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Punctuational evolution is pervasive in distal site metastatic colonization.
Proc Biol Sci
January 2025
Cancer Ecology Center, The Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
The evolution of metastasis, the spread of cancer to distal sites within the body, represents a lethal stage of cancer progression. Yet, the evolutionary dynamics that shape the emergence of metastatic disease remain unresolved. Here, using single-cell lineage tracing data in combination with phylogenetic statistical methods, we show that the evolutionary trajectory of metastatic disease is littered with bursts of rapid molecular change as new cellular subpopulations appear, a pattern known as punctuational evolution.
View Article and Find Full Text PDFCodeine 3-O-demethylase catalyzed biotransformation of morphinan alkaloids in Escherichia coli: site directed mutagenesis of terminal residues improves enzyme expression, stability and biotransformation yield.
J Biol Eng
January 2025
The Department of Chemical Engineering and the Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, 3010, Australia.
The cultivation of opium poppy is the only commercially viable source of most morphinan alkaloids. Bioproduction of morphinan alkaloids in recombinant whole-cell systems provides a promising alternate source of these valuable compounds. The enzyme codeine 3-O-demethylase can transform morphinan alkaloids by O-demethylation and has been applied in single step biotransformation reactions or as part of larger biosynthetic cascade, however, the productivity for these reactions remains low and suboptimal enzyme properties could be improved.
View Article and Find Full Text PDFChildhood obesity poses a significant public health challenge, yet the molecular intricacies underlying its pathobiology remain elusive. Leveraging extensive multi-omics profiling (methylome, miRNome, transcriptome, proteins and metabolites) and a rich phenotypic characterization across two parts of Europe within the population-based Human Early Life Exposome project, we unravel the molecular landscape of childhood obesity and associated metabolic dysfunction. Our integrative analysis uncovers three clusters of children defined by specific multi-omics profiles, one of which characterized not only by higher adiposity but also by a high degree of metabolic complications.
View Article and Find Full Text PDFIssues and Limitations on the Road to Fair and Inclusive AI Solutions for Biomedical Challenges.
Sensors (Basel)
January 2025
School of Mathematics, Physics and Computing, University of Southern Queensland, Springfield, QLD 4300, Australia.
Objective: In this paper, we explore the correlation between performance reporting and the development of inclusive AI solutions for biomedical problems. Our study examines the critical aspects of bias and noise in the context of medical decision support, aiming to provide actionable solutions. Contributions: A key contribution of our work is the recognition that measurement processes introduce noise and bias arising from human data interpretation and selection.
View Article and Find Full Text PDFPopulation Pharmacokinetic Modeling of Certepetide in Human Subjects With Metastatic Pancreatic Ductal Adenocarcinoma.
Clin Pharmacol Drug Dev
January 2025
Department of Pharmacometrics Modeling, A2-Ai LLC, Ann Arbor, MI, USA.
Certepetide (aka LSTA1 and CEND-1) is a novel cyclic tumor-targeting internalizing arginyl glycylaspartic acid peptide being developed to treat solid tumors. Certepetide is designed to overcome existing challenges in treating solid tumors by delivering co-administered anticancer drugs into the tumor while selectively depleting immunosuppressive T cells, enhancing cytotoxic T cells in the tumor microenvironment, and inhibiting the metastatic cascade. A population pharmacokinetic (PK) analysis was conducted to characterize the concentration-time profile of patients with metastatic exocrine pancreatic cancer receiving certepetide in combination with nab-paclitaxel and gemcitabine, and to investigate the effects of clinically relevant covariates on PK parameters.
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