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Medicine accomplished a huge feat at the start of 2020, when researchers produced the first mRNA vaccine to protect humans from SARS-CoV-2 infection. It was certainly not new technologythe vaccine platform had been under development for more than a decade and tested against multiple diseases, from flu to rabies. It represents our rapidly advancing understanding of how the body manufactures proteins, the molecules that are coded for by our genes. The potential to manipulate the very blueprints that our cells use to build the molecules and cells at the heart of disease is undoubtedly a game changer. Beyond vaccines, researchers have been devising treatments for cancer, lymphoma, AIDS, cystic fibrosis, and more, aided by new gene-editing technology, as physician Carolyn Barber (see How Designer DNA Is Changing Medicine) profiles in this collection. The next generation of lifesaving treatments may be manufactured right in our own bodies.

Such genetic advancements are being hyped as a way for prospective parents to screen their embryos for future diseasesbut the technology might not be ready for primetime, as genetic counselor Laura Hercher writes (see A New Era of Designer Babies May Be Based on Overhyped Science). And as always we have updates on the latest COVID newsfrom breakthrough infections (see Breakthrough Infections Do Not Mean COVID Vaccines Are Failing) to a surprising COVID risk (see People with COVID Often Infect Their Pets). Heres to your health, now and in the future!

This article was originally published with the title "The Blueprints of Health" in SA Health & Medicine 3, 5, (October 2021)

Andrea Gawrylewski is the collections editor at Scientific American.

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LEBANON, NH Patients with abnormal variants (mutations) in the DPYD gene are known to be at risk for severe toxicity from treatment with 5-fluorouracil or capecitabinechemotherapies commonly used to treat colorectal cancer, as well as pancreatic, breast, gastroesophageal and other cancers. But previous studies have not reported the extent to which these DPYD gene variants are linked to fatal chemotherapy toxicity, as fatal toxicity is rare in any individual study. Pooling studies is needed to examine the association of DPYD gene variants with this severe outcome.

In a meta-analysis of previously published studies, researchers at Dartmouths and Dartmouth-Hitchcocks Norris Cotton Cancer Center (NCCC), led by Gabriel A. Brooks, MD, MPH, found that uncommon variants in the DPYD gene, present in 4% of all cancer patients, were associated with a 25-times increased risk of fatal toxicity after treatment with standard doses of either chemotherapy drug. The absolute risk of fatal toxicity was 0.1% in patients without DPYD gene variants, and as high as 3.7% in patients with any of the three most severe DPYD gene variants.

The teams study, Pathogenic DPYD variants and treatment-related mortality in patients receiving fluoropyrimidine chemotherapy: A systematic review and meta-analysis, is newly published online in The Oncologist.

Though DPYD and other gene testing has been recommended by the European Medicines Agency since spring of 2020, gene testing is not widely done in the US before patients are administered chemotherapy with 5-fluorouracil or capecitabine. Brooks study suggests that adding pre-treatment screening may help prevent avoidable chemotherapy-related deaths without interrupting standard of care, as most patients who carry abnormal gene variants can still be treated with reduced doses of these chemotherapies. NCCC has already implemented routine screening for DPYD gene variants in most gastrointestinal cancer patients.

US organizations such as the Food & Drug Administration (FDA), the American Society of Clinical Oncology, or the National Comprehensive Cancer Network should consider recommending this testing. The FDA is currently considering a citizens petition advocating for more widespread genetic testing, of which I am a cosigner, says Brooks.

* * *

Gabriel A. Brooks, MD, MPH, is a medical oncologist in the Gastrointestinal Oncology Program and member of the Cancer Population Sciences Research Program at Dartmouths and Dartmouth-Hitchcocks Norris Cotton Cancer Center, and assistant professor of medicine at the Geisel School of Medicine at Dartmouth. His research focuses on systematic approaches to improving the delivery of safe and effective cancer care, with an emphasis on gastrointestinal cancers. @gabe_a_brooks

* * *

About Norris Cotton Cancer CenterNorris Cotton Cancer Center, located on the campus of Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH, combines advanced cancer research at Dartmouth Colleges Geisel School of Medicine in Hanover, NH with the highest level of high-quality, innovative, personalized, and compassionate patient-centered cancer care at DHMC, as well as at regional, multi-disciplinary locations and partner hospitals throughout NH and VT. NCCC is one of only 51 centers nationwide to earn the National Cancer Institutes prestigious Comprehensive Cancer Center designation, the result of an outstanding collaboration between DHMC, New Hampshires only academic medical center, and Dartmouth College. Now entering its fifth decade, NCCC remains committed to excellence, outreach and education, and strives to prevent and cure cancer, enhance survivorship and to promote cancer health equity through its pioneering interdisciplinary research. Each year the NCCC schedules 61,000 appointments seeing nearly 4,000 newly diagnosed patients, and currently offers its patients more than 100 active clinical trials.

About the Geisel School of MedicineFounded in 1797, the Geisel School of Medicine at Dartmouth strives to improve the lives of the communities it serves through excellence in learning, discovery, and healing. The Geisel School of Medicine is renowned for its leadership in medical education, healthcare policy and delivery science, biomedical research, global health, and in creating innovations that improve lives worldwide. As one of Americas leading medical schools, Dartmouths Geisel School of Medicine is committed to training new generations of diverse leaders who will help solve our most vexing challenges in healthcare.

