High mechanical, self-adhesive oxidized guar gum/chitosan hydrogel prepared at room temperature based on a nickel-urushiol catalytic system for wireless wearable sensors.

Recently, sensors constructed on the basis of hydrogel are playing a major role in health detection such as motion detection and breathing monitoring. However, the common hydrogels have poor mechanical properties, insufficient adhesion and complex preparation processes, which hinder the further use of such sensors. In this paper, the conductive hydrogel (P(AA-UH)-OGG-CS/NiCl2) composed of acrylic acid (AA), oxidized guar gum (OGG) and chitosan (CS) was prepared at room temperature through the dynamic redox reaction of nickel chloride (NiCl2) and urushiol (UH). In detail, the reduction group (phenolic hydroxyl) of UH and Ni2+/Ni3+ pair form a semi-quinone/quinone redox dynamic cycle system, allowing the hydrogel to quickly gel at room temperature for 3 min. The catechol group in UH also promotes the hydrogel to have a superior adhesion strength of 25.23 kPa to pig skin and a strong repeated adhesion performance. In addition, the dynamic Schiff base bond created by the interaction of OGG and CS elevated the tensile stress of the hydrogel to 67.54 kPa. After the hydrogel is assembled into the sensor, it has high sensitivity and high stability to different strains, and has great application prospects in the field of actual human health monitoring.

High-Intensity Interval Training Mitigates Sarcopenia and Suppresses the Myoblast Senescence Regulator EEF1E1.

BACKGROUND: The optimal exercise regimen for alleviating sarcopenia remains uncertain. This study aimed to investigate the efficacy of high-intensity interval training (HIIT) over moderate-intensity continuous training (MICT) in ameliorating sarcopenia. METHODS: We conducted a randomized crossover trial to evaluate plasma proteomic reactions to acute HIIT (four 4-min high-intensity intervals at 70% maximal capacity alternating with 4 min at 30%) versus MICT (constant 50% maximal capacity) in inactive adults. We explored the relationship between a HIIT-specific protein relative to MICT, identified via comparative proteomic analysis, eukaryotic translation elongation factor 1 epsilon 1 (EEF1E1) and sarcopenia in a paired case-control study of elderly individuals (aged over 65). Young (3 months old) and aged (20 months old) mice were randomized to sedentary, HIIT and MICT groups (five sessions/week for 4 weeks; n = 8 for each group). Measurements included skeletal muscle index, hand grip strength, expression of atrophic markers Atrogin1 and MuRF1 and differentiation markers MyoD, myogenin and MyHC-II via western blotting. We examined the impact of EEF1E1 siRNA and recombinant protein on D-galactose-induced myoblast senescence, measuring senescence-associated ß-galactosidase and markers like p21 and p53. RESULTS: The crossover trial, including 10 sedentary adults (32 years old, IQR 31-32) demonstrated significant alterations in the abundance of 21 plasma proteins after HIIT compared with MICT. In the paired case-control study of 84 older adults (84 years old, IQR 69-81; 52% female), EEF1E1 was significantly increased in those with sarcopenia compared to those without (14.68 [95%CI, 2.02-27.34] pg/mL, p = 0.03) and was associated with skeletal muscle index (R2 = 0.51, p < 0.001) and hand grip strength (R2 = 0.54, p < 0.001). In the preclinical study, aged mice exhibited higher EEF1E1 mRNA and protein levels in skeletal muscle compared to young mice, accompanied by a lower muscle mass and strength, increased cellular senescence and protein degradation markers and reduced muscle differentiation efficiency (all p < 0.05). HIIT reduced EEF1E1 expression and mitigated age-related muscle decline and atrophy in aged mice more effectively than MICT. Notably, EEF1E1 downregulation via siRNA significantly counteracted D-galactose-induced myoblast senescence as evidenced by reduced markers of muscle protein degradation and improved muscle differentiation efficiency (all p < 0.05). Conversely, treatments that increased EEF1E1 levels accelerated the senescence process (p < 0.05). Further exploration indicated that the decrease in EEF1E1 was associated with increased SIRT1 level and enhanced autophagy. CONCLUSIONS: This study highlights the potential of HIIT as a promising approach to prevent and treat sarcopenia while also highlighting EEF1E1 as a potential intervention target.

