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Archive - Sep 2017

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September 14th

Caloric Restriction Slows Epigenetic Drift and Slower Epigenetic Drift May Be Mechanism Underlying Lifespan Extension

Almost a century ago, scientists discovered that cutting calorie intake could dramatically extend lifespan in certain animal species. Despite numerous studies since, however, researchers have been unable to explain precisely why. Now, investigators at the Lewis Katz School of Medicine at Temple University (LKSOM) have broken past that barrier. In new work published online on September 14, 2017 in Nature Communications, they are the first to show that the speed at which the epigenome changes with age is associated with lifespan across species and that calorie restriction slows this process of change, potentially explaining its effects on longevity. The article is titled “Caloric Restriction Delays Age-Related Methylation Drift.” "Our study shows that epigenetic drift, which is characterized by gains and losses in DNA methylation in the genome over time, occurs more rapidly in mice than in monkeys, and more rapidly in monkeys than in humans," explains Jean-Pierre Issa, MD, Director of the Fels Institute for Cancer Research at LKSOM, and senior investigator on the new study. The findings help to explain why mice live only about two to three years on average, rhesus monkeys about 25 years, and humans 70 or 80 years. Chemical modifications such as DNA methylation control mammalian genes, serving as bookmarks for when a gene should be used - a phenomenon known as epigenetics. "Methylation patterns drift steadily throughout life, with methylation increasing in some areas of the genome, and decreasing in others," says Dr. Issa. Previous studies had shown that these changes occur with age, but whether they were also related to lifespan was unknown.Dr. Issa's team made its discovery after first examining methylation patterns on DNA in blood collected from individuals of different ages for each of three species - mouse, monkey, and human.

Invitation to ASEMV 2017 Annual Meeting (Exosomes & Microvesicles) in Asilomar, California (October 8-12)

The American Society for Exosomes and Microvesicles (ASEMV) is inviting interested scientists to the ASEMV 2017 meeting, to be held October 8-12, 2017 at the Asilomar Conference Center in California. This center is located on the Monterrey peninsula, just south of San Francisco (www.visitasilomar.com). The meeting will cover the full breadth of the exosome field, from basic cell biology to clinical applications, and follow the ASEMV tradition of inclusion and diversity as participants learn about the latest advances in the field. ASEMV 2017 is a forum for learning the latest discoveries in the field of exosomes, microvesicles, and extracellular RNAs. Over the course of four days at the Asilomar Conference Center, ASEMV 2017 will offer presentations from leading scientists and young researchers. Topics will span the breadth of the extracellular vesicle/RNA field, including the basic sciences, disease research, translation efforts, and clinical applications. Talks will be presented in multiple sessions, beginning at 7 pm on Sunday, October 8, 2017, and concluding at 4 pm on Thursday, October 12, 2017. Poster sessions will run throughout the meeting, with ample time to get to know your colleagues in the field and explore the many opportunities in this rapidly expanding field. Please see the links below.

Researchers Find a Possible New Treatment for Aggressive Triple-Receptor-Negative Breast Cancer; New Inhibitor of Cancer Stem-Like Cells Brings New Hope

Scientists from the cluster of excellence BIOSS Centre for Biological Signaling Studies at the University of Freiburg and the Freiburg University Medical Center in Germany have shown that inhibiting the epigenetic regulator KDM4 might offer a potential novel treatment option for breast cancer patients. They used a newly established cell model that enables scientists to isolate cancer stem cells directly from patient tumor. Using this special culture system, they were able to test potential new cancer drugs. One of these, a novel inhibitor of the epigenetic regulator KDM4, co-developed in the lab of Professor Roland Schüle, showed promising results. The researchers published their work online on September 7, 2017 in Cancer Research. The article is titled “KDM4 Inhibition Targets Breast Cancer Stem-Like Cells.” Although the prognosis for breast cancer has been steadily improving in the last decades, patients with triple-receptor-negative breast cancer form a subgroup who receive a considerably worse prognosis in most cases. Roughly 15 percent of all breast cancer patients have triple-receptor-negative breast cancer, which lacks markers for a targeted therapy. In the last few years, a bulk of data pointing to a small population of cells in tumors that maintain tumor growth, are particularly resistant to chemotherapy, are responsible for relapses, and develop metastases. These cells, named cancer stem-like cells, share many characteristics with the body’s normal stem cells. Due to their cancer-driving behavior, researchers have been focusing more and more on targeting these cells. However, there are currently only a few models available to study the biology of cancer stem cells.

