Péter Nyirády

Muscarinic acetylcholine receptors are of utmost importance in physiological regulation of micturition and also in the development of voiding disorders. We demonstrate that the RhoA-Rho-associated kinase (ROCK) pathway plays a crucial role in contractions induced by cholinergic stimulation in detrusor muscle. Activation of RhoA is mediated by both M₂ and M₃ receptors as well as by G_i but not G_q/11 proteins. The G_i-RhoA-ROCK pathway may provide a novel therapeutic target for overactive voiding disorders.

Elevated preoperative plasma level of endoglin has been associated with worse oncologic outcomes in various malignancies. The present large-scale study aimed to determine the predictive and prognostic values of preoperative endoglin with regard to clinicopathologic and survival outcomes in patients treated with radical cystectomy (RC) for nonmetastatic urothelial carcinoma of the bladder (UCB). We prospectively collected preoperative blood samples from 1036 consecutive patients treated with RC for UCB. Logistic and Cox regression analyses were undertaken to assess the correlation of endoglin levels with pathologic and survival outcomes, respectively. The AUC and C-index were used to assess the discrimination. Patients with adverse pathologic features had significantly higher median preoperative endoglin plasma levels than their counterparts. Higher preoperative endoglin level was independently associated with an increased risk for lymph node metastasis, ≥pT3 disease, and nonorgan confined disease (NOCD; all p < 0.001). Plasma endoglin level was also independently associated with cancer-specific and overall survival in both pre- and postoperative models (all p < 0.05), as well as with recurrence-free survival (RFS) in the preoperative model (p < 0.001). The addition of endoglin to the preoperative standard model improved its discrimination for prediction of lymph node metastasis, ≥pT3 disease, NOCD, and RFS (differential increases in C-indices: 10%, 5%, 5.8%, and 4%, respectively). Preoperative plasma endoglin is associated with features of biologically and clinically aggressive UCB as well as survival outcomes. Therefore, it seems to hold the potential of identifying UCB patients who may benefit from intensified therapy in addition to RC such as extended lymphadenectomy or/and preoperative systemic therapy.

Aim: We aimed to compare the mortality rates related to adverse events (AEs) and discontinuation of treatment due to toxicity as well as all AEs of currently used regimens of second-line treatment ... Lay abstract In the era of precision medicine, the challenge is to identify the patients who are most likely to benefit from different treatment strategies. We believe that findings of the present ...

Voiding disorders affect millions of people worldwide. Inflammation can impair urinary bladder functions and contribute to the development of detrusor overactivity. The effects and signal transduction of inflammatory lipid mediator isoprostanes were studied in human and murine urinary bladders ex vivo. We found that isoprostanes evoke contraction, an effect mediated by thromboxane prostanoid receptors. The G_12/13-Rho-Rho kinase signaling pathway plays a significant role in mediating the contraction and therefore may be a potential therapeutic target.

Tachykinins (TKs) are involved in both the physiological regulation of urinary bladder functions and development of overactive bladder syndrome. The aim of the present study was to investigate the signal transduction pathways of TKs in the detrusor muscle to provide potential pharmacological targets for the treatment of bladder dysfunctions related to enhanced TK production. Contraction force, intracellular Ca²⁺concentration, and RhoA activity were measured in the mouse urinary bladder smooth muscle (UBSM). TKs and the NK2 receptor (NK2R)-specific agonist [β-Ala⁸]-NKA(4–10) evoked contraction, which was inhibited by the NKR2 antagonist MEN10376. In Gα_q/11-deficient mice, [β-Ala⁸]-NKA(4–10)-induced contraction and the intracellular Ca²⁺concentration increase were abolished. Although G_q/11proteins are linked principally to phospholipase Cβ and inositol trisphosphate-mediated Ca²⁺release from intracellular stores, we found that phospholipase Cβ inhibition and sarcoplasmic reticulum Ca²⁺depletion failed to have any effect on contraction induced by [β-Ala⁸]-NKA(4–10). In contrast, lack of extracellular Ca²⁺or blockade of voltage-dependent Ca²⁺channels (VDCCs) suppressed contraction. Furthermore, [β-Ala⁸]-NKA(4–10) increased RhoA activity in the UBSM in a G_q/11-dependent manner and inhibition of Rho kinase with Y-27632 decreased contraction force, whereas the combination of Y-27632 with either VDCC blockade or depletion of extracellular Ca²⁺resulted in complete inhibition of [β-Ala⁸]-NKA(4–10)-induced contractions. In summary, our results indicate that NK2Rs are linked exclusively to G_q/11proteins in the UBSM and that the intracellular signaling involves the simultaneous activation of VDCC and the RhoA-Rho kinase pathway. These findings may help to identify potential therapeutic targets of bladder dysfunctions related to upregulation of TKs.

Genome-wide association studies identified or confirmed 15 genomic regions that modulate urinary bladder cancer risk. Little is known whether these genetic variants interact to increase bladder cancer risk. Furthermore, it is likely that different polymorphisms are relevant in smokers and non-smokers. Therefore, we conducted an interaction analysis comprising 12 susceptibility variants and totally 5049 cases and 5452 controls.