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1.
Recurso na Internet em Inglês | LIS - Localizador de Informação em Saúde | ID: lis-48471

RESUMO

Mesothelioma is a malignant tumor that is caused by inhaled asbestos fibers and forms in the lining of the lungs, abdomen or heart. Symptoms can include shortness of breath and chest pain. The life expectancy for most mesothelioma patients is approximately 12 months after diagnosis. Treatment may improve prognosis and can include surgery, chemotherapy or radiation. Português. Site com informações e guia sobre, o mesotelioma tumor maligno causado por fibras de amianto inaladas e se forma no revestimento dos pulmões, abdômen ou coração. Os sintomas podem incluir falta de ar e dor no peito. A expectativa de vida para a maioria dos pacientes com mesotelioma é de aproximadamente 12 meses após o diagnóstico. O tratamento pode melhorar o prognóstico e pode incluir cirurgia, quimioterapia ou radiação


Assuntos
Mesotelioma/terapia , Redes de Comunicação de Computadores , Asbestos , Mesotelioma/prevenção & controle
2.
BMJ Case Rep ; 14(10)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34649858

RESUMO

Apart from the risk of accidents, war theatres present a hazard related to numerous long-lasting toxic agents. For 10 years, a >60-year-old male journalist worked in war theatres in the Far and Near East where he was exposed to asbestos and other toxic substances (metals, silica, clays, polycyclic aromatic hydrocarbons and other organic substances) contained in dust and smoke of destroyed buildings. More than 15 years later, he developed a mucoepidermoid carcinoma of the soft palate and, subsequently, a pleural malignant mesothelioma. The safety of war journalists should focus not only on preventing the risk of being killed, but also on providing protection from toxic and carcinogenic agents. Exposure to substances released during the destruction of buildings can also pose a carcinogenic risk for survivors.


Assuntos
Asbestos , Mesotelioma , Doenças Profissionais , Exposição Ocupacional , Neoplasias Pleurais , Asbestos/toxicidade , Poeira , Humanos , Masculino , Mesotelioma/induzido quimicamente , Pessoa de Meia-Idade , Doenças Profissionais/etiologia , Exposição Ocupacional/efeitos adversos , Dióxido de Silício
3.
Artigo em Chinês | MEDLINE | ID: mdl-34624942

RESUMO

Objective: To investigate the effect and mechanism of PPAR-γ agonist Pioglitazone (PGZ) on the proliferation of malignant mesothelioma (MM) cells. Methods: In December 2019, MM cell lines MSTO-211H and NCI-H2452 were incubated with different final concentrations of PGZ (0, 10, 50, 100, 150, and 200 µmol/L) for different periods of time (24 h, 48 h, and 72 h) , and then the cell proliferation level was detected by CCK8 assay. After given various final concentration of PGZ (0, 10, 50, 100, 150, 200 µmol/L) the for 72 hours, the changes of number and morphology of MM cells were observed under an inverted microscope. The expressions of PPAR-γ and HMGB1 mRNA were determined by real-time fluorescence quantitative reverse transcription-polymerase chain reaction (qRT-PCR) after treatment of MM cells with PGZ of 0, 10, 50, 100 µmol/L for 72 h. The MM cells were treated with PGZ at concentration of 0, 100 µmol/L for 72 h, and the protein expressions of HMGB1 were examined using Western blotting and immunofluorescence; the protein expressions of Ki67 were assessed by immunohistochemistry. Results: The cell viability rate of MM cells was decreased after treated with PGZ (P<0.05) . Cell number in PGZ-treated group was significantly less than that in control group and morphology changes were observed under light microscope. QRT-PCR results revealed significantly increased PPAR-γ mRNA expression in the PGZ-treated group compared to the control group (P<0.05) . There was a significant decrease in the mRNA expression level of HMGB1 in the PGZ-treated group (100 µmol/L) as compared to the control group in MSTO-211H (P<0.05) ; however, the expression level of HMGB1 in NCI-H2452 was an increase or no significant differences (P>0.05) . Western blotting and immunofluorescence results showed that the protein expression of HMGB1 was reduced in the PGZ-treated group compared with the control group in MSTO-211H (P<0.05) , but the protein expression of that in NCI-H2452 was no significant differences (P>0.05) . Immunohistochemistry results showed increased expression of proliferation marker Ki-67. Conclusion: Pioglitazone suppresses the proliferation of MM cells through inhibition of HMGB1 by the activation of PPAR-γ.


