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The treatment of bone metastases is a thorny issue. Immunotherapy may be one of the few hopes for patients with unresectable bone metastases. Immune checkpoint inhibitors are the most commonly used immunotherapy drugs currently. In this review, the characteristics and interaction of bone metastases and their immune microenvironment were systematically discussed, and the relevant research progress of the immunological mechanism of tumor bone metastasis was reviewed. On this basis, we expounded the clinical application of immune checkpoint inhibitors for bone metastasis of common tumors, including non-small-cell lung cancer, renal cell carcinoma, prostate cancer, melanoma, and breast cancer. Then, the deficiencies and limitations in current researches were summarized. In-depth basic research on bone metastases and optimization of clinical treatment is needed.

The primary treatment of tophaceous gout is to control the disease by pharmacological therapy. Additional surgical intervention is used to correct cosmetic deformation in joints or disabling functional disorder; however, one of its reported complications is hyperuricemia and recurrent attacks of pain. Objectives: to access the effectiveness of Low Intensity Laser therapy as addition to urate lowering treatment in patients with tophaceous gout, who underwent joints surgery in the Chengdu Rheumatism Hospital, in comparison to those patients who received only nonsurgical treatment. Subjects and methods. The effectiveness of Low Intensity Laser therapy (LILT) and urate lowering treatment in patients with tophaceous gout was investigated in 63 male patients of Chengdu Rheumatism hospital with tophaceous gout who underwent joints surgery. Control group was formed of 63 gout patients comparable in age and pre-treatment uric acid, who received non-surgical treatment.Results. Patients underwent surgery in one or two sessions, the most common lesion site being foot joints: toes (49.41%), ankle (39.68%) and knee (34.92%), with restricted mobility in the mentioned joints. Levels of CRP before the treatment were elevated in almost all patients (median 3.74 (0.2, 48.75) mg/L), regardless of the other comorbidities. Urate lowering therapy notably reduced the levels of CRP to 2.44 (0, 33.27) mg/L in study group and to 1.3 (0.13, 31.72) mg/L in controls. After surgery and following urate lowering therapy all patients noted functional improvement and reduction of pain. Decrease in serum urate levels were reported in 96.83% of patients in study group and in 93.65% of controls. There was no significant difference in serum UA between patients who underwent joint surgery and who didn’t. Patients, who in addition to surgery received Low-Level Laser Therapy therapy, had a lowest mean serum UA after treatment (280.93 ± 97.05 μmol/L), but due to wide range of variation, difference to other groups wasn’t statistically significant. Addition of laser therapy also helped to reduce the pain almost twice (0.56±0.56 compared to 1.04 ± 0.91). However, we haven’t registered notable anti-inflammatory influence of LILT. There was a weak direct link established between levels of serum UA and CRP after treatment, but in patients receiving laser therapy, CRP was elevated more often, compared to those who weren’t prescribed with LILT or controls. Conclusion. Arthroscopic shaving and other surgical approaches focused on joints often doesn’t affect system hyperuricemia in any way and can’t be viewed as a substitute to urate lowering therapy. However, our experience confirms that timely performed surgery contribute to functional improvement and reduction of pain in gout patients. Low Intensity Laser therapy doesn’t affect hyperuricemia or guarantee long-term systemic anti-inflammatory effect, but help to additionally relieve pain in joints and thus enhance treatment effect and quality of patients’ life.

An increasing number of studies suggest that the renal proximal tubule is a site of injury in diabetic nephropathy (DN), and progressive renal tubulointerstitial fibrosis is an important mediator of progressive kidney dysfunction in DN. In this study, we observed increased expression and activation of YAP (yes-associated protein) in renal proximal tubule epithelial cells (RPTC) in patients with diabetes and in mouse kidneys. Inducible deletion of Yap specifically in RPTC or administration of the YAP inhibitor verteporfin significantly attenuated diabetic tubulointerstitial fibrosis. EGFR-dependent activation of RhoA/Rock and PI3K-Akt signals and their reciprocal interaction were upstream of proximal tubule YAP activation in diabetic kidneys. Production and release of CTGF in culture medium were significantly augmented in human embryonic kidney (HEK)-293 cells transfected with a constitutively active YAP mutant, and the conditioned medium collected from these cells activated and transduced fibroblasts into myofibroblasts. This study demonstrates that proximal tubule YAP-dependent paracrine mechanisms play an important role in diabetic interstitial fibrogenesis; therefore, targeting Hippo signaling may be a therapeutic strategy to prevent the development and progression of diabetic interstitial fibrogenesis.

