With support from the Commonwealth of Virginia’s Alzheimer’s and Related Diseases Research Award Fund (ARDRAF), Fralin Biomedical Research Institute at VTC scientists Sharon Swanger and Shannon Farris are working to understand why this area is especially vulnerable.

Swanger studies how brain cells communicate across synapses in disease-susceptible brain circuits, while Farris focuses on how different circuits in the brain’s memory center function at the molecular level. Their overlapping expertise made the collaboration a natural fit.

“We’ve both been studying how circuits differ at the molecular level for a while,” said Swanger, an assistant professor at the research institute. “This new collaborative project brings together my work on synapses and Shannon’s on mitochondria in a way that addresses a big gap in the Alzheimer’s disease field.”

“This kind of state-level support is critical,” Farris said. “It gives researchers in Virginia the chance to ask questions that may eventually make a difference for people living with Alzheimer’s. It’s meaningful to be part of research that could help people facing that journey.”

A key focus of their research is mitochondria — tiny structures inside brain cells that provide the energy needed for a variety of cellular functions in neurons including synaptic transmission. In Alzheimer’s disease, mitochondria stop working properly in the course of the disease.

Farris and Swanger are investigating whether mitochondria in a vulnerable memory-related circuit may become overloaded with calcium, a key signaling chemical for multiple neuronal and synaptic processes. That overload could contribute to the early breakdown of memory circuits.

“The connection between these cells is one of the first to fail in Alzheimer’s,” Farris said. “We found that this synapse has unusually strong calcium signals in nearby mitochondria — so strong we can see them clearly under a light microscope. Those kinds of signals are hard to ignore. It gives us a model where we can really watch what’s happening as things start to go wrong.”

To test their hypothesis, the researchers will study brain tissue from healthy mice and mice with certain aspects of Alzheimer’s pathology. By comparing how mitochondria function and how brain cells communicate across synapses in each group, they hope to find early signs of stress or failure in the entorhinal cortex-hippocampus circuit.

Swanger and Farris are members of the Fralin Biomedical Research Institute’s Center for Neurobiology Research and also faculty in the Department of Biomedical Sciences and Pathobiology of the Virginia-Maryland College of Veterinary Medicine.

These slight bends and twists in the disc plane, often just a few degrees, bear a striking resemblance to the subtle tilts observed among the planets in our own Solar System. This discovery suggests the initial conditions for planetary systems might be far less orderly than previously thought, with profound implications for how planets grow and settle into their final orbits.

Dr Andrew Winter, the lead author of the study from Queen Mary University of London where he is Royal Society University Research Fellow in astronomy, said: “Our results suggest that protoplanetary discs are slightly warped. This would be quite a change in how we understand these objects and has many consequences for how planets form. Particularly interesting is that the couple of degree warping is similar to the differences in inclination between our own Solar System planets.”

Dr Myriam Benisty, director of the Planet and Star Formation Department at the Max Planck Institute for Astronomy said,”exoALMA has revealed large scale structures in the planet forming discs that were completely unexpected. The warp-like structures challenge the idea of orderly planet formation and pose a fascinating challenge for the future.

To uncover these subtle twists, the team meticulously analysed Doppler shifts – tiny changes in the radio waves emitted by carbon monoxide (CO) molecules swirling within the discs. These shifts act like a cosmic speedometer, revealing the gas’s exact motion. As part of a major ALMA program called exoALMA, researchers used this flagship observatory to map the gas’s velocity across each disc in unprecedented detail. By carefully modelling these intricate patterns, they were able to detect when different regions of a disc were slightly tilted, thus revealing the warps.

“These modest misalignments may be a common outcome of star and planet formation,” Dr Winter added, noting the intriguing parallel with our own Solar System. The research not only provides a fresh perspective on the mechanics of planet formation but also raises new questions about why these discs are warped – a mystery the team is eager to unravel.

