An ultraconserved snoRNA-like element in long noncoding RNA CRNDE promotes ribosome biogenesis and cell proliferation.

Cancer cells frequently upregulate ribosome production to support tumorigenesis. While small nucleolar RNAs (snoRNAs) are critical for ribosome biogenesis, the roles of other classes of noncoding RNAs in this process remain largely unknown. Here we performed CRISPRi screens to identify essential long noncoding RNAs (lncRNAs) in renal cell carcinoma (RCC) cells. This revealed that an alternatively-spliced isoform of lncRNA Colorectal Neoplasia Differentially Expressed containing an ultraconserved element (UCE), referred to as CRNDE UCE, is required for RCC cell proliferation. CRNDE UCE localizes to the nucleolus and promotes 60S ribosomal subunit biogenesis. The UCE of CRNDE functions as an unprocessed C/D box snoRNA that directly interacts with ribosomal RNA precursors. This facilitates delivery of eIF6, a key 60S biogenesis factor, which binds to CRNDE UCE through a sequence element adjacent to the UCE. These findings highlight the functional versatility of snoRNA sequences and expand the known mechanisms through which noncoding RNAs orchestrate ribosome biogenesis.

A non-canonical role for a small nucleolar RNA in ribosome biogenesis and senescence.

Cellular senescence is an irreversible state of cell-cycle arrest induced by various stresses, including aberrant oncogene activation, telomere shortening, and DNA damage. Through a genome-wide screen, we discovered a conserved small nucleolar RNA (snoRNA), SNORA13, that is required for multiple forms of senescence in human cells and mice. Although SNORA13 guides the pseudouridylation of a conserved nucleotide in the ribosomal decoding center, loss of this snoRNA minimally impacts translation. Instead, we found that SNORA13 negatively regulates ribosome biogenesis. Senescence-inducing stress perturbs ribosome biogenesis, resulting in the accumulation of free ribosomal proteins (RPs) that trigger p53 activation. SNORA13 interacts directly with RPL23, decreasing its incorporation into maturing 60S subunits and, consequently, increasing the pool of free RPs, thereby promoting p53-mediated senescence. Thus, SNORA13 regulates ribosome biogenesis and the p53 pathway through a non-canonical mechanism distinct from its role in guiding RNA modification. These findings expand our understanding of snoRNA functions and their roles in cellular signaling.

MTF1 genetic variants are associated with lung cancer risk in the Chinese Han population.

BACKGROUND: Metal-regulatory transcription factor 1 (MTF1), a conserved metal-binding transcription factor in eukaryotes, regulates the proliferation of cancer cells by activating downstream target genes and then participates in the formation and progression of tumors, including lung cancer (LC). The expression level of MTF1 is down-regulated in LC, and high expression of MTF1 is associated with a good prognosis of LC. However, the association between MTF1 polymorphism and LC risk has not been explored. METHODS: The genotyping of MTF1 Single nucleotide polymorphisms (SNPs) including rs473279, rs28411034, rs28411352, and rs3748682 was identified by the Agena MassARRAY system among 670 healthy controls and 670 patients with LC. The odds ratio (OR) and 95% confidence intervals (CI) were calculated by logistics regression to assess the association of these SNPs with LC risk. RESULTS: MTF1 rs28411034 (OR 1.22, 95% CI 1.03-1.45, p = 0.024) and rs3748682 (OR 1.24, 95% CI 1.04-1.47, p = 0.014) were associated with higher LC susceptibility overall. Moreover, the effect of rs28411034 and rs3748682 on LC susceptibility was observed in males, subjects with body mass index (BMI) ≥ 24 kg/m2, smokers, drinkers, and patients with lung squamous carcinoma (OR and 95% CI > 1, p < 0.05). Besides, rs28411352 (OR 0.73, 95% CI 0.55-0.97, p = 0.028,) showed protective effect for reduced LC risk in drinkers. CONCLUSIONS: We were first who reported that rs28411034 and rs3748682 tended to be relevant to increased LC susceptibility among the Chinese Han population. These results of this study could help to recognize the pathogenic mechanisms of the MTF1 gene in LC progress.

