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Adding anti-clotting drugs to stroke care ineffective, clinical trial finds

Stroke patients who survive a blood clot in the brain’s blood vessels are prone to developing new blockages during their recovery periods, even if they receive vessel-clearing interventions. In an effort to avoid further clots, doctors at 57 sites around the U.S. tested a possible solution: the addition of anti-coagulant drugs to medicine that dissolves blood clots.

But results from the clinical trial, led by Opeolu Adeoye, MD, head of the Department of Emergency Medicine at Washington University School of Medicine in St. Louis, indicate two such drugs did not improve outcomes.

The findings are available Sept. 4 in The New England Journal of Medicine.

“We’re a little disappointed in the results,” said Adeoye, who is also the BJC HealthCare Distinguished Professor of Emergency Medicine. “But it’s meaningful to optimal patient care that we’ve answered the question definitively. Neither of the drugs helps prevent further clots.”

The goal of the Multi-arm Optimization of Stroke Thrombolysis (MOST) clinical trial that Adeoye led was to test the efficacy of adding argatroban, a blood thinner, or eptifibatide, which inhibits blood platelets from sticking together, to the routine intravenous thrombolysis treatment.

The trial closed the chapter on this potential use of these medications, but Peter Panagos, MD, professor of emergency medicine and co-author on the study, said that efforts like these inform future advances in medicine, including potential new anti-coagulant treatments.

“Without negative trials, we would not know how to design new trials,” Panagos said. “Future success is built upon the hard work of previous research effort.”

Physicians do not have a lot of treatment options for patients who experience a stroke. Some patients undergo a procedure to remove the clot. Others receive intravenous thrombolysis to relieve the affected blood vessel through clot-dissolving medication delivered to the bloodstream. A number of patients receive both interventions.

“Even with those treatments, over half of patients still have a significant disability three months after their stroke,” said Adeoye, who treats patients at Barnes-Jewish Hospital and Missouri Baptist Medical Center and also provides stroke telemedicine consultation. “After you give the thrombolysis, the clot can re-form, which contributes to the stroke worsening or persisting.”

Preventing these clots with an additional treatment of anti-coagulant drugs seemed like a promising idea, especially as there are FDA-approved medications that earlier studies had suggested could be effective.

In the MOST trial, patients were randomly assigned to receive either argatroban, eptifibatide or placebo. Adeoye explained that the study had checkpoints built in to ensure that treatment outcomes were meeting efficacy thresholds in order to continue. The first checkpoint was set at 500 patients, which the team reached in 2023.

“When we looked at the data, it was readily apparent that neither drug was going to come anywhere close to our threshold,” he said.

In fact, the probability that either drug was helpful was less than 1%. Worse still, argatroban and eptifibatide were linked to greater incidences of disability and mortality within the three-month post-treatment observation window.

This correlation was not necessarily alarming; the safety monitors on the project found that the deaths appeared to have causes unrelated to the medications. The lack of improvement noted with the medications compared with what was noted with the placebo was reason enough to call off the trial.

There are more options to pursue in seeking to improve stroke outcomes. Adeoye said there are drugs in development that target different parts of the blood coagulating and clotting processes that may prove to be more effective than argatroban or eptifibatide, and other procedures such as direct arterial delivery through which such drugs might be more effective.

Panagos, who directs the new Section of Neurologic Emergencies in the Department of Emergency Medicine, added that WashU Medicine’s leadership in trials such as this one benefits the 1,700 stroke patients who are treated by WashU Medicine physicians at Barnes-Jewish Hospital every year.

“Because we are involved in and lead most of the key basic science and clinical research for stroke and cerebrovascular patients nationally and internationally, we can bring the latest interventions to our patients in St. Louis and help advance treatment and prevention strategies,” Panagos said. “Our involvement in clinical trials helps bring the highest quality, most innovative treatments to our community.”

Novel immunotherapy improves recovery from spinal cord injury

Severe injuries to the spinal cord damage nerve cells, disrupt communication with the brain and rest of the body, and lead to lasting disabilities for millions of people worldwide. The injury itself accounts for only a fraction of the overall damage inflicted on the spinal cord, tissue that runs from the brain stem to the lower back. Most of the damage is due to subsequent degenerative processes at the wound.

While there is substantial research into developing interventions to repair injured tissue, scientists at Washington University School of Medicine in St. Louis focused instead on developing, in mice, an immunotherapy to minimize the damage from traumatic spinal cord injury. Their findings show that immunotherapy can lessen such damage by protecting neurons at the injury site from being attacked by immune cells.

The study, published Sept. 4 in Nature, demonstrates success in mice given the immunotherapy and presents a novel approach with potential to help improve outcomes for people recovering from spinal cord injuries.

“Immune cells in the central nervous system have a reputation for being the bad guys that can harm the brain and spinal cord,” said senior author Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology and a BJC Investigator at WashU Medicine. “But our study shows that it’s possible to take advantage of immune cells’ neuroprotective function, while controlling their inherent detrimental abilities, to help in the recovery from central nervous system injury.”

