RESUMO
Intrachromosomal amplification of chromosome 21 (iAMP21) identifies a high-risk subtype of acute lymphoblastic leukaemia (ALL), requiring intensive treatment to reduce their relapse risk. Improved understanding of the genomic landscape of iAMP21-ALL will ascertain whether these patients may benefit from targeted therapy. We performed whole-exome sequencing of eight iAMP21-ALL samples. The mutation rate was dramatically disparate between cases (average 24.9, range 5-51) and a large number of novel variants were identified, including frequent mutation of the RAS/MEK/ERK pathway. Targeted sequencing of a larger cohort revealed that 60% (25/42) of diagnostic iAMP21-ALL samples harboured 42 distinct RAS pathway mutations. High sequencing coverage demonstrated heterogeneity in the form of multiple RAS pathway mutations within the same sample and diverse variant allele frequencies (VAFs) (2-52%), similar to other subtypes of ALL. Constitutive RAS pathway activation was observed in iAMP21 samples that harboured mutations in the predominant clone (⩾35% VAF). Viable iAMP21 cells from primary xenografts showed reduced viability in response to the MEK1/2 inhibitor, selumetinib, in vitro. As clonal (⩾35% VAF) mutations were detected in 26% (11/42) of iAMP21-ALL, this evidence of response to RAS pathway inhibitors may offer the possibility to introduce targeted therapy to improve therapeutic efficacy in these high-risk patients.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 21 , Sistema de Sinalização das MAP Quinases/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas ras/metabolismo , Animais , Benzimidazóis/farmacologia , Sobrevivência Celular , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Taxa de Mutação , Análise de Sequência de DNARESUMO
The aim of this study was to investigate the coaching behaviors of elite English youth soccer coaches in different practice settings and gain insight into the coaches' cognitive processes underpinning these behaviors. The practice setting was split into two types of activities, "training form" and "playing form," and behavioral data were collected using a modified version of the Coach Analysis and Intervention System. Interpretive interview data were triangulated with the behavioral data to ensure that both the "what" and the "why" of the coaches' behavior and practice were considered. The results showed the coaches using more "training form" activities than "playing form," and using high levels of prescriptive instruction, regardless of practice type, in contrast to a stated desire to "developing the whole player," creating "decision makers," and being a "facilitator of knowledge creation." The interviews revealed that the coaches had a low self-awareness about their behavior, with an epistemological gap identified between understanding and practice, with statements of intent not being matched by knowledge and action.
Assuntos
Comportamento , Prática Psicológica , Futebol/educação , Ensino/métodos , Adolescente , Adulto , Inglaterra , Retroalimentação , Humanos , Intenção , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Observação , Reforço Psicológico , Análise e Desempenho de Tarefas , Adulto JovemRESUMO
A father and daughter with colloid cysts of the third ventricle are described. The nine previously reported examples of familial occurrence are reviewed, and the conclusion is reached that inheritance is likely autosomal dominant. The proportion of all cases which are genetic is not known. A plea is made for routine detailed and thorough family histories on all patients with such cysts and a high index of suspicion for non-specific symptoms in relatives such as headaches, migraine, depression, anxiety, nausea and vomiting.
Assuntos
Encefalopatias/genética , Cistos/genética , Genes Dominantes/genética , Terceiro Ventrículo , Idoso , Ansiedade/genética , Depressão/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/genética , Náusea/genética , Linhagem , Síndrome , Vômito/genéticaRESUMO
Three families with X-linked mental retardation caused by a 24 base-pair duplication in ARX[428-451dup(24 bp)] are reported. The clinical features in these and six other published families are reviewed. In general, the clinical picture is variable. Mental retardation ranges from mild to severe. Infantile spasms (West syndrome) occurred in 12.5% and other less severe forms of seizures in 37.5%. Characteristic dystonic movements of the hands were seen in 63% and dysarthria in 54%. The focal dystonia, in association with mental retardation, may prove to be diagnostic of this mutation.
