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

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.

The National Institutes of Health (NIH) is our nation’s medical research agency. Its mission focuses on scientific discoveries that improve health and save lives. Founded in 1870, the NIH conducts its own scientific research through its Intramural Research Program (IRP), which supports approximately 1,200 principal investigators and more than 4,000 postdoctoral fellows conducting basic, translational and clinical research. In this blog, we will highlight recent innovative NIH research.

IRP’s Steven Rosenberg receives HHS Secretary’s Award for Distinguished Service

Dr. Steven Rosenberg, Chief of Surgery at the National Cancer Institute, has been awarded the HHS Secretary’s Award for Distinguished Service in recognition of his groundbreaking research in cancer immunotherapy. He pioneered the development of immunotherapy, resulting in the first effective immunotherapy for selected patients with advanced stage cancer. Dr. Rosenberg is the first researcher to successfully insert foreign genes into humans, leading to the development of gene therapy as a novel technique in the treatment of disease. The award, which celebrates excellence in leadership, ability, and service, is the highest honor given by the US Department of Health and Human Services.

Throughout his 47 year career at NCI, Dr. Rosenberg has been at the forefront of using immunotherapy and gene therapy to treat multiple forms of cancer, including kidney cancer, lymphoma, and melanoma. This innovative treatment directly targets tumors without the destruction of healthy tissue that occurs with traditional methods such as surgery, chemotherapy and radiation treatment. “One of the major advantages of immunotherapy is it can be highly specific in its recognition of affected cells,” Dr. Rosenberg explains. The therapies based upon his work have even proven capable of combating ‘metastatic’ cancers that have spread around the body from the site where they first developed.

As a young surgical resident at what is now Brigham and Women’s Hospital in Boston, Dr. Rosenberg was assigned to work at the VA Hospital in West Roxbury. There, he encountered a patient who needed his gallbladder removed, but a quick review of the patient’s medical records showed something very unusual. Twelve years earlier, the patient had undergone surgery to remove a stomach tumor. The notes indicated that several tumors couldn’t be removed, and the patient had received no further treatment. Yet when Dr. Rosenberg performed the gallbladder surgery, there was no sign of the old cancer.

“It’s one of the rarest events in medicine,” Dr. Rosenberg says. “Somehow his body had learned to defeat the disease, and it seemed likely to me that the immune system was responsible.”

In another case that occurred during his residency, Dr. Rosenberg saw a patient that had received a donated kidney that his doctors later learned contained cancerous cells. With the patient’s immune system disabled so his body would not reject the new kidney, the cancer quickly spread. When his doctors discontinued the immunosuppressive drug regimen, the patient’s body rejected the kidney, as expected, but surprisingly also started attacking the cancer, including the cancer cells that had spread from the donated organ. “That demonstrated to me that if you have a strong enough immune stimulus, the body was capable of rejecting even large, invasive cancers,” Dr. Rosenberg explains.

After joining the NIH in 1974, Dr. Rosenberg focused his work on studying immune cells called lymphocytes, which are white blood cells that fight infection. His research team determined they could remove lymphocytes that had infiltrated the tumor and were already fighting the cancer and treat the extracted cells in in the lab with a hormone naturally produced in the body called interleukin-2 (IL-2), which stimulated them to multiply 1,000-fold. These treated cells could then be injected back into the patient, where they found their way to the tumor and stepped up their attack. “This concept of using the body’s own immune cells as a drug has been the underlying basis of virtually everything I’ve done,” says Dr. Rosenberg.

The first immunotherapies approved for cancer treatment were based upon Dr. Rosenberg’s research with IL-2. In 1985, his team showed that giving patients that hormone could cause tumors to shrink in about 20 percent of people with melanoma and metastatic kidney cancer, with about one-third of those responding to the treatment showing no signs of cancer afterward. The FDA approved IL-2 immunotherapy for kidney cancer in 1992 and for melanoma in 1998.

