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Archive - Aug 24, 2013

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Gene Combinations and Interactions Shown to Affect Risk of Crohn's Disease

A statistical model accounting for dozens of different genes in combination—and the interactions between them—is an important step forward in understanding the genetic factors affecting the risk of Crohn's disease (CD), reports a study in Inflammatory Bowel Diseases, official journal of the Crohn's & Colitis Foundation of America (CCFA). It's not just how many risk genes are present, but how those genes interact with each other that determines the inheritance of CD risk, suggests the report by a research group from the Cleveland Clinic and the University of Pittsburgh. The study is the first to show that information on genetic interactions can improve the ability to predict CD risk and explain its genetic heritability. CD is a chronic inflammatory bowel disease affecting up to 700,000 Americans. Although the exact cause is unknown, CD appears to result from an "inappropriate persistent immune response." In addition to genetics, microbial and environmental factors likely play important roles in the development of CD. Using modern genetic research methods, called genome-wide association studies (GWAS), researchers have identified at least 71 genes that appear to affect CD risk. However, individual genes have only small effects on CD risk. Even after accounting for the combined effects of CD risk genes, less than one-fourth of CD heritability can be explained. To address this issue, the researchers developed a new model exploring "higher-order genetic interactions" among known CD risk genes. The model was designed to evaluate not only the additive effects of having multiple CD risk genes, but also the possible impact of interactions between genes.

Study Finds Genomic Differences in Two Common Types of Cervical Cancer

A new study has revealed marked differences in the genomic terrain of the two most common types of cervical cancer, suggesting that patients might benefit from therapies geared to each type’s molecular idiosyncrasies. The study, published August 23, 2013 in the online version of the journal Cancer by researchers at Dana-Farber Cancer Institute and Brigham and Women’s Hospital (BWH) in Boston, is the first to compare the spectrum of cancer-related gene mutations in the two main subtypes of cervical cancer – adenocarcinoma and squamous cell carcinoma. In tests on 80 cervical tumor samples, the investigators found high rates of mutations in two genes: PIK3CA and KRAS. While PIK3CA mutations appeared in both subtypes, KRAS mutations were found only in adenocarcinomas. By linking their findings to data on patients’ treatment and survival, researchers found that PIK3CA mutations are associated with a shorter survival period: patients whose tumors carried these mutations lived a median of 67 months after diagnosis compared with 90 months for patients whose tumors lacked the mutations. “We have historically treated cervical cancers as one disease,” says the study’s lead author, Alexi Wright, M.D., M.P.H., of the Susan F. Smith Center for Women’s Cancers at Dana-Farber. “However, our findings suggest that some patients may be at higher risk of dying from their disease and might benefit from a more tailored treatment approach.” The discovery of high rates of PIK3CA mutations in the cervical tumor samples suggests that many patients could benefit from drugs known as PI3-kinase inhibitors, which target the family of proteins associated with the gene, the authors say.

BT-R3 Receptor Mediates Killing of the Malaria Vector Anopheles gambiae by Bacillus thuringiensis

Researchers at The University of Texas at Dallas (UTD), led by Dr. Lee Bulla, have demonstrated for the first time the selective cytotoxicity of the Bacillus thuringiensis subsp. israelensis Cry4B toxin is mediated by BT-R3. The Cry toxins produced by Bacillus thuringiensis exert their insecticidal activity by binding with high affinity to their cognate cadherin receptors located on the surface of epithelial cells that line the midgut of susceptible insects. In the case of Anopheles gambiae, binding of the Cry4B toxin by BT-R3, in turn, triggers an internal signaling event that turns on a cell death pathway. The novelty of the research done by the UTD scientists is that they were able to establish the direct involvement of the BT-R3 receptor, cloned from Anopheles gambiae, in mediating toxicity of the Cry4B toxin in living cells. This research is reported in an article published in the July 2013 issue of Experimental Biology and Medicine and is a culmination of proteomics, genomics, and bioinformatics strategies developed in the Bulla laboratory. Validation of BT-R3 as a functional receptor for Cry4B exemplifies the power of proteomics, genomics, and bioinformatics to identify target proteins such as the BT-R3 receptor. The process of target selection starts with data mining of archived protein sequences available in various genome and proteome databases, and results in the selection and annotation of candidate proteins based on their potential to mediate insecticidal action. It brings together genome- and proteome-based target identification and target-directed screening for validating the action of insecticidal proteins such as the Cry4B toxin—engineered or otherwise.