The COVID-19 pandemic is over, but the virus that caused it is still here, sending thousands of people to the hospital each week and spinning off new variants with depressing regularity. The virus’s exceptional ability to change and evade immune defenses has led the World Health Organization (WHO) to recommend annual updates to COVID-19 vaccines.
But some scientists worry that the remarkable success of the first COVID-19 vaccines may work against updated versions, undermining the utility of an annual vaccination program. A similar problem plagues the annual flu vaccine campaign; immunity elicited by one year’s flu shots can interfere with immune responses in subsequent years, reducing the vaccines’ effectiveness.
A new study by researchers at Washington University School of Medicine in St. Louis helps to address this question. Unlike immunity to influenza virus, prior immunity to SARS-CoV-2, the virus that causes COVID-19, doesn’t inhibit later vaccine responses. Rather, it promotes the development of broadly inhibitory antibodies, the researchers report.
The study, available online in Nature, shows that people who were repeatedly vaccinated for COVID-19 — initially receiving shots aimed at the original variant, followed by boosters and updated vaccines targeting variants — generated antibodies capable of neutralizing a wide range of SARS-CoV-2 variants and even some distantly related coronaviruses. The findings suggest that periodic re-vaccination for COVID-19, far from hindering the body’s ability to recognize and respond to new variants, may instead cause people to gradually build up a stock of broadly neutralizing antibodies that protect them from emerging SARS-CoV-2 variants and some other coronavirus species as well, even ones that have not yet emerged to infect humans.
“The first vaccine an individual receives induces a strong primary immune response that shapes responses to subsequent infection and vaccination, an effect known as imprinting,” said senior author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine. “In principle, imprinting can be positive, negative or neutral. In this case, we see strong imprinting that is positive, because it’s coupled to the development of cross-reactive neutralizing antibodies with remarkable breadth of activity.”
Imprinting is the natural result of how immunological memory works. A first vaccination triggers the development of memory immune cells. When people receive a second vaccination quite similar to the first, it reactivates memory cells elicited by the first vaccine. These memory cells dominate and shape the immune response to the subsequent vaccine.
In the case of the flu vaccine, imprinting has negative effects. Antibody-producing memory cells crowd out new antibody-producing cells, and people develop relatively few neutralizing antibodies against the strains in the newer vaccine. But in other cases, imprinting can be positive, by promoting the development of cross-reactive antibodies that neutralize strains in both the initial and subsequent vaccines.

To understand how imprinting influences the immune response to repeat COVID-19 vaccination, Diamond and colleagues including first author Chieh-Yu Liang, a graduate student, studied the antibodies from mice or people who had received a sequence of COVID-19 vaccines and boosters targeting first the original and then omicron variants. Some of the human participants also had been naturally infected with the virus that causes COVID-19.
The first question was the strength of the imprinting effect. The researchers measured how many of the participants’ neutralizing antibodies were specific for the original variant, the omicron variant or both. They found that very few people had developed any antibodies unique to omicron, a pattern indicative of strong imprinting by the initial vaccination. But they also found few antibodies unique to the original variant. The vast majority of neutralizing antibodies cross-reacted with both.
The next question was how far the cross-reactive effect extended. Cross-reactive antibodies, by definition, recognize a feature shared by two or more variants. Some features are shared only by similar variants, others by all SARS-CoV-2 variants or even all coronaviruses. To assess the breadth of the neutralizing antibodies, the researchers tested them against a panel of coronaviruses, including SARS-CoV-2 viruses from two omicron lineages; a coronavirus from pangolins; the SARS-1 virus that caused the 2002-03 SARS epidemic; and the Middle Eastern Respiratory Syndrome (MERS) virus. The antibodies neutralized all the viruses except MERS virus, which comes from a different branch of the coronavirus family tree than the others.
Further experiments revealed that this remarkable breadth was due to the combination of original and variant vaccines. People who received only the vaccines targeting the original SARS-CoV-2 variant developed some cross-reactive antibodies that neutralized the pangolin coronavirus and SARS-1 virus, but the levels were low. After boosting with an omicron vaccine, though, the cross-reactive neutralizing antibodies against the two coronavirus species increased.
Taken together, the findings suggest that regular re-vaccination with updated COVID-19 vaccines against variants might give people the tools to fight off not only the SARS-CoV-2 variants represented in the vaccines, but also other SARS-CoV-2 variants and related coronaviruses, possibly including ones that have not yet emerged.
“At the start of the COVID-19 pandemic, the world population was immunologically naïve, which is part of the reason the virus was able to spread so fast and do so much damage,” said Diamond, also a professor of molecular microbiology and of pathology & immunology. “We do not know for certain whether getting an updated COVID-19 vaccine every year would protect people against emerging coronaviruses, but it’s plausible. These data suggest that if these cross-reactive antibodies do not rapidly wane — we would need to follow their levels over time to know for certain — they may confer some or even substantial protection against a pandemic caused by a related coronavirus.”

