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Author Øverbye, A.; Skotland, T.; Koehler, C.J.; Thiede, B.; Seierstad, T.; Berge, V.; Sandvig, K.; Llorente, A. url  openurl
  Title Identification of prostate cancer biomarkers in urinary exosomes Type Journal Article
  Year 2015 Publication Abbreviated Journal Oncotarget  
  Volume 6 Issue 30 Pages 30357-30376  
  Keywords  
  Abstract Exosomes have recently appeared as a novel source of non-invasive cancer biomarkers since tumour-specific molecules can be found in exosomes isolated from biological fluids. We have here investigated the proteome of urinary exosomes by using mass spectrometry to identify proteins differentially expressed in prostate cancer patients compared to healthy male controls. In total, 15 control and 16 prostate cancer samples of urinary exosomes were analyzed. Importantly, 246 proteins were differentially expressed in the two groups. The majority of these proteins (221) were up-regulated in exosomes from prostate cancer patients. These proteins were analyzed according to specific criteria to create a focus list that contained 37 proteins. At 100% specificity, 17 of these proteins displayed individual sensitivities above 60%. Even though several of these proteins showed high sensitivity and specificity for prostate cancer as individual biomarkers, combining them in a multi-panel test has the potential for full differentiation of prostate cancer from non-disease controls. The highest sensitivity, 94%, was observed for transmembrane protein 256 (TM256; chromosome 17 open reading frame 61). LAMTOR proteins were also distinctly enriched with very high specificity for patient samples. TM256 and LAMTOR1 could be used to augment the sensitivity to 100%. Other prominent proteins were V-type proton ATPase 16 kDa proteolipid subunit (VATL), adipogenesis regulatory factor (ADIRF), and several Rab-class members and proteasomal proteins. In conclusion, this study clearly shows the potential of using urinary exosomes in the diagnosis and clinical management of prostate cancer.  
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  Call Number UofT @ ankit.sinha @ Serial 45334  
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Author Rutten, M.J.; Sonke, G.S.; Westermann, A.M.; van Driel, W.J.; Trum, J.W.; Kenter, G.G.; Buist, M.R. url  openurl
  Title Prognostic Value of Residual Disease after Interval Debulking Surgery for FIGO Stage IIIC and IV Epithelial Ovarian Cancer Type Journal Article
  Year 2015 Publication Abbreviated Journal Obstet Gynecol Int  
  Volume 2015 Issue Pages 464123  
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  Abstract Although complete debulking surgery for epithelial ovarian cancer (EOC) is more often achieved with interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT), randomized evidence shows no long-term survival benefit compared to complete primary debulking surgery (PDS). We performed an observational cohort study of patients treated with debulking surgery for advanced EOC to evaluate the prognostic value of residual disease after debulking surgery. All patients treated between 1998 and 2010 in three Dutch referral gynaecological oncology centres were included. The prognostic value of residual disease after surgery for disease specific survival was assessed using Cox-regression analyses. In total, 462 patients underwent NACT-IDS and 227 PDS. Macroscopic residual disease after debulking surgery was an independent prognostic factor for survival in both treatment modalities. Yet, residual tumour less than one centimetre at IDS was associated with a survival benefit of five months compared to leaving residual tumour more than one centimetre, whereas this benefit was not seen after PDS. Leaving residual tumour at IDS is a poor prognostic sign as it is after PDS. The specific prognostic value of residual tumour seems to depend on the clinical setting, as minimal instead of gross residual tumour is associated with improved survival after IDS, but not after PDS.  
