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BACKGROUND: Despite the effectiveness of current treatment protocols for Ewing sarcoma (ES), many patients still experience relapse, and survival following recurrence is <15%. We aimed to identify genetic variants that predict treatment outcome in children diagnosed with ES. PATIENTS AND METHODS: We carried out a pharmacogenetic study of 384 single-nucleotide polymorphisms (SNPs) in 24 key transport or metabolism genes relevant to drugs used to treat in pediatric patients (<30 years) with histologically confirmed ES. We studied the association of genotypes with tumor response and overall survival (OS) in a discovery cohort of 106 Spanish children, with replication in a second cohort of 389 pediatric patients from across Europe. RESULTS: We identified associations with OS (P < 0.05) for three SNPs in the Spanish cohort that were replicated in the European cohort. The strongest association observed was with rs7190447, located in the ATP-binding cassette subfamily C member 6 (ABCC6) gene [discovery: hazard ratio (HR) = 14.30, 95% confidence interval (CI) = 1.53-134, P = 0.020; replication: HR = 9.28, 95% CI = 2.20-39.2, P = 0.0024] and its correlated SNP rs7192303, which was predicted to have a plausible regulatory function. We also replicated associations with rs4148737 in the ATP-binding cassette subfamily B member 1 (ABCB1) gene (discovery: HR = 2.96, 95% CI = 1.08-8.10, P = 0.034; replication: HR = 1.60, 95% CI = 1.05-2.44, P = 0.029), which we have previously found to be associated with poorer OS in pediatric osteosarcoma patients, and rs11188147 in cytochrome P450 family 2 subfamily C member 8 gene (CYP2C8) (discovery : HR = 2.49, 95% CI = 1.06-5.87, P = 0.037; replication: HR = 1.77, 95% CI = 1.06-2.96, P = 0.030), an enzyme involved in the oxidative metabolism of the ES chemotherapeutic agents cyclophosphamide and ifosfamide. None of the associations with tumor response were replicated. CONCLUSION: Using an integrated pathway-based approach, we identified polymorphisms in ABCC6, ABCB1 and CYP2C8 associated with OS. These associations were replicated in a large independent cohort, highlighting the importance of pharmacokinetic genes as prognostic markers in ES.
Assuntos
Citocromo P-450 CYP2C8/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Sarcoma de Ewing/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Polimorfismo de Nucleotídeo Único , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/patologia , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.
Assuntos
Neoplasias Ósseas/terapia , Comportamento Cooperativo , Comunicação Interdisciplinar , Sarcoma de Ewing/terapia , Neoplasias de Tecidos Moles/terapia , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ósseas/mortalidade , Criança , Ensaios Clínicos como Assunto , Terapia Combinada , Progressão da Doença , Humanos , Terapia Neoadjuvante , Osteotomia , Radioterapia Adjuvante , Sarcoma de Ewing/mortalidade , Neoplasias de Tecidos Moles/mortalidade , Taxa de SobrevidaAssuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Lobo Frontal/patologia , Tumor Rabdoide/patologia , Astrocitoma/diagnóstico por imagem , Astrocitoma/cirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Criança , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/cirurgia , Humanos , Lactente , Imageamento por Ressonância Magnética , Tumor Rabdoide/diagnóstico por imagem , Tumor Rabdoide/cirurgia , Resultado do TratamentoRESUMO
Meningiomas are common central nervous system tumours which present usually in the 4th and 5th decades of life. Loss of constitutional heterozygosity on chromosome 22 in 60% of sporadic meningiomas has implied the involvement of a tumour suppressor gene. The neurofibromatosis type 2 gene (NF2), a prime candidate for involvement in meningioma, was screened for point mutations. After examining eight of the 16 known NF2 exons in 151 meningiomas, 24 inactivating mutations were characterized. Significantly, these aberrations were exclusively detected in tumours which lost the other chromosome 22 allele. These results provide strong evidence that the suppressor gene on chromosome 22, frequently inactivated in meningioma, is the NF2 gene, and suggest that another gene is involved in the development of 40% of meningiomas.
