosecond laser that quickly characterizes millimeter-scale volumes of material in 3D with nanometer resolution. The Helios 5 Laser PFIB combines the best-in-class Thermo Scientific Elstar SEM Columnfor ultra-high-resolution imaging and advanced analytical capabilities with a plasma FIB column for top performance at all operating conditions, and a femtosecond laser that enables in-situ ablation at material removal rates not previously obtained by a commercially available product. The Helios 5 Laser PFIB is part of the fifth generation of the industry-leading Helios family. The Helios 5 Laser PFIB dramatically accelerates the pace of research for both academic and industrial users, allowing them to characterize materials in a matter of minutes versus the days it took before,Rosy Lee, vice president of materials science at Thermo Fisher, said in a press release. Not only can researchers quickly and accurately image statistically relevant, site-specific, millimeter-size cross-sections at nanoscale resolution, they can also set up large-volume 3D analyses to be automatically completed overnight, freeing up the microscope for other uses. The Helios 5 Laser PFIB allows researchers to obtain accurate large-volume 3D and sub-surface data up to 15,000 times faster than a typical Gallium ion source focused ion beam (Ga-FIB). For many materials, a large cross-section of hundreds of microns can be milled by the Helios 5 Laser PFIB in less than 5 minutes. Serial-section tomography is now possible with this combination of Laser and Plasma FIB, and when combined with EDS and EBSD detectors, can be extended to 3D elemental and grain orientation analysis at the millimeter scale. Press release

Following the recent launch of NVIDIAs new DGX A100system, NetApp ONTAP AIannounced it will be among the first converged AI stacks to incorporate the DGX A100 and NVIDIA Mellanox networking. NetApp and NVIDIA have been collaborating for several years to deliver AI solutions that help enterprises accelerate AI adoption. Both companies are working on eliminating AI bottlenecks and advancing the realm of possibilities, Kim Stevenson, Sr. Vice President and General Manager, Foundational Data Services Business Unit, NetApp, said in an official statement. NetApps full stack AI/ML/DL platforms delivered at the edge, core and cloud with ONTAP AI complements NVIDIAs rapidly expanding ecosystem of AI hardware, software, and development toolkits. Blog post

Advanced Biological Laboratories (ABL)announced the CE-IVDmarking of its DeepChek-HIVAssays is now available for in-vitro diagnostics. Intended to be used on HIV-1 Group M viruses from patients diagnosed with HIV infection, the assays deliver standardized, open and flexible solution suited to clinical settings performing sequencing through Capillary Electrophoresis and Next Generation Sequencing (NGS) systems. The DeepChek-HIV CE IVD Assays are covering respectively the Protease / Reverse Transcriptase and the Integrase regions of the virus and are intended to be used from input RNA extracted from plasma, serum or whole blood samples. Both assays are highly sensitive and have been validated to process clinical samples as low as 1,000 copies/mL with outstanding performances (100% agreement of analytical reproducibility and repeatability, 100% clinical reproducibility, 99% clinical sensitivity) in all three regions. Open and flexible, the DeepChek-HIV CE IVD Assays is a unique and versatile system that can be used under a large variety of laboratory throughput configurations. Obtaining CE IVD marking for our DeepChek-HIV assays will allow virology labs to access a unique and innovative technology, for HIV genotyping diagnostics. ABL will keep standardizing its entire portfolio of applications in virology and microbiology following European and International guidelines to improve the management of patients suffering from chronic diseases on a worldwide basis, Chalom Sayada, CEO of ABL, said in an official statement. Press release

Cardinal Healthand Vinetiannounced a collaboration to support cell and gene therapy manufacturers with a fully integrated solution that aligns logistics and commercialization services with digital Chain of Identityand Chain of Custodythroughout the treatment journey. Cardinal Healthsupports the cell and gene therapy market with a robust suite of services that includes end-to-end logistics, regulatory strategy, order-to-cash management and patient access and support services. Vineti offers a digital platform of record to integrate logistics, manufacturing and clinical data for cell and gene therapies. The Vineti platform delivers digital Chain of Identity and Chain of Custody, providing essential patient safety and regulatory compliance across the value chain.Together, Cardinal Health and Vineti will develop best-in-class solutions to support the distribution of transformative, personalized therapies for cancer and other serious diseases.Specifically, Cardinal Health and Vineti will focus on integrated solutions that enable cell and gene therapy manufacturers to accelerate the commercialization of their products, while delivering a more simple, seamless and secure experience to hospitals and patients, from initial patient enrollment through delivery of the final dose of therapy and beyond. Press release

Immunailaunched out of stealth to map the entire immune system for better detection, diagnosis, and treatment of disease. Leveraging single-cell technologies and machine learning algorithms, Immunai has mapped out millions of immune cells and their functions, building the largest proprietary data set in the world for clinical immunological data. The company is also announcing $20M in seed funding, which will be used to further the development of its technology and business functions while expanding its team of scientists, engineers, and machine learning experts. Cell therapies and cancer immunotherapies have revolutionized medicine in the last few years and are expected to continue for the near future. However, due to the incredible complexity of the immune systemits trillions of cells partitioned into hundreds of cell types and states and how they interplay with other cells and proteinsit is prohibitively hard to predict how drugs will affect immune cells. For cell therapies with high manufacturing costs, a slight variation in cell therapy products can have a significant influence on a patients response to the therapy.Immunai has developed a vertically-integrated platform for multi-omic single-cell profiling that offers a broader view of the immune system in states of health, disease, and treatment to examine the bodys response to stimulus. With Immunais platform, pharmaceutical companies can identify more subtle nuances in cell abundances and cell function and mechanisms of action and biomarkers for toxicity response to accurately measure the efficacy of immunotherapies. For cell therapies, in particular, Immunai partners with cell therapy companies to understand cellular products sub-populations in unprecedented detail before and after infusion.Press release

See the article here:
Benchling, BERG, Thermo Fisher Scientific, And More: News From May 2020 - Bio-IT World

CAMBRIDGE, Mass.--(BUSINESS WIRE)--ElevateBio, LLC, a Cambridge-based creator and operator of a portfolio of innovative cell and gene therapy companies, announced that the company will present at the Jefferies Virtual Healthcare Conference on Thursday, June 4, 2020 at 8:30 a.m. ET.

About ElevateBio

ElevateBio, LLC, is a Cambridge-based creator and operator of a portfolio of innovative cell and gene therapy companies. It begins with an environment where scientific inventors can transform their visions for cell and gene therapies into reality for patients with devastating and life-threatening diseases. Working with leading academic researchers, medical centers, and corporate partners, ElevateBios team of scientists, drug developers, and company builders are creating a portfolio of therapeutics companies that are changing the face of cell and gene therapy and regenerative medicine. Core to ElevateBios vision is BaseCamp, a centralized state-of-the-art innovation and manufacturing center, providing fully integrated capabilities, including basic and transitional research, process development, clinical development, cGMP manufacturing, and regulatory affairs across multiple cell and gene therapy and regenerative medicine technology platforms. ElevateBio portfolio companies, as well as select strategic partners are supported by ElevateBio BaseCamp in the advancement of novel cell and gene therapies.

ElevateBios investors include F2 Ventures, MPM Capital, EcoR1 Capital, Redmile Group, Samsara BioCapital, The Invus Group, Surveyor Capital (A Citadel company), EDBI, and Vertex Ventures HC.

ElevateBio is headquartered in Cambridge, Mass, with ElevateBio BaseCamp located in Waltham, Mass. For more information, please visit http://www.elevate.bio.

Go here to read the rest:
ElevateBio to Present at the Jefferies Virtual Healthcare Conference - Business Wire

Gilead CEO Dan ODay has brokered his way to a PD-1 and lined up a front row seat in the TIGIT arena, inking a deal worth close to $2 billion to align the big biotech closely with Terry Rosens Arcus. And $375 million of that comes upfront, with cash for the buy-in plus equity, along with $400 million for R&D and $1.22 billion in reserve to cover opt-in payments and milestones..

Hotly rumored for weeks, the 2 players have formalized a 10-year alliance that starts with rights to the PD-1, zimberelimab. ODay also has first dibs on TIGIT and 2 other leading programs, agreeing to an opt-in fee ranging from $200 million to $275 million on each. Theres $500 million in potential TIGIT milestones on US regulatory events likely capped by an approval if Gilead partners on it and the stars align on the data. And theres another $150 million opt-in payments for the rest of the Arcus pipeline.

Unlock this story instantly and join 82,300+ biopharma pros reading Endpoints daily and it's free.

SUBSCRIBE SIGN IN

Read more from the original source:
European regulators accept FibroGen's anemia drug for review; Passage Bio's lead gene therapy gets more love from the FDA - Endpoints News

CAMBRIDGE, Mass., May 27, 2020 (GLOBE NEWSWIRE) -- TCR2 Therapeutics Inc. (Nasdaq: TCRR), a clinical-stage immunotherapy company developing the next generation of novel T cell therapies for patients suffering from cancer, today announced an expansion of its leadership team to strengthen expertise in business development and regulatory affairs as the Company advances the development of TRuC-T cells addressing solid tumors and hematological malignancies.

As we position TCR2 for our next phase of growth and value creation, we are pleased to announce the addition of experienced leaders in two key competencies business development and regulatory affairs, said Garry Menzel, Ph.D., President and Chief Executive Officer of TCR2 Therapeutics. Clinical progress and the execution of strategic partnerships are important priorities for the Company and having the right expertise in both domains is critical for our success.

Gregg McConnell brings considerable experience to the business development role after his successful tenures at Pfizer and BlueRock Therapeutics, an engineered cell therapy company purchased by Bayer AG for $1.0 billion. He will lead our effort to deliver significant value from the innovation and progress of our TRuC-T cells through deals with strategic partners, added Dr. Menzel.

Viera Muzithras brings very specific cell therapy experience to TCR2, from leading the development of multiple myeloma assets at Bristol Myers Squibb to the global regulatory strategy for Kymriah while at Novartis, ultimately leading to its approval by the FDA, said Alfonso Quints, M.D., Chief Medical Officer of TCR2 Therapeutics. Her deep expertise will be critical as we advance our two current TRuC-T cell programs in the clinic, TC-210 and TC-110, and file an IND for our third CD70-targeted mono TRuC program.

Gregg McConnell joins TCR2 as Head of Business Development. Most recently, he served as Vice President and Head of Business Development at BlueRock Therapeutics, a leading engineered cell therapy company which was acquired by Bayer AG for an implied value of up to $1.0 billion. At BlueRock, he held numerous responsibilities including leading business development and partnering activities for a pipeline of allogeneic cell therapy programs in neurology, cardiology and immunology. Prior to BlueRock, Gregg held several business development and corporate strategy roles at Pfizer, including Senior Director of Worldwide Business Development, where he led and co-managed the execution of buy- and sell-side transactions across multiple structures, development stages and therapeutic areas, including oncology, immunology and gene therapy.

Viera Muzithras joins TCR2 as Vice President of Regulatory Affairs. With over 25 years of global regulatory experience focusing on cell and gene therapy, oncology and vaccines, she most recently served as Executive Director of Global Regulatory Affairs at Bristol Myers Squibb (formerly Celgene Corporation), where she oversaw the development of novel cell and gene therapy products, biologicals such as T-cell engagers and antibody drug conjugates, and small molecules for hematologic diseases in multiple myeloma. Prior to Bristol Myers Squibb, Viera worked at Novartis Pharmaceuticals as Senior Director of Regulatory Affairs and Global Regulatory Director, where she was responsible for leading the global regulatory strategy and preparation and submission of the New Biologics License Application for Kymriah, a genetically modified autologous T cell immunotherapy targeting CD19. Earlier in her career, Viera served in various regulatory affairs roles at Bayer AG, Sanofi S.A., and Pfizer.

About TCR2 Therapeutics

TCR2Therapeutics Inc.is a clinical-stage immunotherapy company developing the next generation of novel Tcell therapies for patients suffering from cancer.TCR2sproprietary T cell receptor (TCR) Fusion Construct Tcells (TRuC-T cells) specifically recognize and kill cancer cells by harnessing signaling from the entire TCR, independent ofhuman leukocyte antigens (HLA). In preclinical studies, TRuC-T cells have demonstrated superior anti-tumor activity compared to chimeric antigen receptor T cells (CAR-T cells), while exhibiting lower levels of cytokine release. The Companys lead TRuC-T cell product candidate targeting solid tumors, TC-210, is currently being studied in a Phase 1/2 clinical trial to treat patients with mesothelin-positive non-small cell lung cancer (NSCLC), ovarian cancer, malignant pleural/peritoneal mesothelioma, and cholangiocarcinoma. The Companys lead TRuC-T cell product candidate targeting hematological malignancies, TC-110, is currently being studied in a Phase 1/2 clinical trial to treat patients with CD19-positive adult acute lymphoblastic leukemia (aALL) and with aggressive or indolent non-Hodgkin lymphoma (NHL). For more information about TCR2, please visitwww.tcr2.com.

Forward-looking Statements

This press release contains forward-looking statements and information within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. The use of words such as "may," "will," "could", "should," "expects," "intends," "plans," "anticipates," "believes," "estimates," "predicts," "projects," "seeks," "endeavor," "potential," "continue" or the negative of such words or other similar expressions can be used to identify forward-looking statements. These forward-looking statements include, but are not limited to, express or implied statements regarding the pre-clinical and clinical development of the Companys TRuC-T cells, potential collaborations and strategic partnerships, the future value of the Companys TRuC-T cell platform, the Companys pre-clinical and clinical regulatory strategy and planned IND filings for the Companys third mono TRuC-T cell program.

The expressed or implied forward-looking statements included in this press release are only predictions and are subject to a number of risks, uncertainties and assumptions, including, without limitation: uncertainties inherent in clinical studies and in the availability and timing of data from ongoing clinical studies; whether interim results from a clinical trial will be predictive of the final results of the trial; whether results from preclinical studies or earlier clinical studies will be predictive of the results of future trials; the expected timing of submissions for regulatory approval or review by governmental authorities, including review under accelerated approval processes; orphan drug designation eligibility; regulatory approvals to conduct trials or to market products; TCR2s ability to maintain sufficient manufacturing capabilities to support its research, development and commercialization efforts, whether TCR2's cash resources will be sufficient to fund TCR2's foreseeable and unforeseeable operating expenses and capital expenditure requirements, the impact of the COVID-19 pandemic on TCR2s ongoing operations; and other risks set forth under the caption "Risk Factors" in TCR2s most recent Annual Report on Form 10-K, most recent Quarterly Report on Form 10-Q and its other filings with theSecurities and Exchange Commission. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this press release may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although TCR2believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur.

Moreover, except as required by law, neither TCR2nor any other person assumes responsibility for the accuracy and completeness of the forward-looking statements included in this press release. Any forward-looking statement included in this press release speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

Investor and Media Contact:

Carl MauchDirector, Investor Relations and Corporate CommunicationsTCR2 Therapeutics Inc.(617) 949-5667carl.mauch@tcr2.com

Read the rest here:
TCR Therapeutics Hires Key Business Development and Regulatory Affairs Cell Therapy Experts to Support Strategic Objectives - GlobeNewswire

Pessac, France Poietis, 4D Bioprinting company, announces formation of Scientific Advisory Board (SAB) and appointment of two first prominent Scientists in Regenerative Medicine. The SAB will serve as a key strategic resource to Poietis as the company expands capabilities of NextGeneration Bioprinting (NGB) platform to therapeutic applications and develops first implantable tissues such as a bioprinted skin substitute in collaboration with the Assistance Publique Hpitaux de Marseille. Poietis appoints Dr. Geoffrey Gurtner, MD, Johnson and Johnson Professor of Surgery, Professor of Materials Science and Engineering at Stanford University and Vice-Chairman of Surgery for Innovation at Stanford University School of Medicine (California, United States) and Dr. Michael H. May, President & CEO of the Center for Commercialization of Regenerative Medicine (CCRM) at Toronto (Canada).

The formation of Poietis SAB is a very important step towards company global deployment in the clinical area says Bruno Brisson, Poietis co-founder and VP Business Development. We are delighted to welcome Dr. Gurtner and Dr. May to our SAB, where they will be key contributors in further enhancing our efforts to bring bioprinting solutions to clinicians and patients with high unmet needs.

To have Dr. Gurtner, a world-renowned expert in tissue-engineering therapies for skin wound healing, join our SAB will enrich our R&D efforts to achieve the first-in-human of a bioprinted skin substitute in the coming years adds Dr. Fabien Guillemot, CEO and Poietis founder. We also believe Dr. May will prove invaluable to Poietis leadership team, and we look forward to his insights and guidance to accelerate the advancement of our bioprinting platform technology to address the key challenges in tissue manufacturing and regenerative medicine.

3D bioprinting is a once-in-a-generation transformative technology. By focusing its 3D printing platform on a clinical application of high unmet need, Poietis is leading the adoption of 3D printing in cell therapy and tissue engineering comments Dr. Michael H. May, PhD, President & CEO of the CCRM.

Dr. Geoffrey Gurtner, MD, is Johnson and Johnson Professor of Surgery and Professor of Materials Science and Engineering at Stanford University, California; USA. He currently serves as the Associate Chairman for Research in the Department of Surgery and is the Executive Director of the Stanford Wound Care Center.

Geoff is a magna cum laude graduate of Dartmouth College and an AOA graduate of the University of California-San Francisco School of Medicine. He completed a general surgery residency at Massachusetts General Hospital, a plastic surgery residency at NYU School of Medicine and received advanced training in microsurgery at the University of Texas-MD Anderson Cancer Center. He is board certified in both general surgery and plastic surgery. He is the author of over 180 peer-reviewed publications in both scientific and surgical literature and editor for two major textbooks in the field: Grabb & Smiths Plastic Surgery and Plastic Surgery. Geoff was awarded the James Barrett Brown Award (for best paper in plastic surgery) in both 2009 and 2010, and has been named Researcher of the Year by the American Society of Plastic Surgeons and the American Association of Plastic Surgeons. His research has led to the development of several novel biomedical technologies. Geoff has co-founded several start-ups focused on wound healing, aesthetics and cardiovascular health.

