The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer

BRG1, a member of the SWI/SNF complex, is mutated in cancer, but it is unclear how it promotes tumourigenesis. We report that re-expression of BRG1 in lung cancer cells up-regulates lung-specific transcripts, restoring the gene expression signature of normal lung. Using cell lines from several cancer types we found that those lacking BRG1 do not respond to retinoic acid (RA) or glucocorticoids (GC), while restoration of BRG1 restores sensitivity. Conversely, in SH-SY5Y cells, a paradigm of RA-dependent differentiation, abrogation of BRG1 prevented the response to RA. Further, our data suggest an antagonistic functional connection between BRG1 and MYC, whereby, refractoriness to RA and GC by BRG1 inactivation involves deregulation of MYC activity. Mechanistically, some of these effects are mediated by BRG1 binding to MYC and MYC-target promoters. The BRG1-MYC antagonism was also evident in primary tumours. Finally, BRG1 restoration significantly dampened invasion and progression and decreased MYC in lung cancer cells orthotopically implanted in nude mice. Thus, BRG1 inactivation enables cancer cells to sustain undifferentiated gene expression programs and prevent its response to environmental stimuli

Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer

Background: acquired resistance to trastuzumab is a major clinical problem in the treatment of HER2-positive (HER2+) breast cancer patients. The selection of trastuzumab-resistant patients is a great challenge of precision oncology. The aim of this study was to identify novel epigenetic biomarkers associated to trastuzumab resistance in HER2+ BC patients. Methods: we performed a genome-wide DNA methylation (450K array) and a transcriptomic analysis (RNA-Seq) comparing trastuzumab-sensitive (SK) and trastuzumab-resistant (SKTR) HER2+ human breast cancer cell models. The methylation and expression levels of candidate genes were validated by bisulfite pyrosequencing and qRT-PCR, respectively. Functional assays were conducted in the SK and SKTR models by gene silencing and overexpression. Methylation analysis in 24 HER2+ human BC samples with complete response or non-response to trastuzumab-based treatment was conducted by bisulfite pyrosequencing. Results: epigenomic and transcriptomic analysis revealed the consistent hypermethylation and downregulation of TGFBI, CXCL2, and SLC38A1 genes in association with trastuzumab resistance. The DNA methylation and expression levels of these genes were validated in both sensitive and resistant models analyzed. Of the genes, TGFBI presented the highest hypermethylation-associated silencing both at the transcriptional and protein level. Ectopic expression of TGFBI in the SKTR model suggest an increased sensitivity to trastuzumab treatment. In primary tumors, TGFBI hypermethylation was significantly associated with trastuzumab resistance in HER2+ breast cancer patients. Conclusions: our results suggest for the first time an association between the epigenetic silencing of TGFBI by DNA methylation and trastuzumab resistance in HER2+ cell models. These results provide the basis for further clinical studies to validate the hypermethylation of TGFBI promoter as a biomarker of trastuzumab resistance in HER2+ breast cancer patients

Water-energy-food nexus and life cycle thinking: A new approach to environmental and nutritional assessment of potato chips

The water-energy-food (WEF) nexus has become a key concept to promote the cross-sectoral coordination toward sustainable development. In particular, understanding the interdependences of these pillars, as well as addressing a life cycle perspective, is essential when evaluating food production systems. This study explores the environmental impacts and nutritional quality of potato chips, addressing life cycle thinking and a WEF nexus approach. For this purpose, the combined application of life cycle assessment (LCA) and the Nutrient-Rich Food 9.3 (NRF9.3) index was considered to identify the main environmental hotspots and advanced opportunities. The results indicated a major contribution of the cultivation stage on water use, whereas the processing accounted for most of the impacts in energy-related indicators and eutrophication potentials. Improvement opportunities reside in the joint application of drip irrigation, allowing to achieve important water savings, as well as the use of natural gas or pellets instead of diesel, which constitute cleaner energy sources. On the other hand, a poor nutritional density of potato chips became evident from the quantification of the NRF9.3, which can be significantly improved if potatoes undergo a roasted process instead of fryingThis research was funded by the Spanish Ministry of Science and Innovation through the KAIROS-BIOCIR project (PID2019-104925RB) (AEO/FEDER, UE)

Fatigue limit of recycled aggregate concrete

This paper presents the main results of the research carried out to obtain the fatigue limit of concrete incorporating recycled aggregate from concrete. In this research, recycled aggregate concretes with partial and total coarse aggregate replacement and control concretes with different increasing water/cement ratios have been cast to study the material’s behavior in response to repeated compressive loads. The results show that, for the same water/cement ratio, the recycled aggregate concretes present a loss of stiffness higher than the control concrete. Furthermore, the use of recycled aggregate in concrete implies a reduction of the fatigue life. These differences are increased for low water/cement ratios, as in this case the main factor is the lower strength capacity of the aggregate. From the results obtained, recommendable mixtures for recycled aggregates exposed to fatigue loads are proposed

Towards a sustainable agri-food system by an energetic and environmental efficiency assessment

