Identification of prognostic biomarkers for cervical cancer based on programmed cell death-related genes and assessment of their immune profile and response to drug therapy.

BACKGROUND: Programmed cell death (PCD) has been widely investigated in various human diseases. The present study aimed to identify a novel PCD-related genetic signature in cervical squamous cell carcinoma (CESC) to provide clues for survival, immunotherapy and drug sensitization prediction. METHODS: Single-sample gene set enrichment analysis (ssGSEA) was used to quantify the PCD score and assess the distribution of PCD in clinicopathological characteristics in The Cancer Genome Atlas (TCGA)-CESC samples. Then, the ConsensusClusterPlus method was used to identify molecular subtypes in the TCGA-CESC database. Genomic mutation analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment, as well as tumor microenvironment (TME) infiltration analysis, were performed for each molecular subtype group. Finally, a prognostic model by Uni-Cox and least absolute shrinkage and selection operator-Cox analysis was established based on differentially expressed genes from molecular subtypes. ESTIMATE (i.e. Estimation of STromal and Immune cells in MAlignantTumours using Expression data) and ssGSEA were performed to assess the correlation between the model and TME. Drug sensitization prediction was carried out with the oncoPredict package. RESULTS: Preliminary analysis indicated that PCD had a potential association clinical characteristics of the TCGA-CESC cohort, and PCD-related genes mutated in 289 (70.59%) CESC patients. Next, four groups of CESC molecular typing were clustered based on 63 significantly prognostic PCD-related genes. Among four subtypes, C1 group displayed the worst prognosis combined with over expressed PCD genes and enriched cell cycle-related pathways. C4 group exhibited the best prognosis accompanied with high degree of immune infiltration. Finally, a five-gene (SERPINE1, TNF, CA9, CX3CL1 and JAK3) prognostic model was constructed. Patients in the high-risk group displayed unfavorable survival. Immune infiltration analysis found that the low-risk group had significantly higher levels of immune cell infiltration such as T cells, Macrophages_M1, relative to the high-risk group, and were significantly enriched in apoptosis-associated pathways, which predicted a higher level of immunity. Drug sensitivity correlation analysis revealed that the high-risk group was resistant to conventional chemotherapeutic drugs and sensitive to the Food and Drug Administration-approved drugs BI.2536_1086 and SCH772984_1564. CONCLUSIONS: In the present study, we first found that PCD-related gene expression patterns were correlated with clinical features of CESC patients, which predicts the feasibility of subsequent mining of prognostic features based on these genes. The five-PCD-associated-gene prognostic model showed good assessment ability in predicting patient prognosis, immune response and drug-sensitive response, and provided guidance for the elucidation of the mechanism by which PCD affects CESC, as well as for the clinical targeting of drugs.

Identifying and characterizing drug sensitivity-related lncRNA-TF-gene regulatory triplets.

Recently, many studies have shown that lncRNA can mediate the regulation of TF-gene in drug sensitivity. However, there is still a lack of systematic identification of lncRNA-TF-gene regulatory triplets for drug sensitivity. In this study, we propose a novel analytic approach to systematically identify the lncRNA-TF-gene regulatory triplets related to the drug sensitivity by integrating transcriptome data and drug sensitivity data. Totally, 1570 drug sensitivity-related lncRNA-TF-gene triplets were identified, and 16 307 relationships were formed between drugs and triplets. Then, a comprehensive characterization was performed. Drug sensitivity-related triplets affect a variety of biological functions including drug response-related pathways. Phenotypic similarity analysis showed that the drugs with many shared triplets had high similarity in their two-dimensional structures and indications. In addition, Network analysis revealed the diverse regulation mechanism of lncRNAs in different drugs. Also, survival analysis indicated that lncRNA-TF-gene triplets related to the drug sensitivity could be candidate prognostic biomarkers for clinical applications. Next, using the random walk algorithm, the results of which we screen therapeutic drugs for patients across three cancer types showed high accuracy in the drug-cell line heterogeneity network based on the identified triplets. Besides, we developed a user-friendly web interface-DrugSETs (http://bio-bigdata.hrbmu.edu.cn/DrugSETs/) available to explore 1570 lncRNA-TF-gene triplets relevant with 282 drugs. It can also submit a patient's expression profile to predict therapeutic drugs conveniently. In summary, our research may promote the study of lncRNAs in the drug resistance mechanism and improve the effectiveness of treatment.