The rich research portfolio of the Monell Chemical Senses Center on sweet taste goes way back: Monell scientists were one of four teams in 2001 that found and described the mammalian sweet taste receptor — TAS1R2-TAS1R3. Twenty years later in 2021, a pair of papers published in Mammalian Genome by Monell researchers covered the genetics of sugar-loving mice.
The sweet taste receptor, expressed in taste bud cells, conveys sweetness from the mouth when it is activated. Earlier this month, a study in PLOS One, led by another Monell researcher, delved into how the sweet-taste receptor might be the first stop in a metabolic surveillance system for sugar. The receptor is also expressed in certain intestinal cells, where it may facilitate glucose absorption and assimilation, as part of this system.
The team found that stimulation and inhibition of TAS1R2-TAS1R3 demonstrates that it helps regulate glucose metabolism in humans and may have implications for managing such metabolic disorders as diabetes. Glucose is the primary type of sugar found in human blood, making it a key source of energy for cells.
“Our objective was to determine whether TAS1R2-TAS1R3 influences glucose metabolism in two directions,” said Monell Member Paul Breslin, PhD, Professor of Nutritional Sciences, Rutgers University, and senior author on the paper.
They showed that a TAS1R2-TAS1R3 agonist (sucralose, a zero-calorie sweetener) or a TAS1R2-TAS1R3 antagonist (lactisole, a sodium salt that inhibits sweet taste) mixed with a glucose meal acutely altered human glucose tolerance in different ways. Here, an agonist binds to a receptor and stimulates a cell and an antagonist binds to a receptor and prevents stimulation.
“The novelty of our findings is that the receptor we studied in this experiment impacts blood glucose and insulin during a glucose meal differently, depending on whether it is stimulated or inhibited,” said Breslin. This work provides further evidence that taste receptors help regulate metabolism and nutrient handling.
Plasma insulin levels were measured in study participants given an oral glucose tolerance test (OGTT), which follows blood sugar levels before and after a person drinks a liquid meal containing glucose. Participants’ ratings of perceived sucralose sweetness correlated with early increases in plasma glucose, as well as increases in plasma insulin levels when sucralose was added to the OGTT. The added sucralose tended to accelerate the release of insulin to the glucose load. On the other hand, participants’ sensitivity to lactisole-driven inhibition of sweetness was correlated with decreased plasma glucose levels. Lactisole also tended to slow insulin release.

