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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.

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.

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.

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.

Researchers Discover Why Redheads Are More Prone to Melanoma; Pharmacological Activation of Palmitoylation in MC1R Prevents Melanoma in Model System

Red-haired people are known for pale skin, freckles, poor tanning ability and, unfortunately, an increased risk for developing skin cancer. Research has shown that they have variants in melanocortin 1 receptor (MC1R), a protein crucial for pigmentation in humans, but how this translates to increased risk for cancer and whether that risk can be reversed has remained an active area of investigation--until now. For the first time, researchers from Boston University School of Medicine (BUSM) have shown that there is a way to reduce cancer risk in redheads. These findings were published online on September 6, 2017 in Nature. The article is titled “Palmitoylation-Dependent Activation of MC1R Prevents Melanomagenesis.” Specifically the scientist proved that MC1R, the protein involved in pigmentation, is affected by a special modification process called palmitoylation that is critical for its function. By enhancing palmitoylation in the variant MC1R proteins of redheads cancer risk can be reduced. Making up one to two percent of the world's population, redheads carry variants of MC1R that are responsible for their characteristic features, but that also increase risk of skin cancers, the most dangerous of which is melanoma, a major public health concern with more than 3 million active cases in 2015. Much public health work has emphasized prevention by reducing sun exposure, particularly to DNA-damaging UV rays, but redheads bear a higher burden of disease making alternative risk reductions strategies an area of active interest.

Immunotherapy Combination Is Safe and 62 Percent Effective In Metastatic Melanoma Patients

Immunotherapy is a promising approach in the treatment of metastatic melanoma, an aggressive and deadly form of skin cancer; but for most patients, immunotherapy drugs so far have so far failed to live up to their promise and provided little or no benefit. In a phase 1b clinical trial with 21 patients, researchers tested the safety and efficacy of combining the immunotherapy drug pembrolizumab with an oncolytic virus called T-VEC. The results suggest that this combination treatment, which had a 62% response rate, may work better than using either therapy on its own. The study was published in the September 7, 2017 issue of Cell. The article is titled “Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy.” "We had a hypothesis about how these treatments would work together, and when we did biopsies of patients' tumors we found that they were cooperating in just the way we thought they would," says lead author Dr. Antoni Ribas, Director of the Immunology Program at the UCLA Jonsson Comprehensive Cancer Center. Pembrolizumab is in a class of drugs called checkpoint inhibitors. These drugs are designed to get around one of the ways that cancer protects itself from the immune system: tumors can activate the body's natural protective response from autoimmunity, called a checkpoint, and thereby thwart cytotoxic T cells. The drugs work by taking the brakes off the checkpoint and allowing T cells to attack the tumor. "Some people put tumors into the categories of either 'hot' and 'cold,'" Dr. Ribas explains. "Hot tumors, also called inflamed tumors, have a lot of immune cells in and around them, but cold tumors do not." Drugs like pembrolizumab boost the response in tumors where immune cells are present but don't work in tumors where there is no immune response to boost.

Technology Unlocks Mold Genomes to Identify New Drug Candidates

Fungi are rich sources of natural molecules for drug discovery, but numerous challenges have pushed pharmaceutical companies away from tapping into this bounty. Now, scientists have developed technology that uses genomics and data analytics to efficiently screen for molecules produced by molds to find new drug leads — maybe even the next penicillin. The research, from scientists at Northwestern University, the University of Wisconsin-Madison, and the biotech company Intact Genomics, was published online on June 12, 2017 in Nature Chemical Biology. The article is titled “A Scalable Platform to Identify Fungal Secondary Metabolites and Their Gene Clusters.” “Drug discovery needs to get back to nature, and molds are a gold mine for new drugs,” said Neil Kelleher (photo), PhD, Director of the Proteomics Center of Excellence and a professor in the Weinberg College of Arts and Sciences and of Medicine in the Division of Hematology and Oncology. “We have established a new platform that can be scaled for industry to provide a veritable fountain of new medicines. Instead of rediscovering penicillin, our method systematically pulls out valuable new chemicals and the genes that make them. They can then be studied in depth.” Scientists believe there are thousands or even millions of fungal molecules waiting to be discovered, with enormous potential health, social, and economic benefits. The new technology systematically identifies powerful bioactive molecules from the microbial world — honed through millennia of evolution — for new drug leads. These small molecules could lead to new antibiotics, immunosuppressant drugs, and treatments for high cholesterol, for example. For four years, Dr. Kelleher has collaborated with Nancy Keller, PhD, the Robert L. Metzenberg and Kenneth B.

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