45 results on '"Javerzat, S"'
Search Results
2. Application of X-ray/Infrared multimodal imaging on nanoparticles in glioma research: S11-2
- Author
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Petibois, C., Bobroff, V., Travo, A., Chen, H.-H., Javerzat, S., and Hwu, Y.
- Published
- 2014
3. HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism
- Author
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Mottet, D, Pirotte, S, Lamour, V, Hagedorn, M, Javerzat, S, Bikfalvi, A, Bellahcène, A, Verdin, E, and Castronovo, V
- Published
- 2009
- Full Text
- View/download PDF
4. The Future of Infrared Spectroscopy in Biosciences: In Vitro, Time-Resolved, and 3D
- Author
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Chen, Hsiang-Hsin, primary, Bobroff, V., additional, Delugin, M., additional, Pineau, R., additional, Noreen, Razia, additional, Seydou, Yao, additional, Banerjee, S., additional, Chatterjee, J., additional, Javerzat, S., additional, and Petibois, C., additional
- Published
- 2016
- Full Text
- View/download PDF
5. Effect of human skin-derived stem cells on vessel architecture, tumor growth, and tumor invasion in brain tumor animal models
- Author
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Pisati, F, Belicchi, M, Acerbi, F, Marchesi, C, Giussani, C, Gavina, M, Javerzat, S, Hagedorn, M, Carrabba, G, Lucini, V, Gaini, S, Bresolin, N, Bello, L, Bikfalvi, A, Torrente, Y, Gaini, SM, Torrente, Y., GIUSSANI, CARLO GIORGIO, Pisati, F, Belicchi, M, Acerbi, F, Marchesi, C, Giussani, C, Gavina, M, Javerzat, S, Hagedorn, M, Carrabba, G, Lucini, V, Gaini, S, Bresolin, N, Bello, L, Bikfalvi, A, Torrente, Y, Gaini, SM, Torrente, Y., and GIUSSANI, CARLO GIORGIO
- Abstract
Glioblastomas represent an important cause of cancer-related mortality with poor survival. Despite many advances, the mean survival time has not significantly improved in the last decades. New experimental approaches have shown tumor regression after the grafting of neural stem cells and human mesenchymal stem cells into experimental intracranial gliomas of adult rodents. However, the cell source seems to be an important limitation for autologous transplantation in glioblastoma. In the present study, we evaluated the tumor targeting and antitumor activity of human skin-derived stem cells (hSDSCs) in human brain tumor models. The hSDSCs exhibit tumor targeting characteristics in vivo when injected into the controlateral hemisphere or into the tail vein of mice. When implanted directly into glioblastomas, hSDSCs distributed themselves extensively throughout the tumor mass, reduced tumor vessel density, and decreased angiogenic sprouts. In addition, transplanted hSDSCs differentiate into pericyte cell and release high amounts of human transforming growth factor-beta1 with low expression of vascular endothelial growth factor, which may contribute to the decreased tumor cell invasion and number of tumor vessels. In long-term experiments, the hSDSCs were also able to significantly inhibit tumor growth and to prolong animal survival. Similar behavior was seen when hSDSCs were implanted into two different tumor models, the chicken embryo experimental glioma model and the transgenic Tyrp1-Tag mice. Taken together, these data validate the use of hSDSCs for targeting human brain tumors. They may represent therapeutically effective cells for the treatment of intracranial tumors after autologous transplantation
- Published
- 2007
6. The Future of Infrared Spectroscopy in Biosciences: In Vitro, Time-Resolved, and 3D.
- Author
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HSIANG-HSIN CHEN, BOBROFF, V., DELUGIN, M., PINEAU, R., NOREEN, RAZIA, YAO SEYDOU, BANERJEE, S., CHATTERJEE, J., JAVERZAT, S., and PETIBOIS, C.
- Subjects
INFRARED spectroscopy ,LIFE sciences ,MICROSCOPY ,BIOCHEMISTRY ,SPATIAL systems - Abstract
Infrared (IR) spectroscopy is at the cross-roads, with the requirement to compete with cutting-edge technologies in biosciences, mostly based on analytical performances dealing with the super-resolutions: time, lateral/ spatial, and contrast. IR microscopy is diffraction limited in most cases, thus not accessing to high lateral/ spatial resolutions. Additionally, it has a poor signal-to-noise ratio on a single scan, thus requiring long-lasting acquisitions that are not suitable to analyze ns-lasting biochemical events. However, it is unique because it provides a broad global chemical information of the sample contents. It is also unique because it does not require heavy sample preparation nor labeling and can be coupled to other techniques (multimodality). Finally, it is again unique because it provides quantitative measurements, thus suitable for 1D to 4D data exploitation procedures. This short review shows that IR spectroscopy will be certainly subjected to a second century of innovations, maintaining its influence in the panorama of cutting-edge analytical techniques. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
7. Studio di inibitori endogeni di angiogenesi in un modello murino transgenico di tumore cerebrale.
- Author
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Colleoni, F, Pisati, F, Carrabba, G, Giussani, C, Acerbi, F, Bertani, G, Lucini, V, Pannacci, M, Scaglione, F, Pineau, R, Javerzat, S, Bikfalvi, A, Torrente, Y, Bello, L, Colleoni, F, Pisati, F, Carrabba, G, Giussani, C, Acerbi, F, Bertani, G, Lucini, V, Pannacci, M, Scaglione, F, Pineau, R, Javerzat, S, Bikfalvi, A, Torrente, Y, and Bello, L
- Published
- 2006
8. The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression
- Author
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Bernard, H, primary, Garmy-Susini, B, additional, Ainaoui, N, additional, Van Den Berghe, L, additional, Peurichard, A, additional, Javerzat, S, additional, Bikfalvi, A, additional, Lane, D P, additional, Bourdon, J C, additional, and Prats, A-C, additional
- Published
- 2012
- Full Text
- View/download PDF
9. R27: Rôles des kinésines mitotiques dans l’angiogenèse physiologique et tumorale
- Author
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Exertier, P., primary, Javerzat, S., additional, Wang, B., additional, Franco, M., additional, Herbert, J., additional, Winandy, M., additional, Bikfalvi, A., additional, Wilting, J., additional, and Hagedorn, M., additional
- Published
- 2010
- Full Text
- View/download PDF
10. HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism
- Author
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Mottet, D, primary, Pirotte, S, additional, Lamour, V, additional, Hagedorn, M, additional, Javerzat, S, additional, Bikfalvi, A, additional, Bellahcène, A, additional, Verdin, E, additional, and Castronovo, V, additional
- Published
- 2008
- Full Text
- View/download PDF
11. HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism.
- Author
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Mottet, D, Pirotte, S, Lamour, V, Hagedorn, M, Javerzat, S, Bikfalvi, A, Bellahcène, A, Verdin, E, and Castronovo, V
- Subjects
CANCER cells ,HISTONE deacetylase ,RNA ,ACETYLATION ,TUMORS - Abstract
Cancer cells have complex, unique characteristics that distinguish them from normal cells, such as increased growth rates and evasion of anti-proliferative signals. Global inhibition of class I and II histone deacetylases (HDACs) stops cancer cell proliferation in vitro and has proven effective against cancer in clinical trials, at least in part, through transcriptional reactivation of the p21
WAF1/Cip1 gene. The HDACs that regulate p21WAF1/Cip1 are not fully identified. Using small interfering RNAs, we found that HDAC4 participates in the repression of p21WAF1/Cip1 through Sp1/Sp3-, but not p53-binding sites. HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21WAF1/Cip1 proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21WAF1/Cip1 . Induction of p21WAF1/Cip1 mediated by silencing of HDAC4 arrested cancer cell growth in vitro and inhibited tumor growth in an in vivo human glioblastoma model. Thus, HDAC4 could be a useful target for new anti-cancer therapies based on selective inhibition of specific HDACs.Oncogene (2009) 28, 243–256; doi:10.1038/onc.2008.371; published online 13 October 2008 [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
- View/download PDF
12. The tyrp1-Tag/tyrp1-FGFR1-DN bigenic mouse: a model for selective inhibition of tumor development, angiogenesis, and invasion into the neural tissue by blockade of fibroblast growth factor receptor activity
- Author
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Rousseau, B., Larrieu-Lahargue, F., Javerzat, S., Guilhem-Ducleon, F., Beermann, F., and Bikfalvi, A.
