RESUMO
Parasite-host interactions depend on a complex interplay between the metabolism of the parasite, their antigens, and the host immune response system [...].
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INTRODUÇÃO: Os cuidados paliativos (CP) são baseados em princípios e auxiliam o paciente no enfrentamento do curso de sua condição clínica através da prevenção e alívio do sofrimento. Realizado através de uma equipe multiprofissional, no contexto de uma internação hospitalar, a psicologia contribui com intervenções na situação psicoemocional do paciente em CP e seus familiares. OBJETIVO: Identificar as intervenções psicológicas mais utilizadas no tratamento de pacientes adultos internados em CP. MÉTODOS: Pesquisa documental de caráter retrospectivo, com delineamento transversal e descritivo. De natureza quantitativa, os dados foram investigados através de Análise Estatística Descritiva. Os dados foram coletados com 70 prontuários de pacientes adultos em CP internados entre os anos de 2019 e 2021 em um hospital público e que foram acompanhados pelo setor de psicologia. RESULTADOS: Foram identificadas 32 categorias de intervenções psicológicas relacionadas ao paciente e 38 ao cuidador. As categorias foram agrupadas por similaridade temática resultando no grupo de intervenções em demandas emocionais, intervenções em demandas cognitivas, condutas de orientação e psicoeducação, condutas de humanização e grupo de intervenções em demandas familiares. DISCUSSÃO: As condutas psicológicas nos CP podem auxiliar no acolhimento do sofrimento, integração das perdas e mudanças de papéis, elaboração do luto antecipatório, ressignificação da vida, morte, planos e objetivos, criação ou validação de recursos funcionais de enfrentamento e a dar condições biopsicossocioespirituais de lidar com o adoecimento. CONCLUSÃO: Evidenciou-se um grande número de intervenções psicológicas utilizadas no tratamento de pacientes de CP e seus cuidadores.
INTRODUCTION: Palliative Care (PC) is based on principles and helps the patient to face the course of their clinical condition through the prevention and relief of suffering. Carried out by a multidisciplinary team, in the context of a hospital stay, psychology contributes with interventions in the psycho-emotional situation of patients undergoing PC and their families. OBJECTIVE: To identify the most used psychological interventions in the treatment of adult patients hospitalized in PC. METHODS: Retrospective documentary research, with a cross-sectional and descriptive design. Quantitative in nature, the data were investigated through Descriptive Statistical Analysis. Data were collected from 70 medical records of adult PC patients admitted between the years 2019 and 2021 in a public hospital and who were followed up by the psychology sector. RESULTS: 32 categories of psychological interventions related to the patient and 38 to the caregiver were identified. The categories were grouped by thematic similarity resulting in the group of interventions in emotional demands, interventions in cognitive demands, guidance and psychoeducation conducts, humanization conducts and group of interventions in family demands. DISCUSSION: Psychological behaviors in PC can help in accepting suffering, integrating losses and changing roles, elaborating anticipatory grief, re-signification of life, death, plans and goals, creation or validation of functional coping resources and providing biopsychosocial-spiritual conditions of dealing with illness. CONCLUSION: There was evidence of a large number of psychological interventions used in the treatment of PC patients and their caregivers.
INTRODUCCIÓN: Los cuidados paliativos (CP) se basan en principios y ayudan al paciente a afrontar el curso de su cuadro clínico a través de la prevención y el alivio del sufrimiento. Realizada por un equipo multidisciplinario, en el contexto de una estancia hospitalaria, la psicología contribuye con intervenciones en la situación psicoemocional de los pacientes en CP y sus familias. OBJETIVO: Identificar las intervenciones psicológicas más utilizadas en el tratamiento de pacientes adultos hospitalizados en CP. MÉTODOS: Investigación documental retrospectiva, con un diseño transversal y descriptivo. De naturaleza cuantitativa, los datos fueron investigados a través del Análisis Estadístico Descriptivo. Se recogieron datos de 70 historias clínicas de pacientes adultos en CP ingresados entre los años 2019 y 2021 en un hospital público y que fueron seguidos por el sector de psicología. RESULTADOS: Se identificaron 32 categorías de intervenciones psicológicas relacionadas con el paciente y 38 con el cuidador. Las categorías fueron agrupadas por similitud temática resultando el grupo de intervenciones en demandas emocionales, intervenciones en demandas cognitivas, conductas de orientación y psicoeducación, conductas de humanización y grupo de intervenciones en demandas familiares. DISCUSIÓN: Los comportamientos psicológicos en CP pueden auxiliar en la aceptación del sufrimiento, la integración de las pérdidas y el cambio de roles, la elaboración del duelo anticipatorio, la resignificación de la vida, la muerte, los planes y metas, la creación o validación de recursos funcionales de afrontamiento y la provisión de condiciones biopsicosociales-espirituales de enfrentamiento de la enfermedad. CONCLUSIÓN: Se evidenció un gran número de intervenciones psicológicas utilizadas en el tratamiento de pacientes en CP y sus cuidadores.
