Increased expression of HMGB1 is associated with poor prognosis in human bladder cancer.

BACKGROUND AND OBJECTIVE: High-mobility group box 1 (HMGB1) is a versatile protein with intranuclear and extracellular functions that is involved in numerous biological and pathological processes, such as transcription, DNA repair, and response to infection and inflammation. HMGB1 overexpression has been reported in a variety of human cancers. However, the clinical significance of HMGB1 expression in bladder cancer (BC) remains unclear. This study is aimed to investigate the correlations between HMGB1 expression and prognosis in patients with BC. METHODS: HMGB1 protein expression in 164 primary BC tissue specimens was analyzed by immunohistochemistry, and its association with clinicopathologic factors and prognosis was also analyzed. RESULTS: HMGB1 protein had high expression in 87 of 164 cases of BC (53%). HMGB1 overexpression was significantly associated with tumor grade (P < 0.001), and stage (P = 0.001). The Kaplan-Meier survival analysis demonstrated that HMGB1 expression was significantly associated with shorter disease-free survival and overall survival (both P < 0.001). Multivariate analysis further demonstrated that HMGB1 was an independent prognostic factor for patients with BC. CONCLUSIONS: HMGB1 might be a new molecular marker to predict the prognosis of patients with BC.

Value of contrast-enhanced sonography with micro flow imaging in the diagnosis of prostate cancer.

BACKGROUND: To evaluate the effectiveness of contrast-enhanced sonographic micro flow imaging (MFI) in the diagnosis of prostate cancer. METHODS: A total of 74 patients referred for prostate biopsy were prospectively evaluated with MFI. The abnormalities were categorized into four patterns: pattern 1: indistinct separation between the inner and outer gland; pattern 2: asymmetrical or focally increased enhancement in the outer gland; pattern 3: enhancement with focal defect; pattern 4: enhancement in the outer gland equal to that of the inner gland. The findings were correlated with Gleason scores. RESULTS: Prostate cancer was detected in 264 sites in 41 patients. The sensitivity, specificity, accuracy, and positive and negative predictive values for MFI were 81.1%, 84.3%, 83.3%, 68.6%, and 91.3%, respectively. Positive predictive values for the four patterns were 46.0 (pattern 1), 53.6 (pattern 2), 94.3 (pattern 3), and 95.4 (pattern 4). Gleason scores of cancers with patterns 3 (7.09) or 4 (7.51) were significantly higher than those with patterns 1 (6.17) or 2 (6.59) (p = 0.001, p = 0.005, p < 0.001, p < 0.001). CONCLUSIONS: Some MFI patterns had high positive predictive values and were associated with more aggressive cancers. This could be used to reduce the number of biopsy sites and detect clinically significant cancers.

CXCR7 in tumorigenesis and progression.

Chemokines, a family of small cytokines, were initially characterized as proinflammatory chemoattractant cytokines that regulated cell trafficking and adhesion. Today, attention focuses on chemokines because evidence shows that they play a critical role in tumor initiation, promotion, and progression. CXCR7, a seven-transmembrane G-protein-coupled CXC chemokine receptor, has recently been identified as binding with high affinity to chemokines CXCL11 (I-TAC) and CXCL12 (SDF-1). In this review, we highlight the current knowledge about the role of CXCR7 in the biologic processes of cancer, including cancer growth, survival, adhesion, invasion, metastasis, angiogenesis, and progression. The use of peptides, small molecules, antibodies, or small interfering RNA to target CXCR7 shows promise as new potential avenues for the treatment of cancer.

[Recent development in ectopic reconstitution of seminiferous tubules].

The testicular development and spermatogenesis of mammalians involve complex processes of cell migration, proliferation and differentiation and cell-cell interaction. In spite of extensive researches, many relevant aspects remain unclear. One of the impediments in the studies of testicular development and spermatogenesis of mammalians is the lack of a suitable model. In the last few years, two valuable models were developed for the study of mammalian spermatogenesis: testis tissue from immature animals transplanted ectopically into immunodeficient mice that could survive and produce functional spermatids, and isolated testis cells able to organize and rearrange into seminiferous cords that subsequently undergo complete spermatogenesis. This article presents an update and the applications and prospects of these two methods.

[Combination of tamsulosin and tolterodine alleviates refractory lower urinary tract symptoms in male patients].

