Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine produced by activated macrophages. Nitric oxide (NO) is a highly reactive nitrogen radical implicated in inflammatory responses. We investigated the signaling pathway involved in inducible nitric oxide synthase (iNOS) expression and NO production stimulated by TNF-alpha in cultured myoblasts. TNF-alpha stimulation caused iNOS expression and NO production in myoblasts (G7 cells). TNF-alpha-mediated iNOS expression was attenuated by integrin-linked kinase (ILK) inhibitor (KP392) and siRNA. Pretreatment with Akt inhibitor, mammalian target of rapamycin (mTOR) inhibitor (rapamycin), NF-kappaB inhibitor (PDTC), and IkappaB protease inhibitor (TPCK) also inhibited the potentiating action of TNF-alpha. Stimulation of cells with TNF-alpha increased ILK kinase activity. TNF-alpha also increased the Akt and mTOR phosphorylation. TNF-alpha mediated an increase of NF-kappaB-specific DNA-protein complex formation, p65 translocation into nucleus, NF-kappaB-luciferase activity was inhibited by KP392, Akt inhibitor, and rapamycin. Our results suggest that TNF-alpha increased iNOS expression and NO production in myoblasts via the ILK/Akt/mTOR and NF-kappaB signaling pathway.

Background & aims It remains limited whether diabetes mellitus (DM) and hypertension (HTN) affect the prognosis of advanced hepatocellular carcinoma (HCC) treated with sorafenib. Our study attempted to elucidate the roles of DM/HTN and the effects of diabetes medications among advanced HCC patients receiving sorafenib. Methods From August 2012 to February 2018, 733 advanced HCC patients receiving sorafenib were enrolled at China Medical University, Taichung, Taiwan. According to the presence/absence of DM or HTN, they were divided into four groups: control [DM(-)/HTN(-), n = 353], DM-only [DM(+)/HTN(-), n = 91], HTN-only [DM(-)/HTN(+), n = 184] and DM+HTN groups [DM(+)/HTN(+), n = 105]. Based on the types of diabetes medications, there were three groups among DM patients (the combined cohort of DM-only and DM+HTN groups), including metformin (n = 63), non-metformin oral hypoglycemic agent (OHA) (n = 104) and regular insulin (RI)/neutral protamine hagedorn (NPH) groups (n = 29). We then assessed the survival differences between these groups. Results DM-only and DM+HTN groups significantly presented longer overall survival (OS) than control group (control vs. DM-only, 7.70 vs. 11.83 months, p = 0.003; control vs. DM+HTN, 7.70 vs. 11.43 months, p = 0.008). However, there was no significant OS difference between control and HTN-only group (7.70 vs. 8.80 months, p = 0.111). Besides, all groups of DM patients showed significantly longer OS than control group (control vs. metformin, 7.70 vs. 12.60 months, p = 0.011; control vs. non-metformin OHA, 7.70 vs. 10.80 months, p = 0.016; control vs. RI/NPH, 7.70 vs. 15.20 months, p = 0.026). Conclusions Rather than HTN, DM predicts better prognosis in advanced HCC treated with sorafenib. Besides, metformin, non-metformin OHA and RI/NPH are associated with longer survival among DM-related advanced HCC patients receiving sorafenib.

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The responsiveness of patients with chronic kidney disease (CKD) to nephrologists’ care is unpredictable. We defined the longitudinal stages (LSs) 1–5 of estimated glomerular filtration rate (eGFR) by group-based trajectory modeling for repeated eGFR measurements of 7135 patients with CKD aged 20–90 years from a 13-year pre-end-stage renal disease (ESRD) care registry. Patients were considered nonresponsive to the pre-dialysis care if they had a more advanced eGFR LS compared with the baseline. Conversely, those with improved or stable eGFR LS were considered responsive. The proportion of patients with CKD stage progression increased with the increase in the baseline CKD stage (stages 1–2: 29.2%; stage 4: 45.8%). The adjusted times to ESRD and all-cause mortality in patients with eGFR LS-5 were 92% (95% confidence interval [CI] 86–96%) and 57% (95% CI 48–65%) shorter, respectively, than in patients with eGFR LS-3A. Among patients with baseline CKD stages 3 and 4, the adjusted times to ESRD and all-cause death in the nonresponsive patients were 39% (95% CI 33–44%) and 20% (95% CI 14–26%) shorter, respectively, than in the responsive patients. Our proposed Renal Care Responsiveness Prediction (RCRP) model performed significantly better than the conventional Kidney Failure Risk Equation in discrimination, calibration, and net benefit according to decision curve analysis. Non-responsiveness to nephrologists’ care is associated with rapid progression to ESRD and all-cause mortality. The RCRP model improves early identification of responsiveness based on variables collected during enrollment in a pre-ESRD program. Urgent attention should be given to characterize the underlying heterogeneous responsiveness to pre-dialysis care.