Publications by authors named "Mette Jorgensen"

61 Publications

Mutation Analysis of Nine Chordoma Specimens by Targeted Next-Generation Cancer Panel Sequencing.

J Cancer 2015 20;6(10):984-9. Epub 2015 Aug 20.

2. Center for Medical Research, Cell Culture Facility, Medical University of Graz, Stiftingtalstrasse 24, 8010 Graz, Austria.

Background: Chordoma is a rare primary malignant bone tumour. Treatment options are mainly restricted to surgical excision, since chordomas are largely resistant to conventional ionising radiation and chemotherapy. Thus, there is a strong need to gain more thorough insights into the molecular biology and genetics of chordoma to allow for the development of new therapeutic options. We performed an ultra-deep sequencing analysis to find novel mutations in cancer associated genes in chordomas to date unseen with Sanger sequencing.

Material And Methods: Nine chordomas (skull base (n=3), mobile spine (n=4), and sacrum/coccyx (n=2) were screened for mutations in 48 cancer genes using the Hot Spot Cancer Panel (Illumina). All putative mutations were compared against multiple databases (e.g. NCBI, COSMIC, PolyPhen, EGB, SIFT) and published Copy Number Variation (CNV) data for chordoma.

Results: Our results showed mutations with a frequency above 5% in tumorsuppressor- and onco-genes, revealing new possible driver genes for chordomas. We detected three different variants accounting for 11 point mutations in three cancer associated genes (KIT, KDR and TP53). None of the detected mutations was found in all samples investigated. However, all genes affected interact or are connected in pathway analysis. There were no correlations to already reported CNVs in the samples analysed.

Conclusions: We identified mutations in the associated genes KIT, KDR, and TP53. These mutations have been described previously and have been predicted to be tolerated. Further results on a larger series are warranted. The driver mechanisms of chordoma still have to be identified.
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http://dx.doi.org/10.7150/jca.11371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565847PMC
September 2015

Improving quality of care among patients hospitalised with schizophrenia: a nationwide initiative.

BJPsych Open 2015 Jun 29;1(1):48-53. Epub 2015 Jul 29.

, MD, PhD, Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark.

Background: The effectiveness of systematic quality improvement initiatives in psychiatric care remains unclear.

Aims: To examine whether quality of care has changed following implementation of a systematic monitoring programme of hospital performance measures.

Method: In a nationwide population-based cohort study, we identified 14 228 patients admitted to psychiatric departments between 2004 and 2011 from The Danish Schizophrenia Registry. The registry systematically monitors the adherence to guideline recommended processes of care.

Results: The overall proportion of all relevant recommended processes of care increased from 64 to 76% between 2004 and 2011. The adherence to individual processes of care increased over time, including assessment of psychopathology using a diagnostic interview (relative risk (RR): 2.01, 95% CI: 1.51-2.68), contact with relatives (RR: 1.44, 95% CI: 1.27-1.62), psychoeducation (RR: 1.33, 95% CI: 1.19-1.48), psychiatric aftercare (RR: 1.06, 95% CI: 1.01-1.11) and suicide risk assessment (RR: 1.31, 95% CI: 1.21-1.42).

Conclusions: Quality of care improved from 2004 to 2011 among patients hospitalised with schizophrenia in Denmark.

Declaration Of Interest: None.

Copyright And Usage: © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.
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http://dx.doi.org/10.1192/bjpo.bp.115.000406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998939PMC
June 2015

Fate and nature of the onychophoran mouth-anus furrow and its contribution to the blastopore.

Proc Biol Sci 2015 Apr;282(1805)

Department of Earth Sciences, Palaeobiology, Uppsala University, Villavägen 16, 75236 Uppsala, Sweden.

The ancestral states of bilaterian development, and which living groups have conserved them the most, has been a controversial topic in biology for well over a hundred years. In recent years, the idea that gastrulation primitively proceeded via the formation of a slit-like blastopore that then evolved into either protostomy or deuterostomy has gained renewed attention and some molecular developmental support. One of the key pieces of evidence for this 'amphistomy' theory comes from the onychophorans, which form a clear ventral groove during gastrulation. The interpretation of this structure has, however, proved problematic. Based on expression patterns of forkhead (fkh), caudal (cad), brachyury (bra) and wingless (wg/Wnt1), we show that this groove does not correspond to the blastopore, even though both the mouth and anus later develop from it. Rather, the posterior pit appears to be the blastopore; the posterior of the groove later fuses with it to form the definitive anus. Onychophoran development therefore represents a case of 'concealed' deuterostomy. The new data from the onychophorans thus remove one of the key pieces of evidence for the amphistomy theory. Rather, in line with other recent results, it suggests that ancestral bilaterian development was deuterostomic.
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http://dx.doi.org/10.1098/rspb.2014.2628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389607PMC
April 2015

Aspects of dorso-ventral and proximo-distal limb patterning in onychophorans.

Evol Dev 2015 Jan-Feb;17(1):21-33

Department of Earth Sciences, Palaeobiology, Uppsala University, Villavägen 16, 75236, Uppsala, Sweden.

