Effects of N6-Methyladenosine Regulators on LAG3 and Immune Infiltrates in Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, which is one of the most commonly diagnosed tumors and the leading causes of death from cancer around the world. Since RNA methylation is a posttranscriptional modification and affects so much biological progress, it is urged to explore the role of N6-methyladenosine (m6A) methylation in LUAD. Methods: We explored the expression of 24 m6A methylation genes, as well as their correlations with LAG3 in 561 LUAD samples from TCGA. Consensus clustering was applied to m6A methylation genes, and two LUAD subgroups were identified. The expression of m6A genes was analyzed by the Wilcoxon test. KEGG and GO enrichment analyses were performed to indicate the pathway affected by differentially expressed genes in the two groups. A prognostic model based on LASSO regression using an eleven-m6A gene signature was constructed according to the expression of these genes. Receiver operating characteristic (ROC) curve was used to confirm the accuracy of the model in the TCGA cohort, as well as in the test cohort from the Gene Expression Omnibus (GEO) database. Results: Compared to cluster 1, cluster 2 showed poorer overall survival (OS) and higher LAG3 expression. In addition, KEGG and GO enrichment analyses indicated that differentially expressed genes are enriched in the immune response. We also observed that the expression of LAG3 is positively correlated with IGF2BP2, CBLL1, and HNRNPA2B1 and negatively correlated with YTHDF2, YTHDF3, and FTO. For patients in the TCGA cohort, the AUC score is 0.7, and the AUC score for the GSE50081 cohort is 0.675. Patients with lower risk scores exhibited better overall survival and lower expression of LAG3 than patients with higher risk scores. Conclusions: In brief, our results indicated the important role of m6 methylation in affecting the tumor immune microenvironment and the survival of patients with LUAD. The m6A methylation gene signatures might serve as promising therapeutic targets and help the immunotherapy of LUAD in the future.

Real-World Efficacy and Safety of Sintilimab-Based Regimens against Advanced Esophageal Cancer: A Single-Center Retrospective Observational Study.

This study is aimed at assessing the sintilimab-based regimens' safety and efficacy for advanced esophageal cancer (EC) treatment in the real world. Cases of advanced EC treated with sintilimab-based regimens in the Anyang Tumor Hospital between 1 January 2020 and 1 August 2021 were retrospectively examined. Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), objective response rate (ORR), and adverse events (AEs) were evaluated. Among the 50 included patients, the median PFS was 11.3 months (95% CI: 5.0-17.6 months), and the 1-year PFS rate was 49.2%. The median OS was not reached, and the 1-year OS rate was 67.1%. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were seen in 14% (n = 7), 46% (n = 23), 32% (n = 16), and 8% (n = 4) of the 50 patients, respectively. Therefore, the ORR and DCR were 60% (30/50) and 92% (46/50), respectively. The CR rate of patients with radiotherapy was higher than that without radiotherapy (25% vs. 3.8%, P = 0.031). The 1-year OS rate was higher in patients with radiotherapy than in patients without radiotherapy (85.9% vs. 53.2%, P = 0.020). The most observed AEs included anemia, decrease in white blood cell count, nausea/vomiting, and hypoproteinemia. Sintilimab-based regimens achieved good disease control and tolerance for treating advanced EC in the real world. Combined radiotherapy can improve the efficacy and deserves further study.

Deep Learning for Automated Contouring of Gross Tumor Volumes in Esophageal Cancer.

Purpose: The aim of this study was to propose and evaluate a novel three-dimensional (3D) V-Net and two-dimensional (2D) U-Net mixed (VUMix-Net) architecture for a fully automatic and accurate gross tumor volume (GTV) in esophageal cancer (EC)-delineated contours. Methods: We collected the computed tomography (CT) scans of 215 EC patients. 3D V-Net, 2D U-Net, and VUMix-Net were developed and further applied simultaneously to delineate GTVs. The Dice similarity coefficient (DSC) and 95th-percentile Hausdorff distance (95HD) were used as quantitative metrics to evaluate the performance of the three models in ECs from different segments. The CT data of 20 patients were randomly selected as the ground truth (GT) masks, and the corresponding delineation results were generated by artificial intelligence (AI). Score differences between the two groups (GT versus AI) and the evaluation consistency were compared. Results: In all patients, there was a significant difference in the 2D DSCs from U-Net, V-Net, and VUMix-Net (p=0.01). In addition, VUMix-Net showed achieved better 3D-DSC and 95HD values. There was a significant difference among the 3D-DSC (mean ± STD) and 95HD values for upper-, middle-, and lower-segment EC (p<0.001), and the middle EC values were the best. In middle-segment EC, VUMix-Net achieved the highest 2D-DSC values (p<0.001) and lowest 95HD values (p=0.044). Conclusion: The new model (VUMix-Net) showed certain advantages in delineating the GTVs of EC. Additionally, it can generate the GTVs of EC that meet clinical requirements and have the same quality as human-generated contours. The system demonstrated the best performance for the ECs of the middle segment.

