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https://www.readbyqxmd.com/read/27815543/genetic-dissection-of-cancer-development-therapy-response-and-resistance-in-mouse-models-of-breast-cancer
#1
Stefano Annunziato, Marco Barazas, Sven Rottenberg, Jos Jonkers
The cancer genomics revolution has rapidly expanded the inventory of somatic mutations characterizing human malignancies, highlighting a previously underappreciated extent of molecular variability between and within patients. Also in breast cancer, the most commonly diagnosed malignancy in women, this heterogeneity complicates the understanding of the stepwise sequence of pathogenic events and the design of effective and long-lasting target therapies. To disentangle this complexity and pinpoint which molecular perturbations are crucial to hijack the cellular machinery and lead to tumorigenesis and drug resistance, functional studies are needed in model systems that faithfully and comprehensively recapitulate all the salient aspects of their cognate human counterparts...
November 4, 2016: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/27798604/lgr6-labels-a-rare-population-of-mammary-gland-progenitor-cells-that-are-able-to-originate-luminal-mammary-tumours
#2
Leander Blaas, Fabio Pucci, Hendrik A Messal, Agneta B Andersson, E Josue Ruiz, Marco Gerling, Iyadh Douagi, Bradley Spencer-Dene, Alexandra Musch, Richard Mitter, Leena Bhaw, Richard Stone, Dorothee Bornhorst, Abdul K Sesay, Jos Jonkers, Gordon Stamp, Ilaria Malanchi, Rune Toftgård, Axel Behrens
The mammary gland is composed of a complex cellular hierarchy with unusual postnatal plasticity. The identities of stem/progenitor cell populations, as well as tumour-initiating cells that give rise to breast cancer, are incompletely understood. Here we show that Lgr6 marks rare populations of cells in both basal and luminal mammary gland compartments in mice. Lineage tracing analysis showed that Lgr6(+) cells are unipotent progenitors, which expand clonally during puberty but diminish in adulthood. In pregnancy or following stimulation with ovarian hormones, adult Lgr6(+) cells regained proliferative potency and their progeny formed alveoli over repeated pregnancies...
October 31, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27680696/erratum-replication-fork-stability-confers-chemoresistance-in-brca-deficient-cells
#3
Arnab Ray Chaudhuri, Elsa Callen, Xia Ding, Ewa Gogola, Alexandra A Duarte, Ji-Eun Lee, Nancy Wong, Vanessa Lafarga, Jennifer A Calvo, Nicholas J Panzarino, Sam John, Amanda Day, Anna Vidal Crespo, Binghui Shen, Linda M Starnes, Julian R de Ruiter, Jeremy A Daniel, Panagiotis A Konstantinopoulos, David Cortez, Sharon B Cantor, Oscar Fernandez-Capetillo, Kai Ge, Jos Jonkers, Sven Rottenberg, Shyam K Sharan, André Nussenzweig
No abstract text is available yet for this article.
September 28, 2016: Nature
https://www.readbyqxmd.com/read/27566577/secretome-proteomics-reveals-candidate-non-invasive-biomarkers-of-brca1-deficiency-in-breast-cancer
#4
Marc Warmoes, Siu W Lam, Petra van der Groep, Janneke E Jaspers, Yvonne H C M Smolders, Leon de Boer, Thang V Pham, Sander R Piersma, Sven Rottenberg, Epie Boven, Jos Jonkers, Paul J van Diest, Connie R Jimenez
Breast cancer arising in female BRCA1 mutation carriers is characterized by an aggressive phenotype and early age of onset. We performed tandem mass spectrometry-based proteomics of secretomes and exosome-like extracellular vesicles from BRCA1-deficient and BRCA1-proficient murine breast tumor models to identify extracellular protein biomarkers, which can be used as an adjunct to current diagnostic modalities in patients with BRCA1-deficient breast cancer. We identified 2,107 proteins, of which 215 were highly enriched in the BRCA1-deficient secretome...
