RESUMO
Motivation: Recognition of biomedical entities from scientific text is a critical component of natural language processing and automated information extraction platforms. Modern named entity recognition approaches rely heavily on supervised machine learning techniques, which are critically dependent on annotated training corpora. These approaches have been shown to perform well when trained and tested on the same source. However, in such scenario, the performance and evaluation of these models may be optimistic, as such models may not necessarily generalize to independent corpora, resulting in potential non-optimal entity recognition for large-scale tagging of widely diverse articles in databases such as PubMed. Results: Here we aggregated published corpora for the recognition of biomolecular entities (such as genes, RNA, proteins, variants, drugs and metabolites), identified entity class overlap and performed leave-corpus-out cross validation strategy to test the efficiency of existing models. We demonstrate that accuracies of models trained on individual corpora decrease substantially for recognition of the same biomolecular entity classes in independent corpora. This behavior is possibly due to limited generalizability of entity-class-related features captured by individual corpora (model 'overtraining') which we investigated further at the orthographic level, as well as potential annotation standard differences. We show that the combined use of multi-source training corpora results in overall more generalizable models for named entity recognition, while achieving comparable individual performance. By performing learning-curve-based power analysis we further identified that performance is often not limited by the quantity of the annotated data. Availability and implementation: Compiled primary and secondary sources of the aggregated corpora are available on: https://github.com/dterg/biomedical_corpora/wiki and https://bitbucket.org/iAnalytica/bioner. Supplementary information: Supplementary data are available at Bioinformatics online.
Assuntos
Mineração de Dados/métodos , Bases de Dados Factuais , Processamento de Linguagem Natural , Aprendizado de Máquina Supervisionado , PubMedRESUMO
Motivation: High-resolution mass spectrometry permits simultaneous detection of thousands of different metabolites in biological samples; however, their automated annotation still presents a challenge due to the limited number of tailored computational solutions freely available to the scientific community. Results: Here, we introduce ChemDistiller, a customizable engine that combines automated large-scale annotation of metabolites using tandem MS data with a compiled database containing tens of millions of compounds with pre-calculated 'fingerprints' and fragmentation patterns. Our tests using publicly and commercially available tandem MS spectra for reference compounds show retrievals rates comparable to or exceeding the ones obtainable by the current state-of-the-art solutions in the field while offering higher throughput, scalability and processing speed. Availability and implementation: Source code freely available for download at https://bitbucket.org/iAnalytica/chemdistillerpython. Supplementary information: Supplementary data are available at Bioinformatics online.
Assuntos
Metabolômica/métodos , Software , Espectrometria de Massas em Tandem/métodos , Bases de Dados FactuaisRESUMO
Septins, cytoskeletal proteins with well-characterised roles in cytokinesis, form cage-like structures around cytosolic Shigella flexneri and promote their targeting to autophagosomes. However, the processes underlying septin cage assembly, and whether they influence S. flexneri proliferation, remain to be established. Using single-cell analysis, we show that the septin cages inhibit S. flexneri proliferation. To study mechanisms of septin cage assembly, we used proteomics and found mitochondrial proteins associate with septins in S. flexneri-infected cells. Strikingly, mitochondria associated with S. flexneri promote septin assembly into cages that entrap bacteria for autophagy. We demonstrate that the cytosolic GTPase dynamin-related protein 1 (Drp1) interacts with septins to enhance mitochondrial fission. To avoid autophagy, actin-polymerising Shigella fragment mitochondria to escape from septin caging. Our results demonstrate a role for mitochondria in anti-Shigella autophagy and uncover a fundamental link between septin assembly and mitochondria.
