Two Anti-inflammatory Compounds Shown to be Capable Of Accelerating Recovery From COVID-19 (Medicine)

Monoclonal antibody tested by researchers at University of São Paulo and experimental drug given to patients in Italy by University of Pennsylvania research group promoted rapid improvement of respiratory function in patients in severe condition.

Two independent clinical studies – one by researchers at the Center for Cell-Based Therapy (CTC) in Ribeirão Preto, state of São Paulo (Brazil), on the monoclonal antibody eculizumab, and the other by scientists at the University of Pennsylvania in Philadelphia (USA) on an experimental drug called AMY-101 – observed a significant anti-inflammatory effect that contributed to a faster recovery by severe COVID-19 patients. The results of the two studies, which set out to compare the compounds’ therapeutic potential, are reported in an article published in Clinical Immunology.

Monoclonal antibody tested at University of São Paulo and experimental drug given to patients in Italy by University of Pennsylvania research group promoted rapid improvement of respiratory function in patients in severe condition. ©Daniel Mezes – HC

The two medications were administered separately. The monoclonal antibody, routinely used to treat blood diseases, was tested on patients at the teaching hospital (“Hospital das Clínicas”) run by the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP). AMY-101, a candidate drug developed by US-based pharmaceutical company Amynda, was given to patients at a hospital in Milan, Italy. Both produced promising results, but because AMY-101 is cheaper and performed better in the clinical trial, the two research groups envisage testing it on a larger number of patients in Brazil.

“Both compounds caused a robust anti-inflammatory response that culminated in a fairly rapid recovery of respiratory function in the patients,” Rodrigo Calado, who led the study at FMRP-USP, told Agência FAPESP. Calado is affiliated with CTC, a Research, Innovation and Dissemination Center (RIDC) funded by FAPESP and based at FMRP-USP’s blood center.

The researchers concluded that the therapeutic benefits of eculizumab and AMY-101 were due to inhibition of a bloodstream cascade of proteins involved in immune response and known as the complement system.

Persistent dysregulated complement activation triggers the exacerbated inflammatory response to SARS-CoV-2 infection characterized by a systemic increase in pro-inflammatory cytokines and often referred to as a “cytokine storm”.

Unable to prevent infection of cells by the virus, the complement system enters a spiral of runaway continuous activation that leads to massive infiltration of monocytes and neutrophils into the infected tissues. This process can result in inflammatory damage to the walls of blood vessels surrounding vital organs, as well as disseminated microvascular injury and thrombosis, potentially culminating in multiple organ failure.

“Previous studies had shown the use of complement inhibitors to be a promising therapeutic strategy to ameliorate thromboinflammation in COVID-19 patients, and there were reports of cases with positive results,” Calado said. “However, as yet no one had elucidated the action or evaluated the efficacy of drugs already in use to treat diseases caused by complement alterations, such as eculizumab, or candidate drugs with this function such as AMY-101.”

To fill the gap the researchers conducted two clinical studies in which they compared the biological efficacy of eculizumab with that of the synthetic peptide AMY-101 in independent small groups of severe COVID-19 patients.

Ten patients aged between 18 and 80 were undergoing treatment at FMRP-USP’s Hospital das Clínicas. Once a week while hospitalized, they were given 900 mg of eculizumab, which inhibits the complement protein C5. Three patients hospitalized in Milan, Italy, were given 5 mg of AMY-101, developed to inhibit complement protein C3, also once a week. These two proteins perform the most important activities in the complement system.

The patients’ clinical responses showed that eculizumab and AMY-101 elicited a robust anti-inflammatory process, a sharp fall in levels of C reactive protein (CRP) and interleukin-6 (IL-6), and a marked improvement in lung function.

Inhibition of C3 by AMY-101 afforded broader therapeutic control, stronger lymphocyte recovery, a pronounced decline in neutrophil count, and more robust attenuation of the thromboinflammation induced by the exacerbated response to viral infection.

“The result of the clinical trials showed that inhibiting components of the complement system sharply reduces inflammation,” Calado said.

New clinical study

In light of the promising results of the two clinical trials, the CTC and UPenn researchers now plan to conduct a Phase 3 trial with more than 100 severe COVID-19 patients, who will be given only AMY-101 in an effort to assess the drug’s efficacy on a wider scale.

The study will be conducted at FMRP-USP’s Hospital das Clínicas, and will probably involve other research institutions in Brazil. “One of the advantages of AMY-101 is its low cost. It’s much less expensive than eculizumab,” Calado said.

