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Immune checkpoint inhibitors, which boost the immune system’s response against tumor cells, have transformed treatment for many advanced cancers, but short-term clinical trials and small observational studies have linked the medications with various side effects, most commonly involving the skin. A more comprehensive, population-level analysis now provides a thorough look at the extent of these side effects and provides insights on which patients may be more likely to experience them. The research was led by investigators at Massachusetts General Hospital (MGH) and is published in the Journal of the American Academy of Dermatology.
“Immunotherapies, which include immune checkpoint inhibitors, are an increasingly common treatment modality for advanced cancers, with more than 200,000 patients being started on these therapies annually,” says co-senior author Yevgeniy R. Semenov, MD, an investigator in the Department of Dermatology at MGH. “As the use of immune checkpoint inhibitors increases, so will the incidence of adverse events, underscoring the importance of research into their incidence, type and severity.”
Semenov and his colleagues used a “Big Data” approach to study the U.S. prevalence of skin-related side effects, as well as when they arise and how they’re treated, in a large population of patients who received immune checkpoint inhibitors.
The study involved analyzing information from a national health insurance claims database pertaining to 8,637 patients who were treated with immune checkpoint inhibitors as well as an equal number of patients with cancer who did not receive these medications. The overall incidence of skin-related side effects was 25.1%, with a median time of onset of 113 days. “We found that only 10 of more than 40 skin conditions previously reported to be linked to immune checkpoint inhibitors are actually seen at a higher incidence among patients on these medications compared with other patients who were matched by demographics, cancer type and comorbidities,” says Semenov.
These conditions manifested with symptoms of itching, inflammation, rash, skin color loss, swelling or blisters. Patients with melanoma or kidney cancer and those receiving multiple types of immune checkpoint inhibitors were at an especially high risk of developing these skin problems.
The investigators’ real-world data also found that skin-related symptoms tended to arise later than those noted in clinical trials. In addition, they found that clinicians often prescribed systemic corticosteroids to treat them even though these drugs should generally be avoided due to concerns that they may blunt the anti-tumor effects of immunotherapy.
“These findings are of particular clinical relevance to both dermatologists and oncologists caring for patients receiving immune checkpoint inhibitors,” says Semenov. For example, clinicians should be on the lookout for the 10 conditions identified in this analysis as patients continue taking these medications. “The real-world delays in the time to presentation of many of these conditions should also revise clinicians’ understanding of when to expect patients to present with these toxicities and not to rule out a delayed onset of symptoms as being unrelated to immunotherapy,” adds Semenov.
The findings also suggest an opportunity for improving care for patients, he says: “Dermatologists can work with oncologists to facilitate evaluations of these vulnerable patients so that they can take steps to prevent progression to more severe toxicities.”
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Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.

When winter storms threaten to make travel dangerous, people often turn to salt, spreading it liberally over highways, streets and sidewalks to melt snow and ice. Road salt is an important tool for safety, because many thousands of people die or are injured every year due to weather related accidents. But a new study led by Sujay Kaushal of the University of Maryland warns that introducing salt into the environment — whether it’s for de-icing roads, fertilizing farmland or other purposes — releases toxic chemical cocktails that create a serious and growing global threat to our freshwater supply and human health.
Previous studies by Kaushal and his team showed that added salts in the environment can interact with soils and infrastructure to release a cocktail of metals, dissolved solids and radioactive particles. Kaushal and his team named these cascading effects of introduced salts Freshwater Salinization Syndrome, and it can poison drinking water and cause negative effects on human health, agriculture, infrastructure, wildlife and the stability of ecosystems.
Kaushal’s new study is the first comprehensive analysis of the complicated and interconnected effects caused by Freshwater Salinization Syndrome and their impact on human health. This work suggests that the world’s freshwater supplies could face serious threats at local, regional and global levels if a coordinated management and regulation approach is not applied to human sources of salt. The study, which calls on regulators to approach salts with the same level of concern as acid rain, loss of biodiversity and other high-profile environmental problems, was published April 12, 2021, in the journal Biogeochemistry.
“We used to think about adding salts as not much of a problem,” said Kaushal, a professor in UMD’s Department of Geology and Earth System Science Interdisciplinary Center. “We thought we put it on the roads in winter and it gets washed away, but we realized that it stuck around and accumulated. Now we’re looking into both the acute exposure risks and the long-term health, environmental, and infrastructure risks of all these chemical cocktails that result from adding salts to the environment, and we’re saying, ‘This is becoming one of the most serious threats to our freshwater supply.’ And it’s happening in many places we look in the United States and around the world.”
When Kaushal and his team compared data and reviewed studies from freshwater monitoring stations throughout the world, they found a general increase in chloride concentrations on a global scale. Chloride is the common element in many different types of salts like sodium chloride (table salt) and calcium chloride (commonly used for road salt). Drilling down into data from targeted regions, they also uncovered a 30-year trend of increasing salinity in places like the Passaic River in northern New Jersey and a 100-mile-plus stretch of the Potomac River that supplies drinking water to Washington, D.C.
The major human-related salt source in areas such the Northeastern U.S. is road salts, but other sources include sewage leaks and discharges, water softeners, agricultural fertilizers and fracking brines enriched with salts. In addition, indirect sources of salts in freshwater include weathering roads, bridges and buildings, which often contain limestone, concrete or gypsum, all of which release salt as they break down. Ammonium-based fertilizers can also lead to the release of salts in urban lawns and agricultural fields. In some coastal environments, sea-level rise can be another source of saltwater intrusion.

