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OBJECTIVE: This study aimed to evaluate psychological and emotional violence in relation with sociodemographic characteristics and anxiety and depression symptoms during the COVID-19 pandemic in a sample of Portuguese residents. METHODS: A cross-sectional online study using snowball sampling collected data on demographics, socioeconomic factors, mental health (anxiety and depression symptoms) and couple psychological and emotional violence. The study spanned three months and included 519 individuals aged 18 or above in a relationship since January 2020 or earlier. Data analysis involved descriptive statistics, t-tests, chi-squared tests, logistic regression models (Odds-Ratio [OR] and 95% Confident Interval [CI]), and cluster analysis (K-medoids) using R software (significance threshold of 0.05). RESULTS: The sample was predominantly composed of women (78.8%) with an average age of 36.8 years and 79% holding higher education degrees. Two clusters emerged: Cluster 1 (n = 420) presented fewer psychological and emotional violence victims, while Cluster 2 (n = 99) presented more. Older age (OR = 1.026, 95%CI 1.000-1.052) and depression symptoms (OR = 1.163, 95%CI 1.080-1.252) increased the likelihood of psychological and emotional abuse. Men also had 2.87 times higher odds of being victims (95%CI 0.203-0.599). CONCLUSIONS: The study underscores the need for comprehensive interventions and prevention measures to address psychological and emotional violence by acknowledging it as a public health concern and pushing for interdisciplinary methods.
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Urban parks are not only important for the wellbeing of the human population, but are also widely considered to be potentially important sites for the conservation of biodiversity. However, they may offer risk parasitic infections, such as schistosomiasis and fascioliasis, which are both transmitted by freshwater snails. The present study investigated the occurrence of freshwater gastropods in urban parks of the Brazilian city of Rio de Janeiro, and their possible infection by helminths of medical-veterinary importance. Gastropods were collected from six parks (2021 - 2022) and examined for the presence of larval helminths. In all, 12 gastropod species from different families were collected: Ampullariidae, Assimineidae, Burnupidae, Lymnaeidae, Physidae, Planorbidae, Succineidae, and Thiaridae. The parasitological examination revealed cercaria of three types in five snail species, with the Pleurolophocerca cercariae type in Melanoides tuberculata (the most abundant species), Echinostoma cercariae in Physella acuta and Pomacea maculata, and Virgulate cercariae, in Pomacea sp. and Pomacea maculata. None of the Biomphalaria tenagophila and Pseudosuccinea columella (the most frequent species) specimens were parasitized by Schistosoma mansoni or Fasciola hepatica, respectively. Even so, some parks may represent a considerable potential risk for transmission of both Schistosoma mansoni and Fasciola hepatica, given the presence of these gastropod vectors and the frequent contact of visitors with the waterbodies.
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Água Doce , Gastrópodes , Parques Recreativos , Animais , Brasil/epidemiologia , Água Doce/parasitologia , Gastrópodes/parasitologia , Gastrópodes/classificação , Humanos , Caramujos/parasitologiaRESUMO
Increased synthesis and deposition of collagen (COL) in the extracellular matrix (ECM) of equine endometrium contributes to endometrosis. Toll-like receptors (TLRs) are transmembrane receptors involved in the innate immune response, recognized for their role in antigen recognition and previously associated with equine endometritis. The TLRs not only recognize pathogen-associated molecular patterns but also regulate inflammations, fibrosis and cancer. The aim of this study was to explore the relationship between TLR expression at different stages of Kenney and Doig's (K-D) grading and COL1 expression during the follicular phase of the oestrous cycle. Forty samples of endometrial tissues were collected post-mortem from mares on the follicular phase of the oestrous cycle (10 samples of each K-D category). Relative mRNA transcription of TLR-2, TLR-4 and COL1A2 genes was assessed using qPCR, and COL1 protein expression by Western blot analysis. The COL1A2 transcription increased in category IIB when compared to categories I, IIA and III endometria (p < .01). The relative protein abundance of COL1 showed no significant differences between endometrial categories (p > .05). As for the TLRs mRNA transcription, TLR-2/-4 transcripts increased in IIA when compared to the other K-D endometria categories (p < .05). Our findings suggest that TLRs may be involved in the initiation of the endometrial inflammatory response. Additional studies are needed to explore TLRs' potential role as diagnostic markers for monitoring inflammation progression and fibrosis development, as well as their involvement in the mechanisms underlying fibrotic pathways.