Multiple machine-learning tools identifying prognostic biomarkers for acute Myeloid Leukemia.

BACKGROUND: Acute Myeloid Leukemia (AML) generally has a relatively low survival rate after treatment. There is an urgent need to find new biomarkers that may improve the survival prognosis of patients. Machine-learning tools are more and more widely used in the screening of biomarkers. METHODS: Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), Random Forest (RF), eXtreme Gradient Boosting (XGBoost), lrFuncs, IdaProfile, caretFuncs, and nbFuncs models were used to screen key genes closely associated with AML. Then, based on the Cancer Genome Atlas (TCGA), pan-cancer analysis was performed to determine the correlation between important genes and AML or other cancers. Finally, the diagnostic value of important genes for AML was verified in different data sets. RESULTS: The survival analysis results of the training set showed 26 genes with survival differences. After the intersection of the results of each machine learning method, DNM1, MEIS1, and SUSD3 were selected as key genes for subsequent analysis. The results of the pan-cancer analysis showed that MEIS1 and DNM1 were significantly highly expressed in AML; MEIS1 and SUSD3 are potential risk factors for the prognosis of AML, and DNM1 is a potential protective factor. Three key genes were significantly associated with AML immune subtypes and multiple immune checkpoints in AML. The results of the verification analysis show that DNM1, MEIS1, and SUSD3 have potential diagnostic value for AML. CONCLUSION: Multiple machine learning methods identified DNM1, MEIS1, and SUSD3 can be regarded as prognostic biomarkers for AML.

The role of the Gas6/TAM signal pathway in the LPS-induced pulmonary epithelial cells injury.

BACKGROUND: Acute lung injury (ALI) is an acute inflammatory respiratory disease. The interaction between growth arrest-specific 6 (Gas6) and tyrosine kinases of the Tyro3, Axl, Mer (TAM) family plays an important role in a variety of physiological and pathological processes, including inflammation. In this study, we mainly clarified the mechanism of the Gas6/TAM signal pathway in lipopolysaccharide (LPS)-induced pulmonary epithelial cells (BEAS-2B cells) injury. METHODS: We cultured BEAS-2B cells in vitro and established a LPS-induced BEAS-2B cells injury model. Then, the siRNA sequence (siGas6-2) was transfected into cells. The expression of Gas6/TAM was measured based on quantitative reverse transcription polymerase chain reaction (qRT-RCR) and western blot (WB). Cell proliferation and apoptosis were measured by cell counting Kit-8 (CCK-8) and flow cytometry. The expression of pro-inflammatory factors was measured by qRT-RCR and WB. RESULTS: Our study showed that when the 40 µg/mL LPS-induced BEAS-2B cells injury model was established, cell viability was significantly reduced, but the Gas6/TAM signal pathway was activated. When transfection with siGas6-2, low expression of Gas6 directly reduced the expression of downstream TAM receptors. Furthermore, the inhibition of the Gas6/TAM signal pathway significantly reduced the occurrence of cell apoptosis and the expression of inflammatory factors, and promoted cell proliferation. CONCLUSION: Our research indicated that Gas6/TAM played an important role in cell proliferation, apoptosis, and inflammatory response in the LPS-induced BEAS-2B cells injury, and Gas6/TAM may be a new target in the treatment of ALI in the future.

Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia.

