Category Archives: Molecular Medicine

image:Amanda Casey, Ph.D. (left), and Hillery F. Gray in the Orth lab. view more

Credit: UT Southwestern Medical Center

An enzyme called Fic, whose biochemical role was discovered at UTSouthwestern more than a dozen years ago, appears to play a crucial part in guiding the cellular response to stress, a new study suggests. The findings, published inPNAS, could eventually lead to new treatments for a variety of diseases.

We think that Fic acts like a thermostat that adjusts a cells response to stressors. If we could gain control of that thermostat and set it how we want in different tissues, we might someday be able to slow or even stop progression of some diseases, saidAmanda Casey, Ph.D., Assistant Professor of Molecular Biology and former postdoctoral fellow in theOrth labat UTSW. Dr. Casey co-led this study withKim Orth, Ph.D., Professor of Molecular Biology and a Howard Hughes Medical Institute Investigator.

Originally discovered in theVibrio parahaemolyticusbacteria known to cause food poisoning, Fic has been a longtime focus of the Orth lab. In 2009, Dr. Orth and her colleagues publishedthe first papershowing that Fic is involved in a process called AMPylation, in which this enzyme facilitates transfer of a phosphate and adenosine group to other proteins, changing their activity. The researchers soon discovered that animals ranging from worms to humans also have a Fic enzyme.

Research in fruit flies suggested that Fic appeared to be important for stress resilience and recovery. Apaperpublished in 2018 by Dr. Orth andDr. Helmut Krmer, Ph.D., Professor of Neuroscience and Cell Biology at UTSW, and colleagues showed that flies constantly exposed to bright light, which damages their eyes, suffered permanent harm if their Fic gene was deleted through genetic engineering. However, the role of this enzyme in mammals was unclear.

To answer this question, the researchers engineered a mouse model without a Fic gene. These animals were initially indistinguishable from littermates with Fic and appeared healthy. However, when the researchers fasted the animals for 14 hours and then allowed them to eat as much as they wanted for two hours a stressor for the pancreas, which controls blood sugar and produces key digestive enzymes blood work on the Fic-deficient animals showed a much higher stress response than the animals with Fic. Further investigation showed that a molecular pathway called the unfolded protein response (UPR) which becomes activated when stressed cells cant keep up with folding newly generated proteins was more strongly activated in the Fic-deficient animals.

The researchers made similar findings when the mouse models were dosed with a drug called caerulein, which acts on the pancreas to force an increased output of digestive enzymes. Although animals with Fic and those without developed pancreatitis, those without this enzyme had significantly worse disease, accompanied by a significantly stronger UPR.

Interestingly, although animals with Fic had a quick recovery, those without Fic developed permanent scarring in their pancreas a sign of significantly lower resilience to stress, Dr. Casey said.

Dr. Orth added that an uncontrolled cellular stress response and UPR play a role in many diseases including cancer, metabolic syndrome, atherosclerosis, retinal degeneration, and various neurodegenerative disorders.

If we can determine how the stress thermostat is set, we could adjust it up or down in various diseases where stress response is a factor, she said.

Other UTSW researchers who contributed to this study include Hillery F. Gray, Suneeta Chimalapati, Genaro Hernandez, Andrew Moehlman, Nathan Stewart, Hazel A. Fields, Burak Gulen, Kelly A. Servage, Karoliina Stefanius, Aubrie Blevins, Bret Evers, and Helmut Kramer.

This research was funded by grants from The Welch Foundation (I-1561), the Once Upon a Time Foundation, the National Institutes of Health (R35 GM130305 and EY10199), and a Life Sciences Research Foundation Fellowship.

Dr. Orth holds the Earl A. Forsythe Chair in Biomedical Science and is a W.W. Caruth, Jr. Scholar in Biomedical Research. She is a member of theHarold C. Simmons Comprehensive Cancer Center.

About UTSouthwestern Medical Center

UTSouthwestern, one of the nations premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in more than 80 specialtiesto more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

Proceedings of the National Academy of Sciences

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UTSW researchers identify key player in cellular response to stress - EurekAlert

The researchers found that the antibody reduced amyloid burden, eased neuron damage, and alleviated cognitive decline.

