TCTN1 Induces Fatty Acid Oxidation to Promote Melanoma Metastasis.

Metabolic reprogramming promotes and sustains multiple steps of melanoma metastasis. Identification of key regulators of metabolic reprogramming could lead to the development of treatments for preventing and treating metastatic melanoma. Here, we identified that the tectonic family member TCTN1 promotes melanoma metastasis by increasing fatty acid oxidation (FAO). In clinical melanoma samples, high expression of TCTN1 correlated with increased metastasis and shorter patient survival. Functionally, TCTN1 promoted melanoma invasion and migration in vitro and distant metastasis in vivo, and TCTN1 induced a mesenchymal-like phenotype switch. Mechanistically, TCTN1 acted as a protein scaffold to promote the binding of HADHA and HADHB, subunits of the mitochondrial trifunctional protein complex, thus leading to FAO activation. TCTN1-mediated FAO activated the p38/MAPK signaling pathway in melanoma cells, promoting tumor EMT and stemness. Molecular docking indicated that the prostaglandin F receptor agonist fluprostenol can block HADHA/HADHB binding, which was confirmed experimentally. Treatment with fluprostenol was able to inhibit TCTN1-induced melanoma invasion and metastasis. Taken together, these findings elucidate the mechanism of TCTN1-mediated promotion of melanoma metastasis and support the potential application of fluprostenol for targeted therapy of metastatic melanoma.

An advanced comprehensive muti-cell-type-specific model for predicting anti-PD-1 therapeutic effect in melanoma.

Rationale: Immune checkpoint inhibitors targeting the programmed cell death (PD)-1/PD-L1 pathway have promise in patients with advanced melanoma. However, drug resistance usually results in limited patient benefits. Recent single-cell RNA sequencing studies have elucidated that MM patients display distinctive transcriptional features of tumor cells, immune cells and interstitial cells, including loss of antigen presentation function of tumor cells, exhaustion of CD8+T and extracellular matrix secreted by fibroblasts to prevents immune infiltration, which leads to a poor response to immune checkpoint inhibitors (ICIs). However, cell subgroups beneficial to anti-tumor immunity and the model developed by them remain to be further identified. Methods: In this clinical study of neoadjuvant therapy with anti-PD-1 in advanced melanoma, tumor tissues were collected before and after treatment for single-nucleus sequencing, and the results were verified using multicolor immunofluorescence staining and public datasets. Results: This study describes four cell subgroups which are closely associated with the effectiveness of anti-PD-1 treatment. It also describes a cell-cell communication network, in which the interaction of the four cell subgroups contributes to anti-tumor immunity. Furthermore, we discuss a newly developed predictive model based on these four subgroups that holds significant potential for assessing the efficacy of anti-PD-1 treatment. Conclusions: These findings elucidate the primary mechanism of anti-PD-1 resistance and offer guidance for clinical drug administration for melanoma.

Circular RNA circFCHO2(hsa_circ_0002490) promotes the proliferation of melanoma by directly binding to DND1.

Circular RNAs (circRNAs) have been documented to play crucial roles in the biology of various cancers. However, their investigation in melanoma is still at an early stage, particularly as a broader mechanism beyond acting as miRNA sponges needs to be explored. We report here that circFCHO2(hsa_circ_0002490), a circRNA encompassing exons 19 and 20 of the FCHO2 gene, exhibited a consistent overexpression in melanoma tissues. Furthermore, elevated circFCHO2 levels demonstrated a positive correlation with the malignant phenotype and poor prognosis among the 158 melanoma patients studied. Besides, we observed that heightened levels of circFCHO2 promoted melanoma cell proliferation, migration, and invasion in vitro, along with contributing to tumor growth in vivo. Furthermore, we found differences in the secondary structure of circFCHO2 compared to most other circular RNA structures. It has fewer miRNA binding sites, while it has more RNA binding protein binding sites. We therefore speculate that circFCHO2 may have a function of interacting with RNA binding proteins. Mechanistically, it was confirmed by fluorescence in situ hybridization (FISH), RNA-pull down, RNA immunoprecipitation (RIP), and western blotting assays that circFCHO2 interacts with dead end protein homolog 1 (DND1) and reverses the inhibition of the PI3K/AKT signaling pathway by binding to DND1. Our findings reveal that circFCHO2 drives melanoma progression by regulating the PI3K/AKT signaling pathway through direct binding to DND1 and may serve as a potential diagnostic biomarker and therapeutic target for the treatment of melanoma.

