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Since Epstein-Barr virus (EBV) was discovered in 1964, it has been reported to be associated with various malignancies as well as benign diseases, and the pathogenicity of EBV has been widely studied. Several databases have been established to provide comprehensive information on the virus and its relation to diseases and introduce convenient analysis tools. Although they have greatly facilitated the analysis of EBV at the genome, gene, protein, or epitope level, they did not provide enough insight into the genomic variants of EBV, which have been suggested as relevant to diseases by multiple studies. Here, we introduce dbEBV, a comprehensive database of EBV genomic variation landscape, which contains 942 EBV genomes with 109,893 variants from different tissues or cell lines in 24 countries. The database enables the visualization of information with varying global frequencies and their relationship with the human health of each variant. It also supports phylogenetic analysis at the genome or gene level in subgroups of different characteristics. Information of interest can easily be reached with functions such as searching, browsing, and filtering. In conclusion, dbEBV is a convenient resource for exploring EBV genomic variants, freely available at http://dbebv.omicsbio.info.

Objective: To investigate the characteristics of three-dimensional distribution of subchondral fracture lines on the surface of the osteonecrosis femoral head, and to discuss the underlying mechanisms that contribute to its collapse. Methods: We retrospectively analyzed computed tomography (CT) images from 75 patients (comprising a total of 77 femoral heads) diagnosed with Association Research Circulation Osseous (ARCO) stage IIIA or IIIB femoral head necrosis. The three-dimensional structures of both the femoral head and the subchondral fracture line were reconstructed and subsequently fitted into normal femoral head model. A heat map of fracture line was generated to visualize its spatial distribution across the femoral heads surface.to observe its distribution. In addition to that, the femoral head was partitioned into four zones, and the frequency of each fracture line traversing different zones was calculated and analysed. Results: Highest and lowest density of subchondral fracture lines was demonstrated in anterolateral and posterolateral zone respectively. and most sparse in posterolateral. Furthermore, the three-dimensional heat map of fracture lines highlighted their most frequent occurrence in the anterolateral area, particularly near the junction of the femoral head and neck. One fracture line may pass through multiple areas, passage frequencies for fracture lines was observed in zones I, II, III and IV for 66 times (85.7 %), 52 times (67.5 %), 25 times (32.5 %) and 46 times (59.7 %), respectively, with a significant difference between zone I and other zones (P

Abstract Background Circulating tumor DNA (ctDNA) is a promising biomarker for predicting relapse in multiple solid cancers. However, the predictive value of ctDNA for disease recurrence remains indefinite in locoregional gastric cancer (GC). Here, we aimed to evaluate the predictive value of ctDNA in this context. Methods From 2016 to 2019, 100 patients with stage II/III resectable GC were recruited in this prospective cohort study (NCT02887612). Primary tumors were collected during surgical resection, and plasma samples were collected perioperatively and within 3 months after adjuvant chemotherapy (ACT). Somatic variants were captured via a targeted sequencing panel of 425 cancer‐related genes. The plasma was defined as ctDNA‐positive only if one or more variants detected in the plasma were presented in at least 2% of the primary tumors. Results Compared with ctDNA‐negative patients, patients with positive postoperative ctDNA had moderately higher risk of recurrence [hazard ratio (HR) = 2.74, 95% confidence interval (CI) = 1.37–5.48; P = 0.003], while patients with positive post‐ACT ctDNA showed remarkably higher risk (HR = 14.99, 95% CI = 3.08‐72.96; P < 0.001). Multivariate analyses indicated that both postoperative and post‐ACT ctDNA positivity were independent predictors of recurrence‐free survival (RFS). Moreover, post‐ACT ctDNA achieved better predictive performance (sensitivity, 77.8%; specificity, 90.6%) than both postoperative ctDNA and serial cancer antigen. A comprehensive model incorporating ctDNA for recurrence risk prediction showed a higher C‐index (0.78; 95% CI = 0.71–0.84) than the model without ctDNA (0.71; 95% CI = 0.64–0.79; P = 0.009). Conclusions Residual ctDNA after ACT effectively predicts high recurrence risk in stage II/III GC, and the combination of tissue‐based and circulating tumor features could achieve better risk prediction.