More recently, Dr. Rosenberg and his team have been developing gene therapies that modify the patient’s own immune cells so that they can more effectively recognize and attack cancer, leading to the 2017 FDA approval of the first-ever gene therapy for cancer. Dr. Rosenberg’s team has also identified hundreds of unique antigens that immune cells could potentially use to identify and attack cancer cells. “These antigens are unique to each individual, so targeting them has to be highly personalized,” he says. Dr. Rosenberg’s team is now working on ways to efficiently produce the modified immune cells needed for this type of treatment and applying it to other cancers such as leukemia and lymphoma.

“This award is a recognition not only of what I’ve done,” Dr. Rosenberg says, “but also an indication and inspiration to continue to make progress toward the goal of developing new immunotherapies for patients with cancer.”

To boost learning, timing may be everything

In a new study, IRP researchers have discovered that transcranial magnetic stimulation (TMS), a noninvasive method of brain stimulation, significantly boosts motor skill learning when precisely administered during specific periods of brain activity.

Groups of neurons in the brain continuously cycle in unison between periods of heightened and suppressed electrical activity called ‘oscillations’ or ‘rhythms.’ When the brain is awake, a cycling of neuronal activity called the ‘mu rhythm’ can be seen in brain regions that are responsible for sensory perception and movement, like the primary motor cortex. Dr. Leonardo Cohen, senior investigator at National Institute of Neurological Disorders and Stroke (NINDS), believes that studying this neuronal rhythm can potentially boost the effects of brain stimulation approaches like TMS, which uses magnetic fields to generate electrical currents in the brain.

The research team led by Dr. Cohen and Dr. Sara Hussain, a former postdoctoral fellow in his lab who is now an assistant professor at the University of Texas at Austin, explored whether delivering TMS during specific phases of neuronal oscillations could enhance learning in a study of 51 individuals practicing a repetitive motor skill task. All participants got better at the task as they practiced on the first and second days of the experiment, however, the participants who had received TMS stimulation only during trough phases of the brain’s mu rhythm improved nearly 50 percent more than the other groups.

“TMS stimulation for therapeutic purposes is usually given regardless of phase,” Dr. Cohen explains. “When we look at our results, we see that TMS during trough phases increases performance by nearly 50 percent, so in reality what researchers are doing right now is a mix of that 50 percent boost when TMS is given during trough phases and the zero percent improvement when TMS is given during peak phases. The mix of those makes the overall size of the effect potentially much smaller.”

Through this research effort, Dr. Cohen hopes to learn how TMS can be more effectively to help patients with neurological problems due to strokes or dementia regain their ability to perform complex movements like walking or grasping objects.

NIH researchers identify how two people controlled HIV after stopping treatment

Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) have identified two methods that individuals with HIV can control the virus for an extended period after stopping antiretroviral therapy (ART) under medical supervision.

The study, led by Dr. Tae-Wook Chun, chief of the HIV Immunovirology Section in the Laboratory of Immunoregulation at NIAID and Dr. Anthony Fauci, NIAID director and chief of the Laboratory of Immunoregulation, involved two adults with HIV who began ART soon after acquiring the virus and continued with treatment to successfully suppress HIV for more than six years. The individuals discontinued ART under a medically supervised HIV clinical trial.

The study team monitored the timing and size of viral rebounds in each participant, that is, times when the amount of HIV in their blood became detectable. One participant suppressed the virus with intermittent rebounds for nearly 3.5 years, at which point he began taking suboptimal ART without informing the study team. The other participant almost completely suppressed HIV for nearly four years, at which point the virus rebounded dramatically because he became infected with a different HIV strain, a phenomenon known as “superinfection.”

The first participant had high levels of HIV-specific immune cells called CD8+ T cells that can kill virus-infected cells while the second participant did not, indicating that different mechanisms of control were at work in each person. The second participant, who had a weaker CD8+ T cell response against HIV, had a very strong neutralizing antibody response throughout the follow-up period until the sudden viral rebound. The scientists hypothesized that neutralizing antibodies may have played a significant role in facilitating near-complete HIV suppression in this individual until he acquired a different strain of the virus. The finding of this study could inform efforts to develop new methods of helping people with HIV put the virus into remission without taking lifelong medication, which can have long-term side-effects.

