Clinical pharmacokinetics and metabolism of irinotecan (CPT-11)

CPT-11 belongs to the class of topoisomerase I inhibitors, and it acts as a prodrug of SN-38, which is approximately 100-1000-fold more cytotoxic than the parent drug. CPT-11 has shown a broad spectrum of antitumor activity in preclinical models as well as clinically, with responses observed in various disease types including colorectal, lung, cervical, and ovarian cancer. The pharmacokinetics and metabolism of CPT-11 are extremely complex and have been the subject of intensive investigation in recent years. Both CPT-11 and SN-38 are known in an active lactone form and an inactive carboxylate form, between which an equilibrium exists that depends on the pH and the presence of binding proteins. CPT-11 is subject to extensive metabolic conversion by various enzyme systems, including esterases to form SN-38, UGT1A1 mediating glucuronidation of SN-38, as well as CYP3A4, which forms several pharmacologically inactive oxidation products. Elimination routes of CPT-11 also depend on the presence of drug-transporting proteins, notably P-glycoprotein and canalicular multispecific organic anion transporter, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. Strategies to individualize CPT-11 administration schedules based on patient differences in enzyme or protein expression or by coadministration of specific agents modulating side effects are under way and may ultimately lead to more selective chemotherapeutic use of this agent

The teaching of recent and violent conflicts as challenges for history education

This paper has been written with the support of Projects EDU2015-65088P from the DGICYT (Ministry of Education, Spain) and also the Project PICT2012-1594 from the ANPCYT (Argentina) coordinated by the autho

Contestation, contingency, and justice in the Nordic low-carbon energy transition

The five Nordic countries have aggressive climate and energy policies in place and have already emerged to be leaders in renewable energy and energy efficiency. Denmark is renowned for its pioneering use of wind energy, Finland and Sweden bioenergy, Norway hydroelectricity and Iceland geothermal energy. All countries aim to be virtually “fossil free” by 2050. This study explores the Nordic energy transition through the lens of three interconnected research questions: How are they doing it? What challenges exist? And what broader lessons result for energy policy? The study firstly investigates the pathways necessary for these five countries to achieve their low-carbon goals. It argues that a concerted effort must be made to (1) promote decentralized and renewable forms of electricity supply; (2) shift to more sustainable forms of transport; (3) further improve the energy efficiency of residential and commercial buildings; and (4) adopt carbon capture and storage technologies for industry. However, the section that follows emphasizes some of the empirical barriers the Nordic transition must confront, namely political contestation, technological contingency, and social justice and recognition concerns. The study concludes with implications for what such historical progress, and future transition pathways, mean for both energy researchers and energy planners

Genetics of decayed sexual traits in a parasitoid wasp with endosymbiont-induced asexuality.

Trait decay may occur when selective pressures shift, owing to changes in environment or life style, rendering formerly adaptive traits non-functional or even maladaptive. It remains largely unknown if such decay would stem from multiple mutations with small effects or rather involve few loci with major phenotypic effects. Here, we investigate the decay of female sexual traits, and the genetic causes thereof, in a transition from haplodiploid sexual reproduction to endosymbiont-induced asexual reproduction in the parasitoid wasp Asobara japonica. We take advantage of the fact that asexual females cured of their endosymbionts produce sons instead of daughters, and that these sons can be crossed with sexual females. By combining behavioral experiments with crosses designed to introgress alleles from the asexual into the sexual genome, we found that sexual attractiveness, mating, egg fertilization and plastic adjustment of offspring sex ratio (in response to variation in local mate competition) are decayed in asexual A. japonica females. Furthermore, introgression experiments revealed that the propensity for cured asexual females to produce only sons (because of decayed sexual attractiveness, mating behavior and/or egg fertilization) is likely caused by recessive genetic effects at a single locus. Recessive effects were also found to cause decay of plastic sex-ratio adjustment under variable levels of local mate competition. Our results suggest that few recessive mutations drive decay of female sexual traits, at least in asexual species deriving from haplodiploid sexual ancestors

The image after Strathern:Art and persuasive relationality in India's sanguinary politics

Publicly-enacted blood extractions (principally blood donation events and petitions or paintings in blood) in mass Indian political contexts (for instance, protest or political memorial events and election rallies) are a noteworthy present-day form of political enunciation in India, for such extractions – made to speak as and on behalf of political subject positions – are intensely communicative. Somewhat akin to the transformative fasts undertaken by Gandhi, such blood extractions seek to persuade from the moral high ground of political asceticism. This essay seeks to shed light on how and why these extractions have become such a means, with a particular focus on blood-based portraiture. What makes such portraits – chiefly of politicians and ‘freedom fighter’ martyrs – interesting from a Strathernian point of view is their immanent persuasive relationality. The insights of Strathern can help us to explicate these objects’ dynamic relational features, while reciprocally, the portraits may help us to illuminate and clarify the very particular and interesting nature of the way Strathern treats (and creates) images

The importance of parameter choice in modelling dynamics of the eye lens

The lens provides refractive power to the eye and is capable of altering ocular focus in response to visual demand. This capacity diminishes with age. Current biomedical technologies, which seek to design an implant lens capable of replicating the function of the biological lens, are unable as yet to provide such an implant with the requisite optical quality or ability to change the focussing power of the eye. This is because the mechanism of altering focus, termed accommodation, is not fully understood and seemingly conflicting theories require experimental support which is difficult to obtain from the living eye. This investigation presents finite element models of the eye lens based on data from human lenses aged 16 and 35 years that consider the influence of various modelling parameters, including material properties, a wide range of angles of force application and capsular thickness. Results from axisymmetric models show that the anterior and posterior zonules may have a greater impact on shape change than the equatorial zonule and that choice of capsular thickness values can influence the results from modelled simulations

Adapting group schema therapy for older adults with personality disorders:Lessons learnt

A first empirical study into group schema therapy in older adults with mood disorders and personality disorder (PD) features has shown that brief group schema therapy has potential to decrease psychological distress and to change early maladaptive schemas (EMS). Effect sizes however were smaller than those found in similar studies in younger adults. Therefore, we set out to adapt the treatment protocol for older adults in order to enhance its feasibility and outcome in this age group. We examined this adapted protocol in 29 older adults (mean age 66 years) with PDs from four Dutch mental health institutes. The primary outcome was symptomatic distress, measured by the Brief Symptom Inventory. Secondary outcomes were measured by the Young Schema Questionnaire, the Schema Mode Inventory, and the short version of the Severity Indices of Personality Problems. Contrary to our expectations, the adapted treatment protocol yielded only a small effect size in our primary outcome, and no significant improvement in EMS, modes and personality functioning. Patients pointed out that they were more aware of their dysfunctional patterns, but maybe they had not been able yet to work on behavioural change due to this schema therapy treatment being too brief. We recommend more intensive treatment for older patients with PDs, as they might benefit from more schema therapy sessions, similar to the treatment dosage in younger PD patients. They might also benefit from a combination of group therapy and individual treatment sessions