Assuntos
Proteína HMGB1 , Mesotelioma/tratamento farmacológico , PPAR gama/agonistas , Pioglitazona/farmacologia , Contagem de Células , Linhagem Celular Tumoral , Proliferação de Células , Humanos
4.
Epidemiol Prev ; 45: 1-120, 2021.
Artigo em Italiano | MEDLINE | ID: mdl-34645127

RESUMO

This Catalogue is a collection of information on the use of raw asbestos and asbestos-containing materials used in several industries and occupational activities, with particular attention to the situation of Tuscany, a region of Central Italy. The work was developed at the Institute for Cancer Research, Prevention and Clinical Network (ISPRO) of Florence, where epidemiologic research and surveillance activities have been developing since 1988 and where the coordination and evaluation of the regional health surveillance programme provided to past asbestos workers started in 2016 and is still ongoing. The Catalogue aims at being a working tool for all health professionals engaged in examining and classifying the occupational asbestos exposures of subjects both affected by diseases that could be associated to this carcinogen and examined within the regional health surveillance programme. It is necessary for the health personnel engaged in the above-mentioned activities to know or to have the possibility to find exact and detailed data on asbestos exposure by occupational sector. These data are briefly described in the 29 factsheets this Catalogue consists of. In each factsheet, the presence and every use of asbestos are described, with reference to a precise occupational sector. Several occupational sectors can be considered together because of analogies on asbestos exposure. Occupations are considered on the basis of existing evidence on the use of raw asbestos or asbestos-containing materials (as semi-finished or finished products or as auxiliary materials in production processes). Besides the presence and use of asbestos, a description of the possible exposures of workers is reported. Sources of information were scientific and grey literature as well as the 7,187 occupational histories of mesothelioma registered by the specific Tuscan registry. Some factsheets have been revised and enhanced by Italian experts on the asbestos exposure with a specific competence in the examined sectors. Each factsheet includes also questions to be addressed to workers in order to examine in depth their possible asbestos exposure. For those who would like to expand their knowledge on this topic, references are reported both at the end of each factsheet and at the end of the volume. In all industrialized countries, also in those which have not already banned asbestos use, a decrease in the use of this material and in the relative exposure have been observing since the end of the Seventies, few years after the general consensus within the scientific community on asbestos carcinogenicity. This decreasing trend has been becoming greater and greater since the end of the Eighties, when more restrictive regulations have been approved and applied, especially in occupational settings. Nevertheless, nowadays asbestos-related diseases are still diagnosed due to past exposures, although during next decade a decreasing incidence of malignant mesothelioma - the cancer most specifically related to this carcinogen and characterized by a very bad prognosis and the longest latency - could be observed. Particular attention will be paid to jobs regarding renovation of old buildings containing asbestos and to decontamination activities. In conclusion, this Catalogue is a working tool - although it is not exhaustive and could be upgraded with new information - for all professionals engaged in asbestos risk prevention activities as health personnel, personnel of insurance companies, employers, and employee representatives.


Assuntos
Asbestos , Mesotelioma , Doenças Profissionais , Exposição Ocupacional , Neoplasias Pleurais , Asbestos/toxicidade , Carcinógenos/toxicidade , Humanos , Itália/epidemiologia , Mesotelioma/induzido quimicamente , Mesotelioma/epidemiologia , Doenças Profissionais/epidemiologia , Exposição Ocupacional/efeitos adversos , Neoplasias Pleurais/epidemiologia , Neoplasias Pleurais/etiologia
5.
J Cardiothorac Surg ; 16(1): 298, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645482

RESUMO

BACKGROUND: Primary pericardial mesothelioma (PPM) is a rare malignancy with a high prevalence of mortality. The diagnosis is usually challenging using a variety of imaging modalities and invasive procedures and is generally performed at the later stages of the disease or in autopsy. This case study points to an unconventional presentation of PPM and the challenges in diagnosing this rare mortal malignancy. CASE PRESENTATION: This study presents a 44-year-old woman with no remarkable medical history with an initial diagnosis of effusive constrictive pericarditis at first hospitalization. Imaging evaluations, including transthoracic echocardiography and chest computed tomography scan, demonstrated visible thickened pericardium, pericardial effusion, and mass-like lesions in pericardium and mediastinum. The definite diagnosis of primary pericardial mesothelioma was established after pericardiectomy and histopathology examinations. Chemotherapy with pemetrexed and carboplatin was administrated to the patient, and she has been through four cycles of chemotherapy with no complications to date. CONCLUSION: Constrictive pericarditis is an uncommon presentation of PPM. Due to the high mortality rate and late presentation, difficulties and uncertainties in diagnosis, being aware of this rare malignant entity in different cardiac manifestations, particularly when there is no clear explanation or response to treatment in such conditions, is highly important.


