Culture

Air pollution has been a problem in Utah since before the territory was officially recognized as a state. The mountain valleys of this high elevation region are particularly vulnerable to the buildup of air pollution from vehicles, household heating and power production. Together with high per-capita energy use, this has resulted in periods of poor air quality. However, with so many types of pollution and regional conditions, determining the overall effects of air pollution on Utah's health and economy has been a major challenge. A new study from 23 Utah-based researchers, including five from the University of Utah, sought to do just that.

The study estimated that air pollution shortens the life of the average Utahn by around 2 years. And pollution costs Utah's economy around $1.9 billion annually. But many state-level actions, such as increasing vehicle and building efficiency, could reduce air pollution by double-digit percentages while benefitting the economy, the researchers found.

The team used an approach called expert assessment, which combines all available research and experience from published and unpublished scientific studies. Combining expertise from public health, atmospheric science and economics, the researchers assessed what types of disease and economic harm could stem from Utah's air pollution. The study was published in the peer-reviewed journal Atmosphere in a special issue on air quality in Utah.

They estimated that air pollution in Utah causes between 2,500 and 8,000 premature deaths each year, decreasing the median life expectancy of Utahns by 1.1 to 3.6 years. This loss of life expectancy is distributed across most of the population, they found, rather than only affecting "sensitive groups." For example, 75% of Utahns may lose 1 year of life or more because of air pollution and 23% may lose 5 years or more.

This substantial health burden is caused by many illnesses and conditions that most people might not associate with air pollution. For example, exposure to particulates and other pollutants increases occurrence of heart and lung diseases, including congestive heart failure, heart attack, pneumonia, COPD and asthma. These conditions account for 62% of the pollution impact on health, according to this study. The remaining 38% of health effects are associated with stroke, cancer, reproductive harm to mothers and children, mental illness, behavioral dysfunction, immune disease, autism and other conditions--all exacerbated by exposure to dirty air.

On the economic side, the researchers estimated that the direct and indirect costs of air pollution cost Utahns around $1.9 billion dollars (in the range of $0.75-3.3 billion) annually. This economic damage results from direct effects such as healthcare expenses, damage to crops and lost earning potential, in addition to indirect costs such as loss of tourism, decreased growth and regulatory burdens.

"It was a real eye-opener to see quantitative estimates of how serious the health and economic costs of air pollution are for the people of Utah," said Isabella Errigo, lead author and a graduate student at Brigham Young University. "The consequences of dirty air can seem very abstract until you read the medical research connecting the quality of our environment to our personal health."

Even though the estimates of cost in this study are on the low end of national estimates, which range up to $9 billion a year for Utah, they are still much higher than figures commonly discussed in the legislature. For example, approximately $10 million was appropriated to clean Utah's air this year, representing only 0.1% to 0.5% of the costs of air pollution.

"Utahns understand that air pollution imposes large hidden costs on our communities which is why it's consistently ranked as a top concern," said Logan Mitchell, a research assistant professor at the U and a co-author of the study. "Thankfully, innovation has made clean energy technologies cost competitive on the market, without even considering those hidden costs. The coming energy transition will mean being good stewards of the environment will also protect our economy."

The mismatch between the size of the problem and the proposed solutions emphasizes one of the central findings from the study: cleaning the air could have immense health and economic benefits for Utah. The authors combined their estimates of cost with the air pollution goals from the recent Utah Roadmap to Clean Air, produced by the U's Kem C. Gardner Policy Institute. If Utah achieves the roadmap's pollution reduction targets, they estimate, Utah could save $500 million per year by 2030 and $1.1 billion per year by 2050.

"The payoff of reducing pollution would be huge in economic terms and the benefits would be incalculable in terms of human life and health," said senior author Ben Abbott, an assistant professor at BYU. "It's a question of choice. Are we going to settle for incremental progress in air quality or take advantage of this immense opportunity to improve the health of our communities and remove this enormous drag on our economy?"

"When I read these results, my thoughts immediately turn to my friends and family who live in Utah," said co-author Rebecca Frei, a graduate student at the University of Alberta. "My grandmother goes walking and my niece plays on the playground every day. Changing some simple things about how we operate means added years of life. To me, that's a no-brainer. This isn't about pushing an agenda, this is about assessing the evidence and acting out of love for our families and community."

The researchers ranked more than 30 recommendations of how to best reduce the amount of air pollution in Utah. At the top of the list: increase efficiency of vehicles and buildings, invest in awareness, remove subsidies for nonrenewable energy, require payment for pollution and expand alternative transportation. They estimated that each of these interventions could result in double-digit decreases in air pollution. The researchers suggested that changes at the state level and community level as the most effective and tractable.

The researchers cautioned that no single change would achieve the desired improvement in air quality alone. "We need long-term implementation of proven pollution control measures," Errigo said. "It's going to take commitment from multiple groups at city to state levels to clean up our air and prepare for future growth."

The findings of this study are directly in line with the recommendations of the Utah Road Map to Clean Air and add quantitative estimates of the health and economic costs. The researchers hope that these estimates provide additional context for state legislators and concerned citizens who want to enact positive change.

"In our efforts to clear the air there are no perfect answers, but there are practical solutions," said Thom Carter, Executive Director of the Utah Clean Air Partnership (UCAIR) and co-author on the study. "When looking at how poor air quality impacts our region, it is important to know that we are making progress and that each person, family, organization, and community can find ways to reduce emissions and improve our quality of life."

The COVID-19 pandemic continues to cause significant illness and death while treatment options remain limited. St. Jude Children's Research Hospital scientists have discovered a potential strategy to prevent life-threatening inflammation, lung damage and organ failure in patients with COVID-19. The research appeared online in the journal Cell.

The scientists identified the drugs after discovering that the hyperinflammatory immune response associated with COVID-19 leads to tissue damage and multi-organ failure in mice by triggering inflammatory cell death pathways. The researchers detailed how the inflammatory cell death signaling pathway worked, which led to potential therapies to disrupt the process.

"Understanding the pathways and mechanism driving this inflammation is critical to develop effective treatment strategies," said corresponding author Thirumala-Devi Kanneganti, Ph.D., vice chair of the St. Jude Department of Immunology. "This research provides that understanding. We also identified the specific cytokines that activate inflammatory cell death pathways and have considerable potential for treatment of COVID-19 and other highly fatal diseases, including sepsis."

