Syndicate content

Archive - Sep 2016

September 30th

In Response to Cold, Connexin 43 Acts to Amplify Signaling Between Fat Cells to Increase Number of Beige Fat Cells; Anti-Diabetic Effect of Beige Fat Cells Also Noted in New Work

When exposed to cold, clusters of cells within the body’s white fat become beige – a color change that reflects the creation of more energy-producing mitochondria, cellular components that enable cells to burn calories and give off heat. But because white fat cells have very few nerves, how do beige fat cells get the message that it’s cold outside? In research that has implications for diabetes and other metabolic diseases, an international study based at the University of Texas (UT) Southwestern Medical Center found that the protein connexin 43 (Cx43) forms cell-to-cell communication channels on the surface of emerging beige fat cells that amplify the signals from those few nerve fibers. The channels act like conduits that speed signals across the gaps between clusters of cells – similar to the way a group email reaches several people at once. The study, published in the September 13, 2016 issue of Cell Metabolism, also found that beige fat, unlike the better-known white and brown fat, has interesting anti-diabetic effects on blood sugar metabolism that seem independent of temperature regulation. Impaired glucose metabolism is a hallmark of diabetes. “The data here show how white fat cells can make maximal use of their limited number of nerves to allow a single nerve fiber to spread the ‘message’ about cold temperatures amongst the connected cells,” explained Dr. Philipp Scherer, lead author of the study and Director of UT Southwestern’s Touchstone Center for Diabetes Research. The Cell Metabolism article is titled “Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals.” “To my knowledge, this is the first time that any fat’s thermal regulatory (warming) and metabolic effects on blood sugar have been observed to work independently.

Capricor Therapeutics Awarded $2.4 Million from U.S. Department of Defense to Support Development of Manufacturing Process for Therapeutic Exosomes; Company’s CAP-2003 Exosomes Targeted Initially at Ocular Graft-Versus-Host Disease

On September 26, 2016 Capricor Therapeutics, Inc. (NASDAQ: CAPR), a clinical-stage biotechnology company developing biological therapies for cardiac and other serious medical conditions, announced that the U.S. Department of Defense (DoD) has awarded the company a grant in the amount of approximately $2.4 million to be used toward establishing a scalable, commercially-ready process to manufacture CAP-2003 (Cardiosphere-Derived Cell Exosomes). Capricor has identified ocular graft-versus-host disease (oGVHD) as the first clinical development opportunity for CAP-2003, and expects to submit an IND for this indication in the first half of 2017. CAP-2003 represents exosomes isolated from the Capricor's proprietary cardiosphere-derived cells (CDCs), which are currently in clinical evaluation by Capricor for the treatment of several cardiac conditions, including that associated with Duchenne muscular dystrophy (DMD). "As we advance and expand our exosomes program, this grant from the DoD will support our objective of achieving a commercial manufacturing process for a candidate which we believe has broad treatment potential," said Linda Marbán (photo), Ph.D., President and Chief Executive Officer of Capricor. "Studies of CAP-2003 in multiple models in which inflammation, scarring, and cell death are intrinsic to the disease process suggest that CAP-2003 possesses potent regenerative capabilities. As a cell-free material, CAP-2003 can be handled and stored in similar fashion to a traditional biopharmaceutical, and may be better suited than cell-based therapeutics for certain applications. The activity CAP-2003 has shown in models of eye injury supports our enthusiasm to enter it into the clinic for ocular graft-versus-host disease next year." Capricor Therapeutics, Inc.