Onychophorans (velvet worms) are closely related to the arthropods, but their limb morphology represents a stage before arthropodization (i.e., the segmentation of the limbs). We investigated the expression of onychophoran homologs of genes that are involved in dorso-ventral (DV) and proximo-distal (PD) limb patterning in arthropods. We find that the two onychophoran optomotor-blind (omb) genes, omb-1 and omb-2, are both expressed in conserved patterns in the dorsal ectoderm of the limbs, including the onychophoran antennae (the frontal appendages). Surprisingly, the expression of decapentaplegic (dpp), which acts upstream of omb in Drosophila, is partially reversed in onychophoran limbs compared to its expression in arthropods. A conserved feature of dpp expression in arthropods and onychophorans, however, is the prominent expression of dpp in the tips of developing limbs, which, therefore, may represent the ancestral pattern. The expression patterns of wingless (wg) and H15 are very diverged in onychophorans. The wg gene is only expressed in the limb tips and the single H15 gene is expressed in a few dorsal limb cells, but not on the ventral side. The expression of wg and dpp at the limb tips is one of the three possible alternatives predicted by the topology model of arthropod limb patterning and is, thus, compatible with a conserved function of wg and dpp in the patterning of the PD axis. On the other hand, DV limb gene expression is less conserved, and the specification of ventral fate appears to involve neither wg nor H15 expression.
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http://dx.doi.org/10.1111/ede.12107DOI Listing
May 2015

Tumour-to-tumour metastasis: male breast carcinoma metastasis arising in an extrapleural solitary fibrous tumour - a case report.

Diagn Pathol 2014 Nov 25;9:203. Epub 2014 Nov 25.

Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036, Graz, Austria.

Background: Tumour-to-tumour metastasis (TTM) occurs when one tumour metastasises to a separate tumour within the same individual. TTM is observed frequently in breast cancer but has not been described in male breast cancer. In addition reports describing solitary fibrous tumours (SFT) of the pleura hosting other neoplasms' metastases are limited. We report an exceptional case of male breast cancer metastasising to an extrapleural SFT, occurring in the subcutaneous tissue of the back of a 68-year old Caucasian patient.

Case Presentation: A 68-year old male was diagnosed with a metastasising ductal breast cancer. He was treated by mastectomy of the right breast and axillary lymph-adenectomy. Further staging revealed an increasing subcutaneous expansion located on the patient's back. Excision biopsy confirmed a SFT hosting a breast cancer metastasis. The patient received palliative chemotherapy but died of disease seven years after initial diagnosis.

Conclusions: The abundance of blood vessels within these lesions might predispose SFTs for an involvement in TTM. This case describes the possibility of concurrent rare occurrences and reminds clinicians, as well as pathologists, to be open-minded and fastidious about their differential diagnoses, sampling and examination of histological specimens.

Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_203.
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http://dx.doi.org/10.1186/s13000-014-0203-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260247PMC
November 2014

A promoter-level mammalian expression atlas.

Authors:
Alistair R R Forrest Hideya Kawaji Michael Rehli J Kenneth Baillie Michiel J L de Hoon Vanja Haberle Timo Lassmann Ivan V Kulakovskiy Marina Lizio Masayoshi Itoh Robin Andersson Christopher J Mungall Terrence F Meehan Sebastian Schmeier Nicolas Bertin Mette Jørgensen Emmanuel Dimont Erik Arner Christian Schmidl Ulf Schaefer Yulia A Medvedeva Charles Plessy Morana Vitezic Jessica Severin Colin A Semple Yuri Ishizu Robert S Young Margherita Francescatto Intikhab Alam Davide Albanese Gabriel M Altschuler Takahiro Arakawa John A C Archer Peter Arner Magda Babina Sarah Rennie Piotr J Balwierz Anthony G Beckhouse Swati Pradhan-Bhatt Judith A Blake Antje Blumenthal Beatrice Bodega Alessandro Bonetti James Briggs Frank Brombacher A Maxwell Burroughs Andrea Califano Carlo V Cannistraci Daniel Carbajo Yun Chen Marco Chierici Yari Ciani Hans C Clevers Emiliano Dalla Carrie A Davis Michael Detmar Alexander D Diehl Taeko Dohi Finn Drabløs Albert S B Edge Matthias Edinger Karl Ekwall Mitsuhiro Endoh Hideki Enomoto Michela Fagiolini Lynsey Fairbairn Hai Fang Mary C Farach-Carson Geoffrey J Faulkner Alexander V Favorov Malcolm E Fisher Martin C Frith Rie Fujita Shiro Fukuda Cesare Furlanello Masaaki Furino Jun-ichi Furusawa Teunis B Geijtenbeek Andrew P Gibson Thomas Gingeras Daniel Goldowitz Julian Gough Sven Guhl Reto Guler Stefano Gustincich Thomas J Ha Masahide Hamaguchi Mitsuko Hara Matthias Harbers Jayson Harshbarger Akira Hasegawa Yuki Hasegawa Takehiro Hashimoto Meenhard Herlyn Kelly J Hitchens Shannan J Ho Sui Oliver M Hofmann Ilka Hoof Furni Hori Lukasz Huminiecki Kei Iida Tomokatsu Ikawa Boris R Jankovic Hui Jia Anagha Joshi Giuseppe Jurman Bogumil Kaczkowski Chieko Kai Kaoru Kaida Ai Kaiho Kazuhiro Kajiyama Mutsumi Kanamori-Katayama Artem S Kasianov Takeya Kasukawa Shintaro Katayama Sachi Kato Shuji Kawaguchi Hiroshi Kawamoto Yuki I Kawamura Tsugumi Kawashima Judith S Kempfle Tony J Kenna Juha Kere Levon M Khachigian Toshio Kitamura S Peter Klinken Alan J Knox Miki Kojima Soichi Kojima Naoto Kondo Haruhiko Koseki Shigeo Koyasu Sarah Krampitz Atsutaka Kubosaki Andrew T Kwon Jeroen F J Laros Weonju Lee Andreas Lennartsson Kang Li Berit Lilje Leonard Lipovich Alan Mackay-Sim Ri-ichiroh Manabe Jessica C Mar Benoit Marchand Anthony Mathelier Niklas Mejhert Alison Meynert Yosuke Mizuno David A de Lima Morais Hiromasa Morikawa Mitsuru Morimoto Kazuyo Moro Efthymios Motakis Hozumi Motohashi Christine L Mummery Mitsuyoshi Murata Sayaka Nagao-Sato Yutaka Nakachi Fumio Nakahara Toshiyuki Nakamura Yukio Nakamura Kenichi Nakazato Erik van Nimwegen Noriko Ninomiya Hiromi Nishiyori Shohei Noma Shohei Noma Tadasuke Noazaki Soichi Ogishima Naganari Ohkura Hiroko Ohimiya Hiroshi Ohno Mitsuhiro Ohshima Mariko Okada-Hatakeyama Yasushi Okazaki Valerio Orlando Dmitry A Ovchinnikov Arnab Pain Robert Passier Margaret Patrikakis Helena Persson Silvano Piazza James G D Prendergast Owen J L Rackham Jordan A Ramilowski Mamoon Rashid Timothy Ravasi Patrizia Rizzu Marco Roncador Sugata Roy Morten B Rye Eri Saijyo Antti Sajantila Akiko Saka Shimon Sakaguchi Mizuho Sakai Hiroki Sato Suzana Savvi Alka Saxena Claudio Schneider Erik A Schultes Gundula G Schulze-Tanzil Anita Schwegmann Thierry Sengstag Guojun Sheng Hisashi Shimoji Yishai Shimoni Jay W Shin Christophe Simon Daisuke Sugiyama Takaai Sugiyama Masanori Suzuki Naoko Suzuki Rolf K Swoboda Peter A C 't Hoen Michihira Tagami Naoko Takahashi Jun Takai Hiroshi Tanaka Hideki Tatsukawa Zuotian Tatum Mark Thompson Hiroo Toyodo Tetsuro Toyoda Elvind Valen Marc van de Wetering Linda M van den Berg Roberto Verado Dipti Vijayan Ilya E Vorontsov Wyeth W Wasserman Shoko Watanabe Christine A Wells Louise N Winteringham Ernst Wolvetang Emily J Wood Yoko Yamaguchi Masayuki Yamamoto Misako Yoneda Yohei Yonekura Shigehiro Yoshida Susan E Zabierowski Peter G Zhang Xiaobei Zhao Silvia Zucchelli Kim M Summers Harukazu Suzuki Carsten O Daub Jun Kawai Peter Heutink Winston Hide Tom C Freeman Boris Lenhard Vladimir B Bajic Martin S Taylor Vsevolod J Makeev Albin Sandelin David A Hume Piero Carninci Yoshihide Hayashizaki

