Publisher Health

Published50 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy Sam CabralBBC NewsAmerican football star Damar Hamlin is in a critical condition after suffering a cardiac arrest during a primetime US National Football League game.The Buffalo Bills player, 24, fell to the ground after colliding with an opponent during the first quarter of a match against the Cincinnati Bengals.He received on-field medical attention for more than 30 minutes before being taken to a local hospital.The NFL suspended the game for the night about an hour after the incident. His team, the Buffalo Bills later confirmed the cardiac arrest in a statement and added that his heartbeat was restored on the field.The emergency sparked an outpouring of support for Hamlin and brought attention back to the dangerous nature of America’s most popular sport as the NFL season approaches its climactic play-off stages.Hamlin was tackling Bengals receiver Tee Higgins in the stadium in Cincinnati, Ohio, when Higgins’ helmet appeared to hit Hamlin in the chest. After initially getting to his feet, he fell on his back.Players from both teams gathered around Hamlin as emergency medical staff gave CPR and oxygen. Several were seen visibly distressed, with many kneeling to pray and some in tears.Television coverage repeatedly broke away from the scene on the field, while the crowd in Cincinnati remained silent during the ordeal.Jordon Rooney, Hamlin’s representative, wrote on Twitter: “His vitals are back to normal and they have put him to sleep to put a breathing tube down his throat. They are currently running tests. We will provide updates as we have them.”NFL games are rarely suspended because of injury. Commentators said the fact that gameplay had stalled was a sign of the shocking and severe nature of the emergency. The two teams are among the top Super Bowl contenders this year, with their head-to-head coming in the primetime Monday night slot in the penultimate week of the NFL’s regular season.The league’s players’ association wrote in a statement: “We have been in touch with Bills and Bengals players and with the NFL. The only thing that matters at this moment is Damar’s health and well-being.”Image source, USA Today Sports/ReutersHamlin, a native of McKees Rock, Pennsylvania, was drafted from the University of Pittsburgh by the Bills in 2021.He has drawn praise for hosting annual Christmas toy drives in his hometown since before he was a paid athlete.An online GoFundMe page for the toy drive was reshared after Hamlin collapsed on Monday and has raised nearly $3m (£2.5m).Buildings across Cincinnati were lit up in blue on Monday evening, including Paycor Stadium where the incident occurred.Image source, USA Today Sports/ReutersBlunt trauma is common in contact sports, but it’s rare that it causes heart issues like this. A direct hit to the chest can result in cardiac arrest. That’s when the heart stops beating properly and is unable to do its job of pumping blood around the body. It’s different to a heart attack, which happens when blood supply to the heart muscle is cut off. In Hamlin’s case, medics were able to quickly get his heart beating again. It’s not yet known what internal injuries he may have sustained from the incident and whether there has been any significant damage to his heart. Good wishes for the stricken player have poured in. Basketball star LeBron James said: “It was a terrible thing to see and I wish nothing but the best for that kid.”Arizona Cardinals defensive end JJ Watt wrote on Twitter: “Please be ok man. Please be ok”, while retired Pittsburgh Steelers safety Ryan Clark told ESPN’s SportsCenter show: “This isn’t about a football player, this is about a human.” Bruce Sharpe, a Bills fan who was in the stadium when it happened, said it was “devastating”. “Everything got dead silent. Even the Bengals fans, you know, you don’t want to see anything like that,” he said. “We’re just praying that everything’s okay.”Additional reporting by Michelle Roberts of BBC’s health team

On Jan. 1, Oregon became the first state to allow adult use of psilocybin “magic” mushrooms. Licensed guides will likely determine whether the program is a success.PORTLAND, Ore. — The curriculum was set, the students were enrolled and Oregon officials had signed off on nearly every detail of training for the first class of “magic” mushroom facilitators seeking state certification.But as the four-day session got underway inside a hotel conference room in early December, an important pedagogical tool was missing: the mushrooms themselves.That’s because state officials, two years after Oregon voters narrowly approved the adult use of psilocybin, were still hammering out the regulatory framework for the production and sale of the tawny hallucinogenic fungi.Instead, the students, most of them seasoned mental health professionals, would have to role play with one another using meditation or intensive breathing practices that could lead to altered states of consciousness — the next best thing to the kind of psychedelic trip they would encounter as licensed guides.Not that anyone was complaining.Like many of the two dozen students who paid nearly $10,000 for the course, Jason Wright, 48, a hospital psychiatric nurse in Portland, said he was thrilled to be part of a bold experiment with national implications. “It’s incredible to be on the front lines of something that has the potential to change our relationship with drugs that should never have been criminalized in the first place,” he said.On Jan. 1, Oregon became the first state in the nation to legalize the adult use of psilocybin, a naturally occurring psychedelic that has shown significant promise for treating severe depression, post-traumatic stress disorder and end-of-life anxiety among the terminally ill, among other mental health conditions.Although scientists are still working to understand their therapeutic dynamics, psilocybin and other psychedelics are thought to promote neuroplasticity, a rewiring of the brain that gives patients fresh perspectives on longstanding psychiatric problems.One recent study on alcohol-use disorder, for example, found that two doses of psilocybin paired with talk therapy led to an 83 percent decline in heavy drinking among participants, and that nearly half of them had stopped drinking entirely by the end of the eight-month trial.The long-term benefits, however, remain unclear.Measure 109, as it’s called, authorized the creation of psilocybin service centers where anyone over 21 can consume the mushrooms in a supervised setting. One key requirement is that a state-certified facilitator must be present during drug-induced journeys, which can last five or six hours.Unlike cannabis, which can be sold at dispensaries, Oregon will not allow the retail sale of psilocybin; consumption must take place at a licensed service center.“It’s incredible to be on the front lines of something that has the potential to change our relationship with drugs,” said Jason Wright, a psychiatric nurse from Portland.Amanda Lucier for The New York TimesFor drug reform supporters, Oregon’s approval of Measure 109 is nothing short of revolutionary, a seismic policy shift they hope will inspire other states and municipalities — and persuade federal authorities to ease longstanding prohibitions.Oregon voters also made history in 2020 by decisively voting to decriminalize the personal possession of small amounts of hard drugs like heroin, cocaine and methamphetamine.Although psilocybin and the other drugs remain illegal at the federal level — a regulatory clash that complicates the state’s headlong embrace of decriminalization — Oregon’s decision to overhaul its relationship with mind-altering compounds is already influencing other jurisdictions.In November, Colorado voters approved a ballot measure that removes criminal penalties for possessing certain psychedelics, and similar ballot measures and reform legislation have been introduced in New York, Washington and a dozen other states. Over the past three years, Washington D.C., Seattle and a score of American cities have also moved to decriminalize psilocybin.Mounting scientific interest in psychedelics has reached the highest levels of government. The Food and Drug Administration in 2018 granted psilocybin “breakthrough therapy” status for major depressive disorder, a designation that paved the way for clinical trials. Researchers say they expect full F.D.A. approval in the coming year or two. Another drug with strong therapeutic potential, MDMA, or Ecstasy, is likely to win F.D.A. approval even sooner for treating post-traumatic stress disorder.