RESUMO
The original article [1] contains errors in Table 1 affecting some of the presented oligonucleotide sequences and readthrough values in Table 1.
RESUMO
BACKGROUND: Intakes of specific fatty acids have been postulated to impact breast cancer risk but epidemiological data based on dietary questionnaires remain conflicting. MATERIALS AND METHODS: We assessed the association between plasma phospholipid fatty acids and breast cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition study. Sixty fatty acids were measured by gas chromatography in pre-diagnostic plasma phospholipids from 2982 incident breast cancer cases matched to 2982 controls. Conditional logistic regression models were used to estimate relative risk of breast cancer by fatty acid level. The false discovery rate (q values) was computed to control for multiple comparisons. Subgroup analyses were carried out by estrogen receptor (ER) and progesterone receptor expression in the tumours. RESULTS: A high level of palmitoleic acid [odds ratio (OR) for the highest quartile compared with the lowest OR (Q4-Q1) 1.37; 95% confidence interval (CI), 1.14-1.64; P for trend = 0.0001, q value = 0.004] as well as a high desaturation index (DI16) (16:1n-7/16:0) [OR (Q4-Q1), 1.28; 95% C, 1.07-1.54; P for trend = 0.002, q value = 0.037], as biomarkers of de novo lipogenesis, were significantly associated with increased risk of breast cancer. Levels of industrial trans-fatty acids were positively associated with ER-negative tumours [OR for the highest tertile compared with the lowest (T3-T1)=2.01; 95% CI, 1.03-3.90; P for trend = 0.047], whereas no association was found for ER-positive tumours (P-heterogeneity =0.01). No significant association was found between n-3 polyunsaturated fatty acids and breast cancer risk, overall or by hormonal receptor. CONCLUSION: These findings suggest that increased de novo lipogenesis, acting through increased synthesis of palmitoleic acid, could be a relevant metabolic pathway for breast tumourigenesis. Dietary trans-fatty acids derived from industrial processes may specifically increase ER-negative breast cancer risk.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/diagnóstico , Dieta , Ácidos Graxos/sangue , Fosfolipídeos/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Europa (Continente) , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Fatores de RiscoRESUMO
The aim of this study was to address whether NP might be a predictive factor for severity of CF. The authors collected data from the literature on NP as a unique or associated sign in CF and reviewed the clinical and molecular aspects of CF associated with NP. CF genotypes and clinical severity in NP(+) vs. NP(-) patients were reviewed, taking into account pulmonary function, frequency of P. aeruginosa lung infection, frequency of allergy, nutritional status, and exocrine pancreatic function. The CFTR gene was also analyzed in a patient with isolated severe NP as the unique feature of CF. This review of the literature showed a `milder` phenotype in `NP+` vs. `NP-` CF patients, contrasting with a marked association between NP and `severe` CF mutations. In addition, a complex genotype was identified, associating four heterozygous variants, namely p.Q493X (a severe mutation) on the paternal allele, and p.V562I, p.A1006E, and (TG)11(T)5 (IVS8-5T) on the maternal allele, in a case of CF presenting as isolated NP. The authors speculate that genetic/environmental factors associated with NP might attenuate the functional impact of `severe` CF mutations. The overrepresentation of CF carriers among patients with isolated NP also advocates the need for CFTR molecular screening in such populations for genetic counselling purposes.
Assuntos
Fibrose Cística/epidemiologia , Pólipos Nasais/epidemiologia , Adulto , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Análise Mutacional de DNA , Humanos , Masculino , Pólipos Nasais/genética , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Studies performed during these last 30 years have had a major impact on the understanding of carcinogenesis. They have opened a new field: cancer genetic predisposition. At the present time, most of the cancer predispositions linked to the alteration of one gene, associated with a high risk of cancer and with a specific phenotype have been identified. About 70 genes have been identified and have led to genetic testing. The indication of genetic testing, the management of at risk patients require the establishment of guidelines. The next challenge is the identification of cancer susceptibility genes associated with low risk or modifying the effect of treatment.
