RESUMO
Leukemia is associated with exposure to radiation, benzene derivatives, and pesticides. Previous research has documented an increase in work-related leukemia in the Latin American Andean region. To date, there are only few studies in Ecuador on the impact of oil exploitation on adjacent indigenous communities. Our study aims to show the impact of leukemia on the working-age population. For the calculation of morbidity and mortality rates, we used hospital discharge and death records from the National Institute of Statistics of Ecuador. These data were collected and adjusted to the corresponding province's population for further analysis. Large differences were observed between provinces in adjusted rates of leukemia mortality and morbidity in the working-age population. The variations in altitude among different areas in Ecuador give the provinces a distinct geographic identity. Likewise, the provinces with the highest morbidity and mortality rankings, such as Azuay, Loja, Imbabura, and Tungurahua, have an average altitude above 2000 meters. As a result, there are variations in the average temperature, exposure to solar and cosmic radiation, and mining and farming methods. The observed differences warrant the future collection of geolocation data for affected individuals. This could help to better understand how leukemia cases have demogrpahic hotspots in the country, identify possible risk factors associated with the disease in each region, and design more effective prevention and control strategies.
La leucemia es una enfermedad a consecuencia, además de factores genéticos, de la exposición a radiaciones, derivados del benceno y pesticidas. Investigaciones anteriores han documentado un aumento de la leucemia ocupacional en la región andina de América Latina. Hasta la fecha, existen sólo unos pocos estudios en Ecuador sobre el impacto de la explotación petrolera en las comunidades indígenas. Nuestro objetivo es mostrar el impacto de la leucemia en la población en edad de trabajar. Para el cálculo de las tasas de morbimortalidad se utilizaron los registros de altas hospitalarias y defunciones del Instituto Nacional de Estadística del Ecuador. Estos datos fueron recopilados y estimadas las tasas ajustadas. Se observaron grandes diferencias entre provincias en las tasas ajustadas de mortalidad y morbilidad por leucemia en la población en edad de trabajar. Asimismo, las provincias con mayor ranking de morbilidad y mortalidad, como Azuay, Loja, Imbabura y Tungurahua, coinciden en tener una altitud promedio superior a los 2000 metros. Hay provincias de baja altitud en la costa y provincias por encima de los 2000 metros en la sierra, lo que le da a las provincias del Ecuador una identidad geográfica distintiva. Como resultado, existen variaciones en la temperatura promedio, la exposición a la radiación solar y cósmica, y actividades de minería y agricultura. Las diferencias observadas, recomiendan la recopilación futura de datos de geolocalización de las personas afectadas. Esto podría ayudarnos a comprender mejor cómo se distribuyen los casos de leucemia, identificar posibles factores de riesgo asociados a la enfermedad en cada región y diseñar estrategias de prevención y control más efectivas.
Assuntos
Leucemia , Humanos , Equador/epidemiologia , Leucemia/epidemiologia , Leucemia/mortalidade , Leucemia/etiologia , Adulto , Fatores de Risco , Pessoa de Meia-Idade , Masculino , Feminino , Altitude , Adulto Jovem , Exposição Ambiental/efeitos adversos , Adolescente , Exposição Ocupacional/efeitos adversosRESUMO
Chimeric antigen receptor (CAR)-T cell therapy has proven to be a powerful treatment for hematological malignancies. The situation is very different in the case of solid tumors, for which no CAR-T-based therapy has yet been approved. There are many factors contributing to the absence of response in solid tumors to CAR-T cells, such as the immunosuppressive tumor microenvironment (TME), T cell exhaustion, or the lack of suitable antigen targets, which should have a stable and specific expression on tumor cells. Strategies being developed to improve CAR-T-based therapy for solid tumors include the use of new-generation CARs such as TRUCKs or bi-specific CARs, the combination of CAR therapy with chemo- or radiotherapy, the use of checkpoint inhibitors, and the use of oncolytic viruses. Furthermore, despite the scarcity of targets, a growing number of phase I/II clinical trials are exploring new solid-tumor-associated antigens. Most of these antigens are of a protein nature; however, there is a clear potential in identifying carbohydrate-type antigens associated with tumors, or carbohydrate and proteoglycan antigens that emerge because of aberrant glycosylations occurring in the context of tumor transformation.
Assuntos
Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Microambiente Tumoral/imunologia , Antígenos de Neoplasias/imunologia , Linfócitos T/imunologia , AnimaisRESUMO
Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS-/-) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS-/- mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS-/- livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.