COVID-19, cytokines, and inflammatory cell death

COVID-19 is caused by the SARS-CoV-2 virus. The infection has killed more than 1.2 million people in less than one year and sickened millions more.

The infection is marked by increased blood levels of multiple cytokines. These small proteins are secreted primarily by immune cells to ensure a rapid response to restrict the virus. Some cytokines also trigger inflammation.

The phrase cytokine storm has been used to describe the dramatically elevated cytokine levels in the blood and other immune changes that have also been observed in COVID-19, sepsis and inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH). But the specific pathways that initiate the cytokine storm and the subsequent inflammation, lung damage and organ failure in COVID-19 and the other disorders was unclear. The cellular and molecular mechanisms that comprehensively define cytokine storm was also lacking.

Kanneganti's team focused on a select set of the most elevated cytokines in COVID-19 patients. The scientists showed that no single cytokine induced cell death in innate immune cells.

The St. Jude investigators then tried 28 cytokine combinations and found just one duo that, working together, induced a form of inflammatory cell death previously described by Kanneganti as PANoptosis. The cytokines are tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. PANoptosis is a unique type of cell death that features coordination of three different cell death pathways--pyroptosis, apoptosis and necroptosis. PANoptosis fuels inflammation through cell death, resulting in the release of more cytokines and inflammatory molecules.

The investigators showed that blocking individual cell death pathways was ineffective in stopping cell death caused by TNF-alpha and IFN-gamma. A closer look at proteins that make up the pathways identified several, including caspase-8 and STAT1, that were essential for PANoptosis in response to these cytokines. Deleting those proteins blocked PANoptosis in innate immune cells called macrophages.

Potential for repurposing TNF-alpha and IFN-gamma blockers to treat COVID-19

Because TNF-alpha and IFN-gamma are produced during COVID-19 and cause inflammatory cell death, the investigators questioned whether these cytokines were responsible for the clinical manifestations and deadly effects of the disease. They found that the TNF-alpha and IFN-gamma combination triggered tissue damage and inflammation that mirror the symptoms of COVID-19 along with rapid death.

Neutralizing antibodies against TNF-alpha and IFN-gamma are currently used to treat inflammatory diseases in the clinic. The investigators found that treatment with these antibodies protected mice from death associated with SARS-CoV-2 infection, sepsis, HLH and cytokine shock.

"The findings link inflammatory cell death induced by TNF-alpha and IFN-gamma to COVID-19," Kanneganti said. "The results also suggest that therapies that target this cytokine combination are candidates for rapid clinical trials for treatment of not only COVID-19, but several other often fatal disorders associated with cytokine storm."

Added co-first author Rajendra Karki, Ph.D., a scientist in the Kanneganti laboratory: "We were excited to connect these dots to understand how TNF-alpha and IFN-gamma trigger PANoptosis." Co-first author Bhesh Raj Sharma, Ph.D., a scientist in the Kanneganti laboratory, added: "Indeed, understanding how PANoptosis contributes to disease and mortality is critical for identifying therapies."

Redefining cytokine storm

Based on this fundamental research, Kanneganti and her colleagues have proposed a definition of cytokine storm that puts the cytokine-mediated inflammatory cell death via PANoptosis at the center of the process. The researchers noted that PANoptosis results in the release of more cytokines and inflammatory molecules, which intensifies systemic inflammation.

"We have solved a major piece of the cytokine storm mystery by characterizing critical factors responsible for initiating this process, and thereby identifying a unique combination therapy using existing drugs that can be applied in the clinic to save lives," Kanneganti said.

There's a classic video demonstrating how our brains process information and allocate attention in which people bounce and pass basketballs and the viewer is asked to count the passes.

If you haven't seen it, go watch it here and then come back. Go ahead. I'll wait.

The experiment highlights a phenomenon called inattentional blindness. We can't pay attention to everything at once, so our brains have to filter information. In the situation in the video, the stakes were low. But what if inattentional blindness causes a radiologist, for example, to miss something obvious and serious?

A study from University of Utah researchers Lauren Williams, Trafton Drew and colleagues finds that even experienced radiologists, when looking for one abnormality, can completely miss another. The results, published in Psychonomic Bulletin & Review, show that inattentional blindness can befall even experts.

"Inattentional blindness reveals the limits of human cognition," says Williams, a recent U graduate and now a postdoctoral scholar at the University of California, San Diego, "and this research demonstrates that even highly trained experts are bound by the same machinery as everyone else."

"If even these experts miss these seemingly obvious findings," adds Drew, associate professor of psychology, "it suggests that this is something really critical we need to understand about how all of us perceive the world."

Missing the gorilla

By some estimates medical errors, including missed radiological abnormalities, are the third leading cause of death in the United States. "We've known for a long time that many errors in radiology are retrospectively visible," Drew says. "This means if something goes wrong with a patient, you can often go back to the imaging for that patient and see that there were visible signs--say, a lung nodule--on something like a chest CT."

So, in 2013, Drew and colleagues conducted an experiment to understand how trained experts could miss those clear signs. In that study, the authors presented radiologists with chest computed tomography (CT) scans and asked them to look for lung cancer nodules. But the authors had also placed an image of a gorilla into the scan--something that obviously doesn't belong in a lung. Drew and his colleagues found that 83% of radiologists did not notice the gorilla.

But that's a gorilla. How would the results be different, they wondered, if instead of a gorilla it was an abnormality that could plausibly come up on a CT scan?

So Williams, Drew and their colleagues from UCLA and Macquarie University set up another experiment. They asked 50 radiologists to evaluate seven chest CT scans for lung cancer, but this time the final scan included two clear abnormalities: a significant breast mass and a lymphadenopathy (an abnormal lymph node). Two-thirds of the radiologists did not notice the potentially cancerous mass. A third did not notice the lymphadenopathy.

"Like anyone that experiences inattentional blindness, I think many radiologists were simply surprised to learn they had missed something," says Williams, who administered the experiment. "Our intuition tells us that if something is fully visible, we'll detect it, but we've all experienced the feeling of missing important information that is retrospectively obvious when our attention is focused elsewhere."

Experience wasn't a factor in whether or not the radiologists noticed the abnormalities, the researchers found, suggesting that years of experience doesn't outweigh universal cognitive truths, and that missing the abnormalities isn't a reflection on the competence or skill of the radiologist.

"It suggests that understanding the situation that led to the missed abnormality may be far more important than focusing on the experience of the individuals that missed it," Williams says.