- Abstract
We describe herein a new transgenic mouse tumor model in which fibroblast growth factor (FGF) receptor activity is selectively inhibited. Tyrp1-Tag mice that develop early vascularized tumors of the retinal pigment epithelium were crossed with tyrp1-FGFR1-DN mice that express dominant-negative FGF receptors in the retinal pigment epithelium to generate bigenic mice. Initial angiogenesis-independent tumor growth progressed equally in tyrp1-Tag and bigenic mice with no significant differences in the number of dividing and apoptotic cells within the tumor. By contrast, at a later stage when tyrp1-Tag tumors rapidly expanded to fill the entire eye posterior chamber and migrate along the optic nerve toward the chiasma, bigenic tumors remained small and were poorly vascularized. Secondary tumors of small size developed in only 20% of bigenic mice by 1 month. Immunohistochemical analysis of secondary tumors from bigenic mice showed a reduction of angiogenesis and an increase in apoptosis in tumor cells. Tumor cells from bigenic mice expressed high levels of truncated FGF receptors and did not induce endothelial tube formation in vitro. All in all, this indicates that the tyrp1-Tag mouse may be a useful model to study selective tumor inhibition and the effect of antitumor therapy that targets a specific growth factor pathway. FGF receptors are required at the onset of tumor invasion and angiogenesis in ocular tumors and are good therapeutic targets in this model. The bigenic mouse may also constitute a useful model to answer more fundamental questions of cancer biology such as the mechanism of tumor escape.
13. R29 - Oral, Club Mex-H Expression de nouveaux gènes endothéliaux dans les tumeurs humaines et corrélations cliniques
- Author
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Javerzat, S., Bikfalvi, A., and Hagedorn
- Published
- 2010
- Full Text
- View/download PDF
14. Effect of Human Skin-Derived Stem Cells on Vessel Architecture, Tumor Growth, and Tumor Invasion in Brain Tumor Animal Models
- Author
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Sergio M. Gaini, Carlo Giussani, Lorenzo Bello, Giorgio Carrabba, Yvan Torrente, Valeria Lucini, Francesco Acerbi, Marzia Belicchi, Andreas Bikfalvi, Federica Pisati, Nereo Bresolin, C. Marchesi, Martin Hagedorn, Sophie Javerzat, M. Gavina, Pisati, F, Belicchi, M, Acerbi, F, Marchesi, C, Giussani, C, Gavina, M, Javerzat, S, Hagedorn, M, Carrabba, G, Lucini, V, Gaini, S, Bresolin, N, Bello, L, Bikfalvi, A, and Torrente, Y
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Human Skin-Derived Stem Cell ,Brain tumor ,Mice, Nude ,Mice, Transgenic ,Cell Growth Processes ,Chick Embryo ,Biology ,Chorioallantoic Membrane ,Transforming Growth Factor beta1 ,Mice ,chemistry.chemical_compound ,Cell Line, Tumor ,Brain Tumor ,Glioma ,medicine ,Animals ,Humans ,Autologous transplantation ,Neoplasm Invasiveness ,Skin ,Neovascularization, Pathologic ,Brain Neoplasms ,Stem Cells ,Mesenchymal stem cell ,medicine.disease ,Xenograft Model Antitumor Assays ,Neural stem cell ,Vascular endothelial growth factor ,medicine.anatomical_structure ,Oncology ,chemistry ,Pericyte ,Stem cell ,Glioblastoma ,Stem Cell Transplantation - Abstract
Glioblastomas represent an important cause of cancer-related mortality with poor survival. Despite many advances, the mean survival time has not significantly improved in the last decades. New experimental approaches have shown tumor regression after the grafting of neural stem cells and human mesenchymal stem cells into experimental intracranial gliomas of adult rodents. However, the cell source seems to be an important limitation for autologous transplantation in glioblastoma. In the present study, we evaluated the tumor targeting and antitumor activity of human skin-derived stem cells (hSDSCs) in human brain tumor models. The hSDSCs exhibit tumor targeting characteristics in vivo when injected into the controlateral hemisphere or into the tail vein of mice. When implanted directly into glioblastomas, hSDSCs distributed themselves extensively throughout the tumor mass, reduced tumor vessel density, and decreased angiogenic sprouts. In addition, transplanted hSDSCs differentiate into pericyte cell and release high amounts of human transforming growth factor-β1 with low expression of vascular endothelial growth factor, which may contribute to the decreased tumor cell invasion and number of tumor vessels. In long-term experiments, the hSDSCs were also able to significantly inhibit tumor growth and to prolong animal survival. Similar behavior was seen when hSDSCs were implanted into two different tumor models, the chicken embryo experimental glioma model and the transgenic Tyrp1-Tag mice. Taken together, these data validate the use of hSDSCs for targeting human brain tumors. They may represent therapeutically effective cells for the treatment of intracranial tumors after autologous transplantation. [Cancer Res 2007;67(7):3054–63]
- Published
- 2007
15. Functional Characterization of Splice Variants in the Diagnosis of Albinism.
- Author
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Diallo M, Courdier C, Mercier E, Sequeira A, Defay-Stinat A, Plaisant C, Mesdaghi S, Rigden D, Javerzat S, Lasseaux E, Bourgeade L, Audebert-Bellanger S, Dollfus H, Hadj-Rabia S, Morice-Picard F, Philibert M, Sidibé MK, Smirnov V, Sylla O, Michaud V, and Arveiler B
- Subjects
- Humans, Female, RNA Splicing, Male, Alternative Splicing genetics, Mutation, Heterozygote, Introns genetics, Exons genetics, Albinism genetics, Albinism diagnosis
- Abstract
Albinism is a genetically heterogeneous disease in which 21 genes are known so far. Its inheritance mode is autosomal recessive except for one X-linked form. The molecular analysis of exonic sequences of these genes allows for about a 70% diagnostic rate. About half (15%) of the unsolved cases are heterozygous for one pathogenic or probably pathogenic variant. Assuming that the missing variant may be located in non-coding regions, we performed sequencing for 122 such heterozygous patients of either the whole genome (27 patients) or our NGS panel (95 patients) that includes, in addition to all exons of the 21 genes, the introns and flanking sequences of five genes, TYR , OCA2 , SLC45A2 , GPR143 and HPS1 . Rare variants (MAF < 0.01) in trans to the first variant were tested by RT-PCR and/or minigene assay. Of the 14 variants tested, nine caused either exon skipping or the inclusion of a pseudoexon, allowing for the diagnosis of 11 patients. This represents 9.8% (12/122) supplementary diagnosis for formerly unsolved patients and 75% (12/16) of those in whom the candidate variant was in trans to the first variant. Of note, one missense variant was demonstrated to cause skipping of the exon in which it is located, thus shedding new light on its pathogenic mechanism. Searching for non-coding variants and testing them for an effect on RNA splicing is warranted in order to increase the diagnostic rate.
- Published
- 2024
- Full Text
- View/download PDF
16. Genotypic spectrum of albinism in Mali.
- Author
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Diallo M, Sylla O, Sidibé MK, Plaisant C, Mercier E, Sequeira A, Javerzat S, Hadid A, Lasseaux E, Michaud V, and Arveiler B
- Abstract
Albinism is a phenotypically and genetically heterogeneous condition characterized by a variable degree of hypopigmentation and by ocular features leading to reduced visual acuity. Whereas numerous genotypic studies have been conducted throughout the world, very little is known about the genotypic spectrum of albinism in Africa and especially in sub-Saharan Western Africa. Here we report the analysis of all known albinism genes in a series a 23 patients originating from Mali. Four were diagnosed with OCA 1 (oculocutaneous albinism type 1), 17 with OCA 2, and two with OCA 4. OCA2 variant NM_000275.3:c.819_822delinsGGTC was most frequently encountered. Four novel variants were identified (two in TYR, two in OCA2). A deep intronic variant was found to alter splicing of the OCA2 RNA by inclusion of a pseudo exon. Of note, the OCA2 exon 7 deletion commonly found in eastern, central, and southern Africa was absent from this series. African patients with OCA 1 and OCA 4 had only been reported twice and once, respectively, in previous publications. This study constitutes the first report of the genotypic spectrum of albinism in a western sub-Saharan country., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2024
