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Abstract Background In recent years, mobile medical technology has made great progress in chronic disease management, but its application in patients with atrial fibrillation (AF) still needs to be clarified. Objective This study aims to determine whether the newly developed smartphone app for patients with AF (Alfalfa App) can improve anticoagulation knowledge, drug treatment compliance, and satisfaction of AF patients. Methods Alfalfa App integrates the functions of patient education, remote consultation, and medication reminder through a simple user interface. From June 2020 to December 2020, patients with AF were recruited in five large tertiary hospitals in China. Patients were randomly divided into the Alfalfa App or routine nursing groups. Patients’ knowledge, medication adherence, and satisfaction with anticoagulation were assessed using validated questionnaires at baseline, 1 month, and 3 months. Results In this randomized controlled trial, 113 patients with AF were included, 57 patients were randomly assigned to the Alfalfa App group, and 56 patients were randomly assigned to the routine nursing group. Forty-eight patients in the Alfalfa App group completed a three-month follow-up, and 48 patients in the routine nursing group completed a three-month follow-up. Basic demographic data were comparable between the two groups. The average age of AF patients was 61.65 ± 11.01 years old, and 61.5% of them were male. With time (baseline to 3 months), the knowledge scores of the Alfalfa App group (P

BackgroundThrombocytopenia is often associated with adverse outcomes in patients with atrial fibrillation. Therefore, we conducted a meta-analysis to comprehensively assess the impact of thrombocytopenia on ischemic stroke/systemic embolism, major bleeding and all-cause mortality in patients with atrial fibrillation.MethodsTwo electronic databases, PubMed and Web of Science, were systematically searched from their inception to December 1, 2023, including the studies on the correlation between atrial fibrillation patients with thrombocytopenia and adverse outcomes. Relevant data was extracted, literature quality was evaluated, meta-analysis was performed by using REVMAN 5.4 software, and the results were reported with odds ratio (OR) of 95% confidence interval (CI).ResultsA total of 12 studies included 73,824 patients with atrial fibrillation (average age: 72.67, males: 42,275, 57.3%), among them, there were 7,673 patients combined with thrombocytopenia. The average follow-up time of these studies was 87 days to 55 months. Compared to no thrombocytopenia, atrial fibrillation patients combined with thrombocytopenia have a significant risk reduction of ischemic stroke/systemic embolism [OR: 0.79, 95% CI: (0.69, 0.91); P

Aiming to address the problem of underactuated unmanned surface vehicles (USVs) performing fixed-point operations at sea without dynamic positioning control systems, this paper introduces an original approach to positioning control: the virtual anchor control method. This method is applicable in environments with currents that change slowly and does not require prior knowledge of current information or vessel motion model parameters, thus offering convenient usability. This method comprises four steps. First, a concise linear motion model with unknown disturbances is proposed. Then, a motion planning law is designed by imitating underlying principles of ship anchoring. Next, an adaptive disturbance observer is proposed to estimate uncertainties in the motion model. In the last step, based on the observer, a sliding-mode method is used to design a heading control law, and a thrust control law is also designed by applying the Lyapunov method. Numerical simulation experiments with significant disturbances and tidal current variations are conducted, which demonstrate that the proposed method has a good control effect and is robust.

Abstract Background There are limited data about the clinical benefits and harm of direct oral anticoagulants (DOACs) in stroke prevention in patients with atrial fibrillation (AF) complicated with anemia or thrombocytopenia. Methods This is a multi-center retrospective cohort study involving 5469 AF patients from 15 hospitals in China. Patients were divided into three groups according to hemoglobin and platelet levels: Group 1 (hemoglobin male ≥ 130 g/L; female ≥ 120 g/L and platelet ≥ 100 × 109/L), Group 2 (hemoglobin male

