Glucagon-like peptide-2: divergent signaling pathways.

Background And Aims: Glucagon-like peptide 2 (GLP-2) is an endogenous hormone with potent and specific intestinotrophic activity in vivo and in vitro. The aim of this study was to define the initial signal transduction mechanisms mediating the proliferative actions of GLP-2 on intestinal epithelial cells.

Methods: The proliferative actions of GLP-2 on the human Caco-2 cell line were assessed.

RETRACTED: Retrovirally mediated RNA interference targeting the M2 subunit of ribonucleotide reductase: A novel therapeutic strategy in pancreatic cancer.

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Ligation of EphA2 by Ephrin A1-Fc inhibits pancreatic adenocarcinoma cellular invasiveness.

The Eph tyrosine kinases interact with ligands of the Ephrin family and have diverse cellular functions. EphA2 has been recognized to be an oncoprotein of importance in a range of cancers. Here, we examine the effect of EphA2 overexpression and ligation by chimeric Ephrin A1-Fc on the invasive phenotype of pancreatic adenocarcinoma cells.

Overexpression of CEACAM6 promotes insulin-like growth factor I-induced pancreatic adenocarcinoma cellular invasiveness.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a glycosylphosphatidylinositol-linked immunoglobulin superfamily member that is overexpressed in a variety of human cancers. We have recently reported that suppression of CEACAM6 expression impairs pancreatic adenocarcinoma progression in vivo. In order to characterize the mechanisms through which CEACAM6 influences the malignant phenotype, CEACAM6-overexpressing Capan2 pancreatic adenocarcinoma cells were established by stable transfection.

siRNA directed against c-Src enhances pancreatic adenocarcinoma cell gemcitabine chemosensitivity.

Background: The c-Src tyrosine kinase is a determinant of malignant cellular behavior in a variety of human cancers. We sought to determine the effect of suppressing c-Src expression on pancreatic adenocarcinoma chemosensitivity to gemcitabine.

Study Design: PANC1, MIAPaCa2, BxPC3, and Capan2 pancreatic adenocarcinoma cell lines were studied.

A novel role for carcinoembryonic antigen-related cell adhesion molecule 6 as a determinant of gemcitabine chemoresistance in pancreatic adenocarcinoma cells.

Most patients with pancreatic adenocarcinoma present with surgically incurable disease. Gemcitabine, the principal agent used to treat such patients, has little impact on outcome. Overexpression of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 6, a feature of this malignancy, is associated with resistance to anoikis and increased metastasis.

Fibronectin-induced COX-2 mediates MMP-2 expression and invasiveness of rhabdomyosarcoma.

Although accumulating evidence suggests the importance of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) in the pathogenesis of many cancers, the mechanism by which this enzyme and its metabolite promote cancer progression is unknown. In this study, we investigated the role of COX-2 in fibronectin-induced up-regulation of rhabdomyosarcoma matrix metalloproteinase (MMP)-2 activity and cellular invasiveness. We tested three human rhabdomyosarcoma cell lines: RMS559, RD, and SJRH30.

Lymphangiogenesis in tissue-engineered small intestine.

Background: Lymphangiogenesis, the formation of lymphatic vessels, has not been reported in engineered tissue. The purpose of this study was to characterize lymphangiogenesis in tissue-engineered small intestine.

Methods: Biodegradable polymer scaffolds seeded with intestinal organoid units were implanted into syngenic recipient rats.

CEACAM6 as a novel target for indirect type 1 immunotoxin-based therapy in pancreatic adenocarcinoma.

Immunotoxins are a potentially powerful approach for targeted anticancer therapy. We evaluated a novel immunotherapeutic strategy targeting the immunoglobulin superfamily member carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6). Using pancreatic adenocarcinoma as a model, we show that crosslinking CEACAM6 induces its cytoplasmic accumulation and that this effect can be utilized to increase the efficacy of antibody-mediated delivery of the ribosomal inhibitory protein saporin.

Inhibition of SRC tyrosine kinase impairs inherent and acquired gemcitabine resistance in human pancreatic adenocarcinoma cells.

Purpose: We tested the hypotheses that Src tyrosine kinase overactivity represents a chemoresistance mechanism and that Src inhibition may enhance gemcitabine cytotoxicity in pancreatic adenocarcinoma cells.

Experimental Design: Pancreatic adenocarcinoma cells PANC1, MiaPaCa2, Capan2, BxPC3, and PANC1(GemRes), a stably gemcitabine-resistant subline of PANC1, were exposed to combinations of gemcitabine and Src tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2). Src expression, phosphorylation (Tyr-416), and activity were analyzed by immunoblotting and in vitro kinase assay.

CEACAM6 cross-linking induces caveolin-1-dependent, Src-mediated focal adhesion kinase phosphorylation in BxPC3 pancreatic adenocarcinoma cells.

Despite lacking transmembrane or intracellular domains, glycosylphosphatidylinositol-anchored proteins can modulate intracellular signaling events, in many cases through aggregation within membrane "lipid raft" microdomains. CEACAM6 is a glycosylphosphatidylinositol-linked cell surface protein of importance in the anchorage-independent survival and metastasis of pancreatic adenocarcinoma cells. We examined the effects of antibody-mediated cross-linking of CEACAM6 on intracellular signaling events and anchorage-independent survival of the CEACAM6-overexpressing pancreatic ductal adenocarcinoma cell line, BxPC3.

c-Src-dependent cross-talk between CEACAM6 and alphavbeta3 integrin enhances pancreatic adenocarcinoma cell adhesion to extracellular matrix components.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is an immunoglobulin superfamily member with a diversity of extracellular ligands that is implicated in the initiation and progression of a variety of malignancies. We sought to characterize the effects of CEACAM6 crosslinking on pancreatic adenocarcinoma cellular interaction with the extracellular matrix (ECM) components fibronectin and vitronectin. Antibody-mediated CEACAM6 crosslinking was performed and the ability of BxPC3 cells, which inherently overexpress CEACAM6, to adhere to fibronectin and vitronectin was quantified.

