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Background: Smith-like (LSM) family members play critical roles in multiple oncologic processes in several types of malignancies. The study on LSM family members of HCC might provide new insights into the tumorigenesis and therapeutic strategies of HCC. Methods: The clinical significance and oncologic biological functions of LSM family members were assessed through multiple bioinformatics methods and in vitro studies. The potential correlation between LSM family members and tumor immunity was also investigated using single sample gene set enrichment analysis (ssGSEA) and the ESTIMATE algorithm. Results: LSM family member overexpression in HCC was significantly correlated with poor clinical outcomes such as higher TNM stage, advanced histologic grade, and worse prognosis. A risk score system based on LSM5, LSM10, LSM12, and LSM14B showed a reliable predictive ability for OS of HCC patients. Functional enrichment analysis demonstrated that LSM family members overexpressed were all involved in cell cycle related biological processes. Besides, LSM12, LSM14A, and LSM14B were found to be significantly associated with PI3K-Akt-mTOR and T cell receptor signaling pathways. Tumors with LSM12, LSM14A, and LSM14B overexpression exhibited lower infiltration of activated CD8+ T cells with declined cytolytic activity and immune score, but increased infiltration of Th2 cells and Th2/Th1. LSM12, LSM14A, and LSM14B overexpression is also associated with higher tumor-related immune checkpoints (e.g., PD-L1, B7-H3, and PVR) expression and increased therapeutic insensitivity to immune checkpoint blockade (ICB). Moreover, the knockdown of LSM12, LSM14A, and LSM14B significantly inhibited the proliferation and invasion of HCC cells. Conclusion: This study systematically investigated the expression pattern and biological values of LSM family members in HCC and identified LSM family members as novel therapeutic targets in HCC. [ABSTRACT FROM AUTHOR]

Evidence for treating hypertension in patients with asymptomatic aortic valve stenosis(AS) is scarce. Given the paucity of data on the relationship between syncope and antihypertensive treatment in aortic stenosis. This study sought to investigate this association in patients admitted to our hospital. A total of 158 patients with asymptomatic moderate or severe aortic stenosis were analyzed. Follow-up was conducted by clinic visit, telephone contact, or review of electronic medical records. Outcomes were syncope. Hypertension were documented in 90 of the 158 patients with moderate or severe AS, and 77 of them received antihypertensive medications. During an average 28 months follow-up period, the occurrence of syncope was observed in 13 patients. Among them, 8 were in antihypertensive group (n = 77) and 5 in normotensive group (n = 68). There was no significant difference in incidence of syncope between the two groups. Patients with treated hypertension and syncope had a lower stroke volume index (SVi), a higher valve arterial impedance (ZVA), a smaller SAC than those without. Kaplan-Meier analysis showed that there was no significant difference in syncope cumulative incidence between antihypertensive group and normotensive group (log rank P =.478). Multivariate cox regression analysis showed that both ZVA (hazard ratio:19.006, 95% confidence interval: 4.664 to77.448;P =.002) and LVMI (hazard ratio:1.484, 95% confidence interval: 1.427 to 5.157;P =.016) were associated with development of syncope, whereas hypertension were not related independently to syncope (hazard ratio:0.935, 95% confidence interval: 0.786 to3.173; P =.869). In patients with moderate or severe AS, concomitant hypertension, and antihypertensive treatment didn't increase the occurrence of syncope, whereas higher ZVA was independently associated with greater risk of syncope. [ABSTRACT FROM AUTHOR]

We developed a series of highly crystalline double‐cable conjugated polymers for application in single‐component organic solar cells (SCOSCs). These polymers contain conjugated backbones as electron donor and pendant perylene bisimide units (PBIs) as electron acceptor. PBIs are connected to the backbone via alkyl units varying from hexyl (C6H12) to eicosyl (C20H40) as flexible linkers. For double‐cable polymers with short linkers, the PBIs tend to stack in a head‐to‐head fashion, resulting in large d‐spacings (e.g. 64 Å for the polymer P12 with C12H24 linker) along the lamellar stacking direction. When the length of the linker groups is longer than a certain length, the PBIs instead adopt a more ordered packing likely via H‐aggregation, resulting in short d‐spacings (e.g. 50 Å for the polymer P16 with C16H32 linker). This work highlights the importance of linker length on the molecular packing of the acceptor units and the influences on the photovoltaic performance of SCOSCs. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the predictive value of lactate for prognosis in critically ill patients with AUD. Methods: A retrospective cohort study was performed using data extracted from a freely accessible critical care database (MIMIC-III). We studied all patients with AUD from the database for whom lactate was available. The clinical outcomes were 30-day mortality. Analyses included LOWESS curve fitting, logistic multivariate regression model, receiver operating characteristic (ROC) analysis and subgroup analysis. Results: A total of 1296 eligible critically ill patients with AUD were included and there were 223 non-survivors (17.2%). The non-survivors had a higher lactate than the survivors (p < 0.001). A nonlinear relationship between lactate and 30-day mortality was observed. Multivariate logistic regression indicated lactate could be an independent risk factors to predict the prognosis of critically ill patients with AUD. According to ROC curve analysis, the area under the curve predicted by lactate for 30-day mortality was 0.672 (95% CI, 0.634 to 0.711). Subgroup analysis did not find obvious interaction in most subgroups. Conclusion: High lactate was associated with increased mortality in critically ill patients with AUD. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNAs (lncRNAs) are reported to play important roles in tumorigenesis of various malignant tumors. However, the clinical significance of aberrant lncRNA expression in hepatocellular carcinoma (HCC) is still elusive. Methods: Firstly, a differentially expressed lncRNA CTC‐297N7.9 in HCC was detected by analyzing the data from The Cancer Genome Atlas (TCGA). Secondly, the expression level of CTC‐297N7.9 was examined in four HCC cell lines and 60 pairs of HCC tissues by polymerase chain reaction (PCR) assay at our center. Thirdly, receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic value of CTC‐297N7.9 for HCC. Correlation and survival analysis of HCC patients from the TCGA and our center were also carried out to assess the predictive value of CTC‐297N7.9. Finally, survival prognostic models were established combining lncRNA expression and other clinical parameters. Results: The expression of CTC‐297N7.9 was downregulated in HCC cell lines and HCC tissues. ROC curve revealed its significant diagnostic value in HCC. CTC‐297N7.9 expression correlated with serum alpha‐fetal protein (AFP), tumor stage, and tumor differentiation. Survival analysis indicated that overall survival (OS) and disease‐free survival (DFS) are all positively associated with CTC‐297N7.9 expression, especially in patients without viral hepatitis or cirrhosis. Cox regression analysis showed that CTC‐297N7.9 expression level is an independent prognostic factor for both OS and DFS in HCC patients. Based on the model, CTC‐297N7.9 was observed to be negatively correlated to risk score, indicating its role as a protective factor for HCC. Conclusion: Our study demonstrated that the low expression of CTC‐297N7.9 is associated with poor prognosis in HCC patients, suggesting its possible role as a potential prognostic marker for HCC. [ABSTRACT FROM AUTHOR]

Background: V-set and immunoglobulin domain containing protein 4 (VSIG4) was reported to play an important role in tumorigenesis. However, the expression and clinical relevance in hepatocellular carcinoma (HCC) remain unknown.Materials and methods: First, the mRNA profiles of HCC were screened from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. VSIG4, a differentially expressed gene that has not been reported in HCC, was distinguished. Second, the correlation between VSIG4 expression and the prognosis of HCC patients from TCGA was analyzed. Third, VSIG4 mRNA level was detected in 36 pairs of HCC tissues and 4 HCC cell lines by PCR assay. And finally, prognosis analysis was assessed for 36 HCC patients with different expression levels of VSIG4.Results: Bioinformatics analysis showed that VSIG4 expression was downregulated in HCC tissues, and the expression level of VSIG4 was negatively correlated with serum alpha fetal protein (AFP) level and tumor distant metastasis. Survival analysis of all HCC patients in TCGA indicated that the overall survival and disease-free survival were not significantly associated with VSIG4 expression. However, subgroup analysis showed that in the patients with hepatitis B virus-related HCC, both overall survival and disease-free survival were shorter in the low VSIG4 expression group. Our PCR results further showed that VSIG4 expression was significantly decreased in HCC tissues and HCC cell lines, and the disease-free survival in hepatitis B virus-related HCC patients with low VSIG4 expression was shorter than in those with high VSIG4 expression, which was consistent with the bioinformatics analysis results.Conclusion: Our study suggests that VSIG4 is downregulated in HCC, and low expression of VSIG4 is associated with poor prognosis in hepatitis B virus-related HCC patients. [ABSTRACT FROM AUTHOR]