References: Dimitrios C. Mastellosa, John D. Lambrisr et al., “Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy”, Clinical Immunology, Volume 220, November 2020, 108598. Link: https://www.sciencedirect.com/science/article/pii/S1521661620307580?via%3Dihub https://doi.org/10.1016/j.clim.2020.108598

Provided by São Paulo Research Foundation (FAPESP)

The Unique Hydraulics in the Barbegal Water Mills, the World’s First Industrial Plant (Archeology)

An elbow-shaped water flume as a special adaptation for the Barbegal mill complex and a symbol of the ingenuity of Roman engineers.

The Barbegal watermills in southern France are a unique complex dating back to the 2nd century AD. The construction with 16 waterwheels is, as far as is known, the first attempt in Europe to build a machine complex on an industrial scale. The complex was created when the Roman Empire was at the height of its power. However, little is known about technological advances, particularly in the field of hydraulics, and the spread of knowledge at the time. A team of scientists led by Professor Cees Passchier from Johannes Gutenberg University Mainz (JGU) has now gained new knowledge about the construction and principle of the water supply to the mills in Barbegal. The research results were published in Scientific Reports.

View of the ruins of the Barbegal mill complex in 2018. photo/©: Robert Fabre, Saint Etienne du Grès, France

A mill complex consisting of a total of 16 water wheels in two parallel rows

Watermills were one of the first sources of energy that did not depend on the muscle strength of humans or animals. In the Roman Empire they were used to make flour and sawing stone and wood. As one of the first industrial complexes in European history, the Barbegal watermills are an outstanding example of the development at that time. The mill complex consisted of 16 water wheels in a parallel arrangement of eight wheels each, separated by central buildings and fed by an aqueduct. The upper parts of the complex were destroyed and no traces of the wooden structures have been preserved, which is why the type of mill wheels and how they worked remained a mystery for a long time.

However, carbonate deposits that had formed from the flowing water on the wooden components remained. These were stored in the archaeological museum in Arles and only recently examined in detail. The researchers found an imprint of an unusual, elbow-shaped flume that must have been part of the mill construction. “We combined measurements of the water basins with hydraulic calculations and were able to show that the flume to which this elbow-shaped piece belonged very likely supplied the mill wheels in the lower basins of the complex with water,” said Professor Cees Passchier. “The shape of this flume was unknown from other watermills, either from Roman or more recent times. We were therefore puzzled as to why the flume was designed this way and what it was used for.”

Carbonate deposits from the side wall of the elbow-shaped water flume, which have formed on the inside of the wooden flume. The vertical patterns are imprints of saw marks on the wood. photo/©: Cees Passchier

An elbow-shaped flume as a unique adaptation for the Barbegal mills

At first glance, the team found such a flume unnecessary and even disadvantageous, because it shortens the height from which the water falls onto the mill wheel. “However, our calculations show that the oddly shaped flume is a unique adaptation for the Barbegal mills,” explained Passchier. The distribution of the carbonate deposits in the elbow-shaped flume shows that it was inclined slightly backwards against the direction of the current. This created a maximum flow rate in the first, steep leg of the flume, and at the same time the water jet to the mill wheel obtained the correct angle and speed. In the complicated mill system, with small water basins, this unique solution was more efficient than using a traditional, straight water channel. “That shows us the ingenuity of the Roman engineers who built the complex,” emphasized Passchier.

“Another discovery was that the wood of the flume was probably cut with a mechanical, water-powered saw, which is possibly the first documented mechanical wood saw – again evidence of industrial activity in ancient times.” The research was carried out by a multidisciplinary team of experts in geology, geochemistry, hydraulics, dendrochronology, and archaeology..

Sketch of the Barbegal mill complex with the lower three water basins with mill wheels and water flumes: The lower basins most probably had elbow-shaped flumes. /©: Cees Passchier

The carbonate deposits that formed on the ancient hydraulic structures are an important tool for the researchers for archaeological reconstructions. In an earlier project, the team led by Professor Cees Passchier was able to show that the flour from the Barbegal mills was probably used to make ship biscuits. “The carbonate deposits give us extremely exciting insights into the skills of Roman technicians at a time that can be seen as the direct predecessor of our civilization,” added Passchier, Professor of Tectonic Physics and Structural Geology at the JGU Institute of Geosciences from 1993 to 2019, now Senior Research Professor in Geoarchaeology.

