Margolin A.A.,Sage Bionetworks |
Bilal E.,IBM |
Huang E.,Sage Bionetworks |
Huang E.,Duke University |
And 40 more authors.
Science Translational Medicine | Year: 2013
Although molecular prognostics in breast cancer are among the most successful examples of translating genomic analysis to clinical applications, optimal approaches to breast cancer clinical risk prediction remain controversial. The Sage Bionetworks-DREAM Breast Cancer Prognosis Challenge (BCC) is a crowdsourced research study for breast cancer prognostic modeling using genome-scale data. The BCC provided a community of data analysts with a common platform for data access and blinded evaluation of model accuracy in predicting breast cancer survival on the basis of gene expression data, copy number data, and clinical covariates. This approach offered the opportunity to assess whether a crowdsourced community Challenge would generate models of breast cancer prognosis commensurate with or exceeding current best-in-class approaches. The BCC comprised multiple rounds of blinded evaluations on held-out portions of data on 1981 patients, resulting in more than 1400 models submitted as open source code. Participants then retrained their models on the full data set of 1981 samples and submitted up to five models for validation in a newly generated data set of 184 breast cancer patients. Analysis of the BCC results suggests that the best-performing modeling strategy outperformed previously reported methods in blinded evaluations; model performance was consistent across several independent evaluations; and aggregating community-developed models achieved performance on par with the best-performing individual models. Copyright 2013 by the American Association for the Advancement of Science; all rights reserved.
Silwal-Pandit L.,University of Oslo |
Silwal-Pandit L.,Institute for Clinical Medicine |
Vollan H.K.M.,University of Oslo |
Vollan H.K.M.,Institute for Clinical Medicine |
And 23 more authors.
Clinical Cancer Research | Year: 2014
Purpose: In breast cancer, the TP53 gene is frequently mutated and the mutations have been associated with poor prognosis. The prognostic impact of the different types of TP53 mutations across the different molecular subtypes is still poorly understood. Here, we characterize the spectrum and prognostic significance of TP53 mutations with respect to the PAM50 subtypes and integrative clusters (IC). Experimental Design: TP53 mutation status was obtained for 1,420 tumor samples from the METABRIC cohort by sequencing all coding exons using the Sanger method. Results: TP53 mutations were found in 28.3% of the tumors, conferring a worse overall and breast cancer-specific survival [HR = 2.03; 95% confidence interval (CI), 1.65-2.48, P<0.001], and were also found to be an independent marker of poor prognosis in estrogen receptor-positive cases (HR = 1.86; 95% CI, 1.39-2.49, P < 0.001). The mutation spectrum of TP53 varied between the breast cancer subtypes, and individual alterations showed subtype-specific association. TP53 mutations were associated with increased mortality in patients with luminal B, HER2-enriched, and normal-like tumors, but not in patients with luminal A and basal-like tumors. Similar observations were made in ICs, where mutation associated with poorer outcome in ICI, IC4, and IC5. The combined effect of TP53 mutation, TP53 LOH, and MDM2 amplification on mortality was additive. Conclusion: This study reveals that TP53 mutations have different clinical relevance in molecular subtypes of breast cancer, and suggests diverse roles for TP53 in the biology underlying breast cancer development. © 2014 American Association for Cancer Research.
Reiche K.,Helmholtz Center for Environmental Research |
Reiche K.,Fraunhofer Institute for Cell Therapy and Immunology |
Kasack K.,Fraunhofer Institute for Cell Therapy and Immunology |
Kasack K.,University of Leipzig |
And 19 more authors.
