Ludwig Center for Cancer Research

Epalinges, Switzerland

Ludwig Center for Cancer Research

Epalinges, Switzerland

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Hingorani P.,Phoenix Childrens Hospital | Missiaglia E.,Swiss Institute of Bioinformatics | Shipley J.,Molecular Therapeutics | Anderson J.R.,University of Nebraska Medical Center | And 9 more authors.
Clinical Cancer Research | Year: 2015

Purpose: Pediatric rhabdomyosarcoma (RMS) has two common histologic subtypes: embryonal (ERMS) and alveolar (ARMS). PAX-FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology, whereas fusion gene- negative (FN) ARMS patients are clinically similar to ERMS patients. A five-gene expression signature (MG5) previously identified two diverse risk groups within the fusion gene-negative RMS (FN-RMS) patients, but this has not been independently validated. The goal of this study was to test whether expression of the MG5 metagene, measured using a technical platform that can be applied to routine pathology material, would correlate with outcome in a new cohort of patients with FN-RMS. Experimental Design: Cases were taken from the Children's Oncology Group (COG) D9803 study of children with intermediate- risk RMS, and gene expression profiling for the MG5 genes was performed using the nCounter assay. The MG5 score was correlated with clinical and pathologic characteristics as well as overall and event-free survival. Results: MG5 standardized score showed no significant association with any of the available clinicopathologic variables. The MG5 signature score showed a significant correlation with overall (N 1/4 57; HR, 7.3; 95% CI, 1.9-27.0; P 1/4 0.003) and failure-free survival (N 1/4 57; HR, 6.1; 95% CI, 1.9-19.7; P 1/4 0.002). Conclusions: This represents the first, validated molecular prognostic signature for children with FN-RMS who otherwise have intermediate-risk disease. The capacity to measure the expression of a small number of genes in routine pathology material and apply a simplemathematical formula to calculate theMG5metagene score provides a clear path toward better risk stratification in future prospective clinical trials. © 2015 American Association for Cancer Research.


Penno M.,University of Adelaide | Ernst M.,Ludwig Center for Cancer Research | Hoffmann P.,University of Adelaide
Methods in Molecular Biology | Year: 2012

Serum is unarguably the most used diagnostic fluid. As it circulates throughout the body, leakage peptides/proteins from damaged and dying cells, host-response proteins including inflammatory mediators, and aberrant secretions from tumors and diseased tissues are released into serum, potentially providing a rich source of disease biomarkers. Here, a method for extending access to the serum proteome by removing highly abundant proteins prior to comparative two-dimensional difference gel electrophoresis (2D DIGE) and subsequent protein digestion for identification by mass spectrometry is described. © 2012 Springer Science+Business Media, LLC.


Etzrodt M.,Harvard University | Cortez-Retamozo V.,Harvard University | Newton A.,Harvard University | Zhao J.,California Institute of Technology | And 12 more authors.
Cell Reports | Year: 2012

Monocytes serve as a central defense system against infection and injury but can also promote pathological inflammatory responses. Considering the evidence that monocytes exist in at least two subsets committed to divergent functions, we investigated whether distinct factors regulate the balance between monocyte subset responses in vivo. We identified a microRNA (miRNA), miR-146a, which is differentially regulated both in mouse (Ly-6Chi/Ly-6Clo) and human (CD14hi/CD14loCD16+) monocyte subsets. The single miRNA controlled the amplitude of the Ly-6Chi monocyte response during inflammatory challenge whereas it did not affect Ly-6Clo cells. miR-146a-mediated regulation was cell-intrinsic and depended on Relb, a member of the noncanonical NF-κB/Rel family, which we identified as a direct miR-146a target. These observations not only provide mechanistic insights into the molecular events that regulate responses mediated by committed monocyte precursor populations but also identify targets for manipulating Ly-6Chi monocyte responses while sparing Ly-6Clo monocyte activity.


Di Narzo A.F.,Swiss Institute of Bioinformatics | Tejpar S.,University Hospital Gasthuisberg | Rossi S.,Swiss Institute of Bioinformatics | Yan P.,University of Lausanne | And 15 more authors.
Journal of the National Cancer Institute | Year: 2014

