RESUMEN
BACKGROUND: In this study, we explored the impact of hypothyroidism and thyroid hormone replacement therapy on the risk of developing cardiovascular diseases, including myocardial infarction, heart failure, and cardiac death, via Mendelian randomization analysis. METHODS: Genetic instrumental variables related to hypothyroidism, levothyroxine treatment (refer to Participants were taking the medication levothyroxine sodium) and adverse cardiovascular events were obtained from a large publicly available genome-wide association study. Two-sample Mendelian randomization analysis was performed via inverse-variance weighting as the primary method. To ensure the reliability of our findings, we performed MRâEgger regression, Cochran's Q statistic, and leave-one-out analysis. Additionally, multivariable Mendelian randomization was employed to regulate confounding factors, including systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), diabetes, cholesterol, low-density lipoprotein (LDL), triglycerides and metformin. A mediation analysis was conducted to assess the mediating effects on the association between exposure and outcome by treating atrial fibrillation and stroke as mediator variables of levothyroxine treatment and bradycardia as mediator variables of hypothyroidism. RESULTS: Genetically predicted hypothyroidism and levothyroxine treatment were significantly associated with the risk of experiencing myocardial infarction [levothyroxine: odds ratio (OR) 3.75, 95% confidence interval (CI): 1.80-7.80; hypothyroidism: OR: 15.11, 95% CI: 2.93-77.88]. Levothyroxine treatment was also significantly related to the risk of experiencing heart failure (OR: 2.16, 95% CI: 1.21-3.88). However, no associations were detected between hypothyroidism and the risk of experiencing heart failure or between hypothyroidism or levothyroxine treatment and the risk of experiencing cardiac death. After adjusting for confounding factors, the results remained stable. Additionally, mediation analysis indicated that atrial fibrillation and stroke may serve as potential mediators in the relationships between levothyroxine treatment and the risk of experiencing heart failure or myocardial infarction. CONCLUSION: The results of our study suggest a positive association between hypothyroidism and myocardial infarction and highlight the potential effects of levothyroxine treatment, the main thyroid hormone replacement therapy approach, on increasing the risk of experiencing myocardial infarction and heart failure.
Asunto(s)
Enfermedades Cardiovasculares , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hipotiroidismo , Análisis de la Aleatorización Mendeliana , Tiroxina , Humanos , Hipotiroidismo/diagnóstico , Hipotiroidismo/genética , Hipotiroidismo/epidemiología , Tiroxina/uso terapéutico , Medición de Riesgo , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/diagnóstico , Terapia de Reemplazo de Hormonas/efectos adversos , Factores de Riesgo , Fenotipo , Femenino , Infarto del Miocardio/genética , Infarto del Miocardio/epidemiología , Infarto del Miocardio/diagnóstico , Polimorfismo de Nucleótido Simple , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Masculino , Variantes Farmacogenómicas , Factores de Riesgo de Enfermedad CardiacaRESUMEN
Objective To investigate the role of ATP citrate lyase(ACLY)in the development of hepatocellular carcinoma(HCC)and the impact of this enzyme on the immune microenvironment of HCC.Methods We utilized the University of Alabama at Birmingham Cancer Data Analysis Portal and the Gene Expression Profiling Interactive Analysis to identify the changes in ACLY expression and prognosis across different tumor types from The Cancer Genome Atlas.With HCC as the disease model,we analyzed the ACLY expression in HCC samples from the gene expression database.Furthermore,we collected the clinical specimens from HCC patients to verify the mRNA and protein levels of ACLY.In addition,we conducted transcriptome sequencing after knocking down the expression of ACLY to analyze the differentially expressed genes and investigated the impact of ACLY expression interference on cell proliferation and other functions.Finally,we explored the correlations of ACLY with immune cells and immune infiltration in the tumor microenvironment,new antigens,and immune checkpoint genes.Results ACLY expression was significantly up-regulated in solid tumors including HCC(all P<0.05),and high ACLY expression was associated with overall survival rate in HCC(P=0.005).Furthermore,high ACLY expression affected the presence of immune cells(e.g.,tumor-associated fibroblasts)and the expression of genes involved in lipid metabolism(all P<0.05).Conclusions ACLY is closely related to the occurrence and development of HCC and lipid metabolism abnormalities.Moreover,it has a specific impact on the immune microenvironment of HCC.
