Publisher Health

Researchers at Karolinska Institutet have evaluated the possibility of alerting drones equipped with automated external defibrillators (AED) to patients with suspected cardiac arrest. In more than half of the cases, the drones were ahead of the ambulance by an average of three minutes. In cases where the patient was in cardiac arrest, the drone-delivered defibrillator was used in a majority of cases. The results have been published in the journal The Lancet Digital Health.
“The use of an AED is the single most important factor in saving lives. We have been deploying drones equipped with AED since the summer of 2020 and show in this follow-up study that drones can arrive at the scene before an ambulance by several minutes. This lead time has meant that the AED could be used by people at the scene in several cases,” says Andreas Claesson, Associate Professor at the Center for Cardiac Arrest Research at the Department of Clinical Research and Education, Södersjukhuset, Karolinska Institutet, and principal investigator of the study.
Every year, around 6000 people in Sweden suffer a sudden cardiac arrest, but only a tenth of those affected survive. Although an early shock with a AED can dramatically increase the chance of survival and there are tens of thousands of AED in the community, they are not available in people’s homes where most cardiac arrests occur.
To shorten the time to defibrillation with an AED, Karolinska Institutet, together with Region Västra Götaland, SOS Alarm and the drone operator Everdrone, has since 2020 tested the possibility of sending out a drone with a AED at the same time as an ambulance is alerted. The project covered an area of approximately 200,000 people in western Sweden. An initial study conducted in the summer of 2020 in Gothenburg and Kungälv showed that the idea was feasible and safe.
“This more comprehensive and follow-up study now shows in a larger material that the methodology works throughout the year, summer and winter, in daylight and darkness. Drones can be alerted, arrive, deliver AED, and people on site have time to use the AED before the ambulance arrives,” says Sofia Schierbeck, PhD student at the same department and first author of the study.
In the study, drones delivered a AED in 55 cases of suspected cardiac arrest. In 37 of these cases, the delivery took place before an ambulance, corresponding to 67 percent, with a median lead of 3 minutes and 14 seconds. In the 18 cases of actual cardiac arrest, the caller managed to use the AED in six cases, representing 33 percent. A shock was recommended by the device in two cases and in one case the patient survived.
“Our study now shows once and for all that it is possible to deliver AED with drones and that this can be done several minutes before the arrival of the ambulance in connection with acute cardiac arrest,” says Andreas Claesson. “This time saving meant that the healthcare emergency center could instruct the person who called the ambulance to retrieve and use the AED in several cases before the ambulance arrived.”
The research was mainly funded by the Swedish Heart-Lung Foundation.