Abstract Colorectal cancer (CRC) patients with liver metastases usually obtain less benefit from immunotherapy, and the underlying mechanisms remain understudied. Here, we identify that fibrinogen-like protein 1 (FGL1), secreted from cancer cells and hepatocytes, facilitates the progression of CRC in an intraportal injection model by reducing the infiltration of T cells. Mechanistically, tumor-associated macrophages (TAMs) activate NF-ĸB by secreting TNFα/IL-1β in the liver microenvironment and transcriptionally upregulate OTU deubiquitinase 1 (OTUD1) expression, which enhances FGL1 stability via deubiquitination. Disrupting the TAM-OTUD1-FGL1 axis inhibits metastatic tumor progression and synergizes with immune checkpoint blockade (ICB) therapy. Clinically, high plasma FGL1 levels predict poor outcomes and reduced ICB therapy benefits. Benzethonium chloride, an FDA-approved antiseptics, curbs FGL1 secretion, thereby inhibiting liver metastatic tumor growth. Overall, this study uncovers the critical roles and posttranslational regulatory mechanism of FGL1 in promoting metastatic tumor progression, highlighting the TAM-OTUD1-FGL1 axis as a potential target for cancer immunotherapy.

Abstract Background Hepatocellular carcinoma (HCC) metastasis and recurrence lead to therapy failure, which are closely associated with the proteome. However, the role of post-translational modification (PTM) in HCC, especially for the recently discovered lysine crotonylation (Kcr), is elusive. Results We investigated the correlation between crotonylation and HCC in 100 tumor tissues and performed stable isotope labeling by amino acids and liquid chromatography tandem mass spectrometry in HCC cells, and we found that crotonylation was positively correlated with HCC metastasis, and higher crotonylation in HCC cells facilitated cell invasiveness. Through bioinformatic analysis, we found that the crotonylated protein SEPT2 was significantly hypercrotonylated in highly invasive cells, while the decrotonylated mutation of SEPT2-K74 impaired SEPT2 GTPase activity and inhibited HCC metastasis in vitro and in vivo. Mechanistically, SIRT2 decrotonylated SEPT2, and P85α was found to be the downstream effector of SEPT2. Moreover, we identified that SEPT2-K74cr was correlated with poor prognosis and recurrence in HCC patients, thus indicating its clinical potential as an independent prognostic factor. Conclusions We revealed the role of nonhistone protein crotonylation in regulating HCC metastasis and invasion. Crotonylation facilitated cell invasion through the crotonylated SEPT2-K74-P85α-AKT pathway. High SEPT2-K74 crotonylation predicted poor prognosis and a high recurrence rate in HCC patients. Our study revealed a novel role of crotonylation in promoting HCC metastasis.

