Single-cell RNA-seq data analysis reveals functionally relevant biomarkers of early brain development and their regulatory footprints in human embryonic stem cells (hESCs).

The complicated process of neuronal development is initiated early in life, with the genetic mechanisms governing this process yet to be fully elucidated. Single-cell RNA sequencing (scRNA-seq) is a potent instrument for pinpointing biomarkers that exhibit differential expression across various cell types and developmental stages. By employing scRNA-seq on human embryonic stem cells, we aim to identify differentially expressed genes (DEGs) crucial for early-stage neuronal development. Our focus extends beyond simply identifying DEGs. We strive to investigate the functional roles of these genes through enrichment analysis and construct gene regulatory networks to understand their interactions. Ultimately, this comprehensive approach aspires to illuminate the molecular mechanisms and transcriptional dynamics governing early human brain development. By uncovering potential links between these DEGs and intelligence, mental disorders, and neurodevelopmental disorders, we hope to shed light on human neurological health and disease. In this study, we have used scRNA-seq to identify DEGs involved in early-stage neuronal development in hESCs. The scRNA-seq data, collected on days 26 (D26) and 54 (D54), of the in vitro differentiation of hESCs to neurons were analyzed. Our analysis identified 539 DEGs between D26 and D54. Functional enrichment of those DEG biomarkers indicated that the up-regulated DEGs participated in neurogenesis, while the down-regulated DEGs were linked to synapse regulation. The Reactome pathway analysis revealed that down-regulated DEGs were involved in the interactions between proteins located in synapse pathways. We also discovered interactions between DEGs and miRNA, transcriptional factors (TFs) and DEGs, and between TF and miRNA. Our study identified 20 significant transcription factors, shedding light on early brain development genetics. The identified DEGs and gene regulatory networks are valuable resources for future research into human brain development and neurodevelopmental disorders.

BOO-ST and CBCEC: two novel hybrid machine learning methods aim to reduce the mortality of heart failure patients.

Heart failure (HF) is a leading cause of mortality worldwide. Machine learning (ML) approaches have shown potential as an early detection tool for improving patient outcomes. Enhancing the effectiveness and clinical applicability of the ML model necessitates training an efficient classifier with a diverse set of high-quality datasets. Hence, we proposed two novel hybrid ML methods ((a) consisting of Boosting, SMOTE, and Tomek links (BOO-ST); (b) combining the best-performing conventional classifier with ensemble classifiers (CBCEC)) to serve as an efficient early warning system for HF mortality. The BOO-ST was introduced to tackle the challenge of class imbalance, while CBCEC was responsible for training the processed and selected features derived from the Feature Importance (FI) and Information Gain (IG) feature selection techniques. We also conducted an explicit and intuitive comprehension to explore the impact of potential characteristics correlating with the fatality cases of HF. The experimental results demonstrated the proposed classifier CBCEC showcases a significant accuracy of 93.67% in terms of providing the early forecasting of HF mortality. Therefore, we can reveal that our proposed aspects (BOO-ST and CBCEC) can be able to play a crucial role in preventing the death rate of HF and reducing stress in the healthcare sector.

Identification of genetic biomarkers, drug targets and agents for respiratory diseases utilising integrated bioinformatics approaches.

