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Archive for the ‘Cardiac Stem Cells’ Category

Researchers Discover a Way To Create Induced Tropoblast Stem Cells – Technology Networks

An international collaboration involving Monash University and Duke-NUS researchers have made an unexpected world-first stem cell discovery that may lead to new treatments for placenta complications during pregnancy.

While it is widely known that adult skin cells can be reprogrammed into cells similar to human embryonic stem cells that can then be used to develop tissue from human organs - known as induced pluripotent stem cells (iPSCs) - the same process could not create placenta tissue.

iPSCs opened up the potential for personalised cell therapies and new opportunities for regenerative medicine, safe drug testing and toxicity assessments, however little was known about exactly how they were made.

An international team led by ARC Future Fellow Professor Jose Polo from Monash University's Biomedicine Discovery Institute and the Australian Research Medicine Institute, together with Assistant Professor Owen Rackham from Duke-NUS in Singapore, examined the molecular changes the adult skin cells went through to become iPSCs. It was during the study of this process that they discovered a new way to create induced trophoblast stem cells (iTSCs) that can be used to make placenta cells.

This exciting discovery, also involving the expertise of three first authors, Dr. Xiaodong Liu, Dr. John Ouyang and Dr. Fernando Rossello, will enable further research into new treatments for placenta complications and the measurement of drug toxicity to placenta cells, which has implications during pregnancy.

"This is really important because iPSCs cannot give rise to placenta, thus all the advances in disease modelling and cell therapy that iPSCs have brought about did not translate to the placenta," Professor Polo said.

"When I started my PhD five years ago our goal was to understand the nuts and bolts of how iPSCs are made, however along the way we also discovered how to make iTSCs," said Dr Liu.

"This discovery will provide the capacity to model human placenta in vitro and enable a pathway to future cell therapies," commented Dr Ouyang.

"This study demonstrates how by successfully combining both cutting edge experimental and computational tools, basic science leads to unexpected discoveries that can be transformative," Professor Rackham said.

Professors Polo and Rackham said many other groups from Australian and international universities contributed to the study over the years, making it a truly international endeavour.

Reference:Liu, X., Ouyang, J.F., Rossello, F.J. et al. Reprogramming roadmap reveals route to human induced trophoblast stem cells. Nature (2020). https://doi.org/10.1038/s41586-020-2734-6

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Researchers Discover a Way To Create Induced Tropoblast Stem Cells - Technology Networks

What Is Covid-19 Doing to Our Hearts? – The New Republic

Brady Feeney hadnt even taken any classes at Indiana University when he fell ill with Covid-19. Three weeks after he moved to Bloomington, the incoming freshman was in the emergency room, struggling to breathe. Before his illness, Feeney had been a perfectly healthy teenager, with no preexisting conditions. In high school, he was a three-time all-state football player and won two state titles in Missouri. But after two weeks of hell fighting the virus, his mother said, his bloodwork indicated possible heart problems.

When SARS-CoV-2 first struck the United States, the medical community had two working assumptions: First, this was primarily a respiratory disease, and second, it seemed to hit older people much harder than younger people, with eight out of 10 confirmed Covid-19 deaths in the U.S. happening in adults 65 or older. But now, new research is challenging both of these assumptions.

Growing evidence suggests that SARS-CoV-2 doesnt only infect the lungs. It also affects the brain, kidneys, and heart. At first, doctors and researchers wondered if these issues beyond the lungs came just from the stress of having Covid-19 and being on a ventilator or life support. But increasingly, research indicates that the virus may be attacking other organs in the body directlyand this may be more common than previously thought, even among those who arent sick enough to be hospitalized. Some have suggested that Covid-19 is actually a blood vessel disease; the lungs are merely the way the virus enters the body, but from there it gets into the bloodstream and takes up residence in major organs, leaving patients with complex, long-lasting symptoms. Moreover, experts now believe, healthy young people can get mild cases of the coronaviruseven not knowing they were sickthat could leave them with lasting cardiovascular damage. Even those who seem to have recovered from the deadly respiratory illness are not free of its complications.

Heart failure could be the next chapter of the coronavirus illness, Dr. Gregg C. Fonarow, interim chief of UCLAs Division of Cardiology, recently argued in a co-authored editorial in the journal JAMA Cardiology. Even if in younger adults Covid-19 may not be fatal, there still may be important health consequences, he told me.

Myocarditis, or inflammation of the heart, is usually a rare condition that can occur with viral infections, including the flu. But from the start of the pandemic, doctors were seeing heart inflammation among patients hospitalized with serious cases of Covid-19, Fonarow said: Early research showed that 20 to 30 percent of those hospitalized had heart issues. Left untreated, myocarditis can damage the heart and lead to heart attacks and arrhythmias, among other complications.

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What Is Covid-19 Doing to Our Hearts? - The New Republic

Astellas and Seattle Genetics Announce PADCEV (enfortumab vedotin-ejfv) Significantly Improved Overall Survival in Phase 3 Trial in Previously Treated…

TOKYO and BOTHELL, Wash., Sept. 18, 2020 /PRNewswire/ --Astellas Pharma Inc.(TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seattle Genetics, Inc. (Nasdaq:SGEN) today announced that a phase 3 trial of PADCEV (enfortumab vedotin-ejfv) met its primary endpoint of overall survival compared to chemotherapy. The results were reviewed by an independent Data Monitoring Committee following a planned interim analysis. The global EV-301 clinical trial compared PADCEV to chemotherapy in adult patients with locally advanced or metastatic urothelial cancer who were previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor.

In the trial, PADCEV significantly improved overall survival (OS), with a 30 percent reduction in risk of death (Hazard Ratio [HR]=0.70; [95% Confidence Interval (CI): 0.56, 0.89]; p=0.001). PADCEV also significantly improved progression-free survival (PFS), a secondary endpoint, with a 39 percent reduction in risk of disease progression or death (HR=0.61 [95% CI: 0.50, 0.75]; p<0.00001).

For patients in the PADCEV arm of the trial, adverse events were consistent with those listed in the U.S. Prescribing Information, with rash, hyperglycemia, decreased neutrophil count, fatigue, anemia and decreased appetite as the most frequent Grade 3 or greater adverse event(s) occurring in more than 5 percent of patients.Data from EV-301 will be submitted for presentation at an upcoming scientific congress. Patients in the chemotherapy arm of the trial will be offered the opportunity to receive PADCEV.

The results will be submitted to the U.S. Food and Drug Administration (FDA) as the confirmatory trial following the drug's accelerated approval in 2019. EV-301 is also intended to support global registrations.

"EV-301 is the first randomized trial to show overall survival results compared to chemotherapy in patients with locally advanced or metastatic urothelial cancer who previously have received platinum-based treatment and a PD-1 or PD-L1 inhibitor, and we are encouraged by the potential this may have in helping patients who have otherwise limited alternatives," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas. "We look forward to discussing these results with global health authorities."

"These survival results from the confirmatory trial for PADCEV are welcome news for patients whose cancer has progressed after platinum-based chemotherapy and immunotherapy," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. "We continue to explore PADCEV's activity across the spectrum of urothelial cancer including its potential for use in earlier lines of therapy."

Globally, approximately 580,000 people will be diagnosed with bladder cancer in 2020.1Urothelial cancer accounts for 90 percent of all bladder cancers and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra.2Approximately 80 percent of people do not respond to PD-1 or PD-L1 inhibitors after a platinum-containing therapy has failed as an initial treatment for advanced disease.3

About the EV-301 TrialThe EV-301 trial (NCT03474107) is a global, multicenter, open-label, randomized phase 3 trial designed to evaluate PADCEV versus physician's choice of chemotherapy (docetaxel, paclitaxel or vinflunine) in approximately 600 patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1 or PD-L1 inhibitor and platinum-based therapies. The primary endpoint is overall survival of participants treated with PADCEV compared to those treated with chemotherapy. Secondary endpoints include progression-free survival, duration of response, and overall response rate, as well as assessment of safety/tolerability and quality-of-life parameters.

For more information about the EV-301 clinical trial, please visit http://www.clinicaltrials.gov.

About PADCEV (enfortumab vedotin-ejfv)PADCEV was approved by the U.S. Food and Drug Administration (FDA) in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. PADCEV was approved under the FDA's Accelerated Approval Program based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.4

PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.4,5 Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).4 PADCEV is co-developed by Astellas and Seattle Genetics.

PADCEV Important Safety Information

Warnings and Precautions

Adverse ReactionsSerious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade 3 adverse reactions (5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Lab AbnormalitiesIn one clinical trial, Grade 3-4 laboratory abnormalities reported in 5% were: lymphocytes decreased (10%), hemoglobin decreased (10%), phosphate decreased (10%), lipase increased (9%), sodium decreased (8%), glucose increased (8%), urate increased (7%), neutrophils decreased (5%).

Drug Interactions

Specific Populations

For more information, please see the full Prescribing Information for PADCEV here.

About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+ healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at https://www.astellas.com/en/.

About Seattle Genetics Seattle Genetics, Inc. is a global biotechnology company that discovers, develops and commercializes transformative medicines targeting cancer to make a meaningful difference in people's lives. The company is headquartered in the Seattle, Washington area, with locations in California, Switzerland and the European Union. For more information on our robust pipeline, visit http://www.seattlegenetics.comand follow @SeattleGeneticson Twitter.

About the Astellas and Seattle Genetics CollaborationAstellas and Seattle Genetics are co-developing PADCEV (enfortumab vedotin-ejfv) under a 50:50 worldwide development and commercialization collaboration that was entered into in 2007 and expanded in 2009.

Astellas Cautionary NotesIn this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development), which is included in this press release is not intended to constitute an advertisement or medical advice.

Seattle Genetics Forward Looking Statements Certain statements made in this press release are forward looking, such as those, among others, relating to the submission of data from the EV-301 trial for presentation at an upcoming scientific congress; intended regulatory actions, including plans to submit the results of the EV-301 trial to the FDA as the confirmatory trial following the drug's accelerated approval in the U.S. and plans to discuss the results with global health authorities and seek global registrations; conduct of a comprehensive clinical development program for PADCEV, which includes exploring PADCEV's activity in other types of urothelial cancer and its potential for use in earlier lines of therapy;the therapeutic potential of PADCEV,including its efficacy, safety and therapeutic uses, and anticipated development activities, including ongoing and future clinical trials. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include that the data from the EV-301 trial may not be selected for presentation at scientific congresses; the possibility of delays in the submission of results to the FDA; that the results from the EV-301 trial may not be enough to convert PADCEV's accelerated approval in the U.S. to regular approval or to support any other global registrations; that, even if PADCEV receives regular approval in the U.S. or any other global registrations, the product labeling may not be as broad or desirable as anticipated; the possibility that ongoing and subsequent clinical trials may fail to establish sufficient activity; the risk of adverse events or safety signals; and the possibility that adverse regulatory actions may occur. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption "Risk Factors" included in the company's Quarterly Report on Form 10-Q for the quarter ended June 30, 2020 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

1 International Agency for Research on Cancer. Cancer Tomorrow: Bladder. http://gco.iarc.fr/tomorrow. Accessed 07-31-2020.2 American Society of Clinical Oncology. Bladder cancer: introduction (10-2017).3 Shah, Manasee V., et al "Targeted Literature Review of the Burden of Illness in UC" (PCN108), Nov 2018.4PADCEV [package insert] Northbrook, IL: Astellas, Inc.5Challita-Eid P, Satpayev D, Yang P, et al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res 2016;76(10):3003-13.

SOURCE Astellas Pharma Inc.

https://www.astellas.com/en/

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Alexion and Caelum Biosciences Announce Start of Phase 3 Studies of CAEL-101 in AL Amyloidosis – BioSpace

Sept. 14, 2020 12:00 UTC

BOSTON & BORDENTOWN, N.J.--(BUSINESS WIRE)-- Alexion Pharmaceuticals Inc.. (NASDAQ:ALXN) and Caelum Biosciences, Inc. today announced the initiation of the Cardiac Amyloid Reaching for Extended Survival (CARES) Phase 3 clinical program to evaluate CAEL-101, a first-in-class amyloid fibril targeted therapy, in combination with standard-of-care (SoC) therapy in AL amyloidosis. The CARES clinical program includes two parallel Phase 3 studies one in patients with Mayo stage IIIa disease and one in patients with Mayo stage IIIb disease and will collectively enroll approximately 370 patients globally. Enrollment is underway in both studies. The primary objective of the clinical program is to assess overall survival.

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In AL amyloidosis, misfolded amyloid proteins can build up in many organs throughout the body, including the heart and kidneys, causing significant damage to these organs and impairing their function. While current treatments address the bone marrow disorder that creates the misfolded amyloid proteins, there are no approved therapies for the significant organ damage the disease causes, said John Orloff, M.D., Executive Vice President and Head of Research and Development at Alexion. CAEL-101 has the potential to be the first treatment to target and remove the amyloid deposits from these organs. Data from Phase 1 studies suggest that this treatment approach may improve organ function and long-term survival. We look forward to investigating this further in the Phase 3 clinical program.

AL amyloidosis is particularly devastating when it affects the heart, with median survival in these patients of less than one year following diagnosis, said Michael Spector, President and Chief Executive Officer of Caelum. Long-term survival data from AL amyloidosis patients treated with CAEL-101 in the Phase 1a/1b study showed that 78 percent were still alive after a median follow-up time of more than three years. We recognize the urgent need for new treatments that address the organ damage caused by AL amyloidosis and are working together with the AL amyloidosis community and Alexion to advance the Phase 3 clinical program as quickly as possible.

About the CARES Phase 3 Clinical Program

The CARES clinical program consists of two parallel double-blind, randomized, event-driven global Phase 3 studies, which are evaluating the efficacy and safety of CAEL-101 in AL amyloidosis patients who are newly diagnosed and nave to standard of care (SoC) treatment (cyclophosphamide-bortezomib-dexamethasone (CyBorD) chemotherapy). One study is enrolling approximately 260 patients with Mayo stage IIIa disease and one study is enrolling approximately 110 patients with Mayo stage IIIb disease. The studies will be conducted at approximately 70 sites across North America, the United Kingdom, Europe, Israel, Japan, and Australia.

In each study, participants are being randomized in a 2:1 ratio to receive either CAEL-101 plus SoC or placebo plus SoC once weekly for four weeks. This will be followed by a maintenance dose administered every two weeks until the last patient enrolled completes at least 50 weeks of treatment. Patients will continue follow-up visits every 12 weeks.

The primary study objectives are overall survival and the safety and tolerability of CAEL-101. Key secondary objectives will assess functional improvement in the six-minute walk test (6MWT), quality of life measures (Kansas City Cardiomyopathy Questionnaire Overall Score & Short Form 36 version 2 Physical Component Score) and cardiac improvement (Global Longitudinal Strain, or GLS).

Phase 2 Study Results

The Phase 2 open-label dose escalation study was conducted to investigate higher doses of CAEL-101 than had been evaluated in Phase 1 studies with a primary objective to identify the best dose to advance into Phase 3 development. The study evaluated the safety and tolerability of CAEL-101 in 13 AL amyloidosis patients at three study sites who received up to 1000 mg/m2 of CAEL-101 (two times the Phase 1 dose) administered in combination with SoC treatment. The study met its primary objectives, supporting the safety and tolerability of CAEL-101 and the selection of the 1000 mg/m2 dose for the Phase 3 study.

Phase 1a/1b Long-Term Follow-Up Results Presented at ISA 2020

As previously reported, the Phase 1a/1b study of CAEL-101 was the first clinical trial to demonstrate improvement in cardiac function via GLS after treatment with an amyloid fibril targeted therapy in AL amyloidosis patients with amyloid cardiac involvement. New long-term follow-up data from the Phase 1a/1b study will be presented at the virtual International Symposium on Amyloidosis (ISA), September 14 to 18, 2020, in the poster titled, Long term follow-up of patients with AL amyloidosis treated on a phase 1 study of Anti-Amyloid Monoclonal Antibody CAEL-101 (Abstract #342, Divaya Bhutani, M.D., et. al, Columbia University Medical Center). These data demonstrate 78 percent survival (15/19) at a median follow-up of more than three years (37 months) in AL amyloidosis patients treated with CAEL-101 as well as durable organ response among evaluable patients, further supporting the advancement of CAEL-101 into Phase 3 development.

About CAEL-101

CAEL-101 is a first-in-class monoclonal antibody (mAb) designed to improve organ function by reducing or eliminating amyloid deposits in the tissues and organs of patients with AL amyloidosis. The antibody is designed to bind to misfolded light chain protein and amyloid and shows binding to both kappa and lambda subtypes. In a Phase 1a/1b study, CAEL-101 demonstrated improved organ function, including cardiac and renal function, in 27 patients with relapsed and refractory AL amyloidosis who had previously not had an organ response to standard of care therapy. CAEL-101 has received Orphan Drug Designation from both the U.S. Food and Drug Administration and European Medicine Agency as a therapy for patients with AL amyloidosis.

About AL Amyloidosis

AL amyloidosis is a rare systemic disorder caused by an abnormality of plasma cells in the bone marrow. Misfolded immunoglobulin light chains produced by plasma cells aggregate and form fibrils that deposit in tissues and organs. This deposition can cause widespread and progressive organ damage and high mortality rates, with death most frequently occurring as a result of cardiac failure. Current standard of care includes plasma cell directed chemotherapy and autologous stem cell transplant, but these therapies do not address the organ dysfunction caused by amyloid deposition, and up to 80 percent of patients are ineligible for transplant.

AL amyloidosis is a rare disease but is the most common form of amyloidosis. There are approximately 22,000 patients across the United States, France, Germany, Italy, Spain and the United Kingdom. AL amyloidosis has a one-year mortality rate of 47 percent, 76 percent of which is caused by cardiac amyloidosis.

About Alexion

Alexion is a global biopharmaceutical company focused on serving patients and families affected by rare diseases and devastating conditions through the discovery, development and commercialization of life-changing medicines. As a leader in rare diseases for more than 25 years, Alexion has developed and commercializes two approved complement inhibitors to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), as well as the first and only approved complement inhibitor to treat anti-acetylcholine receptor (AchR) antibody-positive generalized myasthenia gravis (gMG) and neuromyelitis optica spectrum disorder (NMOSD). Alexion also has two highly innovative enzyme replacement therapies for patients with life-threatening and ultra-rare metabolic disorders, hypophosphatasia (HPP) and lysosomal acid lipase deficiency (LAL-D) as well as the first and only approved Factor Xa inhibitor reversal agent. In addition, the company is developing several mid-to-late-stage therapies, including a copper-binding agent for Wilson disease, an anti-neonatal Fc receptor (FcRn) antibody for rare Immunoglobulin G (IgG)-mediated diseases and an oral Factor D inhibitor as well as several early-stage therapies, including one for light chain (AL) amyloidosis, a second oral Factor D inhibitor and a third complement inhibitor. Alexion focuses its research efforts on novel molecules and targets in the complement cascade and its development efforts on the core therapeutic areas of hematology, nephrology, neurology, metabolic disorders and cardiology. Headquartered in Boston, Massachusetts, Alexion has offices around the globe and serves patients in more than 50 countries. This press release and further information about Alexion can be found at: http://www.alexion.com.

[ALXN-P]

About Caelum Biosciences

Caelum Biosciences, Inc. (Caelum) is a clinical-stage biotechnology company developing treatments for rare and life-threatening diseases. Caelums lead asset, CAEL-101, is a novel antibody for the treatment of patients with amyloid light chain (AL) amyloidosis. In 2019, Caelum entered a collaboration agreement with Alexion under which Alexion acquired a minority equity interest in Caelum and an exclusive option to acquire the remaining equity in the company based on Phase 3 CAEL-101 data. Caelum was founded by Fortress Biotech, Inc. (NASDAQ: FBIO). For more information, visit http://www.caelumbio.com.