According to a team of researchers from the University of Texas Health Houston, a newly created agonistic antibody decreased amyloid pathology in mice with Alzheimers disease, indicating its promise as a possible treatment for the condition.

TREM2 TVD-lg, a tetra-variable domain antibody targeting the triggering receptor expressed on myeloid 2 (TREM2), decreased amyloid burden, eased neuron damage, and alleviated cognitive decline in mice with Alzheimers disease, according to research headed by senior author Zhiqiang An, Ph.D., professor and Robert A. Welch Distinguished University Chair in Chemistry at McGovern Medical School at UTHealth Houston. The study was recently published in the journal Science Translational Medicine.

Antibody-based therapy is a viable drug modality for the treatment of Alzheimers disease, said An, director of the Texas Therapeutics Institute with The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM). One of the major areas of focus at the Texas Therapeutics Institute is developing technologies to deliver antibody-based therapies across the blood-brain barrier for the potential treatment of the disease.

TREM2 is a single-pass receptor expressed by microglia, which are supporting cells in the central nervous system that serve as scavengers. Microglia are important in the removal of amyloids that form clusters surrounding amyloid-beta plaques, which are a hallmark of Alzheimers disease.

While prior research has indicated that TREM2 is crucial in the pathophysiology of Alzheimers disease, the new study suggests that raising TREM2 activation may have therapeutic benefits such as improved cognition.

By leveraging the unique antibody drug discovery capabilities at UTHealth Houston and collaborating with scientists with complementary expertise, we demonstrated the feasibility of engineering multivalent TREM2 agonistic antibodies coupled with TfR-mediated brain delivery to enhance microglia functions and reduce amyloid pathology in vitro and in vivo, said co-senior author Ningyan Zhang, Ph.D., professor at the Texas Therapeutics Institute at IMM at McGovern Medical School. This antibody engineering approach enables the development of effective TREM2-targeting therapies for AD.

Reference: A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimers disease by Peng Zhao, Yuanzhong Xu, LuLin Jiang, Xuejun Fan, Leike Li, Xin Li, Hisashi Arase, Yingjun Zhao, Wei Cao, Hui Zheng, Huaxi Xu, Qingchun Tong, Ningyan Zhang and Zhiqiang An, 7 September 2022, Science Translational Medicine.DOI: 10.1126/scitranslmed.abq0095

The study was funded by the Cancer Prevention and Research Institute of Texas and the Welch Foundation.

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New Antibody Demonstrates Therapeutic Benefits Against Alzheimers - SciTechDaily

Mount Sinai researchers have published one of the first studies to demonstrate the importance of reactive oxygen species in maintaining stem cell function and preventing inflammation during wound repair, which could provide greater insights into the prevention and treatment of inflammatory bowel diseases (IBD), according to findings published in the journal Gut on October 3.

Reactive oxygen species are highly reactive chemicals formed from oxygen. They serve as prime signals of cellular dysfunction that contribute to diseases. Secretion of reactive oxygen species in the intestine is necessary for maintaining stem cell function and important for wound repair; however, it can cause inflammatory effects as well. The Mount Sinai team found the key transcription factors driving abnormal stem cell changes, suggesting a significant role of reactive oxygen species in maintaining healthy intestines.

While its clear that regulation of oxygen and reactive oxygen species plays a critical role in chronic diseases generally, and IBD in particular, this study provides a major advance in defining the key role of oxygen species in maintaining a healthy epithelial barrier for IBD, said senior author Judy H. Cho, MD, Dean for Translational Genetics and Ward-Coleman Chair in Translational Genetics, and Vice Chair of Pathology, Molecular and Cell-Based Medicine at the Icahn School of Medicine at Mount Sinai.

The research team studied the role of reactive oxygen species and NOX1, the protein used to produce these chemicals, by examining single-cell gene expression in vitro and in vivo in mice models, as well as ex vivo in the form of human intestinal biopsies obtained following routine colonoscopies. They measured the amount of reactive oxygen species and analyzed the gene expression profile of intestine barrier cells from mice and human patients with a subtype of IBD known as ulcerative colitis. Intestine barrier cells cover the intestine surface and help to digest food, absorb nutrients, and prevent the invasion of gut bacteria. The Mount Sinai researchers compared gene expression data in both inflamed and uninflamed colon tissues.