BACKGROUND The purpose of this study was to use kinematic gait analysis, to evaluate the clinically curative effects of minimally invasive needle-knife scope therapy in the treatment of rheumatoid arthritis (RA) of the knee joint. METHODS A total of 32 patients with RA of the knee joint were treated with minimally invasive needle-knife scope therapy. All patients were assessed with a kinematic gait analysis system, and then analyzed and compared the measurements with the kinematic gait performances of 28 healthy middle-aged and elderly participants. RESULTS Before receiving the therapy, the ranges of motion (ROMs) of the patients' tibial inward and outward rotation, flexion and extension, anterior and posterior displacement of the tibia, and tibial upward and downward movement were all smaller than those of the healthy middle-aged and elderly group (P

BACKGROUND Patients with primary Sjogren's syndrome (pSS) often suffer from sleep disturbance. Studies suggest it may be related to symptoms, including xerostomia and dry eyes. Clinical studies have confirmed that hydroxychloroquine (HCQ) has a definite effect on pSS, but there is no clear report about its effect on sleep disorders in pSS patients. METHODS A total of 383 pSS patients were enrolled and followed up. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality of the patients, and the World Health Organization Quality of Life Brief Version (WHOQOL-BREF) scale was used to evaluate the quality of life (QoL) of patients. The European League assessed the patient's condition against Rheumatism Sjogren's syndrome patients reported index (ESSPRI). According to PSQI, patients were divided into two groups: good sleep group (GSG) and poor sleep group (PSG). The risk factors of sleep disorder are analyzed by univariate and multivariate analysis. The patients were further divided into HCQ-administered group and non-administered group, and the differences of baseline characteristics and outcome in follow-up between the two groups were compared. RESULTS There were 208 patients with PSG (54.3%) and 175 patients with GSG (45.7%). Further, there is no statistical difference between the two groups in baseline data. Also, there were 112 cases (53.8%) and 118 cases (67.4%) taking HCQ in the two groups, respectively, P=0.007. Univariate and multivariate analysis showed that long-term use of HCQ, menopause, and income were related to sleep quality. The patients were divided into the HCQ-administered group (n=230) and non-administered group (n=153) according to whether they took HCQ. One hundred eighteen patients (51.3%) in the HCQ-administered group had a good sleep, and 58 patients in the non- administered group had a good sleep (37.9%), P

Objective. To explore the optimal time points for deep brain stimulation (DBS) on the treatment of morphine addiction and its possible mechanisms by investigating how high-frequency stimulation (HFS) in bilateral nucleus accumbens (NAc) at different time points influences the addictive behaviors of rats with drug addiction. Methods. The rats were randomly divided into extinction stimulation group (n = 20) and postextinction stimulation group (n = 20). Ten rats in the extinction stimulation group were treated using 120 Hz HFS during extinction stage while another 10 rats with pseudostimulation were served as control group. The CPP scores were evaluated at the second day after intervention, with total 9 sections accomplished. The CPP scores were evaluated at the second day of the intervention. In the postextinction stimulation group, 120 Hz HFS was intervened during the postextinction stage in 10 experimental rats and pseudostimulation was performed in 10 control rats. Stimulation was performed for 7 days continuously, and a small dose of morphine was administrated to induce relapse after the postextinction period. Results. During the extinction phase, CPP scores after HFS were significantly higher. During the postextinction phase, relapse CPP scores after HFS were dramatically lower. Conclusion. HFS of bilateral NAc inhibits the extinction of addictive behavior during the extinction phase, and HFS during the postextinction period suppresses relapse of drug seeking behavior.

