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American Society of Human Genetics (ASHG) Honors Kári Stefánsson with William Allan Award

The American Society of Human Genetics (ASHG) has named Kári Stefánsson, MD, founder of deCODE Genetics, the 2017 recipient of the annual William Allan Award. The Allan Award, which recognizes a scientist for substantial and far-reaching scientific contributions to human genetics, was established in 1961 in memory of William Allan, MD (1881-1943), one of the first American physicians to conduct extensive research on human genetics and hereditary diseases. Dr. Stefánsson was to receive his award, which will include an engraved medal and $25,000 prize, on October 18, 2017 during ASHG’s 67th Annual Meeting in Orlando, Florida. He was to present his William Allan Award address immediately thereafter. In 1996, Dr. Stefánsson founded deCODE Genetics with the vision of a large-scale population study in Iceland, a country with a relatively small, isolated, and homogenous population; a high-quality healthcare system; and extensive genealogical records. Through active engagement with the Icelandic population, deCODE has now collected DNA samples from more than 160,000 individuals and contributed greatly to public education about genetics in the country. Their work has inspired similar large-scale studies in other countries, including the UK Biobank and the United States’ All of Us initiative. Central to Dr. Stefánsson’s approach is the use of a single unique identifier for each individual, which allows researchers to measure hundreds of different genotypes and phenotypes in the context of each other and has led to important insights. His group published an influential genetic map in 2002, and has identified variants associated with varied phenotypes, such as type 2 diabetes, prostate cancer, heart attack, and schizophrenia.

American Society of Human Genetics (ASHG) Honors Arthur Beaudet with Victor A. McKusick Leadership Award

The American Society of Human Genetics (ASHG) named Arthur L. Beaudet (photo), MD, Henry and Emma Mayer Professor in the Department of Molecular and Human Genetics and the Department of Pediatrics at Baylor College of Medicine, as the 2017 recipient of the annual Victor A. McKusick Leadership Award. This award, named in honor of the late Victor A. McKusick, MD, recognizes individuals whose professional achievements have fostered and enriched the development of human genetics as well as its assimilation into the broader context of science, medicine, and health. The ASHG presented the McKusick Award, which included a plaque and $10,000 prize, to Dr. Beaudet on October 17, 2017 during the organization’s 67th Annual Meeting in Orlando, Florida. In the 1980s, Dr. Beaudet and colleagues were the first to document uniparental disomy, a phenomenon in which a person receives two copies of a chromosome from one parent and zero from the other, in humans. In the following years, the researchers drew an important distinction between genetic and epigenetic diseases that both lead to altered expression of the same genes, and identified ways to study these and better understand the conditions they caused. Currently, Dr. Beaudet’s research focuses on neuronal carnitine deficiency as a risk factor for autism; the role of genomic imprinting in diseases such as Prader-Willi syndrome, Angelman syndrome, and autism; and prenatal genetic diagnosis based on fetal cells isolated from maternal blood. In addition to his scientific leadership, ASHG also recognizes Dr. Beaudet’s contributions to the Society and the broader research community. A longtime member of ASHG, he belonged to its Program Committee from 1984-86, its Board of Directors from 1987-90, and its Awards Committee from 2010-12, and served as President in 1998.

Researchers Quantify Breast Cancer Risk Based on Rare Variants and Background Risk

