Publisher Health

A new study finds that people have a very difficult time finding doctors in their networks under the private-sector policies.People with private Medicare coverage may not be getting the mental health services they need because they cannot find a psychiatrist within their plan’s network, according to a new study. More than half of the counties the researchers studied did not have a single psychiatrist participating in a Medicare Advantage plan, the private-sector counterpart to traditional Medicare. Some 30 million people, just over half of all participants in the federal program, are enrolled in these private plans.The researchers, in an article published on Wednesday in the journal Health Affairs, found that of the plans reviewed, nearly two-thirds were narrow, with fewer than a quarter of available psychiatrists in a plan’s network. The networks offered under either an Obamacare plan or Medicaid managed care were not as restrictive and included about 40 percent of the available psychiatrists, according to the study.The more limited “networks present a frustrating additional barrier in mental health services even when, on paper, there are a sufficient number of providers in a geographic region,” the researchers wrote.The pandemic helped expose a widespread need for mental health services among older Americans, many of whom are struggling with loneliness, the loss of a loved one or their own deteriorating health. While roughly one in four people enrolled in Medicare has a mental illness like depression, anxiety or schizophrenia, an estimated half or fewer receive treatment, according to a recent analysis of mental health coverage by the Commonwealth Fund, a nonprofit group.“We need systems in place so people can easily find and afford the care they need,” said Gretchen Jacobson, vice president of Medicare at Commonwealth. “It’s not clear people are able to do so.”The difficulty in finding a psychiatrist is not unique to Medicare Advantage policyholders, in part because of increased demand. The scarcity of psychiatrists, particularly those willing to accept insurance, makes it difficult for plans to find providers. Many psychiatrists have also opted out of seeing patients under traditional Medicare, according to a recent report.“Part of what is going on is we have this big problem of a shortage of psychiatrists and mental health providers writ large,” said Beth McGinty, the chief of the division of health policy and economics at Weill Cornell Medicine and the author of the Commonwealth report. “It is exacerbated here.”Because going out of network is costly, many people will delay or skip treatment, said Dr. Jane M. Zhu, one of the study’s authors and a primary care physician at Oregon Health and Science University. She said her own patients often had difficulty finding help.“I was referring them out, but they could just not get access to any mental health providers,” Dr. Zhu said. One of her patients called more than a dozen providers before getting an appointment, she said.Insurers say their goal is to provide a wide array of mental health services. “Everyone deserves access to effective, affordable and equitable mental health support,” Kristine Grow, a spokeswoman for AHIP, a trade group representing the insurers, said in an email.But Ms. Grow criticized the Health Affairs study for not comparing the plans with traditional Medicare and for not examining other types of mental health services available to patients that would be provided by other clinicians or via telehealth. “In essence, this study uses a very narrow definition of mental health clinician to prove a pre-existing thesis about Medicare Advantage,” she said.More broadly, regulators and lawmakers have voiced concerns that people in the private Medicare plans may not be getting the services they are entitled to under the federal program. Critics have long complained about inadequate access to mental health services.Senator Ron Wyden, the Oregon Democrat who leads the Senate Finance Committee, held a hearing in May about so-called “ghost networks” of mental health providers, in which many of the clinicians listed in the Medicare Advantage plans’ directories are not, in fact, accepting patients. His staff conducted a secret shopper survey and could only obtain an appointment 18 percent of the time.The Health Affairs study may have overstated the availability of psychiatrists because it only looked at which providers were listed in the plan’s directory, Dr. Zhu said. “It likely paints a rosier picture,” she said.Doctors may be unwilling to participate in Medicare Advantage plans because of the low payments paid by the insurers, coupled with all of the required paperwork, said Dr. Robert Trestman, who is the chairman of the council on health care systems and financing for the American Psychiatric Association and testified at the Senate hearing. “Many of the challenges and frustrations are emphasized in the Medicare Advantage plans,” he said.Some insurers pay psychiatrists less under their Medicare Advantage plans than traditional Medicare pays for the same services, the researchers said. The plans may also have an incentive to contract with a smaller group of doctors to have more control over the cost and care being delivered, the researchers said.

