Bashar M. Attar

Resveratrol regulates cellular PKC α and δ to inhibit growth and induce apoptosis in gastric cancer cells

SummaryResveratrol, a dietary phytoalexin, has emerged as a promising chemopreventive agent due to its antiproliferative and pro-apoptotic action toward cancer cells and its ability to inhibit tumor growth in animals. Gastric adenocarcinoma cells respond to resveratrol treatment with suppression of DNA synthesis, activation of nitric oxide synthase, induction of apoptosis and inhibition of total PKC and PKC α activity. Here we demonstrate that treatment of gastric adenocarcinoma SNU-1 cells with resveratrol results in time and concentration dependent accumulation of tumor suppressors p21(cip1/WAF -1) and p53 and is preceded by loss of membrane-associated PKC δ protein and a concomitant increase in cytosolic PKC α. Arrest of the cell cycle at transition of S to G2/M phases correlates with the profile of 3H-thymidine incorporation and accumulation of p21(cip1/WAF -1) and was temporally dependent on increase of p53. SNU-1 cells respond to resveratrol treatment with up-regulation of both Fas and Fas-L proteins, whereas in KATO-III cells, with deleted p53, only Fas-L is increased after resveratrol treatment. Although Fas and Fas-L proteins in SNU-1 cells and Fas-L in KATO-III cells were elevated within 24 h of cell treatment with low concentrations of resveratrol, significant apoptotic response at these concentrations was observed only after 48 h. Altogether, our findings indicate that resveratrol engages PKC α and δ signals in gastric adenocarcinoma SNU-1 cells prior to up-regulation of antiproliferative and pro-apoptotic signals. The specific cell death signals engaged by resveratrol appear to be cell type dependent and suggest that resveratrol has chemopreventive potential even after mutational changes have occurred.

Resveratrol-induced inactivation of human gastric adenocarcinoma cells through a protein kinase C-mediated mechanism

Resveratrol, a polyphenolic phytochemical present in berries, grapes, and wine, has emerged as a promising chemopreventive candidate. Because there is scant information regarding natural agents that prevent, suppress, or reverse gastric carcinogenesis, the aim of the present study was to determine the chemopreventive potential of resveratrol against gastric cancer by investigating cellular and molecular events associated with resveratrol treatment of human gastric adenocarcinoma cells. We determined the action of resveratrol on cellular function and cellular integrity by measuring DNA synthesis, cellular proliferation, cell cycle distribution, cytolysis, apoptosis, and phosphotransferase activities of two key signaling enzymes, protein kinase C (PKC) and mitogen-activated protein kinases (ERK1/ERK2), in human gastric adenocarcinoma KATO-III and RF-1 cells. Resveratrol inhibited [3H]thymidine incorporation into cellular DNA of normally proliferating KATO-III cells and of RF-1 cells whose proliferation was stimulated with carcinogenic nitrosamines. Treatment with resveratrol arrested KATO-III cells in the G(0)/G(1) phase of the cell cycle and eventually induced apoptotic cell death, but had a minimal effect on cell lysis. Resveratrol treatment had no effect on ERK1/ERK2 activity but significantly inhibited PKC activity of KATO-III cells and of human recombinant PKCalpha. Results indicate that resveratrol has potential as a chemopreventive agent against gastric cancer because it exerts an overall deactivating effect on human gastric adenocarcinoma cells. Resveratrol-induced inhibition of PKC activity and of PKCalpha, without any change in ERK1/ERK2 activity, suggests that resveratrol utilizes a PKC-mediated mechanism to deactivate gastric adenocarcinoma cells.

Should bowel preparation, antifoaming agents, or prokinetics be used before video capsule endoscopy? A systematic review and meta-analysis.