Rare variants, combined with background genetic risk factors, may account for many unexplained cases of familial breast cancer, and knowing the specific genes involved could inform choice of prevention and treatment strategies, according to findings presented on October 20, 2017 in a plenary session at the American Society of Human Genetics (ASHG) 2017 Annual Meeting in Orlando, Florida. Researchers Na Li, MD, who presented the work; Ian Campbell, PhD, lead investigator; and their colleagues at the Peter MacCallum Cancer Centre in Melbourne, Australia, focused their study on patients at high risk of breast cancer: those with a personal or family history who were seeking an explanation. “When you know which gene is conferring the risk of breast cancer, you can provide a more precise estimate of risk, know what to expect and watch out for, and tailor risk management strategies to the patient,” said Dr. Campbell. Unfortunately, in about half of these high-risk patients, no known genetic cause was found, suggesting a more complicated explanation. In such cases, cancer geneticists had long suspected that polygenic risk (risk conferred by a combination of genetic variants) was involved. Genes do not work on their own, but rather as part of one’s overall genetic context, explained Dr. Li. “That ‘polygenic risk’ background is like a landscape full of hills and valleys, with each risky variant like a house on top of it,” she said. “If you inherit a high-risk variant – a tall house – but live in a valley, your overall risk of breast cancer may end up being average because your genetic landscape pulls it down.” The concept of background genetic risk is not new, but for many years, scientists did not have the tools to collect and analyze the thousands of genomes needed to quantify it.

Duplications of Noncoding DNA May Have Affected Evolution of Human-Specific Traits

Duplications of large segments of noncoding DNA in the human genome may have contributed to the emergence of differences between humans and nonhuman primates, according to results presented on October 18, 2017 at the American Society of Human Genetics (ASHG) 2017 Annual Meeting in Orlando, Florida. Identifying these duplications, which include regulatory sequences, and their effect on traits and behavior may help scientists explain genetic contributions to human disease. Paulina Carmona-Mora, PhD, who presented the work; Megan Dennis, PhD; and their colleagues at the University of California, Davis, study the history of human-specific duplications (HSDs), segments of DNA longer than 1,000 base pairs that are repeated in humans but not in primates or other animals. In this study, they focused on HSD regions that do not code for genes, but instead regulate the expression of other genes. “What’s special about these regulatory elements is that they have the propensity to impact the expression of genes nearby on the same chromosome, as well as elsewhere in the genome,” said Dr. Dennis. “This means that one duplication could affect many genes, amplifying its impact.” Because duplicated segments are more than 98% identical, it is difficult to distinguish between them, Dr. Dennis explained. As a result, they were discarded in many past genomic analyses. For this reason, the researchers began by creating a new human reference genome that included the duplicated segments. This allowed them to identify areas likely to contain enhancers, which are regulatory elements that increase expression of other genes, and to assess their effect on gene expression across organs and tissue types.

Rapid Whole-Genome Sequencing of Neonatal ICU Patients Is Useful and Cost-Effective, Researchers Report at ASHG Annual Meeting

Rapid whole-genome sequencing (WGS) of acutely ill neonatal intensive care unit (NICU) patients in the first few days of life yields clinically useful diagnoses in many cases, and results in lower aggregate costs than the current standard of care, according to findings presented on October 19, 2017 at the American Society of Human Genetics (ASHG) 2017 Annual Meeting in Orlando, Florida. Shimul Chowdhury, PhD, FACMG, Clinical Laboratory Director at the Rady Children’s Institute for Genomic Medicine in San Diego, California, and his colleagues focused their analysis on a broad swath of NICU patients for whom a genetic diagnosis might help inform treatment decisions and disease management. They studied the clinical utility and cost-effectiveness of sequencing infants and their parents. “Newborns often don’t fit traditional methods of diagnosis, as they may present with non-specific symptoms or display different signs from older children,” said Dr. Chowdhury. In many such cases, he explained, sequencing can pinpoint the cause of illness, yielding a diagnosis that allows doctors to modify inpatient treatment and resulting in dramatically improved medical outcomes in both the short and long term. Because of the potential for early intervention and immediate adjustment in care, the researchers used a rapid WGS procedure that took three to seven days from sample collection to delivering results to patients’ families. The process can be further accelerated if medically necessary. In contrast, most clinical diagnostic tests take four to six weeks.

