Immunological-based approaches for cancer therapy

The immunologic landscape of tumors has been continuously unveiled, providing a new look at the interactions between cancer cells and the immune system. Emerging tumor cells are constantly eliminated by the immune system, but some cells establish a long-term equilibrium phase leading to tumor immunoediting and, eventually, evasion. During this process, tumor cells tend to acquire more mutations. Bearing a high mutation burden leads to a greater number of neoantigens with the potential to initiate an immune response. Although many tumors evoke an immune response, tumor clearance by the immune system does not occur due to a suppressive tumor microenvironment. The mechanisms by which tumors achieve the ability to evade immunologic control vary. Understanding these differences is crucial for the improvement and application of new immune-based therapies. Much effort has been placed in developing in silico algorithms to predict tumor immunogenicity and to characterize the microenvironment via high-throughput sequencing and gene expression techniques. Each sequencing source, transcriptomics, and genomics yields a distinct level of data, helping to elucidate the tumor-based immune responses and guiding the fine-tuning of current and upcoming immune-based therapies. In this review, we explore some of the immunological concepts behind the new immunotherapies and the bioinformatic tools to study the immunological aspects of tumors, focusing on neoantigen determination and microenvironment deconvolution. We further discuss the immune-based therapies already in clinical use, those underway for future clinical application, the next steps in immunotherapy, and how the characterization of the tumor immune contexture can impact therapies aiming to promote or unleash immune-based tumor elimination

DIMINISHED HAND GRIP STRENGTH AND CIRRHOSIS: PREVALENCE AND ASSOCIATED FACTORS

ABSTRACT Background: Sarcopenia is a syndrome characterized by progressive and generalized loss of muscle mass and strength, observed to varying degrees in patients with various chronic conditions. In cirrhotic patients, it reflects protein-energy malnutrition due to metabolic protein imbalance and is associated with worsened prognosis and reduced post-liver transplantation survival. Objective: To evaluate the epidemiological distribution of diminished hand grip (HG) strength in cirrhotic patients at an outpatient clinic of Santa Casa de Misericórdia in Vitória-ES, Brazil, seeking its association with liver function and cirrhosis complications. Methods: Cross-sectional, epidemiological, and single-center study. A questionnaire was administered to patients and HG strength was measured using a dynamometer, with three interval measures taken for 3 seconds each. Results: The study’s total population was 64 cirrhotic patients, with a mean age of 58 years and alcohol as the most prevalent etiology. Reduced HG strength was defined based on two reference values: using cutoff point 1, reduced HG strength was identified in 33 patients (51.6%); according to cutoff point 2, 23 (35.9%) had reduced HG strength. The study showed that, among the parameters observed, there was an association between the female gender and diminished HG strength in both cutoff points. Additionally, it was noted that patients with a score of 15 or more on the Model for End-Stage Liver Disease (MELD) had decreased HG strength at cutoff point 2. The study showed no association between decreased HG strength and the occurrence of cirrhosis complications in the population studied. Conclusion: In our study, we obtained a diminished HG strength variation of 35-52%, which was related to higher MELD scores, suggesting an association with worse clinical outcomes. Therefore, the presence of reduced muscle strength in cirrhotic patients may be linked to prognostic factors and should be valued as clinical data in the management of these patients

Avaliação da resistência ao cisalhamento da união entre duas ligas a base de CoCr e uma cerâmica

INTRODUCTION: Based on the importance of the integrity of the metal/ceramic interface, the purpose of this work was to evaluate the shear bond strength of the metal-ceramic union of two Co-Cr alloys (Wirobond C, Bego; Remanium 2000, Dentaurum) combined with Omega 900 ceramic (Vita Zahnfabrik). MATERIAL and METHOD: Eleven cylindrical matrixes were made for each alloy, and the metallic portion was obtained with the lost wax casting technique with standardized waxing of 4mm of height and of 4mm of diameter. The ceramic was applied according to the manufacturer’s recommendations with the aid of a teflon matrix that allowed its dimension to be standardized in the same size as the metallic portion. The specimens were submitted to the shear bond test in an universal testing machine (EMIC), with the aid of a device developed for such intention, and constant speed of 0.5mm/min. RESULTS and CONCLUSIONS: The mean resistance was 48.387MPa for Wirobond C alloy, with standard deviation of 17.718, and 55.956MPa for Remanium 2000, with standard deviation of 17.198. No statistically significant difference was observed between the shear strength of the two metal-ceramic alloys. ______________________________________________________________________________________________________________ RESUMOINTRODUÇÃO: Baseados na importância da integridade da interface metal-cerâmica, este trabalho tem como objetivo avaliar a resistência ao cisalhamento da união metal-cerâmica de duas ligas de Co-Cr (Wirobond C, Bego; Remanium 2000, Dentaurum) combinadas com a cerâmica Omega 900 (Vita Zahnfabrik). MATERIAIS E MÉTODOS: Foram confeccionados 11 corpos-de-prova cilíndricos para cada liga utilizada, sendo que a porção metálica foi obtida por fundição pela técnica da cera perdida, através de enceramentos padronizados com 4mm de altura por 4mm de diâmetro. A aplicação da cerâmica foi realizada segundo recomendações do fabricante, com auxílio de uma matriz de teflon que permitia sua padronização com as mesmas dimensões da porção metálica. Os corpos-de-prova foram submetidos ao ensaio de resistência ao cisalhamento em máquina de ensaios universal (EMIC), com auxílio de dispositivo desenvolvido para tal propósito, sob velocidade constante de 0,5mm/ min. RESULTADOS E CONCLUSÕES: As médias de resistência obtidas foram 48,387 MPa para a liga Wirobond C, com desvio padrão de 17,718, e 55,956 MPa para a Remanium 2000, com desvio padrão de 17,198. Após análise de variância foi possível observar que não há diferença estatisticamente significante entre os valores de resistência ao cisalhamento das duas ligas metalocerâmicas