“Psychedelic medicine is starting to transcend partisan politics in a way that few issues have,” said Sam Chapman, executive director of the Healing Advocacy Fund, a nonprofit organization that backed Measure 109 and has been working to guide its implementation. “It’s our responsibility to create a golden standard that’s worthy of wider implementation.”Oregon’s experiment has not been without hiccups. The ballot measure’s passage created a backlash in rural, more conservative parts of the state. A subsequent ballot measure in November resulted in 25 of the state’s 36 counties voting to opt out of the program for now.The 120-hour course run by Fluence was open to anyone with a high school diploma but the program largely chose applicants with experience in the field of mental health.Amanda Lucier for The New York TimesThe prolonged regulatory vacuum provided an opening for entrepreneurs who jumped the gun. In early December, police raided Shroom House, a retailer in Portland that the authorities said was illegally selling psilocybin mushrooms and drawing long lines of customers.State officials say they are undaunted, even while acknowledging the gantlet of novel regulatory and logistical challenges. Psilocybin use is legal in a handful of countries, among them Brazil, Nepal and the Bahamas, but none have sought to create a system of supervised use.Angela Allbee, a policy analyst at the Oregon Health Authority who oversees the state’s psilocybin services section, said the process had been slow and bumpy at times, in part because officials sought to maximize public participation through advisory panels, public hearings and meetings with law enforcement officials.The biggest tensions erupted over the issue of affordability, given that psilocybin sessions will not be covered by insurance, at least as long as the federal government lists the drug as a Schedule 1 substance with “no currently accepted medical use.”A single session is likely to cost hundreds, if not thousands of dollars.One debate centered on whether to embrace a therapeutic model that would require more intensive, and costly, oversight by a psychotherapist, or a less rigorous approach that would allow anyone over 21 to access the drug, with or without a mental health diagnosis, as long as trained facilitators were present during the session. Health officials opted for the latter, which they are calling a “non-directed” approach.“Being the first in the nation means we have a responsibility to get this right and that sometimes means learning on the fly,” Ms. Allbee said.There was a palpable sense of excitement as the inaugural cohort of students gathered at the Dossier Hotel in downtown Portland for a 160-hour course run by Fluence, an education and training consultancy that offers certification in the nascent field of psychedelic-assisted therapy.Officials seeking to maximize public participation in the legalization debate said the biggest tensions were over affordability, since psilocybin will not be covered by insurance, at least for the time being.Amanda Lucier for The New York Times“It feels like I’m dreaming,” said Brian Pilecki, 43, a psychotherapist who was one of the instructors. “I never imagined this would happen in my lifetime.”The trainees included an ordained rabbi/clinical therapist who lives at an off-the-grid ranch near the town of Bend; a young psychiatrist disillusioned by the limitations of conventional psychotropic medications; and a trauma specialist who sheepishly described herself as a Christian fundamentalist shaped by a lifetime of antidrug sentiment.But the trauma therapist, Sherry Beckmann, 52, said her recent experience with deeply troubled war veterans convinced her to reconsider that antipathy after some of her patients had breakthroughs after a hallucinogenic experience. “The patients don’t lie,” said Ms. Beckmann, who has come to see the drugs as “spiritual gifts” from God. “It’s part of my own journey too. I mean I don’t know why I’m here today other than trusting a gut feeling.”The certification programs are open to anyone with a high school diploma who has passed a background check. Licensure is limited to Oregon residents until 2025. But the Fluence program largely chose applicants with previous experience in the field of mental health — social workers, hospice nurses and psychiatrists.The curriculum included significant emphasis on nontherapeutic matters, including Indigenous traditions involving hallucinogens, the negative social effects of U.S. drug policy and the impacts of systemic racism on marginalized populations.Although psilocybin is widely considered safe and serious adverse reactions are rare, the practical aspects of the course sought to prepare facilitators for potentially difficult moments, including sexual arousal or intense emotional eruptions, especially among those with repressed trauma.Nathan Howard, the director of operations at InnerTrek, another training company approved by the state, said the company was especially interested in applicants with a quality known as equanimity, or the ability to maintain calm in difficult situations. “You are going to be sitting with people undergoing perhaps one of the most intimate, intense experiences of their lives,” he said. “You don’t want to direct the experience — you’re there to observe — but you also might need to hold their hand at certain moments.”The first day of the Fluence course was largely devoted to self-reflection, with many students voicing frustration with the limitations of psychotropic drugs like Xanax or Zoloft that are used to treat the symptoms of mental illness, not the underlying causes. Others spoke reverentially about their own experiences with psychedelics.At one point, an instructor asked the students to close their eyes, meditate and think about what brought them to the hotel conference room. Later, they broke into small groups to share personal stories about times in their life they felt oppressed or marginalized. They also spoke about the lack of diversity within their ranks, prompting a round of soul-searching about their role in promoting a therapy that, for the time being, will likely only be available to the privileged few.But mostly there was elation that the long-awaited moment of legalized psychedelics had finally arrived. Mr. Wright, the hospital psychiatric nurse, said he had personally experienced the healing power of psychedelics and wanted his patients to experience those benefits as well.The prevailing model of psychiatric care, he said, was focused on calming patients who show up at the emergency room in the throes of a psychotic or manic episode. The drugs, Mr. Wright said, were effective at stabilizing patients, but many of them simply returned again because the underlying trauma or depression remained untreated. “I’m happy to be here,” he told the group, “so I can stop pushing ineffective drugs to my patients.”

Unprecedented views of the interior of cells and other nanoscale structures are now possible thanks to innovations in expansion microscopy. The advancements could help provide future insight into neuroscience, pathology, and many other biological and medical fields.
In the paper “Magnify is a universal molecular anchoring strategy for expansion microscopy,” published Jan. 2 in the journal Nature Biotechnology, collaborators from Carnegie Mellon University, the University of Pittsburgh and Brown University describe new protocols for dubbed Magnify.
“Magnify can be a potent and accessible tool for the biotechnology community,” said Yongxin (Leon) Zhao, the Eberly Family Career Development Associate Professor of Biological Sciences.