The blood vessels and drainage network in a mouse’s brain are outlined in blue and green, and dotted with clumps of the Alzheimer’s protein amyloid beta (red).Learn more about neuroimmunology research at WashU Medicine

Shortly after injury to the nervous system, immune cells flood the site. Among them is a mixture of activated T cells – a subset of immune cells – that either harm or protect the surrounding neurons. Wenqing Gao, PhD, a postdoctoral research associate in the Department of Pathology & Immunology and the study’s first author, analyzed T cells from the spinal cords of injured mice and performed a genetic analysis to decode their identities. Her goal was to separate the harmful from the protective T cells and create numerous copies of the beneficial cells with which to treat the injured mice.

But there was a catch, she found. The protective T cells that swoop into the injury site can mistakenly attack the body’s surrounding tissues when activated for too long, causing autoimmune disease. To improve the therapy’s safety, Gao modified the cells to shut off after a few days.

Mice given the modified T cells had better mobility than did the untreated mice. The researchers saw the biggest improvements when the mice were infused with T cells within a week of the injury. None of the mice receiving immunotherapy developed a destructive autoimmune reaction.

“There are no effective treatments for traumatic injuries to the central nervous system,” explained Gao. “We developed immunotherapy for such injuries by taking advantage of the protective immune cells that infiltrate the injury site and found that it dramatically improved mobility in mice.”

In collaboration with WashU Medicine’s Wilson Zachary Ray, MD, a spinal cord surgeon and the Henry G. & Edith R. Schwartz Professor of Neurosurgery, the researchers also looked every day for a week for T cells in the cerebral spinal fluid of patients with spinal cord injuries. They found a significant expansion of the T cells, confirming the feasibility of expanding protective T cells from such patients to generate the immunotherapy.

“Our future goal is to devise a clinical trial to test the therapy in people with such injuries, while expanding this work to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) as well as Alzheimer’s and Parkinson’s diseases,” Gao said.

Added Kipnis: “Although the initial trigger in neurodegenerative diseases is different, the subsequent death of neurons may very well be mediated by similar processes, opening an opportunity for adapting our engineered cells for use as a therapy in neurodegeneration.”

Groves named head of developmental biology

Noted developmental biologist Andy Groves, PhD, has been named head of the Department of Developmental Biology at Washington University School of Medicine in St. Louis. He studies the intricate, step-by-step processes that lead to the development of the inner ear, with the goal of better understanding the ear’s workings and spurring new treatments for hearing loss. Groves’ appointment will begin April 7.

Groves comes to WashU Medicine from Baylor College of Medicine in Houston, where he is the Vivian L. Smith Endowed Chair in Neuroscience and a professor in the departments of Neuroscience and Molecular & Human Genetics. His appointment was announced by David H. Perlmutter, MD, executive vice chancellor for medical affairs, the George and Carol Bauer Dean of the School of Medicine, and the Spencer T. and Ann W. Olin Distinguished Professor.

“I am so pleased to announce that Andy Groves will be the next head of the Department of Developmental Biology at WashU Medicine,” Perlmutter said. “Our leadership team is deeply impressed by his scientific accomplishments, vision and enthusiasm. We believe he can take the reins of a department that has made myriad significant contributions to the field of developmental biology and propel our faculty and students into the next era of this very important field, from traditional areas of organ and tissue development to aging, as well as the burgeoning fields of regeneration and reprogramming.”

Groves’ research, continuously funded by the National Institutes of Health (NIH) for the past 25 years, focuses on how tiny hair cells in the inner ear develop as an embryo grows, and play a critical role in hearing and balance. When damage – caused by aging, noise exposure and other influences – leads to hair cell loss, any remaining cells cannot regenerate to create new ones. For that reason, their destruction can lead to permanent hearing loss. Groves has used cell reprogramming to change the pattern of gene expression in mature hair cells, promoting the developmental processes that otherwise shut off after birth.

Groves’ research to understand the molecular underpinnings of inner ear development and regeneration may help fine-tune potential gene therapy solutions for hearing loss – a condition that affects over 1.5 billion people. For his expertise in hair cell regeneration, he is often sought out by foundations and societies supporting hearing loss research. He also is a member of the Advisory Council for the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health (NIH).

“I am honored to join WashU Medicine as the new head of the Department of Developmental Biology,” Groves said. “I am excited by the opportunity to recruit and mentor new faculty members to this amazing institution and continue the department’s 100-year record of achievement. In addition to uncovering the fascinating processes of animal development, my new colleagues in the department are making fundamental discoveries relevant to human disease, degeneration and aging. WashU has a strong culture of collaborative research, and I look forward to helping build new collaborations between our department and other departments and centers at WashU and beyond.”

Groves is actively involved in mentoring the next generation of scientists. Recognized as a superb mentor, he has served on numerous graduate students’ advisory committees and is the director of Baylor’s Development, Disease Models & Therapeutics graduate program.

Groves earned his bachelor’s degree from Cambridge University in the United Kingdom before completing his doctoral studies at the Ludwig Institute for Cancer Research in London. After postdoctoral fellowships at the California Institute of Technology in Pasadena, Calif., he started a laboratory at the House Ear Institute in Los Angeles with an academic appointment in the Department of Otolaryngology at the University of Southern California. In 2008, he joined Baylor’s faculty.

Perlmutter also announced that Groves’ wife, Joanna Jankowsky, PhD, will join the WashU Medicine faculty. She is a professor in Baylor’s Department of Neuroscience and also holds a Vivian L. Smith Endowed Chair. Jankowsky studies how aging and genetics impact the risk of developing Alzheimer’s disease. She will join WashU Medicine’s Department of Neuroscience.