Nature 2014 Mar;507(7493):462-70

Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.
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http://dx.doi.org/10.1038/nature13182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529748PMC
March 2014

An atlas of active enhancers across human cell types and tissues.

Nature 2014 Mar;507(7493):455-461

The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark.

Enhancers control the correct temporal and cell-type-specific activation of gene expression in multicellular eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. Here we use the FANTOM5 panel of samples, covering the majority of human tissues and cell types, to produce an atlas of active, in vivo-transcribed enhancers. We show that enhancers share properties with CpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell-type-specific enhancers and gene regulation.
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http://dx.doi.org/10.1038/nature12787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215096PMC
March 2014

The Prdm13 histone methyltransferase encoding gene is a Ptf1a-Rbpj downstream target that suppresses glutamatergic and promotes GABAergic neuronal fate in the dorsal neural tube.

Dev Biol 2014 Feb 24;386(2):340-57. Epub 2013 Dec 24.

Laboratory of Developmental Genetics, Université Libre de Bruxelles (ULB), Institute of Molecular Biology and Medicine, and ULB Neuroscience Institute, B-6041 Gosselies, Belgium. Electronic address:

The basic helix-loop-helix (bHLH) transcriptional activator Ptf1a determines inhibitory GABAergic over excitatory glutamatergic neuronal cell fate in progenitors of the vertebrate dorsal spinal cord, cerebellum and retina. In an in situ hybridization expression survey of PR domain containing genes encoding putative chromatin-remodeling zinc finger transcription factors in Xenopus embryos, we identified Prdm13 as a histone methyltransferase belonging to the Ptf1a synexpression group. Gain and loss of Ptf1a function analyses in both frog and mice indicates that Prdm13 is positively regulated by Ptf1a and likely constitutes a direct transcriptional target. We also showed that this regulation requires the formation of the Ptf1a-Rbp-j complex. Prdm13 knockdown in Xenopus embryos and in Ptf1a overexpressing ectodermal explants lead to an upregulation of Tlx3/Hox11L2, which specifies a glutamatergic lineage and a reduction of the GABAergic neuronal marker Pax2. It also leads to an upregulation of Prdm13 transcription, suggesting an autonegative regulation. Conversely, in animal caps, Prdm13 blocks the ability of the bHLH factor Neurog2 to activate Tlx3. Additional gain of function experiments in the chick neural tube confirm that Prdm13 suppresses Tlx3(+)/glutamatergic and induces Pax2(+)/GABAergic neuronal fate. Thus, Prdm13 is a novel crucial component of the Ptf1a regulatory pathway that, by modulating the transcriptional activity of bHLH factors such as Neurog2, controls the balance between GABAergic and glutamatergic neuronal fate in the dorsal and caudal part of the vertebrate neural tube.
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http://dx.doi.org/10.1016/j.ydbio.2013.12.024DOI Listing
February 2014

Polyadenylation site-induced decay of upstream transcripts enforces promoter directionality.