Assuntos
Cuidados Paliativos , Saúde Pública , Intervenção PsicossocialRESUMO
Leishmaniasis is a parasitic, widespread, and neglected disease that affects more than 90 countries in the world. More than 20 Leishmania species cause different forms of leishmaniasis that range in severity from cutaneous lesions to systemic infection. The diversity of leishmaniasis forms is due to the species of parasite, vector, environmental and social factors, genetic background, nutritional status, as well as immunocompetence of the host. Here, we discuss the role of the immune system, its molecules, and responses in the establishment, development, and outcome of Leishmaniasis, focusing on innate immune cells and Leishmania major interactions.
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Cryptococcosis is an opportunistic disease caused by the fungus Cryptococcus neoformans and Cryptococcus gattii. It starts as a pulmonary infection that can spread to other organs, such as the brain, leading to the most serious occurrence of the disease, meningoencephalitis. The humoral response has already been described in limiting the progression of cryptococcosis where the B-1 cell seems to be responsible for producing natural IgM antibodies, crucial for combating fungal infections. The role of the B-1 cell in C. neoformans infection has been initially described, however the role of the humoral response of B-1 cells has not yet been evaluated during C. gattii infections. In the present study we tried to unravel this issue using XID mice, a murine model deficient in the Btk protein which compromises the development of B-1 lymphocytes. We use the XID mice compared to BALB/c mice that are sufficient for the B-1 population during C. gattii infection. Our model of chronic lung infection revealed that XID mice, unlike the sufficient group of B-1, had early mortality with significant weight loss, in addition to reduced levels of IgM and IgG specific to GXM isolated from the capsule of C. neoformans. In addition to this, we observed an increased fungal load in the blood and in the brain. We described an increase in the capsular size of C. gattii and the predominant presence of cytokines with a Th2 profile was also observed in these animals. Thus, the present study strongly points to a higher susceptibility of the XID mouse to C. gattii, which suggests that the presence of B-1 cells and anti-GXM antibodies is fundamental during the control of infection by C. gattii.
Assuntos
Criptococose/etiologia , Cryptococcus gattii , Suscetibilidade a Doenças/imunologia , Hospedeiro Imunocomprometido , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/complicações , Animais , Biomarcadores , Contagem de Colônia Microbiana , Criptococose/metabolismo , Cryptococcus gattii/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Camundongos , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologiaRESUMO
Toll-like receptor 9 (TLR9) is crucial to the host immune response against fungi, such as Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, but its importance in Cryptococcus gattii infection is unknown. Our study aimed to understand the role of TLR9 during the course of experimental C. gattii infection in vivo, considering that the cryptococcal DNA interaction with the receptor could contribute to host immunity even in an extremely susceptible model. We inoculated C57BL/6 (WT) and TLR9 knock-out (TLR9-/-) mice intratracheally with 104 C. gattii yeast cells. TLR9-/- mice had a higher mortality rate compared to WT mice and more yeast cells that had abnormal size, known as titan cells, in the lungs. TLR9-/- mice also had a greater number of CFUs in the spleen and brain than WT mice, in addition to having lower levels of IFN-γ and IL-17 in the lung. With these markers of aggressive cryptococcosis, we can state that TLR9-/- mice are more susceptible to C. gattii, probably due to a mechanism associated with the decrease of a Th1 and Th17-type immune response that promotes the formation of titan cells in the lungs. Therefore, our results indicate the participation of TLR9 in murine resistance to C. gattii infection.
Assuntos
Criptococose/imunologia , Cryptococcus gattii/imunologia , Pulmão/imunologia , Células Th1/imunologia , Células Th17/imunologia , Receptor Toll-Like 9/imunologia , Animais , Criptococose/genética , Criptococose/patologia , Imunidade Inata , Pulmão/patologia , Camundongos , Camundongos Knockout , Células Th1/patologia , Células Th17/patologia , Receptor Toll-Like 9/genéticaRESUMO
Objetivo: Estimar o custo de tratamento das novas terapias de combinação tripla com lenalidomida no manejo dos pacientes com mieloma múltiplo recidivado/refratário (MMRR) sob a perspectiva do sistema de saúde privado brasileiro. Métodos: Os custos associados da combinação de lenalidomida + dexametasona com carfilzomibe (KRd), daratumumabe (DRd), elotuzumabe (ERd) e ixazomibe (IRd) foram comparados. Para cada terapia, a duração de tratamento foi estimada pela média do tempo de sobrevida livre de progressão (SLP) restrita a três anos a partir de dados de SLP dos estudos pivotais das respectivas terapias. Os custos de tratamento foram estimados para a duração de tratamento, considerando a posologia específica dos regimes terapêuticos. Os preços dos medicamentos foram baseados no preço fábrica de abril de 2020. Não foi considerado o compartilhamento de doses. O custo total do tratamento, o custo médio por ciclo e o custo por taxa de resposta objetiva (TRO) em três anos foram comparados. Resultados: A duração de tratamento no período de três anos foi de 23,3, 27,6, 20,3 e 20,9 meses para KRd, DRd, ERd e IRd, respectivamente. O custo médio total de tratamento foi estimado em 975.557 reais (BRL) para KRd, 1.507.544 BRL para DRd (+55% versus KRd), 1.207.899 BRL para ERd (+24% versus KRd) e 983.917 para IRd (+1% versus KRd). KRd teve o menor custo médio por mês de SLP (horizonte de três anos) entre as terapias, 41.957 BRL versus 54.709 BRL para DRd (+30% versus KRd), 59.635 BRL para ERd (+42% versus KRd) e 47.147 para IRd (+12% versus KRd). Similarmente, o custo por TRO foi 31% menor para KRd (1.119.770 BRL), comparado ao DRd (1.621.015 BRL), 27% menor, comparado ao ERd (1.528.986 BRL), e 11% menor, comparado ao IRd (1.256.064). Conclusões: Resultados da presente análise indicam que KRd está associado a um menor custo médio de tratamento, acompanhado de maior previsibilidade, menor custo por TRO e por mês de SLP, comparado ao DRd, ERd e IRd no horizonte de três anos sob a perspectiva do sistema de saúde privado brasileiro. Os resultados estão associados com alguma incerteza em razão das diferenças nas populações dos estudos, desenho dos estudos (duração fixa de carfilzomibe vs. tratamento até a progressão para daratumumabe, elotuzumabe e ixazomibe) e porque a duração de tratamento é tipicamente menor do que a SLP.