September 11th

DNA Looping Architecture May Lead to Opportunities to Treat Brain Tumors

The discovery of a mechanism by which normal brain cells regulate the expression of the NFIA gene, which is important for both normal brain development and brain tumor growth, might one day help improve therapies to treat brain tumors. The study was published online on September 11, 2017 in Nature Neuroscience. This article is titled “Glia-Specific Enhancers and Chromatin Structure Regulate NFIA Expression and Glioma Tumorigenesis.” "We began this project by studying how three components that regulate the expression of the NFIA gene interact with each other in the developing spinal cord in animal models," said corresponding author Dr. Benjamin Deneen, Associate Professor of Neuroscience at the Center for Stem Cell and Regenerative Medicine and member of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine. The researchers studied primarily glial cells (image), which represent 70 percent of the cells in the central nervous system and support the functions of the neurons. Gene expression, the process by which genes produce proteins, is regulated at different levels, in a coordinated fashion, but scientists don't completely understand how these levels interact. Dr. Deneen and his colleagues explored how three levels of gene regulation coordinated their activities to regulate NFIA gene expression. The researchers studied enhancers, (sections of DNA that are located at a distance from the NFIA gene and can influence gene expression), transcription factors (proteins that bind to enhancers), and the three-dimensional architecture of the associated DNA. First, the scientists identified enhancers involved in the regulation of expression of NFIA gene using a non-traditional approach.

Epigenetic Changes from Cigarette Smoke May Be First Step in Lung Cancer Development

Scientists at the Johns Hopkins Kimmel Cancer Center say they have preliminary evidence in laboratory-grown, human airway cells that a condensed form of cigarette smoke triggers so-called "epigenetic" changes in the cells consistent with the earliest steps toward lung cancer development. Epigenetic processes are essentially switches that control a gene's potentially heritable levels of protein production but without involving changes to underlying structure of a gene's DNA. One example of such an epigenetic change is methylation -- when cells add tiny methyl chemical groups to a beginning region of a gene's DNA sequence, often silencing the gene's activation. "Our study suggests that epigenetic changes to cells treated with cigarette smoke sensitize airway cells to genetic mutations known to cause lung cancers," says Stephen Baylin, MD, the Virginia and D.K. Ludwig Professor for Cancer Research and Professor of Oncology at the Johns Hopkins Kimmel Cancer Center. Details of the scientists' experiments are described in the September 11, 2017 issue of Cancer Cell. The article is titled “Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations.” For two decades, scientists have known some of the genetic culprits that drive lung cancer growth, including mutations in a gene called KRAS, which are present in one-third of patients with smoking-related lung cancers, according to Dr. Baylin. Genetic and epigenetic changes also occur when normal cells undergo chronic stress, such as the repeated irritation and inflammation caused by decades of exposure to cigarette smoke and its contents. Dr.

Internal Mechanism Found Responsible for Limitless Growth Potential of Epithelial Tumors

Researchers from the Development and Growth Control Laboratory at IRB Barcelona have identified the cell types and molecular mechanism responsible for the unlimited growth potential of epithelial tumors (carcinomas) and demonstrated that the growth of these tumors is independent of the tumor’s microenvironment. "In epithelial tumors caused by chromosomal instability or loss of cell polarity, the interaction between two tumor cell populations drives malignant growth," explains Dr. Marco Milán, ICREA Research Professor and Head of the laboratory. Published as the cover story of the August 29, 2017 issue of PNAS, the study analyzes solid tumors of epithelial origin in the fruit fly Drosophila melanogaster. "We have induced tumor development in two ways--by generating genomic instability and the loss of cell polarity. We have validated the causal relation between these two conditions--which are frequently observed in carcinomas--and the development of tumors," explains Dr. Mariana Muzzopappa, first author of the study and postdoctoral fellow in the Development and Growth Control Lab. The PNAS article is titled “Feedback Amplification Loop Drives Malignant Growth in Epithelial Tissues.” To study the effect of the microenvironment on tumor development, the researchers examined tumor growth in the absence of adjacent cell populations, such as cells of the immune system or mesenchymal cells, which can act as a niche by supplying tumors with growth factors. The scientists observed that the tumor continued to grow in the absence of these two cell types. Furthermore, they demonstrated that "the growth of epithelial tumors is dependent on activation of the JNK stress signaling pathway and that this pathway is intrinsically activated in the tumor, regardless of its microenvironment," highlights Dr. Milán.

September 8th

Retina Changes May Signal Frontotemporal Lobe Degeneration; Rapid, Non-Invasive Test May Help in Diagnosis of FTD

Frontotemporal degeneration (FTD) is a progressive neurodegenerative condition that is present in tens of thousands of Americans, but is often difficult to diagnose accurately. Now, in a study published online on September 8, 2017 in Neurology, researchers from the Perelman School of Medicine at the University of Pennsylvania have found evidence that a simple eye exam and retinal imaging test may help improve that accuracy. The article is titled “Optical Coherence Tomography Identifies Outer Retina Thinning in Frontotemporal Degeneration.” Using an inexpensive, non-invasive, eye-imaging technique, the Penn Medicine scientists found that patients with FTD showed thinning of the outer retina--the layers with the photoreceptors through which we see--compared to control subjects. The retina is potentially affected by neurodegenerative disorders because it is a projection of the brain. Prior studies have suggested that patients with Alzheimer's disease and ALS may also have thinning of the retina--although a different part of the retina. Thus, imaging the retina may help doctors confirm or rule out FTD. "Our finding of outer retina thinning in this carefully designed study suggests that specific brain pathologies may be mirrored by specific retinal abnormalities, said study lead author Benjamin J. Kim, MD, Assistant Professor of Ophthalmology at Penn's Scheie Eye Institute. Neurodegenerative diseases in general are challenging to diagnose, and often are confirmed only by direct examination of brain tissue at autopsy. Now that science appears to be on the brink of developing effective treatments for these diseases, the need for better diagnostic methods is becoming acute.

