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Article ; Online: Dyslexia treatment studies: A systematic review and suggestions on testing treatment efficacy with small effects and small samples.

Toffalini, Enrico / Giofrè, David / Pastore, Massimiliano / Carretti, Barbara / Fraccadori, Federica / Szűcs, Denes

2021 Volume 53, Issue 5, Page(s) 1954–1972

Abstract: Poor response to treatment is a defining characteristic of reading disorder. In the present systematic review and meta-analysis, we found that the overall average effect size for treatment efficacy was modest, with a mean standardized difference of 0.38. ...

Abstract	Poor response to treatment is a defining characteristic of reading disorder. In the present systematic review and meta-analysis, we found that the overall average effect size for treatment efficacy was modest, with a mean standardized difference of 0.38. Small true effects, combined with the difficulty to recruit large samples, seriously challenge researchers planning to test treatment efficacy in dyslexia and potentially in other learning disorders. Nonetheless, most published studies claim effectiveness, generally based on liberal use of multiple testing. This inflates the risk that most statistically significant results are associated with overestimated effect sizes. To enhance power, we propose the strategic use of repeated measurements with mixed-effects modelling. This novel approach would enable us to estimate both individual parameters and population-level effects more reliably. We suggest assessing a reading outcome not once, but three times, at pre-treatment and three times at post-treatment. Such design would require only modest additional efforts compared to current practices. Based on this, we performed ad hoc a priori design analyses via simulation studies. Results showed that using the novel design may allow one to reach adequate power even with low sample sizes of 30-40 participants (i.e., 15-20 participants per group) for a typical effect size of d = 0.38. Nonetheless, more conservative assumptions are warranted for various reasons, including a high risk of publication bias in the extant literature. Our considerations can be extended to intervention studies of other types of neurodevelopmental disorders.
MeSH term(s)	Dyslexia ; Humans ; Treatment Outcome
Language	English
Publishing date	2021-03-10
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Systematic Review
ZDB-ID	231560-9
ISSN	1554-3528 ; 0743-3808 ; 1554-351X
ISSN (online)	1554-3528
ISSN	0743-3808 ; 1554-351X
DOI	10.3758/s13428-021-01549-x
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Article ; Online: New insights into the mechanisms of hematopoietic cell transformation by activated receptor tyrosine kinases.

Toffalini, Federica / Demoulin, Jean-Baptiste

Blood

2010 Volume 116, Issue 14, Page(s) 2429–2437

Abstract: A large number of alterations in genes encoding receptor tyrosine kinase (RTK), namely FLT3, c-KIT, platelet-derived growth factor (PDGF) receptors, fibroblast growth factor (FGF) receptors, and the anaplastic large cell lymphoma kinase (ALK), have been ... ...

Abstract	A large number of alterations in genes encoding receptor tyrosine kinase (RTK), namely FLT3, c-KIT, platelet-derived growth factor (PDGF) receptors, fibroblast growth factor (FGF) receptors, and the anaplastic large cell lymphoma kinase (ALK), have been found in hematopoietic malignancies. They have drawn much attention after the development of tyrosine kinase inhibitors. RTK gene alterations include point mutations and gene fusions that result from chromosomal rearrangements. In both cases, they activate the kinase domain in the absence of ligand, producing a permanent signal for cell proliferation. Recently, this simple model has been refined. First, by contrast to wild-type RTK, many mutated RTK do not seem to signal from the plasma membrane, but from various locations inside the cell. Second, their signal transduction properties are altered: the pathways that are crucial for cell transformation, such as signal transducer and activator of transcription (STAT) factors, do not necessarily contribute to the physiologic functions of these receptors. Finally, different mechanisms prevent the termination of the signal, which normally occurs through receptor ubiquitination and degradation. Several mutations inactivating CBL, a key RTK E3 ubiquitin ligase, have been recently described. In this review, we discuss the possible links among RTK trafficking, signaling, and degradation in leukemic cells.
MeSH term(s)	Animals ; Cell Transformation, Neoplastic/genetics ; Hematologic Neoplasms/genetics ; Humans ; Mutation ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/metabolism
Chemical Substances	Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2010-06-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2010-04-279752
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Article ; Online: Critical role of the platelet-derived growth factor receptor (PDGFR) beta transmembrane domain in the TEL-PDGFRbeta cytosolic oncoprotein.

Toffalini, Federica / Hellberg, Carina / Demoulin, Jean-Baptiste

The Journal of biological chemistry

2010 Volume 285, Issue 16, Page(s) 12268–12278

Abstract: The fusion of TEL with platelet-derived growth factor receptor (PDGFR) beta (TPbeta) is found in a subset of patients with atypical myeloid neoplasms associated with eosinophilia and is the archetype of a larger group of hybrid receptors that are ... ...