Objective: To estimate treatment costs for novel triple-combination therapies with lenalidomide in the management of relapsed/refractory multiple myeloma (RRMM) patients from the Brazilian private healthcare perspective. Methods: Treatment costs associated with lenalidomide + dexamethasone combinations with carfilzomib (KRd), daratumumab (DRd), elotuzumab (ERd) and ixazomib (IRd) were compared. For each therapy, treatment duration was estimated as the mean progression-free survival (PFS) time restricted to three years using published PFS data from pivotal trials available for these treatments. Treatment costs were estimated for the modeled treatment duration considering therapy-specific dosing schedules. Drug prices were based on April 2020 Brazilian list prices. No vial sharing was assumed. Total treatment costs, average cost per cycle, and cost per overall response rate (ORR) over the three-year period were compared. Results: Modeled treatment duration over the three-year period was 23.3, 27.6, 20.3 and 20.9 months for KRd, DRd, ERd and IRd respectively. Corresponding average total treatment costs were estimated to be 975,557 Brazilian Real (BRL) for KRd; 1,507,544 BRL for DRd (+55% versus KRd); 1,207,899 BRL for ERd (+24% versus KRd) and 983,917 for IRd (+1% versus KRd). KRd had the lowest average cost per month of restricted PFS (3-year time frame) among the therapies, 41,957 BRL versus 54,709 BRL for DRd (+30% versus KRd); 59,635 BRL for ERd (+42% versus KRd); and 47,147 for IRd (+12% versus KRd). Similarly, the cost per achieved ORR was lower for KRd (1,119,770 BRL) than that for DRd (1,621,015 BRL); ERd (1,528,986 BRL); and IRd (1,256,064) by 31%, 27% and 11%, respectively. Conclusions: Results of the present analysis indicate that KRd is associated with lower mean treatment costs and more predictable costs, lower cost per ORR and per month in PFS than DRd, ERd and IRd over a relevant three-year time horizon from the Brazilian private healthcare perspective. The results are associated with some uncertainty due to differences in trial populations, trial design (fixed duration for carfilzomib vs treatment till progression for daratumumab, elotuzumab and ixazomib) and because treatment duration is typically shorter than PFS.
Assuntos
Dexametasona , Custos e Análise de Custo , Saúde Suplementar , Lenalidomida , Mieloma MúltiploRESUMO
Objetivo: Estimar o custo por evento relacionado ao esqueleto (ERE) e o impacto econômico anual da adoção de denosumabe em pacientes com metástases ósseas secundárias ao câncer de mama, próstata e outros tumores sólidos ou mieloma múltiplo sob a perspectiva do sistema de saúde privado brasileiro. Métodos: Um modelo econômico foi desenvolvido para comparar os custos relacionados com denosumabe versus ácido zoledrônico na prevenção de EREs. O modelo incluiu os seguintes custos: medicamento, administração, monitoramento e manejo de ERE. O custo anual foi apresentado em reais (BRL) para 100 pacientes. Os custos do manejo de ERE [fratura vertebral (FV), fratura não vertebral (FNV), radiação óssea (RO), cirurgia óssea (CO) e compressão da medula espinhal (CME)] foram estimados a partir dos recursos e procedimentos coletados da revisão de literatura, bases de dados e painel Delphi. Dados coletados dos estudos clínicos randomizados relacionados com cada tipo de tumor na análise e de um estudo prospectivo observacional foram utilizados para estimar a eficácia clínica de denosumabe versus ácido zoledrônico. Resultados: O custo por cada tipo de ERE variou de BRL 27.246 a BRL 28.035 para FV, BRL 18.023 a BRL 18.811 para FNV, BRL 42.750 a BRL 43.538 para RO, BRL 18.023 a BRL 18.811 para CO e BRL 12.472 a BRL 13.260 para CME. A introdução de denosumabe foi estimada em economia anual por 100 pacientes de até BRL 1.072.043,14 para câncer de mama, BRL 1.212.822,79 para outros tumores sólidos, BRL 1.929.660,67 para câncer de próstata e BRL 77.965,07 para mieloma múltiplo. Conclusão: Esta análise sugere que EREs adicionam custos substanciais no manejo de pacientes com metástases ósseas. Dessa forma, o uso de denosumabe pode prevenir e retardar EREs em pacientes com câncer e pode possivelmente levar à redução do impacto econômico associado aos EREs sob a perspectiva dos pagadores de saúde privada brasileira.