Buprenorphine misuse decreased among U.S. adults with opioid use disorder from 2015-2019

Buprenorphine is an FDA-approved medication used in the treatment of opioid use disorder and for the relief of severe pain. When used to treat opioid use disorder, buprenorphine works through the partial activation of opioid receptors in the brain, which aids in the reduction of opioid cravings, withdrawal, and overall use of other opioids.

In the National Survey on Drug Use and Health Data, conducted by the National Institute on Drug Abuse (NIDA) and the Centers for Disease Control and Prevention (CDC), nearly three-fourths of adults reporting buprenorphine use in 2019 did not misuse the medication in the past 12 months. Buprenorphine misuse among people with opioid use disorder has been trending downward between 2015-2019, despite increases in the number of people receiving buprenorphine treatment.

In 2020, more than 69,000 people lost their lives due to opioid related drug overdoses. However, in 2019, less than 18% of people with a past-year opioid use disorder received medications to treat their addiction, in part due to stigma and barriers to accessing these medications. Updated guidelines released by the U.S. Department of Health and Human Services in April 2021 has expanded access to buprenorphine for the treatment of opioid use disorder. However, barriers to the use of this treatment remain, including provider unease with managing patients with opioid use disorder, lack of adequate insurance reimbursement, and concerns about risks for diversion, misuse, and overdose.

The study reported roughly 1.7 million people having used buprenorphine as prescribed in the past year, compared with 700,000 people who reported misusing the medication. The study also concluded that people who did not receive treatment for their drug use and those living in rural areas were more likely to misuse the medication, however, being a racial/ethnic minority or living in poverty had no effect on buprenorphine misuse.

“Three-quarters of adults taking buprenorphine do not misuse the drug,” said Dr. Wilson Compton, Deputy Director of NIDA and senior author of the study. “Many people with opioid use disorder want help, and as clinicians, we must treat their illness. The study authors recommended that improvements to the access and quality of buprenorphine treatment for people with opioid use disorder is needed to address the current opioid crisis.

Wearable tech tracks ebbs and flows of bipolar disorder

Bipolar disorder is a mental health condition characterized by alternating periods of extreme elation or depression. This unpredictable change in moods and behavior are severe enough to interfere with work, school, and relationships for nearly 90 percent of people affected with bipolar disorder. While as many as 2.3 million Americans have been diagnosed bipolar disorder, it is likely many more people go undiagnosed.

Researchers at the National Institute of Mental Health (NIMH) are transforming our knowledge of bipolar disorder. In a study led by NIH Distinguished Investigator, Dr. Kathleen Merikangas, wearable activity monitors allowed a team of researchers to investigate how sleep and movement affect the moods of people with bipolar disorder and other mood disorders.

“When we studied adolescents in the general population, we learned that one of the most important characteristics of youth who begin to develop bipolar disorder is increased physical activity and energy rather than changes in mood,” explains Dr. Merikangas. In fact, physical activity has now been included as one of the core features in the diagnosis of bipolar disorder. People with this condition are fidgety, restless and moving around a lot even in situations where they would normally sit still.

To further understand the relationships between physical activity, sleep, and mood in patients with bipolar disorder in real-world settings, the research team studied 242 adults with bipolar disorder, major depression, or no history of mood disorders. The study participants wore monitors on their wrists that collected constant, real-time measurements of their activity and sleep duration for two weeks and were given electronic devices programmed with a survey that asked them several times per day to rate their mood and energy level on a scale from one to seven.

The researchers found that participants reported better moods on the survey when they had been more active earlier in the day. A lack of sleep correlated to reduced energy and activity, whereas changes in mood had no impact on energy levels. The influence of sleep and activity on the moods of bipolar participants was much stronger than in those with depression or no mood disorder, and the sleep- and movement-induced boosts in mood and energy level that they experienced took longer to return to more typical levels. As a result of these findings, Dr. Merikangas suggests that increasing physical activity may show promise in the treatment of bipolar disorder.