Assuntos
Cromossomos Humanos Par 22 , Genes da Neurofibromatose 2/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Adulto , Idoso , Sequência de Bases , Análise Mutacional de DNA , DNA de Neoplasias/análise , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Mutação Puntual/genética , Supressão Genética/genéticaRESUMO
The genes involved in the t(12;22)(q13;q12) translocation found recurrently in malignant melanoma of soft parts have been characterized and shown to form, in four cases studied, hybrid transcripts. The deduced chimaeric protein encoded by the der(22) chromosome consists of the N-terminal domain of EWS linked to the bZIP domain of ATF-1, a transcription factor which may normally be regulated by cAMP. ATF-1 has not previously been implicated in oncogenesis. EWS was first identified as forming a hybrid transcript in Ewing's sarcoma, which links its N-terminal domain to the DNA binding domain of the FLI-1 gene. Thus the oncogenic conversion of EWS follows a common scheme of activation, exchanging its putative RNA binding domain with different DNA binding domains that appear to be tumour-specific.
Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 22 , Clonagem Molecular , Proteínas de Ligação a DNA , Melanoma/genética , Proteínas de Fusão Oncogênica/genética , Oncogenes , Neoplasias de Tecidos Moles/genética , Fatores de Transcrição/genética , Translocação Genética , Fator 1 Ativador da Transcrição , Sequência de Aminoácidos , Sequência de Bases , Rearranjo Gênico , Humanos , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Proteínas de Fusão Oncogênica/biossíntese , Reação em Cadeia da Polimerase , Mapeamento por Restrição , Fatores de Transcrição/biossíntese , Transcrição Gênica , Células Tumorais CultivadasRESUMO
BACKGROUND: Ewing sarcoma (ES) is an aggressive bone or extraosseous tumour with an unfavourable prognosis when bone marrow metastases are present at diagnosis. The gold standard diagnosis for bone marrow (BM) involvement is cytological and pathological analysis through bone marrow aspiration and biopsy (BMAB). Several recent studies suggest that these invasive and painful procedures could be replaced by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography ((18)FDG-PET/CT), as this nuclear imaging technique is highly sensitive at detecting bone and extraosseous metastases of ES. METHODS: In order to study the precision of (18)FDG-PET/CT in the evaluation of bone marrow metastases at diagnosis, we compared the imaging results with cytological/histological analyses performed on BM samples. We retrospectively studied 180 patients with ES recorded at the Léon Bérard Centre over the past 10 years, who were evaluated by (18)FDG-PET/CT and BMAB at diagnosis. RESULTS: Of the 180 patients, 13 displayed marrow metastases by cytological/histological examination, and only one of these did not have (18)FDG-PET/CT signs of bone marrow involvement, whereas the 167 remaining patients without marrow metastasis all had a negative (18)FDG-PET/CT, except for one. Hence, the sensitivity and specificity of (18)FDG-PET/CT in these patients was 92.3% and 99.4%, respectively. The overall survival at five years of all patients was 67.4% but decrease to 38.5% in the group with bone marrow metastases. CONCLUSION: Given the results presented herein the bone sarcoma group of the French Sarcoma Group suggests that invasive BMAB no longer be systematically performed for the staging at the diagnosis of ES.
Assuntos
Neoplasias da Medula Óssea , Neoplasias Ósseas , Sarcoma de Ewing , Sarcoma , Humanos , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/patologia , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Medula Óssea/diagnóstico por imagem , Medula Óssea/patologia , Estudos Retrospectivos , Compostos Radiofarmacêuticos , Neoplasias Ósseas/secundário , Tomografia por Emissão de Pósitrons , Biópsia , Sarcoma/patologia , Neoplasias da Medula Óssea/diagnóstico por imagem , Neoplasias da Medula Óssea/patologiaRESUMO
Zebrafish xenotransplantation models are increasingly applied for phenotypic drug screening to identify small compounds for precision oncology. Larval zebrafish xenografts offer the opportunity to perform drug screens at high-throughput in a complex in vivo environment. However, the full potential of the larval zebrafish xenograft model has not yet been realized and several steps of the drug screening workflow still await automation to increase throughput. Here, we present a robust workflow for drug screening in zebrafish xenografts using high-content imaging. We established embedding methods for high-content imaging of xenografts in 96-well format over consecutive days. In addition, we provide strategies for automated imaging and analysis of zebrafish xenografts including automated tumor cell detection and tumor size analysis over time. We also compared commonly used injection sites and cell labeling dyes and show specific site requirements for tumor cells from different entities. We demonstrate that our setup allows us to investigate proliferation and response to small compounds in several zebrafish xenografts ranging from pediatric sarcomas and neuroblastoma to glioblastoma and leukemia. This fast and cost-efficient assay enables the quantification of anti-tumor efficacy of small compounds in large cohorts of a vertebrate model system in vivo. Our assay may aid in prioritizing compounds or compound combinations for further preclinical and clinical investigations.
