Culture

The closer people are physically to one another, the higher the chance for exchange, of things like ideas, information, and even infection. Now researchers at MIT and Boston Children's Hospital have found that, even in the microscopic environment within a single cell, physical crowding increases the chance for interactions, in a way that can significantly alter a cell's health and development.

In a paper published today in the journal Cell Stem Cell, the researchers have shown that physically squeezing cells, and crowding their contents, can trigger cells to grow and divide faster than they normally would.

While squeezing something to make it grow may sound counterintuitive, the team has an explanation: Squeezing acts to wring water out of a cell. With less water to swim in, proteins and other cell constituents are packed closer together. And when certain proteins are brought in close proximity, they can trigger cell signaling and activate genes within the cell.

In their new study, the scientists found that squeezing intestinal cells triggered proteins to cluster along a specific signaling pathway, which can help cells maintain their stem-cell state, an undifferentiated state in which can quickly grow and divide into more specialized cells. Ming Guo, associate professor of mechanical engineering at MIT, says that if cells can simply be squeezed to promote their "stemness," they can then be directed to quickly build up miniature organs, such as artificial intestines or colons, which could then be used as platforms to understand organ function and test drug candidates for various diseases, and even as transplants for regenerative medicine.

Guo's co-authors are lead author Yiwei Li, Jiliang Hu, and Qirong Lin from MIT, and Maorong Chen, Ren Sheng, and Xi He of Boston Children's Hospital.

Packed in

To study squeezing's effect on cells, the researchers mixed various cell types in solutions that solidified as rubbery slabs of hydrogel. To squeeze the cells, they placed weights on the hydrogel's surface, in the form of either a quarter or a dime.

"We wanted to achieve a significant amount of cell size change, and those two weights can compress the cell by something like 10 to 30 percent of their total volume," Guo explains.

The team used a confocal microscope to measure in 3D how individual cells' shapes changed as each sample was compressed. As they expected, the cells shrank with pressure. But did squeezing also affect the cell's contents? To answer this, the researchers first looked to see whether a cell's water content changed. If squeezing acts to wring water out of a cell, the researchers reasoned that the cells should be less hydrated, and stiffer as a result.

They measured the stiffness of cells before and after weights were applied, using optical tweezers, a laser-based technique that Guo's lab has employed for years to study interactions within cells, and found that indeed, cells stiffened with pressure. They also saw that there was less movement within cells that were squeezed, suggesting that their contents were more packed than usual.

Next, they looked at whether there were changes in the interactions between certain proteins in the cells, in response to cells being squeezed. They focused on several proteins that are known to trigger Wnt/β-catenin signaling, which is involved in cell growth and maintenance of "stemness."

"In general, this pathway is known to make a cell more like a stem cell," Guo says. "If you change this pathway's activity, how cancer progresses and how embryos develop have been shown to be very different. So we thought we could use this pathway to demonstrate how cell crowding is important."

A "refreshing" path

To see whether cell squeezing affects the Wnt pathway, and how fast a cell grows, the researchers grew small organoids -- miniature organs, and in this case, clusters of cells that were collected from the intestines of mice.

"The Wnt pathway is particularly important in the colon," Guo says, pointing out that the cells that line the human intestine are constantly being replenished. The Wnt pathway, he says, is essential for maintaining intestinal stem cells, generating new cells, and "refreshing" the intestinal lining.

He and his colleagues grew intestinal organoids, each measuring about half a millimeter, in several Petri dishes, then "squeezed" the organoids by infusing the dishes with polymers. This influx of polymers increased the osmotic pressure surrounding each organoid and forced water out of their cells. The team observed that as a result, specific proteins involved in activating the Wnt pathway were packed closer together, and were more likely to cluster to turn on the pathway and its growth-regulating genes.

The upshot: Those organoids that were squeezed actually grew larger and more quickly, with more stem cells on their surface than those that were not squeezed.

"The difference was very obvious," Guo says. "Whenever you apply pressure, the organoids grow even bigger, with a lot more stem cells."

He says the results demonstrate how squeezing can affect a organoid's growth. The findings also show that a cell's behavior can change depending on the amount of water that it contains.

"This is very general and broad, and the potential impact is profound, that cells can simply tune how much water they have to tune their biological consequences," Guo says.

Going forward, he and his colleagues plan to explore cell squeezing as a way to speed up the growth of artificial organs that scientists may use to test new, personalized drugs.

"I could take my own cells and transfect them to make stem cells that can then be developed into a lung or intestinal organoid that would mimic my own organs," Guo says. "I could then apply different pressures to make organoids of different size, then try different drugs. I imagine there would be a lot of possibilities."

In cities, humans replace the natural ground cover with roofs, pavement and other artificial materials that are impervious to water. These surfaces significantly change how the land absorbs and releases energy and cause the urban heat island effect, a phenomenon where developed areas get hotter than nearby rural areas. As climate change pushes many cities towards dangerous temperatures, planners are scrambling to mitigate excessive heat.

One strategy is to replace artificial surfaces with vegetation cover. In water-limited regions such as Utah, a state with one of the lowest annual rainfall rates in the United States, municipalities have to balance the benefit of cooler temperatures with using precious water for irrigation.

A new University of Utah study will make those decisions easier for the semi-arid Salt Lake Valley, the largest metropolitan area in Utah located in the northern part of the state. The researchers used 60 sensors to analyze the microclimate in five locations throughout the valley. They found that neighborhoods dominated by impervious surfaces were warmer and drier than the urban parks--up to 2 degrees warmer in both the daytime and nighttime.

"It's intuitive--we've all stood in a parking lot on a hot summer day, and you feel the heat from the ground. And when you're standing on a lawn, it's cooler," said lead author Carolina Gomez-Navarro, postdoctoral researcher at the U. "But we need to back up intuition with data to determine the best strategy for our semi-arid cities."

Gomez-Navarro and the team measured the temperature and humidity inside five parks and in their adjacent residential areas from June through August in 2016. They also analyzed how the surrounding landscape impacted air temperature. Surprisingly, they found that lawns reduced daytime and nighttime temperatures even more than trees did. While trees provide shade, lawns and turfgrass act like a swamp cooler--water moves through the plant, evaporating from tiny holes in the leaves and cooling the air.