Abstract Background Predictive biomarkers for oesophageal squamous cell carcinoma (ESCC) immunotherapy are lacking, and immunotherapy resistance remains to be addressed. The role of long noncoding RNA (lncRNA) in ESCC immune escape and immunotherapy resistance remains to be elucidated. Methods The tumour‐associated macrophage‐upregulated lncRNAs and the exosomal lncRNAs highly expressed in ESCC immunotherapy nonresponders were identified by lncRNA sequencing and polymerase chain reaction assays. CRISPR‐Cas9 was used to explore the functional roles of the lncRNA. RNA pull‐down, MS2‐tagged RNA affinity purification (MS2‐TRAP) and RNA‐binding protein immunoprecipitation (RIP) were performed to identify lncRNA‐associated proteins and related mechanisms. In vivo, the humanized PBMC (hu‐PBMC) mouse model was established to assess the therapeutic responses of specific lncRNA inhibitors and their combination with programmed cell death protein 1 (PD‐1) monoclonal antibody (mAb). Single‐cell sequencing, flow cytometry, and multiplex fluorescent immunohistochemistry were used to analyze immune cells infiltrating the tumour microenvironment. Results We identified a lncRNA that is involved in tumour immune evasion and immunotherapy resistance. High LINC02096 (RIME) expression in plasma exosomes correlates with a reduced response to PD‐1 mAb treatment and poor prognosis. Mechanistically, RIME binds to mixed lineage leukaemia protein‐1 (MLL1) and prevents ankyrin repeat and SOCS box containing 2 (ASB2)‐mediated MLL1 ubiquitination, improving the stability of MLL1. RIME‐MLL1 increases H3K4me3 levels in the promoter regions of programmed death‐ligand 1 (PD‐L1) and indoleamine 2,3‐dioxygenase 1 (IDO‐1), constitutively increasing the expression of PD‐L1/IDO‐1 in tumour cells and inhibiting CD8+ T cells infiltration and activation. RIME depletion in huPBMC‐NOG mice significantly represses tumour development and improves the effectiveness of PD‐1 mAb treatment by activating T‐cell‐mediated antitumour immunity. Conclusions This study reveals that the RIME‐MLL1‐H3K4me3 axis plays a critical role in tumour immunosuppression. Moreover, RIME appears to be a potential prognostic biomarker for immunotherapy and developing drugs that target RIME may be a new therapeutic strategy that overcomes immunotherapy resistance and benefits patients with ESCC.

BackgroundRecent observational studies and meta-analyses have shown that vitamin C reduces cancer incidence and mortality, but the underlying mechanisms remain unclear. We conducted a comprehensive pan-cancer analysis and biological validation in clinical samples and animal tumor xenografts to understand its prognostic value and association with immune characteristics in various cancers.MethodsWe used the Cancer Genome Atlas gene expression data involving 5769 patients and 20 cancer types. Vitamin C index (VCI) was calculated using the expression of 11 genes known to genetically predict vitamin C levels, which were classified into high and low subgroups. The correlation between VCI and patient overall survival (OS), tumor mutational burden (TMB), microsatellite instability (MSI), and immune microenvironment was evaluated, using Kaplan-Meier analysis method and ESTIMATE (https://bioinformatics.mdanderson.org/estimate/). Clinical samples of breast cancer and normal tissues were used to validate the expression of VCI-related genes, and animal experiments were conducted to test the impact of vitamin C on colon cancer growth and immune cell infiltration.ResultsSignificant changes in expression of VCI-predicted genes were observed in multiple cancer types, especially in breast cancer. There was a correlation of VCI with prognosis in all samples (adjusted hazard ratio [AHR] = 0.87; 95% confidence interval [CI] = 0.78–0.98; P = 0.02). The specific cancer types that exhibited significant correlation between VCI and OS included breast cancer (AHR = 0.14; 95% CI = 0.05–0.40; P < 0.01), head and neck squamous cell carcinoma (AHR = 0.20; 95% CI = 0.07–0.59; P < 0.01), kidney clear cell carcinoma (AHR = 0.66; 95% CI = 0.48–0.92; P = 0.01), and rectum adenocarcinoma (AHR = 0.01; 95% CI = 0.001–0.38; P = 0.02). Interestingly, VCI was correlated with altered immunotypes and associated with TMB and MSI negatively in colon and rectal adenocarcinoma (P < 0.001) but positively in lung squamous cell carcinoma (P < 0.05). In vivo study using mice bearing colon cancer xenografts demonstrated that vitamin C could inhibit tumor growth with significant impact on immune cell infiltration.ConclusionVCI is significantly correlated with OS and immunotypes in multiple cancers, and vitamin C might have therapeutic potential in colon cancer.

