StemCell Therapy

A man receives his Covid-19 vaccination at the John Scott Vaccination Centre in Green Lanes, north ... [+] London, where Hatzola, in partnership with the NHS and Hackney Council are delivering a coronavirus vaccine clinic for the local Orthodox Jewish community. Picture date: Sunday March 21, 2021. (Photo by Stefan Rousseau/PA Images via Getty Images)

The Orthodox Jewish community was hit hard by the Covid-19 pandemic. Swift community action ensued; Jewish schools were closed and synagogues were shuttered. While anticipation for the Covid-19 vaccine grew, physicians and leaders within the community wondered: will Orthodox Jews get the Covid-19 vaccine?

A new study published by Dr Ellie Carmody, Assistant Professor, Division of Infectious Diseases and Immunology at NYU Grossman School of Medicine and co-authors, surveyed 102 Orthodox Jews in Brooklyn, NY between December 2020 and January 2021. At that time, 41% were undecided about the vaccine and 47% were strongly hesitant.

While many U.S. citizens fought for access to the vaccine, others were understandably hesitant to take a new vaccine. The vaccine has had its fair share of doubt including concerns about fertility and safety monitoring (neither concern has been proven).

In the past, Shoshana Bernstein, an Orthodox community activist in NY, worked to educate community members about the measles vaccine. Her experience taught her that the majority of Orthodox Jews do indeed vaccinate.There are outliers who are openly anti-vax and the movable middle who are unsure. Unfortunately, it has become more and more the norm for the media to focus on Orthodox Jews which can and does create the erroneous assumptions.

At the same time, Ms. Bernstein explained that the insular lifestyle of many demographics in the Orthodox Jewish community limits their access to credible medical information. Many individuals in these communities dont use the internet, social media, and smartphones. There, Ms. Bernstein recommends it is imperative that culturally sensitive, written and spoken education be written and made available.Unlike the secular world, written publications are very much alive and well in the Orthodox Community.Dial-in hotlines and Yiddish language radio stations reach a large swath of the population and should be utilized.Doctors, nurses, physician assistants and urgent care centers are generally widely trusted and should be provided written material.

Dr Miriam Andrusier, MD, MPH a member of the Hasidic community in Crown Heights, Brooklyn, echoes Ms. Bernsteins concerns about targeted misinformation. Both in terms of how the virus spreads and what information people have available to them are very unique and could be quite insular. The Orthodox Jewish community is very tight knit. The ways in which information is dispensed and shared is very unique: people tend to get a lot of their information from social media and groups like Whats App where it is incredibly easy to pass along misinformation that can be forwarded thousands of times within minutes.

When the pandemic eased in the summer of 2020, anti-vax and anti-medical establishment groups made efforts to spread misinformation specifically in the Orthodox Jewish community. At an event in Crown Heights on February 16th, 2021, Dr. Simone Gold urged attendees not to get the Covid-19 vaccine because dying from Covid-19 itself is exceedingly uncommon. The second speaker, Rabbi Michoel Green told (unverified) stories of individuals who lost relatives and suffered side effects from the vaccine.

The anti-vaccine movement is finding fertile ground in people today in general because they succeed by sowing fear, uncertainty and doubt, and this pandemic is already rampant in all three, says Dr. Alissa Minkin, a pediatrician and Chair of the Jewish Orthodox Womens Medical Association (JOWMA) Preventative Health Committee. Dr Minkin also hosts the JOWMA Podcast, which covers health topics geared towards the Orthodox community. Full disclosure- I serve as president of JOWMA and have been actively involved in JOWMAs educational efforts for the Covid-19 vaccine.

Dr. Minkin believes the politicization and polarization of this pandemic is contributing to anti-vaccine sentiment across the board, not just in the Orthodox community. Because religion is not one of the metrics for vaccine uptake, we do not have exact statistics for percent vaccinated in each of these communities.

While the exacts numbers of those vaccinated in the Orthodox community isnt quite clear, informal surveys by synagogues, physicians, and schools indicate that vaccine uptake is high. Suri Kasirer, President of Kasirer LLC, the #1 lobbying firm in New York, has been working with government and community organizations like JOWMA to educate NY residents about the Covid-19 vaccine. I come from this community, which was among the most impacted by the pandemic. In reaching out to the Orthodox community with timely information about the vaccine, there are unique challenges, such as language barriers, or limited access to TV and the Internet.Were so proud to have helped effectively counter disinformation and build confidence in the vaccine as we see this vibrant community back to good health post-pandemic.

"Most of my elderly patients wanted to get the vaccine as soon as it was available. As part of my work as the medical director of Chevra Hatzalah Volunteer Ambulance Corps, we facilitated hundreds of vaccines to home-bound Holocuast survivors, said Dr Jason Zimmerman, medical director at Boro Park Center for Rehabilitation and Nursing in Brooklyn, NY.

Dr. Zimmerman cares for patients from the Orthodox community in Brooklyn, NY. He shared Many younger patients were initially hesitant to take the vaccine, but over the past few months, they've watched their healthcare providers, family and friends get vaccinated and this visibility has really helped alleviate people's initial hesitation."

Dr. Minkin believes that while we havent yet reached herd immunity, the percent of people who had Covid-19 already are contributing to the percent who are immune along with the vaccinated. There are good reasons to get vaccinated even if you had Covid-19, but public health officials should acknowledge that people who had Covid-19 are making a risk benefit decision from a different position than those who never had it.

Dr. Ellie Carmody MD, MPH, agrees that some hesitancy around the vaccine may be understood from a scientific and health perspective. Within some Orthodoxcommunities that have been very highlyimpacted by Covid-19, reasons for not vaccinating are complex.Some are wary of new technologies and are subject to similar misinformation that circulates within wider anti-vaccination discourse.But for many people who have had Covid-19, there is simplynot a sense of urgency to be vaccinated, given that they observe that symptomatic re-infections in their communities are low and they feel protected.

Dr. Carmody believes that vaccine strategies should be re-evaluated for those who have recovered from Covid-19, as more studies demonstrate that there is a robust immune memory response to one dose of either an mRNA vaccine or adenoviral vector vaccine in people who have recovered from Covid-19.

A one-dose immunity booster may be more well received than a two-dose mRNA vaccineseries, as it validates the contribution of natural immunity toward protection from disease.One-dose mRNA vaccine strategies could also help stretch the world's supply of these vaccines, said Dr Carmody.

In the meantime, educating patients about Covid-19 vaccination remains a priority.

See original here:
Hit Hard By The Pandemic, Orthodox Jews Are Choosing The Covid-19 Vaccine - Forbes

The International Society for Stem Cell Research (ISSCR) today released updated guidelines for stem cell research and its translation to medicine.

Developed in response to recent scientific and clinical advances, the revised guidelines provide a series of detailed and practical recommendations that set out global standards for how these emerging technologies should be harnessed.

Stem cell research has huge potential it could help pave the way for new therapies for ailments ranging from Parkinsons disease to childhood kidney failure. But scientific advances in this field can present unique ethical and policy issues beyond that seen in other areas of medical research.

The science is advancing at breakneck pace. Just in the past couple of months, we have seen model human embryos grown from skin cells, and the creation of human-monkey embryos for use in research.

The ISSCR has long recognised the need to set clear ethical boundaries for stem cell research. Previous guidelines have provided advice on techniques such as the use of human embryos to create stem cells, and set the required standards when using these technologies to create new medicines.

They have also explicitly banned certain practices, such as reproductive cloning and the sale of unproven therapies that claim to be made of stem cells.

The 2021 guidelines an update on the previous version, released in 2016 aim to set standards for the many recent advances in stem cell and human embryo research. These include chimeric embryos containing cells from humans and other animals, organoids grown from stem cells to create tissue that resembles particular human organs, and models of human embryos arrangements of human cells that mimic the early stages of embryo development.

The guidelines contain a clear requirement for certain new stem cell research approaches only to be conducted after a specialised review process. This review should be independent of the researchers, and include community members as well as people with expertise in the relevant science, ethics and law.

This is beyond what is typically required by a university or research institute where medical research is conducted. Besides evaluating the merit of the proposed research, the new reviews should also consider whether there are alternative ways to do the research, the source of stem cells and how they were obtained, and the minimum time required to reach the research goals, particularly in relation to human embryo and related research.

Specialised review is not a new concept. The previous guidelines required it when researchers made stem cells from human embryos or sought to culture human embryos in the lab. But now researchers will now also be required to seek higher review when they create model embryos such as blastoids, or study the development of animal-human embryos in animal wombs.

Researchers developing new therapies for mitochondrial disease will also be required to seek higher-level review before attempting to transfer to the uterus of a woman human embryos in which affected mitochondria (a part of the cells energy-production apparatus) have been replaced.

Importantly, the revised guidelines also clearly rule out certain activities. These continue to include reproductive cloning and attempts to form a pregnancy in a woman from genetically edited human embryos or from model embryos made from stem cells. Prohibited activities also now include using eggs and sperm made from human stem cells for reproduction, or transferring a human-animal chimeric embryo into the uterus of a woman or an ape.

Read more: China's failed gene-edited baby experiment proves we're not ready for human embryo modification

The guidelines also call for a public conversation about whether we should allow limited lab research on human embryos beyond the existing limit of 14 days development. Historically, it has not been possible to support human embryonic development outside the body beyond this stage. However, recent advances in human embryo culture raise the possibility that this may now be technically feasible.

Extending the amount of time in culture - in terms of days - could potentially yield new treatments for developmental conditions or infertility, but will also raise concerns about whether possible benefits justify this research. Any decisions to overturn this long-held signpost would need to be carefully deliberated and take into consideration existing law, community values and discussion around what the new limit should be.

The revised guidelines also reinforce the need for informed consent for the collection of human material and participation in stem cell clinical trials, and reiterate that no new stem cell treatment should be made available before it is tested for safety and effectiveness in well-designed and publicly visible clinical trials. The ISSCR continues to condemn the commercial use of unproven stem cell treatments.

While stem cell science holds much promise, it is paramount that research is scientifically and ethically rigorous, with appropriate oversight, transparency and public accountability.

The fact these guidelines are driven by experts including stem cell scientists, doctors, ethicists, lawyers and industry representatives from across 14 countries indicates a deep sense of responsibility and integrity within the research community, and a desire to ensure science remains in step with community values.

However, these guidelines are recommendations, not laws.

Researchers will need to abide by their respective national or state regulations and ethical standards. Some countries already have regulatory frameworks that are consistent with the new recommendations. In other places there is no national guidance around laboratory and clinical stem cell research at all, or existing law touches on some but not all of the emerging applications of stem cell research.

Read more: As scientists move closer to making part human, part animal organisms, what are the concerns?

For example, in Australia there is already an established pathway for higher-level review of embryo models created from stem cells. However, the same legislation currently bans any attempt to use mitochondrial transfer techniques to create embryos for research or to achieve a pregnancy both of which are permissible under the new ISSCR guidelines.

Rather than attempting to impose a set of hard-and-fast rules on an ever-evolving research field, the new guidelines attempt to address emerging issues and drive important discussions at domestic level. Ultimately, it is the public and the regulators who will need to set the standards.