Much of the heat that builds up during the day dissipates at night. The more open the land, the better heat can escape into the atmosphere. An area with many trees acts like a greenhouse, trapping heat close to the ground. The study concluded that a mixture of dispersed trees and grass is the most effective way to cool temperatures in the Salt Lake Valley.

"Understanding how ground cover impacts temperature is crucial for city planners to weigh the benefits and costs of its landscape design," said Gomez-Navarro. "This land used to be a valley of bushes and bare soil. Any vegetation we add is going to need lots of irrigation and modify the landscape in many ways."

The paper was published on October 13, 2020 in the journal Agricultural and Forest Meteorology.

Is the grass always greener?

Gomez-Navarro focused on five parks and the adjacent neighborhoods throughout the Salt Lake Valley: Hunter (northwest), Lone Peak (southeast), Midvale City (south central), Southridge (northwest) and Sugar House (northeast). Each location had 12 sensors that measured temperature and humidity: six within the park and six in the residential areas. Gomez-Navarro analyzed ground cover in a 10-meter diameter around each sensor using satellite images to estimate the percentage of the roofs, pavement, trees or turfgrass. She found that the more turfgrass in a given area, the lower the temperature.

She analyzed canopy cover by taking photos of the sky above each sensor with a fish eye lens. She used software that calculated the area that trees obstructed the sky. She found that the more open the landscape, the hotter the daytime temperature. The more canopy cover, the more shade reduced temperature.

The authors expected there to be temperature and humidity differences between the parks and neighborhoods. They were surprised, however, that turfgrass had nearly the same impact on air temperature as trees. It seems counterintuitive because of the difference between air temperature and perceived temperature. Perceived temperature is how humans feel the environment. Wind, air temperature, humidity and solar radiation all factor into how comfortable we are.

"We didn't measure human comfort in this study, but we know that the amount of solar radiation on our skin has a big impact on the perceived temperature," said Gomez-Navarro. "Even if the air temperature is the same, we feel much cooler under the shade of a tree because it blocks some of the radiation."

Smart city planning

Next, Gomez-Navarro will study how different landscapes directly affect how humans feel comfortable in their environment, and how plant cover type affect soil water loss.

"It's going to keep getting hotter and parks can be a refuge from the heat. But exactly how many degrees can they cool the air? And what should we plant to maximize this cooling?" said co-author Diane Pataki, professor of biology at the U. "It's getting easier and cheaper to measure temperature all over parks and neighborhoods, and we're going to need this information to make good decisions about future park designs."

Watching high quality nature programmes on TV can uplift people's moods, reduce negative emotions, and help alleviate the kind of boredom associated with being isolated indoors, according to a new study published today in the Journal of Environmental Psychology.

The research has also shown that experiencing nature in virtual reality could have even larger benefits, boosting positive feelings and increasing people's connection to the natural world.

Under laboratory conditions, researchers from the University of Exeter first induced feelings of boredom in 96 participants by asking them to watch a video in which a person describes their work at an office supply company. They then experienced scenes of an underwater coral reef in one of three different ways: on TV; in a VR headset using 360o video; and in a VR headset using computer generated interactive graphics.

The team found that all viewing methods minimised negative feelings such as sadness, as well as significantly reducing boredom. However, only the interactive virtual reality experience led to increases in positive feelings, such as happiness, and strengthened how connected people felt to nature.

Nicky Yeo, lead researcher on the study, believes the findings could have important implications for populations facing extended periods at home. She said:

"Our results show that simply watching nature on TV can help to lift people's mood and combat boredom. With people around the world facing limited access to outdoor environments because of COVID-19 quarantines, this study suggests that nature programmes might offer an accessible way for populations to benefit from a 'dose' of digital nature."

The team worked with the BBC Natural History Unit to create their experimental conditions, which featured several scenes from the Blue Planet II series, including unseen 360o footage. Their findings support initiatives seeking to bring the therapeutic potential of nature to people at home, such as BBC Four's recent Mindful Escapes series.

Dr Mathew White, co-author of the study, said:

"We're particularly excited by the additional benefits immersive experiences of nature might provide. Virtual reality could help us to boost the wellbeing of people who can't readily access the natural world, such as those in hospital or in long term care. But it might also help to encourage a deeper connection to nature in healthy populations, a mechanism which can foster more pro-environmental behaviours and prompt people to protect and preserve nature in the real world."

Non-alcoholic fatty liver disease, NAFLD, affects nearly one in four adults in Europe and the U.S. Earlier research has demonstrated an increased risk of death in patients with NAFLD and advanced fibrosis or cirrhosis. Now, researchers at Karolinska Institutet in Sweden and Massachusetts General Hospital in the U.S. show that mortality increases with disease severity, but even mild fatty liver disease is linked to higher mortality. The findings have been published in the scientific journal Gut.

Non-alcoholic fatty liver disease is often caused by obesity and affects nearly 25 percent of U.S. and European adults. It represents the most common cause of chronic liver disease in Western countries. Small clinical studies have demonstrated that among patients with NAFLD, advanced liver fibrosis is the most important histological predictor of mortality, but until now, population-level data have been missing from cohorts with liver histology.

Given the growing burden of NAFLD, researchers at Karolinska Institutet and Massachusetts General Hospital matched 10,568 individuals with biopsy-confirmed NAFLD to general population controls through Sweden's comprehensive, nationwide registers. They found that all stages of NAFLD were associated with excess mortality risk, even early stages of disease. This risk was driven primarily by deaths from extra-hepatic cancer and cirrhosis, while the risks of cardiovascular mortality or hepatocellular carcinoma (HCC) mortality were relatively modest.

Patients with NAFLD had a 93 percent increased risk of all-cause mortality, but the numbers varied with disease severity. The risk increased progressively from the mildest form of NAFLD (simple steatosis), to non-fibrotic steatohepatitis (NASH), to non-cirrhotic fibrosis and to severe NAFLD with liver cirrhosis.

"This is the first nationwide cohort study with detailed liver histology data to confirm that NAFLD contributes to an increased risk of all-cause mortality," says first author, Tracey G. Simon, researcher and hepatologist at Massachusetts General Hospital. "These findings should be used to develop more targeted interventions designed to reduce mortality, in patients with NAFLD. We need public health strategies that prevent both extra-hepatic cancer and NAFLD progression to cirrhosis, for this rapidly growing population."

