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Doctors who want to prescribe tecovirimat, or Tpoxx, must navigate a gantlet of bureaucratic hurdles that experts say could be quickly lifted.The only drug available to treat monkeypox is so difficult to access that just a fraction of the nearly 7,000 patients in the United States have been given it.Health officials have designated tecovirimat, also called Tpoxx, an “investigational drug,” which they say means it cannot be released from the strategic national stockpile without a series of convoluted bureaucratic steps. But most doctors do not have the time or resources to fill out the required 27-page application or to provide the detailed patient information.It doesn’t have to be this way, experts say: There is no law preventing federal officials from changing those rules and making the drug more widely available.The Food and Drug Administration approved tecovirimat as a smallpox treatment in 2018, based on safety data in people and efficacy data in primates — which, for the purposes of the trial, actually were infected with monkeypox. The so-called animal rule allows the agency to approve drugs when testing them in people would be unethical.Until the current outbreak, tecovirimat was given only rarely to monkeypox patients. As a smallpox treatment, its use against monkeypox is considered experimental. But vaccines developed for smallpox have been assumed to be effective against both diseases. Why not the treatment?Experts say the F.D.A.’s restrictions are a policy choice that can be quickly altered.“The bureaucracy of gaining access to Tpoxx is excessive given the crisis the U.S. is facing with monkeypox,” said Larry O. Gostin, an expert on public health law and director of the O’Neill Institute for National and Global Health Law at Georgetown University.“The law gives the agency considerable flexibility to use scientific assessments to ensure those in need get the medication that can help them,” he added.The Department of Health and Human Services on Thursday declared monkeypox a national health emergency. But Secretary Xavier Becerra did not take an additional step that would have allowed the F.D.A. to grant emergency use authorizations for vaccines and treatments, as the agency did during the coronavirus pandemic.In an article published in the New England Journal of Medicine on Wednesday, federal health officials defended their decision to treat tecovirimat as an investigational drug.While acknowledging that animal data was promising and that the drug seemed safe in healthy patients, they wrote that, without large clinical trials, “we will not know whether tecovirimat would benefit, harm or have no effect on people with monkeypox disease.”What to Know About the Monkeypox VirusCard 1 of 7What is monkeypox?

Empowering Medicare to negotiate prices directly with drug makers has been a Democratic goal for 30 years, one the pharmaceutical industry has fought ferociously.WASHINGTON — For decades, as prescription drug costs have soared, Democrats have battled with the pharmaceutical industry in pursuit of an elusive goal: legislation that could drive down prices by allowing Medicare to negotiate directly with drug makers.Now they are on the verge of passing a broad budget bill that would do just that, and in the process deliver President Biden a political victory that he and his party can take to voters in November.Empowering Medicare to negotiate prices for up to 10 drugs initially — and more later on — along with several other provisions aimed at lowering health care costs, would be the most substantial change to health policy since the Affordable Care Act became law in 2010, affecting a major swath of the population. It could save some older Americans thousands of dollars in medication costs each year.The legislation would extend, for three years, the larger premium subsidies that low- and middle-income people have received during the coronavirus pandemic to get health coverage under the Affordable Care Act, and allow those with higher incomes who became eligible for such subsidies during the pandemic to keep them. It would also make drug makers absorb some of the cost of medicines whose prices rise faster than inflation.Significantly, it also would limit how much Medicare recipients have to pay out of pocket for drugs at the pharmacy to $2,000 annually — a huge benefit for the 1.4 million beneficiaries who spend more than that each year, often on medicines for serious diseases like cancer and multiple sclerosis.Lower prices would make a huge difference in the lives of people like Catherine Horine, 67, a retired secretary and lung recipient from Wheeling, Ill. She lives alone on a fixed income of about $24,000 a year. Her out-of-pocket drug costs are about $6,000 a year. She is digging into her savings, worried she will run out of money before long.