Body

Atherosclerosis is the underlying condition that causes heart attacks and strokes. Researchers at Radboudumc in the Netherlands have discovered a protein that appears to play an important role in atherosclerosis. The protein is called Prosaposin, and its role in atherosclerosis was sofar unknown. "We identified Prosaposin as a new potential target for the Science Translational Medicine.

Atherosclerosis is caused by cholesterol that builds up in the vessel wall and triggers chronic inflammation. It has been well established that cholesterol lowering drugs help to treat atherosclerosis. Recent research has shown that inhibiting inflammation can also help to prevent heart attacks and strokes. The challenge now is to find ways to inhibit inflammation specifically in atherosclerosis, without impeding the rest of the body's defenses that protect us against infections.

Increased metabolic rate

The cells primarily responsible for inflammation in atherosclerosis are macrophages. The inflammatory activation of these cells is an energy demanding process. The cells therefore have to increase their metabolic rate considerably. "Unraveling how they do this provides insight into how we can slow down the inflammatory activity and thereby reduce atherosclerosis".

Switch off the power

An international team of researchers, led by Raphaël Duivenvoorden of the Radboudumc in the Netherlands, has investigated what happens when you "switch off the power" of macrophages. The main metabolic switch is a protein complex called mTOR. Using nanotechnology, they were able to specifically turn off this switch in macrophages and investigate its effect on atherosclerosis in a mouse model. "We saw after only a single week of treatment that atherosclerotic lesions shrinked and the inflammation decreased".

New protein discovered

This result sparked their interest in unraveling the molecular mechanism underlying this potent anti-inflammatory effect. Their analyzes consistently revealed an important role for a protein called Prosaposin. Its role in atherosclerosis was sofar unknown. "In additional experiments we found that Prosaposin has an important effect on macrophage's metabolism. We also observed less development of atherosclerosis and vessel wall inflammation in mice that cannot produce Prosaposin. "

Prosaposin and atherosclerosis in humans

To find out if Prosaposin also plays a role in atherosclerosis in humans, they investigated its expression in human atherosclerotic lesions. "We saw substantial expression of Prosaposin by macrophages in atherosclerotic plaques and this was related to their inflammatory activity. It confirms that Prosaposin plays a key role in atherosclerosis, and is a potential new therapeutic target for the treatment of atherosclerosis."

What The Study Did: In this phase 1 study, a single immunization with Ad26.COV2.S (Janssen/Johnson & Johnson) vaccine induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine.

Authors: Dan H. Barouch, M.D., Ph.D., of Beth Israel Deaconess Medical Center in Boston, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2021.3645)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Breast cancer is harmful enough on its own, but when cancer cells start to metastasize -- or spread into the body from their original location -- the disease becomes even more fatal and difficult to treat.

Thanks to new research published in Oncogene from the lab of University of Colorado Cancer Center associate director of basic research Heide Ford, PhD, in collaboration with Michael Lewis, PhD, from Baylor College of Medicine, doctors may soon have a better understanding of one mechanism by which metastasis happens, and of potential ways to slow it down.

"Metastasis is a huge problem nobody's tackled very well," says Ford, who holds the Grohne Endowed Chair in Cancer Research at the University of Colorado School of Medicine. "People don't know how to inhibit the process of metastasis, nor how to inhibit the growth of metastatic cells at secondary sites. And that's what kills most cancer patients. A lot of common drugs, whether they're targeted drugs or chemotherapies that are less targeted, do pretty well at inhibiting the primary tumor, but by the time cells metastasize, they've changed enough that they don't get inhibited by those drugs."

The transformation Ford and her team are studying happens when cells called epithelial cells, which are more adherent to one another and less likely to spread to other parts of the body, start to take on the characteristics of mesenchymal cells, which are more migratory and more likely to invade other parts of the body. This transformation is referred to as the epithelial-to-mesenchymal transition.

"When the epithelial cancer cells take on these characteristics of mesenchymal cells, they become less attached to their neighbor and they become more able to degrade membranes, so they can get into the bloodstream more easily," Ford says.

In 2017, Ford published a paper showing that the metastasis process is helped along when cells that have undergone the epithelial-to-mesenchymal transition start "talking" to cells that haven't, making those cells more likely to gain metastatic properties.

In a new paper published in December, Ford and her researchers, in a collaborative study done with Lewis and colleagues at Baylor College of Medicine, posit that the crosstalk is facilitated by a naturally occurring protein called VEGF-C.

"VEGF-C is secreted by the cells. It binds to receptors on these neighboring cells and then activates a pathway called the hedgehog signaling pathway, though it bypasses the traditional way of activating this pathway," Ford says. "That turns on a signaling mechanism that ultimately results in activation of a protein called GLI that makes these cells more invasive and more migratory."

In their new paper, Ford, Lewis and their researchers show that if you can inhibit production of VEGF-C, you can significantly slow metastasis.

"If you take out the receptor that receives the signal from the cells that have not undergone a transition, or if you take VEGF-C out of the mix, you can't stimulate metastasis to the same degree," she says. "If you remove that ability for these different cell types to crosstalk, now these cells that never underwent a transition can't move as well anymore. They can't metastasize as efficiently."

The researchers are now in the early stages of animal trials to find out the best way to target that signaling pathway in order to better inhibit metastasis. They want to find out if they can stop metastasis from happening at all, and if they can slow its progression in patients in whom the metastatic process has already begun -- and to see if they can inhibit tumor growth at the secondary site.