Abstract Tumor-associated lncRNAs regulated by epigenetic modification switches mediate immune escape and chemoresistance in ovarian cancer (OC). However, the underlying mechanisms and concrete targets have not been systematically elucidated. Here, we discovered that methylation modifications played a significant role in regulating immune cell infiltration and sensitizing OC to chemotherapy by modulating immune-related lncRNAs (irlncRNAs), which represent tumor immune status. Through deep analysis of the TCGA database, a prognostic risk model incorporating four methylation-related lncRNAs (mrlncRNAs) and irlncRNAs was constructed. Twenty-one mrlncRNA/irlncRNA pairs were identified that were significantly related to the overall survival (OS) of OC patients. Subsequently, we selected four lncRNAs to construct a risk signature predictive of OS and indicative of OC immune infiltration, and verified the robustness of the risk signature in an internal validation set. The risk score was an independent prognostic factor for OC prognosis, which was demonstrated via multifactorial Cox regression analysis and nomogram. Moreover, risk scores were negatively related to the expression of CD274, CTLA4, ICOS, LAG3, PDCD1, and PDCD1LG2 and negatively correlated with CD8+, CD4+, and Treg tumor-infiltrating immune cells. In addition, a high-risk score was associated with a higher IC50 value for cisplatin, which was associated with a significantly worse clinical outcome. Next, a competing endogenous RNA (ceRNA) network and a signaling pathway controlling the infiltration of CD8+ T cells were explored based on the lncRNA model, which suggested a potential therapeutic target for immunotherapy. Overall, this study constructed a prognostic model by pairing mrlncRNAs and irlncRNAs and revealed the critical role of the FTO/RP5-991G20.1/hsa-miR-1976/MEIS1 signaling pathway in regulating immune function and enhancing anticancer therapy.

Abstract Background Based on the few available studies on the prognostic benefit of using direct oral anticoagulants (DOACs) after atrial fibrillation (AF) ablation. Therefore, this study aimed to evaluate the prognostic differences between patients who underwent radiofrequency ablation (RFA) and those without RFA taking DOACs. Methods This is a multicenter retrospective cohort study enrolling 6137 patients with non-valvular AF (NVAF) at 15 hospitals in China. Patient information was collected through a mean follow-up of 10 months and medical record queries. Clinical outcomes included major bleeding, total bleeding, thrombosis, all-cause death, and a composite endpoint of bleeding, thrombosis, and all-cause death. Results After adjusting for confounders and propensity score matching (PSM), patients with RFA of NVAF had a significantly lower risk of major bleeding [OR 0.278 (95% CI, 0.150-0.515), P

Background Rheumatic heart disease (RHD) is a serious global public health problem. Objectives This study aims to characterise the regional burden, trends, and inequalities of RHD in countries and territories in the Asian Region. Methods The RHD disease burden was measured in terms of the numbers of cases and deaths, prevalence, disability-adjusted life years (DALYs), disability-loss healthy life years (YLDs), and years of life lost (YLLs) in 48 countries in the Asian Region. Data on RHD were extracted from the 2019 Global Burden of Disease. This study analysed changing trends in the burden between 1990 and 2019, quantified regional inequalities in mortality, and classified countries by 2019 YLLs. Results There were an estimated 22 246 127 cases of RHD in the Asian Region in 2019 and 249 830 deaths. The prevalence of RHD in the Asian Region in 2019 was 9% lower than the global estimate, while mortality was 41% higher. The mortality rate for RHD in the Asian Region trended downwards from 1990 to 2019, with an average annual percentage change of −3.2% (95% UI −3.3 to −3.1). From 1990 to 2019, absolute inequality in RHD-related mortality decreased in the Asian Region while relative inequality increased. Of the 48 countries studied, twelve had the highest level of RHD YLLs in 2017 and the smallest reduction in YLLs from 1990 to 2019. Conclusion Although the burden of RHD in the Asian Region has steadily decreased since 1990, it remains a serious public health issue requiring greater attention. In the Asian Region, inequalities in the distribution of the RHD burden remain significant, with economically deprived countries typically bearing a greater share of the load.

