A clinical trial led by the National Cancer Institute (NCI), part of the National Institutes of Health, has resulted in the first approval of a treatment for advanced alveolar soft part sarcoma (ASPS). The immunotherapy drug atezolizumab (Tecentriq) was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults and children 2 years and older with ASPS that has spread to other parts of the body or cannot be removed by surgery.
ASPS is an extremely rare cancer that affects mostly adolescents and young adults. The approval was based on data from a non-randomized phase 2 trial funded by NCI and led by Dr. Alice Chen, M.D., of the Developmental Therapeutics Clinic in NCI’s Division of Cancer Treatment and Diagnosis (DCTD). Genentech, a member of the Roche Group and the manufacturer of atezolizumab, provided the drug to NCI through a cooperative research and development agreement. The results of the study are being prepared for publication.
“Forty percent of the patients were treated at the NIH Clinical Center in Bethesda," said James H. Doroshow, M.D., director of DCTD. “Our ability to bring patients in from all over the world was a key factor in the ability to do the study.”
“This approval will make a huge impact in terms of a rare disease that has been particularly challenging to treat,” Dr. Chen noted.
Scientists used patient stem cells and 3D bioprinting to produce eye tissue that will advance understanding of the mechanisms of blinding diseases. The research team from the National Eye Institute (NEI), part of the National Institutes of Health, printed a combination of cells that form the outer blood-retina barrier — eye tissue that supports the retina's light-sensing photoreceptors. The technique provides a theoretically unlimited supply of patient-derived tissue to study degenerative retinal diseases such as age-related macular degeneration (AMD).
"We know that AMD starts in the outer blood-retina barrier," said Kapil Bharti, Ph.D., who heads the NEI Section on Ocular and Stem Cell Translational Research. "However, mechanisms of AMD initiation and progression to advanced dry and wet stages remain poorly understood due to the lack of physiologically relevant human models."
The outer blood-retina barrier consists of the retinal pigment epithelium (RPE), separated by Bruch’s membrane from the blood-vessel rich choriocapillaris. Bruch's membrane regulates the exchange of nutrients and waste between the choriocapillaris and the RPE. In AMD, lipoprotein deposits called drusen form outside Bruch's membrane, impeding its function. Over time, the RPE break down leading to photoreceptor degeneration and vision loss.
Steep, recent increase indicates COVID-19 associated with higher risk of endocarditis, NIH-supported study finds
The incidence rate of infective endocarditis — a rare but often fatal inflammation of the heart valves — among patients with cocaine use disorder or opioid use disorder increased from 2011 to 2022, with the steepest increase occurring from 2021 to 2022, a new study reports. Study findings contribute to expanding evidence of endocarditis as a significant and growing health concern for people who inject drugs, and further demonstrate that this risk has been exacerbated during the COVID-19 pandemic.
Among patients with either substance use disorder, those who were clinically diagnosed with COVID-19 faced a higher risk of a new endocarditis diagnosis as well as hospitalization following this diagnosis than those without COVID-19. Over the full 12-year period, the rate of endocarditis was three to eight times greater in patients with opioid and cocaine use disorder than those without.
The findings also showed that Black and Hispanic people faced a lower risk of COVID-19-associated endocarditis than non-Hispanic white people. The authors note this is consistent with higher prevalence of injection drug use in non-Hispanic white populations, compared to black or Hispanic populations. The study published today in Molecular Psychiatry, funded by agencies across the National Institutes of Health and led by the National Institute on Drug Abuse (NIDA).
“People with substance use disorder already face major impediments to proper healthcare due to lack of access and stigma,” said NIDA Director and co-corresponding study author, Nora D. Volkow, M.D. “Proven techniques like syringe service programs, which help people avoid infection from re-used or shared injection equipment, can help prevent this often fatal and costly condition.”
NIH findings may help researchers understand how genomic variation can affect behavioral differences in humans
National Institutes of Health researchers have shown that areas of the genome related to brain development harbor variants that may account for behavioral differences among different dog lineages. The study, funded by the National Human Genome Research Institute (NHGRI) and published in the journal Cell, involved citizen science projects that used DNA samples and surveys collected from dog owners around the world.
The researchers found that the genomic differences among dog breeds are related to the development of their nervous system. For dogs that herd sheep, the genomic differences involve how brain nerve cells, known as neurons, organize themselves to form neural circuits during the early stages of development.
Some of the genes associated with the different dog lineages may relate to genes that are involved in behavior of other species such as humans. These results suggest that dogs and humans may have similar biological pathways that give rise to the range of differences in brain function and behavior found within a species.
New study uses postmortem brain tissues to understand genomic differences in individuals with attention deficit hyperactivity disorder
Researchers at the National Institutes of Health have successfully identified differences in gene activity in the brains of people with attention deficit hyperactivity disorder (ADHD). The study, led by scientists at the National Human Genome Research Institute (NHGRI), part of NIH, found that individuals diagnosed with ADHD had differences in genes that code for known chemicals that brain cells use to communicate. The results of the findings, published in Molecular Psychiatry, show how genomic differences might contribute to symptoms.
To date, this is the first study to use postmortem human brain tissue to investigate ADHD. Other approaches to studying mental health conditions include non-invasively scanning the brain, which allows researchers to examine the structure and activation of brain areas. However, these studies lack information at the level of genes and how they might influence cell function and give rise to symptoms.
The researchers used a genomic technique called RNA sequencing to probe how specific genes are turned on or off, also known as gene expression They studied two connected brain regions associated with ADHD: the caudate and the frontal cortex. These regions are known to be critical in controlling a person’s attention. Previous research found differences in the structure and activity of these brain regions in individuals with ADHD.