PLoS ONE | Year: 2014
Breast cancer, the second leading cause of cancer death in women, is a highly heterogeneous disease, characterized by distinct genomic and transcriptomic profiles. Transcriptome analyses prevalently assessed protein-coding genes; however, the majority of the mammalian genome is expressed in numerous non-coding transcripts. Emerging evidence supports that many of these non-coding RNAs are specifically expressed during development, tumorigenesis, and metastasis. The focus of this study was to investigate the expression features and molecular characteristics of long non-coding RNAs (lncRNAs) in breast cancer. We investigated 26 breast tumor and 5 normal tissue samples utilizing a custom expression microarray enclosing probes for mRNAs as well as novel and previously identified lncRNAs. We identified more than 19,000 unique regions significantly differentially expressed between normal versus breast tumor tissue, half of these regions were noncoding without any evidence for functional open reading frames or sequence similarity to known proteins. The identified non-coding regions were primarily located in introns (53%) or in the intergenic space (33%), frequently orientated in antisense-direction of protein-coding genes (14%), and commonly distributed at promoter-, transcription factor binding-, or enhancer-sites. Analyzing the most diverse mRNA breast cancer subtypes Basal-like versus Luminal A and B resulted in 3,025 significantly differentially expressed unique loci, including 682 (23%) for non-coding transcripts. A notable number of differentially expressed protein-coding genes displayed non-synonymous expression changes compared to their nearest differentially expressed lncRNA, including an antisense lncRNA strongly anticorrelated to the mRNA coding for histone deacetylase 3 (HDAC3), which was investigated in more detail. Previously identified chromatin-associated lncRNAs (CARs) were predominantly downregulated in breast tumor samples, including CARs located in the protein-coding genes for CALD1, FTX, and HNRNPH1. In conclusion, a number of differentially expressed lncRNAs have been identified with relation to cancer-related protein-coding genes. ©2014 Reiche et al.
Khaleghi A.,University of Oslo |
Chavez-Santiago R.,Institute for Clinical Medicine |
Balasingham I.,Institute for Clinical Medicine
Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS | Year: 2012
Ultra wideband (UWB) technology has big potential for applications in wireless body area networks (WBANs). The inherent characteristics of UWB signals make them suitable for the wireless interface of medical sensors. In particular, implanted medical wireless sensors for monitoring physiological parameters, automatic drug provision, etc. can benefit greatly from this ultra low power (ULP) interface. As with any other wireless technology, accurate knowledge of the channel is necessary for the proper design of communication systems. Only a few models that describe the radio propagation inside the human body have been published. Moreover, there is no comprehensive UWB in-body propagation model that includes the frequency-dependent attenuation. Hence, this paper extends a statistical model for UWB propagation channels inside the human chest in the 1-6 GHz frequency range by including the frequency-dependent attenuation. This is done by modeling the spectrum shape of distorted pulses at different depths inside the human chest. The distortion of the pulse was obtained through numerical simulations using a voxel representation of the human body. We propose a mathematical expression for the spectrum shape of the distorted pulses that act as a window function to reproduce the effects of frequency-dependent attenuation. © 2012 IEEE.
Quigley D.,Norwegian Radium Hospital |
Quigley D.,Institute for Clinical Medicine |
Quigley D.,University of California at San Francisco |
Silwal-Pandit L.,Norwegian Radium Hospital |
And 19 more authors.
Molecular Cancer Research | Year: 2015
Lymphocytic infiltration is associated with better prognosis in several epithelial malignancies including breast cancer. The tumor suppressor TP53 is mutated in approximately 30% of breast adenocarcinomas, with varying frequency across molecular subtypes. In this study of 1,420 breast tumors, we tested for interaction between TP53 mutation status and tumor subtype determined by PAM50 and integrative cluster analysis. In integrative cluster 10 (IC10)/basal-like breast cancer, we identify an association between lymphocytic infiltration, determined by an expression score, and retention of wild-type TP53. The expressionderived score agreed with the degree of lymphocytic infiltration assessed by pathologic review, and application of the Nanodissect algorithm was suggestive of this infiltration being primarily of cytotoxic T lymphocytes (CTL). Elevated expression of this CTL signature was associated with longer survival in IC10/Basal-like tumors. These findings identify a new link between the TP53 pathway and the adaptive immune response in estrogen receptor (ER)-negative breast tumors, suggesting a connection between TP53 inactivation and failure of tumor immunosurveillance.