The study builds on the ESPRESSO cohort (Epidemiology Strengthened by Histopathology Reports in Sweden). Histopathology data from more than two million people have been linked to nationwide Swedish registers such as the Patient Register, the Cause of Death Register, the Prescribed Drug Register and the Cancer Register.

"Through contacting all pathology departments in Sweden, we have managed to construct a nationwide gastrointestinal histopathology cohort that allows us to examine a range of gastrointestinal diseases, including NAFLD," says last author Jonas F. Ludvigsson, pediatrician at Örebro University Hospital and professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. "The current study on NAFLD and risk of death is the 17th study published this year that takes advantage of the ESPRESSO cohort."

The human blood meal is a favorite recipe for female mosquitoes. So drawn to its taste, they can't help but bite--and in the process they spread diseases that claim 500,000 lives each year.

Yet scientists aren't sure how the insects can even sense the complex taste of blood, or how they know that this, of all things, is something to gorge on. Nothing else, not even sweet nectar, makes them pump as ferociously as when they're draining our veins. "When a female mosquito punctures the skin, she sucks so hard that the capillaries sometimes collapse. It's a behavior she specifically reserves for blood," says Leslie Vosshall, neuroscientist at Rockefeller.

Now Vosshall and her colleagues have discovered what turns on this powerful blood pump. In a study published in Neuron, the team describes a unique group of neurons in the female mosquito's syringe-like stylet that don't seem to care about simple tastes like sweet or salty. Rather, they activate only when sugar, salt, and other components of blood are all present at once.

"These neurons break the rules of traditional taste coding, thought to be conserved from flies to humans," says Veronica Jové, a graduate student in Vosshall's lab who led the study. "We knew that the female stylet was unique, but nobody had ever asked what its neurons like to taste."

Homemade blood recipe

Vosshall, Jové, and colleagues began by perfecting their blood recipe. They started with sheep blood, which the mosquitoes swarmed to imbibe. When they exchanged the blood for sugar and saline solutions, the mosquitoes were no longer interested--even in the presence of heat and carbon dioxide, two cues that tell mosquitoes that humans are nearby. The scientists then served their picky eaters a mixture of glucose, salt, sodium bicarbonate, and adenosine triphosphate. The mosquitoes dined with gusto.

To see what's special about the combination of these four ingredients, the researchers first tested how mosquito stylets responded to each component. "There are two neat rows of sensory neurons on both sides of the stylet," Jové says. "We delivered just the tiniest microfluidic drop to the tip of the stylet, and recorded which neurons responded."

Glucose, a sugar that is prominent in both nectar and blood, did not consistently activate any stylet neurons. The other three ingredients, which are unique to blood, each individually activated a specific group of neurons. But one prominent cluster of neurons did not respond to any individual ingredient; it only activated when the entire blood recipe was delivered at once--almost like being unable to taste coffee, milk, or sugar individually, unless all ingredients are stirred together.

The scientists call this group the integrator neurons because they seem to combine signals from several taste components, acting as the final arbiters in the decision to activate the pump for blood rather than nectar or water.

A syringe that can taste blood

Of the forty neurons lining a mosquito's stylet, only half appear to be activated by blood. Future studies will examine the function of those remaining neurons, which may be involved in detecting unique flavors that appear only when the stylet pierces a capillary.

The findings have far-reaching implications for basic science. The study opens the door to further examination of a novel form of taste detection, and provides fascinating insight into how specialist species like mosquitoes develop unique feeding strategies. "The real beauty of this study is: how cool is it that we found a syringe that can taste blood?!" says Vosshall.

A hormone that influences when and how frequently animals eat also appears to affect memory, USC scientists have found.

The study was published in the journal Current Biology on Sept. 17.

Animals and humans have the hormone ghrelin in their stomachs. Ghrelin tells animals, as well as humans, when they are hungry and helps regulate their metabolism, but scientists have never been certain how exactly it works.

To learn more about how ghrelin influences hunger, metabolism and memory, researchers at the USC Dornsife College of Letters, Arts and Sciences collaborated with international scientists on a study on rats.

They disrupted the ability of the ghrelin hormone to communicate to the vagus nerve, a nerve that signals from the gut to the brain, and then monitored the impact on their feeding and cognitive behaviors.

The rats were not anxious, but they began eating more frequently, said the study's lead and corresponding author Scott Kanoski, an Associate Professor of Biological Sciences at USC Dornsife.

The lack of ghrelin signaling to the vagus nerve "not only disrupted their blood glucose regulation, but they also gained more weight," Kanoski said.

"But it didn't seem to be affecting how much food they ate," he added. Instead, "they increased their frequency of eating, so that they consumed more meals and they compensated for that by reducing the size of their meals."

"We think that the increased eating frequency is related to their memory impairment. Memory from when you last ate will influence how soon you eat again. It led the rats in our study to eat sooner," said Kanoski.

Although the rats were able to remember where they had gotten food, they appeared to have forgotten that they had just eaten. Their stomachs were also slower to empty.

"The animals were impaired in a certain type of memory, called episodic memory," said study co-author Elizabeth Davis who was a post-doctoral researcher in Kanoski lab at USC Dornsife. "This is the type of memory that helps you remember your first day of school, or what you ate for breakfast yesterday.?

Davis said scientists are trying to learn more about ghrelin signaling through the vagus nerve because it may help researchers develop better therapies for metabolic-related diseases such as obesity and diabetes or other metabolic diseases, as well as others such as epilepsy and Alzheimer's disease.

However, "a great deal of further research will be needed to uncover how manipulation of ghrelin signaling through the vagus nerve may be valuable in human medicine," said Davis, who recently left USC for a private pharmaceutical company after completing her post-doctoral degree in biological sciences.

Dendritic spines are small protrusions from a neuron's dendrite membrane, where contact with neighboring axons is formed to receive synaptic input. These spines have different sizes, shapes, and density. Changes in the characteristics of the dendritic spines are associated with learning and memory and could be a feature of neurodegenerative disorders like Alzheimer's disease and Huntington's disease. Due to the prominent importance of synaptic contacts, researchers put efforts into reliable visualization and analysis of the dendritic spines. Latter requires dividing them into groups based on the key morphological parameters.