Living cells compete with each other and try to adapt to the local environment. Cells that are unable to do so are eliminated eventually. This cellular competition is crucial as the surrounding normal epithelial cells use it to identify and eliminate mutant cancer cells. Studies have reported that when activating mutants of “Ras” proteins are expressed in mammalian epithelial cells, they are pushed toward the lumen, excreted along with other bodily waste, and eliminated by competition. Epithelial cells containing Ras mutants have been reported to be removed in this manner in several organs, including the small intestine, stomach, pancreas, and lungs. This suggests that cell competition is an innate defense system orchestrated by epithelial cells to prevent the accumulation of incidentally produced cancerous cells and thereby suppress cancer formation.
In general, mutations in multiple genes accumulate in a stepwise manner when normal cells become cancerous. However, it is not known how cell competition is affected by this process. For instance, human colorectal cancer develops when the adenomatous polyposis coli (APC) gene becomes dysfunctional and activates “Wnt signaling,” followed by the activation of Ras signaling.
In a recent study, a team of researchers from Japan, led by Associate Professor Shunsuke Kon of the Department of Cancer Biology, Institute of Biomedical Research and Innovation, Tokyo University of Science (TUS), examined the effects of the accumulation of stepwise gene mutations on cell competition and investigated the role of cell competition in the actual cancer formation process. Their study was published in Nature Communications on November 3, 2023 with Mr. Kazuki Nakai, a third year PhD student at the Graduate School of Life Sciences in TUS, as the lead author.
The study results showed that when Wnt signals were activated in epithelial cells, cell competition function was altered. Activated Ras mutant epithelial cells, which would normally be eliminated into the lumen, instead infiltrated diffusely into the tissue to form highly invasive cancerous tumors.
As senior author Dr. Kon explains, “We discovered that in epithelial tissues where Wnt and Ras signals, which commonly occur in human colorectal cancer, are activated in stages, the function of cell competition is altered. It was revealed that the production of cancer cells that diffusely infiltrate into the interstitium is promoted.”
Further, the research team identified an increased expression of matrix metalloproteinase 21 (MMP21) as one of the mechanisms underlying the production of diffusely invasive cancer cells in early colorectal cancer due to abnormal cell competition. This, in turn, was shown to be directly caused by activation of nuclear factor kappa B (NF-κB) signals via the innate immune system. Blocking NF-κB signaling restored the luminal elimination of Ras mutant epithelial cells. These findings raise some intriguing questions, such as “How do transformed cells sense the cellular content that leads to the NF-B-MMP21 pathway?” and “How do surrounding cells recognize transformed cells and prepare them for cellular extrusion?” These questions will almost certainly need to be addressed in the future.
The results of this research show that cancer cells with accumulated, sequential genetic mutations, alter the function of cell competition and use it to enhance their own invasive ability. Instead of being eliminated to the lumen, they infiltrate into the tissue, producing high-grade cancer cells. While the research team did note that the cancer histopathology of the mice used in this study resembled diffuse-type cancer in humans, future research is needed to determine whether the NF-κB-MMP21 pathway is relevant to other cancers. For instance, investigating scirrhous gastric cancer, a typical diffuse-type cancer, would be particularly interesting.
Overall, these findings demonstrate that Wnt activation disrupts cell competition, and confers invasive properties on transformed cells to escape primary epithelial sites. Understanding how the molecular landscape is re-modeled to change the fate of cancer cells with high mutational burdens could be used for therapeutic purposes. This could be of interest to researchers focused on Wnt signaling or cancer research, such as those at the Koch Institute for Integrative Cancer Research at MIT and Cancer Research UK, who are working towards common goals.
Dr. Kon concludes by saying, “This study further brings forth the prospect that cell competition constrains the order of appearance of mutations during tumor development, highlighting a link between cell competition and carcinogenesis. We hope that this will pave the way for the development of new cancer treatments from the standpoint of cell competition and infiltration for the benefit of our society.”

Researchers at Kyushu University have developed a new tool to help clinicians and researchers assess individuals for pathological social withdrawal, known as Hikikomori. The tool, called Hikikomori Diagnostic Evaluation, or HiDE, can be a practical guide on collecting information on this globally growing pathology.
Hikikomori is a condition characterized by sustained physical isolation or social withdrawal for a period exceeding six months. It was first defined in Japan in 1998, and while thought to be a Japan specific ‘culture-bound’ syndrome, recent evidence has shown a marked growth of it worldwide. Researchers and medical professionals also fear that the recent COVID-19 pandemic has compounded the increase of hikikomori patients across the globe.
However, there is yet to be a standardized tool to identify the hikikomori pathology. The new HiDE assessment tool, developed by Associate Professor Takahiro A. Kato of the Graduate School of Medical Sciences published in World Psychiatry, is intended to be the next step in a transcultural tool to help identify and assess hikikomori individuals.
In 2013, the Kyushu University hospital established the world’s first outpatient clinic for hikikomori in the hopes to research the pathology and find better methods of treatment. Over the years, Kato and his team have developed different methods for early detection of hikikomori and has even been investigating possible biomarkers of the pathology.
“HiDE is a questionnaire we’ve been developing at our clinic at the University Hospital. We’ve refined it over the years, and today it takes roughly 5-20 minutes to complete depending on the answers,” explains Kato. “It’s primarily divided into two sections. The first section looks at the features of the patient’s behavior to see if they exhibit hikikomori. The second section is used to help us gain context to the patient’s extent of social withdrawal.”
The team has also added a screening form to the HiDE in case clinicians lack the time to administer the entire tool. They suggest that the full questionnaire be administered to patients who respond that they ‘spend one hour or less per day out of their home, at least three days a week’ and that ‘their family, others, or are personally bothered by this.’
“The HiDE has proven to be an indispensable tool for the structured assessment of pathological social withdrawal in our clinical practice and research. But more empirical studies must be done to assess its validity beyond our practice,” concludes Kato. “We would like to see this used by our colleagues around the world, so we can work to refine the tool. Hikikomori is becoming a global phenomenon, and a collective effort in recognizing and treating hikikomori is going to be vital.”

