RESUMEN
Accumulating evidence underscores the T-cell immune synapse (IS) as a site of intense vesicular trafficking, on which productive signaling and cell activation crucially depend. Although the T-cell antigen receptor (TCR) is known to exploit recycling to accumulate to the IS, the specific pathway that controls this process remains to be elucidated. Here we demonstrate that the small GTPase Rab29 is centrally implicated in TCR trafficking and IS assembly. Rab29 colocalized and interacted with Rab8, Rab11 and IFT20, a component of the intraflagellar transport system that regulates ciliogenesis and participates in TCR recycling in the non-ciliated T cell, as assessed by co-immunoprecipitation and immunofluorescence analysis. Rab29 depletion resulted in the inability of TCRs to undergo recycling to the IS, thereby compromizing IS assembly. Under these conditions, recycling TCRs accumulated in Rab11(+) endosomes that failed to polarize to the IS due to defective Rab29-dependent recruitment of the dynein microtubule motor. Remarkably, Rab29 participates in a similar pathway in ciliated cells to promote primary cilium growth and ciliary localization of Smoothened. These results provide a function for Rab29 as a regulator of receptor recycling and identify this GTPase as a shared participant in IS and primary cilium assembly.
Asunto(s)
Cilios/fisiología , Sinapsis Inmunológicas , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/inmunología , Proteínas de Unión al GTP rab1/fisiología , Procesos de Crecimiento Celular , Cilios/metabolismo , Cilios/ultraestructura , Humanos , Transporte de Proteínas , Linfocitos T/enzimología , Linfocitos T/ultraestructura , Proteínas de Unión al GTP rabRESUMEN
Epstein-Barr Virus (EBV) is a γ-herpesvirus that infects >90% of the human population. Although EBV persists in its latent form in healthy carriers, the virus is also associated with several human cancers. EBV is strongly associated with Burkitt lymphoma (BL), even though there is still no satisfactory explanation of how EBV participates in BL pathogenesis. However, new insights into the interplay between viruses and microRNAs (miRNAs) have recently been proposed. In particular, it has been shown that B-cell differentiation in EBV-positive BL is impaired at the post-transcriptional level by altered expression of hsa-miR-127. Here, we show that the overexpression of hsa-miR-127 is due to the presence of the EBV-encoded nuclear antigen 1 (EBNA1) and give evidence of a novel mechanism of direct regulation of the human miRNA by this viral product. Finally, we show that the combinatorial expression of EBNA1 and hsa-miR-127 affects the expression of master B-cell regulators in human memory B cells, confirming the scenario previously observed in EBV-positive BL primary tumors and cell lines. A good understanding of these mechanisms will help to clarify the complex regulatory networks between host and pathogen, and favor the design of more specific treatments for EBV-associated malignancies.
RESUMEN
The molecular feature of Burkitt lymphoma (BL) is the translocation that places c-Myc under the control of immunoglobulin gene regulatory elements. However, there is accumulating evidence that some cases may lack an identifiable MYC translocation. In addition, during the EUROFISH project, aiming at the standardization of FISH procedures in lymphoma diagnosis, we found that five cases out of 35 classic endemic BLs were negative for MYC translocations by using a split-signal as well as a dual-fusion probe. Here we investigated the expression pattern of miRNAs predicted to target c-Myc, in BL cases, to clarify whether alternative pathogenetic mechanisms may be responsible for lymphomagenesis in cases lacking the MYC translocation. miRNAs are a class of small RNAs that are able to regulate gene expression at the post-transcriptional level. Several studies have reported their involvement in cancer and their association with fragile sites in the genome. They have also been shown to control cell growth, differentiation, and apoptosis, suggesting that these molecules could act as tumour suppressors or oncogenes. Our results demonstrated a modulation of specific miRNAs. In particular, down-regulation of hsa-let-7c was observed in BL cases, compared to normal controls. More interestingly, hsa-mir-34b was found to be down-regulated only in BL cases that were negative for MYC translocation, suggesting that this event might be responsible for c-Myc deregulation in such cases. This hypothesis was further confirmed by our in vitro experiments, which demonstrated that increasing doses of synthetic hsa-mir-34b were able to modulate c-Myc expression. These results indicate for the first time that hsa-mir-34b may influence c-Myc expression in Burkitt lymphoma as the more common aberrant control exercised by the immunoglobulin enhancer locus.
