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Gastric cancer is one of the most aggressive malignancies, with limited treatment options in both locally advanced and metastatic setting, resulting in poor prognosis. Based on genomic characterization, stomach tumour has recently been described as a heterogeneous disease composed by different subtypes, each of them with peculiar molecular aspects and specific clinical behaviour. With an incidence of 22% among all western gastric tumour cases, stomach cancer with microsatellite instability was identified as one of these subgroups. Retrospective studies and limited prospective trials reported differences between gastric cancers with microsatellite stability and those with instability, mainly concerning clinical and pathological features, but also in regard to immunological microenvironment, correlation with prognostic value, and responses to treatment. In particular, gastric cancer with microsatellite instability constitutes a small but relevant subgroup associated with older age, female sex, distal stomach location, and lower number of lymph-node metastases. Emerging data attribute to microsatellite instability status a favourable prognostic meaning, whereas the poor outcomes reported after perioperative chemotherapy administration suggest a detrimental role of cytotoxic drugs in this gastric cancer subgroup. The strong immunogenicity and the widespread expression of immune-checkpoint ligands make microsatellite instability subtype more vulnerable to immunotherapeutic approach, e.g., with anti-PD-L1 and anti-CTLA4 antibodies. Since gastric cancer with microsatellite instability shows specific features and clinical behaviour not overlapping with microsatellite stable disease, microsatellite instability test might be suitable for inclusion in a diagnostic setting for all tumour stages to guarantee the most targeted and effective treatment to every patient.

Non-coding RNAs are important regulators of differentiation during embryogenesis as well as key players in the fine-tuning of transcription and furthermore, they control the post-transcriptional regulation of mRNAs under physiological conditions. Deregulated expression of non-coding RNAs is often identified as one major contribution in a number of pathological conditions. Non-coding RNAs are a heterogenous group of RNAs and they represent the majority of nuclear transcripts in eukaryotes. An evolutionary highly conserved sub-group of non-coding RNAs is represented by vault RNAs, named since firstly discovered as component of the largest known ribonucleoprotein complexes called “vault”. Although they have been initially described 30 years ago, vault RNAs are largely unknown and their molecular role is still under investigation. In this review we will summarize the known functions of vault RNAs and their involvement in cellular mechanisms.

Why do we use the term ‘resilience’ and what are the implications of this use for urban space? The reflection in this article is based on this question. The purpose of this text is to illustrate – in dialectic form – the way in which resilience has been used in neoliberal strategies of urban transformation, given that it has been instrumentalized to normalize distinct spaces in cities. To respond to the question, document analysis has been used as a research methodology. Among the main conclusions of the study on which this article is based, two aspects regarding urban resilience that had not been studied to-date stand out. First, the use of the term reflects typical characteristics of performative concepts, with the power that that type of notion has for reducing its object to a hegemonic and repetitive narrative – in this case, the urban and its construction. Second, in concordance with critical urban theory and through a genealogical analysis of Foucauldian inspiration applied to the instrumental use of resilience, it is shown how this concept has been converted into a notion that facilitates the neoliberal project, which has dominated processes of change in urban Latin America in the 21st century.

Non-coding RNAs represent a significant proportion of the human genome. After having been considered as ‘junk’ for a long time, non-coding RNAs are now well established as playing important roles in maintaining cellular homeostasis and functions. Some non-coding RNAs show cell- and tissue-specific expression patterns and are specifically deregulated under pathological conditions (e.g. cancer). Therefore, non-coding RNAs have been extensively studied as potential biomarkers in the context of different diseases with a focus on microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) for several years. Since their discovery, miRNAs have attracted more attention than lncRNAs in research studies; however, both families of non-coding RNAs have been established to play an important role in gene expression control, either as transcriptional or post-transcriptional regulators. Both miRNAs and lncRNAs can regulate key genes involved in the development of cancer, thus influencing tumour growth, invasion, and metastasis by increasing the activation of oncogenic pathways and limiting the expression of tumour suppressors. Furthermore, miRNAs and lncRNAs are also emerging as important mediators in drug-sensitivity and drug-resistance mechanisms. In the light of these premises, a number of pre-clinical and early clinical studies are exploring the potential of non-coding RNAs as new therapeutics. The aim of this review is to summarise the latest knowledge of the use of miRNAs and lncRNAs as therapeutic tools for cancer treatment.