Feeding the world’s population sustainably is a major challenge of our society and has been stated as one of the key priorities for development cooperation by the EU policy framework on food security. However, the current pattern of natural resources exploitation to meet humanity’s demand for food threatens long-term food security. Food systems represent around 30 % of final energy use, generating up to 30 % of greenhouse gas (GHG) emissions. Given the expected increase of global population (9 billion people by 2050) and the amount of food losses and waste generated (a third of global food production), improving the efficiency of food systems along the supply chain is essential to ensure food security. This work combines life cycle assessment (LCA) and data envelopment analysis (DEA) to assess the efficiency of Spanish agri-food system and propose improvement actions in order to reduce energy usage and GHG emissions. Results suggest that sweets and vegetable fats categories provide the largest nutritional energy to consumer per unit of embedded energy in its production. Around a 70 % average reduction target is estimated for the Spanish agri-food system to be efficient, with a similar reduction in related greenhouse gas emissions.The authors are grateful for the funding of the Spanish Ministry of Economy and Competitiveness through the Ceres-Procom: Food production and consumption strategies for climate change mitigation (CTM2016-76176- C2-1-R) (AEI/FEDER, UE)

Looking for answers to food loss and waste management in Spain from a holistic nutritional and economic approach

The generation of food loss and waste (FLW) is a global problem for worldwide politics. About one-third of the food produced ends up in the rubbish before it is consumed. For this reason, it is essential to design and implement new strategies along the food supply chain (FSC) with the aim of reducing this FLW at each stage. However, not only mass quantification should be considered, but also economic and nutritional performance. The novelty of this study is the definition of a methodology based on the “distance to target” approach by means of multi-objective optimization to evaluate the economic and nutritional cost produced by this FLW. This methodology was applied to the Spanish food basket in 2015. The results revealed that 80% of the total FLW generated in economic and nutritional terms is concentrated in the agricultural production (53.3%) and consumption (26.3%) stages. In the first stages of the FSC, fruits (Dn eq.= 0.7), cereals (Dn eq.= 0.61), and vegetables (Dn eq.= 0.57) were the furthest from the distance target due to the great amount of FLW generated. Moreover, according to the normalized weighted distances obtained from the minimization of economic and nutritional cost, pulses (Dn eq. = 0.05–0.03) and eggs (Dn eq. = 0.02) were the more efficient food categories. The methodology described in this study proposes a single index to quantify the economic and nutritional cost of different food categories to facilitate the decision-making process. This index makes possible the definition of reduction strategies focused on specific food categories and depending on the FSC stage.This research was funded by Spanish Ministry of Science and Competitiveness, grant number CERES-PROCON Project CTM2016-76176 (AEI/FEDER, UE) and KAIROS-BIOCIR Project PID2019-104925RB (AEO/FEDER, UE)

Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19

Introduction: Loss-of-function TLR7 variants have been recently reported in a small number of males to underlie strong predisposition to severe COVID-19. We aimed to determine the presence of these rare variants in young men with severe COVID-19. Methods: We prospectively studied males between 18 and 50 years-old without predisposing comorbidities that required at least high-flow nasal oxygen to treat COVID-19. The coding region of TLR7 was sequenced to assess the presence of potentially deleterious variants. Results: TLR7 missense variants were identified in two out of 14 patients (14.3%). Overall, the median age was 38 (IQR 30-45) years. Both variants were not previously reported in population control databases and were predicted to be damaging by in silico predictors. In a 30-year-old patient a maternally inherited variant [c.644A>G; p.(Asn215Ser)] was identified, co-segregating in his 27-year-old brother who also contracted severe COVID-19. A second variant [c.2797T>C; p.(Trp933Arg)] was found in a 28-year-old patient, co-segregating in his 24-year-old brother who developed mild COVID-19. Functional testing of this variant revealed decreased type I and II interferon responses in peripheral mononuclear blood cells upon stimulation with the TLR7 agonist imiquimod, confirming a loss-of-function effect. Conclusions: This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but also enables pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions

Food loss and waste metrics: a proposed nutritional cost footprint linking linear programming and life cycle assessment

Purpose: The main purpose of this article is to assess the nutritional and economic efficiency of food loss and waste (FLW) along the supply of 13 food categories included in the Spanish food basket by means of the definition of a new method which combines two indexes. Methods: The nutrient-rich foods index and the economic food loss and waste (EFLW) index were combined by means of linear programming to obtain the nutritional cost footprint (NCF) indicator under a life cycle perspective. The functional unit used was the daily supply of food for a Spanish citizen in year 2015. Results and discussion: Results showed that vegetables and cereals were the food categories most affected by the inefficiencies in the food supply chain under a nutritional perspective, being agricultural production and household consumption the main stages in which the nutritional content of food is lost or wasted. Moreover, according to the NCF index, vegetables represented 27% of total nutritional-economic wastage throughout the entire Spanish agri-food chain. They are followed by fruits, which add up to 19%. Hence, specific food waste management strategies should be established for these specific products and supply stages. Finally, the sensitivity analysis performed highlighted that results were mostly independent from the importance attributed to either nutritional or economic variables. Conclusions: The methodology described in this study proposes an indicator quantifying the nutritional-economic cost of different food categories in the Spanish food basket. This NCF indicator makes it possible to define reduction strategies to promote the use of food waste fractions for waste-to-energy valorization approaches or the extraction of different types of pharmacological, chemical, or cosmetic compounds.The authors are grateful for the funding of the Spanish Ministry of Economy and Competitiveness through the Ceres-Procom: Food production and consumption strategies for climate change mitigation (CTM2016-76176-C2-1-R) (AEI/FEDER, UE)