RESUMO
BACKGROUND: In neuroblastoma (NB), the presence of segmental chromosome alterations (SCAs) is associated with a higher risk of relapse. METHODS: In order to analyse the role of SCAs in infants with localised unresectable/disseminated NB without MYCN amplification, we have performed an array CGH analysis of tumours from infants enrolled in the prospective European INES trials. RESULTS: Tumour samples from 218 out of 300 enroled patients could be analysed. Segmental chromosome alterations were observed in 11%, 20% and 59% of infants enroled in trials INES99.1 (localised unresectable NB), INES99.2 (stage 4s) and INES99.3 (stage 4) (P<0.0001). Progression-free survival was poorer in patients whose tumours harboured SCA, in the whole population and in trials INES99.1 and INES99.2, in the absence of clinical symptoms (log-rank test, P=0.0001, P=0.04 and P=0.0003, respectively). In multivariate analysis, a SCA genomic profile was the strongest predictor of poorer progression-free survival. CONCLUSION: In infants with stage 4s MYCN-non-amplified NB, a SCA genomic profile identifies patients who will require upfront treatment even in the absence of other clinical indication for therapy, whereas in infants with localised unresectable NB, a genomic profile characterised by the absence of SCA identifies patients in whom treatment reduction might be possible. These findings will be implemented in a future international trial.
Assuntos
Aberrações Cromossômicas , Neuroblastoma/patologia , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Humanos , Lactente , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/genética , Prognóstico , Estudos Prospectivos , Recidiva , Análise de SobrevidaRESUMO
Integase interactor 1 (INI1), also known as hSNF5, is a protein that interacts with HIV-1 integrase. We report here that a cytoplasmically localized fragment of INI1 (S6; aa183-294) containing the minimal integrase-interaction domain potently inhibits HIV-1 particle production and replication. Mutations in S6 or integrase that disrupt integrase-INI1 interaction abrogated the inhibitory effect. An integrase-deficient HIV-1 transcomplemented with integrase fused to Vpr was not affected by S6. INI1 was specifically incorporated into virions and was required for efficient HIV-1 particle production. These results indicate that INI1 is required for late events in the viral life cycle, and that ectopic expression of S6 inhibits HIV-1 replication in a transdominant manner via its specific interaction with integrase within the context of Gag-Pol, providing a novel strategy to control HIV-1 replication.