Assuntos
Autofagia , Mitocôndrias/metabolismo , Septinas/metabolismo , Shigella/fisiologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Proteínas do Citoesqueleto/metabolismo , Humanos , Dinâmica Mitocondrial , Proteínas Mitocondriais/metabolismo , Modelos Biológicos , Ligação ProteicaRESUMO
Oxidative stress is implicated in the pathogenesis of many diseases, including serious ocular diseases, keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD). Flap endonuclease 1 (FEN1) plays an important role in the repair of oxidative DNA damage in the base excision repair pathway. We determined the association between two single nucleotide polymorphisms (SNPs), c.-441G>A (rs174538) and g.61564299G>T (rs4246215), in the FEN1 gene and the occurrence of KC and FECD. This study involved 279 patients with KC, 225 patients with FECD and 322 control individuals. Polymerase chain reaction (PCR) and length polymorphism restriction fragment analysis (RFLP) were applied. The T/T genotype of the g.61564299G>T polymorphism was associated with an increased occurrence of KC and FECD. There was no association between the c.-441G>A polymorphism and either disease. However, the GG haplotype of both polymorphisms was observed more frequently and the GT haplotype less frequently in the KC group than the control. The AG haplotype was associated with increased FECD occurrence. Our findings suggest that the g.61564299G>T and c.-441G>A polymorphisms in the FEN1 gene may modulate the risk of keratoconus and Fuchs endothelial corneal dystrophy.
Assuntos
Endonucleases Flap/genética , Distrofia Endotelial de Fuchs/enzimologia , Distrofia Endotelial de Fuchs/genética , Ceratocone/enzimologia , Polimorfismo Genético/genética , Haplótipos/genética , Ceratocone/genética , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Preoperative radiotherapy (RT) plays an important role in the management of locally advanced rectal cancer (RC). Tumor regression after RT shows marked variability, and robust molecular methods are needed to help predict likely response. The aim of this study was to review the current published literature and use Gene Ontology (GO) analysis to define key molecular biomarkers governing radiation response in RC. A systematic review of electronic bibliographic databases (Medline, Embase) was performed for original articles published between 2000 and 2015. Biomarkers were then classified according to biological function and incorporated into a hierarchical GO tree. Both significant and nonsignificant results were included in the analysis. Significance was binarized on the basis of univariate and multivariate statistics. Significance scores were calculated for each biological domain (or node), and a direct acyclic graph was generated for intuitive mapping of biological pathways and markers involved in RC radiation response. Seventy-two individual biomarkers across 74 studies were identified. On highest-order classification, molecular biomarkers falling within the domains of response to stress, cellular metabolism, and pathways inhibiting apoptosis were found to be the most influential in predicting radiosensitivity. Homogenizing biomarker data from original articles using controlled GO terminology demonstrated that cellular mechanisms of response to RT in RC-in particular the metabolic response to RT-may hold promise in developing radiotherapeutic biomarkers to help predict, and in the future modulate, radiation response.
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Biomarcadores Tumorais/análise , Terapia Neoadjuvante/métodos , Tolerância a Radiação , Neoplasias Retais/terapia , Biomarcadores Tumorais/efeitos da radiação , Intervalo Livre de Doença , Humanos , Protectomia , Prognóstico , Radioterapia Adjuvante/métodos , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Resultado do TratamentoRESUMO
Recent data indicate that up-to 30-40% of cancers can be prevented by dietary and lifestyle measures alone. Herein, we introduce a unique network-based machine learning platform to identify putative food-based cancer-beating molecules. These have been identified through their molecular biological network commonality with clinically approved anti-cancer therapies. A machine-learning algorithm of random walks on graphs (operating within the supercomputing DreamLab platform) was used to simulate drug actions on human interactome networks to obtain genome-wide activity profiles of 1962 approved drugs (199 of which were classified as "anti-cancer" with their primary indications). A supervised approach was employed to predict cancer-beating molecules using these 'learned' interactome activity profiles. The validated model performance predicted anti-cancer therapeutics with classification accuracy of 84-90%. A comprehensive database of 7962 bioactive molecules within foods was fed into the model, which predicted 110 cancer-beating molecules (defined by anti-cancer drug likeness threshold of >70%) with expected capacity comparable to clinically approved anti-cancer drugs from a variety of chemical classes including flavonoids, terpenoids, and polyphenols. This in turn was used to construct a 'food map' with anti-cancer potential of each ingredient defined by the number of cancer-beating molecules found therein. Our analysis underpins the design of next-generation cancer preventative and therapeutic nutrition strategies.
