Adenosine Increases the Immunosuppressive Capacity of Cervical Cancer Cells by Increasing PD-L1 Expression and TGF-ß Production through Its Interaction with A2AR/A2BR.

The present study provides evidence showing that adenosine (Ado) increases the expression of programmed death ligand 1 (PD-L1) in cervical cancer (CeCa) cells by interacting with A2AR/A2BR and that TGF-ß1 acts in an autocrine manner to induce PD-L1 expression, enhancing the immunosuppressive effects of CeCa cells on activated T lymphocytes (ATLs) and CD8+ cytotoxic T lymphocytes (CTLs) specific for antigenic peptides derived from E6 and E7 proteins of HPV-16. Interestingly, the addition of the antagonists ZM241385 and MRS1754, which are specific for A2AR and A2BR, respectively, or SB-505124, which is a selective TGF-ß1 receptor inhibitor, to CeCa cell cultures significantly inhibited PD-L1 expression. In addition, supernatants from CeCa cells that were treated with Ado (CeCa-Ado Sup) increased the expression of PD-1, TGF-ß1, and IL-10 and decreased the expression of IFN-γ in ATLs. Interestingly, the addition of an anti-TGF-ß neutralizing antibody strongly reversed the effect of CeCa-Ado Sup on PD-1 expression in ATLs. These results strongly suggest the presence of a feedback mechanism that involves the adenosinergic pathway, the production of TGF-ß1, and the upregulation of PD-L1 expression in CeCa cells that suppresses the antitumor response of CTLs. The findings of this study suggest that this pathway may be clinically important and may be a therapeutic target.

Who and Where are the University of São Paulo Medical School Graduates?

OBJECTIVE: To evaluate the impact of a complex-care-based medical school in the context of the Brazilian health care system on students' career choices. METHODS: This was a retrospective cross-sectional study based on medical regulatory organization records. It included records for 7,419 physicians who graduated from FMUSP. Geographic data were analyzed using Kernel maps, and the statistical analysis was performed with SPSS® version 24.0. A p-value less than 0.05 was considered significant. RESULTS: Of the 7,419 physicians, 68.6% (95% CI 67.5-69.7) were male, and 20.7% (95% CI 19.8%-21.7%) had no medical specialty, compared to 46.4% nationwide. Internal medicine and surgery-based specialties were more popular, accounting for 39.4% (95% CI 38.3%-40.5%) and 16.8% (95% CI 15.5%-17.6%) of our study group, compared to the Brazilian averages of 25.9% and 13.5%. Our graduates also had a higher probability of staying in São Paulo City, especially when born outside the city. CONCLUSION: We believe that FMUSP remains an interesting model for studying the impact of a highly specialized center on the education and career choices of medical students.

Who and Where are the University of São Paulo Medical School Graduates?

OBJECTIVE: To evaluate the impact of a complex-care-based medical school in the context of the Brazilian health care system on students' career choices. METHODS: This was a retrospective cross-sectional study based on medical regulatory organization records. It included records for 7,419 physicians who graduated from FMUSP. Geographic data were analyzed using Kernel maps, and the statistical analysis was performed with SPSS® version 24.0. A p-value less than 0.05 was considered significant. RESULTS: Of the 7,419 physicians, 68.6% (95% CI 67.5-69.7) were male, and 20.7% (95% CI 19.8%-21.7%) had no medical specialty, compared to 46.4% nationwide. Internal medicine and surgery-based specialties were more popular, accounting for 39.4% (95% CI 38.3%-40.5%) and 16.8% (95% CI 15.5%-17.6%) of our study group, compared to the Brazilian averages of 25.9% and 13.5%. Our graduates also had a higher probability of staying in São Paulo City, especially when born outside the city. CONCLUSION: We believe that FMUSP remains an interesting model for studying the impact of a highly specialized center on the education and career choices of medical students.

Perfil epidemiológico dos utentes consumidores de cuidados continuados do distrito de Vila Real / Epidemiological profile of users of long-term care in the district of Vila Real

