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NCBI: db=pubmed; Term=Delft[Affiliation] AND (Reinders M[Author] OR Abeel T[Author] OR Wessels L[Author] OR de Ridder J[Author] OR Lelieveldt B[Author] OR van Ham R[Author])
Updated: 2 hours 17 min ago

Reply to Lee and Howden.

Thu, 10/19/2017 - 17:54
Related Articles

Reply to Lee and Howden.

Clin Infect Dis. 2017 Oct 13;:

Authors: Manson AL, Abeel T, Galagan J, Chandrabose Sundaramurthi J, Shanmugam SK, Palaniyandi K, Narayanan S, Swaminathan S, Earl AM

PMID: 29040415 [PubMed - as supplied by publisher]

Identifying transposon insertions and their effects from RNA-sequencing data.

Fri, 10/13/2017 - 02:30
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Identifying transposon insertions and their effects from RNA-sequencing data.

Nucleic Acids Res. 2017 Jul 07;45(12):7064-7077

Authors: de Ruiter JR, Kas SM, Schut E, Adams DJ, Koudijs MJ, Wessels LFA, Jonkers J

Abstract
Insertional mutagenesis using engineered transposons is a potent forward genetic screening technique used to identify cancer genes in mouse model systems. In the analysis of these screens, transposon insertion sites are typically identified by targeted DNA-sequencing and subsequently assigned to predicted target genes using heuristics. As such, these approaches provide no direct evidence that insertions actually affect their predicted targets or how transcripts of these genes are affected. To address this, we developed IM-Fusion, an approach that identifies insertion sites from gene-transposon fusions in standard single- and paired-end RNA-sequencing data. We demonstrate IM-Fusion on two separate transposon screens of 123 mammary tumors and 20 B-cell acute lymphoblastic leukemias, respectively. We show that IM-Fusion accurately identifies transposon insertions and their true target genes. Furthermore, by combining the identified insertion sites with expression quantification, we show that we can determine the effect of a transposon insertion on its target gene(s) and prioritize insertions that have a significant effect on expression. We expect that IM-Fusion will significantly enhance the accuracy of cancer gene discovery in forward genetic screens and provide initial insight into the biological effects of insertions on candidate cancer genes.

PMID: 28575524 [PubMed - indexed for MEDLINE]

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy.

Thu, 10/05/2017 - 21:29

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy.

Sci Rep. 2017 Oct 03;7(1):12575

Authors: Doorenweerd N, Mahfouz A, van Putten M, Kaliyaperumal R, T' Hoen PAC, Hendriksen JGM, Aartsma-Rus AM, Verschuuren JJGM, Niks EH, Reinders MJT, Kan HE, Lelieveldt BPF

Abstract
Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders. To gain more insights into the role of dystrophin in this cognitive phenotype, we performed a comprehensive analysis of the expression patterns of dystrophin isoforms across human brain development, using unique transcriptomic data from Allen Human Brain and BrainSpan atlases. Dystrophin isoforms show large changes in expression through life with pronounced differences between the foetal and adult human brain. The Dp140 isoform was expressed in the cerebral cortex only in foetal life stages, while in the cerebellum it was also expressed postnatally. The Purkinje isoform Dp427p was virtually absent. The expression of dystrophin isoforms was significantly associated with genes implicated in neurodevelopmental disorders, like autism spectrum disorders or attention-deficit hyper-activity disorders, which are known to be associated to DMD. We also identified relevant functional associations of the different isoforms, like an association with axon guidance or neuron differentiation during early development. Our results point to the crucial role of several dystrophin isoforms in the development and function of the human brain.

PMID: 28974727 [PubMed - in process]

BCM: toolkit for Bayesian analysis of Computational Models using samplers.

Thu, 10/05/2017 - 21:29
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BCM: toolkit for Bayesian analysis of Computational Models using samplers.

