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Archive - 2012

June 29th

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.

June 26th

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.

June 24th

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.

June 22nd

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.

June 20th

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.

June 18th

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.

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: http://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]

Newly Discovered Fruit Fly Gene Could Provide Clues to New Cancer Drugs

Loyola University Chicago Stritch School of Medicine researchers are taking advantage of a quirk in the evolution of fruit fly genes to help develop new weapons against cancer. A newly discovered fruit fly gene is a simplified counterpart of two complex human genes that play important roles in the development of cancer and some birth defects. As this fruit fly gene evolved, it split in two. This split has made it easier to study, and the resulting insights could prove useful in developing new cancer drugs. "Evolution has given us a gift," said Andrew K. Dingwall, Ph.D., senior author of a paper that describes how his team identified and analyzed the split gene. Their findings are published in the June 1, 2012 issue of Development. Based on the importance of the findings, the paper was recently selected as an "Editor's Choice" in Science Signaling, published by the American Association for the Advancement of Science (AAAS). When normal cells develop, they differentiate into particular types, such as bone cells or muscle cells, and reproduce in an orderly manner. The process is governed by genes and hormones that work in concert. Two of these genes are known as MLL2 and MLL3. Cancer cells, by contrast, undergo uncontrolled division and reproduction. Since 2010, a growing number of cancers have been linked to mutations in the MLL2 and MLL3 genes. These cancers include non-Hodgkin’s lymphoma, colorectal cancer, kidney cancer, bladder cancer and a brain tumor called medulloblastoma. There also is evidence that MLL2 and MLL3 mutations are involved in breast and prostate cancers. The MLL2 and MLL3 genes are similar to one another. Each has more than 15,000 building blocks called base pairs -- more than 10 times the number found in a typical gene. Because these genes are so large and complex, they are difficult to study.

June 14th

Atomic-Resolution View Reveals How H. pylori Avoids Stomach Acid

University of Oregon (UO) scientists have discovered how the bacterium Helicobacter pylori navigates through the acidic stomach, opening up new possibilities to inactivate its disease-causing ability without using current strategies that often fail or are discontinued because of side effects. Their report – published online on June 14, 2012 in the journal Structure -- unveils the crystal structure of H. pylori's acid receptor TlpB. The receptor has an external protrusion, identified as a PAS domain, bound by a small molecule called urea and is poised to sense the external environment. TlpB is the first bacterial chemoreceptor of known function shown by crystallography to contain an extracellular PAS domain, the researchers reported. "It is a beautiful structure, and this domain has never been seen before in this class of proteins," said co-author Dr. S. James Remington, professor of physics and member of the UO Institute of Molecular Biology (IMB). Captured at the atomic resolution of 1.38 angstroms, it is the first new, significant structural view in 20 years of the class of receptors used by bacteria to navigate their chemical environment. H. pylori, a Gram-negative bacterium, was first identified in 1982 and shown to be associated with stomach ulcers and stomach cancer. While its mode of transmission is not precisely understood, the bacterium is found in the stomach of half of the people in the world, said co-author Dr. Karen Guillemin, professor of biology and also a member of the IMB. To fight H. pylori infections, patients generally are treated with broad-spectrum antibiotics, but the bacterium is becoming resistant and treatment fails in about 30 percent of cases. As part of the new UO study -- led by postdoctoral researcher Dr. Emily G. Sweeney and doctoral student Dr. J.

Gene May Link Diabetes and Alzheimer's

In recent years, it has become clear that people with diabetes face an ominous prospect – a far greater risk of developing Alzheimer's disease. Now researchers at The City College of New York (CCNY) have shed light on one reason why. Biology Professor Chris Li and her colleagues have discovered that a single gene forms a common link between the two diseases. They found that the gene, known to be present in many Alzheimer's disease cases, affects the insulin pathway. Disruption of this pathway is a hallmark of diabetes. The finding could point to a therapeutic target for both diseases. The researchers report their finding in the June 2012 issue of Genetics. "People with type 2 diabetes have an increased risk of dementia. The insulin pathways are involved in many metabolic processes, including helping to keep the nervous system healthy," said Professor Li, explaining why the link is not far-fetched. Although the cause of Alzheimer's is still unclear, one criterion for diagnosis of the disease after death is the presence of sticky plaques of amyloid protein in decimated portions of patients' brains. Mutations in the human "amyloid precursor protein" (APP) gene, or in genes that process APP, show up in cases of Alzheimer's that run in families. In the study, Professor Li and her colleagues scrutinized a protein called APL-1, made by a gene in the worm Caenorhabditis elegans (C. elegans) that happens to be a perfect stand-in for the human Alzheimer's disease gene. "What we found was that mutations in the worm-equivalent of the APP gene slowed their development, which suggested that some metabolic pathway was disrupted," said Professor Li.