OBJECTIVES-Changes in mucosal serotonin (5-HT) signaling have been detected in a number of functional and inflammatory disorders of the gastrointestinal tract. This study was undertaken to determine whether chronic constipation (CC) is associated with disordered 5-HT signaling and to evaluate whether constipation caused by opiate use causes such changes.METHODS-Human rectal biopsy samples were obtained from healthy volunteers, individuals with idiopathic CC, and individuals taking opiate medication with or without constipation. EC cells were identified by 5-HT immunohistochemistry. 5-HT content and 5-HT release levels were determined Correspondence: Gary M. Mawe, Ph.D., D403A Given Building, Department of Anatomy and Neurobiology, University of Vermont, Burlington, VT, USA 05405, (802) 656-8257 (phone), (802) 656-8704 (fax), gary.mawe@uvm.edu. * MMC and MDC contributed equally to this work, with MMC concentrating primarily on the chronic constipation arm of the study and MDC working primarily on the opiate constipation experiments. Conflict of interest items 1. Guarantor of the manuscriptGary M. Mawe, PhD 2. Roles of each author Meagan M Costedio: patient screening, obtaining consent, tissue acquisition, tissue processing, data analysis, and manuscript preparation and editing Matthew D Coates: patient screening, obtaining consent, tissue acquisition, tissue processing, data analysis, and manuscript preparation and editing Elice M Brooks: tissue acquisition, data acquisition, and data analysis Lisa M Glass: data acquisition, and data analysis. Eric K Ganguly: aided in conception of the project, acquiring IRB approval, obtaining informed consent, and tissue acquisition. Hagen Blaszyk: evaluation of sections and blind scoring of inflammation levels in the chronic constipation component of the study Allison L. Ciolino: evaluation of sections and blind scoring of inflammation levels in the opiate constipation component of the study Michael J Wood: involved in obtaining informed consent, and tissue acquisition. Doris Strader: involved in obtaining informed consent, and tissue acquisition. Neil H Hyman: involved in study conceptualization, planning, and identifying potential candidates for the chronic constipation component of the study. Peter L Moses: involved in study conceptualization, planning, obtaining informed consent, and tissue acquisition, data analysis, and manuscript preparation and editing Gary M Mawe: involved in study conceptualization, planning, data analysis, and manuscript preparation and editing. All authors reviewed and approved the manuscript prior to submission. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript by enzyme immunoassay, and mRNA levels for the synthetic enzyme, tryptophan hydroxylase 1 (TpH1) and the serotonin transporter (SERT) were assessed by quantitative real-time RT-PCR.RESULTS-CC was associated with increases in TpH1 transcript, 5-HT content, and 5-HT release under basal and stimulated conditions, whereas EC cell numbers and SERT transcript leve...

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The protooncogene HER2/neu encodes a 185-kDa transmembrane protein with extensive homology to the epidermal growth factor receptor. It is overexpressed in several human cancers of epithelial origin, such as pancreatic cancer. Previously, we demonstrated that cytotoxic T lymphocytes (CTL) derived from breast, ovarian, and non-small cell lung cancer recognized a peptide derived from HER2/neu. To evaluate whether this HLA-A2-binding peptide is a tumor-associated antigen (TAA) in pancreatic cancer, the ability of HER2/neu-reactive CTL to lyse human pancreatic carcinoma cells was tested. CTL were generated from tumor-associated T lymphocytes from HLA-A2+ HER2/neu+ breast and ovarian cancer patients. All CTL recognized autologous and allogeneic HER2/ neu+ tumor cells in an HLA-A2-restricted fashion. Furthermore, all CTL recognized p654-662 (GP2) derived from HER2/neu. These CTL also recognized HER2/neu+ pancreatic cancer cells in an HLA-A2-restricted fashion. HER2/neu+ HLA-A2- pancreatic cancer were not or only poorly lysed. Repeated stimulation of HLA-A2+ PBL from pancreatic cancer patients using the HER2/neu-derived peptide resulted in specific recognition of this peptide and, more importantly, HER2/neu+ pancreatic tumors in an HLA-A2-restricted fashion. Autologous HLA-A2+ fibroblasts or HLA-A2+ malignant melanoma cells were not recognized. HLA-A2- peptide-stimulated T lymphocytes showed no significant cytotoxicity. These results demonstrate that this HER2/neu-derived peptide is a shared TAA among several adenocarcinomas including pancreatic carcinoma, suggesting a common mechanism of recognition of these human tumors by T lymphocytes. The identification of the HER2/neu-derived peptide GP2 as a TAA in pancreatic cancer provides an opportunity for the design of novel immunotherapy and vaccine strategies.

Patients undergoing screening colonoscopy with conscious sedation are less likely to experience peri-procedural discomfort than those undergoing screening flexible sigmoidoscopy. Although most patients are willing to undergo subsequent screening examinations, patients undergoing screening colonoscopy are significantly more willing to undergo a subsequent examination than those undergoing screening flexible sigmoidoscopy.