RNF183 Promotes Colon Cancer Cell Stemness through Fatty Acid Oxidation.

Colon cancer (COAD) is a prevalent gastrointestinal tumor, composed of a few cancer stem cells (CSCs). High expression of RNF183 drives colorectal cancer metastasis, but its role in COAD cell stemness is still unclear. Bioinformatics analyzed expression and enriched pathway of RNF183 in COAD tissue. IHC analyzed RNF183 protein expression in tumor tissue. CD133 + CD44+ CSCs were sorted by flow cytometry, and RNF183 expression in COAD cells or CSCs was detected by qPCR, western blot and immunofluorescence. CCK-8 assay assessed cell viability, and sphere formation assay tested cell sphere-forming ability. Western blot measured protein expression of stem cell markers. qPCR assayed expression of fatty acid oxidation genes. The ability of fatty acid oxidation was analyzed by detecting fatty acid metabolism. RNF183 was highly expressed in COAD and CD133 + CD44+ CSCs, and was enriched in fatty acid metabolism pathway. RNF183 expression was positively correlated with enzymes involved in fatty acid oxidation. RNF183 could promote COAD stemness and fatty acid oxidation. Rescue experiments showed that Orlistat (a fatty acid oxidation inhibitor) reversed stimulative impact of RNF183 overexpression on COAD stemness. RNF183 promoted COAD stemness by affecting fatty acid oxidation, which may be a new therapeutic target for inhibiting COAD development.

Pd(II)-Catalyzed ß-C(sp3)-H Alkynylation of Alanine in Di- and Tripeptides with Asn as an Endogenous Directing Group.

The introduction of alkyne moieties into peptides remains in demand as it represents a promising approach for further structural diversification of peptides. Herein, we describe the Pd(II)-catalyzed C(sp3)-H alkynylation of Ala-Asn-embedded di- and tripeptides using Asn as the endogenous lead group. In addition, a key building block for the glycopeptide Tyc4PG-14 and Tyc4PG-15 was produced by our methodology.

Identification of novel 3-aryl-1-aminoisoquinolines-based KRASG12C inhibitors: Rational drug design and expedient construction by CH functionalization/annulation.

Developing a synthetic methodology to expediently construct a specific drug scaffold with the desired biological activity remains challenging. Herein, we describe a work on rational application of a synthetic methodology in the synthesis of KRASG12C inhibitors. Novel KRASG12C inhibitors were initially designed with 1-amino-3-aryl isoquinoline scaffold using structure-based drug design strategy. A ruthenium-catalyzed direct monoCH functionalization/annulation cascade reaction of amidines and sulfoxonium ylides was then developed with high versatility of substrates and good tolerance for polar functional groups. By using this reaction, the target compounds 1-amino-3-aryl isoquinolines were facilely prepared. Further in vitro tests led to identification of two novel lead compounds with KRASG12C inhibitory activity.

The Influence Factors of Hypoparathyroidism after Thyroidectomy and the Effect of Recovery Treatment.

