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Abstract Background To explore the pulmonary-vascular-stump filling-defect on CT and investigate its association with cancer progression. Methods Records in our institutional database from 2018 to 2022 were retrospectively analyzed to identify filling-defects in the pulmonary-vascular-stump after lung cancer resection and collect imaging and clinical data of patients. Results Among the 1714 patients analyzed, 95 cases of filling-defects in the vascular stump after lung cancer resection were identified. After excluding lost-to-follow-up cases, a total of 77 cases were included in the final study. Morphologically, the filling-defects were dichotomized as 46 convex-shape and 31 concave-shape cases. Concave defects exhibited a higher incidence of increase compared to convex defects (51.7% v. 9.4%, P = 0.001). Among 61 filling defects in the pulmonary arterial stump, four (6.5%) increasing concave defects showed the nuclide concentration on PET and extravascular extension. The progression-free survival (PFS) time differed significantly among the concave, convex, and non-filling-defect groups (log-rank P

Most existing carbon emission management is based on macro data statistics, representing carbon emissions generated at the production side by static carbon emissions. It is not easy to describe the transfer and apportionment of carbon emissions. This paper studies the relationship between inter-regional power flow and carbon emission flow based on the theory of carbon emission flow of power system. It simplifies the power system in the region, improves the carbon emission flow index, defines the green electricity distribution factor, establishes the regional carbon emission flow calculation method and the carbon emission flow distribution factor analyzes the correlation between the inter-regional carbon emission flow. Finally, taking a Chinese province as an example, the carbon emission flow distribution and green power distribution between provincial municipalities and outward power coupling to other provinces is calculated to verify the method’s feasibility. The calculation results clearly describe the carbon emission levels of the regional power systems and the distribution of carbon emission flow in the province and analyze the impact of different power generation structures on the distribution of regional carbon emission flow and the contribution of green power. It provides a reference basis for regional emission reduction planning and new energy site selection.

Abstract Background The cellular origin of hypopharyngeal diseases is crucial for further diagnosis and treatment, and the microenvironment in tissues may also be associated with specific cell types at the same time. Normal adjacent tissues (NATs) of hypopharyngeal carcinoma differ from non-tumor-bearing tissues, and can influenced by the tumor. However, the heterogeneity in kinds of disease samples remains little known, and the transcriptomic profile about biological information associated with disease occurrence and clinical outcome contained in it has yet to be fully evaluated. For these reasons, we should quickly investigate the taxonomic and transcriptomic information of NATs in human hypopharynx. Results Single-cell suspensions of normal adjacent tissues (NATs) of hypopharyngeal carcinoma were obtained and single-cell RNA sequencing (scRNA-seq) was performed. We present scRNA-seq data from 39,315 high-quality cells in the hypopharyngeal from five human donors, nine clusters of normal adjacent human hypopharyngeal cells were presented, including epithelial cells, endothelial cells (ECs), mononuclear phagocyte system cells (MPs), fibroblasts, T cells, plasma cells, B cells, mural cells and mast cells. Nonimmune components in the microenvironment, including epithelial cells, endothelial cells, fibroblasts and the subpopulations of them were performed. Conclusions Our data provide a solid basis for the study of single-cell landscape in human normal adjacent hypopharyngeal tissues biology and related diseases.

Abstract Background The combinations of PD-1 inhibitors with paclitaxel/cisplatinum (PD-1 + TP) and fluoropyrimidine/cisplatinum (PD-1 + FP) both have been shown to improve overall survival (OS) and progression-free survival (PFS) in patients with previously untreated, advanced esophageal squamous cell carcinoma (ESCC). However, there is no consensus on which chemotherapy regimen combined with PD-1 has better efficacy. To deal with this important issue in the first-line treatment of patients with ESCC, a network meta-analysis (NMA) was performed. Methods Data were collected from eligible studies searched in Medline, Web of Science, PubMed, the Cochrane Library and Embase. The pooled hazard ratio (HR) for the OS, and PFS, odds ratio (OR) for the objective response rate (ORR) and ≥ 3 grade treatment-related adverse events (≥ 3TRAEs) were estimated to evaluate the efficacy of PD-1 inhibitors combined with TP or FP. Results Five RCTs and one retrospective study involving 3685 patients and evaluating four treatments were included in this NMA. Compared to other treatments, PD-1 + TP was better. For the PFS, the HRs for PD-1 + TP compared to PD-1 + FP, TP and FP were 0.59 (0.44, 0.80), 0.56 (0.51, 0.61) and 0.45 (0.37, 0.56) respectively. For the OS, PD-1 + TP was also a better treatment compared to other treatments. The HRs were 0.74 (0.56, 0.96), 0.64 (0.57, 0.71), 0.53 (0.43, 0.67) respectively. For the ORR, there was no significant difference between PD-1 + TP and PD-1 + FP, and the ORs were 1.2 (0.69, 2.11). Compare with TP and FP, PD-1 + TP had an obvious advantage, ORs were 2.5 (2.04, 3.04) and 2.95 (1.91, 4.63). For ≥ 3TRAEs, PD-1 + TP compared to other treatments, ORs were 1.34 (0.74, 2.46) and 1.13 (0.92, 1.38) and 2.23 (1.35, 3.69). Conclusion PD-1 + TP significantly improved both PFS and OS compared to PD-1 + FP. Taking into account both efficacy and safety, PD-1 + TP may be a superior first-line treatment option for ESCC.

Most space shuttle fuel tanks use a center column to hold the Propellant Management Device (PMD). This paper analyzes the gas–liquid interface state in the tanks with a central column during microgravity experiments conducted in the Chinese Space Station. It launches an extended study to investigate the gas–liquid interface state under different gravity conditions. Using the perturbation method and boundary layer theory, we numerically calculated the morphology of the gas–liquid interface under varying gravity conditions based on the Young–Laplace equation. The results were then compared to those obtained from existing commercial software and were found to be consistent. Based on this, the study develops two types of calculation procedures. The first procedure generates the corresponding shape of the liquid surface by inputting the height of the liquid surface endpoints and the gravity level. The second procedure is based on the targeting method and generates the corresponding liquid surface by inputting the volume of the liquid in the storage tank and the gravity level. The procedures were used to analyze the variation of gas–liquid interface properties under different gravity conditions. This study offers theoretical support for liquid management in aerospace engineering fuel tanks.

Temporomandibular joint discs (TMJ discs) are unable to repair themselves in disease states, while induced stem cell differentiation is a common method to repair tissue defects. Nowadays, kinds of stem cells are attempted for tissue regeneration of TMJ disc, but these methods have several downsides, which limit their wide application. The proliferation and differentiation ability of human induced pluripotent stem cells (hiPSC) provides a new research direction for TMJ disc tissue regeneration. In this study, we investigated the feasibility of induced differentiation of hiPSC into TMJ disc cells in vitro and the differentiation efficiency of different methods to clarify the possibility and conditions of hiPSC application in TMJ disc tissue engineering. We collected sheep TMJ disc cells cultures for adding in hiPSC culture environment and treated hiPSC by both direct induction and Transwell co-culture for 7 days, 14 days and 21 days. The secretion of extracellular matrix in TMJ disc cells was detected by Sirius Red and Safranin O staining. Collagen Ⅰ and Collagen Ⅱ were qualitatively detected by immunohistochemical staining. The expression of extracellular matrix genes (type I collagen (COL1A1), type II collagen(COL2), glycosaminoglycan (GAG)), chondrogenic differentiation gene SOX9 and pluripotency gene OCT4 were detected by RT-qPCR. Our results showed that hiPSC had the ability to differentiate to TMJ disc cells by direct induction in TMJ disc cell culture medium and by Transwell co-culture method. The highest degree of differentiation was observed after 14 days of direct induction, while Transwell co-culture showed significant differentiation at different times and with different major directions. Meanwhile, Transwell co-culture not only differentiates hiPSC but also promotes the growth and proliferation of TMJ disc cells. Our study is valuable to investigate the possibility of differentiation of hiPSC toward TMJ disc cells and to determine the time of differentiation. It provides new ideas for the selection of seed cells for TMJ disc tissue engineering.

