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July 16th, 2018

Pre-Clinical Studies in Mice Show Strong Therapeutic Potential of CAR-T Cell Immunotherapy in Colorectal Cancer

(BY RACHEL DERITA, PhD Candidate,Thomas Jefferson University, Department of Cancer Biology) At Thomas Jefferson University in Philadelphia, researchers have recently shown that in mice, a CAR-T cell therapy successfully eliminated primary colorectal tumors and prevented metastatic growth. This is a breakthrough for the potential use of chimeric antigen receptor (CAR) - T cell therapy in the treatment of solid tumors. The University of Pennsylvania (UPenn) has previously made clinical advances recently with its use of CAR-T cell therapy in non-solid tumors, but there is still a great need for new therapeutic options involving the immune system in solid tumors. CAR-T cell therapy involves taking a patient’s own immune cells, then engineering them to target tumor cells specifically, and then infusing them back into the patient. In the current study, led by Dr. Adam Snook, PhD, Assistant Professor, T cells were engineered to target an antigen called GUCY2C. This protein had been previously identified as a biomarker and potential therapeutic target in colorectal cancer by the laboratory of Scott Waldman, PhD, MD, Chair of the Department of Pharmacology & Experimental Therapeutics at Jefferson. Dr. Snook also mentions that other high-mortality cancers such as esophageal and pancreatic cancer also express GUCY2C. This means that this pre-clinical study has implications for treating up to 25% of patients who would otherwise die from their cancer. In the Jefferson study, researchers used a “human-ready” mouse model of colorectal cancer to test CAR-T cell therapy targeted against GUCY2C. None of the mice experienced side effects and the therapy successfully fought the tumor over the duration of 75 days. The average survival time for the control group was only 30 days.

Sulfate Code That Allows Neurodegenerative Proteins into Cells

Researchers at the University of Texas (UT) Southwestern Medical Center, reporting in the July 6, 2018 issue of the Journal of Biological Chemistry, have uncovered details of how cells take in corrupted proteins that can turn normal proteins corrupt, leading to neurodegenerative diseases such as Alzheimer's and Parkinson's. The new article is titled “Specific Glycosaminoglycan Chain Length and Sulfation Patterns Are Required for Cell Uptake of Tau Versus Α-Synuclein and -Amyloid Aggregates.” Understanding the molecular details of how these proteins spread from cell to cell could lead to therapies to halt disease progression. Alzheimer's and Parkinson's are associated with particular proteins in the brain misfolding, aggregating, and inducing normal proteins to misfold and aggregate. Dr. Marc Diamond's group at UT Southwestern discovered in 2013 that to enter new cells and propagate misfolding, the disease-associated proteins tau, alpha-synuclein, and amyloid-beta must bind to a type of sugar-protein molecule called heparan sulfate proteoglycan (HSPG) on the cell's surface. This binding triggers the cell to bring the corrupted protein inside. In the new study, the group sought to understand more about how this process worked. "The question was, how specific is this (process)? Or is it not specific at all?" asked Dr. Barbara Stopschinski, the physician and researcher in Dr. Diamond's lab who oversaw the new work. What were the details of the chemical communication between HSPG and tau that triggered tau's entry into the cells? And was this process different for alpha-synuclein (associated with Parkinson's disease), amyloid-beta, and tau (both associated with Alzheimer's disease)?