Phosphodiesterase 4D interacting protein (PDE4DIP) interacts with cAMP-specific phosphodiesterase 4D and its abnormal expression promotes the development of hematological malignancies, breast cancer, and pineal cell carcinoma. However, there is currently no systematic pan-cancer analysis of the association between PDE4DIP and various cancers. Thus, this study aimed to elucidate the potential functions of PDE4DIP in various cancers. Based on the multiple public databases and online websites, we conducted comprehensive analyses for PDE4DIP in various cancers, including differential expression, prognosis, genetic variation, DNA methylation, and immunity. We thoroughly analyzed the specific role of PDE4DIP in acute myeloid leukemia (LAML). The results indicated that there were differences in PDE4DIP expression in cancers, and in kidney chromophobe, LAML, pheochromocytoma and paraganglioma, thymoma, and uveal melanoma, PDE4DIP had potential prognostic value. PDE4DIP expression was also correlated with genetic variation, DNA methylation, immune cell infiltration, and immune-related genes in cancers. Functional enrichment analysis showed that PDE4DIP was mainly related to immune-related pathways in cancers, and in LAML, PDE4DIP was mainly related to immunoglobulin complexes, T-cell receptor complexes, and immune response regulatory signaling pathways. Our study systematically revealed for the first time the potential prognostic and immunotherapeutic value of PDE4DIP in various cancers, including LAML.

IL1RL1 polymorphisms rs12479210 and rs1420101 are associated with increased lung cancer risk in the Chinese Han population.

Background: Lung cancer is one of the most common human malignant diseases. In this study, we aimed to explore the association between IL1RL1 genetic polymorphisms and lung cancer risk in the Chinese Han population. Methods: We selected and genotyped six SNPs in the IL1RL1 gene using the Agena MassARRAY system in 507 lung cancer patients and 507 healthy controls. The association between IL1RL1 variants and lung cancer risk was assessed using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Multi-factor dimensionality reduction (MDR) was used to analyze the impact of SNP-SNP interactions on the risk of lung cancer. Results: The results of overall analysis indicated that rs12479210 (T vs. C: OR = 1.42, FDR-p = 0.002; TC vs. CC: OR = 1.70, FDR-p < 0.0001; TT vs. CC: OR = 1.77, FDR-p = 0.032; TT-TC vs. CC: OR = 1.71, FDR-p = 0.001; additive: OR = 1.44, FDR-p = 0.001) and rs1420101 (T vs. C: OR = 1.31, FDR-p = 0.036; TT-TC vs. CC: OR = 1.42, FDR-p = 0.031; additive: OR = 1.30, FDR-p = 0.030) were associated with an increased the risk of lung cancer among the Chinese Han population. Stratified analysis also found the association between these two SNPs and lung cancer risk. However, there were no significant association observed between the other four SNPs (rs3771180, rs3771175, rs10208293, and rs10197862) in IL1RL1 and lung cancer risk. Furthermore, MDR analysis showed that rs12479210 was the best single model with the highest testing accuracy (0.566) and perfect CVC (10/10) for predicting lung cancer risk. The expression level of the IL1RL1 gene is lower in lung cancer tissue than normal tissue, and there are significant differences in the expression levels of IL1RL1 between rs12479210 and rs1420101 genetypes in lung cancer tissue (p < 0.05). Conclusion: Our findings suggest that IL1RL1 genetic variants (rs12479210 and rs1420101) are associated with an increased lung cancer risk in the Chinese Han population. These risk variants may serve as biomarkers for the prevention and treatment of lung cancer.

Influence of CYP2C19 genetic variants and smoking on dual antiplatelet efficacy in patients with coronary artery disease.

