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September 7th, 2017

Researchers Discover Why Redheads Are More Prone to Melanoma; Pharmacological Activation of Palmitoylation in MC1R Prevents Melanoma in Model System

Red-haired people are known for pale skin, freckles, poor tanning ability and, unfortunately, an increased risk for developing skin cancer. Research has shown that they have variants in melanocortin 1 receptor (MC1R), a protein crucial for pigmentation in humans, but how this translates to increased risk for cancer and whether that risk can be reversed has remained an active area of investigation--until now. For the first time, researchers from Boston University School of Medicine (BUSM) have shown that there is a way to reduce cancer risk in redheads. These findings were published online on September 6, 2017 in Nature. The article is titled “Palmitoylation-Dependent Activation of MC1R Prevents Melanomagenesis.” Specifically the scientist proved that MC1R, the protein involved in pigmentation, is affected by a special modification process called palmitoylation that is critical for its function. By enhancing palmitoylation in the variant MC1R proteins of redheads cancer risk can be reduced. Making up one to two percent of the world's population, redheads carry variants of MC1R that are responsible for their characteristic features, but that also increase risk of skin cancers, the most dangerous of which is melanoma, a major public health concern with more than 3 million active cases in 2015. Much public health work has emphasized prevention by reducing sun exposure, particularly to DNA-damaging UV rays, but redheads bear a higher burden of disease making alternative risk reductions strategies an area of active interest.

Immunotherapy Combination Is Safe and 62 Percent Effective In Metastatic Melanoma Patients

Immunotherapy is a promising approach in the treatment of metastatic melanoma, an aggressive and deadly form of skin cancer; but for most patients, immunotherapy drugs so far have so far failed to live up to their promise and provided little or no benefit. In a phase 1b clinical trial with 21 patients, researchers tested the safety and efficacy of combining the immunotherapy drug pembrolizumab with an oncolytic virus called T-VEC. The results suggest that this combination treatment, which had a 62% response rate, may work better than using either therapy on its own. The study was published in the September 7, 2017 issue of Cell. The article is titled “Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy.” "We had a hypothesis about how these treatments would work together, and when we did biopsies of patients' tumors we found that they were cooperating in just the way we thought they would," says lead author Dr. Antoni Ribas, Director of the Immunology Program at the UCLA Jonsson Comprehensive Cancer Center. Pembrolizumab is in a class of drugs called checkpoint inhibitors. These drugs are designed to get around one of the ways that cancer protects itself from the immune system: tumors can activate the body's natural protective response from autoimmunity, called a checkpoint, and thereby thwart cytotoxic T cells. The drugs work by taking the brakes off the checkpoint and allowing T cells to attack the tumor. "Some people put tumors into the categories of either 'hot' and 'cold,'" Dr. Ribas explains. "Hot tumors, also called inflamed tumors, have a lot of immune cells in and around them, but cold tumors do not." Drugs like pembrolizumab boost the response in tumors where immune cells are present but don't work in tumors where there is no immune response to boost.

Technology Unlocks Mold Genomes to Identify New Drug Candidates

Fungi are rich sources of natural molecules for drug discovery, but numerous challenges have pushed pharmaceutical companies away from tapping into this bounty. Now, scientists have developed technology that uses genomics and data analytics to efficiently screen for molecules produced by molds to find new drug leads — maybe even the next penicillin. The research, from scientists at Northwestern University, the University of Wisconsin-Madison, and the biotech company Intact Genomics, was published online on June 12, 2017 in Nature Chemical Biology. The article is titled “A Scalable Platform to Identify Fungal Secondary Metabolites and Their Gene Clusters.” “Drug discovery needs to get back to nature, and molds are a gold mine for new drugs,” said Neil Kelleher (photo), PhD, Director of the Proteomics Center of Excellence and a professor in the Weinberg College of Arts and Sciences and of Medicine in the Division of Hematology and Oncology. “We have established a new platform that can be scaled for industry to provide a veritable fountain of new medicines. Instead of rediscovering penicillin, our method systematically pulls out valuable new chemicals and the genes that make them. They can then be studied in depth.” Scientists believe there are thousands or even millions of fungal molecules waiting to be discovered, with enormous potential health, social, and economic benefits. The new technology systematically identifies powerful bioactive molecules from the microbial world — honed through millennia of evolution — for new drug leads. These small molecules could lead to new antibiotics, immunosuppressant drugs, and treatments for high cholesterol, for example. For four years, Dr. Kelleher has collaborated with Nancy Keller, PhD, the Robert L. Metzenberg and Kenneth B.

