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Archive - 2011

March 23rd

Telomerase Inhibitor Proves to Be Key Tumor Suppressor

It's been nearly 10 years since Beth Israel Deaconess Medical Center (BIDMC) scientists Dr. Kun Ping Lu and Dr. Xiao Zhen Zhou discovered PinX1, the first potent endogenous protein shown to inhibit telomerase in mammals. Now the scientific team has discovered a vitally important new function for this telomerase inhibitor. The investigators report online on March 23, 2011, in the Journal of Clinical Investigation (JCI) that low levels of PinX1 contribute to cancer development, providing the first genetic evidence linking telomerase activation to chromosome instability and cancer initiation, and suggesting a new avenue of treatment for cancers. "Although telomerase is activated in 85 to 90 percent of human cancers, little has been known about the significance of telomerase activation in chromosome instability and cancer initiation," explains Dr. Lu, the paper's senior author and a Professor of Medicine at Harvard Medical School. "We have discovered, for the first time, a novel role for abnormal telomerase activation in cancer initiation. This suggests that telomerase inhibition using PinX1 or other small molecules may be used to treat certain cancers with activated telomerase." Of particular note, the group's discovery that most PinX1-mutant mouse tumors share tissues of origin with human cancer types linked to genetic alterations in chromosome 8p23 suggests a possible role for deregulation of the PinX1-telomerase complex for the treatment of several common carcinomas, including breast, lung, liver, and gastrointestinal cancers. Telomeres cap the ends of linear chromosomes and are essential for maintaining chromosome stability. In the majority of human cells, telomeres are slightly shortened each time a cell divides, a process that, over time, leads to cell death.

March 23rd

Zebrafish Model Reveals New Gene for Human Melanoma

Looking at the dark stripes on the tiny zebrafish you might not expect that they hold a potentially important clue for discovering a treatment for the deadly skin disease melanoma. Yet melanocytes, the same cells that are responsible for the pigmentation of zebrafish stripes and for human skin color, are also where melanoma originates. Dr. Craig Ceol, assistant professor of molecular medicine at the University of Massachusetts Medical School, and collaborators at several institutions, used zebrafish to identify a new gene responsible for promoting melanoma. In a paper featured on the cover of the March 24 issue of Nature, Dr. Ceol and colleagues describe the melanoma-promoting gene SETDB1, which codes for a methyl transferase. "We've known for some time that there are a number of genes that are responsible for the promotion and growth of melanoma," said Dr. Ceol, who completed the research while a postdoctoral fellow in the lab of Howard Hughes Medical Institute investigator Dr. Leonard Zon at Children's Hospital Boston. "With existing methods, it had been difficult to identify what those genes are. By developing the new approach described in this paper, we were able to isolate SETDB1 as one of those genes." Cases of melanoma, an aggressive form of skin cancer, have been on the rise in the United States: in 2009 alone, 68,000 new cases were diagnosed and 8,700 people died of the disease. Though it accounts for less than 5 percent of all skin cancers, it is responsible for the majority of deaths from skin cancers and has a poor prognosis when diagnosed in its advanced stages. Early signs of melanoma include changes to the shape or color of existing moles or the appearance of a new lump anywhere on the skin.

Epigenomic Findings Have Implications for Common Disease Studies

Genes make up only a tiny percentage of the human genome. The rest, which has remained measurable but mysterious, may hold vital clues about the genetic origins of disease. Using a new mapping strategy, a collaborative team led by researchers at the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), and MIT has begun to assign meaning to the regions beyond our genes and has revealed how minute changes in these regions might be connected to common diseases. The researchers' findings appeared online on March 23, 2011 in Nature. The results have implications for interpreting genome-wide association studies (GWAS) – large-scale studies of hundreds or thousands of people in which scientists look across the genome for single "letter" changes or SNPs (single nucleotide polymorphisms) that influence the risk of developing a particular disease. The majority of SNPs associated with disease reside outside of genes and, until now, very little was known about the functions of most of them. "Our ultimate goal is to figure out how our genome dictates our biology," said co-senior author Dr. Manolis Kellis, a Broad associate member and associate professor of computer science at MIT. "But 98.5 percent of the genome is non-protein coding, and those non-coding regions are generally devoid of annotation." The term "epigenome" refers to a layer of chemical information on top of the genetic code, which helps determine when and where (and in what types of cells) genes will be active. This layer of information consists of chemical modifications, or "chromatin marks," that appear across the genetic landscape of every cell, and can differ dramatically between cell types.

