Culture

Activating an immune signaling pathway best known for fighting viral and bacterial infections can boost the ability of genetically engineered T cells to eradicate breast cancer in mice, according to a new study by researchers at the University of North Carolina. The study, to be published December 31 in the Journal of Experimental Medicine (JEM), suggests that CAR T cells, which are already used to treat certain blood cancers in humans, may also be successful against solid tumors if combined with other immunotherapeutic approaches.

Chimeric antigen receptor (CAR) T cells are a type of white blood cell that have been genetically engineered to recognize and attack cancer cells expressing specific proteins on their surface. They have been successfully used to treat patients with B cell lymphomas and are currently undergoing clinical trials for the treatment of many other types of blood cancer. “However, the clinical activity of CAR T cells in patients or animal models with solid tumors has been modest,” says Jonathan S. Serody, the Elizabeth Thomas Professor of Medicine, Microbiology, and Immunology and Director of the Cellular Therapy Program at the University of North Carolina School of Medicine.

CAR T cells may be less effective against solid tumors because they have to migrate into the tumors and then survive long enough to kill all of the tumor cells. Moreover, the cells and molecules surrounding tumors are often immunosuppressive, activating an immune checkpoint that causes the CAR T cells to lose their activity.

In the new study, Serody and colleagues tested several strategies to boost the effectiveness of CAR T cells in a mouse model of breast cancer. One effective strategy was to simultaneously treat the mice with drugs, such as cGAMP, that activate the STING pathway, an immune cell signaling pathway that normally induces inflammation in response to invading viruses or bacteria. Activating the STING pathway created a proinflammatory environment within the mouse tumors, improving the CAR T cells’ ability to accumulate and attack the tumor cells. The accumulation was particularly great when the mice were infused with CAR T cells that produce the immune signaling molecule IL-17A, compared with CAR T cells generated using standard techniques.

Serody and colleagues determined that the CAR T cells’ attack could be sustained for longer periods if the mice were also treated with therapeutic antibodies that deplete immunosuppressive cells from the tumor environment and prevent the immune checkpoint from deactivating the CAR T cells. The researchers found that combining all of these approaches led to the complete eradication of breast tumors.

“cGAMP is in clinical trials for the treatment of patients with cancer, there are multiple ongoing clinical trials using approaches to inhibit immunosuppressive cells for patients with malignant disease, and there are clinical trials currently evaluating the combination of CAR T cells with immune checkpoint blockade,” Serody says. “Together therefore, our data suggest a viable strategy for boosting CAR T activity in solid tumors.”

When the COVID-19 pandemic reached Africa, the continent was already struggling to deal with another public health crisis - a growing cancer epidemic characterized by more than one million new cancer cases and nearly 700,000 deaths per year. In a Perspective, Beatrice Wiafe Addai and Wilfred Ngwa discuss the significant challenges COVID-19 imposed on cancer prevention and control in Africa and how the efforts to address these challenges highlight key opportunities where greater investment could improve cancer care globally. At the start of the pandemic, many African governments were forced to rapidly divert already limited medical and healthcare resources away from cancer patients to treat those infected with SARS-CoV-2 and slow the spread of COVID-19. According to the authors, many African countries curtailed or cut cancer prevention activities, including awareness education and outreach, early detection screening, and vaccination, gaps that are likely to persist beyond the COVID-19 era. In addition, closed borders have made the international sharing of hospital-based resources and specialized lab diagnostics nearly impossible. Wiafa and Ngwa argue that, while necessary, this reallocation of critical health resources could lead to an increase in the number of late-stage cancer diagnoses and, thus, mortality across the continent. However, as many African nations have adapted to rise to these challenges, opportunities have also been created, such as cloud-based education and telemedicine, expansion of localized diagnostic capabilities and more efficient radiotherapy administration. The authors suggest that greater investment or policy in these areas could substantially increase access to cancer care worldwide.

For reporters interested in trends, a June 2020 Science Editorial by Norman E. Sharpless, director of the U.S. National Cancer Institute, addressed the likely impact of the pandemic on cancer mortality in the United States. https://science.sciencemag.org/content/368/6497/1290

Countries led by women have not fared significantly better in the COVID-19 pandemic than those led by men- it may be just our Western media bias that makes us think they have!

Very low birthweight infants are at a high risk for anemia and often need blood transfusions to survive. Some doctors use a higher level and some use a lower level of red blood cells to order a transfusion. A National Institutes of Health-funded study suggests that providing a higher threshold of red cells within clinically accepted limits (i.e., using a higher level of red blood cells when ordering a transfusion) offers no advantage in survival or reduction in neurological impairment over a lower threshold.