ExomiRHub: A comprehensive database for hosting and analyzing human disease-related extracellular microRNA transcriptomics data.

Extracellular microRNA (miRNA) expression data generated by different laboratories exhibit heterogeneity, which poses challenges for biologists without bioinformatics expertise. To address this, we introduce ExomiRHub (http://www.biomedical-web.com/exomirhub/), a user-friendly database designed for biologists. This database incorporates 191 human extracellular miRNA expression datasets associated with 112 disease phenotypes, 62 treatments, and 24 genotypes, encompassing 29,198 and 23 sample types. ExomiRHub also integrates 16,012 miRNA transcriptomes of 156 cancer subtypes from The Cancer Genome Atlas. All the data in ExomiRHub were further standardized and curated with annotations. The platform offers 25 analytical functions, including differential expression, co-expression, Weighted Gene Co-Expression Network Analysis (WGCNA), feature selection, and functional enrichment, enabling users to select samples, define groups, and customize parameters for analyses. Moreover, ExomiRHub provides a web service that allows biologists to analyze their uploaded miRNA expression data. Four additional tools were developed to evaluate the functions and targets of miRNAs and miRNA variations. Through ExomiRHub, we identified extracellular miRNA biomarkers associated with angiogenesis for monitoring glioma progression, demonstrating its potential to significantly accelerate the discovery of extracellular miRNA biomarkers.

ExpOmics: a comprehensive web platform empowering biologists with robust multi-omics data analysis capabilities.

MOTIVATION: High-throughput technologies yield a broad spectrum of multi-omics datasets, which offer unparalleled insights into complex biological systems. However, effectively analyzing this diverse array of data presents challenges, considering factors such as species diversity, data types, costs, and limitations of the available tools. RESULTS: Herein, we present ExpOmics, a comprehensive web platform featuring 7 applications and 4 toolkits, with 28 customizable analysis functions spanning various analyses of differential expression, co-expression, Weighted Gene Co-expression Network Analysis (WGCNA), feature selection, and functional enrichment. ExpOmics allows users to upload and explore multi-omics data without organism restrictions, supporting various expression data, including genes, mRNAs, lncRNAs, miRNAs, circRNAs, piRNAs, and proteins and is compatible with diverse gene nomenclatures and expression values. Moreover, ExpOmics enables users to analyze 22 427 transcriptomic datasets of 196 cancer subtypes sourced from 63 projects of The Cancer Genome Atlas Program (TCGA) to identify cancer biomarkers. The analysis results from ExpOmics are presented in high-quality graphical formats suitable for publication and are available for free download. A case study using ExpOmics identified two potential oncogenes, SERPINE1 and SLC43A1, that may regulate colorectal cancer through distinct biological processes. In summary, ExpOmics can serves as a robust platform for global researchers to explore multi-omics data, gain biological insights, and formulate testable hypotheses. AVAILABILITY AND IMPLEMENTATION: ExpOmics is available at http://www.biomedical-web.com/expomics.

Preoperative exercise training decreases complications of minimally invasive lung cancer surgery: A randomized controlled trial.

OBJECTIVE: Limited evidence exists regarding the efficacy of preoperative exercise in reducing short-term complications after minimally invasive surgery in patients with non-small cell lung cancer. This study aims to investigate the impact of preoperative exercise on short-term complications after minimally invasive lung resection. METHODS: In this prospective, open-label, randomized (1:1) controlled trial at Xiangya Hospital, China (September 2020 to February 2022), patients were randomly assigned to a preoperative exercise group with 16-day alternate supervised exercise or a control group. The primary outcome assessed was short-term postoperative complications, with a follow-up period of 30 days postsurgery. RESULTS: A total of 124 patients were recruited (preoperative exercise group n = 62; control n = 62). Finally, 101 patients (preoperative exercise group; n = 51 and control; n = 50) with a median age of 56 years (interquartile range, 50-62 years) completed the study. Compared with the control group, the preoperative exercise group showed fewer postoperative complications (preoperative exercise 3/51 vs control 10/50; odds ratio, 0.17; 95% CI, 0.04-0.86; P = .03) and shorter hospital stays (mean difference, -2; 95% CI, -3 to -1; P = .01). Preoperative exercise significantly improved depression, stress, functional capacity, and quality of life (all P < .05) before surgery. Furthermore, preoperative exercise demonstrated a significantly lower minimum blood pressure during surgery and lower increases in body temperature on day 2 after surgery, neutrophil-to-lymphocyte ratio, and neutrophil count after surgery (all P < .05). Exploratory research on lung tissue RNA sequencing (5 in each group) showed downregulation of the tumor necrosis factor signaling pathway in the preoperative exercise group compared with the control group. CONCLUSIONS: Preoperative exercise training decreased short-term postoperative complications in patients with non-small cell lung cancer.