Respiratory diseases (RD) are significant public health burdens and malignant diseases worldwide. However, the RD-related biological information and interconnection still need to be better understood. Thus, this study aims to detect common differential genes and potential hub genes (HubGs), emphasizing their actions, signaling pathways, regulatory biomarkers for diagnosing RD and candidate drugs for treating RD. In this paper we used integrated bioinformatics approaches (such as, gene ontology (GO) and KEGG pathway enrichment analysis, molecular docking, molecular dynamic simulation and network-based molecular interaction analysis). We discovered 73 common DEGs (CDEGs) and ten HubGs (ATAD2B, PPP1CB, FOXO1, AKT3, BCR, PDE4D, ITGB1, PCBP2, CD44 and SMARCA2). Several significant functions and signaling pathways were strongly related to RD. We recognized six transcription factor (TF) proteins (FOXC1, GATA2, FOXL1, YY1, POU2F2 and HINFP) and five microRNAs (hsa-mir-218-5p, hsa-mir-335-5p, hsa-mir-16-5p, hsa-mir-106b-5p and hsa-mir-15b-5p) as the important transcription and post-transcription regulators of RD. Ten HubGs and six major TF proteins were considered drug-specific receptors. Their binding energy analysis study was carried out with the 63 drug agents detected from network analysis. Finally, the five complexes (the PDE4D-benzo[a]pyrene, SMARCA2-benzo[a]pyrene, HINFP-benzo[a]pyrene, CD44-ketotifen and ATAD2B-ponatinib) were selected for RD based on their strong binding affinity scores and stable performance as the most probable repurposable protein-drug complexes. We believe our findings will give readers, wet-lab scientists, and pharmaceuticals a thorough grasp of the biology behind RD.

dRNASb: a systems biology approach to decipher dynamics of host-pathogen interactions using temporal dual RNA-seq data.

Infection triggers a dynamic cascade of reciprocal events between host and pathogen wherein the host activates complex mechanisms to recognise and kill pathogens while the pathogen often adjusts its virulence and fitness to avoid eradication by the host. The interaction between the pathogen and the host results in large-scale changes in gene expression in both organisms. Dual RNA-seq, the simultaneous detection of host and pathogen transcripts, has become a leading approach to unravelling complex molecular interactions between the host and the pathogen and is particularly informative for intracellular organisms. The amount of in vitro and in vivo dual RNA-seq data is rapidly growing, which demands computational pipelines to effectively analyse such data. In particular, holistic, systems-level, and temporal analyses of dual RNA-seq data are essential to enable further insights into the host-pathogen transcriptional dynamics and potential interactions. Here, we developed an integrative network-driven bioinformatics pipeline, dRNASb, a systems biology-based computational pipeline to analyse temporal transcriptional clusters, incorporate molecular interaction networks (e.g. protein-protein interactions), identify topologically and functionally key transcripts in host and pathogen, and associate host and pathogen temporal transcriptome to decipher potential between-species interactions. The pipeline is applicable to various dual RNA-seq data from different species and experimental conditions. As a case study, we applied dRNASb to analyse temporal dual RNA-seq data of Salmonella-infected human cells, which enabled us to uncover genes contributing to the infection process and their potential functions and to identify putative associations between host and pathogen genes during infection. Overall, dRNASb has the potential to identify key genes involved in bacterial growth or host defence mechanisms for future uses as therapeutic targets.

A classification of MRI brain tumor based on two stage feature level ensemble of deep CNN models.

The brain tumor is one of the deadliest cancerous diseases and its severity has turned it to the leading cause of cancer related mortality. The treatment procedure of the brain tumor depends on the type, location and size of the tumor. Relying solely on human inspection for precise categorization can lead to inevitably dangerous situation. This manual diagnosis process can be improved and accelerated through an automated Computer Aided Diagnosis (CADx) system. In this article, a novel approach using two-stage feature ensemble of deep Convolutional Neural Networks (CNN) is proposed for precise and automatic classification of brain tumors. Three unique Magnetic Resonance Imaging (MRI) datasets and a dataset merging all the unique datasets are considered. The datasets contain three types of brain tumor (meningioma, glioma, pituitary) and normal brain images. From five pre-trained models and a proposed CNN model, the best models are chosen and concatenated in two stages for feature extraction. The best classifier is also chosen among five different classifiers based on accuracy. From the extracted features, most substantial features are selected using Principal Component Analysis (PCA) and fed into the classifier. The robustness of the proposed two stage ensemble model is analyzed using several performance metrics and three different experiments. Through the prominent performance, the proposed model is able to outperform other existing models attaining an average accuracy of 99.13% by optimization of the developed algorithms. Here, the individual accuracy for Dataset 1, Dataset 2, Dataset 3, and Merged Dataset is 99.67%, 98.16%, 99.76%, and 98.96% respectively. Finally a User Interface (UI) is created using the proposed model for real time validation.

