Protein-bound uremic toxins, such as p-cresol sulfate (PCS), can be accumulated with declined renal function and aging and is closely linked with central nervous system (CNS) diseases. In the periphery, PCS has effects on oxidative stress and inflammation. Since oxidative stress and inflammation have substantial roles in the pathogenesis of neurological disorders, the CNS effects of PCS were investigated in unilateral nephrectomized C57/BL/6 mice. Unlike intact mice, unilateral nephrectomized mice showed increased circulating levels of PCS after exogenous administration. Upon PCS exposure, the unilateral nephrectomized mice developed depression-like, anxiety-like, and cognitive impairment behaviors with brain PCS accumulation in comparison with the nephrectomy-only group. In the prefrontal cortical tissues, neuronal cell survival and neurogenesis were impaired along with increased apoptosis, oxidative stress, and neuroinflammation. Circulating brain-derived neurotrophic factors (BDNF) and serotonin were decreased in association with increased corticosterone and repressor element-1 silencing transcription factor (REST), regulators involved in neurological disorders. On the contrary, these PCS-induced changes were alleviated by uremic toxin absorbent AST-120. Taken together, PCS administration in mice with nephrectomy contributed to neurological disorders with increased oxidative stress and neuroinflammation, which were alleviated by PCS chelation. It is suggested that PCS may be a therapeutic target for chronic kidney disease-associated CNS diseases.

PURPOSE: Rogaratinib, an oral pan-fibroblast growth factor receptor (FGFR1-4) inhibitor, showed promising phase I efficacy and safety in patients with advanced urothelial carcinoma (UC) with FGFR1-3 mRNA overexpression. We assessed rogaratinib efficacy and safety versus chemotherapy in patients with FGFR mRNA-positive advanced/metastatic UC previously treated with platinum chemotherapy. METHODS: FORT-1 (ClinicalTrials.gov identifier: NCT03410693 ) was a phase II/III, randomized, open-label trial. Patients with FGFR1/ 3 mRNA-positive locally advanced or metastatic UC with ≥ 1 prior platinum-containing regimen were randomly assigned (1:1) to rogaratinib (800 mg orally twice daily, 3-week cycles; n = 87) or chemotherapy (docetaxel 75 mg/m², paclitaxel 175 mg/m², or vinflunine 320 mg/m² intravenously once every 3 weeks; n = 88). The primary end point was overall survival, with objective response rate (ORR) analysis planned following phase II accrual. Because of comparable efficacy between treatments, enrollment was stopped before progression to phase III; a full interim analysis of phase II was completed. RESULTS: ORRs were 20.7% (rogaratinib, 18/87; 95% CI, 12.7 to 30.7) and 19.3% (chemotherapy, 17/88; 95% CI, 11.7 to 29.1). Median overall survival was 8.3 months (95% CI, 6.5 to not estimable) and 9.8 months (95% CI, 6.8 to not estimable; hazard ratio, 1.11; 95% CI, 0.71 to 1.72; P = .67). Grade 3/4 events occurred in 37 (43.0%)/4 (4.7%) patients and 32 (39.0%)/15 (18.3%), respectively. No rogaratinib-related deaths occurred. Exploratory analysis of patients with FGFR3 DNA alterations showed ORRs of 52.4% (11/21; 95% CI, 29.8 to 74.3) for rogaratinib and 26.7% (4/15; 95% CI, 7.8 to 55.1) for chemotherapy. CONCLUSION: To our knowledge, these are the first data to compare FGFR-directed therapy with chemotherapy in patients with FGFR-altered UC, showing comparable efficacy and manageable safety. Exploratory testing suggested FGFR3 DNA alterations in association with FGFR1/ 3 mRNA overexpression may be better predictors of rogaratinib response.

PURPOSE: Homologous recombination repair gene mutations (HRRm) are common in urothelial carcinoma (UC), rendering tumor cells sensitive to poly (ADP-ribose) polymerase (PARP) inhibition. We assessed efficacy and safety of durvalumab (anti–programmed cell death ligand-1) plus olaparib (PARP inhibitor) in patients with metastatic UC (mUC).METHODS: This randomized, multicenter, double-blind, phase II trial enrolled untreated, platinum-ineligible patients with mUC. Patients (N = 154) were randomly assigned 1:1 to receive durvalumab (1,500 mg intravenously once every 4 weeks) plus olaparib (300 mg orally, twice daily) or durvalumab plus placebo. The primary end point was progression-free survival (PFS) assessed by investigators per RECIST version 1.1. Secondary end points included overall survival in all patients and PFS in patients with HRRm.RESULTS: Overall, median PFS was 4.2 months (95% CI, 3.6 to 5.6) for durvalumab plus olaparib and 3.5 months (95% CI, 1.9 to 5.1) for durvalumab plus placebo (hazard ratio [HR], 0.94; 95% CI, 0.64 to 1.39; log-rank P value, .789). Median overall survival was 10.2 months (95% CI, 7.0 to 13.9) and 10.7 months (95% CI, 7.2 to 17.3), respectively (HR, 1.07; 95% CI, 0.72 to 1.61). In the 20% of patients with HRRm, median PFS was 5.6 months (95% CI, 1.9 to 8.1) and 1.8 months (95% CI, 1.7 to 2.2), respectively (HR, 0.18; 95% CI, 0.06 to 0.47). Treatment-related grade 3 or 4 adverse events occurred in 18% and 9% of patients, respectively.CONCLUSION: Adding olaparib to durvalumab did not improve survival outcomes in an unselected mUC population. Efficacy outcomes with durvalumab were similar to those reported for other anti–programmed cell death-1/programmed cell death ligand-1 agents. However, the results of secondary analyses suggest a potential role for PARP inhibition in patients with UC harboring HRRm.