“Two years ago, I was $8,000 in the hole,” she said. “Last year, I was $15,000 in the hole. I expect to be more this year, because of inflation.”Between 2009 and 2018, the average price more than doubled for a brand-name prescription drug in Medicare Part D, the program that covers products dispensed at the pharmacy, the Congressional Budget Office found. Between 2019 and 2020, price increases outpaced inflation for half of all drugs covered by Medicare, according to an analysis from the Kaiser Family Foundation.The budget office estimates that the bill’s prescription drug provisions will save the federal government $288 billion over 10 years, in part by forcing the pharmaceutical industry to accept lower prices from Medicare for some of its big sellers. Opponents argue that the measure would discourage innovation and cite a new C.B.O. analysis that projects that it would actually lead to higher prices when drugs first come on the market. The Biden PresidencyWith midterm elections looming, here’s where President Biden stands.A Sudden Shift: With progress on major legislation and falling gas prices, President Biden faces the challenge of making those successes resonate.Struggling to Inspire: At a time of political tumult and economic distress, Mr. Biden has appeared less engaged than Democrats had hoped.Low Approval Rating: For Mr. Biden, a pervasive sense of pessimism among voters has pushed his approval rating to a perilously low point.Questions About 2024: Mr. Biden has said he plans to run for a second term, but at 79, his age has become an uncomfortable issue.A Familiar Foreign Policy: So far, Mr. Biden’s approach to foreign policy is surprisingly consistent with the Trump administration, analysts say.Drugs for common conditions like cancer and diabetes that affect older people are most likely to be picked for negotiations. Analysts at the investment bank SVB Securities pointed to the blood thinner Eliquis, the cancer medication Imbruvica and the drug Ozempic, which is given to manage diabetes and obesity, as three of the first likely targets for negotiation.Until recently, the idea that Medicare, which has about 64 million beneficiaries, would be able to use its muscle to cut deals with drug makers was unthinkable. Democrats have been pushing for it since President Bill Clinton proposed his contentious health care overhaul in 1993. The pharmaceutical industry’s fierce lobbying against it has become Washington lore.“This is like lifting a curse,” Senator Ron Wyden, Democrat of Oregon and the architect of the measure, said of the Medicare negotiation provision. “Big Pharma has been protecting the ban on negotiation like it was the Holy Grail.”Senator Ron Wyden is the architect of the drug-price negotiation measure.Haiyun Jiang/The New York TimesDavid Mitchell, 72, is among those who would be helped. A retired Washington, D.C., public relations man, he learned in 2010 that he had multiple myeloma, an incurable blood cancer. He pays $16,000 out of pocket each year for just one of four medicines he takes. He also founded an advocacy group, Patients for Affordable Drugs.“Drugs don’t work if people can’t afford them, and too many people in this country can’t afford them,” Mr. Mitchell said. “Americans are angry and they’re being taken advantage of. They know it.”Still, the measure would not deliver every tool that Democrats would like for reining in prescription drug costs. The negotiated prices would not go into effect until 2026, and even then would apply only to a small fraction of the prescription drugs taken by Medicare beneficiaries. Pharmaceutical companies would still be able to charge Medicare high prices for new drugs.That is a disappointment to the progressive wing of the party; The American Prospect, a liberal magazine, has dismissed the measure as “exceedingly modest.”Prescription drug prices in the United States are far higher than those in other countries. A 2021 report from the RAND Corporation found that drug prices in this country were more than seven times higher than in Turkey, for instance.The pharmaceutical industry spends far more than any other sector to advance its interests in Washington. Since 1998, it has spent $5.2 billion on lobbying, according to Open Secrets, which tracks money in politics. The insurance industry, the next biggest spender, has spent $3.3 billion. Drug makers spread their money around, giving to Democrats and Republicans in roughly equal amounts.At a media briefing last week. Stephen J. Ubl, the chief executive of PhRMA, the drug industry’s main lobbying group, warned that the bill would reverse progress on the treatment front, especially in cancer care — a high priority for Mr. Biden, whose son died of a brain tumor.