Quigley D.,University of California at San Francisco |
Quigley D.,University of Oslo |
Quigley D.,Institute for Clinical Medicine
Journal of Investigative Dermatology | Year: 2014
Psoriasis is a chronic inflammatory skin disease driven by aberrant signals from the immune system. In this issue, Li et al. present the first large RNA-seq analysis of gene expression in normal skin and psoriasis lesions, providing a more comprehensive view of mRNA expression than earlier microarray studies. This study's size enables gene co-expression analysis, a method illustrating which pathways are altered by the presence of disease. © 2014 The Society for Investigative Dermatology.
Grawenda A.M.,University of Oxford |
Moller E.K.,University of Oslo |
Moller E.K.,Institute for Clinical Medicine |
Lam S.,Leiden University |
And 12 more authors.
Cancer Research | Year: 2015
TP53 gene mutation is associated with poor prognosis in breast cancer, but additional biomarkers that can further refine the impact of the p53 pathway are needed to achieve clinical utility. In this study, we evaluated a role for the HDMX-S/FL ratio as one such biomarker, based on its association with other suppressor mutations that confer worse prognosis in sarcomas, another type of cancer that is surveilled by p53. We found that HDMX-S/FL ratio interacted with p53 mutational status to signi fi cantly improve prognostic capability in patients with breast cancer. This biomarker pair offered prognostic utility that was comparable with a microarray-based prognostic assay. Unexpectedly, the utility tracked independently of DNA-damaging treatments and instead with different tumor metastasis potential. Finally, we obtained evidence that this biomarker pair might identify patients who could benefit from anti-HDM2 strategies to impede metastatic progression. Taken together, our work offers a p53 pathway marker, which both re fi nes our understanding of the impact of p53 activity on prognosis and harbors potential utility as a clinical tool. Cancer Res; 75(4); 698 - 708. © 2015 AACR. © 2015 American Association for Cancer Research.
Iversen A.B.,Aarhus University Hospital |
Ringgaard S.,Institute for Clinical Medicine |
Laustsen C.,Institute for Clinical Medicine |
Stodkilde-Jorgensen H.,Institute for Clinical Medicine |
And 3 more authors.
Acta Oncologica | Year: 2015
Introduction. Hypoxic tumor cells are radioresistant, therefore, identification of hypoxia is crucial. Hyperpolarized magnetic resonance spectroscopy (HPMRS) allows real time measurements of the conversion of pyruvate to lactate, the final step of anaerobic energy production, and may thus allow non-invasive identification of hypoxia or treatment-induced changes in oxygenation. The aim of the study was to investigate the usefulness of HPMRS as a means to assess tumor hypoxia and its dynamics during intervention.Material and methods. C3H mammary carcinomas grown in CDF1 mice were used. To manipulate with tumor oxygenation, non-anaesthetized mice were gassed with air, 10% or 100% oxygen prior to administration of hyperpolarized [1-13C]pyruvate and HPMRS analysis. A direct assessment of tumor oxygen partial pressure (pO2) distributions were made using the Eppendorf oxygen electrode in a separate, but similarly treated, group of mice.Results. Even though breathing 100% oxygen improved tumor oxygenation as evidenced by pO2 measurements, the mean (with 1 S.E.) [1-13C]lactate/[1-13C]pyruvate ratio was unaffected by this intervention, being 34 (30-37) in mice breathing air and 37 (33-42) in mice breathing 100% oxygen. In contrast, and in accordance with pO2 measurements, a significant increase in the [1-13C]lactate/[1-13C]pyruvate ratio was seen in 10% oxygen-breathing mice with a ratio of 46 (42-50).Conclusions. Although, no metabolic change was observed during 100% O2 breathing using HPMRS, the significant increase in the [1-13C]lactate/[1-13C]pyruvate ratio during 10% oxygen breathing suggests, that HPMRS can detect hypoxia-driven changes in the metabolic fate of pyruvate. To what extent and for what purposes HPMRS may best supplement or complement established techniques like hypoxia PET needs to be unraveled in future research. © 2015 Informa Healthcare.
