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The second-generation antidepressants (SGAs) are used widely in patients with Alzheimer's disease (AD) for the treatment of mood disorder, sleep disturbance and psychiatric symptoms. Several evidences from AD mice confirmed that antidepressants could delaying cognitive decline. However, the conclusions varied in randomized controlled trials (RCTs) based on patients. This meta-analysis summarizes the cognitive impact of SGAs on AD patients with different neuropsychiatric symptoms (NPS). Results show there is no effect on cognition and depression between SGAs treatment and controls, and this remains in subgroups analyses of duration of medication (12 weeks or ≥12 weeks), drug classes (SSRIs or non-SSRIs), combination with anti-dementia medication, various NPS, and degree of AD. The available evidence provides no support for the efficacy of SGAs for cognition and depression of AD patients. The implications of the findings and their mechanism relevance are also discussed in this paper.

Prostate cancer (PCa) is a leading adult malignant tumor. Recent research has shown that speckle-type BTB/POZ protein (SPOP) mutant is the top frequently mutated gene in PCa, which makes it an important biomarker. In this paper, we aimed at identifying critical genes and pathways related to SPOP mutation in PCa. Recent The Cancer Genome Atlas data showed that 12% of patients with PCa were SPOP mutant. There were 1,570 differentially expressed genes, and online enrichment analysis showed that these genes were mainly enriched in metabolism, pathways in cancer and reactive oxygen species. INS, GNG13, IL6, HTR5A, SAA1, PPY, CXCR5, CXCL13, CD19 and CCL20 were identified as hub genes. The lower SPOP expression level was associated with poor prognosis. In all, our findings showed that various pathways and genes could play critical roles in SPOP mutation in PCa, providing potential options for individualized treatment.

Chalkboard erasers that are commonly used in many schools and education organizations have the poor ability in removing the dust off the chalkboard and collect them. The dust that is not collected will be taken into human bodies via inhalation, which will lead to respiratory diseases. Therefore, it is crucial to design a chalkboard eraser that can collect the dust effectively. If the eraser can be controlled both remotely and manually by people, it can further reduce the amount of dust taken in by human bodies. To achieve remote control, a micro-controller is needed to transfer the infrared radiation (IR) into signals that can control electric motors to move around on the chalkboard. Furthermore, the microfiber is also used as the cleaning material to improve the performance of dust cleaning and collecting. A vacuum pump is needed to create negative pressure between the eraser and the chalkboard so that the eraser can stick to it. The result shows a stronger ability in removing and collecting dust. With the help of the Arduino UNO board, the remote control is successfully achieved, and the eraser can move on the chalkboard freely according to the order.

Combination immunotherapy is a promising strategy to remove the inhibitory effect of the tumor microenvironment on immune effector cells, improving the efficacy of immune checkpoint inhibitor treatment in bladder cancer. However, it is challenging to deliver multiple drugs to the tumor tissue effectively and simultaneously to ensure optimal therapeutic effects. Macrophage-derived exosome-mimetic nanovesicles (EMVs) were designed and validated as a nanoplatform for coloading and delivery of the CD73 inhibitor (AB680) and the monoclonal antibody to programmed cell death ligand 1 (aPDL1). The tumor-targeting, biosafety, and therapeutic effects of these nanocomplexes (AB680@EMVs-aPDL1), as a combined immunotherapy strategy for bladder cancer, were assessed in vitro and in vivo. Our results indicate that the nanodrug system was highly stable, provided adequate biosafety, and enhanced tumor targeting in a mouse model of bladder cancer. Moreover, the CD73 inhibitor reduced extracellular adenosine production, and the combination therapy significantly promoted the activation and infiltration of cytotoxic T-lymphocytes, which helped to optimally suppress tumor growth and extend median survival in vivo. Therefore, using EMVs to deliver a combination of aPDL1 and the CD73 inhibitor may be a useful combined immunotherapy strategy for treating bladder cancer.

We aimed to explore whether chronic psychological stress affects the efficacy of immune checkpoint inhibitors (ICIs) immunotherapy in bladder cancer. The chronic unpredictable mild stress (CUMS) process was applied during the administration of anti-PD-L1 for subcutaneous tumors in mice. Tumor regression was obviously shown in anti-PD-L1 therapy groups, while this effect was notably attenuated by CUMS. Additionally, increased infiltration of regulatory T-cells, decreased amount of CD8+ lymphocytes, and reduced levels of tumor-associated cytokines in tumor sites were observed in mice treated with anti-PD-L1 under CUMS. Therefore, chronic psychological stress could weaken the potency of anti-PD-L1 immunotherapy for bladder cancer.

