Predictive factors affecting cecal intubation failure in colonoscopy trainees.

BACKGROUND: Successful cecal intubation (SCI) is not only a quality indicator but also an important marker in a colonoscopy trainee's progress. We conducted this study to determine factors predicting SCI in colonoscopy trainees, and to compare these factors before and after trainees achieve technical competence. METHODS: Design of this study was a cross-sectional studies of two time series design for one year at a single center. From March 2011 to February 2012, a total 2,050 subjects who underwent colonoscopy by four first-year gastrointestinal fellows were enrolled at Christian hospital, Wonju, Republic of Korea. Four gastrointestinal fellows have filled out the colonoscopic documentation. Main outcome measurement was predictive factors affecting cecal intubation failure and learning curves. RESULTS: Colonoscopy was successfully completed to the cecum in 1,720 patients (83.9%). Success rates gradually increased as trainees performed more colonoscopies: the rate of SCI was 62% in the first 50 cases, and grew to 93% by the 250th case. Logistic regression analysis of factors affecting cecal intubation failure showed that female gender, low BMI (BMI < 18.5 kg/m²), poor bowel preparation, and past history of stomach surgery were more often associated with cecal intubation failure, particularly before the trainees achieved technical competence. CONCLUSION: Several patient characteristics were identified that may predict difficulty of cecal intubation in colonoscopy trainees. Particularly, low BMI, inadequate bowel cleansing, and previous stomach operation were predictors of cecal intubation failure before the trainees have reached technical competency. The results could be informative so that trainees enhance the success rate regarding better colonoscopy training programs.

Upregulation of CD9 in ovarian cancer is related to the induction of TNF-α gene expression and constitutive NF-κB activation.

Ovarian cancer is a gynecological cancer with a high death rate. We utilized global gene expression profiles of ovarian carcinomas obtained by complementary DNA (cDNA) microarray to identify ovarian cancer-specific proteins. CD9 was upregulated in ovarian carcinomas, and overexpression of the CD9 protein was detected in ovarian carcinomas by immunohistochemistry. CD9 was also overexpressed in several cancer cell lines, including ovarian cancer cells. In order to elucidate the biological significance of highly expressed CD9 in cancer cells, functional studies of CD9 were performed by ectopic expression, knockdown of CD9 using small interfering RNA (siRNA) and blockage of CD9 activity using the CD9-specific monoclonal antibody ALB6. Ectopic CD9 induced cell survival. In order to identify signaling pathways related to CD9, the gene expressions of CD9/SKOV3 cells were analyzed by cDNA microarray. Among the many upregulated genes, tumor necrosis factor (TNF)-α was induced in CD9/SKOV3 cells. The effect of overexpressed CD9 on the downstream signaling events of TNF-α was further investigated. In CD9/SKOV3 cells, the nuclear factor-kappaB (NF-κB)-signaling pathway was constitutively activated. Knockdown of CD9 by siRNA and blockage of CD9 activity by ALB6 in ovarian cancer cells demonstrated that constitutive activation of NF-κB is CD9 dependent and that CD9 is involved in anti-apoptosis. A CD9 functional study was performed in an ovarian cancer-xenograft mouse by injecting ALB6 into the peritoneum. ALB6 resulted in reduced tumor weight compared with that of control IgG(1). Collectively, these results demonstrate that CD9 functions as an oncogene and represents a target for the development of cancer-specific therapeutics.

An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases.

CONTEXT: The oncogenic RET/PTC tyrosine kinase causes papillary thyroid cancer (PTC). The use of inhibitors specific for RET/PTC may be useful for targeted therapy of PTC. OBJECTIVE: The objective of the study was to evaluate the efficacies of the recently developed kinase inhibitors SU11248, SU5416, and SU6668 in inhibition of RET/PTC. DESIGN: SU11248, SU5416, and SU6668 were synthesized, and their inhibitory potencies were evaluated using an in vitro RET/PTC kinase assay. The inhibitory effects of the compounds on RET/PTC were evaluated by quantifying the autophosphorylation of RET/PTC, signal transducer and activator of transcription (STAT)-3 activation, and the morphological reversal of RET/PTC-transformed cells. RESULTS: An in vitro kinase assay revealed that SU5416, SU6668, and SU11248 inhibited phosphorylation of the synthetic tyrosine kinase substrate peptide E4Y by RET/PTC3 in a dose-dependent manner with IC(50) of approximately 944 nm for SU5416, 562 nm for SU6668, and 224 nm for SU11248. Thus, SU11248 effectively inhibits the kinase activity of RET/PTC3. RET/PTC-mediated Y705 phosphorylation of STAT3 was inhibited by addition of SU11248, and the inhibitory effects of SU11248 on the tyrosine phosphorylation and transcriptional activation of STAT3 were very closely correlated with decreased autophosphorylation of RET/PTC. SU11248 caused a complete morphological reversion of transformed NIH-RET/PTC3 cells and inhibited the growth of TPC-1 cells that have an endogenous RET/PTC1. CONCLUSION: SU11248 is a highly effective tyrosine kinase inhibitor of the RET/PTC oncogenic kinase.

Regulation of protein kinase B tyrosine phosphorylation by thyroid-specific oncogenic RET/PTC kinases.

Papillary thyroid carcinoma (PTC) is a heterogenous disorder characterized by unique gene rearrangements and gene mutations that activate signaling pathways responsible for cellular transformation, survival, and antiapoptosis. Activation of protein kinase B (PKB) and its downstream signaling pathways appears to be an important event in thyroid tumorigenesis. In this study, we found that the thyroid-specific oncogenic RET/PTC tyrosine kinase is able to phosphorylate PKB in vitro and in vivo. RET/PTC-transfected cells showed tyrosine phosphorylation of endogenous and exogenous PKB, which was independent of phosphorylation of T308 and S473 regulated by the upstream kinases phosphoinositide-dependent kinase-1 and -2, respectively. The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity. The activation of PKB by RET/PTC blocked the activity of the forkhead transcription factor, FKHRL1, but a Y315F mutant of PKB failed to inhibit FKHRL1 activity. In summary, these observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis.

Novel diarylsulfonylurea derivatives as potent antimitotic agents.

A novel series of diarylsulfonylurea derivatives were synthesized and evaluated for interaction with tubulin and for cytotoxicity against human cancer cell lines. These derivatives demonstrated good inhibitory activity against tubulin polymerization, which was well correlated with promising antiproliferative activity as well as G2/M phase cell cycle arrest. Furthermore, several compounds were also efficacious against multidrug-resistant cancer cells, which are resistant to many other known microtubule inhibitors.