Introduction: This study aimed to investigate the effects of smoking and CYP2C19 gene polymorphism on antiplatelet therapy to specify the most optimized and accurate antiplatelet therapy for different populations. Methods: This study included 6,353 patients with coronary artery disease (CAD). In total, 2,256 (35.5%) were smokers and 4,097 (64.5%) were non-smokers. Patients carrying a CYP2C19*2 or *3 allele were considered loss-of-function (LOF) allele carriers. The medical history of patients who had undergone percutaneous coronary intervention (PCI) at Beijing Anzhen Hospital was recorded. The primary endpoint was major adverse cardiovascular or cerebrovascular events (MACCE) during the 6-month follow-up period. A Cox regression model was used to assess the interactions between antiplatelet efficacy and CYP2C19 LOF allele carrier status, stratified by smoking status. Results: Compared to clopidogrel plus aspirin, ticagrelor plus aspirin reduced the MACCE recurrence risk in non-smokers (carrier: 6.0 vs. 2.0%, hazard ratio 0.298, 95% confidence interval 0.204-0.635, P < 0.0001; non-carrier: 5.8 vs. 2.1%, hazard ratio 0.358, 95% confidence interval 0.189-0.678, P = 0.002), and not in smokers. Similar results were discovered regarding the recurrence rate for hospitalization for ischemic cardiac events in non-smokers. No apparent difference was discovered in the bleeding events in either group. There were no significant associations between antiplatelet medication and CYP2C19 LOF allele carrier status for the MACCE recurrence risk among smokers (P = 0.943, respectively) or non-smokers (P = 0.774, respectively). Conclusion: In patients with CAD after PCI, ticagrelor plus aspirin lowered the MACCE recurrence risk in CYP2C19 LOF allele carriers and non-carriers compared with clopidogrel plus aspirin alone among non-smokers. The efficacy of antiplatelet therapy varies between CYP2C19 LOF allele carrier status. No significant interaction between CYP2C19 LOF allele carrier status and antiplatelet effectiveness was observed. However, caution should be used to interpret our results considering the many limitations of our investigation.

Association of CYP19A1 rs28757157 polymorphism with lung cancer risk in the Chinese Han population.

BACKGROUND: Lung cancer is the leading cause of cancer death globally. Recent studies have revealed that CYP19A1 gene plays a crucial role in cancer initiation and development. The aim of this study was to assess the association of CYP19A1 genetic polymorphisms with the risk of lung cancer in the Chinese Han population. METHODS: This study randomly recruited 489 lung cancer patients and 467 healthy controls. The genotypes of four single nucleotide polymorphisms (SNPs) of the CYP19A1 gene were identified by the Agena MassARRY technique. Genetic model analysis was used to assess the association between genetic variations and lung cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the effect of four selected SNPs on lung cancer risk. RESULTS: CYP19A1 rs28757157 might contribute to an increased risk of lung cancer (p = 0.025, OR = 1.30, 95% CI 1.03-1.64). In stratified analysis, rs28757157 was associated with an increased cancer risk in the population aged under 60 years, females, smokers, and drinkers. Besides, rs3751592 and rs59429575 were also identified as risk biomarkers in the population under 60 years and drinkers. Meanwhile, a relationship between an enhanced risk of squamous cell carcinoma and rs28757157 was found, while the rs3751592 CC genotype was identified as a risk factor for lung adenocarcinoma development. CONCLUSIONS: This study has identified revealed that the three SNPs (rs28757157, rs3751592, and rs59429575) of CYP19A1 are associated with lung cancer in the Chinese Han population. These findings will provide theoretical support for further functional studies of CYP19A1 in lung cancer.

Variants in CYP2J2 and CYP2C9 Contribute to Susceptibility of Lung Cancer.