Abstract Metabolic enzymes have an indispensable role in metabolic reprogramming, and their aberrant expression or activity has been associated with chemosensitivity. Hence, targeting metabolic enzymes remains an attractive approach for treating tumors. However, the influence and regulation of cysteine desulfurase (NFS1), a rate-limiting enzyme in iron–sulfur (Fe–S) cluster biogenesis, in colorectal cancer (CRC) remain elusive. Here, using an in vivo metabolic enzyme gene-based clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 library screen, we revealed that loss of NFS1 significantly enhanced the sensitivity of CRC cells to oxaliplatin. In vitro and in vivo results showed that NFS1 deficiency synergizing with oxaliplatin triggered PANoptosis (apoptosis, necroptosis, pyroptosis, and ferroptosis) by increasing the intracellular levels of reactive oxygen species (ROS). Furthermore, oxaliplatin-based oxidative stress enhanced the phosphorylation level of serine residues of NFS1, which prevented PANoptosis in an S293 phosphorylation-dependent manner during oxaliplatin treatment. In addition, high expression of NFS1, transcriptionally regulated by MYC, was found in tumor tissues and was associated with poor survival and hyposensitivity to chemotherapy in patients with CRC. Overall, the findings of this study provided insights into the underlying mechanisms of NFS1 in oxaliplatin sensitivity and identified NFS1 inhibition as a promising strategy for improving the outcome of platinum-based chemotherapy in the treatment of CRC.

Animal gut microbiomes play important roles in the health, diseases, and production of animal hosts. The volume of animal gut metagenomic data, including both 16S amplicon and metagenomic sequencing data, has been increasing exponentially in recent years, making it increasingly difficult for researchers to query, retrieve, and reanalyze experimental data and explore new hypotheses. We designed a database called the domestic animal gut microbiome atlas (ADDAGMA) to house all publicly available, high-throughput sequencing data for the gut microbiome in domestic animals. ADDAGMA enhances the availability and accessibility of the rapidly growing body of metagenomic data. We annotated microbial and metadata from four domestic animals (cattle, horse, pig, and chicken) from 356 published papers to construct a comprehensive database that is equipped with browse and search functions, enabling users to make customized, complicated, biologically relevant queries. Users can quickly and accurately obtain experimental information on sample types, conditions, and sequencing platforms, and experimental results including microbial relative abundances, microbial taxon-associated host phenotype, and P-values for gut microbes of interest. The current version of ADDAGMA includes 290,422 quantification events (changes in abundance) for 3215 microbial taxa associated with 48 phenotypes. ADDAGMA presently covers gut microbiota sequencing data from pig, cattle, horse, and chicken, but will be expanded to include other domestic animals. ADDAGMA is freely available at (http://addagma.omicsbio.info/).

How phosphorylation mediated by Insulin/IGF-1 Signaling kinases regulates lifespan remains unclear. Here the authors perform a large-scale quantitative phosphoproteomic analysis of wildtype and IIS mutant C. elegans strains to reveal detailed functional insights into longevity.

Growing evidence implies a link between DNA methylation and tumor immunity/immunotherapy. However, the global influence of DNA methylation on the characteristics of the tumor microenvironment and the efficacy of immunotherapy remains to be clarified. In this study, we systematically evaluated the DNA methylation regulator patterns and tumor microenvironment characteristics of 1,619 gastric cancer patients by clustering the gene expression of 20 DNA methylation regulators. Three gastric cancer subtypes that had different DNA methylation modification patterns and distinct tumor microenvironment characteristics were recognized. Then, a DNA methylation score (DMS) was constructed to evaluate DNA methylation modification individually. High DMS was characterized by immune activation status, increased tumor mutation burden, and tumor neoantigens, with a favorable prognosis. Conversely, activation of the stroma and absence of immune cell infiltration were observed in the low DMS group, with relatively poor survival. High DMS was also certified to be correlated with enhanced efficacy of immunotherapy in four immune checkpoint blocking treatment cohorts. In conclusion, the characterization of DNA methylation modification patterns may help to enhance our recognition of the tumor immune microenvironment of gastric cancer and guide more personalized immunotherapy strategies in the future.