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Antineoplásicos/química , Inteligência Artificial , Análise de Alimentos , Neoplasias/prevenção & controle , Antineoplásicos/uso terapêutico , Bases de Dados Factuais , Dieta , Reposicionamento de Medicamentos , Alimentos/classificação , Humanos , Redes e Vias Metabólicas , Neoplasias/patologiaRESUMO
Colorectal peritoneal metastases (CPM) are associated with abbreviated survival and significantly impaired quality of life. In patients with CPM, radical multimodality treatment consisting of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has demonstrated oncological superiority over systemic chemotherapy alone. In highly selected patients undergoing CRS + HIPEC, overall survival of over 60% has been reported in some series. These are patients in whom the disease burden is limited and where the diagnosis is made at an early stage in the disease course. Early diagnosis and a deeper understanding of the biological mechanisms that regulate CPM are critical to refining patient selection for radical treatment, personalising therapeutic approaches, enhancing prognostication, and ultimately improving long-term survivorship. In the present study, we outline three broad themes which represent critical future research targets in CPM: (1) enhanced radiological strategies for early detection and staging; (2) identification and validation of translational biomarkers for diagnostic, prognostic, and therapeutic deployment; and (3) development of optimized approaches for surgical cytoreduction as well as more precise strategies for intraperitoneal drug selection and delivery. Herein, we provide a contemporary narrative review of the state of the art in these three areas. A systematic review in accordance with PRISMA guidelines was undertaken on all English language studies published between 2007 and 2017. In vitro and animal model studies were deemed eligible for inclusion in the sections pertaining to biomarkers and therapeutic optimisation, as these areas of research currently remain in the early stages of development. Acquired data were then divided into hierarchical thematic categories (imaging modalities, translational biomarkers (diagnostic/prognostic/therapeutic), and delivery techniques) and subcategories. An interactive sunburst figure is provided for intuitive interrogation of the CPM research landscape.
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The cytoskeleton occupies a central role in cellular immunity by promoting bacterial sensing and antibacterial functions. Septins are cytoskeletal proteins implicated in various cellular processes, including cell division. Septins also assemble into cage-like structures that entrap cytosolic Shigella, yet how septins recognize bacteria is poorly understood. Here, we discover that septins are recruited to regions of micron-scale membrane curvature upon invasion and division by a variety of bacterial species. Cardiolipin, a curvature-specific phospholipid, promotes septin recruitment to highly curved membranes of Shigella, and bacterial mutants lacking cardiolipin exhibit less septin cage entrapment. Chemically inhibiting cell separation to prolong membrane curvature or reducing Shigella cell growth respectively increases and decreases septin cage formation. Once formed, septin cages inhibit Shigella cell division upon recruitment of autophagic and lysosomal machinery. Thus, recognition of dividing bacterial cells by the septin cytoskeleton is a powerful mechanism to restrict the proliferation of intracellular bacterial pathogens.
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Lisossomos/metabolismo , Pseudomonas aeruginosa/fisiologia , Septinas/metabolismo , Shigella flexneri/fisiologia , Staphylococcus aureus/fisiologia , Autofagia , Cardiolipinas/genética , Cardiolipinas/metabolismo , Divisão Celular , Proliferação de Células , Citoesqueleto/metabolismo , Células HeLa , Humanos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/patogenicidade , Septinas/genética , Shigella flexneri/genética , Shigella flexneri/patogenicidade , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidadeRESUMO
Mass Spectrometry Imaging (MSI) holds significant promise in augmenting digital histopathologic analysis by generating highly robust big data about the metabolic, lipidomic and proteomic molecular content of the samples. In the process, a vast quantity of unrefined data, that can amount to several hundred gigabytes per tissue section, is produced. Managing, analysing and interpreting this data is a significant challenge and represents a major barrier to the translational application of MSI. Existing data analysis solutions for MSI rely on a set of heterogeneous bioinformatics packages that are not scalable for the reproducible processing of large-scale (hundreds to thousands) biological sample sets. Here, we present a computational platform (pyBASIS) capable of optimized and scalable processing of MSI data for improved information recovery and comparative analysis across tissue specimens using machine learning and related pattern recognition approaches. The proposed solution also provides a means of seamlessly integrating experimental laboratory data with downstream bioinformatics interpretation/analyses, resulting in a truly integrated system for translational MSI.
