Culture

STONY BROOK, NY, September 29, 2020 - Diet remains an important part of disease prevention and management, and a new study suggests that consumption of fructose may worsen intestinal inflammation common to inflammatory bowel diseases (IBD). Led by David Montrose, PhD, of the Renaissance School of Medicine at Stony Brook University, the study is currently published early online in Cellular and Molecular Gastroenterology and Hepatology.

Rates of IBD have been increasing worldwide. According to the Centers for Disease Control and Prevention (CDC), approximately three million Americans are diagnosed with IBD each year, up one million from incidence in the late 1990s. Consumption of a western diet, including fructose, is associated with increasing rates of obesity and diabetes, and IBD may be an additional disease exacerbated by fructose intake.

“The increasing incidence of IBD parallels higher levels of fructose consumption in the United States and other countries,” says Montrose, an Assistant Professor in the Department of Pathology and faculty researcher in the Stony Brook University Cancer Center. "Our findings provide evidence of a direct link between dietary fructose and IBD and support the concept that high consumption of fructose could worsen disease in people with IBD. This is important because it has the potential to provide guidance on diet choices for IBD patients, something that is currently lacking."

Montrose, along with colleagues at Weill Cornell Medicine, tested three mouse models of IBD. They were fed high amounts of fructose, which worsened colonic inflammation along with notable effects in their gut bacteria including changes in their type, metabolism and localization within the colon. Complementary mechanistic work demonstrated that the microbiota is causally linked to the detrimental effects of the high fructose diet.

The paper concludes that the "excess dietary fructose consumption had a pro-colitic effect that can be explained by changes in the composition, distribution and metabolic function of resident enteric microbiota."

Montrose says several next steps are planned to expand upon these findings. These include the development of interventions to prevent the pro-inflammatory effects of dietary fructose as well as evaluating whether this diet increases colitis-associated tumorigenesis. This second point is particularly important because IBD patients are at increased risk of developing colon cancer due to a lifetime of chronic inflammation of the gut.

In 2016, the world's largest ever data leak dubbed "The Panama Papers" exposed a scandal, uncovering a vast global network of people--including celebrities and world leaders, who used offshore tax havens, anonymous transactions through intermediaries and shell corporations to hide their wealth, grow their fortunes and avoid taxes.

Researchers at USC Viterbi School of Engineering have now conducted a deep analysis of the entities and their interrelationships that were originally revealed in the 11.5 million files leaked to the International Consortium of Investigative Journalists. The academic researchers have made some discoveries about how this network and transactions operate, uncovering uniquely fragmented network behavior, vastly different from more traditional social or organizational networks, demonstrating why these systems of transactions and associations are so robust and difficult to infiltrate or take down. The work has been published in Applied Network Science.

Lead author Mayank Kejriwal is an assistant professor working in the Daniel J. Epstein Department of Industrial and Systems Engineering and USC's Information Sciences Institute who studies complex (typically, social) systems like online trafficking markets using computational methods and network science. He said the research team's aim was to study the Panama Papers network as a whole, in the same way you might study a social network like Facebook, to try to understand what the network behavior can tell us about how money can be moved.

"In general, in any social network like LinkedIn or Facebook, there is something called 'Small World Phenomenon', which means that you're only ever around six people away from anyone in the world," Kejriwal said.

"For instance, if you want get from yourself to Bill Gates, on average you would be around six connections away," he said.

However the team discovered that the Panama Papers network was about as far removed from this traditional social or organizational network behavior as it could possibly be. Instead of a network of highly integrated connections, the researchers discovered a series of secretive disconnected fragments, with entities, intermediaries and individuals involved in transactions and corporations exhibiting very few connections with other entities in the system.

"It was really unusual. The degree of fragmentation is something I have never seen before," said Kejriwal. "I'm not aware of any other network that has this kind of fragmentation."

"So (without any documentation or leak), if you wanted to find the chain between one organization and another organization, you would not be able to find it, because the chances are that that there is no chain - it's completely disconnected," Kejriwal said.

Most social, friendship or organizational networks contain a series of triangular structures in a system known as the 'friend of a friend phenomenon."

"The simple notion is that a friend of a friend is also a friend," Kejriwal said. "And we can measure that by counting the number of triangles in the network."

However, the team discovered that this triangular structure was not a feature of the Panama Papers network.

"It turns out that not only is it not prevalent, but it's far less than prevalent than even for a random network," Kejriwal said. "If you literally randomly connect things, in a haphazard fashion and then you count the triangles in that network, this network is even sparser than that." He added, "Compared to a random network, in this type of network, links between financial entities are scrambled until they are essentially meaningless (so that anyone can be transacting with anyone else)."

It is precisely this disconnectedness that makes the system of secret global financial dealings so robust. Because there was no way to trace relationships between entities, the network could not be easily compromised.

"So what this suggests is that secrecy is built into the system and you cannot penetrate it," Kejriwal said.

"In an interconnected world, we don't expect anyone to be impenetrable. Everyone has a weak link," Kejriwal said. "But not in this network. The fact it is so fragmented actually protects them."

Kejriwal said the network behavior demonstrates that those involved in the Panama Papers network of offshore entities and transactions were very sophisticated, knowing exactly how to move money around in a way that it becomes untraceable and they are not vulnerable through their connections to others in the system. Because it is a global network, there are few options for national or international bodies to intervene in order to recoup taxes and investigate corruption and money laundering.

"I don't know how anyone would try to bring this down, and I'm not sure that they would be able to. The system seems unattackable," Kejriwal said.

PHILADELPHIA (September 29, 2020) - Serious traumatic injuries are a health event that can begin a trajectory toward chronic health and social challenges. Research on patient outcomes following traumatic injuries establishes the pervasive nature of injuries' long-term consequences in physical, psychological, social and economic well-being, which may persist months and even years after an injury hospitalization. In light of this research, emerging interventions have targeted enhanced and coordinated healthcare services to support recovery and address patients' long-term rehabilitative needs.