Abstract Background Numerous reports on microRNAs have illustrated their role in tumor growth and metastasis. Recently, a new prognostic factor, miR‐125b‐2‐3p, has been identified for predicting chemotherapeutic sensitivity in advanced colorectal cancer (CRC). However, the specific mechanisms and biological functions of miR‐125b‐2‐3p in advanced CRC under chemotherapy have yet to be elucidated. Methods MiR‐125b‐2‐3p expression was detected by real‐time PCR (RT‐PCR) in CRC tissues. The effects of miR‐125b‐2‐3p on the growth, metastasis, and drug sensitivity of CRC cells were tested in vitro and in vivo. Based on multiple databases, the upstream competitive endogenous RNAs (ceRNAs) and the downstream genes for miR‐125b‐2‐3p were predicted by bioinformatic analysis, followed by the experiments including luciferase reporter assays, western blot assays, and so on. Results MiR‐125b‐2‐3p was significantly lowly expressed in the tissues and cell lines of CRC. Higher expression of miR‐125b‐2‐3p was associated with relatively lower proliferation rates and fewer metastases. Moreover, overexpressed miR‐125b‐2‐3p remarkably improved chemotherapeutic sensitivity of CRC in vivo and in vitro. Mechanistically, miR‐125b‐2‐3p was absorbed by long noncoding RNA (lncRNA) XIST regulating WEE1 G2 checkpoint kinase (WEE1) expression. The upregulation of miR‐125b‐2‐3p inhibited the proliferation and epithelial‐mesenchymal transition (EMT) of CRC induced by lncRNA XIST. Conclusions Lower miR‐125b‐2‐3p expression resulted in lower sensitivity of CRC to chemotherapy and was correlated with poorer survival of CRC patients. LncRNA XIST promoted CRC metastasis acting as a ceRNA for miR‐125b‐2‐3p to mediate WEE1 expression. LncRNA XIST‐miR‐125b‐2‐3p‐WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC.

Abstract Smad4, a key mediator of the transforming growth factor‐β signaling, is mutated or deleted in 20% of pancreatic ductal adenocarcinoma (PDAC) cancers and significantly affects cancer development. However, the effect of Smad4 loss on the immunogenicity and tumor immune microenvironment of PDAC is still unclear. Here, a surprising function of Smad4 in suppressing mouse PDAC tumor immunogenicity is identified. Although Smad4 deletion in tumor cells enhances proliferation in vitro, the in vivo growth of Smad4‐deficient PDAC tumor is significantly inhibited on immunocompetent C57BL/6 (B6) mice, but not on immunodeficient mice or CD8+ cell‐depleted B6 mice. Mechanistically, Smad4 deficiency significantly increases tumor cell immunogenicity by promoting spontaneous DNA damage and stimulating STING‐mediated type I interferon signaling,which contributes to the activation of type 1 conventional dendritic cells (cDC1) and subsequent CD8+ T cells for tumor control. Furthermore, retarded tumor growth of Smad4‐deficient PDAC cells on B6 mice is largely reversed when Sting is codeleted, or when the cells are implanted into interferon‐alpha receptor‐deficientmice or cDC1‐deficientmice. Accordingly, Smad4 deficiency promotes PDAC immunogenicity by inducing tumor‐intrinsic DNA damage‐elicited type I interferon signaling.

PFKFB3 enhances glycolysis to promote cancer cell proliferation. Here, the authors identify a long noncoding RNA in esophageal squamous cell carcinoma, AGPG, which interacts with PFKFB3 and promotes its stability, leading to increased glycolysis and proliferation.