Dr. Michael May completed his PhD in Chemical Engineering at the University of Toronto in 1998 as an NSERC Scholar and was awarded the Martin Walmsley Fellowship for Technological Entrepreneurship. He is President and Chief Executive Officer of the Center for Commercialization of Regenerative Medicine (CCRM) a Canadian public-private partnership supporting the translation and commercialization of cell & gene therapies and associated enabling technologies through stakeholder networks and with specialized teams, infrastructure and funding. He is also CEO of CCRM Enterprises, the venture creation and investment arm of CCRM.

Prior to CCRM, Michael was the President and co-founder of Rimon Therapeutics Ltd., a Toronto-based tissue engineering company developing novel medical polymers that possess drug-like activity. Rimons initial focus was on advanced wound healing. Michael sits on a number of boards and advisory committees, including: the Entrepreneurship Leadership Council at the University of Toronto; the Commercialization Committee of the International Society for Cell and Gene Therapy, the Alliance for Regenerative Medicine Foundation, CellCan and AgeX Inc. He is Chair of ExcellThera and co-moderates sessions in the health streams of the Creative Destruction Labs.

*****

About Poietis: Bioprinting company specializing in the development of new biomanufacturing solutions, based on Laser-Assisted Bioprinting, for human tissues. Poietis mission is to provide clinicians and patients with tissue engineering therapies thanks to its innovative, proprietary Next-Generation Bioprinting platform (NGB). The multimodal NGB platform is declined in two versions: one for in vitro tissue engineering research (NGB-R) and a clinical version (NGB-C) for the production of implantable bioprinted tissues. This multi-modal, automated biomanufacturing platform enables researchers to achieve superior tissue through high resolution, and enables the fabrication of complex tissues with repeatability and reproducibility. Poietis bioprinting technology is the result of innovative research carried out over ten years at Inserm and the University of Bordeaux. Poietis won the iLab competition in 2014, the World Innovation Challenge Phase II in 2017 and recently the EY Disruptive Strategy Award. The company currently employs 35 people. More information: http://www.poietis.com Contact : bruno.brisson@poietis.com

Read more:
Poietis Announces Formation of Scientific Advisory Board and Appoints Two First Prominent Regenerative Medicine Experts - BioSpace

Get the inside scope of the Sample report @https://www.theinsightpartners.com/sample/TIPHE100001165/

MARKET INTRODUCTION

Gene therapy is the introduction of DNA into a patient to treat a genetic disease or a disorder. The newly inserted DNA contains a correcting gene to correct the effects of a disease, causing mutations. Gene therapy is a promising treatment for genetic diseases and also includes cystic fibrosis and muscular dystrophy. Gene therapy is a suitable treatment for infectious diseases, inherited disease and cancer.

MARKET DYNAMICSThe growth of the gene therapy market is regulated due to various reason which includes the rapid involvement of synthetically modified gene to treat various diseases, it helps in designing the personalized medicine, rise in the research and development of the gene therapy among the others. The gene therapy requires less doses of medicines and is one time treatment, this factor is likely to show growth opportunity for gene therapy market in coming near future.

The report also includes the profiles of key gene therapy market companies along with their SWOT analysis and market strategies. In addition, the report focuses on leading industry players with information such as company profiles, components and services offered, financial information of last 3 years, key development in past five years.

Key Competitors In Market areSangamo Therapeutics, Inc., bluebird bio, Inc., uniQure N.V., AveXis, Inc., Vineti, Solid Biosciences., Spark Therapeutics, Inc., CHIMERON BIO, RENOVA THERAPEUTICS, HORAMA S.A.

TOC of Market Report Contains:

MARKET SCOPE

The Global Gene Therapy Market Analysis to 2027 is a specialized and in-depth study of the biotechnology industry with a special focus on the global market trend analysis. The report aims to provide an overview of gene therapy market with detailed market segmentation by cell type, application and geography. The global gene therapy market is expected to witness high growth during the forecast period. The report provides key statistics on the market status of the leading gene therapy market players and offers key trends and opportunities in the market.

Market segmentation:

Gene Therapy Market to 2027 Global Analysis and Forecasts by Cell Type (Somatic Gene Therapy, Germline Gene Therapy); By Application (Genetic Disorder, Cancer, Neurological Disorder, and Others)

By Geography North America, Europe, Asia-Pacific (APAC), Middle East and Africa (MEA) and South & Central America. And 13 countries globally along with current trend and opportunities prevailing in the region.

Points Covered in The Report:

Click to buy full report with all description:-https://www.theinsightpartners.com/buy/TIPHE100001165/

About Us:

The Insight Partnersis a one stop industry research provider of actionable intelligence. We help our clients in getting solutions to their research requirements through our syndicated and consulting research services. We are committed to provide highest quality research and consulting services to our customers. We help our clients understand the key market trends, identify opportunities, and make informed decisions with our market research offerings at an affordable cost.

We understand syndicated reports may not meet precise research requirements of all our clients. We offer our clients multiple ways to customize research as per their specific needs and budget

Contact Us:

The Insight Partners,

Phone: +1-646-491-9876

Email:[emailprotected]

See original here:
COVID-19 Impact on GENE THERAPY MARKET EXPECTED 2020 WITNESS A SUSTAINABLE GROWTH OVER 2027 WITH SANGAMO THERAPEUTICS, INC., BLUEBIRD BIO, UNIQURE NV,...

The chapter of global growth trends of this Gene Therapy Products Market business report includes industry tendencies, the growth proportion of major producers, and production analysis while studying market size by application. It covers market consumption analysis by application and studies market size by type, analysis of value, product utility, market percentage & production market share by type. Analysis of profiles of manufacturers or commanding players of the global market is performed based on sales area, key products, gross margin, revenue, price, and production. Market value chain and sales channel analysis of this market document includes details of customer, distributor, market value chain, and sales channel analysis.

Get ExclusiveSample Copy of This Report Herehttps://www.databridgemarketresearch.com/request-a-sample?dbmr=global-gene-therapy-products-market

Global gene therapy products market is set to witness a substantial CAGR in the forecast period of 2019- 2026. The report contains data of the base year 2018 and historic year 2017. Rising cancer cases and unused potential for emerging markets are the major factors for the growth of this market.

Few of the major competitors currently working in the globalgene therapy products marketareAdaptimmune., Anchiano Therapeutics, bluebird bio, Inc., CELGENE CORPORATION, GlaxoSmithKline plc., Merck KGaA, Novartis AG, Achieve Life Sciences, Inc., Spark Therapeutics, Inc., Abeona Therapeutics, Inc, Adverum, agtc, Arbutus Biopharma, Audentes Therapeutics, AveXis, Inc., CRISPR Therapeutics, Intellia Therapeutics, Inc and Gilead Sciences,Inc. among others.

Market Definition:Global Gene Therapy Products Market

Gene therapy or human gene therapy is a process which is used to modify gene for the treatment of any disease. Plasmid DNA, bacterial vector, human gene editing technology and viral vectors are some of the most common type of gene therapy products. The main aim of the gene therapy is to replace the dysfunctional genes. Somatic and germline are some of the most common type of the gene therapy.

Complete report on Global Gene Therapy Product Market Research Report 2019-2026 spread across 350 Pages, profiling Top companies and supports with tables and figures

Segmentation: Global Gene Therapy Products Market

Gene Therapy Products Market : By Product

Gene Therapy Products Market : By Application

Gene Therapy Products Market : ByGeography

Read Complete Details with TOC Herehttps://www.databridgemarketresearch.com/toc?dbmr=global-gene-therapy-products-market

Key Developments in the Gene Therapy Products Market:

Gene Therapy Products Market Drivers

Gene Therapy Products Market Restraints

Competitive Analysis: Gene Therapy Products Market

Global gene therapy products market is highly fragmented and the major players have used various strategies such as new product launches, expansions, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of gene therapy products market for Global, Europe, North America, Asia-Pacific, South America and Middle East & Africa.

Key questions answered in the report :-

To get this report at an attractive cost, click herehttps://www.databridgemarketresearch.com/speak-to-analyst?dbmr=global-gene-therapy-products-market

About Data Bridge Market Research:

Data Bridge Market Researchis a versatile market research and consulting firm with over 500 analysts working in different industries. We have catered more than 40% of the fortune 500 companies globally and have a network of more than 5000+ clientele around the globe. Our coverage of industries include Medical Devices, Pharmaceuticals, Biotechnology, Semiconductors, Machinery, Information and Communication Technology, Automobiles and Automotive, Chemical and Material, Packaging, Food and Beverages, Cosmetics, Specialty Chemicals, Fast Moving Consumer Goods, Robotics, among many others.

Data Bridge adepts in creating satisfied clients who reckon upon our services and rely on our hard work with certitude.We are content with our glorious 99.9 % client satisfying rate.

Contact Us

Data Bridge Market Research

US: +1 888 387 2818

UK: +44 208 089 1725

Hong Kong: +852 8192 7475 Mail:[emailprotected]

More:
Covid-19 Impact On Global Gene Therapy Products Market 2020 : Industry Trends, Size, Growth, Swot Analysis By Top Key Players And Forecast Report To...

Gene Therapy for CNS Disorders Market Insights 2018, is a professional and in-depth study on the current state of the global Gene Therapy for CNS Disorders industry with a focus on the Global market. The report provides key statistics on the market status of the Gene Therapy for CNS Disorders manufacturers and is a valuable source of guidance and direction for companies and individuals interested in the industry. Overall, the report provides an in-depth insight of 2018-2025 global Gene Therapy for CNS Disorders market covering all important parameters.

The report on the Gene Therapy for CNS Disorders market provides a birds eye view of the current proceeding within the Gene Therapy for CNS Disorders market. Further, the report also takes into account the impact of the novel COVID-19 pandemic on the Gene Therapy for CNS Disorders market and offers a clear assessment of the projected market fluctuations during the forecast period. The different factors that are likely to impact the overall dynamics of the Gene Therapy for CNS Disorders market over the forecast period (2019-2029) including the current trends, growth opportunities, restraining factors, and more are discussed in detail in the market study.

Get Free Sample PDF (including COVID19 Impact Analysis, full TOC, Tables and Figures) of Market Report @ https://www.marketresearchhub.com/enquiry.php?type=S&repid=2601445&source=atm

The key points of the Gene Therapy for CNS Disorders Market report:

The report provides a basic overview of the Gene Therapy for CNS Disorders industry including its definition, applications and manufacturing technology.

The report explores the international and Chinese major industry players in detail. In this part, the report presents the company profile, product specifications, capacity, production value, and 2018-2025 market shares for each company.

Through the statistical analysis, the report depicts the global total market of Gene Therapy for CNS Disorders industry including capacity, production, production value, cost/profit, supply/demand and Chinese import/export.

The total market is further divided by company, by country, and by application/type for the competitive landscape analysis.

The report then estimates 2018-2025 market development trends of Gene Therapy for CNS Disorders industry. Analysis of upstream raw materials, downstream demand, and current market dynamics is also carried out.

The report makes some important proposals for a new project of Gene Therapy for CNS Disorders Industry before evaluating its feasibility.

Do You Have Any Query Or Specific Requirement? Ask to Our Industry [emailprotected] https://www.marketresearchhub.com/enquiry.php?type=E&repid=2601445&source=atm

There are 3 key segments covered in this report: competitor segment, product type segment, end use/application segment.

For competitor segment, the report includes global key players of Gene Therapy for CNS Disorders are included:

The key players covered in this studyGilead (Kite Pharma)Amgen (BioVex)NovartisRoche (Spark Therapeutics)Bluebird Bio

Market segment by Type, the product can be split intoEx VivoIn VivoMarket segment by Application, split intoHospitalsClinicsOthers

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

The study objectives of this report are:To analyze global Gene Therapy for CNS Disorders status, future forecast, growth opportunity, key market and key players.To present the Gene Therapy for CNS Disorders development in North America, Europe, China, Japan, Southeast Asia, India and Central & South America.To strategically profile the key players and comprehensively analyze their development plan and strategies.To define, describe and forecast the market by type, market and key regions.

In this study, the years considered to estimate the market size of Gene Therapy for CNS Disorders are as follows:History Year: 2015-2019Base Year: 2019Estimated Year: 2020Forecast Year 2020 to 2026For the data information by region, company, type and application, 2019 is considered as the base year. Whenever data information was unavailable for the base year, the prior year has been considered.

You can Buy This Report from Here @ https://www.marketresearchhub.com/checkout?rep_id=2601445&licType=S&source=atm

Reasons to Purchase this Report:

* Estimates 2018-2025 Gene Therapy for CNS Disorders market development trends with the recent trends and SWOT analysis

* Market dynamics scenario, along with growth opportunities of the market in the years to come

* Market segmentation analysis including qualitative and quantitative research incorporating the impact of economic and policy aspects

* Regional and country level analysis integrating the demand and supply forces that are influencing the growth of the market.

* Competitive landscape involving the market share of major players, along with the new projects and strategies adopted by players in the past five years

* Comprehensive company profiles covering the product offerings, key financial information, recent developments, SWOT analysis, and strategies employed by the major market players

Read the original:
The Economic Impact of Coronavirus on Gene Therapy for CNS Disorders Market : In-depth study on Industry Size and Analysis on Emerging Growth Factors...

LONDON--(BUSINESS WIRE)-- MiNA Therapeutics, the pioneer in RNA activation therapeutics, announced today the publication of data from its Phase I liver cancer trial, OUTREACH, in Clinical Cancer Research. It is the first publication in which a small activating RNA treatment (MTL-CEBPA) demonstrated clinical benefit. In addition, the Company provided an update on its ongoing clinical trials for lead program MTL-CEBPA and its drug discovery programs.

This landmark publication in Clinical Cancer Research details for the first time that RNA medicines can activate gene expression, providing clinical benefit to patients, commented Robert Habib, CEO of MiNA Therapeutics. As we enter into the second half of 2020, we continue to advance our clinical development objectives and uncover the vast opportunities inherent in our unique drug discovery pipeline.

Publication and OUTREACH Study Update

The publication in Clinical Cancer Research summarizes the results from MiNAs Phase I, open-label, dose escalation and dose expansion trial of MTL-CEBPA, OUTREACH, in adults with advanced Hepatocellular Carcinoma (HCC). Overall, MTL-CEBPA was well-tolerated and demonstrated pharmacodynamic target engagement, meeting the primary endpoint of the study. Furthermore, a reduction of suppressive immune cells in the tumour microenvironment as well as initial signs of potential synergistic efficacy when combined with standard of care tyrosine kinase inhibitors in HCC could be observed. These encouraging Phase I data validate the targeting of C/EBP- as a novel therapeutic strategy in cancer and prompted a Phase Ib study further evaluating MTL-CEBPA in combination with sorafenib in HCC. Enrolment for the Phase Ib part of the OUTREACH trial was completed in Q1 2020 and initial results will be presented during a poster session at the forthcoming American Society of Clinical Oncology (ASCO) on Friday, May 29, 2020. The framework for a subsequent Phase II clinical trial is currently being designed with the objective of initiating this next stage of clinical development in the second half of 2020.

The full Clinical Cancer Research publication is available on the Publications page of MiNAs website. A similar overview of the Phase I data was most recently presented at the European Society for Medical Oncology (ESMO) in September 2019.

TIMEPOINT Update

In March 2020, TIMEPOINT, a global Phase I/Ib clinical study of MTL-CEBPA in combination with anti-PD1 checkpoint inhibitor pembrolizumab in patients with advanced solid tumours was initiated and the first patient was treated. The study is designed to assess the safety, tolerability, pharmacology and clinical activity of MTL-CEBPA in combination with pembrolizumab in these patients. Recruitment for the study is expected to continue through 2021.

Discovery Programs

In parallel to the clinical trial developments, MiNA is further expanding its drug discovery pipeline with a focus on developing new drug candidates that can address a range of indications including genetic and metabolic diseases. Most recently in January 2020, MiNA validated its metabolic disease capabilities through the entry into a research collaboration with AstraZeneca, a global leader in the discovery and development of prescription medicines to treat metabolic diseases. MiNA remains well-positioned to build out its early-stage pipeline based on its saRNA approach which, through transcriptional activation, enables the modulation of previously undruggable targets.

About MTL-CEBPA

MTL-CEBPA is the first therapy to specifically up-regulate CCAAT/enhancer binding protein alpha (C/EBP-), a transcription factor that acts as a master regulator of myeloid cell lineage determination and differentiation. Dysregulated myeloid cells have been implicated in several diseases and identified as a critical barrier for many therapies to induce clinical responses in solid tumour cancers. In pre-clinical studies MTL-CEBPA has been shown to improve the anti-tumour activity of cancer therapies by targeting dysregulated myeloid cells and reducing their suppression in the tumour microenvironment.

About MiNA Therapeutics

Harnessing an innate mechanism of gene activation, MiNA Therapeutics' platform enables the development of new medicines that restore normal function to patients cells. We are applying our technology and clinical know-how to transform the therapy landscape of cancer and other severe diseases. http://www.minatx.com

View source version on businesswire.com: https://www.businesswire.com/news/home/20200527005028/en/

View post:
MiNA Therapeutics Announces Publication of Phase I Liver Cancer Data in Clinical Cancer Research and Provides Update on Clinical Development and Drug...

DetailsCategory: AntibodiesPublished on Wednesday, 27 May 2020 10:34Hits: 305

In CheckMate -9LA, Opdivo + Yervoy combined with two cycles of chemotherapy demonstrated superior overall survival versus chemotherapy, regardless of PD-L1 expression or tumor histology1

Approval marks sixth indication for Opdivo + Yervoy-based combinations across five types of cancer

Two Opdivo + Yervoy-based combinations are now approved in first-line lung cancer

PRINCETON, NJ, USA I May 26, 2020 IBristol Myers Squibb (NYSE: BMY) today announced that Opdivo (nivolumab) 360 mg plus Yervoy (ipilimumab) 1 mg/kg (injections for intravenous use) given with two cycles of platinum-doublet chemotherapy was approved by the U.S. Food and Drug Administration (FDA) for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations.1 The therapy is approved for patients with squamous or non-squamous disease and regardless of PD-L1 expression.1 This application was reviewed under the FDAs Real-Time Oncology Review (RTOR) pilot program, which aims to ensure that safe and effective treatments are available to patients as early as possible.2 On May 15, the FDA approved Opdivo + Yervoy as a first-line treatment for certain patients with metastatic NSCLC whose tumors express PD-L11% as determined by an FDA-approved test.

