Non-PEGylated liposomes for convection-enhanced delivery of topotecan and gadodiamide in malignant glioma: initial experience

Convection-enhanced delivery (CED) of highly stable PEGylated liposomes encapsulating chemotherapeutic drugs has previously been effective against malignant glioma xenografts. We have developed a novel, convectable non-PEGylated liposomal formulation that can be used to encapsulate both the topoisomerase I inhibitor topotecan (topoCED™) and paramagnetic gadodiamide (gadoCED™), providing an ideal basis for real-time monitoring of drug distribution. Tissue retention of topoCED following single CED administration was significantly improved relative to free topotecan. At a dose of 10 μg (0.5 mg/ml), topoCED had a half-life in brain of approximately 1 day and increased the area under the concentration–time curve (AUC) by 28-fold over free topotecan (153.8 vs. 5.5 μg day/g). The combination of topoCED and gadoCED was found to co-convect well in both naïve rat brain and malignant glioma xenografts (correlation coefficients 0.97–0.99). In a U87MG cell assay, the 50% inhibitory concentration (IC50) of topoCED was approximately 0.8 μM at 48 and 72 h; its concentration–time curves were similar to free topotecan and unaffected by gadoCED. In a U87MG intracranial rat xenograft model, a two-dose CED regimen of topoCED co-infused with gadoCED greatly increased median overall survival at dose levels of 0.5 mg/ml (29.5 days) and 1.0 mg/ml (33.0 days) vs. control (20.0 days; P < 0.0001 for both comparisons). TopoCED at higher concentrations (1.6 mg/ml) co-infused with gadoCED showed no evidence of histopathological changes attributable to either agent. The positive results of tissue pharmacokinetics, co-convection, cytotoxicity, efficacy, and lack of toxicity of topoCED in a clinically meaningful dose range, combined with an ideal matched-liposome paramagnetic agent, gadoCED, implicates further clinical applications of this therapy in the treatment of malignant glioma

Accelerated partial breast irradiation: the case for current use

The treatment of early stage breast cancer is evolving from traditional breast conservation techniques, employing conventionally fractionated whole breast irradiation, to techniques in which partial breast irradiation is used in an accelerated fractionation scheme. A growing body of evidence exists, including favorable findings. Additional studies are under way that may ultimately prove equivalence. The logic behind this approach is reviewed, and the currently available data are presented to support the current use of carefully applied partial breast irradiation techniques in appropriately selected and informed patients

Non-standard management of breast cancer increases with age in the UK: a population based cohort of women ⩾65 years

Evidence suggests that compared to younger women, older women are less likely to receive standard management for breast cancer. Whether this disparity persists once differences in tumour characteristics have been adjusted for has not been investigated in the UK. A retrospective cohort study involving case note review was undertaken, based on the North Western Cancer Registry database of women aged ⩾65 years, resident in Greater Manchester with invasive breast cancer registered over a 1-year period (n=480). Adjusting for tumour characteristics associated with age by logistic regression analyses, older women were less likely to receive standard management than younger women for all indicators investigated. Compared to women aged 65–69 years, women aged ⩾80 years with operable (stage 1–3a) breast cancer have increased odds of not receiving triple assessment (OR=5.5, 95% confidence interval (CI): 2.1–14.5), not receiving primary surgery (OR=43.0, 95% CI: 9.7–191.3), not undergoing axillary node surgery (OR=27.6, 95% CI: 5.6–135.9) and not undergoing tests for steroid receptors (OR=3.0, 95% CI: 1.7–5.5). Women aged 75–79 years have increased odds of not receiving radiotherapy following breast-conserving surgery compared to women aged 65–69 years (OR=11.0, 95% CI: 2.0–61.6). These results demonstrate that older women in the UK are less likely to receive standard management for breast cancer, compared to younger women and this disparity cannot be explained by differences in tumour characteristics

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in &gt;100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P &lt; 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD

Removal of Misincorporated Ribonucleotides from Prokaryotic Genomes: An Unexpected Role for Nucleotide Excision Repair

Stringent steric exclusion mechanisms limit the misincorporation of ribonucleotides by high-fidelity DNA polymerases into genomic DNA. In contrast, low-fidelity Escherichia coli DNA polymerase V (pol V) has relatively poor sugar discrimination and frequently misincorporates ribonucleotides. Substitution of a steric gate tyrosine residue with alanine (umuC_Y11A) reduces sugar selectivity further and allows pol V to readily misincorporate ribonucleotides as easily as deoxynucleotides, whilst leaving its poor base-substitution fidelity essentially unchanged. However, the mutability of cells expressing the steric gate pol V mutant is very low due to efficient repair mechanisms that are triggered by the misincorporated rNMPs. Comparison of the mutation frequency between strains expressing wild-type and mutant pol V therefore allows us to identify pathways specifically directed at ribonucleotide excision repair (RER). We previously demonstrated that rNMPs incorporated by umuC_Y11A are efficiently removed from DNA in a repair pathway initiated by RNase HII. Using the same approach, we show here that mismatch repair and base excision repair play minimal back-up roles in RER in vivo. In contrast, in the absence of functional RNase HII, umuC_Y11A-dependent mutagenesis increases significantly in ΔuvrA, uvrB5 and ΔuvrC strains, suggesting that rNMPs misincorporated into DNA are actively repaired by nucleotide excision repair (NER) in vivo. Participation of NER in RER was confirmed by reconstituting ribonucleotide-dependent NER in vitro. We show that UvrABC nuclease-catalyzed incisions are readily made on DNA templates containing one, two, or five rNMPs and that the reactions are stimulated by the presence of mispaired bases. Similar to NER of DNA lesions, excision of rNMPs proceeds through dual incisions made at the 8th phosphodiester bond 5′ and 4th-5th phosphodiester bonds 3′ of the ribonucleotide. Ribonucleotides misinserted into DNA can therefore be added to the broad list of helix-distorting modifications that are substrates for NER

The ethics of psychopharmacological research in legal minors

Research in psychopharmacology for children and adolescents is fraught with ethical problems and tensions. This has practical consequences as it leads to a paucity of the research that is essential to support the treatment of this vulnerable group. In this article, we will discuss some of the ethical issues which are relevant to such research, and explore their implications for both research and standard care. We suggest that finding a way forward requires a willingness to acknowledge and discuss the inherent conflicts between the ethical principles involved. Furthermore, in order to facilitate more, ethically sound psychopharmacology research in children and adolescents, we suggest more ethical analysis, empirical ethics research and ethics input built into psychopharmacological research design