Monday, April 16, 2018
IRP scientists report single dose elicited long-term protection
Two genetically modified broadly neutralizing antibodies (bNAbs) protected rhesus macaques from an HIV-like virus, report scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. After introducing genetic mutations into two potent HIV bNAbs, researchers prepared intravenous infusions of two bNAbs known as 3BNC117-LS and 10-1074-LS. Single infusions of each modified bNAb protected two groups of six monkeys each against weekly exposures to simian-human immunodeficiency virus (SHIV) for up to 37 weeks, compared with a median of three weeks in 12 monkeys receiving no antibody. SHIV is a manmade virus commonly used in HIV nonhuman primate studies.
The study, led by Malcolm A. Martin, M.D., chief of the NIAID Laboratory of Molecular Microbiology, also assessed the efficacy of injecting a combination of both modified bNAbs into six monkeys subcutaneously — a route of administration considered more feasible in resource-limited clinical settings. This bNAb mixture, administered at a three-fold lower concentration than the individual antibodies infused intravenously, protected this group of monkeys for a median of 20 weeks.
This human T cell (blue) is under attack by HIV (yellow), the virus that causes AIDS. The virus specifically targets T cells, which play a critical role in the body's immune response against invaders like bacteria and viruses.
Monday, April 16, 2018
Study provides insights into the immune system’s role in recovery after concussion in mice
Following head injury, the protective lining that surrounds the brain may get a little help from its friends: immune cells that spring into action to assist with repairs. In a new study, scientists from the National Institutes of Health watched in real-time as different immune cells took on carefully timed jobs to fix the damaged lining of the brain, also known as meninges, in mice. These results may help provide clues to the discovery that the meninges in humans may heal following mild traumatic brain injury (mTBI) and why additional hits to the head can be so devastating.
“The lining of the brain, with help from the immune system, has a remarkable ability to put itself back together again after injury,” said Dorian McGavern, Ph.D., scientist at the NIH’s National Institute of Neurological Disorders and Stroke and the senior author of the study published in Nature Immunology. “As we learn more about all the cells involved in the repair process, we may be able to identify potential targets for therapy that lead to better outcomes for patients.”
The study came about from an observation on MRI scans of adult patients who experienced a concussion or mTBI. Around half of patients with mTBI show evidence of injury to blood vessels in the meninges, which appears on MRI scans as a vascular dye leaking out of the damaged vessels.
One day after head injury (left), bright dye along the edge of the brain suggests damage to the meninges, or the brain’s protective lining. After 35 days (right), the dye no longer appears, indicating the meninges may have healed.
Friday, April 13, 2018
Preliminary IRP study shows increased levels of beta-amyloid
Losing just one night of sleep led to an immediate increase in beta-amyloid, a protein in the brain associated with Alzheimer’s disease, according to a small, new study by researchers at the National Institutes of Health. In Alzheimer’s disease, beta-amyloid proteins clump together to form amyloid plaques, a hallmark of the disease.
While acute sleep deprivation is known to elevate brain beta-amyloid levels in mice, less is known about the impact of sleep deprivation on beta-amyloid accumulation in the human brain. The study is among the first to demonstrate that sleep may play an important role in human beta-amyloid clearance.
“This research provides new insight about the potentially harmful effects of a lack of sleep on the brain and has implications for better characterizing the pathology of Alzheimer's disease,” said George F. Koob, Ph.D., director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, which funded the study.
Beta-amyloid is a metabolic waste product present in the fluid between brain cells. In Alzheimer’s disease, beta-amyloid clumps together to form amyloid plaques, negatively impacting communication between neurons.
Led by Drs. Ehsan Shokri-Kojori and Nora D. Volkow of the NIAAA Laboratory of Neuroimaging, the study is now online in the Proceedings of the National Academy of Sciences. Dr. Volkow is also the director of the National Institute on Drug Abuse at NIH.
Brain imaging after one night of sleep deprivation revealed beta-amyloid accumulation in the hippocampus and thalamus, regions affected by Alzheimer’s disease.
Wednesday, April 11, 2018
Study finds gene mutations that cause “dripping candle wax” bone disease
Researchers at the National Institutes of Health worked with 15 patients from around the world to uncover a genetic basis of “dripping candle wax” bone disease. The rare disorder, known as melorheostosis, causes excess bone formation that resembles dripping candle wax on x-rays. The results, appearing in Nature Communications, offer potential treatment targets for this rare disease, provide important clues about bone development, and may lead to insights about fracture healing and osteoporosis.