BackgroundThe tumor microenvironment in bladder cancer exerts an inhibitory effect on immune effector cells. Thus, removing this inhibitory effect could help improve the efficacy of immune checkpoint inhibitors, and combination immunotherapy is a promising strategy for increasing the proportion of patients with bladder cancer who benefit from immune checkpoint inhibitors. However, it is difficult to effectively and simultaneously deliver multiple drugs to the tumor tissue. In this study, we describe the design and in vivo validation of macrophage-derived exosome-mimetic nanovesicles (EMVs) as a nanoplatform for coloading and targeted delivery of a CD73 inhibitor (AB680) and monoclonal antibodies targeting programmed cell death ligand 1 (aPDL1). ResultsOur results indicated that these nanocomplexes (AB680@EMVs-aPDL1) were highly stable, provided adequate biosafety in vivo, and exhibited enhanced targeting in a mouse model of bladder cancer. Moreover, the CD73 inhibitor reduced extracellular adenosine production, and the combination therapy significantly promoted activation of cytotoxic T lymphocytes, resulting in suppression of tumor growth in vivo. ConclusionsTherefore, using EMVs to deliver a combination of aPDL1 and a CD73 inhibitor may be an effective combined immunotherapy strategy for treating bladder cancer.

Objective The primary aim was to evaluate the influence of depressive and anxiety symptoms on the 1-year recurrence rate of non-muscle invasive bladder cancer (NMIBC) patients. The secondary aim was to examine the risk factors leading to psychological distress.Methods A total of 104 NMIBC patients were enrolled for interviews, and the Hospital Anxiety and Depression Scale (HADS) questionnaire survey was administered 1 month after their operation. Their cystoscopy results were followed up. The risk factors affecting their 1-year recurrence rate were evaluated through univariate analysis, Cox regression and Kaplan-Meier analysis. The risk factors causing depressive and anxiety symptoms were evaluated through univariate analysis and logistic regression.Results In addition to American Urological Association risk stratification, depressive symptoms were another independent risk factor for recurrence in NMIBC patients (HR: 2.493, 95% CI: 1.048–5.930, p=0.039), and the increase in the recurrence rate was highly significant in intermediate-risk patients (HR: 8.496, 95% CI: 2.178–33.138, p=0.019). Anxiety symptoms were not an independent risk factor for recurrence (HR: 1.655, 95% CI: 0.714–3.837, p=0.240). We also observed that the burden of medical expenses of NMIBC on the family was an independent risk factor for depressive symptoms (p=0.029) and anxiety symptoms (p=0.048); chronic pain was an independent risk factor for anxiety symptoms (OR: 3.447, 95% CI: 1.182–10.052, p=0.023).Conclusion Depression symptoms are an independent risk factor for recurrence in NMIBC patients. Moreover, the burden of medical expenses on the family is an independent risk factor for depressive and anxiety symptoms in NMIBC patients. Additionally, chronic pain is a risk factor for anxiety symptoms in NMIBC patients. This study provided a theoretical foundation for clinical oncologists to pay more attention to the mental health of NMIBC patients.

Depression is a common mental disease in bladder cancer patients, leading to a loss of happiness, an increase in the suicide rate, and higher mortality. However, the influence of depression on bladder tumor tissue remains unknown. In this current study, a subcutaneous bladder cancer xenograft model was established on male C57 mice with mouse bladder cell line MB49. Chronic unpredictable mild stress (CUMS) was established to simulate depression in bladder cancer patients. The depression caused by CUMS was confirmed by testing sucrose preference and plasma cortisol and adrenocorticotropic hormone (ACTH) levels. Then, we measured and weighed tumors to demonstrate the promotion of tumor growth by CUMS. Immune-related cells and molecules were examined to reveal the mechanism. There is a significant decrease of CD8+/CD4+T cells ratio, NK cells, IL-2, and IFN-γ and a significant increase of T regs, IL-6, IL-1β, TNF-α, IL-10, and PGE2 in CUMS group, indicating the inhibition of immunity in the tumor microenvironment. Our results supported the perspective that depression exacerbated bladder cancer and revealed a possible mechanism. We suggest attaching importance to the psychological health of bladder cancer patients to prevent a worse prognosis induced by depression.

