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The Replica Set Method: A High-throughput Approach to Quantitatively Measure <em>Caenorhabditis elegans</em> Lifespan

The Replica Set method is an approach to quantitatively measure lifespan or survival of Caenorhabditis elegans nematodes in a high-throughput manner, thus ...

University of Rochester Medical Center

Bristol-Myers Squibb

Understanding the molecular underpinnings of cancer is of critical importance to the development of targeted intervention strategies. Identification of such targets, however, is notoriously difficult and unpredictable. Malignant cell transformation requires the cooperation of a few oncogenic mutations that cause substantial reorganization of many cell features and induce complex changes in gene expression patterns. Genes critical to this multifaceted cellular phenotype have therefore only been identified after signalling pathway analysis or on an ad hoc basis. Our observations that cell transformation by cooperating oncogenic lesions depends on synergistic modulation of downstream signalling circuitry suggest that malignant transformation is a highly cooperative process, involving synergy at multiple levels of regulation, including gene expression. Here we show that a large proportion of genes controlled synergistically by loss-of-function p53 and Ras activation are critical to the malignant state of murine and human colon cells. Notably, 14 out of 24 'cooperation response genes' were found to contribute to tumour formation in gene perturbation experiments. In contrast, only 1 in 14 perturbations of the genes responding in a non-synergistic manner had a similar effect. Synergistic control of gene expression by oncogenic mutations thus emerges as an underlying key to malignancy, and provides an attractive rationale for identifying intervention targets in gene networks downstream of oncogenic gain- and loss-of-function mutations.

Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype.

Although duty hours regulations (DHR) were introduced as a measure to improve patient safety and graduate medical education, new evidence suggests that the opposite might be happening. This study was designed to assess surgery resident perceptions of the impact that DHR have had on their education, the number of hours they believed would be ideal for their training, and to evaluate the effect of seniority on these opinions.

Should all duty hours be the same? Results of a national survey of surgical trainees.

Pancreatic fistula continues to be a source of significant morbidity following distal pancreatic resections. The technique of pancreatic division varies widely among surgeons, and there is no evidence that identifies a single method as superior. In our practice, the technique of distal pancreatic resection has evolved from cut-and-sew to stapled technique with green and recently white cartridge. The aim of our study was to evaluate the rate of clinically significant fistulas [International Study Group on Pancreatic Fistula (ISGPF) grade B or C] following distal pancreatectomy and to identify variables associated with a low rate of fistula development.

The influence of staple size on fistula formation following distal pancreatectomy.

Malignant cell transformation commonly results in the deregulation of thousands of cellular genes, an observation that suggests a complex biological process and an inherently challenging scenario for the development of effective cancer interventions. To better define the genes/pathways essential to regulating the malignant phenotype, we recently described a novel strategy based on the cooperative nature of carcinogenesis that focuses on genes synergistically deregulated in response to cooperating oncogenic mutations. These so-called 'cooperation response genes' (CRGs) are highly enriched for genes critical for the cancer phenotype, thereby suggesting their causal role in the malignant state. Here, we show that CRGs have an essential role in drug-mediated anticancer activity and that anticancer agents can be identified through their ability to antagonize the CRG expression profile. These findings provide proof-of-concept for the use of the CRG signature as a novel means of drug discovery with relevance to underlying anticancer drug mechanisms.

Gene signature critical to cancer phenotype as a paradigm for anticancer drug discovery.

Geography is known to affect cost of care in surgical procedures. Understanding the relationship between geography and hospital costs is pertinent in the effort to reduce healthcare costs. We studied the geographic variation in cost for transsphenoidal pituitary surgery in hospitals across New York State.

Peter Salzman

Department of Biostatistics and Computational Biology

University of Rochester Medical Center

The Replica Set Method: A High-throughput Approach to Quantitatively Measure Caenorhabditis elegans Lifespan