23 research outputs found
The roles of secreted protein acidic and rich in cystiene (Sparc) in intestinal inflammation, healing and fibrosis
No full textSecreted Protein Acidic and Rich in Cysteine (SPARC) is a matricellular protein expressed during tissue repair and regulates cell proliferation and migration. It binds to, and interacts with collagen and regulates matrix metalloproteinase (MMP) expression. The aim was to determine if SPARC modifies intestinal inflammation, healing and fibrogenesis.
Intestinal disease was investigated using SPARC null (KO) and wild-type (WT) mice in which inflammation was induced by 3% dextran sodium sulphate (DSS) in the drinking water for 7 days. Inflammation was assessed endoscopically, clinically and histologically on days 7, 14, 21 and 35 after initiation of DSS treatment. Systemic and colonic cytokines and chemokines were quantitated by ELISA and CBA. Colon, mesenteric lymph node and spleen were analysed by flow cytometry and immunofluorescence for inflammatory cell infiltrates. To determine the effect of SPARC on the extracellular matrix (ECM) genes regulation, RNA from colonic tissue, and colonic myofibroblasts from WT and KO mice, were analysed by real time PCR for expression of ECM related genes.
KO animals had significantly lower endoscopic scores of inflammation, suffered less weight loss, diarrhoea, faecal blood and had lower spleen/body weight ratios compared to WT animals consistent with less colonic and systemic inflammation. WT mice had higher levels of histological inflammation and damage when compared to KO animals and in the majority of KO animals the colonic mucosa had completely regenerated by day 35 in contrast to the WT mice. Compared to WT mice, in KO animal colons at day 7 there was significantly less IL1β and MIG expression while TGFβ1 levels were higher. Flow cytometric analysis identified a significantly greater percentage of FoxP3+ regulatory T cells in the spleen and draining lymph nodes of KO animals. KO mice also had fewer of cells, such as CD68+ macrophages and Ly6G+ neutrophils, of the innate immune e system infiltrating the inflamed colon.
Collagen (Col) 1α1, Col3α1 MMP13 and MMP3 expression levels were reduced in DSS-treated WT colons at day 7 and these were significantly lower than those observed in the KO colons. TIMP1 expression was significantly lower in KO mice at day 35 when healing was complete in this group. TIMP2 and TGFβ1, TGFβ3 were not different between the groups at any time point. The observation by others that collagen fiber diameters in KO colons were noted to be significant smaller than in WT animals suggesting that SPARC modifies the collagen bundling. Compared to unstimulated WT fibroblasts, KO cells had lower Col1α1 and Col3α1 expression. Stimulation with PMA reduced Col1α1 and Col3α1 and increased MMP13 and TIMP1 expression in all the isolated cells, but PMA had no effect on MMP3, TIMP2, TGFβ1 and TGFβ3 expression.