Zhao’s Biophotonics Lab is a leader in the field of enabling super-resolution imaging of biological samples through physically expanding samples in a process known as expansion microscopy. Through the process, samples are embedded in a swellable hydrogel that homogenously expands to increase the distance between molecules allowing them to be observed in greater resolution. This allows nanoscale biological structures that previously only could be viewed using expensive high-resolution imaging techniques to be seen with standard microscopy tools.
Magnify is a variant of expansion microscopy that allows researchers to use a new hydrogel formula, invented by Zhao’s team, that retains a spectrum of biomolecules, offers a broader application to a variety of tissues, and increases the expansion rate up to 11 times linearly or ~1,300 folds of the original volume.
“We overcame some of the longstanding challenges of expansion microscopy,” Zhao said. “One of the main selling points for Magnify is the universal strategy to keep the tissue’s biomolecules, including proteins, nucleus snippets and carbohydrates, within the expanded sample.”
Zhao said that keeping different biological components intact matters because previous protocols required eliminating many various biomolecules that held tissues together. But these molecules could contain valuable information for researchers.

“In the past, to make cells really expandable, you need to use enzymes to digest proteins, so in the end, you had an empty gel with labels that indicate the location of the protein of interest,” he said. With the new method, the molecules are kept intact, and multiple types of biomolecules can be labeled in a single sample.
“Before, it was like having single-choice questions. If you want to label proteins, that would be the version one protocol. If you want to label nuclei, then that would be a different version,” Zhao said. “If you wanted to do simultaneous imaging, it was difficult. Now with Magnify, you can pick multiple items to label, such as proteins, lipids and carbohydrates, and image them together.”
Lab researchers Aleksandra Klimas, a postdoctoral researcher and Brendan Gallagher, a doctoral student, were first co-authors on the paper.
“This is an accessible way to image specimens in high resolution,” Klimas said. “Traditionally, you need expensive equipment and specific reagents and training. However, this method is broadly applicable to many types of sample preparations and can be viewed with standard microscopes that you would have in a biology laboratory.”
Gallagher, who has a background in neuroscience, said their goal was to make the protocols as compatible as possible for researchers who could benefit from adopting the Magnify as part of their tool kits.

“One of the key concepts that we tried to keep in mind was to meet researchers where they are and have them change as few things in their protocols as possible,” Gallagher said. “It works with different tissue types, fixation methods and even tissue that has been preserved and stored. It is very flexible, in that you don’t necessarily need to redesign experiments with Magnify in mind completely; it will work with what you have already.”
For researchers such as Simon Watkins, the founder and director of the Center for Biologic Imaging at the University of Pittsburgh and the Pittsburgh Cancer Institute, the fact that the new protocol is compatible with a broad range of tissue types — including preserved tissue sections — is important. For example, most expansion microscopy methods are optimized for brain tissue. In contrast, Magnify was tested on samples from various human organs and corresponding tumors including breast, brain and colon.
“Let’s say you have a tissue with dense and non-dense components, this gets around tissues that previously wouldn’t expand isometrically,” Watkins said. “Leon has been working hard on this to make this protocol work with tissues that have been archived.”
Xi (Charlie) Ren, an assistant professor of biomedical engineering at Carnegie Mellon, studies the lung tissue and how to model its morphogenesis and pathogenesis. Part of his research involves researching the motile cilia that function to clear mucus in the human conducting airway. At 200 nanometers in diameter and just a few micrometers in length, the structures are too small to see without time-intensive technology such as electron microscopy. Working in collaboration with Zhao’s lab, Ren’s team developed and delivered lung organoid models with specific defects in cilia ultrastructure and function to validate the ability of Magnify to visualize clinically relevant cilia pathology.
“With the latest Magnify techniques, we can expand those lung tissues and start to see some ultrastructure of the motile cilia even with a regular microscope, and this will expedite both basic and clinical investigations” he said.
The researchers also were able to view defects in cilia in patient-specific lung cells known to have genetic mutations.
“The lung tissue engineering community always needs a better way to characterize the tissue system that we work with,” Ren said. He added that this work is an important first step and he hopes the collaborative work with Zhao’s lab will further be refined and applied to pathology samples found in tissue banks.
Finally, the hydrogel used in Magnify and developed in the Zhao lab is more robust than its predecessor, which was very fragile, causing breaks during the process.
“We are hoping to develop this technology to make it more accessible to the community,” he said. “There are different directions this can go. There’s a lot of interest in using this kind of tissue expansion technology for basic science.”
Alison Barth, the Maxwell H. and Gloria C. Connan Professor in the Life Sciences at Carnegie Mellon, studies synaptic connectivity during learning. She said the broad applications provided by the new methods will be a boon for researchers.
“The brain is a great place to take advantage of these super-resolution techniques,” said Barth, who collaborates with the Zhao Lab on several studies. “Microscopy methods will be beneficial for synaptic phenotyping and analysis across different brain conditions.
“One of the major advances in this paper is the method’s ability to work on many different types of tissue specimens.”
Additional study authors include Piyumi Wijesekara, Emma F. DiBernardo, Zhangyu Cheng of Carnegie Mellon; Sinda Fekir and Christopher I. Moore of Brown University; Donna B. Stolz of Pitt; Franca Cambi of Pitt and Veterans Administration; and Steven L Brody and Amjad Horani of Washington University.
This work was supported by Carnegie Mellon, the Kaufman Foundation, and the DSF Charitable Foundation, U.S. Department of Defense (VR190139), the National Institutes of Health (DP2 OD025926-01 and NIH RF1 MH114103), Air Force Office of Scientific Research (FA9550-19-1-13022629), NeuroNex (GR5260228.1001) and Brown University.

A new method can illuminate the identities and activities of cells throughout an organ or a tumor at unprecedented resolution, according to a study co-led by researchers at Weill Cornell Medicine, NewYork-Presbyterian and the New York Genome Center.
The method, described Jan. 2 in a paper in Nature Biotechnology, records gene activity patterns and the presence of key proteins in cells across tissue samples, while retaining information about the cells’ precise locations. This enables the creation of complex, data-rich “maps” of organs, including diseased organs and tumors, which could be widely useful in basic and clinical research.
“This technology is exciting because it allows us to map the spatial organization of tissues, including cell types, cell activities and cell-to-cell interactions, as never before,” said study co-senior author Dr. Dan Landau, an associate professor of medicine in the Division of Hematology and Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and a core faculty member at the New York Genome Center.