The researchers found that a combination of NOX1, loss of functionwhich results in decreased reactive oxygen species, plus the presence of a substance known as TNF that causes inflammation leads to an abnormal increase of microfold cells. Microfold cells, also known as M cells, are crucial to regulating gut immune response. The research team found this abnormal increase in M cells, as a result of loss of reactive oxygen species, in stem cells in both the human and mice models. This increase in epithelial M cells drives increased recruitment of immune cells in mice. By treating intestine cells with reactive oxygen species, they were able to reverse the initial defect caused by losing reactive oxygen species during inflammation.

Reactive oxygen specifies released by stem cells are critical in maintaining a heathy gut via maintaining proper balance of intestine barrier cell types, said lead author Nai-Yun Hsu, PhD, Associate Scientist in the Judy Cho Laboratory. The researchers encourage further studies, which they said could include direct reactive oxygen species-stem cell modulation therapy to IBD patients in future treatments.

The University of Oxford in Oxford, United Kingdom, contributed to the research. The study was supported by funding from the National Institutes of Health and the Sanford J. Grossman Charitable Trust.

About the Mount Sinai Health System

Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.

Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report's Best Hospitals, receiving high Honor Roll status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Reports Best Childrens Hospitals ranks Mount Sinai Kravis Children's Hospital among the countrys best in several pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: It is consistently ranked in the top 20 by U.S. News & World Reports Best Medical Schools, aligned with a U.S. News & World Report Honor Roll Hospital, and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous basic and clinical research areas. Newsweeks Worlds Best Smart Hospitals ranks The Mount Sinai Hospital as No. 1 in New York City and in the top five globally, and Mount Sinai Morningside in the top 30 globally; Newsweek also ranks The Mount Sinai Hospital highly in 11 specialties in Worlds Best Specialized Hospitals, and in Americas Best Physical Rehabilitation Centers.

For more information, visit https://www.mountsinai.org or find Mount Sinai on Facebook, Twitter and YouTube.

NOX1 is essential for TNFa-induced intestinal epithelial ROS secretion and inhibits M cell signatures

3-Oct-2022

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Mount Sinai study uncovers mechanisms of reactive oxygen species in stem cell function and inflammation prevention - EurekAlert

About the position

The position is connected with the Norwegian research infrastructure for bioinformatics, ELIXIR Norway (http://elixir.no), which is a node in the pan-European infrastructure for bioinformatics. ELIXIR Norway is funded by The Research Council of Norway to enable safekeeping, use, and re-use of life science data for research and innovation. ELIXIR Norway is currently expanding its efforts into providing focused support towards open science research in biodiversity and precision medicine in Norway.

The postdoc position will focus on multi-omics analyses within precision medicine. The appointment has a duration of three years with no teaching duties. The postdoc position is available at the Department of Clinical and Molecular Medicine (IKOM) at the bioinformatics and gene regulation research group and the Bioinformatics core facility (BioCore) and will report to professor Pl Strom.

Duties of the position

The postdocs main responsibility will be on developing and implementing methods for multi-omics analyses in secure computational settings (HUNT Cloud, TSD, SAFE) and make such methods available and easily reusable within the ELIXIR infrastructure. This work will be done in the context of ongoing and new precision medicine projects at BioCore, where the postdoc will participate in planning experiments, managing and analysing data, and publishing and presenting results. Focus will be on projects involving diagnosis, prognosis, and patient stratification based on bulk, spatial and single cell omics data.

Requiredselectioncriteria

The appointment is to be made in accordance withRegulations on terms of employment for positions such as postdoctoral fellow, Ph.D Candidate, research assistant and specialist candidate.

Preferred selection criteria

Personal characteristics

Weoffer

Salary and conditions

As a Postdoctoral Fellow (code 1352) you are normally paid from gross NOK 563 500 per annum before tax, depending on qualifications and seniority. From the salary, 2% is deducted as a contribution to the Norwegian Public Service Pension Fund

The period of employment is 3 years (without teaching duties).