Across a numerous of other health conditions, mobile technology-based prevention and treatment interventions have been used successfully to monitor and transform health outcomes. But until now, their potential for addressing inter-related physical, psychological, and social challenges in long-term injury recovery has not been unexplored.

A new study - recently published in mHealth - from the University of Pennsylvania School of Nursing (Penn Nursing) is the first of its kind to examine how mobile health applications and text-based elicitation of patient-reported outcomes can be used better understand persistent challenges to recovery after a serious injury and hospitalization. This study showed that mobile health monitoring was feasible and acceptable including for select biometric indicators of physical activity and sleep, in a sample of Black men recovering from serious trauma in Philadelphia, PA who described past and current barriers to their access to health and social care resources.

"This study adds evidence to support efforts to more systematically and comprehensively conceptualize the aftermath of physical trauma as an often long-term and chronic health condition," writes the article's lead-author Sara F. Jacoby, MPH, MSN, PhD, Assistant Professor in the Department of Family and Community Health. "This pilot research is a first step in identifying the utility and implementation specifications of real-time monitoring for long-term physical, psychological, and social outcomes in trauma patients using mobile technology."

A new treatment for breast cancer patients with hormone receptor (HR+) early stage disease who are at a high risk of recurrence has been shown to reduce the risk by 25%, according to a study led by The Royal Marsden NHS Foundation Trust.

The results of the monarchE study presented at the European Society for Medical Oncology Virtual Congress (ESMO) and published simultaneously in the Journal of Clinical Oncology (JCO) on Sunday 20 September 2020, have been described as one of the most promising breakthroughs for patients with this type of breast cancer in the last 20 years.

The global randomised Phase III study with 5,637 patients in 38 countries tested if patients taking the CDK 4/6 inhibitor abemaciclib along with hormone therapy following standard of care treatments (chemotherapy, surgery and/or radiotherapy) would reduce the risk of recurrence compared with the standard hormone treatment alone.

Approximately 70% of breast cancer patients have hormone receptor positive tumours, and of those a proportion of patients will have a higher risk of relapsing in the first two of years. Patients with disease that has spread to lymph nodes, a large tumour size at the time of diagnosis, or an increased cellular proliferation (determined by high grade of the tumour, or number of dividing cells) were considered to be at "high risk" of recurrence and recruited to the study.

The study found a 25% reduction in recurrence of cancer when abemaciclib was added to the standard hormone therapy compared to the hormone therapy alone for two years. During this time 11.3% of patients in the control group had a relapse of their cancer compared with 7.8% of those in the abemaciclib group.

Professor Stephen Johnston, Consultant Medical Oncologist at The Royal Marsden and Professor of Breast Cancer Medicine at The Institute of Cancer Research, said: "The monarchE research has given us a confidence that we will soon be to offer our high risk HR+ patients a greater chance of keeping them cancer free . While there have been many advances in other early breast cancer subtypes such as HER2 positive disease, there has been no significant advancements for the large group of patients who have hormone receptor positive breast cancer since the late 1990s when aromatase inhibitors were introduced. This research could potentially save many lives in the future."

Patient Sarah Ryder, 57, said: "When I was referred to The Royal Marsden last year and Professor Johnston told me about the monarchE trial I was so pleased to be part of something that could potentially save my life. By that stage my cancer had spread to 23 lymph nodes and I honestly did not feel much hope.

"The trial has helped me believe in a future again. I can see my daughter grow up, go off to university next year and maybe have a family of her own one day."

In the United States, the average American sleeps less than the minimum seven hours of sleep per night recommended by the Center for Disease Control, and nearly half of Americans report negative consequences from insufficient sleep. This problem appears to be especially prevalent in men, who report getting significantly less sleep, on average, than women.

A cultural complication is the notion that getting less than the recommended amount of sleep signals something positive about an individual. For example, US President Donald Trump has boasted about getting less than four hours of sleep per night and regularly derogates his political opponent Joe Biden as "Sleepy Joe."

"The Sleep-Deprived Masculinity Stereotype," a new paper in the Journal of the Association for Consumer Research, examines a possible stereotype connecting sleep and masculinity along with its underlying mechanisms and its social implications.

Authors Nathan B. Warren and Troy H. Campbell conducted 12 experiments involving 2,564 American participants to demonstrate that a sleep-deprived masculinity stereotype exists. In one experiment, participants were asked to imagine seeing a man shopping for a bed. Then, a salesperson asked the man, "How much do you normally sleep?" The results found that the mean masculinity rating for participants in the lots of sleep condition was significantly lower than the mean masculinity rating for participants in the little sleep condition.

In another experiment, participants were asked to ascribe different attributes to a male character, assigned to either a "very masculine and manly" man or a "not very masculine and not very manly" man. Participants in the masculine condition described their character sleeping 33 minutes less sleep per night than the characters described in the not masculine condition. A final experiment showed that participants who imagined stating they sleep more than average felt significantly less masculine than participants who imagined stating they sleep less than average.

Collectively, the experiments found that men who sleep less are seen as more masculine and more positively judged by society. The same patterns were not consistently observed for perceptions of women.

"The social nature of the sleep-deprived masculinity stereotype positively reinforces males who sleep less, even though sleeping less contributes to significant mental and physical health problems," the authors write. This may be particularly detrimental because men frequently have significantly more negative attitudes towards seeking psychological help. "Unfortunately, the problems created by the sleep-deprived masculinity stereotype may reach beyond individuals and into society, as men who sleep less are found to be more aggressive and violent." This is an example of the restrictive and toxic characteristics of masculinity, "which can be harmful to men's health and society at large."

The bright side of this research, the authors say, is that "as society continues to challenge traditional definitions of masculinity, attitudes toward sleep may become more positive, and all people might enjoy more nights full of healthy sleep."