DSS induced less colonic and systemic inflammation in KO compared to WT mice and the inflammation appeared to resolve faster. This may be secondary to increased numbers of regulatory T cells and increased colonic TGF-β levels which may inhibit effector cell activity, including cytokine and chemokine expression and aid in the more rapid resolution of inflammation and restoration of the intestinal mucosa. SPARC is able to modify tissue healing potentially through the regulation of collagen expression, bundling and its degradation by MMPs, which impacts on tissue turnover rate and thus delays healing. Hence, SPARC might represent a promising therapeutic target in clinical management of inflammatory bowel diseases (IBD)
Identification of a Disease-Associated Network of Intestinal Immune Cells in Treatment-Naive Inflammatory Bowel Disease
No full textChronic intestinal inflammation underlies inflammatory bowel disease (IBD). Previous studies indicated alterations in the cellular immune system; however, it has been challenging to interrogate the role of all immune cell subsets simultaneously. Therefore, we aimed to identify immune cell types associated with inflammation in IBD using high-dimensional mass cytometry. We analyzed 188 intestinal biopsies and paired blood samples of newly-diagnosed, treatment-naive patients (n=42) and controls (n=26) in two independent cohorts. We applied mass cytometry (36-antibody panel) to resolve single cells and analyzed the data with unbiased Hierarchical-SNE. In addition, imaging-mass cytometry (IMC) was performed to reveal the spatial distribution of the immune subsets in the tissue. We identified 44 distinct immune subsets. Correlation network analysis identified a network of inflammation-associated subsets, including HLA-DR+CD38+ EM CD4+ T cells, T regulatory-like cells, PD1+ EM CD8+ T cells, neutrophils, CD27+ TCRγδ cells and NK cells. All disease-associated subsets were validated in a second cohort. This network was abundant in a subset of patients, independent of IBD subtype, severity or intestinal location. Putative disease-associated CD4+ T cells were detectable in blood. Finally, imaging-mass cytometry revealed the spatial colocalization of neutrophils, memory CD4+ T cells and myeloid cells in the inflamed intestine. Our study indicates that a cellular network of both innate and adaptive immune cells colocalizes in inflamed biopsies from a subset of patients. These results contribute to dissecting disease heterogeneity and may guide the development of targeted therapeutics in IBD.Pattern Recognition and BioinformaticsComputer Graphics and Visualisatio
Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility
No full textGenome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn’s disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation
The role of family nurse practitioners : promoting oral medication adherence to maintenance treatment among adolescents with inflammatory bowel disease
No full textThe role of family nurse practitioners (FNPs) in promoting medication adherence in adolescents with inflammatory bowel disease (IBD) has not been established. This project provides intervention strategies that FNPs can use to promote oral medication adherence to maintenance treatment in adolescents with IBD. This is a critical need because non-adherence to maintenance therapy is the most significant factor associated with relapses of IBD and a serious health issue in adolescents with IBD. There are no current best practice guidelines in promoting adherence to maintenance medications in IBD patients. Findings from the literature review suggest that non-adherence to maintenance therapy is complex and multi-factorial. No single intervention strategy has been shown to be effective for all patients and conditions. However, individually tailored interventions that attend to behavioural, education and psychosocial factors appear promising. The bio-psychosocial model is used as a conceptual framework to examine the factors affecting medication adherence and to explore the intervention strategies for improving medication adherence. Findings of this project are limited by the paucity of research on medication adherence in adolescents with IBD. Implications and recommendations for family nurse practitioner practice, education and research are discussed.The original print copy of this thesis may be available here: http://wizard.unbc.ca/record=b200684
Differential genetic and functional background in inflammatory bowel disease phenotypes of a Greek population: A systems bioinformatics approach
No full textBackground: Crohn's disease (CD) and Ulcerative colitis (UC) are the two main entities of inflammatory bowel disease (IBD). Previous works have identified more than 200 risk factors (including loci and signaling pathways) in populations of predominantly European ancestry. Our study was conducted on an extended population-specific cohort of 573 Greek IBD patients (364 CD and 209 UC) and 445 controls. Aims: To highlight the different genetic and functional background of IBD and its phenotypes, utilizing contemporary systems bioinformatics methodologies. Methods: Disease-associated SNPs, obtained via our own 89 loci IBD risk GWAS panel, were detected with the whole genome association analysis toolset PLINK. These SNPs were used as input for 2 novel and different pathway analysis methods to detect functional interactions. Specifically, PathwayConnector was used to create complementary networks of interacting pathways whereas; the