Overexpression of the tumor necrosis factor receptor-associated factor 4 (TRAF4) has been detected in many cancer types and is considered to foster tumor progression. However, the role of TRAF4 in hepatocellular carcinoma (HCC) remains elusive. In this study, we found that TRAF4 was highly expressed in HCC cell lines and HCC tissues compared with normal liver cell lines and adjacent noncancerous tissues. TRAF4 overexpression in HCC tissues was correlated with tumor quantity and vascular invasion. In vitro studies showed that TRAF4 was associated with HCC cell migration and invasion. An in vivo study verified that TRAF4 overexpression facilitated metastasis in nude mice. In addition, overexpressed TRAF4 promoted the phosphorylation of Akt and induced Slug overexpression, leading to downregulated E-cadherin and upregulated vimentin, while silencing TRAF4 moderated the phosphorylation of Akt and repressed the expression of Slug, which resulted in upregulated E-cadherin and downregulated vimentin. These effects were inversed after pretreatment of the PI3K/Akt inhibitor LY294002 or overexpression of constitutively active Akt1. Our study demonstrated that TRAF4 was involved in promoting HCC cell migration and invasion. The process was induced by the EMT through activation of the PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

New 7056 aluminum alloy matrix composites reinforced with Zr55Al10Ni5Cu30 metallic glassy particles are successfully fabricated by spark plasma sintering (SPS) combined with gas‐atomization method. The highly dense bulk body is obtained by utilizing the viscous flow behavior of the glassy powder within the supercooled liquid region. The addition of amorphous reinforcing phase significantly increases the yield strength of Al alloys in compression from 322 to 455 MPa, with retaining a fracture strain ranging between 26% and 16%. It is confirmed that the mutual diffusion of elements takes place between Al alloy matrix and glassy reinforcement during SPS process. The imposed stress and temperature by SPS affect the mutual diffusion and elemental distribution at interface. The increased mechanical response is ascribed to the uniform distribution of the glassy particles and good interfacial bonding. The mechanical properties of such composites can be accurately described by the iso‐stress model involving the matrix‐strengthening mechanism. [ABSTRACT FROM AUTHOR]

2D organic–inorganic hybrid Ruddlesden–Popper perovskites have emerged recently as candidates for the light‐absorbing layer in solar cell technology due largely to their impressive operational stability compared with their 3D‐perovskite counterparts. The methods reported to date for the preparation of efficient 2D perovksite layers for solar cells involve a nonscalable spin‐coating step. In this work, a facile, spin‐coating‐free, directly scalable drop‐cast method is reported for depositing precursor solutions that self‐assemble into highly oriented, uniform 2D‐perovskite films in air, yielding perovskite solar cells with power conversion efficiencies (PCE) of up to 14.9% (certified PCE of 14.33% ± 0.34 at 0.078 cm2). This is the highest PCE to date for a solar cell with 2D‐perovskite layers fabricated by nonspin‐coating method. The PCEs of the cells display no evidence of degradation after storage in a nitrogen glovebox for more than 5 months. 2D‐perovskite layer deposition using a slot‐die process is also investigated for the first time. Perovskite solar cells fabricated using batch slot‐die coating on a glass substrate or R2R slot‐die coating on a flexible substrate produced PCEs of 12.5% and 8.0%, respectively. A simple, spin‐coating‐free, and directly scalable drop‐cast method is developed to prepare 2D‐perovskite films at arbitrary shapes. The precursor solutions can self‐assemble into highly oriented 2D‐perovskite films on a preheated substrate, producing perovskite solar cells with power conversion efficiencies (PCE) of up to 14.9%, the highest PCE to date for a solar cell with 2D‐perovskite layers fabricated by a nonspin‐coating method. [ABSTRACT FROM AUTHOR]

Background: Lenvatinib plus PD-1 inhibitors and interventional (LPI) therapy have demonstrated promising treatment effects in unresectable hepatocellular carcinoma (HCC). However, biomarkers for predicting the response to LPI therapy remain to be further explored. We aimed to develop a radiomics model to noninvasively predict the efficacy of LPI therapy., Methods: Clinical data of patients with HCC receiving LPI therapy were collected in our institution. The clinical model was built with clinical information. Nine machine learning classifiers were tested and the multilayer perceptron classifier with optimal performance was used as the radiomics model. The clinical-radiomics model was constructed by integrating clinical and radiomics scores through logistic regression analysis., Results: 151 patients were enrolled in this study (2:1 randomization, 101 and 50 in the training and validation cohorts), of which three achieved complete response, 69 showed partial response, 46 showed stable disease, and 33 showed progressive disease. The objective response rate, disease control rate, and conversion resection rates were 47.7, 78.1 and 23.2%. 