Transcriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis.

BACKGROUND: Heterogeneous nuclear ribonucleoprotein K (HnRNPK) is a nucleic acid-binding protein that regulates diverse biological events. Pathologically, HnRNPK proteins are frequently overexpressed and clinically correlated with poor prognosis in various types of human cancers and are therefore pursued as attractive therapeutic targets for select patients. However, both the transcriptional regulation and degradation of HnRNPK in prostate cancer remain poorly understood. METHODS: qRT-PCR was used to detect the expression of HnRNPK mRNA and miRNA; Immunoblots and immunohistochemical assays were used to determine the levels of HnRNPK and other proteins. Flow cytometry was used to investigate cell cycle stage. MTS and clonogenic assays were used to investigate cell proliferation. Immunoprecipitation was used to analyse the interaction between SPOP and HnRNPK. A prostate carcinoma xenograft mouse model was used to detect the in vivo effects of HnRNPK and miRNA. RESULTS: In the present study, we noted that HnRNPK emerged as an important player in the carcinogenesis process of prostate cancer. miR-206 and miR-613 suppressed HnRNPK expression by targeting its 3'-UTR in PrCa cell lines in which HnRNPK is overexpressed. To explore the potential biological function, proliferation and colony formation of PrCa cells in vitro and tumor growth in vivo were also dramatically suppressed upon reintroduction of miR-206/miR-613. We have further provided evidence that Cullin 3 SPOP is a novel upstream E3 ubiquitin ligase complex that governs HnRNPK protein stability and oncogenic functions by promoting the degradation of HnRNPK in polyubiquitination-dependent proteolysis in the prostate cancer setting. Moreover, prostate cancer-associated SPOP mutants fail to interact with and promote the destruction of HnRNPK proteins. CONCLUSION: Our findings reveal new posttranscriptional and posttranslational modification mechanisms of HnRNPK regulation via miR-206/miR-613 and SPOP, respectively. More importantly, given the critical oncogenic role of HnRNPK and the high frequency of SPOP mutations in prostate cancer, our results provide a molecular rationale for the clinical investigation of novel strategies to combat prostate cancer based on SPOP genetic status.

Roles of the Exogenous H2S-Mediated SR-A Signaling Pathway in Renal Ischemia/ Reperfusion Injury in Regulating Endoplasmic Reticulum Stress-Induced Autophagy in a Rat Model.

OBJECTIVE: This study aims to explore the effects of the exogenous hydrogen sulfide (H2S)-mediated scavenger receptor A (SR-A) signaling pathway on renal ischemia/reperfusion injury (IRI) by regulating endoplasmic reticulum (ER) stress-induced autophagy in rats. METHODS: A total of 48 normal Sprague-Dawley (SD) rats and SR-A knockout rats were selected and divided into six groups (n = 8): wild-type (WT) + sham, WT + ischemia-reperfusion (I/R), WT + I/R + NaHS, SR-A-/- + sham, SR-A-/- + I/R and SR-A-/- + I/R + NaHS. The concentrations of urinary protein, blood urea nitrogen (BUN), serum creatinine (SCR), malondialdehyde (MDA) and H2S in renal tissue were detected. qRT-PCR and Western blotting were used to detect the mRNA and protein levels of IL-6, TGF-ß, SR-A, LC3I, LC3II, P62, PERK, ATF6 and IRE1 pathway-related genes. A TUNEL assay was used to detect cell apoptosis. Electron microscopy was applied to observe the structure of renal autophagosomes. RESULTS: Compared with the WT + sham group, in the rates of the WT + I/R group, the urine volume, urinary protein, BUN, SCR and MDA concentrations, the mRNA and protein expression of IL-6, TGF-ß, LC3II/I, and ER stress pathway-related genes, the cell apoptosis index, and the number of autophagosomes were significantly increased 24 h after I/R, while P62 and SR-A protein expression and SOD and H2S concentrations were significantly decreased (all P < 0.05). The levels of renal injury, autophagy and ER stress pathway-related genes were decreased in the WT + I/R + NaHS group but were increased in the SR-A-/- + I/R group relative to the WT + I/R group. No significant differences were observed in the urine volume; the concentrations of urinary protein, BUN, SCR and MDA; the SOD activity; the mRNA and protein expression of IL-6, TGF-ß, SR-A, GRP78, SR-A, GPR94, ATF4, IRE1, XBP1, ATF6, and eIF2α; the cell apoptosis index; or the number of autophagosomes in rats of the SR-A-/- + I/R and SR-A-/- + I/R + NaHS groups (all P > 0.05). CONCLUSION: These results demonstrate that the exogenous H2S-mediated SR-A signaling pathway reduces renal IRI injury by up-regulating ER stress-induced autophagy in rats.