Malaria remains one of the world’s deadliest diseases. Each year malaria infections result in hundreds of thousands of deaths, with the majority of fatalities occurring in children under five. The Centers for Disease Control and Prevention recently announced that five cases of mosquito-borne malaria were detected in the United States, the first reported spread in the country in two decades.
Fortunately, scientists are developing safe technologies to stop the transmission of malaria by genetically editing mosquitoes that spread the parasite that causes the disease. Researchers at the University of California San Diego led by Professor Omar Akbari’s laboratory have engineered a new way to genetically suppress populations of Anopheles gambiae, the mosquitoes that primarily spread malaria in Africa and contribute to economic poverty in affected regions. The new system targets and kills females of the A. gambiae population since they bite and spread the disease.
Publishing July 5 in the journal Science Advances, first-author Andrea Smidler, a postdoctoral scholar in the UC San Diego School of Biological Sciences, along with former master’s students and co-first authors James Pai and Reema Apte, created a system called Ifegenia, an acronym for “inherited female elimination by genetically encoded nucleases to interrupt alleles.” The technique leverages the CRISPR technology to disrupt a gene known as femaleless (fle) that controls sexual development in A. gambiae mosquitoes.
Scientists at UC Berkeley and the California Institute of Technology contributed to the research effort.
Ifegenia works by genetically encoding the two main elements of CRISPR within African mosquitoes. These include a Cas9 nuclease, the molecular “scissors” that make the cuts and a guide RNA that directs the system to the target through a technique developed in these mosquitoes in Akbari’s lab. They genetically modified two mosquito families to separately express Cas9 and the fle-targeting guide RNA.
“We crossed them together and in the offspring it killed all the female mosquitoes,” said Smidler, “it was extraordinary.” Meanwhile, A. gambiae male mosquitoes inherit Ifegenia but the genetic edit doesn’t impact their reproduction. They remain reproductively fit to mate and spread Ifegenia. Parasite spread eventually is halted since females are removed and the population reaches a reproductive dead end. The new system, the authors note, circumvents certain genetic resistance roadblocks and control issues faced by other systems such as gene drives since the Cas9 and guide RNA components are kept separate until the population is ready to be suppressed.
“We show that Ifegenia males remain reproductively viable, and can load both fle mutations and CRISPR machinery to induce fle mutations in subsequent generations, resulting in sustained population suppression,” the authors note in the paper. “Through modeling, we demonstrate that iterative releases of non-biting Ifegenia males can act as an effective, confinable, controllable and safe population suppression and elimination system.”
Traditional methods to combat malaria spread such as bed nets and insecticides increasingly have been proven ineffective in stopping the disease’s spread. Insecticides are still heavily used across the globe, primarily in an effort to stop malaria, which increases health and ecological risks to areas in Africa and Asia.
Smidler, who earned a PhD (biological sciences of public health) from Harvard University before joining UC San Diego in 2019, is applying her expertise in genetic technology development to address the spread of the disease and the economic harm that comes with it. Once she and her colleagues developed Ifegenia, she was surprised by how effective the technology worked as a suppression system.
“This technology has the potential to be the safe, controllable and scalable solution the world urgently needs to eliminate malaria once and for all,” said Akbari, a professor in the Department of Cell and Developmental Biology. “Now we need to transition our efforts to seek social acceptance, regulatory use authorizations and funding opportunities to put this system to its ultimate test of suppressing wild malaria-transmitting mosquito populations. We are on the cusp of making a major impact in the world and won’t stop until that’s achieved.”
The researchers note that the technology behind Ifegenia could be adapted to other species that spread deadly diseases, such as mosquitoes known to transmit dengue (break-bone fever), chikungunya and yellow fever viruses.
The full author list includes Andrea Smidler, James Pai, Reema Apte, Hector Sanchez C., Rodrigo Corder, Eileen Jeffrey Gutierrez, Neha Thakre, Igor Antoshechkin, John Marshall and Omar Akbari.

