Discovery and biological evaluation of novel CARM1/HDAC2 dual-targeting inhibitors with anti-prostate cancer agents.

Prostate cancer (PCa) is a clinically heterogeneous disease with a progressively increasing incidence. Concurrent inhibition of coactivator-associated arginine methyltransferase 1 (CARM1) and histone deacetylase 2 (HDAC2) could potentially be a novel strategy against PCa. Herein, we identified seven compounds simultaneously targeting CARM1 and HDAC2 through structure-based virtual screening. These compounds possessed potent inhibitory activities at the nanomolar level in vitro. Among them, CH-1 was the most active inhibitor which exhibited excellent and balanced inhibitory effects against both CARM1 (IC50 = 3.71 ± 0.11 nM) and HDAC2 (IC50 = 4.07 ± 0.25 nM). MD simulations presented that CH-1 could stably bind the active pockets of CARM1 and HDAC2. Notably, CH-1 exhibited strong anti-proliferative activity against multiple prostate-related tumour cells (IC50 < 1 µM). In vivo, assessment indicated that CH-1 significantly inhibited tumour growth in a DU145 xenograft model. Collectively, CH-1 could be a promising drug candidate for PCa treatment.

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A.

BACKGROUND: Docetaxel resistance affects prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. Transcription factor Forkhead box M1 (FOXM1), which participates in cell proliferation and cell cycle progression, has been reported to affect the sensitivity of chemotherapy. This study explores the role of FOXM1 in PCa docetaxel resistance and its association with kinesin family member 20 A (KIF20A), which is known to promote therapeutic resistance in some cancers. METHODS: We monitored cell growth using MTT and colony formation assays, and cell apoptosis and cell cycle progression using flow cytometry. Wound-healing and transwell assays were used to detect cell invasion and migration. mRNA and protein expression were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. We monitored FOXM1 binding to the KIF20A promoter using a ChIP assay. Tumorigenicity in nude mice was used to assess in vivo tumorigenicity. RESULTS: FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, suppressing cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). Exogenous FOXM1 overexpression was found in their parental cells. Specific FOXM1 inhibitor thiostrepton significantly weakened docetaxel resistance in vitro and in vivo. We also found that FOXM1 and KIF20A exhibited consistent and highly correlated overexpression in PCa cells and tissues. FOXM1 also regulated KIF20A expression at the transcriptional level by acting directly on a Forkhead response element (FHRE) in its promoter. KIF20A overexpression could partially reverse the effect on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP) of FOXM1 depletion. CONCLUSIONS: Our findings indicate that highly expressed FOXM1 may help promote docetaxel resistance by inducing KIF20A expression, providing insight into novel chemotherapeutic strategies for combatting PCa docetaxel resistance.

Citrus fruit intake and bladder cancer risk: a meta-analysis of observational studies.

Epidemiological studies have investigated the association between citrus fruit and bladder cancer risk; however, the results are inconsistent. To assess these issues, we conducted a meta-analysis of currently available studies. We identified relevant articles by searching the MEDLINE and EMBASE databases. We calculated the summary relative risk (RR) with 95% confidence interval (95% CI) using a random effect model. We included eight case-control studies and six cohort studies in the meta-analysis. There was a significant inverse association between citrus fruit intake and bladder cancer risk in all pooled studies (RR: 0.85; 95% CI, 0.76-0.94) and case-control studies (RR: 0.77; 95% CI, 0.64-0.92), but not in the cohort studies (RR: 0.96; 95% CI, 0.87-1.07). Our results suggest that citrus fruit intake is related to decreased bladder cancer risk. Subsequent well-designed, large prospective studies are needed to obtain better understanding of this relationship.

Internal urethral sphincter reconstruction with anterior bladder neck tube for robotic and laparoscopic radical prostatectomy: improving early return of continence.