Scientists can now pinpoint where someone’s eyes are looking just by listening to their ears.
“You can actually estimate the movement of the eyes, the position of the target that the eyes are going to look at, just from recordings made with a microphone in the ear canal,” said Jennifer Groh, Ph.D., senior author of the new report, and a professor in the departments of psychology & neuroscience as well as neurobiology at Duke University.
In 2018, Groh’s team discovered that the ears make a subtle, imperceptible noise when the eyes move. In a new report appearing the week of November 20 in the journal Proceedings of the National Academy of Sciences, the Duke team now shows that these sounds can reveal where your eyes are looking.
It also works the other way around. Just by knowing where someone is looking, Groh and her team were able to predict what the waveform of the subtle ear sound would look like.
These sounds, Groh believes, may be caused when eye movements stimulate the brain to contract either middle ear muscles, which typically help dampen loud sounds, or the hair cells that help amplify quiet sounds.
The exact purpose of these ear squeaks is unclear, but Groh’s initial hunch is that it might help sharpen people’s perception.
“We think this is part of a system for allowing the brain to match up where sights and sounds are located, even though our eyes can move when our head and ears do not,” Groh said.

Understanding the relationship between subtle ear sounds and vision might lead to the development of new clinical tests for hearing.
“If each part of the ear contributes individual rules for the eardrum signal, then they could be used as a type of clinical tool to assess which part of the anatomy in the ear is malfunctioning,” said Stephanie Lovich, one of the lead authors of the paper and a graduate student in psychology & neuroscience at Duke.
Just as the eye’s pupils constrict or dilate like a camera’s aperture to adjust how much light gets in, the ears too have their own way to regulate hearing. Scientists long thought that these sound-regulating mechanisms only helped to amplify soft sounds or dampen loud ones. But in 2018, Groh and her team discovered that these same sound-regulating mechanisms were also activated by eye movements, suggesting that the brain informs the ears about the eye’s movements.
In their latest study, the research team followed up on their initial discovery and investigated whether the faint auditory signals contained detailed information about the eye movements.
To decode people’s ear sounds, Groh’s team at Duke and Professor Christopher Shera, Ph.D. from the University of Southern California, recruited 16 adults with unimpaired vision and hearing to Groh’s lab in Durham to take a fairly simple eye test.
Participants looked at a static green dot on a computer screen, then, without moving their heads, tracked the dot with their eyes as it disappeared and then reappeared either up, down, left, right, or diagonal from the starting point. This gave Groh’s team a wide-range of auditory signals generated as the eyes moved horizontally, vertically, or diagonally.

An eye tracker recorded where participant’s pupils were darting to compare against the ear sounds, which were captured using a microphone-embedded pair of earbuds.
The research team analyzed the ear sounds and found unique signatures for different directions of movement. This enabled them to crack the ear sound’s code and calculate where people were looking just by scrutinizing a soundwave.
“Since a diagonal eye movement is just a horizontal component and vertical component, my labmate and co-author David Murphy realized you can take those two components and guess what they would be if you put them together,” Lovich said. “Then you can go in the opposite direction and look at an oscillation to predict that someone was looking 30 degrees to the left.”
Groh is now starting to examine whether these ear sounds play a role in perception.
One set of projects is focused on how eye-movement ear sounds may be different in people with hearing or vision loss.
Groh is also testing whether people who don’t have hearing or vision loss will generate ear signals that can predict how well they do on a sound localization task, like spotting where an ambulance is while driving, which relies on mapping auditory information onto a visual scene.
“Some folks have a really reproducible signal day-to-day, and you can measure it quickly,” Groh said. “You might expect those folks to be really good at a visual-auditory task compared to other folks, where it’s more variable.”
Groh’s research was supported by a grant from the National Institutes of Health (NIDCD DC017532).