Assuntos
Cirrose Hepática , Neuroblastoma , Animais , Humanos , Camundongos , Tetracloreto de Carbono/toxicidade , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/tratamento farmacológico , Neuroblastoma/patologia , OncogenesRESUMO
Introduction: The Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory response carried out by the Intestinal Epithelial Cells in the context of Inflammatory Bowel Disease. Methods: We analyzed the transcriptional profile of human Intestinal Epithelial Cell lines treated with an Endoplasmic Reticulum stress inducer (thapsigargin) and/or proinflammatory stimuli. Several genes were further analyzed in colonic biopsies from Ulcerative Colitis patients and healthy controls. Lastly, we generated Caco-2 cells lacking HMGCS2 by CRISPR Cas-9 and analyzed the functional implications of its absence in Intestinal Epithelial Cells. Results: Exposure to a TLR ligand after thapsigargin treatment resulted in a powerful synergistic modulation of gene expression, which led us to identify new genes and pathways that could be involved in inflammatory responses linked to the Unfolded Protein Response. Key differentially expressed genes in the array also exhibited transcriptional alterations in colonic biopsies from active Ulcerative Colitis patients, including NKG2D ligands and the enzyme HMGCS2. Moreover, functional studies showed altered metabolic responses and epithelial barrier integrity in HMGCS2 deficient cell lines. Conclusion: We have identified new genes and pathways that are regulated by the Unfolded Protein Response in the context of Inflammatory Bowel Disease including HMGCS2, a gene involved in the metabolism of Short Chain Fatty Acids that may have an important role in intestinal inflammation linked to Endoplasmic Reticulum stress and the resolution of the epithelial damage.
Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Humanos , Colite Ulcerativa/patologia , Células CACO-2 , Tapsigargina , Estresse do Retículo Endoplasmático/genética , Doenças Inflamatórias Intestinais/metabolismo , Células Epiteliais/metabolismo , Hidroximetilglutaril-CoA SintaseRESUMO
Alcoholic liver disease (ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.
Assuntos
Modelos Animais de Doenças , Etanol/toxicidade , Hepatopatias Alcoólicas/patologia , Fígado/patologia , Alcoolismo/complicações , Animais , Biomarcadores/análise , Humanos , Fígado/efeitos dos fármacos , Hepatopatias Alcoólicas/diagnóstico , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/etiologia , Camundongos , Ratos , Especificidade da EspécieRESUMO
Lenalidomide is an analog of thalidomide, with potent anticancer activity demonstrated in several hematological malignancies. It has immunomodulatory properties, being able to enhance the activation of different types of immune cells, which results in antitumor activities. Dendritic cells (DCs) are pivotal in the immune response, and different immunotherapeutic approaches targeting these cells are being developed. Since little is known about the effect of lenalidomide on DCs, the goal of the present work was to investigate the phenotype and function of human monocyte-derived DCs differentiated in the presence of lenalidomide (L-DCs). Our results showed that L-DCs display a unique phenotype, with increased cell surface expression of some maturation markers such as CD1d, CD83, CD86, and HLA-DR. This phenotype correlates with a lower expression of the E3 ubiquitin-ligase MARCH-I in L-DCs, upregulating the cell surface expression of CD86 and HLA-DR. In addition, immature L-DCs express higher amounts of DC-SIGN on the cell surface than control immature DCs. After LPS stimulation, production of IL-6 and TNF-α was severely decreased, whereas IL-12 and IL-10 secretion was dramatically upregulated in L-DCs, compared to that in the controls. Functionally, L-DCs are more effectively recognized by NKT cells in cytotoxicity experiments. Furthermore, L-DCs display higher opsonin-independent antigen uptake capability than control DCs. Mixed lymphocyte reaction experiments showed that L-DCs could stimulate naïve CD4 T-cells, polarizing them toward a predominant Th1 phenotype. In summary, DCs derived from monocytes in the presence of lenalidomide present a semi-mature phenotype, increased phagocytic capacity, reduced production of proinflammatory cytokines, and the ability to polarize T-cells toward predominant Th1-type responses; these are qualities that might be useful in the development of new immunotherapeutic treatments.
RESUMO
Mucosal-associated invariant T (MAIT) cells are a population of non-conventional T-lymphocytes which are restricted by the MHC-related 1 (MR1) molecule. MR1 is a non-classical member of the MHC class I family of proteins, it is unknown if MR1 presents any kind of antigens to MAIT cells. In the present manuscript we describe that detection of MR1 on the cell surface by conformation-dependent monoclonal antibodies is enhanced upon culture the cells at 26°C; we also show that detection of MR1 on the cell surface is lost after treating the cells at pH 3.3 as in the case of classical MHC class I molecules. Finally, the re-expression of MR1 on the cell surface is independent of proteasome. Taken together these results strongly suggest that MR1 needs to bind proteasome-independent ligands in order to properly reach the cell surface.