BACKGROUND: Cytochrome P450 (CYP) enzymes are involved in the metabolism of xenobiotic and carcinogen. In the study, we evaluated the association of CYP2J2 and CYP2C9 variants with lung cancer. METHOD: Five polymorphisms in CYP2J2 and four polymorphisms in CYP2C9 were genotyped in 507 lung cancer patients and 505 controls with Agena MassARRAY platform. The linkage of variants with lung cancer risk was evaluated by odds ratio (OR) and 95% confidence interval (CI) in genetic models and haplotype analyses. RESULTS: We found that CYP2C9 rs1934967 alleles were associated with lung cancer risk (P < 0.05). In stratified analysis, rs2280274 (women, non-smoker, non-drinker and lymphatic metastasis), rs11207535 (non-smoker and non-drinker), rs10889159 (non-smoker and non-drinker) of CYP2J2, whereas rs1934967 (age ≤ 60m, BMI > 24, squamous carcinoma) of CYP2C9 decreased lung cancer risk (P < 0.05). In addition, the results of linkage disequilibrium (LD) analysis showed that rs2280274|rs4388726 - TG (with adjustment: P = 0.042) of CYP2J2 and rs10509679|rs1934967|rs1934968|rs9332220 - GTGG (without adjustment: P = 0.044) of CYP2C9 were linked with a significantly decreased lung cancer risk. CONCLUSION: Our results indicated genetic variants in CYP2J2 and CYP2C9 might contribute to the susceptibility of lung cancer in Chinese population.

Expression Profiles of Long Noncoding and Messenger RNAs in Epicardial Adipose Tissue-Derived from Patients with Coronary Atherosclerosis.

BACKGROUND: Given its close anatomical location to the heart and its endocrine properties, attention on epicardial adipose tissue (EAT) has increased. OBJECTIVE: This study investigated the expression profiles of long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) in EAT derived from patients with coronary artery disease (CAD). METHODS: EAT samples from 8 CAD, and 8 non-CAD patients were obtained during open-heart surgery, respectively. The expression of lncRNAs and mRNAs in each EAT sample was investigated using microarray analysis and further verified using reverse transcription-quantitative polymerase chain reaction. RESULTS: Overall, 1,093 differentially expressed mRNAs and 2,282 differentially expressed lncRNAs were identified in EAT from CAD vs. non-CAD patients. Analysis using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes showed that these differentially expressed genes were mainly enriched in various inflammatory, immune, and metabolic processes. They were also involved in osteoclast differentiation, B cell receptor and adipocytokine signaling, and insulin resistance pathways. Additionally, lncRNA-mRNA and lncRNA-target pathway networks were built to identify potential core genes (e.g., Lnc-CCDC68-2:1, AC010148.1, NONHSAT104810) involved in atherosclerotic pathogenesis. CONCLUSION: In summary, lncRNA and mRNA profiles in EAT were markedly different between CAD and non-CAD patients. Our study identifies several potential key genes and pathways that may participate in atherosclerosis development.

A Novel Risk Scoring Tool to Predict Saphenous Vein Graft Occlusion After Cardiac Artery Bypass Graft Surgery.

Objectives: Coronary artery bypass grafting (CABG) success is reduced by graft occlusion. Understanding factors associated with graft occlusion may improve patient outcomes. The aim of this study was to develop a predictive risk score for saphenous vein graft (SVG) occlusion after CABG. Methods: This retrospective cohort study enrolled 3,716 CABG patients from January 2012 to March 2013. The development cohort included 2,477 patients and the validation cohort included 1,239 patients. The baseline clinical data at index CABG was analyzed for their independent impact on graft occlusion in our study using Cox proportional hazards regression. The predictive risk scoring tool was weighted by beta coefficients from the final model. Concordance (c)-statistics and comparison of the predicted and observed probabilities of predicted risk were used for discrimination and calibration. Results: A total of 959 (25.8%) out of 3,716 patients developed at least one late SVG occlusion. Significant risk factors for occlusion were female sex [beta coefficients (ß) = 0.52], diabetes (ß = 0.21), smoking (currently) (ß = 0.32), hyperuricemia (ß = 0.22), dyslipidemia (ß = 0.52), prior percutaneous coronary intervention (PCI) (ß = 0.21), a rising number of SVG (ß = 0.12) and lesion vessels (ß = 0.45). On-pump surgery (ß = -0.46) and the use of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) (ß = -0.59) and calcium channel blockers (CCB) (ß = -0.23) were protective factors. The risk scoring tool with 11 variables was developed from the derivation cohort, which delineated each patient into risk quartiles. The c-statistic for this model was 0.71 in the validation cohort. Conclusions: An easy-to-use risk scoring tool which included female sex, diabetes, smoking, hyperuricemia, dyslipidemia, prior PCI, a rising number of SVG and lesion vessels, on-pump surgery, the use of ACEI/ ARB and CCB was developed and validated. The scoring tool accurately estimated the risk of late SVG occlusion after CABG (c-statistic = 0.71).

