RESUMEN
Despite causing regular seasonal epidemics with substantial morbidity, mortality and socioeconomic burden, there is still a lack of research into influenza B viruses (IBVs). In this study, we provide for the first time a systematic investigation on the tropism, replication kinetics and pathogenesis of IBVs in the human respiratory tract.Physiologically relevant ex vivo explant cultures of human bronchus and lung, human airway organoids, and in vitro cultures of differentiated primary human bronchial epithelial cells and type-I-like alveolar epithelial cells were used to study the cellular and tissue tropism, replication competence and induced innate immune response of 16 IBV strains isolated from 1940 to 2012 in comparison with human seasonal influenza A viruses (IAVs), H1N1 and H3N2. IBVs from the diverged Yamagata- and Victoria-like lineages and the earlier undiverged period were included.The majority of IBVs replicated productively in human bronchus and lung with similar competence to seasonal IAVs. IBVs infected a variety of cell types, including ciliated cells, club cells, goblet cells and basal cells, in human airway organoids. Like seasonal IAVs, IBVs are low inducers of pro-inflammatory cytokines and chemokines. Most results suggested a higher preference for the conducting airway than the lower lung and strain-specific rather than lineage-specific pathogenicity of IBVs.Our results highlighted the non-negligible virulence of IBVs which require more attention and further investigation to alleviate the disease burden, especially when treatment options are limited.
Asunto(s)
Virus de la Influenza B/fisiología , Organoides/patología , Organoides/virología , Sistema Respiratorio/patología , Sistema Respiratorio/virología , Tropismo Viral , Animales , Bronquios/patología , Diferenciación Celular , Perros , Células Epiteliales/virología , Eritrocitos/citología , Humanos , Inmunidad Innata , Inmunohistoquímica , Subtipo H1N1 del Virus de la Influenza A/fisiología , Subtipo H3N2 del Virus de la Influenza A/fisiología , Concentración 50 Inhibidora , Pulmón/patología , Células de Riñón Canino Madin Darby , Técnicas de Cultivo de Órganos , PavosAsunto(s)
Betacoronavirus , Infecciones por Coronavirus , Humanos , Sistema Respiratorio , Tropismo , Tropismo Viral , Replicación ViralRESUMEN
Poor human-to-human transmission of influenza A H5N1 virus has been attributed to the paucity of putative sialic acid alpha2-3 virus receptors in the epithelium of the human upper respiratory tract, and thus to the presumed inability of the virus to replicate efficiently at this site. We now demonstrate that ex vivo cultures of human nasopharyngeal, adenoid and tonsillar tissues can be infected with H5N1 viruses in spite of an apparent lack of these receptors.
Asunto(s)
Subtipo H5N1 del Virus de la Influenza A/metabolismo , Gripe Humana/transmisión , Receptores de Superficie Celular/metabolismo , Sistema Respiratorio/virología , Acoplamiento Viral , Células Cultivadas , Epitelio/virología , Histocitoquímica , Hong Kong , Humanos , Subtipo H1N1 del Virus de la Influenza A/metabolismo , Subtipo H3N2 del Virus de la Influenza A/metabolismo , Gripe Humana/metabolismo , Fitohemaglutininas/metabolismo , Replicación Viral/fisiologíaRESUMEN
The production of virus-like particles (VLPs) constitutes a relevant and safe model to study molecular determinants of virion egress. The minimal requirement for the assembly of VLPs for the coronavirus responsible for severe acute respiratory syndrome in humans (SARS-CoV) is still controversial. Recent studies have shown that SARS-CoV VLP formation depends on either M and E proteins or M and N proteins. Here we show that both E and N proteins must be coexpressed with M protein for the efficient production and release of VLPs by transfected Vero E6 cells. This suggests that the mechanism of SARS-CoV assembly differs from that of other studied coronaviruses, which only require M and E proteins for VLP formation. When coexpressed, the native envelope trimeric S glycoprotein is incorporated onto VLPs. Interestingly, when a fluorescent protein tag is added to the C-terminal end of N or S protein, but not M protein, the chimeric viral proteins can be assembled within VLPs and allow visualization of VLP production and trafficking in living cells by state-of-the-art imaging technologies. Fluorescent VLPs will be used further to investigate the role of cellular machineries during SARS-CoV egress.