About Dartmouth-Hitchcock HealthDartmouth-Hitchcock Health (D-HH), New Hampshires only academic health system and the states largest private employer, serves a population of 1.9 million across northern New England. D-H provides access to more than 2,000 providers in almost every area of medicine, delivering care at its flagship hospital, Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH. DHMC was named again in 2020 as the #1 hospital in New Hampshire by U.S. News & World Report, and recognized for high performance in 9 clinical specialties and procedures. Dartmouth-Hitchcock also includes the Norris Cotton Cancer Center, one of only 51 NCI-designated Comprehensive Cancer Centers in the nation; the Children's Hospital at Dartmouth-Hitchcock, the states only childrens hospital; affiliated member hospitals in Lebanon, Keene, and New London, NH, and Windsor, VT, and Visiting Nurse and Hospice for Vermont and New Hampshire; and 24 Dartmouth-Hitchcock clinics that provide ambulatory services across New Hampshire and Vermont. The D-H system trains nearly 400 residents and fellows annually, and performs world-class research, in partnership with the Geisel School of Medicine at Dartmouth and the White River Junction VA Medical Center in White River Junction, VT.

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Pathogenic DPYD variants and treatment-related mortality in patients receiving fluoropyrimidine chemotherapy: A systematic review and meta-analysis

10-Sep-2021

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Rare gene mutations lead to greatly increased risk of fatal chemotherapy toxicity - EurekAlert

ZURICH-SCHLIEREN, Switzerland and LAGUNA HILLS, Calif., Sept. 23, 2021 /PRNewswire/ -- DiNAQOR, a genetic medicine platform company focused on addressing severe inherited cardiac diseases, today announced it has expanded its leadership team by appointing veteran medical device leader Mark Dehdashtian to serve as Executive Vice President, Medical Devices.

Mark Dehdashtian, EVP, Medical Devices, DiNAQOR

As the company grows its U.S. footprint, Mr. Dehdashtian will oversee DiNAQOR's newly formed medical device division including its new manufacturing facility based in Laguna Hills, Calif. He will be responsible for the design, development, and production of genetic medicine delivery devices for the Company's localized, catheter-based multi-organ access platform.

"Mark brings to DiNAQOR the expertise that comes from 30 years of developing innovative medical devices that change patients' lives, and bringing them to market," said Johannes Holzmeister, M.D., Chairman and CEO of DiNAQOR. "We are thrilled to have a real leader in this area take on this important role, especially at such an exciting time for our company."

Mr. Dehdashtian led a distinguished 25-year career at Edwards Lifesciences, where he served in several senior-level positions, including Vice President of Research and Development for the Heart Valve Therapy, Advanced Technology and Cardiac Surgery Systems divisions. At Edwards, Mr. Dehdashtian designed the delivery systems for transcatheter heart valves and was instrumental in commercializing the transcatheter heart valve transapical systems. He holds more than 60 U.S. patents as well as many international patents, most notably for the design of the transcatheter heart valve, and his work has been published in several peer-reviewed journals. Mr. Dehdashtian has served as a member of medical technology steering committees to develop industry-wide standards.

"My career has been devoted to developing and bringing game-changing technologies to patients," commented Mr. Dehdashtian. "DiNAQOR's organ access platform is a real innovation in administering genetic medicines, and gene therapies in particular, that can improve the standard of care for patients. I'm excited to be a part of this, and to help DiNAQOR grow its U.S. presence."

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DiNAQOR's localized, catheter-based organ access platform enables gene therapies to be routed directly to the cardiac muscle, maximizing biodistribution and transduction of the cardiac cells. This new minimally invasive approach, which is actively being used in several pre-clinical studies, may minimize potential adverse effects of systemic gene therapy delivery while lowering the total dose of vectors and thus the cost. DiNAQOR is also developing the platform for other organs.

"A device-based approach to gene therapy holds the promise of minimizing exposure to the viral vector, thereby enhancing both the safety and efficacy of our therapy," said Valeria Ricotti, M.D., Chief Medical Officer of DiNAQOR. "Our aim is to treat a broader population of patients while avoiding the kind of systemic side effects that have caused a number of clinical programs to be put on hold."

About DiNAQOR

DiNAQOR is a genetic medicine platform company focused on advancing novel solutions for patients suffering from severe, inherited forms of heart disease. The company is headquartered in Zurich-Schlieren, Switzerland, with additional presence in London, England; Hamburg, Germany; Laguna Hills, California; and Boston, Massachusetts. For more information visit http://www.dinaqor.com.

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KWM CommunicationsKellie Walsh914-315-6072kwalsh@kwmcommunications.com

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DiNAQOR Appoints Medical Device Leader Mark Dehdashtian to Oversee New U.S.-Based Division, Device Development and Production - Yahoo Finance

NEW YORK and RESEARCH TRIANGLE PARK, N.C., Sept. 23, 2021 (GLOBE NEWSWIRE) -- Sio Gene Therapies Inc. (NASDAQ: SIOX), a clinical-stage company focused on developing gene therapies to radically improve the lives of patients with neurodegenerative diseases, announced today that the company will participate in select upcoming investor and scientific conferences. Details can be found below.

Cantor Fitzgerald Global Healthcare Conference

Chardan Genetic Medicines Conference

Alliance for Regenerative Medicine: Cell & Gene Meeting on the Mesa

About Sio Gene TherapiesSio Gene Therapies combines cutting-edge science with bold imagination to develop genetic medicines that aim to radically improve the lives of patients. Our current pipeline of clinical-stage candidates includes the first potentially curative AAV-based gene therapies for GM1 gangliosidosis and Tay-Sachs/Sandhoff diseases, which are rare and uniformly fatal pediatric conditions caused by single gene deficiencies. We are also expanding the reach of gene therapy to highly prevalent conditions such as Parkinsons disease, which affects millions of patients globally. Led by an experienced team of gene therapy development experts, and supported by collaborations with premier academic, industry and patient advocacy organizations, Sio is focused on accelerating its candidates through clinical trials to liberate patients with debilitating diseases through the transformational power of gene therapies. For more information, visit http://www.siogtx.com.

