Recent NIH Research

Combination Therapy Shows Increased Effectiveness Against Brain Cancer

IRP researchers have released the results of their study suggesting that “a two-pronged approach that relies in part on an existing anti-cancer drug could more effectively thwart a particularly deadly form of brain cancer.”  The report on the study’s effectiveness is subtitled, “Additional Treatment Cuts off Tumor Cells’ Escape Route From Anti-Cancer Drug,” because the addition of an RNA molecule called small interfering RNA (siRNA), to trametinib therapy, showed promise in curbing the production of PRMT5 in glioblastoma cells.

IRP staff scientist Yeshavanth Banasavadi, the study’s first author says, “There have been multiple studies that show siRNAs, being biological agents, are a better option than using those drugs.”  However, Dr. Banasavadi added that “In isolated cells, that’s easy to do, but in animals or humans, it’s more difficult. We are trying to come up with different strategies,” including delivering siRNAs directly to tumors via nanoparticles.

Marburg vaccine shows promising results in first-in-human study

According to a January 30^th NIH report, a vaccine developed by researchers at the National Institute of Allergy and Infectious Diseases (NIAID) could someday be an important tool to against outbreaks of Marburg virus. The report refers to a newly published paper in The Lancet.

The Lancet article describes how this first-in-human, Phase 1 study tested an experimental MARV vaccine candidate, known as cAd3-Marburg (developed at NIAID’s Vaccine Research Center) uses a modified chimpanzee adenovirus (“cAd3”), rendered unable to replicate, displays a glycoprotein found on the surface of MARV to induce immune responses against the virus.

In fact, the Lancet article documents that, “the investigational vaccine appeared to induce strong, long-lasting immunity to the MARV glycoprotein with 95% of participants in the trial exhibiting a robust antibody response after vaccination, and 70% maintaining that response for more than 48 weeks.”

NIH reports that “Plans are in place to conduct further trials of the cAd3-Marburg vaccine in Ghana, Kenya, Uganda, and the United States. If additional data supports the promising results seen in the Phase 1 trial, the cAd3-Marburg virus vaccine could someday be used in emergency responses to MARV outbreaks.” Probiotic markedly reduces S. aureus colonization in Phase 2 trial.

Probiotic markedly reduces S. aureus colonization in Phase 2 trial

A recently published NIH study presents evidence that a probiotic can markedly reduce the presence of potentially life-threatening S. aureus colonization in the human gut.

As published in the Lancet, a Phase 2 clinical trial conducted by Michael Otto, Ph.D., an NIH senior investigator at the National Institute of Allergy and Infectious Diseases (NIAID), have found that using B. subtilis probiotic once daily for four weeks instead of antibiotics – was safe and highly effective against staph infection.  This finding is important because, as the NIH reports, “S. aureus often lives in the nose, on the body, and in the gut without causing any harm. However, if the skin barrier is broken, or the immune system compromised, these colonizing bacteria can cause serious skin, bone, lung, and blood infections.”

Dr. Otto, the trial’s lead researcher, explained that “The probiotic we use does not ‘kill’ S. aureus, but it specifically and strongly diminishes its capacity to colonize. We think we can target the ‘bad’ S. aureus while leaving the composition of the microbiota intact.”

While the use of probiotics takes longer than antibiotics, Dr. Otto and his team are optimistic because, “Our results suggest a way to safely and effectively reduce the total number of colonizing S. aureus and also call for a categorical rethinking of what we learned in textbooks about S. aureus colonization of the human body.”

As reported by the NIH, “the researchers plan to continue their work by testing the probiotic in a larger and longer trial. Study collaborators in Thailand are from Rajamangala University of Technology Srivijaya, and Prince of Songkla University.”

New approach successfully traces genomic variants back to genetic disorders

A genotype-first approach has been shown by NIH researchers to uncover new links to genetic conditions. As reported in January, a study of their results published in the American Journal of Human Genetics has documented that a genotype-first approach to patient care (that involves selecting patients with specific genomic variants and then studying their traits and symptoms) has “uncovered new relationships between genes and clinical conditions, broadened the traits and symptoms associated with known disorders, and offered insights into newly described disorders.”

Caralynn Wilczewski, Ph.D., a genetic counselor at the National Human Genome Research Institute’s (NHGRI) Reverse Phenotyping Core, authored the assessment of 13 studies that took a genotype-first approach to patient care. She reports that, “We demonstrated that genotype-first research can work, especially for identifying people with rare disorders who otherwise might not have been brought to clinical attention.” The report has great potential to aid people with both rare diseases and genetic conditions.

The phenotype-first approach limits researchers from understanding the full spectrum of symptoms of the disorders and the associated genomic variants.

Leslie Biesecker, M.D., NIH distinguished investigator, director of NHGRI’s Center for Precision Health Research, and a senior author of the article added, “Genomics has the potential to change reactive medicine into preventative medicine. Studying how taking a genotype-first approach to research can help us learn how to model predictive and precision medicine in the future.”,

As the NIH reports, NHGRI researchers recommend institutions aiming to establish genotype-first centers create strategic plans, especially for deciding what genomic findings will be returned, which may involve genetic counseling services. Importantly, according to the study, researchers must actively communicate with study participants to build informed and trusting long-term relationships.

“In the future, as more researchers adopt this approach, said Dr. Wilczewskiwe, hope to identify more people who may be helped by the availability of their genome sequence, especially as more diverse populations join genome-sequencing studies.”

Good hydration linked to healthy aging

Expanding on research scientists published in March 2022, which found links between higher ranges of normal serum sodium levels and increased risks for heart failure, researchers in the Laboratory of Cardiovascular Regenerative Medicine at the National Heart, Lung, and Blood Institute (NHLBI), published a report in January with their findings that adults with serum sodium levels at the higher end of a normal range were more likely to develop chronic conditions and show signs of advanced biological aging than those with serum sodium levels in the medium ranges.

The data gathered from 11,255 adults over a 30-year period came from the Atherosclerosis Risk in Communities (ARIC) study, which includes sub-studies involving thousands of Black and white adults from throughout the United States. “The results suggest that proper hydration may slow down aging and prolong a disease-free life,” said Natalia Dmitrieva, Ph.D., a study author. Additionally, through analysis of links between serum sodium levels – which go up when fluid intake goes down – and various indicators of health, researchers showed that adults with higher serum sodium levels were also more likely to die at a younger age.

Researchers noted that, although randomized, controlled trials are needed to determine if optimal hydration can promote healthy aging, prevent disease, and lead to a longer life, associations can still inform clinical practice and guide personal health behavior.

“Decreased body water content is the most common factor that increases serum sodium, which is why the results suggest that staying well hydrated may slow down the aging process and prevent or delay chronic disease.”

Events

Diet and Health 2023: Supplements, Diets, or Food Systems?

Wednesday, Mar 1, 2023, 11:00 AM – 12:00 PM

National Research Summit on Care, Services, and Supports for Persons Living With Dementia and Their Caregivers/care Partners

Monday, Mar 20, 2023, from 9:00 AM – 5:00 PM

Tuesday, Mar 21, 2023, from 9:00 AM – 5:00 PM

Wednesday, Mar 22, 2023, from 9:00 AM – 5:00 PM

NCI Symposium on Cancer Health Disparities

Tuesday, April 4 to Wednesday, April 5, 2023 (register by March 28)

2023 NCI RNA Biology Symposium

Thursday, April 27, 2023, to Friday, A

The post National Institutes of Health (NIH) Research Updates – Feb 2023 appeared first on Astrix.

Recent NIH Research

NIH researchers use 3D bioprinting to create eye tissue

NIH researchers use 3D bioprinting to create eye tissue

National Eye Institute (NEI) scientists used patient stem cells and 3D bioprinting to create eye tissue. The researchers combined cellular material from the outer blood-retina barrier and printed tissue that supports photoreceptors in the retina. This new method provides an unlimited supply of patient-derived tissue for research on degenerative retinal diseases. The NIH team is hopeful that this new technique will help lead to treatments for these debilitating conditions.

“We know that AMD starts in the outer blood-retina barrier,” said Kapil Bharti, Ph.D., who heads the NEI Section on Ocular and Stem Cell Translational Research. “However, mechanisms of AMD initiation and progression to advanced dry and wet stages remain poorly understood due to the lack of physiologically relevant human models.”

They observed similar indications of wet AMD when oxygen levels were reduced, marked by the presence of out-of-control choroid vessels underneath the RPE layer. Fortunately, anti-VEGF drugs – a mainstay treatment for AMD – effectively suppressed these growths and restored normal tissue morphology.

“By printing cells, we’re facilitating the exchange of cellular cues that are necessary for normal outer blood-retina barrier anatomy,” said Bharti. “For example, presence of RPE cells induces gene expression changes in fibroblasts that contribute to the formation of Bruch’s membrane – something that was suggested many years ago but wasn’t proven until our model.”

Bharti’s team encountered various technical hurdles while developing their project, such as creating a biodegradable scaffold and refining the printing pattern by establishing an environmentally sensitive hydrogel.

Co-author Marc Ferrer, Ph.D. (Director of the 3D Tissue Bioprinting Laboratory at NIH’s National Center for Advancing Translational Sciences) and his research team provided their invaluable expertise in biofabrication techniques to create outer blood-retina barrier tissues “in-a-well” along with analytical measurements that enabled drug screening.

“Our collaborative efforts have resulted in very relevant retina tissue models of degenerative eye diseases,” Ferrer said. “Such tissue models have many potential uses in translational applications, including therapeutics development.”

Bharti and colleagues are utilizing printed blood-retina barrier models to examine AMD, with the idea of increasing cell types in the printing process, such as immune cells; this may effectively reflect native tissue better.

Friendly Virus Could Deliver Gene Therapy Under Immune System’s Radar

Friendly Virus Could Deliver Gene Therapy Under Immune System’s Radar

In a new study, IRP researchers revealed that most people have a non-reactive immune system to an innocuous virus, which can serve as a successful delivery vector for gene therapy treatments targeting life-threatening genetic diseases. This novel discovery is highly promising and could offer new hope for those affected by such conditions.

During his time at Children’s Hospital of Philadelphia, Charles Venditti, M.D., Ph.D., Senior IRP investigator, explored technology capable of recognizing methylmalonic acidemia (MMA) in infants only days after birth; however, finding the illness at an early stage did not change its eventual outcome.

“I was involved with meeting families and their babies that had methylmalonic acidemia and were diagnosed in the first one or two weeks of life,” he recalls. “The families would ask, ‘What’s going to happen to my baby?’ As a practitioner of metabolic medicine, I knew that the outlook was predicted to be grim, with a high chance of death and disability. The conversations were difficult.”

In a recent study, the labs of Dr. Chiorini, Ph.D. an IRP senior investigator, and Dr. Venditti partnered to explore if an immune response could neutralize andeo-associated viruses (AAVs) called AAV44.9, which has a unique capsid discovered by Dr. Chiorini’s lab several years ago with the expectation that it will evade detection from the body’s immunity and effectively deliver genes into cells required for treating MMA or other similar genetic ailments.

“The capsid is the molecular truck of the gene therapy vector,” Dr. Chiorini says. “It dictates where the gene is going to be delivered and when it is going to be active, so it’s a really critical component of gene transfer technology.”

After examining blood samples of adults and children who have MMA for AAV44.9 antibodies, researchers discovered that only 26% of adults and 13% of children possessed enough antibodies to fight the virus. Remarkably, these levels were too low to combat it effectively. Additionally, a study of mice found that AAV44.9 was effective in delivering the gene and very promising in correcting a mutation that causes MMA-like symptoms.

The results of the recent study have demonstrated that AAV44.9 may be a remarkably successful technique for gene therapy for MMA; however, further research needs to be done. Dr. Venditti is currently planning on initiating a clinical trial involving a gene therapy utilizing an alternate viral vector which his laboratory has been researching longer than AAV44.9.

Additionally, the study showed a low number of antibodies against AAV44.9 in the studied population of MMA patients; this virus can serve as a valuable alternative vector for gene therapy treatments if existing patient antibodies neutralize other AAVs utilized to deliver these therapies.

“Our collective goal is to widely enable gene therapies for patients with MMA and related disorders because we hope they will be ‘one and done’ treatments,” Dr. Venditti says. “Any new class of vector could help, especially ones that are very potent in living organisms, like AAV44.9”.

NCI clinical trial leads to atezolizumab approval for advanced alveolar soft part sarcoma

NCI clinical trial leads to atezolizumab approval for advanced alveolar soft part sarcoma

Recently, the U.S. Food and Drug Administration granted permission for Atezolizumab (Tecentriq) to be used as an immunotherapy drug on adults and children aged two or older with advanced sarcoma that has metastasized. This decision was based on findings from a non-randomized phase 2 trial supported by the National Cancer Institute (NCT03141684).

The study was conducted by Dr. Alice Chen of the Developmental Therapeutics Clinic in NCI’s Division of Cancer Treatment and Diagnosis (DCTD). Genentech, part of the Roche Group and creator of atezolizumab, supplied NCI with the drug through a cooperative research agreement – results are currently being prepared for publication.

This is the most extensive study on ASPS and the first NCI-funded Experimental Therapeutics Clinical Trials Network study that led to drug approval. This is also the first time atezolizumab has been approved for children due to the participation of the Pediatric Oncology Branch in NCI’s Center for Cancer Research.

“This is a major milestone for investigators in the Experimental Therapeutics Clinical Trials Network, as well as for the ASPS patient community, and for research on rare cancers,” said Elad Sharon, M.D., of DCTD, who is one of the study leaders.

49 ethnically diverse patients aged two and up with metastatic alveolar soft part sarcoma were given an infusion of atezolizumab in the trial on a 21-day rotation. According to doctor evaluations, approximately one-third of the patients saw a positive response to their treatment with noticeable tumor shrinkage. For most other patients, their condition remained stable.

“This approval represents a victory for rare diseases, which are understudied in clinical trials,” said Dr. Chen. “For this approval to go through in a rare disease, and to be able to make an impact on these young people’s lives, is very significant.”

Currently, research teams are further exploring the potential of atezolizumab as a treatment for ASPS. This includes testing its efficacy when combined with other therapies.

Toxic Protein and Aging Combine Forces to Drive Brain Disease

Toxic Protein and Aging Combine Forces to Drive Brain Disease

A recent IRP study has potentially located new therapeutic targets for two age-related illnesses. Alpha synuclein, a protein that accumulates in the brains of those with Parkinson’s disease and some forms of dementia, appears to be particularly prevalent among elderly individuals – offering vital insight into developing more effective treatments for these conditions.

Dr. Eliezer Masliah, Senior Investigator of the NIH’s National Institute on Aging (NIA) worked with co-author and  IRP senior investigator Dr.  Ranjan Sen, PH. D and his group to study how aging interacts with alpha-synuclein in the brains of mice. The researchers injected alpha-synuclein ‘protofibrils’ into young and older mice’s brains.

The IRP study revealed that alpha-synuclein spread far more quickly in the brains of older mice, significantly diminishing their fear response to a sound cue they had been previously conditioned to associate with an electric shock. This shows that memory can be detrimentally affected by such injections. In younger mice, however, injections of alpha-synuclein had a much weaker effect on their reaction to the fear-inducing sound. Interestingly, while IRP researchers observed alpha-synuclein’s impact on cognition in both genders of mouse subjects, they only noticed that it decreased motor coordination in males.

“There has been a lot of interest at NIA about understanding sex differences in neurodegenerative disorders,” Dr. Masliah says. “We know in Lewy body dementia that women are affected differently than men, and Alzheimer’s disease tends to be more common in women than in men. There may be a difference in how sex hormones affect the disease or some other factor that we don’t understand, but that’s why it’s important when designing these sorts of experiments to include both sexes.”

