Polyoxazoline-Based Nanovaccine Synergizes with Tumor-Associated Macrophage Targeting and Anti-PD-1 Immunotherapy against Solid Tumors

Nanovaccines; Tumor immune microenvironment; Tumor-associated macrophagesNanovacunes; Microambient immune tumoral; Macròfags associats al tumorNanovacunas; Microambiente inmune tumoral; Macrófagos asociados al tumorImmune checkpoint blockade reaches remarkable clinical responses. However, even in the most favorable cases, half of these patients do not benefit from these therapies in the long term. It is hypothesized that the activation of host immunity by co-delivering peptide antigens, adjuvants, and regulators of the transforming growth factor (TGF)-β expression using a polyoxazoline (POx)-poly(lactic-co-glycolic) acid (PLGA) nanovaccine, while modulating the tumor-associated macrophages (TAM) function within the tumor microenvironment (TME) and blocking the anti-programmed cell death protein 1 (PD-1) can constitute an alternative approach for cancer immunotherapy. POx-Mannose (Man) nanovaccines generate antigen-specific T-cell responses that control tumor growth to a higher extent than poly(ethylene glycol) (PEG)-Man nanovaccines. This anti-tumor effect induced by the POx-Man nanovaccines is mediated by a CD8+-T cell-dependent mechanism, in contrast to the PEG-Man nanovaccines. POx-Man nanovaccine combines with pexidartinib, a modulator of the TAM function, restricts the MC38 tumor growth, and synergizes with PD-1 blockade, controlling MC38 and CT26 tumor growth and survival. This data is further validated in the highly aggressive and poorly immunogenic B16F10 melanoma mouse model. Therefore, the synergistic anti-tumor effect induced by the combination of nanovaccines with the inhibition of both TAM- and PD-1-inducing immunosuppression, holds great potential for improving immunotherapy outcomes in solid cancer patients.Funding: R.S.-F. and H.F.F. thank the following funding agencies for their generous support: The project that gave rise to these results has received funding from the “la Caixa” Foundation under the grant agreements LCF/PR/HR22/52420016, LCF/PR/HR19/52160021, and LCF/TR/CD20/52700005 (R.S.-F. and H.F.F). H.F.F thanks the generous financial support from The Fundação para a Ciência e Tecnologia-Ministério da Ciência, Tecnologia e Ensino Superior (FCT-MCTES) (EXPL/MED-QUI/1316/2021, PTDC/BTM-SAL/4350/2021, UTAP-EXPL/NPN/0041/2021, UIDB/04138/2020, UIDP/04138/2020). R.S.-F. thanks to the European Research Council (ERC) PoC Grant Agreement no. 101113390 and ERC Advanced Grant Agreement no. 835227, the Israel Science Foundation (1969/18), the Melanoma Research Alliance (Established Investigator Award no. 615808 to R.S.-F.), the Israel Cancer Research Fund (ICRF) Professorship award (no. PROF-18-682), the Morris Kahn Foundation. B.C. is supported by the FCT-MCTES (Ph.D. Fellowship SFRH/BD/131969/2017). The authors also acknowledge the NIH Tetramer Core Facility for the provision of Adpgk tetramers, in addition to the Comparative Pathology Unit of IMM and the Histopathology Facility of IGC for supporting the histopathological study

Panorama das publicações em saúde mental no contexto da pandemia por COVID-19: scoping review

