Toronto General Research Institute

Toronto, Canada

Toronto General Research Institute

Toronto, Canada
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Hui R.,University of Toronto | Hui R.,Toronto General Research Institute | El Bakkouri M.,University of Toronto | Sibley L.D.,University of Washington
Trends in Pharmacological Sciences | Year: 2015

Apicomplexan parasites cause some of the most severe human diseases, including malaria (caused by Plasmodium), toxoplasmosis, and cryptosporidiosis. Treatments are limited by the lack of effective drugs and development of resistance to available agents. By exploiting novel features of protein kinases in these parasites, it may be possible to develop new treatments. We summarize here recent advances in identifying small molecule inhibitors against a novel family of plant-like, calcium-dependent kinases that are uniquely expanded in apicomplexan parasites. Analysis of the 3D structure, activation mechanism, and sensitivity to small molecules had identified several attractive chemical scaffolds that are potent and selective inhibitors of these parasite kinases. Further optimization of these leads may yield promising new drugs for treatment of these parasitic infections. © 2015 Elsevier Ltd. All rights reserved.

Sun X.,Toronto General Research Institute | Altalhi W.,Toronto General Research Institute | Altalhi W.,University of Toronto | Nunes S.S.,Toronto General Research Institute | Nunes S.S.,University of Toronto
Advanced Drug Delivery Reviews | Year: 2016

The primary function of vascular networks is to transport blood and deliver oxygen and nutrients to tissues, which occurs at the interface of the microvasculature. Therefore, the formation of the vessels at the microcirculatory level, or angiogenesis, is critical for tissue regeneration and repair. Current strategies for vascularization of engineered tissues have incorporated multi-disciplinary approaches including engineered biomaterials, cells and angiogenic factors. Pre-vascularization of scaffolds composed of native matrix, synthetic polymers, or other biological materials can be achieved through the use of single cells in mono or co-culture, in combination or not with angiogenic factors or by the use of isolated vessels. The advance of these methods, together with a growing understanding of the biology behind vascularization, has facilitated the development of vascularization strategies for engineered tissues with therapeutic potential for tissue regeneration and repair. Here, we review the different cell-based strategies utilized to pre-vascularize engineered tissues and in making more complex vascularized cardiac tissues for regenerative medicine applications. © 2015 Elsevier B.V.

Feric N.T.,University of Toronto | Radisic M.,University of Toronto | Radisic M.,Toronto General Research Institute
Advanced Drug Delivery Reviews | Year: 2016

Engineering functional human cardiac tissue that mimics the native adult morphological and functional phenotype has been a long held objective. In the last 5. years, the field of cardiac tissue engineering has transitioned from cardiac tissues derived from various animal species to the production of the first generation of human engineered cardiac tissues (hECTs), due to recent advances in human stem cell biology. Despite this progress, the hECTs generated to date remain immature relative to the native adult myocardium. In this review, we focus on the maturation challenge in the context of hECTs, the present state of the art, and future perspectives in terms of regenerative medicine, drug discovery, preclinical safety testing and pathophysiological studies. © 2015 Elsevier B.V.

O'neill T.J.,Toronto General Research Institute
Journal of Acquired Immune Deficiency Syndromes | Year: 2017