Trigger Found for Autoimmune Heart Attacks

People with autoimmune type 1 diabetes, whose insulin-producing cells have been destroyed by the body's own immune system, are particularly vulnerable to a form of inflammatory heart disease (myocarditis) caused by a different autoimmune reaction. Scientists at the Joslin Diabetes Center have now revealed the exact target of this other onslaught, taking a large step toward potential diagnostic and therapeutic tools for the heart condition. Researchers in the lab of Dr. Myra Lipes, have shown in both mice and people that myocarditis can be triggered by a protein called alpha-myosin heavy chain, which is found only in heart muscle and in especially low quantities in human heart tissue. While myocarditis often follows viral attacks or other infections, Dr. Lipes and her colleagues previously demonstrated that mice genetically modified to model type 1 diabetes could generate myocarditis spontaneously. In their latest work, reported online on March 23, 2011, in the Journal of Clinical Investigation, the scientists analyzed blood from such mice and identified two types of autoimmune response directed specifically against the protein, with the first response directed by a specialized kind of immune system cells called T cells and the second by antibodies. In both mice and people, T cells are "trained" by specialized cells in the thymus, a small organ in front of the heart, to recognize the body's own cells and refrain from attacking them. The researchers found, however, that in mice these specialized training cells couldn't train on the alpha-myosin heavy chain protein because none of that protein was being produced in those cells. Next, the scientists showed that the disease didn't develop in similar mice that were genetically engineered to produce the protein in the specialized training cells.

Mechanism of Zeta Toxin Bacterial Suicide Explained

The zeta toxins are a family of proteins that are normally present within various pathogenic bacteria and can mysteriously trigger suicide when the cells undergo stress. A team led by Dr. Anton Meinhart at the Max Planck Institute for Medical Research in Heidelberg has now found the mechanism underlying this programmed bacterial cell death. The team’s paper, published in PLoS Biology, reports that zeta toxins convert a compound required for bacterial cell wall synthesis into a poison that kills bacteria from within. In the future, it may be possible to hijack this mechanism for defense against bacteria and to design drugs that mimic these toxins. Most bacteria harbor toxin-antitoxin (TA) systems, in which a bacterial toxin lies dormant under normal conditions, prevented from being active by its antitoxin counterpart. As long as the antitoxin is present, the bacterium can continue to exist and is not affected by the TA system. Under conditions of stress, however, the antitoxin is degraded, freeing the toxin to attack its host from within. Although the family of zeta toxins was discovered almost 20 years ago, their deadly mechanism has been enigmatic until now. The first author on the paper, Dr. Hannes Mutschler, and his colleagues studied the molecular mechanism of action of the zeta toxin PezT from the PezAT (Pneumococcal epsilon zeta Antitoxin Toxin) system using the model bacterium Escherichia coli. The PezAT system is found in the major human pathogen Streptococcus pneumoniae - a bacterium that causes serious infections such as pneumonia, septicemia, and meningitis. Bacterial cells in which PezT was activated showed symptoms of poisoning similar to the effects of penicillin. This involved first stalling in the middle of their division stage, and later the intersection zone between the two cell bodies burst and the cells died.