The engagement is to be made in accordance with the regulations in force concerningState Employees and Civil Servants, and the acts relating to Control of the Export of Strategic Goods, Services and Technology. Candidates who by assessment of the application and attachment are seen to conflict with the criteria in the latter law will be prohibited from recruitment to NTNU.

After the appointment you must assume that there may be changes in the area of work.

It is a prerequisite you can be present at and accessible to the institution on a daily basis.

About the application

The application and supporting documentation to be used as the basis for the assessment must be in English.

Publications and other scientific work must follow the application.Please note that applications are only evaluated based on the information available on the application deadline. You should ensure that your application shows clearly how your skills and experience meet the criteria which are set out above.

If, for any reason, you have taken a career break or have had an atypical career and wish to disclose this in your application, the selection committee will take this into account, recognizing that the quantity of your research may be reduced as a result.

The application must include:

If all,or parts,of your education has been taken abroad, we also ask you to attach documentation of the scope and quality of your entire education.Description of the documentation required can befoundhere. If you already have a statement from NOKUT,pleaseattachthisas well.

Joint works will be considered. If it is difficult to identify your contribution to joint works, you must attach a brief description of your participation.

In the evaluation of which candidate is best qualified, emphasis will be placed on education, experienceand personal and interpersonalqualities.Motivation,ambitions,and potential will also countin the assessment ofthe candidates.

NTNU is committed to following evaluation criteria for research quality according toThe San Francisco Declaration on Research Assessment - DORA.

General information

Working at NTNU

NTNU believes that inclusion and diversity is a strength. We want our faculty and staff to reflect Norways culturally diverse population and we continuously seek to hire the best minds. This enables NTNU to increase productivity and innovation, improve decision making processes, raise employee satisfaction, compete academically with global top-ranking institutions and carry out our social responsibilities within education and research. NTNU emphasizes accessibility and encourages qualified candidates to apply regardless of gender identity, ability status, periods of unemployment or ethnic and cultural background.

NTNU is working actively to increase the number of women employed in scientific positions and has a number ofresources to promote equality.

The city of Trondheimis a modern European city with a rich cultural scene. Trondheim is the innovation capital of Norway with a population of 200,000.The Norwegian welfare state, including healthcare, schools, kindergartens and overall equality, is probably the best of its kind in the world. Professional subsidized day-care for children is easily available. Furthermore, Trondheim offers great opportunities for education (including international schools) and possibilities to enjoy nature, culture and family life and has low crime rates and clean air quality.

As an employeeatNTNU, you mustat all timesadhere to the changes that the development in the subject entails and the organizational changes that are adopted.

A public list of applicants with name, age, job title and municipality of residence is prepared after the application deadline. If you want to reserve yourself from entry on the public applicant list, this must be justified. Assessment will be made in accordance withcurrent legislation. You will be notified if the reservation is not accepted.

If you have any questions about the position, please contact Professor Pl Strom, telephone +47 98203874, emailpal.satrom@ntnu.no. If you have any questions about the recruitment process, please contact HR advisor Vebjrn F. Andreassen, e-mail:vebjorn.andreassen@ntnu.no

If you think this looks interesting and in line with your qualifications, please submit your application electronically via jobbnorge.no with your CV, diplomas and certificates attached. Applications submitted elsewhere will not be considered.Upon request, you must be able to obtain certified copies of your documentation.

Application deadline:16.10.22

NTNU

NTNU - knowledge for a better world

The Norwegian University of Science and Technology (NTNU) creates knowledge for a better world and solutions that can change everyday life.

The Department of Clinical and Molecular Medicine (IKOM):

The Department of Clinical and Molecular Medicine (IKOM) is NTNUs largest department, with 450 employees. Our research and teaching help to improve treatment and health.

IKOM has expertise in basic, clinical and translational research within broad disciplinary areas. We study childrens and womens health, cancers, blood disorders and infectious diseases, gastroenterology, inflammation, metabolic disorders, laboratory sciences and medical ethics. The Department offers teaching in medicine at masters and PhD level. We also offer continuing education for employees in the health services.

