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Massive Amount of Possible New Target Information Generated in Gene-by-Gene, Genome-Wide CRISPR-Cas9 Screen of Patient-Derived Glioblastoma Cancer Stem Cells; One Existing, Potentially Helpful Small Molecule Drug Identified

Glioblastoma is one of the most devastating forms of cancer, with few existing treatment options. It is also a leading cause of cancer-related death in children and young adults. Scientists have “reverse engineered” brain cancer stem cells gene by gene, uncovering multiple potential targets for this hard-to-treat cancer. This work is a collaboration among the University of Toronto, The Hospital for Sick Children (SickKids), and the University of Calgary. Findings were published online on April 16, 2019 in Cell Reports, making this the first published study to systematically profile a large panel of patient-derived brain tumor cells that have stem cell properties. The open-access article is titled “Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells.” "We think that, in one big experiment, we have uncovered many new targets for glioblastoma, some of which were surprising," says Peter Dirks (photo), MD, PhD, co-principal investigator of the study, Staff Neurosurgeon and Senior Scientist at SickKids. "These glioblastoma stem cells are also resistant to treatment, which is one reason that these tumors are so hard to cure. We need new ways to disrupt these cells specifically if we are going to give people a better chance of survival." The research team also found that adult glioblastoma cells are actually dependent on the same genes that are important for brain development in infancy and early childhood. "This really emphasizes how much research needs to be done to understand the developing human brain," says Dr. Dirks, who, in 2003, was the first to discover the existence of cancer stem cells in brain tumors.

New Role Discovered for Innate Immune Sensor NLPR12: Suppressing Liver Cancer

Researchers at the University of Texas (UT) Southwestern have found that a protein in the body’s innate immune system that responds to gut microbes can suppress the most common type of liver cancer. The study, published online on April 16, 2019 in eLIFE, determined that NLRP12 (Nod-like receptor family pyrin domain containing 12), an innate immune sensor, has a protective effect against hepatocellular carcinoma (HCC), a deadly human cancer associated with chronic inflammation. The open-access article is titled “NLRP12 Suppresses Hepatocellular Carcinoma Via Downregulation of c-Jun N-Terminal Kinase Activation in the Hepatocyte.” HCC is responsible for more than 80 percent of liver cancers in the U.S. It is the third-leading cause of cancer-related deaths worldwide and the ninth-leading cause in America, according to the National Cancer Institute. NLRP12 is a member of the NOD-like family of pattern recognition receptors that help the body sense microbes and other stimuli within the cell to regulate the innate immune response – the body’s first line of defense against infection – in multiple ways. This latest work adds to a growing body of evidence connecting inflammation and the development of tumors in the liver. “In this study, we demonstrated that NLRP12 responds to gut microbes and plays a critical role in suppressing a common form of liver cancer,” said Hasan Zaki (at left in photo), PhD, Assistant Professor of Pathology at UT Southwestern and corresponding author of the study. Major risk factors for HCC include hepatitis B or C viral infection, chronic alcohol abuse, and nonalcoholic fatty liver disease, a condition increasing worldwide along with obesity. Although the precise mechanisms through which these conditions induce liver cancer are unknown, inflammation in the liver is considered a key player.

Insulin Receptor (IR) Moves from Surface to Inside Nucleus After Binding Insulin; IR Then Binds to RNA Polymerase on Chromatin at ~4,000 Different Sites Across the Genome, Primarily in Promoter Regions, Where It Can Regulate Gene Expression