Objectives The ideal bowel preparation regime before small bowel video capsule endoscopy (VCE) is not known. We carried out a systematic review and meta-analysis to study the effect of purgatives, antifoaming agents, and prokinetics on the outcomes associated with VCE. Materials and methods We performed literature searches in MEDLINE and Cochrane Library and included randomized-controlled trials studying the effect of purgatives, antifoaming agents, and prokinetics in patients undergoing VCE. Our outcomes of interest were visualization quality, diagnostic yield, and completion rate. Meta-analyses were carried out using the RevMan software and heterogeneity was assessed using the I2 statistic. Results Fifteen studies fulfilled the inclusion criteria. As compared with no bowel preparation, bowel preparation with polyethylene glycol (PEG) led to adequate visualization in a significantly higher number of patients undergoing VCE [odds ratio (OR) 3.13; 95% confidence interval (CI) 1.70–5.75]. Both PEG and sodium phosphate significantly improved the diagnostic yield (OR 1.68; 95% CI 1.16–2.42 and OR 1.77; 95% CI 1.18–2.64, respectively) but did not affect the completion rate. All studies with simethicone showed significantly improved visualization quality with its use as compared with overnight fasting or purgatives alone. Prokinetics did not significantly improve the completion rate of VCE. Conclusion On the basis of the data available, a combination of PEG and simethicone appears to be the best approach for small bowel preparation before VCE. However, large multicenter randomized-controlled trials are needed to validate this recommendation and to evaluate the ideal dose of PEG and timing of bowel preparation before VCE. Prokinetics administered before VCE do not improve the completion rate and should not be used.

Small cell carcinoma of the esophagus

Small cell carcinoma has been described in the lung, stomach, pancreas, small intestine, larynx, hypopharynx, thymus, kidney, prostate, breast, cervix, skin, and esophagus. Our three cases and review of the literature confirm that the clinical presentation and eventual evolution of small cell carcinomas of the esophagus appear to be basically similar to those of the far more frequently occurring squamous and glandular carcinomas. However, certain differences in age and sex distribution of cases should be noted. Although squamous cell carcinomas occur three to four times more commonly in males, the male-to-female ratio in SCC in 1.6. Squamous cell carcinomas of the esophagus reach a peak in the fifth and sixth decades of life; SCC cases occur a decade later. All of our patients had history of heavy smoking more than 50 pack-years, a factor that has also been implicated in predisposition to squamous cell carcinoma of the esophagus. History of smoking to this extent was also mentioned in three other patients. There are also some differences in the location of the tumor. SCC rarely occurs in the upper third of the esophagus. The most common location of this tumor is the lower third where APUD cells are most abundant. On the other hand, a majority of squamous cell carcinomas of the esophagus are localized to the middle third, the upper and lower third being involved in equal proportions of the cases. Despite the above reported differences in clinical symptoms and course of these two tumors, their gross appearance is similar. Mean survival of both diseases also seems to be similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Utility of confocal laser endomicroscopy in identifying high-grade dysplasia and adenocarcinoma in Barrett's esophagus: a systematic review and meta-analysis.

