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1.
Blood ; 121(25): 5064-7, 2013 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-23673860

RESUMO

The MLLT10 gene, located at 10p13, is a known partner of MLL and PICALM in specific leukemic fusions generated from recurrent 11q23 and 11q14 chromosome translocations. Deep sequencing recently identified NAP1L1/12q21 as another MLLT10 partner in T-cell acute lymphoblastic leukemia (T-ALL). In pediatric T-ALL, we have identified 2 RNA processing genes, that is, HNRNPH1/5q35 and DDX3X/Xp11.3 as new MLLT10 fusion partners. Gene expression profile signatures of the HNRNPH1- and DDX3X-MLLT10 fusions placed them in the HOXA subgroup. Remarkably, they were highly similar only to PICALM-MLLT10-positive cases. The present study showed MLLT10 promiscuity in pediatric T-ALL and identified a specific MLLT10 signature within the HOXA subgroup.


Assuntos
RNA Helicases DEAD-box/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Transcrição/genética , Criança , Humanos , Hibridização in Situ Fluorescente , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma , Translocação Genética
2.
Pediatr Blood Cancer ; 59(7): 1275-9, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22359409

RESUMO

BACKGROUND: Comprehensive care and advances in clinical investigations have reduced morbidity and mortality in sickle cell disease (SCD), but only a minority of children with SCD has access to comprehensive care. In Europe the majority of patients with SCD are immigrants who present barriers in accessing the health system; therefore, new evidence-based models of comprehensive care are needed to ensure that all SCD patients receive high-quality care, overcoming patient- and health system-related barriers. We wanted to verify if addressing the specific needs of immigrant patients contributes to improving adherence. PROCEDURES: Linguistic, cultural, social issues were considered in organizing comprehensive care in 2006. Hospital's records were used to determine access from 2006 to 2010 and to compare adherence before and after 2006. RESULTS: Ninety-four patients with SCD were enrolled in comprehensive care; 94% were first generation immigrants (81% African). Age at diagnosis was higher for children born abroad vs. children born in Italy (66.08 vs 25.36 months, P < 0.005). Since 2006, children were seen at least once a year, with 100% adherence to follow-up appointments. Coverage increased from 26% to 97% for flu vaccination, from 80% to 92% for pneumococcus immunization, from 27% to 100% for Transcranial Doppler (TCD) screening (P < 0.001). Emergency Department access/patient/year and inpatient admissions/patient/year decreased from 2.3 to 0.98 and from 0.30 to 0.25, respectively (P < 0.001). CONCLUSIONS: Comprehensive care can be delivered to vulnerable groups obtaining high adherence if linguistic, cultural, social issues are addressed. This model may merit assessment in other communities where immigrants represent the majority of patients.


Assuntos
Anemia Falciforme/terapia , Assistência Integral à Saúde , Emigrantes e Imigrantes , Qualidade da Assistência à Saúde , África Subsaariana/etnologia , Amoxicilina/uso terapêutico , Antibioticoprofilaxia , Criança , Pré-Escolar , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Imunização , Lactente , Itália , Masculino , Cooperação do Paciente , Apoio Social
3.
Cytometry A ; 79(11): 903-11, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22015731

RESUMO

A number of apoptotic stimuli produce a different response by CD4(+) regulatory and effector lymphocytes. So far, little is known concerning the sensitivity of CD4(+) regulatory T cells (Treg) to genotoxic agents. Observations from a mouse model suggest that Treg are more resistant to DNA damage compared to CD4(+) T effector cells (Teff). By flow cytometry we analysed the apoptotic response to genotoxic stimuli in culture, comparing Treg and Teff. CD4(+) regulatory lymphocytes appeared to be more resistant than CD4(+) effector lymphocytes. Results of costaining experiments for CD45RA suggest that this dissimilarity is not related to the differentiation to a CD45RA negative phenotype. Further, neither the antiapoptotic protein Bcl-2 nor Bcl-xL were found to be expressed in greater amounts by Treg compared to Teff. The differential sensitivity of Treg and Teff to DNA-damage inducing agents may be of clinical relevance in cancer therapy. © 2011 International Society for Advancement of Cytometry.


