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Archive - Jan 2018


January 15th

Western High-Fat Diet Implicated in Fatal Metastasis of Prostate Cancer; Existing Drug That Blocks Lipogenesis Prevents Metastasis in Mouse Model; New Data Is “Tremendously Actionable,” Research Leader Says

Prostate tumors tend to be what scientists call "indolent" - so slow-growing and self-contained that many affected men die with prostate cancer, not of it. But for the percentage of men whose prostate tumors metastasize, the disease is invariably fatal. In a set of papers published online on January 15, 2018 in the journals Nature Genetics and Nature Communications, researchers at the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC) in Boston shed new light on the genetic mechanisms that promote metastasis in the mouse model and also implicated the typical Western high-fat diet as a key environmental factor driving metastasis. The Nature Genetics article is titled An Aberrant SREBP-Dependent Lipogenic Program Promotes Metastatic Prostate Cancer.” The open-access Nature Communications article is titled “Deregulated PP1α Phosphatase Activity Towards MAPK Activation Is Antagonized by a Tumor Suppressive Failsafe Mechanism.” "Although it is widely postulated that a Western diet can promote prostate cancer progression, direct evidence supporting a strong association between dietary lipids and prostate cancer has been lacking," said first author Ming Chen, PhD, a research fellow in the laboratory of Pier Paolo Pandolfi (photo), MD, PhD, Director of the Cancer Center and Cancer Research Institute at BIDMC. Epidemiological data links dietary fats (and obesity) to many types of cancer, and rates of cancer deaths from metastatic cancers including prostate cancer are much higher in the United States than in nations where lower fat diets are more common. While prostate cancer affects about 10 percent of men in Asian nations, that rate climbs to about 40 percent when they immigrate to the U.S., mirroring the rates among the native-born U.S. population.

Genes That Aid Spinal Cord Healing in Lamprey Also Present in Humans; Lamprey Can Fully Recover from Severed Spinal Cord; Wnt Pathway Seems Crucial

Many of the genes involved in natural repair of the injured spinal cord of the lamprey are also active in the repair of the peripheral nervous system in mammals, according to a study by a collaborative group of scientists at the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts, and other institutions. This is consistent with the possibility that, in the long term, the same or similar genes may be harnessed to improve spinal cord injury treatment in humans. "We found a large overlap with the hub of transcription factors that are driving regeneration in the mammalian peripheral nervous system," says Jennifer Morgan, PhD, Director of the MBL's Eugene Bell Center for Regenerative Biology and Tissue Engineering, one of the authors of the study published online on January 15, 2018 in Scientific Reports. The open-access article is titled “Highly Conserved Molecular Pathways, Including Wnt Signaling, Promote Functional Recovery from Spinal Cord Injury in Lampreys.” Lampreys are jawless, eel-like fish that shared a common ancestor with humans about 550 million years ago. This study arose from the observation that a lamprey can fully recover from a severed spinal cord without medication or other treatment. "They can go from paralysis to full swimming behaviors in 10 to 12 weeks," says Dr. Morgan. "Scientists have known for many years that the lamprey achieves spontaneous recovery from spinal cord injury, but we have not known the molecular recipe that accompanies and supports this remarkable capacity," says Ona Bloom, PhD, of the Feinstein Institute for Medical Research and the Zucker School of Medicine at Hofstra/Northwell, a former MBL Whitman Center Fellow who collaborated on the project.

Genetic Analysis May Improve Depression Therapy

The failure of drugs such as selective serotonin reuptake inhibitors (SSRIs), used to treat depression, can be a result of genetic variations in patients. Variations within the gene that encodes the CYP2C19 enzyme results in extreme differences in the levels of escitalopram achieved in patients, according to a new study published online on January 12, 2018 in The American Journal of Psychiatry. Prescribing the dose of escitalopram (Lexapro) based on a patient's specific genetic constitution would greatly improve therapeutic outcomes. The study was conducted at Karolinska Institutet in Sweden in association with researchers at Diakonhjemmet Hospital in Oslo, Norway. The title of the article is “Impact of CYP2C19 Genotype on Escitalopram Exposure and Therapeutic Failure: A Retrospective Study Based on 2,087 Patients.” Pharmaceutical treatment of depression commonly makes use of selective SSRIs, of which escitalopram is the most frequently administered clinically. However, escitalopram therapy is currently limited by the fact that some patients do not respond well to the drug, while others develop adverse reactions requiring discontinuation of treatment. In order to individualize drug therapy, researchers are attempting to establish genetic biomarkers that can predict an individual's response to drugs. In the new study, it was discovered that variation in the gene encoding the enzyme responsible for escitalopram metabolism (CYP2C19) is very important in this respect. Individuals with a variant of the gene promoting increased enzyme expression had blood levels of escitalopram too low to impact the depression symptoms, whereas patients with a defective CYP2C19 gene reached drug levels which were too high.