- Full Text
- View/download PDF
17. A multilayered approach to the analysis of genetic data from individuals with suspected albinism.
- Author
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Sergouniotis PI, Michaud V, Lasseaux E, Campbell C, Plaisant C, Javerzat S, Birney E, Ramsden SC, Black GC, and Arveiler B
- Subjects
- Humans, Genetic Testing, Genotype, Alleles, Albinism genetics, Albinism diagnosis, Albinism, Oculocutaneous diagnosis, Albinism, Oculocutaneous genetics
- Abstract
Albinism is a clinically and genetically heterogeneous group of conditions characterised by visual abnormalities and variable degrees of hypopigmentation. Multiple studies have demonstrated the clinical utility of genetic investigations in individuals with suspected albinism. Despite this, the variation in the provision of genetic testing for albinism remains significant. One key issue is the lack of a standardised approach to the analysis of genomic data from affected individuals. For example, there is variation in how different clinical genetic laboratories approach genotypes that involve incompletely penetrant alleles, including the common, 'hypomorphic' TYR c.1205G>A (p.Arg402Gln) [rs1126809] variant. Here, we discuss the value of genetic testing as a frontline diagnostic tool in individuals with features of albinism and propose a practice pattern for the analysis of genomic data from affected families., Competing Interests: Competing interests: EB is a paid consultant and equity holder of Oxford Nanopore, a paid consultant to Dovetail, and a non-executive director of Genomics England, a limited company wholly owned by the UK Department of Health and Social Care. All other authors declare no competing interests. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2023
- Full Text
- View/download PDF
18. Unsuspected consequences of synonymous and missense variants in OCA2 can be detected in blood cell RNA samples of patients with albinism.
- Author
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Michaud V, Sequeira A, Mercier E, Lasseaux E, Plaisant C, Hadj-Rabia S, Whalen S, Bonneau D, Dieux-Coeslier A, Morice-Picard F, Coursimault J, Arveiler B, and Javerzat S
- Abstract
Oculocutaneous albinism type 2 (OCA2) is the second most frequent form of albinism and represents about 30% of OCA worldwide. As with all types of OCA, patients present with hypopigmentation of hair and skin, as well as severe visual abnormalities. We focused on a subgroup of 29 patients for whom genetic diagnosis was pending because at least one of their identified variants in or around exon 10 of OCA2 is of uncertain significance (VUS). By minigene assay, we investigated the effect of these VUS on exon 10 skipping and showed that not only intronic but also some synonymous variants can result in enhanced exon skipping. We further found that excessive skipping of exon 10 could be detected directly on blood samples of patients and of their one parent with the causal variant, avoiding invasive skin biopsies. Moreover, we show that variants, which result in lack of detectable OCA2 mRNA can be identified from blood samples as well, as shown for the most common OCA2 pathogenic missense variant c.1327G>A/p.(Val443Ile). In conclusion, blood cell RNA analysis allows testing the potential effect of any OCA2 VUS on transcription products. This should help to elucidate yet unsolved OCA2 patients and improve genetic counseling., (© 2023 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
19. The Dct -/- Mouse Model to Unravel Retinogenesis Misregulation in Patients with Albinism.
- Author
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Tingaud-Sequeira A, Mercier E, Michaud V, Pinson B, Gazova I, Gontier E, Decoeur F, McKie L, Jackson IJ, Arveiler B, and Javerzat S
- Subjects
- Animals, Disease Models, Animal, Humans, Intramolecular Oxidoreductases, Levodopa, Melanosomes, Mice, Monophenol Monooxygenase genetics, Albinism genetics, Albinism, Oculocutaneous genetics
- Abstract
We have recently identified DCT encoding dopachrome tautomerase (DCT) as the eighth gene for oculocutaneous albinism (OCA). Patients with loss of function of DCT suffer from eye hypopigmentation and retinal dystrophy. Here we investigate the eye phenotype in Dct
-/- mice. We show that their retinal pigmented epithelium (RPE) is severely hypopigmented from early stages, contrasting with the darker melanocytic tissues. Multimodal imaging reveals specific RPE cellular defects. Melanosomes are fewer with correct subcellular localization but disrupted melanization. RPE cell size is globally increased and heterogeneous. P-cadherin labeling of Dct-/- newborn RPE reveals a defect in adherens junctions similar to what has been described in tyrosinase-deficient Tyrc/c embryos. The first intermediate of melanin biosynthesis, dihydroxyphenylalanine (L-Dopa), which is thought to control retinogenesis, is detected in substantial yet significantly reduced amounts in Dct-/- postnatal mouse eyecups. L-Dopa synthesis in the RPE alone remains to be evaluated during the critical period of retinogenesis. The Dct-/- mouse should prove useful in understanding the molecular regulation of retinal development and aging of the hypopigmented eye. This may guide therapeutic strategies to prevent vision deficits in patients with albinism.- Published
- 2022
- Full Text
- View/download PDF
20. Dopachrome tautomerase variants in patients with oculocutaneous albinism.
- Author
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Pennamen P, Tingaud-Sequeira A, Gazova I, Keighren M, McKie L, Marlin S, Gherbi Halem S, Kaplan J, Delevoye C, Lacombe D, Plaisant C, Michaud V, Lasseaux E, Javerzat S, Jackson I, and Arveiler B
- Subjects
- Animals, Humans, Intramolecular Oxidoreductases, Mice, Mice, Inbred C57BL, Mutation, Albinism, Oculocutaneous genetics, Zebrafish
- Abstract
Purpose: Albinism is a clinically and genetically heterogeneous condition. Despite analysis of the 20 known genes, ~30% patients remain unsolved. We aimed to identify new genes involved in albinism., Methods: We sequenced a panel of genes with known or predicted involvement in melanogenesis in 230 unsolved albinism patients., Results: We identified variants in the Dopachrome tautomerase (DCT) gene in two patients. One was compound heterozygous for a 14-bp deletion in exon 9 and c.118T>A p.(Cys40Ser). The second was homozygous for c.183C>G p.(Cys61Trp). Both patients had mild hair and skin hypopigmentation, and classical ocular features. CRISPR-Cas9 was used in C57BL/6J mice to create mutations identical to the missense variants carried by the patients, along with one loss-of-function indel. When bred to homozygosity the three mutations revealed hypopigmentation of the coat, milder for Cys40Ser compared with Cys61Trp or the frameshift mutation. Histological analysis identified significant hypopigmentation of the retinal pigmented epithelium (RPE) indicating that defective RPE melanogenesis could be associated with eye and vision defects. DCT loss of function in zebrafish embryos elicited hypopigmentation both in melanophores and RPE cells., Conclusion: DCT is the gene for a new type of oculocutaneous albinism that we propose to name OCA8.
- Published
- 2021
- Full Text
- View/download PDF
21. 3D chemical imaging of the brain using quantitative IR spectro-microscopy.
- Author
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Ogunleke A, Recur B, Balacey H, Chen HH, Delugin M, Hwu Y, Javerzat S, and Petibois C
- Abstract
Three-dimensional (3D) histology is the next frontier for modern anatomo-pathology. Characterizing abnormal parameters in a tissue is essential to understand the rationale of pathology development. However, there is no analytical technique, in vivo or histological, that is able to discover such abnormal features and provide a 3D distribution at microscopic resolution. Here, we introduce a unique high-throughput infrared (IR) microscopy method that combines automated image correction and subsequent spectral data analysis for 3D-IR image reconstruction. We performed spectral analysis of a complete organ for a small animal model, a mouse brain with an implanted glioma tumor. The 3D-IR image is reconstructed from 370 consecutive tissue sections and corrected using the X-ray tomogram of the organ for an accurate quantitative analysis of the chemical content. A 3D matrix of 89 × 10
6 IR spectra is generated, allowing us to separate the tumor mass from healthy brain tissues based on various anatomical, chemical, and metabolic parameters. We demonstrate that quantitative metabolic parameters can be extracted from the IR spectra for the characterization of the brain vs. tumor metabolism (assessing the Warburg effect in tumors). Our method can be further exploited by searching for the whole spectral profile, discriminating tumor vs. healthy tissue in a non-supervised manner, which we call 'spectromics'.- Published
