Multiple sclerosis (MS) is most prevalent in Northern Europe and Canada, and more common in the northernmost latitudes. In recent years, the number of cases has grown, particularly among women. The disease causes the patient’s own immune system to attack a protective coating known as myelin that surrounds nerve cells. When this sheath is destroyed, neuronal function decreases and the cells can ultimately die. This can result in visual disturbances, fatigue, mobility difficulties, and other neurological symptoms that may be permanent.

No treatment for neural damage

Current MS drugs suppress the immune system’s overactivation but are unable to repair the neural damage caused. This is a particular problem in the progressive form of the disease, where damage accumulates slowly over the years.

Researchers have long sought ways to initiate remyelination, a process where the destroyed myelin sheath grows back and the neurons recover. However, all drug candidates trialed so far have failed. The problem is that, particularly in the later stages of MS, the disease creates in the central nervous system local tissue conditions that inhibit remyelination.

Two solutions with the same outcome

In his doctoral thesis, Tapani Koppinen from Associate Professor Merja Voutilainen’s research group identified two different approaches for enhancing remyelination.

In the first approach, a drug molecule targets a stress mechanism intrinsic to brain cells. In areas damaged by MS, this stress response is constantly in overdrive, effectively preventing tissue-repairing cells from doing their job. When the mechanism was blocked using the new drug molecule, remyelination was significantly enhanced and accelerated in brain tissue with MS-like damage. The study was published in the Molecular Therapy journal in February.

The second approach focuses on scar tissue formed around affected areas, which serves as a physical barrier to neural regeneration. By affecting the composition of this scar tissue with the second drug molecule, this approach also succeeded in promoting neuronal recovery. An article focusing on this approach was published in November in the journal Neuropharmacology.

Surprisingly, these two drugs based on entirely different mechanisms led to very similar results: significant remyelination and reduced neuroinflammation in disease models, that is, animal and cell tests modeling the tissue pathology of MS.

First drug that boosts remyelination requires further research

For the time being, the results were achieved in laboratory animals and cell models. The more complex tissue conditions of human MS make it necessary to investigate the efficacy of the drug molecules in humans. One challenge for drugs targeting the brain is the blood-brain barrier, which blocks many substances from entering the brain. The researchers nevertheless demonstrated that both molecules effectively reach the central nervous system in laboratory animals.

“The goal is to enable the molecules we have developed to reach clinical trials, which could one day produce the first drugs that enhance remyelination in MS. In the meantime, our findings can help in investigating the pathogenic mechanisms of MS that inhibit remyelination,” Koppinen says.

Low doses of the investigational medicinal product endoxifen reduce breast density to the same extent as the standard treatment tamoxifen, but without causing such troublesome side effects. This is shown by a new study from Karolinska Institutet published in the Journal of the National Cancer Institute. The results may have implications for future preventive treatment of breast cancer.

Why tamoxifen isn’t ideal for all

Tamoxifen is a well-established drug that has been used for more than 40 years to reduce the risk of recurrence in patients with breast cancer. The drug is also approved for prevention of breast cancer in women at increased risk.

However, the side effects of tamoxifen are a major problem. Many women experience menopausal-like symptoms, such as hot flashes, which means that many do not complete the treatment.

How endoxifen was tested in women

Endoxifen is the most active metabolite formed when tamoxifen is broken down in the body. The new study investigated whether endoxifen in tablet form could provide the same biological impact and a more predictable effect than tamoxifen.

A total of 240 healthy, premenopausal women were randomized to receive a placebo or 1 or 2 mg of endoxifen daily for six months. The researchers then measured mammographic breast density. High mammographic density can contribute to an increased risk of breast cancer but a reduction during treatment can be a good measure of therapeutic outcome.

“Both 1 and 2 milligrams of endoxifen resulted in a clear reduction in breast density compared with the placebo,” says Mattias Hammarström, co-author and Ph.D. candidate at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet.

Promising results and remaining questions

The results show that 1 mg of endoxifen reduced breast density by an average of 19% and 2 mg by 26%. Data from a previous study show that 20 mg of tamoxifen reduces density by approximately 18.5%. The effect of low-dose endoxifen thus corresponded to that seen with tamoxifen.