This large, multi-center randomized clinical trial was conducted by Dr. Haresh Kirpalani of the University of Pennsylvania, Dr. Edward Bell of the University of Iowa, and colleagues of the Neonatal Research Network including Dr. Rosemary Higgins of George Mason University's College of Health and Human Services, formerly the Project Scientist of the Neonatal Research Network. The study appears in The New England Journal of Medicine and is the largest study to-date to compare thresholds for blood transfusions in premature babies. View a brief video of the findings here.

Very preterm infants (born before 29 weeks of pregnancy) and those weighing less than 1,000 grams (slightly more than 2 pounds) are at high risk for anemia because of their early stage of development, reduced ability to produce red blood cells, and need for blood sampling as part of their intensive medical care. Previous studies suggest that anemic infants who received transfusions at a higher hemoglobin threshold within the currently accepted range would have a lower risk of death or developmental problems. Measuring hemoglobin, a protein produced in red blood cells, indicates the proportion of red blood cells. Hemoglobin transfusion thresholds for preterm infants vary according to weight, stage of maturity and other factors.

Of 845 infants assigned to a higher hemoglobin threshold, 50.1% died or survived with a neurodevelopmental impairment, compared to 49.8% of 847 infants assigned to a lower threshold. When the two component outcomes were evaluated separately, the two groups also had similar rates of death (16.2% vs. 15%) and of neurodevelopmental impairment (39.6% vs 40.3%). The authors evaluated the babies at two years of age and conclude that a higher hemoglobin threshold increased the number of transfusions, but did not improve the chance of survival without neurodevelopmental impairment.

"The findings are likely to be used to guide transfusion practice in the future for these infants; studies in premature infants are needed to guide care for these small and vulnerable infants; studies funded by NIH in multi-site networks are vitally important to the health of these fragile babies," explains Higgins.

The scientists from St Petersburg University began to study the geology of Central Asia in the middle of the 20th century. Multi-year research and rich field experience have made it possible to create the world's leading school of thought in the geology of the Tien Shan at the University. At present, work continues with active collaboration with scientists throughout the world.

One of the recent discoveries of the international research team is the discovery of this specific rock assemblage that is characteristic of modern oceanic island arcs. The rocks of this complex, found in the Songkultau Mountains in Kyrgyzstan, were formed in the Cambrian ocean about 500 million years ago. This is confirmed by the find of adakites. These are the rocks first described from Adak Island, which is part of the Aleutian island arc in the North Pacific Ocean.

'Studying the conditions of formation of ancient rocks is necessary not only for a better understanding of the geological history of the region. It is important to know this for more practical purposes, especially given that large ore deposits are often associated with adakites, an example of which are the famous copper and gold deposits in Chile,' said Dmitry Konopelko, Head of the research team, Associate Professor at St Petersburg University.

The unique composition of Songkultau granites captured the scientists' attention during regional mapping work carried out in 2007. According to Professor Reimar Seltmann, Head of the Centre for Russian and Central Eurasian Mineral Studies (CERCAMS) at the Natural History Museum in London, this prompted additional research, which led to the discovery of previously unknown fragments of the island arc complex. Professor Johan De Grave from Ghent University in Belgium and Professor Stijn Glorie from the University of Adelaide in Australia were involved in field work in the Tien Shan mountains. Analytical measurements and processing of field data were carried out by: Inna Safonova, a research associate at Novosibirsk State University; and Alla Dolgopolova from the Natural History Museum London. They did it under the guidance of Professor Min Sun in the laboratories of the University of Hong Kong.

The discovery of previously unknown fragments of an ancient island arc in the Kyrgyz Tien Shan is only one of the recent discoveries made within the framework of current projects: IGCP 662 Project 'Orogenic Architecture and Crustal Growth from Accretion to Collision' and grant from the Ministry of Education and Science of the Russian Federation 4.Y26.31.0018. They are aimed at deciphering the structures of the Central Asian Orogenic Belt, which is one of the largest ancient mountain systems on Earth.

DALLAS - Dec. 30, 2020 - When fat cells in the body are stuffed with excess fat, the surrounding tissue becomes inflamed. That chronic, low-level inflammation is one of the driving factors behind many of the diseases associated with obesity. Now, UT Southwestern scientists have discovered a type of cell responsible, at least in mice, for triggering this inflammation in fat tissue. Their findings, published in Nature Metabolism, could eventually lead to new ways to treat obesity.

"The inflammation of fat cells in obese individuals is linked to many of the comorbidities we associate with being overweight - cancer, diabetes, heart disease, and infection," says study leader Rana Gupta, Ph.D., associate professor of internal medicine. "By identifying these cells, we've taken a step toward understanding some of the initial events that contribute to that inflammation."