March 22nd

Complement-Regulating Genes Implicated in Preeclampsia

Scientists have discovered genetic defects that appear to predispose women to a common pregnancy-related medical problem called preeclampsia that can threaten the life of both baby and mother. Lead investigator Dr. Jane Salmon, a rheumatologist and senior scientist at the Hospital for Special Surgery in New York City, and colleagues uncovered genetic mutations in women with certain autoimmune diseases associated with increased risk of preeclampsia, as well as in patients with preeclampsia who did not have an autoimmune disease. Their findings appear in an article published online on March 22, 2011, in PLoS Medicine. Preeclampsia affects up to 10 percent of pregnancies in the United States. The condition claims the lives of more than 60,000 women each year in developing countries. It is diagnosed by the onset of high blood pressure and appearance of protein in the urine. Because the cause of preeclampsia is unknown, there are no reliable means to predict its occurrence and no satisfactory prevention or treatment. When preeclampsia becomes life-threatening, the only option is to deliver the baby pre-term. In the study, Dr. Salmon and colleagues focused on women with systemic lupus erythematosus and/or antiphospholipid antibody syndrome, which are autoimmune diseases. The women are participants in a multi-center research initiative led by Dr. Salmon known as PROMISSE (Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus) and funded by the National Institutes of Health since 2003 to identify biomarkers that predict poor pregnancy outcomes in women with lupus and/or antiphospholipid antibody syndrome. Dr. Salmon is also co-director of the Mary Kirkland Center for Lupus Research at the Hospital for Special Surgery.

Newly Discovered Bunya Virus Implicated in Deadly Chinese Outbreaks

Five years ago, large numbers of farmers in central China began falling victim to a mysterious disease marked by high fever, gastrointestinal disorder, and an appalling mortality rate — as high as 30 percent in initial reports. Investigators from the Chinese Center for Disease Control and Prevention hurried to the scene of the outbreak. On the basis of DNA evidence, they quickly concluded that it had been caused by human granulocytic anaplasmosis (HGA) bacteria, which are transmitted by tick bites. Now, however, subsequent studies have shown that this original conclusion was incorrect, and that a previously unknown and dangerous virus has been responsible for seasonal outbreaks of the disease in six of China's most populated provinces. "We expected to find a bacterial infection behaving in an unexpected way — human anaplasmosis has a less than one percent fatality rate in the U.S., and it rarely causes abdominal pain or vomiting or diarrhea," said Dr. Xue-Jie Yu of the University of Texas Medical Branch at Galveston, lead author of a paper on the discovery published online on March 16, 2011, in the New England Journal of Medicine. "Instead, we found an unknown virus." Researchers have named the newly discovered pathogen Severe Fever with Thrombocytopenia Syndrome virus (SFTSV), and placed it in the Bunyaviridae family, along with the hantaviruses and Rift Valley Fever virus. Later investigation has placed its mortality rate at 12 percent, still alarmingly high. Dr. Yu, a specialist in tick-borne bacteria like the species responsible for HGA, first suspected that a virus might be responsible for the outbreaks after close examination of patients' clinical data showed big differences from symptoms produced by HGA, and blood sera drawn from patients revealed no HGA bacteria or HGA antibodies. Dr.

First Partial Sequencing of an Iberian Pig, Prized for Its Meat

Researchers of the Faculty of Veterinary Medicine at Universitat Autònoma de Barcelona (UAB) and of the Centre for Research in Agricultural Genomics (CRAG), the Centre for Genomic Regulation (CRG) in Barcelona, the National Institute for Agrarian Technology and Research in Madrid and Wageningen Research Center (WUR, the Netherlands) have published the first partial genome sequencing of an Iberian pig. Using next-generation sequencing techniques, researchers have been able to sequence and analyze 1% of the genome. This is the first time an individual pig genome-sequence has been published. The project, coordinated by ICREA researcher Miguel Pérez-Enciso, was published online on March 16, 2011, in the journal Heredity. The sequenced animal is an Iberian sow from the Guadyerbas strain, a highly particular line which has been kept isolated on an experimental farm belonging to the government of Castilla-La Mancha and located in Oropesa, near Toledo, since 1945, thanks to years of work by INIA researchers. The Guadyerbas line thus represents one of the first original strains of the Iberian pig in Spain. These animals have a good appetite, are slow-growing, obese, hairless and black-colored. UAB and INIA teams have used these animals in several experiments aimed at identifying the genetic basis of the highly reputed meat quality of Iberian pigs. Researchers expect therefore that a complete sequencing could offer clues to these and other characteristics. The sequenced animal is highly inbred, because the herd has been isolated for over 50 years. Researchers have taken this into account with the intention of using a particularly 'homogeneous' species presenting little variability. Nevertheless, data from the sequencing offers surprising results, such as a higher than expected level of variability.