Participants who received 2 mg of endoxifen reported a greater worsening of hot flashes and night sweats compared with the lower-dose group, while the 1 mg group had a safety profile similar to that of the placebo with respect to serious side effects and biomarkers.

“Our results suggest that a lower dose may be sufficient to affect breast density, while also appearing to be better tolerated,” says Hammarström.

The study is a so-called proof-of-concept trial, meaning it is designed to demonstrate that a treatment produces the expected biological effect before larger and longer trials are conducted. However, the study cannot show whether endoxifen reduces the risk of breast cancer or recurrence.

Many common mental health disorders, including depression and anxiety, are associated with a tendency to internalize problems or, in other words, to direct feelings inwards instead of expressing them and sharing them with others. Past studies suggest that this tendency to withdraw from others and suppress emotions often emerges early, during childhood and adolescence.

Researchers at the University of Oslo and the Norwegian Institute of Public Health analyzed data collected from families in Norway to investigate the genetic underpinnings of children’s susceptibility to internalize problems.

Their findings, published in Nature Mental Health, show that this susceptibility is influenced both by the children’s genes and by those of their mothers and fathers.

“This paper grew out of a question I asked about four years ago, just after starting my postdoc,” Razieh Chegeni, first author of the paper, told Medical Xpress.

“I was at a conference and asked the behavioral geneticist Meike Bartels: why not put multiple polygenic scores and environmental factors into the same analysis and see which ones matter most for children and adolescent mental health?

“Her answer was that we did not really have the right methods for that yet. That stayed with me. Around the same time, I was starting to learn more about machine learning, especially regularized regression methods.”

Studying parent-child trios in Norway

When exploring the factors associated with a greater risk of developing specific mental health disorders, researchers often rely on polygenic scores. These are numerical estimates of a person’s genetic vulnerability to a specific disorder.

A central challenge in this field of research is that the effects of polygenic scores on the emergence of mental health disorders are typically very small compared to those of psychological and environmental factors, such as parenting styles, traumatic experiences, and friendships.

When the scores are modeled together with psychological and environmental factors, genetic effects tend to get lost and become difficult to uncover.

“Regularized regression made it possible to study many correlated predictors at once and still retain small but meaningful genetic contributions when they improve prediction,” said Chegeni.

“That was really the starting point for this paper. I became especially interested in direct and indirect parental genetic effects, because indirect parental effects sit right at the intersection of genetics and environment: parents’ genetically influenced traits may shape the environments their children grow up in.”

Chegeni and her colleagues wanted to explore the possibility that symptoms of anxiety and depression in children are influenced not only by the children’s own genetic predisposition to these disorders, but also indirectly by genetic characteristics of their parents. The researchers also tried to determine whether these indirect effects of parents’ genes were different in childhood and adolescence.

“One of the reasons this study was possible is that Norway built an extraordinary long-term family health resource,” explained Chegeni.

“Starting in 1999, the Norwegian Mother, Father and Child Cohort Study began recruiting families across the country, collecting information from parents during pregnancy and following children over time. As genetic data were available for mothers, fathers, and children, this gave us a rare opportunity to study mental health risk across the whole family rather than looking at the child alone.”

As part of their study, the researchers analyzed genetic and mental health-related data collected from 9,314 mother-father-child trios residing in Norway.

They specifically focused on reported symptoms of depression and anxiety at two different stages in the children’s development, namely when they were 8 years of age, and when they were 14. When children were 8, the symptoms were typically reported by their mothers, while at 14 they were reported by the adolescents themselves.

“Rosa Cheesman, Ph.D. and Ziada Ayorech, Ph.D. then calculated polygenic scores for 15 traits in each family member, including traits related to well-being, depression, ADHD, smoking, loneliness, and cognitive skills,” said Chegeni.

“A polygenic score is not a single ‘gene for’ a trait, but rather a summary of many small genetic influences associated with that trait. We used a machine-learning method called elastic net regression to analyze these many overlapping signals at the same time.”

Using a machine learning algorithm, the researchers compared four different genetic models to determine which one better accounted for the children’s vulnerability to internalize feelings. The first model only considered a child’s own genetic profile, the second the parents’ genetic profile, the third interaction effects across family members and the fourth combined all these factors.