Scientists from Peter the Great St.Petersburg Polytechnic University (SPbPU) in collaboration with UT Southwestern Medical Center at Dallas, TX, examined a novel approach to analyzing the dendritic spine shapes. Unlike the standard approach of dividing them into three or four predefined subclasses, they suggest considering the clusterization approach. The perspective and potential limitations of using a clusterization approach were published in the journal Frontiers in Synaptic Neuroscience.

Methods for analyzing and understanding the morphology of dendritic spines are critically important for many fields of neuroscience. Between axonal bouton and spines, there is a contact zone for transmission of information from one neuron to another. Despite the fact that neurons and dendrites are rather stable structures, the synaptic spines are very plastic and prone to changes.

"Dendritic spines are quite separate structures living on their own terms. They could change in response to neuronal activity. The strength and number of synaptic connections are correlated with learning and memory. Decreasing in quality or number of synaptic contacts could be a diagnostic feature of early-stage pathological processes. The first symptoms of neurodegeneration could appear much later because our brain has a certain margin of safety", - said Ekaterina Pchitskaya, postdoctoral fellow of Laboratory of molecular neurodegeneration at SPbPU.

Scientists studied relationships between dendritic spines shape, density, and functions. Previous studies mostly rely on the classification approach. It suggests that spines are divided into fixed categories such as thin, mushroom, and stubby. Mushroom spines have a large head and a small neck, separating them from a dendrite. They form strong synaptic connections, have a long lifetime, and thought to be connected with long-term memory. Thin spines have a similar structure, but their head is smaller relative to the neck. Researchers suppose they are responsible for forming new memories. Stubby spines usually do not have a neck. They are known to be the predominant types in the early stages of postnatal development but also could be found in adults as the result of the disappearance of the mushroom spines.

"We concluded that the classification approach is quite rough and suggest to address the highly dynamic nature of spines as a continuum of different shapes. Because of this, we decided to apply algorithms that rely on clusterization. We know quite well the association between the main dendritic subclasses and their functionality. Now there is a challenge to find a link between a concrete shape and functions of the spines", - added Ekaterina Pchitskaya.

Different types of microscopy were applied to obtain images of spines from cultured neurons, fixed brain slices, and intact brain tissue. These include two-photon, confocal, laser, and super-illumination or SIM microscopy. In previous studies, images of the dendritic spines were mainly investigated in 2D projection.

Scientists noted that research of the clusterization approach in dendritic spines' analysis is still at the early stage but is a very perspective approach that will be further developed by scientists in near future. "The size of dendritic spines is very small and comparable to the resolution of a confocal microscope. We need to achieve high-quality 3D images to define the key morphological parameters that will allow us to collect important data on dendritic spines changes. Thus we would be able to apply different algorithms of the clusterization and compare results", - noted Ekaterina Pchitskaya.

Natural killer T (NKT) cells, a type of immune cells known for their potent anti-cancer properties in murine tumor models, have been developed into a novel form of immunotherapy to treat patients with cancer.

Researchers at Baylor College of Medicine and the University of North Carolina at Chapel Hill have genetically modified human NKT cells with a chimeric antigen receptor (CAR) that enables them to specifically recognize and attack neuroblastoma, a form of childhood cancer. Expressed with the CAR is interleukin-15 (IL-15), a natural protein that supports NKT cell survival.

In the study, appearing in Nature Medicine, researchers present interim results from an ongoing clinical trial showing that the modified cells are safe, localize to tumors, and, in one of three patients, induced an objective response with regression of bone metastatic lesions.

Enhancing the tumor-fighting capabilities of NKT cells

The earliest CAR-modified cells were immune T cells. CAR T cells have been proven to be effective in treating certain types of leukemia and lymphoma. However, a number of challenges have been encountered in attempts to treat solid tumors with CAR T cells. Preclinical studies have demonstrated that NKT cells offer a novel approach that may enhance CAR-directed cancer immunotherapy.

"In addition to being able to effectively combat tumors in mouse models, the presence of NKT cells within solid tumors is associated with favorable outcomes in cancer patients," said co-corresponding author Dr. Leonid Metelitsa, professor of pediatric oncology at Baylor and Texas Children's Hospital and member of Baylor's Dan L Duncan Comprehensive Cancer Center.

Previous work has shown that NKT cells have a spectrum of anti-tumor activities. For instance, these cells migrate to tumor sites where they kill tumor-associated macrophages, a type of immune cell that can promote tumor growth and metastasis. Moreover, NKT cell activation indirectly promotes an anti-tumor response mediated by two other types of immune cells, NK and T cells.

"We think that NKT cells have substantial potential to serve as valuable contributors to the fight against cancer," said co-corresponding and first author Dr. Andras Heczey, assistant professor of pediatric oncology at Baylor and Texas Children's and member of the Dan L Duncan Comprehensive Cancer Center. "For the last 10 years, we have been focused on enhancing these cells' tumor-fighting abilities with the ultimate goal of bringing them to the clinic."

Preparing NKT for clinical trials

The journey to develop NKT cells into a form of immunotherapy involved finding solutions for a number of challenges. For example, NKT cells represent a low percentage of the cells in the blood, so Metelitsa, Heczey and their colleagues developed methods to grow NKT cell populations to clinical scale with high purity.

Although NKT cells can combat tumors in several ways, they all seem to be indirect. "Working with Dr. Gianpietro Dotti at UNC, we gave NKT cells a tool - the CAR - that enables them to attack tumors directly," Metelitsa said. "We also equipped them with IL-15, an additional tool to help them survive in the patient while they fight the tumor."

"The field of CAR cellular immunotherapy for cancer has been focused to date primarily on the manipulation of T lymphocytes," said Dotti, professor and director of cancer cellular immunotherapy at UNC Lindberger Comprehensive Cancer Center. "Based on previous clinical evidence that NKT infiltration within the tumor correlates with favorable clinical outcomes, we decided to leverage this intrinsic property of NKTs and to arm them with an additional bullet - the so-called CAR - to further potentiate their capacity to destroy the tumor."

With all these innovations in hand, the researchers moved on to test CAR NKT cells in patients with neuroblastoma in a clinical trial.