Experimental Study of Compatibility between the Eco-friendly Insulation Mixed Gas CF3SO2F/N2 and EPDM and CR Materials.

As a greenhouse gas with strong global warming potential, the use of SF6 needs to be reduced as much as possible. Researching environmentally friendly insulation (EFI) gases to replace SF6 in power electrical equipment is an effective way to reduce its usage. CF3SO2F/N2, as a newly proposed EFI gas, has certain potential to replace SF6. Compatibility of CF3SO2F/N2 gas with rubber sealing materials commonly used in electrical equipment is still unknown. In this article, the compatibility of CF3SO2F/N2 with the ethylene-propylene-diene monomer (EPDM) and chloroprene rubber (CR) was investigated experimentally. It was found that CF3SO2F/N2 would slightly decompose under the influence of EPDM and CR rubber under certain conditions. The surface morphology of EPDM changed slightly under the influence of CF3SO2F/N2, and it was similar to the influence of SF6. While the surface morphology of CR deteriorated significantly with obvious defects. The mechanical properties of EPDM were not significantly affected by CF3SO2F, which is similar to the influence of SF6. But CR was affected greatly by CF3SO2F gas. Permanent deformation compression and surface morphology are two effective indicators for characterizing the compatibility between gas and rubber sealing materials. This research provides a reference for the application of CF3SO2F/N2 as a new EFI gas in power equipment.

An updated overview of some factors that influence the biological effects of nanoparticles.

Nanoparticles (NPs) can be extremely effective in the early diagnosis and treatment of cancer due to their properties. The nanotechnology industry is developing rapidly. The number of multifunctional NPs has increased in the market and hundreds of NPs are in various stages of preclinical and clinical development. Thus, the mechanism underlying the effects of NPs on biological systems has received much attention. After NPs enter the body, they interact with plasma proteins, tumour cell receptors, and small biological molecules. This interaction is closely related to the size, shape, chemical composition and surface modification properties of NPs. In this review, the effects of the size, shape, chemical composition and surface modification of NPs on the biological effects of NPs were summarised, including the mechanism through which NPs enter cells, the resulting oxidative stress response, and the interaction with proteins. This review of the biological effects of NPs can not only provide theoretical support for the preparation of safer and more efficient NPs but also lay the foundation for their clinical application.

Multistage targeting and dual inhibiting strategies based on bioengineered tumor matrix microenvironment-mediated protein nanocages for enhancing cancer biotherapy.

Regulation of the apoptotic pathway plays a critical role in inducing tumor cell death and circumventing drug resistance. Survivin protein is the strongest inhibitor of apoptosis found so far. It is highly expressed in several cancers and is a promising target for cancer therapy. However, clinical applications are limited by incomplete inhibition of survivin expression. Here, we present a novel strategy that extended the release of YM155 (an effective survivin inhibitor that works by inhibiting the activity of survivin promoter) and TATm-survivin (T34A) (TmSm) protein (survivin protein mutant with penetrating peptide, a potential anticancer protein therapeutic) via tumor matrix microenvironment-mediated ferritin heavy chain nanocages (FTH1 NCs), enabling significant inhibition of survivin activity at both transcript and protein levels. FTS (FTH1-matrix metalloproteinase-2-TmSm)/YM155 NC synthesis was easily scaled up, and these NCs could sequentially release TmSm protein through matrix metalloproteinase-2 and promote YM155 to enter the nucleus via transferrin receptor 1 (TfR1) binding, which increased the cytotoxicity and apoptosis of Capan-2 and A549 cells compared to that with individual drugs. Moreover, FTS/YM155 NCs enhanced drug accumulation at tumor sites and had a higher tumor inhibition rate (88.86%) than the compounds alone in A549 tumor-bearing mice. In addition, FTS/YM155 NCs exerted significant survivin downregulation (4.43-fold) and caspase-3 upregulation (4.31-fold) and showed better therapeutic outcomes without inducing organ injury, which highlights their promising future clinical application in precision therapy. This tumor microenvironment-responsive platform could be harnessed to develop an effective therapy via multilevel inhibition of cancer targets.

