Pathological significance and prognostic role of LATS2 in prostate cancer.

BACKGROUND: Large tumor suppressor 2 (LATS2) is an important regulator of the Hippo pathway and it plays crucial roles in cell survival and behaviors. Herein, we evaluated the pathological roles of LATS2 in prostate cancer (PC), for which very little information is available. METHODS: Cell proliferation, migration, and invasion in response to the siRNA-mediated knockdown (KD) LATS2 expression were evaluated in two PC cell lines (LNCaP and PC3). The expression of LATS2 in specimens from 204 PC patients was investigated immunohistochemically, and the relationships between its expression and clinicopathological features, proliferation index (PI; measured using an anti-KI-67 antibody), and biochemical recurrence (BCR) were investigated. RESULTS: KD of LATS2 increased the growth, migration, and invasion in LNCaP cells and only increased migration in PC3 cells. The expression of LATS2 was negatively associated with the grade group, T, N, M stage, and PI. In addition, the expression of LATS2 was a useful predictor of the histological effects of neoadjuvant hormonal therapy and BCR-free survival periods. A multivariate analysis model including clinicopathological features showed that negative expression of LATS2 had a significantly higher risk of BCR (odds ratio = 2.95, P < 0.001). CONCLUSIONS: LATS2 acts as a tumor suppressor in PC. LATS2 expression is a useful predictor for BCR. LATS2-related activities are possibly dependent on the androgen-dependency of PC cells. Therefore, we suggest that LATS2 could be a potential therapeutic target and a useful predictor for outcome in patients with PC.

Age-associated bladder and urethral coordination impairment and changes in urethral oxidative stress in rats.

AIMS: We examined age-associated changes in bladder and urethral coordination involving the nitric oxide (NO)/soluble guanylyl cyclase (sGC) system, which induces urethral smooth muscle relaxation, and urethral ischemic/oxidative stress changes in rats. MAIN METHODS: Sixteen female Sprague-Dawley rats were divided into young (3 months old) and middle-aged (12-15 months old) groups. Urethral activity was evaluated by simultaneously recording intravesical pressure under isovolumetric conditions and urethral perfusion pressure (UPP) under urethane anesthesia. Sodium nitroprusside (SNP, 0.1 mg/kg), an NO donor, and BAY 41-2272, a novel NO-independent stimulator of sGC (0.1 mg/kg), were administered intravenously to both groups. N-nitro-l-arginine methyl ester hydrochloride (l-NAME, 100 mg/kg) was also injected intravenously, to inhibit NO synthase activity in both groups. Staining for the ischemic marker, hypoxia-inducible factor-1α (HIF-1α), and the oxidative stress markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA), was performed on tissue sections of the urethra, in both groups. KEY FINDINGS: Baseline UPP and UPP changes were significantly lower in middle-aged rats than in young rats. After administration of SNP and BAY 41-2272, baseline UPP and UPP nadir were significantly decreased in both groups. After administration of l-NAME, UPP change/bladder contraction amplitude in young rats was still lower than at baseline but was completely restored to control levels in middle-aged rats. Immunoreactivity of HIF-1α, 8-OHdG, and MDA was higher in middle-aged rats than in young rats. SIGNIFICANCE: Age-associated ischemic and oxidative stress in the urethra might be correlated with impairment of the NO/sGC system and with coordination of the bladder and urethra.

Efficacy of salt reduction for managing overactive bladder symptoms: a prospective study in patients with excessive daily salt intake.

This study aimed to investigate the efficacy of salt intake restriction on overactive bladder (OAB) symptoms in patients with excessive salt intake. Patients received a brochure on nutritional guidance regarding salt intake reduction and received health education every 4 weeks for 12 weeks. Data from overactive bladder symptom score (OABSS) questionnaires and frequency volume charts (FVCs) were evaluated. The daily salt intake was estimated by determining the urinary sodium and creatinine concentrations using spot urine samples. Of the 98 patients included, 71 (72.4%) successfully restricted their daily salt intake after 12 weeks (salt restricted [R] group), while 27 (27.6%) did not (salt non-restricted [N-R] group). The scores to each OABSS question and the resulting total score improved significantly in the R group; however, the individual scores remained unchanged and the total score increased in the N-R group. The FVC data indicated improved voided volumes in the R group as compared to in the N-R group. Ultimately, 17 (23.9%) patients in the R group no longer fulfilled the OAB diagnostic criteria after salt intake reduction. Thus, salt intake reduction improved urinary symptoms in patients with OAB and may be a therapeutic option for OAB in patients with excessive daily salt intakes.