Assuntos
Neoplasias/genética , Transformação Celular Neoplásica/genética , Previsões , Genes Neoplásicos , Genes Supressores de Tumor , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Mutação , Síndromes Neoplásicas Hereditárias/genética , Oncogenes , RiscoRESUMO
A reduction of exhaled nitric oxide (NO) fraction and endothelial-mediated dysfunction have been reported in cystic fibrosis (CF). The aims of the present study were to search for relationships between flow-independent NO exchange parameters (bronchial NO flux (J'(aw,NO)) and alveolar NO concentration (C(A,NO))) and lung function tests characterising airflow limitation and pulmonary vascular bed (capillary blood volume and physiological dead space/tidal volume (V(D)/V(T)) ratio on exercise). In total, 34 patients (16 children, 18 adults) with CF, without resting pulmonary hypertension, underwent spirometry, exhaled NO measurement (multiple constant flow analytical method), gas transfer assessment (carbon monoxide and NO, allowing the calculation of capillary volume and membrane conductance) and a graded exercise test with oxygen uptake (V'(O(2))), carbon dioxide production (V'(CO(2))) and arterial blood gas evaluations. Both J'(aw,NO) and C(A,NO )correlated positively with airflow limitation. C(A,NO) correlated positively with capillary/alveolar volume. During exercise, criteria of mild pulmonary vascular disease were evidenced in some patients that participated in exercise limitation (negative correlation between physiological V(D)/V(T) and peak V'(O(2))). C(A,NO )at rest correlated positively with these parameters of wasted ventilation during exercise (physiological V(D)/V(T), minute ventilation (V'(E))/V'(CO(2)) at ventilatory threshold and V'(E)/V'(CO(2)) slope). Flow-independent exhaled NO parameters are linked to airway and early vascular diseases in patients with CF.
Assuntos
Fibrose Cística/diagnóstico , Pulmão/patologia , Óxido Nítrico/metabolismo , Espirometria/métodos , Adolescente , Adulto , Índice de Massa Corporal , Monóxido de Carbono/metabolismo , Criança , Fibrose Cística/metabolismo , Teste de Esforço , Expiração , Feminino , Humanos , Pulmão/metabolismo , Masculino , MutaçãoRESUMO
Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.
Assuntos
Genes p16 , Melanoma/genética , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Proteínas de Transporte/genética , Cromossomos Humanos Par 9 , Inibidor p16 de Quinase Dependente de Ciclina/genética , Éxons , Feminino , Deleção de Genes , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Mutação Puntual , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Supressora de Tumor p14ARF/genéticaRESUMO
We report the case of a child who was infected by HHV-6 and who started an acute lymphoblastic leukemia two months later. This case reminds that an etiologic role have been suggested for many viral infections in some leukemias in childhood, particularly the human herpesvirus 6 (HHV-6).
Assuntos
Herpesvirus Humano 6 , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Infecções por Roseolovirus/complicações , Crise Blástica , Contagem de Células Sanguíneas , Pré-Escolar , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
Lobular emphysema and soft-tissue emphysema can exceptionally complicate malnutrition. We report the case of a teenager presenting malnutrition with cystic fibrosis and anorexia nervosa with soft-tissue emphysema.
Assuntos
Fibrose Cística/complicações , Enfisema Subcutâneo/complicações , Adulto , Anorexia Nervosa/complicações , Feminino , Humanos , Desnutrição/complicações , Pneumotórax/complicaçõesRESUMO
Antibiotherapy is one of the main treatment in cystic fibrosis. Pseudomonas aeruginosa infection is one of the main causes of pulmonary degradation. The chronic sputum colonisation is characterized by the emergence of the mucoid phenotype, the formation of biofilm and the induction of excessive inflammatory response and consecutive tissue lesion. The choice of antibiotics depends on quantitative and qualitative analysis of sputum, bacteria resistance phenotypes and severity of infection. Treatment of P. aeruginosa is different in case of first colonization or chronic infection. In the first case, parenteral antibiotherapy (beta-lactams-aminoglycosids) followed by inhaled antibiotherapy may eradicate the germ. In the other case, superinfections can be treated with parenteral biantibiothérapy (beta-lactams or quinolons and aminoglycosides) during 15 to 21 days. This is associated with a better nutritional and respiratory status and a prolonged survival. Inhaled antibiotics between the courses have decreased the number of superinfections. This prolonged antibiotherapy must be monitored because of possible induction of bacterial resistance, nephrotoxicity and ototoxicity of aminosids and allergy to beta-lactams.