Clinical results

The clinical trial is ongoing, and results from the first three patients with heavily pre-treated, relapsed/refractory metastatic neuroblastoma are presented in this study. The patients were treated with CAR NKT cells, engineered from the patient's own white blood cells at the Center for Cell and Gene Therapy at Baylor and Texas Children's. Researchers engineered 95 percent pure NKT cells, a portion of which was armed with CAR-IL15.

"Our initial results show that NKT cells can be expanded to clinical scale with high purity, genetically engineered to express a CAR and IL15, and used to safely treat patients with advanced neuroblastoma," Metelitsa said.

"In addition, we found that CAR-IL15 NKT cells can be detected in the peripheral blood, where they expand postinfusion, traffic to bone metastases and the bone marrow, and exert anti-tumor activity," Heczey said. "We observed an objective response, elimination of at least 50 percent of metastases, in one of the patients."

Dr. Antonio Montalbano and other co-authors from Immunai, a company specializing in single-cell technologies and AI approaches for immunology, applied its state-of-the-art technology platform that allows for the analysis of all genes at the single-cell level in the CAR-NKT patient products. These analyses revealed new information about the heterogeneity of human NKT cells and molecular details of their therapeutic modifications. The researchers discovered nine subsets of NKT cells, and that the CAR receptor seemed to go preferentially to one set identified as cluster 3. Further studies will help understand the implications of these findings.

"Our study shows that it is possible to employ immune cells with natural anti-tumor capabilities and enhance their tumor fighting power with designer synthetic receptors, opening the possibility of applying this strategy to combat hard-to-treat solid tumors," Metelitsa said.

"By leveraging Immunai's end-to-end platform of artificial intelligence and computational analysis, we were able to zero in on CAR engineered NKT cells from the patients at the single-cell level. The findings from this study are critical toward developing more precise and effective therapies for cancer patients," said Montalbano, genomics technologies lead at Immunai. "We're looking forward to continuing our research with Baylor with the goal of advancing therapeutic discoveries, accelerating drug development and improving patient outcomes."

The NKT platform developed in this research at Baylor has been licensed to Kuur Therapeutics to advance clinical development.

"The Baylor-Kuur Therapeutics relationship is generating exactly the type of outcomes that we had envisioned at the outset," said Shawn Davis, vice president and chief ventures officer at Baylor. "The modified NKT platform developed in the Metelitsa laboratory is differentiated from other cell therapy platforms, offering novel routes for the treatment of cancers that have posed challenges for immunotherapeutic approaches. The encouraging findings announced today support the potential of NKT platform to provide promising alternatives, particularly for the treatment of solid tumors."

A new study looking at data from tens of thousands of children with asthma finds that several widely available interventions are associated with both reduced medical costs and a reduced likelihood that the children will need to visit an emergency room or stay in the hospital.

"This work shows that you can improve the quality of life for children with asthma and you can reduce government spending by implementing these proactive interventions," says Julie Swann, lead author of the study. Swann is the department head and A. Doug Allison Distinguished Professor of the Fitts Department of Industrial and Systems Engineering at North Carolina State University.

The researchers looked at data from 2010 and 2011 on more than 70,000 children with asthma enrolled in the Medicaid programs in New York and Michigan. The researchers focused on four interventions: asthma self-management education (ASME); flu vaccine; the use of spacers, which are low-cost plastic tubes that improve the performance of inhalers; and the use of nebulizers, which are devices that convert liquid medicine into an aerosol that patients can inhale.

Specifically, the researchers analyzed the data to understand the extent to which each of these interventions was associated with three outcomes: asthma-related visits to the emergency room; asthma-related visits to a primary-care physician; and asthma-related stays in the hospital. The researchers also assessed the extent to which each intervention influenced costs associated with each child's asthma medication and so-called "utilization costs" - which are the costs associated with other aspects of a child's asthma treatment, such the cost of visiting a primary-care provider or hospital.

To address these questions, the researchers plugged the healthcare data into models that allowed them to assess the impact of each intervention separately, compared to no intervention.

"One of the key findings, which should be of interest to policymakers, is that all four interventions were associated with lower medication costs and utilization costs," Swann says.

And while the numbers varied between states, the decreases in cost could be substantial. For example, being vaccinated against the flu was associated with a 16.4% reduction in utilization expenses and a 15.6% reduction in medication expenses for children in New York. "There can be significant cost reductions associated with a fairly inexpensive intervention," Swann says.

"Our results suggest that ASME training, and the use of spacers and nebulizers, are also associated with significant decreases in both emergency room visits and hospitalizations," says study co-author Pinar Keskinocak. "And the flu vaccine helps reduce the number of visits to a child's primary care provider." Keskinocak is the William W. George Chair and Professor in Georgia Tech's H. Milton Stewart School of Industrial and Systems Engineering and the director of the Center for Health and Humanitarian Systems at Georgia Tech.

"It's important to note that we looked at the impact of these outcomes separately while accounting for other interventions," Swann says. "You would expect that the more of these pro-active interventions a child has, the greater the positive impact we would expect to see on both their health and on what Medicaid would be asked to spend on their care."

(Vienna, October 13, 2020) A revolutionary endoscopic therapeutic procedure may lead to the discontinuation of insulin treatment in a significant number of people with type 2 diabetes, new research presented today at UEG Week 2020 Virtual has shown.

Researchers from the Netherlands tested a novel, minimally-invasive ablation procedure, which rejuvenates the lining of the duodenum, in combination with daily doses of glucose lowering drugs called glucagon-like peptide agonists (GLP-1 RAs) and mild lifestyle counselling. The study found that 75% of previously insulin-dependent people with type 2 diabetes treated with the ablation technique did not need insulin six months later, with HbA1c (a long-term parameter of glucose control) readings of 7.5% or below. HbA1c readings also fell to 6.7% at 12 months.

Patients who responded to the treatment also saw significant reductions in their body mass index (BMI), which was down from an average of 29.8 kg/m2 at the beginning of the research to 25.5 kg/m2 after 12 months. The percentage of fat in their livers also decreased from 8.1% to 4.6% at 6 months. Obesity and fatty liver are both important risk factors in the development of metabolic syndrome, a term that encompasses diabetes, high blood pressure (hypertension), obesity, and high triglycerides.

In the non-responder patients, who still needed insulin, the median insulin dose they required fell by more than half (from 35 units per day at study entry to 17 units per day at 12 months).

