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Cholesterol-Lowering Drugs Reduce Brown Fat

A certain proportion of the adult population has not only white adipose (or fatty) tissue (left), but also the brown kind (right). This brown adipose tissue helps to convert sugar and fat into heat. People with brown adipose tissue are better at regulating their body temperature in the winter, and are less likely to suffer from excess weight or diabetes. An international team of researchers led by Dr. Christian Wolfrum, Professor for Translational Nutritional Biology at ETH Zurich, has now discovered that the statin class of pharmaceuticals reduces the formation of brown adipose tissue. The article was published online on December 20,2018 in Cell Metabolism. It is titled “Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation.” Statins are prescribed as a way to reduce the risk of a heart attack because they reduce cholesterol levels in the blood. They are among the most commonly prescribed drugs worldwide. Dr. Wolfrum and his colleagues have been researching brown adipose tissue for many years. They looked into the question of how "bad" white fat cells, which form the layer of fat under our skin, become "good" brown fat cells. Having conducted cell culture experiments, they found out that the biochemical pathway responsible for producing cholesterol plays a central role in this transformation. They also discovered that the key molecule regulating the transformation is the metabolite geranylgeranyl pyrophosphate. Earlier studies showed that the cholesterol biochemical pathway is also central to the functioning of statins; one of their effects is to reduce the production of geranylgeranyl pyrophosphate. This is why the researchers wanted to know whether statins also impact the formation of brown adipose tissue.

Study Examines Primary Drivers of Increased Hospitalizations of Homeless Individuals

A homeless individual is one who lacks fixed and reliable housing, and approximately 553,000 people fit that description on any given night in the United States. A new retrospective cohort study led by investigators from Beth Israel Deaconess Medical Center (BIDMC) and Brigham and Women's Hospital in Boston examines patterns, causes, and outcomes of acute hospitalizations between 2007 and 2013 for homeless individuals and non-homeless control groups in three populous and diverse U.S. states: Florida, California, and Massachusetts. Data suggest a rise in acute hospital use among homeless individuals for mental illness and substance use disorder. The results were published in the January 2019 issue of Medical Care. The article is titled “Trends, Causes, and Outcomes of Hospitalizations for Homeless Individuals--A Retrospective Cohort Study.” "The homeless population is aging, and the rate of hospitalizations for homeless individuals is increasing," said lead author Rishi Wadhera, MD, an investigator in the Smith Center for Outcomes Research in Cardiology at BIDMC. "Although there has been a recent push to establish better policy and public health measures to improve the health of homeless adults, few studies have examined the patterns and causes of hospitalizations in this population. We found that hospitalizations among homeless adults tend to be for a very different set of conditions than non-homeless adults, even after accounting for differences in demographics." To examine these trends, hospital discharge data was acquired from Massachusetts and Florida between 2001 and 2013 and from California between 2007 and 2011.

Phage Display Pioneer & Industry Leader Celebrates Success of Revolutionary Technology Together with 2018 Nobel Laureates in Chemistry

IONTAS Limited (IONTAS), a leader in the discovery and optimization of fully human antibodies, announced that its Founder and Chief Executive Officer, Dr. John McCafferty (photo), was invited to attend the Nobel Prize Award Ceremony in recognition of his pivotal contribution to the development of antibody phage display technology. The event, held in Stockholm, Sweden, on December 10, celebrated the 2018 Nobel Laureates and the success of phage display technology in modern drug discovery and development, which the Royal Swedish Academy of Sciences recognized in this year’s Nobel Prize in Chemistry (https://www.nobelprize.org/prizes/chemistry/2018/press-release/). Sir Gregory Winter (MRC Laboratory of Molecular Biology, Cambridge, UK) and Dr. George Smith (University of Missouri, Columbia, Missouri, USA) jointly received one half of the Nobel Prize in Chemistry 2018 “for the phage display of peptides and antibodies.” Dr. Frances Arnold (California Institute of Technology, Pasadena, California, USA) was awarded the other half “for the directed evolution of enzymes.” Dr. Smith published his breakthrough paper on display of peptides on filamentous bacteriophage in 1985. Inspired by this, Dr. Winter and Dr. McCafferty then applied the approach to antibody display, with the aim of producing new pharmaceuticals. While working in Dr. Winter’s group, Dr. McCafferty became the first to demonstrate the display of functional antibodies on the surface of phage (McCafferty et al., Nature, 1990) (https://www.nature.com/articles/348552a0). This landmark achievement, cited by the Nobel committee, made it possible to create “libraries” of phage particles containing billions of different human antibody genes from which antibodies to any target could be easily isolated.