See the rest here:
New global guidelines for stem cell research aim to drive discussions, not lay down the law - The Conversation AU

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Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA, Mercks anti-PD-1 therapy, in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumors express PD-L1 (Combined Positive Score [CPS] 10). The CHMPs recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second quarter of 2021.

Patients with metastatic esophageal cancer currently face five-year survival rates of just 5%, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. There is a critical need for new treatment options in the first-line setting that can potentially extend their lives. Todays positive opinion for KEYTRUDA is an important step forward for patients in Europe with certain types of gastrointestinal cancers.

The positive CHMP opinion is based on results from the pivotal Phase 3 KEYNOTE-590 trial, in which KEYTRUDA plus 5-fluorouracil (5-FU) and cisplatin demonstrated significant improvements in overall survival and progression-free survival compared with 5-FU and cisplatin alone in patients regardless of histology or PD-L1 expression status. KEYTRUDA plus 5-FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p

Merck is studying KEYTRUDA across multiple settings and stages of gastrointestinal cancer including esophageal, gastric, hepatobiliary, pancreatic, colorectal and anal cancers through its broad clinical program.

About Esophageal Cancer

Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. Globally, it is estimated there were more than 604,000 new cases of esophageal cancer diagnosed and approximately 544,000 deaths resulting from the disease in 2020. In Europe, it is estimated there were more than 52,000 new cases of esophageal cancer diagnosed and approximately 45,000 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 1,400 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 in the U.S.

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.

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 HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

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. 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 (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 Carcinoma

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, 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 2 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 Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Carcinoma

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] 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.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently 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. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

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 an antiPD-1/PD-L1 treatment 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-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.

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Merck (MRK) Granted Positive EU CHMP Opinion for KEYTRUDA (pembrolizumab) in Combination with Chemotherapy - StreetInsider.com

Opinion Supports Use of KEYTRUDA in Combination With Platinum- and Fluoropyrimidine-Based Chemotherapy in Patients Whose Tumors Express PD-L1 (CPS 10)

Recommendation Based on Significant Survival Benefit Demonstrated With KEYTRUDA Plus Chemotherapy Versus Chemotherapy in Phase 3 KEYNOTE-590 Trial

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA, Mercks anti-PD-1 therapy, in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumors express PD-L1 (Combined Positive Score [CPS] 10). The CHMPs recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second quarter of 2021.

Patients with metastatic esophageal cancer currently face five-year survival rates of just 5%, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. There is a critical need for new treatment options in the first-line setting that can potentially extend their lives. Todays positive opinion for KEYTRUDA is an important step forward for patients in Europe with certain types of gastrointestinal cancers.

The positive CHMP opinion is based on results from the pivotal Phase 3 KEYNOTE-590 trial, in which KEYTRUDA plus 5-fluorouracil (5-FU) and cisplatin demonstrated significant improvements in overall survival and progression-free survival compared with 5-FU and cisplatin alone in patients regardless of histology or PD-L1 expression status. KEYTRUDA plus 5-FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p

Merck is studying KEYTRUDA across multiple settings and stages of gastrointestinal cancer including esophageal, gastric, hepatobiliary, pancreatic, colorectal and anal cancers through its broad clinical program.

About Esophageal Cancer

Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. Globally, it is estimated there were more than 604,000 new cases of esophageal cancer diagnosed and approximately 544,000 deaths resulting from the disease in 2020. In Europe, it is estimated there were more than 52,000 new cases of esophageal cancer diagnosed and approximately 45,000 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 1,400 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 patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

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.

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 HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

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. 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 (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 Carcinoma

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, 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 2 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 Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Carcinoma

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] 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.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently 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. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

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 an antiPD-1/PD-L1 treatment 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-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%).

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Merck Receives Positive EU CHMP Opinion for KEYTRUDA in Combination With Chemotherapy as First-Line Treatment for Certain Patients With Esophageal...

Introduction

Although novel drugs have successfully entered the clinical arena of heart failure with reduced ejection fraction (HFrEF), such as the PARADIGM-HF-derived angiotensin receptor neprilysin inhibitor (ARNI), disease-modifying therapies with a prognostic impact for patients affected by heart failure with preserved ejection fraction (HFpEF) are still lacking.15 HF is a complex and highly prevalent syndrome for which the heart undergoes a substantial structural remodeling in patients at risk for major cardiovascular diseases (CVDs) (Figure 1).16 Geneenvironment interactions can be mediated by specific patterns of epigenetic-sensitive changes (mainly DNA methylation and histone modifications) which may modulate the individual responsiveness to HF development.614 This complex molecular circuit seems to trigger early cardiomyocyte loss, cardiac-remodeling, and micro- and macrovascular damage contributing to the development of major CVDs which may lead to differential HF clinical phenotypes.614 Of note, the reversible nature of epigenetic-sensitive changes has been translated in the clinical management of specific hematological malignancies with the approval by the Food and Drug Administration (FDA) of some epidrugs, such as decitabine (Dacogen) and azacitidine (Vidaza), as DNA methylation inhibitors, as well as vorinostat (Zolinza), belinostat (Beleodaq), romidepsin (Istodax), and panobinostat (Farydak), as histone deacetylase inhibitors (HDACi).15 Epidrugs are now providing a novel vision for personalized therapy of HF and heart transplantation, opening up novel options for management of the affected patients.1518 At molecular level, we can classify the epidrugs in: direct epidrugs [eg, the bromodomain and extra-terminal (BET) protein inhibitor apabetalone]; and repurposed drugs with potential, indirect (non-classical) epigenetic-oriented interference by which they may exert cardioprotective functions [eg, hydralazine, metformin, statins, and sodium-glucose co-transporter-2 inhibitors (SGLT2i)] or nutraceutical compounds [eg, omega-3 polyunsaturated fatty acids (PUFAs)]. Encouraging results are coming from large randomized trials evaluating the putative beneficial effects of combining epidrugs with the conventional therapy in patients with HF.1422 Our goal is to update on the emerging epigenetic-based strategies which may be useful in the prevention and treatment of HFrEF and HFpEF (Figure 1).

Figure 1 The possible role of epitherapy in the current framework of HFrEF and HFpEF management. The unstable transition state from the ACC/AHA Stage A/B to Stage C/D-Acute/Hospitalized HF is the key point in the treatment of HFrEF and HFpEF. The epitherapy, mainly apabetalone, statins, metformin, SGLT2i, and PUFAs in addition to the standard of the care may improve personalized therapy of affected patients.

Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; SGLT2i, sodium glucose co-transporter 2 inhibitors; PUFAs, polyunsaturated fatty acids.

The bromodomain and extra terminal domain (BET) proteins, including the ubiquitous BRD2, BRD3, BRD4, and the testis-restricted BRDT, are epigenetic readers (via bromodomains) existing in the form of nuclear multidomain docking platforms which control the cell-specific activation of gene expression profiles.23 Experimental data demonstrated that BETs regulate vascular cells, cardiac myocytes, and inflammatory cells,24 and their activity may be extended to the regulation of calcification, thrombosis, as well as lipid and lipoprotein metabolism, all of which participate in atherogenesis.2527 In particular, BRD4 facilitated the expression of multiple proinflammatory and proatherosclerotic targets involved in thrombosis, leukocyte adhesion, and endothelial barrier function, thus identifying BRD4 as a possible therapeutic target in CVD setting.24 The quinazolone (RVX-208), known as apabetalone, is a derivative of the plant polyphenol resveratrol. Apabetalone acts as a direct epidrug by selectively targeting the BET family member BRD4 to block its interaction with acetylated lysines located in histones.28 Apabetalone-BRD4 binding can impact cholesterol levels and inflammation; in fact, apabetalone stimulates ApoA-I gene expression and increases high-density lipoprotein (HDL).29,30 Besides, apabetalone may attenuate the development of cardiac hypertrophy31 and cardiac fibrosis,32 suggesting novel options for the management of HF.

Resverlogix developed apabetalone (RVX-208), a first-in-class, orally available, small molecule for the treatment of atherosclerosis and associated CVDs.20 BETonMACE (NCT02586155) is the first Phase 3 clinical trial evaluating the cardiovascular efficacy and safety of apabetalone.22 Recent results from the BETonMACE study have demonstrated that apabetalone is associated with a reduction in first HF hospitalization and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome as compared to controls (placebo-treated patients).22 Additionally, a significant increase in HDL and a decrease in alkaline phosphatase levels have been observed following 24 weeks of apabetalone treatment as compared to the placebo group.22 However, investigators were unable to make a distinction between HF in the setting of preserved or reduced ejection fraction. Thus, further clinical trials should be designed to evaluate the putative beneficial effects of apabetalone in HFrEF and HFpEF, separately.

Preclinical studies demonstrated that pharmacological HDACi,3336 BET inhibitors,31,37 and DNA methylation inhibitors38 can attenuate cardiac remodeling (cardiomyocyte hypertrophy and fibrosis). Although not originally developed as epidrugs, hydralazine (anti-hypertensive drug), metformin, and SGLT2i (anti-diabetic drugs), statins (anti-dyslipidemic drugs), and PUFAs (nutraceuticals) might have downstream epigenetic-oriented effects in cardiac cells. Hydralazine, for example, lowers blood pressure by a direct relaxation of vascular smooth muscle; additionally, it may reduce DNA methylation and improve cardiac function through increasing sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and modulating calcium homeostasis in cardiomyocytes.39 Statins are used as a first-line treatment to decrease serum cholesterol levels in dyslipidemic patients and as primary and secondary prophylaxis against atherosclerosis and associated CVDs.6 Many of their non-classical pleiotropic properties relevant for endothelial health are mediated by epigenetic mechanisms which improve blood flow, decrease LDL oxidation, enhance atherosclerotic plaque stability and decrease proliferation of vascular smooth muscle cells and platelet aggregation.6 Metformin is a first-line drug in the treatment of overweight and obese type 2 diabetic patients.10 Mechanistically, metformin may also have epigenetic-oriented effects through activating the AMP-activated protein kinase (AMPK) which, in turn, can phosphorylate and inhibit epigenetic enzymes such as histone acetyltransferases (HATs), class II HDAC, and DNA methyltransferases (DNMTs).40 Both metformin41,42 and statins43,44 may reduce cardiac fibrosis; however, whether their beneficial effects are mediated by epigenetic-oriented responses has yet to be demonstrated. Furthermore, SGLT2i are a new group of oral drugs used for treating type 2 diabetes and its cardiovascular/renal complications.45 Animal models have demonstrated that empagliflozin46,47 and dapagliflozin48 may improve hemodynamics in HF by increasing renal protection and cardiac fibrosis. Interestingly, inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by empagliflozin;49 this observation has provided insights about mechanisms by which SGLT2i can reduce cardiovascular mortality in man (EMPA-REG trial).50