The alpha-synuclein injections had a noticeable effect on the production and activity of T cells and microglia among treated mice compared to untreated ones. Upon examining gene expression in affected microglia, researchers observed changes in numerous genes associated with inflammation; these modifications were more intense for older vs. younger rodents even when they did not receive any injection.

After examining how specific genes are regulated, scientists discovered that colony-stimulating factor 2 (CSF2) considerably influences them. This chemical is generated by T cells and other immune system components, verifying recent studies which have linked CSF2 to neurological disorders.

“I think the fact that we found a link to CSF2 suggests that all these excess T cells that are getting into the brain might be secreting more CSF2, and this CSF2 is detected by microglia,” Dr. Masliah explains. “The microglia become activated, and then we see dysregulation in all these other inflammatory pathways. That’s very important because it suggests that targeting either CSF2 or its receptor in microglia might prevent the acceleration of aging in microglia that appears to be triggered by alpha-synuclein.”

To study these factors’ effects, researchers plan to observe mice that lack T cells or microglia in their brains. They will then explore how alpha-synuclein and aging affect those mice with immune cells unable to produce or respond to CSF2.

“Our findings suggest that pro-inflammatory pathways that are triggered by aging could also be triggered in a similar way by accumulation of alpha-synuclein,” Dr. Masliah says. “They are running in parallel and also probably feeding into each other. I think we can develop therapeutic strategies for diseases like Parkinson’s and Lewy body dementia by looking at these age-related inflammatory pathways.”

Endocarditis in patients with cocaine or opioid use disorder saw marked increase between 2011 to 2022

Endocarditis in patients with cocaine or opioid use disorder saw marked increase between 2011 to 2022

From 2011 to 2022, the number of patients with cocaine or opioid use disorder diagnosed with infective endocarditis drastically grew, showing a particularly striking rise from 2021 to 2022. According to the latest research published in Molecular Psychiatry and NIH-funded, there is an ever-growing risk of endocarditis among drug injectors amplified due to COVID-19. These findings highlight the need for public health initiatives and interventions targeting those who have substance abuse disorders.

“People with substance use disorder already face major impediments to proper healthcare due to lack of access and stigma,” said NIDA Director and co-corresponding study author Nora D. Volkow, M.D. “Proven techniques like syringe service programs, which help people avoid infection from re-used or shared injection equipment, can help prevent this often fatal and costly condition.”

Dr. Volkow and researchers from Case Western Reserve University in Cleveland, Ohio, conducted an extensive study that analyzed electronic health record data from more than 109 million individuals collected between January 2011 and August 2022. In 2011, 4 endocarditis cases occurred daily for every 1 million people suffering from opioid use disorder. By 2022, this rate had skyrocketed to 30 cases per day per 1 million individuals with opioid dependence. The same trends were found with cocaine users; the number of endocarditis incidences jumped from 5 cases in 2011 to 23 out of every one million people struggling with cocaine addiction in 2022.

Patients with cocaine or opioid use disorder clinically diagnosed with COVID-19 were twice as likely to be diagnosed with endocarditis than those without. In addition, patients previously diagnosed with COVID-19 were 68% more likely to be hospitalized within 6 months following their endocarditis diagnosis. Furthermore, those infected with coronavirus faced 9% mortality rate in 180 days after a new diagnosis of endocarditis, compared to 8% for people not affected by the virus.

“As the scientific understanding of long COVID develops, we can now include endocarditis as one long-term effect on key organ systems for people who inject drugs. Our study is one of the first to show this,” said Rong Xu, Ph.D., professor of biomedical informatics at Case Western University and co-corresponding author of this study. “It’s critical that we continue to monitor long term, broad impacts of COVID-19 on people who use drugs.”

Canine brain wiring influenced by human-driven breeding practices

The latest research funded by NIH and published in journal cell uncovered that dog-breeding practices driven by humans have an impact on their brains. The conclusions of this study may help researchers to comprehend further how genetic variation can influence various behaviors in human beings.

Researchers discovered that genomic distinctions between dog breeds are linked to the formation of their nervous systems. An example is herding dogs – they have different genomes, which influence how neurons join together to form neural networks during the early stages of development.

The similarities between the genes associated with various canine lineages and those of other species, including humans, suggest that dogs may possess similar biological pathways which account for the varying behaviors within a species. This research sheds light on the potential parallels between dog brain function and the behavior of human brains.

“The results of this study may point us toward how differences in the human genome can contribute to behavioral diversity among humans. Further research can help us draw a stronger link between genes that are important for behavior in dogs and genes that may play a role in human behavioral conditions,” said Elaine Ostrander, Ph.D., distinguished senior investigator and chief of the Cancer Genetics and Comparative Genomics Branch within NHGRI’s Intramural Research Program and corresponding author on the study.

Dr. Emily Dutrow, a research fellow in Dr. Ostrander’s team, spearheaded the study by leveraging genomic data from 4 thousand dogs and behavioral information supplied by the University of Pennsylvania School of Veterinary Medicine’s survey on over 46 thousand canines, which studied traits such as trainability, energy levels and fear towards strangers to track breed evolution through time.

“One of the most surprising findings was that many of the genomic changes that define the major dog lineages can also be found in modern wolves. This indicates that humans co-opted ancient variations among wild ancestors of dogs to create unique types of dogs suited for performing specific tasks,” said Dr. Dutrow.

Until recently, the distinct behavioral traits and personalities associated with various dog breeds, along with how they are connected to their genetic makeup, have been a mystery.

“To study the genomic basis of breeds, researchers typically compare different breeds with different behavior. But the difficulty with that is finding meaningful results among the variation in dog behavior,” said Dr. Ostrander. “Instead of looking at a snapshot in time, our study mapped out how dog breed lineages diversified over hundreds of years and explains how the different breeds we see today are a result of human selection.”

Events

14th Annual James H. Cassedy Lecture in the History of Medicine the Many Faces of Diabetes: Complications and Debility in Late 20th? Century America

Thursday, February 2, 2023 2-3 pm

Diet and Health 2023: Supplements, Diets, or Food Systems?

Wednesday, Mar 1, 2023, 11:00 AM – 12:00 PM

National Research Summit on Care, Services, and Supports for Persons Living With Dementia and Their Caregivers/care Partners

Monday, Mar 20, 2023, from 9:00 AM – 5:00 PM

Tuesday, Mar 21, 2023, from 9:00 AM – 5:00 PM

Wednesday, Mar 22, 2023, from 9:00 AM – 5:00 PM

2023 NCI RNA Biology Symposium

Thursday, April 27, 2023, to Friday, April 28, 2023 (register by April 23)

The post National Institutes of Health (NIH) Research Updates – Jan 2023 appeared first on Astrix.

NIH researchers unlock pattern of gene activity for ADHD

A study just published in Molecular Psychiatry sheds light on ways in which genomic differences may be linked to attention deficit hyperactivity disorder.

Using RNA sequencing to probe gene expression, research scientists at the National Human Genome Research Institute (NHGRI) have shown how individuals diagnosed with ADHD had differences in genes that code for known chemicals that brain cells use to communicate. Their results show how genomic differences might contribute to symptoms.

The study’s results illuminated the exact ways in which differences in gene expression for glutamate neurotransmitters—which are important for brain functions such as attention and learning—are associated with ADHD.

“The study advances our understanding of ADHD by showing how the condition is tied to changes in how certain genes are expressed in the brain. This allows us to inch closer to understanding how genomic differences alter gene expression in the brain and contribute to ADHD symptoms,” says Philip Shaw, M.D., Ph.D., senior investigator in the Social and Behavioral Research Branch, who supervised the study.

NIH reports that this is the first study to utilize postmortem human brain tissue to investigate ADHD. Researchers examined tissue from the caudate and the frontal cortex, two connected brain regions associated with ADHD. These regions are known to be critical in controlling a person’s attention. Previous research found differences in the structure and activity of these brain regions in individuals with ADHD.

Modified Soybeans May Provide Cardiovascular Benefits

A recent NIH Intermural Research Program study suggests that modifying soybeans used in the production of dietary oil may decrease the risk for cardiovascular disease.

The new study compared the health effects in mice of modified soybean oil to those of conventional soybean oil which is high in omega-6 fat. Researchers selected a mouse model for the study that tends to develop atherosclerosis when fed a high-fat diet similar to the standard American diet. Researchers fed mice one of three diets identical in calories, carbohydrates, fat, and protein content. However, the dietary fat in one of the diets came mostly from saturated fat in modified soybean oil.

While the diet using modified oil caused a smaller decrease in VLDL and LDL cholesterol than the diet containing conventional soybean oil, it produced much lower levels of arterial plaque buildup. Also noteworthy, the modified soybean oil actually decreased the activity of inflammation-promoting genes in mice livers and fat cells.

Although researchers cannot be conclusive in their findings for a similar impact on people, if human studies mirror the results of the animal experiment, it could be apparent that using a modified soybean oil significantly lowers the risk for heart attacks and strokes.

Experimental Cancer Vaccine Shows Promise in Animal Studies

Investigators from the National Institute of Allergy and Infectious Diseases (NIAID) report that their experimental therapeutic cancer vaccine produces significant tumor regression in mice through stimulation of two separate immune system responses that reduce malignant cells.

The study demonstrates that IV vaccine delivery enables and enhances T-cell immunity by overcoming tumor-induced immunosuppressive activity.

The candidate vaccine, called SNAPvax designed by Robert Seder, M.D., and his team at the NIAID Vaccine Research Center (VRC) together with collaborators from Vaccitech North America, could be administered intravenously to cancer patients who previously received tumor-specific T cells. SNAPvax could, according to the researchers, improve tumor control by increasing the number of T cells and altering the tumor microenvironment to make them function better. Vaccitech has announced plans to advance the SNAPvax platform in 2023 as a potential technology for treating human papilloma virus-associated (HPV) cancer.

NIH study in mice provides insight into how brain activity is fine-tuned

Researchers at the National Institute of Neurological Disorders and Stroke (NINDS) just published findings, in PLoS Biology, revealing how neural connections known as inhibitory synapses are rebalanced during sleep so that humans can organize new information into long-lasting memories.

The discovery of this new daily rhythm in a type of synapse that dampens brain activity is providing answers to questions about how subtle synaptic changes enhance memory in humans.

“For over two decades, most sleep studies have focused on understanding excitatory synapses,” said Dr. Wei Lu, senior investigator at NINDS. “This is a timely study to try to understand how sleep and wakefulness regulate the plasticity of inhibitory synapses. Inhibition is actually quite powerful because it allows the brain to perform in a fine-tuned manner, which essentially underlies all cognition,” said Dr. Lu.

This study’s findings could contribute to scientists’ understanding of neurological disorders rooted in abnormal brain rhythms, such as epilepsy. Dr. Lu’s group plans to explore the molecular basis of GABA_A receptor trafficking to inhibitory synapses.

Boosting Brain Activity to Suppress Snacking

NIH Intramural Research Program senior investigator Marci Gluck, Ph.D., and her team have found that a non-invasive stimulation method may improve people’s self-regulation of the snacking impulse around food. The results of her most recent research point to ways in which weight loss could be made easier by helping people increase their ‘inhibitory control’ (the ability to suppress an impulse to pursue a particular action).

After completing earlier research showing the success of left dorsolateral prefrontal cortex (dlPFC) stimulation, via a non-invasive technique called transcranial direct current stimulation (tDCS), on behavior-associated weight, Dr. Gluck’s latest research explores ways in which dlPFC stimulation can make weight loss easier by helping people increase their ‘inhibitory control, (the ability to suppress an impulse to pursue a particular action).

Researchers found that the people who received tDCS to the left dlPFC improved significantly on the Go/No Go task over the course of the study and results point to the possibility that reduced food consumption was due to an improvement in inhibitory control among the people who received tDCS to the dlPFC.

“Maybe because there’s less activation in this brain area, it’s harder for some individuals to say no to those things,” explained IRP biostatistician Emma J. Stinson, who led the new study in Dr. Gluck’s lab. “These new ways of stimulating brain activity are non-invasive, and I think that aspect of it is important,” Stinson says. “They can be used in conjunction with nutritional or behavioral interventions to create this package for a weight loss or weight maintenance plan.”

Dr. Gluck’s team has begun a follow-up study employing functional magnetic resonance imaging (fMRI) to document how stimulating the dlPFC with tDCS changes the way the brain responds to images of food in both the short and long term. “These new ways of stimulating brain activity are non-invasive, and I think that aspect of it is important,” Stinson says. “They can be used in conjunction with nutritional or behavioral interventions to create this package for a weight loss or weight maintenance plan”

Upcoming Events:

25th Annual NIEHS Biomedical Career Symposium

Thursday, December 8 to Tuesday, December 13, 2022

NIH Behavioral and Social Sciences Research Festival 2022

Thursday, Dec 8 to Friday, Dec 9, 2022, from 1:00 PM – 4:30 PM (Virtual Meeting)

Diet and Health 2023: Supplements, Diets, or Food Systems?

Wednesday, Mar 1, 2023, 11:00 AM – 12:00 PM

National Research Summit on Care, Services, and Supports for Persons Living With Dementia and Their Caregivers/care Partners

Monday, Mar 20, 2023, from 9:00 AM – 5:00 PM

Tuesday, Mar 21, 2023, from 9:00 AM – 5:00 PM

Wednesday, Mar 22, 2023, from 9:00 AM – 5:00 PM

2023 NCI RNA Biology Symposium

Thursday, April 27, 2023, to Friday, April 28, 2023 (register by April 23)

The post National Institutes of Health (NIH) Research Updates – December 2022 appeared first on Astrix.

Recent NIH Research

Bringing Out the Big Guns Against Blood Cancer

Acute myeloid leukemia (AML) is a highly fatal blood cancer with a high relapse rate. AML patients in remission receive bone marrow transplants to replace diseased ones with healthy ones. However, the procedure has a high failure rate.

Senior IRP investigator Dr. Christopher Hourigan, M.D., D.Phil., has made it his mission to find ways to detect, prevent, and treat AML recurrence. His team is working on developing clinical tools to help doctors make informed decisions about the best treatments for their patients.

Dr. Hourigan and his team studied pre-transplant blood samples from adults with AML who participated in a 2011 NIH-funded Bone and Marrow Transplant Clinical Trials Network study, which compared low and high-intensity preparative therapy for patients in clinical remission. Findings from this initial study quickly showed that less intensive transplants were not as successful at preventing relapse and ended early. Even though the research ended early, his team viewed it as an opportunity to look for biological indicators linked to a higher risk of relapse in AML patients.

“To us, it seemed like the perfect trial to ask that question,” Dr. Hourigan says. “Our hypothesis was that the outcome would be bad mainly for those patients with trace levels of leukemia left after chemotherapy who then received a reduced-intensity transplant. It’s pretty simple but answering the question in a definitive way requires a large randomized clinical trial with hundreds of patients.”

His team discovered that people who had any indication of leukemia cells before a less-intensive transplant were more likely to relapse than those treated with an intensive transplant. However, patients with no residual signs of AML before receiving a less-intense procedure had the same low risk of relapse as those given an intensive transplant.

“I think there are two implications from the findings,” Dr. Hourigan says. “One is that we probably shouldn’t use reduced-intensity transplants, when possible, in people who have detectable residual leukemia. The other point that I think really sparked people’s imagination is the idea that still having measurable residual disease after initial treatment is not just fate. There’s a tangible thing we as doctors can do to improve the outcomes.”

