Machine learning identifies activation of RUNX/AP-1 as drivers of mesenchymal and fibrotic regulatory programs in gastric cancer.

Gastric cancer (GC) is the fifth most common cancer worldwide and is a heterogeneous disease. Among GC subtypes, the mesenchymal phenotype (Mes-like) is more invasive than the epithelial phenotype (Epi-like). Although gene expression of the epithelial-to-mesenchymal transition (EMT) has been studied, the regulatory landscape shaping this process is not fully understood. Here we use ATAC-seq and RNA-seq data from a compendium of GC cell lines and primary tumors to detect drivers of regulatory state changes and their transcriptional responses. Using the ATAC-seq data, we developed a machine learning approach to determine the transcription factors (TFs) regulating the subtypes of GC. We identified TFs driving the mesenchymal (RUNX2, ZEB1, SNAI2, AP-1 dimer) and the epithelial (GATA4, GATA6, KLF5, HNF4A, FOXA2, GRHL2) states in GC. We identified DNA copy number alterations associated with dysregulation of these TFs, specifically deletion of GATA4 and amplification of MAPK9 Comparisons with bulk and single-cell RNA-seq data sets identified activation toward fibroblast-like epigenomic and expression signatures in Mes-like GC. The activation of this mesenchymal fibrotic program is associated with differentially accessible DNA cis-regulatory elements flanking upregulated mesenchymal genes. These findings establish a map of TF activity in GC and highlight the role of copy number driven alterations in shaping epigenomic regulatory programs as potential drivers of GC heterogeneity and progression.

Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities.

OBJECTIVE: Gastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enhancer landscape revealing disease vulnerabilities. DESIGN: Transcriptomic profiles of ~1000 primary GCs and cell lines were analysed to derive a consensus Mes-GC classifier. Clinical and genomic associations were performed across >1200 patients with GC. Genome-wide epigenomic profiles (H3K27ac, H3K4me1 and assay for transposase-accessible chromatin with sequencing (ATAC-seq)) of 49 primary GCs and GC cell lines were generated to identify Mes-GC-specific enhancer landscapes. Upstream regulators and downstream targets of Mes-GC enhancers were interrogated using chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing, CRISPR/Cas9 editing, functional assays and pharmacological inhibition. RESULTS: We identified and validated a 993-gene cancer-cell intrinsic Mes-GC classifier applicable to retrospective cohorts or prospective single samples. Multicohort analysis of Mes-GCs confirmed associations with poor patient survival, therapy resistance and few targetable genomic alterations. Analysis of enhancer profiles revealed a distinctive Mes-GC epigenomic landscape, with TEAD1 as a master regulator of Mes-GC enhancers and Mes-GCs exhibiting preferential sensitivity to TEAD1 pharmacological inhibition. Analysis of Mes-GC super-enhancers also highlighted NUAK1 kinase as a downstream target, with synergistic effects observed between NUAK1 inhibition and cisplatin treatment. CONCLUSION: Our results establish a consensus Mes-GC classifier applicable to multiple transcriptomic scenarios. Mes-GCs exhibit a distinct epigenomic landscape, and TEAD1 inhibition and combinatorial NUAK1 inhibition/cisplatin may represent potential targetable options.

Accurate somatic variant detection using weakly supervised deep learning.

Identification of somatic mutations in tumor samples is commonly based on statistical methods in combination with heuristic filters. Here we develop VarNet, an end-to-end deep learning approach for identification of somatic variants from aligned tumor and matched normal DNA reads. VarNet is trained using image representations of 4.6 million high-confidence somatic variants annotated in 356 tumor whole genomes. We benchmark VarNet across a range of publicly available datasets, demonstrating performance often exceeding current state-of-the-art methods. Overall, our results demonstrate how a scalable deep learning approach could augment and potentially supplant human engineered features and heuristic filters in somatic variant calling.

Accurate Ensemble Prediction of Somatic Mutations with SMuRF2.

Accurate identification of somatic mutations is crucial for discovery and identification of driver mutations in cancer tumors. Here, we describe the updated Somatic Mutation calling method using a Random Forest (SMuRF2), an ensemble method that combines the predictions and auxiliary features from individual mutation callers using supervised machine learning. SMuRF2 provides an efficient workflow to predict both somatic point mutations (SNVs) and small insertions/deletions (indels) in cancer genomes and exomes. We describe the latest method and provide a detailed tutorial for running SMuRF2.

Integrating Taguchi Method and Gray Relational Analysis for Auto Locks by Using Multiobjective Design in Computer-Aided Engineering.