LONDON, ONTARIO - A new study from Lawson Health Research Institute and Western University illustrates how the gut microbiome interacts with an oral medication in prostate cancer patients, suggesting bacteria in the gut play a role in treatment outcomes. The findings, published in Nature Communications, highlight how the drug abiraterone acetate is metabolized by bacteria in the gut to reduce harmful organisms while promoting those that fight cancer. The team suspects this is one of many examples of how the microbiome influences our response to medications.

"Research is beginning to uncover the ways in which the human microbiome influences cancer development, progression and treatment," explains Brendan Daisley, a PhD candidate at Western's Schulich School of Medicine & Dentistry who is conducting research at Lawson. "Our study highlights a key interaction between a cancer drug and the gut microbiome that results in beneficial organisms with anti-cancer properties."

Traditional prostate cancer therapies are designed to deprive the body of hormones called androgens, which are responsible for prostate cancer growth.

"Unfortunately, traditional androgen deprivation therapies are not always effective," explains Dr. Joseph Chin, Lawson Associate Scientist, Professor at Schulich Medicine & Dentistry and Urologist at London Health Sciences Centre (LHSC). "In those cases, alternative therapies are explored."

Abiraterone acetate is a highly effective therapy used in the treatment of prostate cancer that has been resistant to other treatments. While abiraterone acetate also works to reduce androgens in the body, it does so through a different mechanism and, unlike traditional therapies, it is taken orally.

"When drugs are taken orally, they make their way through the intestinal tract where they come into contact with billions of microorganisms," says Dr. Jeremy Burton, Lawson Scientist, Associate Professor at Schulich Medicine & Dentistry and lead researcher on the study. "While it's long been a mystery why abiraterone acetate is so effective, our team wondered if the gut microbiome plays a role."

The team's study included 68 prostate cancer patients from LHSC, including those being treated with abiraterone acetate and those being treated with traditional androgen deprivation therapies. The research team collected and analyzed patient stool samples, and conducted further experiments in their laboratory at St. Joseph's Health Care London.

They discovered that patients' gut microbiomes changed drastically after taking abiraterone acetate. Bacteria in the gut metabolized the drug leading to a significant increase in a bacterium called Akkermansia muciniphila. Referred to as a 'next-generation probiotic,' this bacterium's relevance has recently been explored in several large cancer studies. It's been shown to facilitate a better response to cancer immunotherapy drugs and it can elicit a wide range of other positive health benefits as well. The increase in Akkermansia muciniphila also led to an increased production of vitamin K2 which is known for anti-cancer properties that can inhibit tumour growth.

The team also observed the impact of androgen depletion on the microbiome. Both abiraterone acetate and traditional androgen deprivation therapies led to a decrease in organisms that utilize androgen.

"These findings clearly demonstrate that the gut microbiome is playing a role in treatment response," notes Dr. Burton.

The team hopes to further explore drug-microbiome interactions with a goal of harnessing the microbiome to improve treatment outcomes for a variety of diseases. In another study, they are exploring whether fecal microbiota transplants from a healthy donor can change the microbiome of melanoma patients to increase organisms like Akkermansia muciniphila and improve response to immunotherapy. They also plan to study whether analysis of a patient's microbiome can be used to predict their response to specific therapies.

"While more research is needed, we may one day be able to analyze a patient's microbiome to determine the best course of treatment or even influence the microbiome to improve outcomes," says Dr. Burton. "This could lead to a new frontier in personalized medicine."

Scientists at Boston University's National Emerging Infectious Diseases Laboratories (NEIDL) and the Center for Regenerative Medicine (CReM) joined forces to develop the most relevant research model possible for understanding how the coronavirus virus impacts the lungs, by engineering living, "breathing" human lung cells from stem cells for the task.

Their efforts have borne a leap forward in our understanding of how COVID-19 infections trigger deadly levels of lung inflammation. Their discovery of a pathway that sets the lungs ablaze with inflammation has launched a search for new therapeutics that could block this process before it can take off and turn fatal.

According to their new findings, published in Cell Stem Cell, the trouble starts soon after the air sacs in the lungs are infected with SARS-CoV-2, when the virus activates one of the body's biological pathways known as NFkB (the k is pronounced "kappa"). As that's happening, the virus also suppresses the lungs' ability to call in the help of the immune system to fight off the viral invaders.

When the signal for help finally goes out--several days after infection has taken hold--an army of immune cells swarms into lung tissue heavily laden with infected, dead, and dying cells and with unchecked levels of inflammation triggered by the early activation of NFkB. The incoming immune cells, by attempting to destroy every infected cell in their path, add more fuel to the fire. Every infected cell killed by the virus or by immune cells trying to thwart viral spread tips the scales of inflammation closer to sending the lungs and other organs into total failure.

The discovery of NFkB's role in this deadly cascade makes it a promising target for new therapeutics that could tamp down its activity early on after infection with the novel coronavirus. A new drug could help reduce inflammation before it gets out of control, and give the body critical time to recruit help from immune cells before conditions have deteriorated too far."We've learned [NFkB] is the primary pathway that drives inflammation [in COVID-19 patients]," says one of the study's corresponding authors, Darrell Kotton, who is a director of the CReM and a pulmonologist at BU's teaching hospital, Boston Medical Center (BMC). "Now the challenge is to find effective therapeutics that work in patients who are developing acute respiratory distress syndrome [ARDS]."Kotton says the revelation about NFkB's role in severe coronavirus infections is important because the data was gathered directly from observing human lung cells infected with live SARS-CoV-2 virus. That's different from the vast majority of coronavirus research written about to date, which has been based on infecting much more commonly available types of cells for research: kidney cells derived from African green monkeys. Those kidney cells are easily grown and maintained in culture dishes, but don't accurately represent human lung cells.

"You learn a lot more about how human beings respond to the virus and how drugs might work in them when you infect human lung cells, not kidney cells from monkeys," Kotton says.

