RESUMEN
We report a case of fulminant massive hemolysis due to Clostridium perfringens septicemia in an elderly patient with non-systematic or local predisposing disorder. The patient presented with atypical symptoms but the progress of the disease was extremely rapid and he died almost 3h after his hospital admission. A focal infection or a possible portal of bacterial access was not found.
Asunto(s)
Bacteriemia/sangre , Infecciones por Clostridium/sangre , Clostridium perfringens/aislamiento & purificación , Anciano , Bacteriemia/microbiología , Resultado Fatal , Hemólisis , Humanos , MasculinoRESUMEN
This study examined the geographical distribution and diversity of the intrinsic OXA-51-like class D carbapenemases among Acinetobacter baumannii clones recovered in three major Greek regions from 2000 to 2005. The blaOXA-66 allele was exclusively detected among clonally distinct A. baumannii isolates recovered in the regions of Thessaloniki and Larissa. This sequence was also the most widespread among A. baumannii isolates in Athens, while less frequent were blaOXA-69 and blaOXA-65 alleles. These findings highlight the high prevalence of a specific blaOXA-51-like allele in Greece, possibly indicating that our A. baumannii clones might have originated from a common ancestor. However, the possibility that blaOXA-51-like variants, with blaOXA-66 predominating, are widely disseminated among several unrelated A. baumannii strains cannot be excluded.
Asunto(s)
Acinetobacter baumannii/enzimología , Proteínas Bacterianas/genética , beta-Lactamasas/genética , Acinetobacter baumannii/efectos de los fármacos , Electroforesis en Gel de Campo Pulsado , Variación Genética , Grecia , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
The efficacy of local instillation of fusidic acid in the prevention of post-surgical microbial complications during various types of lung resection was studied. Four hundred ninety two consecutive patients who underwent 504 thoracotomies for non-small cell lung carcinoma during April 1998-May 2004 were reviewed. The 290 patients of the first period who underwent 298 thoracotomies received a chemoprophylactic regimen of intravenous cefuroxime while the 202 patients of the second period who underwent 206 thoracotomies were additionally treated with fusidic acid, irrigated with local instillation into the pleural space, for the prevention of postoperative septic complications. Patients were followed postoperatively for development of septic complications (empyema and bronchopleural fistula) as well as of pneumonia and wound infection. Seventeen patients (5.7%) of the first period developed empyema and 13 fistula (4.4%), whereas only 2 patients (1.0%) of the second period developed empyema and fistula (OR = 5.876; 95% CI, 1.343- 25.716; P = 0.008 and OR = 4.193; 95% CI, 1.003-20.130; P = 0.034, respectively). Cases of pneumonia decreased, but not significantly, from 21 (7.0%) during the first period to 9 (4.4%) during the second period (OR = 1.613; 95% CI, 0.724-3.593; P = 0.257) while cases of wound infection decreased significantly from 19 (6.4%) to 2 (1.0%) (OR = 6.567; 95% CI, 1.513-28.510; P = 0.003). During the first period 23 pathogens were found from cases of empyema and 73 pathogens from cases of pneumonia and wound infection, whereas during the second period 3 and 18 pathogens were respectively found (OR = 5.3; 95% CI, 1.570-17.888; P = 0.003, and OR = 2.804; 95% CI, 1.628-4.838; P <0.001, respectively). These results indicate that local instillation of fusidic acid in the pleural space prior to lung resection seems effective in reducing the rate of septic complications as well as of wound infections.