Anti-rheumatic drugs used for rheumatoid arthritis might prevent the development of autoimmune thyroid disease, according to a new observational study by researchers from Karolinska Institutet published in the Journal of Internal Medicine.
It is well known that patients with rheumatoid arthritis are at increased risk of autoimmune thyroid diseases such as Hashimoto’s disease and Graves’ disease. While patients with RA are usually treated with immunomodulatory drugs that affect the immune system, such drugs are rarely used in autoimmune thyroid diseases. Instead, such patients are treated with thyroid hormone to compensate for the changes in normal thyroid function that accompany autoimmune thyroid disease.
The researchers in the current study wanted to investigate whether immunomodulatory drugs that reduce inflammation in the joints of patients with RA might also reduce the risk of these patients developing autoimmune thyroid disease. Previous studies in mice suggest that so-called DMARDs, a type of immune-modulatory drugs used to treat rheumatoid arthritis, can reduce inflammation in the thyroid gland. Still, knowledge of whether this effect also applies to humans is limited, according to the research team.
The researchers used data between 2006 and 2018 on over 13,000 patients with rheumatoid arthritis and their treatment, as well as data from over 63,000 individuals in a matched control group without rheumatoid arthritis.
The researchers found that the risk of developing an autoimmune thyroid disease among RA patients was lower after their onset of the rheumatic disease than before diagnosis.
The most pronounced reduction in the risk of autoimmune thyroid disease was seen in patients with rheumatoid arthritis treated with immunomodulatory drugs or ‘biological DMARDs’. In these patients, the risk of autoimmune thyroid disease was 46 percent lower than in the control group without rheumatoid arthritis.
“These results support the hypothesis that certain types of immunomodulatory drugs could have a preventive effect on autoimmune thyroid disease,” says Kristin Waldenlind, researcher at the Department of Medicine, Solna, Division of Clinical Epidemiology, Karolinska Institutet, specialist in rheumatology at Karolinska University Hospital and first author of the study. She continues:
“Our results do not prove that it is the treatment with immunomodulatory drugs that led to the reduced risk of autoimmune thyroid disease, but provide support for this hypothesis. The results, if they can be replicated in further studies, open up the possibility of studying more directly in clinical trials whether the immunomodulatory drugs currently used for rheumatoid arthritis could also be used for the early treatment of autoimmune thyroid disease, i.e. for new areas of use of these drugs, known as drug repurposing.
The Swedish Research Council, the Swedish Heart-Lung Foundation and Vinnova mainly financed the study.

A new study in mice, published recently in the journal Cell Metabolism, shows that cutting down the amount of a single amino acid called isoleucine can, among other benefits, extend their lifespan, make them leaner and less frail as they age and reduce cancer and prostate problems, all while the mice ate more calories.
There’s a popular saying in some circles that “a calorie is a calorie,” but science shows that it may not be true. In fact, it may be possible to eat more of some kinds of calories while also improving your health.
“We like to say a calorie is not just a calorie,” says Dudley Lamming, a professor and metabolism researcher at the University of Wisconsin School of Medicine and Public Health. “Different components of your diet have value and impact beyond their function as a calorie, and we’ve been digging in on one component that many people may be eating too much of.”
Lamming is the lead author of a new study in mice, published recently in the journal Cell Metabolism, showing that cutting down the amount of a single amino acid called isoleucine can, among other benefits, extend their lifespan, make them leaner and less frail as they age and reduce cancer and prostate problems, all while the mice ate more calories.
Amino acids are the molecular building blocks of proteins, and Lamming and his colleagues are interested in their connection to healthy aging.
In earlier research, data from UW-Madison’s Survey of the Health of Wisconsin showed the scientists that Wisconsinites with higher body mass index measurements (higher is more overweight or obese) tend to consume more isoleucine, an essential amino acid everyone needs to eat. Isoleucine is plentiful in foods including eggs, dairy, soy protein and many kinds of meat.
To better understand its health effects, Lamming and collaborators from across disciplines at UW-Madison fed genetically diverse mice either a balanced control diet, a version of the balanced diet that was low in a group of about 20 amino acids, or a diet formulated to cut out two-thirds of the diet’s isoleucine. The mice, which began the study at about 6 months of age (equivalent to a 30-year-old person) got to eat as much as they wanted.

“Very quickly, we saw the mice on the reduced isoleucine diet lose adiposity — their bodies got leaner, they lost fat,” says Lamming, while the bodies of the mice on the low-amino-acid diet also got leaner to start, but eventually regained weight and fat.
Mice on the low-isoleucine diet lived longer — on average 33% longer for males and 7% longer for females. And, based on 26 measures of health, including assessments ranging from muscle strength and endurance to tail use and even hair loss, the low-isoleucine mice were in much better shape during their extended lives.
“Previous research has shown lifespan increase with low-calorie and low-protein or low-amino-acid diets starting in very young mice,” says Lamming, whose work is supported by the National Institutes of Health. “We started with mice that were already getting older. It’s interesting and encouraging to think a dietary change could still make such a big difference in lifespan and what we call ‘healthspan,’ even when it started closer to mid-life.”
The mice on the low-isoleucine diets chowed down, eating significantly more calories than their study counterparts — probably to try to make up for getting less isoleucine, according to Lamming. But they also burned far more calories, losing and then maintaining leaner body weights simply through adjustments in metabolism, not by getting more exercise.
At the same time, Lamming says, they maintained steadier blood sugar levels and male mice experienced less age-related prostate enlargement. And while cancer is the leading cause of death for the diverse strain of mice in the study, the low-isoleucine males were less likely to develop a tumor.
Dietary amino acids are linked to a gene called mTOR that appears to be a lever on the aging process in mice and other animals as well as to a hormone that manages the body’s response to cold and has been considered a potential diabetes drug candidate for human patients. But the mechanism behind the stark benefits of low-isoleucine intake is not well understood. Lamming thinks the new study’s results may help future research pick apart causes.