Assuntos
Dano ao DNA/efeitos dos fármacos , Etoposídeo/farmacologia , Citometria de Fluxo/métodos , Antígenos Comuns de Leucócito/análise , Coloração e Rotulagem/métodos , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Anexina A5/análise , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Expressão Gênica , Humanos , Especificidade de Órgãos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
4.
Eur J Haematol ; 83(5): 406-19, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19558506

RESUMO

OBJECTIVE: Gene expression profiles become increasingly more important for diagnostic procedures, allowing clinical predictions including treatment response and outcome. However, the establishment of specific and robust gene signatures from microarray data sets requires the analysis of large numbers of patients and the application of complex biostatistical algorithms. Especially in case of rare diseases and due to these constrains, diagnostic centers with limited access to patients or bioinformatic resources are excluded from implementing these new technologies. METHOD: In our study we sought to overcome these limitations and for proof of principle, we analyzed the rare t(4;11) leukemia disease entity. First, gene expression data of each t(4;11) leukemia patient were normalized by pairwise subtraction against normal bone marrow (n = 3) to identify significantly deregulated gene sets for each patient. RESULT: A 'core signature' of 186 commonly deregulated genes present in each investigated t(4;11) leukemia patient was defined. Linking the obtained gene sets to four biological discriminators (HOXA gene expression, age at diagnosis, fusion gene transcripts and chromosomal breakpoints) divided patients into two distinct subgroups: the first one comprised infant patients with low HOXA genes expression and the MLL breakpoints within introns 11/12. The second one comprised non-infant patients with high HOXA expression and MLL breakpoints within introns 9/10. CONCLUSION: A yet homogeneous leukemia entity was further subdivided, based on distinct genetic properties. This approach provided a simplified way to obtain robust and disease-specific gene signatures even in smaller cohorts.


Assuntos
Cromossomos Humanos Par 11/metabolismo , Cromossomos Humanos Par 4/metabolismo , Regulação Leucêmica da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Translocação Genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 4/genética , Feminino , Perfilação da Expressão Gênica/métodos , Histona-Lisina N-Metiltransferase , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Humanos , Masculino , Proteína de Leucina Linfoide-Mieloide/biossíntese , Proteína de Leucina Linfoide-Mieloide/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Proteínas de Fusão Oncogênica/biossíntese , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
5.
Oncotarget ; 8(26): 42398-42413, 2017 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-28415578

RESUMO

ERG-related leukemia is a B cell precursor acute lymphoblastic leukemia (BCP ALL) subtype characterized by aberrant expression of DUX4 and ERG transcription factors, and highly recurrent ERG intragenic deletions. ERG-related patients have remarkably favorable outcome despite a high incidence of inauspicious IKZF1 aberrations.We describe clinical and genomic features of the ERG-related cases in an unselected cohort of B-other BCP ALL pediatric patients enrolled in the AIEOP ALL 2000 therapeutic protocol. We report a small noncoding RNA signature specific of ERG-related group, with up-regulation of miR-125b-2 cluster on chromosome 21 and several snoRNAs in the Prader-Willi locus at 15q11.2, including the orphan SNORD116 cluster.


Assuntos
Expressão Gênica , MicroRNAs/genética , Família Multigênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , RNA Nucleolar Pequeno/genética , Regulador Transcricional ERG/metabolismo , Adolescente , Antineoplásicos/uso terapêutico , Biomarcadores , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 21/genética , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Masculino , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Locos de Características Quantitativas , Deleção de Sequência , Regulador Transcricional ERG/genética , Transcriptoma , Resultado do Tratamento
6.
F1000Res ; 5: 683, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27508056

RESUMO

Background Publishing in scientific journals is one of the most important ways in which scientists disseminate research to their peers and to the wider public. Pre-publication peer review underpins this process, but peer review is subject to various criticisms and is under pressure from growth in the number of scientific publications. Methods Here we examine an element of the editorial process at eLife, in which the Reviewing Editor usually serves as one of the referees, to see what effect this has on decision times, decision type, and the number of citations. We analysed a dataset of 8,905 research submissions to eLife since June 2012, of which 2,747 were sent for peer review. This subset of 2747 papers was then analysed in detail.   Results The Reviewing Editor serving as one of the peer reviewers results in faster decision times on average, with the time to final decision ten days faster for accepted submissions (n=1,405) and five days faster for papers that were rejected after peer review (n=1,099). Moreover, editors acting as reviewers had no effect on whether submissions were accepted or rejected, and a very small (but significant) effect on citation rates. Conclusions An important aspect of eLife's peer-review process is shown to be effective, given that decision times are faster when the Reviewing Editor serves as a reviewer. Other journals hoping to improve decision times could consider adopting a similar approach.

7.
Oncotarget ; 6(3): 1569-81, 2015 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-25595912

RESUMO

The PAX5 gene is altered in 30% of BCP-ALL patients and PAX5 chromosomal translocations account for 2-3% of cases. Although PAX5 fusion genes significantly affect the transcription of PAX5 target genes, their role in sustaining leukemia cell survival is poorly understood. In an in vitro model of PAX5/ETV6 leukemia, we demonstrated that Lck hyper-activation, and down-regulation of its negative regulator Csk, lead to STAT5 hyper-activation and consequently to the up-regulation of the downstream effectors, cMyc and Ccnd2. More important, cells from PAX5 translocated patients show LCK up-regulation and over-activation, as well as STAT5 hyper-phosphorylation, compared to PAX5 wt and PAX5 deleted cases. As in BCR/ABL1 positive ALL, the hyper-activation of STAT5 pathway can represent a survival signal in PAX5 translocated cells, alternative to the pre-BCR, which is down-regulated. The LCK inhibitor BIBF1120 selectively reverts this phenomenon both in the murine model and in leukemic primary cells. LCK inhibitor could therefore represent a suitable candidate drug to target this subgroup of ALL patients.