Background Prognosis prediction for resected primary colon cancer is based on the T-stage Node Metastasis (TNM) staging system. We investigated if four well-documented gene expression risk scores can improve patient stratification. Methods Microarray-based versions of risk-scores were applied to a large independent cohort of 688 stage II/III tumors from the PETACC-3 trial. Prognostic value for relapse-free survival (RFS), survival after relapse (SAR), and overall survival (OS) was assessed by regression analysis. To assess improvement over a reference, prognostic model was assessed with the area under curve (AUC) of receiver operating characteristic (ROC) curves. All statistical tests were two-sided, except the AUC increase. Results All four risk scores (RSs) showed a statistically significant association (single-test, P < .0167) with OS or RFS in univariate models, but with HRs below 1.38 per interquartile range. Three scores were predictors of shorter RFS, one of shorter SAR. Each RS could only marginally improve an RFS or OS model with the known factors T-stage, N-stage, and microsatellite instability (MSI) status (AUC gains < 0.025 units). The pairwise interscore discordance was never high (maximal Spearman correlation = 0.563) A combined score showed a trend to higher prognostic value and higher AUC increase for OS (HR = 1.74, 95% confidence interval [CI] = 1.44 to 2.10, P < .001, AUC from 0.6918 to 0.7321) and RFS (HR = 1.56, 95% CI = 1.33 to 1.84, P < .001, AUC from 0.6723 to 0.6945) than any single score. Conclusions The four tested gene expression-based risk scores provide prognostic information but contribute only marginally to improving models based on established risk factors. A combination of the risk scores might provide more robust information. Predictors of RFS and SAR might need to be different.


Klingbiel D.,SAKK Swiss Group for Clinical Cancer Research | Klingbiel D.,Swiss Institute of Bioinformatics | Saridaki Z.,University of Crete | Saridaki Z.,Catholic University of Leuven | And 6 more authors.
Annals of Oncology | Year: 2015

Background: Although colon cancer (CC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CC, the impact varies according to clinicopathological parameters. We studied how MSI status affects prognosis in a trial-based cohort of stage II and III CC patients treated with 5-fluorouracil (5-FU)/leucovorin or FOLFIRI. Materials and methods: Tissue specimens of 1254 patients were tested for 10 different loci and were classified as MSI-high (MSI-H) when three or more loci were unstable and MSS otherwise. Study end points were overall survival (OS) and relapse-free survival (RFS). Results: In stage II, RFS and OS were better for patients with MSI-H than with MSS CC [hazard ratio (HR) 0.26, 95% CI 0.10-0.65, P = 0.004 and 0.16, 95% CI 0.04-0.64, P = 0.01). In stage III, RFS was slightly better for patients with MSI-H CC (HR 0.67, 95% CI 0.46-0.99, P = 0.04), but the difference was not statistically significant for OS (HR 0.70, 95% CI 0.44-1.09, P = 0.11). Outcomes for patients with MSI-H CC were not different between the two treatment arms. RFS was better for patients with MSI-H than with MSS CC in the right and left colon, whereas for OS this was significant only in the right colon. For patients with KRAS- and BRAF-mutated CC, but not for double wild-type patients, RFS and OS were significantly better when the tumors were also MSI-H. An interaction test was statistically significant for KRAS and MSI status (P = 0.005), but not for BRAF status (P = 0.14). Conclusions: Our results confirm that for patients with stage II CC but less so for those with stage III MSI-H is strongly prognostic for RFS and OS. In the presence of 5-FU treatment, stage II patients with MSI-H tumors maintain their survival advantage in comparison with MSS patients and adding irinotecan has no added benefit. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Gillessen S.,Kantonsspital | Gnad-Vogt U.S.,Merck KGaA | Gnad-Vogt U.S.,CureVac GmbH | Gallerani E.,Oncology Institute of Southern Switzerland | And 11 more authors.
European Journal of Cancer | Year: 2013

Background: EMD 521873 (Selectikine), an immunocytokine comprising a DNA-targeting antibody, aimed at tumour necrosis, fused with a genetically modified interleukin-2 (IL-2) moiety, was investigated in this first-in-human phase I study. Methods: Patients had metastatic or locally advanced solid tumours failing previous standard therapy. Selectikine was administered as a 1-hour intravenous infusion on 3 consecutive days, every 3 weeks. A subgroup of patients also received 300 mg/m2 cyclophosphamide on day 1 of each cycle. Escalating doses of Selectikine were investigated with the primary objective of determining the maximum tolerated dose (MTD). Results: Thirty-nine patients were treated with Selectikine alone at dose levels from 0.075 to 0.9 mg/kg, and nine were treated at doses of 0.45 and 0.6 mg/kg in combination with cyclophosphamide. A dose-dependent linear increase of peak serum concentrations and area under curve was found. The dose-limiting toxicity was grade 3 skin rash at the 0.9 mg/kg dose-level; the MTD was 0.6 mg/kg. Rash and flu-like symptoms were the most frequent side-effects. No severe cardiovascular side-effects (hypotension or vascular leak) were observed. At all dose-levels, transient increases in total lymphocyte, eosinophil and monocyte counts were recorded. No objective tumour responses, but long periods of disease stabilisation were observed. Transient and non-neutralising Selectikine antibodies were detected in 69% of patients. Conclusions: The MTD of Selectikine with or without cyclophosphamide administered under this schedule was 0.6 mg/kg. The recommended phase II dose was 0.45-0.6 mg/kg. Selectikine had a favourable safety profile and induced biological effects typical for IL-2. © 2012 Elsevier Ltd. All rights reserved.


