BackgroundThe purpose of this study was to develop an effective nomogram capable of estimating the individual survival outcomes of patients with hepatocellular carcinoma (HCC), and compare the predictive accuracy and discriminative ability with other staging systems.MethodsThe nomogram was established based on a retrospective study of 661 patients newly diagnosed with HCC at the Beijing Ditan Hospital (Beijing, China), Capital Medical University, between October 2008 and July 2012. The predictive accuracy and discriminative ability of the previously developed nomogram were assessed by C-index and calibration curves, and were compared to seven current commonly used staging systems. The results were validated, using a bootstrap approach to correct for bias, in a prospective study of 220 patients consecutively enrolled between August 2012 and March 2013.ResultsMultivariate analysis of the primary cohort for survival analysis identified the independent factors to be aspartate aminotransferase, ɣ-glutamyl transpeptidase, white blood cell count, neutrophil-to-lymphocyte ratio, prothrombin activity, α-fetoprotein, tumor number and size, lymph node metastasis, and portal vein involvement, which were all included to build the nomogram. The calibration curve for predicting the probability of survival showed consistency between the nomogram and the actual observation. The C-index of the nomogram was 0.81 (95% confidence interval, 0.79–0.82), which was statistically better than that of the Tumor, Node, Metastasis staging (0.71), Barcelona Clinic Liver Cancer staging (0.77), Okuda (0.62), Japan Integrated Staging (0.73), Cancer of the Liver Italian Program score (0.76), Chinese University Prognostic Index (0.68), and the Groupe d’ Etude et de Traitement du Carcinome Hepatocellulaire Prognostic classification (0.65) (p < 0.001 for all). The results were validated in the prospective validation cohort.ConclusionsThe prognostic nomogram resulted in more accurate individualized risk estimates for overall survival in HCC patients.
The low-voltage activated T-type calcium channels regulate cellular excitability and oscillatory behavior of resting membrane potential which trigger many physiological events and have been implicated with many diseases. Here, we determine structures of the human T-type CaV3.3 channel, in the absence and presence of antihypertensive drug mibefradil, antispasmodic drug otilonium bromide and antipsychotic drug pimozide. CaV3.3 contains a long bended S6 helix from domain III, with a positive charged region protruding into the cytosol, which is critical for T-type CaV channel activation at low voltage. The drug-bound structures clearly illustrate how these structurally different compounds bind to the same central cavity inside the CaV3.3 channel, but are mediated by significantly distinct interactions between drugs and their surrounding residues. Phospholipid molecules penetrate into the central cavity in various extent to shape the binding pocket and play important roles in stabilizing the inhibitor. These structures elucidate mechanisms of channel gating, drug recognition, and actions, thus pointing the way to developing potent and subtype-specific drug for therapeutic treatments of related disorders.
We aimed to investigate the relationship between the Chinese visceral adiposity index (CVAI) and the risk of new-onset myocardial infarction (MI) in patients with hypertension and obstructive sleep apnoea (OSA) and to inspect possible modifiers of the effect. Methods: The Cox regression model was used to evaluate the relationship between baseline CVAI and risk of new-onset MI. A generalized additive model was used to identify the nonlinear relationship. Besides, we conducted subgroup analyses and interaction tests. Results: A total of 2177 patients with hypertension and OSA undergoing polysomnography were enrolled in this study. During a median follow-up period of 87 months, 82 participants developed new-onset MI. Overall, CVAI was positively related to the risk of new-onset MI (per 1 SD increase; HR = 1.54, 95% CI: 1.28-1.85). In multivariable-adjusted models, the risk of new-onset MI increased with quartiles of CVAI, with an HR of 3.64 (95% CI: 1.94-6.83) for quartile 4 compared with quartile 1. The generalized additive model and smoothed curve fit revealed a nonlinear relationship between CVAI and risk of new-onset MI with an inflection point of approximately 112. None of the stratification variables had a significant effect on the relationship between CVAI and newonset MI. Similar outcomes were observed in the sensitivity analysis. The addition of CVAI significantly improved reclassification and discrimination over the conventional model, with a category-free NRI of 0.132 (95% CI 0.021 to 0.236, P = 0.021) and an IDI of 0.012 (95% CI 0.005 to 0.023, P < 0.001). Conclusion:This study demonstrated a nonlinear relationship between CVAI and the risk of new-onset MI in patients with hypertension and OSA. Higher CVAI was significantly associated with the risk of new-onset MI when CVAI was ≥112.
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