Precision Medicine World Conference (PMWC) 2019 Conference in January in Silicon Valley; Q&A Session with Luminary Award Winner MIT Professor Feng Zhang (Optogenetics & CRISPR Advances) Available Now

The Precision Medicine World Conference (PMWC), celebrating ten years of operation, will take place at the Santa Clara Convention Center (Silicon Valley, California) January 20-23, 2019. This is expected to be the largest Precision Medicine World Conference ever, with 2,500 attendees. This amazing gathering of prestigious experts in multiple inter-related fields and those interested in learning more is co-hosted by UCSF, Stanford Health Care/Stanford Medicine, Duke University, Duke Health, and Johns Hopkins University. The program will cover innovative technologies, thriving initiatives, and clinical case studies that enable the translation of precision medicine into direct improvements in health care. Conference attendees (https://www.pmwcintl.com/about/#audience) will have an opportunity to learn first-hand about the latest developments and advancements in precision medicine and cutting-edge new strategies and solutions that are changing how patients are treated. The conference’s five-track program will include sessions on the following major topics, among many others: AI & Data Science; Clinical & Research Tools; Clinical Diagnostics; Creating Clinical Value with Liquid Biopsy ctDNA, etc.; Digital Health/Health and Wellness; Pharmacogenomics; Emerging Technologies in Precision Medicine; Immunotherapy; Large-Scale Bio-Data Resources to Support Drug Development; Rare Disease Diagnosis; and Wellness & Aging. Conference organizers have assembled a hugely impressive lineup of 450+ highly regarded speakers, featuring pioneering researchers and authorities across the healthcare and biotechnology sectors (https://www.pmwcintl.com/2019sv/speakers/). The conference will begin with the presentation of the PMWC’s prestigious Luminary & Pioneer Awards (https://www.pmwcintl.com/2019sv/awards/).

Plants Produce Catnip Terpene (Nepetalactone) in Two-Step Enzymatic Process Not Seen Before; Unusual Process May Be Useful in Synthesis of Anti-Cancer Drugs Such As Vinblastine & Vincristine

Researchers at John Innes Centre in the UK have shed light on how catnip – a plant from the genus Nepeta and also known as catmint - produces the chemical that sends cats into a state of wanton abandon. The remarkable effect catnip has on cats is well known thanks to the scores on online videos showing pets enjoying its intoxicating highs. The substance that triggers this state of feline ecstasy is called nepetalactone, a type of chemical called a terpene. This simple, small molecule is part of an unusual chain of events, not previously seen by chemists. The researchers believe that understanding the production of these nepetalactones could help them recreate the way that plants synthesize other chemicals like vinblastine, which is used for chemotherapy. This could lead to the ability to create these useful medicines more efficiently and quickly than we are currently able to harvest them from nature. Usually in plants, for example peppermint, terpenes are formed by a single enzyme. In their paper published online on December 10, 2018 in Nature Chemical Biology, the John Innes researchers report that, in catnip, terpenes are formed in a two-step process; an enzyme activates a precursor compound which is then acted on by a second enzyme to produce the substance of interest. The article is titled “Uncoupled Activation and Cyclization in Catmint Reductive Terpenoid Biosynthesis.” This two-step process has previously never been observed, and the researchers also expect something similar is occurring in the synthesis of anti-cancer drugs vincristine and vinblastine from Madagascan periwinkle, Catharanthus roseus, and elsewhere in olive and snapdragon. In the publication, the team describe the process by which catmint produces nepetalactone in microscopic glands on the underside of its leaves.

Study Supports Potential for Tailoring Patient-Specific Treatments for Acute Myeloid Leukemia (AML)

Advances in rapid screening of leukemia cells for drug susceptibility and resistance are bringing scientists closer to patient-tailored treatment for acute myeloid leukemia (AML). Research on the drug responses of leukemia stem cells may reveal why some attempts to treat are not successful or why initially promising treatment results are not sustained. AML is a serious disorder of certain blood-forming cells. In this disease, certain early precursor cells in the bone marrow that usually develop into white blood cells don't mature properly. They remain frozen as primitive cells called blasts, unable to further differentiate and mature. These can accumulate and cause low blood counts that reduce the ability to fight infections, and low platelet counts that cause risk of life-threatening hemorrhage. Leukemia stem cells - the progenitors for the immature, cancerous blood cells - propagate AML, and also play a role in the cancer returning after treatment. Cancer researchers are interested in how genes are expressed in this cell population, because this data may hold clues to resistance to standard therapies and answers to why some patients relapse. A study presented at the 60th Annual Meeting of the American Society of Hematology in San Diego (December 1-4, 2018) looked at the drug response patterns of stem cells and blast cells taken from individual patients diagnosed with AML. The information was gathered through high-throughput screening, a state-of-the-art method for quickly evaluating and testing many samples. The researchers found that leukemia stem cells and blast cells diverged in their drug susceptibility patterns, and also that these patterns differed from patient to patient.