Melanoma Derived Exosomes Amplify Radiotherapy Induced Abscopal Effect via IRF7/I-IFN Axis in Macrophages.

Radiotherapy (RT) can induce tumor regression outside the irradiation field, known as the abscopal effect. However, the detailed underlying mechanisms remain largely unknown. A tumor-bearing mouse model is successfully constructed by inducing both subcutaneous tumors and lung metastases. Single-cell RNA sequencing, immunofluorescence, and flow cytometry are performed to explore the regulation of tumor microenvironment (TME) by RT. A series of in vitro assays, including luciferase reporter, RNA Pulldown, and fluorescent in situ hybridization (FISH) assays, are performed to evaluate the detailed mechanism of the abscopal effect. In addition, in vivo assays are performed to investigate combination therapy strategies for enhancing the abscopal effect. The results showed that RT significantly inhibited localized tumor and lung metastasis progression and improved the TME. Mechanistically, RT promoted the release of tumor-derived exosomes carrying circPIK3R3, which is taken up by macrophages. circPIK3R3 promoted Type I interferon (I-IFN) secretion and M1 polarization via the miR-872-3p/IRF7 axis. Secreted I-IFN activated the JAK/STAT signaling pathway in CD8+ T cells, and promoted IFN-γ and GZMB secretion. Together, the study shows that tumor-derived exosomes promote I-IFN secretion via the circPIK3R3/miR-872-3p/IRF7 axis in macrophages and enhance the anti-tumor immune response of CD8+ T cells.

Inhibition of heme oxygenase 1 alleviates thoracic aortic aneurysm via restoration of extracellular matrix.

BACKGROUND: Thoracic aortic aneurysm (TAA) is a silent but life-threatening cardiovascular disease. Heme oxygenase 1 (HO-1) plays an important role in the cardiovascular diseases but is poorly understood in TAA. This study aims at investigating the role of HO-1 in TAA. METHODS: Single-cell RNA sequencing, Western blot and histological assay were performed to identify specific cellular expression of HO-1 in both human and ß-aminopropionitrile (BAPN)-induced mice TAA. Zinc protoporphyrin (ZnPP), a pharmacological inhibitor of HO-1, was used to investigate whether inhibition of HO-1 could attenuate BAPN-induced TAA in rodent model. Histological assay, Western blot assay, and mRNA sequencing were further performed to explore the underlying mechanisms. RESULTS: Single-cell transcriptomic analyses of 113,800 thoracic aortic cells identified an increase of HO-1(+) macrophage in aneurysmal thoracic aorta from BAPN-induced TAA mice and TAA patients. Histological assay verified HO-1 overexpression in clinical TAA specimens, which was co-localized with CD68(+) macrophage. HO-1(+) macrophage was closely associated with pro-inflammatory response and immune activation. Inhibition of HO-1 through ZnPP significantly alleviated BAPN-induced TAA in mice and restored extracellular matrix (ECM) in vivo. Further experiments showed that ZnPP treatment suppressed the expression of matrix metalloproteinases (MMPs) in aneurysmal thoracic aortic tissues from BAPN-induced TAA mice, including MMP2 and MMP9. Macrophages from myeloid specific HO-1 knockout mice displayed weakened pro-inflammatory activity and ECM degradation capability. CONCLUSION: HO-1(+) macrophage subgroup is a typical hallmark of TAA. Inhibition of HO-1 through ZnPP alleviates BAPN-induced TAA in mice, which might work through restoration of ECM via suppressing MMP2 and MMP9 expression.

Delineating the early dissemination mechanisms of acral melanoma by integrating single-cell and spatial transcriptomic analyses.

