13 research outputs found
Can we accurately report PTEN status in advanced colorectal cancer?
No full textBACKGROUND: Loss of phosphatase and tensin homologue (PTEN) function evaluated by loss of PTEN protein expression on immunohistochemistry (IHC) has been reported as both prognostic in metastatic colorectal cancer and predictive of response to anti-EGFR monoclonal antibodies although results remain uncertain. Difficulties in the methodological assessment of PTEN are likely to be a major contributor to recent conflicting results. METHODS: We assessed loss of PTEN function in 51 colorectal cancer specimens using Taqman® copy number variation (CNV) and IHC. Two blinded pathologists performed independent IHC assessment on each specimen and inter-observer variability of IHC assessment and concordance of IHC versus Taqman® CNV was assessed. RESULTS: Concordance between pathologists (PTEN loss vs no loss) on IHC assessment was 37/51 (73%). In specimens with concordant IHC assessment, concordance between IHC and Taqman® copy number in PTEN loss assessment was 25/37 (68%). CONCLUSION: Assessment PTEN loss in colorectal cancer is limited by the inter-observer variability of IHC, and discordance of CNV with loss of protein expression. An understanding of the genetic mechanisms of PTEN loss and implementation of improved and standardized methodologies of PTEN assessment are required to clarify the role of PTEN as a biomarker in colorectal cancer.Christopher Hocking, Jennifer E Hardingham, Vy Broadbridge, Joe Wrin, Amanda R Townsend, Niall Tebbutt, John Cooper, Andrew Ruszkiewicz, Chee Lee, and Timothy J Pric
Proangiogenic tumor proteins as potential predictive or prognostic biomarkers for bevacizumab therapy in metastatic colorectal cancer
No full textTumor biomarkers to more accurately predict a patient's response to a given therapy are much needed in oncology practice. For metastatic colorectal cancer the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab is now commonly included in first-line therapy regimens and has led to modest but significant improvements in patient outcomes compared with chemotherapy. Given the modest gains there is a pressing need for predictive biomarkers to better identify patients who would benefit from this targeted therapy. We used a multiplex protein assay to determine the tumor expression levels of the proangiogenic proteins IL-6, IL-8, bFGF, PDGF-BB and VEGF-A in formalin-fixed paraffin-embedded tumors from the MAX clinical trial patients with available tissue samples. Patients were dichotomized into "low" vs. "high" expression subgroups based on median baseline levels to correlate with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). "Low" tumor VEGF-A level was predictive of better ORR for bevacizumab [ORR (low) 53% vs. (high) 19%, interaction p = 0.03] but not for PFS [hazard ratio, HR (low) 0.73 vs. (high) 0.62, interaction p = 0.68] in the comparison of capecitabine (C) versus C and bevacizumab (CB) and CB plus mitomycin (M). When analyzed as a dichotomized variable, "high" VEGF-A was prognostic for shorter PFS (unadjusted HR 1.34, p = 0.06; adjusted HR 1.55, p = 0.008). The other four proteins were neither predictive of bevacizumab benefits nor prognostic for ORR, PFS or OS. "Low" tumor VEGF-A was associated with longer PFS after adjustment for other baseline factors. Proangiogenic proteins were not predictive of benefit with bevacizumab for PFS.Maressa A. Bruhn, Amanda R. Townsend, Chee Khoon Lee, Aravind Shivasami, Timothy J. Price, Joe Wrin, Georgia Arentz, Niall C. Tebbutt, Christopher Hocking, David Cunningham, and Jennifer E. Hardingham, on behalf of the BHI in collaboration with AGIT
Estimating selection pressures on HIV-1 using phylogenetic likelihood models
No full textHuman immunodeficiency virus (HIV-1) can rapidly evolve due to selection pressures exerted by HIV-specific immune responses, antiviral agents, and to allow the virus to establish infection in different compartments in the body. Statistical models applied to HIV-1 sequence data can help to elucidate the nature of these selection pressures through comparisons of non-synonymous (or amino acid changing) and synonymous (or amino acid preserving) substitution rates. These models also need to take into account the non-independence of sequences due to their shared evolutionary history. We review how we have developed these methods and have applied them to characterize the evolution of HIV-1 in vivo. To illustrate our methods, we present an analysis of compartment-specific evolution of HIV-1 em) in blood and cerebrospinal fluid and of site-to-site variation in the gag gene of subtype C HIV-1. Copyright (C) 2008 John Wiley & Sons, Ltd
Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1
No full textThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Renaturation and Purification of Biologically Active Recombinant Human Macrophage Colony-Stimulating Factor Expressed in E. Coli
No full textClinical deterioration during antituberculosis treatment in a high HIV-1 prevalence setting
No full textTheoretical studies of rolled-up and wrinkled nanomembranes
No full textTitle: Theoretical studies of rolled-up and wrinkled nanomembranes Author: Mgr. Peter Cendula Department: Department of Condensed Matter Physics Thesis Supervisors: Prof. Dr. Oliver G. Schmidt, Prof. RNDr. Václav Holý, CSc. Abstract : The thesis is devoted to three similar topics from the field of rolled-up and wrinkled nanomembranes. We start by recalling classical theory of thin plates, which will be used to describe deformation of nanomembranes. In the first topic, relaxation of internal strain is studied when a flat film is partially released from the substrate by etching the sacrificial layer underneath. Energetic competition of the tube and wrinkle shape is quantitatively investigated. Similar model is used to investigate the limiting maximum value of tube rotations. In the second topic, roll-up of initially wrinkled film is shown to favor tubes forming on the flat edge of rectangular wrinkled pattern, enabling precise control of tube position. Experiment is provided to justify our theoretical predictions. In the third topic, quantum well is assumed inside a wrin- kled nanomembrane. Shift of transition energy induced by lateral modulation due to bending strain is quantified, being of interest for strain-sensitive optical detectors and emitters. In addition, lateral localization of electron and hole due to..