“In simple terms, the child’s scores reflect a more direct genetic liability, while the parents’ scores may also capture indirect effects through the environment they help create for their child,” explained Chegeni.

“We found that the children’s tendency to depression and anxiety was linked not only to their own genetic predispositions, but also to parental genetic characteristics.”

What contributes to the development of depression and anxiety?

Overall, Chegeni and her colleagues found that the children’s depression and anxiety were most accurately predicted when considering both their own genetic profile and that of their parents. The parents’ genetic profile appeared to influence the children via indirect effects, such as their parenting style and the children’s home environment.

When the children reached adolescence, on the other hand, their own genetic profile appeared to play a greater role in their susceptibility to depression and anxiety. This was particularly evident for depression.

“Our findings suggest that risk may operate through more than one pathway: through the genes children inherit directly, and through parents’ genetically influenced traits that may shape caregiving, family climate, and the broader home environment,” said Chegeni.

“Importantly, we found that these patterns changed across development. Predictive accuracy was generally stronger at age 14 than at age 8, and for depression in particular, parental genetic factors appeared relatively more important in childhood, while children’s own genetic liability became more prominent in adolescence.”

Interestingly, the researchers also found that the genes that most contributed to a child’s susceptibility to internalizing problems differed in mothers and fathers. Genes that were found to play a role included father genes linked to well-being and mother genes linked to smoking and cognitive skills.

“Our paper challenges a narrower way of thinking about intergenerational risk,” said Chegeni. “Even in genetics, there has often been an assumption that if we want to understand why depression or anxiety runs in families, we should mainly look at parental depression- or anxiety-related risk. Our results suggest that this can miss a large part of the picture.”

The results of this study highlight the complexity of genetic factors contributing to the emergence of mental health disorders in childhood and adolescence. They also confirm that the risk of developing mental health disorders depends on a series of biological and environmental factors.

“Parental genetic predispositions related to well-being, smoking, cognitive skills, and ADHD also emerged as relevant predictors of offspring internalizing problems,” said Chegeni. “This suggests that intergenerational mental health risk may involve a broader range of parental traits than has often been assumed.”

Avenues for further research

While this study offers some valuable insight, the variance explained by the team’s genetic models was modest. For now, the insight it provides is thus meant to be scientifically informative and is not applicable in clinical settings.

“This study was an important step for me, but I see it as the beginning rather than the end of this line of work,” said Chegeni. “Now that I have a deeper understanding of gene-environment interplay and more experience with machine learning methods, I am moving toward models that bring these pieces together more directly.”

Chegeni and her colleagues are now conducting further studies in which they are combining the parent-child polygenic scores calculated as part of their recent study with a much broader set of environmental factors. For instance, they plan to consider the effects of these scores in conjunction with family history of mental illnesses, adverse life events, peer relationships and parental conflicts.

“Our goal is to better understand how genetic liability and lived experience work together, rather than studying them in isolation,” added Chegeni.

“I am especially interested in identifying which combinations of genetic and environmental factors matter most for adolescent mental health, how these influences change across development, and whether different pathways are more relevant for different outcomes.

“More broadly, I hope this work can help move the field beyond simple one-risk-factor models toward a more realistic understanding of mental health as the product of many small, interacting influences across the family and social environment.”

Scientists at The Wistar Institute and clinical researchers from ChristianaCare’s Helen F. Graham Cancer Center & Research Institute have discovered a vulnerability in pancreatic cancer that could be targeted as a potential therapy. In a new study, published in the Proceedings of the National Academy of Sciences, they show how defective mitochondria within cells spark a process that triggers inflammation. They also show how cancer cells become so dependent on this inflammation to grow that without it, they die.

New target emerges in pancreatic cancer

The discovery is exciting because it suggests that blocking the pathway, called TLR3/TRAF6, could be a promising new therapeutic target for pancreatic cancer, said senior author Dario Altieri, M.D., president and CEO of The Wistar Institute, director of the Ellen and Ronald Caplan Cancer Center, and Robert and Penny Fox Distinguished Professor. It’s the first time this mechanism has been identified as playing a role in cancer, he said.