Lasker-DeBakey Clinical Medical Research Award 2017 Goes to NCI’s Douglas R. Lowy & John T. Schiller for Technological Advances That Enabled Development of HPV Vaccines for Prevention of Cervical Cancer and Other Tumors Caused by HPV

The 2017 Lasker-DeBakey Clinical Medical Research Award honors two scientists whose technological advances enabled the development of human papillomavirus (HPV) vaccines, which prevent cervical cancer and other tumors. Dr. Douglas R. Lowy and Dr. John T. Schiller (both from the National Cancer Institute) took a bold, but calculated, approach toward a major public-health problem whose solution required them to vault formidable hurdles. They devised a blueprint for several safe and effective vaccines that promise to slash the incidence of cervical cancer and mortality, the fourth most common cancer among women worldwide, as well as other malignancies and disorders that arise from human papillomaviruses. More than 500,000 new cases of cervical cancer are diagnosed annually, and each year, more than 250,000 women die from the malignancy. In the 1980s, Dr. Harald zur Hausen (2008 Nobel Prize in Physiology or Medicine) linked the disease to infection with certain types of HPV. Two of the viruses—HPV16 and 18—give rise to about 70 percent of cases, and approximately ten additional types account for the vast majority of the remaining 30 percent. HPV16 and 18 plus these other “high-risk” HPVs also underlie many cancers of the vulva, vagina, penis, anus, and throat. Different HPV family members cause genital warts. Sexual activity transmits these viruses, and infections usually clear spontaneously. Some persist, however, and high-risk HPVs harbor oncogenes, whose activity can lead to unrestrained proliferation of host cells. The process of transforming normal cells into cancerous ones typically takes at least 15 years, usually longer. By the early 1990s, scientists realized that a vaccine that blocks persistent infection with dangerous HPV types would bestow substantial public-health rewards.

September 6th

Lasker Basic Medical Research Award 2017 Goes to Michael N. Hall for Discoveries Concerning Nutrient-Activated TOR Proteins and Their Central Role in the Metabolic Control of Cell Growth

The 2017 Albert Lasker Basic Medical Research Award honors a scientist who discovered the nutrient-activated TOR proteins and their central role in the metabolic control of cell growth. By showing that the TOR system adjusts cell size in response to the availability of raw materials, Dr. Michael N. Hall (photo) (Biozentrum, University of Basel, Switzerland) revealed an unanticipated linchpin of normal cell physiology. TOR balances constructive and destructive activities to match accumulation of cell mass with nutrient supply and other growth signals, such as hormones. Disruption of the TOR network contributes to numerous human illnesses, including diabetes and cancer, and has been implicated in a wide range of other age-related disorders. The story began in the late 1980s, when many researchers were studying the tightly choreographed process by which cells divide. Although scientists recognized that a cell must increase in content and size as part of this process, they were not focused on that aspect. Growth was thought to be spontaneous, so if raw materials such as amino acids and fatty acids were present, the thinking went, cells would manufacture macromolecules such as proteins and lipids. In this scenario, a growth regulator was unnecessary. At that time, Dr. Hall was studying how proteins cross the membrane barrier that separates the main body of the cell, or cytoplasm, from the nucleus, where genes reside. Toward that end, he was exploring how a certain class of drugs (called immunosuppressants) obstruct T-cell activation, the process by which these immune cells rev up and proliferate. Scientists knew that these drugs somehow block transmission of a signal that travels into the nucleus to turn on certain genes.