Decreased Endogenous Hydrogen Sulfide Generation in Penile Tissues of Diabetic Rats with Erectile Dysfunction.

INTRODUCTION: Hydrogen sulfide (H2S) is an endogenous gasotransmitter. The levels of H2S-generating enzyme expression and endogenous H2S production in diabetic rats with erectile dysfunction (ED) remain unknown. The aim of this study was to investigate the expression of the H2S-generating enzymes and endogenous production of H2S in penile tissues of diabetic ED rats. METHODS: Experimental rats were randomly divided into normal control group, apomorphine (APO)-positive group and APO-negative group. Primary rat corpus cavernosum smooth muscle cells (CCSMCs) and aortic endothelial cells (AECs) were isolated and cultured in vitro under 3 different conditions: normal glucose (NG) condition, high glucose (HG) condition, and osmotic control (OC) condition. MAIN OUTCOME MEASURES: Erectile function; H2S concentrations in plasma or penile tissues; expression of H2S-generating enzymes and endogenous H2S production in penile tissues, CCSMCs, and AECs. RESULTS: Erectile function was significantly decreasedin the APO-negative group. In addition to significantly decreased expression of cysteine aminotransferase (CAT), d-amino acid oxidase (DAO), and 3-mercaptopyruvate sulfurtransferase (3-MST), the H2S concentrations in plasma and penile tissues and endogenous H2S production were significantly decreased in the APO-negative group. Endogenous H2S production by cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE) decreased to the same levels in the APO-negative and APO-positive groups as that in the normal control group. However, CBS and CSE expression remained unchanged in the 3 groups. Under HG conditions, H2S-generating enzyme expression in AECs did not change, while CAT, DAO, and 3-MST expression in CCSMCs was significantly decreased. In both cell types, H2S production by these enzymes was decreased in the HG group. CONCLUSION: Endogenous H2S production was significantly decreased in the diabetic ED rats' penile tissues due to downregulated expression of the CAT/3-MST and DAO/3-MST pathways and low activities of CBS and CSE.

Abiraterone acetate for metastatic castration-resistant prostate cancer after docetaxel failure: A randomized, double-blind, placebo-controlled phase 3 bridging study.

OBJECTIVES: To evaluate the efficacy and safety of abiraterone acetate-prednisone versus placebo-prednisone in Asian metastatic castration-resistant prostate cancer patients who have failed docetaxel-based chemotherapy. METHODS: In this double-blind, phase 3 study from China, 214 patients were randomized (2:1) to abiraterone acetate 1000 mg once daily plus prednisone 5 mg twice daily and placebo plus prednisone 5 mg twice daily in 28-day treatment cycles. RESULTS: Abiraterone acetate-prednisone treatment significantly decreased prostate-specific antigen progression risk by 49%, with longer median time to prostate-specific antigen progression of 5.55 months versus 2.76 months in the placebo-prednisone group (hazard ratio 0.506, P = 0.0001, primary end-point). There was a strong trend for improved overall survival in the abiraterone acetate-prednisone group, with a 40% decrease in the risk of death (hazard ratio 0.604, P = 0.0597); however, median survival was not reached in either group because of the short follow-up period (12.9 months) and limited number of observed death events. The prostate-specific antigen response rate was higher in the abiraterone-prednisone group (49.7%) than in the placebo-prednisone group (14.1%). A total of 37.1% patients in this group had pain progression events compared with 50.7% in the placebo-prednisone group. Abiraterone-prednisone significantly decreased the risk of pain progression by 50% (hazard ratio 0.496, P = 0.0014). The incidence of adverse events was similar between the two groups; the most common adverse events being anemia (25.9% for abiraterone-prednisone vs 22.5% for placebo-prednisone), hypokalemia (25.9% and 11.3%), bone pain (23.8% and 21.1%), hypertension (16.1% and 12.7%) and increased aspartate aminotransferase (14.7% and 15.5%), respectively. CONCLUSIONS: Abiraterone-prednisone significantly delays disease and pain progression, and prostate-specific antigen, with a favorable benefit-risk ratio in Asian metastatic castration-resistant prostate cancer patients in the post-docetaxel setting.