"For many years, people said there was no point in finding inhibitors to metastasis because by the time someone comes into the clinic, the horse is out of the barn, so to speak. The cells have already gotten out of the primary tumor and you can't do anything about it," Ford says. "But that's not necessarily true. Now, data show that if you have cells that have metastasized to a second site -- say you have breast cancer and the cells went into the lungs -- those cells that are in the lungs could in fact start metastasizing to other sites. You want to stop that process no matter where you are in this progression."

The global battle against antibiotic resistance can only succeed if local contexts are taken into account. "A tailored approach is needed in each country," says Heiman Wertheim of Radboud university medical center. "There is no "one-size-fits-all' solution." This was the main finding of a study on antibiotic resistance in African and Asian countries funded by the British Wellcome Trust. Wertheim is the lead investigator of a large group of international researchers who recently published an article on this study in The Lancet Global Health.

Antibiotics are powerful treatments for bacterial infections. They are indispensable for controlling infections such as pneumonia, meningitis, or blood poisoning (sepsis) caused by bacteria. But they are ineffective for treating viral infections, such as colds or flu, and do not work against infections with parasites, fungi or yeasts either.

Increasing resistance

Incorrect use of antibiotics increases the risk of antibiotic resistance. This means that bacteria adapt in such a way that the antibiotic is no longer effective and the disease can no longer be controlled. Antibiotic resistance is now a major problem worldwide.

The problem is growing especially in Low- and Middle-income Countries (LMIC), where antibiotic use increased by 35 percent between 2000 and 2010. Research in various countries show that for example 80 percent of children under the age of five with respiratory infections are treated with antibiotics. In many cases, this was unjustified. To gain more insight into this problem, a large group of international researchers led by Heiman Wertheim from Radboud university medical center carried out the ABACUS project. ABACUS stands for AntiBiotic ACces and USe.

Large differences between countries

The results of the study, which was conducted in LMIC countries in Africa (Mozambique, Ghana, South Africa) and Asia (Bangladesh, Vietnam, Thailand), have now been published in The Lancet Global Health. Wertheim: "We looked primarily at how easy or difficult it is to obtain antibiotics in those countries and in which situations they are used. On those aspects alone, we found enormous differences between the six countries. For example, in some countries you can purchase antibiotics in the pharmacy only with a doctor's prescription, while in others there are no restrictions and antibiotics are available at any time from the drug store around the corner. We also saw that antibiotics are much more readily available in Asia than in Africa. And that the situation is relatively better in wealthier countries such as Thailand and South Africa."

Self-medication

Nga Thi Thuy Do, a researcher at the Oxford University Clinical Research Unit in Vietnam and lead author of the paper, summarizes the findings as follows: "Bangladesh and Vietnam have the most places where antibiotics can be purchased without a prescription. In some settings you have one drugseller per 500 inhabitants, which is an awful lot. This is reflected in the extent to which antibiotics are used as self-medication. In Vietnam, Bangladesh and Ghana, 57 percent, 45 percent and 36 percent of the population, respectively, regularly take antibiotics for self-medication. But self-medication is much less frequent in Mozambique, Thailand and South Africa, with rates of 8 percent, 4 percent and 1 percent, respectively. The difference is enormous."

The researchers also observed quite some uncertainty in the local population - even among the sellers of antibiotics - about what an antibiotic actually is and how you can recognize it. For example, painkillers were sometimes confused with antibiotics. In a follow-up study, also funded by the Wellcome Trust, the consortium will investigate whether improved recognition of antibiotics can lead to better use.

Context, context, context

The reasons for opting for self-medication are obvious: getting antibiotics from the drugstore without a prescription is faster, cheaper and easier. But purchasing antibiotics without a prescription is not always possible. And that in turn depends on all kinds of factors such as how the healthcare is organized, whether consumers trust the supplier and the severity of the disease. Wertheim: "Our research makes it clear that a generic approach towards combating antibiotic resistance is ineffective. To have any chance of success, you must consider the context that affects the availability and use of antibiotics in each country. The conclusions of our study provide an excellent starting point for giving shape to global initiatives to improve antibiotic use, so that those who really need it can get the right antibiotic and those with a runny nose can get a 'warm cup of tea'."

Black women have 80% higher risk of preterm birth between 32 and 33 weeks of pregnancy if a Black person who lives in their neighborhood is killed by police during the pregnancy, according to a study by researchers at UC San Francisco and UC Berkeley.

The study by scientists at the UCSF California Preterm Birth Initiative (PTBI-CA) and UC Berkeley School of Public Health, studied the records of 3.8 million pregnant women to assess whether fatal police violence occurring in their neighborhood during pregnancy was associated with extremely early, early, moderate or late preterm delivery.

"Our findings suggest that deaths due to police violence, which already differentially affect Black and Brown communities, adversely affect the health of mothers and babies during pregnancy," said first author Dana Goin, PhD, post-doctoral scholar in the UCSF Department of Obstetrics, Gynecology, and Reproductive Sciences. "In addition, we observed the strongest associations with preterm birth when the victim of the lethal violence and the mother/birth parent were both Black."

The researchers analyzed California Department of Public Health (CDPH) birth records from 2007 to 2015, using the birth parents' addresses to determine the parent's census tract of residence. They examined two different sources of police violence data, specifically CDPH death records that capture deaths due to "legal intervention" and records from the Fatal Encounters database that collects media-based accounts of police violence. They matched the police violence measures to the time range of the pregnancies, using as their control group residents of the same census tract who did not experience police violence during their pregnancy. The study published March 10, 2021, in Paediatric and Perinatal Epidemiology.