COVID vaccine booster increases antibody responses, is protective in rhesus macaques

A collaborative research team from Emory University, Bioqual, Moderna, and Johns Hopkins University, led by scientists at the National Institute of Allergy and Infectious Diseases Vaccine Research Center determined that a booster dose of the mRNA-1273 COVID-19 vaccine given to rhesus macaques about six months after their primary vaccine series significantly increased levels of neutralizing antibodies against all known SARS-CoV-2 variants of concern.

This study was conducted six months ago during a time in which the SARS-CoV-2 Beta variant was a major concern. The Beta variant has consistently shown the greatest ability to resist neutralization, likely reducing vaccine effectiveness. While Delta has become the dominant virus variant in the United States due to its high transmissibility, it only has a moderate ability to resist neutralization.

The researchers observed that increased neutralizing antibody responses were sustained for at least eight weeks after the boost. They also generated a higher level of protection by limiting virus replication in the lungs and nose, than after the primary vaccine series. These data suggest that boosting triggers a strong immune memory response and potentially longer lasting immunity.

The researchers concluded that an mRNA-1273 booster vaccine may improve the duration and potency of protection against upper and lower airway infection by any of the circulating SARS-CoV-2 variants. They note that this would be especially important to maintain protection against severe disease and possibly limit mild infection and virus transmission. Their results of the study support vaccine boosting for the elderly, people with pre-existing health conditions, those at high-risk exposure, and those who responded poorly to primary vaccination.

Upcoming Events:

NIMH Workshop on Advancing Training in Suicide Prevention Clinical Care

Wednesday, November 3, 2021, 11:00 am to Monday, November 8, 2021, 4:00 pm (registration required)

2021 Synthetic Biology Consortium Meeting

Thursday, November 4, 2021, 11:00 am to Friday, November 5, 2021, 3:00 pm (registration required)

The Child Opportunity Index: Health Equity Applications

Thursday, November 4, 2021, 2:00 pm to 3:30 pm

10th Annual David Derse Memorial Lecture and Award

Tuesday, November 16, 2021, 1:30 pm to 3:00 pm

NIH Rural Health Day Seminar

Thursday, November 18, 2021, 11:00 am to 5:30 pm (registration required)

NIH Behavioral and Social Sciences Research Festival

Thursday, November 18, 2021, 1:00 pm to Friday, November 19, 2021, 4:30 pm (registration required)

Cancer-related Emergency and Urgent Care: Prevention, Management, and Care Coordination

Wednesday, December 1, 2021 to Friday, December 3, 2021 (registration required)

NCI Symposium on Mutation Signatures and Cancer

Thursday, December 2, 2021 to Friday, December 3, 2021 (register by November 24)

The Meaning of Eugenics: Historical and Present-Day Discussions of Eugenics and Scientific Racism

Thursday, December 2, 2021, 10:00 am to Friday, December 3, 2021, 4:30 pm (registration required)

The post National Institutes of Health (NIH) Research Updates – November 2021 appeared first on Astrix.

Recent NIH Research

Breakthrough Treatment Brings Hope to Children with Tumor Disorder

September marks the annual Childhood Cancer Awareness month in which many organizations raise funds, host events and create awareness regarding cancers that have taken the lives of thousands of children. These donations help to fund critical research leading to the prevention and cure of childhood cancer in the hopes of reducing the mortality rate of children that are affected by these diseases.

One such disease is Neurofibromatosis type 1 (NF1), a disorder which usually appears in childhood and is predominantly inherited but can arise from a spontaneous genetic mutation. Symptoms are often noticeable as early as birth and almost always before age ten. This rare genetic disorder is characterized by light brown (café au lait) spots on the skin and non-cancerous nerve and skin tumors that can be painful, debilitating and at risk of becoming malignant. Treatment for this disease has been primarily focused on managing

the symptoms and often include surgery or radiation for the removal of tumors. Many of these tumors are inoperable within a tangle of nerves and generally grow back following surgery.

