Detection of pan-cancer surface protein biomarkers via a network-based approach on transcriptomics data.

Cell surface proteins have been used as diagnostic and prognostic markers in cancer research and as targets for the development of anticancer agents. Many of these proteins lie at the top of signaling cascades regulating cell responses and gene expression, therefore acting as 'signaling hubs'. It has been previously demonstrated that the integrated network analysis on transcriptomic data is able to infer cell surface protein activity in breast cancer. Such an approach has been implemented in a publicly available method called 'SURFACER'. SURFACER implements a network-based analysis of transcriptomic data focusing on the overall activity of curated surface proteins, with the final aim to identify those proteins driving major phenotypic changes at a network level, named surface signaling hubs. Here, we show the ability of SURFACER to discover relevant knowledge within and across cancer datasets. We also show how different cancers can be stratified in surface-activity-specific groups. Our strategy may identify cancer-wide markers to design targeted therapies and biomarker-based diagnostic approaches.

Predicting the response of the dental pulp to SARS-CoV2 infection: a transcriptome-wide effect cross-analysis.

Pulpitis, inflammation of the dental pulp, is a disease that often necessitates emergency dental care. While pulpitis is considered to be a microbial disease primarily caused by bacteria, viruses have also been implicated in its pathogenesis. Here, we determined the expression of the SARS-CoV2 receptor, angiotensin converting enzyme 2 (ACE2) and its associated cellular serine protease TPMRSS2 in the dental pulp under normal and inflamed conditions. Next, we explored the relationship between the SARS-CoV-2/human interactome and genes expressed in pulpitis. Using existing datasets we show that both ACE2 and TPMRSS2 are expressed in the dental pulp and, that their expression does not change under conditions of inflammation. Furthermore, Master Regulator Analysis of the SARS-CoV2/human interactome identified 75 relevant genes whose expression values are either up-regulated or down-regulated in both the human interactome and pulpitis. Our results suggest that the dental pulp is vulnerable to SARS-CoV2 infection and that SARS-CoV-2 infection of the dental pulp may contribute to worse outcomes of pulpitis.

Methodologies and experimental platforms for generating and analysing microarray and mass spectrometry-based omics data to support P4 medicine.

Predictive, preventive, personalized and participatory (P4) medicine is an emerging medical model that is based on the customization of all medical aspects (i.e. practices, drugs, decisions) of the individual patient. P4 medicine presupposes the elucidation of the so-called omic world, under the assumption that this knowledge may explain differences of patients with respect to disease prevention, diagnosis and therapies. Here, we elucidate the role of some selected omics sciences for different aspects of disease management, such as early diagnosis of diseases, prevention of diseases, selection of personalized appropriate and optimal therapies based on molecular profiling of patients. After introducing basic concepts of P4 medicine and omics sciences, we review some computational tools and approaches for analysing selected omics data, with a special focus on microarray and mass spectrometry data, which may be used to support P4 medicine. Some applications of biomarker discovery and pharmacogenomics and some experiences on the study of drug reactions are also described.

DMET-Miner: Efficient discovery of association rules from pharmacogenomic data.

Microarray platforms enable the investigation of allelic variants that may be correlated to phenotypes. Among those, the Affymetrix DMET (Drug Metabolism Enzymes and Transporters) platform enables the simultaneous investigation of all the genes that are related to drug absorption, distribution, metabolism and excretion (ADME). Although recent studies demonstrated the effectiveness of the use of DMET data for studying drug response or toxicity in clinical studies, there is a lack of tools for the automatic analysis of DMET data. In a previous work we developed DMET-Analyzer, a methodology and a supporting platform able to automatize the statistical study of allelic variants, that has been validated in several clinical studies. Although DMET-Analyzer is able to correlate a single variant for each probe (related to a portion of a gene) through the use of the Fisher test, it is unable to discover multiple associations among allelic variants, due to its underlying statistic analysis strategy that focuses on a single variant for each time. To overcome those limitations, here we propose a new analysis methodology for DMET data based on Association Rules mining, and an efficient implementation of this methodology, named DMET-Miner. DMET-Miner extends the DMET-Analyzer tool with data mining capabilities and correlates the presence of a set of allelic variants with the conditions of patient's samples by exploiting association rules. To face the high number of frequent itemsets generated when considering large clinical studies based on DMET data, DMET-Miner uses an efficient data structure and implements an optimized search strategy that reduces the search space and the execution time. Preliminary experiments on synthetic DMET datasets, show how DMET-Miner outperforms off-the-shelf data mining suites such as the FP-Growth algorithms available in Weka and RapidMiner. To demonstrate the biological relevance of the extracted association rules and the effectiveness of the proposed approach from a medical point of view, some preliminary studies on a real clinical dataset are currently under medical investigation.

Semantic similarity analysis of protein data: assessment with biological features and issues.

The integration of proteomics data with biological knowledge is a recent trend in bioinformatics. A lot of biological information is available and is spread on different sources and encoded in different ontologies (e.g. Gene Ontology). Annotating existing protein data with biological information may enable the use (and the development) of algorithms that use biological ontologies as framework to mine annotated data. Recently many methodologies and algorithms that use ontologies to extract knowledge from data, as well as to analyse ontologies themselves have been proposed and applied to other fields. Conversely, the use of such annotations for the analysis of protein data is a relatively novel research area that is currently becoming more and more central in research. Existing approaches span from the definition of the similarity among genes and proteins on the basis of the annotating terms, to the definition of novel algorithms that use such similarities for mining protein data on a proteome-wide scale. This work, after the definition of main concept of such analysis, presents a systematic discussion and comparison of main approaches. Finally, remaining challenges, as well as possible future directions of research are presented.

M-Finder: Uncovering functionally associated proteins from interactome data integrated with GO annotations.

BACKGROUND: Protein-protein interactions (PPIs) play a key role in understanding the mechanisms of cellular processes. The availability of interactome data has catalyzed the development of computational approaches to elucidate functional behaviors of proteins on a system level. Gene Ontology (GO) and its annotations are a significant resource for functional characterization of proteins. Because of wide coverage, GO data have often been adopted as a benchmark for protein function prediction on the genomic scale. RESULTS: We propose a computational approach, called M-Finder, for functional association pattern mining. This method employs semantic analytics to integrate the genome-wide PPIs with GO data. We also introduce an interactive web application tool that visualizes a functional association network linked to a protein specified by a user. The proposed approach comprises two major components. First, the PPIs that have been generated by high-throughput methods are weighted in terms of their functional consistency using GO and its annotations. We assess two advanced semantic similarity metrics which quantify the functional association level of each interacting protein pair. We demonstrate that these measures outperform the other existing methods by evaluating their agreement to other biological features, such as sequence similarity, the presence of common Pfam domains, and core PPIs. Second, the information flow-based algorithm is employed to discover a set of proteins functionally associated with the protein in a query and their links efficiently. This algorithm reconstructs a functional association network of the query protein. The output network size can be flexibly determined by parameters. CONCLUSIONS: M-Finder provides a useful framework to investigate functional association patterns with any protein. This software will also allow users to perform further systematic analysis of a set of proteins for any specific function. It is available online at http://bionet.ecs.baylor.edu/mfinder.

Network for network concept offers new insights into host- SARS-CoV-2 protein interactions and potential novel targets for developing antiviral drugs.

SARS-CoV-2, the causal agent of COVID-19, is primarily a pulmonary virus that can directly or indirectly infect several organs. Despite many studies carried out during the current COVID-19 pandemic, some pathological features of SARS-CoV-2 have remained unclear. It has been recently attempted to address the current knowledge gaps on the viral pathogenicity and pathological mechanisms via cellular-level tropism of SARS-CoV-2 using human proteomics, visualization of virus-host protein-protein interactions (PPIs), and enrichment analysis of experimental results. The synergistic use of models and methods that rely on graph theory has enabled the visualization and analysis of the molecular context of virus/host PPIs. We review current knowledge on the SARS-COV-2/host interactome cascade involved in the viral pathogenicity through the graph theory concept and highlight the hub proteins in the intra-viral network that create a subnet with a small number of host central proteins, leading to cell disintegration and infectivity. Then we discuss the putative principle of the "gene-for-gene and "network for network" concepts as platforms for future directions toward designing efficient anti-viral therapies.

A large set of estrogen receptor ß-interacting proteins identified by tandem affinity purification in hormone-responsive human breast cancer cell nuclei.

Estrogen receptors α (ER-α) and ß (ER-ß) play distinct biological roles in onset and progression of hormone-responsive breast cancer, with ER-ß exerting a modulatory activity on ER-α-mediated estrogen signaling and stimulation of cell proliferation by mechanisms still not fully understood. We stably expressed human ER-ß fused to a tandem affinity purification-tag in estrogen-responsive MCF-7 cells and applied tandem affinity purification and nanoLC-MS/MS to identify the ER-ß interactome of this cell type. Functional annotation by bioinformatics analyses of the 303 proteins that co-purify with ER-ß from nuclear extracts identify several new molecular partners of this receptor subtype that represents nodal points of a large protein network controlling multiple processes and functions in breast cancer cells.

A novel algorithm for finding top-k weighted overlapping densest connected subgraphs in dual networks.

The use of networks for modelling and analysing relations among data is currently growing. Recently, the use of a single networks for capturing all the aspects of some complex scenarios has shown some limitations. Consequently, it has been proposed to use Dual Networks (DN), a pair of related networks, to analyse complex systems. The two graphs in a DN have the same set of vertices and different edge sets. Common subgraphs among these networks may convey some insights about the modelled scenarios. For instance, the detection of the Top-k Densest Connected subgraphs, i.e. a set k subgraphs having the largest density in the conceptual network which are also connected in the physical network, may reveal set of highly related nodes. After proposing a formalisation of the approach, we propose a heuristic to find a solution, since the problem is computationally hard. A set of experiments on synthetic and real networks is also presented to support our approach.

Regional Resource Assessment During the COVID-19 Pandemic in Italy: Modeling Study.

BACKGROUND: COVID-19 has been declared a worldwide emergency and a pandemic by the World Health Organization. It started in China in December 2019, and it rapidly spread throughout Italy, which was the most affected country after China. The pandemic affected all countries with similarly negative effects on the population and health care structures. OBJECTIVE: The evolution of the COVID-19 infections and the way such a phenomenon can be characterized in terms of resources and planning has to be considered. One of the most critical resources has been intensive care units (ICUs) with respect to the infection trend and critical hospitalization. METHODS: We propose a model to estimate the needed number of places in ICUs during the most acute phase of the infection. We also define a scalable geographic model to plan emergency and future management of patients with COVID-19 by planning their reallocation in health structures of other regions. RESULTS: We applied and assessed the prediction method both at the national and regional levels. ICU bed prediction was tested with respect to real data provided by the Italian government. We showed that our model is able to predict, with a reliable error in terms of resource complexity, estimation parameters used in health care structures. In addition, the proposed method is scalable at different geographic levels. This is relevant for pandemics such as COVID-19, which has shown different case incidences even among northern and southern Italian regions. CONCLUSIONS: Our contribution can be useful for decision makers to plan resources to guarantee patient management, but it can also be considered as a reference model for potential upcoming waves of COVID-19 and similar emergency situations.

mu-CS: an extension of the TM4 platform to manage Affymetrix binary data.

BACKGROUND: A main goal in understanding cell mechanisms is to explain the relationship among genes and related molecular processes through the combined use of technological platforms and bioinformatics analysis. High throughput platforms, such as microarrays, enable the investigation of the whole genome in a single experiment. There exist different kind of microarray platforms, that produce different types of binary data (images and raw data). Moreover, also considering a single vendor, different chips are available. The analysis of microarray data requires an initial preprocessing phase (i.e. normalization and summarization) of raw data that makes them suitable for use on existing platforms, such as the TIGR M4 Suite. Nevertheless, the annotations of data with additional information such as gene function, is needed to perform more powerful analysis. Raw data preprocessing and annotation is often performed in a manual and error prone way. Moreover, many available preprocessing tools do not support annotation. Thus novel, platform independent, and possibly open source tools enabling the semi-automatic preprocessing and annotation of microarray data are needed. RESULTS: The paper presents mu-CS (Microarray Cel file Summarizer), a cross-platform tool for the automatic normalization, summarization and annotation of Affymetrix binary data. mu-CS is based on a client-server architecture. The mu-CS client is provided both as a plug-in of the TIGR M4 platform and as a Java standalone tool and enables users to read, preprocess and analyse binary microarray data, avoiding the manual invocation of external tools (e.g. the Affymetrix Power Tools), the manual loading of preprocessing libraries, and the management of intermediate files. The mu-CS server automatically updates the references to the summarization and annotation libraries that are provided to the mu-CS client before the preprocessing. The mu-CS server is based on the web services technology and can be easily extended to support more microarray vendors (e.g. Illumina). CONCLUSIONS: Thus mu-CS users can directly manage binary data without worrying about locating and invoking the proper preprocessing tools and chip-specific libraries. Moreover, users of the mu-CS plugin for TM4 can manage Affymetrix binary files without using external tools, such as APT (Affymetrix Power Tools) and related libraries. Consequently, mu-CS offers four main advantages: (i) it avoids to waste time for searching the correct libraries, (ii) it reduces possible errors in the preprocessing and further analysis phases, e.g. due to the incorrect choice of parameters or the use of old libraries, (iii) it implements the annotation of preprocessed data, and finally, (iv) it may enhance the quality of further analysis since it provides the most updated annotation libraries. The mu-CS client is freely available as a plugin of the TM4 platform as well as a standalone application at the project web site (http://bioingegneria.unicz.it/M-CS).

Master Regulator Analysis of the SARS-CoV-2/Human Interactome.

The recent epidemic outbreak of a novel human coronavirus called SARS-CoV-2 causing the respiratory tract disease COVID-19 has reached worldwide resonance and a global effort is being undertaken to characterize the molecular features and evolutionary origins of this virus. In this paper, we set out to shed light on the SARS-CoV-2/host receptor recognition, a crucial factor for successful virus infection. Based on the current knowledge of the interactome between SARS-CoV-2 and host cell proteins, we performed Master Regulator Analysis to detect which parts of the human interactome are most affected by the infection. We detected, amongst others, affected apoptotic and mitochondrial mechanisms, and a downregulation of the ACE2 protein receptor, notions that can be used to develop specific therapies against this new virus.

A grid-based protein complex predictor.

Proteins interact among them and different interactions form a very huge number of possible combinations representable as protein to protein interaction (PPI) networks that are mapped into graph structures. The interest in analyzing PPI networks is related to the possibility of predicting PPI properties, starting from a set of known proteins interacting among each other. For example, predicting the configuration of a subset of nodes in a graph (representing a PPI network), allows to study the generation of protein complexes. Nevertheless, due to the huge number of possible configurations of protein interactions, automatic based computation tools are required. Available prediction tools are able to analyze and predict possible combinations of proteins in a PPI network which have biological meanings. Once obtained, the protein interactions are analyzed with respect to biological meanings representing quality measures. Nevertheless, such tools strictly depend on input configuration and require biological validation. In this paper we propose a new grid-based prediction tool that integrate of different prediction results.

DIETOS: A dietary recommender system for chronic diseases monitoring and management.

BACKGROUND AND OBJECTIVE: Use of mobile and web-based applications for diet and weight management is currently increasing. However, the impact of known apps on clinical outcomes is not well-characterized so far. Moreover, availability of food recommender systems providing high quality nutritional advices to both healthy and diet-related chronic diseases users is very limited. In addition, the potentiality of nutraceutical properties of typical regional foods for improving app utility has not been exerted to this end. We present DIETOS, a recommender system for the adaptive delivery of nutrition contents to improve the quality of life of both healthy subjects and patients with diet-related chronic diseases. DIETOS provides highly specialized nutritional advices in different health conditions. METHODS: DIETOS was projected to provide users with health profile and individual nutritional recommendation. Health profiling was based on user answers to dynamic real-time medical questionnaires. Furthermore, DIETOS contains catalogs of typical foods from Calabria, a southern Italian region. Several Calabrian foods have been inserted because of their nutraceutical properties widely reported in several quality studies. DIETOS includes some well known methods for user profiling (overlay profiling) and content adaptation (content selection) coming from general purpose adaptive web systems. RESULTS: DIETOS has been validated for usability for both patients and specialists and for assessing the correctness of the profiling and recommendation, by enrolling 20 chronic kidney disease (CKD) patients at the Department of Nephrology and Dialysis, University Hospital, Catanzaro (Italy) and 20 age-matched healthy controls. Recruited subjects were invited to register to DIETOS and answer to medical questions to determine their health status. Based on our results, DIETOS has high specificity and sensitivity, allowing to determine a medical-controlled user's health profile and to perform a fine-grained recommendation that is better adapted to each user health status. The current version of DIETOS, available online at http://www.easyanalysis.it/dietos is not intended to be used by general users, but only for review purpose. CONCLUSIONS: DIETOS is a novel food recommender system for healthy people and individuals affected by diet-related chronic diseases. The proposed system builds a users health profile and, accordingly, provides individualized nutritional recommendations, also with attention to food geographical origin.

On the Analysis of Diseases and Their Related Geographical Data.

Electronic medical records (EMRs) store data related to patients information enrolled during their stay in health structures. Data stored into EMRs span from data crawled from biological laboratories to textual description of diseases and diagnostic device results (e.g., biomedical images). Each EMR is related to a diagnosis related group (DRG) record. A DRG record is a record associated with a citizen that has been cured in a hospital. It contains a code, called major diagnostic category (MDC), which summarizes the treated disease and allows to reimburse costs related to patient treatments during his staying in health structures. DRGs are used for administrative process (e.g., costs and reimbursement management) as well as disease monitoring. Associating diagnostic codes with external information (such as environmental and geographical data) and with information filtered from EMRs (e.g., biological results or analytes values) can be useful to monitor citizens wellness status. We propose a methodology to analyze such data based on a multistep process. First, we cross reference data by using a semantics-based clustering procedure, extract information from EMRs, and then, cluster them by looking for similar patterns of diseases. Then, biological records in each disease cluster are analyzed to evaluate intracluster similarity by selecting analytes typologies and values. Finally, biological data is related to diagnosis codes and geometrically projected in areas of interest in order to map calculated outlier patients. We applied the methodology on two case studies: 1) diagnosis codes and biochemical analytes of 20 000 biological analyses about hospitalized patients during one observation year and 2) the correlation between cardiovascular diseases and water quality in a southern Italian region. Preliminary findings show the effectiveness of our method.

Design and Implementation of a Telecardiology System for Mobile Devices.

This paper presents the design and implementation of a system for digital telecardiology on mobile devices called Remote Cardio Consultation (RCC). Using RCC may improve first intervention procedures in case of heart attack. In fact, it allows physicians to remotely consult ECG signals from a mobile device or smartphone by using a so-called app. The remote consultation is implemented by a server application collecting physician availability to answer upon client support requests. The app can be used by first intervention clinicians and allows reducing delays and decision errors in emergency interventions. Thus, best decision, certified and supported by cardiologists, can be obtained in case of heart attacks and first interventions even by base medical doctors able to produce and send an ECG. RCC tests have been performed, and the prototype is freely available as a service for testing.

Analysis of miRNA, mRNA, and TF interactions through network-based methods.

Recent findings have elucidated that the regulation of messenger RNA (mRNA) levels is due to the synergistic and antagonist actions of transcription factors (TFs) and microRNAs (miRNAs). Mutual interactions among these molecules are easily modeled and analyzed using graphs whose nodes are molecules, and directed edges represent the associations among them. In particular, small subgraphs having three nodes also referred to as feed-forward loops (FFLs) or regulatory loops play a crucial role in many different diseases, such as cancer. Available technological platforms enable the investigation of only a single aspect of these mechanisms, e.g., the quantification of levels of mRNA or miRNA. Consequently, there exist different data sources for investigating some aspects of this problem, e.g., miRNA-mRNA or TF-mRNA associations. The comprehensive analysis is made possible only by the integration and the analysis of these data sources. Currently, the interest of researchers in this area is growing, the number of projects is increasing, and the number of challenges and issues for computer scientists is considerable. The need for an introductive survey from a computer science point of view consequently arises. This survey starts by discussing general concepts related to production of data. Then, main existing approaches of analysis are presented and discussed. Future improvements and challenges are also discussed.

Tractography in amyotrophic lateral sclerosis using a novel probabilistic tool: a study with tract-based reconstruction compared to voxel-based approach.

BACKGROUND: Diffusion tensor imaging (DTI) is one of the most sensitive MRI tools for detecting subtle cerebral white matter abnormalities in amyotrophic lateral sclerosis (ALS). Nowadays a plethora of DTI tools have been proposed, but very few methods have been translated into clinical practice. NEW METHOD: The aim of this study is to validate the objective measurement of fiber tracts as provided by a new unbiased and automated tractography reconstruction tool named as TRActs Constrained by UnderLying Anatomy (TRACULA). The reliability of this tract-based approach was evaluated on a dataset of 14 patients with definite ALS compared with 14 age/sex-matched healthy controls. To further corroborate these measurements, we used a well-known voxelwise approach, called tract-based spatial statistics (TBSS), on the same dataset. RESULTS: TRACULA showed specific significant alterations of several DTI parameters in the corticospinal tract of the ALS group with respect to controls. COMPARISON WITH EXISTING METHOD: The same finding was detected using the well-known TBSS analysis. Similarly, both methods depicted also additional microstructural changes in the cingulum. CONCLUSIONS: DTI tractography metrics provided by TRACULA perfectly agree with those previously reported in several post-mortem and DTI studies, thus demonstrating the accuracy of this method in characterizing the microstructural changes occurring in ALS. With further validation (i.e. considering the heterogeneity of other clinical phenotypes), this method has the potential to become useful for clinical practice providing objective measurements that might aid radiologists in the interpretation of MR images and improve diagnostic accuracy of ALS.

AlignNemo: a local network alignment method to integrate homology and topology.

Local network alignment is an important component of the analysis of protein-protein interaction networks that may lead to the identification of evolutionary related complexes. We present AlignNemo, a new algorithm that, given the networks of two organisms, uncovers subnetworks of proteins that relate in biological function and topology of interactions. The discovered conserved subnetworks have a general topology and need not to correspond to specific interaction patterns, so that they more closely fit the models of functional complexes proposed in the literature. The algorithm is able to handle sparse interaction data with an expansion process that at each step explores the local topology of the networks beyond the proteins directly interacting with the current solution. To assess the performance of AlignNemo, we ran a series of benchmarks using statistical measures as well as biological knowledge. Based on reference datasets of protein complexes, AlignNemo shows better performance than other methods in terms of both precision and recall. We show our solutions to be biologically sound using the concept of semantic similarity applied to Gene Ontology vocabularies. The binaries of AlignNemo and supplementary details about the algorithms and the experiments are available at: sourceforge.net/p/alignnemo.