BMC Syst Biol. 2016 Oct 21;10(1):100

Authors: Thijssen B, Dijkstra TM, Heskes T, Wessels LF

Abstract
BACKGROUND: Computational models in biology are characterized by a large degree of uncertainty. This uncertainty can be analyzed with Bayesian statistics, however, the sampling algorithms that are frequently used for calculating Bayesian statistical estimates are computationally demanding, and each algorithm has unique advantages and disadvantages. It is typically unclear, before starting an analysis, which algorithm will perform well on a given computational model.
RESULTS: We present BCM, a toolkit for the Bayesian analysis of Computational Models using samplers. It provides efficient, multithreaded implementations of eleven algorithms for sampling from posterior probability distributions and for calculating marginal likelihoods. BCM includes tools to simplify the process of model specification and scripts for visualizing the results. The flexible architecture allows it to be used on diverse types of biological computational models. In an example inference task using a model of the cell cycle based on ordinary differential equations, BCM is significantly more efficient than existing software packages, allowing more challenging inference problems to be solved.
CONCLUSIONS: BCM represents an efficient one-stop-shop for computational modelers wishing to use sampler-based Bayesian statistics.

PMID: 27769238 [PubMed - indexed for MEDLINE]

Nanopore sequencing enables near-complete de novo assembly of Saccharomyces cerevisiae reference strain CEN.PK113-7D.

Sat, 09/30/2017 - 20:27

Nanopore sequencing enables near-complete de novo assembly of Saccharomyces cerevisiae reference strain CEN.PK113-7D.

FEMS Yeast Res. 2017 Sep 13;:

Authors: Salazar AN, Gorter de Vries AR, van den Broek M, Wijsman M, de la Torre Cortés P, Brickwedde A, Brouwers N, Daran JG, Abeel T

Abstract
The haploid Saccharomyces cerevisiae strain CEN.PK113-7D is a popular model system for metabolic engineering and systems biology research. Current genome assemblies are based on short-read sequencing data scaffolded based on homology to strain S288C. However, these assemblies contain large sequence gaps, particularly in subtelomeric regions, and the assumption of perfect homology to S288C for scaffolding introduces bias. In this study, we obtained a near-complete genome assembly of CEN.PK113-7D using only Oxford Nanopore Technology's MinION sequencing platform. 15 of the 16 chromosomes, the mitochondrial genome, and the 2-micron plasmid are assembled in single contigs and all but one chromosome starts or ends in a telomere cap. This improved genome assembly contains 770 Kbp of added sequence containing 248 gene annotations in comparison to the previous assembly of CEN.PK113-7D. Many of these genes encode functions determining fitness in specific growth conditions and are therefore highly relevant for various industrial applications. Furthermore, we discovered a translocation between chromosomes III and VIII which caused misidentification of a MAL locus in the previous CEN.PK113-7D assembly. This study demonstrates the power of long-read sequencing by providing a high-quality reference assembly and annotation of CEN.PK113-7D and places a caveat on assumed genome stability of microorganisms.

PMID: 28961779 [PubMed - as supplied by publisher]

MRI Mouse Brain Data of Ischemic Lesion after Transient Middle Cerebral Artery Occlusion.

Fri, 09/22/2017 - 12:34
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MRI Mouse Brain Data of Ischemic Lesion after Transient Middle Cerebral Artery Occlusion.

Front Neuroinform. 2017;11:51

Authors: Mulder IA, Khmelinskii A, Dzyubachyk O, de Jong S, Wermer MJH, Hoehn M, Lelieveldt BPF, van den Maagdenberg AMJM

PMID: 28932191 [PubMed]

Computer-aided evaluation of inflammatory changes over time on MRI of the spine in patients with suspected axial spondyloarthritis: a feasibility study.

Fri, 09/22/2017 - 12:34
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Computer-aided evaluation of inflammatory changes over time on MRI of the spine in patients with suspected axial spondyloarthritis: a feasibility study.