SUMMERY Shunt thrombosis remains a major cause of morbidity and mortality, especially during the initial palliation for single-ventricle physiology. The authors present evidence that the P2Y12 inhibitor cangrelor may fill a therapeutic void in thromboprophylaxis. They base this theory on results showing that platelets from neonatal patients with cyanotic congenital heart disease have a robust response to adenosine diphosphate and are amenable to P2Y12 inhibition with cangrelor. Unique to this study was their ability to establish drug efficacy in an avatar mouse model that permits the in vivo evaluation of human platelet–mediated thrombus formation illustrating that this P2Y12 inhibitor yields the intended biological response., Graphical abstract

Background. Stimulation-induced transient nonmotor psychiatric symptoms (STPSs) are side effects following bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD) patients. We designed algorithms which (1) determine the electrode contacts that induce STPSs and (2) provide a programming protocol to eliminate STPS and maintain the optimal motor functions. Our objective is to test the effectiveness of these algorithms. Materials and Methods. 454 PD patients who underwent programming sessions after STN-DBS implantations were retrospectively analyzed. Only STPS patients were enrolled. In these patients, the contacts inducing STPS were found and the programming protocol algorithms used. Results. Eleven patients were diagnosed with STPS. Of these patients, two had four episodes of crying, and two had four episodes of mirthful laughter. In one patient, two episodes of abnormal sense of spatial orientation were observed. Hallucination episodes were observed twice in one patient, while five patients recorded eight episodes of hypomania. There were no statistical differences between the UPDRS-III under the final stimulation parameter (without STPS) and previous optimum UPDRS-III under the STPSs (p=1.000). Conclusion. The flow diagram used for determining electrode contacts that induce STPS and the programming protocol employed in the treatment of these symptoms are effective.

Due to the complicated structure and control difficulties of the HTS-SMES equipment, it is necessary to design a real-time monitoring system which has perfect function, friendly interface and simple operation, so as to realize monitoring various electrical and non-electrical quantity. This paper mainly designed the monitoring interface and communication program based on LabVIEW. Among them, the monitoring system includes data acquisition, waveform display, control strategy and data storage. Finally, a set of HTS-SMES monitoring systems and equipment were developed and functional tests were carried out, the results show that the monitoring system can effectively detect the data of each channel, monitor and control two SMES device, implement multi-target control strategy, also meet the predetermined system functions.

Background Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury. Methods To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines. Results In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells. Conclusions These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.

The mandarin orange canning industry consumes a large quantity of fresh water, and discharges a similarly high volume of wastewater. If insufficiently treated, this effluent can seriously impact the environment. Water conservation and wastewater minimization can facilitate wastewater treatment. In this study, four filtration treatments were investigated to improve effluent quality from the sorting/grading operation at two mandarin canning factories for the purpose of water reclamation. The combined treatment consisting of a bag filter, activated carbon filter and precision filter yielded the best water quality improvement. The resulting elimination ratios for Chroma, turbidity, total sugars, pectin, and chemical oxygen demand were individually 27.64%, 55.56%, 22.55%, 21.35% and 42.22%. The treated water was clear and free of odor, and the pH was 6.7 ± 0.2. When the residual chlorine concentration was greater than 0.5 mg/L, the total bacterial count in the treated effluent was less than 10 CFU/mL and the coliform group was not detected. Further, the physicochemical and microbial parameters of the treated water conformed to the Chinese Standard of Drinking Water Quality except for chemical oxygen demand (38.60 ± 7.00 mg/L), which was mainly due to the saccharides in oranges. The results for the combined treatment of chlorination, bag filter and activated carbon filter at pilot scale indicated the feasibility of water reclamation during the sorting/grading step of full scale mandarin orange processing. At an average usage of 3500 t/d fresh water for a mandarin canning production line having a daily output of 100 metric tons, the water saving efficiency achieved with this combined treatment could reach 34.28%. A factory of this capacity can pay back the required investment for the treatment technology in the third production season, and will simultaneously save 373,840 Yuan. The cost-effective approach to water reclamation identified in this study minimized wastewater generation and facilitated clean production in a mandarin orange canning factory. The results indicate that a recycling process to enable water re-use can be implemented in food processing industries if it will not affect food safety. Such an approach to water management is beneficial to the coordinated and sustained development of economy, society, resources and environment.

