Quercetin has an inhibitory effect on urinary crystal deposit formation.

CD137 (4-1BB) is a T-cell costimulatory molecule, and agonstic CD137 antibodies are currently being evaluated in the clinic as cancer immunotherapy. Recently, it was found that CD137 mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here, we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results. Specifically, CD137L suppressed intratumoral differentiation of IL12-producing CD103 DC and type 1 tumor-associated macrophages (TAM). Differentiation of these cell types is important because they are required to generate IFNγ-producing CD8 cytotoxic T lymphocytes (Tc1). Notably, CD137L blockade increased levels of IL12 and IFNγ, which promoted intratumoral differentiation of IFNγ-producing Tc1, IL12-producing CD103 DC, and type 1 TAM within tumors. Our results offer an explanation for the paradoxical effects of CD137 blockade, based on differential immunomodulatory effects of CD137 signaling and reverse signaling in T cells and DC, respectively. Further, they show how CD137L blockade can seed a forward-feedback loop for activation of CD103 DC/type 1 TAM and Tc1 that can create a self-perpetuating cycle of highly effective immunosurveillance. .

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RESULTSIn univariate analysis, the four-tiered and three-tiered grading systems showed similar accuracies (76.5 vs 76.2%, P = 0.614) for predicting cancer-specific survival, which were greater than that of the two-tiered system (72.5%; both P < 0.05).Of the three grading systems, only the threetiered system was an independent predictor of cancer-specific survival in multivariate analysis ( P = 0.046).When receiver operating characteristicderived areas under the curve (AUCs) of multivariate models for predicting cancerspecific survivals were assessed, AUCs for models including the three-tiered Fuhrman grading system and the conventional fourtiered Fuhrman grading system were the same (95.3%), followed by that of a model incorporating the two-tiered grading system (95.1%). CONCLUSIONA modified, three-tiered Fuhrman grading system can be considered an appropriate option in the application of a nuclear grading system to the prognostication of clear-cell RCC in both univariate analysis and multivariate model setting. KEYWORDS kidney, RCC, Fuhrman grading systemWhat's known on the subject? and What does the study add? Previously, some have suggested that the four-tiered conventional Fuhrman grading system for clear cell renal cell carcinoma is unnecessarily complex. To ease the process of grading, simplified (two-or three-tiered) versions of conventional Fuhrman grading system have been proposed in the literature.Our results showed that the three-tiered Fuhrman grading system can be considered as an appropriate option in the application of a nuclear grading system to the prognostication of clear cell renal cell carcinoma.Study Type -Prognosis (case series) Level of Evidence 4 OBJECTIVETo investigate the efficacy of simplified (two-or three-tiered) Fuhrman grading systems as prognostic indicators in clear-cell renal cell carcinoma (RCC). PATIENTS AND METHODSBy reviewing records, various clinicopathological factors were assessed in 431 patients who received surgical management for clear-cell RCC. A conventional four-tiered Fuhrman grading system was compared with a modified twotiered grading system (Fuhrman grades I and II were combined as one class, and grades III and IV as another) and also with a threetiered grading system (only grades I and II were combined).Efficacies of grading systems were assessed via univariate analyses and multivariate models for prediction of cancer-specific survival.