Though there are only about 400 known cases of this disorder worldwide, 15 unrelated adults with the condition from around the globe volunteered to come to the NIH Clinical Center to undergo biopsies of both affected and unaffected bones. The condition causes pain and bone deformity, which can limit the function of bones.
“Scientists previously assumed that the genetic mutations responsible for melorheostosis occurred in all cells of a person with the disorder,” said co-senior author Timothy Bhattacharyya, M.D., head of the Clinical and Investigative Orthopaedics Surgery Unit at the National Institute on Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at NIH. “Our team hypothesized that mutations might only occur in the affected bone tissue.”
An x-ray image of a patient with melorheostosis shows excess bone formation, likened to dripping candle wax.
Wednesday, April 11, 2018
In a new study, researchers identified genetic subtypes of diffuse large B-cell lymphoma (DLBCL) that could help explain why some patients with the disease respond to treatment and others don’t. The study, led by researchers in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI), part of the National Institutes of Health, with additional authors from several institutions around the world, was published online April 11, 2018, in The New England Journal of Medicine.
DLBCL is the most common type of lymphoma. Although it can be aggressive, it is potentially curable, and in some patients treatment eliminates the disease. However, researchers still don’t have a full understanding of why some lymphomas of this type respond to treatment and others don’t. The standard treatment for the disease is a combination of chemotherapy drugs plus rituximab, a drug known as a monoclonal antibody.
Several years ago, researchers defined two major subgroups of DLBCL that arise from different cells of origin and that have different patterns of gene activity. They found that patients with activated B-cell-like (ABC) DLBCL have about a 40 percent average survival rate, while those with germinal center B-cell-like (GCB) DLBCL have about a 75 percent average survival rate. But even in the GCB subgroup, many patients experience disease relapse after treatment.
“The first question we wanted to tackle was whether there were other molecular features of the tumors that could help us explain why some people were well-served by chemotherapy,” explained Louis M. Staudt, M.D., Ph.D., of NCI’s CCR, who led the new study. “And the second, related question was, if we could understand who was not responding well to treatment, could we understand the genetics of these tumors to suggest new potential therapies beyond chemotherapy? The answer to both questions was ‘yes.’”
Subgroups of DLBCL by gene expression (left) defined several years ago. Genetic subtypes identified in the new study (right) that each share a group of genetic aberrations. Curved connectors indicate relationships between the subgroups and subtypes.
Monday, April 9, 2018
Crimean-Congo hemorrhagic fever (CCHF) is a viral disease spread by ticks in the Middle East, Asia, Africa and parts of Europe. Infection with CCHF virus is fatal in nearly one of every three cases. No specific treatments or vaccines for CCHF exist, primarily because a suitable animal model for studying the disease has not been available. Scientists have used mice to study CCHF but had to weaken their immune systems to cause infection. Studies in larger animals have not consistently replicated human disease.
Now, as reported in Nature Microbiology, researchers have developed a new animal model to study the disease. Scientists at the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, conducted a pilot study using CCHF virus to infect African green monkeys, rhesus macaques, and cynomolgus macaques. The strain of the virus they used, known as Kosova Hoti, was isolated from the blood of a person who died of CCHF. Most prior animal modeling studies had used a different viral strain isolated from a tick found in Nigeria.
The first two monkey species showed no signs of disease using various inoculation methods. Two of three cynomolgus macaques, however, developed disease. That led to a larger study of 12 cynomolgus macaques, four each inoculated under the skin, intravenously, or a combination of both. Within three days, all eight animals in the combination and intravenous groups showed signs of infection that led to severe disease. Two of the four animals inoculated under the skin developed mild signs of disease while the other two remained symptom-free.
Scanning electron micrograph of CCHF viral particles (yellow) budding from the surface of cultured epithelial cells from a patient.
Thursday, April 5, 2018
Results could advance treatments for head and neck and other cancers
Researchers supported by the National Institutes of Health have uncovered molecular characteristics that link the genomic profiles of squamous cell carcinomas (SCCs) from five areas of the body and that set these SCCs apart from other cancers. Using a robust dataset of SCCs from the head and neck, lung, esophagus, cervix, and bladder, the researchers also found defining characteristics in subtypes of SCCs associated with tobacco use or human papillomavirus (HPV) infection. This research may lead to more effective diagnosis and treatment of these cancers by helping researchers develop tailored strategies for specific cancer subtypes.
Published in Cell Reports, the study was led by Carter Van Waes, M.D., Ph.D., and his colleague Zhong Chen, M.D., Ph.D., from the Head and Neck Surgery Branch of NIH’s National Institute on Deafness and Other Communication Disorders (NIDCD). They collaborated with teams of researchers across the United States and Canada through The Cancer Genome Atlas (TCGA) consortium, a joint effort of the NIH’s National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI).