Is it the gravitational pull of unseen companion stars, or perhaps the chaotic dance of gas and dust that twists these stellar cradles? The findings show that these subtle disc warps, often tilting by as little as half a degree to two degrees, can naturally explain many of the prominent large-scale patterns observed in the gas’s motion across the discs. They even suggest these warps could be responsible for creating intriguing spiral patterns and slight temperature variations within these cosmic nurseries.

If these warps are a key driver of how gas moves within the disc, it profoundly changes our understanding of critical processes like turbulence and how material is exchanged – ultimately dictating how planets form and settle into their final orbits. Intriguingly, the nature of these warps appears to be connected to how much material the young star is actively drawing in towards its center. This hints at a dynamic link between the disc’s innermost regions, where the star is fed, and its outer, planet-forming areas.

This discovery offers a thrilling glimpse into the complex and often surprising realities of planet formation, fundamentally changing our cosmic blueprint and opening new avenues for understanding the diverse worlds beyond our Sun.

This research was conducted by the ‘exoALMA’ collaboration that is an international collaboration of institutions including the Max-Planck Institute for Astronomy (MPIA), University of Florida, Leiden Observatory (Leiden University), European Southern Observatory, Università degli Studi di Milano, Massachusetts Institute of Technology, Center for Astrophysics | Harvard & Smithsonian, Univ. Grenoble Alpes, Universidad de Chile, University of St. Andrews, Université Côte d’Azur, The University of Georgia, Monash University, University of Leeds, National Astronomical Observatory of Japan, University of Cambridge, Ibaraki University, Academia Sinica Institute of Astronomy & Astrophysics, The Graduate University for Advanced Studies (SOKENDAI), Wesleyan University, and The Pennsylvania State University.

While breast cancer survival continues to improve, thanks to advances in detection and treatment, when breast cancer relapses — or returns after initial treatment — it is still incurable. For the 30 percent of women and men who do relapse, the only option is continuous and indefinite treatment which cannot eliminate the cancer completely. Some breast cancers, like triple negative and HER2+, recur within a few years, and others like ER+ can recur decades later. Until now, there has not been a way to identify those breast cancer survivors who harbor the dormant cells that lead to recurrence in real time and to intervene with a treatment that can prevent incurable relapse.

In a randomized phase II clinical trial with 51 breast cancer survivors, existing drugs were able to clear dormant tumor cells from 80 percent of the study participants. The three-year survival rate without any disease recurrence was above 90 percent in patients who received one drug and 100 percent for patients who received both study drugs.

“The lingering fear of cancer returning is something that hangs over many breast cancer survivors after they celebrate the end of treatment,” said principal investigator Angela DeMichele, MD, MSCE, FASCO, the Mariann T. and Robert J. MacDonald Professor in Breast Cancer Research. “Right now, we just don’t know when or if someone’s cancer will come back — that’s the problem we set out to solve. Our study shows that preventing recurrence by monitoring and targeting dormant tumor cells is a strategy that holds real promise, and I hope it ignites more research in this area.”

Seizing a window of opportunity to wipe out cancer while it’s sleeping

The study builds on previous research that showed how dormant tumor cells continue to lay in wait in some patients after breast cancer treatment. These so-called “sleeper cells,” also referred to as minimal residual disease (MRD), can reactivate years or even decades later. Because they are not “active” cancer cells and can be scattered throughout the body, they do not show up on standard imaging tests that are used to watch for breast cancer recurrence.

Once the sleeper cells begin to expand and circulate in the bloodstream, it can lead to the spread of metastatic breast cancer. Patients who have MRD are more likely to experience breast cancer recurrence and have decreased overall survival.

Lewis Chodosh, MD, PhD, chair of Cancer Biology and senior author of the study, previously led research to identify the pathways that allow dormant tumor cells to survive in patients for decades.

“Our research shows that this sleeper phase represents an opportunity to intervene and eradicate the dormant tumor cells before they have the chance to come back as aggressive, metastatic disease,” Chodosh said. “Surprisingly, we’ve found that certain drugs that don’t work against actively growing cancers can be very effective against these sleeper cells. This tells us that the biology of dormant tumor cells is very different from active cancer cells.”