August 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27550455/the-parp-inhibitor-azd2461-provides-insights-into-the-role-of-parp3-inhibition-for-both-synthetic-lethality-and-tolerability-with-chemotherapy-in-preclinical-models
#5
Lenka Oplustil O'Connor, Stuart L Rulten, Aaron N Cranston, Rajesh Odedra, Henry Brown, Janneke E Jaspers, Louise Jones, Charlotte Knights, Bastiaan Evers, Attilla Ting, Robert H Bradbury, Marina Pajic, Sven Rottenberg, Jos Jonkers, David Rudge, Niall M B Martin, Keith W Caldecott, Alan Lau, Mark J O'Connor
The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic...
October 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27524621/pten-loss-in-e-cadherin-deficient-mouse-mammary-epithelial-cells-rescues-apoptosis-and-results-in-development-of-classical-invasive-lobular-carcinoma
#6
Mirjam C Boelens, Micha Nethe, Sjoerd Klarenbeek, Julian R de Ruiter, Eva Schut, Nicola Bonzanni, Amber L Zeeman, Ellen Wientjens, Eline van der Burg, Lodewyk Wessels, Renée van Amerongen, Jos Jonkers
Invasive lobular carcinoma (ILC) is an aggressive breast cancer subtype with poor response to chemotherapy. Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients. Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary epithelium, we generated a mouse model of classical ILC (CLC), the main histological ILC subtype. While loss of E-cadherin induced cell dissemination and apoptosis, additional PTEN inactivation promoted cell survival and rapid formation of invasive mammary tumors that recapitulate the histological and molecular features, estrogen receptor (ER) status, growth kinetics, metastatic behavior, and tumor microenvironment of human CLC...
August 23, 2016: Cell Reports
https://www.readbyqxmd.com/read/27490433/understanding-human-immune-function-using-the-resources-from-the-human-functional-genomics-project
#7
Mihai G Netea, Leo A B Joosten, Yang Li, Vinod Kumar, Marije Oosting, Sanne Smeekens, Martin Jaeger, Rob Ter Horst, Melanie Schirmer, Hera Vlamakis, Richard Notebaart, Norman Pavelka, Raul Raul Aguirre-Gamboa, Morris A Swertz, Rahajeng N Tunjungputri, Wouter van de Heijden, Eric A Franzosa, Aylwin Ng, Daniel Graham, Kara Lassen, Kiki Schraa, Romana Netea-Maier, Jan Smit, Quirijn de Mast, Frank van de Veerdonk, Bart Jan Kullberg, Cees Tack, Inge van de Munckhof, Joost Rutten, Jacqueline van der Graaf, Lude Franke, Marten Hofker, Iris Jonkers, Mathieu Platteel, Astrid Maatman, Jingyuan Fu, Alexandra Zhernakova, Jos W M van der Meer, Charles A Dinarello, Andre van der Ven, Curtis Huttenhouwer, Hans Koenen, Irma Joosten, Ramnik J Xavier, Cisca Wijmenga
No abstract text is available yet for this article.
August 4, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27454287/brca1185delag-tumors-may-acquire-therapy-resistance-through-expression-of-ring-less-brca1
#8
Rinske Drost, Kiranjit K Dhillon, Hanneke van der Gulden, Ingrid van der Heijden, Inger Brandsma, Cristina Cruz, Dafni Chondronasiou, Marta Castroviejo-Bermejo, Ute Boon, Eva Schut, Eline van der Burg, Ellen Wientjens, Mark Pieterse, Christiaan Klijn, Sjoerd Klarenbeek, Fabricio Loayza-Puch, Ran Elkon, Liesbeth van Deemter, Sven Rottenberg, Marieke van de Ven, Dick H W Dekkers, Jeroen A A Demmers, Dik C van Gent, Reuven Agami, Judith Balmaña, Violeta Serra, Toshiyasu Taniguchi, Peter Bouwman, Jos Jonkers
Heterozygous germline mutations in breast cancer 1 (BRCA1) strongly predispose women to breast cancer. BRCA1 plays an important role in DNA double-strand break (DSB) repair via homologous recombination (HR), which is important for tumor suppression. Although BRCA1-deficient cells are highly sensitive to treatment with DSB-inducing agents through their HR deficiency (HRD), BRCA1-associated tumors display heterogeneous responses to platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors in clinical trials...