Deadline16th October 2022EmployerNTNU - Norwegian University of Science and TechnologyMunicipalityTrondheimScopeFulltimeDuration ProjectPlace of service

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Postdoctoral Fellow in Bioinformatics job with NORWEGIAN UNIVERSITY OF SCIENCE & TECHNOLOGY - NTNU | 311073 - Times Higher Education

BRIDGEWATER, N.J., Oct. 3, 2022 /PRNewswire/ -- NovoPath LLC. (NovoPath), the leader in laboratory information systems (LIS), today announced the release of enhanced integrated workflows for genetic and molecular testing. With integrated workflows, NovoPath 360 makes it easier than ever for laboratories to produce comprehensive, easy to read diagnostic reports to power the advancements of precision medicine.

"By enabling labs to easily provide an array of tests and become their clients' single testing center, we're not only helping drive the advancements of precision medicine but giving labs a way to stay competitive in a consolidating market." Said Promise Okeke, CEO of NovoPath. "This release gives our clients a better way to provide care and interact with their clients"

NovoPath 360 Powers Precision Medicine by Bridging the Gap Between Pathologists and Oncologists

NovoPath 360 is bridging the gap between Pathologists and Oncologists by providing an enhanced SaaS-based LIS platform empowering diagnostic labs to effortlessly add molecular and genomic ancillary tests to anatomic workflows. Consequently, providing physicians comprehensive, easy to read reports that present the interpretation and impact of all tests in a single file. Additional NovoPath360 enhancements include:

"The future of diagnostics is molecular and as a LIS vendor need to create solutions that drive diagnostic laboratories to be better in communicating results AND help brainstorm predictive measures for patients" says Ed Youssef, Chief Strategy Officer at NovoPath. The team at NovoPath is doing so in many ways, including our most recent release."

About NovoPath LLC. (www.novopath.com)

NovoPath 360 is redefining how pathology laboratories operate. Our award-winning SaaS-based platform enables anatomic, clinical, and molecular pathology labs to automate, track, simplify and complete complex cases from hemes to derm faster than ever before. For over 25 years, we keep raising the bar with one-of-a-kind capabilities helping labs accession, diagnose and generate fully customizable reports. Hundreds of labs around the world are increasing case volume, reducing operating costs and establishing customer loyalty, enabling them for future growth.

See how the labs of tomorrow are operating with NovoPath at http://www.NovoPath.com

Contact:Dayna Carlin, Marketing Director1 732-329-3206[emailprotected]

SOURCE NovoPath LLC

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NovoPath Pushes the Limits of Laboratory Information Systems with Integrated Workflows for Genetic and Molecular Testing - PR Newswire

When exploring the history of the Joyce Murtha Breast Care Center and the Windber Research Institute now the Chan Soon-Shiong Institute for Molecular Medicine Windber you see numerous phenomena that contributed to the amazing technological capabilities that came together to produce such a world-class operation.

The following is a depiction of one such unlikely scenario that combined not only happenstance, but also serendipity and, Im sure, some divine intervention.

The key connector in this story was Gen. Joseph M. Cosumano, whose business card read something like this: Supreme Commander of the Worlds Air and Space Missile Defense Command for the United States Army.

Anyone seeing that title for the first time had to have been impressed and humbled. This individual was in charge of missile defense for not only the continental United States, but for the entire world.

As a breast cancer survivor, Gen. Cosumanos wife, Lydia, was a passionate advocate and supporter of the Clinical Breast Care Project and the work that then Dr. Col. Craig Shriver was undertaking at both the previous Walter Reed Army Hospital and the research institute and breast center in Windber.

She often spoke at the off-site retreats held by Shriver during which the scientists, physicians and staff of both facilities would be apprised of the current research and updated on new treatments and surgical procedures that were substantiated by the discoveries being made by the more than 100 Ph.D.s, doctors and clinical providers working in the program.

Because of Shrivers clinical relationship with Lydia Cosumano, he was invited to a holiday party at the Cosumano home, where he mingled among the guests, both civilian and military. It was during one of those casual interactions that Shriver introduced himself to a senior engineer who is now an honoree of the U.S. Air, Space and Missile Defense Distinguished Civilian Wall of Fame Jess Granone.