Discovery of Six Gene Regions Linked to Preterm Birth Described in Landmark Study Published in NEJM; Results Based on Data from More Than 50,000 Women

A massive DNA analysis of pregnant women has identified six gene regions that influence the length of pregnancy and the timing of birth. The findings, published online on September 6, 2016 in the New England Journal of Medicine, may lead to new ways to prevent preterm birth and its consequences -- the leading cause of death among children under age 5 worldwide. The NEJM article is titled “Genetic Associations with Gestational Duration and Spontaneous Preterm Birth.” The study, coordinated by Louis Muglia, MD, PhD, Co-Director of the Perinatal Institute at Cincinnati Children's and principal investigator of the March of Dimes Prematurity Research Center--Ohio Collaborative, together with Bo Jacobsson, MD, PhD, of Sahlgrenska Academy, University of Gothenburg, Sweden and the Norwegian Institute of Public Health, Oslo, involved data from more than 50,000 women. The globe-spanning team included first author Ge Zhang, MD, PhD, of the Division of Human Genetics at Cincinnati Children's, along with researchers from Norway, Denmark, Finland, Sweden, Yale University, the University of Iowa, and the genetic testing company 23andMe. Vital funding was provided by the March of Dimes, the National Institutes of Health, The Research Council of Norway, Swedish Research Council and the Bill & Melinda Gates Foundation. The March of Dimes Prematurity Research Center--Ohio Collaborative, launched in 2013, is responsible for the gene identification component of the network of five Prematurity Research Centers nationwide established by the March of Dimes to identify the unknown causes of preterm birth. Because preterm birth is a complex disorder with many possible causes, other Prematurity Research Centers are charged with exploring different aspects of preterm birth and how to prevent it.

September 5th

Invitation to ASEMV 2017 Annual Meeting (Exosomes & Microvesicles) in Asilomar, California (October 8-12)

The American Society for Exosomes and Microvesicles (ASEMV) is inviting interested scientists to the ASEMV 2017 meeting, to be held October 8-12, 2017 at the Asilomar Conference Center in California. This center is located on the Monterrey peninsula, just south of San Francisco ( The meeting will cover the full breadth of the exosome field, from basic cell biology to clinical applications, and follow the ASEMV tradition of inclusion and diversity as participants learn about the latest advances in the field. ASEMV 2017 is a forum for learning the latest discoveries in the field of exosomes, microvesicles, and extracellular RNAs. Over the course of four days at the Asilomar Conference Center, ASEMV 2017 will offer presentations from leading scientists and young researchers. Topics will span the breadth of the extracellular vesicle/RNA field, including the basic sciences, disease research, translation efforts, and clinical applications. Talks will be presented in multiple sessions, beginning at 7 pm on Sunday, October 8, 2017, and concluding at 4 pm on Thursday, October 12, 2017. Poster sessions will run throughout the meeting, with ample time to get to know your colleagues in the field and explore the many opportunities in this rapidly expanding field. Please see the links below.

NIH Awards $2.2 Million to Fund Collaborative Research on the Role of Exosomes in Metastasis

Cancer metastasis - the spread of disease from the original site to a distant organ - remains a major challenge in treating cancer and a main cause of morbidity and mortality. A widely accepted explanation for this process - called "the seed and soil" hypothesis - recognizes the need for the cancer cell or "seed" to travel to a hospitable environment - the "soil.” To understand metastasis, many investigators have focused on the cancer cell- or seed. Yves DeClerck, MD, a pediatrician-scientist at Children's Hospital Los Angeles (CHLA) and co-leader of the Tumor Microenvironment Program at the USC-Norris Comprehensive Cancer Center, has studied this topic for his entire career from a slightly different perspective, concentrating on the "soil" or tumor microenvironment. Because of his recognition as a leader in this area, Dr. DeClerck was recently awarded $2.2 million from the National Cancer Institute, to investigate the microenvironment from a relatively new context. The study will focus on a newly identified type of messenger -- extracellular vesicles released by cancer cells into their environment. These vesicles, called exosomes, are small sacs shed by tumor cells that can contain protein, DNA, RNA and/or lipids. Exosomes are taken in by other cells and can modify the behavior of the receiving cell. According to Dr. DeClerck, healthy cells are typically inhospitable to cancer cells. What causes them to change from foe to friend? "There are different ways that cancer cells communicate with normal cells - causing the change - and one of these ways is through exosomes," said Dr. DeClerck, who is a Professor of Pediatrics and Biochemistry and Molecular Medicine at the Keck School of Medicine of USC. He also holds the Richard Call Family Endowed Chair in Pediatric Research Innovation at CHLA. Dr.