OBJECTIVE: To evaluate and compare the clinical efficacy and safety of the highly selective alpha receptor antagonist tamsulosin and its combination with the M receptor antagonist tolterodine in the treatment of refractory lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH). METHODS: We included in this study 184 BPH patients with refractory LUTS with the disease course of 4 weeks to 2 years, whose LUTS were not alleviated after a week's treatment with tamsulosin. The patients were randomly divided into Groups A and B, the former (n=89) treated with tamsulosin at 0.2 mg qd and the latter (n=95) given tolterodine at 2 mg bid in addition to tamsulosin medication, both for 4 weeks. Scores on IPSS, QOL and Qmax were obtained before and after the treatment, and the improvement of LUTS evaluated after the medication. RESULTS: The tamsulosin group showed no significant differences before and after the treatment in the scores on IPSS (13.23 +/- 4.39 vs. 12.21 +/- 4.07), QOL (4.23 +/- 1.27 vs 3.53 +/- 0.95) and Qmax ([12.3 +/- 8.39] ml/s vs. [14.1 +/- 8.62] mls) (P > 0.05), while the combination group exhibited significantly higher scores on IPSS and QOL and lower score on Qmax after the medication than before it (IPSS: 14.45 +/- 5.31 vs. 6.56 +/- 2.03, P < 0.05; QOL: 4.45 +/- 0.79 vs. 2.34 +/- 0.73, P < 0.05; Qmax: [11.4 +/- 9.21] ml/s vs. [15.5 +/- 8.35] ml/s, P < 0.01). No severe complications were found in any of the cases. CONCLUSION: Combination of tamsulosin and tolterodine can significantly alleviate refractory LUTS and improve QOL without causing serious adverse events in BPH patients.

A novel treatment strategy for newly diagnosed high-grade T1 bladder cancer: Gemcitabine and cisplatin adjuvant chemotherapy-A single-institution experience.

BACKGROUND: Management of high-grade T1 (formerly T1G3) bladder cancer continues to be controversial. Should patients with T1G3 bladder cancer have an immediate radical cystectomy or should they receive intravesical bacillus Calmette-Guérin-preserving bladder? Gemcitabine and cisplatin (GC) adjuvant chemotherapy may help to strike a balance between intravesical and early cystectomy. For purposes of this study, we continue to refer high-grade T1 lesion as "T1G3." OBJECTIVE: To evaluate the characteristics and the long-term outcome of GC adjuvant chemotherapy in T1G3 bladder cancer after transurethral resection of bladder tumor (TURBT). MATERIALS AND METHODS: We retrospectively reviewed 48 patients who were newly diagnosed with T1G3 bladder cancer between January 2009 and December 2012. A total of 48 patients received 4 cycles of GC adjuvant chemotherapy after TURBT. One month after 4 cycles of GC adjuvant chemotherapy, response was evaluated by re-TURBT. Median follow-up was 59.5 (range: 18-70) months, all patients have been observed for more than 3 years. Salvage cystectomy was recommended for patients with persistent disease and for tumor progression after initial complete response. RESULT: Complete response was achieved in 44 (91.7%) patients. Of complete responders, 5 patients experienced recurrence and 5 patients showed progression. The progression rate and disease-specific survival rate were 10.4% and 91.7% at 3 years, respectively. More than 80% of survivors preserved their bladder. Kaplan-Meier curves showed that concomitant carcinoma in situ (CIS) was the only factor that had an influence on progression-free survival (P = 0.022) and disease-specific survival (P = 0.017). Concomitant CIS was the prognostic factor for progression rate and disease-specific survival rate at 3 years (P = 0.008 and P = 0.035). CONCLUSION: GC adjuvant chemotherapy is a safe conservative treatment for T1G3 bladder cancer, but effective is really a phase II study. Patients with T1G3 bladder cancer with concomitant CIS should be treated more aggressively because of the high risk of progression.

An unusual intragenic promoter of PIWIL2 contributes to aberrant activation of oncogenic PL2L60.