Qidong Zhou,1,2 Weihong Ding,1,2 Zhiyu Qian,1,2 Guangliang Jiang,3 Chuanyu Sun,1,2 Ke Xu1,2 1Department of Urology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Urology, Ruijin Hospital, Medical School of Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaCorrespondence: Ke XuDepartment of Urology, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai 200040, People’s Republic of ChinaTel/Fax +86 21 52887080Email drkexu@163.comObjective: Chronic psychological stress is common in patients with bladder cancer. An increasing number of evidence demonstrated that psychiatric disorder leads to worse prognostic outcomes in bladder cancer. This study was to investigate the effects of chronic psychological stress on the growth of bladder cancer and its potential mechanisms.Methods: A xenograft mouse model was established by subcutaneously implanting the human bladder cancer cell line T24 into nude mice. All of the tumor-bearing mice (N=20) were randomly separated into two groups. Mice in the control group were subjected to normal feeding conditions, while in another group, a chronic unpredictable mild stress (CUMS) model was established, in which mice were exposed to various types of stressors. Various analyses were performed on parameters including the tumor volume, tumor weight, expression of Caspase-3 and VEGF, proportion of Ki-67 positive cells (Ki-67 index), microvessel density (MVD) and serum concentrations of epinephrine and cortisol.Results: In the CUMS group, the growth of transplanted tumors was distinctly accelerated, with the weight of removed tumors at the end of experiment increased by 34.07% compared to that of the control. Serum levels of epinephrine and cortisol determined by ELISA were significantly increased by CUMS. Immunohistochemistry and Western blot analysis showed that the expression of Caspase-3 was downregulated, whereas the expression of VEGF was upregulated in the CUMS group. Meanwhile, CUMS could increase the Ki-67 index and MVD.Conclusion: Our research supports the hypothesis that CUMS could affect the growth of bladder cancer in nude mice, indicating that the intervention of chronic psychological stress may be a possible therapeutic strategy for bladder cancer.Keywords: bladder cancer, chronic unpredictable mild stress, tumor growth, cell proliferation, angiogenesis

Aim: BAP1 is frequently mutated in clear cell renal cell carcinoma (ccRCC) with a definitive role still unclear. Methods: In silico analysis of BAP1-mutant and wild-type gene enrichment and functional annotation in TCGA-KIRC dataset was performed. Target gene was studied based on functional clustering and was knowledge-based. Validation using in-house pathological sections were performed immunohistochemically. In vitro and in vivo studies on target gene were performed. Results: The TCGA ccRCC dataset included 534 ccRCC samples. BAP1 was frequently mutated and more frequently downregulated in ccRCC compared to normal kidney tissue or benign renal tumors. In the analysis between samples with BAP1 mutation (N = 33) and pan-negative (N = 33), we found that cancers with BAP1 mutation was significantly enriched for 14 pathways, of which 3 were DNA repair pathways, in which EZH2 played a role. CcRCC patients with lower BAP1 expression had poor prognosis and showed higher EZH2 expression, which also conferred worsened survival. Genetic and pharmaceutical inhibition of EZH2 not only inhibited BAP1-mutatn ccRCC cell viability and invasion but also abrogated genetic replenishing of BAP1 expression. Validation cohort encompassing 62 ccRCC samples confirmed the worsened phenotype for cases with higher EZH2 expression and significant positive correlation between expressions of EZH2 and BAP1. EZH2 inhibitor also inhibited tumor growth in xenograft mouse model with BAP1-mutated ccRCC cells with unremarkable toxicity. Conclusion: CcRCC with decreased BAP1 level has poor prognosis and is associated with higher EZH2 expression. Inhibition of EZH2 in BAP1-mutated entity holds promise for further investigation.