“It’s been known that mitochondria could release double-stranded RNA and generate inflammation, but not in cancer, and not as a cancer driver,” Altieri explained. “Similarly, this pair of molecules, TLR3 and TRAF6, were known to act as a sensor for double-stranded RNA, but again, not in cancer. So this could be a therapeutic target for pancreatic cancer, where we are in desperate need of therapeutic targets, but perhaps also for other types of cancers.”

“For pancreatic cancer patients, options remain far too limited and the prognosis far too often devastating,” said co-author Nicholas Petrelli, M.D., director of the Cawley Center for Translational Cancer Research at ChristianaCare’s Helen F. Graham Cancer Center & Research Institute. “What makes this finding so exciting is that it points us toward a genuine vulnerability in the cancer itself—one we may be able to exploit therapeutically.”

Why mitochondria matter in tumors

Pancreatic cancer is one of the most aggressive and deadly forms of cancer, with few treatment options. It remains highly resistant to treatment and is typically discovered late, when it’s already at the metastatic stage. Most patients have a very poor prognosis.

Mitochondria are organelles found within cells that convert nutrients into energy. Previous studies showed that many tumor cells have mitochondria that are low in an important structural protein called Mic60. These mitochondria are severely damaged but remain present in the cell. Researchers found that these “ghost mitochondria” became powerful signaling hubs for inflammation, but they didn’t understand why.

The new study helps solve that mystery.

Leaky mitochondria trigger inflammation

Normal, healthy mitochondria are sealed inside a membrane. But the team found that in the mitochondria lacking Mic60, that membrane becomes defective and starts to leak. Double-stranded RNA drains out of the mitochondria into the surrounding cell. The cell’s internal warning system mistakes this for a sign that the cell is infected.

Researchers found two proteins that act as sensors, detecting the double-stranded RNA and activating a massive inflammatory response, Altieri said. The cancer cells then use this inflammation to grow.

Cancer’s addiction to inflammation

Importantly, the team also found that the cancer becomes so “addicted” to inflammation that it comes to depend on it not just for growth, but survival. When they used drugs to block the sensor proteins, the cancer cells died, while healthy cells survived. In a murine model, this approach caused pancreatic cancer tumors to stop growing.

Altieri said the discovery was a surprise.

“The idea that the reduction of a structural protein could play a role in the damaged mitochondria becoming hubs for stress response signaling, which would translate to a very potent inflammatory response—that was totally unexpected,” he said. “We had no idea that this was a possibility.”

Next steps toward potential therapies

Next, researchers want to learn more about how Mic60 damages the mitochondria’s membrane to release double-stranded RNA, starting the inflammation process—and whether this mechanism can be stopped. They also want to continue investigating and developing a TLR3/TRAF6 inhibitor as a potential cancer therapy.

Bipolar disorder is a mental health condition estimated to affect between 1% and 3% of people worldwide. Its main symptoms include extreme mood swings, ranging from periods of high activity and emotional high (i.e., mania) to depressive periods marked by a low mood, reduced motivation and a loss of interest in everyday activities.

Bipolar disorder typically cannot be treated solely with psychotherapy, although some approaches and lifestyle adjustments can help affected individuals to better manage the condition. Its effective treatment also heavily relies on medications that stabilize mood, reduce anxiety, or treat acute mania and psychosis (i.e., a state that entails losing touch with reality, hallucinations and/or false beliefs).

One particular mood stabilizer called lithium has long been considered the most effective drug for regulating the mood fluctuations associated with bipolar disorder. While many patients respond well to lithium, others are forced to discontinue it, either because it does not work for them or due to side effects that are difficult to manage.

Researchers at Niuvanniemi Hospital in Finland, Karolinska Institute in Sweden and Stockholm City Council recently carried out a large-scale observational study exploring the effectiveness of other available treatments for bipolar disorder over time, when these are taken in conjunction with lithium or instead of it. Their findings, published in Nature Mental Health, highlight specific treatment plans and combinations of drugs that appeared to be linked to fewer relapses and psychiatric hospital admissions.