Abstract	The fusion of TEL with platelet-derived growth factor receptor (PDGFR) beta (TPbeta) is found in a subset of patients with atypical myeloid neoplasms associated with eosinophilia and is the archetype of a larger group of hybrid receptors that are produced by rearrangements of PDGFR genes. TPbeta is activated by oligomerization mediated by the pointed domain of TEL/ETV6, leading to constitutive activation of the PDGFRbeta kinase domain. The receptor transmembrane (TM) domain is retained in TPbeta and in most of the described PDGFRbeta hybrids. Deletion of the TM domain (DeltaTM-TPbeta) strongly impaired the ability of TPbeta to sustain growth factor-independent cell proliferation. We confirmed that TPbeta resides in the cytosol, indicating that the PDGFRbeta TM domain does not act as a transmembrane domain in the context of the hybrid receptor but has a completely different function. The DeltaTM-TPbeta protein was expressed at a lower level because of increased degradation. It could form oligomers, was phosphorylated at a slightly higher level, co-immunoprecipitated with the p85 adaptor protein, but showed a much reduced capacity to activate STAT5 and ERK1/2 in Ba/F3 cells, compared with TPbeta. In an in vitro kinase assay, DeltaTM-TPbeta was more active than TPbeta and less sensitive to imatinib, a PDGFR inhibitor. In conclusion, we show that the TM domain is required for TPbeta-mediated signaling and proliferation, suggesting that the activation of the PDGFRbeta kinase domain is not enough for cell transformation.
MeSH term(s)	Amino Acid Sequence ; Animals ; Cell Line ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cytosol/metabolism ; Humans ; Leukemia, Myeloid/etiology ; Leukemia, Myeloid/genetics ; Leukemia, Myeloid/metabolism ; Molecular Sequence Data ; Myeloid Cells/metabolism ; Myeloid Cells/pathology ; Oncogene Proteins, Fusion/chemistry ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Sequence Deletion ; Signal Transduction ; Swine
Chemical Substances	Oncogene Proteins, Fusion ; Recombinant Proteins ; TEL-PDGFRbeta fusion protein, human
Language	English
Publishing date	2010-02-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M109.076638
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Article: Critical Role of the Platelet-derived Growth Factor Receptor (PDGFR) β Transmembrane Domain in the TEL-PDGFRβ Cytosolic Oncoprotein

Toffalini, Federica / Hellberg, Carina / Demoulin, Jean-Baptiste

Journal of biological chemistry. 2010 Apr. 16, v. 285, no. 16

2010

Abstract: The fusion of TEL with platelet-derived growth factor receptor (PDGFR) β (TPβ) is found in a subset of patients with atypical myeloid neoplasms associated with eosinophilia and is the archetype of a larger group of hybrid receptors that are produced by ... ...

Abstract	The fusion of TEL with platelet-derived growth factor receptor (PDGFR) β (TPβ) is found in a subset of patients with atypical myeloid neoplasms associated with eosinophilia and is the archetype of a larger group of hybrid receptors that are produced by rearrangements of PDGFR genes. TPβ is activated by oligomerization mediated by the pointed domain of TEL/ETV6, leading to constitutive activation of the PDGFRβ kinase domain. The receptor transmembrane (TM) domain is retained in TPβ and in most of the described PDGFRβ hybrids. Deletion of the TM domain (ΔTM-TPβ) strongly impaired the ability of TPβ to sustain growth factor-independent cell proliferation. We confirmed that TPβ resides in the cytosol, indicating that the PDGFRβ TM domain does not act as a transmembrane domain in the context of the hybrid receptor but has a completely different function. The ΔTM-TPβ protein was expressed at a lower level because of increased degradation. It could form oligomers, was phosphorylated at a slightly higher level, co-immunoprecipitated with the p85 adaptor protein, but showed a much reduced capacity to activate STAT5 and ERK1/2 in Ba/F3 cells, compared with TPβ. In an in vitro kinase assay, ΔTM-TPβ was more active than TPβ and less sensitive to imatinib, a PDGFR inhibitor. In conclusion, we show that the TM domain is required for TPβ-mediated signaling and proliferation, suggesting that the activation of the PDGFRβ kinase domain is not enough for cell transformation.
Language	English
Dates of publication	2010-0416
Size	p. 12268-12278.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
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Article ; Online: Transcription factor regulation can be accurately predicted from the presence of target gene signatures in microarray gene expression data.