“When glucose stimulates taste receptors before being absorbed into the body, signals are sent via the mouth and intestine to regulatory organs such as the pancreas. Perhaps, we could devise ways of using TAS1R2-TAS1R3 to help the body handle glucose better by anticipating when glucose will appear in the blood,” said Breslin. When the body senses glucose, it speeds up the absorption to deliver glucose to tissues that may need it and possibly also to prevent glucose from moving too far along the intestine, which may not be good for maintaining a healthy gut microbiome.
“This system is elegant in its simplicity,” said Breslin. The same taste receptor is all over the body — the mouth, gastrointestinal tract, pancreas, liver, and fat cells, with the last three being major metabolic regulatory tissues, all part of the body’s 24/7 metabolic watch.
Is there a relationship between a person’s health status and the activity of their TAS1R2-TAS1R3 receptors? Study authors say likely, suggesting that the degree of receptor activation exerts acute influences on plasma glucose and insulin levels and their timing of onset, which is important for metabolic health.
The team maintains that, in general, the current dietary habits of excessive consumption of food and beverages high in sucrose, high fructose corn syrup, and high-potency sweeteners could hyperstimulate TAS1R2-TAS1R3, contributing to the improper regulation of glucose in the blood. This could lead to a diagnosis of metabolic syndrome, a cluster of risk factors including elevated plasma glucose and insulin insensitivity (along with obesity, hypertension, and elevated plasma fats) that increases the risk of heart disease, stroke, and diabetes. The authors say that future studies should examine the effects of TAS1R2-TAS1R3 stimulation and inhibition in people who are at risk for metabolic syndrome to determine the therapeutic potential of manipulating TAS1R2-TAS1R3 for better metabolic control instead of worse.
“Studies like these — using Monell’s technical capability and deep expertise in the chemical senses — show that the sweet taste receptor TAS1R2-TAS1R3 helps to regulate glucose differently, depending on the sweetness of the food or beverage,” said Breslin. The team’s hope is to apply what they learned to make what we eat and drink healthier.
“A small metabolic change for the positive can add a lot more to the life and health of humans when compounded over decades and millions of people,” said Breslin.

A Cleveland Clinic-led team of scientists and physicians have discovered that the immune checkpoint protein VISTA can directly turn off tumor-fighting T-cells during immunotherapy and resist treatment.
The study, published in Science Immunology, explains that VISTA can bind to a protein called LRIG1 in T cells, which was previously only thought to promote bone and fat development. When VISTA binds to LRIG1, the researchers found, LRIG1 sends signals that suppress T cell replication, survival and function. This interaction can happen between molecules on tumor cells and on T cells, molecules on healthy cells and T cells and even between molecules on the same T cell. Their preclinical work suggests that blocking LRIG1 function can halt tumor growth in many cancers. In human melanoma and endometrial cancer, LRIG1 expression in tumor-associated T cells was correlated with resistance to immunotherapy.
VISTA modulates the immune responses of healthy cells to keep them from attacking our own bodies, protecting us from autoimmune issues. However, studies from a group led by Li Lily Wang, PhD, of Cleveland Clinic, have shown that during immunotherapy, VISTA impairs immune activation and prevents T cells from attacking cancer cells. Pharmeceutical companies have tried to make therapeutics to block VISTA from working during immunotherapy. Success has been limited, because the field still does not know exactly how VISTA works.
The findings from this study follow another discovery from the laboratory of Dr. Wang, Translational Hematology and Oncology that showed VISTA indirectly suppresses our immune systems by promoting cells called myeloid-derived suppressor cells (MDSCs) that are well known to block T-cell function.
“Our two discoveries combined create a paradigm that explains how VISTA can act as a ‘super villain’ that uses many different weapons to impair antitumor responses during cancer treatments,” says Dr. Wang. “This is an insight that drug developers need to consider if they want to boost treatment response rates to their full potential.”
Immunotherapies and immune checkpoint therapies were a huge breakthrough in cancer treatments, providing hope for individuals affected by previously incurable cancers. But with response rates of only 20% — 30% and high recurrence rates, Dr. Wang says there is still much room to improve.
“Studying the molecular aspect of how LRIG1 functions as VISTA’s receptor on T cells can provide insights on how to successfully block VISTA and improve the clinical outcomes of the patients who don’t respond to existing immune therapies” says lead first author Hieu Minh Ta, PhD.