Seeing the gorilla

In a subsequent experiment, however, instead of asking the radiologists to look for lung cancer nodules, the researchers asked radiologists to look at the same scan and report on a broader range of abnormalities. This time, only 3% missed the mass and 10% missed the lymphadenopathy.

"There a huge amount of information in the ever-growing amount of data we gather on each patient, and what we actually notice depends very strongly on what you are looking for," Drew says. "Cataloging how often radiologists miss something in plain sight misses a really important piece of the puzzle: What were they looking for when they missed the thing in plain sight?"

"Our research demonstrates that focusing narrowly on one task may cause radiologists to miss unexpected abnormalities, even if those abnormalities are critical for patient outcomes," Williams adds. "However, focused attention is probably beneficial when the abnormalities match the radiologist's expectations." Any changes to clinical process would need to find the balance between the two, she says. Some possibilities might be a general assessment of a scan before looking for specific abnormalities, or using checklists to scan for commonly missed findings.

Would the use of artificial intelligence, which doesn't have the same cognitive limitations that humans do, resolve the problem of inattentional blindness? Not necessarily, Drew says. AI is only as good as its training and programming. Algorithms are good at finding narrowly defined abnormalities, he says, but not as good at detecting all possible findings on a scan.

"Radiologists might benefit from being thoughtful about what they are looking for rather assuming that if they see it they will perceive it," Drew says. "AI has in some ways, the same limitation: it's only going to be good at detecting what it has been taught to detect."

Williams says that advancements in radiological technology have produced increasingly clear medical imaging. "However, if radiologists frequently miss a large, clearly visible abnormality when their attention is focused on another task, it suggests that having a clear image is not enough."

Drew says the study can help us understand how we often find only what we're looking for.

"Everyone, even experts, can miss things that seem really obvious if we are not looking for them," he says. "If you've searched through your whole apartment for your phone, you might assume you would have noticed your keys during that search. Our research suggests a reason why you will probably have to search again specifically for the keys."

OAK BROOK, Ill. - Some patients with COVID-19 are at higher risk of neurological complications like bleeding in the brain and stroke, according to a study being presented at the annual meeting of the Radiological Society of North America (RSNA). The researchers said these potentially life-threatening findings were more common in patients with hypertension and diabetes.

The virus that causes COVID-19 first attacks cells in the respiratory system, often leading to an inflammation of the lungs that puts people at risk of contracting pneumonia. But the virus' impact has also been felt in other systems of the body.

"COVID-19's effects extend far beyond the chest," said study lead author Colbey W. Freeman, M.D., chief resident in the Department of Radiology at Penn Medicine in Philadelphia. "While complications in the brain are rare, they are an increasingly reported and potentially devastating consequence of COVID-19 infection."

To learn more about the phenomenon, Dr. Freeman and colleagues in the Perelman School of Medicine at the University of Pennsylvania looked at COVID-19 patients who underwent head CT and/or MRI in their health system from January to April 2020. Of the 1,357 patients with COVID-19 admitted to the system in those four months, 81 had a brain scan performed. The most common reasons for the brain scans were altered mental state and focal neurologic deficits such as speech and vision problems.

Out of 81 patients with brain scans, 18, or just over one in five, had findings that were considered emergency or critical, including strokes, brain bleeds and blocked blood vessels. At least half the patients had pre-existing histories of high blood pressure and/or type 2 diabetes. Three patients with emergent/critical findings died while admitted.

"COVID-19 is associated with neurologic manifestations, and hypertension and type 2 diabetes mellitus are common in individuals who develop these manifestations," Dr. Freeman said. "These populations may be at higher risk for neurologic complications and should be monitored closely."

Two-thirds of the patients with critical results in the study were African American, suggesting that these patients also may require closer monitoring.

The exact mechanisms for COVID-19's harmful neurological effects are not known and may involve multiple factors, although a popular theory holds that inflammation associated with the infection is the primary culprit. In the study, blood markers of inflammation were high in people with critical results.

"When your body is in an inflammatory state, it produces all these molecules called cytokines to help recruit the immune system to perform its function," Dr. Freeman said. "Unfortunately, if cytokines are overproduced, the immune response actually starts doing damage."

The study is ongoing, Dr. Freeman said, and the researchers will continue to publish findings as more data comes in. They are also investigating the incidence of neurologic complications in COVID-19 patients on extracorporeal membrane oxygenation (ECMO), a pump system to circulate and replenish oxygen in the blood. Several patients in the study needed ECMO during their time at the hospital.

"In addition, we have plans to initiate a larger prospective study evaluating delayed, long-term, and chronic neurologic manifestations that may not be known in this early period in the pandemic," Dr. Freeman said.

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.

Denmark trial measures effectiveness of adding a mask recommendation to other public health measures for preventing SARS-CoV-2 infection

HD video soundbites of the authors and Annals editors discussing the findings are available to download at http://www.dssimon.com/MM/ACP-danmask.
Abstract: https://www.acpjournals.org/doi/10.7326/M20-6817
Editorial: https://www.acpjournals.org/doi/10.7326/M20-7448
Editorial: https://www.acpjournals.org/doi/10.7326/M20-7499
URLs are live when the embargo lifts

A randomized trial of more than 6,000 participants in Denmark adds new evidence to what is known about whether masks protect the wearer from SARS-CoV-2 infection in a setting where public health measures, including social distancing, are in effect but others are not wearing masks. The DANMASK-19 trial randomized participants to follow those public health measures with or without an additional recommendation to wear a surgical mask when outside the home. Mask use outside of hospitals was uncommon in Denmark at the time. After 1 month of follow-up, 1.8% of participants in the mask group and 2.1% in the control group developed infection. While the evidence excludes a large personal protective effect of mask wearing, it weakly supports lesser degrees of protection, and cannot definitively exclude no effect. The findings are published in Annals of Internal Medicine.

Researchers from Copenhagen University Hospital recruited 6,024 adults who spent at least 3 hours per day outside their homes, whose occupations did not require masks, and who did not have a previous known diagnosis of SARS-CoV-2 infection. Participants were randomized into the mask group or the control group and those in the mask group were given a supply of surgical masks. All participants completed weekly surveys and antibody tests with PCR testing if COVID-19 symptoms developed, and at 1 month. At the conclusion of the trial, infection rates were similar between the two groups.