An effective therapy for HFpEF has yet to be established. Hydralazine is frequently used in HFrEF, and represents a potential DNA methylation inhibitor.39 DNA methylation is the most studied direct epigenetic change with potential clinical implications in major CVDs and the development of HF.7,14 This epigenetic signature mainly involves methylation of CpG islands in the gene promoters leading to a specific long-term silencing of gene expression.7,14 A completed Phase 2 clinical trial (NCT01516346) evaluated the effect of prolonged therapy (24 weeks) with isosorbide dinitrate (ISDN) hydralazine on arterial wave reflections (primary endpoint) as well as left ventricular (LV) mass, fibrosis and diastolic function, and exercise capacity (6-minute walk test) in patients with HFpEF, New York Heart Association (NYHA) Class IIIV symptoms, and standard therapy as defined by ACEi, ARB, beta-blockers, or calcium channel blockers (CCBs).51 Results from this trial reported that ISDN, with or without hydralazine, had deleterious effects on reflection magnitude, LV remodeling, or submaximal exercise thus not supporting their routine use in patients with HFpEF.51

Metformin has been associated with a reduced mortality in patients with HFpEF, even if female gender was associated with worse outcomes.52 Recently, it has been observed that a long-term treatment with metformin can improve LV diastolic function and hypertrophy, decrease the incidence of new-onset HFpEF, and delay disease progression in patients with type 2 diabetes and hypertension.53 Besides, a prospective phase 2 clinical trial (NCT03629340) is testing the therapeutic efficacy of metformin in patients with pulmonary hypertension and HFpEF by evaluating exercise hemodynamics, functional capacity, skeletal muscle signaling, and insulin sensitivity. However, results have not been published. A recent study based on the JASPER registry, a multicenter, observational, prospective cohort of Japanese patients aged 20 years requiring hospitalization for acute HFpEF has reported that the use of statins could reduce mortality in affected patients without coronary heart disease.54 Furthermore, the use of statins was associated with improved clinical outcomes in patients with HFpEF but not in patients with HFrEF (or mid-range ejection fraction).55 A reduced rate of major adverse cardiac events, cardiovascular death and all-cause mortality was associated with SGLT2i treatment in both HFpEF and HFrEF patients as compared to placebo.56,57 However, the observed cardiovascular and renal benefits cannot be fully explained by improvement in risk factors (such as glycemia, blood pressure or dyslipidemias) suggesting that other molecular mechanisms may explain the cardiovascular benefits.56 Interestingly, the SGLT2i-related epigenetic interference may arise from their ability to increase the circulating and tissue levels of -hydroxybutyrate, a specific molecule able to generate a pattern of histone modifications (known as -hydroxybutyrylation) which are associated with the beneficial effects of fasting.58 Besides, the DELIVER (NCT03619213) multicenter, randomized, double-blind, placebo-controlled study of 6263 HFpEF patients will evaluate the effect of dapagliflozin 10 mg (1 per day) as compared to placebo in addition to the standard of care in order to reduce the composite of cardiovascular death or HF events. However, results have not yet been published.

The use of metformin has been generally considered a contraindication in HFrEF patients owing the potential risk of lactic acidosis; however, recent evidence has reported that metformin can provide beneficial effects in reducing the risk of incident HF and mortality in diabetic patients.5961 A completed, observational clinical trial (NCT03546062) has recently performed the evaluation of seriated cardiac biopsies from healthy implanted hearts in type 2 diabetes recipients during 12-month follow-up upon heart transplantation.21 Even if the intra-cardiomyocyte lipid accumulation in type 2 diabetes recipients may start in the early stages after heart transplantation, metformin therapy could reduce lipid accumulation independently of immunosuppressive therapy.21 The DANHEART trial (NCT03514108), a multicenter, randomized, double-blind, placebo-controlled study in 1500 patients with HFrEF will evaluate: 1) whether hydralazine-isosorbide dinitrate as compared to placebo may reduce the incidence of death and HF hospitalization, and 2) if metformin as compared to placebo may reduce the incidence of death, worsening of HF, acute myocardial infarction, and stroke in patients with diabetes or prediabetes. Two large randomized trials demonstrated that statins did not have beneficial effects in management of patients with HFrEF.62,63 Specifically, the CORONA phase 3 trial randomized more than 5000 patients with ischemic HFrEF to rosuvastatin as compared to placebo resulting in no benefits on the primary endpoints, as death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke.62 According to CORONA trial, the GISSI-HF study randomized almost 5000 patients with clinically apparent HF of any cause to rosuvastatin as compared to placebo and observed no benefits on the primary endpoints, as all-cause death or cardiovascular hospitalization.63 However, it is needed to highlight that both trials demonstrated that statins are safe in HF patients. In contrast with the previous evidence, the trial based on the Swedish Heart Failure Registry (21,864 patients with HFrEF, of whom 10,345 were treated with statins) reported an association between the use of statins and improved outcomes, as all-cause mortality, cardiovascular mortality, HF hospitalization, and combined all-cause mortality or cardiovascular hospitalization, especially in patients with ischemic HF.64 Thus, further randomized controlled trials focused on ischemic HF may be warranted. Omega-3 polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are key players in modulating inflammatory process by limiting leucocyte chemotaxis, adhesion molecule expression, leucocyte-endothelium interaction as well as T cell reactivity.65 EPA and DHA are mainly gained from marine food consumption and large population-based studies have shown that Mediterranean diet with PUFA supplementation may aid to prevent CVDs owing to their ability in promoting the release of nitric oxide from endothelial cells and decreasing serum levels of triglycerides.66 Recent evidence has indicated that PUFAs can significantly affect the cellular epigenome mainly thought DNA methylation-sensitive mechanisms.67,68 The GISSI multicenter, double-blind trial enrolled 6975 HF patients (New York Heart Association class IIIV, irrespective of cause and LV ejection fraction) and randomized them to low dose (0.84 g per day) of PUFAs as compared to placebo. PUFAs supplementation reduced risk for total mortality and HF hospitalization when added to standard therapy.19 Furthermore, in the OMEGA-REMODEL trial, high-dose of PUFAs (3.4 g per day) for 6 months post-myocardial infarction reduced infarct size and non-infarct myocardial fibrosis as well as improved ventricular systolic function.69 Taken together, these results suggest that PUFAs may aid to prevent HFrEF. More recently, the MESA longitudinal trial including 6562 participants 45 to 84 years has demonstrated that higher plasma levels of EPA were significantly associated with reduced risk both in HFpEF and HFrEF.70

Although the possibility of improving the HF standard of care with epidrugs is still in its infancy, the BETonMACE study has provided promising results about the use of apabetalone in reducing hospitalization and cardiovascular death. Preclinical models of cardiac remodeling demonstrated that metformin, statins, SGLT2i, and PUFAs4148 can improve vascular health and cardiac fibrosis by modulating specific molecular pathways, and, in part, through downstream epigenetic interference, especially for hydralazine39 and empagliflozin (Figure 2).49 Of note, metformin and SGLT2i can impact on the epigenetic memory phenomenon. This latter suggests that an early glycemia normalization can arrest hyperglycemia-induced epigenetic processes associated with enhanced oxidative stress and glycation of cellular proteins and lipids.71,72 In parallel, an increasing number of clinical trials is evaluating the putative beneficial repurposing of metformin, statins, SGLT2i, and PUFAs in patients with HFpEF and/or HFrEF;19,6264,69,7375 however, despite experimental evidence, none of these trials evaluated their potential epigenetic effects involved in improving the cardiac function. This gap should be overcome to improve personalized therapy of patients with HF. Thus, further randomized trials are needed to clarify whether apabetalone, as well as non-canonical repurposed epidrugs, will really be able to save failing hearts in different HF clinical phenotypes or prevent irreversible damages in high-risk patients. In this context, Network Medicine approaches may help to evaluate a possible repurposing of epidrugs in patients with major CVDs.15,76,77

Figure 2 Direct and indirect epigenetic drugs in preclinical models of HF. Cardiac remodeling includes different pathological phenotypes and each type of drug can selectively improve inflammation, cardiac fibrosis and hypertrophy, calcium homeostasis, and lipid metabolism.

Abbreviations: HF, heart failure; SGLT2i, sodium glucose co-transporter 2 inhibitors.

This work was supported by PRIN2017F8ZB89 from Italian Ministry of University and Research (MIUR) (PI Prof Napoli) and Ricerca Corrente (RC) 2019 from Italian Ministry of Health (PI Prof. Napoli).

The authors report no conflicts of interest in this work.

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Epigenetic therapies for heart failure | VHRM - Dove Medical Press

Newswise Irvine, CA May 13, 2021 A new University of California, Irvine-led study finds low serum levels of the sugar N-acetylglucosamine (GlcNAc), is associated with progressive disability and neurodegeneration in multiple sclerosis (MS).

The study, done in collaboration with researchers from Charit Universittsmedizin Berlin, Germany, and the University of Toronto, Canada, is titled, Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration, The study was published this week in JAMA Neurology.

The study suggests that GlcNAc, which has been previously shown to promote re-myelination and suppress neurodegeneration in animal models of MS, is reduced in serum of progressive MS patients and those with worse clinical disability and neurodegeneration.

We found the serum levels of a marker of GlcNAc was markedly reduced in progressive MS patients compared to healthy controls and patients with relapsing-remitting multiple sclerosis explained Michael Demetriou, MD, PhD, FRCP(C), professor of neurology, microbiology and molecular genetics at UCI School of Medicine, and senior author on the paper.

First author of the study, Alexander Brandt, MD, adjunct associate professor of neurology at the UCI School of Medicine and previously associated with the Experimental and Clinical Research Center, Charit Universittsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Germany, added, Lower GlcNAc serum marker levels correlated with multiple measures of neurodegeneration in MS, namely worse expanded disability status scale scores, lower thalamic volume, and thinner retinal nerve fiber layer. Also, low baseline serum levels correlated with a greater percentage of brain volume loss at 18 months, he said.

GlcNAc regulates protein glycosylation, a fundamental process that decorates the surface of all cells with complex sugars. Previous preclinical, human genetic and ex vivo human mechanistic studies revealed that GlcNAc reduces proinflammatory immune responses, promotes myelin repair, and decreases neurodegeneration. Combined with the new findings, the data suggest that GlcNAc deficiency may promote progressive disease and neurodegeneration in patients with MS. However, additional human clinical studies are required to confirm this hypothesis.

Our findings open new potential avenues to identify patients at risk of disease progression and neurodegeneration, so clinicians can develop and adjust therapies accordingly, said Michael Sy, MD, PhD, assistant professor in residence in the Department of Neurology at UCI and a co-author of the study.

MS is characterized by recurrent episodes of neurologic dysfunction resulting from acute inflammatory demyelination. Progressive MS is distinguished by continuous inflammation, failure to remyelinate, and progressive neurodegeneration, causing accrual of irreversible neurologic disability. Neurodegeneration is the major contributor to progressive neurological disability in MS patients, yet mechanisms are poorly understood and there are no current treatments for neurodegeneration.

This study was funded in part by a grant from the National Institute of Allergy and Infectious Disease and the National Center for Complimentary and Integrative Health as well as the Excellence Initiative and the Excellence Strategy of the German Federal and State Governments.