This project was a collaboration between labs led by Dr. Wang and Timothy Chan, MD, PhD, Chair of Cleveland Clinic’s Center for Immunotherapy & Precision Immuno-Oncology, Director of the Global Center for Immunotherapy and Sheikha Fatima bint Mubarak Endowed Chair in Immunotherapy. The paper has four co-first authors: postdoctoral fellows Dr. Ta and Dia Roy, PhD; research associate Keman Zhang, PhD; and project staff Tyler Alban, PhD.
The scientists worked closely with physicians including Brian Gastman, MD, Cleveland Clinic surgical oncologist, and Case Western Reserve University cancer pathologist Stefanie Avril, MD. Drs. Gastman and Avril provided the research team with melanoma and endometrial samples for studying the expression of LRIG1.
The results were striking. Patients who had been more resistant to immunotherapy had higher levels of LRIG1 in their tumor-fighting T cells.
“Our findings in human cancer samples inform and support the decision to go after LRIG1 as a potential drug target for new immune checkpoint therapies,” says study co-first author Dia Roy, PhD.

Roughly one in five cancer patients benefits from immunotherapy — a treatment that harnesses the immune system to fight cancer. Such an approach to beating cancer has seen significant success in lung cancer and melanoma, among others. Optimistic about its potential, researchers are exploring strategies to improve immunotherapy for cancers that don’t respond well to the treatment, with the hope of benefiting more patients.
Now, researchers at Washington University School of Medicine in St. Louis have found, in mice, that a strain of gut bacteria – Ruminococcus gnavus — can enhance the effects of cancer immunotherapy. The study, which appears May 17 in Science Immunology, suggests a new strategy of using gut microbes to help unlock immunotherapy’s untapped cancer-fighting potential.
“The microbiome plays an important role in mobilizing the body’s immune system to attack cancer cells,” explained the study’s senior author, Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology. “Our findings shine a light on one bacterial species in the intestine that helps an immunotherapy drug eliminate tumors in mice. Identifying such microbial partners is an important step in developing probiotics to help improve the effectiveness of immunotherapy drugs and benefit more cancer patients.”
Cancer immunotherapy employs the body’s immune cells to target and destroy tumors. One such treatment uses immune checkpoint inhibitor drugs to unleash the immune system by releasing the natural brakes that keep immune T cells quiet, a feature that prevents the body from harming itself. But some tumors fight back to suppress the attacking immune cells, damping the effectiveness of such inhibitors.
Colonna and first co-author Martina Molgora, PhD, a postdoctoral researcher, previously established a collaboration with colleague Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor, in which they completely eliminated sarcoma tumors in mice using a two-pronged inhibition approach. The researchers inhibited TREM2, a protein made by tumor macrophages to stop T cells from attacking the growing tumor. They then showed that a cancer immunotherapy drug was more effective when TREM2 was blocked. The result indicated that TREM2 dampens immunotherapy’s efficacy.
In an experiment that formed the basis of the new study, the researchers made a surprise observation. TREM2 mice had the same beneficial response to the checkpoint inhibitor when they were housed with mice lacking the protein. This result came about when the researchers deviated from their typical protocol of separating the mice before treating them with the inhibitor.
Cohabiting mice share microbes with one another. The researchers suspected the effects might have been due to exchanges of gut bacteria. The researchers worked with Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor, and co-first author Blanda Di Luccia, PhD, a postdoctoral researcher, to study the microbes in the intestines of the mice that were treated successfully with immunotherapy. They found an expansion of Ruminococcus gnavus, compared with a lack of such microbes in mice that didn’t respond to the therapy.

R. gnavus has been found in gut microbiota of cancer patients who respond well to immunotherapy, Colonna explained. In clinical trials, fecal transplants from such individuals have helped some unresponsive patients reap immunotherapy’s benefits.
The researchers, including co-first author and graduate student Darya Khantakova, introduced R. gnavus to the mice and then treated the tumors with a checkpoint inhibitor. The tumors shrank, even when TREM2 was available as a weapon to dampen the effect of the immunotherapy.
Gordon, director of the Edison Family Center for Genome Sciences & Systems Biology, noted that evidence is mounting that the microbiota boosts immunotherapy. Identifying relevant species, such as R. gnavus, could lead to a next-generation probiotic that could synergize with immunotherapy to improve cancer care, he explained.
The scientists next aim to understand how R. gnavus assists in tumor rejection, which may reveal new ways to help cancer patients. For example, if the microbe produces an immune-activating metabolite through the process of digesting food, that knowledge opens the opportunity to use metabolites as immunotherapy enhancers. Microbes also can leak out of the gut and trigger an immune response in the tumor or activate gut T cells that migrate to the tumor to mount an attack, Colonna explained. The researchers are exploring the three possibilities.

