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Archive - Apr 2015

April 15th

Paternal Sperm and Altered DNA Methylation Patterns May Hold Clues to Autism Risk, Hopkins Study Suggests

In a small study, Johns Hopkins researchers found that DNA from the sperm of men whose children had early signs of autism shows distinct patterns of regulatory tags that could contribute to the condition. A detailed report of these new findings was published online on April 14, 2015 in an open-access article in the International Journal of Epidemiology. The article is titled “Paternal Sperm DNA Methylation Associated with Early Signs of Autism Risk in an Autism-Enriched Cohort.” Autism spectrum disorder (ASD) affects one in 68 children in the U.S. Although studies have identified some culprit genes, most cases remain unexplained. But most experts agree that autism is usually inherited, because the condition tends to run in families. In this study, investigators looked for possible causes for the condition not in genes themselves, but in the "epigenetic tags" that help regulate genes' activity. "We wondered if we could learn what happens before someone gets autism," says Andrew Feinberg, M.D., M.P.H., the King Fahd Professor of Molecular Medicine and Director of the Center for Epigenetics at the Johns Hopkins University School of Medicine. "If epigenetic changes are being passed from fathers to their children, we should be able to detect them in sperm," adds co-lead investigator Daniele Fallin, Ph.D., Professor and Chair of the Department of Mental Health in the Bloomberg School of Public Health and director of the Wendy Klag Center for Autism and Developmental Disabilities. In addition to being easier to sample than egg cells from women, sperm are more susceptible to environmental influences that could alter the epigenetic tags on their DNA. Dr. Feinberg, Dr. Fallin, and their team assessed the epigenetic tags on DNA from sperm from 44 dads.

Controlled Activation of ERBB2 for Short Time After Heart Attack Almost Completely Regenerates Damaged Heart Tissue in Mouse Model; Senior Author Terms Results “Amazing”

When a heart attack strikes, heart muscle cells die and scar tissue forms, paving the way for heart failure. Cardiovascular diseases are a major cause of death worldwide, in part, because the cells in our most vital organ do not get renewed. As opposed to blood, hair, or skin cells that can renew themselves throughout life, our heart cells cease to divide shortly after birth, and there is very little renewal in adulthood. New research at the Weizmann Institute of Science provides insight into the question of why the mammalian heart fails to regenerate, on one hand, and demonstrated, in adult mice, the possibility of turning back this fate. This research was published online on April 6, 2015 in Nature Cell Biology. The article is titled “ERBB2 Triggers Mammalian Heart Regeneration by Promoting Cardiomyocyte Dedifferentiation and Proliferation.” Professor Eldad Tzahor, of the Institute’s Biological Regulation Department and senior author of the article, thought that part of the answer to the regeneration puzzle might lie in his area of expertise: embryonic development, especially of the heart. Indeed, it was known that a protein called ERBB2 – which is well studied because it can pass along growth signals promoting certain kinds of cancer – plays a role in heart development. ERBB2 is a specialized receptor – a protein that transmits external messages into the cell. ERBB2 generally works together with a second, related, receptor by binding a growth factor called Neuregulin 1 (NRG1) to transmit its message. NGR1 is already being tested in clinical studies for treating heart failure. Dr. Gabriele D’Uva, a postdoctoral fellow in the research group of Professor Eldad Tzahor, wanted to know exactly how NRG1 and ERBB2 are involved in heart regeneration.

Arginine Deprivation May Play Key Role in Causing Alzheimer’s, Duke Study Indicates; Senior Researcher Says Such a Different Perspective on Long-Perplexing Disease Is Highly Desirable

Increasingly, evidence supports the idea that the immune system, which protects our bodies from foreign invaders, plays a part in Alzheimer's disease. But the exact role of immunity in the disease is still a mystery. A new Duke University study in mice suggests that in Alzheimer's disease, certain immune cells that normally protect the brain begin to abnormally consume an important nutrient: arginine (image). Blocking this process with a small-molecule drug prevented the characteristic brain plaques and memory loss in a mouse model of the disease. Published in the April 15, 2015 issue of the Journal of Neuroscience, the new research not only points to a new potential cause of Alzheimer's, but also may eventually lead to a new treatment strategy. The article is titled “"Arginine Deprivation and Immune Suppression in a Mouse Model of Alzheimer's Disease." "If indeed arginine consumption is so important to the disease process, maybe we could block it and reverse the disease," said senior author Dr. Carol Colton, Professor of Neurology at the Duke University School of Medicine, and a member of the Duke Institute for Brain Sciences. The brains of people with Alzheimer's disease show two hallmarks, “plaques” and “tangles,” that researchers have puzzled over for some time. Plaques are the build-up of sticky proteins called beta amyloid, and tangles are twisted strands of a protein called tau. In the current study, the scientists used a type of mouse, called CVN-AD, that they had created several years ago by swapping out a handful of important genes to make the animal's immune system more similar to a human's. Compared with other mice used in Alzheimer's research, the CVN-AD mouse has it all: plaques and tangles, behavior changes, and neuron loss.

Antibody-Bound IL-2 Stimulates T-Cell Killing of Cancer Cells; This New Version of IL-2 Use Halts Aggressive Melanoma in Mice

The human immune system is poised to spring into action at the first sign of a foreign invader, but it often fails to eliminate tumors that arise from the body’s own cells. Cancer biologists hope to harness that untapped power using an approach known as cancer immunotherapy. Orchestrating a successful immune attack against tumors has proven difficult so far, but a new study from MIT suggests that such therapies could be improved by simultaneously activating both arms of the immune system. Until now, most researchers have focused on one of two strategies: attacking tumors with antibodies, which activate the innate immune system, or stimulating T cells, which form the backbone of the adaptive immune system. By combining these approaches, the MIT team was able to halt the growth of a very aggressive form of melanoma in mice. “An anti-tumor antibody can improve adoptive T-cell therapy to a surprising extent,” says Dr. Dane Wittrup, the Carbon P. Dubbs Professor in Chemical Engineering at MIT. “These two different parts of the immune therapy are interdependent and synergistic.” Dr. Wittrup, an associate director of MIT’s Koch Institute for Integrative Cancer Research and also a faculty member in the Department of Biological Engineering, is the senior author of a paper describing the work in the April 13, 2015 issue of the journal Cancer Cell. The article is titled “Synergistic Innate and Adaptive Immune Response to Combination Immunotherapy with Anti-Tumor Antigen Antibodies and Extended Serum Half-Life IL-2.” Lead authors are graduate students Eric Zhu and Cary Opel and recent Ph.D. recipient Dr. Shuning Gai.

April 13th

Mystery of Rett Syndrome Lag in Symptom Onset Possibly Explained

For decades, scientists and physicians have puzzled over the fact that infants with the post-natal neuro-developmental disorder Rett syndrome (RTT) show symptoms of the disorder beginning from 6 tp 18 months after birth. In a report published online on April 13, 2015 in PNAS, Dr. Huda Zoghbi and her colleagues from Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, unravel the mystery by looking at when and how the causal gene involved (methyl-CpG binding protein 2 or MeCP2) binds to methylated cytosine over the course of brain development. Using mice in which the MeCP2 protein is tagged with a fluorescent green protein, the scientists determined genome-wide MeCP2 binding profiles in the adult animal brain. In addition to the expected finding of MeCP2 binding to methylated cytosine with guanine (CG) with high affinity, they also found that MeCP2 binds to cytosine when it is followed by either adenine, cytosine, or thymine instead of guanine (non-CG methylation or "mCH" where H is either adenine, cytosine, or thymine). In the PNAS article, the reesearchers said that “unexpectedly, we discovered that genes that acquire elevated mCH after birth become preferentially misregulated in mouse models of MeCP2 disorders, suggesting that MeCP2 binding at mCH loci is key for regulating neuronal gene expression in vivo. This pattern is unique to the maturing and adult nervous system, as it requires the increase in mCH after birth to guide differential MeCP2 binding among mCG, mCH, and nonmethylated DNA elements. Notably, MeCP2 binds mCH with higher affinity than nonmethylated identical DNA sequences to influence the level ofBdnf, a gene implicated in the pathophysiology of RTT.

April 13th

Mayo Develops Profile of Those at Greatest Risk of Pancreatic Cancer

When people find out, usually from a diagnostic scan looking at something else, that they have a lesion in their pancreas that could morph into pancreatic cancer, they often panic. They insist on having frequent CT scans and biopsies to monitor the lesion, or they ask for surgery. Physicians also don't know if these abnormalities are dangerous, so the patients end up in surgery having part of their pancreas removed. Often, the lesion is nothing to worry about. But an international team of physicians, led by researchers at the Mayo Clinic campus in Jacksonville, Florida, has now developed a profile of the patient s who would be most at risk of developing lesions that are most likely to develop into cancer. The Mayo analysis was published online on April 10, 2015 in the journal Digestive and Liver Diseases. The article is titled “Risk Factors for Malignant Progression of Intraductal Papillary Mucinous Neoplasms.” "The factors we found that increase risk of pancreatic cancer now allow us to separate patients as either low or high risk," says the study's senior author, Michael B. Wallace, M.D., M.P.H., a gastroenterologist at the Mayo Clinic. "High-risk patients can then be scanned and biopsied more frequently or can opt for surgery, but low-risk patients don't need such surveillance. They can be watched much less intensively. Pancreatic cancer is difficult to detect early -- most patients are diagnosed at later stages when its 95 percent fatal -- so we're seeking ways to understand who is at risk," Dr. Wallace says. "Our study offers valuable insight into the problem." The lesions evaluated in this study that can become cancerous are known as intraductal papillary mucinous neoplasms. They are common. "Between 10 and 40 percent of people have them," Dr. Wallace says.

Two Cancer-Suppressing Proteins Identified in Lab of Israeli Nobel Laureate in Chemistry

A new study by researchers at the Technion-Israel Institute of Technology in Haifa, Israel could hold a key to control cancer cell growth and development. In a paper publishedin the April 9, 2015 issue of Cell, the team reports on the discovery of two cancer-suppressing proteins (KPC-1 and p50). The article is titled “KPC1-Mediated Ubiquitination and Proteasomal Processing of NF-κB1 p105 to p50 Restricts Tumor Growth.” The research was conducted in the laboratory of Distinguished Professor Aaron Ciechanover (photo), of the Technion Rappaport Faculty of Medicine. Dr. Ciechanover shared the 2004 Nobel Prize in Chemistry for the “discovery of ubiquitin-mediated protein degradation.” The team was led by Research Associate Dr. Yelena Kravtsova-Ivantsiv and included additional research students and colleagues, as well as physicians from the Rambam, Carmel, and Hadassah Medical Centers, who are studying tumors and their treatment. KPC1 (Kip1 ubiquitylation-promoting complex 1) is the catalytic subunit of the ubiquitin ligase KPC, which regulates the degradation of the cyclin-dependent kinase inhibitor p27(kip1) at the G1 phase of the cell cycle. The KPC1 pathway is vital in the life of the cell, which is responsible for the degradation of defective proteins that could damage the cell if not removed. The ubiquitin system tags these proteins and sends them for destruction in the cellular complex known as the proteasome. The system also removes functional and healthy proteins that are not needed anymore, thereby regulating the processes that these proteins control. Usually, the proteins that reach the proteasome are completely broken down, but there are some exceptions, and the current line of research examined p105, a long precursor of a key regulator in the cell called NF-kB.

April 12th

Selenide Can Reduce Heart Muscle Damage After Cardiac Arrest by Nearly 90% If Administered Before Blood Flow Restored; Action Apparently Supplements Body’s Naturally Protective Mechanism of Providing Selenide to Injured Tissue

Damage to heart muscle from insufficient blood supply during cardiac arrest and reperfusion injury after blood flow is restored can be reduced by nearly 90 percent if selenide, a form of the essential nutrient selenium, is administered intravenously in the wake of the attack, according to a new preclinical study by researchers at Fred Hutchinson Cancer Research Center in Seattle, Washington. Mark Roth, Ph.D., and colleagues in the Fred Hutch Basic Sciences Division have published their findings online on April 6, 2015 in Critical Care Medicine. The article is titled “"Selenide Targets to Reperfusing Tissue and Protects it From Injury.” "We found that administration of selenide after the heart has been deprived of blood flow and before blood flow is restored significantly protects the heart tissue in a mouse model of acute myocardial infarction and reperfusion injury," Dr. Roth said. Ischemia, or insufficient blood supply, as occurs during a heart attack or stroke, causes tissues to become starved of oxygen. In the highly oxygenated tissues of the heart and brain, ischemia can cause irreversible damage in as little as three to four minutes at normal body temperature. Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function. Using two different mouse models of ischemia reperfusion injury, Dr. Roth and colleagues found that selenium is specifically taken up by injured tissues following temporary loss of blood flow while blood selenium levels simultaneously decrease.

First Small Molecule Inhibitors of mRNA-Binding HuR Oncoprotein Identified; Results Hold Promise for Possible Treatments of Wide Variety of Cancers; Molecules May Be Active in Inhibiting Cancer Stem Cells

A team of scientists at the University of Kansas (KU) has pinpointed six chemical compounds that thwart HuR, an "oncoprotein" that binds to RNA and promotes tumor growth. The findings, which could lead to a new class of cancer drugs, were published online on March 9, 2015 in the journal ACS Chemical Biology. The article is titled “Identification and Validation of Novel Small Molecule Disruptors of HuR-mRNA Interaction.” "These are the first reported small-molecule HuR inhibitors that competitively disrupt HuR-RNA binding and release the RNA, thus blocking HuR function as a tumor-promoting protein," said Liang Xu, M.D., Ph.D., Associate Professor of Molecular Biosciences and corresponding author of the paper. The results hold promise for treating a broad array of cancers in people. The researcher said HuR has been detected at high levels in almost every type of cancer tested, including cancers of the colon, prostate, breast, brain, ovaries, pancreas, and lung. "HuR inhibitors may be useful for many types of cancer," Dr. Xu said. "Because HuR is involved in many stem cell pathways, we expect HuR inhibitors will be active in inhibiting 'cancer stem cells,' or the seeds of cancer, which have been a current focus in the cancer drug discovery field." HuR has been studied for many years, but, until now, no direct HuR inhibitors have been discovered, according to Dr. Xu. "The initial compounds reported in this paper can be further optimized and developed as a whole new class of cancer therapy, especially for cancer stem cells," he said. "The success of our study provides a first proof-of-principle that HuR is druggable, which opens a new door for cancer drug discovery. Many other RNA-binding proteins like HuR, which are so far undruggable, can also be tested for drug discovery using our strategy."

NMR Study of Xylan in Wood Reveals Unexpected Shape of This Polymer in Cell Walls; Discovery Could Accelerate Use of Plants for Renewable Materials, Energy, and Building Construction

Major steps forward in the use of plants for renewable materials, energy and for building construction could soon arise, thanks to a key advance in understanding the structure of wood. The step forward follows research by the Universities of Warwick and Cambridge and the unexpected discovery of a previously unknown arrangement of molecules in plant cell walls. The paper describing this work was Editors' Choice for the American Chemical Society (ACS) for March 25, 2015. The article, titled “Probing the Molecular Architecture of Arabidopsis thaliana Secondary Cell Walls Using Two- and Three-Dimensional 13C Solid State Nuclear Magnetic Resonance Spectroscopy,” was published online on March 4, 2015 in the ACS journal Biochemistry. As an Editor’s Choice article, the paper is fully and freely available as an open-access publication. The researchers investigated the polymer xylan, which comprises a third of wood matter. Professor Ray Dupree from the University of Warwick, one of the research's authors, says: "Using advanced NMR techniques we found that the xylan polymer, which comprises about a third of wood, has an unexpected shape inside the plant cell walls." The structure of the xylan was ascertained by creating 2D maps of the molecular structure of the woody stalks of thale cress in the UK's most advanced solid-state Nuclear Magnetic Resonance (NMR) Facility, based at the University of Warwick. Professor Paul Dupree of the University of Cambridge (son of Professor Ray Dupree) says, "For the first time, we have been able to study the arrangement of molecules in woody plant materials. Plant cell walls provide the mechanical strength to plants. This major step forward in understanding the molecular architecture of plant cell walls will impact the use of plants for renewable materials, energy, and for building construction."