References : C. C. W. Passchier et al., Reconstructing the hydraulics of the world’s first industrial complex, the second century CE Barbegal watermills, France, Scientific Reports 10, 21 October 2020,
DOI:10.1038/s41598-020-74900-5

Provided by Johannes Gutenberg Universität Mainz

New Medicine Reduced Risk for Heart Failure Emergencies, Hospital Visits (Medicine)

Omecamtiv mecarbil, a new, investigational heart medication, reduced the risk of heart failure-related events in patients with heart failure with reduced ejection fraction, according to late-breaking research presented today at the American Heart Association’s Scientific Sessions 2020. The virtual meeting is Friday, November 13 – Tuesday, November 17, 2020, and is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science for health care worldwide. The manuscript of this study is simultaneously published today in The New England Journal of Medicine.

Ejection fraction is a measurement of the proportion of blood the heart pumps out with each contraction. Heart failure with reduced ejection fraction, or HFrEF, occurs when the left ventricle, the heart’s largest pumping chamber, loses its ability to contract normally. The heart can’t pump with enough force to push blood into circulation. An ejection fraction of 40% or less is used to define HFrEF. For this study, an EF of ? 35% was required.

The GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) study assessed omecamtiv mecarbil, an investigational medication that was granted “fast track” designation as a new heart failure treatment option by the U.S. Food and Drug Administration in May 2020.

Omecamtiv mecarbil binds to cardiac myosin, the protein in the heart that transforms chemical energy into mechanical work, thus powering muscle contraction. In previous studies, it was found to improve cardiac function by increasing the effectiveness by which myosin interacts with actin, another protein involved in heart muscle contraction.

“Omecamtiv mecarbil is the first in a class of heart medicines called myotropes that selectively target cardiac muscle to improve cardiac performance,” said John R. Teerlink, M.D., lead author of the study, director of heart failure and of the Echocardiography Laboratory at the San Francisco Veterans Affairs Medical Center and professor of medicine at the University of California San Francisco. “In the phase 2 study that led to GALACTIC-HF, omecamtiv mecarbil increased measures of cardiac performance and function. GALACTIC-HF focused on evaluating the effect of this potential medication on outcomes in patients with chronic heart failure.”

GALACTIC-HF was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. The study enrolled more than 8,000 patients in 35 countries with chronic heart failure who were either currently hospitalized for heart failure or with a recent history of hospitalization or emergency department visit for heart failure within one year prior to screening.

Participants were predominantly male (79%) and white* (78%), with an average age of 66 years and average ejection fraction of 27%. In addition:

* 62% had coronary artery disease; * 40% had Type 2 diabetes;
* 70% had high blood pressure;
* 36% had chronic kidney disease; and
* 25% were hospitalized at the time of enrollment.

  • While only 7% of participants self-reported as Black, more Black patients were enrolled in GALACTIC-HF than in any contemporary, international heart failure trial.
    Patients were randomized to receive either an oral placebo or omecamtiv mecarbil. The study investigated how much time passed before the first heart failure event such as hospitalization, an urgent visit requiring intravenous therapy for heart failure or cardiovascular death.

The study found that patients receiving omecamtiv mecarbil had less risk of experiencing a heart failure event or cardiovascular death. The medicine had a greater effect for patients with lower ejection fraction (ejection fraction ?28%), an indicator of more advanced heart failure. In addition, the concentration in the blood of N-terminal B-type natriuretic peptide, a hormone that is increased with worsening heart failure, was reduced in patients treated with omecamtiv mecarbil. There were no significant imbalances in adverse events between patients randomized to treatment or placebo. In addition, side effects that typically limit the use of current heart failure therapies, such as adverse effects on blood pressure, heart rate, potassium levels or kidney function, were not observed.

“This study provides substantial evidence characterizing the efficacy and safety of this novel therapy,” said Teerlink. “The trial included a wide range of patients from both the inpatient and outpatient settings, and these findings will inform potential future implementation of omecamtiv mecarbil to treat chronic heart failure.”

Provided by American Heart Association

Heat And Dust Help Launch Martian Water Into Space, Scientists Find (Planetary Science)

Scientists using an instrument aboard NASA’s Mars Atmosphere and Volatile EvolutioN, or MAVEN, spacecraft have discovered that water vapor near the surface of the Red Planet is lofted higher into the atmosphere than anyone expected was possible. There, it is easily destroyed by electrically charged gas particles — or ions — and lost to space.

This graph shows how the amount of water in the atmosphere of Mars varies depending on the season. During global and regional dust storms, which happen during southern spring and summer, the amount of water spikes. ©University of Arizona/Shane Stone/NASA Goddard/Dan Gallagher

Researchers said that the phenomenon they uncovered is one of several that has led Mars to lose the equivalent of a global ocean of water up to hundreds of feet (or up to hundreds of meters) deep over billions of years. Reporting on their finding on Nov. 13 in the journal Science, researchers said that Mars continues to lose water today as vapor is transported to high altitudes after sublimating from the frozen polar caps during warmer seasons.