Uniparental disomy (UPD) refers to as both homologous chromosomes inherited from only one parent without identical copies from the other parent. Studies on clinical phenotypes in UPDs are usually focused on the documented UPD 6, 7, 11, 14, 15, and 20, which directly lead to imprinting disorders. This study describes clinical phenotypes and genetic findings of three patients with UPD 2, 9, and 14, respectively. Chromosomal microarray (CMA), UPDtool, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and whole-exome sequencing (WES) analysis were performed to characterize the genetic etiology. The CMA revealed a homozygous region involving the whole chromosome 2 and 9, a partial region of homozygosity in chromosome 14. UPD-tool revealed a paternal origin of the UPD2. MS-MLPA showed hypomethylation of imprinting gene MEG3 from maternal origin in the UPD14 case. In addition, UPD14 case displayed complex symptoms including growth failure, hypotonia and acute respiratory distress syndrome (ARDS), accompanied by several gene mutations with heterozygous genotype by WES analysis. Furthermore, we reviewed the documented UPDs and summarized the clinical characteristics and prognosis. This study highlighted the importance to confirm the diagnosis and origin of UPD using genetic testing. Therefore, it is suggested that expanding of the detailed phenotypes and genotypes provide effective guidance for molecule testing and genetic counseling, and promote further biological investigation to the underlying mechanisms of imprinted disorders and accompanied copy number variations.

Background: There is no validated tool to assess patients’ knowledge of oral anticoagulant therapy in atrial fibrillation in China.Methods: Using a standard translation program, the Jessa Atrial fibrillation Knowledge Questionnaire (JAKQ) was translated into Chinese. The reliability of the JAKQ was assessed by internal consistency (Cronbach’s α coefficient), repeatability (test-retest reliability), and sensitivity tests. Effectiveness was assessed by hypothesizing that a lower JAKQ score was a risk factor for bleeding. A total of 447 patients with atrial fibrillation (AF) who were hospitalized between July 2019 and December 2021 were studied and followed up. Participants were followed up 1, 3, 6, and 12 months after enrollment. Bleeding during follow-up was recorded. Data were obtained from hospital databases and telephone follow-up.Result: A total of 447 patients with AF completed JAKQ. The mean age of patients was 67.7 ± 10.2 years. The median JAKQ score was 31.3% (12.5–43.8). The Cronbach’s α coefficient of JAKQ was 0.616–0.637, and the test-retest reliability value was 0.902 (p < 0.001). Multivariate logistic regression showed that the higher knowledge level of AF was associated with secondary education or above, an income of more than 2000 yuan, and a history of AF of more than 1 year. Bleeding was associated with a lower JAKQ score, hypertension, and a history of bleeding. Non-bleeding patients on VKA had a better understanding of how often INR should be monitored and what to do if an OAC dose was missed.Conclusion: The Chinese version of JAKQ shows good reliability and validity, indicating that it is a valuable tool for AF and oral anticoagulation (OAC) knowledge assessment. It can be used in clinical practice to guide educational activities and improve the effectiveness and safety of treatment. It was shown that Chinese patients with AF have insufficient knowledge about AF and OAC. Lower JAKQ scores are associated with bleeding, so targeted education is necessary. Targeted educational efforts should focus on patients recently diagnosed with AF and those with lower formal education and income.

Objectives An up-to-date, detailed global analysis of the current status of the metabolic-attributed cardiovascular disease (CVD) burden has not been reported. Therefore, we investigated the global burden of metabolic-attributed CVD and its association with socioeconomic development status over the past 30 years.Methods Data on the burden of metabolic-attributed CVD were taken from the 2019 Global Burden of Disease (GBD) study. Metabolic risk factors of CVD included high fasting plasma glucose, high low-density lipoprotein cholesterol (LDL-c), high systolic blood pressure (SBP), high body mass index (BMI) and kidney dysfunction. Numbers and age-standardised rates (ASR) of disability-adjusted life-years (DALYs) and deaths were extracted and stratified by sex, age, Socio-demographic Index (SDI) level, country and region.Results The ASR of metabolic-attributed CVD DALYs and deaths decreased by 28.0% (95% UI 23.8% to 32.5%) and 30.4% (95% UI 26.6% to 34.5%), respectively, from 1990 to 2019. The highest burden of metabolic-attributed total CVD and intracerebral haemorrhage was mainly in low SDI locations, while the highest burden of ischaemic heart disease and IS was mainly in high SDI locations. The burden of DALYs and deaths in CVD was higher in men than women. In addition, the number and ASR of DALYs and deaths were highest in those over 80 years old.Conclusion Metabolic-attributed CVD threatens public health, especially in low-SDI locations and among the elderly. Low SDI location should strengthen the control of metabolic factors such as high SBP, high BMI, and high LDL-c and increase the knowledge of metabolic risk factors for CVD. Countries and regions should enhance screening and prevention of metabolic risk factors of CVD in the elderly. Policy-makers should use 2019 GBD data to guide cost-effective interventions and resource allocation.