Of note, Danish authorities did not recommend masks during the study period and their use in the community was uncommon. Public transportation and shops remained open and recommended public health measures included quarantine of persons with SARS-CoV-2 infection, social distancing, limiting the number of people seen, frequent hand hygiene and cleaning, and limited visitors to hospitals and nursing homes.

According to the study authors, their findings offer evidence about the degree of protection mask wearers can anticipate in a setting where others are not wearing masks and where other public health measures, including social distancing, are in effect. The findings, however, should not be used to conclude that a recommendation for everyone to wear masks in the community would not be effective in reducing SARS-CoV-2 infections, because the trial did not test the role of masks in source control (transmission from an infected person to others) of SARS-CoV-2 infection.

The editors of Annals of Internal Medicine chose to publish the DANMASK-19 trial because it is a well-designed study that provides an important piece of evidence to understand the puzzle of how to control the COVID-19 pandemic. They also note that the U.S. Centers for Disease Control recently updated their guidance to acknowledge that masks, when worn by all, may reduce transmission by both source control and personal protection. They say that the DANMASK-19 trial does not conflict with these guidelines, but shows that any contribution to risk reduction through personal protection is likely to be less than through source control.

An early Edo period document stipulating the Hosokawa clan code of conduct for vassals dispatched on a national project to rebuild Sunpu Castle has been discovered by Kumamoto University researchers. The thirteen articles from the head of the Hosokawa clan in the Kokura domain (area), Tadaoki Hosokawa at the time, delegate full authority to the vassals to lead construction and prevent conflicts with other clans. It is the second original code of conduct document related to the Sunpu Castle reconstruction effort to be discovered.

During the Edo period (1603-1867), the Japanese central government mobilized feudal lords from all over the country to build and repair important castles and carry out extensive infrastructure development. It is commonly believed that these national projects prevented clans from accumulating wealth by forcing them to send out materials and men, thereby establishing a system of control in the territory. Sunpu Castle, located in the center of Japan in Shizuoka Prefecture, was closely associated with the first of the Edo Shogunate (Ieyasu Tokugawa) and was an important base for the Edo Shogunate. A major expansion of the castle was delayed by a fire in December of 1607, but was quickly rebuilt by the following year. A number of daimyo clans were mobilized from all over Japan for this series of restoration projects.

The document found by researchers was issued by the head of the Hosokawa clan, Tadaoki Hosokawa, on January 8th, 1608, and outlined the Hosokawa clan code of conduct for vassals during reconstruction and their journey from Kokura (now northern Kyushu) to the Sunpu Castle reconstruction site (southwest of Tokyo). Consistent throughout this code is a strict prohibition of any action that might lead to quarrels with vassals or workers of other clans. Articles 9 and 10 delegated full authority of the renovation site to the four persons named and the superintendent in charge of the Hosokawa clan.

Article 1 instructs the entire Hosokawa workforce to follow the instructions of the superintendent, Masazumi Honda - Aide to the Shogun, in all matters of discipline. Article 2 stipulates that fighting within the clan must be strictly avoided. Those engaged in fighting, as well as those who supported them, were punished (usually by death).

Articles 3 to 5 are provisions aimed at preventing fights with other clans. Going to watch another clan's fight was a punishable offense (Article 3). If a servant escaped to another house, he was not returned forcefully. On the other hand, those who escaped from other clans were to be returned after the completion of the project (Article 4). Lodging fees from Kokura to Sunpu were to be paid in accordance with the "Gohatto" (laws & regulations) (Article 5).

The second half of the code provides a glimpse into the life of the soldier class (ashi-garu) mobilized for the project. Alcohol (sake) was strictly prohibited. They could bring their own food (bento), but were not to drink more than three small flat sake cups (sakazuki) of alcohol (Article 6). When going to town, they were supposed to declare the nature of their errand to the magistrate and obtain a permit (Article 7). Meetings with people from other clans or the shogunate were strictly forbidden (Article 8). Hot baths in another clan's facilities were not allowed (Article 11). Sumo wrestling and spectating were strictly forbidden during the period of the project, and violators would be punished (Article 12). On the round trip between Kokura and Sunpu, workers were to travel in groups as indicated on an attached sheet (Article 13). This purpose of this historical document was to maintain peace at the project site and vividly conveys the aspects of the samurai society during its transition from a time of war to peace and prosperity.

When asked about the academic significance of this document, Professor Tsuguharu Inaba said, "This discovery provides us with a great deal of information about the politics concerning feudal lord mobilization by the shogunate to build castles." Professor Inaba discovered the document and was part of the Eiseibunko Research Center team at Kumamoto University who deciphered it.

Until now, only two documents related to the reconstruction of Sunpu Castle were known: an original code of conduct written by Mori Terumoto, feudal lord of the Choshu clan, and another, which is a copy of the Choshu clan document, from Maeda Toshinaga, feudal lord of the Kaga clan. The discovery of this ancient document and the fact that the three documents are similar means that each clan was likely presented with a general code of conduct framework by the shogunate. Each clan then established the rules in the name of their feudal lord and required their vassals to enforce them.

The Hosokawa and Mori clans had been enemies in a major civil war (culminating in the Battle of Sekigahara) only seven years earlier and if something had sparked an old grudge, a major conflict could have evolved. The shogunate dared to mobilize the adversarial clans for the same national project to discipline them and make their joint efforts more visible. This ancient document reveals an attempt to thoroughly prevent conflicts between the clans and suggests that the shogunate was trying to eliminate the seeds of civil war by reconciling relations between clans. In other words, the government strategically implemented a national project to establish peace within Japan.

This document was made public for the first time on the 4th of November 2020 at the Kumamoto University Library Online Exhibition of Rare and Valuable Materials.

Hormones are key players of the endocrine system and have a major influence on our emotional and sexual wellbeing. The hormone oxytocin is involved in a wide range of emotions from social bonding to maternal behaviors like nursing and lactation. But the most popular and well-known role of oxytocin, lending it its popular moniker of 'love hormone,' is its role in romantic and sexual emotions.

The functional mechanism of oxytocin in male sexual function and behavior is not clearly understood, but there is some evidence supporting the role of oxytocin-specific nerve cells or neurons in the brain that project to the lower spinal cord and control penile erection and ejaculation in male rats. Now, in a brand new study published in Current Biology, a group of researchers led by Professor Hirotaka Sakamoto from Okayama University, Japan, has explored this potential role of oxytocin and the underlying mechanisms in modulating male sexual function using rats as a model system.