Asunto(s)
Linfoma de Burkitt/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Adolescente , Adulto , Linfoma de Burkitt/patología , Niño , Preescolar , Femenino , Expresión Génica , Genes de Inmunoglobulinas , Genes myc , Humanos , Hibridación Fluorescente in Situ/métodos , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Translocación Genética , Adulto JovenRESUMEN
The role of HPV in the carcinogenesis of intraepithelial and invasive anogenital lesions is currently well established. E6 and E7 oncoproteins of high-risk HPV genotypes are known to inactivate p53 and pRb pathways. Several studies have described an increased prevalence and recurrence of both cervical HPV infection and invasive cervical cancer among HIV-1 positive women compared to HIV-1 negative cases. For these reasons, cervical cancer is considered an AIDS-defining neoplasm. Unlike other AIDS-associated neoplasms, the occurrence of cervical cancer is independent of immune suppression. HIV-1 infection in patients with high grade precancerous lesions and invasive cervical cancers results in a therapy refractory and more aggressive disease phenotype, which is not yet well understood at the molecular level. An upregulation of HPV E6 and E7 gene expressions by HIV-1 proteins such as Tat has been documented by some authors. However, the role of HIV-1 in cervical carcinomas is still unclear. It is already known that HIV-1 Tat protein is able to influence cell cycle progression. Altogether, these facts led us to investigate the effects of Tat on the expression of cell cycle regulator genes. After transfection of HeLa cells with Tat, we analyzed the expression of cell cycle regulators from these cells by IHC and Real-time PCR. A significant reduction in the expression of cell cycle inhibitors of transcription and an increase in the levels of proliferation markers were observed. These results suggest that HIV-1 may enhance cervical carcinogenesis by promoting cell cycle progression. We also found that this HIV-1 Tat-induced cell proliferation was not dependent on the E2F family of transcription factors, and therefore postulate that Sp factors may be involved.
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Ciclo Celular/fisiología , Productos del Gen tat/fisiología , VIH-1 , Neoplasias del Cuello Uterino/patología , División Celular/fisiología , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Femenino , Genotipo , Humanos , ARN Mensajero/genética , ARN Viral/genética , Neoplasias del Cuello Uterino/virología , Productos del Gen tat del Virus de la Inmunodeficiencia HumanaRESUMEN
The "Careggi Safety" project has like objective to guarantee the safety execution of Careggi Hospital (Florence) restoration and development works, thanks to an in itinere training program into building sites and through tutor figure using. The project aim is to overcomes traditional indoor training limits, not effective in complex and dynamics reality like as building sites, constrained by contracts deadline and high labour turnover (subcontracts) inside carry out process. Solutions chose are: (a) a training projected in itinere, following site works evolution and safety and coordination plan, and through a constant agreement between customer and operative enterprises; (b) a building site's tutor, standing beside workers during realization phases, contributing to form on respective safety carry out job. In to "Careggi Safety" project training has been chose as preliminary and obligatory condition for labours admission and control into the building site.
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Hospitales , Industrias , Capacitación en Servicio , Salud Laboral , ItaliaRESUMEN
An anoxic titrimetric test was investigated for measuring denitrification potential of different wastewaters, both municipal and industrial, and to quantify the denitrifying activity in an activated sludge system. The method measures the amount of acid that is required to maintain the pH set-point value in a batch denitrification experiment, and it was performed using a DENICON (denitrification controller) biosensor. The amount of acid is proportional to the nitrate used to oxidise the biodegradable chemical oxygen demand present in the wastewater, while the acid consumption rate is used to derive the denitrifying activity. The wastewaters tested were a municipal wastewater (MW), an industrial-municipal wastewater (MIW; 70% and 30%, respectively), and four industrial wastewaters drawn from an ice-cream factory (IW1), a beet-sugar factory (IW2), a brewery (IW3), and a tuna cannery industry (IW4). Good correlation between titration data and analyses was found.
Asunto(s)
Técnicas Biosensibles/métodos , Residuos Industriales , Nitratos/metabolismo , Agua/química , Aguas del Alcantarillado/químicaRESUMEN
In this experimental study the characterization of 2 industrial wastewaters, coming from an ice cream production industry (IW1) and a beet-sugar factory (IW2), with respect to their readily biodegradable fraction and denitrification potential, has been performed. To this end physical-chemical and biological characterization methods, both anoxic and aerobic, were used. Moreover a pilot scale SBR fed with municipal wastewater was started to verify the effect of the gradual addition of the concentrated organic wastewaters during the anoxic phase. The SBR was initially fed only with a primary municipal wastewater, then the organic load was increased by adding to the feed, during the anoxic phase, a small amount of the IW1 (second period). Once the initial conditions were restored the load was again raised using the second industrial wastewater (IW2) (third period). With those additions the nitrogen removal efficiency increased from 26% to 50%, in the case of the IW1 and from 23% to 53% in the case of the wastewater IW2, without any negative effect on the global performance of the system. In addition, periodical kinetic studies of denitrification and nitrification in the SBR, were performed.