ASEMV 2017— Exosomes from Ginger Plant Inhibit Activation of NLRP3 Inflammasome

On Thursday morning, October 12, Jiujiu Yu, PhD, Assistant Professor, Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, spoke on the inhibitory effects of ginger exosomes on NLRP3 inflammasome activation. She said that the aim of her group’s study was to screen and identify dietary exosomes that inhibit the activation of the NLRP3 inflammasome in macrophages. The NLRP3 inflammasome, a key sensor of the innate immune system, is a cytoplasmic complex consisting of the sensor NLRP3, the adaptor ASC, and the effector caspase-1. The NLRP3 inflammasome detects a variety of pathogens and cellular stress, mediates the release of inflammatory mediators, and, as such, its aberrant activation is implicated in many diseases, including metabolic syndromes and autoinflammatory diseases. Therefore, Dr. Yu said, identification of inhibitors that effectively dampen the activity of NLRP3 inflammasomes could be instrumental in controlling undesirable inflammatory conditions. In the work, the scientists purified exosomes from different plants using ultracentrifugation and screened their inhibitory effects on NLRP3 inflammasomes in bone-marrow-derived macrophages. The researchers determined that exosomes purified from ginger strongly inhibited activation of NLRP3 inflammasomes. The ginger exosomes were approximately 134 nanometers in diameter. The inhibitory effects of ginger exposure on NLRP3 inflammasome activation required long incubation (more than 12 hours), suggesting that the cargo inside of the vesicles mediated the inhibitory effects. Ginger exosomes had no effects on the protein levels of inflammasome subunits, including NLRP3, ASC, and caspase-1, or its cofactor Nek7. Based on these results, Dr.

ASEMV 2017—EV Secretion by Primary Cilia

On Monday evening, Octobe 9, Maxense Nachury, PhD, Stanford & UCSF, spoke on “Molecular Mechanisms and Functional Significance of EV Secretion by Primary Cilia.” He noted that the primary cilium, present on almost all cells, is a microtubule-based projection with its own complement of protein, lipids, and second messengers. The primary cilia have long been recognized for their roles in phototransduction and olfactory signaling. In recent years, cilia have been found to organize the developmental signaling pathway Sonic Hedgehog and various neuronal signaling pathways mediated by G-protein-coupled receptors (GPCRs). Dr. Nachury said that a hallmark of ciliary signaling pathways is the dynamic delivery and removal of ciliary proteins. Activated ciliary GPCRs are retrieved back into the cell through beta-arrestin2- and BBSome-mediated transport. (The BBSome is an octameric protein complex that is a component of the basal body and is involved in trafficking cargos to the primary cilium). Surprisingly, Dr. Nachury said, when retrieval is compromised, activated GPCRs become selectively concentrated into membranous buds at the tip of cilia, and actin-mediated scission releases extracellular vesicles (EVs) packaged with activated GPCRs. The microtubule-actin crosslinker Drebrin and Myosin VII localize to the site of ectosome release at the ciliary tip under ectosome-producing conditions and are required for the scission of EVs from the tip of cilia. Signal-dependent ectocytosis also applies to physiological context, where it removes, from cilia, specific GPCRs such as anorexigenic receptor NPY2R that lack retrieval determinants. Functionally, ciliary ectocytosis is required for the appropriate reulation of Hedgehog signaling in retrieval mutants. Dr.

ASEMV 2017—Exosomal miRNAs As Potential Biomarkers for Energy Expenditure by Human Brown Fat

On Tuesday morning, October 10, Alexander Pfeifer, PhD, Institute of Pharmacology and Toxicology, University of Bonn, addressed the interesting topic of exosomal miRNAs, energy expenditure, and brown fat. He began by noting the brown adipose tissue (BAT) is essential for non-shivering thermogenesis and regulates whole-body metabolism. He said brown fat activity correlates with leanness and has, therefore, received significant attention as a potential target for anti-obesity therapies. However, he noted, there is presently a lack of BAT diagnostics, and that novel diagnostic tools are need to develop BAT-centered therapies. In the current work, Dr. Pfeifer focused on exosomes released from BAT in order to identify biomarkers of BAT activity. Exosomes were isolated from brown adipocytes, explanted brown fat depots, and also from serum of mice. Brown adipocytes released exosomes in an activation-dependent manner. Physiologically, norepinephrine (NE) induces BAT energy expenditure by activating the cyclic AMP signaling pathway in brown adipocytes. Increasing cyclic AMP levels resulted in activation of brown adipocytes and induced a five-fold increase in exosome release. In addition, BAT isolated from mice exposed to cold released nine-fold more exosomes than BAT from mice kept at room temperature. The conclusion drawn is that exosome release is increased after activation of BAT. In order to identify potential biomarkers of BAT activity, the scientists focused on miRNAs. They and other groups had previously identified miRNAs that regulat BAT function. Dr. Pfeifer’s group profiled the miRNAs contained in exosomes released from brown adipocytes and BAT.