Contacts:

Media Josephine Belluardo, Ph.D. LifeSci Communications(646) 751-4361jo@lifescicomms.cominfo@siogtx.com

Investors and AnalystsParag V. MeswaniSio Gene Therapies Inc.Chief Commercial Officerinvestors@siogtx.com

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Sio Gene Therapies to Participate in Upcoming Conferences - GlobeNewswire

DetailsCategory: More NewsPublished on Tuesday, 21 September 2021 18:32Hits: 653

BASEL, Switzerland I September 21, 2021 I Novartis today announced that it has acquired Arctos Medical, adding a pre-clinical optogenetics-based AAV gene therapy program and Arctos proprietary technology to its ophthalmology portfolio. The acquisition underscores the Novartis commitment to finding treatments for patients with vision loss and the potential of optogenetics as the basis of successful therapeutics.

Optogenetics is emerging as a promising therapeutic approach that might restore sight to patients who are legally blind, said Jay Bradner, President of the Novartis Institutes for BioMedical Research. The Arctos technology builds on our conviction that optogenetic gene therapies may meaningfully help patients battling devastating eye diseases.

Arctos developed its technology as a potential method for treating inherited retinal dystrophies (IRDs) and other diseases that involve photoreceptor loss, such as age-related macular degeneration (AMD). Existing gene therapy treatments aim to correct a specific gene, so only a small subset of patients can benefit. The Arctos technology is not limited to a specific gene, and thus can potentially address many forms of IRDs regardless of the underlying mutation. Arctos proprietary, light-sensitive optogene is delivered to specific retinal cells using gene therapy, thus turning the targeted cells into replacement photoreceptor-like cells. If successful, a therapeutic based on such a technology could be used to treat any disease that causes blindness due to photoreceptor death.

Weve watched this technology develop and mature into a therapeutic program that complements our existing portfolio and gives us new optogenetics technology to wield in our efforts to bring desperately needed therapeutic options to patients for these blinding diseases, said Cynthia Grosskreutz, Global Head of Ophthalmology at the Novartis Institutes for BioMedical Research.

IRDs, which impact more than 2 million people globally and often result in complete blindness, can be caused by mutations in over 100 different genes.1 AMD is the leading cause of visual disability, affecting an estimated 170 million people globally.2 There are no curative therapies currently available for AMD.

The Arctos technology was based on discoveries by its scientific co-founders Drs. Sonja Kleinlogel and Michiel van Wyk of University of Bern, Switzerland. Arctos was originally incubated by +ND Capital and was later supported by Novartis Venture Fund through a Series A financing round led by +ND Capital.

About NovartisNovartis is reimagining medicine to improve and extend peoples lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the worlds top companies investing in research and development. Novartis products reach nearly 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 109,000 people of more than 140 nationalities work at Novartis around the world. Find out more athttps://www.novartis.com.

Novartis is on Twitter. Sign up to follow @Novartis at https://twitter.com/novartisnewsFor Novartis multimedia content, please visit https://www.novartis.com/news/media-libraryFor questions about the site or required registration, please contact This email address is being protected from spambots. You need JavaScript enabled to view it.">This email address is being protected from spambots. You need JavaScript enabled to view it.

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Nwamaka Eneanya, MD, MPH, an assistant professor of Medicine and Epidemiology, has been a vocal advocate for the removal of race from the kidney function algorithm and is a member of the joint task force that generated the new clinical recommendations.

A national task force announced Thursday that it is recommending the immediate implementation of a new diagnostic equation for measuring kidney function, which advocates say will promote health equity and increase access to transplantation for Black patients. The recommendation is supported by ongoing research from clinical researchers in the Perelman School of Medicine at the University of Pennsylvania, who have played a critical role in quantifying the benefits and risks of abandoning race in kidney function estimation. The clinical change, which is anticipated to go into effect at Penn Medicine this year, was identified as a key priority for the health systems Action for Cultural Transformation (ACT) strategic plan that launched in 2020.

My hope is that this change will spearhead a movement across all of medicine for clinicians to reevaluate whether they are using race responsibly, said Nwamaka Eneanya, MD, MPH, a nephrologist, an assistant professor of Medicine and Epidemiology, and director of Health Equity, Anti-Racism, and Community Engagement in the Division of Renal-Electrolyte and Hypertension at Penn.

Eneanya has been a vocal advocate for the removal of race from the kidney function algorithm and is a member of the joint task force of the American Society of Nephrology and the National Kidney Foundation, which generated the recommendations. She is also a co-author on a paper published this week in the New England Journal of Medicine (NEJM), which introduces new equations for measuring kidney function that do not include race. A second NEJM paper published this week co-led by Harold Feldman, MD, MSCE, a professor of Epidemiology and Medicine at Penn recommends that, as a more long-term solution, national efforts should be made to increase the widespread use of the protein cystatin C as a biomarker of kidney health.

Because the direct measurement of kidney function is infeasible at the bedside, clinicians instead evaluate its level using an estimating equation called eGFR, which stands for estimated glomerular filtration rate. eGFR estimates how much creatinine is in a patients blood to give a picture of how well their kidneys are working. Its value is an important part of the information used to determine if and when a patient is referred to some types of clinical care, including kidney transplantation.

The problem, critics of the current equation say, is that it assigns a higher eGFR to patients who self-identify as Black. This means that Black patients must reach a higher creatinine level than white patients to be put on the kidney transplant waitlist.

In a widely-cited opinion piece published in JAMA in 2020, Penn Medicine researchers argued that it is harmful for eGFR equations to assert that existing organ function is different between individuals who are otherwise identical except for race. They write that population studies reveal only small differences in gene distributions between racial groups, and that the history of medicine offers abundant evidence that racial categories were often generated arbitrarily and at times implemented to reinforce social inequality.