About the UCI School of Medicine

Each year, the UCI School of Medicine educates more than 400 medical students, and nearly 150 doctoral and masters students. More than 700 residents and fellows are trained at UCI Medical Center and affiliated institutions. The School of Medicine offers an MD; a dual MD/PhD medical scientist training program; and PhDs and masters degrees in anatomy and neurobiology, biomedical sciences, genetic counseling, epidemiology, environmental health sciences, pathology, pharmacology, physiology and biophysics, and translational sciences. Medical students also may pursue an MD/MBA, an MD/masters in public health, or an MD/masters degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Leadership Education to Advance Diversity-African, Black and Caribbean (LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit som.uci.edu.

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New study finds low levels of a sugar metabolite associates with disability and neurodegeneration in multiple sclerosis - Newswise

Sara Cernadas-Martn with the research vessel Seawolf behind her. Photo by John Griffin

Sara Cernadas-Martn is a self-described interdisciplinary scientist with knowledge spanning the fields of marine biology, molecular genetics, and conservation ecology, with an M.S. and a PhD from Stony Brook University.

Beyond her passion for studying and preserving the diversity of marine life in our local waters, Cernadas-Martn is equally as dedicated to fostering diversity within the human race, making her the ideal person to serve as co-chair for the School of Marine and Atmospheric Science (SoMAS) Diversity, Equity and Inclusivity Committee.

As an Hispanic scientist, I am committed to increasing diversity on campus and making an extra effort to promote higher education within the Hispanic community and other underrepresented racial, ethnic and social groups, Cernadas-Martn said.Hispanics are highly underrepresented in undergraduate and graduate schools in America, which is especially discouraging when considering that the Hispanic population is the largest ethnic minority group in the country. I strongly believe that having a diverse student body benefits everyone involved.

For her masters project, Sara studied the distribution of ammonia oxidizing bacteria in the Cariaco Basin near Venezuela, an oxygen minimum zone with a permanently anoxic (oxygen-depleted) deep layer, under the supervision of Professor Gordon Taylor. Her PhD thesis focused on the multidisciplinary ecological characterization of summer flounder (Paralichthys dentatus) in Shinnecock Bay using acoustic telemetry, diet analysis and otolith (earstones in bony fishes) microchemistry under the supervision of Professor Ellen Pikitch.

Cernadas-Martn is currently working with the Institute for Ocean Conservation Science (IOCS) as a senior postdoctoral associate at Stony Brook, where her work focuses on managing the research component of ShiRP fisheries (Shinnecock Bay Restoration Program) and establishing a new environmental DNA program for tracking fish species richness in the South Shore Long Island estuaries.

In 2019, Cernadas-Martn was also selected as the recipient of the distinguished Nuria Protopopescu Memorial Teaching Award, presented annually to a graduate student based on demonstrated excellence in teaching, innovation and creativity in instructional plans and materials, and engagement with and dedication to their students.

Although I enjoy working with students of all backgrounds, I have always taken special interest in Latinx students, making sure they felt motivated, included and most importantly, had fun while doing science, she said. At first, many of these students were hesitant to be assertive while in the field or in the classroom. I came to realize, in sharing the same language, I could help students to overcome their natural timidity and become more engaged in their research and learning experience.

Of particular interest to Cernadas-Martn is extending educational opportunities to students from diverse backgrounds, including first-generation college students, international students, and students with a wide range of educational experiences and goals.

Her academic achievements and community involvement, along with her focused effort on student diversity and integration, have been recognized by Stony Brook University with the prestigious W. Burghardt Turner Fellowship, a highly competitive fellowship which acknowledges the academic and research achievements of underrepresented doctoral students and requires a strong commitment to inclusivity and community development.

Another of Cernadas-Martns personal goals is to help improve the integration of international students into the wider academic community.

I remember when I first got to Stony Brook University from Spain. I was in shock, she recalled. I was happy for having made it into graduate school, but at the same time had to deal with a language barrier and being away from my family and friends. The first few months are critical times in the life of an international student and can potentially handicap academic performance.

Cernadas-Martn believes efficient integration is key to helping international students realize that there are opportunities in this new chapter of their lives. During my first years of graduate school, I did my best to help improve social interactions among students in my department, she said. One example were the flamenco nights I hosted once a month at a Spanish restaurant open to everyone in my department, where I was able to share the culinary, musical and folkloric traditions of my culture.

To that end, Cernadas-Martn has volunteered with the Graduate Student Club of her department as the activities coordinator, creating and running a departmental photo competition since 2012, among other undertakings.

Perhaps some of her compassion originated from her own medical struggles.As a college freshman, she overcame bone cancer, which impeded her from attending school. She recovered, but suffered a relapse in the middle of her sophomore year.

During my graduate career I have been, once again, plagued with health issues, which included three major spinal surgeries, she said, adding that the surgeries set back her graduation timeline and consequently constrained the ability of her research grants to cover laboratory costs and living expenses.

However, I was lucky enough to have a few professors, family and friends who supported me and encouraged me to finish my degree, she said. It did take me longer than most people, but I did it. Looking back, I cant thank those people in my life enough. I aim to be a support system for as many students as possible, motivating them to move forward despite setbacks and encouraging them to pursue their passion.

Glenn Jochum

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Cernadas-Martn Is a Champion for Marine and Human Diversity | | SBU News - Stony Brook News

Four Penn Faculty: Election to the National Academy of Sciences

Four members of the University of Pennsylvania faculty have been elected to the United States National Academy of Sciences (NAS). They join 120 members, 59 of whom are women, the most elected in a single year, and 30 international members, elected by their peers this year to NAS. Recognized for distinguished and continuing achievements in original research, this new class brings the total number of active members to 2,461 and of international members to 511.

Marisa Bartolomei is the Perelman Professor of Cell and Developmental Biology in the department of cell and developmental biology in the Perelman School of Medicine. She is also the co-director of the Penn Epigenetics Institute. Crossing into the disciplines of cell and molecular biology, pharmacology, and neuroscience, Dr. Bartolomei and her lab investigate genomic imprinting in mice. Specifically, they focus on the H19 gene, which is only expressed in maternal alleles, in order to better uncover the mechanisms behind imprinting and the effects of the environment, assisted reproductive technologies, and endocrine disruptors. Her lab also looks into the molecular and genetic systems behind X inactivation in mice. Her research has been published widely in journals including Nature, Nature Biotechnology, Development, and PLoS Genetics.

Michael Kearns is the National Center Professor of Management & Technology in the department of computer and information science in the School of Engineering and Applied Science. He also holds secondary appointments in the School of Arts & Sciences department of economics and the departments of statistics and operations, information and decisions at the Wharton School. He is an expert in machine learning, algorithmic game theory, and microeconomics, and applies both theoretical research and experimental techniques to better understand the social dimensions of new information technology, such as its impact on privacy and fairness. Dr. Kearns is also the founding director of Penns Warren Center for Network and Data Sciences, which draws on researchers from around the University to study some of the most pressing problems of the digital age. Dr. Kearns is also the co-author of The Ethical Algorithm, which shows how seemingly objective data science techniques can produce biased outcomes.

Diana Mutz is the Samuel A. Stouffer Professor of Political Science and Communication in the Annenberg School for Communication. She also serves as director of the Institute for the Study of Citizens and Politics; she is also an affiliate of the Warren Center. She studies political communication, political psychology, and public opinion, and her research focuses on how the American mass public relates to the political world and how people form opinions on issues and candidates. She received a 2017 Carnegie Fellowship and a 2016 Guggenheim Fellowship to pursue research on globalization and public opinion, and in 2011 received the Lifetime Career Achievement Award in Political Communication from the American Political Science Association. In addition to many journal articles, Dr. Mutz is the author of Impersonal Influence: How Perceptions of Mass Collectives Affect Political Attitudes, Hearing the Other Side: Deliberative Versus Participatory Democracy, and In-Your-Face Politics: The Consequences of Uncivil Media.

M. Celeste Simon is the Arthur H. Rubenstein, MB BCh, Professor in the department of cell and developmental biology in the Perelman School of Medicine and the scientific director of The Abramson Family Cancer Research Institute. She and her lab research the metabolism of cancer cells, tumor immunology, metastasis, and how healthy cells and cancer cells respond to a lack of oxygen and nutrients. Her work uses both animal models and cancer patient samples, and her goal is to create techniques to treat various tumors like kidney cancer, soft tissue sarcoma, liver cancer, and pancreatic cancer. Dr. Simon was the recipient of a National Cancer Institute Outstanding Investigator Award in 2017, and she has authored more than 275 articles in journals including Cell, Science, Nature, Cancer Discovery, Nature Genetics, and Cancer Cell.

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Four Penn Faculty: Election to the National Academy of Sciences - UPENN Almanac

The controversy over genetically engineered organisms (sometimes called genetically modified organisms, or GMOs) is genuine, not faux but only because of uninformed, exaggerated concerns about the most recent techniques newness. What is faux and disingenuous are the arguments put forth by genetic engineerings opponents.

Humans have been modifying the DNA of our food for thousands of years (even though we didnt know that DNA was mediating the changes until the 20th century).We call it agriculture.Early farmers (>10,000 years ago) used selective breeding to guide DNA changes in crops and animals to better suit our needs.Approximately a hundred years ago plant breeders began using harsh chemicals and/or radiation to randomly change, or mutate, the DNA of crop plants.These mutagens caused innumerable changes to the DNA, none of which was characterized or examined for safety.The plant breeders looked and selected for desired traits of various kinds.Problems were rare.

Today more than half of all food crops have mutagenesis breeding as part of their pedigree. Ancestral varieties bear little resemblance to the domesticated crops we eat today. There are many striking pictorial examples here.

Approximately 40 years ago agricultural scientists and plant breeders began to use recombinant DNA technology (gene splicing) to make far more precise and predictable changes to the DNA in our crop plants.This molecular genetic engineering (GE) typically takes a gene with a known function, e.g., one that expresses a protein toxic to certain insect predators, and transfers it into a crop, enabling the GE crop to protect itself from insect pests. This one trait, resulting from the introduction of a gene from the bacterium Bacillus thuringiensis (abbreviated Bt) into plants, has allowed farmers around the world to reduce broad spectrum insecticide spraying by billions of pounds.

Since the advent in the 1970s of this recombinant DNA technology, which enables segments of DNA to be moved readily and more precisely from one organism to another, molecular genetic engineering techniques have become increasingly more sophisticated, precise, and predictable. This evolution has culminated in the most recent discoveries, the CRISPR-Cas9 system and base editing.

CRISPR (short for Clustered Regularly Interspaced Short Palindromic Repeats) is a natural defense system that bacteria use against invading viruses. CRISPR can recognize specific DNA sequences, while the enzyme Cas9 cuts the DNA at the recognized sequence. As often happens in scienceand reminiscent of mutagenesis a century ago and recombinant DNA technology in the 1970smolecular biologists quickly copied, adapted, and improved the naturally occurring system. Using CRISPR-Cas9, scientists can target and edit DNA at precise locations, deleting, inserting, or modifying genes in microorganisms, plants and animals, and even humans.