September 8th

Vampire Folklore May Have Had Roots in Real People with Genetic Mutation That Causes Blood Disorder

Porphyrias, a group of eight known blood disorders, affect the body's molecular machinery for making heme, which is a component of the oxygen-transporting protein, hemoglobin. When heme binds with iron, it gives blood its hallmark red color. The different genetic variations that affect heme production give rise to different clinical presentations of porphyria -- including one form that may be responsible for vampire folklore. Erythropoietic protoporphyria (EPP), the most common kind of porphyria to occur in childhood, causes people's skin to become very sensitive to light. Prolonged exposure to sunshine can cause painful, disfiguring blisters. "People with EPP are chronically anemic, which makes them feel very tired and look very pale with increased photosensitivity because they can't come out in the daylight," says Barry Paw MD, PhD, of the Dana-Farber/Boston Children's Cancer and Blood Disorders Center. "Even on a cloudy day, there's enough ultraviolet light to cause blistering and disfigurement of the exposed body parts, ears, and nose." Staying indoors during the day and receiving blood transfusions containing sufficient heme levels can help alleviate some of the disorder's symptoms. In ancient times, drinking animal blood and emerging only at night may have achieved a similar effect -- adding further fuel to the legend of vampires. Now, Dr. Paw and his team of international investigators report -- in a paper published online on September 5, 2017 in PNAS -- a newly discovered genetic mutation that triggers EPP. It illuminates a novel biological mechanism potentially responsible for stories of " vampires" and identifies a potential therapeutic target for treating EPP.

Researchers Report Successful Tranplants of Islets Cells into Muscle; Possible New Approach to Treatment of Type 1 Diabetes

Patients suffering from type 1 diabetes may soon have access to improved approaches to treat the disease, courtesy of new research out of Sydney, Australia’s Westmead Institute for Medical Research. A team of researchers, led by Professor Jenny Gunton, discovered that pancreatic islets transplants delivered into the quadriceps muscle work just as successfully as the current clinical practice of transplanting islets into a patient's liver via the portal vein. Lead researcher Ms. Rebecca Stokes said that transplants into the liver can present certain risks for the patient, so their research investigated safer and more beneficial treatment options for transplant recipients. "Islets are cells in the pancreas that produce insulin," Ms Stokes explained. "Pancreatic islet transplantation is used as a cure for type 1 diabetes as it allows the recipient to produce and regulate insulin after their own islet cells have been destroyed by the disease. Currently, islet transplants are infused into a patient's liver via the portal vein. This site is used for islet transplants due to its exposure to both nutrients and insulin in the body. However, islet infusion into the liver also presents certain risks for the patient, including potential complications from bleeding, blood clots and portal hypertension. This suggests that there may be better treatment options for patients receiving islet transplants. We investigated alternative transplantation sites for human and mouse islets in recipient mice, comparing the portal vein with quadriceps muscle and kidney, liver and spleen capsules.

September 7th

Discovery of Chromosome Motor in Condensin Comlex Supports DNA Loop Extrusion Model for DNA Packaging in Cell Division

It is one of the great mysteries in biology: how does a cell neatly distribute its replicated DNA between two daughter cells? For more than a century, it has been known that DNA in the cell is comparable to a plate of spaghetti: a big jumble of intermingled strands. If a human cell wants to divide, it has to pack two meters of DNA into tidy little packages: chromosomes. This packing occurs using proteins called condensin, but how? When it comes to this question, scientists are split into two camps: the first argues that the protein works like a hook, randomly grasping somewhere in the jumble of DNA and tying it all together. The other camp thinks that the ring-shaped protein pulls the DNA inwards to create a loop. With an article published online on September 7, 2017 in Science, researchers from TU Delft, Heidelberg, and Columbia University give the “loop-extrustion camp” a significant boost: they demonstrate that condensin does indeed have the putative 'motor power' on board. The article is titled “The Condensin Complex Is a Mechanochemical Motor That Translocates Along DNA.” As early as 1882, the renowned biologist Walter Flemming recorded the process of “condensation” of DNA. Looking through a microscope, he saw how a cell neatly organized the bundles of DNA and subsequently divided them into two new cells. However, the exact details of this process have remained a mystery for more than 100 years. “There are different schools on this question within the field of cell biology,” explains nanobiologist and Head of Research Professor Cees Dekker from TU Delft's Kavli Institute. “In recent years, the hypothesis that condensin extrudes loops has been winning ground, supported by computer simulations. The idea is that that the ring-shaped condensin grabs the DNA and pulls it through its ring in a loop-like fashion.