BACKGROUND:: The prevalence of self-reported GI symptoms and distress is high, but few studies have quantified their impact on HRQOL. METHODS:: We conducted a prospective cohort study of HIV patients in care in Ontario, Canada (2007-2014). General linear mixed models were used to assess the impact of GI symptoms (diarrhea/soft stool, nausea/vomiting, bloating/painful abdomen, loss of appetite, weight loss/wasting) and distress (range: 0 to 4) on physical and mental HRQOL summary scores (range: 0 to 100) measured by the Medical Outcomes Survey SF-36. RESULTS:: A total of 1787 participants completed one or more questionnaires (median 3 (IQR 1,4)). At baseline, 59.0% were men who had sex with men, 53.7% Caucasian, median age 45 (IQR: 38, 52), median CD4+ count 457 (IQR: 315, 622), and 71.0% had undetectable HIV viremia. The median mental and physical HRQOL scores were 48.5 (IQR: 36.4, 55.7) and 51.2 (IQR: 44.4, 55.1), respectively. In adjusted models, compared to those reporting no symptoms, all GI symptom distress scores from 2 (‘have symptom, bothers me a little’) to 4 (‘have symptom, bothers a lot’) were associated with lower mental HRQOL. Loss of appetite distress scores ≥1;scores ≥2 for diarrhea, nausea/vomiting, and bloating; and a score ≥3 for weight loss were independently associated with lower physical HRQOL scores (p <0.0001). Increasing GI symptom distress is associated with impaired mental and physical HRQOL (p <0.0001). CONCLUSIONS:: Increasing GI symptom distress is associated with impaired mental and physical HRQOL. Identifying, treating, and preventing GI symptoms may reduce overall symptom burden and improve HRQOL for HIV patients. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Markle J.G.,Rockefeller University | Fish E.N.,Toronto General Research Institute | Fish E.N.,University of Toronto
Trends in Immunology | Year: 2014

The significant contributions of sex to an immune response, specifically in the context of the sex bias observed in susceptibility to infectious and autoimmune diseases and their pathogenesis, have until recently, largely been ignored and understudied. This review highlights recent findings related to sex-specific factors that provide new insights into how sex determines the transcriptome, the microbiome, and the consequent immune cell functional profile to define an immune response. Unquestionably, accumulating data confirm that sex matters and must be a consideration when decisions around therapeutic intervention strategies are developed. © 2013 Elsevier Ltd.

Branch D.R.,Toronto General Research Institute
Current Opinion in Hematology | Year: 2010

Purpose of Review: Histo-blood group antigens belonging to the P1PK and GLOB blood group systems are involved in bacterial infections, but a substantial body of evidence is emerging that some of these glycosphingolipids play a role in HIV infection. These recent findings have raised additional questions regarding the possible role of the Pk/Gb3 histo-blood group antigen in HIV-1 infection. Recent Findings: Early studies implicated a number of glycosphingolipids able to interact with HIV envelope glycoprotein 120. It has been recently reported that cellular or soluble P k/Gb3 histo-blood group antigen provides protection from HIV-1 infection. This resistance mechanism appears to be mediated through inhibition of fusion of the HIV-1 envelope to the cell target membrane. Protection has been shown to be provided to both HIV-1 X4 and R5 tropic strains. Indeed, an inverse correlation has been documented between the expression of Pk/Gb3 on the cellular membrane and susceptibility to HIV infection. Moreover, soluble Pk/Gb3 analogues have been shown to inhibit HIV infection. Summary: The Pk/Gb3 histo-blood group antigen is the first described cell surface expressed natural resistance factor for prevention of HIV infection. Increased expression of Pk/Gb3 correlates to decreased HIV infection, whereas decreased or absent Pk/Gb3 increases HIV susceptibility. Soluble Pk/Gb3 analogues can inhibit HIV by two mechanisms: direct inhibition of the free virus and inhibition of viral entry. Future development of soluble Pk/Gb3 analogues, pharmacologic means of increasing cell surface expression of P k/Gb3 on HIV susceptible target cells or both may result in novel therapeutic modalities for the prevention and eradication of HIV/AIDS. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Galligan C.L.,Toronto General Research Institute | Fish E.N.,Toronto General Research Institute
Arthritis and Rheumatism | Year: 2012