When a person consumes more calories than needed, the excess calories are stored in the form of triglycerides inside fat tissue, also known as white adipose tissue (WAT). Researchers know that in obese people, WAT becomes overworked, fat cells begin to die, and immune cells become activated. But the exact mechanism by which this inflammation occurs isn't fully understood.

While many studies have focused on the signaling molecules produced by the fat cells or immune cells in WAT that might contribute to inflammation, Gupta's team took a different approach. They focused instead on the vessels that carry blood - as well as immune cells and inflammatory molecules - into WAT.

In 2018, Gupta and his colleagues identified a new type of cell lining these blood vessels in mice - an adipose progenitor cell (APC), or precursor cell that goes on to generate mature fat cells. But unlike most APCs, the new cells - dubbed fibro-inflammatory progenitors, or FIPs - produced signals that encouraged inflammation. In the new work, the researchers looked more closely at the role of the FIPs in mediating inflammation.

Within just one day of switching young male mice to a high-fat diet, Gupta and his colleagues discovered that the FIPs quickly increased the number of inflammatory molecules produced. After 28 days on a high-fat diet, they found a substantial increase in the proportion of FIPs compared with other APCs.

"This is the first study to demonstrate that these cells play a very active, early role in being gatekeepers of inflammation in fat tissue," says Gupta.

To show that the increase in the number and activity of the FIPs was not just a side effect of already-inflamed fat cells, the team removed a key immune signaling gene, Tlr4, from the FIPs in some mice. After five months on a high-fat diet, the mice lacking Tlr4 had gained just as much weight, and just as much fat, as other mice on a high-fat diet. But the genetically engineered mice - with FIPs that could no longer generate the same signals - no longer had high levels of inflammation. Instead, the levels of inflammatory molecules in their WAT were closer to the levels seen in mice on low-fat diets.

Gupta and his colleagues went on to show that increasing levels of a related signaling molecule, ZFP423, in FIPs can also ameliorate the inflammation in mouse fat cells. The findings point toward possible avenues to pursue to lower the risk of disease in people with obesity.

"It looks like ZFP423 could be an important brake in terms of slowing the inflammatory signals in these cells," says Gupta. "Of course, it remains to be seen if that's true in humans as well as mice."

Gupta's group is planning future experiments to better understand what aspect of a high-fat diet initiates the increased inflammatory signaling in FIPs, as well as whether the results hold true in human fat.

Mobile apps have revolutionised the way people meet in Switzerland and elsewhere in recent years. Unlike traditional dating sites, these apps do not feature detailed user profiles but are largely based on rating photos using a swipe review system. As dating apps escalated in popularity, so has criticism about them encouraging casual dating only, threatening the existence of long-term commitment, and possibly damaging the quality of intimacy. There is no scientific evidence, however, to validate these claims. A study by the University of Geneva (UNIGE), Switzerland, provides a wealth of information about couples who met through dating apps, drawing on data from a 2018 Swiss survey. The results, published in the journal PLOS ONE, indicate that app-formed couples have stronger cohabitation intentions than couples who meet in a non-digital environment. What is more, women who found their partner through a dating app have stronger desires and intentions to have children than those who found their partner offline. Despite fears concerning a deterioration in the quality of relationships, partners who met on dating apps express the same level of satisfaction about their relationship as others. Last but not least, the study shows that these apps play an important role in modifying the composition of couples by allowing for more educationally diverse and geographically distant couples.

The meteoric rise of romantic encounters on the internet is on its way of becoming the leading place where couples are formed in Switzerland, on a par with meeting via friends. "The Internet is profoundly transforming the dynamics of how people meet," confirms Gina Potarca, a researcher at the Institute of Demography and Socioeconomics in UNIGE's Faculty of Social Sciences, and holder of an Ambizione research grant awarded by the Swiss National Science Foundation to study the effects of digital ways of communicating on marriage formation and sorting. "It provides an unprecedented abundance of meeting opportunities, and involves minimal effort and no third-party intervention." These new dating technologies include the smartphone apps like Tinder or Grindr, where users select partners by browsing and swiping on pictures. These apps, however, have raised fears: "Large parts of the media claim they have a negative impact on the quality of relationships since they render people incapable of investing in an exclusive or long-term relationship. Up to now, though, there has been no evidence to prove this is the case," continues Dr Potarca.

Facilitated encounters

The Geneva-based researcher decided to investigate couples' intentions to start a family, their relationship satisfaction and individual well-being, as well as to assess couple composition. Dr Potarca used a 2018 family survey by the Swiss Federal Statistical Office. The analysis presented in this study looks at a sub-sample of 3,235 people over the age of 18 who were in a relationship and who had met their partner in the last decade.