Asunto(s)
Antibacterianos/uso terapéutico , Profilaxis Antibiótica , Infecciones Bacterianas/prevención & control , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Ácido Fusídico/uso terapéutico , Neoplasias Pulmonares/cirugía , Complicaciones Posoperatorias/prevención & control , Anciano , Antibacterianos/administración & dosificación , Infecciones Bacterianas/microbiología , Fístula Bronquial/microbiología , Fístula Bronquial/prevención & control , Cefuroxima/administración & dosificación , Cefuroxima/uso terapéutico , Quimioterapia Combinada , Empiema Pleural/microbiología , Empiema Pleural/prevención & control , Femenino , Ácido Fusídico/administración & dosificación , Humanos , Instilación de Medicamentos , Masculino , Persona de Mediana Edad , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/prevención & control , Complicaciones Posoperatorias/microbiología , Estudios Retrospectivos , Infección de la Herida Quirúrgica/microbiología , Infección de la Herida Quirúrgica/prevención & control , ToracotomíaRESUMEN
AIM: The investigation of three fatal cases during a nationwide cluster of cases of an upper respiratory tract infection (URTI) associated with myocarditis and/or pericarditis in Greece in 2002. METHODS: In the three women who died, necropsies were performed and tissue sections were taken for histological examination, antigen detection by immunohistochemistry and indirect immunofluorescence assay (IFA), amplification of viral genomes by nested reverse transcription polymerase chain reaction (RT-PCR), and sequence analysis. RESULTS: All samples showed histological signs of active myocarditis. Immunohistochemistry revealed the presence of the enterovirus VP1 family of proteins and IFA revealed the presence of coxsackievirus B3 antigen. Nested RT-PCR amplified enteroviral alleles of the 5'-untranslated region which were identical to each other and to the coxsackievirus B3 sequences. CONCLUSIONS: This study provides pathological evidence of enteroviral infection among fatal myocarditis cases in a nationwide URTI cluster of cases associated with myocarditis and/or pericarditis.
Asunto(s)
Enterovirus Humano B/aislamiento & purificación , Infecciones por Enterovirus/virología , Corazón/virología , Miocarditis/virología , Enfermedad Aguda , Brotes de Enfermedades , Enterovirus Humano B/genética , Infecciones por Enterovirus/mortalidad , Femenino , Genoma Viral , Grecia , Humanos , Persona de Mediana Edad , Miocarditis/mortalidadRESUMEN
We report the absence of beta-catenin mutations in 63 sporadic colorectal carcinomas (SCRCs) with demonstrated decreased beta-catenin and E-cadherin mRNA expression and E-cadherin protein expression in a subset of carcinomas examined, suggesting that beta-catenin mutations are an extremely rare phenomenon in SCRCs and are not responsible for the transcriptional impairment of the beta-catenin/E-cadherin adhesion complex observed in these tumours.
Asunto(s)
Adenocarcinoma/genética , Cadherinas/genética , Neoplasias Colorrectales/genética , Proteínas del Citoesqueleto/genética , Mutación , Transactivadores/genética , Transcripción Genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Cadherinas/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Proteínas del Citoesqueleto/metabolismo , ADN Complementario/genética , ADN Complementario/metabolismo , Exones , Femenino , Regulación Neoplásica de la Expresión Génica , Reordenamiento Génico , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , ARN Mensajero/metabolismo , Transactivadores/metabolismo , beta CateninaRESUMEN
AIMS: Reports concerning the expression of cytoplasmic components of the mitogen-activating protein kinase (MAPK) pathway in lung cancer are limited. One of the molecules participating in this pathway is the product of the c-mos proto-oncogene. In vitro investigations, in somatic cells, have shown that c-mos expression has opposing effects on cell cycle progression suggesting that it may represent an important determinant of aberrant cell function. In this study we analysed, by immunohistochemical means, its status in a series of lung carcinomas and correlated the findings with clinicopathological parameters and survival of the patients. METHODS AND RESULTS: Sixty cases of lung carcinomas were included in the study. These comprised 52 non-small (NSCLCs) and eight small cell lung carcinomas (SCLCs). Sections from the carcinomas were immunostained with the polyclonal anti-c-mos antibody P-19. Specificity was tested by using the appropriate control peptide and control cell lines. Expression was observed in 63% of the cases, with NSCLCs showing higher reactivity (67%) than SCLCs (37.5%). Staining was observed mainly to the cytoplasm and membranes of the cancerous cells, but some nuclei reacted as well. An intratumour heterogeneous immunoreactivity was noticed. The most interesting and unexpected finding was that c-mos positive staining was associated with better recurrence-free survival in our series, regardless of histological type (P = 0.035). Furthermore, favourable disease-related and recurrence-free survival was observed in the SqC group with c-mos immunoreactivity (P < 0. 001). CONCLUSIONS: c-mos proto-oncogene is expressed in a significant proportion of lung carcinomas and may play a role in its development. The fact that its expression is associated with a relatively good prognosis may be indicative of a negative impact on tumour growth.