The discovery of insulin in the 1920s marked the breakthrough in the almost 3,500-year-long mystery of diabetes, a disease first described in ancient Egyptian papyruses. Until its discovery, physicians struggled to explain how symptoms such as sugary urine, constant thirst, and frequent urination could lead to ailments ranging from blindness and nerve damage to coma and death. Over the past century, scientists have detailed the hormone’s central role as a regulator of blood sugar, mapped its cell-signaling pathways, and established its involvement in diabetes and a staggering array of other chronic conditions, including neurodegeneration, cardiovascular disease, and cancer. Still, many aspects of insulin signaling remain unclear, particularly its long-term effects on cells, and there are currently no effective cures for the hundreds of millions of people around the world living with diabetes. Now, researchers from Harvard Medical School (HMS) have made key new insights into the molecular behavior of insulin. In article, published online on April 4, 2019 in Cell, the Harvard scientists describe an unexpected mechanism by which insulin triggers changes to the expression of thousands of genes throughout the genome. Their analyses show that the insulin receptor—a protein complex at the cell surface—physically relocates to the cell nucleus after it detects and binds insulin. Once in the nucleus, the insulin receptor helps initiate the expression of genes involved in insulin-related functions and diseases. This process was impaired in mice with insulin resistance.

Immunotherapy-Resistant Tumors Export PD-L1-Packed Exosomes That Travel to Lymph Nodes to Remotely Inhibit Immune Cell Activation; Understanding Biology of Exosomal PD-L1 May Be First Step Toward Novel Therapies

Immunotherapy drugs known as checkpoint inhibitors have recently revolutionized cancer treatment: many patients with malignancies that, until recently, would have been considered untreatable are experiencing long-term remissions. But the majority of patients do not respond to these drugs, and they work far better in some cancers than others, for reasons that have befuddled scientists. Now, researchers at the University of California, San Francisco (UCSF), and a collaborator at UC Berkeley, have identified a surprising phenomenon that may explain why many cancers don’t respond to these drugs, and hints at new strategies to unleash the immune system against disease. “In the best-case scenarios, like melanoma, only 20 to 30 percent of patients respond to immune checkpoint inhibitors, while in other cases, like prostate cancer, there is only a single-digit response rate,” said Robert Blelloch (, MD, PhD, Professor of Urology at UCSF and senior author of the new study, published online on April 4, 2019 in Cell. “That means a majority of patients are not responding. We wanted to know why.” In malignant tissue, a protein called PD-L1 functions as an “invisibility cloak”: by displaying PD-L1 on their surfaces, cancer cells protect themselves from attacks by the immune system. Some of the most successful immunotherapies work by interfering with PD-L1 or with its receptor, PD-1, which resides on immune cells. When the interaction between PD-L1 and PD-1 is blocked, tumors lose their ability to hide from the immune system and become vulnerable to anti-cancer immune attacks.

Mother Nature to the Rescue--Flavonoid Derivatives from Hyacinth Family Could Prevent Blindness Caused by Diabetes, Retinopathy of Prematurity, and Wet Age-Related Macular Degeneration

Mother Nature could have the answer to treating several causes of blindness, according to a ground-breaking study involving scientists from the University of Surrey (UK), the Eugene and Marilyn Glick Eye Institute at Indiana University School of Medicine in the USA, and Kingston University-London. The scientists have found and tested compounds from a group of plants that could possibly be used to treat the causes of degenerative eye diseases such as proliferative diabetic retinopathy. This abnormal growth of new blood vessel cells in the eye is linked to a number of types of blindness, including in premature babies (retinopathy of prematurity), in diabetics (proliferative diabetic retinopathy), and in older adults (wet age-related macular degeneration). In a paper published online on April 5, 2019 in the American Chemical Society’s Journal of Natural Products, scientists from the University of Surrey, together with experts from Indiana University in America and Kingston University-London, detailed their testing of naturally occurring homoisoflavonoids found in the Hyacinthaceae plant family and their synthetic derivatives. The team tested how well these compounds were able to stop the growth of new blood vessels and isolated several active compounds. One synthetic derivative, in particular, could be used to develop future treatments. Further work is continuing to synthesize more related compounds. The article is titled “The Antiangiogenic Activity of Naturally Occurring and Synthetic Homoisoflavonoids from the Hyacinthaceae (sensu APGII).” According to Great Ormond Street Hospital (London), retinopathy of prematurity affects approximately 20 per cent of premature babies and mainly occurs mainly in those babies who are born before week 32 of pregnancy or weigh less than 1500 grams.