For study co-corresponding author Elke Mühlberger, a virologist at the NEIDL who typically works with some of the world's most lethal viruses, like Ebola and Marburg, it was remarkable to witness the effect SARS-CoV-2 virus has on human lung cells.

"It was scary to see how much damage the virus does to these cells," Mühlberger says. "It disrupts the [membrane surrounding the cell nucleus], and causes significant changes to the cell's organelles," which are the internal parts of a cell that carry out essential functions. "The cells really suffer," she says, and not even Ebola or Marburg viruses have as much impact on the cell's internal organelles as the novel coronavirus does, she adds.

"I don't think the senior members of our research team and I have ever experienced anything like this in our careers," Kotton says. He and co-corresponding author Andrew Wilson, also a CReM scientist and a pulmonologist at BMC, have avoided stepping foot in their own labs in the CReM in order to protect their colleagues from the coronavirus exposure risks they endure inside BMC's intensive care unit.

At BMC, Kotton and Wilson frequently saw patients infected with the coronavirus who, despite having mild cold-like symptoms and feeling pretty healthy for a week or so, would suddenly crash, needing to be intubated and ventilated. "We saw this process taking place right in front of our eyes. It was so evident to us that we were trying to keep patients alive after the damage to their lungs had already happened," Kotton says.

That fueled their interest in looking at what's happening inside the lungs' air sac cells at the onset of coronavirus infection.

"We had to get a glance at what the cells are doing when the disease first takes off, because after that, it's probably too late to stop the process except to help keep patients alive with a ventilator," Kotton says. "The first day a lung cell gets infected, what is the cell telling us? We hypothesized that time frame might be a much more effective window to intervene." Peering into that window, they identified NFkB as the primary culprit.

To make that discovery, Adam Hume, a co-lead author of the study and a senior research scientist in Mühlberger's lab, performed the SARS-CoV-2 infections on sophisticated lung models created by stem cell researchers in Kotton and Wilson's CReM labs--Jessie Huang, Rhiannon Werder, and Kristy Abo, also co-lead study authors. Their models of human lung tissue--three-dimensional structures of lung cells, called "lung organoids"--are grown from human stem cells. The CReM's organoids have been used by researchers at BU and with collaborators elsewhere to study a range of chronic and acute lung diseases.

For coronavirus research, CReM scientists leveraged their organoid expertise to grow lung air sac cells, the type of cell that lines the inside of lungs. Air sac cells are usually difficult to grow and maintain in traditional culture and difficult to extract directly from patients for research purposes. That's why many labs rely on the use of more readily available cell types, like kidney cells from monkeys.

"Our organoids, developed by our CReM faculty, are engineered from stem cells--they're not identical to the living, breathing cells inside our bodies, but they are the closest thing to it," Kotton says.

The CReM team then placed the human air sac cells into an experimental model they had previously developed to study the effects of smoking cigarettes. The cells are plated on a mesh membrane; on one side they are exposed to air, just like air sac cells experience in the lungs when we breathe. On the other side of the membrane, the cells are fed by a liquid concoction that mimics the nutrients and growth factors supplied by lungs' blood vessel network.

From there, the NEIDL team stepped in to infect the lung model. Hume added droplets of live coronavirus on top of the lung cells, infecting them from the air side of the membrane, similar to the way the virus infects cells lining the inside of the lungs when air containing the virus is breathed into the body. He and Mühlberger have run these experiments inside one of the NEIDL's Biosafety Level 4 (BSL-4) laboratories, the highest possible level of biosafety containment used for infectious agents that pose especially high risk to humans.

Based on the experiments implicating NKfB's role in severe coronavirus cases, the CReM and NEIDL researchers are now collaborating with researchers at BU and beyond who have libraries of drugs and novel chemical compounds. Together, the collaborators plan to screen for potential therapeutics that could block the train of inflammation from leaving the station.

Using the CReM lung model at the NEIDL, the researchers have confirmed that existing drugs remdesivir and camostat are effective in combating the virus, though neither is a perfect fix for controlling the inflammation unleashed by NFkB.

Remdesivir, a broad-use antiviral, has already been used clinically in coronavirus patients. Camostat, an antiviral and cancer drug sometimes used to treat pancreatitis, has previously been tested in a type of cell found higher up in the lungs, in the airway, and found to be effective. With the BU team's experiments confirming it also works to treat coronavirus infection in the lungs' air sac cells, Kotton says camostat is a good candidate for clinical trials.

"It's been wonderful to finally be on the offense, rather than on the defense, like we were early on in April and May," Wilson says. At BMC, he recalls during the springtime surge of coronavirus cases, "There was a period of time where overhead announcements, calling code teams to assist with a patient doing poorly, would go off at least once an hour. It was really, really intense."

As patients struggled to survive, Wilson says he and other clinicians felt like there was relatively little they could offer in terms of specific therapies for the coronavirus. "That was so hard--you so badly want to do something to help someone get better," he says.

Now, untangling the workings of the virus through research, he feels there has been an important change of mindset.

"How can we attack this virus? The cells we're using in these experiments are the cell type most prominently affected in sick patients, the patients we're caring for who have developed ARDS," Wilson says. "It's really important to do research on the right type of cell. It tells us how the virus is working and also what parts of the body's normal immune mechanisms aren't working like they're supposed to."

New research from the University of Georgia supports growing evidence for airborne transmission of COVID-19 in enclosed spaces.

Researchers were able to link a community outbreak of COVID-19 in China to a source patient who likely spread the virus to fellow bus riders through the bus's air conditioning system.

"The possibility of airborne transmission has long been suspected, but with limited empirical evidence. Our study provided epidemiologic evidence of transmission over long distances, which was likely airborne," said Ye Shen, an associate professor of epidemiology and biostatistics at UGA's College of Public Health and lead author on the study.

The study, which was published recently in JAMA Internal Medicine, calls into question the prevailing thought on how COVID-19 can spread.