Ivanov K.I.,University of Lausanne | Ivanov K.I.,University of Helsinki | Agalarov Y.,University of Lausanne | Valmu L.,University of Helsinki | And 15 more authors.
Molecular and Cellular Biology | Year: 2013

One of the key mechanisms linking cell signaling and control of gene expression is reversible phosphorylation of transcription factors. FOXC2 is a forkhead transcription factor that is mutated in the human vascular disease lymphedema-distichiasis and plays an essential role in lymphatic vascular development. However, the mechanisms regulating FOXC2 transcriptional activity are not well understood. We report here that FOXC2 is phosphorylated on eight evolutionarily conserved proline-directed serine/ threonine residues. Loss of phosphorylation at these sites triggers substantial changes in the FOXC2 transcriptional program. Through genome-wide location analysis in lymphatic endothelial cells, we demonstrate that the changes are due to selective inhibition of FOXC2 recruitment to chromatin. The extent of the inhibition varied between individual binding sites, suggesting a novel rheostat-like mechanism by which expression of specific genes can be differentially regulated by FOXC2 phosphorylation. Furthermore, unlike the wild-type protein, the phosphorylation-deficient mutant of FOXC2 failed to induce vascular remodeling in vivo. Collectively, our results point to the pivotal role of phosphorylation in the regulation of FOXC2-mediated transcription in lymphatic endothelial cells and underscore the importance of FOXC2 phosphorylation in vascular development. © 2013, American Society for Microbiology.


Puppo F.,Ecole Polytechnique Federale de Lausanne | Doucey M.-A.,Ludwig Center for Cancer Research | Delaloye J.-F.,Center du Sein | Moh T.S.Y.,Technical University of Delft | And 4 more authors.
Proceedings of IEEE Sensors | Year: 2014

Sensitive analysis of proteins is central to disease diagnosis. Their detection and investigation in the tumor tissue can further improve the level of knowledge of the cancer disease by capturing the tumor microenvironment. In previous works we demonstrated that high quality Silicon Nanowire Field Effect Transistors (SiNW-FETs) can be used to sense very low concentration (fM) of pathogenic factors in controlled Phosphate Buffered Saline (PBS). In this work we show, SiNW-FETs as biosensors for the detection of bioanalytes in tumor extract. In particular, we achieved the detection of exogenously added rabbit antigen in a much more complex environment, i.e. a human breast tumor extract. Our results show specific and high sensitive antigen detection with p-type SiNW-FETs in the range of 5-200 fM. Further and most importantly, the wires sense rabbit antigen molecules in the presence of a 100 000 mass excess of non-specific protein, indicating that the sensor is extremely resistant to noise. © 2014 IEEE.


Tzouvadaki I.,Ecole Polytechnique Federale de Lausanne | Puppo F.,Ecole Polytechnique Federale de Lausanne | Doucey M.-A.,Ludwig Center for Cancer Research | De Micheli G.,Ecole Polytechnique Federale de Lausanne | Carrara S.,Ecole Polytechnique Federale de Lausanne
2015 IEEE SENSORS - Proceedings | Year: 2015

In the present work, a computational study is carried out investigating the relationship between the biosensing and the electrical characteristics of two-terminal Schottky-barrier silicon nanowire devices. The model suggested successfully reproduces computationally the experimentally obtained electrical behavior of the devices prior to and after the surface bio-modification. Throughout modeling and simulations, it is confirmed that the nanofabricated devices present electrical behavior fully equivalent to that of a memristor device, according to literature. Furthermore, the model introduced successfully reproduces computationally the voltage gap appearing in the current to voltage characteristics for nanowire devices with bio-modified surface. Overall, the present study confirms the implication of the memristive effect for bio sensing applications, therefore demonstrating the Memristive Biosensors. © 2015 IEEE.


Lotfi A.,PoliTO | Demarchi D.,PoliTO | Puppo F.,Ecole Polytechnique Federale de Lausanne | De Micheli G.,Ecole Polytechnique Federale de Lausanne | And 2 more authors.
Proceedings - 2015 6th IEEE International Workshop on Advances in Sensors and Interfaces, IWASI 2015 | Year: 2015

In this paper, we have investigated the redundancy in array of Memristive-Biosensors and find optimum number for devices to accomplish reliable biodetection. Our results lead less expensive sensor and reduce the low-reproducibility of this memristive method for the detection of rabbit antigen. Several experiments have been performed with 17 memristive biosensors in several conditions. These conditions give us relevant informations about the overall behavior of memristor biosensor's array, after functionalization with antibody and exposure to antigen. The statistics made on different conditions, related to the standard deviation and the mean value of voltage gap, prove that such a sensor, with a minimum memristive biosensors in array, can be counted as reliable sensor for the detection of antigen. © 2015 IEEE.

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