Acral melanoma (AM) is a rare subtype of melanoma characterized by a high incidence of lymph node (LN) metastasis, a critical factor in tumor dissemination and therapeutic decision-making. Here, we employ single-cell and spatial transcriptomic analyses to investigate the dynamic evolution of early AM dissemination. Our findings reveal substantial inter- and intra-tumor heterogeneity in AM, alongside a highly immunosuppressive tumor microenvironment and complex intercellular communication networks, particularly in patients with LN metastasis. Notably, we identify a strong association between MYC+ Melanoma (MYC+MEL) and FGFBP2+NKT cells with LN metastasis. Furthermore, we demonstrate that LN metastasis requires a metabolic shift towards fatty acid oxidation (FAO) induced by MITF in MYC+MEL cells. Etomoxir, a clinically approved FAO inhibitor, can effectively suppress MITF-mediated LN metastasis. This comprehensive dataset enhances our understanding of LN metastasis in AM, and provides insights into the potential therapeutic targeting for the management of early AM dissemination.

Decoding the metastatic potential and optimal postoperative adjuvant therapy of melanoma based on metastasis score.

Metastasis is a formidable challenge in the prognosis of melanoma. Accurately predicting the metastatic potential of non-metastatic melanoma (NMM) and determining effective postoperative adjuvant treatments for inhibiting metastasis remain uncertain. In this study, we conducted comprehensive analyses of melanoma metastases using bulk and single-cell RNA sequencing data, enabling the construction of a metastasis score (MET score) through diverse machine-learning algorithms. The reliability and robustness of the MET score were validated using various in vitro assays and in vivo models. Our findings revealed a distinct molecular landscape in metastatic melanoma characterized by the enrichment of metastasis-related pathways, intricate cell-cell communication, and heightened infiltration of pro-angiogenic tumor-associated macrophages compared to NMM. Importantly, patients in the high MET score group exhibited poorer prognoses and an immunosuppressive microenvironment, featuring increased infiltration of regulatory T cells and decreased infiltration of CD8+ T cells, compared to the low MET score patient group. Expression of PD-1 was markedly higher in patients with low MET scores. Anti-PD-1 (aPD-1) therapy profoundly affected antitumor immunity activation and metastasis inhibition in these patients. In summary, our study demonstrates the effectiveness of the MET score in predicting melanoma metastatic potential. For patients with low MET scores, aPD-1 therapy may be a potential treatment strategy to inhibit metastasis. Patients with high MET scores may benefit from combination therapies.

Prediction of survival and immunotherapy response by the combined classifier of G protein-coupled receptors and tumor microenvironment in melanoma.

BACKGROUND: Melanoma is the deadliest form of skin tumor, and G protein-coupled receptors (GPCRs) play crucial roles in its carcinogenesis. Furthermore, the tumor microenvironment (TME) affects the overall survival (OS) and the response to immunotherapy. The combination of GPCRs and TME from a multi-omics perspective may help to predict the survival of the melanoma patients and their response to immunotherapy. METHODS: Bulk-seq, single-cell RNA sequencing (scRNA-seq), gene mutations, immunotherapy responses, and clinicopathologic feature data were downloaded from public databases, and prognostic GPCRs and immune cells were screened using multiple machine learning algorithms. The expression levels of GPCRs were detected using real-time quantitative polymerase chain reaction (qPCR) in A375 and HaCaT cell lines. The GPCR-TME classifier was constructed and verified using different cohorts and multi-omics. Gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and tracking tumor immunophenotype (TIP) were used to identify the key biological pathways among the GPCR-TME subgroups. Then, tumor mutational burden (TMB), vital mutant genes, antigen presentation genes, and immune checkpoints were compared among the subgroups. Finally, the differences in immunotherapy response rates among the GPCR-TME subgroups were investigated. RESULTS: A total of 12 GPCRs and five immune cell types were screened to establish the GPCR-TME classifier. No significant differences in the expression levels of the 12 GPCRs were found in the two cell lines. Patients with high GPCR score or low TME score had a poor OS; thus, the GPCRlow/TMEhigh subgroup had the most favorable OS. The scRNA-seq result revealed that immune cells had a higher GPCR score than tumor and stromal cells. The GPCR-TME classifier acted as an independent prognostic factor for melanoma. GSEA, WGCNA, and TIP demonstrated that the GPCRlow/TMEhigh subgroup was related to the activation and recruitment of anti-tumor immune cells and the positive regulation of the immune response. From a genomic perspective, the GPCRlow/TMEhigh subgroup had higher TMB, and different mutant genes. Ultimately, higher expression levels of antigen presentation genes and immune checkpoints were observed in the GPCRlow/TMEhigh subgroup, and the melanoma immunotherapy cohorts confirmed that the response rate was highest in the GPCRlow/TMEhigh cohort. CONCLUSIONS: We have developed a GPCR-TME classifier that could predict the OS and immunotherapy response of patients with melanoma highly effectively based on multi-omics analysis.