The prognostic and therapeutic values of fibronectin have been reported in patients with renal cell carcinoma (RCC). However, the underlying mechanisms of malignancy in RCC are not completely understood. We found that silencing of fibronectin expression attenuated human RCC 786-O and Caki-1 cell growth and migration. Silencing of potential fibronectin receptor integrin α5 and integrin β1 decreased 786-O cell ability in movement and chemotactic migration. Biochemical examination revealed a reduction of cyclin D1 and vimentin expression, transforming growth factor-β1 (TGF-β1) production, as well as Src and Smad phosphorylation in fibronectin-silenced 786-O and Caki-1 cells. Pharmacological inhibition of Src decreased 786-O cell growth and migration accompanied by a reduction of cyclin D1, fibronectin, vimentin, and TGF-β1 expression, as well as Src and Smad phosphorylation. In 786-O cells, higher activities in cell growth and migration than in Caki-1 cells were noted, along with elevated fibronectin and TGF-β1 expression. The additions of exogenous fibronectin and TGF-β1 promoted Caki-1 cell growth and migration, and increased cyclin D1, fibronectin, vimentin, and TGF-β1 expression, as well as Src and Smad phosphorylation. These findings highlight the role of fibronectin in RCC cell growth and migration involving Src and TGF-β1 signaling.

Bladder dysfunction is a common complication after chronic spinal cord injury (SCI). Patients may experience renal function loss, urinary tract infection (UTI), urolithiasis, bladder cancer, and even life-threatening events such as severe sepsis or renal failure. Suitable patient care may prevent UTI and urinary incontinence, decrease medication use, and preserve renal function. As the primary goal is to preserve renal function, management should be focused on facilitating bladder drainage, the avoidance of UTI, and the maintenance of a low intravesical pressure for continence and complete bladder emptying. Currently, several bladder management options are available to SCI patients: (1) reflex voiding; (2) clean intermittent catheterization; (3) indwelling catheterization. The target organ may be the bladder or the bladder outlet. The purposes of intervention include the following: (1) increasing bladder capacity and/or decreasing intravesical pressure; (2) increasing bladder outlet resistance; (3) decreasing bladder outlet resistance; (4) producing detrusor contractility; (5) urinary diversion. Different bladder management methods and interventions may have different results depending on the patient’s lower urinary tract dysfunction. This review aims to report the current management options for long-term bladder dysfunction in chronic SCI patients. Furthermore, we summarize the most suitable care plans for improving the clinical outcome of SCI patients.

Microglia polarization of classical activation state is crucial to the induction of neuroinflammation, and has been implicated in the pathogenesis of numerous neurodegenerative diseases. Fungal immunomodulatory proteins are emerging health-promoting natural substances with multiple pharmacological activities, including immunomodulation. Herein, we investigated the anti-inflammatory and neuroprotective potential of fungal immunomodulatory protein extracted from Ganoderma microsporum (GMI) in an in vitro rodent model of primary cultures. Using primary neuron/glia cultures consisting of neurons, astrocytes, and microglia, a GMI showed an alleviating effect on lipopolysaccharide (LPS)/interferon-γ (IFN-γ)-induced inflammatory mediator production and neuronal cell death. The events of neuroprotection caused by GMI were accompanied by the suppression of Nitric Oxide (NO), Tumor Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β), and Prostaglandin E2 (PGE2) production, along with the inhibition of microglia activation. Mechanistic studies showed that the suppression of microglia pro-inflammatory polarization by GMI was accompanied by the resolution of oxidative stress, the preservation of protein tyrosine phosphatase and serine/threonine phosphatase activity, and the reduction of NF-κB, AP-1, cyclic AMP response element-binding protein (CREB), along with signal transducers and activators of transcription (Stat1) transcriptional activities and associated upstream activators. These findings suggest that GMI may have considerable potential towards the treatment of neuroinflammation-mediated neurodegenerative diseases.