BMC Med Imaging. 2017 Sep 19;17(1):55

Authors: Aizenberg E, van den Berg R, Ez-Zaitouni Z, van der Heijde D, Reijnierse M, Dzyubachyk O, Lelieveldt BPF

Abstract
BACKGROUND: Evaluating inflammatory changes over time on MR images of the spine in patients with suspected axial Spondyloarthritis (axSpA) can be a labor-intensive task, requiring readers to manually search for and perceptually align a set of vertebrae between two scans. The purpose of this study was to assess the feasibility of computer-aided (CA) evaluation of such inflammatory changes in a framework where scans from two time points are fused into a single color-encoded image integrated into an interactive scoring tool.
METHODS: For 30 patients from the SPondyloArthritis Caught Early (SPACE) cohort (back pain ≥ 3 months, ≤ 2 years, onset < 45 years), baseline and follow-up MR scans acquired 9-12 months apart were fused into a single color-encoded image through locally-rigid image registration to evaluate inflammatory changes in 23 vertebral units (VUs). Scoring was performed by two expert readers on a (-2, 2) scale using an interactive scoring tool. For comparison of direction of change (increase/decrease) indicated by an existing reference, Berlin method scores ((-3, 3) scale) of the same MR scans from a different ongoing study were used. The distributions of VU-level differences between CA readers and between the CA and Berlin methods (sign of change scores) across patients were analyzed descriptively. Patient-level agreement between CA readers was assessed by intraclass correlation coefficient (ICC).
RESULTS: Five patients were excluded from evaluation due to failed vertebrae segmentation. Patient-level inter-reader agreement ICC was 0.56 (95% CI: 0.22 to 0.78). Mean VU-level inter-reader differences across 25 patients ranged (-0.04, 0.12) with SD range (0, 0.45). Across all VUs, inter-reader differences ranged (-1, 1) in 573/575 VUs (99.7%). Mean VU-level inter-method differences across patients ranged (-0.04, 0.08) with SD range (0, 0.61). Across all VUs, inter-method differences ranged (-1, 1) in 572/575 VUs (99.5%).
CONCLUSIONS: Fusion of MR scans of the spine from two time points into a single color-encoded image allows for direct visualization and measurement of inflammatory changes over time in patients with suspected axSpA.

PMID: 28927390 [PubMed - in process]

Endogenous androgen receptor proteomic profiling reveals genomic subcomplex involved in prostate tumorigenesis.

Thu, 09/21/2017 - 10:35
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Endogenous androgen receptor proteomic profiling reveals genomic subcomplex involved in prostate tumorigenesis.

Oncogene. 2017 Sep 18;:

Authors: Stelloo S, Nevedomskaya E, Kim Y, Hoekman L, Bleijerveld OB, Mirza T, Wessels LFA, van Weerden WM, Altelaar AFM, Bergman AM, Zwart W

Abstract
Androgen receptor (AR) is a key player in prostate cancer development and progression. Here we applied immunoprecipitation mass spectrometry of endogenous AR in LNCaP cells to identify components of the AR transcriptional complex. In total, 66 known and novel AR interactors were identified in the presence of synthetic androgen, most of which were critical for AR-driven prostate cancer cell proliferation. A subset of AR interactors required for LNCaP proliferation were profiled using chromatin immunoprecipitation assays followed by sequencing, identifying distinct genomic subcomplexes of AR interaction partners. Interestingly, three major subgroups of genomic subcomplexes were identified, where selective gain of function for AR genomic action in tumorigenesis was found, dictated by FOXA1 and HOXB13. In summary, by combining proteomic and genomic approaches we reveal subclasses of AR transcriptional complexes, differentiating normal AR behavior from the oncogenic state. In this process, the expression of AR interactors has key roles by reprogramming the AR cistrome and interactome in a genomic location-specific manner.Oncogene advance online publication, 18 September 2017; doi:10.1038/onc.2017.330.

