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September 6th, 2020

Mosquito Immune System Mapped to Help Fight Malaria; Scientists Study “Sweet Spot” of Mosquito’s Immunity to Plasmodium—Enough Not to Get Sick, But Not Enough to Eliminate the Parasite; May Find Clues to Aid Struggles Against This Still Invincible Disease

Scientists from Umeå and the United States have created the first cell atlas of mosquito immune cells, in an attempt to understand how mosquitoes fight malaria and other infections. The scientists have discovered a rare immune cell type that could be involved in limiting malaria infection and identified molecular pathways involved in controlling the malaria parasite. The results were published in the August 28, 2020 issue of Science. The article is titled “Mosquito Cellular Immunity at Single-Cell Resolution.” The study was conducted by scientists from Umeå University, the Wellcome Sanger Institute, and the National Institutes of Health (NIH), USA. “Our results provide an opportunity to reveal new ways to break the chain of malaria transmission and prevent mosquitoes from spreading the malaria parasite to humans. “The atlas will also be a valuable resource for researchers trying to understand and control other mosquito-borne diseases such as dengue or Zika,” says Oliver Billker, PhD, Professor at the research center Molecular Infection Medicine Sweden (MIMS) at Sweden’s Umeå University, and joint senior author on the paper. Malaria is a life-threatening disease that affects more than 200 million people worldwide and caused an estimated 405,000 deaths in 2018 alone, the majority of which were children under five. It is caused by Plasmodium parasites, which are spread via the bites of female Anopheles mosquitoes. Breaking the chain of transmission from human to mosquito to human is key for reducing the burden of malaria. The mosquito immune system controls how the insect can tolerate or transmit parasites or viruses, however little is known about the exact cell types involved.

Novel Insights on How Prostate Cancer Causes Secondary Tumors; Smad7 Enhances TGF-β-Induced Transcription of c-Jun and HDAC6, Promoting Metastasis of Prostate Cancer Cells; One Amino Acid in Smad7 Proves Key; HDAC6 Inhibitors May Prove Helpful

An increased awareness on a molecular level of what mechanisms prostate cancer cells use to become mobile and start spreading may, in the long run, provide new opportunities for treatment of aggressive prostate cancer. This is suggested by new results reported in a just-published study by researchers at Umeå University, Sweden, in collaboration with researchers in Uppsala, Sweden, and Tokyo, Japan. The study was published online on September 3, 2020 in iScience. The open-access article is titled “Smad7 Enhances TGF-β-Induced Transcription of c-Jun and HDAC6 Promoting Invasion of Prostate Cancer Cells.” (Se graphcial summary of article at end. “We can show that one specific amino acid in a signaling molecule plays an important role in mobilizing the cancer cells, and in that way increases the risk of metastases,” says Maréne Landström (photo), MD, PhD, Professor of Pathology, Umeå University. This research has studied the growth factor TGF-β (transforming growth factor beta), which regulates how cells grow and specialize. Previous studies have shown an overproduction of TGF-β in many forms of cancer, one being prostate cancer. High levels of TGF-β have proven to be strongly linked with poor prognosis and low survival rates as a consequence of the growth factor stimulating cancer cells to spread in the human body and cause life-threatening secondary tumors, so-called metastases. TGF-β regulates the expression of the protein Smad7--an active component in the TGF-β signaling chain. In healthy cells, Smad7 can prevent continued TGF-β signaling via negative feedback. However, Dr. Landström and her research group at Umeå University, and colleagues, have now shown, contrary to previous belief, that, in cancer cells, Smad7 can reinforce the development of tumors by regulating the gene expression of HDAC6 and c-Jun.