Abstract Head neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors which ranks the sixth incidence in the world. Although treatments for HNSCC have improved significantly in recent years, its recurrence rate and mortality rate remain high. Myosin genes have been studied in a variety of tumors, however its role in HNSCC has not been elucidated. GSE58911 and GSE30784 gene expression profile analysis were performed to detect significantly dys-regulated myosin genes in HNSCC. The Cancer Genome Atlas (TCGA) HNSCC database was used to verify the dys-regulated myosin genes and study the relationship between these genes and prognosis in HNSCC. The results showed that MYL1, MYL2, MYL3, MYH2, and MYH7 were down-regulated, while MYH10 was up-regulated in patients with HNSCC. Interestingly, MYL1, MYL2, MYH1, MYH2, and MYH7 were shown to be unfavorable prognostic markers in HNSCC. It is also worth noting that MYL1 was a specific unfavorable prognostic biomarker in HNSCC. MYL1, MYL2, MYL3, MYH2, MYH7, and MYH10 promoted CD4 + T cells activation in HNSCC. MYL1 was proved to be down-regulated in HNSCC tissues compared to normal tissues at protein levels. MYL1 overexpression had no effect on proliferation, but significantly promoted migration of Fadu cells. MYL1 increased EGF and EGFR protein expression levels. Moreover, there is a positive correlation between MYL1 expression and Tcm CD8 cells, Tcm CD4 + cells, NK cells, Mast cells, NKT cells, Tfh cells and Treg cells in HNSCC. Overall, MYL1 facilitates tumor metastasis and correlates with tumor immune infiltration in HNSCC and these effects may be associated with the EGF/EGFR pathway.

Abstract Objective This study aims to compare the efficacy of intra-articular injections of hyaluronic acid (HA), platelet-rich plasma (PRP), and platelet-rich fibrin (PRF) for treating temporomandibular disorders (TMDs) and summarize their mechanisms of action. Methods Randomized controlled trials (RCTs) published until November 13, 2021, were identified using electronic and manual searches. Each study was evaluated for the risk of bias using the Cochrane risk of bias tool. The studies found via searches were categorized by follow-up time (1, 3, or 6 months). Evidence quality was graded according to the GRADE system. Results Twelve RCTs were included that involved 421 patients with TMD. The network meta-analysis showed that all treatment groups improved compared to the placebo groups in terms of pain and maximal mouth opening (MMO). For pain evaluated via the visual analog scale, PRF exhibited better analgesic effects than PRP or HA after 1 and 3 months. PRP appeared to be more effective than PRF was after 6 months but there were no statistically significant differences between the two. For MMO, the effect of PRP was superior to those of PRF and HA after 1 month. However, after 3 and 6 months, PRF provided more encouraging results in improving MMO. Conclusion PRP and PRF exhibited similar short-term efficacy in treating TMD, while PRF was more advantageous in terms of long-term efficacy. Therefore, PRF was recommended for treating TMD.

The 20th National Congress of the Communist Party of China and the 14th Five Year Plan for Education Informatization focus on digital technology and intelligent learning and implement innovation-driven education environment reform. An immersive virtual reality (IVR) environment has both immersive and interactive characteristics, which are an important way of virtual learning and are also one of the important ways in which to promote the development of smart education. Based on the above background, this article proposes an intelligent analysis system for Teaching and Learning Cognitive engagement in an IVR environment based on computer vision. By automatically analyzing the cognitive investment of students in the IVR environment, it is possible to better understand their learning status, provide personalized guidance to improve learning quality, and thereby promote the development of smart education. This system uses Vue (developed by Evan You, located in Wuxi, China) and ECharts (Developed by Baidu, located in Beijing, China) for visual display, and the algorithm uses the Pytorch framework (Developed by Facebook, located in Silicon Valley, CA, USA), YOLOv5 (Developed by Ultralytics, located in Washington, DC, USA), and the CRNN model (Convolutional Recurrent Neural Network) to monitor and analyze the visual attention and behavioral actions of students. Through this system, a more accurate analysis of learners’ cognitive states and personalized teaching support can be provided for the education field, providing certain technical support for the development of smart education.

ABSTRACT: With the advent of the “Big Data Era”, improving data storage density and computation speed has become more and more urgent due to the rapid growth in different types of data. Flash memory with a floating gate (FG) structure is attracting great attention owing to its advantages of miniaturization, low power consumption and reliable data storage, which is very effective in solving the problems of large data capacity and high integration density. Meanwhile, the FG memory with charge storage principle can simulate synaptic plasticity perfectly, breaking the traditional von Neumann computing architecture and can be used as an artificial synapse for neuromorphic computations inspired by the human brain. Among many candidate materials for manufacturing devices, van der Waals (vdW) materials have attracted widespread attention due to their atomic thickness, high mobility, and sustainable miniaturization properties. Owing to the arbitrary stacking ability, vdW heterostructure combines rich physics and potential 3D integration, opening up various possibilities for new functional integrated devices with low power consumption and flexible applications. This paper provides a comprehensive review of memory devices based on vdW materials with FG structure, including the working principles and typical structures of FG structure devices, with a focus on the introduction of various high-performance FG memories and their versatile applications in neuromorphic computing. Finally, the challenges of neuromorphic devices based on FG structures are also discussed. This review will shed light on the design and fabrication of vdW material-based memory devices with FG engineering, helping to promote the development of practical and promising neuromorphic computing.

The non-intrusive appliance load monitoring (NILM) decomposes the total power consumption of a power system into its contributing appliances. Previous studies only considered using the total power consumption information of appliances to decompose the load consumption. Besides the total electricity consumption, there is also important information such as current, voltage, and time in the total electricity consumption data, which can be used to analyze the load consumption information. Therefore, we proposed a sequence-to-sequence network enhanced by an attention mechanism, which effectively integrated the external features besides the total electricity consumption in grid data. Finally, we applied and evaluated the proposed model on the electricity consumption data of a gas station with 12 appliances, and our model achieved a 90.5% accuracy in load decomposition. Our solution provides a new solution on the application of NILM in the industrial field and helps to manage energy more rationally.

In this study, we introduce a novel framework for the semantic segmentation of point clouds in autonomous driving scenarios, termed PVI-Net. This framework uniquely integrates three different data perspectives—point clouds, voxels, and distance maps—executing feature extraction through three parallel branches. Throughout this process, we ingeniously design a point cloud–voxel cross-attention mechanism and a multi-perspective feature fusion strategy for point images. These strategies facilitate information interaction across different feature dimensions of perspectives, thereby optimizing the fusion of information from various viewpoints and significantly enhancing the overall performance of the model. The network employs a U-Net structure and residual connections, effectively merging and encoding information to improve the precision and efficiency of semantic segmentation. We validated the performance of PVI-Net on the SemanticKITTI and nuScenes datasets. The results demonstrate that PVI-Net surpasses most of the previous methods in various performance metrics.

BackgroundKnowledge graph–based recommender systems offer the possibility of meeting the personalized needs of people with dementia and their caregivers. However, the usability of such a recommender system remains unknown. ObjectiveThis study aimed to evaluate the usability of a knowledge graph–based dementia care intelligent recommender system (DCIRS). MethodsWe used a convergent mixed methods design to conduct the usability evaluation, including the collection of quantitative and qualitative data. Participants were recruited through social media advertisements. After 2 weeks of DCIRS use, feedback was collected with the Computer System Usability Questionnaire and semistructured interviews. Descriptive statistics were used to describe sociodemographic characteristics and questionnaire scores. Qualitative data were analyzed systematically using inductive thematic analysis. ResultsA total of 56 caregivers were recruited. Quantitative data suggested that the DCIRS was easy for caregivers to use, and the mean questionnaire score was 2.14. Qualitative data showed that caregivers generally believed that the content of the DCIRS was professional, easy to understand, and instructive, and could meet users’ personalized needs; they were willing to continue to use it. However, the DCIRS also had some shortcomings. Functions that enable interactions between professionals and caregivers and that provide caregiver support and resource recommendations might be added to improve the system’s usability. ConclusionsThe recommender system provides a solution to meet the personalized needs of people with dementia and their caregivers and has the potential to substantially improve health outcomes. The next step will be to optimize and update the recommender system based on caregivers’ suggestions and evaluate the effect of the application.