Network based systems biology approach to identify diseasome and comorbidity associations of Systemic Sclerosis with cancers.

Systemic Sclerosis (SSc) is an autoimmune disease associated with changes in the skin's structure in which the immune system attacks the body. A recent meta-analysis has reported a high incidence of cancer prognosis including lung cancer (LC), leukemia (LK), and lymphoma (LP) in patients with SSc as comorbidity but its underlying mechanistic details are yet to be revealed. To address this research gap, bioinformatics methodologies were developed to explore the comorbidity interactions between a pair of diseases. Firstly, appropriate gene expression datasets from different repositories on SSc and its comorbidities were collected. Then the interconnection between SSc and its cancer comorbidities was identified by applying the developed pipelines. The pipeline was designed as a generic workflow to demonstrate a premise comorbid condition that integrate regarding gene expression data, tissue/organ meta-data, Gene Ontology (GO), Molecular pathways, and other online resources, and analyze them with Gene Set Enrichment Analysis (GSEA), Pathway enrichment and Semantic Similarity (SS). The pipeline was implemented in R and can be accessed through our Github repository: https://github.com/hiddenntreasure/comorbidity. Our result suggests that SSc and its cancer comorbidities share differentially expressed genes, functional terms (gene ontology), and pathways. The findings have led to a better understanding of disease pathways and our developed methodologies may be applied to any set of diseases for finding any association between them. This research may be used by physicians, researchers, biologists, and others.

BARD: A Structured Technique for Group Elicitation of Bayesian Networks to Support Analytic Reasoning.

In many complex, real-world situations, problem solving and decision making require effective reasoning about causation and uncertainty. However, human reasoning in these cases is prone to confusion and error. Bayesian networks (BNs) are an artificial intelligence technology that models uncertain situations, supporting better probabilistic and causal reasoning and decision making. However, to date, BN methodologies and software require (but do not include) substantial upfront training, do not provide much guidance on either the model building process or on using the model for reasoning and reporting, and provide no support for building BNs collaboratively. Here, we contribute a detailed description and motivation for our new methodology and application, Bayesian ARgumentation via Delphi (BARD). BARD utilizes BNs and addresses these shortcomings by integrating (1) short, high-quality e-courses, tips, and help on demand; (2) a stepwise, iterative, and incremental BN construction process; (3) report templates and an automated explanation tool; and (4) a multiuser web-based software platform and Delphi-style social processes. The result is an end-to-end online platform, with associated online training, for groups without prior BN expertise to understand and analyze a problem, build a model of its underlying probabilistic causal structure, validate and reason with the causal model, and (optionally) use it to produce a written analytic report. Initial experiments demonstrate that, for suitable problems, BARD aids in reasoning and reporting. Comparing their effect sizes also suggests BARD's BN-building and collaboration combine beneficially and cumulatively.

Adverse Effects of COVID-19 Vaccination: Machine Learning and Statistical Approach to Identify and Classify Incidences of Morbidity and Postvaccination Reactogenicity.

Good vaccine safety and reliability are essential for successfully countering infectious disease spread. A small but significant number of adverse reactions to COVID-19 vaccines have been reported. Here, we aim to identify possible common factors in such adverse reactions to enable strategies that reduce the incidence of such reactions by using patient data to classify and characterise those at risk. We examined patient medical histories and data documenting postvaccination effects and outcomes. The data analyses were conducted using a range of statistical approaches followed by a series of machine learning classification algorithms. In most cases, a group of similar features was significantly associated with poor patient reactions. These included patient prior illnesses, admission to hospitals and SARS-CoV-2 reinfection. The analyses indicated that patient age, gender, taking other medications, type-2 diabetes, hypertension, allergic history and heart disease are the most significant pre-existing factors associated with the risk of poor outcome. In addition, long duration of hospital treatments, dyspnoea, various kinds of pain, headache, cough, asthenia, and physical disability were the most significant clinical predictors. The machine learning classifiers that are trained with medical history were also able to predict patients with complication-free vaccination and have an accuracy score above 90%. Our study identifies profiles of individuals that may need extra monitoring and care (e.g., vaccination at a location with access to comprehensive clinical support) to reduce negative outcomes through classification approaches.

