RESUMO
The original article [1] contains errors in Table 1 affecting some of the presented oligonucleotide sequences and readthrough values in Table 1.
Assuntos
Urticária Crônica , Urticária , Humanos , Neutrófilos/patologia , Urticária/diagnóstico , Urticária/patologiaRESUMO
BACKGROUND: The effect of BRCA1/2 gene test result on anxiety, depression, cancer-related thought intrusion or avoidance and perceived control over cancer risk was assessed in breast cancer (BC) patients, according to their perceived probability of genetic predisposition to cancer. METHODS: Two hundred and forty-three (89% response rate) women with BC completed questionnaires after an initial genetic counselling visit (T1), of which 180 (66%) completed questionnaires again after receiving the BRCA1/2 results (T2). The discrepancy between women's perceived probability of cancer genetic predisposition at T1 and the geneticist's computed estimates was assessed. RESULTS: In all, 74% of women received a negative uninformative (NU), 11% a positive BRCA1/2 and 15% an unclassified variant (UV) result. On hierarchical regression analysis, in women with a positive BRCA1/2 result (vs NU or UV), a lower perceived probability of cancer genetic predisposition than objective estimates at T1 predicted lower levels of anxiety at T2 (ß=-0.28; P<0.01), whereas in women receiving a UV result (vs NU or positive BRCA1/2), a lower perceived probability of cancer genetic predisposition than objective estimates at T1 predicted higher levels of anxiety (ß=0.20; P<0.01), depression (ß=0.19; P<0.05) and intrusion (ß=0.18; P<0.05) at T2. CONCLUSION: The type of BRCA1/2 test result differently affects distress according to women's perceived probability of genetic predisposition before testing.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Testes Genéticos , Percepção , Adulto , Ansiedade/psicologia , Depressão/psicologia , Feminino , Aconselhamento Genético , Humanos , Pessoa de Meia-Idade , Mutação , Fatores de Risco , Estresse Psicológico/psicologia , Fatores de TempoRESUMO
Several genes might explain BRCA1/2 negative breast and ovarian family cases. Deleterious mutations in few genes involved in the Fanconi complex are responsible for Fanconi anemia at the homozygous state and breast cancer (BC) susceptibility at the heterozygous state (BRCA2, PALB2, BRIP1). RAD51C plays an important role in the double-strand break repair pathway and a biallelic missense mutation in the RAD51C gene was found in a Fanconi anemia-like disorder. Subsequently, six monoallelic pathogenic mutations were identified after screening 480 BRCA1/2 negative breast and ovarian cancer (BC/OC) pedigrees. Several reports were unsuccessful to replicate these results. To investigate whether germline mutations in RAD51C are associated with an increased risk of developing BC/OC, we screened, by Sanger sequencing of the coding sequence, 117 index cases of breast and ovarian families from French or European origin, and negative for BRCA1/2 mutations. In our study, we found 3 pathogenic mutations among 117 families screened which corresponds to a 2.6% frequency. Our results confirm that RAD51C is a susceptibility gene for ovarian and BC and that this gene should be screened for mutations in families with multiple BC/OC.