Presurgical bladder wall thickness is a useful marker to predict the postsurgical improvement of symptoms in patients with pelvic organ prolapse-related overactive bladder.

OBJECTIVES: Pelvic organ prolapse (POP) is a cause of overactive bladder (OAB), and transvaginal mesh (TVM) surgery can improve the symptoms. Bladder wall thickness (BWT) is a useful and safe marker to evaluate bladder function in urinary disorders. The main purpose of this study is to clarify the relationship between BWT and changes in the OAB symptom score (OABSS) after TVM operation in patients with POP. METHODS: BWT was measured by ultrasonography before and 6 months after surgery at three sites in the bladder: the anterior wall, trigone, and dome. Similarly, the OABSS was evaluated at the time of BWT measurement. Changes induced in BWT at each site and the mean BWT at all sites after TVM surgery were analyzed. Similarly, the relationship between presurgical BWT and the decrease in OABSS was investigated. RESULTS: TVM surgery improved OABSS in 30 patients (responders; 73.2%), while 11 patients were judged as nonresponders (26.8%). BWT at the anterior bladder wall and dome as well as the mean BWT at all three sites were significantly decreased by TVM surgery (P < .001). Similar trends were identified in OABSS responders; however, all markers showed no significant changes in OABSS nonresponders. All the BWT-related markers before surgery were significantly lower in OABSS responders than in OABSS nonresponders. CONCLUSIONS: BWT at the bladder anterior wall and dome, but not the trigone, were decreased by TVM surgery. We conclude that presurgical BWT may be a useful marker to predict the improvement in OAB symptoms by TVM surgery in patients with POP-related OAB.

Pharmacological Effects and Potential Clinical Usefulness of Polyphenols in Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is arguably the most common benign disease among men. This disease is often associated with lower urinary tract symptoms (LUTS) in men and significantly decreases the quality of life. Polyphenol consumption reportedly plays an important role in the prevention of many diseases, including BPH. In recent years, in addition to disease prevention, many studies have reported the efficacy and safety of polyphenol treatment against various pathological conditions in vivo and in vitro. Furthermore, numerous studies have also revealed the molecular mechanisms of the antioxidant and anti-inflammatory effects of polyphenols. We believe that an improved understanding of the detailed pharmacological roles of polyphenol-induced activities at a molecular level is important for the prevention and treatment of BPH. Polyphenols are composed of many members, and their biological roles differ. In this review, we first provide information regarding the pathological roles of oxidative stress and inflammation in BPH. Next, the antioxidant and anti-inflammatory effects of polyphenols, including those of flavonoids and non-flavonoids, are discussed. Finally, we talk about the results and limitations of previous clinical trials that have used polyphenols in BPH, with particular focus on their molecular mechanisms of action.

Excessive accumulation of visceral fat is associated with lower urinary symptoms including overactive bladder in female patients.

OBJECTIVE: To assess the relationship between visceral fat accumulation and lower urinary tract symptoms in female patients. METHODS: In this single-center study, we enrolled all women who underwent screening abdominal computed tomography 3 months before the study, irrespective of whether they experienced lower urinary tract symptoms. The Overactive Bladder Symptom Score was used to assess subjective symptoms. Uroflowmetry and ultrasound assessment of post-void residual urine were carried out to assess objective signs. We analyzed the relationship between lower urinary tract symptoms and various body fat accumulation parameters, including visceral fat area, visceral fat volume and total abdominal fat volume, assessed using computed tomography scans. RESULTS: A total of 182 patients were divided into the overactive bladder (n = 71, 39.0%) and the non-overactive bladder (n = 111, 61.0%) groups. The visceral fat area, visceral fat volume and visceral fat volume/total abdominal fat volume values were all significantly higher in the overactive bladder group than in the non-overactive bladder group (P < 0.001). Of these parameters, the visceral fat volume/total abdominal fat volume ratio showed the strongest correlation with the total Overactive Bladder Symptom Score (r = 0.394, P < 0.001). The maximum urine flow rate correlated negatively with the visceral fat volume/total abdominal fat volume value (visceral fat volume/total abdominal fat volume r = -0.289, P < 0.001). Subsequent multivariate analysis showed that a high visceral fat volume/total abdominal fat volume value, age and metabolic syndrome-related diseases were independent risk factors for the presence of overactive bladder. CONCLUSIONS: Excessive accumulation of visceral fat is independently associated with overactive bladder in females.

