12403
2012
eng
379
13
article
1
2016-01-12
--
--
Treatment-independent miRNA signature in blood of wilms tumor patients
Background
Blood-born miRNA signatures have recently been reported for various tumor diseases. Here, we compared the miRNA signature in Wilms tumor patients prior and after preoperative chemotherapy according to SIOP protocol 2001.
Results
We did not find a significant difference between miRNA signature of both groups. However both, Wilms tumor patients prior and after chemotherapy showed a miRNA signature different from healthy controls. The signature of Wilms tumor patients prior to chemotherapy showed an accuracy of 97.5% and of patients after chemotherapy an accuracy of 97.0%, each as compared to healthy controls.
Conclusion
Our results provide evidence for a blood-born Wilms tumor miRNA signature largely independent of four weeks preoperative chemotherapy treatment.
BMC Genomics
10.1186/1471-2164-13-379
urn:nbn:de:bvb:20-opus-124034
BMC Genomics 2012, 13:379. doi:10.1186/1471-2164-13-379
Jana Schmitt
Christina Backes
Nasenien Nourkami-Tutdibi
Petra Leidinger
Stephanie Deutscher
Markus Beier
Manfred Gessler
Norbert Graf
Hans-Peter Lenhof
Andreas Keller
Eckart Meese
eng
uncontrolled
miRNA
Menschliche Anatomie, Zytologie, Histologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12403/Schmitt_10.1186_1471-2164-13-379.pdf
15830
2017
eng
234–248
3
article
1
2018-03-01
--
--
TP53 alterations in Wilms tumour represent progression events with strong intratumour heterogeneity that are closely linked but not limited to anaplasia
TP53 mutations have been associated with anaplasia in Wilms tumour, which conveys a high risk for relapse and fatal outcome. Nevertheless, TP53 alterations have been reported in no more than 60% of anaplastic tumours, and recent data have suggested their presence in tumours that do not fulfil the criteria for anaplasia, questioning the clinical utility of TP53 analysis. Therefore, we characterized the TP53 status in 84 fatal cases of Wilms tumour, irrespective of histological subtype. We identified TP53 alterations in at least 90% of fatal cases of anaplastic Wilms tumour, and even more when diffuse anaplasia was present, indicating a very strong if not absolute coupling between anaplasia and deregulation of p53 function. Unfortunately, TP53 mutations do not provide additional predictive value in anaplastic tumours since the same mutation rate was found in a cohort of non-fatal anaplastic tumours. When classified according to tumour stage, patients with stage I diffuse anaplastic tumours still had a high chance of survival (87%), but this rate dropped to 26% for stages II–IV. Thus, volume of anaplasia or possible spread may turn out to be critical parameters. Importantly, among non-anaplastic fatal tumours, 26% had TP53 alterations, indicating that TP53 screening may identify additional cases at risk. Several of these non-anaplastic tumours fulfilled some criteria for anaplasia, for example nuclear unrest, suggesting that such partial phenotypes should be under special scrutiny to enhance detection of high-risk tumours via TP53 screening. A major drawback is that these alterations are secondary changes that occur only later in tumour development, leading to striking intratumour heterogeneity that requires multiple biopsies and analysis guided by histological criteria. In conclusion, we found a very close correlation between histological signs of anaplasia and TP53 alterations. The latter may precede development of anaplasia and thereby provide diagnostic value pointing towards aggressive disease.
The Journal of Pathology: Clinical Research
10.1002/cjp2.77
urn:nbn:de:bvb:20-opus-158302
The Journal of Pathology: Clinical Research 3: 234–248 (2017). DOI: 10.1002/cjp2.77
CC BY-NC: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell 4.0 International
Jenny Wegert
Christian Vokuh
Barbara Ziegler
Karen Ernestus
Ivo Leuschner
Rhoikos Furtwängler
Norbert Graf
Manfred Gessler
eng
uncontrolled
tumour heterogeneity
eng
uncontrolled
Wilms tumour
eng
uncontrolled
nephroblastoma
eng
uncontrolled
anaplasia
eng
uncontrolled
TP53
Medizin und Gesundheit
open_access
Pathologisches Institut
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2017
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/15830/Wegert_The_Journal_of_Pathology_Clinical_Research.pdf
5003
1992
eng
article
1
2011-08-23
--
--
The potassium channel gene HK1 maps to human chromosome 11p14.1, close to the FSHB gene
Transiently activating (A-type) potassium (K) channels are important regulators of action potential and action potential firing frequencies. HK1 designates the firsthuman cDNA that is highly homologous to the rat RCK4 cDNA that codes for an A-type K-channel. The HK1 channel is expressed in heart. By somatic cell hybrid analysis, the HK1 gene has been assigned to human chromosome 11p13-pl4, the WAGR deletion region (Wilms tumor, aniridia, genito-urinary abnormalities and mental retardation). Subsequent pulsed field gel (PFG) analysis and comparison with the well-established PFG map of this region localized the gene to 11p14, 200-600 kb telomeric to the FSHB gene.
