RESUMO
OBJECTIVE: To conduct a randomized, controlled trial to evaluate the efficacy of the Early Start Denver Model (ESDM), a comprehensive developmental behavioral intervention, for improving outcomes of toddlers diagnosed with autism spectrum disorder (ASD). METHODS: Forty-eight children diagnosed with ASD between 18 and 30 months of age were randomly assigned to 1 of 2 groups: (1) ESDM intervention, which is based on developmental and applied behavioral analytic principles and delivered by trained therapists and parents for 2 years; or (2) referral to community providers for intervention commonly available in the community. RESULTS: Compared with children who received community-intervention, children who received ESDM showed significant improvements in IQ, adaptive behavior, and autism diagnosis. Two years after entering intervention, the ESDM group on average improved 17.6 standard score points (1 SD: 15 points) compared with 7.0 points in the comparison group relative to baseline scores. The ESDM group maintained its rate of growth in adaptive behavior compared with a normative sample of typically developing children. In contrast, over the 2-year span, the comparison group showed greater delays in adaptive behavior. Children who received ESDM also were more likely to experience a change in diagnosis from autism to pervasive developmental disorder, not otherwise specified, than the comparison group. CONCLUSIONS: This is the first randomized, controlled trial to demonstrate the efficacy of a comprehensive developmental behavioral intervention for toddlers with ASD for improving cognitive and adaptive behavior and reducing severity of ASD diagnosis. Results of this study underscore the importance of early detection of and intervention in autism.
Assuntos
Transtorno Autístico/diagnóstico , Transtorno Autístico/terapia , Terapia Comportamental/métodos , Deficiências do Desenvolvimento/prevenção & controle , Intervenção Educacional Precoce/métodos , Análise de Variância , Desenvolvimento Infantil/fisiologia , Pré-Escolar , Cognição/fisiologia , Deficiências do Desenvolvimento/etiologia , Diagnóstico Precoce , Feminino , Seguimentos , Humanos , Lactente , Masculino , Testes Neuropsicológicos , Probabilidade , Medição de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: We examined baseline demographic and clinical profiles of youths enrolled from 2001 to 2006 in the publicly funded multicenter, randomized controlled trial Treatment of Early-Onset Schizophrenia Spectrum Disorders. METHOD: Youths (8-19 years) with schizophrenia (SZ) and schizoaffective disorder were recruited at four academic sites. Diagnosis was made via structured and clinical interviews. Assessments of psychiatric symptoms and social and global functioning were included. RESULTS: A total of 119 youths were enrolled. The mean age at illness onset was 11.1 +/- 3.5 years. Patients with SZ and schizoaffective disorder had similar ratings on the Positive and Negative Symptom Scale, Brief Psychiatric Rating Scale for Children, and Clinical Global Impression-Severity Scale. The overall level of functioning was similar in the two groups. A comparison to published reports of adults with SZ indicates that these youths may have more severe symptoms based on results of the Positive and Negative Symptom Scale. CONCLUSIONS: This is one of the largest samples of youths with SZ spectrum disorders studied to date and the largest assessment of youths with schizoaffective disorder. High rates of symptoms and general psychopathology were noted. There was a substantial degree of social and functional impairment. The symptom profiles are consistent with, but more severe than, those reported in the adult literature.
Assuntos
Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/epidemiologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/epidemiologia , Adolescente , Adulto , Idade de Início , Antipsicóticos/uso terapêutico , Encéfalo/fisiopatologia , Escalas de Graduação Psiquiátrica Breve , Criança , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/fisiopatologia , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Prevalência , Transtornos Psicóticos/diagnóstico , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Índice de Gravidade de DoençaRESUMO
Pathological mutations in BRCA1, BRCA2 and TP53 are associated with an increased risk of breast cancer. This study evaluated mutation frequency of these genes in early-onset breast cancer patients, and correlated this with family history and determined relative risks to family members. Patients with breast adenocarcinoma diagnosed 30 years were ascertained between 1980 and 1997. Family history was established and mutation screening of BRCA1, BRCA2 and TP53 genes was performed. Estimates of penetrance and relative risk were undertaken. DNA was obtained from 100/139 women. 17/36 familial cases had a BRCA1, BRCA2 or TP53 mutation. Of 64 non-familial cases, one BRCA2, two BRCA1 and two TP53 mutations were detected. Penetrance estimates (by age 70) for breast cancer were 84% for BRCA1 mutations and 91% for BRCA2 mutations and for ovarian cancer, 60% and 26%, respectively. Relative risks associated with mutations were consistent with previous studies. BRCA1 and BRCA2 mutations in patients with breast cancer 30 years are predicted strongly by family history. The majority of families with ovarian cancer were due to mutations in BRCA1/2 whereas these mutations only accounted for 30-50% of the excess breast cancers.