However, a breakthrough treatment is on the horizon. An IRP research team, led by Dr. Brigitte Widemann, senior investigator at the National Cancer Institute (NCI), Pediatric Oncology Branch, developed the first-ever drug approved by the FDA for the treatment of NF1. In honor of this ground-breaking work, Dr. Widemann, her IRP research team, and her collaborators outside NIH were named as finalists for the 2020 Samuel J. Heyman Service to America Medals, also known as the ‘Sammies,’ an award that honors exceptional work by government employees.

Dr. Widemann is a pediatric oncologist with the primary interest of developing effective therapies for children and adults with genetic tumor predisposition syndromes, such as NF1 and rare solid tumors for which there are no effective treatments. Prior research has shown that the mutation disrupts the RAS signaling pathway responsible for controlling normal cell growth and division. Mutations can keep the RAS pathway permanently switched on, leading to uncontrolled cell division and growth which result in the formation of tumors. Dr. Widemann and her colleagues set their focus on small molecule drugs that could inhibit or turn off the RAS pathway and ultimately slow or even stop progression of NF1 and possibly other tumor predisposition conditions.

Following a series of largely unsuccessful early-stage clinical trials with various therapies for children and young adults with NF1 and inoperable plexiform neurofibromas, Dr. Widemann and her team turned to a drug developed by AstraZeneca called selumetinib (Koselugo) that inhibits the activity of an enzyme involved in the RAS pathway. Although selumetinib had failed in a clinical trial for the treatment of metastatic breast cancer, it showed promising results for NF1 in a Phase I clinical trial conducted by Dr. Widemann’s group.

“For the first time ever, we were able to show that in the majority of patients, not only did the tumor stop growing, but there was actually shrinkage,” Dr. Widemann says. “That was really an amazing finding after many years of work, not only here in the Intramural program, but also with colleagues at our other study sites.”

In partnership with colleagues in NCI’s Cancer Therapy Evaluation Program, collaborators outside NIH, and AstraZeneca, Dr. Widemann and her team subsequently ran a second clinical trial with the intention of applying for FDA approval if results were positive. The trial was ultimately a success.

To further support the findings from the second clinical trial, the team also utilized data from a ‘natural history’ study of NF1, which provided a baseline understanding of how plexiform neurofibromas progress without treatment. Researchers could then compare that baseline with the rates of tumor growth seen in clinical trials. That long-term observational study followed 259 children over 10 years, and comparing tumor growth in children treated with selumetinib to children of the same age in the natural history study revealed that selumetinib not only shrank existing tumors, but also delayed the growth of new ones. As a result of their work, the FDA approved selumetinib as a treatment for children with NF1 and inoperable symptomatic plexiform neurofibromas in April 2020, with approval in Brazil and Europe following in 2021.

To continue their work, Dr. Widemann and her team are moving forward with additional clinical trials to determine if selumetinib is effective in adults with NF1, as well as looking for an effective therapy for patients whose NF1 tumors become aggressively cancerous. The team is also applying the knowledge learned from their work with NF1 to medullary thyroid cancer and other rare tumors. After years of working so closely with researchers both within and outside NIH, Dr. Widemann is pleased to see the group’s efforts recognized by the Sammy awards.

The American Childhood Cancer Organization (ACCO) encourages everyone to wear gold for the kids – all the survivors, the victims, as well as those who are still fighting the disease.

Monoclonal antibody prevents malaria in small NIH trial

Malaria is a serious and sometime fatal mosquito-borne disease caused by a parasite that commonly infects female Anopheles mosquitos that feed on humans. People with malaria often experience a flu-like illness, including a high fever and shaking chills.

In 2019 an estimated 229 million cases of malaria occurred worldwide and 409,000 people died, mostly children in the African Region. About 2,000 cases of malaria are diagnosed in the United States each year. The vast majority of cases in the United States are in travelers returning from countries where malaria transmission occurs, many from sub-Saharan Africa and South Asia.

In a new study, researchers from the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center (VRC) discovered and developed a new one-dose monoclonal antibody treatment capable of preventing malaria for up to nine months in people who were exposed to the malaria parasite. The small, carefully monitored clinical trial is the first to demonstrate that a monoclonal antibody can prevent malaria in people.

