Medicine and Health Sciences Commons^™

Leg Ulcers In Sickle Cell Disease., Caterina P Minniti, James Eckman, Paola Sebastiani, Martin H Steinberg, Samir K. Ballas

Department of Medicine Faculty Papers

Sickle cell disease is a single amino acid molecular disorder of hemoglobin leading to its pathological polymerization, red cell rigidity that causes poor microvascular blood flow, with consequent tissue ischemia and infarction. The manifestations of this disease are protean.Among them, leg ulcers represent a particularly disabling and chronic complication, often associated with a more severe clinical course.Despite the fact that this complication has been recognized since the early times of SCD, there has been little improvement in the efficacy of its management and clinical outcome over the past 100 years. Recently, vasculopathic abnormalities involving abnormal vascular tone and activated, adhesive …

Survival Associated Pathway Identification With Group Lp Penalized Global Auc Maximization., Zhenqiu Liu, Laurence S Magder, Terry Hyslop, Li Mao

Department of Pharmacology and Experimental Therapeutics Faculty Papers

It has been demonstrated that genes in a cell do not act independently. They interact with one another to complete certain biological processes or to implement certain molecular functions. How to incorporate biological pathways or functional groups into the model and identify survival associated gene pathways is still a challenging problem. In this paper, we propose a novel iterative gradient based method for survival analysis with group Lp penalized global AUC summary maximization. Unlike LASSO, Lp (p < 1) (with its special implementation entitled adaptive LASSO) is asymptotic unbiased and has oracle properties 1. We first extend Lp for individual gene identification to group Lp penalty for pathway selection, and then develop a novel iterative gradient algorithm for penalized global AUC summary maximization (IGGAUCS). This method incorporates the genetic pathways into global AUC summary maximization and identifies survival associated pathways instead of individual genes. The tuning parameters are determined using 10-fold cross validation with training data only. The prediction performance is evaluated using test data. We apply the proposed method to survival outcome analysis with gene expression profile and identify multiple pathways simultaneously. Experimental results with simulation and gene expression data demonstrate that the proposed procedures can be used for identifying important biological pathways that are related to survival phenotype and for building a parsimonious model for predicting the survival times.

Human Papillomavirus And Survival Of Patients With Oropharyngeal Cancer., K Kian Ang, Jonathan Harris, Richard Wheeler, Randal Weber, David I Rosenthal, Phuc Felix Nguyen-Tân, William H Westra, Christine H Chung, Richard C Jordan, Charles Lu, Harold Kim, Rita S. Axelrod, Md, C Craig Silverman, Kevin P Redmond, Maura L Gillison

Jefferson Hospital Staff Papers and Presentations

BACKGROUND: Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown.

METHODS: We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive …

The Risks And Benefits Of Long-Term Use Of Hydroxyurea In Sickle Cell Anemia: A 17.5 Year Follow-Up., M. H. Steinberg, W. F. Mccarthy, O. Castro, S. K. Ballas, F. D. Armstrong, W. Smith, K. Ataga, P. Swerdlow, A. Kutlar, L. Decastro, M. A. Waclawiw, E. Orringer, S. Jones, D. Strayhorn, W. Rosse, G. Phillips, D. Pearce, A. Johnson-Telfair, L. Daitch, P. Milner, A. Tracy, S. Valdez, G. E. Allen, J. Moshang, B. Scott, C. Bigelow, A. Anderson, V. Sabahi, T. Harrington, W. Labrousse, C. Pegelow, D. Temple, E. Case, R. Harrell, S. Childerie, S. Embury, B. Schmidt, D. Davies, Y. Saunthararajah, M. Koshy, N. Talischy-Zahed, L. Dorn, G. Pendarvis, M. Mcgee, M. Telfer, A. Davis, O. C. Onyekwere, C. Nwokolo, H. Finke, E. Perlin, J. Siteman, M. Bryan, T. Saunders, Y. Barber, P. Gascon, P. Di Paolo, S. Gargiulo, J. Eckman, E. Carter-Randall, J. H. Bailey, A. Platt, L. Waller, G. Ramirez, V. Knors, S. Hernandez, E. M. Rodriguez, E. Wilkes, E. Vichinsky, W. Hagar, C. Hoehner, E. Hackney-Stevens, S. Claster, A. Earles, K. Kleman, K. Mclaughlin, L. White, B. Maddox, L. Usry, A. Brenner, K. Williams, R. O'Brien, K. Genther, S. Shurin, B. Berman, K. Chiarucci, L. Keverline, N. Olivieri, J. Chow, M. Hui, D. Shaw, N. Lewis, M. Okam, E. Mandell, A. Palmer, K. Bridges, B. Tynan, C. Winograd, R. Bellevue, H. Dosik, M. Sheikhai, P. Ryans, H. Souffrant, B. Adler, A. Johnson-Telfair, L. Eskridge, J. Prchal, J. Braddock, T. Mcardle, T. Carlos, A. Roundtree-Schmotzer, D. Gardner

