Benzyl isothiocyanate promotes miR-99a expression through ERK/AP-1-dependent pathway in bladder cancer cells.

Benzyl isothiocyanate (BITC), a bioactive natural product present in cruciferous vegetables, has been proved to prevent cancer progression through various mechanisms. In our previous report, we proved that BITC exhibits antitumor effects in bladder cancer by suppressing IGF1R, FGFR3, and mTOR, which is mediated by miR-99a expression. In this study, we identified the signal pathway involved in regulating miR-99a expression after BITC exposure in bladder cancer. Treatment with different BITC concentrations resulted in induction of miR-99a expression in bladder cancer cell lines. Activation of extracellular signal-regulated protein kinase (ERK) and c-jun N-terminal kinase was observed in bladder cancer after BITC treatment for 24 hours. Interestingly, by using a chemical inhibitor of candidate pathways, we found that only the ERK signal pathway is required for miR-99a expression. Furthermore, we evaluated the transcription factor that may contribute to miR-99a expression in response to BITC treatment. The results indicated that c-Jun/AP-1 was activated after BITC treatment. Moreover, we confirmed c-Jun/AP-1 activation through immunofluorescence and the luciferase reporter assay. The results showed that BITC treatment markedly improved nuclear translocation of c-Jun/AP-1 and luciferase activity dose dependently. Finally, pretreatment with the ERK inhibitor U0126 diminished c-Jun phosphorylation and transcriptional activation, suggesting that BITC elicits ERK/c-Jun signal transduction, which is responsible for miR-99a expression in bladder cancer. The present work identifies the mechanism involved in upregulation miR-99a after BITC treatment, which provides an explanation for BITC biological function in our previous work.

Programmed Cell Death 1 (PD-1) Inhibitors in Renal Transplant Patients with Advanced Cancer: A Double-Edged Sword?

Given advancements in cancer immunity, cancer treatment has gained breakthrough developments. Immune checkpoint inhibitors, such as programmed cell death 1 (PD-1) inhibitors, are the most promising drugs in the field and have been approved to treat various types of cancer, such as metastatic melanoma, head and neck squamous cell carcinoma, and urothelial carcinoma. However, whether PD-1 inhibitors should be administered to renal transplant patients with advanced cancer remains unclear because the T-cells produced after administration of these inhibitors act against not only tumor antigens but also donor alloantigens. Thus, the use of PD-1 inhibitors in kidney-transplanted patients with advanced cancer is limited on account of the high risk of graft failure due to acute rejection. Hence, finding optimal treatment regimens to enhance the tumor-specific T-cell response and decrease T-cell-mediated alloreactivity after administration of a PD-1 inhibitor is necessary. Thus far, no recommendations for the use of PD-1 inhibitors to treat cancer in renal transplant patients are yet available, and very few cases reporting kidney-transplanted patients treated with PD-1 inhibitors are available in the literature. Therefore, in this work, we review the published cases and suggest feasible approaches for renal transplant patients with advanced malignancy treated by a PD-1 inhibitor. Of the 22 cases we obtained, four patients maintained intact grafts without tumor progression after treatment with a PD-1 inhibitor. Among these patients, one maintained steroid dose before initiation of anti-PD1, two received immunosuppressive regimens with low-dose steroid and calcineurin inhibitor (CNI)-elimination with sirolimus before initiation of anti-PD-1 therapy, and one received combined anti-PD-1, anti-vascular endothelial growth factor (VEGF), and chemotherapy with unchanged immunosuppressive regimens. mammalian target of rapamycin (mTOR) inhibitors and anti-VEGF may act as regulators of tumor-specific and allogenic T-cells. However, more studies are necessary to explore the optimal therapy and ensure the safety and efficacy of PD-1 inhibitors in kidney-transplanted patients.

The Detection Performance of 18 F-Prostate-Specific Membrane Antigen-1007 PET/CT in Primary Prostate Cancer : A Systemic Review and Meta-analysis.

