Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.

Copper (Cu) is an essential trace element required for mitochondrial respiration. Late-stage clear cell renal cell carcinoma (ccRCC) accumulates Cu and allocates it to mitochondrial cytochrome c oxidase. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis, promoting tumor growth and progression of ccRCC. Specifically, Cu induces TCA cycle-dependent oxidation of glucose and its utilization for glutathione biosynthesis to protect against H 2 O 2 generated during mitochondrial respiration, therefore coordinating bioenergy production with redox protection. scRNA-seq determined that ccRCC progression involves increased expression of subunits of respiratory complexes, genes in glutathione and Cu metabolism, and NRF2 targets, alongside a decrease in HIF activity, a hallmark of ccRCC. Spatial transcriptomics identified that proliferating cancer cells are embedded in clusters of cells with oxidative metabolism supporting effects of metabolic states on ccRCC progression. Our work establishes novel vulnerabilities with potential for therapeutic interventions in ccRCC. Accumulation of copper is associated with progression and relapse of ccRCC and drives tumor growth.Cu accumulation and allocation to cytochrome c oxidase (CuCOX) remodels metabolism coupling energy production and nucleotide biosynthesis with maintenance of redox homeostasis.Cu induces oxidative phosphorylation via alterations in the mitochondrial proteome and lipidome necessary for the formation of the respiratory supercomplexes. Cu stimulates glutathione biosynthesis and glutathione derived specifically from glucose is necessary for survival of Cu Hi cells. Biosynthesis of glucose-derived glutathione requires activity of glutamyl pyruvate transaminase 2, entry of glucose-derived pyruvate to mitochondria via alanine, and the glutamate exporter, SLC25A22. Glutathione derived from glucose maintains redox homeostasis in Cu-treated cells, reducing Cu-H 2 O 2 Fenton-like reaction mediated cell death. Progression of human ccRCC is associated with gene expression signature characterized by induction of ETC/OxPhos/GSH/Cu-related genes and decrease in HIF/glycolytic genes in subpopulations of cancer cells. Enhanced, concordant expression of genes related to ETC/OxPhos, GSH, and Cu characterizes metabolically active subpopulations of ccRCC cells in regions adjacent to proliferative subpopulations of ccRCC cells, implicating oxidative metabolism in supporting tumor growth.

Influence of culinary treatment on the concentration and on the bioavailability of cadmium, chromium, copper, and lead in seafood.

BACKGROUND: Seafood present important advantages for human nutrition, but it can also accumulate high levels of toxic and potentially toxic elements. Culinary treatments could influence seafood chemical element content and element bioavailability. In this study, the influence of culinary treatments on the total concentration and on the bioavailability of Cd, Cr, Cu and Pb in shark, shrimp, squid, oyster, and scallop was assessed. METHODS: Boiling, frying, and sautéing with or without seasonings (salt, lemon juice and garlic) were evaluated. Total concentration and bioavailability of Cd, Cr, Cu and Pb in seafood after all these culinary treatments were compared with those in uncooked samples. Analytes were determined by triple-quadrupole inductively coupled plasma mass spectrometry (ICP-MS/MS). An alternative to express the results avoiding underestimated or overestimated values was proposed. RESULTS: The analytes concentration in seafood without culinary treatment varied from 0.0030 µg g-1 (shrimp) to 0.338 µg g-1 (oyster) for Cd; 0.010 µg g-1 (squid) to 0.036 µg g-1 (oyster) for Cr; 0.088 µg g-1 (scallop) to 8.63 µg g-1 (oyster) for Cu, and < 0.005 µg g-1 (shrimp, squid and oyster) to 0.020 µg g-1 (shark) for Pb. Only Cd (in scallop) was influenced by culinary treatments (reduction from 37 to 53 % after boiling, frying, and sautéing). Bioavailability percentage varied from 11% (oyster) for Cd; 18% (oyster) to 41% (shark) for Cr; 6% (shark) for Cu, and 8% (oyster) for Pb. Bioavailability percentage was not influenced by culinary treatments. CONCLUSION: Cadmium concentration was reduced in scallop after some culinary treatments (reduction o 37-53% after boiling, frying, and sautéing), but bioavailability percentage was not influenced. The employed analytical method was adequate for the purpose, presenting import results for food safety assessment about the influence of culinary treatments on metals concentration and bioavailability in seafood.

Hearing prevention program: how speech-language pathologists and audiologists work in the occupational health area / Programa de preservação auditiva: como atuam os fonoaudiólogos da área da saúde do trabalhador

ABSTRACT Objective: to characterize speech-language pathologists/audiologists and their interventions in the occupational health area, regarding the Hearing Prevention Program (HPP). Methods: a cross-sectional, quantitative study with 74 speech-language pathologists/audiologists from several regions of Brazil, working in the areas of Occupational Health and Audiology. The participants answered a questionnaire on their professional and educational profile, as well as on their work related to the HCP components. For data analysis, statistical procedures were used (Chi-Square Test and the test of difference in proportions, at the significance level of 0.05 - 5%), in relation to the variables of gender, age, job position, time since their graduation and academic training in occupational safety and health. Results: the speech-language pathologists/audiologists, mostly women, who reported performing the HPP, were older than 30 years, had specific postgraduate courses, but still had doubts about the Program implementation, they worked for companies with over 1,000 employees, disregarding their employment status, performing interventions, such as: hearing management and guidance on the correct use of ear protectors. Conclusion: a high number of speech-language pathologists in the Occupational Health area have not developed a complete hearing conservation program to this date.

RESUMO Objetivo: caracterizar os fonoaudiólogos e as ações que desenvolvem na área da saúde do trabalhador com relação ao Programa de Preservação Auditiva (PPA). Métodos: estudo quantitativo, transversal, com 74 fonoaudiólogos de diversas regiões do Brasil que trabalham em Saúde do Trabalhador e Audiologia. Os participantes responderam a um questionário sobre seu perfil profissional, formação e atuação em relação aos componentes do PPA. Para a análise dos dados utilizou-se procedimentos estatísticos (teste Qui-Quadrado e o teste de diferença de proporções, ao nível de significância 0,05 - 5%) em relação às variáveis sexo, idade, função, tempo de formado e formação acadêmica em saúde e segurança do trabalho. Resultados: os fonoaudiólogos, a maioria mulheres, que relataram realizar o PPA, tinham idade superior a 30 anos; fizeram cursos de pós-graduação específica, mas ainda apresentavam dúvidas em relação à implantação do Programa; estavam em empresas com mais de 1000 funcionários, independentemente de seu regime de trabalho, realizando ações como: gerenciamento auditivo e orientação sobre utilização correta de protetores auriculares. Conclusão: há ainda um número elevado de fonoaudiólogos na área de Saúde do Trabalhador que não desenvolvem um programa de preservação auditiva na íntegra.