Dr. Hourigan’s lab has been working to see if changes could be made to the clinical standard of care for leukemia patients by using genomic tests that are much more sensitive and can detect very low numbers of cancer cells. The first stage of this project, dubbed Pre-MEASURE, examined banked pre-transplant blood samples from patients in remission and discovered evidence of residual cancer cells strongly linked to later relapse. His group and its collaborators are conducting a more extensive multi-center study, MEASURE, to see if this testing can be incorporated into clinical practice across the country.

“I think there has been incredible value for our intramural laboratory to collaborate with clinical networks outside NIH to add value to the efforts they are already making by adding an initial layer of scientific investigation,” Dr. Hourigan says. “I think that, for my program, specifically, this is a model of how we’re going to go forward. It’s a win-win for everyone. It’s great for us in that we have access to relevant, clinically annotated, important samples with meaningful outcomes, and it’s great for the bone marrow transplant community because they get extra value from the clinical work and trials that have already been done. Most importantly, it is better for patients who will ultimately have more accurate information on the status of their cancer after initial treatment and personalized, evidence-based advice on what best to do next.”

Novel imaging approach reveals important details about rare eye disease choroideremia

Researchers at the National Eye Institute have used traditional eye imaging techniques and adaptive optics to show how different eye tissue layers are affected in people with choroideremia for the first time.

Choroideremia is a rare degenerative eye disease caused by a mutation in a gene on the X chromosome that disrupts these tissues to a previously unseen degree. The condition is more common in males because they only have one copy of the X chromosome, resulting in more severe symptoms.

Johnny Tam, Ph.D., head of the NEI Clinical and Translational Imaging Unit, and his team looked at live cells in the retina, including light-sensitive photoreceptors and retinal pigment epithelium (RPE) and choroidal blood vessels, to see how choroideremia affects these tissues in detail, providing insights that may be used to develop treatments for other illnesses.

“One major finding of our study was that the RPE cells are dramatically enlarged in males and females with choroideremia,” said Tam. “We were surprised to see many cells enlarged by as much as five-fold.”

Their study showed that female participants had a mix of enlarged and healthier-looking RPE cells, which is likely why women with choroideremia tend to have milder symptoms overall. However, the photoreceptor and blood vessel layers were less affected in male and female study participants, suggesting that the RPE disruption plays a more vital role in choroideremia than previously thought.

While Tam’s adaptive optics is not a regular part of eye clinic diagnostic testing, his team found that enlarged RPE cells can be detected using commercially available scanning laser ophthalmoscope and indocyanine green dye.

“It’s not obvious at first, but using an existing tool in the clinic, we can monitor and track the cellular status of the RPE layer. This could prove valuable in identifying which patients would benefit the most from therapeutic interventions,” said Tam.

With this new information, better treatments can be designed for this disease and others.

Overzealous Immune Cells Hamper Healing

Diabetic foot ulcers (DFUs) are a severe complication of diabetes that can lead to reduced quality of life and high mortality rates. DFUs are characterized by a deregulated immune response with decreased neutrophils due to the loss of the transcription factor FOXM1. Diabetes primes neutrophils to form neutrophil extracellular traps (NETs), contributing to tissue damage and impaired healing.

“The main reason that NET production occurs is to prevent the spread of infection, but when there are excessive amounts of NETs, it can damage the tissue,” said Andrew Sawaya, Ph.D., who led the new study as a postdoctoral fellow in the lab of IRP senior investigator Maria Morasso, Ph.D., “What’s impairing wound healing is too much NET production.”

The new study from IRP researchers found that FOXM1 controls neutrophil ROS levels and inhibition of FOXM1 cause an increase in ROS, resulting in NET formation. They discovered that a gene called TREM1, typically highly active in neutrophils, was less involved in DUFs. Furthermore, they found that TREM1 expression was linked with DFU clinical healing outcomes, suggesting that TREM1 may be used as a biomarker or a potential therapeutic target.

“Right now, it takes four or five weeks for clinicians to know whether their patients are healers or non-healers,” Dr. Morasso says. “Knowing a month ahead of time is a very big advantage for patients and clinicians.”

Their study revealed the clinical importance of TREM1 and suggests that the FOXM1 pathway has a role in regulating NET formation during diabetic wound healing. This could lead to novel therapeutic strategies for promoting healing in DFUs. However, before developing such therapies, Dr. Morasso’s team and other scientists must first understand how TREM1, FOXM1, and NET production interact during the healing process.

“We know that TREM1 is active in other types of cells that are very important not only for normal wound healing, but also in the context of diabetic non-healing wounds,” Dr. Morasso says. “The more we know about how TREM1 is doing this, the better able we’ll be to apply it for therapeutics.”

A healthy lifestyle may help former smokers lower their risk of death from all causes

Previous research has shown that individuals who follow healthy lifestyle recommendations such as maintaining healthy body weight, being physically active, eating a nutritious diet, and limiting alcohol consumption have a reduced risk of illness and death. Quitting smoking has been linked to several health advantages. People who have previously smoked have a greater chance of disease and death than those who have never done so. However, few studies have investigated the significance of living a healthy lifestyle among former smokers.

A new study by researchers at NCI found that maintaining a healthy lifestyle—which includes regular physical activity and eating nutritiously—was linked to reducing the risk of death by 27% over 19 years, compared with not living healthily. The findings come from an analysis of a large group of former smokers who participated in the NIH-AARP Diet and Health Study.

“I was surprised to see the robust associations [with lifestyle],” said Maki Inoue-Choi, Ph.D., of the Division of Cancer Epidemiology and Genetics at NCI, lead author of the paper. “Former smokers who adhered to evidence-based recommendations for body weight, diet, physical activity, and alcohol intake had a lower risk of mortality than former smokers who didn’t adhere to these recommendations.”

Researchers calculated a total adherence score ranging from none to full adherence. Participants with the most significant total adherence scores had a 27% reduced risk of death from any cause than those with the lowest scores. Furthermore, individuals with the best scores had a 24% lower risk of dying from cancer, a 28% reduction in the chance of dying from heart disease, and a 30% decreased risk of respiratory failure.

“To have the greatest benefit, it is better to adhere to many lifestyle recommendations,” Dr. Inoue-Choi noted. “But even those who adopted a single lifestyle recommendation experienced benefits.”

The researchers noted that studies that rely on self-reported information could only reveal delicate relationships, not develop hypotheses about causality. Although the team controlled many variables that could have influenced their findings, they said other factors might be at play.

Heart medication shows potential as treatment for alcohol use disorder

There are three approved medications for alcohol use disorder in the United States. While effective, treatment options must be broader to target the diverse biological processes contributing to this condition. A recent study by scientists at the National Institute on Drug Abuse (NIDA) and Yale School of Medicine in New Haven, Connecticut, suggests that spironolactone, a medication, may play a part in decreasing alcohol consumption.

Spironolactone blocks mineralocorticoid receptors, and past research has revealed that mineralocorticoid receptors, located in various parts of the brain and other organs, might help manage fluid and electrolyte balance in the human body. These could also play a role in alcohol use and cravings. Furthermore, preclinical studies point to greater mineralocorticoid receptor activity leading to increased alcohol consumption.

“Combining findings across three species and different types of research studies and then seeing similarities in those data gives us confidence that we are onto something potentially important scientifically and clinically. These findings support further study of spironolactone as a potential treatment for alcohol use disorder. This medical condition affects millions of people in the U.S,” said Lorenzo Leggio, M.D., Ph.D., chief of the Clinical Psych neuroendocrinology and Neuropsychopharmacology Section, a joint laboratory of NIDA and NIAAA and one of the senior authors.

NIAAA and NIDA researchers found that spironolactone, when given in increasing doses to male and female mice and rats that engage in excessive alcohol drinking, decreases the animals’ alcohol consumption levels without any adverse side effects. In another study conducted in collaboration with this team, researchers found that spironolactone treatment significantly reduced self-reported alcohol consumption, as measured by the Alcohol Use Disorders Identification Test-Consumption.

“These are very encouraging findings,” said NIAAA Director George F. Koob, Ph.D., a co-author of the study. “Taken together, the present study argues for conducting randomized, controlled studies of spironolactone in people with alcohol use disorder to further assess its safety and potential efficacy in this population, as well as additional work to understand how spironolactone may reduce alcohol drinking.”

Genomics study identifies unique set of proteins that restores hearing in zebrafish

Hearing loss affects around 37.5 million Americans, and most cases come from the loss of hearing receptors known as “hair cells” in the inner ear. Although hair cell loss cannot be reversed in people, many species, such as zebrafish, may recover hearing by regenerating hair cells. Because zebrafish and humans have 70% of their genes in common, researchers from the National Institutes of Health were intrigued by the regenerative potential of the fish and its hair cells.

Dr. Erin Jimenez, a postdoctoral fellow in the laboratory of Dr. Shawn Burgess – a senior investigator in the National Human Genome Research Institute’s (NHGRI) Translational and Functional Genomics Branch – led the study with help from researchers Ivan Ovcharenko, Ph.D., and Wei Song, Ph.D., at NLM’s National Center for Biotechnology Information.

“Humans and other mammals are born with a set number of hair cells that are slowly lost through aging and trauma. However, some animals, such as zebrafish, can regenerate hair cells and recover hearing after injury,” said Burgess, “How and why regeneration happens in these animals remains a mystery that many scientists would like to unravel.”

Using new genomic techniques and a single-cell assay for transposase-accessible chromatin using sequencing, Jimenez and her study collaborators discovered that hair cell regeneration in zebrafish depends on a network of proteins called transcription factors, which can turn genes on and off.

“Our study identified two families of transcription factors that work together to activate hair cell regeneration in zebrafish, called Sox and Six transcription factors,” said Jimenez.

Hair cells die in zebrafish when their stem cells are damaged, causing adjacent support cells to proliferate. These support cells are similar to stem cells since they can differentiate into other cell types. Researchers have identified some switches that turn on and coordinate genes encoding those factors with various unknown elements, but not how or where they activate.

“We have identified a unique combination of transcription factors that trigger regeneration in zebrafish. Further down the line, this group of zebrafish transcription factors might become a biological target that may lead to developing a novel therapy to treat hearing loss in humans,” Jimenez said.

Upcoming Events:

Irreducible Subjects: Disability and Genomics in the Past, Present, and Future 

Thursday, October 6, 2022, 10:00 am to Friday, October 7, 2022, 5:00 pm (registration required)

NIH Director’s Seminar Series: Development of Targeted and Immune-Based Therapies for Urothelial Carcinomas and Rare Genitourinary Tumors

Friday, October 7, 2022, 12:00 pm to 1:00 pm

NICHD 60th Anniversary Symposium

Monday, October 17, 2022, 8:10 am to 4:45 pm

2023 NCI RNA Biology Symposium

Thursday, April 27, 2023, to Friday, April 28, 2023 (register by April 23)

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Recent National Institutes of Health Research

NIH study finds loss of ‘youth’ protein may drive aging in the eye

According to new research in mice from the National Eye Institute (NEI), the protein pigment epithelium-derived factor (PEDF), which safeguards retinal support cells, may be lost due to aging and lead to age-related changes in the eye.

“People have called PEDF the ‘youth’ protein because it is abundant in young retinas, but it declines during aging,” said Patricia Becerra, Ph.D., chief of NEI’s Section of Protein Structure and Function and senior author of the study. “This study showed for the first time that just removing PEDF leads to a host of gene changes that mimic aging in the retina.”

Past research from Becerra’s lab and others has shown that PEDF protects retinal cells from damage and abnormal blood vessel growth, thanks to its ability to promote the differentiation of retinal precursor cells. When PEDF binds to its receptor, PEDF-R, it activates it to break down lipid molecules (a crucial component of the outer segment recycling process). PEDF also directly inhibits VEGF (vascular endothelial growth factor), a protein that promotes abnormal blood vessel growth.

To investigate the retinal function of PEDF, Becerra and colleagues studied a mouse model lacking the PEDF gene (Serpin1). The retinas of these PEDF-negative mice appeared normal at first, but when the cellular structure of the retina was examined, it showed that RPE cell nucleus sizes had increased. RPE cells also activated four genes linked to again and cellular senescence, showed significantly low PEDF receptor levels, and accumulated unprocessed lipids and other photoreceptor outer segment components in the RPE layer of the retina.

*”One of the most striking things was this reduction in the PEDF receptor on the surface of the RPE cells in the mouse lacking the PEDF protein,” said the study’s lead author, Ivan Rebustini, Ph.D., a staff scientist in Becerra’s lab. “It seems there’s some sort of feedback-loop involving PEDF that maintains the levels of PEDF-R and lipid metabolism in the RPE.”

The study was made possible by the NEI intramural program. The federal government’s research on the visual system and eye diseases is led by the National Eye Institute (NEI). For more information about NIH and its programs, visit www.nih.gov.

National Institutes of Health launches clinical trial of mRNA Nipah virus vaccine

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has launched an early-stage clinical study evaluating a vaccine to prevent Nipah virus infection.

Nipah virus is a zoonotic pathogen that can cause severe respiratory and neurological diseases in humans. The virus is found in several Southeast Asian countries, including Bangladesh, India, and Malaysia. No specific treatment or vaccine is available for Nipah virus infection, which has a high fatality rate.

“Nipah virus poses a considerable pandemic threat because it mutates relatively easily, causes disease in a wide range of mammals, can transmit from person to person, and kills a large percentage of the people it infects,” said NIAID Director Anthony S. Fauci, M.D. “The need for a preventive Nipah virus vaccine is significant.”

The experimental vaccine is based on the same mRNA technology used for the COVID-19 vaccine and was created by Moderna, Inc and the NAID Vaccine Research Center. The novel mRNA-1215 Nipah virus vaccine will be studied in a dose-escalation clinical trial to assess its safety, tolerability, and immune response-generating capacity in 40 adults 18 to 60.

For more information about the clinical trial, visit ClinicalTrials.gov using the study identifier NCT05398796.

The NIAID funds and supports research at NIH throughout the United States and worldwide to investigate the causes of infectious and immunological diseases and develop more effective ways to prevent, detect, and treat these illnesses. The NIAID website provides news releases, fact sheets, and other NIAID-related materials.

Dabrafenib–Trametinib Combination Approved for Solid Tumors with BRAF Mutations

The Food and Drug Administration (FDA) has approved the combined treatment of dabrafenib (Tafinlar) and trametinib (Mekinist) for patients with nearly any sort of advanced solid tumor that contains a specific mutation in the gene BRAF. Dabrafenib and trametinib block different growth-promoting signals in tumor cells activated by the V600E BRAF mutation.

The FDA’s decision was based on data from three clinical trials, including two with adult patients and one with children. Some participants in the study had rare tumors, such as biliary tract cancer, ovarian cancer, and glioma (a type of brain tumor).

“Many types of metastatic cancers are tested for BRAF mutations, and the FDA approval is one more reason to have this testing,” said Lyndsay Harris, M.D. She leads NCI’s Cancer Diagnosis Program. She is also a lead investigator with NCI-MATCH, one of the clinical trials that led to the new approval.

The clinical trials enrolled adult patients with different types of tumors and assigned them to baskets based on criteria such as the molecular features of their tumors. The Novartis pediatric trial included low-grade gliomas and Langerhans cell histiocytosis patients who had relapsed after initial therapy or resisted treatment.

Overall response rates were 46%, 33%, and 50% for adults with biliary tract cancer, high-grade gliomas, and low-grade gliomas, respectively. In children, the overall response rate was 25%. Most of these individuals had responses that persisted for at least six months, and 44 percent had responses that lasted longer than a year.