According to the analysis, neighborhoods where at least one incident of fatal police violence occurred tended to be where birth parents were Black or Latinx, had less than high school education and had public insurance, compared to all the births in California.

The World Health Organization lists preterm birth as a baby born at 37 weeks or earlier, compared to a 40-week "full-term" pregnancy, and considers birth at 32 to 33 weeks to be "moderate preterm. The Centers for Disease Control and Prevention (CDC) lists the rate of preterm births among Black women as 50% higher than the rate of preterm births among white or Latina women.

The researchers also discovered that the associations of fatal police violence with preterm birth were stronger among female infants. Since male fetuses are more sensitive to stress during pregnancy, it is plausible that male fetuses exposed to police violence may have been more likely than female fetuses to be miscarried earlier in the pregnancy, said Goin, who intends to explore this possibility further in a subsequent study.

"Our research provides evidence that policing practices that differentially harm Black people in California can also contribute to their disproportionate risk for preterm delivery," she said. "This work contributes to the evidence that additional forms of stress and hardship experienced from racism and institutional violence significantly affect their health and the health of the next generation."

When the body detects a pathogen, such as bacteria or viruses, it mounts an immune system response to fight this invader. In some people, the immune system overreacts, resulting in an overactive immune response that causes the body to injure itself, which may prove fatal in some cases.

Now, scientists from Nanyang Technological University, Singapore (NTU Singapore) have created a compound that could help to reduce this overactivation without impairing the body's entire immune response.

An overactive immune system leads to many autoimmune disorders - when the immune system mistakenly attacks healthy tissues - such as rheumatoid arthritis and type 1 diabetes. More recently, it has also been linked to severe COVID-19 infections, in which immune-system signalling proteins ramp up to dangerous levels, leading to damage to the body's own cells.

This compound designed by the NTU research team, called ASO-1, targets tyrosine kinase 2 (TYK2), a member from the Janus kinase (JAK) family of enzymes that play a key role in regulating the body's immune response. A recent study led by the University of Edinburgh and published in the leading scientific journal Nature found that high levels of TYK2 have been associated with severe COVID-19 .

Through lab experiments using human cells grown in a dish, the NTU scientists found that ASO-1 potently reduced TYK2 levels over a sustained period and inhibited immune signalling pathways that have been associated with autoimmune disorders.

This points to the potential of the ASO-1 compound forming the basis for treatment of autoimmune conditions, said the team led by Professor Phan Anh Tuan from NTU Singapore's School of Physical and Mathematical Sciences (SPMS).

Professor Phan, who is also the interim director of the NTU Institute of Structural Biology, said: "Human genetic studies have suggested that deactivating TYK2 could provide protection against a broad range of autoimmune conditions such as rheumatoid arthritis, psoriasis, lupus, and type 1 diabetes."

Dr Lim Kah Wai, NTU senior research fellow and co-lead author of the study, added: "With the UK-led study of critically ill COVID-19 patients published in Nature linking high TYK2 expression to severe COVID-19, ASO-1 could be a therapeutic agent worth investigating further. We are planning to conduct further pre-clinical work to validate its therapeutic potential."

The findings were published in February in the scientific journal ImmunoHorizons, a publication of The American Association of Immunologists, and the research team has filed a patent for the compound they designed.

Targeting genetic material that leads to TYK2 production

A number of drugs that reduce inflammation resulting from an overactive immune response target the Janus kinase (JAK) family of four proteins: JAK1, JAK2, JAK3 and TYK2.

Recently, TYK2 has emerged as researchers' preferred target. As the structures of the four members are highly similar, it is important to selectively target TYK2 to limit unwanted side effects.

The ASO-1 compound designed by the NTU research team is an antisense oligonucleotide (ASO). ASOs are a type of RNA therapeutics - they target the messenger RNA (mRNA), which carries genetic instructions that cells 'read' to make proteins. ASO-1 is designed to bind to TYK2 mRNA, thus preventing cells from producing TYK2 protein.

The research team conducted lab experiments on human cell cultures and found ASO-1 to be highly potent and selective for TYK2, with no effect against the other JAK proteins. Dr Lim noted that this high potency of ASO-1 rivals that of recent ASO drug candidates that have advanced to clinical trials or have been approved for clinical use.

The NTU team discovered ASO-1 from over 200 potentially effective ASOs, which were designed based on their in-house expertise on nucleic acids.

The team has established an integrated platform spanning the design, synthesis, and cellular testing of RNA therapeutics. TYK2 stands among a range of therapeutic targets for immunology and cancer therapy, which is the primary focus of the team.

The NTU researchers plan to partner several academic collaborators to test ASO-1 in animal models and are open to industrial collaboration on the development of the ASO-1 compound towards clinical use.

The Telomeres and Telomerase Group led by Maria A. Blasco at the Spanish National Cancer Research Centre (CNIO) continues to make progress in unravelling the role that telomeres -the ends of chromosomes that are responsible for cellular ageing as they shorten- play in cancer. The CNIO team was among the first to propose that shelterins, proteins that wrap around telomeres and act as a protective shield, might be therapeutic targets for cancer treatment. Subsequently, they found that eliminating one of these shelterins, TRF1, blocks the initiation and progression of lung cancer and glioblastoma in mouse models and prevents glioblastoma stem cells from forming secondary tumours. Now, in a study published in PLOS Genetics, they go one step further and describe for the first time how telomeres can be regulated by signals outside the cell that induce cell proliferation and have been implicated in cancer. The finding opens the door to new therapeutic possibilities targeting telomeres to help treat cancer.

