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Natural killer (NK) cells play a crucial role in the immune system's response against cancer. However, the challenge of obtaining the required quantity of NK cells for effective therapeutic response necessitates the development of strategies for their ex vivo expansion. This study aimed to develop a novel feeder cell line, K562.Clone1, capable of promoting the ex vivo expansion of NK cells while preserving their cytotoxic potential. he K562 leukemic cell line was transduced with mbIL-21 and 4-1BBL proteins to generate K562.Clone1 cells. NK cells were then co-cultured with these feeder cells, and their expansion rate was monitored over 14 days. The cytotoxic potential of the expanded NK cells was evaluated against acute myeloid leukemia blasts and tumor cell lines of leukemia and glial origin. Statistical analysis was performed to determine the significance of the results. The K562.Clone1 co-cultured with peripheral NK showed a significant increase in cell count, with an approximate 94-fold expansion over 14 days. Expanded NK cells demonstrated cytotoxicity against the tested tumor cell lines, indicating preservation of their cytotoxic characteristics. Additionally, the CD56, CD16, inhibitory KIRs, and activation receptors were conserved and present in a well-balanced manner. The study successfully developed a feeder cell line, K562.Clone1, that effectively promotes the expansion of NK cells ex vivo while maintaining their cytotoxic potential. This development could significantly contribute to the advancement of NK cell therapy, especially in Brazil.
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Objetivos:Demonstrar os saberes e as práticas de indivíduos sobre prevenção e tratamento de queimaduras no ambiente domiciliar e descrever o cuidado educativo de enfermagem na prevenção e tratamento de queimaduras no ambiente domiciliar. Método: Pesquisa convergente-assistencial realizada de maneira virtual, no período de junho a agosto de 2021, com pessoas residentes na cidade de Macaé (RJ). Resultados: A pesquisa incluiu 16 participantes, sendo 81,25% (n = 13) do sexo feminino, com idades entre 19 e 59 anos. Na análise das entrevistas, foi possível identificar saberes e práticas equivocados sobre a prevenção e o tratamento de queimaduras, a serem discutidos neste estudo. Conclusão: Embora haja conhecimento acerca dos saberes e práticas adequados sobre prevenção e tratamento de queimaduras no ambiente domiciliar, houve identificação de práticas equivocadas que podem prejudicar o correto tratamento e prevenção de agravos. Os achados deste estudo apontam para a necessidade de construir materiais e de realizar práticas educativas com essa população para reforço de medidas preventivas de queimaduras.
Objectives:To demonstrate the knowledge and practices of individuals on the prevention and treatment of burns in the home environment and to describe the educational nursing care in the prevention and treatment of burns in the home environment. Method: Convergent care research was carried out virtually, from June to August 2021, with people residing in the city of Macaé/RJ, Brazil. Results: The survey included 16 participants, 81.25% (n = 13) female, aged between 19 and 59 years old. In the analysis of the interviews, it was possible to identify mistaken knowledge and practices about the prevention and treatment of burns, to be discussed in this study. Conclusion: Although there is knowledge about adequate knowledge and practices on the prevention and treatment of burns in the home environment, there was identification of wrong practices that can harm the correct treatment and prevention of injuries. The findings of this study point to the need to build materials and carry out educational practices with this population to reinforce preventive measures for burns.
Objetivos:Demostrar los conocimientos y prácticas de los individuos sobre la prevención y tratamiento de quemaduras en el ambiente domiciliario y describir el cuidado educativo de enfermería en la prevención y tratamiento de quemaduras en el ambiente domiciliario. Método: Investigación de Atención Convergente (PCA) realizada virtualmente, de junio a agosto de 2021, con personas residentes en la ciudad de Macaé/RJ. Resultados: La encuesta contó con 16 participantes, 81,25% (n=13) mujeres, con edades entre 19 y 59 años. En el análisis de las entrevistas, fue posible identificar conocimientos y prácticas erróneas sobre la prevención y el tratamiento de las quemaduras, para ser discutidas en este estudio. Conclusión: Si bien existe conocimiento sobre los saberes y prácticas sobre la prevención y tratamiento de quemaduras en el ámbito domiciliario, se identificaron prácticas incorrectas que pueden perjudicar el correcto tratamiento y prevención de lesiones. Los hallazgos de este estudio apuntan para la necesidad de construir materiales y realizar prácticas educativas con esta población para reforzar las medidas preventivas de quemaduras.