Nearly 700,000 people in the United States die from heart disease every year, and one-third of those deaths result from complications in the first weeks or months following a traumatic heart-related event.
To help prevent those deaths, researchers at Northwestern and George Washington (GW) universities have developed a new device to monitor and treat heart disease and dysfunction in the days, weeks or months following such events. And, after the device is no longer needed, it harmlessly dissolves inside the body, bypassing the need for extraction.
About the size of a postage stamp, the soft, flexible device uses an array of sensors and actuators to perform more complicated investigations than traditional devices, such as pacemakers, can accomplish. Not only can it be placed on various sections of the heart, the device also continuously streams information to physicians, so they can remotely monitor a patient’s heart in real time. The device also is highly transparent, allowing physicians to observe specific heart regions to make a diagnosis or provide a treatment.
The research will be published on Wednesday (July 5) in the journal Science Advances.
“Several serious complications, including atrial fibrillation and heart block, can follow cardiac surgeries or catheter-based therapies,” said Northwestern’s Igor Efimov, an experimental cardiologist who co-led the study. “Current post-surgical monitoring and treatment of these complications require more sophisticated technology than currently available. We hope our new device can close this gap in technology. Our transient electronic device can map electrical activity from numerous locations on the atria and then deliver electrical stimuli from many locations to stop atrial fibrillation as soon as it starts.”
“Many deaths that occur following heart surgery or a heart attack could be prevented if doctors had better tools to monitor and treat patients in the delicate weeks and months after these events take place,” added GW’s Luyao Lu, who co-led the work with Efimov. “The tool developed in our work has great potential to address unmet needs in many programs of fundamental and translational cardiac research.”
Efimov is a professor of biomedical engineering at Northwestern’s McCormick School of Engineering and professor of medicine at Northwestern University Feinberg School of Medicine. Lu is an assistant professor of biomedical engineering at GW.
This work builds on Efimov’s previous work to develop cardiac implants to monitor and temporarily pace the heart. In 2021, Efimov and Northwestern professor John A. Rogers introduced the first-ever transient pacemaker, published in Nature Biomedical Engineering. Then, earlier this year, Efimov’s team unveiled a graphene “tattoo” for treating cardiac arrhythmia, published in Advanced Materials.
“After heart surgeries, surgeons sometimes insert temporary wires, which are connected to external current generators, to provide electrical stimulation during temporary heart block caused by the surgery,” Efimov said. “Recently, we developed a bioresorbable pacemaker to replace such a wire. Post-operative atrial fibrillation requires a more complicated approach based on a multi-electrode array for sensing and stopping atrial fibrillation. Now, we present a novel technology to achieve this goal.”
Tested in small animal models, the new device provides functions beyond those of a traditional pacemaker. While a pacemaker only can provide one overall picture of the heart (whether or not the heart is beating), the transient device provides a more nuanced picture. Not only can it restore normal heart rhythms, it also can show which areas of the heart are functioning well and which areas are not. The device’s transparent nature also allows researchers to optically map many important cardiac physical parameters through the device to better study heart function and heart disease mechanisms.
After a clinically relevant period, the device — which is made of biocompatible materials approved by the U.S. Food and Drug Administration — simply dissolves into benign products. Similar to absorbable stitches, the device degrades and then completely disappears through the body’s natural biological processes. The device’s bioresorbable nature could reduce healthcare costs and improve patient outcomes by avoiding complications from surgical extraction and lowering infection risks.
The study, “Soft, bioresorbable, transparent microelectrode arrays for multimodal spatiotemporal mapping and modulation of cardiac physiology,” was supported by the National Science Foundation and the National Institutes of Health.

An antisense therapy developed by Joel D. Richter, PhD, Sneha Shah, PhD, and Jonathan K. Watts, PhD, at UMass Chan Medical School and Elizabeth Berry-Kravis, MD, PhD, at RUSH University Medical Center, restores production of the protein FMRP in cell samples taken from patients with fragile X syndrome. Published in the Proceedings of the National Academy of Sciences, this breakthrough was possible because of the novel findings, also presented in the study, that aberrant alternative splicing of messenger RNA (mRNA) plays a principal role in fragile X syndrome, the most common form of inherited intellectual disability and the most frequent single-gene cause of autism.
“This discovery offers real hope that a therapy to mitigate fragile X syndrome may be possible and could be translated to the clinic sooner than we once thought,” said Dr. Richter, the Arthur F. Koskinas Chair in Neuroscience and professor of molecular medicine. “These findings are unconventional and weren’t something we were expecting. If you do good basic science, believe in your data and follow where it takes you, the results can change our fundamental understanding of biology and disease.”
Fragile X syndrome is a genetic condition resulting from a CGG repeat expansion in the DNA sequence of the fragile X (FMR1) gene. People with fragile X suffer from intellectual disability as well as behavioral and learning challenges. Cognitive disabilities can range from mild to severe and afflict boys more frequently than girls. There is no cure for fragile X syndrome although interventions such as special education, speech therapy, physical therapy or behavioral therapy and drugs providing symptomatic relief can provide the opportunity for optimizing a full range of skills.
When viewed under the microscope, the FMR1 gene containing the repeat expansion is detected as a narrowed band pinching the tip of one arm of the X chromosome (identified as the fragile site). The main function of the protein product of the FMR1 gene (FMRP) is to bind as many as 1,000 different mRNAs and inhibit their translation When FMRP is absent, as in fragile X syndrome, there is excess production of hundreds of different proteins in the brain. Although it’s not fully understood how, FMRP control of mRNA translation plays a critical role in synaptic plasticity and higher brain function. Without FMRP, normal neurological development doesn’t occur.
Normally, humans have between five and 55 CGG repeats in the FMR1 gene. Fragile X syndrome occurs when an individual has more than 200 CGG repeats in the FMR1 gene sequence. The conventional model of the disease holds that once a CGG repeat length reaches 200 or more, the gene becomes methylated and shut down, and does not produce FMR1 RNA or FMRP.
Utilizing blood samples from males with fragile X provided by Dr. Berry-Kravis, professor of pediatrics, neurological sciences and anatomy and cell biology, Drs. Richter and Shah found something unexpected.