Avaliação da citotoxicidade de agentes clareadores dentais de uso profissional variando o mecanismo de ativação, fibroblastos de polpa humana

A proposta deste estudo foi avaliar a citotoxicidade do peróxido de hidrogênio (PH) liberado por dois géis clareadores, utilizados para a técnica de consultório, sobre cultura de fibroblastos de polpa humana (FP5). As células foram cultivadas em DMEM. Foram utilizadas células entre a quinta e décima passagens. Colocou-se sobre as células meios de cultura condicionados de acordo com os grupos de estudo (n=4): G1- PH 35% sem fotoativação; G2- PH 35% ativado por luz alógena; G3- PH 35% ativado por diodo emissor de luz (LED); G4- PH 38% sem fotoativação; G5- PH 38% ativado por luz alógena; G6- PH 38% ativado por LED. Uma curva padrão de viabilidade e crescimento celular foi obtida a partir de células que não receberam tratamento (controle). O ensaio com MTT ocorreu após 0, 24 e 48 horas, para avaliar a viabilidade e crescimento celular. Paralelamente, mediu-se colorimetricamente a quantidade de PH liberado nas condições experimentais, utilizando-se solução tampão de acetato no lugar do meio de cultura. Os dados foram analisados através do teste de Dunnet, ANOVA e teste de Tukey. Todos os grupos apresentaram diferença significativa em relação ao controle. O PH 38% apresentou maior citotoxicidade e quantidade de peróxido de hidrogênio liberada que o PH 35% nas condições experimentais. A ativação por luz alógena ocasinou maior citotoxicidade e maior quantidade de PH liberado, e a ativação com LED foi estatisticamente semelhante à ausência de ativação. A avaliação após 48 horas apresentou diferença estatística das avaliações de 0 e 24 horas. Concluiu-se que: a citotoxicidade foi proporcional à concentração do agente clareador; a fotoativação com luz alógena aumentou a liberação de peróxido de hidrogênio, e o metabolismo celular foi menor imediatamente após o contato com o meio condicionado, aumentando após 24 e/ ou48 horas.The propose of this study was to evaluate hydrogen peroxide (HP) cytotoxicity, from two in office bleaching agents, on human pulp fibroblasts (FP5) culture. The cells were cultured in DMEM. Only cells between fifith and tenth passages were used. Each well of culture plate, corresponding to experimental groups, received conditioned middle according to the experimental groups: G1- HP 35% without light activation; G2- HP 35% activated by halogen light; G3- HP 35% activated by LED; G4- HP 38% without light activation; G5- HP 38% activated by halogen light; G6- HP 38% activated by LED. Viability and growth standard curve was obtained from an untreated group and was used as control. MTT assay was performed in four wells for each group, in periods of 0, 24 or 48 hours, to measure cells viability and growth. Hydrogen peroxide leased in experimental conditions was also measured, using acetate buffer instead culture middle. Results were analyzed by Dunnet test, variance analysis and Tukey test. All experimental groups showed difference from control. The cytotoxicity and quantity of hydrogen peroxide was higher with 38% hydrogen peroxide (Opalescence Xtra Boost) than with 35% hydrogen peroxide (Whiteness HP). Activation by halogen light caused smaller cell growth and viability but higher hydrogen peroxide amount, and LED was statically similar to the group without activation. 48 hours evaluation was different then 0 and 24 hour evaluations. Conclusions: cytotoxicity was proportional to quantity of hydrogen peroxide leased; halogen light activation increased the leased hydrogen peroxide, and cell viability was lower immediately after contact with conditioned middle, increasing after 24 and/or 48 hours.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Immunological-based approaches for cancer therapy