In automobiles, lock parts are matched with inserts, and this is a crucial quality standard for the dimensional accuracy of the molding. This study employed moldflow analysis to explore the influence of various injection molding process parameters on the warpage deformation. Deformation of the plastic part is caused by the nonuniform product temperature distribution in the manufacturing process. Furthermore, improper parameter design leads to substantial warpage and deformation. The Taguchi robust design method and gray correlation analysis were used to optimize the process parameters. Multiobjective quality analysis was performed for achieving a uniform temperature distribution and reducing the warpage deformation to obtain the optimal injection molding process parameters. Subsequently, three water cooling system designs-original cooling, U-shaped cooling, and conformal cooling-were tested to modify the temperature distribution and reduce the warpage. Taguchi gray correlation analysis revealed that the main influencing parameter was the mold temperature followed by the holding pressure. Moreover, the results indicated that the conformal cooling system improved the average temperature distribution.

Classification of age-related macular degeneration using convolutional-neural-network-based transfer learning.

BACKGROUND: To diagnose key pathologies of age-related macular degeneration (AMD) and diabetic macular edema (DME) quickly and accurately, researchers attempted to develop effective artificial intelligence methods by using medical images. RESULTS: A convolutional neural network (CNN) with transfer learning capability is proposed and appropriate hyperparameters are selected for classifying optical coherence tomography (OCT) images of AMD and DME. To perform transfer learning, a pre-trained CNN model is used as the starting point for a new CNN model for solving related problems. The hyperparameters (parameters that have set values before the learning process begins) in this study were algorithm hyperparameters that affect learning speed and quality. During training, different CNN-based models require different algorithm hyperparameters (e.g., optimizer, learning rate, and mini-batch size). Experiments showed that, after transfer learning, the CNN models (8-layer Alexnet, 22-layer Googlenet, 16-layer VGG, 19-layer VGG, 18-layer Resnet, 50-layer Resnet, and a 101-layer Resnet) successfully classified OCT images of AMD and DME. CONCLUSIONS: The experimental results further showed that, after transfer learning, the VGG19, Resnet101, and Resnet50 models with appropriate algorithm hyperparameters had excellent capability and performance in classifying OCT images of AMD and DME.

Application of Intelligent Modeling Method to Optimize the Multiple Quality Characteristics of the Injection Molding Process of Automobile Lock Parts.

This study focuses on applying intelligent modeling methods to different injection molding process parameters, to analyze the influence of temperature distribution and warpage on the actual development of auto locks. It explores the auto locks using computer-aided engineering (CAE) simulation performance analysis and the optimization of process parameters by combining multiple quality characteristics (warpage and average temperature). In this experimental design, combinations were explored for each single objective optimization process parameter, using the Taguchi robust design process, with the L18 (21 × 37) orthogonal table. The control factors were injection time, material temperature, mold temperature, injection pressure, packing pressure, packing time, cooling liquid, and cooling temperature. The warpage and temperature distribution were analysed as performance indices. Then, signal-to-noise ratios (S/N ratios) were calculated. Gray correlation analysis, with normalization of the S/N ratio, was used to obtain the gray correlation coefficient, which was substituted into the fuzzy theory to obtain the multiple performance characteristic index. The maximum multiple performance characteristic index was used to find multiple quality characteristic-optimized process parameters. The optimal injection molding process parameters with single objective are a warpage of 0.783 mm and an average temperature of 235.23 °C. The optimal parameters with multi-objective are a warpage of 0.753 mm and an average temperature of 238.71 °C. The optimal parameters were then used to explore the different cooling designs (original cooling, square cooling, and conformal cooling), considering the effect of the plastics temperature distribution and warpage. The results showed that, based on the design of the different cooling systems, conformal cooling obtained an optimal warpage of 0.661 mm and a temperature of 237.62 °C. Furthermore, the conformal cooling system is smaller than the original cooling system; it reduces the warpage by 12.2%, and the average temperature by 0.46%.

Ensemble-Based Somatic Mutation Calling in Cancer Genomes.

Identification of somatic mutations in tumor tissue is challenged by both technical artifacts, diverse somatic mutational processes, and genetic heterogeneity in the tumors. Indeed, recent independent benchmark studies have revealed low concordance between different somatic mutation callers. Here, we describe Somatic Mutation calling method using a Random Forest (SMuRF), a portable ensemble method that combines the predictions and auxiliary features from individual mutation callers using supervised machine learning. SMuRF has improved prediction accuracy for both somatic point mutations (single nucleotide variants; SNVs) and small insertions/deletions (indels) in cancer genomes and exomes. Here, we describe the method and provide a tutorial on the installation and application of SMuRF.

SMuRF: portable and accurate ensemble prediction of somatic mutations.