Oxytocin is transferred from the brain to various parts of the body by the blood, and from neuron to neuron through structures called "synapses." However, the precise mechanisms by which sparsely dispersed oxytocin fibers--structures responsible for responding to oxytocin in the central nervous system--cause the activation of widely distributed receptors remain unclear.

The researchers from Japan investigated a novel non-synaptic mode of oxytocin transport across the central nervous system. When asked to explain this process, Prof Sakamoto refers to an interesting analogy: "Overall, the endocrine system, which acts on widespread distant organs via the circulation, resembles a 'broadcasting satellite' communication, whereas synaptic transmission resembles the hard-wired 'ethernet.' Accordingly, the localized volume transmission of peptides resembles 'Wi-Fi' communication, since it is a hybrid of both endocrine (satellite) and synaptic (ethernet) systems, and may be the predominant mechanism of oxytocinergic modulation of socio-sexual behavior and cognition throughout the central nervous system."

It is already known that spinal regions like the spinal ejaculation generator (SEG) are known to control sexual functions in male rodents. To assess the role of oxytocin in copulatory and ejaculatory responses, the team injected oxytocin into the spine of male rats. The gastrin-releasing peptide or GRP neurons are an important component of the SEG, as they control the lower lumbar region connected to muscles at the base of the penis, thereby controlling erection and ejaculation.

Oxytocin caused an increased sexual activity and neuronal activity in injected animals. More specifically, oxytocin was found to directly activate SEG/GRP neurons via oxytocin receptors, which detect oxytocin, and influence male sexual function in the rat lumbar spinal cord. Using an oxytocin receptor antagonist, which reduces the activity of oxytocin receptors, resulted in a latency and decrease in number of sexual activity and ejaculatory responses in majority of the animals, confirming the importance of oxytocin.

The question remained about the transport of oxytocin, however. Electron microscopy images acquired from slices of the lumbar region ruled out the presence of synaptic vesicles or connections. Upon stimulation of exocytosis ex-vivo, they were able to observe oxytocin transport mediated by a more passive diffusion in extracellular spaces at non-synaptic sites.

Highlighting the importance of the study, Prof Sakamoto remarks, "Now that we have uncovered a novel neural mechanism-the 'localized volume transmission' of oxytocin from axons-involved in controlling male sexual function in the spinal cord, we can hope that this may lead to the development of treatments for male sexual dysfunction."

This study thus presents a completely unprecedented role for oxytocin in male sexual function, in addition to its long-standing "female-centric" role. Learning more about this "love hormone" may indeed help us foster healthier and long-lasting loving relationships!

New research from the University of Eastern Finland explores the role of diabetes in the cellular and molecular changes underlying Alzheimer's disease (AD). In an AD mouse model, diabetes induced through a diet rich in fats and sugars weakened the accumulation of microglial cells around amyloid plaques and increased the formation of neuritic plaques with prominent tau pathology. Besides the mouse model, a similar observation was also made in hydrocephalus patients with type 2 diabetes, who had fewer microglia around amyloid plaques than patients without diabetes. The findings provide valuable new insight into the cellular mechanisms by which type 2 diabetes contributes to the risk and development of AD.

Alzheimer's disease is the most common form of dementia, with no cure to date. AD is characterised by the accumulation of beta-amyloid peptides and phosphorylated tau proteins in the brain, leading to the activation of the immune cells in brain: microglia and astrocytes. AD also causes damage to axons and dendrites and, ultimately, leads to neuronal cell death. Recent genetic studies suggest that microglia play a key role in the development of AD. In addition to genetics, environmental and lifestyle factors, and diseases associated with them, such as type 2 diabetes, affect the risk of AD. Type 2 diabetes has long been known to increase the risk of AD and to influence the disease course, but the underlying cellular and molecular events are still elusive.

In the new study, transgenic AD model mice were put on a six-month regimen resembling the typical Western diet, i.e. one that is rich in fats and sugars, and this led to the development of diabetes in the mice. In behavioural analysis, diabetic mice showed impaired learning and memory compared to mice on standard diet. Bulk RNA expression analysis of brain samples of the mice suggested weakened response of microglial cells to amyloid-β, as well as attenuation of Trem2 and PI3K-Akt signalling pathways. Immunohistochemical analyses of entorhinal and hippocampal brain sections supported these findings, as the diabetic mice had fewer microglia and more dystrophic neurites around amyloid plaques than mice on the standard diet.

"This study sheds new light on the cellular level how diabetes contributes to the development of AD, and specifically highlights the importance of brain immune cells in the disease process. Our findings suggest that diabetes can weaken the ability of microglia to react to harmful amyloid-β. It seems that diabetes can lead to the formation of neuritic plaques, which are characteristic pathological changes in the AD brain," Senior Researcher Teemu Natunen from the Institute of Biomedicine at the University of Eastern Finland says.

Western diet did not associate with the overall accumulation of amyloid-β in the brain of AD mice.

"A diet that is rich in fat and sugar, i.e. the typical Western diet, is known to increase the risk of type 2 diabetes, and this way, it possibly also contributes to the development of AD," Professor Heikki Tanila from the A. I. Virtanen Institute for Molecular Sciences at the University of Eastern Finland says.

The researchers further analysed cortical biopsies of idiopathic normal pressure hydrocephalus patients, collected and studied by Professor Ville Leinonen's research group at Kuopio University Hospital. Human cortical samples showed changes that were similar to those observed in mice: in normal pressure hydrocephalus patients with type 2 diabetes, the number of microglia around amyloid plaques was lower than in non-diabetic patients.

"The set of data from patients with normal pressure hydrocephalus constituted an important part of our study, because it allowed us to show that also humans with type 2 diabetes have an impaired microglia response. This type of collaboration between research groups at the University of Eastern Finland and Kuopio University Hospital, which makes it possible for us to verify findings from basic research in patient samples, is crucial for the high-level research carried out in the Neuroscience Research Community at UEF," Professor Mikko Hiltunen from the Institute of Biomedicine at the University of Eastern Finland says.

The ability to "see" the inner workings of structures (organelles) within cells, in real time, offers the promise of advancements in disease diagnosis and treatment. Organelle dynamics drive the self-efficient micro-world of cells, but current super-resolution microscopy techniques used to track these interactions have limitations.