Forward-Looking Statement

This press release contains forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Alexion and Caelum, including statements related to: the safety and efficacy CAEL-101 as a treatment for AL amyloidosis; CAEL-101 has the potential to be the first treatment to target and remove the amyloid deposits from the heart, kidney and other organs; data from the Phase 1 studies suggest that the treatment approach may improve organ function and long-term survival and enrollment of the Phase 3 trials. Forward-looking statements are subject to factors that may cause Alexion's and Caelums results and plans to differ materially from those expected by these forward looking statements, including for example: the anticipated safety profile and the benefits of the CAEL-101 may not be realized (and the results of the clinical trials may not be indicative of future results); the inability to enroll and complete the Phase 3 trial; results of clinical trials may not be sufficient to satisfy regulatory authorities; results in clinical trials may not be indicative of results from later stage or larger clinical trials (or in broader patient populations); the possibility that results of clinical trials are not predictive of safety and efficacy and potency of our products (or we fail to adequately operate or manage our clinical trials) which could cause us to discontinue sales of the product (or halt trials, delay or prevent us from making regulatory approval filings or result in denial of approval of our product candidates); the severity of the impact of the COVID-19 pandemic on Alexions or Caelums business, including on commercial and clinical development programs; unexpected delays in clinical trials; unexpected concerns regarding products and product candidates that may arise from additional data or analysis obtained during clinical trials or obtained once used by patients following product approval; future product improvements may not be realized due to expense or feasibility or other factors; delays (expected or unexpected) in the time it takes regulatory agencies to review and make determinations on applications for the marketing approval of our products; inability to timely submit (or failure to submit) future applications for regulatory approval for our products and product candidates; inability to timely initiate (or failure to initiate) and complete future clinical trials due to safety issues, IRB decisions, CMC-related issues, expense or unfavorable results from earlier trials (among other reasons); future competition from biosimilars and novel products; decisions of regulatory authorities regarding the adequacy of our research, marketing approval or material limitations on the marketing of our products; delays or failure of product candidates to obtain regulatory approval; delays or the inability to launch product candidates due to regulatory restrictions, anticipated expense or other matters; interruptions or failures in the manufacture and supply of our products and our product candidates; failure to satisfactorily address matters raised by regulatory agencies regarding our products and product candidates; uncertainty of long-term success in developing, licensing or acquiring other product candidates or additional indications for existing products; the adequacy of our pharmacovigilance and drug safety reporting processes; failure to protect and enforce our data, intellectual property and proprietary rights and the risks and uncertainties relating to intellectual property claims, lawsuits and challenges against us; the risk that third party payors (including governmental agencies) will not reimburse for the use of our products at acceptable rates or at all; delay of collection or reduction in reimbursement due to adverse economic conditions or changes in government and private insurer regulations and approaches to reimbursement; adverse impacts on supply chain, clinical trials, manufacturing operations, financial results, liquidity, hospitals, pharmacies and health care systems from natural disasters and global pandemics, including COVID-19 and a variety of other risks set forth from time to time in Alexion's filings with the SEC, including but not limited to the risks discussed in Alexion's Quarterly Report on Form 10-Q for the period ended June 30, 2020 and in their other filings with the SEC. Alexion disclaims any obligation to update any of these forward-looking statements to reflect events or circumstances after the date hereof, except when a duty arises under law.

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David Shavelle, MD, Named Medical Director of Adult Cardiology for the MemorialCare Heart & Vascular Institute at Long Beach Medical Center -…

The MemorialCare Heart & Vascular Institute at Long Beach Medical Centeris expanding its leadership team with accomplishedSouthern Californiacardiologist,David Shavelle, M.D., being named medical director of adult cardiology. Dr. Shavelle is bringing his extensive leadership experience in cardiology to this new role that will provide leadership and strategic direction for adult cardiology programs, as well as oversight for the interventional catheterization laboratories.

Dr. Shavelle, a Millikan High School (Long Beach, Calif.) graduate, is returning toLong Beachwith more than 20 years of cardiology practice, research leadership, and teaching experience. He joins Long Beach Medical Center from KeckMedical Center at the University of Southern California, where he served as the Director of Interventional Cardiology while leading a multitude of clinical research trials, including several focused on implanted devices for heart failure. He plans on increasing the availability ofclinical research trialsfor cardiology patients at Long Beach Medical Center.

The MemorialCare Heart & Vascular Institute has a rich history of research and pioneering new treatment techniques, says Ike Mmeje, chief operating officer, Long Beach Medical Center.

Dr. Shavelles passion for research makes him a perfect fit to continue that legacy and find the next cutting-edge treatment for our cardiology patients.

MemorialCare Heart & Vascular Institute facilities are among the most comprehensive centers for diagnosis, treatment and rehabilitation of cardiac disease, providing groundbreaking care for complex heart conditions, including myocardial infarction, heart failure, arrhythmias and peripheral vascular disease. In addition to his hopes to expand research opportunities, Dr. Shavelle plans on expanding the programs for heart failure and structural heart disease.

I am excited to join the MemorialCare Heart & Vascular Institute at Long Beach Medical Center, says Dr. Shavelle. My dad was a physician here, and many of my mentors and fellows are at Long Beach Medical Center. Im looking forward to creating more collaboration among cardiologists, surgeons, residents and the entire team to expand the already comprehensive cardiology care available to the community.

After earning his medical degree from theUniversity of California, Los Angeles(UCLA), Dr. Shavelle completed his internal medicine internship and residency at Harbor-UCLA Medical Center. He completed General Cardiology Fellowship at theUniversity of Washingtonand Interventional Cardiology Fellowship at Harbor-UCLA Medical Center/Good Samaritan Hospital. Dr. Shavelle served as Associate Professor at both the David Geffen School of Medicine atUCLAand the Keck School of Medicine at theUniversity of Southern California. He alsoserveson the editorial boards for theJournal of Cardiovascular Pharmacology and Therapeutics, Current Medical Research and Opinion and Cardiology Clinics.

The MemorialCare Heart & Vascular Institute delivering nearly 20,000 cardiovascular diagnostic tests and treatments last year continues to push the boundaries of discovery with many firsts. These began 70 years ago when world-renowned cardiologist, researcher and educator, the lateMervyn Ellestad, M.D., co-invented at Long Beach Medical Center the modern-day maximum stress test to detect heart disease. Today, millions of exercise stress tests performed annually save hundreds of thousands of lives globally.

It is amazing how the field of cardiology has grown and how many treatment options are available through minimally invasive techniques, says Dr. Shavelle. Many of these new treatment options have come from research trials, and Im looking forward to expanding the opportunities for patients in theLong Beacharea. The studies we have in the pipeline include trials with stem cells and heart failure devices.

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David Shavelle, MD, Named Medical Director of Adult Cardiology for the MemorialCare Heart & Vascular Institute at Long Beach Medical Center -...

Seattle Genetics and Merck Announce Two Strategic Oncology Collaborations – BioSpace

Sept. 14, 2020 10:45 UTC

BOTHELL, Wash. & KENILWORTH, N.J.--(BUSINESS WIRE)-- Seattle Genetics, Inc. (Nasdaq: SGEN) and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced two new strategic oncology collaborations.

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The companies will globally develop and commercialize Seattle Genetics ladiratuzumab vedotin, an investigational antibody-drug conjugate (ADC) targeting LIV-1, which is currently in phase 2 clinical trials for breast cancer and other solid tumors. The collaboration will pursue a broad joint development program evaluating ladiratuzumab vedotin as monotherapy and in combination with Mercks anti-PD-1 therapy KEYTRUDA (pembrolizumab) in triple-negative breast cancer, hormone receptor-positive breast cancer and other LIV-1-expressing solid tumors. Under the terms of the agreement, Seattle Genetics will receive a $600 million upfront payment and Merck will make a $1.0 billion equity investment in 5.0 million shares of Seattle Genetics common stock at a price of $200 per share. In addition, Seattle Genetics is eligible for progress-dependent milestone payments of up to $2.6 billion.

Separately, Seattle Genetics has granted Merck an exclusive license to commercialize TUKYSA (tucatinib), a small molecule tyrosine kinase inhibitor, for the treatment of HER2-positive cancers, in Asia, the Middle East and Latin America and other regions outside of the U.S., Canada and Europe. Seattle Genetics will receive $125 million from Merck as an upfront payment and is eligible for progress-dependent milestones of up to $65 million.

Collaborating with Merck on ladiratuzumab vedotin will allow us to accelerate and broaden its development program in breast cancer and other solid tumors, including in combination with Mercks KEYTRUDA, while also positioning us to leverage our U.S. and European commercial operations, said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. The strategic collaboration for TUKYSA will help us reach more patients globally and benefit from the established commercial strength of one of the worlds premier pharmaceutical companies.

These two strategic collaborations will enable us to further diversify Mercks broad oncology portfolio and pipeline, and to continue our efforts to extend and improve the lives of as many patients with cancer as possible, said Dr. Roger M. Perlmutter, President, Merck Research Laboratories. We look forward to working with the team at Seattle Genetics to advance the clinical program for ladiratuzumab vedotin, which has shown compelling signals of efficacy in early studies, and to bring TUKYSA to even more patients with cancer around the world.

Ladiratuzumab Vedotin Collaboration Details

Under the terms of the agreement, Seattle Genetics and Merck will collaborate and equally share costs on the global development of ladiratuzumab vedotin and other LIV-1-targeting ADCs. The companies have agreed to jointly develop and share future costs and profits for ladiratuzumab vedotin on a 50:50 basis worldwide. Merck will pay Seattle Genetics $600 million upfront and make a $1.0 billion equity investment in 5.0 million shares of Seattle Genetics common stock at a price of $200 per share. In addition, Seattle Genetics will be eligible to receive up to $2.6 billion in milestone payments, including $850 million in development milestones and $1.75 billion in sales milestones.

The companies will jointly develop and commercialize ladiratuzumab vedotin and equally share profits worldwide. The companies will co-commercialize in the U.S. and Europe. Seattle Genetics will be responsible for marketing applications for approval in the U.S. and Canada, and will record sales in the U.S., Canada and Europe. Merck will be responsible for marketing applications for approval in Europe and in countries outside the U.S. and Canada, and will record sales in countries outside the U.S., Europe and Canada. Including the upfront payment, equity investment proceeds and potential milestone payments, Seattle Genetics is eligible to receive up to $4.2 billion.

The closing of the equity investment is contingent on completion of review under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 (HSR Act).

TUKYSA Collaboration Details

Under the terms of the agreement, Merck has been granted exclusive rights to commercialize TUKYSA in Asia, the Middle East and Latin America and other regions outside of the U.S., Canada and Europe. Seattle Genetics retains commercial rights and will record sales in the U.S., Canada and Europe. Merck will be responsible for marketing applications for approval in its territory, supported by the positive results from the HER2CLIMB clinical trial.

Merck will also co-fund a portion of the TUKYSA global development plan, which encompasses several ongoing and planned trials across HER2-positive cancers, including breast, colorectal, gastric and other cancers set forth in a global product development plan. Seattle Genetics will continue to lead ongoing TUKYSA global development planning and operational execution. Merck will solely fund and conduct country-specific clinical trials necessary to support anticipated regulatory applications in its territory.

Seattle Genetics will receive from Merck $125 million as an upfront payment and is eligible to receive progress-dependent milestones of up to $65 million. Seattle Genetics will also receive $85 million in prepaid research and development payments to be applied to Mercks global development funding obligations. In addition, Seattle Genetics would receive tiered royalties on sales of TUKYSA in Mercks territory.

The financial impact of these collaborations is not included in Seattle Genetics 2020 guidance.

Seattle Genetics Conference Call Details

Seattle Genetics management will host a conference call to discuss these collaborations today at 6:00 a.m. Pacific Time (PT); 9:00 a.m. Eastern Time (ET). The event will be simultaneously webcast and available for replay from the Seattle Genetics website at http://www.seattlegenetics.com, under the Investors section. Investors may also participate in the conference call by calling 844-763-8274 (domestic) or +1 412-717-9224 (international). The conference ID is 10147850.

About Ladiratuzumab Vedotin

Ladiratuzumab vedotin is a novel investigational ADC targeted to LIV-1. Most metastatic breast cancers express LIV-1, which also has been detected in several other cancers, including lung, head and neck, esophageal and gastric. Ladiratuzumab vedotin utilizes Seattle Genetics proprietary ADC technology and consists of a LIV-1-targeted monoclonal antibody linked to a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker. This novel ADC is designed to bind to LIV-1 on cancer cells and release the cell-killing agent into target cells upon internalization. Ladiratuzumab vedotin may also cause antitumor activity through other mechanisms, including activation of an immune response by induction of immunogenic cell death.

About TUKYSA (tucatinib)

TUKYSA is an oral, small molecule tyrosine kinase inhibitor (TKI) of HER2, a protein that contributes to cancer cell growth. TUKYSA in combination with trastuzumab and capecitabine was approved by the U.S. Food and Drug Administration (FDA) in April 2020 for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. In addition, TUKYSA received approval in Canada, Singapore, Australia and Switzerland under the Project Orbis initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology products among international partners. A marketing application is under review in the European Union.

TUKYSA is being evaluated in several ongoing clinical trials and additional studies are planned. Current trials include the following:

For additional information, visit http://www.clinicaltrials.gov.

TUKYSA Important Safety Information

Warnings and Precautions

If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

Adverse Reactions

Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in 2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.

Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; those occurring in 1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; those occurring in 2% of patients were hepatotoxicity (8%) and diarrhea (6%).

The most common adverse reactions in patients who received TUKYSA (20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

Lab Abnormalities

In HER2CLIMB, Grade 3 laboratory abnormalities reported in 5% of patients who received TUKYSA were: decreased phosphate, increased ALT, decreased potassium, and increased AST. The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

Drug Interactions

Use in Specific Populations

For more information, please see the full Prescribing Information for TUKYSA here.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

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

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

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

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

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

Non-Small Cell Lung Cancer

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

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

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

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

Small Cell Lung Cancer

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

Head and Neck Squamous Cell Cancer

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

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

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

Classical Hodgkin Lymphoma

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

Primary Mediastinal Large B-Cell Lymphoma

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

Urothelial Carcinoma

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

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

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

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

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

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

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

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

Gastric Cancer

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

Esophageal Cancer

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

Cervical Cancer

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

Hepatocellular Carcinoma

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

Merkel Cell Carcinoma

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

Renal Cell Carcinoma

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

Tumor Mutational Burden-High

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

Cutaneous Squamous Cell Carcinoma

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

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

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

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

Immune-Mediated Colitis

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

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

Immune-Mediated Hepatitis

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

Hepatotoxicity in Combination With Axitinib

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

Immune-Mediated Endocrinopathies

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

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

Immune-Mediated Nephritis and Renal Dysfunction

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

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Seattle Genetics and Merck Announce Two Strategic Oncology Collaborations - BioSpace

How the coronavirus causes ‘carnage’ in the heart – The Daily Briefing

New research shows that the novel coronavirus can essentially dice the muscle fibers of the human heart into pieces, sparking concerns about the potential for heart failure among Covid-19 survivors, Elizabeth Cooney reports for STAT News.

Resources to support your CV telehealth strategy

For the study, which was published preprint on bioRxiv and has not yet been peer reviewed, researchers added the new coronavirus, SARS-CoV-2, to three types of human heart cellscardiomyocytes, cardiac fibroblasts, and endothelial cellsthat were grown in lab dishes from stem cells.

Only the cardiomyocytes, which are muscle cells, showed indication of viral infection that spread to other muscle cells, the researchers said. However, what they found in the infected cells was remarkable: The sarcomeres, which are the long muscle fibers that keep the heart beating, had been sliced into small bits. According to the researchers, the fibers looked as if they had been surgically sliced.

The researchers also found black holes where DNA was supposed to be in the nucleus of the infected cells. The researchers said they found similar, but not identical, changes when they observed autopsy specimens from patients with Covid-19, the disease caused by the novel coronavirus.

It's unclear whether the heart is able to reassemble the sarcomeres after they're severed, but that might be possible after the coronavirus infection clears, the researchers said. However, the researchers said they felt an urgency to share their results as quickly as possible, because their findings may help to further scientists' understanding of how the coronavirus causes heart damagesand possibly how to prevent or treat the injuries.

"When we saw this disruption in those microfibers that was when we made the decision to pull the trigger and put out this preprint," Todd McDevitt, a senior investigator at Gladstone Institutes and a co-author of the study, said. "I'm not a scientist who likes to stoke these things [but] I did not sleep, honestly, while we were finishing this paper and putting it out there."

Bruce Conklin, also a senior investigator at Gladstone and a co-author of the study, said the virus caused "carnage in the human cells" unlike anything seen with other diseases. "Nothing that we see in the published literature is like this in terms of this exact cutting and precise dicing," he explained.

Conklin said the findings should alter the way providers and scientists think about the novel coronavirus and Covid-19. "We should think about this as not only a pulmonary disease, but also potentially a cardiac one."

Gregg Fonarow, interim chief of the UCLA Division of Cardiology and director of the Ahmanson-UCLA Cardiomyopathy Center, said the study is "really important and elegant work, helping to define the potential mechanisms by which SARS-CoV-2 is leading to the observed heart damage and clinical manifestations."

Sahil Parikh, an interventional cardiologist at Columbia University Irving Medical Center, called findings "provocative," but added, "[t]he challenge here is that this paper has not been peer-reviewed by people who are experts in cardiology, who have not had a chance to tear it apart." She said, "I am reluctant to make a lot out of a pre-publication manuscript, no matter how provocative the finding."

The researchers who worked on the study agreed that their work should be reviewed, and they've submitted the study to a leading scientific journal (Cooney, STAT News, 9/4).

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How the coronavirus causes 'carnage' in the heart - The Daily Briefing

Innovative treatments for heart failure – Open Access Government

Concerning heart failure (HF), the current COVID-19 pandemic is having a dramatic effect on the daily life of each individual, ranging from social distancing measures applied in most countries to getting severely diseased due to the virus. Cardiovascular Disease (CVD) is among the most common conditions in people that die of the infection. The burden of CVD accounts for over 60 million people in the EU alone, therefore, it is the leading cause of death in the world.

Although COVID-19 shows us the direct impact of a potential treatment for peoples health, CVD is a stealthy pandemic killer. HF is a chronic disease condition in which the heart is not able to fill properly or efficiently pump blood throughout your body, caused by different stress conditions including myocardial infarction, atherosclerosis, diabetes and high blood pressure. Several measures are commonly used to treat heart disease, such as lifestyle changes and medications like beta-blockers and ACE inhibitors, yet these typically only slow down the progression of the disease.

Biomedical research is exploring new avenues by combining scientific insights with new technologies to overcome chronic diseases like HF. Among the most appealing and promising technologies are the use of cardiac tissue engineering and extracellular vesicles-mediated repair strategies.

Upon an initial cell loss post-infarction, it is appealing to replace this massive loss in contractile cells for new cells and thereby not treating patients symptoms, but repairing the cause of the disease. Cardiac cell therapy has been pursued for many years with variable results in small initial trials upon injection into patients. Different cell types have been used to help the myocardium in need, but the most promising approaches aim to use induced pluripotent cells (iPS) from reprogrammed cells from the patient themselves that can be directed towards contractile myocardial cells. These cells in combination with natural materials, in which the cells are embedded in the heart, can be used for tissue engineering strategies (1). Together with different international partners, Sluijters team are trying to develop strategies to use these iPS-derived contractile cells for myocardial repair via direct myocardial injection (H2020-Technobeat-66724) or to make a scaffold that can be used as a personalised biological ventricular assist device (H2020-BRAV-874827). A combination of engineering and biology to mimic the native myocardium aims to replace the chronically ill tissue for healthy and well-coupled heart tissue that can enhance the contractile performance of the heart.