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Queimaduras , Enfermagem , Prevenção de Doenças , EstomaterapiaRESUMO
ABSTRACT Introduction: Telomere length (TL) is a biomarker of cellular proliferative history. In healthy individuals, leukocyte TL shortens with age and associates with the lifespan of men and women. However, most of studies had used linear regression models to address the association of the TL attrition, aging and sex. Methods: We evaluated the association between the TL, aging and sex in a cohort of 180 healthy subjects by quantile regression. The TL of nucleated blood cells was measured by fluorescent in situ hypridization (flow-FISH) in a cohort of 89 men, 81 women, and 10 umbilical cord samples. The results were validated by quantitative polymerase chain reaction (qPCR) and compared to a linear regression analysis. Results: By quantile regression, telomere dynamics slightly differed between sexes with aging: women had longer telomeres at birth and slower attrition rate than men until the sixth decade of life; after that, TL eroded faster and became shorter than that in men. These differences were not observed by linear regression analysis, as the overall telomere attrition rates in women and men were similar (42 pb per year, p < 0.0001 vs. 45 pb kb per year, p < 0.0001). Also, qPCR did not recapitulate flow-FISH findings, as the telomere dynamics by qPCR followed a linear model. Conclusion: The quantile regression analysis accurately reproduced a third-orderpolynomial TL attrition rate in both women and men, but it depended on the technique applied to measure TL. The Flow-FISH reproduced the expected telomere dynamics through life and, differently from the qPCR, was able to detect the subtle TL variations associated with sex and aging.
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Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Análise de Regressão , Telômero , Homeostase do Telômero , SexoRESUMO
Cytogenetic aberrations may emerge in human mesenchymal stromal cells (MSC) during ex vivo expansion for cell therapy. We have detected clonal trisomy 5 in two distinct autologous MSC products expanded from bone marrow which, based on the current quality control criteria, could not be released for clinical use. Although a safety concern, it is still unclear to what extent recurrent aneuploidies detected in MSC products may affect the threshold for neoplastic transformation or the medicinal properties of these cells. We have carried out an exploratory preclinical study to evaluate these MSC products with clonal trisomy 5, regarding their oncogenic and immunomodulatory potential. Cell population growth in vitro was reduced in MSC cultures with clonal trisomy 5 compared with the population growth of their euploid MSC counterparts, based on a lower cumulative population doubling level, reduced cell proliferation index, and increased senescence-associated beta-galactosidase activity. Subcutaneous injection of clinically relevant amount of MSC population, either with or without clonal trisomy 5, did not generate tumors in immunodeficient mice within a follow-up period of six months. Most importantly, MSC population with clonal trisomy 5 kept immunomodulatory properties upon interferon gamma (IFNγ) licensing, displaying overexpression of IDO, CXCL9, CXCL10, and CXCL11, in a similar fashion than that of IFNγ-licensed euploid MSC. Our findings suggest that bone marrow MSC products with clonal trisomy 5 may retain their therapeutic potential, based on poor tumor initiating capability and preserved immunomodulatory potency. This preclinical evidence may further support the definition of release criteria of autologous MSC products for cell therapy under critical clinical scenarios. This trial is registered with Clinical Study registration number: RBR-29x2pr.
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Mesenchymal stem cells (MSCs) are multipotent cells found in various tissues and are easily cultivated. For use in clinical protocols, MSCs must be expanded to obtain an adequate number of cells, but a senescence state may be instituted after some passages, reducing their replicative potential. In this study, we report a case where MSC derived from an elderly donor acquired a senescence state after three passages. The bone marrow was aspirated from a female patient submitted to a cell therapy for the incontinency urinary protocol; MSCs were cultivated with DMEM low glucose, supplemented with 10% autologous serum (AS) plus 1% L-glutamine and 1% antibiotic/antimycotic. Senescence analysis was performed by ß-galactosidase staining after 24 and 48 h. Controls were established using BM-MSC from healthy donors and used for senescence and gene expression assays. Gene expression was performed using RT-PCR for pluripotency genes, such as SOX2, POU5F1, NANOG, and KLF4. MSC telomere length was measured by the Southern blotting technique, and MSCs were also analyzed for their capacity to differentiate into adipocytes, chondrocytes, and osteocytes. The patient's MSC expansion using AS displayed an early senescence state. In order to understand the role of AS in senescence, MSCs were then submitted to two different culture conditions: 1) with AS or 2) with FBS supplementation. Senescence state was assessed after 24 h, and no statistical differences were observed between the two conditions. However, patients' cells cultured with AS displayed a higher number of senescence cells than FBS medium after 48 h (p = 0.0018). Gene expression was performed in both conditions; increased expression of KLF4 was observed in the patient's cells in comparison to healthy controls (p = 0.0016); reduced gene expression was observed for NANOG (p = 0.0016) and SOX2 (p = 0.0014) genes. Telomere length of the patient's cells was shorter than that of a healthy donor and that of a patient of similar age. Osteocyte differentiation seemed to be more diffuse than that of the healthy donor and that of the patient of similar age. MSCs could enter a senescence state during expansion in early passages and can impact MSC quality for clinical applications, reducing their efficacy when administered.