Now an advanced technique called SPOT (Spectrum and Polarization Optical Tomography) is giving researchers a "street view" of the vital lipid membranes surrounding organelles and by so doing opens up the opporutnies to study the sophisticated world of lipid dynamics.

The researchers say it's a significant development, building on earlier work on super-resolution polarization microscopy.

The research, published in Nature Communications was developed through a collaboration between University of Technology Sydney-Southern University of Science and Technology (UTS-SUStech) Joint Research Centre for Biomedical Materials & Devices, and Peking University.

Lead author Dr Karl Zhangao from UTS-SUSTech Joint Research Centre said that lipid membranes surround most organelles and play a significant role.

"Their shape, composition and phase synergistically regulate biophysical membrane properties, membrane protein function and lipid-protein interactions."

"However it is challenging to observe such a level of complexity due to their similar chemical composition," he said.

Simply using one dye that universally stains the lipid membranes, SPOT can simultaneously reveal lipid membrane morphology, polarity, and phase from measuring the intensity, spectrum, and polarization, respectively. Combined with lipophilic probes, the team successfully revealed more than ten types of organelles simultaneously, and their sophisticated lipid dynamics.

Using the new imaging platform established at SUStech, researchers observed the multi-organelle interactive activities of cell division, lipid dynamics during plasma membrane separation, tunneling nanotubules formation, and mitochondrial cristae dissociation.

"This is the first time researchers have been able to quantitatively study the lipid heterogeneity inside subcellular organelles," senior author Professor Dayong Jin says. Professor Jin is Director of UTS-SUStech Joint Research Centre and Director of UTS Institute for Biomedical Materials and Devices.

"This is a very powerful tool for super-resolution imaging the inner working of each single cells, that will advance our knowledge in understanding how cells function, diagnose when a "factory" or a transportation doesn't work properly within the cell, and monitor the progression of disease," Professor Jin said

"With such information it isn't too big a leap to identify pathways for potential drug treatments, as well as examine their efficacy right on the SPOT" he said.

Matching prices aren't the only reason oysters and champagne pair so well. According to a study published by the University of Copenhagen today, an uncanny umami synergy makes the combination of yeast-brewed bubbly and fresh molluscs a match made in heaven for some. Ironically, the new knowledge could help us consume more vegetables in the future.

Oysters and champagne are considered a perfect pairing. Now, researchers from the University of Copenhagen's Department of Food Science have found flavours in a range of champagnes and variety of Danish oysters that for the first time provide the scientific explanation for why these two foods complement one another so well.

"The answer is to be found in the so-called umami taste, which along with sweet and salty, is one of the five basic flavours detectable to human taste buds. Many people associate umami with the flavour of meat. But now, we have discovered that it is also found in both oysters and champagne," states Professor Ole G. Mouritsen from the Department of Food Science at UCPH.

In champagne, dead yeast cells contribute greatly to an umami flavour (glutamate). And as for oysters, the umami emerges from the mollusc's muscles (nucleotides).

"Food and drink pair well when they spark an umami synergy from combinations of glutamate and certain nucleotides. Champagne and oysters create a notably synergistic effect that greatly enhances the taste of the champagne. Furthermore, champagne contributes to the overall impression with, for example, its acidity and bubbles. That explains the harmony of these two foods," explains PhD student Charlotte Vinther Schmidt, the study's lead author.

Could get people to consume more vegetables

Besides the more luxurious example of oysters and champagne, the professor also points to ham and cheese, eggs and bacon and tomato and meat as gastronomic companions with umami synergy.

The professor believes that this synergy and taste is important to us humans for food choices. According to him, we are evolutionarily encoded to crave umami, as it is a sign of protein-rich food that is important to our bodies.

The encoding may be responsible for us being less enthusiastic about eating umami-less vegetables.

"Understanding the umami principle is particularly important because it can help get us to eat more vegetables. By being cognizant of umami synergy, one can make any vegetable tasty. And, it is my firm belief that if we want more people to eat more vegetables, we need to deal with the fact that greens lack umami," says Ole G. Mouritsen.

Local oysters and old champagne

For the ultimate combination of New Year's Eve oysters and champagne, Professor Mouritsen suggests native Danish Limfjord oysters and an older vintage champagne.

"One gets the most bang for the buck and best taste experience by tracking down flat Limfjord oysters and an unfortunately slightly more expensive bottle of older champagne. Older vintage champagnes have more dead yeast cells, which provide more umami. And Limfjord oysters contain large quantities of the substances that give umami synergy. Still, one shouldn't hesitate from purchasing the invasive Pacific oysters that are harvested in the same area as our native Limfjord species. They too can share an umami synergy with champagne, as the study shows," says Mouritsen

The research was published in Scientific Reports and conducted by Charlotte Vinther Schmidt, Karsten Olsen and Ole G. Mouritsen of the University of Copenhagen's Department of Food Science.

Facts:

In the study, the researchers examined a variety of champagnes, along with both Limfjord oysters and Pacific oysters. The study marks the first time that a scientific explanation has been provided for why oysters and champagne pair so well.

It is the combination of the amino acid glutamic acid and nucleotides from the breakdown of muscles from fish, molluscs and shellfish, for example, that greatly enhance umami taste.

The umami taste is derived from the concurrent binding of the salt (glutamate) of a free amino acid (glutamic acid) along with nucleotides to the umami receptor found in the taste buds of our tongues and in the oral cavity.

RIVERSIDE, Calif. -- Last year, researchers at the University of California, Riverside, identified the early origins of neural crest cells -- embryonic cells in vertebrates that travel throughout the body and generate many cell types -- in chick embryos. Now the researchers have used a human model to figure out when neural crest cells acquire distinctive molecular and functional attributes.

The study, published in Stem Cell Research, provides new insight into the formation of neural crest cells and outlines transient prospective stages in their development. It also shows the neural crest lineage is distinct from pluripotent stem cells.

The neural crest is an important embryonic cell population in the developing embryo that generates cells such as neurons, glia, and melanocytes, along with cells that make up bone and cartilage. Its improper development is linked to a wide range of pathologies, from craniofacial malformations such as palate clefts to aggressive cancers such as melanoma and neuroblastoma.

