Differential whole-genome doubling based signatures for improvement on clinical outcomes and drug response in patients with breast cancer.

Whole genome doublings (WGD), a hallmark of human cancer, is pervasive in breast cancer patients. However, the molecular mechanism of the complete impact of WGD on survival and treatment response in breast cancer remains unclear. To address this, we performed a comprehensive and systematic analysis of WGD, aiming to identify distinct genetic alterations linked to WGD and highlight its improvement on clinical outcomes and treatment response for breast cancer. A linear regression model along with weighted gene co-expression network analysis (WGCNA) was applied on The Cancer Genome Atlas (TCGA) dataset to identify critical genes related to WGD. Further Cox regression models with random selection were used to optimize the most useful prognostic markers in the TCGA dataset. The clinical implication of the risk model was further assessed through prognostic impact evaluation, tumor stratification, functional analysis, genomic feature difference analysis, drug response analysis, and multiple independent datasets for validation. Our findings revealed a high aneuploidy burden, chromosomal instability (CIN), copy number variation (CNV), and mutation burden in breast tumors exhibiting WGD events. Moreover, 247 key genes associated with WGD were identified from the distinct genomic patterns in the TCGA dataset. A risk model consisting of 22 genes was optimized from the key genes. High-risk breast cancer patients were more prone to WGD and exhibited greater genomic diversity compared to low-risk patients. Some oncogenic signaling pathways were enriched in the high-risk group, while primary immune deficiency pathways were enriched in the low-risk group. We also identified a risk gene, ANLN (anillin), which displayed a strong positive correlation with two crucial WGD genes, KIF18A and CCNE2. Tumors with high expression of ANLN were more prone to WGD events and displayed worse clinical survival outcomes. Furthermore, the expression levels of these risk genes were significantly associated with the sensitivities of BRCA cell lines to multiple drugs, providing valuable insights for targeted therapies. These findings will be helpful for further improvement on clinical outcomes and contribution to drug development in breast cancer.

MultiDS-MDA: Integrating multiple data sources into heterogeneous network for predicting novel metabolite-drug associations.

Metabolic processes in the human body play an important role in maintaining normal life activities, and the abnormal concentration of metabolites is closely related to the occurrence and development of diseases. The use of drugs is considered to have a major impact on metabolism, and drug metabolites can contribute to efficacy, drug toxicity and drug-drug interaction. However, our understanding of metabolite-drug associations is far from complete, and individual data source tends to be incomplete and noisy. Therefore, the integration of various types of data sources for inferring reliable metabolite-drug associations is urgently needed. In this study, we proposed a computational framework, MultiDS-MDA, for identifying metabolite-drug associations by integrating multiple data sources, including chemical structure information of metabolites and drugs, the relationships of metabolite-gene, metabolite-disease, drug-gene and drug-disease, the data of gene ontology (GO) and disease ontology (DO) and known metabolite-drug connections. The performance of MultiDS-MDA was evaluated by 5-fold cross-validation, which achieved an area under the ROC curve (AUROC) of 0.911 and an area under the precision-recall curve (AUPRC) of 0.907. Additionally, MultiDS-MDA showed outstanding performance compared with similar approaches. Case studies for three metabolites (cholesterol, thromboxane B2 and coenzyme Q10) and three drugs (simvastatin, pravastatin and morphine) also demonstrated the reliability and efficiency of MultiDS-MDA, and it is anticipated that MultiDS-MDA will serve as a powerful tool for future exploration of metabolite-drug interactions and contribute to drug development and drug combination.

Lysine-specific histone demethylase 1A (KDM1A/LSD1) inhibition attenuates DNA double-strand break repair and augments the efficacy of temozolomide in glioblastoma.