Present Status, Limitations and Future Directions of Treatment Strategies Using Fucoidan-Based Therapies in Bladder Cancer.

Bladder cancer (BC) is a common urological cancer, with poor prognosis for advanced/metastatic stages. Various intensive treatments, including radical cystectomy, chemotherapy, immune therapy, and radiotherapy are commonly used for these patients. However, these treatments often cause complications and adverse events. Therefore, researchers are exploring the efficacy of natural product-based treatment strategies in BC patients. Fucoidan, derived from marine brown algae, is recognized as a multi-functional and safe substrate, and has been reported to have anti-cancer effects in various types of malignancies. Additionally, in vivo and in vitro studies have reported the protective effects of fucoidan against cancer-related cachexia and chemotherapeutic agent-induced adverse events. In this review, we have introduced the anti-cancer effects of fucoidan extracts in BC and highlighted its molecular mechanisms. We have also shown the anti-cancer effects of fucoidan therapy with conventional chemotherapeutic agents and new treatment strategies using fucoidan-based nanoparticles in various malignancies. Moreover, apart from the improvement of anti-cancer effects by fucoidan, its protective effects against cancer-related disorders and cisplatin-induced toxicities have been introduced. However, the available information is insufficient to conclude the clinical usefulness of fucoidan-based treatments in BC patients. Therefore, we have indicated the aspects that need to be considered regarding fucoidan-based treatments and future directions for the treatment of BC.

Erratum: Oral intake of royal jelly improves anti-cancer effects and suppresses adverse events of molecular targeted therapy by regulating TNF-α and TGF-ß in renal cell carcinoma: A preliminary study based on a randomized double-blind clinical trial.

[This corrects the article DOI: 10.3892/mco.2020.2099.].

Mechanisms Underlying the Inhibition of Tyrosine Kinase Inhibitor-Induced Anorexia and Fatigue by Royal Jelly in Renal Cell Carcinoma Patients and the Correlation between Macrophage Colony Stimulating Factor and Inflammatory Mediators.

Inflammation is a common adverse event of anti-cancer therapy. Royal jelly (RJ) modulates inflammation by regulating the levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß, and interleukin (IL)-6 produced by macrophages. Macrophage colony stimulating factor (M-CSF) is a crucial regulator of macrophage activities, and we hypothesized that RJ alters M-CSF levels. In this randomized controlled trial, we investigated the association between M-CSF and adverse events in renal cell carcinoma patients treated with tyrosine kinase inhibitors (TKIs) after an oral intake of RJ (n = 16) or placebo (n = 17). The serum levels of M-CSF, TNF-α, TGF-ß, and IL-6 were measured by an enzyme-linked immunosorbent assay, and their temporal changes and correlation between such changes were analyzed. The post-/pretreatment ratio of M-CSF levels was associated with anorexia after 2 weeks and fatigue after 2, 4, and 12 weeks. The M-CSF level in the RJ group was higher than that in the placebo group at the same timepoints. The TNF-α level in the RJ group was lower than that in the placebo group between 6 and 12 weeks, and the TGF-ß level in the RJ group was higher than that in the placebo group; however, contrasting findings were detected after 12 weeks. Additionally, the M-CSF level was significantly correlated with the TGF-ß level after 4 weeks and IL-6 level after 8 and 10 weeks. Among TNF-α, TGF-ß, and IL-6, the post-/pretreatment ratio of TGF-ß after 12 weeks was associated with TKI-induced anorexia, and the ratios after 10 and 12 weeks were associated with fatigue. Our results demonstrated that an oral intake of RJ suppressed anorexia and fatigue via complex mechanisms associated with inflammation-related factors, such as M-CSF and TGF-ß in renal cell carcinoma patients treated with TKIs. In addition, we newly found that such RJ-related effects were dependent on the treatment duration.

Relationship Between Stage-specific Embryonic Antigen-4 and Anti-cancer Effects of Neoadjuvant Hormonal Therapy in Prostate Cancer.