January 11th

Racist Trump Must Go, Says BioQuick News

BioQuick News can not stand quiet in the face of today’s racist comments by US President Donald Trump. Editor & Publisher Michael D. O’Neill believes that honor and justice demand that this draft-dodging racist bully be removed from office as soon as possible. Millions of Americans have died to defend liberty, justice, and honor, and this one evil man must not be allowed to constantly flout these sacred values. Martin Luther King’s birthday on Monday would be a fitting time to say good-bye to this disgrace to our nation. (Photo shows the bully Trump mocking a disabled reporter in a speech during the presidential campaign.)

Dimerization Appears to Be Crucial Event for Mutated Forms of RAS to Cause Cancer

Mutated RAS genes are some of the most common genetic drivers of cancer, especially in aggressive cancers like pancreatic cancer and lung cancer, but no medicines that target RAS are available, despite decades of effort. Researchers at the University of Texas (UT) Southwestern’s Simmons Cancer Center have now shown that RAS proteins act in pairs, known as dimers, to cause cancer, and these new findings could help guide them to a treatment. “RAS mutations are one of the most common causes of cancer and there are no options for attacking them. The dimerization activity of RAS gives us a solid lead for moving forward,” said Dr. Kenneth Westover, Assistant Professor of Radiation Oncology and Biochemistry with the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, which is recognizing its 75th anniversary this year. The question of RAS dimerization has been hotly debated, he said, but researchers previously have not been able to prove what RAS dimers look like, limiting the ability to design experiments that assess their importance in normal physiology and cancer. The UT Southwestern team led by Dr. Westover used X-ray crystallography data to predict what a RAS dimer might look like, then tested the model in cells using a method called fluorescence resonance energy transfer (FRET) to show when RAS forms dimers and when it does not. The new study, published online on January 11, 2017 in Cell, provides a foundation for further studies that delve into RAS biology and could potentially pave the way to develop new cancer drugs that target RAS dimerization. The article is titled “KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS.” “The primary function of RAS is to transmit signals that tell a cell to grow and divide, a pathway commonly hijacked in cancer.

January 9th

Research Reveals a Physiologic Function for Prion-Like Domains in Cell’s Adaptation to, and Survival from, Environmental Stress

Prions are self-propagating protein aggregates that can be transmitted between cells. The aggregates are associated with human diseases. Indeed, pathological prions cause mad cow disease and, in humans, Creutzfeldt-Jakob disease. The aggregation of prion-like proteins is also associated with neurodegeneration as in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The regions within prion-like proteins that are responsible for their aggregation have been termed prion-like domains. Despite the important role of prion-like domains in human diseases, a physiological function has remained enigmatic. Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), the Biotechnology Center of the TU Dresden (BIOTEC), and Washington University in St. Louis, USA have now identified, for the first time, a benign, albeit biologically relevant, function of prion domains as protein-specific stress sensors that allow cells to adapt to and survive environmental stresses. Uncovering the physiological function is an essential first step towards closing a gap in understanding the biological role of prion-like domains and their transformation into a pathological disease-causing state. The discoveries were published in the January 5, 2018 issue of Science. The article is titled “Phase Separation of a Yeast Prion Protein Promotes Cellular Fitness.” The aggregation of prion-like proteins is associated with human diseases. Their infectious behavior is comparable to the spread of a viral infection. This raises the question of why evolution has kept these proteins around: are these sequences good for anything?

January 8th

Appetite Control Depends on Signaling at Primary Cilia in Brain Neurons, UCSF Mouse Study Shows

University of California-San Francisco (UCSF) researchers have discovered that the brain's ability to regulate body weight depends on a novel form of signaling in the brain's "hunger circuit" via antenna-like structures on neurons called primary cilia. Primary cilia are distinct from motile cilia, the finger-like projections that act as a sort of cellular conveyer belt, with functions such as removing debris from the lungs and windpipe. Immotile primary cilia were once thought to be vestigial, like a cellular appendix, but in the past decade, research at UCSF and elsewhere has revealed that these structures play a key role in many forms of hormonal signaling in the body. Now, the new UCSF study, published online on January 8, 2018 in Nature Genetics, shows that primary cilia also play a crucial role in signaling within the brain. The article is titled “Subcellular Localization of MC4R with ADCY3 at Neuronal Primary Cilia Underlies a Common Pathway for Genetic Predisposition to Obesity.” Neuroscientists are accustomed to thinking of brain signaling in terms of direct chemical or electrical communication among neurons at sites called synapses, but the new findings reveal that chemical signaling at primary cilia may also play an important, and previously overlooked role. In addition, the findings suggest potential new therapeutic approaches to the growing global obesity epidemic, the researchers say. "We're building a unified understanding of the human genetics of obesity," said senior author Christian Vaisse, MD, PhD, a professor in the Diabetes Center at UCSF and a member of the UCSF Institute for Human Genetics.