BACKGROUND: Multiple tools are now available to determine the requirement for a biopsy to diagnose prostate cancer, and PET/CT with radiolabeled prostate-specific membrane antigen (PSMA)-targeting radiotracers has been recommended for detecting primary prostate cancer. Particularly, the radiotracer 18 F-PSMA-1007 was found to be more favorable for primary tumors compared with other PSMA-targeting radiotracers because of its low clearance via the urinary tract and better image resolution. Thus, we performed a systematic review and meta-analysis to more accurately evaluate the detection performance of 18 F-PSMA-1007 PET/CT in primary prostate cancer patients. METHODS: An update on the databases of PubMed/MEDLINE, EMBASE, and Cochrane Library for comprehensive literature search was performed on September 30, 2021. The pooling detection rate was calculated on a per-patient basis. The pooling median of the SUV max was analyzed from the included studies. Furthermore, the positive predictive value of 18 F-PSMA-1007 PET/CT with pathologic lesions was analyzed using the criterion standard. RESULTS: Twelve studies (540 patients total) were included in the meta-analysis. The overall pooling detection rate of 18 F-PSMA-1007 per patient was 94%, and the pooling median of SUV max located at the intraprostate tumor was 16 (range, 3.7-77.7). The positive predictive value of 18 F-PSMA-1007 per lesion with histopathological validation was 0.90, detecting regional lymph node metastasis was 0.94, and detecting localized prostatic tumors was 0.84. CONCLUSIONS: In the current meta-analysis, we revealed the excellent performance of 18 F-PSMA-1007 to detect localized prostatic tumor lesions and regional lymph node metastasis. Moreover, the uptake of localized tumors in primary prostate cancer was nearly liver uptake and may be considered a suspicious malignancy if it was equal to or greater than the liver uptake.

A survey of erectile dysfunction in Taiwan: use of the erection hardness score and quality of erection questionnaire.

INTRODUCTION: There are currently no studies in the Asia-Pacific region using the erection hardness score (EHS) and Quality of Erection Questionnaire (QEQ) to assess erectile dysfunction (ED). AIMS: To provide up-to-date data on the prevalence of ED in Taiwanese men and to validate the EHS and QEQ in this population. METHODS: A representative sample of 1,060 men aged ≥ 30 years completed a telephone interview. ED status was confirmed via direct questioning and using the abridged five-item version of the 15-item International Index of Erectile Function (IIEF-5). Responses regarding EHS, QEQ, marital and sexual satisfaction, and attitude to treatment were also recorded. MAIN OUTCOME MEASURES: IIEF, EHS, and QEQ. RESULTS: The prevalence of ED, as defined by IIEF-5, was 27% among all respondents and 29% among those aged ≥ 40 years. Although, the prevalence of ED increased with age, men of all ages tended to underestimate their erectile problems. Among men who indicated that they did not have ED, 25% were found to have mild to moderate ED according to the IIEF-5 assessment. An EHS ≤ 3, indicating the presence of ED, was reported in 26% of men. The EHS was consistent with the QEQ: When the EHS was 4, the satisfaction of each domain of QEQ ranged from 85% to 90%. The QEQ score correlated well with the IIEF-5 score and significantly affected both sexual and marital satisfaction (P < 0.005). CONCLUSIONS: These data indicate that EHS is a simple, practical tool for clinical use. QEQ scores appear to be independently associated with sexual and marital satisfaction, and may be of value in the assessment and monitoring of ED patients. While ED is a common health problem in Taiwan and the prevalence of ED increases with age, affected men lack awareness regarding the presence of erectile problems and the importance of initiating timely and effective treatment.

Technical modification of retroperitoneal laparoscopic adrenalectomy for primary hyperaldosteronism and clinical outcomes.