Identification of differentially expressed genes associated with coronary in-stent restenosis by integrated bioinformatics approaches.

BACKGROUND: In-stent restenosis (ISR) is a common complication following percutaneous coronary intervention (PCI). Designing ISR-specific therapeutic targets is important for optimizing coronary stenosis therapy. This study aims to find new potential key genes related to ISR and the usefulness of differentially expressed genes (DEGs) as diagnostic biomarkers for ISR. METHODS: Microarray datasets of peripheral blood was downloaded from the Gene Expression Omnibus (GEO) public database (GSE46560, n=11). The DEGs between the ISR group and the control were obtained through the limma package analysis of the R language. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to obtain the related signal pathways. STRING database was used to constructed a protein-to-protein interaction network with DEGs. Networkanalyst database was used to predict the target miRNA of the target gene. The area under the curve (AUC) value obtained from receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic effectiveness of the hub gene in distinguishing ISR patients from normal individuals. RESULTS: A total of 154 DEGs were identified between ISR group and control group, including 57 up-regulated and 97 down-regulated DEGs. GO enrichment analysis showed that genes were enriched in homeostasis, cell morphology and cell connection. KEGG pathway analysis shows that genes are mainly involved in human papillomavirus infection, salmonella infection, human T-cell leukemia virus type 1 infection, axon guidance and MAPK signaling pathway. CLTA, CAT, STAT5A, CD300A, CA1, NCF2, HBQ1, AHSP, SLC4A1 and EPB42 were identified as 10 hub genes. A total of 151 target miRNAs of 7 DEGs were obtained, and 149 mRNA-miRNA pairs were identified. ROC curve indicates that CA1, STAT5A and HBQ1 have high diagnostic value in ISR. CONCLUSIONS: CA1, STAT5A and HBQ1 are identified as specific related genes for ISR patients. These genes may provide new targets for the early identification and treatment of ISR.

circMine: a comprehensive database to integrate, analyze and visualize human disease-related circRNA transcriptome.

Many circRNA transcriptome data were deposited in public resources, but these data show great heterogeneity. Researchers without bioinformatics skills have difficulty in investigating these invaluable data or their own data. Here, we specifically designed circMine (http://hpcc.siat.ac.cn/circmine and http://www.biomedical-web.com/circmine/) that provides 1 821 448 entries formed by 136 871 circRNAs, 87 diseases and 120 circRNA transcriptome datasets of 1107 samples across 31 human body sites. circMine further provides 13 online analytical functions to comprehensively investigate these datasets to evaluate the clinical and biological significance of circRNA. To improve the data applicability, each dataset was standardized and annotated with relevant clinical information. All of the 13 analytic functions allow users to group samples based on their clinical data and assign different parameters for different analyses, and enable them to perform these analyses using their own circRNA transcriptomes. Moreover, three additional tools were developed in circMine to systematically discover the circRNA-miRNA interaction and circRNA translatability. For example, we systematically discovered five potential translatable circRNAs associated with prostate cancer progression using circMine. In summary, circMine provides user-friendly web interfaces to browse, search, analyze and download data freely, and submit new data for further integration, and it can be an important resource to discover significant circRNA in different diseases.

Association of miR-155 and MIR155HG polymorphisms with cancer risk: A meta-analysis.