“This study grew out of a very practical problem I faced in my clinical practice,” Johannes Lieslehto, first author of the paper, told Medical Xpress. “Lithium is widely considered the gold-standard treatment for bipolar disorder, but in real life many patients either do not respond sufficiently or cannot tolerate it. At the same time, clinicians often need to combine medications or switch strategies, yet there is surprisingly little high-quality evidence on which specific combinations work best in the long term.”

Pinpointing effective bipolar treatments beyond lithium

The main goal of this research study was to identify treatment strategies that tend to be particularly effective, particularly in cases where lithium alone does not treat all symptoms or needs to be discontinued. To do this, Lieslehto and colleagues analyzed a large pool of data collected from over 160,000 people who were being treated for bipolar disorder in Sweden and Finland, over the course of several years.

“What makes our approach a bit different is that we compared each patient to themselves over time,” explained Lieslehto. “So, instead of comparing different people who were taking different medications, we looked at how the same person did during periods when they were on different treatments. This approach helps reduce bias, because factors like genetics, illness severity, or lifestyle are naturally controlled for (i.e., they don’t change within the same person).”

To gain insight into the effectiveness of different treatment plans, the researchers specifically looked at relapse rates. These were measured by looking at psychiatric hospitalization records, which offer an indication of whether a patient started struggling with symptoms again and required medical care.

The team’s analyses ultimately led to the identification of specific drug combinations and treatment strategies that were linked to a lower risk of relapse and hospitalization. These treatments often included clozapine or other antipsychotic medications, particularly long-acting drugs that patients received periodically via injections.

“We also identified specific treatment options for patients who discontinue lithium, such as combinations like quetiapine with lamotrigine or olanzapine with valproate, which were linked to better outcomes,” said Lieslehto. “Clinically, the key message is that there are viable alternatives when lithium is not sufficient or cannot be used. Importantly, the results also highlight that the way medications are combined matters. Not all combinations are equally effective. Importantly, however, these findings are observational and should be interpreted carefully.”

Informing future research and clinical decision-making

The insight gathered by Lieslehto and colleagues could soon prove useful for clinical psychiatrists, as it could offer some guidance for the treatment of lithium-resistant bipolar disorder. Nonetheless, the team’s findings need to be validated in randomized clinical trials before they can be broadly applied in psychiatric settings or used to update official treatment protocols.

“In the future, we would like to study outcomes beyond hospitalization, such as functional recovery and quality of life, to get a more complete picture of treatment effectiveness,” added Lieslehto. “We are also increasingly interested in more personalized approaches. For example, combining clinical data with genetic information or other biomarkers to better predict (e.g., using machine learning) which treatment works best for a given individual.”

Johns Hopkins Medicine researchers have added to evidence that using cannabis edibles and alcohol together worsens driving impairment compared with consuming either substance alone. The study also found that cannabis (alone or with alcohol) did not impair performance on standard field sobriety tests.

These findings, published May 1 in JAMA Network, highlight the urgent need for wider public education about possible augmented effects from combining cannabis and alcohol and for improved roadside driver impairment detection methods. The study also revealed that the legal alcohol intoxication limit in most of the U.S. (0.08% breath alcohol level, or BrAC) is likely too liberal if a driver has used cannabis and alcohol together.

“Our findings indicate that co-use of cannabis and alcohol produces significantly greater driving impairment and subjective intoxication than either substance alone,” says the study’s lead author, Austin Zamarripa, Ph.D., assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “Importantly, these findings suggest that the interaction between cannabis edibles and alcohol is not merely additive, but may be synergistic in producing impairment, which has important implications for real-world risk.”

For the study, the research team used a rigorous, controlled design in which participants attended several outpatient experimental sessions. During each session, they were given either a cannabis-infused brownie (10 or 25mg THC) or a placebo brownie, followed by either an alcoholic beverage or a non-alcoholic placebo drink. Alcohol doses were tailored to each participant to achieve BrACs of 0.05% or 0.08%.