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INTRODUCTION: Telomere length (TL) is a biomarker of cellular proliferative history. In healthy individuals, leukocyte TL shortens with age and associates with the lifespan of men and women. However, most of studies had used linear regression models to address the association of the TL attrition, aging and sex. METHODS: We evaluated the association between the TL, aging and sex in a cohort of 180 healthy subjects by quantile regression. The TL of nucleated blood cells was measured by fluorescent in situ hypridization (flow-FISH) in a cohort of 89 men, 81 women, and 10 umbilical cord samples. The results were validated by quantitative polymerase chain reaction (qPCR) and compared to a linear regression analysis. RESULTS: By quantile regression, telomere dynamics slightly differed between sexes with aging: women had longer telomeres at birth and slower attrition rate than men until the sixth decade of life; after that, TL eroded faster and became shorter than that in men. These differences were not observed by linear regression analysis, as the overall telomere attrition rates in women and men were similar (42 pb per year, pâ¯<â¯0.0001 vs. 45 pb kb per year, pâ¯<â¯0.0001). Also, qPCR did not recapitulate flow-FISH findings, as the telomere dynamics by qPCR followed a linear model. CONCLUSION: The quantile regression analysis accurately reproduced a third-order polynomial TL attrition rate in both women and men, but it depended on the technique applied to measure TL. The Flow-FISH reproduced the expected telomere dynamics through life and, differently from the qPCR, was able to detect the subtle TL variations associated with sex and aging.
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Objetivo: apresentar as experiências do processo de implantação até as ações recentes da Comissão Permanente UFRJ-MACAÉ Acessível e Inclusiva, da UFRJ-Campus Macaé Professor Aloísio Teixeira. Métodos: O estudo apresenta um relato de experiências vividas por membros da CPAI, no período entre o segundo semestre de 2016 e 2019. Para a estruturação deste relato, foram reunidas as memórias dos encontros, atas de reuniões da CPAI, publicações de matérias referentes a CPAI tanto na mídia impressa como digital. Resultados: Foram identificados quatro aspetos relevantes: História da consolidação das instâncias voltadas às pessoas com deficiência na UFRJ; Implantação da CPAI; Entrada dos estudantes com deficiência na UFRJ-Campus Macaé; Ações da CPAI. Considerações finais: A CPAI tem realizado ações que propiciam um frequente diálogo sobre a acessibilidade e inclusão de estudantes com deficiência, sendo relevante para a atenção a estes no âmbito do ensino superior, por muitas vezes acessível apenas para uma parcela da população com deficiência.
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In approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34+ samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinical studies on AML cells provided evidence on the pro-differentiation benefits of EGFR inhibitors when combined with ATRA or ATO in vitro. Despite the success of ATRA and ATO in the treatment of patients with acute promyelocytic leukemia (APL), therapy-associated resistance is observed in 5-10% of the cases, pointing to a clear need for new therapeutic strategies for those patients. In this context, the functional role of EGFR tyrosine-kinase inhibitors has never been evaluated in APL. Here, we investigated the EGFR pathway in primary samples along with functional in vitro and in vivo studies using several APL models. We observed that total and phosphorylated EGFR (Tyr992) was expressed in 28% and 19% of blast cells from APL patients, respectively, but not in healthy CD34+ samples. Interestingly, the expression of the EGF was lower in APL plasma samples than in healthy controls. The EGFR ligand AREG was detected in 29% of APL patients at diagnosis, but not in control samples. In vitro, treatment with the EGFR inhibitor gefitinib (ZD1839) reduced cell proliferation and survival of NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Moreover, the combination of gefitinib with ATRA and ATO promoted myeloid cell differentiation in ATRA- and ATO-resistant APL cells. In vivo, the combination of gefitinib and ATRA prolonged survival compared to gefitinib- or vehicle-treated leukemic mice in a syngeneic transplantation model, while the gain in survival did not reach statistical difference compared to treatment with ATRA alone. Our results suggest that gefitinib is a potential adjuvant agent that can mitigate ATRA and ATO resistance in APL cells. Therefore, our data indicate that repurposing FDA-approved tyrosine-kinase inhibitors could provide new perspectives into combination therapy to overcome drug resistance in APL patients.