CRISPR-Cas9 presages a revolution in agriculture and human medicine because it is so much more precise and predictable than earlier techniques. Precision and predictability are important to ensure that results are safe and achieve their desired ends. There are notable historical examples of older, pre-molecular techniques of genetic modification in agriculture that misfired.Examples include:

Despite their success for farmers of all types, from subsistence to huge-scale commercial, GE crops have been discriminated against by regulators and demonized by activists. In the early 1970s, at a conclave now referred to as the Asilomar Conference, a group of scientists none involved in agriculture or food science raised concerns about hypothetical hazards that might arise from the use of the newly discovered molecular genetic modification technique recombinant DNA technology, or gene-splicing. However, they failed to appreciate the history of genetic modification by means of cruder, less predictable technologies, described below.

The Asilomar Conference led to guidelines published by the U.S. National Institutes of Health (NIH) for the application of these techniques for any purpose.These process-based guidelines, which were applicable exclusively to recombinant DNA technology, were in addition to the preexisting product-focused regulatory requirements of other federal agencies that had statutory oversight of food, drugs, certain plants, pesticides, and so on.

The NIH guidelines, which were in effect the original sin of precautionary, unscientific regulation, were quite stringent. For example, without regulatory approval, the intentional release of recombinant DNA-modified organisms into the environment, or fermentation (in contained fermenters) at volumes greater than ten liters, required explicit prior approval by the NIH and local Institutional Biosafety Committees.

Given the seamless continuum of techniques for genetic modification described above, such requirements were unwarranted.No analogous blanket restrictions existed for similar or even virtually identical plants, microorganisms, or other organisms modified by traditional techniques, such as chemical or irradiation mutagenesis or wide-cross hybridizations.

Thus, uninformed, ill-founded, and exaggerated concerns about the risks of recombinant DNA-modified organisms in medical, agricultural, and environmental applications precipitated the regulation of recombinant organismsregulation triggered simply by the process, or technique, of genetic modification, rather than the product, i.e., the characteristics of the modified organism itself. This was an unfortunate precedentas was entrusting technology regulation to a research agency, the NIH, whose legacy plagues regulation worldwide today. Most industrial countries, including the US, have specific regulatory agencies like the US Food and Drug Administration and European Medicines Agency that regulate product safety. Research agencies rarely are involved in regulating products or processes.

The regulatory burden on the use of recombinant DNA technologywhich some people (mostly activists and regulators) consider gives rise to a mythical category of organisms called Genetically Modified Organisms, or GMOs, was, and remains, disproportionate to its risk, and the opportunity costs of regulatory delays and expenses are formidable. According to Wendelyn Jones at DuPont Crop Protection, a survey found that the cost of discovery, development and authorization of a new plant biotechnology trait introduced between 2008 and 2012 was $136 million. On average, about 26 percent of those costs ($35.1 million) were incurred as part of the regulatory testing and registration process.

A salient question currently for regulators, scientists, and consumers is whether gene editing will fall down the same rabbit hole. Unfortunately, much of the discussion focuses on irrelevant issues such as whether organisms that could arise naturally or that are not transgenic (containing DNA from different sources) should be subject to more lenient regulation than GMOs. As should be evident from the discussion above, such issues have no implications for riskand, therefore, for regulation. In fact, modern plant breeding techniques, including genome editing, are more precise, circumscribed, and predictable than other methods in other words, if anything, likely to be safer. This assessment is neither new nor novel. A landmark report from the U.S. National Research Council concluded in 1989:

These critical points, clearly articulated more than 30 years ago and about which there is virtual unanimity in the scientific community, have not sunk in.

There is an ongoing need for genetic modification in agriculture. Gene editing could play a key role in Englands sugar beet sector, for example, and Britains farming and in February, environment minister George Eustice told the annual conference of the National Farmers Union that the sugar beet sector could use the assistance of gene editing technologies to overcome yield reduction due to virus infection. He added: Gene editing is really just a more targeted, faster approach to move traits from one plant to another but within the same species so in that respect it is no different from conventional breeding.

The first part of Eustaces statement is accurate, but the second part gives the misimpression that although gene edited crops are analogous to conventional breedingand, therefore, presumably harmlessthey are sufficiently far removed from dreaded GMOs that they should be exempt from the onerous regulation appropriate for the latter. Until now, in the European Union, gene editing has been strictly regulated in the same way as GMOs. Their oversight might diverge in the future, however, inasmuch as serious attention is being paid to this new technology and its enormous potential.

But preferential regulatory treatment of gene editing over recombinant DNA-mediated modifications would represent expediency over logic: The NRC report (as well as other, innumerable, similar analyses) makes it clear that an approach that deregulates gene editing but not recombinant DNA modifications would ignore the seamless continuum that exists among methods of genetic modification, and that it would be unscientific.There is no reason to throw transgenic recombinant DNA constructions under the regulatory bus.

The relationships among genome editing, plant breeding, and GMO crops are more interconnected, complex and nuanced than it may appear at first glance.Plant breeding itself has long been a murky science in terms of genetics and heredity.While Britains Eustice lauds genome editing because it involves only intra-species modification, the history of plant breeding has long included distant or wide crosses to move beneficial traits such as disease resistance from one plant species or one genus to another.Almost a century of wide cross hybridizations, which involve the movement of genes from one species or genus to another, has given rise to plantsincluding everyday varieties of corn, oats, pumpkin, wheat, black currants, tomatoes, and potatoes, among othersthat do not and could not exist in nature. Indeed, with the exception of wild berries, wild game, wild mushrooms, and fish and shellfish, virtually everything in North American and European diets has been genetically improved in some way.Compared to the new molecular modification technologies, these wide crosses are crude and less predictable.

Another wrinkle is that plant scientists have discovered what have been termed natural GMOs, which further confounds the terminology.These include whiteflies harboring plant genes that protect them from pesticides, horizontal gene transfer between different species of grasses, sweet potato harboring sequences from the bacterium Agrobacterium, and aphids which express a red fungal pigment to protect them from would-be predators.This is more evidence that the term GMO itself has become meaningless.

This brings us back to the regulatory conundrum surrounding the way forward with the various products of genetic engineering using different technologies. Eager to avoid the delays, impasses and rejections and inflated opportunity costs that have confounded GMOs, many in the scientific and commercial communities are willing to play down the novelty of genome editing, while, in effect, conceding that recombinant DNA constructions should continue to be stringently regulated.

However, as we have discussed, the comparison of genome editing and recombinant DNA is a distinction without a difference, especially when viewed against the backdrop of the crude constructions of (largely unregulated) traditional plant breeding.Trying to draw meaningful distinctions between molecular genetic engineering and other techniques for the purpose of regulation is rather like debating how many angels can dance on the head of a pin.Its way past time that for purposes of regulatory policy, we began to think in terms of the risk posed by organisms and their products, rather than which technology(ies) was employed.

Kathleen Hefferon, Ph.D., teaches microbiology at Cornell University. Find Kathleen on Twitter@KHefferon

Henry Miller, a physician and molecular biologist, is a senior fellow at the Pacific Research Institute. He was a Research Associate at the NIH and the founding director of the U.S. FDAs Office of Biotechnology. Find Henry on Twitter@henryimiller

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Is there a difference between a gene-edited organism and a 'GMO'? The question has important implications for regulation - Genetic Literacy Project

This year, five Wesleyan students were inducted into the American Society for Biochemistry and Molecular Biology (ASBMB) Honor Society. Thirty-one students nationwide were given this honor.

Inducted students must be juniors or seniors with a GPA of 3.4 or higher on a 4.0 scale, belong to a student chapter of the ASBMB, and demonstrate exceptional achievement in academics, undergraduate research and science outreach, according to the website.

The inducted students include the following:

Nour-Sada Harzallah 21, a College of Integrative Sciences student majoring in molecular biology & biochemistry (MB&B) and physics. Harzallah, from Tunisia, works in Professor Francis Starrs physics lab, belongs to the Wesleyan Women in Science steering committee, and is a STEM intern for the Office of Equity and Inclusion.

Her involvement in racial and gender equity in STEM has shaped her commitment to work on projects that serve the underrepresented and marginalized outside the lab and from the lab bench, reads her ASBMB bio. Her wildest dream is to develop initiatives that translate cutting-edge technologies into accessible and marketable means of diagnosis and therapeutics in her home country of Tunisia.

Jack Kwon 21, who works with Professor of Biology Michael Weir to study the ribosome.

We are aiming to elucidate the function of a highly conserved region of the ribosome called the CAR interaction surface through wet lab experiments and dry lab Molecular Dynamics simulations, Kwon wrote in his ASBMB bio. Kwon intends to graduate with a masters degree in MB&B through Wesleyans BA/MA program before pursuing a PhD in a related field.

Shawn Lin 22, who is majoring in biology, MB&B, and biophysics. Lin works in the MB&B lab of Professor Ishita Mukerji and the physics lab of Professor Candice Etson.

His research topic is Elucidation of interactions between integration host factor and a DNA four-way junction, reads Lins ASBMB bio. In addition to research, he is also the founder of NORDSAC (National Organization for Rare Disorders Student Association Connecticut). The goal of this organization is to raise awareness of rare disorders among students in Connecticut through fundraising, guest lectures, and rare disease day events.

Alex Poppel, a masters student in the MB&B department. Poppell works in Professor Amy MacQueens MB&B lab.

As a member of Wesleyans ASBMB Student Chapter, his outreach involvement has mainly focused on improving his schools community, such as by promoting undergraduate research opportunity awareness and equity and inclusion efforts in the sciences, Poppels ASBMB bio reads.

Maya Vaishnaw 21, a double major in psychology and MB&B. Vaishnaw works with Professor Erika Taylor in her chemistry lab.

The Taylor Lab takes a multidisciplinary approach to characterizing enzymes with applied chemical and biomedicinal applications, Vaishnaws ASBMB bio reads. In the future, Maya hopes to pursue research in clinical genetics.

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5 Students Inducted Into American Society for Biochemistry and Molecular Biology Honor Society - Wesleyan Connection

All cellular life on Earth is based on DNA, which transfers informationabout everything from hair color to personality traitsfrom one generation to the next. The four chemical bases that convey this information are adenine (A), cytosine (C), guanine (G), and thymine (T).

The other essential information molecule on Earth is RNA, in which thymine (T) is replaced by uracil (U). RNA has a one-string structure rather than a double-string structure like DNA. The first cellular life on our planet is thought to have relied exclusively on this means of transferring genetic informationin the so-called RNA worldand even today there are viruses (like the one that causes COVID) that only use RNA.

In a paper recently published in Science, a research group led by Dona Sleiman from the Institute Pasteur in Paris has discovered that some viruses show more variation in their genetic coding than was previously known. In the RNA of these viruses, adenine (A) is replaced with Z, where Z stands for diaminopurine.