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Endométrio , Doenças dos Cavalos , RNA Mensageiro , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Animais , Cavalos , Feminino , Endométrio/metabolismo , Endométrio/patologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Doenças dos Cavalos/genética , Doenças dos Cavalos/metabolismo , Doenças dos Cavalos/patologia , Fase Folicular , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Endometrite/veterinária , Endometrite/metabolismo , Endometrite/patologia , Endometrite/genéticaRESUMO
BACKGROUND: Successful management of canine atopic dermatitis (cAD) is challenging and effective pet owner education is crucial to successful outcomes. However, there are limited proven educational strategies in this area. Our goal was to create an effective and engaging educational tool for owners of dogs with cAD. HYPOTHESIS: Video-based education efficacy would be comparable to traditional verbal delivery. Secondary objectives included assessing client perception of the intervention, and determining if there were clinical benefits for the dogs and improved client adherence to treatment. SUBJECTS: Twenty-nine dogs with cAD and their owners were recruited from a teaching hospital of a European veterinary medicine faculty. MATERIALS AND METHODS: In this 8 week, prospective, randomised controlled study, clients in the control group (CG, n = 13) received verbal education and those in the intervention group (IG, n = 16) watched a video. Client knowledge was assessed at Day (D)0 and D56. Treatment adherence and perceived utility and appeal ratings were measured at D56. Clinical progress was assessed at D0 and D56 using CADESI-04 and PVAS10. RESULTS: The differences found in the means of cAD knowledge score, clinical outcomes, utility and appeal ratings and owners' adherence score between groups were not statistically significant. A significant association between the outcome and the intervention group concerning education success [CG, six of 13 (46.15%); IG, 15 of 16 (93.75%)] was found (p = 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Video-based instructions positively impacted owners' education and demonstrated their potential as a valuable tool. The authors believe that video-based education could be a time-efficient alternative for initial cAD education in veterinary clinics.
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Dermatite Atópica , Doenças do Cão , Cães , Animais , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/veterinária , Estudos Prospectivos , Doenças do Cão/tratamento farmacológicoRESUMO
The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (Mpro) using DCM compounds as ligands. Multiple receptors and two different docking scoring functions were employed to identify the best molecular docking poses. The selected structures were subjected to extensive conventional and Gaussian accelerated molecular dynamics. From the results, four compounds with the best molecular behavior and binding energy were selected for experimental testing, one of which presented inhibitory activity with a Ki value of 48 ± 5 µM. Through virtual screening, we identified a significant starting point for drug development, shedding new light on DCM compounds.
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Antivirais , Proteases 3C de Coronavírus , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Antivirais/farmacologia , Antivirais/química , Humanos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , COVID-19/virologia , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Ligação Proteica , LigantesRESUMO
LRP1B remains one of the most altered genes in cancer, although its relevance in cancer biology is still unclear. Recent advances in gene editing techniques, particularly CRISPR/Cas9 systems, offer new opportunities to evaluate the function of large genes, such as LRP1B. Using a dual sgRNA CRISPR/Cas9 gene editing approach, this study aimed to assess the impact of disrupting LRP1B in glioblastoma cell biology. Four sgRNAs were designed for the dual targeting of two LRP1B exons (1 and 85). The U87 glioblastoma (GB) cell line was transfected with CRISPR/Cas9 PX459 vectors. To assess LRP1B-gene-induced alterations and expression, PCR, Sanger DNA sequencing, and qRT-PCR were carried out. Three clones (clones B9, E6, and H7) were further evaluated. All clones presented altered cellular morphology, increased cellular and nuclear size, and changes in ploidy. Two clones (E6 and H7) showed a significant decrease in cell growth, both in vitro and in the in vivo CAM assay. Proteomic analysis of the clones' secretome identified differentially expressed proteins that had not been previously associated with LRP1B alterations. This study demonstrates that the dual sgRNA CRISPR/Cas9 strategy can effectively edit LRP1B in GB cells, providing new insights into the impact of LRP1B deletions in GBM biology.
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Sistemas CRISPR-Cas , Edição de Genes , Glioblastoma , Humanos , Edição de Genes/métodos , Glioblastoma/genética , Proteômica , Receptores de LDL/genética , RNA Guia de Sistemas CRISPR-CasRESUMO
To respond to the consequences felt by the COVID-19 pandemic, a community-led intervention was developed by the Portuguese national Movement of Sex Workers. With this exploratory study, we aimed to document their work and analyze their perceptions of this impact. To do so, we interviewed them individually, between May and August of 2020. Additionally, we analysed an Excel Sheet that contained the needs assessment and the support provided by the Movement. The content analysis of both suggests that the impact of the pandemic might have been exacerbated by the social inequalities caused by the prostitution stigma and characteristics such as gender, migration status, race, and socioeconomic status. This study calls for the inclusion of sex workers' voices in the design of policies and responses related to the commerce of sex. The consolidation of a Portuguese Movement of Sex Workers is also noted.
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OBJECTIVE: There is still a lack of health indicators for monitoring and evaluating health planning at the local level. In Portugal, local health plans (LHP) include a prioritized set of health priorities, which should be monitored and evaluated. This study is an example of a low-resource method to identify and reuse indicators for LHP monitoring and evaluation already collected for other purposes. DESIGN AND SAMPLE: A modified Delphi consensus method was applied, with three rounds of email rating questionnaires and a final meeting, between January 2018 and January 2019. The Delphi panel consisted of eight members from the Planning and Administration Group of the Espinho/Gaia Local Public Health Unit. MEASUREMENTS: Panelists were asked to assess the indicators' validity for monitoring diseases/determinants from a pre-selected list of potential binomials between 140 PHC indicators and 15 diseases/determinants. RESULTS: After four rounds, there was consensus in considering 141 binomials (34.0%) as appropriate, diabetes mellitus being the disease with more appropriate indicators. CONCLUSION: This study portrays the applicability of a commonly used, easy and low-resource method in a Portuguese Local Public Health Unit to select and reuse primary health care indicators for LHP monitoring and evaluation.
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Planejamento em Saúde , Indicadores de Qualidade em Assistência à Saúde , Consenso , Técnica Delphi , Humanos , Inquéritos e QuestionáriosRESUMO
Chaperone Mediated Autophagy (CMA) is a selective autophagy pathway deregulated in many cancers. In this study, we were aiming at understanding the importance of CMA in breast cancer. To this end, we examined the expression of the CMA markers HSP8 and LAMP2A in different breast cancer cell lines and found a wide range of LAMP2A expression levels across the cell lines analyzed. Next, we applied a specific immunohistochemical staining protocol to a tissue microarray derived from a cohort of 365 breast cancer patients. Therefore, we were able to find a correlation of high LAMP2A but not HSPA8 (HSC70) with worse disease free survival in patients with HER2 negative tumors (p = 0.026) which was independent prognostic parameter from pT category, pN category and grading in a multivariate model (HR = 1.889; 95% CI = 1.039-3.421; p = 0.037). In line, low LAMP2A levels decrease proliferation of the breast cancer cell lines T47D and MCF-7 in vitro. Our data suggest that LAMP2A supports a more severe breast cancer cell phenotype.