Assuntos
Proteínas de Ligação a DNA/fisiologia , HIV-1/ultraestrutura , Vírion/metabolismo , Sequência de Bases , Linhagem Celular , Núcleo Celular/metabolismo , Proteínas Cromossômicas não Histona , Citoplasma/metabolismo , Primers do DNA , Proteínas de Ligação a DNA/genética , Genes Dominantes , Humanos , Proteína SMARCB1 , Fatores de TranscriçãoRESUMO
BACKGROUND: Rhabdomyosarcomas (RMSs) are primarily paediatric sarcomas that resemble developing skeletal muscle. Our aim was to determine the effects of microRNAs (miRNA) that have been implicated in muscle development on the clinical behaviour of RMSs. METHODS: Expression levels of miR-1, miR-206, miR-133a and miR-133b were quantified by RT-PCR in 163 primary paediatric RMSs, plus control tissues, and correlated with clinico-pathological features. Correlations with parallel gene expression profiling data for 84 samples were used to identify pathways associated with miR-206. Synthetic miR-206 was transfected into RMS cell lines and phenotypic responses assessed. RESULTS: Muscle-specific miRNAs levels were lower in RMSs compared with skeletal muscle but generally higher than in other normal tissues. Low miR-206 expression correlated with poor overall survival and was an independent predictor of shorter survival in metastatic embryonal and alveolar cases without PAX3/7-FOXO1 fusion genes. Low miR-206 expression also significantly correlated with high SIOP stage and the presence of metastases at diagnosis. High miR-206 expression strongly correlated with genes linked to muscle differentiation and low expression was associated with genes linked to MAPkinase and NFKappaB pathway activation. Increasing miR-206 expression in cell lines inhibited cell growth and migration and induced apoptosis that was associated with myogenic differentiation in some, but not all, cell lines. CONCLUSION: miR-206 contributes to the clinical behaviour of RMSs and the pleiotropic effects of miR-206 supports therapeutic potential.
Assuntos
MicroRNAs/metabolismo , Rabdomiossarcoma/genética , Adolescente , Adulto , Diferenciação Celular , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Músculo Esquelético/metabolismo , Rabdomiossarcoma/mortalidade , Transfecção , Proteínas Supressoras de TumorRESUMO
SMARCB1 is a tumor suppressor gene, which is part of SWI/SNF complex involved in transcriptional regulation. Recently, loss of SMARCB1 expression has been reported in gastrointestinal carcinomas. Our purpose was to evaluate the incidence and prognostic value of SMARCB1 loss in colon carcinoma (CC). Patients with stage III CC (n= 1695), and a second cohort of 23 patients with poorly differentiated CC were analyzed. Immunohistochemistry for SMARCB1 was performed on tissue microarrays, and cases with loss of expression were controlled on whole sections. Loss of SMARCB1 was compared with the clinico-pathological and molecular characteristics, and the prognostic value was evaluated. Loss of SMARCB1 was identified in 12 of 1695 (0.7%) patients with stage III CC. Whole section controls showed a complete loss in only one of these cases, corresponding to a medullary carcinoma. SMARCB1 loss was not associated with histological grade, tumor size nor survival. In the cohort of poorly differentiated CC, we detected 2/23 (8.7%) cases with loss of SMARCB1; one was rhabdoid while the other had medullary and mucinous histology. These 2 cases were deficient for MisMatched Repair (dMMR) and mutated for BRAF. SMARCB1 loss is rare in stage III CC, but appears more frequent in poorly differentiated CC.
Assuntos
Neoplasias do Colo/metabolismo , Proteína SMARCB1/deficiência , Adulto , Idoso , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteína SMARCB1/biossíntese , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Adulto JovemRESUMO
The t(11;22) chromosomal translocation specifically linked to Ewing sarcoma and primitive neuroectodermal tumor results in a chimeric molecule fusing the amino-terminus-encoding region of the EWS gene to the carboxyl-terminal DNA-binding domain encoded by the FLI-1 gene. As the function of the protein encoded by the EWS gene remains unknown, we investigated the putative role of EWS in RNA polymerase II (Pol II) transcription by comparing its activity with that of its structural homolog, hTAFII68. We demonstrate that a portion of EWS is able to associate with the basal transcription factor TFIID, which is composed of the TATA-binding protein (TBP) and TBP-associated factors (TAFIIs). In vitro binding studies revealed that both EWS and hTAFII68 interact with the same TFIID subunits, suggesting that the presence of EWS and that of hTAFII68 in the same TFIID complex may be mutually exclusive. Moreover, EWS is not exclusively associated with TFIID but, similarly to hTAFII68, is also associated with the Pol II complex. The subunits of Pol II that interact with EWS and hTAFII68 have been identified, confirming the association with the polymerase. In contrast to EWS, the tumorigenic EWS-FLI-1 fusion protein is not associated with either TFIID or Pol II in Ewing cell nuclear extracts. These observations suggest that EWS and EWS-FLI-1 may play different roles in Pol II transcription.