Assuntos
Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: It can be hypothesised that inherited polymorphisms in the drug-transporter ABCB1 gene may interfere with interindividual variations in drug response in breast cancer patients. Docetaxel is a substrate for ABCB1 whose function has been shown to be modulated by oestrogen and progesterone. METHODS: Whether ABCB1 polymorphisms including T-129C, A61G, C1236T, G2677T/A and C3435T polymorphisms could account for variations in the disposition of docetaxel and whether menopausal status at the time of diagnosis might interact with this effect were analysed in women receiving neoadjuvant chemotherapy for breast cancer (n=86). RESULTS: A highly significant association was observed, but restricted to premenopausal women (n=53), between the pharmacokinetics of docetaxel and C3435T polymorphism, as patients with CC genotype had lower mean values of the area under the plasma concentration-time curve (AUC) of docetaxel than patients with CT and TT genotypes (P<0.0001). Comparison between pre- and postmenopausal women with the same C3435T genotype yielded a significant difference in docetaxel AUC only for CC genotype (P<0.0001). CONCLUSION: These results suggest that C3435T polymorphism genotyping and menopausal status at the time of diagnosis might be useful when considering chemotherapy regimens including docetaxel in breast cancer patients.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacocinética , Neoplasias da Mama/genética , Taxoides/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adulto , Idoso , Antineoplásicos/uso terapêutico , Área Sob a Curva , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Docetaxel , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Polimorfismo Genético , Pós-Menopausa , Pré-Menopausa , Taxoides/uso terapêuticoRESUMO
BACKGROUND: Despite promising results, the efficacy of polymerase chain reaction (PCR) for clinical management of cytomegalovirus (CMV) infection in transplanted patients is still controversial. METHODS: A prospective study of CMV detection, with concurrent shell vial cultures and PCR in blood and bronchoalveolar lavage (BAL), was conducted in 13 lung transplant recipients, monitored for 15 months (range: 1-42 months). CMV DNA was detected by PCR amplification of a 406-bp fragment in the Us region and a 290-bp fragment in the immediate early region of the viral genome. RESULTS: When comparing PCR to viral culture, the sensitivity and specificity of CMV DNA detection were 100% and 65.7% in blood (n=122) and 100% and 75% in BAL (n=104). The positive and negative predictive values of PCR for a forthcoming diagnosis of CMV infection were 50% and 97% in blood, and 67% and 85% in BAL. Seventeen CMV infections were evaluated at the end of treatment: when PCR was still positive either in blood or BAL, CMV infection relapsed within 35+/-5 days; when PCR was negative, CMV infection relapsed after 142+/-57 days (P=0.01). CONCLUSIONS: Negative CMV detection by PCR strongly advocates against a forthcoming CMV infection. PCR assay seems to be a good predictor for early recurrence of CMV infection, and would be useful for monitoring the response to antiviral therapy.
Assuntos
Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/virologia , Citomegalovirus/genética , DNA Viral/sangue , Transplante de Pulmão/fisiologia , Adolescente , Adulto , Antivirais/uso terapêutico , Avaliação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
The MRP (multidrug resistance-associated protein) transmembrane transporter, which actively transports a wide variety of lipophilic substrates out of cancer cells, has been suggested to play a major role in cell detoxification via efflux of glutathione conjugates. Because bronchial epithelial cells are constantly exposed to environmental pollutants, MRP might be a particularly important defense mechanism against xenobiotics. This study was therefore designed to investigate MRP localization by immunohistochemistry in bronchial epithelial cells collected by scraping from surgical specimens. In parallel, MRP mRNA was detected by reverse transcriptase chain reaction (rt-PCR) in bronchial cell lysates. However, the pattern of protein expression differed markedly according to cell type. In ciliated epithelial cells, immunostaining was restricted to the basolateral surface, without any labeling at the apical surface, which is at variance with the localization of CFTR and MDR1 proteins, other members of the same family of transporters. In basal cells, MRP was present over the entire circumference of the plasma membrane. Basal cells were identified by their morphology and specifically after incubation with an anticytokeratin 17 monoclonal antibody. In conclusion, the different patterns of localization suggest specific roles for MRP in basal and ciliated cells.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Brônquios/metabolismo , Brônquios/citologia , Cílios/metabolismo , Resistência a Múltiplos Medicamentos/fisiologia , Epitélio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Queratinas/metabolismo , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Reação em Cadeia da Polimerase , Transcrição GênicaRESUMO
