Montreal Childrens Hospital Research Institute

Montréal, Canada

Montreal Childrens Hospital Research Institute

Montréal, Canada
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Zhang Z.,Montreal Childrens Hospital Research Institute | Hueber P.-A.,McGill University | Chu L.,Montreal Childrens Hospital Research Institute | Bichet D.G.,University Of Montre Al | And 4 more authors.
Journal of the American Society of Nephrology | Year: 2010

The ureteric bud (UB) expresses high levels of the EGF receptor (EGFR) during kidney development, but its function in this setting is unclear. Here, Egfr mRNA was abundant in medullary portions of the UB trunk but absent from the branching UB tips during embryogenesis. Homozygous Egfr knockout did not affect the pattern of UB arborization, but renal papillae were hypoplastic and exhibited widespread apoptosis of tubular cells. Because these EGFR-deficient mice die within 1 week of life, we targeted Egfr inactivation to the renal collecting ducts using Cre-lox technology with a Hoxb7-Cre transgene. This targeted inactivation of Egfr led to a thin renal medulla, and at 7 weeks of age, the mice had moderate polyuria and reduced urine-concentrating ability. At 30 to 33 weeks, water deprivation demonstrated a continued urine-concentrating defect despite similar levels of vasopressin between knockout mice and littermate controls. Taken together, these results suggest that unlike other tyrosine kinases expressed at the UB tip, EGFR functions primarily to drive elongation of the emerging collecting ducts and to optimize urine-concentrating ability. Copyright © 2010 by the American Society of Nephrology.

Platt R.W.,McGill University | Platt R.W.,Montreal Childrens Hospital Research Institute | Delaney J.A.C.,University of Florida | Suissa S.,McGill University | Suissa S.,Jewish General Hospital
European Journal of Epidemiology | Year: 2012

Estimates of the average causal effect (ACE) of warfarin on the risk of bleeding may be confounded by indication as patients at high risk of bleeding are unlikely to be prescribed warfarin. One approach to estimating the ACE is inverse probability of treatment weighting (IPTW). This study was designed to examine the use of IPTW in this setting, and to demonstrate problems with the violation of the positivity assumption. We analyzed a case-control study on 4,028 cases of gastro-intestinal bleeding and 79,239 controls set in the United Kingdom's General Practice Research Database. Warfarin exposure was defined as a prescription issued in the 90 days before the index date. Secondary analyses were conducted restricted to patients more likely to receive warfarin and with a truncated weight distribution, to exclude subjects highly unlikely to be treated. The estimated association between warfarin use and bleeding was stronger with IPTW [odds ratio (OR): 17.2; 95% confidence interval (CI): 6.5-37.7] than with a standard logistic regression model (OR: 2.1; 95% CI: 1.7-2.5). The presence of large weights (five subjects with stabilized weight >500) indicated a potential violation of the positivity assumption. In the restricted analysis, both IPTW (OR: 2.0; 95% CI: 0.4-9.6) and standard regression (OR: 1.6; 95% CI: 1.3-2.0) were compatible with a meta-analysis of randomized trials inverse probability of treatment weighting is sensitive to the positivity assumption; however, such sensitivity may assist in diagnosing off-support inference. © Springer Science+Business Media B.V. 2011.

Itzkovitz B.,Montreal Childrens Hospital Research Institute | Jiralerspong S.,Montreal Childrens Hospital Research Institute | Nimmo G.,Montreal Childrens Hospital Research Institute | Loscalzo M.,University of South Florida | And 7 more authors.
Human Mutation | Year: 2012

Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. It is commonly caused by defects in the peroxisome transporter, PEX7 (RCDP1), and less frequently due to defects in the peroxisomal enzymes required to initiate plasmalogen synthesis, GNPAT (RCDP2) and AGPS (RCDP3). PEX7 transports AGPS into the peroxisome, where AGPS and GNPAT partner on the luminal membrane surface. The presence of AGPS is thought to be required for GNPAT activity. We present six additional probands with RCDP2 and RCDP3, and the novel mutations identified in them. Using cell lines from these and previously reported patients, we compared the amounts of both AGPS and GNPAT proteins present for the first time. We used protein modeling to predict the structural consequences of AGPS mutations and transcript analysis to predict consequences of GNPAT mutations, and show that milder RCDP phenotypes are likely to be associated with residual protein function. In addition, we propose that full GNPAT activity depends not only on the presence of AGPS, but also on the integrity of substrate channeling from GNPAT to AGPS. © 2011 Wiley Periodicals, Inc.