Asunto(s)
Proteínas de la Nucleocápside/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , Proteínas del Envoltorio Viral/metabolismo , Proteínas de la Matriz Viral/metabolismo , Ensamble de Virus , Animales , Chlorocebus aethiops , Proteínas M de Coronavirus , Proteínas de la Nucleocápside de Coronavirus , Humanos , Glicoproteínas de Membrana/metabolismo , Microscopía Electrónica de Transmisión , Proteínas de la Nucleocápside/genética , Glicoproteína de la Espiga del Coronavirus , Células Vero , Proteínas del Envoltorio Viral/genética , Proteínas de la Matriz Viral/genética , Proteínas Viroporinas , Virosomas/metabolismo , Virosomas/ultraestructuraRESUMEN
BACKGROUND: The quality of clinical specimens is a crucial determinant for virological diagnosis. OBJECTIVES: We compared the viral diagnostic yield for influenza A and respiratory syncytial virus (RSV) from the recently developed nasopharyngeal flocked swabs (NPFS) with nasopharyngeal aspirates (NPA) collected in parallel from 196 hospitalized children with acute respiratory infection during the peak period of influenza A and RSV activity in Hong Kong. Specimens were tested by RT-PCR for influenza A and RSV and viral load determined. They were also tested by direct immunofluorescence (DIF) for influenza A and B, RSV, parainfluenza types 1-3 and adenovirus. RESULTS: Both NPA and NPFS had excellent sensitivity (100%) for detecting influenza A by RT-PCR but NPA was slightly more sensitive than NPFS for detecting RSV by both RT-PCR (100% vs. 92.3%) and DIF (87.2% vs. 84.6%) and for detecting influenza A by DIF (90.2% vs. 82.9%). Viral load for influenza A in NPA and NPFS was not significantly different but that for RSV was higher in NPA. CONCLUSION: NPA remains the optimal specimen for diagnosis of respiratory infections by RT-PCR and DIF. However, collection of NPFS is easier to perform in an out-patient setting, was more acceptable to parents and less likely to generate aerosols than NPA engendering potentially less infection control hazard.
Asunto(s)
Nasofaringe/virología , Infecciones del Sistema Respiratorio/virología , Manejo de Especímenes/métodos , Virosis/virología , Virus/aislamiento & purificación , Adolescente , Niño , Preescolar , Técnica del Anticuerpo Fluorescente Directa/métodos , Hong Kong , Humanos , Lactante , Virus de la Influenza A/aislamiento & purificación , Virus de la Parainfluenza 1 Humana/aislamiento & purificación , Virus de la Parainfluenza 2 Humana/aislamiento & purificación , Virus de la Parainfluenza 3 Humana/aislamiento & purificación , Virus Sincitiales Respiratorios/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Sensibilidad y Especificidad , Virus/genéticaRESUMEN
A 53-year-old woman presented in 1979 with a posterior fossa meningeal haemangiopericytoma (HPC) for which she underwent surgical resection and post-operative radiotherapy. Repeated tumour recurrences occurred 18 years afterwards which were treated with resections and stereotactic radiotherapy. Surgery for tumour recurrence in 2005 revealed features of rhabdomyosarcomatous transformation. To our knowledge, this is the first reported case of rhabdomyosarcomatous transformation within a HPC which was likely to be radiation-induced, and was associated with relentless disease progression more than 20 years after the initial presentation.