Assuntos
Proteínas de Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , RNA Polimerase II/metabolismo , Proteínas de Ligação a RNA/metabolismo , Sarcoma de Ewing/metabolismo , Fatores Associados à Proteína de Ligação a TATA , Fatores de Transcrição TFII/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Humanos , Proteínas de Neoplasias/genética , Mapeamento de Peptídeos , Proteína Proto-Oncogênica c-fli-1 , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética , Coelhos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Sarcoma de Ewing/genética , Spodoptera/citologia , Transativadores/metabolismo , Fator de Transcrição TFIID , Fatores de Transcrição/genética , Células Tumorais CultivadasRESUMO
The 5' half of the EWS gene has recently been described to be fused to the 3' regions of genes encoding the DNA-binding domain of several transcriptional regulators, including ATF1, FLI-1, and ERG, in several human tumors. The most frequent occurrence of this situation results from the t(11;22)(q24;q12) chromosome translocation specific for Ewing sarcoma (ES) and related tumors which joins EWS sequences to the 3' half of FLI-1, which encodes a member of the Ets family of transcriptional regulators. We show here that this chimeric gene encodes an EWS-FLI-1 nuclear protein which binds DNA with the same sequence specificity as the wild-type parental FLI-1 protein. We further show that EWS-FLI-1 is an efficient sequence-specific transcriptional activator of model promoters containing FLI-1 (Ets)-binding sites, a property which is strictly dependent on the presence of its EWS domain. Comparison of the properties of the N-terminal activation domain of FLI-1 to those of the EWS domain of the fusion protein indicates that EWS-FLI-1 has altered transcriptional activation properties compared with FLI-1. These results suggest that EWS-FLI-1 contributes to the transformed phenotype of ES tumor cells by inducing the deregulated and/or unscheduled activation of genes normally responsive to FLI-1 or to other close members of the Ets family. ES and related tumors are characterized by an elevated level of c-myc expression. We show that EWS-FLI-1 is a transactivator of the c-myc promoter, suggesting that upregulation of c-myc expression is under control of EWS-FLI-1.
Assuntos
Neoplasias Ósseas/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 22 , Proteínas de Ligação a DNA/metabolismo , Genes , Proteínas Recombinantes de Fusão/metabolismo , Sarcoma de Ewing/genética , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Translocação Genética , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico , Primers do DNA , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Humanos , Dados de Sequência Molecular , Plasmídeos , Reação em Cadeia da Polimerase , Proteína Proto-Oncogênica c-fli-1 , Proteínas Proto-Oncogênicas/isolamento & purificação , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-ets , Proteínas Recombinantes de Fusão/biossíntese , Mapeamento por Restrição , Transativadores/biossíntese , Transativadores/genética , Transcrição GênicaRESUMO
Ewing sarcoma is characterized by chromosomal translocations fusing the EWS gene with various members of the ETS family of transcription factors, most commonly FLI1. EWS-FLI1 is an aberrant transcription factor driving Ewing sarcoma tumorigenesis by either transcriptionally inducing or repressing specific target genes. Herein, we showed that Sprouty 1 (SPRY1), which is a physiological negative feedback inhibitor downstream of fibroblast growth factor (FGF) receptors (FGFRs) and other RAS-activating receptors, is an EWS-FLI1 repressed gene. EWS-FLI1 knockdown specifically increased the expression of SPRY1, while other Sprouty family members remained unaffected. Analysis of SPRY1 expression in a panel of Ewing sarcoma cells showed that SPRY1 was not expressed in Ewing sarcoma cell lines, suggesting that it could act as a tumor suppressor gene in these cells. In agreement, induction of SPRY1 in three different Ewing sarcoma cell lines functionally impaired proliferation, clonogenic growth and migration. In addition, SPRY1 expression inhibited extracellular signal-related kinase/mitogen-activated protein kinase (MAPK) signaling induced by serum and basic FGF (bFGF). Moreover, treatment of Ewing sarcoma cells with the potent FGFR inhibitor PD-173074 reduced bFGF-induced proliferation, colony formation and in vivo tumor growth in a dose-dependent manner, thus mimicking SPRY1 activity in Ewing sarcoma cells. Although the expression of SPRY1 was low when compared with other tumors, SPRY1 was variably expressed in primary Ewing sarcoma tumors and higher expression levels were significantly associated with improved outcome in a large patient cohort. Taken together, our data indicate that EWS-FLI1-mediated repression of SPRY1 leads to unrestrained bFGF-induced cell proliferation, suggesting that targeting the FGFR/MAPK pathway can constitute a promising therapeutic approach for this devastating disease.