“We had reason to believe that there were defects in a number of the mRNAs being produced by fragile X patients,” said Dr. Shah, assistant professor of molecular medicine. “We ran the experiments and began looking at the various RNA readouts, however, we were surprised to find that the cells were producing fragile X mRNA even though no protein was being made. They shouldn’t have been producing any fragile X mRNA. This wasn’t supposed to be happening. It made us rethink how the disease was occurring on a basic biological level.”
Looking closely at the mutation-carrying fragile X mRNA, Shah found a little-known abnormal splice isoform, a sequence variation, referred to as FMR1-217. Before mRNA can be translated by the ribosome into a functioning protein it undergoes a process called splicing. This intermediary process removes all the non-coding regions of the RNA (introns) and splices back together the protein coding regions (exons). It’s believed that variations in this splicing mechanism, called alternative splicing, allows a single gene to create different RNA isoforms. These isoforms, because they each contain different coding regions, allow a single gene to make multiple proteins.
The CGG repeats found in the FMR1 gene mutation, however, were causing a mis-splicing event that left a crucial piece of an intron (a pseudo-exon) in the mature mRNA. This simple splicing error was the reason the FMRP wasn’t being made, not methylation of the gene, as had been previously believed. Richter and Shah hypothesized that if this mis-splicing could be corrected or avoided, then normal fragile X protein production could be restored.
One way to alter RNA splicing is to create an antisense oligonucleotide (ASO), a short piece of DNA with a complementary sequence, which will bind to the target mRNA. This binding causes the splicing machinery to skip over the improper splice sites on the RNA, resulting in normal splicing and mature mRNA formation. It’s also a technique that is already being employed in the clinic to treat the neuromuscular disorder spinal muscular atrophy (SMA) and is in clinical trials for other neurological diseases.
To design an ASO targeting the fragile X mRNA, Richter and colleagues turned to Dr. Watts, an ASO expert who also works on neurological diseases such as Huntington’s disease and ALS. Watts, professor of RNA therapeutics, designed 11 ASOs attempting to find one that would block mis-splicing of the fragile X RNA and restore FMRP production. A combination of two ASOs developed by Watts successfully inhibited the aberrant splicing and rescued proper FMR1 mRNA splicing in patient-derived cells. This led to production of normal levels of FMRP in these cells.

“We never would have found this using a mouse model of fragile X,” said Richter. “The mouse model is a gene knockout. Because it simply doesn’t have the fragile X gene, there is no mRNA that is made. The FMR1 mRNA mis-splicing is a gene regulation mechanism that depends on the CGG expansion, which may be unique to human and primates. We only discovered this mis-splicing because we were working in human cells.”
Richter and colleagues hope that translating this discovery to the clinic can be expediated because current treatments for SMA are based on a similar technology. The only difference between the two is the genetic sequence of the ASO used to treat the fragile X mis-splicing.
“This is a very exciting finding that has high therapeutic potential,” said Berry-Kravis. “It is very early in development, however, and much work is needed to determine how effectively the ASO strategy can restore FMRP, in what percent of brain cells and in which individuals with fragile X. If the ASO strategy turns out to be successful in cells from a significant percent of individuals with fragile X, this may provide a genetic reversal of disease that could have high clinical impact and improve the functional level of people living with fragile X and reduce the burden on their caregivers.”
Funding for the research was provided, in part, by the National Institutes of Health, the Simons Foundation for Autism Research, the FRAXA Research Foundation and the UMass Chan BRIDGE Fund. The next step for the fragile X team will be to secure a partnership with a commercial enterprise that can help bring the ASO work to an eventual human clinical trial to treat fragile X syndrome.
“FRAXA funded the Richter and Berry-Kravis labs to conduct an innovative study of abnormal splicing events in Fragile X with an eye toward potential use as a biomarker,” said Michael Tranfaglia, MD, chief scientific officer of the FRAXA Research Foundation. “In the course of this research, these superb scientists serendipitously discovered something truly transformative which changed our fundamental understanding of fragile X itself. Beyond that, the therapeutic potential of this discovery is truly remarkable.”
Dr. Richter and colleagues also received funding from the BRIDGE Fund at UMass Chan in 2022 to design and test the ASO used to restore fragile X protein production.
“With the help of a BRIDGE Fund award, Dr. Richter’s lab demonstrates that antisense oligonucleotides efficiently block improper FMR1 splicing and restore FMRP to normal levels,” said Huseyin Mehmet, PhD, executive director of BRIDGE Innovation and Business Development at UMass Chan.
The next step for the fragile X team will be to secure a partnership with a commercial enterprise that can help bring the ASO work to an eventual human clinical trial to treat fragile X syndrome.