July 15th

Mitochondrial DNA in Exosomes Is Warning That Initiates Antiviral Response

Researchers at the Carlos III National Center for Cardiovascular Research (CNIC) in Madrid, Spain have provided valuable information about the defense mechanisms of the immune system in early learning to respond to pathogens such as viruses or bacteria. The data from this research, published online on July 9, 2018 in Nature Communications, contribute to the understanding of cellular processes that begin in the first moments and explain how the different cellular components of the immune system communicate to give an effective response to pathogens. The CNIC researchers have determined that the mitochondrial DNA contained in certain nanovesicles causes a state of alert in the receptor cells that allows the activation of the antiviral genetic program. These nanovesicles, known as exosomes, are produced by T lymphocytes and captured by dendritic cells via intercellular contacts. The immune response against pathogens requires the specific interaction between T lymphocytes and antigen-presenting cells, especially dendritic cells, a process known as immune synapses. During this process, the researchers explain, intercellular information is exchanged both by receptor connections and their ligands, which exist on the cell surface, and by the transfer of exosomes. Until now, the activation routes in the T cells after the immune synapse had been studied; however, both the identity of the signals received and their functional effects on the dendritic cells had received less attention. The laboratory of Professor Francisco Sánchez-Madrid, principal investigator of the Intercellular Communication Group of the CNIC, Head of the Hospital la Princesa, and Professor of Immunology of the Autonomous University of Madrid, had previously described the ability of T cells to transfer exosomes to the dendritic cells during the immune synapse.

Antioxidant Benefits of Sleep Suggested in Fly Study

Understanding sleep has become increasingly important in modern society, where chronic loss of sleep has become rampant and pervasive. As evidence mounts for a correlation between lack of sleep and negative health effects, the core function of sleep remains a mystery. But in a new study published on July 12, 2018 in the open-access journal PLOS Biology, Dr. Vanessa Hill, Dr. Mimi Shirasu-Hiza, and colleagues at Columbia University, New York, found that short-sleeping fruit fly mutants shared the common defect of sensitivity to acute oxidative stress, and that sleep supports antioxidant processes. Understanding this ancient bi-directional relationship between sleep and oxidative stress in the humble fruit fly could provide much-needed insight into modern human diseases such as sleep disorders and neurodegenerative diseases. The article is titled “A Bidirectional Relationship Between Sleep and Oxidative Stress in Drosophila.” Why do we sleep? During sleep, animals are vulnerable, immobile, and less responsive to their environments; they are unable to forage for food, to mate, or to run from predators. Despite the cost of sleep behavior, almost all animals sleep, suggesting that sleep fulfills an essential and evolutionarily conserved function from humans to fruit flies. The researchers reasoned that if sleep is required for a core function of health, animals that sleep significantly less than usual should all share a defect in that core function. For this study, they used a diverse group of short-sleeping Drosophila (fruit fly) mutants. They found that these short-sleeping mutants do indeed share a common defect: they are all sensitive to acute oxidative stress. Oxidative stress results from excess free radicals that can damage cells and lead to organ dysfunction.

Massive Genome Havoc in Breast Cancer Is Revealed Using Long-Read Sequencing Technology from Pacific Biosciences

In cancer cells, genetic errors wreak havoc. Misspelled genes, as well as structural variations -- larger-scale rearrangements of DNA that can encompass large chunks of chromosomes -- disturb carefully balanced mechanisms that have evolved to regulate cell growth. Genes that are normally silent are massively activated and mutant proteins are formed. These and other disruptions cause a plethora of problems that cause cells to grow without restraint, cancer's most infamous hallmark. On June 28, 2018, scientists at Cold Spring Harbor Laboratory (CSHL) published online in Genome Research one of the most detailed maps ever made of structural variations in a cancer cell's genome. The map reveals about 20,000 structural variations, few of which have ever been noted due to technological limitations in a long-popular method of genome sequencing. The article is titled “Complex Rearrangements and Oncogene Amplifications Revealed by Long-Read DNA and RNA Sequencing of a Breast Cancer Cell Line.” The team, led by sequencing experts Dr. Michael C. Schatz and Dr. W. Richard McCombie, read genomes of the cancer cells with so-called long-read sequencing technology from Pacific Biosciences. This technology reads much lengthier segments of DNA than older short-read technology. When the results are interpreted with two sophisticated software packages recently published by the team, two advantages are evident: long-read sequencing is richer in terms of both information and context. It can, for instance, make better sense of repetitive stretches of DNA letters - which pervade the genome - in part by seeing them within a physically larger context.