Nat Struct Mol Biol 2013 Aug 14;20(8):923-8. Epub 2013 Jul 14.

Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.

Active human promoters produce promoter-upstream transcripts (PROMPTs). Why these RNAs are coupled to decay, whereas their neighboring promoter-downstream mRNAs are not, is unknown. Here high-throughput sequencing demonstrates that PROMPTs generally initiate in the antisense direction closely upstream of the transcription start sites (TSSs) of their associated genes. PROMPT TSSs share features with mRNA-producing TSSs, including stalled RNA polymerase II (RNAPII) and the production of small TSS-associated RNAs. Notably, motif analyses around PROMPT 3' ends reveal polyadenylation (pA)-like signals. Mutagenesis studies demonstrate that PROMPT pA signals are functional but linked to RNA degradation. Moreover, pA signals are under-represented in promoter-downstream versus promoter-upstream regions, thus allowing for more efficient RNAPII progress in the sense direction from gene promoters. We conclude that asymmetric sequence distribution around human gene promoters serves to provide a directional RNA output from an otherwise bidirectional transcription process.
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http://dx.doi.org/10.1038/nsmb.2640DOI Listing
August 2013

Cross-correlated imaging of single-mode photonic crystal rod fiber with distributed mode filtering.

Opt Express 2013 Apr;21(8):9215-29

DTU Fotonik, Department of Photonics Engineering, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.

Photonic crystal bandgap fibers employing distributed mode filtering design provide near diffraction-limited light outputs, a critical property of fiber-based high-power lasers. Microstructure of the fibers is tailored to achieve single-mode operation at specific wavelength by resonant mode coupling of higher-order modes. We analyze the modal regimes of the fibers having a mode field diameter of 60 µm by the cross-correlated (C(2)) imaging method in different wavelength ranges and evaluate the sensitivity of the modal content to various input-coupling conditions. As a result, we experimentally identify regimes of resonant coupling between higher-order core modes and cladding band. We demonstrate a passive fiber design in which the higher-order modal content inside the single-mode guiding regime is suppressed by at least 20 dB even for significantly misaligned input-coupling configurations.
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http://dx.doi.org/10.1364/OE.21.009215DOI Listing
April 2013

Mind bomb 1 is required for pancreatic β-cell formation.

Proc Natl Acad Sci U S A 2012 May 23;109(19):7356-61. Epub 2012 Apr 23.

Department of Developmental Biology, Hagedorn Research Institute, DK-2820 Gentofte, Denmark.

During early pancreatic development, Notch signaling represses differentiation of endocrine cells and promotes proliferation of Nkx6-1(+)Ptf1a(+) multipotent progenitor cells (MPCs). Later, antagonistic interactions between Nkx6 transcription factors and Ptf1a function to segregate MPCs into distal Nkx6-1(-)Ptf1a(+) acinar progenitors and proximal Nkx6-1(+)Ptf1a(-) duct and β-cell progenitors. Distal cells are initially multipotent, but evolve into unipotent, acinar cell progenitors. Conversely, proximal cells are bipotent and give rise to duct cells and late-born endocrine cells, including the insulin producing β-cells. However, signals that regulate proximodistal (P-D) patterning and thus formation of β-cell progenitors are unknown. Here we show that Mind bomb 1 (Mib1) is required for correct P-D patterning of the developing pancreas and β-cell formation. We found that endoderm-specific inactivation of Mib1 caused a loss of Nkx6-1(+)Ptf1a(-) and Hnf1β(+) cells and a corresponding loss of Neurog3(+) endocrine progenitors and β-cells. An accompanying increase in Nkx6-1(-)Ptf1a(+) and amylase(+) cells, occupying the proximal domain, suggests that proximal cells adopt a distal fate in the absence of Mib1 activity. Impeding Notch-mediated transcriptional activation by conditional expression of dominant negative Mastermind-like 1 (Maml1) resulted in a similarly distorted P-D patterning and suppressed β-cell formation, as did conditional inactivation of the Notch target gene Hes1. Our results reveal iterative use of Notch in pancreatic development to ensure correct P-D patterning and adequate β-cell formation.
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http://dx.doi.org/10.1073/pnas.1203605109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358874PMC
May 2012

Cross-species ChIP-seq studies provide insights into regulatory strategies of PPARγ in adipocytes.

Transcription 2012 Jan-Feb;3(1):19-24

Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.

Three recent studies have investigated interspecies retention of binding sites of peroxisome proliferator-activated receptor γ (PPARγ), the master regulator of adipocyte differention, between mouse and human adipocytes. Here we discuss the major findings and demonstrate that retention of binding events is highly context-dependent.
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http://dx.doi.org/10.4161/trns.3.1.19302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679271PMC
June 2012

Optimizing single mode robustness of the distributed modal filtering rod fiber amplifier.

Opt Express 2012 Mar;20(7):7263-73

DTU Fotonik, Department of Photonics Engineering, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.