Free-edge effect is one of the factors affecting the mechanical properties of three-dimensional woven composites under tensile load. However, current research is relatively poorly understood regarding the effect of free-edge on the stiffness and strength of the material. This paper aims at examining the influence of free-edge effect on the mechanical properties of 3D woven composites under tension through experimental and simulation methods. The three-dimensional digital image correlation (DIC) technique is used to collect the full-field strains on the specimen surface during the test, and the stress-strain differences in different regions in the width direction are analyzed, and the overlap of the curves in each region is found to be high, indicating that the boundary effect has a small influence on the tensile properties of 3D woven composites. Experimental studies are conducted on specimens of different widths (within the range of 15–20 mm), and the results indicate that the differences in mechanical properties of 3D woven composites under tension loading in this width range are not significant. A progressive damage finite element model is developed for calculation and compared with experimental results. It is found that the tensile properties of the material decreased when the width of the specimen is less than twice the size of the single cell. This study can provide certain data support for the study of the mechanical properties of 3D woven composites and enable the subsequent more in-depth study to provide a certain foundation.

BackgroundHuman hypopharygeal squamous cell carcinoma (HSCC) is a common head and neck cancer with a poor prognosis in advanced stages. The occurrence and development of tumor is the result of mutual influence and co-evolution between tumor cells and tumor microenvironment (TME). Tumor immune microenvironment (TIME) refers to the immune microenvironment surrounding tumor cells. Studying TIME in HSCC could provide new targets and therapeutic strategies for HSCC.MethodsWe performed single-cell RNA sequencing (scRNA-seq) and analysis of hypopharyngeal carcinoma, paracancerous, and lymphoid tissues from five HSCC patients. Subdivide of B cells, T cells, macrophages cells, and monocytes and their distribution in three kinds of tissues as well as marker genes were analyzed. Different genes of IGHG1 plasma cells and SPP1+ macrophages between HSCC tissues, adjacent normal tissues and lymphatic tissues were analyzed. Additionally, we studied proliferating lymphocytes, T cells exhaustion, and T cell receptor (TCR) repertoire in three kinds of tissues.ResultsTranscriptome profiles of 132,869 single cells were obtained and grouped into seven cell clusters, including epithelial cells, lymphocytes, mononuclear phagocytics system (MPs), fibroblasts, endothelial cells (ECs), plasmacytoid dendritic cells (pDCs), and mast cells. Tumor metastasis occurred in three lymphoid tissues. Four distinct populations were identified from lymphocytes, including B cells, plasma cells, T cells and proliferating lymphocytes. We found IGHA1 and IGHG1 specific plasma cells significantly overexpressed in HSCC tissues compared with normal hypopharygeal tissues and lymphatic tissues. Five distinct populations from MPs were identified, including macrophages, monocytes, mature dendritic cells (DCs), Type 1 conventional dendritic cells (cDC1) and Type 2 conventional dendritic cells (cDC2). SPP1+ macrophages were significantly overexpressed in HSCC tissues and lymphatic tissues compared with normal hypopharygeal tissues, which are thought to be M2-type macrophages. Exhaustion of CD8+ Teff cells occurred in HSCC tissues. At last, we verified that IgA and IgG1 protein expression levels were significantly up-regulated in HSCC tissues compared to adjacent normal tissues.ConclusionOverall, this study revealed TIME in HSCC and lymphatic metastasis, and provided potential therapeutic targets for HSCC.

Objective: To identify the status of knowledge, attitude, and behaviour toward evidence-based practice (EBP) among Chinese psychiatric nurses, and to examine the influencing factors of EBP behaviour. Methods: We utilised a cross-sectional design. A total of 923 psychiatric nurses from 168 hospitals in 27 provinces in the mainland of China participated in our survey. The EBP questionnaire, the barriers to research utilisation scale and the facilitators to research utilisation scale were used for data collection via WeChat group from July 2018 to April 2019. Multiple regression analysis was used to analyse the influencing factors of psychiatric nurses’ evidence-based practice behaviour. Results: The score of Chinese psychiatric nurses’ EBP attitude, behaviour and knowledge were 4.81 ± 1.34, 4.11 ± 1.36 and 3.53 ± 1.29, respectively. Multiple regression analysis showed that nurses’ EBP behaviour was mainly determined by knowledge and attitude, which together explained 61.8% of the variance. The two top barriers were the dimensions of presentation and research. Facilitators include managerial support, employing nurses with research skills as models and providing advanced education on evidence-based nursing. Conclusion: Psychiatric nurses have positive attitudes toward EBP, but their level of knowledge and behaviour is insufficient. Heavy workload, insufficient time, and a lack of knowledge and skills is the main barrier. Managerial support, employing nurses with research skills as models and providing advanced education are the main facilitators.

BackgroundHypopharyngeal squamous cell cancer (HSCC) is one of the most malignant tumors of the head and neck. It is not easy to detect in the early stage due to its hidden location; thus, lymph node metastasis is highly likely at diagnosis, leading to a poor prognosis. It is believed that epigenetic modification is related to cancer invasion and metastasis. However, the role of m6A-related lncRNA in the tumor microenvironment (TME) of HSCC remains unclear.MethodsThe whole transcriptome and methylation sequencing of 5 pairs of HSCC tissues and adjacent tissues were performed to identify the methylation and transcriptome profiles of lncRNAs. The biological significance of lncRNAs differentially expressing the m6A peak was analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. By constructing an m6A lncRNA-microRNA network, the mechanism of m6A lncRNAs in HSCC was analyzed. The relative expression levels of selected lncRNAs were examined by quantitative polymerase chain reaction. The CIBERSORT algorithm was used to evaluate the relative proportion of immune cell infiltration in HSCC and paracancerous tissues.ResultsBased on an in-depth analysis of the sequencing results, 14413 differentially expressed lncRNAs were revealed, including 7329 up-regulated and 7084 down-regulated lncRNAs. Additionally, 4542 up-methylated and 2253 down-methylated lncRNAs were detected. We demonstrated methylation patterns and gene expression profiles of lncRNAs of HSCC transcriptome. In the intersection analysis of lncRNAs and methylated lncRNAs, 51 lncRNAs with up-regulated transcriptome and methylation and 40 lncRNAs with down-regulated transcriptome and methylation were screened, and significantly differentiated lncRNAs were further studied. In the immune cell infiltration analysis, B cell memory was significantly elevated in cancer tissue, while γδT cell amount was significantly decreased.Conclusionm6A modification of lncRNAs might be involved in HSCC pathogenesis. Infiltration of immune cells in HSCC might provide a new direction for its treatment. This study provides new insights for exploring the possible HSCC pathogenesis and searching for new potential therapeutic targets.