August 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27443740/replication-fork-stability-confers-chemoresistance-in-brca-deficient-cells
#9
Arnab Ray Chaudhuri, Elsa Callen, Xia Ding, Ewa Gogola, Alexandra A Duarte, Ji-Eun Lee, Nancy Wong, Vanessa Lafarga, Jennifer A Calvo, Nicholas J Panzarino, Sam John, Amanda Day, Anna Vidal Crespo, Binghui Shen, Linda M Starnes, Julian R de Ruiter, Jeremy A Daniel, Panagiotis A Konstantinopoulos, David Cortez, Sharon B Cantor, Oscar Fernandez-Capetillo, Kai Ge, Jos Jonkers, Sven Rottenberg, Shyam K Sharan, André Nussenzweig
Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks...
July 20, 2016: Nature
https://www.readbyqxmd.com/read/27411687/p120-catenin-is-critical-for-the-development-of-invasive-lobular-carcinoma-in-mice
#10
Milou Tenhagen, Sjoerd Klarenbeek, Tanya M Braumuller, Ilse Hofmann, Petra van der Groep, Natalie Ter Hoeve, Elsken van der Wall, Jos Jonkers, Patrick W B Derksen
Loss of E-cadherin expression is causal to the development of invasive lobular breast carcinoma (ILC). E-cadherin loss leads to dismantling of the adherens junction and subsequent translocation of p120-catenin (p120) to the cytosol and nucleus. Although p120 is critical for the metastatic potential of ILC through the regulation of Rock-dependent anoikis resistance, it remains unknown whether p120 also contributes to ILC development. Using genetically engineered mouse models with mammary gland-specific inactivation of E-cadherin, p120 and p53, we demonstrate that ILC formation induced by E-cadherin and p53 loss is severely impaired upon concomitant inactivation of p120...
July 13, 2016: Journal of Mammary Gland Biology and Neoplasia
https://www.readbyqxmd.com/read/27381808/extended-foot-ankle-musculoskeletal-models-for-application-in-movement-analysis
#11
Tiago M Malaquias, Carolina Silveira, Wouter Aerts, Friedl De Groote, Greta Dereymaeker, Jos Vander Sloten, Ilse Jonkers
Multibody simulations of human motion require representative models of the anatomical structures. A model that captures the complexity of the foot is still lacking. In the present work, two detailed 3D multibody foot-ankle models generated based on CT scans using a semi-automatic tool are described. The proposed models consists of five rigid segments (talus, calcaneus, midfoot, forefoot and toes), connected by five joints (ankle, subtalar, midtarsal, tarsometatarsal and metatarsophalangeal), one with 15DOF and the other with 8DOF...
February 2017: Computer Methods in Biomechanics and Biomedical Engineering
https://www.readbyqxmd.com/read/27381626/mechanisms-of-therapy-resistance-in-patient-derived-xenograft-models-of-brca1-deficient-breast-cancer
#12
Petra Ter Brugge, Petra Kristel, Eline van der Burg, Ute Boon, Michiel de Maaker, Esther Lips, Lennart Mulder, Julian de Ruiter, Catia Moutinho, Heidrun Gevensleben, Elisabetta Marangoni, Ian Majewski, Katarzyna Jóźwiak, Wigard Kloosterman, Markus van Roosmalen, Karen Duran, Frans Hogervorst, Nick Turner, Manel Esteller, Edwin Cuppen, Jelle Wesseling, Jos Jonkers
BACKGROUND: Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer. METHODS: A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined...
November 2016: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27340177/modeling-invasive-lobular-breast-carcinoma-by-crispr-cas9-mediated-somatic-genome-editing-of-the-mammary-gland
#13
Stefano Annunziato, Sjors M Kas, Micha Nethe, Hatice Yücel, Jessica Del Bravo, Colin Pritchard, Rahmen Bin Ali, Bas van Gerwen, Bjørn Siteur, Anne Paulien Drenth, Eva Schut, Marieke van de Ven, Mirjam C Boelens, Sjoerd Klarenbeek, Ivo J Huijbers, Martine H van Miltenburg, Jos Jonkers
Large-scale sequencing studies are rapidly identifying putative oncogenic mutations in human tumors. However, discrimination between passenger and driver events in tumorigenesis remains challenging and requires in vivo validation studies in reliable animal models of human cancer. In this study, we describe a novel strategy for in vivo validation of candidate tumor suppressors implicated in invasive lobular breast carcinoma (ILC), which is hallmarked by loss of the cell-cell adhesion molecule E-cadherin. We describe an approach to model ILC by intraductal injection of lentiviral vectors encoding Cre recombinase, the CRISPR/Cas9 system, or both in female mice carrying conditional alleles of the Cdh1 gene, encoding for E-cadherin...