Spanking may affect a child’s brain development in similar ways to more severe forms of violence, according to a new study led by Harvard researchers.
The research, published recently in the journal Child Development, builds on existing studies that show heightened activity in certain regions of the brains of children who experience abuse in response to threat cues.
The group found that children who had been spanked had a greater neural response in multiple regions of the prefrontal cortex (PFC), including in regions that are part of the salience network. These areas of the brain respond to cues in the environment that tend to be consequential, such as a threat, and may affect decision-making and processing of situations.
“We know that children whose families use corporal punishment are more likely to develop anxiety, depression, behavior problems, and other mental health problems, but many people don’t think about spanking as a form of violence,” said Katie A. McLaughlin, John L. Loeb Associate Professor of the Social Sciences, director of the Stress & Development Lab in the Department of Psychology, and the senior researcher on the study. “In this study, we wanted to examine whether there was an impact of spanking at a neurobiological level, in terms of how the brain is developing.”
According to the study’s authors, corporal punishment has been linked to the development of mental health issues, anxiety, depression, behavioral problems, and substance use disorders. And recent studies show that approximately half of parents in U.S. studies reported spanking their children in the past year and one-third in the past week. However, the relationship between spanking and brain activity has not previously been studied.
McLaughlin and her colleagues — including Jorge Cuartas, first author of the study and a doctoral candidate in the Harvard Graduate School of Education, and David Weissman, a post-doctoral fellow in the Department of Psychology’s Stress & Development Lab — analyzed data from a large study of children between the ages of three and 11. They focused on 147 children around ages 10 and 11 who had been spanked, excluding children who had also experienced more severe forms of violence.

The state of Pennsylvania and the city of Los Angeles are accelerating plans for wider Covid-19 vaccine eligibility this week, as the United States approaches universal eligibility for adults.Most states and U.S. territories have already expanded access to include anyone over 16. Others, including Massachusetts, New Jersey, Oregon and Washington state, have plans in place for universal adult access to start in the next few days. All states are expected to get there by Monday, a deadline set by President Biden.Some states have local variations in eligibility, including Illinois, where Chicago did not join a statewide expansion that began Monday.California as a whole has set Thursday as its date, but Mayor Eric Garcetti of Los Angeles said on Sunday that all residents age 16 or older in his city, the nation’s second largest, would become eligible two days earlier. In Pennsylvania, Gov. Tom Wolf said on Monday that all adults there would be eligible on Tuesday, six days earlier than previously planned.“We need to maintain acceleration of the vaccine rollout, especially as case counts and hospitalization rates have increased,” Mr. Wolf said in a statement.Expanded eligibility has not always brought immediate access. Demand for vaccination continues to outstrip supply in much of the nation, with people scrambling to book scarce appointments as they become available. And supplies of Johnson & Johnson’s one-dose vaccine will be extremely limited until federal regulators approve production at a Baltimore manufacturing plant with a pattern of quality-control lapses, the White House’s pandemic response coordinator said on Friday.“We urge patience as we continue to ramp up our operations, obtain more doses, and enter this new phase of our campaign to end the pandemic,” Mr. Garcetti said.More than 119 million people — or more than one-third of the U.S. population — have now received at least one dose of a Covid-19 vaccine, according to the Centers for Disease Control and Prevention. The nation is administering about 3 million doses a day on average.Two of the three vaccines authorized for use in the U.S. — those made by Moderna and Johnson & Johnson — are authorized for use in adults. The third, from Pfizer-BioNTech, is authorized for anyone 16 or older, and the company is seeking to expand that range to include youths 12 to 15. No vaccine has yet been authorized for use in younger children.When All Adults Are Eligible for the Vaccine in Each StateSee more detail on eligibility in your state as of April 9 »