BACKGROUND: Analysis of emerging data shows that miRNAs, including miR-155, play important roles in tumorigenesis. Several studies have indicated that miR-155 and MIR155HG polymorphisms may be related to cancer risk, but the association was controversial. Therefore, we conducted this first-reported comprehensive meta-analysis of the association of miR-155 and MIR155HG polymorphisms with cancer risk. MATERIALS AND METHODS: We searched several databases, including PubMed, Embase, and Web of Science, to identify the eligible studies reporting the association of miR-155 and MIR155HG polymorphisms with cancer risk. We calculated the pooled odds ratios (ORs) and 95% confidence intervals (CIs) to analyze the association. Stata software (version 16.0) was used to analyze the data we collected. RESULTS: After being carefully and strictly screened, eight articles reporting on six common single-nucleotide polymorphisms consisting of 6184 cases and 6896 controls were included in this meta-analysis. The six polymorphisms included were rs767649 (T>A), rs928883 (A>G), rs2829803 (G>A), rs1893650 (T>C), rs4143370 (G>C), and rs12482371 (T>C). Our results showed that, in the overall analysis, heterozygotes increased cancer risk, with a marginal P value, compared with wild-type (OR = 1.06, 95% CI = 1.00-1.12, P = 0.062). Subsequent analyses showed that only rs767649 was associated with an increased risk of non-small-cell lung cancer (NSCLC) in an allele model (T vs. A: OR = 1.15, 95% CI = 1.04-1.26, P = 0.007), a homozygote model (TT vs. AA: OR = 1.31, 95% CI = 1.06-1.60, P = 0.011), and a recessive model (TT vs. AT + AA: OR = 1.30, 95% CI = 1.08-1.55, P = 0.005). CONCLUSION: The present meta-analysis indicates that the rs767649 polymorphism might be a potential factor for NSCLC risk; however, more studies should be conducted to confirm these findings.

CanImmunother: a manually curated database for identification of cancer immunotherapies associating with biomarkers, targets, and clinical effects.

As immunotherapy is evolving into an essential armamentarium against cancers, numerous translational studies associated with relevant biomarkers, targets, and clinical effects have been reported in recent years. However, a large amount of associated experimental data remains unexplored due to the difficulty in accessibility and utilization. Here, we established a comprehensive high-quality database for cancer immunotherapy called CanImmunother (http://www.biomedical-web.com/cancerit/) through manual curation on 4515 publications. CanImmunother contains 3267 experimentally validated associations between 218 cancer sub-types across 34 body parts and 484 immunotherapies with 642 biomarkers, 108 targets, and 121 control therapies. Each association was manually curated by professional curators, incorporated with valuable annotation and cross references, and assigned with an association score for prioritization. To help clinicians and researchers in identifying and discovering better cancer immunotherapy and their respective biomarkers and targets, CanImmunother offers user-friendly web applications including search, browse, excel table, association prioritization, and network visualization. CanImmunother presents a landscape of experimental cancer immunotherapy association data, serving as a useful resource to improve our insight and to facilitate further discovery of advanced immunotherapy options for cancer patients.

The association between prior physical fitness and depression in young adults during the COVID-19 pandemic-a cross-sectional, retrospective study.

BACKGROUND: The COVID-19 pandemic has led to a spike in deleterious mental health. This dual-center retrospective cross-sectional study assessed the prevalence of depression in young adults during this pandemic and explored its association with various physical fitness measures. METHODS: This study enrolled 12,889 (80% female) young adults (mean age 20 ± 1) who performed a National Student Physical Fitness battery from December 1st, 2019, to January 20th, 2020, and completed a questionnaire including Beck's Depression Inventory in May 2020. Independent associations between prior physical fitness and depression during the pandemic were assessed using multivariable linear and binary logistic regressions accordingly, covariates including age, dwelling location, economic level, smoking, alcohol, living status, weight change, and exercise volume during the pandemic. Sex- and baseline stress-stratified analyses were performed. RESULTS: Of the study population 13.9% of men and 15.0% of women sampled qualified for a diagnosis of depression. After multivariable adjustment, anaerobic (mean change 95% CI -3.3 [-4.8 to 1.8]) aerobic (-1.5 [-2.64 to -0.5]), explosive (-1.64 [-2.7 to -0.6]) and muscular (-1.7 [-3.0 to -0.5]) fitness were independently and inversely associated with depression for the overall population. These remained consistent after sex- and baseline stress-stratification. In binary logistic regression, the combined participants with moderate, high or excellent fitness also showed a much lower risk compared to those least fit in anaerobic (odd ratio (OR) 95% CI 0.68 [0.55-0.82]), aerobic (0.80 [0.68-0.91]), explosive (0.72 [0.61-0.82]), and muscular (0.66 [0.57-0.75]) fitness. CONCLUSIONS: These findings suggest that prior physical fitness may be inversely associated with depression in young adults during a pandemic.