[Concentration of basic fibroblast growth factor in plasma and cavernous corpus of aged rat].

OBJECTIVE: To investigate the concentration of basic fibroblast growth factor (bFGF) in aged rat plasma and penile tissues. METHODS: Twelve 24-month-old rats and ten 12-week-old rats were selected. We assessed the erectile responses of rats to cavernous nerve electrostimulation. Then the concentrations of bFGF in the rats' plasma and penile tissues were detected by ELISA kit and smooth muscle contents in the rats' cavernous corpus were evaluated by masson trichrome staining. RESULTS: Compared with the young rats, we found that the erectile function of the aged rats were significantly attenuated (The Max ICP/MAP in the aged rats were 0.41±0.05, 0.44±0.04 and 0.51±0.06 at 2.5 volts, 5.0 volts and 7.5 volts respectively while the Max ICP/MAP in the normal controls were 0.70±0.06, 0.75±0.07 and 0.81±0.04 at 2.5 volts, 5 volts and 7.5 volts respectively, P<0.05). The concentrations of bFGF [The bFGF levels in plasma and penile tissues in the aged rat were (6.43±0.51) µg/L and (598.6±51.7) pg/mg protein respectively while the bFGF levels in the normal control were (10.53±0.42) µg/L and (985.8±76.8) pg/mg protein] were significantly reduced (P<0.05). Furthermore, the smooth muscle contents in the aged rats' penile tissues (0.038±0.005) were dramatically decreased compared with the normal control (0.075±0.006, P<0.05). CONCLUSION: The reduced levels of bFGF may be related to the decreased smooth muscle contents in the penile tissues of the aged rats.

[Androgen may improve erectile function in castrated rats by regulating the ERK1/2 pathway].

OBJECTIVE: To investigate the role of the extracellular signal-regulated protein kinase 1/2 (ERK1/2) pathway in erectile dysfunction (ED) caused by the absence of testosterone (T). METHODS: We randomly divided 30 eight-week-old healthy male SD rats into groups A (control) , B (castration), and C (castration + androgen replacement). The rats in groups B and C were castrated surgically, and those in C injected with T undecanoate (100 mg/kg) at 1 week after castration, while the others with 0.9% normal saline instead. At 1 month after treatment, we determined the serum T level, intracavernous pressure (ICP), and mean carotid arterial pressure (MAP) of the rats, and detected the expressions of ERK1/2 and endothelial nitric oxide synthase (eNOS) by Western blot. RESULTS: The serum T level was significantly lower in group B ([1.27 ± 0.48] nmol/L) than in A ([17.14 ± 1.07] nmol/L) and C ([16.24 ± 1.90] nmol/L) (P < 0.05), and so were ICP and MAP (P < 0.05). The expression of ERK1/2 showed no statistically significant differences among the three groups (P > 0.05), that of phosphatase ERK1/2 was markedly higher while that of eNOS remarkably lower in group B than in A and C (both P < 0.05). CONCLUSION: Androgen replacement may improve the erectile function of castrated rats by regulating the ERK1/2 pathway.

[Long noncoding RNAs in prostate cancer].

Long non-coding RNAs (lncRNAs) are a group of RNA molecules which are longer than 200 nucleotides. They do not have functional open reading frames and cannot encode proteins. Recent studies have demonstrated that lncRNAs are widely involved in the regulation of gene expression network at epigenetic, transcriptional and post-transcriptional levels, which may affect the growth, proliferation, differentiation, metabolism, apoptosis and other important physiological processes of cells. The abnormal expression of lncRNAs is closely associated with the development, invasion, metastasis and prognosis of tumors. The development of prostate cancer is a multi-factor and multi-step process, in which abnormal gene expression may play an important role. This review focuses on the recent progress in the studies on the role of lncRNAs in prostate cancer, aiming for some new clues to the clinical prevention, diagnosis and treatment of this malignancy.

Promoter-associated small double-stranded RNA interacts with heterogeneous nuclear ribonucleoprotein A2/B1 to induce transcriptional activation.

