Oxygen vacancy-rich nickel oxide nanoplatforms for enhanced photothermal and chemodynamic therapy combat methicillin-resistant Staphylococcus aureus.

Bacterial infections pose a global concern due to high fatality rates, particularly with the rise of drug-resistant bacteria and biofilm formation. There is an urgent need for innovative strategies to combat this issue. A study on chemodynamic therapy (CDT) using nanozymes in conjunction with photothermal therapy (PTT) has displayed potential in addressing drug-resistant bacterial infections. However, the effectiveness of this combined approach is limited by inadequate light absorption. This work suggests the NiOx nanoparticles enriched with oxygen vacancies enhance CDT and PTT to overcome this challenge. The presence of oxygen vacancies in NiOx can reduce the energy gap between its valence band and conduction band, facilitating oxygen adsorption. NiOx has exhibited notable antibacterial properties and complete eradication of biofilms in both laboratory and animal trials. In animal abscess models, NiOx demonstrated antibacterial and anti-inflammatory effects in the initial stages, while also promoting wound healing and tissue regeneration by influencing immune factors and encouraging collagen deposition and neovascularization. With positive biosafety and biocompatibility profiles, the oxygen vacancy-enhanced CDT and PTT therapy proposed in this article hold promise for effective sterilization, deep biofilm removal, and treatment of infections caused by drug-resistant bacteria. STATEMENT OF SIGNIFICANCE: This study constructs oxygen vacancies NiOx nanoparticles (NiOx NPs) to improve the efficacy of photothermal therapy and chemodynamic therapy. The presence of oxygen vacancies in NiOx NPs helps bridge the energy gap between its valence band and conduction band, facilitating oxygen adsorption and improving catalytic efficiency. In both in vivo and in vitro antibacterial experiments, NiOx NPs demonstrate effective antibacterial and anti-inflammatory properties. Furthermore, it aids in wound healing and tissue regeneration by modulating immune factors, collagen deposition, and angiogenesis. This approach presents a promising collaborative strategy for utilizing nickel-based defective nanomaterials in combating deep drug-resistant bacterial infections.

Chalcone Derivatives Suppress Proliferation and Migration of Castration-resistant Prostate Cancer Cells Through FAK-mediated DNA Damage.

BACKGROUND/AIM: Castration-resistant prostate cancer (CRPC) contributes to the deaths of most men from prostate cancer. Focal adhesion kinase (FAK) is abnormally up-regulated in CRPC. Chalcone possesses potent anticancer activity with clinical potential. However, it remains unknown whether its derivatives can be exploited as promising oncotherapeutic agents in CRPC treatment by inhibiting FAK-related signaling pathway. AIM: This study aimed to investigate the anticancer effects and the underlying mechanisms of action of chalcone derivatives against CRPC cells. MATERIALS AND METHODS: Two chalcone derivatives (compounds 1 and 2) were synthesized, and their anti-CRPC activity toward DU145 and PC3 cells was evaluated. The effect of chalcone derivatives on CRPC cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony-formation, 5-ethynyl-2'-deoxyuridine staining, flow cytometric, cell adhesion and transwell assays. The study of mechanisms was conducted through comet, immunofluorescence and western blot assay, analysis of The Cancer Genome Atlas and molecular docking. RESULTS: The results revealed that both compounds exhibited stronger cytotoxicity to CRPC cells along with significant inhibition of colony formation, especially compound 1 Further experimental evidence indicated that 1 significantly inhibited DNA replication, induced cell-cycle arrest and cell apoptosis. Additionally, treatment with 1 inhibited cell-matrix adhesion and migration of CRPC cells. Mechanistically, the results suggest that 1 inhibited FAK expression and phosphorylation, as well as affected its distribution, resulting in intense DNA damage and strong DNA damage response. CONCLUSION: We discovered two chalcone derivatives and collective results indicated that 1 inhibited CRPC cell proliferation and migration through FAK-mediated DNA damage and may be a potential therapeutic drug against CRPC.

Prognostic Value of Site-Specific Metastases and Therapeutic Roles of Surgery and Chemotherapy for Patients With Metastatic Renal Pelvis Cancer: A SEER Based Study.