Gastric cancer is one of the most common malignant tumours in the world. As one of the crucial hallmarks of cancer reprogramming of metabolism and the relevant researches have a promising application in the diagnosis treatment and prognostic prediction of malignant tumours. This study aims to identify a group of metabolism-related genes to construct a prediction model for the prognosis of gastric cancer.A large cohort of gastric cancer cases (1121 cases) from public database was included in our analysis and classified patients into training and testing cohorts at a ratio of 7: 3. After identifying a list of metabolism-related genes having prognostic value, we constructed a risk score based on metabolism-related genes using LASSO-COX method. According to the risk score, patients were divided into high- and low-risk groups. Our results revealed that high-risk patients had a significantly worse prognosis than low-risk patients in both the training (high-risk vs low-risk patients; five years overall survival: 37.2% vs 72.2%; p

Abstract Background Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target. Methods We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo. Results LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N6-methyladenosine (m6A) ‘reader’. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models. Conclusion LINRIS is an independent prognostic biomarker for CRC. The LINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.

Abstract Background Deregulation of protein translation control is a hallmark of cancers. Eukaryotic initiation factor 4A2 (EIF4A2) is required for mRNA binding to ribosome and plays an important role in translation initiation. However, little is known about its functions in colorectal cancer (CRC). Methods Analysis of CRC transcriptome data from TCGA identified that EIF4A2 was associated with poor prognosis. Immunohistochemistry study of EIF4A2 was carried out in 297 paired colorectal tumor and adjacent normal tissue samples. In vitro and in vivo cell-biological assays were performed to study the biological functions of EIF4A2 on experimental metastasis and sensitivity to oxaliplatin treatment. Bioinformatic prediction, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay were carried out to unveil the transcription factor of EIF4A2 regulation. Results EIF4A2 Expression is significantly higher in colorectal tumors. Multivariate analysis suggests EIF4A2 as an independent predictor of overall, disease-free and progression-free survival. Dysfunction of EIF4A2 by genetic knock-down or small-molecule inhibitor silvestrol dramatically inhibited CRC invasion and migration, sphere formation and enhanced sensitivity to oxaliplatin treatment in vitro and in vivo. Notably, EIF4A2 knock-down also suppressed lung metastasis in vivo. qRT-PCR and immunoblotting analyses identified c-Myc as a downstream target and effector of EIF4A2. ChIP and dual-luciferase reporter assays validated the bioinformatical prediction of ZNF143 as a specific transcription factor of EIF4A2. Conclusions EIF4A2 promotes experimental metastasis and oxaliplatin resistance in CRC. Silvestrol inhibits tumor growth and has synergistic effects with oxaliplatin to induce apoptosis in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models.

Abstract It has been proposed that the circadian rhythm generally plays important roles in tumor suppression, but there is also evidence that disruption of the canonical circadian pathway has anticancer effects. In this study, we systematically analyzed the aberrances of circadian clock genes across cancers based on data from The Cancer Genome Atlas (TCGA). These data showed that the frequencies of mutations and copy number alterations in core clock genes (PER1/2/3, CLOCK, CRY1/2, and ARNTL) were low, but that the expression levels of core clock genes were downregulated by the higher levels of DNA methylation in most tumors. The circadian clock index (CCI) was established through a principal component analysis, and this measure well represents the overall expression of the core clock genes. In fact, the CCI was significantly lower in hepatocellular carcinoma with HBV infection than in other cancers. Furthermore, pathways such as the MAPK, JAK‐STAT, and immune‐related signaling pathways were enriched in tumors with high CCI values. Interestingly, the CCI was generally positively related to the immunophenoscores and immunophenotypes of tumors. Additionally, the expression levels of core clock genes and the CCI were also generally positively related to survival across cancers. Taken together, the results of this study provide a comprehensive analysis of circadian clock aberrances in cancer, and the results should aid further investigations of the molecular mechanisms of cancer and the development of therapeutic strategies.