“That we see less benefit for female mice than male mice is something we may be able to use to get to that mechanism,” he says.
While the results are promising, humans do need isoleucine to live. And winnowing a significant amount of isoleucine out of a diet that hasn’t been preformulated by a mouse chow company is not an easy task.
“We can’t just switch everyone to a low-isoleucine diet,” Lamming says. “But narrowing these benefits down to a single amino acid gets us closer to understanding the biological processes and maybe potential interventions for humans, like an isoleucine-blocking drug.”
The Survey of the Health of Wisconsin showed that people vary in isoleucine intake, with leaner participants tending to eat a diet lower in isoleucine. Other data from Lamming’s lab suggest that overweight and obese Americans may be eating significantly more isoleucine than they need.
“It could be that by choosing healthier foods and healthier eating in general, we might be able to lower isoleucine enough to make a difference,” Lamming says.
This research was funded in part by grants from the National Institutes of Health (AG056771, AG062328, AG081482, AG084156, DK125859, F31AG066311, R01AG062328-03S1, F31AG081115, F31AG082504, T32AG000213, F32AG077916, RF1AG056771-06S1, K01AG059899, R01DK133479, P30DK020579, K12HD101368, R01AA029124, P30 CA014520, P50DE026787, U54DK104310, R01DK131175 and P30CA014520) and the U.S. Department of Veterans Affairs (I01-BX004031).

The term ‘leukemia’ encompasses various forms of blood cancer, including acute myeloid leukemia (AML). In AML, blood cells in the early stages — the stem cells and the precursor cells that develop out of them — degenerate. AML is the second most common leukemia in children, accounting for around four percent of all malignant diseases in childhood and adolescence. Despite intensive chemotherapy, only around half of those affected survive without relapsing. About one third of children are dependent on a stem cell donation. Since non-specific chemotherapies have severe side effects, there is an urgent need to find new and specific therapy approaches.
A team led by Jan-Henning Klusmann from the Department of Pediatrics and Dirk Heckl from the Institute for Experimental Pediatric Hematology and Oncology at Goethe University Frankfurt has now discovered an unusual “Achilles heel” in AML cells. For their study, which has now been published, they looked at a specific group of nucleic acids in leukemia cells: noncoding RNAs. Just like regular messenger RNAs (mRNAs), these are produced through gene transcription. However, unlike mRNAs, noncoding RNAs are not translated into proteins but instead often assume regulatory functions, for example in cell growth and cell division. A typical characteristic of cancer cells is a massive disruption of regulatory processes. This makes noncoding RNAs an interesting starting point in the fight against cancer.
Against this background, the researchers led by Klusmann and Heckl wanted to know more about the role of noncoding RNAs in AML cells. For this purpose, they compiled a kind of inventory of these molecules in cancer cells taken from sick children and compared the resulting pattern with that of healthy blood stem cells. AML cells differentially expressed almost 500 noncoding RNAs in comparison to healthy cells — an indication that they could perform an important function in cancer cells. To validate this, the researchers turned off every single one of these RNA molecules by preventing the coding gene in the genome from being read. The most distinct effect they found was for the gene MYNRL15: Cancer cells in which this gene was turned off lost their ability to replicate indefinitely and died off.
Surprisingly, however, it was not the absence of noncoding RNAs that was responsible for this effect, as Klusmann comments: “The regulatory function we observed is due to the MYNRL15 gene itself.” The team was able to show that destroying the gene altered the spatial organization of the chromatin, i.e. the three-dimensional structure of the genome. “This led to the deactivation of genes that AML cells need for survival,” says Klusmann. This offers a new and unforeseen possibility for fighting leukemia.
What is significant against this background is the fact that the inhibitory effect triggered by the modified MYNRL15 gene could be observed in different AML cell lines. These cells originated both from children as well as adults and included various subtypes of the disease — among them one common in people with Down syndrome. “The fact that all the leukemias we studied were dependent on this gene locus tells us it must be important,” concludes Klusmann. The researchers now hope that the cancer cells’ dependence on MYNRL15 can be used to develop a specific gene therapy. “In our study, we systematically examined noncoding RNAs and their genes in AML cells for the first time, and in the process we identified a gene locus that constitutes a promising target for developing a therapy in the future,” says Klusmann, summing up.