Dr Potarca found that dating websites - the digital tools for meeting partners that preceded apps - mainly attracted people over the age of 40 and / or divorcees who are looking for romance. "By eliminating lengthy questionnaires, self-descriptions, and personality tests that users of dating websites typically need to fill in to create a profile, dating apps are much easier to use. This normalized the act of dating online, and opened up use among younger categories of the population."

Searching for a lasting relationship

Dr Potarca sought to find out whether couples who met on dating apps had different intentions to form a family. The results show that couples that formed after meeting on an app were more motivated by the idea of cohabiting than others. "The study doesn't say whether their final intention was to live together for the long- or short-term, but given that there's no difference in the intention to marry, and that marriage is still a central institution in Switzerland, some of these couples likely see cohabitation as a trial period prior to marriage. It's a pragmatic approach in a country where the divorce rate is consistently around 40%." In addition, women in couples that formed through dating apps mentioned wanting and planning to have a child in the near future, more so than with any other way of meeting.

But what do couples who met in this way think about the quality of their relationship? The study shows that, regardless of meeting context, couples are equally satisfied with their lives and the quality of their relationship.

Couples with a diverse socio-educational profile

The study highlights a final aspect. Dating apps encourage a mixing of different levels of education, especially between high-educated women and lower educated men. Partners having more diversified socio-educational profiles "may have to do with selection methods that focus mainly on the visual," says the researcher. Since users can easily connect with partners in their immediate region (but also in other spaces as they move around), the apps make it easier to meet people more than 30 minutes away - leading to an increase in long-distance relationships.

"Knowing that dating apps have likely become even more popular during this year's periods of lockdown and social distancing, it is reassuring to dismiss alarming concerns about the long-term effects of using these tools," concludes Dr Potarca.

Very low birthweight infants often need blood transfusions to survive. A National Institutes of Health-funded study suggests that providing a higher threshold of red cells within accepted limits offers no advantage in survival or reduction in neurological impairment over a lower threshold. The research was conducted by Haresh Kirpalani, B.M., of the University of Pennsylvania, Philadelphia, and colleagues and was funded by the NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Heart, Lung, and Blood Institute, and National Center for Advancing Translational Sciences. The study appears in The New England Journal of Medicine.

Very preterm infants (born before 29 weeks of pregnancy) and those weighing less than 1,000 grams (slightly more than 2 pounds) are at high risk for anemia because of their early stage of development, reduced ability to produce red blood cells and need for increased blood sampling as part of their intensive medical care. Previous studies suggest that anemic infants would have a lower risk of death, cognitive delay, cerebral palsy and hearing and vision loss if they received transfusions leading to higher hemoglobin thresholds within the currently accepted range. Measuring hemoglobin, a protein produced in red blood cells, indicates the proportion of red blood cells. Hemoglobin transfusion thresholds for preterm infants vary according to weight, stage of maturity and other factors.

Of 845 infants assigned to a higher hemoglobin threshold, 50.1% died or survived with a neurodevelopmental impairment, compared to 49.8% of 847 infants assigned to a lower threshold. When the two component outcomes were evaluated separately, the two groups also had similar rates of death (16.2% vs. 15%) and of neurodevelopmental impairment (39.6% vs 40.3%). The authors conclude that a higher hemoglobin threshold increased the number of transfusions, but did not improve the chance of survival without neurodevelopmental impairment.

Women awaiting liver transplants in the United States are known to be about one-third more likely than men to become too ill to undergo surgery or die before receiving a liver. Now a study headed by UC San Francisco and Columbia University highlights the role that frailty plays in this gender gap.

The study followed 1,405 patients with cirrhosis, of whom 41 percent were women, awaiting liver transplantation at nine transplant centers in the United States. The men, whose ages ranged from 49 to 63, were more likely to have chronic hepatitis C and alcoholic liver disease (27 percent versus 22, and 33 percent versus 19 percent). The women, whose ages ranged from 50 to 63, were more likely to have non-alcoholic fatty liver disease and autoimmune cholestatic liver disease (23 percent versus 16 percent, and 23 percent versus 9 percent).

The researchers, led by first author Jennifer Lai, MD, MBA, a general and transplant hepatologist at the UCSF Department of Medicine, found that both genders had similar levels of liver disease severity, but fewer women had high blood pressure and coronary artery disease. Despite this, they were significantly frailer according to testing using the Liver Frailty Index (LFI), which showed weaker gender-adjusted grip, worse balance and that they were slower to stand up from a sitting position.