The piece authored by Eneanya, along with Peter Reese, PhD, MD, MSCE, a professor of Medicine and Epidemiology, and Wei Yang, PhD, an associate professor of Biostatistics helped to spark a national conversation about removing race from the kidney function algorithm. In response, the American Society of Nephrology and the National Kidney Foundation created a joint task force to reassess the inclusion of race in eGFR, as well as its implications for diagnosis and subsequent management of patients with kidney diseases.

The task forces final report recommends that U.S. clinical laboratories immediately implement a newly refit CKD-EPI creatinine equation that does not incorporate race information. This new equation has acceptable performance characteristics and potential consequences that do not disproportionately affect any one group of individuals, the authors say.

However, the task force report also notes that there should be long-term national efforts to increase the routine and timely measurement of cystatin C, rather than or in addition to creatinine, to estimate kidney function. This is because as data from 1,248 patients in the Chronic Renal Insufficiency Cohort (CRIC) Study published in the NEJM paper co-authored by Feldman shows estimating GFR using cystatin C generates similar results to estimates based on creatinine and race while eliminating the negative consequences of todays race-based approaches. Currently, Feldman says, cystatin C tests are costly and less readily available at hospitals and other clinical laboratories around the country.

While increasing access to cystatin C-based lab tests will be an important future step in the nephrology field, the removal of race from the eGFR algorithm is a major milestone toward advancing health equity, according to Eneanya and the authors of the joint task force report.

Penn Medicineis one of the worlds leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of theRaymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nations first medical school) and theUniversity of Pennsylvania Health System, which together form a $8.9 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according toU.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $496 million awarded in the 2020 fiscal year.

The University of Pennsylvania Health Systems patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Centerwhich are recognized as one of the nations top Honor Roll hospitals byU.S. News & World ReportChester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nations first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 44,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2020, Penn Medicine provided more than $563 million to benefit our community.

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Backed by Penn Medicine Research, National Task Force Recommends Removing Race from Kidney Function Equation - pennmedicine.org

Researchers at Johns Hopkins Medicine have discovered how a set of proteins work in tandem to build the vascular supply lines that deliver oxygen and nutrients to tumors, enabling them to survive and grow. The studies, in human cancer cells and mouse models, showed that the protein pair, peptidylarginine deiminase 4 (PADI4) and hypoxia-inducible factor 1 (HIF-1), ramp up their activity under low-oxygen conditions that are typically found in a fast-growing tumor, to allow the formation of new blood vessels that feed the cancers growth. The researchers say their findings provide new possible avenues for developing anticancer therapies that interfere with blood vessel development.

The discovery gives us an opportunity to find combinations of existing or new drugs that target these pathways to treat cancer and prevent drug resistance, stated research lead Gregg Semenza, MD, PhD, the C. Michael Armstrong professor of genetic medicine, pediatrics, oncology, medicine, radiation oncology, and biological chemistry at the Johns Hopkins University School of Medicine. Semenza and colleagues reported on their study in Science Advances, in a paper titled, Histone citrullination by PADI4 is required for HIF-dependent transcriptional responses to hypoxia and tumor vascularization.

Reduced oxygen availability (hypoxia) is a characteristic feature of the tumor microenvironment, the authors explained. Rapid responses to hypoxia are critical to maintain cellular viability, and the HIF system is poised to respond. In response to oxygen deficit, HIFs activate the transcription of hundreds of genes that play key roles in angiogenesis, metabolic reprogramming, extracellular matrix remodeling, invasion and metastasis, cancer stem cell specification, and immune evasion. The molecular mechanism by which HIFs activate transcription is an area of active investigation.

Semenza serves as director of the vascular program at the Johns Hopkins Institute for Cell Engineering, and shared the 2019 Nobel Prize in Physiology or Medicine for the discovery of how HIF-1 controls the ability of cells to adapt to low oxygen levels. His lab and others have found that HIF-1 activates more than 5,000 genes under low-oxygen conditions. However, it was unclear precisely how HIF-1 turned on those genes to spur blood vessel growth.

Within the cell, DNA is negatively charged, which allows it to interact with positively charged proteins called histones. The DNA is wound like a spool of thread around the histones when it is not being used. Specifically, Semenza said, PADI4 incites a reaction that causes the histones to lose their positive charge, allowing the DNA to unwind. A less well-known posttranslational modification of histones that decreases their net positive charge is the hydrolysis of arginine (Arg) residues to citrulline (Cit), which is catalyzed by the peptidylarginine deiminases PADI2 and PADI4, the team further noted.

To explore the partnership between HIF-1 and PADI4, the researchers studied human breast cancerincluding triple negative breast cancer (TNBC)and liver cancer (hepatocellular carcinoma; HCC cells) grown in the laboratory. The team first interfered with the cells ability to produce PADI4, and then exposed the cells to low oxygen conditions for 24 hours. By analyzing gene activity within these cells, the researchers found that 87% of the 1,300 genes turned on by HIF-1 in response to hypoxia were not turned on in cells lacking PADI4 protein. The results, they said, demonstrate that PAD14 expression is induced by hypoxia in a HIF-dependent manner in breast and liver cancer cell lines and that, in turn, PAD14 is required for activation of HIF target gene transcription RNA sequencing revealed that almost all HIF target genes in breast cancer cells are PADI4 dependent.

The researchers then injected the cancer cells into the breast tissue of mice and tracked tumor growth. Tumors without PADI4 were five times smaller and developed five times fewer blood vessels compared with tumors formed from cells with normal levels of PADI4. This showed that in a living organism, elimination of PADI4 impaired the tumors ability to grow. The findings in mice, the researchers said, allow them to tie together studies from human cancers where higher HIF-1 activity in patients primary tumor biopsies correlates with higher rates of mortality.