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  Call Number UofT @ ankit.sinha @ Serial 45336  
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Author Surinova, S.; Choi, M.; Tao, S.; Schüffler, P.J.; Chang, C.Y.; Clough, T.; Vysloužil, K.; Khoylou, M.; Srovnal, J.; Liu, Y.; Matondo, M.; Hüttenhain, R.; Weisser, H.; Buhmann, J.M.; Hajdúch, M.; Brenner, H.; Vitek, O.; Aebersold, R. url  openurl
  Title Prediction of colorectal cancer diagnosis based on circulating plasma proteins Type Journal Article
  Year 2015 Publication Abbreviated Journal EMBO Mol Med  
  Volume 7 Issue 9 Pages 1166-1178  
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  Abstract Non-invasive detection of colorectal cancer with blood-based markers is a critical clinical need. Here we describe a phased mass spectrometry-based approach for the discovery, screening, and validation of circulating protein biomarkers with diagnostic value. Initially, we profiled human primary tumor tissue epithelia and characterized about 300 secreted and cell surface candidate glycoproteins. These candidates were then screened in patient systemic circulation to identify detectable candidates in blood plasma. An 88-plex targeting method was established to systematically monitor these proteins in two large and independent cohorts of plasma samples, which generated quantitative clinical datasets at an unprecedented scale. The data were deployed to develop and evaluate a five-protein biomarker signature for colorectal cancer detection.  
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  Notes Approved no  
  Call Number UofT @ ankit.sinha @ Serial 45345  
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Author Gros, A.; Syvannarath, V.; Lamrani, L.; Ollivier, V.; Loyau, S.; Goerge, T.; Nieswandt, B.; Jandrot-Perrus, M.; Ho-Tin-Noé, B. openurl 
  Title Single platelets seal neutrophil-induced vascular breaches via GPVI during immune complex-mediated inflammation in mice Type Journal Article
  Year 2015 Publication Abbreviated Journal Blood  
  Volume Issue Pages  
  Keywords Confocal; IVM; Microscopy; Model: Mouse; Mouse; Multiphoton; Thrombosis  
  Abstract Platelets protect vascular integrity during inflammation. Recent evidence suggests that this action is independent of thrombus formation and requires the engagement of glycoprotein VI (GPVI), but it remains unclear how platelets prevent inflammatory bleeding. We investigated whether platelets and GPVI act primarily by preventing detrimental effects of neutrophils using models of immune complex(IC)-mediated inflammation in mice immuno-depleted in platelets and/or neutrophils or deficient in GPVI. Depletion of neutrophils prevented bleeding in thrombocytopenic and GPVI-/- mice during IC-mediated dermatitis. GPVI deficiency did not modify neutrophil recruitment, which was however reduced by thrombocytopenia. Neutrophil cytotoxic activities were reduced in thrombocytopenic and GPVI-/- mice during IC-mediated inflammation. Intravital microscopy revealed that in this setting, intravascular binding sites for platelets were exposed by neutrophils, and GPVI supported the recruitment of individual platelets to these spots. Furthermore, the platelet secretory response accompanying IC-mediated inflammation was partly mediated by GPVI and blocking of GPVI signalling impaired the vasculoprotective action of platelets. Together, our results show that GPVI plays a dual role in inflammation by enhancing neutrophil damaging activities while supporting the activation and hemostatic adhesion of single platelets to neutrophil-induced vascular breaches.  
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  Call Number UofT @ mathieu.lemaire @ Serial 45622  
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Author Aoki-Kinoshita, K.F. isbn  openurl
  Title Glycoinformatics: Overview Type Book Chapter
  Year 2015 Publication Glycoinformatics: Overview Abbreviated Journal  
  Volume Glycoscience: Biology and Medicine Issue Pages 185-192  
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  Abstract Because of the many different glycan-related databases now publicly available, a number of different glycan structure representations are used to graphically and textually display glycans structures. This overview provides an easy reference to each representation format as well as links to several major databases and web resources that may be useful for glycobiologists. Many of the major databases, glycan sequence and structure representation formats, and tools that are currently available and used in the glycoscience field will be …  
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  Publisher Springer Place of Publication Tokyo Editor Endo, T.; Seeberger, P.H.; Hart, G.W.; Wong, C.-H.; Taniguchi, N.  