September 5th

COVID-19 Vaccine Candidate from Johnson & Johnson Prevents Severe Clinical Disease in Susceptible Animals; Phase 1/2 Clinical Trial Ongoing in Humans; Pending Success, Phase 3 Efficacy Trial in 60,000 Participants on Track for September 2020 Start

Most people with COVID-19 have relatively mild disease, but a subset of people develop severe pneumonia and respiratory failure, potentially leading to death. Beth Israel Deaconess Medical Center (BIDMC) immunologist Dan H. Barouch, MD, PhD, and colleagues showed in recently published previous work that a candidate COVID-19 vaccine raised neutralizing antibodies that robustly protected non-human primates (NHPs) against SARS-CoV-2, the virus that causes COVID-19. Now, in new research published online on September 3, 2020 in Nature Medicine, Dr. Barouch and colleagues have demonstrated that the optimal vaccine elicited robust immune response in Syrian golden hamsters and prevented severe clinical disease--including weight loss, pneumonia, and death. The open-access article is titled “Ad26 Vaccine Protects Against SARS-CoV-2 Severe Clinical Disease in Hamsters.” "We recently reported that an Ad26-based SARS-CoV-2 vaccine provided robust protection in rhesus macaques, and this vaccine is currently being evaluated in humans," said Dr. Barouch, who is Director of BIDMC's Center for Virology and Vaccine Research. "However, nonhuman primates typically don't get severe clinical disease, and thus it was important to study whether this vaccine could prevent severe pneumonia and death due to SARS-CoV-2 in hamsters, which are more susceptible to clinical disease." The vaccine--developed through a collaboration between BIDMC and Johnson & Johnson (J&J)--uses a common cold virus, called adenovirus serotype 26 (Ad26), to deliver the SARS-CoV-2 spike protein into host cells, where it stimulates the body to raise immune responses against the coronavirus. Dr.

September 3rd

Drug Plan Hatched by Brown Undergrads Blossoms into Potentially Helpful Therapy for Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig’s Disease); Experimental Two-Drug Combination Slows Disease Progression in Small Study Published in NEJM

An experimental combinational medication slows the progression of the neurodegenerative disease called amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease (named for baseball star (photo) who died of ALS at age 37, according to recently released results from a clinical trial run by investigators at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH) and Amylyx Pharmaceuticals, Inc., the company that manufactures the medication. The findings, reported in the September 3, 2020 issue of the New England Journal of Medicine, offer hope that a treatment may one day be available for patients with ALS, a fatal condition, with no known cure, that attacks the nerve cells in the brain and the spinal cord to progressively hinder individuals’ ability to move, speak, eat, and even breathe. Called AMX0035, the oral medication is a combination of two drugs, sodium phenylbutyrate and taurursodiol, that each target a different cell component important for protecting against nerve cell death. AMX0035 targets endoplasmic reticulum- and mitochondrial-dependent neuronal degeneration pathways in ALS and other neurodegenerative diseases. The NEJM article, titled “Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis” (https://www.nejm.org/doi/full/10.1056/NEJMoa1916945?query=featured_home), is accompanied by an editorial titled “Incremental Gains in the Battle Against ALS” (https://www.nejm.org/doi/full/10.1056/NEJMe2021144?query=recirc_curatedR...). In the so-called “CENTAUR” clinical trial, 137 participants with ALS were randomized in a two-to-one ratio to receive AMX0035 or placebo.

August 29th

Inflammatory Bowel Disease Linked to Specialized Tissue-Resident Memory T-Cell Run Amok; Finding May Provide New Therapeutic Target

Inflammatory bowel disease (IBD) is a group of intestinal disorders affecting an estimated six to eight million people worldwide. Although there are many treatments for IBD, a number of patients fail to respond long-term, leaving those afflicted with a host of chronic issues, from abdominal pain and cramping to frequent, bloody stools. In a new study, published August 21, 2020 in Science Immunology, an international team of researchers, led by scientists at the University of California San Diego School of Medicine, report that the lasting nature of IBD may be due to a type of long-lived immune cell that can provoke persistent, damaging inflammation in the intestinal tract. The open-access article is titled” Heterogeneity and Clonal Relationships of Adaptive Immune Cells in Ulcerative Colitis Revealed by Single-Cell Analyses.” Led by co-senior authors John T. Chang, MD, Professor of Medicine, and Gene W. Yeo, PhD, Professor of Cellular and Molecular Medicine, the research team performed mRNA and antigen receptor sequencing from immune cells isolated from samples taken from rectal biopsies or blood of IBD patients and healthy controls. "We took advantage of a state-of-the-art approach allowing us to generate mRNA and antigen receptor sequencing data from the same single-cells," said Dr. Yeo, "and analyzed thousands of individual cells, which is quite exciting." It has long been believed that immune system dysfunction, in concert with genetic susceptibility and changes in the gut microbiome, plays a significant role in IBD. However, the types of immune cells involved and their specific contributions to IBD have remained unclear.