High-power fiber amplifiers for pulsed applications require large mode area (LMA) fibers having high pump absorption and near diffraction limited output. Photonic crystal fibers allow realization of short LMA fiber amplifiers having high pump absorption through a pump cladding that is decoupled from the outer fiber diameter. However, achieving ultra low NA for single mode (SM) guidance is challenging, thus different design strategies must be applied. The distributed modal filtering (DMF) design enables SM guidance in ultra low NA fibers with very large cores, where large preform tolerances can be compensated during the fiber draw. Design optimization of the SM bandwidth of the DMF rod fiber is presented. Analysis of band gap properties results in a fourfold increase of the SM bandwidth compared to previous results, achieved by utilizing the first band of cladding modes, which can cover a large fraction of the Yb emission band including wavelengths of 1030 nm and 1064 nm. Design parameters tolerating refractive index fabrication uncertainties of ± 10⁻⁴ are targeted to yield stable SM bandwidths.
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http://dx.doi.org/10.1364/OE.20.007263DOI Listing
March 2012

Hybrid Ytterbium-doped large-mode-area photonic crystal fiber amplifier for long wavelengths.

Opt Express 2012 Mar;20(6):6010-20

DTU Fotonik, Department of Photonics Engineering, Technical University of Denmark, Denmark.

A large-mode-area Ytterbium-doped photonic crystal fiber amplifier with build-in gain shaping is presented. The fiber cladding consists of a hexagonal lattice of air holes, where three rows are replaced with circular high-index inclusions. Seven missing air holes define the large-mode-area core. Light confinement is achieved by combined index and bandgap guiding, which allows for single-mode operation and gain shaping through distributed spectral filtering of amplified spontaneous emission. The fiber properties are ideal for amplification in the long wavelength regime of the Ytterbium gain spectrum above 1100 nm, and red shifting of the maximum gain to 1130 nm is demonstrated.
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http://dx.doi.org/10.1364/OE.20.006010DOI Listing
March 2012

Distributed mode filtering rod fiber amplifier delivering 292W with improved mode stability.

Opt Express 2012 Feb;20(5):5742-53

DTU Fotonik, Department of Photonics Engineering, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.

We demonstrate a high power fiber (85 μm core) amplifier delivering up to 292 Watts of average output power using a mode-locked 30 ps source at 1032 nm. Utilizing a single mode distributed mode filter bandgap rod fiber, we demonstrate 44% power improvement before the threshold-like onset of mode instabilities by operating the rod fiber in a leaky waveguide regime. We investigate the guiding dynamics of the rod fiber and report a distinct bandgap blue-shifting as function of increased signal power level. Furthermore, we theoretically analyze the guiding dynamics of the DMF rod fiber and explain the bandgap blue-shifting with thermally induced refractive index change of the refractive index profile.
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http://dx.doi.org/10.1364/OE.20.005742DOI Listing
February 2012

Ptf1a-mediated control of Dll1 reveals an alternative to the lateral inhibition mechanism.

Development 2012 Jan 17;139(1):33-45. Epub 2011 Nov 17.

Department of Developmental Biology, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark.

Neurog3-induced Dll1 expression in pancreatic endocrine progenitors ostensibly activates Hes1 expression via Notch and thereby represses Neurog3 and endocrine differentiation in neighboring cells by lateral inhibition. Here we show in mouse that Dll1 and Hes1 expression deviate during regionalization of early endoderm, and later during early pancreas morphogenesis. At that time, Ptf1a activates Dll1 in multipotent pancreatic progenitor cells (MPCs), and Hes1 expression becomes Dll1 dependent over a brief time window. Moreover, Dll1, Hes1 and Dll1/Hes1 mutant phenotypes diverge during organ regionalization, become congruent at early bud stages, and then diverge again at late bud stages. Persistent pancreatic hypoplasia in Dll1 mutants after eliminating Neurog3 expression and endocrine development, together with reduced proliferation of MPCs in both Dll1 and Hes1 mutants, reveals that the hypoplasia is caused by a growth defect rather than by progenitor depletion. Unexpectedly, we find that Hes1 is required to sustain Ptf1a expression, and in turn Dll1 expression in early MPCs. Our results show that Ptf1a-induced Dll1 expression stimulates MPC proliferation and pancreatic growth by maintaining Hes1 expression and Ptf1a protein levels.
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http://dx.doi.org/10.1242/dev.071761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3231770PMC
January 2012

Prediction of RNA Polymerase II recruitment, elongation and stalling from histone modification data.

BMC Genomics 2011 Nov 3;12:544. Epub 2011 Nov 3.

The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, Copenhagen University, Ole Maaloes Vej 5, DK-2200 Denmark.

Background: Initiation and elongation of RNA polymerase II (RNAPII) transcription is regulated by both DNA sequence and chromatin signals. Recent breakthroughs make it possible to measure the chromatin state and activity of core promoters genome-wide, but dedicated computational strategies are needed to progress from descriptive annotation of data to quantitative, predictive models.

Results: Here, we describe a computational framework which with high accuracy can predict the locations of core promoters, the amount of recruited RNAPII at the promoter, the amount of elongating RNAPII in the gene body, the mRNA production originating from the promoter and finally also the stalling characteristics of RNAPII by considering both quantitative and spatial features of histone modifications around the transcription start site (TSS).As the model framework can also pinpoint the signals that are the most influential for prediction, it can be used to infer underlying regulatory biology. For example, we show that the H3K4 di- and tri- methylation signals are strongly predictive for promoter location while the acetylation marks H3K9 and H3K27 are highly important in estimating the promoter usage. All of these four marks are found to be necessary for recruitment of RNAPII but not sufficient for the elongation. We also show that the spatial distributions of histone marks are almost as predictive as the signal strength and that a set of histone marks immediately downstream of the TSS is highly predictive of RNAPII stalling.