Groves will succeed Lila Solnica-Krezel, PhD, who has led the department since 2010. An Alan A. and Edith L. Wolff Distinguished Professor, Solnica-Krezel will continue her research at WashU Medicine, where she studies tiny, transparent zebrafish as a model system to glean insights into human health and development.

“Lila truly has been a transformational leader for the Department of Developmental Biology and the Center for Regenerative Medicine since she took the helm,” Perlmutter said. “An extraordinarily dedicated scientist and a forward-thinking member of the university community, she also has made an indelible impact on positive developments at WashU Medicine through her work with colleagues on the Executive Faculty.”

Multiple sclerosis appears to protect against Alzheimer’s disease

People with multiple sclerosis (MS) are far less likely than those without the condition to have the molecular hallmarks of Alzheimer’s disease, according to new research from Washington University School of Medicine in St. Louis.

The discovery suggests a new avenue of research through which to seek Alzheimer’s treatments, said Matthew Brier, MD PhD, an assistant professor of neurology and radiology and the study’s first author.

“Our findings imply that some component of the biology of multiple sclerosis, or the genetics of MS patients, is protective against Alzheimer’s disease,” Brier said. “If we could identify what aspect is protective and apply it in a controlled way, that could inform therapeutic strategies for Alzheimer’s disease.”

The study, an example of clinical observations directly impacting research, was published in the Annals of Neurology.

A collaboration between WashU Medicine experts in Alzheimer’s and MS, the study was prompted by a suspicion Brier’s mentor and collaborator Anne Cross, MD, had developed over decades of treating patients with MS, an immune-mediated disease that attacks the central nervous system. Although her patients were living long enough to be at risk of Alzheimer’s or had a family history of the neurodegenerative disease, they weren’t developing the disease.

“I noticed that I couldn’t find a single MS patient of mine who had typical Alzheimer’s disease,” said Cross, the Manny and Rosalyn Rosenthal and Dr. John Trotter MS Center Chair in Neuroimmunology. “If they had cognitive problems, I would send them to the memory and aging specialists here at the School of Medicine for an Alzheimer’s assessment, and those doctors would always come back and tell me, ‘No, this is not due to Alzheimer’s disease.’”

Cognitive impairment caused by MS can be confused with symptoms of Alzheimer’s disease; Alzheimer’s can be confirmed with blood and other biological tests.

To confirm Cross’ observation, the research team used a new, FDA-approved blood test that was developed by Washington University researchers. Known as PrecivityAD2, the blood test is highly effective at predicting the presence of amyloid plaques in the brain. Such plaques are an indicator of Alzheimer’s disease and previously only could be verified with brain scans or spinal taps.

Brier, Cross and their colleagues recruited 100 patients with MS to take the blood test, 11 of whom also underwent PET scans at the School of Medicine’s Mallinckrodt Institute of Radiology. Their results were compared with the results from a control group of 300 individuals who did not have MS but were similar to those with MS in age, genetic risk for Alzheimer, and cognitive decline.

“We found that 50% fewer MS patients had amyloid pathology compared to their matched peers based on this blood test,” Brier said. This finding supported Cross’ observation that Alzheimer’s appeared to be less likely to develop among those with MS. It is not clear how amyloid accumulation is linked to the cognitive impairment typical of Alzheimer’s, but the accumulation of plaques is generally understood to be the first event in the biological cascade that leads to cognitive decline.

The researchers also found that the more typical the patient’s MS history was, in terms of age of onset, severity and overall disease progression, the less likely they were to have amyloid plaque accumulation in that patient’s brain compared with those with atypical presentations of MS. This suggests there is something about the nature of MS itself that is protective against Alzheimer’s disease, which Brier and Cross are planning to investigate.

MS patients generally have multiple flare-ups of the illness over the course of their lifetimes. During these flare-ups, the immune system attacks the central nervous system, including within the brain. It’s possible that this immune activity also reduces amyloid plaques, the researchers said.

“Perhaps when the Alzheimer’s disease amyloid pathology was developing, the patients with MS had some degree of inflammation in their brains that was spurred by their immune responses,” Brier said. Referring to work by co-author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology, Brier noted that activated microglia, which are part of the brain’s immune response in MS, have been shown to clear amyloid from the brain in animal models.

Brier and Cross have begun the next steps of this research, both to tease out the possible human genetics involved, as well as to test amyloid plaque development in animal models representing MS.

Several of Brier’s and Cross’ coauthors on this study are affiliated with C2N Diagnostics, a Washington University startup that provided support for the investigation. The PrecivityAD2 test is based on technology licensed to C2N by the university.

Cooper named inaugural French professor

Megan A. Cooper, MD, PhD, an internationally recognized physician-scientist who specializes in rare genetic diseases that affect children’s immune systems, has been named the inaugural Anthony R. French, MD, PhD, Professor in Pediatrics at Washington University School of Medicine in St. Louis. Cooper also is director of the Division of Rheumatology & Immunology in the Department of Pediatrics and treats patients with immune disorders at St. Louis Children’s Hospital.

French is the Alan L. Schwartz, PhD, MD, Professor in Pediatrics, as well as a professor of biomedical engineering and of pathology & immunology at Washington University. The professorship is funded by the St. Louis Children’s Hospital Foundation to honor French’s esteemed career and vital contributions to the fields of pediatric immunology and rheumatology.