Objective: This study aims to investigate the influencing factors of transient hypoparathyroidism following thyroidectomy and assess the effects of rehabilitation treatment, focusing on enhancing management and outcomes for patients. Methods: In this retrospective study, 90 patients who underwent thyroidectomy in our hospital from February 2021 to February 2023 were collected. According to the postoperative level of parathyroid hormone (PTH), the patients were divided into normal group [(no hypoparathyroidism, ≥ 0.27 pmol/l), n=65] and hypoparathyroidism (transient hypoparathyroidism, < 0.27 pmol/l, n=25). We retrospectively analyzed 90 thyroidectomy patients, categorizing them into normal and hypoparathyroidism groups based on postoperative parathyroid hormone levels. Logistic regression and ROC curve analysis were employed to evaluate the factors influencing transient hypoparathyroidism and predict recovery.Clinical data of the two groups of patients were collected, and the relationship between postoperative 1dPTH (Parathyroid hormone levels on the first postoperative day) level and recovery effect was analyzed. Logistic regression was used to analyze the influencing factors of temporary hypoparathyroidism after thyroidectomy, and a ROC curve was used to predict the efficacy of the 1dPTH level on postoperative PTH recovery time. Results: There were no differences in gender, hypertension, diabetes and hyperlipidemia between the two groups (P > .05). The age and tumor diameter of the normal group were lower than those of the hypoactive group, and the proportion of patients with thyroiditis and malignant tumors, as well as patients undergoing total thyroidectomy and removal of tracheoesophageal lymph nodes in the normal group were significantly lower than those in the hypoactive group. The above differences were statistically significant (P < .05). Logistic regression analysis showed that older age, malignant tumor, larger tumor diameter, total thyroidectomy, and tracheoesophageal lymph node dissection were independent risk factors for transient hypoparathyroidism after thyroidectomy (P < .05). The level of PTH on the 1st day after surgery in patients with recovery time ≤ 1 month was higher than that in patients with recovery time > 1 month, and the difference was statistically significant (P < .05). ROC curve showed that the PTH level on the 1st day after surgery had a certain predictive value on PTH recovery time, and the AUC value (area under the curve) was 0.873 (P < .05). These findings suggest that patients with older age, malignancy, larger tumor diameter, total thyroidectomy, and removal of tracheoesophageal lymph nodes are more likely to develop transient hypoparathyroidism after thyroidectomy. This understanding is crucial for the management of postoperative patients, and physicians may need to pay special attention to these high-risk patients and implement appropriate interventions to reduce the occurrence of hypoparathyroidism. Significant factors contributing to transient hypoparathyroidism included older age, malignant tumors, larger tumor diameter, total thyroidectomy, and tracheoesophageal lymph node dissection. These findings, backed by statistical significance, underline the clinical relevance of these risk factors in postoperative management. Conclusion: The study identifies key risk factors for transient hypoparathyroidism post-thyroidectomy, emphasizing the need for tailored postoperative care. The predictive value of immediate postoperative PTH levels could guide clinical management to mitigate hypoparathyroidism risks.

The Discovery of Highly Efficient and Promising ABA Receptor Antagonists for Agricultural Applications Based on APAn Modification.

Abscisic acid (ABA) is one of the many naturally occurring phytohormones widely found in plants. This study focused on refining APAn, a series of previously developed agonism/antagonism switching probes. Twelve novel APAn analogues were synthesized by introducing varied branched or oxygen-containing chains at the C-6' position, and these were screened. Through germination assays conducted on A. thaliana, colza, and rice seeds, as well as investigations into stomatal movement, several highly active ABA receptor antagonists were identified. Microscale thermophoresis (MST) assays, molecular docking, and molecular dynamics simulation showed that they had stronger receptor affinity than ABA, while PP2C phosphatase assays indicated that the C-6'-tail chain extending from the 3' channel effectively prevented the ligand-receptor binary complex from binding to PP2C phosphatase, demonstrating strong antagonistic activity. These antagonists showed effective potential in promoting seed germination and stomatal opening of plants exposed to abiotic stress, particularly cold and salt stress, offering advantages for cultivating crops under adverse conditions. Moreover, their combined application with fluridone and gibberellic acid could provide more practical agricultural solutions, presenting new insights and tools for overcoming agricultural challenges.

Photocatalytic Upgrading of Polylactic Acid Waste into Alanine under Mild Conditions.

Polylactic acid (PLA) has attracted increasing interest as a sustainable plastic because it can be degraded into CO2 and H2O in nature. However, this process is sluggish, and even worse, it is a CO2-emitting and carbon resource waste process. Therefore, it is highly urgent to develop a novel strategy for recycling post-consumer PLA to achieve a circular plastic economy. Herein, we report a one-pot photoreforming route for the efficient and selective amination of PLA waste into value-added alanine using CoP/CdS catalysts under mild conditions. Results show the alanine production rate can reach up to 2.4 mmol gcat -1 h-1, with a high selectivity (>75 %) and excellent stability. Time-resolved transient absorption spectra (TAS) reveal that CoP can rapidly extract photogenerated electrons from CdS to accelerate proton reduction, favoring hole-dominated PLA oxidation to coproduce alanine. This study offers an appealing way for upcycling PLA waste and creates new opportunities for green synthesis of amino acids.