Participants were healthy adults ages 21–55, confirmed through medical and psychiatric screening, physical examination and routine bloodwork at the initial visit. Thirty participants were enrolled and randomized in the study and 25 completed all study visits. All participants reported binge drinking within the past 90 days, prior experience using cannabis and alcohol together within the past year and limited cannabis use (fewer than three times per week, with at least one use in the past year) to reduce the influence of tolerance. Participants had no recent use of other illicit drugs, as verified by urine drug testing.

After medical eligibility was confirmed through an initial screening visit, participants completed a second pre-study visit to become familiar with the driving simulator and other performance tests to reduce learning effects in the experiment. After this training visit, participants completed seven experimental sessions where they either ingested cannabis alone, alcohol alone, cannabis and alcohol together or placebo cannabis and placebo alcohol. Session order was carefully balanced across participants to ensure unbiased results.

At each experimental session before dosing, participants completed baseline assessments, including a simulated drive, standard field sobriety tests, cognitive/psychomotor performance tests, subjective drug effect questionnaires and a blood sample to measure THC and THC metabolite levels. Participants consumed either a cannabis-infused brownie or a placebo brownie one hour after breakfast, and 45 minutes later, they were given either alcoholic beverages or placebo drinks — which provided similar sensory cues as the alcohol drinks to maintain dose blinding — consumed over a 15-minute period. Participants completed the same series of driving and other assessments repeatedly throughout the day for up to 7.5 hours after brownie consumption. Study sessions were spaced at least one week apart to ensure enough time for the drug to leave the body between visits.

Findings showed that combining cannabis edibles with alcohol led to greater and longer-lasting driving impairment and feelings of intoxication compared with either substance used alone, yet standard field sobriety tests only deemed participants as intoxicated in the high alcohol dose condition (0.08% BrAC) relative to placebo.

“We designed this study because people are increasingly co-using alcohol with edible cannabis products, yet controlled research has largely focused on smoked cannabis. This is the first controlled study to examine how cannabis edibles and alcohol interact, despite their growing combined use,” says Tory Spindle, Ph.D., the study’s principal investigator and associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “Consuming typical retail doses of cannabis edibles alongside even low doses of alcohol can produce driving impairment comparable to — or greater than — alcohol alone at the legal limit.”

As cannabis legalization expands and access to cannabis products increases, the researchers emphasize the importance of considering the heightened risks associated with combining cannabis and alcohol in public health messaging, policy and regulatory decisions. They also note a need for continued research to better understand impairment from co-use and to develop improved biological or behavioral tools for detecting cannabis-related driving impairment.

The saying “cold hands, warm heart” is usually meant metaphorically—but new research from UC Davis School of Medicine and collaborating institutions suggests it has a striking biological parallel.

In a study of TRPM4 ion channel mutations, researchers found that body temperature plays a key role in which tissues are affected. One mutation becomes active only in cooler skin, and another exerts its effects only at the heart’s warmer, core body temperature. Cell type and local chemical signals also play a role.

The findings, published in the Proceedings of the National Academy of Sciences (PNAS), offer a clear explanation for why disease-causing TRPM4 mutations lead to mutually exclusive conditions.

“This has been a mystery in the field for years,” said Yuhua Tian, first author of the study, and a visiting assistant professor in the Department of Physiology and Membrane Biology. “We now understand that it’s not just the mutation itself that matters, but where in the body the protein is active and under what conditions.”

What is TRPM4?

The TRPM4 gene, found on Chromosome 19, provides instructions for making a protein that acts like a gate in the cell membrane.

When calcium levels inside the cell rise, the gate opens, allowing cations (small ions with a positive charge, such as sodium) to flow into the cell. This alters the cell’s electrical state and sends multiple signals to the cell.

This process is important in many organs, including the heart, where electrical signaling plays a major role in maintaining a normal heart rhythm.

In the skin and immune system, this gated activity helps regulate inflammation and cell migration.

A medical mystery

Doctors and researchers have known for years that some TRPM4 mutations cause inherited heart disorders. These include progressive familial heart block, which alters the normal beating of the heart, and Brugada syndrome, a condition that disrupts the heart’s normal rhythm.

Other TRPM4 mutations cause rare, but severe, skin diseases, including progressive symmetric erythrokeratodermia (PSEK).

Strikingly, however, patients never develop both, even though the mutations increase TRPM4 activity.