Abstract Based on the policy document analysis method and a conceptual framework derived from Science and Technology Studies, this paper analyses the construction of institutionally legitimated forms of discursive limitation of energy governance in Brazil. The paper analyzes a subset of selected vital policy documents produced by regulatory bodies such as the National Energy Agency (ANEEL) and the Energy Research Office (EPE). As an insight for further research on the governance of energy policy, the paper’s contribution to the debate is to bring to the fore the relevance of recasting the whole process of regulation of distributed energy in terms of an attempt to build a narrative of control over socio-technical innovation with the potential to democratize access to and use of energy services. This policy narrative’s unspoken goal is to retain control of the Brazilian energy transition at the central level. Resumo Com base no método de análise de documentos de política e a abordagem da teoria dos Estudos da Ciência e a Tecnologia, analisamos neste artigo a construção de formas institucionalmente legitimadas de limitação discursiva da energia distribuída no Brasil. No artigo analisa-se um subconjunto de documentos centrais para a definição da política energética da energia distribuída, entre aqueles produzidos por órgãos reguladores, como a Agência Nacional de Energia Elétrica (ANEEL) e a Agência de Pesquisa Energética (EPE). Como contribuição para pesquisas futuras sobre a governança da política energética trazemos à tona a relevância de reformular todo o processo de regulação da energia distribuída em termos de uma tentativa de construir uma narrativa de controle sobre as inovações técnicas com potencial para democratizar o acesso e uso dos serviços de energia. O objetivo tácito dessa narrativa política é manter o controle e a centralização Resumen Con base en el método de análisis de documentos de política y el enfoque teórico de los Estudios Sociales de la Ciencia y la Tecnología (STS por el acrónimo en inglés), este artículo analiza la construcción de formas institucionalmente legítimas de normalización discursiva de la energía distribuida en Brasil. El artículo analiza un subconjunto de documentos que se destacan como fundamentales para la definición de la política energética para de energía distribuida, incluidos aquellos elaborados por organismos reguladores como la Agencia Nacional de Energía Eléctrica (ANEEL) y la Agencia de Investigación Energética (EPE). Como contribución a la investigación futura sobre la gobernanza de la política energética, el artículo destaca la relevancia de reformular todo el proceso de regulación de la energía distribuida en términos de un intento de construir una narrativa de control sobre las innovaciones técnicas y su potencial de democratizar el acceso y el uso de los servicios energéticos. El objetivo tácito de esta narrativa política es mantener el control centralizado de la transición energética brasileña.

ObjectiveRegorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.DesignPatients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.ResultsTwenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06).ConclusionsCombining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

Pancreatic cancer is one of the most aggressive malignancies with limited treatment options thus resulting in high morbidity and mortality. Among all cancers, with a five-year survival rates of only 2–9%, pancreatic cancer holds the worst prognostic outcome for patients. To improve the overall survival, an earlier diagnosis and stratification of cancer patients for personalized treatment options are urgent needs. A minority of pancreatic cancers belong to the spectrum of Lynch syndrome-associated cancers and are characterized by microsatellite instability (MSI). MSI is a consequence of defective mismatch repair protein functions and it has been well characterized in other gastrointestinal tumors such as colorectal and gastric cancer. In the latter, high levels of MSI are linked to a better prognosis and to an increased benefit to immune-based therapies. Therefore, the same therapies could offer an opportunity of treatment for pancreatic cancer patients with MSI. In this review, we summarize the current knowledge about immune-based therapies and MSI in pancreatic cancer.

There are limited data on circulating, cell-free, tumour (ct)DNA analysis in locally advanced rectal cancer (LARC). Digital droplet (dd)PCR was used to investigate KRAS/BRAF mutations in ctDNA from baseline blood samples of 97 LARC patients who were treated with CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in a randomised phase II trial. KRAS mutation in G12D, G12V or G13D was detected in the ctDNA of 43% and 35% of patients with tumours that were mutant and wild-type for these hotspot mutations, respectively, according to standard PCR-based analyses on tissue. The detection rate in the ctDNA of 10 patients with less common mutations was 50%. In 26 cases ctDNA analysis revealed KRAS mutations that were not previously found in tissue. Twenty-two of these (84.6%) were detected following repeat tissue testing by ddPCR. Overall, the ctDNA detection rate in the KRAS mutant population was 66%. Detection of KRAS mutation in ctDNA failed to predict prognosis or refine patient selection for cetuximab. While this study confirms the feasibility of ctDNA analysis in LARC and the high sensitivity of ddPCR, larger series are needed to better address the role of ctDNA as a prognostic or predictive tool in this setting.