Cooper’s research program, funded in large part by the National Institutes of Health (NIH), incorporates basic and translational studies to investigate the underlying genetic causes of rare pediatric immune deficiencies. These disorders put children at high risk of dangerous infections and other problems such as autoimmunity, inflammation and a predisposition to cancer. Her research also focuses on the metabolic regulation of natural killer (NK) cells, which are an important part of the body’s immune defenses. Normal NK cells play important roles in attacking virus-infected cells as well as cells that have become cancerous. Understanding the metabolic pathways of these cells could lead to their harnessing for the treatment of viral infections and some cancers.

“Megan Cooper is an impressive physician-scientist, an exceptional educator and a dedicated mentor,” said Gary A. Silverman, MD, PhD, the Harriet B. Spoehrer Professor and head of the Department of Pediatrics. “This professorship is meant to ensure that the curiosity, compassion and scholarship exemplified by Dr. French will continue to inspire the next generation of pediatric scientists. Megan is the model recipient: Her commitment to her patients and her continual pursuit of knowledge are inspiring.”

In recent years, Cooper and members of her lab have identified two inherited immune conditions in children, along with the genetic errors at their roots, which together provide a foundation for developing targeted therapies for these conditions. This work also has led to international collaborations identifying multiple other genetic errors of immunity and shaping additional options for future treatments.

“It is a great pleasure to recognize Dr. Cooper’s outstanding contributions to pediatric immunology with this endowed professorship named for Dr. French, whose long and distinguished career advanced this field in such important ways for our patients and their families,” said Trish Lollo, president of St. Louis Children’s Hospital.

Cooper’s research also has led to the identification and characterization of a class of natural killer cells referred to as cytokine-induced memory-like natural killer cells. A deficiency in natural killer cells — part of the body’s innate immune response — can result in uncontrolled, deadly infections. In addition to fighting viruses, natural killer cells also can kill cancer cells. As such, cytokine-induced memory-like natural killer cells are now being studied as targeted therapies in clinical trials for pediatric and adult cancers.

In 2019, Cooper was recognized with the School of Medicine’s Emil Unanue Prize for Innovative Research in Immunology, and in 2023 was elected to the American Society for Clinical Investigation. She serves as an elected councilor for the Clinical Immunology Society and the Society for Pediatric Research and is an associate editor for the Journal of Clinical Immunology.

Cooper also is the scientific director of the Center for Pediatric Immunology, which recently received $5.3 million in funding from the Children’s Discovery Institute, a collaboration between the School of Medicine and St. Louis Children’s Hospital. The center’s primary goal is to provide scientific infrastructure to help investigate and create novel therapies for pediatric genetic diseases impacting immunity. In addition, she is the inaugural director of the Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies at St. Louis Children’s Hospital and a former associate director of Washington University’s Medical Scientist Training Program.

A distinguished researcher, clinician and mentor, French was director of the Division of Pediatric Rheumatology & Immunology from 2017-23 and was co-scientific director of the Children’s Discovery Institute. He currently serves as vice chair for physician-scientist training in the Department of Pediatrics.

French’s work is motivated by the hypothesis that a clearer understanding of the regulation of natural killer cell functional responses may lead to novel therapeutic interventions in autoimmune disorders and in host defense against large DNA viruses. He has long focused on the role of natural killer cells in initial immune responses to infection, especially the specifics of their behavior during viral infections.

French also is interested in understanding what happens when children have deficits in NK cell function, especially in the context of severe herpes virus infections. He studies the contribution of dysfunctional NK cells in triggering autoimmune diseases in children, including juvenile dermatomyositis, which causes skin rashes and muscle inflammation.

Cooper earned her bachelor’s degree from The College of Wooster and her doctorate and medical degrees from The Ohio State University. She joined the pediatric residency program at St. Louis Children’s Hospital in 2004, went on to complete a fellowship in pediatric rheumatology at Washington University and joined the faculty in 2010.

Zebrafish use surprising strategy to regrow spinal cord

Zebrafish are members of a rarefied group of vertebrates capable of fully healing a severed spinal cord. A clear understanding of how this regeneration takes place could provide clues toward strategies for healing spinal cord injuries in people. Such injuries can be devastating, causing permanent loss of sensation and movement.

A new study from Washington University School of Medicine in St. Louis maps out a detailed atlas of all the cells involved — and how they work together — in regenerating the zebrafish spinal cord. In an unexpected finding, the researchers showed that survival and adaptability of the severed neurons themselves is required for full spinal cord regeneration. Surprisingly, the study showed that stem cells capable of forming new neurons — and typically thought of as central to regeneration — play a complementary role but don’t lead the process.

The study is published Thursday, Aug. 15, in the journal Nature Communications.

Unlike humans’ and other mammals’ spinal cord injuries, in which damaged neurons always die, the damaged neurons of zebrafish dramatically alter their cellular functions in response to injury, first to survive and then to take on new and central roles in orchestrating the precise events that govern healing, the researchers found. Scientists knew that zebrafish neurons survive spinal cord injury, and this new study reveals how they do it.