The other co-senior author was Dr. Marlon Stoeckius of 10x Genomics, a California-based biotechnology company that makes laboratory equipment for the profiling of cells within tissue samples. The three co-first authors were Dr. Nir Ben-Chetrit, Xiang Niu, and Ariel Swett, respectively a postdoctoral researcher, graduate student, and research technician in the Landau laboratory during the study.
The new method is part of a broad effort by scientists and engineers to develop better ways of “seeing” at micro scale how organs and tissues work. Researchers in recent years have made big advances particularly in techniques for profiling gene activity and other layers of information in individual cells or small groups of cells. However, these techniques typically require the dissolution of tissues and the separation of cells from their neighbors, so that information about profiled cells’ original locations within the tissues is lost. The new method captures that spatial information as well, and at high resolution.
The method, called Spatial PrOtein and Transcriptome Sequencing (SPOTS), is based in part on existing 10x Genomics technology. It uses glass slides that are suitable for imaging tissue samples with ordinary microscope-based pathology methods, but are also coated with thousands of special probe molecules. Each of the probe molecules contains a molecular “barcode” denoting its two-dimensional position on the slide. When a thinly sliced tissue sample is placed on the slide and its cells are made permeable, the probe molecules on the slide grab adjacent cells’ messenger RNAs (mRNAs), which are essentially the transcripts of active genes. The method includes the use of designer antibodies that bind to proteins of interest in the tissue — and also bind to the special probe molecules. With swift, automated techniques, researchers can identify the captured mRNAs and selected proteins, and map them precisely to their original locations across the tissue sample. The resulting maps can be considered alone, or compared to standard pathology imaging of the sample.
The team demonstrated SPOTS on tissue from a normal mouse spleen, revealing the complex functional architecture of this organ including clusters of different cell types, their functional states, and how those states varied with the cells’ locations.
Highlighting SPOTS’ potential in cancer research, the investigators also used it to map the cellular organization of a mouse breast tumor. The resulting map depicted immune cells called macrophages in two distinct states as denoted by protein markers — one state active and tumor-fighting, the other immune-suppressive and forming a barrier to protect the tumor.
“We could see that these two macrophage subsets are found in different areas of the tumor and interact with different cells — and that difference in microenvironment is likely driving their distinct activity states,” said Dr. Landau, who is also an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.
Such details of the tumor immune environment — details that often can’t be resolved due to immune cells’ sparseness within tumors — might help explain why some patients respond to immune-boosting therapy and some don’t, and thus could inform the design of future immunotherapies, he added.
This initial version of SPOTS has a spatial resolution such that each “pixel” of the resulting dataset sums gene activity information for at least several cells. However, the researchers hope soon to narrow this resolution to single cells, while adding other layers of key cellular information, Dr. Landau said.
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see profile for Dr. Landau.

Vaccination and boosting, especially when recent, helped to limit the spread of COVID-19 in California prisons during the first Omicron wave, according to an analysis by researchers at UC San Francisco that examined transmission between people living in the same cell.
The study demonstrates the benefits of vaccination and boosting, even in settings where many people are still getting infected, in reducing transmission. And it shows the cumulative effects from boosting and the additional protection that vaccination gives to those who were previously infected. The likelihood of transmission fell by 11 percent for each additional dose.
“A lot of the benefits of vaccines to reduce infectiousness were from people who had received boosters and people who had been recently vaccinated,” said Nathan Lo, MD, PhD, a faculty research fellow in the Division of HIV, Infectious Diseases and Global Medicine at UCSF and the senior author of the study, published Jan. 2, 2022, in Nature Medicine. “Our findings are particularly relevant to improving health for the incarcerated population.”
The researchers analyzed deidentified data collected by the California Department of Corrections and Rehabilitation (CDCR). This included COVID-19 test results, vaccine status and housing locations for 111,687 residents, 97% of whom were male, between Dec. 15, 2021, and May 20, 2022.
Breakthrough infections were common, despite the residents’ relatively high vaccination rate of 81% with the primary vaccine series. But the rate of serious illness was low. In just over five months, there were 22,334 confirmed SARS-CoV-2 Omicron infections, 31 hospitalizations and no COVID-19 deaths.
Vaccinated residents with breakthrough infections were significantly less likely to transmit them: 28% versus 36% for those who were unvaccinated. But the likelihood of transmission grew by 6% for every five weeks that passed since someone’s last vaccine shot.

Natural immunity from a prior infection also had a protective effect, and the risk of transmitting the virus was 23% for someone with a reinfection compared to 33% for someone who had never been infected.
Those with hybrid immunity, from both infection and vaccination, were 40% less likely to transmit the virus. Half of that protection came from the immunity that one acquires from fighting an infection and the other half came from being vaccinated.
The researchers said they were gratified to see that vaccination confers addition protection even for those who had already been infected, but they were surprised by how much the infection continued to spread, despite the residents’ relatively high vaccination rates.
“Regardless of the benefits you see in vaccination and prior infection, there is still a high amount of transmission in this study,” said Sophia Tan, a researcher in Lo’s lab and the study’s first author. “We hope these findings can support ongoing efforts to protect this vulnerable population.”
This includes making efforts to keep residents current with boosters and increasing the vaccination rate of the prison staff, only 73 percent of whom had received the primary series at the time of the study.
The general rate of boosting could also be improved significantly. At the time of the study, just 59% of residents and 41% of staff had received all the doses recommended by the U.S. Centers for Disease Control and Prevention (CDC), based on their age and health status.
“Within the two months following vaccination, people are the least infectious, which indicates that boosters and large timed vaccination campaigns may have a role to reduce transmission in surges,” Lo said. “New ideas are needed since the risk of infection in this vulnerable population remains so great.”
Authors: In addition to Lo and Tan, authors include Ada Kwan, PhD, MHS, Isabel Rodríguez-Barraquer, MD, PhD, Benjamin Singer, PhD, Hailey Park, and David Sears, MD, of UCSF; and Joseph Lewnard, PhD, of UC Berkeley.
Funding: National Institutes of Health, NIAID New Innovator Award (DP2AI170485).

Adults who stay well-hydrated appear to be healthier, develop fewer chronic conditions, such as heart and lung disease, and live longer than those who may not get sufficient fluids, according to a National Institutes of Health study published in eBioMedicine.
Using health data gathered from 11,255 adults over a 30-year period, researchers analyzed links between serum sodium levels — which go up when fluid intake goes down — and various indicators of health. They found that adults with serum sodium levels at the higher end of a normal range were more likely to develop chronic conditions and show signs of advanced biological aging than those with serum sodium levels in the medium ranges. Adults with higher levels were also more likely to die at a younger age.
