Systematic Investigation of the Homology Sequences Around the Human Fusion Gene Breakpoints in Pan-Cancer - Bioinformatics Study for a Potential Link to MMEJ

Microhomology-mediated end joining (MMEJ), an error-prone DNA damage repair mechanism, frequently leads to chromosomal rearrangements due to its ability to engage in promiscuous end joining of genomic instability and also leads to increasing mutational load at the sequences flanking the breakpoints (BPs). In this study, we systematically investigated the homology sequences around the genomic breakpoint area of human fusion genes, which were formed by the chromosomal rearrangements initiated by DNA double-strand breakage. Since the RNA-seq data is the typical data set to check the fusion genes, for the known exon junction fusion breakpoints identified from RNA-seq data, we have to infer the high chance of genomic breakpoint regions. For this, we utilized the high feature importance score area calculated from our recently developed fusion BP prediction model, FusionAI and identified 151 K microhomologies among ~24 K fusion BPs in 20 K fusion genes. From our multiple bioinformatics studies, we found a relationship between sequence homologies and the immune system. This in-silico study will provide novel knowledge on the sequence homologies around the coded structural variants

FusionNeoAntigen: A Resource of Fusion Gene-Specific Neoantigens

Among the diverse sources of neoantigens (i.e. single-nucleotide variants (SNVs), insertions or deletions (Indels) and fusion genes), fusion gene-derived neoantigens are generally more immunogenic, have multiple targets per mutation and are more widely distributed across various cancer types. Therefore, fusion gene-derived neoantigens are a potential source of highly immunogenic neoantigens and hold great promise for cancer immunotherapy. However, the lack of fusion protein sequence resources and knowledge prevents this application. We introduce \u27FusionNeoAntigen\u27, a dedicated resource for fusion-specific neoantigens, accessible at https://compbio.uth.edu/FusionNeoAntigen. In this resource, we provide fusion gene breakpoint crossing neoantigens focused on ∼43K fusion proteins of ∼16K in-frame fusion genes from FusionGDB2.0. FusionNeoAntigen provides fusion gene information, corresponding fusion protein sequences, fusion breakpoint peptide sequences, fusion gene-derived neoantigen prediction, virtual screening between fusion breakpoint peptides having potential fusion neoantigens and human leucocyte antigens (HLAs), fusion breakpoint RNA/protein sequences for developing vaccines, information on samples with fusion-specific neoantigen, potential CAR-T targetable cell-surface fusion proteins and literature curation. FusionNeoAntigen will help to develop fusion gene-based immunotherapies. We will report all potential fusion-specific neoantigens from all possible open reading frames of ∼120K human fusion genes in future versions

A Novel Integrated Approach to Predicting Cancer Immunotherapy Efficacy

Immunotherapies have revolutionized cancer treatment modalities; however, predicting clinical response accurately and reliably remains challenging. Neoantigen load is considered as a fundamental genetic determinant of therapeutic response. However, only a few predicted neoantigens are highly immunogenic, with little focus on intratumor heterogeneity (ITH) in the neoantigen landscape and its link with different features in the tumor microenvironment. To address this issue, we comprehensively characterized neoantigens arising from nonsynonymous mutations and gene fusions in lung cancer and melanoma. We developed a composite NEO2IS to characterize interplays between cancer and CD8+ T-cell populations. NEO2IS improved prediction accuracy of patient responses to immune-checkpoint blockades (ICBs). We found that TCR repertoire diversity was consistent with the neoantigen heterogeneity under evolutionary selections. Our defined neoantigen ITH score (NEOITHS) reflected infiltration degree of CD8+ T lymphocytes with different differentiation states and manifested the impact of negative selection pressure on CD8+ T-cell lineage heterogeneity or tumor ecosystem plasticity. We classified tumors into distinct immune subtypes and examined how neoantigen-T cells interactions affected disease progression and treatment response. Overall, our integrated framework helps profile neoantigen patterns that elicit T-cell immunoreactivity, enhance the understanding of evolving tumor-immune interplays and improve prediction of ICBs efficacy