LungNet: A hybrid deep-CNN model for lung cancer diagnosis using CT and wearable sensor-based medical IoT data.

Lung cancer, also known as pulmonary cancer, is one of the deadliest cancers, but yet curable if detected at the early stage. At present, the ambiguous features of the lung cancer nodule make the computer-aided automatic diagnosis a challenging task. To alleviate this, we present LungNet, a novel hybrid deep-convolutional neural network-based model, trained with CT scan and wearable sensor-based medical IoT (MIoT) data. LungNet consists of a unique 22-layers Convolutional Neural Network (CNN), which combines latent features that are learned from CT scan images and MIoT data to enhance the diagnostic accuracy of the system. Operated from a centralized server, the network has been trained with a balanced dataset having 525,000 images that can classify lung cancer into five classes with high accuracy (96.81%) and low false positive rate (3.35%), outperforming similar CNN-based classifiers. Moreover, it classifies the stage-1 and stage-2 lung cancers into 1A, 1B, 2A and 2B sub-classes with 91.6% accuracy and false positive rate of 7.25%. High predictive capability accompanied with sub-stage classification renders LungNet as a promising prospect in developing CNN-based automatic lung cancer diagnosis systems.

Effects of Bacille Calmette Guerin (BCG) vaccination during COVID-19 infection.

The coronavirus disease 2019 (COVID-19) is caused by the infection of highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as the novel coronavirus. In most countries, the containment of this virus spread is not controlled, which is driving the pandemic towards a more difficult phase. In this study, we investigated the impact of the Bacille Calmette Guerin (BCG) vaccination on the severity and mortality of COVID-19 by performing transcriptomic analyses of SARS-CoV-2 infected and BCG vaccinated samples in peripheral blood mononuclear cells (PBMC). A set of common differentially expressed genes (DEGs) were identified and seeded into their functional enrichment analyses via Gene Ontology (GO)-based functional terms and pre-annotated molecular pathways databases, and their Protein-Protein Interaction (PPI) network analysis. We further analysed the regulatory elements, possible comorbidities and putative drug candidates for COVID-19 patients who have not been BCG-vaccinated. Differential expression analyses of both BCG-vaccinated and COVID-19 infected samples identified 62 shared DEGs indicating their discordant expression pattern in their respected conditions compared to control. Next, PPI analysis of those DEGs revealed 10 hub genes, namely ITGB2, CXCL8, CXCL1, CCR2, IFNG, CCL4, PTGS2, ADORA3, TLR5 and CD33. Functional enrichment analyses found significantly enriched pathways/GO terms including cytokine activities, lysosome, IL-17 signalling pathway, TNF-signalling pathways. Moreover, a set of identified TFs, miRNAs and potential drug molecules were further investigated to assess their biological involvements in COVID-19 and their therapeutic possibilities. Findings showed significant genetic interactions between BCG vaccination and SARS-CoV-2 infection, suggesting an interesting prospect of the BCG vaccine in relation to the COVID-19 pandemic. We hope it may potentially trigger further research on this critical phenomenon to combat COVID-19 spread.

Machine Learning Approaches to Identify Patient Comorbidities and Symptoms That Increased Risk of Mortality in COVID-19.