A new AI tool to more quickly and accurately classify brain tumours has been developed by researchers at The Australian National University (ANU).
According to Dr Danh-Tai Hoang, precision in diagnosing and categorising tumours is crucial for effective patient treatment.
“The current gold standard for identifying different kinds of brain tumours is DNA methylation-based profiling,” Dr Hoang said.
“DNA methylation acts like a switch to control gene activity, and which genes are turned on or off.
“But the time it takes to do this kind of testing can be a major drawback, often requiring several weeks or more when patients might be relying on quick decisions on therapies.
“There’s also a lack of availability of these tests in nearly all hospitals worldwide.”
To address these challenges, the ANU researchers, in collaboration with experts from the National Cancer Institute in the United States (US), developed DEPLOY, a way to predict DNA methylation and subsequently classify brain tumours into 10 major subtypes.

DEPLOY draws on microscopic pictures of a patient’s tissue called histopathology images.
The model was trained and validated on large datasets of approximately 4,000 patients from across the US and Europe.
“Remarkably, DEPLOY achieved an unprecedented accuracy of 95 per cent,” Dr Hoang said.
“Furthermore, when given a subset of 309 particularly difficult to classify samples, DEPLOY was able to provide a diagnosis that was more clinically relevant than what was initially provided by pathologists.
“This shows the potential future role of DEPLOY as a complementary tool, adding to a pathologist’s initial diagnosis, or even prompting re-evaluation in the case of disparities.”
The researchers believe DEPLOY could eventually be used to help classify other types of cancer as well.

Stroke is the leading cause of disability worldwide and the second leading cause of death, but the right early intervention can prevent severe consequences. A new study led by investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, and collaborators developed a new test by combining blood-based biomarkers with a clinical score to identify patients experiencing large vessel occlusion (LVO) stroke with high accuracy. Their results are published in the journal Stroke: Vascular and Interventional Neurology.
“We have developed a game-changing, accessible tool that could help ensure that more people suffering from stroke are in the right place at the right time to receive critical, life-restoring care,” said senior author Joshua Bernstock, MD, PhD, MPH, a clinical fellow in the Department of Neurosurgery at Brigham and Women’s Hospital.
Most strokes are ischemic, in which blood flow to the brain is obstructed. LVO strokes are an aggressive type of ischemic stroke that occurs when an obstruction occurs in a major artery in the brain. When blood supply to the brain is compromised, the lack of oxygen and nutrients causes brain cells to die within minutes. LVO strokes are major medical emergencies and require the swift treatment with mechanical thrombectomy, a surgical procedure that retrieves the blockage.
“Mechanical thrombectomy has allowed people that otherwise would have died or become significantly disabled be completely restored, as if their stroke never happened,” said Bernstock. “The earlier this intervention is enacted, the better the patient’s outcome is going to be. This exciting new technology has the potential to allow more people globally to get this treatment faster.”
The research team previously targeted two specific proteins found in capillary blood, one called glial fibrillary acidic protein (GFAP), which is also associated with brain bleeds and traumatic brain injury, and one called D-dimer. In this study, they demonstrated that the levels of these blood-based biomarkers combined with field assessment stroke triage for emergency destination (FAST-ED) scores could identify LVO ischemic strokes while ruling out other conditions such as bleeding in the brain. Brain bleeds cause similar symptoms to LVO stroke, making them hard to distinguish from one another in the field, yet treatment for each is vastly different.
In this prospective, observational diagnostic accuracy study, the researchers looked at data from a cohort of 323 patients coded for stroke in Florida between May 2021 and August 2022. They found that combining the levels of the biomarkers GFAP and D-dimer with FAST-ED data less than six hours from the onset of symptoms allowed the test to detect LVO strokes with 93 percent specificity and 81 percent sensitivity. Other findings included that the test ruled out all patients with brain bleeds, signaling that the technology may ultimately also be employed to detect intracerebral hemorrhage in the field.
Bernstock’s team also sees promising potential future use of this accessible diagnostic tool in low- and middle-income countries, where advanced imaging is not always available. It might also be useful in assessing patients with traumatic brain injuries. Next, they are carrying out another prospective trial to measure the test’s performance when used in an ambulance. They have also designed an interventional trial that leverages the technology to expedite the triage of stroke patients by having them bypass standard imaging and move directly to intervention.
“In stroke care, time is brain,” Bernstock said. “The sooner a patient is put on the right care pathway, the better they are going to do. Whether that means ruling out bleeds or ruling in something that needs an intervention, being able to do this in a prehospital setting with the technology that we built is going to be truly transformative.”
Disclosures: Edoardo Guade declares grant funding from the UK Research and Innovation small business research initiative. Edoardo Guade and Joshua Bernstock have positions and equity in Pockit Diagnostics Ltd. Joshua Bernstock also has an equity position in Treovir Inc. and is on the boards of Centile Bio and NeuroX1.
Funding: This study was supported by Innovate UK grant 104640 and by private funding.