Scientists at St. Jude Children’s Research Hospital found immune and tumor cells compete over glutamine, a major nutrient in their local environment, with significant implications for anti-cancer activity. If cancer cells monopolize glutamine, they can prevent immune cells from destroying cancer. The findings show that supplying glutamine directly to tumors helps initiate the immune system’s cancer-killing activity. The researchers also identified a molecular pathway that could serve as a potential drug target to achieve the same effect. The findings were published today in Nature.
“It’s a nutrient tug-of-war between tumor cells and immune cells,” said corresponding author Hongbo Chi, Ph.D., St. Jude Department of Immunology. “If tumor cells use all the available glutamine, then a specialized immune cell type known as the dendritic cell is starved of glutamine, leading to impaired anti-tumor immune function. But if we can supplement enough glutamine to the tumor microenvironment, that will inhibit tumor growth because dendritic cells will use it and activate the adaptive immune response.” Dendritic cells turn on cancer-killing immune cells called T cells.
The group showed that resupplying glutamine in the tumor microenvironment severely reduced tumor growth because dendritic cells were then better able to activate anti-cancer T cells. The tumor microenvironment is composed of chemicals and cells around cancer cells. Infamously, cancer cells secrete many signals to turn the immune response “off” in this area, especially the T cells that threaten their destruction. The St. Jude team is the first to identify a nutrient as a major signal between cancer cells and dendritic cells in this local environment.
Improving anti-cancer therapies
“We are very excited to establish the link between glutamine, therapeutic effect and dendritic cells,” said first author Chuansheng Guo, Ph.D., St. Jude Department of Immunology. “It’s critical for the efficacy of immune checkpoint blockade and adoptive cell transfer therapy.”
Immune checkpoint blockade therapy inhibits the “off” signals cancer cells send to immune cells that suppress the immune response in the tumor microenvironment. These therapies have been highly effective, but only in a small number of patients. The researchers found that supplying glutamine in combination with checkpoint therapy enhanced anti-cancer activity in mice.

“This paper provides a proof of concept that nutrients could act synergistically with checkpoint inhibitors for tumor treatment as a new strategy for combination therapy,” Chi said.
The mechanism of helping or hindering cancer-killing
While much cancer research has focused on T cells because of their direct cancer-killing activity, this study is one of the first to examine how the tumor microenvironment affects the dendritic cells, which activate T cells. The researchers found that without glutamine, dendritic cells failed to activate the T cells that directly kill cancer cells.
“Even though T cells are the cornerstone for anti-cancer immunity, they cannot do the job by themselves,” Chi explained. “We can think of dendritic cells as the driver and the T cell as the car. If you do not have a driver, the car will not move. Moreover, nutrients like glutamine serve as the license for the driver.”
Similarly, when the researchers removed the proteins that respond to or take up glutamine in dendritic cells, the immune cells failed to activate cancer-killing cells. These proteins, called FLCN and SLC38A2, are important in sensing and acquiring nutrients but have not previously been connected to immune cells’ reactions to tumors. They may serve as potent drug targets to improve cancer therapy.
“We’re extremely excited about these findings,” Chi said. “In addition to enhancing the therapeutic intervention, we have provided a conceptual advance by showing how nutrients mediate cell-cell communication, an understudied concept in the field of immunometabolism.”
The study’s other authors are Zhiyuan You, Hao Shi, Gustavo Palacios, Cliff Guy, Sujing Yuan, Nicole Chapman, Seon Ah Lim, Xiang Sun, Jordy Saravia, Sherri Rankin, Yogesh Dhungana, of St. Jude, and Yu Sun and Xingrong Du, formerly of St. Jude.
The study was supported by grants from the National Institutes of Health (AI105887, AI131703, AI140761, AI150241, AI150514 and CA253188) and ALSAC, the fundraising and awareness organization of St. Jude.