The Establishment of Quantitatively Regulating Expression Cassette with sgRNA Targeting BIRC5 to Elucidate the Synergistic Pathway of Survivin with P-Glycoprotein in Cancer Multi-Drug Resistance.

Quantitative analysis and regulating gene expression in cancer cells is an innovative method to study key genes in tumors, which conduces to analyze the biological function of the specific gene. In this study, we found the expression levels of Survivin protein (BIRC5) and P-glycoprotein (MDR1) in MCF-7/doxorubicin (DOX) cells (drug-resistant cells) were significantly higher than MCF-7 cells (wild-type cells). In order to explore the specific functions of BIRC5 gene in multi-drug resistance (MDR), a CRISPR/Cas9-mediated knocking-in tetracycline (Tet)-off regulatory system cell line was established, which enabled us to regulate the expression levels of Survivin quantitatively (clone 8 named MCF-7/Survivin was selected for further studies). Subsequently, the determination results of doxycycline-induced DOX efflux in MCF-7/Survivin cells implied that Survivin expression level was opposite to DOX accumulation in the cells. For example, when Survivin expression was down-regulated, DOX accumulation inside the MCF-7/Survivin cells was up-regulated, inducing strong apoptosis of cells (reversal index 118.07) by weakening the release of intracellular drug from MCF-7/Survivin cells. Also, down-regulation of Survivin resulted in reduced phosphorylation of PI3K, Akt, and mTOR in MCF-7/Survivin cells and significantly decreased P-gp expression. Previous studies had shown that PI3K/Akt/mTOR could regulate P-gp expression. Therefore, we speculated that Survivin might affect the expression of P-gp through PI3K/Akt/mTOR pathway. In summary, this quantitative method is not only valuable for studying the gene itself, but also can better analyze the biological phenomena related to it.

ATF4 activation promotes hepatic mitochondrial dysfunction by repressing NRF1-TFAM signalling in alcoholic steatohepatitis.

OBJECTIVE: Mitochondrial dysfunction plays a dominant role in the pathogenesis of alcoholic liver disease (ALD); however, the underlying mechanisms remain to be fully understood. We previously found that hepatic activating transcription factor 4 (ATF4) activation was associated with mitochondrial dysfunction in ALD. This study aimed to investigate the function and mechanism of ATF4 in alcohol-induced hepatic mitochondrial dysfunction. DESIGN: ATF4 activation was detected in the livers of patients with severe alcoholic hepatitis (AH). The role of ATF4 and mitochondrial transcription factor A (TFAM) in alcohol-induced liver damage was determined in hepatocyte-specific ATF4 knockout mice and liver-specific TFAM overexpression mice, respectively. RESULTS: Hepatic PERK-eIF2α-ATF4 ER stress signalling was upregulated in patients with AH. Hepatocyte-specific ablation of ATF4 in mice ameliorated alcohol-induced steatohepatitis. ATF4 ablation also attenuated alcohol-impaired mitochondrial biogenesis and respiratory function along with the restoration of TFAM. Cell studies confirmed that TFAM expression was negatively regulated by ATF4. TFAM silencing in hepatoma cells abrogated the protective effects of ATF4 knockdown on ethanol-mediated mitochondrial dysfunction and cell death. Moreover, hepatocyte-specific TFAM overexpression in mice attenuated alcohol-induced mitochondrial dysfunction and liver damage. Mechanistic studies revealed that ATF4 repressed the transcription activity of nuclear respiratory factor 1 (NRF1), a key regulator of TFAM, through binding to its promoter region. Clinical relevance among ATF4 activation, NRF1-TFAM pathway disruption and mitochondrial dysfunction was validated in the livers of patients with AH. CONCLUSION: This study demonstrates that hepatic ATF4 plays a pathological role in alcohol-induced mitochondrial dysfunction and liver injury by disrupting the NRF1-TFAM pathway.