Summary: Poplar coma, commonly referred to as “seed hairs”, is a tuft of trichomes attached to the seed coat that helps seed dispersal. However, they can also trigger health impacts for humans, including sneezing, shortness of breath, and skin irritation. Despite efforts to study the regulatory mechanism of herbaceous trichome formation, poplar coma remains poorly understood. In this study, we showed that the epidermal cells of the funiculus and placenta are the origin of poplar coma based on observations of paraffin sections. Small RNA (sRNA) and degradome libraries were also constructed at three stages of poplar coma development, including initiation and elongation stages. Based on 7,904 miRNA-target pairs identified by small RNA and degradome sequencing, we constructed a miRNA-transcript factor and a stage-specific miRNA regulatory network. By combining paraffin section observation and deep sequencing, our research will provide greater insight into the molecular mechanisms of poplar coma development.

Abstract Chemoresistance is a severe outcome among patients with epithelial ovarian cancer (EOC) that leads to a poor prognosis. YBX-1 has been shown to cause treatment failure and cancer progression in EOC. However, strategies that directly target YBX-1 are not yet conceivable. Here, we identified that SIAH1 which was downregulated in chemoresistant EOC samples and cell lines functioned as novel E3 ligases to trigger degradation of YBX-1 at cytoplasm by RING finger domain. Mechanistic studies show that YBX-1 was ubiquitinated by SIAH1 at lys304 that lead to the instability of its target m5C-modified mRNAs, thus sensitized EOC cells to cDDP. Overexpression of SIAH1 enhanced the antitumor efficacy of cisplatin in vitro and in vivo, which were partially impaired by ectopic expression of YBX-1 or depletion of YBX-1 ubiquitination. In summary, our data identify the SIAH1/YBX-1 interaction as a therapeutic target for overcoming EOC chemoresistance.

In this study, the functions of Hydrogen peroxide (H2O2) on the synthesis of isoflavones in germinated soybean under UV-B radiation were investigated. Results showed that the activity, gene, and protein expression of NADPH oxidase were up-regulated by 1.46, 6.92, and 1.34 times with UV-B radiation, while endogenous H2O2 content was also significantly increased. UV-B radiation and exogenous H2O2 treatment significantly increased the activities, gene and protein expression of phenylalanine ammonia lyase (PAL), chalcone synthase (CHS), and isoflavone synthase (IFS) involved in isoflavones synthesis, and there was a synergistic effect with combining treatment. However, these up-regulation effects were suppressed by the supplementary diphenylene iodonium (DPI), which is the inhibitor of NADPH oxidase. Interestingly, the inhibition effect was largely reversed by exogenous H2O2, indicating that H2O2 was indispensable in regulating the isoflavones synthesis in germinated soybeans under UV-B radiation. Overall, H2O2 is an essential signaling molecule, mediating UV-B-induced isoflavone accumulation.

Exosomes are nanosized vesicles, derived from the endolysosomal compartment of cells and can shuttle diverse biomolecules such as nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their origin cells. Delivery of these cargoes to recipient cells enables exosomes to influence diverse cellular functions. As one of the most abundant immune cells in the tumor microenvironment, tumor-associated macrophages (TAMs) are educated by the tumor milieu, which is rich in cancer cells and stroma components, to exert functions such as the promotion of tumor growth, immunosuppression, angiogenesis, and cancer cell dissemination. Herein, we focus on exosomes-mediated intercellular communication between tumor cells and TAM in the tumor microenvironment, which may provide new targets for anti-tumor treatment. In this review, we highlight the most recent studies on the effect of tumor/macrophage-derived exosomes on macrophage/tumor function in different cancer types.