"It was largely believed that close contact through droplets is a major route of transmission for COVID-19. However, the widely adopted social distancing and hand washing did not effectively prevent the transmission globally. Instead, the number of new COVID-19 cases increased steadily," said Shen.

Shen and his co-authors worked with epidemiologists from two regional Centers for Disease Control and Prevention in China to trace infections following a large outdoor worship event in Zhejiang province. Some of the attendees, it turns out, took two buses to the event creating a unique natural experiment for the researchers.

Both buses had closed windows and had air conditioning running, said Changwei Li, an associate professor of epidemiology at Tulane University and study co-author - but one bus carried a patient infected with the virus, and the other did not.

Of the passengers who later got sick, the majority of them rode on the same bus as the source patient. Even though the two groups later mixed in with the larger crowd at the worship event, the number of new cases attributed to the event were much lower, suggesting that the bus was the major point of transmission.

Further, some of the bus passengers who later showed symptoms of COVID-19, the authors found, were not sitting close to the infected passenger.

These findings highlight scenarios where COVID-19 could be spread through fine aerosol particles being circulated in an enclosed space, and as the weather turns colder, Shen and Li hope this work will persuade more people to wear face masks in public areas, particularly in indoor spaces.

"Understanding the transmission routes of COVID-19 is critical to contain the pandemic, so that effective prevention strategies can be developed targeting all potential transmission routes," said Shen. "Our findings provide solid support for wearing face covering in enclosed environments with poor ventilation."

BIRMINGHAM, Ala. - Science has long known that recovery from experimental heart attacks is improved by injection of a mixture of heart muscle cells, endothelial cells and smooth muscle cells, yet results have been limited by poor engraftment and retention, and researchers worry about potential tumorigenesis and heart arrhythmia.

Now research in pigs shows that using the exosomes naturally produced from that mixture of heart muscle cells, endothelial cells and smooth muscle cells -- which were all derived from human induced pluripotent stem cells -- yields regenerative benefits equivalent to the injected human induced pluripotent stem cell-cardiac cells, or hiPSC-CCs.

Exosomes are membrane-bound extracellular vesicles that contain biologically active proteins, RNAs and microRNAs. Exosomes are well known to participate in cell-to-cell communication, and they are actively studied as potential clinical therapies.

"The hiPSC-CC exosomes are acellular and, consequently, may enable physicians to exploit the cardioprotective and reparative properties of hiPSC-derived cells while avoiding the complexities associated with tumorigenic risks, cell storage, transportation and immune rejection," said Ling Gao, Ph.D., and Jianyi "Jay" Zhang, M.D., Ph.D., University of Alabama at Birmingham corresponding authors of the study, published in Science Translational Medicine. "Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury."

At UAB, Gao was a postdoctoral fellow in Biomedical Engineering, a joint department of the UAB School of Medicine and the UAB School of Engineering. Zhang is chair of the department.

Studies in large animals are necessary to identify, characterize and quantify responses to potential treatments. Prior to this current study, the feasibility of hiPSC-CC exosomes for cardiac therapy had been shown only in mouse models and in vitro work.

In the UAB experiments, juvenile pigs with experimental heart attacks had one of three treatments injected into the damaged myocardium: 1) a mixture of cardiomyocytes, endothelial cells and smooth muscle cells derived from human induced pluripotent stem cells, 2) exosomes extracted from the three cell types, or 3) homogenized fragments from the three cell types.

The researchers had two primary findings from the pig studies. First, they found that measurements of left-ventricle function, infarct size, wall stress, cardiac hypertrophy, apoptosis and angiogenesis in animals treated with hiPSC-CCs, hiPSC-CC fragments or hiPSC-CC exosomes were similar and significantly improved compared to animals that recovered without any of the three experimental treatments. Second, they found that exosome therapy did not increase the frequency of arrhythmia.

In experiments with cells or aortic rings grown in culture, they found that exosomes produced by hiPSC-CCs promoted blood vessel growth in cultured endothelial cells and isolated aortic rings. Furthermore, the exosomes protected cultured hiPSC-cardiomyocytes from the cytotoxic effects of serum-free low-oxygen media by reducing the programmed cell death called apoptosis and by maintaining intracellular calcium homeostasis, which has a direct beneficial effect on heart conductivity. The exosomes also increased cellular ATP content, which is beneficial since deficiencies in cellular ATP metabolism are believed to contribute to the progressive decline in heart function for patients with left ventricle hypertrophy and heart failure.

The researchers also found that some of these in vitro beneficial effects could also be mediated by synthetic mimics of the 15 most abundant microRNAs found in the hiPSC-CC exosomes. The researchers noted that knowledge of the potential role of microRNAs in clinical applications is still far from complete.

RIVERSIDE, Calif. -- A team of researchers led by biomedical scientist Declan F. McCole at the University of California, Riverside, has found that the drug tofacitinib, also called Xeljanz and approved by the FDA to treat rheumatoid arthritis and ulcerative colitis, can repair permeability defects in the intestine.

"Our work could help improve identification of patients who will be better responders to this drug," said McCole, a professor of biomedical sciences in the School of Medicine.

Study results appear in the Journal of Crohn's and Colitis.

Affecting roughly 1 million Americans, ulcerative colitis, an inflammatory bowel disease, is a chronic disease of the large intestine, in which the lining of the colon becomes inflamed and leaky.

A single layer of cells that plays a critical role in human health, the intestinal epithelium provides a barrier while also allowing nutrient and water absorption. Intestinal epithelial cells are critical for regulating immune function, communicating with the intestinal microbiota, and protecting the gut from pathogen infection -- all of which critically depend on an intact epithelial barrier. The body's largest pool of immune cells can be found directly beneath the epithelial cell layer.

The current study is a follow-up to two recently published studies from McCole's lab. In the first study, published in December 2019, the researchers used a cell culture model system to show that tofacitinib can directly act on epithelial cells that line the gut to correct defects in the barrier properties of these cells that occur in inflammation. The second study, published in July 2020, showed a loss-of-function mutation in the gene "protein tyrosine phosphatase non-receptor Type 2," or PTPN2, disrupted normal beneficial interactions between epithelial cells and macrophages -- a type of white blood cell that constitutes a considerable fraction of intestinal immune cells -- and increased gut leakiness.