“We were all surprised to find water so high in the atmosphere,” said Shane W. Stone, a doctoral student in planetary science at the University of Arizona’s Lunar and Planetary Laboratory in Tucson. “The measurements we used could have only come from MAVEN as it soars through the atmosphere of Mars, high above the planet’s surface.”

To make their discovery, Stone and his colleagues relied on data from MAVEN’s Neutral Gas and Ion Mass Spectrometer (NGIMS), which was developed at NASA’s Goddard Space Flight Center in Greenbelt, Maryland. The mass spectrometer inhales air and separates the ions that comprise it by their mass, which is how scientists identify them.

Stone and his team tracked the abundance of water ions high over Mars for more than two Martian years. In doing so, they determined that the amount of water vapor near the top of the atmosphere at about 93 miles, or 150 kilometers, above the surface is highest during summer in the southern hemisphere. During this time, the planet is closest to the Sun, and thus warmer, and dust storms are more likely to happen.

The warm summer temperatures and strong winds associated with dust storms help water vapor reach the uppermost parts of the atmosphere, where it can easily be broken into its constituent oxygen and hydrogen. The hydrogen and oxygen then escape to space. Previously, scientists thought that water vapor was trapped close to the Martian surface like it is on Earth.

“Everything that makes it up to the higher part of the atmosphere is destroyed, on Mars or on Earth,” Stone said, “because this is the part of the atmosphere that is exposed to the full force of the Sun.”

This illustration shows how water is lost on Mars normally vs. during regional or global dust storms. ©NASA/Goddard/CI Lab/Adriana Manrique Gutierrez/Krysrofer Kim

The researchers measured 20 times more water than usual over two days in June 2018, when a severe global dust storm enveloped Mars (the one that put NASA’s Opportunity rover out of commission). Stone and his colleagues estimated Mars lost as much water in 45 days during this storm as it typically does throughout an entire Martian year, which lasts two Earth years.

“We have shown that dust storms interrupt the water cycle on Mars and push water molecules higher in the atmosphere, where chemical reactions can release their hydrogen atoms, which are then lost to space,” said Paul Mahaffy, director of the Solar System Exploration Division at NASA Goddard and principal investigator of NGIMS.

Other scientists have also found that Martian dust storms can lift water vapor far above the surface. But nobody realized until now that the water would make it all the way to the top of the atmosphere. There are abundant ions in this region of the atmosphere that can break apart water molecules 10 times faster than they’re destroyed at lower levels.

“What’s unique about this discovery is that it provides us with a new pathway that we didn’t think existed for water to escape the Martian environment,” said Mehdi Benna, a Goddard planetary scientist and co-investigator of MAVEN’s NGIMS instrument. “It will fundamentally change our estimates of how fast water is escaping today and how fast it escaped in the past.”

Provided by NASA Goddard

Why Do So Many Parents Avoid Talking About Race? (Psychology)

Research highlights ways adults can talk honestly about race with children.

All too often, kids are given less information than they deserve when it comes to complex phenomena, like how a virus such as COVID-19 spreads, or how to confront deeply painful societal issues like racism. If you are a parent or adult who has struggled to talk about race with kids, you are certainly not alone.

“Parents are generally afraid that they don’t have all the answers, and that has to go out the window,” says Judith Scott, a Boston University School of Social Work assistant professor, whose research focuses on how parents can prepare kids to deal with racial discrimination, and how families and peers transmit messages about identity and culture to kids. “It’s okay to say, ‘I’m still learning myself,’ and learn together with your children,” Scott says.

Adults avoid conversations with their kids about race for a whole host of reasons–from feeling unqualified, or uncomfortable, or like they don’t know enough. Now a recent study from Boston University researchers published in the Journal of Experimental Psychology finds there might be another reason parents hold off on talking about race with kids: adults assume children are too young to be aware of race.

The new data suggests that the majority of adults in the United States have false perceptions about how and when kids learn about race, says Evan Apfelbaum, a BU social psychologist and Questrom School of Business associate professor of management and organizations, who coauthored the study with assistant professors Leigh Wilton and Jessica Sullivan, social and developmental psychologists at Skidmore College.

“Regardless of whether [study participants] were a parent, regardless of whether they were white or Black, they had similar misconceptions about when kids first process race, which was very unexpected and surprising,” Apfelbaum says.

To figure out adults’ assumptions about the onset of children’s racial processing, the study authors asked a demographically representative sample of US adults basic questions about childhood development milestones, children’s processing of race, and what factors influence their ability to talk about race. On average, participants were off by about four and a half years when asked when they think kids start processing race, which can begin before one year old. Their data suggests that this misconception was the biggest reason why adults didn’t want to talk about race with kids, even compared to other personal reasons, like feeling uncomfortable or afraid of inflicting racist views.