Recently, a Dutch national programme started, called RegMedXB, in which the reparative treatment of the heart is aimed to be performed outside the patients body. During the time the heart is outside the body; the patient is connected to the heart-lung machine, and after restoring function, it will be re-implanted. The so-called Cardiovascular Moonshot aims to create a therapy that best suits the individual patient, by having their heart beating in a bioreactor, outside the body. Although it sounds very futuristic, many small lessons will be learned to feet novel therapeutic insights.

The initial injection of stem cells did result in a nice improvement of myocardial performance. We have now learned that rather than these delivered cells helping the heart themselves, the release of small lipid carriers called extracellular vesicles (EVs) (2) from these cells occur. These EVs carry different biological molecules, including nucleotides, proteins and lipids, and are considered to be the bodies nanosized messengers for communication. The use of stem cell-derived EVs are now being explored as a powerful means to change the course of the disease. Via these small messengers, natural biologics are delivered to diseased cells and thereby help them to overcome the stressful circumstances. EVs carry reparative signals that can be transferred to the diseased heart and thereby change the course of heart disease in some patients.

Within the EVICARE program (3) (H2020-ERC-725229), Sluijters team are using stem cell-derived EVs to change the response of the heart to injury. Also, to understand which heart cells and processes are being affected, they use materials to facilitate a slow release of biomaterials over an extended period rather than a single dose, which is probably essential for a chronic disease like HF. For now, improved blood flow is the main aim but the team have seen other effects as well, such as cardiovascular cell proliferation (4) by which the heart cells themselves start to repair the organ.

The use of EVs basically aims to enhance the endogenous repair mechanisms of the heart. These natural carriers can be mimicked with synthetic materials, or used as a hybrid of the two, thereby creating an engineered nanoparticle, that is superior in the intracellular delivery of genetic materials. The possibility of loading different biological materials allows a further tuning of its effectiveness and use in different disease conditions, creating a new off-the-shelf delivery system for nanomedicine to treat cancer and CVD (H2020-Expert-825828).

As is true of the current COVID-19 pandemic, HF is also a growing chronic disease that affects millions of people worldwide. The chronic damaged myocardium needs reparative strategies in the future to lower the social burden for patients, but also to keep the economic consequences affordable. New scientific insights with cutting edge technological developments will help to address these needs of CVD patients and their families.

References

(1) Madonna R, Van Laake LW, Botker HE, Davidson SM, De Caterina R, Engel FB, Eschenhagen T, Fernandez-Aviles F, Hausenloy DJ, Hulot JS, Lecour S, Leor J, Menasch P, Pesce M, Perrino C, Prunier F, Van Linthout S, Ytrehus K, Zimmermann WH, Ferdinandy P, Sluijter JPG. ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure. Cardiovasc Res. 2019 Mar 1;115(3):488-500.

(2) Sluijter JPG, Davidson SM, Boulanger, CM, Buzs EI, de Kleijn DPV, Engel FB, Giricz Z, Hausenloy DJ, Kishore R, Lecour S, Leor J, Madonna R, Perrino C, Prunier F, Sahoo S, Schiffelers RM, Schulz R, Van Laake LW, Ytrehus K, Ferdinandy P. Extracellular vesicles in diagnostics and therapy of the ischaemic heart: Position Paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res. 2018 Jan 1;114(1):19-34.

(3) https://www.sluijterlab.com/extracellular-vesicle-inspired-ther

(4) Maring JA, Lodder K, Mol E, Verhage V, Wiesmeijer KC, Dingenouts CKE, Moerkamp AT, Deddens JC, Vader P, Smits, AM, Sluijter JPG, Goumans MJ. Cardiac Progenitor Cell-Derived Extracellular Vesicles Reduce Infarct Size and Associate with Increased Cardiovascular Cell Proliferation. J Cardiovasc Transl Res. 2019 Feb;12(1):5-17.

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Innovative treatments for heart failure - Open Access Government

Autologous Stem Cell and Non-Stem Cell Based Therapies Market Scope And Price Analysis 2020 | Major Giants Fibrocell, Genesis Biopharma, Georgia…

A proficient data and brilliant forecasting techniques used in this Autologous Stem Cell and Non-Stem Cell Based Therapies Market report are synonymous with accurateness and correctness. The document is a meticulous analysis of existing scenario of the market, which covers several market dynamics. This market research report endows with the plentiful insights and business solutions that will support to stay ahead of the competition. The most precise way to forecast what future holds is to understand the trend today and hence Autologous Stem Cell and Non-Stem Cell Based Therapies Marketing report has been structured by chewing over numerous fragments of the present and upcoming market scenario.

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This Autologous Stem Cell and Non-Stem Cell Based Therapies Market report is the consequence of incessant efforts lead by clued-up forecasters, innovative analysts and bright researchers who indulge in detailed and attentive research on different markets, trends and emerging opportunities in the consecutive direction for the business needs. Company snapshot, geographical presence, product portfolio, and recent developments are taken into account for studying the company profiles that are part of this report. Quality and transparency has been strictly maintained while carrying out research studies to offer an exceptional market research report for a niche. A thoughtful knowledge of industrial unanimity, market trends and incredible techniques via this Autologous Stem Cell and Non-Stem Cell Based Therapies Market report gives an upper hand in the market.

TheGlobalAutologous Stem Cell and Non-Stem Cell Based Therapies Marketis expected to reach USD113.04 billion by 2025, from USD 87.59 billion in 2017 growing at a CAGR of 3.7% during the forecast period of 2018 to 2025. The upcoming market report contains data for historic years 2015 & 2016, the base year of calculation is 2017 and the forecast period is 2018 to 2025.

Some of the major players operating in the globalautologous stem cell and non-stem cell based therapies marketareAntria (Cro), Bioheart, Brainstorm Cell Therapeutics, Cytori, Dendreon Corporation, Fibrocell, Genesis Biopharma, Georgia Health Sciences University, Neostem, Opexa Therapeutics, Orgenesis, Regenexx, Regeneus, Tengion, Tigenix, Virxsys and many more.

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Market Definition:Global Autologous Stem Cell and Non-Stem Cell Based Therapies Market

In autologous stem-cell transplantation persons own undifferentiated cells or stem cells are collected and transplanted back to the person after intensive therapy. These therapies are performed by means of hematopoietic stem cells, in some of the cases cardiac cells are used to fix the damages caused due to heart attacks. The autologous stem cell and non-stem cell based therapies are used in the treatment of various diseases such as neurodegenerative diseases, cardiovascular diseases, cancer and autoimmune diseases, infectious disease.

According to World Health Organization (WHO), cardiovascular disease (CVD) causes more than half of all deaths across the European Region. The disease leads to death or frequently it is caused by AIDS, tuberculosis and malaria combined in Europe. With the prevalence of cancer and diabetes in all age groups globally the need of steam cell based therapies is increasing, according to article published by the US National Library of Medicine National Institutes of Health, it was reported that around 382 million people had diabetes in 2013 and the number is growing at alarming rate which has increased the need to improve treatment and therapies regarding the diseases.

Market Segmentation:Global Autologous Stem Cell and Non-Stem Cell Based Therapies Market

Major Autologous Stem Cell and Non-Stem Cell Based Therapies Market Drivers and Restraints:

Introduction of novel autologous stem cell based therapies in regenerative medicine

Reduction in transplant associated risks

Prevalence of cancer and diabetes in all age groups

High cost of autologous cellular therapies

Lack of skilled professionals

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Autologous Stem Cell and Non-Stem Cell Based Therapies Market Scope And Price Analysis 2020 | Major Giants Fibrocell, Genesis Biopharma, Georgia...

Microengineered 3D pulmonary interstitial mimetics highlight a critical role for matrix degradation in myofibroblast differentiation – Science…

Abstract

Fibrosis, characterized by aberrant tissue scarring from activated myofibroblasts, is often untreatable. Although the extracellular matrix becomes increasingly stiff and fibrous during disease progression, how these physical cues affect myofibroblast differentiation in 3D is poorly understood. Here, we describe a multicomponent hydrogel that recapitulates the 3D fibrous structure of interstitial tissue regions where idiopathic pulmonary fibrosis (IPF) initiates. In contrast to findings on 2D hydrogels, myofibroblast differentiation in 3D was inversely correlated with hydrogel stiffness but positively correlated with matrix fibers. Using a multistep bioinformatics analysis of IPF patient transcriptomes and in vitro pharmacologic screening, we identify matrix metalloproteinase activity to be essential for 3D but not 2D myofibroblast differentiation. Given our observation that compliant degradable 3D matrices amply support fibrogenesis, these studies demonstrate a departure from the established relationship between stiffness and myofibroblast differentiation in 2D, and provide a new 3D model for studying fibrosis and identifying antifibrotic therapeutics.

Fibrosis is implicated in nearly 45% of all deaths in the developed world and plays a role in numerous pathologies, including pulmonary fibrosis, cardiac disease, atherosclerosis, and cancer (1). In particular, interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF), are fatal and incurable with a median survival of only 2 to 5 years (2). Often described as dysregulated or incessant wound healing, fibrosis involves persistent cycles of tissue injury and deposition of extracellular matrix (ECM) by myofibroblasts (MFs). These critical cellular mediators of fibrogenesis are primarily derived from tissue-resident fibroblasts (1). MFs drive eventual organ failure through excessive fibrous ECM deposition, force generation and tissue contraction, and eventual disruption of parenchymal tissue function (1). As organ transplantation remains the only curative option for late-stage disease, effective antifibrotic therapeutics that slow MF expansion or even reverse fibrosed tissue remain a major unmet clinical need. Undoubtedly, the limited efficacy of antifibrotic drugs at present underscores limitations of existing models for identifying therapeutics, the complexity of the disease, and an incomplete understanding of MF biology.

A strong correlation between lung tissue stiffening and worse patient outcomes suggests an important role for matrix mechanosensing in fibrotic disease progression (3). Preclinical models of fibrosis in mice have supported the link between tissue stiffening and disease progression. However, a precise understanding of how physical cues from the microenvironment influence MF differentiation in vivo is confounded by concurrent structural (e.g., collagen density and laminin/elastin degradation) and biochemical (e.g., matrix composition and inflammatory) changes to the microenvironment (4). Consequently, natural and synthetic in vitro tissue models have provided great utility for the study of MF mechanobiology. Seminal studies using natural type I collagen gels have elucidated the role of profibrotic soluble cues [e.g., transforming growth factor1 (TGF-1)] in promoting cell contractility, ECM compaction, and MF differentiation, and more recently, precision-cut lung slices, have emerged as a powerful tool to study the complexity of the pulmonary microenvironment in IPF (4, 5). However, their utility in identifying physical microenvironmental determinants of MF differentiation suffers from an intrinsic coupling of multiple biochemical and mechanical material properties (6). Rapid degradation kinetics (1 to 3 days) and resulting issues with material stability (1 to 2 weeks) further impede the use of natural materials for studying fibrogenic events and drug responses, which occur over weeks to months in in vivo models or years in patients (7, 8).

Synthetic hydrogels that are more resistant to cell-mediated degradation have provided a better controlled setting for long-term studies of disease-related processes (9). For example, synthetic hydrogel-based cell culture substrates with tunable stiffness have helped establish a paradigm for mechanosensing during MF differentiation in two-dimensions (2D), where compliant matrices maintain fibroblast quiescence in contrast to stiffer matrices that promote MF differentiation (10, 11). Extensive findings in 2D suggest a causal role for matrix mechanics (e.g., stiffness) during MF differentiation in vitro and potentially in human disease, but these models lack the 3D nature of interstitial spaces where fibrosis originates (12). The interstitium surrounding alveoli is structurally composed of two key components: networks of fibrous ECM proteins (namely, type I collagen fibers) and interpenetrating ground substance, an amorphous hydrogel network rich in glycosaminoglycans such as heparan sulfate proteoglycan. Mechanical cues from fibrotic ECM that promote MF differentiation may arise from changes to the collagen fiber architecture or the gel-like ground substance; whether matrix stiffness is a prerequisite for MF differentiation in 3D fibrous interstitial spaces remains unclear (13). Furthermore, the limited efficacy of antifibrotic therapies identified in preclinical and in vitro models of IPF motivates the development of 3D tissue-engineered systems with improved structural and mechanical biomimicry, relevant pharmacokinetics, and the potential to incorporate patient cells (9). Furthermore, recapitulating key features of the fibrotic progression in an in vitro setting that better approximates interstitial tissues could (i) improve our current understanding of MF mechanobiology and (ii) serve as a more suitable test bed for potential antifibrotic therapeutics.

Accordingly, here, we describe a microengineered pulmonary interstitial matrix that recapitulates mechanical and structural features of fibrotic tissue as well as key biological events observed during IPF progression. Design parameters of these engineered microenvironments were informed by mechanical and structural characterization of fibrotic lung tissue from a bleomycin mouse model. We then investigated the influence of dimensionality, matrix cross-linking/stiffness, and fiber density on TGF-1induced MF differentiation in our pulmonary interstitial matrices. Increased hydrogel cross-linking/stiffness substantially hindered MF differentiation in 3D in contrast to findings in 2D, while fibrotic matrix architecture (i.e., high fiber density) potently promoted fibroblast proliferation and differentiation into MFs. Long-term (21 days) culture of hydrogels with a fibrotic architecture engendered tissue stiffening, collagen deposition, and secretion of profibrotic cytokines, implicating fiber density as a potent fibrogenic cue in 3D microenvironments. Pharmacologic screening in fibrotic pulmonary interstitial matrices revealed matrix metalloproteinase (MMP) activity and hydrogel remodeling as a key step during 3D fibrogenesis, but not in traditional 2D settings. To explore the clinical relevance of our findings, we leveraged a multistep bioinformatics analysis of transcriptional profiles from 231 patients, highlighting increased MMP gene expression and enriched signaling domains associated with matrix degradation in patients with IPF. Together, these results highlight the utility of studying fibrogenesis in a physiologically relevant 3D hydrogel model, underscore the requirement of matrix remodeling in IPF, and establish a new platform for screening antifibrotic therapies.

To inform key design criteria for our pulmonary interstitial matrices, we began by characterizing mechanical properties of fibrotic interstitial tissue in a bleomycin-induced lung injury model in mouse. Nave C57BL/6 mice were intratracheally challenged with bleomycin to induce lung injury and subsequent fibro-proliferative repair, with saline-treated animals maintained as a control group. After 2 weeks, animals were sacrificed and lung tissue was dissected out, sectioned and stained, and then mechanically tested by atomic force microscopy (AFM) nanoindentation to map the stiffness of interstitial tissue surrounding alveoli. While single-dose bleomycin administration does not recapitulate human IPF, the fibro-proliferative response is well characterized and leads to MF differentiation, collagen deposition, and lung stiffening events that are reminiscent of what occurs in human disease over longer time scales. As previously documented (14), bleomycin treatment corresponded to an increase in the thickness of interstitial tissue regions surrounding alveoli, a structural change that occurred alongside matrix stiffening (Fig. 1, A and B); bleomycin-treated lungs had elastic moduli nearly fivefold greater than healthy control tissues. To generate synthetic hydrogels with elastic moduli tunable over this range, we functionalized a biocompatible and protein-resistant polysaccharide, dextran, with pendant vinyl sulfone groups amenable to peptide conjugation (termed DexVS; Fig. 1C). To permit cell-mediated proteolytic hydrogel degradation and thus spreading of encapsulated cells, we cross-linked DexVS with a bifunctional peptide (GCVPMSMRGGCG, abbreviated VPMS) primarily sensitive to MMP9 and MMP14, two MMPs implicated in fibrosis-associated matrix remodeling (15, 16). Tuning input VPMS cross-linker concentration yielded stable hydrogels spanning the full range of elastic moduli we measured by AFM nanoindentation of lung tissue (Fig. 1D). Additional functionalization with cell-adhesive moieties (CGRGDS, abbreviated RGD) facilitated adhesion of primary normal human lung fibroblasts (NHLFs) (Fig. 1E).

(A) Histological preparations of healthy control and bleomycin-treated murine lung tissue (n = 3 mice per group) stained for collagen by picrosirius red (scale bar, 100 m). (B) Youngs modulus of mouse lung tissue as measured by AFM nanoindentation, with data fit to the Hertz contact model to determine Youngs modulus (n = 3 mice per group, n = 50 indentations per group on n = 9 tissue sections). (C) Schematic of proteolytically sensitive, cell-adhesive DexVS-VPMS bulk hydrogels. (D) Youngs modulus determined by AFM nanoindentation of DexVS-VPMS hydrogels formed with different concentrations of VPMS cross-linker (n = 4 samples per group, n = 20 total indentations per group). (E and F) Representative images of F-actin (cyan), nuclei (yellow), and -SMA (magenta); image-based quantification of -SMA expression (left axis, magenta bars, day 9) and nuclear Ki67 (right axis, gray bars, day 5) in 2D and 3D (n = 4 samples per group, n = 10 fields of view per group, n > 50 cells per field of view; scale bars, 200 m). All data presented are means SDs with superimposed data points; asterisk denotes significance with P < 0.05 determined by one-way analysis of variance (ANOVA). AU, arbitrary units.

To confirm the role of matrix mechanics on cell proliferation and MF differentiation, we seeded patient-derived NHLFs on 2D DexVS protease-sensitive hydrogel surfaces varying in VPMS cross-linker density and resulting stiffness and stimulated cultures with TGF-1 to promote MF differentiation. In accordance with previous literature, we observed a stiffness-dependent stepwise increase in cell proliferation (day 5) and MF differentiation (day 9) as measured by Ki67 and -smooth muscle actin (-SMA) immunofluorescence, respectively (Fig. 1E) (11). As the influence of matrix elasticity on MF differentiation in 3D synthetic matrices has not previously been documented, we also encapsulated NHLFs in 3D within identical DexVS hydrogels. The opposing trend with respect to stiffness was noted for cells encapsulated in 3D; compliant (E = 560 Pa) hydrogels that limited -SMA expression in 2D plated cells instead exhibited the highest levels of MF differentiation in 3D (Fig. 1F). Decreasing proliferation and cell-cell contact formation as a function of increasing hydrogel stiffness were also noted in 3D matrices and may be one reason why rigid hydrogels limit differentiation in 3D. Similar findings have been reported for mesenchymal stem cells encapsulated in hyaluronic acid matrices, where compliant gels promoted stem cell proliferation and yes-associated protein (YAP) activity in 3D, yet inhibited YAP activity and proliferation in 2D (17). These results suggest that while stiff, cross-linked 2D surfaces promote cell spreading, proliferation, and MF differentiation, an equivalent relationship does not directly translate to 3D settings. High cross-linking and stiffness (E = 6.1 kPa) in 3D matrices sterically hinder cell spreading, proliferation, and the formation of cell-cell contacts, all well-established promoters of MF differentiation (18).

Cell-degradable synthetic hydrogels with elastic moduli approximating that of fibrotic tissue proved nonpermissive to MF differentiation in 3D. Although matrix cross-linking and densification of ground substance has previously been implicated in fibrotic tissue stiffening, remodeled collagenous architecture can also engender changes in tissue mechanics and may modulate MF development in IPF independently. To characterize the fibrous matrix architecture within healthy and fibrotic lung interstitium, we used second-harmonic generation (SHG) microscopy to visualize collagen microstructure in saline- and bleomycin-treated lungs, respectively. Per previous literature, saline-treated lungs contained limited numbers of micrometer-scale (~1-m-diameter) collagen fibers, primarily localized to the interstitial spaces supporting the alveoli (Fig. 2A) (19). In contrast, bleomycin-treated lungs had, on average, fourfold higher overall SHG intensity, with collagen fibers localized to both an expanded interstitial region and in disrupted alveolar networks. While no difference in fiber diameter was noted with bleomycin treatment, we did observe thick (~2- to 5-m) collagen bundles containing numerous individual fibers in fibrotic lungs, potentially arising from physical remodeling by resident fibroblasts (Fig. 2A and fig. S1). Given that typical synthetic hydrogels amenable to cell encapsulation (as in Fig. 1) lack fibrous architecture, we leveraged a previously established methodology for generating fiber-reinforced hydrogel composites (20). Electrospun DexVS fibers approximating the diameter of collagen fibers characterized by SHG imaging (fig. S1) were co-encapsulated alongside NHLFs in DexVS-VPMS hydrogel matrices, yielding a 3D interpenetrating network of DexVS fibers ensconced within proteolytically cleavable DexVS hydrogel (Fig. 2B). To recapitulate the adhesive nature of collagen and fibronectin fibers within interstitial tissues, we functionalized DexVS fibers with RGD to support integrin engagement and 3D cell spreading. While increasing the weight % of type I collagen matrices increases collagen fiber density and simultaneously increases hydrogel stiffness (fig. S2), our synthetic matrix platform enables changes to fiber density (0.0 to 5.0%) without altering mechanical properties assessed by AFM nanoindentation (Fig. 2C), likely due to the constant weight percentage of DexVS and VPMS cross-linker within the bulk hydrogel.