Department of Medicine Faculty Papers

A randomized, controlled clinical trial established the efficacy and safety of short-term use of hydroxyurea in adult sickle cell anemia. To examine the risks and benefits of long-term hydroxyurea usage, patients in this trial were followed for 17.5 years during which they could start or stop hydroxyurea. The purpose of this follow-up was to search for adverse outcomes and estimate mortality. For each outcome and for mortality, exact 95% confidence intervals were calculated, or tests were conducted at alpha = 0.05 level (P-value <0.05 for statistical significance). Although the death rate in the overall study cohort was high (43.1%; 4.4 per 100 person-years), mortality was reduced in individuals with long-term exposure to hydroxyurea. Survival curves demonstrated a significant reduction in deaths with long-term exposure. Twenty-four percent of deaths were due to pulmonary complications; 87.1% occurred in patients who never took hydroxyurea or took it for <5 years. Stroke, organ dysfunction, infection, and malignancy were similar in all groups. Our results, while no longer the product of a randomized study because of the ethical concerns of withholding an efficacious treatment, suggest that long-term use of hydroxyurea is safe and might decrease mortality.

Transgenic Rat Model Of Neurodegeneration Caused By Mutation In The Tdp Gene., Hongxia Zhou, Cao Huang, Han Chen, Dian Wang, Carlisle P Landel, Pedro Yuxing Xia, Robert Bowser, Yong-Jian Liu, Xu Gang Xia

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

TDP-43 proteinopathies have been observed in a wide range of neurodegenerative diseases. Mutations in the gene encoding TDP-43 (i.e., TDP) have been identified in amyotrophic lateral sclerosis (ALS) and in frontotemporal lobe degeneration associated with motor neuron disease. To study the consequences of TDP mutation in an intact system, we created transgenic rats expressing normal human TDP or a mutant form of human TDP with a M337V substitution. Overexpression of mutant, but not normal, TDP caused widespread neurodegeneration that predominantly affected the motor system. TDP mutation reproduced ALS phenotypes in transgenic rats, as seen by progressive degeneration of motor neurons …

Expression Of The Intestinal Biomarkers Guanylyl Cyclase C And Cdx2 In Poorly Differentiated Colorectal Carcinomas., Brody Winn, Rosemarie Tavares, Andres Matoso, Lelia Noble, Jacqueline Fanion, Scott A Waldman, Murray B Resnick

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Guanylyl cyclase C, a receptor for bacterial diarrheagenic enterotoxins, is expressed selectively by intestinal epithelium and is an endogenous downstream target of CDX2. The expression of Guanylyl cyclase C is preserved throughout the adenoma/carcinoma sequence in the colorectum. Detection of Guanylyl cyclase C expression by reverse transcriptase-polymerase chain reaction is currently being validated as a technique to identify occult lymph node metastases in patients with colorectal cancer and for circulating cells in the blood for postoperative surveillance. Although Guanylyl cyclase C is widely expressed by well-differentiated colorectal cancer, its expression in poorly differentiated colorectal cancer has not been evaluated. A …

Imaging Spontaneous Mmtvneu Transgenic Murine Mammary Tumors: Targeting Metabolic Activity Versus Genetic Products., Mathew L Thakur, Devakumar Devadhas, Kaijun Zhang, Richard G Pestell, Chenguang Wang, Peter Mccue, Eric Wickstrom

Department of Radiology Faculty Papers

INTRODUCTION: Despite the great strides made in imaging breast cancer (BC) in humans, the current imaging modalities miss up to 30% of BC, do not distinguish malignant lesions from benign ones, and require histologic examinations for which invasive biopsy must be performed. Annually in the United States, approximately 5.6 million biopsies find benign lesions. More than 50% of human BCs overexpress cyclin D1, and all BCs exhibit VPAC1 oncogene products. Together, these gene products may provide an excellent biomarker for the early and accurate detection of BC. We have evaluated 4 biologically active peptide analogs that have high affinity for …