In the preclinical part of the latest research publication, Chodosh’s team conducted a series of experiments in mice to better understand the underlying mechanisms. They showed that two different drugs — approved by the FDA to treat other conditions — could effectively clear MRD in mice, resulting in longer survival without cancer recurrence. The drugs target autophagy and mTOR signaling, which the researchers found were key mechanisms to allow the tumor cells to remain dormant.

Translating science into original clinical trials

DeMichele’s team first enrolled breast cancer survivors who had completed treatment within the last five years and had clear scans into a screening study that looked for dormant tumor cells in participant’s bone marrow.

If dormant tumor cells were found, patients were then eligible to enroll in the Phase II CLEVER clinical trial, which randomized patients to receive six cycles of either monotherapy with one of two study drugs, or combination therapy with both drugs. The treatment cleared dormant tumor cells in most patients after six to 12 months. After a median follow-up time of 42 months, only two patients on the study have experienced a cancer recurrence.

“We want to be able to give patients a better option than ‘wait and see’ after they complete breast cancer treatment,” DeMichele said. “We’re encouraged by these results that we’re on the right track.”

The team is already enrolling patients in two larger, ongoing studies to confirm and extend the results of the CLEVER study: the Phase II ABBY clinical trial and the Phase II PALAVY clinical trial, available at several cancer centers across the country. Patients interested in learning more about these or other breast cancer clinical trials at Penn Medicine should contact [email protected].

The research was made possible with funding from the National Cancer Institute (R01CA208273) and Department of Defense (BC160784), with additional support from the V Foundation, Breast Cancer Research Foundation, QVC “Shoes on Sale,” Avon Foundation, Raynier Institute & Foundation, and generous philanthropic donations. DeMichele previously reported interim outcomes data from the study at the European Society for Medical Oncology (ESMO) Congress 2023.

Now Tufts researchers led by Krishna Kumar, Robinson Professor of Chemistry, have designed a new, next-generation compound with hopes that it could be more effective with fewer side effects, which they report in a paper in the Journal of the American Chemical Society.

While weight loss drugs currently on the market and in development target one, two, or even three hormone receptors related to glucose metabolism and the desire to eat, the Tufts team has identified a fourth target that could potentially further enhance the control strategy.

“Obesity is linked to over 180 different disease conditions, including cancer, cardiovascular disease, osteoarthritis, liver disease, and type 2 diabetes, and affects over 650 million people worldwide,” said Kumar. “What drives us is the idea that we can design a single drug to treat obesity and simultaneously mitigate the risk of developing a long list of health problems plaguing society.”

How the Drugs Work

After we eat a meal, our gut and brain trigger a hormonal “fuel gauge” that regulates levels of glucose and tells us when we have had enough to eat.

The hormone glucagon-like peptide 1 (GLP-1) is released to help stimulate the production of insulin and the uptake of glucose in muscle and other tissues. With the cells now loaded with fuel, the level of glucose in the blood returns to normal. Ozempic uses GLP-1 with slight modifications to increase its availability in the bloodstream. Its success in controlling blood glucose has prompted the American Diabetes Association to recommend it and other GLP-1-based drugs as the new first line injectable treatments for diabetes, ahead of insulin.

But GLP-1 also acts directly on the brain, making us feel full after having a meal, and it slows down the rate that the stomach contents are emptied into the intestines, creating a more evenly paced release of nutrients and glucose into the bloodstream. That’s why it has also become extremely popular as a weight loss treatment.

It’s still not a perfect drug strategy for weight loss, though. “The biggest problem with GLP-1 drugs is that they have to be injected once a week, and they can induce a very strong feeling of nausea,” said Kumar. “As much as 40% of people using these drugs give up after the first month.”