Objective: To estimate the cost per SRE and annual economic impact of denosumab adoption in patients with bone metastases (BM) secondary to breast cancer, prostate cancer, other solid tumors or multiple myeloma from the Brazilian private healthcare system's perspective. Methods: An economic model was developed to compare the cost outcomes associated with denosumab instead of zoledronic acid for SRE prevention. The model included the following costs: drug, administration, monitoring and SRE management. Annual costs per 100 patients were reported in 2019 Brazilian currency (BRL). The SRE management costs (vertebral fracture (VF), non-vertebral fracture (NVF), radiation to bone (RB), surgery to bone (SB) and spinal cord compression (SCC)) were estimated from the resources and procedures collected from literature review, official database, and a Delphi panel. Data collected from randomized clinical trials related to each tumor type in the analysis and from a prospective observational study was used to estimate the clinical efficacy of denosumab vs zoledronic acid. Results: The cost per each type of SREs across all tumors ranged BRL 27,246 BRL 28,035 for VF, BRL 18,023 BRL 18,811 for NVF, BRL 42,750 BRL 43,538 for RB, BRL 18,023 BRL 18,811 for SB and BRL 12,472 BRL 13,260 for SCC. The introduction of denosumab was estimated to result in annual savings per 100 patients of up to BRL 1,072,043.14 for breast cancer, BRL 1,212,822.79 for other solid tumors, BRL 1,929,660.67 for prostate cancer and BRL 77,965.07 for multiple myeloma. Conclusion: This analysis suggests that SREs add substantial costs to the management of patients with bone metastases. In this way, the use of denosumab would prevent and delay SREs in cancer patients and might possibly lead to reduce the economic burden associated with SREs, borne by Brazilian private healthcare payers.
Assuntos
Neoplasias da Próstata , Neoplasias da Mama , Denosumab , Ácido Zoledrônico , Mieloma Múltiplo , Metástase NeoplásicaRESUMO
Malaria is an infectious disease of major worldwide clinical importance that causes a variety of severe, or complicated, syndromes including cerebral malaria, which is often fatal. Leukocyte integrins are essential for host defense but also mediate physiologic responses of the innate and adaptive immune systems. We previously showed that targeted deletion of the αD subunit (αD-/-) of the αDß2 integrin, which is expressed on key leukocyte subsets in mice and humans, leads to absent expression of the integrin heterodimer on murine macrophages and reduces mortality in mice infected with Plasmodium berghei ANKA (P. berghei ANKA). To further identify mechanisms involved in the protective effect of αD deletion in this model of severe malaria we examined wild type C57BL/6 (WT) and αD-/- mice after P. berghei ANKA infection and found that vessel plugging and leukocyte infiltration were significantly decreased in the brains of αD-/- animals. Intravital microscopy demonstrated decreased rolling and adhesion of leukocytes in cerebral vessels of αD-/- mice. Flow cytometry analysis showed decreased T-lymphocyte accumulation in the brains of infected αD-/- animals. Evans blue dye exclusion assays demonstrated significantly less dye extravasation in the brains of αD-/- mice, indicating preserved blood-brain barrier integrity. WT mice that were salvaged from P. berghei ANKA infection by treatment with chloroquine had impaired aversive memory, which was not observed in αD-/- mice. We conclude that deletion of integrin αDß2 alters the natural course of experimental severe malaria, demonstrating previously unrecognized activities of a key leukocyte integrin in immune-inflammatory responses that mediate cerebral involvement.