Abstract This paper analyzes the historical trends in the energy supply and demand for the Macrometrópole Paulista Energy System, as well as the existing options for harnessing the renewable energy potential of the region. The research included a case study covering the 174 municipalities that belong to the macro-metropolis to characterize the energy system from 2006 to 2017 while analyzing the CO2 emissions of the system. The results indicated that, in 2017, the Paulista macro-metropolis accounted for 73% of the total energy demand of the entire state of São Paulo. Moreover, considering the energy generated from within the administrative limits of the 174 municipalities, the macro-metropolis accounted for about 17% of the total installed capacity of the state for electricity generation. This study found that the installed capacity for electricity generation in the region can be increased by ~ 112%. There so, an understanding of the local energy systems is of utmost importance for the formulation of coherent and integrated public policies, which are necessary to cope with the effects of climate change. Resumo Este artigo analisa a oferta e demanda de energia e investiga as opções de aproveitamento de recursos energéticos locais da Macrometrópole Paulista a partir de fontes renováveis. Para tanto, foi conduzido um estudo abrangendo os 174 municípios da macrometrópole para identificar o Sistema de Energia da região, através do levantamento dos dados históricos sobre consumo e oferta de energia (2006-2017) e de emissões de CO2 decorrentes. Resultados do estudo indicam que a região consumiu em 2017, 73% da demanda total por energia do estado de São Paulo e possui, dentro de seus limites municipais, cerca de 17% da capacidade instalada total para geração de eletricidade do estado. Ainda, seria possível aumentar em 112% a capacidade instalada para geração de eletricidade na região. Conclui-se que a compreensão dos sistemas energéticos locais é indispensável para a formulação de políticas públicas coerentes e integradas, necessárias ao enfrentamento das mudanças climáticas. Resumen Este artículo analizala oferta y la demanda de energía, así como las opciones para aprovechar el potencial energético local en la Macrometrópolis Paulista con base en el uso de fuentes renovables. Se realizó un estudio que abarca los 174 municipios de la Macrometrópolis para identificar el Sistema de Energía de esa región mediante la construcción de un banco de datos sobre el consumo y el suministro de energía (2006-2017), así como sobre las emisiones de CO2. Los resultados indican que en 2017 la región consumió el 73% de la demanda total de energía del estado de São Paulo y posee, dentro de sus límites administrativos, alrededor del 17% de la capacidad instalada total para la generación de electricidad del estado. Sin embargo, sería posible aumentar en un 112% dicha capacidad instalada. Se concluye que la comprensión de los sistemas energéticos locales es indispensable para la formulación de políticas públicas coherentes e integradas, necesarias para hacer frente al cambio climático.

Cancer organoids are miniature, three-dimensional cell culture models that can be made from primary patient tumors and studied in the laboratory. Vlachogiannis et al. asked whether such “tumor-in-a-dish” approaches can be used to predict drug responses in the clinic. They generated a live organoid biobank from patients with metastatic gastrointestinal cancer who had previously been enrolled in phase I or II clinical trials. This allowed the authors to compare organoid drug responses with how the patient actually responded in the clinic. Encouragingly, the organoids had similar molecular profiles to those of the patient tumor, reinforcing their value as a platform for drug screening and development. Science , this issue p. 920 Organoids can recapitulate patient responses in the clinic, with potential for drug screening and personalized medicine. Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living biobank of PDOs from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients recruited in phase 1/2 clinical trials. Phenotypic and genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors. Molecular profiling of tumor organoids was matched to drug-screening results, suggesting that PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses. We compared responses to anticancer agents ex vivo in organoids and PDO-based orthotopic mouse tumor xenograft models with the responses of the patients in clinical trials. Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs.