RESUMO
OBJECTIVE: Megestrol acetate (MA) is used to manage anorexia and cachexia in patients with advanced cancer. This study investigated the prescription patterns of MA in patients with metastatic gastric cancer, as well as evaluated its impact on survival outcomes and the incidence of venous thromboembolism (VTE). METHODS: A Health Insurance Review and Assessment (HIRA) service database was used to investigate differences in baseline characteristics, survival, and the incidence of VTE according to MA prescription patterns (i.e., prescription vs. no prescription) in patients diagnosed with metastatic gastric cancer from July 2014 to December 2015. RESULTS: A total of 1938 patients were included in this study. In total, 65% of the patients were prescribed MA. Older age, treatment in tertiary hospitals, and palliative chemotherapy were statistically significant predictive factors for MA prescription. Continuous prescription of MA was observed in 37% of patients. There was no statistically significant difference in survival between the MA and non-MA prescription groups on multivariate analysis. Among the 1427 patients included in the analysis for VTE incidence, 4.3% and 2.9% were diagnosed with VTE during the follow-up period in the MA and non-MA prescription groups, respectively. However, there was no statistically significant difference in VTE diagnosis between the groups on multivariate analysis. CONCLUSION: MA is commonly prescribed for metastatic gastric cancer, especially in elderly patients and those undergoing palliative chemotherapy, without significantly affecting survival or VTE risk.
Assuntos
Neoplasias Gástricas , Tromboembolia Venosa , Humanos , Idoso , Acetato de Megestrol/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Caquexia/etiologia , Seguro Saúde , Fatores de Transcrição/uso terapêutico , Proteínas de Ciclo Celular/uso terapêutico , Chaperonas de Histonas/uso terapêuticoRESUMO
Despite that the docectaxel-cisplatin-5-fluorouracil (TPF) induction chemotherapy has greatly improved patients' survival and became the first-line treatment for advanced nasopharyngeal carcinoma (NPC), not all patients could benefit from this therapy. The mechanism underlying the TPF chemoresistance remains unclear. Here, by analyzing gene-expression microarray data and survival of patients who received TPF chemotherapy, we identify transcription factor ATMIN as a chemoresistance gene in response to TPF chemotherapy in NPC. Mass spectrometry and Co-IP assays reveal that USP10 deubiquitinates and stabilizes ATMIN protein, resulting the high-ATMIN expression in NPC. Knockdown of ATMIN suppresses the cell proliferation and facilitates the docetaxel-sensitivity of NPC cells both in vitro and in vivo, while overexpression of ATMIN exerts the opposite effect. Mechanistically, ChIP-seq combined with RNA-seq analysis suggests that ATMIN is associated with the cell death signaling and identifies ten candidate target genes of ATMIN. We further confirm that ATMIN transcriptionally activates the downstream target gene LCK and stabilizes it to facilitate cell proliferation and docetaxel resistance. Taken together, our findings broaden the insight into the molecular mechanism of chemoresistance in NPC, and the USP10-ATMIN-LCK axis provides potential therapeutic targets for the management of NPC.
Assuntos
Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , Docetaxel/uso terapêutico , Neoplasias Nasofaríngeas/patologia , Fatores de Transcrição/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/uso terapêutico , Quimiorradioterapia/métodos , Cisplatino/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ubiquitina TiolesteraseRESUMO
BACKGROUND: Fat infiltration in muscle, called 'myosteatosis', precedes muscle atrophy, which subsequently results in sarcopenia. Myosteatosis is frequently observed in patients with nonalcoholic fatty liver disease (NAFLD). We have previously reported that retinoic acid receptor-related orphan receptor-α (RORα) regulates mitochondrial dynamics and mitophagy in hepatocytes, resulting in an alleviation of NAFLD. In this study, we aimed to investigate the role of RORα in skeletal muscle and to understand molecular mechanisms by which RORα controls mitochondrial capacity, using an NAFLD-associated myosteatosis mouse model. METHODS: To establish a myosteatosis model, 7-week-old C57BL/6N mice were fed with high-fat diet (HFD). After 15 weeks of diet feeding, an adeno-associated virus vector encoding RORα (AAV-RORα) was injected to gastrocnemius (GA) muscles, or after 7 weeks of HFD feeding, JC1-40, an RORα agonistic ligand, was administered daily at a dose of 5 mg/kg/day by oral gavage for 5 weeks. Histological, biochemical and molecular analyses in various in vivo and in vitro experiments were performed. RESULTS: First, the number of oxidative MyHC2a fibres with intensive lipid infiltration increased by 3.8-fold in the red region of the GA of mice with myosteatosis (P < 0.001). RORα was expressed around MyHC2a fibres, and its level increased by 2.7-fold after HFD feeding (P < 0.01). Second, treatment of RORα ligands in C2C12 myoblasts, such as cholesterol sulfate and JC1-40, enhanced the number of oxidative fibres stained for MyHC1 and MyHC2a by two-fold to four-fold (P < 0.01), while it reduced the lipid levels in MyHC2a fibres by 20-50% (P < 0.001) in the presence of palmitic acids. Third, mitochondrial membrane potential (P < 0.01) and total area of mitochondria (P < 0.01) were enhanced by treatment of these ligands. Chromatin immunoprecipitation analysis showed that RORα bound the promoter of GA-binding protein α subunit gene that led to activation of mitochondrial transcription factor A (TFAM) in C2C12 myoblasts (P < 0.05). Finally, intramuscular transduction of AAV-RORα alleviated the HFD-induced myosteatosis with fatty atrophy; lipid contents in MyHC2a fibres decreased by 48% (P < 0.001), whereas the number of MyHC2b fibre increased by 22% (P < 0.001). Also, administration of JC1-40 improved the signs of myosteatosis in that it decreased the level of adipose differentiation-related protein (P < 0.01) but increased mitochondrial proteins such as cytochrome c oxidase 4 and TFAM in GA muscle (P < 0.01). CONCLUSIONS: RORα plays a versatile role in regulating the quantity of mitochondria and the oxidative capacity, ultimately leading to an improvement in myosteatosis symptoms.