Confocal laser endomicroscopy (CLE) is a novel endoscopic technique that has emerged as an important tool in the in-vivo visualization and detailed assessment of the mucosal layer and subcellular structures in Barrett’s esophagus. Current guidelines recommend four-quadrant random biopsies for identification of high-grade dysplasia (HGD) in Barrett’s esophagus. However, random biopsies are associated with sampling error and inconsistent histopathologic interpretation. CLE, by providing targeted biopsies, could decrease the sampling error and increase the yield of detection of HGD/adenocarcinoma [esophageal adenocarcinoma (EAC)]. We carried out a meta-analysis to evaluate the diagnostic accuracy of the CLE-based targeted biopsies in detecting HGD/adenocarcinoma compared with four-quadrant random biopsies. A search using medical subject headings (MeSH) terms and keywords was performed in the MEDLINE and Cochrane review databases and relevant studies were identified. All the studies that compared the diagnostic yield from CLE-based targeted biopsies to detect HGD/adenocarcinoma with a gold standard of histopathology were included and a meta-analysis was carried out to estimate the pooled sensitivity, specificity, and positive and negative likelihood ratios using Meta-Disc software. There were a total of seven studies with 345 patients and 3080 lesions that were finally included in the meta-analysis. All the studies had reported per-lesion analyses; however, only four of the seven studies had data reported on per-patient analyses. ‘Per-lesion’ analysis for the diagnosis of HGD/adenocarcinoma yielded a pooled sensitivity and specificity of 68% [95% confidence interval (CI) of 64–73%] and 88% (95% CI of 87–89%), respectively. The pooled positive and negative likelihood ratios were 6.56 (95% CI of 3.61–11.90) and 0.24 (95% CI of 0.09–0.63), respectively. Similar numbers were calculated on the basis of ‘per-patient’ basis, which showed a pooled sensitivity and specificity of 86% (95% CI of 74–96%) and 83% (95% CI of 77–88%), respectively. The pooled positive and negative likelihood ratios were 5.61 (95% CI of 2.00–15.69) and 0.21 (95% CI of 0.08–0.59), respectively. CLE, by providing targeted biopsies, has a good diagnostic accuracy in identifying HGD/EAC; however, the overall prevalence of HGD/EAC in the studies included was much higher than what would be seen in clinical practice and these results should be interpreted with caution. Because of its relatively low sensitivity and negative predictive value, CLE may currently not replace standard biopsy techniques for the diagnosis of HGD/EAC in Barrett’s esophagus.

Platelet count/spleen diameter ratio to predict the presence of esophageal varices in patients with cirrhosis: a systematic review.

Background Esophageal variceal bleeding remains the leading cause of acute mortality in patients with cirrhosis. Platelet count to spleen diameter (PC/SD) ratio less than 909 is one of several parameters proposed for the noninvasive prediction of esophageal varices. The aim of this study is to systematically review the evidence on the diagnostic accuracy of the 909 ratio. Methods We identified relevant studies from a MEDLINE search and performed a meta-analysis to estimate the pooled sensitivity, specificity, and positive and negative likelihood ratios (LRs) using Meta-Disc software. Results Eight studies met the inclusion criteria and included a total of 1275 patients. Meta-analysis yielded a pooled sensitivity of 89% [95% confidence interval (CI) 87–92%; I2 statistic 92.9%] and a pooled specificity of 74% (95% CI 70–78%; I2 statistic 94.5%). The pooled positive LR was 3.5 (95% CI 1.92–6.25; I2 statistic 94.0%) and the pooled negative LR was 0.12 (95% CI 0.05–0.32; I2 statistic 90.8%). The quality of the evidence as assessed by the GRADE methodology was low. Conclusion In its present form, the test characteristics of PC/SD ratio of 909 may not be adequate to completely replace esophagogastroduodenoscopy as a noninvasive screening tool for esophageal varices, given the low grade of evidence. However, it may be potentially useful as part of a prediction rule incorporating other clinical characteristics or varying PC/SD cutoffs. When compared with other noninvasive predictor tools, the PC/SD ratio is elegant, simple, and inexpensive. With some minor modifications, it may become a helpful tool to limit the number of endoscopies in primary prophylaxis to be performed in patients with portal hypertension.

Cholesterol Ester Storage Disease (CESD) Diagnosed in an Asymptomatic Adult

Cholesterol ester storage disease (CESD) is a rare, autosomal-recessive, lysosomal storage disorder. It is characterized by deficiency of lysosomal acid lipase (LAL) enzyme, which is responsible for intracellular hydrolysis of triaclyglycerols and cholesteryl esters. The deficiency state of LAL can be expressed in two major phenotypic variants: Wolman’s disease, which is the severe infantile form, uniformly fatal within 1–2 years of life, and the more benign CESD, which is associated with some residual LAL activity [1–4]. Patients with CESD often present in the first or second decade of life with hepatosplenomegaly and elevated cholesterol levels. Hepatomegaly caused by hepatic steatosis and fibrosis can lead to micro-nodular cirrhosis. Hypercholesterolemia as a result of upregulation of hepatic very low density lipoprotein B-100 synthesis [5] and low plasma levels of high density lipoproteins (HDL) [6] may lead to premature atherosclerosis and vascular complications. In this paper, we report a completely asymptomatic 43-year-old male, who was found to have CESD incidentally while undergoing workup for chronic hepatitis C infection.