  Language Summary Language Original Title  
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  Series Volume Series Issue Edition  
  ISSN (up) ISBN 978-4-431-54836-2 Medium  
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  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45629  
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Author isbn  openurl
  Title Mechanobiology of the Endothelium Type Book Whole
  Year 2015 Publication Abbreviated Journal  
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  Abstract The endothelium is an excellent example of where biology meets physics and engineering. It must convert mechanical forces into chemical signals to maintain homeostasis. It also controls the immune response, drug delivery through the vasculature, and cancer metastasis. Basic understanding of these processes is starting to emerge and the knowledge gained from research is now being used in applications from drug delivery to imaging modalities. This book reviews current knowledge in mechanobiology of the endothelium and its implications for the development of theranostic devices.  
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  Publisher CRC Press Place of Publication Editor  
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  ISSN (up) ISBN 9781482207255 Medium  
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  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45932  
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Author Allegretti, A.S.; Hundemer, G.; Chorghade, R.; Cosgrove, K.; Bajwa, E.; Bhan, I. openurl 
  Title Perspectives of continuous renal replacement therapy in the intensive care unit: a paired survey study of patient, physician, and nurse views Type Journal Article
  Year 2015 Publication Abbreviated Journal BMC Nephrol  
  Volume 16 Issue Pages 105  
  Keywords KRESCENT, jclub  
  Abstract BACKGROUND: Recent studies suggest discrepancies between patients and providers around perceptions of hemodialysis prognosis. Such data are lacking for continuous renal replacement therapy (CRRT). We aim to assess patient and provider understanding of outcomes around CRRT.
METHODS: From February 1 to August 31, 2013, a triad of (1) a patient on CRRT (or health care proxy [HCP]), (2) physician and (3) primary nurse from the intensive care unit (ICU) team were surveyed. Univariate chi-square and qualitative analysis techniques were used.
RESULTS: Ninety-six total participants (32 survey triads) were completed. Ninety one percent of patients/HCPs correctly identified that CRRT replaced the function of the kidneys. Six percent of patients/HCPs, 44 % of physicians, and 44 % of nurses identified rates of survival to hospital discharge that were consistent with published literature. Both physicians and nurses were more likely than patients/HCPs to assess survival consistently with published data (p = 0.001). Patients/HCPs were more likely to overestimate survival rates than physicians and nurses (p < 0.001). Thirty eight percent of patients/HCPs, 38 % of physicians, and 28 % of nurses identified rates of lifelong dialysis-dependence among surviving patients that were consistent with published literature.
CONCLUSIONS: There is mismatch between patients, HCPs, and providers around prognosis of CRRT. Patients/HCPs are more likely to overestimate chances of survival than physicians or nurses. Further intervention is needed to improve this knowledge gap.
 
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  Call Number UofT @ mathieu.lemaire @ Serial 46000  
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Author Sokkar, P.; Boulanger, E.; Thiel, W.; Sanchez-Garcia, E. url  openurl
  Title Hybrid Quantum Mechanics/Molecular Mechanics/Coarse Grained Modeling: A Triple-Resolution Approach for Biomolecular Systems Type Journal Article
  Year 2015 Publication Abbreviated Journal J Chem Theory Comput  
  Volume 11 Issue 4 Pages 1809-1818  
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  Abstract We present a hybrid quantum mechanics/molecular mechanics/coarse-grained (QM/MM/CG) multiresolution approach for solvated biomolecular systems. The chemically important active-site region is treated at the QM level. The biomolecular environment is described by an atomistic MM force field, and the solvent is modeled with the CG Martini force field using standard or polarizable (pol-CG) water. Interactions within the QM, MM, and CG regions, and between the QM and MM regions, are treated in the usual manner, whereas the CG-MM and CG-QM interactions are evaluated using the virtual sites approach. The accuracy and efficiency of our implementation is tested for two enzymes, chorismate mutase (CM) and p-hydroxybenzoate hydroxylase (PHBH). In CM, the QM/MM/CG potential energy scans along the reaction coordinate yield reaction energies that are too large, both for the standard and polarizable Martini CG water models, which can be attributed to adverse effects of using large CG water beads. The inclusion of an atomistic MM water layer (10 Å for uncharged CG water and 5 Å for polarizable CG water) around the QM region improves the energy profiles compared to the reference QM/MM calculations. In analogous QM/MM/CG calculations on PHBH, the use of the pol-CG description for the outer water does not affect the stabilization of the highly charged FADHOOH-pOHB transition state compared to the fully atomistic QM/MM calculations. Detailed performance analysis in a glycine-water model system indicates that computation times for QM energy and gradient evaluations at the density functional level are typically reduced by 40-70% for QM/MM/CG relative to fully atomistic QM/MM calculations.  
