Tumor-Targeting Immune System Engagers (ISErs) Activate Human Neutrophils after Binding to Cancer Cells.

Immune system engagers (ISErs) make up a new class of immunotherapeutics against cancer. They comprise two or more tumor-targeting peptides and an immune-stimulating effector peptide connected by inert polymer linkers. They are produced by solid phase peptide synthesis and share the specific targeting activities of antibodies (IgGs) but are much smaller in size and exploit a different immune-stimulating mechanism. Two ISErs (Y-9 and Y-59) that bind to the cancer cell markers integrin α3 and EphA2, respectively, are analyzed here with respect to their immune cell stimulation. We have previously shown that they activate formyl peptide receptors on myeloid immune cells and induce respiratory burst in neutrophils and myeloid chemotaxis in solution. It remained, however, unclear whether these molecules can stimulate immune cells while bound to tumor cells, an essential step in the hypothesized mode of action. Here, we demonstrate that ISEr Y-9 induced respiratory burst and caused a change in the shape of neutrophils when bound to the surface of protein A beads as a model of tumor cells. More importantly, tumor cell lines carrying receptor-bound Y-9 or Y-59 also activated neutrophils, evidenced by a significant change in shape. Interestingly, similar activation was induced by the supernatants of the cells incubated with ISEr, indicating that ISErs released from tumor cells, intact or degraded into fragments, significantly contributed to immune stimulation. These findings provide new evidence for the mode of action of ISErs, namely by targeting cancer cells and subsequently provoking an innate immune response against them.

Synthetic Cancer-Targeting Innate Immune Stimulators Give Insights into Avidity Effects.

Multispecific and multivalent antibodies are seen as promising cancer therapeutics, and numerous antibody fragments and derivatives have been developed to exploit avidity effects that result in increased selectivity. Most of these multispecific and multivalent antibody strategies make use of recombinant expression of antigen-binding modules. In contrast, chemical synthesis and chemoselective ligations can be used to generate a variety of molecules with different numbers and combinations of binding moieties in a modular and homogeneous fashion. In this study we synthesized a series of targeted immune system engagers (ISErs) by using solid-phase peptide synthesis and chemoselective ligations. To explore avidity effects, we constructed molecules bearing different numbers and combinations of two "binder" peptides that target ephrin A2 and integrin α3 receptors and an "effector" peptide that binds to formyl peptide receptors and stimulates an immune response. We investigated various strategies for generating multivalent and multispecific targeted innate immune stimulators and studied their activities in terms of binding to cancer cells and stimulation of immune cells. This study gives insights into the influence that multivalency and receptor density have on avidity effects and is useful for the design of potential anticancer therapeutics.

Reduced sputum expression of interferon-stimulated genes in severe COPD.

BACKGROUND: Exacerbations of COPD are frequent and commonly triggered by respiratory tract infections. The purpose of our study was to investigate innate immunity in stable COPD patients. METHODS: Induced sputum was collected from 51 stable consecutive COPD patients recruited from the COPD Clinic of CHU Liege and 35 healthy subjects. Expression of interferons beta (IFN-ß) and lambda1 (IL-29), IFN-stimulated genes (ISGs) MxA, OAS, and viperin were measured in total sputum cells by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The presence of Picornaviruses was assessed by RT-PCR, while potential pathogenic microorganisms (PPM) were identified by sputum bacteriology. RESULTS: Expression of IL-29 was found in 16 of 51 COPD patients (31%) and in nine of 35 healthy subjects (26%), while IFN-ß was detected in six of 51 COPD patients (12%) and in two of 35 healthy subjects (6%). ISGs were easily detectable in both groups. In the whole group of COPD patients, OAS expression was decreased (P<0.05), while that of viperin was increased (P<0.01) compared to healthy subjects. No difference was found with respect to MxA. COPD patients from group D of Global Initiative for Chronic Obstructive Lung Disease (GOLD) had reduced expression of all three ISGs (P<0.01 for MxA, P<0.05 for OAS, and P<0.01 for viperin) as compared to those of group B patients. Picornaviruses were detected in eight of 51 (16%) COPD patients vs four of 33 (12%) healthy subjects, while PPM were detected in seven of 39 (18%) COPD patients and associated with raised sputum neutrophil counts. IFN-ß expression was raised when either picornavirus or PPM were detected (P=0.06), but no difference was seen regarding IL-29 or ISGs. CONCLUSION: ISGs expression was reduced in severe COPD that may favor exacerbation and contribute to disease progress by altering response to infection.

Quality of life of patients with hepatitis C.

INTRODUCTION: Self-report on the quality of life (QOL) is increasingly studied in the evaluation of various diseases, especially in chronic ones. However, there are few data in the literature focusing the QOL of patients living with chronic hepatitis C. The objective of this study was to evaluate the QOL in patients with hepatitis C assessed by the World Health Organization Quality of Life Assessment (WHOQOL)-bref scale. METHODS: One hundred and eight hepatitis C patients attending the Outpatient Healthcare Medical Specialties in Tubarão, State of Santa Catarina, Brazil, were contacted from May 2010 to February 2011. Patients answered the WHOQOL-bref scale and a questionnaire about their treatment and risk factors to hepatitis C virus (VHC) infection. RESULTS: Although most of patients with chronic hepatitis C considered their QoL good or very good (58.1%), 47 (44.8%) patients were poorly or very poorly satisfied with their health. About the WHOQOL answers, the environment domain had the highest score (25.15 + 5.77), while the lowest score was the social relationships domain (9.19 + 2.5). There was statistically significant association between household income and quality of life in all domains (p<0.001) and statistically significant association between education and the physical, psychological and social domains of quality of life (p<0.05). CONCLUSIONS: Based on the answers given in WHOQOL-bref, patients with chronic hepatitis C have a generally poor QOL, especially in social relationship domain. Household income and educational level were factors that interfered significantly with patients' QOL assessment.