A second hormone released after eating is glucose-dependent insulinotropic peptide (GIP). It also makes us feel full after a meal. GIP looks a lot like GLP-1, so rather than administer two drugs, researchers created one peptide that incorporates structural elements of both — what’s called in drug development a chimera. That drug, called Mounjaro or Zepbound (the brand names for tirzepatide), has the added benefit of significantly reducing nausea. As a more tolerable treatment, it may overtake Ozempic in the weight loss market.

“And then there is a third hormone, glucagon,” said Kumar. “Paradoxically, it actually increases blood glucose, but at the same time increases the expenditure of energy in cells of the body, raises body temperature, and suppresses appetite.” By adding glucagon to the mix, GLP-1 and GIP end up neutralizing its glucose-enhancing effect, leaving the remaining functionalities of all three hormones working together to enhance weight loss.

Glucagon is also similar in structure to GLP-1 and GIP, so drug developers created a single chimera peptide that incorporates elements of all three hormones, which can be recognized by their three separate receptors. That drug, called retatrudide, is currently in clinical trials that indicate even greater achievable weight loss (up to 24%) compared to the original GLP-1 drugs (6-15%).

Going for the Weight Loss Gold Standard with a Fourth Target

“The goal that people are trying to shoot for is bariatric surgery,” said Kumar. That’s a surgical procedure significantly reducing the size of the stomach, which can achieve long-lasting weight loss up to 30%. “For individuals with persistent obesity and potential deadly associated conditions, it becomes a necessary but invasive treatment.”

Current injectable weight loss drugs still fall short of that gold standard, so the Tufts chemists are focused on a drug redesign that could match the 30% weight loss outcome.

“There is one more hormone we wanted to bring in to complete a weight control quartet,” said Tristan Dinsmore, a graduate student in the Kumar lab and the lead author of the study. “It’s called peptide YY (PYY). This molecule is also secreted by the gut after we eat a meal, and its job is to reduce appetite and slow the process of emptying food from the stomach, but via different mechanisms than either GLP-1 or GIP. It may also be involved in directly ‘burning off’ fat.”

PYY is from a separate and structurally unrelated class of hormones than the first three, so blending its structure into a chimeric peptide that also mimics GLP-1, GIP, and glucagon was not easy. Instead, the Tufts team was able to join two peptide segments end-to-end, creating a new ‘tetra-functional’ clinical candidate.

“One of the limitations of the current drugs is that individual variation, possibly including how people express target receptors or respond to their corresponding hormones, can lead to lesser than desired weight loss outcomes in many patients,” said Martin Beinborn, visiting scholar in the Department of Chemistry. “By hitting four different hormone receptors at the same time, we hope to improve the chances of averaging out such variation toward the goal of achieving greater and more consistent overall effectiveness.”

“A second issue is that patients tend to regain weight after discontinuing currently available GLP-1 related drugs,” said Beinborn, who notes that lifestyle changes should ideally be a complement to medication treatment. This two-pronged approach will not only support reaching and keeping one’s target weight, but may also help preserve bone and muscle mass.

“Recent studies indicate that weight rebound after drug discontinuation is delayed with the newer, more effective GLP-1 mimetics,” he said. “Extending from this observation, one may speculate that multi-chimeras along the lines of the one we discovered could get us closer to the bariatric surgery standard of lasting weight loss.”

The researchers come to the conclusion that these olfactory dysfunctions arise because immune cells of the brain called “microglia” remove connections between two brain regions, namely the olfactory bulb and the locus coeruleus. The olfactory bulb, located in the forebrain, analyzes sensory information from the nose’s scent receptors. The locus coeruleus, a region of the brainstem, influences this processing by means of long nerve fibers originating from neurons in the locus coeruleus and extending all the way to the olfactory bulb. “The locus coeruleus regulates a variety physiological mechanisms. These include, for example, cerebral blood flow, sleep-wake cycles, and sensory processing. The latter applies, in particular, also to the sense of smell,” says Dr. Lars Paeger, a scientist at DZNE and LMU. “Our study suggests that in early Alzheimer’s disease, changes occur in the nerve fibers linking the locus coeruleus to the olfactory bulb. These alterations signal to the microglia that affected fibers are defective or superfluous. Consequently, the microglia break them down.”