Providing appropriate care for people suffering from COVID-19, the disease caused by the pandemic SARS-CoV-2 virus, is a significant global challenge. Many individuals who become infected may have pre-existing conditions that may interact with COVID-19 to increase symptom severity and mortality risk. COVID-19 patient comorbidities are likely to be informative regarding the individual risk of severe illness and mortality. Determining the degree to which comorbidities are associated with severe symptoms and mortality would thus greatly assist in COVID-19 care planning and provision. To assess this we performed a meta-analysis of published global literature, and machine learning predictive analysis using an aggregated COVID-19 global dataset. Our meta-analysis suggested that chronic obstructive pulmonary disease (COPD), cerebrovascular disease (CEVD), cardiovascular disease (CVD), type 2 diabetes, malignancy, and hypertension as most significantly associated with COVID-19 severity in the current published literature. Machine learning classification using novel aggregated cohort data similarly found COPD, CVD, CKD, type 2 diabetes, malignancy, and hypertension, as well as asthma, as the most significant features for classifying those deceased versus those who survived COVID-19. While age and gender were the most significant predictors of mortality, in terms of symptom-comorbidity combinations, it was observed that Pneumonia-Hypertension, Pneumonia-Diabetes, and Acute Respiratory Distress Syndrome (ARDS)-Hypertension showed the most significant associations with COVID-19 mortality. These results highlight the patient cohorts most likely to be at risk of COVID-19-related severe morbidity and mortality, which have implications for prioritization of hospital resources.

Integrative resource for network-based investigation of COVID-19 combinatorial drug repositioning and mechanism of action.

An effective monotherapy to target the complex and multifactorial pathology of SARS-CoV-2 infection poses a challenge to drug repositioning, which can be improved by combination therapy. We developed an online network pharmacology-based drug repositioning platform, COVID-CDR (http://vafaeelab.com/COVID19repositioning.html), that enables a visual and quantitative investigation of the interplay between the primary drug targets and the SARS-CoV-2-host interactome in the human protein-protein interaction network. COVID-CDR prioritizes drug combinations with potential to act synergistically through different, yet potentially complementary, pathways. It provides the options for understanding multi-evidence drug-pair similarity scores along with several other relevant information on individual drugs or drug pairs. Overall, COVID-CDR is a first-of-its-kind online platform that provides a systematic approach for pre-clinical in silico investigation of combination therapies for treating COVID-19 at the fingertips of the clinicians and researchers.

Bioinformatics and system biology approaches to identify the diseasome and comorbidities complexities of SARS-CoV-2 infection with the digestive tract disorders.

Coronavirus Disease 2019 (COVID-19), although most commonly demonstrates respiratory symptoms, but there is a growing set of evidence reporting its correlation with the digestive tract and faeces. Interestingly, recent studies have shown the association of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with gastrointestinal symptoms in infected patients but any sign of respiratory issues. Moreover, some studies have also shown that the presence of live SARS-CoV-2 virus in the faeces of patients with COVID-19. Therefore, the pathophysiology of digestive symptoms associated with COVID-19 has raised a critical need for comprehensive investigative efforts. To address this issue we have developed a bioinformatics pipeline involving a system biological framework to identify the effects of SARS-CoV-2 messenger RNA expression on deciphering its association with digestive symptoms in COVID-19 positive patients. Using two RNA-seq datasets derived from COVID-19 positive patients with celiac (CEL), Crohn's (CRO) and ulcerative colitis (ULC) as digestive disorders, we have found a significant overlap between the sets of differentially expressed genes from SARS-CoV-2 exposed tissue and digestive tract disordered tissues, reporting 7, 22 and 13 such overlapping genes, respectively. Moreover, gene set enrichment analysis, comprehensive analyses of protein-protein interaction network, gene regulatory network, protein-chemical agent interaction network revealed some critical association between SARS-CoV-2 infection and the presence of digestive disorders. The infectome, diseasome and comorbidity analyses also discover the influences of the identified signature genes in other risk factors of SARS-CoV-2 infection to human health. We hope the findings from this pathogenetic analysis may reveal important insights in deciphering the complex interplay between COVID-19 and digestive disorders and underpins its significance in therapeutic development strategy to combat against COVID-19 pandemic.

Discovering novel cancer bio-markers in acquired lapatinib resistance using Bayesian methods.