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Neoplasias da Mama/metabolismo , Técnicas de Cultura de Células/métodos , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Autofagia Mediada por Chaperonas/genética , Intervalo Livre de Doença , Feminino , Humanos , Proteína 2 de Membrana Associada ao Lisossomo/genética , Células MCF-7 , Pessoa de Meia-Idade , Interferência de RNARESUMO
Background The high volume of data in digital breast tomosynthesis (DBT) and the lack of agreement on how to best implement it in screening programs makes its use challenging. Purpose To compare radiologist performance when reading single-view wide-angle DBT images with and without an artificial intelligence (AI) system for decision and navigation support. Materials and Methods A retrospective observer study was performed with bilateral mediolateral oblique examinations and corresponding synthetic two-dimensional images acquired between June 2016 and February 2018 with a wide-angle DBT system. Fourteen breast screening radiologists interpreted 190 DBT examinations (90 normal, 26 with benign findings, and 74 with malignant findings), with the reference standard being verified by using histopathologic analysis or at least 1 year of follow-up. Reading was performed in two sessions, separated by at least 4 weeks, with a random mix of examinations being read with and without AI decision and navigation support. Forced Breast Imaging Reporting and Data System (categories 1-5) and level of suspicion (1-100) scores were given per breast by each reader. The area under the receiver operating characteristic curve (AUC) and the sensitivity and specificity were compared between conditions by using the public-domain iMRMC software. The average reading times were compared by using the Wilcoxon signed rank test. Results The 190 women had a median age of 54 years (range, 48-63 years). The examination-based reader-averaged AUC was higher when interpreting results with AI support than when reading unaided (0.88 [95% CI: 0.84, 0.92] vs 0.85 [95% CI: 0.80, 0.89], respectively; P = .01). The average sensitivity increased with AI support (64 of 74, 86% [95% CI: 80%, 92%] vs 60 of 74, 81% [95% CI: 74%, 88%]; P = .006), whereas no differences in the specificity (85 of 116, 73.3% [95% CI: 65%, 81%] vs 83 of 116, 71.6% [95% CI: 65%, 78%]; P = .48) or reading time (48 seconds vs 45 seconds; P = .35) were detected. Conclusion Using a single-view digital breast tomosynthesis (DBT) and artificial intelligence setup could allow for a more effective screening program with higher performance, especially in terms of an increase in cancers detected, than using single-view DBT alone. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Chan and Helvie in this issue.
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Inteligência Artificial , Neoplasias da Mama/diagnóstico por imagem , Competência Clínica , Técnicas de Apoio para a Decisão , Interpretação de Imagem Assistida por Computador/métodos , Mamografia/métodos , Aprendizado Profundo , Detecção Precoce de Câncer , Feminino , Humanos , Programas de Rastreamento , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
Neisseria meningitidis is a major cause of meningitis and septicaemia. A MenB vaccine (4CMenB) was licensed by the European Medicines Agency in January 2013. Here we describe the blood transcriptome and proteome following infant immunisations with or without concomitant 4CMenB, to gain insight into the molecular mechanisms underlying post-vaccination reactogenicity and immunogenicity. Infants were randomised to receive control immunisations (PCV13 and DTaP-IPV-Hib) with or without 4CMenB at 2 and 4 months of age. Blood gene expression and plasma proteins were measured prior to, then 4 h, 24 h, 3 days or 7 days post-vaccination. 4CMenB vaccination was associated with increased expression of ENTPD7 and increased concentrations of 4 plasma proteins: CRP, G-CSF, IL-1RA and IL-6. Post-vaccination fever was associated with increased expression of SELL, involved in neutrophil recruitment. A murine model dissecting the vaccine components found the concomitant regimen to be associated with increased gene perturbation compared with 4CMenB vaccine alone with enhancement of pathways such as interleukin-3, -5 and GM-CSF signalling. Finally, we present transcriptomic profiles predictive of immunological and febrile responses following 4CMenB vaccine.