Zearalenone (ZEA) is a common mycotoxin that induces oxidative stress (OS) and affects the male reproductive system in animals. Resveratrol (RSV) has good antioxidant activity and can activate nuclear factor erythroid 2-related factor (Nrf2) to protect cells through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. The objective of this study was to investigate the protective effect and the mechanism of RSV on OS and apoptosis in TM4 cells induced by ZEA. Prior to being exposed to ZEA, TM4 cells were pretreated with RSV or the PI3K/Akt inhibitor LY294002. Cell viability was measured by Cell Counting Kit-8 (CCK-8) assays. Flow cytometry was used to determine the level of apoptosis and intracellular reactive oxygen species (ROS). The expression of poly ADP-ribose polymerase (PARP), caspase-3, BCL2-associated X (Bax)/B-cell lymphoma-2 (Bcl-2), and PI3K/Akt-mediated Nrf2/heme oxygenase 1 (HO-1) signaling pathway-related proteins was evaluated by Western blotting. Nrf2 siRNA transfection and LY294002 treatment were used to investigate the role of the Nrf2/HO-1 and PI3K/Akt signaling pathways in RSV alleviation of ZEA-induced OS. The results showed that pretreatment with RSV significantly reduced the expression of apoptosis-related proteins and increased cell viability. Catalase (CAT) activity and glutathione (GSH) levels were also increased, whereas malondialdehyde (MDA) and ROS levels decreased (p < 0.05). RSV also upregulated Akt phosphorylation, Nrf2 nuclear translocation, and HO-1 expression under conditions of OS (p < 0.05). Transfection with Nrf2 siRNA abolished the protective effects of RSV against ZEA-induced cytotoxicity (p < 0.05), ROS accumulation (p < 0.05), and apoptosis (p < 0.05). LY294002 completely blocked the RSV-mediated increase in Nrf2 nuclear translocation (p < 0.05), HO-1 expression (p < 0.05), and cytoprotective activity (p < 0.05). Collectively, the above findings indicate that RSV can protect against ZEA-induced OS and apoptosis in TM4 cells by PI3K/Akt-mediated activation of the Nrf2/HO-1 signaling pathway.

Abstract Background The Na+/H+ exchanger (NHE1) plays a crucial role in cancer cell proliferation and metastasis. However, the mechanism underlying chemotherapeutic resistance in cancer cells has not been completely elucidated. The NHE1 inhibitor cariporide has been demonstrated to inhibit human cancer cell lines. The goal of this study was to provide new sights into improved cancer cell chemosensitivity mediated by cariporide with activation of the apoptosis pathway. Methods The NHE1 expression levels were first evaluated using the online database Oncomine and were determined by RT-PCR and western blot in vitro and in vivo. Cell proliferation was assessed In vitro through a CCK-8 assay, and apoptosis was analyzed by flow cytometry. An in vivo analysis was performed in BALB/c nude mice, which were intraperitoneally injected with MCF-7/ADR cells. Results NHE1 levels were significantly higher in breast cancer tissue than adjacent tissue, as well as in resistant cancer cells compared to sensitive cells. Cariporide induced the apoptosis of MCF-7/ADR cells and was associated with the intracellular accumulation of doxorubicin and G0/G1 cell cycle arrest. Moreover, cariporide decreased MDR1 expression and activated cleaved caspase-3 and caspase-9, promoting caspase-independent apoptosis in vitro. In vivo, cariporide significantly improved doxorubicin sensitivity in a xenograft model, enhancing tumor growth attenuation and diminishing tumor volume. Conclusions Our results demonstrate that cariporide significantly facilitates the sensitivity of breast cancer to doxorubicin both in vitro and in vivo. This finding suggests that NHE1 may be a novel adjuvant therapeutic candidate for the treatment of resistant breast cancer.

Abstract Background How exosomal microRNAs (miRNAs) derived from macrophages contribute to the development of drug resistance in the context of the hypoxic tumor microenvironment in epithelial ovarian cancer (EOC) remains poorly understood. Methods The miRNA levels were detected by qRT-PCR. Protein levels of HIF-1α, CD163 and PTEN-PI3K/AKT pathway were assessed by Western blot (WB) and Immunohistochemistry (IHC). Exosomes were isolated, and then confirmed by Transmission electron microscopy (TEM), Nanoparticle Tracking Analysis (NTA) and WB. Internalization of macrophages-secreted exosomes in EOC cells was detected by Confocal microscope. Subsequently, Dual-luciferase reporter assay verified PTEN was the target of miR-223. Gain- and loss-of-function experiments, rescue experiments, and SKOV3 xenograft models were performed to uncover the underlying mechanisms of miR-223 and PTEN-PI3K/AKT pathway, as well as the exosomal miR-223 in inducing multidrug resistance in vitro and in vivo. Results Here, we showed hypoxic EOC cells triggered macrophages recruitment and induced macrophages into a tumor-associated macrophage (TAM)-like phenotype; exosomes derived from hypoxic macrophages enhanced the malignant phenotype of EOC cells, miR-223 was enriched in exosomes released from macrophages under hypoxia, which could be transferred to the co-cultivated EOC cells, accompanied by enhanced drug resistant of EOC cells. Besides, results from a functional assay revealed that exosomal miR-223 derived from macrophages promoted the drug resistance of EOC cells via the PTEN-PI3K/AKT pathway both in vivo and in vitro. Furthermore, patients with high HIF-1a expression had statistically higher CD163+ cell infiltration and intertumoral levels of miR-223. Finally, circulating exosomal miR-223 levels were closely related to the recurrence of EOC. Conclusions These data indicate a unique role of exosomal miR-223 in the cross-talk between macrophages and EOC cells in chemotherapy resistance, through a novel exosomal miR-223/PTEN-PI3K/AKT signaling pathway.