In order to compare PCR with rapid virus culture for the early detection of CMV in bronchoalveolar lavage (BAL) after bone marrow transplantation, 26 asymptomatic patients were routinely evaluated for the presence of CMV on day 35 using these two techniques. Concurrent blood samples were also analyzed in all cases. CMV was detected synchronously by both culture and PCR in six of 26 (23%) BAL and in five of 26 (19%) blood specimens. Among these positive specimens, three BAL and blood samples were positive in the same patients. Five (19%) BAL and five (19%) blood samples were culture-negative but PCR-positive. No BAL or blood specimens were positive by culture alone. When considering matched BAL-blood samples, five were positive in only one fluid, BAL (n = 3) or blood (n = 2) using culture, while seven were positive in only one fluid, BAL (n = 4) or blood (in = 3) using PCR. Overall, six of 26 (23%) patients had culture-negative but PCR-positive results. Three of these six patients were positive only in BAL and two of them subsequently received antiviral therapy for development of symptoms suggestive of CMV infection. We suggest that asymptomatic patients with negative-culture but PCR-positive results on day 35 in BAL should be subsequently closely monitored for the presence of CMV.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Infecções por Citomegalovirus/virologia , Citomegalovirus/isolamento & purificação , Adulto , Lavagem Broncoalveolar , Infecções por Citomegalovirus/diagnóstico , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase/métodos , Valor Preditivo dos Testes , Transplante AutólogoRESUMO
OBJECTIVE: The study was undertaken to determine if critically ill patients under mechanical ventilation could reactivate latent cytomegalovirus (CMV) in either lung or blood. DESIGN: Prospective study in critically ill patients was performed in a multidisciplinary intensive care unit in a university hospital. PATIENTS: 23 non-immunocompromised, mechanically ventilated patients who were anti-CMV immunoglobulin G-positive. Ten immunocompromised patients with active CMV infection and 16 asymptomatic CMV seropositive non-immunocompromised patients constituted the positive and negative control groups. MEASUREMENTS AND RESULTS: The presence of CMV in blood and bronchoalveolar lavage (BAL) was evaluated by both viral cultures and polymerase chain reaction (PCR). Thirty-seven blood and 22 BAL samples were investigated. Sequential samples were evaluated in 8 patients. For PCR, a 290 bp fragment in the first exon of the immediate early 1 gene was amplified. In order to exclude inhibitors of PCR amplification, a 268 bp fragment of the beta-globin gene was concurrently amplified in all samples. Viral cultures of blood and BAL were negative in all 23 non-immunocompromised, mechanically ventilated patients. Moreover, no CMV DNA could be amplified in blood BAL samples, whereas a beta-globin amplification was observed in all samples. CONCLUSION: In a series of 23 critically ill patients under mechanical ventilation who were seropositive for CMV, no reactivation of CMV in blood or lung was demonstrated.
Assuntos
Cuidados Críticos , Infecção Hospitalar/virologia , Infecções por Citomegalovirus/diagnóstico , Pneumopatias/virologia , Respiração Artificial , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido da Lavagem Broncoalveolar/virologia , Estudos de Casos e Controles , Estado Terminal , Infecção Hospitalar/imunologia , Sondas de DNA , DNA Viral/genética , Feminino , Humanos , Leucócitos/virologia , Pneumopatias/imunologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/virologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/virologiaRESUMO
BACKGROUND: Cytomegalovirus (CMV) pneumonitis has been shown to be associated with lymphocytic alveolitis after lung transplantation. In the present study, we investigated a series of bronchoalveolar (BAL) and blood samples, collected in the absence of rejection or acute infectious episodes. in order -1: to evaluate intra-alveolar cell population changes concomitant with CMV replication and -2: to reappraise the value of cell population analysis in the management of patients after lung transplantation. METHODS: We used flow cytometry to investigate modifications of lymphocyte subpopulations related to pulmonary cytomegalovirus infections in blood and BAL samples from a series of 13 lung transplant recipients. After exclusion of samples obtained during pulmonary rejection, bronchiolitis obliterans or acute bacterial infection, 48 blood and BAL samples were retained for analysis: 17 were CMV positive by shell-vial assay and 31 were CMV negative in blood and BAL. RESULTS: Our results demonstrate that pulmonary CMV infection is associated with a significant increase in the total lymphocyte population in BAL samples, but with minor modifications of the various lymphocyte subpopulations and a significantly higher absolute number of B lymphocytes in blood samples. CONCLUSIONS: Cytomegalovirus pulmonary infection is accompanied by only minor changes in BAL lymphocyte subpopulations. The study of BAL lymphocyte subpopulations therefore appears to be of limited clinical value in the diagnosis of pulmonary CMV infection. However, increased blood B-lymphocytes seems to be a clinical feature associated with CMV infection.
