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More Structured Senescence May Be Another Clue to Long Life Span and Cancer Resistance of Naked Mole Rat

With their large buck teeth and wrinkled, hairless bodies, naked mole rats won't be winning any awards for cutest rodent. But their long life span--they can live up to 30 years, the longest of any rodent--and remarkable resistance to age-related diseases, offer scientists key clues to the mysteries of aging and cancer. That's why University of Rochester biology professors Vera Gorbunova, PhD, and Andrei Seluanov, PhD, and postdoctoral associate Yang Zhao, PhD, studied naked mole rats to see if the rodents exhibit an anticancer mechanism called cellular senescence--and, if so, "how the mechanism might work differently than in short-lived animals, like mice," says Dr. Zhao, the lead author of the study, published online on February 5, 2018 in PNAS. The article is titled “Naked Mole Rats Can Undergo Developmental, Oncogene-Induced and DNA Damage-Induced Cellular Senescence.” Cellular senescence is an evolutionary adaptation that prevents damaged cells from dividing out of control and developing into full-blown cancer. However, senescence has a negative side too: by stopping cell division in order to prevent potential tumors, it also accelerates aging. Previous studies indicated that when cells that had undergone senescence were removed from mice, the mice were less frail in advanced age as compared to mice that aged naturally with senescent cells intact. Researchers therefore believed senescence held the key to the proverbial fountain of youth; removing senescent cells rejuvenated mice, so perhaps it could work with human beings. Companies began investigating drugs--known as senolytic agents--that would kill senescent cells and translate the anti-aging effects to humans.

Structure of Full-Length Serotonin Receptor Imaged for First Time by Cryo-EM; Results May Drive “Targeted Drug Design and Better Therapeutic Strategies”

A team of researchers from Case Western Reserve University School of Medicine has used Nobel-prize-winning electron microscope technology (cryo-EM) to image full-length serotonin receptors for the first time. The tiny proteins--approximately a billionth of a meter long--are common drug targets, despite limited available information about their structure. Now, new images published online on February 6, 2018 in Nature Communications provide snapshots of the receptors, including details about molecular binding sites that could lead to more precise drug design. The open-access article is titled “Cryo-EM Structure of 5-HT3A Receptor in Its Resting Conformation.” Serotonin receptors sit in cell membranes throughout the body, including membranes in the brain, stomach, and nerves. These receptors are highly dynamic with many moving parts, making them difficult subjects to capture in images. Researchers commonly break the receptor into pieces to study it. But by studying full-length serotonin receptors, researchers in the new study showed how its different portions interact. The researchers describe "a finely-tuned orchestration of three domain movements" that allows the receptors to elegantly control passageways across cell membranes. The study reveals how serotonin receptors work, says study first author Sandip Basak, PhD, a postdoctoral fellow in the Department of Physiology and Biophysics at Case Western Reserve University School of Medicine. "The serotonin receptor acts as a gateway, or channel, from outside the cell to inside," he says. "When serotonin binds onto the receptor, the channel switches conformation from closed to open. It eventually twists into a 'desensitized' state, where the channel closes but serotonin remains attached.

New CRISPR/Cas9 Gene-Editing Technique Abolishes Splice Sites for Frequently Mutated Exons in Duchenne Muscular Dystrophy (DMD) Heart Muscle Cells

Scientists have developed a CRISPR/Cas9 gene-editing technique that can potentially correct a majority of the 3,000 mutations that cause Duchenne muscular dystrophy (DMD) by making a single cut at strategic points along the patient’s DNA, according to a study from the University of Texas (UT) Southwestern Medical Center. The method, successfully tested in heart muscle cells from patients, offers an efficient alternative to the daunting task of developing an individualized molecular treatment for each gene mutation that causes DMD. It also opens up possible new treatment approaches for other diseases that have thus far required more intrusive methods to correct single-gene mutations. Scientists say the new strategy enhances the accuracy for surgical-like editing of the human genome, correcting mistakes in the DNA sequence that cause devastating diseases like DMD, a deadly condition caused by defects in the dystrophin gene. Normally, the dystrophin protein helps strengthen muscle fibers. “This is a significant step,” said Dr. Eric Olson, Director of UT Southwestern’s Hamon Center for Regenerative Science and Medicine. “We’re hopeful this technique will eventually alleviate pain and suffering, perhaps even save the lives, of DMD patients who have a wide range of mutations and, unfortunately, have had no other treatment options to eliminate the underlying cause of the disease.” A study published online on January 31, 2018 in Science Advances documents the success of the new CRISPR/Cas9 gene-editing technique designed to treat DMD. The open-access article is titled “Correction of Diverse Muscular Dystrophy Mutations in Human Engineered Heart Muscle by Single-Site Genome Editing.” In the article abstract, the authors, including Dr. Olson, state the following.