Asunto(s)
Transformación Celular Neoplásica/efectos de la radiación , Irradiación Craneana/efectos adversos , Hemangiopericitoma/patología , Neoplasias Meníngeas/patología , Recurrencia Local de Neoplasia/patología , Neoplasias Inducidas por Radiación/patología , Rabdomiosarcoma/patología , Transformación Celular Neoplásica/patología , Terapia Combinada , Fosa Craneal Posterior/cirugía , Progresión de la Enfermedad , Resultado Fatal , Femenino , Hemangiopericitoma/radioterapia , Hemangiopericitoma/cirugía , Humanos , Neoplasias Meníngeas/radioterapia , Neoplasias Meníngeas/cirugía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/cirugía , Radiocirugia , Radioterapia Adyuvante , Reoperación , Tomografía Computarizada por Rayos XRESUMEN
The Asian countries chronically infected with avian influenza A H5N1 are 'global hotspots' for biodiversity conservation in terms of species diversity, endemism and levels of threat. Since 2003, avian influenza A H5N1 viruses have naturally infected and killed a range of wild bird species, four felid species and a mustelid. Here, we report fatal disseminated H5N1 infection in a globally threatened viverrid, the Owston's civet, in Vietnam, highlighting the risk that avian influenza H5N1 poses to mammalian and avian biodiversity across its expanding geographic range.
Asunto(s)
Conservación de los Recursos Naturales , Subtipo H5N1 del Virus de la Influenza A , Infecciones por Orthomyxoviridae/veterinaria , Viverridae/virología , Animales , Biodiversidad , Aves/virología , Femenino , Subtipo H5N1 del Virus de la Influenza A/clasificación , Subtipo H5N1 del Virus de la Influenza A/genética , Subtipo H5N1 del Virus de la Influenza A/aislamiento & purificación , Infecciones por Orthomyxoviridae/transmisión , Infecciones por Orthomyxoviridae/virología , Filogenia , Viverridae/anatomía & histología , Viverridae/fisiologíaRESUMEN
Potentiation of the EBV-specific CTL response by immunization with CTL epitopes has been proposed as a logical approach for immune-targeting nasopharyngeal carcinoma (NPC) cells in vivo. This approach will undoubtedly be influenced by the ability of these malignant cells to endogenously process and present target epitopes on their cell surface for immune recognition by CTLs. Analysis of NPC cells in fresh tumor biopsies and long-term, established NPC tumors in nude mice revealed normal expression of the MHC-encoded putative peptide transporters TAP1 and TAP2, as well as the proteasome components LMP2 and LMP7, which have been shown previously to be essential components of the class I processing pathway. Moreover, these tumor cells also showed high levels of HLA class I alleles on the cell surface, suggesting that peptides are available for binding to nascent MHC molecules in the endoplasmic reticulum. Using a recombinant vaccinia virus to transiently express the EBV nuclear antigens, we studied the antigen-processing efficiency of NPC cells. Our findings demonstrate that, in contrast to cells from another EBV-associated malignancy, Burkitt's lymphoma, NPC cells display normal antigen-processing function and are efficiently recognized by HLA class I-restricted, virus-specific CTLs. These studies also provide a rationale for focusing on strategies designed to activate CTLs specific for EBV antigens that are expressed in NPC cells in vivo.
Asunto(s)
Presentación de Antígeno/fisiología , Carcinoma/inmunología , Herpesvirus Humano 4/inmunología , Neoplasias Nasofaríngeas/inmunología , Linfocitos T Citotóxicos/inmunología , Transportadoras de Casetes de Unión a ATP/metabolismo , Adulto , Anciano , Animales , Carcinoma/metabolismo , Carcinoma/patología , Cartilla de ADN/química , Epítopos/inmunología , Femenino , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/virología , Linfocitos T Citotóxicos/virologíaRESUMEN
Cellular senescence is a programmed cell response leading to growth arrest in human diploid fibroblasts. We have shown that a nasopharyngeal carcinoma cell line, CNE1, following treatment by the DNA-damaging agent cisplatin, can undergo cellular senescent-like growth arrest, similar to fibroblasts, judged by cellular morphological changes and the expression of senescence-associated beta-galactosidase (SA-beta-gal). This senescent-like change was dose related; at 0.5 microgram/ml, the percentage of cisplatin-induced SA-beta-gal-positive cells was high (40-96%), and the staining was intense. Higher doses (1.0 and 2.0 micrograms/ml) of cisplatin induced lower SA-beta-gal expression (30-70%), and the process was irreversible. This cisplatin-induced cellular senescent-like response was not due to the inhibition of telomerase activity. Our results indicate that cellular senescent-like pathways exist in nasopharyngeal carcinoma cells and can be induced by cisplatin. Our evidence suggests that cellular senescent-like responses may be a cellular protection mechanism that acts differently in response to different degrees of cellular damage.