NIH researchers find IV administration improves tumor-fighting action
An experimental therapeutic cancer vaccine induced two distinct and desirable immune system responses that led to significant tumor regression in mice, report investigators from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
The researchers found that intravenous (IV) administration of the vaccine boosted the number of cytotoxic T cells capable of infiltrating and attacking tumor cells and engaged the innate immune system by inducing type I interferon. The innate immune response modified the tumor microenvironment, counteracting suppressive forces that otherwise would tamp down T-cell action. Modification of the tumor microenvironment was not seen in mice that received the vaccine via needle injection into the skin (subcutaneous administration).
Dubbed “vax-innate” by the scientific team, the approach achieves an important goal in the quest for more effective immunotherapeutic vaccines for cancer. The study demonstrates that IV vaccine delivery enables and enhances T-cell immunity by overcoming tumor-induced immunosuppressive activity. The researchers say the candidate vaccine might also be given intravenously to people who have already received tumor-specific T cells as a therapy. It also could improve tumor control by increasing the number of T cells and altering the tumor microenvironment to make them function better, the researchers note.
Lawrence A. Tabak, D.D.S., Ph.D., who is performing the duties of the National Institutes of Health director, has selected Joni L. Rutter, Ph.D., as director of NIH’s National Center for Advancing Translational Sciences (NCATS). Dr. Rutter has served as NCATS acting director since April 2021. She officially began her role as NCATS director on Nov. 6, 2022.
Dr. Rutter will oversee a diverse portfolio of research activities focused on improving the translational process of turning scientific discoveries into health interventions. The portfolio includes the Clinical and Translational Science Awards (CTSA) Program, which is one of NIH’s largest supported programs and has played an important role in the agency’s COVID-19 response. In addition, she will direct innovative research programs to advance diagnoses and treatments, including gene therapies, for some of the more than 10,000 known rare diseases. She also will lead labs at NIH that drive team science with the private sector to create and test innovative methods for improving the drug development process.
“Dr. Rutter took the helm at NCATS during the most critical public health challenge of our time,” said Dr. Tabak. “Throughout her scientific career and leadership roles at NIH, she has been at the forefront of many exciting and innovative initiatives, and I have great confidence that she will lead NCATS in accelerating the development paths for turning discoveries into treatments.”
NIH researchers develop new tools to demonstrate how environmental agents can lead to diseases
Researchers have developed a three-dimensional model that shows how exposure to cadmium might lead to congenital heart disease. Affecting nearly 40,000 newborns a year, congenital heart disease is the most common type of birth defect in the United States. The model was created by scientists at the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health.
Cadmium is a metal that can be released into the environment through mining and various industrial processes, and it has been found in air, soil, water, and tobacco. The metal can enter the food chain when plants absorb it from soil. Previous studies suggested that maternal exposure to cadmium might be a significant risk factor for congenital heart disease.
Using models derived from human cells and tissues, called in vitro models, researchers designed a 3D organoid model that mimics how the human heart develops. The researchers saw how exposure to low levels of cadmium can block usual formation of cardiomyocytes, which are the major type of cells that form the heart. In doing so, they revealed the biological mechanisms that might explain how cadmium could induce heart abnormalities.
“The models we created are useful for not only studying cadmium, but for studying other chemicals and substances as well,” said study lead Erik Tokar, Ph.D., from the Mechanistic Toxicology Branch of the NIEHS Division of Translational Toxicology (DTT).
Research explores how new information is consolidated across the sleep-wake cycle
Using a mouse model, researchers have discovered a new daily rhythm in a type of synapse that dampens brain activity. Known as inhibitory synapses, these neural connections are rebalanced so that we can consolidate new information into long-lasting memories during sleep. The findings, published in PLOS Biology, may help explain how subtle synaptic changes enhance memory in humans. The study was led by researchers at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
“Inhibition is important for every aspect of brain function. But for over two decades, most sleep studies have focused on understanding excitatory synapses,” said Dr. Wei Lu, senior investigator at NINDS. “This is the first study to try to understand how sleep and wakefulness regulate inhibitory synapses.”
In the study, Kunwei Wu, Ph.D., a postdoctoral fellow in Dr. Lu’s lab, examined what happens at inhibitory synapses during sleep and wakefulness in mice. Electrical recordings from neurons in the hippocampus — a brain region important for memory formation — showed a previously unappreciated pattern of activity. During wakefulness, steady 'tonic' inhibitory activity increased, while fast 'phasic' inhibition decreased. They also found much larger activity-dependent enhancement of inhibitory electrical responses in neurons from awake mice suggesting that wakefulness, but not sleep, could strengthen these synapses to a greater degree.
One dose of an antibody drug safely protected healthy, non-pregnant adults from malaria infection during an intense six-month malaria season in Mali, Africa, a National Institutes of Health clinical trial has found. The antibody was up to 88.2% effective at preventing infection over a 24-week period, demonstrating for the first time that a monoclonal antibody can prevent malaria infection in an endemic region. These findings were published today in The New England Journal of Medicine and presented at the American Society of Tropical Medicine & Hygiene 2022 Annual Meeting in Seattle.
“We need to expand the arsenal of available interventions to prevent malaria infection and accelerate efforts to eliminate the disease,” said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. “These study results suggest that a monoclonal antibody could potentially complement other measures to protect travelers and vulnerable groups such as infants, children, and pregnant women from seasonal malaria and help eliminate malaria from defined geographical areas.”
NIAID sponsored and funded the trial, which was led by Peter D. Crompton, M.D., M.P.H., and Kassoum Kayentao, M.D., M.P.H., Ph.D. Dr. Crompton is chief of the Malaria Infection Biology and Immunity Section in the NIAID Laboratory of Immunogenetics, and Dr. Kayentao is a professor at the University of Sciences, Techniques and Technologies (USTTB) of Bamako, Mali.