Arginine May Have Played Key Role in Origin of Life; Finding Would Put Constraints on Types of Scenarios That Could Have Given Rise to the Genetic Code

Life as we know it originated roughly 3.5 to 4 billion years ago in the form of a prebiotic soup of organic molecules that somehow began to replicate themselves and pass along a genetic formula--or so goes the thinking behind the RNA World, one of the most robust hypotheses on the origin of life. Researchers at the University of California-Santa Barbara (UCSB) have now found evidence that the amino acid arginine (or its prebiotic world equivalent) may have been a more important ingredient in this soup than previously thought. "People tend to think of arginine as not being prebiotic," said Irene Chen, MD, PhD, a biophysicist whose research focuses on the chemical origins of life. "They tend to think of the simpler amino acids as being plausible, such as glycine and alanine." Arginine, by contrast, is relatively more complex, and was therefore thought to have entered the game at a later stage. Primordial Earth, according to the RNA World theory, had the conditions to host several types of biomolecules, including nucleic acids (which become genetic material), amino acids (which eventually link to form the proteins that are responsible for structure and function of cells), and lipids (which store energy and protect cells). Under what circumstances and how these biomolecules worked together is a source of ongoing investigation for researchers of the origins of life. For their investigation, the UCSB scientists analyzed a dataset of in vitro evolved complexes of proteins and aptamers (short RNA and DNA molecules that bind to specific target proteins).

Exosomes from Non-Metastatic Melanoma Can Stimulate Immune Response That Prevents Metastasis, Study Shows

Northwestern Medicine scientists have demonstrated that tiny vesicles (exosomes) released from non-metastatic melanoma cells trigger an immune response that prevents the cancer from spreading throughout the body. Michael Plebanek, a doctoral student in Feinberg’s Driskill Graduate Program in Life Sciences (DGP) at Northwestern Medicine, is the first author of the study, published on November 6, 2017 in Nature Communications. The open-access article is titled “Pre-Metastatic Cancer Exosomes Induce Immune Surveillance by Patrolling Monocytes at the Metastatic Niche.” Exosomes are nano-sized delivery vehicles that are released by cells into the bloodstream. In recent years, significant research has focused on the role of exosomes released by cancer cells in promoting the spread of cancer. This study, however, is the first to demonstrate that exosomes can also suppress metastasis, depending on the state of the cancer cell. “Mike’s paper is important because it provides data on the mechanisms by which these natural nanovesicles enhance the ability of the immune system to clear tumor cells and prevent cancer from spreading,” said C. Shad Thaxton, MD, PhD, Associate Professor of Urology and a co-author of the Nature Communications paper. Dr. Thaxton is also Plebanek’s advisor and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “Because the spread of cancer cells throughout the body is devastating for cancer patients, developing a deeper understanding of the process is critically important and adds to the knowledge that may result in new treatments.” Previously, it had been established that exosomes released from highly metastatic tumor cells support the spread of cancer by traveling to other organs in the body, where the exosomes nurture an environment for incoming cancer cells.