Association between polymorphisms in the CYP1A1, CYP2E1 and GSTM1 genes, and smoking, alcohol and upper digestive tract carcinomas in a high-incidence area of northern China.

Metabolic gene variants, smoking, and alcohol consumption are important upper digestive tract cancer (UDTC) risk factors. However, the gene-gene and gene-environment interactions remain unclear. A case-control study in a high incidence area for upper digestive tract cancer was conducted in China. DNA was extracted from buffy coat samples for PCR or PCR-restriction fragment length polymorphism. Smoking and alcohol drinking status was determined by questionnaires. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the associations. After adjusting for confounding factors, smoking increased esophageal cancer (EC), gastric cardia cancer (GCC) and gastric antral carcinoma (GAC) risk by 3.594, 4.658, and 3.999-fold, respectively. Alcohol consumption increased EC, GCC and GAC risk by 1.953, 2.442 and 1.765-fold, respectively. The cytochrome P4501A1 (CYP1A1) rs4646903 T>C polymorphism increased GCC risk, the cytochrome P4502E1 (CYP2E1) rs2031920 C>T polymorphism increased EC risk, while the GSTM1 null genotype decreased EC risk. An association existed between the following: CYP1A1 rs4646903 and smoking in EC, GCC and GAC; CYP1A1 rs4646903 and alcohol consumption in EC and GCC; CYP2E1 rs2031920 and smoking in EC, GCC and GAC and CYP2E1 rs2031920 and alcohol consumption in EC and GCC. No association was observed between CYP1A1 and CYP2E1. The glutathione S-transferase mu 1 (GSTM1) null genotype decreased EC risk (OR=0.510). Smoking/drinking are upper digestive tract cancer risk factors. The CYP1A1 rs4646903 and CYP2E1 rs2031920 polymorphisms were risk factors of GCC or EC, and the GSTM1 null genotype may serve a protective role against EC. The results of the present study indicated that gene-environment interactions increase the risk of UDTC.

Investigation of the eddy current effect on the high frequency response of the Mirnov probe on J-TEXT.

This paper investigates the high frequency response of the Mirnov probe based on a test platform, which is capable of generating a uniform AC magnetic field within the frequency range of 1-300 kHz. The eddy current effect is quantitatively reflected by the phase shift ϕc and normalized amplitude δ of the measured magnetic field between cases with and without a conducting plate located near the Mirnov probe. This method compensates the resonant effect in the Mirnov probe circuit and hence reflects purely the eddy current effect. The eddy current effect increases with the decrease in the distance between the probe and the conducting plate. With the increase in frequency, the magnitude of δ decreases to a saturated value at 10 kHz but increases significantly above 100 kHz for 304-stainless steel, while the eddy current effect with graphite appears at around 10 kHz and the magnitude of δ decreases to the minimum at 125 kHz, followed by a significant increase above 125 kHz. With the increase in f, the magnitude of ϕc increased until 2.5 kHz and 40 kHz for steel and graphite, respectively, then decreased with a further increase in f. The phasor expression is introduced to describe the AC magnetic field and allows an easy expression of the eddy current field. The phase of the eddy current field decreases toward -180° with f. The amplitude of the eddy current field increases with f and reaches its maximum when the skin depth reduces to a critical value. The eddy current field decreases with a further increase in the frequency.

Compensation of the pick-up fluxes on the plasma position control system when resonant magnetic perturbations are applied in J-TEXT.

In the J-TEXT tokamak the displacement coils, which serve as sensors for feedback control of plasma position, are significantly affected by the resonant magnetic perturbation (RMP) coils. To eliminate the deviation of plasma position caused by the RMP, the responses of the displacement coils to the RMP are studied with a view to compensate for the pick-up fluxes. Both the linear and eddy responses on the displacement coils are taken into account and adjusted accordingly. It was found that positional correction in the vertical direction was required when the RMP was operated in the poloidal mode m = 1 and horizontal positional correction was required when the RMP was operated in the m = 2 mode. When compensation was applied to the position control system, correction of plasma position was successfully achieved, as observed from soft X-ray imaging, as well as from the evolution of the current of the horizontal and vertical fields.

