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November 13th, 2019

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.

November 12th

Batty Microbiomes Defy Predictions

Right now, there are trillions of bacteria living in your gut, making up about one percent of your body weight. They're supposed to be there--we need them to help us digest food and fight off diseases. The same is true for most mammals; in general, just about every mammal from dogs to dolphins relies on a community of helpful bacteria, called a microbiome, living inside them for health and survival. Many animals have even evolved along with their gut bacteria to work together better, to the point that closely related host species typically share more similar microbiomes. But a new study has identified one group of mammals that seems to buck that trend: bats. A new paper, published online on November 12, 2019 in mSystems, reveals that the microbiomes of closely-related bats can be totally different from each other, which suggests that having a community of helpful gut bacteria may not be so important for this already eccentric group of mammals. The open-access article is titled “Ecology and Host Identity Outweigh Evolutionary History in Shaping the Bat Microbiome.” "It shifts the paradigm we've been operating under, that animals require microbes for digestion and nutrient acquisition. That's true for us, but it may not be true for all species," says lead author Holly Lutz, PhD, a research associate at Chicago's Field Museum and post-doctoral researcher at the University of California, San Diego. "The trends we're seeing suggest that bats may not depend on bacteria the same way many other mammals do, and that they can survive just fine without a strict suite of bacteria in their guts to help them digest their food." To learn about the relationships between bats and their microbes, Dr. Lutz and her colleagues took samples of bacteria from the skin, tongues, and guts of 497 bats from 31 different species in Kenya and Uganda.

Anthrax Toxin May Be Effective Weapon in Fighting Bladder Cancer

Anthrax may soon help more people win the fight against bladder cancer, which the Centers for Disease Control and Prevention (CDC) says strikes approximately 72,000 Americans each year and kills about 16,000, and is one of the most expensive cancers to treat. The current treatments for bladder cancer are invasive for patients - who often must sit for hours at a time with a bladder full of an agent designed to kill cancer cells and tumors. Bladder cancer also is one of the most reoccurring for people diagnosed with the disease. Now, researchers at Purdue University have come up with a way to combine the anthrax toxin (image) with a growth factor to kill bladder cancer cells and tumors. The research was published online on October 4, 2019 in the International Journal of Cancer. "We have effectively come up with a promising method to kill the cancer cells without harming the normal cells in the bladder," said R. Claudio Aguilar, PhD, an Associate Professor and the Assistant Head of Biological Sciences in Purdue's College of Science. "It is basically like creating a special solution that targets cancer cells, while leaving healthy cells alone." Dr. Aguilar said the bladder has its own protective layer, which saves the good cells from the anthrax mixture but offers no protection for the cancer cells and tumors. He said the Purdue system works within minutes - instead of the usual hours for bladder cancer treatment - to target the cancer cells in the bladder. "We have seen outstanding results with our treatment," said Dr. Aguilar, who works as part of a team focused on cell identity and signaling at the Purdue University Center for Cancer Research. "It is fast and effective, both of which are critical for people dealing with this devastating disease." Dr. Aguilar and his group worked with the Purdue teams led by Dr.

Frequent Technical Bias Occurs in RNA-Seq Expression Studies, Leading to Widespread Misinterpretation of Gene Expression Data; Authors Present Approach to Removing This Bias

Reproducibility is a major challenge in experimental biology, and with the increasing complexity of data generated by genomic-scale, this concern is immensely amplified. RNA-seq, one of the most widely used methods in modern molecular biology, allows in a single test the simultaneous measurement of the expression level of all the genes in a given sample. New research, published online on November 12, 2019 in the open-access journal PLOS Biology by Shir Mandelbaum, Zohar Manber, Orna Elroy-Stein, and Ran Elkon from Tel Aviv University, identifies a frequent technical bias in data generated by RNA-seq technology, which recurrently leads to false results. The article is titled “Recurrent Functional Misinterpretation of RNA-Seq Data Caused By Sample-Specific Gene Length Bias.” Analyzing dozens of publicly available RNA-seq datasets, which profiled the cellular responses to numerous different stresses, Dr. Mandelbaum and colleagues noticed that sets of particularly short or long genes repeatedly showed changes in expression level (as shown by the apparent number of RNA transcripts from a given gene). Puzzled by this recurring pattern, the authors then asked whether it reflects some universal biological response common to many different triggers or if it, rather, stems from some experimental artefact. To tackle this question, they compared replicate samples from the same biological condition. Differences in gene expression between replicates can reflect technical effects that are not related to the experiment's biological factor of interest. Unexpectedly, the same pattern of particularly short or long genes showing changes in expression level was observed in these comparisons between replicates, demonstrating that this pattern is the result of a technical bias that seemed to be coupled with gene length.