Granone was the director of the U.S. Army Space and Missile Defense Technical Center and, as the story goes, he casually said to Shriver, I am in charge of Star Wars.

That was the initiative that had been touted by President Ronald Reagan as a means of protecting the United States from a nuclear attack by any enemy.

After that brief introduction, Granone said to Shriver, What do you do?

At that point, Shriver replied, Im in charge of the Clinical Breast Care Project at Walter Reed.

That resulted in Granone taking a step back and becoming very serious while he explained to Shriver that his sister-in-law had recently died prematurely from breast cancer and how completely devastated the family was over this loss.

He went on to further explain that every day, he sat in front of multiple computer monitors watching simulations of a nuclear attack where hundreds of missiles were flying toward the United States, some with warheads and some as decoys.

He explained that the scientists and engineers under him were responsible for creating algorithms that would sort through the images of these missiles to attempt to determine which of them had the lethal-tipped hydrogen explosives.

This is when things became somewhat more intense.

Granone looked Shriver directly in the eye and said, I came to realize searching for these killer warheads was very much like what a radiologist must have been dealing with while exploring a digital mammography image.

After a short pause, he said, I will get as many of these algorithms declassified as possible and make them available to you for use in your research.

Months later, at a breast conference, the digital image of a mammogram was placed on a screen, and as the algorithms were applied to this image, unusual or potentially dangerous cells and lumps were identified.

Shriver and the teams at both Windber and Walter Reed went on to work with General Electric and the Space and Missile Defense Command in an attempt to perfect what was, in effect, a spell-check for mammography, a program that would double check the scan to ensure not even one malignant cell would be overlooked.

None of this, not one single part of this, could have been possible without the vision, commitment and dedication to our military that emanated from the late Rep. John P. Murtha.

At a ceremony recognizing an anniversary of the Windber Research Institute, when this program was explained, Murtha jokingly took a jab at one of his Republican friends by saying, Well, Im glad that trillion dollars from Star Wars finally resulted in something positive.

And indeed, positive it was as hundreds of thousands of breast cancer screens are now double-checked by the same algorithms used to find and stop nuclear missiles.

It was a partnership that will have a long-lasting impact.

Nick Jacobs, of Windber, is a health care consultant and author of the book Taking the Hell Out of Healthcare.

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Breast Cancer Awareness | Nick Jacobs | An unlikely partnership: The United States Army Space and Missile Defense Command and the Joyce Murtha Breast...

DALLAS Oct. 3, 2022 Expected to be diagnosed in 2% of men and 1% of women in the U.S., kidney cancer has traditionally been one of the most challenging cancers to treat. Until 2005, only one drug had been approved by the Food and Drug Administration (FDA) to treat kidney cancer, which is resistant to both chemotherapy and conventional radiation. Since then, discoveries about its biology have led to a flurry of targeted and immune therapies. But despite these advances, still today, most patients succumb to the disease once the cancer has spread.

Discovered at UTSouthwestern Medical Center (UTSW), theHIF2 protein is the most important driver of kidney cancer, which has traditionally been regarded as undruggable. UTSW scientists identified avulnerability in the HIF2 protein structure and identifiedchemicals blocking HIF2. Licensed to Peloton Therapeutics in the UTSW BioCenter, these chemicals set the foundation for the development of PT2977 (also called belzutifan), which receivedFDA approval for the treatment of hereditary kidney cancer in 2021, and is currently being evaluated against nonfamilial kidney cancer in multiple phase 3 clinical trials by Merck, which acquired Peloton.

However, studies inmice and subsequently inpatients have shown that kidney tumors develop resistance. Resistance arises as a result of mutations, including mutations that block the attachment of the drug to HIF2.

James Brugarolas, M.D., Ph.D.

For the last seven years, scientists in theBrugarolas lab at UTSW have partnered withArrowhead Pharmaceuticals to develop a second-generation inhibitor with activity not only against unmodified but also mutated HIF2. Using the sameplatform of patient tumors transplanted in mice that provided the first evidence ofanti-cancer activity by Pelotons HIF2 blocking drugs, the authors now showthat this second-generation drug is also active against kidney cancer. Proof of principle of activity is also provided in humans from thephase 1 trial led by James Brugarolas, M.D., Ph.D., Professor of Internal Medicine and Director of theKidney Cancer Program at theHarold C. Simmons Comprehensive Cancer Center of UTSW.