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Dialogando com reflexão de Canclini na quarentena da Cidade do México em 2009 pela epidemia de H1N1, nosso artigo aborda as cidades de São Paulo e Rio de Janeiro para discutir desdobramentos da pandemia da Covid-19. O agravamento da crise denuncia e expõe as flagrantes desigualdades sociais fomentadas pelo modelo de gestão dos espaços urbanos que associa o político ao econômico, favorecendo a concentração de renda e limitando o acesso a recursos de toda ordem. Comunicação, vigilância, sociabilidade e cidadania são os eixos temáticos da discussão apresentada. Ao final, argumentamos sobre a urgência em constituirmos um revigorado horizonte comum de debate e ação coletiva unindo o político ao social.
In dialogue with Canclini's reflection during the quarantine of Mexico City in 2009 due to the H1N1 epidemic, our article focuses on the cities of São Paulo and Rio de Janeiro to discuss the unfolding of the Covid-19 pandemic. The worsening of the crisis denounces and exposes the flagrant social inequalities fostered by the current model of management of urban spaces that associates the political with the economic, favoring the concentration of income and limiting access to all kinds of resources. Communication, surveillance, sociability, and citizenship are interwoven in this discussion. In the end, we argue about the urgency of creating an invigorated common horizon of debate and collective action by uniting the political and the social spheres.
En diálogo con la reflexión de Canclini en la cuarentena de la Ciudad de México en 2009 debido a la epidemia de H1N1, nuestro artículo se centra en las ciudades de São Paulo y Rio de Janeiro para discutir los desarrollos de la pandemia de Covid-19. El agravamiento de la crisis denuncia y expone las flagrantes desigualdades sociales fomentadas por el modelo actual de gestión de espacios urbanos que asocia lo político con lo económico, favoreciendo la concentración de ingresos y limitando el acceso a todo tipo de recursos. Comunicación, vigilancia, sociabilidad y ciudadanía se entrelazan en esta discusión. Al final, discutimos sobre la urgencia de crear un vigorizado horizonte común de debate y acción colectiva uniendo lo político y lo social.
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Humanos , Fatores Socioeconômicos , Cidades , Comunicação , Participação da Comunidade , Pandemias , Política , Isolamento Social , População Urbana , Quarentena , Infecções por CoronavirusRESUMO
PURPOSE: Acute lymphoblastic leukemia (ALL) is an aggressive hematological cancer with limited therapeutic options for adult patients. Aurora kinases have drawn attention as potential targets in hematological neoplasms due to their high expression and biological functions. Aurora kinase A (AURKA) and AURKB are essential for a successful mitosis, acting in spindle mitotic organization and cytokinesis. Reversine is a synthetic purine analog that acts as a multi-kinase inhibitor with anti-neoplastic activity by targeting AURKA and AURKB. METHODS: ALL patient gene expression data were retrieved from the Amazonia! DATABASE: For functional assays, Jurkat (T-ALL) and Namalwa (B-ALL) cells were exposed to increasing concentrations of reversine and submitted to various cellular and molecular assays. RESULTS: We found that AURKB expression was higher in ALL patient samples compared to normal lymphocytes (p < 0.0001). The ALL cell lines tested displayed aberrant AURKA and AURKB expression. In Jurkat and Namalwa cells, reversine reduced cell viability in a dose- and time-dependent manner (p < 0.05). Reversine also significantly reduced the viability of primary ALL cells. Reversine induced apoptosis and autophagy, and reduced cell proliferation in both cell lines (p < 0.05). Mitotic catastrophe markers, including cell cycle arrest at G2/M, increased cell size and DNA damage, were observed upon reversine exposure. Short- and long-term treatment with reversine inhibited autonomous clonogenicity (p < 0.05). At the molecular level, reversine reduced AURKB activity, induced SQSTM1/p62 consumption, and increased LC3BII and γ-H2AX levels. In Namalwa cells, reversine modulated 25 out of 84 autophagy-related genes, including BCL2, BAD, ULK1, ATG10, IRGM and MAP1LC3B, which indicates that reversine acts by initiating and sustaining autophagy signals in ALL cells. CONCLUSIONS: From our data we conclude that reversine reduces the viability of ALL cells by triggering multiple cell death mechanisms, including apoptosis, mitotic catastrophe, and autophagy. Our findings highlight reversine as a potential anticancer agent for ALL.