“Democrats are about to make a historic mistake that will devastate patients desperate for new cures,” Mr. Ubl said, adding, “Fewer new medicines is a steep price to pay for a bill that doesn’t do enough to make medicines more affordable.”But Dr. Aaron S. Kesselheim, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, said he believed the measure would spur innovation, by “encouraging investment in important new products rather than encouraging pharmaceutical companies to try to keep pushing the same product and delaying generic entry as long as possible.”President Bill Clinton proposed a contentious health care overhaul in 1993. Doug Mills/Associated PressIn 1999, after his health care plan failed, Mr. Clinton resurrected the idea of Medicare prescription drug coverage. But this time, instead of proposing that Medicare negotiate with companies, he suggested leaving that to the private sector.“At that point, what we were trying to do was to accommodate the recognition that Republicans were lockstep in opposition to any type of government role,” said Tom Daschle, the former Senate Democratic leader.But it took a Republican president, George W. Bush, and a Republican Congress to push the prescription drug benefit over the finish line.Medicare Part D, as the benefit is known, had the backing of the drug industry for two reasons: The companies became convinced they would gain millions of new customers, and the bill contained a “noninterference clause,” which explicitly barred Medicare from negotiating directly with drug makers. Repealing that clause is at the heart of the current legislation.The architect of the benefit was a colorful Louisiana Republican congressman, Billy Tauzin, who led the House Energy and Commerce committee at the time. In Washington, Mr. Tauzin is best remembered as an example of the drug industry’s influence: He left Congress in January 2005 to run PhRMA, drawing accusations that he was being rewarded for doing the companies’ bidding — an accusation Mr. Tauzin insists is a false “narrative” created by Democrats to paint Republicans as corrupt.Joel White, a Republican health policy consultant who helped write the 2003 law that created Medicare Part D, said the program was designed for private insurers, pharmacy benefit managers and companies that already negotiate rebates for Medicare plan sponsors to use their leverage to drive down prices.“The whole model was designed to promote private competition,” he said.In the years since Medicare Part D was introduced, polling has consistently found that a vast majority of Americans from both parties want the federal government to be allowed to negotiate drug prices. Former President Donald J. Trump embraced the idea, though only during his campaign.President Biden is on the verge of being able to sign legislation that could save older Americans thousands of dollars in medication costs annually.Tom Brenner for The New York TimesThe new legislation targets widely used drugs during a specific phase of their existence — when they have been on the market for a number of years but still lack generic competition. The industry has come under criticism for deploying strategies to extend the patent period, like slightly tweaking drug formulas or reaching “pay for delay” deals with rival manufacturers to postpone the arrival of cheap generics and “biosimilars,” as the generic versions of biotechnology drugs are called.The drug maker AbbVie, for instance, piled up new patents to maintain a monopoly on its blockbuster anti-inflammatory medicine Humira — and it has reaped roughly $20 billion a year from the drug since its main patent expired in 2016.Ten drugs would qualify for negotiation in 2026, with more added in subsequent years. The bill outlines criteria by which the drugs would be chosen, but the ultimate decision would rest with the health secretary — a provision that Mr. White, the Republican consultant, warned would lead to “an incredible lobbying campaign” to get drugs on the list or keep them off it.Analysts say the bill would hurt drug makers’ bottom lines. Analysts at the investment bank RBC Capital Markets estimated that most companies affected by the measure would bring in 10 to 15 percent less revenue annually by the end of the decade.But while PhRMA has warned that a decline in revenue will make drug makers less willing to invest in research and development, the Congressional Budget Office projected that only 15 fewer drugs would reach the market over the next 30 years, out of an estimated 1,300 expected in that time.The Senate is expected to take up the bill as early as Saturday, then send it to the House. If it passes, as expected, it will pierce the drug industry’s aura of power in Washington, opening the door for more drugs to become subject to negotiations, said Leslie Dach, founder of Protect Our Care, an advocacy group.“Once you lose your invincibility,” he said, “it’s a lot easier for people to take the next step.”