Osteoarthritis is the most common degenerative joint disease, affecting 22% of adults over 40 globally. Although the condition has been extensively studied through a medical perspective, the molecular changes associated with osteoarthritis remain unclear. In a new study, researchers have used a combination of techniques to track the progression of the disease and the changes associated with it.
The cartilage in the joints, along with a lubricant known as the synovial fluid, provides a smooth surface that helps withstand weight-bearing movements. The fluid contains several molecules, including hyaluronan (HA) and phospholipids. Since the cartilage environment cannot be quickly healed or repaired, researchers have tried to diagnose the early stages of joint disease by monitoring the molecular weight and concentration of HA.
“Although we know that in healthy joints there is very low friction, it is unclear which other molecules are involved and how they change during osteoarthritis,” said Rosa Espinosa-Marzal (EIRH), Donald Biggar Willett Faculty Scholar and a professor of environmental engineering & science, and materials science & engineering. “During the early stages of osteoarthritis, cartilage starts degrading, and previous research has shown that the molecular composition of the synovial fluid changes. We wanted to see if the two changes are related to each other.”
In a healthy joint, the molecular weight of HA varies between 2-20 MDa with a concentration ranging from 1-4 mg/ml. However, in diseased joints, HA is broken down resulting in a lower molecular weight. Additionally, its concentration is also reduced by ten times. Based on these observations, made by other researchers, the study looked at how the concentration and molecular weight of HA influences the structure of healthy and diseased joints.
To do so, the researchers combined vesicles with high and low molecular weight HA. Using neutron scattering and light scattering, they discovered that the molecular weight of HA can vastly change the structure of the vesicles. Lower molecular weight HA, which mimics osteoarthritis-diseased joints, results in larger vesicle size. They also observed that the molecular weight of HA changes the thickness of the phospholipid layers in the joints.
The researchers also studied how these differences can influence the formation of a protective film; in joints this film is responsible for the very low friction we need for unhindered motion. Once again, they used a combination of techniques, quartz crystal microbalance and atomic force microscopy, to examine how these molecules assemble on gold surfaces.
“The formation of a film is possible only when there is an optimal concentration of HA and phospholipids. Even though the gold surfaces have very little in common with cartilage, our studies indicate that there could also be an optimum concentration under biological conditions,” Espinosa-Marzal said. “This is an important observation because we can use the concentration changes as a diagnostic tool.”
“We are at a point where you need to use multiple techniques on a complex system like this,” said Mark Rutland, a professor of surface science at the KTH Royal Institute of Technology. “None of these techniques alone would have given us any insight. The key was to look at all the different effects and put the pieces together to show that the molecular weight of HA has a huge effect on the characteristics of the layer that is formed with phospholipids.”
The researchers are now working on using cartilage to understand whether their observations with gold surfaces also hold true in a biologically relevant system. They are also interested in studying the other molecular components that are found in joints to build a more comprehensive model of the changes that are associated with osteoarthritis.

New research from Sanford Burnham Prebys has helped explain how melanoma evades the immune system and may guide the discovery of future therapies for the disease. The study found that a protein known to be active in immune cells is also active inside melanoma cells, helping promote tumor growth. The findings, published in the journal Science Advances, suggest that targeting this protein with new drugs may deliver a powerful double hit to melanoma tumors.
“The immune system’s control of a tumor is influenced by both internal factors within tumor cells, as well as factors from the tumor’s surroundings,” says first author Hyungsoo Kim, Ph.D., a research assistant professor at Sanford Burnham Prebys in the lab of senior author Ze’ev Ronai, Ph.D. “We found that the protein we’re studying is involved in both, which makes it an ideal target for new cancer therapies.”
One of the most significant breakthroughs in cancer therapy in the last century is the development of immunotherapy, an approach that helps improve the immune system’s ability to fight cancer on its own without the use of toxic chemotherapy drugs.
“Immunotherapy is the first-line therapy for several cancers now, but the success of immunotherapy is limited because many cancers either don’t respond to it or become resistant over time,” says Kim. “An important goal remains to improve the effectiveness of immunotherapy.”
To find ways to boost immunotherapy in melanoma, the research team analyzed data from patient tumors to identify genes that may coincide with patients’ responsiveness to immunotherapy. This led to the identification of a protein that helps tumors evade the immune system — called NR2F6 — which was found not only in tumor cells, but also in the surrounding noncancerous cells.
“Often we find that a protein has the opposite effect outside of tumors compared to what it does within a tumor, which is less effective for therapy,” says Kim. “In the case of NR2F6, we found that it elicits the same change in the tumor and in its surrounding tissues, pointing to a synergistic effect. This means that treatments that block this protein’s activity could be twice as effective.”
To confirm their findings in mice, the researchers genetically removed the NR2F6 protein in both melanoma tumors and in the tumors’ environment. This inhibited melanoma growth more strongly, compared to when this effect occurs in either the tumor or its microenvironment alone. The cancer’s response to immunotherapy was also enhanced upon loss of NR2F6 in both tumors and their microenvironment.
“This tells us that NR2F6 helps melanoma evade the immune system, and without it, the immune system can more readily suppress tumor growth,” adds Kim.
To help advance their discovery further, the team is working with the Institute’s Conrad Prebys Center for Chemical Genomics to identify new drugs that can target NR2F6.
“Discovering drugs that can target this protein are expected to offer a new way to treat melanomas, and possibly other tumors, that would otherwise resist immunotherapy,” says Kim.