BACKGROUND: Efficient DNA repair in response to standard chemo and radiation therapies often contributes to glioblastoma (GBM) therapy resistance. Understanding the mechanisms of therapy resistance and identifying the drugs that enhance the therapeutic efficacy of standard therapies may extend the survival of GBM patients. In this study, we investigated the role of KDM1A/LSD1 in DNA double-strand break (DSB) repair and a combination of KDM1A inhibitor and temozolomide (TMZ) in vitro and in vivo using patient-derived glioma stem cells (GSCs). METHODS: Brain bioavailability of the KDM1A inhibitor (NCD38) was established using LS-MS/MS. The effect of a combination of KDM1A knockdown or inhibition with TMZ was studied using cell viability and self-renewal assays. Mechanistic studies were conducted using CUT&Tag-seq, RNA-seq, RT-qPCR, western blot, homologous recombination (HR) and non-homologous end joining (NHEJ) reporter, immunofluorescence, and comet assays. Orthotopic murine models were used to study efficacy in vivo. RESULTS: TCGA analysis showed KDM1A is highly expressed in TMZ-treated GBM patients. Knockdown or knockout or inhibition of KDM1A enhanced TMZ efficacy in reducing the viability and self-renewal of GSCs. Pharmacokinetic studies established that NCD38 readily crosses the blood-brain barrier. CUT&Tag-seq studies showed that KDM1A is enriched at the promoters of DNA repair genes and RNA-seq studies confirmed that KDM1A inhibition reduced their expression. Knockdown or inhibition of KDM1A attenuated HR and NHEJ-mediated DNA repair capacity and enhanced TMZ-mediated DNA damage. A combination of KDM1A knockdown or inhibition and TMZ treatment significantly enhanced the survival of tumor-bearing mice. CONCLUSIONS: Our results provide evidence that KDM1A inhibition sensitizes GBM to TMZ via attenuation of DNA DSB repair pathways.

Deep learning-based transcription factor activity for stratification of breast cancer patients.

Transcription factors directly bind to DNA and regulate the expression of the gene, causing epigenetic modification of the DNA. They often mediate epigenetic parameters of transcriptional and posttranscriptional mechanisms, and their expression activities can be used to characterize genomic aberrations in cancer cell. In this study, the activity profile of transcription factors inferred by VIPER algorithm. The autoencoder model was applied for compressing the transcription factor activity profile for obtaining more useful transformed features for stratifying patients into two different breast cancer subtypes. The deep learning-based subtypes exhibited superior prognostic value and yielded better risk-stratification than the transcription factor activity-based method. Importantly, according to transformed features, a deep neural network was constructed to predict the subtypes, and achieved the accuracy of 94.98% and area under the ROC curve of 0.9663, respectively. The proposed subtypes were found to be significantly associated with immune infiltration, tumor immunogenicity and so on. Furthermore, the ceRNA network was constructed for the breast cancer subtypes. Besides, 11 master regulators were found to be associated with patients in cluster 1. Given the robustness performance of our deep learning model over multiple breast cancer cohorts, we expected this model may be useful in the area of prognosis prediction and lead some possibility for personalized medicine in breast cancer patients.

Integrated multi-cohorts for characterizing the immunogenomic landscape and predicting drug response in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the breast cancer subtype with the highest fatality rate, and it seriously threatens women's health. Recent studies found that the level of immune cell infiltration in TNBC was associated with tumor progression and prognosis. However, due to practical constraints, most of these TNBC immune infiltration studies only used a small number of patient samples and a few immune cell types. Therefore, it is necessary to integrate more TNBC patient samples and immune cell types to comprehensively study immune infiltration in TNBC to contribute to the prognosis and treatment of patients. In this study, 12 TNBC datasets were integrated and an extensive collection of 182 gene sets with immune-related signatures were included to comprehensively investigate tumor immune microenvironment of TNBC. A single sample gene set enrichment analysis was performed to calculate the infiltration score of each immune-related signature in each patient, and an immune-related risk scoring model for TNBC was constructed to accurately assess patient prognosis. Significant differences were found in immunogenomic landscape between different immune risk subtypes. In addition, the immunotherapy response and chemotherapy drug sensitivity of patients with different immune risk subtypes were also analyzed. The results showed that there were significant differences in these characteristics. Finally, a prediction model for immune risk subtypes of TNBC patients was constructed to accurately predict patients with unknown subtypes. Based on the aforementioned findings, we believed that the immune-related risk score constructed in this study can assist in providing personalized medicine to TNBC patients.