Background KEYNOTE-181 (NCT02564263) was an open-label, randomized, phase 3 trial of pembrolizumab (pembro) vs investigator choice of single-agent paclitaxel/docetaxel/irinotecan (chemo) in advanced/metastatic esophageal AC or SCC. Pts were enrolled in partially overlapping periods, initially globally and then in China with an extension period. We present results from the global and China cohorts. Methods Pts were randomized 1:1 to receive pembro or chemo. Randomization was stratified by histology (SCC vs AC) and region (Asia vs rest of world). Primary end points were OS in the ITT, SCC, and PD-L1 CPS ≥10 populations. Results There were 628 and 123 pts in the global and China cohorts, respectively. In the global cohort, 314 pts were randomized to receive pembro (199 [63%] had SCC; 107 [34%] had CPS ≥10 tumors); 314 pts to chemo (204 [65%] had SCC; 115 [37%] had CPS ≥10 tumors). Median follow-up was 7.1 mo (pembro) vs 6.9 mo (chemo). Median OS with pembro vs chemo was similar in the ITT group (7.1 vs 7.1 mo) and longer in the SCC (8.2 vs 7.1 mo) and CPS ≥10 groups (9.3 vs 6.7 mo). 12-month OS rates were higher with pembro in all groups (ITT 32% vs 24%; SCC 39% vs 25%; CPS ≥10 42% vs 20%). In the China cohort, 62 pts were randomized to pembro (60 had SCC; 25 had CPS ≥10 tumors); and 61 pts to chemo (59 had SCC; 29 had CPS ≥10 tumors). Median follow-up was 8.3 mo (pembro) vs 5.6 mo (chemo). Median OS was higher with pembro in the ITT (8.4 vs 5.6 mo; HR 0.55; 95% CI 0.36-0.82), SCC (8.4 vs 5.6 mo; HR 0.55; 95% CI 0.37-0.83), and CPS ≥10 groups (12.0 vs 5.3 mo; HR 0.34; 95% CI 0.17-0.69). 12-month OS rates were higher with pembro in all groups (ITT 36% vs 17%; SCC 36% vs 16%; CPS ≥10 53% vs 16%). Fewer pts had TRAEs with pembro than chemo (global 64% vs 86%; China 76% vs 83%). TRAE rates resulting in discontinuation with pembro vs chemo were comparable in the global cohort (6% each) and lower with pembro in the China cohort (6% vs 12%). Conclusions Pembro and chemo showed comparable OS as 2L therapy for esophageal AC/SCC in the global ITT cohort. Pembro showed favorable OS in SCC and CPS ≥10 groups in the global cohort and in all groups in the China cohort, in which most patients had SCC. Pembro showed favorable safety in both cohorts. Clinical trial identification NCT02564263. Editorial acknowledgement Medical writing and/or editorial assistance was provided by Traci Stuve, MA, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure S-B. Kim: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sanofi-Aventis; Research grant / Funding (institution): Kyowa-Kirin; Research grant / Funding (institution): DongKook Pharmaceutical. T. Doi: Advisory / Consultancy: Kyowa Hakko Kirin, MSD, Daiichi Sankyo, Amgen, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, AbbVie, Novartis, Bayer; Research grant / Funding (institution): Taiho Pharmaceutical, Novartis, Merck Serono, MSD, Boehringer Ingelheim, Pfizer, Lilly Japan, Sumitomo Group, Kyowa Hakko Kirin, Daiichi Sankyo, Bristol-Myers Squibb, AbbVie, Quintiles, Eisai. K. Kato: Research grant / Funding (institution): MSD, ONO Pharmaceutical, Shionogi, Merck Serono. M. Shah: Research grant / Funding (institution): Merck, Roche, Boston Biomedical. A. Adenis: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier. T. Kojima: Non-remunerated activity/ies, Other- Patents, Royalties, other Intellectual Property: Ono Pharmaceutical, MSD, Shionogi Pharma, Oncolys BioPharma, Astellas Amgen BioPharama; Honoraria (self): Oncolys BioPharma. J-P. Metges: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck; Honoraria (self): Bayer-Health; Honoraria (self): Lilly; Advisory / Consultancy: ERYTECH Pharma; Advisory / Consultancy: Sanofi. E. Francois: Research grant / Funding (institution): MSD; Non-remunerated activity/ies, +Personal Fees: Roche; Non-remunerated activity/ies, +Personal Fees: Servier; Non-remunerated activity/ies, +Personal Fees: Merck; Non-remunerated activity/ies, +Personal Fees: Amgen; Non-remunerated activity/ies, +Personal Fees: Sanofi; Non-remunerated activity/ies, +Personal Fees: Novartis; Non-remunerated activity/ies, +Personal Fees: Bayer. K. Muro: Honoraria (self): Takeda, Chugai Pharma, Yakult Honsha, Merck Serono, Taiho Pharmaceutical, Lilly, Ono Pharmaceutical, Bayer; Research grant / Funding (institution): Ono Pharmaceutical, MSD, Daiichi Sankyo, Shionogi, Kyowa Hakko Kirin, Gilead Sciences, Merck Serono, Pfizer, Sanofi. R. Wang: Full / Part-time employment: Merck & Co., Inc. Y. Cui: Full / Part-time employment: MSD China. P. Bhagia: Full / Part-time employment: Merck & Co., Inc. All other authors have declared no conflicts of interest.

