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Alzheimer's disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age‐related vascular alterations, a hallmark of AD onset and progression, are consistently associated with sexual dimorphism. Here, we conducted an integrative meta‐analysis of 335,803 single‐nucleus transcriptomes and 667 bulk transcriptomes from the vascular system in AD and normal aging to address the underlying sex‐dependent vascular aging in AD. All vascular cell types in male AD patients exhibited an activated hypoxia response and downstream signaling pathways including angiogenesis. The female AD vasculature is characterized by increased antigen presentation and decreased angiogenesis. We further confirmed that these sex‐biased alterations in the cerebral vascular emerged and were primarily determined in the early stages of AD. Sex‐stratified analysis of normal vascular aging revealed that angiogenesis and various stress‐response genes were downregulated concurrently with female aging. Conversely, the hypoxia response increased steadily in males upon aging. An investigation of upstream driver transcription factors (TFs) revealed that altered communication between estrogen receptor alpha (ESR1) and hypoxia induced factors during menopause contributes to the inhibition of angiogenesis during normal female vascular aging. Additionally, inhibition of CREB1, a TF that targets estrogen, is also related to female AD. Overall, our study revealed a distinct cerebral vascular profile in females and males, and revealed novel targets for precision medicine therapy for AD. [ABSTRACT FROM AUTHOR]

Background. Growing evidence has revealed that m6A modification of long noncoding RNAs (lncRNAs) dynamically controls tumor stemness and tumorigenesis-related processes. However, the prognostic significance of m6A-related lncRNAs and their associations with stemness in low-grade glioma (LGG) remain to be clarified. Methods. A multicenter transcriptome analysis of lncRNA expression in 1,247 LGG samples was performed in this study. The stemness landscape of LGG tumors was presented and associations with clinical features were revealed. The m6A-related lncRNAs were identified between stemness groups and were further prioritized via least absolute shrinkage and selection operator Cox regression analysis. A risk score model based on m6A-related lncRNAs was constructed and validated in external LGG datasets. Results. Based on the expression of LINC02984, PFKP-DT, and CRNDE, a risk model and nomogram were constructed; they successfully predicted the survival of patients and were extended to external datasets. Significant correlations were observed between the risk score and tumor stemness. Moreover, patients in different risk groups exhibited distinct tumor immune microenvironments and immune signatures. We finally provided several potential compounds suitable for specific risk groups, which may aid in LGG treatment. Conclusions. This novel signature presents noteworthy value in the prediction of prognosis and stemness status for LGG patients and will foster future research on the development of clinical regimens. [ABSTRACT FROM AUTHOR]

Background: Forkhead box (FOX) proteins belong to one of the largest transcription factor families and play crucial roles in the initiation and progression of cancer. Prior research has linked several FOX genes, such as FOXA1 and FOXM1, to the crucial process of carcinogenesis. However, the overall picture of FOX gene family across human cancers is far from clear. Methods: To investigate the broad molecular signatures of the FOX gene family, we conducted study on multi‐omics data (including genomics, epigenomics and transcriptomics) from over 11,000 patients with 33 different types of human cancers. Results: Pan‐cancer analysis reveals that FOX gene mutations were found in 17.4% of tumor patients with a substantial cancer type‐dependent pattern. Additionally, high expression heterogeneity of FOX genes across cancer types was discovered, which can be partially attributed to the genomic or epigenomic alteration. Co‐expression network analysis reveals that FOX genes may exert functions by regulating the expression of both their own and target genes. For a clinical standpoint, we provided 103 FOX gene‐drug target‐drug predictions and found FOX gene expression have potential survival predictive value. All of the results have been included in the FOX2Cancer database, which is freely accessible at http://hainmu‐biobigdata.com/FOX2Cancer. Conclusion: Our findings may provide a better understanding of roles FOX genes played in the development of tumors, and help to offer new avenues for uncovering tumorigenesis and unprecedented therapeutic targets. [ABSTRACT FROM AUTHOR]

