Publisher Health

Genetic research from China suggests to some experts that the coronavirus may have sprung from a market in Wuhan. Now the data are missing from a scientific database.The World Health Organization rebuked Chinese officials on Friday for withholding research that may link Covid’s origin to wild animals, asking why the data had not been made available three years ago and why it is now missing.Before the Chinese data disappeared, an international team of virus experts downloaded and began analyzing the research, which appeared online in January. They say it supports the idea that the pandemic could have begun when illegally traded raccoon dogs infected humans at a Wuhan seafood market.But the gene sequences were removed from a scientific database once the experts offered to collaborate on the analysis with their Chinese counterparts.“These data could have — and should have — been shared three years ago,” Dr. Tedros Adhanom Ghebreyesus, the W.H.O.’s director general, said. The missing evidence now “needs to be shared with the international community immediately,” he said.According to the experts who are reviewing it, the research offers evidence that raccoon dogs, fox-like animals known to spread coronaviruses, had left behind DNA in the same place in the Wuhan market that genetic signatures of the new coronavirus also were discovered.To some experts, that finding suggests that the animals may have been infected and may have transmitted the virus to humans.With huge amounts of genetic information drawn from swabs of animal cages, carts and other surfaces at the Wuhan market in early 2020, the genetic data had been the focus of restless anticipation among virus experts since they learned of it a year ago in a paper by Chinese scientists.A French biologist discovered the genetic sequences in the database last week, and she and a team of colleagues began mining them for clues about the origins of the pandemic.That team has not yet released a paper outlining the findings. But the researchers delivered an analysis of the material to a W.H.O. advisory group studying Covid’s origins this week in a meeting that also included a presentation by Chinese researchers regarding the same data.“These data could have — and should have — been shared three years ago,” Dr. Tedros Adhanom Ghebreyesus, the W.H.O.’s director general, said. Cyril Zingaro/EPA, via ShutterstockThe analysis seemed to clash with earlier contentions by Chinese scientists that samples taken in the market that were positive for the coronavirus had been ferried in by sick people alone, said Sarah Cobey, an epidemiologist and evolutionary biologist at the University of Chicago who was not involved in the latest analysis.“It’s just very unlikely to be seeing this much animal DNA, especially raccoon dog DNA, mixed in with viral samples, if it’s simply mostly human contamination,” Dr. Cobey said.Questions remain about how the samples were collected, what precisely they contained and why the evidence had disappeared. In light of the ambiguities, many scientists reacted cautiously, saying that it was difficult to assess the research without seeing a complete report.The idea that a lab accident could have accidentally set off the pandemic has become the focus of renewed interest in recent weeks, thanks in part to a fresh intelligence assessment from the Department of Energy and hearings led by the new Republican House leadership.But a number of virus experts not involved with the latest analysis said that what was known about the swabs gathered in the market buttressed the case that animals sold there had sparked the pandemic.“It’s exactly what you’d expect if the virus was emerging from an intermediate or multiple intermediate hosts in the market,” Dr. Cobey said. “I think ecologically, this is close to a closed case.”Dr. Cobey was one of 18 scientists who signed an influential letter in the journal Science in May 2021 urging serious consideration of a scenario in which the virus could have spilled out of a laboratory in Wuhan.On Friday, she said lab leaks continued to pose enormous risks and that more oversight of research into dangerous pathogens was needed. But Dr. Cobey added that an accumulation of evidence — relating to the clustering of human cases around the Wuhan market, the genetic diversity of viruses there, and now the raccoon dog data — strengthened the case for a market origin.The new genetic data do not appear to prove that a raccoon dog was infected with the coronavirus. Even if it had been, the possibility would remain that another animal could have passed that virus to people, or even that someone infected with the virus could have transmitted it to a raccoon dog.Some scientists stressed those points on Friday, saying that the new genetic data did not appreciably shift the discussion about the pandemic’s origins.“We know it’s a promiscuous virus that infects a bunch of species,” said David Fisman, an epidemiologist at the University of Toronto, who also signed the May 2021 letter in Science.Chinese scientists had released a study in February 2022 looking at the market samples. Some scientists speculated that the Chinese researchers might have posted the data in January because they were required to make them available as part of a review of their study by a scientific journal.The Chinese study had suggested that samples that were positive for the virus had come from infected people, rather than from animals sold in the market. That fit with a narrative long promulgated by Chinese officials: that the virus sprang not only from outside the market, but also from outside the country altogether.But the Chinese report had left clues that viral material at the market had been jumbled together with genetic material from animals. And scientists said that the new analysis by the international team illustrated an even stronger link with animals.“Scientifically, it doesn’t prove that raccoon dogs were the source, but it sure smells like infected raccoon dogs were at the market,” said Jeremy Kamil, a virologist at Louisiana State University Health Sciences Center Shreveport.He added, “It raises more questions about what the Chinese government really knows.”Scientists cautioned that it was not clear that the genetic material from the virus and from raccoon dogs had been deposited at the same time.Depending on the stability of genetic material from the virus and the animals, said Michael Imperiale, a virologist at the University of Michigan, “they could have been deposited there at potentially widely different times.”Still, Dr. Arturo Casadevall, an immunologist at the Johns Hopkins Bloomberg School of Public Health who co-authored a recent study with Dr. Imperiale examining the origin of the coronavirus, said that linking animal and viral material nevertheless added to the evidence of a natural spillover event.“I would say it strengthens the zoonotic idea,” he said, “that is, the idea that it came from an animal at the market.”In the absence of the actual animal that first spread the virus to people, Dr. Casadevall said, assessing the origins of an outbreak would always involve weighing probabilities. In this case, animals sold at the market were removed before researchers began taking samples in early 2020, making it impossible to find a culprit.Tim Stearns, the dean of graduate and postgraduate studies at the Rockefeller University in New York, said that the latest finding was “an interesting piece of the puzzle,” though he said it was “not in itself definitive and highlights the need for a more thorough investigation.”For all the missing elements, some scientists said that the new findings highlighted just how much information scientists had managed to assemble about the beginnings of the pandemic, including home addresses for early patients and sequence data from the market.Theodora Hatziioannou, a virologist at the Rockefeller University, said that it was critical that the raw data be released. But, she said, “I think the evidence is overwhelming at the moment toward a market origin.”And the latest data, she said, “makes it even more unlikely that this started somewhere else.”Felicia Goodrum, an immunobiologist at the University of Arizona, said that finding the virus in an actual animal would be the strongest evidence of a market origin. But finding virus and animal material in the same swab was close.“To me,” she said, “this is the next best thing.”

