A tumor cord model for Doxorubicin delivery and dose optimization in solid tumors

<p>Abstract</p> <p>Background</p> <p>Doxorubicin is a common anticancer agent used in the treatment of a number of neoplasms, with the lifetime dose limited due to the potential for cardiotoxocity. This has motivated efforts to develop optimal dosage regimes that maximize anti-tumor activity while minimizing cardiac toxicity, which is correlated with peak plasma concentration. Doxorubicin is characterized by poor penetration from tumoral vessels into the tumor mass, due to the highly irregular tumor vasculature. I model the delivery of a soluble drug from the vasculature to a solid tumor using a tumor cord model and examine the penetration of doxorubicin under different dosage regimes and tumor microenvironments.</p> <p>Methods</p> <p>A coupled ODE-PDE model is employed where drug is transported from the vasculature into a tumor cord domain according to the principle of solute transport. Within the tumor cord, extracellular drug diffuses and saturable pharmacokinetics govern uptake and efflux by cancer cells. Cancer cell death is also determined as a function of peak intracellular drug concentration.</p> <p>Results</p> <p>The model predicts that transport to the tumor cord from the vasculature is dominated by diffusive transport of free drug during the initial plasma drug distribution phase. I characterize the effect of all parameters describing the tumor microenvironment on drug delivery, and large intercapillary distance is predicted to be a major barrier to drug delivery. Comparing continuous drug infusion with bolus injection shows that the optimum infusion time depends upon the drug dose, with bolus injection best for low-dose therapy but short infusions better for high doses. Simulations of multiple treatments suggest that additional treatments have similar efficacy in terms of cell mortality, but drug penetration is limited. Moreover, fractionating a single large dose into several smaller doses slightly improves anti-tumor efficacy.</p> <p>Conclusion</p> <p>Drug infusion time has a significant effect on the spatial profile of cell mortality within tumor cord systems. Therefore, extending infusion times (up to 2 hours) and fractionating large doses are two strategies that may preserve or increase anti-tumor activity and reduce cardiotoxicity by decreasing peak plasma concentration. However, even under optimal conditions, doxorubicin may have limited delivery into advanced solid tumors.</p

Short Day Transcriptomic Programming During Induction of Dormancy in Grapevine

Bud dormancy in grapevine is an adaptive strategy for the survival of drought, high and low temperatures and freeze dehydration stress that limit the range of cultivar adaptation. Therefore, development of a comprehensive understanding of the biological mechanisms involved in bud dormancy is needed to promote advances in selection and breeding, and to develop improved cultural practices for existing grape cultivars. The seasonally indeterminate grapevine, which continuously develops compound axillary buds during the growing season, provides an excellent system for dissecting dormancy, because the grapevine does not transition through terminal bud development prior to dormancy. This study used gene expression patterns and targeted metabolite analysis of two grapevine genotypes that are short photoperiod responsive (Vitis riparia) and non-responsive (V. hybrid, Seyval) for dormancy development to determine differences between bud maturation and dormancy commitment. Grapevine gene expression and metabolites were monitored at seven time points under long (LD, 15 h) and short (SD, 13 h) day treatments. The use of age-matched buds and a small (2 h) photoperiod difference minimized developmental differences and allowed us to separate general photoperiod from dormancy specific gene responses. Gene expression profiles indicated three distinct phases (perception, induction and dormancy) in SD-induced dormancy development in V. riparia. Different genes from the NAC DOMAIN CONTAINING PROTEIN 19 and WRKY families of transcription factors were differentially expressed in each phase of dormancy. Metabolite and transcriptome analyses indicated ABA, trehalose, raffinose and resveratrol compounds have a potential role in dormancy commitment. Finally, a comparison between V. riparia compound axillary bud dormancy and dormancy responses in other species emphasized the relationship between dormancy and the expression of RESVERATROL SYNTHASE and genes associated with C3HC4-TYPE RING FINGER and NAC DOMAIN CONTAINING PROTEIN 19 transcription factors

The Role of Magnetic Resonance Imaging in Diagnosis and Management of Breast Cancer

A review of the literature on the current applications of breast magnetic resonance imaging (MRI) indications, their rationale and their place in diagnosis and management of breast cancer was given. Contrast-enhanced breast MRI is developing as a valuable adjunct to mammography and sonography. Its high sensitivity for invasive breast cancer establishes its superiority in evaluation of multifocality/multicentricity, tumor response to neoadjuvant chemotherapy, detection of recurrence, and staging. Emerging applications include spectroscopy, usage of new contrast agents, and MRI-guided interventions, including noninvasive treatment of breast cancer. Its potential benefit in screening high-risk women has yet to be established with prospective studies, particularly with regard to false positive results