The most common side effects of the combination therapy in adults included fever, fatigue, nausea, and rash. “The treatment was well tolerated,” Dr. Harris said. “The side effects were identical to those reported in previous trials of the dabrafenib–trametinib combination.”

The adverse effects in pediatric participants were comparable to those in the adult trials.

Basket trials like these might help researchers overcome current clinical restrictions by allowing them to compare various therapies in a wide range of unconventional malignancies.

“As we learn more about the molecular underpinnings of cancer, [basket trials] will continue to become more common,” predicted Dr. Salama, director of the melanoma program at Duke Cancer Institute and co-lead of the NCI-MATCH sub-study. “These studies are complicated to conduct, but they may also be one of the best ways to bring new treatment options to the clinic.”

Preterm Birth More Likely With Exposure to Phthalates

According to a study by the National Institutes of Health (NIH), women with higher levels of phthalate metabolites in their urine were more likely to give birth preterm. Phthalates are used in personal care items, such as fragrances and cleansers, solvents, detergents, and food packaging.

“Having a preterm birth can be dangerous for both baby and mom, so it is important to identify risk factors that could prevent it,” According to Dr. Kelly Ferguson, an epidemiologist at the National Institute of Environmental Health Sciences (NIEHS) and the lead author of the study.

Ferguson and her team analyzed data from 16 studies of over 6 thousand pregnant women in the USA who delivered between 1983-2018. The study found that higher levels of many phthalate metabolites were linked to a higher risk of preterm delivery. 9% or 539 of the women in the study delivered preterm, and Phthalate metabolites were detected in over 96% of urine samples.

Interventions that target behaviors, such as attempting to purchase phthalate-free personal care goods (if mentioned on the label), corporate initiatives to decrease phthalates in their goods, or adjustments in standards and regulations, can help reduce exposure and safeguard pregnancies.

“It is difficult for people to completely eliminate exposure to these chemicals in everyday life, but our results show that even small reductions within a large population could have positive impacts on both mothers and their children,” said Barrett Welch, Ph.D., a postdoctoral fellow at NIEHS and first author on the study.

Additional research is needed to understand how phthalates might harm pregnancy and if there are any methods for moms to reduce their exposures.

Researchers discover how sound reduces pain in mice

A new study of how sound reduces pain in mice may point to more effective pain therapies. The study was led by researchers at the National Institute of Dental and Craniofacial Research (NIDCR), the University of Science and Technology of China, Hefei; and Anhui Medical University, Hefei, China.

“We need more effective methods of managing acute and chronic pain, and that starts with gaining a better understanding of the basic neural processes that regulate pain,” said NIDCR Director Rena D’Souza, D.D.S., Ph.D. “By uncovering the circuitry that mediates the pain-reducing effects of sound in mice, this study adds critical knowledge that could ultimately inform new approaches for pain therapy.”

The researchers exposed mice with inflamed paws to three types of sound: pleasant music, an unpleasant rearrangement of the same piece, and white noise. When all three sounds were played at a low level relative to background noise, their ability to reduce pain sensitivity was comparable. Higher volumes of the same noises did not affect pain perceptivity.

“We were really surprised that the intensity of sound, and not the category or perceived pleasantness of sound, would matter,” said co-senior author Yuanyuan (Kevin) Liu, Ph.D., a Stadtman tenure-track investigator at NIDCR.

Researchers used non-infectious viruses and bright colors to map connections between regions to understand how this impact works in the brain. They located a pathway from the auditory cortex. In the absence of sound, light- and small molecule-based techniques that suppressed the pathway reproduced the pain-killing effects of low-intensity noise while turning it on restored sensitivity to pain.

The findings may be a starting point for future research to determine whether animal data apply to humans and, if they do, whether they are linked with other health concerns.

Small NIH study reveals how immune response triggered by COVID-19 may damage the brain

A new study by researchers from the National Institute of Neurological Disorders and Stroke (NINDS) shows that COVID-19 infection causes an immune response in the brain’s blood vessels, resulting in short- and long-term neurological issues.

“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” said Avindra Nath, M.D., clinical director at NINDS and the senior author of the study. “We had previously shown blood vessel damage and inflammation in patients’ brains at autopsy, but we didn’t understand the cause of the damage. I think in this paper we’ve gained important insight into the cascade of events.”

When studying the brain of nine individuals who died from the virus, Dr. Nath and his team discovered immune complexes on the cell surface, demonstrating that COVID-19 antibodies may mistakenly target blood-brain barrier cells (made up of tightly packed endothelial cells). The findings suggest that the immune system is involved in an antibody-driven assault that activates endothelial cells.

“Activation of the endothelial cells brings platelets that stick to the blood vessel walls, causing clots and leakage to occur. At the same time the tight junctions between the endothelial cells get disrupted causing them to leak,” Dr. Nath explained. “Once leakage occurs, immune cells such as macrophages may come to repair the damage, setting up inflammation. This, in turn, causes damage to neurons.”

In regions with endothelial cell damage, researchers discovered that 300 genes linked to oxidative stress, DNA damage, and metabolic dysregulation were downregulated, while six others were upregulated. It’s possible that antibodies against the SARS-CoV-2 spike protein could bind to the ACE2 receptor, which the virus uses to enter cells. However, it remains unclear what antigen the immune response targets as the virus was not detected in the brains of the individuals they studied.

“It is quite possible that this same immune response persists in Long COVID patients resulting in neuronal injury,” said Dr. Nath. “There could be a small, indolent immune response that is continuing, which means that immune-modulating therapies might help these patients. So these findings have very important therapeutic implications.”

Understanding how COVID-19 SARS-CoV-2 infection might cause brain damage may aid the development of treatments for COVID-19 patients who suffer from long-term neurological disorders.

Upcoming Events:

The history of genomics told through machine learning

Aug 4, 2022, 1:00 PM — 2:00 PM

Accelerating Precision Environmental Health: Demonstrating the Value of the Exposome

August 5, 12, 19, 26: Virtual Workshop Series

Complex Exposures in Breast Cancer: Unraveling the Role of Environmental Mixtures

Wednesday, August 24 – Thursday, August 25, 2022

NIH Hosting Two-Part Webinar on Implementing the NIH Data Management and Sharing Policy

Thursday, August 11, 2022, from 1:30–3:00 p.m. (ET) and Thursday, September 22, 2022, from 1:30–3:00 p.m. (ET)

Irreducible Subjects: Disability and Genomics in the Past, Present and Future 

Thursday, October 6, 2022, 10:00 am to Friday, October 7, 2022, 5:00 pm (registration required)

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Recent NIH Research

NIH researchers discover new genetic eye disease

National Eye Institute (NEI) researchers discovered a new disease affecting the macula. NEI is part of the National Institutes of Health (NIH), a medical research agency that is a part of the U.S. Department of Health and Human Services.

Macular dystrophies are a group of degenerative diseases that cause progressive vision loss by damaging the macula, the small central area of the retina responsible for sharp, straight-ahead vision. These diseases are typically due to mutations in genes such as ABCA4, BEST1, PRPH2, and TIMP3.

Patients with Sorsby Fundus Dystrophy, a genetic eye disease characterized by TIMP3 variants, typically experience symptoms in adulthood. They frequently have rapid visual acuity fluctuations resulting from choroidal neovascularization– new, abnormal blood vessels that develop beneath the retina and leak fluid, causing vision impairment. The TIMP3 gene variants identified so far are all in the mature protein after cleaving from the RPE cells.

“We found it surprising that two patients had TIMP3 variants not in the mature protein but in the short signal sequence the gene uses to ‘cut’ the protein from the cells. We showed these variants prevent cleavage, causing the protein to be stuck in the cell, likely leading to retinal pigment epithelium toxicity,” said Bin Guan, Ph.D., lead author.

To confirm that the two new TIMP3 variants are linked to this unusual maculopathy, the research team conducted clinical investigations and genetic testing of family members.

“Discovering novel disease mechanisms, even in known genes like TIMP3, may help patients that have been looking for the correct diagnosis, and will hopefully lead to new therapies for them,” said Rob Hufnagel, M.D., Ph.D., senior author and director of the Ophthalmic Genomics Laboratory at NEI.

NEI Intramural Research Program supported this research. The National Eye Institute (NEI) is a medical research body in the United States government, part of the National Institutes of Health. The NEI is the federal government’s primary agency for studying the visual system and eye diseases. NEI funds basic and clinical science programs to create sight-saving medications and address the specific needs of individuals with vision loss. For further information, visit https://www.nei.nih.gov.

Treating Parkinson’s Disease with Pinpoint Precision

Parkinson’s disease affects an estimated seven to ten million people worldwide. In the United States, approximately one million people live with Parkinson’s disease. Dopamine-producing neurons in the brains of individuals with Parkinson’s disease deteriorate and stop communicating messages. People experience physical symptoms such as tremors, stiffness, and poor coordination as dopamine levels fall.

Five distinct dopamine receptors differ somewhat in structure and function. The most common drug, levodopa, or L-DOPA can worsen some movement problems when taken for long periods. That is because L-DOPA and similar medicines cannot differentiate between these receptors, so they interact with either the wrong ones or all of them simultaneously.

“That’s a problem if you’re trying to develop drugs to target individual receptor subtypes,” explains Dr. Sibley, IRP senior investigator. “Many drugs available today cross-react with other receptors, which can lead to side effects.”

IRP researchers are developing a drug that, when taken alongside other treatments, could more effectively slow the progression of Parkinson’s disease while reducing side effects. IRP scientists used high-throughput drug screening robots to sift through the nearly 400,000 compounds in NCATS’ library to find something that worked. They conducted the screen twice: once looking for ‘antagonists’ that shut down the D3 receptor and once to see that they activated the receptor-activated receptor.

“You go through many rounds of testing slightly different versions of a starting compound to see what changes on the molecule improve activity and selectivity and which changes decrease activity,” postdoctoral fellow and co-investigator Dr. Moritz explains.

The IRP researchers eventually narrowed it down to one highly selective for the D3 receptor, meaning it interacted strongly with that receptor but weakly or not at all with other types of dopamine receptors. To enhance the compound’s effects on the D3 receptor, the IRP team collaborated with Kevin Frankowski, Ph.D., a medicinal chemist at the University of North Carolina, to synthesize and test variants with minor chemical modifications. They found a drug candidate called ML417 that showed promise.

“In our manuscript, we showed that ML417 is actually the most selective D3 agonist currently known,” Dr. Sibley says. “We then worked with a computational chemist at NIH, Dr. Lei Shi, to learn why this compound is so selective. We found that it interacts with the D3 receptor in a way that is unique compared with other molecules that activate that receptor.

Because ML417 targets D3 receptors, it has significant potential as a drug to treat Parkinson’s disease-related mobility issues. The D3 receptor is predominantly expressed in the brain regions that control movement.

Although more research is needed, preliminary studies in animal models conducted in collaboration with IRP senior investigator Judith Walters, Ph.D., suggest that ML417 may have immunomodulatory effects.

The IRP team is also working with outside NIH colleagues to test the hypothesis that lowering D3 receptors can help prevent relapse in opioid pill users attempting to quit.

“Translational science is just so important,” notes Dr. Sibley. “It’s the way forward for developing novel therapeutics for treating many different diseases and disorders.”

Leveraging Turncoat Immune Cells to Combat Cancer

Macrophages are a type of white blood cell that normally help protect the body from infection and disease. They have a receptor protein on their surfaces known as CD206 that activates the phagocytosis process, which is more formally defined as ‘cell eating.’ When CD206 is activated, macrophages capture and bind to foreign threats before pushing them into their interior for digestion. However, cancer cells can push back by switching the CD206 receptor off which allows them to hijack the macrophages turning them into tumor-associated macrophages that supports tumor growth.

A new study by IRP senior investigators Udo Rudloff, M.D., Ph.D., and Juan Marugan, Ph.D. found a way to fight back against this cancer defense mechanism. The approach uses a small molecule drug to “reprogram” macrophages and other cells that have been hijacked by the tumor, restoring their anti-tumor activity.

“Initially, immunotherapy was all about immune cells such as T cells,” says Dr. Rudloff, “but in the last decade people have recognized that other cells, like these macrophages, can be very helpful as well.”

Dr. Rudloff and his research team searched the NIH’s National Center for Advancing Translational Sciences (NCATS) library of molecules for a molecule with a similar CD206. In computer modeling, they discovered a few that met this criterion. They picked one to test in animal models to see how well it worked and how long it stayed in the body before being broken down once they had narrowed down the candidate molecules to a small set.

“We were able to find molecules that worked very efficiently doing the same thing that the CD206 receptor did: activate the immune system and change the immune environment to suppress the growth of all kinds of tumors,” says Dr. Marugan. “This will be a new modality of immunotherapy using a small molecule.”

This potential new therapy also appears to be “tumor agnostic,” which means it may work on any tumor that displays a high quantity of tumor-associated macrophages with CD206 receptors. Current animal and cell studies are showing that the therapy is highly effective against pancreatic, colorectal, breast, skin malignancy melanoma, and bone cancer osteosarcoma. The researchers are now in the final stages of testing and seeking a pharmaceutical industry partner to help begin the first-in-class human clinical trials for cancer.

Reprogramming macrophages may also be beneficial in other conditions. Dr. Rudloff and Dr. Marugan are collaborating with Japanese researchers who are developing a potential therapy for diabetic retinopathy, a disease complication caused by hyperglycemia in which macrophages with the CD206 receptor play an essential role.

Trial of potential universal flu vaccine opens at NIH Clinical Center

A novel influenza vaccine has been developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID). It is now being tested in Phase 1 clinical trial at the NIH Clinical Center in Bethesda, Maryland. The safety of a candidate vaccine, BPL-1357, and its capacity to elicit immune responses will be evaluated in the study.

“Influenza vaccines that can provide long-lasting protection against a wide range of seasonal influenza viruses as well as those with pandemic potential would be invaluable public health tools,” said NIAID Director Anthony S. Fauci, M.D. “The scientific community is making progress on this pressing global health priority. The BPL-1357 candidate influenza vaccine being tested in this clinical trial performed very well in pre-clinical studies, and we look forward to learning how it performs in people.”

BPL-1357 is a “live attenuated” vaccine, meaning that it uses weakened influenza viruses to help the body build immunity against infection by natural influenza viruses. The weakened viruses in the vaccine are unable to cause illness.

An animal study by NIAID investigator Jeffery K. Taubenberger showed that mice intramuscularly or intranasally administered two doses of BPL-1357 vaccine survived exposure to each of the six different influenza virus strains and subtypes not included in the vaccine at lethal doses.

The single-site trial can enroll up to 100 people aged 18 to 55 years, will last approximately seven months for each participant, and is led by NIAID investigator Matthew J. Memoli. In the Phase 1 trial, participants will be assigned to one of three groups and given two doses of placebo or vaccine, each administered 28 days apart, in a 1:1:1 ratio. Group A gets BPL-1357 intramuscularly plus nasal saline placebo. Group B will be administered intranasal doses of the candidate vaccine with an intramuscular placebo at both visits to the clinic. In contrast, Group C gets the inactive substance injections only once. Neither the researchers nor participants are aware of group assignments. Volunteers must have not received any vaccination for the flu in the previous eight weeks and must commit to avoiding seasonal flu vaccines for two months after the second dose.

“With the BPL-1357 vaccine, especially when given intranasally, we are attempting to induce a comprehensive immune response that closely mimics immunity gained following a natural influenza infection,” said Dr. Memoli. “This is very different than nearly all other vaccines for influenza or other respiratory viruses, which focus on inducing immunity to a single viral antigen and often do not induce mucosal immunity.”