Assuntos
Mesotelioma Maligno , Mesotelioma , Derrame Pericárdico , Pericardite Constritiva , Adulto , Feminino , Humanos , Mesotelioma/diagnóstico , Derrame Pericárdico/diagnóstico , Derrame Pericárdico/etiologia , Pericardiectomia , Pericardite Constritiva/diagnóstico , Pericárdio
7.
Epidemiol Prev ; 45(4): 289-295, 2021.
Artigo em Italiano | MEDLINE | ID: mdl-34549571

RESUMO

Pleural mesothelioma clusters from outdoor environmental exposure have been highlighted also in Italy and, on the basis of epidemiological surveillance coordinated by the Italian National Mesothelioma Register, their frequency has been estimated at about 4.5%. Epidemiological studies and evaluations of some regional mesothelioma registers have made it possible to highlight that the dispersion of asbestos fibers in the outdoor environment was the only ascertained cause of mesothelioma in subjects from asbestos-cement factories, from the Balangero mine (Piedmont Region), from some serpentine rock quarries with tremolite outcrops in the Southern Apennines and in Alta Val di Susa (Piedmont Region); from chrysotile and serpentine caves in Valmalenco (Lombardy Region). Furthermore, cases of pleural mesothelioma were clearly caused by environmental pollution from fluoroedenite fibers in Biancavilla (Sicily Region). On the other hand, regional mesothelioma registers have also reported other circumstances of environmental asbestos exposure, like in the case of steel industry, shipbuilding, chemical plants, railway lines, and repair/demolition of railway carriages. However, these reports have not found confirmation on the basis of ad-hoc studies and it is likely that there is a lack of homogeneity in the assessment of individual cases. Apart from the scenarios which have been the subject of ad-hoc studies, the assessment of the causal role of environmental exposure to "in place" asbestos in the onset of pleural mesothelioma is problematic without an effort to more carefully examine the circumstances of possible exposure, harmonization of the attribution criteria used in the individual regional registers, analytical assessment of the impact of such exposure on the risk of onset of mesothelioma.


Assuntos
Asbestos , Mesotelioma Maligno , Mesotelioma , Exposição Ocupacional , Neoplasias Pleurais , Asbestos/efeitos adversos , Exposição Ambiental/efeitos adversos , Humanos , Itália/epidemiologia , Mesotelioma/epidemiologia , Mesotelioma/etiologia , Exposição Ocupacional/efeitos adversos , Neoplasias Pleurais/epidemiologia , Neoplasias Pleurais/etiologia , Sicília
8.
Rofo ; 193(10): 1229-1231, 2021 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-34530460
9.
Integr Cancer Ther ; 20: 15347354211043508, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34472358

RESUMO

PURPOSE: Health utility, which is a measure of patient-reported outcome (PRO), has recently been used in health-related quality of life for patients with various cancers. However, the relationship between health utility and the physical function and of patients undergoing pleurectomy/decortication (P/D) as surgical treatment for malignant pleural mesothelioma (MPM) has not been reported in the perioperative and convalescent phases. This study aimed to evaluate the perioperative and postoperative health utility of patients undergoing P/D for MPM at one year postoperatively and to examine the relationship with physical function. METHODS: We included patients underwent P/D. Grip strength, knee extension strength, 6-minute walk distance (6MWD), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) were measured to assess physical function, and the Short-Form Six-Dimension (SF-6D) was completed to assess health utility. These assessments were performed preoperatively, postoperatively, and one year postoperatively. Statistical analysis was performed using one-way analysis of variance for comparison of pre and postoperative and one year mean values. RESULTS: There were 24 subjects (23 males, 65.5±8.3 year). SF-6D, 6MWD, FVC, and FEV1 values one year operatively improved significantly compared with postoperative. Additionally, SF-6D was correlated with 6MWD. CONCLUSION: Health utility were also correlated with exercise capacity.


Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Mesotelioma/cirurgia , Neoplasias Pleurais/cirurgia , Pneumonectomia , Qualidade de Vida , Resultado do Tratamento
10.
Cancer Imaging ; 21(1): 48, 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344472

RESUMO

OBJECTIVES: Tumor thickness and tumor volume measured by computed tomography (CT) were suggested as valuable prognosticator for patients' survival diagnosed with malignant pleural mesothelioma (MPM). The purpose was to assess the accuracy of CT scan based preoperatively measured tumor volume and thickness compared to actual tumor weight of resected MPM specimen and pathologically assessed tumor thickness, as well as an analysis of their impact on overall survival (OS). METHODS: Between 09/2013-08/2018, 74 patients were treated with induction chemotherapy followed by (extended) pleurectomy/decortication ((E)PD). In 53 patients, correlations were made between CT-measured volume and -tumor thickness (cTV and cTT) and actual tumor weight (pTW) based on the available values. Further cTV and pT/IMIG stage were correlated using Pearson correlation. Overall survival (OS) was calculated with Kaplan Meier analysis and tested with log rank test. For correlation with OS Kaplan-Meier curves were made and log rank test was performed for all measurements dichotomized at the median. RESULTS: Median pathological tumor volume (pTV) and pTW were 530 ml [130 ml - 1000 ml] and 485 mg [95 g - 982 g] respectively. Median (IQR) cTV was 77.2 ml (35.0-238.0), median cTT was 9.0 mm (6.2-13.7). Significant association was found between cTV and pTV (R = 0.47, p < 0.001) and between cTT and IMIG stage (p = 0,001) at univariate analysis. Multivariate regression analysis revealed, that only cTV correlates with pTV. Median follow-up time was 36.3 months with 30 patients dead at the time of the analysis. Median OS was 23.7 months. 1-year and 3-year survival were 90 and 26% respectively and only the cTV remained statistically associated with OS. CONCLUSION: Preoperatively assessed CT tumor volume and actual tumor volume showed a significant correlation. CT tumor volume may predict pathological tumor volume as a reflection of tumor burden, which supports the integration of CT tumor volume into future staging systems.


Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Mesotelioma/diagnóstico por imagem , Mesotelioma/terapia , Estadiamento de Neoplasias , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Carga Tumoral
11.
Abdom Radiol (NY) ; 46(11): 5105-5113, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34342707

RESUMO

PURPOSE: To identify correlation between CT imaging features and histologic subtypes of Malignant Peritoneal Mesothelioma (MPM). METHODS: This was a retrospective single-center study of 51 consecutive patients with the diagnosis of Malignant Peritoneal Mesothelioma (MPM). The tumors were classified into pure epithelioid type and those with sarcomatoid component (pure sarcomatoid and biphasic type). Imaging features of these subtypes were compared for extent and type of peritoneal thickening, omental thickening, abdominal visceral infiltration, abdominal wall infiltration, and loco-regional and distant metastases. Fisher's Exact test was used to correlate the association of imaging features with histology types followed by multivariate analysis using logistic regression test. RESULTS: 32 males and 19 females with a median age of 63 years (range 35-86 years) were included in the study. 41/51 (80%) were epithelioid histology type and 10/51 (20%) had sarcomatoid component (3 pure sarcomatoid type, 7 biphasic type). Abdominal visceral infiltration was seen more commonly in cases of MPM with sarcomatoid component (p = 0.001). Sarcomatoid type also had a frequent association with metastases (p = 0.001) and discrete masses (p = 0.01). Epithelioid type was commonly associated with ascites (p = 0.04). On multivariate analysis, most significant correlation was identified between the sarcomatoid type and imaging features of metastases (p = 0.001) and visceral infiltration (p = 0.019). CONCLUSION: Sarcomatoid type of MPM showed significant correlation with more aggressive imaging features of metastases and visceral infiltration as compared to epithelioid type.


