Thursday, January 11, 2018
Finding promises to improve drug design for common forms of cancer.
The first three-dimensional structure of DHHC proteins — enzymes involved in many cellular processes, including cancer — explains how they function and may offer a blueprint for designing therapeutic drugs. Researchers have proposed blocking DHHC activity to boost the effectiveness of first-line treatments against common forms of lung and breast cancer. However, there are currently no licensed drugs that target specific DHHC enzymes. The study, led by researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), appears in the latest issue of Science. NICHD is part of the National Institutes of Health.
DHHC enzymes, also called palmitoyltransferases, modify other proteins by attaching to them a chain of lipids, or fatty acids, of varying lengths. This modification, called palmitoylation, can change many properties of a target protein, such as its structure, function and location within a cell. Researchers estimate that nearly 1,000 human proteins undergo palmitoylation, including epidermal growth factor receptors (EGFRs). A well-known EGFR is HER2, which is overactivated in aggressive forms of breast cancer. EGFRs can also be overactivated in colon cancer, and non-small cell lung cancer, the most common type of lung cancer.
The current study details the structures of a human DHHC enzyme, DHHC20, and the zebrafish version of another DHHC enzyme, DHHC15. Importantly, DHHC20 is the enzyme that palmitoylates EGFR. Previous studies have shown that blocking DHHC20 makes cancer cells more vulnerable to existing FDA-approved treatments that target EGFR. Therefore, understanding the structure of DHHC20 may be important for treating EGFR-driven cancers.
“Mutations in DHHC enzymes are associated with various cancers and neurological disorders,” according to Anirban Banerjee, Ph.D., the study’s lead author and head of NICHD’s Unit on Structural and Chemical Biology of Membrane Proteins. “Our study offers a starting point for developing DHHC20 inhibitors that may aid in treatment of common cancers and advance the field of protein palmitoylation.”
Molecular view of DHHC palmitoyltransferases. Human DHHC20 (yellow) is embedded in the Golgi membrane (green), a compartment located inside cells. DHHC20 attaches a fatty acid chain (white) to a target protein (blue, foreground), which anchors the protein to the Golgi membrane.
Thursday, January 11, 2018
Findings may aid design of trials to assess strategies to control HIV without drugs.
A short-term pause in HIV treatment during a carefully monitored clinical trial does not lead to lasting expansion of the HIV reservoir nor cause irreversible damage to the immune system, new findings suggest.
Antiretroviral therapy (ART) benefits the health of people living with HIV, prolongs their lives and prevents transmission of the virus to others. If taken daily as directed, ART can reduce viral load — the amount of HIV in the blood — to levels that are undetectable with standard tests. However, the virus remains dormant in a small number of immune cells, and people living with HIV must take ART daily to keep the virus suppressed. If a person with ART-suppressed HIV stops taking medication, viral load will almost invariably rebound to high levels.
Researchers are working to develop therapeutic strategies to induce sustained ART-free remission — the absence of viral rebound following discontinuation of ART. Clinical trials to assess the efficacy of such experimental therapies may require participants to temporarily stop taking ART, an approach known as analytical treatment interruption, or ATI.
A pill box containing once-daily antiretroviral treatments for HIV infection.
Wednesday, January 10, 2018
An experimental treatment developed from cattle plasma for Middle East respiratory syndrome (MERS) coronavirus infection shows broad potential, according to a small clinical trial led by National Institutes of Health scientists and their colleagues. The treatment, SAB-301, was safe and well tolerated by healthy volunteers, with only minor reactions documented.
The first confirmed case of MERS was reported in Saudi Arabia in 2012. Since then, the MERS coronavirus has spread to 27 countries and sickened more than 2,000 people, of whom about 35 percent have died, according to the World Health Organization. There are no licensed treatments for MERS.
SAB-301 was developed by SAB Biotherapeutics of Sioux Falls, South Dakota, and has been successfully tested in mice. The treatment comes from so-called “transchromosomic cattle.” These cattle have genes that have been slightly altered to enable them to produce fully human antibodies instead of cow antibodies against killed microbes with which they have been vaccinated — in this case the MERS virus. The clinical trial, conducted by NIH’s National Institute of Allergy and Infectious Diseases, took place at the NIH Clinical Center.
