The generalized Hamiltonian model for the shafting transient analysis of the hydro turbine generating sets.

yesTraditional rotor dynamics mainly focuses on the steady- state behavior of the rotor and shafting. However, for systems such as hydro turbine generating sets (HTGS) where the control and regulation is frequently applied, the shafting safety and stabilization in transient state is then a key factor. The shafting transient state inevitably involves multiparameter domain, multifield coupling, and coupling dynamics. In this paper, the relative value form of the Lagrange function and its equations have been established by defining the base value system of the shafting. Takingthe rotation angle and the angular speed of the shafting as a link, the shafting lateral vibration and generator equations are integrated into the framework of generalized Hamiltonian system. The generalized Hamiltonian control model is thus established. To make the model more general, additional forces of the shafting are taken as the input excitation in proposed model. The control system of the HTGS can be easily connected with the shafting model to form the whole simulation system of the HTGS. It is expected that this study will build a foundation for the coupling dynamics theory using the generalized Hamiltonian theory to investigate coupling dynamic mechanism among the shafting vibration, transient of hydro turbine generating sets, and additional forces of the shafting.National Natural Science Foundation of China under Grant Nos. 51179079 and 5083900

MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours

Combining drugs, which target different signalling pathways, often decreases adverse side effects while increasing the efficacy of treatment. The objective of our study was to determine if the combination of our novel atypical retinoic acid metabolism-blocking agent (RAMBA) VN/66-1 and a promising histone deacetylase inhibitor N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxy-carbonyl)aminomethyl]benzamide (MS-275) would show enhanced antineoplastic activity on human PC-3 prostate cancer cells/tumours and also to decipher the molecular mechanisms of action. The combination of VN/66-1+MS-275 was found to be synergistic in inhibiting PC-3 cell growth, caused cell cytostaticity/cytotoxicity and induced marked G2/M phase arrest and apoptosis. In mice with well-established PC-3 tumours, VN/66-1 (5 and 10 mg kg−1 day−1) caused significant suppression of tumour growth compared with mice receiving vehicle alone. Furthermore, treatment with VN/66-1 (10 mg kg−1 day−1)+MS-275 (2.5 mg kg−1 day−1) for 18 days resulted in an 85% reduction in final mean tumour volume compared with control and was more effective than either agent alone. Mechanistic studies indicated that treatment of PC-3 cells/tumours with VN/66-1+MS-275 caused DNA damage (upregulation of γH2AX), hyperacetylation of histones H3 and H4, upregulation of retinoic acid receptor-β, p21WAF1/CIP1, E-cadherin, and Bad and downregulation of Bcl-2. These data suggest that the mechanism of action of the combination of agents is DNA damage-induced p21 activation, resulting in inhibition of the Cdc2/cyclin B complex and accumulation of cells in G2/M phase. In addition, the combination caused modulation and induction of apoptosis. These results suggest that VN/66-1 or its combination with MS-275 may be a novel therapy for the treatment of prostate carcinoma

Distribution and biological role of the oligopeptide-binding protein (OppA) in Xanthomonas species

In this study we investigated the prevalence of the oppA gene, encoding the oligopeptide binding protein (OppA) of the major bacterial oligopeptide uptake system (Opp), in different species of the genus Xanthomonas. The oppA gene was detected in two Xanthomonas axonopodis strains among eight tested Xanthomonas species. The generation of an isogenic oppA-knockout derivative of the Xac 306 strain, showed that the OppA protein neither plays a relevant role in oligopeptide uptake nor contributes to the infectivity and multiplication of the bacterial strain in leaves of sweet orange (Citrus sinensis) and Rangpur lime (Citrus limonia). Taken together these results suggest that the oppA gene has a recent evolutionary history in the genus and does not contribute in the physiology or pathogenesis of X. axonopodis

5-FU-hydrogel inhibits colorectal peritoneal carcinomatosis and tumor growth in mice