Asunto(s)
Antineoplásicos/farmacología , Senescencia Celular/efectos de los fármacos , Cisplatino/farmacología , beta-Galactosidasa/metabolismo , Biomarcadores , Ciclo Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inducción Enzimática , Humanos , Neoplasias Nasofaríngeas/patología , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
Undifferentiated nasopharyngeal carcinoma (NPC) is an epithelial malignancy that is consistently associated with Epstein-Barr virus (EBV) but which very rarely has p53 gene mutations in primary tumours. Since the tumour suppressor p53 is mutated in most human cancers or the wild type protein is inactivated in a significant number of the remainder, here we have investigated cellular factors that could compromise p53 function in primary NPC. Twenty-five primary tumours were judged to carry only wild type p53 by SSCP analysis of all exons and sequence determination of exons 4-9. Only one tumour was found to express significant levels of hMdm2 and in 24/25 there were no detectable mutations or deletions in exons 1beta and 2 of the p14(ARF) gene. However, immunohistochemistry consistently revealed that all the tumour cells express substantial amounts of the p53-related protein p63. Semi-quantitative RT-PCR analysis of mRNA from tumour biopsies showed that the dominant species expressed was invariably the truncated deltaN-isotype. Since this can block p53-mediated transactivation, it is potentially a dominant-negative isoform. In normal nasopharyngeal epithelium the distribution of p63 was restricted to the proliferating basal and suprabasal layers. We suggest that deltaN-p63 is a good candidate as a suppressor of wild type p53 function in these tumours and also that it may prove to be a valuable diagnostic marker for undifferentiated NPC.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Proteínas de la Membrana , Neoplasias Nasofaríngeas/genética , Proteínas Nucleares , Fosfoproteínas/genética , Transactivadores , Proteína p53 Supresora de Tumor/genética , Proteínas Portadoras/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Proteínas de Unión al ADN , Humanos , Neoplasias Nasofaríngeas/patología , Fosfoproteínas/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas/genética , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas c-mdm2 , Factores de Transcripción , Proteína p14ARF Supresora de Tumor , Proteína p53 Supresora de Tumor/biosíntesis , Proteínas Supresoras de TumorRESUMEN
Human disease associated with influenza A subtype H5N1 re-emerged in January, 2003, for the first time since an outbreak in Hong Kong in 1997. Patients with H5N1 disease had unusually high serum concentrations of chemokines (eg, interferon induced protein-10 [IP-10] and monokine induced by interferon gamma [MIG]). Taken together with a previous report that H5N1 influenza viruses induce large amounts of proinflammatory cytokines from macrophage cultures in vitro, our findings suggest that cytokine dysfunction contributes to the pathogenesis of H5N1 disease. Development of vaccines against influenza A (H5N1) virus should be made a priority.
