Corpus annotation for mining biomedical events from literature

<p>Abstract</p> <p>Background</p> <p>Advanced Text Mining (TM) such as semantic enrichment of papers, event or relation extraction, and intelligent Question Answering have increasingly attracted attention in the bio-medical domain. For such attempts to succeed, text annotation from the biological point of view is indispensable. However, due to the complexity of the task, semantic annotation has never been tried on a large scale, apart from relatively simple term annotation.</p> <p>Results</p> <p>We have completed a new type of semantic annotation, event annotation, which is an addition to the existing annotations in the GENIA corpus. The corpus has already been annotated with POS (Parts of Speech), syntactic trees, terms, etc. The new annotation was made on half of the GENIA corpus, consisting of 1,000 Medline abstracts. It contains 9,372 sentences in which 36,114 events are identified. The major challenges during event annotation were (1) to design a scheme of annotation which meets specific requirements of text annotation, (2) to achieve biology-oriented annotation which reflect biologists' interpretation of text, and (3) to ensure the homogeneity of annotation quality across annotators. To meet these challenges, we introduced new concepts such as Single-facet Annotation and Semantic Typing, which have collectively contributed to successful completion of a large scale annotation.</p> <p>Conclusion</p> <p>The resulting event-annotated corpus is the largest and one of the best in quality among similar annotation efforts. We expect it to become a valuable resource for NLP (Natural Language Processing)-based TM in the bio-medical domain.</p

Modulation of Human Mesenchymal Stem Cell Immunogenicity through Forced Expression of Human Cytomegalovirus US Proteins

BACKGROUND: Mesenchymal stem cells (MSC) are promising candidates for cell therapy, as they migrate to areas of injury, differentiate into a broad range of specialized cells, and have immunomodulatory properties. However, MSC are not invisible to the recipient's immune system, and upon in vivo administration, allogeneic MSC are able to trigger immune responses, resulting in rejection of the transplanted cells, precluding their full therapeutic potential. Human cytomegalovirus (HCMV) has developed several strategies to evade cytotoxic T lymphocyte (CTL) and Natural Killer (NK) cell recognition. Our goal is to exploit HCMV immunological evasion strategies to reduce MSC immunogenicity. METHODOLOGY/PRINCIPAL FINDINGS: We genetically engineered human MSC to express HCMV proteins known to downregulate HLA-I expression, and investigated whether modified MSC were protected from CTL and NK attack. Flow cytometric analysis showed that amongst the US proteins tested, US6 and US11 efficiently reduced MSC HLA-I expression, and mixed lymphocyte reaction demonstrated a corresponding decrease in human and sheep mononuclear cell proliferation. NK killing assays showed that the decrease in HLA-I expression did not result in increased NK cytotoxicity, and that at certain NK∶MSC ratios, US11 conferred protection from NK cytotoxic effects. Transplantation of MSC-US6 or MSC-US11 into pre-immune fetal sheep resulted in increased liver engraftment when compared to control MSC, as demonstrated by qPCR and immunofluorescence analyses. CONCLUSIONS AND SIGNIFICANCE: These data demonstrate that engineering MSC to express US6 and US11 can be used as a means of decreasing recognition of MSC by the immune system, allowing higher levels of engraftment in an allogeneic transplantation setting. Since one of the major factors responsible for the failure of allogeneic-donor MSC to engraft is the mismatch of HLA-I molecules between the donor and the recipient, MSC-US6 and MSC-US11 could constitute an off-the-shelf product to overcome donor-recipient HLA-I mismatch

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Patients with chronic idiopathic neutropenia of adults have increased serum concentrations of inflammatory cytokines and chemokines

Serum levels of inflammatory cytokines and chemokines were measured in 132 patients with chronic idiopathic neutropenia of adults (CINA) and 34 healthy Volunteers (controls) using commercially available micro-ELISA determination kits, We found that serum interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), transforming growth factor-beta (1) (TGF-beta (1)), and soluble tumor necrosis factor receptor p55 (sTNF-RI) were all significantly increased in CINA patients compared to controls. Individual cytokine values inversely correlated with the number of circulating neutrophils. Serum levels of interleukin-8 (IL-8) and RANTES, two potent chemokines for neutrophils and lymphocytes, respectively, were also significantly increased in the group of patients and they inversely correlated with the number of circulating neutrophils, Contrarily, serum levels of interleukin-l (IL-4), interferon-gamma (IFN gamma), soluble CD23 (sCD23), and soluble interleukin-a receptor (sIL-2R) did not show any significant change in the patients studied, We assume that CINA patients have increased serum concentrations of inflammatory cytokines and chemokines mainly produced by activated macrophages, while they disclose normal levels of inflammatory molecules mainly released from activated lymphocytes. These findings provide further evidence for an underlying low-grade chronic inflammatory process in CINA patients, as we previously have suggested, If this chronic inflammation is really the cause of the disorder or it simply represents the result of neutropenia remains to be elucidated. (C) 2000 Wiley-Liss, Inc

