Publisher Health

In the progressing field of immunotherapy, surprisingly little is known about immunity to metastatic tumors in locations such as lymph nodes, a frequent place where cancers first spread. Not only do lymph nodes act as a gateway for cancer cells to travel throughout the body, but they are also home to infection-fighting white blood cells called T cells. In some cases, T cells in lymph nodes activate to kill invading cancer cells. In other cases, that process clearly fails.
To address the need to understand why, researchers in the laboratory of Mary Jo Turk, PhD, Co-Director of the Immunology and Cancer Immunotherapy Research Program at Dartmouth’s and Dartmouth-Hitchcock’s Norris Cotton Cancer Center (NCCC) have spent the past year studying immunity to metastatic cancer within lymph nodes.
While T cells can freely travel from lymph nodes into the bloodstream and back to the lymph nodes, researchers in Turk’s lab have discovered a novel population of tumor-fighting T cells that do not circulate, but rather stay in lymph nodes where they provide protection against melanoma. “These T cells, for whatever reason, have changed their program and stay in the lymph nodes where they persist and kill tumor cells for many months while never entering circulation,” says Turk.
These long-lived T cells, called “lymph node resident memory Tcells,” were shown to counteract melanoma spreading in mice. Turk’s team found that when melanoma cells were put back into mice that had been cured of cancer with immunotherapy a month earlier, the lymph nodes were still resistant to the cancer — the melanoma would not grow.
“We also identified T cells with similar characteristics in melanoma-invaded patient lymph nodes, showing that similar populations exist in humans,” reveals Turk.
Computational analysis of melanoma specimen data from The Cancer Genome Atlas revealed that the presence of T cells with this gene signature predicted better outcomes and improved survival for human melanoma patients with lymph node metastases. “These studies reveal a new population of T cells that is vital for counteracting the earliest stages of cancer metastasis,” says Turk.
Although the concept of T cells taking up residence in lymph nodes is not entirely new, it has never been shown in cancer. The team’s findings, “Resident memory T cells in regional lymph nodes mediate immunity to metastatic melanoma,” are newly published in Immunity.
The team, including clinicians at Dartmouth-Hitchcock Medical Center, as well as researchers at Baylor College of Medicine led by computational biologist, Chao Cheng, PhD, employed innovative sequencing techniques to identify the unique transcriptional profile that makes these resident T cells specific to lymph nodes and to cancer. “We found that these cells have a unique gene expression profile that differentiates them from cells in circulation, and from memory T cells that reside in and protect other tissues such as the skin,” says Cheng.
Other collaborators on this work include the University of Michigan and University of Texas, San Antonio.
In the coming year, the Turk research team hopes to better understand how these memory T cells are most effectively generated and activated within lymph nodes. The ultimate goal is to understand how memory T cells can be positioned throughout tissues to efficiently block cancer from spreading.
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Materials provided by Dartmouth-Hitchcock Medical Center. Note: Content may be edited for style and length.

A Michigan Medicine study found that most patients with mild COVID-19 infections produce antibodies that persist and protect them from reinfection for up to six months.
Researchers analyzed nearly 130 subjects with PCR-confirmed COVID-19 illness between three and six months after initial infection. Three patients were hospitalized while the rest were treated as outpatients and experienced mild infection, with symptoms including headaches, chills and loss of taste or smell.
The results, published in Microbiology Spectrum, reveal approximately 90% of participants produced spike and nucleocapsid antibody responses, and all but one had persistent antibody levels at follow up.
“Previously, there was a lot of concern that only those with severe COVID-19 produced strong antibody responses to infection,” said Charles Schuler, M.D., lead author of the paper and clinical assistant professor of allergy and immunology at Michigan Medicine. “We’re showing that people with mild bouts of COVID-19 did really well after their infection, made antibodies, and kept them.”
The prospective study’s participants were either Michigan Medicine health care workers or patients with a high risk of exposure to COVID-19. Most subjects took part in the same research team’s previous study, which found that COVID antibody tests are effective at predicting prior infection.
During the observation period, none of the subjects who produced antibodies were re-infected, compared to 15 antibody-negative patients. Schuler’s team also found that the antibodies’ ability to neutralize COVID-19 did not differ significantly from the first visit, which occurred three months after infection, to the second visit at the six-month mark.