The CNIO group was also the first to find a link between TRF1 and the PI3K/AKT signalling pathway. This metabolic pathway, which also encompasses mTOR, is one of the pathways most frequently affected in numerous tumorigenic processes. However, it was not known whether preventing TRF1 regulation by this pathway can have an impact on telomere length and its ability to form tumours. AKT acts as a transmitter of extracellular signals triggered by, among others, nutrients, growth factors and immune regulators, to the interior of cells. CNIO researchers Raúl Sánchez and Paula Martínez, directed by Maria A Blasco, set out to determine the involvement of telomeres in this signalling pathway.

To do this, the researchers modified the TRF1 protein in cells to make it unresponsive to AKT, using the gene-editing tool CRISPR/Cas9. This way, TRF1 and the telomeres became invisible to any extracellular signals transmitted by AKT. Telomeres in these cells shortened and accumulated more damage; most importantly, the cells were no longer able to form tumours, indicating that telomeres are important targets of AKT and its role in cancer development.

"Most importantly, we found that when TRF1 can't be phosphorylated by AKT, the latter has a lower potential to generate tumours," explains Blasco.

The paper shows that telomeres are among the most important intracellular targets of the AKT pathway to form tumours, since, although neither the function of AKT nor of any of the thousands of proteins that are regulated by it was altered, only blocking AKT's ability to modify telomeres was sufficient to slow tumour growth.

The next step will be to generate genetically modified mice with telomeres that are invisible to AKT. The authors anticipate that these mice will be more resistant to cancer.

Aspirin is an established, safe, and low-cost medication in long-standing common use in prevention and treatment of cardiovascular diseases, and in the past a pain relief and fever reducing medication. The use of aspirin was very popular during the 1918 Spanish Influenza pandemic, several decades before in-vitro confirmation of its activity against RNA viruses. Studies showed that aspirin, in addition to its well-known anti-inflammatory effects, could modulate the innate and adaptive immune responses helping the human immune system battle some viral infections.

With this information in mind Israeli researchers hypothesized that pre-infection treatment with low-dose aspirin (75mg) use might have a potential beneficial effect on COVID-19 susceptibility and disease duration. A joint team from Leumit Health Services, Bar-Ilan University, and Barzilai Medical Center conducted an observational epidemiological study, utilizing data from Leumit Health Services, a national health maintenance organization in Israel. Their findings were recently published in The FEBS Journal.

The researchers analyzed data of 10,477 persons who had been tested for COVID-19 during the first COVID-19 wave in Israel from February 1, 2020 to June 30, 2020. Aspirin use to avoid the development of cardiovascular diseases in healthy individuals was associated with a 29% lower likelihood of COVID-19 infection, as compared to aspirin non-users. The proportion of patients treated with aspirin was significantly lower among the COVID-19-positive individuals, as compared to the COVID-19-negative ones. And those subjects who had been treated with aspirin were less associated with the likelihood of COVID-19 infection than those who were not. Moreover, the group observed that the conversion time of SARS-CoV-2 PCR test results from positive to negative among aspirin-using COVID-positive patients was significantly shorter, and the disease duration was two-three days shorter, depending upon the patients' pre-existing conditions.

"This observation of the possible beneficial effect of low doses of aspirin on COVID-19 infection is preliminary but seems very promising," says Prof. Eli Magen from the Barzilai Medical Center, who led the study.

Study principal investigator Dr. Eugene Merzon, from Leumit Health Services, emphasizes the importance of repeating the study results using larger samples, and including patients from other hospitals and countries, to verify the results.

Dr. Milana Frenkel-Morgenstern, of the Azrieli Faculty of Medicine of Bar-Ilan University: "The present study sought to better understand the potential favorable effects of aspirin in aiding the human immune system battle COVID-19. We intend to investigate a larger cohort of patients and in randomized clinical trials."

On December 6, 2016, a high-energy particle called an electron antineutrino was hurtling through space at nearly the speed of light. Normally, the ghostly particle would zip right through the Earth as if it weren't even there.

But this particle just so happened to smash into an electron deep inside the South Pole's glacial ice. The collision created a new particle, known as the W- boson. That boson quickly decayed, creating a shower of secondary particles.

The whole thing played out in front of the watchful detectors of a massive telescope buried in the Antarctic ice, the IceCube Neutrino Observatory. This enabled IceCube to make the first ever detection of a Glashow resonance event, a phenomenon predicted 60 years ago by Nobel laureate physicist Sheldon Glashow.

This detection provides the latest confirmation of the Standard Model, the name of the particle physics theory explaining the universe's fundamental forces and particles.

"Finding it wasn't necessarily a surprise, but that doesn't mean I wasn't very happy to see it," said Claudio Kopper, an associate professor in Michigan State University's Department of Physics and Astronomy in the College of Natural Science. Kopper and his departmental colleague, assistant professor Nathan Whitehorn, lead IceCube's Diffuse and Atmospheric Flux Working Group behind the discovery.

The international IceCube Collaboration published this result online on March 11 in the journal Nature.

"Even three years ago, I didn't think IceCube would be able to make this measurement, or at least as well as we did," Whitehorn said.