The aim was to map the scientific literature on the mental health of the population in the context of the COVID-19 pandemic. Scoping review carried out by searching six electronic databases, electronic search engines and through the references of selected articles. Complete articles were included, in Portuguese, English or Spanish on mental health in the context of the COVID-19 pandemic. Articles that were published more than 1 year ago were excluded because there was no relationship with the beginning of the pandemic. 48 studies published in the year 2020 (100%) were mapped, 45 (93.75%) in English, 27 (56.25%) were from China; 30 (62.5%) were cross-sectional studies; 30 (62.5%) had evidence level IV. The data were organized into three themes: Mental health of the general population and vulnerable groups related to the impacts of the pandemic; Mental health of health professionals; Mental health strategies in the face of the COVID-19 pandemic. Knowledge of the mental health impacts of the population during the COVID-19 pandemic requires strategies for coping during and after the pandemic. Collaborative, multicenter, and interdisciplinary research is suggested to deepen the understanding of the health implications of the current crisis.Objetivou-se mapear a literatura científica sobre a saúde mental da população no contexto da pandemia de COVID-19. Scoping review realizada através da busca em seis bases de dados eletrônicas, buscadores eletrônicos e por meio das referências dos artigos selecionados. Foi incluído artigos completos, nos idiomas português, inglês ou espanhol sobre saúde mental no contexto da pandemia de COVID-19. Excluiu-se artigos com publicação há mais de 1 ano por não haver relação com o início da pandemia. Mapeou-se 48 estudos publicados no ano de 2020 (100%), 45 (93,75%) em inglês, 27 (56,25%) foi proveniente da China; 30 (62,5%) eram estudos transversais; 30 (62,5%) tinham o nível de evidência IV. Os dados foram organizados em três temáticas: Saúde mental da população geral e grupos vulneráveis relacionados com os impactos da pandemia; Saúde mental dos profissionais de saúde; Estratégias de saúde mental diante da pandemia por COVID-19. O conhecimento dos impactos na saúde mental da população durante a pandemia por COVID-19 exige estratégias para enfrentamento durante e após pandemia. Sugere-se pesquisas colaborativas, multicêntricas e interdisciplinares a fim de aprofundar a compreensão das implicações para a saúde da crise atual

Neurotensin Decreases the Proinflammatory Status of Human Skin Fibroblasts and Increases Epidermal Growth Factor Expression

Fibroblasts colonization into injured areas during wound healing (WH) is responsible for skin remodelling and is also involved in the modulation of inflammation, as fibroblasts are immunologically active. Herein, we aimed to determine neurotensin effect on the immunomodulatory profile of fibroblasts, both in homeostatic and inflammatory conditions. Neurotensin mediated responses occurred through NTR1 or NTR3 receptors, while under inflammatory conditions NTR1 expression increase seemed to modulate neurotensin responses. Among different immunomodulatory genes, CCL11, IL-8, and IL-6 were the most expressed genes, while CCL4 and EGF were the less expressed genes. After neurotensin exposure, IL-8 mRNA expression was increased while CCL11 was decreased, suggesting a proinflammatory upregulation and chemoattractant ability downregulation of fibroblasts. Under inflammatory conditions, gene expression was significantly increased. After neurotensin exposure, CCL4 and IL-6 mRNA expression were decreased while CCL11 was increased, suggesting again a decrease in the chemoattractant capacity of fibroblasts and in their proinflammatory status. Furthermore, the expression of EGF, a crucial growth factor for skin cells proliferation and WH, was increased in all conditions. Overall, neurotensin, released by nerve fibers or skin cells, may be involved in the decrease of the chemotaxis and the proinflammatory status in the proliferation and remodelling phases of WH

Análise físico-química e sensorial de iogurtes produzidos com leite de búfala, cabra e vaca / Physical-chemical and sensorial analysis of yogurts produced with buffala milk, goat and cow

Os leites e seus derivados são alimentos funcionais e são bastante consumidos por ser uma rica fonte de cálcio que previne a osteoporose e possivelmente câncer de cólon. O objetivo do trabalho foi realizar a avaliação físico-química e sensorial de iogurtes elaborados com leite de búfala, cabra e vaca. Na produção dos iogurtes, foram inoculadas as bactérias Streptococcus thermophilus e Lactobacillus delbruek subspécie bulgariccus. A composição centesimal e a pós-acidificação foram realizadas de acordo as metodologias do Instituto Adolfo Lutz (2008) e apresentou diferença entre os três iogurtes. As análises de efetividade das bactérias iniciadora e lácteas citadas anteriormente foram realizadas durante o período de estocagem refrigerada dos produtos, e nos mesmos as bactérias lácticas apresentaram baixa viabilidade. Para análise sensorial foram preparados os iogurtes com qualidade higiênico sanitária conforme a legislação vigente. O iogurte de leite de vaca seguiu como iogurte controle e obteve as melhores notas para todos os atributos avaliados

