Apoptosis is induced by many kinds of therapy-related inducers, such as hyperthermia and chemotherapeutic agents. However, differences in apoptotic pathways between these inducers remain unclear, although knowing the differences is important to map out a therapeutic strategy. Therefore, we focused on the localization and phosphorylation of Bcl-2 and Bax, key mediators of the apoptotic pathway, after hyperthermia and paclitaxel treatment of PC-10 squamous cell carcinoma cells that excessively expressed Bcl-2 and Bax in the cytoplasm. Paclitaxel treatment markedly induced qualitative changes in Bcl-2, whereas hyperthermia did only quantitative changes in Bax. The levels of Bax increased gradually with the duration of hyperthermia, whereas Bcl-2 levels slightly decreased. On the other hand, paclitaxel treatment induced dose-and time-dependent phosphorylation of Bcl-2. Interestingly, phosphorylated Bcl-2 was observed in the specific subcellular sites, mitochondria-and lysosomerich fractions. Both treatments disturbed the heterodimerization of Bax with Bcl-2. Hyperthermia, but not paclitaxel treatment, induced a gradual Bax translocation from the cytoplasm to the nucleus. Although both treatments induced a prominent cell cycle disturbance in the G2M phase, paclitaxel treatment induced typical apoptosis, and hyperthermia hardly induced apoptosis. Our results suggest that the subcellular redistribution of Bax and the phosphorylation of Bcl-2 depend on the type of apoptosis inducers, such as hyperthermia and paclitaxel, and Bcl-2 has a central role in the decision of apoptotic outcome. Our data may afford new insights in apoptosis from the aspect of an association of Bcl-2 phosphorylation with intracellular Bax localization. © 2002 Wiley-Liss, Inc. Key words: Bcl-2; Bax; hyperthermia; paclitaxel; lung cancer cellsPaclitaxel, microtubule-stabilizing agents, demonstrates a marked activity against several kinds of tumors 1 by arresting cell-cycle progression and inducing apoptosis. 2-4 Mild hyperthermia disturbs functions of the microtubule system and triggers apoptosis as well. 5 In addition, local or systemical hyperthermia is used in conjunction with paclitaxel in cancer tretment, 6 but whether a combined thermo-chemotherapy enhanced 5,7,8 or inhibited 9,10 the susceptibility of cells to apoptotic stimuli is still controversial. Therefore, understanding how paclitaxel and hyperthermia modalities induce apoptosis is critical to map out a better anticancer strategy that may offer synergistic benefits when used concurrently.Cellular apoptotic potential is mainly regulated by the relative levels of Bcl-2 and Bax, Bcl-2 family members with opposite functions and their interactions. 11 These proteins mainly act on mitochondria at a critical decision point to irreversible cellular damage. 12-15 The antiapoptotic Bcl-2 suppresses apoptosis, whereas the proapoptotic Bax counteracts the Bcl-2 function to accelerate apoptosis. These proteins exert their activity via protein/ protein interactions, such as homodimerization and heter...