Prognostic and predictive value of a metabolic risk score model in breast cancer: an immunogenomic landscape analysis.

Breast cancer is a kind of malignant tumor that occurs in breast tissue, which is the most common cancer in women. Cellular metabolism is a critical determinant of the viability and function of cancer cells in tumor microenvironment. In this study, based on the gene expression profile of metabolism-related genes, the prognostic value of 20 metabolic pathways in patients with breast cancer was identified. A universal risk stratification signature that relies on 20 metabolic pathways was established and validated in training cohort, two testing cohorts and The Cancer Genome Atlas pan cancer cohort. Then, the relationship between metabolic risk score subtype, prognosis, immune infiltration level, cancer genotypes and their impact on therapeutic benefit were characterized. Results demonstrated that the patients with the low metabolic risk score subtype displayed good prognosis, high level of immune infiltration and exhibited a favorable response to neoadjuvant chemotherapy and immunotherapy. Taken together, the work presented in this study may deepen the understanding of metabolic hallmarks of breast cancer, and may provide some valuable information for personalized therapies in patients with breast cancer.

Beneficial Effects of Green Tea EGCG on Skin Wound Healing: A Comprehensive Review.

Epigallocatechin gallate (EGCG) is associated with various health benefits. In this review, we searched current work about the effects of EGCG and its wound dressings on skin for wound healing. Hydrogels, nanoparticles, micro/nanofiber networks and microneedles are the major types of EGCG-containing wound dressings. The beneficial effects of EGCG and its wound dressings at different stages of skin wound healing (hemostasis, inflammation, proliferation and tissue remodeling) were summarized based on the underlying mechanisms of antioxidant, anti-inflammatory, antimicrobial, angiogenesis and antifibrotic properties. This review expatiates on the rationale of using EGCG to promote skin wound healing and prevent scar formation, which provides a future clinical application direction of EGCG.

Integrated analysis of telomerase enzymatic activity unravels an association with cancer stemness and proliferation.

Active telomerase is essential for stem cells and most cancers to maintain telomeres. The enzymatic activity of telomerase is related but not equivalent to the expression of TERT, the catalytic subunit of the complex. Here we show that telomerase enzymatic activity can be robustly estimated from the expression of a 13-gene signature. We demonstrate the validity of the expression-based approach, named EXTEND, using cell lines, cancer samples, and non-neoplastic samples. When applied to over 9,000 tumors and single cells, we find a strong correlation between telomerase activity and cancer stemness. This correlation is largely driven by a small population of proliferating cancer cells that exhibits both high telomerase activity and cancer stemness. This study establishes a computational framework for quantifying telomerase enzymatic activity and provides new insights into the relationships among telomerase, cancer proliferation, and stemness.

Systematic analysis of lncRNA and microRNA dynamic features reveals diagnostic and prognostic biomarkers of myocardial infarction.

Analyses of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) implicated in myocardial infarction (MI) have increased our understanding of gene regulatory mechanisms in MI. However, it is not known how their expression fluctuates over the different stages of MI progression. In this study, we used time-series gene expression data to examine global lncRNA and miRNA expression patterns during the acute phase of MI and at three different time points thereafter. We observed that the largest expression peak for mRNAs, lncRNAs, and miRNAs occurred during the acute phase of MI and involved mainly protein-coding, rather than non-coding RNAs. Functional analysis indicated that the lncRNAs and miRNAs most sensitive to MI and most unstable during MI progression were usually related to fewer biological functions. Additionally, we developed a novel computational method for identifying dysregulated competing endogenous lncRNA-miRNA-mRNA triplets (LmiRM-CTs) during MI onset and progression. As a result, a new panel of candidate diagnostic biomarkers defined by seven lncRNAs was suggested to have high classification performance for patients with or without MI, and a new panel of prognostic biomarkers defined by two lncRNAs evidenced high discriminatory capability for MI patients who developed heart failure from those who did not.