November 11th

Biomarker Blood Test Could Reveal High-Risk Heart Patients in Need of Treatment

Without occasionally looking under the hood, it’s difficult topredict whether expensive car repairs lie ahead. In a similar way, preventive cardiologists are looking for ways to detect early-stage heart disease in people who aren’t currently in treatment. Preventive cardiology researchers at the University of Texas (UT) Southwestern Medical Center believe that a new blood test for protein biomarkers could identify these individuals. Their new study, published online on November 11, 2019 in Circulation, pooled patient data from three major patient populations including multiple ethnicities and totaling nearly 13,000 people. The team asked whether measuring levels of two biomarkers – proteins in the blood – would identify people in need of treatment. The researchers found that approximately one-third of adults with mild hypertension who are not currently recommended for treatment have slight elevations of one of these two biomarkers; these individuals were more likely to have heart attacks, strokes, or congestive heart failure over the next 10 years. In other words, these patients are “flying under the radar” and do not know that they are at greater risk of cardiovascular events. The Circulation article is titled “Incorporation of Biomarkers Into Risk Assessment for Allocation of Antihypertensive Medication According to the 2017 ACC/AHA High Blood Pressure Guideline: A Pooled Cohort Analysis.” Dr. Ambarish Pandey (left in photo) and Dr. Parag Joshi (right in photo) believe some patients at risk of heart disease could be helped by a biomarker blood test.“We think this type of test can help in the shared decision-making process for patients who need more information about their risk,” said preventive cardiologist Dr. Parag Joshi, Assistant Professor of Internal Medicine.

Study Reveals How Two Strains of One Bacterium Combine to Cause Flesh-Eating Infection

In recent years, scientists have found that serious infections that progress rapidly and resist treatment are often caused by multiple microbes interacting with one another. Very little is known about these so-called “polymicrobial infections,” but traditional diagnostic methods often misidentify them as monomicrobial, or single-microbe, infections. A new study by a team of scientists that included researchers from the University of Maryland, the University of Texas Medical Branch, and CosmosID, Inc., used genetic analysis to reveal how two different strains of a single species of flesh-eating bacteria worked in concert to become more dangerous than either one strain alone. The study was published online in the Proceedings of the National Academy of Sciences on November 11, 2019. The article is titled “T6SS and ExoA of Flesh-Eating Aeromonas Hydrophila In Peritonitis And Necrotizing Fasciitis During Mono- And Polymicrobial Infections.” "This research provides clear evidence that a very severe infection considered to be caused by a single species of a naturally occurring bacterium actually had two strains," said Rita Colwell (photo), PhD, a Distinguished University Professor in the University of Maryland Institute for Advanced Computer Studies and a co-author of the study. "One of the strains produces a toxin that breaks down muscle tissue and allows the other strain to migrate into the blood system and infect the organs." The original infection--cultured from a patient who developed the severe flesh-eating disease known as necrotizing fasciitis--was diagnosed as a monomicrobial disease. Traditional diagnostics could only determine that the infection was caused by a single species of bacteria called Aeromonas hydrophila.