The minimally-invasive technique, called Duodenal Mucosal Resurfacing (DMR), is performed in an outpatient setting and is delivered via an integrated over-the-wire catheter attached to a custom console that performs a synchronized lifting of the duodenal mucosa and then ablation of the treatment area. Although the process is not yet fully understood, mucosal cells are believed to undergo alterations in a response to unhealthy diets, high in fat and sugar. This leads to changes in the production and signalling of key hormones that impact insulin resistance and diabetes. Resurfacing the lining appears to rejuvenate and reset this process.

The pilot study, undertaken in 16 patients, was led by Dr Suzanne Meiring, Dr. Annieke van Baar, and Professor Jacques Bergman from the Amsterdam University Medical Center in the Netherlands.

Dr Meiring explained: "This could be a game-changing approach in the treatment of metabolic syndrome. A single endoscopic DMR ablation with GLP-1 drugs and lifestyle counselling can lead to discontinuation of insulin therapy in a subset of patients with type 2 diabetes, while improving their blood glucose control and overall metabolic health. Many patients with type 2 diabetes are very happy to be able to discontinue insulin therapy, since insulin therapy comes with weight gain and hypoglycaemic events. Our earlier study, (Revita-1) with patients that used only oral medication for their diabetes type 2, showed that the effect of a single DMR was comparable to adding one glucose lowering drug."

There are about 60 million people in Europe with diabetes and the vast majority (around 90%) of cases are type 2. As well as age and a family history of the condition, high blood pressure and being overweight are major risk factors for type 2 diabetes.

"Based on the results of this study, a large international randomised controlled trial, called Revita T2Di Pivotal, will soon start to further investigate its effectiveness in greater numbers", added Dr Meiring.

In Alzheimer's disease, impaired blood flow to brain regions coincides with tau protein buildup. This relationship strengthens as cognition declines, according to new research published in JNeurosci.

Vascular function declines and amyloid-β and tau protein accumulate as Alzheimer's disease progresses, resulting in neuron death. Like the proverbial chicken and egg, it remains unclear if impaired blood flow causes or is caused by errant protein buildup, or if the two symptoms occur for unrelated reasons.

Albrecht et al. used MRI and PET to compare blood flow and tau buildup in the brains of older adults, with cognition ranging from cognitively normal to showing signs of mild cognitive impairment. Areas with increased tau levels had diminished blood flow, particularly in the inferior temporal gyrus, one of the first regions to show tau buildup in Alzheimer's disease, even before cognitive symptoms manifest. The relationship held true for a separate data pool from the Alzheimer's Disease Neuroimaging Initiative, which included people with mild cognitive impairment and Alzheimer's dementia. The correlation between tau and vascular function was stronger in people with greater cognitive impairment and higher amyloid-β levels. It also appeared in more brain regions as the disease progressed in severity. These findings suggest targeting vascular function could be key to preventing and treating Alzheimer's dementia.

Below please find summaries of new articles that will be published in the next issue of Annals of Internal Medicine. The summaries are not intended to substitute for the full articles as a source of information. This information is under strict embargo and by taking it into possession, media representatives are committing to the terms of the embargo not only on their own behalf, but also on behalf of the organization they represent.

1. Nearly 1 in 8 patients receive unexpected out-of-network bills after colonoscopy

Abstract: https://www.acpjournals.org/doi/10.7326/M20-2928
URL goes live when the embargo lifts

Nearly 1 in 8 commercially insured patients nationwide who underwent an elective colonoscopy between 2012 and 2017 performed by an in-network provider received potential "surprise" bills for out-of-network expenses, often totaling hundreds of dollars or more. These findings are concerning, as federal regulations eliminate consumer cost-sharing when screening colonoscopies are performed in-network. A brief research report is published in Annals of Internal Medicine.

Colonoscopy is the most effective colorectal cancer prevention strategy. However, researchers suggest that surprise billing may deter patients from getting recommended screening.

Researchers from the University of Virginia and the University of Michigan reviewed 1.1 million claims from a large national insurer to estimate the prevalence, amount, and source of out-of-network claims for commercially insured patients having an elective colonoscopy when all of the endoscopists and facilities were in-network. The researchers found that 12.1 percent of cases received out-of-network claims, with an average surprise bill of $418. The bills often came because of the use of out-of-network anesthesiologists and out-of-network pathologists.

The researchers suggest that to spare patients surprise bills, endoscopists and hospitals should partner with anesthesia and pathology providers who are in-network, and they should consider cost-saving strategies such as endoscopist-provided sedation rather than use of deeper anesthesia. They also suggest that not all low-risk polyps need to be sent for pathological evaluation, which could offer further savings.

Media contacts: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. To reach the corresponding author, James M. Scheiman, MD., please contact Joshua Barney at JDB9A@hscmail.mcc.virginia.edu.

2. Excess Days in Acute Care provide a more comprehensive picture of hospital performance compared to 30-day readmission rates
Using the EDAC measurement would change penalty status for about one-quarter of hospitals

Abstract: https://www.acpjournals.org/doi/10.7326/M19-3486
Editorial: https://www.acpjournals.org/doi/10.7326/M20-6254
URL goes live when the embargo lifts

The Excess Days in Acute Care (EDAC) measure provides a more comprehensive assessment of hospital performance compared to the 30-day readmission measure, which is currently used by the Centers for Medicare and Medicaid Services (CMS) to evaluate quality in the Hospital Readmissions Reduction Program (HRRP). Using the EDAC measure in the HRRP would change penalty status for about one-quarter of hospitals. These findings are published in Annals of Internal Medicine.

CMS currently uses 30-day readmission rates to evaluate hospital performance and to issue penalties to those that underperform. Hospitals have been penalized more than $3 billion to date under the HRRP. However, the 30-day readmission measure has increasingly been scrutinized because it provides an incomplete picture of hospital visits after discharge. In contrast, the EDAC measure captures all hospital encounters - inpatient, Emergency Department, and observation stays - that occur within 30-days of discharge and provides a more comprehensive picture of performance.