A 3-D plot with columns of green, blue, yellow and orange spheres and other round shapes give a visual representation of the Glashow resonance event detection.

This detection further demonstrates the ability of IceCube, which observes nearly massless particles called neutrinos using thousands of sensors embedded in the Antarctic ice, to do fundamental physics.

Although the Spartans lead the working group, they emphasized that this discovery was a team effort, powered by the paper's three lead analysts: Lu Lu, an assistant professor at University of Wisconsin-Madison; Tianlu Yuan, an assistant scientist at the Wisconsin IceCube Particle Astrophysics Center, or WIPAC; and Christian Haack, a postdoc at the Technical University of Munich.

"We lead weekly meetings, we talk about how the work is done, we ask hard questions," said Kopper. "But without the people doing the actual analysis, we wouldn't have anything."

"Our job is to be the doubters-in-chief," Whitehorn said. "The lead authors did a great job convincing everyone that this event was a Glashow resonance."

The particle physics community has been anticipating such a detection, but Glashow resonance events are extremely rare by nature and technologically challenging to detect.

"When Glashow was a postdoc at Niels Bohr, he could never have imagined that his unconventional proposal for producing the W- boson would be realized by an antineutrino from a faraway galaxy crashing into Antarctic ice," said Francis Halzen, professor of physics at the University of Wisconsin-Madison, the headquarters of IceCube maintenance and operations, and principal investigator of IceCube.

A Glashow resonance event requires an electron antineutrino with a cosmic amount of energy -- at least 6.3 peta-electronvolts, or PeV. For comparison, that's about 1,000 times more energy than that of the most energetic particles produced by the Earth's most powerful particle accelerators.

Since IceCube started fully operating in 2011, it has detected hundreds of high-energy neutrinos from space. Yet the neutrino in December 2016 was only the third with an energy higher than 5 PeV.

And simply having a high-energy neutrino is not sufficient to detect a Glashow resonance event. The neutrino then has to interact with matter, which is not a guarantee. But IceCube encompasses quite a bit of matter in the form of Antarctic ice.

The IceCube Laboratory, lighted red against the night sky, is small in this landscape photograph of the South Pole white tundra, which also captures yellow stars and light green auroras.

The observatory's detector array has been built into the ice, spanning nearly 250 acres with sensors reaching up to about a mile deep. All told, IceCube boasts a cubic kilometer of coverage, watching over a billion metric tons of extremely clear ice.

That's what it takes to detect neutrinos, along with a team of scientists who have the skill and determination to spot rare events.

IceCube's more than 5,000 detectors take in a tremendous firehose of light, Whitehorn said. Detecting the Glashow resonance meant researchers had to pick out a handful of telltale photons, individual particles of light, from that firehose spray.

"This is some of the most impressive technical work I've ever seen," Whitehorn said, calling the team unstoppable over the years-long effort to confirm this was a Glashow resonance event.

Making the work even more impressive was the fact that the lead authors -- Lu, Yuan and Haack -- were in three countries on three different continents during the analysis. Lu was a postdoc at Chiba University in Japan, Yuan was at WIPAC in the U.S. and Haack was a doctoral student at Rheinisch-Westfälische Technische Hochschule Aachen University in Germany.

"It was amazing to me just seeing that that is possible," Kopper said.

But this is very much in keeping with the ethos of IceCube, an observatory built on international collaboration. IceCube is operated by a group of scientists, engineers and staff from 53 institutions in 12 countries, together known as the IceCube Collaboration. The project's headquarters is WIPAC, a research center of UW-Madison in the United States.

To confirm the detection and usher in a new chapter of neutrino astronomy, the IceCube Collaboration is working to detect more Glashow resonances. And they need IceCube-Gen2, a proposed expansion of the IceCube detector, to make it happen.

"We already know that the astrophysical spectrum does not end at 6 PeV," Lu said. "The key is to detect more Glashow resonance events and to identify the sources that accelerate those antineutrinos. IceCube-Gen2 will be key to making such measurements in a statistically significant way."

Glashow himself echoed that sentiment about validation. "To be absolutely sure, we should see another such event at the very same energy as the one that was seen," said Glashow, now an emeritus professor of physics at Boston University. "So far there's one, and someday there will be more."

MAYWOOD, IL - A recent Loyola Medicine study found that reducing the standard dose of IV-administered ketamine in half is as effective as the larger, standard dose in reducing pain in adults.

Ketamine is known to provide pain relief comparable to opioid medications, which are highly addictive. In the recent study, appearing in the journal Academic Emergency Medicine, researchers studied 98 patients, ages 18 to 59, who presented to the emergency department with acute, moderate to severe pain. The patients were randomized prospectively to receive either 0.15 mg/kg of ketamine (low dose) or 0.30 mg/kg (high dose). Patients and providers were blinded to dose, with the primary outcome of pain measured on the 11-point numerical rating scale (NRS) at 30 minutes. At 15 minutes, the high dose group had a greater decrease in pain on the NRS but more adverse events. At 30 minutes, adverse events and pain were similar.

Overall, patients generally reported that they would take ketamine again for pain - 75.6% in the low-dose group and 61.7% in the high-dose group.

"We challenged the conventional ketamine dose used to treat pain," said lead study author Shannon Lovett, MD, emergency medicine physician at Loyola University Medical Center (LUMC) and associate professor in the Department of Emergency Medicine at Loyola University Chicago Stritch School of Medicine. "Our study should help demonstrate that a lower dose is sufficient to treat pain."

