Pharmacodynamic Modeling of Anti-Cancer Activity of Tetraiodothyroacetic Acid in a Perfused Cell Culture System

Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin αvβ3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro-apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti-proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations

Perspectives and Integration in SOLAS Science

Why a chapter on Perspectives and Integration in SOLAS Science in this book? SOLAS science by its nature deals with interactions that occur: across a wide spectrum of time and space scales, involve gases and particles, between the ocean and the atmosphere, across many disciplines including chemistry, biology, optics, physics, mathematics, computing, socio-economics and consequently interactions between many different scientists and across scientific generations. This chapter provides a guide through the remarkable diversity of cross-cutting approaches and tools in the gigantic puzzle of the SOLAS realm. Here we overview the existing prime components of atmospheric and oceanic observing systems, with the acquisition of ocean–atmosphere observables either from in situ or from satellites, the rich hierarchy of models to test our knowledge of Earth System functioning, and the tremendous efforts accomplished over the last decade within the COST Action 735 and SOLAS Integration project frameworks to understand, as best we can, the current physical and biogeochemical state of the atmosphere and ocean commons. A few SOLAS integrative studies illustrate the full meaning of interactions, paving the way for even tighter connections between thematic fields. Ultimately, SOLAS research will also develop with an enhanced consideration of societal demand while preserving fundamental research coherency. The exchange of energy, gases and particles across the air-sea interface is controlled by a variety of biological, chemical and physical processes that operate across broad spatial and temporal scales. These processes influence the composition, biogeochemical and chemical properties of both the oceanic and atmospheric boundary layers and ultimately shape the Earth system response to climate and environmental change, as detailed in the previous four chapters. In this cross-cutting chapter we present some of the SOLAS achievements over the last decade in terms of integration, upscaling observational information from process-oriented studies and expeditionary research with key tools such as remote sensing and modelling. Here we do not pretend to encompass the entire legacy of SOLAS efforts but rather offer a selective view of some of the major integrative SOLAS studies that combined available pieces of the immense jigsaw puzzle. These include, for instance, COST efforts to build up global climatologies of SOLAS relevant parameters such as dimethyl sulphide, interconnection between volcanic ash and ecosystem response in the eastern subarctic North Pacific, optimal strategy to derive basin-scale CO2 uptake with good precision, or significant reduction of the uncertainties in sea-salt aerosol source functions. Predicting the future trajectory of Earth’s climate and habitability is the main task ahead. Some possible routes for the SOLAS scientific community to reach this overarching goal conclude the chapter

Impact of educational interventions on adolescent attitudes and knowledge regarding vaccination: A pilot study

© 2018 Carolan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Current immunisation levels in England currently fall slightly below the threshold recommended by the World Health Organization, and the three-year trend for vaccination uptake is downwards. Attitudes towards vaccination can affect future decisions on whether or not to vaccinate, and this can have significant public health implications. Interventions can impact future vaccination decisions, and these interventions can take several forms. Relatively little work has been reported on the use of vaccination interventions in young people, who form the next generation of individuals likely to make vaccination decisions. Method We investigated the impact of two different types of educational intervention on attitudes towards vaccination in young people in England. A cohort of young people (n = 63) was recruited via a local school. This group was divided into three sub-groups; one (n = 21) received a presentation-based intervent ion, one (n = 26) received an interactive simulation-based intervention, and the third (n = 16) received no intervention. Participants supplied information on (1) their attitudes towards vaccination, and (2) their information needs and views on personal choice concerning vaccination, at three time points: immediately before and after the intervention, and after six months. Results Neither intervention had a significant effect on participants’ attitudes towards vaccination. However, the group receiving the presentation-based intervention saw a sustained uplift in confidence about information needs, which was not observed in the simulation-based intervention group. Discussion Our findings with young people are consistent with previous work on vaccination interventions aimed at adults, which have shown limited effectiveness, and which can actually reduce intention to vaccinate. Our findings on the most effective mode of delivery for the intervention should inform future discussion in the growing “games for health” domain, which proposes the use of interactive digital resources in healthcare education

Human p32: A coactivator for Epstein-Barr virus nuclear antigen-1-mediated transcriptional activation and possible role in viral latent cycle DNA replication

The Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1) is required for the maintenance of the viral chromosome in latently infected, proliferating cells and plays a role in latent cycle DNA replication. EBNA-1 also functions as a positive and negative regulator of EBV gene expression. We have investigated the interaction of EBNA-1 with p32, a host mitochondrial protein that associates with EBNA-1 in EBV-positive Burkitt's lymphoma cells. Using a chromatin immunoprecipitation assay, we found that a fraction of p32 localizes to the viral latent cycle origin of DNA replication oriP in vivo, p32 binds EBNA-1 independently of other proteins or DNA. EBNA-1 variants lacking one of two p32 binding elements did not interact stably with p32 in cultured cells and were defective for both transcriptional activation of a reporter gene linked to oriP FR and replication and/or maintenance of a plasmid bearing oriP These results support a role for p32 in transcriptional activation by EBNA-1 and suggest that p32 plays a role in EBV latent cycle DNA replication. (C) 2000 Academic Press