Bacterial Enzyme Inhibits Formation of Dental Plaque

Investigators from Japan show in vitro that the bacterium Streptococcus salivarius, a non-biofilm forming, and otherwise harmless inhabitant of the human mouth, actually inhibits the formation of dental biofilms, otherwise known as plaque. Two enzymes this bacteria produces are responsible for this inhibition. The research is published in the March 1, 2011 issue of the journal Applied and Environmental Microbiology. "FruA may be useful for prevention of dental caries," corresponding author Dr. Hidenobu Senpuku, of the National Institute of Infectious Diseases, Tokyo, said of one of the enzymes. "The activity of the inhibitors was elevated in the presence of sucrose, and the inhibitory effects were dependent on the sucrose concentration in the biofilm formation assay medium," the researchers wrote. "We show that FruA produced by S. salivarius inhibited S. mutans biofilm formation completely in the in vitro assay supplemented with sucrose," the researchers wrote. S. salivarius is the primary species of bacteria inhabiting the mouth, according to the report. The authors suggest that FruA may actually regulate microbial pathogenicity in the oral cavity. They found that a commercial FruA, produced by Aspergillus niger, was as effective as S. salivarius FruA at inhibiting S. mutans biofilm formation, despite the fact that its amino acid composition is somewhat different from that of S. salivarius. FruA is produced not only by S. salivarius, but by other oral streptococci. Much of the oral microbial flora consists of many beneficial species of bacteria that help maintain oral health and control the progression of oral disease. [Press release] [AEM abstract]

Cell Studies Yield Breakthrough in Niemann-Pick Type C Research

A paper announcing a breakthrough discovery in the fight against Niemann-Pick Type C (NPC), co-authored by Drs. Olaf Wiest and Paul Helquist of the University of Notre Dame's Department Chemistry & Biochemistry and Dr. Frederick Maxfield, Chair of Biochemistry at Cornell University Weill College of Medicine, was published online on March 21, 2011, in PNAS. The reported research shows, in cell culture, how use of a histone deacetylase inhibitor corrects the damage done by the genetic disorder and allows once-diseased cells to function normally. NPC involves a genetic flaw that keeps cells from using lipids appropriately and leaves the lipids trapped in the cell. Brain cells are especially impacted, and destruction of brain cells typically kills victims by their teen years and there is currently no treatment available in the U.S. NPC is an inherited cholesterol metabolism disorder that strikes one in every 150,000 children. It has been referred to by the National Institutes of Health as "childhood Alzheimer's" because of similarities in the brains of NPC and Alzheimer's disease patients. Three of the four grandchildren of former Notre Dame head football coach Ara Parseghian died of NPC, and the University has been involved in research on the disorder for years. Last year, it formally united with the Parseghian Foundation, which sponsored this work. Last summer, Notre Dame College of Science Dean Gregory Crawford and his wife Renate bicycled 2,300 miles from Tucson to Notre Dame to raise awareness of the newly strengthened partnership with the Parseghian Foundation. Notre Dame's Center for Rare and Neglected Diseases works to develop therapies and outreach efforts for people suffering from rare conditions, like NPC, that have been largely ignored by pharmaceutical companies. A team of researchers led by Drs.