Giant pseudopolyps presenting as colocolic intussusception in crohn's colitis

Bowel obstruction is a well-known complication of Crohns disease and is usually a result of stricture formation. Intussusception due to giant pseudopolyps is a rare form of bowel obstruction even in Crohns disease. These giant pseudopolyps rarely regress with medical management alone and often require surgical resection.

Selenomethionine Stimulates MAPK (ERK) Phosphorylation, Protein Oxidation, and DNA Synthesis in Gastric Cancer Cells

Abstract: Selenium is an essential trace element and is required for the synthesis of cellular enzymes that protect against oxidative stress. Epidemiological findings indicate that low selenium intake is associated with increased cancer risk, and, although the majority of studies show that exposure of transformed cells to selenium results in apoptotic cell death, there are reports indicating that cells exposure to low selenium concentrations promotes cellular proliferation. Gastric adenocarcinoma SNU-1 cells responded to selenomethionine with a biphasic proliferative curve: enhanced incorporation of 3H-thymidine into DNA within a very narrow range of selenomethionine concentrations followed by decreased 3H-thymidine uptake at higher levels. Concentrations of selenomethionine that stimulate cellular proliferation also induce cellular oxidation and phosphorylation of MAPK (ERK), a component of cell signaling cascades. MAPK (ERK) phosphorylation is synonymous with MAPK activation and enhanced cell growth. Our findings support previous observations of enhanced proliferation in response to low levels of selenium and suggest that, at certain concentrations, selenomethionine induces mild oxidative stress that, in turn, stimulates DNA synthesis.

Endoscopic retrograde cholangiopancreatography under moderate sedation and factors predicting need for anesthesiologist directed sedation: A county hospital experience.

AIM To evaluate variables associated with failure of gastroenterologist directed moderate sedation (GDS) during endoscopic retrograde cholangiopancreatography (ERCP) and derive a predictive model for use of anesthesiologist directed sedation (ADS) in selected patients. METHODS With institutional review board approval, we retrospectively analyzed consecutive records of all patients who underwent ERCPs between July 1, 2009 to October 1, 2011 to identify patient related and procedure related factors which could predict failure of GDS. For patient related factors, we abstracted and analyzed data regarding the age, gender, ethnicity, alcohol and illicit drug use habits. For procedure related factors, we abstracted data regarding initial or repeat procedures, indication for performing ERCP, the interventions performed during ERCP, and the grade d difficulty of cannulation as defined in the American Society for Gastrointestinal Endoscopy guidelines. Our outcome of interest was procedural success. If the procedure was not successful, the reasons for failure of procedures were recorded along with immediate post procedure complications. Multivariate analysis was then performed to define factors associated with failure of GDS and a model constructed to predict requirement of ADS. RESULTS Fourteen percent of patients undergoing GDS could not complete the procedure due to intolerance and 2% due to cardiovascular complications. Substance abuse, male gender, black race and alcohol use were significant predictors of failure of GDS on univariate analysis and substance abuse and higher grade of procedure remained significant on multivariate analysis. Using our predictive model where the presence of substance abuse was given 1 point and planned grade of intervention was scored from 1-3, only 12% patients with a score of 1 would require ADS due to failure of GDS, compared to 50% with a score of 3 or higher. CONCLUSION We conclude that ERCP under GDS is safe and effective for low grade procedures, and ADS should be judiciously reserved for procedures which have a higher risk of failure with moderate sedation.