The study did not find a significant reduction in side effects from the lower dose.

"As we continue with our research, we hope to find data that supports diminished side effects with the lower dose of ketamine with equal efficacy in treating pain," said senior study author Megan A. Rech, emergency medicine clinical pharmacist at LUMC and an adjunct assistant professor and research coordinator at Stritch.

A team of pediatricians at the Medical University of South Carolina (MUSC) was the first in the nation to enroll patients with multisystem inflammatory syndrome in children (MIS-C), a rare but life-threatening complication of COVID-19, in a trial of remestemcel-L. This investigational cell therapy, developed and manufactured by Mesoblast, New York, New York, had previously been shown safe and effective for other inflammatory conditions. The MUSC team reports in Pediatrics that the two children enrolled thus far showed significant improvement within 24 hours of remestemcel-L administration.

"While it appears to many people that COVID is no big deal in children, this potential complication, although rare, is very, very serious," said MUSC Children's Health pediatric infectious disease physician, Allison Eckard, M.D., who is leading the local trial. "In South Carolina, we have had over 70 cases of MIS-C and one death. That is way more than we'd like to see in children."

Too often, MIS-C is not recognized until children are already critically ill.

"The tricky part about MIS-C is that, in many cases, the families don't know that the children ever had COVID because, in general, children have very mild symptoms," said Eckard.

MIS-C can also be missed because its symptoms are vague, and so it can easily be mistaken for other illnesses.

Although the cause of MIS-C is unknown, Eckard speculates that the body's reaction to COVID-19 likely sets off a cascade of unchecked inflammation.

"Although inflammation has a role to play in the body, excessive inflammation is bad and causes organ damage, organ failure and a lot of other complications," she said.

The current standard of care for MIS-C is nonspecific. It consists of using steroids or antibodies derived from donated plasma to turn down all aspects of the immune system.

"The novel treatment we are using is a little bit more specific," said Eckard.

Remestemcel-L is a cellular therapy derived from a special type of cell that forms in bone marrow.

"These bone marrow cells, donated by healthy adults, are known to turn down inflammation," said Eckard. They are able to target the specific parts of the immune system that are most relevant to MIS-C.

The cells are also able to improve the inner lining of the blood vessel, targeting the most serious and potentially long-term effects of MIS-C: cardiac and cardiovascular involvement. Remestemcel-L improves blood pressure and the flow of blood to where it needs to be.

"We rely on the heart to pump blood adequately to all the other organs," said Eckard. "The same applies to blood vessels and the cardiovascular system. When they don't work properly, your body can't pump blood effectively to vital organs."

Nationwide studies have already been conducted on the use of remestemcel-L to treat graft-vs-host disease in children, a condition that can develop after receiving a bone marrow transplant, and MUSC participated in some of them. Other studies have also assessed its usefulness for treating cardiac complications in adults. However, MUSC is the only institution thus far to use remestemcel-L for the purpose of MIS-C.

"We always worry in pediatrics about the safety of new therapies. But because of our experience here at MUSC with hundreds of children enrolled in a remestemcel-L trial for graft-vs. host disease, we felt really good about its safety profile," said Eckard.

Thus far, two children have been enrolled in the trial and treated with remestemcel-L. They were chosen because they still had underlying inflammation and cardiac dysfunction despite having received standard-of-care therapy. Eckard hopes that the investigational therapy will help to protect these children from long-term cardiovascular complications.

"People are always very hesitant to try new things if they think the current therapy is working. But what I say to that is we do not know the long-term effects of MIS-C," said Eckard.

Although it is too early to know if the novel therapy will protect against long-term complications, Eckard is heartened by the therapy's short-term effects, which were reported in the Pediatrics article.

"There were some dramatic improvements within 24 hours of giving the treatment in both of the children, and that is what compelled us to publish those two cases," said Eckard.

The remestemcel-L trial for use in MIS-C aims to enroll 50 children with cardiac dysfunction nationwide. If the investigational treatment proves effective at treating MIS-C, it might also be studied in children with other inflammatory syndromes.

Future studies will aim to determine if the administration of remestemcel-L is alone responsible for the improvement of patients or if it still needs to be administered with plasma antibodies, which is the current but more expensive standard of care. The current standard-of-care therapies also have unwanted side effects that might be avoided if remestemcel-L is used instead.

"We want people to be more aware of the condition, but we also want to show people that we've had success with this therapy, in terms of safety and effectiveness, and encourage others to consider using it at their own institutions," said Eckard.

New Haven, Conn. -- Mailing a package of SARS-CoV-2 tests to every household in America and asking people to use them once a week could greatly reduce total infections and mortality at a justifiable cost, a new study led by the Yale School of Public Health finds.

The research, published today in Annals of Internal Medicine, considers rapid antigen tests that warn people, in real-time, that they are potentially contagious and that they should isolate themselves before unknowingly spreading the disease to others. Investigators, led by Professor A. David Paltiel, assembled data on the epidemiology of SARS-CoV-2 and the natural history of COVID-19. They then used a mathematical model to estimate how many infections, hospitalizations, and deaths could be averted - and at what cost - by providing households with the technology to self-identify and self-isolate before they infect others.

"Home-based antigen testing for SARS-CoV-2 combined with self-enforced isolation for those who have a positive result hasn't received the attention it deserves as a complement to social distancing and vaccination for containing the pandemic," said Paltiel.