Signalling transduction pathways (STPs) are commonly hijacked by many cancers for their growth and malignancy, but demystifying their underlying mechanisms is difficult. Here, we developed methodologies with a fully Bayesian approach in discovering novel driver bio-markers in aberrant STPs given high-throughput gene expression (GE) data. This project, namely 'PathTurbEr' (Pathway Perturbation Driver) uses the GE dataset derived from the lapatinib (an EGFR/HER dual inhibitor) sensitive and resistant samples from breast cancer cell lines (SKBR3). Differential expression analysis revealed 512 differentially expressed genes (DEGs) and their pathway enrichment revealed 13 highly perturbed singalling pathways in lapatinib resistance, including PI3K-AKT, Chemokine, Hippo and TGF-$\beta $ singalling pathways. Next, the aberration in TGF-$\beta $ STP was modelled as a causal Bayesian network (BN) using three MCMC sampling methods, i.e. Neighbourhood sampler (NS) and Hit-and-Run (HAR) sampler that potentially yield robust inference with lower chances of getting stuck at local optima and faster convergence compared to other state-of-art methods. Next, we examined the structural features of the optimal BN as a statistical process that generates the global structure using $p_1$-model, a special class of Exponential Random Graph Models (ERGMs), and MCMC methods for their hyper-parameter sampling. This step enabled key drivers identification that drive the aberration within the perturbed BN structure of STP, and yielded 34, 34 and 23 perturbation driver genes out of 80 constituent genes of three perturbed STP models of TGF-$\beta $ signalling inferred by NS, HAR and MH sampling methods, respectively. Functional-relevance and disease-relevance analyses suggested their significant associations with breast cancer progression/resistance.

A comprehensive integrated drug similarity resource for in-silico drug repositioning and beyond.

Drug similarity studies are driven by the hypothesis that similar drugs should display similar therapeutic actions and thus can potentially treat a similar constellation of diseases. Drug-drug similarity has been derived by variety of direct and indirect sources of evidence and frequently shown high predictive power in discovering validated repositioning candidates as well as other in-silico drug development applications. Yet, existing resources either have limited coverage or rely on an individual source of evidence, overlooking the wealth and diversity of drug-related data sources. Hence, there has been an unmet need for a comprehensive resource integrating diverse drug-related information to derive multi-evidenced drug-drug similarities. We addressed this resource gap by compiling heterogenous information for an exhaustive set of small-molecule drugs (total of 10 367 in the current version) and systematically integrated multiple sources of evidence to derive a multi-modal drug-drug similarity network. The resulting database, 'DrugSimDB' currently includes 238 635 drug pairs with significant aggregated similarity, complemented with an interactive user-friendly web interface (http://vafaeelab.com/drugSimDB.html), which not only enables database ease of access, search, filtration and export, but also provides a variety of complementary information on queried drugs and interactions. The integration approach can flexibly incorporate further drug information into the similarity network, providing an easily extendable platform. The database compilation and construction source-code has been well-documented and semi-automated for any-time upgrade to account for new drugs and up-to-date drug information.

Bayesian model of signal rewiring reveals mechanisms of gene dysregulation in acquired drug resistance in breast cancer.

