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Purpose: Therapies targeting the programmed death 1 (PD-1)/ programmed death ligand 1 (PD-L1) pathway promote antitumor immunity and have shown promising results in various tumors. Preliminary data further indicate that immunohistochemically detected PD-L1 may be predictive for anti-PD-1 therapy. So far, no data are available on PD-L1 expression in primary prostate cancer.Experimental Design: Following validation of a monoclonal antibody, immunohistochemical analysis of PD-L1 expression was performed in two independent, well-characterized cohorts of primary prostate cancer patients following radical prostatectomy (RP), and resulting data were correlated to clinicopathological parameters and outcome.Results: In the training cohort (n ¼ 209), 52.2% of cases expressed moderate to high PD-L1 levels, which positively correlated with proliferation (Ki-67, P < 0.001), Gleason score (P ¼ 0.004), and androgen receptor (AR) expression (P < 0.001).Furthermore, PD-L1 positivity was prognostic for biochemical recurrence [BCR; P ¼ 0.004; HR, 2.37; 95% confidence interval (CI), 1.32-4.25]. In the test cohort (n ¼ 611), moderate to high PD-L1 expression was detected in 61.7% and remained prognostic for BCR in univariate Cox analysis (P ¼ 0.011; HR, 1.49; 95% CI, 1.10-2.02). The correlation of Ki-67 and AR with PD-L1 expression was confirmed in the test cohort (P < 0.001).In multivariate Cox analysis of all patients, PD-L1 was corroborated as independently prognostic for BCR (P ¼ 0.007; HR, 1.46; 95% CI, 1.11-1.92).Conclusions: We provide first evidence that expression of the therapy target PD-L1 is not only highly prevalent in primary prostate cancer cells but is also an independent indicator of BCR, suggesting a biologic relevance in primary tumors. Further studies need to ascertain if PD-1/PD-L1-targeted therapy might be a treatment option for hormone-na€ ve prostate cancers.

Abstract. Mass action systems capture chemical reaction networks in homogeneous and dilute solutions. We suggest a notion of generalized mass action systems that admits arbitrary power-law rate functions and serves as a more realistic model for reaction networks in intracellular environments. In addition to the complexes of a network and the related stoichiometric subspace, we introduce corresponding kinetic complexes, which represent the exponents in the rate functions and determine the kinetic-order subspace. We show that several results of Chemical Reaction Network Theory carry over to the case of generalized mass action kinetics. Our main result essentially states that, if the sign vectors of the stoichiometric and kinetic-order subspace coincide, there exists a unique complex balancing equilibrium in every stoichiometric compatibility class. However, in contrast to classical mass action systems, multiple complex balancing equilibria in one stoichiometric compatibility class are possible in general.

BackgroundMicroRNA expression is altered in cancer cells, and microRNAs could serve as diagnostic/prognostic biomarker for cancer patients. Our study was designed to analyze circulating serum microRNAs in patients with renal cell carcinoma (RCC).Methodology/Principal FindingsWe first explored microRNA expression profiles in tissue and serum using TaqMan Low Density Arrays in each six malignant and benign samples: Although 109 microRNAs were circulating at higher levels in cancer patients' serum, we identified only 36 microRNAs with up-regulation in RCC tissue and serum of RCC patients. Seven candidate microRNAs were selected for verification based on the finding of up-regulation in serum and tissue of RCC patients: miR-7-1*, miR-93, miR-106b*, miR-210, miR-320b, miR-1233 and miR-1290 levels in serum of healthy controls (n = 30) and RCC (n = 33) patients were determined using quantitative real-time PCR (TaqMan MicroRNA Assays). miR-1233 was increased in RCC patients, and thus validated in a multicentre cohort of 84 RCC patients and 93 healthy controls using quantitative real-time PCR (sensitivity 77.4%, specificity 37.6%, AUC 0.588). We also studied 13 samples of patients with angiomyolipoma or oncocytoma, whose serum miR-1233 levels were similar to RCC patients. Circulating microRNAs were not correlated with clinical-pathological parameters.Conclusions/SignificanceMicroRNA levels are distinctly increased in cancer patients, although only a small subset of circulating microRNAs has a tumor-specific origin. We identify circulating miR-1233 as a potential biomarker for RCC patients. Larger-scaled studies are warranted to fully explore the role of circulating microRNAs in RCC.