Assuntos
Neoplasias Pulmonares , Mesotelioma , Neoplasias Pleurais , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Mesotelioma/diagnóstico por imagem , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
12.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445720

RESUMO

Malignant Pleural Mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural mesothelium, mainly associated with asbestos exposure and still lacking effective therapies. Modern targeted biological strategies that have revolutionized the therapy of other solid tumors have not had success so far in the MPM. Combination immunotherapy might achieve better results over chemotherapy alone, but there is still a need for more effective therapeutic approaches. Based on the peculiar disease features of MPM, several strategies for local therapeutic delivery have been developed over the past years. The common rationale of these approaches is: (i) to reduce the risk of drug inactivation before reaching the target tumor cells; (ii) to increase the concentration of active drugs in the tumor micro-environment and their bioavailability; (iii) to reduce toxic effects on normal, non-transformed cells, because of much lower drug doses than those used for systemic chemotherapy. The complex interactions between drugs and the local immune-inflammatory micro-environment modulate the subsequent clinical response. In this perspective, the main interest is currently addressed to the development of local drug delivery platforms, both cell therapy and engineered nanotools. We here propose a review aimed at deep investigation of the biologic effects of the current local therapies for MPM, including cell therapies, and the mechanisms of interaction with the tumor micro-environment.


Assuntos
Mesotelioma Maligno/patologia , Mesotelioma Maligno/terapia , Terapia Combinada , Sistemas de Liberação de Medicamentos/métodos , Humanos , Imunoterapia/métodos , Mesotelioma/patologia , Mesotelioma/terapia , Neoplasias Pleurais/patologia , Neoplasias Pleurais/terapia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-34444165

RESUMO

Sailors have long been known to experience high rates of injury, disease, and premature death. Many studies have shown asbestos-related diseases among shipyard workers, but few have examined the epidemiology of asbestos-related disease and death among asbestos-exposed sailors serving on ships at sea. Chrysotile and amphibole asbestos were used extensively in ship construction for insulation, joiner bulkhead systems, pipe coverings, boilers, machinery parts, bulkhead panels, and many other uses, and asbestos-containing ships are still in service. Sailors are at high risk of exposure to shipboard asbestos, because unlike shipyard workers and other occupationally exposed groups, sailors both work and live at their worksite, making asbestos standards and permissible exposure limits (PELs). based on an 8-h workday inadequate to protect their health elevated risks of mesothelioma and other asbestos-related cancers have been observed among sailors through epidemiologic studies. We review these studies here.


Assuntos
Asbestos , Mesotelioma , Militares , Asbestos/análise , Asbestos/toxicidade , Asbestos Serpentinas , Humanos , Mesotelioma/induzido quimicamente , Mesotelioma/epidemiologia , Navios
15.
BMJ Open ; 11(8): e046456, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34373297

RESUMO

OBJECTIVES: This paper aims to establish hospitalisation costs of mesothelioma in Italy and to evaluate hospital-related trends associated with the 1992 asbestos ban. DESIGN: This is a retrospective population-based study of Italian hospitalisations treating pleura, peritoneum and pericardium mesothelioma in the period 2001-2018. SETTINGS: Public and private Italian hospitals reached by the Ministry of Health (coverage close to 100%). PARTICIPANTS: 157 221 admissions with primary or contributing diagnosis of pleural, peritoneal or hearth cancer discharged from 2001 to 2018.Primary and secondary outcome measures: number, length and cost of hospitalisations with related percentages. RESULTS: Each year, Italian hospitals treated a mesothelioma in 6025 admissions on average. Mean annual costs by site were €20 293 733, €3183 632 and €40 443 for pleura, peritoneum and pericardium, respectively. Pericardial mesothelioma showed the highest cost per admission (€6117), followed by peritoneal (€4549) and pleural cases (€3809). Percentage of hospitalisation costs attributable to mesothelioma was higher when it is located in pleura (53.4%) and pericardium (51.8%) with respect to peritoneum (41.2%). Overall annual hospitalisation cost, percentages of number and length of admissions showed an inverted U-shape, with maxima (of €25 850 276, 0.064% and 0.096%, respectively) reached in 2011-2013. Mean age at discharge and percentages of surgery and of urgent cases increased over time. CONCLUSIONS: The highest impact of mesothelioma on the National Health System was recorded 20 years after the asbestos ban (2011-2013). Hospitals should expect soon fewer but more severe patients needing more cares. To study the disease prevalence could help assistance planning of next decade.