Multiple types of beta cells produce insulin in the pancreas, helping to balance blood sugar levels. Losing a particularly productive type of beta cell may contribute to the development of diabetes, according to a new study by Weill Cornell Medicine investigators.
In the study, published March 16 in Nature Cell Biology, Dr. James Lo, associate professor of medicine at Weill Cornell Medicine, and colleagues measured gene expression in individual beta cells collected from mice to determine how many different types of beta cells exist in the pancreas. The team discovered four distinct beta cell types, including one that stood out. The cluster 1 group of beta cells produced more insulin than other beta cells and appeared better able to metabolize sugar. The study also showed that loss of this beta cell type might contribute to type 2 diabetes.
“Before this, people thought a beta cell was a beta cell, and they just counted total beta cells,” said Dr. Lo, who is also a member of the Weill Center for Metabolic Health and the Cardiovascular Research Institute at Weill Cornell Medicine and a cardiologist at NewYork-Presbyterian/Weill Cornell Medical Center. “But this study tells us it might be important to subtype the beta cells and that we need study the role of these special cluster 1 beta cells in diabetes.”
Drs. Doron Betel, Jingli Cao, Geoffrey Pitt and Shuibing Chen at Weill Cornell Medicine teamed up with Dr. Lo to carry out the study.
The investigators used a technique called single-cell transcriptomics to measure all the genes expressed in individual mouse beta cells and then used that information to group them into four types. The cluster 1 beta cells had a unique gene expression signature that included high expression of genes that help cellular powerhouses called mitochondria to break down sugar and power them to secrete more insulin. Additionally, they could distinguish the cluster 1 beta cells from the other beta cell types by its high expression of the CD63 gene, which enabled them to use the CD63 protein as a marker for this specific beta cell type.
“CD63 expression provided us a way to identify the cells without destroying them and allowed us to study the live cells,” he said.

When the team looked at both human and mouse beta cells, they found that cluster 1 beta cells with high CD63 gene expression produce more insulin in response to sugar than the three other types of beta cells with low CD63 expression.
“They are very high-functioning beta cells,” Dr. Lo said. “We think they may carry the bulk of the workload of producing insulin, so their loss might have profound impacts.”
In mice fed an obesity-inducing, high-fat diet and mice with type 2 diabetes, the numbers of these insulin-producing-powerhouse beta cells decreased.
“Because the numbers of cluster 1/high CD63 cells went down, you may have less insulin production, which may play a major role in diabetes development,” he said.
Transplanting beta cells with high CD63 production into mice with type 2 diabetes restored their blood sugar levels to normal. But removing the transplanted cells caused high blood sugar levels to return. Transplanting low CD63 production beta cells into the mice didn’t restore blood sugar to normal levels. The transplanted low CD63 beta cells instead appeared dysfunctional.