<p>Abstract</p> <p>Background</p> <p>Colorectal peritoneal carcinomatosis (CRPC) is a common form of systemic metastasis of intra-abdominal cancers. Intraperitoneal chemotherapy is a preferable option for colorectal cancer. Here we reported that a new system, 5-FU-loaded hydrogel system, can improve the therapeutic effects of intraperitoneal chemotherapy.</p> <p>Methods</p> <p>A biodegradable PEG-PCL-PEG (PECE) triblock copolymer was successfully synthesized. The biodegradable and temperature sensitive hydrogel was developed to load 5-FU. Methylene blue-loaded hydrogel were also developed for visible observation of the drug release. The effects and toxicity of the 5-FU-hydrogel system were evaluated in a murine CRPC model.</p> <p>Results</p> <p>The hydrogel system is an injectable flowing solution at ambient temperature and forms a non-flowing gel depot at physiological temperature. 5-FU-hydrogel was subsequently injected into abdominal cavity in mice with CT26 cancer cells peritoneal dissemination. The results showed that the hydrogel delivery system prolonged the release of methylene blue; the 5-FU-hydrogel significantly inhibited the peritoneal dissemination and growth of CT26 cells. Furthermore, intraperitoneal administration of the 5-FU-hydrogel was well tolerated and showed less hematologic toxicity.</p> <p>Conclusions</p> <p>Our data indicate that the 5-FU-hydrogel system can be considered as a new strategy for peritoneal carcinomatosis, and the hydrogel may provide a potential delivery system to load different chemotherapeutic drugs for peritoneal carcinomatosis of cancers.</p

Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy

High activity of histone deacetylases (HDACs) causes epigenetic alterations associated with malignant cell behaviour. Consequently, HDAC inhibitors have entered late-phase clinical trials as new antineoplastic drugs. However, little is known about expression and function of specific HDAC isoforms in human tumours including prostate cancer. We investigated the expression of class I HDACs in 192 prostate carcinomas by immunohistochemistry and correlated our findings to clinicopathological parameters including follow-up data. Class I HDAC isoforms were strongly expressed in the majority of the cases (HDAC1: 69.8%, HDAC2: 74%, HDAC3: 94.8%). High rates of HDAC1 and HDAC2 expression were significantly associated with tumour dedifferentiation. Strong expression of all HDACs was accompanied by enhanced tumour cell proliferation. In addition, HDAC2 was an independent prognostic marker in our prostate cancer cohort. In conclusion, we showed that the known effects of HDACs on differentiation and proliferation of cancer cells observed in vitro can also be confirmed in vivo. The class I HDAC isoforms 1, 2 and 3 are differentially expressed in prostate cancer, which might be important for upcoming studies on HDAC inhibitors in this tumour entity. Also, the highly significant prognostic value of HDAC2 clearly deserves further study

Synergistic Antitumor Effects of Novel HDAC Inhibitors and Paclitaxel In Vitro and In Vivo

Preclinical studies support the therapeutic potential of histone deacetylases inhibitors (HDACi) in combination with taxanes. The efficacy of combination has been mainly ascribed to a cooperative effect on microtubule stabilization following tubulin acetylation. In the present study we investigated the effect of paclitaxel in combination with two novel HDACi, ST2782 or ST3595, able to induce p53 and tubulin hyperacetylation. A synergistic effect of the paclitaxel/ST2782 (or ST3595) combination was found in wild-type p53 ovarian carcinoma cells, but not in a p53 mutant subline, in spite of a marked tubulin acetylation. Such a synergistic interaction was confirmed in additional human solid tumor cell lines harboring wild-type p53 but not in those expressing mutant or null p53. In addition, a synergistic cytotoxic effect was found when ST2782 was combined with the depolymerising agent vinorelbine. In contrast to SAHA, which was substantially less effective in sensitizing cells to paclitaxel-induced apoptosis, ST2782 prevented up-regulation of p21WAF1/Cip1 by paclitaxel, which has a protective role in response to taxanes, and caused p53 down-regulation, acetylation and mitochondrial localization of acetylated p53. The synergistic antitumor effects of the paclitaxel/ST3595 combination were confirmed in two tumor xenograft models. Our results support the relevance of p53 modulation as a major determinant of the synergistic interaction observed between paclitaxel and novel HDACi and emphasize the therapeutic interest of this combination