Objectives: To analyze the correlation between pharmacogenomic biomarkers and the efficacy of pirarubicin (THP, also named 4’-O-tetrahydropyranyl-adriamycin) and to explore potential associations of individual genetic backgrounds with the clinical outcomes of non-muscle-invasive bladder cancer (NMIBC) patients. Methods: Between July 2003 and June 2011, a total of 91 patients were treated with transurethral resection (TUR) of the bladder tumor and were histopathologically confirmed to have NMIBC. Patients received an immediate instillation and maintenance therapy with THP. All patients underwent follow-up for recurrence. We genotyped 13 single nucleotide polymorphisms (SNPs) from blood and saliva DNA samples of all patients. Results: The associations of patients’ genotypes with tumor recurrence risks were analyzed by survival analysis. A total of 16 (17.6%) of the 91 patients with NMIBC had tumor recurrences with a median follow-up of 17 months (range, 2–83 months). We confirmed the effect of the European Organization for Research and Treatment of Cancer (EORTC) risk score for predicting tumor recurrence (p = 0.002, log-rank test). We adjusted for the EORTC score and found that 2 SNPs, NOS3 895G>T (rs1799983) (p = 0.02, HR = 4.32, 95% CI, 1.30–14.39, GT+TT vs. GG) and CBR3 730G>A (rs1056892) (p = 0.04, HR = 2.57, 95% CI, 1.07–6.18, GA+AA vs. GG), were significantly associated with a higher recurrence risk after TUR and instillations of THP in NMIBC patients. Conclusions: Our results suggest that NOS3 895G>T and CBR3 730G>A are genetic markers that can be used to predict tumor recurrence in NMIBC patients receiving intravesical instillations of THP. The effects of those 2 SNPs are independent of the EORTC scores. Further studies with larger sample sizes and longer follow-ups are needed to confirm our results.

A simple self-assembly photochemical reduction method has been proposed to prepare highly photocatalytic TiO 2 nanowire/g-C 3 N 4 nanosheet/graphene heterostructures (TiO 2 /g-C 3 N 4 /G). In this hybrid structure, graphene enhances the charge transportation during photocatalytic process, and TiO 2 nanowires prevent graphene and g-C 3 N 4 from restacking. Meanwhile, g-C 3 N 4 with a more suitable band gap, extends the adsorption edge of the TiO 2 /g-C 3 N 4 /G composite to visual-region. Benefiting from the positive synergetic effect, 97% of nitrobenzene can be selectively reduced within 4 h by using TiO 2 /g-C 3 N 4 /G as the photocatalyst. The TiO 2 /g-C 3 N 4 /G composite with 3D structure demonstrates a great potential in selective oxidation and reduction of organics for the synthesis of high added-value organic compounds.

Prostate cancer is the most common malignancy in men in developed countries. Overexpression of enhancer of zeste homolog 2 (EZH2), the major histone H3 lysine 27 methyltransferase, has been connected to prostate cancer malignancy. However, its downstream genes and pathways have not been well established. Here, we show tumor suppressor Hepatocyte Nuclear Factor 1β (HNF1B) as a direct downstream target of EZH2. EZH2 binds HNF1B locus and suppresses HNF1B expression in prostate cancer cell lines, which is further supported by the reverse correlation between EZH2 and HNF1B expression in clinical samples. Consistently, restored HNF1B expression significantly suppresses EZH2-mediated overgrowth and EMT processes, including migration and invasion of prostate cancer cell lines. Mechanistically, we find that HNF1B primarily binds the promoters of thousands of target genes, and differentially regulates the expression of 876 genes. We also identify RBBP7/RbAP46 as a HNF1B interacting protein which is required for HNF1B-mediated repression of SLUG expression and EMT process. Importantly, we find that higher HNF1B expression strongly predicts better prognosis of prostate cancer, alone or together with lower EZH2 expression. Taken together, we have established a previously underappreciated axis of EZH2-HNF1B-SLUG in prostate cancer, and also provide evidence supporting HNF1B as a potential prognosis marker for metastatic prostate cancer.

Epithelial-mesenchymal transition (EMT) was reported to have an important effect on malignant metastasis; however, it remained largely unknown if EMT marker expression of neoplastic tissue had predictive value for prognosis of prostate cancer.We searched for published studies which measured EMT marker expression and analyzed its association with clinical outcomes of patients after Radical Prostatectomy (RP). We reviewed and pooled-analyzed the association of EMT marker expression and biochemical recurrence-free survival (BFS), as well as the difference in strong or weak expression of EMT markers in tumors of high Gleason score (≥8).A total of 25 studies with 14 EMT markers were included for review and meta-analysis. Only mesenchymal markers of N-cadherin, snail, twist, vimentin, and slug seemed to be significantly associated with decreased BFS in strongly expressed patients. Weak expression of epithelial markers (E-cadherin and α-catenin) and strong expression of mesenchymal markers (N-cadherin, snail, twist, and vimentin) seemed to be more frequent in tumors of Gleason ≥8.Strong expression of mesenchymal markers (N-cadherin, snail, twist, and vimentin) seemed to have significant predictive value for decreased BFS in patients after RP.

