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Yousef E.M.,University Of Montre Al | St-Pierre Y.,Laval University | Gaboury L.A.,University Of Montre Al
BMC Cancer | Year: 2014

Background: In 2014, breast cancer remains a major cause of mortality worldwide mostly due to tumor relapse and metastasis. There is currently a great interest in identifying cancer biomarkers and signalling pathways mechanistically related to breast cancer progression. Matrix metalloproteinase-9 (MMP-9) is a member of matrix degrading enzymes involved in cancer development, invasion and metastasis. Our objective was to investigate MMP-9 expression in normal human breast tissue and to compare it to that of breast cancer of various histological grades and molecular subtypes. We also sought to correlate MMP-9 expression with the incidence of metastasis, survival rates and relapse in breast cancer patients. Methods: MMP-9 was first studied using in silico analysis on available DNA microarray and RNA sequencing data of human breast cancer tissues and human breast cancer cell lines. We next ascertained MMP-9 expression in both normal breast tissue and in human breast carcinoma tissue microarrays. Results: Significant increase in MMP-9 expression was found in breast cancer cells where compared to normal breast tissue. A positive correlation could also be established between elevated levels of MMP-9 and breast cancer of high histological grade. Furthermore, our results indicate that not only MMP-9 is differentially expressed between each molecular subset but also, more importantly MMP-9 overexpression revealed itself as a startling feature of triple-negative and HER2-positive breast cancers. Lastly, the clinical relevance of MMP-9 overexpression is strongly supported by its significant association with a higher incidence of metastasis and relapse. Conclusions: Differential expression of MMP-9 reflects the extent of cellular differentiation in breast cancer cells and is closely related to the most aggressive subtypes of breast cancer. Hence, MMP-9 is a promising prognostic biomarker of high-grade breast cancer. In our opinion, MMP-9 expression could help segregate subsets of aggressive breast cancer into clinically meaningful subtypes. © 2014 Yousef et al.; licensee BioMed Central Ltd.


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.


Haghighi A.,University of Toronto | Melka M.G.,University of Toronto | Bernard M.,University of Toronto | Abrahamowicz M.,McGill University | And 14 more authors.
Molecular Psychiatry | Year: 2014

Dietary preference for fat may increase risk for obesity. It is a complex behavior regulated in part by the amygdala, a brain structure involved in reward processing and food behavior, and modulated by genetic factors. Here, we conducted a genome-wide association study (GWAS) to search for gene loci associated with dietary intake of fat, and we tested whether these loci are also associated with adiposity and amygdala volume. We studied 598 adolescents (12-18 years) recruited from the French-Canadian founder population and genotyped them with 530 011 single-nucleotide polymorphisms. Fat intake was assessed with a 24-hour food recall. Adiposity was examined with anthropometry and bioimpedance. Amygdala volume was measured by magnetic resonance imaging. GWAS identified a locus of fat intake in the μ-opioid receptor gene (OPRM1, rs2281617, P=5.2 × 10 -6), which encodes a receptor expressed in the brain-reward system and shown previously to modulate fat preference in animals. The minor OPRM1 allele appeared to have a 'protective' effect: it was associated with lower fat intake (by 4%) and lower body-fat mass (by ∼2 kg, P=0.02). Consistent with the possible amygdala-mediated inhibition of fat preference, this allele was additionally associated with higher amygdala volume (by 69 mm 3, P=0.02) and, in the carriers of this allele, amygdala volume correlated inversely with fat intake (P=0.02). Finally, OPRM1 was associated with fat intake in an independent sample of 490 young adults. In summary, OPRM1 may modulate dietary intake of fat and hence risk for obesity, and this effect may be modulated by subtle variations in the amygdala volume. © 2014 Macmillan Publishers Limited All rights reserved.


Berl T.,University of Colorado at Denver | Quittnat-Pelletier F.,University of Toronto | Verbalis J.G.,Georgetown University | Schrier R.W.,University of Colorado at Denver | And 3 more authors.
Journal of the American Society of Nephrology | Year: 2010