BACKGROUND/AIM: Stage-specific embryonic antigen-4 (SSEA-4) expression is associated with malignant aggressiveness and is useful as a marker for identifying cancer stem cells. Our aim was to assess the relationship between hormonal therapy and SSEA-4 expression in prostate cancer (PC). MATERIALS AND METHODS: SSEA-4 expression in paired specimens from PC patients who underwent neoadjuvant hormonal therapy (NHT) and radical prostatectomy (60 pre-NHT specimens and 60 post-NHT specimens) was evaluated using immunohistochemistry. Proliferation index (PI) and apoptotic index (AI) were also evaluated. RESULTS: Post-NHT tissues had significantly elevated SSEA-4 expression whereas anti-tumor effects of NHT were inversely correlated with SSEA-4 expression level. SSEA-4 expression in post-NHT tissues was significantly associated with biochemical recurrence-free survival. SSEA-4 expression in the post-NHT tissues was positively associated with PI and negatively done with AI. CONCLUSION: SSEA-4 is a potential therapeutic target for limiting the malignant potential in hormone-naïve PC when considering the use of NHT.

Oral intake of royal jelly improves anti-cancer effects and suppresses adverse events of molecular targeted therapy by regulating TNF-α and TGF-ß in renal cell carcinoma: A preliminary study based on a randomized double-blind clinical trial.

Molecular targeted therapies are commonly used in patients with metastatic renal cell carcinoma (RCC). However, the efficacy and safety of these therapeutic interventions require enhancement to improve prognosis in these patients. Royal jelly (RJ) has anti-cancer effects and adverse events across a variety of types of malignancy. The present study investigated the detailed mechanism underlying the effects of oral administration of RJ in patients with advanced RCC that were treated with molecular targeted agents in a randomized clinical trial. The study cohort comprised 16 patients treated with RJ and 17 patients treated with a placebo. Serum levels of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-ß were measured using enzyme-linked immunosorbent assays. The results of the present study demonstrated a larger decrease in tumor size upon supplementing patients with RJ following molecular targeted therapy compared with that in patients administered with the placebo. Patients exhibited reduced anorexia and fatigue in the RJ group compared with the placebo group. The relative dose intensity for patients in the RJ group was higher than that in patients in the placebo group. Post- and pre-treatment ratios of the serum levels of TNF-α and TGF-ß in patients in the RJ group were lower than those in patients in the placebo group, and these ratios correlated with decreasing tumor size and frequency of anorexia or fatigue in patients. In conclusion, the results of the present study indicated that oral intake of RJ improved the efficacy and safety of molecular targeted therapy in patients with RCC and changed the levels of TNF-α and TGF-ß in the serum of patients, which is speculated to serve an important role in RJ-induced biological activities.

Pathological roles of c-Met in bladder cancer: Association with cyclooxygenase-2, heme oxygenase-1, vascular endothelial growth factor-A and programmed death ligand 1.

c-Met is a receptor tyrosine kinase that binds a specific ligand, namely hepatocyte growth factor (HGF). The HGF/c-Met system is important for malignant aggressiveness in various types of cancer, including bladder cancer (BC). However, although phosphorylation is the essential step required for biological activation of c-Met, pathological roles of phosphorylated c-Met at the clinical and molecular levels in patients with BC are not fully understood. In the present study, the expression levels of c-Met and the phosphorylation of two of its tyrosine residues (pY1234/pY1235 and pY1349) were immunohistochemically examined in 185 BC tissues. The associations between these expression levels and cancer cell invasion, metastasis, and cyclooxygenase-2 (COX-2), heme oxygenase-1 (HO-1), VEGF-A and programmed death ligand 1 (PD-L1) levels were investigated. c-Met was associated with muscle invasion (P=0.021), as well as the expression levels of HO-1 (P=0.028) and PD-L1 (P<0.001), whereas pY1349 c-Met was associated with muscle invasion (P=0.003), metastasis (P=0.025), and COX-2 (P=0.017), HO-1 (P=0.031) and PD-L1 (P=0.001) expression. By contrast, pY1234/1235 c-Met was associated with muscle invasion and metastasis (P=0.006 and P=0.012, respectively), but not with the panel of cancer-associated molecules. Furthermore, COX-2 and PD-L1 expression were associated with muscle invasion and metastasis, respectively (P=0.045 and P=0.036, respectively). Hence, c-Met serves important roles in muscle invasion by regulating HO-1 and PD-L1, whereas its phosphorylation at Y1349 is associated with muscle invasion and metastasis via the regulation of COX-2, HO-1 and PD-L1 in patients with BC. Furthermore, phosphorylation at Y1234/1235 may lead to muscle invasion and metastasis via alternate mechanisms associated with c-Met and pY1349 c-Met.