The immunologic landscape of tumors has been continuously unveiled, providing a new look at the interactions between cancer cells and the immune system. Emerging tumor cells are constantly eliminated by the immune system, but some cells establish a long-term equilibrium phase leading to tumor immunoediting and, eventually, evasion. During this process, tumor cells tend to acquire more mutations. Bearing a high mutation burden leads to a greater number of neoantigens with the potential to initiate an immune response. Although many tumors evoke an immune response, tumor clearance by the immune system does not occur due to a suppressive tumor microenvironment. The mechanisms by which tumors achieve the ability to evade immunologic control vary. Understanding these differences is crucial for the improvement and application of new immune-based therapies. Much effort has been placed in developing in silico algorithms to predict tumor immunogenicity and to characterize the microenvironment via high-throughput sequencing and gene expression techniques. Each sequencing source, transcriptomics, and genomics yields a distinct level of data, helping to elucidate the tumor-based immune responses and guiding the fine-tuning of current and upcoming immune-based therapies. In this review, we explore some of the immunological concepts behind the new immunotherapies and the bioinformatic tools to study the immunological aspects of tumors, focusing on neoantigen determination and microenvironment deconvolution. We further discuss the immune-based therapies already in clinical use, those underway for future clinical application, the next steps in immunotherapy, and how the characterization of the tumor immune contexture can impact therapies aiming to promote or unleash immune-based tumor elimination

Caracterização dos fatores ambientais e o controle cervical de lactentes nascidos pré-termo

Objetivo: Caracterizar os fatores ambientais e a aquisição do controle cervical dos lactentes nascidos pré-termo, de recém-nascido aos 4 meses de idade corrigida, nas posturas prona e sentada. Metodologia: Participaram do estudo 18 lactentes, sendo 9 pré-termo (33 semanas ± 2 semanas) e 9 a termo (39 semanas ± 1 semana). Foi aplicado o Test of Infant Motor Performance (TIMP), para avaliar o controlecervical dos lactentes, e um questionário para as mães, mês a mês. Resultados: Não houve diferença significativa no desenvolvimento do controle cervical entre os grupos no decorrer dos meses, mas os lactentes nascidos a termo apresentaram escore superior ao pré-termo nos itens 32, 35 e 36 da escala TIMP na idade de recém-nascido. Conclusão: Sugere-se que a diferença de escore na idade de RN entre os grupos pode estar relacionada tanto com as alterações orgânicas que os lactentes pré-termo apresentam quanto aos fatores ambientais

Caracterização dos fatores ambientais e o controle cervical de lactentes nascidos pré-termo

OBJETIVO: Caracterizar os fatores ambientais e a aquisição do controle cervical dos lactentes nascidos pré-termo, de recém-nascido aos 4 meses de idade corrigida, nas posturas prona e sentada. METODOLOGIA: Participaram do estudo 18 lactentes, sendo 9 pré-termo (33 semanas ± 2 semanas) e 9 a termo (39 semanas ± 1 semana). Foi aplicado o Test of Infant Motor Performance (TIMP), para avaliar o controle cervical dos lactentes, e um questionário para as mães, mês a mês. RESULTADOS: Não houve diferença significativa no desenvolvimento do controle cervical entre os grupos no decorrer dos meses, mas os lactentes nascidos a termo apresentaram escore superior ao pré-termo nos itens 32, 35 e 36 da escala TIMP na idade de recém-nascido. CONCLUSÃO: Sugere-se que a diferença de escore na idade de RN entre os grupos pode estar relacionada tanto com as alterações orgânicas que os lactentes pré-termo apresentam quanto aos fatores ambientais

Dietary Protein Restriction Improves Metabolic Dysfunction in Patients with Metabolic Syndrome in a Randomized, Controlled Trial

Dietary restriction (DR) reduces adiposity and improves metabolism in patients with one or more symptoms of metabolic syndrome. Nonetheless, it remains elusive whether the benefits of DR in humans are mediated by calorie or nutrient restriction. This study was conducted to determine whether isocaloric dietary protein restriction is sufficient to confer the beneficial effects of dietary restriction in patients with metabolic syndrome. We performed a prospective, randomized controlled dietary intervention under constant nutritional and medical supervision. Twenty-one individuals diagnosed with metabolic syndrome were randomly assigned for caloric restriction (CR; n = 11, diet of 5941 ± 686 KJ per day) or isocaloric dietary protein restriction (PR; n = 10, diet of 8409 ± 2360 KJ per day) and followed for 27 days. Like CR, PR promoted weight loss due to a reduction in adiposity, which was associated with reductions in blood glucose, lipid levels, and blood pressure. More strikingly, both CR and PR improved insulin sensitivity by 62.3% and 93.2%, respectively, after treatment. Fecal microbiome diversity was not affected by the interventions. Adipose tissue bulk RNA-Seq data revealed minor changes elicited by the interventions. After PR, terms related to leukocyte proliferation were enriched among the upregulated genes. Protein restriction is sufficient to confer almost the same clinical outcomes as calorie restriction without the need for a reduction in calorie intake. The isocaloric characteristic of the PR intervention makes this approach a more attractive and less drastic dietary strategy in clinical settings and has more significant potential to be used as adjuvant therapy for people with metabolic syndrome