Treatment outcomes associated with surgery for gallbladder cancer: a 20-year experience.

The aim of this study was to evaluate contemporary outcomes associated with the management of gallbladder cancer. The medical records of 48 consecutive patients with gallbladder cancer treated at our institution from January 1981 through November 2001 were reviewed. Survival was analyzed using the Kaplan-Meier method (mean follow-up period 24 months) and the log-rank test.

Ribosomal protein P2: a potential molecular target for antisense therapy of human malignancies.

Background: Ribosomal protein P2 is an important component of protein translation machinery. We hypothesized that antisense-mediated depletion may disrupt the proteome of cancer cells. This study includes experiments to ascertain whether this could be a useful approach for cancer therapies.

Appendiceal adenocarcinoma: long-term outcomes after surgical therapy.

Purpose: Appendiceal adenocarcinomas are very rare. We analyzed contemporary outcomes associated with surgical therapies for these malignancies.

Methods: Retrospective outcomes for patients treated at a tertiary academic medical center from 1981 through 2001 were analyzed.

EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma.

The EphA2 receptor tyrosine kinase is overexpressed in a variety of human cancers. We sought to characterize the role of EphA2 in pancreatic adenocarcinoma and, using RNA interference (RNAi) mediated by small interfering RNA (siRNA), we determined the effects of suppressing EphA2 expression in vitro and in vivo. EphA2 expression in PANC1, MIAPaCa2, BxPC3 and Capan2 cells was assessed by Northern and Western blot.

CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells.

Anoikis is the apoptotic response induced in normal cells by inadequate or inappropriate adhesion to substrate. It is postulated that resistance to anoikis facilitates tumorigenesis and metastasis. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is an immunoglobulin superfamily member overexpressed in a number of human cancers and implicated in anoikis resistance.

Inhibition of pancreatic adenocarcinoma cellular invasiveness by blebbistatin: a novel myosin II inhibitor.

Blebbistatin is a novel 1-phenyl-2-pyrrolidinone derivative capable of inhibiting non-muscle myosin II activity with a high degree of specificity. We examined the effects of blebbistatin on pancreatic adenocarcinoma cellular migration, invasion, adhesion, and spreading. Blebbistatin dose-dependently inhibited cellular migration and invasiveness, quantified by modified Boyden chamber assay.

The efficacy of tyrosine kinase inhibitors on human pancreatic cancer cell lines.

We attempted to determine potential therapeutic targets in pancreatic cancer by performing microarray analysis and targeted chemotherapy on three human pancreatic cancer cell lines. We used a microarray to screen 847 genes involved in cytokine signaling, signal transduction, and transcription. Tyrosine kinases represented a common target driving proliferation among the three cell types.

Angiogenesis in tissue-engineered small intestine.

Tissue-engineered intestine offers promise as a potential novel therapy for short bowel syndrome. In this study we characterized the microvasculature and angiogenic growth factor profile of the engineered intestine. Twenty-three tissue-engineered small intestinal grafts were harvested from Lewis rat recipients 1 to 8 weeks after implantation.

RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine.

Ribonucleotide reductase is emerging as an important determinant of gemcitabine chemoresistance in human cancers. Activity of this enzyme, which catalyses conversion of ribonucleotide 5'-diphosphates to their 2'-deoxynucleotides, is modulated by levels of its M2 subunit (RRM2). Here we show that RRM2 overexpression is associated with gemcitabine chemoresistance in pancreatic adenocarcinoma cells, and that suppression of RRM2 expression using RNA interference mediated by small interfering RNA (siRNA) enhances gemcitabine-induced cytotoxicity in vitro.

RNA interference targeting focal adhesion kinase enhances pancreatic adenocarcinoma gemcitabine chemosensitivity.

Focal adhesion kinase (FAK) is an important regulator of cellular signaling, migration, apoptosis, and cell cycle progression. We tested the hypothesis that FAK is a determinant of gemcitabine chemoresistance in pancreatic adenocarcinoma cells and examined the effect of inhibiting FAK expression on gemcitabine-induced cytotoxicity in vitro and in vivo. FAK expression was quantified by Western and Northern blots.

Surgical treatment of small bowel cancer: a 20-year single institution experience.

Small bowel malignancies are rare. The aims of this study were to evaluate the outcomes associated with surgical therapy for small bowel cancers and to define prognostic factors. The medical records of 96 consecutive patients with primary small bowel cancer (excluding lymphoma) treated at our institution over a 20 year period were reviewed.

Work hours reform: perceptions and desires of contemporary surgical residents.

Background: New Accreditation Council for Graduate Medical Education (ACGME) requirements on resident duty hours are scheduled to undergo nationwide implementation in July 2003. General surgery residents, because of their long duty hours, are likely to be among those most affected by changes imposed to comply with the ACGME requirements. There are few contemporary data on their attitudes toward work hours reform.