Asunto(s)
ATP Citrato (pro-S)-Liasa , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , ATP Citrato (pro-S)-Liasa/genética , ATP Citrato (pro-S)-Liasa/metabolismo , Relevancia Clínica , Metabolismo de los Lípidos , Microambiente TumoralRESUMEN
Background and objectives: Obstructive jaundice is common in patients with pancreaticobiliary malignancies. Preoperative biliary drainage (PBD) can alleviate cholestasis; however, no consensus has been reached on the impact of PBD on the incidence of surgery-related complications and patient survival. This study aimed to evaluate the effect among patients treated with PBD. Methods: This retrospective study examined the clinical and follow-up prognostic data of 160 patients with pancreaticobiliary malignancies who underwent pancreaticoduodenectomy (PD) at Beijing Friendship Hospital, Capital Medical University, from January 2016 to July 2020. Outcomes were compared between patients who underwent PBD (PBD group) and those who did not (control group). Changes in biochemical indicators were evaluated before and after drainage in the PBD group. Between-group differences in inflammatory indicators after PD were assessed using the Wilcoxon signed-rank test. Postoperative complications were classified according to the Clavien-Dindo classification system. The effects of PBD and biliary drainage efficiency on postoperative complications were evaluated using the chi-square test and binary logistics regression. The Kaplan-Meier analysis was used for between-group comparison of survival analysis. Univariate and multivariate regression analyses were performed to identify prognostic factors of survival. Results: Total 160 patients were enrolled,the mean age of the study sample was 62.75 ± 6.75 years. The distribution of pancreaticobiliary malignancies was as follows: 34 cases of pancreatic head cancer, 61 cases of distal bile duct cancer, 20 cases of duodenal papilla cancer, 39 cases of duodenal ampullary cancer, and 6 cases of malignant intraductal papillary mucinous neoplasm (IPMN). PBD was performed in 90 of the 160 patients, with PBD performed using an endoscopic retrograde cholangiopancreatography (ERCP) approach in 55 patients and with percutaneous transhepatic cholangiography (PTC) used in the remaining 35 cases. The mean duration of drainage in the PBD group was 12.8 ± 8.8 days. The overall rate of complications was 48.05% (37/77) in the control group and 65.55% (59/90) in the PBD group with non-significant difference (χ2 = 3.527, p=0.473). In logsitics regression analysis, PBD was also not a risk factor for postoperative complications OR=1.77, p=0.709). The overall rate of postoperative complications was significantly higher among patients who underwent PBD for >2 weeks (χ2 = 6.102, p=0.013), with the rate of severe complications also being higher for this subgroup of PBD patients (χ2 = 4.673, p=0.03). The overall survival time was 47.9 ± 2.45 months, with survival being slightly lower in the PBD group (43.61 ± 3.26 months) than in the control group (52.24 ± 3.54 months), although this difference was not significant (hazard ratio (HR)=0.65, p=0.104). Conclusion: In patients with malignant biliary obstruction, PBD does not affect the incidence of postoperative complications after pancreaticoduodenectomy nor does it affect patient survival. Prolonged biliary drainage (>2 weeks) may increase the incidence of overall postoperative complications and severe complications.
