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Archive - Apr 2012

April 26th

Advanced Pancreatic Tumors Depend on Continued Oncogene Activity

Researchers at the Dana-Farber Cancer Institute have shown that advanced pancreatic cancers in mice cannot survive without continued expression of a mutant oncogene that "rewires" key metabolic pathways to fuel the cancer cells. The findings, published in the April 27, 2012 issue of Cell, suggest that some of these altered metabolic pathways might be potential targets for future drugs to treat the deadly cancer. The investigators report that when they experimentally shut down the expression of the Kras oncogene in mice, the pancreatic tumors rapidly shrank, and, in some cases, left no visible signs of cancer. This outcome, they said, provides evidence that advanced pancreatic cancers are "addicted" to the Kras oncogene for their continued growth. "This experiment allowed us to demonstrate that pancreatic cancers in their native setting are dependent on continued oncogenic Kras expression for tumor maintenance," says Alec Kimmelman, M.D., Ph.D., co-corresponding author of the report along with Ronald DePinho, M.D., formerly at Dana-Farber and now at M.D. Anderson Cancer Center in Houston. Dr. Kimmelman said they also discovered that oncogenic Kras "basically reprograms the glucose metabolism of the cell by regulating the expression of key metabolic enzymes, some of which might provide novel therapeutic targets." If that is the case, then attacking these pathways might be more feasible than attempting to block KRAS directly, since KRAS has proven frustratingly difficult to hit with designer drugs. It is estimated that pancreatic ductal adenocarcinoma will be diagnosed in more than 43,000 people in the United States in 2012, according to the American Cancer Society, and more than 37,300 will die from the disease, which has a 5-year survival rate of only 5 percent.

April 25th

Stem Cell Line from Charcot-Marie-Tooth Embryo Available for Research

The University of Michigan's (U-M's) second human embryonic stem cell line has just been placed on the U.S. National Institutes of Health's registry, making the cells available for federally-funded research. It is the second of the stem cell lines derived at U-M to be placed on the registry. The line, known as UM11-1PGD, was derived from a cluster of about 30 cells removed from a donated five-day-old embryo roughly the size of the period at the end of this sentence. That embryo was created for reproductive purposes, tested, and found to be affected with a genetic disorder, deemed not suitable for implantation, and would therefore have otherwise been discarded when it was donated in 2011. It carries the gene defect responsible for Charcot-Marie-Tooth (CMT) disease, a hereditary neurological disorder characterized by a slowly progressive degeneration of the muscles in the foot, lower leg, and hand. CMT is one of the most common inherited neurological disorders, affecting one in 2,500 people in the United States. People with CMT usually begin to experience symptoms in adolescence or early adulthood. The embryo used to create the cell line was never frozen, but rather was transported from another in vitro fertilization (IVF) laboratory in the state of Michigan to the U-M in a special container. This may mean that these stem cells will have unique characteristics and utilities in understanding CMT disease progression or screening therapies in comparison to other human embryonic stem cells. "We are proud to provide this cell line to the scientific community, in hopes that it may aid the search for new treatments and even a cure for CMT," says Gary Smith, Ph.D., who derived the line and also is co-director of the U-M Consortium for Stem Cell Therapies, part of the A. Alfred Taubman Medical Research Institute.