Researchers from Beth Israel Deaconess Medical Center studied more than 3,100 hospitals that participated in the HRRP in fiscal year 2019 to compare whether using the EDAC measure instead of readmissions would change hospitals' penalty status for three conditions targeted by the HRRP. They found that one-quarter of hospitals' penalty status would change if the EDAC measure were used instead of the readmission measure in the program. In addition, fewer small hospitals and rural hospitals would receive financial penalties if the EDAC measure were used. According to the study authors, these findings suggest that CMS should consider using the EDAC measure rather than the 30-day readmission measure to evaluate health care system performance under federal quality reporting and value-based programs.

Media contacts: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. To speak with the corresponding author, Rishi K. Wadhera, MD, MPP, please contact Lindsey Diaz-MacInnis at ldiaz2@bidmc.harvard.edu.

PRINCETON, N.J.--As the planet continues to warm, people living in the world's most vulnerable regions -- like arid or low-lying nations -- must contend with the decision to stay in a place where livability is decreasing or leave for countries with more stable climate and economic conditions.

New Princeton University research suggests that restrictive border policies could increase many people's vulnerability to extreme climate conditions and weaken economic prosperity by limiting their ability to emigrate from countries that are facing worsening conditions due to climate change, such as drought, heat waves, and rising seas.

When allowed to move freely, however, both migrants and the developing countries from which they came are less vulnerable and better off financially, the researchers reported in the journal the Proceedings of the National Academy of Sciences.

The researchers built migration into a standard model typically employed by policymakers to estimate the social cost of carbon and other climate change effects, explained co-lead author Hélène M. Benveniste, a Ph.D. candidate at the Princeton School of Public and International Affairs (SPIA).

"In discussions about international migration and global climate policy, it seemed that many were looking through the lens of the people coming in, focusing only on the destination country, and not what it would mean for both the migrant population and origin countries," said Benveniste, who was supported by the Princeton Energy and Climate Scholars program based in the Princeton Environmental Institute (PEI). "Our work shows these conversations need to be brought closer together."

Benveniste conducted the work with Michael Oppenheimer, the Albert G. Milbank Professor and Geosciences and International Affairs and the PEI, and Marc Fleurbaey, a professor at the Paris School of Economics who conducted the work as a Princeton professor.

The researchers centered their work around two questions: What does exposure to climate change mean for people around the world, as well as their ability to deal with the impacts? And who would be able to move, and who would be constrained to stay?

They employed a standard climate-global economy model known as the Integrated Assessment Models, which typically includes a simplified representation of migration. In their version of the model, they included dynamics for both migration and remittance, cash being exchanged between people in the two countries. Remittance is an important feature of the model, as cash received from family members abroad can be a powerful resource in developing countries.

Money can also help people prepare for the effects of climate change. The researchers measured "exposure" to climate change by quantifying how people might be affected by it, where they are and where they might go, as well as how much money they might have.

First, they tested the accuracy of the model by looking at different border policies, making them both easier and more difficult to cross than they are today. They also investigated the effects of these border policies on different income levels and on people's ability to relocate.

Then, using actual migration flows compiled by past researchers and derived from the World Bank, they made projections up until the year 2100. Using what scientists call a "gravity model," they took into account economics, demography, migration and income differences between places to determine the number of people moving.

They found that exposure and vulnerability to impacts of climate change tend to be higher in developing countries. Over the 21st century, most migrants from these developing countries tend to move to areas where they are less exposed to such impacts than where they came from. The researchers can't say how many of these migrants moved because of climate change, as many relocated for other financial reasons as well.

The results also show that open borders have a positive impact on developing countries themselves, especially in places like Central America, Southeast Asia, and small island nations. When people are allowed to move freely, they tend to send more money "back home," which provides an important source of income for the origin country. This income could also be used to reduce vulnerability to climate change.

Researchers at SPIA have been studying the relationship of climate change to migration for more than a decade using a variety of modeling approaches. "Our motivation in projecting climate-related migration is to provide a basis for public policy that will improve outcomes for migrants and for people at migration destinations as well as the communities they left behind," Oppenheimer said.

Fewer college-age Americans drink alcohol, compared to nearly 20 years ago, according to a new study.

Between 2002 and 2018, the number of adults aged 18-22 in the U.S. who abstained from alcohol increased from 20% to 28% for those in college and from about 24% to 30% for those not in school, say researchers at the University of Michigan and Texas State University. And alcohol abuse among both groups decreased by roughly half.

However, the study found that the number of young adults using marijuana, as well as co-using alcohol and marijuana, has increased.

Overall, the mixed findings show more positive than negative trends for alcohol and marijuana use and misuse among this age group, but the progression still bears close monitoring, the researchers say.

The study, appearing in JAMA Pediatrics Oct. 12, examined how alcohol and marijuana abstinence, co-use and use disorders have changed in 18-to-22-year-olds as a function of college status, using data from a nationally representative survey of 182,722 young adults. It also looked at prescription drug use and misuse as a function of alcohol and marijuana use, from 2015 to 2018.

The researchers were particularly surprised at the drop in alcohol use and misuse.

"We're encouraged by the significant decreases in alcohol use disorder--for both college and noncollege students," said lead author Sean Esteban McCabe, director of the Center for the Study of Drugs, Alcohol, Smoking and Health at the U-M School of Nursing.

"The prevalence of alcohol use disorder in both groups in 2018 was roughly half of what it was in 2002. We are excited to learn about these drops in disordered drinking, as alcohol-related consequences are one of the leading causes of mortality and morbidity for young adults."

Co-author Ty Schepis, professor of psychology at Texas State, said "even with increases in marijuana use disorder and co-use of alcohol and marijuana, there is a lot of hope in our study's results."

"Points of concern that deserve more attention are the rise in co-use of alcohol and marijuana, as we know that polysubstance use can have more negative consequences and be more difficult to treat," he said.

The study also found that more than three-fourths of those who had disordered use of both alcohol and marijuana reported past-year prescription drug use and illicit drug use, while the majority reported prescription drug misuse.

The findings indicate that the substance use landscape has changed over the past 20 years, with more young adults using or misusing several different substances, as opposed to just marijuana or alcohol.

"For example, from 2015 to 2018, only 2.5% of young adults who abstained from both alcohol and marijuana reported misusing prescription drugs, while 25.1% of co-users misused prescription drugs," Schepis said. "That is a tenfold difference with potentially dangerous consequences."

Abusing multiple substances is often more dangerous than abusing a single substance.