Exosomes are secreted by different types of cells in tumor microenvironment (TME) and participate in multiple biological processes of tumors. Non-coding RNAs (ncRNAs) enveloped in exosomes and released to the TME are shown to be involved in tumorigenesis and development, as well as act as important intracellular communication mediators. However, the understanding on the exact regulatory functions and substrates of exosomal RNA is still at an early stage. In this review, we provided an overview on recent studies on exosomes mediating the modulation of both tumor cells and immune cells, then summarized the exosomal ncRNAs [such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)] secreted by tumor cells and stromal cells that exhibited potential capabilities to regulate tumor cell growth, progression, metastasis, drug resistance, and immune response. Our review may hopefully inspire a deeper understanding on the ncRNAs’ function as useful biomarkers for the diagnosis, prognosis, and as novel targets therapy for cancer.

Beauvericin (BEA), a food-borne mycotoxin metabolite derived from the fungus Beauveria Bassiana, is proven to exhibit high hepatotoxicity. However, the molecular mechanism underlying BEA-induced liver damage is not fully understood. Herein, the effect of Nrf2 nuclear translocation-induced by BEA in hepatocytes was investigated. CCK8 solution was used to determine the appropriate concentrations of BEA (0, 1, 1.5 and 2 μmol/L), and BRL3A cells were then exposed to different concentrations of BEA for 12 h. Our results reveal that BEA exposure is associated with high cytotoxicity, lowered cell viability, damaged cellular morphology, and increased apoptosis rate. BEA could lead to oxidative damage through the overproduction of ROS and unbalanced redox, trigger the activation of Nrf2 signaling pathway and Nrf2 nuclear translocation for transcriptional activation of downstream antioxidative genes. Additionally, BEA treatment upregulated the expression of autophagy-related proteins (LC3, p62, Beclin1, and ATG5) indicating a correlation between Nrf2 activation and autophagy, which warrants further studies. Furthermore, ML385, an Nrf2 inhibitor, partially ameliorated BEA-induced cell injury while CDDO, an Nrf2 activator, aggravated liver damage. The present study emphasizes the role of Nrf2 nuclear translocation in BEA-induced oxidative stress associated with the hepatotoxic nature of BEA.

Increasing evidence has revealed close relationships between long non-coding RNAs (lncRNAs) and chemoresistance in multiple types of tumors; however, functional lncRNAs in breast cancer (BC) have not been completely identified. In this study, we aimed to identify novel lncRNAs that might play critical roles in doxorubicn resistance, which could reveal potential biomarkers of BC. Using a BC dataset (GSE81971), we identified 452 lncRNAs that were upregulated and 659 that were downregulated; furthermore, there were 1896 differentially expressed mRNAs, of which 1137 were upregulated and 758 were downregulated in MCF-7/ADR cells compared with the expression in MCF-7 cells. We constructed an lncRNA–mRNA network by integrating probe reannotation and regulatory interactions. To elucidate the key lncRNAs in BC, we further analyzed dysregulated lncRNA–mRNA crosstalk, and six candidate lncRNAs (lnc-TRDMT1-5, ZNF667-AS1, lnc-MPPE1-13, DSCAM-AS1:5, DSCAM-AS1:2, and lnc-CFI-3) were identified. Notably, the expression level of lnc-TRDMT1-5 was significantly upregulated in resistant cells compared with sensitive cells, and its levels were increased in BC tissues compared with adjacent tissues. Levels were positively associated with estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) expression levels. High expression of lnc-TRDMT1-5 predicted poor prognosis in ER-positve and HER2-positive BC patients, especially in patients with chemoresistance. Bioinformatic and functional analysis revealed that lnc-TRDMT1-5 was involved in many crucial pathways in cancer, such as the PI3K/AKT and Wnt signaling pathways. Subcellular localization predicted that lnc-TRDMT1-5 was located in the cytoplasm, and the lncRNA–miRNA–mRNA network showed that lnc-TRDMT1-5 might serve as a regulator in BC. Here, our results demonstrated a dysregulated lncRNA–mRNA network that might provide new treatment strategies for chemoresistant BC, and the results identified a new lncRNA, lnc-TRDMT1-5, with oncogenic and prognostic functions in human BC.