Abstract Background Advanced gastric cancer (AGC) is a disease with poor prognosis due to the current lack of effective therapeutic strategies. Immune checkpoint blockade treatments have shown effective responses in patient subgroups but biomarkers remain challenging. Traditional classification of gastric cancer (GC) is based on genomic profiling and molecular features. Therefore, it is critical to identify the immune-related subtypes and predictive markers by immuno-genomic profiling. Methods Single-sample gene-set enrichment analysis (ssGSEA) and ESTIMATE algorithm were used to identify the immue-related subtypes of AGC in two independent GEO datasets. Weighted gene co-expression network analysis (WGCNA) and Molecular Complex Detection (MCODE) algorithm were applied to identify hub-network of immune-related subtypes. Hub genes were confirmed by prognostic data of KMplotter and GEO datasets. The value of hub-gene in predicting immunotherapeutic response was analyzed by IMvigor210 datasets. MTT assay, Transwell migration assay and Western blotting were performed to confirm the cellular function of hub gene in vitro. Results Three immune-related subtypes (Immunity_H, Immunity_M and Immunity_L) of AGC were identified in two independent GEO datasets. Compared to Immunity_L, the Immuntiy_H subtype showed higher immune cell infiltration and immune activities with favorable prognosis. A weighted gene co-expression network was constructed based on GSE62254 dataset and identified one gene module which was significantly correlated with the Immunity_H subtype. A Hub-network which represented high immune activities was extracted based on topological features and Molecular Complex Detection (MCODE) algorithm. Furthermore, ADAM like decysin 1 (ADAMDEC1) was identified as a seed gene among hub-network genes which is highly associated with favorable prognosis in both GSE62254 and external validation datasets. In addition, high expression of ADAMDEC1 correlated with immunotherapeutic response in IMvigor210 datasets. In vitro, ADAMDEC1 was confirmed as a potential protein in regulating proliferation and migration of gastric cancer cell. Deficiency of ADAMDEC1 of gastric cancer cell also associated with high expression of PD-L1 and Jurkat T cell apoptosis. Conclusions We identified immune-related subtypes and key tumor microenvironment marker in AGC which might facilitate the development of novel immune therapeutic targets.

Abstract Hypopharyngeal squamous cell carcinoma (HSCC) accounts 95% of hypopharyngeal cancer, which is characterized by high early metastasis rate and poor prognosis. It is reported that circular RNA is involved in the occurrence and development of cancer; however, the role of circRNA in hypopharyngeal cancer has little been investigated. We performed hypopharyngeal carcinoma circRNA microarray and qRT-PCR verification. The results showed circ_0058106 expression level was significantly upregulated in tumor tissues than in corresponding normal tissues. We found that circ_0058106 upregulation promoted proliferation, migration and invasion of HSCC cells, while knockdown of circ_0058106 inhibited proliferation, migration and invasion of HSCC cells both in vitro and in vivo. Bioinformatics predicted circ_0058106 may interact with miR-185-3p. We verified circ_0058106 directly bound miR-185-3p and downregulated miR-185-3p expression by using dual-luciferase reporter assay and qRT-PCR. Moreover, we proved circ_0058106 promoted HSCC cells tumorigenesis and EMT process by regulating Wnt2b/β-catenin/c-Myc pathway via miR-185-3p. In conclusion, our findings firstly confirmed the carcinogenic effect of circ_0058106 in promoting HSCC cells tumorigenesis, metastasis, invasion and EMT process by regulating Wnt2b/β-catenin/c-Myc pathway through sponging miR-185-3p, indicating that circ_0058106 may be a new therapeutic target and prognostic marker for HSCC.

Transcranial magnetic stimulation (TMS) modulation over the cerebellum, primary motor cortex, and supplementary motor cortex individually can improve the balance function of patients with stroke. However, whether their combination could have a better balance modulation effect is uncertain. Therefore, we hypothesized that performing TMS over a combination of these targets can regulate the balance function of patients with stroke. We compared the effects of one-session TMS on eye-open and eye-closed balance conditions in patients with stroke, using different target pairs of unilateral cerebellar (CB-single), cerebellar–primary motor cortex (CB-M1), and cerebellar–supplementary motor area (CB-SMA) targets. A total of 31 patients with stroke were enrolled and randomly divided into three groups to receive single sessions of intermittent theta burst stimulation each. Functional near-infrared spectrum data on resting and standing task states (eye-open and eye-closed) and center of pressure parameters (eye-open and eye-closed) were collected before and after the intervention. Compared with the results in the CB-single group, five intergroup differences in the changes in the center of pressure parameters in the CB-M1 group and two significant differences in the CB-SMA group were observed after one session of intermittent theta burst stimulation. In the CB-SMA group, 12 out of the 14 parameters improved significantly in the EC condition after the intervention. Meanwhile, the functional near-infrared spectrum results showed that the CB-SMA group exhibited a significant inhibitory pattern in the resting-state functional connectivity, which was not observed in the other two groups. In conclusion, we believe that paired targeting of the CB-SMA can reshape the brain network and improve the balance function of patients with stroke.

San Wei Tan Xiang (SWTX) capsule has been proved to have significant curative effect on depression in clinic and have less side effects in the treatment. Based on network pharmacology, the mechanism of depression treatment by SWTX capsule was studied. The related targets of depression were collected in the GeneCards database. The active ingredients and potential target genes of SWTX were screened out in the TCMSP database, and the chemical formulas of the active ingredients were confirmed in the PubChem database. As a result, Oleic, quercetin, and beta-sitosterol were screened to be the main ingredients correlated with depression. And NCOA2, GABRA1, and RXRA were analyzed to be the main targets of SWTX on depression. Moreover, the results of molecular docking showed that Oleic and quercetin successfully docked with RXRA. Taken together, using the method of network pharmacology, the main active ingredients of SWTX, and its target points and related pathways on depression are initially revealed, which provides a new idea for depression treatment.

Hypopharyngeal squamous cell carcinoma (HSCC) is a kind of head and neck squamous cell carcinoma (HNSCC) with poor prognosis. Metabolic reprogramming may regulate the tumor microenvironment (TME) by adapting quickly to cellular stress and regulating immune response, but its role in HSCC has not been reported. We used the nCounter® Metabolic Pathways Panel to investigate metabolic reprogramming, cellular stress, and their relationship in HSCC tissues and adjacent normal tissues. Metabolism-related pathways nucleotide synthesis and glycolysis pathways were significantly upregulated, while amino acid synthesis and fatty acid oxidation pathways were significantly downregulated in HSCC tissues compared to adjacent normal tissues. There is a significant correlation between metabolism-related pathways and cellular stress pathways. Enrichment of immune cell and tumor infiltrating lymphocyte (TIL) analysis showed changes in immune responses between HSCC tissues and adjacent normal tissues. Overall survival analysis showed that upregulated genes CD276, LDHB, SLC3A2, EGFR, SLC7A5, and HPRT1 are potential unfavorable prognostic markers in HNSCC, while downregulated genes EEA1, IDO1, NCOA2, REST, CCL19, and ALDH2 are potential favorable prognostic markers in HNSCC. Moreover, metabolism-related genes IDO1, ALDH2, NCOA2, SLC7A5, SLC3A2, LDHB, and HPRT1 are correlated with immune infiltrates in HNSCC. These results suggest that metabolic reprogramming occurs and correlates with cellular stress and immune response in HSCC, which may help researchers understand mechanisms of metabolic reprogramming and develop effective immunotherapeutic strategies in HNSCC.

Composite laminated bolted joints are increasingly used in the aerospace industry, and most researchers are involved in the study of the failure behavior of composite bolted joints’ structures. Because of the complexity and stability of the structure, precisely predicting the damage evolution and failure behavior of the composite laminated bolted joint becomes rather difficult. In this paper, an asymptotic damage model is proposed to predict the failure behavior of the composite bolted joint structure. The model is based on the frame of mainstream criteria and some improvements are made to adapt to the particularity of composite laminated bolted joints. Combining the damage model with the finite element method, the failure behavior of single-lap and double-lap bolted joint structures are predicted and analyzed. In order to guarantee the reliability of the model, the corresponding experimental study is conducted, and the results show that the simulation curve and the experimental data are in good agreement. This damage model can further predict the failure behavior of various types of complex composite laminated bolted joints effectively.