In this study, we have identified a previously unidentified regulatory feature in which HIF-dependentPADI4 gene transcription and HIF-dependent recruitment of PADI4 to target genes leads to increased HIF occupancy of HREs [hypoxia responsive elements], histone citrullination, additional histone modifications, and transcriptional activation, the team concluded. They pointed out that the high level of PAD14 expression in breast and liver cancer contrasts with its expression in normal human tissues, which is restricted to bone marrow and spleen. Further studies are required to identify the oncogenic switch that is responsible for PADI4 gene expression in breast and liver cancers, they wrote. both HIF-1 and PADI4 expression are correlated with breast and liver cancer vascularization and patient mortality. And with the relative lack of effective therapies for patients with TNBC or advanced HCC, The current study suggests that pharmacologic inhibition of HIF and/or PADI4 activity may represent novel therapeutic strategies for these patients.

The investigators further noted that because both HIF-1 and PAD14 overexpression are associated with patient mortality in other cancers, further studies are warranted to determine whether this pathway plays an important role different tumor types. Semenza concluded, The more we know about the cellular ecosystem of cancer, the better shot we have at controlling it.

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Protein Pair Promote Vascularization of Breast and Liver Tumors: Suggest Potential Therapeutic Targets - Genetic Engineering & Biotechnology News

1Medical School, Southeast University, Nanjing, Peoples Republic of China; 2Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Peoples Republic of China

Background: Sepsis is the leading cause of death in critically ill patients. Although it is well known that the immune system plays a key role in sepsis, exactly how it works remains unknown.Methods: In our study, we used weighted gene co-expression network analysis (WGCNA) to screen out the immune-related genes that may play a critical role in the process of sepsis.Results: A total of three sepsis-related hub genes were screened for further verification. Subsequent analysis of immune subtypes suggested their potential predictive effect in the clinic.Conclusion: Our study shows that three immune-related genes CHMP1A, MED15 and MGAT1 are important biomarkers of sepsis. The screened genes may help to distinguish normal individuals from patients with different degrees of sepsis.

Sepsis is the leading cause of death in critically ill patients, accounting for 3050% of hospital mortality in the United States.13 From the perspective of pathophysiology, sepsis occurs with complex pro-inflammatory and anti-inflammatory process disorders, further leading to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS).47 Although a variety of interventions are currently available for the treatment of sepsis, the lack of targeted drugs leads to limited overall clinical efficacy.810 In addition, the complexity and variability of sepsis make it hard to grasp its severity, so early prediction of sepsis progression will be particularly important in guiding treatment.11,12

Biomarkers are increasingly being used to predict the pathophysiological characteristics of diseases, including sepsis.1315 However, the predictive function of most sepsis-related biomarkers is limited, and it is urgently needed to explore high-efficiency biomarkers in clinical practice. To the best of our knowledge, sepsis is a heterogeneous, life-threatening syndrome that coexists with multiple diseases.7 The innate immune system is the first line of defense against infection when sepsis occurs, and it often collaborates with adaptive immune responses to protect the host. Genetic differences among different individuals contribute to the diversity of immune responses to sepsis.16 This is partly due to the fact that the quantitative characteristics of pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) interactions are not similar across all patients.17 The interaction between PAMPs and PRRs results in the production and subsequent release of pro-inflammatory and anti-inflammatory mediators, coordinating the clinical state of the host. And immune cells are direct participants in this response. Therefore, based on this premise, it is of potential value to search for immune-related markers in the process of sepsis for disease prediction.

With the rapid development and application of gene chip technology, weighted gene co-expression network analysis (WGCNA) is gradually used to analyze the molecular mechanism and network relationships of disease.18,19 Obviously, this revolutionary technological advance allows the search for biomarkers of sepsis at genetic level to guide clinical practice. In our study, we used WGCNA to screen out the immune-related genes that may play a critical role in the process of sepsis. We screened out promising immune-related candidate biomarkers of sepsis in which highly correlated genes clustered. From this perspective, the hub genes we screened also provide us with the possibility to better understand the mechanism and occurrence of sepsis.

We downloaded the GEO database to analyze the gene expression profiles of sepsis. Inclusion criteria: (1) the whole-genome expression profiling of whole blood of sepsis patients or healthy control samples were available in the datasets; (2) no less than 15sepsis samples and/or 15 healthy control samples were included in each dataset. Exclusion criteria: (1) a history of treatment prior to sample collection; (2) a clear risk of systemic disease in the control group. In our study, we downloaded the gene expression profiles of sepsis GSE54514 and GSE63042 for further analysis. GSE54514 and GSE63042 contained 53 (normal: 18; sepsis: 35) and 129 (normal: 23; sepsis: 106) samples, respectively.

We used WGCNA package in R to establish the co-expression network based on the profile of differentially expressed genes (DEGs).20 Furthermore, we performed sample clustering to plot the sample tree and detect outliers.

We used STRING (search tool for the retrieval of interacting genes/proteins) database for GO Enrichment and KEGG pathway analysis. P < 0.05 was considered as the cut-off value of enriched GO terms and KEGG pathway.

Pearsons correlation of module membership >0.2 and P < 0.05 was used to evaluate the connectivity of hub modules. Furthermore, hub module genes were carried out to establish a proteinprotein interaction (PPI) network. Finally, we obtained the real hub genes in the overlapping part of this PPI network.

CIBERSORT is a deconvolution algorithm that converts normalized gene expression matrix into components of infiltrating immune cells. During CIBERSORT calculations, we quantified the abundance of specific cell types in whole blood and verified CIBERSORT results by fluorescent-activated cell sorting (FACS). P value <0.05 of CIBERSORT output was defined as more accurate prediction of immune cell composition. Then, the samples satisfying the constraints were further analyzed.