Assuntos
Antígenos CD11/metabolismo , Cadeias alfa de Integrinas/metabolismo , Malária/fisiopatologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Antígenos CD11/fisiologia , Cloroquina/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Cadeias alfa de Integrinas/fisiologia , Integrinas/imunologia , Integrinas/metabolismo , Contagem de Leucócitos , Leucócitos/metabolismo , Leucócitos/fisiologia , Macrófagos/metabolismo , Malária/genética , Malária Cerebral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmodium berghei/metabolismoRESUMO
Cryptococcosis is a systemic fungal infection caused by Cryptococcus neoformans. In immunocompetent patients, cryptococcal infection is often confined to the lungs. In immunocompromised individuals, C. neoformans may cause life-threatening illness, either from novel exposure or through reactivation of a previously acquired latent infection. For example, cryptococcal meningitis is a severe clinical disease that can manifest in people that are immunocompromised due to AIDS. The major constituents of the Cryptococcus polysaccharide capsule, glucuronoxylomannan (GXM), and galactoxylomannan (GalXM), also known as glucuronoxylomanogalactan (GXMGal), are considered the primary virulence factors of Cryptococcus. Despite the predominance of GXM in the polysaccharide capsule, GalXM has more robust immunomodulatory effects on host cellular immunity. This review summarizes current knowledge regarding host-Crytococcus neoformans interactions and the role of capsular polysaccharides in host immunomodulation. Future studies will likely facilitate a better understanding of the mechanisms involved in antigenic recognition and host immune response to C. neoformans and lead to the development of new therapeutic pathways for cryptococcal infection.
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O Glioblastoma (GBM) é o tumor cerebral mais comum e maligno, caracterizado por sua alta agressividade e respostas ineficazes aos tratamentos disponíveis. O diagnóstico impõe uma elevada taxa de mortalidade aos pacientes acometidos, que apresentam um tempo de sobrevida médio menor do que dois anos. A nível molecular, GBMs apresentam alterações em componentes chave das vias de sinalização de receptores tirosina quinase (RTKs), Ras/ERK e PI3K/AKT/mTORC1. A família das "ribosomal protein S6 kinases" (RSKs), ativada pela via Ras/ERK, foi proposta como um regulador da via de mTORC1, convergindo na regulação da síntese de proteínas. Em humanos, foram descritas quatro isoformas de RSKs (RSK1 - 4), que apresentam alta homologia e regulam diferentes funções celulares, sendo a desregulação das RSKs responsável por diferentes processos oncogênicos em diversos tipos tumorais. Contudo, a função das RSKs na regulação da síntese proteica global e de mRNAs específicos em GBMs ainda não foi descrita. Com a finalidade de se estabelecer um modelo robusto para o estudo dos efeitos das RSKs, especialmente do papel específico das isoformas no processo de tradução, foram geradas células nocaute para RSK1, RSK2 e duplo nocautes para RSK1 e RSK2 na linhagem celular de GBM LN-18, através da técnica CRISPR/Cas9. Os estudos com os clones nocautes validou o alvo P(S1798)-TSC2 para avaliação dos efeitos das RSKs. Além disso, detectamos que o alvo de RSKs, P(S422)-eIF4B, pode ser preferencialmente regulado pelas RSKs e não por mTORC1. Importantemente, realizamos a translatômica das células nocaute e analisamos os mRNAs diferencialmente traduzidos na presença ou ausência do inibidor de mTOR, Torin1, para estabelecer um modelo para o estudo da tradução de mRNAs dependentes de RSKs. A análise por meio de microarranjos mostrou que as isoformas RSK1 e RSK2 regulam diferentes conjuntos de mRNAs. A família de mRNAs contendo sequências 5'TOP são um dos principais alvos de mTORC1. De maneira surpreendente, observamos que a maioria dos 5'TOP mRNAs tem a tradução dependente de RSK1, em um mecanismo visualizado somente quando mTORC1 está inativado. Essa observação indica fortemente que RSK1, mas não RSK2 estaria mediando um mecanismo redundante e de resistência contra a inativação de mTORC1. Além disso, propomos um mecanismo inédito de controle da tradução de 5'TOP mRNAs. Desse modo, descrevemos um importante modelo para o entendimento das funções biológicas da família das RSKs em GBMs, que contribuirá com o desenho de alvos terapêuticos mais eficientes (AU)
Glioblastoma (GBM) is the most frequent and malignant brain tumor, characterized by its aggressiveness and poor response to the available treatments. Once diagnosed, GBM patients are inflicted with high mortality rates, and a mean survival lower than two years. From a molecular point of view, GBMs display alterations in key components of receptor tyrosine kinases (RTK), Ras/ERK and/or PI3K/AKT/mTORC1 pathways. The p90 ribosomal S6 kinase family (RSK) is directly regulated by the Ras/ERK pathway, and is thought to regulate mTORC1 pathway, converging on regulation of protein synthesis. Human cells display four RSK isoforms (RSK 1 - 4) that share high levels of sequence homology and regulate several cellular functions. The deregulation of RSKs seems to be responsible for different oncogenic outcomes in several types of tumors. Nevertheless, the function of RSKs in regulation of global protein synthesis and in translation of specific subsets of mRNA in GBM was not