“I wouldn’t say this is the only reason,” Apfelbaum says. “But it’s a surprisingly large factor, according to our data.” As a follow-up to the survey, participants received a quick science lesson on childhood development and race. And after their lesson, the majority of people were more willing to talk about race with kids, possibly because they were more assured that the kids can handle it.

In their paper, Apfelbaum and his coauthors note that past research has found toddlers and children under the age of five can detect messages and ideas about race, while infants at six months old can notice differences in skin color. By five years old, kids begin to associate racial characteristics with traits, stereotypes, and social status, and start to internalize messages about race they have inferred from adults and people around them.

“I’ve had young kids, at four years old, who I’ve worked with come up to me and ask, ‘Why are you brown and I’m white?'” says Scott. And in those situations, “parents freak out,” she says, “because parents automatically associate race with racism.”

With ongoing protests against police brutality, systemic racism, and racial injustice happening across the country since George Floyd was killed, Scott and Apfelbaum both agree that now is as good a time as ever to talk honestly about racism, since young kids and teens are very likely putting pieces together themselves, or possibly talking and sharing information on social media with their peers.

Even if children are a bit older, there’s still time for parents and educators to start talking about race. “There’s work to be done earlier, but kids start to develop a more sophisticated understanding about unfairness and inequality in society, and about how their actions will be perceived by others at around 10 years old,” Apfelbaum says.

“Kids understand the nature of unfairness,” says Scott. “And I think that foundation is a way to start having conversations about racism.”

Netflix sci-fi series Raising Dion is a great example of why some parents have to start talking about racism, Scott says, because in one episode, Dion–who is a young Black boy with superpowers–is distressed after experiencing discrimination in school and his mother has to talk to him about racism for the first time. It’s important to keep in mind that motivations for having these conversations differ; it could be triggered by something on the news, times that kids are hearing about racism issues at school or experiencing racial discrimination themselves, or talking about race with peers. Scott has found in her research that context is crucial when families decide how to talk about race and racism as issues or questions arise, since every situation and child is different.

Generally, when it comes to engaging kids and teens in conversations about racism, Scott emphasizes using the power of stories and positive examples. Such stories could be about young activists fighting against racist systems, like 13-year-old Mari Copeny–better known as “Little Miss Flint”–who spoke up about environmental racism with the ongoing water crisis in Flint, Mich.

“It’s important for kids to understand that society is trying to do something about it, and people are fighting the fight,” says Scott. The key is understanding your child, seeing if they want opportunities to engage in small or big ways, and to keep checking in.

“As kids get older, the information you give them about race and racism has a different meaning to them because of where they are developmentally or their experiences, and so if your child is 12 or 14 and the last conversation you had about race was when they were 8, that is not going to cut it,” says Scott. Contributing with small actions, making signs, drawing positive messages or images on the sidewalk, or even attending a protest or organizing virtual events, are a few possibilities for kids who want to engage in antiracism work.

“For parents of color, people who have had bad experiences, it’s important to–after those conversations–take care of yourself,” says Scott. “Finding time to talk about these things when you’re emotionally ready, and only if you’re ready, is okay.”

References: Sullivan, J., Wilton, L., & Apfelbaum, E. P. (2020). Adults delay conversations about race because they underestimate children’s processing of race. Journal of Experimental Psychology: General. Advance online publication. https://doi.apa.org/doiLanding?doi=10.1037%2Fxge0000851 https://doi.org/10.1037/xge0000851

Provided by Boston University

Worms Reveal Why Melatonin Promotes Sleep (Neuroscience)

Research in C. elegans shows how melatonin activates the BK channel in the brain.

Melatonin is used as a dietary supplement to promote sleep and get over jet lag, but nobody really understands how it works in the brain. Now, researchers at UConn Health show that melatonin helps worms sleep, too, and they suspect they’ve identified what it does in us.

The Caennorhabditis elegans worm’s neurons expressing the receptor for melatonin glow green. ©Bojun Chen/UConn Health.

Our bodies produce melatonin in darkness. It’s technically a hormone, but you can readily buy melatonin as a supplement in pharmacies, nutrition stores, and other retail shops. It’s widely used by adults and often in children as well.