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Reactores Biológicos , Hipoxia/metabolismo , Residuos Industriales , Nitrógeno/aislamiento & purificación , Eliminación de Residuos Líquidos/métodos , Purificación del Agua/métodos , Amoníaco/aislamiento & purificación , Bacterias Aerobias , Cinética , Nitratos/química , Nitratos/metabolismo , Nitritos/química , Nitritos/metabolismo , Aguas del Alcantarillado/químicaAsunto(s)
Oncología Médica/historia , Sociedades Médicas/historia , Congresos como Asunto/historia , Europa (Continente) , Femenino , Neoplasias de los Genitales Femeninos/historia , Neoplasias de los Genitales Femeninos/terapia , Ginecología/historia , Historia del Siglo XX , Humanos , Medicina Reproductiva/historiaRESUMEN
The problem of quality of life and lifestyle in elderly women is today a very important social problem all over the world but particularly in rich western countries. Life expectancy of the population will be longer and longer in the future and for both females and males the biological involution correlated with the aging process must be delayed. The gonadal hormones stimulate the healthy state of the entire body (heart, skin, brain, bones, urogenital apparatus and so on) and consequently hormonal replacement therapy (HRT) is mandatory. In women the biological clock of menopause allows us to intervene at the right time, with personalized estrogenic, estroprogestinic or estroandrogenic treatments. Health benefits and groundless risks allow today a careful hormonal management even in women treated for gynaecological cancers (breast and endometrium as well).
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Neoplasias de los Genitales Femeninos/inducido químicamente , Terapia de Reemplazo de Hormonas , Posmenopausia/fisiología , Anciano , Anciano de 80 o más Años , Estrógenos/efectos adversos , Estrógenos/uso terapéutico , Femenino , Terapia de Reemplazo de Hormonas/efectos adversos , Humanos , Esperanza de Vida , Persona de Mediana Edad , Posmenopausia/efectos de los fármacos , Progesterona/uso terapéuticoRESUMEN
OBJECTIVES: The purpose of this study was to evaluate the health consequences of employment in the lead-smelting industry. METHODS: A mortality study of 1388 workers and laborers in production and maintenance departments was conducted in an Italian lead-smelting plant. The vital status of cohort members was determined from 1950 to 1992. Standardized mortality ratios were calculated for specific causes of death on the basis of national and regional reference rates. The relative risk for selected causes of death was also modeled as a function of age, calendar period, latency, and duration of employment with Poisson regression analysis. RESULTS: A significant 4.5-fold excess mortality from pneumoconiosis and other diseases of the respiratory system was observed, but the risk of pneumoconiosis did not show a significant trend by duration of employment. Mortality from all cancers, stomach cancer, and lung cancer was lower than expected. The standardized mortality ratios for genitourinary diseases and kidney cancer were not significantly elevated, but the Poisson regression analysis showed that both risks increased significantly by duration of employment. CONCLUSIONS: These findings provide limited evidence that long-term employment in lead-smelting plants increases the risk of genitourinary diseases and kidney cancer. The observed increase in mortality from pneumoconiosis and other diseases of the respiratory system was more likely related to silica exposure in other workplaces.
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Causas de Muerte , Intoxicación por Plomo/complicaciones , Metalurgia , Enfermedades Profesionales/inducido químicamente , Enfermedades Profesionales/mortalidad , Adulto , Estudios de Seguimiento , Humanos , Italia , Masculino , Análisis de Regresión , Factores de RiesgoRESUMEN
The authors studied the prognostic value of EGFR and c-erbB-2 overexpression in adenocarcinoma of the uterine cervix. The aim of this research was to find a new pathway to prognosis for more adequate therapy.
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Adenocarcinoma/metabolismo , Receptores ErbB/biosíntesis , Receptor ErbB-2/biosíntesis , Neoplasias del Cuello Uterino/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/terapia , Femenino , Humanos , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/terapiaRESUMEN
A proliferating cell nuclear antigen (Ki-67) expression was investigated in 73 cases of invasive vulvar cancer, to detect new diagnostic and prognostic factors. We individualized, like Hendriks (1994), two general patterns of reactivity: 1) diffused positivity in all tumoral tissue with a bad prognosis; 2) focal positivity, localized at the edge of tumoral aggregates. Moreover, within focal patterns, one group with positivity to MIB-l of 0.2-6% and another group of 7-9% with different prognoses (better in the first group). Histotype, lymph-nodal status, FIGO stage are strictly correlated with distribution of Ki-67; on the contrary, no correlation was found with grading and number of mitoses.
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Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/fisiopatología , Antígeno Ki-67/análisis , Neoplasias de la Vulva/patología , Neoplasias de la Vulva/fisiopatología , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales , Carcinoma de Células Escamosas/diagnóstico , Femenino , Humanos , Inmunohistoquímica , Metástasis Linfática , Persona de Mediana Edad , Pronóstico , Sensibilidad y Especificidad , Tasa de Supervivencia , Neoplasias de la Vulva/diagnósticoRESUMEN
Eighty-eight patients out of 396 were treated for advanced ovarian cancer first by some cycles of chemotherapy--neoadjuvant chemotherapy-- and after by surgery. An improvement in the quality of surgery and disease-free period was observed while survival rate did not improve, compared with the patients treated by surgery before chemotherapy. It should be stressed that neoadjuvant chemotherapy was applied only in very advanced PS Figo stages. The results are the same in the three studied decades: even in the last one, when cases were selected following new protocols. In our case series all patients after chemotherapy underwent surgery and not only those with partial or complete response to chemotherapy.