The National Institutes of Health (NIH) funds and directs research on the causes of infectious and immune-mediated diseases and develops new methods to prevent, diagnose, and treat these illnesses. For additional information about the trial, visit clinicaltrials.gov and search on the trial identifier NCT05027932.

Upcoming Events:

Health Disparities in Osteoarthritis Workshop

Tuesday, July 12, 2022, to Wednesday, July 13, 2022

Healthy Reference Tissue and Standards Workshop

Monday, July 25, 2022, 10 AM. Registration deadline: July 22, 2022

Irreducible Subjects: Disability and Genomics in the Past, Present and Future 

Thursday, October 6, 2022, 10:00 am to Friday, October 7, 2022, 5:00 pm (registration required)

The post National Institutes of Health (NIH) Research Updates – July 2022 appeared first on Astrix.

Recent NIH Research

A Computational Approach to Curbing Chemotherapy’s Side Effects

Chemotherapy can be an effective treatment for cancer, but it often comes with unpleasant side effects like nausea, vomiting, and diarrhea. Now, researchers think they may have found a way to reduce those side effects by targeting the gut microbiome.

The human gut is home to trillions of microbes, including many different species of bacteria. Some of these bacteria produce an enzyme called beta-glucuronidase that can remove a sugar molecule from chemotherapy medications, making them more active and thus more likely to cause side effects.

A cutting-edge computational technique was used in a new IRP research by Min Shen, Ph.D. who leads the Informatics group in the Division of Preclinical Innovation at NIH’s National Center for Advancing Translational Sciences (NCATS) to help identify compounds that target one of those bacterial molecules, which might lead to the development of anti-tumor medications that alleviate some chemotherapy side effects.

“Many people can’t tolerate the side effects and can’t complete the full course of their chemotherapy,” says Min Shen, Ph.D., “Normally, chemotherapy will be administered multiple times, but many people quit in the middle.”

That is why Dr. Shen’s team is attempting to discover chemicals that can stop bacterial beta-glucuronidase enzymes, which exacerbate chemotherapy’s negative effects. Her team screened more than 400,000 molecules using the computational technique and found 69 molecules that inhibited beta-glucuronidase and 13 that were very effective.

One of the chemicals discovered by Dr. Shen’s research may be developed into a drug to treat digestive issues caused by chemotherapy treatments. However, before this can happen, Dr. Shen’s team must conduct additional research as well as collaborate with chemists at NCATS to change the chemicals for better drug efficacy.

Vaccine for rare but deadly mosquito-borne viruses shows promise in clinical trial

Mosquito-borne viruses classified as potential biological warfare agents include western (WEEV), eastern (EEEV), and Venezuelan (VEEV) equine encephalitis viruses, which are viral diseases that may be spread by mosquitoes. Infection with any of these viruses can cause flu-like symptoms and even severe neurological damage or death in humans.

The WEEV, EEEV, and VEEV viruses are all classified as potential biological warfare agents due to their ability to be transferred by aerosol droplets under specific lab conditions. There is currently no vaccine or treatment available for any of these diseases, but a recent clinical trial sponsored and funded by the National Institute of Health (NIAID) has shown that a new vaccine is safe and well-tolerated.

Scientists at the NIAID Vaccine Research Center (VRC) part of the National Institutes of Health, created a virus-like particle (VLP) vaccine candidate (abbreviated WEVEE) that incorporates proteins from the EEE, WEE, and VEE viruses’ outer shells to stimulate an immune response. This response is similar to the one that would be elicited by the actual viruses but does not contain infectious material and thus poses no risk of infection.

The VRC researchers conducted a Phase I clinical trial in which 30 adult volunteers were given an initial dose of the VEVEE vaccine and a booster of the same dose 8 weeks later.  The study found that the vaccine was safe and well-tolerated with no serious adverse events reported. The participants also showed the development of EEEV, WEEV, and VEEV-specific neutralizing antibodies in their blood.

This is encouraging news and supports further clinical evaluation for the development of a potential vaccine to protect against these viruses, which have no current prevention or treatment options available.

The NIAID has granted Emergent BioSolutions, a life-sciences firm located in Gaithersburg, Maryland, a commercialization license for the advanced study of the WEVEE vaccine candidate.

Retinal cell map could advance precise therapies for blinding disease

A new study funded by the NEI Intramural Research Program and conducted by researchers from The National Eye Institute (NEI) used artificial intelligence (AI) to assess RPE cell morphometry, the external form, and the size of each cell. The Retinal Pigment Epithelium (RPE) is a layer of cells that support the function of photoreceptors, the light-sensitive cells responsible for vision.

They trained a computer to examine the entire human RPE monolayer from nine cadaver donors with no history of significant eye disease by feeding it fluorescently labeled pictures of RPE. They discovered five distinct RPE cell subpopulations, dubbed P1-P5, positioned in concentric circles around the fovea, the light-sensitive center of the macula, and the retina’s most sensitive region. Foveal RPE are typically perfectly hexagonal and compactly positioned, with more neighboring cells than peripheral RPE.

“These results provide a first-of-its-kind framework for understanding different RPE cell subpopulations and their vulnerability to retinal diseases, and for developing targeted therapies to treat them,” said Michael F. Chiang, M.D., director of the NEI, part of the National Institutes of Health.

“The findings will help us develop more precise cell and gene therapies for specific degenerative eye diseases,” said the study’s lead investigator, Kapil Bharti, Ph.D., who directs the NEI Ocular and Stem Cell Translational Research Section.

They were surprised to find that the peripheral retina contains a ring of RPE cells (P4) with a cell area comparable to that of RPE in and around the macula.

“The presence of the P4 subpopulation highlights the diversity within retinal periphery, suggesting that there could be functional differences among RPE that we are currently unaware of,” said the study’s first author, Davide Ortolan, Ph.D. a research fellow in the NEI Ocular and Stem Cell Translational Research Section.

To further test the hypothesis that various retinal diseases affect specific RPE subpopulations, they examined ultrawide-field fundus autofluorescence images from persons with choroideremia, L-ORD, or a retinal degeneration for which no molecular cause was identified. Although this research was conducted in a single setting at one point in time, it showed that various RPE subpopulations are susceptible to different types of retinal degenerative diseases.

“Overall, the results suggest that AI can detect changes of RPE cell morphometry prior to the development of visibly apparent degeneration,” said Ortolan.

Some RPE subpopulations may show age-related morphometric changes before others. These findings will aid future research utilizing noninvasive imaging technologies, such as adaptive optics, which image retinal cells at much greater resolution and might be used to predict changes in RPE health in living patients.

Reprogramming Cancer

The growth mechanism in prostate cancer is simple compared to other types of cancer. The androgen receptor, a cellular protein that testosterone must bind to function, is required for prostate cancer cells.

However, prostate cancer has proved difficult to treat because it frequently develops resistance to androgen deprivation therapy. The therapy may initially shrink the tumors, but they will eventually resurgence, at which time there is little that can be done.

David Takeda, M.D., Ph.D., a researcher at the Intramural Research Program (IRP), is developing a new strategy to treat cancer that relies on epigenetic manipulation. He thinks that changing epigenetics may provide an effective new approach to treatment.

“Prostate cancer is not like other cancers where we don’t know what the main driver is,” Dr. Takeda says. “In prostate cancer, we know the androgen receptor is the main driver, but even though we know that, we still can’t cure it.”

Dr. Takeda is now working to study further his discovery conducted at the Dana-Farber Cancer Institute in Boston, Massachusetts, which showed that shutting down the regulatory region in prostate cancer cells (enhancer) slows down cancer growth.

“Can you tell a cancer cell what to do?” wonders Dr. Takeda. “It would be really cool if you could program a cancer cell to do something. You could dictate its identity epigenetically, and maybe you could change it to a state that’s amenable to treatment or a state where it doesn’t grow, but we don’t yet know if that’s possible.”

“That’s kind of what NIH is for: to try out these big ideas to see if they could possibly work,” he continues. “If it turns out to not work, at least we thought big.”

Dr. David Takeda is a Lasker Clinical Research Scholar and the director of the Functional Genomics Section in the Laboratory of Genitourinary Pathogenesis at the National Cancer Institute (NCI).

The Center for Cancer Research (CCR) was founded to educate and empower the entire cancer research community by making essential discoveries in basic and clinical cancer research and developing them into innovative treatments for individuals afflicted with cancer or infected with HIV. To learn more about the Center for Cancer Research, visit their website.

Viruses on the Brain

Viruses may cause long-term damage to the brain, even when a person is not actively sick.

Dr. Avindra Nath is the Clinical Director at the National Institute of Neurological Disorders and Stroke (NINDS) and the head of its Section of Infections of the Nervous System. His lab focuses on understanding the pathophysiology of retroviral infections of the nervous system and the development of new diagnostic and therapeutic approaches for these diseases.

Dr. Nath’s team has discovered a protein in the brains of HIV-positive patients, even when antiretroviral therapy has reduced the amount of HIV in their blood to undetectable levels. The team’s work has also suggested that this protein, known as Tat, could be responsible for the neurological problems seen in some HIV-positive patients. He believes that HIV lives in brain cells and is unaffected by antiretroviral medications, continuing to produce Tat and causing brain inflammation and neuron death.

Dr. Nath and his team are working on creating single-stranded, DNA-like molecules called antisense oligonucleotide that can target and silence the gene that encodes Tat. The lab is also studying ‘checkpoint inhibitors, drugs that have recently been used in cancer immunotherapy.

“The common thread among all of these illnesses is their under-recognized effects on the brain,” Dr. Nath says. “What happens with most pandemics and viral infections is that people get focused on the effects on the organ system that causes the acute symptoms,” he says. “If patients forget things or are not behaving normally, their doctors just blame some other explanation for it rather than thinking that the disease itself might be the cause.”

Similarly, they have found evidence of brain damage in deceased COVID-19 patients, suggesting that the virus can cause long-term problems even after a person has recovered from the acute illness.

Discoveries like those being conducted in Dr. Nath’s lab have the potential to revolutionize how viral infections are treated long-term.

“You have to be very careful,” he says. “People who had COVID-19, this serious respiratory illness, are also complaining of neurological symptoms, and these symptoms may actually be persistent. We have to pay attention to this and not ignore it.”

Upcoming Events:

Sex/Gender-Specific COVID-19 Outcomes Relevant for HLBS Disorders

Thursday, June 16, 2022, 11:00 am to Friday, June 17, 2022, 5:30 pm (registration required)

Advancing Research on Emotional Well-Being and Regulation of Eating

Thursday, June 23, 2022, 12:00 p.m. ET to 1:00 p.m. ET

NIH OBSSR Director’s Webinar: Guest Presenter Irene Dankwa-Mullan M.D., M.P.H. (July 19, 2022)

July 19, 2022, 2:00 – 3:00pm | Online

Irreducible Subjects: Disability and Genomics in the Past, Present and Future 

Thursday, October 6, 2022, 10:00 am to Friday, October 7, 2022, 5:00 pm (registration required)

The post National Institutes of Health (NIH) Research Updates – June 2022 appeared first on Astrix.

Recent NIH Research

A One-Stop Shop for Pain Research

Established in 2019, the NIH’s Pain Research Center provides world-leading expertise and cutting-edge technology that can assist IRP researchers in identifying the specific causes and distinct features of pain in its many forms to help make that goal a reality as swiftly as possible.

The goal of the Pain Research Center is to gather knowledge about pain in a variety of situations and utilize that information to assist researchers in developing more effective treatments. Researchers are particularly interested in finding non-addictive alternatives to opioid-based painkillers such as oxycodone and morphine, which have been linked to tens of thousands of fatalities due to overdoses in recent years.

“Our ability to better study and understand pain and develop better treatments for pain is a public health priority,” says Dr. Shurtleff, Deputy Director of the National Center for Complementary and Integrative Health (NCCIH) at the NIH.

The facility offers a wealth of resources to help, including separate testing rooms dedicated to pain tolerance and the ability to feel various stimuli such as heat and cold, pressure, and vibration. Stress response instruments and machines that allow researchers to view and even influence brain activity are all available.

“We sort of run as a center to provide resources to the NIH community, but we also run as a lab and do our own work as well,” Says Dr. Drangos, Lead Scientific Officer and one of the staff members who conduct and provide guidance to other IRP research teams on how to complete their research.

The Pain Research Center has now opened and is assisting several IRP research initiatives in various ways. You may learn more about the Pain Research Center by visiting its website.

Overturning the Orthodoxy About the Brain’s Stress Chemical

Norepinephrine, a chemical produced by certain neurons in the brain, is an essential target for anti-anxiety medicines. Often known as noradrenaline — it has long been considered a “stress hormone” that causes anxiety. Drugs designed to target the cells that produce them do not always work as intended.

IRP senior investigator Patricia Jensen, Ph.D., and her National Institute of Environmental Health Sciences (NIEHS) colleagues are digging into the mouse brain to figure out what these neurons do and how they function.

In a 2013 study published by Dr. Jensen and her team, four genetically distinct populations of noradrenergic neurons in mice were discovered, located outside the locus coeruleus, some of which seem to work differently from those in the locus coeruleus. Furthermore, one set of these neurons is connected to areas in the prefrontal cortex, a part of the brain that plays a crucial role in many aspects of behavior, including planning and decision making.

In another study published in 2019, Dr. Jensen’s team discovered that those neurons communicate with regions of the brain concerned with central autonomic control — the body’s nervous system’s part that regulates bodily functions we don’t have to think about, such as breathing and blood pressure.

Also, when stimulated in mice, those neurons had an antidepressant-like effect: they promoted better-coping responses to stressors such as being placed in water and reduced the rodents’ anxious behaviors.

After successfully breeding mice in which they can experimentally modulate stress-blunting noradrenergic neurons, Dr. Jensen and her research team have been working on breeding mice with the ability to shut down those nerve cells in adult mice’ brains.

“This is when the most exciting science happens when you pick up on some little thing that’s different, and you ask, ‘What’s this all about?'” Dr. Jensen reflects. “We try to encourage our students and trainees not to ignore what they’re seeing. Do the experiment and replicate it, but if you keep seeing the same thing, don’t worry if the dogma says the opposite.”

Asthma, allergy risk may be higher for children conceived with infertility treatment

According to a study by Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institute of Environmental Health Sciences scientists at the National Institutes of Health, children born due to infertility treatment are at an increased risk of asthma and allergies.

The study, published on April 21, 2022, included 5,000 mothers and 6,000 children born between 2008 and 2020. Mothers were regularly asked about their and their children’s health and medical histories as part of the study. Infertility is treated with in vitro fertilization (sperms and eggs are combined in a laboratory dish and inserted into the uterus), ovulation-stimulating medications, and a procedure in which sperm are injected into the womb.

Children conceived after infertility treatment were more likely to have persistent wheeze by age 3, a sign of asthma, than children conceived without treatment. At 7 to 9 years old, the risk of asthma was 30% higher, eczema (an allergic condition resulting in rashes and itchy skin) was 77% more likely, and allergy medication usage was 45% more common among children born through treatment.

The study authors recommended further research to assess how infertility therapy and reduced parental fertility influence asthmatic and allergy development in children.

Languishing Cellular Batteries Foretell Movement Problems

Mitochondria are energy-generating complexes in the cells that measure energy levels. Doctors may be able to forecast physical capabilities in older persons by measuring the function of cellular energy-producers called mitochondria. According to recent research at the IRP, a study of our muscle cell batteries may forecast our physical abilities declining. Those who slowed down the most were more likely to get Alzheimer’s disease and have a greater chance of dying.