- 2017
- Full Text
- View/download PDF
22. Quantitative IR microscopy and spectromics open the way to 3D digital pathology.
- Author
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Bobroff V, Chen HH, Delugin M, Javerzat S, and Petibois C
- Subjects
- Animals, Brain blood supply, Brain cytology, Brain diagnostic imaging, Brain metabolism, Mice, Pattern Recognition, Automated, Imaging, Three-Dimensional methods, Microscopy methods, Spectroscopy, Fourier Transform Infrared methods
- Abstract
Currently, only mass-spectrometry (MS) microscopy brings a quantitative analysis of chemical contents of tissue samples in 3D. Here, the reconstruction of a 3D quantitative chemical images of a biological tissue by FTIR spectro-microscopy is reported. An automated curve-fitting method is developed to extract all intense absorption bands constituting IR spectra. This innovation benefits from three critical features: (1) the correction of raw IR spectra to make them quantitatively comparable; (2) the automated and iterative data treatment allowing to transfer the IR-absorption spectrum into a IR-band spectrum; (3) the reconstruction of an 3D IR-band matrix (x, y, z for voxel position and a 4
th dimension with all IR-band parameters). Spectromics, which is a new method for exploiting spectral data for tissue metadata reconstruction, is proposed to further translate the related chemical information in 3D, as biochemical and anatomical tissue parameters. An example is given with oxidative stress distribution and the reconstruction of blood vessels in tissues. The requirements of IR microscopy instrumentation to propose 3D digital histology as a clinical routine technology is briefly discussed., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2017
- Full Text
- View/download PDF
23. Impaired angiogenesis and tumor development by inhibition of the mitotic kinesin Eg5.
- Author
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Exertier P, Javerzat S, Wang B, Franco M, Herbert J, Platonova N, Winandy M, Pujol N, Nivelles O, Ormenese S, Godard V, Becker J, Bicknell R, Pineau R, Wilting J, Bikfalvi A, and Hagedorn M
- Subjects
- Animals, Cell Growth Processes drug effects, Cell Line, Tumor, Chick Embryo, Chorioallantoic Membrane blood supply, Chorioallantoic Membrane drug effects, Gene Expression drug effects, Glioma drug therapy, Glioma enzymology, Human Umbilical Vein Endothelial Cells, Humans, Kinesins genetics, Kinesins metabolism, Mice, Mitosis drug effects, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic enzymology, Quinazolines pharmacology, Recombinant Proteins pharmacology, Thiones pharmacology, Vascular Endothelial Growth Factor A pharmacology, Zebrafish, Glioma blood supply, Kinesins antagonists & inhibitors
- Abstract
Kinesin motor proteins exert essential cellular functions in all eukaryotes. They control mitosis, migration and intracellular transport through interaction with microtubules. Small molecule inhibitors of the mitotic kinesin KiF11/Eg5 are a promising new class of anti-neoplastic agents currently evaluated in clinical cancer trials for solid tumors and hematological malignancies. Here we report induction of Eg5 and four other mitotic kinesins including KIF20A/Mklp2 upon stimulation of in vivo angiogenesis with vascular endothelial growth factor-A (VEGF-A). Expression analyses indicate up-regulation of several kinesin-encoding genes predominantly in lymphoblasts and endothelial cells. Chemical blockade of Eg5 inhibits endothelial cell proliferation and migration in vitro. Mitosis-independent vascular outgrowth in aortic ring cultures is strongly impaired after Eg5 or Mklp2 protein inhibition. In vivo, interfering with KIF11/Eg5 function causes developmental and vascular defects in zebrafish and chick embryos and potent inhibition of tumor angiogenesis in experimental tumor models. Besides blocking tumor cell proliferation, impairing endothelial function is a novel mechanism of action of kinesin inhibitors.
- Published
- 2013
- Full Text
- View/download PDF
24. FTIR spectro-imaging of collagen scaffold formation during glioma tumor development.
- Author
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Noreen R, Chien CC, Chen HH, Bobroff V, Moenner M, Javerzat S, Hwu Y, and Petibois C
- Subjects
- Animals, Brain Neoplasms chemistry, Brain Neoplasms genetics, Collagen genetics, Disease Progression, Extracellular Matrix chemistry, Gene Expression, Glioma chemistry, Glioma genetics, Image Interpretation, Computer-Assisted, Male, Principal Component Analysis, Protein Structure, Secondary, Rats, Brain Neoplasms diagnosis, Collagen chemistry, Glioma diagnosis, Spectroscopy, Fourier Transform Infrared
- Abstract
Evidence has recently emerged that solid and diffuse tumors produce a specific extracellular matrix (ECM) for division and diffusion, also developing a specific interface with microvasculature. This ECM is mainly composed of collagens and their scaffolding appears to drive tumor growth. Although collagens are not easily analyzable by UV-fluorescence means, FTIR imaging has appeared as a valuable tool to characterize collagen contents in tissues, specially the brain, where ECM is normally devoid of collagen proteins. Here, we used FTIR imaging to characterize collagen content changes in growing glioma tumors. We could determine that C6-derived solid tumors presented high content of triple helix after 8-11 days of growth (typical of collagen fibrils formation; 8/8 tumor samples; 91 % of total variance), and further turned to larger α-helix (days 12-15; 9/10 of tumors; 94 % of variance) and β-turns (day 18-21; 7/8 tumors; 97 % of variance) contents, which suggest the incorporation of non-fibrillar collagen types in ECM, a sign of more and more organized collagen scaffold along tumor progression. The growth of tumors was also associated to the level of collagen produced (P < 0.05). This study thus confirms that collagen scaffolding is a major event accompanying the angiogenic shift and faster tumor growth in solid glioma phenotypes.
- Published
- 2013
- Full Text
- View/download PDF
25. Inhibition of angiogenesis and the angiogenesis/invasion shift.
- Author
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Bikfalvi A, Moenner M, Javerzat S, North S, and Hagedorn M
- Subjects
- Angiogenesis Inhibitors pharmacology, Drug Resistance, Neoplasm drug effects, Humans, Interleukin-6 antagonists & inhibitors, Interleukin-6 metabolism, Neoplasm Invasiveness, Neoplasms drug therapy, Angiogenesis Inhibitors therapeutic use, Neoplasms blood supply, Neoplasms pathology, Neovascularization, Pathologic drug therapy
- Abstract
Angiogenesis has become a major target in cancer therapy. However, current therapeutic strategies have their limitations and raise several problems. In most tumours, anti-angiogenesis treatment targeting VEGF (vascular endothelial growth factor) has only limited overall survival benefit compared with conventional chemotherapy alone, and reveals several specific forms of resistance to anti-VEGF treatment. There is growing evidence that anti-VEGF treatment may induce tumour cell invasion by selecting highly invasive tumour cells or hypoxia-resistant cells, or by up-regulating angiogenic alternative pathways such as FGFs (fibroblast growth factors) or genes triggering new invasive programmes. We have identified new genes up-regulated during glioma growth on the chick CAM (chorioallantoic membrane). Our results indicate that anti-angiogenesis treatment in the experimental glioma model drives expression of critical genes which relate to disease aggressiveness in glioblastoma patients. We have identified a molecular mechanism in tumour cells that allows the switch from an angiogenic to invasive programme. Furthermore, we are focusing our research on alternative inhibitors that act, in part, independently of VEGF. These are endogenous molecules that play a role in the control of tumour growth and may constitute a starting point for further development of novel therapeutic or diagnostic tools.
- Published
- 2011
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26. A combined metabonomic and transcriptomic approach to investigate metabolism during development in the chick chorioallantoic membrane.
- Author
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Cavill R, Sidhu JK, Kilarski W, Javerzat S, Hagedorn M, Ebbels TM, Bikfalvi A, and Keun HC
- Subjects
- Animals, Chick Embryo, Chickens, Chorioallantoic Membrane growth & development, Cluster Analysis, Nuclear Magnetic Resonance, Biomolecular methods, Chorioallantoic Membrane chemistry, Chorioallantoic Membrane metabolism, Gene Expression Profiling methods, Metabolomics methods
- Abstract
The chick chorioallantoic membrane (CAM) is a powerful alternative to rodent models for the study of physiological or pathological angiogenesis. We investigated metabolic changes during the maturation of the CAM by (1)H NMR-based metabolic profiling (metabonomics/metabolomics), allowing simultaneous measurements of many metabolites in an untargeted fashion. Specifically, we examined the time course of the measured metabolites to elucidate common patterns of regulation. Three clusters of metabolites were observed that correspond to essential biological processes active in the CAM with similar dynamics. The time courses common to the metabolite clusters distinguished specific stages of vessel growth, identifying waste product metabolites being stored in the CAM and energy-related substrates decreasing during embryonic growth. Using this top-down approach, combined with existing microarray data, we could link gene expression to metabolic consequences during the growth of a vascularized organ. For example, transcriptomic analysis demonstrated that many transcripts involved in the TCA cycle were down-regulated during CAM development, which correlated with the decrease in levels of TCA precursors and intermediates seen in the metabolite data. Taken together, this paper provides the first metabonomic study in an embryonic tissue where vessel development is the most active morphogenic process.