April 24th

“Junk DNA” Can Sense Viral Infection

Once considered unimportant "junk DNA," scientists have learned that DNA that codes for non-coding RNA (ncRNA) — RNA molecules that do not translate into proteins — plays a crucial role in cellular function. Mutations in ncRNA are already known to be associated with a number of conditions, such as cancer, autism, and Alzheimer's disease. Now, through the use of "deep sequencing," a technology used to sequence the genetic materials of the human genome, Dr. Noam Shomron of Tel Aviv University's Sackler Faculty of Medicine has discovered that when infected with a virus, ncRNA gives off biological signals that indicate the presence of an infectious agent. Not only does this finding give researchers a more complete picture of the interactions between pathogens and the body, but it provides scientists with a new avenue for fighting off infections. Dr. Shomron’s findings were first published online on March 9, 2012 in the journal Nucleic Acids Research. "If we see that the number of particular RNA molecules increases during a specific viral infection, we can develop treatments to stop or slow their proliferation," explains Dr. Shomron. In the lab, the researchers conducted a blind study in which some cells were infected with the HIV virus and others were left uninfected. Using the deep sequencer, which can read tens of millions of sequences per experiment, they analyzed the ncRNA to discover if the infection could be detected in non-coding DNA materials. The researchers were able to identify with 100% accuracy both infected and non-infected cells — all because the ncRNA was giving off significant signals, explains Dr. Shomron. These signals, which can include either the increase or decrease of specific ncRNA molecules within a cell, most likely have biological significance, he says.

Study Suggests Alternative Cause and Different Drug Target for Depression

Princeton University researchers have observed a self-degradation response to the antidepressant Zoloft in yeast cells that could help provide new answers to lingering questions among scientists about how antidepressants work, as well as support the idea that depression is not solely linked to the neurotransmitter serotonin. In findings published online on April 18, 2012 in PLoS ONE, researchers based in the lab of Dr. Ethan Perlstein, an associate research scholar in Princeton's Lewis-Sigler Institute for Integrative Genomics and senior lecturer in molecular biology, report that sertraline — trademarked as Zoloft — accumulated in the internal membranes of baker's yeast cells. This buildup caused a swelling and sharp curvature in the membranes of vesicles, bubble-like cell components with a hand in cell metabolism, movement, and energy storage. The vesicles then went into autophagy, a protective response in which cells recycle excess or damaged membrane. But yeast cells lack serotonin, which is the primary target of antidepressants, Dr. Perlstein said. By observing a reaction to sertraline in an organism that does not contain the drug's conventional target, Dr. Perlstein and his co-authors have found significant evidence suggesting that antidepressants engage in pharmacological activity beyond regulating serotonin. Dr. Perlstein worked with co-first authors Drs. Jingqui Chen and Daniel Korostyshevsky, as well as Dr. Sean Lee, all three senior research specialists in Dr. Perlstein's lab. Although antidepressants are known to regulate serotonin, it is not completely understood how antidepressants interact with the body's brain cells and what effect, if any, this activity has on treating depression, Dr. Perlstein said.

April 22nd

San Francisco Personalized Medicine Conference 5.0 Will Focus on Epigenetics

The fifth annual Personalized Medicine Conference (5.0) hosted by San Francisco State University, this year with a focus on epigenetics, will be held on Thursday, May 24, 2012 from 8:00 am to 7:30 pm at the South San Francisco Conference Center. To view the conference website and to register for the conference, please go to http://personalizedmedicine.sfsu.edu/. Scheduled speakers include Michael Snyder, M.D., Ph.D., Chair/Director, Department of Genetics & Stanford Center for Genomics and Personalized Medicine, Stanford University; Brian Kennedy, Ph.D., CEO, Buck Institute for Age Research; Cristina Gentilini, Ph.D., Commercial Research Scientist, Swedish Biomimetics 3000; Jorge A. Leon, President/CEO, Leomics Associates, Inc.; and Stephen M. Anderson, Ph.D., CSO of Oncology and Genetics, LabCorp. The organizers note that epigenetics, or genetic changes above and beyond the DNA sequence level, have profound implications for personalized medicine, pharmacogenomics, aging, and oncology. While personalized medicine is poised to transform healthcare over the next several decades, it has become abundantly clear that the DNA sequence itself is only part of the story. The regulation of gene expression, and how it changes in health and disease, and in response to therapy, are crucial. The organizers invite you to attend this conference and learn the latest information on how epigenetics is and will be impacting personalized medicine. The conference will also be an excellent networking opportunity for health and industry professionals, educators, and scientists. Seating is limited and if you register early, you can save $100 on the registration fee. Sponsors of the conference include Genentech, Celgene, LabCorp, and BioMarin, among many others.