BACKGROUND/OBJECTIVE: Standard laparoscopic adrenalectomy requires early control of the main adrenal vein; however, the small retroperitoneal working space is challenging for beginners to perform this maneuver. We report a technical modification of retroperitoneal laparoscopic adrenalectomy (RLA) for primary hyperaldosteronism (PHA) and the clinical outcomes. METHODS: A total of 38 RLAs were performed for the patients with PHA. The patients were placed in true lateral position with mild bending to expand the surgical field. Instead of attempting to control the main adrenal vein initially, we adopted a technical modification that manipulating and freeing the gland first before controlling the main adrenal vein. RESULTS: The RLAs were successfully performed in all but one case, which was converted to open surgery due to pancreatic injury. Mean operative time was 124 minutes and estimated blood loss was 74 ml. Mean maximal fluctuation of systolic blood pressure was 29 mmHg. For the right-side RLA, less operative time (113.5 vs. 137.9 minutes) and estimated blood loss (59.5 vs. 91.2 ml) were noted compared with the left-side procedure. Postoperative complications included cerebrovascular accident in one patient, one surgical site hematoma, and two patients had postoperative fever. Potassium level returned to normal in all patients and 70% of the patients reduced their antihypertensives. CONCLUSION: Technical modification RLA for PHA without initial control of the main adrenal vein is a safe and feasible procedure. No vigorous blood pressure fluctuation was intraoperatively noted. No vascular injury occurred. Moreover, the right-side procedure became easier.

Impact of alfuzosin on sexual function in Taiwanese men with benign prostatic hyperplasia.

To assess the effect of alfuzosin (XATRAL) 10 mg once daily on sexual function in men with moderate to severe lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH), patients with suggestive symptomatic BPH, an International Prostate Symptom Score (IPSS) >8 (range of scores, 0-35), and sexual attempts at least once per month were enrolled. All patients received alfuzosin 10 mg once daily for 24 weeks and were asked to complete the IPSS test and Male Sexual Health Questionnaire at weeks 0 (baseline), 1, 4, 12, and 24. Other assessments included the International Index of Erectile Function-five-item version (range of scores: 5-25), as well as onset of action and peak urinary flow rate (Q(max)). From September 2006 to May 2008, 279 patients were enrolled from nine centers in Taiwan. At 24 weeks, alfuzosin effectively improved LUTS and quality of life, as demonstrated by a reduction in the IPSS total score (17.3 vs. 9.9, p < 0.001) and the IPSS bother score (3.8 vs. 2.5, p < 0.001). The majority (85%) of patients perceived an improvement of urinary symptoms within 1 month of administration. In patients with an International Index of Erectile Function-five-item version score of ≤16, alfuzosin significantly improved erectile disorder and satisfaction subscores at each time point (p ≤ 0.02). Prolonged-release alfuzosin effectively improved LUTS, quality of life, erectile function, and sexual satisfaction in men with BPH and mild to severe erectile dysfunction. Alfuzosin is an effective treatment option for the management of patients with BPH/LUTS and concomitant sexual dysfunction.

Low-dose testosterone treatment decreases oxidative damage in TM3 Leydig cells.

Testosterone replacement therapy has benefits for aging men and those with hypogonadism. However, the effects of exogenous testosterone on Leydig cells are still unclear and need to be clarified. In this report, we demonstrate that testosterone supplementation can reduce oxidative damage in Leydig cells. The TM3 Leydig cell line was used as an in vitro cell model in this study. Cytoprotective effects were identified with 100-nmol l⁻¹ testosterone treatment, but cytotoxic effects were found with ≥ 500-nmol l⁻¹ testosterone supplementation. Significantly reduced reactive oxygen species (ROS) generation, lipid peroxide contents and hypoxia induction factor (HIF)-1α stabilization and activation were found with 100-nmol l⁻¹ testosterone treatment. There was a 1.72-fold increase in ROS generation in the 500-nmol l⁻¹ compared to the 100-nmol l⁻¹ testosterone treatment. A 1.58-fold increase in steroidogenic acute regulatory protein (StAR) expression was found in 50-nmol l⁻¹ testosterone-treated cells (P < 0.01). Chemically induced hypoxia was attenuated by testosterone supplementation. Leydig cells treated with low-dose testosterone supplementation showed cytoprotection by decreasing ROS and lipid peroxides, increasing StAR expression and relieving hypoxia stress as demonstrated by HIF-1α stabilization. Increased oxidative damage was found with ≥ 500-nmol l⁻¹ testosterone manipulation. The mechanism governing the differential dose effects of testosterone on Leydig cells needs further investigation in order to shed light on testosterone replacement therapy.