Like the FDA-approved Pfizer-BioNTech and Moderna COVID-19 vaccines, this second-generation HIF2 inhibitor (ARO-HIF2) is an RNA-based drug. ARO-HIF2 is a dsRNA drug that blocks the production of HIF2 in cancer cells. A particular advantage of ARO-HIF2 is the presence of a "homing device" that specifically targets it to cancer cells by interacting with a protein on their surface.

Downregulation of HIF2 by ARO-HIF2 in patient tumor biopsies. Courtesy of Dr. Payal Kapur

RNA-based medicines hold promise to treat many different diseases, as evidenced by a recent string of new FDA approvals. However, the unsolved challenge in cancer is delivery. Developing delivery systems to target tumor cells, something that was accomplished with ARO-HIF2, is an area of expanding research, said Daniel Siegwart, Ph.D., Associate Professor of Biochemistry at UTSW and a member of the Simmons Cancer Center.

These studies were supported by Arrowhead Pharmaceuticals as well as the National Cancer Institute through a Specialized Program of Research Excellence (SPORE) award. Dr. Brugarolas has previously served as a consultant for Arrowhead Pharmaceuticals and has several patent applications pertaining to HIF2.

Dr. Brugarolas holds The Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D. Dr. Siegwart holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research.

About UTSouthwestern Medical Center

UTSouthwestern, one of the nations premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in more than 80 specialtiesto more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

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Tackling resistance to HIF2 drugs with an RNA-based therapy - UT Southwestern

Saveetha Institute of Medical and Technical Sciences (SIMATS) organized the induction ceremony to welcome the Second batch of students who have joined the M.Tech/M.Sc programme in Molecular Medicine for the session 2022-24 was held recently.

Prof. (Dr) Suresh Kumar Rayala, Chairman of GATE/JAM and Professor Department of Biotechnology, IIT Madras, Chennai was the chief guest on the occasion. The Induction ceremony was felicitated by Dr. Sheeja Varghese, Registrar, SIMATS and Dr Aravind Kumar, Dean, Saveetha Dental College and Hospitals, Chennai.

SIMATS started this programme in 2021 for the first time in the state of Tamil Nadu. This course in Molecular Medicine is an interdisciplinary programme with an emphasis on 12 months of dissertation/research work. The programme expands upon the scientific and medical knowledge acquired in bachelor programmes and explores in-depth molecular aspects of medicine.

It should enable students to engage in independent and creative research at the crossroads of medicine and basic science. This year students from diverse fields including graduates and postgraduates in Medicine, Dentistry, Life sciences and Allied Health Sciences joined the programme.

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SIMATS organizes Induction Ceremony - Afternoonnews - Afternoon News

SOUTHLAKE, Texas--(BUSINESS WIRE)--OncoNano Medicine, Inc. today announced positive interim clinical results from an ongoing Phase 2 study of its lead clinical development candidate, pegsitacianine, for the detection of residual disease following cytoreductive surgery (CRS). Study results were presented by Patrick Wagner, MD, Department of Surgical Oncology, Allegheny Health Network Cancer Institute, during an oral presentation at the World Molecular Imaging Congress (WMIC) in Miami, FL on September 29th. The interim results from this trial provide evidence that pegsitacianine could offer surgeons a real-time optical imaging capability that enhances their ability to detect residual cancerous tissue that would otherwise be left behind from their standard of care process for cytoreductive surgery of peritoneal metastases.

We are encouraged by the Phase 2 study results for pegsitacianine in the detection of residual disease for both mucinous and non-mucinous metastatic nodules across multiple cancer types and look forward to further exploring the clinical utility of this novel molecular imaging agent in cancer surgery, said Patrick Wagner, MD, one of the lead investigators on the trial.