Study Reveals Reversibility of Friedreich’s Ataxia in Novel Mouse Model

Friedreich’s ataxia is an inherited disease that causes damage to the nervous system and a loss of coordination that typically progresses to muscle weakness. It can begin causing symptoms in childhood or early adulthood and, over time, it can also lead to vision loss and diabetes. Scientists seeking a better understanding of the disease have tried for years to replicate the disease’s symptoms and progression in laboratory mice, but until recently have been largely unsuccessful. Now, a team of UCLA researchers has recreated aspects of Friedreich’s ataxia in mice and shown that many early symptoms of the disease are completely reversible when the genetic defect linked to the ataxia is reversed. The findings were published online on December 19, 2017 in eLife. The open-access article is titled “Inducible and Reversible Phenotypes in a Novel Mouse Model of Friedreich’s Ataxia.” “Remarkably, most of the dysfunction we were seeing in the mice was reversible even after the mice showed substantial neurologic dysfunction,” said Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics, a UCLA Professor of Neurology and Psychiatry, and the study’s senior author. “We were very surprised by the extent to which the mice improved.” The results, however, need to be replicated in humans before researchers know whether they can lead to new therapeutics for people with Friedreich’s ataxia. Friedreich’s ataxia is known to be caused by a genetic mutation in a gene called FXN. The mutation leads to reduced levels of frataxin, the protein encoded by FXN. Although doctors can manage some of the symptoms, there are no treatments for the disease.

January 7th

Penn Study on Super-Silenced DNA Hints at New Ways to Reprogram Cells

Newly described stretches of super-silenced DNA reveal a fresh approach to reprogram cell identity to use in regenerative medicine studies and one day in the clinic, according to a study published in the December 21, 2017 issue of Molecular Cell by investigators from the Perelman School of Medicine at the University of Pennsylvania. The study is titled “Genomic and Proteomic Resolution of Heterochromatin and Its Restriction of Alternate Fate Genes.” "In the past, most labs, including my own, used gene activators to turn on a new program to change the identity in a given cell," said senior author Ken Zaret, PhD, Director of the Penn Institute for Regenerative Medicine and a Professor of Cell and Developmental Biology. "Our study shows that in some cases we will need to disassemble a cell's gene repression machinery to activate important genes to reprogram a cell's identity." The team attempted to reprogram skin cells to make new liver cells. Conversions of one cell type to another usually have low efficiencies, and this study identifies one reason why. The long-term goal of this preclinical research is to be able to replenish diseased liver tissue with healthy tissue derived from a different tissue, such as skin cells, from the same individual in a process called direct-cell reprogramming. The Zaret lab untangled an extreme form of gene silencing, opening up regions of tightly wound DNA that is difficult for activators to reach to turn on certain genes. The researchers found the regions by characterizing an increase in chemical cross-linking due to DNA being more compacted in the scaffolding of repressed regions of chromosomes. "Think of a piece of fishing line that has been used for a while, with several knots along its length," Dr. Zaret said.

Worm Species Lost 7,000 Genes After Evolving to Fertilize Itself; Genes for Sperm Competition Proteins Among Those Lost

Reproduction in most animal species requires breeding between two individuals. But some worms have evolved the ability to go it alone. In these species, a single individual can breed with itself to produce offspring. A new University of Maryland (UMD)-led study found that gaining this ability, known as "selfing," may have caused a worm species to lose a quarter of its genome, including genes that give male sperm a competitive edge during mating. "Our results suggest that genes that are essential for tens of millions of years can suddenly become useless or liabilities, even, when the sex system changes," said Eric Haag, PhD, a Professor of Biology at UMD and lead investigator of the study, which was published in the January 5, 2018 issue of Science. The article is titled “Rapid Genome Shrinkage in a Self-Fertile Nematode Reveals Sperm Competition Proteins.” A million years ago, a species of tiny worms called Caenorhabditis briggsae evolved the ability to breed via selfing. As a result, most C. briggsae are hermaphrodites with both male and female sex organs. Dr. Haag's group, which focuses on the evolution of sex, has long studied C. briggsae because of their unusual reproductive behavior. To study how selfing shaped the evolution of C. briggsae, Erich Schwarz, PhD, an Assistant Research Professor of Molecular Biology and Genetics at Cornell University and co-corresponding author of the study, sequenced the genome of Caenorhabditis nigoni, the closest relative of C. briggsae. C. nigoni always reproduce by mating with other individuals, or outcrossing. By comparing the genomes of the two species, the researchers found that the selfing C. briggsae worms had 7,000 fewer genes than C. nigoni. Over time, C. briggsae lost approximately a quarter of its genome.