July 14th

First-Line Treatment with Checkpoint Inhibitors Associated with Improved Overall Survival for Patients with Melanoma Brain Metastases

Among patients with cutaneous melanoma who had melanoma brain metastases (MBM), first-line treatment with a checkpoint inhibitor was associated with a 1.4-fold increase in median overall survival, according to results from a national cohort. These results were published online on July 12, 2018 in Cancer Immunology Research. The article is titled “Improved Risk-Adjusted Survival for Melanoma Brain Metastases in the Era of Checkpoint Blockade Immunotherapies: Results from a National Cohort.” The first author of the study is J. Bryan Iorgulescu, MD, postdoctoral fellow in the Department of Pathology at Brigham and Women's Hospital/Harvard Medical School and Department of Medical Oncology at the Dana-Farber Cancer Institute. Senior authors are Timothy Smith, MD, PhD, MPH, Director of the Computational Neuroscience Outcomes Center at the Department of Neurosurgery at Brigham and Women's Hospital/Harvard Medical School; and mentor to Dr. Iorgulescu, and David A. Reardon, MD, Clinical Director of the Center for Neuro-Oncology at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. "Checkpoint blockade immunotherapies have revolutionized how we care for patients with advanced melanoma, leading to long-lasting treatment responses in many patients," said Dr. Iorgulescu. "However, many of the early clinical trials of checkpoint blockade immunotherapies included few melanoma patients with brain metastases - despite their high incidence - and so the survival benefits of these exciting therapies remained unclear for this substantial subset of patients." Dr. Iorgulescu and colleagues evaluated data collected from the National Cancer Database (NCDB), which includes information for approximately 70 percent of newly diagnosed patients with cancer in the United States.

Yale Researchers Identify Target for Novel Malaria Vaccine

A Yale-led team of researchers has created a vaccine that protects against malaria infection in mouse models, paving the way for the development of a human vaccine that works by targeting the specific protein that parasites use to evade the immune system. The study was published online on July 13, 2018 in Nature Communications. The open-access article is titled “Neutralization of the Plasmodium-Encoded MIF Ortholog Confers Protective Immunity Against Malaria Infection.” Malaria is the second leading cause of infectious disease worldwide, and took more than a half million lives in 2013. To date, no completely effective vaccine exists, and infected individuals only develop partial immunity against disease symptoms. In a prior study, senior author Richard Bucala, MD, described a unique protein produced by malaria parasites, Plasmodium macrophage migration inhibitory factor (PMIF) (image), which suppresses memory T cells, the infection-fighting cells that respond to threats and protect the body against reinfection. In the new study, Dr. Bucala and his co-authors collaborated with Novartis Vaccines, Inc. to test an RNA-based vaccine designed to target PMIF. First, using a strain of the malaria parasite with PMIF genetically deleted, they observed that mice infected with that strain developed memory T cells and showed stronger anti-parasite immunity. Next, the research team used two mouse models of malaria to test the effectiveness of a vaccine using PMIF. One model had early-stage liver infection from parasites carried by mosquitos, and the other, a severe, late-stage blood infection. In both models, the vaccine protected against reinfection. As a final test, the researchers transferred memory T cells from the immunized mice to "naïve" mice never exposed to malaria. Those mice were also protected.

July 12th

BioQuick News Wins 2018 Publishing Excellence Award

BioQuick Online News (R) (http://www.bioquicknews.com) has recently been awarded an APEX 2018 Award for Publishing Excellence in the category of Electronic Media: Electronic Publications. BioQuick has won nine consecutive previous APEX Publishing Excellence Awards in the years 2010-2018, i.e., one in every year of its existence. BioQuick presently features over 4,700 online articles on major life science advances in the last nine years and articles on topics of interest are readily accessible by means of the publication’s powerful search engine. New articles are published on a daily basis. BioQuick has readers in over 160 countries and includes a Japanese language edition (http://www.biomarket.jp/bioquicknews/) directed by Yoshimitsu Obata, MS, in Tokyo (https://biomarket.jp/). BioQuick currently offers free and open access to all of its content. To subscribe for free biweekly emailed updates of highlights from BioQuick News, please go to (http://www.bioquicknews.com/node/3817). To learn more about the highly competitive international APEX Publishing Awards, please visit the awards web site at (http://www.apexawards.com). One indicator of the overall quality of the APEX publications competition is the high caliber of organizations numbering among the winners. This year, these winners include the University of Michigan Comprehensive Cancer Center, Fox Chase Cancer Center, Hospital for Special Surgery, National Science Foundation, American Society of Clinical Oncology (ASCO), Sandia National Laboratories, NASA, Purdue University, American Society of Hematology, American Academy of Dermatology, College of American Pathologists, Thermo Fisher Scientific, Multiple Sclerosis Association of America, National Library of Medicine, and Children’s Hospital Los Angeles.