Assuntos
Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/genética , Proteínas de Homeodomínio/genética , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação , Fatores de Transcrição/genética , Adulto , Heterozigoto , Humanos , Masculino , Linhagem , SíndromeRESUMO
The usual description of the Börjeson-Forssman-Lehmann syndrome (BFLS) is that of a rare, X-linked, partially dominant condition with severe intellectual disability, epilepsy, microcephaly, coarse facial features, long ears, short stature, obesity, gynecomastia, tapering fingers, and shortened toes. Recently, mutations have been identified in the PHF6 gene in nine families with this syndrome. The clinical history and physical findings in the affected males reveal that the phenotype is milder and more variable than previously described and evolves with age. Generally, in the first year, the babies are floppy, with failure to thrive, big ears, and small external genitalia. As schoolboys, the picture is one of learning problems, moderate short stature, with emerging truncal obesity and gynecomastia. Head circumferences are usually normal, and macrocephaly may be seen. Big ears and small genitalia remain. The toes are short and fingers tapered and malleable. In late adolescence and adult life, the classically described heavy facial appearance emerges. Some heterozygous females show milder clinical features such as tapering fingers and shortened toes. Twenty percent have significant learning problems, and 95% have skewed X inactivation. We conclude that this syndrome may be underdiagnosed in males in their early years and missed altogether in isolated heterozygous females.
Assuntos
Anormalidades Múltiplas/genética , Doenças Genéticas Ligadas ao Cromossomo X , Mutação , Insuficiência de Crescimento/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Hipotonia Muscular/genética , Anormalidades Musculoesqueléticas/genética , Linhagem , Fenótipo , SíndromeRESUMO
Recently it has been reported that late-onset tremor, gait unsteadiness and dementia can be associated with brain atrophy in males of normal intelligence and the pre-mutation carrier state of the fragile X syndrome. We have shown, by means of a telephone survey, that this association is probably causal rather than coincidental. These findings have uncovered another testable cause of late-onset neurological symptoms in males, which also has serious genetic implications for their daughters who are at risk of having sons with full mutations causing mental handicap - the fragile X syndrome.
Assuntos
Ataxia/genética , Demência/genética , Síndrome do Cromossomo X Frágil/genética , Tremor/genética , Idoso , Idoso de 80 Anos ou mais , Heterozigoto , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Congenital hydrocephalus results from a variety of causes, some of the most common include spina bifida (myelomeningocele), aqueductal stenosis, and Dandy-Walker malformation. In addition, a number of cases result from genetic causes, other malformations, postinfectious, or neoplastic conditions. Outcome varies with cause but can be favorable. Most cases still are managed with shunting, although endoscopic modalities also can be considered.
Assuntos
Hidrocefalia/etiologia , Encéfalo/patologia , Diagnóstico Diferencial , Humanos , Hidrocefalia/diagnóstico , Hidrocefalia/genética , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Exame Neurológico , SíndromeAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ependimoma/diagnóstico , Ependimoma/tratamento farmacológico , Neoplasias da Medula Espinal/diagnóstico , Neoplasias da Medula Espinal/tratamento farmacológico , Adolescente , Quimioterapia Adjuvante , Ependimoma/complicações , Ependimoma/cirurgia , Moduladores de Receptor Estrogênico/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Laminectomia , Dor Lombar/etiologia , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia , Radioterapia Adjuvante , Neoplasias da Medula Espinal/complicações , Neoplasias da Medula Espinal/cirurgia , Tamoxifeno/administração & dosagem , Resultado do TratamentoAssuntos
Anormalidades Múltiplas/genética , Aneuploidia , Cromossomos Humanos Par 4/genética , Deficiência Intelectual/genética , Translocação Genética/genética , Adolescente , Criança , Pré-Escolar , Bandeamento Cromossômico , Quebra Cromossômica/genética , Humanos , Recém-Nascido , Cariotipagem , Masculino , Núcleo Familiar , Mapeamento Físico do Cromossomo , SíndromeRESUMO
The clinical genetic diagnosis was reviewed in 429 subjects with intellectual disability in the Australian Child and Adolescent Development (ACAD) study of behavioural problems. With minor differences, the overall "general distribution by causation" was similar to that to that found by the Consensus Conference of the American College of Medical Genetics in 1995. There was a significant male excess in the whole series which was shown to reside in those with "autism," those with undiagnosed nonsyndromic mental retardation (NSMR) and those with X-linked monogenic disorders. It is argued that a substantial proportion of undiagnosed NSMR is caused by genes on the X chromosome. Some of the practical problems of assigning individuals to diagnostic groups are discussed.