Comparison of transradial coronary intervention for left main bifurcation disease using the new Braidin® slender 7 Fr sheath and a standard 6 Fr sheath.

OBJECTIVES: To compare the effectiveness and safety of the Braidin® slender 7 Fr sheath with a standard 6 Fr sheath for treating left main bifurcation disease. METHODS: From January 2017 to March 2019, 277 patients with left main bifurcation disease who underwent the transradial approach for percutaneous coronary intervention were divided into the slender 7 Fr sheath group (Braidin® slender 7 Fr sheath, n = 154) and standard 6 Fr sheath group (n = 123). Pathological features, surgical effect, and complications were evaluated. RESULTS: The rate of using the classic crush technique was significantly higher in the slender 7 Fr sheath group than in the standard 6 Fr sheath group. The slender 7 Fr sheath group had a significantly shorter operation time than the standard 6 Fr sheath group. There were no significant differences in the radial artery occlusion rate after surgery and at 1 month of follow-up between the groups. Multivariate logistic regression analysis showed that 6 Fr and Braidin slender 7 Fr sheaths did not predict radial artery occlusion. CONCLUSION: The Braidin slender 7 Fr sheath has a superior operative process and similar safety for the radial artery as that of the standard 6 Fr sheath for treating left main bifurcation disease.

CRISPR-GEMM Pooled Mutagenic Screening Identifies KMT2D as a Major Modulator of Immune Checkpoint Blockade.

Immune checkpoint blockade (ICB) has shown remarkable clinical efficacy in several cancer types. However, only a fraction of patients will respond to ICB. Here, we performed pooled mutagenic screening with CRISPR-mediated genetically engineered mouse models (CRISPR-GEMM) in ICB settings, and identified KMT2D as a major modulator of ICB response across multiple cancer types. KMT2D encodes a histone H3K4 methyltransferase and is among the most frequently mutated genes in patients with cancer. Kmt2d loss led to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements. In addition, Kmt2d-mutant cells exhibited increased protein turnover and IFNγ-stimulated antigen presentation. In turn, Kmt2d-mutant tumors in both mouse and human were characterized by increased immune infiltration. These data demonstrate that Kmt2d deficiency sensitizes tumors to ICB by augmenting tumor immunogenicity, and also highlight the power of CRISPR-GEMMs for interrogating complex molecular landscapes in immunotherapeutic contexts that preserve the native tumor microenvironment. SIGNIFICANCE: ICB is ineffective in the majority of patients. Through direct in vivo CRISPR mutagenesis screening in GEMMs of cancer, we find Kmt2d deficiency sensitizes tumors to ICB. Considering the prevalence of KMT2D mutations, this finding potentially has broad implications for patient stratification and clinical decision-making.This article is highlighted in the In This Issue feature, p. 1775.

Prognostic value of CHADS2 and CHA2DS2-VASc scores for post-discharge outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