"Interventions that focus solely on one substance will be less effective than interventions that take a more holistic polysubstance use perspective," McCabe said. "The findings of our study reinforce the complex task health professionals have of detecting and developing effective interventions to reduce consequences associated with polysubstance use, such as co-use of alcohol and marijuana."

Schools and employers may require more resources to scale interventions to address both young adults with and without a disorder, including screening and brief interventions for co-use of alcohol and marijuana, McCabe said.

"The finding that abstinence is increasing among college students and young adults not in college is very important for U.S. colleges and universities to take into account moving forward," he said. "These findings reinforce the importance of the need to support those young adults in recovery and abstinence for other reasons. There are over 1 million U.S. young adults in recovery and a wide variety of resources are needed to support these individuals."

In first-of-their-kind observations in the human brain, an international team of researchers has revealed two well-known neurochemicals -- dopamine and serotonin -- are at work at sub-second speeds to shape how people perceive the world and take action based on their perception.

The discovery shows researchers can continually and simultaneously measure the activity of both dopamine and serotonin -- whose receptor and uptake sites are therapeutic targets for disorders ranging from depression to Parkinson's disease -- in the human brain.

Furthermore, the neurochemicals appear to integrate people's perceptions of the world with their actions, indicating dopamine and serotonin have far more expansive roles in the human nervous system than previously known.

Known as neuromodulators, dopamine and serotonin have traditionally been linked to reward processing -- how good or how bad people perceive an outcome to be after taking an action.

The study online today in the journal Neuron opens the door to a deeper understanding of an expanded role for these systems and their roles in human health.

"An enormous number of people throughout the world are taking pharmaceutical compounds to perturb the dopamine and serotonin transmitter systems to change their behavior and mental health," said P. Read Montague, senior author of the study and a professor and director of the Center for Human Neuroscience Research and the Human Neuroimaging Laboratory at the Fralin Biomedical Research Institute at Virginia Tech Carilion. "For the first time, moment-to-moment activity in these systems has been measured and determined to be involved in perception and cognitive capacities. These neurotransmitters are simultaneously acting and integrating activity across vastly different time and space scales than anyone expected."

Better understanding of the underlying actions of dopamine and serotonin during perception and decision-making could deliver important insight into psychiatric and neurological disorders, the researchers said.

"Every choice that someone executes involves taking in information, interpreting that information, and making decisions about what they perceived," said Kenneth Kishida, a corresponding author of the study and an assistant professor of physiology and pharmacology, and neurosurgery, at Wake Forest School of Medicine. "There's a whole host of psychiatric conditions and neurological disorders where that process is altered in the patients, and dopamine and serotonin are prime suspects."

Lack of chemically specific methods to study neuromodulation in humans at fast time scales has impeded understanding of these systems, according to Montague, who is an honorary professor at the Wellcome Center for Human Neuroimaging at University College London and a professor of physics at the Virginia Tech College of Science.

But now, in first-ever measurements, scientists used an electrochemical method called "fast scan cyclic voltammetry," which employs a small carbon fiber microelectrode that has low voltages ramped across it for real-time detection of dopamine and serotonin activity.

In the study, researchers recorded fluctuations in dopamine and serotonin using specially designed electrodes in five patients undergoing deep brain stimulation electrode implantation surgery to treat essential tremor or Parkinson's disease. Patients were awake during surgery, playing a computer game designed to quantify aspects of thought and behavior while the measurements were taken.

On each round of the game, patients briefly viewed a cloud of dots and were asked to judge the direction they were moving. The method, designed by corresponding author Dan Bang, a Sir Henry Wellcome Postdoctoral Fellow, and Steve Fleming, a Sir Henry Dale/Royal Society Fellow, both at the Wellcome Center for Human Neuroimaging at University College London, helped indicate that dopamine and serotonin were involved in simple perceptual decisions, outside of the traditional context of rewards and losses.

"These neuromodulators play a much broader role in supporting human behavior and thought, and in particular they are involved in how we process the outside world," Bang said. "For example, if you move through a room and the lights are off, you move differently because you're uncertain about where objects are. Our work suggests these neuromodulators -- serotonin in particular-- are playing a role in signaling how uncertain we are about the outside environment."

Montague and Kishida, along with Terry Lohrenz, a research assistant professor, and Jason White, a senior research associate, now both at the Fralin Biomedical Research Institute, started working on a new statistical approach to identify dopamine and serotonin signals while still at the Baylor College of Medicine in Houston, Texas.

"Ken rose to the challenge of doing fast neurochemistry in human beings during active cognition," Montague said. "A lot of other good groups of scientists were not able to do it. Aside from the computation of enormous amounts of data, there are complicated issues to solve, including great, fundamental algorithmic tasks."

Until recently, only slow methodologies such as PET scanning could measure the impact of neurotransmitters, but they were nowhere near the frequency or volume of the second-to-second measurements of fast scan cyclic voltammetry.

The measurements in the new study were taken at the Wake Forest Baptist Medical Center, and involved neurosurgical teams led by Adrian W. Laxton and Stephen B. Tatter.

"The enthusiasm the neurosurgeons have for this research is derived from the same reasons that drove them to be doctors -- first and foremost, they want to do the best for their patients, and they have a real passion for understanding how the brain works to improve patient outcomes," said Kishida, who oversaw the data collection in the operating room during the surgeries. "Both are collaborative scientists along with Charles Branch, the chair of the neurosurgery department at Wake Forest, who has been an amazing advocate for this work."

Likewise, Montague said, "You can't do it without the surgeons being real, shoulder-to-shoulder partners, and certainly not without the people who let you make recordings from their brains while they are having electrodes implanted to alleviate the symptoms of a neurological disorder."

Montague had read a study in the Proceedings of the National Academy of Sciences that prompted him to approach colleagues Bang and Fleming at University College London to tailor a task for patients to perform during surgery that would reveal sub-second dopamine and serotonin signaling in real-time inference about the external world - separate from their often-reported roles in reward-related processes.

"I said I have this new method to measure dopamine and serotonin, but I need you to help with the task," Montague said. "They ended up in the study. The research really took a lot of hard work and an integrated a constellation of people to obtain these results."

The research was funded by grants to various researchers from the Wellcome Trust, the National Institutes of Health including the National Institute on Drug Abuse, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke.