Epigenetics Alters Genes in Rheumatoid Arthritis

It’s not just our DNA that makes us susceptible to disease and influences its impact and outcome. Scientists are beginning to realize more and more that important changes in genes that are unrelated to changes in the DNA sequence itself – a field of study known as epigenetics – are equally influential. A research team at the University of California (UC), San Diego – led by Dr. Gary S. Firestein, professor in the Division of Rheumatology, Allergy, and Immunology at UC San Diego School of Medicine – investigated a mechanism usually implicated in cancer and in fetal development, called DNA methylation, in the progression of rheumatoid arthritis (RA). The researchers found that epigenetic changes due to methylation play a key role in altering genes that could potentially contribute to inflammation and joint damage. Their study was published online on June 26, 2012 in the Annals of the Rheumatic Diseases. “Genomics has rapidly advanced our understanding of susceptibility and severity of rheumatoid arthritis,” said Dr. Firestein. “While many genetic associations have been described in this disease, we also know that if one identical twin develops RA that the other twin only has a 12 to 15 percent chance of also getting the disease. This suggests that other factors are at play – epigenetic influences.” DNA methylation is one example of epigenetic change, in which a strand of DNA is modified after it is duplicated by adding a methyl group to any cytosine molecule (C) – one of the 4 main bases of DNA. This is one of the methods used to regulate gene expression, and is often abnormal in cancers and plays a role in organ development.

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Honey Bees Can Reverse Brain Aging

Scientists at Arizona State University (ASU) have discovered that older honey bees effectively reverse brain aging when they take on nest responsibilities typically handled by much younger bees. While current research on human age-related dementia focuses on potential new drug treatments, researchers say these findings suggest that social interventions may be used to slow or treat age-related dementia. In a study published online on May 21, 2012 in Experimental Gerontology, a team of scientists from ASU and the Norwegian University of Life Sciences, led by Dr. Gro Amdam, an associate professor in ASU’s School of Life Sciences, presented findings that show that tricking older, foraging bees into doing social tasks inside the nest causes changes in the molecular structure of their brains. “We knew from previous research that when bees stay in the nest and take care of larvae – the bee babies – they remain mentally competent for as long as we observe them,” said Dr. Amdam. “However, after a period of nursing, bees fly out gathering food and begin aging very quickly. After just two weeks, foraging bees have worn wings, hairless bodies, and more importantly, lose brain function – basically measured as the ability to learn new things. We wanted to find out if there was plasticity in this aging pattern so we asked the question, ‘What would happen if we asked the foraging bees to take care of larval babies again?” During experiments, scientists removed all of the younger nurse bees from the nest – leaving only the queen and babies. When the older, foraging bees returned to the nest, activity diminished for several days. Then, some of the old bees returned to searching for food, while others cared for the nest and larvae.

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BioQuick Wins Publishing Excellence Award

BioQuick Online News has just been awarded an APEX 2012 Award for Publishing Excellence in the category of electronic publications. Other award recipients included the Walt Disney Company, the American Society of Clinical Oncology, Sandia National Laboratories, WGBH-Boston, Ernst & Young, FedEx, American Cancer Society, Merrill Lynch, Ford Motor Company, National Football League, US Tennis Association, Time Inc., Deloitte LLP, American Academy of Dermatology, NYU Langone Medical Center, Wiley, Takeda Pharmaceuticals, Northwestern Memorial Hospital, USC Health Sciences, American Airlines, Arizona State University, McKesson Corporation, American Medical Writers Association, American Academy of Pediatrics, American Medical Communications, Los Alamos National Laboratory, Memorial Sloan-Kettering Cancer Center, Baylor College of Medicine, World Wildlife Fund, ESPN X Games, Elsevier, Multiple Sclerosis Association of America, American Association for Clinical Chemistry, AARP, and the American Society for Biochemistry and Molecular Biology. BioQuick also won APEX Publishing Excellence Awards in 2011 and 2010. BioQuick presently features nearly 900 articles on major science advances in the last three years and articles of interest are readily accessible by means of a powerful search engine. BioQuick has readers in over 160 countries and includes a Japanese language edition. To find out more information about BioQuick and to pursue advertising and sponsorship possibilities, please contact editor & publisheer Mike O’Neill at logophile2000@yahoo.com. To learn more about the APEX Publishing Awards, please visit their web site at www.apexawards.com.

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New Drug Dramatically Improves Survival in Hodgkin Lymphoma Patients

A new cancer drug with remarkably few side effects is dramatically improving survival in Hodgkin lymphoma patients who fail other treatments and are nearly out of options. Loyola University Medical Center oncologist Scott E. Smith, M.D., Ph.D., presented survival data for the drug, brentuximab vedotin (Adcetris®), at the 17th Congress of the European Hematology Association. Dr. Smith is director of Loyola’s Hematological Malignancies Research Program. The multi-center study included 102 Hodgkin lymphoma patients who had relapsed after stem cell transplants. Tumors disappeared in 32 percent of patients and shrank by at least half in 40 percent of patients. An additional 21 percent of patients experienced some tumor shrinkage. Only 6 percent of patients had no response to the drug. Sixty five percent of patients were alive at 24 months, and in 25 percent of patients, the cancer had not progressed at all. These are “encouraging results in patients with historically poor prognosis,” researchers said. Loyola patient Michelle Salerno had failed two stem cell transplants — one using her own cells and one using cells donated by her brother — and multiple rounds of chemotherapy before going on brentuximab vedotin. After three or four infusions, she stopped suffering chills, sweats, high fevers and itchy pain from head to toe. And she experienced almost none of the side effects common to chemotherapy. “I kept my hair, and never felt like vomiting,” she said. “You get the drug, you go home, you feel good.” The standard regimen is a 30-minute infusion every three weeks. A patient typically receives 16 doses over 48 weeks. Loyola has administered about 500 doses to 60 patients. “A lot of our patients are doing great on this regimen,” Dr. Smith said. Hodgkin lymphoma is a cancer of the immune system.

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Glucose Deprivation Activates Feedback Loop That Kills Cancer Cells

Compared to normal cells, cancer cells have a prodigious appetite for glucose, the result of a shift in cell metabolism known as aerobic glycolysis or the “Warburg effect.” Researchers focusing on this effect as a possible target for cancer therapies have examined how biochemical signals present in cancer cells regulate the altered metabolic state. Now, in a unique study, a UCLA research team led by Dr. Thomas Graeber, a professor of molecular and medical pharmacology, together with collaborators, has investigated the reverse aspect: how the metabolism of glucose affects the biochemical signals present in cancer cells. In research published as a featured article online on June 26, 2012 in the journal Molecular Systems Biology, Dr. Graeber and his colleagues demonstrate that glucose starvation — that is, depriving cancer cells of glucose —activates a metabolic and signaling amplification loop that leads to cancer cell death as a result of the toxic accumulation of reactive oxygen species, the cell-damaging molecules and ions targeted by antioxidants like vitamin C. The research, which involved UCLA scientists from the Crump Institute for Molecular Imaging, the Institute for Molecular Medicine, the California NanoSystems Institute, the Jonsson Comprehensive Cancer Center, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, and the Department of Pathology and Laboratory Medicine, demonstrates the power of systems biology in uncovering relationships between metabolism and signaling at the network level. The research team also included collaborators from the department of neurology and the human oncology and pathogenesis program at Memorial Sloan–Kettering Cancer Center and the department of pharmacology at Weill–Cornell Medical College.

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Somatic Gene Mutations Cause Massive Brain Asymmetry

Hemimegalencephaly is a rare but dramatic condition in which the brain grows asymmetrically, with one hemisphere becoming massively enlarged. Though frequently diagnosed in children with severe epilepsy, the cause of hemimegalencephaly is unknown and current treatment is radical: surgical removal of some or all of the diseased half of the brain. In a paper published in the June 24, 2012 online issue of Nature Genetics, a team of doctors and scientists, led by researchers at the University of California (UC) San Diego School of Medicine and the Howard Hughes Medical Institute, say de novo somatic mutations in a trio of genes that help regulate cell size and proliferation are likely culprits for causing hemimegalencephaly, though perhaps not the only ones. De novo somatic mutations are genetic changes in non-sex cells that are neither possessed nor transmitted by either parent. The scientists’ findings – a collaboration among Joseph G. Gleeson, M.D., professor of neurosciences and pediatrics at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego; Gary W. Mathern, M.D., a neurosurgeon at UC Los Angeles’ Mattel Children’s Hospital; and colleagues – suggest it may be possible to design drugs that inhibit or turn down signals from these mutated genes, reducing or even preventing the need for surgery. Dr. Gleeson’s lab studied a group of 20 patients with hemimegalencephaly upon whom Dr. Mathern had operated, analyzing and comparing DNA sequences from removed brain tissue with DNA from the patients’ blood and saliva. “Mathern had reported a family with identical twins, in which one had hemimegalencephaly and one did not. Since such twins share all inherited DNA, we got to thinking that there may be a new mutation that arose in the diseased brain that causes the condition,” said Dr. Gleeson.