This issue is a typical NP-hard problem for an unrelated parallel machine scheduling problem with makespan minimization as the goal and no sequence-related preparation time. Based on the idea of tabu search (TS), this paper improves the iterative greedy algorithm (IG) and proposes an IG-TS algorithm with deconstruction, reconstruction, and neighborhood search operations as the main optimization process. This algorithm has the characteristics of the strong capability of global search and fast speed of convergence. The warp knitting workshop scheduling problem in the textile industry, which has the complex characteristics of a large scale, nonlinearity, uncertainty, and strong coupling, is a typical unrelated parallel machine scheduling problem. The IG-TS algorithm is applied to solve it, and three commonly used scheduling algorithms are set as a comparison, namely the GA-TS algorithm, ABC-TS algorithm, and PSO-TS algorithm. The outcome shows that the scheduling results of the IG-TS algorithm have the shortest manufacturing time and good robustness. In addition, the production comparison between the IG-TS algorithm scheduling scheme and the artificial experience scheduling scheme for the small-scale example problem shows that the IG-TS algorithm scheduling is slightly superior to the artificial experience scheduling in both planning and actual production. Experiments show that the IG-TS algorithm is feasible in warp knitting workshop scheduling problems, effectively realizing the reduction of energy and the increase in efficiency of a digital workshop in the textile industry.

Abstract Background Epidermal growth factor receptor-tyrosinase kinase inhibitor (EGFR-TKI) resistance is the major obstacle in the treatment of lung adenocarcinoma (LUAD) patients harboring EGFR-sensitive mutations. However, the long non-coding RNAs (lncRNAs) related to EGFR-TKIs resistance and their functional mechanisms are still largely unknown. This study aimed to investigate the role and regulatory mechanism of lncRNA APCDD1L-AS1 in icotinib resistance of lung cancer. Methods Molecular approaches including qRT-PCR, MTT assay, colony formation, RNA interference and cell transfection, RNA immunoprecipitation (RIP), dual luciferase reporter assay, RNA fluorescence in situ hybridization, TUNEL assay, flow cytometry, immunoblotting, xenograft model and transcriptome sequencing were used to investigate the mechanism of APCDD1L-AS1 in icotinib resistance. Results A novel lncRNA, APCDD1L-AS1 was identified as the most significantly upregulated lncRNA in icotinib-resistant LUAD cells by the transcriptome sequencing and differential lncRNA expression analysis. We found that APCDD1L-AS1 not only promoted icotinib resistance, but also upregulated the protein expression level of EGFR. Mechanistically, APCDD1L-AS1 promoted icotinib resistance and EGFR upregulation by sponging with miR-1322/miR-1972/miR-324-3p to remove the transcription inhibition of SIRT5. Furthermore, SIRT5 elevated EGFR expression and activation by inhibiting the autophagic degradation of EGFR, finally promoting icotinib resistance. Consistently, the autophagy initiator rapamycin could decrease EGFR levels and increase the sensitivity of icotinib-resistant LUAD cells to icotinib. Conclusion APCDD1L-AS1 could promote icotinib resistance by inhibiting autophagic degradation of EGFR via the miR-1322/miR-1972/miR-324-3p-SIRT5 axis. The combination of autophagy initiator and EGFR-TKIs might serve as a potential new strategy for overcoming EGFR-TKIs resistance in LUAD patients.

Carbon source starvation can promote steel corrosion in the presence of a pure culture through extracellular electron transfer (EET). However, the impact of carbon source starvation on corrosion induced by mixed strains is still unknown. This work investigated the impact of carbon source starvation on EH40 steel corrosion in the presence of Desulfovibrio vulgaris and Pseudomonas aeruginosa, typical species of sulfate- and nitrate-reducing bacteria. It was found that the impact of carbon source starvation on corrosion depended on nitrate addition. When nitrate (5 g∙L−1 NaNO3) was not added, the corrosion was promoted by carbon source starvation. However, the corrosion was initially promoted by carbon source starvation, but later inhibited with nitrate addition. The corrosion behaviors in different systems were closely related to different numbers of the strains in biofilms and their metabolic activities, and the mechanisms were revealed.

In recent, neuromorphic computing has been proposed to simulate the human brain system to overcome bottlenecks of the von Neumann architecture. Memristors, considered emerging memory devices, can be used to simulate synapses and neurons, which are the key components of neuromorphic computing systems. To observe the resistive switching (RS) behavior microscopically and probe the local conductive filaments (CFs) of the memristors, conductive atomic force microscopy (CAFM) with the ultra-high resolution has been investigated, which could be helpful to understand the dynamic processes of synaptic plasticity and the firing of neurons. This review presents the basic working principle of CAFM and discusses the observation methods using CAFM. Based on this, CAFM reveals the internal mechanism of memristors, which is used to observe the switching behavior of memristors. We then summarize the synaptic and neuronal functions assisted by CAFM for neuromorphic computing. Finally, we provide insights into discussing the challenges of CAFM used in the neuromorphic computing system, benefiting the expansion of CAFM in studying neuromorphic computing-based devices.

Histone acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). It is associated with gene transcription and expression. 4-Phenylbutyric acid (4-PBA), an HDAC inhibitor (HDACi), can inhibit cancer cell proliferation by increasing the level of histone acetylation. However, 4-PBA did not show any efficacy in clinical trials. In this study, we found that 4-PBA induced epithelial–mesenchymal transition (EMT) in gastric cancer cell lines MGC-803 and BGC-823 with ectopic E-cadherin expression. Based on the expression profile microarray, IL-8 was the most significantly up-regulated gene by 4-PBA, and was selected for further investigation. Knockdown of IL-8 partially prevented 4-PBA-induced-EMT by blocking the activation of the downstream Gab2-ERK pathway. Furthermore, CHIP assay confirmed that acetyl-H3 directly combined with the promoter region of IL-8 to promote its transcription. Therefore, the results of this study demonstrated that 4-PBA-mediated inhibition of HDAC activity could induce EMT in gastric cancer cells via acetyl-histone-mediated IL-8 upregulation, and the downstream Gab2/ERK activation. These data indicated the possible reason for the failure of 4-PBA in clinical trials.

Point set registration is a key method in computer vision and pattern recognition. In this paper, the correntropy and bi-directional distance are introduced into registration framework and a new robust registration model for RGB-D data is proposed. Firstly, as registering point sets with smooth structure, such as surface or plane, is easy failed, the color and position information is fused to establish more precise correspondence between two RGB-D data sets. Secondly, to reduce the influence of noises and eliminate outliers, the registration model based on the maximum correntropy criterion is established. Thirdly, the bi-directional distance measurement is introduced into the registration framework to avoid the model being trapped into local extremum. In addition, to solve this new registration problem, a new iterative closest point (ICP) algorithm is proposed, which converges to the local optimal solution by iterations. In the experiments, the proposed algorithm achieves more robustness and precise registration results than other algorithms.

Automatic and accurate detection of chest X-ray lesion is a challenging task. In the chest X-ray image, the lesions are shown with blurred boundary contours, different sizes, variable shapes, uneven density, etc. Besides, the deep convolutional neural network (CNN) consists of traditional convolution units, which has the limitations of rectangular sampling. The CNN extracts difficultly the deformation and refined features of chest X-ray lesions. Because of these factors, the accuracy of the lesion detection algorithm is not high. To deal with problems, we propose the deformation and refined features based lesion detection on the chest X-ray algorithm called DRCXNet. Firstly, the deformable convolution with amplitude modulation (AMDCN) is built to extract the deformation features of the lesions on the chest X-ray. Secondly, to obtain the refined feature, the global features and local features are fused, which can enrich the feature space of the lesion. Thirdly, the pooling layer combines with the AMDCN and region proposal network to establish the deformable pooling layer, which enhances the model's sensitivity to the lesion location. During the training, the model is optimized by the improved regression loss function with a gradient control factor. On the public datasets RSNA and ChestX-ray8, the proposed method outperforms seven popular detection algorithms. The proposed method is a significant performance in both qualitative and quantitative experiments. Its comprehensive evaluation scores, sensitivity, precision, and the mean dice similarity coefficient are 0.866, 0.914, 0.836 and 0.859 respectively. The proposed algorithm achieves a very satisfactory result.

Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb. However, the molecular mechanism underlying its efficacy remains unclear. In this study, a middle cerebral artery occlusion (MCAO) rat model was produced by the suture method. Rats received modified constraint-induced movement therapy 1 hour a day for 14 consecutive days, starting from the 7th day after middle cerebral artery occlusion. Day 1 of treatment lasted for 10 minutes at 2 r/min, day 2 for 20 minutes at 2 r/min, and from day 3 onward for 20 minutes at 4 r/min. CatWalk gait analysis, adhesive removal test, and Y-maze test were used to investigate motor function, sensory function as well as cognitive function in rodent animals from the 1st day before MCAO to the 21st day after MCAO. On the 21st day after MCAO, the neurotransmitter receptor-related genes from both contralateral and ipsilateral hippocampi were tested by micro-array and then verified by western blot assay. The glutamate related receptor was shown by transmission electron microscopy and the glutamate content was determined by high-performance liquid chromatography. The results of behavior tests showed that modified constraint-induced movement therapy promoted motor and sensory functional recovery in the middle cerebral artery-occluded rats, but had no effect on cognitive function. The modified constraint-induced movement therapy upregulated the expression of glutamate ionotropic receptor AMPA type subunit 3 (Gria3) in the hippocampus and downregulated the expression of the beta3-adrenergic receptor gene Adrb3 and arginine vasopressin receptor 1A, Avpr1a in the middle cerebral artery-occluded rats. In the ipsilateral hippocampus, only Adra2a was downregulated, and there was no significant change in Gria3. Transmission electron microscopy revealed a denser distribution the more distribution of postsynaptic glutamate receptor 2/3, which is an α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor, within 240 nm of the postsynaptic density in the contralateral cornu ammonis 3 region. The size and distribution of the synaptic vesicles within 100 nm of the presynaptic active zone were unchanged. Western blot analysis showed that modified constraint-induced movement therapy also increased the expression of glutamate receptor 2/3 and brain-derived neurotrophic factor in the hippocampus of rats with middle cerebral artery occlusion, but had no effect on Synapsin I levels. Besides, we also found modified constraint-induced movement therapy effectively reduced glutamate content in the contralateral hippocampus. This study demonstrated that modified constraint-induced movement therapy is an effective rehabilitation therapy in middle cerebral artery-occluded rats, and suggests that these positive effects occur via the upregulation of the postsynaptic membrane α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor expression. This study was approved by the Institutional Animal Care and Use Committee of Fudan University, China (approval No. 201802173S) on March 3, 2018.

Abstract Background The incidence and mortality rates of gastric cancer (GC) rank in top five among all malignant tumors. Chemokines and their receptor-signaling pathways reportedly play key roles in the metastasis of malignant tumor cells. Receptor activator of nuclear factor κB ligand (RANKL) is a member of the tumor necrosis factor family, with strong chemokine-like effects. Some studies have pointed out that the RANKL/RANK pathway is vital for the metastasis of cancer cells, but the specific mechanisms in GC remain poorly understood. Results This study reports original findings in cell culture models and in patients with GC. Flow cytometry and western blotting analyses showed that RANK was expressed in BGC-823 and SGC-7901 cells in particular. Chemotaxis experiments and wound healing assay suggested that RANKL spurred the migration of GC cells. This effect was offset by osteoprotegerin (OPG), a decoy receptor for RANKL. RANKL contributed to the activation of human epidermal growth factor receptor (HER) family pathways. The lipid raft core protein, caveolin 1 (Cav-1), interacted with both RANK and human epidermal growth factor receptor-1(EGFR). Knockdown of Cav-1 blocked the activation of EGFR and cell migration induced by RANKL. Moreover, RANK-positive GC patients who displayed higher levels of EGFR expression had poor overall survival. Conclusions In summary, we confirmed that with the promotion of RANKL, RANK and EGFR can form complexes with the lipid raft core protein Cav-1, which together promote GC cell migration. The formation of the RANK-Cav-1-EGFR complex provides a novel mechanism for the metastasis of GC. These observations warrant confirmation in independent studies, in vitro and in vivo. They also inform future drug target discovery research and innovation in the treatment of GC progression.

The median survival time of patients with advanced gastric cancer (GC) who received radiotherapy and chemotherapy was

River dynamics have been hypothesized to substantially influence the genetic structure of freshwater fish taxa. Southern China harbors abundant independent river systems, which have undergone historical rearrangements. This river system is thus an excellent model with which to test the abovementioned hypothesis. In this study, a cyprinid widespread in many independent rivers in southern China, Toxabramis houdemeri, was chosen as an exemplar species with which to explore the effects of river configuration changes on spatial genetic structure using mitochondrial and nuclear markers. The results indicated that the T. houdemeri populations fell into four mitochondrial haplotype groups, each genetically endemic to a single river or two adjacent river systems. The mitochondrial haplotype network recovered a clear genetic boundary between Hainan Island populations and mainland populations. Notable genetic differentiation was observed within populations from distinct river systems in both mitochondrial and nuclear loci. River system separation, mountain barriers, and mobility were the key factors shaping the genetic structure of T. houdemeri populations. Late Pleistocene divergence and historical immigration were identified within the four mitochondrial haplotype groups, indicating that river rearrangements triggered by the Late Pleistocene glacial cycles were important drivers of the complex genetic structure and demographic history of T. houdemeri. Historical demographics suggested that T.houdemeri populations expanded during the Late Pleistocene. The present study has important consequences for the management and conservation of T. houdemeri.

Abnormal RNA m6A methylation is known to lead to the occurrence and progression of multiple cancers including gastric cancer (GC). However, the integrative effects of all m6A methylation regulators on GC prognosis are unclear. Our research aimed to globally analyze the prognosis values of all 33 m6A RNA methylation regulators in GC by univariate and multivariate Cox regression analyses. Among all 33 m6A RNA methylation regulators, fat mass and obesity-associated protein (FTO), an m6A demethylase, was identified as a key prognostic risk factor on overall survival (OS) of GC patients. It was found that FTO could promote GC cell migration and invasion abilities, and we predicted that ITGB1 was a demethylated target of FTO. Knockdown (KD) of FTO significantly down-regulated ITGB1 expression at both mRNA and protein levels and augmented ITGB1 mRNA m6A modification level. Moreover, overexpression (OE) of ITGB1 could partially reverse FTO-KD-inhibited migration and invasion of GC cells. Our study found that FTO was an independent risk factor for overall survival (OS) of GC patients and FTO could promote GC metastasis by upregulating the expression of Integrin β1(ITGB1) via decreasing its m6A level. These results indicated that FTO can be a potent GC biomarker for prognosis prediction as well as a potential target in GC treatment.

Resolving the species composition of a larval pool in a spawning ground can provide novel insights into regional fish stocks and can support the development of effective monitoring and conservation policies. However, it is challenging to identify fish larvae to species due to their high diversity and dramatic phenotypic changes over development. In this study, we collected fish larvae in the Dongta spawning ground (Guiping City, Guangxi Province, China) in the middle reaches of the Pearl River between May and August 2018. We used a DNA barcoding approach to determine the species composition of the larval pool. A total of 905 larvae were chosen for molecular identification, of which 750 yielded high-quality barcoding sequences. Of these, 597 (≈79.6%), 151 (≈20.1%)/and 2 (≈0.3%) were assigned to 28 species, 8 genera, and 1 subfamily using the Barcode of Life Data System and GenBank nucleotide databases, respectively. Among the 28 identified species, 21 were cyprinids. Two species (Mugilogobius myxodermus and Pseudolaubuca engraulis) that were present only infrequently in previous adult surveys were abundant in the larval pool. Six invasive species were identified in the larval pool, implying that these species had successfully colonized the studied river section. Several migratory species common in the lower Pearl River were rare or absent in the investigated region, suggesting that dam construction in the Pearl River has had adverse effects on these migratory species. In summary, our study confirmed the applicability of DNA barcoding to studies of fish larval ecology and provided important reference data for fishery management and conservation in the Pearl River.

BackgroundAtezolizumab plus chemotherapy has been recommended as a first-line treatment option for patients with advanced non-small cell lung carcinoma (NSCLC) irrespective of programmed cell death-ligand 1 (PD-L1) expression. Currently, little is known about the efficacy and treatment-related adverse effects (TRAEs) of subtracting chemotherapy from the combination for patients with high PD-L1 expression. Thus, we performed an indirect comparison between atezolizumab plus chemotherapy and atezolizumab alone.MethodsA total of five eligible randomized controlled trials (RCTs) were identified from PubMed, EMBASE, and Cochrane Central controlled trial registries, using keywords including atezolizumab, PD-1, PD-L1, NSCLC, and RCT. The clinical outcomes of objective response rate (ORR), progression-free survival (PFS), OS, and TRAEs were extracted and evaluated. Using indirect analysis, the efficacy and TRAEs were compared between arm A (atezolizumab plus chemotherapy) and arm C (atezolizumab), linked by arm B (chemotherapy).ResultsDirect comparison revealed that both atezolizumab plus chemotherapy (HR 0.65, P = 0.003) and atezolizumab alone (HR 0.59, P = 0.010) significantly improved OS compared with chemotherapy. More importantly, the indirect comparison showed that atezolizumab plus chemotherapy was not superior to atezolizumab regarding OS (RR 1.10, P =0.695) and ORR (RR 1.11, P = 0.645). However, patients who received atezolizumab combined with chemotherapy experienced more ≥ grade 3 TRAEs (RR 4.23, P

BackgroundGastric cancer (GC) still represents the third leading cause of cancer-related death worldwide. Peritoneal relapse (PR) is the most frequent metastasis occurring among patients with advanced gastric cancer. Increasingly more evidence have clarified the tumor immune microenvironment (TIME) may predict survival and have clinical significance in GC. However, tumor-transcriptomics based immune signatures derived from immune profiling have not been established for predicting the peritoneal recurrence of the advanced GC.MethodsIn this study, we depict the immune landscape of GC by using transcriptome profiling and clinical characteristics retrieved from GSE62254 of Gene Expression Omnibus (GEO). Immune cell infiltration score was evaluated via single-sample gene set enrichment (ssGSEA) analysis algorithm. The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to select the valuable immune cells and construct the final model for the prediction of PR. The receiver operating characteristic (ROC) curve and the Kaplan-Meier curve were used to check the accuracy of PRIs. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to explore the molecular pathways associated with PRIs.ResultsA peritoneal recurrence related immune score (PRIs) with 10 immune cells was constructed. Compared to the low-PRIs group, the high-PRIs group had a greater risk. The upregulation of the focal adhesion signaling was observed in the high-PRIs subtype by GSEA and KEGG. Multivariate analysis found that both in the internal training cohort and the internal validation cohort, PRIs was a stable and independent predictor for PR. A nomogram that integrated clinicopathological features and PRIs to predict peritoneal relapse was constructed. Subgroup analysis indicated that the PRIs could obviously distinguish peritoneal recurrence in different molecular subtypes, pathological stages and Lauren subtypes, in which PRIs of Epithelial-Mesenchymal Transitions (EMT) subtype, III-IV stage and diffuse subtype are higher respectively.ConclusionOverall, we performed a comprehensive evaluation of the immune landscape of GC and constructed a predictive PR model based on the immune cell infiltration. The PRIs represents novel promising feature of predicting peritoneal recurrence of GC and sheds light on the improvement of the personalized management of GC patients after surgery.

Abstract Background S-phase kinase-associated protein 2 (SKP2) is an oncogene and cell cycle regulator that specifically recognizes phosphorylated cell cycle regulator proteins and mediates their ubiquitination. Programmed cell death protein 4 (PDCD4) is a tumor suppressor gene that plays a role in cell apoptosis and DNA-damage response via interacting with eukaryotic initiation factor-4A (eIF4A) and P53. Previous research showed SKP2 may interact with PDCD4, however the relationship between SKP2 and PDCD4 is unclear. Methods To validate the interaction between SKP2 and PDCD4, mass spectrometric analysis and reciprocal co-immunoprecipitation (Co-IP) experiments were performed. SKP2 stably overexpressed or knockdown breast cancer cell lines were established and western blot was used to detect proteins changes before and after radiation. In vitro and in vivo experiments were performed to verify whether SKP2 inhibits cell apoptosis and promotes DNA-damage response via PDCD4 suppression. SMIP004 was used to test the effect of radiotherapy combined with SKP2 inhibitor. Results We found that SKP2 remarkably promoted PDCD4 phosphorylation, ubiquitination and degradation. SKP2 promoted cell proliferation, inhibited cell apoptosis and enhanced the response to DNA-damage via PDCD4 suppression in breast cancer. SKP2 and PDCD4 showed negative correlation in human breast cancer tissues. Radiotherapy combine with SKP2 inhibitor SMIP004 showed significant inhibitory effects on breast cancer cells in vitro and in vivo. Conclusions We identify PDCD4 as an important ubiquitination substrate of SKP2. SKP2 promotes breast cancer tumorigenesis and radiation tolerance via PDCD4 degradation. Radiotherapy combine with SKP2-targeted adjuvant therapy may improve breast cancer patient survival in clinical medicine.

A wide variety of vehicle detection approaches using the deep convolutional neural network (CNN) have achieved great success in recent years. However, the existing CNN-based feature extraction algorithms, especially residual network, cannot obtain powerful semantic information in the vehicle detection task, and thus suffer from the problem of a missing detection, error detection, or repeated detection. In this paper, we present a connect-and-merge convolutional neural network (CMNet) for fast detecting vehicles in complex scenes. First, we propose a connect-and-merge residual network (CMRN) for performing feature extraction. Specifically, the CMRN assembles residual branches in parallel through a connect-and-merge mapping: Connect the input to the outputs of two residual branches separately (Connect), and merge the outputs of the connection as the input of the subsequent residual block (Merge), respectively. Second, we present a multi-scale prediction network (MSPN) to accurately regress the vehicle shape and classify vehicle fine-grained categories. In addition, the feature maps from the CMRN are merged with their corresponding upsampled features from the MSPN using concatenation. Thus, we can improve the information flow of the framework and make it easy to train. The experimental results on the KITTI dataset and the UA-DETRAC dataset demonstrate that the CMNet can achieve efficient detection performance in terms of accuracy and speed for the real-world traffic surveillance data.

Ground Penetrating Radar (GPR) is a shallow geophysical method for detecting and locating subsurface targets. The GPR image echo characteristics of complex underground structures can be obtained by carrying out GPR forward modeling research. The traditional finite-difference time-domain (FDTD) method has low efficiency and accuracy. The alternating direction implicit FDTD (ADI-FDTD) algorithm surmounts the stability limitations of the traditional FDTD method, making it possible to select a larger time step for higher computational efficiency. For circular underground structures, a pseudowave produced by the ladder approximation method can be corrected using the surface conformal technique. This paper proposes a high-efficiency and high-accuracy GPR forward modeling method that combines the ADI-FDTD algorithm and surface conformal technology. The performance of the conformal ADI-FDTD algorithm is verified by a simple two-layer model. Based on the proposed algorithm, the GPR image features of three complex underground structure models are obtained. Finally, a field experiment is used to support the accuracy and usefulness of the conformal ADI-FDTD algorithm. The numerical simulation results and experimental results show that the conformal ADI-FDTD algorithm reduces the pseudodiffraction wave caused by the ladder approximation method and can significantly improve the computing efficiency for complex underground structure models.