Poly C Binding Protein 1 Regulates p62/SQSTM1 mRNA Stability and Autophagic Degradation to Repress Tumor Progression.

Accumulating evidence show that Poly C Binding Protein 1 (PCBP1) is deleted in distinct types of tumors as a novel tumor suppressor, but its tumor suppression mechanism remains elusive. Here, we firstly describe that downregulation of PCBP1 is significantly associated with clinical ovarian tumor progression. Mechanistically, PCBP1 overexpression affects various autophagy-related genes expression at various expression levels to attenuate the intrinsic cell autophagy, including the autophagy-initiating ULK, ATG12, ATG7 as well as the bona fide marker of autophagosome, LC3B. Accordingly, knockdown of the endogenous PCBP1 in turn enhances autophagy and less cell death. Meanwhile, PCBP1 upregulates p62/SQSTM1 via inhibition p62/SQSTM1 autophagolysome and proteasome degradation as well as its mRNA stability, consequently accompanying with the caspase 3 or 8 activation for tumor cell apoptosis. Importantly, clinical ovary cancer sample analysis consistently validates the relevance of PCBP1 expression to both p62/SQSTM1 and caspase-8 to overall survival, and indicates PCBP1 may be a master player to repress tumor initiation. Taken together, our results uncover the tumorigenic mechanism of PCBP1 depletion and suggest that inhibition of tumor cell autophagy with autophagic inhibitors could be an effective therapeutical strategy for PCBP1-deficient tumor.

Multiple targeting strategies achieve novel protein drug delivery into proapoptosis lung cancer cells by precisely inhibiting survivin.

Therapeutic recombinant proteins have numerous advantages and benefits over chemical drugs, particularly high specificity and good biocompatibility. However, the therapeutic potential and clinical application of current anticancer protein drugs are limited as most biomarkers are located within cells, and multiple physiological barriers exist between the point of administration and the intracellular biomarker. Herein, we report a novel strategy to accurately deliver a cell-permeable dominant-negative TATm-Survivin (TmSm) protein (T34A) to intracellular survivin in cancer cells by overcoming multiple barriers in vivo. A poly(d,l-lactide-co-glycolide) (PLGA) inner core, a polyethylene glycol (PEG) modification, and a TATm peptide were simultaneously introduced to mediate tumor tissue targeting and response to pH-triggered TmSm release. Compared to free TmSm, the PEGylated-PLGA nanoparticle platform achieved a significantly higher cellular uptake efficiency (1.79-fold for A549 and 1.77-fold for Capan-2), effectively decreased IC50 (1.22-fold for A549 and 1.17-fold for Capan-2), and largely elevated apoptosis in different cancer cells (1.17-fold for A549 and 1.15-fold for Capan-2). Besides, this newly developed nanoplatform showed increased protein drug accumulation in the tumor site in A549-bearing nude mice and reached a tumor inhibition rate of 55.81% (1.35-fold versus free TmSm) by reducing the expression of intracellular survivin. All these results confirmed that our newly developed delivery strategy is a very promising tool, which helps protein drugs to cross multiple barriers in vivo and achieves precise targeting to intracellular biomarkers. This strategy could also be applied to other types of protein drugs to further improve their clinical anticancer therapeutic efficacy.

ncRPheno: a comprehensive database platform for identification and validation of disease related noncoding RNAs.

