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Archive - May 5, 2013

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Portable Device Provides Rapid, Accurate Diagnosis of TB, Other Bacterial Infections

A handheld diagnostic device that Massachusetts General Hospital (MGH) investigators first developed to diagnose cancer has been adapted to rapidly diagnose infections by Mycobacterium tuberculosis (TB) and other important infectious bacteria. Two papers, one appearing in the journal Nature Communications, and the other in Nature Nanotechnology describe portable devices that combine microfluidic technology with nuclear magnetic resonance (NMR) to not only diagnose these important infections, but also determine the presence of antibiotic-resistant bacterial strains. "Rapidly identifying the pathogen responsible for an infection and testing for the presence of resistance are critical not only for diagnosis but also for deciding which antibiotics to give a patient," says Ralph Weissleder, M.D., Ph.D., director of the MGH Center for Systems Biology (CSB) and co-senior author of both papers. "These described methods allow us to do this in two to three hours, a vast improvement over standard culturing practice, which can take as much as two weeks to provide a diagnosis." Investigators at the MGH CSB previously developed portable devices capable of detecting cancer biomarkers in the blood or in very small tissue samples. Target cells or molecules are first labeled with magnetic nanoparticles, and the sample is then passed through a micro NMR system capable of detecting and quantifying levels of the target. But initial efforts to adapt the system to bacterial diagnosis had trouble finding antibodies – the detection method used in the earlier studies – that would accurately detect the specific bacteria. Instead the team switched to targeting specific nucleic acid sequences. The system described in the Nature Communications paper, published online on April 23, 2013, detects DNA from the tuberculosis bacteria in small sputum samples.

Genetics of Pulmonary Fibrosis

Researchers from the University of Colorado Denver and colleagues have carried out a genome-wide association study to identify susceptibility loci for fibrotic idiopathic pneumonia. Their results sugget that genes involved in host defense, cell-cell adhesion, and DNA repair contribute to risk for this disease. Specifically, the scientists confirmed association with TERT at 5p15, MUC5B at 11p15, and the 3q26 region near TERC. In addition, they identified seven newly associated loci: FAM13A at 4q22, DSP at 6p24, OBFC1 at 10q24, ATP11A at 13q34,DPP9 at 19p13, and chromosomal regions 7q22 and 15q14-15. The results of this study were published online in Nature Genetics on April 14, 2013. [Nature Genetics abstract]

Platyfish Genome Sequenced

The sequence and analysis of the platyfish genome was published in the May 2013 issuee of Nature Genetics. The work represents the first genome sequence of a poeciliid fish and provides insights into evolutionary adaptation in this freshwater fish as well as a potential model for cancer research. Dr. Wesley Warren of the Genome Institue, the Washington University School of Medicine, and an international group of colleagues report the sequencing. The authors use this as a model to examine the evolution of a number of traits, including a live-bearing reproductive mode, pigmentation patterns, cancer, and behavioral traits. They identify a gene implicated in both pigmentation patterning and melanoma development in the platyfish. They also find evidence for selection of genes associated with viviparity—the development of the embryo inside the body of the mother, eventually leading to a live birth. In addition, they identify selective retention of duplicate genes implicated in cognition during the evolution of teleost fish, suggesting a model for the evolution of behavioral complexity in fish. [Press release] [Nature Genetics abstract]

