Systems biology based drug repositioning for development of cancer therapy.

Drug repositioning is a powerful method that can assists the conventional drug discovery process by using existing drugs for treatment of a disease rather than its original indication. The first examples of repurposed drugs were discovered serendipitously, however data accumulated by high-throughput screenings and advancements in computational biology methods have paved the way for rational drug repositioning methods. As chemotherapeutic agents have notorious side effects that significantly reduce quality of life, drug repositioning promises repurposed noncancer drugs with little or tolerable adverse effects for cancer patients. Here, we review current drug-related data types and databases including some examples of web-based drug repositioning tools. Next, we describe systems biology approaches to be used in drug repositioning for effective cancer therapy. Finally, we highlight examples of mostly repurposed drugs for cancer treatment and provide an overview of future expectations in the field for development of effective treatment strategies.

Systems biomarkers for papillary thyroid cancer prognosis and treatment through multi-omics networks.

The identification of biomolecules associated with papillary thyroid cancer (PTC) has upmost importance for the elucidation of the disease mechanism and the development of effective diagnostic and treatment strategies. Despite particular findings in this regard, a holistic analysis encompassing molecular data from different biological levels has been lacking. In the present study, a meta-analysis of four transcriptome datasets was performed to identify gene expression signatures in PTC, and reporter molecules were determined by mapping gene expression data onto three major cellular networks, i.e., transcriptional regulatory, protein-protein interaction, and metabolic networks. We identified 282 common genes that were differentially expressed in all PTC datasets. In addition, six proteins (FYN, JUN, LYN, PML, SIN3A, and RARA), two Erb-B2 receptors (ERBB2 and ERBB4), two cyclin-dependent receptors (CDK1 and CDK2), and three histone deacetylase receptors (HDAC1, HDAC2, and HDAC3) came into prominence as proteomic signatures in addition to several metabolites including lactaldehyde and proline at the metabolome level. Significant associations with calcium and MAPK signaling pathways and transcriptional and post-transcriptional activities of 12 TFs and 110 miRNAs were also observed at the regulatory level. Among them, six miRNAs (miR-30b-3p, miR-15b-5p, let-7a-5p, miR-130b-3p, miR-424-5p, and miR-193b-3p) were associated with PTC for the first time in the literature, and the expression levels of miR-30b-3p, miR-15b-5p, and let-7a-5p were found to be predictive of disease prognosis. Drug repositioning and molecular docking simulations revealed that 5 drugs (prochlorperazine, meclizine, rottlerin, cephaeline, and tretinoin) may be useful in the treatment of PTC. Consequently, we report here biomolecule candidates that may be considered as prognostic biomarkers or potential therapeutic targets for further experimental and clinical trials for PTC.

MicroRNA-Mediated Drug Repurposing Unveiled Potential Candidate Drugs for Prolactinoma Treatment.

INTRODUCTION: Prolactinomas, also called lactotroph adenomas, are the most encountered type of hormone-secreting pituitary neuroendocrine tumors in the clinic. The preferred first-line therapy is a medical treatment with dopamine agonists (DAs), mainly cabergoline, to reduce serum prolactin levels, tumor volume, and mass effect. However, in some cases, patients have displayed DA resistance with aggressive tumor behavior or are faced with recurrence after drug withdrawal. Also, currently used therapeutics have notorious side effects and impair the life quality of the patients. METHODS: Since the amalgamation of clinical and laboratory data besides tumor histopathogenesis and transcriptional regulatory features of the tumor emerges to exhibit essential roles in the behavior and progression of prolactinomas; in this work, we integrated mRNA- and microRNA (miRNA)-level transcriptome data that exploit disease-specific signatures in addition to biological and pharmacological data to elucidate a rational prioritization of pathways and drugs in prolactinoma. RESULTS: We identified 8 drug candidates through drug repurposing based on mRNA-miRNA-level data integration and evaluated their potential through in vitro assays in the MMQ cell line. Seven repurposed drugs including 5-fluorocytosine, nortriptyline, neratinib, puromycin, taxifolin, vorinostat, and zileuton were proposed as potential drug candidates for the treatment of prolactinoma. We further hypothesized possible mechanisms of drug action on MMQ cell viability through analyzing the PI3K/Akt signaling pathway and cell cycle arrest via flow cytometry and Western blotting. DISCUSSION: We presented the transcriptomic landscape of prolactinoma through miRNA and mRNA-level data integration and proposed repurposed drug candidates based on this integration. We validated our findings through testing cell viability, cell cycle phases, and PI3K/Akt protein expressions. Effects of the drugs on cell cycle phases and inhibition of the PI3K/Akt pathway by all drugs gave us promising output for further studies using these drugs in the treatment of prolactinoma. This is the first study that reports miRNA-mediated repurposed drugs for prolactinoma treatment via in vitro experiments.

Novel molecular signatures and potential therapeutics in renal cell carcinomas: Insights from a comparative analysis of subtypes.

Renal cell carcinomas (RCCs) are among the highest causes of cancer mortality. Although transcriptome profiling studies in the last decade have made significant molecular findings on RCCs, effective diagnosis and treatment strategies have yet to be achieved due to lack of adequate screening and comparative profiling of RCC subtypes. In this study, a comparative analysis was performed on RNA-seq based transcriptome data from each RCC subtype, namely clear cell RCC (KIRC), papillary RCC (KIRP) and kidney chromophobe (KICH), and mutual or subtype-specific reporter biomolecules were identified at RNA, protein, and metabolite levels by the integration of expression profiles with genome-scale biomolecular networks. This approach revealed already-known biomarkers in RCCs as well as novel biomarker candidates and potential therapeutic targets. Our findings also pointed out the incorporation of the molecular mechanisms of KIRC and KIRP, whereas KICH was shown to have distinct molecular signatures. Furthermore, considering the Dipeptidyl Peptidase 4 (DPP4) receptor as a potential therapeutic target specific to KICH, several drug candidates such as ZINC6745464 were identified through virtual screening of ZINC molecules. In this study, we reported valuable data for further experimental and clinical efforts, since the proposed molecules have significant potential for screening and therapeutic purposes in RCCs.

Identification of Prognostic Biomarker Signatures and Candidate Drugs in Colorectal Cancer: Insights from Systems Biology Analysis.

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world, but early diagnosis ameliorates the survival of CRC. This report aimed to identify molecular biomarker signatures in CRC. We analyzed two microarray datasets (GSE35279 and GSE21815) from the Gene Expression Omnibus (GEO) to identify mutual differentially expressed genes (DEGs). We integrated DEGs with protein⁻protein interaction and transcriptional/post-transcriptional regulatory networks to identify reporter signaling and regulatory molecules; utilized functional overrepresentation and pathway enrichment analyses to elucidate their roles in biological processes and molecular pathways; performed survival analyses to evaluate their prognostic performance; and applied drug repositioning analyses through Connectivity Map (CMap) and geneXpharma tools to hypothesize possible drug candidates targeting reporter molecules. A total of 727 upregulated and 99 downregulated DEGs were detected. The PI3K/Akt signaling, Wnt signaling, extracellular matrix (ECM) interaction, and cell cycle were identified as significantly enriched pathways. Ten hub proteins (ADNP, CCND1, CD44, CDK4, CEBPB, CENPA, CENPH, CENPN, MYC, and RFC2), 10 transcription factors (ETS1, ESR1, GATA1, GATA2, GATA3, AR, YBX1, FOXP3, E2F4, and PRDM14) and two microRNAs (miRNAs) (miR-193b-3p and miR-615-3p) were detected as reporter molecules. The survival analyses through Kaplan⁻Meier curves indicated remarkable performance of reporter molecules in the estimation of survival probability in CRC patients. In addition, several drug candidates including anti-neoplastic and immunomodulating agents were repositioned. This study presents biomarker signatures at protein and RNA levels with prognostic capability in CRC. We think that the molecular signatures and candidate drugs presented in this study might be useful in future studies indenting the development of accurate diagnostic and/or prognostic biomarker screens and efficient therapeutic strategies in CRC.

Genome reprogramming in Saccharomyces cerevisiae upon nonylphenol exposure.

Bioaccumulative environmental estrogen, nonylphenol (NP; 4-nonylphenol), is widely used as a nonionic surfactant and can affect human health. Since genomes of Saccharomyces cerevisiae and higher eukaryotes share many structural and functional similarities, we investigated subcellular effects of NP on S. cerevisiae BY4742 cells by analyzing genome-wide transcriptional profiles. We examined effects of low (1 mg/l; <15% cell number reduction) and high (5 mg/l; >65% cell number reduction) inhibitory concentration exposures for 120 or 180 min. After 120 and 180 min of 1 mg/l NP exposure, 187 (63 downregulated, 124 upregulated) and 103 genes (56 downregulated, 47 upregulated), respectively, were differentially expressed. Similarly, 678 (168 repressed, 510 induced) and 688 genes (215 repressed, 473 induced) were differentially expressed in cells exposed to 5 mg/l NP for 120 and 180 min, respectively. Only 15 downregulated and 63 upregulated genes were common between low and high NP inhibitory concentration exposure for 120 min, whereas 16 downregulated and 31 upregulated genes were common after the 180-min exposure. Several processes/pathways were prominently affected by either low or high inhibitory concentration exposure, while certain processes were affected by both inhibitory concentrations, including ion transport, response to chemicals, transmembrane transport, cellular amino acids, and carbohydrate metabolism. While minimal expression changes were observed with low inhibitory concentration exposure, 5 mg/l NP treatment induced substantial expression changes in genes involved in oxidative phosphorylation, cell wall biogenesis, ribosomal biogenesis, and RNA processing, and encoding heat shock proteins and ubiquitin-conjugating enzymes. Collectively, these results provide considerable information on effects of NP at the molecular level.

Analysis of transcriptional profiles of Saccharomyces cerevisiae exposed to bisphenol A.

Bisphenol A (BPA), an endocrine disrupting chemical, is used as a monomer in the production of epoxy resins and polycarbonates, and as a plasticizer in polyvinyl chloride. As such, it is produced in large quantities worldwide and continuously leaches into the environment. To capture the genome reprogramming in eukaryotic cells under BPA exposure, here, we used Saccharomyces cerevisiae as model organism and analyzed the genome-wide transcriptional profiles of S. cerevisiae BY4742 in response to BPA, focusing on two exposure scenarios: (1) exposure to a low inhibition concentration (50 mg/L; resulting in <10 % inhibition in cell number) and (2) a high inhibition concentration (300 mg/L; resulting in >70 % inhibition in cell number). Based on the transcriptional profiling analyses, 81 genes were repressed and 104 genes were induced in response to 50 mg/L BPA. Meanwhile, 378 genes were downregulated and 606 genes were significantly upregulated upon exposure to 300 mg/L BPA. While similar processes were affected by exposure to distinct BPA concentrations, including mitochondrial processes, nucleobase-containing small molecule metabolic processes, transcription from the RNA polymerase II promoter, and mitosis and associated processes, the number and magnitude of differentially expressed genes differ between low and high inhibition concentration treatments. For example, exposure to 300 mg/L BPA resulted in severe changes in the expression levels of several genes involved in oxidative phosphorylation, the tricarboxylic acid cycle, ribosomal activity, replication, and chemical responses. Conversely, only slight changes were observed in the expression of genes involved in these processes in cells exposed to 50 mg/L BPA. These results demonstrate that yeast cells respond to BPA in a concentration-dependent manner at the transcriptional level via different genes and provide insight into the molecular mechanisms underlying the modes of action of BPA.

Transcriptomic analysis displays the effect of (-)-roemerine on the motility and nutrient uptake in Escherichia coli.

Among the different families of plant alkaloids, (-)-roemerine, an aporphine type, was recently shown to possess significant antibacterial activity in Escherichia coli. Based on the increasing demand for antibacterials with novel mechanisms of action, the present work investigates the potential of the plant-derived alkaloid (-)-roemerine as an antibacterial in E. coli cells using microarray technology. Analysis of the genome-wide transcriptional reprogramming in cells after 60 min treatment with 100 µg/mL (-)-roemerine showed significant changes in the expression of 241 genes (p value <0.05 and fold change >2). Expression of selected genes was confirmed by qPCR. Differentially expressed genes were classified into functional categories to map biological processes and molecular pathways involved. Cellular activities with roles in carbohydrate transport and metabolism, energy production and conversion, lipid transport and metabolism, amino acid transport and metabolism, two-component signaling systems, and cell motility (in particular, the flagellar organization and motility) were among metabolic processes altered in the presence of (-)-roemerine. The down-regulation of the outer membrane proteins probably led to a decrease in carbohydrate uptake rate, which in turn results in nutrient limitation. Consequently, energy metabolism is slowed down. Interestingly, the majority of the expressional alterations were found in the flagellar system. This suggested reduction in motility and loss in the ability to form biofilms, thus affecting protection of E. coli against host cell defense mechanisms. In summary, our findings suggest that the antimicrobial action of (-)-roemerine in E. coli is linked to disturbances in motility and nutrient uptake.

Integration of multiple biological features yields high confidence human protein interactome.

The biological function of a protein is usually determined by its physical interaction with other proteins. Protein-protein interactions (PPIs) are identified through various experimental methods and are stored in curated databases. The noisiness of the existing PPI data is evident, and it is essential that a more reliable data is generated. Furthermore, the selection of a set of PPIs at different confidence levels might be necessary for many studies. Although different methodologies were introduced to evaluate the confidence scores for binary interactions, a highly reliable, almost complete PPI network of Homo sapiens is not proposed yet. The quality and coverage of human protein interactome need to be improved to be used in various disciplines, especially in biomedicine. In the present work, we propose an unsupervised statistical approach to assign confidence scores to PPIs of H. sapiens. To achieve this goal PPI data from six different databases were collected and a total of 295,288 non-redundant interactions between 15,950 proteins were acquired. The present scoring system included the context information that was assigned to PPIs derived from eight biological attributes. A high confidence network, which included 147,923 binary interactions between 13,213 proteins, had scores greater than the cutoff value of 0.80, for which sensitivity, specificity, and coverage were 94.5%, 80.9%, and 82.8%, respectively. We compared the present scoring method with others for evaluation. Reducing the noise inherent in experimental PPIs via our scoring scheme increased the accuracy significantly. As it was demonstrated through the assessment of process and cancer subnetworks, this study allows researchers to construct and analyze context-specific networks via valid PPI sets and one can easily achieve subnetworks around proteins of interest at a specified confidence level.

Genomic analysis of Brevibacillus thermoruber 423 reveals its biotechnological and industrial potential.

Brevibacillus thermoruber 423 is a Gram-positive, motile, red-pigmented, spore-forming, aerobic, and thermophilic bacterium that is known to produce high levels of exopolysaccharide (EPS) with many potential uses in food, feed, cosmetics, and pharmaceutical and chemical industries. This bacterium not only is among the limited number of reported thermophilic EPS producers but also exceeds other thermophilic producers in light of the high level of polymer synthesis. By a systems-based approach, whole-genome analysis of this bacterium was performed to gain more insight about the biological mechanisms and whole-genome organization of thermophilic EPS producers and hence to develop rational strategies for the genetic and metabolic optimization of EPS production. Also with this study, the first genome analysis was performed on a thermophilic Brevibacillus species. Essential genes associated with EPS biosynthesis were detected by genome annotation, and together with experimental evidences, a hypothetical mechanism for EPS biosynthesis was generated. B. thermoruber 423 was found to have many potential applications in biotechnology and industry because of its capacity to utilize xylose and to produce EPS, isoprenoids, ethanol/butanol, lipases, proteases, cellulase, and glucoamylase enzymes as well as its resistance to arsenic.

Tumor Mutation Burden as a Cornerstone in Precision Oncology Landscapes: Effect of Panel Size and Uncertainty in Cutoffs.

Tumor mutation burden (TMB) has profound implications for personalized cancer therapy, particularly immunotherapy. However, the size of the panel and the cutoff values for an accurate determination of TMB are still controversial. In this study, a pan-cancer analysis was performed on 22 cancer types from The Cancer Genome Atlas. The efficiency of gene panels of different sizes and the effect of cutoff values in accurate TMB determination was assessed on a large cohort using Whole Exome Sequencing data (n = 9929 patients) as the gold standard. Gene panels of four different sizes (i.e., 0.44-2.54 Mb) were selected for comparative analyses. The heterogeneity of TMB within and between cancer types is observed to be very high, and it becomes possible to obtain the exact TMB value as the size of the panel increases. In panels with limited size, it is particularly difficult to recognize patients with low TMB. In addition, the use of a general TMB cutoff can be quite misleading. The optimal cutoff value varies between 5 and 20, depending on the TMB distribution of the different tumor types. The use of comprehensive gene panels and the optimization of TMB cutoff values for different cancer types can make TMB a robust biomarker in precision oncology. Moreover, optimization of TMB can help accelerate translational medicine research, and by extension, delivery of personalized cancer care in the future.

Exploring COVID-19 Pandemic Disparities with Transcriptomic Meta-analysis from the Perspective of Personalized Medicine.

Infection with SARS-CoV2, which is responsible for COVID-19, can lead to differences in disease development, severity and mortality rates depending on gender, age or the presence of certain diseases. Considering that existing studies ignore these differences, this study aims to uncover potential differences attributable to gender, age and source of sampling as well as viral load using bioinformatics and multi-omics approaches. Differential gene expression analyses were used to analyse the phenotypic differences between SARS-CoV-2 patients and controls at the mRNA level. Pathway enrichment analyses were performed at the gene set level to identify the activated pathways corresponding to the differences in the samples. Drug repurposing analysis was performed at the protein level, focusing on host-mediated drug candidates to uncover potential therapeutic differences. Significant differences (i.e. the number of differentially expressed genes and their characteristics) were observed for COVID-19 at the mRNA level depending on the sample source, gender and age of the samples. The results of the pathway enrichment show that SARS-CoV-2 can be combated more effectively in the respiratory tract than in the blood samples. Taking into account the different sample sources and their characteristics, different drug candidates were identified. Evaluating disease prediction, prevention and/or treatment strategies from a personalised perspective is crucial. In this study, we not only evaluated the differences in COVID-19 from a personalised perspective, but also provided valuable data for further experimental and clinical efforts. Our findings could shed light on potential pandemics.

Pharmacomicrobiomics-Guided Precision Oncology: A New Frontier of P4 (Predictive, Personalized, Preventive, and Participatory) Medicine and Microbiome-Based Therapeutics.

Pharmacomicrobiomics is a rapidly developing field that promises to make significant contributions to predictive, personalized, preventive, and participatory (P4) medicine. This is becoming evident particularly in the field of precision (P4) oncology by taking seriously the crucial role microbiome plays in health and disease. Several studies have already shown that clinicians can harness insights from the microbiome to better predict treatment response, reduce side effects, and improve overall outcomes for cancer patients. Furthermore, pharmacomicrobiomics will undoubtedly play a crucial role in shaping the future of cancer treatment in the era of P4 oncology as we continue to unravel the intricate relationships between the microbiome and cancer. This perspective and innovation analysis discusses the emerging intersection of P4 medicine and P4 oncology, as seen through a lens of pharmacomicrobiomics. A key promise of pharmacomicrobiomics is the development of personalized microbiome-based therapeutics. In all, we suggest that optimizing cancer treatment and prevention by harnessing pharmacomicrobiomics has vast potentials for precision oncology, and personalized medicine using the right drug, at the right dose, for the right patient, and at the right time.

A 19-Gene Signature of Serous Ovarian Cancer Identified by Machine Learning and Systems Biology: Prospects for Diagnostics and Personalized Medicine.

Ovarian cancer is a major cause of cancer deaths among women. Early diagnosis and precision/personalized medicine are essential to reduce mortality and morbidity of ovarian cancer, as with new molecular targets to accelerate drug discovery. We report here an integrated systems biology and machine learning (ML) approach based on the differential coexpression analysis to identify candidate systems biomarkers (i.e., gene modules) for serous ovarian cancer. Accordingly, four independent transcriptome datasets were statistically analyzed independently and common differentially expressed genes (DEGs) were identified. Using these DEGs, coexpressed gene pairs were unraveled. Subsequently, differential coexpression networks between the coexpressed gene pairs were reconstructed so as to identify the differentially coexpressed gene modules. Based on the established criteria, "SOV-module" was identified as being significant, consisting of 19 genes. Using independent datasets, the diagnostic capacity of the SOV-module was evaluated using principal component analysis (PCA) and ML techniques. PCA showed a sensitivity and specificity of 96.7% and 100%, respectively, and ML analysis showed an accuracy of up to 100% in distinguishing phenotypes in the present study sample. The prognostic capacity of the SOV-module was evaluated using survival and ML analyses. We found that the SOV-module's performance for prognostics was significant (p-value = 1.36 × 10-4) with an accuracy of 63% in discriminating between survival and death using ML techniques. In summary, the reported genomic systems biomarker candidate offers promise for personalized medicine in diagnosis and prognosis of serous ovarian cancer and warrants further experimental and translational clinical studies.

Genome-scale metabolic models in translational medicine: the current status and potential of machine learning in improving the effectiveness of the models.

The genome-scale metabolic model (GEM) has emerged as one of the leading modeling approaches for systems-level metabolic studies and has been widely explored for a broad range of organisms and applications. Owing to the development of genome sequencing technologies and available biochemical data, it is possible to reconstruct GEMs for model and non-model microorganisms as well as for multicellular organisms such as humans and animal models. GEMs will evolve in parallel with the availability of biological data, new mathematical modeling techniques and the development of automated GEM reconstruction tools. The use of high-quality, context-specific GEMs, a subset of the original GEM in which inactive reactions are removed while maintaining metabolic functions in the extracted model, for model organisms along with machine learning (ML) techniques could increase their applications and effectiveness in translational research in the near future. Here, we briefly review the current state of GEMs, discuss the potential contributions of ML approaches for more efficient and frequent application of these models in translational research, and explore the extension of GEMs to integrative cellular models.

HPV16 status predicts potential protein biomarkers and therapeutics in head and neck squamous cell carcinoma.

Human papillomavirus (HPV) infection, especially HPV16, is one of the causative factors for the development of head and neck squamous cell (HNSC) carcinoma. HPV-positive and HPV-negative HNSC patients differ significantly in their molecular profiles and clinical features, so they should be evaluated differently depending on their HPV status. Given the tremendous variation in HNSC cancers depending on HPV, our goal in this study was to present biomarkers and treatment options tailored to the patient's HPV status. Gene expression levels of HPV16-positive and -negative patients were used as proxies, and the differential interactome algorithm was employed to identify the differential interacting proteins (DIPs). By assessing the prognostic capabilities and druggabilities of DIPs and their interacting partners (DIP-centered modules), we introduce eight modules as potential biomarkers specialized for either positive or negative phenotype. Finally, raloxifene was repositioned for the first time as a drug candidate for the treatment of HPV16-positive HNSC patients.

A Differential Transcriptional Regulome Approach to Unpack Cancer Biology: Insights on Renal Cell Carcinoma Subtypes.

Cancer research calls for new approaches that account for the regulatory complexities of biology. We present, in this study, the differential transcriptional regulome (DIFFREG) approach for the identification and prioritization of key transcriptional regulators and apply it to the case of renal cell carcinoma (RCC) biology. Of note, RCC has a poor prognosis and the biomarker and drug discovery studies to date have tended to focus on gene expression independent from mutations and/or post-translational modifications. DIFFREG focuses on the differential regulation between transcription factors (TFs) and their target genes rather than differential gene expression and integrates transcriptome profiling with the human transcriptional regulatory network to analyze differential gene regulation between healthy and RCC cases. In this study, RNA-seq tissue samples (n = 1020) from the Cancer Genome Atlas (TCGA), including healthy and tumor subjects, were integrated with a comprehensive human TF-gene interactome dataset (1122603 interactions between 1289 TFs and 25177 genes). Comparative analysis of DIFFREG profiles, consisting of perturbed TF-gene interactions, from three common subtypes (clear cell RCC, papillary RCC and chromophobe RCC) revealed subtype-specific alterations, supporting the hypothesis that these signatures in the transcriptional regulome profiles may be considered potential biomarkers that may play an important role in elucidating the molecular mechanisms of RCC development and translating knowledge about the genetic basis of RCC into the clinic. In addition, these indicators may help oncologists make the best decisions for diagnosis and prognosis management.

Drug repositioning via host-pathogen protein-protein interactions for the treatment of cervical cancer.

Introduction: Integrating interaction data with biological knowledge can be a critical approach for drug development or drug repurposing. In this context, host-pathogen-protein-protein interaction (HP-PPI) networks are useful instrument to uncover the phenomena underlying therapeutic effects in infectious diseases, including cervical cancer, which is almost exclusively due to human papillomavirus (HPV) infections. Cervical cancer is one of the second leading causes of death, and HPV16 and HPV18 are the most common subtypes worldwide. Given the limitations of traditionally used virus-directed drug therapies for infectious diseases and, at the same time, recent cancer statistics for cervical cancer cases, the need for innovative treatments becomes clear. Methods: Accordingly, in this study, we emphasize the potential of host proteins as drug targets and identify promising host protein candidates for cervical cancer by considering potential differences between HPV subtypes (i.e., HPV16 and HPV18) within a novel bioinformatics framework that we have developed. Subsequently, subtype-specific HP-PPI networks were constructed to obtain host proteins. Using this framework, we next selected biologically significant host proteins. Using these prominent host proteins, we performed drug repurposing analysis. Finally, by following our framework we identify the most promising host-oriented drug candidates for cervical cancer. Results: As a result of this framework, we discovered both previously associated and novel drug candidates, including interferon alfacon-1, pimecrolimus, and hyaluronan specifically for HPV16 and HPV18 subtypes, respectively. Discussion: Consequently, with this study, we have provided valuable data for further experimental and clinical efforts and presented a novel bioinformatics framework that can be applied to any infectious disease.

The Versatility of Plectin in Cancer: A Pan-Cancer Analysis on Potential Diagnostic and Prognostic Impacts of Plectin Isoforms.

Plectin, encoded by PLEC, is a cytoskeletal and scaffold protein with a number of unique isoforms that act on various cellular functions such as cell adhesion, signal transduction, cancer cell invasion, and migration. While plectin has been shown to display high expression and mislocalization in tumor cells, our knowledge of the biological significance of plectin and its isoforms in tumorigenesis remain limited. In this study, we first performed pathway enrichment analysis to identify cancer hallmark proteins associated with plectin. Then, a pan-cancer analysis was performed using RNA-seq data collected from the Cancer Genome Atlas (TCGA) to detect the mRNA expression levels of PLEC and its transcript isoforms, and the prognostic as well as diagnostic significance of the transcript isoforms was evaluated considering cancer stages. We show here that several tissue specific PLEC isoforms are dysregulated in different cancer types and stages but not the expression of PLEC. Among them, PLEC 1d and PLEC 1f are potential biomarker candidates and call for further translational and personalized medicine research. This study makes a contribution as a stride to unravel the molecular mechanisms underpinning plectin isoforms in cancer development and progression by revealing the potent plectin isoforms in different stages of cancer as potential early cancer detection biomarkers. Importantly, uncovering how plectin isoforms guide malignancy and particular cancer types by comprehensive functional studies might open new avenues toward novel cancer therapeutics.

SVM-DO: identification of tumor-discriminating mRNA signatures via support vector machines supported by Disease Ontology.

Background/aim: The complicated nature of tumor formation makes it difficult to identify discriminatory genes. Recently, transcriptome-based supervised classification methods using support vector machines (SVMs) have become popular in this field. However, the inclusion of less significant variables in the construction of classification models can lead to misclassification. To improve model performance, feature selection methods such as enrichment analysis can be used to extract useful variable sets. The detection of genes that can discriminate between normal and tumor samples in the association of cancer and disease remains an area of limited information. We therefore aimed to discover novel and practical sets of discriminatory biomarkers by utilizing the association of cancer and disease. Materials and methods: In this study, we employed an SVM classification method for differentially expressed genes enriched by Disease Ontology and filtered nondiscriminatory features using Wilk's lambda criterion prior to classification. Our approach uses the discovery of disease-associated genes as a viable strategy to identify gene sets that discriminate between tumor and normal states. We analyzed the performance of our algorithm using comprehensive RNA-Seq data for adenocarcinoma of the colon, squamous cell carcinoma of the lung, and adenocarcinoma of the lung. The classification performance of the obtained gene sets was analyzed by comparison with different expression datasets and previous studies using the same datasets. Results: It was found that our algorithm extracts stable small gene sets that provide high accuracy in predicting cancer status. In addition, the gene sets generated by our method perform well in survival analyses, indicating their potential for prognosis. Conclusion: By combining gene sets for both diagnosis and prognosis, our method can improve clinical applications in cancer research. Our algorithm is available as an R package with a graphical user interface in Bioconductor (https://doi.org/10.18129/B9.bioc.SVMDO) and GitHub (https://github.com/robogeno/SVMDO).