Interfullerene Electronic Interactions and Excited-State Dynamics in Fullerene Dumbbell Conjugates.

Several dumbbell conjugates featuring M3N@Ih-C80 (M = Sc, Y) and C60 were prepared to systematically investigate interfullerene electronic interactions and excited state dynamics. From electrochemical investigations, we concluded that the redox potentials of our M3N@Ih-C80 (M = Sc, Y) dumbbells depend largely on the interfullerene electronic interactions. Assisted by DFT calculation, the unique role of metal atoms was highlighted. Most importantly, ultrafast spectroscopy experiments revealed symmetry-breaking charge separation in Sc3N@C80-dumbbell to yield an unprecedented (Sc3N@C80)•+-(Sc3N@C80)•- charge separated state. This is, to the best of our knowledge, the first time that symmetry-breaking charge separation following photoexcitation is corroborated in a fullerene system. As such, our work shed light on the significance of interfullerene electronic interactions and their uniqueness for modulating excited state properties.

CiTSA: a comprehensive platform provides experimentally supported signatures of cancer immunotherapy and analysis tools based on bulk and scRNA-seq data.

Immunotherapy has greatly changed the status of cancer treatment, and many patients do not respond or develop acquired resistance. The related research is blocked by lacking of comprehensive resources for researchers to discovery and analysis signatures, then further exploring the mechanisms. Here, we first offered a benchmarking dataset of experimentally supported signatures of cancer immunotherapy by manually curated from published literature works and provided an overview. We then developed CiTSA ( http://bio-bigdata.hrbmu.edu.cn/CiTSA/ ) which stores 878 entries of experimentally supported associations between 412 signatures such as genes, cells, and immunotherapy across 30 cancer types. CiTSA also provides flexible online tools to identify and visualize molecular/cell feature and interaction, to perform function, correlation, and survival analysis, and to execute cell clustering, cluster activity, and cell-cell communication analysis based on single cell and bulk datasets of cancer immunotherapy. In summary, we provided an overview of experimentally supported cancer immunotherapy signatures and developed CiTSA which is a comprehensive and high-quality resource and is helpful for understanding the mechanism of cancer immunity and immunotherapy, developing novel therapeutic targets and promoting precision immunotherapy for cancer.

Cascade Alkenylation/Intramolecular Friedel-Crafts Alkylation: High Selectivity at the C7-Position of BINOL.

An efficient and straightforward approach for the synthesis of C7 site-selective BINOL derivatives has been achieved via cost-effective Co(III)-catalyzed C-H cascade alkenylation/intramolecular Friedel-Crafts alkylation of BINOL units and propargyl cycloalkanols. Under the advantage of the pyrazole directing group, the protocol allows the rapid synthesis of various BINOL-tethered spiro[cyclobutane-1,1'-indenes].

C-O Coupling/[4+2] Cycloaddition Tandem Reactions via Oxidative Dearomatization of BINOLs: Access to Bridged Polycyclic Compounds.

Intramolecular C-H activation/C-O coupling, dearomatization, and [4+2] cycloaddition of BINOL units have been well developed in a one-pot approach with maleimide derivatives as the dienophiles. This tandem catalytic system generates a variety of functionalized bridged polycyclic products in a step-economical manner, which greatly enriches the modification methods and strategies for the BINOL skeletons.

MicroRNA-3653-3p inhibited papillary thyroid carcinoma progression by regulating CRIPTO-1.