The discovery may have important implications for the use of beta cell transplants to treat diabetes, Dr. Lo said. For example, it may be better to transplant only high CD63- beta cells. He noted that it might also be possible to transplant fewer of these highly productive cells. Dr. Lo’s team also found that humans with type 2 diabetes had lower levels of high CD63 beta cells compared to those without diabetes.
Next, Dr. Lo and his colleagues would like to find out what happens to the high CD63-producing beta cells in mice with diabetes and how to keep them from disappearing.
“If we can figure out how to keep them around longer, surviving and functional, that could lead to better ways to treat or prevent type 2 diabetes,” he said.
They would also like to study how existing diabetes treatments affect all types of beta cells. GLP-1 agonists, which help increase the release of insulin in people with diabetes, interact with high and low CD63-producing beta cells.
“Our study also shows that GLP-1 agonists might also be a way to get the low CD63-producing beta cells to work better,” Dr. Lo said.

Cancer treatments have long been moving toward personalization — finding the right drugs that work for a patient’s unique tumor, based on specific genetic and molecular patterns. Many of these targeted therapies are highly effective, but aren’t available for all cancers, including non-small cell lung cancers (NSCLCs) that have an LKB1 genetic mutation. A new study led by Salk Institute Professor Reuben Shaw and former postdoctoral fellow Lillian Eichner, now an assistant professor at Northwestern University, revealed FDA-approved trametinib and entinostat (which is currently in clinical trials) can be given in tandem to produce fewer and smaller tumors in mice with LKB1-mutated NSCLC.
The findings were published in Science Advances on March 17, 2023.
“For non-small cell lung cancer cases with the LKB1 mutation, standard chemotherapy and immunotherapy treatments are not effective,” says Shaw, senior and co-corresponding author of the study, and director of Salk’s Cancer Center. “Our findings demonstrate there is a way to target these cases using drugs that are FDA-approved or already in clinical trials, so this work could easily be used for a clinical trial in humans.”
Roughly 20 percent of all NSCLCs have the LKB1 genetic mutation, which means there are no effective targeted therapies currently on the market for patients with this cancer type. To create a therapy that could target the LKB1 mutation, the researchers turned to histone deacetylases (HDACs). HDACs are proteins associated with tumor growth and cancer metastasis, with characteristic overexpression in solid tumors. Several HDAC-inhibitor drugs are already FDA-approved (safe for human use) for specific forms of lymphoma, but data on their efficacy in solid tumors or whether tumors bearing specific genetic alterations may exhibit heightened therapeutic potential has been lacking.
Based on previous findings connecting the LKB1 gene to three other HDACs that all rely on HDAC3, the team started by conducting a genetic analysis of HDAC3 in mouse models of NSCLC, discovering an unexpectedly critical role for HDAC3 in multiple models. After establishing that HDAC3 was critical for the growth of the difficult-to-treat LKB1-mutant tumors, the researchers next examined whether pharmacologically blocking HDAC3 could give a similarly potent effect.
The team was curious about testing two drugs, entinostat (an HDAC inhibitor in clinical trials known to target HDAC1 and HDAC3) and FDA-approved trametinib (an inhibitor for a different class of enzymes related to cancer). Tumors often become quickly resistant to trametinib, but co-treatment with a drug that inhibits a protein downstream of HDAC3 helps reduce this resistance. Because that protein relies on HDAC3, the researchers believed that a drug that targets HDAC3 — like entinostat — would help manage trametinib resistance, too.

After treating mice with LKB1-mutated lung cancer with variable treatment regimens for 42 days, the team found that mice given both entinostat and trametinib had 79 percent less tumor volume and 63 percent fewer tumors in their lungs than the untreated mice. Additionally, the team confirmed that entinostat was a viable treatment option in cases where a tumor was resistant to trametinib.
“We thought the whole HDAC enzyme class was directly linked to the cause of LKB1 mutant lung cancer. But we didn’t know the specific role of HDAC3 in lung tumor growth,” says first and co-corresponding author Eichner. “We’ve now shown that HDAC3 is essential in lung cancer, and that it is a druggable vulnerability in therapeutic resistance.”
The findings may lead to clinical trials to test the new regimen in humans, since entinostat is already in clinical trials and trametinib is FDA-approved. Importantly, Shaw sees this discovery as transformative for cancers beyond NSCLC, with potential applications in lymphoma, melanoma, and pancreatic cancer.
“Our lab has committed years to this project, taking small and meaningful steps toward these findings,” says Shaw, holder of the William R. Brody Chair. “This is truly a success story for how basic discovery science can lead to therapeutic solutions in the not-so-distant future.”
“My independent laboratory is fortunate to be part of the Lurie Cancer Center at the Feinberg School of Medicine at Northwestern University, which is very supportive of translational research. We hope that this environment will facilitate the initiation of a clinical trial based on these findings,” says Eichner.
Other authors include Stephanie D. Curtis, Sonja N. Brun, Joshua T. Baumgart, Elijah Trefts, Debbie S. Ross, and Tammy J. Rymoff of Salk; and Caroline K. McGuire and Irena Gushterova of Northwestern University.
The work was supported by the National Institutes of Health (R35CA220538, P01CA120964, K22CA251636, 5T32CA009370, 5F32CA206400, CCSG P30CA014195, and CCSG P30CA23100), Leona M. and Harry B. Helmsley Charitable Trust (#2012-PG-MED002), American Cancer Society (PF-15-037-01-DMC), and Chapman Foundation.