The Phase 2 study (NCT04950166) remains open to enrollment and is designed to evaluate the ability of pegsitacianine, a micellar fluorescence agent, to detect residual malignancies following CRS, an operation to completely resect peritoneal metastases. As an adjunct to tactile and visual cues for detecting residual disease, pegsitacianine may allow surgeons a more accurate evaluation of the completeness of surgery, or potentially to augment the results by removing additional lesions. A total of 27 patients were administered pegsitacianine at a dose of 1 mg/kg, proceeded to surgery with intra-operative imaging occurring between 24- and 72-hours post-dose, and completed pathology examination of resected specimens. The data presented revealed that 15 patients (55%) have demonstrated a clinically significant detection of pathology-confirmed residual disease following the completion of intended surgery. In this ongoing study, pegsitacianine continues to be well-tolerated with no observed drug-related serious adverse events. The most common adverse event observed with the use of pegsitacianine has been infusion-related reactions that have been mild to moderate and self-resolving.

About Pegsitacianine

Pegsitacianine is an intraoperative fluorescence imaging agent under development by OncoNano Medicine for the detection of cancerous tissue in patients undergoing surgical resection. Relying on an ultra pH-sensitive activation mechanism of OncoNanos ON-BOARD platform, pegsitacianine exists in a fluorescently dark Off state at physiological pH but transitions rapidly to a fluorescently On state in the presence of the elevated acidic tumor microenvironment. Pegsitacianines unique mechanism of action provides it with the potential for intraoperative near infrared imaging across a variety of solid tumor types. Pegsitacianine has previously been studied in Phase 1 and 2 clinical trials where breast, head and neck, colorectal, and esophageal cancers were successfully imaged following an intravenous dose of pegsitacianine.

About OncoNano Medicine

OncoNano Medicine is developing a new class of products that utilize principles of molecular cooperativity in their design to exploit pH as a biomarker to diagnose and treat cancer with high specificity. Our product candidates and interventions are designed to help patients across the continuum of cancer care and include solid tumor therapeutics, agents for real-time image guided surgery and a platform of immune-oncology therapeutics that activate and guide the bodys immune system to target cancer.

OncoNanos lead development candidate is pegsitacianine, a novel fluorescent nanoprobe using the ONBOARD platform, that is currently under study in Phase 2 clinical trials as a real-time surgical imaging agent for use in multiple cancer surgeries. ONM-501, OncoNanos second development program, is a next generation STING (STimulator of INterferon Genes) agonist that is advancing towards a first in human trial in the first half of 2023. Pegsitacianine and ONM-501 have been supported by grants received from the Cancer Prevention Research Institute of Texas. Learn more at http://www.OncoNano.com.

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OncoNano Medicine Announces Positive Phase 2 Data for Pegsitacianine as an adjunct to Cytoreductive Surgery of Peritoneal Carcinomatosis - Business...

Madeline Mayday, BS, a fourth-year Experimental Pathology graduate student in the Laboratory of Diane Krause, MD, PhD, was recently awarded a 2022 National Institute of Diabetes and Digestive and Kidney Diseases Hematology Centers Program Type B Pilot and Feasibility grant for her project entitled, Investigation of RBM15 and the m6A Epitranscriptome in Megakaryopoiesis.

The NIDDK is an institute within the National Institutes of Health. The NIDDK Hematology Centers Program provides a novel support mechanism for researchers to pursue new directions in benign hematology. The grants are designed to support innovative pilot research projects in benign hematology, including the generation of preliminary data for larger research grants.

Madeline is a PhD candidate in the Department of Pathology and is part of the Medical Research Scholars Program. She is originally from Muskoka, Ontario, and graduated with a BS in Cell and Molecular Biology from San Francisco State University. She then worked as a Research Associate at UCSF to develop a protocol for detection of pathogens causing respiratory failure in pediatric HSC transplant patients.

Madeline began her graduate studies in the Translational Molecular Medicine, Pharmacology and Physiology (TMMPP) program at Yale in Fall 2019 and joined the Krause Lab in May 2022 with an interest in translational research and hematopoiesis.

Submitted by Terence P. Corcoran on September 20, 2022

Link:
ExPath Grad Student Madeline Mayday Awarded Grant from the NIDDK Cooperative Centers of Excellence in Hematology - Yale School of Medicine