Asunto(s)
Gripe Aviar/epidemiología , Gripe Humana/epidemiología , Gripe Humana/transmisión , Zoonosis/epidemiología , Animales , China/epidemiología , Brotes de Enfermedades/estadística & datos numéricos , Hong Kong/epidemiología , Humanos , Subtipo H5N1 del Virus de la Influenza A , Virus de la Influenza A/aislamiento & purificación , Gripe Aviar/transmisión , Gripe Aviar/virología , Gripe Humana/virología , Aves de Corral , Enfermedades de las Aves de Corral/epidemiología , Enfermedades de las Aves de Corral/transmisiónRESUMEN
BACKGROUND: Fatal human respiratory disease associated with influenza A subtype H5N1 has been documented in Hong Kong, and more recently in Vietnam, Thailand and Cambodia. We previously demonstrated that patients with H5N1 disease had unusually high serum levels of IP-10 (interferon-gamma-inducible protein-10). Furthermore, when compared with human influenza virus subtype H1N1, the H5N1 viruses in 1997 (A/Hong Kong/483/97) (H5N1/97) were more potent inducers of pro-inflammatory cytokines (e.g. tumor necrosis factor-a) and chemokines (e.g. IP-10) from primary human macrophages in vitro, which suggests that cytokines dysregulation may play a role in pathogenesis of H5N1 disease. Since respiratory epithelial cells are the primary target cell for replication of influenza viruses, it is pertinent to investigate the cytokine induction profile of H5N1 viruses in these cells. METHODS: We used quantitative RT-PCR and ELISA to compare the profile of cytokine and chemokine gene expression induced by H5N1 viruses A/HK/483/97 (H5N1/97), A/Vietnam/1194/04 and A/Vietnam/3046/04 (both H5N1/04) with that of human H1N1 virus in human primary alveolar and bronchial epithelial cells in vitro. RESULTS: We demonstrated that in comparison to human H1N1 viruses, H5N1/97 and H5N1/04 viruses were more potent inducers of IP-10, interferon beta, RANTES (regulated on activation, normal T cell expressed and secreted) and interleukin 6 (IL-6) in primary human alveolar and bronchial epithelial cells in vitro. Recent H5N1 viruses from Vietnam (H5N1/04) appeared to be even more potent at inducing IP-10 than H5N1/97 virus. CONCLUSION: The H5N1/97 and H5N1/04 subtype influenza A viruses are more potent inducers of proinflammatory cytokines and chemokines in primary human respiratory epithelial cells than subtype H1N1 virus. We suggest that this hyper-induction of cytokines may be relevant to the pathogenesis of human H5N1 disease.
Asunto(s)
Bronquios/inmunología , Bronquios/patología , Citocinas/inmunología , Subtipo H5N1 del Virus de la Influenza A/inmunología , Alveolos Pulmonares/inmunología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Células Cultivadas , Células Epiteliales/inmunología , Células Epiteliales/patología , Humanos , Factores Inmunológicos , Subtipo H1N1 del Virus de la Influenza A/inmunologíaAsunto(s)
Conjuntiva , Infecciones por Coronavirus , Pandemias , Neumonía Viral , Betacoronavirus , COVID-19 , Humanos , Inmunidad Innata , Sistema Respiratorio , SARS-CoV-2 , TropismoRESUMEN
Severe acute respiratory syndrome (SARS) is a new infectious disease that first emerged in Guangdong province, China, in November, 2002. A novel coronavirus was later identified in patients with SARS. The detection of the virus in these patients, its absence in healthy controls or other patients with atypical pneumonia, and the reproduction of a similar disease in a relevant animal model fulfilled Koch's postulates for implicating this coronavirus as the causal agent of SARS. The full genome sequence was determined within weeks of the virus's identification. The rapid progress in the aetiology, the development of laboratory diagnostic tests, and the defining of routes of viral transmission were facilitated through a unique WHO-coordinated virtual network of laboratories, which shared information on a real-time basis through daily teleconferences. Subsequent studies have indicated that the SARS coronavirus is of animal origin, that its precursor is still present in animal populations within the region, and that live-animal markets in southern China may have provided the animal-human interphase that allowed this precursor virus to adapt to human-human transmission. These findings underscore the potential for the re-emergence of SARS and the need for laboratory tests for early diagnosis. However, the low viral load in the respiratory tract makes early diagnosis of SARS a diagnostic challenge, although improvements in the sensitivity of molecular diagnostic methods continue to be made.