After years of pioneering research into inherited disorders, mostly in children, he spoke openly about his struggle with mental illness.Dr. Leon E. Rosenberg, who after spending decades as a pioneer in the field of medical genetics revealed that he had spent just as long struggling with manic depression, and who then urged doctors to be more open about their own mental health, died on July 22 at his home in Lawrenceville, N.J. He was 89.His wife, Diane Drobnis Rosenberg, said the cause was pneumonia.Dr. Rosenberg straddled the worlds of clinical and laboratory medicine. He labeled himself a “physician-scientist” whose research methods began and ended at the bedside of a patient with an undiagnosed condition, which he then tried to define and treat.Beginning in the early 1960s, he specialized in inherited metabolic disorders — cases in which the body is unable to process certain compounds, which then accumulate and poison a patient.Most of his patients were children, including one of his first, a 9-year-old boy named Steven, whose skeletal muscles were rapidly wasting away. Dr. Rosenberg, who was then a fellow at the National Institutes of Health, found nothing wrong except a high level of amino acids in Steven’s urine. He interviewed Steven’s parents, who said they had had two other children with similar conditions, both of whom had died. Steven died not long after.“I was unable to change the course of Steven’s illness,” Dr. Rosenberg wrote in a 2014 article. “But he changed the course of my professional life. He showed me that asking research questions based on seeing patients was like medical detective work. Even more important, he ignited my interest in genetic disorders and kindled it.”Dr. Rosenberg moved to the Yale School of Medicine in 1965, intent on solving mysteries like Steven’s — which he did, many times over. He was the founding chairman of the school’s department of human genetics and, later, the school’s president.He scaled the peaks of his profession, sitting on corporate boards and joining the National Academy of Sciences. In 1989 he was shortlisted to run the National Institutes of Health, alongside Dr. Anthony Fauci.But, as Dr. Rosenberg revealed much later, Steven’s case also came not long after his own first episode of crippling depression, what he called his “unwanted guest.” His first months at the National Institutes of Health had been difficult; he felt like a failure and wanted to leave research entirely.Though similar episodes struck later, often around major career changes, he never talked about them, or sought treatment, until he attempted suicide in 1998. His doctor diagnosed bipolar II disorder, and Dr. Rosenberg underwent electroshock therapy and took lithium.Doctors can suffer from depression just like anyone else, but Dr. Rosenberg was the rare physician who spoke openly about it — first in classroom and professional lectures, then in a series of articles and, ultimately, in a book, “Genes, Medicines, Moods: A Memoir of Success and Struggle” (2020).“I am proof,” Dr. Rosenberg wrote in his memoir, “that it is possible to live a highly successful career in medicine and science, and to struggle with a complex, serious mental illness at the same time.”He called on his fellow doctors to speak up as well, both for their own sake and for the sake of their families, colleagues and patients.“The list of writers who have described their suicidal attempts and suicidal thoughts is long and illustrious,” he wrote in a 2002 article. “Yet physicians and scientists, who commit and attempt suicide at least as often as artists, writers, politicians and business leaders, have been remarkably silent.”Several of Dr. Rosenberg’s relatives had similarly suffered from mental illness, and he marveled at the coincidence that his professional career and personal struggles both revolved around inherited disorders.“I am proof,” he wrote in his memoir, “that it is possible to live a highly successful career in medicine and science, and to struggle with a complex, serious mental illness at the same time.”Leon Emanuel Rosenberg was born on March 3, 1933, in Madison, Wis. Both his parents, Abraham and Celia (Mazursky) Rosenberg, had fled pogroms in present-day Belarus, though they did not meet until they settled in Waunakee, a Madison suburb.After working for a while as a peddler, Abraham made enough money to open his own general store. He learned English quickly and even perfected a rural Wisconsin accent, which helped him relate to his customers. Celia, a homemaker, maintained her thick Yiddish accent.A childhood accident involving a mill at Celia’s family farm had mutilated her left hand, leaving all but her thumb and forefinger useless. “Sometime around age 5,” Dr. Rosenberg wrote in his memoir, “while holding her left hand in both of mine, I told her that I intended to be a doctor so I could repair her hand.”Leon was an exemplary student: He was valedictorian of his high school and finished summa cum laude at the University of Wisconsin, where he graduated in 1954 and received his medical degree in 1957. He interned at NewYork-Presbyterian Hospital before moving to the National Institutes of Health as a research fellow in 1959.His first marriage, to Elaine Lewis, ended in divorce. Along with his wife, he is survived by his brother, Irwin, the former dean of the School of Nutrition Science and Policy at Tufts University; his sons, Robert Rosenberg and David Korish; his daughters, Diana Clark and Alexa Rosenberg; six grandchildren; and one great-grandchild.It was while at Yale that Dr. Rosenberg led research into inherited metabolic disorders, despite skepticism from colleagues about the very basis of such work. “Don’t be silly,” he recalled one Yale nephrologist telling him. “There is no such thing.”Dr. Rosenberg proved him wrong. He filled lectures with case studies of children — Steven, of course, followed by Dana, Lorraine, Robby and others — who presented inexplicable disorders, which he repeatedly showed to be caused by their bodies’ inability to metabolize various acids, and which could often be easily treated.His research brought him public prominence, both as a researcher and as an advocate for equity in medicine. As the dean of the Yale School of Medicine from 1984 to 1991, he made it easier for people of color and women to rise to senior faculty positions, and he placed students as volunteers in New Haven public schools.He left Yale in 1991 to become the chief science officer at Bristol Myers Squibb. In 1998 he moved to Princeton University as a lecturer in molecular biology, with a joint appointment, also as a lecturer, in the Woodrow Wilson School of Public and International Affairs (now the Princeton School of Public and International Affairs).Dr. Rosenberg made national headlines in 1981 when he testified before a Senate subcommittee on a bill that would define life as beginning at conception, in effect overturning Roe v. Wade. Of the eight doctors invited to speak, he was the only one to disagree with the bill’s premise — and he said so forcefully.“Don’t ask science or medicine to help justify that course, because they cannot,” he said. “Ask your conscience, your minister, your priest, your rabbi, or even your god, because it is in their domain that this matter resides.”The bill failed soon after.