Duct Tape Occlusion Therapy in the Treatment of Plantar Warts

This case study was written in 2004 and submitted to the Journal of the Canadian Medical Association. The paper was accepted, however, was never resubmitted. Manuscript was updated Sept. 2020.ABSTRACT Background: Plantar warts are generally unsightly, often painful, and they can resist typical forms of treatment. Generally, these treatments involve a combination of procedures including topical application, excision, and cryotherapy and can require numerous office visits. This paper reports on the efficacy of duct tape occlusion therapy in the treatment of plantar warts that resisted all other forms of treatment over a ten-year period. Methods: At the time the patient began duct tape occlusion therapy he had developed a 2.5 cm diameter verrucous plaque on his right heal with nine additional solitary plantar warts distributed from the head to the ball of the foot. Strips of duct tape 8-10 cm in length were applied over the affected area and changed every 1-3 days. Occasionally the warts were pared down with a razor blade. Results: A two-month treatment of plantar warts by duct-tape occlusion therapy resulted in complete disappearance of a 2.5 cm verrucous plaque and nine solitary plantar warts distributed from the heel to the ball of the foot, including warts that had never been covered by the tape. Conclusion: Duct tape occlusion therapy proved to be an effective therapy for treatment of plantar warts that had resisted repeated treatment by traditional methods

Array of Interdigitated Bipolar Electrodes for Selective Capture and Analysis of Melanoma Cells

We report a method for dielectrophoretic capture of melanoma cells and their electrochemical analysis for tumor-specific markers, using a microfluidic device composed of microwells overlying an array of interdigitated bipolar electrodes (IDBPEs). In this device, cells are captured on each IDBPE by dielectrophoresis, and microfabricated wells allow for retention of the cells to enable their subsequent electrochemical analysis. This advancement is significant because it addresses a need for cancer diagnostics with few- to single-cell resolution amenable to use in low-resource settings. Specifically, this approach combines the selectivity of dielectrophoresis for cell phenotype, the low cost of electrochemical methods, and the ability of BPEs to be arrayed, with the sensitivity afforded by interdigitation. The IDBPE detects a redox-active species produced by an enzyme-linked antibody targeted to a cell surface antigen, and reports the current by electrochemiluminescence. In this work, we first characterize cell capture by dielectrophoresis at the IDBPE array. Second, the retention of cells in the microwells and their viability is demonstrated. Then, the sensitivity of the IDBPE for the redox-active species is quantified. Finally, we demonstrate capture and analysis of melanoma cells at the IDBPE array, which underscores the ability of the IDBPE to achieve biologically relevant detection limits.This article is published as Borchers, Janis S., Morgan J. Clark, Savanah B. Van Scoy, and Robbyn K. Anand. "Array of Interdigitated Bipolar Electrodes for Selective Capture and Analysis of Melanoma Cells." ChemElectroChem (2024): e202300345. doi: https://doi.org/10.1002/celc.202300345. © 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution License

Array of Interdigitated Bipolar Electrodes for Selective Capture and Analysis of Melanoma Cells

Abstract We report a method for dielectrophoretic capture of melanoma cells and their electrochemical analysis for tumor‐specific markers, using a microfluidic device composed of microwells overlying an array of interdigitated bipolar electrodes (IDBPEs). In this device, cells are captured on each IDBPE by dielectrophoresis, and microfabricated wells allow for retention of the cells to enable their subsequent electrochemical analysis. This advancement is significant because it addresses a need for cancer diagnostics with few‐ to single‐cell resolution amenable to use in low‐resource settings. Specifically, this approach combines the selectivity of dielectrophoresis for cell phenotype, the low cost of electrochemical methods, and the ability of BPEs to be arrayed, with the sensitivity afforded by interdigitation. The IDBPE detects a redox‐active species produced by an enzyme‐linked antibody targeted to a cell surface antigen, and reports the current by electrochemiluminescence. In this work, we first characterize cell capture by dielectrophoresis at the IDBPE array. Second, the retention of cells in the microwells and their viability is demonstrated. Then, the sensitivity of the IDBPE for the redox‐active species is quantified. Finally, we demonstrate capture and analysis of melanoma cells at the IDBPE array, which underscores the ability of the IDBPE to achieve biologically relevant detection limits