“We found that most, if not all, aspects of neural repair that we’re trying to achieve in people occur naturally in zebrafish,” said senior author Mayssa Mokalled, PhD, an associate professor of developmental biology. “The surprising observation we made is that there are strong neuronal protection and repair mechanisms happening right after injury. We think these protective mechanisms allow neurons to survive the injury and then adopt a kind of spontaneous plasticity — or flexibility in their functions — that gives the fish time to regenerate new neurons to achieve full recovery. Our study has identified genetic targets that will help us promote this type of plasticity in the cells of people and other mammals.”

By mapping out the evolving roles of various cell types involved in regeneration, Mokalled and her colleagues found that the flexibility of the surviving injured neurons and their capacity to immediately reprogram after injury lead the chain of events that are required for spinal cord regeneration. If these injury-surviving neurons are disabled, zebrafish do not regain their normal swim capacity, even though regenerative stem cells remain present.

When the long wiring of the spinal cord is crushed or severed in people and other mammals, it sets off a chain of toxicity events that kills the neurons and makes the spinal cord environment hostile against repair mechanisms. This neuronal toxicity could provide some explanation for the failure of attempts to harness stem cells to treat spinal cord injuries in people. Rather than focus on regeneration with stem cells, the new study suggests that any successful method to heal spinal cord injuries in people must start with saving the injured neurons from death.

Learn about the zebrafish facility at WashU Medicine that enabled this study.

 

“Neurons by themselves, without connections to other cells, do not survive,” Mokalled said. “In zebrafish, we think severed neurons can overcome the stress of injury because their flexibility helps them establish new local connections immediately after injury. Our research suggests this is a temporary mechanism that buys time, protecting neurons from death and allowing the system to preserve neuronal circuitry while building and regenerating the main spinal cord.”

There is some evidence that this capacity is present but dormant in mammalian neurons, so this may be a route to new therapies, according to the researchers.

“We are hopeful that identifying the genes that orchestrate this protective process in zebrafish — versions of which also are present in the human genome — will help us find ways to protect neurons in people from the waves of cell death that we see following spinal cord injuries,” she said.

While this study is focused on neurons, Mokalled said spinal cord regeneration is extremely complex, and future work for her team will delve into a new cell atlas to understand the contributions of other cell types to spinal cord regeneration, including non-neuronal cells, called glia, in the central nervous system as well as cells of the immune system and vasculature. They also have ongoing studies comparing the findings in zebrafish to what is happening in mammalian cells, including mouse and human nerve tissue.

Obituary: Anjali Bhorade, associate professor of ophthalmology, 51

Anjali Bhorade, MD, an associate professor of ophthalmology & visual sciences at Washington University School of Medicine in St. Louis, died June 12, 2024, after battling metastatic breast cancer for nearly three years. She died in St. Louis, comfortably surrounded by family and friends. She was 51.

“Our community has lost an outstanding clinician-scientist dedicated to improving the lives of patients with glaucoma,” said Todd P. Margolis, MD, PhD, the Alan A. and Edith L. Wolff Distinguished Professor and head of the John F. Hardesty, MD, Department of Ophthalmology & Visual Sciences. “A sought-after physician, she provided the highest quality of medical and surgical care with compassion and empathetic advocacy. She brought her patients comfort with her ability to listen and understand their concerns, treating each patient with respect and dignity.”

Bhorade specialized in caring for patients with glaucoma, a group of eye diseases that affect the nerve in the back of the eye and can cause vision loss and blindness. Her research, supported by the National Institutes of Health (NIH), was focused on the impact of visual field loss on driving in glaucoma patients and the potential for improvements in home lighting on visual function. She was involved in clinical research projects, including a study on how cataract removal affects eye pressure. She also was part of a multicenter clinical research network focused on diabetic retinopathy.

For her commitment to advancing the field of ophthalmology through research and clinical care, she received numerous accolades, including from the American Glaucoma Society and the American Academy of Ophthalmology.

Bhorade also was a devoted educator who served as the director of Washington University’s one-year glaucoma fellowship. She inspired and mentored numerous medical students, ophthalmology residents, fellows and students in the university’s Program in Occupational Therapy.

She received her bachelor’s degree in biology from Cornell University and her medical degree from the University of Illinois College of Medicine in Chicago, where she also completed her residency training in ophthalmology. She then completed a fellowship in glaucoma at Bascom Palmer Eye Institute in Miami. Bhorade joined the Washington University faculty in 2004.

Bhorade is survived by her husband, Wesley Green, MD, a St. Louis ophthalmologist and glaucoma specialist; sons Kiren Nicholas Greuloch and Alexander Bhorade Greuloch; stepdaughters Harper and Mila Green; parents Maruti Bhorade and Suman Bhorade; siblings Sangeeta (Siddharth) Bhorade and Rajeev Bhorade; two nephews; and numerous friends, relatives and colleagues.

A memorial service to celebrate her life will be held in the fall in St. Louis.

Read more on the Department of Ophthalmology & Visual Sciences website. 

Mahajan named Urologic Surgery Research Professor

Nupam Mahajan, PhD, a pioneering prostate cancer researcher, has been named the inaugural Urologic Surgery Research Professor at Washington University School of Medicine in St. Louis. Mahajan’s work has changed his field’s understanding of how prostate cancer progresses to become resistant to treatment and has advanced investigations into potential new treatments for prostate tumors.