Melatonin binds to melatonin receptors in the brain to produce its sleep-promoting effects. Think of a receptor as a keyhole, and melatonin as the key. The two keyholes for melatonin are called MT1 and MT2 in human brain cells. But scientists didn’t really know what happens when the keyhole is unlocked. Now UConn Health School of Medicine neuroscientists Zhao-Wen Wang and Bojun Chen and their colleagues have identified that process through their work with C. elegans worms, as reported in PNAS on Sept. 21. When melatonin fits into the MT1 receptor in the worm’s brain, it opens a potassium channel known as the BK channel.

A major function of the BK channel in neurons is to limit the release of neurotransmitters, which are chemical substances used by neurons to talk to each other. In their search for factors related to the BK channel, the Wang and Chen labs found that a melatonin receptor is needed for the BK channel to limit neurotransmitter release. They subsequently found that melatonin promotes sleep in worms by activating the BK channel through the melatonin receptor. Worms that lack either melatonin secretion, the melatonin receptor, or the BK channel spend less time in sleep.

But wait–worms sleep?

Indeed they do, says Chen. There’s actually been quite a lot of research on worm sleep, and researchers found that sleep is similar between worms and mammals like humans and mice.

Wang and Chen next plan to see if the melatonin-MT1-BK relationship holds in mice. The BK channel is involved in all kinds of bodily happenings, from epilepsy to high blood pressure. By learning more about the relationships between the BK channel, sleep, and behavioral changes, the researchers hope both to understand melatonin better and also help people who suffer from other diseases related to the BK channel.

References: http://dx.doi.org/10.1073/pnas.2010928117

Provided by University of Connecticut

Rare Angiosarcoma Tumors Respond Well to Immunotherapy Combination (Medicine)

Researchers from SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute’s (NCI) Division of Cancer Diagnosis and Treatment (DCTD), part of the National Institutes of Health, have shown that the immunotherapy combination of ipilimumab and nivolumab shrinks rare angiosarcoma tumors in 25 percent of all patients, with some having an even stronger response to the drug combination.

SWOG Cancer Research Network investigator Dr. Michael Wagner. ©Seattle Cancer Care Alliance

Results of the SWOG study, led by Michael Wagner, MD, of the University of Washington, the Fred Hutchinson Cancer Research Center, and the Seattle Cancer Care Alliance, and conducted by the NCI National Clinical Trials Network (NCTN), were shared in a virtual oral presentation today at The Society for Immunotherapy of Cancer’s (SITC) 35th Anniversary Annual Meeting. The findings provide the first rigorous evidence that immunotherapies can treat angiosarcoma, a rare cancer of blood and lymph vessels that often develops in the skin. About 500 Americans are diagnosed with angiosarcoma each year.

Wagner’s study is part of a path-breaking clinical trial called DART, short for Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors. Launched in 2017 with sponsorship by the NCI, DART is proving a successful model for the study of rare cancers. Using an innovative “basket” design, DART tests the effectiveness of the ipilimumab and nivolumab combination in a variety of rare tumor types, thanks to a Cooperative Research and Development Agreement (CRADA) between the NCI and Bristol-Myers Squibb, the maker of both immunotherapy drugs. Through DART, the drug combination has completed testing in 36 cohorts of rare cancer patients, with another 12 cohorts still taking the drugs, and four cohorts temporarily closed for data analysis. Promising results have previously been reported in patients with other rare cancers, including neuroendocrine tumors and metaplastic breast cancer, while results from patients with thyroid tumors will also be reported at the 2020 SITC meeting.

An expert in sarcoma, Wagner wanted to replace anecdotal reports that immune checkpoint inhibitors like ipilimumab and nivolumab can successfully treat angiosarcoma with a prospective phase II trial. Wagner and his SWOG team enrolled 16 patients, all with advanced or inoperable cancer and all of whom were previously treated with chemotherapy. They found that 25 percent of patients saw their tumors shrink, regardless of where in the body their angiosarcoma occurred. The news was even better for patients whose cancer presented on the face or scalp. Those patients saw a 60 percent response rate to the drugs. In some cases, the response was long lasting. Two patients remain cancer free one year after treatment.

“These results open a new way to treat angiosarcoma – with immunotherapy,” Wagner said. “At SWOG, we’re planning a larger follow-up study to see if this combination can work as a first line of treatment.”

The SWOG team also found that most patients – 75 percent – experienced side effects from the drugs and 25 percent experienced severe side effects.