June 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/27197267/the-brca1-%C3%AE-11q-alternative-splice-isoform-bypasses-germline-mutations-and-promotes-therapeutic-resistance-to-parp-inhibition-and-cisplatin
#14
Yifan Wang, Andrea J Bernhardy, Cristina Cruz, John J Krais, Joseph Nacson, Emmanuelle Nicolas, Suraj Peri, Hanneke van der Gulden, Ingrid van der Heijden, Shane W O'Brien, Yong Zhang, Maribel I Harrell, Shawn F Johnson, Francisco J Candido Dos Reis, Paul D P Pharoah, Beth Karlan, Charlie Gourley, Diether Lambrechts, Georgia Chenevix-Trench, Håkan Olsson, Javier J Benitez, Mark H Greene, Martin Gore, Robert Nussbaum, Siegal Sadetzki, Simon A Gayther, Susanne K Kjaer, Alan D D'Andrea, Geoffrey I Shapiro, David L Wiest, Denise C Connolly, Mary B Daly, Elizabeth M Swisher, Peter Bouwman, Jos Jonkers, Judith Balmaña, Violeta Serra, Neil Johnson
Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform...
May 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27160562/foot-ankle-simulators-a-tool-to-advance-biomechanical-understanding-of-a-complex-anatomical-structure
#15
Tassos Natsakis, Josefien Burg, Greta Dereymaeker, Ilse Jonkers, Jos Vander Sloten
In vitro gait simulations have been available to researchers for more than two decades and have become an invaluable tool for understanding fundamental foot-ankle biomechanics. This has been realised through several incremental technological and methodological developments, such as the actuation of muscle tendons, the increase in controlled degrees of freedom and the use of advanced control schemes. Furthermore, in vitro experimentation enabled performing highly repeatable and controllable simulations of gait during simultaneous measurement of several biomechanical signals (e...
May 2016: Proceedings of the Institution of Mechanical Engineers. Part H, Journal of Engineering in Medicine
https://www.readbyqxmd.com/read/27135926/landscape-of-somatic-mutations-in-560-breast-cancer-whole-genome-sequences
#16
Serena Nik-Zainal, Helen Davies, Johan Staaf, Manasa Ramakrishna, Dominik Glodzik, Xueqing Zou, Inigo Martincorena, Ludmil B Alexandrov, Sancha Martin, David C Wedge, Peter Van Loo, Young Seok Ju, Marcel Smid, Arie B Brinkman, Sandro Morganella, Miriam R Aure, Ole Christian Lingjærde, Anita Langerød, Markus Ringnér, Sung-Min Ahn, Sandrine Boyault, Jane E Brock, Annegien Broeks, Adam Butler, Christine Desmedt, Luc Dirix, Serge Dronov, Aquila Fatima, John A Foekens, Moritz Gerstung, Gerrit K J Hooijer, Se Jin Jang, David R Jones, Hyung-Yong Kim, Tari A King, Savitri Krishnamurthy, Hee Jin Lee, Jeong-Yeon Lee, Yilong Li, Stuart McLaren, Andrew Menzies, Ville Mustonen, Sarah O'Meara, Iris Pauporté, Xavier Pivot, Colin A Purdie, Keiran Raine, Kamna Ramakrishnan, F Germán Rodríguez-González, Gilles Romieu, Anieta M Sieuwerts, Peter T Simpson, Rebecca Shepherd, Lucy Stebbings, Olafur A Stefansson, Jon Teague, Stefania Tommasi, Isabelle Treilleux, Gert G Van den Eynden, Peter Vermeulen, Anne Vincent-Salomon, Lucy Yates, Carlos Caldas, Laura van't Veer, Andrew Tutt, Stian Knappskog, Benita Kiat Tee Tan, Jos Jonkers, Åke Borg, Naoto T Ueno, Christos Sotiriou, Alain Viari, P Andrew Futreal, Peter J Campbell, Paul N Span, Steven Van Laere, Sunil R Lakhani, Jorunn E Eyfjord, Alastair M Thompson, Ewan Birney, Hendrik G Stunnenberg, Marc J van de Vijver, John W M Martens, Anne-Lise Børresen-Dale, Andrea L Richardson, Gu Kong, Gilles Thomas, Michael R Stratton
We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures...