Trans-vaccenic acid (TVA), a long-chain fatty acid found in meat and dairy products from grazing animals such as cows and sheep, improves the ability of CD8+ T cells to infiltrate tumors and kill cancer cells, according to a new study by researchers from the University of Chicago.
The research, published this week in Nature, also shows that patients with higher levels of TVA circulating in the blood responded better to immunotherapy, suggesting that it could have potential as a nutritional supplement to complement clinical treatments for cancer.
“There are many studies trying to decipher the link between diet and human health, and it’s very difficult to understand the underlying mechanisms because of the wide variety of foods people eat. But if we focus on just the nutrients and metabolites derived from food, we begin to see how they influence physiology and pathology,” said Jing Chen, PhD, the Janet Davison Rowley Distinguished Service Professor of Medicine at UChicago and one of the senior authors of the new study. “By focusing on nutrients that can activate T cell responses, we found one that actually enhances anti-tumor immunity by activating an important immune pathway.”
Finding nutrients that activate immune cells
Chen’s lab focuses on understanding how metabolites, nutrients and other molecules circulating in the blood influence the development of cancer and response to cancer treatments. For the new study, two postdoctoral fellows, Hao Fan, PhD and Siyuan Xia, PhD, both co-first authors, started with a database of around 700 known metabolites that come from food and assembled a “blood nutrient” compound library consisting of 235 bioactive molecules derived from nutrients. They screened the compounds in this new library for their ability to influence anti-tumor immunity by activating CD8+ T cells, a group of immune cells critical for killing cancerous or virally infected cells.
After the scientists evaluated the top six candidates in both human and mouse cells, they saw that TVA performed the best. TVA is the most abundant trans fatty acid present in human milk, but the body cannot produce it on its own. Only about 20% of TVA is broken down into other byproducts, leaving 80% circulating in the blood. “That means there must be something else it does, so we started working on it more,” Chen said.
The researchers then conducted a series of experiments with cells and mouse models of diverse tumor types. Feeding mice a diet enriched with TVA significantly reduced the tumor growth potential of melanoma and colon cancer cells compared to mice fed a control diet. The TVA diet also enhanced the ability of CD8+ T cells to infiltrate tumors.

The team also performed a series of molecular and genetic analyses to understand how TVA was affecting the T cells. These included a new technique for monitoring transcription of single-stranded DNA called kethoxal-assisted single-stranded DNA sequencing, or KAS-seq, developed by Chuan He, PhD, the John T. Wilson Distinguished Service Professor of Chemistry at UChicago and another senior author of the study. These additional assays, done by both the Chen and He labs, showed that TVA inactivates a receptor on the cell surface called GPR43 which is usually activated by short-chain fatty acids often produced by gut microbiota. TVA overpowers these short-chain fatty acids and activates a cellular signaling process known as the CREB pathway, which is involved in a variety of functions including cellular growth, survival, and differentiation. The team also showed that mouse models where the GPR43 receptor was exclusively removed from CD8+ T cells also lacked their improved tumor fighting ability.
Finally, the team also worked with Justin Kline, MD, Professor of Medicine at UChicago, to analyze blood samples taken from patients undergoing CAR-T cell immunotherapy treatment for lymphoma. They saw that patients with higher levels of TVA tended to respond to treatment better than those with lower levels. They also tested cell lines from leukemia by working with Wendy Stock, MD, the Anjuli Seth Nayak Professor of Medicine, and saw that TVA enhanced the ability of an immunotherapy drug to kill leukemia cells.
Focus on the nutrients, not the food
The study suggests that TVA could be used as a dietary supplement to help various T cell-based cancer treatments, although Chen points out that it is important to determine the optimized amount of the nutrient itself, not the food source. There is a growing body of evidence about the detrimental health effects of consuming too much red meat and dairy, so this study shouldn’t be taken as an excuse to eat more cheeseburgers and pizza; rather, it indicates that nutrient supplements such as TVA could be used to promote T cell activity. Chen thinks there may be other nutrients that can do the same.
“There is early data showing that other fatty acids from plants signal through a similar receptor, so we believe there is a high possibility that nutrients from plants can do the same thing by activating the CREB pathway as well,” he said.
The new research also highlights the promise of this “metabolomic” approach to understanding how the building blocks of diet affect our health. Chen said his team hopes to build a comprehensive library of nutrients circulating in the blood to understand their impact on immunity and other biological processes like aging.
“After millions of years of evolution, there are only a couple hundred metabolites derived from food that end up circulating in the blood, so that means they could have some importance in our biology,” Chen said. “To see that a single nutrient like TVA has a very targeted mechanism on a targeted immune cell type, with a very profound physiological response at the whole organism level — I find that really amazing and intriguing.”
The study, “Trans-vaccenic acid reprograms CD8+ T cells and anti-tumor immunity,” was supported by the National Institutes of Health (grants CA140515, CA174786, CA276568, 1375 HG006827, K99ES034084), a UChicago Biological Sciences Division Pilot Project Award, the Ludwig Center at UChicago, the Sigal Fellowship in Immuno-oncology, the Margaret E. Early Medical Research Trust, the AASLD Foundation a Harborview Foundation Gift Fund, and the Howard Hughes Medical Institute.

