Calcium-binding proteins S100A8 and S100A9 as novel diagnostic markers in human prostate cancer.

PURPOSE: S100 proteins comprise a family of calcium-modulated proteins that have recently been associated with epithelial tumors. We examined the expression of two members of this family, S100A8 and S100A9, together with the S100 receptor RAGE (receptor for advanced glycation end products) in human prostate adenocarcinomas and in prostatic intraepithelial neoplasia. EXPERIMENTAL DESIGN: Tissue specimens of 75 patients with organ-confined prostate cancer of different grades were analyzed by immunohistochemistry for expression of S100A8, S100A9, and RAGE. In addition, in situ hybridization of S100A8 and S100A9 was done for 20 cases. An ELISA was applied to determine serum concentrations of S100A9 in cancer patients compared with healthy controls or to patients with benign prostatic hyperplasia (BPH). RESULTS: S100A8, S100A9, and RAGE were up-regulated in prostatic intraepithelial neoplasia and preferentially in high-grade adenocarcinomas, whereas benign tissue was negative or showed weak expression of the proteins. There was a high degree of overlap of S100A8 and S100A9 expression patterns and of S100A8 or S100A9 and RAGE, respectively. Frequently, a gradient within the tumor tissue with an increased expression toward the invaded stroma of the prostate was observed. S100A9 serum levels were significantly elevated in cancer patients compared with BPH patients or healthy individuals. CONCLUSION: Our data suggest that enhanced expression of S100A8, S100A9, and RAGE is an early event in prostate tumorigenesis and may contribute to development and progression or extension of prostate carcinomas. Furthermore, S100A9 in serum may serve as useful marker to discriminate between prostate cancer and BPH.     

The impact of rapid atrial pacing on ADMA and endothelial NOS

Background

The endothelial nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine (ADMA) is a well-established risk factor for oxidative stress, vascular dysfunction, and congestive heart failure. The aim of the present study was to determine the impact of rapid atrial pacing (RAP) on ADMA levels and eNOS expression.

Methods and results

ADMA levels were studied in 60 age- and gender-matched patients. Thirty five patients had persistent atrial fibrillation (AF) ≥ 4 months. In AF-patients, parameters were studied before and 24 h after electrical cardioversion. Moreover, ADMA, eNOS expression, and calcium-handling proteins were studied in pigs subjected to RAP as well as in endothelial cell (EC) cultures. ADMA level was significantly higher in AF compared to sinus rhythm patients (p = 0.024). ADMA was highest in AF-patients, who also showed elevated troponin T (TnT) levels. Moreover, ADMA showed a significant linear correlation to TnT (r = 0.47; p < 0.01). After electrical cardioversion ADMA returned to normal within 24 h. In pigs, RAP for 7 h increased ADMA levels (p = 0.018) and TnI (p < 0.05), and reduced mRNA expression of ventricular and aortic eNOS (− 80%; p < 0.05) compared to sham-control. However, ADMA per se did not affect eNOS mRNA level in EC cultures.

Conclusion

The current study shows that acute and persistent episodes of atrial tachyarrhythmia are associated with elevated ADMA levels accompanied by increased ischemic myocardial markers. Moreover, RAP increases ADMA and down-regulates eNOS expression in an ADMA-independent manner. We conclude that the combination of these two separate and potentially synergistic mechanisms may contribute to long-term vascular injury during atrial tachyarrhythmia.     

Comparison of intrarenal pelvic pressure during micro-percutaneous nephrolithotomy and conventional percutaneous nephrolithotomy

The micro-percutaneous nephrolithotomy (microperc) is a recently introduced percutaneous nephrolithotomy (PNL) technique that is performed through a 4.8Fr all-seeing needle. We aimed to measure the intrarenal pelvic pressure (IPP) during microperc and compare it with the levels of conventional PNL. A total of 20 patients with 1- to 3-cm renal calculi resistant to shock wave lithotripsy were treated either with microperc (Group-1, n: 10) or conventional PNL (Group-2, n: 10) by the same surgical team. The IPP was measured during different stages (entrance into the collecting system, stone fragmentation, and before termination) of the procedures by an urodynamic machine using the 6Fr ureteral catheter. All the variables were statistically compared between the two groups. The demographic values of the patients were similar. The operation time and duration of hospitalization were significantly prolonged in conventional PNL group (p = 0.034, p = 0.01, respectively). The mean drop in hematocrit levels was significantly lower in microperc group (3.5 ± 1.5 vs. 1.8 ± 0.8; p = 0.004). The IPP was significantly higher in microperc group during all steps of the procedure. The highest level of the IPP was measured as 30.3 ± 3.9 and 20.1 ± 3.1 mmHg in Group 1 and Group 2, respectively (p < 0.0001). However, the complication and success rates were found comparable. In conclusion, we demonstrate that the level of IPP is significantly increased during microperc compared to conventional PNL. Microperc should be used cautiously in cases with impaired drainage of the collecting system.     

VEGF Blockade Enables Oncolytic Cancer Virotherapy in Part by Modulating Intratumoral Myeloid Cells

Understanding the host response to oncolytic viruses is important to maximize their antitumor efficacy. Despite robust cytotoxicity and high virus production of an oncolytic herpes simplex virus (oHSV) in cultured human sarcoma cells, intratumoral (ITu) virus injection resulted in only mild antitumor effects in some xenograft models, prompting us to characterize the host inflammatory response. Virotherapy induced an acute neutrophilic infiltrate, a relative decrease of ITu macrophages, and a myeloid cell-dependent upregulation of host-derived vascular endothelial growth factor (VEGF). Anti-VEGF antibodies, bevacizumab and r84, the latter of which binds VEGF and selectively inhibits binding to VEGF receptor-2 (VEGFR2) but not VEGFR1, enhanced the antitumor effects of virotherapy, in part due to decreased angiogenesis but not increased virus production. Neither antibody affected neutrophilic infiltration but both partially mitigated virus-induced depletion of macrophages. Enhancement of virotherapy-mediated antitumor effects by anti-VEGF antibodies could largely be recapitulated by systemic depletion of CD11b⁺ cells. These data suggest the combined effect of oHSV virotherapy and anti-VEGF antibodies is in part due to modulation of a host inflammatory reaction to virus. Our data provide strong preclinical support for combined oHSV and anti-VEGF antibody therapy and suggest that understanding and counteracting the innate host response may help enable the full antitumor potential of oncolytic virotherapy.     

Association Between Dual Partnership and Sexual and Injecting Behaviors Among Persons Who Inject Drugs in 23 US Cities, 2018

Archives of Sexual Behavior - Persons who inject drugs (PWID) engaging in receptive syringe sharing with their sex partner (dual partnership) may have different behavior patterns than people who...