PMID: 28925401 [PubMed - as supplied by publisher]

Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1β in tumor-associated macrophages.

Wed, 09/20/2017 - 09:12
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Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1β in tumor-associated macrophages.

Oncoimmunology. 2017;6(8):e1334744

Authors: Kersten K, Coffelt SB, Hoogstraat M, Verstegen NJM, Vrijland K, Ciampricotti M, Doornebal CW, Hau CS, Wellenstein MD, Salvagno C, Doshi P, Lips EH, Wessels LFA, de Visser KE

Abstract
Patients with primary solid malignancies frequently exhibit signs of systemic inflammation. Notably, elevated levels of neutrophils and their associated soluble mediators are regularly observed in cancer patients, and correlate with reduced survival and increased metastasis formation. Recently, we demonstrated a mechanistic link between mammary tumor-induced IL17-producing γδ T cells, systemic expansion of immunosuppressive neutrophils and metastasis formation in a genetically engineered mouse model for invasive breast cancer. How tumors orchestrate this systemic inflammatory cascade to facilitate dissemination remains unclear. Here we show that activation of this cascade relies on CCL2-mediated induction of IL1β in tumor-associated macrophages. In line with these findings, expression of CCL2 positively correlates with IL1Β and macrophage markers in human breast tumors. We demonstrate that blockade of CCL2 in mammary tumor-bearing mice results in reduced IL17 production by γδ T cells, decreased neutrophil expansion and enhanced CD8(+) T cell activity. These results highlight a new role for CCL2 in facilitating the breast cancer-induced pro-metastatic systemic inflammatory γδ T cell - IL17 - neutrophil axis.

PMID: 28919995 [PubMed]

Mass Cytometry of the Human Mucosal Immune System Identifies Tissue- and Disease-Associated Immune Subsets.

Sun, 09/17/2017 - 05:39
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Mass Cytometry of the Human Mucosal Immune System Identifies Tissue- and Disease-Associated Immune Subsets.

Immunity. 2016 May 17;44(5):1227-39

Authors: van Unen V, Li N, Molendijk I, Temurhan M, Höllt T, van der Meulen-de Jong AE, Verspaget HW, Mearin ML, Mulder CJ, van Bergen J, Lelieveldt BP, Koning F

Abstract
Inflammatory intestinal diseases are characterized by abnormal immune responses and affect distinct locations of the gastrointestinal tract. Although the role of several immune subsets in driving intestinal pathology has been studied, a system-wide approach that simultaneously interrogates all major lineages on a single-cell basis is lacking. We used high-dimensional mass cytometry to generate a system-wide view of the human mucosal immune system in health and disease. We distinguished 142 immune subsets and through computational applications found distinct immune subsets in peripheral blood mononuclear cells and intestinal biopsies that distinguished patients from controls. In addition, mucosal lymphoid malignancies were readily detected as well as precursors from which these likely derived. These findings indicate that an integrated high-dimensional analysis of the entire immune system can identify immune subsets associated with the pathogenesis of complex intestinal disorders. This might have implications for diagnostic procedures, immune-monitoring, and treatment of intestinal diseases and mucosal malignancies.

PMID: 27178470 [PubMed - indexed for MEDLINE]

Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study.

Sat, 09/16/2017 - 04:46
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Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study.