Jedrychowski W.A.,Jagiellonian University |
Perera F.P.,Columbia University |
Maugeri U.,Institute for Clinical Medicine |
Spengler J.,Harvard University |
And 7 more authors.
Cardiovascular Toxicology | Year: 2012
Exposure to fine particulate matter (PM) is a recognized risk factor for elevated blood pressure (BP) and cardiovascular disease in adults, and this prospective cohort study was undertaken to evaluate whether gesta-tional exposure to PM2.5 has a prohypertensive effect. We measured personal exposure to fine particulate matter (PM2.5) by personal air monitoring in the second trimester of pregnancy among 431 women, and BP values in the third trimester were obtained from medical records of prenatal care clinics. In the general estimating equation model, the effect of PM 2.5 on BP was adjusted for relevant covariates such as maternal age, education, parity, gesta-tional weight gain (GWG), prepregnancy BMI, environmental tobacco smoke (ETS), and blood lead level. Systolic blood pressure (SBP) increased in a linear fashion across a dosage of PM2.5 and on average augmented by 6.1 mm Hg (95% CI, 0.6-11.6) with log unit of PM 2.5 concentration. Effects of age, maternal education, prepre-gnancy BMI, blood lead level, and ETS were insignificant. Women with excessive gestational weight gain ([18 kg) had higher mean SBP parameters by 5.5 mmHg (95% CI, 2.7-8.3). In contrast, multiparous women had significantly lower SBP values (coeff. = -4.2 mm Hg; 95% CI, -6.8 to -1.6). Similar analysis performed for diastolic blood pressure (DBP) has demonstrated that PM2.5 also affected DBP parameters (coeff. = 4.1; 95% CI, -0.02 to 8.2), but at the border significance level. DBP values were positively associated with the excessive GWG (coeff. = 2.3; 95% CI, 0.3-4.4) but were inversely related to parity (coeff. = -2.7; 95% CI, -4.6 to -0.73). In the observed cohort, the exposure to fine particulate matter during pregnancy was associated with increased maternal blood pressure. © 2011 Springer Science+Business Media, LLC.
Unden J.,Institute for Clinical science |
Ingebrigtsen T.,Institute for Clinical Medicine |
Romner B.,Institute for Clinical Medicine
BMC Medicine | Year: 2013
Background: The management of minimal, mild and moderate head injuries is still controversial. In 2000, the Scandinavian Neurotrauma Committee (SNC) presented evidence-based guidelines for initial management of these injuries. Since then, considerable new evidence has emerged.Methods: General methodology according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II framework and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Systematic evidence-based review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, based upon relevant clinical questions with respect to patient-important outcomes, including Quality Assessment of Diagnostic Accuracy Studies (QUADAS) and Centre of Evidence Based Medicine (CEBM) quality ratings. Based upon the results, GRADE recommendations, guidelines and discharge instructions were drafted. A modified Delphi approach was used for consensus and relevant clinical stakeholders were consulted.Conclusions: We present the updated SNC guidelines for initial management of minimal, mild and moderate head injury in adults including criteria for computed tomography (CT) scan selection, admission and discharge with suggestions for monitoring routines and discharge advice for patients. The guidelines are designed to primarily detect neurosurgical intervention with traumatic CT findings as a secondary goal. For elements lacking good evidence, such as in-hospital monitoring, routines were largely based on consensus. We suggest external validation of the guidelines before widespread clinical use is recommended. © 2013 Undén et al; licensee BioMed Central Ltd.