(A) SHG imaging of collagen microstructure within healthy and bleomycin-treated lungs on day 14, with quantification of average signal intensity (arrows indicate interstitial tissue regions adjacent to alveoli; n = 3 mice per group, n = 10 fields of view per group; scale bar, 100 m). (B) Schematic depicting polymer cross-linking and functionalization for generating fibrous DexVS hydrogel composites to model changes in fiber density within lung interstitial tissue ECM. (C) Images and intensity quantification of fluorophore-labeled fibers within composites varying in fiber density (n = 4 samples per group, n = 10 fields of view per group; scale bar, 100 m). Youngs modulus determined by AFM nanoindentation of fibrous composites formed with different concentrations of VPMS cross-linker (n = 4 samples per group, n = 20 measurements per group). (D) Representative high-resolution images of NHLFs on day 1 in fibrous composites formed with bulk hydrogels (12.5 mM VPMS) functionalized with integrin ligand arginylglycylaspartic acid (RGD) or heparin-binding peptide (HBP) [F-actin (cyan), nuclei (yellow), and DexVS fibers (magenta); scale bar, 50 m]. Quantification of fiber recruitment as measured by contact between cells and DexVS fibers (n = 10 fields of view per group, n > 25 cells analyzed). (E) Representative high-resolution images of NHLF on day 1 fibrous composites formed with bulk hydrogels functionalized with integrin ligand RGD or HBP [F-actin (cyan), fibronectin (yellow), and DexVS fibers (magenta); scale bar, 5 m]. Quantification of fibronectin deposition into tshe hydrogel matrix as measured by immunostain intensity (n = 10 fields of view per group, n > 25 cells analyzed). All data presented are means SDs with superimposed data points; asterisk denotes significance with P < 0.05 determined by one-way ANOVA or Students t test, where appropriate; NS denotes nonsignificant comparison.

Beyond recapitulating the multiphase structural composition of interstitial ECM, we also sought to mimic the adhesive ligand presentation and protein sequestration functions of native interstitial tissue. More specifically, the gel-like ground substance within fibrotic tissue intrinsically lacks integrin-binding moieties and is increasingly rich in heparan sulfate proteoglycans, primarily serving as a local reservoir for nascent ECM proteins, growth factors, and profibrotic cytokines. In contrast, synthetic hydrogels are often intentionally designed to have minimal interactions with secreted proteins and require uniform functionalization with a cell-adhesive ligand to support cell attachment and mechanosensing. We hypothesized that RGD-presenting fibers alone would support cell spreading (20), enabling the use of a nonadhesive bulk DexVS hydrogel functionalized with heparin-binding peptide (HBP; CGFAKLAARLYRKAG) (21). While both RGD- and HBP-functionalized bulk DexVS gels supported cell spreading upon incorporation of RGD-presenting fibers, HBP-functionalized hydrogels encouraged matrix remodeling in the form of cell-mediated fiber recruitment (Fig. 2D) and enhanced the deposition of fibronectin fibrils into the adjacent matrix (Fig. 2E). Given the multiphase structure of lung interstitium, changes in collagen fiber density noted with fibrotic progression, and the importance of physical and biochemical matrix remodeling to fibrogenesis, we used HBP-tethered 560-Pa DexVS-VPMS bulk hydrogels with tunable density of RGD-presenting fibers in all subsequent studies.

We next investigated whether changes in fiber density reflecting fibrosis-associated alterations to matrix architecture could influence MF differentiation in our 3D model. NHLFs were encapsulated in compliant DexVS-VPMS hydrogels ranging in fiber density (E = 560 Pa, 0.0 to 5.0 volume % fibers). Examining cell morphology after 3 days of culture, we noted increased cell spreading (Fig. 3, A and B) and evident F-actin stress fibers (fig. S3) in fibrous conditions compared to nonfibrous controls. Increased frequency of direct cell-cell interactions was also observed as a function of fiber density, as evidenced by higher area:perimeter ratios and the number of fibroblasts per contiguous multicellular cluster (Fig. 3A and fig. S3). As evidenced by changes in the ratio of nuclear to cytosolic YAP localization, we detected changes in mechanosensing as a function of fiber density, with the highest nuclear ratio measured in samples containing the highest fiber density examined. Given that nuclear YAP activity (a transcriptional coactivator required for downstream mechanotransduction) has been implicated as a promoter of MF differentiation (22), we also assayed other markers associated with fibroblast activation. With increases in fiber density, we found significant increases in cell proliferation and local fibronectin deposition (Fig. 3, A and B). Luminex quantification of cytokine secretion at this time point revealed elevated secretion of inflammatory and profibrotic cytokines (Fig. 3C), suggesting that matrix fibers may modulate the soluble milieu known to regulate the response to tissue damage and repair in vivo (2325). While no -SMA expression or collagen deposition was observed at this early time point, F-actin stress fibers, YAP activity, and fibronectin expression have been previously established as proto-MF markers in vivo (26), suggesting that physical interactions with matrix fibers prime fibroblasts for activation into MFs. Supplying the profibrotic soluble factor TGF-1 prompted increases in the expression of various profibrotic YAP-target genes (ACTA2, COL1A1, FN1, CD11, and CTGF) relative to nonfibrous (FD 0.0%) controls at day 5 (Fig. 3D). Together, these data suggest that heightened fiber density promotes a fibrotic phenotype (Fig. 3, A to C) and gene expression (Fig. 3D), despite the absence of a stiff surrounding hydrogel.

(A) Immunofluorescence images of NHLFs in hydrogel composites over a range of fiber densities after 3 days of culture [F-actin (cyan), fibronectin (FN, yellow), YAP (magenta), Ki67 (white), and nuclei (blue); scale bars, 100 m (F-actin), 20 m (FN), 20 m (YAP), and 100 m (Ki67/nuclei)]. (B) Corresponding image-based quantification of cell area, deposited FN, YAP nuclear to cytosolic ratio, and % of proliferating cells (n = 4 samples per group; for cell spread area analysis, n > 50 cells per group; for FN, YAP, and Ki67 analyses, n = 10 fields of view per group and n > 25 cells per field of view). (C) Cytokine secretion into culture medium on day 3 (all data were normalized to background levels in control medium, n = 4 samples per condition). (D) Expression of MF-related genes in NHLFs stimulated with TGF-1 on day 3, in either highly fibrous (FD 5.0%) or nonfibrous (FD 0.0%) hydrogels (data presented are GAPDH-normalized fold changes relative to NHLFs within an FD 0% hydrogel lacking TGF-1 supplementation). All data presented are means SDs with superimposed data points; asterisk denotes significance with P < 0.05 determined by one-way ANOVA or Students t test where appropriate.

To explore whether fibrotic matrix cues in the form of heightened fiber density could promote 3D MF differentiation over longer-term culture, NHLFs were encapsulated within hydrogels varying in fiber density and maintained in medium supplemented with TGF-1 beginning on day 1. Immunofluorescent imaging and cytokine quantification were performed on days 3, 5, 7, and 9 to capture dynamic changes in cellular phenotype and secretion, respectively. No -SMApositive stress fibers or changes in total cytokine secretion were observed on day 3 or 5. On day 7, we noted the sparse appearance of -SMApositive cells alongside increased total cytokine secretion (Fig. 4D) in FD 5.0% conditions containing TGF-1, indicating the beginning of a potential phenotypic shift. Extensive MF differentiation (designated by -SMApositive cells) and a sixfold increase in total cytokine secretion occurred rapidly between days 7 and 9 (Fig. 4, B, D, and E) in the highest fiber density (FD 5.0%) condition. Despite the high proliferation within high fiber density hydrogels (Fig. 4C), -SMApositive cells were not evident in samples lacking exogenous TGF-1 supplementation. Moreover, -SMApositive cells were also absent in TGF-1 supplemented conditions that lacked fibrous architecture, indicating a requirement for both soluble and physical fibrogenic cues in 3D. Furthermore, inhibiting integrin engagement by incorporating fibers lacking RGD also abrogated MF differentiation and proliferation despite the presence of TGF-1 (Fig. 4, A and B), suggesting that a fibrotic matrix architecture drives -SMA expression primarily through integrin engagement and downstream mechanosensing pathways. These results were replicated with primary human dermal fibroblasts and mammary fibroblasts, where similar trends with -SMA expression as a function of fiber density were observed (fig. S4). While high fiber density promoted proliferation in dermal fibroblasts, mammary fibroblasts underwent MF differentiation in the absence of higher proliferation rates, demonstrating intrinsic differences between cell populations originating from different tissues. Nevertheless, these results suggest that fibrotic matrix architecture may be promoting MF differentiation in other pathologies, namely, dermal scarring in systemic sclerosis and desmoplasia in breast cancer.

(A) Representative immunofluorescence images of NHLFs in microenvironmental conditions leading to low (top row) or high (bottom row) MF differentiation after 9 days in culture [-SMA (magenta) and nuclei (cyan); n = 4 samples per group, n = 10 fields of view per group, and n > 50 cells per field of view; scale bar, 200 m], with corresponding image-based quantification in (B) and (C). Insets depict representative fiber densities. (D) Measurement of total cytokine secretion over time as a function of fiber density (n = 4 samples per condition; * indicates significant differences between FD 5.0% and all other groups at a given time point; NS denotes nonsignificant comparison). (E) Secretion of specific cytokines and chemoattractants as a function of fiber density on day 9 (n = 4 samples per condition). (F) Representative images and quantification of tissue contraction within day 14 fibroblast-laden hydrogels of varying fiber density (n = 4 samples per group, dashed line indicates initial diameter of 5 mm). Photo credit: Daniel Matera, University of Michigan. (G) AFM measurements of day 14 fibroblast-laden hydrogels of varying fiber density (n = 20 measurements from n = 4 samples per group). Dashed line indicates original hydrogel stiffness. (H) SHG images of fibrous collagen within fibroblast-laden hydrogels after 21 days of culture in medium supplemented with ascorbic acid (scale bar, 100 m). (I) Measurement of total collagen content within digested DexVS hydrogels at day 21 as measured by biochemical assay (n = 4 samples per group). All data presented are means SDs with superimposed data points; asterisk denotes significance with P < 0.05 determined by one-way ANOVA; NS denotes nonsignificant comparison.

While proliferation and -SMA expression are accepted markers of activated fibroblasts, fibrotic lesions contribute to patient mortality through airway inflammation, collagen secretion, tissue contraction, and lung stiffeningpathogenic events that hinder the physical process of respiration (27). Luminex screening of 41 cytokines and chemokines within hydrogel supernatant revealed elevated total cytokine secretion as a function of fiber density over time (Fig. 4D), many of which were soluble mediators known to regulate airway inflammation (Fig. 4E) (23). Numerous other cytokines were additionally secreted at day 9 but did not change as a function of fiber density despite differences in cell number at this time point (fig. S5), suggesting that cell number alone cannot account for the increased cytokine secretion in high fiber density conditions. By generating free-floating hydrogels that allow contraction over time, we also examined macroscale changes in tissue geometry. Consistent with the influence of fiber density on -SMA expression, hydrogels containing high fiber densities underwent greater hydrogel contraction compared to nonfibrous or low fiber density conditions (Fig. 4F). Day 14 fibrotic hydrogels (FD 5.0%) were also fourfold stiffer (2.0 versus 0.5 kPa) as measured by AFM nanoindentation (Fig. 4G) compared to conditions that yielded low rates of MF differentiation in shorter-term studies (i.e., FD 0.0 or FD 0.5% in Fig. 4, A and B). When medium was supplemented with ascorbic acid to permit procollagen hydroxylation, collagen deposition into the surrounding matrix was evident by SHG microscopy by day 21 in high fiber density hydrogels (Fig. 4H) as compared to nonfibrous controls. Further biochemical analysis of hydrogel collagen content confirmed a stepwise increase in collagen production as a function of fiber density (Fig. 4I). Together, these findings demonstrate a clear influence of fiber density on MF differentiation and phenotype in 3D and furthermore suggest that this in vitro model recapitulates key pathogenic events associated with the progression of fibrosis in vivo.

Having established microenvironmental cues that promote robust 3D MF differentiation, we next evaluated the potential of our fibrous hydrogel model for use as an antifibrotic drug screening platform. Nintedanib, a broad-spectrum receptor tyrosine kinase inhibitor, and pirfenidone, an inhibitor of the mitogen-activated protein kinase (MAPK)/nuclear factor B (NF-B) pathway, were selected due to their recent Food and Drug Administration approval for use in patients with IPF (28). We also included dimethyl fumarate, an inhibitor of the YAP/TAZ pathway clinically approved for treatment of systemic sclerosis, and marimastat, a broad-spectrum MMP inhibitor that has shown efficacy in murine preclinical models of fibrosis (29, 30). We generated fibrotic matrices (560-Pa DexVS-VPMS-HBP bulk hydrogels containing 5.0 volume % DexVS-RGD fibers) that elicited the highest levels of MF differentiation, matrix contraction, and collagen secretion in our previous studies (Fig. 4). As a comparison to the current standard for high-throughput compound screening, we also seeded identical numbers of NHLFs on 2D tissue culture plastic in parallel. Cultures were stimulated with TGF-1 on day 1, and pharmacologic treatments were added on day 3, following extensive fibroblast spreading, cell-cell junction formation, and proliferation (Fig. 3A).

As in our earlier studies, TGF-1 supplementation promoted proliferation and -SMA expression within 3D constructs as well as on rigid tissue culture plastic (Fig. 5A). Nintedanib and pirfenidone had differential effects on NHLFs depending on culture format; NHLFs on 2D tissue culture plastic were resistant to pirfenidone/nintedanib treatment with no difference in proliferation or -SMA expression relative to vehicle controls, whereas modest but significant decreases in -SMA expression (pirfenidone and nintedanib) and proliferation (nintedanib) were detected in 3D (Fig. 5, A to E). Combined treatment with pirfenidone and nintedanib provided an antifibrotic effect only in fibrotic matrices, supporting ongoing clinical studies exploring their use as a combinatorial therapy (ClinicalTrials.gov identifier NCT03939520). Dimethyl fumarate abrogated cell proliferation and -SMA expression across all conditions, suggesting that inhibition of downstream mechanosensing inhibits MF differentiation in both 2D and 3D contexts in support of the general requirement for mechanosensing during MF differentiation independent of culture substrate (11). Inhibition of YAP activity in vivo has been shown to mitigate fibrosis and may be an advantageous therapeutic target (22). Blockade of MMP activity via marimastat treatment proved ineffectual in reducing -SMA expression or proliferation on 2D tissue culture plastic, but surprisingly fully abrogated the proliferation and differentiation response in 3D fibrotic matrices (Fig. 5, A to E). Given the role of protease activity in tissue remodeling in vivo (30) and in cellular outgrowth within 3D hydrogels (17, 31), our data suggest that degradative matrix remodeling is a requirement for MF differentiation in 3D, but not in more simplified 2D settings. To summarize, multiple antifibrotic agents (pirfenidone, nintedanib, dimethyl fumarate, and marimastat) demonstrating efficacy in clinical literature elicited an antifibrotic effect in our engineered fibrotic pulmonary interstitial matrices, but not in the 2D tissue culture plastic contexts traditionally used for compound screening.

(A) Representative confocal images stained for -SMA (magenta), F-actin (cyan), and nuclei (yellow) of NHLFs after 9 days of culture on tissue culture plastic (TCP) (top row) or 3D fibrotic matrices (bottom row) with pharmacologic treatment indicated from days 3 to 9 (scale bar, 100 m). Imaged regions were selected to maximize the number of -SMA+ cells per field of view within each sample. (B) Quantification of -SMA and (C) total cell count within 2D NHLF cultures. (D) Quantification of -SMA and (E) total cell count within 3D fibrotic matrices (n = 4 samples per group, n = 10 fields of view per group, and n > 50 cells per field of view). All data presented are means SDs with superimposed data points; asterisk denotes significance with P < 0.05 determined by one-way ANOVA; NS denotes nonsignificant comparison.

As the protease inhibitor marimastat fully ablated TGF-1induced -SMA expression and proliferation in our 3D fibrotic matrices, we leveraged bioinformatics methodologies to investigate the role of matrix proteases in patients with IPF on a network (Reactome) and protein (STRING) basis. Differential expression analysis of microarray data within the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) (dataset #GSE47460) was used to generate an uncurated/unbiased dataset composed of the top 1000 differentially regulated genes in IPF, revealing MMP1 as the most up-regulated gene in patients with IPF, with other matrix proteases (MMP1, MMP3, MMP7, MMP9, MMP10, MMP11, and MMP12) and matrix remodeling proteins (COL1A2, LOX, ACAN, DCN, and HS6ST2) similarly up-regulated (Fig. 6B, table S1, and data file S1). To focus on genes associated with MF differentiation for subsequent analyses, we performed Gene Ontology (GO) term enrichment (via GEO2R) to compile a curated dataset containing 188 key genes associated with MF differentiation (data file S1) and used Reactome and STRING analyses to investigate network signaling within both the uncurated and curated datasets. Analyses revealed 103 (uncurated) and 89 (curated) enriched signaling pathways in IPF (data file S1). The top 3/5 (uncurated) and 5/5 (curated) significantly enriched pathways in IPF involved matrix degradation and remodeling (Fig. 6C). Subsequent STRING protein-protein interaction analysis of datasets revealed that top signaling nodes were MMPs (uncurated: MMP1 and MMP3; Fig. 6D), fibrous collagens (uncurated: COL1A2 and COL3A1), or cytokines (curated: IL6, VEGFA, IL1B, and IGF1; Fig. 6D) known to increase MMP expression in fibroblasts (3235). These results emphasize the interdependence between MMP activity and systems-level pathogenic signaling in IPF and, in combination with our 3D drug screening results, highlight fibroblast-specific protease activity as a potential therapeutic target. Furthermore, given that protease inhibition had no effect on MF differentiation in 2D culture, these data also support the growing sentiment that simplified 2D screening models may be masking the identification of potentially viable antifibrotics.

(A) Schematic representation of bioinformatics workflow: Whole-genome transcriptomes from 91 healthy and 140 patients with lung fibrosis were fetched from the NCBI GEO. Differential expression analysis was used to assemble an uncurated list of the top 1000 differentially expressed genes. GO enrichment of choice biological pathways was used to assemble a curated list of genes associated with MF differentiation. Datasets were fed through a previous knowledgebased analysis pipeline to identify enriched signaling pathways (Reactome) and key protein signaling nodes (STRING) within patients with IPF. (B) Heatmaps of the top 20 differentially expressed genes within specified GO categories, which were manually selected for curated analysis. CN values indicate a high degree of interaction between proteins selected for curated analysis. Colors are based on differential expression values that were not log-normalized. (C) Summary of the top 5 significantly enriched pathways in the curated and uncurated gene set. (D) Representative STRING diagram depicting protein interactions within the curated dataset, with summary of the top 5 signaling nodes in the uncurated and curated gene set. Blue nodes and edges represent interactions within the top 5 signaling nodes for the curated dataset.