Male Sex Determination Can Occur in Absence of Y Chromsome in Animl Model

In an online article published on September 9, 2016 in Scientific Reporets, Hokkaido University researchers have revealed that key sex-determining genes continue to operate in a mammalian species that lacks the Y chromosome, taking us one step farther toward understanding sex differentiation. The open-access article is titled “Molecular Mechanism of Male Differentiation Is Conserved in the SRY-Absent Mammal, Tokudaia osimensis.” In most placental mammals, the Y chromosome induces male differentiation during development, whereas embryos without it become female. The sex-determining gene SRY is present on the Y chromosome and induces other regulatory genes that suppress female differentiation. The Amami spiny rat (Tokudaia osimensis) is exceptional as it lacks a Y chromosome and thus the SRY gene, raising the question as to how male differentiation can still occur in this animal. Tomofumi Otake, Ph.D., and Asako Kuroiwa, Ph.D., of Hokkaido University in Japan performed gene mapping to determine the chromosomal locations of sex-related genes in the T. osimensis genome. They then compared T. osimensis nucleotide and amino acid sequences of T. osimensis with those of the mouse and other rats. Furthermore, using cultured cells, the scientists examined how the sex-related genes were regulated. SRY has been well-investigated in previous research and is known to turn on a range of regulatory genes such as Sox9 and AMH that play an important role in male differentiation. The team’s results suggest that, even though there is no SRY gene in T. osimensis , the regulatory genes that SRY normally turns on are present and operate as they do in other placental mammals. “We speculate that there is an unknown gene that acts as a substitute for SRY in T. osimensis,” says Professor Kuroiwa.

September 29th

Neutrophils May Be Key to Harnessing Whole-Body Anti-Tumor Immune Response "Abscopal Effect" from Radiation Therapy; G-CSF Potentiates Anti-Tumor Effects of Neutrophils

Combining targeted radiation therapy with a neutrophil stimulant enhances anti-tumor immunity, according to new research into cancer immunology at the Univerity of Texas (UT) Southwestern Medical Center. Radiation therapy is one of three core modalities to treat cancer. Researchers found that radiation therapy targeted against a tumor can act as a “cancer vaccine” by causing neutrophil-mediated tumor cell death that alerts the immune system to fight the cancer cells at other anatomical sites. The so-called “abscopal effect,” in which radiation therapy delivered to a primary site of cancer also results in shrinkage or elimination of cancer cells in non-irradiated metastatic sites has been observed for decades. “The abscopal effect is only seen sporadically, but when it does happen, the effect induces a long-lasting, anti-tumor response in patients,” said senior author Dr. Raquibul Hannan (photo), Assistant Professor of Radiation Oncology and a member of the Harold C. Simmons Comprehensive Cancer Center. “Our study in mice was designed to understand this phenomenon and identify strategies to enhance it.” Findings from the study were reported on September 20, 2016 in PNAS. The open-access article is titled “Key Role for Neutrophils in Radiation-Induced Antitumor Immune Responses: Potentiation with G-CSF. Researchers discovered what happens inside the tumor after radiation and how these events not only kill tumor cells but also lead to a whole-body anti-tumor response. Study results show that neutrophils, the most abundant white blood cell in the body, are key players in the radiation-induced anti-tumor immune response. In the absence of radiotherapy, cancer cells transform neutrophils into tumor-associated neutrophils (TANs) to help promote cancer cell growth.

Scientists Find Possible Lethal Vulnerability in Treatment-Resistant Lung Cancer; New Studies Show That XPO1 Inhibitors Can Kill KRAS-Driven Lung Cancer Cells; Existing Drug Selinexor Targets XPO1

Researchers working in four labs at The University of Texas (UT) Southwestern Medical Center have found a chink in a so-called “undruggable” lung cancer’s armor – and located an existing drug that might provide a treatment. The study, published online on September 28, 2016 in Nature, describes how the drug Selinexor (KPT-330) killed lung cancer cells and shrank tumors in mice when used against cancers driven by the aggressive and difficult-to-treat KRAS cancer gene. Selinexor is already in clinical trials for treatment of other types of cancer, primarily leukemia and lymphoma. but also gynecological, brain, prostate, and head and neck cancers. The new Nature article is titled “XPO1-Dependent Nuclear Export is a Druggable Vulnerability in KRAS-Mutant Lung Cancer.” Lung cancer is the No. 1 cancer killer in the U.S., responsible for more than 158,000 deaths a year, according to the National Cancer Institute (NCI), and the KRAS oncogene is believed to be responsible for about 25 percent of all lung cancer cases. The 5-year survival rate for lung cancer is below 18 percent. Cancers caused by the KRAS mutation have been a target for researchers since the mutation was discovered in humans in 1982. But, due in part to this oncogene’s almost impervious spherical shape, no one was able to find an opening for attack, said Dr. Pier Scaglioni, Associate Professor of Internal Medicine at UT Southwestern and a contributing author to the study. Dr. Michael A. White (photo), Adjunct Professor of Cell Biology and senior author of the study, assembled multiple research teams and used robotic machines to create and sift through trays with thousands of cancer cell/potential drug combinations to uncover the KRAS mutation’s weakness.