This paper investigates influences of internal ion channel fluctuations and external synaptic noise on the spatiotemporal dynamics of an excitatory Erdos-Renyi neuronal network. The impact of stochastic coupling between pre- and post-synaptic neurons in the network is also studied. First, we show that channel noise induces a spatiotemporal coherence resonance for a moderate-sized membrane, which is further enhanced with the increase of the strength and probability of the connections. Second, in networks with low connectivity probabilities, the presence of an external synaptic noise to each neuron, in addition to internal channel noise, further increases the channel noise-induced spatiotemporal coherence (CNI-STC). However, in networks with high probability of connections, the CNI-STC characterized by the coherence measure of firing spikes, the variability of interspike interval, as well as the mean power, remains almost unchanged to the external noise perturbation. Finally, comparing the effects of channel fluctuations with external synaptic noise has revealed several key features: in a dense network, population dynamics described by the population firing rate, the coherence measure, and the mean power, is highly susceptible to channel fluctuations, while it is relatively robust to external noise. Furthermore, in a sparse network, the external synaptic noise alone is sufficient to induce a stronger spatiotemporal coherence resonance but a lower population firing rate, in comparison to the phenomena in the presence of both intrinsic and extrinsic noises. The mechanisms of the above phenomena are explained from the interaction of intrinsic dynamics which is controlled by channel fluctuations and network topology with external synaptic noise.

This research intended to explore the effect of FLNA on cell proliferation, invasion and migration in bladder carcinoma (BC). Microarray analysis was performed with the TCGA data, and the results were confirmed on 20 paired BC tissues and adjacent tissues using qRT-PCR and immunohistochemistry. Transmission electron microscope (TEM) and cell fluorescence assay were used to observe the quantity of autophagosomes. The expression of autophagy-related protein (LC3-I/II, p62) was detected by western blot. Cell proliferation was detected using CCK-8 and colony formation. The invasion and migration ability of the cell were tested by transwell and wound-healing assay. Tumor xenograft in BALB/c nude mice and HE staining were utilized to probe into the effects of FLNA-induced regulation of volume, weight and metastasis of tumors. We confirmed that FLNA was down-regulated in BC tissues. TEM and fluorescence analysis proved that FLNA overexpression promoted autophagy in BC cells. Colony formation assay and CCK-8 experiment showed that FLNA overexpression suppressed the proliferation of BC cells. In addition, FLNA blocked cell cycle and promoted apoptosis of BC cell. Transwell assay and wound-healing assay further proved that FLNA suppressed invasion and migration ability in BC cell. Meanwhile, in vivo study indicated that FLNA inhibited the tumor growth. Overexpression of FLNA suppressed the proliferation, migration and invasion of the BC cell, suggesting the potential role of FLNA in clinical treatment.

The purpose of the present study was to investigate whether genetic variants that influence angiogenesis and sorafenib pharmacokinetics are associated with clinical outcomes and toxic effects in advanced renal cell carcinoma patients treated with this drug. One hundred patients with advanced renal cell carcinoma were enrolled. Forty-two polymorphisms in 15 genes were selected for genotyping and analyzed for associations with progression-free survival, overall survival and toxic effects. We found that rs1570360 in VEGF and rs2239702 in VEGFR2 were significantly associated with progression-free. Specifically, patients carrying the variant genotypes (AG + AA) of these two polymorphisms both had an unfavorable progression-free. In addition, compared with those with the rs2239702 GG genotype, patients with the AG + AA genotype suffered an unfavorable OS. We found that the VEGF rs2010963 CG + GG genotypes had a significantly increased risk of hand-foot syndrome and the ABCB1 rs1045642 CT + TT genotypes had an increased risk of high blood pressure. Our results suggest that polymorphisms in VEGF and VEGFR2 are associated with sorafenib clinical outcomes and polymorphisms in VEGF and ABCB1 are associated with sorafenib-related toxicities. Larger studies are warranted to validate our findings.

CYR61 (cysteine-rich protein 61, also named IGFBP10) is a secreted signaling molecule that promotes angiogenesis and tumor growth. The goal of this study is to determine whether a functional polymorphism in the promoter region of the CYR61 gene (rs3753793) is associated with prostate cancer (PCa) risk and gene expression in Chinese patients.A total of 665 patients diagnosed with PCa and 703 cancer-free controls were genotyped in this hospital-based case-control study, and 26 PCa tissue samples were evaluated for mRNA expression of CYR61 by real-time quantitative reverse-transcription PCR.Men carrying the G allele of rs3753793 (TG+GG) had significantly lower risk of PCa when compared with the TT genotype (odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.61-0.95). The association was generally more pronounced among subgroups of PCa patients with advanced stage (OR = 0.70, 95% CI = 0.53-0.94), Gleason score7 (OR = 0.63, 95% CI = 0.46-0.86) and PSA20 ng ml(-1) (OR = 0.68, 95% CI = 0.53-0.88). Prostate tumors derived from cases with the GT/GG genotypes had significantly lower levels of CYR61 mRNA when compared with cases with the TT genotypes (P = 0.02).Our results indicate that the genetic variation of rs3753793 in the CYR61 promoter may contribute to genetic predisposition to PCa and intra-tumor expression gene expression.

Background The von Hippel–Lindau (VHL) tumor suppressor gene and hypoxia-inducible factor-1α (HIF1A) play a pivotal role in renal carcinogenesis. This study was aimed to clarify the influence of VHL and HIF1A polymorphisms on renal cell cancer (RCC) susceptibility and survival. Subjects and methods We genotyped four potentially functional single-nucleotide polymorphisms (rs779805 in VHL and rs11549465, rs11549467, and rs2057482 in HIF1A) and assessed their associations with RCC risk, clinicopathologic parameters in a case–control study of 620 patients and 623 controls, and the prognosis of RCC in a cohort of 311 patients. Results No significant differences in VHL or HIF1A genotypes were observed between RCC cases and controls. However, individuals with ≥2 variant alleles of the four polymorphisms were associated with less frequent lymph node metastasis and lower clinical stage (P = 0.032 and P = 0.041, respectively). And the number of variant alleles was associated with improved survival in a dose–response manner (Ptrend = 0.013). Furthermore, multivariate Cox regression analysis showed that the number of variant alleles (≥1 versus 0) was an independent prognostic factor for RCC survival (P = 0.036) together with clinical stage and tumor grade. Conclusion The VHL and HIF1A polymorphisms may not influence RCC susceptibility but may jointly influence RCC progression and survival.

The molecular mechanisms underlying renal growth and renal growth-induced nephron damage remain poorly understood. Here, we report that in murine models, deletion of the tuberous sclerosis complex protein 1 (Tsc1) in renal proximal tubules induced strikingly enlarged kidneys, with minimal cystogenesis and occasional microscopic tumorigenesis. Signaling studies revealed hyperphosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and increased phosphorylation of ribosomal protein S6 (rpS6) in activated renal tubules. Notably, knockin of a nonphosphorylatable rpS6 in these Tsc1-mutant mice exacerbated cystogenesis and caused drastic nephron damage and renal fibrosis, leading to kidney failure and a premature death rate of 67% by 9 weeks of age. In contrast, Tsc1 single-mutant mice were all alive and had far fewer renal cysts at this age. Mechanistic studies revealed persistent activation of mammalian target of rapamycin complex 1 (mTORC1) signaling causing hyperphosphorylation and consequent accumulation of 4E-BP1, along with greater cell proliferation, in the renal tubules of Tsc1 and rpS6 double-mutant mice. Furthermore, pharmacologic treatment of Tsc1 single-mutant mice with rapamycin reduced hyperphosphorylation and accumulation of 4E-BP1 but also inhibited phosphorylation of rpS6. Rapamycin also exacerbated cystic and fibrotic lesions and impaired kidney function in these mice, consequently leading to a premature death rate of 40% within 2 weeks of treatment, despite destroying tumors and decreasing kidney size. These findings indicate that Tsc1 prevents aberrant renal growth and tumorigenesis by inhibiting mTORC1 signaling, whereas phosphorylated rpS6 suppresses cystogenesis and fibrosis in Tsc1-deleted kidneys.