Integrated mRNA Sequence Optimization Using Deep Learning

The coronavirus disease of 2019 pandemic has catalyzed the rapid development of mRNA vaccines, whereas, how to optimize the mRNA sequence of exogenous gene such as severe acute respiratory syndrome coronavirus 2 spike to fit human cells remains a critical challenge. A new algorithm, iDRO (integrated deep-learning-based mRNA optimization), is developed to optimize multiple components of mRNA sequences based on given amino acid sequences of target protein. Considering the biological constraints, we divided iDRO into two steps: open reading frame (ORF) optimization and 5\u27 untranslated region (UTR) and 3\u27UTR generation. In ORF optimization, BiLSTM-CRF (bidirectional long-short-term memory with conditional random field) is employed to determine the codon for each amino acid. In UTR generation, RNA-Bart (bidirectional auto-regressive transformer) is proposed to output the corresponding UTR. The results show that the optimized sequences of exogenous genes acquired the pattern of human endogenous gene sequence. In experimental validation, the mRNA sequence optimized by our method, compared with conventional method, shows higher protein expression. To the best of our knowledge, this is the first study by introducing deep-learning methods to integrated mRNA sequence optimization, and these results may contribute to the development of mRNA therapeutics

Stemdriver: a Knowledgebase of Gene Functions for Hematopoietic Stem Cell Fate Determination

StemDriver is a comprehensive knowledgebase dedicated to the functional annotation of genes participating in the determination of hematopoietic stem cell fate, available at http://biomedbdc.wchscu.cn/StemDriver/. By utilizing single-cell RNA sequencing data, StemDriver has successfully assembled a comprehensive lineage map of hematopoiesis, capturing the entire continuum from the initial formation of hematopoietic stem cells to the fully developed mature cells. Extensive exploration and characterization were conducted on gene expression features corresponding to each lineage commitment. At the current version, StemDriver integrates data from 42 studies, encompassing a diverse range of 14 tissue types spanning from the embryonic phase to adulthood. In order to ensure uniformity and reliability, all data undergo a standardized pipeline, which includes quality data pre-processing, cell type annotation, differential gene expression analysis, identification of gene categories correlated with differentiation, analysis of highly variable genes along pseudo-time, and exploration of gene expression regulatory networks. In total, StemDriver assessed the function of 23 839 genes for human samples and 29 533 genes for mouse samples. Simultaneously, StemDriver also provided users with reference datasets and models for cell annotation. We believe that StemDriver will offer valuable assistance to research focused on cellular development and hematopoiesis

A Geometric Accuracy Error Analysis Method for Turn-Milling Combined NC Machine Tool

Turn-Milling Combined NC machine tool is different from traditional machine tools in structure and process realization. As an important means in the design stage, the analysis method of geometric accuracy error is also different from the traditional method. The actual errors and the error compensation values are a pair of "symmetry" data sets which are connected by the movement of machine tools. The authors try to make them more consistent through this work. The geometric error terms were firstly determined by topological structure analysis, then based on homogeneous coordinate transformation and multibody system theory, the geometric error model was established. With the interval theory, the function rule of sensitivity of geometric error sources to spatial errors was analyzed in detail, and the global maximum interval sensitivity of nine geometric error sources was extracted, providing a theoretical basis for error compensation and precision distribution. The geometric error sensitivity analysis method proposed in this paper can accurately evaluate the influence weights of each error term on the machining accuracy, and identify the important sensitive error terms with great influence on the machining accuracy from many error terms

Similarities and differences in core symptoms of problematic smartphone use among Chinese students enrolled in grades 4 to 9: A large national cross-sectional study

Children and adolescents are highly susceptible to problematic smartphone usage. We employed network analysis to explore the similarities and differences in the core symptoms of problematic smartphone use across grades 4-9, using a large nationwide sample. This study included 8552 children and adolescents (Mage M age = 12.98, SD =1.51) who met the critical value for problematic smartphone use. The results showed that the core symptoms of problematic smartphone use exhibit both similarities and differences between grades 4 and 9. 'Withdrawal symptoms' and 'preoccupation symptoms' were the stable core symptoms of problematic smartphone use across grades 4 to 9, suggesting that problematic smartphone use begin to appear from earlier grades, such as grade 4. 'Feel impatient and fretful', 'never give up' and 'always thinking about' were the core symptoms in grades 4 and 5. 'Longer than I had intended' and 'hard to concentrate' emerged as additional core symptoms in grade 6, with the intensity indicators peaking in grades 8 and 9, suggesting that the issue of problematic smartphone use among Chinese children and adolescents has become intensified and intricate. Symptoms of problematic smartphone use vary across grades and exhibit both continuity and stage specificity. Consequently, to address this issue, the formulation of intervention measures should comprehensively consider both the grade levels and symptoms

Study on the Mechanical Behavior of Fluid–Solid Coupling in Shallow Buried Tunnels under Different Biased Terrain