- Published
- 2010
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27. Selective osteopontin knockdown exerts anti-tumoral activity in a human glioblastoma model.
- Author
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Lamour V, Le Mercier M, Lefranc F, Hagedorn M, Javerzat S, Bikfalvi A, Kiss R, Castronovo V, and Bellahcène A
- Subjects
- Animals, Apoptosis physiology, Blotting, Western, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation, Chick Embryo, Enzyme-Linked Immunosorbent Assay, Glioblastoma genetics, Humans, Immunohistochemistry, Neovascularization, Pathologic genetics, Osteopontin genetics, RNA Interference, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Transfection, Glioblastoma metabolism, Osteopontin metabolism
- Abstract
Osteopontin (OPN), a member of the SIBLING (Small Integrin-Binding LIgand N-linked Glycoprotein) family, is overexpressed in human glioblastoma. Higher levels of OPN expression correlate with increased tumor grade and enhanced migratory capacity of tumor cells. Based on these observations, we explored the possibility that knocking down OPN expression in glioblastoma cells could exert an anti-tumoral activity using an avian in vivo glioblastoma model that mimics closely human gliobastoma. Human U87-MG glioma cells transfected with specific anti-OPN small interfering RNAs (siRNAs) were grafted onto the chicken chorio-allantoic membrane (CAM). OPN-deficient U87-MG cells gave rise to tumors that were significantly smaller than tumors formed from untransfected cells (paired t-test, p < 0.05). Accordingly, the amount of proliferating cells in OPN-deficient tumors showed a six-fold reduction when compared to control tumors. However, OPN inhibition did not affect significantly tumor-associated angiogenesis. In vitro, OPN-silenced U87-MG and U373-MG cells showed decreased motility and migration. This is the first demonstration that OPN inhibition blocks glioma tumor growth, making this invasion-related protein an attractive target for glioma therapy.
- Published
- 2010
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28. Correlating global gene regulation to angiogenesis in the developing chick extra-embryonic vascular system.
- Author
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Javerzat S, Franco M, Herbert J, Platonova N, Peille AL, Pantesco V, De Vos J, Assou S, Bicknell R, Bikfalvi A, and Hagedorn M
- Subjects
- Animals, Chick Embryo, Chorioallantoic Membrane metabolism, Cluster Analysis, Dose-Response Relationship, Drug, Gene Expression Profiling, Humans, Immunohistochemistry methods, Mitosis, Models, Biological, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Gene Expression Regulation, Developmental, Neovascularization, Physiologic
- Abstract
Background: Formation of blood vessels requires the concerted regulation of an unknown number of genes in a spatial-, time- and dosage-dependent manner. Determining genes, which drive vascular maturation is crucial for the identification of new therapeutic targets against pathological angiogenesis., Methodology/principal Findings: [corrected] We accessed global gene regulation throughout maturation of the chick chorio-allantoic membrane (CAM), a highly vascularized tissue, using pan genomic microarrays. Seven percent of analyzed genes showed a significant change in expression (>2-fold, FDR<5%) with a peak occurring from E7 to E10, when key morphogenetic and angiogenic genes such as BMP4, SMO, HOXA3, EPAS1 and FGFR2 were upregulated, reflecting the state of an activated endothelium. At later stages, a general decrease in gene expression occurs, including genes encoding mitotic factors or angiogenic mediators such as CYR61, EPAS1, MDK and MYC. We identified putative human orthologs for 77% of significantly regulated genes and determined endothelial cell enrichment for 20% of the orthologs in silico. Vascular expression of several genes including ENC1, FSTL1, JAM2, LDB2, LIMS1, PARVB, PDE3A, PRCP, PTRF and ST6GAL1 was demonstrated by in situ hybridization. Up to 9% of the CAM genes were also overexpressed in human organs with related functions, such as placenta and lung or the thyroid. 21-66% of CAM genes enriched in endothelial cells were deregulated in several human cancer types (P<.0001). Interfering with PARVB (encoding parvin, beta) function profoundly changed human endothelial cell shape, motility and tubulogenesis, suggesting an important role of this gene in the angiogenic process., Conclusions/significance: Our study underlines the complexity of gene regulation in a highly vascularized organ during development. We identified a restricted number of novel genes enriched in the endothelium of different species and tissues, which may play crucial roles in normal and pathological angiogenesis.
- Published
- 2009
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29. Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness.
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Saidi A, Hagedorn M, Allain N, Verpelli C, Sala C, Bello L, Bikfalvi A, and Javerzat S
- Subjects
- Angiogenesis Inhibitors therapeutic use, Animals, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Bevacizumab, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Brain Neoplasms blood supply, Cell Movement drug effects, Cell Proliferation, Drug Synergism, Drug Therapy, Combination, Gene Expression Profiling, Glioma blood supply, Humans, Immunoenzyme Techniques, Interleukin-6 metabolism, Mice, Mice, Nude, Oligonucleotide Array Sequence Analysis, Tumor Cells, Cultured, Vascular Endothelial Growth Factor A metabolism, Xenograft Model Antitumor Assays, Brain Neoplasms pathology, Glioma pathology, Interleukin-6 genetics, Neovascularization, Pathologic prevention & control, RNA, Small Interfering physiology, Vascular Endothelial Growth Factor A genetics
- Abstract
Interleukin-6 (IL6) and vascular endothelial growth factor (VEGFA) are abundantly produced by glioma cells and contribute to malignancy by promoting angiogenesis, cell proliferation and resistance to apoptosis. We compared the effect of inhibiting IL6 and VEGF on U87-derived experimental glioma grown on the chick chorio-allantoic membrane (CAM) or in the brain of xenografted mice. Tumor growth was monitored by biomicroscopy and immunohistology. In vitro, IL6 knockdown had no effect on proliferation but substantially enhanced invasion. In the CAM experimental glioma, IL6 or VEGF knockdown reduced growth and vascularization of the tumors with a comparable efficiency, but increased invasion of residual tumor cells. In contrast, combined IL6/VEGF knockdown not only showed enhanced reduction of tumor growth and angiogenesis but also significantly prevented invasion of residual tumor cells. In mice, combining IL6 knockdown and Avastin treatment completely abrogated tumor development and infiltration. Molecular response of tumor cells to single or combined treatment was studied by transcriptomic profiling. Many cell cycle promoting genes and chromatin components were silenced in the double knockdown. In addition, specific migratory signatures detected in tumors under single IL6 or VEGF knockdown were partially erased in combined IL6/VEGF knockdown tumors. Our results show that treatment with a combination of IL6 and VEGF inhibitors brings synergistic antitumoral benefit and reduces global activity of major pathways of cell survival, proliferation and invasiveness in remaining tumor cells that may be induced by using VEGF or IL6 inhibitors alone., (2009 UICC.)
- Published
- 2009
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30. Experimental anti-angiogenesis causes upregulation of genes associated with poor survival in glioblastoma.