Comparative analysis of novel and conventional Hsp90 inhibitors on HIF activity and angiogenic potential in clear cell renal cell carcinoma: implications for clinical evaluation

<p>Abstract</p> <p>Background</p> <p>Perturbing Hsp90 chaperone function targets hypoxia inducible factor (HIF) function in a von Hippel-Lindau (VHL) independent manner, and represents an approach to combat the contribution of HIF to cell renal carcinoma (CCRCC) progression. However, clinical trials with the prototypic Hsp90 inhibitor 17-AAG have been unsuccessful in halting the progression of advanced CCRCC.</p> <p>Methods</p> <p>Here we evaluated a novel next generation small molecule Hsp90 inhibitor, EC154, against HIF isoforms and HIF-driven molecular and functional endpoints. The effects of EC154 were compared to those of the prototypic Hsp90 inhibitor 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589.</p> <p>Results</p> <p>The findings indicate that EC154 is a potent inhibitor of HIF, effective at doses 10-fold lower than 17-AAG. While EC154, 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589 impaired HIF transcriptional activity, CCRCC cell motility, and angiogenesis; these effects did not correlate with their ability to diminish HIF protein expression. Further, our results illustrate the complexity of HIF targeting, in that although these agents suppressed HIF transcripts with differential dynamics, these effects were not predictive of drug efficacy in other relevant assays.</p> <p>Conclusions</p> <p>We provide evidence for EC154 targeting of HIF in CCRCC and for LBH589 acting as a suppressor of both HIF-1 and HIF-2 activity. We also demonstrate that 17-AAG and EC154, but not LBH589, can restore endothelial barrier function, highlighting a potentially new clinical application for Hsp90 inhibitors. Finally, given the discordance between HIF activity and protein expression, we conclude that HIF expression is not a reliable surrogate for HIF activity. Taken together, our findings emphasize the need to incorporate an integrated approach in evaluating Hsp90 inhibitors within the context of HIF suppression.</p

Epigenetic regulation of prostate cancer

Prostate cancer is a commonly diagnosed cancer in men and a leading cause of cancer deaths. Whilst the underlying mechanisms leading to prostate cancer are still to be determined, it is evident that both genetic and epigenetic changes contribute to the development and progression of this disease. Epigenetic changes involving DNA hypo- and hypermethylation, altered histone modifications and more recently changes in microRNA expression have been detected at a range of genes associated with prostate cancer. Furthermore, there is evidence that particular epigenetic changes are associated with different stages of the disease. Whilst early detection can lead to effective treatment, and androgen deprivation therapy has a high response rate, many tumours develop towards hormone-refractory prostate cancer, for which there is no successful treatment. Reliable markers for early detection and more effective treatment strategies are, therefore, needed. Consequently, there is a considerable interest in the potential of epigenetic changes as markers or targets for therapy in prostate cancer. Epigenetic modifiers that demethylate DNA and inhibit histone deacetylases have recently been explored to reactivate silenced gene expression in cancer. However, further understanding of the mechanisms and the effects of chromatin modulation in prostate cancer are required. In this review, we examine the current literature on epigenetic changes associated with prostate cancer and discuss the potential use of epigenetic modifiers for treatment of this disease

Search for neutral MSSM Higgs bosons decaying to a pair of tau leptons in pp collisions

Peer reviewe

Measurement of prompt J/ψ pair production in pp collisions at √s = 7 Tev

Peer reviewe