A study carried out at 19 workplace cafeterias has shown that reducing portion sizes and replacing higher calorie food and drinks with lower calorie options led to workers buying food and drink with fewer calories.
Researchers at the University of Cambridge, who led the study, say that even simple interventions such as these could contribute towards tackling levels of obesity.
Unhealthy eating, including eating more calories than are needed, plays a major role in the increasing rates of obesity. This in turn increases the risk of diseases such as type 2 diabetes, heart disease and many cancers, contributing to increasing rates of premature death worldwide.
The environments in which we live and work influence the types of food and drink that we consume. Local areas of deprivation in particular magnify this effect — people living in less affluent areas or with lower socioeconomic status tend to have reduced access to healthy foods and higher rates of obesity.
One important environment where interventions could be implemented is cafeterias, such as those in schools, universities, and workplaces. The workplace is the most common place to eat outside of the home, typically 15% of working adults’ energy intake.
In the largest study of its kind, a team from the University of Cambridge tested the impact on calories purchased of changing both portion sizes and availability of some higher calorie food and drink in 19 workplace cafeterias over a six month period. The results of their study are published today in PLOS Medicine.

A University at Buffalo-led research team has shown that a protein named for the mythical land of youth in Irish folklore is effective at reversing aging in skeletal muscle cells.
Published Sept. 3 in Science Advances, the study centers on the protein NANOG, which is derived from Tír na nÓg, a place in Irish lore renowned for everlasting youth, beauty and health.
In a series of experiments, researchers overexpressed NANOG in myoblasts, which are the embryonic precursors to muscle tissue. The myoblasts were senescent, meaning they were no longer able to divide and grow.
The overexpression ameliorated some of the primary characteristics associated with age-related deterioration of cells, including autophagy, energy homeostasis, genomic stability, nuclear integrity and mitochondrial function.
Most notably, NANOG increased the number of muscle stem cells in the muscle of prematurely aging mice. This demonstrated the feasibility of reversing cellular aging in the body without the need to reprogram cells to an embryonic pluripotent state, a process that’s often used in stem cell therapy but runs the risk of tumorigenesis.
“Our work focuses on understanding the mechanisms of NANOG’s actions in hopes of discovering druggable targets in signaling or metabolic networks that mimic the anti-aging effects of NANOG. Ultimately, the work could help lead to new treatments or therapies that help reverse cellular senescence, and aid the many people suffering from age-related disorders,” says the study’s corresponding author Stelios T. Andreadis, PhD, SUNY Distinguished Professor in the Department of Chemical and Biological Engineering at the UB School of Engineering and Applied Sciences.
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Materials provided by University at Buffalo. Original written by Cory Nealon. Note: Content may be edited for style and length.

Autism affects about 2% of children in the United States, and about 30% of these children have seizures. Recent large-scale genetic studies revealed that genetic variants in a sodium channel, called voltage-gated sodium channel Nav1.2, is a leading cause of autism. Overactive sodium channels in the neuron cause seizures. Doctors often treat seizures by giving the patient a medication meant to close the sodium channels, reducing the flow of sodium through axons. For many patients such treatment works, but in some cases — up to 20 or 30% — the treatment doesn’t work. These children have “loss-of-function” variants in Nav1.2, which is expected to reduce the sodium channel activity as “anti-seizures.” Thus, how the deficiency in sodium channel Nav1.2 leads to seizures is a major mystery in the field that puzzles physicians and scientists.
Yang Yang, an assistant professor of medicinal chemistry and molecular pharmacology at Purdue University, and his team, including first-author of the paper post-doctoral researcher Jingliang Zhang, tackled the issue. They discovered that in Nav1.2 deficient neurons, the expressions of many potassium channels are surprisingly reduced. The Nav1.2 deficiency itself doesn’t cause seizures; the issue arises when the potassium channels over-compensate for the sodium channels’ deficiency by shutting down too many potassium channels, making the neuron hyperexcitable, which causes seizures. In such cases, treating the sodium channel clearly does not work. Yang and his team suggest that developing medicines to open the potassium channels would help control seizures in these patients. Notably, researchers from the University of California, San Francisco led by Kevin Bender’s research group made a similar observation independently. Yang and Bender’s papers were published back-to-back in the same issue of Cell Reports.
“We’re looking at genetic makeup, so doctors can proscribe a drug and gene therapy based on genes identified — personalized medicines,” Yang said. “Our research points toward a direction for future research, maybe future treatments. We are peacetime warriors, fighting humanity’s biggest enemy: disease. There are kids dying because of these conditions. Our goal is to help them, to help their parents and their families. This kind of basic research is a vital part of finding new drugs.”
Funding
This work is supported by the Showalter Research Trust and the Purdue Big Idea Challenge 2.0 on Autism (to Y.Y.). The research reported in this publication was also supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (R01NS117585 and R01NS123154 to Y.Y.). The authors gratefully acknowledge support from the FamilieSCN2A Foundation for Action Potential Grant support, and Purdue Institute for Drug Discovery and Purdue Institute for Integrative Neuroscience for additional funding support. This project was supported in part by the Indiana Spinal Cord and Brain Injury Research Fund and the Indiana CTSI, funded in part by UL1TR002529 from the NIH. The Yang lab appreciates bioinformatics support from the Collaborative Core for Cancer Bioinformatics (C3B) of the IU Simon Comprehensive Cancer Center (P30CA082709), PCCR (P30CA023168) and the Walther Cancer Foundation.
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Materials provided by Purdue University. Original written by Brittany Steff. Note: Content may be edited for style and length.