Conclusions: In this study we introduce a general framework to accurately predict the level of RNAPII recruitment, elongation, stalling and mRNA expression from chromatin signals. The versatility of the method also makes it ideally suited to investigate other genomic data.
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http://dx.doi.org/10.1186/1471-2164-12-544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228824PMC
November 2011

A BAC transgenic Hes1-EGFP reporter reveals novel expression domains in mouse embryos.

Gene Expr Patterns 2011 Oct 2;11(7):415-26. Epub 2011 Jul 2.

Department of Beta Cell Regeneration, Hagedorn Research Institute, Gentofte, Denmark.

Expression of the basic helix-loop-helix factor Hairy and Enhancer of Split-1 (Hes1) is required for normal development of a number of tissues during embryonic development. Depending on context, Hes1 may act as a Notch signalling effector which promotes the undifferentiated and proliferative state of progenitor cells, but increasing evidence also points to Notch independent regulation of Hes1 expression. Here we use high resolution confocal scanning of EGFP in a novel BAC transgenic mouse reporter line, Tg(Hes1-EGFP)(1Hri), to analyse Hes1 expression from embryonic day 7.0 (e7.0). Our data recapitulates some previous observations on Hes1 expression and suggests new, hitherto unrecognised expression domains including expression in the definitive endoderm at early somite stages before gut tube closure and thus preceding organogenesis. This mouse line will be a valuable tool for studies addressing the role of Hes1 in a number of different research areas including organ specification, development and regeneration.
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http://dx.doi.org/10.1016/j.gep.2011.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163761PMC
October 2011

MMSET is highly expressed and associated with aggressiveness in neuroblastoma.

Cancer Res 2011 Jun 28;71(12):4226-35. Epub 2011 Apr 28.

Biotech Research and Innovation Centre, University of Copenhagen, Denmark.

MMSET (WHSC1/NSD2) is a SET domain-containing histone lysine methyltransferase the expression of which is deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation associated with poor prognosis. Recent studies have shown that MMSET mRNA levels are increased in other tumor types as well. We have carried out immunohistochemical staining of tissue microarrays and found that MMSET protein is frequently and highly expressed in neuroblastoma (MMSET positive in 75% of neuroblastomas, n = 164). The expression level of MMSET in neuroblastomas was significantly associated with poor survival, negative prognostic factors, and metastatic disease. Moreover, a subset of neuroblastomas for which pre- and postchemotherapy biopsies were available displayed a strong decrease in MMSET protein levels after chemotherapy. In agreement with neuroblastomas becoming more differentiated after treatment, we show that retinoic acid-induced differentiation of human neuroblastoma cells in vitro also leads to a strong decrease in MMSET levels. Furthermore, we show that the high levels of MMSET in normal neural progenitor cells are strongly downregulated during differentiation. Importantly, we show that MMSET is required for proliferation of neuroblastoma cells and brain-derived neural stem cells. Taken together, our results suggest that MMSET is implicated in neuroblastomagenesis possibly by supporting proliferation of progenitor cells and negatively regulating their differentiation. In this respect, MMSET might be a strong candidate therapeutic target in a subset of neuroblastomas with unfavorable prognosis.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-3810DOI Listing
June 2011

Cross species comparison of C/EBPα and PPARγ profiles in mouse and human adipocytes reveals interdependent retention of binding sites.

BMC Genomics 2011 Mar 16;12:152. Epub 2011 Mar 16.

Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.

Background: The transcription factors peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) are key transcriptional regulators of adipocyte differentiation and function. We and others have previously shown that binding sites of these two transcription factors show a high degree of overlap and are associated with the majority of genes upregulated during differentiation of murine 3T3-L1 adipocytes.

Results: Here we have mapped all binding sites of C/EBPα and PPARγ in human SGBS adipocytes and compared these with the genome-wide profiles from mouse adipocytes to systematically investigate what biological features correlate with retention of sites in orthologous regions between mouse and human. Despite a limited interspecies retention of binding sites, several biological features make sites more likely to be retained. First, co-binding of PPARγ and C/EBPα in mouse is the most powerful predictor of retention of the corresponding binding sites in human. Second, vicinity to genes highly upregulated during adipogenesis significantly increases retention. Third, the presence of C/EBPα consensus sites correlate with retention of both factors, indicating that C/EBPα facilitates recruitment of PPARγ. Fourth, retention correlates with overall sequence conservation within the binding regions independent of C/EBPα and PPARγ sequence patterns, indicating that other transcription factors work cooperatively with these two key transcription factors.

Conclusions: This study provides a comprehensive and systematic analysis of what biological features impact on retention of binding sites between human and mouse. Specifically, we show that the binding of C/EBPα and PPARγ in adipocytes have evolved in a highly interdependent manner, indicating a significant cooperativity between these two transcription factors.
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http://dx.doi.org/10.1186/1471-2164-12-152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068983PMC
March 2011

The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors.

Clin Cancer Res 2011 May 8;17(9):2919-33. Epub 2011 Mar 8.

Biotech Research and Innovation Centre, Rigshospitalet, University of Copenhagen, Denmark.

Purpose: Multiple myeloma SET (Suppressor of variegation, Enhancer of zeste, and Trithorax) domain (MMSET) is a histone lysine methyltransferase deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation and poor prognosis. With the aim of understanding, if MMSET can be involved in other types of cancer we investigated the expression of MMSET protein in different types of human tumors.