The Urologic Surgery Research Professorship was established by the Department of Surgery to promote research aimed at improving clinical outcomes and broadening treatment options in the field of urology. Mahajan was installed by Chancellor Andrew D. Martin and David H. Perlmutter, MD, the George and Carol Bauer Dean of the School of Medicine, executive vice chancellor for medical affairs, and the Spencer T. and Ann W. Olin Distinguished Professor.

“Dr. Mahajan’s pioneering research is paving the way for innovative treatments geared to the many patients whose prostate tumors eventually develop resistance to hormone therapies,” Martin said. “There is a dire need to develop new therapies to help these patients, and this endowed professorship will help support critical studies to further this important translational research.”

Mahajan’s work occupies a significant place in our understanding of how prostate cancer develops and progresses. He was among the first to identify triggers at the cellular level that change how prostate cancer-linked genes are upregulated. Specifically, he showed how tyrosine kinases – proteins key to certain genetic signaling processes – can allow androgen receptors to be independent of testosterone and accelerate prostate cancer cell growth in patients receiving testosterone-reducing medications. With that information, Mahajan is working to develop targeted therapies to manipulate those mechanisms to suppress tumor growth while also bolstering the patient’s cancer-fighting immune response.

Mahajan hopes to test such therapies in clinical trials next year.

“Dr. Mahajan’s work on prostate cancer exemplifies how understanding the mechanisms underlying this cancer can be used to establish new therapeutic targets and move them forward into clinical application as quickly as possible,” Perlmutter said. “We look forward to continuing to see the results of Dr. Mahajan’s findings, probing the depths of basic science to put new innovations into practice for the benefit of patients.”

Mahajan, who joined the School of Medicine faculty in 2018, holds 10 patents derived from his work, almost all of which have been licensed for commercial development.

The new professorship is the latest in a number of honors for Mahajan, among them the Bankhead-Coley Award, the Movember-PCF Foundation Challenge Award and the Celgene Award. He also has received continuous RO1 funding from the National Cancer Institute of the National Institutes of Health (NIH).

“Nupam Mahajan is exactly the type of translationally focused researcher we want to support in the Department of Surgery, and it is our hope that his discoveries in particular will lead to better treatments for patients with prostate cancer,” said John A. Olson Jr., MD, PhD, the William K. Bixby Professor of Surgery and head of the Department of Surgery. “He also is generous with his time and expertise, and a great role model for trainees.”

Mahajan earned his PhD from the Indian Institute of Science in Bangalore and completed his postdoctoral studies at the University of North Carolina at Chapel Hill.

Robinson, Schwarz recognized by radiation oncology society

Two professors of radiation oncology at Washington University School of Medicine in St. Louis – Clifford G. Robinson, MD, and Julie K. Schwarz, MD, PhD – have been named fellows of the American Society for Radiation Oncology (ASTRO). Additionally, Robinson has been elected to the ASTRO Board of Directors.

The ASTRO fellows program recognizes individuals who have made substantial contributions to the society and to the field of radiation oncology through research, education, patient care and service. Robinson and Schwarz will be recognized Oct. 1 during ASTRO’s annual meeting, in Washington, D.C.

Robinson and Schwarz treat patients at Siteman Cancer Center, based at Barnes-Jewish Hospital and Washington University School of Medicine. Schwarz is the vice chair for research and director of the Cancer Biology Division in radiation oncology. Robinson is chief of the Stereotactic Body Radiation Therapy service and associate director of clinical programs in radiation oncology.

The two co-lead Washington University’s MicroEnvironment and Tumor Effects of Radiotherapy Center (METEOR), one of only five centers in a National Institutes of Health (NIH) network aimed at understanding the biologic effects of radiation therapy in cancer treatment.

Drug bypasses suppressive immune cells to unleash immunotherapy

By recruiting the immune system to combat tumor cells, immunotherapy has improved survival rates, offering hope to millions of cancer patients. However, only about one in five people responds favorably to these treatments.

With a goal of understanding and addressing immunotherapy’s limitations, researchers at Washington University School of Medicine in St Louis have found that the immune system can be its own worst enemy in the fight against cancer. In a new study in mice, a subset of immune cells – type 1 regulatory T cells, or Tr1 cells – did its normal job of preventing the immune system from overreacting but did so while inadvertently restraining immunotherapy’s cancer-fighting power.

“Tr1 cells were found to be a heretofore unrecognized obstacle to immunotherapy’s effectiveness against cancer,” said senior author Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor in the Department of Pathology & Immunology, and director of the Bursky Center for Human Immunology & Immunotherapy at Washington University School of Medicine. “By removing or circumventing that barrier in mice, we successfully reenergized the immune system’s cancer-fighting cells and uncovered an opportunity to expand the benefits of immunotherapy for more cancer patients.”

The study is available in Nature.

Cancer vaccines represent a new approach to personalize cancer immunotherapy. Aimed at the mutant proteins specific to a patient’s tumor, such vaccines induce killer T cells to attack tumor cells while leaving healthy cells unharmed. Schreiber’s group previously showed that more effective vaccines also activate helper T cells, another immune cell type, that recruit and expand additional killer T cells to destroy the tumors. But when they tried to add increased amounts of the helper T cell target to supercharge the vaccine they found they generated a different type of T cell that inhibited rather than promoted tumor rejection.

“We tested the hypothesis that by increasing helper T cell activation we would induce enhanced elimination of the sarcoma tumors in mice,” said first author Hussein Sultan, PhD, an instructor in pathology & immunology. So he injected groups of tumor bearing mice with vaccines that activated killer T cells equally while triggering a different degree of helper T cell activation.