IRB staff scientist Dr. Tian, and her team in the lab of IRP senior investigator Luigi Ferrucci, M.D., Ph.D., are especially interested in the notion that analyzing the energy-generating mitochondria that power our muscle cells might let them forecast age-related mobility decline.

“Mitochondrial function declines with aging, and this mitochondrial decline has been identified as a hallmark of aging,” Dr. Tian says. “Mitochondria play an important role in all cells of the body, but they are particularly critical in tissue that requires a lot of energy, such as the central nervous system, the musculoskeletal system, and the cardiovascular system, which are very important for healthy aging.”

The IRP researchers put their hypothesis to the test by analyzing data from the Baltimore Longitudinal Study of Aging (BLSA), a long-term study of human aging collecting data since 1958. They also studied how well participants’ muscles’ mitochondria functioned in a test.

When researchers measured participants’ walking speed several times over the study’s time frame, those with a lower mitochondrial oxidative capacity when their walking speed was assessed for the first time were significantly slower on all four walking tests a year or more later.

Further research was then conducted to see whether the link between mitochondrial health and mobility could be explained by changes in muscular strength between the initial and follow-up walking tests, suggesting that mitochondrial health could influence mobility via a variety of mechanisms.

“The fact that we established this predictivity of lower mitochondrial function in a longitudinal study has great implications towards causality,” Dr. Tian says. “This is not an experimental study, this is not an intervention study, but the value of this study is that we were able to demonstrate the temporal sequence: mitochondrial function predicted future change in mobility decline.”

If future research confirms that conclusion, doctors may one day evaluate how well older individuals’ mitochondria function to identify those most likely to see their physical abilities deteriorate. This would allow clinicians to recommend treatments such as exercise regimens or medicines already being developed that improve mitochondrial functionality to prevent mobility decline.

Upcoming Events:

Retirement Symposium for NIDCD Clinical Director Carter Van Waes

Friday, May 13, 2022, 9:30 am to 4:15 pm

How Does Diversity Impact Science?

Tuesday, May 17, 2022, 1:00 pm to 2:30 pm (registration required)

National Cancer Institute Health Disparity Workshop

Wednesday, May 25, 2022, 1:00 pm to Thursday, May 26, 2022, 5:00 pm (registration required)

Current and Future Research Needs in the Era of Highly Effective Modulator Therapies for Cystic Fibrosis

Thursday, June 2, 2022, 9:00 am to Friday, June 3, 2022, 5:00 pm (register by May 30)

The post National Institutes of Health (NIH) Research Updates – May 2022 appeared first on Astrix.

Recent NIH Research

Drug Duo Stokes Body’s Fat-Burning Furnace

Abdominal obesity increases the risk of adverse health conditions including cardiovascular disease, type 2 diabetes, and metabolic disease. The excess fat carried in the abdominal region of obese individuals causes widespread inflammation throughout the body leading to a vicious cycle with the inability for the body to use overloaded fat stores. In a recent study, IRP scientists discovered a drug combination capable of decreasing inflammation while simultaneously revving up the ability of obese mice to burn fat.

Several types of fat cells are found within various regions of the body, each having different functions. White fat calls store excess calories in the form of molecules called triglycerides, while brown fat cells use the stored triglycerides to produce heat. White fat cells release their stored triglycerides into the blood when chemicals called catecholamines bind to specific sites on the cells’ surface, known as beta-adrenergic receptors, which also triggers brown fat to burn triglycerides and generate heat. However, inflammation creates catecholamine resistance causing fat cells to expel or use fewer triglycerides when stimulated by catecholamines.

“A white fat cell is an amazing cell,” says Dr. Aaron Cypess, IRP investigator at the Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases and senior author of the study. “It can grow up to 10 times its original size to store triglycerides, but we push this as far as we can until it bends and then breaks. If you have too much fat stored in a fat cell, the cell doesn’t like it.”

To further explore the mechanism for stimulating the release of stored fat from catecholamine-resistant cells, Dr. Cypess and his team studied the effects of combining CL-316,243 (called CL), a molecule that stimulates beta-adrenergic receptors, with an anti-inflammatory dietary supplement called alpha-lipoic acid.

“By themselves, alpha-lipoic acid and CL do certain things, but when you put them together, you get a significant reduction in pro-inflammatory molecules and an increase in anti-inflammatory molecules,” says Dr. Cypess. “We are still working on defining the mechanism, but part of it is probably that the alpha-lipoic acid is reducing the inflammation and making it less problematic, and that allows the CL to work better.”

Good hydration may reduce long-term risks for heart failure

In a recent study at the National Heart Lung and Blood Institute (NHLBI), researchers found that staying well-hydrated supports essential body functioning and may reduce the risk of developing severe heart problems in the future.

Preclinical research conducted as an initial phase of the study suggested connections between dehydration and cardiac fibrosis, a hardening of the heart muscles. To explore this hypothesis further, Dr. Natalia Dmitrieva, the lead study author at NHLBI, and the team of researchers looked for similar associations in large-scale population studies by analyzing data from more than 15,000 adults, ages 45-66, who had enrolled in the Atherosclerosis Risk in Communities (ARIC) study between 1987-89 and shared information from medical visits over a 25-year period.

For the retrospective review, the selected participants had hydration levels within a normal range and did not have diabetes, obesity, or heart failure at the start of the study. Approximately 11,814 adults were included in the final analysis, and of those, the researchers found, 1,366 (11.56%) later developed heart failure.

To assess potential links with hydration, the team looked at levels of serum sodium, which increases as the body’s fluid levels decrease. This method helped to identify participants with an increased risk for developing heart failure. It also helped identify older adults with an increased risk for developing both heart failure and left ventricular hypertrophy, an enlargement and thickening of the heart. Based upon their findings, the authors concluded that serum sodium levels above 142 mEq/L in middle age are associated with increased risks for developing left ventricular hypertrophy and heart failure.

“Serum sodium and fluid intake can easily be assessed in clinical exams and help doctors identify patients who may benefit from learning about ways to stay hydrated,” says Dr. Manfred Boehm, who leads the Laboratory of Cardiovascular Regenerative Medicine, NHLBI.

Mouse Study Supercharges Neurons to Detect Parkinson’s Disease

Parkinson’s disease is a progressive central nervous system disorder caused by the death of neurons in the brain that release a chemical called dopamine. The resulting dopamine deficit, leads to improper signaling in the brain, thereby impairing the patients’ ability to move. The hallmark symptoms of Parkinson’s such as slow movement, tremors, rigidity, and problems maintaining balance generally do not occur until the patient has lost more than half of the dopamine neurons in their brains. This degenerative process can begin years or even decades before they receive a diagnosis.

“Parkinson’s is a progressive disease, so the earlier we can diagnose it, the earlier we can start the intervention, which can help to slow the progression of the disease,” says Dr. Guohong Cui, IRP researcher at the NIEHS Neurobiology Laboratory, and the study’s senior author.

Parkinson’s disease can be very difficult to diagnose in its early stages as there is a range of neurological disorders that can present many of the same symptoms. Research efforts in the past have focused on the detection of a malformed protein called alpha-synuclein as a biomarker, however, the differences between Parkinson’s patients and healthy people were not readily discernable.

Dr. Cui’s lab is pursuing a completely new approach utilizing the measurement of dopamine metabolites, such as DOPAC and HVA, which are produced when dopamine that has been released from neurons has been broken down. Unlike dopamine itself, some of these metabolites can pass through the blood-brain barrier into the bloodstream and can also show up in the cerebrospinal fluid (CSF) surrounding the brain and spinal cord.

“If you look at the average, Parkinson’s patients show lower levels of dopamine metabolites in CSF samples,” explains Dr. Cui. “The issue is that the difference is very small because the variation among patients is large, so the sensitivity of this measure will not be good enough as a diagnostic method. Our idea is to increase the dynamic range so we can make these two groups — the patients and the healthy control group — more different from each other.”

To test this theory, the research team stimulated the dopamine neurons of 20-week-old mouse models of Parkinson’s disease by administering two FDA-approved drugs: haloperidol, which induces dopamine neurons to release more dopamine, and methylphenidate, which inhibits cells from recapturing the release dopamine.

Initially, the levels of the two metabolites in the CSF and blood were the same in both the healthy mice and Parkinson’s mice. However, after one hour, the CSF of the Parkinson’s mice contained significantly less HVA and DOPAC than CSF from the healthy animals, and their blood had decreased levels of HVA as well.

The study shows promising results in the early detection of Parkinson’s; however, the side effects of haloperidol may be an obstacle for use in humans. Dr. Cui’s lab is continuing their research efforts to test two experimental drugs having fewer side effects to replace haloperidol in the diagnostic test while also working on treatments to slow down the loss of dopamine neurons in Parkinson’s patients.

Vision scientists discover new angle on path of light through photoreceptors

Scientists at the National Eye Institute (NEI) have determined that mitochondria in the eye’s photoreceptor cells serve as microlenses to channel light to the outer segments of these cells where it’s converted into nerve signals. This new study, conducted in ground squirrels, provides a more precise picture of the retina’s optical properties that could aid in the early detection of eye disease.

“We were surprised by this fascinating phenomenon that mitochondria appear to have a dual purpose: their well-established metabolic role producing energy, as well as this optical effect,” said Dr. Wei Li, who leads the NEI Retinal Neurophysiology Section and is the study’s lead investigator.

The 13-lined ground squirrel has a highly cone-rich retina, which see color, as opposed to rods that enable night vision. Dr. Li’s team used this animal model to study the causes of human eye diseases that primarily affect cone photoreceptors. The researchers used a modified confocal microscope to observe the optical properties of living cone mitochondria exposed to light. Far from scattering light, the tightly packed mitochondria concentrated light along a thin, pencil-like trajectory onto the outer segment. Computational modeling using high-resolution mitochondrial reconstructions corroborated the live-imaging findings.

Scientists measuring retinal responses to light have observed that when light enters the eye near the center of the pupil, it appears brighter compared to light of equal intensity entering the eye near the edge of the pupil. In this new study, Dr. Li found that the lens-like effect of mitochondria followed a similar directional light intensity profile. Depending on light source location, the mitochondria focused light into the outer segment of the cell along trajectories that mirrored those observed from the Stiles-Crawford effect.

Linking the mitochondria’s lens-like function to the Stiles-Crawford effect has potential clinical implications for non-invasively detecting retinal diseases, many of which are thought to involve mitochondrial dysfunction at their origin. For example, patients with retinitis pigmentosa have been reported to have abnormal Stiles-Crawford effect even when they have good visual acuity. Further research is needed to explore the structural and functional changes in cone mitochondria and their manifestations in detectable optic features.

Upcoming Events:

The Brain Across the Lifespan: Tools and Methodologies for Measuring the Changing Brain

Monday, April 18, 2022, 11:00 am to Tuesday, April 19, 2022, 5:00 pm (registration required)

RNA Imaging and Intracellular Dynamics Workshop

Tuesday, April 26, 2022 (registration required)

Precision Probiotic Therapies — Challenges and Opportunities

Tuesday, April 26, 2022, 10:00 am to Wednesday, April 27, 2022, 5:30 pm (registration required)

Environmental Impacts on Women’s Health Disparities and Reproductive Health

Wednesday, April 27, 2022 to Thursday, April 28, 2022 (registration required)

NIH Social, Behavioral, and Economic Health Impacts of COVID-19 Initiative Webinar

Wednesday, April 27, 2022, 12:00 pm to Thursday, April 28, 2022, 5:00 pm (registration required)

The post National Institutes of Health (NIH) Research Updates – April 2022 appeared first on Astrix.

Recent NIH Research

Scientists pinpoint mechanisms associated with severe COVID-19 blood clotting

A team of researchers, which includes those who work at the National Heart, Lung, and Blood Institute (NHLBI) have identified “rogue antibodies” that correlate with severe Covid-19 illness. The finding of this new study, may help shed light on the mechanisms leading to severe blood clotting associated with this disease.

Blood samples from 244 patients that were hospitalized for COVID-19 were analyzed and found to contain higher levels of the antibody IgG, which works in conjunction with other immune cells to fight off bacterial, viral and fungal infections. Elevated levels of IgG are also indicators of severe COVID-19 disease, such as in patients who required breathing assistance. While the role of IgG is to protect the body from pathogenic infection, in some cases, the response can become excessive and exacerbate illness.

The researchers also found that removing IgG from the COVID-19 blood samples led to a decrease in the molecular indicators of “blood vessel stickiness”. Conversely, when adding these same IgG antibodies to the control samples, the research team observed a blood vessel inflammatory response that can lead to clotting.

Circulating factors that lead to the “stickiness” of healthy blood vessels during COVID-19 infection may help explain why the virus can affect many organs, including the heart, lungs, and brain. The researchers note the potential benefits of screening patients with COVID-19 or other forms of critical illness for antiphospholipids and other autoantibodies, at earlier points of infection, may help identify patients at risk for extreme blood clotting, vascular inflammation, and respiratory failure and could inform treatments to protect blood vessels or fine-tune the immune system of these patients.

Gene expression profile could enable rapid identification of anti-tumor immune cells for personalized immunotherapy

IRP scientists have discovered unique expression profiles in 50 genes that aid in identifying tumor-infiltrating lymphocytes (TIL) targeting metastatic solid epithelial tumors. The recent study was led by Dr. Steven Rosenberg, chief of the Surgery Branch at the Center for Cancer Research, National Cancer Institute (NCI), who pioneered the development of cell-based immunotherapy, a highly personalized form of cancer treatment that uses a person’s own immune system to fight tumor cells. His work led to the adoptive transfer of genetically modified immune cells which has resulted in tumor regression in patients with metastatic cancer.

In prior studies, Rosenberg’s team needed to look at every potential mutation in a tumor that could be a target. Years of research led to the development of a highly sensitive assay capable of identifying the gene expression profiles of a few rare lymphocytes that recognize mutated cell surface proteins of cancerous cell and is agnostic to the type of tumor a patient has. The identification of these lymphocytes could help advance the development and effectiveness of personalized cancer immunotherapies for patients whose cancers do not respond to standard treatments.

NIH study advances personalized immunotherapy for metastatic breast cancer

A new study led by researchers at the National Cancer Institute’s (NCI) Center for Cancer Research showed promising results in using an individual’s own tumor-fighting immune cells (TILs) to treat people with metastatic breast cancer.

Immunotherapy is a treatment that helps a person’s own immune system fight cancer. However, most available immunotherapies, such as immune checkpoint inhibitors, have shown limited effectiveness against hormone receptor–positive breast cancers, which are the majority of breast cancers. The immunotherapy approach using TILs, T cells that are found around the tumor, was pioneered in the late 1980s by Dr. Steven Rosenberg and his colleagues at NCI. TILs can target tumor cells that have specific proteins on their surface, called neoantigens that are produced when mutations occur in the tumor DNA, that the immune cells recognize.

In an ongoing clinical trial of 42 women with metastatic breast cancer, 28 were able to generate an immune reaction against their cancer. This new approach was used to treat six women using reactive TILs that were grown to large numbers in the lab. The researchers then returned the immune cells to each patient via intravenous infusion. Each patient was given four doses of the immune checkpoint inhibitor pembrolizumab (Keytruda) before the infusion to prevent the newly introduced T cells from becoming inactivated.

Following treatment, tumors shrank in three of the six women. One who was part of the original 2018 study remains cancer free to this day. The other two women experienced tumor shrinkage of 52% and 69% after 6 months and 10 months, respectively. However, some disease returned and was surgically removed. Now, those women now have no evidence of cancer approximately five years and 3.5 years, respectively, after their TIL treatment.