PIWIL2-like (PL2L) protein 60 (PL2L60), a product of aberrantly activated PIWIL2 gene, is widely expressed in various types of tumors and may promote tumorigenesis. However, the mechanisms underlying the activation of expression of PL2L60 remain unknown. In this study, an intragenic promoter responsible for the activation of PL2L60 within the human PIWIL2 gene has been identified, cloned and characterized. The promoter of PL2L60 is located in the intron 10 of the host gene PIWIL2. Bioinformatic and mutagenic analysis reveals that this intragenic promoter within the sequence of 50 nucleotides contains two closely arranged cis-acting elements specific for the hepatic leukemia factor (HLF) in the positive strand and signal transducer and activator of transcription 3 (STAT3) in the negative strand. Chromatin immunoprecipitation analysis demonstrates that both the HLF and polymerase II (Pol II), a hallmark of active promoters, directly bind to the sequence, although STAT3 does not. Knockdown of HLF and STAT3 alone or both by RNA interference significantly reduced both promoter activity and the PL2L60 protein expression, although there is no additive effect. The expression of PL2L60 proteins was enhanced when host gene Piwil2 was genetically disrupted in a murine cell model. Taken together, we have identified a PL2L60-specific intragenic promoter in the host gene of PIWIL2, which is interdependently activated by HLF and STAT3 through steric interaction. This activation is dependent on cellular milieu rather than the integrity of host gene PIWIL2, highlighting a novel, important mechanism for a cancer-causing gene to be activated during tumorigenesis.

Metformin can block precancerous progression to invasive tumors of bladder through inhibiting STAT3-mediated signaling pathways.

BACKGROUND: Metformin is the first line of oral antidiabetic drug in the biguanide class for treatment of type 2 diabetes. Increasing evidence has suggested that it is a potential anti-tumor drug. However, the mechanisms underlying inhibiting tumor development remain elusive, especially in bladder tumors. METHODS: T24 and J82 cell lines were used as an in vitro model, and 24 female SD rats were used to build an N-methyl-N-nitrosourea (MNU)-induced orthotopic rat bladder cancer model. Transfection of lentivirus-based shRNA was used to construct the STAT3-KNOCKDOWN T24 cell line. After metformin treatment, the viability of bladde cancer cells was determined by CCK8. Cell cycle distribution and apoptosis were assessed by flow cytometry. The migration and invasion abilities of cells were evaluated by wound healing and transwell asssays. The inactivation of stat3 pahtway was examined by qRTPCR, western blot and Immunofluorescence. RESULTS: Metformin can effectively inhibit precancerous progression to invasive cancer in an MNU-induced rat orthotopic bladder tumor model, although it could not completely suppress normal cells transforming into tumor cells. While the MNU could induce 50 % rats (4/8) to develop invasive bladder cancers, the rats co-administrated with metformin failed to develop invasive tumors but retained at precancerous or non-invasive stages, exhibiting as dysplasia, papillary tumor and/or carcinoma in situ (CIS). Accordingly, phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is a well known oncogene, was significantly inhibited in the tumors of rats treated with metformin. In vitro experiments revealed that the metformin could efficiently inhibit STAT3 activation, which was associated with the cell cycle arrest, reduction of cell proliferation, migration and invasiveness, and increase in apoptotic cell death of bladder cancer cell lines. CONCLUSIONS: These findings provide for the first time the evidence that metformin can block precancerous lesions progressing to invasive tumors through inhibiting the activation of STAT3 pathway, and may be used for treatment of the non-invasive bladder cancers to prevent them from progression to invasive tumors.

[The effect of endothelin receptor in androgen-independent prostate cancer].

OBJECTIVE: To study the expression of ET receptor and the apoptosis after intervened with ET receptor antagonist in androgen-independent prostate cancer. METHODS: PC3, an androgen-independent prostate cancer cell line, was used. The expression of ETA and ETB receptor in PC3 was measured through RT-PCR. After intervened with selective ETA and ETB receptor antagonist, the apoptosis in PC3 was studied through flow cytometry and electron microscope. RESULTS: Clear signal was obtained in PC3 for ETA receptor mRNA transcript, while the signal for ETB receptor mRNA transcript was very weak. The expression of ETA receptor mRNA was obviously reduced and the apoptosis of PC3 cell was observed after intervened with selective ETA receptor antagonist. There was no change after intervened with selective ETB receptor antagonist. CONCLUSION: ET-1 exerts its effects through the ETA receptor subtype and ETB receptor is silenced in PC3. The expression of ETA was reduced and the apoptosis was observed in PC3 when ETA receptor was blocked. It was dose-dependent.

Increased expression of forkhead box M1 protein is associated with poor prognosis in clear cell renal cell carcinoma.