Assuntos
Deficiência Intelectual/genética , Cromossomo X/genética , Adolescente , Adulto , Austrália , Criança , Aberrações Cromossômicas , Feminino , Ligação Genética , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/classificação , Masculino , Aberrações dos Cromossomos Sexuais , Distribuição por Sexo , Fatores SexuaisAssuntos
Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Adolescente , Adulto , Criança , Feminino , Síndrome do Cromossomo X Frágil/genética , Humanos , Deficiência Intelectual/etiologia , Estudos Longitudinais , Masculino , Núcleo Familiar , Linhagem , Recidiva , Estudos Retrospectivos , Fatores de RiscoRESUMO
An astroblastoma of high-grade type arising in the brain of a 3-year-old child is reported. The first description of the ultrastructural, immunohistochemical, and cytogenetic findings in this rare tumor variant are presented.
Assuntos
Neoplasias Encefálicas/ultraestrutura , Neoplasias Neuroepiteliomatosas/ultraestrutura , Lobo Parietal , Aneuploidia , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/química , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Pré-Escolar , Feminino , Humanos , Técnicas Imunoenzimáticas , Cariotipagem , Recidiva Local de Neoplasia , Neoplasias Neuroepiteliomatosas/química , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/cirurgiaAssuntos
Encéfalo/patologia , Doenças Neurodegenerativas/patologia , Biópsia , Anormalidades Craniofaciais/etiologia , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Humor Irritável , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/psicologiaAssuntos
Adenocarcinoma/patologia , Neoplasias do Colo/patologia , Adulto , Humanos , Metástase Linfática , MasculinoRESUMO
BACKGROUND/PURPOSE: The aim of this study was to investigate driveway-related injuries in children, identify associated risk factors, and evaluate outcome compared with other mechanisms of blunt trauma. METHODS: A 6-year review (1991 to 1996) of pediatric (age less than 18 years) pedestrian injuries treated at two urban trauma centers was conducted: one regional pediatric trauma center and one level I trauma center with pediatric commitment. Five hundred twenty-seven children injured in pedestrian accidents were identified from the trauma registry; 51 children (10%) sustained traumatic injuries as a result of being struck in their driveway. Data are reported as mean +/- SEM. RESULTS: Children less than 5 years of age (n = 41) had an injury severity score (ISS) of 12.3+/-2.3, 15 (37%) sustained closed head injury, 13 (37%) had torso trauma, 19 (46%) skeletal trauma, and eight (20%) died. Children > or = 5 years old (n = 10) had an ISS of 10.7+/-2.4, three (30%) sustained closed head injury, four (40%) torso trauma, six (60%) skeletal trauma, and none died. In contrast, all other pediatric pedestrian accidents analyzed over the same time period had a mortality rate of only 2% (11 of 476). CONCLUSIONS: Pediatric driveway trauma carries a significant risk of head injury and a 10-fold increase in mortality in children under 5 years of age when compared with all other pediatric pedestrian accidents. More emphasis must be placed on injury prevention and public education to prevent this devastating mechanism of injury in these young, vulnerable children.