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Saidi A, Javerzat S, Bellahcène A, De Vos J, Bello L, Castronovo V, Deprez M, Loiseau H, Bikfalvi A, and Hagedorn M
- Subjects
- Adipokines, Adult, Astrocytoma blood supply, Astrocytoma metabolism, Astrocytoma mortality, Biomarkers, Tumor genetics, Brain metabolism, Brain pathology, Brain Neoplasms blood supply, Brain Neoplasms metabolism, Brain Neoplasms mortality, Cell Proliferation, Chitinase-3-Like Protein 1, Elafin metabolism, Female, Gene Expression Profiling, Glioblastoma metabolism, Glycoproteins metabolism, Humans, Immunoenzyme Techniques, Lectins, Male, Middle Aged, Neovascularization, Pathologic, Oligonucleotide Array Sequence Analysis, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Small Interfering pharmacology, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Up-Regulation, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Biomarkers, Tumor metabolism, Gene Expression Regulation, Neoplastic, Glioblastoma blood supply, Glioblastoma mortality, Vascular Endothelial Growth Factor A antagonists & inhibitors
- Abstract
Vascular endothelial growth factor (VEGF) inhibitors are the most promising anti-angiogenic agents used increasingly in the clinic. However, to be efficient, anti-VEGF agents need to be associated with classic chemotherapy. Exploring gene regulation in tumor cells during anti-angiogenesis might help to comprehend the molecular basis of response to treatment. To generate a defined anti-angiogenic condition in vivo, we transfected human glioma cells with short-interfering RNAs against VEGF-A and implanted them on the chick chorio-allantoic membrane. Gene regulation in avascular tumors was studied using human Affymetrixtrade mark GeneChips. Potentially important genes were further studied in glioma patients. Despite strong VEGF inhibition, we observed recurrent formation of small, avascular tumors. CHI3L2, IL1B, PI3/elafin and CHI3L1, which encodes for YKL-40, a putative prognosticator for various diseases, including cancer, were strongly up-regulated in avascular glioma. In glioblastoma patients, these genes showed coregulation and their expression differed significantly from low-grade glioma. Importantly, high levels of CHI3L1 (p = 0.036) and PI3/elafin mRNA (p = 0.0004) were significantly correlated with poor survival. Cox regression analysis further confirmed that PI3 and CHI3L1 levels are survival markers independent from patient age and sex. Elafin-positive tumor cells were only found in glioblastoma, where they were clustered around necrotic areas. PI3/elafin is strongly induced by serum deprivation and hypoxia in U87 glioma cells in vitro. Our results indicate that anti-angiogenesis in experimental glioma drives expression of critical genes which relate to disease aggressiveness in glioblastoma patients. In particular, CHI3L1 and PI3/elafin may be useful as new prognostic markers and new therapeutic targets., ((c) 2008 Wiley-Liss, Inc.)
- Published
- 2008
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31. Effect of human skin-derived stem cells on vessel architecture, tumor growth, and tumor invasion in brain tumor animal models.
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Pisati F, Belicchi M, Acerbi F, Marchesi C, Giussani C, Gavina M, Javerzat S, Hagedorn M, Carrabba G, Lucini V, Gaini SM, Bresolin N, Bello L, Bikfalvi A, and Torrente Y
- Subjects
- Animals, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Growth Processes physiology, Cell Line, Tumor, Chick Embryo, Chorioallantoic Membrane blood supply, Glioblastoma metabolism, Glioblastoma pathology, Humans, Mice, Mice, Nude, Mice, Transgenic, Neoplasm Invasiveness, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Neovascularization, Pathologic therapy, Transforming Growth Factor beta1 biosynthesis, Xenograft Model Antitumor Assays, Brain Neoplasms blood supply, Brain Neoplasms therapy, Glioblastoma blood supply, Glioblastoma therapy, Skin cytology, Stem Cell Transplantation, Stem Cells physiology
- Abstract
Glioblastomas represent an important cause of cancer-related mortality with poor survival. Despite many advances, the mean survival time has not significantly improved in the last decades. New experimental approaches have shown tumor regression after the grafting of neural stem cells and human mesenchymal stem cells into experimental intracranial gliomas of adult rodents. However, the cell source seems to be an important limitation for autologous transplantation in glioblastoma. In the present study, we evaluated the tumor targeting and antitumor activity of human skin-derived stem cells (hSDSCs) in human brain tumor models. The hSDSCs exhibit tumor targeting characteristics in vivo when injected into the controlateral hemisphere or into the tail vein of mice. When implanted directly into glioblastomas, hSDSCs distributed themselves extensively throughout the tumor mass, reduced tumor vessel density, and decreased angiogenic sprouts. In addition, transplanted hSDSCs differentiate into pericyte cell and release high amounts of human transforming growth factor-beta1 with low expression of vascular endothelial growth factor, which may contribute to the decreased tumor cell invasion and number of tumor vessels. In long-term experiments, the hSDSCs were also able to significantly inhibit tumor growth and to prolong animal survival. Similar behavior was seen when hSDSCs were implanted into two different tumor models, the chicken embryo experimental glioma model and the transgenic Tyrp1-Tag mice. Taken together, these data validate the use of hSDSCs for targeting human brain tumors. They may represent therapeutically effective cells for the treatment of intracranial tumors after autologous transplantation.
- Published
- 2007
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32. FBXW7/hCDC4 controls glioma cell proliferation in vitro and is a prognostic marker for survival in glioblastoma patients.
- Author
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Hagedorn M, Delugin M, Abraldes I, Allain N, Belaud-Rotureau MA, Turmo M, Prigent C, Loiseau H, Bikfalvi A, and Javerzat S
- Abstract
Background: In the quest for novel molecular mediators of glioma progression, we studied the regulation of FBXW7 (hCDC4/hAGO/SEL10), its association with survival of patients with glioblastoma and its potential role as a tumor suppressor gene in glioma cells. The F-box protein Fbxw7 is a component of SCFFbxw7, a Skp1-Cul1-F-box E3 ubiquitin ligase complex that tags specific proteins for proteasome degradation. FBXW7 is mutated in several human cancers and functions as a haploinsufficient tumor suppressor in mice. Any of the identified targets, Cyclin E, c-Myc, c-Jun, Notch1/4 and Aurora-A may have oncogenic properties when accumulated in tumors with FBXW7 loss., Results: We tested the expression of FBXW7 in human glioma biopsies by quantitative PCR and compared the transcript levels of grade IV glioma (glioblastoma, G-IV) with those of grade II tumors (G-II). In more than 80% G-IV, expression of FBXW7 was significantly reduced. In addition, levels of FBXW7 were correlated with survival indicating a possible implication in tumor aggressiveness. Locus 4q31.3 which carries FBXW7 was investigated by in situ hybridization on biopsy touchprints. This excluded allelic loss as the principal cause for low expression of FBXW7 in G-IV tumors. Two targets of Fbxw7, Aurora-A and Notch4 were preferentially immunodetected in G-IV biopsies. Next, we investigated the effects of FBXW7 misregulation in glioma cells. U87 cells overexpressing nuclear isoforms of Fbxw7 lose the expression of the proliferation markers PCNA and Ki-67, and get counterselected in vitro. This observation fits well with the hypothesis that Fbxw7 functions as a tumor suppressor in astroglial cells. Finally, FBXW7 knockdown in U87 cells leads to defects in mitosis that may promote aneuploidy in progressing glioma., Conclusion: Our results show that FBXW7 expression is a prognostic marker for patients with glioblastoma. We suggest that loss of FBXW7 plays an important role in glioma malignancy by allowing the accumulation of multiple oncoproteins and that interfering with Fbxw7 or its downstream targets would constitute a new therapeutic advance.
- Published
- 2007
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33. [Understanding in treating gliomas: an adequate experimental model for each question].
- Author
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Javerzat S, Bikfalvi A, and Hagedorn M
- Subjects
- Animals, Chick Embryo, Humans, Mice, Microarray Analysis methods, Neoplasm Transplantation methods, Rats, Brain Neoplasms genetics, Brain Neoplasms pathology, Chorioallantoic Membrane, Disease Models, Animal, Glioma genetics, Glioma pathology
- Abstract
Malignant glioma are especially difficult to model in vivo. Here we review the most recent strategies for designing relevant models of glioma. These should greatly contribute to identification of new tumor regulating molecules and facilitate testing of inhibitors to be used in therapeutical trials as well as the drug resistance that they might confer.
- Published
- 2005
34. Accessing key steps of human tumor progression in vivo by using an avian embryo model.
- Author
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Hagedorn M, Javerzat S, Gilges D, Meyre A, de Lafarge B, Eichmann A, and Bikfalvi A
- Subjects
- Animals, Benzamides, Cell Line, Tumor, DNA Primers, Disease Models, Animal, Disease Progression, Enzyme Inhibitors pharmacology, Humans, Imatinib Mesylate, In Situ Hybridization, Oligonucleotide Array Sequence Analysis, Piperazines pharmacology, Polymerase Chain Reaction, Pyrimidines pharmacology, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Vascular Endothelial Growth Factor Receptor-2 genetics, Cell Transformation, Neoplastic, Chick Embryo cytology, Gene Expression Regulation, Neoplastic, Glioma pathology
- Abstract
Experimental in vivo tumor models are essential for comprehending the dynamic process of human cancer progression, identifying therapeutic targets, and evaluating antitumor drugs. However, current rodent models are limited by high costs, long experimental duration, variability, restricted accessibility to the tumor, and major ethical concerns. To avoid these shortcomings, we investigated whether tumor growth on the chick chorio-allantoic membrane after human glioblastoma cell grafting would replicate characteristics of the human disease. Avascular tumors consistently formed within 2 days, then progressed through vascular endothelial growth factor receptor 2-dependent angiogenesis, associated with hemorrhage, necrosis, and peritumoral edema. Blocking of vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor signaling pathways by using small-molecule receptor tyrosine kinase inhibitors abrogated tumor development. Gene regulation during the angiogenic switch was analyzed by oligonucleotide microarrays. Defined sample selection for gene profiling permitted identification of regulated genes whose functions are associated mainly with tumor vascularization and growth. Furthermore, expression of known tumor progression genes identified in the screen (IL-6 and cysteine-rich angiogenic inducer 61) as well as potential regulators (lumican and F-box-only 6) follow similar patterns in patient glioma. The model reliably simulates key features of human glioma growth in a few days and thus could considerably increase the speed and efficacy of research on human tumor progression and preclinical drug screening.