Assuntos
Proteína Tirosina Quinase p56(lck) Linfócito-Específica/biossíntese , Fator de Transcrição PAX5/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Fator de Transcrição STAT5/metabolismo , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Lactente , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Proteínas Proto-Oncogênicas c-ets/biossíntese , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Fator de Transcrição STAT5/genética , Transdução de Sinais , Regulação para Cima , Variante 6 da Proteína do Fator de Translocação ETS
8.
Cancer Biol Ther ; 16(8): 1160-71, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26023803

RESUMO

Preoperative chemoradiotherapy is widely used to improve local control of disease, sphincter preservation and to improve survival in patients with locally advanced rectal cancer. Patients enrolled in the present study underwent preoperative chemoradiotherapy, followed by surgical excision. Response to chemoradiotherapy was evaluated according to Mandard's Tumor Regression Grade (TRG). TRG 3, 4 and 5 were considered as partial or no response while TRG 1 and 2 as complete response. From pretherapeutic biopsies of 84 locally advanced rectal carcinomas available for the analysis, only 42 of them showed 70% cancer cellularity at least. By determining gene expression profiles, responders and non-responders showed significantly different expression levels for 19 genes (P < 0.001). We fitted a logistic model selected with a stepwise procedure optimizing the Akaike Information Criterion (AIC) and then validated by means of leave one out cross validation (LOOCV, accuracy = 95%). Four genes were retained in the achieved model: ZNF160, XRCC3, HFM1 and ASXL2. Real time PCR confirmed that XRCC3 is overexpressed in responders group and HFM1 and ASXL2 showed a positive trend. In vitro test on colon cancer resistant/susceptible to chemoradioterapy cells, finally prove that XRCC3 deregulation is extensively involved in the chemoresistance mechanisms. Protein-protein interactions (PPI) analysis involving the predictive classifier revealed a network of 45 interacting nodes (proteins) with TRAF6 gene playing a keystone role in the network. The present study confirmed the possibility that gene expression profiling combined with integrative computational biology is useful to predict complete responses to preoperative chemoradiotherapy in patients with advanced rectal cancer.


Assuntos
Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/radioterapia , Adulto , Idoso , Biomarcadores Tumorais/genética , Quimiorradioterapia , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Retais/genética , Resultado do Tratamento , Células Tumorais Cultivadas/efeitos dos fármacos , Adulto Jovem
9.
Ital J Pediatr ; 39: 36, 2013 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-23735165

RESUMO

BACKGROUND: Sickle Cell Disease (SCD) is the most common genetic disease worldwide. Neurological events are among the most worrisome clinical complications of SCD and are frequently accompanied by cognitive impairment. Intellectual function in SCD may vary according to genetic and environmental factors. Immigrant children with SCD are increasing at a global level and display specific health care needs. The aim of our multicenter study was to describe the intellectual function of first generation African immigrants with SCD and the influence of sociodemographic factors on its characteristics. METHODS: The Wechsler Intelligence Scales were administered to evaluate broad intellectual functions in children with SCD and in age-matched healthy siblings. Patients' clinical, socio-demographic, Magnetic Resonance Imaging (MRI) and Angiography (MRA) data were correlated to intellectual function scores. RESULTS: 68 children, mean age 8.95 years were evaluated. 72% spoke three languages, 21% two. FSIQ was <75 in 25% of the children. Mean VIQ was lower than PIQ in 75%. Mean verbal subtest scores were lower than performance scores. Female gender, number of languages spoken at home and mother's employment were associated with single subtest performances (p < 0.05). MRA was abnormal in 73.4% and MRI in 35.9%. No significant correlation was established between silent lesions and intellectual function, even if patients with lesions performed worse. Fifteen siblings performed better than patients on cognitive domains, including language (p < 0.05). CONCLUSIONS: Immigrant bilingual children with SCD seem to display a rate of cognitive impairment similar to their monolingual counterparts but a more pronounced and precocious onset of language difficulties. Adjunctive tests need to be considered in this group of patients to better define their specific deficits.