Assuntos
Asbestos , Mesotelioma Maligno , Mesotelioma , Exposição Ocupacional , Neoplasias Pleurais , Asbestos/efeitos adversos , Hospitalização , Hospitais , Humanos , Incidência , Itália/epidemiologia , Mesotelioma/epidemiologia , Mesotelioma/terapia , Alta do Paciente , Sistema de Registros , Estudos Retrospectivos
16.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445271

RESUMO

This study aimed to identify the proteomic changes produced by curcumin treatment following stimulation of the host immune system in a rat model of malignant mesothelioma. We analyzed the proteomes of secondary lymphoid organs from four normal rats, four untreated tumor-bearing rats, and four tumor-bearing rats receiving repeated intraperitoneal administrations of curcumin. Cross-comparing proteome analyses of histological sections of the spleen from the three groups first identified a list of eighty-three biomarkers of interest, thirteen of which corresponded to proteins already reported in the literature and involved in the anticancer therapeutic effects of curcumin. In a second step, comparing these data with proteomic analyses of histological sections of mesenteric lymph nodes revealed eight common biomarkers showing a similar pattern of changes in both lymphoid organs. Additional findings included a partial reduction of the increase in spleen-circulating biomarkers, a decrease in C-reactive protein and complement C3 in the spleen and lymph nodes, and an increase in lymph node purine nucleoside phosphorylase previously associated with liver immunodeficiency. Our results suggest some protein abundance changes could be related to the systemic, distant non-target antitumor effects produced by this phytochemical.


Assuntos
Biomarcadores Tumorais/metabolismo , Curcumina/farmacologia , Linfonodos/metabolismo , Mesotelioma , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais , Neoplasias Peritoneais , Proteoma/metabolismo , Animais , Masculino , Mesotelioma/tratamento farmacológico , Mesotelioma/metabolismo , Mesotelioma/patologia , Invasividade Neoplásica , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Ratos , Ratos Endogâmicos F344
19.
Cell Death Dis ; 12(7): 663, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34230456

RESUMO

A majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.


Assuntos
Adenoviridae/genética , Proteínas E1 de Adenovirus/genética , Antineoplásicos/farmacologia , Imidazóis/farmacologia , Imidazolinas/farmacologia , Mesotelioma/terapia , Neurofibromina 1/metabolismo , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Adenoviridae/crescimento & desenvolvimento , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Regulação Neoplásica da Expressão Gênica , Mesotelioma/genética , Mesotelioma/metabolismo , Mesotelioma/virologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Neurofibromina 1/genética , Vírus Oncolíticos/crescimento & desenvolvimento , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Front Immunol ; 12: 666107, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194430

RESUMO

Macrophages are not only derived from circulating blood monocytes or embryonic precursors but also expand by proliferation. The origin determines macrophage fate and functions in steady state and pathological conditions. Macrophages predominantly infiltrate fibre-induced mesothelioma tumors and contribute to cancer development. Here, we revealed their ontogeny by comparing the response to needle-like mesotheliomagenic carbon nanotubes (CNT-7) with tangled-like non-mesotheliomagenic CNT-T. In a rat peritoneal cavity model of mesothelioma, both CNT induced a rapid macrophage disappearance reaction (MDR) of MHCIIlow resident macrophages generating an empty niche available for macrophage repopulation. Macrophage depletion after mesotheliomagenic CNT-7 was followed by a substantial inflammatory reaction, and macrophage replenishment completed after 7 days. Thirty days after non-mesotheliomagenic CNT-T, macrophage repopulation was still incomplete and accompanied by a limited inflammatory reaction. Cell depletion experiments, flow cytometry and RNA-seq analysis demonstrated that, after mesotheliomagenic CNT-7 exposure, resident macrophages were mainly replaced by an influx of monocytes, which differentiated locally into MHCIIhigh inflammatory macrophages. In contrast, the low inflammatory response induced by CNT-T was associated by the accumulation of self-renewing MHCIIlow macrophages that initially derive from monocytes. In conclusion, the mesotheliomagenic response to CNT specifically relies on macrophage niche recolonization by monocyte-derived inflammatory macrophages. In contrast, the apparent homeostasis after non-mesotheliomagenic CNT treatment involves a macrophage regeneration by proliferation. Macrophage depletion and repopulation are thus decisive events characterizing the carcinogenic activity of particles and fibres.


Assuntos
Macrófagos/imunologia , Mesotelioma/imunologia , Monócitos/imunologia , Nanotubos de Carbono/efeitos adversos , Animais , Diferenciação Celular , Proliferação de Células , Antígenos de Histocompatibilidade Classe II/metabolismo , Inflamação , Macrófagos/citologia , Macrófagos/metabolismo , Mesotelioma/induzido quimicamente , Monócitos/citologia , Monócitos/metabolismo , Neutrófilos/citologia , Neutrófilos/imunologia , Cavidade Peritoneal/citologia , Ratos
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