Asunto(s)
Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogénicas c-mos/metabolismo , Anciano , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/mortalidad , Carcinoma de Células Pequeñas/patología , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Proto-Oncogenes Mas , Análisis de SupervivenciaRESUMEN
Deletions in the 5q14 region have been described in a variety of neoplasms, such as testicular germ cell tumors, ovarian, gastric and lung cancer. The high frequency of allelic losses observed in this region implies the presence of putative tumor suppressor gene(s) (TSGs). In the present study, we investigated in a series of 56 non-small cell lung carcinomas (NSCLCs) the allelic imbalance (Alm) within the 5q14 region, employing the D5S644 marker, and its relationship with p53 abnormalities, the kinetic parameters [proliferation index (PI) and apoptotic index (AI)] and the ploidy status of the carcinomas. AI at D5S644 was found at a frequency of 51.2%. The rather high percentage of Alm in stage I tumors suggests an early involvement in NSCLC development. LOH at 5q14 was associated with decreased AR in lung tumors insinuating the presence of a putative TSG(s) (P=0.008). Simultaneous alterations of both p53 and D5S644 locus were the most frequent pattern observed (37.5%). Cases demonstrating this profile also exhibited a marked decrease in AI (P=0.001). These findings imply a synergistic mechanism of co-operation between different TSGs. However, proliferation activity was dependent only on p53 status, leading to the assumption that the putative TSG(s) present at 5q14 may probably be involved in normal apoptotic procedures. Further studies are needed to identify the candidate gene(s).
Asunto(s)
Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Cromosomas Humanos Par 5/genética , ADN de Neoplasias/análisis , Genes p53/genética , Pérdida de Heterocigocidad , Neoplasias Pulmonares/genética , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , División Celular , Cartilla de ADN/química , Femenino , Frecuencia de los Genes/genética , Humanos , Etiquetado Corte-Fin in Situ , Pérdida de Heterocigocidad/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Estadificación de Neoplasias , Ploidias , Pronóstico , Tasa de SupervivenciaRESUMEN
A polymerase chain reaction (PCR) assay targeted to the immunogenic protein MPB64 gene was used to detect members of the Mycobacterium tuberculosis complex, and an outward-primed PCR (OPPCR) designed on the IS6110 element allowed differentiation between Mycobacterium bovis and Mycobacterium tuberculosis. Additionally, the amplification of IS1110 and 16S ribosomal RNA sequences combined with a dot blotting assay were able to differentially detect Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium paratuberculosis. The validity of the experimental procedure was tested on reference material and formalin-fixed paraffin-embedded samples from patients with tuberculosis, sarcoidosis, or Crohn disease. We demonstrated mycobacterial DNA in 59 of 75 cases with histologic lesions typical of tuberculosis; we detected M tuberculosis and M paratuberculosis in 6 of 25 sarcoidosis cases and in 7 of 20 Crohn disease specimens, respectively. The proposed diagnostic procedure is directly applicable to archival material and allows differentiation of genetically related mycobacterial pathogens in more detail than other molecular methods. It provides a tool for the diagnostic study of tuberculosis, sarcoidosis, and Crohn disease.
