• MeSH
• Risk Assessment MeSH
• Carcinogens, Environmental MeSH
• Disease Models, Animal MeSH
• Environmental Illness MeSH
• Environmental Exposure MeSH

• Conspectus
• Veřejné zdraví a hygiena
• NML Fields
• environmentální vědy

• MeSH
• Risk Assessment MeSH
• Carcinogens, Environmental MeSH
• Disease Models, Animal MeSH
• Environmental Illness MeSH
• Environmental Exposure MeSH

• Conspectus
• Veřejné zdraví a hygiena
• NML Fields
• environmentální vědy

The lack of exact definition of the concept of biological age (BA) is a typical feature of works concerning BA. That is why comparison of results of various published methods makes little sense and eventual proof of their optimality is impossible. Based on natural and simple presumptions, an attempt to express mathematically the supposed relation between chronological age (CA) and BA has proven to be unexpectedly fruitful. In the present paper, an optimum method of estimation of BA, which is easily applicable even in nonlinear cases, is derived. Moreover, the method allows evaluating the precision of the estimates and also offers tools for validation of presumptions of the method. A special feature of the method is that CA should be used as a standard biomarker, leading to essential improving the precision of BA-estimate and illuminating relativity of the known "paradox of biomarkers". All theoretical results of the method were fully approved by means of a special simulation program. Further, the theory and the results of the simulation have proven that many published results of BA-estimates using multiple linear regression (MLR) are very probably disserviceable because CA is typically more precise estimate of BA than estimates computed by MLR. This unpleasant conclusion also concerns methods, which use MLR as the final step after transformation of the battery of biomarkers by factor analysis or by principal component analysis.

• MeSH
• Models, Biological MeSH
• Financing, Organized MeSH
• Humans MeSH
• Aging physiology   MeSH
• Computational Biology methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH

• MeSH
• Environmental Monitoring methods   MeSH
• Data Collection MeSH
• Models, Theoretical MeSH
• Toxicity Tests MeSH
• Environmental Exposure MeSH

• Conspectus
• Lékařské vědy. Lékařství
• NML Fields
• environmentální vědy
• toxikologie
• management, organizace a řízení zdravotnictví
• environmentální vědy
• environmentální vědy
• farmacie a farmakologie
• veřejné zdravotnictví
• NML Publication type
• publikace WHO

• MeSH
• Environmental Health trends   MeSH
• Publication type
• Periodical MeSH

• Conspectus
• Hygiena. Lidské zdraví
• NML Fields
• environmentální vědy

• MeSH
• Behavior MeSH
• Psychology, Applied MeSH
• Publication type
• Monograph MeSH

• Conspectus
• Psychologie
• NML Fields
• psychologie, klinická psychologie

• MeSH
• Delivery of Health Care organization & administration   MeSH
• Health Services Administration MeSH
• Publication type
• Congress MeSH
• Collected Work MeSH

• Conspectus
• Veřejné zdraví a hygiena
• NML Fields
• management, organizace a řízení zdravotnictví
• veřejné zdravotnictví

Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that the disulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregase to suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxic effects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, and mechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diverse human cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed by features of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein and its functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomics profiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolonged exposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneous pharmacological inhibition of RiBi and/or autophagy that further enhanced CuET's tumor cytotoxicity, using both cell culture and zebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET's anti-cancer activity, inform about the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in light of cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET in oncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, rather than old, approved drugs with their, often complex, metabolic profiles.

• MeSH
• Zebrafish metabolism   MeSH
• Disulfiram * metabolism   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Neoplasms * metabolism   MeSH
• Ribosomes metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Health Care Economics and Organizations MeSH
• Medical Informatics MeSH
• Health Care Surveys MeSH
• Health Care Reform MeSH
• Quality Assurance, Health Care MeSH
• Publication type
• Congress MeSH

• Conspectus
• Veřejné zdraví a hygiena
• NML Fields
• veřejné zdravotnictví

• MeSH
• Biology MeSH
• Publication type
• Monograph MeSH

• Conspectus
• Obecná biologie
• NML Fields
• biologie