BACKGROUND AND AIMS: There is a lack of research on metastatic renal pelvis cell carcinoma in the current literature. In this study, we aimed to detect distant metastatic patterns in renal pelvis cell carcinoma, and illustrated the affection of different metastatic sites, surgery to primary site and chemotherapy on prognosis outcomes in patients with diverse conditions. METHODS: We collected data between 2010 and 2015 from the Surveillance, Epidemiology and End Results database. Kaplan-Meier analysis with log-rank test was used for survival comparisons. Multivariate Cox regression model was employed to analyze the effect of distant metastatic sites on overall survival (OS) and cancer-specific survival (CSS). RESULTS: A total of 424 patients were included in the analysis, the median follow-up time was 5 months (interquartile range (IQR): 2-12) and 391 deaths (92.2%) in all patients were recorded. Among them, 192 (45.3%), 153 (36.1%), 137 (32.3%) and 127 (30.0%) patients were diagnosed with lung, bone, liver and brain metastases, respectively, while only 12 (2.8%) patients had brain metastases. The bi-organ, tri-organ and tetra-organ metastatic pattern was found in 135 (31.8%), 32 (7.5%) and 11 (2.6%) patients, respectively. The multivariate Cox analyses showed that distant lymph nodes (DL) metastases was not an independent prognostic factor for both OS and CSS (OS: Hazard ratios (HR) = 1.1, 95% CI = 0.8-1.4, P = 0.622; CSS: HR = 1.0, 95% CI = 0.8-1.3, P = 0.906). Besides, there was no significant difference of survival in patients with T3-T4 stage (OS: HR = 0.8, 95% CI = 0.5-1.2, P = 0.296; CSS: HR = 0.8, 95% CI = 0.5-1.2, P = 0.224), N2-3 stage (OS: HR = 0.8, 95% CI = 0.5-1.3, P = 0.351; CSS: HR = 0.7, 95% CI = 0.4-1.2, P = 0.259) and multi-organ metastases (OS: HR = 0.8, 95% CI = 0.5-1.3, P = 0.359; CSS: HR = 0.7, 95% CI = 0.4-1.2, P = 0.179) between surgery to primary site group and no-surgery to primary site group. CONCLUSION: we described the metastatic patterns of mRPCC and the prognosis outcomes of DL metastases, surgery to primary site and chemotherapy. Our findings provide more information for clinical therapeutic intervention and translational study designs.

The Significance of Circular RNA DDX17 in Prostate Cancer.

Circular RNA DDX17 (circDDX17) has been demonstrated as a tumor suppressor in colorectal cancer. However, mechanisms underlying circDDX17 effects in cases of prostate cancer (PCa) are not well understood. Thus, herein, we determined measures of circDDX17 expression by use of the TCGA database. Expression of circDDX17 in prostate cancer-afflicted tissue samples was determined by qRT-PCR. Functionally, circDDX17 induced remarkable inhibition of cell colonizing ability, invasion, and epithelial-mesenchymal transition (EMT) progression in vitro. Mechanistically, dual-luciferase reporter assays, RNA immunoprecipitation, and RNA pull-down experiments helped verify interactions between circDDX17 and miR-346. Low expression of circDDX17 occurred in TCGA PCa samples. Furthermore, circDDX17 expression was downregulated significantly in PCa. These results suggested that circDDX17 suppressed PC cell mobility, proliferation, and invasion. Mechanistic experiments indicated that circDDX17 might serve as a ceRNA of miR-346 to relieve repressive effects of miR-346 upon phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP). LHPP expression itself was downregulated in TCGA PCa samples. Overall, our findings indicated that the circDDX17/miR-346/LHPP pathway inhibited the progression of prostate cancer and that circDDX17 may be a new potential therapeutic or diagnostic target for treating and diagnosing prostate cancer. As our study also demonstrated for the first time that LHPP might act as an anticancer gene in prostate cancer, the findings could have wide-ranging implications for the treatment of this affliction.

U-shaped relationship of age at diagnosis and cancer-specific mortality in primary urachal adenocarcinoma: a cohort study.

BACKGROUND: To examine the association between age at diagnosis and cancer-specific mortality (CSM) in primary urachal adenocarcinoma. METHODS: The data was obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results program (SEER). A total of 393 patients were included in the study. Smooth curve fitting and two-piecewise Cox proportional hazards models were used to identify the nonlinearity between the age at initial diagnosis and cancer-specific survival rate. Survival time between different groups was compared using Kaplan-Meier survival curves and the log-rank test. RESULTS: Using smooth curve fitting we found that the relationship between age at diagnosis and cancer-specific survival takes on a U-shaped curve. The inflection point that we identified for the age at initial diagnosis was 60 years. The log-likelihood ratio test (P<0.05) indicated that the two-piecewise Cox regression model was more appropriate for fitting the correlation of age at diagnosis and CSM. The two-piecewise Cox regression model showed that when the age was <60 years, reduced risk of CSM was significantly associated with increased age (HR: 0.95, P=0.0002). Conversely, when age was >60 years, increased risk of CSM was significantly associated with increased age (HR: 1.05, P=0.0499). CONCLUSIONS: In summary, our study suggested that the relationship between age at diagnosis and cancer-specific survival is nonlinear, and takes on a U-shaped curve. Both younger and older age at initial diagnosis age were associated with increased CSM.

Mitochondrial ATP synthase regulates corpus cavernosum smooth muscle cell function in vivo and in vitro.

Adenosine triphosphate (ATP) levels are closely associated with diabetes-related erectile dysfunction (DMED). Mitochondrial ATP synthase serves a key role in ATP production. The present study aimed to investigate the relationship between F1-ATP synthase and DMED in vivo and in vitro. The F1-ATP synthase expression levels in corpus cavernosum tissues from rats with DMED were examined. F1-ATP synthase expression was found to be lower in corpus cavernosum tissues from rats with DMED compared with healthy controls, suggesting a role for ATP synthase under high glucose conditions. In addition, the present study also demonstrated that hyperglycemia could downregulate F1-ATP synthase expression in rat corpus cavernosum smooth muscle cells (CCSMCs) in vitro. The overexpression of F1-ATP synthase in CCSMCs influenced the phenotypic CCSMC transformation, upregulated eNOS expression, increased cGMP levels and reduced CCSMC apoptosis under high glucose in vitro. In conclusion, the present study indicates that the upregulation of mitochondrial ATP synthase expression may improve CCSMC function, suggesting that mitochondrial ATP synthase could serve as a potential therapeutic target for the treatment of DMED.

Development and validation of a nomogram to predict survival in patients with metastatic testicular germ cell tumors.

BACKGROUND: To develop a nomogram to predict cancer-specific survival (CSS) in patients with metastatic testicular germ cell tumors (mTGCTs). METHODS: Data were obtained from the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox regression models were used to identify factors associated with CSS. Survival times between different groups were compared using Kaplan-Meier survival curves and the log-rank test. A nomogram visualization model was established using the R language to predict survival rates. Harrell's concordance index (C-index), the area under the receiver operating characteristic curve (AUC) and calibration plots were used to assess the performance of the model. RESULTS: We analyzed the data of 949 patients. The median follow-up time was 32 months (range 0 to 83 months), and 224 (23.60%) patients died before the last follow-up, of whom 193 (20.33%) died of mTGCTs. The site of distant metastases was an independent prognostic factor for CSS. Compared to patients without involvement of the corresponding organ, patients with bone, brain, liver, and lung involvement had worse CSS. We also found that age, histological type, surgery, radiation therapy, chemotherapy, metastatic site and insurance status affected the CSS of patients with mTGCTs. We used these prognostic factors to construct our nomogram. Harrell's C-index for CSS was 0.739. The AUC and calibration plots indicated good performance of the nomogram. CONCLUSIONS: A nomogram for predicting CSS in patients with mTGCTs has been developed, which can help patients and clinicians accurately predict mortality risk and recommend personalized treatment modalities.

The influence of sex on the prognostic value of body mass index in non-metastasis renal cell carcinoma.