Em Portugal, tal como na Europa, as Unidades de Cuidados Continuados foram criadas pelo fato de Portugal apresentar uma enorme prevalência de população idosa, pela mudança de perfil das patologias e das famílias e essencialmente pela situação de dependência e fragilidade com alta necessidade de apoio social e familiar. Objetivo: Identificar/analisar as caraterísticas sociais, demográficas, familiares e clínicas dos utentes consumidores de cuidados continuados no distrito de Vila Real, com o intuito de adequação e contribuição de cuidados e promoção da satisfação das necessidades individuais. Metodologia: É um estudo transversal e retrospetivo de metodologia quantitativa. A amostra deste estudo é constituída por 1 505 utentes. A colheita de dados foi realizada pela investigadora, entre julho e dezembro de 2014, nas Unidades de Murça, Peso da Régua, Sabrosa e Ribeira de Pena, através de uma Checklist, baseada no programa Gestcare para o Cuidados Continuados Integrados. Foram respeitados os princípios da Declaração de Helsínquia e obtida autorização das Instituições para realização do estudo. Resultados: A amostra é constituída, maioritariamente, 51,9%, por pessoas do sexo do sexo feminino. Em relação às Habilitações Literárias, os utentes apresentam baixa escolaridade, 37% não têm habilitações. Relativamente ao Local de Residência, a maioria dos inquiridos é proveniente de concelhos do distrito de Vila Real, em particular, Vila Real (11%) e Chaves (12%). O Cuidador Principal existe em 82,5% dos utentes e o seu grau de parentesco, que mais prevalece, é o cônjuge. Pela aplicação do teste do qui-quadrado verificou-se que o Tempo de Internamento (p<0,001), o Diagnóstico Inicial (p<0,001), a Proveniência dos utentes para as UCC (p<0,001), Origem Geográfica (p<0,001) e Motivo de saída (p<0,001) estão significativamente associados à Unidade de Cuidados Continuados. Conclusões: Este estudo pretende deixar contributos para o avanço do conhecimento científico na área dos cuidados continuados através da identificação das caraterísticas dos utentes consumidores dos cuidados continuados. Os resultados demonstraram que a maior parte dos utentes tem patologias do sistema circulatório, teve alta das Unidades por atingir os objetivos e o seu principal cuidador é o cônjuge. Estes resultados dão suporte a possíveis propostas para os cuidados continuados, nomeadamente na adequação e promoção dos cuidados para a satisfação das necessidades individuais.

In Portugal, as in Europe, the Continuing Care Units have been created by the fact that Portugal has a huge prevalence of elderly population, the changing profile of diseases and their families and essentially the situation of dependence and fragility with high need for support social and family. Objective: Identify/analyze the social characteristics, demographic, family and clinical consumers continuing care clients in the Vila Real district, with the suitability of purpose and contribution of care and promoting the satisfaction of individual needs. Methodology: It is a cross-sectional and retrospective study of quantitative methodology. The sample consists of 1505 users. Data collection was performed by the researcher, between July and December 2014, in Murça Units Weight Ruler, Sabrosa and Ribeira de Pena, through a checklist, based on Gestcare program for the Continuous Care. The principles of the Declaration of Helsinki and obtaining the approval of institutions to conduct the study were respected. Results: In the sample 51.9% are female. In the Qualifications, the user has a low educational level, because the bulk sample, 37% have no qualifications. In the Place of Residence most respondents from the municipalities of Vila Real district, in particular, Vila Real (11%) and Chaves (12%). The Primary Caregiver exists in 82.5% of patients and their degree of kinship that prevails is the most spouses. By applying the chi-square test was found that the internment time (p <0.001), Initial Diagnosis (p <0.001), the Provenance of users for UCC (p <0.001), Provenance Zone (p <0.001) and output Reason (p <0.001) were significantly associated with the Continuing Care Unit. Conclusions: Of users of the sample, most are Married / de facto union. Regarding Educational Qualifications, 37% have no qualifications. The Professional Status of the majority of users is reformed with 89.4%. The Home Diagnostics, more than 50% of the users hold pathologies associated with the circulatory system, under veins and lymphatic. Most had high Units for achieving the goals.

Long-term adaptation of Saccharomyces cerevisiae to the burden of recombinant insulin production.

High-level production of heterologous proteins is likely to impose a metabolic burden on the host cell and can thus affect various aspects of cellular physiology. A data-driven approach was applied to study the secretory production of a human insulin analog precursor (IAP) in Saccharomyces cerevisiae during prolonged cultivation (80 generations) in glucose-limited aerobic chemostat cultures. Physiological characterization of the recombinant cells involved a comparison with cultures of a congenic reference strain that did not produce IAP, and time-course analysis of both strains aimed at identifying the metabolic adaptation of the cells towards the burden of IAP production. All cultures were examined at high cell density conditions (30 g/L dry weight) to increase the industrial relevance of the results. The burden of heterologous protein production in the recombinant strain was explored by global transcriptome analysis and targeted metabolome analysis, including the analysis of intracellular amino acid pools, glycolytic metabolites, and TCA intermediates. The cellular re-arrangements towards IAP production were categorized in direct responses, for example, enhanced metabolism of amino acids as precursors for the formation of IAP, as well as indirect responses, for example, changes in the central carbon metabolism. As part of the long-term adaptation, a metabolic re-modeling of the IAP-expressing strain was observed, indicating an augmented negative selection pressure on glycolytic overcapacity, and the emergence of mitochondrial dysfunction. The evoked metabolic re-modeling of the cells led to less optimal conditions with respect to the expression and processing of the target protein and thus decreased the cellular expression capacity for the secretory production of IAP during prolonged cultivation.