Rare cancers make up about a quarter of all cancers diagnosed worldwide. But because there are hundreds of types, and because each is so scarce, rare cancers are notoriously difficult to study. With expert advice from the NCI and the SWOG statistical team, the study leadership – Sandip Patel, MD, and Razelle Kurzrock, MD, both of UCSD Moores Cancer Center, and Young Kwang Chae, MD, of Northwestern University – came up with DART’s unique basket design. It’s proven successful. The study has successfully enrolled 755 with rare disease who may not otherwise have been eligible for a clinical trial. It also is plowing important ground in translational medicine. Tumor and blood specimens from DART patients will soon undergo DNA and RNA sequencing to shed light on their molecular makeup and how immunotherapies may help disarm certain rare cancer types. This work will be done through the Cancer Immune Monitoring and Analysis Centers (CIMACs), which were established by the NCI through its Cancer Moonshot initiative.

Provided by SWOG

Rare Angiosarcoma Tumors Respond Well to Immunotherapy Combination (Medicine)

Researchers from SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute’s (NCI) Division of Cancer Diagnosis and Treatment (DCTD), part of the National Institutes of Health, have shown that the immunotherapy combination of ipilimumab and nivolumab shrinks rare angiosarcoma tumors in 25 percent of all patients, with some having an even stronger response to the drug combination.

SWOG Cancer Research Network investigator Dr. Michael Wagner. ©Seattle Cancer Care Alliance

Results of the SWOG study, led by Michael Wagner, MD, of the University of Washington, the Fred Hutchinson Cancer Research Center, and the Seattle Cancer Care Alliance, and conducted by the NCI National Clinical Trials Network (NCTN), were shared in a virtual oral presentation today at The Society for Immunotherapy of Cancer’s (SITC) 35th Anniversary Annual Meeting. The findings provide the first rigorous evidence that immunotherapies can treat angiosarcoma, a rare cancer of blood and lymph vessels that often develops in the skin. About 500 Americans are diagnosed with angiosarcoma each year.

Wagner’s study is part of a path-breaking clinical trial called DART, short for Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors. Launched in 2017 with sponsorship by the NCI, DART is proving a successful model for the study of rare cancers. Using an innovative “basket” design, DART tests the effectiveness of the ipilimumab and nivolumab combination in a variety of rare tumor types, thanks to a Cooperative Research and Development Agreement (CRADA) between the NCI and Bristol-Myers Squibb, the maker of both immunotherapy drugs. Through DART, the drug combination has completed testing in 36 cohorts of rare cancer patients, with another 12 cohorts still taking the drugs, and four cohorts temporarily closed for data analysis. Promising results have previously been reported in patients with other rare cancers, including neuroendocrine tumors and metaplastic breast cancer, while results from patients with thyroid tumors will also be reported at the 2020 SITC meeting.

An expert in sarcoma, Wagner wanted to replace anecdotal reports that immune checkpoint inhibitors like ipilimumab and nivolumab can successfully treat angiosarcoma with a prospective phase II trial. Wagner and his SWOG team enrolled 16 patients, all with advanced or inoperable cancer and all of whom were previously treated with chemotherapy. They found that 25 percent of patients saw their tumors shrink, regardless of where in the body their angiosarcoma occurred. The news was even better for patients whose cancer presented on the face or scalp. Those patients saw a 60 percent response rate to the drugs. In some cases, the response was long lasting. Two patients remain cancer free one year after treatment.

“These results open a new way to treat angiosarcoma – with immunotherapy,” Wagner said. “At SWOG, we’re planning a larger follow-up study to see if this combination can work as a first line of treatment.”

The SWOG team also found that most patients – 75 percent – experienced side effects from the drugs and 25 percent experienced severe side effects.

Rare cancers make up about a quarter of all cancers diagnosed worldwide. But because there are hundreds of types, and because each is so scarce, rare cancers are notoriously difficult to study. With expert advice from the NCI and the SWOG statistical team, the study leadership – Sandip Patel, MD, and Razelle Kurzrock, MD, both of UCSD Moores Cancer Center, and Young Kwang Chae, MD, of Northwestern University – came up with DART’s unique basket design. It’s proven successful. The study has successfully enrolled 755 with rare disease who may not otherwise have been eligible for a clinical trial. It also is plowing important ground in translational medicine. Tumor and blood specimens from DART patients will soon undergo DNA and RNA sequencing to shed light on their molecular makeup and how immunotherapies may help disarm certain rare cancer types. This work will be done through the Cancer Immune Monitoring and Analysis Centers (CIMACs), which were established by the NCI through its Cancer Moonshot initiative.

Provided by SWOG

Link Between Alzheimer’s Disease And Gut Microbiota Is Confirmed (Neuroscience)

Swiss and Italian scientists prove a correlation between gut microbiota and the appearance of amyloid plaques in the brain, typical of Alzheimer’s Disease.