The round, spiked objects at center are MERS coronavirus particles.
Tuesday, January 2, 2018
Stem cell-derived retinal cells need primary cilia to support survival of light-sensing photoreceptors.
Scientists at the National Eye Institute (NEI), part of the National Institutes of Health, report that tiny tube-like protrusions called primary cilia on cells of the retinal pigment epithelium (RPE) — a layer of cells in the back of the eye — are essential for the survival of the retina’s light-sensing photoreceptors. The discovery has advanced efforts to make stem cell-derived RPE for transplantation into patients with geographic atrophy, otherwise known as dry age-related macular degeneration (AMD), a leading cause of blindness in the U.S. The study appears in the January 2 Cell Reports.
“We now have a better idea about how to generate and replace RPE cells, which appear to be among the first type of cells to stop working properly in AMD,” said the study’s lead investigator, Kapil Bharti, Ph.D., Stadtman Investigator at the NEI. Bharti is leading the development of patient stem cell-derived RPE for an AMD clinical trial set to launch in 2018.
In a healthy eye, RPE cells nourish and support photoreceptors, the cells that convert light into electrical signals that travel to the brain via the optic nerve. RPE cells form a layer just behind the photoreceptors. In geographic atrophy, RPE cells die, which causes photoreceptors to degenerate, leading to vision loss.
Mature iPSC-derived RPE cells under super resolution
Friday, December 22, 2017
Since 2016, when Zika was declared by WHO as a public health emergency of international concern, the virus has become established in more than 80 countries, infected millions of people, and left many babies with birth defects (collectively called congenital Zika syndrome). Although scientists have made progress in their understanding of the virus and its mosquito carrier, and are working toward treatments and a preventive vaccine, it would be premature to think that the Zika pandemic is now under control and will not reemerge, perhaps more aggressively, say leaders from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The Journal of Infectious Diseases published online December 16 a special supplement of articles examining current scientific knowledge about the Zika virus and the key research questions that remain. The supplement was sponsored and edited by NIAID and features several articles written by NIAID scientists.
Zika virus particles (red) shown in African green monkey kidney cells
Thursday, December 21, 2017
Plant molecule could be used to block postoperative incisional pain.
A promising approach to post-operative incision-site pain control uses a naturally occurring plant molecule called resiniferatoxin (RTX). RTX is found in Euphorbia resinifera, a cactus-like plant native to Morocco, which is 500 times more potent than the chemical that produces heat in hot peppers, and may help limit the use of opioid medication while in the hospital and during home recovery.
In a paper published online in Anesthesiology, the peer-reviewed medical journal of the American Society of Anesthesiologists, researchers found that RTX could be used to block postoperative incisional pain in an animal model. Many medical providers turn to opioids, such as morphine or fentanyl, for moderate to severe post-operative pain relief, but these often come with side effects that can interfere with recovery, including respiratory depression, inhibition of gut motility and constipation, nausea and vomiting. Prolonged use of opioids can produce tolerance and introduces the risk of misuse. RTX is not an opioid and does not act in the brain but rather on the nerve endings in the skin. Scientists found that it can be used to block pain from the surgical incision selectively for approximately 10 days.
Wednesday, December 20, 2017
Using fruit flies, NIH researchers provide molecular basis for theory of aging.
A shorter life may be the price an organism pays for coping with the natural assaults of daily living, according to researchers at the National Institutes of Health and their colleagues in Japan. The scientists used fruit flies to examine the relationship between lifespan and signaling proteins that defend the body against environmental stressors, such as bacterial infections and cold temperatures. Since flies and mammals share some of the same molecular pathways, the work may demonstrate how the environment affects longevity in humans.
Appearing in the Proceedings of the National Academy of Sciences, the research identified Methuselah-like receptor-10 (Mthl10), a protein that moderates how flies respond to inflammation. The finding provides evidence for one theory of aging, which suggests longevity depends on a delicate balance between proinflammatory proteins, thought to promote aging, and anti-inflammatory proteins, believed to prolong life. These inflammatory factors are influenced by what an organism experiences in its every day environment.