Critics have argued that home testing will suffer from poor uptake, imperfect adherence, frequent false-negative results (leading to unfounded reassurance) and frequent false-positive findings (resulting in needless isolation and lost work productivity).

"We went to elaborate lengths to address these concerns, leaning heavily on the scales to tip the analysis against our own findings and deliberately portraying the strategy in a highly unfavorable light," said study co-author Paul D. Sax, of Brigham and Women's Hospital and Harvard Medical School.

For example, the investigators assumed that as many as 75% of households would elect to discard the package without opening it, that as many as 75% of the people would ignore a positive result, and that fewer than 25% of persons who elected to self-isolate would do so for a full week, as recommended. "We made equally pessimistic assumptions about the costs and accuracy of the tests. And still we found that it would confer an outstanding value," Sax said.

The study found that over a 60-days period, weekly availability of testing would avert 2.8 million infections and 15,700 deaths in the United States at an incremental cost of roughly $68 per person. This figure includes $38 for testing, $32 in additional workday productivity losses, and savings of $2 in inpatient hospitalization. This works out to a cost-effectiveness ratio of $1.43 million per death averted.

The investigators also noted that no single intervention will be sufficient to contain the pandemic, adding that their analysis highlights the importance of high-frequency testing as a complement to social distancing, vaccination, and other mitigation strategies.

"Don't let the perfect be the enemy of the good," said Paltiel. "Home-based antigen testing could save millions of infections and thousands of lives at a reasonable cost."

WHAT:

Approximately two years after establishing a human cerebral organoid system to study Creutzfeldt-Jakob disease (CJD), National Institutes of Health researchers have further developed the model to screen drugs for potential CJD treatment. The scientists, from NIH's National Institute of Allergy and Infectious Diseases (NIAID), describe their work in Scientific Reports.

Human cerebral organoids are small balls of human brain cells ranging in size from a poppy seed to a pea; scientists use human skin cells to create them. CJD, a fatal neurodegenerative brain disease of humans caused by infectious prion proteins, affects about 1 in 1 million people each year. It can arise spontaneously, result from a hereditary mutation within the prion gene, or arise due to infection, for example, from eating contaminated meat products. A notable example of this occurred in the United Kingdom in the mid-1990s following an outbreak of bovine spongiform encephalopathy in cattle. There are no preventive or therapeutic treatments for CJD.

The lack of a completely human CJD model has been a considerable barrier hindering the discovery of potential therapies. Studies in mice have failed to identify treatments that were then effective when tried in patients. The human cerebral organoid CJD model holds promise that this barrier can be eliminated. Cerebral organoids have organization, structure, and electrical signaling systems similar to human brain tissue. Because they can survive in a controlled environment for months to years, cerebral organoids also are ideal for studying nervous system diseases over lengthy periods of time. Cerebral organoids have been used as models to study Zika virus infection, Alzheimer's disease, and Down syndrome.

The CJD study was conducted at NIAID's Rocky Mountain Laboratories in Hamilton, Montana. Scientists tested pentosan polysulfate (PPS) to determine its potential preventive and therapeutic benefits. In the experiments, PPS treatment reduced the disease indicators by 10-fold or more without causing tissue death. PPS is a benchmark anti-prion compound in laboratory experiments, but it is rarely used clinically because it requires direct administration into the brain.

While it may extend a patient's life, PPS has not been shown to improve quality of life. However, using the anti-prion properties of PPS with the new human organoid CJD model allowed the researchers to assess the value of this model system for drug discovery. The scientists showed that the human organoid model can be used to screen compounds that may be useful for preventive treatment. Such treatment could be used for people carrying genetic mutations that cause the disease, but who have not yet developed symptoms, or for people who may have been exposed to infectious prion proteins that might cause CJD. The model further proved useful for screening drugs against established CJD after a patient is diagnosed and starts showing symptoms of disease.

The scientists are working to expand the organoid model for screening larger numbers of novel drug candidates. Their goal is to find treatment options for people who are susceptible to CJD because of their genetics or who accidentally are exposed, as well as for those who develop sporadic disease. They are optimistic that with their fully human model of disease, they can now identify compounds with promise for benefitting patients with CJD.

Philadelphia, March 9, 2021 - Schizophrenia is a neurodevelopmental disorder that disrupts brain activity producing hallucinations, delusions, and other cognitive disturbances. Researchers have long searched for genetic influences in the disease, but genetic mutations have been identified in only a small fraction--fewer than a quarter--of sequenced patients. A new study now shows that "somatic" gene mutations in brain cells could account for some of the disease neuropathology.

The study, led by senior author Jeong Ho Lee, MD, PhD, at Korea Advanced Institute of Science and Technology and the team of Stanley Medical Research Institute, appears in Biological Psychiatry, published by Elsevier.

Traditional genetic mutations, called germline mutations, occur in sperm or egg cells and are passed on to offspring by their parents. Somatic mutations, in contrast, occur in an embryo after fertilization, and they can appear throughout the body or in isolated pockets of tissues, making them much harder to detect from blood or saliva samples, which are typically used for such sequencing studies.

Recently, more-advanced genetic sequencing techniques have allowed researchers to detect somatic mutations, and studies have shown that even mutations present at very low levels can have functional consequences. A previous study hinted that brain somatic mutations were associated with schizophrenia (SCZ), but it was not powerful enough to cement such an association.