Background: In recent years, despite several surgical techniques having been applied, the early incontinence rate after radical prostatectomy (RP) remains high. In this study, we reconstructed an internal urethral sphincter (IUS) with anterior bladder neck tube (ABNT) to improve early return of continence and find a more effective technique for early urinary incontinence after RP. Methods: In this study, 96 previous patients who did not receive an ABNT between October 2018 and May 2020 were compared as historical controls (the control group). A total of 210 consecutive patients underwent robotic or laparoscopic RP with ABNT between May 2020 and February 2023 (the ABNT group). The inclusion criteria included Eastern Cooperative Oncology Group (ECOG) score 0-1 and localized prostate cancer (clinical stages cT1-3, cN0, cM0). The exclusion criteria included patients with diabetes, neurologic diseases, previous pelvic operations, symptoms of urinary incontinence, prior radiation, focal therapy, or androgen deprivation therapy for prostate cancer. ABNT was reconducted with a U-shaped flap from the anterior wall of the bladder neck, and was then anastomosed with the urethra. In the control group, the bladder outlet was directly anastomosed with the urethra. Continence, as defined if 0 pads were used per day and International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) score ≤6, was assessed at 1, 4, 8, 12, and 24 weeks after catheter removal. At 2 weeks after catheter removal, urethral pressure profilometry (UPP) and upright urethrography were performed to evaluate the function of ABNT in the ABNT group. Results: More patients in the ABNT group were continent than those in the control group at 1 week (85.2% vs. 22.9%, P<0.001), 4 weeks (91.4% vs. 27.1%, P<0.001), 8 weeks (95.2% vs. 40.6%, P<0.001), 12 weeks (100% vs. 71.9%, P<0.001), and at 24 weeks (100% vs. 87.5%, P<0.001) after catheter removal. Stricture was presented in 5.2% and 2.1% (P=0.34) in the ABNT group and control group, respectively. UPP showed that a functional IUS was reconstructed with ABNT. Upright urethrography showed that the ABNT was filled with contrast medium in the urination period and with no contrast medium during the storage period and interruption of urination. Conclusions: The ABNT technique significantly improved early return of continence in comparison with the no ABNT technique, especially the immediate continence. The ABNT technique reconstructed the functional IUS with acceptable urethral stricture. The limitations of the present study include that the comparison was conducted retrospectively with a historical cohort and lack of randomization, and the single center setting. A prospective, randomized, and multicenter evaluation is expected.

Ferroptosis Induction Improves the Sensitivity of Docetaxel in Prostate Cancer.

Docetaxel resistance seriously affects its clinical application in prostate cancer (PCa). Ferroptosis is a type of iron-dependent cell death driven by lipid peroxidation. It has been recently found that ferroptosis influences various biological processes. However, the potential role of ferroptosis in docetaxel chemotherapy for PCa is still elusive. In this study, we aimed to explore whether altering the level of ferroptosis can affect docetaxel sensitivity in PCa. The results indicated that docetaxel promoted ferroptotic cell death in several PCa cells, and ferroptosis inducers, erastin, and RSL3 markedly increased the cytotoxic effect of docetaxel. Furthermore, our results showed that ferroptosis resistance was closely associated with docetaxel insensitivity in PCa-resistant cells. Erastin or RSL3 rendered resistant PCa cells susceptible to docetaxel, with elevated levels of lipid ROS and decreased protein expression of GPX4 and SLC7A11. Moreover, treatment with erastin and RSL3 led to significant suppression of resistant tumors, and the combination of RSL3 with docetaxel significantly halted tumor growth in vivo when compared with either drug. Taken together, our findings indicate that ferroptosis is involved in docetaxel resistance, and its inducers are promising therapeutic strategies for advanced PCa.

Isoquercitrin Attenuates Renal Ischemia/Reperfusion Injury Through Antioxidation, Anti-inflammation, and Antiapoptosis in Mice.