online database of protein interactions STRING provided protein-protein association networks and their derived pathways. Network analyses metrics were employed to identify proteins with high significance and subsequently to rank the signaling pathways those participate in. Results: The reported complementary pathway and enriched protein-protein association networks reveal several novel and well-known key players, in the functional background of IBD like Toll-like receptor, TNF, Jak-STAT, PI3K-Akt, T cell receptor, Apoptosis, MAPK and B cell receptor signaling pathways. IBD subphenotypes are found to have distinct genetic and functional profiles which can contribute to their accurate identification and classification. As a secondary result we identify an extended network of diseases with common molecular background to IBD. Conclusions: IBD's burden on the quality of life of patients and intricate functional background presents us constantly with new challenges. Our data and methodology provide researchers with new insights to a specific population, but also, to possible differentiation markers of disease classification and progression. This work, not only provides new insights into the interplay among IBD risk variants and their related signaling pathways, elucidates the mechanisms underlying IBD and its clinical sequelae, but also, introduces a generalized bioinformatics-based methodology which can be applied to studies of different disorders. © 2019 The Author(s)
NETWORK FORM OF EDUCATIONAL PROGRAMS IN THE PREPARATION OF BACHELORS VOCATIONAL TRAINING: PROBLEMS AND PROSPECTS
No full text<p>The article provides an overview of research relating to various aspects of networking, especially network interaction models, used in educational practice institutions. Here are considered some of the existing concept of networking. The article offers a detailed considering of networking in higher education, which is characterized by several basic processes, namely the development of distance education, academic mobility of teachers, distribution of student exchange programs, the development of research activities, including the international level. As an example, we consider the networking of vocational training in the preparation of bachelors in the branch FSAEI HE (Federal State Autonomous Educational Institution of Higher Education) "Russian State Vocational Pedagogical University" in Kemerovo. The purpose of training teachers of SVE (secondary vocational education) in accordance with the professional standards of the teacher and the federal state educational standards is to design the network of educational programs and the participation of educational institutions in networking. The author offers criteria of efficiency networking IBD (Integrated base department) (VTE) (vocational teacher education) and base organizations.</p></jats:p
Using network inference to discover molecular pathways underlying cytokine synergism and age-related neurodegeneration
No full textThesis: M. Eng. in Computer Science and Molecular Biology, Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2018.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (pages 83-90).New high-throughput "omic" methods can help shed light on molecular pathways underpinning diseases ranging from cancers to neurodegenerative disorders. However, effectively integrating information across these diverse data types is challenging. Network modeling approaches can help bridge this gap. In particular, the Prize- Collecting Steiner Forest approach (PCSF) is a network modeling method that provides high-confidence subnetworks of physically interacting molecules by integrating diverse "omics" data with prior knowledge from protein-protein interaction networks (PPIs). However, PCSF is sensitive to initial parameterization and generating biological hypotheses from the resulting subnetworks can often be difficult. This study increases the interpretability of subnetwork solutions generated PCSF by studying the effect of varying PCSF free parameters and adding annotations for subcellular localization. The PCSF approach is then used to elucidate pathways underlying synergy between cytokines, pro-inflammatory molecules that mediate diverse biological phenomena ranging from anti-viral immunity to autoimmune disorders like inflammatory bowel disease (IBD). In addition, PCSF approach is applied in a cross-species context to integrate information from Drosophila models for neurodegeneration and human Alzheimer's Disease (AD) patients to investigate proximal conserved mechanisms of age-related neurodegeneration.by Bryce Hwang.M. Eng. in Computer Science and Molecular Biolog
Alternatively activated macrophages protect mice during induced intestinal inflammation
No full textInflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic intestinal
inflammation and ulceration. Canada has the highest incidence of IBD in the world with 1 in
150 people affected. While treatment options target symptoms and attempt to dampen down
inflammation, an increasing population of patients is refractory to current therapeutic
options. Macrophages are heterogeneous in their functions and while it is clear that
inflammatory macrophages contribute to inflammation in IBD, multiple lines of evidence
suggest that alternatively activated macrophages may offer protection during intestinal
inflammation. In vivo SHIP deficient mouse macrophages are alternatively activated so
SHIP deficient mice provide a unique genetic model of alternative macrophage activation.