Noncoding RNAs (ncRNAs) play critical roles in many critical biological processes and have become a novel class of potential targets and bio-markers for disease diagnosis, therapy, and prognosis. Annotating and analysing ncRNA-disease association data are essential but challenging. Current computational resources lack comprehensive database platforms to consistently interpret and prioritize ncRNA-disease association data for biomedical investigation and application. Here, we present the ncRPheno database platform (http://lilab2.sysu.edu.cn/ncrpheno), which comprehensively integrates and annotates ncRNA-disease association data and provides novel searches, visualizations, and utilities for association identification and validation. ncRPheno contains 482,751 non-redundant associations between 14,494 ncRNAs and 3,210 disease phenotypes across 11 species with supporting evidence in the literature. A scoring model was refined to prioritize the associations based on evidential metrics. Moreover, ncRPheno provides user-friendly web interfaces, novel visualizations, and programmatic access to enable easy exploration, analysis, and utilization of the association data. A case study through ncRPheno demonstrated a comprehensive landscape of ncRNAs dysregulation associated with 22 cancers and uncovered 821 cancer-associated common ncRNAs. As a unique database platform, ncRPheno outperforms the existing similar databases in terms of data coverage and utilities, and it will assist studies in encoding ncRNAs associated with phenotypes ranging from genetic disorders to complex diseases. ABBREVIATIONS: APIs: application programming interfaces; circRNA: circular RNA; ECO: Evidence & Conclusion Ontology; EFO: Experimental Factor Ontology; FDR: false discovery rate; GO: Gene Ontology; GWAS: genome wide association studies; HPO: Human Phenotype Ontology; ICGC: International Cancer Genome Consortium; lncRNA: long noncoding RNA; miRNA: micro RNA; ncRNA: noncoding RNA; NGS: next generation sequencing; OMIM: Online Mendelian Inheritance in Man; piRNA: piwi-interacting RNA; snoRNA: small nucleolar RNA; TCGA: The Cancer Genome Atlas.

Mitochondria Redistribution in Enterovirus A71 Infected Cells and Its Effect on Virus Replication.

Enterovirus A71 (EV-A71) is one of the main causative agents of hand, foot and mouth disease (HFMD) and it also causes severe neurologic complications in infected children. The interactions between some viruses and the host mitochondria are crucial for virus replication and pathogenicity. In this study, it was observed that EV-A71 infection resulted in a perinuclear redistribution of the mitochondria. The mitochondria rearrangement was found to require the microtubule network, the dynein complex and a low cytosolic calcium concentration. Subsequently, the EV-A71 non-structural protein 2BC was identified as the viral protein capable of inducing mitochondria clustering. The protein was found localized on mitochondria and interacted with the mitochondrial Rho GTPase 1 (RHOT1) that is a key protein required for attachment between the mitochondria and the motor proteins, which are responsible for the control of mitochondria movement. Additionally, suppressing mitochondria clustering by treating cells with nocodazole, EHNA, thapsigargin or A23187 consistently inhibited EV-A71 replication, indicating that mitochondria recruitment played a crucial role in the EV-A71 life cycle. This study identified a novel function of the EV-A71 2BC protein and provided a potential model for the regulation of mitochondrial motility in EV-A71 infection.

LncRNA GAS5 suppresses proliferation, migration, invasion, and epithelial-mesenchymal transition in oral squamous cell carcinoma by regulating the miR-21/PTEN axis.

Growth-arrest-specific transcript 5 (GAS5) functions as a tumor suppressor in a variety of cancers. GAS5 has been reported to be down-regulated in oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the mechanisms of how GAS5 acts as a tumor suppressor in OSCC. qRT-PCR, cell viability, wound-healing, and transwell assays showed that knockdown of GAS5 increased miR-21 expression and promoted proliferation, migration, invasion, and epithelial-mesenchymal transition of OSCC cells. In contrast, overexpression of GAS5 showed the opposite effects. Furthermore, miR-21 overexpression reversed the effect of GAS5. Western blot showed that knockdown of GAS5 suppressed PTEN, while phosphorylation of Akt was promoted. PCNA, cyclinD1, and Ki-67 were up-regulated, indicating enhanced proliferation. E-cadherin was down-regulated, while N-cadherin, vimentin, and snail1 were increased, indicating augmented epithelial-mesenchymal transition. Overexpression of GAS5 regulated these proteins inversely. Overexpression of miR-21 reversed the effect of GAS5 on these proteins. Taken together, GAS5 suppresses proliferation, migration, invasion, and epithelial-mesenchymal transition in OSCC through the miR-21/PTEN axis and might be a novel therapeutic target for OSCC.