"Defining the molecular signature required for the formation of the neural crest better equips us to understand human neural crest related pathologies and develop diagnostic and therapeutic efforts," said lead study author Maneeshi S. Prasad, an assistant project scientist in the lab of Martin I. Garcia-Castro, an associate professor of biomedical sciences at the UC Riverside School of Medicine. "The knowledge of the precise time and molecular signals involved, when exactly the neural crest acquires the potential to form jaw and tooth cells, for example, will enable scientists to replicate and modulate their potential in stem cell therapies designed to aid regenerative craniofacial repair approaches, among many others."

The study used a robust human model of neural crest formation to demonstrate a fast transition from the pluripotent stem cell state to the neural crest precursor state. According to this model, a sequential loss of pluripotency markers occurs during the pluripotent stem cell state as cells transition to neural crest cells.

"We address the precise timing when pluripotent stem cells diverge toward the neural crest cell lineage by exploring the distinctive molecular and functional attributes of early neural crest cells -- something that had never been established," Prasad said. "We also identified unique molecular signatures during the transition stages of neural crest formation from pluripotent stem cells."

The researchers provide a high-resolution temporal map of gene expression and epigenetic changes with well-defined stages of neural crest formation they say should be a valuable resource for scientists identifying and studying the role of various genes involved in human neural crest formation.

Neural crest cells have been thought to originate in the ectoderm, one of the three germ layers formed in the earliest stages of embryonic development, but their capacity to form derivatives, such as bone- and tooth-forming cells, are in conflict with fundamental concepts in developmental and stem cell biology.

Garcia-Castro noted the study also establishes a novel in vitro specification test to determine the differentiation capacity of specified neural crest cells into other germ layers such as mesoderm and endoderm cell types. The specification test involves exposing the potentially specified cells to precise level of signals that stimulate the formation of other germ layers such as mesoderm and endoderm from pluripotent embryonic stem cells.

"Our work demonstrates that neural crest cells depart from the pluripotent stem cell state soon after the activation of Wnt signaling, an ancient and evolutionarily conserved pathway that regulates crucial aspects of the cell," he said. "Importantly, using our novel specification test we found that prospective neural crest cells lose the mesodermal and endodermal potential characteristic of pluripotent stem cells just hours upon their induction."

Garcia-Castro and Prasad were joined in the research by postdoctoral fellow Rebekah M. Charney and undergraduate researcher Lipsa J. Patel.

The research was funded by the National Institutes of Health.

The title of the research paper is "Distinct molecular profile and restricted stem cell potential defines the prospective human cranial neural crest from embryonic stem cell state."

The number of people who went missing during the first national lockdown in England fell by over a third, compared to data from the previous year. However, a new report out today shows that those who did go missing were deemed more vulnerable and at higher risk.

Researchers from the University of Portsmouth and University of Liverpool worked with six police forces from across the UK, to understand the impact of lockdown on missing people and recommend changes for the future.

Missing people are one of the most challenging issues for modern police forces, with the number of reported cases reaching 382,960 in 2018/2019 (NCA, 2020). The recent pandemic, and the resultant national as well as localised lockdowns, have placed unique demands on the emergency services (WHO, 2020).

The study aimed to compare the characteristics of missing people cases reported to participating forces during the period of the COVID-19 lockdown in England, with sample of cases taken from the same time period last year. The sample comprised of reports of adults and children who went missing between 23rd March 2020 until 20th May 2020, and the same time period in 2019.

As expected, the lockdown period led to a substantial reduction in the overall number of missing persons. There was a 35% decrease in missing children reports and 36% reduction in reports of missing adults.

However, the research also highlighted that those who went missing were more likely to be high risk of harming themselves or others. Adults who went missing during this period were more prone to mental health issues; domestic abuse; have relationship, drug or alcohol problems; or have a history of self-harm or suicidal thoughts.

Dr Karen Shalev Greene, Reader in Criminology, Director of the Centre for the Study of Missing Persons, University of Portsmouth explains: "The reduction in missing people is entirely expected, it is much harder to go missing, when the country is locked down. However, what is significant about these figures is it highlights how desperate some people must have been."

"The report emphasises the vulnerability of people that go missing during lockdown. Perhaps they live in situations that impact their mental health more making them determined for freedom. Whatever the reason, this is a reflection of society as a whole, including criminal organisations, exploitation, vulnerability and those that need support. To help prevent high risk missing adults from going missing the response needs to be multi agency. Efforts should also focus on after care and support once they return."

The report also highlighted that children were more likely to be classified as low risk during lockdown. The reason for this needs further investigation and understanding.

Dr Freya O'Brien, Senior Lecturer in Psychology, University of Liverpool, explains: "Particular attention should be given to understanding the reasons why children from care homes frequently went missing during lockdown and why children travelled long distances. One theory is that children in care were trying to get home to their families. It is important to bear regional differences in mind. Each force should study the patterns of missing in their force and consider local context."

National Police Chiefs' Council Lead for Missing People, Assistant Chief Constable Catherine Hankinson, said: "This research helps us to understand the changing trends in missing people and the different reasons they went missing during the first lockdown. The trend in more incidents being categorised as high risk suggests some of us really struggled with being isolated from our normal support networks. Police and our partners in health, social care and local authorities need to learn from that experience and consider how we can support people, particularly those with mental health issues, through ongoing restrictions.

"The research found that missing children were more likely to be categorised as low risk which is partly because some of them were reported missing for breaking the lockdown rules but then often returned safe and well after a short time. However, we will closely consider the research in the context of child exploitation, county lines and organised crime. Police are already aware of how these criminals are changing the way they operate but there is always more to do and we're committed to tackling those who are intent on causing harm to our communities and young people.

"Our work with partners in local authorities and social services will consider how we maintain contact with vulnerable children during any further restrictions, as it is vital we all do everything possible to protect them from abuse and exploitation at home."

T cell responses are critical for providing early control and clearance of many viral infections, but there remain many unknowns concerning T cell immunity in COVID-19. Some T cell responses may even have a detrimental impact on the clinical outcome and contribute to long COVID, a phenomenon that affects roughly 10% of COVID-19 patients, causing them to experience an array of symptoms for a month or longer. In this Perspective, Annika Karlsson and colleagues discuss unresolved questions surrounding T cell immunity against SARS-CoV-2 infection, including one that's important to consider for development of T cell-targeted vaccines: are T cells critical to generate durable immunity to the virus? Other unknown areas include the roles and longevity of SARS-CoV-2-specific memory T cells; the location and function of tissue resident memory T cells; and whether preexisting immunity to SARS-CoV-2 via cross-reactive T cells helps protect against the virus or, rather, exacerbates harmful inflammation. As well, scientists have yet to determine how T cell responses differ depending on disease severity (mild or asymptomatic versus severe or long COVID), and whether genetic factors, such as a patient's HLA type, could influence disease severity. Filling these gaps in knowledge using both animal models and longitudinal studies in large patient cohorts is vital for the formulation of effective COVID-19 vaccines and treatments, the authors say.