Several recent reports have demonstrated that small activating dsRNA [double-stranded RNA; saRNA (small activating dsRNA)] complementary to promoter regions can up-regulate gene expression in mammalian cells, a phenomenon termed RNAa (RNA activation). However, the mechanism of RNAa remains obscure with regard to what is the target molecule for promoter-targeted saRNA and what are the proteins involved in this process. p21Waf1/Cip1 (p21) [CDKN1A (cyclin-dependent kinase inhibitor 1A)], an important tumour suppressor gene, is among the genes that can be activated by RNAa in tumour cells. In the present study, we provide direct evidence that p21 promoter-targeted saRNA interact with its intended target on the p21 promoter to activate p21 expression. This process is associated with recruitment of RNA polymerase II and AGO2 (argonaute 2) protein to the saRNA-target site. Additionally, we found that several hnRNPs (heterogeneous nuclear ribonucleoproteins) (A1, A2/B1 and C1/C2) are associated with saRNA. Further studies show that hnRNPA2/B1 interacts with the saRNA in vivo and in vitro and is required for RNAa activity. These findings indicate that RNAa results from specific targeting of promoters and reveals additional mechanistic details of RNAa.

Curcumin induces cell cycle arrest and apoptosis of prostate cancer cells by regulating the expression of IkappaBalpha, c-Jun and androgen receptor.

Curcumin possesses chemopreventive properties against several types of cancer, but the molecular mechanisms by which it induces apoptosis of cancer cells and inhibits cancer cell proliferation are not clearly understood. To evaluate the antitumor activity of curcumin for prostate cancer, we used an androgen dependent LNCaP prostate cancer cell line and an androgen independent PC-3 prostate cancer cell line as experimental models. We treated these cells with curcumin and then evaluated the effects of curcumin on cell cycle profiling and apoptosis, as well as the activation of NF-kaapaB and c-jun in these cells. The results showed that the ratios of apoptosis in LNCaP and PC-3 cells were significantly elevated in a dose dependent manner after exposure to curcumin. In addition, curcumin induces the G2/M cell cycle arrest of LNCaP and PC-3 cells in a dose dependent manner. Mechanistically, we found that curcumin upregulated the protein level of NF-kappaB inhibitor IkappaBalpha and downregulated protein levels of c-Jun and AR. These data suggest that curcumin is a promising agent for the treatment of both androgen-dependent and androgen-independent prostate cancer.

Over-expression of LRIG3 suppresses growth and invasion of bladder cancer cells.

The purpose of this study was to investigate the impact of leucine-rich repeats and immunoglobulin-like domains 3 (LRIG3) on the biological features of bladder cancer cell lines. The plasmids of over-expressed LRIG3 and the blank plasmid serving as control were transfected into the bladder cancer cell lines, T24, EJ and BIU-87, and the expression levels of LRIG3 mRNA and protein were detected by using real-time PCR and Western blotting. The changes in the cell cycle and apoptosis were examined by using flow cytometry. The invasive ability was measured by Transwell assay, and CCK-8 assays were used to measure the proliferation of cells. As compared with the control group, the LRIG3 mRNA and protein expression levels in LRIG3 cDNA-transfected group were raised significantly (P<0.05). The average number of cells with up-regulated LRIG3 passing through the inserted filter was decreased significantly as compared with the control group (P<0.05). Up-regulation of LRIG3 also could inhibit proliferation and induce apoptosis of T24, EJ and BIU-87 cells. Except BIU-87, the T24 and EJ cells transfected with LIRG3 cDNA were arrested in G(0)/G(1) phase compared to the control group (P<0.05). In conclusion, the over-expression of LRIG3 could influence the cell cycle and invasion, inhibit proliferation and induce apoptosis in the three bladder cancer cell lines.

[Influence of photoselective vaporization of prostate on erectile function in patients with benign prostatic hyperplasia].

