AKR1C enzymes sustain therapy resistance in paediatric T-ALL

BACKGROUND: Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (TALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.METHODS: Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.RESULTS: We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.CONCLUSIONS: Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy

The effects of warming on the ecophysiology of two co-existing kelp species with contrasting distributions

The northeast Atlantic has warmed significantly since the early 1980s, leading to shifts in species distributions and changes in the structure and functioning of communities and ecosystems. This study investigated the effects of increased temperature on two co-existing habitat-forming kelps: Laminaria digitata, a northern boreal species, and Laminaria ochroleuca, a southern Lusitanian species, to shed light on mechanisms underpinning responses of trailing and leading edge populations to warming. Kelp sporophytes collected from southwest United Kingdom were maintained under 3 treatments: ambient temperature (12 °C), +3 °C (15 °C) and +6 °C (18 °C) for 16 days. At higher temperatures, L. digitata showed a decline in growth rates and Fv/Fm, an increase in chemical defence production and a decrease in palatability. In contrast, L. ochroleuca demonstrated superior growth and photosynthesis at temperatures higher than current ambient levels, and was more heavily grazed. Whilst the observed decreased palatability of L. digitata held at higher temperatures could reduce top-down pressure on marginal populations, field observations of grazer densities suggest that this may be unimportant within the study system. Overall, our study suggests that shifts in trailing edge populations will be primarily driven by ecophysiological responses to high temperatures experienced during current and predicted thermal maxima, and although compensatory mechanisms may reduce top-down pressure on marginal populations, this is unlikely to be important within the current biogeographical context. Better understanding of the mechanisms underpinning climate-driven range shifts is important for habitat-forming species like kelps, which provide organic matter, create biogenic structure and alter environmental conditions for associated communities

Re-evaluating syndicalist opposition to the First World War

It has been argued that support for the First World War by the important French syndicalist organisation, the Confédération Générale du Travail (CGT) has tended to obscure the fact that other national syndicalist organisations remained faithful to their professed workers’ internationalism: on this basis syndicalists beyond France, more than any other ideological persuasion within the organised trade union movement in immediate pre-war and wartime Europe, can be seen to have constituted an authentic movement of opposition to the war in their refusal to subordinate class interests to those of the state, to endorse policies of ‘defencism’ of the ‘national interest’ and to abandon the rhetoric of class conflict. This article, which attempts to contribute to a much neglected comparative historiography of the international syndicalist movement, re-evaluates the syndicalist response across a broad geographical field of canvas (embracing France, Italy, Spain, Ireland, Britain and America) to reveal a rather more nuanced, ambiguous and uneven picture. While it highlights the distinctive nature of the syndicalist response compared with other labour movement trends, it also explores the important strategic and tactical limitations involved, including the dilemma of attempting to translate formal syndicalist ideological commitments against the war into practical measures of intervention, and the consequences of the syndicalists’ subordination of the political question of the war to the industrial struggle

Ten golden rules for optimal antibiotic use in hospital settings: the WARNING call to action

Antibiotics are recognized widely for their benefits when used appropriately. However, they are often used inappropriately despite the importance of responsible use within good clinical practice. Effective antibiotic treatment is an essential component of universal healthcare, and it is a global responsibility to ensure appropriate use. Currently, pharmaceutical companies have little incentive to develop new antibiotics due to scientific, regulatory, and financial barriers, further emphasizing the importance of appropriate antibiotic use. To address this issue, the Global Alliance for Infections in Surgery established an international multidisciplinary task force of 295 experts from 115 countries with different backgrounds. The task force developed a position statement called WARNING (Worldwide Antimicrobial Resistance National/International Network Group) aimed at raising awareness of antimicrobial resistance and improving antibiotic prescribing practices worldwide. The statement outlined is 10 axioms, or “golden rules,” for the appropriate use of antibiotics that all healthcare workers should consistently adhere in clinical practice

Adoption of EU directive on road infrastructure safety and development of additional standards to manage safety on Ireland’s roads

This paper looks at the work undertaken in Ireland on updating and implementing design standards in compliance with the recent requirements set out in the EU Directive on Road Infrastructure Safety Management (RISM). These improved standards complement the actions in Ireland’s Road Safety Strategy (RSS) that aim to reduce road deaths and serious injuries on our roads. Issues dealing with the practical problems associated with collecting large volumes of data, during drive through route inspections, are addressed. Solutions described herein and adopted have helped resolve some of the challenges associated with this type of data collection programme. Significant progress has been made in this area over a relatively short period. The RISM programme in Ireland has moved from data collection through analysis and review. Currently there is a programme underway implementing solutions on the ground. In tandem with the inspection programme, the principles behind forgiving roadsides have been catered for in the design process and new guidelines issued. This philosophy sits well with the move to a safe systems approach, as set out in the Road Safety Strategy, currently in operation in Ireland. The guidelines and standards developed in recent years are expected to deliver substantial safety benefits. However the priority for now is ensuring these standards are disseminated to designers and programmes like the road safety inspection programme (RSI) put into operation. Beyond the design standards introduced for motorways and major interurban routes, this paper includes a section on Ireland’s new urban street standards. Other notable inclusions within the paper relate to the development of credible speed limits for the older legacy rural road network, in a progressive move away from a blanket speed limit based on road function. Ireland will continue to improve its road design standards and much of this work will be informed from Ireland’s participation with research as administrated by Conference of European Directors of Roads (CEDR TG Road Safety

Implementing road safety inspections in Ireland and initial results

This paper will focus on changes to the implementation of road safety inspections in Ireland following the requirement, under EU Directive 2008/96/EC on Road Infrastructure Safety Management, for the establishment of periodic road safety inspections (RSI) of existing roads, along with safety impact assessments, high accident concentration ranking and road safety audits (RSA). Ireland, along with fellow EU member states, were required to adopt guidelines ensuring road safety inspections were carried out by a competent entity in order to safeguard adequate safety levels for road infrastructure. By using a case study, this paper will outline the transition Transport Infrastructure Ireland (TII) has made by embracing new technology. This proactive approach to improving road safety contrasts with the reactive ‘black spot’ approach based on historical collision data. Incorporating RSI and the additional requirements (e.g. RSA) of the Directive 2008/96/EC into existing design standards has provided TII complimentary tools to better enable designers’ effect positive change to the road environment in Ireland

Melanin Distribution in Human Skin: Influence of Cytoskeletal, Polarity, and Centrosome-Related Machinery of Stratum basale Keratinocytes

Melanin granules cluster within supra-nuclear caps in basal keratinocytes (KCs) of the human epidermis, where they protect KC genomic DNA against ultraviolet radiation (UVR) damage. While much is known about melanogenesis in melanocytes (MCs) and a moderate amount about melanin transfer from MC to KC, we know little about the fate of melanin once inside KCs. We recently reported that melanin fate in progenitor KCs is regulated by rare asymmetric organelle movement during mitosis. Here, we explore the role of actin, microtubules, and centrosome-associated machinery in distributing melanin within KCs. Short-term cultures of human skin explants were treated with cytochalasin-B and nocodazole to target actin filaments and microtubules, respectively. Treatment effects on melanin distribution were assessed by the Warthin–Starry stain, on centrosome-associated proteins by immunofluorescence microscopy, and on co-localisation with melanin granules by brightfield microscopy. Cytochalasin-B treatment disassembled supra-nuclear melanin caps, while nocodazole treatment moved melanin from the apical to basal KC domain. Centrosome and centriolar satellite-associated proteins showed a high degree of co-localisation with melanin. Thus, once melanin granules are transferred to KCs, their preferred apical distribution appears to be facilitated by coordinated movement of centrosomes and centriolar satellites. This mechanism may control melanin’s strategic position within UVR-exposed KCs