A new study led by Shan Siddiqi, MD, from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, suggests that depression after traumatic brain injury (TBI) could be a clinically distinct disorder rather than traditional major depressive disorder, with implications for patient treatment. The findings are published in Science Translational Medicine.
“Our findings help explain how the physical trauma to specific brain circuits can lead to development of depression. If we’re right, it means that we should be treating depression after TBI like a distinct disease,” said corresponding author Shan Siddiqi, MD, of the Brigham’s Department of Psychiatry and Center for Brain Circuit Therapeutics. “Many clinicians have suspected that this is a clinically distinct disorder with a unique pattern of symptoms and unique treatment response, including poor response to conventional antidepressants — but until now, we didn’t have clear physiological evidence to prove this.”
Siddiqi collaborated with researchers from Washington University in St. Louis, Duke University School of Medicine, the University of Padua, and the Uniformed Services University of the Health Sciences on the study. The work started as a side project seven years ago when Siddiqi was motivated by a patient he shared with David Brody, MD, PhD, a co-author on the study and a neurologist at Uniformed Services University. The two started a small clinical trial that used personalized brain mapping to target brain stimulation as a treatment for TBI patients with depression. In the process, they noticed a specific pattern of abnormalities in these patients’ brain maps.
The current study included 273 adults with TBI, usually from sports injuries, military injuries, or car accidents. People in this group were compared to other groups who did not have a TBI or depression, people with depression without TBI, and people with posttraumatic stress disorder. Study participants went through a resting-state functional connectivity MRI, a brain scan that looks at how oxygen is moving in the brain. These scans gave information about oxygenation in up to 200,000 points in the brain at about 1,000 different points in time, leading to about 200 million data points in each person. Based on this information, a machine learning algorithm was used to generate an individualized map of each person’s brain.
The location of the brain circuit involved in depression was the same among people with TBI as people without TBI, but the nature of the abnormalities was different. Connectivity in this circuit was decreased in depression without TBI and was increased in TBI-associated depression. This implies that TBI-associated depression may be a different disease process, leading the study authors to propose a new name: “TBI affective syndrome.”
“I’ve always suspected it isn’t the same as regular major depressive disorder or other mental health conditions that are not related to traumatic brain injury,” said Brody. “There’s still a lot we don’t understand, but we’re starting to make progress.”
One limitation of the trial is that with so much data, the researchers were not able to do detailed assessments of each patient beyond brain mapping. As a future step, investigators would like to assess participants’ behavior in a more sophisticated way and potentially define different kinds of TBI-associated neuropsychiatric syndromes.
Siddiqi and Brody are also using this approach to develop personalized treatments. Originally, they set out to design a new treatment in which they used this brain mapping technology to target a specific brain region for people with TBI and depression, using transcranial magnetic stimulation (TMS). They enrolled 15 people in the pilot and saw success with the treatment. Since then, they have received funding to replicate the study in a multicenter military trial.
“We hope our discovery guides a precision medicineapproach to managing depression and mild TBI, and perhaps even intervene in neuro-vulnerable trauma survivors before the onset of chronic symptoms,” said Rajendra Morey, MD, a professor of psychiatry at Duke University School of Medicine, and co-author on the study.

New research from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London and City University New York, published today (Wednesday 5 July) in JAMA Psychiatry, has found that the way childhood abuse and/or neglect is remembered and processed has a greater impact on later mental health than the experience itself. The authors suggest that, even in the absence of documented evidence, clinicians can use patients’ self-reported experiences of abuse and neglect to identify those at risk of developing mental health difficulties and provide early interventions.
Researchers conducted a large longitudinal study following 1,196 participants to age 40 years to investigate how experiences of childhood abuse and/or neglect (maltreatment) impact the development of emotional disorders in adulthood.
The study found that young adults who retrospectively self-reported experiences of childhood maltreatment before age 12 had a greater number of depressive or anxiety episodes over the subsequent decade than those who did not remember maltreatment, even if they had an official court record.
In contrast, participants who had an official record of childhood maltreatment, but no retrospective recall of the experience, had a similar number of emotional disorder episodes in adulthood as those with no experience of maltreatment.
Andrea Danese, Professor of Child & Adolescent Psychiatry at King’s IoPPN and joint author of the study, said: “Our study reveals that how a person perceives and remembers experiences of childhood abuse or neglect has greater implications on future emotional disorders than the experience itself. The findings show that, even in the absence of documented evidence of childhood maltreatment, clinicians can use information provided by their clients to identify those at greater risk for subsequent mental health difficulties. The findings also suggest that early interventions that help cope with memories of abuse and/or neglect may prevent emotional problems later on.”
Participants were interviewed about their self-reported retrospective experiences of childhood maltreatment and their current and past mental health. They were then re-interviewed to measure the course of depression and anxiety symptoms.
Further analyses revealed that the association between self-reported experiences of childhood maltreatment and a greater number of subsequent anxiety and depression episodes was partly explained by participants’ current and past mental health, which was reported during their first interview. The authors explain that this could be because emotional disorders can negatively bias memories, making participants’ more likely to recall negative events.
Professor Danese said: “A better understanding of how memories of child maltreatment are maintained and exacerbated over time, and of how the memories affect daily functioning, could provide new insights to develop effective interventions.”
This work is part of the King’s Maudsley Partnership for Children and Young People, a unique collaboration between specialist clinicians from the South London and Maudsley NHS Foundation Trust and leading academics at King’s College London to find new ways to predict, prevent and treat mental health disorders in children and young people. The Partnership will be based in the new Pears Maudsley Centre which will be home to Child and Adolescent Mental Health Services (CAMHS) inpatient and outpatient services and clinical research facilities, set to open in 2024.
The research was supported by the National Institute of Mental Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Drug Abuse, National Institute on Alcohol Abuse and Alcoholism, National Institute on Aging, National Institute of Justice, Doris Duke Charitable Foundation, Medical Research Council and National Institute for Health and Care Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.