14 features were selected from the initially extracted 1223 for radiomics model construction. The area under the curves of the radiomics model (0.900 for training and 0.893 for validation) were comparable to that of the clinical-radiomics model (0.912 for training and 0.892 for validation), and both were superior to the clinical model (0.669 for training and 0.585 for validation). Meanwhile, the radiomics model can categorize participants into high-risk and low-risk groups for progression-free survival (PFS) and overall survival (OS) in the training (HR 1.913, 95% CI 1.121 to 3.265, p=0.016 for PFS; HR 4.252, 95% CI 2.051 to 8.816, p=0.001 for OS) and validation sets (HR 2.347, 95% CI 1.095 to 5.031, p=0.012 for PFS; HR 2.592, 95% CI 1.050 to 6.394, p=0.019 for OS)., Conclusion: The promising machine learning radiomics model was developed and validated to predict the efficacy of LPI therapy for patients with HCC and perform risk stratification, with comparable performance to clinical-radiomics model., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sol-gel processed zinc oxide (ZnO) is one of the most widely used electron transport layers (ETLs) in inverted organic solar cells (OSCs). The high annealing temperature (≈200 °C) required for sintering to ensure a high electron mobility however results in severe damage to flexible substrates. Thus, flexible organic solar cells based on sol-gel processed ZnO exhibit significantly lower efficiency than rigid devices. In this paper, an indium-doping approach is developed to improve the optoelectronic properties of ZnO layers and reduce the required annealing temperature. Inverted OSCs based on In-doped ZnO (IZO) exhibit a higher efficiency than those based on ZnO for a range of different active layer systems. For the PM6:L8-BO system, the efficiency increases from 17.0% for the pristine ZnO-based device to 17.8% for the IZO-based device. The IZO-based device with an active layer of PM6:L8-BO:BTP-eC9 exhibits an even higher efficiency of up to 18.1%. In addition, a 1.2-micrometer-thick inverted ultrathin flexible organic solar cell is fabricated based on the IZO ETL that achieves an efficiency of 17.0% with a power-per-weight ratio of 40.4 W g -1 , which is one of the highest efficiency for ultrathin (less than 10 micrometers) flexible organic solar cells., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Purpose: Ferroptosis has been reported to regulate multiple biological behaviors. However, the prognostic and oncologic values of ferroptosis-related genes (FRGs) have not been comprehensively elucidated in hepatocellular carcinoma (HCC). Here, we aimed to construct FRGs-associated signature for stratification of the prognosis of HCC patients., Methods: A list of FRGs was generated from FerrDb. Public databases were used to extract expression matrices and clinical information. TCGA cohort was randomly divided into a training set and a validation set. Prognostic signature for Overall Survival (OS) was established in training set and validated in internal cohorts (TCGA validation set and entire set) and external cohort (ICGC cohort). Additionally, the role of signature in HCC was well investigated by analysis of mutations, gene set enrichment analysis (GSEA), analysis of immune infiltrates, and analysis of response to immune checkpoint blockade (ICB) treatment. The oncogenic effects of ZFP69B on HCC were also investigated in vitro., Results: We identified 12 FRGs-based signature for OS with LASSO regression. Patients were partitioned into different risk groups based on the signature. Overall, patients in different groups had different prognosis. The signature independently predicted OS in multivariate Cox regression analyses. Anti-tumor immune cells including activated CD8 T cells, cytolytic activity, and Th1 cells were negatively correlated with risk score in both TCGC and ICGC cohorts. Furthermore, low-risk patients responded better to ICB than high-risk patients. In addition, knockdown of ZFP69B reduced proliferation, migration, and invasion, and promoted erastin-induced ferroptosis of HCC cells., Conclusion: We developed a prognostic signature based on FRGs to predict OS of HCC patients. And the signature may facilitate clinicians in identifying those who are likely to benefit from ICIs. The results also indicated that ZFP69B might regulate the process of ferroptosis and could be used as a novel potential target for HCC., Competing Interests: Qingbin Wang and Bingkun Wang are co-first authors for this study. The authors report no conflicts of interest in this work., (© 2023 Wang et al.)