In the new study, the authors show tofacitinib can reverse gut leakiness in mice caused by loss of PTPN2 activity. Until now, the effects of tofacitinib on intestinal barrier function in an animal model were largely unknown.

McCole explained that increased intestinal permeability -- or leakiness -- is a feature of inflammatory bowel disease and plays a critical role in promoting inflammation. His team also tested tofacitinib in a system where PTPN2 expression was reduced in human intestinal epithelial cell lines and macrophages that were then cultured together to study the effects on epithelial permeability. The team also studied mice that had increased gut leakiness resulting from removal of PTPN2 only in macrophages. The researchers found tofacitinib repaired inflammation-induced permeability defects in both the cell culture system and in mice.

"Patients with the loss-of-function mutations in PTPN2 have an increased risk of inflammatory bowel disease," McCole said. "Our work improves our understanding of how this drug is useful for treating ulcerative colitis and suggests that patients with loss-of-function mutations in the PTPN2 gene may have a better response to tofacitinib. This could help with improved targeting of drug treatments to specific groups of patients."

210 scientists from around the world highlight the state of the world's plants and fungi in a landmark Plants, People, Planet Special Issue, in collaboration with the Royal Botanic Gardens, Kew

The Special Issue, 'Protecting and sustainably using the world's plants and fungi', brings together the research - from 210 scientists across 42 countries - behind the 2020 State of the World's Plants and Fungi report, also released today by the Royal Botanic Gardens, Kew.

This is the first time that over 200 scientists have come together and collaborated to deliver a vital update, not only on the status of the world's plant life, but also the world's fungi. Humanity's existence and well-being depends on plants and fungi - from our food and energy, to our physical and mental health. The scientists' findings plot a global roadmap that sets out what we must do to protect and sustainably use plants and fungi, now and in the future.

The data and expert opinion behind Kew's report have, for the first time, been published in a landmark Plants, People, Planet Special Issue and are freely available to read and share. This Special Issue points the way forward for future research and conservation efforts around the world for the benefit of people and the sustainable future of our planet. It highlights the strength of researchers working together and the importance of collaboration between scientific journals and botanic gardens like RBG Kew.

"We are delighted to be partnering with Kew to publish the scientific papers behind the State of the World's Plants and Fungi 2020 report," said Prof. Simon Hiscock, Editor in Chief of Plants, People, Planet. "Plants, People, Planet was founded to highlight how fundamentally important plants are to people and all life on Earth. We embrace Kew's transformative agenda to curate, conserve and explore the world's plant and fungal diversity as outlined in this landmark collection," he added.

"The data in this year's report paint a picture of a world that has turned its back on the incredible potential of the plant and fungal kingdoms to address some of the biggest challenges we face," said Professor Alexandre Antonelli, Director of Science at the Royal Botanic Gardens, Kew. "We have particularly earmarked the gaps in our knowledge, the changes we are seeing, the species being named new to science and the shocking pace of biodiversity loss."

"The rigour and collaborative nature of the scientific work underlying the articles in the New Phytologist Foundation's Plants, People, Planet, which accompany the State of the World's Plants and Fungi report, is testimony to the incredible wealth of knowledge that exists and is now being brought to surface," added Professor Antonelli. "This has been a truly fantastic and rewarding collaboration; Plants, People, Planet is a prestigious journal that shares Kew's mission and provides free access to its contents for the benefit of all. I hope this work will help inform decisions here in the UK and all over the world as we start the most critical decade our planet has ever faced".

Using the research included in the Plants, People, Planet Special Issue we can understand and make use of the full extent of plant and fungal diversity while recognising the threats to their survival, so that we can halt biodiversity loss and unlock its full potential.

A new precision drug which stops cancer from repairing its DNA has shown promise in an early-stage clinical trial - highlighting the potential of a new class of drugs known as ATR inhibitors.

The drug candidate, tested in humans for the first time, was shown to be well tolerated and stopped the growth of tumours in over half of patients treated.

People in the trial had a range of advanced, heavily pre-treated cancers including breast, bowel and prostate tumours. It is remarkable to see the new drug - which works by blocking a key molecule called ATR, involved in repairing DNA - showing promising clinical benefit in a phase I trial, in patients who were very sick.

The trial, led by The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, involved 21 patients with advanced solid tumours with defects in various genes which help coordinate DNA repair. Eleven patients had tumours with defects or deletions affecting a key gene called ATM.

The aim of the trial was to evaluate the safety of the ATR inhibitor BAY1895344 and to identify the maximum tolerated dose that could be safely given to a group of cancer patients who had already previously been treated with multiple other drugs.

The researchers found that the drug was well tolerated by patients - and better still, that there were encouraging signs that it was effective against advanced cancers with defects in the ATM gene.

The new results are published in the prestigious journal Cancer Discovery today (Tuesday), and the trial was funded by the manufacturer of the drug, Bayer.

The team found that BAY1895344 stopped tumour growth in eight out of the 21 patients and shrunk the tumours of another four patients with ATM mutations - which is remarkably positive for a phase I trial, since its primary aim is to test the safety of a drug, rather than its effectiveness.

The effectiveness of the drug seemed to be long lasting, with an average period of response of 316 days. In addition, three out of four patients who saw their tumours shrink remained on treatment for more than a year.

The most common side effect reported was anaemia, which was managed with the help of blood transfusions and did not usually require the treatment to be stopped.

The researchers also analysed the biochemical and pharmacological effects of the drug, and were able to show that it exercised its effects in patients by increasing damage to DNA.

DNA damage is the fundamental cause of cancer - leading to mutations in key genes that allow cancer cells to divide uncontrollably. But it can also be a key weakness of tumours that can be exploited, since cancer cells can be killed by further damaging their DNA or stopping them from repairing it.