- Published
- 2005
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35. VEGF coordinates interaction of pericytes and endothelial cells during vasculogenesis and experimental angiogenesis.
- Author
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Hagedorn M, Balke M, Schmidt A, Bloch W, Kurz H, Javerzat S, Rousseau B, Wilting J, and Bikfalvi A
- Subjects
- Animals, Capillaries metabolism, Capillaries ultrastructure, Cell Differentiation, Cell Division, Chick Embryo, Desmin biosynthesis, Endothelial Cells cytology, Image Processing, Computer-Assisted, Immunohistochemistry, Mice, Microcirculation, Microscopy, Confocal, Microscopy, Electron, Pericytes chemistry, Time Factors, Endothelial Cells metabolism, Gene Expression Regulation, Developmental, Neovascularization, Pathologic, Neovascularization, Physiologic, Pericytes metabolism, Platelet Endothelial Cell Adhesion Molecule-1 biosynthesis, Vascular Endothelial Growth Factor A metabolism
- Abstract
Biological activities of vascular endothelial growth factor (VEGF) have been studied extensively in endothelial cells (ECs), but few data are available regarding its effects on pericytes. In murine embryoid body cultures, VEGF-induced expression of desmin and alpha-smooth muscle actin (alpha-SMA) in CD-31+ cells. The number of CD-31+/desmin+ vascular chords increased with VEGF treatment time and peaked during a differentiation window between 6 and 9 days after plating. In vivo, VEGF-induced elongation and migration of desmin-positive pericytes and coverage of angiogenic capillaries, as revealed by analysis of Sambucus nigra lectin-stained vascular beds of the chick chorioallantoic membrane. VEGF also caused significant decrease of intercapillary spaces, an indicator for intussusceptive vascular growth. These VEGF-mediated effects point at a more intricate interaction between ECs and pericytes cells than previously demonstrated and suggest that pericytes may be derived from EC progenitors in vitro and not only stabilize capillaries but also participate in vascular remodeling in vivo., (Copyright 2004 Wiley-Liss, Inc.)
- Published
- 2004
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36. The tyrp1-Tag/tyrp1-FGFR1-DN bigenic mouse: a model for selective inhibition of tumor development, angiogenesis, and invasion into the neural tissue by blockade of fibroblast growth factor receptor activity.
- Author
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Rousseau B, Larrieu-Lahargue F, Javerzat S, Guilhem-Ducléon F, Beermann F, and Bikfalvi A
- Subjects
- Animals, Brain Neoplasms blood supply, Brain Neoplasms genetics, Cattle, Cell Division genetics, Cell Division physiology, Cell Line, Tumor, Coculture Techniques, Endothelium, Vascular cytology, Female, Male, Membrane Glycoproteins biosynthesis, Membrane Glycoproteins genetics, Mice, Neoplasm Invasiveness, Neovascularization, Pathologic genetics, Neovascularization, Pathologic pathology, Receptor Protein-Tyrosine Kinases biosynthesis, Receptor Protein-Tyrosine Kinases genetics, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Fibroblast Growth Factor biosynthesis, Receptors, Fibroblast Growth Factor genetics, Retinal Neoplasms blood supply, Retinal Neoplasms genetics, Brain Neoplasms pathology, Membrane Glycoproteins physiology, Oxidoreductases, Receptor Protein-Tyrosine Kinases physiology, Receptors, Fibroblast Growth Factor antagonists & inhibitors, Receptors, Fibroblast Growth Factor physiology, Retinal Neoplasms pathology
- Abstract
We describe herein a new transgenic mouse tumor model in which fibroblast growth factor (FGF) receptor activity is selectively inhibited. Tyrp1-Tag mice that develop early vascularized tumors of the retinal pigment epithelium were crossed with tyrp1-FGFR1-DN mice that express dominant-negative FGF receptors in the retinal pigment epithelium to generate bigenic mice. Initial angiogenesis-independent tumor growth progressed equally in tyrp1-Tag and bigenic mice with no significant differences in the number of dividing and apoptotic cells within the tumor. By contrast, at a later stage when tyrp1-Tag tumors rapidly expanded to fill the entire eye posterior chamber and migrate along the optic nerve toward the chiasma, bigenic tumors remained small and were poorly vascularized. Secondary tumors of small size developed in only 20% of bigenic mice by 1 month. Immunohistochemical analysis of secondary tumors from bigenic mice showed a reduction of angiogenesis and an increase in apoptosis in tumor cells. Tumor cells from bigenic mice expressed high levels of truncated FGF receptors and did not induce endothelial tube formation in vitro. All in all, this indicates that the tyrp1-Tag mouse may be a useful model to study selective tumor inhibition and the effect of antitumor therapy that targets a specific growth factor pathway. FGF receptors are required at the onset of tumor invasion and angiogenesis in ocular tumors and are good therapeutic targets in this model. The bigenic mouse may also constitute a useful model to answer more fundamental questions of cancer biology such as the mechanism of tumor escape.
- Published
- 2004
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37. Regulation of vascular development by fibroblast growth factors.
- Author
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Auguste P, Javerzat S, and Bikfalvi A
- Subjects
- Animals, Humans, Ischemia physiopathology, Lymphatic System growth & development, Models, Biological, Neoplasms metabolism, Receptors, Fibroblast Growth Factor metabolism, Signal Transduction, Blood Vessels growth & development, Fibroblast Growth Factors metabolism, Neovascularization, Pathologic, Neovascularization, Physiologic
- Abstract
Fibroblast growth factors (FGFs) are potent stimulators of angiogenesis in vitro and in vivo. However, the precise role of FGFs and vascular development in normal and pathological tissue has long remained ill defined. Recently, substantial progress has been made toward a better understanding of their role. Genetic studies in mice or in culture systems indicate a role for FGFs in vessel assembly and sprouting. FGFs also stimulate blood vessel branching and lymphangiogenesis. The molecular mechanisms by which FGFs mediate angiogenesis are also better understood. Finally, the FGF/FGF-receptor system has become a focus for the development of novel therapeutic strategies for the treatment of angiogenesis-related diseases such as tissue ischemia.
- Published
- 2003
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38. Involvement of fibroblast growth factors in choroidal angiogenesis and retinal vascularization.
- Author
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Rousseau B, Larrieu-Lahargue F, Bikfalvi A, and Javerzat S
- Subjects
- Animals, Cell Differentiation, Cell Division, Choroid embryology, Immunohistochemistry, Mice, Mice, Inbred C57BL, Mice, Transgenic, Retina cytology, Choroid blood supply, Fibroblast Growth Factors physiology, Neovascularization, Physiologic physiology, Receptors, Fibroblast Growth Factor antagonists & inhibitors, Retina embryology, Retinal Vessels embryology
- Abstract
Fibroblast growth factors such as FGF-2 are potent mitogens for endothelial cells and induce their assembly into vascular-like structures in culture and in in vivo assays. However, their putative functions during physiological vascularization are poorly documented. In this study, the eye was used as a model for analyzing the vascular defects caused by targeted FGF inhibition in transgenic mice. Choroidal and retinal vascularizations were studied by immunohistochemistry on whole-mount preparations. Soon after activation of the transgene, angiogenesis that normally occurs during the second half of gestation in the choroid was strongly inhibited resulting in poor capillary density and branching. Later retinas strikingly failed to develop a primary vascular plexus suggesting a defect in induction of vessel assembly. Hyaloid vessels that supply the retina during the fetal period did not regress at birth and later gave rise to unexpected massive neovascularization. This model illustrates major functions of FGFs at different early stages of physiological vascularization. Both the failure in hyaloid regression and the intense angiogenic invasion of endothelial cells into the retina may serve as a model for some related human ocular pathologies.