If fruit fly wings do not develop into the right shape, the flies will die. UC Riverside researchers have learned how fly embryo cells develop as they need to, opening a window into human development and possible treatments for birth defects.
Biologists often investigate tissue development by studying parts of individual cells. In contrast, the UCR team used some of the most powerful supercomputers in California to simulate many cells working together.
The team examined the mechanical properties of the cells, such as their elasticity and fluid pressure. They also studied how a group of different cell types called a ‘wing disc’ divide and eventually become wing tissue. Their findings are detailed in the journal Nature Communications.
“We modeled hundreds of cells, trying to figure out how they interact with each other, in this case to become the wing of a fruit fly,” said Mark Alber, UCR distinguished mathematics professor and senior co-author of the study.
In close collaboration with bioengineers and quantitative biologists from the University of Notre Dame, the researchers saw that in the earlier stages of development the wing disc is uniformly curved. But in later stages, the top keeps its curvature while the bottom flattens.
“The disc, in a cross-section view, begins as something flat that transitions into a rainbow-like shape. Later, the top keeps the shape, but the middle bottom flattens out, so we have a top and bottom that don’t mirror each other anymore,” said Jennifer Rangel Ambriz, UCR mathematics doctoral student and paper co-first author.
“We wanted to understand what causes this shape, because the flies won’t fly, or survive, if development doesn’t happen properly,” Rangel Ambriz said.

The group found that a subcellular structure called actomyosin drives much of the development process, especially the lower wing disc flattening. This structure is a dynamic network of actin fibers that affects how stiff or tall the cells become.
During cell division and growth, actomyosin pushes the nuclei of different cells back and forth to influence the shapes of individual cells that make up the wing disc.
“For a cell to divide, the nucleus has to move into the top region of a cell, and it does so based on the actomyosin network,” Rangel Ambriz said. “It’s like a fist on a tube of toothpaste. When you squeeze the bottom, it moves everything to the top.”
Actomyosin also connects to a key component called the extracellular matrix, or ECM, which is composed of collagen. The cells in the wing disc adhere to the ECM, which keeps them from drifting too far from one another, especially when cells are dividing. The relative flexibility or stiffness of the ECM also has an important effect on tissue shape and development.
Going forward, the researchers hope to gain a better understanding of the genetic and chemical signals that affect actomyosin. While mechanical factors, such as pressure and membrane surface tension in the cells, also influence tissue shape, different chemical signals likely play an important role.
This project is funded by a grant from the National Science Foundation on which Alber is the principal investigator, along with co-investigators Weitao Chen of UCR, and Jeremiah J. Zartman and Alexander Dowling of UND. The team is working toward the goal of determining mechanisms that help restore damaged tissues to their normal function.
“In the embryo, if you cut a cell or even several cells, the tissue still goes on to develop as it should,” Alber said. “What we know now about factors that affect tissue development could have applications beyond fruit flies and might enable tissue regeneration in humans or animals.”
Furthermore, the team is hopeful their findings also can be used to correct defects in human tissue formation.
“Our fly models may allow us to connect the factors that control tissue development to specific genes, identify ones that are promoting certain birth defects, and eventually reprogram or correct them,” Rangel Ambriz said.