Free Electron Laser Reveals Nanocyrstal Structure of BinAB Toxin That Kills Culex and Anopheles Mosquito Larvae; Advance May Permit Broadening of BinAB Toxicity Spectrum to Include Aedes Mosquito Larvae

The BinAB toxin, produced in crystal form by a bacterium, specifically kills the larvae of Culex and Anopheles mosquitoes, but it is inactive on Aedes mosquitoes, the vectors for dengue, chikungunya, and zika viruses. Knowledge of the molecular structure of BinAB is necessary if scientists are to broaden its spectrum of action. Having long been inaccessible, this structure has been published online on September 28, 2016 in Nature by an international consortium involving scientists from the multiple institutions. The Nature article is titled “De novo Phasing with X-Ray Laser Reveals Mosquito Larvicide BinAB Structure.” Mosquitoes are vectors for numerous devastating diseases, including malaria that is spread by Anopheles mosquitoes, and filariasis transmitted by Culex mosquitoes. The BinAB toxin, produced in the form of nanocrystals by the bacterium Bacillus sphaericus, specifically targets the larvae of these two groups of mosquitoes. A complex, five-step intoxication process (see description below) explains the environmental safety of BinAB, which is harmless to other insects, crustaceans, and humans. BinAB is therefore used in many countries to regulate mosquito populations. Unfortunately, the strength of BinAB is also its weakness: the toxin is ineffective on the larvae of Aedes mosquitoes, which spread the viruses for dengue, zika, and chikungunya. A remodeling of BinAB might allow a broadening of its spectrum, but to achieve this it is necessary to understand its structure. X-ray crystallography is an excellent method to reveal the structure of a protein, but it is generally only applicable to large crystals measuring approximately a tenth of a millimeter.

MeCP2, HDAC1, & HDAC2 Act Together to Regulate SAPAP3 to Influence Repetitive Behavior in Animal Model of Rett Syndrome

Three-year-old Naomi slaps her forehead a few times, bites her fingers, and toddles across the doctor’s office in her white and pink pajamas before turning her head into a door with a dull thud. Her mother quickly straps on a helmet and adjusts the rainbow chinstrap, then watches as Naomi puts a hand back in her mouth and continues exploring the room. “She keeps me busy,” acknowledges her mother, Laura Elguea. Naomi was diagnosed at age 2 with Rett syndrome, a rare, debilitating disease in which patients progressively lose brain function and the ability to walk. While she laughs, smiles, and toddles around like most 3-year-olds, Naomi’s repetitive hand behaviors offer clues to her condition. Relatively little is known about the neuronal causes of Rett syndrome, but University of Texas (UT) Southwestern Medical Center scientists have now identified a process in the brains of mice that might explain the repetitive actions – research that could be a key step in developing treatments to eliminate symptoms that drastically impair the quality of life in Rett patients. The finding from UT Southwestern’s Peter O’Donnell Jr. Brain Institute could also potentially benefit people with autism spectrum disorder, though more research is needed to evaluate the link to this disease in humans. “We are exploring the processes that contribute to Rett syndrome in an effort to develop treatments that may prove useful in the disease,” said Dr. Lisa Monteggia, Professor of Neuroscience with the O’Donnell Jr. Brain Institute, who led the research published online on Septembder 28, 2016 in Nature Neuroscience.