The new study supports further investigation of a treatment strategy that targets the DNA repair protein ATR, especially in patients whose cancers already have certain defects in DNA repair genes like ATM or BRCA1 - weakening their ability to cope with DNA damage.

Further clinical trials are warranted to further evaluate the safety and efficacy before it can be licensed by a regulatory authority. Clinical trials investigating BAY 1895344 as a single agent or in combination with other drugs are now under way, and the hope is that it could be developed into a new targeted treatment for patients with a variety of cancers with certain defects in DNA repair.

Recently, another phase I trial led by The Institute of Cancer Research (ICR) and The Royal Marsden also showed benefits for an ATR inhibitor (called berzosertib) in patients with very advanced tumours, either on its own or with chemotherapy.

Other cancer drugs that attack DNA repair mechanisms already exist. The ICR pioneered the genetic targeting of the first approved precision medicine attacking cancer's ability to repair DNA, the PARP inhibitor olaparib.

In future, ATR inhibitors may become a new class of targeted drugs that could help overcome resistance to other precision medicines like PARP inhibitors.

The ICR, a charity and research institute, will be focusing on how to overcome drug resistance in its new Centre for Cancer Drug Discovery, which is nearing completion. The ICR is now raising money for the Centre's state-of-the-art equipment, so that researchers in the building can get off to the strongest possible start.

Study leader Professor Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:

"Our new trial shows that this promising new treatment is safe and can benefit some patients even with very advanced cancers.

"The new drug, which is currently known only by the code BAY1895344, works by blocking a molecule called ATR which is involved in repairing DNA. It seems to be especially effective in patients whose tumours have defects in a gene called ATM which mean their ability to repair DNA is already weakened - suggesting that this could become a new form of targeted treatment.

"It is very promising to see patients responding in an early-stage trial like this, and we are looking forward to further clinical trials to test the drug's efficacy."

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

"It is exciting to see a new class of precision medicine showing such promise in early trials. At the ICR, we have pioneered ways of treating cancer by exploiting the weaknesses that tumours often have in repairing their DNA. I am hopeful that later-stage trials will show that this new class of ATR inhibitors can prove effective against cancers with defective systems for DNA repair, and we are keen to investigate whether they could prevent tumours from developing resistance to another important class of medicine called PARP inhibitors, which work in a similar way.

"One of our main goals is to find new targeted treatments and drug combinations that can tackle cancer evolution and drug resistance - and this will be the main focus of research in our pioneering new Centre for Cancer Drug Discovery."

CHICAGO: Hospital resources and infrastructure dedicated to improving quality and safety are essential for achieving safe and high-quality surgical outcomes. A comprehensive review of four key principles of the American College of Surgeons (ACS) Quality Verification Program demonstrates the importance of an overall hospital culture of quality and safety, including top- and mid-level, quality-focused leadership and a committee dedicated to quality improvement. Results of the review are published as an "article in press" on the Journal of the American College of Surgeons website in advance of print.

"This peer-reviewed article highlights how important it is for hospitals to have infrastructure and resources for building a surgical quality improvement program. Leadership, in the corporate suite, mid-level leadership involved in improving quality, committees focused on surgical quality and safety, and an overall culture of safety and high-reliability help assure the delivery of high-quality care to patients," said Chelsea Fischer, MD, MS, ACS Clinical Scholar in Residence and co-first-author of the literature review.

The ACS Quality Verification Program helps surgeons and hospitals identify the resources needed for robust surgical quality improvement. The program is based on a set of principles or standards at the foundation of surgical quality. These principles were gleaned from the knowledge and experience of surgical experts as well as the ACS' experience with 3,000 hospitals that participate in the ACS Quality Program. The principles were published in the Optimal Resources for Surgical Quality and Safety, also known as the ACS Red Book.

"By using the ACS Red Book framework, the ACS Quality Verification Program provides a structured mechanism by which hospitals can focus on their surgical quality efforts in a standardized manner. The program has been developed to assure hospital leadership, surgeons, clinical staff, and patients that there's a core infrastructure in place underpinning quality across all departments and divisions of surgery," said David B. Hoyt, MD, FACS, article coauthor and ACS Executive Director.

The basis of the Quality Verification Program rests on 12 standards: leadership commitment and engagement, surgical quality officer, surgical quality and safety committee, safety culture, data collection and surveillance, continuous quality improvement using data, case review, surgeon review, surgical credentialing and privileging, standardized and team-based processes of care, disease-based management, and compliance with regulatory performance metrics.

The literature review in JACS is the first of three investigations to examine the evidence that supports these standards. The study gathered and analyzed evidence associated with the first four principles that address institutional and administrative factors necessary for high quality surgical care: a top-down commitment to quality, mid-level leadership, and committee structure, including the scope and governance of a quality program and infrastructure.

"This article provides a robust body of evidence for the foundation of the ACS Quality Verification Program. The program is based on standardization and a system approach to surgical care. This program has been developed to reduce patient complications, minimize waste for surgical care teams, and increase the value of surgery for our patients," explained article coauthor, Clifford Y. Ko, MD, MSHS, FACS,

FASCRS, Director of the ACS Division of Research and Optimal Patient Care.

The U.S. National Library of Medicine's Medline database was searched for articles published between its inception in 1964 and January 2019. Articles evaluated the relationship between one of the Red Book principles and patient or organizational quality outcomes. Two reviewers synthesized and summarized information from these studies.

After identifying 5,332 studies involving the four principles, a total of 477 were selected for systematic review. Several primary studies also were included for assessment.

Leadership

Individual articles covering 30 years of research on senior or executive leadership in health care were included in four systematic reviews. Evidence from these investigations showed clinical quality improved when senior leaders were engaged and committed to quality. Higher levels of incident reporting that reduced medical errors, better compliance with guidelines, improved efficiency and safety, and interventions targeted at improving specific health outcomes were some of the findings linked to the actions of executive leaders.