Approval for Opdivo + Yervoy with limited chemotherapy is based on the pre-specified interim analysis from the Phase 3 CheckMate -9LA trial in which Opdivo + Yervoy combined with two cycles of platinum-doublet chemotherapy demonstrated superior overall survival (OS) versus chemotherapy (hazard ratio [HR] 0.69; 96.71% confidence interval [CI]: 0.55 to 0.87; P=0.0006) regardless of PD-L1 expression or tumor histology (minimum 8.1 months follow up).1,3 Median overall survival (mOS) was 14.1 months (95% CI: 13.2 to 16.2) versus 10.7 months (95% CI: 9.5 to 12.5), respectively.1 In a follow-up analysis at 12.7 months, the hazard ratio improved numerically to 0.66 (95% CI: 0.55 to 0.80), with mOS of 15.6 months (95% CI: 13.9 to 20.0) and 10.9 months (95% CI: 9.5 to 12.5).1,3 At one year, 63% of patients treated with Opdivo + Yervoy with limited chemotherapy and 47% of those treated with chemotherapy were still alive.3

Opdivo is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion-related reactions; embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when Opdivo is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.1,4 Please see the Important Safety Information section below, including Boxed WARNING for Yervoy regarding immune-mediated adverse reactions.4

We have come a long way in understanding the role of dual immunotherapy-based approaches in cancer and the potential impact on patients long-term outcomes, said David P. Carbone, MD, PhD, CheckMate -9LA investigator and Director of the James Thoracic Oncology Center at The Ohio State University. The positive findings from CheckMate -9LA demonstrate the benefit of combining dual immunotherapy with limited chemotherapy for NSCLC patients regardless of PD-L1 status. With todays approval, more patients now have access to an Opdivo + Yervoy-based option and a chance at a longer life.1

In the trial, the overall response rate (ORR) per Blinded Independent Central Review (BICR) was 38% (95% CI: 33 to 43) for patients treated with Opdivo + Yervoy with limited chemotherapy and 25% (95% CI: 21 to 30) for patients treated with chemotherapy.

Non-small cell lung cancer is a complex disease that requires multiple treatment options to address the needs of different patient populations,5 said Adam Lenkowsky, general manager and head, U.S., Oncology, Immunology, Cardiovascular, Bristol Myers Squibb. This second approval of an Opdivo + Yervoy-based combination for the first-line treatment of advanced NSCLC now gives more patients access to a dual immunotherapy approach that can be administered with or without limited chemotherapy, depending on the patient and their PD-L1 status, and the possibility of a chance to live longer.1

Opdivo + Yervoy is a unique combination of immune checkpoint inhibitors, featuring a potentially synergistic mechanism of action that targets two different checkpoints (PD-1 and CTLA-4) to help destroy tumor cells: Yervoy helps activate and proliferate T cells, while Opdivo helps existing T cells discover the tumor.1,4,6 Some of the T cells stimulated by Yervoy can become memory T cells, which may allow for a long-term immune response.6,7,8,9,10,11 Targeting of normal cells can also occur and result in immune-mediated adverse reactions, which can be severe and potentially fatal.1 Please see the Important Safety Information section, including Boxed WARNING for Yervoy (ipilimumab) regarding immune-mediated adverse reactions.4

Receiving a diagnosis of advanced lung cancer is devastating,12 said Andrea Ferris, president and chief executive officer, LUNGevity. Todays announcement is welcome news as it provides a new dual immunotherapy-based option for previously untreated patients searching for a treatment that may help extend their lives.1

This application is part of the FDAs Project Orbis initiative, enabling concurrent review by the FDA and the health authorities in Australia, Canada and Singapore.

About CheckMate -9LA

CheckMate -9LA (NCT03215706) is a Phase 3, randomized open-label, multi-center study evaluating Opdivo + Yervoy combined with two cycles of platinum-doublet chemotherapy versus platinum-doublet chemotherapy (four cycles followed by optional pemetrexed maintenance therapy if eligible) as a first-line treatment in patients with metastatic or recurrent NSCLC regardless of PD-L1 expression and histology.1 A total of 361 patients were treated with Opdivo + Yervoy with platinum-doublet chemotherapy until disease progression, unacceptable toxicity or for up to two years.1 A total of 358 patients were treated with platinum-doublet chemotherapy for four cycles and optional pemetrexed maintenance for non-squamous patients (if eligible) until disease progression or toxicity.1 The primary efficacy outcome measure of the trial was OS.1 Additional efficacy outcome measures included progression-free survival, ORR and duration of response as assessed by BICR.1

Select Safety Profile from CheckMate -9LA Study

Serious adverse reactions occurred in 57% of patients.1 Opdivo + Yervoy in combination with platinum-doublet chemotherapy were discontinued for adverse reactions in 24% of patients and 56% had at least one treatment withheld for an adverse reaction.1 The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis and respiratory failure.1 Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia and massive hemoptysis in the setting of thrombocytopenia.1 The most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%) and pruritus (21%).1

About Lung Cancer

Lung cancer is the leading cause of cancer death in the United States.12 The two main types of lung cancer are non-small cell and small cell.13 Non-small cell lung cancer is one of the most common types of lung cancer, and accounts for approximately 84% of diagnoses.13 Survival rates vary depending on the stage and type of the cancer when diagnosed.12

INDICATIONS

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. For this indication, OPDIVO 3 mg/kg is administered every 2 weeks with YERVOY 1 mg/kg every 6 weeks.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), 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 overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.

Bristol Myers Squibb: Advancing Cancer Research

At Bristol Myers Squibb, patients are at the center of everything we do. The goal of our cancer research is to increase patients quality of life, long-term survival and make cure a possibility. We harness our deep scientific experience, cutting-edge technologies and discovery platforms to discover, develop and deliver novel treatments for patients.

Building upon our transformative work and legacy in hematology and Immuno-Oncology that has changed survival expectations for many cancers, our researchers are advancing a deep and diverse pipeline across multiple modalities. In the field of immune cell therapy, this includes registrational CAR T cell agents for numerous diseases, and a growing early-stage pipeline that expands cell and gene therapy targets, and technologies. We are developing cancer treatments directed at key biological pathways using our protein homeostasis platform, a research capability that has been the basis of our approved therapies for multiple myeloma and several promising compounds in early- to mid-stage development. Our scientists are targeting different immune system pathways to address interactions between tumors, the microenvironment and the immune system to further expand upon the progress we have made and help more patients respond to treatment. Combining these approaches is key to delivering potential new options for the treatment of cancer and addressing the growing issue of resistance to immunotherapy. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines a reality for patients.

About Bristol Myers Squibbs Patient Access Support

Bristol Myers Squibb remains committed to providing assistance so that cancer patients who need our medicines can access them and expedite time to therapy.

BMS Access Support, the Bristol Myers Squibb patient access and reimbursement program, is designed to help appropriate patients initiate and maintain access to BMS medicines during their treatment journey. BMS Access Support offers benefit investigation, prior authorization assistance, as well as co-pay assistance for eligible, commercially insured patients. More information about our access and reimbursement support can be obtained by calling BMS Access Support at 1-800-861-0048 or by visiting http://www.bmsaccesssupport.com.

About the Bristol Myers Squibb and Ono Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol Myers Squibb further expanded the companies strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies as single agents and combination regimens for patients with cancer in Japan, South Korea and Taiwan.

About Bristol Myers Squibb

Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram.

Celgene and Juno Therapeutics are wholly owned subsidiaries of Bristol-Myers Squibb Company. In certain countries outside the U.S., due to local laws, Celgene and Juno Therapeutics are referred to as, Celgene, a Bristol Myers Squibb company and Juno Therapeutics, a Bristol Myers Squibb company.

References

SOURCE: Bristol-Myers Squibb

See the rest here:
US Food and Drug Administration Approves Opdivo (nivolumab) + Yervoy (ipilimumab) Combined with Limited Chemotherapy as First-Line Treatment of...

TheGlobal Canavan Disease Marketwas estimated to be valued at USD XX million in 2019 and is projected to reach USD XX million by 2026, at a CAGR of XX% during 2019 to 2026.

Canavan disease is an autosomal recessive degenerative disorder that causes progressive damage to nerve cells in the brain. The market is primarily driven by increasing prevalence of life threatening cerebral diseases. However, lack of awareness and lack of skilled neurologist might impede the market growth.

Get Sample Copy of this Report @https://www.orianresearch.com/request-sample/1040619

Development policies and plans are discussed as well as manufacturing processes and cost structures are also analyzed. This report also states import/export consumption, supply and demand Figures, cost, price, revenue and gross margins.

The key players profiled in the market include:Johnson & Johnson, GlaxoSmithKline plc., Novartis AG, Sanofi, F. Hoffmann-La Roche Ltd., Amgen, Inc., Turing Pharmaceuticals AG, Pfizer Inc., Aspa Therapeutics and BridgeBio

Key Benefits of the Report:

Global Canavan DiseaseMarket is spread across 121 pages

Inquire more or share questions if any before the purchase on this report @https://www.orianresearch.com/enquiry-before-buying/1040619

On the basis of types, the market is split into:

Based on applications, the market is divided into:

Moreover, the market is classified based on regions and countries as follows:

Order a Copy of Global Canavan Disease Market Report @https://www.orianresearch.com/checkout/1040619

Target Audience:

Table Of Content

1 Introduction

2 Research Methodology

3 Executive Summary

4 Global Canavan Disease Market Overview

5 Global Canavan Disease Market, by Product Type

6 Global Canavan Disease Market, by Application

7 Global Canavan Disease Market by Region

8 Competitive Landscape

9 Company Profiles

10 Key Insights

Customization Service of the Report:Orian Research provides customisation of reports as per your need. This report can be personalised to meet your requirements. Get in touch with our sales team, who will guarantee you to get a report that suits your necessities.

Contact Us:Ruwin MendezVice President Global Sales & Partner RelationsOrian Research ConsultantsUS +1 (415) 830-3727 | UK +44 020 8144-71-27Email:[emailprotected]Website: http://www.orianresearch.com/

About UsOrian Research is one of the most comprehensive collections of market intelligence reports on the World Wide Web. Our reports repository boasts of over 500000+ industry and country research reports from over 100 top publishers. We continuously update our repository so as to provide our clients easy access to the worlds most complete and current database of expert insights on global industries, companies, and products. We also specialize in custom research in situations where our syndicate research offerings do not meet the specific requirements of our esteemed clients.

Read this article:
COVID-19 Impact on Global Canavan Disease Market 2020: Industry Share, Size, Applications, Top Key Players and Forecast Research to 2026 - 3rd Watch...

Magarpatta SEZ, Pune, ReportsnReportsprovides in depth study ofHemophilia Gene Therapy Marketusing SWOT analysis i.e. Strength, Weakness, Opportunities and Threat to the organisation. The Hemophilia Gene Therapy Market report also provides an in-depth survey of key players in the market which is based on the various objectives of an organisation such as profiling, the product outline, the quantity of production, required raw material, and the financial health of the organisation.

The global Hemophilia Gene Therapy Market is expected to witness a promising growth in the next few years. The rising level of competition among the leading players and the rising focus on the development of new products are likely to offer promising growth opportunities throughout the forecast period. The research study on the global Hemophilia Gene Therapy Market offers a detailed overview, highlighting the key aspects that are expected to enhance the growth of the market in the near future. The key segmentation and the competitive landscape of the market have also been mentioned at length in the research study.

GetFree Sample PDF Copy of Hemophilia Gene Therapy Market with Figures, Graphs and Tocs:https://www.reportsnreports.com/contacts/requestsample.aspx?name=2840557

The global Hemophilia Gene Therapy Market is highly fragmented. Small market players operating at regional and local levels are challenging the market shares of the leading players (on the basis of cost differentiation and technical support services). In order to maintain their market shares, leading players are continuously developing new technologies and upgrading their existing products and services to enhance their product portfolios. Increasing competition is expected to drive innovation in the market, thereby helping the industry to overcome existing challenges in the field of healthcare mobility and at the same time address user compliance issues and unmet needs of the market.

Analysis on Strategies of Leading Players: Market players can use this evaluation to gain competitive advantage over their competition inside the global Hemophilia Gene Therapy Market.

Summary

Market OverviewThe global Hemophilia Gene Therapy market size is expected to gain market growth in the forecast period of 2020 to 2025, with a CAGR of xx% in the forecast period of 2020 to 2025 and will expected to reach USD xx million by 2025, from USD xx million in 2019.The Hemophilia Gene Therapy market report provides a detailed analysis of global market size, regional and country-level market size, segmentation market growth, market share, competitive Landscape, sales analysis, impact of domestic and global market players, value chain optimization, trade regulations, recent developments, opportunities analysis, strategic market growth analysis, product launches, area marketplace expanding, and technological innovations.

Market segmentationHemophilia Gene Therapy market is split by Type and by Application. For the period 2015-2025, the growth among segments provide accurate calculations and forecasts for sales by Type and by Application in terms of volume and value. This analysis can help you expand your business by targeting qualified niche markets.By Type, Hemophilia Gene Therapy market has been segmented into Hemophilia A, Hemophilia B, etc.By Application, Hemophilia Gene Therapy has been segmented into Hemophilia A Gene Therapy, Hemophilia B Gene Therapy, etc.

Regions and Countries Level AnalysisRegional analysis is another highly comprehensive part of the research and analysis study of the global Hemophilia Gene Therapy market presented in the report. This section sheds light on the sales growth of different regional and country-level Hemophilia Gene Therapy markets. For the historical and forecast period 2015 to 2025, it provides detailed and accurate country-wise volume analysis and region-wise market size analysis of the global Hemophilia Gene Therapy market.The report offers in-depth assessment of the growth and other aspects of the Hemophilia Gene Therapy market in important countries (regions), including United States, Canada, Mexico, Germany, France, United Kingdom, Russia, Italy, China, Japan, Korea, India, Southeast Asia, Australia, Brazil and Saudi Arabia, etc. It also throws light on the progress of key regional Hemophilia Gene Therapy markets such as North America, Europe, Asia-Pacific, South America and Middle East & Africa.

Competitive Landscape and Hemophilia Gene Therapy Market Share AnalysisHemophilia Gene Therapy competitive landscape provides details by vendors, including company overview, company total revenue (financials), market potential, global presence, Hemophilia Gene Therapy sales and revenue generated, market share, price, production sites and facilities, SWOT analysis, product launch. For the period 2015-2020, this study provides the Hemophilia Gene Therapy sales, revenue and market share for each player covered in this report.The major players covered in Hemophilia Gene Therapy are: Spark Therapeutics, Freeline Therapeutics, Sangamo Therapeutics, Ultragenyx, uniQure, Shire PLC, BioMarin, Bioverativ, etc. Among other players domestic and global, Hemophilia Gene Therapy market share data is available for global, North America, Europe, Asia-Pacific, Middle East & Africa and South America separately. Global Info Research analysts understand competitive strengths and provide competitive analysis for each competitor separately.

The Hemophilia Gene Therapy Market industry development trends and marketing channels are analyzed. Finally, the feasibility of new investment projects is assessed, and overall research conclusions offered.

Enquire More About Hemophilia Gene Therapy Market:https://www.reportsnreports.com/contacts/discount.aspx?name=2840557

This report studies the Hemophilia Gene Therapy Marketstatus and outlook of Global and major regions, from angles of players, countries, product types and end industries; this report analyzes the top players in global market, and splits the Hemophilia Gene Therapy Marketby product type and applications/end industries. These details further contain a basic summary of the company, merchant profile, and the product range of the company in question. The report analyzes data regarding the proceeds accrued, product sales, gross margins, price patterns, and news updates relating to the company.

Other than the aforementioned parameters which Hemophilia Gene Therapy Market report focuses on, another imperative objective of the report is to present the Hemophilia Gene Therapy Market development across the globe especially in North America, Europe, China, Japan, Southeast Asia, India and Central and South America. In the report, the market has been categorized into manufacturers, type, application and regions.

Avail 20% offer on Full Report Using Coupon Code Available on website @https://www.reportsnreports.com/purchase.aspx?name=2840557

The report helps to identify the main Hemophilia Gene Therapy Marketplayers. It assists in analyzing Hemophilia Gene Therapy Market competitive environment, including company overview, company total revenue, market opportunities, value, production sites and facilities, SWOT analysis, product details. The study also reveals the sales, revenue and market share for each market player included in this report for the period of 2015-2020. It also helps to ascertain the growth drivers and future prospects for the forecast timeline.

Conclusively, this report is a one stop reference point for the industrial stakeholders to get Hemophilia Gene Therapy Marketforecast of till 2025. This report helps to know the estimated market size, market status, future development, growth opportunity, challenges, growth drivers of by analyzing the historical overall data of the considered market segments.

About Us: ReportsnReports.com is your single source for all market research needs. Our database includes 500,000+ market research reports from over 95 leading global publishers & in-depth market research studies of over 5000 micro markets.

We provide 24/7 online and offline support to our customers.

E-mail: [emailprotected]

Phone: +1 888 391 5441

Read the original post:
Hemophilia Gene Therapy Market 2020 by Global Industry Trends, Sales Revenue, Industry Growth, Development Status, Top Leaders, Future Plans and...

Global Viral Vector & Plasmid DNA Manufacturing Market Report is a finished appraisal of current market Status, Opportunities, Trends, and individual pieces of the pie of the absolute most conspicuous players in this scene. The investigation contains mindful experiences, realities, chronicled information, and factually bolstered and industry-approved market information. This examination additionally investigates Business models, Key techniques, and Growth openings in the up and coming years.

