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

The patriation of Canadian corporate law

Canadian corporate law belongs within a broader Anglo-American legal tradition, sharing many of the features of other common law jurisdictions, most notably England and the United States. Prior to Confederation, Canadian corporate law first emerged from nineteenth-century English legislation and continued to resemble English law – at least superficially – well into the twentieth century. Legislation is only one source of corporate law, however. Just as important is the creation of legal rules through the common law adjudicatory process. Thus, examining case law raises an important empirical question distinct from, though relevant to, the issue of legislative influence – namely, what have been the major influences on Canadian judicial law-making? This article addresses this question through a comprehensive citation analysis of substantially all corporate law decisions by Canadian courts of appeal since 1867. The primary findings are as follows: (a) over the past 150 years, Canadian corporate law – once dominated by English precedent – has become increasingly characterized by domestic Canadian precedent; (b) historically, the Judicial Committee of the Privy Council played an important role in maintaining English influence, such that the prominence of English precedent decreased after 1949; and (c) despite the increasing influence of Canadian precedent throughout the Canadian legal system, Canadian courts continue to cite English cases when addressing unsettled legal issues, preserving a channel for the continuing influence of English jurisprudence in Canada. Surprisingly, Canadian judicial decisions rarely cite American cases, challenging the notion that Canadian courts have been significantly influenced by American law. Ultimately – and despite residual English influence – Canadian corporate law has formed its own distinct identity

Made in Italy e cultura. Indagine sull'identità culturale italiana

il volume raccoglie una serie di studi scientifici sull'Italia contemporanea su più discipline: economia, agricoltura, design, moda, pubblicità, letteratura, cinema, filosofia, linguistica, musica. Lo scopo è quello di provare a comprendere la genealogia culturale del "made in Italy" come chiave per accedere all'identità italiana contemporanea.The book brings together a series of scientific studies on contemporary Italy in a number of disciplines: economics, agriculture, design, fashion, advertising, literature, cinema, philosophy, linguistics and music. The aim is to try to understand the cultural genealogy of "made in Italy" as a key to accessing contemporary Italian identity

Leaves of the Arabidopsis maltose exporter1 Mutant Exhibit a Metabolic Profile with Features of Cold Acclimation in the Warm

BACKGROUND: Arabidopsis plants accumulate maltose from starch breakdown during cold acclimation. The Arabidopsis mutant, maltose excess1-1, accumulates large amounts of maltose in the plastid even in the warm, due to a deficient plastid envelope maltose transporter. We therefore investigated whether the elevated maltose level in mex1-1 in the warm could result in changes in metabolism and physiology typical of WT plants grown in the cold. PRINCIPAL FINDINGS: Grown at 21 °C, mex1-1 plants were much smaller, with fewer leaves, and elevated carbohydrates and amino acids compared to WT. However, after transfer to 4 °C the total soluble sugar pool and amino acid concentration was in equal abundance in both genotypes, although the most abundant sugar in mex1-1 was still maltose whereas sucrose was in greatest abundance in WT. The chlorophyll a/b ratio in WT was much lower in the cold than in the warm, but in mex1-1 it was low in both warm and cold. After prolonged growth at 4 °C, the shoot biomass, rosette diameter and number of leaves at bolting were similar in mex1-1 and WT. CONCLUSIONS: The mex1-1 mutation in warm-grown plants confers aspects of cold acclimation, including elevated levels of sugars and amino acids and low chlorophyll a/b ratio. This may in turn compromise growth of mex1-1 in the warm relative to WT. We suggest that elevated maltose in the plastid could be responsible for key aspects of cold acclimation