Assuntos
Anemia Falciforme/etnologia , Anemia Falciforme/psicologia , População Negra/estatística & dados numéricos , Transtornos Cognitivos/etnologia , Transtornos Cognitivos/psicologia , Idioma , Pobreza , Anemia Falciforme/complicações , Anemia Falciforme/diagnóstico , Criança , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Emigrantes e Imigrantes , Feminino , Humanos , Itália/epidemiologia , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Masculino , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Fatores Socioeconômicos , Escalas de Wechsler
10.
Leuk Res ; 37(8): 928-35, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23735857

RESUMO

Multiple lesions in genes that are involved in cell cycle control, proliferation, survival and differentiation underlie T-cell acute lymphoblastic leukaemia (T-ALL). We translated these biological insights into clinical practice to improve diagnostic work-ups and patient management. Combined interphase fluorescence in situ hybridization (CI-FISH), single nucleotide polymorphism (SNP), and gene expression profiles (GEP) were applied in 51 children with T-ALL who were stratified according to minimal residual disease (MRD) risk categories (AIEOP-BFM ALL2000). CI-FISH identified type A abnormalities in 90% of patients. Distribution of each was in line with the estimated incidence in childhood T-ALL: 37.5% TAL/LMO, 22.5% HOXA, 20% TLX3, 7.5% TLX1, and 2.5% NKX2-1. GEP predictions concurred. SNP detected type B abnormalities in all cases, thus linking type A and B lesions. This approach provided an accurate, comprehensive genomic diagnosis and a complementary GEP-based classification of T-ALL in children. Dissecting primary and secondary lesions within MRD categories could improve prognostic criteria for the majority of patients and be a step towards personalized diagnosis.


Assuntos
Genômica/métodos , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Predisposição Genética para Doença/genética , Genótipo , Humanos , Hibridização in Situ Fluorescente/métodos , Cariótipo , Masculino , Polimorfismo de Nucleotídeo Único , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
11.
Cancer Cell ; 19(2): 206-17, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21295523

RESUMO

We investigated the engraftment properties and impact on patient outcome of 50 pediatric acute lymphoblastic leukemia (ALL) samples transplanted into NOD/SCID mice. Time to leukemia (TTL) was determined for each patient sample engrafted as weeks from transplant to overt leukemia. Short TTL was strongly associated with high risk for early relapse, identifying an independent prognostic factor. This high-risk phenotype is reflected by a gene signature that upon validation in an independent patient cohort (n = 197) identified a high-risk cluster of patients with early relapse. Furthermore, the signature points to independent pathways, including mTOR, involved in cell growth and apoptosis. The pathways identified can directly be targeted, thereby offering additional treatment approaches for these high-risk patients.


Assuntos
Perfilação da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Apoptose/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recidiva , Análise de Sobrevida , Transplante Heterólogo
12.
PLoS One ; 5(10): e13552, 2010 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-21042412

RESUMO

BACKGROUND: In spite of leukemia therapy improvements obtained over the last decades, therapy is not yet effective in all cases. Current approaches in Acute Lymphoblastic Leukemia (ALL) research focus on identifying new molecular targets to improve outcome for patients with a dismal prognosis. In this light phosphoproteomics seems to hold great promise for the identification of proteins suitable for targeted therapy. METHODOLOGY/PRINCIPAL FINDINGS: We employed Reverse Phase Protein Microarrays to identify aberrantly activated proteins in 118 pediatric B-cell precursor (BCP)-ALL patients. Signal transduction pathways were assayed for activation/expression status of 92 key signalling proteins. We observed an increased activation/expression of several pathways involved in cell proliferation in poor clinical prognosis patients. MLL-rearranged tumours revealed BCL-2 hyperphosphorylation through AMPK activation, which indicates that AMPK could provide a functional role in inhibiting apoptosis in MLL-rearranged patients, and could be considered as a new potential therapeutic target. Second, in patients with poor clinical response to prednisone we observed the up-modulation of LCK activity with respect to patients with good response. This tyrosine-kinase can be down-modulated with clinically used inhibitors, thus modulating LCK activity could be considered for further studies as a new additional therapy for prednisone-resistant patients. Further we also found an association between high levels of CYCLIN E and relapse incidence. Moreover, CYCLIN E is more expressed in early relapsed patients, who usually show an unfavourable prognosis. CONCLUSIONS/SIGNIFICANCE: We conclude that functional protein pathway activation mapping revealed specific deranged signalling networks in BCP-ALL that could be potentially modulated to produce a better clinical outcome for patients resistant to standard-of-care therapies.


Assuntos
Leucemia de Células B/tratamento farmacológico , Adenilato Quinase/metabolismo , Western Blotting , Linhagem Celular Tumoral , Criança , Pré-Escolar , Humanos , Imunoprecipitação , Lactente , Leucemia de Células B/metabolismo , Leucemia de Células B/patologia , Proteínas de Neoplasias/metabolismo , Prednisona/uso terapêutico , Prognóstico , Proteômica , Transdução de Sinais
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