Purpose: The prognostic value of obesity in patients with renal cell carcinoma (RCC) remains controversial. This study aimed to assess the sex-dependent prognostic role of body mass index (BMI) in patients with nonmetastatic RCC who underwent radical or partial nephrectomy. Patients and methods: We retrospectively analyzed 643 consecutive patients with nonmetastatic RCC who underwent curative nephrectomy in our center between 2004 and 2014. Associations among BMI, sex, overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS) were analyzed. Results: Males were more likely to have a higher BMI than females (BMI as a categorical variable: P<0.001; BMI as a continuous variable: P=0.002). In men, a high BMI was significantly correlated with better 5-year OS, CSS, and MFS rates (P=0.001, 0.014, and 0.001, respectively), and multivariate analysis identified that a high BMI was independently associated with greater OS, CSS, and MFS (OS: hazard ratio [HR]=0.207, P=0.011; CSS: HR=0.225, P=0.005; MFS: HR=0.243, P=0.004). However, in women, there was no significant difference in 5-year OS, CSS, and MFS rates according to BMI (P=0.781, 0.812, and 0.538, respectively). Moreover, a high BMI was no longer independently associated with OS, CSS, or MFS (P=0.821, 0.832, and 0.801, respectively). Among patients with clear cell RCC, BMI was significantly associated with OS, CSS, and MFS only among men (all P<0.05) and not among women (all P>0.05). Conclusion: Among patients with nonmetastatic RCC, a high BMI was a favorable prognostic factor in males rather than females. Therefore, sex might influence the correlation between obesity and urological outcomes in nonmetastatic RCC.

Impact of diabetes mellitus on the prognostic value of the neutrophil-lymphocyte ratio in renal cell carcinoma.

The aim of the present study was to evaluate the effect of diabetes mellitus (DM) on the neutrophil-lymphocyte ratio (NLR)-based prediction of the prognosis of patients with renal cell carcinoma (RCC). The data of 662 patients who had undergone nephrectomy for RCC between January 2004 and July 2014 were retrospectively reviewed. X-tile analysis was used to determine the optimal cutoff value for the NLR. Kaplan-Meier curves were drawn and the log-rank test was applied to determine the impact of the NLR (high vs. low) on the overall survival (OS) and metastasis-free survival (MFS). Univariate and multivariate Cox regression analyses were used to identify prognostic factors for OS and MFS. The median follow-up period after surgery was 50.35 months (range, 30.30-85.08 months). The optimal cutoff value of the NLR was determined to be 3.2 using X-tile software. In the analysis of total subjects, patients with a high NLR (≥3.2) had significantly worse OS and MFS rates than those with a low NLR (<3.2) (21.60% vs. 78.40%, P=0.001 for OS and 21.60% vs. 78.40%, P<0.0001 for MFS). In the non-DM subgroup, the OS and MFS rates of patients with a high NLR were significantly worse compared with those of patients with a low NLR (21.69% vs. 78.31%, P=0.003 for OS and 21.69% vs. 78.31%, P<0.001 for MFS). In the DM subgroup, although a high NLR was still associated with the MFS (NLR≥3.2, 21.43% vs. NLR<3.2, 78.57%; P=0.015), it was no longer associated with the OS (NLR≥3.2, 21.43% vs. NLR<3.2, 78.57%; P=0.192). Furthermore, multivariate analysis identified the NLR as a risk factor for OS and MFS in all patients [hazard ratio (HR)=1.77, 95% confidence interval (CI): 1.04-3.01, P=0.037; and HR=2.31, 95% CI: 1.45-3.70, P<0.001, respectively) and in the non-DM subgroup (HR=2.03, 95% CI: 1.05-3.93, P=0.036; and HR=2.57, 95% CI: 1.47-4.49, P=0.001, respectively), but not in the DM subgroup (P>0.05). In conclusion, DM is a factor that impairs the evaluation of the prognosis of RCC using NLR.

[Low-dose PDE5 inhibitors for erectile dysfunction with subclinical metabolic syndrome].