“We’re using a patient’s own lymphocytes as a drug to treat the cancer by targeting the unique mutations in that cancer,” says Dr. Rosenberg. “This is a highly personalized treatment.” He noted that this new immunotherapy approach could potentially be used for treating people with other types of cancer as well.

Scientists identify new features of a rare lung disease

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that mostly affects women of reproductive age. This progressive condition is caused by the abnormal growth of cells in the lungs, kidneys, lymph nodes and other organs and tissues. Diagnosis can be difficult due to the rare nature of the disease and current therapies target symptom management and slowing the progression of the disease.

In a recent study, a team of researchers, including scientists from the National Institute of Health (NIH), have identified a “mixed phenotype,” or differences in physical expression in the lymphatic endothelial cells. These cells appeared to resemble cells in lymphatics as well as blood endothelial cells. The characteristics were also noted in a small percentage of lung cells provided by people living with idiopathic pulmonary fibrosis (IPF), another rare lung disease, but were not observed in cells from Kaposi’s sarcoma patients or healthy individuals.

The accumulation of LAM cells within the lungs form cysts that can impede airflow, making it hard to breathe. LAM cells in the lung reside in nodules, which are small clusters of LAM and other cells that line the cysts and may be disseminated. These lung nodules also contain lymphatics, part of the lymphatic system, which supports circulation and immune function. Lymphatic endothelial cells line the nodules and provided new insight about LAM. Researchers are hopeful that ongoing research and future studies will lead to personalized therapies for people living with LAM and other rare lung conditions.

Upcoming Events:

Leveraging the Intramural Research Program to Effect Foundational Progress in Neurodegenerative Disease

Wednesday, March 30, 2022, 3:00 pm to 4:00 pm

Hereditary Gastric Cancer Symposium

Monday, April 4, 2022 to Tuesday, April 5, 2022 (registration required)

RNA Imaging and Intracellular Dynamics Workshop

Tuesday, April 26, 2022 (registration required)

The post National Institutes of Health (NIH) Research Updates – March 2022 appeared first on Astrix.

Recent NIH Research

NIH researchers develop first stem cell model of albinism to study related eye conditions

Oculocutaneous albinism (OCA) is a group of inherited disorders characterized by the reduction of pigmentation in the eye, skin, and hair resulting from mutations in the genes that are responsible for melanin pigment production. Abnormalities caused by a lack of sufficient melanin pigment production include vision problems and susceptibility to sun damage to the skin.

Researchers at the National Eye Institute (NEI) have developed the first patient-derived stem cell model for studying eye conditions related to OCA. “This ‘disease-in-a-dish’ system will help us understand how the absence of pigment in albinism leads to abnormal development of the retina, optic nerve fibers, and other eye structures crucial for central vision,” said Dr. Aman George, staff scientist in the NEI Ophthalmic Genetics and Visual Function Branch, and the lead author of the report.

Pigment is present in the retinal pigment epithelium (RPE) of the eye which aids vision by preventing the scattering of light. Scientists think that RPE plays a key role in forming these structures and want to better understand how lack of pigment affects their development. People with OCA have misrouted optic nerve fibers, lack pigmented RPE, and have an underdeveloped fovea, an area within the retina that is necessary for central vision. Scientists think that RPE plays a role in forming these structures and want to understand how lack of pigment affects their development.

“Treating albinism at a very young age, perhaps even prenatally, when the eye’s structures are forming, would have the greatest chance of rescuing vision,” said Dr. Brian Brooks, NEI clinical director and chief of the Ophthalmic Genetics and Visual Function Branch “In adults, benefits might be limited to improvements in photosensitivity, for example, but children may see more dramatic effects.” The team is now exploring how to use their model for high-throughput screening of potential therapies for the treatment of OCA.

Oral immunotherapy induces remission of peanut allergy in some young children

Peanut allergy, one of the most common food allergies, affects about 2% of children in the United States, or nearly 1.5 million individuals under the age of 18. Exposure to even a small amount of peanut protein can lead to a life-threatening allergic reaction know as anaphylaxis.

In a recent clinical trial funded by the National Institutes of Health (NIH), a team of researchers concluded that providing peanut oral immunotherapy to highly peanut-allergic children safely desensitized the majority of them to peanut protein and induced remission of peanut allergy in one-fifth of the study participants. Nearly 150 children ages 1 to 3 years took part in the IMPACT trial at five academic medical centers in the United States. Only children who had an allergic reaction after eating half a gram of peanut protein or less were eligible to join the study.

The immunotherapy consisted of a daily oral dose of peanut flour for 2.5 years. Remission was defined as being able to eat 5 grams of peanut protein, equivalent to 1.5 tablespoons of peanut butter, without having an allergic reaction six months after completing immunotherapy. The youngest children and those who started the trial with lower levels of peanut-specific antibodies were most likely to achieve remission.

The research team found two key predictive factors that a child would achieve remission following the therapy: lower levels of peanut-specific immunoglobulin E antibodies at the start of the trial and being younger in age. The study data indicated an inverse relationship between age at the start of the trial and remission, with 71% of the 1-year-olds, 35% of the 2-year-olds and 19% of the 3-year-olds experiencing remission.

“The landmark results of the IMPACT trial suggest a window of opportunity in early childhood to induce remission of peanut allergy through oral immunotherapy,” said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). “It is our hope that these study findings will inform the development of treatment modalities that reduce the burden of peanut allergy in children.” NIAID sponsored the trial and funded it through its Immune Tolerance Network.

NIH study classifies vision loss and retinal changes in Stargardt disease

In a recent study conducted by the National Eye Institute (NEI), a team of researchers developed an artificial-intelligence-based method to evaluate patients with Stargardt, an inherited an eye disease that begins in childhood and leads to the progressive loss of vision. An estimated 1 in 10,000 people have Stargardt disease. This novel method quantifies disease-related loss of light-sensing retina cells that will enable a better understanding of the genetic causes of the disease and insights into the development of therapies for the treatment of the disease.

The most common form of Stargardt is ABCA4-associated retinopathy, an autosomal-recessive disease caused by variants to the ABCA4 gene, which contains genetic information for a transmembrane protein in light-sensing photoreceptor cells. People develop Stargardt when they inherit two mutated copies of ABCA4, one from each parent. People who have just one mutated copy of ABCA4 are genetic carriers, but do not develop the disease. More rare forms of Stargardt are associated with variants of other genes.

Among patients who all have ABCA4 gene variants, there can be a wide spectrum in terms of age of onset and disease progression.

“Different variants of the ABCA4 gene are likely driving the different disease characteristics, or phenotypes. However, conventional approaches to analyzing structural changes in the retina have not allowed us to correlate genetic variants with phenotype,” said the study’s co-leader, Dr. Brian Brooks, chief of the NEI Ophthalmic Genetics & Visual Function Branch. Dr. Brooks co-led the study with Dr. Brett Jeffrey, head of the Human Visual Function Core of the NEI’s Ophthalmic Genetics and Visual Function Branch.

The study followed 66 Stargardt patients for a period of five years using a retinal imaging technology called spectral-domain optical coherence tomography (SD-OCT). The 3D cross-sectional retinal images were and analyzed using deep learning, a type of artificial intelligence (AI) in which vast amounts of imaging data can be fed into an algorithm, which then learns to detect patterns that allow the images to be classified. This methodology allowed the researchers to quantify and compare the loss of photoreceptors and various layers of the retina according to the patient’s phenotype and ABCA4 variant and provided a way of classifying the severity of 31 different ABCA4 variants.

“These results provide a framework to evaluate Stargardt disease progression, which will help control for the significant variability from patient to patient and facilitate therapeutic trials,” said Dr. Michael Chiang, director of the NEI.

Researchers highlight COVID-19 neurological symptoms and need for rigorous studies

Acute COVID-19 infection, caused by the SARS-CoV-2 virus, can sometimes lead to long-lasting effects, collectively termed as “Long Covid”. This can include a wide variety of symptoms in the brain and nervous system that range from a loss of taste and smell, impaired concentration, fatigue, pain, headache, sleep disorders, and autonomic disorders to psychological effects such as depression or psychosis.

Although SARS-CoV-2 was initially identified as a respiratory virus, it can affect the entire body. Neurological symptoms that have been reported with acute COVID-19 include loss of taste and smell, headaches, stroke, delirium, and brain inflammation. There does not seem to be extensive infection of brain cells by the virus, but the neurological effects may be caused by immune activation, neuroinflammation, and damage to brain blood vessels.

In a recent Viewpoint published in Science by Dr. Avindra Nath, clinical director of the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS), and Dr. Serena Spudich, Yale School of Medicine, highlight current scientific insights surrounding the effects of SARS-CoV-2 on the brain, and how physiological responses to acute COVID-19 infection could lead to Long Covid symptoms. Dr. Nath and Dr. Spudich also outline common risk factors between individuals with Long Covid and those living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or post-Lyme disease.

The authors emphasize the need for the further study of individuals with Long Covid, categorized by their specific symptoms, as being crucial to the development of diagnostic and therapeutic tools to identify and treat what is becoming a significant public health concern.

NIH launches first phase of $9.8 million competition to accelerate development of neuromodulation therapies

The National Institutes of Health (NIH) has launched the first phase of the Neuromod Prize, a $9.8 million competition dedicated to accelerating the development of targeted neuromodulation therapies. The Neuromod Prize is part of the SPARC (Stimulating Peripheral Activity to Relieve Conditions) initiative from the NIH Common Fund and focuses on novel uses of peripheral nerve stimulation treatments that selectively target multiple organs and functions. The competition seeks scientists, engineers, and clinicians to submit innovative concepts and clinical development plans to demonstrate solutions for precisely stimulating the peripheral nervous system to treat disease and improve human health.

The first phase of the competition (Concepts and plans for development) will select up to eight winners who will receive a share of the up to $800,000 prize pool and will exclusively be invited to participate in phase two of the competition. The second phase (Proof-of-concept studies) will award a planned prize pool of $4 million. Up to four winners from the second phase may be selected to continue on to phase three (IDE-enabling studies), awarding up to $5 million. The competition is subject to change along with the availability of funds. Details surrounding phases two and three are expected to be announced at a future date.

“Through the Neuromod Prize, we’re asking potential solvers to use the foundational knowledge and technologies that have come out of our SPARC program and take it to the next level with their innovative concepts and ideas,” said ​​Dr. James Anderson, director of the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI), which oversees the NIH Common Fund. “This competition is an exciting opportunity to come up with tangible plans for harnessing the power of the body’s electrical system to help transform treatments for millions of people living with chronic or acute illnesses.”

For more information about the Neuromod Prize, visit neuromodprize.com.

Upcoming Events:

NCI Myelodysplastic Syndromes Symposium

Friday, February 25, 2022, 12:30 pm (register by February 21)

Rare Disease Day at NIH

Monday, February 28, 2022, 10:00 am to 6:00 pm

Leveraging the Intramural Research Program to Effect Foundational Progress in Neurodegenerative Disease\

Wednesday, March 30, 2022, 3:00 pm to 4:00 pm

Hereditary Gastric Cancer Symposium

Monday, April 4, 2022 to Tuesday, April 5, 2022 (registration required)

RNA Imaging and Intracellular Dynamics Workshop

Tuesday, April 26, 2022 (registration required)

The post National Institutes of Health (NIH) Research Updates – February 2022 appeared first on Astrix.

Recent NIH Research

A high-fiber diet may lead to an improved immunotherapy response in melanoma patients

IRP Scientists have determined that a high-fiber diet may improve the immunotherapeutic response from patients being treated for melanoma. A recent study led by the Center for Cancer Research at the National Cancer Institute (NCI) in collaboration with the University of Texas MD Anderson Cancer Center focused on the ability of the gut microbiome to modulate the immune system thereby having the potential to influence the therapeutic response of cancer patients.

Immune checkpoint inhibitors have shown significant promise in the treatment of melanoma and other difficult to treat cancers, improving the longevity of people with advanced stages of the disease by restoring the immune system’s natural ability to recognize and kill tumor cells.

In this study, patients with advanced melanoma who underwent immunotherapy with immune checkpoint inhibitors who consumed at least 20 grams a day of dietary fiber survived the longest without progression of the disease than those who consumed less dietary fiber. Every 5-gram increase in daily dietary fiber intake corresponded to a 30% lower risk of progression of the disease. In contrast, the use of probiotics, which are supplements containing live microorganisms typically consumed to improve gut health, somewhat decreased the effectiveness of immune checkpoint inhibitor regimens.

“The data suggest that one can target the composition of the gut microbiota and affect the ability of the patient to respond to immunotherapy,” said Dr. Giorgio Trinchieri, chief of the Laboratory of Integrative Cancer Immunology at NCI and coleader of the study.  “Consuming a diet rich in fiber, like fruits, vegetables, and legumes, could improve your ability to respond to immunotherapy. The data also suggest that it’s probably better for people with cancer receiving immunotherapy not to use commercially available probiotics.”

Suppressing a blood-clotting protein prevents gum disease in mice

A new study led by the National Institute of Dental and Craniofacial Research (NIDCR) suggests that suppressing the abnormal activity of fibrin, a blood-clotting protein, may lead to the prevention or treatment of periodontal disease. Nearly 50% of adults over the age of 30 and greater than 70% of adults over age 65 have some form of periodontal disease. Bacteria in the mouth can infect the tissue surrounding a tooth, causing inflammation in its early stages. As periodontal progresses, the underlying bone becomes damaged, leading to tooth loss.  The advanced stage of this disease, called periodontitis, is driven in part of an elevated immune cell response. Until now it has been unclear what triggered this response and the mechanism by which it caused tissue and bone damage.

Fibrin normally plays a protective role at sites of injury of inflammation by helping to form blood clots and activating immune cells to fight infection. However, the buildup of excess fibrin has been linked with health problems, including a rare form of periodontitis due to a condition called plasminogen (PLG) deficiency. In affected people, mutations in the PLG gene lead to the accumulation of fibrin at various body sites, including the mouth.

To explore the connection between abnormal fibrin buildup and periodontitis, the research team, led by NIDCR investigators Dr. Niki Moutsopoulos and Dr. Thomas Bugge studied PLG deficiency in mice and performed a genetic analysis of over 1,000 people. Their findings concluded that even in the absence of PLG deficiency, variations in the PLG gene were linked to an increased risk of severe periodontitis, consistent with the idea that similar processes contribute to rare and common forms of the disease. The study further suggests that excessive buildup of fibrin in the gums—whether due to changes in genes like PLG, chronic inflammation from a bacterial infection, or some combination of the two—triggers an elevated and ultimately harmful neutrophil response that causes periodontal disease.

NIH researchers identify potential AMD drugs with stem cell-based model

Researchers at the National Eye Institute (NEI) have identified two promising drug candidates that may slow dry age-related macular degeneration (AMD), a leading cause of blindness for which no permanent cure exists. Dry AMD is when parts of the macula become thinner with age and tiny clumps of protein called drusen form causing the progressive loss of central vision.

Two of the drugs tested prevented the stem cell model from accumulating drusen, lipid-rich deposits in the retina, and the atrophy, or shrinkage, of retinal pigment epithelium (RPE) cells. RPE is a layer of tissue that nourishes the retina’s light-sensing photoreceptors. In AMD, RPE cells shrink and die leading to the death of photoreceptors and ultimately to loss of vision.

The research team led by Dr. Kapil Bharti, director of the NEI Ocular and Stem Cell Translational Research Section, and Dr. Ruchi Sharma, staff scientist in the lab and lead author of the paper, developed the experimental model using stem cell-derived mature RPE cells. Dr. Bharti’s group initially developed the cells using skin fibroblasts or blood samples donated from AMD patients. The fibroblasts or blood cells were programmed to become induced pluripotent stem cells (iPSC), and then programmed again to become RPE cells.