During a battle with cancer, T cells can become exhausted and are no longer able to function properly. The early phase of exhaustion can sometimes be reversed with immunotherapy drugs, but once T cells become too exhausted, it had been thought that this state was irreversible. However, new insights from University of Pittsburgh and UPMC researchers suggest that even the most fatigued T cells can be revived.
In a study, published today in Science Immunology, the team profiled molecular features of T cells as they progressed from early to terminal exhaustion in a mouse model of melanoma. They unexpectedly found that even the most terminally exhausted T cells retain some capacity to be functional again and identified approaches to overcome exhaustion, opening potential new avenues for cancer immunotherapy.
“People think about terminally exhausted T cells as a lost cause, that there’s no coming back from this state,” said co-senior author Amanda Poholek, Ph.D., assistant professor of pediatrics and immunology at Pitt’s School of Medicine and director of the Health Sciences Sequencing Core at UPMC Children’s Hospital of Pittsburgh. “But given the right circumstances — the T cell version of rest — we show that they can come back. This finding could have incredible potential for immunotherapy.”
Over time, tumor-fighting T cells may enter the early phase of exhaustion, a progenitor-like cell, which eventually differentiates into poorly functional, terminally exhausted cells. While current cancer immunotherapies can be successful at reversing exhaustion in these progenitor cells, giving T cells renewed energy to attack cancer cells, those that are terminally exhausted tend not to respond to such therapy.
“To bring the promise of immunotherapy to more cancer patients, we need to uncover more about why T cells fail,” said co-senior author Greg Delgoffe, Ph.D., associate professor of immunology at Pitt and director of the Tumor Microenvironment Center at UPMC Hillman Cancer Center .
With this goal, Poholek, Delgoffe and their team deeply analyzed early and terminally exhausted T cells in mice with an aggressive form of melanoma. They profiled the cells’ epigenome — the inheritable molecular marks that attach to DNA and control gene expression.

We have recently witnessed the stunning images of distant galaxies revealed by the James Webb telescope, which were previously visible only as blurry spots. Washington University in St. Louis researchers have developed a novel method for visualizing the proteins secreted by cells with stunning resolution, making it the James Webb version for visualizing single cell protein secretion.
The researchers, led by Srikanth Singamaneni, the Lilyan & E. Lisle Hughes Professor of Mechanical Engineering & Materials Science in the McKelvey School of Engineering, and Anushree Seth, a former postdoctoral scholar in Singamaneni’s lab, developed the FluoroDOT assay, which they introduced in a paper on August 5, 2022 in the journal Cell Reports Methods. The highly sensitive assay is able to see and measure proteins secreted by a single cell in about 30 minutes.
In collaboration with researchers in the Washington University School of Medicine and other universities, they found that the FluoroDOT assay is versatile, low-cost and adaptable to any laboratory setting and has the potential to provide a more comprehensive look at these proteins than the widely used existing assays. Biomedical researchers look to these secreted proteins for information on cell-to-cell communication, cell signaling, activation and inflammation, among other actions, but existing methods are limited in sensitivity and can take up to 24 hours to process.
What makes the FluoroDOT assay different from existing assays is that it uses a plasmonic-fluor, a plasmon-enhanced nanolabel developed in Singamaneni’s lab that is 16,000 times brighter than conventional fluorescence labels and has a signal-to-noise ratio of nearly 30 times higher.
“Plasmonic-fluors are composed of metal nanoparticles that serve as antenna to pull in the light and enhance the fluorescence emission of molecular fluorophores, thus making it an ultrabright nanoparticle,” Singamaneni said.
