ABSTRACT
BACKGROUND: Nonvariceal upper gastrointestinal bleeding (NVUGIB) is associated with significant mortality. OBJECTIVE: To examine several factors that may impact the mortality and 30-day rebleed rates of patients presenting with NVUGIB. METHODS: A retrospective study of the charts of patients admitted to hospital in either the Saskatoon Health Region (SHR) or Regina Qu'Appelle Health Region (RQHR) (Saskatchewan) in 2008 and 2009 was performed. Mortality and 30-day rebleed end points were stratified according to age, sex, day of admission, patient status, health region, specialty of the endoscopist and time to endoscopy. Logistic regression modelling was performed, controlling for the Charlson comorbidity index, age and sex as covariates. RESULTS: The overall mortality rate observed was 12.2% (n=44), while the overall 30-day rebleed rate was 20.3% (n=80). Inpatient status at the time of the rebleeding event was associated with a significantly increased risk of both mortality and rebleed, while having endoscopy performed in the RQHR versus SHR was associated with a significantly decreased risk of rebleed. A larger proportion of endoscopies were performed both within 24 h and by a gastroenterologist in the RQHR. CONCLUSION: Saskatchewan has relatively high rates of mortality and 30-day rebleeding among patients with NVUGIB compared with published rates. The improved outcomes observed in the RQHR, when compared with the SHR, may be related to the employ of a formal call-back endoscopy team for the treatment of NVUGIB.
Subject(s)
Gastrointestinal Hemorrhage/epidemiology , Upper Gastrointestinal Tract , Endoscopy, Gastrointestinal , Female , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/mortality , Gastrointestinal Hemorrhage/pathology , Gastrointestinal Hemorrhage/therapy , Hemostasis, Endoscopic , Humans , Male , Middle Aged , Recurrence , Risk Factors , Saskatchewan/epidemiology , Severity of Illness IndexABSTRACT
A number of viral and eukaryotic proteins which undergo a lipophilic modification by the enzyme N-myristoyltransferase (NMT: NMT1 and NMT2) are required for signal transduction and regulatory functions. To investigate whether NMT2 contributes to the pathogenesis of colorectal carcinoma, we observed a higher expression of NMT2 in most of the cases of cancerous tissues compared to normal tissues (84.6% of cases; P < 0.05) by Western blot analysis. Furthermore, protein-protein interaction of NMTs revealed that m-calpain interacts with NMT1 while caspase-3 interacts with NMT2. Our findings provide the first evidence of higher expression of NMT2 in human colorectal adenocarcinomas and the interaction of both forms of NMT with various signaling molecules.
Subject(s)
Acyltransferases/metabolism , Calpain/metabolism , Caspases/metabolism , Colonic Neoplasms/enzymology , Gene Expression Regulation, Neoplastic , Colonic Neoplasms/metabolism , Humans , Peptide Hydrolases/metabolism , Protein Binding , Proto-Oncogene Proteins c-bcl-2/metabolism , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolismABSTRACT
Histone deacetylase inhibitors (HDIs) induce cell cycle arrest, differentiation and/or apoptosis in numerous cancer cell types and have shown promise in clinical trials. These agents are particularly novel, given their ability to selectively influence gene expression. Previously, we demonstrated that the HDIs butyrate and trichostatin A (TSA) directly repress c-Src proto-oncogene expression in many cancer cell lines. Activation and/or overexpression of c-Src have been frequently observed in numerous malignancies, especially of the colon. Therefore, our observation was particularly interesting since butyrate is a naturally abundant component of the large intestine and has been suggested to be a cancer-preventive agent. However, c-Src is not the only Src family kinase (SFK) member to be implicated in the development of human cancers, including those of the colon. Therefore, the relative expression levels of known SFKs were examined in a panel of human colon cancer cell lines. We found a surprisingly diverse expression pattern but noted that most cell lines expressed relatively high levels of at least 2 SFKs. When the effects of butyrate and TSA were examined in representative cell lines, the expression of all SFKs was repressed in a dose- and time-dependent manner. Further, detailed examination of Lck, Yes and Lyn demonstrated that this repression had a direct effect on transcription and was independent of new protein synthesis. These results mirror our earlier data obtained with c-Src and suggest that SFKs are a major target of HDIs and likely account in part for the anticancer effects of these promising new drugs.
Subject(s)
Butyrates/pharmacology , Colonic Neoplasms/metabolism , Histone Deacetylase Inhibitors , Hydroxamic Acids/pharmacology , Transcription, Genetic/drug effects , src-Family Kinases/metabolism , Chloramphenicol O-Acetyltransferase/antagonists & inhibitors , Chloramphenicol O-Acetyltransferase/metabolism , Colonic Neoplasms/genetics , Dose-Response Relationship, Drug , Down-Regulation , Humans , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism , Oncogene Protein pp60(v-src)/antagonists & inhibitors , Oncogene Protein pp60(v-src)/genetics , Oncogene Protein pp60(v-src)/metabolism , Proto-Oncogene Mas , Proto-Oncogene Proteins c-yes/antagonists & inhibitors , Proto-Oncogene Proteins c-yes/genetics , Proto-Oncogene Proteins c-yes/metabolism , Time Factors , Tumor Cells, Cultured , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/geneticsABSTRACT
Luman is a human basic leucine zipper transcription factor that, like the herpes simplex virus transcription factor VP16, requires the host cell factor, HCF, for activity. Although both HCF and Luman have been implicated in cell growth, their biological roles have not been clearly defined. Luman conforms to a type II membrane-associated glycoprotein with its carboxyl terminus embedded in cellular membranes and its amino terminus, which contains all its identified functional domains, in the cytoplasm. Here we show that Luman is processed by regulated intramembrane proteolysis (RIP). The site 1 protease (S1P), a Golgi apparatus-resident enzyme responsible for catalyzing the first step in the RIP pathway of the sterol regulatory element binding proteins (SREBPs) and ATF6, may also be involved in the processing of Luman. Thus, processing of Luman was highly stimulated by brefeldin A, a compound that causes the reflux of Golgi apparatus enzymes to the endoplasmic reticulum (ER). In addition, coexpression of Luman with S1P containing a KDEL ER retrieval signal resulted in virtually quantitative cleavage of Luman in the absence of any treatment. Finally, Luman contains a sequence, RQLR, immediately downstream from the transmembrane domain which bears similarity to the consensus S1P cleavage site identified by others. Substitution of arginine residues within this motif abolished S1P cleavage, providing robust evidence that S1P is involved in Luman processing. We observed that following S1P cleavage, the majority of the cleaved Luman was retained in cytoplasmic membranes, indicating that an additional step or enzymes yet to be identified are involved in complete cleavage and release to yield the product which ultimately enters the nuclei of cells.