A new algorithm can predict which genes cause cancer, even if their DNA sequence is not changed. A team of researchers in Berlin combined a wide variety of data, analyzed it with “Artificial Intelligence” and identified numerous cancer genes. This opens up new perspectives for targeted cancer therapy in personalized medicine and for the development of biomarkers.
In cancer, cells get out of control. They proliferate and push their way into tissues, destroying organs and thereby impairing essential vital functions. This unrestricted growth is usually induced by an accumulation of DNA changes in cancer genes — i.e. mutations in these genes that govern the development of the cell. But some cancers have only very few mutated genes, which means that other causes lead to the disease in these cases.
A team of researchers at the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin and at the Institute of Computational Biology of Helmholtz Zentrum München developed a new algorithm using machine learning technology to identify 165 previously unknown cancer genes. The sequences of these genes are not necessarily altered — apparently, already a dysregulation of these genes can lead to cancer. All of the newly identified genes interact closely with well-known cancer genes and have been shown to be essential for the survival of tumor cells in cell culture experiments.
Additional targets for personalized medicine
The algorithm, dubbed “EMOGI” for Explainable Multi-Omics Graph Integration, can also explain the relationships in the cell’s machinery that make a gene a cancer gene. As the team of researchers headed by Annalisa Marsico describe in the journal Nature Machine Intelligence, the software integrates tens of thousands of data sets generated from patient samples. These contain information about DNA methylations, the activity of individual genes and the interactions of proteins within cellular pathways in addition to sequence data with mutations. In these data, a deep-learning algorithm detects the patterns and molecular principles that lead to the development of cancer.
“Ideally, we obtain a complete picture of all cancer genes at some point, which can have a different impact on cancer progression for different patients,” says Marsico, head of a research group at the MPIMG until recently and now at Helmholtz Zentrum München. “This is the foundation for personalized cancer therapy.”
Unlike with conventional cancer treatments such as chemotherapy, personalized therapy approaches tailor medication precisely to the type of tumor. “The goal is to select the best therapy for each patient — that is, the most effective treatment with the fewest side effects. Additionally, we would be able to identify cancers already at early stages, based on their molecular characteristics.”

What exactly happens when the corona virus SARS-CoV-2 infects a cell? In an article published in Nature, a team from the Technical University of Munich (TUM) and the Max Planck Institute of Biochemistry paints a comprehensive picture of the viral infection process. For the first time, the interaction between the coronavirus and a cell is documented at five distinct proteomics levels during viral infection. This knowledge will help to gain a better understanding of the virus and find potential starting points for therapies.
When a virus enters a cell, viral and cellular protein molecules begin to interact. Both the replication of the virus and the reaction of the cells are the result of complex protein signaling cascades. A team led by Andreas Pichlmair, Professor of Immunopathology of Viral Infections at the Institute of Virology at TUM, and Matthias Mann, Head of the Department of Proteomics and Signal Transduction at the Max Planck Institute of Biochemistry, has systematically recorded how human lung cells react to individual proteins of the covid-19 pathogen SARS-CoV-2 and the SARS coronavirus, the latter of which has been known for some time.
A detailed interaction map
To this end, more than 1200 samples were analyzed using the state-of-the-art mass spectrometry techniques and advanced bioinformatic methods. The result is a freely accessible dataset that provides information on which cellular proteins the viral proteins bind to and the effects of these interactions on the cell. In total, 1484 interactions between viral proteins and human cellular proteins were discovered. “Had we only looked at proteins, however, we would have missed out on important information,” says Andreas Pichlmair. “A database that only includes the proteome would be like a map containing just the place names but no roads or rivers. If you knew about the connections between the points on that map, you could gain much more useful information.”
According to Pichlmair, important counterparts to the network of traffic routes on a map are protein modifications called phosphorylation and ubiquitination. Both are processes in which other molecules are attached to proteins, thereby altering their functions. In a listing of proteins, these changes are not measured, so that there is no way of knowing whether proteins are active or inactive, for example. “Through our investigations, we systematically assign functions to the individual components of the pathogen, in addition to the cellular molecules that are switched off by the virus,” explains Pichlmair. “There has been no comparable mapping for SARS-CoV-2 so far,” adds Matthias Mann. “In a sense, we have taken a close look at five dimensions of the virus during an infection: its own active proteins and its effects on the host proteome, ubiquitinome, phosphoproteome and transcriptome.”
Insights into how the virus works
Among other things, the database can also serve as a tool to find new drugs. By analyzing protein interactions and modifications, vulnerability hotspots of SARS-CoV-2 can be identified. These proteins bind to particularly important partners in cells and could serve as potential starting points for therapies. For example, the scientists concluded that certain compounds would inhibit the growth of SARS-CoV-2. Among them were some whose antiviral function is known, but also some compounds which have not yet been studied for efficacy against SARS-CoV-2. Further studies are needed to determine whether they show efficacy in clinical use against Covid-19.
“Currently, we are working on new anti Covid-19 drug candidates, that we have been able to identify through our analyses,” says Andreas Pichlmair. “We are also developing a scoring system for automated identification of hotspots. I am convinced that detailed data sets and advanced analysis methods will enable us to develop effective drugs in a more targeted manner in the future and limit side effects in advance.”
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Materials provided by Technical University of Munich (TUM). Note: Content may be edited for style and length.

