Effects of IL-6 and AG490 on regulation of Stat3 signaling pathway and invasion of human pancreatic cancer cells in vitro

<p>Abstract</p> <p>Background</p> <p>Signal transducer and activator of transcription 3 (Stat3) is a member of the Janus-activated kinase(Jak)/Stat signaling pathway. Abnormal activation of Stat3 plays a critical role in metastasis and invasion in varieties of human tumors including pancreatic cancer. This study aimed to investigate the mechanisms of activation and blocking of the Stat3 signaling pathway and its effects on invasion and metastasis of human pancreatic cancer cells.</p> <p>Methods</p> <p>The Jak inhibitor AG490 and interleukin-6 (IL-6) were added to the culture media of human pancreatic cancer cells SW1990 and Capan-2, respectively. Cell growth was measured by MTT assays. Western blotting and immunocytochemistry were performed to detect phosphorylated Stat3 (p-Stat3) protein, while VEGF and MMP-2 mRNA and protein expression were examined with fluorescence quantitative polymerase chain reaction and Western blotting, respectively. The invasion ability of SW1990 and Capan-2 cells was determined by cell invasion assay.</p> <p>Results</p> <p>Stat3 was activated by IL-6 in Capan-2 cells; protein expression of p-Stat3 was increased significantly in Capan-2 cells. IL-6 remarkably promoted the growth of Capan-2 cells (<it>P </it>< 0.05), and VEGF and MMP-2 mRNA and protein expression were increased significantly. Also, IL-6 increased the invasion ability of Capan-2 cells. AG490 inhibited Stat3 activation in SW1990 cells. Western blotting and immunocytochemistry analysis showed that p-Stat3 protein expression was decreased significantly with AG490 treatment in SW1990 cells. AG490 remarkably inhibited the growth of Capan-2 cells (<it>P </it>< 0.05), and VEGF and MMP-2 mRNA and protein expression was decreased significantly. And AG490 decreased the invasion ability of SW1990 cells.</p> <p>Conclusions</p> <p>Abnormal activation of Stat3 plays an important role in the invasion and metastasis of pancreatic cancer. Activation and blocking of the Stat3 signaling pathway can affect invasion ability and expression of the VEGF and MMP-2 genes in pancreatic cancer cells. The Stat3 signaling pathway may provide a novel therapeutic target for treatment of pancreatic cancer.</p

Vibration control for active magnetic bearing high-speed flywheel rotor system with modal separation and velocity estimation strategy

The active magnetic bearing (AMB) high-speed flywheel rotor system is a multivariable, nonlinear, and strongly coupled system with significant gyroscopic effect, which puts a strain on its stability and control performances. It is very difficult for traditional decentralized controllers, such as proportional-derivative controller (PD controller), to deal with such complex system. In order to improve the stability, control performances and robustness against noise of the AMB high-speed flywheel rotor system, a new control strategy was proposed based on the mathematical model of the AMB high-speed flywheel rotor system in this paper. The proposed control strategy includes two key subsystems: the modal separation subsystem, which allows direct control over the rotor rigid modes, and the velocity estimation controller, which improves the robustness against noise. Integration of modeling results into the final controller was also described. Its ability and effectiveness to control the AMB high-speed flywheel rotor system was investigated by simulations and experiments. The results show that proposed control strategy can separately regulate the stiffness and the damping of conical mode and parallel mode of the AMB high-speed flywheel rotor system, and obviously improve the stability, dynamic behaviors and robustness against noise of the AMB high-speed flywheel rotor system in the high rotating speed region

Vibration control for active magnetic bearing high-speed flywheel rotor system with modal separation and velocity estimation strategy

The active magnetic bearing (AMB) high-speed flywheel rotor system is a multivariable, nonlinear, and strongly coupled system with significant gyroscopic effect, which puts a strain on its stability and control performances. It is very difficult for traditional decentralized controllers, such as proportional-derivative controller (PD controller), to deal with such complex system. In order to improve the stability, control performances and robustness against noise of the AMB high-speed flywheel rotor system, a new control strategy was proposed based on the mathematical model of the AMB high-speed flywheel rotor system in this paper. The proposed control strategy includes two key subsystems: the modal separation subsystem, which allows direct control over the rotor rigid modes, and the velocity estimation controller, which improves the robustness against noise. Integration of modeling results into the final controller was also described. Its ability and effectiveness to control the AMB high-speed flywheel rotor system was investigated by simulations and experiments. The results show that proposed control strategy can separately regulate the stiffness and the damping of conical mode and parallel mode of the AMB high-speed flywheel rotor system, and obviously improve the stability, dynamic behaviors and robustness against noise of the AMB high-speed flywheel rotor system in the high rotating speed region

Short-term and medium-term clinical outcomes of laparoscopic-assisted and open surgery for colorectal cancer: a single center retrospective case-control study