Ducks Reach 22,000 Feet in Migration Flight Over Himalayas

A high-flying duck species reaches altitudes of up to 6,800 meters (22,000 feet) to cross the Himalayas, new research shows. Ruddy shelducks are known to breed north of the Himalayan mountain range, but spend their winters at sea level south of the Tibetan Plateau. They need to fly over the Himalayas in the spring to get back to their breeding grounds, a huge challenge that sees them cross terrain higher than 4,000 meters, where oxygen levels are halved. Scientists from the University of Exeter used satellite tracking to discover that the ducks fly through valleys in the mountain range - avoiding massive peaks like Mount Everest. "This is the first evidence of extreme high-altitude flight in a duck," said lead researcher Dr. Nicole Parr, of the Centre for Ecology and Conservation on the University of Exeter's Penryn Campus in Cornwall, UK. "This species has probably evolved a range of adaptations to be able to cope with flying so high, where oxygen levels are half those at sea level. We don't yet know the nature of these adaptations. "Our research also shows that the ruddy shelduck has a faster climb rate than the bar-headed goose, the only waterfowl known to fly even higher." Dr. Lucy Hawkes, the supervisor of the work at the University of Exeter, had previously tracked bar-headed geese to 7,290 meters altitude near Everest in 2014. They were long thought to be the world's highest-flying bird based on flapping flight (some birds soar higher on thermals), but the new research suggests that the bar-headed geese may not be the only species flying at these high altitudes. However, more research is needed to find out whether ruddy shelducks reach similar heights to bar-headed geese. The scientists used satellite data collected from 15 ruddy shelducks from two populations spending their winter south of the Tibetan Plateau.

Discovery of Sugar “Warehouse” in Dendritic Cells Could Lead to Improvement of Vaccines and New Approaches to Treatment of Autoimmune Diseases

A surprising discovery that immune cells possess an internal warehouse of glycogen used to activate immune responses could help to increase immune activity in vaccines or suppress immune reactions in autoimmune disease or hyper-inflammatory conditions. Results of the new study were published online in Cell Metabolism and show that the immune responses of dendritic cells are fueled by an intracellular storage of sugar as opposed to external sugar, where prior research has focused. The novel finding adds an important missing piece to the puzzle of how early immune responses are powered from a metabolic standpoint, and provides immunologists with a new area of focus in their ongoing effort to regulate immune activity. "By either enhancing or depleting this sugar warehouse within the cell, the hope would be that we could either influence or dampen immune reactions," says study author Dr. Eyal Amiel, Assistant Professor at the University of Vermont in the Department of Medical Laboratory and Radiation Science in the College of Nursing and Health Sciences. "What we're really in the business of is finding new switches to toggle to that effect and this finding provides us with a new regulatory target that regulates immune activity." The finding gives immunologists a key piece of new information to better understand how the early part of the bioenergetics of a dendritic cell immune response is generated. This is especially significant given the importance of timing when it comes to immune response and the speed at which the switch of inflammation can be either increased or suppressed. "What's surprising is that the intracellular sugar pool is the more important one early on," says Dr. Amiel, who co-authored the paper with Phyu Thwe, a PhD student in Dr. Amiel's lab, and three external researchers.