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  Call Number AG @ matthewjvarga @ Serial 46216  
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Author Suarez, J.; Schramm, V.L. doi  openurl
  Title Isotope-specific and amino acid-specific heavy atom substitutions alter barrier crossing in human purine nucleoside phosphorylase Type Journal Article
  Year 2015 Publication Abbreviated Journal Proceedings of the National Academy of Sciences  
  Volume 112 Issue 36 Pages 11247-11251  
  Keywords Born--Oppenheimer enzymes femtosecond dynamics heavy enzymes pre--steady-state chemistry transition state coupling  
  Abstract <jats:p>Computational chemistry predicts that atomic motions on the femtosecond timescale are coupled to transition-state formation (barrier-crossing) in human purine nucleoside phosphorylase (PNP). The prediction is experimentally supported by slowed catalytic site chemistry in isotopically labeled PNP (<jats:sup>13</jats:sup>C, <jats:sup>15</jats:sup>N, and <jats:sup>2</jats:sup>H). However, other explanations are possible, including altered volume or bond polarization from carbon-deuterium bonds or propagation of the femtosecond bond motions into slower (nanoseconds to milliseconds) motions of the larger protein architecture to alter catalytic site chemistry. We address these possibilities by analysis of chemistry rates in isotope-specific labeled PNPs. Catalytic site chemistry was slowed for both [<jats:sup>2</jats:sup>H]PNP and [<jats:sup>13</jats:sup>C, <jats:sup>15</jats:sup>N]PNP in proportion to their altered protein masses. Secondary effects emanating from carbon–deuterium bond properties can therefore be eliminated. Heavy-enzyme mass effects were probed for local or global contributions to catalytic site chemistry by generating [<jats:sup>15</jats:sup>N, <jats:sup>2</jats:sup>H]His<jats:sub>8</jats:sub>-PNP. Of the eight His per subunit, three participate in contacts to the bound reactants and five are remote from the catalytic sites. [<jats:sup>15</jats:sup>N, <jats:sup>2</jats:sup>H]His<jats:sub>8</jats:sub>-PNP had reduced catalytic site chemistry larger than proportional to the enzymatic mass difference. Altered barrier crossing when only His are heavy supports local catalytic site femtosecond perturbations coupled to transition-state formation. Isotope-specific and amino acid specific labels extend the use of heavy enzyme methods to distinguish global from local isotope effects.</jats:p  
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  Notes Times cited: 18 Approved no  
  Call Number AG @ matthewjvarga @ Serial 46225  
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Author Zoi, I.; Motley, M.W.; Antoniou, D.; Schramm, V.L.; Schwartz, S.D. url  openurl
  Title Enzyme homologues have distinct reaction paths through their transition states Type Journal Article
  Year 2015 Publication Abbreviated Journal J Phys Chem B  
  Volume 119 Issue 9 Pages 3662-3668  
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  Abstract Recent studies of the bacterial enzymes EcMTAN and VcMTAN showed that they have different binding affinities for the same transition state analogue. This was surprising given the similarity of their active sites. We performed transition path sampling simulations of both enzymes to reveal the atomic details of the catalytic chemical step, which may be the key for explaining the inhibitor affinity differences. Even though all experimental data would suggest the two enzymes are almost identical, subtle dynamic differences manifest in differences of reaction coordinate, transition state structure, and eventually significant differences in inhibitor binding. Unlike EcMTAN, VcMTAN has multiple distinct transition states, which is an indication that multiple sets of coordinated protein motions can reach a transition state. Reaction coordinate information is only accessible from transition path sampling approaches, since all experimental approaches report averages. Detailed knowledge could have a significant impact on pharmaceutical design.  
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  Call Number AG @ matthewjvarga @ Serial 46250  
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