This follows an earlier study by Zunyi Yang and colleagues at the Foundation for Applied Molecular Evolution in Gainesville, Florida, showing that an artificial genetic system could be created by adding two additional non-standard bases to ordinary DNA. Amazingly, the artificial six-base system continued to evolve rather than reverting back to the natural four-base system. This implies that the DNA we take as standardmade of A, C, G, and Tis just one of many viable solutions to the challenge of biological information transfer.

The variability does not stop here. Strings of DNA are organized in base triplets that determine which of the standard 20 amino acids are assigned to synthesize proteins. However, these triplet assignments are not universal. For example, CUG, which usually codes for the amino acid serine, instead codes for the amino acid leucine in some types of fungi. Also, some organisms naturally encode for two additional amino acids instead of the standard 20 amino acids.

What does this brief excursion into genetics have to do with alien life? While it is believed that all life on our planet derives from one common ancestor, the genetic code is much more flexible and diverse than usually appreciated. The biochemistry of information transfer in an alien species would almost certainly use different building blocks and encodings, and perhaps even a different number of bases. Our genetic code is surely highly optimized for life on Earth, but I feel certain that there are many optimal solutionsperhaps some that are even betterfor transferring information chemically from one generation to the next.

We, of course, cannot say what type of genetic code an alien species would use. But given that it would most likely be biochemically different, it would mostly likely be easily distinguishable from life on Earth. It may even be more different than we expect. A fascinating out-of-the-box genetic system has been suggested by Gerald Feinberg and Robert Shapiro, based on magnetic orientations rather than chemistry. They showed how magnetized particles, when approaching a magnetic chain, will align with the chain. As a result, the chain is duplicated, and this method could in principle be used to convey information in a binary code.

So, while alien life may well transmit genetic information using structures similar to RNA and DNA, we should always be prepared to expect the unexpected.

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The Science of Aliens, Part 2: What Kind of Genetic Code Would Extraterrestrials Have? - Air & Space Magazine

A UT Austin faculty member, Dr. Shelley Marshall Payne, has been named a recipient of the prestigious Piper Professor Award, an annual award that recognizes outstanding college professors from colleges and universities across the state of Texas.

Dr. Shelley Marshall Payne is a professor in the department of Medical Education and Molecular Biosciences housed in the College of Natural Sciences. Her research interests are in genetics and regulation of virulence factors of gram negative pathogens, including Shigella and Vibrio cholerae.

We are so proud of Dr. Payne and thrilled to see her recognized for her superior teaching and advancement of our students learning during what has been an especially challenging year for all, said senior vice provost of faculty affairs, Tasha Beretvas. We are also very grateful to the Minnie Stevens Piper Foundation for their support for teaching excellence through these awards. And we acknowledge the honor that one of our faculty members receiving this award reflects on The University of Texas at Austin.

The Piper Professor Award was established by the San Antoniobased Minnie Stevens Piper Foundation in 1958 and honors 10 professors per academic year for their dedication to the teaching profession and for their outstanding academic, scientific and scholarly achievement. Each Piper Professor receives a certificate of merit, a gold pin and a $5,000 honorarium.

Selection is made on the basis of nominations; each two and four-year college and university in the state may submit only one nominee annually.

More information is available on the Texas Comptroller website.

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UT Austin Faculty Member Receives 2021 Piper Professor Award - Office of the Executive Vice President and Provost - UT News | The University of Texas...

One of the University's leading scientists, Professor Vernonica (Noni) Franklin-Tong has been elected a Fellow of the Royal Society.

Professor Franklin-Tong, a plant scientist, was recognised for her pioneering work on self-incompatibility in plants the mechanism which prevents plants from inbreeding. Using the common field poppy as a model system, she has identified novel mechanisms pivotal to regulation of cell growth and programmed cell death in plants.

She joins more than 60 outstanding scientists from around the globe who have been elected to the Royal Society this year as Fellows and Foreign Members.

Announcing the new appointments, Sir Adrian Smith, President of the Royal Society, said: The global pandemic has demonstrated the continuing importance of scientific thinking and collaboration across borders. Each Fellow and Foreign Member bring their area of scientific expertise to the Royal Society and when combined, this expertise supports the use of science for the benefit of humanity.

Our new Fellows and Foreign Members are all at the forefronts of their fields from molecular genetics and cancer research to tropical open ecosystems and radar technology. It is an absolute pleasure and honour to have them join us.

Professor Franklin-Tong said: "I am absolutely delighted to be elected as a Fellow of The Royal Society. It's a huge honour to have this recognition and to join this prestigious group of scientists. I'm indebted to the contribution of my team of researchers over the years.

"As a female professor of mixed ethnicity, I am especially proud of this achievement. I hope it inspires others to reach for the seemingly impossible."

Dr Neil Hotchin, Head of the School of Biosciences, said: Noni is an outstanding plant biologist and her election to the Royal Society is a well-deserved recognition of her truly ground-breakingwork on self-incompatibility in plantswhich has resultedin multiple high impactpapers in journals such asScience and Nature.

For media enquiries please contact Beck Lockwood, Press Office, University of Birmingham, tel: +44 (0)781 3343348.

The University of Birmingham is ranked amongst the worlds top 100 institutions. Its work brings people from across the world to Birmingham, including researchers, teachers and more than 6,500 international students from over 150 countries.

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Distinguished University of Birmingham plant scientist elected to the Royal Society - University of Birmingham

When you pair graduate students with undergraduates, what do they talk about? In the case of the University of Virginias Double Hoo Awards, they discuss interactive machine learning, the genesis of false memories, how the brain controls infection and politicization in the field of intelligence, among other things.

This year, UVA awarded 21 Double Hoo Awards to new pairings of undergraduates and graduate student mentors, with the teams receiving up to $6,000. One team from last years recipients was awarded a renewal to continue their research, receiving $3,000 in support. The Double Hoo Award is funded by the Robert C. Taylor Fund.

We love seeing the ways that these student pairs have come together to pursue research and creative inquiry, Andrus G. Ashoo, director of the Office of Undergraduate Research, said. The funded projects represent disciplines across the institution and are pursuing some fascinating questions. It gets me excited for next years research symposium, where they will all present.

While undergraduate research is typically done in close collaboration with faculty members, the Double Hoo Awards add another element: the involvement of a graduate student mentor who plays a key role in defining the project. In the Double Hoo process, the undergraduate student submits the application with a project proposal and budget and identifies a graduate student with whom he or she will work. The graduate student also submits a statement of mentorship as part of the application process.

Not only will the research these students pursue be valuable to their development intellectually, it will also help these students professionally and socially as they learn to navigate a new relational dynamic, Ashoo said. In addition, an opportunity like this can be an experience that helps to clarify questions that the undergraduate or graduate might have about their future goals. For the graduate students, this is an invaluable opportunity to develop as a mentor, learning to provide supervision and incorporating the undergraduate into the larger project goals. This experience will be important, whether they go on to roles in academia, industry or public service.

This years Double Hoo recipients are:

One of last years projects has been renewed for a second year:

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Double Hoo Research: Undergrads and Grads Team Up to Create Knowledge - University of Virginia

Global Genetic Testing Market research report has been prepared with a nice combination of industry insight, smart solutions, practical solutions and newest technology to give better user experience. Under market segmentation chapter, research and analysis is done based on several market and industry segments such as application, vertical, deployment model, end user, and geography. To perform this market research study, competent and advanced tools and techniques have been utilized that include SWOT analysis and Porters Five Forces Analysis. Businesses can surely anticipate the reduced risk and failure with the winning research report.

Global Genetic Testing Market, By Type (Predictive & Presymptomatic Testing, Carrier Testing, Prenatal & Newborn Testing, Diagnostic Testing, Pharmacogenomic Testing, Others), Technology (Cytogenetic Testing, Biochemical Testing, and Molecular Testing), Application (Cancer Diagnosis, Genetic Disease Diagnosis, Cardiovascular Disease Diagnosis, Others), Disease (Alzheimers Disease, Cancer, Cystic Fibrosis, Sickle Cell Anemia, Duchenne Muscular Dystrophy, Thalassemia, Huntingtons Disease, Rare Diseases, Other Diseases), Product (Equipment, Consumables), Country (U.S., Canada, Mexico, Germany, Italy, U.K., France, Spain, Netherlands, Belgium, Switzerland, Turkey, Russia, Rest of Europe, Japan, China, India, South Korea, Australia, Singapore, Malaysia, Thailand, Indonesia, Philippines, Rest of Asia- Pacific, Brazil, Argentina, Rest of South America, South Africa, Saudi Arabia, UAE, Egypt, Israel, Rest of Middle East & Africa) Industry Trends and Forecast to 2028

Genetic testing market is expected to gain market growth in the forecast period of 2021 to 2028. Data Bridge Market Research analyses the market to reach at an estimated value of 585.81 billion and grow at a CAGR of 11.85% in the above-mentioned forecast period. Increase in incidences of genetic disorders and cancer drives the genetic testing market.

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The major players covered in the genetic testing market report are 23andMe, Inc., Abbott., Ambry Genetics., BGI, Biocartis, BIO-HELIX, bioMrieux SA, Blueprint Genetics Oy, Cepheid., deCODE genetics, GeneDx, Inc., Exact Sciences Corp, HTG Molecular Diagnostics, Genomictree., Illumina, Inc, Invitae Corporation, Laboratory Corporation of America Holdings, Luminex Corporation., ICON plc, Myriad Genetics, Inc, Natera, Inc., Pacific Biosciences of California, Inc, Pathway Genomics, QIAGEN, Quest Diagnostics Incorporated, F. Hoffmann-La Roche Ltd and Siemens Healthcare Private Limited among other domestic and global players.

Competitive Landscape and Genetic Testing Market Share Analysis

Genetic testing market competitive landscape provides details by competitor. Details included are company overview, company financials, revenue generated, market potential, investment in research and development, new market initiatives, global presence, production sites and facilities, production capacities, company strengths and weaknesses, product launch, product width and breadth, application dominance. The above data points provided are only related to the companies focus related to genetic testing market.

Genetic tests are the type of tests which are defined as medical devices available in the form of kits and panels that are used for testing genetic diseases in humans. The testing is generally performed by collecting samples ofbloodfrom patients and the samples are then run on laboratory machines using test kits. There are numerous types of tests which are used in testing of genetic disorders which includes, predictive and presymptomatic testing, carrier testing, prenatal and newborn testing, diagnostic testing, pharmacogenomic testing among others.

Rise in awareness and acceptance of personalized medicines is the vital factor escalating the market growth, also rising advancements in genetic testing techniques, rising demand for direct-to-consumer genetic testing, rising consumer interest in personalized medicines in Europe, rising application of genetic testing in oncology and genetic diseases in North America and rising physician adoption of genetic tests into clinical care are the major factors among others driving the genetic testing market. Moreover, rising untapped emerging markets in developing countries and rising research and development activities in the machinery used inhealthcarewill further create new opportunities for genetic testing market in the forecasted period of 2021-2028.

However, rising standardization concerns of genetic testing-based diagnostics and rising stringent regulatory requirements for product approvals are the major factors among others which will obstruct the market growth, and will further challenge the growth ofgenetic testing marketin the forecast period mentioned above.