The immune system plays a central role in many processes of age‐related disorders and it remains unclear if the innate immune system may play roles in shaping extreme longevity. By an integrated analysis with multiple bulk and single cell transcriptomic, so as DNA methylomic datasets of white blood cells, a previously unappreciated yet commonly activated status of the innate monocyte phagocytic activities is identified. Detailed analyses revealed that the life cycle of these monocytes is enhanced and primed to a M2‐like macrophage phenotype. Functional characterization unexpectedly revealed an insulin‐driven immunometabolic network which supports multiple aspects of phagocytosis. Such reprogramming is associated to a skewed trend of DNA demethylation at the promoter regions of multiple phagocytic genes, so as a direct transcriptional effect induced by nuclear‐localized insulin receptor. Together, these highlighted that preservation of insulin sensitivity is a key to healthy lifespan and extended longevity, via boosting the function of innate immune system in advanced ages. [ABSTRACT FROM AUTHOR]

Background: N6‐methyladenosine (m6A) plays an essential role in tumorigenesis and cancer progression. Long noncoding RNAs (lncRNAs) are discovered to be important targets of m6A modification, and they play fundamental roles in diverse biological processes. However, there is still a lack of knowledge with regards to the association between m6A and lncRNAs in human tumors. Methods: The relationship between lncRNAs and 21 m6A regulators was comprehensively explored, through the integration of multi‐omics data from M6A2Target, m6A‐Atlas, and TCGA (The Cancer Genome Atlas). In order to explore the potential roles of m6A‐related lncRNAs in human tumors, three applicable methods were introduced, which include the construction of ceRNA networks, drug sensitivity estimation, and survival analysis. Results: A substantial number of positive correlation events across 33 cancer types were found. Moreover, cancer‐specific lncRNAs were associated with tissue specificity, and cancer‐common lncRNAs were conserved in cancer‐related biological function. In particular, the m6A‐related lncRNA FGD5‐AS1 was found to be associated with cancer treatment, through its influence on cisplatin resistance in breast cancer patients. Finally, a user‐friendly interface Lnc2m6A, which is enriched with various browsing sections resource for the exhibition of relationships and putative biogenesis between lncRNAs and m6A modifications, is offered in http://hainmu‐biobigdata.com/Lnc2m6A. Conclusions: In summary, the results from this paper will provide a valuable resource that guides both mechanistic and therapeutic roles of m6A‐related lncRNAs in human tumors. [ABSTRACT FROM AUTHOR]

Pediatric central nervous system (CNS) tumors are the second most common cancer diagnosis among children. Long noncoding RNAs (lncRNAs) emerge as critical regulators of gene expression, and they play fundamental roles in immune regulation. However, knowledge on epigenetic changes in lncRNAs in diverse types of pediatric CNS tumors is lacking. Here, we integrated the DNA methylation profiles of 2,257 pediatric CNS tumors across 61 subtypes with lncRNA annotations and presented the epigenetically regulated landscape of lncRNAs. We revealed the prevalent lncRNA methylation heterogeneity across pediatric pan-CNS tumors. Based on lncRNA methylation profiles, we refined 14 lncRNA methylation clusters with distinct immune microenvironment patterns. Moreover, we found that lncRNA methylations were significantly correlated with immune cell infiltrations in diverse tumor subtypes. Immune-related lncRNAs were further identified by investigating their correlation with immune cell infiltrations and potentially regulated target genes. LncRNA with methylation perturbations potentially regulate the genes in immune-related pathways. We finally identified several candidate immune-related lncRNA biomarkers (i.e., SSTR5-AS1, CNTN4-AS1, and OSTM1-AS1) in pediatric cancer for further functional validation. In summary, our study represents a comprehensive repertoire of epigenetically regulated immune-related lncRNAs in pediatric pan-CNS tumors, and will facilitate the development of immunotherapeutic targets. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) is a common virus, and about 5% of all cancers worldwide is caused by persistent high-risk HPV infections. Here, we reported a comprehensive analysis of the molecular features for HPV-related cancer types using TCGA (The Cancer Genome Atlas) data with HPV status. We found that the HPV-positive cancer patients had a unique oncogenic process, tumor microenvironment, and drug response compared with HPV-negative patients. In addition, HPV improved overall survival for the four cancer types, namely, cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC). The stronger activity of cell-cycle pathways and lower driver gene mutation rates were observed in HPV-positive patients, which implied the different carcinogenic processes between HPV-positive and HPV-negative groups. The increased activities of immune cells and differences in metabolic pathways helped explain the heterogeneity of prognosis between the two groups. Furthermore, we constructed HPV prediction models for different cancers by the virus infection score (VIS) which was linearly correlated with HPV load and found that VIS was associated with drug response. Altogether, our study reveals that HPV-positive cancer patients have unique molecular characteristics which help the development of precision medicine in HPV-positive cancers. [ABSTRACT FROM AUTHOR]