"This is the first time that frailty has been identified and quantified as a risk factor among women with cirrhosis who are waiting for liver transplants," said Lai. "The importance of this finding is that this gender gap can potentially be mitigated through early interventions as basic as providing adequate caloric and protein intake and engaging in regular exercise. Clinicians can advise women on diet and exercise interventions that build strength." These steps may be helpful for women undergoing other organ transplants, since frailty may play a role there too, the authors noted.

While the causes of frailty were not explored, Lai said that it is generally attributed to physical inactivity, chronic liver failure and poor diet.

Over the course of the study, the women had a 36 percent higher risk of waitlist mortality, which was defined as death or delisting for being too sick for transplantation. After adjusting for LFI scores and other variables, the researchers concluded that frailty accounted for 13 percent of the gender gap in waitlist mortality. While the study does not address the other factors that make up for the gender disparity, the authors note differences in kidney function and the higher percentage of male donors, who may be poor matches for women given their smaller stature.

The greatest significance of the study, said Lai, is at the level of the population of liver transplant patients in the United States.

"The waitlist mortality gender gap has persisted for 15 years across the entire U.S. liver transplant system and will continue to persist if it is not recognized," she said. Fortunately, "now that it has been recognized, it can be addressed."

The U.S. Department of Energy's (DOE) Princeton Plasma Physics Laboratory (PPPL) is collaborating with private industry on cutting-edge fusion research aimed at achieving commercial fusion energy. This work, enabled through a public-private DOE grant program, supports efforts to develop high-performance fusion grade plasmas. In one such project PPPL is working in coordination with MIT's Plasma Science and Fusion Center (PSFC) and Commonwealth Fusion Systems, a start-up spun out of MIT that is developing a tokamak fusion device called "SPARC."

The goal of the project is to predict the leakage of fast "alpha" particles produced during the fusion reactions in SPARC, given the size and potential misalignments of the superconducting magnets that confine the plasma. These particles can create a largely self-heated or "burning plasma" that fuels fusion reactions. Development of burning plasma is a major scientific goal for fusion energy research. However, leakage of alpha particles could slow or halt the production of fusion energy and damage the interior of the SPARC facility.

New superconducting magnets

Key features of the SPARC machine include its compact size and powerful magnetic fields enabled by the ability of new superconducting magnets to operate at higher fields and stresses than existing superconducting magnets. These features will enable design and construction of smaller and less-expensive fusion facilities, as described in recent publications by the SPARC team -- assuming that the fast alpha particles created in fusion reactions can be contained long enough to keep the plasma hot.

"Our research indicates that they can be," said PPPL physicist Gerrit Kramer, who participates in the project through the DOE Innovation Network for Fusion Energy (INFUSE) program. The two-year-old program, which PPPL physicist Ahmed Diallo serves as deputy director, aims to speed private-sector development of fusion energy through partnerships with national laboratories.

Well-confined

"We found that the alpha particles are indeed well confined in the SPARC design," said Kramer, coauthor of a paper in the Journal of Plasma Physics that reports the findings. He worked closely with the lead author Steven Scott, a consultant to Commonwealth Fusion Systems and former long-time physicist at PPPL.

Kramer used the SPIRAL computer code developed at PPPL to verify the particle confinement. "The code, which simulates the wavy pattern, or ripples, in a magnetic field that could allow the escape of fast particles, showed good confinement and lack of damage to the SPARC walls," Kramer said. Moreover, he added, "the SPIRAL code agreed well with the ASCOT code from Finland. While the two codes are completely different, the results were similar."

The findings gladdened Scott. "It's gratifying to see the computational validation of our understanding of ripple-induced losses," he said, "since I studied the issue experimentally back in the early 1980s for my doctoral dissertation."

Fusion reactions combine light elements in the form of plasma -- the hot, charged state of matter composed of free electrons and atomic nuclei, or ions, that comprises 99 percent of the visible universe -- to generate massive amounts of energy. Scientists around the world are seeking to create fusion as a virtually unlimited source of power for generating electricity.

Key guidance

Kramer and colleagues noted that misalignment of the SPARC magnets will increase the ripple-induced losses of fusion particles leading to increased power striking the walls. Their calculations should provide key guidance to the SPARC engineering team about how well the magnets must be aligned to avoid excessive power loss and wall damage. Properly aligned magnets will enable studies of plasma self-heating for the first time and development of improved techniques for plasma control in future fusion power plants.

813 years of annual river discharge at 62 stations, 41 rivers in 16 countries, from 1200 to 2012. That is what researchers at the Singapore University of Technology and Design (SUTD) produced after two years of research in order to better understand past climate patterns of the Asian Monsoon region.

Home to many populous river basins, including ten of the world's biggest rivers (Figure 1), the Asian Monsoon region provides water, energy, and food for more than three billion people. This makes it crucial for us to understand past climate patterns so that we can better predict long term changes in the water cycle and the impact they will have on the water supply.