described so far. In order to establish a robust model for studying the effects of RSKs focusing on isoform-specific roles in the control of translation, we generated knockout cells using CRISPR/Cas9 system technology for RSK1, RSK2 and double-knockout cells for RSK1 and RSK2 in LN-18 cell line. The studies with knockout cells validated the target P(S1798)-TSC2 to evaluate the effects of RSKs. Also, we found that the RSK target P(S422)-eIF4B might be preferably regulated by RSKs, rather than mTORC1 in LN-18 cells. Importantly, we performed the translatomics on knockout cells and analyzed differentially translated mRNAs in the presence or absence of the mTOR inhibitor, Torin1, in order to determine a model for studying the translation of RSK-dependent mRNAs. Microarray data analysis revealed that RSK1 and RSK2 regulate different sets of mRNAs. The family of mRNAs containing a 5'TOP motif is the main target of mTORC1. Surprisingly, we observed that the majority of 5'TOP mRNAs have its translation dependent on RSK1, in a mechanism that emerges only when mTORC1 is inactivated. This observation strongly suggests that RSK1, but not RSK2, is mediating a mechanism of resistance against mTORC1 inactivation. Moreover, we propose an unprecedented mechanism for translation control of 5'TOP mRNAs. With this study, we were able to describe an important model for understanding the biological functions of RSK in GBMs that will contribute with development of more efficient therapeutic targets (AU)
Assuntos
Humanos , Polirribossomos , Biossíntese de Proteínas , RNA Mensageiro , Transdução de Sinais , Expressão Gênica , Glioblastoma , Proteínas Quinases S6 RibossômicasRESUMO
The present study aimed to evaluate the distribution and origin of 16 Priority PAHs in surficial sediment samples of Todos os Santos Bay (TSB, Brazil). Total PAHs concentrations ranged from below the method detection limit (Assuntos
Sedimentos Geológicos/análise
, Hidrocarbonetos Policíclicos Aromáticos/análise
, Poluentes Químicos da Água/análise
, Baías
, Brasil
, Carvão Mineral
, Monitoramento Ambiental
, Combustíveis Fósseis
, Sedimentos Geológicos/química
, Análise Multivariada
RESUMO
Cryptococcus neoformans is an opportunistic fungus that can cause lethal brain infections in immunosuppressed individuals. Infection usually occurs via the inhalation of a spore or desiccated yeast which can then disseminate from the lung to the brain and other tissues. Dissemination and disease is largely influence by the production of copious amounts of cryptococcal polysaccharides, both which are secreted to the extracellular environment or assembled into a thick capsule surrounding the cell body. There are two important polysaccharides: glucuronoxylomannan (GXM) and galactoxylomannan, also called as glucuronoxylomanogalactan (GXMGal or GalXM). Although GXM is more abundant, GalXM has a more potent modulatory effect. In the present study, we show that GalXM is a potent activator of murine dendritic cells, and when co-cultured with T cells, induces a Th17 cytokine response. We also demonstrated that treating mice with GalXM prior to infection with C. neoformans protects from infection, and this phenomenon is dependent on IL-6 and IL-17. These findings help us understand the immune biology of capsular polysaccharides in fungal pathogenesis.
Assuntos
Criptococose/metabolismo , Cryptococcus neoformans/fisiologia , Cápsulas Fúngicas/metabolismo , Interleucina-17/metabolismo , Polissacarídeos/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Criptococose/imunologia , Cryptococcus neoformans/metabolismo , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Interferon gama/biossíntese , Interleucina-17/biossíntese , Camundongos , Células Th17/citologia , Células Th17/efeitos dos fármacosRESUMO
Kinetoplastida trypanosomatidae microorganisms are protozoan parasites exhibiting a developmental stage in the gut of insect vectors and tissues of vertebrate hosts. During the vertebrate infective stages, these parasites alter the differential expression of virulence genes, modifying their biological and antigenic properties in order to subvert the host protective immune responses and establish a persistent infection. One of the hallmarks of kinetoplastid parasites is their evasion mechanisms from host immunity, leading to disease chronification. The diseases caused by kinetoplastid parasites are neglected by the global expenditures in research and development, affecting millions of individuals in the low and middle-income countries located mainly in the tropical and subtropical regions. However, investments made by public and private initiatives have over the past decade leveraged important lines of intervention that if well-integrated to health care programs will likely accelerate disease control initiatives. This review summarizes recent advances in public health care principles, including new drug discoveries and their rational use with chemotherapeutic vaccines, and the implementation of control efforts to spatially mapping the kinetoplastid infections through monitoring of infected individuals in epidemic areas. These approaches should bring us the means to track genetic variation of parasites and drug resistance, integrating this knowledge into effective stewardship programs to prevent vector-borne kinetoplastid infections in areas at risk of disease spreading.