BackgroundGastric signet ring cell carcinoma (GSRCC) is a rare disease associated with poor prognosis. A prognostic nomogram was developed and validated in this study to assess GSRCC patients’ overall survival (OS).MethodsPatients diagnosed with GSRCC from the Surveillance, Epidemiology, and End Results (SEER) database (2004–2016) and the First Hospital of China Medical University (CMU1h) were enrolled in this retrospective cohort study. Univariate and multivariate COX analysis was used to determine independent prognostic factors to construct the prognostic nomogram. Predictions were evaluated by the C-index and calibration curve. In addition, the receiver operating characteristic (ROC) curve, decision curve analysis (DCA), and Kaplan-Meier analysis were employed to assess the clinical utility of the survival prediction model.ResultsPatients were classified into two cohorts. We randomly divided patients in the SEER database and CMU1h cohort into a training group (n=3068, 80%) and a validation group (n=764, 20%). Age, race, T stage, N stage, M stage, therapy, and tumor size were significantly associated with the prognosis of GSRCC patients. On this basis, a nomogram was constructed, with a C-index in the training and the validation cohorts at 0.772 (95% CI: 0.762–0.782) and 0.774 (95% CI: 0.752–0.796), respectively. The accuracy of the generated nomogram was verified through calibration plots. Similarly, compared with the traditional AJCC staging system, the results of the area under curve (AUC) calculated by ROC, DCA, and Kaplan-Meier curves, demonstrated a good predictive value of the constructed nomogram, compared to the traditional AJCC staging system.ConclusionIn the present study, seven independent prognostic factors of GSRCC were screened out. The established nomogram models based on seven variables provided a visualization of each prognostic factor’s risk and assisted clinicians in predicting the 1-, 3-, and 5-year OS of GSRCC.

As a vital feature of the microenvironment, hypoxia, especially long-term hypoxia, is known to promote metastasis and lead to poor prognosis in solid tumors. Circular RNAs (circRNAs) participate in important processes of cell proliferation and metastasis in cancers. However, the contribution of circRNAs to metastasis under long-term hypoxia is obscure. In this study, we aim to explore specific functions of circHIPK3 in long-term hypoxia-promoting metastasis of gastric cancer (GC). The hypoxic resistant gastric cancer (HRGC) cell lines we established previously, which were tolerant to 2% O2 conditions, were used as the long-term hypoxia model. We found that circHIPK3 was upregulated by HIF-2α in HRGC cells, and circHIPK3 facilitated the migration and invasion ability of HRGC cells. Further investigation proved that circHIPK3 promoted metastasis of HRGC cells directly by interacting with miR-653-5p and miR-338-3p to relieve the suppression of neuropilin 1 (NRP1), resulting in the activation of downstream ERK and AKT pathways. Our study identified oncogene functions of circHIPK3 under a long-term hypoxic microenvironment and the possibility of using circHIPK3 as a potential biomarker of long-term hypoxia in GC. In conclusion, circHIPK3 could promote GC metastasis via the miR-653-5p/miR-338-3p-NRP1 axis under a long-term hypoxic microenvironment.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received extensive attention as a cancer therapeutic due to its high propensity for tumor targeting with minimal toxicity to healthy tissue. Gastric cancer (GCa) cells show high levels of TRAIL resistance. Epidermal growth factor receptor (EGFR) antagonizes TRAIL-induced apoptosis, but the mechanisms of these effects remain unclear. Our past research confirmed TRAIL-resistant (BGC823 and SGC7901) and TRAIL-sensitive cells (HGC27 and MKN45). miR-429 associated with TRAIL sensitivity was screened using microRNA arrays. The transfection of mimics and inhibitors confirmed that miR-429 negatively correlated with GCa TRAIL resistance. The target gene of miR-429 was identified as PD-L1, which positively correlated with TRAIL resistance through gene silencing and recovery experiments. Using co-immunoprecipitation (co-IP) and proximity ligation assay, we demonstrated that the pro-survival effects of PD-L1 are mediated through the binding and activation of EGFR. Cell viability experiments demonstrated that PD-L1 is key to the maintenance of cell viability in TRAIL-treated cells. This indicated that PD-L1 binds to and participates in EGFR activation through miR-429 regulation to antagonize TRAIL-induced apoptosis. This provides a new theoretical basis for the combination of the EGFR monoclonal antibodies including cetuximab, PD-L1 inhibitors, and human recombinant TRAIL in gastric cancer therapy and can filter patients who are currently sensitive to TRAIL treatment.

Anti-PD-1 therapy has been approved for cancer treatment. However, the response rate is unsatisfactory. The expression of PD-L1 in tumor tissues is unreliable to predict the treatment response. Recent studies have suggested that exosomal PD-L1 not only exerts immunosuppressive effects but also plays a significant role in the development of tumor microenvironment. Thus, the present study aims to investigate exosomal PD-L1 in improving its predictive value and efficacy. A total of 44 patients of advanced tumors of several types, treated with anti-PD-1 therapy, were enrolled. Exosomes were collected and purified from plasma. The exosomal PD-L1 was detected with ELISA. The cytokines were measured with the MILLIPLEX magnetic bead assay. Compared to the responders, exosomal PD-L1 of the non-responders was significantly higher than that of the responders (P = 0.010) before the treatment. Concurrently, exosomal PD-L1 and tumor burden decreased when the therapy was effective. And, the baseline expression of CD28 was higher in the responders than that in the non-responders (P = 0.005). Univariate and multivariate analyses validated with 1,000 times bootstrapping suggested that high exosomal PD-L1 and low CD28 expressions were negative factors for progression-free survival (PFS) of the patients who underwent anti-PD-1 treatment. The combination of exosomal PD-L1 and CD28 obtained more area under the curve (AUC) of receiver operating characteristic (ROC) (AUC 0.850 vs. 0.784 vs. 0.678) and showed a higher probability of no progression via nomograph. These findings suggested that the expression of exosomal PD-L1 and CD28 could serve as the predictive biomarkers for clinical responses to anti-PD-1 treatment.

Although the cytotoxic chemotherapeutic agent 5-fluorouracil (5-FU) is generally considered to directly kill cancer cells and exert immunostimulatory effects in advanced gastric cancer, accumulating evidence indicates that it upregulates the expression of PD-L1, a representative immune checkpoint blockade molecule involved in negative regulation of the immune response. It was reported that exosomes could transfer functional PD-L1 locally and distantly to suppress the antitumor immune response. However, whether 5-FU alters the expression of exosomal PD-L1 and induces immunosuppression in gastric cancer remains unclear. Herein, we found that 5-FU increased gastric cancer-derived exosomal PD-L1. Importantly, compared with baseline levels, circulating exosomal PD-L1 was significantly upregulated in 21 stage III–IV gastric cancer patients after two, four, and six repeated cycles of fluoropyrimidine treatment (P = 0.009, P = 0.047, and P = 0.023, respectively), accompanied by decreased amounts of IFN-γ, TNF-α, IL-2, IL-6, and GM-CSF (P = 0.014, P = 0.004, P = 0.009, P = 0.031, and P = 0.014, respectively). Additionally, circulating exosomal PD-L1 was increased more significantly in clinical non-responders compared with responders (P = 0.018). Furthermore, exosomal PD-L1 induced apoptosis in Jurkat T cells and inhibited T cell activation in PBMCs, which could be partly reversed by nivolumab. These results suggested that 5-FU-induced upregulation of exosomal PD-L1 causes systemic immunosuppression in advanced gastric cancer following multiple cycles of chemotherapy, especially after two cycles.

Oncolytic virotherapy is emerging as an important agent in cancer treatment. In a previous study, we designed and constructed Ad-Apoptin-hTERTp-E1a (Ad-VT), a dual cancer-selective anti-tumor recombinant adenovirus. In this study, crystal violet staining and WST-1 assays showed that Ad-VT has a significant tumor killing effect in a time and dose dependent manner. The combination of Ad-VT (10 MOI) and gemcitabine (10 nM) significantly inhibited NCI-H226 cells, but did not increase the killing effect of gemcitabine on human normal bronchial epithelial cells BEAS-2B. Hoechst, JC-1 and Annexin V experiments demonstrated that the combination of Ad-VT and gemcitabine mainly inhibited NCI-H226 cell proliferation by inducing apoptosis (mitochondrial pathway). The combination also significantly inhibited the migration and invasion abilities of NCI-H226 cells. In vivo, Ad-VT in combination with low-dose gemcitabine could effectively inhibit tumor growth and prolong survival of mice. Ad-VT has the characteristics of tumor-selective replication and killing, in vitro and in vivo. The combined application of Ad-VT and gemcitabine has a synergistic effect, which can increase the anti-tumor effect and reduce the toxicity of chemotherapy drugs, indicating that Ad-VT has a potential clinical value in the treatment of lung squamous cell carcinoma.