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Febre/genética , Imunidade/genética , Vacinas Meningocócicas/imunologia , Animais , Análise Química do Sangue , Vacina contra Difteria, Tétano e Coqueluche/efeitos adversos , Vacina contra Difteria, Tétano e Coqueluche/imunologia , Feminino , Febre/sangue , Febre/epidemiologia , Febre/etiologia , Perfilação da Expressão Gênica , Vacinas Anti-Haemophilus/efeitos adversos , Vacinas Anti-Haemophilus/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Incidência , Lactente , Masculino , Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Vacinas Pneumocócicas/efeitos adversos , Vacinas Pneumocócicas/imunologia , Vacina Antipólio de Vírus Inativado/efeitos adversos , Vacina Antipólio de Vírus Inativado/imunologia , Proteoma/análise , Transcriptoma , Vacinação/efeitos adversos , Vacinas Conjugadas/efeitos adversos , Vacinas Conjugadas/imunologiaRESUMO
BACKGROUND: The use of psychoactive substances frequently starts at a younger age than adulthood. Considering the perspective of young people, this retrospective study tried to provide them with a role in identifying their own needs regarding drug use and interventions focused on it; the obstacles in accessing both general health and harm reduction services; the changes needed for a more effective, congruent and empowering response to the use of psychoactive substances before the age of 18. METHODS: The study was divided into two parts having both parts a qualitative focus. In the first part of the study, an online questionnaire was sent to all harm reduction teams and two focus groups were carried out with eight harm reduction professionals and six people who use(d) drugs. The second part used an online questionnaire applied to 143 participants aged between the age of 18 and 25 complemented by two semi-structured interviews. RESULTS: The need for education about psychoactive substances, namely in the educational context; the lack of information about available services; and the need for confidentiality were the most mentioned issues by the young people. Also, the informal network played a significant role in the participants relationship with psychoactive substances. CONCLUSIONS: The lack of information was the most highlighted obstacle. Also, there is a confluence of various vulnerabilities such as being under 18, using drugs and the different social situations that they live in. To improve policy and practice regarding drug use among young people, harm reduction interventions must be scaled-up as well as intentionally driven to empower youth to deal with. School environment was chosen by participants as one of the elected environments to implement harm reduction services.
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Preparações Farmacêuticas , Transtornos Relacionados ao Uso de Substâncias , Adolescente , Adulto , Idoso , Redução do Dano , Humanos , Estudos Retrospectivos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , TabuRESUMO
The high plasticity of cancer stem-like cells (CSCs) allows them to differentiate and proliferate, specifically when xenotransplanted subcutaneously into immunocompromised mice. CSCs are highly tumorigenic, even when inoculated in small numbers. Thus, in vivo limiting dilution assays (LDA) in mice are the current gold standard method to evaluate CSC enrichment and activity. The chick embryo chorioallantoic membrane (CAM) is a low cost, naturally immune-incompetent and reproducible model widely used to evaluate the spontaneous growth of human tumor cells. Here, we established a CAM-LDA assay able to rapidly reproduce tumor specificities-in particular, the ability of the small population of CSCs to form tumors. We used a panel of organotropic metastatic breast cancer cells, which show an enrichment in a stem cell gene signature, enhanced CD44+/CD24-/low cell surface expression and increased mammosphere-forming efficiency (MFE). The size of CAM-xenografted tumors correlate with the number of inoculated cancer cells, following mice xenograft growth pattern. CAM and mice tumors are histologically comparable, displaying both breast CSC markers CD44 and CD49f. Therefore, we propose a new tool for studying CSC prevalence and function-the chick CAM-LDA-a model with easy handling, accessibility, rapid growth and the absence of ethical and regulatory constraints.
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Neoplasias da Mama/patologia , Membrana Corioalantoide , Células-Tronco Neoplásicas/patologia , Animais , Apoptose , Neoplasias da Mama/metabolismo , Movimento Celular , Proliferação de Células , Embrião de Galinha , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Coded data are the basis of information systems in all countries that rely on Diagnosis Related Groups in order to reimburse/finance hospitals, including both administrative and clinical data. To identify the problems and barriers that affect the quality of the coded data is paramount to improve data quality as well as to enhance its usability and outcomes. This study aims to explore problems and possible solutions associated with the clinical coding process. Problems were identified according to the perspective of ten medical coders, as the result of four focus groups sessions. This convenience sample was sourced from four public hospitals in Portugal. Questions relating to problems with the coding process were developed from the literature and authors' expertise. Focus groups sessions were taped, transcribed and analyzed to elicit themes. Variability in the documents used for coding, illegibility of hand writing when coding on paper, increase of errors due to an extra actor in the coding process when transcribed from paper, difficulties in the diagnoses' coding, coding delay and unavailability of resources and tools designed to help coders, were some of the problems identified. Some problems were identified and solutions such as the standardization of the documents used for coding an episode, the adoption of the electronic coding, the development of tools to help coding and audits, and the recognition of the importance of coding by the management were described as relevant factors for the improvement of the quality of data.