September 27th

MIT Scientists Identify Neural Circuit That Is Activated During “Exposure Therapy” for Phobias in Animal Model; Fear Extinction Result Is Extended in Time; Finding May Lead to Improved Treatment of Phobias and PTSD in Humans

People who are too frightened of flying to board an airplane, or too fearful of spiders to venture into the basement, can seek a kind of treatment called exposure therapy. In a safe environment, they repeatedly face cues such as photos of planes or black widows, as a way to stamp out their fearful response — a process known as extinction. Unfortunately, the effects of exposure therapy are not permanent, and many people experience a relapse. MIT scientists have now identified a way to enhance the long-term benefit of extinction in rats, offering a way to improve the therapy in people suffering from phobias and more complicated conditions such as post-traumatic stress disorder (PTSD). Work conducted in the laboratory of Ki Goosens, Ph.D., an Assistant Professor in MIT’s Department of Brain and Cognitive Sciences and a member of the McGovern Institute for Brain Research, has pinpointed a neural circuit that becomes active during exposure therapy in the rats. In a study published online on September 27, 2016 in eLife, the researchers showed that they could stretch the therapy’s benefits for at least two months by boosting the circuit’s activity during treatment. The open-access article is titled “Amygdala-Ventral Striatum Circuit Activation Decreases Long-Term Fear.” “When you give extinction training to humans or rats, and you wait long enough, you observe a phenomenon called spontaneous recovery, in which the fear that was originally learned comes back,” Dr. Goosens explains. “It’s one of the barriers to this type of therapy. You spend all this time going through it, but then it’s not a permanent fix for your problem.” According to statistics from the National Institute of Mental Health, 18 percent of U.S.

Oldest-Yet Protein Fragments Identified in 3.8-Million-Year-Old Ostrich Eggshell; Mineral Binding in Eggshell Extends Survival of Certain Protein Fragments; New Tool for Deep Evolutionary Analysis

Scientists have identified fossil proteins in a 3.8-million-year-old ostrich eggshell, suggesting that proteins could provide valuable new insights into the evolutionary tree, much farther back in time than was previously thought. The study, published online on Octber 27, 2016 in the journal eLife, suggests that survival of protein fragments in the ancient eggshell could provide genetic information almost 50 times older than any DNA record. The open-access article is titled “Protein Sequences Bound to Mineral Surfaces Persist Into Deep Time.” The findings shed new light on how animals and humans lived and interacted in the past, how some species became extinct, and why some evolved and continue to thrive today. Crucially, the research provides archaeologists with the ability to be more targeted in which fossils they submit for deeper analysis. The team at the Universities of York, Sheffield, and Copenhagen analyzed and tracked egg fossils from well-dated sites in Tanzania and South Africa, where it is expected DNA and proteins would not survive the extreme environmental conditions. Professor Matthew Collins, from the University of York’s Department of Archaeology, who led the team, said: “To date, DNA analysis from frozen sediments has been able to reach back to about 700,000 years ago, but human evolution left most of its traces in Africa and the higher temperature there takes its toll on DNA preservation.

September 25th

Mitochondrial DNA Testing May Reveal Unknown Ancestry That May Influence Risk of Breast Cancer

Genetic testing of mitochondrial DNA could reveal otherwise unknown ancestry that can influence a person’s risk for certain types of breast cancer, a new study finds. University of Texas (UT) Southwestern Medical Center cancer researchers studying mitochondrial DNA (mtDNA) in a group of triple negative breast cancer patients found that 13 percent of participants were unaware of ancestry that could influence their risk of cancer. “We found 12 differences among 92 patients, a significant amount,” said lead author Dr. Roshni Rao, Director of the George N. Peters, M.D. Center for Breast Surgery at UT Southwestern. “Some patients who self-identified as Hispanic had African-American ancestry. One Hispanic woman was found to be Ashkenazi Jewish. Both African Americans and some Ashkenazi Jewish populations have a higher risk for triple negative breast cancer,” said Dr. Rao, Associate Professor of Surgery and with the Harold C. Simmons Comprehensive Cancer Center. Triple negative breast cancer is characterized by tumors that do not express receptors for estrogen, progesterone, or Her2-Neu, and accounts for about 15 to 20 percent of all breast cancer cases. This form of the disease is known to be particularly aggressive, and challenging to treat. Patients with triple negative breast cancer have a higher incidence of metastatic disease – cancer spreading to other parts of the body – and an overall higher rate of death from breast cancer, compared to patients with other types of breast cancer. “This study is the first to perform mtDNA testing for self-described African-Americans, Caucasians, and Hispanics with triple negative breast cancer and to identify unexpected mtDNA patterns,” said senior author Dr. Barbara Haley, Professor of Internal Medicine, who holds the Charles Cameron Sprague, M.D. Chair in Clinical Oncology.