OBJECTIVE: To assess the influence of photoselective vaporization of the prostate (PVP) on the erectile function of the patient with benign prostatic hyperplasia (BPH). METHODS: Using IIEF-5, we conducted a questionnaire investigation among 210 BPH patients before and after treated by PVP (n = 80) and transurethral resection of the prostate (TURP, n = 130). We also reviewed the clinical data and compared the pre- and post-operative penile erectile function between the two groups of patients. RESULTS: Follow-up was completed in 76 cases of PVP and 123 of TURP. The baseline data showed no statistically significant differences between the two groups in age, prostate volume, IPSS, QOL, Qmax, post void urine residual volume and IIEF-5 scores (P>0.05). Compared with the IEFF-5 score at the baseline (21.88 +/- 2.46), those at 3, 6 and 12 months after PVP were 16.72 +/- 3.17, 19.34 +/- 2.46 and 19.29 +/- 2. 18, respectively, significantly decreased at 3 months (P = 0.042), but with no remarkable difference at 6 and 12 months (P >0.05). Nor were there significant differences in the IIEF-5 score between the PVP and TURP groups at any time points (P>0.05). At 6 months after surgery, the incidence rates of erectile dysfunction were 11.7% and 13.7% in the TURP and PVP groups, respectively (P>0.05). CONCLUSION: PVP may reduce erectile function in some cases in the early stage after surgery, but this adverse effect does not last long and is basically similar to that of TURP.

Apalutamide for metastatic castration-sensitive prostate cancer: final analysis of the Asian subpopulation in the TITAN trial.

The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan-Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg ( n = 111) or placebo ( n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.42-1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21-0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13-0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44-1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.

[Case-control study on the correlation of bladder cancer incidence and occupational factors].

OBJECTIVE: To explore the relationship between occupational factors and the incidence of bladder cancer. METHODS: The present research was based on a hospital-based case-control study. The cases were frequency matched. The non-conditional Logistic regression was used to calculate the odds ratio (OR) of each occupation. RESULTS: The OR of business and administration professionals, male electricians and electronic workers were 3.88 and 7.40; the OR of janitors and helpers was 0.21; the OR of handcrafted and printing clerks was 0.71, but there was no significant difference. CONCLUSION: Business and administration professionals, male electricians and electronic workers tend to have bladder cancer. The occupation of janitors and helpers has a protective effect on bladder cancer while the occupation of printing clerks shows no statistical significance on bladder cancer.

[Levels of cytokines and heat-shock protein 70 in the seminal plasma of patients with chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome].

OBJECTIVE: To assess the diagnostic value and potentially protective capacity of tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta) and heat-shock protein 70 (HSP70) in chronic bacterial prostatitis (CBP) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: We determined the levels of cytokines TNF-alpha, IL-1beta and HSP70 by ELISA in the seminal plasma of 150 men: 36 with CBP, 43 with CP/CPPS IIIA, 46 with CP/CPPS IIIB, and 25 healthy controls. We analyzed the correlation of the HSP70 expression in the CBP and CP/CPPS patients with the chronic prostatitis symptom index (CPSI). RESULTS: Significantly increased levels of TNF-alpha, IL-1beta and HSP70 were observed in the seminal plasma of the CBP patients as compared with the CP/CPPS patients and healthy controls. The expression of IL-1beta was significantly higher in the patients with CP/CPPS IIIA than in those with CP/CPPS III B and the controls, while the HSP70 level remarkably lower in those with CP/CPPS than in the controls, and its concentration in the seminal plasma of the CBP patients was negatively correlated with CPSI. CONCLUSION: The levels of HSP70 and IL-1beta in the seminal plasma appear to be most reliable molecular biological markers for the diagnosis of CBP and CP/CPPS, respectively. HSP7O has an important protective role in the regulation of cell functions in CBP patients. CP/CPPS is probably detrimental to the function of T cells and consequently suppresses the expression of HSP70.

Apalutamide for patients with metastatic castrationsensitive prostate cancer in East Asia: a subgroup analysis of the TITAN trial.

Ethnicity might be associated with treatment outcomes in advanced prostate cancer. This study aimed to evaluate the efficacy and safety of androgen deprivation therapy (ADT) combined with apalutamide in East Asians with metastatic castration-sensitive prostate cancer (mCSPC). The original phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial was conducted at 260 sites in 23 countries. This subgroup analysis included patients enrolled in 62 participating centers in China, Japan, and Korea. Radiographic progression-free survival (PFS), time to prostate-specific antigen (PSA) progression, and PSA changes from baseline were compared between groups in the East Asian population. The intent-to-treat East Asian population included 111 and 110 participants in the apalutamide and placebo groups, respectively. The 24-month radiographic PFS rates were 76.1% and 52.3% in the apalutamide and placebo groups, respectively (apalutamide vs placebo: hazard ratio [HR] = 0.506; 95% confidence interval [CI], 0.302-0.849; P = 0.009). Median time to PSA progression was more favorable with apalutamide than placebo (HR = 0.210; 95% CI, 0.124-0.357; P < 0.001). Median maximum percentages of PSA decline from baseline were 99.0% and 73.9% in the apalutamide and placebo groups, respectively. The most common adverse event (AE) was rash in the apalutamide group, with a higher rate than that in the placebo group (37.3% vs 9.1%). The most common grade 3 or 4 AEs were rash (12 [10.9%]) and hypertension (12 [10.9%]) for apalutamide. The efficacy and safety of apalutamide in the East Asian subgroup of the TITAN trial are consistent with the global results.