GSE63042 data set was used for WGCNA analysis, and key modules and their genes were selected. The GSE54514 data set was classified, and immune infiltration analysis was conducted to explore the differences in the proportion of immune cells in individuals with three different states. Finally, the correlation between the biomarkers and immune cells was calculated and the credibility of the correlation was verified by significance analysis. We examined the expression of real hub genes in these samples. P value <0.05 was considered statistically significant.

Heat-maps were conducted by using the R software. Statistical analyses were conducted with the R package. P value <0.05 was considered statistically significant.

The gene was divided into dozens of modules, and the co-expression matrix was established. The minimum number of genes in each gene module was set to 50, and a total of 32 modules were aggregated (Figure 1A). Grey defaults were genes that could not be classified into any modules, further merging the previous 32 modules into 13 (Figure 1B).

Figure 1 Modular clustering and its analysis correlation with clinical characteristics. (A) Module cluster tree diagram. (B) Cluster dendrogram. (C) Moduletrait relationships.

Correlation analysis was conducted between gene modules and clinical features, and the selected clinical features were the severity of the disease. During the analysis, phenotypic traits were transformed into quantitative traits (0 represents normal samples; the disease ranges from 1 to 4, with a higher value indicating a more severe disease). Among the 13 co-expression modules, MEdarkturquoise had the maximal relevance to sepsis (Figure 1C).

The R software cluster Profiler package was used for enrichment analysis to find the common functions and related pathways in differentially expressed gene set. Through enrichment analysis of the 901 hub module genes obtained above, the bubble chart of top 10 term related to biological processes (BP) was obtained (Figure 2).

Figure 2 The bubble diagram of BP-related TOP10 term obtained by GO enrichment of HUB module gene.

We analyzed the protein network interaction relationship of 901 module genes (confidence = 0.7) and obtained 410 hub genes. We selected the top 10 proteins and used Cytoscape software to beautify the protein network, and screened out the proteins with the top 10 proteins and extended to the outer layer (Figure 3).

Figure 3 The protein interaction network of key genes.

We selected a total of four gene sets: 410 PPI hub genes, 68 key genes of hub module and the set of two DEGs. The intersection of these four gene sets was used to obtain the biomarkers of this study. Finally, three biomarkers were selected from the intersection part, namely CHMP1A, MED15 and MGAT1 (Figure 4).

Figure 4 Screening of biomarkers.

In order to explore whether these three genes have an impact on survival and death of patients, we collated the data of these two datasets into different groups and visualized their significance through box plots. The disease samples were divided into survival and non-survival samples (normal samples were not used). MED15 gene had a significant effect on survival and death in GSE54514 dataset (Figure 5A). CHMP1A and MGAT1 gene had a significant effect on survival and death in GSE63042 dataset (Figure 5B).

Figure 5 Analysis of the relationship between biomarkers and survival. (A) The significance of biomarkers on survival in the GSE54514 dataset. (B) Significant effect of biomarkers on survival in the GSE63042 dataset.

We calculated the correlation coefficient between the expression of all genes and CHMP1A gene, and performed gene set enrichment analysis (GSEA) according to the sequence of correlation coefficient, which was not enriched in the pathway but enriched to 9 GO terms (Figure 6A). One of the immune-related GO was visualized separately (Figure 6B).

Figure 6 Single-gene GSEA enrichment analysis of biomarkers. (A) GO term bubble image: CHMP1A single gene GESA enrichment. (B) GO myeloid leukocyte mediated immunity (CHMP1A). (C) GO term bubble image: MED15 single gene GESA enrichment. (D) GO term bubble image: MGAT1 single gene GESA enrichment. (E) GO myeloid leukocyte mediated immunity (MGAT1).

We calculated the correlation coefficient between the expression of all genes and MED15 gene, and performed GSEA according to the sequence of correlation coefficient, which was not enriched in the pathway but enriched to 7 GO terms (Figure 6C).

We calculated the correlation coefficient between the expression of all genes and MGAT1 gene, and performed GSEA according to the sequence of correlation coefficient, which was not enriched in the pathway but enriched to 46 GO terms (Figure 6D). One of the immune-related GO was visualized separately (Figure 6E).

In our study, 21 immune cells in the samples were screened out by using CIBERSORT algorithm and LM22 gene marker. Among these immune cells, T cells CD4 memory activated, T cells regulatory (Tregs), NK cells, macrophages (M0), mast cells and neutrophils had most significant differences in the proportion of normal/survival/non-survival individuals (Figure 7).

Figure 7 Immune cell infiltration in normal/living/dead individuals.*P<0.05, **P<0.01,***P<0.001.

Abbreviation: ns, not significant.

The above three biomarkers were used for correlation analysis of each immune cell. CHMP1A gene was positively correlated with T cells CD4 naive and macrophages (M2) but negatively correlated with macrophages (M0) and T cells CD8 (Figure 8A). MED15 gene was positively correlated with mast cells activated and T cells CD4 naive but negatively correlated with macrophages (M0) and neutrophils (Figure 8B). MGAT1 gene was positively correlated with T cells CD4 nave and monocytes but negatively correlated with neutrophils and T cells CD8 (Figure 8C).

Figure 8 Correlation analysis between biomarkers and immune cells. (A) Correlation diagram of CHMP1A gene and immune cells. (B) Correlation diagram of MED15 gene and immune cells. (C) Correlation diagram of MGAT1 gene and immune cells.

Early prediction of sepsis biomarkers is important for effective clinical intervention.21 In our study, WGCNA was used to explore the pathological process and marker genes in whole blood samples of sepsis. After data preprocessing and weighted gene network construction, the modules were associated with feature and function enrichment analysis. According to the module recognition heat-map and scatter diagram, the module related to sepsis onset was turquoise module (p < 0.05). Finally, we selected three sepsis-related biomarkers: CHMP1A, MED15 and MGAT1.