Assuntos
Antibacterianos/uso terapêutico , Fibrose Cística/complicações , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/etiologia , Antibacterianos/farmacocinética , Criança , Doença Crônica , HumanosRESUMO
OBJECTIVE: Comprehensive analysis of the 9p21 locus including the CDKN2A, ARF, and CDKN2B genes in 53 individuals from melanoma index cases considered to be at heightened risk of melanoma. METHODS AND RESULTS: Using a combination of DNA sequencing, gene copy number by real time quantitative PCR, linkage analysis, and transcript analysis in haploid somatic cell hybrids, we found no evidence for germline alteration in either coding or non-coding domains of CDKN2A and CDKN2B. However, we identified a p14ARF exon 1beta missense germline mutation (G16D) in a melanoma-neural system tumour syndrome (CMM+NST) family and a 8474 bp germline deletion from 196 bp upstream of p14ARF exon 1beta initiation codon to 11233 bp upstream of exon 1alpha of p16(INK4A) in a family with five melanoma cases. For three out of 10 families with at least three melanoma cases, the disease gene was unlinked to the 9p21 region, while linkage analysis was not fully conclusive for seven families. CONCLUSIONS: These data reinforce the hypothesis that ARF is a melanoma susceptibility gene and suggest that germline deletions specifically affecting p14ARF may not be solely responsible for NST susceptibility. Predisposition to CMM+NST could either be due to complete disruption of the CDKN2A locus or be the result of more complex genetic inheritance. In addition, the absence of any genetic alteration in 50 melanoma prone families or patients suggests the presence of additional tumour suppressor genes possibly in the 9p21 region, and on other chromosomes.
Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Melanoma/genética , Proteína Supressora de Tumor p14ARF/genética , Linhagem Celular Tumoral , Cromossomos Humanos Par 9/genética , Análise Mutacional de DNA , Éxons/genética , Deleção de Genes , Genes Neoplásicos , Ligação Genética , Mutação em Linhagem Germinativa/genética , Humanos , Mutação de Sentido Incorreto/genética , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA não Traduzido/genética , Fatores de RiscoRESUMO
A new mutation of the Noggin gene in a French Fybrodysplasia ossificans progressiva (FOP) family: Fibrodysplasia ossificans progressiva (FOP) is a very rare disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of the muscles. We previously located a FOP gene in the 17q21-22 region and described several mutations of the noggin (NOG) gene (located in 17q22) in four FOP patients, including the G91C mutation which is transmitted dominantly in a Spanish FOP family. We describe in the present study a new mutation of the NOG gene in a French FOP family. This new mutation is a guanine to adenine change at nucleotide 283 (283G --> A) of the NOG gene, and is transmitted in the family (in the heterozygote form) by the affected mother to her two affected children. At the peptide level this mutation (A95T) substitutes an Alanine residue by a Threonine at position 95 of the Noggin protein. The Alanine mutated residue is located just adjacent to the myristoylation site of the protein, where all the mutations we described until now are located.
Assuntos
Análise Mutacional de DNA , Miosite Ossificante/genética , Adenosina , Proteínas de Transporte , Cromossomos Humanos Par 17 , Triagem de Portadores Genéticos , Guanina , Hallux Valgus/diagnóstico , Hallux Valgus/genética , Humanos , Recém-Nascido , Masculino , Miosite Ossificante/diagnóstico , Linhagem , Peptídeos/genética , Análise de Sequência de DNARESUMO
A recent report based on 68 families, including 17 with mutations in BRCA1, suggested that there was an excess of female offspring born to BRCA1 mutation carriers. We have examined the gender ratio among offspring of 511 mutation carriers from 116 BRCA1 families, 77 and 39 from Australia and the United States, respectively. We found no evidence for a significant deviation from the expected proportion of female offspring in the Australian pedigrees, but there was an excess of female offspring in pedigrees from the USA. Ascertainment bias probably explains this bias, rather than a link with X-chromosome inactivation as previously suggested, because the families from the USA were ascertained for the purposes of linkage studies whereas those from Australia were ascertained through Familial Cancer Clinics to which they had been referred for clinical genetic counseling and mutation testing.
Assuntos
Genes BRCA1 , Genes BRCA2 , Heterozigoto , Razão de Masculinidade , Adulto , Austrália/epidemiologia , Neoplasias da Mama/genética , Cromossomos Humanos X , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Masculino , Neoplasias Ovarianas/genética , Linhagem , Estados Unidos/epidemiologiaRESUMO
Cystic fibrosis (CF) is considered as a rare disease in black Africans. In fact, this disease is likely to be underestimated since clinical features consistent with CF diagnosis are often ascribed to environmental factors such as malnutrition. Very little is known about CFTR mutations in affected patients from Central Africa. We report here four novel mutations, i.e., IVS2 + 28 (intron 2), 459T > A (exon 4), EX17a_EX18del (exons 17-18), and IVS22 + IG > A (intron 22), in such patients. An update of CFTR mutations reported in black patients from various ethnies is included. These data might be helpful for genetic counselling regarding CF in black patients.