Penn Scientists Uncover Dose of Medication More Likely to Put Patients with Pemphigus (Chronic, Sometimes Fatal Skin Disease) into Remission; Findings May Inform Use of Recent FDA Approved Drug Rituximab to Better Treat Patients with Pemphigus

Pemphigus, an autoimmune disease mediated by B cells and which causes painful blisters and sores on the skin and mucous membranes, is a rare chronic autoimmune condition that can be fatal if not treated. Treatment for pemphigus, most commonly through an oral medication, was often slow and would not result in complete remission. Now, new research from a team in the Perelman School of Medicine at the University of Pennsylvania shows that a lymphoma-dose regimen of rituximab, a medication regularly used to treat lymphoma and rheumatoid arthritis, is more likely to put patients with pemphigus into complete remission as compared to a rheumatoid arthritis (RA) regimen of the same medication. The findings--which were published online on October 23, 2019 in JAMA Dermatology -- have direct implications for patient care. The article is titled " Factors Associated with Complete Remission After Rituximab Therapy for Pemphigus.” When rituximab, an antibody which was first used to treat B cell lymphoma, became a treatment for pemphigus vulgaris, clinicians could choose to prescribe either a "lymphoma dose" or an "RA dose." A lymphoma-dose regimen of rituximab is a more aggressive approach to treatment compared to the dosing method for patients with rheumatoid arthritis. What's more, the U.S. Food and Drug Administration (FDA) now has an approved dosing regimen for pemphigus vulgaris, but it closely resembles the often less-effective RA dose. While both lymphoma and RA dosing approaches deplete B cells that cause disease, the lymphoma regimen takes into account a person's height and weight to determine a dose and is given weekly for four weeks. A rheumatoid arthritis dose is a fixed dose of two 1000 mg infusions given two weeks apart.

Computer Analysis Reveals Over 1 Million Nucleic Acid Polymer Molecules That Are Possible Alternatives to DNA & RNA

Biology encodes information in DNA and RNA, which are complex molecules finely tuned to their functions. But are they the only way to store hereditary molecular information? Some scientists believe life as we know it could not have existed before there were nucleic acids, thus understanding how they came to exist on the primitive Earth is a fundamental goal of basic research. The central role of nucleic acids in biological information flow also makes them key targets for pharmaceutical research, and synthetic molecules mimicking nucleic acids form the basis of many treatments for viral diseases, including HIV. Other nucleic acid-like polymers are known, yet much remains unknown regarding possible alternatives for hereditary information storage. Using sophisticated computational methods, scientists from the Earth-Life Science Institute (ELSI) at the Tokyo Institute of Technology, the German Aerospace Center (DLR), and Emory University explored the "chemical neighborhood" of nucleic acid analogues. Surprisingly, they found well over a million variants, suggesting a vast unexplored universe of chemistry relevant to pharmacology, biochemistry and efforts to understand the origins of life. The molecules revealed by this study could be further modified to gives hundreds of millions of potential pharmaceutical drug leads. The study results were published on September 9, 2019, in the Journal of Chemical Information and Modeling.

Genetic Diversity Facilitates Effectiveness of Cancer Therapy; Cancer Patients with Broader Diversity of HLA Genes Respond Better to Treatment with Checkpoint Inhibitors

The constant battle against infectious pathogens has had a decisive influence on the human immune system over the course of our evolution. A key role in our adaptation to pathogens is played by HLA molecules. These proteins activate the immune system by presenting it with fragments of pathogens that have entered the body. People with a wide variety of different HLA proteins are thus better armed against a large number of pathogens. Researchers at the Max Planck Institute for Evolutionary Biology in Plön, Germany, together with colleagues in New York, have been investigating the diversity of HLA genes in cancer patients being treated with immune checkpoint inhibitors. This form of immunotherapy activates the body's own immune cells to enable them to identify and eliminate tumor cells. The researchers discovered that patients with a wide variety of HLA molecules derive more benefit from this type of therapy. This means that in future, doctors may be able to offer improved individual treatment based on a patient's HLA gene profile. In the evolution of an organism, the characteristics which often prevail are those which increase the chances of survival and reproduction of their carrier. In contrast, for a robust immune system it could be advantageous for it to be variable, keeping as many options open as possible - a hypothesis which has been tested and confirmed in an early study carried out specifically on HLA molecules by Fr. Federica Pierini and Dr. Tobias Lenz at the Max Planck Institute for Evolutionary Biology. It is therefore essential for the effectiveness of an immune system to have many different variants of HLA molecules, Because each variant can bind to several different pathogen or cancer cell protein fragments.