SAMHD1 expression is a surrogate marker of immune infiltration and determines prognosis after neoadjuvant chemotherapy in early breast cancer.

PURPOSE: The lack of validated surrogate biomarkers is still an unmet clinical need in the management of early breast cancer cases that do not achieve complete pathological response after neoadjuvant chemotherapy (NACT). Here, we describe and validate the use of SAMHD1 expression as a prognostic biomarker in residual disease in vivo and in vitro. METHODS: SAMHD1 expression was evaluated in a clinical cohort of early breast cancer patients with stage II-III treated with NACT. Heterotypic 3D cultures including tumor and immune cells were used to investigate the molecular mechanisms responsible of SAMHD1 depletion through whole transcriptomic profiling, immune infiltration capacity and subsequent delineation of dysregulated immune signaling pathways. RESULTS: SAMHD1 expression was associated to increased risk of recurrence and higher Ki67 levels in post-NACT tumor biopsies of breast cancer patients with residual disease. Survival analysis showed that SAMHD1-expressing tumors presented shorter time-to-progression and overall survival than SAMHD1 negative cases, suggesting that SAMHD1 expression is a relevant prognostic factor in breast cancer. Whole-transcriptomic profiling of SAMHD1-depleted tumors identified downregulation of IL-12 signaling pathway as the molecular mechanism determining breast cancer prognosis. The reduced interleukin signaling upon SAMHD1 depletion induced changes in immune cell infiltration capacity in 3D heterotypic in vitro culture models, confirming the role of the SAMHD1 as a regulator of breast cancer prognosis through the induction of changes in immune response and tumor microenvironment. CONCLUSION: SAMHD1 expression is a novel prognostic biomarker in early breast cancer that impacts immune-mediated signaling and differentially regulates inflammatory intra-tumoral response.

Quality of public urban parks for physical activity practice in Bucaramanga, Colombia / Qualidade dos parques públicos urbanos para a prática de atividades físicas em Bucaramanga, Colômbia

Abstract The characteristics of parks (availability, accessibility, conservation, quality, safety, etc.) are important predictors of their use for physical activity practices. The aim of this study was to verify the association among the socioeconomic level of neighborhoods, the characteristics and quality of urban public parks for physical activity in Bucaramanga, Colombia. Cross-sectional study, conducted in 2015, in which 10 parks with structures for physical activity were evaluated. The socioeconomic level of the district was evaluated based on the neighborhoods around the parks and classified in "low" and "high". The number of residents in the surrounding area of parks were evaluated with Geographic Information System (GIS), site characteristics and quality with the System for Observing Play and Recreation in Communities (SOPARC) and the Physical Activity Resource Assessment (PARA), respectively. The association was analyzed with Mann Whitney U test and Spearman correlation (rho) on STATA 14 and the significance level was maintained at 5%. A positive association was found between the socioeconomic level and the presence of walking paths (marginal, p=0.056), accessibility (rho=0.875; p=0.001) and general quality of parks (rho=0.657; p=0.039). The low socioeconomic level was associated with the presence of sports courts (p=0.032). These results can guide the actions of public managers for the modification of the built environment and structures of the parks for physical activity.

Resumo As características dos parques (disponibilidade, acessibilidade, conservação, qualidade, segurança, etc.) são importantes preditores da sua utilização para a prática de atividades físicas. O objetivo deste estudo foi verificar a associação entre o nível socioeconômico dos bairros com as características e a qualidade dos parques públicos urbanos para a prática de atividades físicas em Bucaramanga, Colômbia. Estudo transversal, realizado em 2015, no qual foram avaliados 10 parques com estruturas para atividades físicas. O nível socioeconômico da região foi avaliado com base nos bairros próximos aos parques e classificado em "baixo" e "alto". O número de residentes próximos foi avaliado com o Sistema de Informação Geográfica (SIG), as características do local e a qualidade foram avaliadas, respectivamente, com o System for Observing Play and Recreation in Communities (SOPARC) e o Physical Activity Resource Assessment (PARA). A associação foi analisada com o teste U de Mann Whitney e a correlação de Spearman (rho) no STATA 14 e o nível de significância mantido em 5%. Foi verificada associação positiva entre o nível socioeconômico e a presença de pistas de caminhada (marginal, p=0,056), acessibilidade (rho=0,875; p=0,001) e qualidade geral dos parques (rho=0,657; p=0,039). O baixo nível socioeconômico foi associado à presença de quadras para esportes (p=0,032). Esses resultados podem orientar as ações dos gestores públicos para a modificação do ambiente construído e estruturas dos parques para a atividade física.

Optimization of genetics to create therapies for metastatic (stage IV) non-small-cell lung cancer.

IMPORTANCE OF THE FIELD: Non-small-cell lung cancer (NSCLC) is a disseminated disease in 50% of cases, with a gloomy prognosis and median survivals of < 1 year. AREAS COVERED IN THIS REVIEW: Based on substantial advances, cancer biology insights and novel biotechnology tools, customized treatment provides hints that cisplatin-based treatment can be optimized in favorable subgroups of patients according to gene expression DNA repair profiles. In 2004, it was discovered that 10-15% of NSCLC can harbor a new class of EGFR mutation conferring specific sensitivity to EGFR tyrosine kinase inhibitors. WHAT THE READER WILL GAIN: The homologous recombination pathway provides information for customizing cisplatin-based chemotherapy. BRCA1 plays a central role in this pathway that can be used in tailoring chemotherapy. Patient subgroups can obtain significant increases in progression-free survival. For EGFR lung-addicted cancers, treatment with EGFR tyrosine kinase inhibitors like erlotinib provide impressive improvement in progression-free survival--up to 14 months with significant enhanced survival. TAKE HOME MESSAGE: Customized chemotherapy based on BRCA1 models can contribute to demonstrating this approach's clinical relevance, and the implementation of EGFR mutation assessment is warranted to identify EGFR-addicted lung cancers with a different prognosis that could benefit from a specifically targeted therapy approach.

Non-small-cell lung cancer harbouring mutations in the EGFR kinase domain.

Key "driver" mutations have been discovered in specific subgroups of non-small-cell lung cancer (NSCLC) patients. Activating mutations in the form of deletions in exon 19 (del 19) or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict outcome to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Pooled data from several phase II studies show that gefitinib and erlotinib induce responses in over 70% of NSCLC patients harbouring EGFR mutations, with progression-free survival (PFS) ranging from 9 to 13 months and median survival of around 23 months. Two studies in Caucasian and Asian patients have confirmed that these subgroups of patients attain response rates of 70% with erlotinib and ge- fitinib, including complete responses, PFS up to 14 months and median survival up to 27 months. These landmark outcomes have been accompanied by new challenges: the additional role of chemotherapy and the management of tumours with the secondary T790M mutation that confers resistance to EGFR TKIs. Mechanisms of resistance to reversible EGFR TKIs should be further clarified and could be related to modifications in DNA repair. The presence of double mutations (T790M plus either L858R or del 19) at the time of diagnosis could be much more frequent than originally thought. The sensitivity to EGFR TKIs could be greatly influenced by the expression of genes involved in the repair of DNA double-strand breaks by homologous recombination and non-homologous end joining.