A research team at Duke Health has identified a set of biomarkers that could help distinguish whether cysts on the pancreas are likely to develop into cancer or remain benign.
Appearing online March 17 in the journal Science Advances, the finding marks an important first step toward a clinical approach for classifying lesions on the pancreas that are at highest risk of becoming cancerous, potentially enabling their removal before they begin to spread.
If successful, the biomarker-based approach could address the biggest impediment to decreasing the chance of developing pancreatic cancer, which is on the rise and is notorious for silently growing before being discovered, often incidentally, during abdominal scans.
“Even when pancreas cancer is detected at its earliest stage, it almost always has shed cells throughout the body, and the cancer returns,” said senior author Peter Allen, M.D., chief of the Division of Surgical Oncology at in the Department of Surgery at Duke University School of Medicine.
“That’s why we shifted our focus to these precancerous cysts, known as intraductal papillary mucinous neoplasms, or IPMNs,” Allen said. “Most IPMNs will never progress to pancreas cancer, but by distinguishing which ones will progress, we are creating an opportunity to prevent an incurable disease from developing.”
Allen and colleagues used a sophisticated molecular biology tool called digital spatial RNA profiling to home in on specific areas of the cyst with high- and low-grade areas of abnormal cell growth.

Previous methods to characterize IPMNs have been less precise and have not been able to identify particularly accurate markers of cancer risk. Digital spatial profiling, however, allows researchers to choose individual groups of cells for analysis. This enabled the Duke researchers to identify a host of genetic mutations that both fuel and potentially suppress pancreatic cancer development.
The team also identified markers for discriminating between the two leading variants of IPMN and found distinct markers for defining a third common variant that generally results in less aggressive disease.
“We found very distinct markers for high-grade cell abnormalities, as well as for slow-growing subtypes,” Allen said. “Our work now is focusing on finding it in the cyst fluid. If we can identify these unique markers in cyst fluid, it could provide the basis for a protein biopsy that would guide whether we should remove the cyst before cancer develops and spreads.”
Allen said current diagnostic strategies — including clinical, radiographic, laboratory, endoscopic, and cytologic analysis — have an overall accuracy of approximately 60%.
“Pancreatic cancer is on the rise and, if the current trajectory continues, it will become the second-leading cause of cancer death in the United States in the next few years,” Allen said, noting it’s unknown what is driving the cancer’s increased prevalence.
He said some studies suggest inflammation plays a role. A clinical trial at Duke, led by Allen, is testing whether an anti-inflammatory therapy could reduce the development of cancer in patients with IPMN.
In addition to Allen, study authors include Matthew K. Iyer, Chanjuan Shi, Austin M. Eckhoff, Ashley Fletcher, and Daniel P. Nussbaum.
The study received funding support from the National Cancer Institute (RO1 CA182076).

A study in the Journal of The National Cancer Institute Cancer Spectrum looked at chatbots and artificial intelligence (AI), as they become popular resources for cancer information. They found these resources give accurate information when asked about common cancer myths and misconceptions. In the first study of its kind, Skyler Johnson, MD, physician-scientist at Huntsman Cancer Institute and assistant professor in the department of radiation oncology at the University of Utah (the U), evaluated the reliability and accuracy of ChatGPT’s cancer information.
Using the National Cancer Institute’s (NCI) common myths and misconceptions about cancer, Johnson and his team found that 97% of the answers were correct. However, this finding comes with some important caveats, including a concern amongst the team that some of the ChatGPT answers could be interpreted incorrectly. “This could lead to some bad decisions by cancer patients. The team suggested caution when advising patients about whether they should use chatbots for information about cancer,” says Johnson.
The study found reviewers were blinded, meaning they didn’t know whether the answers came from the chatbot or the NCI. Though the answers were accurate, reviewers found ChatGPT’s language was indirect, vague, and in some cases, unclear.
“I recognize and understand how difficult it can feel for cancer patients and caregivers to access accurate information,” says Johnson. “These sources need to be studied so that we can help cancer patients navigate the murky waters that exist in the online information environment as they try to seek answers about their diagnoses.”
Incorrect information can harm cancer patients. In a previous study by Johnson and his team published in the Journal of the National Cancer Institute, they found that misinformation was common on social media and had the potential to harm cancer patients.
The next steps are to evaluate how often patients are using chatbots to seek out information about cancer, what questions they are asking, and whether AI chatbots provide accurate answers to uncommon or unusual questions about cancer.
The study was supported by the National Institutes of Health/National Cancer Institute including P30 CA042014 and Huntsman Cancer Foundation.