Assuntos
Infecções por Citomegalovirus/imunologia , Pneumopatias/imunologia , Transplante de Pulmão/efeitos adversos , Lavagem Broncoalveolar , Relação CD4-CD8 , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/patologia , Humanos , Pneumopatias/sangue , Pneumopatias/patologia , Pneumopatias/virologia , Subpopulações de Linfócitos/imunologiaRESUMO
The authors report a case of multivisceral sarcoidosis which started in childhood and presented at radiography as multiple air-filled round cavities without signs of pulmonary fibrosis. The course of the disease was marked by progression of the bullae from apex to base and by the development of intracavitary aspergillosis responsible for haemoptysis.
Assuntos
Aspergilose/complicações , Pneumopatias/complicações , Sarcoidose/complicações , Criança , Humanos , Pneumopatias/diagnóstico por imagem , Masculino , Sarcoidose/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
High risk may be defined as either an absolute risk greater than 20 % or a relative risk greater than 4. Concerning breast and ovarian cancer, high risk patients include carriers of a constitutive deleterious mutation of BRCA1 or BRCA2 genes, patients with a significant family history of breast or ovarian cancer, and patients who have been diagnosed a benign breast lesion with a high risk of degeneration, i.e. atypical hyperplasia. Following up such patients relies on specific strategies. A center including a large panel of physicians involved in the various modalities for patients' management (geneticians, radiologists, gynecologists, plastic surgeons, pathologists, endocrinologists, psychologists, medical oncologists) has been created at Tenon Hospital with this purpose. The collaboration of these different specialists with the referent physician of the patient allows for the definition and the implementation of a patient-centered follow-up continuously updated to take into account the different periods of a woman's life, according to best practices recommendations and the evolving state-of-the art.
Assuntos
Neoplasias da Mama/prevenção & controle , Unidades Hospitalares/organização & administração , Neoplasias Ovarianas/prevenção & controle , Especialização , Mama/patologia , Doenças Mamárias/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , França , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Humanos , Hiperplasia , Mutação , Neoplasias Ovarianas/genética , Médicos , Encaminhamento e Consulta , Fatores de RiscoRESUMO
Fine-needle aspiration cytology, which is well established to be accurate for the diagnosis of thyroid cancer, may be inconclusive for the follicular thyroid neoplasms. As galectin-3 was suggested to be a marker of malignant thyrocytes, we investigated whether this protein might be helpful in the diagnosis of aspirates classified as undeterminate by cytology. After establishing an easy processing of aspirates for galectin-3 immunodetection, a series of aspirates categorised as benign (n=63), malignant (n=17) or undeterminate (n=34) was prospectively analysed for galectin-3. Only the patients with malignant or undeterminate lesions underwent surgery. Most lesions (86%) diagnosed as malignant by cytology or after surgery were positive for galectin-3. The majority of lesions (94%) classified as benign by cytology or after surgery was negative for galectin-3. The positive and negative predictive values were 83 and 95%, respectively. When focusing on the undeterminate lesions, the sensitivity and specificity were 75 and 90%, respectively, while the positive and negative predictive values were 82 and 87%, respectively. The specificity and the positive predictive value were higher (100%) when considering the percentage of stained cells. Altogether these results show that galectin-3 constitutes a useful marker in the diagnosis of thyroid lesions classified as undeterminate by conventional cytology.
Assuntos
Adenocarcinoma Folicular/metabolismo , Adenocarcinoma Folicular/patologia , Biomarcadores Tumorais/análise , Galectina 3/análise , Galectina 3/imunologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma Folicular/classificação , Biomarcadores Tumorais/imunologia , Biópsia por Agulha Fina , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica , Estudos Prospectivos , Neoplasias da Glândula Tireoide/classificaçãoRESUMO
Somatostatin (SS) can inhibit growth hormone (GH) secretion from the pituitary and tumor cell proliferation via membrane-bound receptors (SST). Five SST subtypes have been cloned and can be discriminated by specific peptides. In order to evaluate the human tissue distribution of the SSTs, we first used the cross-linking assay with the 125I-SS-14. A cross-linked complex of 57 kDa was detected in a majority (76%) of the surgical biopsies of normal and tumoral tissues examined (N = 222) and in all tested cell lines (N = 20). However, in regard to the organs, the incidence varied from 33% (epiploon metastases) to 100% (colorectal adenocarcinoma, prostate). Additional, minor SS-14 cross-linked complexes were detected in a few samples, suggesting the simultaneous existence of other SST subtypes. In tumor cell lines, the 57-kDa complex was reduced by the SST2-selective SS analogs BIM23014, BIM23060, and BIM23068, and by SS-14 but not by the non-SST2-selective BIM23052 and BIM23056. Its pharmacological profile therefore corresponded to SST2. Northern blot analysis showed one 2.5-kb human SST2 mRNA in these cell lines. We demonstrate that SST2 is detectable in normal and tumoral human tissues and thus represents an SST subtype target for the development of more specific SS analogs.