“The results suggest that proper hydration may slow down aging and prolong a disease-free life,” said Natalia Dmitrieva, Ph.D., a study author and researcher in the Laboratory of Cardiovascular Regenerative Medicine at the National Heart, Lung, and Blood Institute (NHLBI), part of NIH.
The study expands on research the scientists published in March 2022, which found links between higher ranges of normal serum sodium levels and increased risks for heart failure. Both findings came from the Atherosclerosis Risk in Communities (ARIC) study, which includes sub-studies involving thousands of Black and white adults from throughout the United States. The first ARIC sub-study started in 1987 and has helped researchers better understand risk factors for heart disease, while shaping clinical guidelines for its treatment and prevention.
For this latest analysis, researchers assessed information study participants shared during five medical visits — the first two when they were in their 50s, and the last when they were between ages 70-90. To allow for a fair comparison between how hydration correlated with health outcomes, researchers excluded adults who had high levels of serum sodium at baseline check-ins or with underlying conditions, like obesity, that could affect serum sodium levels.
They then evaluated how serum sodium levels correlated with biological aging, which was assessed through 15 health markers. This included factors, such as systolic blood pressure, cholesterol, and blood sugar, which provided insight about how well each person’s cardiovascular, respiratory, metabolic, renal, and immune system was functioning. They also adjusted for factors, like age, race, biological sex, smoking status, and hypertension.

They found that adults with higher levels of normal serum sodium — with normal ranges falling between 135-146 milliequivalents per liter (mEq/L) — were more likely to show signs of faster biological aging. This was based on indictors like metabolic and cardiovascular health, lung function, and inflammation. For example, adults with serum sodium levels above 142 mEq/L had a 10-15% associated increased odds of being biologically older than their chronological age compared to ranges between 137-142 mEq/L, while levels above 144 mEq/L correlated with a 50% increase. Likewise, levels of 144.5-146 mEq/L were associated with a 21% increased risk of premature death compared to ranges between 137-142 mEq/L.
Similarly, adults with serum sodium levels above 142 mEq/L had up to a 64% increased associated risk for developing chronic diseases like heart failure, stroke, atrial fibrillation and peripheral artery disease, as well as chronic lung disease, diabetes, and dementia. Conversely, adults with serum sodium levels between 138-140 mEq/L had the lowest risk of developing chronic disease.
The findings don’t prove a causal effect, the researchers noted. Randomized, controlled trials are necessary to determine if optimal hydration can promote healthy aging, prevent disease, and lead to a longer life. However, the associations can still inform clinical practice and guide personal health behavior.
“People whose serum sodium is 142 mEq/L or higher would benefit from evaluation of their fluid intake,” Dmitrieva said. She noted that most people can safely increase their fluid intake to meet recommended levels, which can be done with water as well as other fluids, like juices, or vegetables and fruits with a high water content. The National Academies of Medicine, for example, suggest that most women consume around 6-9 cups (1.5-2.2 liters) of fluids daily and for men, 8-12 cups (2-3 liters).
Others may need medical guidance due to underlying health conditions. “The goal is to ensure patients are taking in enough fluids, while assessing factors, like medications, that may lead to fluid loss,” said Manfred Boehm, M.D., a study author and director of the Laboratory of Cardiovascular Regenerative Medicine. “Doctors may also need to defer to a patient’s current treatment plan, such as limiting fluid intake for heart failure.”
The authors also cited research that finds about half of people worldwide don’t meet recommendations for daily total water intake, which often starts at 6 cups (1.5 liters).
“On the global level, this can have a big impact,” Dmitrieva said. “Decreased body water content is the most common factor that increases serum sodium, which is why the results suggest that staying well hydrated may slow down the aging process and prevent or delay chronic disease.”
This research was supported by the Division of Intramural Research at NHLBI. The ARIC study has been supported by research contracts from NHLBI, NIH, and the Department of Health and Human Services.

In 1938, researchers at Harvard set out to learn what makes a person thrive.They recruited 724 participants, a combination of students at Harvard College and low-income teenage boys in Boston. All were willing to let the researchers track their lives, from childhood troubles to first loves to final days.Every five years, the researchers gathered health records from the participants. They asked detailed questions about their lives at two-year intervals, and, in later years, took DNA samples and performed brain scans. Twenty-five of the participants even donated their brains to the study after their deaths.Now, 85 years later, the Harvard Study of Adult Development has expanded to three generations and more than 1,300 descendants of the original subjects; it is, according to the researchers, the longest-running in-depth study on human happiness in the world.From all the data, one very clear finding has emerged: Strong relationships are what make for a happy life. More than wealth, I.Q. or social class, it’s the robustness of our bonds that most determines whether we feel fulfilled.How to build your social bonds for more joyIn a new book, “The Good Life: Lessons From the World’s Longest Scientific Study of Happiness,” Dr. Bob Waldinger, a professor of psychiatry at Harvard Medical School and the study’s fourth director, and Marc Schulz, an associate director of the study and a psychology professor at Bryn Mawr College, have distilled the study’s insights.If you’re going to do one thing this year to ensure your own health and happiness, the authors maintain, find the time to nurture and develop relationships. To help get you started, Dr. Waldinger and I have created this challenge — seven simple exercises, starting with taking today’s quiz.Dr. Waldinger and Dr. Shultz have coined a term for the process of assessing and treating the health of our relationships: “social fitness.” It’s just as crucial as physical fitness, said Dr. Waldinger, who added that neglected relationships can atrophy, like muscles. “Our social life is a living system, and it needs exercise,” he said. “It’s a choice you make to invest in, week by week, year by year — one that has huge benefits.”Why ‘social fitness’ mattersThe Harvard study is far from the only one to have found a link between our relationships and happiness. Ample research shows that people who are more socially connected live longer and are more protected against stress, depression and declines in memory and language.Loneliness, on the other hand, damages our physical health. “I believe loneliness is one of the defining public health concerns of our time,” Surgeon General Vivek Murthy told me in an email. While the pandemic exacerbated loneliness, he added, “it also helped many people take stock of their lives and reflect more deeply on how important their relationships are. That means taking steps in our day-to-day lives to invest in them.”It’s not just your bonds with friends and family that are crucial to happiness. It’s your relationships with romantic partners and community groups. It’s the friendly conversation with your mail carrier or the acquaintance you see at the dog run.Take the quizToday, you will identify the areas of your life in which you would like to be more connected. “Maybe you’ve got lots of people to have fun with, but you don’t have