Thiol groups on cysteines can undergo multiple post-translational modifications (PTMs), acting as a molecular switch to maintain redox homeostasis and regulating a series of cell signaling transductions. Identification of sophistical protein cysteine modifications is crucial for dissecting its underlying regulatory mechanism. Instead of a time-consuming and labor-intensive experimental method, various computational methods have attracted intense research interest due to their convenience and low cost. Here, we developed the first comprehensive deep learning based tool pCysMod for multiple protein cysteine modification prediction, including S-nitrosylation, S-palmitoylation, S-sulfenylation, S-sulfhydration, and S-sulfinylation. Experimentally verified cysteine sites curated from literature and sites collected by other databases and predicting tools were integrated as benchmark dataset. Several protein sequence features were extracted and united into a deep learning model, and the hyperparameters were optimized by particle swarm optimization algorithms. Cross-validations indicated our model showed excellent robustness and outperformed existing tools, which was able to achieve an average AUC of 0.793, 0.807, 0.796, 0.793, and 0.876 for S-nitrosylation, S-palmitoylation, S-sulfenylation, S-sulfhydration, and S-sulfinylation, demonstrating pCysMod was stable and suitable for protein cysteine modification prediction. Besides, we constructed a comprehensive protein cysteine modification prediction web server based on this model to benefit the researches finding the potential modification sites of their interested proteins, which could be accessed at http://pcysmod.omicsbio.info. This work will undoubtedly greatly promote the study of protein cysteine modification and contribute to clarifying the biological regulation mechanisms of cysteine modification within and among the cells.

Background The advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival.Methods Whole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study.Results The HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1.Conclusions The combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

Methyltransferase-like 3 (METTL3), a major component of the N6-methyladenosine (m6A) methyltransferase complex, has been suggested to function as an oncogene in several cancers. However, its biological mechanism and the involved pathways in gastric cancer (GC) remain unknown. Here, we reported that frequent upregulation of METTL3 was responsible for the aberrant m6A levels in gastric carcinoma. On the other hand, a high level of METTL3 was significantly associated with several clinicopathological features and poor survival in patients with GC. The knockdown of METTL3 effectively inhibited cell proliferation and migration and invasion capacity. Moreover, overexpression of METTL3 considerably augmented its oncogenic function. Integrated RNA-seq and m6A-seq analysis first indicated that several component molecules (e.g., MCM5, MCM6, etc.) of MYC target genes were mediated by METTL3 via altered m6A modification. Our work uncovers the oncogenic roles of METTL3 in GC and suggests a critical mechanism of GC progression.

Abstract Objectives Although the genomic landscape of small‐cell carcinoma of the oesophagus (SCCE) has been dissected, its transcriptome‐level aberration and immune microenvironment status are unknown. Methods Using ultra‐deep whole transcriptome sequencing, we analysed the expression profile of nine paired SCCE samples and compared the transcriptome with public transcriptomic data set of normal oesophageal mucosa and other cancer types. Based on the transcriptome data, the immune signatures were investigated. The genomic data of 55 SCCE samples were also applied for immune checkpoint blockade therapy (ICBT) biomarker evaluation including microsatellite instability (MSI) status, tumor mutation burden (TMB) and neoantigen burden (TNB). Also, we evaluated the CD8, CD68 and programmed death‐ligand 1 (PD‐L1) in 62 retrospective SCCE samples with IHC assay. Results Differential expression analysis revealed that the cell cycle, p53, and Wnt pathways are significantly deregulated in SCCE. Immune microenvironment analysis showed that high leucocyte infiltration and adaptive immune resistance did occur in certain individuals, while the majority showed a relatively suppressive immune status. Immune checkpoints such as CD276 and LAG‐3 were upregulated, and higher M2 macrophage infiltration in tumor tissues. Furthermore, normal tissues adjacent to the tumors of SCCE presented a more activated inflammatory status than tumor‐free healthy controls. These observations showed that ICBT might benefit SCCE patients. As the critical biomarker of ICBT, TMB of SCCE was 3.64 with the predictive objective response rate 13.2%, while the PD‐L1‐positive rate was 43%. Conclusions Our study systematically characterized the immune microenvironment in small‐cell carcinoma of the esophagus and provided evidence that several patients with SCCE may benefit from immune checkpoint blockade therapy.