OBJECTIVE: To investigate the effects of low-dose PDE5 inhibitors on metabolic parameters and erectile function in ED patients with subclinical metabolic syndrome (SCMS). METHODS: Totally, 132 ED patients, aged 21－61 (mean 34.5) years, were treated in the Andrology Clinic of the First Hospital of Wenzhou Medical University from April 2017 to May 2018. According to the diagnostic criteria, we divided the patients into groups A (simple ED, n = 40), B (ED with SCMS, n = 34) and C (ED with MS, n = 58) to receive 3 months of oral administration of tadalafil at 5 mg qd at bedtime, and followed them up for 3 months after drug withdrawal. During the treatment, we advised the patients to keep a healthy diet, change bad habits, participate in regular physical exercise, and maintain psychological balance. Before and right after medication and at 3 months after drug withdrawal, we recorded the changes in the IIEF-5 scores, abdominal circumference, blood pressure and levels of fasting blood sugar (FBS), triglyceride (TG) and high-density lipoprotein (HDL) of the patients. RESULTS: The IIEF-5 scores showed statistically significant differences at different time points between groups A and C (P < 0.01), remarkably higher right after treatment than before treatment and at 3 months after drug withdrawal in group B (19.71 ± 2.40 vs 10.21 ± 3.92 and 16.29 ± 2.41, P < 0.01). At 3 months after drug withdrawal, the abdominal circumference was significantly smaller in group A than in B and C (ï¼»78.10 ± 6.00ï¼½ vs ï¼»84.15 ± 8.17ï¼½ and ï¼»91.53 ± 11.49ï¼½ cm, P < 0.01) and the HDL level lower in group C than in A and B (ï¼»0.96 ± 0.15ï¼½ vs ï¼»1.27 ± 0.14ï¼½ and ï¼»1.16 ± 0.2ï¼½] mmol/L, P < 0.01). Systolic blood pressure exhibited statistically significant differences between any two time points in group C (P < 0.05 or P < 0.01) but not in group A (P > 0.05) or B (P > 0.05). Diastolic blood pressure was markedly lower in group B right after medication and at 3 months after drug withdrawal than before treatment (ï¼»75.62 ± 10.70ï¼½ and ï¼»74.65 ± 9.90ï¼½ vs ï¼»78.00 ± 11.42ï¼½ mmHg, P < 0.05), and so was it in group C (ï¼»82.19 ± 10.36ï¼½ and ï¼»82.40 ± 10.09ï¼½ vs ï¼»86.71 ± 12.32ï¼½ mmHg, P < 0.05), but manifested no significant difference between any two time points in group A (P > 0.05). There were statistically significant differences in the FBS level among different time points in groups A and C (P < 0.05) but not in B between post-treatment and 3 months after drug withdrawal (ï¼»5.34 ± 0.60ï¼½ vs ï¼»5.36 ± 0.40ï¼½ mmol/L, P > 0.05), and so were there in the TG level among different time points in groups A and C (P < 0.05) but not in B between pre- and post-treatment (ï¼»1.80 ± 0.98ï¼½ vs ï¼»1.64 ± 1.19ï¼½ mmol/L, P > 0.05). CONCLUSIONS: Periodic administration of low-dose sustained-release PDE5 inhibitors with health education and lifestyle guidance may reverse ED with SCMS and improve most of the related metabolic parameters.

Prognostic impact of the Controlling Nutritional Status score following curative nephrectomy for patients with renal cell carcinoma.

We aimed to evaluate the prognostic significance of the preoperative Controlling Nutritional Status (CONUT) score in patients with renal cell carcinoma (RCC), and then compared its accuracy of the prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) as predictors of survival.We included 635 patients who underwent nephrectomy for RCC from January 2004 to July 2014. The X-tile program was used to determine the optimal cut-off values for CONUT score, PNI, NLR, and PLR.The median follow-up duration after surgery was 48.40 (29.30-80.10) months. The optimal cutoff values were 2 for CONUT score, 48 for PNI, 3.5 for NLR and 204.7 for PLR by X-tile program with cancer-specific survival (CSS) as end-point. Higher CONUT score, NLR and PLR, and lower PNI were statistically associated with worse OS and CSS in the univariate analysis. Multivariate analysis showed that higher CONUT score was an independent predictor for OS (HR = 3.012; 95% CI, 1.525-5.948; P = .001) and CSS (HR = 3.001; 95% CI, 1.290-6.984; P = .011), and CONUT score was superior to PNI, NLR, and PLR according to the HR.Therefore, preoperative CONUT score can be a strong independent predictor in RCC patients after nephrectomy.