Oncotarget. 2017 Aug 15;8(33):55582-55592

Authors: Weeber F, Cirkel GA, Hoogstraat M, Bins S, Gadellaa-van Hooijdonk CGM, Ooft S, van Werkhoven E, Willems SM, van Stralen M, Veldhuis WB, Besselink NJM, Horlings HM, Steeghs N, de Jonge MJ, Langenberg MHG, Wessels LFA, Cuppen EPJG, Schellens JH, Sleijfer S, Lolkema MP, Voest EE

Abstract
BACKGROUND: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type.
METHODS: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK. Treatment benefit was determined according to TTP ratio and RECIST. We tested for associations between treatment benefit and single molecular aberrations, clusters of aberrations and pathway perturbation.
RESULTS: Cell line screens indicated several genes, such as PTEN (P = 0.016; Wald test), to be associated with sensitivity to mTOR inhibition. Subsequently 73 patients were included, of which 59 started treatment with everolimus. Response and molecular data were available from 43 patients. PTEN aberrations, i.e. copy number loss or mutation, were associated with treatment benefit (P = 0.046; Fisher's exact test).
CONCLUSION: Loss-of-function aberrations in PTEN potentially represent a tumor type agnostic biomarker for benefit from everolimus and warrants further confirmation in subsequent studies.

PMID: 28903445 [PubMed - in process]

Tissue characterization with depth-resolved attenuation coefficient and backscatter term in intravascular optical coherence tomography images.

Fri, 09/15/2017 - 03:04
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Tissue characterization with depth-resolved attenuation coefficient and backscatter term in intravascular optical coherence tomography images.

J Biomed Opt. 2017 Sep;22(9):1-16

Authors: Liu S, Sotomi Y, Eggermont J, Nakazawa G, Torii S, Ijichi T, Onuma Y, Serruys PW, Lelieveldt BPF, Dijkstra J

Abstract
An important application of intravascular optical coherence tomography (IVOCT) for atherosclerotic tissue analysis is using it to estimate attenuation and backscatter coefficients. This work aims at exploring the potential of the attenuation coefficient, a proposed backscatter term, and image intensities in distinguishing different atherosclerotic tissue types with a robust implementation of depth-resolved (DR) approach. Therefore, the DR model is introduced to estimate the attenuation coefficient and further extended to estimate the backscatter-related term in IVOCT images, such that values can be estimated per pixel without predefining any delineation for the estimation. In order to exclude noisy regions with a weak signal, an automated algorithm is implemented to determine the cut-off border in IVOCT images. The attenuation coefficient, backscatter term, and the image intensity are further analyzed in regions of interest, which have been delineated referring to their pathology counterparts. Local statistical values were reported and their distributions were further compared with a two-sample t-test to evaluate the potential for distinguishing six types of tissues. Results show that the IVOCT intensity, DR attenuation coefficient, and backscatter term extracted with the reported implementation are complementary to each other on characterizing six tissue types: mixed, calcification, fibrous, lipid-rich, macrophages, and necrotic core.

PMID: 28901053 [PubMed - in process]

BrainScope: interactive visual exploration of the spatial and temporal human brain transcriptome.

Thu, 09/14/2017 - 02:34
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BrainScope: interactive visual exploration of the spatial and temporal human brain transcriptome.

Nucleic Acids Res. 2017 Jun 02;45(10):e83

Authors: Huisman SMH, van Lew B, Mahfouz A, Pezzotti N, Höllt T, Michielsen L, Vilanova A, Reinders MJT, Lelieveldt BPF

Abstract
Spatial and temporal brain transcriptomics has recently emerged as an invaluable data source for molecular neuroscience. The complexity of such data poses considerable challenges for analysis and visualization. We present BrainScope: a web portal for fast, interactive visual exploration of the Allen Atlases of the adult and developing human brain transcriptome. Through a novel methodology to explore high-dimensional data (dual t-SNE), BrainScope enables the linked, all-in-one visualization of genes and samples across the whole brain and genome, and across developmental stages. We show that densities in t-SNE scatter plots of the spatial samples coincide with anatomical regions, and that densities in t-SNE scatter plots of the genes represent gene co-expression modules that are significantly enriched for biological functions. We also show that the topography of the gene t-SNE maps reflect brain region-specific gene functions, enabling hypothesis and data driven research. We demonstrate the discovery potential of BrainScope through three examples: (i) analysis of cell type specific gene sets, (ii) analysis of a set of stable gene co-expression modules across the adult human donors and (iii) analysis of the evolution of co-expression of oligodendrocyte specific genes over developmental stages. BrainScope is publicly accessible at www.brainscope.nl.