Objectives: As a distinct type of cardiomyopathy, diabetic cardiomyopathy (DCM) is featured as diastolic or systolic cardiac dysfunction in diabetic patients. In order to broaden the understanding of molecular mechanisms in DCM, we intended to explore the mechanism of the interaction between PDK4 protein and Hmgcs2 in high glucose (HG)-induced myocardial damage., Methods: PDK4 and Hmgcs2 expression in the myocardium of diabetes mellitus (DM) model rats and HG-incubated cardiomyocyte line H9C2 was analyzed by western blot analysis. Echocardiography and TUNEL assay were utilized for respective assessment of cardiac structure and function and cardiomyocyte apoptosis in DM rats after silencing PDK4 or/and Hmgcs2. In vitro, the impact of PDK4 and Hmgcs2 on HG-induced cardiomyocyte injuries was identified with cell counting kit-8 and flow cytometry assays, along with detection of LDH release, caspase-3/7 activities, and reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Moreover, a coimmunoprecipitation assay was utilized to test the interaction between PDK4 and Hmgcs2., Results: Both PDK4 and Hmgcs2 were highly expressed in the myocardial tissues of DM rats. Mechanistically, PDK4 interacted with Hmgcs2 to upregulate Hmgcs2 expression in HG-induced H9C2 cells. Silencing PDK4 improved cardiac function and reduced cardiomyocyte apoptosis in DM rats. In HG-induced H9C2 cells, PDK4 or Hmgcs2 silencing enhanced cell viability and reduced LDH release, caspase-3/7 activities, cell apoptosis, and ROS and MDA levels, and these trends were further promoted by the simultaneous silencing of PDK4 and Hmgcs2., Conclusion: In summary, the silencing of PDK4 and Hmgcs2 alleviated HG-induced myocardial injuries through their interaction., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Solute carrier family 39 member 1 (SLC39A1) has been identified as a zinc ion transport protein that possesses oncogenic properties in various types of cancers. However, its potential function in hepatocellular carcinoma (HCC) remains unknown. This study aimed to investigate the expression profile and potential mechanisms of SLC39A1 in HCC., Methods: SLC39A1 expression was analyzed using multiple databases. The clinical significance and associated biological pathways of SLC39A1 were investigated using bioinformatics analysis. Potential correlations between SLC39A1 expression and tumor immunity in HCC were also evaluated using single-sample gene set enrichment analysis (GSEA). Sixty paired HCC samples were used to verify the expression pattern of SLC39A1. In vitro studies were performed to investigate the oncogenic effects of SLC39A1 in HCC. Western blot analysis was conducted to further investigate the possible involved signaling pathways., Results: The overexpression of SLC39A1 in HCC was determined by bioinformatics analysis and was confirmed in tissues from our center. SLC39A1 overexpression was also significantly correlated with worse prognosis, advanced TNM stage, and histological grade. GSEA analysis demonstrated that SLC39A1 overexpression was involved in various tumor-related pathways, such as the cell cycle and Wnt signaling pathway. SLC39A1 knockdown repressed the proliferation, invasion, and migration abilities of HCC cells. Furthermore, SLC39A1 knockdown decreased the expression of the tumor progression-related proteins (eg, cyclin D1 and MMP2) and Wnt signaling pathway-related proteins (eg, Wnt3A and β-catenin). In addition, SLC39A1 overexpression may be associated with impaired tumor immunity in HCC, as evidenced by the increased infiltration of Th2 cells and reduced infiltration of cytotoxic cells., Conclusion: These findings preliminarily suggested the crucial effect of SLC39A1 overexpression on HCC tumor progression and immunosuppression, suggesting its potential as a novel prognostic and therapeutic target in HCC., Competing Interests: All authors declare that they have no conflicts of interest for this work., (© 2022 Ma et al.)