anyone to confide in about really personal, private things,” Dr. Waldinger said. “Or maybe you’ve got lots of people to confide in but don’t have anyone to have fun with.”A few things before you begin:There is no right number of friends. Don’t get hung up on numbers, Dr. Waldinger said. It’s the quality of your relationships, not the quantity, so try to discern what is most fulfilling for you (our quiz will help give you some perspective).You don’t need to be an extrovert to improve your social fitness. While adult friendships require effort, happiness is not out of reach for you if you are shy or introverted, Dr. Waldinger said. You can engage with others in quieter settings around things that you care about. Try small, controlled activities such as a knitting group, a computer programming class, hiking or working in a community garden.It’s never too late. People often assume that it’s too late for them to build relationships, Dr. Waldinger said, but that’s never the case. He points to many stories in “The Good Life” about people who made connections later in life, like a lonely 68-year-old who joined a gym after he’d retired. Three months later, he had amassed more friends than he’d ever had in his life.From the Friendship Files: Amy and AlEach day of the challenge, we’ll be sharing stories of meaningful friendships collected from readers across the country. We’d love to hear yours — tell your own tale of friendship here.Amy Pechukas met her friend Al in 2018 when she rented the apartment under his in Northampton, Mass. They didn’t connect immediately. Amy, now 42, worked four jobs and thought Al, 76, was a curmudgeon with questionable boundaries. He helped look after their two-family home and would frequently enter her apartment to check on her two cats and two dogs.But Al’s peculiar brand of kindness grew on her. “He often pops in for a conversation spontaneously, at times when I need a lift, and we end up talking for hours,” she said. “We go for evening walks and argue about the route.”Covid brought them even closer. During lockdown, they would meet in the driveway to talk about the virus or politics. Amy made a Thanksgiving meal, which they ate outside on their porch with electric blankets on their laps. They have celebrated the holiday together ever since.Al can still be overbearing. He has firm ideas about the way things should be done around the home, like the “right” way to rake the leaves. Every summer, he frets that Amy’s elderly cat, who grows lazy in the heat, is on the verge of death.But Amy feels deep gratitude for their unexpected friendship, and for the constant, unselfish care Al has shown her and her pets. “When my dog got very sick a year ago and needed me to do round-the-clock care for her, I would come home on occasion to find Al in my kitchen doing my dishes,” she recalled. “‘You can’t do everything, Amy,’ he’d say. ‘You’re doing a great job.’”Though Al does not say it outright, Amy knows he worries she might move out. She recently interviewed for a position out of state, and Al told her several times that it sounded terrible — reminding her that there were other jobs closer by.“We just have a lot of fun,” she said. “We like to quote movie lines endlessly, we’ll do that for, like, two hours straight. Last winter we went ice skating in the cemetery because it was flooded. Al’s just a good person.” — Catherine Pearson

The question at the heart of America’s abortion debate is the most elemental — and the most complicated. It was […]

JENNINGS, Mo. — Brittnee Marsaw was born to a 15-year-old mother in St. Louis and raised by a grandmother who had given birth even younger. Half grown by the time her mother could support her, Ms. Marsaw joined her three states away but never found the bond she sought and calls the teen births of preceding generations “the family curse.”Ana Alvarez was born in Guatemala to a teenage mother so poor and besieged that she gave her young daughter to a stranger, only to snatch her back. Soon her mother left to seek work in the United States, and after years of futilely awaiting her return Ms. Alvarez made the same risky trip, becoming an undocumented teenager in Washington, D.C., to reunite with the mother she scarcely knew.While their experiences diverge, Ms. Marsaw and Ms. Alvarez share a telling trait. Stung by the struggles of their teenage mothers, both made unusually self-conscious vows not to become teen mothers themselves. And both say that delaying motherhood gave them — and now their children — a greater chance of success.Their decisions highlight profound changes in two related forces that shape how opportunity is conveyed or impeded from one generation to the next. Teen births have fallen by more than three-quarters in the last three decades, a change of such improbable magnitude that experts struggle to fully explain it. Child poverty also plunged, raising a complex question: Does cutting teen births reduce child poverty, or does cutting child poverty reduce teen births?Ana Alvarez with her daughter, Emily. Ms. Alvarez was born in Guatemala to a poor teenage mother.Shuran Huang for The New York TimesWhile both may be true, it is not clear which dominates. One theory holds that reducing teen births lowers child poverty by allowing women to finish school, start careers and form mature relationships, raising their income before they raise children. Another says progress runs the other way: Cutting child poverty reduces teen births, since teenagers who see opportunity have motives to avoid getting pregnant.Ms. Marsaw, who waited until 24 to have a child — a daughter, Zaharii — has considered the issue at length and embraces both views.“This is a very, very, very good topic — it touches home with me in so many ways!” she said, adding that teen pregnancy and child poverty reinforce each other. “If you escape one, you have a better chance of escaping the other.”Teen births have fallen by 77 percent since 1991, and among young teens the decline is even greater, 85 percent, according to an analysis by Child Trends, a research group that studies children’s well-being. Births have fallen at roughly equal rates among teenagers who are white, Hispanic and Black, and they have fallen by more than half in every state.The decline is accelerating: Teen births fell 20 percent in the 1990s, 28 percent in the 2000s and 55 percent in the 2010s. Three decades ago, a quarter of 15-year-old girls became mothers before turning 20, according to Child Trends estimates, including nearly half of those who were Black or Hispanic. Today, just 6 percent of 15-year-old girls become teen mothers.Teen births have fallen by 77 percent since 1991, and among young teens the decline is 85 percent.Shuran Huang for The New York Times“These are dramatic declines — impressive, surprising, and good for both teenagers and the children they eventually have,” said Elizabeth Wildsmith, a Child Trends researcher who did the analysis with a colleague, Jennifer Manlove.Not all teen mothers are poor, of course, and many who do experience poverty escape it.The reasons teen births have fallen are only partly understood. Contraceptive use has grown and shifted to more reliable methods, and adolescent sex has declined. Civic campaigns, welfare restrictions and messaging from popular culture may have played roles.But with progress so broad and sustained, many researchers argue the change reflects something more fundamental: a growing sense of possibility among disadvantaged young women, whose earnings and education have grown faster than their male counterparts.