RESUMEN
BACKGROUND: To assess the role of atrial fibrillation on perioperative outcomes in patients with pancreatic cancer undergoing open pancreaticoduodenectomy (OPD). METHODS: We investigated patients with pancreatic cancer undergoing OPD during 2012-2014 within National Inpatient Sample database. The study population was divided into two groups based on the presence of atrial fibrillation. In-hospital mortality, length of stay, cost of hospitalization, and in-hospital complications were compared between the two groups. Logistic regression models and linear regression were used to adjust for potential confounders. Propensity score matching was also utilized. RESULTS: Of the 12,785 patients aged ≥18 years undergoing OPD during years 2012-2014, 11,469 (90%) had no atrial fibrillation and 1,316 (10%) had atrial fibrillation. Patients with atrial fibrillation were found to have significantly higher cost, but similar mortality and LOS compared to those without atrial fibrillation. The risk of gastrointestinal anastomotic leakage, cardiac complications, respiratory complications, pulmonary embolism, and perioperative shock were found to be significantly higher in atrial fibrillation group than non-atrial fibrillation group in both multivariate regression model and propensity score matching model. In older patients (>65 years), atrial fibrillation was found to be associated with a significantly higher cost, longer hospital stays, higher incidence of cardiac complications, respiratory complications, and postoperative shock, yet similar mortality. CONCLUSIONS: Atrial fibrillation was found to be associated with higher cost in pancreatic cancer patients undergoing OPD, as well as increased occurrence of cardiac complications, respiratory complications, pulmonary embolism, and perioperative shock. Surgeons should pay special attention to patients with atrial fibrillation, and consider working together with cardiologists and anesthesiologists to jointly develop a management plan.
RESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Discerning oncogenic drivers from passengers remain a major effort in understanding of the essence of the initiation and development of hepatocellular carcinoma (HCC), which is the most common primary liver malignancy and the third leading cause of cancer mortality worldwide. Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. Genome-wide identification of the transcriptional targets of the ZNF774/NuRD complex by ChIP-seq indicated that ZNF774 represses a cohort of genes including NOTCH2 that are critically involved in the growth and mobility of HCC. We demonstrated that the ZNF774/NuRD complex inhibits the proliferation and invasion of HCC cells in vitro and suppresses HCC growth and metastasis in vivo. Importantly, the expression of ZNF774 is significantly downregulated in HCC, and low ZNF774 expression strongly correlated with high NOTCH2 expression, advanced pathological stages, and poor overall survival of the patients. Together, these results uncover a key role for the ZNF774/NuRD-NOTCH2 axis in hepatocarcinogenesis.
Asunto(s)
Carcinogénesis , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Receptor Notch2/metabolismo , Transducción de Señal , Secuencia de Aminoácidos , Carcinoma Hepatocelular/genética , Proliferación Celular , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia , Transcripción GenéticaRESUMEN
Discerning oncogenic drivers from passengers remains a major effort in understanding of the essence of the initiation and development of hepatocellular carcinoma (HCC), the most common primary liver malignancy and the third leading cause of cancer mortality worldwide. Here we report that MTA2, Metastasis Associated 1 Family Member 2, is significantly up-regulated in HCC. We show that high level of MTA2 expression is strongly correlated with advanced pathological stages and poor overall survival of the patients. Genome-wide identification of the transcriptional targets of MTA2 by ChIP-seq indicates that MTA2 represses a cohort of genes including FRMD6 that are critically involved in the growth and mobility of HCC. We demonstrate that the MTA2 promotes the proliferation and metastasis of HCC in vitro and in vivo through suppressing Hippo signaling pathway. Together, these results reveal a key role for the MTA2-FRDM6-Hippo axis in human hepatocarcinogenesis.