I drink a lot of unsweetened seltzer. Does that have the same health benefits as drinking regular water?There’s still water and then there’s what my 4-year-old calls “spicy water,” better known as seltzer or sparkling water. Crisp, bubbly and effervescent, carbonated water has become a daily ritual for many and a growing segment of the beverage industry, with yearly sales now topping $4 billion in the United States.For those who crave it, carbonated water offers a sensory experience that flat water cannot: There’s the satisfying snap as you pull back the tab on the can. The sound of the fizz as you unscrew the bottle cap to pour yourself a glass. The tingly sensation as the beverage hits your tongue, sometimes with a hint of “natural” flavor.Still water is great for hydration, “but you would be surprised at the number of people who don’t like the taste and are unwilling to drink it,” said Anne Linge, a registered dietitian-nutritionist at the University of Washington Medical Center in Seattle. “Adding carbonation may make it more acceptable.”More acceptable, perhaps, but also just as healthy?Nutritionists agree that carbonated water (a category that includes seltzer water, which is artificially carbonated, and naturally sparkling water) is just as hydrating as regular water, however tap water has the added benefit of fluoride, which helps prevent tooth decay. “If you are using fluoridated water for brushing your teeth, cooking and some of your hydration, you can also include sparkling water in your diet,” Ms. Linge said. But keep in mind that carbonated water is more acidic in our mouths than flat water. Bubbly water contains carbon dioxide, which is converted to carbonic acid when it mingles with saliva, lowering the pH level of your mouth. The pH scale indicates whether a solution is more acidic (lower pH) or alkaline (higher pH). Drinks with a lower pH can be erosive to teeth, making them more susceptible to cavities; however, unsweetened carbonated water is not nearly as erosive as soda or fruit juice, according to a 2016 study published in the Journal of the American Dental Association.Some carbonated water brands include ingredients like citric acid for taste, which can raise the acidity level. Adding your own slices of lemon or lime would have a similar effect. And because the ingredient list will often say “natural flavor,” it is hard to know exactly what was added.Even so, “it would take quite a lot of consumption throughout the day to have damaging effects similar to what we’d see with fruit juice or soda,” said Dr. Brittany Seymour, an associate professor at the Harvard School of Dental Medicine and a spokeswoman for the American Dental Association.Aileen Son for The New York TimesThe bottom line: Because carbonated water still has the potential to be erosive, think of it as a once-a-day treat rather than your main source of water, Dr. Seymour said.“If you want to have two or three sparkling waters a day, perhaps pair them with a meal,” she added. When you eat, your mouth produces additional saliva, which can help neutralize acids on the surface of your teeth.If you prefer drinking it alone, without food — Dr. Seymour usually drinks unsweetened seltzer while cooking dinner — use a straw to help the water bypass your teeth. In general, try not to sip it for more than an hour. Drinking carbonated water over a long time period prolongs the amount of time that your teeth are exposed to acidity.If you love fizzy water and like to drink it multiple times a day, without meals, consider brushing your teeth with a fluoride toothpaste afterward to stave off tooth decay. Just make sure to wait at least 30 minutes after your last drink, Dr. Seymour said.Why? The acidity of the carbonated water softens the enamel of your teeth. Taking a break gives your enamel a chance to re-mineralize and return to its normal hardened state, which is the ideal surface for brushing because it can better tolerate abrasives, she added.If you have kids who also like to indulge in bubbly water, “I would say in general it’s fine,” Dr. Seymour said. But, she added, “I wouldn’t do it everyday with my daughter.” Ideally, parents should encourage their children to drink still, fluoridated water to guard against cavities, she said, and reserve the sparkling water for special occasions.Carbonated beverages can also contribute to gas and bloating, but the degree varies from person to person.“When you swallow carbonation it has to come out somewhere, so you either belch it out or it’s passed through flatulence,” said Courtney Schuchmann, a registered dietitian at University of Chicago Medicine who specializes in gastrointestinal health. “If you’re someone who already has issues with gas and bloating, it can cause more symptoms for you.”Carbonation can also make acid reflux worse and have a “filling effect,” which may diminish your appetite by creating distention in your belly, she added.Regardless of what type of water you prefer, each day aim to drink about half your body weight in ounces, with most of that being flat water, Ms. Schuchmann said. For example, if you weigh 150 pounds you should drink around 75 ounces of water to stay hydrated.Something else to keep in mind: Many people assume club soda and seltzer water are interchangeable, however club soda usually has sodium.“For someone watching their blood pressure, that is something to take into consideration,” Ms. Schuchmann said. “It depends on what the rest of your diet looks like and how much sodium is coming from other sources.”