August 19th

Observational Study Identifies Drug (Tocilizumab) That Improves Survival in Sickest COVID-19 Patients

Researchers at Hackensack Meridian Health, New Jersey's largest and most comprehensive health network, have utilized its statewide observational database of more than 5,000 hospitalized COVID-19 patients to show that a drug (tocilizumab) normally used in rheumatoid arthritis and cancer treatments, improves hospital survival in critically-ill patients admitted to the intensive care unit (ICU). The findings were published online on August 14, 2020 in The Lancet Rheumatology, and Hackensack Meridian Health researchers have updated the U.S. FDA and other national leaders of the findings to potentially accelerate improved outcomes. The Lancet article is titled “Tocilizumab Among Patients with COVID-19 in the Intensive Care Unit: A Multicentre Observational Study.” "Our clinicians and researchers at Hackensack Meridian Health have moved quickly and intelligently since the start of this global health crisis," said Robert C. Garrett, FACHE, Chief Executive Officer of Hackensack Meridian Health. "Their work in treating this terrible virus, and learning more about it each day, continues to benefit thousands of patients as the pandemic continues." The study included 630 patients who were admitted to the ICUs of 13 Hackensack Meridian Health hospitals from March 1 to April 22--the height of the pandemic in New Jersey. Among other treatments, tocilizumab was considered for off-label usage for the patients whose respiratory symptoms were declining; many of whom were requiring mechanical ventilator support. In the observational study 210 patients received tocilizumab, and the other 420 did not.

August 18th

Preexisting Drug (Ebselen) Shows Promise in Fight Against COVID-19; Drug Interferes with Key Virus Enzyme

First appearing in late 2019 in Wuhan City, China, the SARS-CoV-2 virus continues to cause sickness and death across the globe. Researchers and scientists have been looking at multiple solutions to treat COVID-19, including repurposing approved pharmaceutical drugs. This research points to very promising treatment options. A team of researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago used state-of-the-art computer simulations to identify a preexisting drug that could fast-track a solution to this worldwide pandemic. Their findings appear in the open-access artilce, "Molecular Characterization of Ebselen Binding Activity to SARS CoV 2 Main 4 Protease," which was published online on August 14, 2020 in Science Advances. Early in February, concerned by the rapid progress of the pandemic, Professor Juan de Pablo, PhD, and his students used their molecular modeling expertise to help find a treatment against the disease. They were not the only ones. Other groups around the world were beginning to use supercomputers to rapidly screen thousands of existing compounds for potential use against the SARS-CoV-2 virus. "By virtue of the large number of compounds considered in high-throughput screens, those calculations must necessarily involve a number of simplifications, and the results must then be evaluated using experiments and more refined calculations," Dr. de Pablo explained. Researchers first focused on finding a weakness in the virus to target. They chose its main protease: Mpro. Mpro is a key coronavirus enzyme that plays a central role in the virus' life cycle. It facilitates the virus' ability to transcribe its RNA and replicate its genome within the host cell. A pharmaceutical drug that shows promise as a weapon against Mpro is Ebselen (image).