“This didn’t make sense under traditional genetic models,” said Jie Zheng, senior author and professor of physiology and membrane biology at UC Davis. “If the same channel is overactive, why doesn’t it affect every tissue the same way?”

What the researchers discovered

The researchers combined electrophysiology, molecular modeling and mouse genetics to examine how disease-linked TRPM4 mutations respond to calcium, membrane lipids and temperature. By measuring ion channel activity and cell behavior under skin-like and heart-like temperature conditions, they uncovered how heat and cold determine where these mutations cause disease.

The research shows that TRPM4 is controlled by a three-part system:

• Calcium levels inside the cell
• A membrane lipid called PIP2 (phosphatidylinositol 4,5-bisphosphate), which acts as an on-off switch for activity in a cell
• Temperature, which differs between the skin and the internal organs

Together, these factors determine when and where TRPM4 is active.

Why temperature matters

Skin disease mutations break TRPM4’s control by PIP2, allowing the channel to stay active at cooler skin temperatures (25 to 30°C or 77 to 86°F). Extremities like hands and feet, where skin diseases like PSEK can strike, generally have lower temperatures than core body temperature.

The channel loses its abnormal activity at normal body-core temperature (37°C or 98.6°F).

By comparison, heart disease mutations increase the number of TRPM4 channels in heart cells and boost electrical signaling—but only at body-core temperature (37°C or 98.6°F). The heart disease mutations were largely inactive in cooler skin tissue.

“This explains why skin mutations cause damage only in the skin, and heart mutations affect only the heart,” Zheng said. “The channel is responding to its environment.”

Clinical implications

Samuel Hwang, professor and chair of the Department of Dermatology at UC Davis Health, is a co-author of the study. Hwang treats people with inherited skin conditions in his clinic, but has never seen a case of PSEK. “It is a very rare disease. And the good news is that people often outgrow it after puberty.” He notes the findings could reshape how doctors think about genetic diseases, including skin diseases.

“This work shows that a mutation’s effects depend on tissue context, not just DNA sequence,” Hwang said. “That insight helps explain why some patients develop skin disease without heart involvement, and it suggests new strategies for treating these conditions more precisely.”

Future applications

Zheng emphasized that the results came from an interdisciplinary collaboration among clinicians, biophysicists, computational biologists and dermatologists.

“We hope these findings help clinicians find better treatment strategies for patients and that they give pharmaceutical companies strategies that may lead to new treatments for people with these inherited conditions,” Zheng said.

Respiratory syncytial virus (RSV), mostly infects the lungs, nose, throat, and respiratory tract, and can cause illness ranging from mild cold and fever-like symptoms to severe pneumonia and bronchitis. A recent study has found that having a respiratory infection can act as a shield against the spread of cancer cells.

A natural antiviral chemical called type I interferons is produced by our body as one of the earliest responders in the fight against RSV infections. These molecules can also help prevent breast cancer from spreading to the lungs by changing the lung environment in a way that makes it difficult for cancer cells to survive or thrive. The findings are published in PNAS.

From infection to protection

The lungs may seem safely tucked inside the ribcage, but with every breath, they are in constant contact with the outside world. As we inhale air, lung cells are continuously exposed to germs, allergens, harmful gases, and pollution. While our immune system is designed to react strongly to anything foreign, the lungs must keep this response under control to avoid overreacting to everything we breathe in.

This carefully maintained calm can come at the cost of creating an environment where cancer cells can quietly settle and begin to grow. The spread of cancer cells can alter the biochemical environment of the lungs, and so can respiratory infections such as RSV or COVID. Not much is known about how respiratory infections and lung cancer metastasis interact. Do they support each other and coexist, or do they actually hold each other back?

In this study, the researchers explored this mystery with the help of a mouse model. They first exposed the mice to RSV, and then, exactly a day later, introduced breast cancer cells into their bloodstream.

They compared these mice with a control group that received the cancer cells but was not infected, allowing them to see whether the virus influenced the number of tumors formed in the lungs. They observed that in mice infected with RSV, cancer cells struggled to take hold and grow in the lungs, resulting in fewer metastatic tumors.