RESUMO
Trypanosoma cruzi infects and replicates within a wide variety of immune and non-immune cells. Here, we investigated early cellular responses induced in NIH-3T3 fibroblasts upon infection with trypomastigote forms of T. cruzi. We show that fibroblasts were susceptible to T. cruzi infection and started to release trypomastigotes to the culture medium after 4 days of infection. Also, we found that T. cruzi infection reduced the number of fibroblasts in 3-day cell cultures, by altering fibroblast proliferation. Infected fibroblasts displayed distinctive phenotypic alterations, including enlarged and flattened morphology with a nuclei accumulation of senescence-associated heterochromatin foci. In addition, infection induced an overexpression of the enzyme senescence-associated ß-galactosidase (SA-ß-gal), an activation marker of the cellular senescence program, as well as the production of cytokines and chemokines involved with the senescence-associated secretory phenotype (SASP) such as IL-6, TNF-α, IL-1ß, and MCP-1. Infected fibroblasts released increased amounts of stress-associated factors nitric oxide (NO) and reactive oxygen species (ROS), and the treatment with antioxidants deferoxamine (DFO) and N-acetylcysteine reduced ROS generation, secretion of SASP-related cytokine IL-6, SA-ß-gal activity, and parasite load by infected fibroblasts. Taken together, our data suggest that T. cruzi infection triggers a rapid cellular stress response followed by induction of a senescent-like phenotype in NIH-3T3 fibroblasts, enabling them to act as reservoirs of parasites during the early stages of the Chagas disease.
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ß2 integrins are critical in host defense responses to invading pathogens and inflammation. Previously, we reported that genetic deficiency of integrin αDß2 in mice altered outcomes in experimental systemic infections including accelerated mortality in animals infected with Salmonella enterica serovar Typhimurium. Here, we show that deficiency of αDß2 results in impaired accumulation of leukocytes in response to peritoneal infection by S. Typhimurium, impaired pathogen clearance in vivo, defective bacterial elimination by cultured peritoneal macrophages, and enhanced pyroptosis, a cell death process triggered by Salmonella. Salmonella-infected animals deficient in αDß2 had increased levels of peritoneal cytokines in addition to other markers of pyroptosis, which may contribute to inflammatory injury and increased mortality in the context of impaired bacterial killing. These observations indicate important contributions of leukocyte integrins to the host response in experimental Salmonella infection and reveal previous activities of αDß2 in bacterial infection.
Assuntos
Antígenos CD11/metabolismo , Antígenos CD18/metabolismo , Cadeias alfa de Integrinas/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Infecções por Salmonella/imunologia , Infecções por Salmonella/metabolismo , Salmonella typhimurium/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno/imunologia , Contagem de Leucócitos , Lipopolissacarídeos/imunologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Knockout , Piroptose/imunologia , Infecções por Salmonella/microbiologiaRESUMO
Few studies investigate the major protein antigens targeted by the antibody diversity of infected mice with Trypanosoma cruzi. To detect global IgG antibody specificities, sera from infected mice were immunoblotted against whole T. cruzi extracts. By proteomic analysis, we were able to identify the most immunogenic T. cruzi proteins. We identified three major antigens as pyruvate phosphate dikinase, Hsp-85, and ß-tubulin. The major protein band recognized by host IgG was T. cruzi ß-tubulin. The T. cruzi ß-tubulin gene was cloned, expressed in E. coli, and recombinant T. cruzi ß-tubulin was obtained. Infection increased IgG reactivity against recombinant T. cruzi ß-tubulin. A single immunization of mice with recombinant T. cruzi ß-tubulin increased specific IgG reactivity and induced protection against T. cruzi infection. These results indicate that repertoire analysis is a valid approach to identify antigens for vaccines against Chagas disease.
Assuntos
Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Doença de Chagas/imunologia , Imunoglobulina G/imunologia , Proteínas de Protozoários/imunologia , Trypanosoma cruzi/imunologia , Tubulina (Proteína)/imunologia , Animais , Modelos Animais de Doenças , Imunização , Masculino , Camundongos Endogâmicos BALB C , Camundongos MutantesRESUMO
Octyl p-methoxycinnamate (OMC) is one of the most widely used sunscreen agents. However, the efficiency of OMC as UV filter over time is affected due to the formation of the cis-isomer which presents a markedly lower extinction coefficient (εcis=12,600L mol-1cm-1 at 291nm) than the original trans-isomer (εtrans=24,000L mol-1cm-1 at 310nm). In this work, a novel carrier for OMC based on an oil-in-water microemulsion is proposed in order to improve the photostability of this sunscreen. The formulation was composed of 29.2% (w/w) of a 3:1 mixture of ethanol (co-surfactant) and decaethylene glycol mono-dodecyl ether (surfactant), 1.5% (w/w) of oleic acid (oil phase) and 69.2% (w/w) of water. This microemulsion was prepared in a simple way, under moderate stirring at 25°C and using acceptable, biocompatible and accessible materials for topical use. OMC was incorporated in the vehicle at a final concentration of 5.0% (w/w), taking into account the maximum permitted levels established by international norms. Then, a photolysis study of the loaded formulation was performed using a continuous flow system. The direct photolysis was monitored over time by molecular fluorescence. The recorded spectra data between 370 y 490nm were analyzed by multivariate curve resolution-alternating least squares algorithm. The kinetic rate constants corresponding to the photolysis of the trans-OMC were calculated from the concentration profiles, resulting in 0.0049s-1 for the trans-OMC loaded microemulsion and 0.0131s-1 for the trans-OMC in aqueous media. These results demonstrate a higher photostability of the trans-OMC when loaded in the proposed vehicle with respect to the free trans-OMC in aqueous media.