April 22nd

Swiftly Spreading Gene Linked to Asian Epidemic of Resistant Staph Aureus

National Institutes of Health (NIH) scientists and their colleagues in China, together with a collaborator at the University of California, San Francisco, have described a rapidly emerging Staphylococcus aureus gene, called sasX, which plays a pivotal role in establishing methicillin-resistant S. aureus (MRSA) epidemics in most of Asia. Senior author Michael Otto, Ph.D., of NIH's National Institute of Allergy and Infectious Diseases, says these findings illustrate at the molecular level how MRSA epidemics may emerge and spread. Moreover, the study identifies a potential target for novel therapeutics. MRSA is a leading cause of severe infections that occur predominantly in hospitals. The results were published online in Nature Medicine on April 22, 2012. MRSA epidemics happen in waves, with old clones of MRSA bacteria disappearing and new clones emerging, a process whose molecular underpinnings are not fully understood. Previous data indicated that the sasX gene is extremely rare. Therefore, the researchers were surprised when they analyzed 807 patient samples of invasive S. aureus taken over the past decade from three Chinese hospitals. Their data showed that sasX is more prevalent in MRSA strains from China than previously thought, and the gene's frequency is increasing significantly: From 2003 to 2011, the percentage of MRSA samples containing sasX almost doubled, from 21 to 39 percent. This finding suggests that the sasX gene is involved in molecular processes that help MRSA spread and cause disease. The researchers determined in laboratory and mouse studies that sasX helps bacteria to colonize in the nose, cause skin abscesses and lung disease, and evade human immune defenses.

Fragile X Syndrome Can Be Substantially Reversed in Adult Mouse Brain

A recent study finds that a new compound reverses many of the major symptoms associated with Fragile X syndrome (FXS), the most common form of inherited intellectual disability and a leading cause of autism. The paper, published by Cell Press in the April 12 issue of the journal Neuron, describes the exciting observation that the FXS correction can occur in adult mice, after the symptoms of the condition have already been established. Fragile X patients suffer from a complex set of neuropsychiatric symptoms of varying severity which include anxiety, hyperactivity, learning and memory deficits, low IQ, social and communication deficits, and seizures. Previous research has suggested that inhibition of mGlu5, a subtype of receptor for the excitatory neurotransmitter glutamate, may be useful for ameliorating many of the major symptoms of the disease. The new study, a collaboration between a group at F. Hoffmann-La Roche Ltd. in Switzerland, led by Dr. Lothar Lindemann, and a group at the Picower Institute for Learning at the Massachusetts Institute of Technology, led by Dr. Mark Bear, used a newly developed mGlu5 inhibitor called CTEP to examine whether pharmacologic inhibition of mGlu5 could reverse FXS symptoms. The researchers used a mouse model of FXS and administered CTEP after the brain had matured. "We found that even when treatment with CTEP was started in adult mice, it reduced a wide range of FXS symptoms, including learning and memory deficits and auditory hypersensitivity, as well as morphological changes and signaling abnormalities characteristic of the disease," reports Dr. Lindemann. Although the CTEP drug itself is not being developed for humans, the findings have significance for human FXS.