Molecular Mechanisms of the Anti-Cancer Effects of Isothiocyanates from Cruciferous Vegetables in Bladder Cancer.

Bladder cancer (BC) is a representative of urological cancer with a high recurrence and metastasis potential. Currently, cisplatin-based chemotherapy and immune checkpoint inhibitors are used as standard therapy in patients with advanced/metastatic BC. However, these therapies often show severe adverse events, and prolongation of survival is unsatisfactory. Therefore, a treatment strategy using natural compounds is of great interest. In this review, we focused on the anti-cancer effects of isothiocyanates (ITCs) derived from cruciferous vegetables, which are widely cultivated and consumed in many regions worldwide. Specifically, we discuss the anti-cancer effects of four ITC compounds-allyl isothiocyanate, benzyl isothiocyanate, sulforaphane, and phenethyl isothiocyanate-in BC; the molecular mechanisms underlying their anti-cancer effects; current trends and future direction of ITC-based treatment strategies; and the carcinogenic potential of ITCs. We also discuss the advantages and limitations of each ITC in BC treatment, furthering the consideration of ITCs in treatment strategies and for improving the prognosis of patients with BC.

Efficacy of Tadalafil Therapy and Changes in Oxidative Stress Levels in Male Patients with Lower Urinary Tract Symptoms and Overactive Bladder.

OBJECTIVE: To evaluate the effects of tadalafil monotherapy on lower urinary tract symptoms, urodynamic parameters, and oxidative stress levels in male patients. METHODS: This prospective study included 53 male patients with urinary symptoms, who met the criteria for overactive bladder (OAB) (≥ 2 points for Q3 [urgency] in the OAB symptom score [OABSS] assessment and ≥ 3 points for the total score). The patients received 5 mg tadalafil orally once daily, and their symptoms were assessed before and after the 12-week treatment. The OABSS and international prostate symptom score (IPSS) were used to evaluate the subjective symptoms. The objective findings were assessed using uroflowmetry. Oxidative stress was assessed by determining urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels with an adjustment for urinary creatinine (CR) concentration. RESULTS: After tadalafil administration, total and individual indices of the OABSS assessment showed significant improvement. In addition, total storage and voiding symptoms that contributed to the IPSS were also significantly improved. The voided volume was increased, and the maximum flow rate was improved after tadalafil treatment (P = .002 and < 0.001, respectively). Urinary 8-OHdG/CR decreased from 12.4 ± 9.7 ng/mg CR to 7.6 ± 11.6 ng/mg CR (P < .001). In patients who showed OAB improvement and did not meet the criteria for OAB after the treatment (44 patients, 83.0%), the urinary 8-OHdG/CR level was significantly decreased from 11.6 ± 8.4 ng/mg CR to 6.4 ± 10.3 ng/mg CR (P < .001). CONCLUSIONS: Tadalafil treatment improves OAB symptoms and urodynamic parameters by decreasing oxidative stress level.

Four-weekly Low-dose Gemcitabine and Paclitaxel in Patients With Platinum-resistant Urothelial Cancer and Performance Status 2/3.

BACKGROUND/AIM: Immune check-point inhibitors are often unsuitable for patients with urothelial cancer with a poor performance status (PS 2 or 3). The aim of this study was to assess the safety and usefulness of combined therapy with low-dose gemcitabine and paclitaxel every 4 weeks. PATIENTS AND METHODS: Thirty patients were treated with gemcitabine (700 mg/m2 on day 1) and paclitaxel (70 mg/m2 on day 1) every 4 weeks. The predictive value of human antigen-R (HuR) and class III ß-tubulin (TUBB3) were also analyzed. RESULTS: There was no severe adverse event nor significant decrease in quality of life. The survival period of patients treated with this regimen was significantly longer than that of those treated with best supportive care. The expression pattern of HuR negativity and TUBB3 positivity predicted significantly worse overall survival. CONCLUSION: Our regimen was suitable as second-line therapy for patients with advanced platinum-resistant UC with a poor PS. However, a HuR-negative and TUBB3-positive expression pattern appears to confer poorer outcome.