Quality of life of patients with hepatitis C / Qualidade de vida de pacientes com hepatite C

INTRODUCTION: Self-report on the quality of life (QOL) is increasingly studied in the evaluation of various diseases, especially in chronic ones. However, there are few data in the literature focusing the QOL of patients living with chronic hepatitis C. The objective of this study was to evaluate the QOL in patients with hepatitis C assessed by the World Health Organization Quality of Life Assessment (WHOQOL)-bref scale. METHODS: One hundred and eight hepatitis C patients attending the Outpatient Healthcare Medical Specialties in Tubarão, State of Santa Catarina, Brazil, were contacted from May 2010 to February 2011. Patients answered the WHOQOL-bref scale and a questionnaire about their treatment and risk factors to hepatitis C virus (VHC) infection. RESULTS: Although most of patients with chronic hepatitis C considered their QoL good or very good (58.1%), 47 (44.8%) patients were poorly or very poorly satisfied with their health. About the WHOQOL answers, the environment domain had the highest score (25.15 + 5.77), while the lowest score was the social relationships domain (9.19 + 2.5). There was statistically significant association between household income and quality of life in all domains (p<0.001) and statistically significant association between education and the physical, psychological and social domains of quality of life (p<0.05). CONCLUSIONS: Based on the answers given in WHOQOL-bref, patients with chronic hepatitis C have a generally poor QOL, especially in social relationship domain. Household income and educational level were factors that interfered significantly with patients' QOL assessment.

INTRODUÇÃO: O autorrelato sobre a qualidade de vida (QV) é cada vez mais estudado na avaliação de várias doenças, especialmente nas crônicas. No entanto, existem poucos dados na literatura focando a QV de pacientes vivendo com hepatite C crônica. O objetivo deste estudo foi avaliar a QV em pacientes com hepatite C através da escala World Health Organization Quality of Life Assessment versão breve (WHOQOL-bref). MÉTODOS: Foi feito contato com 108 pacientes de hepatite C que frequentavam o Ambulatório Médico de Especialidades em Tubarão, Santa Catarina, Brasil, de maio de 2010 a fevereiro de 2011. Os pacientes responderam ao WHOQOLbref e a um questionário sobre o seu tratamento e fatores de risco à infecção pelo vírus da hepatite C (VHC). RESULTADOS: Embora a maioria dos pacientes com hepatite C crônica considerasse sua QV boa ou muito boa (58,1%), 47 (44,8%) dos pacientes estavam nada ou muito pouco satisfeitos com a sua saúde. Sobre as respostas do WHOQOL, o domínio ambiental obteve o escore mais alto (25,15 + 5,77), enquanto o menor escore foi do domínio relações sociais (9,19 + 2,5). Houve associação estatística significativa entre renda familiar e qualidade de vida em todos os domínios (p<0,001) e associação estatística significativa entre educação e os domínios físico, psicológico e social da qualidade de vida (p<0,05). CONCLUSÕES: Baseado nas respostas dadas no WHOQOL-bref, pacientes com hepatite C crônica têm uma QV geralmente pobre, especialmente no domínio relações sociais. A renda familiar e o nível de educação foram fatores que interferiram significativamente na auto-avaliação da qualidade de vida dos pacientes.

Prevalência de dermatite atópica em adolescentes escolares do município de São José - SC / Prevalence of atopic dermatitis in school adolescents in São José - SC

Objetivo: determinar a prevalência e a gravidade do eczema atópico em adolescentes escolares da cidade de São José-SC, utilizando o módulo eczema do questionário escrito do International Study of Asthma and Allergies in Childhood (ISAAC).Métodos: a população pesquisada consistia em adolescentes de 12 a 15 anos matriculados em escolas das redes públicas e privadas da cidade de São José-SC. As escolas foram selecionadas aleatoriamente, respeitando-se a proporção geográfica da distribuição dos alunos e por tipo de escola (pública e particular), e os alunos que, por meio dos pais ou responsáveis, aceitaram participar da pesquisa responderam o questionário.Resultados: a prevalência de eczema atópico foi de 13,2%, com predominância significativa do sexo feminino (p<0,001). A prevalência dos sintomas nos últimos 12 meses (doença ativa) foi de 8,8%, sem diferença significativa entre os sexos. Dentre os adolescentes com doença ativa, 45,1% apresentava lesões em locais característicos e 37,8% deles tiveram o sono perturbado devido ao prurido, não havendo diferença significativa entre os gêneros. Em 11,7% dos casos, os adolescentes reconheceram o termo eczema, o que sugere diagnóstico médico da doença antes da realização da pesquisa.Conclusões: foi possível determinar a prevalência de eczema atópico, seus sintomas e gravidade entre os adolescentes escolares de 12 a 15 anos da cidade de São José-SC, que foram semelhantes aos resultados encontrados em outras cidades brasileiras.