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Morfolinas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Purinas/farmacologia , Apoptose/efeitos dos fármacos , Aurora Quinase B/metabolismo , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Clonais , Dano ao DNA , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologiaRESUMO
Este artigo busca apresentar de que formas e sob quais circunstâncias a Baía de Guanabara pôde emergir como importante pauta jornalística ambiental. Analisando matérias do jornal O Globo entre as décadas de 1940 e 1970, período crucial para se entender a poluição daquele ambiente, identificamos a transformação de um referencial idílico da baía para a representação de um lugar de perigo. Nesse sentido, exploramos a importância que a saúde humana adquire para que esta pauta ambiental atingisse um alto patamar de noticialização, semelhantes aos níveis atuais. Refletimos, ainda, sobre as maneiras pelas quais a pauta ambiental pode ser construída, longe de síndromes comuns a esta especialidade jornalística, mas associada a marcos teóricos importantes do campo, como a imprescindibilidade do ativismo ecológico e a necessidade de ampliação do enfoque noticioso e abarcamento de conhecimentos de povos tradicionais.
This article seeks to present in which ways and circumstances Guanabara Bay could emerge as an important environmental journalistic agenda. Analyzing articles from the O Globo newspaper between the 1940s and the 1970s, a crucial period to understand the pollution of the bay, we identified the changes of an idyllic reference point of the bay to represent a place of danger. In this sense, we explore the importance that human health acquires for the environmental agenda of the bay to reach levels of reporting similar to the current ones. We also reflect about how the environmental agenda can be built away from syndromes common to this journalistic field, but associated with important theories in the field, such as the indispensability of ecological activism and the need to expand the news focus and to encompass the knowledge of traditional people.
Este artículo busca presentar de qué maneras y bajo qué circunstancia la Bahía de Guanabara podría emerger como una importante agenda periodística ambiental. Analizando artículos del periódico O Globo entre las décadas de 1940 y 1970, un período crucial para comprender la contaminación de la bahía, identificamos la transformación de un punto de referencia idílico de la bahía para representar un lugar de peligro. Em este sentido, exploramos la importancia que adquiere la salud humana para que la agenda ambiental de la bahía alcance niveles de informes similares a los actuales. También reflejamos las formas em que la agenda ambiental se puede construir a partir de síndromes comunes a este campo periodístico, asociada con importantes teorías en el campo, como la indispensabilidad del activismo ecológico y la necesidad de expandir el enfoque de las noticias y abarcar el conocimiento de las personas tradicionales.
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Humanos , Comunicação , Meio Ambiente , Poluição Ambiental , Jornalismo Ambiental , Jornais como Assunto , Publicações Seriadas , Brasil , Baías , Pesquisa QualitativaRESUMO
RAS-pathway mutations are recurrent events in myeloid malignancies. However, there is limited data on the significance of RAS-pathway mutations in patients with myelofibrosis (MF). We analyzed next-generation sequencing data of 16 genes, including RAS-pathway genes, from 723 patients with primary and secondary MF across three international centers and evaluated their significance. N/KRAS variants were present in 6% of patients and were typically sub-clonal (median VAF = 20%) relative to other genes variants. RAS variants were associated with advanced MF features including leukocytosis (p = 0.02), high somatic mutation burden (p < 0.01) and the presence of established "molecular high-risk" (MHR) mutations. MF patients with N/KRAS mutations had shorter 3-year overall survival (OS) (34% vs 58%, p < 0.001) and higher incidence of acute myeloid leukemia at 3 years (18% vs 11%, p = 0.03). In a multivariate Cox model, RAS mutations were associated with decreased OS (HR 1.93, p < 0.001). We created a novel score to predict OS incorporating RAS mutations, and it predicted OS across training and validation cohorts. Patients with intermediate risk/high-risk DIPSS with RAS mutations who received ruxolitinib had a nonsignificant longer 2-year OS relative to those who did not receive ruxolitinib. These data demonstrate the importance of identifying RAS mutations in MF patients.
