Health-related quality of life in patients with type 1 diabetes mellitus in the different geographical regions of Brazil : data from the Brazilian Type 1 Diabetes Study Group

Background: In type 1 diabetes mellitus (T1DM) management, enhancing health-related quality of life (HRQoL) is as important as good metabolic control and prevention of secondary complications. This study aims to evaluate possible regional differences in HRQoL, demographic features and clinical characteristics of patients with T1DM in Brazil, a country of continental proportions, as well as investigate which variables could influence the HRQoL of these individuals and contribute to these regional disparities. Methods: This was a retrospective, cross-sectional, multicenter study performed by the Brazilian Type 1 Diabetes Study Group (BrazDiab1SG), by analyzing EuroQol scores from 3005 participants with T1DM, in 28 public clinics, among all geographical regions of Brazil. Data on demography, economic status, chronic complications, glycemic control and lipid profile were also collected. Results: We have found that the North-Northeast region presents a higher index in the assessment of the overall health status (EQ-VAS) compared to the Southeast (74.6 ± 30 and 70.4 ± 19, respectively; p < 0.05). In addition, North- Northeast presented a lower frequency of self-reported anxiety-depression compared to all regions of the country (North-Northeast: 1.53 ± 0.6; Southeast: 1.65 ± 0.7; South: 1.72 ± 0.7; Midwest: 1.67 ± 0.7; p < 0.05). These findings could not be entirely explained by the HbA1c levels or the other variables examined. Conclusions: Our study points to the existence of additional factors not yet evaluated that could be determinant in the HRQoL of people with T1DM and contribute to these regional disparities

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Mundos mesclados, espaços segregados: cultura material, mestiçagem e segmentação no sítio Aldeia em Santarém (PA)

This article discusses the processes of cultural exchange between Portuguese, Portuguese-Brazilian, Amerindians, and mestizos based on the analysis of the material culture from households of Santarém (PA), occupied during the eighteenth and nineteenth centuries,. Although these social groups manipulated material culture aiming to express different values, related to hierarchy, social segmentation, and affirmation of identities, ambiguity also characterizes these assemblages. This material ambiguity informs about the mixtures of both practices and cultural references that brought about the building of a mestizo society.Com base na análise da cultura material proveniente de unidades domésticas do núcleo urbano de Santarém (PA), ocupadas nos séculos XVIII e XIX, o presente artigo discute os processos de trocas culturais entre portugueses, luso-brasileiros, indígenas e mestiços. Embora esses grupos sociais tenham manipulado a cultura material visando expressar diferentes valores, relacionados à hierarquia, segmentação social e afirmação de identidades, a ambigüidade é uma característica das amostras analisadas, informando sobre as misturas de práticas e de referenciais culturais que levaram à construção de uma sociedade mestiça

Aderência aço-concreto: simulação numéricadosensaios de arranchamento pull-out e APULOT usando o programa ATENA

The bond between steel and concrete is essential for the existence of reinforced concrete structures, as both materials act together to absorb structural strain. The bond phenomenon is considered to be complex regarding many factors that affect it. Several types of bond tests have been proposed over years. One is the modified proposed of pull-out test, which was elaborated by Lorrain and Barbosa [1] called APULOT test (Appropriete pull-out-test). Based on experimental results obtained by Vale Silva[2] either by conventional pull-out tests, or by modified pull-out test, APULOT, seeks to know the numeric behavior of bond steel-concrete through a numerical simulation using a calculation code ATENA which is based on the Finite Element Method (FEM). The numerical simulation provided better evaluate the stress distribution and cracking that occurs during the test, thereby becoming a valuable tool to support the experimental project that aims to validation, validation partially or not recommend the modified bond test steel-concrete - APULOT test - as quality control test of structural concrete. The numerical results showed good representation compared to experimental results.A aderência entre o aço e o concreto é fundamental para a existência das estruturas de concreto armado, uma vez que os dois materiais atuamem conjunto para absorver os esforços solicitantes. O fenômeno da aderência é considerado complexo no que se refere aos vários fatores queo influenciam. Vários tipos de ensaios de aderência foram propostos ao longo dos anos. Um deles é a proposta modificada do ensaio de arrancamento pull-out-test, que foi elaborada por Lorrain e Barbosa [1] denominado de ensaio APULOT (Appropriete Pull-Out-Test). Com basenos resultados experimentais obtidos por Vale Silva [2] para os ensaios pull-out convencionais e para o ensaio pull-out modificado, APULOT,procura-se conhecer o comportamento numérico da aderência aço-concreto através de uma simulação numérica utilizando um código decálculo chamado ATENA que é baseado no Método dos Elementos Finitos (MEF). A simulação numérica permitiu melhor avaliar a fissuraçãoe a distribuição de tensões que ocorre durante o ensaio de arrancamento, tornando-se com isso, uma ferramenta de apoio preciosa ao projeto experimental que visa à validação, validação parcial, ou não recomendação do ensaio de aderência aço-concreto modificado - EnsaioAPULOT - como ensaio de controle de qualidade do concreto armado. Os resultados numéricos obtidos apresentaram boa representatividadequando comparados aos resultados experimentais