People who use metformin are less likely to develop a myeloproliferative neoplasm (MPN) over time, indicating that the treatment may help prevent the development of certain types of cancers, according to a study published in Blood Advances.
Metformin is a therapy used to treat high blood sugar in people with type 2 diabetes that increases the effect of insulin, reduces how much glucose is released from the liver and helps the body absorb glucose. A meta-analysis of previous studies connected the therapy with a reduction in the risk of gastrointestinal, breast, and urologic cancers, while a retrospective study of U.S. veterans found that metformin users have a reduced risk for solid and hematological cancers.
“Our team was interested in understanding what other effects we see with commonly prescribed treatments like metformin,” said Anne Stidsholt Roug, MD, PhD, chief physician at Aarhus University Hospital and clinical associate professor at Aalborg University Hospital in Denmark. “The anti-inflammatory effect of metformin interested us, as MPNs are very inflammatory diseases. This is the first study to investigate the association between metformin use and risk of MPN.”
MPNs are a group of diseases that affect how bone marrow produces blood cells, resulting in an overproduction of red blood cells, white blood cells, or platelets that can lead to bleeding problems, a greater risk of stroke or heart attack, and organ damage.
The researchers compared metformin use among patients diagnosed with MPNs and a matched population from the Danish general population between 2010 and 2018. Of the 3,816 MPN cases identified from the sample, a total of 268 (7.0%) individuals with MPN had taken metformin as compared to 8.2% (1,573 out of 19,080) of the control group of people who had taken metformin but were not diagnosed with MPN. Just 1.1% of MPN cases had taken metformin for more than five years, as compared to 2.0% of controls. The protective effect of metformin was seen in all subtypes of MPN when adjusting for potential confounders.
“We were surprised by the magnitude of the association we saw in the data,” said Daniel Tuyet Kristensen, MD, PhD student, at Aalborg University Hospital and lead author of the study. “We saw the strongest effect in people who had taken metformin for more than five years as compared to those who had taken the treatment for less than a year.” Dr. Kristensen added that this makes clinical sense, as MPNs are diseases that develop over a long period of time, like other types of cancer.
The researchers noted that while the protective effect of long-term metformin use was seen in all subtypes of MPN, the study was limited by its registry-based retrospective design. Further, they could not account for lifestyle factors that can affect cancer risk, such as smoking, obesity, and dietary habits.
Dr. Roug noted that while the study team were unable to assess exactly why metformin seems to protect against the development of MPN, they hope additional research will be conducted to better understand why this may be. Moving forward, the researchers aim to identify any similar trends with myelodysplastic syndromes and acute myeloid leukemia in population-level data for future study.

An HIV vaccine candidate developed at the Duke Human Vaccine Institute triggered low levels of an elusive type of broadly neutralizing HIV antibodies among a small group of people enrolled in a 2019 clinical trial.
The finding, reported May 17 in the journal Cell, not only provides proof that a vaccine can elicit these antibodies to fight diverse strains of HIV, but that it can also initiate the process within weeks, setting in motion an essential immune response.
The vaccine candidate targets an area on the HIV-1 outer envelope called the membrane proximal external region (MPER), which remains stable even as the virus mutates. Antibodies against this stable region in the HIV outer coat can block infection by many different circulating strains of HIV.
“This work is a major step forward as it shows the feasibility of inducing antibodies with immunizations that neutralize the most difficult strains of HIV,” said senior author Barton F. Haynes, M.D., director of the Duke Human Vaccine Institute (DHVI). “Our next steps are to induce more potent neutralizing antibodies against other sites on HIV to prevent virus escape. We are not there yet, but the way forward is now much clearer.”
The research team analyzed data from a phase 1 clinical trial of a vaccine candidate developed by Haynes and S. Munir Alam, Ph.D., at DHVI.
Twenty healthy, HIV-negative people enrolled in the trial. Fifteen participants received two of four planned doses of the investigational vaccine, and five received three doses.
After just two immunizations, the vaccine had a 95% serum response rate and a 100% blood CD4+ T-cell response rate — two key measurements that demonstrated strong immune activation. Most of the serum responses mapped to the portion of the virus targeted by the vaccine.