Assuntos
População Negra/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Mutação , Pré-Escolar , Códon sem Sentido , Fibrose Cística/etnologia , Análise Mutacional de DNA , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Mutação Puntual , Sítios de Splice de RNA/genética , Deleção de SequênciaRESUMO
Asplenic and hyposplenic patients have an increased risk for overwhelming pneumococcal infections, even several decades after splenectomy. Pneumococcal vaccination and daily oral administration of penicillin V are recommended to prevent such infections, 2-5 years after splenectomy, and for at least 5 years in children affected with sickle cell disease. In order to assess whether the infectious risk is actually known and prevented, we interviewed physicians (belonging to a general practitioner and pediatrician network) who followed patients having undergone a splenectomy and/or children with sickle cell disease under 5 years of age. We received replies from 104 physicians monitoring 152 patients replied. Potential infection risk was not known for 28% of the asplenic patients and 40% of the children with sickle cell disease. Only 75% of the asplenic patients and 36% of the children with sickle cell disease had been vaccinated against pneumococcus. Of the patients who had undergone splenectomy, 27% had been treated with an antibiotic after surgery and 60% had discontinued it, the vast majority of them during the same year. Of the children with sickle cell disease, 48% were not receiving an antibiotic. This study demonstrates that risk of infections in asplenic patients is widely misunderstood, indicating the urgent need to improve their management.
Assuntos
Antibacterianos/uso terapêutico , Antibioticoprofilaxia , Infecções Pneumocócicas/prevenção & controle , Esplenectomia/efeitos adversos , Adolescente , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Antibioticoprofilaxia/estatística & dados numéricos , Criança , Pré-Escolar , Seguimentos , Humanos , Entrevistas como Assunto , Infecções Pneumocócicas/etiologia , Estudos Retrospectivos , Fatores de Risco , VacinaçãoRESUMO
BACKGROUND: A major consequence of malnutrition in cystic fibrosis (CF) patients is the loss of lean body mass (LBM) and the subsequent impairment of respiratory muscle function. AIM: To determine whether insulin-like growth factor I (IGF-I) could be related to the LBM depletion and the evolution of respiratory disease in CF patients. METHODS: LBM was evaluated by dual energy x ray absorptiometry; serum concentrations of IGF-I were measured in 24 CF patients twice with a one year interval. Both values were expressed as SD score (SDS) calculated from normal data for age, sex, and pubertal stage and analysed with respect to anthropometric evaluation and disease related conditions. RESULTS: At the initial evaluation, IGF-I SDS had a mean value of -0.98 (range -3.6 to 3.2) and correlated with weight for age index, LBM SDS, and lung disease related conditions. Multiple regression analysis showed that only LBM remained independently related to IGF-I, suggesting that the relation of IGF-I to LBM was independent of weight and that the correlation between IGF-I and the respiratory conditions was related to the level of LBM. IGF-I SDS at the first evaluation was lower for the patients who lost > or =5% of weight for age index or > or =1 SD of LBM between the two evaluations. CONCLUSION: Low levels of IGF-I could be crucial for clinical outcome by impairing LBM and respiratory function. IGF-I could be a tool for nutritional evaluation by identifying the CF patients at risk of LBM depletion.