ESCOLHA E COMPROMETIMENTO DE CARREIRA: PERCEPÇÃO DE PROFISSIONAIS DAS GERAÇÕES X E Y

Este artigo tem como objetivo identificar se há diferenças entre as gerações X e Y quanto aos motivos de escolha e comprometimento de carreira em profissionais dos setores do comércio e indústria de Ijuí/RS. Metodologicamente trata-se de uma pesquisa com abordagem qualitativa e quantitativa, de natureza descritiva e, quanto aos procedimentos técnicos, foram utilizados levantamento (survey) através da utilização de 2 instrumentos validados, amostra de 170 profissionais. Os resultados demonstram que, para esta amostra tanto os motivos de escolha de carreira quanto o comprometimento de carreira de ambas as gerações foram os mesmos, ou seja, foram considerados interesses, habilidades e vocação pessoal

Níveis de IL-6 e IL-10 no sangue de cordão umbilical de recém-nascidos com história de exposição intrauterina ao crack/cocaína : um estudo comparativo

Introduction: Prenatal cocaine exposure (PCE) is associated with neurobehavioral problems during childhood and adolescence. Early activation of the inflammatory response may contribute to such changes. Our aim was to compare inflammatory markers (IL-6 and IL-10) both in umbilical cord blood and in maternal peripheral blood at delivery between newborns with history of crack/cocaine exposure in utero and non-exposed newborns. Methods: In this cross-sectional study, 57 newborns with a history of crack/cocaine exposure in utero (EN) and 99 non-exposed newborns (NEN) were compared for IL-6 and IL-10 levels. Sociodemographic and perinatal data, maternal psychopathology, consumption of nicotine and other substances were systematically collected in cases and controls. Results: After adjusting for potential confounders, mean IL-6 was significantly higher in EN than in NEN (10,208.54, 95% confidence interval [95%CI] 1,328.54-19,088.55 vs. 2,323.03, 95%CI 1,484.64-3,161.21; p = 0.007; generalized linear model [GLM]). Mean IL-10 was also significantly higher in EN than in NEN (432.22, 95%CI 51.44-812.88 vs. 75.52, 95%CI 5.64- 145.39, p = 0.014; GLM). Adjusted postpartum measures of IL-6 were significantly higher in mothers with a history of crack/cocaine use (25,160.05, 95%CI 10,958.15-39,361.99 vs. 8,902.14, 95%CI 5,774.97-12,029.32; p = 0.007; GLM), with no significant differences for IL-10. There was no correlation between maternal and neonatal cytokine levels (Spearman test, p ≥ 0.28 for all measures). Conclusions: IL-6 and IL-10 might be early biomarkers of PCE in newborns. These findings could help to elucidate neurobiological pathways underlying neurodevelopmental changes and broaden the range of possibilities for early intervention.Introdução: A exposição pré-natal à cocaína está associada a problemas neurocomportamentais durante a infância e adolescência. A ativação precoce da resposta inflamatória pode contribuir para tais alterações. Nosso objetivo foi comparar marcadores inflamatórios (IL-6 e IL-10) no sangue do cordão umbilical e no sangue periférico materno na hora do parto, entre recém-nascidos expostos ao crack intraútero e recém-nascidos não expostos. Métodos: Neste estudo transversal, 57 recém-nascidos expostos ao crack intraútero (RNE) e 99 recém-nascidos não expostos (RNNE) foram comparados quanto aos níveis de IL-6 e IL-10. Dados sociodemográficos e perinatais, psicopatologia materna, consumo de nicotina e outras substâncias foram sistematicamente coletados em casos e controles. Resultados: Após o ajuste para potenciais confundidores, a média de IL-6 foi significativamente maior nos RNE em comparação aos RNNE [10.208,54, intervalo de confiança (IC95%) 1.328,54- 19.088,55 versus 2.323,03, IC95% 1.484,64-3.161,21; p = 0,007; modelo linear generalizado (MLG)]. A média ajustada de IL-10 foi significativamente maior nos RNE do que nos RNNE (432,2189, IC95% 51,44-812,88 versus 75,52, IC95% 5,64- 145,39, p = 0,014; MLG). Medidas pós-parto ajustadas de IL-6 foram significativamente maiores nas mães que usaram de crack/ cocaína (25.160,05, IC95% 10.958,15-39.361,99 versus 8.902,14, IC95% 5.774,97-12.029,32; p = 0,007; MLG), sem diferenças significativas para IL-10. Não houve correlação entre níveis maternos e neonatais de citocinas (teste de Spearman, p ≥ 0,28 para todas as medidas). Conclusões: IL-6 e IL-10 podem ser biomarcadores precoces da exposição pré-natal a cocaína em recém-nascidos. Esses resultados podem ajudar a elucidar as vias neurobiológicas subjacentes a alterações do desenvolvimento e aumentar a gama de possibilidades para intervenção precoce