Identifying FL11 subtype by characterizing tumor immune microenvironment in prostate adenocarcinoma via Chou's 5-steps rule.

Prostate cancer is one of the leading causes of death in men worldwide, revealing a substantial heterogeneity in terms of molecular and clinical behaviors. Tumor infiltrating immune cell is associated with prognosis and response to immunotherapy in several cancer types. However, until now, the immune infiltrate profile of distinct subtypes for prostate cancer remains poorly characterized. In this study, using immune infiltration profiles as well as transcriptomic datasets, we characterized this subtype of prostate tumors. We observed that the FLI1 subtype of prostate tumors was highly enriched in immune system processes, immune related KEGG pathways and biological processes. We also expanded this approach to explore the immune infiltration profile of the high FLI1 expression subtype for skin cutaneous melanoma, similar results were found. Investigation of the association of immune infiltration features with the FLI1 expression demonstrated that many important features were associated with the FLI1 expression.

Prediction of Non-coding RNAs as Drug Targets.

MiRNA is a class of small non-coding RNA molecule that regulates gene expression at post-transcriptional level. Increasing evidences show aberrant expression of miRNAs in a variety of diseases. Targeting the dysregulated miRNAs with small molecule drugs has become a novel therapeutics for many human diseases, especially cancers. In this chapter, we introduced a series of computational studies for prediction of small molecule and miRNA associations. Based on different hypotheses, such as transcriptional response similarity, functional consistence or network closeness, the small molecule-miRNA networks were constructed and further analyzed. In addition, several resources that collected experimentally validated relationships or computational predicted associations between small molecules and miRNAs were provided. Collectively, these computational frameworks and databases pave a new way for miRNA-targeted therapy and drug repositioning.

Characterize the difference between TMPRSS2-ERG and non-TMPRSS2-ERG fusion patients by clinical and biological characteristics in prostate cancer.

The TMPRSS2-ERG gene fusion were frequently found in prostate cancer, and thought to play some fundamental mechanisms for the development of prostate cancer. However, until now, the clinical and prognostic significance of TMPRSS2-ERG gene fusion was not fully understood. In this study, based on the 281 prostate cancers that constructed from a historical watchful waiting cohort, the statistically significant associations between TMPRSS2-ERG gene fusion and clinicopathologic characteristics were identified. In addition, the Elastic Net algorithm was used to predict the patients with TMPRSS2-ERG fusion status, and good predictive results were obtained, indicating that this algorithm was suitable to this prediction problem. The differential gene network was constructed from the network, and the KEGG enrichment analysis demonstrated that the module genes were significantly enriched in several important pathways.

Clinical significance of the immune microenvironment in ovarian cancer patients.

Ovarian cancer is one of the leading causes of death from gynecologic malignancy in women. High-grade serous carcinomas, low-grade serous carcinomas, endometrioid carcinomas, clear cell carcinomas, and mucinous carcinomas with distinct pathological and clinical characteristics are the main histological subtypes of ovarian cancer. The majority of ovarian cancer patients are diagnosed at an advanced stage due to a lack of suitable screening tests for early detection and specific early symptoms. Despite progress in therapy improvements in ovarian cancer, most patients develop a recurrence within months or years after initial treatment. Given that the presence of tumor infiltrating lymphocytes is associated with prognosis and ovarian cancer is among the first cancers with an established association of immune cell infiltration, identification of the immune microenvironment in ovarian cancer is thought to be promising. In this study, to increase the understanding of tumor immune cell interactions, we undertook a study of tumor infiltrating lymphocytes in a large group of ovarian cancer patients. Our results suggested that tumor immune infiltrates of ovarian cancer were quite cohort and subtype dependent, and activated CD4+ T and CD8+ T tumor infiltrating lymphocytes were associated with good overall survival in the high-grade serous tumors. We found that high expression levels of the immune-related genes were associated with good prognosis in high-grade serous carcinomas. In addition, two different groups of prognostic genes were found in the high-grade and low-grade serous carcinomas, indicating that these two subtypes of serous carcinomas were two biologically and clinically different cancer types.

