Mary Jo Atten

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.

The survival of stage III gastric cancer patients is affected by the number of lymph nodes removed

BACKGROUND Lymph node (LN) removal has been an important component in surgical treatment of gastric cancer. However, it is not clear whether the number of lymph nodes resected affects patient survival. METHODS We retrospectively reviewed the records of 147 patients with adenocarcinoma of the stomach who had undergone gastrectomy with curative intent between 1992 and 2001. Patients were divided into two groups: group I patients had < or =15 (n=124) and group II patients had >15 (n=23) LN reported. RESULTS The two groups were similar in age, gender distribution, and tumor locations. Group II patients had more advanced tumor, node, and overall staging. The median survival was 23.0 and 31.8 months for groups I and II, respectively. In stage III patients, median survival was 14.4 months for group I and 33.8 months for group II (P=.006). Group II patients also had more proximal lesions (P<.001) and a decreased positive to removed LN ratio (P=.014). CONCLUSION For stage III disease, removal of >15 LN appears to contribute to a considerable survival advantage. Because extended lymphadenectomy will most reliably allow >15 LN removed and add no operative morbidity and mortality, we strongly recommend it be considered in curative resections of gastric cancer.

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.

Acute Pancreatitis as a Rare Initial Manifestation of Wegener's Granulomatosis. A Case Based Review of Literature

CONTEXT Vasculitis is a known cause of pancreatitis and other gastrointestinal symptoms; however, most of these patients have medium vessel vasculitis like polyarteritis nodosa and often there are other associated conditions like hepatitis B or clinical manifestations that suggest the diagnosis. Wegeners granulomatosis is predominantly a reno-pulmonary disorder, rarely having gastrointestinal manifestations. CASE REPORT We report a case of Wegeners granulomatosis initially presenting as acute pancreatitis and then rapidly progressing to severe multi-organ involvement over the next few months. DISCUSSION Pancreatic association as an initial presentation of Wegeners granulomatosis is limited to only a few reports. This extremely rare initial presentation makes the diagnostic process challenging. Two different pancreatic manifestations have been reported: as a pancreatic mass mimicking a tumor or as acute pancreatitis. The patients who presented as pancreatic head masses underwent extensive surgical procedures before the diagnosis was established. Acute pancreatitis as the initial presentation is usually associated with an aggressive course of the vasculitis and often results in a fatal outcome. CONCLUSIONS This case illustrates Wegeners granulomatosis as a rare cause of acute pancreatitis. It emphasizes the need for thorough continued systemic clinical evaluation of patients when the etiology is not readily evident. Also, since most patients with pancreatitis due to Wegeners granulomatosis rapidly progress to severe multiorgan involvement, knowledge of a broad differential of potential etiologies and a low index of suspicion is required for timely diagnosis and treatment.

Antioxidants up-regulate PPAR|[gamma]| and decrease fibrosis in chronic pancreatitis

Purpose: Pancreatic fibrosis results from repeated episodes of inflammation and chronic oxidative stress within the pancreas. PPAR is a ligand-activated transcription factor that modulates inflammation in different tissues, and has been shown to block activation of pancreatic stellate cells in vitro.The aim of this study was to investigate the antifibrotic/anti-inflammatory effect of the antioxidants, vitamin C and vitamin E, in chronic pancreatitis.

Shunt patency required for effective management of endotipsitis

Transjugular intrahepatic portosystemic shunt (TIPS) infections have been reported in up to 20% of newly placed shunts. All of the reported cases responded to antibiotics alone and did not require shunt revision to clear the infection. We report a case that required repeated shunt revision and ultimately a patent shunt in order to clear the infection. A 59 year-old female with advanced liver disease due to autoimmune hepatitis presented with a 2-wk history of fatigue, somnolence and fever. She had TIPS placement 20 months earlier for refractory ascites. She underwent revision of an occluded shunt 3 months later and was found to have good flow through the shunt 1-yr later. On presentation she was febrile, icteric and had ascites and a leukocytosis of 13,000. Blood cultures grew E. coli that was treated with ceftriaxone. Investigation for an alternative source of infection was negative and included CXR, urinalysis and culture, paracentesis, abdominal CT, and echocardiogram. Doppler ultrasound showed TIPS occlusion. She remained febrile for 10 days despite appropriate antibiotics. A shunt revision with balloon angioplasty was completed with good post-procedure flow. During the procedure the patient experienced high-grade fever and chills, tachycardia and tachypnea. She defervesced over the next 48-hrs. However, she again became febrile and the shunt was again found to be occluded. Antibiotic coverage was broadened, however, her fever continued. A second TIPS revision was performed, again with good post-procedure flow. She defervesced over the next 48-hrs and remained afebrile. Good flow was documented through the shunt 3 days later. Since histopathologic confirmation is not possible, endotipsitis, like endocarditis, is diagnosed on positive blood cultures, exclusion of other sources of infection, and imaging studies showing a thrombus. The infection is typically cleared with long-term antibiotics. This case illustrates symptoms of acute bacteremia during shunt manipulation, another criterion for diagnosis of shunt infection, and the need for shunt patency in order to clear the infection.