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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.

Precision Medicine World Conference (PMWC) 2018 Holds Opening Awards Ceremony at Mission Bay Campus of UCSF; Emmanuelle Charpentier, Alan Ashworth, John Bell, & Ron Levy Honored

The Precision Medicine World Conference 2018 Silicon Valley (PMWC 2018 SV) kicked off on Sunday evening January 21 with a special awards ceremony at Genentech Hall on the Mission Bay campus of the University of California-San Francisco (UCSF). UCSF hosted the ceremony and Keith Yamamoto, PhD, Vice Chancellor for Research, Executive Vice Dean of the School of Medicine, and Professor of Cellular and Molecular Pharmacology at UCSF, MC’d the event. The PMWC 2018 Luminary Award was presented to Emmanuelle Charpentier (photo receiving award from Dr. Yamamoto), 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, 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. The general PMWC 2018 SV meeting officially opens on Monday, January 22 and runs through Wednesday, January 24 (http://www.pmwcintl.com/2018sv-info/). It will be held at the Computer History Museum in Mountain View.

“Superior Genome” May Allow Down Syndrome Fetuses to Survive Pregnancy with Average Life Expectancy of 60 Years--Authors Propose That Embryonic Selection for Reduced Burden of Slightly Deleterious Variants Permits Survival of Extremely Deleterious Variant

Trisomy 21 is a serious genetic disorder, with four pregnancies out of five not reaching term naturally if the fetus is affected. However, 20% of conceptuses with Down's syndrome are born live, grow up and many live into their 60s and 70s (the average life span is 60). How is this possible? Researchers from the Universities of Geneva (UNIGE) and Lausanne (UNIL) have found that children born with Down's syndrome have an “excellent” genome – “better” in terms of certain measurable criteria (gene variation, gene regulation, gene expression), in fact, than the average genome of people without the genetic abnormality. It is possible that this “higher-quality” genome offsets the disabilities caused by the extra chromosome, helping the fetus to survive and the child to grow and develop. In their abstract of an article published in the January 2018 issue of Genome Research, the researchers say the following. “Here, we investigate if the survival probability of aneuploid fetuses is affected by the genome-wide burden of slightly deleterious variants. We analyzed two cohorts of live-born Down syndrome individuals (388 genotyped samples and 16 fibroblast transcriptomes) and observed a deficit of slightly deleterious variants on chromosome 21 and decreased transcriptome-wide variation in the expression level of highly constrained genes. We interpret these results as signatures of embryonic selection, and propose a genetic handicap model whereby an individual bearing an extremely severe deleterious variant (such as aneuploidy) could escape embryonic lethality if the genome-wide burden of slightly deleterious variants is sufficiently low.

Can Mesenchymal Stem Cell Exosomes Be Effective Therapy for Heart Disease in Diabetes? $2.6 Million Grant Awarded for Study

Macrophage cells routinely remove dead or dying cells to maintain the body homeostasis. Such removal becomes crucial after serious injury, especially the repair of dead heart muscle after a heart attack. According to a recent January 18, 2018 news release, University of Alabama (UAB) at Birmingham researchers have preliminary data, with cultured cells or diabetic hearts, suggesting that diabetes impairs this removal of dead heart-muscle cells. The scientists believe this impairment may be the reason diabetes increases the risk for cardiovascular disease, including heart failure. Aided by a new, four-year, $2.64-million grant from the National Institutes of Health (NIH), Prasanna Krishnamurthy, DVM, PhD, and Jianyi “Jay” Zhang, MD, PhD, both investigators in the UAB Department of Biomedical Engineering, will study whether mesenchymal stem cells (MSCs) or their exosomes can boost dead cell removal and also reduce damaging inflammation after heart attacks in animal models of diabetes. The removal of dead cells by macrophages or other scavenger cells is called efferocytosis, which sometimes is referred to as “the burying of dead cells.” Exosomes are tiny vesicles released by cells. One role of exosomes, which can contain proteins and RNA from the cell that releases them, is communicating among cells. Dr. Krishnamurthy and Dr. Zhang hypothesize that exosomes from MSCs are enriched with factors that promote the removal of dead cells by macrophage cells. The scientists further hypothesize that delivery of exosomes derived from MSCs to the injured heart will enhance removal of dead cells and improve healing of the heart attack wound, thus aiding efficient regeneration and repair of heart tissue and preventing further damage. They will test this in murine and porcine models of heart disease.