Background: The molecular pathways along with the clinical significance of long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) remain uncertain. Our study sought to identify and characterize lncRNAs associated with HCC. Methods: LncRNA TMCO1-AS1 was identified by differential expression analysis, receiver operating characteristic (ROC) analysis, and univariate analysis using RNA sequencing and clinical information of HCC from the public database. Then clinical correlations and survival analysis were conducted to further appraise the prognostic significance of lncRNA TMCO1-AS1 in HCC. Hepatoma and adjoining normal tissues from 66 patients who received surgical operation at our center were used to verify the results of the bioinformatics analysis. A survival prognostic model was established combining TMCO1-AS1 expression and other clinical characteristics. Results: Bioinformatics analysis showed the aberrant high expression of TMCO1-AS1 in HCC tissue. TMCO1-AS1 expression was positively correlated with alpha-fetoprotein (AFP) level, vascular invasion, tumor stage, as well as tumor differentiation. Moreover, survival analysis found a significant inverse association between the expression of TMCO1-AS1 and the survival of patients with HCC. Cox analysis indicated that TMCO1-AS1 was an independent factor for HCC prognosis. Analysis of the HCC tissues from patients at our center provided results similar to those of the bioinformatics analysis. Risk models for overall survival (OS) and recurrence-free survival (RFS) incorporating TMCO1-AS1 exhibited better sensitivity and specificity than using clinical characteristics alone. Conclusion: High TMCO1-AS1 expression is significantly correlated with the unfavorable poor prognosis of HCC, indicating its potential of being a novel prognostic marker for HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Zhu, Zhang, Tan, Chen and Shang.)

microRNA (miR) -22-3p has been confirmed to be engaged in the phenotype transformation and proliferation of vascular smooth muscle cells (VSMCs), which is intimately correlated with restenosis. The current research set out to explore the detailed mechanism and function of miR-22-3p in VSMC proliferation, phenotype transformation, and migration via the translocase of outer mitochondrial membrane (TOMM40). Peripheral blood samples were acquired from patients with in-stent restenosis (ISR) after percutaneous coronary intervention (PCI), with subsequent quantitative reverse transcription (qRT) -polymerase chain reaction (PCR) and Western blot analyses of miR-22-3p and TOMM40 expression. After miR-22-3p-inhibitor, oe-TOMM40, and sh-TOMM40 were transfected into VSMCs, Cell Counting Kit (CCK) -8 assay, scratch test, and Western blot analysis were implemented to measure the VSMC proliferation, migration, and matrix metallopeptidase 9 (MMP9), α-smooth muscle actin (SMA), smooth muscle-myosin heavy chain (SM-MHC), and osteopontin (OPN) expressions, respectively. In addition, human umbilical vein endothelial cell (HUVEC) proliferation was examined by CCK-8 assay. The binding relationship between miR-22-3p and TOMM40 was assessed by dual luciferase reporter and RNA immunoprecipitation assays. The peripheral blood of patients with ISR after PCI had low expression of miR-22-3p and high expression of TOMM40. The mechanistic analysis reported the negative targeting relationship between miR-22-3p and TOMM40. Down-regulating miR-22-3p or up-regulating TOMM40 elevated the proliferation, migration, and phenotype transformation of VSMCs. miR-22-3p inhibitor had no evident impact on HUVEC proliferation. In addition, rescue assays displayed that TOMM40 silencing annulled miR-22-3p inhibition-enhanced VSMC proliferation, migration, and phenotype transformation. Conclusively, miR-22-3p could repress VSMC proliferation, phenotypic transformation, and migration by targeting TOMM40, which might be a possible treatment candidate for restenosis after PCI in patients with cardiovascular disease.