The monogamous, hibernating canids, which are related to foxes, are sold for meat and fur.On Thursday, scientists unveiled new data on the possible origins of the Covid-19 pandemic — and put a strange, squat creature squarely in the spotlight.Meet the raccoon dog; it earns its name from its black facial markings, which give the animal a masked appearance and a more-than-passing resemblance to those infamous raiders of urban trash cans.The animals were at least occasionally sold at the Huanan Seafood Wholesale Market, where many virologists suspect that the Covid-19 pandemic may have started.Scientists had previously announced that swabs from the market had tested positive for the coronavirus that causes Covid-19. The new data revealed that some of these same swabs also contained substantial genetic material from raccoon dogs.The findings did not prove that raccoon dogs were infected with the virus or that they had passed it on to humans. But they are consistent with the possibility that wild animals at the market may have set off the Covid-19 pandemic.Here’s what to know about the animal in the news.What are raccoon dogs?Despite their name, raccoon dogs are not close relatives of raccoons. They are members of the canid family, a group that also includes domestic dogs, and are most closely related to foxes.Raccoon dogs are omnivores, dining on food sources like rodents and berries. Although they appear svelte in the summer, they pack on the pounds for winter, when their fur also becomes thicker. They are the only canid species known to hibernate and are monogamous, often living in pairs.Where do they live?Raccoon dogs are native to East Asia, including parts of China, Korea and Japan, where they are known as tanuki.They have also become widespread in parts of Europe, where they are considered an invasive species. They are sometimes hunted as pests.Why are they farmed and sold?Raccoon dogs have long been farmed for their fur. China is a leading producer of raccoon dog pelts; in 2014, the country produced more than 14 million pelts, 100 times as many as Europe, according to one report.They are also sold for their meat in live animal markets. They were sold at the Huanan Seafood Wholesale Market at least as late as November 2019, researchers have reported.Are they the source of the virus that causes Covid-19?Not necessarily. Laboratory experiments have shown that raccoon dogs are susceptible to, and capable of transmitting, the novel coronavirus. But that does not mean that they are the natural reservoir for the virus. Even if raccoon dogs at the market were infected, they might have been an intermediate host, picking up the virus from bats or another species.Raccoon dogs and bats were both common on and around some of the farms that supplied the market, scientists have noted.A similar scenario may have unfolded two decades ago, after the emergence of SARS, which is also caused by a coronavirus. In 2003, scientists found evidence of infected palm civets and raccoon dogs at a live animal market in Shenzen, China. But subsequent research ultimately pointed to bats as the natural reservoir for the virus that causes SARS; raccoon dogs appeared to be intermediate hosts.Can I pet a raccoon dog if I see one?It’s probably not a good idea, as tempting as it might be. Covid-19 aside, the animals are known to be vectors for other diseases, including rabies. The Royal Society for the Prevention of Cruelty to Animals recommends against keeping raccoon dogs as pets.

About 17% of women with unexplained infertility also have gene variants known to cause disease, from common conditions like heart disease to rare problems like ALS, Medical College of Georgia researchers report.
Theirs appears to be the first study to identify an increased prevalence of disease-causing genetic variants in females with unexplained infertility, the team, led by Lawrence C. Layman, MD, reports in the New England Journal of Medicine.
They hypothesized that genetic disease creates a predisposition to infertility and subsequent medical illness and their findings support that link, they write. Females with infertility, for example, have been noted to have an increased risk of cardiovascular disease.
“The connection to diseases has been known, but what has not been known was if there was a genetic connection. That was the purpose of this study,” says Layman, a reproductive endocrinologist and geneticist who is chief of the MCG Section of Reproductive Endocrinology, Infertility and Genetics at Augusta University
The investigators note that while clear, common pathways between infertility and conditions like heart disease, still have not been established, “a strong association between infertility and future disease can still assist in early detection, genetic counseling and intervention.” Fertility could be in effect a “biomarker” for future medical illness, they write.
They sequenced the exomes, which contain the protein-coding regions of genes, of 197 females ages 18 to 40 with unexplained infertility, a percentage that comprises about 30% of infertile females, to look for variants in genes that were known or suspected to cause disease.