Despite fibrosis widely contributing to mortality worldwide, inadequate understanding of fibrotic disease pathogenesis has limited the development of efficacious therapies (12). Preclinical studies in vivo, while indispensable, often fail to translate to clinical settings as evidenced by the failure of ~90% of drugs identified in animal studies (36). In addition, limitations in current technologies (e.g., the embryonic lethality of many genetic ECM knockouts and the limited resolution/imaging depth of intravital microscopy) have hindered the application of preclinical in vivo models for the study of cell-ECM interactions that underlie fibrogenesis (37). In contrast, existing in vitro models use patient-derived cells that are affordable, scalable, and amenable to microscopy, but often fail to recapitulate the complex 3D matrix structure of the interstitial tissue regions where fibrotic diseases such as IPF originate. We leveraged electrospinning and bio-orthogonal chemistries to engineer novel pulmonary interstitial matrices that are 3D and have fibrous architecture with biomimetic ligand presentation. In the presence of profibrotic soluble factors, these settings reproduce hallmarks of fibrosis at cellular and tissue levels (Figs. 2 to 4). Examining the influence of physical microenvironmental cues (cross-linking/stiffness and fiber density) on MF differentiation, we find that cross-linking/stiffness has opposing effects on MF differentiation in 2D versus 3D (Fig. 1) and that incorporation of a fibrous architecture in 3D is a prerequisite to MF differentiation (Fig. 4). Furthermore, supported by the importance of protease signaling in IPF (Fig. 6), we performed proof-of-concept pharmacologic screening within our 3D fibrotic matrices (Fig. 5) and highlighted enhanced biomimicry as compared to traditional 2D drug screening substrates where matrix remodeling appears to be dispensable for MF differentiation.

While tunable synthetic hydrogels have identified mechanosensing pathways critical to MF differentiation in 2D, these observations have yet to be translated to 3D fibrous settings relevant to the interstitial spaces where fibrosis originates. Given that late-stage IPF progresses in the absence of external tissue damage, current dogma implicates fibrotic matrix stiffness as the continual driver of MF differentiation in vivo (10, 11, 38). While we cannot disregard this hypothesis, our work elucidates a contrasting MMP-dependent mechanism at play in 3D, whereby a compliant, degradable, and fibrous matrix architecture supports MF differentiation, with matrix contraction and stiffening occurring downstream of -SMA expression, nearly a week later. Given numerous 2D studies indicating matrix stiffness as a driver of MF differentiation, the finding that a compliant matrix promotes MF differentiation may appear counterintuitive (10, 11). However, MF accumulation has been documented before tissue stiffening in human disease (3), and a recent phase 2 clinical trial (ClinicalTrials.gov Identifier: NCT01769196) targeting the LOX pathway (the family of enzymes responsible for matrix stiffening in vivo) failed to prevent disease progression in patients with IPF and was terminated due to lack of efficacy (39). Furthermore, compelling recent work by Fiore et al. (3) combined immunohistochemistry with high-resolution AFM to characterize human IPF tissue mechanics and found that regions of active fibrogenesis were highly fibrous but had a similar Youngs modulus as healthy tissue. In concert with our in vitro data, these findings suggest that MF differentiation is possible within soft provisional ECM in vivo and that the initiation of fibrogenesis may not be dependent on heightened tissue stiffness so long as matrix fibers and appropriate soluble cues (e.g., TGF-1) are present.

Consequently, understanding the source of profibrotic soluble cues in vivo is of critical importance when identifying therapeutic targets for IPF. Luminex screening of supernatant from 3D fibrotic matrices revealed sixfold increases in cytokine secretion during fibrogenesis, most of which were potent inflammatory factors [e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), IL-8, and vascular endothelial growth factor A (VEGF-A)] and chemoattractants (e.g., CCL2, CCL7, CCL11, and CXCL1) (Fig. 4E). Furthermore, IL-6 and VEGF-A were found to be major signaling nodes in patients with IPF (Fig. 6D). While not typically regarded as an immunomodulatory cell population, these findings suggest that MFs may maintain localized inflammation to support continual fibrogenesis. Mitogens such as IL-6 and IL-8 promote endothelial- and epithelial-to-mesenchymal transition, a process that gives rise to matrix-producing MF-like cells in IPF (40). CCR2 (CCL2 and CCL7) and CXCR1 (CXCL1 and IL-8) ligation facilitates macrophage chemotaxis, potentially leading to a sustained influx of TGF-1producing cells in IPF, and glycoproteins such as GM-CSF inhibit caspase activity in mononuclear cells, potentially preventing apoptotic events required for the resolution of wound repair and return to homeostasis (23, 41). In addition, secretion of nearly all cytokines was increased as a function of fiber density, highlighting a potential feed-forward loop distinct from canonical TGF-1 signaling. Further model development (e.g., coculture platforms) will be required to examine these hypotheses and the role of MF-derived cytokines in persistent inflammation and fibrosis.

In addition to documenting the role of fibrotic matrix architecture in 3D fibrogenesis, we demonstrate proof-of-concept pharmacologic screening within our synthetic pulmonary interstitial matrices and highlight their improved relevance to human disease. Previous work in vitro has documented profound reductions in MF differentiation after treatment with clinically approved antifibrotics (pirfenidone and nintedanib), whereas in the clinic, pirfenidone and nintedanib impede disease progression but are far from curative (4, 28, 42, 43). Pirfenidone or nintedanib had insignificant effects in 2D settings in our hands and only modest effects in 3D (Fig. 5). One reason for this discrepancy may be the use of supraphysiologic pirfenidone and nintedanib concentrations in previous in vitro studies, whereas we selected dosages based on plasma concentrations in patients with IPF (44). Differences in pharmacokinetics, nutrient/growth factor diffusion, and cell metabolism between 2D and 3D tissue constructs likely also play a role. Furthermore, as evidenced by the preventative effect of the protease inhibitor marimastat in 3D hydrogels but not 2D settings (Fig. 5), pharmacologics that influence matrix degradation and remodeling are likely to have a minimized effect in 2D settings due to the less dynamic nature of tissue culture plastic and flat hydrogels (45). Nintedanib and pirfenidone have been shown to influence protease activity and matrix remodeling in vivo (16), and may be mediating their effects within fibrotic matrices through modulation of ECM remodeling. Given the identification of numerous potential antifibrotic agents (microRNA, TGF-1 inhibitors, IL-4, IL-13 neutralizing antibodies, and integrin blockers) in preclinical models, application of the system described here could elucidate how choice pharmacologics affect MF differentiation and matrix remodeling processes that are difficult to recapitulate in 2D culture. Further development of our interstitial matrices as an arrayed platform, as has been elegantly implemented with collagen matrices (42), is a critical next step to moving this technology toward high-throughput screening applications.

It is important to note that this work has several potential limitations. Our material approach allows facile control of initial microenvironmental conditions (e.g., dimensionality, fiber density, ligand density, and elastic modulus), and of note, composites of RGD-bearing nondegradable fibers and degradable bulk hydrogel decouple degradation-induced changes in matrix mechanics and ligand availability. However, we have no experimental control over subsequent dynamic cell-driven remodeling events (e.g., MMP-mediated hydrogel softening, fibronectin and collagen deposition, and hydrogel contraction/stiffening from resident cells) that likely affect local matrix mechanics, cellular mechanosensing, and MF differentiation. Exciting recent technologies such as 3D traction force microscopy (TFM) and magnetic bead microrheology could enable future examination of how these dynamic changes in cell-scale mechanics potentiate MF differentiation in 3D. Along similar lines, although our study suggests a requirement for initial adhesion to the surrounding matrix, how the dynamics of ligand presentation due to matrix remodeling regulates mechanosensing was not explored here. We present this platform as a reductionist approach to modeling the activation of fibroblasts within the 3D fibrous interstitia associated with fibrosis, a pathology that develops over years in vivo and involves multiple cell types. Human pulmonary tissue and fibrotic foci, in particular, also have viscoelastic and nonlinear mechanical behaviors (3, 46) that were not explored in our AFM measurements of murine lung or hydrogel composites. Given the important role such mechanical features can play in ECM mechanosensing, incorporating new synthetic material strategies in combination with cell-scale mechanical measurements will be essential to modeling physiologic complexity. Given that the development of lung organoids is still in its infancy, decellularized precision-cut lung slices currently represent the best culture platform to capture the full complexity of the lung microenvironment (5).

In summary, we designed a tunable 3D and fibrous hydrogel model that recapitulates dynamic physical (e.g., stiffening and contraction) and biochemical (e.g., secretion of fibronectin, collagen, and cytokines) alterations to the microenvironment observed during the progression of IPF. Implementation of our model allowed us to establish a developing mechanism for MF differentiation in 3D compliant environments, whereby cell spreading upon matrix fibers drives YAP activity, cytokine release, and proteolysis-dependent MF differentiation. Furthermore, we leveraged bioinformatics techniques to explore protease signaling in clinical IPF and, in concert with our therapeutic screening data, establish a strong role for proteases during IPF pathogenesis and in 3D MF differentiation. Whether protease activity promoted MF differentiation directly through modulation of intracellular signaling or indirectly through affects on the local matrix environment has yet to be explored in these settings but will be the focus of future efforts. Consequently, these results highlight critical design parameters (3D degradability and matrix architecture) frequently overlooked in established synthetic models of MF differentiation. Future work incorporating macrophages, endothelial cells, and epithelial cells may expand current understanding of how developing MF populations influence otherwise homeostatic cells and how matrix remodeling influences paracrine signaling networks and corresponding drug response. Given the low translation rate of drugs identified in high-throughput screening assays, we show that the application and development of engineered biomimetics, in combination with preclinical models, can improve drug discovery and pathophysiological understanding.

All reagents were purchased from Sigma-Aldrich and used as received, unless otherwise stated.

Dextran vinyl sulfone. A previously described protocol for vinyl sulfonating polysaccharides was adapted for use with linear highmolecular weight (MW) dextran (MW 86,000 Da; MP Biomedicals, Santa Ana, CA) (20). Briefly, pure divinyl sulfone (12.5 ml; Thermo Fisher Scientific, Hampton, NH) was added to a sodium hydroxide solution (0.1 M, 250 ml) containing dextran (5 g). This reaction was carried out at 1500 rpm for 3.5 min, after which the reaction was terminated by adjusting the pH to 5.0 via the addition of hydrochloric acid. A lower functionalization of DexVS was used for hydrogels, where the volume of divinyl sulfone reagent was reduced to 3.875 ml. All reaction products were dialyzed for 5 days against Milli-Q ultrapure water, with two water exchanges daily, and then lyophilized for 3 days to obtain the pure product. Functionalization of DexVS was characterized by 1H nuclear magnetic resonance (NMR) spectroscopy in D2O and was calculated as the ratio of the proton integral [6.91 parts per million (ppm)] and the anomeric proton of the glucopyranosyl ring (5.166 and 4.923 ppm); here, vinyl sulfone/dextran repeat unit ratios of 0.376 and 0.156 were determined for electrospinning and hydrogel DexVS polymers, respectively.

DexVS was dissolved at 0.6 g ml1 in a 1:1 mixture of Milli-Q ultrapure water and dimethylformamide with 0.015% Irgacure 2959 photoinitiator. Methacrylated rhodamine (0.5 mM; Polysciences Inc., Warrington, PA) was incorporated into the electrospinning solution to fluorescently visualize fibers under 555 laser. This polymer solution was used for electrospinning within an environment-controlled glovebox held at 21C and 30% relative humidity. Electrospinning was performed at a flow rate of 0.3 ml hour1, gap distance of 5 cm, and voltage of 10.0 kV onto a grounded collecting surface attached to a linear actuator. Fiber layers were collected on glass slabs and primary cross-linked under ultraviolet light (100 mW cm2) and then secondary cross-linked (100 mW cm2) in an Irgacure 2959 solution (1 mg ml1). After polymerization, fiber segments were resuspended in a known volume of phosphate-buffered saline (PBS) (typically 3 ml). The total volume of fibers was then calculated via a conservation of volume equation: total resulting solution volume = volume of fibers + volume of PBS (3 ml). After calculating total fiber volume, solutions were re-centrifuged, supernatant was removed, and fiber pellets were resuspended to create a 10 volume % fiber solution, which were then aliquoted and stored at 4C. To support cell adhesion, 2.0 mM RGD was coupled to vinyl sulfone groups along the DexVS backbone via Michael-type addition chemistry for 30 min, followed by quenching of excess VS groups in a 300 mM cysteine solution for 30 min.

DexVS gels were formed via a thiol-ene click reaction at 3.3% (w/v) (pH 7.4, 37C, 45 min) with VPMS cross-linker (12.5, 20, and 27.5 mM) (GCRDVPMSMRGGDRCG, GenScript, George Town, KY) in the presence of varying amounts of arginylglycylaspartic acid (RGD, CGRGDS, 2.0 mM; GenScript, George Town, KY), HBP (GCGAFAKLAARLYRKA, 1.0 mM; GenScript, George Town, KY), and fiber segments (0.0 to 5.0%, v/v). For experiments comparing hydrogels of varying ligand type (1 mM HBP versus 2 mM RGD), cysteine was added to precursor solutions to maintain a final vinyl sulfone concentration of 60 mM. All hydrogel and peptide precursor solutions were made in PBS containing 50 mM Hepes. To create fibrous hydrogels, a defined stock solution (10% v/v) of suspended fibers in PBS/Hepes was mixed into hydrogel precursor solutions before gelation. By controlling the dilution of the fiber suspension, fiber density was readily tuned within the hydrogel at a constant hydrogel weight percentage. For gel contraction experiments, DexVS was polymerized within a 5-mm-diameter polydimethylsiloxane (PDMS) gasket to ensure consistent hydrogel area on day 0.

NHLFs (University of Michigan Central Biorepository), normal human dermal fibroblasts (Lonza, Basel, Switzerland), and normal human mammary fibroblasts (Sciencal, Carlsbad, CA) were cultured in Dulbeccos modified Eagles medium containing 1% penicillin/streptomycin, l-glutamine, and 10% fetal bovine serum (Atlanta Biologicals, Flowery Branch, GA). NHLFs derived from three separate donors were used for experiments. Cells were passaged upon achieving 90% confluency at a 1:4 ratio and used for studies until passage 7. For all hydrogel studies, cells were trypsinized, counted and either encapsulated into or seeded onto 25-l hydrogels at a density of 1,000,000 cells ml1 of hydrogel, and subsequently cultured at 37C and 5% CO2 in serum-containing medium. For studies comparing 3D hydrogels to tissue culture plastic, the number of cells seeded into 2D conditions was analogous to the total cell number within hydrogel matrices. Medium was refreshed the day after encapsulation and every 2 days after. In selected experiments, recombinant human TGF-1 (5 ng/ml; PeproTech, Rocky Hill, NJ) was supplemented into the medium at 5 ng ml1. For pharmacological studies, nintedanib (50 nM; Thermo Fisher Scientific, Hampton, NH), pirfenidone (100 M; Thermo Fisher Scientific, Hampton, NH), marimastat (1.0 M), and dimethyl fumarate (100 nM) were supplemented in serum-containing medium and refreshed every 2 days.

Cultures were fixed with 4% paraformaldehyde for 30 min at room temperature. To stain the actin cytoskeleton and nuclei, samples were permeabilized in PBS solution containing Triton X-100 (5%, v/v), sucrose (10%, w/v), and magnesium chloride (0.6%, w/v); blocked in 1% bovine serum albumin (BSA); and stained simultaneously with phalloidin and 4,6-diamidino-2-phenylindole (DAPI). For immunostaining, samples were permeabilized, blocked for 8 hours in 1% (w/v) BSA, and incubated with mouse monoclonal anti-YAP antibody (1:1000; Santa Cruz Biotechnology, SC-101199), mouse monoclonal anti-fibronectin antibody (FN, 1:2000; Sigma-Aldrich, #F6140), rabbit monoclonal anti-Ki67 (1:500; Sigma-Aldrich #PIMA514520), or mouse monoclonal anti-SMA (1:2000; Sigma-Aldrich, #A2547) followed by secondary antibody for 6 hours each at room temperature with 3 PBS washes in between. High-resolution images of YAP, FN, and actin morphology were acquired with a 40 objective. Unless otherwise specified, images are presented as maximum intensity projections of 100-m Z-stacks. Hydrogel samples were imaged on a Zeiss LSM 800 laser scanning confocal microscope. SHG imaging of lung tissue was conducted on a Leica SPX8 laser scanning confocal microscope with an excitation wavelength of 820 nm and a collection window of 400 to 440 nm. Single-cell morphometric analyses (cell spread area) were performed using custom Matlab scripts with sample sizes >50 cells per group, while YAP, -SMA, Ki67, and FN immunostains were quantified on an image basis with a total of 10 frames of view. MFs were denoted as nucleated, F-actin+, -SMA+ cells. For cell density (number of nuclei) calculations, DAPI-stained cell nuclei were thresholded and counted in six separate 600 m 600 m 200 m image volumes, allowing us to calculate a total number of cells per mm3 of gel. Fiber recruitment analysis was conducted via a custom Matlab script; briefly, cell outlines were created via actin masking and total fiber fluorescence was quantified under each actin mask on a per-cell basis. A similar analysis method using Matlab was used for cell-cell junction analysis as published previously, with higher area:perimeter ratios and clusters/cell indicative as more pronounced network formation (47).

For all experiments, additional hydrogel replicates were finely minced and degraded in dextranase solution (4 IU/ml; Sigma-Aldrich) for 20 min and homogenized in buffer RLT (Qiagen, Venlo, The Netherlands), and RNA was isolated according to the manufacturers protocols. Complementary DNA (cDNA) was generated from deoxyribonuclease (DNase)free RNA and amplified, and gene expression was normalized to the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Experiments were run with technical triplicates across three individual biological experiments. For a complete list of primers, see table S2.

To determine the elastic modulus of lung tissue and DexVS hydrogels, indentation tests were used with a Nanosurf FlexBio AFM (Nanosurf, Liestal, Switzerland). Samples were indented via a 5-m bead at a depth of 10 m and an indentation rate of 0.333 m/s. Resulting force-displacement curves were fit to a spherical Hertz model using AtomicJ. Poissons ratios of 0.5 and 0.4 were used for hydrogels and lung tissue, respectively.

All animal studies were approved by the Animal Care and Use Committee at the University of Michigan. Bleomycin (0.025 U; Sigma-Aldrich) was instilled intratracheally in C57BL6 mice (8 weeks of age; The Jackson Laboratory, Bar Harbor, ME, USA) on day 0. Briefly, mice were anesthetized with sodium pentobarbital, the trachea was exposed and entered with a 30-gauge needle under direct visualization, and a single 30-l injection containing 0.025 U of bleomycin (Sigma-Aldrich) diluted in normal saline was injected. Lungs were collected on day 14 for mechanical and histological analysis. For histology samples, lungs were perfused with saline and inflated with 4% paraformaldehyde, sectioned, and stained with picrosirius red. For mechanical characterization via AFM, lungs were perfused with saline, infused with OCT (optimal cutting temperature) compound (Thermo Fisher Scientific), and flash-frozen in a slurry of dry ice and ethanol. Sections were mechanically tested via AFM nanoindentation immediately upon thawing.

To characterize the inflammatory secretome associated with various DexVS-VPMS environments, medium was collected from NHLF cultures 3, 5, 7, and 9 days after encapsulation. A Luminex FlexMAP 3D (Luminex Corporation, Austin, TX) systems technology was used to measure 41 cytokines/chemokines (HCTYMAG-60 K-PX41, Milliplex, EMD Millipore Corporation) in the medium samples according to the manufacturers instructions. Total secretion was reported as the sum of all 41 analytes measured for each respective condition. Cell-secreted collagen was measured using the established colorimetric Sircol assay in hydrogels cultured with serum-free medium in the presence of ascorbic acid (25 g ml1).