Amyloid protein made in the liver can cause neurodegeneration in the brain, according to a new study in the open-access journal PLOS Biology, by John Mamo of Curtin University in Bentley, Australia, and colleagues. Since the protein is thought to be a key contributor to development of Alzheimer’s disease (AD), the results suggest that the liver may play an important role in the onset or progression of the disease.
Deposits of amyloid-beta (A-beta) in the brain are one of the pathological hallmarks of AD and are implicated in neurodegeneration in both human patients and animal models of the disease. But A-beta is also present in periphereral organs, and blood levels of A-beta correlate with cerebral amyloid burden and cognitive decline, raising the possibility that peripherally produced a-beta may contribute to the disease. Testing that hypothesis has been difficult, since the brain also produces A-beta, and distinguishing protein from the two sources is challenging.
In the current study, the authors surmounted that challenge by developing a mouse that produces human a-beta only in liver cells. They showed that the protein was carried in the blood by triglyceride-rich lipoproteins, just as it is in humans, and passed from the periphery into the brain. They found that mice developed neurodegeneration and brain atrophy, which was accompanied by neurovascular inflammation and dysfunction of cerebral capillaries, both commonly observed with Alzheimer’s disease. Affected mice performed poorly on a learning test that depends on function of the hippocampus, the brain structure that is essential for the formation of new memories.
The findings from this study indicate that peripherally derived A-beta has the ability to cause neurodegeneration and suggest that A-beta made in the liver is a potential contributor to human disease. If that contribution is significant, the findings may have major implications for understanding Alzheimer’s disease. To date, most models of the disease have focused on brain overproduction of A-beta, which mimics the rare genetic cases of human Alzheimer’s. But for the vast majority of AD cases, overproduction of A-beta in the brain is not thought to be central to the disease etiology. Instead, lifestyle factors may play a more important role, including a high-fat diet, which might accelerate liver production of A-beta.
The effects of peripheral A-beta on brain capillaries may be critical in the disease process, Mamo adds. “While further studies are now needed, this finding shows the abundance of these toxic protein deposits in the blood could potentially be addressed through a person’s diet and some drugs that could specifically target lipoprotein amyloid, therefore reducing their risk or slowing the progression of Alzheimer’s disease.”
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A family of proteins best known for their role in diminishing HIV infectivity may have the goods to outwit other emerging and re-emerging viruses, scientists have found.
The key to their newly discovered power: enhancing the signals sent within immune cells to unleash one of the most potent fighters in the innate antiviral response, proteins called type I interferons.
Experiments in cell cultures showed that the cell-signaling activities of these proteins, from the SERINC family, helped protect cells from infection by HIV, Ebola and Zika viruses. The researchers are currently testing whether this function is also effective against SARS-CoV-2, the virus that causes COVID-19.
It’s one thing for a protein to act directly against a specific virus, as SERINC5 has been shown to do by incorporating itself into the HIV particle during viral production. But it’s another thing entirely to reveal that a protein has an enhancing effect on an essential antiviral cell signaling pathway upon infection of host cells, said senior study author Shan-Lu Liu, professor of virology in the Department of Veterinary Biosciences at The Ohio State University.
“Viruses can get around direct antiviral effects,” said Liu, also an investigator and associate director in Ohio State’s Center for Retrovirus Research. “But if this protein can also modulate key pathways without acting directly on the virus, then a virus may have limited capacity to counteract it.
“If this family of molecules can do this in animals and humans, then you may think about whether it could be used in a broad antiviral therapy.”
The research is published today (Sept. 14, 2021) in the journal Science Signaling.