Small molecule inhibitors, such as lapatinib, are effective against breast cancer in clinical trials, but tumor cells ultimately acquire resistance to the drug. Maintaining sensitization to drug action is essential for durable growth inhibition. Recently, adaptive reprogramming of signaling circuitry has been identified as a major cause of acquired resistance. We developed a computational framework using a Bayesian statistical approach to model signal rewiring in acquired resistance. We used the p1-model to infer potential aberrant gene-pairs with differential posterior probabilities of appearing in resistant-vs-parental networks. Results were obtained using matched gene expression profiles under resistant and parental conditions. Using two lapatinib-treated ErbB2-positive breast cancer cell-lines: SKBR3 and BT474, our method identified similar dysregulated signaling pathways including EGFR-related pathways as well as other receptor-related pathways, many of which were reported previously as compensatory pathways of EGFR-inhibition via signaling cross-talk. A manual literature survey provided strong evidence that aberrant signaling activities in dysregulated pathways are closely related to acquired resistance in EGFR tyrosine kinase inhibitors. Our approach predicted literature-supported dysregulated pathways complementary to both node-centric (SPIA, DAVID, and GATHER) and edge-centric (ESEA and PAGI) methods. Moreover, by proposing a novel pattern of aberrant signaling called V-structures, we observed that genes were dysregulated in resistant-vs-sensitive conditions when they were involved in the switch of dependencies from targeted to bypass signaling events. A literature survey of some important V-structures suggested they play a role in breast cancer metastasis and/or acquired resistance to EGFR-TKIs, where the mRNA changes of TGFBR2, LEF1 and TP53 in resistant-vs-sensitive conditions were related to the dependency switch from targeted to bypass signaling links. Our results suggest many signaling pathway structures are compromised in acquired resistance, and V-structures of aberrant signaling within/among those pathways may provide further insights into the bypass mechanism of targeted inhibition.

Integrating Heterogeneous Datasets for Cancer Module Identification.

The availability of multiple heterogeneous high-throughput datasets provides an enabling resource for cancer systems biology. Types of data include: Gene expression (GE), copy number aberration (CNA), miRNA expression, methylation, and protein-protein Interactions (PPI). One important problem that can potentially be solved using such data is to determine which of the possible pair-wise interactions among genes contributes to a range of cancer-related events, from tumorigenesis to metastasis. It has been shown by various studies that applying integrated knowledge from multi-omics datasets elucidates such complex phenomena with higher statistical significance than using a single type of dataset individually. However, computational methods for processing multiple data types simultaneously are needed. This chapter reviews some of the computational methods that use integrated approaches to find cancer-related modules.

Prediction of signaling cross-talks contributing to acquired drug resistance in breast cancer cells by Bayesian statistical modeling.

BACKGROUND: Initial success of inhibitors targeting oncogenes is often followed by tumor relapse due to acquired resistance. In addition to mutations in targeted oncogenes, signaling cross-talks among pathways play a vital role in such drug inefficacy. These include activation of compensatory pathways and altered activities of key effectors in other cell survival and growth-associated pathways. RESULTS: We propose a computational framework using Bayesian modeling to systematically characterize potential cross-talks among breast cancer signaling pathways. We employed a fully Bayesian approach known as the p 1-model to infer posterior probabilities of gene-pairs in networks derived from the gene expression datasets of ErbB2-positive breast cancer cell-lines (parental, lapatinib-sensitive cell-line SKBR3 and the lapatinib-resistant cell-line SKBR3-R, derived from SKBR3). Using this computational framework, we searched for cross-talks between EGFR/ErbB and other signaling pathways from Reactome, KEGG and WikiPathway databases that contribute to lapatinib resistance. We identified 104, 188 and 299 gene-pairs as putative drug-resistant cross-talks, respectively, each comprised of a gene in the EGFR/ErbB signaling pathway and a gene from another signaling pathway, that appear to be interacting in resistant cells but not in parental cells. In 168 of these (distinct) gene-pairs, both of the interacting partners are up-regulated in resistant conditions relative to parental conditions. These gene-pairs are prime candidates for novel cross-talks contributing to lapatinib resistance. They associate EGFR/ErbB signaling with six other signaling pathways: Notch, Wnt, GPCR, hedgehog, insulin receptor/IGF1R and TGF- ß receptor signaling. We conducted a literature survey to validate these cross-talks, and found evidence supporting a role for many of them in contributing to drug resistance. We also analyzed an independent study of lapatinib resistance in the BT474 breast cancer cell-line and found the same signaling pathways making cross-talks with the EGFR/ErbB signaling pathway as in the primary dataset. CONCLUSIONS: Our results indicate that the activation of compensatory pathways can potentially cause up-regulation of EGFR/ErbB pathway genes (counteracting the inhibiting effect of lapatinib) via signaling cross-talk. Thus, the up-regulated members of these compensatory pathways along with the members of the EGFR/ErbB signaling pathway are interesting as potential targets for designing novel anti-cancer therapeutics.