Vasopressin antagonists increase the serum sodium concentration in patients who have euvolemia and hypervolemia with hyponatremia in the short term (≤30 days), but their safety and efficacy with longer term administration is unknown. SALTWATER was a multicenter, open-label extension of the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2). In total, 111 patients with hyponatremia received oral tolvaptan for a mean follow-up of 701 days, providing 77,369 patient-days of exposure. All patients had hyponatremia at randomization in SALT-1 and SALT-2, and 85% continued to have hyponatremia at entry in SALTWATER. The most common adverse effects attributed to tolvaptan were pollakiuria, thirst, fatigue, dry mouth, polydipsia, and polyuria. Six drug-related adverse effects led to study discontinuation. The increase in serum sodium exceeded the desired 1 mmol/L per h at initiation in five patients. Hypernatremia (>145 mmol/L) led to discontinuation in one patient. Mean serum sodium increased from 130.8 mmol/L at baseline to >135 mmol/L throughout the observation period (P < 0.001 versus baseline at most points). Responses were comparable between patients with euvolemia and those with heart failure but more modest in patients with cirrhosis. In conclusion, prolonged administration of tolvaptan maintains an increased serum sodium with an acceptable margin of safety. Copyright © 2010 by the American Society of Nephrology.


Lehnertz B.,University of British Columbia | Lehnertz B.,University Of Montre Al | Rogalski J.,University of British Columbia | Schulze F.,University of British Columbia | And 4 more authors.
Molecular Cell | Year: 2011

Methylation of specific lysine residues in the C terminus of p53 is thought to govern p53-dependent transcription following genotoxic and oncogenic stress. In particular, Set7/9 (KMT7)-mediated monomethylation of human p53 at lysine 372 (p53K372me1) was suggested to be essential for p53 activation in human cell lines. This finding was confirmed in a Set7/9 knockout mouse model (Kurash et al., 2008). In an independent knockout mouse strain deficient in Set7/9, we have investigated its involvement in p53 regulation and find that cells from these mice are normal in their ability to induce p53-dependent transcription following genotoxic and oncogenic insults. Most importantly, we detect no impairment in canonical p53 functions in these mice, indicating that Set7/9-mediated methylation of p53 does not seem to represent a major regulatory event and does not appreciably control p53 activity in vivo. © 2011 Elsevier Inc.


Castellanos-Ryan N.,University Of Montre Al | Seguin J.R.,University Of Montre Al | Vitaro F.,University Of Montre Al | Parent S.,University Of Montre Al | And 3 more authors.
British Journal of Psychiatry | Year: 2013

Background: Adolescent substance use is associated with both earlier childhood behavioural problems and serious lifetime addiction problems later in life. Aims: To examine whether, and through which mechanisms, targeting risk factors in early childhood prevents substance use across adolescence. Method: Disruptive kindergarten boys (n = 172) living in Montreal were randomly allocated to a preventive intervention and a control condition. The intervention was delivered over 2 years (7-9 years of age) with two main components: (a) social and problem-solving skills training for the boys; and (b) training for parents on effective child-rearing skills. Results: Adolescent substance use, up to 8 years post-intervention, was reduced in those who received the intervention (d = 0.48-0.70). Of most interest, the intervention effects were explained partly by reductions in impulsivity, antisocial behaviour and affiliation with less deviant peers during pre-adolescence (11-13 years). Conclusions: Adolescent substance use may be indirectly prevented by selectively targeting childhood risk factors that disrupt the developmental cascade of adolescent risk factors for substance use.


Bourgeois-Daigneault M.-C.,University Of Montre Al | Thibodeau J.,University Of Montre Al
Journal of Cell Science | Year: 2013

MARCH1, a member of the membrane-associated RING-CH family of E3 ubiquitin ligases, regulates antigen presentation by downregulating the cell surface expression of Major Histocompatibility Complex class II and CD86 molecules. MARCH1 is a transmembrane protein that exposes both its N- and C-terminus to the cytoplasm. We have conducted a structure-function analysis of its two cytoplasmic tails to gain insights into the trafficking of MARCH1 in the endocytic pathway. Fusion of the N-terminal portion of MARCH1 to a type II transmembrane reporter molecule revealed that this cytoplasmic tail contains endosomal sorting motifs. The Cterminal domain also appears to contain intracellular sorting signals because it reduced surface expression of a type I transmembrane reporter molecule. Mutation of the two putative C-terminal tyrosine-based sorting signals did not affect the activity of human MARCH1; however, it did reduce its incorporation into exosomes. Moreover, site-directed mutagenesis pointed to a functional C-terminal 221VQNC224 sequence that affects the spatial organization of the two cytoplasmic regions. This motif is also found in other RING-type E3 ubiquitin ligases, such as parkin. Altogether, these findings highlight the complex regulation of MARCH1 trafficking in the endocytic pathway as well as the intricate interactions between its cytoplasmic tails. © 2013. Published by The Company of Biologists Ltd.