Renal ischemia-reperfusion injury (RIRI) occurs after several surgical procedures such as kidney transplantation and partial nephrectomy. Isoquercitrin (IQ) exhibited protective effects in cerebral ischemia-reperfusion injury. In the present study, we aimed to evaluate the effects of IQ on the prevention of RIRI. The mouse model of RIRI was induced by 30-minute clamping of the left renal pedicle after excising of the right kidney, followed by 24-hour reperfusion. Thirty mice were randomly divided into the following 3 groups: sham operation, RIRI model group, and IQ pretreatment + RIRI. Serum creatinine and blood urea nitrogen (BUN) were used for evaluating renal function. Kidney cell apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining. Moreover, the pro-inflammatory cytokines (TNF-α, IL-6), the oxidative stress associated factors (malondialdehyde, superoxide dismutase), and the apoptotic factors (Bcl-2, Bax) were assessed. After RIRI, BUN, creatinine, TNF-α, IL-6, malondialdehyde, and Bax were significantly increased, and levels of superoxide dismutase and Bcl-2/Bax ratio and Bcl-2 expression were decreased markedly. As expect, IQ reversed these changes. These data indicate that IQ plays a protective role during RIRI, which may be partially mediated through the actions of antioxidation, anti-inflammation, and antiapoptosis.

Diagnostic performance of cytomegalovirus (CMV) immune monitoring with ELISPOT and QuantiFERON-CMV assay in kidney transplantation: A PRISMA-compliant article.

BACKGROUND: Cytomegalovirus (CMV) infection is part of major infection complications following kidney transplantation. However, more rapid and low-complexity assays are needed for CMV infection. Our study is to investigate the diagnostic efficacy of 2 novel tests, CMV-ELISPOT and QuantiFERON-CMV tests, in CMV DNA viremia and CMV infection following renal transplant. METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the Web of Science. Case-control or cohort study designed to explore the CMV-ELISPOT and/or QuantiFERON-CMV tests in the recipients with CMV infection was considered to be eligible for this study. Sensitivity (SEN), specificity (SPE), diagnostic odds ratio (DOR), and summary receiver-operating characteristic (SROC) curves were calculated. RESULTS: We selected a total of 12 articles for systematic review and 11 of them were included in meta-analysis. For CMV-pp65 assay, the pooled SEN, SPE, and DOR were 0.73 (95% confidence interval [CI], 0.67-0.78), 0.61 (95% CI, 0.56-0.65), and 4.46 (95% CI, 3.11-6.39), respectively. For CMV-IE-1 assay, the pooled SEN, SPE, and DOR were 0.84 (95% CI, 0.78-0.88), 0.46 (95% CI, 0.42-0.51), and 5.07 (95% CI, 3.26-7.89), respectively, whereas the pooled SEN, SPE, and DOR of QuantiFERON-CMV test were 0.38 (95% CI, 0.28-0.49), 0.38 (95% CI, 0.32-0.44), and 1.02 (95% CI, 0.17-6.00). CONCLUSIONS: We reported that CMV-ELISPOT tests, including CMV-pp65 and CMV-IE-1, perform well in the diagnosis and prediction of CMV infection in renal transplant recipients, whereas QuantiFERON-CMV test needs further exploration.

Aberrant microRNA-137 promoter methylation is associated with lymph node metastasis and poor clinical outcomes in non-small cell lung cancer.