PMID: 28132031 [PubMed - indexed for MEDLINE]

Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance.

Thu, 09/07/2017 - 18:38
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Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance.

Nat Genet. 2017 Mar;49(3):395-402

Authors: Manson AL, Cohen KA, Abeel T, Desjardins CA, Armstrong DT, Barry CE, Brand J, TBResist Global Genome Consortium, Chapman SB, Cho SN, Gabrielian A, Gomez J, Jodals AM, Joloba M, Jureen P, Lee JS, Malinga L, Maiga M, Nordenberg D, Noroc E, Romancenco E, Salazar A, Ssengooba W, Velayati AA, Winglee K, Zalutskaya A, Via LE, Cassell GH, Dorman SE, Ellner J, Farnia P, Galagan JE, Rosenthal A, Crudu V, Homorodean D, Hsueh PR, Narayanan S, Pym AS, Skrahina A, Swaminathan S, Van der Walt M, Alland D, Bishai WR, Cohen T, Hoffner S, Birren BW, Earl AM

Abstract
Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome sequences from 5,310 M. tuberculosis isolates from five continents. Despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. We have identified harbinger mutations that often precede multidrug resistance. In particular, the katG mutation encoding p.Ser315Thr, which confers resistance to isoniazid, overwhelmingly arose before mutations that conferred rifampicin resistance across all of the lineages, geographical regions and time periods. Therefore, molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of polymorphisms that occur before the emergence of multidrug resistance, particularly katG p.Ser315Thr, into molecular diagnostics should enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB.

PMID: 28092681 [PubMed - indexed for MEDLINE]

Calculating the fetal fraction for noninvasive prenatal testing based on genome-wide nucleosome profiles.

Sat, 09/02/2017 - 10:33
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Calculating the fetal fraction for noninvasive prenatal testing based on genome-wide nucleosome profiles.

Prenat Diagn. 2016 Jul;36(7):614-21

Authors: Straver R, Oudejans CB, Sistermans EA, Reinders MJ

Abstract
OBJECTIVE: While large fetal copy number aberrations can generally be detected through sequencing of DNA in maternal blood, the reliability of tests depends on the fraction of DNA that originates from the fetus. Existing methods to determine this fetal fraction require additional work or are limited to male fetuses. We aimed to create a sex-independent approach without additional work.
METHODS: DNA fragments used for noninvasive prenatal testing are cut only by natural processes; thus, influences on cutting by the packaging of DNA in nucleosomes will be preserved in sequencing. As cuts are expected to be made preferentially in linker regions, the shorter fetal fragments should be enriched for reads starting in nucleosome covered positions.
RESULTS: We generated genome-wide nucleosome profiles based on single end sequencing of cell-free DNA. We found a difference between DNA digestion of fetal cell-free DNA and maternal cell-free DNA and used this to calculate the fraction of fetal DNA in maternal plasma for both male and female fetuses.
CONCLUSION: Our method facilitates cost-effective noninvasive prenatal testing, as the fetal DNA fraction can be estimated without the need for expensive paired-end sequencing or additional tests. The methodology is implemented as a tool, which we called SANEFALCON (Single reAds Nucleosome-basEd FetAL fraCtiON). It is available for academic and non-profit purposes under Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International Public License. github.com/rstraver/sanefalcon. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

PMID: 26996738 [PubMed - indexed for MEDLINE]

Genomic Determinants of Protein Abundance Variation in Colorectal Cancer Cells.

Fri, 09/01/2017 - 08:30
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Genomic Determinants of Protein Abundance Variation in Colorectal Cancer Cells.