Papillary thyroid carcinoma (PTC) is the most common endocrine malignant tumor and the metastasis of PTC often leads to unfavorable prognosis. Thus, the purpose of the current research was to mainly explore the role of miR-3653-3p in PTC progression. The expression level of miR-3653-3p in PTC was determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), and Cell Counting Kit-8 (CCK-8) assay and colony formation assay were recruited to assess the ability of miR-3653-3p on cell proliferation. Next, transwell assay and Matrigel assay were involved to examine the ability of miR-3653-3p on cell migration and invasion. At last, Dual-Luciferase reporter assay and Western blotting were recruited to validate the down-stream target of miR-3653-3p. Results showed that miR-3653-3p was down-expressed in PTC, and upregulated miR-3653-3p inhibited cell proliferation, cell migration, and cell invasion in vitro. In addition, CRIPTO-1 was a downstream target of miR-3653-3p, and miR-3653-3p inhibited PTC progression via regulating CRIPTO-1. In sum, this research verifies that miR-3653-3p suppresses cell proliferation, migration, and invasion in PTC via regulating CRIPTO-1. These findings provide new insight into the underlying mechanism of PTC progression and may be useful in finding biomarkers and therapeutic targets of PTC.

MiRNA-21-5p Accelerates EMT and Inhibits Apoptosis of Laryngeal Carcinoma via Inhibiting KLF6 Expression.

The incidence of laryngeal carcinoma accounts for 1 to 5% of systemic malignancies and ranks second among head and neck malignancies. Screening more effective targets are meaningful for the treatment of laryngeal carcinoma. The purpose was to research the action of miR-21-5p in the occurrence of laryngeal carcinoma. Genecards combined with g:profiler was used for cluster analysis to predict gene-related miRNAs. Q-PCR assay was performed for measuring the level of miR-21-5p and Kruppel-like factor 6 (KLF6). miR-21-5p-mimic, miR-21-5p-inhibitor and sh-KLF6 were transfected using LipofectamineTM 2000. Both CCK-8 and EdU experiments were undertaken to detect cell proliferation ability. Western blot was used to detect apoptosis and epithelial-mesenchymal transition (EMT) related proteins. Wound healing assay and transwell assay were undertaken for migration and invasion, respectively. Three online software (ENCORI, miRWalk, and miRDB) were applied to screen the downstream of miR-21-5p. At the same time, a dual-luciferase reporter experiment was processed to verify the binding. Finally, a rescue experiment was applied to reveal the mediating role of miR-21-5p and KLF6. MiR-21-5p expressed highly in laryngeal carcinoma tissues and cell lines. Knockdown of miR-21-5p reduced the EMT, while enhancing apoptosis of laryngeal carcinoma cell lines. MiR-21-5p targeted KLF6 with negative relationships. The rescue assay results confirmed that sh-KLF6 rescued the action of miR-21-5p knockdown in developing laryngeal carcinoma cells. MiR-21-5p promotes the occurrence and development of laryngeal cancer by targeting KLF6. This finding may provide new insights into miRNA as a biomarker for diagnosing and treating laryngeal carcinoma in the future.

Mortality burden based on the associations of ambient PM2.5 with cause-specific mortality in China: Evidence from a death-spectrum wide association study (DWAS).

Although studies have estimated the associations of PM2.5 with total mortality or cardiopulmonary mortality, few have comprehensively examined cause-specific mortality risk and burden caused by ambient PM2.5. Thus, this study investigated the association of short-term exposure to PM2.5 with cause-specific mortality using a death-spectrum wide association study (DWAS). Individual information of 5,450,764 deaths during 2013-2018 were collected from six provinces in China. Daily PM2.5 concentration in the case and control days were estimated by a random forest model. A time-stratified case-crossover study design was applied to estimate the associations (access risk, ER) of PM2.5 with cause-specific mortality, which was then used to calculate the population-attributable fraction (PAF) of mortality and the corresponding mortality burden caused by PM2.5. Each 10 µg/m3 increase in PM2.5 concentration (lag03) was associated with a 0.80 % [95 % confidence interval (CI): 0.73 %, 0.86 %] rise in total mortality. We found greater mortality effect at PM2.5 concentrations < 50 µg/m3. Stratified analyses showed greater ERs in females (1.01 %, 95 %CI: 0.91 %, 1.11 %), children ≤ 5 years (2.17 %, 95 %CI: 0.85 %, 3.51 %), and old people ≥ 70 years. We identified 33 specific causes (level 2) of death which had significant associations with PM2.5, including 16 circulatory diseases, 9 respiratory diseases, and 8 other causes. The PAF estimated based on the overall association between PM2.5 and total mortality was 3.16 % (95 %CI: 2.89 %, 3.40 %). However, the PAF was reduced to 2.88 % (95 %CI: 1.88 %, 3.81 %) using the associations of PM2.5 with 33 level 2 causes of death, based on which 250.15 (95 %CI: 163.29, 330.93) thousand deaths were attributable to short-term PM2.5 exposure across China in 2019. Overall, this study provided a comprehensive picture on the death-spectrum wide association between PM2.5 and morality in China. We observed robust positive cause-specific associations of PM2.5 with mortality risk, which may provide more precise basis in assessing the mortality burden of air pollution.