The catchphrase showcase report looks at the financial status and anticipation of worldwide and significant areas, in the possibility all things considered, types and end-client application/ventures; this report analyzes the most striking players in major and worldwide locales, likewise partitions the Viral Vector & Plasmid DNA Manufacturing advertise by portions and applications/end organizations.

Solicitation for Sample Copy @ http://www.researchreportsinc.com/report-sample/821488

Significant Key Vendors:-

Worldwide Viral Vector & Plasmid DNA Manufacturing Market bits of knowledge spread qualities, development, and size, division, provincial retreats, serious scene, pieces of the pie, patterns, and plans. The qualities part of this catchphrase report characterizes and clarifies the development. The Viral Vector & Plasmid DNA Manufacturing showcase size office gives industry income, covering the verifiable development of this and foreseeing the since quite a while ago run. Viral Vector & Plasmid DNA Manufacturing Drivers and limitations with the factors influencing the development of this market. The division isolate the fundamental catchphrase sub-businesses that structure the market.

Types are separated into:

Applications are separated into:

Noteworthy areas shrouded in this report:

North America, China, Rest of Asia-Pacific, UK, Europe, Central South America, Middle East Africa

Get Discount on this report @ http://www.researchreportsinc.com/check-discount/821488

The Viral Vector & Plasmid DNA Manufacturing investigation consolidates authentic information from 2014 to 2019 and forecasts until 2025 assisting with making the reports an important asset for industry administrators, advancement, item and project leads, counselors, experts, and various individuals attempting to discover essential catchphrase industry information in promptly available records with unmistakably showed tables and diagrams.

Significant Points Covered In The Report:

Connect With Us:

Name: David

Email: [emailprotected]

Website: http://www.researchreportsinc.com

Telephone: UK: +4403308087757 USA: +18554192424

Originally posted here:
Impact COVID-19 on Viral Vector & Plasmid DNA Manufacturing Market Along with Major Market Players | Merck, uniQure, The Cell and Gene Therapy...

Can melatonin make you as sleepy as this pup?

Sleep: We all want more. Most of us are in perpetual sleep debt, accruing lost hours every time we hit the hay. Waking up puffy-eyed and groggy is not ideal, yet many people accept it as their normal. The occasional late night at work or weekend of partying doesn't help our quest for more shut-eye.

If only there was a supplement that promised to improve your sleep cycle so you could bounce out of bed bright-eyed and bushy-tailed every morning.

Our Health & Wellness newsletter puts the best products, updates and advice in your inbox.

Melatonin, per various marketing claims, pill bottles and social media hype, could be that supplement. Is it really that easy, though? Can you just pop a sleep supplement before bed and quickly enter dreamland -- and stay there till sunrise?

If you're itching to grab a bottle of melatonin gummies next time you're at your local drugstore, first read up on the potential benefits and risks, plus how to supplement melatonin smartly and avoid dangerous drug interactions.

Read more: Collagen supplements promise smooth skin, but you should eat these foods instead

What is melatonin?

Melatonin is a hormone that animals, including humans, produce to regulate circadian rhythms. Melatonin may have some other functions, but its role in sleep-wake cycles is the most extensively studied and understood.

Read more: Caffeine: How bad is it really?

Now playing: Watch this: 9 sleep myths, busted by a sleep doctor

7:07

How does melatonin work?

Your body naturally produces melatonin in response to darkness and reduces production of melatonin in response to light. It's referred to as the "sleep hormone" because it essentially tells your body when to sleep and when to wake up.

Everyone has a circadian rhythm or "internal clock" that runs on a 24-hour cycle and is affected by your body's production of melatonin.

How it works: A certain area of your brain -- specifically thesuprachiasmatic nucleusin the hypothalamus -- controls this body clock, and it's primarily influenced by light and environment.

Your SCN processes that information and signals your body to produce melatonin accordingly. Various tissues in your body produce melatonin, but the main source is the pineal gland, a small gland inside your brain.

Melatonin production can be suppressed by constant exposure to light, which is primarily where all of the advice about shutting down screens an hour before bed comes from: Feeding your eyes bright light up until the point you shut your eyes can result in a wacky melatonin-production schedule, thus a messed up sleep schedule.

Melatonin supplementation is supposed to aid your body's natural production of melatonin -- if done correctly, this theoretically can help regulate your circadian rhythm and result in better sleep. While potentially beneficial if used properly, supplemental melatonin can be detrimental or, at best, useless, if not used with care.

Read more: Vitamin D is crucial for immune health -- make sure you're getting enough

Melatonin benefits

The obvious benefit is that melatonin can help you sleep more and sleep better, if used correctly (more on that later). However, melatonin can do much more than boost just one night of sleep -- it can also help you reset your circadian rhythm and result in a firmly established, healthy sleep cycle. You don't need a doctor to tell you that a healthy sleep cycle can help you be more alert, motivated and productive.

Basically, the benefits of melatonin mirror those of getting more sleep, and they can extend much further into your life than you may initially think. Sleep is the foundation of human function: Without it, we are at risk for an array of emotional and physical health problems, not to mention things like auto accidents and other dangerous mistakes.

Melatonin can also benefit people who have secondary sleep disorders, or a sleep disorder that's a symptom of a different condition or circumstance. This includes people whose jobs require shift work, poor sleep caused by jet lag and sleep-wake disorders in people who are blind.

Read more: Vitamin C: Why you need it and how to get enough of it

Melatonin risks and side effects

All supplements come with risks -- melatonin is no different.

Short-term side effects of melatonin are generally mild, but can still be frustrating or inconvenient. Side effects reported in clinical trials related to melatonin include:

Other than those listed, melatonin doesn't appear to induce any serious conditions, although some health organizations and practitioners worry that supplementing melatonin may mess with your body's natural production of the hormone. There's no evidence to currently support the idea that people build a tolerance to melatonin, though.

Certain people should use caution with melatonin to avoid any potential complications, including people who are pregnant or breastfeeding, people who are on dialysis treatment, people who have liver problems and people with autoimmune conditions.

Read more: Zinc and coronavirus: The supplement may help reduce severity of symptoms, but it's no cure

Is melatonin safe?

Melatonin is generally considered safe for short-term use, although some health agencies express concern about product quality and efficacy, as well as labels with misinformation. Here's the lowdown from some of the biggest health agencies:

As for the stance of the Food and Drug Administration on melatonin, there isn't really one. In the US, melatonin is classified as a dietary supplement, which means it is less strictly regulated than food ingredients or medications. The FDA has sent warning letters in the past to food and beverage companies who make questionable claims about melatonin in their products.

Melatonin is probably one of the most studied supplements currently available to consumers. Evidence in individual scientific studies sways both ways, but meta-analyses generally come to the same conclusion: Melatonin is generally safe and well-tolerated, even in the absence of sleep improvements.

Does melatonin actually work?

The scientific evidence on melatonin points in both directions: Many studies say it works, many say it doesn't. This could be because melatonin affects everyone differently (as do all supplements), so to find out if melatonin works for you, you'd have to try it yourself.

For argument's sake, here are some recent peer-reviewed studies on the efficacy of melatonin:

If you do decide to take melatonin, consider discussing potential benefits and risks with your doctor first, as well as proper dosing and timing guidelines, which are outlined below.

There are also many research studies on the efficacy of melatonin as it pertains to specific conditions, such as melatonin for sleep following a traumatic brain injury, melatonin for Parkinson's disease and melatonin for ADHD. If you have a health condition you think may benefit from melatonin, perusing studies can help you learn more, although you should definitely check with your doctor, too.

Is melatonin addictive?

There's no evidence that melatonin as a substance is addictive. No studies have reported that melatonin can cause people to build a dependence on or tolerance of the hormone, and it isn't known to cause symptoms of withdrawal.

What you may become "addicted" to, though, is the feeling of improved sleep. Once you know what it feels like to fall asleep quickly, stay asleep through the night and wake up energetic, it's tough to go back to the exact opposite. This may make it hard for you to fall asleep without the help of melatonin.

Even though melatonin isn't known to be addictive, if you have a history of addiction to any substance, it may be a good idea to discuss melatonin with your doctor before trying it.

Best time to take melatonin

Studies support taking melatonin between 30 minutes and two hours before bedtime. The range exists because everyone absorbs medications at different rates and your own body's melatonin production can affect how quickly supplemental melatonin works.

The most important thing is to avoid taking melatonin too late at night -- like way after your bedtime -- lest your sleep cycle get shifted and you have to drag yourself out of a cycle of late nights.

How much melatonin should you take?

There's no exact dosage of melatonin that everyone should take, as it can vary based on factors such as gender, age, health conditions, body size and more. According to the NIH, no effective dosing has been established, and dosing in studies has ranged from 0.1 up to 10 milligrams.

The National Sleep Foundation recommends a dose of 0.2 milligrams to 5 milligrams for adults, although it's not clear where that determination came from. If you plan to take melatonin, try starting with the smallest possible dose and working your way up to a dose that helps you fall asleep but doesn't cause any side effects.

Keep in mind that the FDA doesn't regulate melatonin, so what you see on the product label may not be what you get.

Can you take melatonin every night?

There's no evidence that warrants advising against taking melatonin every day, but keep in mind that the majority of clinical trials to date have only tested short-term use of melatonin (three months or less), and that more research is needed to determine if it's safe to take melatonin every day for a long time.

Should you take melatonin for insomnia?

If you have or think you have insomnia, you should chat with your doctor about melatonin as a potential treatment. Some major health agencies advise against using melatonin to treat insomnia and instead advocate for cognitive behavioral therapy or another drug-free intervention.

Your doctor may want you to try lifestyle modifications first, such as increasing your daily exercise, changing your eating habits or reducing alcohol consumption. Your provider will also want to rule out other conditions that can coexist with insomnia, such as anxiety or depression. Sometimes, when drug-free interventions don't suffice, prescription medication is needed to treat insomnia.

Can you take melatonin with...?

Before you take melatonin, check with your doctor if you have any existing health conditions. According to drugs.com, which is powered in part by theAmerican Society of Health-System Pharmacists, Harvard Health and Mayo Clinic, you should take caution -- and ask your doctor if you can take melatonin -- if you have any of the following health conditions:

You should also check with your doctor about melatonin drug interactions if you're currently on any other medications, including other sedatives.

Remember, when taking any dietary supplement, use it wisely.

The information contained in this article is for educational and informational purposes only and is not intended as health or medical advice. Always consult a physician or other qualified health provider regarding any questions you may have about a medical condition or health objectives.

View post:
Melatonin: Is it safe, does it work and other FAQs - CNET

Menopause is a natural phase of a womans life and is marked by the complete cessation of periods for one whole year. The average age at which Indian women undergo menopause is approximately 46 years. The main physiological change is that the ovaries stop producing the female reproductive hormone- estrogen.The years prior to menopause are called pre-menopause and they involve many changes such as irregular periods, vasomotor symptoms such as hot flashes(feeling hot suddenly for a few seconds to minutes especially in the face), cold sweats(i.e., sweating for no reason), mood disturbances including irritability, emotional lability and bouts of anger and crying etc. Other changes include urogenital symptoms such as urinary leakage, urgency and vaginal dryness and irritation; skin changes such as thinning, dryness, itching etc and loss and thinning of scalp hair. These symptoms can be variable in presentation and severity. About 80% women experience symptoms like hot flashes, which is the most common symptom.The health risks revolve around the effects of lack of estrogen such as bone loss leading to osteoporosis and associated fragility fractures, heart disease such as atherosclerosis, myocardial infarction, dementia, psychological disorders, certain cancers like breast, colon cancer etc.Being well-informed is the first step towards self-care. It is important that women in their premenopausal years undergo certain baseline tests to determine if there are any underlying diseases. Common disorders that may be pre-existing or new-onset are anaemia, hypocalcemia, vitamin D deficiency, osteoporosis, diabetes mellitus, hypertension and hypothyroidism, hypercholesterolemia and depression and anxiety. Also a baseline cancer screening is important and involves tests like Pap smear for cervical cancer, clinical breast examination and mammography and an ultrasound scan of the abdomen and pelvis.Lifestyle modification forms the fundamental preventive strategy at this age. Consistent moderate exercises such as weight bearing exercises, strength and balance exercises, yoga asanas and surya namaskar, regular walking or jogging go a long way in maintaining physical and emotional health. Nutrition at this stage is also important and should aim to get enough calcium, iron and other micronutrients along with soya based protein which is rich in phytoestrogens (plant based estrogen). Calcium supplements and vitamin D supplementation may be required to prevent weakening of bones. About one fifth of menopausal women may have severe symptoms for which various medications may need to be initiated. Menopausal hormone therapy can be given in selected individuals after a thorough evaluation, and helps alleviate symptoms substantially. Although, fertility rates drop substantially in perimenopause, women must use effective contraception until menopause is complete i.e., a year has passed since the last period.Regular follow up with physician, gynaecologist, urologist, psychiatrist, orthopaedician, ophthalmologist etc is vital to maintain health over the long term. Annual or more frequent health checks would help in identifying diseases earlier.Being fit at forty, strong at sixty and independent at eighty should be the motto for us women.May 25th 2020By Dr. Aruna Muralidhar, senior consultant obstetrician and gynaecologist, Fortis La Femme, Richmond Town, Bengaluru

Disclaimer: The views and opinions expressed by the doctors are their independent professional judgment and we do not take any responsibility for the accuracy of their views. This should not be considered as a substitute for physician's advice. Please consult your treating physician for more details.

See the original post here:
Menopause: How to prepare your body for it - Times of India

A month following surgery for thyroid cancer, a Hartford Hospital patients tumor grew to 10 inches. The case was presented to the hospitals tumor board, which involved 30 doctors from different specialties.

The gene mutation found to be controlling the patients tumor growth was already well-established as a driver of melanoma, the deadliest form of skin cancer, says Dr. Sope Olugbile, medical oncologist at Hartford HealthCare.Chemotherapy wouldnt work fast enough against the aggressive tumor. Tumor board members recommended a targeted therapy already treating patients with melanoma. Without that genetic information, we wouldnt have been able to come up with that therapy, he says. The treatment saved the patients life, so far. Our goal is to use more of the genetic information to drive the treatment of cancer patients.

This type of personalized care, known as precision medicine and its subset, genomic medicine, has been offered for years at world-renowned cancer-treatment hospitals such as Memorial Sloan Kettering Cancer Center in New York, Dana-Farber Cancer Institute in Boston and University of Texas MD Anderson Cancer Center in Houston. Its now the standard of care in Connecticuts Hartford HealthCare Cancer Institute, UConn Health Center in Farmington, Connecticut Childrens Medical Center in Hartford and Smilow Cancer Center at Yale New Haven Health.Cancer therapy has become precision therapy, says Dr. Roy Herbst, professor of medicinal oncology and pharmacology, and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital.

Dr. Roy Herbst, of Yale Cancer Center and Smilow Cancer Hospital, says that precision care is often used in cancer treatment these days.

While its most commonly used with cancer patients, precision medicine is also making inroads into other areas of health care including the treatment of some cardiac patients. Its also being studied and used on a limited basis to treat those with rare diseases. In the U.S., newborns are screened with a blood test for hearing loss and heart defects. If detected and treated early, this can prevent death and disability in some cases. For some doctors and researchers, precision medicine holds the promise of effective targeted diseases and chronic conditions, and, even more revolutionary, the chance to prevent illness before it arises. The race is on to gather as much data as possible in order to increase understanding of the connection between genes and overall health; here in Connecticut, Yales Center for Genetic Health last fall launched its Generations project to collect DNA from 100,000 volunteers (see sidebar below).

Precision medicine involves the study of human genes, called the genome. The human genome contains 23 pairs of chromosomes within all human cells, and each chromosome contains hundreds to thousands of genes. Using high-level computing and mathematics, genomics researchers analyze massive amounts of DNA-sequence data to find variations or mutations that affect health, disease or response to drugs, according to an online description by The Jackson Laboratory for Genomic Medicine in Farmington.

Researchers can sequence an entire tumor to look for markers or abnormalities that can be treated with a targeted medication that attacks that mutation, unlike traditional chemotherapy that kills healthy cells along with cancer cells, says Herbst, also associate director for translational science at the Yale School of Medicine.

These days, when Yales precision medicine tumor board meets weekly, they dont focus on where the tumor began, he says. They look at what errors occurred in the DNA of the tumor, because once they know whats driving the tumor, they can treat it.For example, lung cancer is the most common cancer in the world. When a nonsmoker gets lung cancer, doctors sequence the tumors DNA to see if it contains one of eight genes known to mutate.

Each cancer cell has about 18,000 to 20,000 genes, and there are some cancers where just one of those genes is directing the growth of the cancer, Olugbile says. We call that the driver gene. The other 17,999 are just following the lead of that driver gene, he says. That means if we tag just that one gene with the medication then we can actually shut down the growth of the entire cancer.

Traditional chemotherapy can only be given for 4-6 months because of the side effects, while targeted oral medications have very few side effects and patients remain on them for an average of two years, Olugbile says.

In the past five years, genetic testing has become standard of care for some cancers specifically colon, lung and melanoma because those types of cancers tend to have genetic mutations that have been known to respond to therapy, says Sara Patterson, manager of clinical analytics and curation at Jackson Labs, which works with UConn and Yale researchers.But targeted therapy is not a cure-all, and researchers are still a long way from using precision medicine to treat all cancer patients. Even if cancers have the same genomic change and mutation, theres no guarantee they will all respond to the same therapy, she says.Overall, precision medicine is only effective at stopping the spread of cancer in an average of 20 percent of cancer patients treated, Olugbile says, with variations by cancer. Sometimes the cancer returns because the tumor changes to resist the therapy, Patterson adds.

As doctors and researchers do more genomic sequencing, the data pool will grow and so will knowledge of what medications work most effectively against various tumor types.The more information we gather, the better well know how to treat specific patients, Patterson says.

