Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) often make headlines. Read the news releases that describe our most recent findings:
Whether you’re shedding pounds with the help of effective new medicines, slimming down after weight loss surgery or cutting calories and adding exercise, there will come a day when the numbers on the scale stop going down, and you hit the dreaded weight loss plateau.
In a recent study, Kevin Hall, a researcher at the National Institutes of Health who specializes in measuring metabolism and weight change, looked at when weight loss typically stops depending on the method people were using todrop pounds. He broke down the plateau into mathematical models using data from high-quality clinical trials of different ways to lose weight to understand why people stop losing when they do. The study published Monday in the journal Obesity.
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.
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.
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.
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.
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.”
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.
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.
NIH scientists discover macromolecular complexes that could enable medication development
Scientists at the National Institute on Drug Abuse (NIDA) Intramural Research Program (IRP) have uncovered evidence that shows a more complex and elaborate role for the body’s hard-working G protein-coupled receptors (GPCRs) than previously thought, suggesting a conceptual advance in the fields of biochemistry and pharmacology. With more than 800 members in the human genome, GPCRs are the largest family of proteins involved in decoding signals as they come into the cell and then adapt the cell’s function in response. NIDA is part of the National Institutes of Health.
Manipulating how cells respond to signals is key to developing new medications. Although pharmacologists have studied GPCRs for many years, there is still a debate on how they operate — are they isolated units that randomly collide with each other or are they deliberately coupled together to receive signals? The NIDA scientists conclude that GPCRs form part of very elaborate pre-coupled macromolecular complexes. Simply put, they act as little computing devices that optimally gather and process information coming into the cell, allowing the cells to adapt and change their function.
“These findings represent many years of complex and highly nuanced science, following the trail as chemical signals travel through the body at the cellular level,” said NIDA Director Nora D. Volkow, M.D. “This remarkable discovery will open new avenues for medication development for addiction, pain and other conditions, offering more precise targets with fewer side effects.”
“The specific macromolecular complex investigated in this study has therapeutic implications not only for addiction, but also for Parkinson’s disease and schizophrenia,” said Dr. Sergi Ferré, who led the team of scientists. “Discovering that these protein interact with other signals in preformed complexes gives us more precise targets for medication development.”
Diuretic therapy — commonly given to extremely preterm infants to help them overcome respiratory problems — appears to offer no benefit for this purpose, according to an analysis by researchers at the National Institutes of Health. Surprisingly, infants in the study who received diuretic therapy were more likely to require respiratory support, compared to extremely preterm infants with similar respiratory problems who did not receive the therapy. The study is published in The Journal of Pediatrics.
Diuretic medicines prompt the kidneys to make more urine. The therapy is commonly given to preterm infants to help drain fluid from the lungs, but there is little research evidence to support the practice.
Researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Heart, Lung, and Blood Institute (NHLBI) analyzed data collected as part of the Prematurity and Respiratory Outcomes Program study, an effort to understand respiratory difficulties in extremely premature infants during the first year of life. The study included 835 infants born between 23 and 28 weeks at 13 U.S. neonatal intensive care units. An infant is considered full term at 39 weeks.
NIH discovery in mice could lead to therapies to reduce vision loss from diseases of the retina
Immune cells called microglia can completely repopulate themselves in the retina after being nearly eliminated, according to a new study in mice from scientists at the National Eye Institute (NEI). The cells also re-establish their normal organization and function. The findings point to potential therapies for controlling inflammation and slowing progression of rare retinal diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), the most common cause of blindness among Americans 50 and older. A report on the study was published online today in Science Advances. The NEI is part of the National Institutes of Health.
“Neuroinflammation is an important driver of the death of neurons in retinal diseases,” said Wai T. Wong, M.D., Ph.D., chief of the NEI Section on Neuron-Glia Interactions in Retinal Disease, and the study’s lead investigator. “Our study is foundational for understanding ways to control the immune system in the retina.” Control of the immune system is important for developing new treatments for a variety of eye conditions, including AMD, RP, or for certain types of retinal injury.