Using the dextran sodium sulfate (DSS)-induced model of colitis, I found that SHIP-/- mice
are protected during induced intestinal inflammation, the protection is macrophage mediated,
and can be conferred to a susceptible host. To determine how SHIP contributes to alternative
activation of macrophages, I demonstrate that SHIP-deficient murine macrophages are more
sensitive to IL-4-mediated skewing to an alternatively activated phenotype. Moreover, SHIP
levels are reduced in alternatively activated macrophages and this is required for alternative
activation because it is dependent on PI3K activity. Arginase (ArgI) induction is specifically
dependent on the PI3Kp110δ isoform of class IA PI3K. As such, mice deficient in
PI3Kp110δ catalytic subunit activity have increased clinical disease activity and histological
damage during DSS-induced colitis. Colitis severity correlates with reduced numbers of
ArgI+ M2 macrophages in the colon, increased nitric oxide production, and is macrophagedependent. Importantly, adoptive transfer of IL-4-treated macrophages from wild type mice,
but not from PI3Kp110δ deficient mice, protects mice during DSS-induced colitis. Protection is lost when mice are treated with inhibitors that block arginase activity showing that ArgI
activity is required for M2 macrophage-mediated protection from intestinal inflammation.
These findings identify SHIP and the PI3K pathway as critical regulators of alternative
macrophage activation and as potential targets for manipulation in IBD. In addition,
adoptive transfer of alternatively activated macrophages to patients with IBD also offers a
promising, new strategy for treatment that may be particularly useful in patients who are
refractory to conventional therapies
British Society of Gastroenterology guidelines on colorectal surveillance in inflammatory bowel disease
No full text\ua9 Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.Patients with inflammatory bowel disease (IBD) remain at increased risk for colorectal cancer and death from colorectal cancer compared with the general population despite improvements in inflammation control with advanced therapies, colonoscopic surveillance and reductions in environmental risk factors. This guideline update from 2010 for colorectal surveillance of patients over 16 years with colonic inflammatory bowel disease was developed by stakeholders representing UK physicians, endoscopists, surgeons, specialist nurses and patients with GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodological support. An a priori protocol was published describing the approach to three levels of statement: GRADE recommendations, good practice statements or expert opinion statements. A systematic review of 7599 publications, with appraisal and GRADE analysis of trials and network meta-analysis, where appropriate, was performed. Risk thresholding guided GRADE judgements. We made 73 statements for the delivery of an IBD colorectal surveillance service, including outcome standards for service and endoscopist audit, and the importance of shared decision-making with patients. Core areas include: risk of colorectal cancer, IBD-related post-colonoscopy colorectal cancer; service organisation and supporting patient concordance; starting and stopping surveillance, who should or should not receive surveillance; risk stratification, including web-based multivariate risk calculation of surveillance intervals; colonoscopic modalities, bowel preparation, biomarkers and artificial intelligence aided detection; chemoprevention; the role of non-conventional dysplasia, serrated lesions and non-targeted biopsies; management of dysplasia, both endoscopic and surgical, and the structure and role of the multidisciplinary team in IBD dysplasia management; training in IBD colonoscopic surveillance, sustainability (green endoscopy), cost-effectiveness and patient experience. Sixteen research priorities are suggested
The strategic response of full service airlines to the low cost carrier threat and the perception of passengers to each type of carrier
No full textLow cost carriers have changed the competitive dynamics of the short-haul market
forever. They have revolutionised the way of doing business in aviation by adopting a
fresh approach on both strategic and operational issues. Simplicity has become their
universal principle over network airlines and subsequently they have achieved
substantial cost advantages which are passed onto the consumer as lower fares.
Network airlines have found it difficult to reshape their structural barriers and have
been slow to incorporate the components that low cost carriers deemed very
significant in impacting their operating margins. However, a restructuring of their
internal weaknesses should spur initiatives to design long-term strategies to address
those shortcomings. Network airlines rely on producing value-adding and consumerdriven
product differentiation beyond the basics of the low cost carrier product. To
further differentiate themselves network airlines need to focus on: customer
satisfaction; develop long term mutually beneficial relationships with both passengers
and corporations; collaborate with a wide range of bipartisan partners; retain
differentiated flight products that add value; and to incorporate strategies that other
network carriers deemed paradigmatic. Network carriers should resist reducing costs
associated with value-added services and need to become innovative in generating
alternative revenue streams