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Codificação Clínica/normas , Grupos Diagnósticos Relacionados/classificação , Controle de Formulários e Registros/normas , Prontuários Médicos/normas , Competência Profissional/normas , Grupos Focais , Humanos , Classificação Internacional de Doenças , PortugalAssuntos
Dermatite Atópica , Animais , Cães , Dermatite Atópica/terapia , Imunoterapia , Testes CutâneosRESUMO
BACKGROUND: Gastric cancer with lymphoid stroma (GCLS) is characterized by prominent stromal infiltration of T-lymphocytes. The aim of this study was to investigate GCLS biology through analysis of clinicopathological features, EBV infection, microsatellite instability (MSI), immune gene-expression profiling and PD-L1 status in neoplastic cells and tumor immune microenvironment. METHODS: Twenty-four GCLSs were analyzed by RNA in situ hybridization for EBV (EBER), PCR/fragment analysis for MSI, immunohistochemistry (PD-L1, cytokeratin, CD3, CD8), co-immunofluorescence (CK/PD-L1, CD68/PD-L1), NanoString gene-expression assay for immune-related genes and PD-L1 copy number alterations. CD3+ and CD8+ T-cell densities were calculated by digital analysis. Fifty-four non-GCLSs were used as control group. RESULTS: GCLSs displayed distinctive clinicopathological features, such as lower pTNM stage (p = 0.02) and better overall survival (p = 0.01). EBV+ or MSI-high phenotype was found in 66.7 and 16.7% cases, respectively. GCLSs harbored a cytotoxic T-cell-inflamed profile, particularly at the invasive front of tumors (p < 0.01) and in EBV+ cases (p = 0.01). EBV+ GCLSs, when compared to EBV- GCLSs, showed higher mRNA expression of genes related to Th1/cytotoxic and immunosuppressive biomarkers. PD-L1 protein expression, observed in neoplastic and immune stromal cells (33.3 and 91.7%, respectively), and PD-L1 amplification (18.8%) were restricted to EBV+/MSI-high tumors and correlated with high values of PD-L1 mRNA expression. CONCLUSIONS: This study shows that GCLS has a distinctive clinico-pathological and molecular profile. Furthermore, through an in-depth study of tumor immune microenvironment-by digital analysis and mRNA expression profiling-it highlights the role of EBV infection in promoting an inflamed tumor microenvironment, with putative therapeutic implications.
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Linfócitos do Interstício Tumoral/imunologia , Neoplasias Gástricas/patologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Antígeno B7-H1/biossíntese , Infecções por Vírus Epstein-Barr/complicações , Feminino , Herpesvirus Humano 4 , Humanos , Imunofenotipagem , Inflamação/genética , Inflamação/imunologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Transcriptoma , Microambiente Tumoral/genéticaRESUMO
The prognosis of the association between Breast Cancer (BC) and Meningioma (M) is unknown. To evaluate the survival impact of tumor exposure sequence in patients with both tumors. Patients were divided in groups according to the tumors sequence: BC before M (group 1), synchronous BC + M (group 2) and BC after M (group 3). The SEER database was used. Demographics, meningioma and breast cancer variables were analyzed. The primary outcome was oncological survival. A total of 1715 patients were included (median follow-up:84 months). Group 2 had the shortest survival (median:32 months) and group 1 the longest (median:110 months). On the unadjusted analysis, group 2 had the shortest survival (HR:3.13, 95% CI 1.62-6.04) and adjusted analysis confirmed this finding (HR 3.11, 95% CI 1.58-6.19), with no statistical difference between the metachronous tumors groups. Increasing age (HR:1.13, 95% CI 1.11-1.15, p < 0.005) and grade III meningioma (HR:4.51, 95% CI 1.90-10.69, p < 0.005) were related with lower survival. Meningioma treatment had no influence on the survival (p > 0.05). The association between surgery and radiotherapy in BC treatment improved the outcome (HR 0.37, 95% CI 0.23-0.93, p < 0.05). Grade III meningioma and receptor hormonal status influenced synchronous tumors (p < 0.05) but had no influence on metachronous tumors survival (p > 0.05) on stratified analysis. Synchronous tumors were associated with lower survival. Increasing age had a negative influence on patient survival. Although surgery and radiotherapy for breast cancer had a positive influence in the outcome, meningioma treatment was not related with survival. Grade III meningioma and hormonal receptor status only influenced synchronous tumors patient survival.
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Neoplasias da Mama Masculina/mortalidade , Neoplasias da Mama/mortalidade , Neoplasias Meníngeas/mortalidade , Meningioma/mortalidade , Idoso , Neoplasias da Mama/complicações , Neoplasias da Mama Masculina/química , Neoplasias da Mama Masculina/complicações , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Neoplasias Meníngeas/complicações , Meningioma/complicações , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/mortalidade , Segunda Neoplasia Primária/mortalidade , Estudos RetrospectivosRESUMO
Deregulation of tRNAs, aminoacyl-tRNA synthetases and tRNA modifying enzymes are common in cancer, raising the hypothesis that protein synthesis efficiency and accuracy (mistranslation) are compromised in tumors. We show here that human colon tumors and xenograft tumors produced in mice by two epithelial cancer cell lines mistranslate 2- to 4-fold more frequently than normal tissue. To clarify if protein mistranslation plays a role in tumor biology, we expressed mutant Ser-tRNAs that misincorporate Ser-at-Ala (frequent error) and Ser-at-Leu (infrequent error) in NIH3T3 cells and investigated how they responded to the proteome instability generated by the amino acid misincorporations. There was high tolerance to both misreading tRNAs, but the Ser-to-Ala misreading tRNA was a more potent inducer of cell transformation, stimulated angiogenesis and produced faster growing tumors in mice than the Ser-to-Leu misincorporating tRNA. Upregulation of the Akt pathway and the UPR were also observed. Most surprisingly, the relative expression of both misreading tRNAs increased during tumor growth, suggesting that protein mistranslation is advantageous in cancer contexts. These data highlight new features of protein synthesis deregulation in tumor biology.
Assuntos
Carcinoma , Códon , Neoplasias do Colo , Proteínas de Neoplasias , Proteoma , RNA Neoplásico , RNA de Transferência , Animais , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Embrião de Galinha , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Camundongos , Células NIH 3T3 , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteoma/biossíntese , Proteoma/genética , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , RNA de Transferência/genética , RNA de Transferência/metabolismoRESUMO
Epithelial-cadherin (Ecad) deregulation affects cell-cell adhesion and results in increased invasiveness of distinct human carcinomas. In gastric cancer, loss of Ecad expression is a common event and is associated with disease aggressiveness and poor prognosis. However, the molecular mechanisms underlying the invasive process associated to Ecad dysfunction are far from understood. We hypothesized that deregulation of cell-matrix interactions could play an important role during this process. Thus, we focussed on LM-332, which is a major matrix component, and in Ecad/LM-332 crosstalk in the process of Ecad-dependent invasion. To verify whether matrix deregulation was triggered by Ecad loss, we used the Drosophila model. To dissect the key molecules involved and unveil their functional significance, we used gastric cancer cell lines. The relevance of this relationship was then confirmed in human primary tumours. In vivo, Ecad knockdown induced apoptosis; nonetheless, at the invasive front, cells ectopically expressed Laminin A and ßPS integrin. In vitro, we demonstrated that, in two different gastric cancer cell models, Ecad-defective cells overexpressed Laminin γ2 (LM-γ2), ß1 and ß4 integrin, when compared with Ecad-competent ones. We showed that LM-γ2 silencing impaired invasion and enhanced cell death, most likely via pSrc and pAkt reduction, and JNK activation. In human gastric carcinomas, we found a concomitant decrease in Ecad and increase in LM-γ2. This is the ï¬rst evidence that ectopic Laminin expression depends on Ecad loss and allows Ecad-dysfunctional cells to survive and invade. This opens new avenues for using LM-γ2 signalling regulators as molecular targets to impair gastric cancer progression.