Genetics of Beauty—Genes Associated with Facial Attractiveness Vary Depending on Sex, According to New Study from University of Wisconsin-Madison

Genes play a role in determining the beauty of a person's face, but that role varies with the person's sex, according to a new study by Qiongshi Lu, PhD, Assistant Professor, Department of Biostatistics & Medical Bionformatics, and colleagues at the University of Wisconsin-Madison, published on April 4, 2019 in PLOS Genetics. The open-access article is titled “Genome-Wide Association Study Reveals Sex-Specific Genetic Architecture of Facial Attractiveness.” Humans tend to be preoccupied with beauty - a person's attractiveness is associated with academic performance, career success and economic mobility. But despite its importance, scientists know little about the genetic basis for having a pretty face. In the current work, researchers performed a genome-wide association study (GWAS) using genetic information from 4,383 individuals to pinpoint parts of the genome linked to facial beauty. They had volunteers score yearbook photos based on attractiveness from participants with European ancestry and compared the scores to each person's genetic information. The researchers identified several genes related to facial attractiveness, but their roles and relatedness to other human traits varied by sex. In women, certain genetic variations linked to beauty also appeared to be related to genes impacting body mass, while in males, variants in facial attractiveness were linked to genes affecting blood cholesterol levels. The study provides new insights into the genetic factors underlying facial attractiveness and highlights the complex relationships between beauty and other human traits. "Similar to many other human traits, there is not a 'master gene' that determines a person's attractiveness," author Qiongshi Lu observed. "Instead, it is most likely associated with a large number of genetic components with weak effects.

Dr. Andrew Hill, World-Class Biochemist & President of International Society for Extracellular Vesicles (ISEV) Named Winner of Prestigious 2019 Beckman Coulter Discovery Science Award

On April 2, 2019, the Australian Society for Biochemistry and Molecular Biology (ASBMB) announced that the Beckman Coulter Discovery Science Award has been awarded to Andrew Hill, PhD, Director of Australia's La Trobe Institute for Molecular Science(LIMS); Head of the Department of Biochemistry and Genetics, LIMS; Director of the La Trobe’s University-Wide Research Focus Area “Understanding Disease;” and President of the International Society for Extracellular Vesicles (ISEV). This award is presented annually to an ASBMB member for distinguished contributions to the field of biochemistry and molecular biology. Recipients have demonstrated involvement in research innovation, technology transfer, and communication. The Award is intended as a Travelling Lectureship to enable the awardee to present his/her work at a number of centers within Australia and New Zealand. The awardee will also present a Symposium talk at the ASBMB 2019 annual conference October 1-3 in Perth, Western Australia ( Nominees must have been members of the Society for at least two years before the year in which the Award nomination is to be considered. The contribution to travel expenses is provided through the generosity of Beckman Coulter. Award winner Dr. Hill briefly described his distinguished career thus far as follows. “I gained my BSc(Hons) in Biochemistry and Molecular Biology from Victoria University of Wellington in New Zealand, where my Honors project involved using DNA fingerprinting on sheep to identify potential disease biomarkers. “In 1992, I travelled to the UK in search of a PhD position and began working on prion diseases, firstly as a research assistant and subsequently studying for a PhD in Professor John Collinge’s group at Imperial College.

Scientists Discover First Organism with Chlorophyll Genes That Does Not Photosynthesize; Unusual Organism May Provide Clues on How to Protect Endangered Coral Reefs

For the first time, scientists have found an organism that can produce chlorophyll, but does not engage in photosynthesis. The peculiar organism is dubbed “corallicolid” because it is found in 70 per cent of corals around the world and may provide clues as to how to protect coral reefs in the future. "This is the second most abundant cohabitant of coral on the planet and it hasn't been seen until now," says Patrick Keeling, a University of British Columbia (UBC) botanist and senior researcher overseeing the study published online on April 3, 2019 in Nature. The article is titled “A Widespread Coral-Infecting Apicomplexan with Chlorophyll Biosynthesis Genes.” "This organism poses completely new biochemical questions. It looks like a parasite, and it's definitely not photosynthetic. But it still makes chlorophyll." Chlorophyll is the green pigment found in plants and algae that allows them to absorb energy from sunlight during photosynthesis. "Having chlorophyll without photosynthesis is actually very dangerous because chlorophyll is very good at capturing energy, but without photosynthesis to release the energy slowly it is like living with a bomb in your cells," Dr. Keeling says. Corallicolids live in the gastric cavity of a wide array of corals responsible for building reefs, as well as in black corals, fan corals, mushroom corals, and anemones. They are an apicomplexan, part of a vast group of parasites that have a cellular compartment called a plastid, which is the part of plant and algal cells where photosynthesis takes place. The most famous apicomplexan is the parasite (Plasmodium falciparum and other Plasmodium species), responsible for malaria.