urn:nbn:de:bvb:20-opus-59184
5918
In: Human Genetics (1992) 90, S. 319 - 321.
Deutsches Urheberrecht
Manfred Gessler
Andrew Grupe
Karl-Heinz Grzeschik
Olaf Pongs
deu
swd
Biochemie
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/5003/Gessler11.pdf
5014
1990
eng
article
1
2011-08-24
--
--
The human MyoD1 (MYF3) gene maps on the short arm of chromosome 11 but is not associated with the WAGR locus or the region for the Beckwith-Wiedemann syndrome
The human gene encoding the myogenic determination factor myf3 (mouse MyoD1) has been mapped to the short arm of chromosome 11. Analysis of several somatic cell hybrids containing various derivatives with deletions or translocations revealed that the human MyoD (MYF3) gene is not associated with the WAGR locus at chromosomal band 11pl3 nor with the loss of the heterozygosity region at 11p15.5 related to the Beckwith-Wiedemann syndrome. Subregional mapping by in situ hybridization with an myf3 specific probe shows that the gene resides at the chromosomal band llp14, possibly at llp14.3.
urn:nbn:de:bvb:20-opus-59221
5922
In: Human Genetics (1990) 86, S. 135 - 138.
Deutsches Urheberrecht
Manfred Gessler
H. Hameister
I. Henry
C. Junien
T. Braun
H. H. Arnold
deu
swd
Biochemie
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/5014/Gessler17.pdf
5004
1992
eng
article
1
2011-08-23
--
--
The genomic organization and expression of the WT1 gene
The Wilms tumor gene WTl, a proposed tumor suppressor gene, has been identifled based on its location within a homozygous deletion found in tumor tissue. The gene encodes a putative transcription factor containing a Cys/His zinc finger domain. The critical homozygous deletions, however, are rarely seen, suggesting that in many cases the gene may be inactivated by more subtle alterations. To facilitate the seareh for smaller deletions and point mutations we have established the genomic organization of the WTl gene and have determined the sequence of all 10 exons and flanking intron DNA. The pattern of alternative splicing in two regions has been characterized in detail. These results will form the basis for future studies of mutant alleles at this locus.
urn:nbn:de:bvb:20-opus-59195
5919
In: Genomics (1992) 12, S. 807 - 813.
Deutsches Urheberrecht
Manfred Gessler
A. König
G. A. P. Bruns
deu
swd
Biochemie
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/5004/Gessler12.pdf
6501
2012
eng
article
1
2013-03-25
--
--
Target Gene Analysis by Microarrays and Chromatin Immunoprecipitation Identifies HEY Proteins as Highly Redundant bHLH Repressors
HEY bHLH transcription factors have been shown to regulate multiple key steps in cardiovascular development. They can be induced by activated NOTCH receptors, but other upstream stimuli mediated by TGFß and BMP receptors may elicit a similar response. While the basic and helix-loop-helix domains exhibit strong similarity, large parts of the proteins are still unique and may serve divergent functions. The striking overlap of cardiac defects in HEY2 and combined HEY1/HEYL knockout mice suggested that all three HEY genes fulfill overlapping function in target cells. We therefore sought to identify target genes for HEY proteins by microarray expression and ChIPseq analyses in HEK293 cells, cardiomyocytes, and murine hearts. HEY proteins were found to modulate expression of their target gene to a rather limited extent, but with striking functional interchangeability between HEY factors. Chromatin immunoprecipitation revealed a much greater number of potential binding sites that again largely overlap between HEY factors. Binding sites are clustered in the proximal promoter region especially of transcriptional regulators or developmental control genes. Multiple lines of evidence suggest that HEY proteins primarily act as direct transcriptional repressors, while gene activation seems to be due to secondary or indirect effects. Mutagenesis of putative DNA binding residues supports the notion of direct DNA binding. While class B E-box sequences (CACGYG) clearly represent preferred target sequences, there must be additional and more loosely defined modes of DNA binding since many of the target promoters that are efficiently bound by HEY proteins do not contain an Ebox motif. These data clearly establish the three HEY bHLH factors as highly redundant transcriptional repressors in vitro and in vivo, which explains the combinatorial action observed in different tissues with overlapping expression.