Reimbursement from insurance companies can be a challenge. If precision treatment for a particular type of cancer hasnt been approved by the insurance industry, its difficult to get reimbursed for genomic testing, says Sue Mockus, director of product innovation and strategic commercialization at Jackson Labs.Its a catch-22. Even though a patient with pancreatic cancer could benefit from a targeted therapy, unless that patient is part of a clinical trial that would pay for the genomic testing, the patient would have to pay out of pocket, the annual cost of which can run into the hundreds of thousands of dollars. If you do have a mutation identified and your physician wants to give you the medication off label, you have to fight with the insurance company, Mockus says.

Experts have suggested a value-based approach to precision medicine, reports the International Journal of Public Health. This means policy decisions about reimbursement and investment in research and development will factor in how long patients lives are prolonged and the quality of those lives, the Journal reports.

Oncologists also offer cancer patients immunotherapy, another form of personalized medicine, Patterson says. Theyre using diagnostic tests on tumors, independent of genomic sequencing, to determine if their tumor profiles make them a good immunotherapy candidate. Immunotherapy is approved for multiple tumor types, as long as they have certain markers, she says.

Former President Jimmy Carter became cancer free after receiving radiation and immunotherapy to treat the melanoma that had spread to his brain and liver. While immunotherapy can cure cancer for some, its only effective about 20 percent of the time, Olugbile says. It varies a bit by cancer, with some cancers having a higher success rate, he adds.

Through a collaboration with Memorial Sloan Kettering, Hartford HealthCares Advanced Disease Clinic was scheduled to open this spring to give patients even more options, he says. If targeted therapies and immunotherapies dont work or are not a match for patients, doctors will look for suitable clinical trials that offer potential treatments, Olugbile says.Our goal is to create awareness on two fronts, one is among the doctors. Yes, we are available to help if patients have gone through standard of care who didnt respond, he says. Its also an option for patients who want to be treated with precision medicine closer to home. The goal is to make it available so they dont have to go to New York or Boston, he says. Its right here in Hartford and hopefully at other cancer centers over time.

From Yale, Herbst leads a clinical trial through the National Cancer Institute where he and his team are trying to match the right patient to the right drug.Every tumor is getting sequenced. Thats accelerating the field. The sequencing techniques have gotten cheaper and faster, so we can analyze them at the point of care, Herbst says. This is why clinical trials are so important. Whats a clinical trial today is standard of care tomorrow.

In a study published in the journal Science Translational Medicine, a multi-institutional research team including a Connecticut doctor developed an advanced method to analyze existing data from thousands of clinical trials, comparing which genes FDA-approved drugs work against to the genes active in pediatric brain tumor patients. This sped up the lengthy process of developing cancer drugs.

Dr. Ching Lau, head of the oncology-hematology division at Connecticut Childrens Medical Center and the pediatric oncology-hematology department at UConn School of Medicine, is accessing the World Community Grid, an IBM-funded program that allows researchers worldwide to perform tens of thousands of virtual experiments. Instead of screening thousands and thousands of compounds to try to find a potential drug, we found we could use genomics data already available and do a more systems-approach analysis to figure out the predominant pathways driving the tumor cells, Lau, professor at The Jackson Laboratory, says in an email. Then we asked if there were any existing FDA-approved drugs that could potentially modulate those pathways.

The researchers identified eight drugs that could potentially fight medulloblastoma (MB) tumors, the most common malignant brain tumor in children. One of the drugs showed an increased survival rate in mice with MB tumors, and a clinical trial is being pursued.

Personalized medicineand heart disease

Precision medicines applications have expanded beyond cancer care. At first, much heart disease research relied on a genetic analysis of whether someone was predisposed to a disease. Thanks to a growing database of patient information that is shared worldwide, researchers can mine huge data sets with hundreds of thousands of cases for patterns and abnormalities that lead to discoveries, says Beth Taylor, associate professor of kinesiology at UConn and director of exercise physiology research in cardiology at Hartford Hospital. Researchers and clinicians know that about half the people who have heart attacks dont have the typical risk factors such as high blood pressure, obesity and diabetes. To determine why physically active people with healthy diets have heart attacks, researchers are using precision medicine to comb through large studies to find small predictors, Taylor says. Often the influence of any one factor is hard to detect unless you have a big sample size, she says.

The National Institutes of Health requires grant recipients to share their data to a national registry so that researchers have access to big data, she says. (Personal information such as date of birth, name and address are removed from files used for research studies.)

When we first began to really measure genetic variations, it was believed that was going to be the big hope in treatment, Taylor says. But genes are complex and environmental factors modify genetics for multiple generations.

For the first time ever, weve got wide-scale computing ability to analyze huge data points. This can better allow us to predict disease progression and optimize treatment, she says. Many of us would say that this concept of big data is as or more important than genetic risk. Genetic risks are not the whole picture.

For the first time ever, weve got wide-scale computing ability to analyze huge data points. This can better allow us to predict disease progression and optimize treatment.

Progress with diabetes

Precision medicine is not widely used in the treatment ofdiabetesin the U.S., except when it comes to a rare form of diabetes called neonatal diabetes mellitus. While type 1 and type 2 diabetes are controlled by two or more genesand additional genetic factors,neonatal diabetes mellitus involves a single gene and develops in babies under 6 months old.

Through genetic testing of babies with elevated blood sugar levels,researchers learnedthat about half the patients have gene mutations that respond well to a pill used to treat type 2 diabetes and they dont need to be on insulin for the rest of their lives like type 1 diabetics, says Karel Erion,director of research stewardship and communications for the American Diabetes Association.

When infants show signs of type 1 diabetes at Yale New Haven Childrens Hospital or Connecticut Childrens Medical Center, they are automatically tested for neonatal diabetes, hospital doctors say.

An example of precision medicine as a predictor of disease is the TrialNet database, which uses genetic testing to determine whether the relatives of those with type 1 diabetes have two or more of the five diabetes-related autoantibodies (proteins produced by the immune system directed against the persons own proteins) linked to increased risk of developing type 1 diabetes. Type 1 diabetics must take insulin for the rest of their lives to survive, and theres no known way to prevent the autoimmune disease. Type 1 diabetes, formerly called juvenile diabetes, typically strikes children and adolescents, causing the pancreas to stop producing insulin, a hormone needed to process sugar, or glucose, from food. Type 2 diabetes was formerly known as adult-onset diabetes, but the disorder is being seen in more children, thought to be the result of a rise in childhood obesity. Screening identifies the early stages of the disease years before any symptoms appear, according to the TrialNet website.

In a study published in the New England Journal of Medicine, researchers from the TrialNet Study Group, led by Yale Universitys Dr. Kevan Herold, found that an experimental medication delayed the onset of type 1 diabetes in high-risk participants by two years compared to the control group. The disease was diagnosed in 43 percent of the participants who received the medication, teplizumab, and 72 percent of those who received the placebo.

Alzheimers disease and dementia

Only 1 to 3 percent of the 5 million people living with Alzheimers disease have a genetic mutation that leads to whats called genetic or familial Alzheimers. But one in three older adults will eventually develop some form of dementia, says Rebecca Edelmayer, the Alzheimers Association director of scientific engagement.

Like other diseases that strike large segments of the population, researchers rely on big data to learn about Alzheimers and which genes play a role in who gets it.Researchers have learned that there are several risk factors that contribute to dementia, she says. Specifically, the presence of heart disease, high blood pressure, diabetes, social and cognitive isolation, poor nutrition and the level of education, can contribute to cognitive decline, she says.

Scientists from around the world share research data and draw from data in the Global Alzheimers Association Interactive Network, she says.The field has made some dramatic advances in understanding of how genetics play a role and how other underlying diseases play a role, Edelmayer says. We need to give doctors evidence-based recommendations.

Read more here:
For cancer treatment and more, genetic-based precision medicine holds a lot of promise - Connecticut Magazine

What makes the coronavirus pandemic unlike any other collective tragedy is that we can't commiserate together.

Post-layoff drinks at a dive bar near the office; embracing someone you haven't seen in months; pats on the back these are seemingly small comforts that have morphed into luxuries in the past few months.

While there are many things I miss about the Before, these touches of comfort are high on the list. As we round the corner into another month of social distancing I find myself thinking about touch constantly. One look at dating apps or porn sites and I know I'm not alone in that.

The phrase "touch starved" might once have sounded dramatic, evoking Victorian-era courting where couples couldn't even bear witness to each other's ankles. In a time where I haven't high-fived let alone hugged someone in months, though, it doesn't sound overdramatic at all.

While there's limited research on "touch starvation" itself, according to Dr. Natasha Bhuyan, MD, a practicing family physician in Phoenix, Arizona, there's emerging touch research that emphasizes its positive impact. "Physical touch activates brain neurotransmitters that can lift our mood, reduce stress, and even improve sleep quality," she said.

Dr. Lori Whatley, clinical psychologist and author of Connected and Engaged, reaffirmed those benefits. "As humans we are wired for connection, and connection also means touch," she said. "Touch with other humans is at the foundation of connection and an essential part of our being and forming healthy relationships."

Unfortunately, many are currently going without any physical connection for months on end. A lack of touch intensifies feelings of isolation, said Dr. Mitchell Hicks, core faculty in Walden University's PhD in Clinical Psychology program. When we can't touch anyone it leaves the impression that we lack that connection we're wired for, that we're truly alone.

"For many, touch from a loved and trusted person increases their visceral sense of connection and soothes them," said Hicks. "No amount of videoconferencing can really make up for that."

It's not just that touch gives the impression of connection, either. Touch actually has an impact on the brain. Humans deprived of connection experience a decrease in oxytocin a hormone known to increase positive feelings and a simultaneous increase in the stress hormone cortisol, explained Dr. Alexis Parcells, MD. High levels of cortisol can lead to a slew of physical and mental health problems, such as increased blood pressure.

"People suffering with touch deprivation report high rates of depression, anxiety, and insomnia," said Parcells.

"People suffering with touch deprivation report high rates of depression, anxiety, and insomnia."

Despite the consequences of lack of touch, there is good news. You can do something to help and I don't mean stopping social distancing. (Do not stop social distancing.) The benefit of touch has to do with moving the skin, said Dr. Tiffany Field, founder and director of the Touch Research Institute said in an interview with To the Best of Our Knowledge. Moving the skin stimulates the brain. This means that exercise, such as yoga or dance, can produce some of the benefits we see from touch.

Furthermore, it's okay to go months without touch if you're taking care of your mental health in other ways, according to Bhuyan. While there's no "real" substitute for human touch, there are activities you can do to give the same benefits.

While exercise can give you some of the physical benefits, it doesn't do much when it comes to creating that connection with your loved ones. Bhuyan suggests exercising with a friend over video while it seems silly, it can actually be beneficial. "The mutual body movement can create a powerful connection," said Bhuyan. "Its also important to invest in your own self-care and mindfulness."

Parcells suggested any virtual meetup, not just working out. While it's not the same as meeting in person, it still has a positive impact. Parcells said, "Research has shown that a virtual connection is about 80% as effective in increasing the release of oxytocin as seeing that same person face-to-face."

Whatley reiterated, "When we connect personally with others via FaceTime we can release oxytocin and lower stress." This is exactly the opposite of what occurs when we lack touch.

Another suggestion of Parcells has already been heeded by people across the United States: adopting a pet. "Time and time again," said Pacells, "Studies have shown pets to be therapeutic during a stressful time." Not only do they provide comfort, but they're a tactile substitute for human interaction.

As monks have demonstrated over millennia, we won't die from not having been touched in a while. There's no direct substitute from human touch, but through exercise and speaking to our loved ones even virtually we can maintain some of these benefits. Maybe we don't have to be touch starved; maybe we just need a little nosh.

Read the rest here:
The real impact of not having been touched in months - Mashable

Updated: May 26, 2020 7:57:00 pm

By Dr Shweta Goswami

In the past few decades, Polycystic ovary syndrome (PCOS) has emerged as one of the leading and most talked about health issues among women who are in their reproductive phase i.e. in the age group of 16 to 40 years. Speaking of the statistics, the problem affects 1 out of 10 women globally. If we talk about India alone, PCOS has a prevalence of nearly 20 per cent with one in five women being affected by it.

It is advisable that with the current lockdown, it is important to manage your PCOD or PCOS symptoms. PCOS is a problem triggered by elevated levels of the androgen hormones in a female body. Since androgen is mainly a male hormone that plays a vital role in the development of traits like facial and body hair growth, PCOS is likely to induce the same traits in women. Some of the common symptoms that indicate PCOS include:

*Irregular menstrual cycles with a gap of more than 35 to 40 days between two consecutive periods.*Acne-breakout on the face, chest and back.*Excessive hair loss and dandruff.*Dark patches in areas around the neck, groin and under the breasts.*Persistent mood swings and anxiety.*Unhealthy weight gain.

Read| How to get pregnant: A gynaecologists guide to boosting your fertility

To understand how PCOS affects your ability to conceive, it is very important to first understand these two terms fertility and ovulation. Fertility refers to the capability to reproduce i.e. to conceive a child naturally, whereas ovulation is a part of the mensuration cycle marked by the monthly release of an ovum (female gamete) from the ovaries. Regular and healthy ovulation is extremely important for female fertility.

Since PCOS interferes with the normal mensuration cycle, it is likely to disrupt the process of ovulation and negatively impact fertility. This happens because the ovaries are not able to release the ovum and even if they do, elevated levels of hormones like testosterone and estrogen affect the egg quality; thereby increasing the chances of infertility, miscarriage and stillbirth. PCOS can also prevent the uterine lining from developing properly, thereby hindering the implantation of the matured egg.

Read| How to calculate your pregnancy in weeks and months

This is a question that concerns almost every woman who has been detected with PCOS as it is one of the leading causes of female infertility. The problem can be easily tackled by adapting to healthy lifestyle modifications and simple medication.

So, the answer to this question is yes, it is possible to conceive a child even after being detected with PCOS, provided you opt for the treatment and stick to a healthy lifestyle.

Read| The challenges for fertility treatment in India

Here are a few tips that can help you to manage PCOS effectively during this current lockdown:

Keep your weight under check- The bond between obesity and PCOS is inseparable. Approximately 40 to 80 per cent of women suffering from PCOS are either obese or overweight. The reason behind this is that women with PCOS have an increased resistance to insulin owing to which they gain weight very easily and find it quite difficult to get rid of the same. Studies have shown that even 10 per cent weight loss can significantly improve ovulation and fertility. Here is what you need to do:

Whatever goes inside our body has a direct impact on our health. It is very important to have a balanced and healthy diet, making sure that you are not missing out on any important nutrients. You can easily get a personalized diet plan from a dietician which consists of all the haves and have nots. Diet management is very important. Since junk food is not easily available due to the lockdown use this as an opportunity to lose weight by shunning high-calorie foods and going for oats, dalia, and poha.

Take your medication on time- For women who find it rather difficult to lose weight naturally, certain medication may be prescribed for assisting in weight loss by decreasing insulin resistance. However, the medication alone will not be effective if you do not resort to healthy lifestyle changes.

Indulge in physical activities- A sedentary lifestyle promotes obesity. At least 150 minutes of exercise per week is required to keep your weight under check. You can join a gym or perform simple mat exercises at home depending upon your convenience.

Stress management A happy life is key to a healthy life. Excessive stress and strain can have a very negative impact on your reproductive health by releasing stress hormones as well as triggering problems like stress-eating which eventually lead to obesity.Maintain a balance between your work and personal life.

Here are some other tips to keep in mind:

*Indulge in activities that you love to do*Focus on self-love*Get enough sleep*Exercise regularly*Go out with family and friends

The mainstay of treatment in PCOS, after lifestyle modification is ovulation induction and follicular monitoring, to correct the problem of egg development. Your physician will be able to guide you on the treatment module depending upon the level of PCOD in your body. This is helpful for patients to understand their ovulation cycles before opting for other treatment options like IVF. It is important to note that in certain rare cases women might still find it difficult to conceive after the treatment. Such women can opt for assisted reproduction methods like IVF (In Vitro Fertilisation). The procedure is carried out by inducing artificial fertilization of male and female gametes using a combination of medicines, therapies and surgical procedures.

(The author is associate Director, fertility, Cloudnine Group of Hospitals, Noida.)

The Indian Express is now on Telegram. Click here to join our channel (@indianexpress) and stay updated with the latest headlines

For all the latest Parenting News, download Indian Express App.

IE Online Media Services Pvt Ltd

Original post:
Does PCOS affect your ability to conceive? - The Indian Express

How myeloma promotes bone loss

Multiple myeloma can lead to bone loss by reducing the differentiation of mesenchymal stem cells (MSCs) into osteoblasts. Using a combination of single-cell RNA sequencing, in vitro coculture, and experiments with human myeloma cells and MSCs in mice, Liu et al. demonstrated how direct contact between myeloma cells and MSCs shifted the balance of MSC differentiation to favor adipogenesis over osteoblastogenesis. Integrin 4 on the surface of myeloma cells activated the adhesion molecule VCAM1 on MSCs, leading to protein kinase C 1 (PKC1)dependent repression of the E3 ubiquitin ligase MURF1 and subsequent stabilization of the adipocyte transcription factor PPAR2. These findings suggest a possible avenue for preventing or treating myeloma-induced bone loss in patients.

The suppression of bone formation is a hallmark of multiple myeloma. Myeloma cells inhibit osteoblastogenesis from mesenchymal stem cells (MSCs), which can also differentiate into adipocytes. We investigated myeloma-MSC interactions and the effects of such interactions on the differentiation of MSCs into adipocytes or osteoblasts using single-cell RNA sequencing, in vitro coculture, and subcutaneous injection of MSCs and myeloma cells into mice. Our results revealed that the 4 integrin subunit on myeloma cells stimulated vascular cell adhesion molecule1 (VCAM1) on MSCs, leading to the activation of protein kinase C 1 (PKC1) signaling and repression of the muscle ring-finger protein-1 (MURF1)mediated ubiquitylation of peroxisome proliferatoractivated receptor 2 (PPAR2). Stabilized PPAR2 proteins enhanced adipogenesis and consequently reduced osteoblastogenesis from MSCs, thus suppressing bone formation in vitro and in vivo. These findings reveal that suppressed bone formation is a direct consequence of myeloma-MSC contact that promotes the differentiation of MSCs into adipocytes at the expense of osteoblasts. Thus, this study provides a potential strategy for treating bone resorption in patients with myeloma by counteracting tumor-MSC interactions.