Gaskins A.J.,National Health Research Institute | Wilchesky M.,Montreal Childrens Hospital Research Institute | Mumford S.L.,National Health Research Institute | Whitcomb B.W.,University of Massachusetts Amherst | And 4 more authors.
American Journal of Epidemiology | Year: 2012

C-reactive protein (CRP) is one of the most commonly used markers of acute phase reaction in clinical settings and predictors of cardiovascular risk in healthy women; however, data on its physiologic regulation in premenopausal women are sparse. The objective of this study was to evaluate the association between endogenous reproductive hormones and CRP in the BioCycle Study (2005-2007). Women aged 18-44 years from western New York were followed prospectively for up to 2 menstrual cycles (n = 259). Serum levels of CRP, estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured up to 8 times per cycle, timed by fertility monitors. CRP levels varied significantly across the cycle (P < 0.001). More women were classified as being at elevated risk of cardiovascular disease (CRP, >3 mg/L) during menses compared with other phases (12.3% vs. 7.4%; P < 0.001). A 10-fold increase in estradiol was associated with a 24.3% decrease in CRP (95% confidence interval: 19.3, 29.0). A 10-fold increase in luteal progesterone was associated with a 19.4% increase in CRP (95% confidence interval: 8.4, 31.5). These results support the hypothesis that endogenous estradiol might have antiinflammatory effects and highlight the need for standardization of CRP measurement to menstrual cycle phase in reproductive-aged women. © The Author 2012.

Foster B.J.,McGill University | Foster B.J.,Montreal Childrens Hospital Research Institute | Dahhou M.,Montreal Childrens Hospital Research Institute | Zhang X.,Montreal Childrens Hospital Research Institute | And 4 more authors.
American Journal of Transplantation | Year: 2014

As HLA matching has been progressively de-emphasized in the American deceased donor (DD) kidney allocation algorithm, concerns have been raised that poor matching at first transplant may lead to greater sensitization and more difficulty finding an acceptable donor for a second transplant should the first transplant fail. We compared proportion of total observed lifetime with graft function after first transplant, and waiting times for a second transplant between individuals with different levels of HLA mismatch (MM) at first transplant. We studied patients recorded in the United States Renal Data System (1988-2009) who received a first DD transplant at age ≤21 years (n=8433), and the subgroup who were listed for a second DD transplant following first graft failure (n=2498). Compared with recipients of 2-3 MM first grafts, 4-6 MM graft recipients spent 12% less of their time and 0-1 MM recipients 15% more time with a functioning graft after the first transplant (both p<0.0001); 4-6 MM recipients were significantly less likely (hazard ratio [HR] 0.87 [95% confidence interval 0.76, 0.98]; p=0.03), and 0-1 MM recipients more likely (HR 1.26 [0.99, 1.60]; p=0.06) to receive a second transplant after listing. The benefits of better HLA matching at first transplant on lifetime with graft function are significant, but relatively small. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

Cohen J.M.,Montreal Childrens Hospital Research Institute | Hutcheon J.A.,Biostatistics and Occupational Health | Kramer M.S.,Biostatistics and Occupational Health | Kramer M.S.,McGill University | And 4 more authors.
Ultrasound in Obstetrics and Gynecology | Year: 2010

Objectives To explore the effects of ultrasound-todelivery interval and maternal-fetal characteristics on the distribution of measurement error in estimated fetal weights (EFWs), and to determine the predictive ability of EFW for diagnosis of small-for-gestational age (SGA) and large-for-gestational age (LGA) among infants delivered within 1 day of an ultrasound examination. Methods Percentage differences between EFW and birth weights were calculated in 3697 pregnancies. Linear regression was used to compare the accuracy of EFW for births on each of the 6 days after an ultrasound scan with the accuracy observed among births on the same day. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value for diagnosis of SGA and LGA according to EFW was assessed. Results The mean ±} SD percentage difference among deliveries within 1 day of the last ultrasound scan was 0.2 ±} 9.0%. Mean percentage differences were not significantly different from day 0 on days 1, 2 and 3; however, combining the data from these 4 days obscured a slight bias towards an overestimation of weight evident on day 0 and day 1. Among deliveries within 1 day of an ultrasound scan, the PPV was 61% for SGA diagnosis and 54% for LGA diagnosis. Conclusion Combining data from births>1 day after the last ultrasound examinationmay lead to a false conclusion that there is systematic underestimation of weight. EFW tended to underestimate the weight of macrosomic fetuses and overestimate that of small fetuses which limitedsensitivity and PPV. Maternal-fetal characteristics are weak predictors of individual errors in EFW. Copyright ©2010 ISUOG. Published by John Wiley & Sons, Ltd.

