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Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare liver cancer with a poor prognosis, often diagnosed at an advanced stage. The management of cHCC-CCA with distant metastasis remains challenging, and prognostic factors are not well-defined. This study aimed to investigate prognostic factors and treatment outcomes for cHCC-CCA patients with distant metastasis. Methods: Retrospective analysis was conducted using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database. Patients with distant metastasis [stage M1, according to the American Joint Committee on Cancer (AJCC) 7th edition] between January 2010 and December 2020 were included. Their characteristics, clinical profiles, and prognostic information were evaluated. Cox multifactorial survival analysis and Kaplan-Meier survival curves were used for statistical analysis. Results: A total of 130 patients were included, with 78 (60%) receiving chemotherapy. Cox multivariate survival analysis revealed worse prognosis for Black individuals compared to White individuals (P<0.05). The median overall survival was 2 months for Black patients and 5 months for White patients. Chemotherapy significantly improved patient prognosis (P<0.05), while lung metastasis emerged as an independent risk factor (P<0.05). Kaplan-Meier survival curves confirmed the impact of lung metastasis and chemotherapy on overall survival. Patients with lung metastasis had lower survival rates (P<0.05), and those receiving chemotherapy had higher survival rates (P<0.05). Subgroup analysis based on age showed lower survival rates in patients aged 75 years or older compared to those below 75 years. Chemotherapy showed significant beneficial effects on the prognosis of patients below 75 years old, but no significant difference was observed in patients aged 75 years or above. Conclusions: Chemotherapy improves the prognosis of cHCC-CCA patients with distant metastasis, especially for those under 75 years old. Black race and lung metastasis are poor prognostic factors.
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Aim: Adipose tissue (AT) dysfunction that occurs in both obesity and lipodystrophy is associated with the development of cardiomyopathy. However, it is unclear how dysfunctional AT induces cardiomyopathy due to limited animal models available. We have identified vacuolar H+-ATPase subunit Vod1, encoded by Atp6v0d1, as a master regulator of adipogenesis, and adipose-specific deletion of Atp6v0d1 (Atp6v0d1AKO) in mice caused generalized lipodystrophy and spontaneous cardiomyopathy. Using this unique animal model, we explore the mechanism(s) underlying lipodystrophy-related cardiomyopathy. Methods and Results: Atp6v0d1AKO mice developed cardiac hypertrophy at 12 weeks, and progressed to heart failure at 28 weeks. The Atp6v0d1AKO mouse hearts exhibited excessive lipid accumulation and altered lipid and glucose metabolism, which are typical for obesity- and diabetes-related cardiomyopathy. The Atp6v0d1AKO mice developed cardiac insulin resistance evidenced by decreased IRS-1/2 expression in hearts. Meanwhile, the expression of forkhead box O1 (FoxO1), a transcription factor which plays critical roles in regulating cardiac lipid and glucose metabolism, was increased. RNA-seq data and molecular biological assays demonstrated reduced expression of myocardin, a transcription coactivator, in Atp6v0d1AKO mouse hearts. RNA interference (RNAi), luciferase reporter and ChIP-qPCR assays revealed the critical role of myocardin in regulating IRS-1 transcription through the CArG-like element in IRS-1 promoter. Reducing IRS-1 expression with RNAi increased FoxO1 expression, while increasing IRS-1 expression reversed myocardin downregulation-induced FoxO1 upregulation in cardiomyocytes. In vivo, restoring myocardin expression specifically in Atp6v0d1AKO cardiomyocytes increased IRS-1, but decreased FoxO1 expression. As a result, the abnormal expressions of metabolic genes in Atp6v0d1AKO hearts were reversed, and cardiac dysfunctions were ameliorated. Myocardin expression was also reduced in high fat diet-induced diabetic cardiomyopathy and palmitic acid-treated cardiomyocytes. Moreover, increasing systemic insulin resistance with rosiglitazone restored cardiac myocardin expression and improved cardiac functions in Atp6v0d1AKO mice. Conclusion: Atp6v0d1AKO mice are a novel animal model for studying lipodystrophy- or metabolic dysfunction-related cardiomyopathy. Moreover, myocardin serves as a key regulator of cardiac insulin sensitivity and metabolic homeostasis, highlighting myocardin as a potential therapeutic target for treating lipodystrophy- and diabetes-related cardiomyopathy.