Dias J.P.,University Of Montre Al | Talbot S.,University Of Montre Al | Senecal J.,University Of Montre Al | Carayon P.,Sanofi S.A. | Couture R.,University Of Montre Al
PLoS ONE | Year: 2010

Background: Kinin B1 receptor (B1R) is induced by the oxidative stress in models of diabetes mellitus. This study aims at determining whether B1R activation could perpetuate the oxidative stress which leads to diabetic complications. Methods and Findings: Young Sprague-Dawley rats were fed with 10% D-Glucose or tap water (controls) for 8-12 weeks. A selective B1R antagonist (SSR240612) was administered acutely (3-30 mg/kg) or daily for a period of 7 days (10 mg/kg) and the impact was measured on systolic blood pressure, allodynia, protein and/or mRNA B1R expression, aortic superoxide anion (O2 ·-) production and expression of superoxide dismutase (MnSOD) and catalase. SSR240612 reduced dosedependently (3-30 mg/kg) high blood pressure in 12-week glucose-fed rats, but had no effect in controls. Eight-week glucose-fed rats exhibited insulin resistance (HOMA index), hypertension, tactile and cold allodynia and significant increases of plasma levels of glucose and insulin. This was associated with higher aortic levels of O2 ·-, NADPH oxidase activity, MnSOD and catalase expression. All these abnormalities including B1R overexpression (spinal cord, aorta, liver and gastrocnemius muscle) were normalized by the prolonged treatment with SSR240612. The production of O2 ·- in the aorta of glucose-fed rats was also measured in the presence and absence of inhibitors (10-100 μM) of NADPH oxidase (apocynin), xanthine oxidase (allopurinol) or nitric oxide synthase (L-NAME) with and without Sar[D-Phe8]des-Arg9-BK (20 mM; B1R agonist). Data show that the greater aortic O2 ·- production induced by the B1R agonist was blocked only by apocynin. Conclusions: Activation of kinin B1R increased O2 ·- through the activation of NADPH oxidase in the vasculature. Prolonged blockade of B1R restored cardiovascular, sensory and metabolic abnormalities by reducing oxidative stress and B1R gene expression in this model. © 2010 Dias et al.


Masson J.-F.,University Of Montre Al
Bragg Gratings, Photosensitivity, and Poling in Glass Waveguides, BGPP 2014 | Year: 2014

Surface chemistries based on peptides and ionic liquids are competent to create biosensors working in crude biofluids. Surface plasmon resonance sensors using these monolayers were effective to detect proteins and small molecules. © 2014 OSA.


Safdie M.,National University of Costa Rica | Safdie M.,Queen's University | Cargo M.,University of South Australia | Richard L.,University Of Montre Al | Le vesque L.,Queen's University
International Journal of Behavioral Nutrition and Physical Activity | Year: 2014

Background: Ecological intervention programs are recommended to prevent overweight and obesity in children. The National Institute of Public Health (INSP) in Mexico implemented a successful ecological intervention program to promote healthy lifestyle behaviors in school age children. This study assessed the integration of ecological principles and Social Cognitive Theory (SCT) constructs in this effective school-based obesity prevention program implemented in 15 elementary schools in Mexico City. Methods: Two coders applied the Intervention Analysis Procedure (IAP) to "map" the program's integration of ecological principles. A checklist gauged the use of SCT theory in program activities. Results: Thirty-two distinct intervention strategies were implemented in one setting (i.e., school) to engage four different target-groups (students, parents, school representatives, government) across two domains (Nutrition and Physical Activity). Overall, 47.5% of the strategies targeted the school infrastructure and/or personnel; 37.5% of strategies targeted a key political actor, the Public Education Secretariat while fewer strategies targeted parents (12.5%) and children (3%). More strategies were implemented in the Nutrition domain (69%) than Physical Activity (31%). The most frequently used SCT construct within both intervention domains was Reciprocal Determinism (e.g., where changes to the environment influence changes in behavior and these behavioral changes influence further changes to the environment); no significant differences were observed in the use of SCT constructs across domains. Conclusions: Findings provide insight into a promising combination of strategies and theoretical constructs that can be used to implement a school-based obesity prevention program. Strategies emphasized school-level infrastructure/personnel change and strong political engagement and were most commonly underpinned by Reciprocal Determinism for both Nutrition and Physical Activity. © 2014 Safdie et al.; licensee BioMed Central Ltd.

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