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Biologia Computacional/métodos , Histocitoquímica/métodos , Processamento de Imagem Assistida por Computador/métodos , Espectrometria de Massas/métodos , Aprendizado de Máquina , Metabolômica/métodos , Reconhecimento Automatizado de Padrão , Proteômica/métodosRESUMO
Colon cancer induces a state of mucosal dysbiosis with associated niche specific changes in the gut microbiota. However, the key metabolic functions of these bacteria remain unclear. We performed a prospective observational study in patients undergoing elective surgery for colon cancer without mechanical bowel preparation (n = 18). Using 16 S rRNA gene sequencing we demonstrated that microbiota ecology appears to be cancer stage-specific and strongly associated with histological features of poor prognosis. Fusobacteria (p < 0.007) and ε- Proteobacteria (p < 0.01) were enriched on tumour when compared to adjacent normal mucosal tissue, and fusobacteria and ß-Proteobacteria levels increased with advancing cancer stage (p = 0.014 and 0.002 respecitvely). Metabonomic analysis using 1H Magic Angle Spinning Nuclear Magnetic Resonsance (MAS-NMR) spectroscopy, demonstrated increased abundance of taurine, isoglutamine, choline, lactate, phenylalanine and tyrosine and decreased levels of lipids and triglycerides in tumour relative to adjacent healthy tissue. Network analysis revealed that bacteria associated with poor prognostic features were not responsible for the modification of the cancer mucosal metabonome. Thus the colon cancer mucosal microbiome evolves with cancer stage to meet the demands of cancer metabolism. Passenger microbiota may play a role in the maintenance of cancer mucosal metabolic homeostasis but these metabolic functions may not be stage specific.
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Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Microbioma Gastrointestinal , Mucosa Intestinal/química , Mucosa Intestinal/microbiologia , Metaboloma , Análise por Conglomerados , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Humanos , Espectroscopia de Ressonância Magnética , Metabolômica , Metagenômica , Microbiota , Filogenia , Estudos Prospectivos , RNA Ribossômico 16S/genética , Análise de Sequência de DNARESUMO
Hierarchical classification (HC) stratifies and classifies data from broad classes into more specific classes. Unlike commonly used data classification strategies, this enables the probabilistic prediction of unknown classes at different levels, minimizing the burden of incomplete databases. Despite these advantages, its translational application in biomedical sciences has been limited. We describe and demonstrate the implementation of a HC approach for "omics-driven" classification of 15 bacterial species at various taxonomic levels achieving 90-100% accuracy, and 9 cancer types into morphological types and 35 subtypes with 99% and 76% accuracy, respectively. Unknown bacterial species were probabilistically assigned with 100% accuracy to their respective genus or family using mass spectra (n = 284). Cancer types were predicted by mRNA data (n = 1960) for most subtypes with 95-100% accuracy. This has high relevance in clinical practice where complete datasets are difficult to compile with the continuous evolution of diseases and emergence of new strains, yet prediction of unknown classes, such as bacterial species, at upper hierarchy levels may be sufficient to initiate antimicrobial therapy. The algorithms presented here can be directly translated into clinical-use with any quantitative data, and have broad application potential, from unlabeled sample identification, to hierarchical feature selection, and discovery of new taxonomic variants.
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Algoritmos , Bactérias/genética , Ciência de Dados , Bases de Dados Factuais , ProteômicaRESUMO
Colorectal cancer is a global disease with increasing incidence. Mortality is largely attributed to metastatic spread and therefore, a mechanistic dissection of the signals which influence tumor progression is needed. Cancer stroma plays a critical role in tumor proliferation, invasion and chemoresistance. Here, we sought to identify and characterize exosomal microRNAs as mediators of stromal-tumor signaling. In vitro, we demonstrated that fibroblast exosomes are transferred to colorectal cancer cells, with a resultant increase in cellular microRNA levels, impacting proliferation and chemoresistance. To probe this further, exosomal microRNAs were profiled from paired patient-derived normal and cancer-associated fibroblasts, from an ongoing prospective biomarker study. An exosomal cancer-associated fibroblast signature consisting of microRNAs 329, 181a, 199b, 382, 215 and 21 was identified. Of these, miR-21 had highest abundance and was enriched in exosomes. Orthotopic xenografts established with miR-21-overexpressing fibroblasts and CRC cells led to increased liver metastases compared to those established with control fibroblasts. Our data provide a novel stromal exosome signature in colorectal cancer, which has potential for biomarker validation. Furthermore, we confirmed the importance of stromal miR-21 in colorectal cancer progression using an orthotopic model, and propose that exosomes are a vehicle for miR-21 transfer between stromal fibroblasts and cancer cells.