More than 80% of patients with multiple myeloma suffer from bone destruction, which greatly reduces their quality of life and has a severe negative impact on survival (1). New bone formation, which usually occurs at sites of previously resorbed bone, is strongly suppressed in patients with myeloma, and bone destruction rarely heals in these patients (2). Therefore, prevention of bone disease is a priority in myeloma treatment, and understanding the mechanisms by which myeloma cells disturb the bone marrow (BM) is fundamental to myeloma-associated bone diseases.

Osteoblasts originate from mesenchymal stem cells (MSCs) and are responsible for bone formation. It has been reported that myeloma cells inhibit MSC differentiation into mature osteoblasts (35). Osteoblasts and adipocytes arise from a common MSC-derived progenitor and exhibit lineage plasticity, which further complicates the relationship between these two cell types in myeloma cellinfiltrated BM (6). Traditionally, initiation of adipogenesis and osteogenesis has been widely regarded as mutually exclusive, and factors that inhibit osteoblastogenesis activate adipogenesis and vice versa (7). Previous studies have demonstrated that MSCs differentiate into either adipocytes or osteoblasts depending on the stimulator (8), and adipocytes transdifferentiate into osteoblasts in patients with several benign diseases (9). However, the underlying effects of myeloma cells on the activation of adipogenic transcriptional factors and the molecular mechanisms involved are still obscure.

Peroxisome proliferatoractivated receptor 2 (PPAR2) is a key transcription factor for the regulation of fatty acid storage and glucose metabolism (10), and it activates genes important for adipocyte differentiation and function (11). Previous findings have demonstrated that PPAR2 plays important roles not only in the activation of adipogenesis but also in the suppression of osteoblastogenesis (12, 13). In vitro coculture of MSCs from multiple myeloma patients with malignant plasma cell lines enhances adipocyte differentiation of the MSCs due to increased PPAR2 in the MSCs (14), suggesting that PPAR2 mediates myeloma-induced adipogenesis. However, the mechanism by which myeloma cells activate PPAR2 in MSCs, thereby causing MSCs to differentiate into adipocytes rather than osteoblasts, remains unclear.

In the present study, we demonstrated that myeloma cells enhanced the differentiation of human MSCs into adipocytes rather than osteoblasts by stabilizing PPAR2 protein through an integrin 4protein kinase C 1 (PKC1)muscle ring-finger protein-1 (MURF1) signaling pathway in MSCs. Our study thus provides a potential therapeutic strategy for myeloma-associated bone disease.

To determine whether myeloma cells affect MSC fate, we characterized the heterogeneity of human BMderived MSCs after exposure to myeloma cells. We cultured MSCs alone (controls) or cocultured them with myeloma cells in a 1:1 mixture of adipocyte:osteoblast (1:1 AD:OB) medium (Fig. 1A). An aliquot of cells was cultured for 48 hours and then subjected to single-cell RNA sequencing (scRNA-seq). We cultured another aliquot of cells for 2 weeks, removed the myeloma cells, and assessed the ability of the MSCs to differentiate into mature osteoblasts or adipocytes using Alizarin red-S, which stains calcium deposits, and Oil red O, which stains lipids (Fig. 1A). Trajectory analysis indicated the dynamic cellular transition processes of MSCs in vitro, in line with the in vivo MSC fates, reported by Wolock et al. (15). We observed a fate shift in MSC differentiation when MSCs were cocultured with myeloma cells (Fig. 1B). T-distributed stochastic neighbor embedding cluster analysis based on the entire transcriptome gene signature showed that both control and cocultured MSCs had specific transcriptome characteristics (Fig. 1C). After identification of genes with highly variable expression across the dataset, clusters were identified in each of the control and coculture groups (Fig. 1C). Enrichment analysis demonstrated that the adipokine signaling pathway and the mineral absorption pathway were among the 20 pathways most significantly changed in MSCs cocultured with myeloma cells (Fig. 1D). We identified clusters 0, 1, 6, and 8 in the MSCs cocultured with myeloma cells as being of adipogenic lineage because their expression of the specific markers of adipogenesis, the ADD1 and PPAR genes, were markedly higher than that of other clusters (Fig. 1E). These results demonstrated that myeloma cells at least partially increase MSC transformation into adipocytes.

(A) System for coculturing of human MSCs with the human multiple myeloma cell (MM) line MM.1S in a 1:1 mixture of adipocyte (AD) and osteoblast (OB) medium. Cells were cocultured for 48 hours and then MSC-derived cells were subjected to single-cell RNA sequencing (scRNA-seq). As a control, scRNA-seq was also performed on MSCs cultured alone in 1:1 AD:OB medium. (B) The single-cell trajectory reconstructed by Monocle in the control (Ctrl) and coculture (Coculture) groups. Each point represents a cell, and colors indicate their respective group. n = 2 independent experiments. The trajectory constructed by Monocle is in black. (C) T-distributed stochastic neighbor embedding (t-SNE) plot depicting clusters of MSCs cultured alone (Ctrl) or cocultured with MM cells. The first two dimensions are shown. Each cluster represents individual cells with similar transcriptional profiles of MSCs or different MSC lineages, with total of 10 clusters from aggregated samples of two biologically independent experiments. (D) Enrichment analysis showing the 20 most significantly changed pathways in the MSCs cocultured with MM cells. Red indicates activated pathways, and green indicates repressed pathways. (E) Distributions of unique transcripts per cell and PPARG and CEBPB gene expression in all cell clusters. The red frame shows the highest expression among the clusters. TGF-, transforming growth factor.

The coculture of MSCs and myeloma cells resulted in lower Alizarin red-S staining and higher Oil red O staining in MSCs, indicating an increase in the generation of adipocytes, compared to culture of MSCs alone (Fig. 2A). We further labeled cocultured MSCs with antibodies recognizing the osteoblast marker osteocalcin or the adipocyte marker fatty acid binding protein 4 (FABP4) and analyzed them using flow cytometry. We observed that culturing MSCs in osteoblast medium increased the osteocalcin+ population and that coculturing MSCs with myeloma cells inhibited this increase. Also, culturing MSCs in adipocyte medium increased the FABP4+ population, and coculturing them with myeloma cells further increased it. When we cultured MSCs alone in the 1:1 AD:OB medium, both the osteocalcin+ and FABP4+ populations increased, whereas coculturing MSCs with myeloma cells reduced the osteocalcin+ population but increased the FABP4+ population (Fig. 2, B and C). We obtained similar effects on osteoblastogenesis (Fig. 2D) and adipogenesis (Fig. 2E) when we cocultured MSCs with six other myeloma cell lines or with CD138+ primary myeloma cells isolated from BM aspirates from five patients with myeloma, but not with plasma cells from healthy donors (Fig. 2, F and G). Real-time polymerase chain reaction (PCR) analysis further showed lower expression of the osteoblast differentiationassociated genes alkaline phosphatase (ALP), secreted phosphoprotein 1 (SPP1), collagen type I alpha 1 chain (COL1A1), and bone gamma-carboxyglutamate protein (BGLAP; Fig. 2H) and higher expression of the adipocyte differentiationassociated genes delta-like noncanonical Notch ligand 1 (DLK1), diacylglycerol O-acyltransferase 1 (DGAT1), FABP4, and fatty acid synthase (FASN; Fig. 2I) in MSCs cocultured with ARP-1 or MM.1S myeloma cells than in MSCs cultured alone. These results demonstrate that myeloma cells directed the differentiation of MSCs preferentially toward adipocytes than to osteoblasts.

(A) Representative images of Alizarin red-S and Oil red O staining (whole wells and enlarged views) of MSCs cultured alone or cocultured with ARP-1 or MM.1S myeloma cell lines in MSC medium, adipocyte (AD) medium, osteoblast (OB) medium, or mixed 1:1 AD:OB medium as indicated. n = 3 independent experiments. Scale bars, 5 mm (whole wells) and 20 m (enlargements). (B and C) Flow cytometric analysis showing the percentage of osteocalcin+ (B) and FABP4+ (C) cells in cultures of MSCs alone or in direct contact with ARP-1 cells in the indicated medium. Data are representative of three independent experiments with each sample analyzed in triplicate. (D and E) Quantification of Alizarin red-S (D) and Oil red O (E) staining of MSCs cultured alone (No MM) or cocultured with the six indicated myeloma cell lines. Combined data are from three biologically independent experiments. (F and G) Quantification of Alizarin red-S (F) and Oil red O (G) staining of MSCs cultured alone or cocultured with primary myeloma cells isolated from BM aspirates of five patients with myeloma (P1 to P5) or normal plasma cells from the BM of two healthy donors (PC1 and PC2). Combined data are from n = 3 experiments using the same donor source material. (H and I) Quantitative reverse transcription PCR showing the expression of the osteoblast differentiationassociated genes ALP, SPP1, COL1A1, and BGLAP (H) and the adipocyte differentiationassociated genes DLK1, DGAT1, FABP4, and FASN (I) in cells generated by coculture of MSCs with myeloma cells relative to expression of each gene in MSCs cultured alone. Combined data are from n = 3 independent experiments. All data are means SD. *P 0.05 and **P 0.01. P values were determined using one-way ANOVA with Tukeys multiple comparisons test.

We next investigated the mechanism of myeloma-induced shifting of MSCs from osteoblastogenesis to adipogenesis. We focused on PPAR2 because it is a key transcriptional factor for the activation of adipogenesis. scRNA-seq showed higher PPAR2 mRNA expression in MSCs cocultured with myeloma cells compared to MSCs cultured alone (Fig. 1E). Using the coculture system with MSCs and myeloma cells in a 1:1 mixture of adipocyte and osteoblast medium, we again observed the transformation of osteoblastogenesis into adipogenesis in MSCs cocultured with myeloma cells (Fig. 3A), as well as an increase in the abundance of PPAR2 in MSCs cultured with myeloma cells (Fig. 3B and fig. S1). To determine the importance of PPAR2 in MSC transformation, we added the PPAR2 antagonist G3335 to cocultures. G3335 inhibited the myeloma cellinduced increase in PPAR2 protein (Fig. 3B and fig. S1). Consistent with the Western blot results, G3335 treatment decreased Oil red O staining (Fig. 3C) and adipocyte gene expression (Fig. 3D) and increased Alizarin red-S staining (Fig. 3E) and osteoblast gene expression (Fig. 3F). These results suggest that PPAR2 mediated myeloma-induced MSC transformation into adipocytes.

(A) Representative images of Oil red O or Alizarin red-S staining of MSCs cultured alone or cocultured with ARP-1 or MM.1S myeloma cells in 1:1 OB:AD medium and treated with the PPAR2 antagonist G3335 as indicated. Scale bar, 5 mm. (B) Representative Western blot for PPAR2 in cells treated as in (A). Quantitation is presented in fig. S1. Actin is a loading control. (C to F) Quantitative analysis of Oil red O staining (C), adipocyte differentiationassociated gene expression (D), Alizarin red-S staining (E), and osteoblast differentiationassociated gene expression (F) in cells treated as in (A). Data are means SD from n = 3 independent experiments. *P 0.05 and **P 0.01. P values were determined using Students t test for paired samples (D and F) and one-way ANOVA with Tukeys multiple comparisons test (C and E).

To determine whether myeloma cells distort MSC transformation through myeloma-secreted soluble factors or cell-to-cell contact, we cocultured MSCs with ARP-1 or MM.1S myeloma cells in 1:1 AD:OB medium either together or separated by transwell inserts. We observed that the transwell coculture had a slight effect on increased Oil red O staining, whereas cell-to-cell contact coculture in the mixed medium produced much more significant boost of this staining, suggesting that direct interaction between MSCs and myeloma cells was needed for enhancing adipogenesis from MSCs (Fig. 4A). When we added supernatants collected from 24-hour cultures of ARP-1 or MM.1S cells to MSC cultures, we obtained results similar to those for the transwell coculture (Fig. 4A), reaffirming the importance of direct contact of MSCs with myeloma cells.

(A) Oil red O staining in MSCs cultured alone (No MM) or cocultured with ARP-1 or MM.1S myeloma cells in 1:1 AD:OB medium directly (cell-cell) or separated by transwell inserts (Trans) or in myeloma cell culture media (sup). Staining was quantified relative to the No MM condition. Representative data are from three independent experiments. (B to D) Relative Oil red O staining (B) and the relative expression of the indicated osteoblast (C) and adipocyte (D) marker genes in MSCs cultured alone (No MM) or cocultured with ARP-1 or MM.1S cells with or without neutralizing antibodies against integrin subunits 4, 5, V, or L. Combined data are from three independent experiments. (E) Western blot showing integrin 4 and integrin 1 in ARP-1 and MM.1S cells expressing shRNA targeting integrin 4 (4 KD) or nontargeted control shRNAs (NT Ctrl). Actin is a loading control. (Blot is a representative of three independent experiments, and blot quantitation data are presented in fig. S2C. (F to J) PPAR2 protein (F), Alizarin red-S staining (G), Oil red O staining (H), osteoblast marker gene expression (I), and adipocyte marker gene expression (J) in MSCs cultured alone or cocultured with ARP-1 or MM.1S cells expressing NT Ctrl or 4 KD shRNA. Blots in (E) and (F) are representative of three independent experiments, and blot quantitation is presented in fig. S2 (A and D). Data in (G) to (J) are means SD from n = 3 independent experiments using MSCs derived from BM aspirates of three healthy donors. Data are **P 0.01. P values were determined using one-way ANOVA with Tukeys multiple comparisons test.

To identify the specific molecules involved in adipocyte differentiation, we tested the effect of blocking antibodies against various integrins, which are highly expressed in myeloma cells, in cocultures of MSCs with ARP-1 or MM.1S cells in 1:1 AD:OB medium. The addition of an antibody against integrin 4but not antibodies against integrins 5, V, or L or a control immunoglobulin G (IgG)markedly reduced Oil red O staining in cocultures with both myeloma cell lines (Fig. 4B). The addition of the antibody recognizing integrin 4 to cocultures of MSCs and ARP-1 cells in the mixed medium also increased osteoblast gene expression (Fig. 4C) and decreased adipocyte gene expression (Fig. 4D) substantially more than did the addition of the control IgG. To determine whether integrin 4 affected PPAR2 production in MSCs, we infected ARP-1 and MM.1S cells with a lentivirus carrying short hairpin RNAs (shRNAs) targeting integrin 4 (fig. S2A). Integrin 4 knockdown (4 KD) reduced integrin 4 production without changing the cell viability or proliferation, whereas integrin 1 remained unchanged in ARP-1 and MM.1S cells (Fig. 4E and fig. S2, A to C). We also cocultured MSCs with control or 4 KD myeloma cells in the mixed medium. Western blot analysis demonstrated that 4 KD in myeloma cells reduced PPAR2 protein production in MSCs more than did myeloma cells expressing a nontargeting control shRNA (Fig. 4F and fig. S2D). In addition, coculture of MSCs with 4 KD myeloma cells induced higher Alizarin red-S staining (Fig. 4G) and osteoblast gene expression (Fig. 4H) but lower Oil red O staining (Fig. 4I) and adipocyte gene expression (Fig. 4J) compared to MSCs cocultured with myeloma cells expressing the control shRNA.

Because vascular cell adhesion molecule1 (VCAM1) is a major ligand of integrin 4, we investigated whether it mediated myeloma-induced MSC transformation by adding a blocking antibody against VCAM1 or control IgG to MSC and myeloma cell cocultures. Addition of the antibody, but not IgG, increased Alizarin red-S staining (Fig. 5A) and osteoblast gene expression (Fig. 5B) but decreased Oil red O staining (Fig. 5C) and adipocyte gene expression (Fig. 5D) in MSCs. To determine whether binding of integrin 4 to VCAM1 induced an increase in PPAR2, we constructed MSCs with reduced expression of VCAM1 using a lentivirus carrying VCAM1 shRNAs (VCAM1 KD) (Fig. 5E and fig. S3A) and cocultured myeloma cells with control or VCAM1 KD MSCs. Western blot analysis showed that cocultured VCAM1 KD MSCs had reduced PPAR2 protein production compared to cocultured MSCs expressing nontargeting control shRNA (Fig. 5F and fig. S3B). We also found that VCAM1 KD in MSCs considerably abrogated myeloma-induced suppression of osteoblastogenesis and activation of adipogenesis, because Oil red O staining and adipocyte gene expression decreased significantly (Fig. 5, G and H), whereas Alizarin red-S staining and osteoblast gene expression both increased (Fig. 5, I and J).

(A to D) Alizarin red-S staining (A), Oil red O staining (B), and real-time PCR analysis of the expression of osteoblast (C) and adipocyte (D) marker genes in MSCs cultured alone (No MM) or cocultured with ARP-1 or MM.1S myeloma cells in the presence of a neutralizing antibody against VCAM1 or IgG (control). Data are from n = 3 independent experiments. (E) Western blotting analysis showing VCAM1 in the MSCs infected with a lentivirus carrying nontargeted control shRNAs (NT Ctrl-MSCs) or human VCAM1 shRNAs (VCAM1 KD-MSCs). Actin is a loading control. Blot is a representative of three independent experiments, and blot quantitation is presented in fig. S3A. (F to J) PPAR2 protein (F), adipocyte gene expression (G), Oil red O staining (H), Alizarin red-S staining (I), and osteoblast gene expression (J) in MSCs expressing NT Ctrl or VCAM1 shRNAs cocultured with ARP-1 or MM.1S cells in 1:1 OB:AD medium. Blot in (F) is a representative of three independent experiments, and blot quantitation is presented in fig. S3B. Data are means SD from n = 3 independent experiments. *P 0.05 and **P 0.01. P values were determined using one-way ANOVA with Tukeys multiple comparisons test except in (G) and (J), where Students t test for paired samples were used.