Corresponding author Stephen Shears, Ph.D., of the National Institute of Environmental Health Sciences (NIEHS) at NIH, explained that Mthl10 appears on the surface of insect cells and acts as the binding partner to a signaling molecule known as growth-blocking peptide (GBP). Once Mthl10 and GBP connect, they initiate the production of proinflammatory proteins, which, in turn, shortens the fly’s life. However, removing the Mthl10 gene makes the flies unable to produce Mthl10 protein and prevents the binding of GBP to cells. As a result, the flies experienced low levels of inflammation and longer lifespans.
"Fruit flies without Mthl10 live up to 25 percent longer," Shears said. "But, they exhibit higher death rates when exposed to environmental stressors."
The binding of GBP to Mthl10 promotes inflammation, which decreases the lifespan of a fruit fly. In contrast, the removal of GBP’s binding partner Mthl10, produces less inflammation and increases the lifespan of the fly.
Tuesday, December 19, 2017
Researchers find target to protect hearing during chemotherapy treatment.
Scientists have found a new way to explain the hearing loss caused by cisplatin, a powerful drug used to treat many forms of cancer. Using a highly sensitive technique to measure and map cisplatin in mouse and human inner ear tissues, researchers found that forms of cisplatin build up in the inner ear. They also found a region in the inner ear that could be targeted for efforts to prevent hearing loss from cisplatin. The study is published in Nature Communications, and was supported by the National Institute on Deafness and other Communications Disorders (NIDCD), part of the National Institutes of Health.
Cisplatin and similar platinum-based drugs are prescribed for an estimated 10 to 20 percent of all cancer patients. The NIH’s National Cancer Institute supported research that led to the 1965 discovery of cisplatin and continued development leading to its success as an essential weapon in the battle against cancer. The drugs cause permanent hearing loss in 40 to 80 percent of adult patients and at least half of children who receive the drug. The new findings help explain why cisplatin is so toxic to the inner ear, and why hearing loss gets worse after each treatment, can occur long after treatment, and is more severe in children than adults.
Cisplatin (appearing in green) in the stria vascularis of a mouse inner ear.
Thursday, December 14, 2017
Scientists have identified differences in a group of genes they say might help explain why some people need a lot more sleep — and others less — than most. The study, conducted using fruit fly populations bred to model natural variations in human sleep patterns, provides new clues to how genes for sleep duration are linked to a wide variety of biological processes.
Researchers say a better understanding of these processes could lead to new ways to treat sleep disorders such as insomnia and narcolepsy. Led by scientists with the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, the study will be published on Dec. 14 in PLOS Genetics.
“This study is an important step toward solving one of the biggest mysteries in biology: the need to sleep,” says study leader Susan Harbison, Ph.D., an investigator in the Laboratory of Systems Genetics at NHLBI. “The involvement of highly diverse biological processes in sleep duration may help explain why the purpose of sleep has been so elusive.”
Graph showing sleep duration (in minutes) of wild fruit flies—long sleepers, normal sleepers, and short sleepers—artificially bred across 13 generations.
Monday, December 4, 2017
Vaccine developed by NIH scientists shows promise in Phase 1 testing.
Results from two Phase 1 clinical trials show an experimental Zika vaccine developed by government scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is safe and induces an immune response in healthy adults. The findings will be published on Dec. 4 in The Lancet. NIAID is currently leading an international effort to evaluate the investigational vaccine in a Phase 2/2b safety and efficacy trial.
“Following early reports that Zika infection during pregnancy can lead to birth defects, NIAID scientists rapidly created one of the first investigational Zika vaccines using a DNA-based platform and began initial studies in healthy adults less than one year later,” said NIAID Director Anthony S. Fauci, M.D. “NIAID has begun Phase 2 testing of this candidate to determine if it can prevent Zika virus infection, and the promising Phase 1 data published today support its continued development.”
Investigators from NIAID’s Vaccine Research Center (VRC) and Laboratory of Viral Diseases, part of the Division of Intramural Research, developed the investigational vaccine, which includes a small, circular piece of DNA called a plasmid. Scientists inserted genes into the plasmid that encode two proteins found on the surface of the Zika virus. After the vaccine is injected into muscle, the body produces proteins that assemble into particles that mimic the Zika virus and trigger the body to mount an immune response.