To ensure that immune cells weren’t interfering with this phenomenon, the team used specific antibodies to temporarily remove different types of immune cells one by one. Even after this, the anti-cancer effect of the lung infection remained almost entirely intact. This gave the researchers a hint that the help was coming from the lungs themselves.

When the body detects a virus, it sends out a chemical alarm signal called type I interferons—which include IFN- β and IFN- α subtypes, which are powerful antiviral proteins. To test the idea that these chemical signals might be preventing the cancer cells from invading, they treated healthy mice with lab-made interferons and waited for the molecules to block cancer—and they did.

Further investigation revealed that interferons don’t directly attack tumor cells. Instead, they reshape the lung’s own epithelial and endothelial cells, making it harder for cancer cells to enter the lung tissue from the bloodstream and find the support they need to grow into tumors.

The researchers also discovered that a protein called Galectin-9, activated by interferons, is elevated during this process and can directly prevent cancer cells from settling in the lungs.

These findings suggest that viral infections and type I interferons can reshape the lung environment in ways that hinder cancer from taking hold, which can be exploited when developing new anti-metastatic therapies. Before that can move forward, studies first need to show whether similar effects can be seen in humans.

Partial meniscectomy does not improve patient symptoms or function, reveals a 10-year follow-up of the FIDELITY, a placebo-surgery controlled trial published in the New England Journal of Medicine.

Trimming a degenerated meniscus, or partial meniscectomy, is one the most common orthopedic surgeries in the world. Even though the number of procedures in Finland has decreased significantly in recent years, the surgery continues to be performed widely internationally.

A 10-year follow-up study has revealed that, compared to sham surgery, partial meniscectomy did not improve patients’ symptoms or function. On the contrary, the 10-year follow-up of patients who had undergone partial meniscectomy found them to have more symptoms, more reduced function, increased progression of osteoarthritis and a higher probability of subsequent knee surgery when compared to sham surgery.

The Finnish Degenerative Meniscal Lesion Study (FIDELITY) study is unique both with regard to its research design, i.e., the sham surgery control group, and its 10-year patient follow-up. In the study, patients with degenerative meniscal tears were randomized to undergo a partial meniscectomy or sham surgery.

Teppo Järvinen, Professor at the University of Helsinki and the principal investigator of the FIDELITY, emphasizes the broader significance of the results:

“Our findings suggest that this may be an example of what is known as a medical reversal , where broadly used therapy proves ineffective or even harmful.”

“The surgery is based on the assumption that pain in the inside of the knee is caused by a medial meniscus tear, which can be treated surgically. Such reasoning—assumption based on biological credibility—is still very common in medicine, but in this case, the assumption does not withstand critical examination. Based on current understanding, pain in various joints, such as the knee joint in this case, is related to degeneration brought about by aging,” says Raine Sihvonen, Specialist in Orthopedics and Traumatology and the other principal investigator of the FIDELITY study.

Concerns about the adverse effects of surgery
The registry and other observational data published in recent years have elicited concern about the potential harm caused by partial meniscectomy. Based on this data, the risk of arthroplasty, or joint replacement surgery, as well as a potentially higher risk of complications following the surgery has been associated with partial meniscectomy. However, the evidence provided by observational studies is inherently indirect and cannot be used to demonstrate a causal effect.

“Several randomized studies have already demonstrated that partial meniscectomy has not improved patients’ symptoms or function in the short (1–2 years) or medium (5 years) term. Regardless, the procedure has remained widely used in many countries,” says Doctoral Researcher and Specialist in Orthopedics and Traumatology, Dr. Roope Kalske.

“For nearly a decade, many independent, non-orthopedic organizations providing clinical guidelines have recommended that the procedure should be discontinued. Still, for example, the American Academy of Orthopaedic Surgeons (AAOS) and the British Association for Surgery of the Knee (BASK) have continued to endorse the surgery. This effectively illustrates how difficult it is to give up inefficient therapies,” Järvinen says.

“The study conducted in five hospitals is an example of smooth multicenter collaboration, as well as the commitment of research patients to an interesting project. Of the original 146 participants, more than 90% took part in the final stage of the study,” says the research manager Pirjo Toivonen.