- Published
- 2003
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39. The role of fibroblast growth factors in vascular development.
- Author
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Javerzat S, Auguste P, and Bikfalvi A
- Subjects
- Animals, Embryo, Mammalian physiology, Humans, Models, Biological, Neoplasms metabolism, Receptors, Fibroblast Growth Factor metabolism, Signal Transduction physiology, Blood Vessels growth & development, Fibroblast Growth Factors metabolism, Neovascularization, Pathologic, Neovascularization, Physiologic
- Abstract
Fibroblast growth factors (FGFs) are considered angiogenic factors, yet the exact relationship between FGF and vascular development in normal and pathological tissue has long remained elusive. However, recent results from gene inactivation and transgenic studies in mice and in culture systems have demonstrated the role of FGFs in vessel assembly and sprouting. FGFs also promote blood-vessel branching and induce lymphangiogenesis. Novel players in FGF-mediated angiogenesis have been identified, such as p38 mitogen-activated protein kinase. Tumour angiogenesis is regulated by FGFs directly or indirectly via secondary angiogenesis factors, such as vascular endothelial growth factor. The newly established angiogenic role of FGFs makes FGF or molecules targeting FGF and its receptor promising candidates for the development of novel therapeutics.
- Published
- 2002
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40. Exploration, anxiety, and spatial memory in transgenic anophthalmic mice.
- Author
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Buhot MC, Dubayle D, Malleret G, Javerzat S, and Segu L
- Subjects
- Animals, Anophthalmos physiopathology, Anxiety physiopathology, Anxiety psychology, Escape Reaction physiology, Male, Maze Learning physiology, Mice, Proprioception physiology, Species Specificity, Visual Perception physiology, Anophthalmos genetics, Anxiety genetics, Exploratory Behavior physiology, Mental Recall physiology, Mice, Transgenic genetics, Orientation physiology
- Abstract
Contradictory results are found in the literature concerning the role of vision in the perception of space or in spatial navigation, in part because of the lack of murine models of total blindness used so far. The authors evaluated the spatial abilities of anophthalmic transgenic mice. These mice did not differ qualitatively from their wild-type littermates in general locomotor activity, spontaneous alternation, object exploration, or anxiety, but their level of exploratory activity was generally lower. In the spatial version of the water maze, they displayed persistent thigmotaxic behavior and showed severe spatial learning impairments. However, their performances improved with training, suggesting that they may have acquired a rough representation of the platform position. These results suggest that modalities other than vision enable some degree of spatial processing in proximal and structured spaces but that vision is critical for accurate spatial navigation.
- Published
- 2001
41. Neural and angiogenic defects in eyes of transgenic mice expressing a dominant-negative FGF receptor in the pigmented cells.
- Author
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Rousseau B, Dubayle D, Sennlaub F, Jeanny JC, Costet P, Bikfalvi A, and Javerzat S
- Subjects
- Animals, Cell Communication physiology, Cell Survival, Eye blood supply, Mice, Mice, Transgenic, Microscopy, Electron, Scanning, Neovascularization, Physiologic, Photoreceptor Cells, Vertebrate physiology, Pigment Epithelium of Eye cytology, Retinal Degeneration genetics, Retinal Degeneration pathology, Eye Abnormalities genetics, Pigment Epithelium of Eye physiology, Receptors, Fibroblast Growth Factor physiology
- Abstract
Fibroblast growth factors (FGF) are multipotent cytokines with demonstrated mitogenic, neurotrophic and angiogenic properties. There is evidence that they have multiple functions during and after development of the vertebrate eye. Amongst these, the role of FGF receptor mediated signaling in the retinal pigmented epithelium (RPE) is not yet well understood. FGF-2 is produced in RPE cells and may play a role in photoreceptor development and/or survival in vivo. It may also stimulate growth of melanocytes and angiogenesis in the choroid. To address these questions, we have specifically disrupted FGF signaling by generating lines of transgenic mice expressing dominant-negative FGF receptor 1 (FGFR-1) in the pigmented cells. Histological analysis of the eyes were conducted on hemizygous and homozygous mice at different ages. In homozygotes, eye growth is strongly impaired during embryogenesis leading to massive eye degeneration seen in the early post-natal stages. In hemizygotes, the choroid is thinned and the finger-like junctions between RPE cells and photoreceptors are disrupted. Scanning electron microscopy of the choroid vasculature showed that choriocapillary density, diameter and branching are strongly affected. As mice age, they develop progressive retinal degeneration as evidenced by photoreceptor cell loss. Our results are in agreement with the hypothesis that FGF signaling in the RPE participates in photoreceptor survival in vivo. Our model provides evidence that FGF signaling is also involved in choroidal angiogenesis by a process that could relate to induction of terminal branching., (Copyright 2000 Academic Press.)
- Published
- 2000
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42. White-based brown (Tyrp1B-w) is a dominant mutation causing reduced hair pigmentation owing to a chromosomal inversion.
- Author
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Javerzat S and Jackson IJ
- Subjects
- Animals, Base Sequence, Male, Mice, Mice, Inbred C3H, Molecular Sequence Data, Restriction Mapping, Chromosome Inversion, Hair Color genetics, Membrane Glycoproteins, Mutation, Oxidoreductases, Proteins genetics
- Published
- 1998
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43. New insights in the biology of fibroblast growth factor-2.
- Author
-
Bikfalvi A, Savona C, Perollet C, and Javerzat S
- Abstract
Fibroblast growth factor (FGF)-2 stimulates endothelial cell proliferation and is a potent angiogenic molecule in vitro and in vivo. In this review, we have focused on recent findings that relate to the mechanism of action and function of FGF-2. FGF-2 is expressed as four different isoforms: one 18 kDa FGF-2 form that is mainly cytoplasmic and three high molecular weight (HMW) FGF-2 forms that are preferentially localized in the nucleus. It has been demonstrated that these different isoforms lead to specific cellular phenotypes when expressed in cells. HMW FGF-2 controls proliferation by a receptor-independent mechanism, whereas 18 kDa FGF-2 stimulates migration by autocrine receptor activation. Intracellularly, HMW FGF-2 may directly associate with molecules that are involved in growth control. The action of FGF-2 at the cell surface may be altered by angiogenic inhibitors. Angiogenic inhibitors may directly interfere with FGF receptor activation or downstream signaling and thus inhibit FGF activity.
- Published
- 1998
- Full Text
- View/download PDF
44. [Angiogenesis and neoangiogenesis].
- Author
-
Savona C, Javerzat S, Perollet C, and Bikfalvi A
- Subjects
- Angiogenesis Inducing Agents metabolism, Humans, Neovascularization, Pathologic enzymology, Urokinase-Type Plasminogen Activator metabolism, Endothelium, Vascular physiopathology, Neovascularization, Pathologic physiopathology, Neovascularization, Physiologic drug effects
- Abstract
Angiogenesis, the development of new capillary networks from the normal vasculature, is a fundamental process during embryogenesis. In adulthood, angiogenesis contributes to corpus luteum formation, placental implantation and wound healing and is also required in some pathological conditions such as several intraocular syndromes, growth of solid tumors, and metastasis. Many factors are involved in the regulation of neovascularisation among which FGF-2 (fibroblast growth factor-2) and VEGF (vascular endothelial growth factor) are considered as key inducers. Their biological activity is highly controlled by extracellular matrix components and angiostatic factors. Better understanding of the molecular mechanisms regulating angiogenesis should contribute to the development of new molecules to be used for the treatment of neovascularisation-linked diseases.
- Published
- 1997
45. [Angiogenesis and cancer].
- Author
-
Bikfalvi A, Javerzat S, Perollet C, and Savona C
- Subjects
- Humans, Neoplasm Invasiveness pathology, Neoplasm Metastasis pathology, Neoplasms blood supply, Growth Substances genetics, Growth Substances metabolism, Neoplasms pathology, Neovascularization, Pathologic
- Abstract
Tumor invasion and dissemination is tightly controlled by angiogenesis. In recent years, a number of angiogenic factors and inhibitors have been identified. However, the molecular mechanisms leading to this phenomenon are still incompletely understood. In this review, we focus on recent developments in the angiogenesis field. We will summarize our present knowledge about the molecular mechanisms involved in angiogenesis and about the factors that control this phenomenon. We will then shortly discuss the pharmacological modulation and the therapeutic and clinical implications for cancer biology.
- Published
- 1997
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