Asunto(s)
Síndrome Respiratorio Agudo Grave/diagnóstico , Síndrome Respiratorio Agudo Grave/epidemiología , Animales , China/epidemiología , Enfermedades Transmisibles Emergentes , Brotes de Enfermedades , Reservorios de Enfermedades , Genoma Viral , Humanos , Filogenia , ARN Viral/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , Síndrome Respiratorio Agudo Grave/prevención & control , Síndrome Respiratorio Agudo Grave/transmisión , Síndrome Respiratorio Agudo Grave/virologíaRESUMEN
In a recent study, it was shown that DNA damaging agent cisplatin-induced growth arrest and cell death in cancer cells by a pathway sharing some of the characteristics of replicative senescence. The aim of this study was to determine the role of p53, p21WAF1 and p16INK4A proteins in this alternative route to cancer cell death in additional human cancer cell lines. After exposure to cisplatin, all the cell lines underwent growth arrest and expressed the senescence marker senescence-associated beta-galactosidase, but showed none of the features of apoptosis. However, there was no change in p53 protein expression, and neither p21WAF1 nor p16INK4A was expressed before or up to 4 days after cisplatin exposure. These findings provide further evidence that cells carrying mutations resulting in loss of function in the p53 gene can be killed by cisplatin via a p53-independent route with some similarities to replicative senescence, but not apoptosis.
Asunto(s)
Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Cisplatino/farmacología , Proteína p53 Supresora de Tumor/fisiología , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Inhibidor p16 de la Quinasa Dependiente de Ciclina/efectos de los fármacos , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/efectos de los fármacos , Ciclinas/metabolismo , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Factores de Tiempo , Células Tumorales Cultivadas/citología , Células Tumorales Cultivadas/efectos de los fármacos , Proteína p53 Supresora de Tumor/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , beta-Galactosidasa/efectos de los fármacos , beta-Galactosidasa/metabolismoRESUMEN
The p16INK4a tumor suppressor gene is frequently inactivated in nasopharyngeal carcinoma (NPC) and hence it may play an important role in the suppression of this tumor. In order to study the effect of p16INK4a restoration in NPC cells, full-length human p16INK4a gene was transfected into a NPC cell line, CNE1. Four individual clones with differential levels of p16INK4a protein expression, were selected for further studies. The introduction of p16INK4a into CNE1 cells induced growth suppression through G0/G1 cell cycle arrest; however, the cell growth rate was not correlated to the levels of p16INK4a protein expression. To study whether transfection of p16INK4a could protect NPC cells from radiation, cisplatin and 5-fluorouracil (5FU), the cellular sensitivity of p16INK4a transfectants and vector control were investigated. An increase in sensitivity to 5FU was observed (2-fold compared to IC50) in all 4 clones compared to vector-transfected control. P16INK4a transfection also resulted in increased sensitivity to cisplatin (1.5-1.8-fold) in 3 out of 4 cell lines. However, no difference in radiosensitivity was found between the p16INK4a transfectants and the control. These findings indicate that p16INK4a suppresses NPC cell growth through G0/G1 arrest and modulating cellular response to chemotherapeutic drugs in NPC cells. Therefore, restoration of p16INK4a may have a therapeutic purpose in the treatment of NPC.