This ultrabright emission of plasmonic-fluor allows the user to see extremely small quantities of secreted protein, which they are unable to do in existing assays, and measure the high-resolution signals digitally using the number of particles, or dot pattern, per cluster, or spot, using a custom-built algorithm. In addition, it doesn’t require special equipment. Singamaneni and his collaborators first published their work with the plasmonic-fluor in Nature Biomedical Engineering in 2020.
The patent-pending plasmonic fluor technology is licensed by the Office of Technology Management at Washington University in St. Louis to Auragent Bioscience LLC.
“Using a simple fluorescence microscope, we are able to simultaneously image a cell along with the spatial distribution of the proteins secreted around it,” said Seth, who worked on this project as a postdoctoral scholar in Singamaneni’s lab and continues to work on it as a principal scientist (cellular applications) for Auragent Bioscience. “We saw interesting secretion patterns for different cell types. This assay also enables concurrent visualization of two types of proteins from individual cells. When the multiple cells are subjected to the same stimuli, we can distinguish the cells that are secreting two proteins at the same time from the ones that are only secreting one protein or are not secreting at all.”
To validate the technology, the team used proteins secreted from both human and mouse cells, including immune cells infected with Mycobacterium tuberculosis.
One of the collaborators and co-authors, Jennifer A. Philips, MD, PhD, the Theodore and Bertha Bryan Professor in the departments of Medicine and Molecular Microbiology and co-director of the Division of Infectious Diseases in the School of Medicine, has used the FluoroDOT assay in her lab.
“When Mycobacterium tuberculosis infects immune cells, those cells respond by secreting important immune proteins, called cytokines,” Philips said. “But not all cells respond to infection the same way. The FluoroDOT assay allowed us to see how individual cells in a population respond to infection — to see which cells are secreting and in which direction. This was not possible with the older technology.”
Story Source:
Materials provided by Washington University in St. Louis. Original written by Beth Miller. Note: Content may be edited for style and length.

Researchers at Michigan State University have shown that locusts can not only “smell” the difference between cancer cells and healthy cells, but they can also distinguish between different cancer cell lines. 
However, patients need not worry about locusts swarming their doctors’ offices. Rather, the researchers say this work could provide the basis for devices that use insect sensory neurons to enable the early detection of cancer using only a patient’s breath.   
Although such devices aren’t on the immediate horizon, they’re not as far-fetched as they might sound, said the authors of the new research shared May 25 on the website BioRxiv. (BioRxiv, pronounced “bio archive,” is a pre-print server that hosts research articles before they’ve been peer reviewed.) 
Part of that is because people have grown accustomed to technology that augments or outperforms our natural senses. For example, telescopes and microscopes reveal otherwise invisible worlds. The success of engineered devices can make it easy to overlook the performance of our natural tools, especially the sense organ right in front of our eyes.   
“Noses are still state of the art,” said Debajit Saha, an assistant professor of biomedical engineering at MSU. “There’s really nothing like them when it comes to gas sensing.”  
That’s why we trust dogs and their super-sniffers to detect telltale smells of drugs, explosives and, more recently, health conditions including low blood sugar and even COVID-19.    
Scientists are working on technology that can mimic the sense of smell, but nothing they’ve engineered can yet compete with the speed, sensitivity and specificity of old-fashioned biological olfaction. 

Cardiovascular diseases remain a leading cause of death around the world. A primary contributor to these afflictions is high blood pressure, or hypertension.
While treatments exist for the condition, which affects tens of millions of Americans, these remedies are not without side effects, and some variants of the disorder are treatment-resistant. The need for more effective therapies to address hypertension-related disease is therefore acute.The illustration shows a portion of the receptor pGC-A, known as the extracellular domain, which protrudes from cell surfaces in the cardiovascular system. Small molecules bind with the receptor and exert subtle control over blood pressure. The new research offers the first sneak peek at the full-length receptor, a vital step in the development of new drugs to treat hypertension and other afflictions.
To accomplish this however, biologists need more detailed maps of the mechanisms underlying cardiovascular regulation. One such regulator is a protein receptor that sits atop cardiovascular cells, acting as a conduit for messages that are transmitted when specific hormone molecules bind with them.