Cell Rep. 2017 Aug 29;20(9):2201-2214

Authors: Roumeliotis TI, Williams SP, Gonçalves E, Alsinet C, Del Castillo Velasco-Herrera M, Aben N, Ghavidel FZ, Michaut M, Schubert M, Price S, Wright JC, Yu L, Yang M, Dienstmann R, Guinney J, Beltrao P, Brazma A, Pardo M, Stegle O, Adams DJ, Wessels L, Saez-Rodriguez J, McDermott U, Choudhary JS

Abstract
Assessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells.

PMID: 28854368 [PubMed - in process]

The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting.

Fri, 09/01/2017 - 08:30
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The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting.

Breast Cancer Res. 2017 Aug 25;19(1):99

Authors: Severson TM, Wolf DM, Yau C, Peeters J, Wehkam D, Schouten PC, Chin SF, Majewski IJ, Michaut M, Bosma A, Pereira B, Bismeijer T, Wessels L, Caldas C, Bernards R, Simon IM, Glas AM, Linn S, van 't Veer L

Abstract
BACKGROUND: Patients with BRCA1-like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1-like and non-BRCA1-like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments.
METHODS: A diagnostic gene expression signature (BRCA1ness) was developed using a centroid model with 128 triple-negative breast cancer samples from the EU FP7 RATHER project. This BRCA1ness signature was then tested in HER2-negative patients (n = 116) from the I-SPY 2 TRIAL who received an oral PARP inhibitor veliparib in combination with carboplatin (V-C), or standard chemotherapy alone. We assessed the association between BRCA1ness and pathologic complete response in the V-C and control arms alone using Fisher's exact test, and the relative performance between arms (biomarker × treatment interaction, likelihood ratio p < 0.05) using a logistic model and adjusting for hormone receptor status (HR).
RESULTS: We developed a gene expression signature to identify BRCA1-like status. In the I-SPY 2 neoadjuvant setting the BRCA1ness signature associated significantly with response to V-C (p = 0.03), but not in the control arm (p = 0.45). We identified a significant interaction between BRCA1ness and V-C (p = 0.023) after correcting for HR.
CONCLUSIONS: A genomic-based BRCA1-like signature was successfully translated to an expression-based signature (BRC1Aness). In the I-SPY 2 neoadjuvant setting, we determined that the BRCA1ness signature is capable of predicting benefit of V-C added to standard chemotherapy compared to standard chemotherapy alone.
TRIAL REGISTRATION: I-SPY 2 TRIAL beginning December 31, 2009: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2), NCT01042379 .

PMID: 28851423 [PubMed - in process]

TANDEM: a two-stage approach to maximize interpretability of drug response models based on multiple molecular data types.

Thu, 08/03/2017 - 13:16
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TANDEM: a two-stage approach to maximize interpretability of drug response models based on multiple molecular data types.

Bioinformatics. 2016 Sep 01;32(17):i413-i420

Authors: Aben N, Vis DJ, Michaut M, Wessels LF

Abstract
MOTIVATION: Clinical response to anti-cancer drugs varies between patients. A large portion of this variation can be explained by differences in molecular features, such as mutation status, copy number alterations, methylation and gene expression profiles. We show that the classic approach for combining these molecular features (Elastic Net regression on all molecular features simultaneously) results in models that are almost exclusively based on gene expression. The gene expression features selected by the classic approach are difficult to interpret as they often represent poorly studied combinations of genes, activated by aberrations in upstream signaling pathways.
RESULTS: To utilize all data types in a more balanced way, we developed TANDEM, a two-stage approach in which the first stage explains response using upstream features (mutations, copy number, methylation and cancer type) and the second stage explains the remainder using downstream features (gene expression). Applying TANDEM to 934 cell lines profiled across 265 drugs (GDSC1000), we show that the resulting models are more interpretable, while retaining the same predictive performance as the classic approach. Using the more balanced contributions per data type as determined with TANDEM, we find that response to MAPK pathway inhibitors is largely predicted by mutation data, while predicting response to DNA damaging agents requires gene expression data, in particular SLFN11 expression.
AVAILABILITY AND IMPLEMENTATION: TANDEM is available as an R package on CRAN (for more information, see http://ccb.nki.nl/software/tandem).
CONTACT: m.michaut@nki.nl or l.wessels@nki.nl
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 27587657 [PubMed - indexed for MEDLINE]

Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas.