Intratumoral CD73: An immune checkpoint shaping an inhibitory tumor microenvironment and implicating poor prognosis in Chinese melanoma cohorts.

Background: As a novel immune checkpoint, CD73 has been reported to play prominent roles in several malignancies. However, the significance of CD73 in melanoma remains ambiguous. This study sought to reveal the impact of CD73 on the tumor microenvironment (TME) and patients' prognosis, and to investigate whether CD73 could be a therapeutic target in Chinese melanomas, which were dominated by acral and mucosal subtypes. Methods: Two independent Chinese cohorts of 194 patients with melanoma were enrolled. CD73 and PD-L1 expression as well as CD8+ and CD56+ cell infiltrations were evaluated by immunohistochemistry in 194 resected melanoma samples. Clinical outcomes of patients were assessed utilizing the Kaplan-Meier plotter and Cox proportional hazard analysis. RNA-seq data was obtained from TCGA database. Gene set functional annotations were performed based on GO, KEGG and GSEA analysis. CIBERSORT, ssGSEA and TIMER were used to explore the association between CD73 and immune infiltration. These findings were validated by establishing tumor xenograft model, and functions of tumor-infiltrating immune cells were examined by flow cytometry and immunofluorescence. Results: High CD73 expression showed poorer clinical outcomes and was identified as an independent prognostic indicator for survival in two cohorts. Expression of CD73 was more prevalent than PD-L1 in Chinese melanoma cohorts (54.6% vs 23.2%). Co-expression of both immune checkpoints was infrequent (12.9%) in melanoma, and 54.4% of PD-L1 negative cases showed elevated expression of CD73. CD73high tumors showed a microenvironment with fewer CD8+ T cells and CD56+ NK cells infiltration, which displayed a dysfunctional phenotype. With the treatment of CD73 inhibitor APCP, the amount of CD8+ T cells and CD56+ NK cells infiltrated in tumors was elevated and the immunosuppressive effect of CD73 was eliminated. Conclusions: High CD73 expression was associated with an inhibitory TME and adverse clinical outcomes of melanoma. In comparison to PD-L1, CD73 was more prevalent and possessed more definite prognostic significance. Therefore, it may serve as a prognostic indicator and immunotherapeutic target next to PD-L1 in melanoma for Chinese population.

Genome-wide screening and immune landscape suggest a potential-m6A-related lncRNA risk signature for predicting prognosis of melanoma.

Background: Melanoma is the most dangerous form of skin cancer because of its high metastatic potential. Potential-N6-methyladenosine (m6A)-related long noncoding RNAs (pMRlncRNAs) play a vital role in malignancy. The identification of prognostic-related pMRlncRNAs and development of risk signatures could improve the prognosis and promote the precise treatment of melanoma. Methods: Gene expression and relevant clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Prognostic-related pMRlncRNAs were selected using univariate Cox regression analysis. Patients with melanoma were classified into different subtypes using the "ConsensusClusterPlus" package, and the ESTIMATE algorithm was applied to depict their immune landscape. A pMRlncRNA risk signature was developed using least absolute shrinkage and selection operator regression analysis and verified using survival analysis and receiver operating characteristic curves. Gene set enrichment analysis (GSEA) was used to investigate the underlying biological pathways. The relationships between risk score and clinicopathological characteristics, as well as programmed cell death-ligand 1 (PD-L1) expression level, were investigated. A nomogram with calibration curves was established to comprehensively predict the outcome of melanoma. Results: Fifteen pMRlncRNAs were significantly associated with overall survival (OS). Two cluster subtypes were identified by consensus clustering. Patients in cluster 2 were associated with better OS, higher PD-L1 expression level, lower T stage, and higher ESTIMATEScore, ImmuneScore, and StromalScore than those in cluster 1. There were differences in immune cell infiltration between the 2 clusters. Ten pMRlncRNAs with prognostic value were selected to develop a risk signature, that functioned as an independent prognostic factor for melanoma. Patients with low-risk scores had a better prognosis in general. The area under the curve (AUC) value (0.720), as well as 1-, 3-, and 5-year calibration curves, revealed that the risk signature has suitable predictive power for prognosis. GSEA revealed 10 pathways that might play important roles in melanoma. Moreover, patients with high-risk scores were associated with advanced T stage, cluster 1, lower ImmuneScore, and higher PD-L1 expression level. Conclusions: We developed a novel 10-pMRlncRNA risk signature that could elucidate the crucial role of pMRlncRNAs in the immune landscape of melanoma and predict prognosis.