Known as pGC-A, this membrane receptor acts a bit like a thermostat, sensitively adjusting the body’s blood pressure to maintain a homeostatic balance essential for health. The receptor acts not only as a vital cellular component for vascular and cardiac homeostasis, but also plays an important role in lipid metabolism and is implicated in cancer development.
In a new study, published in the current issue of the journal Scientific Reports, researchers from Arizona State University’s Biodesign Center for Applied Structural Discovery and their colleagues, in collaboration with Mayo Clinic, Rochester, make critical progress toward unveiling the structure of pGC-A.
The study provides the first purification, characterization and preliminary structural analysis of the full-length protein receptor. The research advances include crystallizing the protein and showing that these crystals diffract X-rays — two critical steps essential to solving the structure.

Mount Sinai researchers have achieved an unprecedented understanding of the genetic and molecular machinery in human microglia — immune cells that reside in the brain — that could provide valuable insights into how they contribute to the development and progression of Alzheimer’s disease (AD). The team’s findings were published in Nature Genetics.
Working with fresh human brain tissue harvested via biopsy or autopsy from 150 donors, researchers identified 21 candidate risk genes and highlighted one, SPI1, as a potential key regulator of microglia and AD risk.
“Our study is the largest human fresh-tissue microglia analysis to date of genetic risk factors that might predispose someone to Alzheimer’s disease,” says senior author Panos Roussos, MD, PhD, Professor of Psychiatry, and Genetic and Genomic Sciences, at the Icahn School of Medicine at Mount Sinai and Director of the Center for Disease Neurogenomics. “By better understanding the molecular and genetic mechanisms involved in microglia function, we’re in a much better position to unravel the regulatory landscape that controls that function and contributes to AD. That knowledge could, in turn, pave the way for novel therapeutic interventions for a disease that currently has no effective treatments.”
Microglia are primarily responsible for the immune response in the brain, and are also critical to the development and maintenance of neurons. While previous studies, including some at Mount Sinai, have identified microglia as playing a key role in the genetic risk and development of Alzheimer’s disease, little is known about the epigenetic mechanics of how that occurs. Because microglia are challenging to isolate within the human brain, most previous studies have used either animal- or cell-line-based models which do not reflect the true complexity of microglia function in the brain. Another challenge has been relating AD genetic risk variation to specific molecular function because these risk factors are frequently found in the non-coding part of the genome (what used to be called “junk DNA”), which is more difficult to study.
The Mount Sinai team’s solution was to access fresh brain tissue from biopsies or autopsies made possible by a collaboration between four brain bio-depositories, three at Mount Sinai and the other from Rush University Medical Center/Rush Alzheimer’s Disease Center. “Using a total of 150 samples from these sources, we were able to isolate high-quality microglia, which provided unprecedented insights into genetic regulation by reflecting the entire set of regulatory components of microglia in both healthy and neurodegenerative patients,” explains Dr. Roussos.
That process — comparing epigenetic, gene expression, and genetic information from the samples of both AD and healthy aged patients — allowed researchers to comprehensively describe how microglia functions are genetically regulated in humans. As part of their statistical analysis, they expanded the findings of prior genome-wide association studies to link identified AD-predisposing genetic variants to specific DNA regulatory sequences and genes whose dysregulation is known to directly contribute to the development of the disease. They further described the cell-wide regulatory mechanisms as a way of identifying genetic regions involved in specific aspects of the microglial activity.
From their investigation emerged new knowledge about the SPI1 gene, already known to scientists, as the main microglial transcription factor regulating a network of other transcription factors and genes that are genetically linked to AD. Data the team is generating could also be important to deciphering the molecular and genetic mysteries behind other neurodegenerative diseases in which microglia play a role, including Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis.
Dr. Roussos concedes that much work remains for his team to fully understand how the identified genes contribute to the development and progression of Alzheimer’s disease, and how they could be targeted with new therapeutics. He is greatly encouraged, though, by the results of single-cell analysis by his lab of microglia using highly sophisticated instruments that are uncovering the unique interactions between different types of immune cells in the brain and its periphery that are related to neurodegenerative disease. “We’re seeing very exciting results through our single-cell data,” Dr. Roussos reports, “and that’s bringing us ever closer to understanding the genetically driven variations and cell-specific interactions of inheritable diseases like Alzheimer’s.”