Essaghir, Ahmed / Toffalini, Federica / Knoops, Laurent / Kallin, Anders / van Helden, Jacques / Demoulin, Jean-Baptiste

Nucleic acids research

2010 Volume 38, Issue 11, Page(s) e120

Abstract: Deciphering transcription factor networks from microarray data remains difficult. This study presents a simple method to infer the regulation of transcription factors from microarray data based on well-characterized target genes. We generated a catalog ... ...

Abstract	Deciphering transcription factor networks from microarray data remains difficult. This study presents a simple method to infer the regulation of transcription factors from microarray data based on well-characterized target genes. We generated a catalog containing transcription factors associated with 2720 target genes and 6401 experimentally validated regulations. When it was available, a distinction between transcriptional activation and inhibition was included for each regulation. Next, we built a tool (www.tfacts.org) that compares submitted gene lists with target genes in the catalog to detect regulated transcription factors. TFactS was validated with published lists of regulated genes in various models and compared to tools based on in silico promoter analysis. We next analyzed the NCI60 cancer microarray data set and showed the regulation of SOX10, MITF and JUN in melanomas. We then performed microarray experiments comparing gene expression response of human fibroblasts stimulated by different growth factors. TFactS predicted the specific activation of Signal transducer and activator of transcription factors by PDGF-BB, which was confirmed experimentally. Our results show that the expression levels of transcription factor target genes constitute a robust signature for transcription factor regulation, and can be efficiently used for microarray data mining.
MeSH term(s)	Catalogs as Topic ; Cell Line, Tumor ; Cells, Cultured ; Data Interpretation, Statistical ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Oligonucleotide Array Sequence Analysis ; Platelet-Derived Growth Factor/pharmacology ; Proto-Oncogene Proteins c-sis ; Reproducibility of Results ; STAT Transcription Factors/metabolism ; Software ; Transcription Factors/metabolism ; User-Computer Interface
Chemical Substances	Platelet-Derived Growth Factor ; Proto-Oncogene Proteins c-sis ; STAT Transcription Factors ; Transcription Factors ; becaplermin (1B56C968OA)
Language	English
Publishing date	2010-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Validation Studies
ZDB-ID	2205588-5
ISSN	1362-4962 ; 1746-8272 ; 0305-1048 ; 0261-3166
ISSN (online)	1362-4962 ; 1746-8272
ISSN	0305-1048 ; 0261-3166
DOI	10.1093/nar/gkq149
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Article: Role des récepteurs du PDGF et du FGF dans les cancers.

Demoulin, J B / Medves, Sandrine / Toffalini, Federica / Essaghir, Ahmed / Kallin, Anders / Montano, Carmen / Velghe, Amélie / Duhoux, François

Bulletin et memoires de l'Academie royale de medecine de Belgique

2010 Volume 165, Issue 5-6, Page(s) 310–315

Abstract: Growth factors of the PDGF and FGF families act through receptor tyrosine kinases. These receptors can be activated by chromosomal rearrangements in myeloid neoplasms associated with hypereosinophilia. We identified a new fusion gene between KANK1 and ... ...

Title translation	Role of PDGF and FGF receptors in cancer.
Abstract	Growth factors of the PDGF and FGF families act through receptor tyrosine kinases. These receptors can be activated by chromosomal rearrangements in myeloid neoplasms associated with hypereosinophilia. We identified a new fusion gene between KANK1 and PDGFRbeta in a patient with thrombocythemia. We showed that such fusion oncoproteins derived from PDGF and FGF receptors escape the normal degradation pathways, leading to their accumulation in cells. This process amplifies signalling leading to cell proliferation. Using microarrays and bioinformatics, we showed that several transcription factors contribute to the control cell growth, including STATS, FOXO and SREBP.
MeSH term(s)	Humans ; Neoplasms/metabolism ; Neoplasms/pathology ; Receptors, Fibroblast Growth Factor/physiology ; Receptors, Platelet-Derived Growth Factor/physiology
Chemical Substances	Receptors, Fibroblast Growth Factor ; Receptors, Platelet-Derived Growth Factor (EC 2.7.10.1)
Language	French
Publishing date	2010
Publishing country	Belgium
Document type	English Abstract ; Journal Article
ZDB-ID	1445946-2
ISSN	0377-8231
ISSN	0377-8231
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Article ; Online: The tyrosine phosphatase SHP2 is required for cell transformation by the receptor tyrosine kinase mutants FIP1L1-PDGFRα and PDGFRα D842V.