Alzheimer’s disease is the most common cause of dementia. Still incurable, it directly affects nearly one million people in Europe, and indirectly millions of family members as well as society as a whole. In recent years, the scientific community has suspected that the gut microbiota plays a role in the development of the disease. A team from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG) in Switzerland, together with Italian colleagues from the National Research and Care Center for Alzheimer’s and Psychiatric Diseases Fatebenefratelli in Brescia, University of Naples and the IRCCS SDN Research Center in Naples, confirm the correlation, in humans, between an imbalance in the gut microbiota and the development of amyloid plaques in the brain, which are at the origin of the neurodegenerative disorders characteristic of Alzheimer’s disease. Proteins produced by certain intestinal bacteria, identified in the blood of patients, could indeed modify the interaction between the immune and the nervous systems and trigger the disease. These results, to be discovered in the Journal of Alzheimer’s Disease, make it possible to envisage new preventive strategies based on the modulation of the microbiota of people at risk.

The research laboratory of neurologist Giovanni Frisoni, director of the HUG Memory Centre and professor at the Department of Rehabilitation and Geriatrics of the UNIGE Faculty of Medicine, has been working for several years now on the potential influence of the gut microbiota on the brain, and more particularly on neurodegenerative diseases. «We have already shown that the gut microbiota composition in patients with Alzheimer’s disease was altered, compared to people who do not suffer from such disorders,» he explains. «Their microbiota has indeed a reduced microbial diversity, with an over-representation of certain bacteria and a strong decrease in other microbes. Furthermore, we have also discovered an association between an inflammatory phenomenon detected in the blood, certain intestinal bacteria and Alzheimer’s disease; hence the hypothesis that we wanted to test here: could inflammation in the blood be a mediator between the microbiota and the brain?

The brain under influence

Intestinal bacteria can influence the functioning of the brain and promote neurodegeneration through several pathways: they can indeed influence the regulation of the immune system and, consequently, can modify the interaction between the immune system and the nervous system. Lipopolysaccharides, a protein located on the membrane of bacteria with pro-inflammatory properties, have been found in amyloid plaques and around vessels in the brains of people with Alzheimer’s disease. In addition, the intestinal microbiota produces metabolites – in particular some short-chain fatty acids – which, having neuroprotective and anti-inflammatory properties, directly or indirectly affect brain function.

«To determine whether inflammation mediators and bacterial metabolites constitute a link between the gut microbiota and amyloid pathology in Alzheimer’s disease, we studied a cohort of 89 people between 65 and 85 years of age. Some suffered from Alzheimer’s disease or other neurodegenerative diseases causing similar memory problems, while others did not have any memory problems,» reports Moira Marizzoni, a researcher at the Fatebenefratelli Center in Brescia and first author of this work. «Using PET imaging, we measured their amyloid deposition and then quantified the presence in their blood of various inflammation markers and proteins produced by intestinal bacteria, such as lipopolysaccharides and short-chain fatty acids.»

A very clear correlation

«Our results are indisputable: certain bacterial products of the intestinal microbiota are correlated with the quantity of amyloid plaques in the brain,» explains Moira Marizzoni. «Indeed, high blood levels of lipopolysaccharides and certain short-chain fatty acids (acetate and valerate) were associated with both large amyloid deposits in the brain. Conversely, high levels of another short-chain fatty acid, butyrate, were associated with less amyloid pathology.»

This work thus provides proof of an association between certain proteins of the gut microbiota and cerebral amyloidosis through a blood inflammatory phenomenon. Scientists will now work to identify specific bacteria, or a group of bacteria, involved in this phenomenon.

A strategy based on prevention

This discovery paves the way for potentially highly innovative protective strategies – through the administration of a bacterial cocktail, for example, or of pre-biotics to feed the «good» bacteria in our intestine. «However, we shouldn’t be too quick to rejoice,» says Frisoni. «Indeed, we must first identify the strains of the cocktail. Then, a neuroprotective effect could only be effective at a very early stage of the disease, with a view to prevention rather than therapy. However, early diagnosis is still one of the main challenges in the management of neurodegenerative diseases, as protocols must be developed to identify high-risk individuals and treat them well before the appearance of detectable symptoms.» This study is also part of a broader prevention effort led by the UNIGE Faculty of Medicine and the HUG Memory Centre.

References: Marizzoni, Moira, et al., “Short-Chain Fatty Acids and Lipopolysaccharide as Mediators Between Gut Dysbiosis and Amyloid Pathology in Alzheimer’s Disease”, Journal of Alzheimer’s Disease, vol. 78, no. 2, pp. 683-697, 2020. Link: https://content.iospress.com/articles/journal-of-alzheimers-disease/jad200306 http://dx.doi.org/10.3233/JAD-200306

Provided by University of Geneve