Prediction of Survival and Tumor Microenvironment Infiltration Based on Pyroptosis-Related lncRNAs in Pancreatic Cancer.

Pancreatic cancer (PC) is a fatal tumor with high mortality. Pyroptosis plays a tumor suppressor role as a novel cell death. However, the influences of the pyroptosis-related lncRNAs (PRlncRNAs) on the prognosis and tumor microenvironment (TME) infiltration have not been fully studied in PC. Using coexpression analysis and univariate Cox regression analysis, we identified seventeen prognostic PRlncRNAs from The Cancer Genome Atlas (TCGA) dataset, which were all expressed differently in normal and tumor samples. A seven-PRlncRNA risk signature was constructed and validated using the least absolute shrinkage and selection operator (LASSO) regression. Furthermore, we verified its independence and created a nomogram to validate the clinical viability of the risk signature. We then identified its relationship with clinical factors and evaluated its values in TME infiltration, functional enrichment, tumor mutation, and therapeutic responses in PC. Lower ImmuneScore, ESTIMATEScore, and advanced tumor stage were connected with high-risk score. The low-risk group was characterized by better OS, elevated immune activation, and higher susceptibility of pazopanib and sunitinib. The high-risk group possessed a worse immune infiltration and poor survival, with higher tumor mutations and lapatinib and paclitaxel that may be better choices in this group. In conclusion, we developed an original seven-PRlncRNA risk signature to predict prognosis, TME infiltration, tumor mutation, and therapeutic options for PC patients.

Overcoming chemoresistance to b-raf inhibitor in melanoma via targeted inhibition of phosphoenolpyruvate carboxykinase1 using 3-mercaptopropionic acid.

The resistance of melanoma to BRAF inhibitors remains a tough clinical challenge. In order to explore the underlying mechanism of drug resistance in melanoma, we established the resistant cell line to vemurafenib, and assessed the changes of drug-resistant cells on proliferation, apoptosis, oxidative stress and tumor stemness. Our results suggest that phosphoenolpyruvate carboxykinase1 (PCK1) is activated and inhibits the oxidative stress caused by vemurafenib in drug-resistant cells. Long term treatment of vemurafenib increases the expression of PCK1 which reduces the production of reactive oxygen species (ROS) by activating PI3K/Akt pathway. After the inhibition of PCK1 by 3-mercaptopropionic acid (3-MPA), the therapeutic sensitivity of vemurafenib is restored. In conclusion, this study disclosed that drug-resistant cells appeared to regulate their own proliferation, oxidative stress and tumor dryness by activating Akt/PCK1/ROS pathway, and shed new insights into acquiring drug resistance in melanoma.

Gene Expression Profiling in Human Brain Microvascular Endothelial Cells in Response to Treponema pallidum Subspecies pallidum.

Neurosyphilis (NS) is a neurological disorder caused by Treponema pallidum subspecies pallidum (T. pallidum), but how T. pallidum attach to and cross the blood-brain barrier (BBB) and how BBB response to this bacteria remain unclear. To explore how the human brain microvascular endothelial cells (HBMECs) response to T. pallidum, the Agilent SurePrint G3 Human Gene Expression 8×60K microarray was used. The results revealed that 249 genes were differentially expressed in HBMECs infected with T. pallidum. In particular, genes encoding proteins involved in bacterial adhesion, endothelial cell activation and immune response were regulated by T. pallidum. Furthermore, Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to determine the biological functions of differentially expressed genes. In summary, T. pallidum changes the gene expression profile in HBMECs, and differentially expressed genes are associated with widespread biological and pathophysiological functions. Above all, this is the first paper reporting the effects of T. pallidum on HBMECs. These data develop a new platform for further molecular experiments on the pathogenesis of NS.