To reconstruct histories of river discharge, the researchers relied on tree rings. An earlier study by Cook et al. (2010) developed an extensive network of tree ring data sites in Asia and created a paleodrought record called the Monsoon Asia Drought Atlas (MADA). SUTD researchers used the MADA as an input for their river discharge model.

They developed an innovative procedure to select the most relevant subset of the MADA for each river based on hydroclimatic similarity. This procedure allowed the model to extract the most important climate signals that influence river discharge from the underlying tree ring data.

"Our results reveal that rivers in Asia behave in a coherent pattern. Large droughts and major pluvial periods have often occurred simultaneously in adjacent or nearby basins. Sometimes, droughts stretched as far as from the Godavari in India to the Mekong in Southeast Asia (Figure 2). This has important implications for water management, especially when a country's economy depends on multiple river basins, like in the case of Thailand," explained first author Nguyen Tan Thai Hung, a PhD student from SUTD.

Using modern measurements, it has been known that the behaviour of Asian rivers is influenced by the oceans. For instance, if the Pacific Ocean becomes warmer in its tropical region in an El Nino event, this will alter atmospheric circulations and likely cause droughts in South and Southeast Asian rivers. However, the SUTD study revealed that this ocean-river connection is not constant over time. The researchers found that rivers in Asia were much less influenced by the oceans in the first half of the 20th century compared to the 50 years before and 50 years after that period.

"This research is of great importance to policy makers; we need to know where and why river discharge changed during the past millennium to make big decisions on water-dependent infrastructure. One such example is the development of the ASEAN Power Grid, conceived to interconnect a system of hydropower, thermoelectric, and renewable energy plants across all ASEAN countries. Our records show that 'mega-droughts' have hit multiple power production sites simultaneously, so we can now use this information to design a grid that is less vulnerable during extreme events," said principal investigator Associate Professor Stefano Galelli from SUTD.

New Orleans, LA - Research conducted at LSU Health New Orleans Neuroscience Center of Excellence reports that a combination of an LSU Health-patented drug and selected DHA derivatives is more effective in protecting brain cells and increasing recovery after stroke than a single drug. The findings are published in Brain Circulation, available here.

Nicolas Bazan, MD, PhD, Boyd Professor, Professor of Neurology and Director of the Neuroscience Center of Excellence at LSU Health New Orleans School of Medicine, and Ludmila Belayev, MD, LSU Health New Orleans Professor of Neuroscience, Neurology, and Neurosurgery, discovered this novel therapeutic strategy for ischemic stroke using an experimental model.

During an ischemic stroke, signals are produced from arriving blood white cells and primary brain immune cells called microglia that cause neuroinflammation leading to a buildup of chemicals that harm the brain. Platelet-activating factor (PAF) accumulates, and inhibition of this process plays a critical role in neuronal survival. Dr. Bazan's earlier studies also showed that in addition to its anti-inflammatory properties, DHA, an essential omega-3 fatty acid, stimulates the production of Neuroprotectin D1 (NPD1), a molecule that protects brain cells and promotes their survival. One complicating factor in developing neuroprotective strategies for stroke are the multiple routes and events that occur in the brain during a stroke, which has been approached mainly by monotherapeutic agents that were mostly unsuccessful.

Because no single therapy has proven effective in treating the complexity of stroke, the team aimed at two different events - blocking pro-inflammatory platelet-activating factor receptors (PAF-R) and activating cell-survival pathways. They found that treatment with LAU-0901, a synthetic molecule discovered in the Bazan lab that blocks pro-inflammatory platelet-activating factor, plus aspirin-triggered NPD1 (AT-NPD1) reduced the size of the damaged area in the brain, initiated repair mechanisms, and remarkably improved behavioral recovery.

Total lesion volumes were reduced with LAU?0901 plus NPD1 by 62% and LAU?0901 plus AT?NPD1 by 90%. Combinatory treatment with LAU?0901 plus AT?NPD1 improved the behavioral score up to 54% on day three. LAU?0901 and LAU?0901 plus DHA decreased the production of 12?hydroxyeicosatetraenoic acid, a pro?inflammatory mediator.

"The biological activity of LAU-0901 and AT-NPD1 is due to specific activation or modulation of signaling pathways associated with the immune system, inflammation, cell survival, and cell-cell interactions," notes Dr. Bazan. "These findings provide a major conceptual advance of broad therapeutic relevance for cell survival, brain function and, particularly, stroke and neurodegenerative diseases."

"We discovered that these novel molecules promote neuronal cell survival with important anti-inflammatory activity," explains Dr. Belayev. "This combinatorial therapy may hold promise for future therapeutic development against ischemic stroke."