Asunto(s)
Antígenos Bacterianos , ADN Bacteriano/análisis , Mycobacterium/genética , Tuberculosis/patología , Proteínas Bacterianas , Enfermedad de Crohn/patología , Análisis Citogenético , Humanos , Hibridación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , ARN Ribosómico 16S , Reproducibilidad de los Resultados , Sarcoidosis/patología , Sensibilidad y EspecificidadRESUMEN
The 9p21-23 chromosome region harbors a number of known and putative tumor-suppressor genes (TSGs). The best characterized gene in this area is p16(INK4A) (CDKN2A). Alterations of its product have been observed in various malignancies, including non-small-cell lung carcinomas (NSCLCs). We earlier investigated the mechanisms underlying p16(INK4A) inactivation. In the present study, we examined, in a series of 87 NSCLCs, its relationship with the kinetic parameters [proliferation index (PI) and apoptotic index (Al)] and the ploidy status of the tumors. In addition, we extended our previous LOH analysis of the 9p21-23 region by examining flanking areas of p16(INK4A). Aberrant p16 expression was observed in 41.4% of the carcinomas. A significant association was found with increased PI (p = 0.037), but not with apoptosis. Aneuploid tumors were more frequently correlated with abnormal p16 staining (p = 0. 05). A high frequency of allelic imbalance (Alm) was noticed at the D9S161 (51.3%) and D9S157 (64.5%) loci, which lie approximately 4cM centromeric and 7cM telomeric, respectively, to CDKN2A. Abnormal p16(INK4A) expression was strongly correlated with Alm at D9S161 (p = 0.004). Allelic losses at D9S157 occurred more frequently in early stages (p = 0.018) and were significantly associated with deletions at D9S161 (p = 0.035). We conclude that, in a sub-set of NSCLCs, (i) abnormal p16 expression contributes to tumor growth mainly by increasing the proliferative activity in the initial stages of carcinogenesis; (ii) the association with aneuploidy merely reflects the impact of aberrant p16 on proliferative activity; and (iii) other putative TSGs possibly reside within the 9p21-23 region that possibly co-operate in certain cases with CDKN2A in the development of NSCLCs.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Cromosomas Humanos Par 9/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/biosíntesis , Genes p16/genética , Pérdida de Heterocigocidad , Neoplasias Pulmonares/metabolismo , Ploidias , Anciano , Alelos , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/metabolismo , División Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
The aims of the present study were: (1) to design a sensitive and specific polymerase chain reaction-based method that would allow detection of most common human typical and atypical mycobacterial strains and (2) to apply the method on formalin-fixed paraffin-embedded (FFPE) tissue and sputum samples from patients with clinicopathological evidence of tuberculosis and sarcoidosis. Three sets of primers were selected. The first detects specifically members of the Mycobacterium tuberculosis (M. tuberculosis) complex, amplifying a 243 bp fragment of the gene encoding the immunogenic protein MPB 64, whereas the second traces members of the Mycobacterium avium (M. avium) complex producing a 91 bp fragment of the IS1110 element. The third pair of primers is specific for slow-growing mycobacteria, amplifying a 383 bp region of the 65 kDa mycobacterial antigen gene. Our multiplex polymerase chain reaction assay identified mycobacterial DNA of 10(-3) colony-forming units (CFU)/mL from sputum samples, 10(-5) CFU/mL from FFPE tissue samples and 10(-6) CFU/mL from pure broth cultures. By performing the method on 75 FFPE tissue samples with histological and clinical evidence of tuberculosis and 300 sputum specimens from patients suspected of tuberculosis, we found 38 M. tuberculosis complex, 7 M. avium complex, and 14 slow-growing mycobacteria positive samples in the first case and in the second we found 95 M. tuberculosis complex, 21 M. avium complex, and 35 slow-growing mycobacteria positive samples. The sensitivity of the assay was significantly higher than that of Ziehl-Neelsen and in some cases higher than culture, especially when applied on atypical mycobacteria. In addition, 25 cases histologically and clinically characterized as sarcoidosis were investigated for mycobacterial DNA sequences and in nine of these, DNA corresponding to M. tuberculosis complex was detected. The method described can be applied directly on FFPE and sputum samples and allows not only the detection of mycobacterial DNA, but also an assessment concerning the species involved.
Asunto(s)
ADN Bacteriano/análisis , Mycobacterium tuberculosis/genética , Reacción en Cadena de la Polimerasa/métodos , Sarcoidosis/microbiología , Tuberculosis/microbiología , ADN Bacteriano/genética , Humanos , Microtomía , Mycobacterium/genética , Mycobacterium avium/genética , Sarcoidosis/genética , Sarcoidosis/patología , Sensibilidad y Especificidad , Esputo/microbiología , Tuberculosis/genética , Tuberculosis/patologíaRESUMEN
Early prostatic carcinoma is a slowly progressing, localized malignant tumor which has been recently discovered with increased frequency due to the use of improved diagnostic methods. The combination of digital rectal examination, serum PSA level and transrectal ultrasound is currently the best available diagnostic tool, although other putative diagnostic markers and techniques are being investigated. Core needle biopsy may follow if there is suspicion of malignancy and in doubtful cases the most useful antibody for the immunohistochemical diagnosis of early, low grade prostatic carcinoma is clone 34 beta E12. Cytogenetic techniques and molecular biological methods are increasingly being used for further investigating localized prostate carcinomas in order to identify early molecular targets and alterations, which may lead to progression. Chromosome abnormalities, cell to cell and cell to matrix interactions, changes in the status of steroid hormone receptors, oncogenes and tumor suppressor genes, as well as other, as yet unclear, events may be of importance in prostate carcinogenesis and the progression of early malignant tumors to aggressive phenotypes. A variety of putative prognostic markers, apart from serum PSA levels, histological grade and tumor volume, such as neuroendocrine differentiation, angiogenesis, cell proliferation labeling index and ploidy analysis may prove useful in evaluating tumor progression in early prostatic carcinomas. The final and most important goal of all investigations related to early prostate cancer is to contribute to the best therapeutic management of the individual patient.