Providing resources or visibly engaging in quality and safety endeavors also fostered successful quality improvement efforts.

Surgical Quality Officer

Medline articles and systematic reviews of studies over 32 years related effective mid-level management in quality improvement with better patient and organizational outcomes. The evidence showed that a surgical quality officer positively affected quality improvement efforts and the way they were conducted.

Surgical Quality and Safety Committee

The evidence indicated that a quality and safety committee must have wide clinical representation, well-defined goals, and clear lines of communication and authority to ensure quality improvement efforts will be effective.

Culture of Safety and Reliability

Medline articles and studies covering a 20-year period showed that organizational culture improved patient outcomes and safety in the workplace. Among the most effective aspects of institutional culture were education programs, communication tools, leadership walk-arounds, and comprehensive unit-based programs.

"Principles related to leadership, resources, and culture help keep surgery safe and reliable. With these concepts in place, hospitals can deliver consistent, quality surgical care to patients and improve patient outcomes," said Dr. Fischer.

Philadelphia, September 28, 2020--Researchers at Children's Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania have identified a cellular pathway that can be targeted with a naturally occurring drug to stimulate lung tissue regeneration, which is necessary for recovery from multiple lung injuries. The findings, which were published today in Nature Cell Biology, could lead to better therapies for patients with lung disease, including acute respiratory distress syndrome (ARDS) due to COVID-19.

"Using cutting-edge technology, including genome-wide and single-cell analyses, we have identified a specific cellular pathway involved in lung tissue regeneration and found a drug that enhances this process," said senior author G. Scott Worthen, MD, a physician-scientist in CHOP's Division of Neonatology and member of the Penn-CHOP Lung Biology Institute. "These findings provide identification of precision targets and thus allow for rational development of therapeutic interventions for lung disease caused by COVID-19 and other illnesses."

Conditions like pneumonia, influenza and ARDS - one of the known complications of COVID-19 - can damage the lining of the air sacs in the lungs, known as the alveolar epithelium, which prevents oxygen from passing from the lungs to the bloodstream and can lead to death. Patients with COVID-19 who develop ARDS become critically ill, and to date, no drugs have been developed specifically to treat ARDS in COVID-19 patients. Understanding which genetic targets and pathways are involved in regenerating epithelial tissue is critical in developing effective therapies for ARDS and similar conditions.

Previous research has shown that type II alveolar pneumocytes (AT2) are important cells involved in lung repair, both through self-renewal and transdifferentiation into type I alveolar pneumocytes (AT1), which facilitate gas exchange between the lung air sacs and nearby capillaries. Yet prior to this study, it was unknown what changes in gene accessibility occurred in AT2 cells following disease-related injury to promote repair and how regenerating AT2 cells influence interactions with nearby mesenchymal cells, which are also important in tissue repair.

Using genome-wide analyses, the research team assessed changes in AT2 after lung injury, which opens up the chromosomes within the cells and makes specific genes available to the machinery of the cell. The researchers then used single-cell analysis of AT2 cells and mesenchymal cells to better understand how the two cell types interact during injury and what cell signaling pathways are involved. The two approaches converged on a single pathway, in which a transcription factor known as STAT3 increased the expression of brain-derived neurotrophic factor (BDNF), which in turn increased lung tissue regeneration.

In further analyzing this pathway, the researchers identified a naturally-occurring compound known as 7,8-Dihydroflavone (7,8-DHF), which targeted a receptor in the pathway, stimulating and accelerating lung tissue repair in multiple mouse models of lung injury.

"We believe these findings could lead to the development of a new therapeutic that could help patients recovering from COVID-19 and similar diseases," said the study's first author, Andrew J. Paris, MD, Instructor of Medicine and a pulmonary specialist in the Perelman School of Medicine at the University of Pennsylvania. "Based on the results of this study, we think 7,8-DHF is an excellent candidate for entering clinical trials for patients with lung diseases."

Mitochondria are present in all eukaryotic cells: in our cells, in mammalian cells, in the cells of plants and even of fungi. Mitochondria produce energy for cells to function as multicellular organisms, and are known as the "powerhouses" of the cell. Inside mitochondria lie the genetic information for making this energy.

EPFL biophysicist Suliana Manley and her team collaborated with Jean-Claude Martinou's cell biology group from the University of Geneva to look deep within living cells. Inside mitochondria there rests RNA granules that are smaller than the diffraction limit of light, i.e. smaller than one one-thousandth the width of a strand of hair. Using super-resolution microscopy, they discovered that mitochondrial RNA's are packaged into tiny liquid droplets that can fuse together and break apart. The results are published in today's issue of Nature Cell Biology.

"The organization of genetic information contained within mitochondria is highly dynamic thanks to this liquid-like aspect of its RNA granules," explains Manley. "The way they continuously exchange material gives us insight into how mitochondria are able to make sure they have the genetic information they require to produce energy within cells."

What led the scientists to inspect RNA granules is linked to the unique identity of mitochondria. In fact, the mitochondrial genome is independent of the cell's genome, so the genetic identity of the mitochondria is separate from the genetic identity of the cell and the rest of the organism. Mitochondria's genome is only around 16 thousand base pairs long whereas the DNA of the human cell, more than 100,000 times as long, consists of 3 billion base pairs. The mitochondria's genome is inherited from the maternal lineage, so the way your cells produce energy essentially comes from your mother. Mitochondria is hypothesized to have its origins in bacteria: 1.5 billion years ago during the course of evolution, bacteria may have been engulfed by another cell to start an endo-symbiotic relationship; with time, the bacteria evolved to become this highly specialized organelle that produces energy for the cell.

Determining the way mitochondria work is important for understanding how the cell functions, but also for understanding how a cell malfunctions. Especially in cells that require large amounts of energy like nerve and muscle cells, dysfunctional mitochondria can have devastating consequences, resulting in severe disease.