“They’re going to school and seeing new career paths open,” said Melissa S. Kearney, an economist at the University of Maryland. “Whether they are excited about their own opportunities or feel that unreliable male partners leave them no choice, it leads them in the same direction — not becoming a young mother.”Mindful of their mothers’ struggles, Ms. Marsaw, 29, and Ms. Alvarez, 34, each offer a study of why teen births are falling and how the decline might affect upward mobility. One woman found that it brought the prosperity she had sought. One hopes it still will.Ms. Alvarez quit school after fourth grade to help her grandfather care for her younger siblings.Shuran Huang for The New York TimesA Path to CollegeMs. Alvarez felt left behind even before her mother left Guatemala. Nineteen and single when she had her second child, her mother left the family farm to work in the city, and their contact shrank to monthly visits.After her mother had more children, a woman she met in a clinic waiting room offered to adopt one. Ms. Alvarez was equally surprised first to be given away and then to be reclaimed months later. Then her mother departed for Washington, and Ms. Alvarez came to think of a mother as “something I hoped that someday I will have.”She quit school after fourth grade to help her grandfather care for her younger siblings. For her 15th birthday, she asked her mother to hire a smuggler to bring her north.The reunion disappointed. To Ms. Alvarez’s surprise, her mother was married and had another child. She seemed distant, stern and impatient with questions about why she had left. “I had more resentment than I understood,” Ms. Alvarez said.Ms. Alvarez’s daughters, Emily, left, and Madeline, with her mother, JuanaShuran Huang for The New York TimesWhile Ms. Alvarez did not find reconciliation, she did find opportunity. Starting high school as an undocumented Spanish-speaking migrant with a fourth-grade education, she was a better student than she knew. A counselor at a Washington clinic, Mary’s Center, said she could earn a college scholarship.Looking no further than her mother’s life, she saw a threat. “I realized if I get pregnant, I’m not going to college,” she said.It was one thing to set her goal, another to sustain it though a precarious adolescence. Of the two ways to avoid pregnancy, Ms. Alvarez judged abstinence more certain than contraception and ignored girls who teased her for avoiding sex.In her junior year, a suitor named Fredy who worked as a cook asked her to move in. He was seven years older, fun and supportive, and she needed a place to stay, having left her mother’s apartment for a rented room. But she forced herself to stop taking his calls. She graduated from high school at 20 with the college scholarship — neither a teen nor a parent.Ms. Alvarez met Fredy in her junior year of high school, from which she graduated at 20. They later married after reconnecting.Shuran Huang for The New York Times“Wow, I made it all the way to college!” she told herself.Ms. Marsaw may be even more inclined to see her life through the prism of adolescent pregnancy. Her grandmother raised her on a food stamp budget in a house with a dozen aunts, uncles and cousins, while her mother, who had given birth at 15, came and went and finished her teens with a second child.When Ms. Marsaw let slip in third grade that her mother had a different address, she was transferred to a distant school, and care fell to a rotating cast of relatives. She came to think of her mother as “a person I needed that I couldn’t reach.”Her mother moved to Atlanta to work as a medical technician. Ms. Marsaw followed but felt frustrated by her mother’s long hours and emotional remove. Where others might see a parent striving to get ahead, Ms. Marsaw felt a new way of being left behind. “The reason I’m a fast talker is because I wanted to get my point across before she walked out for her 16-hour shift,” she said.She identified the cause of her mother’s struggles — teen motherhood — and pledged to avoid it. In 10th grade, she insisted that her boyfriend use condoms. In 11th grade, she stopped dating. Classmates taunted her, but loner status was a price she was willing to pay. “I did what it took not to have children,” she said.She returned to Missouri for her senior year and wrote herself a letter years later, celebrating what she achieved: “U finished high school w/no children so pat yourself on the back.”Abortion does not appear to have driven the decline in teen births.Shuran Huang for The New York Times‘Greater Confidence’On the surface, the decline in teen births is easy to explain: Contraception rose, and sex fell.The share of female teens who did not use birth control the last time they had sex dropped by more than a third over the last decade, according to an analysis of government surveys by the Guttmacher Institute. The share using the most effective form, long-acting reversible contraception (delivered through an intrauterine device or arm implant), rose fivefold to 15 percent. The use of emergency contraception also rose.Contraception use has grown in part because it is easier to get, with the 2010 Affordable Care Act requiring insurance plans, including Medicaid, to provide it for free.At the same time, the share of high school students who say they have had sexual intercourse has fallen 29 percent since 1991, Child Trends found. Some analysts, including Brad Wilcox, a sociologist at the University of Virginia, say the postponement of sex, which has intensified since 2013, stems in part from the time teens spend in front of screens.Abortion does not appear to have driven the decline in teen births. As a share of teenage pregnancy, it has remained steady over the past decade, although the data, from the Centers for Disease Control and Prevention, omits medication abortions, and analysts say the recent Supreme Court decision in Dobbs v. Jackson Women’s Health Organization, eliminating the constitutional right to abortion, could cause teen births to rise.If adolescent girls are more cautious with sex and birth control, what explains the caution? A common answer is that more feel they have something to lose. “There is just a greater confidence among young women that they have educational and professional opportunities,” Mr. Wilcox said.In 2013, the economists David Autor and Melanie Wasserman found that women in their mid-30s were nearly 25 percent more likely than men to have a four-year college degree, and at every educational level earnings had grown faster for women than men.The reasons teen births have fallen are only partly understood. Shuran Huang for The New York TimesWith teen births and child poverty falling in tandem, the chicken-egg question that follows, is which caused which?It may seem intuitive that postponing motherhood helps teens escape poverty. But some researchers say the opposite dynamic drives change: Cutting child poverty reduces teen births. They cite studies that have found that most adolescents who become teen mothers are so disadvantaged their prospects would not improve even if they postponed childbirth.The studies compared women who gave birth as teens with those from similar backgrounds who avoided teen birth (in some cases sisters), and found the groups fared similarly as adults.“Research has shown that among those who grow up in disadvantaged circumstances teen childbearing has little independent effect on economic outcomes,” said Ms. Wildsmith, the Child Trends analyst.Skeptics see limits in the data and note that the payoff to education is growing.“I strongly disagree with the argument that teen births have no effect on social mobility,” said Isabel V. Sawhill of the Brookings Institution. “It’s a lot easier to move out of poverty if you’re not responsible for a child in your teenage years.”The debate is more than academic. Some progressives worry that a narrow focus on preventing teen births will undermine broader anti-poverty plans and risks blaming adolescents for their poverty. Other see reducing poverty and teen births as complementary causes meant not to blame young women but empower them.Ms. Marsaw identified the cause of her mother’s struggles as teen motherhood and pledged to avoid it.Shuran Huang for The New York TimesAchieving a DreamAs a test of whether postponing birth reduces poverty, Ms. Marsaw’s life yields ambiguous conclusions. Even without a child, her transition to adulthood proved difficult. She was slowed by an immobilizing bout of depression, which she blamed in part on her childhood separations from her mother.