Alterations in the membrane

Specifically, the team of Dr. Lars Paeger and Prof. Dr. Jochen Herms, who is a co-author of the current publication, found evidence of changes in the composition of the membranes of the affected nerve fibers: Phosphatidylserine, a fatty acid that usually occurs inside a neuron’s membrane, had been moved to the outside. “Presence of phosphatidylserine at the outer site of the cell membrane is known to be an “eat-me” signal for microglia. In the olfactory bulb, this is usually associated with a process called synaptic pruning, which serves to remove unnecessary or dysfunctional neuronal connections,” explains Paeger. “In our situation, we assume that the shift in membrane composition is triggered by hyperactivity of the affected neurons due to Alzheimer’s disease. That is, these neurons exhibit abnormal firing.”

A wide range of data

The findings of Paeger and colleagues are based on a plethora of observations. These include studies on mice with features of Alzheimer’s disease, analysis of brain samples from deceased Alzheimer’s patients, and positron emission tomography (PET) scans of the brains of individuals with Alzheimer’s or mild cognitive impairment. “Smell issues in Alzheimer’s disease and damage to the associated nerves have been discussed for some time. However, the causes were unclear until yet. Now, our findings point to an immunological mechanism as cause for such dysfunctions – and, in particular, that such events already arise in the early stages of Alzheimer’s disease,” says Joachim Herms, a research group leader at DZNE and LMU as well as a member of the Munich-based “SyNergy” Cluster of Excellence.

Perspectives for early diagnosis

So-called amyloid-beta antibodies have recently become available for the treatment of Alzheimer’s. For this novel therapy to be effective, it needs to be applied at an early stage of the disease, and this is precisely where the current research could be significant. “Our findings could pave the way for the early identification of patients at risk of developing Alzheimer’s, enabling them to undergo comprehensive testing to confirm the diagnosis before cognitive problems arise. This would allow earlier intervention with amyloid-beta antibodies, increasing the probability of a positive response,” says Herms.

RSV causes substantial seasonal illness during fall and winter in the U.S., with an estimated 100,000-150,000 hospitalizations and 4,000-8,000 deaths occurring annually among adults 60 or older.

The results reinforce the recommendations for RSV vaccines in older adults and lay the groundwork for understanding how long a single dose of the vaccine may be effective, according to Wesley Self, MD, MPH, principal investigator for the IVY Network and Senior Vice President for Clinical Research at Vanderbilt University Medical Center.

“These results clearly demonstrate that the RSV vaccines prevent hospitalizations and critical illness due to RSV infection among older Americans,” Self said. “It is exciting to see the public health benefits of this new vaccination program.”

Investigators used data from a multicenter hospital network known as the IVY Network (The Investigating Respiratory Viruses in the Acutely Ill Network) to assess RSV vaccine effectiveness. They used a test-negative, case-control study design among 6,958 persons 60 years or older who had been hospitalized with acute respiratory illness at one of 26 hospitals in 20 US states during two RSV seasons from October 1, 2023-March 31, 2024 and October 1, 2024-April 30, 2025.

Overall, vaccination reduced the risk of RSV hospitalization by 58% during two RSV seasons, including 69% in the first year after vaccination and 48% in the second year after vaccination.

“Our data show that the beneficial effects of RSV vaccines appear to wane over time,” Self said. “Redosing the vaccine at some interval after the initial dose could be a strategy to maintain protection over longer periods of time. It will be important to continue to closely monitor vaccine effectiveness over time to understand how long the benefit lasts after a single dose and if repeat dosing should be considered.”

Current RSV vaccine recommendations are for all adults aged 75 years and older and those aged 60-74 years who are at an increased risk of severe RSV.

This study was funded by the U.S. Centers for Disease Control and Prevention (CDC) via award 75D30122C14944.