The study is one of 27 papers published in Cell journals this month, that describe important results from the PanCancer Atlas, a detailed analysis from a dataset containing molecular and clinical information on more than 10,000 tumors from 33 forms of cancer. The PanCancer Atlas is a culmination of more than a decade of work by more than 150 TCGA researchers at institutions across North America.
Monday, April 2, 2018
NIH researchers suggest lifestyle changes may reduce hypertension risk
Elevated blood pressure before conception may increase the chances for pregnancy loss, according to an analysis by researchers at the National Institutes of Health. The authors conclude that lifestyle changes to keep blood pressure under control could potentially reduce the risk of loss. The study appears in Hypertension.
The analysis found that for every 10 mmHg increase in diastolic blood pressure (pressure when the heart is resting between beats), there was an 18-percent-higher risk for pregnancy loss among the study population. Millimeter of mercury, or mmHg, is the unit of measure used for blood pressure. The researchers also found a 17 percent increase in pregnancy loss for every 10 mmHg increase in mean arterial pressure, a measure of the average pressure in the arteries during full heart beat cycles. The study was conducted by researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
“Elevated blood pressure is linked to heart disease, stroke, and kidney disease” said the study’s senior author, Enrique Schisterman, Ph.D., chief of the Epidemiology Branch at NICHD. “Our findings suggest that attaining a healthy blood pressure before pregnancy could not only have benefits later in life, but also reduce the chances for pregnancy loss.”
Monday, April 2, 2018
Scientists have developed a novel technique that prevents coronary artery obstruction during transcatheter aortic valve replacement (TAVR), a rare but often fatal complication. The method, called Bioprosthetic Aortic Scallop Intentional Laceration to prevent Iatrogenic Coronary Artery obstruction (BASILICA), will increase treatment options for high-risk patients who need heart valve procedures. The findings by researchers at the National Institutes of Health will publish in the Journal of the American College of Cardiology: Cardiovascular Interventions on April 2.
TAVR, a procedure used to treat aortic valve stenosis, involves threading a long, thin, flexible tube, called a catheter, through the femoral artery in the leg to the heart. Aortic valve stenosis is a fatal narrowing of the valve controlling blood leaving the heart to the rest of the body. This narrowing reduces blood flow to vital organs, resulting in shortness of breath, chest pain, blackouts, and heart failure.
For elderly or frail patients, TAVR offers an effective and less invasive alternative to open heart surgery. However, a small subset of these patients may develop coronary artery obstruction during the TAVR procedure. For more than half the patients who experience coronary artery obstruction during the TAVR, this complication has been fatal.
BASILICA was developed by Jaffar M. Khan, M.D., at the National, Heart, Lung, and Blood Institute (NHLBI), part of NIH, to increase the safety of TAVR for this subset of patients.
“These patients are either not eligible for conventional TAVR, or they are at high risk for it,” said Robert J. Lederman, M.D., the senior investigator in NHLBI’s Division of Intramural Research who led the study with Khan.
Illustration of the BASILICA procedure. (A) a catheter directs an electrified guidewire through the base of the left aortic cusp into a snare in the left ventricular outflow tract; (B) after snare retrieval, the mid-shaft of the guidewire is electrified to lacerate the leaflet (C); (D) the leaflet splays after TAVR permitting coronary flow.
Thursday, March 29, 2018
Researchers identify protective role of iron export protein and its mutation
Researchers at the National Institutes of Health have a possible explanation for why iron can sometimes worsen malaria infection. By studying mice and samples from malaria patients, the researchers found that extra iron interferes with ferroportin, a protein that prevents a toxic buildup of iron in red blood cells and helps protect these cells against malaria infection. They also found that a mutant form of ferroportin that occurs in African populations appears to protect against malaria. These basic findings, published in Science, may help researchers and healthcare officials develop strategies to prevent and treat malaria infections, which numbered nearly 216 million worldwide in 2016.
“Our study helps solve a long-standing mystery,” said Tracey Rouault, M.D., the study’s senior author and a senior investigator at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). “Iron supplements can sometimes worsen malaria infection and, conversely, iron deficiency can be protective in some cases. Our findings reveal that ferroportin — its function, as well as its regulation by iron levels — helps to explain these observations.”
Electron micrograph of red blood cells infected with Plasmodium falciparum, the parasite that causes malaria in humans. During its development, the parasite forms protrusions called 'knobs' on the surface of its host red blood cell which enable it to avoid destruction and cause inflammation.