ASEMV 2017—Possible Role for Natural Killer Cell-Derived Exosomes and Exosomal miRNAs in Cancer Therapy

On Tuesday evening, Octobere 10, Muller Fabbri, MD, PhD, Children’s Hospital Los Angeles, discussed the possible role of NK cell-derived exosomes and NK cell-derived microRNAs (miRNAs) in cancer therapy. He noted first that NK cell-derived exosomes exhibit cytotoxic activity against MYCN-amplified neuroblastoma cell lines. In addition, these exosomes carry tumor suppressor miRNAs whose expression in tumors correlates with NK activation markers (i.e., NKG2D and DNAM-1) and harbor prognostic implications. Importantly, the scientists found that NK-derived exosomal miRNAs target key driver oncogenes in neuroblastoma and the TGF pathway that is responsible for NK immune-suppression within the tumor microenvironment. Targeted delivery of NK-derived exosomal miRNAs by nanoparticles to MYCN-amplified neuroblastoma or NK cells, resulted in inhibition of neuroblastoma tumorigenic potential and prevented the TGF1-dependent inhibition of NK cells. Taken together, Dr. Fabbri said, these data support a role for NK-derived exosomes and exosomal miRNAs as a potential therapeutic option alongside NK cell-based therapy. The American Society for Exosomes and Microvesicles (ASEMV) 2017 Annual Meeting was held October 8-12 at the Asilomar Conference Grounds in Pacific Grove, California. The event was attended by 180 scientists from around the United States and world. This year’s meeting was organized by ASEMV President Dr. Stephen J. Gould of Johns Hopkins University, and sponsors of the meeting included Particle Metrix, CARIS Life Sciences, ReNeuron, Malvern, QIAGEN, Hitachi Chemical, iZON, System Biosciences, Beckman Coulter, Norgen Biotek Corporation, Hansa Bio Med Life Sciences, Lonza, and nanoView Diagnostics.

ASEMV 2017—Engineered Exosomes with Super Repressor IkB, a Potent Inhibitor of NF-kB Pathway, for Treatment of Septic Shock

On Monday morning, October 9, Chulhee Choi, MD, PhD, of the Department of Bio and Bioengineering, KAIST, Korea; and CEO of Cellex Life Sciences, Inc., described the potential for a new system to treat acute inflammatory diseases, including septic shock. To emphasize the need for improvements in the treatment of septic shock, Dr. Choi noted that there are 20 million cases of this disease each year and that it is the leading cause of death in intensive care units. Previously, Dr. Choi’s group had developed an opto-generated engineered exosome system, named “exosomes for protein loading via optically reversible protein-protein interaction” (EXPLOR) that can deliver soluble proteins into the cytosol via controlled reversible protein-protein interactions (PPI). Treatment with protein-loaded EXPLORs was shown to significantly increase intracellular levels of cargo proteins and their function in recipient cells in both a time- and dose-dependent manner. In the current study, the group sought to test the feasibility of using EXPLOR technology for the delivery of super repressor IkB (SRI), a potent inhibitor of the NF-kB pathway, as a potential treatment for acute inflammatory diseases such as septic shock syndrome. The group was able to load SRI into engineered exosomes by transiently or stably expressing fusion proteins in exosome-producing cells. The scientists further demonstrated the intracellular delivery of SRI as functional proteins in the target cells in vitro and target organs in vivo. Finally, the researchers observed a beneficial effect of SRI-loaded exosomes in septic shock animal models compared to what is seen with naïve exosomes. Dr.

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