Forkhead box protein M1 (FoxM1) is crucial in the regulation of various biological processes, including cell proliferation, organogenesis, and angiogenesis. Overexpression of FoxM1 is associated with carcinogenesis. In this study, immunohistochemistry was carried out to examine FoxM1 expression in clear cell renal cell carcinoma (ccRCC), and these data were examined for correlation with clinicopathological parameters and prognosis. FoxM1 protein had high expression in 37 of 87 cases of ccRCC (42.5 %), which was significantly higher than in normal tissues, and FoxM1 overexpression was significantly associated with tumor stage (P = 0.005) and recurrence (P = 0.027). The Kaplan-Meier survival analysis demonstrated that FoxM1 expression was significantly associated with shorter recurrence-free survival and overall survival (P = 0.007 and P = 0.008, respectively). Multivariate analysis further demonstrated that FoxM1 was an independent prognostic factor for patients with ccRCC. So FoxM1 might be a potential molecular marker to predict the prognosis of patients with ccRCC.

Renal mucinous tubular and spindle cell carcinoma: a report of 8 cases and review of the literature.

BACKGROUND: Mucinous tubular and spindle cell carcinoma of kidney (MTSCC-K) is a rare variant of renal tumor. The current data show most of MTSCCs are of low malignant potential and rare cases metastatic to lymph nodes have been reported; however, the recorded computed tomography (CT) and follow up data are limited. MATERIAL AND METHOD: In the present study, we retrospectively analyzed CT and clinicopathological data of eight patients with renal MTSCC-K. RESULTS: A total of eight cases, including six females and two males, were included in this analysis with a mean age of 48.4 (range 25 to 81) years. Mean tumor size was 4.2 (range 2.5 to 10.0) cm. Preoperative CT demonstrated that all tumors were slightly enhanced on both corticomedullary and nephrographic phase, which was different from many other renal cell carcinomas. Three of them were treated with open radical nephrectomy, three with laparoscopic radical nephrectomy and the other two with laparoscopic partial nephrectomy. No postoperative therapy was applied. Patients were followed up for 15 to 64 months and there was no evidence of recurrence and metastasis. CONCLUSIONS: The MTSCC-K has special clinicopathological characteristics, low degree of malignancy and relative good prognosis. The diagnosis mainly depends on the histopathological examination and CT may help to differentiate with papillary renal cell carcinoma. Surgical treatment is recommended and additional therapies are not necessary. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8435581771088249.

UHRF1 is associated with tumor recurrence in non-muscle-invasive bladder cancer.

Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) is a novel anti-apoptotic gene, and overexpression of UHRF1 is involved in tumorigenicity. Here, immunohistochemistry was used to detect UHRF1 expression in non-muscle-invasive bladder cancer (NMIBC), and these data were examined for correlation with clinicopathological parameters and prognosis. The UHRF1 expression rate was 49.2% in a total of 118 bladder cancer tissues, which was significantly higher than in normal tissues, and UHRF1 expression has a significantly positive correlation with tumor grade (P = 0.027) and recurrence (P = 0.013). Survival analysis showed that UHRF1 high expression patients' mean survival time (42.59 months) was significantly shorter than that (71.36 months) of UHRF1 low expression patients (P = 0.0002). Multivariate analysis showed that UHRF1 overexpression was an independent prognostic factor for tumor recurrence (P < 0.0001). So UHRF1 may be a molecular marker to predict the recurrence of NMIBC.

Androgen deprivation therapy through bilateral orchiectomy: increased metabolic risks.

Prostate cancer is one of the most common malignancies in men. Previous research has determined that androgen deprivation therapy (ADT) may be accompanied by an unfavourable metabolic profile. In this prospective study, 133 men were recruited, including 46 prostate cancer patients who had undergone bilateral orchiectomy and been on flutamide (the ADT group), 37 men with prostate cancer who had undergone radical prostatectomy (the non-ADT group) and 50 normal control subjects (the control group). All subjects were followed for at least 12 months. From baseline to 3 months, men in the ADT group had increased levels of fasting serum insulin and low-density lipoprotein compared to the other two groups (P<0.05). No obvious changes were found in the other parameters (P>0.05). After 12 months, men in the ADT group had increased levels of waist circumference, fasting serum insulin and glucose, total cholesterol, high-density lipoprotein and low-density lipoprotein compared to the other two groups (P<0.05). Additionally, the morbidity rate of metabolic syndrome in the ADT group was higher (P<0.05) compared to the other two groups. ADT through surgical castration for men with prostate cancer may be associated with unfavourable metabolic changes. The benefits of the therapy should be balanced prudently against these risks.