Noël, Laura A / Arts, Florence A / Montano-Almendras, Carmen P / Cox, Luk / Gielen, Olga / Toffalini, Federica / Marbehant, Catherine Y / Cools, Jan / Demoulin, Jean-Baptiste

Molecular oncology

2014 Volume 8, Issue 3, Page(s) 728–740

Abstract: Activated forms of the platelet derived growth factor receptor alpha (PDGFRα) have been described in various tumors, including FIP1L1-PDGFRα in patients with myeloproliferative diseases associated with hypereosinophilia and the PDGFRα(D842V) mutant in ... ...

Abstract	Activated forms of the platelet derived growth factor receptor alpha (PDGFRα) have been described in various tumors, including FIP1L1-PDGFRα in patients with myeloproliferative diseases associated with hypereosinophilia and the PDGFRα(D842V) mutant in gastrointestinal stromal tumors and inflammatory fibroid polyps. To gain a better insight into the signal transduction mechanisms of PDGFRα oncogenes, we mutated twelve potentially phosphorylated tyrosine residues of FIP1L1-PDGFRα and identified three mutations that affected cell proliferation. In particular, mutation of tyrosine 720 in FIP1L1-PDGFRα or PDGFRα(D842V) inhibited cell growth and blocked ERK signaling in Ba/F3 cells. This mutation also decreased myeloproliferation in transplanted mice and the proliferation of human CD34(+) hematopoietic progenitors transduced with FIP1L1-PDGFRα. We showed that the non-receptor protein tyrosine phosphatase SHP2 bound directly to tyrosine 720 of FIP1L1-PDGFRα. SHP2 knock-down decreased proliferation of Ba/F3 cells transformed with FIP1L1-PDGFRα and PDGFRα(D842V) and affected ERK signaling, but not STAT5 phosphorylation. Remarkably, SHP2 was not essential for cell proliferation and ERK phosphorylation induced by the wild-type PDGF receptor in response to ligand stimulation, suggesting a shift in the function of SHP2 downstream of oncogenic receptors. In conclusion, our results indicate that SHP2 is required for cell transformation and ERK activation by mutant PDGF receptors.
MeSH term(s)	Animals ; Cell Line ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cells, Cultured ; Humans ; MAP Kinase Signaling System ; Mice ; Mutation ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Phosphorylation ; Protein Binding ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism ; Receptor, Platelet-Derived Growth Factor alpha/genetics ; Receptor, Platelet-Derived Growth Factor alpha/metabolism ; STAT5 Transcription Factor/metabolism ; Signal Transduction ; mRNA Cleavage and Polyadenylation Factors/genetics ; mRNA Cleavage and Polyadenylation Factors/metabolism
Chemical Substances	Oncogene Proteins, Fusion ; STAT5 Transcription Factor ; mRNA Cleavage and Polyadenylation Factors ; FIP1L1-PDGFRA fusion protein, human (EC 2.7.10.1) ; Receptor, Platelet-Derived Growth Factor alpha (EC 2.7.10.1) ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 (EC 3.1.3.48)
Language	English
Publishing date	2014-02-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1016/j.molonc.2014.02.003
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Article: Transcription factor regulation can be accurately predicted from the presence of target gene signatures in microarray gene expression data

Essaghir, Ahmed / Toffalini, Federica / Knoops, Laurent / Kallin, Anders / van Helden, Jacques / Demoulin, Jean-Baptiste

Nucleic acids research. 2010 June, v. 38, no. 11

2010

Abstract	Deciphering transcription factor networks from microarray data remains difficult. This study presents a simple method to infer the regulation of transcription factors from microarray data based on well-characterized target genes. We generated a catalog containing transcription factors associated with 2720 target genes and 6401 experimentally validated regulations. When it was available, a distinction between transcriptional activation and inhibition was included for each regulation. Next, we built a tool (www.tfacts.org) that compares submitted gene lists with target genes in the catalog to detect regulated transcription factors. TFactS was validated with published lists of regulated genes in various models and compared to tools based on in silico promoter analysis. We next analyzed the NCI60 cancer microarray data set and showed the regulation of SOX10, MITF and JUN in melanomas. We then performed microarray experiments comparing gene expression response of human fibroblasts stimulated by different growth factors. TFactS predicted the specific activation of Signal transducer and activator of transcription factors by PDGF-BB, which was confirmed experimentally. Our results show that the expression levels of transcription factor target genes constitute a robust signature for transcription factor regulation, and can be efficiently used for microarray data mining.
Keywords	data collection ; fibroblasts ; gene expression ; genes ; humans ; melanoma ; microarray technology ; models ; nucleic acids ; platelet-derived growth factor ; signal transduction ; transactivators ; transcription (genetics) ; transcriptional activation
Language	English
Dates of publication	2010-06
Size	p. e120.
Document type	Article
ZDB-ID	186809-3
ISSN	0301-5610 ; 0305-1048
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkq149
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Article ; Online: The fusion proteins TEL-PDGFRbeta and FIP1L1-PDGFRalpha escape ubiquitination and degradation.