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Genes ras , Mutação , Mielofibrose Primária/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Policitemia Vera/genética , Mielofibrose Primária/diagnóstico , Prognóstico , Modelos de Riscos Proporcionais , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirazóis/farmacologia , Pirimidinas , Estudos Retrospectivos , Risco , Trombocitemia Essencial/genética , Resultado do Tratamento , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Dialogando com reflexão de Canclini na quarentena da Cidade do México em 2009 pela epidemia de H1N1,nosso artigo aborda as cidades de São Paulo e Rio de Janeiro para discutir desdobramentos da pandemiada Covid-19. O agravamento da crise denuncia e expõe as flagrantes desigualdades sociais fomentadas pelomodelo de gestão dos espaços urbanos que associa o político ao econômico, favorecendo a concentração derenda e limitando o acesso a recursos de toda ordem. Comunicação, vigilância, sociabilidade e cidadania sãoos eixos temáticos da discussão apresentada. Ao final, argumentamos sobre a urgência em constituirmosum revigorado horizonte comum de debate e ação coletiva unindo o político ao social
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Pandemias , Cidadania , História do Século XXI , BrasilRESUMO
Graft versus host disease (GVHD) is a common condition in patients subjected to allogeneic hematopoietic stem cell transplantation (HSCT). The immune cells derived from the grafted stem cells attack recipient's tissues, including those from the skin, liver, eyes, mouth, lungs, gastrointestinal tract, neuromuscular system, and genitourinary tract, may lead to severe morbidity and mortality. Acute GVHD can occur within few weeks after the allogeneic cells have engrafted in the recipient while chronic GVHD may occur any time after transplant, typically within months. Although treatable by systemic corticosteroid administration, effective responses are not achieved for a significant proportion of patients, a condition associated with poor prognosis. The use of multipotent mesenchymal stromal cells (MSCs) as an alternative to treat steroid-refractory GVHD had improved last decade, but the results are still controversial. Some studies have shown improvement in the life quality of patients after MSCs treatment, while others have found no significant benefits. In addition to variations in trial design, discrepancies in protocols for MSCs isolation, characterization, and ex vivo manipulation, account for inconsistent clinical results. In this review, we discuss the immunomodulatory properties supporting the therapeutic use of MSCs in GVHD and contextualize the main clinical findings of recent trials using these cells. Critical parameters for the clinical translation of MSCs, including consistent production of MSCs according to Good Manufacturing Practices (GMPs) and informative potency assays for product quality control (QC), are addressed.
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Telomeropathies are a group of phenotypically heterogeneous diseases molecularly unified by pathogenic mutations in telomere-maintenance genes causing critically short telomeres. X-linked dyskeratosis congenita (DC), the prototypical telomere disease, manifested with ectodermal dysplasia, cancer predisposition, and severe bone marrow failure, is caused by mutations in DKC1, encoding a protein responsible for telomerase holoenzyme complex stability. To investigate the effects of pathogenic DKC1 mutations on telomere repair and hematopoietic development, we derived induced pluripotent stem cells (iPSCs) from fibroblasts of a DC patient carrying the most frequent mutation: DKC1 p.A353V. Telomeres eroded immediately after reprogramming in DKC1-mutant iPSCs but stabilized in later passages. The telomerase activity of mutant iPSCs was comparable to that observed in human embryonic stem cells, and no evidence of alternative lengthening of telomere pathways was detected. Hematopoietic differentiation was carried out in DKC1-mutant iPSC clones that resulted in increased capacity to generate hematopoietic colony-forming units compared to controls. Our study indicates that telomerase-dependent telomere maintenance is defective in pluripotent stem cells harboring DKC1 mutation and unable to elongate telomeres, but sufficient to maintain cell proliferation and self-renewal, as well as to support the primitive hematopoiesis, the program that is recapitulated with our differentiation protocol.
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Proteínas de Ciclo Celular/genética , Diferenciação Celular , Hematopoese , Proteínas Nucleares/genética , Telômero/metabolismo , Células Cultivadas , Reprogramação Celular , Disceratose Congênita/genética , Disceratose Congênita/patologia , Fibroblastos/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Cariótipo , Mutação , Telomerase/genética , Telomerase/metabolismo , Encurtamento do TelômeroRESUMO
Este texto pretende discutir, a partir de uma perspectiva comunicacional, a relação entre circulação urbana e cidadania. Em um primeiro momento introdutório, nos deteremos principalmente nos conceitos de sistemas comunicacionais, comum e comunicação. Em seguida, pensaremos como o paradigma moderno de circulação, histórica e contemporaneamente, interfere na organização do comum e nos espaços da cidade de modo a privilegiar circuitos domésticos e de consumo em detrimento de usos e ocupações mais livres do espaço público. Por fim, discutiremos sobre a ideia de cidadania no Brasil para pensar com há uma relação explícita no modo como se circula na cidade, se constitui o comum urbano e se dispõe de certos direitos, especificamente o de liberdade de locomoção, ou, se quisermos, o direito de ir e vir.
This text intends to discuss, from a communicational perspective, the relationship between urban circulation and citizenship. In the first introductory moment, we will focus mainly on the concepts of communication, common and communication systems. Next, we will think about how the modern paradigm of circulation, historically and contemporarily, interferes with the organization of the commons and the city spaces in order to privilege domestic and consumption circuits over the freer uses and occupations of public space. Finally, we will discuss about the idea of citizenship in Brazil to think with there is an explicit relation in the way it circulates in the city, if it constitutes the urban common and if it has certain rights, specifically freedom of movement, or, if we wish, the right to come and go.
Este texto pretende discutir, desde una perspectiva comunicacional, la relación entre la circulación urbana y la ciudadanía. En el primer momento introductorio, nos centraremos principalmente en los conceptos de comunicación, sistemas comunes y de comunicación. A continuación, pensaremos cómo el paradigma moderno de la circulación, histórica y contemporáneamente, interfiere con la organización de los espacios comunes y municipales para privilegiar los circuitos domésticos y de consumo sobre los usos y ocupaciones más libres del espacio público. Finalmente, discutiremos sobre la idea de ciudadanía en Brasil para pensar que existe una relación explícita en la forma en que circula en la ciudad, si constituye el común urbano y si tiene ciertos derechos, específicamente la libertad de movimiento o, si lo deseamos, El derecho a ir y venir.
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Humanos , Meios de Transporte , Comunicação , Área Urbana , Participação da Comunidade , Reforma Urbana , Cidades , Planejamento de Cidades , Veículos Automotores , Direitos Socioeconômicos , Território SocioculturalRESUMO
JAK2/STAT signaling participates in the Ph-negative myeloproliferative neoplasms (MPN) pathophysiology and has been targeted by ruxolitinib, a JAK1/2 inhibitor. In the present study, the impact of ruxolitinib treatment on cytoskeleton-related genes expression was explored. In SET2 cells, AURKA and AURKB expression/activity were downregulated in a dose- and time-dependent manner by ruxolitinib. Reversine, a multikinase inhibitor selective for aurora kinases, reduced cell viability in a dose- and/or time-dependent manner in JAK2V617F cells. Reversine significantly increased apoptosis and mitotic catastrophe, and reduced cell proliferation and clonogenic capacity in SET2 and HEL cells. In the molecular scenario, reversine induced DNA damage and apoptosis markers, as well as, reduced AURKA and AURKB expression/activity. In SET2 cells, reversine modulated the expression of 32 out of 84 apoptosis-related genes investigated, including downregulation of antiapoptotic (BCL2, BCL2L1, and BIRC5) and upregulation of proapoptotic (BIK, BINP3, and BNIP3L) genes. Synergism experiments indicated that low dose of reversine had a potentiating effect under ruxolitinib treatment at low doses in SET2 cells. In summary, our exploratory study establishes new targets, related to the regulation of the cellular cytoskeleton, for potential pharmacological intervention in MPN. These findings indicate that AURKA and AURKB participate in the JAK2/STAT signaling pathway and contribute to the MPN phenotype.
Assuntos
Apoptose , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Janus Quinase 2/metabolismo , Morfolinas/farmacologia , Mutação , Transtornos Mieloproliferativos/patologia , Purinas/farmacologia , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Aurora Quinase B/genética , Aurora Quinase B/metabolismo , Biomarcadores Tumorais/genética , Ciclo Celular , Proliferação de Células , Humanos , Janus Quinase 2/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Inibidores de Proteínas Quinases , Células Tumorais CultivadasRESUMO
RESUMO Introdução: Os profissionais de enfermagem estão expostos a acidentes com equipamentos perfurocortantes em função do contato contínuo e direto. Objetivos: Apresentar os fatores predisponentes que influenciam na ocorrência do acidente perfurocortante. Métodos: Estudo com abordagem qualitativa, com base na Teoria Fundamentada nos Dados. O referencial teórico deste estudo compreendeu o Interacionismo Simbólico. A investigação alcançou 20 profissionais de enfermagem em um hospital público municipal do estado do Rio de Janeiro. Os dados foram colhidos por meio da entrevista semiestruturada. Foram analisados à luz dos procedimentos de codificação cabíveis ao método, a saber: aberta, axial e seletiva. Resultados: Duas categorias revelam o significado atribuído pelos profissionais acerca do acidente com equipamento perfurocortante: encontrando fatores predisponentes frente à dinâmica do serviço; percebendo a imprudência e imperícia na prática dos profissionais de enfermagem. Conclusões: As dificuldades que marcam a estrutura física, o inadequado dimensionamento de pessoal, o estado físico-psíquico dos trabalhadores de enfermagem e o déficit de recursos materiais contribuem de forma significativa para a ocorrência do acidente com perfurocortante(AU)