“Malaria continues to be a major cause of illness and death in many regions of the world, especially in infants and young children; therefore, new tools are needed to prevent this deadly disease,” said NIAID Director Dr. Anthony Fauci. “The results reported suggest that a single infusion of a monoclonal antibody can protect people from malaria for at least nine months. Additional research is needed, however, to confirm and extend this finding.”

Malaria is caused by Plasmodium parasites, which are transmitted to people through the bite of an infected mosquito. The mosquito injects the parasites in a form called sporozoites into the skin and bloodstream. These travel to the liver, where they mature and multiply, spreading throughout the body via the bloodstream to cause illness. P. falciparum is the species most likely to cause severe malaria infections and may lead to death if not promptly treated.

Prior studies have determined that antibodies can prevent malaria by neutralizing the sporozoites of P. falciparum in the skin and blood before they can infect liver cells. The NIAID clinical trial tested whether a neutralizing monoclonal antibody called CIS43LS could safely provide a high level of protection from malaria in adults following careful, voluntary, laboratory-based exposure to infected mosquitos in the United States.

A team of researchers led by Dr. Robert Seder, chief of the Cellular Immunology Section of the VRC, isolated a naturally occurring neutralizing antibody called CIS43 from the blood of a volunteer who had received an investigational malaria vaccine. The scientists found that CIS43 binds to a unique site on a parasite surface protein that is important for facilitating malaria infection and is common to all variants of P. falciparum sporozoites worldwide. The research team derived CIS43LS through modification to the CIS43 antibody, enabling it to remain in the bloodstream for an extended amount of time.

Following a successful study of CIS43LS for the prevention of malaria in animals, a Phase 1 clinical trial of the experimental antibody was launched voluntarily with 40 healthy adults ages 18 to 50 years who had never had malaria or been vaccinated for the disease. The trial, led by Dr. Martin Gaudinski, medical director of the VRC Clinical Trials Program, was conducted at the NIH Clinical Center, and the Walter Reed Army Institute of Research (WRAIR).

During the first half of the trial, the study team gave 21 participants one dose of CIS43LS by either an intravenous infusion or an injection under the skin. Investigators followed the participants for 6 months to learn whether the infusions and subcutaneous injections of the various doses of the experimental antibody were safe and well tolerated and the amount of CIS43LS in the blood was measured to determine its durability over time.

In the second half of the trial, nine participants who had received CIS43LS and six participants who served as controls voluntarily underwent controlled human malaria infection (CHMI) and were closely monitored for 21 days. Within that period, none of the nine participants who had received CIS43LS developed malaria, but five of the six controls did. The participants with malaria received standard therapy to eliminate the infection.

The results of the study indicate that just one dose of the experimental antibody can prevent malaria for 1 to 9 months after infusion. Collectively, these data provide the first evidence that administration of an anti-malaria monoclonal antibody is safe and can prevent malaria infection in humans. A larger NIAID Phase 2 clinical trial is underway in Mali to evaluate the safety and efficacy of CIS43LS at preventing malaria infection in adults during the six-month malaria season with results expected in early 2022.

NIH scientists develop faster COVID-19 test

Diagnostic testing is of vital importance in the fight against the COVID-19 pandemic. Standard tests for detection of SARS-CoV-2, the virus responsible for causing COVID-19, involve the amplification of viral RNA to detectable levels using a technique called real-time quantitative reverse transcription PCR (RT-qPCR). But first, the RNA must be extracted from the patient sample. Manufacturers of RNA extraction kits have had difficulty keeping up with the high demand during the COVID-19 pandemic, hindering testing capacity worldwide. With new virus variants emerging, the need for better, faster COVID-19 diagnostics tests is greater than ever.

To address this critical issue, research teams from the National Eye Institute (NEI), the NIH Clinical Center (CC), and the National Institute of Dental and Craniofacial Research (NIDCR) collaborated to develop a rapid sample preparation method to aid in the detection of SARS-Cov-2. This novel method eliminates the need for the extraction of the viral RNA, streamlining the testing process while decreasing the test time and the overall cost.