Background: Sorafenib can prolong the survival of patients with advanced hepatocellular carcinoma (HCC). However, drug resistance remains the main obstacle to improving its efficiency. This study aimed to explore the likely molecular mechanism of sorafenib resistance., Methods: Differentially expressed microRNAs (miRNAs) related to sorafenib response were analyzed with the Limma package in R software. The expression levels of miR-126-3p and sprouty-related EVH1 domain-containing protein 1 (SPRED1) in HCC cells were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell viability and proliferation were detected with Cell Counting Kit-8 (CCK-8), EdU proliferation, and clone formation assays. Transwell assays were performed to measure cell migration and invasion. TargetScan, MicroRNA Target Prediction Database (miRDB), and StarBase v2.0 were used to predict the targets of miR-126-3p. SPRED1 was confirmed as a target gene of miR-126-3p by dual-luciferase reporter assay and Western blotting. Finally, the in vivo anti-tumor effect of LV-miR-126-3p inhibitor combined with sorafenib was evaluated via subcutaneous tumor models., Results: HCC cells with high expression of miR-126-3p exhibited increased resistance to sorafenib. The results of bioinformatics analysis and the dual-luciferase reporter assay showed that miR-126-3p directly targeted SPRED1. The sensitivity of HCC cells to sorafenib was markedly enhanced by SPRED1 upregulation. Gain- and loss-of function experiments verified that miR-126-3p induced sorafenib resistance in HCC through downregulating SPRED1. Furthermore, the inhibition of miR-126-3p markedly increased the effectiveness of sorafenib against HCC in vivo . Mechanistically, our results suggested that miR-126-3p promoted sorafenib resistance via targeting SPRED1 and activating the ERK signaling pathway., Conclusions: Our study demonstrates that regulating the miR-126-3p/SPRED1 axis might be a promising strategy for enhancing the antitumor effect of sorafenib in the treatment of HCC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-2081). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background : Sorafenib appears to increase the survival rate of hepatocellular carcinoma (HCC) patients, but its response rate is seriously limited due to drug resistance. Molecular mechanisms underlying sorafenib resistance are still unknown. Herein, we explored the possible role of miR-1226-3p in sorafenib resistance of HCC. Methods : The miR-1226-3p expression level in HCC cell lines was evaluated by qRT-PCR. Cell viabilities to sorafenib were measured by CCK-8 assay. Cell apoptosis and proliferation were detected by flow cytometry and EdU proliferation assay. A luciferase reporter of DUSP4 3'-UTR was used for validation as a target gene of miR-1226-3p. Finally, the effects of in vivo antitumor efficacy of miR-1226-3p combined with sorafenib were evaluated by HCC tumor xenografts in nude mice. Results : Bioinformatics analysis from Gene Expression Omnibus (GEO) datasets GSE56059 suggested that miR-1226-3p expression was downregulated in HCC patients who showed progressive disease (PD) after sorafenib treatment. SK-HEP-1 cells expressed lower levels of miR-1226-3p than HepG2 cells. We confirmed that SK-HEP-1 cells were more resistant to sorafenib compared to HepG2 cells. In addition, miR-1226-3p mimic increased cell apoptosis of SK-HEP-1 cells, whereas miR-1226-3p inhibitor significantly impaired cell apoptosis of HepG2 cells after sorafenib treatment. Moreover, we validated that miR-1226-3p directly targeted dual specificity phosphatase 4 (DUSP4), and further demonstrated that knockdown of DUSP4 reduced sorafenib resistance by regulating the JNK-Bcl-2 axis. Conclusions : miR-1226-3p promotes sorafenib sensitivity of HCC through downregulation of DUSP4 expression, and targeting miR-1226-3p may be a novel therapeutic strategy for overcoming sorafenib resistance., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: The role of tumor necrosis factor alpha (TNF-α) in targeted therapy for hepatocellular carcinoma (HCC) remains largely unknown. The current study aimed to clarify the mechanistic effects of targeting TNF-α to overcome sorafenib resistance in HCC., Methods: A correlation of TNF-α expression with the prognosis was analyzed in 62 HCC patients who