Overcoming oxidative stress is a critical step for tumor growth and metastasis, however the underlying mechanisms in gastric cancer remain unclear. In this study, we found that overexpression of nicotinamide nucleotide transhydrogenase (NNT) was associated with shorter overall and disease free survival in gastric cancer. The NNT is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Knockdown of NNT caused significantly NADPH reduction, induced high levels of ROS and significant cell apoptosis under oxidative stress conditions such as glucose deprival and anoikis. In vivo experiments showed that NNT promoted tumor growth, lung metastasis and peritoneal dissemination of gastric cancer. Moreover, intratumoral injection of NNT siRNA significantly suppressed gastric tumor growth in patient-derived xenograft (PDX) models. Overall, our study highlights the crucial functional roles of NNT in redox regulation and tumor progression and thus raises an important therapeutic hypothesis in gastric cancer. Keywords: NNT, Gastric cancer, NADPH, Anoikis resistance, Metastasis

As a widespread post-translational modification of proteins, calpain-mediated cleavage regulates a broad range of cellular processes, including proliferation, differentiation, cytoskeletal reorganization, and apoptosis. The identification of proteins that undergo calpain cleavage in a site-specific manner is the necessary foundation for understanding the exact molecular mechanisms and regulatory roles of calpain-mediated cleavage. In contrast with time-consuming and labor-intensive experimental methods, computational approaches for detecting calpain cleavage sites have attracted wide attention due to their efficiency and convenience. In this study, we established a novel computational tool named DeepCalpain (http://deepcalpain.cancerbio.info/) for predicting the potential calpain cleavage sites by adopting deep neural network and the particle swarm optimization algorithm. Through critical evaluation and comparison, DeepCalpain exhibited superior performance against other existing tools. Meanwhile, we found that protein interactions could enrich the calpain-substrate regulatory relationship. Since calpain-mediated cleavage was critical for cancer development and progression, we comprehensively analyzed the calpain cleavage associated mutations across 11 cancers with the help of DeepCalpain, which demonstrated that the calpain-mediated cleavage events were affected by mutations and heavily implicated in the regulation of cancer cells. These prediction and analysis results might provide helpful information to reveal the regulatory mechanism of calpain cleavage in biological pathways and different cancer types, which might open new avenues for the diagnosis and treatment of cancers.

Background: With comparable overall survival and local recurrence rates with mastectomy, breast-conserving surgery (BCS) has become the cornerstone of therapy for breast cancer; however, the difference in the incidence of suicide between BCS and mastectomy among breast cancer survivors remains unclear. This study evaluated the mortality risk from suicide among breast cancer survivors and compared suicide risk between BCS and mastectomy using a population-based cohort. Materials and methods: Female patients newly diagnosed with first primary breast cancer, recorded in the Surveillance, Epidemiology and End Results database, were included. Standardized mortality ratio (SMR) and cumulative mortality rate from suicide among those who underwent BCS and mastectomy were compared. Results: A total of 1 190 991 patients with newly diagnosed first primary breast cancer were included in the study, of whom 56.5% underwent BCS and 36.1% underwent mastectomy. During the follow-up period, 667 suicides were recorded. Patients who underwent mastectomy exhibited significantly higher suicide mortality than the general population [mortality rate, 8.16 per 100 000 person-years; SMR 1.18 (95% CI 1.05-1.33)], while there was no significant difference in suicide rate between patients who underwent BCS and the general population [SMR 0.92 (95% CI 0.83-1.02)]. Multivariate Cox analysis revealed that BCS, compared with mastectomy, was associated with a significantly decreased risk of suicide among females with breast cancer [hazard ratio 0.80 (95% CI 0.68-0.95); P = 0.009]. Conclusion: BCS was associated with a significantly lower incidence of suicide among females with breast cancer. BCS offers a compelling option for improving the quality of life and self-esteem of patients with cancer and provides a novel perspective on cancer management. [ABSTRACT FROM AUTHOR]