Association of genotypes of rs671 withinALDH2 with risk for gastric cardia adenocarcinoma in the Chinese Han population in high- and low-incidence areas.

OBJECTIVE: : This study aimed to determine if gastric cardia adenocarcinoma (GCA) risk was associated with the lys (A or *2) allele at the rs671 (glu504lys) polymorphism within the aldehyde dehydrogenase 2 (ALDH2) gene in a Chinese Han population. We also aimed to investigateALDH2 genotypic distributions between subjects from high- and low-incidence areas for both GCA and esophageal squamous cell carcinoma (ESCC). METHODS: : We designed a case-control study including 2,686 patients with GCA and 3,675 control subjects from high- and low-incidence areas for both GCA and ESCC in China. TaqMan allele discrimination assay was used to genotype the rs671 polymorphism.χ2 test and binary logistic regression analysis were used to estimate the odds ratios for the development of GCA, and multivariate ordinal logistic regression was used to analyzeALDH2 genotypic distributions among different groups. RESULTS: : Compared withALDH2*1/*1 homozygotes,ALDH2*1/*2 andALDH2*2/*2 carriers did not increase the risk for GCA in the Chinese Han population (P>0.05). Interestingly, the ratio of homozygous or heterozygousALDH2 *2 carriers in high-incidence areas for both GCA and ESCC was lower than that in low-incidence areas (P<0.001). CONCLUSIONS: : Genotypes of rs671 atALDH2 may not increase GCA susceptibility in Chinese Han populations. In addition, theALDH2 genotypic distribution differs between Chinese Han populations from high- and low-incidence areas for both GCA and ESCC. Our findings may shed light on the possible genetic mechanism for the dramatic geographic differences of GCA occurrence in China.

Upgrade of the Mirnov probe arrays on the J-TEXT tokamak.

The magnetic diagnostic of Mirnov probe arrays has been upgraded on the J-TEXT tokamak to measure the magnetohydrodynamic instabilities with higher spatial resolution and better amplitude-frequency characteristics. The upgraded Mirnov probe array contains one poloidal array with 48 probe modules and two toroidal arrays with 25 probe modules. Each probe module contains two probes which measure both the poloidal and the radial magnetic fields (Bp and Br). To ensure that the Mirnov probe possess better amplitude-frequency characteristics, a novel kind of Mirnov probe made of low temperature co-fired ceramics is utilized. The parameters and frequency response of the probe are measured and can meet the experiment requirement. The new Mirnov arrays have been normally applied for a round of experiments, including the observation of tearing modes and their coupling as well as high frequency magnetic perturbation due to the Alfvén eigenmode. In order to extract useful information from raw signals, visualization processing methods based on singular value decomposition and cross-power spectrum are applied to decompose the coupled modes and to determine the mode number.

Breakdown assisted by a novel electron drift injection in the J-TEXT tokamak.

A novel electron drift injection (EDI) system aiming to improve breakdown behavior has been designed and constructed on the Joint Texas EXperiment Tokamak Tokamak. Electrons emitted by the system undergo the E×B drift, ∇B drift and curvature drift in sequence in order to traverse the confining magnetic field. A local electrostatic well, generated by a concave-shaped plate biased more negative than the cathode, is introduced to interrupt the emitted electrons moving along the magnetic field line (in the parallel direction) in an attempt to bring an enhancement of the injection efficiency and depth. A series of experiments have demonstrated the feasibility of this method, and a penetration distance deeper than 9.5 cm is achieved. Notable breakdown improvements, including the reduction of breakdown delay and average loop voltage, are observed for discharges assisted by EDI. The lower limit of successfully ionized pressure is expanded.

Identification of a DNA methylome profile of esophageal squamous cell carcinoma and potential plasma epigenetic biomarkers for early diagnosis.