Some, if not all, early sharks that lived 300 to 400 million years ago not only dropped their lower jaws downward but rotated them outwards when opening their mouths. This enabled them to make the best of their largest, sharpest and inward-facing teeth when catching prey, paleontologists at the Universities of Zurich and Chicago have now shown using CT scanning and 3D printing.

Many modern sharks have row upon row of formidable sharp teeth that constantly regrow and can easily be seen if their mouths are just slightly opened. But this was not always the case. The teeth in the ancestors of today's cartilaginous fish (chondrichthyan), which include sharks, rays and chimaeras, were replaced more slowly. With mouths closed, the older, smaller and worn out teeth of sharks stood upright on the jaw, while the younger and larger teeth pointed towards the tongue and were thus invisible when the mouth was closed.

Jaw reconstruction thanks to computed tomography

Paleontologists at the University of Zurich, the University of Chicago and the Naturalis Biodiversity Center in Leiden (Netherlands) have now examined the structure and function of this peculiar jaw construction based on a 370-million-year-old chondrichthyan from Morocco. Using computed tomography scans, the researchers were able not only to reconstruct the jaw, but also print it out as a 3D model. This enabled them to simulate and test the jaw's mechanics.

What they discovered in the process was that unlike in humans, the two sides of the lower jaw were not fused in the middle. This enabled the animals to not only drop the jaw halves downward but at the same automatically rotate both outwards. "Through this rotation, the younger, larger and sharper teeth, which usually pointed toward the inside of the mouth, were brought into an upright position. This made it easier for animals to impale their prey," explains first author Linda Frey. "Through an inward rotation, the teeth then pushed the prey deeper into the buccal space when the jaws closed."

Jaw joint widespread in the Paleozoic era

This mechanism not only made sure the larger, inward-facing teeth were used, but also enabled the animals to engage in what is known as suction-feeding. "In combination with the outward movement, the opening of the jaws causes sea water to rush into the oral cavity, while closing them results in a mechanical pull that entraps and immobilizes the prey."

Since cartilaginous skeletons are barely mineralized and generally not that well preserved as fossils, this jaw construction has evaded researchers for a long time. "The excellently preserved fossil we've examined is a unique specimen," says UZH paleontologist and last author Christian Klug. He and his team believe that the described type of jaw joint played an important role in the Paleozoic era. With increasingly frequent tooth replacement, however, it became obsolete over time and was replaced by the often peculiar and more complex jaws of modern-day sharks and rays.

CHAPEL HILL, NC--Cutaneous angiosarcoma is a rare, highly aggressive skin tumor found primarily on the scalps of older White people, but based on new research from the University of North Carolina School of Medicine and the Lineberger Comprehensive Cancer Center, immunotherapies effective against lung cancer and melanoma may also work against this cancer. The study's findings are published in the American Journal of Dermatopathology.

The investigators found that two markers that could help guide the choice of immunotherapy to fight this disease: tumor-infiltrating lymphocytes (TILs), which are white blood cells that can kill cancer cells, and surface protein markers, known as PD-1 and PD-L1. Combined, these markers are enabling researcher's efforts in clinical trials for cutaneous angiosarcomas.

"Current treatments for cutaneous angiosarcomas incorporate surgery, radiation and chemotherapy, but are not overly effective," said Paul Googe, MD, a professor in the UNC School of Medicine Dermatology Department and lead author. "Most skin cancers regress in response to inflammation and since immunotherapies that provoke an inflammatory response have proven successful in melanoma, immunotherapies targeted at non-melanoma skin cancers, such as angiosarcomas, also now show promise."

This research was possible due to the efforts of teams of UNC scientists from different fields working together. "It is a big advantage for pushing forward research to have inter-departmental collaboration as seen with this study," said UNC Lineberger's Nancy E. Thomas, MD, PhD, chair of the Dermatology Department at the UNC School of Medicine. "This project required true team science, with investigators bringing complementary and integrated expertise to the project."

"Cutaneous angiosarcomas can be advanced at diagnosis, so treatment is usually multidisciplinary, involving dermatologists, surgical oncologists, radiation therapists and oncologists," said Googe. "Dermatology experts have been invaluable in helping identify patients for a clinical trial and dermatologic follow-up should be helpful in assessing response to therapy."

In this study, the researchers sampled tumor tissue from five men and five women between the ages of 59 and 82 who were newly diagnosed with cutaneous angiosarcoma. They looked at patient tissue samples for the presence of TILs as well as surface proteins PD-1 or PD-L1, which can act as immune checkpoints. Immunotherapy drugs can block PD-1, thereby releasing the brakes on the immune system so that it can attack cancer cells.

In their investigation, all 10 of the patient tumor samples were positive for PD-L1; seven of the tumors expressed PD-L1 at high levels. TILs were all found in all 10 tumors, and more specifically were found at the edge of the tumor and widely comingled with tumor cells in seven of the tumors, indicating a higher likelihood of immune-effectiveness against the cancer.

There have been some individual case reports of success using immunotherapy agents such as pembrolizumab, a PD-1 inhibitor, against cutaneous angiosarcomas. In this study, four of the people showed benefit from pembrolizumab.

"This study is a wonderful example of the bedside to bench, back to bedside," said UNC Lineberger's Juneko Grilley-Olson, MD, an associate professor of medicine at the UNC School of Medicine's Division of Oncology and final author on the article. "Trials in a rare disease require broad-reaching cooperative efforts, and through an extensive network of trial sites supported by the National Cancer Institute, we are bringing our next trial to where patients are, and ask the question of drug effectiveness in the most rigorous scientific way."

The phase II trial, run through the NCI-sponsored Alliance for Clinical Trials in Oncology network, is looking to enroll as many as 90 patients with angiosarcoma to fully evaluate genetic and other abnormalities in the disease. For the first time in this cancer, investigators will try to determine how responsive the disease might be to immunotherapy in combination with conventional chemotherapy, noted Grilley-Olson.