August 17th

New Research Reveals Subtype of Autism Associated With Lipid Abnormalities

Researchers at Harvard Medical School, Massachusetts Institute of Technology, and Northwestern University have identified a subtype of autism arising from a cluster of genes that regulate cholesterol metabolism and brain development. The researchers say their findings, published online on August 10, 2020 in Nature Medicine, can inform both the design of precision-targeted therapies for this specific form of autism and enhance screening efforts to diagnose autism earlier. The article is titled “A Multidimensional Precision Medicine Approach Identifies an Autism Subtype Characterized by Dyslipidemia.” The team identified the shared molecular roots between lipid dysfunction and autism through DNA analysis of brain samples--findings that they then confirmed by examining medical records of individuals with autism. Indeed, both children with autism and their parents had pronounced alterations in lipid blood, the analysis showed. The results of the study, the researchers said, raise many questions; key among them are: Just how do lipid alterations drive neurodevelopmental dysfunction and could normalizing lipid metabolism affect disease outcomes? The new findings set the stage for future studies to answer these questions and others. "Our results are a striking illustration of the complexity of autism and the fact that autism encompasses many different conditions that each arise from different causes--genetic, environmental, or both," said study senior investigator Isaac Kohane, MD, PhD, Chair of the Department of Biomedical Informatics in the Blavatnik Institute at Harvard Medical School. "Identifying the roots of dysfunction in each subtype is critical to designing both treatments and screening tools for correct and timely diagnosis--that is the essence of precision medicine."

August 16th

Progress Made in Understanding How Selective Serotonin-Reuptake Inhibitors (SSRIs) Work to Ease Depression

Some highly effective medications also happen to be highly mysterious. Such is the case with the antidepressant drugs known as selective serotonin re-uptake inhibitors, or SSRIs: They are the most common treatment for major depression and have been around for more than 40 years, yet scientists still do not know exactly how they work. Nor is it known why only two out of every three patients respond to SSRI treatment, or why it typically takes several weeks for the drugs to take effect—a significant shortcoming when you’re dealing with a disabling mood disorder that can lead to impaired sleep, loss of appetite, and even suicide. New research by a team of Rockefeller University scientists helps elucidate how SSRIs combat depression. Their work, published online on May 21, 2020 in Molecular Psychiatry (https://www.nature.com/articles/s41380-020-0767-8#Abs1), could one day make it possible to predict who will respond to SSRIs and who will not, and to reduce the amount of time it takes for the drugs to act. The open-access article is titled “AP-1 Controls the p11-Dependent Antidepressant Response.” Major depression—also known as clinical depression—is firmly rooted in biology and biochemistry. The brains of people who suffer from the disease show low levels of certain neurotransmitters, the chemical messengers that allow neurons to communicate with one another. And studies have linked depression to changes in brain volume and impaired neural circuitry.

DNA Test Accurately IDs People Whose Gonorrhea Can Be Cured with Simple Oral Antibiotic

A test designed by UCLA researchers can pinpoint which people with gonorrhea will respond successfully to the inexpensive oral antibiotic ciprofloxacin, which had previously been sidelined over concerns the bacterium that causes the infection was becoming resistant to it. In research published online on August 7, 2020 in Clinical Infectious Diseases, a UCLA-led team found that of 106 subjects the test identified as having a strain of gonorrhea called wild-type gyrA serine, all were cured with a single dose of oral ciprofloxacin. Though the test has been available for three years, this is the first time it has been systematically studied in humans. The new test gives doctors more choices to treat the sexually transmitted infection and could help slow down the spread of drug-resistant gonorrhea, said Jeffrey Klausner, MD, MPH, the study’s lead author and a Professor of Medicine in the Division of Infectious Diseases at the David Geffen School of Medicine at UCLA. The article is titled “Resistance-Guided Treatment of Gonorrhea: A Prospective Clinical Study.” “Gonorrhea is one of the most common drug-resistant infections worldwide and is becoming harder to treat. Current treatment methods require an antibiotic injection, which is expensive and painful,” said Dr. Klausner, who is also an adjunct professor of epidemiology at the UCLA Fielding School of Public Health. “This new test could make it easier and safer to treat gonorrhea with different antibiotics, including one pill given by mouth. Using a pill instead of a shot would also make it easier and faster to treat sex partners of patients with gonorrhea,” he added.