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Archive - 2019

November 23rd

Scientists Clarify How RNA Molecules Are Folded in Ribosomes; Findings Reveal Unprecedented Detail

A team of scientists from Scripps Research and Stanford University has recorded in real time a key step in the assembly of ribosomes--the complex and evolutionarily ancient "molecular machines" that make proteins in cells and are essential for all life forms. The achievement, reported on November 21, 2019 in Cell, reveals, in unprecedented, detail how strands of ribonucleic acid (RNA), cellular molecules that are inherently sticky and prone to misfold, are "chaperoned" by ribosomal proteins into folding properly and forming one of the main components of ribosomes. The Cell article is titled “Transient Protein-RNA Interactions Guide Nascent Ribosomal RNA Folding.” The findings overturn the longstanding belief that ribosomes are assembled in a tightly controlled, step-wise process. "In contrast to what had been the dominant theory in the field, we revealed a far more chaotic process," says James R. Williamson, PhD, a professor in the Department of Integrative Structural & Computational Biology at Scripps Research. "It's not a sleek Detroit assembly line--it's more like a trading pit on Wall Street." For the study, Williamson's lab collaborated with the lab of Joseph Puglisi, PhD, a Professor at Stanford University. Although the work is a significant feat of basic cell biology, it should enable important advances in medicine. For example, some current antibiotics work by inhibiting bacterial ribosomes; the new research opens up the possibility of designing future antibiotics that target bacterial ribosomes with greater specificity--and thus, fewer side effects. More generally, the research offers biologists a powerful new approach to the study of RNA molecules, hundreds of thousands of which are active at any given time in a typical cell.

Researchers Show Immunotherapy Highly Effective in Extending Life in Those with Heat & Neck Cancer and Also Expressing High Levels of PD-L1 Marker

Immunotherapy is better than standard ‘extreme’ chemotherapy as first-line treatment for advanced head and neck cancer and can keep some patients alive for more than three years, a major new trial reports. The immunotherapy drug pembrolizumab (Keytruda) alone or in combination with chemotherapy extended patients’ lives compared with standard treatment – with some groups of patients treated with single-agent pembrolizumab responding for five times longer than with standard extreme chemotherapy. Crucially, the researchers showed it was possible to predict in advance who was more likely to benefit from pembrolizumab by testing for the PD-L1 immune marker in tumors and on surrounding cells – a key step in establishing the drug’s use as a new standard of care. Pembrolizumab has recently been approved in Europe as first-line treatment for patients diagnosed with advanced head and neck cancer, marking a key milestone in the use of immunotherapy as a standard part of cancer treatment. The phase III trial was led in the UK by The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and involved 882 patients from all over the world who were diagnosed with advanced head and neck cancer. The research, published online on October 31, 2019 in The Lancet, was funded by the treatment’s manufacturer, Merck & Co., Inc., known as MSD outside the US and Canada. The article is titled “Pembrolizumab Alone or with Chemotherapy Versus Cetuximab with Chemotherapy for Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (KEYNOTE-048): A Randomised, Open-Label, Phase 3 Study.” Currently, many patients diagnosed in the UK with advanced head and neck cancer first receive an “extreme” triple combination of two chemotherapies and targeted drug cetuximab.

November 22nd

Mount Sinai Researchers Uncover New Molecular Drivers of Parkinson's Disease; New Approach May Lead to a Better Understanding of Most Cases

Scientists at the Icahn School of Medicine at Mount Sinai have uncovered new molecular drivers of Parkinson's disease using a sophisticated statistical technique called multiscale gene network analysis (MGNA). The team was also able to determine how these molecular drivers impact the functions of genes involved in the disease. The results, which may point to potential new treatments, were published online on November 20, 2019 in Nature Communications. The open-access article is titled “The Landscape of Multiscale Transcriptomic Networks and Key Regulators in Parkinson’s Disease.” Some cases of Parkinson's are directly caused by genetic mutations, but these cases are rare. Approximately 80 percent of cases have no known cause, and though there are some genes that may slightly increase an individual's risk of developing the disease, the biological impacts of these genes remain unclear. "This study offers a novel approach to understanding the majority of cases of Parkinson's," said Bin Zhang, PhD, Professor of Genetics and Genomic Sciences at the Icahn Institute for Data Science and Genomic Technology and Director of the Mount Sinai Center for Transformative Disease Modeling at the Icahn School of Medicine at Mount Sinai. "The strategy not only reveals new drivers, but it also elucidates the functional context of the known Parkinson's disease risk factor genes."

November 20th

Study Suggests Deep Involvement of Transposable Elements in Emergence of the Mammary Gland and Its Evolution Within Mammals

The human genome contains 4.5 million copies of transposable elements (TEs), so-called selfish DNA sequences capable of moving around the genome through cut-and-paste or copy-and-paste mechanisms. Accounting for 30-50% of all of the DNA in the average mammalian genome, these TEs have conventionally been viewed as genetic freeloaders, hitchhiking along in the genome without providing any benefit to the host organism. More recently, however, scientists have begun to uncover cases in which TE sequences have been co-opted by the host to provide a useful function, such as encoding part of a host protein. In a new study published online on October 23, 2019 in Nucleic Acids Research, Professor Hidenori Nishihara has undertaken one of the most comprehensive analyses of TE sequence co-option to date, uncovering tens of thousands of potentially co-opted TE sequences and suggesting that they have played a key role in mammalian evolution. The open-access NAR article is titled “Retrotransposons Spread Potential Cis-Regulatory Elements During Mammary Gland Evolution.” "I was specifically interested in the potential influence of TE sequences on the evolution of the mammary gland," notes Dr. Nishihara, "an organ that is responsible for producing milk and is, as the name suggests, a key distinguishing feature of mammals." To identify potentially co-opted TE sequences, Dr. Nishihara used four proteins--ERα, FoxA1, GATA3, and AP2γ--that bind to DNA to regulate the production of proteins involved in mammary gland development. Dr. Nishihara then located all of the DNA sequences in the genome to which these proteins bind. Surprisingly, 20-30% of all of the binding sites across the genome were located in TEs, with as many as 38,500 TEs containing at least one binding site.

November 15th

Genome-Wide Screen of Malaria Parasite Genome with Corresponding Metabolic Models Represents Major Breakthrough in Malaria Research; Allows Researchers to Focus on Essential Genes

Despite great efforts in medicine and science, more than 400,000 people worldwide are still dying of malaria. The infectious disease is transmitted by the bite of mosquitoes infected with the malaria parasite Plasmodium (image). The genome of the parasite is relatively small, with about 5,000 genes. In contrast to human cells, Plasmodium parasites only have a single copy of each individual gene. If one removes a gene from the entire genome of the parasite, this leads therefore directly to a change in the phenotype of the parasite. An international consortium led by Professors Volker Heussler from the Institute of Cell Biology (ICB) at the University of Bern and Oliver Billker from the Umeå University in Sweden and formerly at the Sanger Institute in Great Britain has taken advantage of this fact. The researchers have carried out a genome-wide gene deletion study on malaria parasites: They specifically removed over 1300 individual genes, observed the effects during the entire life cycle of the parasite and were thus able to identify many new targets in the pathogen. The present study was published in the November 14, 2019 issue of Cell. The open-access article is titled “Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage.” The researchers used a malaria mouse model established at the Institute of Cell Biology at the University of Bern. Each of the 1,300 parasite genes was replaced by an individual genetic code to analyze how the removal of the individual genes affects the parasite. The use of individual codes allows the scientists to study many parasites simultaneously and thus drastically shortens the time of their analysis.

November 13th

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.

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.