Toffalini, Federica / Kallin, Anders / Vandenberghe, Peter / Pierre, Pascal / Michaux, Lucienne / Cools, Jan / Demoulin, Jean-Baptiste

Haematologica

2009 Volume 94, Issue 8, Page(s) 1085–1093

Abstract: Background: Chimeric oncogenes encoding constitutively active protein tyrosine kinases are associated with chronic myeloid neoplasms. TEL-PDGFRbeta (TPbeta, also called ETV6-PDGFRB) is a hybrid protein produced by the t(5;12) translocation, FIP1L1- ... ...

Abstract	Background: Chimeric oncogenes encoding constitutively active protein tyrosine kinases are associated with chronic myeloid neoplasms. TEL-PDGFRbeta (TPbeta, also called ETV6-PDGFRB) is a hybrid protein produced by the t(5;12) translocation, FIP1L1-PDGFRalpha (FPalpha) results from a deletion on chromosome 4q12 and ZNF198-FGFR1 is created by the t(8;13) translocation. These fusion proteins are found in patients with myeloid neoplasms associated with eosinophilia. Wild-type receptor tyrosine kinases are efficiently targeted for degradation upon activation, in a process that requires Cbl-mediated monoubiquitination of receptor lysines. Since protein degradation pathways have been identified as useful targets for cancer therapy, the aim of this study was to compare the degradation of hybrid and wild-type receptor tyrosine kinases. Design and methods: We used Ba/F3 as a model cell line, as well as leukocytes from two patients, to analyze hybrid protein degradation. Results: In contrast to the corresponding wild-type receptors, which are quickly degraded upon activation, we observed that TPbeta, FPalpha and the ZNF198-FGFR1 hybrids escaped down-regulation in Ba/F3 cells. The high stability of TPbeta and FPalpha hybrid proteins was confirmed in leukocytes from leukemia patients. Ubiquitination of TPbeta and FPalpha was much reduced compared to that of wild-type receptors, despite marked Cbl phosphorylation in cells expressing hybrid receptors. The fusion of a destabilizing domain to TPbeta induced protein degradation. Instability was reverted by adding the destabilizing domain ligand, Shield1. The destabilization of this modified TPbeta reduced cell transformation and STAT5 activation. Conclusions: We have shown that chimeric receptor tyrosine kinases escape ubiquitination and down-regulation and that their stabilization is critical to efficient stimulation of cell proliferation.
MeSH term(s)	Aged ; Animals ; Becaplermin ; Blotting, Western ; Cell Line ; Cell Proliferation ; Cells, Cultured ; Genotype ; Humans ; Hypereosinophilic Syndrome/blood ; Leukemia, Myelomonocytic, Chronic/blood ; Leukocytes/cytology ; Leukocytes/drug effects ; Leukocytes/metabolism ; Male ; Middle Aged ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Phosphorylation ; Platelet-Derived Growth Factor/pharmacology ; Proto-Oncogene Proteins c-cbl/metabolism ; Proto-Oncogene Proteins c-sis ; Receptor, Platelet-Derived Growth Factor alpha/genetics ; Receptor, Platelet-Derived Growth Factor alpha/metabolism ; Receptor, Platelet-Derived Growth Factor beta/genetics ; Receptor, Platelet-Derived Growth Factor beta/metabolism ; Transfection ; Ubiquitination ; mRNA Cleavage and Polyadenylation Factors/genetics ; mRNA Cleavage and Polyadenylation Factors/metabolism
Chemical Substances	Oncogene Proteins, Fusion ; Platelet-Derived Growth Factor ; Proto-Oncogene Proteins c-sis ; TEL-PDGFRbeta fusion protein, human ; mRNA Cleavage and Polyadenylation Factors ; Becaplermin (1B56C968OA) ; Proto-Oncogene Proteins c-cbl (EC 2.3.2.27) ; FIP1L1-PDGFRA fusion protein, human (EC 2.7.10.1) ; Receptor, Platelet-Derived Growth Factor alpha (EC 2.7.10.1) ; Receptor, Platelet-Derived Growth Factor beta (EC 2.7.10.1)
Language	English
Publishing date	2009-07-30
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2008.001149
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