Abstract Background MicroRNAs are small RNAs (~ 22 nt) that modulate the expression of thousands of genes in tumors and play important roles in the formation of multidrug resistance. In this study, we firstly investigated that miR-4532 involved in the multidrug resistance formation of breast cancer by targeting hypermethylated in cancer 1 (HIC-1), a tumor-suppressor gene. Methods To identify and characterize the possible miRNAs in regulating multidrug resistance, we employed the transcriptome sequencing approach to profile the changes in the expression of miRNAs and their target mRNAs were obtained by bioinformatics prediction. Then the molecular biology experiments were conducted to confirm miR-4532 involved in multidrug resistance formation of breast cancer. Results The luciferase reporter assay experiment was employed to confirm that HIC-1 was the target of miR-4532. Transfection with an miR-4532 mimic indicated miR-4532 mimic significantly increased breast cancer cell resistance to adriamycin. Cell proliferation and invasion assay experiments showed overexpression of HIC-1 inhibited the invasion and metastasis of breast cancer cells. Meanwhile, the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway was confirmed to be involving in multidrug resistance by western blotting experiments. Conclusions These results suggest that downregulation of hypermethylated in cancer-1 by miR-4532 could promote adriamycin resistance in breast cancer cells, in which the IL-6/STAT3 pathway was regulated by the HIC-1. This finding might contribute to new therapeutic target for reversal of tumor resistance.

Chemical engineering intensification technology is regarded as an effective means to address the problems of “high consumption of energy,high pollution and high consumption of raw materials” in chemical engineering industry,and is expected to bring significant innovations to the chemical engineering industry. The principle and application of ultrasonic technology in chemical engineering intensification in China are reviewed to provide a theoretical basis and technical parameters for its application in chemical engineering in this paper. Keywords: chemical engineering, process intensification, ultrasound, principle and applic

Based on the ABAQUS/Explicit code, A 3D elastic–plastic and coupled thermo-mechanical FE model of radial ring rolling of AZ31 Magnesium alloy has been proposed to analyze the influence of rotational speed of driver roll to study the inhomogeneity distribution of strain and temperature, fishtail coefficient, rolling force parameters. The results show that: (1) when the rotational speed of driver roll n increases, the strain distribution of the rolled ring becomes less homogeneous, and the temperature distribution more homogeneous yet, and leading to an optimal n value; (2) the fishtail coefficient firstly decreases, then increases with the increase of n; (3) the rolling force, contact area and rolling moment gradually descend with the increase of n.

Baoan Chen1*, Jian Cheng1*, Mingfang Shen1, Feng Gao1, Wenlin Xu2, et al1Department of Hematology;2Department of Hematology, The Affiliated People’s Hospital, Jiangsu University, Zhenjiang, P.R China, et al *These authors have contributed equally to this work.Abstract: Apoptosis is a common pathway that finally mediated the killing functions of anticancer drugs, which is an important cause of multidrug resistance (MDR). The aim of this study was to investigate the potential benefit of combination therapy with magnetic nanoparticle of Fe3O4 (MNP(Fe3O4)) and 5-bromotetrandrin (BrTet). Analysis of the apoptosis percentage showed that combination of daunorubicin (DNR) with either MNP(Fe3O4) or BrTet exerted a potent cytotoxic effect on K562/A02 cells, while MNP(Fe3O4) and BrTet cotreatment can synergistically enhance DNR-induced apoptosis. Importantly, we confirmed that the distinct synergism effect of that composite on reverse multidrug resistance may owe to the regulation of various proliferative and antiapoptotic gene products, including P53 and caspase-3. Thus our in vitro data strongly suggests a potential clinical application of MNP(Fe3O4) and BrTet combination on CML.Keywords: K562/A02 leukemic cells, multidrug resistance, magnetic nanoparticle of Fe3O4, 5-bromotetrandrine, apoptosis, P53, caspase-3