Assuntos
Índice de Massa Corporal , Fibrose Cística/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Absorciometria de Fóton , Adolescente , Adulto , Antropometria , Composição Corporal , Criança , Pré-Escolar , Fibrose Cística/complicações , Fibrose Cística/patologia , Feminino , Seguimentos , Humanos , Masculino , Estado Nutricional , Estudos Prospectivos , Análise de Regressão , Transtornos Respiratórios/etiologia , Magreza/etiologiaRESUMO
We used partial 16S rRNA gene (16S DNA) sequencing for the prospective identification of nonfermenting Gram-negative bacilli recovered from patients attending our cystic fibrosis center (hôpital Necker-Enfants malades), which gave problematic results with conventional phenotypic tests. During 1999, we recovered 1093 isolates of nonfermenting Gram-negative bacilli from 702 sputum sampled from 148 patients. Forty-six of these isolates (27 patients) were not identified satisfactorily in routine laboratory tests. These isolates were identified by 16S DNA sequencing as Pseudomonas aeruginosa (19 isolates, 12 patients), Achromobacter xylosoxidans (10 isolates, 8 patients), Stenotrophomonas maltophilia (9 isolates, 9 patients), Burkholderia cepacia genomovar I/III (3 isolates, 3 patients), Burkholderia vietnamiensis (1 isolate), Burkholderia gladioli (1 isolate) and Ralstonia mannitolilytica (3 isolates, 2 patients). Fifteen isolates (33%) were resistant to all antibiotics in routine testing. Sixteen isolates (39%) resistant to colistin were recovered on B. cepacia-selective medium: 2 P. aeruginosa, 3 A. xylosoxidans, 3 S. maltophilia and the 8 Burkholderia--Ralstonia isolates. The API 20NE system gave no identification for 35 isolates and misidentified 11 isolates (2 P. aeruginosa, 2 A. xylosoxidans and 1 S. maltophilia classified as B. cepacia ). Control measures and/or treatment were clearly improved as a result of 16S DNA sequencing in three of these cases. This study confirms the weakness of phenotypic methods for identification of atypical nonfermenting Gram-negative bacilli recovered from cystic fibrosis patients. The genotypic methods, such as 16S DNA sequencing which allows identification of strains in routine practice, appears to have a small, but significant impact on the clinical management of CF patients.
Assuntos
Fibrose Cística/microbiologia , Bactérias Gram-Negativas/classificação , Bactérias Gram-Negativas/isolamento & purificação , Achromobacter/genética , Achromobacter/isolamento & purificação , Alcaligenes/genética , Alcaligenes/isolamento & purificação , Burkholderia/genética , Burkholderia/isolamento & purificação , DNA Ribossômico/genética , Fermentação , Genótipo , Bactérias Gram-Negativas/genética , Humanos , Fenótipo , Pseudomonas/genética , Pseudomonas/isolamento & purificação , RNA Ribossômico 16S/isolamento & purificação , Ralstonia/genética , Ralstonia/isolamento & purificação , Escarro/microbiologiaRESUMO
Since the cloning of the defective gene in cystic fibrosis, much has been learned on the function of CFTR and on the mechanisms regulating its expression. Based on the current understanding of the processes involved in lung disease progression, a number of approaches have been developed using gene therapy and pharmacological agents. Several of these agents have been reported to restitute a function to CFTR with specific mutations. Other molecules act on channels other than CFTR, and may be effective by bypassing CFTR itself. In the present review the various therapeutical strategies currently investigated are discussed.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/terapia , Colchicina/uso terapêutico , Fibrose Cística/genética , Genótipo , Humanos , FenótipoRESUMO
Oesopharyngeal brush (OPB) sampling with cytological analysis can yield exfoliated cells from asymptomatic tumours of the upper aero-digestive tract and the oesophagus. In this study, we compared cytological evaluation and molecular analysis for the detection of exfoliated cancer cells sampled with an OPB. A total of 56 patients with a known unique head and neck squamous cell carcinoma (HNSCC) and five healthy controls were enrolled prospectively. Exfoliated cells from these 61 patients were collected with an OPB before initial endoscopy. p53 mutations and UT 5085 microsatellite instability (MI) were analysed in the HNSCC tumour, lymphocytes and the corresponding OPB DNA samples. p53 mutations and UT5085 MI were detected in 31 out of 56 and 14 out of 56 HNSCC, respectively, but not in any of the five controls. Direct sequencing of p53 was able to detect mutations in OPB DNA in only two out of 29 patients harbouring a p53-mutated primary tumour. Microsatellite instability was detected in OPB DNA of 11 out of 13 informative (bandshift detected in tumour) patients, whereas cytological analysis detected abnormal cells in only six of the same 13 patients (P=0.03). In informative patients, all positive OPB samples at cytological analysis were also positive at molecular analysis of UT5085, and both analyses confirmed the two negative samples. Molecular analysis of OPB from eight uninformative patients and from five healthy controls were all negative. OPB sampling with MI-based molecular analysis could be efficient for early detection of recurrent HNSCC. This result prompts us to use other microsatellite markers in order to maximise the percentage of informative patients.