urn:nbn:de:bvb:20-opus-75341
7534
In: PLoS Genetics (2012) 8: 5, doi:10.1371/journal.pgen.1002728
Julia Heisig
David Weber
Eva Englberger
Anja Winkler
Susanne Kneitz
Wing-Kin Sung
Elmar Wolf
Martin Eilers
Chia-Lin Wei
Manfred Gessler
deu
swd
Biologie
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2012
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6501/026_journal.pgen.1002728.pdf
5015
1990
eng
article
1
2011-08-24
--
--
Role for the Wilms tumor gene in genital development?
No abstract available
urn:nbn:de:bvb:20-opus-59238
5923
In: Proceedings of the National Academy of Sciences of the United States of America (1990) 87, S. 5383 - 5386.
Deutsches Urheberrecht
V. van Heyningen
W. A. Bickmore
A. Seawright
J. M. Fletcher
J. Maule
G. Fekete
Manfred Gessler
G. A. Bruns
C. Huerre-Jeanpierre
C. Junien
deu
swd
Biochemie
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/5015/Gessler19.pdf
6292
2011
eng
article
1
2012-11-26
--
--
Retinoic acid pathway activity in Wilms tumors and characterization of biological responses in vitro
Background: Wilms tumor (WT) is one of the most common malignancies in childhood. With current therapy protocols up to 90% of patients can be cured, but there is still a need to improve therapy for patients with aggressive WT and to reduce treatment intensity where possible. Prior data suggested a deregulation of the retinoic acid (RA) signaling pathway in high-risk WT, but its mode of action remained unclear. Results: The association of retinoid signaling and clinical parameters could be validated in a large independent tumor set, but its relevance in primary nephrectomy tumors from very young children may be different. Reduced RA pathway activity and MYCN overexpression were found in high risk tumors as opposed to tumors with low/ intermediate risk, suggesting a beneficial impact of RA especially on advanced WT. To search for possible modes of action of retinoids as novel therapeutic options, primary tumor cell cultures were treated in vitro with all-trans-RA (ATRA), 9cis-RA, fenretinide and combinations of retinoids and a histone deacetylase (HDAC) inhibitor. Genes deregulated in high risk tumors showed opposite changes upon treatment suggesting a positive effect of retinoids. 6/7 primary cultures tested reduced proliferation, irrespective of prior RA signaling levels. The only variant culture was derived from mesoblastic nephroma, a distinct childhood kidney neoplasm. Retinoid/HDAC inhibitor combinations provided no synergistic effect. ATRA and 9cis-RA induced morphological changes suggestive of differentiation, while fenretinide induced apoptosis in several cultures tested. Microarray analysis of ATRA treated WT cells revealed differential expression of many genes involved in extracellular matrix formation and osteogenic, neuronal or muscle differentiation. The effects documented appear to be reversible upon drug withdrawal, however. Conclusions: Altered retinoic acid signaling has been validated especially in high risk Wilms tumors. In vitro testing of primary tumor cultures provided clear evidence of a potential utility of retinoids in Wilms tumor treatment based on the analysis of gene expression, proliferation, differentiation and apoptosis.