[Prostatic adenocarcinoma with glomeruloid structure].

OBJECTIVE: To investigate the architectural features and frequency of glomeruloid features in pathological section of prostatic adenocarcinoma and evaluate the association between glomerulations and its clinical data. METHODS: We studied 196 prostatic adenocarcinoma specimens obtained from needle biopsies or radical prostatectomy and their clinical data, and reviewed related literatures. RESULTS: Three of the 196 cases showed glomeruloid features, the Gleason score of which was 7, 8, and 8, respectively. Of the 3 cases 1 had osseous metastasis and 2 extraprostatic nervus extension. After 5 to 15 months' follow-up, 1 case died and the other 2 still under treatment. CONCLUSION: Glomeruloid structures in the prostate represented an uncommon but distinctive growth pattern that was specific for malignancy. Glomeruloid structures were usually seen in high-grade adenocarcinoma, often with extraprostatic extension.

[Clinical features on chromophobe renal cell carcinoma].

OBJECTIVES: To explore the clinical, pathological features and prognosis of patients with chromophobe renal cell carcinoma. METHODS: From January 1998 to January 2008, clinical data of 29 patients with chromophobe renal cell carcinoma including clinical manifestations, imaging examinations, treatment models, pTNM stages and follow-up results, were summarized to investigate its features and prognosis. RESULTS: All cases had no obvious clinical and preoperative imaging presentation. There were 23 patients underwent radical nephrectomy, and 6 cases underwent nephron sparing surgery. Postoperative pathological findings confirmed the diagnosis of chromophobe renal cell carcinoma. Macroscopically, the cut surface of the tumors were generally beige in color. Histologically, it showed polygonal chromophobe cells and small round eosinophilic cells with eccentric hyaline degeneration. These tumor cells had a clear and sharp membrane, lightly stained abundant cytoplasm with a fine reticular translucent pattern and irregular nuclei. And a perinuclear halo was often seen in these cells. Histochemically, the tumor cells generally show a diffuse and strong reaction for CK-8 with a negative expression of Vimentin. The pTNM stages of the tumor were as follows, pT1N0M0 in 11 cases, pT2N0M0 in 8 cases, pT3aN0M0 in 5 cases, pT1N1M0 in 3 cases, pT2N1M0 in 2 cases. Twenty-six cases of patients were followed up (24 to 144 months, with an average of 90 months), 3 cases died of cardio-cerebrovascular disease, and local recurrence involved in 6 cases with reoperation in 4 cases, as well as distant metastasis in 1 case. Twenty-one cases survived with tumor-free. The statistical results indicated that the survival rates of the patients with chromophobe renal cell carcinoma in five years and ten years were 83.9%, 77.9%, respectively, compared with renal cell carcinoma of the same stage 63.8% and 49.9% at the same periods, and there is no difference in the survival rate of five years (P > 0.05) but significant difference in that of ten years (P < 0.01). CONCLUSIONS: Chromophobe renal cell carcinoma is a morphologically uncommon subtype of renal cell carcinoma with the good prognosis. Definite diagnosis depends on its typical pathological feature. Radical nephrectomy is the first choice for the treatment of chromophobe renal cell carcinoma.

Rapamycin regulates Akt and ERK phosphorylation through mTORC1 and mTORC2 signaling pathways.