Experimental Design: A monoclonal antibody against MMSET was developed and immunohistochemical staining of tissue microarrays (TMA) containing a large number of tumor samples (n = 3774) and corresponding normal tissues (n = 904) was carried out. Further validations of MMSET expression were carried out on independent, tumor-specific sets of TMAs for urinary bladder (n = 1293) and colon cancer (n = 1206) with corresponding clinicopathological data and long-term follow-up.

Results: MMSET protein was highly expressed in different tumor types compared to normal counterparts. Particular frequent and/or high MMSET expression was found in carcinomas of the gastrointestinal tract (stomach, colon, anal canal), small cell lung carcinoma, tumors of the urinary bladder, female genitals, and skin. In bladder cancer, MMSET expression correlated with tumor aggressiveness. In contrast, MMSET expression was associated with good prognostic factors in colon cancer and was more pronounced in early stages of colon carcinogenesis (dysplasias) than in adenocarcinomas. However, colon cancer patients with high MMSET levels showed a worse 5-year survival.

Conclusions: Our data suggest that MMSET has a broader role in cancer than previously anticipated, and further analysis might qualify it as a prognostic marker and a target for the development of therapy against several types of cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-1302DOI Listing
May 2011

Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase.

J Cell Biol 2010 Mar 1;188(5):629-38. Epub 2010 Mar 1.

Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen N, Denmark.

Maintenance of genome integrity is of critical importance to cells. To identify key regulators of genomic integrity, we screened a human cell line with a kinome small interfering RNA library. WEE1, a major regulator of mitotic entry, and CHK1 were among the genes identified. Both kinases are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single-stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC25A. Conversely, DNA damage after CHK1 inhibition is highly dependent on CDC25A. Furthermore, the inferior proliferation of CHK1-depleted cells is improved substantially by codepletion of CDC25A. We conclude that the mitotic kinase WEE1 and CHK1 jointly maintain balanced cellular control of Cdk activity during normal DNA replication, which is crucial to prevent the generation of harmful DNA lesions during replication.
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http://dx.doi.org/10.1083/jcb.200905059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835936PMC
March 2010

Invasive pneumococcal disease following treatment for choroid plexus carcinoma.

Support Care Cancer 2010 May 15;18(5):647-50. Epub 2010 Jan 15.

Department of Haematology/Oncology, Great Ormond Street Hospital, London WC1N 3JH, UK.

Introduction: A 13-month-old child was treated for choroid plexus carcinoma with partial embolisation, complete surgical excision and chemotherapy. The patient's course was complicated by the presence of chronic bilateral subdural collections.

Case Report: Four months from completing treatment, the child presented with an empyema in the subdural space caused by Streptococcus pneumoniae subtype 6A.

Discussion: The case highlights a number of questions about pneumococcal immunisation after standard chemotherapy. Evidence-based guidelines are required urgently to direct best practice.
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http://dx.doi.org/10.1007/s00520-009-0804-2DOI Listing
May 2010

Retinoic acid signaling organizes endodermal organ specification along the entire antero-posterior axis.

PLoS One 2009 Jun 10;4(6):e5845. Epub 2009 Jun 10.

Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

Background: Endoderm organ primordia become specified between gastrulation and gut tube folding in Amniotes. Although the requirement for RA signaling for the development of a few individual endoderm organs has been established a systematic assessment of its activity along the entire antero-posterior axis has not been performed in this germ layer.

Methodology/principal Findings: RA is synthesized from gastrulation to somitogenesis in the mesoderm that is close to the developing gut tube. In the branchial arch region specific levels of RA signaling control organ boundaries. The most anterior endoderm forming the thyroid gland is specified in the absence of RA signaling. Increasing RA in anterior branchial arches results in thyroid primordium repression and the induction of more posterior markers such as branchial arch Hox genes. Conversely reducing RA signaling shifts Hox genes posteriorly in endoderm. These results imply that RA acts as a caudalizing factor in a graded manner in pharyngeal endoderm. Posterior foregut and midgut organ primordia also require RA, but exposing endoderm to additional RA is not sufficient to expand these primordia anteriorly. We show that in chick, in contrast to non-Amniotes, RA signaling is not only necessary during gastrulation, but also throughout gut tube folding during somitogenesis. Our results show that the induction of CdxA, a midgut marker, and pancreas induction require direct RA signaling in endoderm. Moreover, communication between CdxA(+) cells is necessary to maintain CdxA expression, therefore synchronizing the cells of the midgut primordium. We further show that the RA pathway acts synergistically with FGF4 in endoderm patterning rather than mediating FGF4 activity.

Conclusions/significance: Our work establishes that retinoic acid (RA) signaling coordinates the position of different endoderm organs along the antero-posterior axis in chick embryos and could serve as a basis for the differentiation of specific endodermal organs from ES cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005845PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690404PMC
June 2009

Testing for 22q11 microdeletion in 146 fetuses with nuchal translucency above the 99th percentile and a normal karyotype.

Acta Obstet Gynecol Scand 2008 ;87(11):1252-5

Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.