Asunto(s)
Proteínas Portadoras/fisiología , Ciclo Celular/fisiología , Cisplatino/toxicidad , Fluorouracilo/toxicidad , Genes Supresores de Tumor , Proteínas Portadoras/genética , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , División Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Clonales , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Humanos , Neoplasias Nasofaríngeas , Proteínas Recombinantes/metabolismo , Transfección , Células Tumorales CultivadasRESUMEN
Nasopharyngeal carcinoma is a common malignancy in Hong Kong and is treated by external radiotherapy. After 6.5 weeks of radiotherapy, the nasopharynx of 100 patients was examined and biopsy specimens were taken. All patients had repeated examination and biopsies done every 2 weeks until exophytic tumor was not seen and biopsy samples were negative on more than one examination of the nasopharynx. The interval between the cessation of therapy and biopsy ranged from 1 day to 11 weeks. Twenty-three patients had atypical findings and five of these had residual tumor requiring gold grain implantation brachytherapy. We identified a number of distinct pathologic changes in the post-biopsy material. Most of these changes disappeared 8 weeks after the cessation of therapy, but the presence of residual tumor after this time was an indication for subsequent therapy. If the date of the first biopsy was delayed until 6 weeks after the completion of radiotherapy, the percentage of atypical biopsies containing residual tumor rose from 21% to 55%. The posttreatment biopsy should be performed twice, as four patients had negative biopsy findings due to sampling error.
Asunto(s)
Carcinoma/patología , Carcinoma/radioterapia , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/radioterapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inducción de RemisiónRESUMEN
Immunoreactivity for intercellular adhesion molecule-1 (ICAM-1) and for vascular cell adhesion molecule-1 (VCAM-1), two adhesion molecules of the immunoglobulin (Ig) superfamily, was tested and measured on tissue sections from 16 undifferentiated nasopharyngeal carcinomas (U-NPC), 12 keratinizing squamous cell carcinomas (SCCs) of the head and neck region, and 54 malignant epithelial tumors of various origin. Neoplastic cells of all cases of U-NPC were diffusely and intensely stained for ICAM-1 and VCAM-1. Moreover, ICAM-1 messenger RNA (mRNA) and VCAM-1 mRNA were detected by Northern blot analysis of RNA extracts from two tumors. In the other epithelial tumors focal or diffuse staining for ICAM-1 was observed in 40 cases (66%), whereas reactivity for VCAM-1 was detected in a single case of metastatic undifferentiated carcinoma of unknown origin. The biopsy specimens of U-NPC showed variable infiltration by leukocytes, which were positive for the integrins lymphocyte function antigen-1 (LFA-1) and alpha-4/beta-1, the corresponding ligands for ICAM-1 and VCAM-1. The possibility that ICAM-1 and VCAM-1 on neoplastic cells may favor the intratumoral recruitment of leukocytes in a way similar to that occurring in crypt epithelium of the palatine tonsil is discussed.
Asunto(s)
Carcinoma/patología , Moléculas de Adhesión Celular/análisis , Neoplasias Nasofaríngeas/patología , Adolescente , Adulto , Anciano , Carcinoma/inmunología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Niño , Femenino , Humanos , Técnicas para Inmunoenzimas , Molécula 1 de Adhesión Intercelular , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/inmunología , Molécula 1 de Adhesión Celular VascularRESUMEN
Eighty-three cases of nasopharyngeal carcinoma were evaluated for the presence of Epstein-Barr virus (EBV) infection in tumor cells by in situ hybridization to EBER1 transcripts, and for p53 expression by immunostains using the D07 antibody which detects native and mutant forms of the p53 protein. A highly significant association was found between EBV infection and p53 overexpression (P = .0004), with 77% of cases coexpressing both markers. This newly discovered association suggests that EBV is not an innocent bystander with respect to p53 accumulation. One possible mediator of the interaction between EBV and p53, viral BZLF1, was not colocalized with p53 in these tumors, suggesting that BZLF1 is not the factor responsible for p53 accumulation. From an epidemiological standpoint, this series of cancers represents an international cohort in which cases from an endemic part of the world (Hong Kong) were examined alongside cases from the United States, where the disease is 50-fold less prevalent. The cancers from Hong Kong tended to be less differentiated and more frequently associated with EBV, suggesting that biological differences might underlie epidemiological variations in tumor prevalence. Finally, we examined 18 potential premalignant lesions of the surface epithelium of the nasopharynx. Although our numbers are small, our data suggest that p53 accumulation might precede EBV infection in the transition from metaplasia to carcinoma in situ. Further studies are needed to dissect the stepwise progression of nasopharyngeal carcinogenesis.