This genetic testing market report provides details of new recent developments, trade regulations, import export analysis, production analysis, value chain optimization, market share, impact of domestic and localised market players, analyses opportunities in terms of emerging revenue pockets, changes in market regulations, strategic market growth analysis, market size, category market growths, application niches and dominance, product approvals, product launches, geographic expansions, technological innovations in the market. To gain more info on genetic testing market contact Data Bridge Market Research for anAnalyst Brief,our team will help you take an informed market decision to achieve market growth.

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Genetic Testing Market Scope and Market Size

Genetic testing market is segmented on the basis of type, technology, application, disease and product. The growth amongst these segments will help you analyse meagre growth segments in the industries, and provide the users with valuable market overview and market insights to help them in making strategic decisions for identification of core market applications.

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Global Genetic Testing MarketCountry Level Analysis

Genetic testing market is analysed and market size insights and trends are provided by country, type, technology, application, disease and product as referenced above.

The countries covered in the genetic testing market report are U.S., Canada and Mexico in North America, Germany, France, U.K., Netherlands, Switzerland, Belgium, Russia, Italy, Spain, Turkey, Rest of Europe in Europe, China, Japan, India, South Korea, Singapore, Malaysia, Australia, Thailand, Indonesia, Philippines, Rest of Asia-Pacific (APAC) in the Asia-Pacific (APAC), Saudi Arabia, U.A.E, South Africa, Egypt, Israel, Rest of Middle East and Africa (MEA) as a part of Middle East and Africa (MEA), Brazil, Argentina and Rest of South America as part of South America.

North America dominates the genetic testing market due to rising demand for direct-to-consumer genetic testing and rising consumer interest in personalized medicines. Asia-Pacific is the expected region in terms of growth in genetic testing market due to rise in affordability, increasing surge in healthcare expenditure, and increase in awareness toward early screening of genetic disorders in this region.

The country section of the genetic testing market 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 consumption volumes, production sites and volumes, import export analysis, price trend analysis, cost of raw materials, down-stream and upstream value chain analysis 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 domestic tariffs and trade routes are considered while providing forecast analysis of the country data.

Healthcare Infrastructure growth Installed base and New Technology Penetration

Genetic testing market also provides you with detailed market analysis for every country growth in healthcare expenditure for capital equipments, installed base of different kind of products for genetic testing market, impact of technology using life line curves and changes in healthcare regulatory scenarios and their impact on the genetic testing market. The data is available for historic period 2010 to 2019.

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An absolute way to forecast what future holds is to comprehend the trend today!Data Bridge set forth itself as an unconventional and neoteric Market research and consulting firm with unparalleled level of resilience and integrated approaches. We are determined to unearth the best market opportunities and foster efficient information for your business to thrive in the market. Data Bridge endeavors to provide appropriate solutions to the complex business challenges and initiates an effortless decision-making process.

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Global Genetic Testing Market Top Countries Analysis and Manufacturers With Impact of COVID-19 | 2021-2028 Detail Analysis focusing on Application,...

Quebec Premier FranoisLegault, announced the appointment of 43 (35 from 2020) individuals to the National Order of Quebec today, including Dr. Morag Park, Director of McGill Universitys Rosalind and Morris Goodman Cancer Research Centre (GCRC) who was appointed Chevalire. Dr. Park was nominated by Maryse Lassonde, President of the Quebec Superior Council of Education with the support of the Quebec Breast Cancer Foundation (QBCF), with the additional support of McGills Faculty of Medicine and Health Sciences as well as the GCRC.

McGill University is proud that the Government of Quebec has chosen to honour Dr. Morag Park for her outstanding contributions in cancer research, said Martha Crago, Vice-Principal, Research and Innovation. Her work has improved our understanding of cancer and has made a mark on Quebecs culture of research excellence. I extend my heartfeltcongratulationsto Dr. Park on behalf of McGills research community.

It is a great honour to be appointed to the Order of Quebec. I am grateful for my incredible colleagues and trainees in the health and research community who have supported me throughout the years and whose collaborations have enabled the progress weve made to date. However, there remains a long road ahead in the fight against cancer, and support for this research is critical, perhapseven more so as we exit the COVID-19 pandemic, where, like so many fields, cancer care and research has been impacted, said Dr. Morag Park on receiving her appointment.

From the very beginning of her career as a researcher, the Foundation believed in Dr. Morag Parks research projects by awarding her very first research grant in breast cancer. She is a pioneer with her work on breast cancer in Quebec. We are proud to support her since her beginnings and the recognition she receives from the Order of Quebec, said Karine-Iseult Ippersiel, President and CEO of the Quebec Breast Cancer Foundation.

A trailblazer, builder and innovator during a career spanning over thirty years, Dr. Park has made contributions to a wide spectrum of cancer research, from the molecular level to the complex cellular interactions within tissues that dictate the biology of human cancers.

Her trajectory began with her identification and characterization of a key oncogene, the receptor tyrosine kinase (RTK) MET, as a post-doctoral fellow. On this foundation, Dr. Park built a research program of sustained excellence, developing elegant molecular and cell biology approaches to systematically discover key signaling proteins and pathways dictating the functional output of MET and other RTKs which are now key targets in precision medicine for many cancers. Her innovative approach, which set an example followed by many others in the field, identified critical molecular mechanisms of aberrant RTK activation that drive many prevalent cancers. These discoveries have significantly increased our understanding of many crucial processes underlying cancer development, including cell growth and proliferation, survival, motility and invasion and key cell fate decisions.

For the past 20 years, Dr. Park has also built world-leading translational research programs, including innovative pre-clinical models and comprehensive patient sample and data repositories, particularly for breast cancer. These are built on the premise of multidisciplinary collaborations between surgeons, oncologists, pathologists, and informaticians, as well as basic and translational researchers, through her role as Co-Principal Investigator of a Quebec-wide cancer biobanking network of clinicians and researchers. Her work led to a new understanding of the role of non-tumor cells, referred to as the tumor microenvironment in breast cancer, a concept that is now accepted for many cancers. More recently, living biobanks of live cells and tissues harvested during surgeries, developed under Dr. Parks leadership, have allowed the development of patient derived models of breast and other cancers to understand why some patients do not respond to therapy and to develop new therapeutic strategies.

Dr. Parks leadership and expertise in bridging the laboratory and clinic have allowed her to assume leading roles in consortia dedicated to improving outcomes for cancer patients by expanding the reach of precision medicine. These include Qubec Cancer Consortium (QCC), uniting six leading Montreal hospitals, cancer research centres, non-profit and pharmaceutical industry partners, and the Quebec node of the Terry Fox Research Institutes Marathon of Hope Cancer Centres Network (MoHCCN).

Dr. Park has received many prizes and honours including the Canadian Cancer Society (CCS) Robert L. Noble Prize (2017), the Canadian Society for Molecular Biosciences (CSMB) Arthur Wynne Gold Medal Award (2016), and the Grand Prix Scientifique of the Quebec Breast Cancer Foundation (2019). A fellow of the Royal Society of Canada (2007) and of the Canadian Academy of Health Sciences (2017), she was elected Chair of the American Association for Cancer Research (AACR) Tumor Microenvironment Network (2015-2017). She has been recognized consistently through academic appointments of the highest level, including a Distinguished James McGill Professorship (2020-present) and the Diane and Sal Guerrera Chair in Molecular Genetics (2003-present). Nationally, as the Scientific Director of CIHRs Institute of Cancer Research (2008-13), Dr. Park spearheaded key initiatives on personalized medicine, childhood cancers initiation and progression, the role of lifestyle and the environment. She also co-chaired the Canadian Cancer Research Alliance (CCRA), where she led the development of the first Pan-Canadian Cancer Research Strategic Plan. For these and her other efforts she received the CCRA Award for Exceptional Leadership in Cancer Research in 2015.

Congratulations Dr. Park!

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Morag Park named to the Order of Quebec - McGill Reporter - McGill Reporter

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Third Rock Ventures has closed a Series A financing round thatraised $82 million, funding which will be used to launchFlare Therapeutics, a new biotech startup focused on developing precision treatments for cancer and other diseases. Significant contributions were made to the Series A by Boxer Capital, Nextech Invest, Casdin Capital, Invus Financial Advisors, and Eventide Asset Management.

Flare uses a switch-site based drug discovery approach, which helped the company develop a pipeline of therapeutic programs that target pivotal cancer drivers such as transcription factor dysregulation and mutations. The new financing from the Series A will support its ability to advance its lead precision oncology program toward the clinic.

Flare currently has three lead precision oncology programs. The first program is expected to move into the clinic in 2023 or 2024, while the following two programs are expected to enter the clinic in the two years following.

Abbie Celniker, Ph.D., Flares interim Chief Executive Officer, and Third Rock Ventures partner, said in a statement that the new startup company was created to pursue the mission of conquering transcription factors which have been one of the most sought-after targets of drug developers based on the central role they play in cancer and other diseases.

Transcription factors appear to play a central role in cancer, among other diseases, according to emerging data and scientific discoveries published over the past ten years. Yet, transcription factors have continued to be elusive for finding targetable sites for drug discovery, with less than 1% of transcription factors successfully targeted for medicines, according to a statement made by Flares Scientific Co-Founder, Fraydoon Rastinejad, Ph.D., a professor of biochemistry and structural biology at the University of Oxford.

The novel drug discovery paradigm established by Flare uses an approach that targets transcription factors. According to the company, this strategy is based primarily on a broader understanding of the cooperative communication and allosteric interaction among the elements of the transcriptional molecular complex, in contrast to the previous scientific focus on only single, isolated transcription factor domains.

Recent work by the companys Scientific Co-Founders has helped Flare gain a greater understanding of the molecular mechanisms involved in targeting transcription factors. This understanding, according to Flare, has helped its research team to recognize the broad potential to generalize these principles to the switch site as a focal point for drugging transcription factors in a new way.

Scientific Co-Founder of Flare, Steven McKnight, Ph.D., a professor at the University of Texas, Southwestern, noted, Maturation of the fields of human genetics and the biochemistry of gene regulation now point us towards opportunities for therapeutic intervention using conventional, small molecule drugs.

Likely, Flare will also plan to use the new Series A funding to grow its staff to 25 employees. Currently, the company employs 12 to 15 full-time staffers, mainly relying on contractors and partners to fulfill its operational needs.

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Third Rock Ventures Launches Flare Therapeutics With $82 Million Series A - BioSpace

Over 60 outstanding scientists from all over the globe have joined the Royal Society as Fellows and Foreign Members. The distinguished group of scientists consists of 52 Fellows, 10 Foreign Members and one Honorary Fellow and were all selected for their exceptional contributions to science.

The Royal Society is a self-governing Fellowship made up of the most eminent scientists, engineers and technologists from the UK and the Commonwealth. Its Foreign Members are drawn from the rest of the world.

The Societys fundamental purpose is to recognise, promote, and support excellence in science and to encourage the development and use of science for the benefit of humanity.