urn:nbn:de:bvb:20-opus-69137
6913
In: Molecular Cancer (2011) 10:136, doi:10.1186/1476-4598-10-136
Jenny Wegert
Sabrina Bausenwein
Susanne Kneitz
Sabine Roth
Norbert Graf
Eva Geissinger
Manfred Gessler
deu
swd
Krebs
eng
uncontrolled
Wilms tumor
eng
uncontrolled
nephroblastoma
eng
uncontrolled
primary tumor cell culture
eng
uncontrolled
tumor model
eng
uncontrolled
retinoic acid
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2011
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6292/Gessler138_1476_4598_10_136.pdf
13349
2012
eng
e1002577
3
8
article
1
2016-05-13
--
--
Physiological Notch Signaling Maintains Bone Homeostasis via RBPjk and Hey Upstream of NFATc1
Notch signaling between neighboring cells controls many cell fate decisions in metazoans both during embryogenesis and in postnatal life. Previously, we uncovered a critical role for physiological Notch signaling in suppressing osteoblast differentiation in vivo. However, the contribution of individual Notch receptors and the downstream signaling mechanism have not been elucidated. Here we report that removal of Notch2, but not Notch1, from the embryonic limb mesenchyme markedly increased trabecular bone mass in adolescent mice. Deletion of the transcription factor RBPjk, a mediator of all canonical Notch signaling, in the mesenchymal progenitors but not the more mature osteoblast-lineage cells, caused a dramatic high-bone-mass phenotype characterized by increased osteoblast numbers, diminished bone marrow mesenchymal progenitor pool, and rapid age-dependent bone loss. Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass. Interestingly, Hey1 bound to and suppressed the NFATc1 promoter, and RBPjk deletion increased NFATc1 expression in bone. Finally, pharmacological inhibition of NFAT alleviated the high-bone-mass phenotype caused by RBPjk deletion. Thus, Notch-RBPjk signaling functions in part through Hey1-mediated inhibition of NFATc1 to suppress osteoblastogenesis, contributing to bone homeostasis in vivo.
PLoS Genetics
10.1371/journal.pgen.1002577
urn:nbn:de:bvb:20-opus-133490
PLoS Genetics 8(3): e1002577. doi:10.1371/journal.pgen.1002577
Xiaolin Tu
Jianquan Chen
Joohyun Lim
Courtney M. Karner
Seung-Yon Lee
Julia Heisig
Cornelia Wiese
Kameswaran Surendran
Raphael Kopan
Manfred Gessler
Fanxin Long
eng
uncontrolled
expression
eng
uncontrolled
axial skeletal defects
eng
uncontrolled
transcription factor
eng
uncontrolled
alagille syndrome
eng
uncontrolled
osteoblast differentiation
eng
uncontrolled
human jagged1
eng
uncontrolled
aortic-valve
eng
uncontrolled
T cells
eng
uncontrolled
mutations
eng
uncontrolled
mice
Menschliche Anatomie, Zytologie, Histologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13349/Tu_PLoS_2012.pdf
4994
1993
eng
article
1
2011-08-19
--
--
Pericentric intrachromosomal insertion responsible for recurrence of del(11)(p13p14) in a family
The combined use of qualitative and quantitative analysis of I I p I 3 polymorphic markers tagether with chromosomal in situ suppression hybridization (CISS) with biotin labeled probes mapping to I I p allowed us to characterize a complex rearrangement segregating in a family. We detected a pericentric intrachromosomal insertion responsible (or recurrence of del( I I )(p 13p 14) in the family: an insertion of band I I p 13-p 14 carrying the genes for predisposition to Wilms' tumor, WT I, and for aniridia, AN2, into the long arm of chromosome I I in II q 13-q 1<4. Asymptomatic balanced carriers were observed over three generations. Classical cytogenetics had failed to detect this anomaly in the balanced carriers, who were first considered to be somatic mosaics for del( II )(p 13). Two of these women gave birth to children carrying a deleted chromosome II. most likely resulting from the loss of the I I p 13 band inserted in I I q. Although in both cases the deletion encompassed exactly the same maternally inherited markers, there was a wide Variation in clinical expression. One child, with the karyotype 46,XY,del(ll)(pllpl4), presented the full-blown WAGR syndrome with anlridia, mental retardation, Wilms' tumor, and pseudohermaphroditism, but also had proteinuria and glomerular sclerosis reminiscent of Drash syndrome. In contrast, the other one, a girl with the karyotype 46,XX,del( I I )(p I 3), only had aniridia. Although a specific set of mutational sites has been observed in Drash patients, these findings suggest that the loss of one copy of the WTI gene can result in similar genital and kidney abnormalities.
urn:nbn:de:bvb:20-opus-59157
5915
In: Genes Chromosomes & Cancer (1993) 7, S. 57 - 62.
Deutsches Urheberrecht
Isabelle Henry
Jan Hoovers
Fernande Barichard
Marie-Francoise Berthéas
Anne Puech
Fabienne Prieur
Manfred Gessler
Gail Bruns
Marcel Mannens
Claudine Junien
deu
swd
Biochemie
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/4994/Gessler08.pdf