Comprehensive analysis of ncRNA involvement in brain microglia immunology.

Microglia is a major class of brain-resident myeloid cells and non-coding RNAs (ncRNAs) serves as key regulators in microglia homeostasis and inflammatory process. Here, we constructed the systematical association between microglia and ncRNAs including miRNAs, lncRNAs and circRNAs from two aspects, manual retrieval and computational detection. A total of 648 experimental verified ncRNA-microglia associations were obtained from published studies, including ncRNA regulatory patterns within different experimental models. Furthermore, we extracted 9 miRNA and 1 lncRNA expression profiles from the GEO database. Also, we obtained 31 sample-match miRNA and mRNA expression profiles, containing a total of 2335 normal or disordered brain samples. Finally, we developed a platform named MG-ncRexplorer (http://bio-bigdata.hrbmu.edu.cn/MG-ncRexplorer/), exploring the associations between ncRNAs and microglia among experimental validated and computational detection. To demonstrate the usage of MG-ncRexplorer, we constructed regulatory target networks based on manual retrieval associations and identified risk glioma miRNAs among multiple high-throughput expression profiles.

A comprehensive overview of oncogenic pathways in human cancer.

Alterations of biological pathways can lead to oncogenesis. An overview of these oncogenic pathways would be highly valuable for researchers to reveal the pathogenic mechanism and develop novel therapeutic approaches for cancers. Here, we reviewed approximately 8500 literatures and documented experimentally validated cancer-pathway associations as benchmarking data set. This data resource includes 4709 manually curated relationships between 1557 paths and 49 cancers with 2427 upstream regulators in 7 species. Based on this resource, we first summarized the cancer-pathway associations and revealed some commonly deregulated pathways across tumor types. Then, we systematically analyzed these oncogenic pathways by integrating TCGA pan-cancer data sets. Multi-omics analysis showed oncogenic pathways may play different roles across tumor types under different omics contexts. We also charted the survival relevance landscape of oncogenic pathways in 26 tumor types, identified dominant omics features and found survival relevance for oncogenic pathways varied in tumor types and omics levels. Moreover, we predicted upstream regulators and constructed a hierarchical network model to understand the pathogenic mechanism of human cancers underlying oncogenic pathway context. Finally, we developed `CPAD' (freely available at http://bio-bigdata.hrbmu.edu.cn/CPAD/), an online resource for exploring oncogenic pathways in human cancers, that integrated manually curated cancer-pathway associations, TCGA pan-cancer multi-omics data sets, drug-target data, drug sensitivity and multi-omics data for cancer cell lines. In summary, our study provides a comprehensive characterization of oncogenic pathways and also presents a valuable resource for investigating the pathogenesis of human cancer.

RNAactDrug: a comprehensive database of RNAs associated with drug sensitivity from multi-omics data.