Asunto(s)
Neoplasias de la Próstata , Biomarcadores de Tumor/análisis , Biopsia con Aguja , Aberraciones Cromosómicas , Progresión de la Enfermedad , Humanos , Masculino , Estadificación de Neoplasias , Pronóstico , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapiaRESUMEN
The p16 protein is encoded by the CDKN2 gene, and functions as an inhibitor of cyclin-dependent kinase 4 and 6 (CDK4/6). Phosphorylation of the retinoblastoma protein (pRb) by CDK4/6 represents a vital step in cell cycle progression. Alterations of p16INK4A are frequent events in human malignancies. In non-small cell lung carcinoma (NSCLC) the data concerning the mechanisms of p16INK4A inactivation suggest that point mutations and aberrant methylation of its promoter can only account for a proportion of the cases with abnormal p16 immunoexpression. The role of deletions in this procedure is not yet clarified. In order to gain more insight into the role of deletions in p16INK4A deregulated expression, we investigated the state of the chromosomal region 9p21-22 in a series of 57 NSCLCs, by performing a detailed mapping analysis, using a tight cluster of highly polymorphic microsatellite markers, and correlating the findings with p16 immunostaining. Abnormal p16 expression was observed in 46% of the NSCLCs examined. No relationship was observed between p16 abnormal staining and various clinicopathological parameters. Abnormal p16 protein staining was strongly associated with hemizygous deletions at the IFNA and D9S171 microsatellite loci, which demarcate the region encoding the p16INK4A gene (P = 0.002). These findings suggest that deregulated expression of p16 is involved in the multistage process of NSCL carcinogenesis and that deletions may represent a predominant mechanism of p16INK4A inactivation. A significant percentage also of LOH was noticed at the D9S162 (35%) and D9S126 (38%) loci which lie 6cM and 4cM, respectively, far from the area which encodes p16INK4A, implying that other tumor suppressor genes (TSGs) may reside in this region. Although the overall incidence of LOH at the examined region was high (58%), we did not observe any correlation with smoking habits, histology and lymph node status. Another noteworthy finding was the existence of microsatellite instability (MI) in 11% of the patients. MI provides a marker for replication error phenotype (RER+), a recently defined manifestation of genetic instability observed in a wide range of tumors. In conclusion, alterations (LOH + MI) at the 9p21-22 chromosome region are frequent events in NSCLCs and may affect directly or indirectly the expression of p16.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Cromosomas Humanos Par 9/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/biosíntesis , Genes p16 , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Eliminación de Secuencia , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Transformación Celular Neoplásica/genética , Cromosomas Humanos Par 9/ultraestructura , Inhibidor p16 de la Quinasa Dependiente de Ciclina/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Pérdida de Heterocigocidad , Neoplasias Pulmonares/metabolismo , Masculino , Repeticiones de Microsatélite , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/fisiologíaRESUMEN
BACKGROUND: Mutations on the X-chromosome clinically manifesting different phenotypes of hearing loss have been mapped to the long arm at different loci, DFN1-DFN3. Another defect in a family with sex-linked, postlingual, progressive sensorineural hearing loss was mapped to Xq. METHODS: Clinically, the family was evaluated by physical and audiometric examination of 17 members including computerized tomographic (CT) evaluation of the proband. Molecular evaluation consisted of polymerase chain reaction amplification of patient genomic DNA and resolution 32P-labeled fragments by polyacrylamide gels. Inheritance of DNA alleles and deafness were analyzed using the MLINK computer program. RESULTS: Five affected males demonstrated symmetrical sensorineural hearing loss as significant as 100 decibels (dB). Two carrier females had a milder loss with frequency findings of 10 dB to 60 dB. Computerized tomography (CT) evaluation of the temporal bones of the proband was normal. The odds were 200:1 that the responsible gene was linked to locus DXS986 (maximum lod score = 2.3 at 0 = 0). Analysis of recombination events defined by family members demonstrates that the responsible gene lies in a 21 cM (30 MB) interval, between loci DXS12175 and 1106. The disease locus in this family does not appear to map to DFN1 or DFN3. CONCLUSION: The family described here, with affected males who have progressive, postlingual sensorineural hearing loss and mildly affected females maps most compatibly to the DFN2 locus. Analysis of hereditary deafness in this family refines the DFN2 locus to a 9.2 Mb region in chromosome X band q21 between DXS990 and DXS106.
