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The two cytosolic/nuclear isoforms of the molecular chaperone HSP90, stress-inducible HSP90α and constitutively expressed HSP90β, fold, assemble and maintain the three-dimensional structure of numerous client proteins. Because many HSP90 clients are important in cancer, several HSP90 inhibitors have been evaluated in the clinic. However, little is known concerning possible unique isoform or conformational preferences of either individual HSP90 clients or inhibitors. In this report, we compare the relative interaction strength of both HSP90α and HSP90β with the transcription factors HSF1 and HIF1α, the kinases ERBB2 and MET, the E3-ubiquitin ligases KEAP1 and RHOBTB2, and the HSP90 inhibitors geldanamycin and ganetespib. We observed unexpected differences in relative client and drug preferences for the two HSP90 isoforms, with HSP90α binding each client protein with greater apparent affinity compared to HSP90β, while HSP90β bound each inhibitor with greater relative interaction strength compared to HSP90α. Stable HSP90 interaction was associated with reduced client activity. Using a defined set of HSP90 conformational mutants, we found that some clients interact strongly with a single, ATP-stabilized HSP90 conformation, only transiently populated during the dynamic HSP90 chaperone cycle, while other clients interact equally with multiple HSP90 conformations. These data suggest different functional requirements among HSP90 clientele that, for some clients, are likely to be ATP-independent. Lastly, the two inhibitors examined, although sharing the same binding site, were differentially able to access distinct HSP90 conformational states. [ABSTRACT FROM AUTHOR]

As a result of the dramatic improvements in the resolution, wearability, and weight of head-mounted displays (HMDs), they have become increasingly applied in the medical field as personal imaging monitors. The combined use of a multiplexer with an HMD allows the wearer to simultaneously and seamlessly monitor multiple streams of imaging information through the HMD. We developed a multitask imaging monitor for surgical navigation by combining a touchless surgical imaging control system with an HMD. This system is composed of a standard color digital video camera mounted on the HMD and computer software that enables the identification of the number of pictured fingertips from the video camera image. The HMD wearer uses this information as a touchless interface for the operating multiplexer, which can control the arrays and types of imaging information displayed on the HMD. We used this system in an experimental demonstration during a single-port gasless partial nephrectomy. The use of this multitask imaging monitor using a touchless interface would refine the surgical workflow, especially during surgical navigation. [ABSTRACT FROM AUTHOR]

Background: To eradicate hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) using a stepwise infection control strategy that includes an avoidance of antimicrobial prophylaxis (AMP) based on surgical wound classification and an improvement in operative procedures in gasless single-port urologic surgery. Methods: The study was conducted at an 801-bed university hospital. Since 2001, in the urology ward, we have introduced the stepwise infection control strategy. In 2007, surveillance cultures for MRSA in all urological patients were commenced. The annual incidence of MRSA was calculated as a total number of newly identified MRSA cases per 1,000 patient days. Trend analysis was performed using a Poisson regression. Results: Over the study period, 139,866 patients, including 10,201 urology patients, were admitted to our hospital. Of these patients, 3,719 patients, including 134 ones in the urology ward, were diagnosed with MRSA throughout the entire hospital. Although the incidence of MRSA increased throughout the entire hospital (p = 0.002), it decreased significantly in the urology ward (p < 0.0001). Of the 134 cases, 45 (33.6%) were classified as "imported," and 89 (66.4%) as "acquired." In the urology ward, the incidence of acquired MRSA decreased significantly over time (p < 0.0001), whereas the incidence of imported MRSA did not change over time (p = 0.66). A significant decrease (p < 0.0001) in the incidence of clinically significant MRSA infection over time was found. Conclusions: Stepwise infection control strategy that includes a reduction or avoidance of antimicrobial prophylaxis in minimally invasive surgery can contribute to a reduction in hospital-acquired MRSA. Trial registration: Current study has approved by the institutional ethical review board (No.1141). [ABSTRACT FROM AUTHOR]

Zoledronic acid (ZOL), a third-generation bisphosphonate that strongly inhibits osteoclast activity, is widely used for the treatment of bone metastasis from a variety of malignancies, including renal cell carcinoma (RCC). We previously reported that zoledronic acid (ZOL) clinically potentiates antitumor effects of radiotherapy (RT) on bone metastases from RCC. To date, however, it remains unknown whether ZOL radiosensitizes RCC and if it does, how. Here, we demonstrated that ZOL directly radiosensitizes RCC cells independent of osteoclast activity by potentiating the caspase-3-mediated apoptosis pathway. The radiosensitization by ZOL was observed in 786-O, A-498, and ACHN cells but not in Caki-1 cells. As its underlying molecular mechanism, we found that the signal transducer and activator of transcription 1 (STAT1) plays a key role. The three RCC cell lines, in which ZOL exerted a radiosensitizing effect, expressed STAT1 abundantly but Caki-1 cells did not. ZOL downregulated endogenous STAT1 expression in 786-O, A-498, and ACHN cells by a post-transcriptional modification. We confirmed that knockdown of endogenous STAT1 by siRNA sensitized 786-O cells to RT equivalently to ZOL, and that introduction of exogenous STAT1 rendered Caki-1 cells more RT-resistant. This is the first study to clarify the molecular mechanism by which ZOL directly radiosensitizes tumor cells. Because tumor cells commonly overexpress STAT1 and ZOL reportedly radiosensitizes various types of tumor cells, ZOL warrants further clinical and translational studies as a potent radiosensitizer against RT-resistant tumors overexpressing STAT1. [ABSTRACT FROM AUTHOR]

Radical cystectomy for muscle-invasive bladder cancer (MIBC) patients frequently impairs their quality of life (QOL) due to urinary diversion. To improve their QOL, a bladder-sparing alternative strategy using chemoradiation has been developed. In bladder-sparing protocols, complete response (CR) to induction chemoradiation is a prerequisite for bladder preservation and favorable survival. Thus predicting chemoradiation resistance and overcoming it would increase individual MIBC patients' chances of bladder preservation. The aim of this study is to investigate putative molecular targets for treatment aimed at improving chemoradiation response. Expression levels of erbB2, NFκB, p53, and survivin were evaluated immunohistochemically in pretreatment biopsy samples from 35 MIBC patients in whom chemoradiation sensitivity had been pathologically evaluated in cystectomy specimens, and associations of these expression levels with chemoradiation sensitivity and cancer-specific survival (CSS) were investigated. Of the 35 patients, 11 (31%) achieved pathological CR, while tumors in the remaining 24 patients (69%) were chemoradiation-resistant. Multivariate analysis identified erbB2 and NFκB overexpression and hydronephrosis as significant and independent risk factors for chemoradiation resistance with respective relative risks of 11.8 (P = 0.014), 15.4 (P = 0.024) and 14.3 (P = 0.038). The chemoradiation resistance rate was 88.5% for tumors overexpressing erbB2 and/or NFκB, but only 11.1% for those negative for both (P <0.0001). The 5-year CSS rate was 74% overall. Through multivariate analysis, overexpression of erbB2 and/or NFκB was identified as an independent risk factor for bladder cancer death with marginal significance (hazard ratio 21.5, P = 0.056) along with chemoradiation resistance (P = 0.003) and hydronephrosis (P = 0.018). The 5-year CSS rate for the 11 patients achieving pathological CR was 100%, while that for the 24 with chemoradiation-resistant disease was 61% (P = 0.018). Thus, erbB2 and NFκB overexpression are relevant to chemoradiation resistance and are putative targets aimed at overcoming chemoradiation resistance in MIBC. [ABSTRACT FROM AUTHOR]