Because VCAM1 stimulates intracellular signaling that results in the activation of protein kinase C (PKC), we examined PKC activation in cocultures. Coculture of myeloma cells and MSCs enhanced the phosphorylation of PKC1 but did not affect phosphorylation of the PKC isoforms PKC, PKC, or PKC/ or the abundance of total PKC and reduced the phosphorylation of PKC and PKC (Fig. 6, A and B). Addition of the PKC inhibitor Go6976 to the cocultures markedly reduced PKC1 phosphorylation and PPAR2 protein in MSC cells cocultured with ARP-1 or MM.1S cells (Fig. 6C and fig. S4). Functionally, treatment of cocultures with Go6976 reduced Oil red O staining and increased Alizarin red-S staining (Fig. 6, D to F). Together, these results demonstrate that myeloma cells activated PPAR2 in MSCs and induced MSC differentiation into adipocytes rather than osteoblasts through the integrin 4-VCAM1-PKC1 pathway.

(A) Western blotting for all phosphorylated PKCs (p-PKC pan), the indicated phosphorylated PKC isoforms, and total PKC in MSCs cultured alone or cocultured with ARP-1 or MM.1S myeloma cells. The abundances of total PKC served as protein loading controls. (B) Quantification of the phosphorylation of PKC isoforms in MSCs cocultured with myeloma cells in (A) relative to the MSC-only control. The cutoff values are fold change more than twofold or less than 0.5-fold. (C) Western blotting for phosphorylated PKC1, total PKC, and PPAR2 in MSCs cocultured with ARP-1 or MM.1S cells in the presence of the PKC inhibitor Go6976 or DMSO (control). Actin is a loading control. Blot is a representative of three independent experiments, and blot quantitation is presented in fig. S4. (D) Representative images of Oil red O staining and Alizarin red-S staining of MSCs cultured alone or cocultured with ARP-1 or MM.1S myeloma cells in the presence of the PKC inhibitor Go6976 or DMSO (control). Scale bar, 5 mm. (E and F) Quantification of Oil red O staining (E) and Alizarin red-S staining (F), in cells treated as in (D). Data are means SD from n = 3 independent experiments. *P 0.05 and **P 0.01. P values were determined using one-way ANOVA with Tukeys multiple comparisons test.

Because a key mechanism of regulation of PPAR2 is its ubiquitylation-dependent proteasome-mediated degradation (16), we added the proteasome inhibitor MG132 to cultures of MSCs. We found that treatment with MG132 increased the presence of PPAR2 protein in MSCs in a time- and dose-dependent manner (Fig. 7A and fig. S5A). MG132 treatment causes the accumulation of ubiquitylated PPAR2 in MSCs, and coculturing these cells with myeloma cells reduced PPAR2 ubiquitylation (Fig. 7B and fig. S5B). However, the addition of a neutralizing antibody against VCAM1 to the cocultures restored ubiquitylation of PPAR2 (Fig. 7C and fig. S5C). These results suggested that myeloma cells activate PPAR2 in MSCs through inhibition of its ubiquitylation.

(A) Western blotting analysis for PPAR2 in MSCs cultured in 1:1 OB:AD medium and treated with the proteasome inhibitor MG132 for the indicated amounts of time. Actin is a loading control. (B) Immunoblotting (IB) for ubiquitin in PPAR2 immunoprecipitates (IP) from MSCs cultured alone or cocultured with ARP-1 or MM.1S myeloma cells in the presence of MG132. (C) Western blotting for ubiquitin in PPAR2 immunoprecipitates from MSCs cocultured with ARP-1 or MM.1S cells in the presence of MG132 and an antibody against VCAM1 or IgG (control). (D) Expression of the E3 ligaseencoding genes USP7, MURF1, MKRN1, CRBN, CRL4B, and TRIM23 in MSCs cocultured with myeloma cells relative to the expression in MSCs cultured alone (No MM). Data are means SD from n = 3 independent experiments. **P 0.01. P values were determined using one-way ANOVA with Tukeys multiple comparisons test. (E) Western blotting for USP7, MURF1, and MKRN1 in MSCs cultured alone or cocultured with myeloma cells. (F) Western blotting for MURF1 in MSCs cocultured with ARP-1 or MM.1S myeloma cells and treated with Go6976 or DMSO (control) as indicated. (G) Immunoblotting for MURF1 or PPAR2 in PPAR2 or MURF1 immunoprecipitates, respectively, from MSCs. IgG immunoprecipitates and whole-cell lysate (input) were used as controls. (H) Immunoblotting for ubiquitin in PPAR2 immunoprecipitates from MSCs expressing nontarget control (NT Ctrl) or MURF1 shRNAs in the presence of MG132. Each blot is representative of n = 3 independent experiments, and blot quantitation is presented in fig. S5.

To investigate the mechanism by which myeloma cells inhibited PPAR2 ubiquitylation, we examined the E3 ubiquitin ligases known to induce ubiquitylation of PPARs (17). Among the tested ligases, we found that MURF1 mRNA (Fig. 7D) and MURF1 protein (Fig. 7E and fig. S5D) were reduced in MSCs cocultured with myeloma cells. Addition of the PKC inhibitor Go6976 to the cocultures increased MURF1 protein in MSCs (Fig. 7F and fig. S5E), indicating that myeloma cells inhibited MURF1 production in MSCs through the PKC signaling pathway. Because the effects of MURF1 on PPAR2 ubiquitylation are unclear, we examined the interaction of these two proteins in MSCs. Co-immunoprecipitation of PPAR2 from MSCs demonstrated an interaction between MURF1 and PPAR2 (Fig. 7G), and knockdown of MURF1 in MSCs reduced the ubiquitylation of PPAR2 (Fig. 7H and fig. S5, F and G). These results demonstrate that myeloma cells activated PPAR2 in MSCs by reducing MURF1-mediated ubiquitylation of PPAR2.

To test the influence of myeloma cells on MSC differentiation in vivo, we established an extramedullary bone formation model in mice. Matrigel containing MSCs and Matrigel containing MSCs plus -irradiated ARP-1 cells were subcutaneously implanted into the right and left flanks of nonobese diabetic/severe combined immunodeficiency/interleukin-2rnull mice, respectively (Fig. 8A). Each sample also included human endothelial colony-forming cells (ECFCs) to stimulate blood vessel formation in the implant. In line with results of a previous study (18), we observed lower bone density in the extramedullary bones that formed in the left flanks, which were implanted with MSCs plus irradiated myeloma cells, compared to the extramedullary bones that formed on the right side, which were implanted with MSCs alone (Fig. 8A). Furthermore, we examined subcutaneous tissues on both sides of mice using histologic or immunohistochemical staining with antibodies against the mature osteoblast marker osteocalcin, the adipocyte marker perilipin, the myeloma marker CD138, and human MURF1. We observed lower numbers of new bones and osteocalcin+ osteoblasts and higher numbers of perilipin+ adipocytes in tissues on the sides of mice implanted with both MSCs and myeloma cells, reduction of MURF1 abundance in tissues on the sides of mice implanted with MSCs alone, and CD138+ cells only in tissues on the sides of mice implanted with myeloma cells (Fig. 8B).

(A) Representative images of subcutaneous tissues and bone density in mice implanted with human MSCs plus ECFCs in the right flank and MSCs plus ECFCs mixed with ARP-1 myeloma cells in the left flank. The arrows indicate bone formation in subcutaneous tissue, and the bars indicate bone density. (B) Representative hematoxylin and eosin (H&E) and immunohistochemical staining for the osteoblast marker osteocalcin, the adipocyte marker perilipin, the myeloma cell marker CD138+, and MURF1 of the subcutaneous tissues from (A). Scale bar, 20 m. Data represent n = 3 independent experiments with five mice each. (C) Expression of MURF1 in MSCs from BM aspirates from 12 patients with myeloma and 12 age-matched healthy donors relative to expression in a randomly selected sample from healthy donor. Data are from n = 3 experiments using the same donor source material. *P 0.05. P values were determined using Students t test. (D and E) Western blotting for MURF1 and PPAR2 (D) and Alizarin red-S and Oil red O staining (E) in MSCs from BM aspirates from three healthy donors and three patients with myeloma. Blots and images are representative of three experiments using the same donor materials, and blot quantitation is presented in fig. S6. Scale bars, 5 mm (whole wells) and 100 m (enlargements). (F) Quantitation of Alizarin red-S and Oil red O staining in the cultures of MSCs from BM aspirates from healthy donors and patients with myeloma in (C). Data are from n = 3 experiments using the same donor source material. P values were determined using Students t test. OD490, optical density at 490 nm.

We also isolated MSCs from the BM of 12 healthy human donors and 12 age-matched patients with myeloma and found markedly lower MURF1 mRNA expression in patient-derived MSCs compared to healthy donor MSCs (Fig. 8C). Western blotting validated the negative correlation between MURF1 and PPAR2 at the protein level in MSCs isolated from 3 of 12 samples in both groups (Fig. 8D and fig. S6). When we cultured these primary MSCs in 1:1 AD:OB medium, we found lower Alizarin red-S staining and higher Oil red O staining in cultures of patient-derived MSCs than in cultures of healthy donor MSCs (Fig. 8, E and F). These findings demonstrate that myeloma cells reduced MURF1 in MSCs and skewed MSC differentiation to favor adipogenesis, resulting in the suppression of osteoblast-mediated new bone formation in myeloma-bearing mice and in cells from patients with myeloma.

Using scRNA-seq, an in vitro coculture system, and mouse models, we demonstrated that myeloma cells shift the differentiation of MSCs into adipocytes rather than osteoblasts. Mechanistic studies revealed that integrin 4 on myeloma cells bound to VCAM1 on MSCs and inhibited ubiquitylation of PPAR2 through PKC-MURF1 signaling. The resulting increase in PPAR2 enhanced adipogenesis and suppressed osteoblastogenesis from MSCs. Thus, our study elucidates a previously unknown mechanism underlying myeloma-induced suppression of osteoblast-mediated bone formation and provides a potential approach for treating bone resorption in patients with myeloma.

Suppressed differentiation of osteoblasts is well known to be a key reason for bone loss and skeleton-related events in patients with myeloma (19). The molecules and pathways involved in myeloma-induced suppression of osteoblastogenesis include the Wnt signaling inhibitor Dickkopf-related protein 1 (DKK-1) (2, 20). However, antibody-mediated blocking of DKK-1 function cannot restore new bone formation completely or heal myeloma-induced resorbed bone, suggesting that additional factors expressed by myeloma cells critically affect bone formation. In the present study, we demonstrated that the 4 subunit of integrin, which is highly abundant in myeloma cells, promoted MSC differentiation into adipocytes, demonstrating that adhesion moleculesbut not soluble factorsproduced by myeloma cells primarily mediated the shift from osteoblastogenesis to adipogenesis. Integrin 41, also known as very late antigen-4, is a cell surface heterodimer present on malignant cells in patients with many types of cancer, including myeloma (21). It is a key adhesion molecule that acts as a receptor for the extracellular matrix protein fibronectin and the cellular receptor VCAM1. Interaction between integrin 41 and VCAM1 can activate mature osteoclast formation in patients with bone-metastatic breast cancer (22). In patients with multiple myeloma, this interaction promotes the secretion of interleukin-7 by tumor cells, which inhibits the expression of RUNX-2, which encodes a transcription factor that is essential for osteoblast differentiation, and RUNX-2 transcriptional regulatory activity in MSCs (23). This interaction also increases DKK-1 secretion by myeloma cells. Adding to these known mechanisms, we revealed that binding of myeloma cell integrin 41 to VCAM1 on the MSC surface activated the PKC signaling pathway. We also identified activation of PKC1, suppression of the downstream mediator MURF1, and the fundamental roles of such signaling pathways in the promotion of the MSC-derived adipocyte lineage. PKCs are also reportedly associated with Jagged-Notch signaling pathways, and they can regulate the transition of embryonic stem cells differentiating into postmitotic neurons (24). Some immunomodulatory drugs, such as lenalidomide, may affect osteoblast differentiation through this pathway (25), indicating the important role of Jagged-Notch in osteoblast differentiation from MSCs. We may further investigate their impacts and mechanisms on myeloma-induced the shift of MSC fates in our next studies.

BM adipocytes are recognized as important regulators of bone remodeling rather than just being inert filler cells (26, 27). Normal BM adipocytes have been shown to be reprogrammed by myeloma cells and gain the ability to resorb bone in myeloma patients in remission (13). Focusing on the determination of MSC fate in this study, we investigated the molecular mechanism underlying the shift from osteoblastogenesis to adipogenesis induced by myeloma cells. Lineage-tracing experiments have revealed that adipocytes can also originate from osterix-positive cells and are closely related to osteoblasts (28). Chan et al. (29) reported that BM adipocytes were derived from a progenitor cell that was also the progenitor for osteoblasts. In addition, Gao et al. (30) reported plasticity between BM adipocytes and osteoblasts and potential transdifferentiation and transformation between these two identities after initiating differentiation. Despite this new knowledge about the balance between osteoblastogenesis and adipogenesis, how myeloma cells regulate this balance and transformation of MSCs is still unclear.

scRNA-seq can identify subpopulations using the transcriptome to avoid the complicated isolation procedures after cell-cell contact culture (15). We found that MSCs could be naturally divided into two populations by transcriptomic data, and at least one cluster of MSCs cocultured with myeloma cells highly expressed adipocyte marker genes. Coculture of myeloma cells pushed MSC differentiation toward adipocytes rather than osteoblasts, resulting in the suppression of bone formation in the in vivo extramedullary bone assay. Because MSCs are pluripotent stem cells capable of differentiation into other cell types, such as chondrocytes and skeletal muscle cells (31), whether myeloma cells affect MSC transformation into these cell types instead of osteoblasts remains unclear. It is possible that the observed differentiation from MSC to adipocyte in the presence of myeloma cells might have been rather the result of a differentiation of MSCs into osteoblasts followed by a transdifferentiation from osteoblast into adipocyte. Further investigation is needed to address this possibility.

Like other transcription factors and coregulators, PPAR2 can undergo posttranslational modifications, such as phosphorylation, acetylation, and SUMOylation (32). Researchers have identified the key enzymes and target amino acid sites involved in these modifications, but modification of PPAR2 by ubiquitylation, especially that induced by myeloma cells, is still unclear. Many E3 ligases, such as MURF1 and makorin ring finger protein 1 (MKRN1), are reported to be regulators of ubiquitylation of PPAR proteins (17, 3335), whereas investigators have identified only polyubiquitylation at Lys184 and Lys185 (K184/185) mediated by MKRN1 (16). In the present study, we demonstrated that the E3 ligase MURF1 contributed to PPAR2 ubiquitylation, and inhibition of MURF1 by myeloma cells reduced PPAR2 ubiquitylation, leading to enhanced protein stability in MSCs. MURF1 contains a canonical N-terminal RING-containing E3 ligase that is required for its ubiquitin ligase activity (36). Others have reported dysregulation of MURF1 in experimental models of fasting, diabetes, cancer, denervation, and immobilization (37). However, none have reported the substrate proteins, such as PPAR2, that are targeted for proteasomal degradation by MURF1 in patients with myeloma bone disease. Although the amino acids in PPAR2 that MURF1 targets remain to be identified, we demonstrated that the reduced MURF1 production in MSCs induced by myeloma cells was critical for the inhibition of PPAR2 ubiquitylation and thus stabilization of the PPAR2 protein. Other posttranslational modifications may also regulate PPAR2 protein, especially SUMOylation, which was not addressed in the current study. For example, the transcriptional activity of PPAR2 can be inhibited by SUMOylation at Lys107 to regulate insulin sensitivity (38), and growth differentiation factor 11 promotes osteoblastogenesis through enhancement of PPAR2 SUMOylation (39). A logical next step could be the investigation of the role of SUMOylation in myeloma-induced MSC transformation and how it interplays with the mechanisms described here.

In summary, our results shed light on the cross-talk between myeloma cells and MSCs and the impact of this interaction on the determination of the MSC-derived adipocyte lineage and the suppression of osteoblastogenesis from MSCs. Myeloma cell integrin 4 promoted phosphorylation of PKC1 through VCAM1, and the activated PKC1 reduced the production of MURF1 in MSCs, leading to reduced PPAR2 ubiquitylation. Therefore, counteracting 4-VCAM1-MURF1mediated adipogenesis from MSCs may be a promising strategy to heal myeloma-induced bone resorption.

Myeloma cell lines ARP-1 and ARK were provided by University of Arkansas for Medical Sciences (Little Rock, AR, USA), and others were purchased from American Type Culture Collection. Primary myeloma cells or normal plasma cells were isolated from the BM aspirates of patients with myeloma or healthy donors using antibody-coated magnetic beads against CD138, respectively (Miltenyi Biotec Inc.) (40). The cells were maintained in RPMI 1640 medium with 10% fetal bovine serum (FBS). MSCs from BM of healthy donors or patients with myeloma were maintained and augmented in Dulbeccos modified Eagles medium (DMEM) with 10% FBS (13). Information of healthy donors and patients were listed in table S1. The study was approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center.

Human MSCs were generated from BM mononuclear cells from fetal bones of healthy human donors, characterized using flow cytometry, and labeled with antibodies against MSC markers (CD44, CD90, and CD166) (41). Mature adipocytes were generated from MSCs using an adipocyte medium, which was formulated of DMEM medium with 10% FBS, 1 M dexamethasone, 0.2 mM indomethacin, insulin (10 g/ml), and 0.5 mM 3-isobutyl-l-methylxanthine (41). Mature adipocytes were fixed with 4% paraformaldehyde, stained with Oil red O for 1 hour, and observed under a light microscope. Mature osteoblasts were generated from MSCs using an osteoblast medium, which was formulated of alpha MEM medium with 10% FBS, 100 nM dexamethasone, 10 mM -glycerophosphate, and 0.05 mM l-ascorbic acid 2-phosphate (42). The bone-forming activity of osteoblasts was determined using Alizarin red-S staining (43, 44). Human MSCs were cultured alone or cocultured with myeloma cells at a ratio of 5:1 in MSC medium, osteoblast medium, adipocyte medium, or 1:1 mixed of osteoblast and adipocyte medium with or without inhibitors (G3335 or Go6976) or neutralizing antibodies for 2 weeks. Addition of dimethyl sulfoxide (DMSO) served as vehicle control for inhibitor-treatment experiments, and addition of IgG served as control for antibody-neutralizing experiments. In the transwell nondirect contact model, adipocytes were seeded onto the bottom of culture wells and cocultured with the myeloma cells on the insert. In direct contact coculture system, MSCs were seeded together with the myeloma cells in the culture wells to allow direct cell-cell contact. Supernatants collected from 24-hour cultures of myeloma cells were added to the MSCs in mixed osteoblast and adipocyte medium at a ratio of 1:5. In the experiments with primary cells, MSCs were cultured in the mixed medium for a week (45) and then cocultured with primary myeloma cells isolated from BM aspirates from patients with myeloma or normal plasma cells from BM of healthy donors for another week. Medium, inhibitors, and antibodies were refreshed every 3 days. After culture, the myeloma cells were removed, and the residual cells were stained with Alizarin red-S to assess osteoblast differentiation and with Oil red O to assess adipocyte differentiation. Culture of MSCs alone served as a control.