Characterization of dysregulated lncRNA-mRNA network based on ceRNA hypothesis to reveal the occurrence and recurrence of myocardial infarction.

Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) play important roles in initiation and development of human diseases. However, the mechanism of ceRNA regulated by lncRNA in myocardial infarction (MI) remained unclear. In this study, we performed a multi-step computational method to construct dysregulated lncRNA-mRNA networks for MI occurrence (DLMN_MI_OC) and recurrence (DLMN_MI_Re) based on "ceRNA hypothesis". We systematically integrated lncRNA and mRNA expression profiles and miRNA-target regulatory interactions. The constructed DLMN_MI_OC and DLMN_MI_Re both exhibited biological network characteristics, and functional analysis demonstrated that the networks were specific for MI. Additionally, we identified some lncRNA-mRNA ceRNA modules involved in MI occurrence and recurrence. Finally, two new panel biomarkers defined by four lncRNAs (RP1-239B22.5, AC135048.13, RP11-4O1.2, RP11-285F7.2) from DLMN_MI_OC and three lncRNAs (RP11-363E7.4, CTA-29F11.1, RP5-894A10.6) from DLMN_MI_Re with high classification performance were, respectively, identified in distinguishing controls from patients, and patients with recurrent events from those without recurrent events. This study will provide us new insight into ceRNA-mediated regulatory mechanisms involved in MI occurrence and recurrence, and facilitate the discovery of candidate diagnostic and prognosis biomarkers for MI.

Prediction of presynaptic and postsynaptic neurotoxins by combining various Chou's pseudo components.

Presynaptic and postsynaptic neurotoxins are two groups of neurotoxins. Identification of presynaptic and postsynaptic neurotoxins is an important work for numerous newly found toxins. It is both costly and time consuming to determine these two neurotoxins by experimental methods. As a complement, using computational methods for predicting presynaptic and postsynaptic neurotoxins could provide some useful information in a timely manner. In this study, we described four algorithms for predicting presynaptic and postsynaptic neurotoxins from sequence driven features by using Increment of Diversity (ID), Multinomial Naive Bayes Classifier (MNBC), Random Forest (RF), and K-nearest Neighbours Classifier (IBK). Each protein sequence was encoded by pseudo amino acid (PseAA) compositions and three biological motif features, including MEME, Prosite and InterPro motif features. The Maximum Relevance Minimum Redundancy (MRMR) feature selection method was used to rank the PseAA compositions and the 50 top ranked features were selected to improve the prediction accuracy. The PseAA compositions and three kinds of biological motif features were combined and 12 different parameters that defined as P1-P12 were selected as the input parameters of ID, MNBC, RF, and IBK. The prediction results obtained in this study were significantly better than those of previously developed methods.

Molecular classification of prostate adenocarcinoma by the integrated somatic mutation profiles and molecular network.

Prostate cancer is one of the most common cancers in men and a leading cause of cancer death worldwide, displaying a broad range of heterogeneity in terms of clinical and molecular behavior. Increasing evidence suggests that classifying prostate cancers into distinct molecular subtypes is critical to exploring the potential molecular variation underlying this heterogeneity and to better treat this cancer. In this study, the somatic mutation profiles of prostate cancer were downloaded from the TCGA database and used as the source nodes of the random walk with restart algorithm (RWRA) for generating smoothed mutation profiles in the STRING network. The smoothed mutation profiles were selected as the input matrix of the Graph-regularized Nonnegative Matrix Factorization (GNMF) for classifying patients into distinct molecular subtypes. The results were associated with most of the clinical and pathological outcomes. In addition, some bioinformatics analyses were performed for the robust subtyping, and good results were obtained. These results indicated that prostate cancers can be usefully classified according to their mutation profiles, and we hope that these subtypes will help improve the treatment stratification of this cancer in the future.

Large-scale identification of adverse drug reaction-related proteins through a random walk model.

