Pathomic model based on histopathological features and machine learning to predict IDO1 status and its association with breast cancer prognosis.

PURPOSE: To establish a pathomic model using histopathological image features for predicting indoleamine 2,3-dioxygenase 1 (IDO1) status and its relationship with overall survival (OS) in breast cancer. METHODS: A pathomic model was constructed using machine learning and histopathological images obtained from The Cancer Genome Atlas database to predict IDO1 expression. The model performance was evaluated based on the area under the curve, calibration curve, and decision curve analysis (DCA). Prediction scores (PSes) were generated from the model and applied to divide the patients into two groups. Survival outcomes, gene set enrichment, immune microenvironment, and tumor mutations were assessed between the two groups. RESULTS: Survival analysis followed by multivariate correction revealed that high IDO1 is a protective factor for OS. Further, the model was calibrated, and it exhibited good discrimination. Additionally, the DCA showed that the proposed model provided a good clinical net benefit. The Kaplan-Meier analysis revealed a positive correlation between high PS and improved OS. Univariate and multivariate Cox regression analyses demonstrated that PS is an independent protective factor for OS. Moreover, differentially expressed genes were enriched in various essential biological processes, including extracellular matrix receptor interaction, angiogenesis, transforming growth factor ß signaling, epithelial mesenchymal transition, cell junction, tryptophan metabolism, and heme metabolic processes. PS was positively correlated with M1 macrophages, CD8 + T cells, T follicular helper cells, and tumor mutational burden. CONCLUSION: These results indicate the potential ability of the proposed pathomic model to predict IDO1 status and the OS of breast cancer patients.

Identification and Validation of Three-Gene Signature in Lung Squamous Cell Carcinoma by Integrated Transcriptome and Methylation Analysis.

Since DNA methylation (DNAm) is associated with the carcinogenesis of various cancers, this study aimed to explore potential DNAm prognostic signatures of lung squamous cell carcinoma (LUSC). First, transcriptomic and methylation profiles of LUSC were obtained from The Cancer Genome Atlas database (TCGA). DNAm-related genes were screened by integrating DNAm and transcriptome profiles via MethylMix package. Subsequently, a prognostic signature was conducted with the least absolute shrinkage and selector operation (LASSO) Cox analysis. This signature combined with the clinicopathological parameters was then utilized to construct a prognostic nomogram via the rms package. A signature based on three DNAm-related genes claudin 1 (CLDN1), ATP-binding cassette subfamily C member 5 (ABCC5), and cystatin A (CSTA) that were hypomethylated and upregulated in LUSC was constructed. Univariate and multivariate Cox regression analysis suggested that this signature, combined with age and TNM.N stage, was significantly correlated with survival rate. Time-dependent receiver operating characteristics and calibration curves suggested the nomogram constructed with age and TNM.N stage variables could accurately evaluate the 3- and 5-year outcome of LUSC. Finally, the average mRNA and protein expression levels of CLDN1, ABCC5, and CSTA in LUSC were verified to be significantly higher than those in paracancerous tissues. Moreover, silencing CLDN1, ABCC5, and CSTA expressions could significantly reduce the carcinogenesis of the A549 cell line. The DNAm-driven prognostic signature consists of CLDN1, ABCC5, and CSTA incorporated with age and TNM. N stage could facilitate the prediction outcome of LUSC.

Knockdown of miR-384-3p Protects Against Myocardial Ischemia-Reperfusion Injury in Rats Through Targeting HSP70.

BACKGROUND: Myocardial infarction (MI) and heart failure remain critical states of heart disease with high mortality. Previous studies have indicated that miRNA has cardioprotective effects and can resist myocardial ischemia-reperfusion (I/R) injury. However, the role of mir-384-3p in MI has not been reported, and whether this miRNA can regulate the apoptosis of cardiomyocytes needs to be verified. METHODS: The effect of hypoxia-reperfusion (H/R) on cardiomyocyte activity was detected using MTT assay. MiR-384-3p was knocked down or overexpressed in cardiomyocytes H/R models by pretreatment with miR-384-3p mimic or inhibitor to verify the function of miR-384-3p in H/R. Circulating levels of miR-384-3p was detected by quantitative realtime PCR, and protein expression was detected by western blotting. TUNEL staining and flow cytometry demonstrated a high degree of myocardium apoptosis after H/R induction. Dual-Luciferase Reporter Assay detected dynamic expression of miR-384-3p and HSP70. The infarction size of I/R rats was detected by 2,3,5-triphenyltetrazolium chloride (TTC) staining. RESULTS: MiR-384-3p was closely related to cardiomyocyte activity in H/R progression. Increased expression of mir-384-3p can promote the production of cleaved caspase-3 and cleaved PARP, thereby regulating cardiomyocyte apoptosis. HSP70 was a target of miR-384-3p and HSP70 silencing aggravated H/R-induced cardiomyocyte dysfunction. In an animal model, the expression level of HSP70 is regulated by miR-384-3p, and miR-384-3p inhibition remarkably reduced I/R-induced MI in rats. CONCLUSION: In conclusion, the present report identified that HSP70 was a potential target of miR-384-3p, and miR-384-3p inhibition remarkably reduced I/R-induced MI in rats. Therefore, this study provides a novel therapeutic approach for the treatment of MI from bench to clinic.