In the current study, the researchers used deep whole-exome sequencing to determine the genetic code of all exomes, the parts of genes that encode proteins. The scientists sequenced postmortem samples from 27 people with schizophrenia and 31 control participants both from brain and from liver, heart or spleen tissue, allowing them to compare the sequences in the two tissues. Using a powerful analytic technique, the team identified an average of 4.9 somatic single-nucleotide variants (SNV), or mutations, in brain samples from people with SCZ and 5.6 somatic SNVs in brain samples from control subjects.

Although there was no significant quantitative difference in somatic SNVs between SCZ and control tissues, the researchers found that the mutations in SCZ patients were found in genes already associated with SCZ. Of the germline mutations that had previously been associated with schizophrenia, the genes affected encoding proteins associated with synaptic neural communication, particularly in a brain region called the dorsolateral prefrontal cortex.

The researchers then determined which proteins might be affected by the newly identified somatic mutations. Remarkably, a protein called GRIN2B emerged as highly affected, and two patients with SCZ carried somatic mutations on the GRIN2B gene itself. GRIN2B is a protein component of NMDA-type glutamate receptors, which are critical for neural signaling. Faulty glutamate receptors have long been suspected to contribute to SCZ pathology; GRIN2B ranks among the most-studied genes in schizophrenia.

John Krystal, MD, Editor of Biological Psychiatry, said of the work, "The genetics of schizophrenia has received intensive study for several decades. Now a new possibility emerges, that in some cases, mutations in the DNA of brain cells contributes to the biology of schizophrenia. Remarkably this new biology points to an old schizophrenia story: NMDA glutamate receptor dysfunction. Perhaps the path through which somatic mutations contribute to schizophrenia converges with other sources of abnormalities in glutamate signaling in this disorder."

Dr. Lee and the team next wanted to assess the functional consequences of the somatic mutations. Because of the location of the GRIN2B mutations found in SCZ patients, the researchers hypothesized that they might interfere with the receptors' localization on neurons. Experiments in cortical neurons from mice showed that the mutations indeed disrupted the receptors' usual localization to dendrites, the "listening" ends of neurons, which in turn prevented the formation of normal synapses in the neurons. The finding suggests that the somatic mutations could disrupt neural communication, contributing to SCZ pathology.

The somatic mutations identified in the study had a variant allele frequency of only about 1 percent, indicating that the mutations were rare among brain cells as a whole. Nevertheless, they have the potential to create widespread cortical dysfunction.

Dr. Lee said of the findings: "Besides the comprehensive genetic analysis of brain-only mutations in postmortem tissues from schizophrenia patients, this study experimentally showed the biological consequence of identified somatic mutations, which led to neuronal abnormalities associated with SCZ. Thus, this study suggests that brain somatic mutations can be a hidden major contributor to SCZ and provides new insights into the molecular genetic architecture of SCZ."

BUFFALO, N.Y. -- New research from the University at Buffalo suggests that breast cancer patients who drink sugar-sweetened beverages regularly are at increased risk for death from any cause and breast cancer in particular.

Compared to women who never or rarely drank non-diet soda, those who reported drinking non-diet soda five times or more per week had a 62% higher likelihood of dying from any causes, and were 85% more likely to die from breast cancer specifically. The findings were published online ahead of print March 2 in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Research on soda and breast cancer is fairly new, says study first author Nadia Koyratty, a PhD candidate in the Department of Epidemiology and Environmental Health in UB's School of Public Health and Health Professions. Because breast cancer is so common, recommendations regarding lifestyle choices to breast cancer survivors are of considerable importance. And, despite the negative health outcomes associated with drinking soda, such as weight gain, Type 2 diabetes and cardiovascular disease, many people continue to drink sugar-sweetened sodas.

There have been only a few observational studies examining the association between sugar-sweetened beverages and cancer mortality. "This study is one of the few that looks at the prognosis of women with breast cancer with respect to non-diet soda consumption," Koyratty says.

Researchers assessed the relationship between sugar-sweetened soda and both all-cause and breast cancer mortality among 927 women who had been diagnosed with breast cancer, aged 35 to 79. Participants were enrolled in the Western New York Exposures and Breast Cancer (WEB) Study, and followed for a median of nearly 19 years.

The study used a food frequency questionnaire to assess participants' food and beverage intake in the 12 to 24 months prior to diagnosis of breast cancer. Of the more than 900 women diagnosed with breast cancer, 41% had died by the end of the follow-up period. Among the participants who had died, there was a higher percentage of women who reported high frequency of sugar-sweetened soda consumption compared to the women who were still living.

The associations did not change when researchers included diet soda consumption as a variable.

Why the focus on non-diet soda?

"Non-diet sodas are the highest contributors of sugar and extra calories to the diet, but they do not bring anything else that is nutritionally beneficial," Koyratty explains. "On the other hand, teas, coffees and 100% fruit juices, unless sugars are added, are healthier beverage options because they do add to the nutritive value through antioxidants and vitamins."

Sugar-sweetened sodas contain large quantities of sucrose and fructose, which give them the highest glycemic load compared to other foods or beverages. These higher concentrations of glucose and insulin may lead to conditions that have been associated with higher risk of breast cancer, the researchers note.

"There are more than 3.5 million breast cancer survivors alive in the U.S. today. We need to better understand the factors that affect their health," said study senior author Jo L. Freudenheim, PhD, SUNY Distinguished Professor in the Department of Epidemiology and Environmental Health in UB's School of Public Health and Health Professions.

"While we need more studies to confirm our findings, this study provides evidence that diet may impact longevity of women after breast cancer," Freudenheim added.