The global pandemic has demonstrated the continuing importance of scientific thinking and collaboration across borders, said President of the Royal Society, Sir Adrian Smith.

Each Fellow and Foreign Member bring their area of scientific expertise to the Royal Society and when combined, this expertise supports the use of science for the benefit of humanity.

Our new Fellows and Foreign Members are all at the forefronts of their fields from molecular genetics and cancer research to tropical open ecosystems and radar technology. It is an absolute pleasure and honour to have them join us.

Read the full story and see the list of Cambridge Fellows

Reproduced courtesy of the University of Cambridge

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The Royal Society announces election of new Fellows 2021 - Cambridge Network

UCLA life scientists have identified six "words" that specific immune cells use to call up immune defense genes -- an important step toward understanding the language the body uses to marshal responses to threats.

In addition, they discovered that the incorrect use of two of these words can activate the wrong genes, resulting in the autoimmune disease known as Sjgren's syndrome. The research, conducted in mice, is published this week in the peer-reviewed journal Immunity (Cell Press).

"Cells have evolved an immune response code, or language," said senior author Alexander Hoffmann, the Thomas M. Asher Professor of Microbiology and director of the Institute for Quantitative and Computational Biosciences at UCLA. "We have identified some words in that language, and we know these words are important because of what happens when they are misused. Now we need to understand the meaning of the words, and we are making rapid progress. It's as exciting as when archaeologists discovered the Rosetta stone and could begin to read Egyptian hieroglyphs."

Immune cells in the body constantly assess their environment and coordinate their defense functions by using words -- or signaling codons, in scientific parlance -- to tell the cell's nucleus which genes to turn on in response to invaders like pathogenic bacteria and viruses. Each signaling codon consists of several successive actions of a DNA binding protein that, when combined, elicit the proper gene activation, in much the same way that successive electrical signals through a telephone wire combine to produce the words of a conversation.

The researchers focused on words used by macrophages, specialized immune cells that rid the body of potentially harmful particles, bacteria and dead cells. Using advanced microscopy techniques, they "listened" to macrophages in healthy mice and identified six specific codon-words that correlated to immune threats. They then did the same with macrophages from mice that contained a mutation akin to Sjgren's syndrome in humans to determine whether this disease results from the defective use of these words.

"Indeed, we found defects in the use of two of these words," Hoffmann said. "It's as if instead of saying, 'Respond to attacker down the street,' the cells are incorrectly saying, 'Respond to attacker in the house.'"

The findings, the researchers say, suggest that Sjgren's doesn't result from chronic inflammation, as long thought, but from a codon-word confusion that leads to inappropriate gene activation, causing the body to attack itself. The next step will be to find ways of correcting the confused word choices.

Many diseases are related to miscommunication in cells, but this study, the scientists say, is the first to recognize that immune cells employ a language, to identify words in that language and to demonstrate what can happen when word choice goes awry. Hoffman hopes the team's discovery will serve as a guide to the discovery of words related to other diseases.

"The macrophage is capable of responding to different types of pathogens and mounting different kinds of defenses. The defense units -- army, navy, air force, special operations -- are mediated by groups of genes," he said. "For each immune threat, the right groups of genes must be mobilized. That requires precise and reliable communication with those units about the nature of the threat. NFB dynamics provide the communication code. We identified the words in this code, but we don't yet fully understand how each defense unit interprets the various combinations of the codon-words."

And of course, calling up the wrong unit is not only ineffective, Hoffmann notes, but may do damage, as vehicles destroy roads, accidents happen and worse, as in the case of Sjogren's and, possibly, other diseases.

Then, using an algorithm originally developed in the 1940s for the telecommunications industry, they monitored which of the potential words tended to show up when macrophages responded to a stimulus, such as a pathogen-derived substance. They discovered that six specific dynamical features, or "words," were most frequently correlated with that response.

An analogy would be listening to someone in a conversation and finding that certain three-letter words tend to be used, such as "the," "boy," "toy," and "get," but not "biy" or "bey," said lead author Adewunmi Adelaja, who earned his Ph.D. in Hoffmann's laboratory and is now working toward his M.D. at UCLA.

The team then used a machine learning algorithm to model the immune response of macrophages. If they taught a computer the six words, they asked, would it be able to recognize the stimulus when computerized versions of cells were "talking?" They confirmed that it could. Drilling down further, they explored what would happen if the computer only had five words available. They found that the computer made more mistakes in recognizing the stimulus, leading the team to conclude that all six words are required for reliable cellular communication.

The scientists also used calculus to study the biochemical molecular interactions inside the immune cells that produce the words.

Hoffmann and his colleagues revealed in the journal Science in 2014 how and why the immune system's B cells respond only to true threats. In a study published in Cell in 2013, his team showed for the first time that it was possible to correct a cellular miscommunication involving the connection of receptors to genes during inflammation without severe side effects.

Reference:Adelaja A, Taylor B, Sheu KM, et al. Six distinct NFB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses. Immunity. 2021;54(5):916-930.e7. doi:10.1016/j.immuni.2021.04.011

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Researchers Decode the "Language" of Immune Cells - Technology Networks

Early identification of unique cell markers is expected to have valuable impact on patents, clinical efficacy, and manufacturing optimization

VANCOUVER, BC / ACCESSWIRE / May 11, 2021 / RepliCel Life Sciences Inc. (OTC PINK:REPCF)(TSXV:RP)(FRA:P6P2) ("RepliCel" or the "Company") is pleased to announce it has now signed and launched a new collaborative research project agreement with the University of British Columbia ("UBC") that enables the second stage of its cell marker research. The project is being co-led by RepliCel's Dr. Kevin McElwee and UBC's Professor Youwen Zhou.

The project commenced in 2017, is designed to deliver a gene and protein expression "map" of healthy hair follicle cells expected to be critically important to improving key components of the manufacturing, regulatory, and clinical profile of RepliCel's cell therapy products.

The initial stage of the study examined multiple cell types from human hair follicles to identify differences, and similarities, in gene and protein expression with the goal of finding markers of interest that would allow potential optimization in target cell isolation from the initial patient tissue biopsy as well as post-manufacturing final product formulation and correlation of specific cellular sub-populations to clinical efficacy. New patents filed around the discoveries made during this collaboration will accrete value to RepliCel's overall technology and product portfolio.

This second stage of the project specifically aims to confirm the presence and in situ localization of cells expressing unique markers selected from the initial project's indicative data and establish robust selection technologies and protocols for the use of the markers in cell isolation and manufacturing of RepliCel's proprietary tissue regenerative cell therapy products.

About Professor Youwen Zhou, M.D., Ph.D.

Dr. Youwen Zhou is a physician-scientist who is a Professor at UBC's Department of Dermatology and Skin Science. He received his BS degree from Nankai University, China, a PhD in Molecular Genetics from the State University of New York, and an MD degree from the University of Toronto. After completing dermatology specialty training at UBC, he joined UBC Faculty of Medicine as a physician-scientist in dermatology in 2000, and was promoted to full professor in 2013. He founded the UBC Molecular Medicine Lab and Chieng Genomics Center at Vancouver Coastal Health Research Institute (VCHRI) with infrastructure funding from the Canada Foundation for Innovation in 2001. Dr. Zhou's research is centered on biomarkers of skin diseases such as skin lymphoma, melanoma, and vitiligo, using a wide variety of methods and approaches, including genome-wide association studies (GWAS), linkage analysis, next generational sequencing, transcriptional profiling, cellular models, as well as genome editing.

Dr. Zhou has published more than 100 articles in journals such as Nature, Cell, Nature Genetics, and Blood, and holds multiple patents in skin lymphoma diagnostic biomarkers. In 2013, Dr. Zhou was awarded a Barney Usher Award for Outstanding Achievements in Dermatology Research from the Canadian Dermatology Association. Dr. Zhou specializes in the diagnosis and treatment of skin cancers and skin pigmentation disorders and is a consultant dermatologist at Vancouver General Hospital and British Columbia Cancer Agency. He teaches graduate students, medical students, dermatology residents, and postdoctoral fellows. Dr. Zhou is the past president of the Canadian Society of Investigative Dermatology and served as a board member for Canadian Institutes for Health Research (CIHR) Institute of Musculoskeletal Health and Arthritis (IMHA). He is also a grant reviewer for CIHR, the Canadian Dermatology Foundation, and the Natural Sciences Foundation of China.

About Dr. Kevin McElwee, Ph.D.

Dr. McElwee, co-discoverer of the Company's technology and co-founder of RepliCel, is a former Professor of Biomedical Sciences at the University of Bradford's Center for Skin Sciences. Previously, he was an Associate Professor in the Department of Dermatology and Skin Health at the University of British Columbia, and Director of the Hair Research Laboratory in the Vancouver Coastal Health Research Institute at Vancouver General Hospital. His research has been funded by competitive grants awarded by multiple organizations including the Canadian Institutes for Health Research (the equivalent of the National Institutes for Health in the USA).

Dr. McElwee is one of only a small group of research scientists worldwide who studies hair biology and associated diseases. He has worked as a hair research scientist for 25 years and has published over 120 medical journal articles and academic book chapters on hair loss research. Dr. McElwee received his Bachelor of Science degree from the University of Aberdeen, Scotland, and his PhD from the University of Dundee, Scotland. Postdoctoral training included three years at the Jackson Laboratory in Maine and four years at the University of Marburg, Germany, studying various hair loss diseases. Dr. McElwee continues to serve as the Company's Chief Scientific Officer.

About RepliCel Life Sciences

RepliCel is a regenerative medicine company focused on developing cell therapies for aesthetic and orthopedic conditions affecting what the Company believes is approximately one in three people in industrialized nations, including aging/sun-damaged skin, pattern baldness, and chronic tendon degeneration. These conditions, often associated with aging, are caused by a deficit of healthy cells required for normal tissue healing and function. These cell therapy product candidates are based on RepliCel's innovative technology, utilizing cell populations isolated from a patient's healthy hair follicles.

The Company's product pipeline is comprised of RCT-01 for tendon repair, RCS-01 for skin rejuvenation, and RCH-01 for hair restoration. RCH-01 is exclusively licensed in Asia to Shiseido Company. RepliCel maintains the rights to RCH-01 for the rest of the world. RCT-01 and RCS-01 are exclusively licensed in Greater China to YOFOTO (China) Health Company. RepliCel and YOFOTO are currently co-developing these products in China. RepliCel maintains the rights to these products outside of Greater China.

RepliCel has also developed a proprietary injection device, RCI-02, and related consumables, which is expected to improve the administration of its cell therapy products and certain other injectables. YOFOTO has exclusively licensed the commercial rights for the RCI-02 device and consumables in Greater China for dermatology applications and is expected to first launch the product in Hong Kong upon it being approved for market launch in either the United States or Europe.

Please visit http://www.replicel.com for additional information.

Notable Facts:

For more information, please contact: Lee Buckler, CEO and President info@replicel.com

SOURCE: RepliCel Life Sciences, Inc.

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RepliCel Launches the Next Stage of a Research Project with the University of British Columbia to Build World-Class Hair Follicle Cell Data Map -...