BAF Protein Complex May Play Role in Preventing Many Forms of Cancer

Researchers at the Stanford University School of Medicine have identified a group of proteins that are mutated in about one-fifth of all human cancers. This finding suggests that the proteins, which are members of a protein complex that affects how DNA is packaged in cells, normally work to suppress the development of tumors in many types of tissues. The broad reach of the effect of mutations in the complex, called BAF, rivals that of another well-known tumor suppressor called p53. It also furthers a growing notion that these so-called chromatin-regulatory complexes may function as much more than mere cellular housekeepers. "Although we knew that this complex was likely to play a role in preventing cancer, we didn't realize how extensive it would be," said postdoctoral scholar Cigall Kadoch, Ph.D. "It's often been thought that these complexes play supportive, maintenance-like roles in the cell. But this is really changing now." Dr. Kadoch shares lead authorship of the study with postdoctoral scholar Diana Hargreaves, Ph.D. Gerald Crabtree, M.D., professor of developmental biology and of pathology, is the senior author of the study, which was published online on May 5, 2013 in Nature Genetics. Chromatin-regulatory complexes work to keep DNA tightly condensed, while also granting temporary access to certain portions for replication or to allow the expression of genes necessary for the growth or function of the cell. Members of Dr. Crabtree's laboratory have been interested in BAF complexes and their function for many years. Recently, they reported in the journal Nature that switching subunits within these complexes can convert human fibroblasts to neurons, which points to their instructive role in development and, possibly, cancer.

Why Dense Breasts Predispose to Metastasis in Breast Cancer

Researchers at Washington University School of Medicine in St. Louis have discovered why breast cancer patients with dense breasts are more likely than others to develop aggressive tumors that spread. The finding opens the door to drug treatments that may prevent metastasis. It has long been known that women with denser breasts are at higher risk for breast cancer. This greater density is caused by an excess of a structural protein called collagen. "We have shown how increased collagen in the breasts could increase the chances of breast tumors spreading and becoming more invasive," says Gregory D. Longmore, M.D., professor of medicine. "It doesn't explain why women with dense breasts get cancer in the first place. But once they do, the pathway that we describe is relevant in causing their cancers to be more aggressive and more likely to spread." The results were published online on May 5, 2013 in Nature Cell Biology. Working in mouse models of breast cancer and with breast tumor samples from patients, Dr. Longmore and his colleagues showed that a protein that sits on the surface of tumor cells, called DDR2, binds to collagen and activates a multi-step pathway that encourages tumor cells to spread. "We had no idea DDR2 would do this," says Dr. Longmore, also professor of cell biology and physiology. "The functions of DDR2 are not well understood, and it has not been implicated in cancer -- and certainly not in breast cancer -- until now.” At the opposite end of the chain of events initiated by DDR2 is a protein called SNAIL1, which has long been associated with breast cancer metastasis. Dr. Longmore and his colleagues found that DDR2 is one factor helping to maintain high levels of SNAIL1 inside a tumor cell's nucleus, a necessary state for a tumor cell to spread.

Epileptic Seizures Halted in Mouse Model

University of California San Francisco (UCSF) cell therapy raises hope for severe human forms of epilepsy. UCSF scientists controlled seizures in epileptic mice with a one-time transplantation of medial ganglionic eminence (MGE) cells, which inhibit signaling in overactive nerve circuits, into the hippocampus, a brain region associated with seizures, as well as with learning and memory. Other researchers had previously used different cell types in rodent cell transplantation experiments and failed to stop seizures. Cell therapy has become an active focus of epilepsy research, in part because current medications, even when effective, only control symptoms and not underlying causes of the disease, according to Scott C. Baraban, Ph.D., who holds the William K. Bowes Jr. Endowed Chair in Neuroscience Research at UCSF and led the new study. In many types of epilepsy, he said, current drugs have no therapeutic value at all. "Our results are an encouraging step toward using inhibitory neurons for cell transplantation in adults with severe forms of epilepsy," Dr. Baraban said. "This procedure offers the possibility of controlling seizures and rescuing cognitive deficits in these patients." The findings, which are the first ever to report stopping seizures in mouse models of adult human epilepsy, were published online on May 5, 2013 in Nature Neuroscience. During epileptic seizures, extreme muscle contractions and, often, a loss of consciousness can cause seizure sufferers to lose control, fall, and sometimes be seriously injured. The unseen malfunction behind these effects is the abnormal firing of many excitatory nerve cells in the brain at the same time.