To analyze the correlation between pharmacogenomic biomarkers and the efficacy of pirarubicin (THP, also named 4'-O-tetrahydropyranyl-adriamycin) and to explore potential associations of individual genetic backgrounds with the clinical outcomes of non-muscle-invasive bladder cancer (NMIBC) patients.Between July 2003 and June 2011, a total of 91 patients were treated with transurethral resection (TUR) of the bladder tumor and were histopathologically confirmed to have NMIBC. Patients received an immediate instillation and maintenance therapy with THP. All patients underwent follow-up for recurrence. We genotyped 13 single nucleotide polymorphisms (SNPs) from blood and saliva DNA samples of all patients.The associations of patients' genotypes with tumor recurrence risks were analyzed by survival analysis. A total of 16 (17.6%) of the 91 patients with NMIBC had tumor recurrences with a median follow-up of 17 months (range, 2-83 months). We confirmed the effect of the European Organization for Research and Treatment of Cancer (EORTC) risk score for predicting tumor recurrence (p = 0.002, log-rank test). We adjusted for the EORTC score and found that 2 SNPs, NOS3 895GT (rs1799983) (p = 0.02, HR = 4.32, 95% CI, 1.30-14.39, GT+TT vs. GG) and CBR3 730GA (rs1056892) (p = 0.04, HR = 2.57, 95% CI, 1.07-6.18, GA+AA vs. GG), were significantly associated with a higher recurrence risk after TUR and instillations of THP in NMIBC patients.Our results suggest that NOS3 895GT and CBR3 730GA are genetic markers that can be used to predict tumor recurrence in NMIBC patients receiving intravesical instillations of THP. The effects of those 2 SNPs are independent of the EORTC scores. Further studies with larger sample sizes and longer follow-ups are needed to confirm our results.

Designing a discriminative speed function plays a vital role in conducting contour evolution in level set-based tracking framework. In this work, we propose a superpixel-driven speed function modeling method by fusion of two supplementary cues: appearance and motion. Based on kernel density estimation, a discriminative model separating object from background is constructed in appearance channel. Meanwhile, by making use of the statistical characteristics of the optical flow field, the relative motion between object and background can be distinguished and enhanced by an adaptively chosen threshold. Finally, we combine these two cues in a decision level to propose a speed function with more discriminative power under the Semi-Naive Bayes framework. Experimental results on a number of challenging video sequences demonstrate the effectiveness and robustness of the proposed tracking methods.

In this paper, we propose a human tracking method by fusion of the scene information for underground coal mines environment, which aims to improve the tracking accuracy and robustness in the presence of complicated factors (e.g. low illumination and low intensity contrast, bright spots and shadow disturbance). For object detection, in order to decrease the influence of bright spots, we present a pixel-to-region hierarchical bright spots removing criterion by fusion of the learned background model priors. Moreover, within the particle filtering tracking framework, we propose a novel particle weight calculation method, which adopts the nonparametric kernel density estimation method to evaluate the likelihoods of each particle belonging to the object and the background, respectively. The final tracking results are refined based on a shadow removing mechanism by making use of the background priors. Experimental results on several real underground coal mine video sequences demonstrate the effectiveness and robustness of our tracking method.

Collider experiment is an efficient way to verify and improve the hadronic interaction models. Abundant of energy flow in the forward region of the collisions are believed to have large influence to the development of air-shower. LHCf is the experiment dedicate to verify the models by measuring the forward neutral particle production at the LHC. According to the LHCf results, no simulation model can predict the LHCf data perfectly. Thus, it is necessary to classify the LHCf observables into specific interaction types; diffraction and non-diffraction. Several Monte Carlo simulation samples in p-p collisions at $\sqrt{s}$ = 13 TeV were analyzed for studying the presence of differences among specific interaction types on the LHCf observables. Combining the information of ATLAS, LHCf can identify these specific interaction types experimentally, especially, the low mass diffraction. LHCf and ATLAS have succeed the common data-taking in p-p collisions at $\sqrt{s}$ = 13 TeV. The recent joint analysis result will be reported.