Assuntos
Proteínas de Membrana/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Fosfoproteínas/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patologia , Proteínas ras/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos SCID , Transdução de Sinais , Proteínas ras/metabolismoRESUMO
Ewing sarcoma is characterized by the expression of the chimeric EWSR1-FLI1 transcription factor. Proteomic analyses indicate that the decrease of EWSR1-FLI1 expression leads to major changes in effectors of the dynamics of the actin cytoskeleton and the adhesion processes with a shift from cell-to-cell to cell-matrix adhesion. These changes are associated with a dramatic increase of in vivo cell migration and invasion potential. Importantly, EWSR1-FLI1 expression, evaluated by single-cell RT-ddPCR/immunofluorescence analyses, and activity, assessed by expression of EWSR1-FLI1 downstream targets, are heterogeneous in cell lines and in tumours and can fluctuate along time in a fully reversible process between EWSR1-FLI1high states, characterized by highly active cell proliferation, and EWSR1-FLI1low states where cells have a strong propensity to migrate, invade and metastasize. This new model of phenotypic plasticity proposes that the dynamic fluctuation of the expression level of a dominant oncogene is an intrinsic characteristic of its oncogenic potential.
Assuntos
Proteínas de Ligação a Calmodulina/biossíntese , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/biossíntese , Proteína Proto-Oncogênica c-fli-1/biossíntese , Proteínas de Ligação a RNA/biossíntese , Sarcoma de Ewing/metabolismo , Animais , Proteínas de Ligação a Calmodulina/genética , Linhagem Celular Tumoral , Camundongos , Camundongos SCID , Invasividade Neoplásica , Metástase Neoplásica , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Peixe-ZebraAssuntos
Proteínas E1A de Adenovirus/genética , Neoplasias Ósseas/genética , Sarcoma de Ewing/genética , Translocação Genética , Adenovírus Humanos/genética , Adenovírus Humanos/patogenicidade , Neoplasias Ósseas/virologia , Transformação Celular Neoplásica/genética , Transformação Celular Viral/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 22/genética , Humanos , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1 , Proteína EWS de Ligação a RNA , Sarcoma de Ewing/virologia , Fatores de Transcrição/genética , Células Tumorais CultivadasRESUMO
We report three cases of complete traumatic tibialis posterior tendon rupture which occurred after ankle fracture. Diagnosis was established at surgery. Repair of the non-degenerative tendon was achieved during the procedure for osteosynthesis of the malleolar fracture. Fractures healed a few months after surgery. The posterior tibialis muscle tendon functioned plantar arch was normal, except in one patient with multiple injuries who died in intensive care thirteen days after the accident. Although exceptional, injury of the tibialis posterior tendon should not be overlooked after ankle fracture. These injuries become apparent only at surgery for the malleolar fracture since pain hinders clinical examination. Primary suture best guarantees a good functional outcome. Residual pain, deficit in active inversion of the foot, modified medial longitudinal arch, or progression to planovalgus are retrospective diagnostic signs.