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Crystal Structure of Argonaute Protein Determined

Researchers at the Whitehead Institute and Memorial Sloan-Kettering Cancer Center have defined and analyzed the crystal structure of a yeast Argonaute protein bound to RNA. This complex plays a key role in the RNA interference (RNAi) pathway that silences gene expression. Describing the molecular structure of a eukaryotic Argonaute protein has been a goal of the RNAi field for close to a decade. “You can learn a lot from biochemical experiments, but to more fully understand a protein like Argonaute, it’s useful to know where all of the atoms are and which amino acids are playing important roles,” says Whitehead Institute Member Dr. David Bartel, who is also an MIT professor of biology and a Howard Hughes Medical Institute (HHMI) investigator. “Learning the Argonaute crystal structure is an important step in understanding the RNAi biochemical pathway and will be the basis for many future experiments.” The yeast Argonaute structure is described in the June 21, 2012 issue of Nature. In humans and most other eukaryotes, the RNAi pathway can reduce cellular protein production by reducing the proteins’ RNA templates. By exploiting this pathway, scientists are able to knock down the expression of specific proteins and thereby determine their roles within the cell or organism. The RNAi pathway has also been of considerable interest for the treatment of human disease. RNAi depends on two proteins, Dicer and Argonaute. Dicer recognizes double-stranded RNA (dsRNA), latches onto it, and chops it into pieces 21-23 nucleotides long. Argonaute recognizes the dsRNA bits, discards one strand, and uses the other as a guide. When a single-stranded RNA matches the guide RNA’s sequence, Argonaute cleaves the targeted RNA, thereby preventing it from serving as a template for protein production.

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Six Loci Are Newly Associated with Early-Onset Male Pattern Baldnesss

Using data from its unique online research platform, 23andMe, a leading personal genetics company, has contributed to the finding of six novel genetic associations for early-onset male pattern baldness (androgenetic alopecia) in a genome-wide association study published online on May 31, 2012 in the journal PLoS Genetics. “The 23andMe Research Platform is a robust source of new genetic discoveries. Nearly 90 percent of our more than 150,000 customers participate in our online research,” stated 23andMe CEO and co-founder Anne Wojcicki. “23andMe is making discoveries faster and more cost effectively than traditional research models,” Wojcicki claimed. The study, led by Dr. Brent Richards of McGill University, combined genome-wide association data from seven cohorts, comparing men with “early-onset” male pattern baldness with older men who had experienced little or no hair loss. 23andMe customers represented more than half of all the cases in the study. The combined analysis was able to identify six new loci associated with early-onset baldness, in addition to replicating two previously known loci. Additional data collected from 23andMe participants showed that a risk score based on genotypes at the eight associated loci was strongly predictive of whether someone would report early-onset male pattern baldness or not. Two of the new loci are in or near histone deacetylase genes HDAC4 and HDAC9. Histone deacetylases regulate expression of other genes by modifying histones, which are proteins responsible for DNA packaging. Both of these genes are thought to have roles in regulation of androgen hormone pathways, which are important in prostate cancer as well as male pattern baldness.

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Implanted Device Has Therapeutic Potential in Huntington’s Disease

Studies suggest that neurotrophic factors, which play a role in the development and survival of neurons, have significant therapeutic and restorative potential for neurologic diseases such as Huntington’s disease. However, clinical applications are limited because these proteins cannot easily cross the blood-brain barrier, have a short half-life, and cause serious side effects. Now, a group of scientists has successfully treated neurological symptoms in laboratory rats by implanting a device to deliver a genetically engineered neurotrophic factor directly to the brain. The scientists report on their results in the May 31, 2012 issue of Restorative Neurology and Neuroscience. Researchers used Encapsulated Cell (EC) biodelivery, a platform which can be applied using conventional minimally invasive neurosurgical procedures to target deep brain structures with therapeutic proteins. “Our study adds to the continually increasing body of preclinical and clinical data positioning EC biodelivery as a promising therapeutic delivery method for larger biomolecules. It combines the therapeutic advantages of gene therapy with the well-established safety of a retrievable implant,” says lead investigator Dr. Jens Tornøe, NsGene A/S, Ballerup, Denmark. Investigators made a catheter-like device consisting of a hollow fiber membrane encapsulating a polymeric “scaffold,” which provides a surface area to which neurotrophic factor-producing cells can attach. When implanted in the brain, the membrane allows the neurotrophic factor to flow out of the device, as well as allowing nutrients in. Dr. Tornøe and his colleagues used the neurotrophic factor Meteorin, which plays a role in the development of striatal projection neurons, whose degeneration is a hallmark of Huntington’s disease.

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Anti-Cocaine Vaccine Effective in Mouse Study

A single-dose vaccine capable of providing immunity against the effects of cocaine offers a novel and groundbreaking strategy for treating cocaine addiction [Referential web site: drugabuse.com/library/how-to-help-a-cocaine-addict/ and is described in an article published in the May 2012 issue of Human Gene Therapy. “This is a very novel approach for addressing the huge medical problem of cocaine addiction,” says James M. Wilson, M.D., Ph.D., Editor-in-Chief, and Director of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia. In the article, a team of researchers from Weill Cornell Medical College, The Scripps Research Institute, and Cornell University used a virus-based delivery vehicle in mice to transfer a gene that produces a protein capable of binding to cocaine present in the blood, preventing the cocaine from crossing into the brain. The protein is a monoclonal antibody that sequesters cocaine, making the vaccinated mice resistant to the drug’s effects. Whereas unvaccinated mice exhibited hyperactivity when exposed to intravenous cocaine, the immunized mice showed no effects, according to the authors. [Press release] [Human Gene Therapy article]

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