RESUMEN Introducción: Los profesionales de enfermería están expuestos a accidentes con equipos punzocortantes en función del contacto continuo y directo con ellos. Objetivo: Presentar los factores predisponentes que influyen en la ocurrencia del accidente punzocortante. Métodos: Estudio con enfoque cualitativo, basado en la Teoría Fundamentada en los Datos. El referencial teórico de este estudio comprendió el Interaccionismo Simbólico. La investigación alcanzó a 20 profesionales de enfermería en un hospital público municipal del estado de Río de Janeiro. Los datos fueron recogidos por medio de una entrevista semiestructurada, y se analizaron a la luz de los procedimientos de codificación adecuados al método, a saber: Abierta, axial y selectiva. Resultados: Dos categorías revelan el significado atribuido por los profesionales al accidente con equipo punzocortante: factores predisponentes frente a la dinámica del servicio y la imprudencia e impericia en la práctica de los profesionales de enfermería. Conclusiones: Las dificultades que marcan la estructura física, el inadecuado dimensionamiento de personal, el estado físico-psíquico de los trabajadores de enfermería y el déficit de recursos materiales contribuyen de forma significativa a que ocurran accidentes con equipos punzocortantes(AU)
ABSTRACT Introduction: Nursing professionals are exposed to accidents with sharp and cutting tools due to continuous and direct contact with them. Objective: To identify the predisposing factors influencing the occurrence of accidents with sharp and cutting tools. Methods: Study with a qualitative approach and based upon the theory grounded on the data. The theoretical referential of this study included the topic of symbolic interactionism. The sample consisted of 20 nursing professionals from a municipal public hospital in the state of Rio de Janeiro. The data were collected through a semi-structured interview and analyzed under the coding procedures appropriate to the method, namely: open, axial and selective. Results: Two categories reveal the meaning attributed by the professionals to the accident with sharp and cutting tools: predisposing factors in the face of the dynamics of the service and the imprudence and inaccuracy in the practice of nursing professionals. Conclusions: The difficulties that mark the physical structure, the inadequate distribution of the staff, the physical-psychic state of the nursing workers and the deficit of material resources contribute significantly to the occurrence of accidents with sharp and cutting tools(AU)
Assuntos
Humanos , Acidentes de Trabalho/prevenção & controle , Causalidade , Profissionais de Enfermagem , Saúde Ocupacional , Recursos em Saúde/normasRESUMO
BACKGROUND: Telomeres are specialized DNA structures that are critical to maintain cell homeostasis and to avoid genomic instability. Epidemiological studies have examined the association between leukocyte telomere length (LTL) and risk of cancers, but the findings remain conflicting. METHODS: Mean LTL was measured by quantitative PCR in 97 patients with head and neck cancer (HNC) and 262 healthy controls. The association between LTL and patients' clinical status, such as smoke, alcoholism, and overall survival, were also evaluated. RESULTS: The age-adjusted LTL was significantly shorter in patients with HNC in comparison to healthy controls (P = .0003). Patients with shortest LTL had an increased risk to develop HNC (P < 0.0001). No significant correlation was observed between LTL and patients' clinical features and personal habits. CONCLUSIONS: Our data support the hypothesis that LTL is a risk factor for HNC. The use of LTL as a biomarker can help physicians to identify high-risk individuals for HNC.
Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Leucócitos/patologia , Encurtamento do Telômero , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de Sobrevida , Homeostase do TelômeroRESUMO
OBJECTIVE: We evaluated the association between cognitive deficits and leukocyte telomere length (LTL) in HIV-1-infected individuals. DESIGN: 73 HIV-1-infected patients undergoing neuropsychological evaluation and 91 healthy controls were included in this study. Fifteen HIV-1 positive patients did not have cognitive disorders whereas 26 had asymptomatic neurocognitive disorder (ANI), 13 presented mild to moderate neurocognitive disorder (MND), and 10 had HIV-associated dementia (HAD). METHODS: DNA from the peripheral blood of HIV-1-infected patients was used for measurement of telomere length by real-time PCR. HIV-1 viral load was determined in blood. RESULTS: LTL decreased with age in healthy controls (p=0.0001). Regardless of the HIV status, age-matched LTL from HIV patients, including those with ANI and MND, were shortened in comparison to the healthy control group (p=0.0073); however, no association was found among the HIV-1-infected individuals with cognitive deficits (p=0.01). In addition, no gender-related association with LTL was observed (p=0.80), smoking, physical exercise, and plasma viral load were not correlated to telomere length (p=0.66). CONCLUSIONS: We concluded that leukocyte telomere length may not be a marker of cellular senescence in individuals with HIV infection and neurocognitive disorders.