Cardiovascular rhythmicity in overweight and obese children

Abstract Introduction: Obesity is thought to play a role in the disruption of cardiac rhythmicity in obese children, but this is mostly an unexplored field of investigation. We aimed to evaluate the impact of overweight and obesity on circadian and ultradian cardiovascular rhythmicity of prepubertal children, in comparison with normal weight counterparts. Methods: We performed a cross sectional study of 316 children, followed in the birth cohort Generation XXI (Portugal). Anthropometrics and 24-hour ambulatory blood pressure were measured and profiles were examined with Fourier analysis for circadian and ultradian blood pressure (BP) and heart rate (HR) rhythms. Results: Overweight/obese children presented more frequently a non-dipping BP pattern than normal weight counterparts (31.5% vs. 21.6%, p = 0.047). The prevalence of 24-hour mean arterial pressure (MAP) and 8-hour HR rhythmicity was significantly lower in obese children (79.3% vs. 88.0%, p = 0.038 and 33.3% vs. 45.2%, p = 0.031, respectively). The prevalence of the remaining MAP and HR rhythmicity was similar in both groups. No differences were found in the median values of amplitudes and acrophases of MAP and HR rhythms. Discussion: The alterations found in rhythmicity suggest that circadian and ultradian rhythmicity analysis might be sensitive in detecting early cardiovascular dysregulations, but future studies are needed to reinforce our findings and to better understand their long-term implications

Gerenciamento e integração das pessoas com as tecnologias: relações entre a Indústria 4.0 e Lean Kata

Vincular a Indústria 4.0 com Lean pode promover resultados econômicos, sociais e ambientais em muitos setores industriais. Mas para que isto ocorra, há necessidade de promover a colaboração entre empresas e entre pessoas. O pensamento lean engloba: qualidade, cooperação e comunicação, ou seja, está diretamente relacionado às pessoas que atuam no processo produtivo e kata de melhoria promove, através da mudança comportamental, cooperação e o envolvimento das pessoas para atingir os objetivos organizacionais. Assim, o objetivo deste estudo foi desenvolver um estudo teórico a fim de encontrar e quantificar os documentos existentes, denominados trabalhos relacionados ao tema em estudo e que evidenciam as relações entre Indústria 4.0 e lean kata. Para esta revisão foi realizada uma busca na base de dados Scopus a partir dos termos de busca “Industry 4.0”, “lean” e “kata”. Dos principais resultados encontrados destacam-se os 10 documentos. A pesquisa também indicou um campo de pesquisa ainda não explorado, abrindo oportunidades para novos estudos, assim como destaca a importância da integração entre as diversas áreas da organização quanto a implementação de ambos os programas

Effect of the Combined Intervention with Passive Whole-Body Vibration and Auriculotherapy on the Quality of Life of Individuals with Knee Osteoarthritis Assessed by the WHOQOL-Bref: A Multi-Arm Clinical Trial

The aim of this study was to determine the effect on the quality of life of two non-pharmacological interventions isolated or in combination: (i) passive whole-body vibration exercise (WBVE), and (ii) auriculotherapy (AT). One hundred three participants with knee osteoarthritis (KOA) were allocated to: (a) a vibration group (WBVEG; n = 17) that performed WBVE (peak-to-peak displacement: 2.5 to 7.5 mm, frequency: 5 to 14 Hz, Peak acceleration: 0.12 to 2.95 g), two days/weekly for five weeks, (b) an AT group (ATG; n = 21), stimulation of three specific auriculotherapy points (Kidney, Knee and Shenmen) in each ear pavilion, (c) WBVE + AT (WBVE + AT; n = 20) and (d) respective control groups (WBVE_CG, n = 15; AT_CG, n = 12; WBVE + AT_CG, n = 18). The participants filled out the WHOQOL-bref Questionnaire before the first and after the last sessions. Statistical differences in the various domains of the WHOQOL-bref were not found. In conclusion, WBVE or AT alone or combined did not contribute in altering the quality of life of individuals exposed to these interventions