In the construction of mountain tunnels, biased and water-rich strata are often encountered. During tunnel excavation, the fluid–solid coupling has a great influence on the stability of the surrounding rock. This effect will be more severe when the terrain is biased. The bias tunnel points out the asymmetric load of the rocks which are surrounding the tunnels through the drilling or construction process due to the topographic situation. These loads can cause inverse actions during tunnel construction. Therefore, the effect of fluid–solid coupling on the displacement field, stress field, and seepage field of the tunnel surrounding rock under different biased terrains are studied in this paper. In the context of the Youzishu tunnel project, the numerical model is established to define the degree of terrain bias. Besides, the concept of bias coefficient is introduced. To achieve what is needed, 10 sets of increasing bias coefficients are obtained, by changing the inclination of the terrain to study the influence of formation bias degree on tunnel excavation in water-rich formations. After an in-depth analysis of the simulation results, it is found that the influence of fluid–structure interaction cannot be ignored. By analyzing ten groups of data under different working conditions, the biased terrain will aggravate this effect. As far as the displacement field of the surrounding rock is concerned, the biased formation has a greater impact on the deeply buried side than on the shallow-buried side, and has a greater impact on the vault than on the arch bottom. In addition, by analyzing the stress field and seepage field of the surrounding rock, a similar result can be obtained: the influence of formation bias on the deeply buried side is greater than that on the shallow-buried side, and the biased terrain will increase the pore pressure outside the tunnel lining and increase the water inflow. Finally, the locations where the displacement, stress, water pressure, and water inflow are the largest during the tunnel excavation process are found by the simulations and analyzed. Thus, attention can be paid to these locations, permitting a focus on protection during the construction process

Neoadjuvant radiotherapy for resectable retroperitoneal sarcoma: a meta-analysis

Abstract Background Neoadjuvant radiotherapy (NRT) for resectable retroperitoneal sarcoma (RPS) has been shown to be systematically feasible. Whether NRT has equivalent or better clinical effects compared to surgery alone for RPS patients remains controversial. Methods We performed a systematic literature search of PubMed, Web of Science, Embase, ASCO Abstracts, and Cochrane library databases for studies in humans with defined search terms. Articles were independently assessed by 2 reviewers, and only randomized controlled trials and cohort studies were included. The hazard ratios (HRs) of overall survival (OS), recurrence-free survival (RFS), and local recurrence (LR) were extracted from included studies. Heterogeneity among study-specific HRs was assessed by the Q statistic and I2 statistic. Overall HR was assessed by random-effects or fixed-effects models. Publication bias was tested by Begg’s tests, and the quality of each study was assessed with the Newcastle Ottawa Scale. Results A total of 12 eligible studies with 7778 resectable RPS patients were finally included in this study. The pooled analysis revealed the distinct advantages of NRT as compared to surgery alone, including longer OS (HR = 0.81, P < 0.001), longer RFS (HR = 0.58, P = 0.04), and lower LR (HR = 0.70, P = 0.03). No evidence of publication bias was observed. Conclusion NRT is likely to be beneficial for resectable RPS patients in terms of OS and RFS. However, more multicenter clinical trials are needed to confirm these findings

Study on the Mechanical Behavior of Fluid–Solid Coupling in Shallow Buried Tunnels under Different Biased Terrain

In the construction of mountain tunnels, biased and water-rich strata are often encountered. During tunnel excavation, the fluid–solid coupling has a great influence on the stability of the surrounding rock. This effect will be more severe when the terrain is biased. The bias tunnel points out the asymmetric load of the rocks which are surrounding the tunnels through the drilling or construction process due to the topographic situation. These loads can cause inverse actions during tunnel construction. Therefore, the effect of fluid–solid coupling on the displacement field, stress field, and seepage field of the tunnel surrounding rock under different biased terrains are studied in this paper. In the context of the Youzishu tunnel project, the numerical model is established to define the degree of terrain bias. Besides, the concept of bias coefficient is introduced. To achieve what is needed, 10 sets of increasing bias coefficients are obtained, by changing the inclination of the terrain to study the influence of formation bias degree on tunnel excavation in water-rich formations. After an in-depth analysis of the simulation results, it is found that the influence of fluid–structure interaction cannot be ignored. By analyzing ten groups of data under different working conditions, the biased terrain will aggravate this effect. As far as the displacement field of the surrounding rock is concerned, the biased formation has a greater impact on the deeply buried side than on the shallow-buried side, and has a greater impact on the vault than on the arch bottom. In addition, by analyzing the stress field and seepage field of the surrounding rock, a similar result can be obtained: the influence of formation bias on the deeply buried side is greater than that on the shallow-buried side, and the biased terrain will increase the pore pressure outside the tunnel lining and increase the water inflow. Finally, the locations where the displacement, stress, water pressure, and water inflow are the largest during the tunnel excavation process are found by the simulations and analyzed. Thus, attention can be paid to these locations, permitting a focus on protection during the construction process