In partial-liver transplantation, the use of small grafts sometimes results in graft failure, usually caused by portal hypertension after transplantation (Tx). Portal hypertension after Tx can be decreased with a porto-caval shunt (PCS). The purpose of this study is to clarify the effect of the PCS on extremely reduced-size liver Tx. In a pig model, the posterior segment of 25% of a whole liver was transplanted orthotopically. The pigs were divided two groups: group A, graft with PCS (n = 7), and group B, graft without PCS (n = 7). The PCS was made by means of side-to-side anastomosis of the portal vein and the inferior vena cava. We examined the portal vein pressure, survival rate, regeneration rate of the graft, Ki-67 as an index of cell proliferation, and histological findings, and carried out liverfunction tests. In group A, five pigs survived for more than 4 days and the remaining two died of a perforated gastric ulcer on post-operative day (POD) 2. In group B, all pigs except one died of graft failure within 24 h. Portal vein pressure after reperfusion in group A and group B was of statistically significant difference ( P < 0.05), 14.2 f 3.2 and 18.9 * 4.7 cmH20, respectively.In group A, the regeneration rate of the graft was 94%, 4 days after Tx, and Ki-67 stained remarkably in the parenchymal hepatocytes. In TEM finding, structure of the sinusoid was also well maintained after Tx. From these results we can conclude that the key to success in liver Tx with extremely small grafts lies in the control of the portal vein pressure,
HIROSHI SHIBUYA, NOBUHIRO OHKOHCHI, SHIGEKI TSUKAMOTO, AND SUSUMU SATOMI Ischemia/reperfusion injury is one of the most important The mechanisms of hepatic ischemia/reperfusion injury are causes of graft nonfunction and a determinant of successful complicated and multifactorial. This study was designed to liver transplantation. 1 Many efforts have been made to eluciexamine superoxide generation and neutrophil accumulation date the mechanisms of this injury. Cellular damage might be in cold ischemic-reperfused rat livers after elimination of partially related to the generation of reactive oxygen species Kupffer cells and to determine the role of superoxide/tumor (ROS), because scavengers for ROS and allopurinol, an inhibnecrosis factor (TNF) interactions. Rat Kupffer cells were itor of xanthine oxidase, have a protective effect against iseliminated by liposome-encapsulated dichloromethylene dichemia/reperfusion injury. 2,3 However, several studies have phosphonate injected intravenously. Livers from control and questioned whether the quantity of ROS generated during treated rats were isolated and preserved in University of Wisreperfusion is sufficient to cause direct injury through lipid consin solution (4ЊC) for 0, 12, and 24 hours and then perperoxidation. 4 Alternatively, ROS act in signal transduction fused for 60 minutes with oxygenated Krebs-Henseleit bicarfor subsequent injurious events. 5 Thus, the impact of ROS on bonate buffer (37ЊC) by adding neutrophils into the perfusate.the pathogenesis of reperfusion injury remains controversial, Superoxide generation was measured by using real-time and the extent of the injury cannot be explained by ROS chemiluminescence (CL) during perfusion, and neutrophil acalone. cumulation was assessed by measuring myeloperoxidase acPolymorphonuclear leukocytes (PMNs) have been implitivity in the liver tissue. In the control livers, CL intensity cated as a causal factor in the development of reperfusion markedly increased on reoxygenation, and after neutrophil injury, 6 and functional and structural aggravation of the reinfusion it increased again with a lag period of 10 minutes.perfused liver is associated with the presence and the degree Total CL intensity and myeloperoxidase activity increased of PMN infiltration. 7 PMN accumulation in reperfused liver with the duration of cold preservation. TNF release into the after warm ischemia is mediated by superoxide anions. 8 Fureffluent perfusate was detectable only after 24 hours of preserthermore, tumor necrosis factor (TNF) may attract PMNs to vation, and lactate dehydrogenase release was high. Eliminathe site of inflammation 9 and stimulates superoxide generation of Kupffer cells attenuated CL intensity and TNF and tion by in situ perfused rat liver. 10 Thus, the mechanisms of lactate dehydrogenase release and resulted in reduced myelohepatic ischemia/reperfusion injury seem to be very compliperoxidase activity. Electron microscopy revealed amelioracated and multifactorial; moreover, there has not been definition of hepatocyte...
Background : We investigated the advantages of intraoperative transesophageal echocardiography (TEE) during inferior vena caval tumor thrombectomy in renal cell carcinoma (RCC). Methods : Five patients with RCC that extended into the inferior vena cava (IVC) underwent radical nephrectomy. To remove the tumor thrombus in the IVC, an inflated Fogarty balloon catheter was used to pull the thrombus below the level of the hepatic veins with real-time TEE monitoring. Results : In all cases, TEE monitoring during surgery provided an accurate and excellent view of the IVC thrombus. TEE was particularly helpful for the thrombectomy to minimize hepatic mobilization by using occlusion balloon catheter in two patients whose thrombus extended to the intrahepatic IVC. Conclusions : Intraoperative real-time TEE monitoring is a safe, minimally invasive technique that can provide accurate information regarding the presence and extent of IVC involvement, guidance for placement of a vena caval clamp, confirmation of complete removal of the IVC thrombus and intervention using catheters to assist in thrombectomy.
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