Codelivery of ERCC2 small interfering RNA and cisplatin with macrophage-derived mimetic nanovesicles for enhanced bladder cancer treatment.

Cisplatin-based chemotherapy plays a vital role in the management of muscle-invasive bladder cancer (MIBC); however, off-tumor toxicity and resistance often lead to cancer recurrence and eventual treatment failure. The loss of function of the nucleotide excision repair gene excision repair cross-complementing rodent repair deficiency gene 2 ( ERCC2 ) in cancer cells correlates with sensitivity to cisplatin, while its overexpression causes cisplatin resistance. Small interfering RNA (siRNA) knockdown of ERCC2 combined with cisplatin treatment may improve therapeutic outcomes in patients with bladder cancer. Here, we aimed to develop macrophage-derived mimetic nanovesicles (MNVs) as a nanoplatform for the simultaneous delivery of cisplatin and ERCC2 siRNA for enhancing the efficacy of bladder cancer chemotherapy. The cellular uptake, gene down-regulation, tumor inhibition effects, and biosafety of the synthesized nanodrugs (MNV-Co) as a synergistic therapeutic strategy for MIBC were evaluated in vitro and in vivo . The results indicated high efficacy of MNV-Co against MIBC and low off-tumor toxicity. Furthermore, by down-regulating ERCC2 mRNA and protein levels, MNV-Co improved chemosensitivity, promoted cancer cell apoptosis, and effectively suppressed tumor growth. This study presents a potential approach for delivering cisplatin and ERCC2 siRNA concurrently to treat bladder cancer using a biomimetic nanosystem.

Chronic Psychological Stress Attenuates the Efficacy of anti-PD-L1 Immunotherapy for Bladder Cancer in Immunocompetent Mice.

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.

Immunotherapy Strategy Targeting Programmed Cell Death Ligand 1 and CD73 with Macrophage-Derived Mimetic Nanovesicles to Treat Bladder Cancer.

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.

NOS3 895G>T and CBR3 730G>A Are Associated with Recurrence Risk in Non-Muscle-Invasive Bladder Cancer with Intravesical Instillations of THP.

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.

Decreased GABA levels of the anterior and posterior cingulate cortex are associated with executive dysfunction in mild cognitive impairment.

Background and purpose: Executive function impairment, a slight but noticeable cognitive deficit in mild cognitive impairment (MCI) patients, is influenced by gamma-aminobutyric acid (GABA) levels. Reduced cognitive function is accompanied by thinning of the cerebral cortex, which has higher GABA levels than white matter. However, the relationships among GABA levels, cortical thickness, and executive function in MCI patients have not yet been elucidated. We investigated the relationships among GABA levels, cortical thickness, and executive function in MCI patients. Methods: In this study, a total of 36 MCI patients and 36 sex-, age-, and education-matched healthy controls (HC) were recruited. But 33 MCI patients and 35 HC were included because of head motion or poor data quality for three MCI patients and one HC. The levels of gamma-aminobutyric acid plus relative to creatine (GABA+/Cr) and glutamate-glutamine relative to creatine (Glx/Cr) in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) were measured using the Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) sequence. Metabolite ratios, cortical thickness, and executive function and their interrelationships were determined in the MCI and HC groups. Results: Patients with MCI showed lower GABA+/Cr levels in the ACC and PCC. Combined levels of GABA+ and Glx in the ACC and GABA+ in the PCC showed good diagnostic efficacy for MCI (AUC: 0.82). But no differences in cortical thickness were found between the two groups. In the MCI group, lower GABA+/Cr level was correlated to worse performance on the digit span test backward, and the shape trail test-B. The cortical thickness was not associated with GABA+ levels and executive function in patients. Conclusion: These results implied that decreased GABA levels in the ACC and PCC had a critical role in the early diagnosis of impaired executive function of MCI. Therefore, GABA in the ACC and PCC could be a potential diagnostic marker of the executive function decline of MCI.

Global cognitive effects of second-generation antidepressants in patients with Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials.

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.

Depression Induced by CUMS Leads to Bladder Cancer Development and Local Tumor Immunosuppression in Mice.

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-1ß, 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.

Increased Risk of Recurrence of Non-Muscle Invasive Bladder Cancer Associated With Psychological Distress: A Prospective Cohort Study.

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.

The Clinical Implications and Molecular Mechanism of CX3CL1 Expression in Urothelial Bladder Cancer.

BACKGROUND: CX3CL1 is a chemokine that may play important roles in cancer immune regulation. Its mechanism in bladder cancer (BCa) is poorly understood. The objective of the current study was to evaluate the association between CX3CL1 and BCa and the related biological mechanisms. METHODS: A total of 277 patients with BCa were enrolled in the present study. The association between CX3CL1 expression and disease outcome was evaluated. In vitro and in vivo experiments were performed using the TCCSUP cell line to investigate the function of CX3CL1 in BCa. RESULTS: Compared with low expression, high expression of CX3CL1 was significantly associated with poorer progression-free survival (hazard ratio [HR]=2.03, 95% confidence interval [95% CI]: 1.26-3.27, P=0.006), cancer-specific survival (HR=2.16, 95% CI: 1.59-2.93, P<0.001), and overall survival (HR=1.55, 95% CI: 1.08-2.24, P=0.039). Multivariable Cox regression analysis suggested that CX3CL1 was an independent prognostic factor for BCa outcomes. In vitro and in vivo experiments indicated that high expression of CX3CL1 was significantly associated with cell proliferation (P<0.001) and invasion (P<0.001). Gene expression profiling results showed that after CX3CL1 knockdown, CDH1 was significantly upregulated, while ETS1, RAF1, and EIF4E were significantly downregulated. Pathway enrichment analysis suggested that the ERK/MAPK signaling pathway was significantly inhibited (P<0.001). CONCLUSIONS: CX3CL1 is an independent predictor of a poor prognosis in BCa and can promote the proliferation and invasion of BCa cells.

Chronic Unpredictable Mild Stress Accelerates the Growth of Bladder Cancer in a Xenograft Mouse Model.

OBJECTIVE: 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.