Sat, 07/29/2017 - 08:24
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Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas.

Cancer Res. 2016 Jul 01;76(13):3773-84

Authors: Droog M, Nevedomskaya E, Kim Y, Severson T, Flach KD, Opdam M, Schuurman K, Gradowska P, Hauptmann M, Dackus G, Hollema H, Mourits M, Nederlof P, van Boven H, Linn SC, Wessels L, van Leeuwen FE, Zwart W

Abstract
Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERα) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ERα transcriptional action in breast and endometrial tumors have been found that might explain this effect. In this study, we addressed this issue with a genome-wide assessment of ERα-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERα was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. These ERα binding sites were highly conserved between breast and endometrial cancer and enriched in binding motifs for the transcription factor FOXA1, which displayed substantial overlap with ERα binding sites proximal to genes involved in classical ERα target genes. Multifactorial ChIP-seq data integration from the endometrial cancer cell line Ishikawa illustrated a functional genomic network involving ERα and FOXA1 together with the enhancer-enriched transcriptional regulators p300, FOXM1, TEAD4, FNFIC, CEBP8, and TCF12. Immunohistochemical analysis of 230 primary endometrial tumor specimens showed that lack of FOXA1 and ERα expression was associated with a longer interval between breast cancer and the emergence of endometrial cancer, exclusively in tamoxifen-treated patients. Our results define conserved sites for a genomic interplay between FOXA1 and ERα in breast cancer and tamoxifen-associated endometrial cancer. In addition, FOXA1 and ERα are associated with the interval time between breast cancer and endometrial cancer only in tamoxifen-treated breast cancer patients. Cancer Res; 76(13); 3773-84. ©2016 AACR.

PMID: 27197147 [PubMed - indexed for MEDLINE]

Cortical Spreading Depression Causes Unique Dysregulation of Inflammatory Pathways in a Transgenic Mouse Model of Migraine.

Sun, 07/09/2017 - 09:46
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Cortical Spreading Depression Causes Unique Dysregulation of Inflammatory Pathways in a Transgenic Mouse Model of Migraine.

Mol Neurobiol. 2017 May;54(4):2986-2996

Authors: Eising E, Shyti R, 't Hoen PAC, Vijfhuizen LS, Huisman SMH, Broos LAM, Mahfouz A, Reinders MJT, Ferrari MD, Tolner EA, de Vries B, van den Maagdenberg AMJM

Abstract
Familial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the α1A subunit of voltage-gated CaV2.1 calcium channels. Transgenic knock-in mice that carry the human FHM1 R192Q missense mutation ('FHM1 R192Q mice') exhibit an increased susceptibility to cortical spreading depression (CSD), the mechanism underlying migraine aura. Here, we analysed gene expression profiles from isolated cortical tissue of FHM1 R192Q mice 24 h after experimentally induced CSD in order to identify molecular pathways affected by CSD. Gene expression profiles were generated using deep serial analysis of gene expression sequencing. Our data reveal a signature of inflammatory signalling upon CSD in the cortex of both mutant and wild-type mice. However, only in the brains of FHM1 R192Q mice specific genes are up-regulated in response to CSD that are implicated in interferon-related inflammatory signalling. Our findings show that CSD modulates inflammatory processes in both wild-type and mutant brains, but that an additional unique inflammatory signature becomes expressed after CSD in a relevant mouse model of migraine.

PMID: 27032388 [PubMed - indexed for MEDLINE]