The aim of this study was to examine the value of testing for a 22q11 microdeletion in fetuses with nuchal translucency (NT) above the 99th percentile (>3.5 mm). A 22q11 microdeletion results in the development of 22q11 deletion syndrome, a spectrum of disorders also known as DiGeorge/Velocardiofacial syndrome. A total of 146 pregnancies met the inclusion criteria of NT >3.5 mm between 11+2 and 13+6 weeks' gestation, no structural malformation and normal karyotype. Chorionic villi samples were tested with either multiplex ligation-dependent probe amplification (MLPA) or fluorescent in situ hybridization (FISH) analysis for 22q11 microdeletion. None were diagnosed with the microdeletion. The estimated prevalence of 22q11 microdeletion in these otherwise normal fetuses with increased NT is below 2.7%.
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http://dx.doi.org/10.1080/00016340802482994DOI Listing
December 2008

Specificity of four monoclonal anti-NKx6-1 antibodies.

J Histochem Cytochem 2008 Apr 22;56(4):415-24. Epub 2008 Jan 22.

Hagedorn Research Institute, Niels Steensensvej 6, DK-2820 Gentofte, Denmark.

The homeodomain transcription factor Nkx6-1 is essential for proper motor neuron development and development of insulin-producing pancreatic beta-cells. Nkx6-1 is closely related to Nkx6-2 and Nkx6-3, and all three are expressed in the developing central nervous system and in the developing foregut. Immunohistochemical detection of protein expression is an important tool for description of the temporal differences in expression patterns. When several gene family members like the Nkx6 factors have overlapping or juxtaposed expression domains, there is an elevated risk of unrecognized cross-reactivity, and it is therefore crucial to determine the specificities of antibodies against such targets. In this study we have determined the epitope consensus sequences of four monoclonal antibodies against Nkx6-1 using SPOT membranes, and we refined the results by combined peptide recognition and blocking assays. We show that two of the monoclonal anti-Nkx6-1 antibodies specifically recognize Nkx6-1 and do not cross-react to Nkx6-2 and Nkx6-3. The other two monoclonal anti-Nkx6-1 antibodies are specific to Nkx6-1 in mice but do not recognize Nkx6-1 in chicken and human.
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http://dx.doi.org/10.1369/jhc.7A7350.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2326102PMC
April 2008

An illustrated review of early pancreas development in the mouse.

Endocr Rev 2007 Oct 19;28(6):685-705. Epub 2007 Sep 19.

Hagedorn Research Institute, Department of Developmental Biology, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark.

Pancreas morphogenesis and cell differentiation are highly conserved among vertebrates during fetal development. The pancreas develops through simple budlike structures on the primitive gut tube to a highly branched organ containing many specialized cell types. This review presents an overview of key molecular components and important signaling sources illustrated by an extensive three-dimensional (3D) imaging of the developing mouse pancreas at single cell resolution. The 3D documentation covers the time window between embryonic days 8.5 and 14.5 in which all the pancreatic cell types become specified and therefore includes gene expression patterns of pancreatic endocrine hormones, exocrine gene products, and essential transcription factors. The 3D perspective provides valuable insight into how a complex organ like the pancreas is formed and a perception of ventral and dorsal pancreatic growth that is otherwise difficult to uncover. We further discuss how this global analysis of the developing pancreas confirms and extends previous studies, and we envisage that this type of analysis can be instrumental for evaluating mutant phenotypes in the future.
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http://dx.doi.org/10.1210/er.2007-0016DOI Listing
October 2007

An improved method for three-dimensional reconstruction of protein expression patterns in intact mouse and chicken embryos and organs.

J Histochem Cytochem 2007 Sep 3;55(9):925-30. Epub 2007 May 3.

Department of Developmental Biology, Hagedorn Research Institute, Gentofte, Denmark.

We have developed a wholemount immunofluorescence protocol for the simultaneous detection of up to three proteins in mouse and chicken embryos. Combined with Murray's clearing reagent (BABB) and microscope objectives with long working ranges and high numerical apertures mounted on a confocal microscope, cellular resolution can be obtained in depths offering the possibility of examining expression patterns in entire organs or embryos. Three-dimensional projections of the optical confocal sections can be computed with computer software allowing rotation around any axis. The protocol is robust and we find that most antibodies working on tissue sections also work with this protocol. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.
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http://dx.doi.org/10.1369/jhc.7A7226.2007DOI Listing
September 2007

Generation and characterization of monoclonal antibodies against the transcription factor Nkx6.1.

J Histochem Cytochem 2006 May 9;54(5):567-74. Epub 2006 Jan 9.

Antibody Core, Beta Cell Biology Consortium.

We present the generation of a panel of monoclonal antibodies (F55A10, F55A12, F64A6B4, and F65A2) against the homeodomain transcription factor Nkx6.1, one of the essential transcription factors that regulates the multistep differentiation process of precursor cells into endocrine beta-cells in the pancreas. Expression of Nkx6.1 can be detected in developing pancreatic epithelium and in adult insulin-producing beta-cells, making this transcription factor a unique beta-cell marker. For production of monoclonal antibodies, RBF mice were immunized with a GST-Nkx6.1 fusion protein containing a 66-amino acid C-terminal fragment of rat Nkx6.1. Four clones were established as stable hybridoma cell lines and the produced antibodies were of the mouse IgG1/kappa subtype. When applied for immunohistochemistry on frozen sections of adult mouse pancreas, monoclonal antibodies stain specifically the beta-cells in the endocrine islets of Langerhans with patterns comparable to that of a previously produced polyclonal rabbit serum. Monoclonal antibodies can be divided into two groups that appear to recognize different epitopes, as determined by competition ELISA. The presented antibodies are useful tools for the further characterization of the role and function of Nkx6.1 in pancreatic development, especially for use in double-labeling experiments with existing polyclonal rabbit antibodies.
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http://dx.doi.org/10.1369/jhc.5A6827.2006DOI Listing
May 2006