Researchers report in the journal Nature that they have found a way to get antibacterial drugs through the nearly impenetrable outer membrane of Pseudomonas aeruginosa, a bacterium that — once it infects a person — is notoriously difficult to treat.
By bombarding P. aeruginosa with hundreds of compounds and using machine learning to determine the physical and chemical traits of those molecules that accumulated inside it, the team discovered how to penetrate the bacterium’s defenses. They used this information to convert an antibacterial drug that previously had no activity against P. aeruginosa into one that did.
“Pseudomonas is still the most difficult to treat gram-negative infection, and gram-negative infections are very challenging to treat in general,” said University of Illinois Urbana-Champaign chemistry professor Paul Hergenrother, who led the work with former graduate student Emily Geddes, a handful of other graduate students and postdoctoral researchers in the Hergenrother lab and collaborators at Roche. “The Food and Drug Administration has not approved a new class of antibiotic drugs against gram-negatives in over 50 years.”
Gram-negative bacteria differ from gram-positive in the composition of their cell walls. P. aeruginosa has a tightly packed outer membrane that’s negatively charged, Geddes said. “This makes it really hard for other molecules to get through by passive diffusion.”
P. aeruginosa also has other defenses, including highly specialized porins that allow it to bring in specific nutrients while keeping out everything else, and efflux pumps that eject unwanted compounds, Geddes said.
Pseudomonas has 12 efflux pumps, Geddes said. “That really gives it a diversity of drug-resistance mechanisms that some other bacterial species just don’t have.
“Our goal here was to basically test a bunch of compounds to see what types of molecules get in the bacterial cell and stay in the cell, and hopefully learn some design principles from that,” she said.

Earlier studies of P. aeruginosa focused primarily on antibiotics, testing which ones could kill or weaken the bacterium, Hergenrother said.
“We took a different approach — testing a variety of nonantibiotic compounds and tracking which ones accumulated inside. We then used machine learning to make sense of the chemical traits that were common to the accumulators,” he said.
This approach revealed that, among other traits, compounds with a positive charge on the surface and those with more hydrogen-bond-donor surface area were more likely to accumulate inside P. aeruginosa.
Such compounds “can create sort of a gap in the bacterial membrane and destabilize it to let other things come through,” Geddes said.
Once they knew what characteristics a compound must have to penetrate Pseudomonas, the researchers chose to test those rules by modifying an existing antibiotic drug, fusidic acid, that is used to treat gram-positive infections but has no activity against gram-negative bacteria. The researchers modified the drug to create a derivative form, called FA prodrug, that included the features identified in the machine-learning exercise.
The experiment worked, Geddes said.

“As we increased the positive charge and as we increased the hydrogen-bond-donor surface area, we saw a corresponding increase in accumulation of the FA prodrug in Pseudomonas,” she said. “We saw a 64-fold improvement in activity with those changes.”
“Fusidic acid alone has no activity whatsoever against Pseudomonas,” Hergenrother said. “And so being able to build that in is a pretty powerful demonstration of the rules.”
The FA prodrug itself probably will not be pursued as a candidate drug to fight Pseudomonas infections, Geddes said. But the principles learned in the study will aid the design of new compounds to fight these dangerous, drug-resistant infections.
Hergenrother also is a professor in the Carle Illinois College of Medicine and the Carl R. Woese Institute for Genomic Biology, and deputy director of the Cancer Center at Illinois.
The National Institutes of Health supported this research.