When the COVID-19 pandemic hit in early 2020, many families found themselves suddenly isolated together at home. A year later, new research has linked this period with a variety of large, detrimental effects on individuals’ and families’ well-being and functioning.
The study — led by Penn State researchers — found that in the first months of the pandemic, parents reported that their children were experiencing much higher levels of “internalizing” problems like depression and anxiety, and “externalizing” problems such as disruptive and aggressive behavior, than before the pandemic. Parents also reported that they themselves were experiencing much higher levels of depression and lower levels of coparenting quality with their partners.
Mark Feinberg, research professor of health and human development at Penn State, said the results — recently published in the journal Family Process — give insight into just how devastating periods of family and social stress can be for parents and children, and how important a good coparenting relationship can be for family well-being.
“Stress in general — whether daily hassles or acute, crisis-driven stress — typically leads to greater conflict and hostility in family relationships,” Feinberg said. “If parents can support each other in these situations, the evidence from past research indicates that they will be able to be more patient and more supportive with their children, rather than becoming more harsh and angry.”
Feinberg added that understanding what can help parents maintain positive parenting practices, such as a positive coparenting relationship, is key for helping protect children during future crises — whether those crises are pandemics, economic shocks or natural disasters.
While cross-sectional studies have suggested there has been a negative impact of the pandemic on families, the researchers said this study is one of the first to measure just how much these factors have changed within families before and after the pandemic hit.

New research from McMaster University suggests the pandemic has created a paradox where mental health has become both a motivator for and a barrier to physical activity.
People want to be active to improve their mental health but find it difficult to exercise due to stress and anxiety, say the researchers who surveyed more than 1,600 subjects in an effort to understand how and why mental health, physical activity and sedentary behavior have changed throughout the course of the pandemic.
The results are outlined in the journal PLOS ONE.
“Maintaining a regular exercise program is difficult at the best of times and the conditions surrounding the COVID-19 pandemic may be making it even more difficult,” says Jennifer Heisz, lead author of the study and an associate professor in the Department of Kinesiology at McMaster.
“Even though exercise comes with the promise of reducing anxiety, many respondents felt too anxious to exercise. Likewise, although exercise reduces depression, respondents who were more depressed were less motivated to get active, and lack of motivation is a symptom of depression,” she says.
Respondents reported higher psychological stress and moderate levels of anxiety and depression triggered by the pandemic. At the same time, aerobic activity was down about 20 minutes per week, strength training down roughly 30 minutes per week, and sedentary time was up about 30 minutes per day compared to six months prior to the pandemic.
Those who reported the greatest declines in physical activity also experienced the worst mental health outcomes, the researchers reported, while respondents who maintained their physical activity levels fared much better mentally.
Researchers also found economic disparities played a role, particularly among younger adults.
“Just like other aspects of the pandemic, some demographics are hit harder than others and here it is people with lower income who are struggling to meet their physical activity goals,” says Maryam Marashi, a graduate student in the Department of Kinesiology and co-lead author of the study. “It is plausible that younger adults who typically work longer hours and earn less are lacking both time and space which is taking a toll.”
After analysing the data, the researchers designed an evidence-based toolkit which includes the following advice to get active: Adopt a mindset: Some exercise is better than none. Lower exercise intensity if feeling anxious. Move a little every day. Break up sedentary time with standing or movement breaks. Plan your workouts like appointments by blocking off the time in your calendar.”Our results point to the need for additional psychological supports to help people maintain their physical activity levels during stressful times in order to minimize the burden of the pandemic and prevent the development of a mental health crisis,” says Heisz.
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Materials provided by McMaster University. Note: Content may be edited for style and length.