The NCBI GEO database was consulted [dataset GSE47460 (GP14550)] to fetch gene expression data from 91 healthy patients and 140 patients with IPF; patients with chronic obstructive pulmonary disease and nonidiopathic fibrotic lung diseases were excluded from the analysis (48). GEO2R (www.ncbi.nlm.nih.gov/geo/geo2r/) software was used for GO term enrichment, with keywords ECM, MMP, integrin, cytoskeleton, cytokine, chemokine, and MAPK used as search terms for dataset curation (48). Noncurated datasets were composed of the top 1000 differentially expressed genes between healthy and interstitial lung disease (ILD) conditions. Differential expression was calculated on the basis of subtracting normalized expression values between diseased and healthy patients. All genes were normalized before analysis with GEO2R via a pairwise cyclic losses approach. For pathway and protein-protein enrichment analyses, a curated pathway database [Reactome (49)] and Search Tool for Retrieval of Interacting Genes/Proteins [STRING (50)] methodology were consulted, respectively. For STRING analyses, up-regulated genes within the druggable genome were focused upon. A tabulated list of top genes, pathways, and nodes can be seen in data file S1.

Statistical significance was determined by one-way analysis of variance (ANOVA) or Students t test where appropriate, with significance indicated by P < 0.05. All data are presented as means SD.

Acknowledgments: We thank E. S. White (University of Michigan) for providing patient-derived lung fibroblasts used in these studies. Funding: This work was supported, in part, by the NIH (HL124322, R35HL144481). D.L.M. and C.D.D. acknowledge financial support from the NSF Graduate Research Fellowship Program (DGE1256260). Author contributions: D.L.M. and B.M.B. conceived and supervised the project. D.L.M. designed and performed the experiments. K.M.D. and K.B.A. performed and aided in analysis of the Luminex experiments. M.R.S. and C.D.D. helped with data analysis. R.P. and M.S. aided in polymer syntheses and microfiber fabrication. I.M.L. provided equipment for and assisted in polymerase chain reaction experiments. C.A.W. and B.B.M. helped perform the animal experiments for the bleomycin-induced lung fibrosis model. All authors edited and approved the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Microengineered 3D pulmonary interstitial mimetics highlight a critical role for matrix degradation in myofibroblast differentiation - Science...

COVID-19 Drug Discovery and Development Why Diverse Strategies Are Critical – Technology Networks

There is no silver bullet at the moment, and there might never be, said World Health Organization Director-General Tedros Adhanom at a virtual press conference at the beginning of August. While it was this bleak sound bite that made the headlines, Tedros also had words of praise for the progress made towards identifying treatments that aid the recovery of COVID-19 patients with the most serious forms of the disease.Research towards treatments for COVID-19 has been developing at a phenomenal speed, even though it feels as though solutions cant come soon enough; the widespread transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had significant health, economic and social impacts across the globe, and as of September 8th more than 27 million cases and 890,000 deaths have been recorded in 188 countries.

Research groups across the world have set about identifying drugs for the treatment of COVID-19, by screening both novel and existing drugs for their ability to alleviate symptoms and stem viral replication. Here, we provide an update on ongoing global efforts to develop and test drugs for the treatment of COVID-19 and explore the range of strategies being employed.

COVID-19 is a disease which can leave you with anything between a mild sniffle to an unpleasant combination of high fever, heavy fatigue, and lung inflammation and damage. The drivers of clinical symptoms can be roughly divided into two categories: the virus itself and the hyperinflammatory response to the virus that occurs in the most severely ill people. Consequently, efforts to identify appropriate treatments are often focused on one category, and sometimes, a particular patient group or stage of disease. Given the nature of COVID-19, it is highly likely that a combination of drugs (drug cocktail) will be needed to both neutralize the virus and suppress the symptoms of COVID-19. Antiviral treatments may target viral components directly, or other cellular processes involved in viral infection or replication. To date, interventional studies for COVID-19 have attempted to achieve a wide range of goals, including:

Addressing the threat of new and potentially life-threatening pathogens requires deep understanding and accurate, reproducible techniques for developing better tests, vaccines, and treatments. Agilent provides the complete breadth of systems, consumables, software, services, and knowledge you need to support your success.

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Meet the scientists on the frontline with coronavirus. Video credit: Sanford Burnham Prebys Medical Discovery Institute

Of the ~12,000 compounds screened, 100 inhibited SARS-CoV-2 replication in mammalian cells, 21 of which did so in a dose-response fashion. Achieving a sufficiently high dose concentration to elicit antiviral effects in vivo was predicted to be practical and possible for 13 of these compounds based on EC50 values in various cell lines. The most potent of these were evaluated for antiviral activity in human induced pluripotent stems cell (iPSC)-derived pneumocyte-like cells (five candidates) and in an ex vivo lung culture system (one candidate). The latter candidate is called apilimod, a small molecule inhibitor of an enzyme (phosphoinositide 5-kinase or PIKfyve, an endosomal lipid kinase) important to the endocytic pathway in which SARS-CoV-2 travels along during its journey through the cell. Encouragingly, apilimod potently antagonized viral replication in these tissues, and the findings are in agreement with those of another research group. This month, Kang et al. published an article in PNAS, describing the potent inhibition of SARS-CoV-2 by apilimod, providing further evidence to suggest PIKfyve-inhibition as a potential strategy that could limit infection and disease pathogenesis. The authors also noted that apilimod has passed safety tests in previous clinical trials for nonviral indications.

Chanda highlights the incredible pace at which this work was produced. Typically, a project like this would take years, rather than months. He points out that by wanting to do something quickly, there were sacrifices (and not just weekends). For example, they ran with the assay and the cell lines that allowed them to produce results quickly. This is the reason we put the entire dataset out there not one/three/20 molecules, we put all 100 molecules out there. These are the ones we found because of our experimental system, but please keep testing the others because youll probably find other things that work, said Chanda.

To design multiple peptide sequences that can competitively bind to the SARS-CoV-2 receptor binding domain, the University of Michigan research group used a protein design system called EvoDesign.EvoDesign is the first de novo protein design protocol developed in our lab; it performs design simulation by combining the evolution-based information collected from protein databases and an accurate physics- and knowledge-based energy function, namely EvoEF2, for computing atomic interactions such as van der Waals forces, electrostatics, hydrogen bonding, and desolvation energies, said Huang.

Overall, these sophisticated computational tools represent a promising new avenue for the de novo development of drug discovery studies.

Michele Wilson is a freelance science writer for Choice Science Writing.

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COVID-19 Drug Discovery and Development Why Diverse Strategies Are Critical - Technology Networks

Much-loved son Joe Brown saved three lives after tragic death at just 29 – Birmingham Live

A piercing smile that beams out of his photos is not the only legacy left behind by much-loved Joe Brown.

At just 29, his life was cut short, but not before he made a decision that would save the lives of three other people.

Prior to his untimely death, the avid gamer signed up to donate all his organs to help those waiting for a life-saving transplant.

For his mother and siblings, nothing could prepare them for losing "kind and generous" Joe so suddenly, but they have found solace in knowing part of him lives on.

Big sister, Louise Edwards, told Black Country Live: "He had opted to donate all his organs. Initially, my mum struggled with this decision but its what he wanted.

"He saved two 29-year-old men who had been waiting nearly two years for a life-saving transplant and he also helped a lady in her 50s.

Joes liver and kidneys were donated shortly after his death at Walsall Manor Hospital on July 23 this year.

Louise said: "My brother was a caring person and, even on his deathbed, he wanted to help. He chose to do it so we had to support it. He agreed to have his stem cells taken to help children. Although he is no longer here, he is still helping people.

"Its comforting to know he saved the lives of three people and his legacy lives on."

According to figures released by the NHS blood and transplant service, there are currently around 6,000 people on the UK transplant waiting list.

Last year, more than 350 people died while waiting for a transplant. Just eight per cent of organs donated were from those of African, Caribbean or Asian heritage.

While his final gesture represented the gift of life, Joe was hiding a silent battle with mental health.

An inquest hearing held at Black Country Coroners Court decided he had tragically taken his own life.

Louise said: "He didnt talk about his struggles with mental health, he always said he didnt want to be a burden. He had stopped talking to us, we only got him back two weeks before his death."

During the inquest, it was revealed that, in the weeks before Joe's death, he had tried to contact the emergency mental health crisis team but was denied a face-to-face appointment because of the COVID-19 outbreak.

"He only used to confide in his friends on the Xbox, he talked about his past, his troubles in his relationship and previous suicide attempts, his sister continued.

She added: "He was a family person, he was a kind and generous person, thats the legacy that he left behind. More than 200 people came to pay their respects at his funeral, he didnt know how loved he was.

"To those struggling with mental health, speak out. It doesnt make you weak to speak out. If he had told us how he was feeling we could have helped to get him the help he needed.

Samaritans (116 123) samaritans.org operates a 24-hour service available every day of the year. If you prefer to write down how youre feeling, or if youre worried about being overheard on the phone, you can email Samaritans at jo@samaritans.org , write to Freepost RSRB-KKBY-CYJK, PO Box 9090, STIRLING, FK8 2SA and visit http://www.samaritans.org/branches to find your nearest branch.

CALM (0800 58 58 58) thecalmzone.net has a helpline is for men who are down or have hit a wall for any reason, who need to talk or find information and support. They're open 5pm to midnight, 365 days a year.

Childline (0800 1111 ) runs a helpline for children and young people in the UK. Calls are free and the number wont show up on your phone bill. PAPYRUS (0800 068 41 41) is a voluntary organisation supporting teenagers and young adults who are feeling suicidal.

Depression Alliance is a charity for people with depression. It doesnt have a helpline, but offers a wide range of useful resources and links to other relevant information depressionalliance.org Students Against Depression is a website for students who are depressed, have a low mood or are having suicidal thoughts. Bullying UK is a website for both children and adults affected by bullying studentsagainstdepression.org The Sanctuary (0300 003 7029 ) helps people who are struggling to cope - experiencing depression, anxiety, panic attacks or in crisis. You can call them between 8pm and 6am every night.There are other depression charities.

"The family are distraught, my kids and the younger siblings dont understand why Joe isnt here. Im the oldest and I never thought he would be gone before me."

At the hearing, coroner, Joanne Lees, told the court that Joe had been found unresponsive in his room by his ex-girlfriend on July 20, 2020.

Paramedics were able to resuscitate him and he was rushed to Walsall Manor Hospital but, due to a cardiac arrest, he suffered a brain injury which led to his death.

Fondly recalling her sons warm character, Vicky Spriggs told the court: "He was a happy go lucky person who didnt believe in mental health, he would always say, 'suck it up' or 'man up'.

"He was bubbly and outgoing. Joe was always smiling and joking around.

Ms Lees recorded a verdict of suicide and offered her condolences to the family.

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Much-loved son Joe Brown saved three lives after tragic death at just 29 - Birmingham Live

Market Growth of Global Stem Cells to Remain Sluggish through 2020 2030 – The News Brok

The success of approved stem cell therapies has caused a surge in interest of biopharma developers in this field; many innovator companies are currently progressing proprietary leads across different phases of clinical development, with cautious optimism

Roots Analysis has announced the addition of Global Stem Cells Market: Focus on Clinical Therapies, 20202030 (Based on Source (Allogeneic, Autologous); Origin (Adult, Embryonic); Type (Hematopoietic, Mesenchymal, Progenitor); Lineage (Amniotic Fluid, Adipose Tissue, Bone Marrow, Cardiosphere, Chondrocytes, Corneal Tissue, Cord Blood, Dental Pulp, Neural Tissue Placenta, Peripheral Blood, Stromal Cells); and Potency (Multipotent, Pluripotent)) report to its list of offerings.

There is a growing body of evidence supporting the vast applicability and superiority of treatment outcomes of stem cell therapies, compared to conventional treatment options. In fact, the unmet needs within this domain have spurred the establishment of many start-ups in recent years.

To order this 500+ page report, which features 185+ figures and 220+ tables, please visit this link

Over 280 stem cell therapies are under development, most of which are allogeneic productsMore than 50% of the pipeline candidates are in the mid to late phase trials (phase II and above), and allogenic therapies (majority of which are derived from the bone marrow) make up 65% of the pipeline.

70% of pipeline candidates are based on mesenchymal stem cellsIt is worth highlighting that the abovementioned therapies are designed to treat musculoskeletal (22%), neurological (21%) and cardiovascular (15%) disorders. On the other hand, hematopoietic stem cell-based products are mostly being evaluated for the treatment of oncological disorders, primarily hematological malignancies.

Close to 85% stem cell therapy developers are based in North America and Asia-Pacific regionsWithin these regions, the US, China, South Korea and Japan, have emerged as key R&D hubs for stem cell therapies. It is worth noting that majority of the initiatives in this domain are driven by small / mid-sized companies

Over 1,500 grants were awarded for stem cell research, since 2015More than 45% of the total amount was awarded under the R01 mechanism (which supports research projects). The NCI, NHLBI, NICHD, NIDDK, NIGMS and OD emerged as key organizations that have offered financial support for time periods exceeding 25 years as well.

Outsourcing has become indispensable to R&D and manufacturing activity in this domainPresently, more than 80 industry / non-industry players, based in different regions across the globe, claim to provide contract development and manufacturing services to cater to the unmet needs of therapy developers. Examples include (in alphabetical order) Bio Elpida, Cell and Gene Therapy Catapult, Cell Tech Pharmed, GenCure, KBI Biopharma, Lonza, MEDINET, Nikon CeLL innovation, Roslin Cell Therapies, WuXi Advanced Therapies and YposKesi.

North America and Asia-Pacific markets are anticipated to capture over 80% share by 2030The stem cell therapies market is anticipated to witness an annualized growth rate of over 30% during the next decade. Interestingly, the market in China / broader Asia-Pacific region is anticipated to grow at a relatively faster rate.

To request a sample copy / brochure of this report, please visit this link

The USD 8.5 billion (by 2030) financial opportunity within the stem cell therapies market has been analyzed across the following segments:

The report features inputs from eminent industry stakeholders, according to whom stem cell therapies are currently considered to be a promising alternatives for the treatment of a myriad of disease indications, with the potential to overcome challenges associated with conventional treatment options. The report includes detailed transcripts of discussions held with the following experts:

The research covers brief profiles of several companies (including those listed below); each profile features an overview of the company, financial information (if available), stem cell therapy portfolio and an informed future outlook.

For additional details, please visithttps://www.rootsanalysis.com/reports/view_document/stem-cells-market/296.html

or email [emailprotected]

You may also be interested in the following titles:

Contact:

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Market Growth of Global Stem Cells to Remain Sluggish through 2020 2030 - The News Brok

Global and Asia Pacific Progenitor Cell Product Market to Witness Huge Growth by 2027 Major Manufacturers included in report NeuroNova AB, StemCells,…

Global Coronavirus pandemic has impacted all industries across the globe, Progenitor Cell Product market being no exception. As Global economy heads towards major recession post 2009 crisis, Cognitive Market Research has published a recent study which meticulously studies impact of this crisis on Global Progenitor Cell Product market and suggests possible measures to curtail them. This press release is a snapshot of research study and further information can be gathered by accessing complete report. To Contact Research Advisor Mail us @ [emailprotected] or call us on +1-312-376-8303.

Report is a detailed study of the Progenitor Cell Product market, which covers all the essential information required by a new market entrant as well as the existing players to gain a deeper understanding of the market. Report has been segmented into Geographical Segmentation, Key players, Key Topics Industry Value and Demand Analysis Forecast to 2027 and provides comprehensive investigation.

Global Progenitor Cell Product Market: Product analysis: Pancreatic progenitor cells, Cardiac Progenitor Cells, Intermediate progenitor cells, Neural progenitor cells (NPCs), Endothelial progenitor cells (EPC), Others

Global Progenitor Cell Product Market: Application analysis: Medical care, Hospital, Laboratory

Major Market Players with an in-depth analysis: NeuroNova AB, StemCells, ReNeuron Limited, Asterias Biotherapeutics, Thermo Fisher Scientific, STEMCELL Technologies, Axol Bio, R&D Systems, Lonza, ATCC, Irvine Scientific, CDI

Any query? Enquire Here For Discount (COVID-19 Impact Analysis Updated Sample): Click Here>Download Sample Report of Progenitor Cell Product Market Report 2020 (Coronavirus Impact Analysis on Progenitor Cell Product Market)

The research comprises primary information about the products. Similarly, it includes supply-demand statistics, and segments that constrain the growth of an industry. It also includes raw materials used and manufacturing process of Progenitor Cell Product market. Additionally, report provides market drivers and challenges & opportunities for overall market in the particular provincial sections.

The report gives detailed account on each segment which helps to understand market more effectively. The company profiling of key players include: business overview, product description, research and development investment, key development, business strategy, and SWOT analysis. It also involves sales revenue of each division and geographical coverage for two consecutive years.

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The industry intelligence study of the Progenitor Cell Product market covers the estimation size of the market each in phrases of value (Mn/Bn USD) and volume (x units). Further, report consists of Porters Five Forces and BCG matrix as well as product life cycle to help you in taking wise decisions. Additionally, this report covers the inside and out factual examination and the market elements and requests which give an entire situation of the business.

Regional Analysis for Progenitor Cell Product Market:North America (United States, Canada)Europe (Germany, Spain, France, UK, Russia, and Italy)Asia-Pacific (China, Japan, India, Australia, and South Korea)Latin America (Brazil, Mexico, etc.)The Middle East and Africa (GCC and South Africa)

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About Us:Cognitive Market Research is one of the finest and most efficient Market Research and Consulting firm. The company strives to provide research studies which include syndicate research, customized research, round the clock assistance service, monthly subscription services, and consulting services to our clients. We focus on making sure that based on our reports, our clients are enabled to make most vital business decisions in easiest and yet effective way. Hence, we are committed to delivering them outcomes from market intelligence studies which are based on relevant and fact-based research across the global market.Contact Us: +1-312-376-8303Email: [emailprotected]Web: https://www.cognitivemarketresearch.com/

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Global and Asia Pacific Progenitor Cell Product Market to Witness Huge Growth by 2027 Major Manufacturers included in report NeuroNova AB, StemCells,...

Autologous Stem Cell and Non-Stem Cell Based Therapies Market 2020-2025 | Major Giants Fibrocell, Genesis Biopharma, Georgia Health Sciences…

Global Autologous Stem Cell and Non-Stem Cell Based Therapies Market research report estimates a considerable growth of market in percentage during the forecast period of 2020-2026. This report also explains market definitions, classifications, applications, and engagements in the Healthcare industry. In addition, the scope of this market report can be broadened from market scenarios to comparative pricing between major players, cost & profit of the specified market regions. Autologous Stem Cell and Non-Stem Cell Based Therapies Market report is very consistent as all the data and information regarding the Healthcare industry is derived via authentic sources such as websites, journals, annual reports of the companies, and magazines.

For In depth Information Get Sample Copy of this Report @https://www.databridgemarketresearch.com/request-a-sample/?dbmr=global-autologous-stem-cell-and-non-stem-cell-based-therapies-market

TheGlobalAutologous Stem Cell and Non-Stem Cell Based Therapies Marketis expected to reach USD113.04 billion by 2025, from USD 87.59 billion in 2017 growing at a CAGR of 3.7% during the forecast period of 2018 to 2025. The upcoming market report contains data for historic years 2015 & 2016, the base year of calculation is 2017 and the forecast period is 2018 to 2025.

Some of the major players operating in the globalautologous stem cell and non-stem cell based therapies marketareAntria (Cro), Bioheart, Brainstorm Cell Therapeutics, Cytori, Dendreon Corporation, Fibrocell, Genesis Biopharma, Georgia Health Sciences University, Neostem, Opexa Therapeutics, Orgenesis, Regenexx, Regeneus, Tengion, Tigenix, Virxsys and many more.

