The ubiquitin-like protein FAT10 and the homeobox protein HOXB9 each promote metastatic progression in hepatocellular carcinoma (HCC). In this study, we investigated the clinicopathologic significance of FAT10 and HOXB9 in HCC and investigated a mechanistic role for FAT10 in HOXB9-mediated invasiveness and metastasis. Relative to adjacent normal tissues, FAT10 and HOXB9 were markedly overexpressed in HCC, where a positive correlation in their expression and associated malignant characteristics were found. RNAi-mediated silencing of FAT10 decreased HOXB9 expression and inhibited HCC invasion and metastasis in vitro and in vivo. The effects of FAT10 silencing were reversed by HOXB9 overexpression, whereas RNAi-mediated silencing of HOXB9 decreased HCC invasion and metastasis driven by FAT10 overexpression. Mechanistically, FAT10 regulated HOXB9 expression by modulating the β-catenin/TCF4 pathway, directly binding to β-catenin and preventing its ubiquitination and degradation. Together, our results identified a novel HCC regulatory circuit involving FAT10, β-catenin/TCF4, and HOXB9, the dysfunction of which drives invasive and metastatic character in HCC. Cancer Res; 74(18); 5287–300. ©2014 AACR.

Background Several studies have investigated the impact of body mass index (BMI) on the prognosis of atrial fibrillation, but the results remain controversial. We sought to estimate the association of BMI with atrial fibrillation–related outcomes. Methods and Results We systematically searched the Cochrane Library, PubMed, and Elsevier databases for all studies reporting associations between BMI and atrial fibrillation–related outcomes. Relative risks (RRs) and 95% CIs were extracted and pooled. Nine studies with 49 364 participants were included. Underweight BMI was associated with an increased risk of stroke or systemic embolism (RR 1.67, 95% CI 1.12–2.49), all‐cause mortaliity (RR 2.61, 95% CI 2.21–3.09), and cardiovascular death (RR 2.49, 95% CI 1.38–4.50). Nevertheless, the pooled RRs of overweight and obese patients were lower than those of normal‐weight patients for stroke or systemic embolism (overweight: RR 0.91, 95% CI 0.80–1.04; obese: RR 0.84, 95% CI 0.72–0.98; grade 1 obesity: RR 0.89, 95% CI 0.71–1.11; grade 2 obesity: RR 0.64, 95% CI 0.45–0.91; grade 3 obesity: RR 0.82, 95% CI 0.54–1.25), all‐cause death (overweight: RR 0.78, 95% CI 0.62–0.96; obese: RR 0.84, 95% CI 0.64–1.10; grade 1 obesity: RR 0.64, 95% CI 0.57–0.73; grade 2 obesity: RR 0.70, 95% CI 0.47–1.03; grade 3 obesity: RR 0.72, 95% CI 0.59–0.88), and cardiovascular death (overweight: RR 0.79, 95% CI 0.58–1.08; obese: RR 0.99, 95% CI 0.79–1.24). Conclusions Underweight BMI is associated with an increased risk of stroke or systemic embolism, cardiovascular death, and all‐cause death in Asian patients with atrial fibrillation, whereas in all atrial fibrillation patients, overweight and obese BMI was not associated with increased risks of these outcomes.

Background: Cardiovascular medications are vital for the secondary prevention of coronary arterial disease (CAD). However, the effect of cardiovascular medication may depend on the optimal adherence of the patients. This meta‐analysis aims to determine the magnitude of adherence to vascular medications that influences the absolute and relative risks (RRs) of mortality in patients with CAD in real‐world settings.Methods: The Cochrane Library, PubMed, and EMBASE databases were searched through March 1, 2022. Prospective studies reporting association as RR and 95% confidence interval between cardiovascular medication adherence and any cardiovascular events and/or all‐cause mortality in patients with CAD were included. A one‐stage robust error meta‐regression method was used to summarize the dose‐specific relationships.Results: A total of 18 studies were included. There is a significant inverse linear association between cardiovascular medication adherence and cardiovascular events (p_nonlinearity = .68) or mortality (p_nonlinearity = .82). The exposure‐effect analysis showed that an improvement of 20% cardiovascular medication adherence was associated with 8% or 12% lower risk of any cardiovascular events or mortality, respectively. In subgroup analysis, the benefit was observed in adherence of stain (RR: 0.90, for cardiovascular events, RR: 0.85, for mortality), angiotensin‐converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB)(RR: 0.90, for mortality), and antiplatelet agent (RR: 0.89 for mortality) but not in beta‐blocker (RR: 0.90, p = .14, for cardiovascular events, RR: 0.97, p = .32 for mortality). Estimated absolute differences per 1 million individuals per year for mortality associated with 20% improvement were 175 cases for statin, 129 cases for antiplatelet, and 117 cases for ACEI/ARB.Conclusion: Evidence from the real word showed poor adherence to vascular medications contributes to a considerable proportion of all cardiovascular disease events and mortality in patients with CAD.

Two validated scoring systems for predicting embolic risk, CHADS₂ and CHA₂DS₂-VASc, contribute to optimizing antithrombotic prescription practices in patients who have atrial fibrillation. However, data about anticoagulated patients are sparse. We compared CHADS₂ and CHA₂DS₂-VASc, in terms of their predictive risk evaluation, in patients with atrial fibrillation who were and were not taking anticoagulants. We systematically searched the Cochrane Library, PubMed, and Embase databases for studies of the comparative diagnostic performance of CHADS₂ and CHA₂DS₂-VASc. We identified 12 cohort studies for meta-analysis. With regard to the occurrence of cardiovascular events individually, patients with CHA₂DS₂-VASc scores ≥2 have a greater risk of stroke (risk ratio [RR]=5.15; 95% confidence interval [CI], 3.85–6.88; P <0.00001) and thromboembolism (RR=5.96; 95% CI, 5.50–6.45; P <0.00001) (P_diff=0.34) than do patients with CHA₂DS₂-VASc scores <2, independent of anticoagulation therapy (RR=5.76; 95% CI, 5.23–6.35; P <0.00001 in anticoagulated patients; and RR=6.12; 95% CI, 5.40–6.93; P <0.00001 in patients not taking anticoagulants; P_diff=0.45). The pooled RR estimates indicate an approximate 6-fold increase in the risk of endpoint events in patients with CHA₂DS₂-VASc scores ≥2 (RR=5.90; 95% CI, 5.46–6.37; P <0.0001). These results clearly indicate the discriminative capacity of the CHA₂DS₂-VASc score for stroke, thromboembolic events, or both, independent of optimal anticoagulation. The CHA₂DS₂-VASc score enables the identification of patients who are at genuinely high risk and can direct the selection of appropriate therapeutic approaches.