The Role of Innate APOBEC3G and Adaptive AID Immune Responses in HLA-HIV/SIV Immunized SHIV Infected Macaques
No full textThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Teoretické studie rolovaných a zvlněných nanomenbrán
No full textTitle: Theoretical studies of rolled-up and wrinkled nanomembranes Author: Mgr. Peter Cendula Department: Department of Condensed Matter Physics Thesis Supervisors: Prof. Dr. Oliver G. Schmidt, Prof. RNDr. Václav Holý, CSc. Abstract : The thesis is devoted to three similar topics from the field of rolled-up and wrinkled nanomembranes. We start by recalling classical theory of thin plates, which will be used to describe deformation of nanomembranes. In the first topic, relaxation of internal strain is studied when a flat film is partially released from the substrate by etching the sacrificial layer underneath. Energetic competition of the tube and wrinkle shape is quantitatively investigated. Similar model is used to investigate the limiting maximum value of tube rotations. In the second topic, roll-up of initially wrinkled film is shown to favor tubes forming on the flat edge of rectangular wrinkled pattern, enabling precise control of tube position. Experiment is provided to justify our theoretical predictions. In the third topic, quantum well is assumed inside a wrin- kled nanomembrane. Shift of transition energy induced by lateral modulation due to bending strain is quantified, being of interest for strain-sensitive optical detectors and emitters. In addition, lateral localization of electron and hole due to...Názov práce: Teoretické štúdie rolovaných a zvlnených nanomembrán Autor: Mgr. Peter Cendula Katedra: Katedra fyziky kondenzovaných látok Vedúci dizertačnej práce: Prof. Dr. Oliver G. Schmidt, Prof. RNDr. Václav Holý, CSc. Abstrakt: Táto dizertačná práca sa zaoberá tromi blízkymi témami z oblasti rolo- vaných a zvlnených nanomembrán. Najprv zhrnieme klasické poznatky z mechanickej teórie tenkých dosiek, ktoré budeme používať pri popise nanomembrán. V prvej časti študujeme relaxáciu vnútorného napätia membrány po jej uvoľnení od substrátu pomo- cou odleptania pomocnej medzivrstvy. Súperenie medzi rolovaním do trubičky alebo zvlnením je kvalitatívne vysvetlené energetickou úvahou. Podobný model je použitý aj na určenie maximálneho počtu otáčok rolovanej trubičky. V druhej časti teoreticky a experimentálne ukážeme ako rolovanie zvlnenej obdĺžnikovej vrstvy zvýhodňuje for- movanie trubičiek na plochej hrane zvlnenej vrstvy. To umožňuje precíznu kontrolu pozície trubičky na substráte. V tretej časti študujeme rozdelenie energie optického prechodu kvantovej jamy pozdĺž zvlnenej membrány ako následok meniacej sa ohy- bovej deformácie. Tento efekt môže byť vhodný pre optické detektory a žiariče citlivé na deformáciu. Dôsledkom ohybovej deformácie je tiež lokalizácia stavu elektrónu a diery v rôznych miestach pozdĺž...Katedra fyziky kondenzovaných látekDepartment of Condensed Matter PhysicsFaculty of Mathematics and PhysicsMatematicko-fyzikální fakult
Assessment of IL-6, IL-8, bFGF, PDGF-BB, and VEGF-A as prognostic and predictive biomarkers for anti-VEGF in metastatic colorectal cancer (mCRC).
No full text 502 Background: There remains a need for predictive biomarkers in mCRC to better identify patients who clinically benefit from anti-VEGF therapy, in particular bevacizumab (BEV). The AGITG MAX trial compared capecitabine (C) with capecitabine (+/- mitomycin C (M)) and BEV and PFS was superior in the CB+/-M arm. Here we have taken a panel of pro-angiogenic proteins to assess whether there is a signal for a predictive factor for bevacizumab outcome in the MAX trial tissue population (TTP). Methods: Protein was isolated from FFPE tumour tissue and assayed using custom Bio-plex arrays to assess the expression levels of candidate tumour biomarkers IL-6, IL-8, bFGF, PDGF-BB and VEGF-A. As there are no accepted cutoff points for these analytes we chose the medians of distribution of each of these biomarkers as cutoff points for dichotomization into “high” v “low”. We then correlated levels of the biomarkers with objective response rate, disease-free and overall survival. Results: Total protein was isolated from FFPE tumour sections from 41.5% of patients (n=196) recruited into the MAX clinical trial and assayed for the proteins using a multiplex platform. Patients were generally balanced, tumour tissue population v intention to treat. Median follow up time is 30.2 mths. For patients receiving BEV there was no relationship between the level of IL-6, IL-8, bFGF, PDGF-BB and VEGF-A and PFS and OS. In patients treated with BEV/C vs. C alone, low tumor VEGF-A was predictive of better ORR as compared to those with a high level (ORR 53% vs 38%, p = 0.03). Multivariate analyses showed low VEGF-A expression level was a significant prognostic factor for longer progression free survival (median PFS 9.3 months low VEGF-A v 7.2 months high VEGF-A, multivariate adjusted HR 1.55 (95% CI 1.12-2.13), p = 0.008). Conclusions: We have shown that the chosen panel of pro-angiogenic proteins was not predictive for PFS or OS outcomes when B is added to C in mCRC. However low VEGF-A level did predict for higher ORR and was an independent prognostic marker for PFS in this cohort. </jats:p