According to the Centers for Disease Control and Prevention, someone in the United States has a stroke every 40 seconds. Every 4 minutes, someone dies of stroke. Every year, more than 795,000 people in the United States have a stroke. About 87% of all strokes are ischemic strokes, in which blood flow to the brain is blocked. Stroke-related costs in the United States came to nearly $46 billion between 2014 and 2015. This total includes the cost of health care services, medicines to treat stroke, and missed days of work. Stroke is a leading cause of serious long-term disability. Stroke reduces mobility in more than half of stroke survivors age 65 and over.

In some cases, immune cells in the lungs can contribute to worsening a virus attack. In a new study, researchers at Karolinska Institutet in Sweden describe how different kinds of immune cells, called macrophages, develop in the lungs and which of them may be behind severe lung diseases. The study, which was published in Immunity, may contribute to future treatments for COVID-19, among other diseases.

The structure of the lungs exposes them to viruses and bacteria from both the air and the blood. Macrophages are immune cells that, among other things, protect the lungs from such attacks. But under certain conditions, lung macrophages can also contribute to severe lung diseases, such as chronic obstructive pulmonary disease (COPD) and COVID-19.

To date, research on the development of human lung macrophages has been limited.

Macrophages can have different origins and develop, among other things, from white blood cells, monocytes, that are divided into different genetically determined main types. In humans, two of these are "classical" CD14+ monocytes and "non-classical" CD16+ monocytes.

In a new study at Karolinska Institutet, researchers have used a model to study the development of lung macrophages directly in a living lung. This has been combined with a method to study gene activity in individual cells, RNA sequencing, and thereby discovered how blood monocytes become human lung macrophages.

"In our study, we show that classical monocytes migrate into airways and lung tissue and are converted into macrophages that protect the health and function of the lungs. We have also identified a special kind of monocyte, HLA-DRhi, which is an intermediate immune cell between a blood monocyte and an airway macrophage. These HLA-DRhi monocytes can leave the blood circulation and migrate into the lung tissue," says Tim Willinger, Associate Professor at the Department of Medicine, Huddinge, Karolinska Institutet, who led the study.

The non-classical monocytes, however, develop into macrophages in the many blood vessels of the lungs and do not migrate into the lung tissue.

"Certain macrophages in the lungs probably have a connection to a number of severe lung diseases. In respiratory infections, for example, monocytes in the lungs develop into macrophages, which combat viruses and bacteria. But a certain type of macrophage may also contribute to severe inflammation and infections," says the study's first author Elza Evren, a doctoral student in Tim Willinger's research team.

In an infection with the novel coronavirus, SARS-COV-2, which causes COVID-19, researchers believe that protective, anti-inflammatory macrophages are replaced by pro-inflammatory lung macrophages from blood monocytes.

"The existence of these blood monocyte-derived macrophages has been shown in other studies to correlate with how severely ill a person becomes in COVID-19 and how extensive the damage to the lungs is. Patients with severe COVID-19 also have fewer HLA-DRhi monocytes in their blood, probably because they move away from the blood into the lungs. Given their important role in rapid inflammatory responses, our results indicate that future treatments should focus on inflammatory macrophages and monocytes to reduce lung damage and mortality from severe COVID-19," says Tim Willinger.

East Hanover, NJ. December 30, 2020. A team of rehabilitation researchers has studied processing speed deficits in individuals with spinal cord injury (SCI), comparing their brain activation patterns with those of healthy age-matched controls, and older healthy individuals. They found that the SCI group and older controls had similar activation patterns, but the SCI group differed significantly from their age-matched controls.

The article, "The neural mechanisms underlying processing speed deficits in individuals who have sustained a spinal cord injury: A pilot study" (doi: 10.1007/s10548-020-00798-x) was epublished on September 25, 2020 by Brain Topography. The authors are scientists with expertise in research in cognitive rehabilitation and SCI rehabilitation: Glenn Wylie, DPhil, Nancy D. Chiaravalloti, PhD, Erica Weber, PhD, Helen Genova, PhD, and Trevor Dyson-Hudson, MD, from Kessler Foundation, and Jill M. Wecht, EdD, from the James J. Peters VA Medical Center.

Individuals with chronic SCI have an increased risk for cognitive deficits that resemble the deficits associated with the aging process, giving rise to the theory of "accelerated cognitive aging." As reported previously by this team, the deficits affect processing speed, new learning and memory, and verbal fluency, which are the domains affected during aging. This study is the first to examine the neural mechanisms of higher order cognitive tasks of individuals with SCI. The focus was on processing speed, which is known to be affected by SCI and aging, and is integral to cognitive function and everyday life activities.