Al-Halabi H.,McGill University | Nantel A.,NRC Biotechnology Research Institute | Klekner A.,Debrecen University | Guiot M.-C.,Montreal Neurological Institute | And 12 more authors.
Acta Neuropathologica | Year: 2011

Medulloblastoma (MB) represents approximately 4% of adult brain tumours, and as such is a poorly studied disease. Although many adult MB are treated using paediatric MB protocols, the reported outcomes are inferior to those observed in children. It remains unclear whether biologic differences underlie these clinical observations. We investigated the molecular characteristics of 31 adult MB. Twelve and 19 adult MB were respectively examined using Affymetrix-HG-U133-plus-2.0-genechips and immunohistochemical analyses. 26/31 (84%) of adult MB examined by gene expression and/or immunohistochemical analysis showed evidence of sonic hedgehog (SHH) pathway activation. A comparison of adult and paediatric MB showed that most adult tumours cluster within the SHH-active subgroup of paediatric MB. The preponderance of SHH activity in adult MB tumours was also shown by positive SFRP1 immunostaining in 16/19 adult paraffin-embedded adult MB tumour blocks. A smaller proportion of adult tumours exhibited evidence of WNT pathway activation, as confirmed by nuclear β-catenin staining (9.7%; 3/31). Notably, we found PTCH1 gene mutation in 4/8 samples tested. Similar to children, adult MB has abnormalities in developmental signalling pathways including SHH and WNT. Importantly, we found a preponderance of SHH pathway activation amongst MB tumours in adults. This SHH signature does not appear to correlate with a long-term favourable outcome. Differences in molecular profiles exist between adult and paediatric SHH-driven MB and further investigations are needed to better characterize age-related molecular profiles in this subgroup. © 2010 Springer-Verlag.

PubMed | McGill University and Montreal Childrens Hospital Research Institute
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2015

The mammalian kidney is derived from progenitor cells in intermediate mesoderm. During embryogenesis, progenitor cells expressing the Wilms tumor suppressor gene, WT1, are induced to differentiate in response to WNT signals from the ureteric bud. In hereditary Wilms tumors, clonal loss of WT1 precludes the -catenin pathway response and leads to precancerous nephrogenic rests. We hypothesized that WT1 normally primes progenitor cells for differentiation by suppressing the enhancer of zeste2 gene (EZH2), involved in epigenetic silencing of differentiation genes. In human amniotic fluid-derived mesenchymal stem cells, we show that exogenous WT1B represses EZH2 transcription. This leads to a dramatic decrease in the repressive lysine 27 trimethylation mark on histone H3 that silences -catenin gene expression. As a result, amniotic fluid mesenchymal stem cells acquire responsiveness to WNT9b and increase expression of genes that mark the onset of nephron differentiation. Our observations suggest that biallelic loss of WT1 sustains the inhibitory histone methylation state that characterizes Wilms tumors.

PubMed | McGill University and Montreal Childrens Hospital Research Institute
Type: | Journal: European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery | Year: 2016

Cisplatin is a commonly used chemotherapeutic agent and causes serious side effects, including progressive and irreversible hearing loss. No treatment is currently available for cisplatin-induced ototoxicity. We have previously demonstrated that erdosteine, a potent antioxidant, partially protected the cochlea against cisplatin toxicity in vivo. The aims of this study were to (1) evaluate the protein profiles of the cochlea following cisplatin administration and (2) evaluate the impact of erdosteine on the protein profile using a proteomics-based approach. Thirty Sprague-Dawley rats were injected intraperitoneally with saline (n=10), cisplatin (n=10) or with cisplatin and erdosteine (n=10). The cisplatin dosage was 14mg/kg and for erdosteine, 500mg/kg. Following euthanasia, protein lysates were obtained from fresh-frozen cochleae and were processed for mass spectrometry and western blotting. We detected 445 proteins that exhibited a twofold change or greater in the cisplatin group as compared to the control group. Of these, 18 proteins showed a fourfold or greater change in expression associated with cisplatin administration, including ras-related protein Rab-2A, Rab-6A, cd81, ribosomal protein S5, and myelin basic protein, which were downregulated, while Ba1-647 and fibrinogen (alpha chain), amongst others, were upregulated. Co-administration of erdosteine revealed a reversal of these changes in the expression of ras-related protein Rab-2A, ribosomal protein S5, myelin basic protein, and fibrinogen (alpha chain); erdosteine also upregulated glutathione reductase. In this study, we identified various proteins that may play a role in cisplatin-induced ototoxicity. We also observed the changes resulting from co-treatment with an antioxidant.

Gerges N.,Montreal Childrens Hospital Research Institute | Jabado N.,Montreal Childrens Hospital Research Institute
Bioanalysis | Year: 2010

Despite considerable advances in the field of solid tumors, disseminated malignancy remains the cause of the vast majority of cancer-related deaths. In patients with no overt metastasis, early spread of tumor cells is usually undetected by current imaging technologies. In addition, the metastatic process is complex and depends on multiple interactions (crosstalk) of disseminating tumor cells with the individual homeostatic mechanisms, which the tumor cells can usurp. Despite these many variables, a flurry of surrogate biomarkers to detect micrometastasis has been developed in the last decade. These biomarkers open avenues for understanding cancer dormancy and metastasis, have the potential to provide novel therapeutic targets and may help predict outcome and therapeutic decisions at diagnosis and during follow-up of cancer patients. This review focuses on ongoing efforts to unravel metastasis biology, surrogate biomarkers currently investigated to monitor micrometastasis and tools used to identify, quantify and determine their capacity to efficiently establish metastasis. © 2010 Future Science Ltd.

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