DNA methylation is a critical epigenetic mechanism involved in key cellular processes. Its deregulation has been linked to many human cancers including esophageal squamous cell carcinoma (ESCC). This study was designed to explore the whole methylation status of ESCC and to identify potential plasma biomarkers for early diagnosis. We used Infinium Methylation 450k array to analyze ESCC tissues (n = 4), paired normal surrounding tissues (n = 4) and normal mucosa from healthy individuals (n = 4), and combined these with gene expression data from the GEO database. One hundred and sixty eight genes had differentially methylated CpG sites in their promoter region and a gene expression pattern inverse to the direction of change in DNA methylation. These genes were involved in several cancer-related pathways. Three genes were validated in additional 42 ESCC tissues and paired normal surrounding tissues. The methylation frequency of EPB41L3, GPX3, and COL14A1 were higher in tumor tissues than in normal surrounding tissues (P < 0.017). The higher methylation frequency of EPB41l3 was correlated with large tumor size (P = 0.044) and advanced pT tumor stage (P = 0.001). The higher methylation frequency of GPX3 and COL14A1 were correlated with advanced pN tumor stage (P = 0.001 and P < 0.001). The methylation of EPB41L3, GPX3, and COL14A1 genes were only found in ESCC patients' plasma, but not in normal individuals upon testing 42 ESCC patients and 50 healthy individuals. Diagnostic sensitivity was increased when methylation of any of the 3 genes were counted (64.3% sensitivity and 100% specificity). These differentially methylated genes in plasma may be used as biomarkers for early diagnosis of ESCC.

miR-145 inhibits proliferation and invasion of esophageal squamous cell carcinoma in part by targeting c-Myc.

BACKGROUND: Accumulating evidence has shown that microRNAs (miRNAs) are aberrantly expressed in human esophageal cancer and crucial to tumorigenesis. Herein, we identified the role of miR-145 in esophageal squamous cell carcinoma (ESCC) development in vitro and in vivo. MATERIAL AND METHODS: miR-145 expression was investigated in 40 ESCC samples as well as 5 ESCC cell lines by real-time polymerase chain reaction. Crystal violet and transwell assays were conducted to explore the effects of miR-145 on the proliferation and invasion of human ESCC cell lines, respectively. The impact of overexpression of miR-145 on putative target c-Myc was subsequently confirmed via Western blot. RESULTS: miR-145 expression was frequently downregulated in ESCC specimens and cell lines compared with adjacent normal tissues (p < 0.05). Overexpression of miR-145 suppressed (p < 0.05) ESCC cell proliferation and invasion, as well as the growth of xenograft tumors in mice. Overexpression of miR-145 significantly decreased (p < 0.05) the protein level of c-Myc which has previously been identified as a direct target of miR-145. CONCLUSION: Our results demonstrate that overexpression of miR-145 inhibits tumor growth in part by targeting c-Myc. Our findings revealed that miR-145 may act as a tumor suppressor in ESCC, and its dysregulation may be involved in the initiation and development of human ESCC.

Image quality assessment by visual gradient similarity.

A full-reference image quality assessment (IQA) model by multiscale visual gradient similarity (VGS) is presented. The VGS model adopts a three-stage approach: First, global contrast registration for each scale is applied. Then, pointwise comparison is given by multiplying the similarity of gradient direction with the similarity of gradient magnitude. Third, intrascale pooling is applied, followed by interscale pooling. Several properties of human visual systems on image gradient have been explored and incorporated into the VGS model. It has been found that Stevens' power law is also suitable for gradient magnitude. Other factors such as quality uniformity, visual detection threshold of gradient, and visual frequency sensitivity also affect subjective image quality. The optimal values of two parameters of VGS are trained with existing IQA databases, and good performance of VGS has been verified by cross validation. Experimental results show that VGS is competitive with state-of-the-art metrics in terms of prediction precision, reliability, simplicity, and low computational cost.

Fast tree search for a triangular lattice model of protein folding.

Using a triangular lattice model to study the designability of protein folding, we overcame the parity problem of previous cubic lattice model and enumerated all the sequences and compact structures on a simple two-dimensional triangular lattice model of size 4+5+6+5+4. We used two types of amino acids, hydrophobic and polar, to make up the sequences, and achieved 2(23)+2(12) different sequences excluding the reverse symmetry sequences. The total string number of distinct compact structures was 219,093, excluding reflection symmetry in the self-avoiding path of length 24 triangular lattice model. Based on this model, we applied a fast search algorithm by constructing a cluster tree. The algorithm decreased the computation by computing the objective energy of non-leaf nodes. The parallel experiments proved that the fast tree search algorithm yielded an exponential speed-up in the model of size 4+5+6+5+4. Designability analysis was performed to understand the search result.