Browse Detailed TOC Herehttps://www.databridgemarketresearch.com/toc/?dbmr=global-autologous-stem-cell-and-non-stem-cell-based-therapies-market

Market Definition:Global Autologous Stem Cell and Non-Stem Cell Based Therapies Market

In autologous stem-cell transplantation persons own undifferentiated cells or stem cells are collected and transplanted back to the person after intensive therapy. These therapies are performed by means of hematopoietic stem cells, in some of the cases cardiac cells are used to fix the damages caused due to heart attacks. The autologous stem cell and non-stem cell based therapies are used in the treatment of various diseases such as neurodegenerative diseases, cardiovascular diseases, cancer and autoimmune diseases, infectious disease.

According to World Health Organization (WHO), cardiovascular disease (CVD) causes more than half of all deaths across the European Region. The disease leads to death or frequently it is caused by AIDS, tuberculosis and malaria combined in Europe. With the prevalence of cancer and diabetes in all age groups globally the need of steam cell based therapies is increasing, according to article published by the US National Library of Medicine National Institutes of Health, it was reported that around 382 million people had diabetes in 2013 and the number is growing at alarming rate which has increased the need to improve treatment and therapies regarding the diseases.

Market Segmentation:Global Autologous Stem Cell and Non-Stem Cell Based Therapies Market

Major Autologous Stem Cell and Non-Stem Cell Based Therapies Market Drivers and Restraints:

Introduction of novel autologous stem cell based therapies in regenerative medicine

Reduction in transplant associated risks

Prevalence of cancer and diabetes in all age groups

High cost of autologous cellular therapies

Lack of skilled professionals

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Autologous Stem Cell and Non-Stem Cell Based Therapies Market 2020-2025 | Major Giants Fibrocell, Genesis Biopharma, Georgia Health Sciences...

Keio University gets OK for iPS-based heart cell transplant plan – The Japan Times

A health ministry panel on Thursday approved a Keio University clinical research project to transplant heart muscle cells made from induced pluripotent stem (iPS) cells into heart disease patients.

The research will be carried out by a team led by Prof. Keiichi Fukuda for three people between 20 and 74 suffering from dilated cardiomyopathy, which lowers the hearts power to pump blood. The first transplant will be conducted by the end of this year at the earliest.

The team will use iPS cells made by Kyoto University from the blood of a person who has a special immunological type with less risk of rejection.

The team will transform the iPS cells into heart muscle cells and inject about 50 million of them into the heart using a special syringe. Immunosuppressive drugs will be used for about half a year, and the team will spend a year checking to see whether the treatment leads to the development of tumors and irregular heartbeat or whether it restores heart function.

In January, Osaka University conducted the worlds first transplant of heart muscle cells made from iPS cells. The heart muscle cells were made into sheets and pasted on the surface of the patients heart so that a substance they emit can help regenerate the heart muscles. The cells themselves, however, disappear quickly.

Meanwhile, Keio University has confirmed in an experiment on monkeys that cells colonize after a transplant and heart function improves.

The university expects that transplanted cells will colonize over a long period also in the upcoming clinical research project.

According to the team, there are about 25,000 dilated cardiomyopathy patients in Japan.

A startup led by Fukuda is planning a clinical trial aimed at commercializing the iPS-derived cells, hoping they will also be used for the treatment of other cardiac diseases.

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Keio University gets OK for iPS-based heart cell transplant plan - The Japan Times

Scientists grow the first functioning mini human heart model – MSUToday

Michigan State University researchers have created for the first time a miniature human heart model in the laboratory, complete with all primary heart cell types and a functioning structure of chambers and vascular tissue.

Aitor Aguirre, assistant professor of biomedical engineering at MSUs Institute for Quantitative Health Science and Engineering.

These minihearts constitute incredibly powerful models in which to study all kinds of cardiac disorders with a degree of precision unseen before, said Aitor Aguirre, the studys senior author and assistant professor of biomedical engineering at MSUs Institute for Quantitative Health Science and Engineering.

This study, Generation of Heart Organoids Modeling Early Human Cardiac Development Under Defined Conditions, appears on the bioRxiv preprint server and was funded by grants from the American Heart Association and the National Institutes of Health. In the United States, heart disease is the No. 1 cause of death.

The human heart organoids, or hHOs for short, were created by way of a novel stem cell framework that mimics the embryonic and fetal developmental environments.

Organoids meaning resembling an organ are self-assembling 3D cell constructs that recapitulate organ properties and structure to a significant extent, said Yonatan Israeli, a graduate student in the Aguirre Lab and first author of the study.

The innovation deploys a bioengineering process that uses induced pluripotent stem cells adult cells from a patient to trigger embryonic-like heart development in a dish generating a functional mini heart after a few weeks. The stem cells are obtained from consenting adults and therefore free of ethical concerns.

This process allows the stem cells to develop, basically as they would in an embryo, into the various cell types and structures present in the heart, Aguirre said. We give the cells the instructions and they know what they have to do when all the appropriate conditions are met.

Because the organoids followed the natural cardiac embryonic development process, the researchers studied, in real time, the natural growth of an actual fetal human heart.

This technology allows for the creation of numerous hHOs simultaneously with relative ease, contrasting with existing tissue engineering approaches that are expensive, labor intensive and not readily scalable.

One of the primary issues facing the study of fetal heart development and congenital heart defects is access to a developing heart. Researchers have been confined to the use of mammalian models, donated fetal remains and in vitro cell research to approximate function and development.

Now we can have the best of both worlds, a precise human model to study these diseases a tiny human heart without using fetal material or violating ethical principles. This constitutes a great step forward, Aguirre said.

Whats next? For Aguirre, the process is twofold. First, the heart organoid represents an unprecedented look into the nuts and bolts of how a fetal heart develops.

In the lab, we are currently using heart organoids to model congenital heart disease the most common birth defect in humans affecting nearly 1% of the newborn population, Aguirre said. With our heart organoids, we can study the origin of congenital heart disease and find ways to stop it.

And second, while the hHO is complex, it is far from perfect. For the team, improving the final organoid is another key avenue of future research. The organoids are small models of the fetal heart with representative functional and structural features, Israeli said. They are, however, not as perfect as a human heart yet. That is something we are working toward.

Aguirre and team are excited about the wide-ranging applicability of these miniature hearts. They enable an unprecedented ability to study many other cardiovascular-related diseases from chemotherapy-induced cardiotoxicity to the effect of diabetes, during pregnancy, on the developing fetal heart.

Other researchers involved in this study were Aaron Wasserman, Mitchell Gabalski and Kristen Ball at MSU; and Chao Zhou, Jinyon Zhou and Guangming Ni at Washington University in St. Louis.

(Note for media: Please include a link to the original paper in online coverage: https://www.biorxiv.org/content/10.1101/2020.06.25.171611v2)

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Scientists grow the first functioning mini human heart model - MSUToday

First lab-made ‘mini-hearts’ mimic the real thing – Futurity: Research News

Share this Article

You are free to share this article under the Attribution 4.0 International license.

Researchers have created, for the first time, a miniature human heart model in the laboratory.

The mini-hearts are complete with all primary heart cell types and a functioning structure of chambers and vascular tissue.

The organoids are small models of the fetal heart with representative functional and structural features. They are, however, not as perfect as a human heart yet. That is something we are working toward.

These mini-hearts constitute incredibly powerful models in which to study all kinds of cardiac disorders with a degree of precision unseen before, says Aitor Aguirre, assistant professor of biomedical engineering at Michigan State Universitys Institute for Quantitative Health Science and Engineering and senior author of the study on the work on the bioRxiv preprint server. In the United States, heart disease is the leading cause of death.

The researchers created the human heart organoids, or hHOs for short,by way of a novel stem cell framework that mimics the embryonic and fetal developmental environments.

Organoidsmeaning resembling an organare self-assembling 3D cell constructs that recapitulate organ properties and structure to a significant extent, says first author Yonatan Israeli, a graduate student in Aguirres lab.

The innovation deploys a bioengineering process that uses induced pluripotent stem cellsadult cells from a patient to trigger embryonic-like heart development in a dishgenerating a functional mini-heart after a few weeks. The stem cells are obtained from consenting adults and therefore free of ethical concerns.

This process allows the stem cells to develop, basically as they would in an embryo, into the various cell types and structures present in the heart, Aguirre says. We give the cells the instructions and they know what they have to do when all the appropriate conditions are met.

Because the organoids followed the natural cardiac embryonic development process, the researchers studied, in real time, the natural growth of an actual fetal human heart.

This technology allows for the creation of numerous hHOs simultaneously with relative ease, contrasting with existing tissue engineering approaches that are expensive, labor intensive and not readily scalable.

One of the primary issues facing the study of fetal heart development and congenital heart defects is access to a developing heart. Researchers have been confined to the use of mammalian models, donated fetal remains, and in vitro cell research to approximate function and development.

Now we can have the best of both worlds, a precise human model to study these diseasesa tiny human heartwithout using fetal material or violating ethical principles. This constitutes a great step forward, Aguirre says.

Whats next? For Aguirre, the process is twofold. First, the heart organoid represents an unprecedented look into the nuts and bolts of how a fetal heart develops.

In the lab, we are currently using heart organoids to model congenital heart diseasethe most common birth defect in humans affecting nearly 1% of the newborn population, Aguirre says. With our heart organoids, we can study the origin of congenital heart disease and find ways to stop it.

And second, while the hHO is complex, it is far from perfect. For the team, improving the final organoid is another key avenue of future research.

The organoids are small models of the fetal heart with representative functional and structural features, Israeli says. They are, however, not as perfect as a human heart yet. That is something we are working toward.

The researchers are excited about the wide-ranging applicability of these miniature hearts. They enable an unprecedented ability to study many other cardiovascular-related diseasesincluding chemotherapy-induced cardiotoxicity and the effect of diabetes, during pregnancy, on the developing fetal heart.

Additional researchers from Michigan State and Washington University in St. Louis contributed to the work.

The American Heart Association and the National Institutes of Health funded the study.

Source: Michigan State University

Original Study DOI: 10.1101/2020.06.25.171611

Original post:
First lab-made 'mini-hearts' mimic the real thing - Futurity: Research News

Merck’s KEYTRUDA (pembrolizumab) in Combination With Chemotherapy Significantly Improved Overall Survival and Progression-Free Survival Compared With…

KENILWORTH, N.J.--(BUSINESS WIRE)--Aug 19, 2020--

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the pivotal Phase 3 KEYNOTE-590 trial evaluating KEYTRUDA, Mercks anti-PD-1 therapy, in combination with chemotherapy (cisplatin plus 5-fluorouracil [5-FU]), met its primary endpoints of overall survival (OS) and progression-free survival (PFS) for the first-line treatment of patients with locally advanced or metastatic esophageal cancer. Based on an interim analysis conducted by an independent Data Monitoring Committee, KEYTRUDA in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS and PFS compared with chemotherapy (cisplatin plus 5-FU), the current standard of care, in the intention-to-treat (ITT) population. The study also met the key secondary endpoint of objective response rate (ORR), with significant improvements for KEYTRUDA in combination with chemotherapy compared with chemotherapy alone. The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies. Results will be shared with global regulatory authorities and have been submitted for presentation at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

Esophageal cancer is a devastating malignancy with a high mortality rate and few treatment options in the first-line setting beyond chemotherapy, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. In this pivotal study, KEYTRUDA plus chemotherapy resulted in superior overall survival compared with the current standard of care in the full study population and across all patient groups evaluated. These results build upon our research reinforcing the survival benefits of KEYTRUDA, and we look forward to engaging regulatory authorities as quickly as possible.

KEYTRUDA is currently approved in the U.S. and China as monotherapy for the second-line treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (Combined Positive Score [CPS] 10). Merck is continuing to study KEYTRUDA across multiple settings and stages of gastrointestinal cancer including gastric, hepatobiliary, esophageal, pancreatic, colorectal and anal cancers through its broad clinical program.

About KEYNOTE-590

KEYNOTE-590 is a randomized, double-blind, Phase 3 trial (ClinicalTrials.gov, NCT03189719 ) evaluating KEYTRUDA in combination with chemotherapy compared with placebo plus chemotherapy for the first-line treatment of patients with locally advanced or metastatic esophageal carcinoma (adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type 1 adenocarcinoma of the esophagogastric junction). The primary endpoints are OS and PFS. The secondary endpoints include ORR, duration of response and safety. The study enrolled 749 patients who were randomized to receive:

About Esophageal Cancer

Esophageal cancer, a type of cancer that is particularly difficult to treat, begins in the inner layer (mucosa) of the esophagus and grows outward. The two main types of esophageal cancer are squamous cell carcinoma and adenocarcinoma. Esophageal cancer is the seventh most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. Globally, it is estimated there were more than 572,000 new cases of esophageal cancer diagnosed and nearly 509,000 deaths resulting from the disease in 2018. In the U.S. alone, it is estimated there will be nearly 18,500 new cases of esophageal cancer diagnosed and more than 16,000 deaths resulting from the disease in 2020.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

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

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

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

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

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

Non-Small Cell Lung Cancer

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

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

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

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

Small Cell Lung Cancer

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

Head and Neck Squamous Cell Cancer

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

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

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

Classical Hodgkin Lymphoma

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

Primary Mediastinal Large B-Cell Lymphoma

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

Urothelial Carcinoma

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

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

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

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

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

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

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

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

Gastric Cancer

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

Esophageal Cancer

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

Cervical Cancer

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

Hepatocellular Carcinoma

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

Merkel Cell Carcinoma

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

Renal Cell Carcinoma

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

Tumor Mutational Burden-High

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

Cutaneous Squamous Cell Carcinoma

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

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

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

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

Immune-Mediated Colitis

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

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

Immune-Mediated Hepatitis

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

Hepatotoxicity in Combination With Axitinib

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

Immune-Mediated Endocrinopathies

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

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

Immune-Mediated Nephritis and Renal Dysfunction

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

Immune-Mediated Skin Reactions

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

Other Immune-Mediated Adverse Reactions

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

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

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

Infusion-Related Reactions

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

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

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

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

Increased Mortality in Patients With Multiple Myeloma

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

Embryofetal Toxicity

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

Adverse Reactions

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

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

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

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

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

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

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

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

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

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

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

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

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

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Merck's KEYTRUDA (pembrolizumab) in Combination With Chemotherapy Significantly Improved Overall Survival and Progression-Free Survival Compared With...

Exosome Therapeutic Market (Covid 19 Impact Analysis) Data Highlighting Major Vendors, Promising Regions, Anticipated Growth Forecast To 2027 -…

Global Exosome Therapeutic Market By Type (Natural Exosomes, Hybrid Exosomes), Source (Dendritic Cells, Mesenchymal Stem Cells, Blood, Milk, Body Fluids, Saliva, Urine Others), Therapy (Immunotherapy, Gene Therapy, Chemotherapy), Transporting Capacity (Bio Macromolecules, Small Molecules), Application (Oncology, Neurology, Metabolic Disorders, Cardiac Disorders, Blood Disorders, Inflammatory Disorders, Gynecology Disorders, Organ Transplantation, Others), Route of administration (Oral, Parenteral), End User (Hospitals, Diagnostic Centers, Research & Academic Institutes), Geography (North America, Europe, Asia-Pacific and Latin America)

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

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

This exosome therapeutic market report provides details of market share, new developments, and product pipeline analysis, impact of domestic and localised market players, analyses opportunities in terms of emerging revenue pockets, changes in market regulations, product approvals, strategic decisions, product launches, geographic expansions, and technological innovations in the market. To understand the analysis and the market scenario contact us for an Analyst Brief, our team will help you create a revenue impact solution to achieve your desired goal.

Increasing demand for anti-aging therapies will also drive the market. Unmet medical needs such as very few therapeutic are approved by the regulatory authority for the treatment in comparison to the demand in global exosome therapeutics market will hamper the market growth market. Availability of various exosome isolation and purification techniques is further creates new opportunities for exosome therapeutics as they will help company in isolation and purification of exosomes from dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, and urine and from others sources. Such policies support exosome therapeutic market growth in the forecast period to 2019-2026.

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Exosome is an extracellular vesicle which is released from cells, particularly from stem cells. Exosome functions as vehicle for particular proteins and genetic information and other cells. Exosome plays a vital role in the rejuvenation and communication of all the cells in our body while not themselves being cells at all. Research has projected that communication between cells is significant in maintenance of healthy cellular terrain. Chronic disease, age, genetic disorders and environmental factors can affect stem cells communication with other cells and can lead to distribution in the healing process.

The growth of the global exosome therapeutic market reflects global and country-wide increase in prevalence of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases, along with increasing demand for anti-aging therapies. Additionally major factors expected to contribute in growth of the global exosome therapeutic market in future are emerging therapeutic value of exosome, availability of various exosome isolation and purification techniques, technological advancements in exosome and rising healthcare infrastructure.

The major players covered in the report are evox THERAPEUTICS, EXOCOBIO, Exopharm, AEGLE Therapeutics, United Therapeutics Corporation, Codiak BioSciences, Jazz Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH, ReNeuron Group plc, Capricor Therapeutics, Avalon Globocare Corp., CREATIVE MEDICAL TECHNOLOGY HOLDINGS INC., Stem Cells Group among other players domestic and global. Exosome therapeutic market share data is available for Global, North America, Europe, Asia-Pacific, and Latin America separately. DBMR analysts understand competitive strengths and provide competitive analysis for each competitor separately.

The country section of the report also provides individual market impacting factors and changes in regulation in the market domestically that impacts the current and future trends of the market. Data points such as new sales, replacement sales, country demographics, regulatory acts and import-export tariffs are some of the major pointers used to forecast the market scenario for individual countries. Also, presence and availability of global brands and their challenges faced due to large or scarce competition from local and domestic brands, impact of sales channels are considered while providing forecast analysis of the country data.

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Exosome Therapeutic Market (Covid 19 Impact Analysis) Data Highlighting Major Vendors, Promising Regions, Anticipated Growth Forecast To 2027 -...

Stem Cell Therapy Market Landscape Assessment By Type and Analysis Current Trends by Forecast To 2025 – The Daily Chronicle

Global Stem Cell Therapy Market: Overview

Also called regenerative medicine, stem cell therapy encourages the reparative response of damaged, diseased, or dysfunctional tissue via the use of stem cells and their derivatives. Replacing the practice of organ transplantations, stem cell therapies have eliminated the dependence on availability of donors. Bone marrow transplant is perhaps the most commonly employed stem cell therapy.

Osteoarthritis, cerebral palsy, heart failure, multiple sclerosis and even hearing loss could be treated using stem cell therapies. Doctors have successfully performed stem cell transplants that significantly aid patients fight cancers such as leukemia and other blood-related diseases.

Know the Growth Opportunities in Emerging Markets

Global Stem Cell Therapy Market: Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

The regional analysis covers:

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Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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Stem Cell Therapy Market Landscape Assessment By Type and Analysis Current Trends by Forecast To 2025 - The Daily Chronicle

ASU engineers get to the heart of organs-on-a-chip – ASU Now

August 17, 2020

Denver is known for its relatively mild climate and its four distinct seasons. Its also known for its temperature fluctuations over the course of a day or even hours. But what does that mean for the citys residents and for that matter, the rest of the inhabitants of the continental United States when it comes to temperature extremes?

Thats what Ashley Broadbentwanted to know. Specifically, he wanted to know how populations throughout the United States will experience heat and cold during the 21st century.

So, Broadbent, an assistant research professor in Arizona State Universitys School of Geographical Sciences and Urban Planning, used state-of-the-art modeling tools to analyze how three key variables would affect human exposure to extreme temperatures from the beginning of this century to its end.