Drug–target association plays an important role in drug discovery, drug repositioning, drug synergy prediction, etc. Currently, a lot of drug-related databases, such as DrugBank and BindingDB, have emerged. However, these databases are separate, incomplete and non-uniform with different criteria. Here, we integrated eight drug-related databases; collected, filtered and supplemented drugs, target genes and experimentally validated (highly confident) associations and built a highly confident drug–target (HCDT: http://hainmu-biobigdata.com/hcdt) database. HCDT database includes 500 681 HCDT associations between 299 458 drugs and 5618 target genes. Compared to individual databases, HCDT database contains 1.1 to 254.2 times drugs, 1.8–5.5 times target genes and 1.4–27.7 times drug–target associations. It is normative, publicly available and easy for searching, browsing and downloading. Together with multi-omics data, it will be a good resource in analyzing the drug functional mechanism, mining drug-related biological pathways, predicting drug synergy, etc. Database URL : http://hainmu-biobigdata.com/hcdt [ABSTRACT FROM AUTHOR]

Melioidosis is a serious infectious disease caused by the environmental Gram-negative bacillus Burkholderia pseudomallei. It has been shown that the host immune system, mainly comprising various types of immune cells, fights against the disease. The present study was to specify correlation between septicemic melioidosis and the levels of multiple immune cells. First, the genes with differential expression patterns between patients with septicemic melioidosis (B. pseudomallei) and health donors (control/healthy) were identified. These genes being related to cytokine binding, cell adhesion molecule binding, and MHC relevant proteins may influence immune response. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed 23 enriched immune response pathways. We further leveraged the microarray data to investigate the relationship between immune response and septicemic melioidosis, using the CIBERSORT analysis. Comparison of the percentages of 22 immune cell types in B. pseudomallei vs. control/healthy revealed that those of CD4 memory resting cells, CD8+ T cells, B memory cells, and CD4 memory activated cells were low, whereas those of M0 macrophages, neutrophils, and gamma delta T cells were high. The multivariate logistic regression analysis further revealed that CD8+ T cells, M0 macrophages, neutrophils, and naive CD4+ cells were strongly associated with the onset of septicemic melioidosis, and M2 macrophages and neutrophils were associated with the survival in septicemic melioidosis. Taken together, these data point to a complex role of immune cells on the development and progression of melioidosis. [ABSTRACT FROM AUTHOR]