Information on the women was pulled from the AMIGOS Trial of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network, a group of some 900 couples from multiple institutions with no obvious cause for infertility, like problems with ovulation or unhealthy sperm.
They found 6.6% of the females they studied had variants in 59 genes termed “medically actionable,” which means they are likely to cause conditions like heart disease and breast cancer but there are interventions, lifestyle and/or medical, that might remove or at least reduce their risk. By comparison about 2.5% of the general population have been found to have variants in these genes.
An additional 10% of the females had gene variants known to cause disease for which little to no action could be taken to ameliorate the problem, like Parkinson’s disease, Layman says.
They found 14 variants of the medically actionable genes in 13 of the females; one woman had two variants. The most common were those that contribute to cardiovascular disease and cancer, the nation’s top two killers.
Those included relatively well-known variants, like four women with variants of BRCA1 and BRCA2, which are associated with a high risk of breast or ovarian cancer. Six females had variants in five genes associated with the increased risk of cardiovascular disease, things like having a genetic predisposition to high cholesterol levels and irregular heart rhythms, some of which can be lethal.

One female had a variant in the gene MYH11, which is associated with increased risk of a rupture of the aorta, the largest blood vessel in the body. Numerous rare variants of uncertain significance also were found in the medically actionable genes.
Comparatively large datasets that better represent the entire population, like 50,000 people in the United Kingdom Biobank and nearly 22,000 in the National Human Genome Research Institute-funded eMERGE network, yielded percentages of 2 and 2.5% respectively.
That translates to about a threefold increase in variants in medically actionable genes among the females who were infertile compared with the general population, Layman says.
Additionally, they found 20 variants in 21 other females in genes associated with conditions that likely could not be mitigated, like a dramatically increased risk of developing muscle wasting ALS, or Lou Gehrig’s disease, and kidney-destroying polycystic kidney disease, which will ultimately require dialysis and/or a kidney transplant, a finding that requires more study, Layman and his colleagues write.
All told about 17% of the females with unexplained infertility had variants that are known to cause or suspected to cause a future medical illness. They note that their findings are likely relevant only to this group of women.
While more study is needed before moves are made like recommending genetic testing for all females or males with unexplained infertility, the investigators say their findings support the notion that the higher incidence of future medical problems in these women may have a genetic component.
At the moment, genetic testing in infertility is done selectively, such as if the suspected problem points to a genetic cause, like a male having no sperm, which may indicate Klinefelter syndrome, where males are born with an extra copy of the X chromosome that results from a random genetic error.
“We don’t do genetic testing right now because there hasn’t been good evidence for it and it’s not going to be covered by insurance,” Layman says. Their new study provides more evidence that genetic testing might need to be considered a handful of years down the road if findings continue to hold.
“We need to study a lot more people and other people need to do that too,” Layman says.
Another area that needs further exploration is whether some of the gene variants may be causative of both infertility and disease, Layman says. Right now, the only variants familiar to him that appear to have a role in both are cancer-causing BRCA 1 and 2, because they also are involved in meiosis, which is important to sperm and egg formation and function. They also are both involved in repairing double-strand breaks in the DNA, which has been associated with ovarian aging and cancer risk, Layman says.
Another is a variant that causes early menopause, which is known to increase the risk of heart disease, because estrogen is considered protective of the female cardiovascular system.
He hopes the new findings will inspire others to further explore whether the disease-causing variants they found present in these females also are factors in their infertility.
Layman also notes that the database they studied happened to be largely white females, but that infertility is a problem common to both Blacks and whites as well as other races, and needs to be studied in these populations.
Infertility also affects men and women equally, according to the American Society for Reproductive Medicine.
One of Layman’s many pursuits include a larger study that also includes males. He wants to do genetic studies on couples then continue to follow them past the point of their seeking reproductive help to specifically assess when and if diseases associated with the genetic variants they found start to surface.
While Layman has some patients that he follows long term, most of his patients come to him during the years they are working toward having a child while some of the conditions, like breast cancer, that can result from the gene variants they found, tend to occur a decade or more later. He has wondered about what happened in his patients’ lives long term because of associations that have been made between infertility and a handful of diseases.
When the National Institutes of Health issued a funding opportunity in 2020 for research exploring infertility as a marker for overall health in light of increasing evidence that “fertility status can be a window into overall health,” he decided to further explore the associations.
Dr. Michael Diamond, a reproductive endocrinologist who is senior vice president for research at AU, is a longtime principal investigator on the National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network. Diamond enabled the university to join the cooperative, designed to enable large clinical trials that improve the diagnosis and treatment of reproductive health issues, a decade ago when he came to MCG and AU from Wayne State University in Detroit. Diamond is a coauthor on the new study in the NEJM.
Dr. Michael P. Dougherty, who completed his reproductive endocrinology fellowship with Layman and is now in practice in New Jersey, is first author.
Today 72 genes are considered medically actionable by the American College of Medical Genetics and Genomics.