Single-cell preparation, complementary DNA (cDNA) library synthesis, RNA sequencing, and data analysis were performed by Gene Denovo Inc. Briefly, 1 106 MSCs were plated for 6 hours, 5 106 myeloma cells were added to the MSCs directly, and the cells were cocultured in mixed culture media for 48 hours; control MSC cells were cultured alone at the same media and then mixed with myeloma cells at the same ratio just before preparation for analysis. After removal of dead cells, the cells in these groups were counted using a Countess II Automated Cell Counter, and the concentration was adjusted to 1000 cells/l. The single-cell suspensions were bar-coded labeled and reverse-transcribed into scRNA-seq library using the Chromium Single Cell 3 GEM, Library and Gel Bead Kit (10X Genomics). The cDNA libraries from two independent experiments were sequenced on the Illumina HiSeq X-Ten platform, and data were pooled for the analysis. Myeloma cells were excluded using CD138 markers. The raw scRNA-seq data were aligned, filtered, and normalized using Cell Ranger (10X Genomics) software (tables S2 to S6). The cell subpopulation was grouped by graph-based clustering based on the gene expression profile of each cells in Seurat (tables S7 and S8). Subsequent data analysis including standardization, cell subpopulation, difference of gene expression, and marker gene screening were achieved by Seurat software.

MSCs were cultured alone or cocultured with myeloma cells with or without G3335 or neutralizing antibodies for 48 hours. In some experiments, MG132 was added to the cultures 6 hours before the cell collection. Addition of DMSO served as vehicle control for inhibitor experiment; addition of IgG served as neutralizing antibody control.

Quantitative real-time PCR was performed as described (46). The primers are listed in table S9. For Western blotting, cells were lysed with 1 lysis buffer (Cell Signaling Technology), subjected to 4 to 20% gradient gel electrophoresis, transferred to, and immunoblotted with antibodies against integrin 4 (R&D Systems), integrin 1, VCAM1, PKC, MURF1, and phosphorylated isoforms of PKC along with p-PKC-pan (Cell Signaling Technology) and PPAR2 (Santa Cruz Biotechnology). The membrane was stripped and reprobed with an antibody against -actin to ensure equal protein loading, and last, signals were detected using peroxidase-conjugated secondary antibody followed by enhanced chemiluminescence system (Millipore) in the MiniChem system (Saizhi Biotech), and quantitative analysis of blots were performed using the Fiji-based ImageJ software (version 1.51n, National Institutes of Health, Bethesda, MA, USA).

Viral particles were produced by human embryonic kidney 293T cells transfected with PMD2G and PSPAX2 packaging plasmids (Addgene) together with lentivirus-expressing shRNA vectors targeting 4, MURF1, or VCAM1 (Sigma-Aldrich). Nontargeted shRNA control (Sigma-Aldrich) was used as control. Sequences for knocking down specific genes are the following: 4, 5-CCGGGCTCCGTGTTATCAAGATTATCTCGAGATAATCTTGATAACACGGAGCTTTTT-3; VCAM1, 5-CCGGGGAATTAATTATCCAAGTTACCTCGAGGTAACTTGGATAATTAATTCCTTTTTTG-3; MURF1, 5-CCGGGAAGAGGAAGAGTCCACAGAACTCGAGTTCTGTGGACTCTTCCTCTTCTTTTTG-3 or 5-CCGGGTATAATAATGCCTGGTCATTCTCGAGAATGACCAGGCATTATTATACTTTTTG-3. Supernatants carrying the viral particles were harvested 48 hours later and concentrated to a 100 volume using polyethylene glycol 8000 (Sigma-Aldrich). MSCs (1 106 cells) were seeded 6 hours before the infection. Concentrated viral particles were added to MSCs or myeloma cells, respectively, in the presence of polybrene (8 g/ml) for 12 hours. The medium was then changed, and cells were cultured for another 48 hours until further management.

Cells were harvested and lysed using NP-40 lysis buffer supplemented with complete protease inhibitors, and the supernatant was precleaned with protein G beads (Thermo Fisher Scientific) and incubated with a mouse antibody against MURF1 (Santa Cruz Biotechnology) or monoclonal rabbit antibody against PPAR2 antibody (Santa Cruz Biotechnology) at 4C overnight with protein A/G agarose beads (Thermo Fisher Scientific). The next day, the pellet was washed four times with lysis buffer and then subjected to Western blot analysis using the antibodies against PPAR2 or MURF1. IgG was used as a control and total cell lysates (5%) were used as input controls.

For a ubiquitylation assay, diluted lysates were incubated with an antibody against PPAR2 at 4C overnight after precleaning with protein G beads (Thermo Fisher Scientific). Protein G beads were added to the washed lysate/antibody mixture at 4C for 4 hours. The resin was washed and applied to Western blot analysis using an antibody against ubiquitin.

MSCs were cultured alone or cocultured with myeloma cells for 2 weeks. Abundance of FABP4 and osteocalcin was assessed by immunofluorescence using fluorescein isothiocyanate or allophycocyanin-conjugated antibodies (BD Biosciences). After staining, cells were resuspended in phosphate-buffered saline with 1% FBS and analyzed using a BD LSR Fortessa flow cytometer.

The animal experiments in the present study were approved by the MD Anderson Institutional Animal Care and Use Committee. In vivo extramedullary bone formation in nonobese diabetic/severe combined immunodeficiency/interleukin-2rnull mice was established and examined (18). Briefly, MSCs alone or a mixture of human MSCs (1.5 106) and human ECFCs (1.5 106) in 0.2 ml of Matrigel (Corning Inc.) was subcutaneously injected into the right flanks of mice. This mixture and an additional 2 105 -irradiated (5000 centigrays) myeloma cells were injected into the left flanks of the mice. At 8 weeks after implantation, subcutaneous tissues were established, and the mice were intraperitoneally injected with OsteoSense 750 to assess new bone formation in those tissues. The subcutaneous tissues were collected after the mice were sacrificed and subjected to hematoxylin and eosin or immunohistochemical staining of cells labeled with an antibody against osteocalcin (a marker of mature osteoblasts), an antibody against perilipin (a marker of mature adipocytes), or an antibody against CD138 (a marker of myeloma cells).

The subcutaneous tissues were extracted from the mice and then formalin-fixed and paraffin-embedded. Tissue sections were deparaffinized with xylene and rehydrated to water through a graded alcohol series. Endogenous peroxidase activity was quenched with 3% hydrogen peroxide. The presence of CD138 (R&D Systems), osteocalcin, perilipin, and MURF1 (Abcam) in tissues was detected using specific antibodies. Signals were detected using secondary biotinylated antibodies and streptavidin/horseradish peroxidase. Chromagen 3,3-diaminobenzidine/H2O2 (Dako) was used, and slides were counterstained with hematoxylin. All slides were observed under a light microscope, and images were captured using a SPOT RT camera (Diagnostic Instruments).

Experimental values were expressed as means SD unless indicated otherwise. Statistical significance was analyzed using the GraphPad Prism v7.0 with two-tailed unpaired Students t tests for comparison of two groups and one-way analysis of variance (ANOVA) with Tukeys multiple comparisons test for comparison of more than two groups. P values less than 0.05 were considered statistically significant. All results were reproduced in at least three independent experiments.

stke.sciencemag.org/cgi/content/full/13/633/eaay8203/DC1

Fig. S1. G3335 inhibits PPAR2 accumulation in MSCs cocultured with myeloma cells.

Fig. S2. 4 KD in myeloma cells.

Fig. S3. VCAM1 knockdown in MSCs.

Fig. S4. PKC inhibition reduces PKC1 phosphorylation and PPAR2 abundance in MSCs cocultured with myeloma cells.

Fig. S5. Coculture with myeloma cells reduces ubiquitylation of PPAR2 in MSCs.

Fig. S6. MSCs from patients with myeloma show decreased MURF1 and increased PPAR2.

Table S1. Characteristics of patients with myeloma and healthy donors.

Table S2. Read quality control of the samples for scRNA-seq.

Table S3. Mapping quality control of aligned scRNA-seq data.

Table S4. Basic information of the aggregated samples for scRNA-seq before and after normalization.

Table S5. Information of each sample after aggregation.

Table S6. Cell quality control showing the cell numbers before and after the filtration.

Table S7. Number of cells in each subpopulation.

Table S8. Number of cells in each subpopulation of control and cocultured samples.

Table S9. Primers used in the quantitative reverse transcription PCR analysis.

Data file S1. scRNA-seq data from control sample.

Data file S2. scRNA-seq data from coculture sample.

Acknowledgments: We thank M. J. Li from Department of Genetics, Tianjin Medical University for the evaluation of our statistical analysis. Funding: This work was supported by R01 grants from NCI (CA190863 and CA193362 to J.Y.) and by the Research Scholar Grant from the American Cancer Society (127337-RSG-15-069-01-TBG to J.Y.). It was also supported by NIH/NCI (Core Labs at UT MD Anderson Cancer Center, P30CA016672) for the Small Animal Imaging and Research Histopathology Facilities. Author contributions: Z.L. and J.Y. designed all experiments and wrote the manuscript. H.L., Z.L., and J.H performed all experiments and statistical analysis. P.L. provided and interpreted patient samples. Q.T. provided critical suggestions. Conflict of interests: The authors declare that they have no competing interests. Data and materials availability: All of the data needed to evaluate the conclusions in the paper are provided in the main text or the Supplementary Materials. Stable cell lines carrying targeted shRNA are available with a materials transfer agreement between Houston Methodist Research Institute and the requesting institution.

See the original post:
Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells - Science

IN A stark hospital room, Damian Cross waits for his 14-year-old daughter to save his life.

Shauna is less than 10km away at the Queensland Children's Hospital having her bone marrow extracted.

Despite only being a half match for her father, it was the best solution during a time when full match bone marrow was difficult to come by due to COVID-19 travel restrictions.

The family are a long way from their Coraki home where for a year Damian has been in remission from leukaemia after five rounds of chemotherapy.

"Leukaemia has come back and my only hope for cure now is my 14-year-old daughter," he said.

At Royal Brisbane Hospital with his partner Amy Rolfe by his side, the 33-year-old was under sedation for a bone marrow biopsy.

Shauna's bone marrow will be collected through a needle in her neck.

"Shauna has a fear of needles but hasn't batted an eye at the catheter in her neck," Amy said.

Coraki's Damian Cross in hospital in Brisbane waiting for a bone marrow transplant from his 14 year old daughter. PIC: AMY ROLFE Amy Rolfe

In preparation to receive his daughter's bone marrow, Damian will undergo three days of chemotherapy and four days of radiation to wipe out his cells.

"Then he gets her cells," Amy said.

Donor cells, especially when they are a half match, could attack Damian's cells.

"He'll be here for 100 days after the transplant," Amy said.

"Three to four weeks in hospital and then we have to stay in Brisbane for three months."

Damian will be on anti-rejection drugs and the procedure can fail within a three-year period.

The family is hopeful though and urge Australians to consider registering for bone marrow donation through the Australian Bone Marrow Donor Registry.

The World Marrow Donor Association operates a global database to find the best stem cell

source with a database of 36,214,535 donors from 98 different registries in 53 different countries.

Amy said Germany had the best bone marrow donor rate.

The WMDA said COVID-19 infection had the potential to impact and interfere with the timely provision of cells across international borders.

It is currently uncertain whether COVID-19 is transmissible parenterally, and it seems prudent to defer donors from countries with a high rate of COVID-19 infection, WMDA said.

Support the family through their crowdfunding campaign.

The rest is here:
14-year-old girl is only chance to save dad's life - Chinchilla News

Key points:

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

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

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

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

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

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

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

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

About RYONCILTMMesoblasts lead product candidate, RYONCIL (remestemcel-L), is an investigational therapy comprising culture-expanded mesenchymal stem cells derived from the bone marrow of an unrelated donor. It is administered to patients in a series of intravenous infusions. RYONCIL is believed to have immunomodulatory properties to counteract the inflammatory processes that are implicated in SR-aGVHD by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

References1. Niederwieser D, Baldomero H, Szer J. Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.Bone Marrow Transplant 2016; 51(6):778-85.2. Westin, J., Saliba, RM., Lima, M. (2011) Steroid-refractory acute GVHD: predictors and outcomes. Advances in Hematology 2011;2011:601953.3. Axt L, Naumann A, Toennies J (2019) Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation. Bone Marrow Transplantation 2019;54(11):1805-1814.

Story continues

About MesoblastMesoblast Limited (Nasdaq:MESO; ASX:MSB) is a world leader in developing allogeneic (off-the-shelf) cellular medicines. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of commercial products and late-stage product candidates. The Companys proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

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

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

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

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

Release authorized by the Chief Executive.

For further information, please contact:

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

In the current situation of restricted movement and reduced workforce, (due to COVID-19 Pandemic) new technologies have been developed to provide end-to-end automation in different sectors such as food processing. Automated systems are hired by the companies to ensure continued supply and manufacturing of products with the least manual interference

The advent of Health Information Technology (HIT) components such as electronic health records (EHR), hospital information systems (HIS), picture archiving and communication systems (PACS), and vendor neutral archives (VNA) has had just as transformational an impact on the overall healthcare sector as the concerns regarding security and privacy. Data theft, undue access to personal health records, and cyber-attacks are very real threats that the healthcare sector faces today.

Myelofibrosis or osteomyelofibrosis is a myeloproliferative disorder which is characterized by proliferation of abnormal clone of hematopoietic stem cells. Myelofibrosis is a rare type of chronic leukemia which affects the blood forming function of the bone marrow tissue. National Institute of Health (NIH) has listed it as a rare disease as the prevalence of myelofibrosis in UK is as low as 0.5 cases per 100,000 population. The cause of myelofibrosis is the genetic mutation in bone marrow stem cells. The disorder is found to occur mainly in the people of age 50 or more and shows no symptoms at an early stage. The common symptoms associated with myelofibrosis include weakness, fatigue, anemia, splenomegaly (spleen enlargement) and gout. However, the disease progresses very slowly and 10% of the patients eventually develop acute myeloid leukemia. Treatment options for myelofibrosis are mainly to prevent the complications associated with low blood count and splenomegaly.

To Understand How Our Report Information Can Bring Difference, Ask for a brochure @https://www.persistencemarketresearch.com/samples/11341

The global market for myelofibrosis treatment is expected to grow moderately due to low incidence of a disease. However, increasing incidence of genetic disorders, lifestyle up-gradation and rise in smoking population are the factors which can boost the growth of global myelofibrosis treatment market. The high cost of therapy will the growth of global myelofibrosis treatment market.

The global market for myelofibrosis treatment is segmented on basis of treatment type, end user and geography:

As myelofibrosis is considered as non-curable disease treatment options mainly depend on visible symptoms of a disease. Primary stages of the myelofibrosis are treated with supportive therapies such as chemotherapy and radiation therapy. However, there are serious unmet needs in myelofibrosis treatment market due to lack of disease modifying agents. Approval of JAK1/JAK2 inhibitor Ruxolitinib in 2011 is considered as a breakthrough in myelofibrosis treatment. Stem cell transplantation for the treatment of myelofibrosis also holds tremendous potential for market growth but high cost of therapy is foreseen to limits the growth of the segment.

Looking for Exclusive Market Insights from Business Experts? Request a Custom Report here @https://www.persistencemarketresearch.com/request-customization/11341

On the basis of treatment type, the global myelofibrosis treatment market has been segmented into blood transfusion, chemotherapy, androgen therapy and stem cell or bone marrow transplantation. Chemotherapy segment is expected to contribute major share due to easy availability of chemotherapeutic agents. Ruxolitinib is the only chemotherapeutic agent approved by the USFDA specifically for the treatment of myelofibrosis, which will drive the global myelofibrosis treatment market over the forecast period.

Geographically, global myelofibrosis treatment market is segmented into five regions viz. North America, Latin America, Europe, Asia Pacific and Middle East & Africa. Northe America is anticipated to lead the global myelofibrosis treatment market due to comparatively high prevalence of the disease in the region.

Some of the key market players in the global myelofibrosis treatment market are Incyte Corporation, Novartis AG, Celgene Corporation, Mylan Pharmaceuticals Ulc., Bristol-Myers Squibb Company, Eli Lilly and Company, Taro Pharmaceuticals Inc., AllCells LLC, Lonza Group Ltd., ATCC Inc. and others.

The report covers exhaustive analysis on:

Regional analysis includes

Report Highlights:

Our unmatched research methodologies set us apart from our competitors. Heres why:PMRs set of research methodologies adhere to the latest industry standards and are based on sound surveys.We are committed to preserving the objectivity of our research.Our analysts customize the research methodology according to the market in question in order to take into account the unique dynamics that shape the industry.Our proprietary research methodologies are designed to accurately predict the trajectory of a particular market based on past and present data.PMRs typical operational model comprises elements such as distribution model, forecast of market trends, contracting and expanding technology applications, pricing and transaction model, market segmentation, and vendor business and revenue model.

More:
Global Myelofibrosis Treatment Market to Register Growth in Incremental Opportunity During the Forecast Period 2016 2022 - Cole of Duty