Testosterone gel monotherapy improves sexual function of hypogonadal men mainly through restoring erection: evaluation by IIEF score.

OBJECTIVES: To use the International Index of Erectile Function (IIEF) to evaluate the improvement of erectile function and other sexual functions after testosterone monotherapy. Testosterone replacement therapy alone was reported to be effective for the improvement in sexual function in hypogonadal males. However, it is still unclear that which kind of the sexual function is most beneficial and to what extent the sexual function could be improved. METHODS: A double-blind, randomized, placebo-controlled study was conducted with a treatment group (n = 20) and control group (n = 20). Using a critical review of the different sexual functional domain scores of the IIEF-15 and the scores of the IIEF-5, we evaluated the sexual function of men in hypogonadal status before and after 3 months of testosterone gel treatment. Effect size was used to compare the drug effects for each sexual functional domain, and the results were confirmed by multivariate analysis. RESULTS: A total of 30 men remained at the end of the study. After 3 months of testosterone gel therapy for the hypogonadal men, the most beneficial effect on sexual function was erectile function, with sexual desire and orgasmic satisfaction insignificantly affected. CONCLUSIONS: The results of our study have shown that transdermal testosterone gel treatment for hypogonadal patients can improve their sexual dysfunction mainly through restoring erectile function.

Increase of oxidative stress in human sperm with lower motility.

OBJECTIVE: To investigate the causal role of oxidative-stress status on human sperm motility. DESIGN: To demonstrate that sperm with higher oxidative damage have a lower antioxidant capacity. SETTING: University hospital infertility center. PATIENT(S): Seventy-eight semen samples were obtained from 35 healthy donors who had normal semen characteristics and from 43 infertile or subfertile males. INTERVENTION(S): The levels of oxidative damage (8-hydroxy-2'-deoxyguanosine [8-OHdG] and lipid peroxides) and antioxidants (retinol, alpha-tocopherol, ascorbate, and protein thiols) in the spermatozoa and/or seminal plasma were measured. MAIN OUTCOME MEASURE(S): We analyzed the specific content of 8-OHdG and lipid peroxides by using high-performance liquid chromatography (HPLC)-electrochemical detection and HPLC-fluorescence analysis, respectively. Retinol and alpha-tocopherol were analyzed by using an HPLC system, whereas ascorbate and protein thiols were determined by using spectrophotometry. 8-Hydroxy-2'-deoxyguanosine was visualized by immunofluorescent staining with an anti-8-OHdG antibody that was conjugated with fluorescein isothiocyanate conjugate. Lipid peroxides in spermatozoa were stained with a fluorescent dye, C11-BODIPY(581/591). RESULT(S): Statistically significant negative correlations were revealed between sperm motility and 8-OHdG and between motility and lipid peroxides. Statistically significant positive correlations were found between sperm motility and the levels of retinol, alpha-tocopherol, ascorbate, and protein thiols of seminal plasma. 8-Hydroxy-2'-deoxyguanosine and lipid peroxides in spermatozoa were found to be present mostly in mitochondria. CONCLUSION(S): Oxidative stress and oxidative damage were increased significantly in spermatozoa with declined motility, and the antioxidant capacities in the spermatozoa and seminal plasma were lower in males who had infertility or subfertility.