In the study, more than 1,200 drugs were screened via the stem cell model from a library of pharmacological agents that had been tested for a range of other conditions. Two drugs were flagged for their ability to inhibit RPE atrophy and drusen formation: A protease inhibitor called aminocaproic acid, which likely directly blocks the complement pathway outside cells and L745, which was originally tested by Merck & Co. for treating schizophrenia.  L745 stops complement induced inflammation inside the cell indirectly via inactivation of the dopamine pathway.

“This stem cell-derived model of dry AMD is a game-changer. Scientists have struggled to unravel this incredibly complex disease, and this model could prove to be invaluable for understanding the causes of AMD and discovering new therapies,” said Dr. Michael Chiang, director of the NEI.

NIH study suggests women with disabilities have increased risk of birth complications

In new study conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), researchers have determined that pregnant women with disabilities have an increased risk for a broad spectrum of pregnancy and birth related complications, including mortality.

Based upon an analysis of more than 223,000 deliveries in 19 U.S. hospitals, approximately 2,199 pregnant women had a physical, sensory or intellectual disability. Compared to women without disabilities, women with disabilities had:

• Greater than twice the risk for severe preeclampsia
• 48% higher risk for mild preeclampsia
• 25% higher risk for gestational diabetes
• 52% higher risk for placenta previa
• 16% higher risk for premature rupture of the membranes
• 27% higher risk for hemorrhage
• 11 times the risk for maternal death
• more than six times the risk for blood clots
• four times the risk for cardiovascular events, such as heart attacks
• nearly three times the risk for infection
• 33% greater likelihood of receiving the drug oxytocin to stimulate labor, delivery with forceps or other devices to extract the fetus, or cesarean delivery

“Additional research is needed to understand the reasons for this increased risk and to develop needed interventions to reduce it,” said Dr. Jessica Gleason, NICHD research fellow and lead author of the study. The authors noted that women with disabilities are more likely to live in poverty, which may make accessing health care in a timely manner difficult. Other factors that may increase their health risks are higher rates of smoking, substance use and depression.

Experimental mRNA HIV vaccine shows promise in animals

An experimental HIV vaccine shows promise in mice and non-human primates, according to researchers at the National Institute of Allergy and Infectious Diseases (NIAID). Based upon this new study, the vaccine was determined to be safe and triggered an antibody response against an HIV-like virus. Rhesus macaques receiving a priming vaccine followed by multiple booster inoculations had a 79% lower per-exposure risk of infection by simian-human immunodeficiency virus (SHIV) compared to unvaccinated animals.

“Despite nearly four decades of effort by the global research community, an effective vaccine to prevent HIV remains an elusive goal,” said Dr. Anthony Fauci, NIAID Director, chief of the Laboratory and co-author of the paper. “This experimental mRNA vaccine combines several features that may overcome shortcomings of other experimental HIV vaccines and thus represents a promising approach.”

The research team, led by Dr. Paolo Lusso, of NIAID’s Laboratory of Immunoregulation, in collaboration with other NIAID scientists, investigators from Moderna, Inc. and colleagues at other institutions, developed an mRNA vaccine that delivers coded instructions for making two key HIV proteins, Env and Gag. Muscle cells in an inoculated animal assemble these two proteins to produce virus-like particles (VLPs) studded with numerous copies of Env on their surface. The Env proteins produced in the mice from the mRNA instructions closely resembled those in the whole virus, an improvement over previous experimental HIV vaccines.

After 13 weekly inoculations, two out of seven immunized macaques remained uninfected, while the other immunized animals had an overall delay in infection, which occurred, on average, after eight weeks. In contrast, unimmunized animals became infected on average after three weeks. Dr. Lusso noted, “The display of multiple copies of authentic HIV envelope protein on each VLP is one of the special features of our platform that closely mimics natural infection and may have played a role in eliciting the desired immune responses.”

Upcoming Events:

NIH Workshop on Psychedelics as Therapeutics: Gaps, Challenges and Opportunities

Wednesday, January 12, 2022, 9:00 am to Thursday, January 13, 2022, 2:55 pm (registration required)

Technology to Improve Maternal Health

Tuesday, January 18, 2022, 12:00 pm to 6:30 pm (registration required)

The Centriculum: a Centrosome Associated Membrane Reticulum That Affects Centrosome Structure and (maybe) Centrosome Nuclear Envelope Interactions

Tuesday, January 25, 2022,  12:00 pm to 1:30 pm

NCI Myelodysplastic Syndromes Symposium

Friday, February 25, 2022, 12:30 pm (register by February 21)

Rare Disease Day at NIH

Monday, February 28, 2022, 10:00 am to 6:00 pm

Hereditary Gastric Cancer Symposium

Monday, April 4, 2022 to Tuesday, April 5, 2022 (registration required)

RNA Imaging and Intracellular Dynamics Workshop

Tuesday, April 26, 2022 (registration required)

The post National Institutes of Health (NIH) Research Updates – January 2022 appeared first on Astrix.

Recent NIH Research

ALS drug shows promise in mouse model of rare childhood genetic disorder

New IRP research showed promising results for slowing the progression of Niemann-Pick disease type C1 (NPC1) using riluzole, an FDA approved drug for the treatment of amyotrophic lateral sclerosis (ALS). Niemann-Pick disease type C1 is an inherited, neurogenerative disorder that causes a massive accumulation of lipids in the liver, brain, spleen and bone marrow. Approximately 50% of cases of NPC1 present in childhood, before 10 years of age. There is no known cure for this fatal disease, other than symptomatic relief.

This rare metabolic disorder leads to the progressive deterioration of the nervous system and loss of function of the brain and other organs. NPC1 results from the impaired ability to transport cholesterol and other lipids through cells, leading to difficulty controlling movements, liver and lung disease, impaired swallowing, intellectual decline and death. Much of the movement difficulties in NPC1 result from a gradual loss of brain cells known as Purkinje neurons.

The collaborative study was conducted by Dr. Forbes Porter, senior investigator at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and colleagues in the National Human Genome Research Institute (NHGRI) and National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS).

The team of researchers discovered that mice with a form of NPC1 have a diminished ability to lower the levels of glutamate, a brain chemical that stimulates neurons after it has bound to a neuron’s surface. The team believes that the buildup of glutamate contributes to the brain cell loss seen in the disease, as high levels of glutamate are known to cause cell toxicity.

Riluzole, while it is not a cure for ALS, delays the progression of the disease in humans by blocking the release of glutamate. As part of the current study, mice with NPC1 that were treated with riluzole had a survival rate of 12% longer than untreated mice. The research team hypothesizes that riluzole or similar drugs may provide a viable way to slow disease progression in patients with NPC1.

Inflammation Contributes to Cancer-Related Fatigue

A recent IRP study led by the National Institute of Nursing Research (NINR) suggests that intense exhaustion experienced by cancer patients may be caused in part by inflammation resulting from radiation therapy.

Chemotherapy, a drug therapy used to stop the growth of cancer cells and prevent them from spreading, introduces potent chemicals into the bloodstream. Since chemotherapy effects healthy cells as well as cancer cells, it can cause extreme fatigue as the body fights to repair the damage caused by the treatment. Total body irradiation is known to have severe side effects include excessive fatigue or tiredness. However, even when radiation is targeted to just one area, it can still lead to debilitating cancer-related fatigue.

Dr. Leorey Saligan, senior investigator at NINR has studied the effect of targeted radiation treatment on patients with prostate cancer and noted that while they initially do not experience cancer-related fatigue, they do, however, develop debilitating fatigue following radiation treatment targeted to the prostate. As many as 40% of the treated patients will continue to experience chronic fatigue for as long as one to two years after the end of their treatment period.

As patients in the study had not reported experiencing fatigue from the cancer itself, Dr. Saligan and his research team investigated how the radiation treatment might be a cause of the extreme fatigue. Although there have been frequent reports of significant inflammation in patients with cancer-related fatigue, none had determined this to be the potential source of the fatigue.

The researchers used a mouse model of cancer-related fatigue to further explore the effects of inflammation following radiation treatment. In this study, it was noted that healthy male mice that received radiation targeted to the pelvis spent significantly less time running on their wheels than control mice not exposed to radiation. However, mice that were given minocycline, an antibiotic that also reduces inflammation, showed a noticeably smaller decrease in their wheel running than mice not given the antibiotic, though they still ran much less than mice that were not exposed to radiation. Similarly, after pelvic radiation treatment, mice lacking a gene involved in the body’s inflammatory response ran more on their wheels than genetically normal mice.

“This is a big first step to really show some causality between fatigue and inflammation,” says Dr. Saligan. “We’re hoping that with these initial results that show a causal relationship, we can provide avenues to address the role of inflammation in cancer-related symptoms such as fatigue.”

Extreme eating problems in early childhood linked to increased likelihood of developmental delay

Researchers at the Epidemiology Branch of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) have determined that young children with a history of eating problems during their first three years of life had a higher likelihood of receiving low scores on assessments of child development.

The findings suggest that children with multiple eating problems such as frequent crying during meals, pushing food away, and gagging while eating may benefit from screening for developmental delay. Early diagnosis of developmental disorders is key to getting children the help they need.

In this new study, led by IRP scientist Dr. Diane Putnick, NICHD, a team of researchers analyzed data on more than 3,500 children from Upstate KIDS, a study of children born between 2008 and 2010 in New York State. Mothers responded to questionnaires, rating their children’s eating patterns and developmental milestones when the children were 18, 24 and 30 months old. Compared to children who did not have eating problems, those who scored high on eating problems at one or two time points were more than twice as likely to miss a developmental milestone. Children with feeding problems at all three ages were four or more times as likely to miss a milestone.

The researchers noted that while feeding problems are not likely the cause of developmental delay, the problems associated with developmental delay, such as undiagnosed neurological issues, communication difficulties or lack of fine motor skills may underlie feeding problems. Children with feeding problems only at 18 and 24 months could potentially be the result of temporary variations in maturation, while feeding problems that persist until 30 months are at greatest risk for developmental delay and are the strongest candidates for screening.

Researchers target a mouse’s own cells, instead of antibiotics, to treat pneumonia

Researchers at the National Institute of Environmental Health Sciences (NIEHS) have discovered a novel method for the treatment of pneumococcal pneumonia, the leading cause of pneumonia deaths worldwide as reported by the World Health Organization (WHO).

While antibiotics are prescribed as the common course of treatment for bacterial pneumonia, caused by Streptococcus pneumoniae, the treatment is not always successful, and in some cases the bacteria even become resistant.

IRP scientist and co-lead author of the study, Dr. Matthew Edin, wanted to find a way to augment the body’s own immune system as an alternative method to resolve the infection. The research team focused on developing a therapy targeting host cells rather than bacterial cells in rodents.

To keep tissues healthy, epoxyeicosatrienoic acids (EETs) work to limit inflammation within the body, but during infections, such as bacterial pneumonia, inflammation ramps up after lung cells induce certain substances that prompt macrophages to digest the bacteria. The research team found that one way to get macrophages to eat more bacteria is to decrease the ability of EETs to limit inflammation. Using a synthetic molecule called EEZE to block EET activity boosted the eating capacity of the macrophages, leading to a reduction in the amount of bacteria in the lungs of mice. The scientists saw the same result when they placed bacteria and macrophages harvested from lung and blood samples of human volunteers in test tubes at the NIEHS Clinical Research Unit.

“EEZE is safe and effective in mice, but scientists could develop similar compounds to give to humans,” said Dr. Edin. “These new molecules could be used in an inhaler or pill to promote bacterial killing and make the antibiotics more effective.”

Repurposed cancer treatments could be potential Alzheimer’s drugs

According to a recent IRP study, existing and emerging cancer drugs showed promise for being repurposed as therapies to be tested in clinical trials for people at genetic risk of Alzheimer’s disease. The analysis of brain protein alterations in these individuals as well as laboratory experiments in animal models and cell cultures could assist scientists in quickly identifying existing drugs to test their potential as Alzheimer’s interventions.

Researchers from the National Institute on Aging (NIA) in collaboration with NIA-supported teams at the University of California, San Francisco; Rush University, Chicago; and the Icahn School of Medicine at Mount Sinai, New York City identified brain protein changes related to the APOE4 genetic risk variant in young postmortem study participants (average age at death was 39 years) and compared these changes with those in the autopsied brains of people with Alzheimer’s and those without (average age at death was 89 years). The analyses included brain samples from the Baltimore Longitudinal Study of Aging, the Religious Orders Study, and other NIA-funded studies. Existing FDA-approved or experimental drugs for other diseases were then tested for activity upon these proteins.

Their findings show that an experimental drug for the treatment of liver cancer and Dasatinib, an approved for chronic myeloid leukemia, was found to act upon some of the Alzheimer’s disease related proteins, suggesting they could be potential Alzheimer’s therapies. The drugs also reduced neuroinflammation, amyloid secretion, and tau phosphorylation in cell culture experiments, underscoring their potential as candidates to be tested in Alzheimer’s clinical trials.

Lung autopsies of COVID-19 patients reveal treatment clues

Scientists at the National Institutes of Health and their collaborators have a clearer picture of how SARS-CoV-2, the virus that causes COVID-19 disease, spreads and damages lung tissue. These important findings could assist in predicting severe and prolonged cases of COVID-19 and inform effective treatments, particularly among those at high risk.

A small study using lung and plasma samples autopsied from people who died of COVID-19 and had at least one high-risk condition such as diabetes, obesity or being elderly, revealed trends that could help develop new COVID-19 therapeutics and fine-tune when to use existing therapeutics at various stages of disease progression or caring for high-risk patients. The findings of the study include details about how SARS-CoV-2 spreads in the lungs, manipulates the immune system, causes widespread thrombosis that does not resolve, and targets signaling pathways that promote lung failure, fibrosis and impair tissue repair.

The study included patients who died between March and July 2020, with time of death ranging from 3 to 47 days following the onset of symptoms. This enabled the scientists to compare short, intermediate, and long-term cases. Every case showed findings consistent with diffuse alveolar damage, which prevents proper oxygen flow to the blood and eventually makes lungs thickened and stiff. The scientists also determined that SARS-CoV-2 directly infected basal epithelial cells within the lungs, impeding their essential function of repairing damaged airways and lungs and generating healthy tissue. The process is different from the way influenza viruses attack cells in the lungs, which provides scientists with additional information to use in the development of antiviral therapeutics.

Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) led the project in collaboration with the National Institute of Biomedical Imaging and Bioengineering | (nih.gov) and the FDA. Other collaborators included the Institute for Systems Biology in Seattle; University of Illinois, Champaign; Saint John’s Cancer Institute in Santa Monica, California.; the USC Keck School of Medicine in Los Angeles; University of Washington Harborview Medical Center, Seattle; University of Vermont Medical Center, Burlington; and Memorial Sloan Kettering Cancer Center in New York City.

Upcoming Events:

Building Unifying Systems of Care Addressing Comorbidities in Women and Girls

Thursday, December 16, 2021, 11:00 am to Friday, December 17, 2021, 5:30 pm (register by December 10)

NIH Workshop on Psychedelics as Therapeutics: Gaps, Challenges and Opportunities

Wednesday, January 12, 2022, 9:00 am to Thursday, January 13, 2022, 2:55 pm (registration required)

Technology to Improve Maternal Health

Tuesday, January 18, 2022, 12:00 pm to 6:30 pm (registration required)

RNA Imaging and Intracellular Dynamics Workshop

Tuesday, April 26, 2022 (registration required)

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