The IRP research team, led by Dr. Robert Hufnagel, chief of the NEI Medical Genetics and Ophthalmic Genomics Unit, and Dr. Bin Guan, a fellow at the NEI Ophthalmic Genomics Laboratory, used Bio-Rad’s Chelex 100 chelating resin to preserve SARS-CoV-2 RNA in samples for detection by RT-qPCR. The team made their discovery by testing a variety of chemicals using synthetic and human samples to identify those that could preserve the RNA in samples with minimal degradation while allowing direct detection of the virus by RT-qPCR.

“We used nasopharyngeal and saliva samples with various virion concentrations to evaluate whether they could be used for direct RNA detection,” said Dr. Guan, “The answer was yes, with markedly high sensitivity. Also, this preparation inactivated the virus, making it safer for lab personnel to handle positive samples.” In addition to the significant increase in sensitivity and RNA stability, this novel methodology will provide a reduction in cost and time for COVID-19 diagnostic testing.

Explosive Blasts Wreak Havoc in Inner Ear

The war on terrorism has increased the exposure of both military personnel and civilians to explosive blasts that can lead to long-term or permanent hearing and balance difficulties, among other adverse health effects. In a recent collaborative IRP study, research teams at  the National Institute on Deafness and Other Communication Disorders (NIDCD) and the Walter Reed Army Institute of Research (WRAIR) have gained important insights into the biological basis of those disabilities, which could eventually lead to more effective approaches to the prevention and treatment of concussive blast disorders.

During the wars in Afghanistan and Iraq, nearly half of American military deaths and 80 percent of injuries incurred have been related to home-made bombs called ‘improvised explosive devices’ (IEDs). Even when the heat and debris released by an IED doesn’t cause apparent bodily harm, the detonation can still produce a fast-moving wall of pressurized air, known as a ‘blast wave’, capable of causing damage to the brain and the delicate biological structures inside the ear involved in hearing and balance.

Despite the prevalence of the problem, little is known about exactly how blast waves lead to hearing and balance disorders. One reason is that much of the research surrounding how these forces affect the body rely on small, home-made ‘blast simulators’ that are often made from plastic PVC pipe, which are highly variable and generally do a poor job of approximating real-world explosions.

To solve this problem, NIDCD senior investigator, Dr. Matthew Kelley and his

lab teamed up with researchers at WRAIR who had access to a more advanced blast simulator that was carefully designed by engineers to produce more consistent blast waves that closely resemble those produced by real-life explosions. This new method was tested by exposing mice to simulated blasts either once or three times, and the effects on their hearing was assessed over a six month period. All the mice showed initial signs of severe hearing loss, and mice exposed to three blasts showed only minimal signs of recovery six months later.

To further explore the underlying cause of hearing loss, researchers examined the sensory hair cells located on the cochlea, the part of the inner ear responsible for converting sounds into electrical signals the brain can interpret. The inner hair cells did not show a decrease in number after the mice were exposed to blast waves. However, a decrease the number of connections between the inner hair cells and the spiral ganglion neurons that serve as the first stop for auditory signals traveling from the inner hair cells to the brain was observed. In humans, this change could contribute to a phenomenon called ‘hidden hearing loss’, which has been reported by many service members who have encountered explosions. This form of hearing loss causes difficulty hearing in noisy environments but does not show up on traditional hearing tests that rely on simple, pure tones produced in quiet surroundings.

“Hidden hearing loss is a relatively recent discovery,” says Dr. Beatrice Mao, the study’s first author and a postdoctoral fellow in Dr. Kelley’s lab. “It has to do not with a loss of cells, but a loss of the cells’ ability to transmit signals. It’s only identified when someone is given a test where they need to detect a specific sound amongst noise.”

The research team further observed a significant decrease in the number of outer hair cells, which assist in the pre-amplification of sounds before they reach the inner hair cells, and once lost they cannot grow back. Additionally, all mice in the study incurred damage to their eardrums, which help transfer sound energy to the hair cells in the inner ear.

