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Archive - Nov 13, 2019

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Phage Therapy Shows Promise for Alcoholic Liver Disease; Gut Bacteria Toxin Linked to Worse Clinical Outcomes; Treatment With Bacteriophages Clears the Harmful Bacteria and Eliminates Disease In Mice

Bacteriophages (phages) are viruses that specifically attack and destroy bacteria. In the early 20th century, researchers experimented with phages as a potential method for treating bacterial infections. But then antibiotics emerged and phages fell out of favor. With the rise of antibiotic-resistant infections, however, researchers have renewed their interest in phage therapy. In limited cases, patients with life-threatening multidrug-resistant bacterial infections have been successfully treated with experimental phage therapy after all other alternatives were exhausted. Researchers at the University of California San Diego School of Medicine and their collaborators have now, for the first time, successfully applied phage therapy in mice for a condition that's not considered a classic bacterial infection: alcoholic liver disease. The study was published in the November 13, 2019 issue of Nature. The article is titled “Bacteriophage Targeting of Gut Bacterium Attenuates Alcoholic Liver Disease.” "We not only linked a specific bacterial toxin to worse clinical outcomes in patients with alcoholic liver disease, we found a way to break that link by precisely editing gut microbiota with phages," said senior author Bernd Schnabl, MD, Professor of Medicine and Gastroenterology at UC San Diego School of Medicine and Director of the NIH-funded San Diego Digestive Diseases Research Center. Up to 75 percent of patients with severe alcoholic hepatitis, the most serious form of alcohol-related liver disease, die within 90 days of diagnosis. The condition is most commonly treated with corticosteroids, but these drugs are not highly effective. Early liver transplantation is the only cure, but is only offered at select medical centers to a limited number of patients.

After Decades of Little Progress, Researchers May Be Catching Up to Sepsis; PERSEVERE Platform Assays Five Risk-Associated Biomarkers

After decades of little or no progress, biomedical researchers are finally making some headway at detecting and treating sepsis, a deadly medical complication that sends a surge of pathogenic infection through the body and remains a major public health problem. Researchers at Cincinnati Children's Hospital Medical Center report in the November 13, 2019 issue of Science Translational Medicine that they have developed and successfully tested a new rapid blood assay that measures five biomarkers and accurately predicts which patients are at low, medium, or high risk for death from sepsis (colloquially referred to as blood poisoning). Called PERSEVERE, the new test allows physicians to detect and stratify sepsis at its earliest moments, just as the body is about to unleash a storm of bacterial infection, according to study's senior investigator, Hector Wong (photo), MD, Director of Critical Care Medicine at Cincinnati Children's. By knowing which five proteins/genes make up the assay's five-biomarker blood panel, physicians should be able to start medical interventions much earlier and with greater precision. Dr. Wong said, not only can patients be stratified into low, medium and high-risk groups, the biomarker test allows physicians to pick the right interventions for specific patients, including which drugs and dosages. The article is titled “Prospective Clinical Testing and Experimental Validation of the Pediatric Sepsis Biomarker Risk Model.” "The PERSEVERE platform focuses on stratification and prognostication, not diagnostics," says Dr. Wong. "Prognostic enrichment is a fundamental tool of precision medicine.

Exosomes Enable Delivery of Severe Prostate Cancer-Promoting Transfer Factors; Inhibition of Exosome Release May Prove Helpful in Treatment

A transcription factor that aids neuron function also appears to enable a cell conversion in the prostate gland that can make an already recurrent cancer even more deadly, scientists say. The transcription factor BRN4 is mostly expressed in the central nervous system and inner ear, but now scientists have the first evidence it’s amplified and overexpressed in patients with the rare, but increasing, neuroendocrine prostate cancer, they report in an article published online on September 18, 2019 in the journal Clinical Cancer Research. The article is titled “BRN4 Is a Novel Driver of Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer and Is Selectively Released in Extracellular Vesicles with BRN2.” As their name implies, neuroendocrine cells also are more common in the brain, but the walnut-sized prostate gland also has a small percentage of them and they appear to become more numerous and deadly in the face of newer, more powerful hormone therapy. The sex hormone androgen is a major driver of prostate cancer so hormone therapy to suppress it or its receptor — called chemical castration — is a standard frontline therapy, says Sharanjot Saini (left in photo), PhD, a cancer biologist in the Department of Biochemistry and Molecular Biology at the Medical College of Georgia (MCG) at Augusta University. Still, as high as 40 percent of patients develop castration-resistant prostate cancer within a few years. This more aggressive cancer is harder to treat, and patients may get a newer, more powerful hormone therapy like enzalutamide, which was first approved in 2012 for this recurring prostate cancer. It’s the far more common luminal cell type in the prostate gland that typically becomes cancerous, says Dr. Saini, the study’s corresponding author.

Research Points to Possible Treatment Target in Idiopathic Pulmonary Fibrosis (IPF); Targeting Mevalonate Pathway May Abrogate Role of Macrophages in Dysregulated Fibrotic Repair

Long-held dogma says lung fibrosis in diseases like idiopathic pulmonary fibrosis(IPF) results from recurrent injury to alveolar epithelium that is followed by dysregulated repair. Research at the University of Alabama at Birmingham (UAB) uproots that paradigm, and suggests a possible treatment target for IPF. A. Brent Carter(photo, courtesy of UAB), MD, and colleagues reported online on Octobr 14, 2019 in the Journal of Clinical Investigation that the recruited monocyte-derived macrophages, which have an increased flux in the mevalonate metabolic pathway -- without any experimental injury -- can induce lung fibrosis in a mouse model. When there is prior lung injury, the increased flux through the mevalonate pathway exacerbates the resulting fibrosis. The mechanism polarizes macrophages to a profibrotic state that causes pathogenic macrophage/fibroblast signaling. Furthermore, study of humans with IPF showed that three hallmarks of the mechanism that leads to lung fibrosis in the absence of injury in mice are also found in bronchoalveolar (BAL) cells from these patients, as compared to healthy individuals. These three hallmarks are 1) activation of the small GTPase protein Rac1 and its localization into the intermembrane space of mitochondria in the BAL cells, 2) increased production of mitochondrial reactive oxygen species by BAL cells from patients with IPF, and 3) evidence of increased flux through the non-sterol arm of the mevalonate pathway in the BAL cells results in the augmented activation of Rac1. "Here, we show a paradigm shift that indicates a critical and essential role for monocyte-derived macrophage/fibroblast crosstalk in the development and progression of fibrosis in the absence of epithelial injury," said Dr.