May 2, 2016: Nature
https://www.readbyqxmd.com/read/27102147/musculoskeletal-modelling-in-dogs-challenges-and-future-perspectives
#17
Billy Dries, Ilse Jonkers, Walter Dingemanse, Benedicte Vanwanseele, Jos Vander Sloten, Henri van Bree, Ingrid Gielen
Musculoskeletal models have proven to be a valuable tool in human orthopaedics research. Recently, veterinary research started taking an interest in the computer modelling approach to understand the forces acting upon the canine musculoskeletal system. While many of the methods employed in human musculoskeletal models can applied to canine musculoskeletal models, not all techniques are applicable. This review summarizes the important parameters necessary for modelling, as well as the techniques employed in human musculoskeletal models and the limitations in transferring techniques to canine modelling research...
May 18, 2016: Veterinary and Comparative Orthopaedics and Traumatology: V.C.O.T
https://www.readbyqxmd.com/read/26774285/helb-is-a-feedback-inhibitor-of-dna-end-resection
#18
Ján Tkáč, Guotai Xu, Hemanta Adhikary, Jordan T F Young, David Gallo, Cristina Escribano-Díaz, Jana Krietsch, Alexandre Orthwein, Meagan Munro, Wendy Sol, Abdallah Al-Hakim, Zhen-Yuan Lin, Jos Jonkers, Piet Borst, Grant W Brown, Anne-Claude Gingras, Sven Rottenberg, Jean-Yves Masson, Daniel Durocher
DNA double-strand break repair by homologous recombination is initiated by the formation of 3' single-stranded DNA (ssDNA) overhangs by a process termed end resection. Although much focus has been given to the decision to initiate resection, little is known of the mechanisms that regulate the ongoing formation of ssDNA tails. Here we report that DNA helicase B (HELB) underpins a feedback inhibition mechanism that curtails resection. HELB is recruited to ssDNA by interacting with RPA and uses its 5'-3' ssDNA translocase activity to inhibit EXO1 and BLM-DNA2, the nucleases catalyzing resection...
February 4, 2016: Molecular Cell
https://www.readbyqxmd.com/read/26700554/a-patient-specific-guide-for-optimizing-custom-made-glenoid-implantation-in-cases-of-severe-glenoid-defects-an-in%C3%A2-vitro-study
#19
Koen Eraly, Danny Stoffelen, Jos Vander Sloten, Ilse Jonkers, Philippe Debeer
BACKGROUND: Glenoid component and screw malpositioning in cases of severe glenoid defects might result in complications. We examined the efficacy of a surgical method to treat severe glenoid defects, including a custom-made glenoid component and accurate screw positioning, using a patient-specific positioning guide. METHODS: Glenoid defects were created in 10 cadaveric shoulders. Computed tomography images were used to plan reversed shoulder arthroplasty and design patient-specific glenoid components...
May 2016: Journal of Shoulder and Elbow Surgery
https://www.readbyqxmd.com/read/26492136/using-the-gemm-esc-strategy-to-study-gene-function-in-mouse-models
#20
Ivo J Huijbers, Jessica Del Bravo, Rahmen Bin Ali, Colin Pritchard, Tanya M Braumuller, Martine H van Miltenburg, Linda Henneman, Ewa M Michalak, Anton Berns, Jos Jonkers
Preclinical in vivo validation of target genes for therapeutic intervention requires careful selection and characterization of the most suitable animal model in order to assess the role of these genes in a particular process or disease. To this end, genetically engineered mouse models (GEMMs) are typically used. However, the appropriate engineering of these models is often cumbersome and time consuming. Recently, we and others described a modular approach for fast-track modification of existing GEMMs by re-derivation of embryonic stem cells (ESCs) that can be modified by recombinase-mediated transgene insertion and subsequently used for the production of chimeric mice...
November 2015: Nature Protocols
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