Baoan Chen1,* Jian Cheng1,* Yanan Wu1, Feng Gao1, Wenlin Xu2, et al 1Department of Hematology;2Department of Hematology, The Affiliated People’s Hospital, Jiangsu University, Zhenjiang, PR China *These authors have contributed equally to this workAbstract: In this paper we establish the xenograft leukemia model with stable multidrug resistance in nude mice and to investigate the reversal effect of 5-bromotetrandrine (5-BrTet) and magnetic nanoparticle of Fe3O4 (MNP-Fe3O4) combined with daunorubicin (DNR) in vivo. Two subclones of K562 and K562/A02 cells were inoculated subcutaneously into the back of athymic nude mice (1 × 107 cells/each) respectively to establish leukemia xenograft models. Drug-resistant and sensitive tumor-bearing nude mice were assigned randomly into five groups which were treated with normal saline; DNR; NP-Fe3O4 combined with DNR; 5-BrTet combined with DNR; 5-BrTet and MNP-Fe3O4 combined with DNR, respectively. The incidence of formation, growth characteristics, weight, and volume of tumors were observed. The histopathologic examination of tumors and organs were detected. For resistant tumors, the protein levels of Bcl-2, and BAX were detected by Western blot. Bcl-2, BAX, and caspase-3 genes were also detected. For K562/A02 cells xenograft tumors, 5-BrTet and MNP-Fe3O4 combined with DNR significantly suppressed growth of tumor. A histopathologic examination of tumors clearly showed necrosis of the tumors. Application of 5-BrTet and MNP-Fe3O4 inhibited the expression of Bcl-2 protein and upregulated the expression of BAX and caspase-3 proteins in K562/A02 cells xenograft tumor. It is concluded that 5-BrTet and MNP-Fe3O4 combined with DNR had a significant tumor-suppressing effect on a MDR leukemia cells xenograft model.Keywords: 5-bromotetrandrine, magnetic nanoparticle of Fe3O4, multidrug-resistance, xenograft model

Tetrandrine, a bis-benzylisoquinoline alkaloid isolated from the dried root of Hang-Fang-Chi (Stephaniatetrandra S. Moore), has been reported to possess anti-cancer effects on many tumors. In this study, we investigated tetrandrine-induced apoptosis on human gastric cancer BGC-823 cells in vitro and in vivo. The results showed that tetrandrine significantly inhibited cell viability in a dose- and time-dependent manner and induced apoptosis. It increased the apoptosis; upregulation of Bax, Bak, and Bad; and downregulation of Bcl-2 and Bcl-xl in BGC-823 cells. Moreover, tetrandrine increased the activation of caspase-3 and -9, release of cytochrome c, and upregulation of apaf-1, suggesting that tetrandrine-induced apoptosis was related to the mitochondrial pathway. Meanwhile, pretreatment with the pan-caspase inhibitor z-VAD-fmk in BGC-823 cells reduced tetrandrine-induced apoptosis by blocking activation of caspases. Furthermore, tetrandrine effectively inhibited tumor growth via apoptosis induction, which was verified by immunohistochemical analysis in a nude mouse xenograft model. Taken together, we concluded that tetrandrine significantly inhibited the proliferation of gastric cancer BGC-823 cells through mitochondria-dependent apoptosis, which may play a promising role in gastric cancer therapy.

We have shown that inhibition of WT1/+17AA protein expression following transfection with a vector-based small interfering RNA expression construct in K562 cell lines, leads to a decrease in MDR1 and P-glycoprotein levels, accumulation of Rh123, and enhancement of the doxorubicin cytotoxicity. Our findings suggest that WT1/+17AA exerts its oncogenic function by modulating multidrug resistance in leukemia cells.