Tyrosine kinase inhibitors are a type of targeted cancer medicine that can attack specific types of cancer cells and prevent them from multiplying. Although these inhibitors, called TKIs, can be very useful in fighting certain cancers, they also cause serious inflammatory side effects that limit their use. A Japanese research team has discovered the underlying mechanism that causes this inflammation.
“This study revealed the underlying mechanism by which the TKIs cause inflammation, and therefore provides the molecular basis that is essential to overcome the inflammatory-based side effects,” said Atsushi Matsuzawa, a professor at the Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University.
The team’s findings were published in The Journal of Immunology on February 6, 2023.
These TKIs are essential anticancer drugs. However, the use of TKIs frequently initiates inflammation in the body, such as the lung disease interstitial pneumonitis. From their earlier studies, the team had learned that a representative TKI called Gefitinib (GF) causes lung inflammation. GF is a helpful cancer medication used in treating certain breast, lung, and other cancers. It works by targeting the epidermal growth factor receptors. When the GF is used to treat the cancer, it can also cause inflammation in the patient’s lungs, through the NLRP3 inflammasome. The NLRP3 inflammasome is part of the body’s immune system and plays an important role in innate immunity. But when the NLRP3 inflammasome is improperly activated, it can contribute to the development of a wide range of inflammatory diseases.
Until now, scientists have not fully understood why the NLRP3 inflammasome is activated, but the evidence seems to point to mitochondrial dysfunction. When mitochondria are healthy, they work like batteries, producing energy in the body’s cells. Mitochondrial dysfunction happens when the mitochondria do not work as they should because of disease. In their earlier study, the team learned that the GF activated the NLRP3 inflammasome through mitochondrial damage that led to the interstitial pneumonitis in patients. However, they had not understood how GF initiates the mitochondrial damage and whether or not other TKIs also shared this mechanism.
To conduct their study, the team looked at the tyrosine kinases, those enzymes that work as a kind of “on” and “off” switch in many of the cells’ functions. They specifically studied the Src family kinases, called SFKs. The SFKs are nonreceptor tyrosine kinases that regulate many cell processes. There are 11 types of SFKs in the human genome. Some of these SFKs are in the mitochondria and they play an essential role in the function of the mitochondria. The team found that all the TKIs they tested inhibit the kinase activity of the SKFs in the mitochondria which is responsible for the NLRP3 inflammasome.
The team’s comprehensive analysis of the TKIs they tested revealed that these TKIs act as powerful agonists. In addition, the team observed off-target activity that could contribute to the side effects. “As an important finding, all TKIs we tested share a common off-target activity against the mitochondrial SFKs. Therefore, blocking the access of TKIs to mitochondria is a good way to prevent the inflammation,” said Matsuzawa. They also noted that the other TKIs that do not affect the activity of the mitochondrial SFKs may overcome the inflammatory-based side effects. As another approach, when effective inhibitors of the NLRP3 inflammasome are developed, administering the TKIs at the same time as the NLRP3 inhibitors can counteract the side effects. The team’s results provide insight into both the biological and the clinical significance of the NLRP3 inflammasome and the SFKs.
Looking ahead, the team’s next step is to propose a new approach to avoid the inflammatory-based side effects of TKIs. They hope to lead in the development of new TKIs that do not initiate inflammation.
The research team includes Yuto Sekiguchi, Saya Takano, Takuya Noguchi, Tomohiro Kagi, Ryuto Komatsu, Maoko Tan, Yusuke Hirata, and Atsushi Matsuzawa from the Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan.