Assuntos
Adenocarcinoma/genética , Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Genes p53/genética , Mutação/genética , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Linhagem , Penetrância , Fatores de RiscoRESUMO
To investigate the clinical value of somatic TP53 mutations in breast cancer, we assembled clinical and molecular data on 1,794 women with primary breast cancer with long-term follow-up and whose tumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing. TP53 mutations were more frequent in tumors of ductal and medullar types, aggressive phenotype (high grade, large size, node positive cases, and low hormone receptor content) and in women <60 years old. TP53 mutations within exons 5 to 8 conferred an elevated risk of breast cancer-specific death of 2.27 (relative risk >10 years; P < 0.0001) compared with patients with no such mutation. The prognostic value of TP53 mutation was independent of tumor size, node status, and hormone receptor content, confirming and reconciling previous findings in smaller series. Moreover, an interaction between TP53 mutation and progesterone receptor (PR) status was revealed, TP53 mutation combined with the absence of progesterone receptor being associated with the worst prognosis. Whereas previous studies have emphasized the fact that missense mutations in the DNA-binding motifs have a worse prognosis than missense mutations outside these motifs, we show that non-missense mutations have prognostic value similar to missense mutations in DNA-binding motifs. Nonetheless, specific missense mutants (codon 179 and R248W) seem to be associated with an even worse prognosis. These results, obtained on the largest series analyzed thus far, show that TP53 mutations identified by gene sequencing have an independent prognostic value in breast cancer and could have potential uses in clinical practice.
Assuntos
Neoplasias da Mama/patologia , Mutação , Proteína Supressora de Tumor p53/genética , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Análise Mutacional de DNA , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Taxa de SobrevidaRESUMO
Multiple early-onset tumors, frequently associated with germ line TP53 mutations characterize the Li-Fraumeni familial cancer syndrome (LFS). LFS-like (LFS-L) families have lower rates of germ line TP53 alteration and do not meet the strict definition of LFS. This study examined 7 LFS cell lines and 30 LFS and 36 LFS-L primary leukocyte samples for mutations in the proapoptotic p53-regulated gene BAX. No germ line BAX mutations were found. A known BAX polymorphism was observed, yet there was no correlation between polymorphism frequency and TP53 status in either LFS or LFS-L. In summary, alterations of BAX are not responsible for cancers in TP53 wild-type LFS or LFS-L families.
Assuntos
Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Síndrome de Li-Fraumeni/genética , Polimorfismo Genético , Proteína Supressora de Tumor p53/genética , Alelos , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Frequência do Gene , Humanos , Incidência , Síndrome de Li-Fraumeni/epidemiologia , Masculino , Linhagem , Prognóstico , Medição de Risco , Estudos de AmostragemRESUMO
We aimed to assess frequency and penetrance of BRCA1, BRCA2,and TP53 mutations in women diagnosed with breast cancer aged 30 years or younger, and then correlate this frequency with family history. 17 of 36 familial cases had a BRCA1, BRCA2, or TP53 mutation, compared with three of 63 non-familial cases. The calculated population frequency of TP53 mutations was one in 5000, substantially greater than previous estimates. This finding underlines the importance of accurate elucidation of a family history from young women diagnosed with breast cancer. Establishment of family history could help with development of patient-specific management and tumour surveillance protocols.
Assuntos
Neoplasias da Mama/genética , Análise Mutacional de DNA , Predisposição Genética para Doença/genética , Adulto , Fatores Etários , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/epidemiologia , Testes Genéticos , Humanos , Penetrância , Medição de Risco/estatística & dados numéricos , Proteína Supressora de Tumor p53/genéticaRESUMO
The majority of families with classic Li-Fraumeni Syndrome (LFS) and a significant proportion of Li-Fraumeni-like (LFL) families have a germline mutation in the TP53 tumor suppressor gene. However around 20% of LFS and 60% of LFL families have no identifiable genetic defect in the coding region or splice junctions of TP53, and the genetic basis for cancer susceptibility in these families remains largely uncharacterized. To determine whether promoter mutations could be responsible for the Li-Fraumeni phenotype, we sequenced the TP53 promoter in index cases from members of classic LFS and LFL families without detectable TP53 mutations. We identified an identical single nucleotide deletion within the C/EBP- like site of the promoter in two out of eighteen such families (11%), compared to only one of a total of 366 control samples (0.3%). Although this result is highly significant (P=0.006, Fischer's exact test), the mutation did not affect the expression of TP53 in our hands. We provide evidence that this site is not utilized in the wild type TP53 promoter and further, that mutation of this site in LFS/LFL does not have a functional effect. We conclude that the sequence variant is a rare polymorphism arising within the TP53 promoter. However, the significantly increased frequency of this variant in LFS/LFL remains intriguing.
Assuntos
Genes p53 , Síndrome de Li-Fraumeni/genética , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Pareamento Incorreto de Bases , Análise Mutacional de DNA , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
RNA polymerase (pol) III synthesizes essential small RNAs, including tRNA and 5S rRNA. Wild-type p53 can repress pol III transcription both in vitro and in vivo. Many tumours carry substitutions in p53 which have selective effects on its functions. We identify tumour-derived mutations that compromise the ability of p53 to regulate pol III transcription. Furthermore, substitution R175H, the most common mutation in cancers, converts p53 from a repressor to an activator of pol III. Oncoproteins neutralize p53 in some tumours; we show that human papillomavirus E6 and cellular hdm2 can both release pol III from repression by p53. These data suggest that the restraining influence of p53 on pol III will be lost in many tumours. In addition to these features of sporadic cancers, some individuals inherit mutant forms of p53 and consequently suffer from Li-Fraumeni syndrome, showing genetic predisposition to certain malignancies. We find that pol III transcriptional activity is often highly elevated in primary fibroblasts from Li-Fraumeni patients, especially if the germline p53 mutation is followed by loss of the remaining allele. Our data suggest that p53 status can have a profound effect upon pol III transcription and hence on the biosynthetic capacity of cells.