Much to the researchers’ surprise in this latest study, the vaccine meant to hyperactivate helper T cells produced the opposite effect and inhibited tumor rejection.

“We thought that more helper T cell activation would optimize elimination of the sarcoma tumors in mice,” Sultan said. “Instead, we found that vaccines containing high doses of helper T cell targets induced inhibitory Tr1 cells that completely blocked tumor elimination. We know that Tr1 cells normally control an overactive immune system, but this is the first time they have been shown to dampen its fight against cancer.”

Tr1 cells normally put the brakes on the immune system to prevent it from attacking the body’s healthy cells. But their role in cancer has not been seriously explored. Looking through previously published data, the researchers found that tumors from patients who had responded poorly to immunotherapy had more Tr1 cells compared with tumors of patients who had responded well. The number of Tr1 cells also increased in mice as tumors grew bigger, rendering the mice insensitive to immunotherapy.

To bypass the inhibiting cells, the researchers treated the vaccinated mice with a drug that enhances killer T cells’ fighting power. The drug, developed by biotechnology startup Asher Biotherapeutics, carries modifications in the immune-boosting protein called interleukin 2 (IL-2) that specifically revs up killer T cells and reduces the toxicity of unmodified IL-2 treatments. The additional boost from the drug overcame Tr1 cells’ inhibition and rendered the immunotherapy more effective.

“We are committed to personalizing immunotherapy and broadening its effectiveness,” said Schreiber. “Decades of researching basic tumor immunology have expanded our understanding of how to trigger the immune system to achieve the most robust antitumor response. This new study adds to our understanding of how to improve immunotherapy to benefit more people.”

As co-founder of Asher Biotherapeutics – which provided the mouse version of the modified IL-2 drugs – Schreiber is indirectly involved in the company’s clinical trials testing the human version of the drug as a monotherapy in cancer patients. If successful, the drug has the potential to be tested in combination with cancer treatment vaccines.

Potential drug effective against flesh-eating bacteria

Researchers at Washington University School of Medicine in St. Louis have developed a novel compound that effectively clears bacterial infections in mice, including those that can result in rare but potentially fatal “flesh-eating” illnesses. The potential drug could be the first of an entirely new class of antibiotics, and a gift to clinicians seeking more effective treatments against bacteria that can’t be tamed easily with current antibiotics.

The research is published Aug. 2 in Science Advances.

The compound targets gram-positive bacteria, which can cause drug-resistant staph infections, toxic shock syndrome and other illnesses that can turn deadly. It was developed through a collaboration between the Washington University labs of Scott Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology, and Michael Caparon, PhD, a professor of molecular microbiology, and Fredrik Almqvist, a professor of chemistry at the University of Umeå in Sweden.

A new type of antimicrobial would be very good news for clinicians seeking effective treatments against dangerous pathogens that are becoming more resistant to currently available drugs.

“All of the gram-positive bacteria that we’ve tested have been susceptible to that compound. That includes enterococci, staphylococci, streptococci, C. difficile, which are the major pathogenic bacteria types,” said Caparon, the co-senior author. “The compounds have broad-spectrum activity against numerous bacteria.”

It’s based on a type of molecule called ring-fused 2-pyridone. Initially, Caparon and Hultgren had asked Almqvist to develop a compound that might prevent bacterial films from attaching to the surface of urethral catheters, a common cause of hospital-associated urinary tract infections. Discovering that the resulting compound had infection-fighting properties against multiple types of bacteria was a happy accident.

The team named their new family of compounds GmPcides (for gram-positive-icide). In past work, the authors showed that GmPcides can wipe out bacteria strains in petri dish experiments. In this latest study, they decided to test it on necrotizing soft-tissue infections, which are fast-spreading infections usually involving multiple types of gram-positive bacteria, for which Caparon already had a working mouse model. The best known of these, necrotizing fasciitis or “flesh-eating disease,” can quickly damage tissue severely enough to require limb amputation to control its spread. About 20% of patients with flesh-eating disease die.

This study focused on one pathogen, Streptococcus pyogenes, which is responsible for 500,000 deaths every year globally, including flesh-eating disease. Mice infected with S. pyogenes and treated with a GmPcide fared better than did untreated animals in almost every metric. They had less weight loss, the ulcers characteristic of the infection were smaller, and they fought off the infection faster.

The compound appeared to reduce the virulence of the bacteria and, remarkably, speed up postinfection healing of the damaged areas of the skin.

It is not clear how GmPcides accomplish all of this, but microscopic examination revealed that the treatment appears to have a significant effect on bacterial cell membranes, which are the outer wrapping of the microbes.

“One of the jobs of a membrane is to exclude material from the outside,” Caparon said. “We know that within five to ten minutes of treatment with GmPcide, the membranes start to become permeable and allow things that normally should be excluded to enter into the bacteria, which suggests that those membranes have been damaged.”

This can disrupt the bacteria’s own functions, including those that cause damage to their host, and make the bacteria less effective at combating the host’s immune response to infections.

In addition to their antibacterial effectiveness, GmPcides appear to be less likely to lead to drug-resistant strains. Experiments designed to create resistant bacteria found very few cells able to withstand treatment and thus pass on their advantages to the next generation of bacteria.