Genome Medical, Luna DNA, Blockchain Technology, All-of-Us Program, and Human Genome Variation Map Featured on Final Afternoon of Precision Medicine World Conference (PMWC) 2018

The afternoon Track 2 (Genomic Medicine) sessions of the final day of the Precision Medicine World Conference (PMWC) 2018 began with a talk by Lisa Alderson, Co-Founder and CEO, Genome Medical, that was titled “Harnessing Genetic Insights to Improve Patient Care.” Ms. Alderson had previously served as CSO at Invitae and as CEO and President of CrossLoop, Inc. She had also been the manager of Strategic Planning at Walt Disney, Co. The other co-founders of Genome Medical are Randy Scott, former CEO, Invitae; and Dr. Robert Green, Professor of Medicine, Harvard Medical School, and Director of the Genomes2People Research Program. Ms. Alderson opened her talk by posing the question—how do you tap the health-improving potential of the 325 million genomes in the US, with only about 6,000 genetic experts to rely on? She said that Genome Medical is the country’s first nationwide genomics practice. By offering easy access to clinical genetics experts through a digital health platform, Genome Medical is accelerating the integration of genomics into everyday health care. According to its web site, Genome Medical was founded to bridge the growing gap between available genome technology and current medical practice. In an age of incredible medical achievements and the advancement of DNA sequencing, many physicians, patients, and healthy individuals lack access to the advantages of genetic testing. Genome Medical exists to improve the logistics of ordering pertinent genetic tests and combine them with the appropriate genetic counseling for the benefit of individuals and their families. Each person’s unique genome significantly impacts health, severity of disease, and response to therapy. The genome isn’t responsible for all disease, but it is connected to virtually every aspect of well-being throughout a lifetime and across many conditions.

Novel Combination Cancer Therapy, Innovative Approach to Regional Cancer Care, Tissue-Agnostic Drug Approvals, Liquid Biopsy, and Metabolomics Featured on Morning of Day 3 of Precision Medicine World Conference (PMWC) 2018

Track 1 (Patient-Centered Care) of Day 3 of the Precision Medicine World Conference (PMWC) 2018 began with a presentation by Ron Levy (photo), MD, Professor and Chief, Division of Oncology, Stanford University School of Medicine. Over a decade ago, Dr. Levy developed the first FDA-approved antibody for the treatment of cancer, rituximab, which is now used for every lymphoma patient, either as a standalone treatment on in combination with other therapies. Dr. Levy’s talk on this day was titled “A Better Way to Trigger the Immune Response Against Cancer.” Dr. Levy outlined a new combination immunotherapy approach that is described in a January 31, 2018 Science Translational Medicine article (http://stm.sciencemag.org/content/10/426/eaan4488). In a mouse model, Dr. Levy’s group showed that intratumor injection of the combination of unmethylated CG-enriched oligodeoxynucleotide (CpG), a Toll-like receptor 9 ligand (TLR9), and anti-OX40 antibody led to shrinkage of distant tumors and long-term survival of the animals, even in a stringent spontaneous tumor model. Low doses of CpG injected into the tumor induce the expression of OX40 on CD4+ T-cells in the microenvironment of the tumor. An agonistic anti-OX40 antibody can then trigger a T-cell immune response that is specific to the antigens of the originally injected tumor. TLRs are components of the innate immune system that recognize molecular patterns on pathogens. In mice, the combination of CpG, TLR9, and anti-OX40 was shown to cure multiple types of cancer and to prevent spontaneous genetically driven cancers. Dr. Levy noted that one of the most spectacular results was seen in a model of spontaneous breast cancer where the combination treatment eliminated the cancer from all ten mammary glands in a very short time. Dr.

Liquid Biopsy & Cancer Commons Presentations Highlight Afternoon of Day 2 of Precision Medicine World Conference (PMWC) 2018

In the afternoon sessions of Day 2 of the Precision Medicine World Conference (PMWC) 2018, the Track 2 Liquid Biopsy Showcase continued with a series of talks. The first was given by George Karlin-Neumann, PhD, Director of Scientific Affairs, Digital Biology Center, Bio-Rad Laborartories. At Bio-Rad, Dr. Karlin-Neumann is helping to drive the research and clinical adoption of droplet digital PCR through collaborations and internal research programs, especially in cancer liquid biopsy. He noted that the benefits of droplet digital PCR include absolute quantitation, high precision and sensitivity, high throughput, and removal of PCR efficiency bias. A second talk was delivered by Andre Marziali, PhD, President & CEO, Boreal Genomics; and Professor, University of British Columbia. Dr. Marziali and the R&D team at Boreal hold 19 issued patents on methods for high-accuracy next-generation sequencing library preparation technologies to reduce the cost of liquid biopsy assays. Dr. Marziali highlighted Boreal’s OnTarget Circulating Tumor DNA (ctDNA) Analysis technology. The customer can select pre-configured or custom panels of up to 100 mutations; submit plasma, FFPE and fresh-frozen tissue, or DNA samples; and receive a report with mutations quantified at ≥0.01% abundance. The OnTarget™ services are for research-use only, not for diagnostic use. The next presentation was delivered by Atul Sharan, President & CEO of CellMax Life. Sharan is a trained engineer who was previously President & CEO at AutoESL, and Founder, President, & CEO at Clear Shape Technologies. Sharan founded CellMax Life after his wife had been cleared of breast cancer in a mammogram and then, just weeks later, was diagnosed with breast cancer via additional testing.