MicroRNA-137 (miR-137) functions as a tumor suppressor and is silenced by aberrant promoter methylation. Previous studies have demonstrated that miR-137 is downregulated in lung cancer. The purpose of the present study was to investigate miR-137 promoter methylation and to assess its prognostic value in non-small cell lung cancer (NSCLC). The expression of miR-137 was analyzed inhuman lung cancer A549 and H1299 cells and normal bronchial epithelial BEAS-2B cells, 10 paired formalin-fixed paraffin-embedded lung cancer and normal tissue samples, and 56 archived paraffin-embedded lung cancer tissues. Quantitative methylation-specific polymerase chain reaction analysis was used to assess the miR-137 methylation status. The associations between miR-137 promoter methylation and the clinicopathological features and prognosis of patients with NSCLC (n=56) were analyzed using analysis of variance. miR-137 was markedly downregulated in lung cancer cells and lung cancer tissue specimens compared with expression in BEAS-2B cells and matched adjacent normal lung tissues. A significant negative correlation between miR-137 expression and miR-137 promoter methylation was observed in human lung cancer tissues (r=-0.343; P=0.01). Smoking, lymph node metastasis and advanced clinical stage were associated with significantly lower expression of miR-137 in variance analysis. High levels of miR-137 promoter methylation were associated with a significantly poorer disease-free survival rate (P=0.034), but were not associated with overall survival, in Kaplan-Meier analysis and univariate analysis. In conclusion, the results of the present study indicated that miR-137 is downregulated and that its promoter is aberrantly methylated in lung cancer, and that high levels of miR-137 promoter methylation may have prognostic value for poor disease-free survival.

Menopausal status and the risk of lung cancer in women: A PRISMA-compliant meta-analysis.

BACKGROUND: Quantification of the association between menopausal status and risk of lung cancer is inconsistent. We carried out a meta-analysis of available studies to examine this issue. METHODS: Relevant articles were identified by searching PudMed and Embase databases. Reference lists from selected papers were also reviewed. A random-effect model was used to calculate summary odds ratios (OR) and relative risk (RR) with 95% confidence interval (CI). Publication bias was estimated using Egger regression asymmetry test. RESULTS: Eight eligible studies, including 5 case-control studies and 3 cohort studies, provided data for meta-analysis. Postmenopausal women had a statistically significant increased risk of lung cancer in all included studies (RR = 1.44, 95% CI: 1.12-1.85) and cohort studies (RR = 1.39, 95% CI: 1.05-1.86), but not in case-control studies (OR = 1.46, 95% CI: 0.95-2.24). CONCLUSIONS: Overall, there was evidence that postmenopause is related to increased lung cancer risk. However, studies have produced slightly heterogeneous results (I = 38.40%). To obtain a better indication of relationship, well-designed large prospective studies are required.

Height and lung cancer risk: A meta-analysis of observational studies.

BACKGROUND: The association between height and lung cancer risk has been investigated by epidemiological studies but the results are inconsistent. This meta-analysis was to evaluate whether the height is associated with lung cancer. METHODS: We identified relevant articles by searching the MEDLINE and EMBASE databases, and reviewed the reference lists of selected papers. A random effect model was used to calculate summary odds ratios (OR) and relative risk (RR) with 95% confidence intervals (95% CI). Publication bias was estimated using Egger's regression asymmetry test. RESULTS: We included a total 16 studies (15 prospective studies and one case-control study) on adult height and lung cancer risk in the meta-analysis. Overall, per 10-cm height increases were associated with increased risk of lung cancer (RR 1.06; 95% CI 1.03-1.09, I2 = 43.6%). CONCLUSIONS: In this meta-analysis, high adult height is related to increased lung cancer risk. Well-designed, large prospective studies are required to obtain a better indication of the relationship.

Height and kidney cancer risk: a meta-analysis of prospective studies.

PURPOSE: The aim of this study was to perform a meta-analysis to summarize the available evidence from prospective studies on the association between height and kidney cancer risk. METHODS: Relevant studies were identified through the MEDLINE and EMBASE databases up to July 2014, as well as through the references from the retrieved articles. Relative risks (RRs) from individual studies were pooled by using a random-effects model. RESULTS: A total of fourteen prospective studies of adult height and kidney cancer risk with 18,766 cases were included in the meta-analysis. Overall, per 10-cm increase in height was associated with an increased risk of kidney cancer (RR 1.23; 95 % confidence interval 1.18-1.28, I(2) = 11.8 %). Subgroup analysis showed a basically consistent result with the overall analysis. There was no evidence of publication bias. CONCLUSIONS: High adult height was positively associated with the risk of kidney cancer in both men and women in this meta-analysis. Future prospective studies are needed to determine the generalizability of these findings to non-Caucasians.