Lifespan Extension at Low Temperatures Is Actively Controlled by Genes, Not by Passive Lowering of Metabolic Rate Reducing Reactive Oxygen Species (ROS), New Study Suggests

Why do we age? Despite more than a century of research (and a vast industry of youth-promising products), what causes our cells and organs to deteriorate with age is still largely unknown. One known factor is temperature: Many animal species live longer at lower temperature than they do at higher temperatures. As a result, "there are people out there who believe, strongly, that if you take a cold shower every day it will extend your lifespan," says Kristin Gribble (photo), PhD, an Assistant Scientist at the Marine Biological Laboratory(MBL) in Woods Hole, Massachusetts (the MBL is an affiliate of the University of Chicago). But a new study from Dr. Gribble's lab indicates that it's not just a matter of turning down the thermostat. Rather, the extent to which temperature affects lifespan depends on an individual's genes. The study from Dr. Gribble's group, which was published in Experimental Gerontology (114: 99-106; 2018), was conducted in the rotifer, a tiny animal that has been used in aging research for more than 100 years. Gribble's team exposed 11 genetically distinct strains of rotifers (Brachionus) to low temperature, with the hypothesis that if the mechanism of lifespan extension is purely a thermodynamic response, all strains should have a similar lifespan increase. However, the median lifespan increase ranged from 6 percent to 100 percent across the strains, they found. They also observed differences in mortality rate. The new study is titled “Congeneric Variability in Lifespan Extension and Onset of Senescence Suggest Active Regulation of Aging in Response to Low Temperature.” This study clarifies the role of temperature in the free-radical theory of aging, which has dominated the field since the 1950s.

A-T Children’s Project Announces Selection of First Child to Receive ASO Gene Therapy for Ataxia-Telangiectasia

On November 30, 2018, the Ataxia-Telangiectasia (A-T) Children’s Project and its President Brad Margus announced that the Project has selected a little, 18-month girl on the west coast of the U.S. to be the first A-T child in history to receive gene therapy. The Project had the pleasure of letting th girl's parents know the exciting news last week. How was the first child selected? The laboratory of Dr. Tim Yu at Boston Children’s Hospital/Harvard collected and grew skin, blood, and stem cells from three different young children who we believed had the right type of mutations in their A-T genes to be treated with an antisense oligonucleotide (ASO) gene therapy approach. The scientists then made many different oligonucleotides designed to silence each of the children’s mutations and tested them in each child’s cells. In the end, the group identified several oligonucleotide molecules that worked really well in this little girl’s cells, not only silencing her mutation and causing the A-T protein to be made correctly, but also causing downstream biological pathways to be activated as though her cells were from a healthy child (confirming this downstream function took us longer than planned to do, but now gives us more confidence to move forward). This means that we now have both our drug and our patient selected. Very soon, we’ll be signing a contract to begin the manufacture of enough quantity of the drug to run our “n of 1” clinical trial (we’ll keep the other oligonucleotides that worked as backups). We’ll also make sure that the drug produced will be clinical-grade to satisfy the FDA. As soon as we receive the first batch of this final version of the drug, we’ll test it for safety in rats before applying to the FDA for approval to start testing it in a human.

Sugars & Microbiome in Mother's Milk Influence Neonatal Rotavirus Infection

Using a multidisciplinary approach, an international team of researchers from several institutions, including Baylor College of Medicine, reveals that complex interactions between sugars and the microbiome in human milk influence neonatal rotavirus infection. Reported online on November 27, 2018 in the journal Nature Communications, this study provides new understanding of rotavirus infections in newborns and identifies maternal components that could improve the performance of live, attenuated rotavirus vaccines. The open-access article is titled “Human Milk Oligosaccharides, Milk Microbiome and Infant Gut Microbiome Modulate Neonatal Rotavirus Infection.” "Rotavirus infection causes diarrhea and vomiting primarily in children younger than 5, with the exception of babies younger than 28 days of age, who usually have no symptoms. However, in some places, infections in newborns are associated with severe gastrointestinal problems. What factors mediate differences between newborns with and without symptoms are not clearly understood," said first and corresponding author Dr. Sasirekha Ramani (photo), Assistant Professor of Molecular Virology and Microbiology at Baylor College of Medicine. "We began our investigation years ago by determining that a particular strain of rotavirus was associated with both asymptomatic infections and clinical symptoms in newborns." Dr. Ramani and her colleagues first looked for answers from the perspective of the virus. They investigated whether factors such as the amount of virus in newborns or the genome of the virus could be linked to the presence of symptoms in newborns, but did not find any connection between those factors. The researchers then posed the question from the perspective of the newborn.

International Society for Extracellular Vesicles (ISEV) Releases 2018 Update of 2014 Guidelines for Studies of Extracellular Vesicles

On November 23, 2018, The International Society for Extracellular Vesicles (ISEV) published online an open-access position paper titled “Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV2018); A Position Statement of the International Society for Extracellular Vesicles and Update of the MISEV2014 Guidelines.” The article is scheduled for hard-copy publication in Volume 8, Issue 1, of the 2019 Journal of Extracellular Vesicles. In the article abstract, the authors note the following: “The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The ISEV proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation.

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