A clinical trial is only as powerful as its participants. For years, researchers have struggled to fill clinical trials and enroll sufficiently diverse groups of patients for results to reflect the broader population, in part because of stringent guidelines on who can participate.
In an effort to include a larger and more diverse population, an international team of researchers and policymakers has written new recommendations on how to determine eligibility criteria for lung cancer clinical trials. The group was led in part by David Gerber, M.D., Associate Director for Clinical Research at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, along with representatives from the Food and Drug Administration (FDA), National Cancer Institute, European Medicines Agency, pharmaceutical companies, and the LUNGevity Foundation.
The recommendations, published today in JAMA Oncology, offer the first publicly available outline of upcoming FDA draft guidance on lung cancer clinical trials that are expected to make it easier to include more patients.
“This paper is the public’s first look at the FDA’s proposed changes to how we determine who can participate in a lung cancer clinical trial,” said Dr. Gerber, Professor of Internal Medicine in the Hematology/Oncology Division at UTSW. “If these changes are successful, they could make clinical trials for lung cancer as well as other cancers more powerful and more representative.”
Ensuring that people from diverse backgrounds join clinical trials is key to properly evaluating how a new treatment will work among patients of all races and ethnicities. But today, only about 5% of all cancer patients enroll in a clinical trial, and only 11% of cancer clinical trial participants identify as a racial or ethnic minority.
For patients with cancer, participation in clinical trials requires not just a decision to try an experimental treatment, but time and energy spent understanding the trial, enrolling in it, and often attending extra testing or clinic appointments. Many researchers agree that complicated, inconsistent, poorly explained, and overly strict eligibility requirements to join a cancer clinical trial exacerbate this problem and are a key reason for the low number of underrepresented minorities in clinical trials.

The immune boosting benefits of a tuberculosis vaccine can be seen in infants more than one year after vaccination, according to a new study.
The research, led by the Murdoch Children’s Research Institute (MCRI) and published in Science Advances, has shown how the BCG vaccine, developed to prevent the risk of tuberculosis, can produce a ‘trained immunity response’ lasting more than 14 months after the vaccine is administered.
The randomised controlled trial involved 130 infants from the Melbourne Infant Study: BCG for the Prevention of Allergy and Infection (MIS BAIR) and cell dish models to study the immune system’s response to BCG vaccination. Those randomised to be vaccinated received their jab within 10 days of birth.
Murdoch Children’s Dr Samantha Bannister said 14 months after having the BCG vaccination they saw reprogramming, a process where genes were switched off or on, in a specific blood cell type, called the monocyte.
“The off-target effects of the BCG vaccine against a range of viruses are explained in part by the reprogramming of how your genes work in the monocyte due to environmental and behavioural factors,” she said. The reprogramming of monocytes, a cell previously thought to have no capacity for memory, leads to trained immunity.”
Murdoch Children’s Associate Professor Boris Novakovic said the off-target effects were first identified in Africa, where BCG vaccinated children had reduced overall death rates.
“The off-target effects in Africa were known to last more than a year, but previous studies looking at BCG-associated monocyte signatures only looked at one month and three months following vaccination in adults,” he said. For the first time we have shown how the BCG vaccine can have long-lasting effects on the immune system of infants.
“As babies are the main population given the BCG vaccine, this study is important because findings in adults do not always translate to children.”
For the trial the research team collaborated with the lab of Professor Mihai Netea from the Radboud University Medical Center in the Netherlands that first described trained immunity and scientists from the International Trained Immunity (INTRIM) Consortium.
Murdoch Children’s and University of Melbourne’s Professor Nigel Curtis said the next step was to see what impact this early trained immunity offered later in childhood and into adulthood.
Professor Curtis’ team at the Murdoch Children’s is leading the BRACE trial, the world’s largest examination of the off-target effects of the BCG vaccine in more than 6800 healthcare workers in Australia, Brazil, Spain, the Netherlands and the United Kingdom. BRACE is testing whether the vaccine can protect those exposed to SARS-CoV-2 from developing severe symptoms by boosting their frontline immunity.
Researchers from the University of Melbourne, The Royal Children’s Hospital, Radboud University Medical Center in The Netherlands, the Walter and Eliza Hall Institute of Medical Research and the University of Bonn in Germany also contributed to the findings.
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Materials provided by Murdoch Childrens Research Institute. Note: Content may be edited for style and length.