Clinical Diagnostics and Artificial Intelligence Tracks Offer Key Insights in Morning Session of Day 2 of Precision Medicine World Conference (PMWC) 2018

The Track 5 (Clinical Diagnostics Showcase) session of Day 2 of the Personalized Medicine World Conference (PMWC) 2018 began with a talk by Bernhard Zimmerman, PhD, Vice President R&D, at Natera. Dr. Zimmerman was the lead scientist in Natera’s development of the massively multiplex PCR and market-leading Panorama non-invasive prenatal test. More recently, his team has developed multiple workflows for analysis of circulating tumor DNA (ctDNA) using fixed and personalized panels. In particular, Dr. Zimmerman described Natera’s Signatera ctDNA technology, which is is truly personalized in that it focuses on 16 or more mutations known to be present in a patient’s tumor sample (“tumor signatures”). This unique approach enables high sensitivity and specificity for ctDNA detection and monitoring, Dr. Zimmerman noted. He also cited a Nature study, published on May 25, 2017, in which Natera technology was used to enable a tumor-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants (https://www.nature.com/articles/nature22364). The next speaker was John Heimer, President & CEO, Olink Proteomics. Olink’s goal is to facilitate and implement precision medicine via discovery and development of validated protein targets to identify smaller protein signatures for, e.g., stratification and prediction, and to advance them in clinical decision-making. Olink’s precision proteomics panels are able to achieve a high level of multiplexing while maintaining exceptional data quality thanks to its proprietary Proximity Extension Assay (PEA) technology. Each biomarker is addressed by a matched pair of antibodies, coupled to unique, partially complementary oligonucleotides, and measured by quantitative real-time PCR.

Precision Medicine World Conference (PMWC) 2018 Opens in California’s Silicon Valley

The ninth annual Precision Medicine World Conference (PMWC) 2018-Silicon Valley opened on Monday, Janaury 22, at the Computer History Museum in Mountain View, Calfornia. This year’s premier three-day event is expected to attract almost 1,500 attendees and will feature over 350 speakers, 250 companies, and scores of exhibitors. The meeting is organized by Tal Behar and her husband Gadi Behar. Monday’s official opening was preceded by a special awards ceremony Sunday evening at which four highly distinguished scientists were presented with special awards. The PMWC 2018 Luminary Award was presented to Emmanuelle Charpentier, PhD, for spearheading the development of the groundbreaking CRISPR-Cas9 genome editing technology. With this award, the PMWC recognizes recent contributions of preeminent figures who have accelerated personalized medicine into the clinical marketplace. The PMWC 2018 Pioneer Awards were presented to Alan Ashworth, PhD, for co-discovering the BRCA2 gene mutation and making discoveries leading to PARP inhibition in breast and other cancers; to Professor Sir John Bell (photo), of Oxford University, for leading genetic and genomic research initiatives that enable precision medicine in the UK and globally; and to Ronald Levy, MD, for developing the first FDA-approved antibody for the treatment of cancer (rituximab). With its Pioneer Awards, the PMWC recognizes rare individuals who have presaged the advent of personalized medicine when less evolved technology and encouragement from peers existed, but still made major advances in the field. Previous PMWC award recipients include Jennifer Douda, Lee Hood, George Church, and Francis Collins. Day One of PMWC 2018 was divided into five parallel tracks focusing on areas crucial for precision medicine.

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