Revolutionary New Blood Test (CancerSEEK) Detects & Localizes Eight Different Cancers, Including Pancreatic; Approach Involves Liquid Biopsy and Use of Machine Learning, Legendary Bert Vogelstein Among Reporting Hopkins Scientists

Johns Hopkins Kimmel Cancer Center researchers have developed a single blood test that screens for eight common cancer types and helps identify the location of the cancer. The test, called CancerSEEK, is a unique noninvasive, multi-analyte test that simultaneously evaluates levels of eight cancer proteins and the presence of cancer gene mutations from circulating DNA in the blood. The test is aimed at screening for eight common cancer types that account for more than 60 percent of cancer deaths in the U.S. Five of the cancers covered by the test currently have no screening test. “The use of a combination of selected biomarkers for early detection has the potential to change the way we screen for cancer, and it is based on the same rationale for using combinations of drugs to treat cancers,” says Nickolas Papadopoulos, PhD, senior author and professor of oncology and pathology. The findings were published online by Science on January 18, 2018. The article is titled “Detection and Localization of Surgically Resectable Cancers with a Multi-Analyte Blood Test” “Circulating tumor DNA mutations can be highly specific markers for cancer. To capitalize on this inherent specificity, we sought to develop a small, yet robust, panel that could detect at least one mutation in the vast majority of cancers,” says Joshua Cohen, an MD, PhD student at the Johns Hopkins University School of Medicine and the paper’s first author. “In fact, keeping the mutation panel small is essential to minimize false-positive results and keep such screening tests affordable.” The investigators initially explored several hundred genes and 40 protein markers, whittling the number down to segments of 16 genes and 8 proteins.

30-Year Study Shows Women Who Breastfeed for 6 Months or More Reduce Their Type 2 Diabetes Risk by Almost 50%

In a long-term national study, breastfeeding for six months or longer was found to cut the risk of developing type 2 diabetes nearly in half for women throughout their childbearing years, according to new Kaiser Permanente research published online on January 16, 2016 in JAMA Internal Medicine. The open-access article is titled “Lactation Duration and Progression to Diabetes in Women Across the Childbearing Years: The 30-Year CARDIA Study.” "We found a very strong association between breastfeeding duration and lower risk of developing diabetes, even after accounting for all possible confounding risk factors," said lead author Erica P. Gunderson, PhD, MS, MPH, Senior Research Scientist with the Kaiser Permanente Division of Research. Women who breastfed for six months or more across all births had a 47 percent reduction in their risk of developing type 2 diabetes compared to those who did not breastfeed at all. Women who breastfed for six months or less had a 25 percent reduction in diabetes risk. Dr. Gunderson and colleagues analyzed data during the 30 years of follow-up from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a national, multi-center investigation of cardiovascular disease risk factors that originally enrolled approximately 5,000 adults aged 18 to 30 in 1985 to 1986, including more than 1,000 members of Kaiser Permanente Northern California. The new findings add to a growing body of evidence that breastfeeding has protective effects for both mothers and their offspring, including lowering a mother's risk of breast and ovarian cancer. The CARDIA findings are also consistent with those of the NIH-funded Study of Women, Infant Feeding and Type 2 Diabetes after GDM Pregnancy (SWIFT), also led by Dr.

Hepatic Leukemia Factor (HLF) Protects Blood Stem Cells by Maintaining Them in Resting State

"The study confirms several previous studies that show the HLF gene's significance in blood formation,” says Mattias Magnusson, PhD, of Lund University, who led a new study, the results of which were published in the December 19, 2017 issue of Cell Reports. The open-access article is titled “Hepatic Leukemia Factor Maintains Quiescence of Hematopoietic Stem Cells and Protects the Stem Cell Pool During Regeneration.” The results can have important applications in bone marrow transplants, as well as contribute to our knowledge of how leukemia develops. Maintaining blood production, especially in the case of injury, chemotherapy, or a transplantation, is dependent on a limited number of stem cells in the bone marrow. These blood stem cells have the unique capacity to make an identical copy of themselves and to mature into all the different types of blood cells. To ensure lifelong maintenance of normal blood stem cell function, most blood stem cells are held in a resting state. This protects them from exhaustion and external Impact. However, the blood stem cells can be rapidly deployed to reconstruct the blood system in the case of trauma, after which they revert to their resting state. "Identifying the factors that control blood stem cells provides knowledge needed to be able to propagate the stem cells outside the body. This has long been one of the major goals in the blood stem cell field, as it would increase possibilities for blood stem cell transplantation when, for example, there is a shortage of stem cells or donors. In addition, we will increase our understanding of how leukemia arises,” explains Dr. Magnusson. Several research teams have previously identified the HLF gene as a possible stem cell regulator for both normal and carcinogenic blood formation.

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