Asunto(s)
Carcinoma Hepatocelular/genética , Proteínas del Citoesqueleto/genética , Histona Desacetilasas/genética , Neoplasias Hepáticas/genética , Proteínas de la Membrana/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Represoras/genética , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Proteínas del Citoesqueleto/metabolismo , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Vía de Señalización Hippo , Histona Desacetilasas/metabolismo , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Masculino , Proteínas de la Membrana/metabolismo , Ratones SCID , Proteínas Serina-Treonina Quinasas/metabolismo , Tratamiento con ARN de Interferencia/métodos , Proteínas Represoras/metabolismo , Transducción de Señal/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Gemcitabine-based chemotherapy is the first-line treatment for pancreatic cancer. However, chemoresistance is a major obstacle to drug efficacy, leading to poor prognosis. Little progress has been achieved although multiple mechanisms are investigated. Therefore, effective strategies are urgently needed to overcome drug resistance. Here, we demonstrate that the transcription factor GATA binding protein 1 (GATA1) promotes gemcitabine resistance in pancreatic cancer through antiapoptotic pathway. GATA1 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) tissues, and GATA1 status is an independent predictor of prognosis and response to gemcitabine therapy. Further investigation demonstrates GATA1 is involved in both intrinsic and acquired gemcitabine resistance in PDAC cells. Mechanistically, we find that GATA1 upregulates Bcl-XL expression by binding to its promoter and thus induces gemcitabine resistance through enhancing Bcl-XL mediated antiapoptosis in vitro and in vivo. Moreover, in PDAC patients, Bcl-XL expression is positively correlated with GATA1 level and predicts clinical outcomes and gemcitabine response. Taken together, our results indicate that GATA1 is a novel marker and potential target for pancreatic cancer. Targeting GATA1 combined with Bcl-XL may be a promising strategy to enhance gemcitabine response.
RESUMEN
Hyperactivation of EGFR/PI3K/AKT is a prominent feature of various human cancers. Thus, understanding how this molecular cascade is balanced is of great importance. We report here that the ubiquitin-specific protease USP43 is physically associated with the chromatin remodeling NuRD complex and catalyzes H2BK120 deubiquitination. Functionally this coordinates the NuRD complex to repress a cohort of genes, including EGFR, which are critically involved in cell proliferation and carcinogenesis. We show that USP43 strongly suppresses the growth and metastasis of breast cancer in vivo. Interestingly, USP43 also exists in the cytoplasm, where it is phosphorylated by AKT, enabling its binding to the 14-3-3ß/ε heterodimer and sequestration in the cytoplasm. Significantly, hyperactivation of EGFR/PI3K/AKT in breast cancer is associated with the cytoplasmic retention of USP43 and thus, the inhibition of its transcriptional regulatory function. Moreover, cancer-associated mutations of USP43 affect its subcellular localization and/or epigenetic regulatory functions. Nuclear USP43 is significantly reduced in breast carcinomas and is associated with EGFR accumulation and AKT hyperactivation. A low level of nuclear USP43 correlates with higher histologic grades and poor prognosis. Our study identifies USP43 to be an H2BK120 deubiquitinase and a potential tumor suppressor and reveals a reciprocally inhibitory loop between USP43 and EGFR/PI3K/AKT, whose imbalance drives breast carcinogenesis.
Asunto(s)
Neoplasias de la Mama/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteasas Ubiquitina-Específicas/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Receptores ErbB/metabolismo , Femenino , Humanos , Proteasas Ubiquitina-Específicas/genéticaRESUMEN
BACKGROUND: CD8+ central memory T cells (CD8+ Tcm) have superior roles in antitumor immunity. The purpose of this study was to detect CD8+ Tcm in the peripheral blood of patients with pancreatic adenocarcinoma and to analyze its clinic significance. METHODS: Seventy two patients with primary pancreatic adenocarcinoma who underwent curative operation were enrolled. The percentage and absolute count of CD8+ Tcm in the peripheral blood of patients were analyzed through flow cytometry and the multiplatform predicate method, respectively, and these values were compared to those of the healthy control. The correlation between CD8+ Tcm and survival was analyzed by the Kaplan-Meier with log-rank test and Cox's regression methods, respectively. RESULTS: The percentage of CD8+ Tcm from pancreatic adenocarcinoma was higher than the healthy control (16.79 ± 9.43% vs. 11.41 ± 4.67%, p = 0.028), which also had a relationship with the lymph node status. Patients with high-level CD8+ Tcm had a significantly higher median survival than those with low CD8+ Tcm (18 vs. 12 months, p = 0.004); a similar result was obtained in absolute CD8+ Tcm count. It was revealed in multivariate analysis that both percentage and absolute count of CD8+ Tcm was an independent prognostic factor for overall survival. CONCLUSIONS: CD8+ Tcm can be considered an independent prognostic factor for operable pancreatic adenocarcinoma, which was also associated with the lymph nodes metastasis.