Assuntos
Ácidos/metabolismo , Membrana Celular/metabolismo , Temperatura Baixa , Antígenos de Histocompatibilidade Classe I/biossíntese , Complexo de Endopeptidases do Proteassoma/metabolismo , Ácidos/farmacologia , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Antígenos de Histocompatibilidade MenorRESUMO
MHC-related 1 (MR1) molecule is a non-classical member of the MHC class I family of proteins. The sequence homology between classical MHC class I molecules and MR1 is very high, although the MR1 gene is not polymorphic and is highly conserved between species. MR1 is the restriction molecule of a sub-population of T lymphocytes, which are CD4-,CD8- and display conserved TCR alpha chain. The function of these cells is currently unknown, but they are believed to have regulatory properties similar to those of the CD1d restricted NKT cells. The MR1 gene is ubiquitously transcribed; however it is unknown what types of cells express the MR1 protein "in vivo". In the present work we analyzed the expression of the MR1 protein using specific antisera and monoclonal antibodies in different human cell lines, in primary cells and in mucosal tissues. We found some lymphoid cell lines that express MR1 on the cell surface but at levels much lower than the MR1 transfected cell lines. In addition, we observed that expression of MR1 in the mucosa is restricted to a subpopulation of plasma cells or plasmablasts, CD38+ or CD138+ and IgA+, located in the human intestinal mucosa. This suggests a function for MR1 in the development of IgA producing plasma cells.
Assuntos
Antígenos de Histocompatibilidade Classe I/biossíntese , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/metabolismo , Plasmócitos/metabolismo , ADP-Ribosil Ciclase 1/imunologia , ADP-Ribosil Ciclase 1/metabolismo , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Western Blotting , Eletroforese em Gel de Poliacrilamida , Citometria de Fluxo , Imunofluorescência , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Microscopia Confocal , Antígenos de Histocompatibilidade Menor , Plasmócitos/citologia , Plasmócitos/imunologia , Reação em Cadeia da PolimeraseRESUMO
The cytotoxic activity of NK cells can be inhibited by classical and nonclassical MHC molecules. The CD1 system is formed by a family of glycoproteins that are related to classical MHC. CD1a, b, and c molecules present lipids or glycolipids to T cells and are involved in defense against microbial infections, especially mycobacteria. It has been shown recently that these molecules can inhibit target cell lysis by human NK cells. It has also been shown that mouse CD1d molecules can protect cells from NK cell-mediated cytotoxicity. In the present study, we describe how human CD1d, orthologous to murine CD1 molecules, can inhibit NK cell-mediated cytolysis. We have expressed CD1d in the HLA class I-deficient cell lines L721.221 and C1R. The inhibitory effect is observed when effector NK cells from different donors are used, as well as in different cell lines with NK activity. The inhibitory effect was reversed by incubating the target cells with a mAb specific for human CD1d. Incubation of target cells with the ligands for CD1d, alpha-galactosylceramide (alpha-GalCer), and beta-GalCer abolishes the protective effect of CD1d in our in vitro killing assays. Staining the effector cells using CD1d tetramers loaded with alpha-GalCer was negative, suggesting that the putative inhibitory receptor does not recognize CD1d molecules loaded with alpha-GalCer.
Assuntos
Antígenos CD1/imunologia , Citotoxicidade Imunológica , Células Matadoras Naturais/imunologia , Anticorpos Monoclonais/farmacologia , Antígenos CD1/genética , Antígenos CD1/farmacologia , Antígenos CD1d , Células CACO-2 , Células Cultivadas , Citotoxicidade Imunológica/efeitos dos fármacos , Galactosilceramidas/farmacologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Substâncias Protetoras , Linfócitos T/imunologiaRESUMO
In this report, we describe the characterization of a novel activation antigen on porcine lymphocytes recognized by mAb 5A6/8. This antigen was detected on B and T cells 24 h after treatment with various stimuli. It was also found on alveolar macrophages, and at low levels on untreated monocytes. MAb 5A6/8 precipitated two bands of 45 and 50 kDa under non-reducing conditions, and of 22 and 28 kDa under reducing conditions. The cellular distribution, expression kinetics and/or molecular size of the 5A6/8 antigen differ from those of other known lymphocyte activation antigens. MAb 5A6/8 was able to inhibit lymphocyte proliferative responses driven by different stimuli, suggesting a role for this molecule in the events that lead to lymphocyte activation.