Staphylococcus aureus. You may have had it in connection with a wound infection. In most cases, it will pass without treatment, while severe cases may require antibiotics, which kills the bacteria. This is the case for the majority of the population. In fact, many of us — though we feel perfectly fine — carry staphylococci in the nose, a good, moist environment in which the bacteria thrive.
However, more and more staphylococci are becoming resistant to antibiotics (also known as multi resistant staphylococcus aureus or MRSA), and these infections can be difficult to treat.
“Antibiotics resistance is an increasing problem, especially on a global scale. And when you have this relatively simple infection which suddenly cannot be treated with antibiotics, the situation can turn serious, sometimes life-threatening,” says Professor Niels Ødum from the LEO Foundation Skin Immunology Research Center at the University of Copenhagen.
Therefore, all over the world, a lot of resources are being invested in fighting antibiotics resistance in staphylococcus aureus infections, and a new study among skin lymphoma patients has produced positive results. A new substance called endolysins has proven capable of killing both resistant and non-resistant staphylococcus aureus — without the need for antibiotics. But we will get back to that.
The discovery is good news to patients with a weak immune system to whom a staphylococcus aureus infection can be serious and, at worst, fatal. But it also adds to the knowledge we have of other forms of treatment.
“To people who are severely ill with e.g. skin lymphoma, staphylococci can be a huge, sometimes insoluble problem, as many are infected with a type of staphylococcus aureus that is resistant to antibiotics,” says Niels Ødum and adds:
“That is why we are careful not to give antibiotics to everyone, because we do not want to have to deal with more resistant bacteria. Therefore, it is important that we find new ways of treating — and not the least to prevent — these infections.”

New substance may be the answer
In some patients, a staphylococcus aureus will cause the cancer to worsen. And even though antibiotics appear to work in some cases, it is not without its problems.
“We can tell that giving high doses of antibiotics to patients with serious infections causes their health, skin and cancer symptoms to improve. But once we stop giving them antibiotics, the symptoms and staphylococci quickly return. Patients experience many adverse effects, and some risk getting resistant bacteria,” says Niels Ødum.
Therefore, treating staphylococcus aureus can be tricky. At worst, cancer patients may die of an infection which doctors are unable to treat.
And this is where endolysins enter the scene, as this new substance may be part of the solution to antibiotics resistance like MRSA.

“This particular endolysin is a brand new, artificially produced enzyme that has been improved several times and designed as a new drug,” explains Postdoc Emil Pallesen, who is first author of the study. He adds:
“The great thing about this enzyme is that it has been designed to penetrate the wall of staphylococcus aureus. This enables it to target and kill the harmful staphylococcus and leave harmless skin bacteria unharmed.”
And that is what made the researchers decide to test the new substance; they expected it to be able to kill both resistant and non-resistant staphylococcus bacteria.
“We have been testing the substance on skin samples from patients, and it does appear to kill staphylococcus aureus from patients. Endolysins do not care whether the bacterium is resistant to antibiotics or not, because it does not work in the same way as antibiotics,” says Niels Ødum and adds:
“The really good news is that our lab tests have showed that endolysins do not just eradicate staphylococcus aureus; they also inhibit their ability to promote cancer growth.”

New scientific research has found that attending live sporting events improves levels of wellbeing and reduces feelings of loneliness.
Published in the journal Frontiers in Public Health, the research is the first large-scale study to examine the benefits of attending any type of live sporting event.
The study, carried out by academics from Anglia Ruskin University’s School of Psychology and Sport Science, used data from 7,209 adults, aged 16-85, living in England who participated in the Taking Part Survey, which was commissioned by the British Government’s Department for Digital, Culture, Media and Sport.
It found that attending live sporting events results in higher scores of two major measurements of subjective wellbeing — life satisfaction and a sense of “life being worthwhile” — as well as lower levels of loneliness.
These results are significant as previous studies have shown that higher life satisfaction scores are associated with fewer life-limiting conditions and better physical health, successful ageing, and lower mortality rates.
The new study also found that attending live sporting events leads to an increase in people’s sense that “life is worthwhile,” and the size of this increase is comparable to that of gaining employment.
Many initiatives currently promote the benefits of physical participation in sport, but the researchers believe that watching live sporting events can also offer an accessible and effective public health tool for improving wellbeing and reducing loneliness.
Lead author Dr Helen Keyes, Head of the School of Psychology and Sport Science at Anglia Ruskin University (ARU), said: “Previous research has focused on specific sports or small population samples, such as college students in the United States. Ours is the first study to look at the benefits of attending any sporting event across an adult population, and therefore our findings could be useful for shaping future public health strategies, such as offering reduced ticket prices for certain groups.
“The live events covered by the survey ranged from free amateur events, such as watching village sports teams, right through to Premier League football matches. Therefore, further research needs to be carried out to see if these benefits are more pronounced for elite level sport, or are more closely linked to supporting a specific team.
“However, we do know that watching live sport of all types provides many opportunities for social interaction and this helps to forge group identity and belonging, which in turn mitigates loneliness and boosts levels of wellbeing.”