“Forgive ur mom,” she later wrote to herself. “She was so young.”In her early 20s, she followed her mother to Texas, got a job at an indoor amusement park and dated a man who parked cars. For all her teenage vigilance, she stopped using contraception, figuring “if happens, it won’t be a crisis.”She gave birth at 24, nearly nine years later than her mother.Hardship followed nonetheless. Her depression returned and her relationship ended. Unable to pay the rent alone, she returned to St. Louis. She and Zaharii, 5, have lived in at least seven places — eight, counting times when they slept in a car — though Ms. Marsaw is proud that unlike her mother she never left her daughter in someone else’s care. As an anti-poverty strategy, postponing motherhood was not foolproof.Ms. Marsaw returned to St. Louis after she was unable to afford rent.Shuran Huang for The New York TimesStill, Ms. Marsaw sees benefits to the wait. She is more “emotionally intelligent” as a parent, she said, more savvy about jobs, and more resilient. She also said an earlier start might have left her with a second child before she was ready.Last year she got a commercial driver’s license and spent months as a cross-country trucker, with Zaharii sharing the cab. She is driving a child care van for the winter, and with an income of about $40,000 she managed to buy a small house. Her mother sometimes helps, and their relationship has improved, with Ms. Marsaw more sympathetic to the sacrifices she made to advance.“I don’t feel as though I have completely accomplished who I am or where I want to be,” she said. “But I’m no longer in poverty.”For Ms. Alvarez, the story is simpler: Her future unfolded as planned. Though still working on her English, she managed the transition to the University of the District of Columbia. In her second year, fortune smiled: She boarded a city bus and ran into Fredy, the man who had pursued her in high school.Like Ms. Marsaw, she no longer feared pregnancy as she had in her teens. When a lapse in contraceptive use had a predictable effect, the news solidified her plans more than it disrupted them. She married shortly before giving birth at 23. “You’ve never ready to become a mother, but I felt like I can do this,” she said.Ms. Alvarez practiced abstinence in high school and ignored girls who teased her for avoiding sex.Shuran Huang for The New York TimesA baby did slow her educational progress. Working two jobs, she took six years to earn a bachelor’s degree, then started a job at Mary’s Center, the clinic that had encouraged her to seek scholarships.She coordinates care for cancer patients and has legal protection under Deferred Action for Childhood Arrivals, a program for undocumented migrants who came to the United States as youths. With a family income above the national average, she and her husband recently bought their first house.“If I die tomorrow, I can say I achieved the American dream,” Ms. Alvarez said. “But if I had gotten pregnant as a teenager? I’m not sure, but I don’t think so.”

Researchers at The University of Texas MD Anderson Cancer Center have discovered a novel immunotherapy combination, targeting checkpoints in both T cells and myeloid suppressor cells, that successfully reprogrammed the tumor immune microenvironment (TIME) and significantly improved anti-tumor responses in preclinical models of pancreatic cancer.
In this study, published today in Nature Cancer, researchers used comprehensive immune profiling in mouse and human pancreatic cancers to systematically identify mechanisms of immunotherapy resistance and investigate potential therapeutic targets. They found that neutralizing several distinct immunosuppressive mechanisms of the TIME dramatically improved survival rates in laboratory models, pointing to a potential treatment option for this notoriously lethal and unresponsive cancer.
“This triple combination therapy led to an unprecedented curative response in our models,” said corresponding author Ronald DePinho, M.D., professor of Cancer Biology. “The prevailing view has been that pancreatic cancer is impervious to immunotherapy, but this preclinical study shows that it can be vulnerable to the right combination therapy. Moreover, the presence of these targets in human pancreatic cancer specimens raises the exciting possibility that such therapeutic combinations could one day help our patients.”
Pancreatic cancer is one of the leading causes of cancer death in the United States, partially because 80% of cases are diagnosed at an advanced stage. Pancreatic cancer is also considered to be “non-immunogenic,” meaning it is unresponsive to commonly used anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors. This is due in part to the immunosuppressive conditions in the TIME, but the mechanisms behind this resistance are not fully understood.
The researchers used high-dimensional immune profiling and single-cell RNA sequencing to study how the TIME is affected by a variety of immunotherapies. They identified specific immune checkpoint proteins, 41BB and LAG, that were highly expressed in exhausted T cells.
In testing antibodies targeting these checkpoints, the researchers observed that models treated with a 41BB agonist and LAG3 antagonist in combination had slower tumor progression, higher levels of anti-tumor immunity indicators and significantly improved survival rates compared to treatment with either antibody alone or with other checkpoint inhibitors. Notably, these preclinical studies faithfully mirrored the human data in their lack of efficacy of anti-PD1 or anti-CTLA-4 therapy.
The researchers also confirmed these two therapeutic targets are present in human pancreatic cancer samples, with 81% and 93% of patients analyzed having T cells with 41BB and LAG3 expression, respectively.
Because this dual-therapy combination did not completely eliminate established tumors, the investigators also examined efforts to reprogram the TIME to further sensitize tumors to immunotherapy. At baseline, the TIME contained an abundance of myeloid-derived suppressor cells (MDSCs) expressing CXCR2, a protein associated with recruiting immunosuppressive cells. Inhibiting CXCR2 alone decreased MDSC migration and blocked tumor growth, but it was not curative. This prompted the investigators to consider a combination targeting 41BB, LAG3 and CXCR2.
It was this triple combination that resulted in complete tumor regression and improved overall survival in 90% of preclinical models. In a more stringent lab model that develops multiple spontaneously arising tumors with higher treatment resistance, the combination achieved complete tumor regression in over 20% of cases.
“These are encouraging results, especially considering the lack of effective immunotherapy options in pancreatic cancer,” DePinho said. “By targeting multiple synergistic mechanisms that get in the way of the immune response, we can give T cells a fighting chance to attack these tumors. Of course, we still need to see how this combination translates into a safe and effective regimen in the clinic, and we invite other researchers to build upon these results. We are optimistic that pancreatic cancers, and hopefully other non-immunogenic cancers, can ultimately be rendered vulnerable to combination immunotherapy.”
The authors point out that these particular immunotherapy agents currently are undergoing clinical trials as monotherapies, suggesting potential opportunities to rapidly translate this triple combination into clinical studies.
This work was supported by the National Institutes of Health/National Cancer Institute (P01 CA117969, RO1CA240526, RO1CA236864, R01CA231349, R01CA220236, P50CA221707), the Elsa U. Pardee Foundation, MD Anderson’s Advanced Scholar Program, the Eleanor Russo Fund for Pancreatic Research, Ralph A. Loveys Family Charitable Foundation, the Cultural & Charitable Club of Somerset Run, the New Jersey Health Foundation, the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, and MD Anderson’s Pancreatic Cancer Moon Shot®.