Assuntos
Traumatismos do Tornozelo/complicações , Articulação do Tornozelo/patologia , Fraturas Ósseas/complicações , Traumatismos dos Tendões , Adulto , Traumatismos do Tornozelo/cirurgia , Evolução Fatal , Fixação Interna de Fraturas/métodos , Fraturas Ósseas/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Traumatismo Múltiplo , Ruptura , Técnicas de Sutura , Tendões/cirurgia , Resultado do TratamentoRESUMO
Loss of bone stock in the elbow joint raises serious problems for reconstruction surgery. Total allograft-prosthesis composite arthroplasty is an attractive alternative to revision prosthesis and isolated osteoarticular allografts known to have many drawbacks. Use of this method is rather recent for revision procedures and tumor surgery and posttraumatic cases are rare (five reported cases). We report a case of posttraumatic floating elbow treated with this technique. At 75 months follow-up, the clinical result was excellent with the Mayo Clinic performance score at 100/100. Allograft-native bone fusion was complete and there were no complications, particularly no loosening. This composite technique is particularly well adapted for patients with major bone and joint loss. It can avoid the specific problems associated with each of the techniques used alone. The allograft reconstructs bone stock while the prosthetic component avoids the clinical expression of graft epiphyseal lysis.
Assuntos
Artroplastia de Substituição , Transplante Ósseo , Articulação do Cotovelo/cirurgia , Úmero/cirurgia , Seguimentos , Humanos , Fraturas do Úmero/cirurgia , Luxações Articulares/cirurgia , Instabilidade Articular/cirurgia , Prótese Articular , Masculino , Pessoa de Meia-Idade , Amplitude de Movimento Articular/fisiologia , Transplante Homólogo , Lesões no CotoveloRESUMO
The chromatin-remodeling hSNF5/INI1 gene has recently been shown to act as a tumor suppressor gene in rhabdoid tumors (RTs). In an attempt to further characterize the main chromosomal mechanisms involved in hSNF5/INI1 inactivation in RTs, we report here the molecular cytogenetic data obtained in 12 cell lines harboring hSNF5/INI1 mutations and/or deletions in relation to the molecular genetic analysis using polymorphic markers extended to both extremities of chromosome 22q. On the whole, mitotic recombination occurring in the proximal part of chromosome 22q, as demonstrated in five cases, and nondisjunction/duplication, highly suspected in two cases (processes leading respectively to partial or complete isodisomy), appear to be major mechanisms associated with hSNF5/INI1 inactivation. Such isodisomy accompanies each of the RTs exhibiting two cytogenetically normal chromosomes 22. This results in homozygosity for the mutation at the hSNF5/INI1 locus. An alternate mechanism accounting for hSNF5/INI1 inactivation observed in these tumors is homozygous deletion in the rhabdoid consensus region. This was observed in each of the four tumors carrying a chromosome 22q abnormality and, in particular, in the three tumors with chromosomal translocations. Only one case of our series illustrates the mutation/deletion classical model proposed for the double-hit inactivation of a tumor suppressor gene.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 22 , Proteínas de Ligação a DNA/genética , Deleção de Genes , Mutação , Recombinação Genética , Tumor Rabdoide/genética , Proteínas Cromossômicas não Histona , Mapeamento Cromossômico , Sequência Consenso , Genes Supressores de Tumor , Marcadores Genéticos , Homozigoto , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Repetições de Microssatélites , Mitose , Polimorfismo Genético , Proteína SMARCB1 , Fatores de Transcrição , Translocação Genética , Células Tumorais CultivadasRESUMO
Over-reduction is a classical complication following pinning of distal radius fractures. Indeed, the pinning techniques derived from Kapandji's technique do not allow anterior stabilization. A literature review and our experience show that it is an underestimated complication that can affect up to one-third of cases, but that is well tolerated if the anterior tilt is less than 20°. Excessive angulation of the dorsal intrafocal K-wires becomes a significant risk factor beyond 60°. Volar comminution of the fracture is an obvious predisposing factor. We will outline our ideas on the topic and present a new pinning technique, which has reduced the over-reduction rate to below 3 %: multiple mixed pinning combines two dorsal intrafocal K-wires with two trans-styloid K-wires along the anterior and posterior cortices of the radius to provide true sagittal stabilization of the fracture. This technique is suitable for fractures without major instability or associated anterior comminution-Milliez types 1 and 2 are its best indications. In our practice, there still is a place for pinning of non-complex fractures in young active subjects. More than 20° malunion in flexion can lead to symptoms; in this instance, isolated opening osteotomy of the radius is the most suitable technique.