July 12th

Nitroprusside Treatment Prevents Symptoms of Schizophrenia in Tests with Rats

Researchers at the Federal University of São Paulo (UNIFESP) in Brazil have tested a treatment with sodium nitroprusside in a strain of rats that spontaneously develop some of the symptoms associated with schizophrenia. The results obtained with a group of adolescent animals suggest that preventive treatment of the disease may be possible in the future for young people considered at risk owing to cases of schizophrenia in their family history - 15% to 30% of risk cases develop the disease later in life. The research was supported by the São Paulo Research Foundation - FAPESP. The principal investigator was Dr. Vanessa Costhek Abílio, a professor in the Pharmacology Department of UNIFESP's Medical School (Escola Paulista de Medicina). The findings were published online on April 14, 2018 in CNS Neuroscience & Therapeutics. The article is titled “Sodium Nitroprusside Is Effective in Preventing and/or Reversing the Development of Schizophrenia‐Related Behaviors in an Animal Model: The SHR Strain.” "What if we could develop a safe preventive treatment for these children so as to avert development of schizophrenia in adulthood?" Dr. Abílio wondered. Schizophrenia is an incurable neuropsychiatric disorder that typically develops in late adolescence or early adulthood. Sodium nitroprusside is a salt that acts as a significant donor of nitric oxide, a powerful vasodilator. For this reason, it has been prescribed since the 1920s for severe hypertension. More recently, evidence has been found that it might also benefit patients with schizophrenia. (read about it further in this article). The experiment used rats that spontaneously become hypertensive and also display behavioral alterations. These rats belong to a strain selected in Japan in the 1960s and used since then in animal models of hypertension and cardiovascular problems.

July 11th

The Highly Complex Sugarcane Genome Has Finally Been Sequenced

CIRAD and its partners* had to use cunning to establish the first sugarcane reference sequence. The plant's genome is so complex that conventional sequencing techniques had proved useless. This meant that sugarcane was the last major cultivated plant to have its genome sequenced. (CIRAD is Centre de Coopération Internationale en Recherche Agronomique pour le Développement.) The team took up the gauntlet using a novel approach based on a discovery made at CIRAD some 20 years previously: the genome structures of sugarcane and sorghum are very similar. The term used for this is "collinearity,” which means that there is a degree of parallelism, with numerous genes occurring in the same order. Dr. Olivier Garsmeur, a CIRAD researcher and lead author of the study, was thus able to use the sorghum genome as a template to assemble and select the sugarcane chromosome fragments to sequence. "Thanks to this novel method, the reference sequence obtained for a cultivar from Réunion, R570, is very good quality", says Dr. Angélique D'Hont, a CIRAD geneticist who coordinated the study. That reference sequence is a vital step towards fully sequencing the sugarcane genome and analysing the variations between the various sugarcane varieties more effectively. Dr. D'Hont had the same experience with the banana genome in 2012. As she says, "having a reference sequence for a species radically changes all the genomic and more broadly genetic approaches for that species.” The sugarcane genome sequencing was described online on July 6, 2018 in Nature Genetics. The open-access article is titled “A Mosaic Monoploid Reference Sequence for the Highly Complex Genome of Sugarcane." As with all other cultivated plants before it, sugarcane breeding will now be able to enter the age of molecular biology.