Most people have at some point in their life suffered an intestinal infection or food poisoning forcing them to stay close to the bathroom. It is very uncomfortable. Most of the time, though, it passes quickly.
But around 60,000-100,000 Danes suffer from a form of chronic diarrhea called bile acid malabsorption or bile acid diarrhea.
It is a chronic condition characterised by frequent and sudden diarrhea more than 10 times a day. Even though the disease is not life-threatening, it can seriously affect the patient’s everyday life, especially their social life, and be extremely disabling.
“You have to rush to the bathroom several times a day. Therefore, keeping a job or maintaining social relations can be difficult, and a lot of people isolate themselves. The disease controls their life,” says Professor Jesper Bøje Andersen from the Biotech Research & Innovation Centre.
He and his research group and clinical cooperation partners at Herlev and Gentofte Hospital headed by Professor and Consultant Doctor Filip Krag Knop are responsible for a new study, which provides new ways of diagnosing bile acid diarrhea and identifying the most effective treatment for the individual patient.
“A lot of people with chronic diarrhea don’t realise that they suffer from bile acid diarrhea and what has caused it. This is a result of lack of knowledge among healthcare workers and the relatively complex and expensive — and for the patient difficult — process of diagnosing the disease,” says Filip Krag Knop.

Jesper Bøje Andersen adds:
“We have developed a new concept which may be used to diagnose the disease based on a simple blood sample. Today, diagnostics involves radiopharmaceuticals, which means that there is a radiation risk. The process is not necessarily dangerous, but unpleasant and arduous, and not all countries in the world support the method, including the US.”
The new method means that doctors should be able to determine whether the patient has bile acid diarrhea based on a simple blood sample. They focus on molecules known as metabolites in the blood.
“A blood sample contains lots of different metabolites. Right now we are able to identify almost 1,300 different metabolites, and around a handful of these can be used to diagnose bile acid diarrhea. The metabolites of bile acid diarrhea patients form a particular pattern that makes them recognisable,” says Jesper Bøje Andersen.
Which treatment?
The researchers analysed blood samples from 50 patients and they quickly realised that the samples — and patients — could be divided into two groups.

“First, we did not understand why. All the blood samples had been taken before treatment, typically at the time of diagnosis,” says Jesper Bøje Andersen.
The patients then participated in a randomised clinical study at the Center for Clinical Metabolic Research at Herlev and Gentofte Hospital. Here the doctors studied the effect of two different treatments: the conventional treatment involving bile acid sequestrant colesevelam and a new treatment involving liraglutide, which is normally used to treat type 2 diabetes and severe overweight.
“What is interesting is that the metabolites in the patients’ blood divided them into two groups: one that responds well to colesevelam and one that responds well to liraglutide. This suggests that we should be able to say which treatment is the most effective by analysing the patient’s blood at the time of diagnosis,” says Jesper Bøje Andersen.
The clinical study showed that colesevelam treatment eased the bile acid diarrhea symptoms of 50 per cent of the patients, while liraglutide treatment eased the symptoms of 77 per cent of the patients.
Jesper Bøje Andersen, Filip Krag Knop and their research groups hope the new study will benefit the 60,000-100,000 Danes who suffer from bile acid diarrhea.
The majority of cases of bile acid diarrhea is diagnosed at a very late stage or never diagnosed at all.
“Around 40 per cent of the patients suffer from this condition for up to five years before it is diagnosed. Of course, this may be because they do not realise that it is a disease and that it can be treated. But it may also be because chronic diarrhea is a tabooed disease,” says Filip Krag Knop.