RESUMO
Multivariate models have been widely used in analytical problems involving quantitative and qualitative analyzes. However, there are cases in which a model is not applicable to spectra of samples obtained under new experimental conditions or in an instrument not involved in the modeling step. A solution to this problem is the transfer of multivariate models, usually performed using standardization of the spectral responses or enhancement of the robustness of the model. This present paper proposes two new criteria for selection of robust variables for classification transfer employing the successive projections algorithm (SPA). These variables are then used to build models based on linear discriminant analysis (LDA) with low sensitivity with respect to the differences between the responses of the instruments involved. For this purpose, transfer samples are included in the calculation of the cost for each subset of variables under consideration. The proposed methods are evaluated for two case studies involving identification of adulteration of extra virgin olive oil (EVOO) and hydrated ethyl alcohol fuel (HEAF) using UV-Vis and NIR spectroscopy, respectively. In both cases, similar or better classification transfer results (obtained for a test set measured on the secondary instrument) employing the two criteria were obtained in comparison with direct standardization (DS) and piecewise direct standardization (PDS). For the UV-Vis data, both proposed criteria achieved the correct classification rate (CCR) of 85%, while the best CCR obtained for the standardization methods was 81% for DS. For the NIR data, 92.5% of CCR was obtained by both criteria as well as DS. The results demonstrated the possibility of using either of the criteria proposed for building robust models as an alternative to the standardization of spectral responses for transfer of classification.
Assuntos
Algoritmos , Análise Discriminante , Etanol/análise , Azeite de Oliva/análise , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
O preenchimento cutâneo figura entre os procedimentos cosméticos mais realizados. Apesar de os tratamentos estéticos possuírem perfil de segurança favorável, ocorreu um aumento nos processos jurídicos deles resultantes nos Estados Unidos. No Brasil, o número de procedimentos não cirúrgicos apresentou crescimento nos últimos anos devido não apenas ao maior número de opções de materiais para preenchimento disponíveis no mercado, mas também devido à maior quantidade de profissionais com permissão para executar esses procedimentos. O objetivo do presente estudo foi revisar a literatura, assim como delinear um guia prático para prevenção, diagnóstico e manejo das complicações secundárias ao uso de preenchedores semipermanentes e temporários.
Filler injections are among the most popular cosmetic procedures performed worldwide. Although fillers have a safety profile, there has been a rise in litigation as a result of treatments in the USA. In the Brazilian scenario, the number of non-surgical procedures has increased in the past years, mainly due to the increase of filler options available in the Brazilian market, as well as in the type of professionals allowed to perform injectable procedures. Therefore we sought to review the related literature regarding semi-permanent and temporary fillers adverse effects and outline a practical guide for complications avoidance, diagnosis and management.
RESUMO
BACKGROUND: The latex from the medicinal plant Calotropis procera is often used in folk medicine against infectious and inflammatory diseases. PURPOSE: In this study, we investigate a protein fraction with immunomodulatory properties, named LPPI, against experimental infections, in vitro and in vivo, with a virulent strain of Listeria monocytogenes. STUDY DESIGN: LPPI was exposed to cultured macrophages or Swiss mice and then challenged with L. monocytogenes. METHODS: Peritoneal macrophages were obtained from Swiss mice, and cultured in 96-well microplates. Soluble latex proteins (LP) were subjected to fractionation by ion-exchange chromatography. The major peak (LPPI) was added into wells at 10 or 100µg/ml. Albumin (100µg/ml) was used for comparison between protein treatments. After incubation for 1h at 5% CO2/ 37°C, the supernatant was discarded and 0.2ml of L. monocytogenes overnight culture was added in the wells. Following 4h and 24h infection, the cytokine mRNA expression was evaluated as well as the number of intracellular colony forming units. Swiss mice (n=16) were injected intraperitoneally (i.p.) with LPPI (5 and 10mg/kg) while the control mice received albumin (10mg/kg) or LP (10mg/kg). After 24h, all animal groups were challenged with L. monocytogenes (10(6) CFU/ ml), also by i.p. route. RESULTS: LPPI was not toxic to uninfected macrophages (pMØ) and significantly increased mRNA expression of TNF-α, IL-6, IL-1ß and iNOS. Following infection, cell viability was reduced by 50% in albumin-treated pMØ (control); but only 17% in pMØ treated with LPPI at 100µg/ml. In this case, LPPI increased expression of TNF-α and IL-6 whereas the number of bacterial colony-forming units was reduced 100-fold in comparison to control groups. Swiss mice pretreated with LPPI showed dose-dependent survival rates that reached 80%, while mice that received albumin died 1-3 days after infection. After 24h infection, leukocyte migration to the infectious foci was high in LPPI-treated mice whereas the number of viable bacteria in the peritoneal fluid, liver and bloodstream were significantly reduced. CONCLUSION: We conclude that LPPI present immunomodulatory properties that are beneficial for prevention of systemic bacterial infections caused by the intracellular bacteria L. monocytogenes.