BACKGROUND: Laparoscopic procedure is a rapid developed technique in colorectal surgery. In this investigation we aim at assessing the diversities of short-term and medium-term clinical outcomes of laparoscopic-assisted versus open surgery for colorectal cancer. METHODS: A total number of 519 patients with non-metastatic colorectal cancer were enrolled for this study. The patients underwent either laparoscopic-assisted surgery (LAP) (n = 254) or open surgery (OP) (n = 265). Surgical techniques, perioperative managements and clinical follow-ups were standardized. Short-term perioperative data and medium-term recurrence and survival were compared and analyzed between the two groups. RESULTS: There were no differences in perioperative parameters between the two groups except in regards to a trend of faster recovery in laparoscopic procedures. There was no statistically significant difference in postoperative complications, reoperation rate, or perioperative mortality. Statistically significant differences in a faster return of gastrointestinal function and shorter hospital stay were identified in favor of laparoscopic-assisted resection. In colon and rectal cancer cases separately, the overall survival, cancer-free survival and recurrence rate were similar in two groups. There was also no tendency of significant differences in overall survival, cancer-free survival and recurrence in stage I-II and stage III patients in two cancer categories between the two groups, respectively. pT, lymph node metastasis, and clinical stage were independent predictors of overall death risk, while pT, pN, lymph node metastasis and clinical stage were found to be the independent predictors of recurrence risk in enrolled patients database. CONCLUSIONS: Laparoscopic-assisted procedure has more benefits on postoperative recovery, while has the same effects on medium-term recurrence and survival compared with open surgery in the treatment of non-metastatic colorectal cancer

ATF4 activation by the p38MAPK–eIF4E axis mediates apoptosis and autophagy induced by selenite in Jurkat cells

AbstractPrevious studies have shown that selenite exerts pro-apoptosis and pro-autophagy effects and is associated with the activation of ER stress in T-cell acute lymphoblastic leukemia (T-ALL). Herein we demonstrate the underlying mechanisms by which the activation of p38MAPK plays essential roles in apoptosis and autophagy and the coordination of cellular metabolic processes during leukemia therapy. MKK3/6-dependent activation of p38MAPK is required for the phosphorylation of eIF4E, thus initiating the translation of ER stress-related transcription factor ATF4. Upregulated ATF4 results in the transcriptional initiation of the apoptosis-related chop gene and autophagy-related map1lc3b gene, through which selenite links ER stress to apoptosis and autophagy during leukemia treatment. Moreover, autophagy induction enhances cell apoptosis under this condition

Sodium selenite alters microtubule assembly and induces apoptosis in vitro and in vivo

BACKGROUND: Previous studies demonstrated that selenite induced cancer-cell apoptosis through multiple mechanisms; however, effects of selenite on microtubules in leukemic cells have not been demonstrated. METHODS: The toxic effect of selenite on leukemic HL60 cells was performed with cell counting kit 8. Selenite effects on cell cycle distribution and apoptosis induction were determined by flow cytometry. The contents of cyclin B1, Mcl-1, AIF, cytochrome C, insoluble and soluble tubulins were detected with western blotting. Microtubules were visualized with indirect immunofluorescence microscopy. The interaction between CDK1 and Mcl-1 was assessed with immunoprecipitation. Decreasing Mcl-1 and cyclin B1 expression were carried out through siRNA interference. The alterations of Mcl-1 and cyclin B1 in animal model were detected with either immunohistochemical staining or western blotting. In situ detection of apoptotic ratio was performed with TUNEL assay. RESULTS: Our current results showed that selenite inhibited the growth of HL60 cells and induced mitochondrial-related apoptosis. Furthermore, we found that microtubule assembly in HL60 cells was altered, those cells were arrested at G2/M phase, and Cyclin B1 was up-regulated and interacted with CDK1, which led to down-regulation of the anti-apoptotic protein Mcl-1. Finally, in vivo experiments confirmed the in vitro microtubule disruption effect and alterations in Cyclin B1 and Mcl-1 levels by selenite. CONCLUSIONS: Taken together, the results from our study indicate that microtubules are novel targets of selenite in leukemic HL60 cells

Laparoscopic and open resection for colorectal cancer: an evaluation of cellular immunity

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer is one kind of frequent malignant tumors of the digestive tract which gets high morbidity and mortality allover the world. Despite the promising clinical results recently, less information is available regarding the perioperative immunological effects of laparoscopic surgery when compared with the open surgery. This study aimed to compare the cellular immune responses of patients who underwent laparoscopic(LCR) and open resections(OCR) for colorectal cancer.</p> <p>Methods</p> <p>Between Mar 2009 and Sep 2009, 35 patients with colorectal carcinoma underwent LCR by laparoscopic surgeon. These patients were compared with 33 cases underwent conventional OCR by colorectal surgeon. Clinical data about the patients were collected prospectively. Comparison of the operative details and postoperative outcomes between laparoscopic and open resection was performed. Peripheral venous blood samples from these 68 patients were taken prior to surgery as well as on postoperative days(POD) 1, 4 and 7. Cell counts of total white blood cells, neutrophils, lymphocyte subpopulations, natural killer(NK) cells as well as CRP were determined by blood counting instrument, flow cytometry and hematology analyzer.</p> <p>Results</p> <p>There was no difference in the age, gender and tumor status between the two groups. The operating time was a little longer in the laparoscopic group (<it>P </it>> 0.05), but the blood loss was less (<it>P </it>= 0.039). Patients with laparoscopic resection had earlier return of bowel function and earlier resumption of diet as well as shorter median hospital stay (<it>P </it>< 0.001). Compared with OCR group, cell numbers of total lymphocytes, CD4⁺T cells and CD8⁺T cells were significant more in LCR group (<it>P </it>< 0.05) on POD 4, while there was no difference in the CD45RO⁺T or NK cell numbers between the two groups. Cellular immune responds were similar between the two groups on POD1 and POD7.</p> <p>Conclusions</p> <p>Laparoscopic colorectal resection gets less surgery stress and short-term advantages compared with open resection. Cellular immune respond appears to be less affected by laparoscopic colorectal resection when compared with open resection.</p

Exploring Off-Targets and Off-Systems for Adverse Drug Reactions via Chemical-Protein Interactome — Clozapine-Induced Agranulocytosis as a Case Study

In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs