Ontology Mediated Information Extraction with MASTRO SYSTEM-T

In several data-centric application domains, the need arises to extract valuable information from unstructured text documents. The recent paradigm of Ontology Mediated Information Extraction (OMIE) faces this problem by taking into account the knowledge expressed by a domain ontology, and reasoning over it to improve the quality of extracted data. MASTRO SYSTEM-T is a novel tool for OMIE, developed by Sapienza University and IBM Almaden Research. In this work, we demonstrate its usage for information extraction over real-world financial text documents from the U.S. EDGAR system

Automatic Information Extraction from Investment Product Documents

In this paper we report on the activities carried out within a collaboration between Consob and Sapienza University. The developed project focus on Information Extraction from documents describing financial investment products. We discuss how we automate this task, via both rule-based and machine learningbased methods, and describe the performances of our approach

Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer

Background: acquired resistance to trastuzumab is a major clinical problem in the treatment of HER2-positive (HER2+) breast cancer patients. The selection of trastuzumab-resistant patients is a great challenge of precision oncology. The aim of this study was to identify novel epigenetic biomarkers associated to trastuzumab resistance in HER2+ BC patients. Methods: we performed a genome-wide DNA methylation (450K array) and a transcriptomic analysis (RNA-Seq) comparing trastuzumab-sensitive (SK) and trastuzumab-resistant (SKTR) HER2+ human breast cancer cell models. The methylation and expression levels of candidate genes were validated by bisulfite pyrosequencing and qRT-PCR, respectively. Functional assays were conducted in the SK and SKTR models by gene silencing and overexpression. Methylation analysis in 24 HER2+ human BC samples with complete response or non-response to trastuzumab-based treatment was conducted by bisulfite pyrosequencing. Results: epigenomic and transcriptomic analysis revealed the consistent hypermethylation and downregulation of TGFBI, CXCL2, and SLC38A1 genes in association with trastuzumab resistance. The DNA methylation and expression levels of these genes were validated in both sensitive and resistant models analyzed. Of the genes, TGFBI presented the highest hypermethylation-associated silencing both at the transcriptional and protein level. Ectopic expression of TGFBI in the SKTR model suggest an increased sensitivity to trastuzumab treatment. In primary tumors, TGFBI hypermethylation was significantly associated with trastuzumab resistance in HER2+ breast cancer patients. Conclusions: our results suggest for the first time an association between the epigenetic silencing of TGFBI by DNA methylation and trastuzumab resistance in HER2+ cell models. These results provide the basis for further clinical studies to validate the hypermethylation of TGFBI promoter as a biomarker of trastuzumab resistance in HER2+ breast cancer patients

Query Answering in Probabilistic Data and Knowledge Bases

Probabilistic data and knowledge bases are becoming increasingly important in academia and industry. They are continuously extended with new data, powered by modern information extraction tools that associate probabilities with knowledge base facts. The state of the art to store and process such data is founded on probabilistic database systems, which are widely and successfully employed. Beyond all the success stories, however, such systems still lack the fundamental machinery to convey some of the valuable knowledge hidden in them to the end user, which limits their potential applications in practice. In particular, in their classical form, such systems are typically based on strong, unrealistic limitations, such as the closed-world assumption, the closed-domain assumption, the tuple-independence assumption, and the lack of commonsense knowledge. These limitations do not only lead to unwanted consequences, but also put such systems on weak footing in important tasks, querying answering being a very central one. In this thesis, we enhance probabilistic data and knowledge bases with more realistic data models, thereby allowing for better means for querying them. Building on the long endeavor of unifying logic and probability, we develop different rigorous semantics for probabilistic data and knowledge bases, analyze their computational properties and identify sources of (in)tractability and design practical scalable query answering algorithms whenever possible. To achieve this, the current work brings together some recent paradigms from logics, probabilistic inference, and database theory

Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer

Altres ajuts: This work was supported in part by La Marató de TV3 (20131530, TPuig), financial support was from the University of Girona (MPCUdG2016/036), and the University of Girona and La Caixa Foundation awarded S. Palomeras with a predoctoral grant.Background: Acquired resistance to trastuzumab is a major clinical problem in the treatment of HER2-positive (HER2+) breast cancer patients. The selection of trastuzumab-resistant patients is a great challenge of precision oncology. The aim of this study was to identify novel epigenetic biomarkers associated to trastuzumab resistance in HER2+ BC patients. Methods: We performed a genome-wide DNA methylation (450K array) and a transcriptomic analysis (RNA-Seq) comparing trastuzumab-sensitive (SK) and trastuzumab-resistant (SKTR) HER2+ human breast cancer cell models. The methylation and expression levels of candidate genes were validated by bisulfite pyrosequencing and qRT-PCR, respectively. Functional assays were conducted in the SK and SKTR models by gene silencing and overexpression. Methylation analysis in 24 HER2+ human BC samples with complete response or non-response to trastuzumab-based treatment was conducted by bisulfite pyrosequencing. Results: Epigenomic and transcriptomic analysis revealed the consistent hypermethylation and downregulation of TGFBI, CXCL2, and SLC38A1 genes in association with trastuzumab resistance. The DNA methylation and expression levels of these genes were validated in both sensitive and resistant models analyzed. Of the genes, TGFBI presented the highest hypermethylation-associated silencing both at the transcriptional and protein level. Ectopic expression of TGFBI in the SKTR model suggest an increased sensitivity to trastuzumab treatment. In primary tumors, TGFBI hypermethylation was significantly associated with trastuzumab resistance in HER2+ breast cancer patients. Conclusions: Our results suggest for the first time an association between the epigenetic silencing of TGFBI by DNA methylation and trastuzumab resistance in HER2+ cell models. These results provide the basis for further clinical studies to validate the hypermethylation of TGFBI promoter as a biomarker of trastuzumab resistance in HER2+ breast cancer patients

A Bioinformatics-Assisted Review on Iron Metabolism and Immune System to Identify Potential Biomarkers of Exercise Stress-Induced Immunosuppression

The immune function is closely related to iron (Fe) homeostasis and allostasis. The aim of this bioinformatics-assisted review was twofold; (i) to update the current knowledge of Fe metabolism and its relationship to the immune system, and (ii) to perform a prediction analysis of regulatory network hubs that might serve as potential biomarkers during stress-induced immunosuppression. Several literature and bioinformatics databases/repositories were utilized to review Fe metabolism and complement the molecular description of prioritized proteins. The Search Tool for the Retrieval of Interacting Genes (STRING) was used to build a protein-protein interactions network for subsequent network topology analysis. Importantly, Fe is a sensitive double-edged sword where two extremes of its nutritional status may have harmful effects on innate and adaptive immunity. We identified clearly connected important hubs that belong to two clusters: (i) presentation of peptide antigens to the immune system with the involvement of redox reactions of Fe, heme, and Fe trafficking/transport; and (ii) ubiquitination, endocytosis, and degradation processes of proteins related to Fe metabolism in immune cells (e.g., macrophages). The identified potential biomarkers were in agreement with the current experimental evidence, are included in several immunological/biomarkers databases, and/or are emerging genetic markers for different stressful conditions. Although further validation is warranted, this hybrid method (human-machine collaboration) to extract meaningful biological applications using available data in literature and bioinformatics tools should be highlighted.The ‘Bioinformatics-assisted Review’ is a project developed and supported by the Research Division at the Dynamical Business and Science Society—DBSS International SAS. The APC was funded by the Exercise & Sport Nutrition Laboratory (ESNL) at Texas A&M University, the POWER LAB at University of Central Florida and the Sport Genomics Research Group at University of the Basque Country UPV/EHU

The role of the FACT complex in differentiation of multipotent stem cells

Cellular differentiation is accompanied by dramatic changes in chromatin structure which are associated with the activation of lineage-specific transcriptional programs. Facilitates Chromatin Transcription (FACT) is a histone chaperone complex which is important for chromatin-associated processes such as transcription, DNA replication and DNA repair. However, the role of FACT during differentiation of undifferentiated or stem-cell like cells has not yet been elucidated. We investigated the role of the FACT component Structure Specific Recognition Protein 1 (SSRP1) in adipocyte and osteoblast differentiation. Depletion of SSRP1 in human mesenchymal stem cells (hMSC) elicited lineage-specific effects where the adipocyte-specific genes PPARG, RASD1 and PDK4 were significantly increased while markers of osteoblast differentiation markedly decreased. Consistently, Oil Red O staining was increased during adipocyte differentiation while alkaline phosphatase staining was decreased in osteoblast differentiation following knockdown of SSRP1. Osteoblast differentiation plays a pivotal role in maintenance of bone homeostasis important for different bone-associated diseases including age-related bone loss. Thus this study was further focused on the molecular regulation of SSRP1-mediated effects on osteoblast differentiation. Transcriptome-wide RNA-seq revealed a specific enrichment of down-regulation of the canonical Wnt signaling pathway following SSRP1 depletion in osteoblasts. Furthermore a number of biological processes important for osteoblast differentiation including glycosylation, cell-cell contact, adhesion, extra cellular matrix, ossification, osteoblast differentiation, bone and skeletal development were affected by SSRP1 knockdown. In addition a significant nuclear co-localization of SSRP1 and β-catenin was observed where depletion of SSRP1 diminished accumulation of active β-catenin in the nucleus. Together, our data suggest a previously unknown specific role for SSRP1 in promoting the activation of canonical Wnt signaling during lineage-specific differentiation

Innovations in the Integrated Management of Breast Cancer

Breast cancer is acknowledged as an international priority in healthcare. It is currently the most common cancer in women worldwide, with demographic trends indicating a continuous increase in incidence. Over the years, increasing efforts and resources have been devoted to the search for a systematic and optimized strategy in breast cancer diagnosis and treatment. Today, the Breast Unit model is considered the gold standard in order to ensure optimal patient-centered and research-based clinical services through multidisciplinary and integrated management.Surgical treatment has gradually evolved toward less aggressive approaches with the adoption of new therapeutic strategies. The evolution of evidence-based guidelines in such leading disciplines as radiation and medical oncology has led to a steady improvement in survival rates. This Special Issue will highlight innovations in the integrated management of breast cancer, their potential advantages, and the many open issues that still need to be properly defined and addressed

Immunopathogenesis of Asthma and Atopic Diseases – The specific Role of a selected Panel of Genes in human T helper Cell Differentiation

T helper cell (Th) functions are crucial for proper immune defence against various intra- and extracellular pathogens. According to the specific immune responses, Th cells can be classified into subtypes, Th1 and Th2 cells being the most frequently characterized classes. Th1 and Th2 cells interact with other immune cells by regulating their functions with specific cytokine production. IFN, IL-2 and TNF- are the cytokines predominantly produced by Th1 cells whereas Th2 cells produce Th2-type cytokines, such as IL-4, IL-5 and IL-13. Upon TCR activation and in the presence of polarizing cytokines, Th cells differentiate into effector subtypes from a common precursor cell. IFN and IL-12 are the predominant Th1 polarizing cytokines whereas IL-4 directs Th2 polarization. The cytokines mediate their effects through specific receptor signalling. The differentiation process is complex, involving various signalling molecules and routes, as well as functions of the specific transcription factors. The functions of the Th1/Th2 cells are tightly regulated; however, knowledge on human Th cell differentiation is, as yet, fairly poor. The susceptibility for many immune-mediated disorders often originates from disturbed Th cell responses. Thus, research is needed for defining the molecular mechanisms involved in the differentiation and balanced functions of the Th cells. Importantly, the new information obtained will be crucial for a better understanding of the pathogenesis of immune-mediated disorders, such as asthma or autoimmune diseases. In the first subproject of this thesis, the role of genetic polymorphisms in the human STAT6, GATA3 and STAT4 genes were investigated for asthma or atopy susceptibility in Finnish asthma families by association analysis. These genes code for key transcription factors regulating Th cell differentiation. The study resulted in the identification of a GATA3 haplotype that associated with asthma and related traits (high serum IgE level). In the second subproject, an optimized method for human primary T cell transfection and enrichment was established. The method can be utilized for functional studies for the selected genes of interest. The method was also utilized in the third subproject, which aimed at the identification of novel genes involved in early human Th cell polarization (0-48h) using genome-wide oligonucleotide arrays. As a result, numerous genes and ESTs with known or unknown functions were identified in the study. Using an shRNA knockdown approach, a panel of novel IL-4/STAT6 regulated genes were identified in the functional studies of the genes. Moreover, one of the genes, NDFIP2, with a previously uncharacterized role in the human Th differentiation, was observed to promote IFN production of the differentiated Th1 cells. Taken together, the results obtained have revealed potential new relevant candidate genes serving as a basis for further studies characterizing the detailed networks involved in the human Th cell differentiation as well as in the genetic susceptibility of Th-mediated immune disorders.Siirretty Doriast

Reasoning with Contexts in Description Logics

Harmelen, F.A.H. van [Promotor]Schlobach, K.S. [Copromotor