Discrimination between malignant and nonmalignant ascites using serum and ascitic fluid proteins in a multivariate analysis model

Our objectives were to study the value of different proteins in the serum and ascitic fluid and assess their potential in discriminating between malignant and nonmalignant ascites in a model that could be developed to aid clinical diagnosis. In all, 57 different measurements (30 in serum and 27 in ascitic fluid) including erythrocyte sedimentation rate, number of white blood cells, cytokines, interleukin-la (IL-1a), IL-lb, IL-2, IL-G! IL-8, tumor necrosis factor-alpha, immunoglobulins (IgG, IgA, IgM), complement factors C3 and C4, acute-phase proteins such as alpha(1)-acid glycoprotein, alpha(2)-macroglobulin, alpha(1)-antitrypsin, haptoglobin, C-reactive protein, ferritin, cerulo-plasmin and transferin, were performed in 61 patients with ascites (25 with malignant exudates, 13 with nonmalignant exudates, and 23 with transudates). Patients with sepsis were excluded. Correlation tests and one-way ANOVAs were used for comparisons between different groups. Discriminant analyses were used to assess the significance of each parameter in the differentiation process. Correct classification of 100% of cases required the use of all 57 ascitic fluid measurements in the model, which was not considered practical in clinical diagnosis. Discriminant analysis showed that five ascitic fluid measurements-total protein, LDH, TNF-alpha, C4, and haptoglobin-were sufficient for a model to correctly classify 89% of cases. Cross-validation showed that 70% of unknown cases were correctly classified using this model. In conclusion, we have shown that five easily taken protein measurements in the ascitic fluid can differentiate to a large extent between eases with ascites and have proposed a relatively simple statistical model with these parameters that could be developed to be extremely useful in the clinical setting

DEFECTIVE MITOGEN-INDUCED CELLULAR CYTOTOXICITY IN UNTREATED PATIENTS WITH ACTIVE RHEUMATOID-ARTHRITIS

Peripheral blood mitogen-induced cellular cytotoxicity (MICC) was studied in 13 untreated patients with active rheumatoid arthritis (RA; group A) and in 5 RA patients with inactive disease (group B), using phytohemagglutinin (PHA) as stimulating agent and K562 cells as target cells in the chromium-51 release assay. MICC was found to be significantly reduced in the patients of group A compared with normal subjects (P&lt;0.01) and the patients of group B (P&lt;0.05). No differences were noted in MICC between group B patients and normal subjects. A statistically significant negative correlation was found between values of patients’ MICC and serum C-reactive protein levels (r = -0.685, P&lt;0.01). Furthermore, patients’ MICC correlated well with patients’ peripheral blood natural killer cell activity (P&lt;0.02), as well as with the absolute number of circulating CD8(+) cells. No correlation was found between MICC and duration of disease, erythrocyte sedimentation rate, serum alpha(2)-globulins, or the titre of serum rheumatoid factor in the patients studied. We concluded that defective MICC in untreated patients with active RA is probably due to the diminution of the number of CD8(+) cells, although a qualitative defect of these cells cannot be excluded

Significance of alpha-2-macroglobulin, alpha-1-acid glycoprotein, and C-reactive protein in pleural effusion differentiation

Background: The differentiation between exudates and transudates is fundamental when investigating the cause of pleural effusions. Acute-phase proteins could be potentially useful markers in this discrimination. Objective: The present study was designed to evaluate whether the acute-phase proteins: alpha(2)-macroglobulin (AMG), alpha(1)-acid glycoprotein (AAG) and C-reactive protein (CRP) are useful in investigating the pleural effusions. Methods:We prospectively measured the concentrations of the above proteins in the serum and pleural fluid of 84 consecutive patients with various diseases using a nephelometric assay. Results: Pleural effusion AMG, AAG and CRP were all significantly elevated in the group of patients with exudates compared to patients with transudates (p &lt; 0.001, p &lt; 0.001 and p &lt; 0.01, respectively). An AAG value &gt;63 mg/dl in a pleural effusion is predictive of an exudate with a sensitivity of 90% and a specificity 85%. Similarly, an AMG value &gt;44 mg/dl in a pleural effusion is predictive of an exudate with a sensitivity and a specificity of 90% and 60%, respectively. Moreover, pleural AAG was significantly higher in cancerous exudates than in exudates and transudates of all other cause taken together (p &lt; 0.001). Finally, to differentiate the same pleural effusion, the cut-off value of 1.0 mg/dl of pleural CRP has a sensitivity and a specificity of 74% and 74%, respectively. Conclusions: We conclude that both AAG and AMG concentrations in pleural effusions have a high sensitivity and are therefore useful parameters in distinguishing exudates from transudates, but the latter is inferior due to its unacceptably low specificity. Copyright (C) 2000 S. Karger AG, Basel