Voting-based cancer module identification by combining topological and data-driven properties.

Recently, computational approaches integrating copy number aberrations (CNAs) and gene expression (GE) have been extensively studied to identify cancer-related genes and pathways. In this work, we integrate these two data sets with protein-protein interaction (PPI) information to find cancer-related functional modules. To integrate CNA and GE data, we first built a gene-gene relationship network from a set of seed genes by enumerating all types of pairwise correlations, e.g. GE-GE, CNA-GE, and CNA-CNA, over multiple patients. Next, we propose a voting-based cancer module identification algorithm by combining topological and data-driven properties (VToD algorithm) by using the gene-gene relationship network as a source of data-driven information, and the PPI data as topological information. We applied the VToD algorithm to 266 glioblastoma multiforme (GBM) and 96 ovarian carcinoma (OVC) samples that have both expression and copy number measurements, and identified 22 GBM modules and 23 OVC modules. Among 22 GBM modules, 15, 12, and 20 modules were significantly enriched with cancer-related KEGG, BioCarta pathways, and GO terms, respectively. Among 23 OVC modules, 19, 18, and 23 modules were significantly enriched with cancer-related KEGG, BioCarta pathways, and GO terms, respectively. Similarly, we also observed that 9 and 2 GBM modules and 15 and 18 OVC modules were enriched with cancer gene census (CGC) and specific cancer driver genes, respectively. Our proposed module-detection algorithm significantly outperformed other existing methods in terms of both functional and cancer gene set enrichments. Most of the cancer-related pathways from both cancer data sets found in our algorithm contained more than two types of gene-gene relationships, showing strong positive correlations between the number of different types of relationship and CGC enrichment [Formula: see text]-values (0.64 for GBM and 0.49 for OVC). This study suggests that identified modules containing both expression changes and CNAs can explain cancer-related activities with greater insights.

Prediction of plant promoters based on hexamers and random triplet pair analysis.

BACKGROUND: With an increasing number of plant genome sequences, it has become important to develop a robust computational method for detecting plant promoters. Although a wide variety of programs are currently available, prediction accuracy of these still requires further improvement. The limitations of these methods can be addressed by selecting appropriate features for distinguishing promoters and non-promoters. METHODS: In this study, we proposed two feature selection approaches based on hexamer sequences: the Frequency Distribution Analyzed Feature Selection Algorithm (FDAFSA) and the Random Triplet Pair Feature Selecting Genetic Algorithm (RTPFSGA). In FDAFSA, adjacent triplet-pairs (hexamer sequences) were selected based on the difference in the frequency of hexamers between promoters and non-promoters. In RTPFSGA, random triplet-pairs (RTPs) were selected by exploiting a genetic algorithm that distinguishes frequencies of non-adjacent triplet pairs between promoters and non-promoters. Then, a support vector machine (SVM), a nonlinear machine-learning algorithm, was used to classify promoters and non-promoters by combining these two feature selection approaches. We referred to this novel algorithm as PromoBot. RESULTS: Promoter sequences were collected from the PlantProm database. Non-promoter sequences were collected from plant mRNA, rRNA, and tRNA of PlantGDB and plant miRNA of miRBase. Then, in order to validate the proposed algorithm, we applied a 5-fold cross validation test. Training data sets were used to select features based on FDAFSA and RTPFSGA, and these features were used to train the SVM. We achieved 89% sensitivity and 86% specificity. CONCLUSIONS: We compared our PromoBot algorithm to five other algorithms. It was found that the sensitivity and specificity of PromoBot performed well (or even better) with the algorithms tested. These results show that the two proposed feature selection methods based on hexamer frequencies and random triplet-pair could be successfully incorporated into a supervised machine learning method in promoter classification problem. As such, we expect that PromoBot can be used to help identify new plant promoters. Source codes and analysis results of this work could be provided upon request.