The influence of P-glycoprotein expression and its inhibitors on the distribution of doxorubicin in breast tumors

Abstract Background Anti-cancer drugs access solid tumors via blood vessels, and must penetrate tumor tissue to reach all cancer cells. Previous studies have demonstrated steep gradients of decreasing doxorubicin fluorescence with increasing distance from blood vessels, such that many tumor cells are not exposed to drug. Studies using multilayered cell cultures show that increased P-glycoprotein (PgP) is associated with better penetration of doxorubicin, while PgP inhibitors decrease drug penetration in tumor tissue. Here we evaluate the effect of PgP expression on doxorubicin distribution in vivo. Methods Mice bearing tumor sublines with either high or low expression of PgP were treated with doxorubicin, with or without pre-treatment with the PgP inhibitors verapamil or PSC 833. The distribution of doxorubicin in relation to tumor blood vessels was quantified using immunofluorescence. Results Our results indicate greater uptake of doxorubicin by cells near blood vessels in wild type as compared to PgP-overexpressing tumors, and pre-treatment with verapamil or PSC 833 increased uptake in PgP-overexpressing tumors. However, there were steeper gradients of decreasing doxorubicin fluorescence in wild-type tumors compared to PgP overexpressing tumors, and treatment of PgP overexpressing tumors with PgP inhibitors led to steeper gradients and greater heterogeneity in the distribution of doxorubicin. Conclusion PgP inhibitors increase uptake of doxorubicin in cells close to blood vessels, have little effect on drug uptake into cells at intermediate distances, and might have a paradoxical effect to decrease doxorubicin uptake into distal cells. This effect probably contributes to the limited success of PgP inhibitors in clinical trials

Charting Disaster Recovery via Google Street View: A Social Science Perspective on Challenges Raised by the Fukushima Nuclear Disaster

There is increasing interest in using Google Street View (GSV) for research purposes, particularly with regard to “virtually auditing” the built environment to assess environmental quality. Research in this field to date generally suggests GSV is a reliable means of understanding the “real world” environment. But limitations around the dates and resolution of images have been identified. An emerging strand within this literature is also concerned with the potential of GSV to understand recovery post-disaster. Using the GSV data set for the evacuated area around the Fukushima Dai’ichi nuclear power plant as a case study, this article evaluates GSV as a means of assessing disaster recovery in a dynamic situation with remaining uncertainty and a significant value and emotive dimension. The article suggests that GSV does have value in giving a high-level overview of the post-disaster situation and has potential to track recovery and resettlement over time. Drawing on social science literature relating to Fukushima, and disasters more widely, the article also argues it is imperative for researchers using GSV to reflect carefully on the wider socio-cultural contexts that are often not represented in the photo montage

A Novel Capacitance-Based Emulsion Monitoring Technology

AbstractThe objective of this paper is to introduce a capacitance-based fixture to assess and monitor crude oil and water emulsion separation kinetics in Gas Oil Separation Plants (GOSPs). The technology provides an online phase separation assessment through dielectric response analysis.The principle of operation of this technology is based on measuring the changes in the capacitance of water/crude oil system versus time as the separation process develops. Free water, emulsion and dry crude oil have different electrical properties, and provide a unique signature to describe the physical composition of the system they form. The evolution of electrical properties of crude oil emulsions at different temperatures, and with or without the addition of chemical demulsifiers is reported.The monitoring tool consists of a cylindrical fixture where the emulsion electrical properties are monitored during the phase separation. The fixture is connected to an Inductance Capacitance Resistance meter (LCR) to measure the change in electrical impedance of the emulsion. The fixture has a cylindrical geometry and its design was adapted to discretize the phase distribution of complex fluid mixtures. The fixture electrical properties were estimated based on its shape and material of construction, and verified by measuring the electrical impedance of fluids of known dielectric properties. The technology was tested under different conditions of temperature and concentration of demulsifier and was able to measure accurately the sample water cut and to monitor water separation kinetics in real time.The results are driving the development of an online emulsion stability assessment tool to characterize emulsion separation kinetics at process conditions. In addition, this tool will improve the accuracy of emulsion separation measurements in crude oil processing facilities by avoiding emulsion alteration due to degassing, shearing and aging inherent to bottle test procedure.</jats:p