Drug sensitivity has always been at the core of individualized cancer chemotherapy. However, we have been overwhelmed by large-scale pharmacogenomic data in the era of next-generation sequencing technology, which makes it increasingly challenging for researchers, especially those without bioinformatic experience, to perform data integration, exploration and analysis. To bridge this gap, we developed RNAactDrug, a comprehensive database of RNAs associated with drug sensitivity from multi-omics data, which allows users to explore drug sensitivity and RNA molecule associations directly. It provides association data between drug sensitivity and RNA molecules including mRNAs, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) at four molecular levels (expression, copy number variation, mutation and methylation) from integrated analysis of three large-scale pharmacogenomic databases (GDSC, CellMiner and CCLE). RNAactDrug currently stores more than 4 924 200 associations of RNA molecules and drug sensitivity at four molecular levels covering more than 19 770 mRNAs, 11 119 lncRNAs, 438 miRNAs and 4155 drugs. A user-friendly interface enriched with various browsing sections augmented with advance search facility for querying the database is offered for users retrieving. RNAactDrug provides a comprehensive resource for RNA molecules acting in drug sensitivity, and it could be used to prioritize drug sensitivity-related RNA molecules, further promoting the identification of clinically actionable biomarkers in drug sensitivity and drug development more cost-efficiently by making this knowledge accessible to both basic researchers and clinical practitioners. Database URL: http://bio-bigdata.hrbmu.edu.cn/RNAactDrug.

Identification and comprehensive characterization of lncRNAs with copy number variations and their driving transcriptional perturbed subpathways reveal functional significance for cancer.

Numerous studies have shown that copy number variation (CNV) in lncRNA regions play critical roles in the initiation and progression of cancer. However, our knowledge about their functionalities is still limited. Here, we firstly provided a computational method to identify lncRNAs with copy number variation (lncRNAs-CNV) and their driving transcriptional perturbed subpathways by integrating multidimensional omics data of cancer. The high reliability and accuracy of our method have been demonstrated. Then, the method was applied to 14 cancer types, and a comprehensive characterization and analysis was performed. LncRNAs-CNV had high specificity in cancers, and those with high CNV level may perturb broad biological functions. Some core subpathways and cancer hallmarks widely perturbed by lncRNAs-CNV were revealed. Moreover, subpathways highlighted the functional diversity of lncRNAs-CNV in various cancers. Survival analysis indicated that functional lncRNAs-CNV could be candidate prognostic biomarkers for clinical applications, such as ST7-AS1, CDKN2B-AS1 and EGFR-AS1. In addition, cascade responses and a functional crosstalk model among lncRNAs-CNV, impacted genes, driving subpathways and cancer hallmarks were proposed for understanding the driving mechanism of lncRNAs-CNV. Finally, we developed a user-friendly web interface-LncCASE (http://bio-bigdata.hrbmu.edu.cn/LncCASE/) for exploring lncRNAs-CNV and their driving subpathways in various cancer types. Our study identified and systematically characterized lncRNAs-CNV and their driving subpathways and presented valuable resources for investigating the functionalities of non-coding variations and the mechanisms of tumorigenesis.

Comprehensive analysis of microglia gene and subpathway signatures for glioma prognosis and drug screening: linking microglia to glioma.

Glioma is the most common malignant tumors in the brain. Previous studies have revealed that, as the innate immune cells in nervous system, microglia cells were involved in glioma pathology. And, the resident microglia displayed its specific biological roles which distinguished with peripheral macrophages. In this study, an integrated analysis was performed based on public resource database to explore specific biological of microglia within glioma. Through comprehensive analysis, the biological characterization underlying two conditions, glioma microglia compared to glioma macrophage (MicT/MacT) as well as glioma microglia compared to normal microglia (MicT/MicN), were revealed. Notably, nine core MicT/MicN genes displayed closely associations with glioma recurrence and prognosis, such as P2RY2, which was analyzed in more than 2800 glioma samples from 25 studies. Furthermore, we applied a random walk based strategy to identify microglia specific subpathways and developed SubP28 signature for glioma prognostic analysis. Multiple validation data sets confirmed the predictive performance of SubP28 and involvement in molecular subtypes. The associations between SuP28 score and microglia M1/M2 polarization were also explored for both GBM and LGG types. Finally, a comprehensive drug-subpathway network was established for screening candidate medicable molecules (drugs) and identifying therapeutic subpathway targets. In conclusions, the comprehensive analysis of microglia related gene and functional signatures in glioma pathobiologic events by large-scale data sets displayed a framework to dissect inner connection between microglia and glioma, and identify robust signature for glioma clinical implications.