Assuntos
Neoplasias/ultraestrutura , Receptores de Somatostatina/metabolismo , Biópsia , Reagentes de Ligações Cruzadas/metabolismo , Humanos , RNA/metabolismo , RNA Mensageiro/metabolismo , RNA Neoplásico/metabolismo , Ensaio Radioligante , Somatostatina/análogos & derivados , Somatostatina/metabolismo , Distribuição Tecidual , Células Tumorais CultivadasRESUMO
Platinum and trace metal distributions of a human ovarian adenocarcinoma cell line, IGROV1, and a subline resistant to the antitumor agent cisplatin were compared using nuclear microprobe analysis. The cisplatin-resistant cell line IGROV1-DDP exhibited a cytologically heterogeneous cell population. Two subpopulations were distinguished, small mononuclear cells, morphologically similar to the parental cells IGROV1, and enlarged polynuclear cells. Quantitative mapping of platinum and essential trace metal such as manganese, iron, copper and zinc was performed at the cellular level. Elemental maps were obtained with 2 mu m spatial resolution. Platinum appeared uniformly distributed within the cells, in all cell types. The same was true for copper and zinc. In some cases, iron maps showed preferential localization in the perinuclear region, especially in IGROV1-DDP polynuclear cells. Cisplatin resistance was associated with decreased platinum and iron concentrations and increased levels of copper and zinc. Decreased drug accumulation was encountered in both subpopulations of the resistant cell line. In contrast, high inter-individual variation of copper content was noticed in this cell line suggesting that in vitro cisplatin selection of human ovarian adenocarcinoma resistant cells can bring about the emergence of distinct cellular phenotypes.
Assuntos
Adenocarcinoma/metabolismo , Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Neoplasias Ovarianas/metabolismo , Platina/farmacocinética , Oligoelementos/análise , Adenocarcinoma/química , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Ovarianas/química , Espectrometria por Raios X/métodos , Células Tumorais CultivadasRESUMO
Cisplatin-induced apoptosis and p53 gene status were analyzed in human ovarian carcinoma using a parental IGR-OV1 line and a derived cisplatin-resistant IGR-OV1/DDP subline. Compared with parental cells, cisplatin-resistant cells exhibited a 5-fold higher resistance index and a 2-fold longer doubling time. Cisplatin induced apoptosis in both cell lines, as assessed by cell morphology and the presence of a DNA ladder. However, high concentrations were necessary to induce apoptosis in resistant cells. These cells elicited a 5-fold decrease in the number of platinum atoms bound per nucleotide. IGR-OV1/DDP cells also exhibited enhanced drug efflux and a higher glutathione content. Our data suggest that the levels of cisplatin-DNA lesions are critical for drug sensitivity and apoptosis induction in this in vitro ovarian carcinoma model. Comparative analysis of the p53 gene in sensitive and resistant cells revealed the presence of the same heterozygous mutation in exon 5. A 2-fold increase in p53 mRNA and protein amounts was observed in resistant cells as assessed by Northern and Western blots, respectively. Immunocytochemical staining revealed a higher percentage of p53 stained nuclei in resistant cells. RT-PCR analysis of p53 transcripts showed that both wild-type and mutated alleles were transcribed in sensitive as well as in resistant cells. However, mutated transcripts were 1.5-fold more abundant than wild-type transcripts in sensitive cells, whereas they were 2-fold higher in resistant cells. In addition, mdm-2 protein was over-expressed in resistant cells. Our results address the question of the functionality of p53 protein and its possible role in apoptosis induction in this model. In resistant cells, p53 protein might be inactivated by 2 mechanisms: mutation and complexation with mdm-2 protein. Therefore, the presence of non-functional p53 in resistant cells might be involved in the relative failure of cisplatin-induced apoptosis in these cells.