The CHADS2 and CHA2DS2-VASc scores were initially developed to assess the risk of stroke or systemic embolism in patients with atrial fibrillation (AF). Recently, these two scoring systems have been demonstrated to predict long- and short-term cardiovascular (CV) outcomes in many patient cohorts. However, to the best of our knowledge, their prognostic value has not been fully elucidated in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). This study aimed to investigate the association of CHADS2 and CHA2DS2-VASc scores with CV outcomes in such patients.We included a total of 915 ACS patients undergoing PCI in this study. CHADS2 and CHA2DS2-VASc scores were calculated from data collected before discharge. The primary endpoint was defined as a composite of major adverse CV events (MACE) including overall death, nonfatal stroke, nonfatal myocardial infarction (MI) and unplanned repeat revascularization. We assessed MACE's relationship to CHADS2 and CHA2DS2-VASc scores using Cox proportional-hazard regression analyses.Mean follow-up duration was 918 days. MACE occurred in 167 (18.3%) patients. A higher CHADS2 score was associated with reduced event-free survival (EFS) from MACE (logrank test, P = .007) with differences potentiated if stratified by CHA2DS2-VASc score (logrank test, P < .001). Univariate analysis showed that both CHADS2 and CHA2DS2-VASc scores were good predictors of MACE. In the multivariate Cox proportional-hazard regression analysis, CHA2DS2-VASc score (hazard ratio [HR], 1.15; 95% confidence interval [CI] 1.04-1.27; P = .007) remained a useful predictor of MACE; however, CHADS2 score was no longer associated with increased risk of MACE. C-statistics for CHA2DS2-VASc score, GRACE (Global Registry of Acute Coronary Events) hospital discharge risk score (GRACE Score) and SYNTAX (Synergy between PCI with TAXUS and Cardiac Surgery) Score II (SS II) in predicting MACE were 0.614, 0.598, and 0.609, respectively.CHA2DS2-VASc score was an independent and significant predictor of MACE in ACS patients undergoing PCI, and its discriminatory performance was not inferior to those of GRACE Score and SS II.

Risk Factors for Postoperative Events in Patients on Antiplatelet Therapy Undergoing Off-Pump Coronary Artery Bypass Grafting Surgery.

This retrospective study assessed the risk factors for adverse events following off-pump coronary artery bypass graft (CABG) surgery with dual antiplatelet therapy (DAPT). Records (between 2013 and 2017) were reviewed for patients who discontinued DAPT (clopidogrel 75 mg and aspirin 100 mg) ≤5 days before off-pump CABG. The primary outcome was the incidence of a Bleeding Academic Research Consortium (BARC) type 4 major event. Factors associated with bleeding events and perioperative myocardial ischemia were evaluated using multivariable logistic regression. The incidence of major bleeding events was 17.6% in 2012 patients. Adjusted multiple logistic regression analysis showed that the risk of postoperative bleeding increased when DAPT was discontinued <3 days before surgery (day 2: adjusted odds ratio [OR]: 1.70, 95% confidence interval [CI]: 1.09-2.64; day 1: adjusted OR: 2.37, 95% CI: 1.49-3.77; day 0: adjusted OR: 2.45, 95% CI: 1.53-3.92). The adjusted risk of mortality (OR: 13.14, 95% CI: 4.55-37.94) was increased with bleeding complications. In subgroup analysis, perioperative myocardial ischemia was related to increased blood loss (adjusted OR: 1.10, 95% CI: 1.02-1.18). Aspirin and clopidogrel should optimally be discontinued >3 days before CABG to reduce the risk of bleeding complications, myocardial ischemia, and death.

Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer.

Metastasis, the development of secondary malignant growths at a distance from a primary tumor, is the cause of death for 90% of cancer patients, but little is known about how metastatic cancer cells adapt to and colonize new tissue environments. Here, using clinical samples, patient-derived xenograft (PDX) samples, PDX cells, and primary/metastatic cell lines, we discovered that liver metastatic colorectal cancer (CRC) cells lose their colon-specific gene transcription program yet gain a liver-specific gene transcription program. We showed that this transcription reprogramming is driven by a reshaped epigenetic landscape of both typical enhancers and super-enhancers. Further, we identified that the liver-specific transcription factors FOXA2 and HNF1A can bind to the gained enhancers and activate the liver-specific gene transcription, thereby driving CRC liver metastasis. Importantly, similar transcription reprogramming can be observed in multiple cancer types. Our data suggest that reprogrammed tissue-specific transcription promotes metastasis and should be targeted therapeutically.