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, but whether the neurodegenerative process influences the pharmacodynamics of propofol remains unclear. We aimed to evaluate the effect of PD on pharmacodynamics of propofol. A total of 31 PD patients undergoing surgical treatment (PD group) and 31 pair-controlled non-PD patients undergoing intracranial surgery (NPD group) were recruited to investigate the propofol requirement for unconsciousness induction. Unconsciousness was induced in all patients with target-controlled infusion of propofol. The propofol concentration at which unconsciousness was induced was compared between the two groups. EC50and EC95were calculated as well. Demographic data, bispectral index, and hemodynamic values were comparable between PD and NPD groups. The mean target concentration of propofol when unconsciousness was achieved was 2.32 ± 0.38 μg/mL in PD group, which was significantly lower than that in NPD group (2.90 ± 0.35 μg/mL). The EC50was 2.05 μg/mL (95% CI: 1.85–2.19 μg/mL) in PD group, much lower than the 2.72 μg/mL (95% CI: 2.53–2.88 μg/mL) in NPD group. In conclusion, the effective propofol concentration needed for induction of unconsciousness in 50% of patients is reduced in PD patients. (This trial is registered withNCT01998204.)

Diabetic nephropathy (DN) is one of the most important complications of diabetes mellitus (DM), and it continues to rank as the leading cause of end-stage renal disease (ESRD) in the U.S. In our recently published manuscript, both in vitro and in vivo data showed that in response to high glucose, YAP expression and activation in renal proximal tubule epithelial cells were upregulated through activation of an EGFR- PI3K-Akt-CREB dependent pathway and subsequent activation of CTGF and AREG gene expression. The existence of crosstalk between EGFR and Hippo signaling pathway in diabetic kidney indicates the Hippo pathway may serve as an alternative novel therapeutic target of DN treatment.

With the development of society and new epoch, more and more multi-campus universities come out. Many colleges and universities have more than one campus because of merging of universities and construction of university's new campus. And this has caused a series of problems. The problem about multi-campus has become a key research field in the development of higher education. It has a great effect on sustainable development of higher education in China. At present, people focus on the study of management question fundamental research about multi-campus. This article tries to analyze how to achieve good teaching quality as a teacher in multi-campus education according to the basic principles of education and teaching. College teacher should pay attention to the phenomenon inwardly, and try to put into practice. And college teacher should also adopt flexible and various teaching methods according to the ideological level and learning ability of students and the learning environment in different campus. Good teaching quality would be achieved in different multi-campus.

Background— In vivo testing of novel antiplatelet agents requires informative biomarkers. By genetically modifying mouse von Willebrand factor (VWF R1326H ), we have developed a small animal model that supports human but not mouse platelet-mediated thrombosis. Here, we evaluate the use of this biological platform as a pharmacodynamic biomarker for antithrombotic therapies. Methods and Results— The antithrombotic effects of several αIIbβ3 inhibitors were determined in VWF R1326H mutant mice infused with human platelets. Administration of abciximab, eptifibatide, or tirofiban at doses recommended for percutaneous coronary intervention (per 1 kg of body weight) significantly reduced human platelet-mediated thrombus formation in laser-injured arterioles by >75% ( P P >0.05), results consistent with observed species differences in IC 50 values obtained by aggregometry. To further demonstrate that our biological platform is unique among standard mouse models, we evaluated the thrombogenic potential of platelets from healthy volunteers before and after clopidogrel therapy. Consistent with the antithrombotic effect of this agent, platelets postdrug administration formed smaller thrombi than cells before therapy and were less responsive to ADP-induced aggregation ( P Conclusions— The ability of αIIbβ3 and P2Y 12 inhibitors to limit human platelet clot formation at doses recommended by the American College of Cardiology/American Heart Association suggests that VWF R1326H mutant mice can serve as both a pharmacodynamic and a functional response biomarker, attributes essential for not only expediting drug development but also designing clinical studies.

Efficient railway management requires up-to-date and locally relevant decision support tools. In this paper, a primary integration method using Geographical Information Systems (GIS) is proposed. The results show that GIS can be used effectively to approach complex problems for the management of railway infrastructure. The potential benefits obtained will be significant.