Chromatin modifying protein 1A (CHMP1A) is a member of the endosomal sorting complex required for transport (ESCRT-III) family found in both cytoplasmic and nuclear matrix fractions, which identified as roles of chromatin modification, fundamental proteins required for multivesicular sorting in eukaryotes and regulation of cell-cycle progression.22,23 To the best of our knowledge, CHMP1A is encoded by PRSM1 gene and found in mitotic chromosome scaffold and nuclear matrix.2426 Over-expression of CHMP1A interferes with nuclear structure and DNA replication, etc.23 Recent studies showed that CHMP1A acts as a tumor suppressor through the p53 signaling pathway in human embryonic kidney and ductal pancreatic tumor cells.27,28 Subsequently, some scholars further discovered that CHMP1A plays a role of regulating the proliferation and differentiation of retinal progenitor cells.22 For the first time, our analysis suggested that CHMP1A is associated with sepsis and is positively associated with T cells CD4 nave and macrophages (M2), but a strong negative correlation with macrophages (M0) and T cells CD8.

The mediator complex is a four module transcriptional co-activator among eukaryotes, in which the tail module primarily recruits multiple transcriptional regulators to the transcription unit.29,30 As one of the tail subunits, MED15 acts as a linker between regulatory proteins and RNA polymerase II.3133 Abnormal expression of MED15 is associated with a variety of human malignant tumors. The expression of MED15 was up-regulated to varying degrees in different parts of head and neck squamous cell carcinoma tissue.34,35 In addition, compared with androgen-sensitive prostate cancer (PCA) and benign tissue, MED15 was over-expressed in approximately 70% of locally recurrent and distantly metastatic castrated resistant PCA.36 Some scholars indicated that the degree of malignancy of renal cell carcinoma was significantly reduced by knocking down MED15.29 For the first time, our study proved that MED15 is significantly involved in the immune regulation process of sepsis. MED15 has a strong positive correlation with mast cells activated and T cells CD4 naive, but a strong negative correlation with macrophages (M0) and neutrophils.

MGAT1 is a microsomal enzyme that catalyzes the synthesis of diacylglycerol (DAG) and triacylglycerol (TAG).37,38 Mammalian TAG synthesis occurs in two ways, with the MGAT mentioned directly catalyzing the synthesis of DAG by monoacylglycerol via an alternative pathway. Finally, the action of DGAT1 or DGAT2 converts DAG to TAG.39 In addition, MGAT1 is a novel transcriptional target of Wnt/-Catenin signaling pathway. This signaling pathway plays a key role in controlling tumor progression.4042 From this perspective, MGAT1 functions in promoting the synthesis of triglycerides and the development of tumors. Our study indicated that MGAT1 has a strong positive correlation with T cells CD4 naive and monocytes but a strong negative correlation with neutrophils and T cells CD8.

Many scholars have attempted to find a group of biomarkers to better identify patients with sepsis at adverse risk. However, none of the biomarkers can fully reflect the potential deterioration of the disease in patients with sepsis. Currently, the three best predictors of sepsis are IL-1 receptor antagonist (IL-1ra), protein C and neutrophil gelatinase associated lipocalin (NGAL).43 Each of them may serve as a potential biomarker for sepsis, either as an anti-inflammatory protein (IL-1ra), an important component of coagulation (protein C), or as a marker of organ damage (NGAL). However, it is difficult to predict whether these three biomarkers are superior to traditional biomarkers.

Genome-wide association studies (GWASs) have provided valuable insights by pinpointing associations to both innate and adaptive immune response loci, as well as novel unexpected risk factors for infection susceptibility.44,45 Recently, some scholars used WGCNA to screen regulatory factors related to sepsis, and finally found that transcription factors CEBPB and ETV6 were the main regulatory factors.46 Meanwhile, our study provided effective biomarkers for the prediction of sepsis progression, and we found that CHMP1A, MED15 and MGAT1 play an important role in the prediction and immune response state of sepsis.

We visualized the samples and screened out 21 types of immune cells. Among them, T cells CD4 memory activated, T cells regulatory (Tregs), NK cells, macrophages (M0), mast cells and neutrophils had most significant differences in the proportion of normal/survival/non-survival individuals. We speculated that the analyzed genes may distinguish between normal individuals and patients with varying degrees of sepsis. From another perspective, new therapeutic approaches of sepsis by rebalancing multiple immune cell subset homeostasis may become potential targeted therapies. The limitation of this study is that we did not conduct an experimental study. Therefore, a further study on immune cells can identify ideal immunotherapy targets and improve the autoimmune regulation ability of patients with sepsis.

In conclusion, our study is the first to discover the predictive role of CHMP1A, MED15 and MGAT1 in the immunologic process of sepsis through WGCNA. The screened genes may help to distinguish normal individuals from patients with different degrees of sepsis.

The datasets used or analysed during the current study are available at: http://www.ncbi.nlm.nih.gov/ geo.

All authors have agreed to publish this article.

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work.

National Natural Science Foundation of China (No. 82070669).

Dr Cheng Qu is now affiliated at General Surgery Department, Drum Tower Hospital, Nanjing University. The authors declare that they have no competing interests.

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Novel biomarkers of sepsis occurrence and progression | IJGM - Dove Medical Press

Newswise ROCHESTER, MN September 23, 2021 AANEM is pleased to announce Michael S. Cartwright, MD, MS is the winner of the 2021 Jun Kimura Outstanding Educator Award. This award is characterized by a members significant contributions relating to neuromuscular and electrodiagnostic medicine education, whether that be serving as a faculty member at the annual meetings or providing educational opportunities outside of AANEM.