The study results indicate that extremely loud sounds can damage the inner ear even without passing through the ear drum, such as by sending powerful vibrations to the inner ear through the skull. If this is the case, it would mean that in-ear hearing protection like earplugs may not be enough to protect hearing in these situations. Furthermore, since none of the mice showed obvious behavioral signs of balance problems nor changes to the vestibular hair cells in the inner ear that send balance-related information to the brain, the team hypothesized that the balance problems some people experience after encountering explosive blasts might be caused by traumatic brain injury or other mechanisms rather than damage to vestibular hair cells.

The findings of this study suggest that researchers working on treatments for blast-induced hearing loss might want to focus their efforts on preventing the loss of the outer hair cells or stimulating their regeneration.

NIH hamster study evaluates airborne and fomite transmission of SARS-CoV-2

In a new study, researchers from the National Institute of Allergy and Infectious Diseases (NIAID) Rocky Mountain Laboratories analyzed how different routes of exposure to SARS-CoV-2, the virus that causes COVID-19, are linked to disease severity.

To investigate how the various routes of exposure affected the development of COVID-19 disease, the team of researchers exposed Syrian hamsters to SARS-CoV-2 via both aerosols and contact with contaminated surfaces, called fomites. For aerosol exposure, the scientists used equipment that controlled the size of virus-loaded droplets. For fomite exposure, they placed a dish contaminated with SARS-CoV-2 in the animal cages.

The scientists determined that aerosol exposure directly deposited SARS-CoV-2 deep into the lungs, whereas fomite exposure resulted in initial virus replication in the nose. In both cases, the mice had SARS-CoV-2 replicating in the lungs, but lung damage was more severe in aerosol-exposed mice as compared to the fomite group.

The team also compared animal-to-animal transmission of the virus through the air and in contaminated cage environments (fomites). Airborne transmission was significantly more efficient than the fomite transmission, suggesting that airborne droplets are a key route of SARS-CoV-2 transmission. Additional testing, using air flowing from infected to uninfected mice, supported the finding. Reversing the airflow from uninfected to infected mice greatly reduced transmission efficiency. The study concluded that exposure from contaminated surface contact is markedly less efficient than airborne transmission but does occur.

The findings of this study support public health guidance focused on interventions to reduce indoor airborne transmission of SARS-CoV-2. These recommendations include masking, increasing air filtration and social distancing, as well as handwashing and regular surface disinfection, particularly in clinical settings.

Upcoming Events:

Bioinformatics and Computational Biology Symposium

Thursday, September 9, 2021, 9:30 am to 3:00 pm (registration required)

NINR Methodologies Boot Camp on Artificial Intelligence

Monday, September 13, 2021, 1:00 pm to Monday, September 27, 2021, 3:00 pm (registration required

Addressing One of the Most Enduring Challenges in Health Care: End-of-Life Decision Making

Tuesday, September 14, 2021, 10:00 am to 11:00 am (registration required)

Cancer Epidemiology in Hispanic Populations Workshop

Tuesday, September 14, 2021, 12:00 pm to Thursday, September 16, 2021, 4:30 pm (registration required)

Genetic Modifiers: Lessons from Nervous System Disorders

Tuesday, September 21, 2021, 10:00 am to Thursday, September 23, 2021, 2:00 pm (registration required)

Food Insecurity, Neighborhood Food Environment, and Nutrition Health Disparities: State of the Science

Tuesday, September 21, 2021, 12:30 pm to Thursday, September 23, 2021, 5:30 pm (registration required)

Department of Transfusion Medicine 40th Annual Symposium: Immunohematology & Blood Transfusion

Thursday, September 23, 2021, 9:00 am to 4:00 pm (register by September 8)

Methodological Approaches for Whole Person Research Workshop

Wednesday, September 29, 2021, 11:30 am to Thursday, September 30, 2021, 5:30 pm (registration required)

Advancing NIH Research on the Health of Women

Wednesday, October 20, 2021, 8:30 am to 5:00 pm (registration required)

NIH Behavioral and Social Sciences Research Festival

Friday, November 19, 2021, 9:00 am to 5:00 pm

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