Experimental Immune-Based Therapy Completely Clears HPV in One-Third of Cervical Cancer Precursor Neoplasias; Injection of Genes for Three Proteins Triggers Immune System Response to High-Risk HPV Types

A potential new immune-based therapy to treat pre-cancers in the cervix completely eliminated both the lesion and the underlying HPV infection in a third of women enrolled in a clinical trial. The shot, a therapeutic vaccine, injects genes for three specific proteins that trigger an immune system response to attack high-risk human papilloma virus (HPV) types that cause nearly all cervical cancer precursors, known as cervical intraepithelial neoplasia (CIN). "There are very few products trying to cure women who already have an HPV infection," says Diane Harper (photo), MD, MPH, MS, Professor of Family Medicine and Obstetrics and Gynecology at Michigan Medicine. "It's very exciting. This is the first time we've seen something with this success rate that is relatively easy to implement." Cervical precancerous lesions are divided into three grades of severity: CIN 1 lesions generally clear up on their own; CIN 2 lesions often clear up on their own, but can also progress to CIN 3 lesions; CIN 3 is the most severe--it's a very slow-growing disease, though, with less than half of CIN 3 lesions becoming cancer within 30 years. "But we have no way to determine which women with CIN 3 will progress to cancer and which women will not. So, we treat all women with CIN 2 or 3 as if they are likely to develop cancer," Dr. Harper says. The study enrolled 192 women diagnosed with CIN2 or CIN3, randomizing 129 to receive the vaccine and 63 to receive a placebo. Women were given three shots in their thigh, one per week for three weeks. Six months later, the women were treated with standard surgical procedures for CIN 2/3 and the removed tissue was examined.

Violet Light Therapy Activates Opsin 5 Signaling to Restore Proper Timing Cues; May Help Prevent/Treat Retinopathy of Prematurity & Myopia in Premature Babies; Opsin-5-Dopamine Pathway Mediates Light-Dependent Vascular Development in Eye

Scientists have discovered a light-dependent molecular pathway that regulates how blood vessels develop in the eye. The findings, published online on April 1, 2019 in Nature Cell Biolog, suggest it may be possible to use light therapy to help premature infants, whose eyes are still developing, avoid certain vision problems associated with premature birth, such as retinopathy of prematurity (ROP) ( and myopia (sever near-sightedness), according to researchers at Cincinnati Children's Hospital Medical Center. The article is titled “An Opsin 5–Dopamine Pathway Mediates Light-Dependent Vascular Development in the Eye.” The novel molecular process, called the opsin 5-dopamine pathway helps ensure that blood-vessel development in the eye is appropriately balanced to prepare it for visual function. The process can be thrown out of balance in medically fragile premature babies. Researchers are looking for ways to prevent or treat the eye diseases known as retinopathy of prematurity (ROP) and myopia that can often result. Myopia is becoming a more common condition in adults around the globe. "Our study indicates that the opsin 5-dopamine pathway is probably part of a light-dependent disease process for conditions like myopia, which is now a worldwide epidemic," said Richard A. Lang, PhD, Director of the Visual Systems Group at Cincinnati Children's and study senior author. "It raises the interesting possibility that we might be able to use light exposure to treat conditions like retinopathy of prematurity after a premature infant is born or in people with myopia." The new study is a collaboration of research institutions in the United States and the Czech Republic that was led by Dr. Lang's team in Cincinnati.

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