Numerous studies have shown that mammalian target of rapamycin (mTOR) inhibitor activates Akt signaling pathway via a negative feedback loop while inhibiting mTORC1 signaling. In this report, we focused on studying the role of mTORC1 and mTORC2 in rapamycin-mediated Akt and ERK phosphorylation, and the antitumor effect of rapamycin in cancer cells in combination with Akt and ERK inhibitors. Moreover, we analyzed the effect of mTORC1 and mTORC2 on regulating cell cycle progression. We found that low concentrations rapamycin increased Akt and ERK phosphorylation through a mTORC1-dependent mechanism because knockdowned raptor induced the activation of Akt and ERK, but higher doses of rapamycin inhibited Akt and ERK phosphorylation mainly via the mTORC2 signaling pathway because that the silencing of rictor led to the inhibition of Akt and ERK phosphorylation. We further showed that mTORC2 was tightly associated with the development of cell cycle through an Akt-dependent mechanism. Therefore, we combined PI3K and ERK inhibitors prevent rapamycin-induced Akt activation and enhanced antitumor effects of rapamycin. Collectively, we conclude that mTORC2 plays a much more important role than mTORC1 in rapamycin-mediated phosphorylation of Akt and ERK, and cotargeting AKT and ERK signaling may be a new strategy for enhancing the efficacy of rapamycin-based therapeutic approaches in cancer cells.

[Enoxacin for type III A prostatitis: a clinical observation].

OBJECTIVE: Chronic prostatitis, especially type III A, is a common disease in adult males, for which there are quite a few therapeutic methods. This study aimed to investigate the clinical efficacy of enoxacin in the treatment of III A prostatitis. METHODS: We selected 198 cases of III A prostatitis with complete treatment and follow-up data from the outpatients, all treated by enoxacin injection for 1 week, followed by oral medication of enoxacin for 2 weeks. Then we evaluated the therapeutic effect based on the NIH-CPSI scores and changes in the indexes of expressed prostatic secretions (EPS). RESULTS: The rate of total effectiveness was 86.4%, cure 8.6% (17/198), remarkable effectiveness 58.1% (115/198), improvement 19.7% (39/198), and ineffectiveness 13.6% (27/198). Only 16 cases (8.1%) complained of transitory gastrointestinal tract discomfort and/or skin itching. CONCLUSION: Enoxacin has desirable efficacy and few adverse effects on type III A prostatitis.

[Chronic prostatitis with non-neurogenic detrusor sphincter dyssynergia: diagnosis and treatment].

OBJECTIVE: To investigate the features of chronic prostatitis with non-neurogenic detrusor sphincter dyssynergia (NNDSD) and the effects of pelvic floor biofeedback in the treatment of the disease. METHODS: We included in this study 113 male patients, aged 15 - 48 (mean 36) years and diagnosed as having chronic prostatitis for 1 -2 (mean 1.2) years based on such typical symptoms as frequent micturition, urgent micturition, voiding pain, difficult void, etc, that lasted over 3 months, and the score > or = 1 on the first and second parts of NIH-CPSI. Urethritis, interstitial cystitis, urethral stricture and neurogenic bladder were excluded. All the patients underwent urodynamic examinations for the uroflow curve, Q(max), Pdet. max and MUCP. Biofeedback was carried out for those with non-neurogenic detrusor sphincter dyssynergia, and the effects were evaluated at 10 weeks. RESULTS: Twenty-one (18.6%) of the 113 cases were found to be NNDSD. Biofeedback treatment achieved obvious decreases in Q(max) (8.2 +/- 4.1), Pdet. max (125.1 +/- 75.3), MUP (124.3 +/- 23.3) and MUCP (101.5 +/- 43.6), as compared with 15.1 +/- 7.3, 86.3 +/- 54.2, 65.4 +/- 23.0 and 43.5 +/- 16.7 before the treatment (P < 0.05). Statistically significant differences were observed between pre- and post-treatment scores on voiding pain (4.0 +/- 2.0 vs 2.2 +/- 1.7), urination (7.9 +/- 2.1 vs 2.2 +/- 1.9), life impact (9.6 +/- 2.7 vs 2.9 +/- 2.6) and total scores (21.7 +/- 4.8 vs 8.4 +/- 4.6) (P < 0.05). CONCLUSION: Chronic prostatitis patients with LUTS may have NNDSD, which is urodynamically characterized by low Q(max), high intra-bladder pressure and increased urethral pressure in some patients. Urodynamic examinations may contribute to definite diagnosis and appropriate choice of treatment. Pelvic floor biofeedback has satisfactory short-term effects in the treatment of these patients.