He and his collaborator Matei Georgescu, an associate professor in the School of Geographical Sciences and Urban Planning, concentrated on the following three key factors: climate change brought about by greenhouse gas emissions, urban development-induced impacts arising from the growth of cities, and population change in individual cities.

The paper, "The motley drivers of heat and cold exposure in 21st century U.S. cities," was published onlineAug. 17 in the Proceedings of the National Academy of Sciences. It is the first study of its kind to consider population-weighted heat and cold exposure that directly and simultaneously account for greenhouse gas and urban development-induced warming.

Graphic by Alex Davis/ASU Media Relations and Strategic Communications

To describe how these three variables would affect temperatures, and in turn populations, Broadbent, Georgescu and co-author Eric Scott Krayenhoff, assistant professor at the University of Guelph, Ontario, in Canada, used a metric they dubbed person-hours, to describe humans exposure to extreme heat and cold.

Its an intuitive metric, Broadbent said. For example, when one person is exposed to one hour of an extreme temperature, that exposure equals one person-hour of exposure. Likewise, if 10 people are exposed to 10 hours of an extreme temperature, that exposure equals 100 person-hours.

I think this definition is more representative of what people experience, which is what this study is about versus a study that simply communicates temperature changes without any human element attached to it, Broadbent said.

Overall, the researchers found that the average annual heat exposure at the start of this century in the United States was about 5.2 billion person-hours. Assuming a worst-case scenario of peak global warming, population growth and urban development, the annual heat exposure would rise to 150 billion person-hours by the end of the century, a nearly 30-fold increase.

The combined effect of these three drivers will substantially increase the average heat exposure across the United States, but heat exposure is not projected to increase uniformly in all cities across the U.S., Broadbent said. There will be hot spots where heat exposure grows sharply.

To that end, the researchers defined heat thresholds based on local city definitions, something previous studies have not done. Instead, prior studies have used fixed-temperature thresholds that may be inappropriate for some cities. Afterall, a 90-degree day in Phoenix feels much different than a 90-degree day in New York City, given relative humidity differences.

Its well-known that cities have locally defined thresholds where heat and cold cause mortality and morbidity, Broadbent explained. In other words, people die at different temperatures in different cities because what is extreme in one city may be normal in another.

Importantly, areas of the United States where human exposure would increase the most is where climate change and population increase in tandem. Meanwhile, urban development has a smaller, yet not negligible effect.

According to the results of the study, the largest absolute changes in population heat exposure are projected to occur in major U.S. metropolitan regions, such as New York, Los Angeles and Atlanta.

The study also finds the largest relativechanges in person-hours related to heat exposure are projected to occur in rapidly growing cities located in the Sun Belt, including Austin, Texas; Orlando, Florida; and Atlanta.

The increase in exposure is quite large if you look at it relative to the start of the century, Broadbent said. Some cities across the Sun Belt, according to our projections, will have 90 times the number of person-hours of heat exposure. For example, cities in Texas that see substantial population growth and strong greenhouse gas-induced climate warming could be markedly affected.

One way to prepare for increased heat exposure is to reduce greenhouse gas emissions on a global scale, which would reduce the number of hours people are exposed to extreme temperatures. Other options include localized infrastructure adaptation that provides buffering effects against rising temperatures such as planting trees, providing shade and cooling areas and constructing buildings using materials that absorb less heat.

Although the average temperature in the United States will be warmer in the future, the study finds that cold exposure will increase slightly compared with the start of the century, primarily because of population growth. While there is a generaldecreasein the number of projected extreme cold events by the end of this century, the number of individuals exposed to extreme cold is projected toincrease,as population growth means that the total number of person-hours of cold exposure will go up, Broadbent said.

Cold is currently more of a national health problem than heat, but our results suggest that by the end of the century heat exposure may become a larger health problem than cold exposure, Broadbent said. However, cold exposure will not disappear completely as the climate warms. In fact, according to one of the teams simulations, Denver is projected to have more extreme cold at the end of the century compared with the beginning, according to the study.

Thats the interesting thing about climate change. We know the average temperature is going to increase, said Broadbent. But we know less about how the extremes are going to change, and often the extremes are the most important part of our daily lives.

There are several takeaway messages from this work, but one of the central ones concerns the future resiliency of our cities, Georgescu said.

The successful steps taken will require holistic thinking that embraces contributions from urban planners, engineers, social scientists and climate scientists with a long-range vision of how we want our cities to be.

"We therefore call on cities to start asking some very foundational questions regarding the projected exposure of their constituents to future environmental change," Georgescu said. "Is the work of the urban climate modeling community being integrated into their environmental adaptation plans? If so, how, and if not, why not?

This work was funded by the National Science Foundation.

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ASU engineers get to the heart of organs-on-a-chip - ASU Now

bluebird bio to Present New Data from Clinical Studies of elivaldogene autotemcel (eli-cel, Lenti-D) Gene Therapy for Cerebral Adrenoleukodystrophy…

CAMBRIDGE, Mass.--(BUSINESS WIRE)--bluebird bio, Inc. (Nasdaq: BLUE) today announced that new data from the clinical development program for its investigational elivaldogene autotemcel (eli-cel, Lenti-D) gene therapy in patients with cerebral adrenoleukodystrophy (CALD), including data from the Phase 2/3 Starbeam study (ALD-102) and available data from the Phase 3 ALD-104 study, will be presented at the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT 2020), taking place virtually from August 29 - September 1, 2020.

New Cerebral Adrenoleukodystrophy (CALD) Data at EBMT 2020

Lenti-D hematopoietic stem cell gene therapy stabilizes neurologic function in boys with cerebral adrenoleukodystrophy (ALD-102 and ALD-104)Presenting Author: Dr. Jrn-Sven Khl, Department of Pediatric Oncology, Hematology and Hemostaseology, Center for Womens and Childrens Medicine, University Hospital LeipzigPoster Session & Number: Gene Therapy; ePoster O077

Additional bluebird bio data at EBMT 2020 includes encore presentations from the companys CALD, sickle cell disease (SCD), transfusion-dependent -thalassemia (TDT) and multiple myeloma programs.

Cerebral Adrenoleukodystrophy (CALD) Encore Data at EBMT 2020

Outcomes of allogeneic hematopoietic stem cell transplant in patients with cerebral adrenoleukodystrophy vary by donor cell source, conditioning regimen, and stage of cerebral disease status (ALD-103)Presenting Author: Dr. Jaap Jan Boelens, Chief, Pediatric Stem Cell Transplantation and Cellular Therapies Service, Memorial Sloan Kettering Cancer CenterPoster Session & Number: Haemoglobinopathy and inborn errors; ePoster O106

Multiple Myeloma Correlative Encore Data at EBMT 2020

Markers of initial and long-term responses to idecabtagene vicleucel (ide-cel; bb2121) in the CRB-401 study in relapsed/refractory multiple myelomaPresenting Author: Dr. Ethan G. Thompson, Bristol Myers SquibbPoster Session & Number: CAR-based Cellular Therapy clinical; ePoster A089

Sickle Cell Disease (SCD) Encore Data at EBMT 2020

LentiGlobin for sickle cell disease (SCD) gene therapy (GT): updated results in Group C patients from the Phase 1/2 HGB-206 studyPresenting Author: Dr. Markus Y. Mapara, Director, Adult Blood and Marrow Transplantation Program, Columbia University Medical CenterOral Session & Number: Inborn Errors; O080Date & Time: September 1, 2020; 4:35 4:42 PM CET/10:35 10:42 AM ET

Transfusion-Dependent -Thalassemia (TDT) Encore Data at EBMT 2020

Clinical outcomes following autologous hematopoietic stem cell transplantation with LentiGlobin gene therapy in the Phase 3 Northstar-2 and Northstar-3 studies for transfusion-dependent -thalassemiaPresenting Author: Professor Franco Locatelli, Director, Department of Pediatric Hematology and Oncology, Ospedale Pediatrico Bambino GesPoster Session & Number: Gene Therapy; ePoster O074

LentiGlobin gene therapy treatment of two patients with transfusion-dependent -thalassemia (case report)Presenting Author: Dr. Mattia Algeri, Department of Pediatric Oncohematology - Transplantation Unit and Cell Therapies, Ospedale Pediatrico Bambino GesPoster Session & Number: Haemoglobinopathy and inborn errors; ePoster A328

Cross Indication Encore Data at EBMT 2020

Safety of autologous hematopoietic stem cell transplantation with gene addition therapy for transfusion-dependent -thalassemia, sickle cell disease, and cerebral adrenoleukodystrophyPresenting Author: Dr. Evangelia Yannaki, Director, Gene and Cell Therapy Center, Hematology Department, George Papanicolaou HospitalPoster Session & Number: Gene Therapy; ePoster O078

Abstracts outlining bluebird bios accepted data at EBMT 2020 are available on the Annual Meeting website. On August 29, 2020, at 12:30 PM CET/6:30 AM ET, the embargo will lift for ePosters and oral presentations accepted for EBMT 2020. Presentations will be available for virtual viewing throughout the duration of the live meeting and content will be accessible online following the close of the meeting until November 1, 2020.

About elivaldogene autotemcel (eli-cel, Lenti-D gene therapy)In July 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) granted an accelerated assessment to eli-cel gene therapy for cerebral adrenoleukodystrophy (CALD). bluebird bio is currently on track to submit the Marketing Authorization Application (MAA) in the EU for eli-cel for CALD by year-end 2020, and the Biologics License Application (BLA) in the U.S. in mid-2021.

bluebird bio is currently enrolling patients for a Phase 3 study (ALD-104) designed to assess the efficacy and safety of eli-cel after myeloablative conditioning using busulfan and fludarabine in patients with CALD. Contact clinicaltrials@bluebirdbio.com for more information and a list of study sites.

Additionally, bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-304) for patients who have been treated with eli-cel for CALD and completed two years of follow-up in bluebird bio-sponsored studies.

The Phase 2/3 Starbeam study (ALD-102) has completed enrollment. For more information about the ALD-102 study visit: http://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT01896102.

Adrenoleukodystrophy (ALD) is a rare, X-linked metabolic disorder that is estimated to affect one in 21,000 male newborns worldwide. Approximately 40 percent of boys with ALD will develop CALD, the most severe form of ALD. CALD is a progressive neurogenerative disease that involves breakdown of myelin, the protective sheath of the nerve cells in the brain that are responsible for thinking and muscle control. Symptoms of CALD usually occur in early childhood and progress rapidly, if untreated, leading to severe loss of neurologic function, and eventual death, in most patients.

The European Medicines Agency (EMA) accepted eli-cel gene therapy for the treatment of CALD into its Priorities Medicines scheme (PRIME) in July 2018, and previously granted Orphan Medicinal Product designation to eli-cel.

The U.S. Food and Drug Administration (FDA) granted eli-cel Orphan Drug status, Rare Pediatric Disease designation, and Breakthrough Therapy designation for the treatment of CALD.

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

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

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

In July 2020, Bristol Myers Squibb (BMS) and bluebird bio submitted the Biologics License Application for ide-cel to the U.S. Food and Drug Administration for the treatment of adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody. Ide-cel is the first CAR T cell therapy submitted for regulatory review to target BCMA and for multiple myeloma.

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

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

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

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

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

SCD is a serious, progressive and debilitating genetic disease caused by a mutation in the -globin gene that leads to the production of abnormal sickle hemoglobin (HbS). HbS causes red blood cells (RBCs) to become sickled and fragile, resulting in chronic hemolytic anemia, vasculopathy and painful vaso-occlusive crises (VOCs). For adults and children living with SCD, this means painful crises and other life-altering or life-threatening acute complicationssuch as acute chest syndrome (ACS), stroke and infections. If patients survive the acute complications, vasculopathy and end-organ damage, resulting complications can lead to pulmonary hypertension, renal failure and early death; in the U.S. the median age of death for someone with sickle cell disease is 43 - 46 years.

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

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

bluebird bio reached general agreement with the U.S. Food and Drug Administration (FDA) that the clinical data package required to support a Biologics Licensing Application (BLA) submission for LentiGlobin for SCD will be based on data from a portion of patients in the HGB-206 study Group C that have already been treated. The planned submission will be based on an analysis using complete resolution of severe vaso-occlusive events (VOEs) as the primary endpoint with at least 18 months of follow-up post-treatment with LentiGlobin for SCD. Globin response will be used as a key secondary endpoint.

bluebird bio anticipates additional guidance from the FDA regarding the commercial manufacturing process, including suspension lentiviral vector. bluebird bio announced in a May 11, 2020 press release it plans to seek an accelerated approval and expects to submit the U.S. BLA for SCD in the second half of 2021.

LentiGlobin for SCD is investigational and has not been approved in any geography.

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

In the HGB-207 clinical study supporting the conditional marketing approval of ZYNTEGLO, the primary endpoint was transfusion independence (TI) by Month 24, defined as a weighted average Hb 9 g/Dl without any RBC transfusions for a continuous period of 12 months at any time during the study after infusion of ZYNTEGLO. Ten patients were evaluable for assessment of TI. Of these, 9/10 (90.0%, 95% CI 55.5-99.7%) achieved TI at last follow-up. Among these nine patients, the median (min, max) weighted average Hb during TI was 12.22 (11.4, 12.8) g/dLl.

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

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

Non-serious adverse events (AEs) observed during the clinical studies that were attributed to betibeglogene autotemcel included abdominal pain, thrombocytopenia, leukopenia, neutropenia, hot flush, dyspnoea, pain in extremity, and non-cardiac chest pain. Two serious adverse events (SAE) of thrombocytopenia were considered possibly related to beti-cel.

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

The CMA for beti-cel is valid in the 27 member states of the EU as well as UK, Iceland, Liechtenstein and Norway. For details, please see the Summary of Product Characteristics (SmPC).

The U.S. Food and Drug Administration granted beti-cel Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT. Beti-cel is not approved in the United States.

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

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

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

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

Follow bluebird bio on social media: @bluebirdbio, LinkedIn, Instagram and YouTube.

Lenti-D and bluebird bio are trademarks of bluebird bio, Inc.

Forward-Looking StatementsThis release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the companys financial condition, results of operations, as well as statements regarding the plans for regulatory submissions for beti-cel (marketed as ZYTENGLO in the European Union), eli-cel, ide-cel, and LentiGlobin for SCD, including anticipated endpoints to support regulatory submissions and timing expectations; the companys expectations regarding the potential for the suspension manufacturing process for lentiviral vector; its expectations for commercialization efforts for ZYNTEGLO in Europe; as well as the companys intentions regarding the timing for providing further updates on the development and commercialization of ZYNTEGLO and the companys product candidates. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risks that the COVID-19 pandemic and resulting economic conditions will have a greater impact on the companys operations and plans than anticipated; that our amended collaboration with BMS will not continue or be successful; that preliminary positive efficacy and safety results from our prior and ongoing clinical trials will not continue or be repeated in our ongoing or future clinical trials; the risk that our plans for submitting a BLA for LentiGlobin for SCD may be delayed if the FDA does not accept our comparability plans for the use of the suspension manufacturing process for lentiviral vector; the risk that the submission of BLA for ide-cel is not accepted for filing by the FDA or approved in the timeline we expect, or at all; the risk of cessation or delay of any of the ongoing or planned clinical studies and/or our development of our product candidates, including due to delays from the COVID-19 pandemics impact on healthcare systems; the risk that the current or planned clinical trials of our product candidates will be insufficient to support regulatory submissions or marketing approval in the United States and European Union; the risk that regulatory authorities will require additional information regarding our product candidates, resulting in delay to our anticipated timelines for regulatory submissions, including our applications for marketing approval; the risk that we will encounter challenges in the commercial launch of ZYNTEGLO in the European Union, including in managing our complex supply chain for the delivery of drug product, in the adoption of value-based payment models, or in obtaining sufficient coverage or reimbursement for our products; and the risk that any one or more of our product candidates, will not be successfully developed, approved or commercialized. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in our most recent Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and bluebird bio undertakes no duty to update this information unless required by law.

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bluebird bio to Present New Data from Clinical Studies of elivaldogene autotemcel (eli-cel, Lenti-D) Gene Therapy for Cerebral Adrenoleukodystrophy...

Re: Management of post-acute covid-19 in primary care – The BMJ

Dear EditorExcellent review and so needed and well-timedThe only issue that did not get the attention it needs are the neuropsychiatric symptoms of mild COVID-19. This is important for medical professionals to know, to avoid labeling the patients' problems as psychiatric and even hysterical as some recently did in a major newspaper here in Belgium.There are two sides to the mental sequelae of mild COVID.a) the consequences of the impact of going through a global pandemic, of lockdown, of COVID patients in their immediate environment, of the fear of infection or infecting others, of losing their job, and finally of their own infection.b) the mental symptoms of an organic disorder.In the subject literature about COIVD-19 (and MERS, SARS and other infections) several mechanisms are mentioned.-A direct neurotropic impact of the virus, especially, but not only via ACE2, both in neurons and glial cells, especially targeting the brain stem which plays a role in emotions. and brought there, among other things, via the direct connection of the olfactory bulb.-Inflammatory and immune reactions that result in cognitive and psychiatric symptoms:(the "misty brain" cited by many patients)-Reactions of the autonomic nervous system, eg cardiac arrhythmias can also be very scary.-Alteration of the gas exchange -oxygen nd carbon dioxide- due to damage to the alveoli resulting in a suboptimal pH.These results in mental symptoms of an organic disorder: memory problems, word finding disorders, confusion, major sleeping problems, insecure motor skills, anorexia, etc. and of course very often chronic fatigue, muscle weakness and anxiety.Of course, fear or anger of the patient are amplified when the doctor labels this as purely psychological, while the patient who has never been ill before, clearly experiences its not.

Because we have only known the disease for six months and we still know so little about it, it is therefore better to take the experiences of the patients seriously, instead of brushing them off as purely psychological or psychiatric.

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Re: Management of post-acute covid-19 in primary care - The BMJ

RT-PCR is the most reliable test in the covid diagnosis: Dr A. Velumani, CEO, Thyrocare Technologies Ltd. – ETHealthworld.com

Shahid Akhter, editor, ETHealthworld, spoke to. Dr A. Velumani, Promoter, Chairman, Managing Director and Chief Executive Officer, Thyrocare Technologies, to know more about the challenges and opportunities associated with Covid diagnostics business.

Covid-19 : ChallengesBecause of the lockdown, the existing non-covid healthcare and diagnostics business collapsed. It collapsed to 2% suddenly within a week and it didn't allow it to resume for three months.Multiple advisory's multiple tests, whom to test and whom not to, along with plenty of show cause notice because a lot of administrators wanted to under-report positivity and some probably wanted the professional gains, so a lot of time they took in the review. These were the challenges but there were a lot of opportunities as well.

Covid-19: LearningsIn my opinion, Lockdown is not the solution, repeating lockdowns, having every different strict guideline for every different state is not the solution. It won't help to reduce. Secondly, Rapid antigen kits are useless, it doesn't solve anything so we've learned the RT-PCR is the most reliable one in the covid diagnosis.Covid-19: Government's InitiativeAlso, the government labs have contributed significantly which wasn't expected, we were all thinking it is just the private labs who are truly scaling up but government labs too scaled up and contributed more in more than 50% of the testing.

Covid-19: Immunity and antibodyImmunity matters, I don't think lockdown can stop Covid. It is the antibodies that can stop the Covid and India is blessed as only 30% tests are there per million whereas in the US there are 600 tests per million. The antibody power is important to be seen as well if not then there is a problem.

Covid-19: Towards a new normalWork from home will continue, even in healthcare, it is just 17% which is working from home. Also, there will be two different religions in healthcare that will be Covid and Non-Covid so that infection will not pass on to one covid patient to another and non-covid will not move to covid hospitals. The spending on hygiene needs to be high because the general population is scared, medical doctors are scared and the patients are scared.

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RT-PCR is the most reliable test in the covid diagnosis: Dr A. Velumani, CEO, Thyrocare Technologies Ltd. - ETHealthworld.com

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