The Efficiency of Type-Specific High-Risk Human Papillomavirus Models in the Triage of Women with Atypical Squamous Cells of Undetermined Significance.

PURPOSE: To evaluate the performance of different high-risk human papillomavirus (HR-HPV) genotype models in triaging women with cytological diagnosis of atypical squamous cells of undetermined significance (ASCUS). PATIENTS AND METHODS: A total of 36,679 Chinese women who underwent cytology and HR-HPV genotyping assessments during cervical cancer screening were enrolled in this study. Women with cytology-proven ASCUS were referred for further screening by colposcopy and biopsy. The study endpoint was histological detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) at any of the follow-up visits. The sensitivity, specificity, positive predictive values (PPVs), negative predictive values (NPVs), positive likelihood ratio (PLR) and negative likelihood ratio (NLR) of different HR-HPV genotype combination models were estimated. RESULTS: In all, 1675 (4.9%) women were identified as having ASCUS, 1454 women underwent colposcopy and biopsy, and 6.0% (87/1454) women were identified as having CIN2+ lesions. Among those with ASCUS who were identified as having CIN2+, the HR-HPV infection rate was 97.7%, and the prevalence rates of HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68 were 48.3%, 8.0%, 6.9%, 4.6%, 1.1%, 2.3%, 3.4%, 3.4%, 26.4%, 1.1%, 17.2%, 2.3%, 0.0% and 0.0%, respectively. Compared to other HR-HPV-type combination models, the HPV16/18/31/33/52/58 model achieved a higher sensitivity [93.1 (87.8-98.4)], specificity [73.0 (70.7-75.4)], PPV [18.0 (14.5-21.5)], NPV [99.4 (98.9-99.9)], PLR [3.7 (3.1-3.8)] and NLR [0.06 (0.03-0.18)] for the triage of ASCUS patients, but the colposcopy referral rate (30.9%) was significantly lower than that of the recommended HR-HPV model (44.0%). CONCLUSION: This study confirms that the specific HR-HPV genotype HPV16/18/31/33/52/58 is an alternative strategy for ASCUS triage and can effectively reduce the high burden of colposcopy referrals in China.

A novel drug repurposing approach for non-small cell lung cancer using deep learning.

Drug repurposing is an attractive and pragmatic way offering reduced risks and development time in the complicated process of drug discovery. In the past, drug repurposing has been largely accidental and serendipitous. The most successful examples so far have not involved a systematic approach. Nowadays, remarkable advances in drugs, diseases and bioinformatic knowledge are offering great opportunities for designing novel drug repurposing approach through comprehensive understanding of drug information. In this study, we introduced a novel drug repurposing approach based on transcriptomic data and chemical structures using deep learning. One strong candidate for repurposing has been identified. Pimozide is an anti-dyskinesia agent that is used for the suppression of motor and phonic tics in patients with Tourette's Disorder. However, our pipeline proposed it as a strong candidate for treating non-small cell lung cancer. The cytotoxicity of pimozide against A549 cell lines has been validated.

MicroRNA­200a promotes esophageal squamous cell carcinoma cell proliferation, migration and invasion through extensive target genes.