Adverse drug reactions (ADRs) are responsible for drug failure in clinical trials and affect life quality of patients. The identification of ADRs during the early phases of drug development is an important task. Therefore, predicting potential protein targets eliciting ADRs is essential for understanding the pathogenesis of ADRs. In this study, we proposed a computational algorithm,Integrated Network for Protein-ADR relations (INPADR), to infer potential protein-ADR relations based on an integrated network. First, the integrated network was constructed by connecting the protein-protein interaction network and the ADR similarity network using known protein-ADR relations. Then, candidate protein-ADR relations were further prioritized by performing a random walk with restart on this integrated network. Leave-one-out cross validation was used to evaluate the ability of the INPADR. An AUC of 0.8486 was obtained, which was a significant improvement compared to previous methods. We also applied the INPADR to two ADRs to evaluate its accuracy. The results suggested that the INPADR is capable of finding novel protein-ADR relations. This study provides new insight to our understanding of ADRs. The predicted ADR-related proteins will provide a reference for preclinical safety pharmacology studies and facilitate the identification of ADRs during the early phases of drug development.

Characterize the relationship between essential and TATA-containing genes for S. cerevisiae by network topologies in the perturbation sensitivity network.

Essential genes are those that are indispensable for the survival and propagation of an organism. TATA-containing genes are associated with responses to various stresses and are highly regulated. Although both essential genes and TATA genes are very important in the function of biological systems, their relationship remains unclear because they have typically been researched independently. In this study, to investigate the relationship between essential genes and TATA genes, S. cerevisiae genes were classified as: essential TATA-containing, non-essential TATA-containing, essential non-TATA, and non-essential non-TATA genes. Network-based methods were applied to analyze these four gene categories in the S. cerevisiae perturbation sensitivity (PS) network, which was created from the transcriptional profiling of hundreds of different gene disruptions. All of the topological properties were found to be statistically discriminative among the four gene categories, and the non-essential TATA-containing genes had the most important roles in the yeast PS network.

Characterization of BioPlex network by topological properties.

Protein-protein interaction (PPI) networks are emerging as valuable prototypes to study important problems in molecular cellular biology and systems biomedicine. An analysis of the topological properties of a PPI network is very helpful for understanding the function and structure of networks. In this study, we analyzed the topological patterns in the BioPlex network containing interactions among 10,961 proteins; most interactions were previously undocumented. The BioPlex network is a comprehensive map of human protein interactions and represents the first phase of a long-term effort to profile the entire human ORFEOME collection. Similar to other biological networks, we observed that the BioPlex network has several topological properties. We also quantified correlations profiles for the BioPlex network and compared them to randomized versions of the same network. We found that for the BioPlex network, edges between proteins with intermediate degrees were strongly suppressed, whereas edges between low-connected proteins were favored. Finally, the degrees of essential genes were compared with the degrees of non-essential genes and randomly selected proteins. There were no significant differences between the groups.

Comparative analysis of housekeeping and tissue-selective genes in human based on network topologies and biological properties.

Housekeeping genes are genes that are turned on most of the time in almost every tissue to maintain cellular functions. Tissue-selective genes are predominantly expressed in one or a few biologically relevant tissue types. Benefitting from the massive gene expression microarray data obtained over the past decades, the properties of housekeeping and tissue-selective genes can now be investigated on a large-scale manner. In this study, we analyzed the topological properties of housekeeping and tissue-selective genes in the protein-protein interaction (PPI) network. Furthermore, we compared the biological properties and amino acid usage between these two gene groups. The results indicated that there were significant differences in topological properties between housekeeping and tissue-selective genes in the PPI network, and housekeeping genes had higher centrality properties and may play important roles in the complex biological network environment. We also found that there were significant differences in multiple biological properties and many amino acid compositions. The functional genes enrichment and subcellular localizations analysis was also performed to investigate the characterization of housekeeping and tissue-selective genes. The results indicated that the two gene groups showed significant different enrichment in drug targets, disease genes and toxin targets, and located in different subcellular localizations. At last, the discriminations between the properties of two gene groups were measured by the F-score, and expression stage had the most discriminative index in all properties. These findings may elucidate the biological mechanisms for understanding housekeeping and tissue-selective genes and may contribute to better annotate housekeeping and tissue-selective genes in other organisms.