Genetic polymorphisms in IL-7 and IL-7R are correlated with lung cancer risk in the Chinese Han population.

PURPOSE: IL-7/IL-7R axis participates in the initiation and progression of lung cancer (LC). This study aimed to explore the potential influence of IL-7/IL-7R polymorphisms on LC risk. PATIENTS AND METHODS: In total, 1,010 participants (507 LC patients and 503 healthy controls) were enrolled. Five single-nucleotide polymorphisms (SNPs) in IL-7R and one SNP in IL-7 were genotyped in included samples with Agena MassARRAY system. OR and 95% CIs were computed by logistic regression analysis after adjusting for age and gender. Stratified analyses with demographic and clinical characteristics were also performed. Finally, linkage disequilibrium (LD) analysis was conducted with the PLINK version 1.07 software . RESULTS: IL-7R rs10053847 variant was related to a decreased LC risk under the allele gene (OR =0.78, P=0.043) and additive model (OR =0.77, P=0.042). The results of stratified analysis indicated that this SNP was associated with a lower LC risk among nonsmokers (AA/GG: OR =0.09, P=0.033; AA/AG+GG: OR =0.10 P=0.037) or nondrinkers (AA/GG: OR =0.07, P=0.047; AA/AG+GG: OR =0.18 P=0.049). Moreover, carriers of IL-7R rs10213865-C allele had an increased lung adenocarcinoma risk (CA/AA: OR =1.60, P=0.011; CC+CA/AA: OR =1.62, P=0.007; CA/CA/AA: OR =1.50, P=0.007). Additionally, AGAA haplotype (rs10213865, rs969129, rs118137916 and rs10053847) increased LC risk (OR =1.30, P=0.041). CONCLUSION: IL-7R rs10053847 was correlated with a decreased LC risk, while IL-7R rs10213865 was correlated with an elevated lung adenocarcinoma risk, implying these two SNPs might play essential roles in LC risk evaluation.

TNIP1 Polymorphisms with the Risk of Hepatocellular Carcinoma Based on Chronic Hepatitis B Infection in Chinese Han Population.

Chronic hepatitis B virus (HBV) infection is an important etiology for the development of hepatocellular carcinoma (HCC). Tumor necrosis factor-α-induced protein 3-interacting protein 1 (TNIP1) is linked to specific inflammatory diseases as a novel type of endogenous inflammatory regulator. However, presently, rare information is found about the association between TNIP1 polymorphisms and HBV-induced HCC risk. In this case control study, we genotyped four single nucleotide polymorphisms (SNPs) in TNIP1 gene in 248 HCC patients and 242 chronic HBV carriers using Sequenom Mass-ARRAY technology. Genetic model and haplotype analysis were performed to evaluate the association between candidate SNPs polymorphisms and HBV-induced HCC susceptibility using Pearson's χ2 test and unconditional logistic regression analysis. Overall, we found two risk alleles in TNIP1 for HBV-induced HCC in patients: the allele "G" of rs7708392 by genotype model ("G/C" vs. "C/C": OR 1.88, 95% CI 1.17-3, P = 0.009) and dominant model ("G/C-G/G" vs. "C/C": OR 1.69, 95% CI 1.08-2.65, P = 0.023), and the allele "C" of rs10036748 by genotype model ("C/T" vs. "T/T": OR 1.83, 95% CI 1.14-2.92, P = 0.012) and dominant model ("C/T-C/C" vs. "T/T": OR 1.65, 95% CI 1.05-2.59, P = 0.03). However, rs3792792 and rs4958881 polymorphisms didn't significantly correlate with the risk of HBV-induced HCC. Haplotype analysis showed no significant association between haplotypes and the HCC risk in HBV carriers. This study provides evidence for HBV-induced HCC susceptibility gene TNIP1 in the Chinese Han population.