underwent surgical resection and subsequent received adjuvant sorafenib treatment. The relation of TNF-α expression and sorafenib sensitivity was determined in different HCC cell lines. The combined therapeutic effects of sorafenib and ulinastatin, which could inhibit TNF-α expression, on HCC were examined in vitro and in vivo., Findings: High TNF-α expression was correlated with poor outcomes in HCC patients who received adjuvant sorafenib after surgery. In vitro experiments showed that TNF-α promotes HCC cell resistant to sorafenib through inducing epithelial-mesenchymal transition (EMT). Notably, the current study revealed that sorafenib has no significant influence on the expression and secretion of TNF-α, and sorafenib had limited effectiveness on reversing EMT in HCC cells with high TNF-α expression. Inhibiting the expression of TNF-α with ulinastatin significantly enhanced the anti-tumor effect of sorafenib on HCC cells with high expression of TNF-α in vitro and in vivo., Interpretation: Our findings indicate that TNF-α may serve as a novel predictor of sorafenib sensitivity in HCC patients. Sorafenib combined with ulinastatin may improve the effectiveness of treatment of HCC in patients with high expression of TNF-α. FUND: This work was supported by grants from the National Natural Science Foundation of China (no.81572398; no.81672419), the Science and Technology Planning Project of Guangdong Province (no. 2017A010105003; no.2015A050502023; no.2016A020216010), and the Natural Science Foundation of Guangdong Province (no.2014A030313061; no. 2013B021800101)., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Sorafenib has been globally approved as the standard treatment for patients with advanced hepatocellular carcinoma (HCC). However, the response rate of HCC patients to sorafenib is limited because of tumor recurrence and metastasis. Therefore, seeking combined therapeutic strategies with sorafenib is necessary to improve the antitumor efficiency. Here we demonstrated that expression of MMP-2 is positively correlated with the migration ability of HCC cells. Cells with a higher MMP-2 expression (SK-HEP-1 cells) were less sensitive to sorafenib than those with lower MMP-2 expression (HepG2 cells). Cotreatment of cells with SB-3CT and sorafenib more strongly inhibited migration ability than with sorafenib treatment alone in both HCC cells with high and low expression of MMP-2. In vivo cell metastasis experiments confirmed the synergistic effects of sorafenib and SB-3CT in reducing lung metastasis of SK-HEP-1 cells. Mechanistically, we showed that the synergistic antitumor effect may be attributed to inhibition of the PI3K/AKT/mTOR signaling pathway, but not the RAF/MEK/ERK signaling pathway. With these results taken together, the current study demonstrates that inhibiting MMP-2 expression can enhance the antitumor effect of sorafenib in HCC cells with a high MMP-2 expression, which may provide a novel strategy to improve therapeutic efficiency in HCC.

Overexpression of the tumor necrosis factor receptor-associated factor 4 (TRAF4) has been detected in many cancer types and is considered to foster tumor progression. However, the role of TRAF4 in hepatocellular carcinoma (HCC) remains elusive. In this study, we found that TRAF4 was highly expressed in HCC cell lines and HCC tissues compared with normal liver cell lines and adjacent noncancerous tissues. TRAF4 overexpression in HCC tissues was correlated with tumor quantity and vascular invasion. In vitro studies showed that TRAF4 was associated with HCC cell migration and invasion. An in vivo study verified that TRAF4 overexpression facilitated metastasis in nude mice. In addition, overexpressed TRAF4 promoted the phosphorylation of Akt and induced Slug overexpression, leading to downregulated E-cadherin and upregulated vimentin, while silencing TRAF4 moderated the phosphorylation of Akt and repressed the expression of Slug, which resulted in upregulated E-cadherin and downregulated vimentin. These effects were inversed after pretreatment of the PI3K/Akt inhibitor LY294002 or overexpression of constitutively active Akt1. Our study demonstrated that TRAF4 was involved in promoting HCC cell migration and invasion. The process was induced by the EMT through activation of the PI3K/Akt signaling pathway.