Comparison of thermal ablation and routine surgery for the treatment of papillary thyroid microcarcinoma: a systematic review and Meta-analysis.

BACKGROUND: Thermal ablation (TA), as an alternative to surgery, has shown some benefits in the treatment of papillary thyroid microcarcinoma (PTMC) patients, especially for those who are at high risk for surgery or refuse surgery. We performed a systematic review and meta-analysis to evaluate the efficiency, safety, and economy of TA, compared with those of routine surgery (RS), for the treatment of PTMC. METHODS: PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases were retrieved from inception to 10 January 2020 to identify relevant original studies on comparison of TA and RS for treatment of PTMC. The recurrence rate, recurrence-free survival (RFS), complication rate, operation time, postoperative length of stay, and cost during the perioperative period were extracted as main indices. The pooled standardized mean difference (SMD) or odds ratio (OR) with 95% confidence intervals (CI) were calculated and analyzed. Chi-square test and I2 statistic were applied to determine the heterogeneity among studies. The sensitivity analysis was applied to explore the origin of heterogeneity, and the publication bias was evaluated by Egger's test. RESULTS: Seven retrospective studies with a total of 867 patients met the eligibility criteria and were included in the final meta-analysis. Our study demonstrated that TA showed significant reduction in complication with a pooled OR 0.24 (95% CI 0.13 to 0.43), postoperative length of stay with a pooled SMD -3.14 (95% CI -4.77 to -1.51) and cost during the perioperative period with a pooled SMD of -1.69 (95% CI -3.18 to -0.20). It also demonstrated that both TA and RS had similar pooled proportion of recurrence of OR 0.93 (95% CI 0.38 to 2.30) and recurrence-free survive (RFS). The sensitivity analysis showed that each included study had no significant effect on the results and the results were stable and reliable. The Egger's test demonstrated publication bias was acceptable. CONCLUSIONS: TA may not be oncologically inferior to RS, and it is a relatively safe and economical alternative for the treatment of PTMC.

A comparison between drug-eluting bead-transarterial chemoembolization and conventional transarterial chemoembolization in patients with hepatocellular carcinoma: A meta-analysis of six randomized controlled trials.

OBJECTIVE: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate hepatocellular carcinoma. Drug-eluting beads (DEB)-TACE is a promising approach expected to improve the efficiency and safety of conventional (c) TACE. However, controversy remains whether DEB-TACE performs better than cTACE. This meta-analysis aimed to compare cTACE and DEB-TACE in terms of overall survival (OS), adverse events, and response rate. Literature search was performed in PubMed, Cochrane, Embase, and Web of Science. Complete response (CR), partial response (PR), disease control (DC), stable disease (SD), OS, and major complications were compared between these two modalities. The pooled relative risk and 95% confidence interval were calculated for assessment. Six randomized controlled trials were included for further analysis after a comprehensive search. No significant difference was found in overall response at 3, 6, 9, and 12 months, CR, PR, DC (SD), OS and complications between cTACE and DEB-TACE. CONCLUSION: DEB-TACE had similar therapeutic effects to those of cTACE. Furthermore, major complications in both therapies were similar. The superiority of DEB-TACE over cTACE remains unclear, and further research with high-quality evidence is needed.

Isoniazid causes heart looping disorder in zebrafish embryos by the induction of oxidative stress.

BACKGROUND: The cardiotoxicity of isoniazid on zebrafish embryos and its underlying mechanism is unclear. METHODS: Here, we exposed zebrafish embryos at 4 h post-fertilization to different levels of isoniazid and recorded the morphology and number of malformed and dead embryos under the microscope. RESULTS: The high concentration of isoniazid group showed more malformed and dead embryos than the low concentration of isoniazid group and control group. The morphology of the heart and its alteration were visualized using transgenic zebrafish (cmlc2: GFP) and confirmed by in situ hybridization. The negative effects of isoniazid on the developing heart were characterized by lower heart rate and more heart looping disorders. Mechanistically, PCR showed decreased expression of heart-specific transcription factors when exposed to isoniazid. Oxidative stress was induced by isoniazid in cardiomyocytes, mediated by decreased activities of catalase and superoxide dismutase, which were rescued by scavengers of reactive oxygen species. CONCLUSION: In conclusion, this study demonstrated that isoniazid led to heart looping disturbance by the downregulation of cardiac-specific transcription factors and induction of cardiomyocyte apoptosis.