Cystatin E/M (CST6), a representative cysteine protease inhibitor, plays both tumor-promoting and tumor-suppressing functions and is pursued as an epigenetically therapeutic target in special cancer types. However, a comprehensive and systematic analysis for CST6 in pan-cancer level is still lacking. In the present study, we explored the expression pattern of CST6 in multiple cancer types across ∼10,000 samples from TCGA (The Cancer Genome Atlas) and ∼8,000 samples from MMDs (Merged Microarray-acquired Datasets). We found that the dynamic expression alteration of CST6 was consistent with dual function in different types of cancer. In addition, we observed that the expression of CST6 was globally regulated by the DNA methylation in its promoter region. CST6 expression was positively correlated with the epithelial cell infiltration involved in epithelial-to-mesenchymal transition (EMT) and proliferation. The relationship between CST6 and tumor microenvironment was also explored. In particular, we found that CST6 serves a protective function in the process of melanoma metastasis. Finally, the clinical association analysis further revealed the dual function of CST6 in cancer, and a combination of the epithelial cell infiltration and CST6 expression could predict the prognosis for SKCM patients. In summary, this first CST6 pan-cancer study improves the understanding of the dual functional effects on CST6 in different types of human cancer. [ABSTRACT FROM AUTHOR]

Differential co-expression-based pathway analysis is still limited and not widely used. In most current methods, the pathways were considered as gene sets, but the gene regulation relationships were not considered, and the computational speed was slow. In this article, we proposed a novel Dysregulated Pathway Identification Analysis (DysPIA) method to overcome these shortcomings. We adopted the idea of Correlation by Individual Level Product into analysis and performed a fast enrichment analysis. We constructed a combined gene-pair background which was much more sufficient than the background used in Edge Set Enrichment Analysis. In simulation study, DysPIA was able to identify the causal pathways with high AUC (0.9584 to 0.9896). In p53 mutation data, DysPIA obtained better performance than other methods. It obtained more potential dysregulated pathways that could be literature verified, and it ran much faster (∼1,700–8,000 times faster than other methods when 10,000 permutations). DysPIA was also applied to breast cancer relapse dataset and breast cancer subtype dataset. The results show that DysPIA is effective and has a great biological significance. R packages "DysPIA" and "DysPIAData" are constructed and freely available on R CRAN (https://cran.r-project.org/web/packages/DysPIA/index.html and https://cran.r-project.org/web/packages/DysPIAData/index.html), and on GitHub (https://github.com/lemonwang2020). [ABSTRACT FROM AUTHOR]

Noncoding RNAs (ncRNAs), especially microRNA (miRNA) and long noncoding RNA (lncRNA), have an impact on a variety of important biological processes during colon adenocarcinoma (COAD) progression. This includes chromatin organization, transcriptional and posttranscriptional regulation, and cell-cell signaling. The aim of this study is to identify the ncRNA-regulated modules that accompany the progression of COAD and to analyze their mechanisms, in order to screen the potential prognostic biomarkers for COAD. An integrative molecular analysis was carried out to identify the crosstalks of gene modules between different COAD stages, as well as the essential ncRNAs in the posttranscriptional regulation of these modules. 31 ncRNA regulatory modules were found to be significantly associated with overall survival in COAD patients. 17 out of the 31 modules (in which ncRNAs played essential roles) had improved the predictive ability for COAD patient survival compared to only the mRNAs of those modules, which were enriched in the core cancer hallmark pathways with closer interactions. These suggest that the ncRNAs' regulatory modules not only exhibit close relation to COAD progression but also reflect the dynamic significant crosstalk of genes in the modules to the different malignant extent of COAD. [ABSTRACT FROM AUTHOR]

Autophagy is a self-degradation process that maintains homeostasis against stress in cells. Autophagy dysfunction plays a central role in the development of tumors, such as colorectal cancer (CRC). In this study, autophagy-related differentially expressed genes, their downstream functions, and upstream regulatory factors including RNA-binding proteins (RBP) involved in programmed cell death in the CRC were investigated. Transcription factors (TFs) and miRNAs have been shown to mainly regulate autophagy genes. Interestingly, we found that some of the RBP in the CRC, such as DDX17, SETDB1, and POLR3A, play an important regulatory role in maintaining autophagy at a basal level during growth by acting as TFs that regulate autophagy. Promoter methylations showed negative regulations on differentially expressed autophagy gene (DEAG), while copy number variations revealed a positive role in them. A proportional hazards regression analysis indicated that using autophagy-related prognostic signature can divide patients into high-risk and low-risk groups. Autophagy associated FDA-approved drugs were studied by a prognostic network. This would contribute to the identifications of new potential molecular therapeutic targets for CRC. [ABSTRACT FROM AUTHOR]