Caparon explained that there is a long way to go before GmPcides are likely to find their way into local pharmacies. Caparon, Hultgren and Almqvist have patented the compound used in the study and licensed it to a company, QureTech Bio, in which they have an ownership stake, with the expectation that they will be able to collaborate with a company that has the capacity to manage the pharmaceutical development and clinical trials to potentially bring GmPcides to market.

Hultgren said that the kind of collaborative science that created GmPcides is what is needed to treat intractable problems like antimicrobial resistance.

“Bacterial infections of every type are an important health problem, and they are increasingly becoming multidrug resistant and thus harder to treat,” he said. “Interdisciplinary science facilitates the integration of different fields of study that can lead to synergistic new ideas that have the potential to help patients.”

Aging-related genomic culprit found in Alzheimer’s disease

Researchers at Washington University School of Medicine in St. Louis have developed a way to capture the effects of aging in the development of Alzheimer’s disease. They have devised a method to study aged neurons in the lab without a brain biopsy, an advancement that could contribute to a better understanding of the disease and new treatment strategies.

The scientists transformed skin cells taken from patients with late-onset Alzheimer’s disease into brain cells called neurons. Late-onset Alzheimer’s develops gradually over many decades and only starts to show symptoms at age 65 or older. For the first time, these lab-derived neurons accurately reproduced the hallmarks of this type of dementia, including the amyloid beta buildup, tau protein deposits and neuronal cell death.

By studying these cells, the researchers identified aspects of cells’ genomes — called retrotransposable elements, which change their activity as we age — in the development of late-onset Alzheimer’s disease. The findings suggest new treatment strategies targeting these factors.

The study appears Aug. 2 in the journal Science.

“Sporadic, late-onset Alzheimer’s disease is the most common type of Alzheimer’s disease, representing more than 95% of cases,” said senior author Andrew Yoo, PhD, a professor of developmental biology. “It has been very difficult to study in the lab due to the complexity of the disease stemming from various risk factors, including aging as an important contributor. Until now, we did not have a way to capture the effects of aging in the cells to study late-onset Alzheimer’s.”

To date, animal studies of Alzheimer’s disease have, by necessity, focused on mice with rare genetic mutations known to cause inherited, early-onset Alzheimer’s in younger people — a strategy that has shed light on the condition but differs from disease development for the vast majority of patients with the sporadic, late-onset form. To more faithfully recapitulate the disease in the lab, Yoo’s team turned to an approach called cellular reprogramming.

The method to transform easily obtained human skin cells from living patients directly into neurons makes it possible to study Alzheimer’s effects on the brain without the risk of a brain biopsy and in a way that retains the consequences of the patient’s age on the neurons. Past work by Yoo and his colleagues, who pioneered this transformation technique using small RNA molecules called microRNAs, has focused on understanding the development of Huntington’s disease — an inherited neurological condition that typically shows adult-onset symptoms.

After transforming skin cells into brain cells, the researchers found that the new neurons can grow in a thin gel layer or self-assemble into small clusters — called spheroids — mimicking the 3D environment of the brain. The researchers compared neuronal spheroids generated from patients with sporadic, late-onset Alzheimer’s disease, inherited Alzheimer’s disease and healthy individuals of similar ages.

The Alzheimer’s disease patients’ spheroids quickly developed amyloid beta deposits and tau tangles between neurons. Activation of genes associated with inflammation also emerged, and then the neurons began to die, mimicking what is seen in brain scans of patients. Spheroids from older, healthy donors in the study showed some amyloid deposition but much less than those from patients. The small amyloid deposits in older, healthy spheroids are evidence that the technique is capturing the effects of age and suggest that amyloid beta and tau accumulation correlated with aging. It further demonstrates that the Alzheimer’s disease process makes the buildup far worse.

The researchers, including first author Zhao Sun, PhD, a staff scientist in Yoo’s lab, found that treating spheroids from late-onset Alzheimer’s disease patients with drugs that interfere with the formation of amyloid beta plaques early in the disease process, before neurons start forming toxic amyloid beta buildup, significantly reduced the amyloid beta deposits. But treating at later time points, after some buildup was already present, had no effect or only modestly reduced subsequent amyloid beta deposits. Such data emphasize the importance of identifying and treating the disease early.

The study further found a role for retrotransposable elements — small pieces of DNA that jump to different locations in the genome — in the development of late-onset Alzheimer’s disease. Inhibition of such “jumping genes” with the drug lamivudine (also called 3TC) — an anti-retroviral drug that can dampen the activity of retrotransposable elements — had a positive effect: The spheroids from late-onset Alzheimer’s disease patients had reduced amyloid beta and tau tangles and showed less neuronal death compared with the same spheroids treated with a placebo. Lamivudine treatment had no beneficial effect on spheroids from patients with early-onset, inherited Alzheimer’s disease, providing evidence that sporadic late-onset Alzheimer’s development related to aging has distinct molecular features compared with inherited autosomal dominant Alzheimer’s disease.

“In these patients, our new model system has identified a role for retrotransposable elements associated with the disease process,” Yoo said. “We were pleased to see that we could reduce the damage with a drug treatment that suppresses these elements. We look forward to using this model system as we work toward new personalized therapeutic interventions for late-onset Alzheimer’s disease.”

The researchers are planning future studies with spheroids that include multiple types of brain cells, including neurons and glia.