Genome-wide screening of abberant methylated drivers combined with relative risk loci in bladder cancer.

BACKGROUND: To explore important methylation-driven genes (MDGs) and risk loci to construct risk model for prognosis of bladder cancer (BCa). METHODS: We utilized TCGA-Assembler package to download 450K methylation data and corresponding transcriptome profiles. MethylMix package was used for identifying methylation-driven genes and functional analysis was mainly performed based on ConsensusPathDB database. Then, Cox regression method was utilized to find prognostic MDGs, and we selected 17 hub genes via stepwise regression and multivariate Cox models. Kruskal-Wallis test was implemented for comparisons between risk with other clinical variables. Moreover, we constructed the risk model and validated it in GSE13507. Gene set enrichment analysis was performed using the levels of risk score as the phenotype. Additionally, we further screened out the relative methylation sites associated with the 17 hub genes. Cox regression and Survival analysis were conducted to find the specifically prognostic sites. RESULTS: Two hundred and twenty-eight MDGs were chosen by ConsensusPathDB database. Results revealed that most conspicuous pathways were transcriptional mis-regulation pathways in cancer and EMT. After Cox regression analysis, 17 hub epigenetic MDGs were identified. We calculated the risk score and found satisfactory predictive efficiency by ROC curve (AUC = 0.762). In the validation group from GSE13507, 17 hub genes remained higher predictive value with AUC = 0.723 and patients in high-risk group. Meanwhile, Kruskal-Wallis test revealed that higher risk score correlated with a higher level of TNM stage, tumor grade, and advanced pathological stages. Then, identified 38 risk methylated loci that highly associated with prognosis. Last, gene set enrichment analysis revealed that high-risk level of MDGs may correlate with several important pathways, including MAPK signaling pathway and so on. CONCLUSION: Our study indicated several hub-MDGs, calculated novel risk score and explored the prognostic value in BCa, which provided a promising approach to BCA prognosis assessment.

A comparison between radiofrequency ablation combined with transarterial chemoembolization and surgical resection in hepatic carcinoma: A meta-analysis.

OBJECTIVE: This study determined whether the effect of combination therapy for hepatic carcinoma (HCC) is comparable to surgical resection (SR). According to the guidelines of the American Association for the Study of Liver Disease, radiofrequency ablation (RFA) and SR are recommended for early HCC. However, patients treated with RFA had worse long-term survival than those who received SR. Many studies utilizing the combination therapy with RFA and transarterial chemoembolization (TACE) have reported better prognosis as compared to RFA alone. MATERIALS AND METHODS: A comprehensive search in databases was conducted. Six retrospective studies and one cohort were enrolled in this meta-analysis. The overall survival (OS), disease-free survival (DFS), and major complications were compared between RFA plus TACE and SR. The pooled hazard ratio and 95% confidence interval (CI) were calculated and analyzed. RESULTS: After comparison, no significant difference in the OS and DFS at 1 and 3 years between the combination therapy and SR was observed (OS1: pooled relative risk [RR]: 0.82, 95% CI [0.56, 1.21]; OS3: pooled RR: 1.07, 95% CI [0.82, 1.39]; DFS1: pooled RR: 0.92, 95% CI [0.58, 1.45]; DFS3: pooled RR: 1.18, 95% CI [1.00, 1.40]). SR had better clinical outcomes than combination therapy with respect to long-term survival and disease progression (OS5: pooled RR: 1.12, 95% CI [1.03, 1.23]; DFS5: pooled RR: 1.15, 95% CI [1.03, 1.28]). Major complications were reduced with combination therapy (pooled RR: 0.46, 95% CI [0.25, 0.85]). CONCLUSION: SR should remain as the first-line therapy for early HCC.