Despite investigations into microRNA (miRNA) expression in esophageal cancer (EC) tissue, miRNAs that participate in EC pathogenesis and their subsequent mechanisms of action remain to be determined. The present study aimed to identify important miRNAs that contribute to EC development, and to assess miRNA biomarkers that could be used in EC diagnosis, prognosis and therapy. Bioinformatics analysis was performed to reanalyze EC tissue miRNA expression microarray dataset GSE113776, which was followed by in vitro verification of miRNA functions using reverse transcription­quantitative PCR, western blot analysis and a dual­luciferase reporter assay. Out of 93 miRNAs extracted, only miR­200a was significantly increased in EC tissues. Transfection of KYSE150 esophageal squamous cell carcinoma (ESCC) cells with miR­200a mimics significantly increased their proliferative, migratory and invasive ability, whereas the opposite cell behaviors were observed in ESCC cells transfected with a miR­200a inhibitor. A total of six miR­200a target genes [catenin ß1 (CTNNB1), cadherin­1 (CDH1), PTEN, adenomatous polyposis coli (APC), catenin α1 (CTNNA1) and superoxide dismutase 2 (SOD2)] were selected for further analysis based on Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein­protein interaction network map data and protein expression in esophageal tissue. These target genes were downregulated under miR­200a expression and upregulated in the presence of the miR­200a inhibitor. The association between miR­200a and the 3'­untranslated region of target genes in ESCC cells was confirmed using a dual­luciferase reporter assay. In conclusion, the present study demonstrated that miR­200a may participate in the promotion of ESCC cell proliferation, migration and invasion, and provided novel evidence for the direct interaction between miR­200a and CTNNB1, CDH1, PTEN, APC, CTNNA1 and SOD2, which may contribute to the observed altered cell behavior.

Multiple Fatigue Failure Behaviors and Long-Life Prediction Approach of Carburized Cr-Ni Steel with Variable Stress Ratio.

Axial loading tests with stress ratios R of -1, 0 and 0.3 were performed to examine the fatigue failure behavior of a carburized Cr-Ni steel in the long-life regime from 104 to 108 cycles. Results show that this steel represents continuously descending S-N characteristics with interior inclusion-induced failure under R = -1, whereas it shows duplex S-N characteristics with surface defect-induced failure and interior inclusion-induced failure under R = 0 and 0.3. The increasing tension eliminates the effect of compressive residual stress and promotes crack initiation from the surface or interior defects in the carburized layer. The FGA (fine granular area) formation greatly depends on the number of loading cycles, but can be inhibited by decreasing the compressive stress. Based on the evaluation of the stress intensity factor at the crack tip, the surface and interior failures in the short life regime can be characterized by the crack growth process, while the interior failure with the FGA in the long life regime can be characterized by the crack initiation process. In view of the good agreement between predicted and experimental results, the proposed approach can be well utilized to predict fatigue lives associated with interior inclusion-FGA-fisheye induced failure, interior inclusion-fisheye induced failure, and surface defect induced failure.

Interior Fracture Mechanism Analysis and Fatigue Life Prediction of Surface-Hardened Gear Steel under Axial Loading.

The interior defect-induced fracture of surface-hardened metallic materials in the long life region has become a key issue on engineering design. In the present study, the axial loading test with fully reversed condition was performed to examine the fatigue property of a surface-carburized low alloy gear steel in the long life region. Results show that this steel represents the duplex S-N (stress-number of cycles) characteristics without conventional fatigue limit related to 107 cycles. Fatigue cracks are all originated from the interior inclusions in the matrix region due to the inhabitation effect of carburized layer. The inclusion induced fracture with fisheye occurs in the short life region below 5 × 105 cycles, whereas the inclusion induced fracture with fine granular area (FGA) and fisheye occurs in the long life region beyond 106 cycles. The stress intensity factor range at the front of FGA can be regarded as the threshold value controlling stable growth of interior long crack. The evaluated maximum inclusion size in the effective damage volume of specimen is about 27.29 µm. Considering the size relationships between fisheye and FGA, and inclusion, the developed life prediction method involving crack growth can be acceptable on the basis of the good agreement between the predicted and experimental results.

Very High Cycle Fatigue Failure Analysis and Life Prediction of Cr-Ni-W Gear Steel Based on Crack Initiation and Growth Behaviors.

The unexpected failures of structural materials in very high cycle fatigue (VHCF) regime have been a critical issue in modern engineering design. In this study, the VHCF property of a Cr-Ni-W gear steel was experimentally investigated under axial loading with the stress ratio of R = -1, and a life prediction model associated with crack initiation and growth behaviors was proposed. Results show that the Cr-Ni-W gear steel exhibits the constantly decreasing S-N property without traditional fatigue limit, and the fatigue strength corresponding to 108 cycles is around 485 MPa. The inclusion-fine granular area (FGA)-fisheye induced failure becomes the main failure mechanism in the VHCF regime, and the local stress around the inclusion play a key role. By using the finite element analysis of representative volume element, the local stress tends to increase with the increase of elastic modulus difference between inclusion and matrix. The predicted crack initiation life occupies the majority of total fatigue life, while the predicted crack growth life is only accounts for a tiny fraction. In view of the good agreement between the predicted and experimental results, the proposed VHCF life prediction model involving crack initiation and growth can be acceptable for inclusion-FGA-fisheye induced failure.