Recent evidence has suggested that competitive endogenous RNAs (ceRNAs) are important regulatory molecules in clear cell kidney carcinoma (KIRC) and their dysregulation may contribute to cancer pathogenesis. However, the critical roles of dysregulated ceRNAs in KIRC remain unknown. In the present study, a KIRC dysregulated ceRNA‑ceRNA network (KDCCNet) was constructed based on the ʻceRNA hypothesisʼ by integrating microRNA regulation and expression profiles in cancerous and normal tissues. Two dysregulated patterns of ceRNAs interaction (gain and loss) exist in KDCCNet. The two modules, which are 95% loss interactions and 97% gain interactions, were demonstrated to be able to distinguish normal samples from cancer samples. Two long non‑coding (lnc)‑RNAs (glucuronidase β pseudogene 11 and LIFR antisense RNA 1) demonstrated significant associations with KIRC prognosis. The present study of the KDCCNet revealed a novel biological mechanism for KIRC and provides novel lncRNAs as candidate prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Gene expression profiles have drawn broad attention in deciphering the pathogenesis of human cancers. Cancer-related gene modules could be identified in co-expression networks and be applied to facilitate cancer research and clinical diagnosis. In this paper, a new method was proposed to identify lung cancer-risk modules and evaluate the module-based disease risks of samples. The results showed that thirty one cancer-risk modules were closely related to the lung cancer genes at the functional level and interactional level, indicating that these modules and genes might synergistically lead to the occurrence of lung cancer. Our method was proved to have good robustness by evaluating the disease risk of samples in eight cancer expression profiles (four for lung cancer and four for other cancers), and had better performance than the WGCNA method. This method could provide assistance to the diagnosis and treatment of cancers and a new clue for explaining cancer mechanisms. [ABSTRACT FROM AUTHOR]

Ovarian cancer remains a dismal disease with diagnosing in the late, metastatic stages, therefore, there is a growing realization of the critical need to develop effective biomarkers for understanding underlying mechanisms. Although existing evidences demonstrate the important role of the single genetic abnormality in pathogenesis, the perturbations of interactors in the complex network are often ignored. Moreover, ovarian cancer diagnosis and treatment still exist a large gap that need to be bridged. In this work, we adopted a network-based survival-associated approach to capture a 12-gene network module based on differential co-expression PPI network in the advanced-stage, high-grade ovarian serous cystadenocarcinoma. Then, regulatory genes (protein-coding genes and non-coding genes) direct interacting with the module were found to be significantly overlapped with cell death genes. More importantly, these overlapping genes tightly clustered together pointing to the module, deciphering the crosstalk between network-based survival-associated module and cell death in ovarian cancer. [ABSTRACT FROM AUTHOR]

Synthetic biologists have developed DNA/molecular modules that perform genetic logic operations in living cells to track key moments in a cell's life or change the fate of a cell. Increasing evidence has also revealed that diverse genetic logic gates capable of generating a Boolean function play critically important roles in synthetic biology. Basic genetic logic gates have been designed to combine biological science with digital logic. SynBioLGDB (http://bioinformatics.ac.cn/synbiolgdb/) aims to provide the synthetic biology community with a useful resource for efficient browsing and visualization of genetic logic gates. The current version of SynBioLGDB documents more than 189 genetic logic gates with experimental evidence involving 80 AND gates and 16 NOR gates, etc. in three species (Human, Escherichia coli and Bacillus clausii). SynBioLGDB provides a user-friendly interface through which conveniently to query and browse detailed information about these genetic logic gates. SynBioLGDB will enable more comprehensive understanding of the connection of genetic logic gates to execute complex cellular functions in living cells. [ABSTRACT FROM AUTHOR]