Asunto(s)
Ligamiento Genético/genética , Pérdida Auditiva Sensorineural/genética , Mutación/genética , Cromosoma X/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Audiometría , Mapeo Cromosómico , Progresión de la Enfermedad , Femenino , Pérdida Auditiva Sensorineural/diagnóstico , Heterocigoto , Humanos , Escala de Lod , Masculino , Linaje , FenotipoRESUMEN
Wild-type (wt) p53 is a tumor-suppressor protein which acts via transcriptional and transcriptional-independent mechanisms. The transcriptional function of p53 is mediated by specific responsive elements (REs). The MDM2, WAF1/Cip1 and Bax genes possess p53REs and their activation by wt p53 induces cell cycle progression, arrest and programmed cell death (apoptosis), respectively. Mutations of the p53 gene are detected in more than 50% of the human malignant tumors. p53 mutants seem to have a more stable conformation and are suggested to exert dominant-negative inhibition of wt p53 in cells containing both wt and mutant (mt) alleles. However, recent studies show that certain mt p53 proteins posses a "gain of function" phenotype. In the present study, we examined the effects of the second most frequent p53 mutant R273H on the p53REs of the MDM2, WAF1/Cip1 and Bax genes in the H1299 non-small cell lung carcinoma cell line. Although mt p53 R273H alone was unable to bind and transactivate the corresponding p53REs, it enhanced the MDM2-p53RE mediated gene transcription of wt p53 (positive-dominant effect) and prevented the wt p53 transactivation of the p53REs of WAF1/Cip1 and Bax genes (negative-dominant effect). Our data suggest that in the appropriate environment, differential transcription of critical p53 target genes by certain p53 mutant proteins may illustrate another mechanism implicated in tumor development.
Asunto(s)
Ciclinas/genética , Neoplasias Pulmonares/genética , Mutación , Proteínas Nucleares , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas/genética , Elementos de Respuesta , Proteína p53 Supresora de Tumor/fisiología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , ADN/metabolismo , Humanos , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-mdm2 , Transcripción Genética , Transfección , Proteína X Asociada a bcl-2Asunto(s)
Pérdida Auditiva Bilateral/diagnóstico , Pérdida Auditiva/diagnóstico , Acueducto Vestibular/anomalías , Enfermedades Vestibulares/diagnóstico , Adolescente , Niño , Preescolar , Femenino , Pérdida Auditiva/etiología , Pérdida Auditiva Bilateral/etiología , Humanos , Lactante , Masculino , Tomografía Computarizada por Rayos X , Pruebas de Función VestibularRESUMEN
We report a novel locus responsible for postlingual progressive sensorineural hearing loss (designated DFNA9) that maps to chromosome 14q12-13. A large kindred with autosomal dominant transmission of non-syndromic hearing loss was clinically studied. Hearing in affected individuals deteriorated at approximately 20 years of age and progressed to anacusis in the fifth decade. A random genome-wide search using polymorphic short tandem repeats demonstrated linkage with D14S121 (maximum two point LOD score = 6.19, theta = 0). Haplotype analysis of recombination events defined a 9 cM disease interval, between D14S252 and D14S49.