When you eagerly dig into a long-awaited dinner, signals from your stomach to your brain keep you from eating so much you’ll regret it — or so it’s been thought. That theory had never really been directly tested until a team of scientists at UC San Francisco recently took up the question.
The picture, it turns out, is a little different.
The team, led by Zachary Knight, PhD, a UCSF professor of physiology in the Kavli Institute for Fundamental Neuroscience, discovered that it’s our sense of taste that pulls us back from the brink of food inhalation on a hungry day. Stimulated by the perception of flavor, a set of neurons — a type of brain cell — leaps to attention almost immediately to curtail our food intake.
“We’ve uncovered a logic the brainstem uses to control how fast and how much we eat, using two different kinds of signals, one coming from the mouth, and one coming much later from the gut,” said Knight, who is also an investigator with the Howard Hughes Medical Institute and a member of the UCSF Weill Institute for Neurosciences. “This discovery gives us a new framework to understand how we control our eating.”
The study, which appears Nov. 22, 2023 in Nature, could help reveal exactly how weight-loss drugs like Ozempic work, and how to make them more effective.
New views into the brainstem
Pavlov proposed over a century ago that the sight, smell and taste of food are important for regulating digestion. More recent studies in the 1970s and 1980s have also suggested that the taste of food may restrain how fast we eat, but it’s been impossible to study the relevant brain activity during eating because the brain cells that control this process are located deep in the brainstem, making them hard to access or record in an animal that’s awake.

Over the years, the idea had been forgotten, Knight said.
New techniques developed by lead author Truong Ly, PhD, a graduate student in Knight’s lab, allowed for the first-ever imaging and recording of a brainstem structure critical for feeling full, called the nucleus of the solitary tract, or NTS, in an awake, active mouse. He used those techniques to look at two types of neurons that have been known for decades to have a role in food intake.
The team found that when they put food directly into the mouse’s stomach, brain cells called PRLH (for prolactin-releasing hormone) were activated by nutrient signals sent from the GI tract, in line with traditional thinking and the results of prior studies.
However, when they allowed the mice to eat the food as they normally would, those signals from the gut didn’t show up. Instead, the PRLH brain cells switched to a new activity pattern that was entirely controlled by signals from the mouth.
“It was a total surprise that these cells were activated by the perception of taste,” said Ly. “It shows that there are other components of the appetite-control system that we should be thinking about.”
While it may seem counterintuitive for our brains to slow eating when we’re hungry, the brain is actually using the taste of food in two different ways at the same time. One part is saying, “This tastes good, eat more,” and another part is watching how fast you’re eating and saying, “Slow down or you’re going to be sick.”
“The balance between those is how fast you eat,” said Knight.

The activity of the PRLH neurons seems to affect how palatable the mice found the food, Ly said. That meshes with our human experience that food is less appetizing once you’ve had your fill of it.
Brain cells that inspire weight-loss drugs
The PRLH-neuron-induced slowdown also makes sense in terms of timing. The taste of food triggers these neurons to switch their activity in seconds, from keeping tabs on the gut to responding to signals from the mouth.
Meanwhile, it takes many minutes for a different group of brain cells, called CGC neurons, to begin responding to signals from the stomach and intestines. These cells act over much slower time scales — tens of minutes — and can hold back hunger for a much longer period of time.
“Together, these two sets of neurons create a feed-forward, feed-back loop,” said Knight. “One is using taste to slow things down and anticipate what’s coming. The other is using a gut signal to say, ‘This is how much I really ate. Ok, I’m full now!'”
The CGC brain cells’ response to stretch signals from the gut is to release GLP-1, the hormone mimicked by Ozempic, Wegovy and other new weight-loss drugs.
These drugs act on the same region of the brainstem that Ly’s technology has finally allowed researchers to study. “Now we have a way of teasing apart what’s happening in the brain that makes these drugs work,” he said.
A deeper understanding of how signals from different parts of the body control appetite would open doors to designing weight-loss regimens designed for the individual ways people eat by optimizing how the signals from the two sets of brain cells interact, the researchers said.
The team plans to investigate those interactions, seeking to better understand how taste signals from food interact with feedback from the gut to suppress our appetite during a meal.