Smoking cannabis when you’re young may increase your risk of developing heart disease later, according to a recent University of Guelph study.
In the first study to look at specific risk indicators for cardiovascular disease (CVD) in young, healthy cannabis users, researchers found subtle but potentially important changes in heart and artery function.
Cigarette smoking is known to affect cardiovascular health, causing changes to blood vessels and the heart. Less is known about the impact of smoking cannabis on long-term CVD risk, even as use of the substance grows in Canada and abroad. Cannabis is the most commonly used recreational substance worldwide after alcohol.
“Cannabis is really widely used as a recreational substance all around the world and is becoming increasingly so,” said Christian Cheung, a PhD student in the Human Performance and Health Research Lab, part of the Department of Human Health and Nutritional Sciences (HHNS). “Scientists haven’t done that research with cannabis.”
Cheung is the lead author of the study, published recently in the Journal of Applied Physiology. His co-authors were Dr. Jamie Burr and Dr. Philip Millar, both professors in HHNS and PhD student Alexandra Coates.
The team studied 35 subjects aged 19 to 30, half of whom were cannabis users. For all subjects, they used ultrasound imaging to look at the heart and arteries. They measured arterial stiffness and arterial function, or the ability of arteries to appropriately expand with greater blood flow. All three measures are indicators of cardiovascular function and potential disease risk.

The plasticisers contained in many everyday objects can impair important brain functions in humans. Biologists from the University of Bayreuth warn of this danger in an article in Communications Biology. Their study shows that even small amounts of the plasticisers bisphenol A and bisphenol S disrupt the transmission of signals between nerve cells in the brains of fish. The researchers consider it very likely that similar interference can also occur in the brains of adult humans. They therefore call for the rapid development of alternative plasticisers that do not pose a risk to the central nervous system.
Bisphenols are plasticisers that are found in a large number of plastic products worldwide — for example, in food packaging, plastic tableware, drinking bottles, toys, tooth fillings, and babies’ dummies. In recent years, numerous health risks have already been associated with them, especially with bisphenol A (BPA). The Bayreuth research team led by Dr. Peter Machnik at the Animal Physiology research group (led by Prof. Dr. Stefan Schuster) has now for the first time investigated the effects of plasticisers on signal transmission between nerve cells in the adult brain. The study covers not only BPA, but also bisphenol S (BPS), which is often considered less harmful to health. Their findings: Both plasticisers impair communication between the nerve cells of the brain.
Permanent damage to the nervous system
The harmful effects on the brain mainly affect the delicate balance between different neuronal functions. While some brain cells transmit signals that trigger a state of excitation in downstream cells, other brain cells have the function of inhibiting downstream cells. However, the coordination of both excitation and inhibition is essential for an intact central nervous system. “It is well known that numerous disorders in the nervous system of vertebrates are triggered by the fact that excitatory signals and inhibitory signals are not or only inadequately coordinated. So, it is all the more alarming that the plasticisers BPA and BPS significantly impair precisely this coordination,” explains Dr. Peter Machnik, lead author of the study.
“We were surprised how many vital brain functions in fish are affected by the plasticisers used in numerous industries. This damage, as we were able to show, does not occur immediately. However, when the brain cells are exposed to small amounts of BPA or BPS for a month, the damage is unmistakable,” says Elisabeth Schirmer, a doctoral student from Bayreuth and first author of the study. It turns out that the plasticisers influence the action potential of brain cells. They alter the chemical and electrical transmission of signals through the synapses. In addition, they disrupt the circuits that are important for the perception and processing of acoustic and visual stimuli.
Studies on Mauthner cells in goldfish
The discovery of the damage caused by plasticisers came from detailed studies on live goldfish. The focus was on the two largest nerve cells in fish brain, the Mauthner cells. They integrate all sensory stimuli, all of which must be processed quickly and in a precisely coordinated manner when predators approach. In this case, the Mauthner cells trigger life-saving escape reactions. Due to this function, which is essential for survival, they have become particularly robust in the course of evolution. Mauthner cells are able to ward off damaging influences to a certain extent, or to compensate for damage afterwards. This makes it all the more significant that plasticisers are able to cause considerable damage to these cells.
Transferability of the results to humans — Demand for alternative plasticisers
“The findings obtained through studies on fish brains justify the assessment that BPA and BPS can also seriously damage the brains of adult humans. Against this background, it is essential that science and industry develop new plasticisers to replace these bisphenols, while being safe for human health,” says Dr. Peter Machnik. Prof. Dr. Stefan Schuster adds: “The efficiency of the research techniques we used in our study could, in addition, prove a valuable aid in the development of alternative plasticisers. They make it possible to quickly and inexpensively test how a substance under consideration affects brain cells.”
The research was funded by the German Research Foundation (DFG) as part of a Reinhart Koselleck project.
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