In baseball, a pitch can take as little as 400 milliseconds to reach the plate. With a typical reaction time of 200 milliseconds and a swing of about 150 milliseconds, a batter must decide whether to swing and how to swing based only on the first 10 to 20 percent of the ball’s flight. At that point, there is still a lot of uncertainty about the pitch’s speed and trajectory. And yet, major league baseball hitters still manage to hit the ball about 25 percent of the time — 40 percent if it were Ted Williams or Tony Gwynn in their primes.
How batters and other athletes process this uncertain information has long fascinated scientists.
“The fact that humans can do this at all is an incredible feat,” said Laith Alhussein, a graduate student at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).
The mechanisms underlying these feats are at the center of new research from Alhussein and Maurice Smith, the Gordon McKay Professor of Bioengineering at SEAS. The research was published recently in the journal eLife.
The research resolves a long-standing question about how the brain selects an action to execute when there is uncertainty about its ultimate goal, providing fundamental insight into motor planning in the nervous system.
“In the real world, we often interact with dynamic environments that can change rapidly in unpredictable ways, and so understanding the mechanisms by which we tame this uncertainty is critical for understanding, in general, the mechanisms the brain uses to select and plan our actions in real time,” said Smith.

Gut microbiota influences the ability to lose weight in humans, according to new research. The findings were published this week in mSystems, an open-access journal of the American Society for Microbiology.
“Your gut microbiome can help or cause resistance to weight loss and this opens up the possibility to try to alter the gut microbiome to impact weight loss,” said lead study author Christian Diener, Ph.D., a research scientist at the Institute for Systems Biology in Seattle, Washington.
To conduct their research, Dr. Diener and colleagues focused on a large cohort of individuals who were involved in a lifestyle intervention study. Instead of a specific diet or exercise program, this intervention involved a commercial behavioral coaching program paired with advice from a dietician and nurse coach. The researchers focused on 48 individuals who lost more than 1% of their body weight per month over a 6 to 12 month period and 57 individuals who did not lose any weight and had a stable body mass index (BMI) over the same period. The researchers relied on metagenomics, the study of genetic material recovered from blood and stool samples. The individuals analyzed blood metabolites, blood proteins, clinical labs, dietary questionnaires and gut bacteria in the two groups.
After controlling for age, sex and baseline BMI, the researchers identified 31 baseline stool metagenomic functional features that were associated with weight loss responses. These included complex polysaccharide and protein degradation genes, stress-response genes, respiration-related genes, cell wall synthesis genes and gut bacterial replication rates. A major finding was that the ability of the gut microbiome to break down starches was increased in people who did not lose weight. Another key finding was that genes that help bacteria grow faster, multiply, replicate and assemble cell walls were increased in people who lost more weight.
“Before this study, we knew the composition of bacteria in the gut were different in obese people than in people who were non-obese, but now we have seen that there are a different set of genes that are encoded in the bacteria in our gut that also responds to weight loss interventions,” said Dr. Diener. “The gut microbiome is a major player in modulating whether a weight loss intervention will have success or not. The factors that dictate obesity versus nonobesity are not the same factors that dictate whether you will lose weight on a lifestyle intervention.”
Research has already shown that if you change your diet, you can alter the composition of bacteria in your gut. According to Dr. Diener, if someone has a composition of gut bacterial genes that confers resistance to weight loss, then perhaps you can alter their diet to shift to a composition that would help them lose weight.
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Materials provided by American Society for Microbiology. Note: Content may be edited for style and length.