Objective Rheumatoid arthritis (RA) is a systemic autoimmune disease resulting in joint inflammation. Fibroblast-like synoviocytes in affected joints are responsible for pannus formation and cytokine/chemokine production, resulting in leukocyte recruitment and bone/cartilage destruction. Previously, we identified a multipotent stem cell population of activated fibrocytes in the blood of patients with RA that may have a role in disease pathogenesis, perhaps as fibroblast-like synoviocyte precursors. The aim of this study was to further characterize the contribution of circulating fibrocytes to the pathogenesis of RA. Methods Circulating fibrocytes were isolated from mice with collagen-induced arthritis and transferred intravenously into recipient mice with collagen antibody-induced arthritis (CAIA). The activation status of circulating fibrocytes was determined using multidimensional phosphoflow cytometric analysis of the signaling effectors STAT-5, STAT-1, AKT, and JNK. Circulating fibrocyte trafficking and matrix metalloproteinase (MMP) activity were assessed in real time using fluorescence molecular tomography, specifically labeling circulating fibrocytes with CellVue Maroon and measuring MMP activity using MMPSense 680. Results The numbers of circulating fibrocytes were increased early during the onset of CAIA, concomitant with their activation, as measured by phosphorylation of STAT-5. Adoptive transfer of circulating fibrocytes augmented disease scores and increased class II major histocompatibility complex expression and peripheral blood phosphoactivation profiles in recipient mice with CAIA. Notably, adoptively transferred fluorescence-labeled circulating fibrocytes rapidly migrated into the affected joints of recipient mice with CAIA, and this was associated with augmented neutrophil recruitment into affected joints and MMP activation. Conclusion Circulating fibrocytes migrate to joints and influence the onset of disease processes in arthritis. Copyright © 2012 by the American College of Rheumatology.

Galligan C.L.,Toronto General Research Institute
Rheumatology (Oxford, England) | Year: 2010

RA is a common, relapsing autoimmune disease primarily affecting the joints. Fibroblast-like synovial (FLS) cells are thought to be responsible for pannus formation and secretion of factors that recruit leucocytes to affected joints, thereby promoting bone and cartilage destruction. Fibrocytes are multipotent circulating stem cells that may have a role in RA pathogenesis, perhaps as the precursors of the FLS cells, or by regulating FLS cell function. We utilized multidimensional phospho-specific flow cytometry to characterize the activation status of peripheral blood (PB) fibrocytes derived from human RA patients at different stages of disease and from mice with CIA. Human PB fibrocytes from RA patients exhibited phosporylation activation of the p44/42 and p38 MAP kinases (MAPKs), and STAT3 (signal transducer and activator of transcription) and STAT-5 early in disease, within the first year of diagnosis. Similarly, in murine CIA, an increase in the total number of PB phosphoSTAT5-positive fibrocytes was observed at early time points in disease. Notably, in the affected paws of mice with CIA, we identified an increased number of fibrocytes, in contrast to the paws of control mice. These data suggest that activated fibrocytes may influence the disease process in RA and may serve as surrogate markers for disease in the PB of affected patients.

Radhakrishnan J.,Columbia University | Cattran D.C.,Toronto General Research Institute
Kidney International | Year: 2012

The KDIGO guideline for glomerulonephritis is designed to assist health-care providers in treating patients with glomerular diseases. A guideline is not a set of rules but is intended to allow the practitioner to make an informed decision based on the available evidence. Due to its general nature and the variability of strength of the available studies, it is often difficult to directly apply a guideline to the care of an individual patient. This commonly relates to the limited generalizability of the evidence, i.e., does not cover every clinical scenario. To underscore this point, we have introduced within the context of the glomerulonephritis guideline cases with specific features to illustrate the constant need for clinical judgment. These vignettes are intended to demonstrate how the best treatment plans should be individualized and take into account patient preference and clinical acumen, as well as the best available evidence. © 2012 International Society of Nephrology.

Stewart D.E.,Toronto General Research Institute
New England Journal of Medicine | Year: 2011

A 24-year-old married woman presents with a 1-month history of diminished concentration and interest, insomnia, fatigue, tearfulness, and depressed mood. She is 10 weeks pregnant, stopped working 3 weeks ago, and mostly stays in bed. Two years ago, she was successfully treated briefly with sertraline at a daily dose of 50 mg for depression after a suicide attempt. She reports that she wants to continue the pregnancy and says that she does not feel suicidal. What would you advise? Copyright © 2011 Massachusetts Medical Society.

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