The 30 participants were participants of a larger study who underwent optional neuroimaging studies at the Rocco Ortenzio Neuroimaging Center at Kessler Foundation -- 10 individuals with cervical SCI, 10 age-matched controls, and 10 healthy older individuals. In addition to traditional neuropsychological testing methods, processing speed was tested in the scanner, using timed letter comparison tasks during functional magnetic resonance imaging (fMRI). This study was the first to use the modified letter comparison test.

Significant differences in brain activation were found between the SCI group and the age-matched control group, but the SCI and older groups had similar patterns, including activation of the hippocampal, frontal and parietal areas. "This suggests that individuals with SCI are compensating for deficits in processing speed by relying on the areas of the brain involved in executive control and memory," noted Dr. Chiaravalloti, "which supports the theory of accelerated brain aging after SCI."

Despite the limitations of sample size and level of injury, the study is an important contribution to our understanding of the impact of SCI on cognition, according to Dr. Wylie, director of the Ortenzio Center. "Our ability to observe brain activation while the individual performs specific cognitive tasks provides new information on the mechanisms that underlie the cognitive deficits that we now know affect a substantial proportion of the SCI population," Dr. Wylie said. "Developing treatments targeted to these deficits depends on our pursuit of this line of research, which may benefit other populations affected by delayed processing speed."

BOSTON -- A peer-reviewed paper published in The New England Journal of Medicine provides data from the much-anticipated COVE study, which evaluated mRNA-1273, a vaccine candidate against COVID-19 manufactured by Moderna, Inc. Results from the primary analysis of the study, which will continue for two years, provide evidence that the vaccine can prevent symptomatic infection. Among the more than 30,000 participants randomized to receive the vaccine or a placebo, 11 of those in the vaccine group developed symptomatic COVID-19 compared to 185 participants who received the placebo, demonstrating 94.1 percent efficacy in preventing symptomatic COVID-19. Cases of severe COVID-19 occurred only in participants who received the placebo.

Brigham and Women's Hospital served as a site for the trial as part of the COVID-19 Prevention Network (CoVPN), funded by the National Institutes of Health. In addition, Lindsey Baden, MD, an infectious diseases specialist at the Brigham and an expert in vaccine development for viral diseases, served as co-principal investigator for the study and lead author of the paper.

"Our work continues. Over the next months, we'll have increasing amounts of data to better define how this vaccine works, but the results so far show a 94.1 percent efficacy. These numbers are compelling," said Baden. "And, importantly, the data suggest protection from severe illness, indicating that the vaccine could have an impact on preventing hospitalizations and deaths, at least in the first several months post-vaccination."

The study enrolled 30,420 adult participants at 99 U.S. sites, including over 600 participants enrolled at the Brigham. Eligible participants were 18 years old or older with no known history of SARS-CoV-2 infection, and whose locations or circumstances put them at appreciable risk of SARS-CoV-2 infection and/or high risk of severe COVID-19. The race and ethnicity proportions of the trial were generally representative of U.S. demographics (79 percent white; 10 percent Black or African American; 20 percent Hispanic or Latino participants).

Participants received their first injection between July 27 and Oct. 23, 2020, followed by a second injection 28 days later. Each injection, given intramuscularly, had a volume of 0.5 mL, containing 100 μg of mRNA-1273 or saline placebo.

In the placebo group, 185 participants developed symptomatic COVID-19 illness; in the vaccine group, 11 participants did. In secondary analyses, the vaccine's efficacy was similar across groups of key interest, including those who already had antibodies against SARS-CoV-2 at the time of enrollment (indicating previous infection with COVID-19) and among those who were 65 years of age or older. Thirty participants had severe COVID-19 -- all in the placebo group.

Starting from randomization, cases of COVID-19 and severe COVID-19 were continuously monitored throughout the trial by the Data Safety Monitoring Board, empaneled by the NIAID. Participants were closely monitored for adverse events in the weeks following their injection. Investigators have collected and will continue to collect data on any serious adverse events or adverse events that require medical attention through two years post-injection.

Overall, reactions to the vaccine were mild -- about half of recipients experienced fatigue, muscle aches, joint pain and headaches, more so after the second dose. In most cases, these effects started about 15 hours after the vaccine and resolved after two days without sequelae. A similar number of adverse events were reported in the placebo and vaccine groups.

"While these results are encouraging, they are limited by the short duration of follow-up so far. Longer term data from the ongoing study may allow us to more carefully evaluate the vaccine's efficacy among different groups, determine the impact on asymptomatic infection, understand when immunity wanes, and determine whether vaccines affect infectiousness," said Baden. "But we shouldn't lose sight of the progress that we have made, which shows what is possible when we come together to tackle an immensely challenging problem."