SUMMARY: Somatic Mutation calling method using a Random Forest (SMuRF) integrates predictions and auxiliary features from multiple somatic mutation callers using a supervised machine learning approach. SMuRF is trained on community-curated matched tumor and normal whole genome sequencing data. SMuRF predicts both SNVs and indels with high accuracy in genome or exome-level sequencing data. Furthermore, the method is robust across multiple tested cancer types and predicts low allele frequency variants with high accuracy. In contrast to existing ensemble-based somatic mutation calling approaches, SMuRF works out-of-the-box and is orders of magnitudes faster. AVAILABILITY AND IMPLEMENTATION: The method is implemented in R and available at https://github.com/skandlab/SMuRF. SMuRF operates as an add-on to the community-developed bcbio-nextgen somatic variant calling pipeline. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Advances in genomic hepatocellular carcinoma research.

Background: Hepatocellular carcinoma (HCC) is the cancer with the second highest mortality in the world due to its late presentation and limited treatment options. As such, there is an urgent need to identify novel biomarkers for early diagnosis and to develop novel therapies. The availability of next-generation sequencing (NGS) data from tumors of liver cancer patients has provided us with invaluable resources to better understand HCC through the integration of data from different sources to facilitate the identification of promising biomarkers or therapeutic targets. Findings: Here, we review key insights gleaned from more than 20 NGS studies of HCC tumor samples, comprising approximately 582 whole genomes and 1,211 whole exomes mainly from the East Asian population. Through consolidation of reported somatic mutations from multiple studies, we identified genes with different types of somatic mutations, including single nucleotide variations, insertion/deletions, structural variations, and copy number alterations as well as genes with multiple frequent viral integration. Pathway analysis showed that this curated list of somatic mutations is critically involved in cancer-related pathways, viral carcinogenesis, and signaling pathways. Lastly, we addressed the future directions of HCC research as more NGS datasets become available. Conclusions: Our review is a comprehensive resource for the current NGS research in HCC, consolidating published articles, potential gene candidates, and their related biological pathways.

Mutation hotspots at CTCF binding sites coupled to chromosomal instability in gastrointestinal cancers.

Tissue-specific driver mutations in non-coding genomic regions remain undefined for most cancer types. Here, we unbiasedly analyze 212 gastric cancer (GC) whole genomes to identify recurrently mutated non-coding regions in GC. Applying comprehensive statistical approaches to accurately model background mutational processes, we observe significant enrichment of non-coding indels (insertions/deletions) in three gastric lineage-specific genes. We further identify 34 mutation hotspots, of which 11 overlap CTCF binding sites (CBSs). These CBS hotspots remain significant even after controlling for a genome-wide elevated mutation rate at CBSs. In 3 out of 4 tested CBS hotspots, mutations are nominally associated with expression change of neighboring genes. CBS hotspot mutations are enriched in tumors showing chromosomal instability, co-occur with neighboring chromosomal aberrations, and are common in gastric (25%) and colorectal (19%) tumors but rare in other cancer types. Mutational disruption of specific CBSs may thus represent a tissue-specific mechanism of tumorigenesis conserved across gastrointestinal cancers.

Suspected malignant hyperthermia during sevoflurane anesthesia.

Malignant hyperthermia is a rare anesthetic-related disorder. We present a case with unusual presentation. A boy aged 3 years and 9 months who was scheduled for Hotz's operation presented normally before the operation. Anesthesia was induced by atropine, thiopental and sevoflurane. Trachea intubation was facilitated by succinylcholine. Jaw stiffness was first noted although trachea was intubated without difficulty. The following tachycardia, hypercapnia and hyperthermia led to the diagnosis of malignant hyperthermia. Symptoms were relieved dramatically after the discontinuation of sevoflurane. Molecular genetic testing identified a novel ryanodine receptor (RYR1) mutation in exon 39, which confirmed malignant hyperthermia susceptibility in this patient.

Clinical comparisons between GlideScope video laryngoscope and Trachlight in simulated cervical spine instability.

STUDY OBJECTIVE: To compare the time taken for tracheal intubation, hemodynamic changes, and perioperative morbidities between the GlideScope (GS) video laryngoscope and the Trachlight (TL) with manual inline stabilization. DESIGN: Prospective, controlled, randomized study. SETTING: Operating room. PATIENTS: 60 ASA physical status I and II patients scheduled for elective surgery with general anesthesia. INTERVENTIONS: Patients were randomly assigned to the GS group or TL group (n = 30 for each group). MEASUREMENTS: Noninvasive blood pressure and heart rate at preinduction; preintubation and one, three, and 5 minutes after successful intubation; grade of face mask ventilation; number of intubation attempts; intubation time; apnea duration; mucosal trauma; lip or dental injury; and presence of hypoxia, were all recorded. MAIN RESULTS: The intubation attempts and perioperative safety data were comparable between the two groups. Intubation time and apnea duration were significantly shorter in the TL group than the GS group. All variables one minute after intubation were greater than baseline values except systolic blood pressure (SBP) in TL group. Both systolic blood pressure (SBP) and the degree of change of SBP from the baseline value one minute after intubation in TL group were significantly less than those of the GS group. CONCLUSIONS: Trachlight offers a faster intubation and a milder hemodynamic response than GS.