Dr. Cartwright is currently a Professor of Neurology, Neuromuscular Fellowship Director, and MDA Clinic Director. He has been a member of AANEM since 2004. Dr. Cartwright has been a practicing neurologist/physiatrist for more than 15 years and has made many significant contributions, including helping with more than 85 peer-reviewed papers, reviewing more than 25 journals, and editing two textbooks. Dr. Cartwright has also helped organize Wake Forests NM US Workshop, typically held in June of each year.

Dr. Cartwright enjoys educating and working in this subspecialty because of the variety. I enjoy doing clinic, EMG sessions, educational events, research, and patient advocacy, he says. Through the years, patient stories have impacted Dr. Cartwright. One development, in particular, has changed his outlook on how he practices medicine. In the past several years, Dr. Cartwright begins, the development of genetic therapies has been absolutely incredible. We can now effectively treat spinal muscular atrophy, a condition that had no medications fewer than five years ago. In May 2021, we began universal newborn screening for SMA in all children born in North Carolina. In early June 2021 the first positive test occurred. I was able to prescribe gene therapy for this child within weeks of birth, which has the potential to completely alter her clinical course.

For Dr. Cartwright, there are two aspects of educating he finds most rewarding. I really enjoy it when a medical student has an aha! moment, especially when it pertains to neurology, he states. And it is great to hear from previous fellows. They sometimes call with tough cases, but after talking through the case with them, it is clear they have a very deep understanding of their patient and really did not need my assistance. That is quite rewarding to an educator.

Dr. Cartwright will be awarded with the Jun Kimura Outstanding Educator Award on Friday, October 15, 2021, at the AANEM Annual Meeting in Aurora, Colorado. His academic interests include running EMG sessions, educational events, and participating in research and patient advocacy.

He adds that this award is particularly meaningful to him as his mentor, Dr. Francis O. Walker, was trained directly under Jun Kimura, MD, for who this award is named.

###

About AANEM

The American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) is a nonprofit membership association dedicated to the advancement of neuromuscular (NM), musculoskeletal (MSK), and electrodiagnostic (EDX) medicine. For more information about AANEM, visit http://www.aanem.org or find us on Facebook and Twitter.

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Michael S. Cartwright, MD, MS Awarded the Jun Kimura Outstanding Educator Award From AANEM - Newswise

TORONTO, Sept. 22, 2021 /CNW/ - Vertex Pharmaceuticals Incorporated(Canada)(Nasdaq: VRTX) today announced its Supplement to a New Drug Submission for PrKALYDECO (ivacaftor) has been accepted for priority review by Health Canada for the treatment of cystic fibrosis (CF) in patients from 4 months to 18 years of age and weighing at least 5 kg with the R117H mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

"We are pleased this submission has been accepted for Priority Review by Health Canada, and we hope that this will enable access for patients with the R117H mutation as soon as possible," said Duncan McKechnie, Senior Vice President, North America Commercial Operations, Vertex Pharmaceuticals."It's our goal to ensure as many people as possible with cystic fibrosis are able to access treatments for the underlying cause of their CF."

About Cystic Fibrosis

Cystic fibrosis (CF) is a rare, life-shortening genetic disease affecting more than 80,000 people globally. CF is a progressive, multi-system disease that affects the lungs, liver, GI tract, sinuses, sweat glands, pancreas and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in theCFTRgene. Children must inherit two defectiveCFTRgenes one from each parent to have CF. While there are many different types ofCFTRmutations that can cause the disease, the vast majority of all people with CF have at least oneF508delmutation. These mutations, which can be determined by a genetic test, or genotyping test, lead to CF by creating non-working and/or too few CFTR proteins at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the early 30s.

About KALYDECO (ivacaftor)

Ivacaftor is the first medicine to treat the underlying cause of CF in people with specific mutations in theCFTRgene. Known as a CFTR potentiator, ivacaftor is an oral medicine designed to keep CFTR proteins at the cell surface open longer to improve the transport of salt and water across the cell membrane, which helps hydrate and clear mucus from the airways.

AboutVertex

Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has multiple approved medicines that treat the underlying cause of cystic fibrosis (CF) a rare, life-threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational small molecule medicines in other serious diseases where it has deep insight into causal human biology, including pain, alpha-1 antitrypsin deficiency and APOL1-mediated kidney diseases. In addition, Vertex has a rapidly expanding pipeline of cell and genetic therapies for diseases such as sickle cell disease, beta thalassemia, Duchenne muscular dystrophy and type 1 diabetes mellitus.

Founded in 1989 inCambridge, Mass., Vertex's global headquarters is now located inBoston'sInnovation District and its international headquarters is inLondon. Additionally, the company has research and development sites and commercial offices inNorth America,Europe,AustraliaandLatin America. Vertex is consistently recognized as one of the industry's top places to work, including 11 consecutive years on Science magazine's Top Employers list and a best place to work for LGBTQ equality by the Human Rights Campaign.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements made by Duncan McKechnie in this press release, including expectations for patient access to our medicine. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that the New Drug Submission to Health Canada may not be approved in the expected timeline, or at all, that data from the company's development programs may not support registration or further development of its compounds due to safety, efficacy or other reasons, and other risks listed under the heading "Risk Factors" in Vertex's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission at http://www.sec.gov and available through the company's website at http://www.vrtx.com. You should not place undue reliance on these statements. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

SOURCE Vertex Pharmaceuticals Incorporated (Canada)

Originally posted here:
Vertex's Supplement to a New Drug Submission for KALYDECO (ivacaftor) for Patients with Cystic Fibrosis Between the Ages of 4 Months and 18 Years with...