Early Treatment Improves Outcome in Mysterious Form of Encephalitis

A mysterious, difficult-to-diagnose, and potentially deadly disease that was only recently discovered can be controlled most effectively if treatment is started within the first month that symptoms occur, according to a new report by researchers from the Perelman School of Medicine at the University of Pennsylvania. The researchers analyzed 565 cases of this recently discovered paraneoplastic condition, called anti-NMDA receptor encephalitis, and determined that if initial treatments fail, second-line therapy significantly improves outcomes compared with repeating treatments or no additional treatments (76 percent versus 55 percent). The research will be presented on April 25, 2012 at the American Academy of Neurology's 64th Annual Meeting in New Orleans. The condition occurs most frequently in women (81 percent of cases), and predominantly in younger people (36 percent of cases occurring in people under 18 years of age, the average age is 19). Symptoms range from psychiatric symptoms, memory issues, speech disorders, seizures, involuntary movements, to decreased levels of consciousness and breathing. Within the first month, movement disorders were more frequent in children, while memory problems and decreased breathing predominated in adults. "Our study establishes the first treatment guidelines for NMDA-receptor encephalitis, based on data from a large group of patients, experience using different types of treatment, and extensive long-term follow-up," said lead author Maarten Titulaer, M.D., Ph.D., clinical research fellow in Neuro-oncology and Immunology in the Perelman School of Medicine at the University of Pennsylvania.

April 21st

New Genetic Mechanism of Immune Deficiency Discovered

Researchers at National Jewish Health have discovered a novel genetic mechanism of immune deficiency. Magdalena M. Gorska, M.D., Ph.D., and Rafeul Alam, M.D., Ph.D., identified a mutation in Unc119 that causes an immunodeficiency known as idiopathic CD4 lymphopenia. Unc119 is a signaling protein that activates and induces T-cell proliferation. The mutation impairs Unc119’s ability to activate T-cells. Dr. Gorska presented the findings on April 20, 2012 at Translational Science 2012, an NIH-funded conference in Washington D.C. “A better understanding of the molecular mechanisms associated with this mutation will improve diagnosis and pave the way for development of new therapies,” said Dr. Gorska. Drs. Gorska and Alam previously published their findings in the February 9, 2012 issue of Blood, and Dr. Gorska delivered a Presidential Plenary lecture on the topic at the annual meeting of the American Academy of Allergy Asthma & Immunology. Nearly a decade ago, Drs. Alam and Gorska identified Unc119 as a novel activator of SRC-type tyrosine kinases, important regulators of cellular function. Since then, they have published numerous papers in which they characterized the function of this protein in various aspects of the immune system. Idiopathic CD4 lymphopenia is a rare and heterogeneous syndrome defined by low levels of CD4 T-cells in the absence of HIV infection, which predisposes patients to infections and malignancies. Recent research by others had linked the syndrome to reduced activation of the SRC-type kinase known as Lck. The latter kinase is involved in T-cell development, activation, and proliferation. So, Drs. Alam and Gorska thought Unc119, an activator of Lck, might be involved.

Cancer Drug Development May Be Aided by Discovery of How “Checkpoint Proteins” Bind Chromosomes

The development of more effective cancer drugs could be a step closer thanks to the discovery, by scientists at Warwick Medical School, of how an inbuilt ‘security check’ operates to guarantee cells divide with the correct number of chromosomes. Most cells in our bodies contain 23 pairs of chromosomes that encode our individual genetic identities. The process of chromosome segregation is monitored by a system called the spindle checkpoint that ensures daughter cells receive the correct number of chromosomes. If daughter cells receive an unequal number of chromosomes, known as ‘aneuploidy,’ this drives normal cells to become cancerous. Indeed, the cells of aggressive human tumors are frequently ‘aneuploid’ with many components of the spindle checkpoint being mutated or mis-expressed. Therefore, determining how the spindle checkpoint operates is vital to understanding what causes, and what can prevent, the formation of tumors. On April 19, 2012, online, Current Biology published research by Professor Jonathan Millar at the University of Warwick, UK, and colleagues, that pinpoints the precise mechanism by which spindle checkpoint proteins bind chromosomes. Professor Millar explained, “Components of the spindle assembly checkpoint were first discovered 22 years ago by researchers in America and yet, until now, the binding sites for these proteins on chromosomes have remained unknown. We have been able to answer this question and as a result, we are now in a much better position to design more selective and effective drugs.” Currently, some of the most frequently used anti-cancer drugs are taxanes, which prevent proper inactivation of the spindle checkpoint and result in selective death of cancer, but not normal, cells.