Importantly, broadly neutralizing antibodies were induced after just two doses.
The trial was halted when one participant experienced a non-life-threatening allergic reaction, similar to rare incidents reported with COVID-19 vaccinations. The team investigated the cause of the event, which was likely from an additive.
“To get a broadly neutralizing antibody, a series of events needs to happen, and it typically takes several years post-infection,” said lead author Wilton Williams, Ph.D., associate professor in Duke’s Department of Surgery and member of DHVI. “The challenge has always been to recreate the necessary events in a shorter space of time using a vaccine. It was very exciting to see that, with this vaccine molecule, we could actually get neutralizing antibodies to emerge within weeks.”
Other features of the vaccine were also promising, most notably how the crucial immune cells remained in a state of development that allowed them to continue acquiring mutations, so they could evolve along with the ever-changing virus.
The researchers said there is more work to be done to create a more robust response, and to target more regions of the virus envelope. A successful HIV vaccine will likely have at least three components, all aimed at distinct regions of the virus.
“Ultimately, we will need to hit all the sites on the envelope that are vulnerable so that the virus cannot escape,” Haynes said. “But this study demonstrates that broadly neutralizing antibodies can indeed be induced in humans by vaccination. Now that we know that induction is possible, we can replicate what we have done here with immunogens that target the other vulnerable sites on the virus envelope.”
In addition to Haynes and Williams, study authors include S. Munir Alam, Gilad Ofek, Nathaniel Erdmann, David Montefiori, Michael S. Seaman, Kshitij Wagh, Bette Korber, Robert J. Edwards, Katayoun Mansouri, Amanda Eaton, Derek W. Cain, Mitchell Martin, Robert Parks, Maggie Barr, Andrew Foulger, Kara Anasti, Parth Patel, Salam Sammour, Ruth J. Parsons, Xiao Huang, Jared Lindenberger, Susan Fetics, Katarzyna Janowska, Aurelie Niyongabo, Benjamin M. Janus, Anagh Astavans, Christopher B. Fox, Ipsita Mohanty, Tyler Evangelous, Yue Chen, Madison Berry, Helene Kirshner, Elizabeth Van Itallie, Kevin Saunders, Kevin Wiehe, Kristen W. Cohen, M. Juliana McElrath, Lawrence Corey, Priyamvada Acharya, Stephen R. Walsh, and Lindsey R. Baden.

Many couples find it hard to open up about their intimate lives, but these tips can guide the way.As a reporter who covers sex and intimacy, I spend a lot of time listening to experts extol the virtues of open, honest communication. To have good sex — and to keep having good sex over time — couples must be willing to talk about it, they say.But some people would rather leave their relationships than have those conversations, said Jeffrey Chernin, a marriage and family therapist and the author of “Achieving Intimacy: How to Have a Loving Relationship That Lasts” — especially if things in the bedroom aren’t going particularly well.“One of the things I often say to couples who are having trouble is: ‘I wish there was another way through this,’” he said. “But the only way I know to have a better sex life, or to resume your sex life, is to discuss it.”Dr. Chernin acknowledged how stressful those conversations can be, sometimes deteriorating into finger-pointing, belittling or stonewalling. That said, these suggestions may help.Embrace the awkwardness.It’s common for partners to have trouble talking about intimacy and desire. Research suggests that even in long-term relationships, people know only about 60 percent of what their partner likes sexually, and only about 25 percent of what they don’t like.Cyndi Darnell, a sex and relationships therapist in New York City, said her patients frequently tell her that talking about sex is “awkward” — which is especially true “if you’ve spent months or years avoiding it,” she said.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.