Overcoming steroid resistance in T cell acute lymphoblastic leukemia

In a Perspective, Pieter Van Vlierberghe and Steven Goossens discuss Meijerink and colleagues' findings on steroid resistance in pediatric T cell acute lymphoblastic leukemia

The physiology of movement

Movement, from foraging to migration, is known to be under the influence of the environment. The translation of environmental cues to individual movement decision making is determined by an individual's internal state and anticipated to balance costs and benefits. General body condition, metabolic and hormonal physiology mechanistically underpin this internal state. These physiological determinants are tightly, and often genetically linked with each other and hence central to a mechanistic understanding of movement. We here synthesise the available evidence of the physiological drivers and signatures of movement and review (1) how physiological state as measured in its most coarse way by body condition correlates with movement decisions during foraging, migration and dispersal, (2) how hormonal changes underlie changes in these movement strategies and (3) how these can be linked to molecular pathways. We reveale that a high body condition facilitates the efficiency of routine foraging, dispersal and migration. Dispersal decision making is, however, in some cases stimulated by a decreased individual condition. Many of the biotic and abiotic stressors that induce movement initiate a physiological cascade in vertebrates through the production of stress hormones. Movement is therefore associated with hormone levels in vertebrates but also insects, often in interaction with factors related to body or social condition. The underlying molecular and physiological mechanisms are currently studied in few model species, and show -in congruence with our insights on the role of body condition- a central role of energy metabolism during glycolysis, and the coupling with timing processes during migration. Molecular insights into the physiological basis of movement remain, however, highly refractory. We finalise this review with a critical reflection on the importance of these physiological feedbacks for a better mechanistic understanding of movement and its effects on ecological dynamics at all levels of biological organization

Iterative CT reconstruction using shearlet-based regularization

In computerized tomography, it is important to reduce the image noise without increasing the acquisition dose. Extensive research has been done into total variation minimization for image denoising and sparse-view reconstruction. However, TV minimization methods show superior denoising performance for simple images (with little texture), but result in texture information loss when applied to more complex images. Since in medical imaging, we are often confronted with textured images, it might not be beneficial to use TV. Our objective is to find a regularization term outperforming TV for sparse-view reconstruction and image denoising in general. A recent efficient solver was developed for convex problems, based on a split-Bregman approach, able to incorporate regularization terms different from TV. In this work, a proof-of-concept study demonstrates the usage of the discrete shearlet transform as a sparsifying transform within this solver for CT reconstructions. In particular, the regularization term is the 1-norm of the shearlet coefficients. We compared our newly developed shearlet approach to traditional TV on both sparse-view and on low-count simulated and measured preclinical data. Shearlet-based regularization does not outperform TV-based regularization for all datasets. Reconstructed images exhibit small aliasing artifacts in sparse-view reconstruction problems, but show no staircasing effect. This results in a slightly higher resolution than with TV-based regularization

A reinforcement sensitivity perspective on adolescents' susceptibility to the influence of soap opera viewing on alcohol attitudes

Previous research found support for an association between exposure to alcohol-related media content and alcohol attitudes, intentions and behavior. Nevertheless, research on what makes young people susceptible to the occurrence of this relationship is scarce. The current study examined the behavioral activation (BAS) and inhibition system (BIS) as moderators of the relationship between soap opera viewing and alcohol attitudes. A cross-sectional survey was carried out among a sample of 922 adolescents (M-age=14.96years, SD=.85, 56% girls). Regression analyses showed no association between total television viewing and alcohol attitudes, but did confirm that soap opera viewing is associated with positive attitudes towards alcohol use. Moderation analyses indicated that BAS did not moderate this relationship, while BIS did; the relationship between soap opera viewing and positive attitudes toward alcohol was only significant for adolescents with a low BIS-profile. These results provide support for the premise that an elevated BIS protects adolescents from the effect of soap opera viewing frequency on their alcohol attitudes

Strategies to rescue the consequences of inducible arginase-1 deficiency in mice

Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain <2 % enzyme in the liver. Standard clinical care regimens for arginase-1 deficiency (low-protein diet, the nitrogen-scavenging drug sodium phenylbutyrate, ornithine supplementation) either failed to extend lifespan (ornithine) or only minimally prolonged lifespan (maximum 8 days with low-protein diet and drug). A conditional, tamoxifen-inducible arginase-1 transgenic mouse strain expressing the enzyme from the Rosa26 locus modestly extended lifespan of neonatal mice, but not that of 4-week old mice, when crossed to the inducible arginase-1 knockout mouse strain. Delivery of an arginase-1/enhanced green fluorescent fusion construct by adeno-associated viral delivery (rh10 serotype with a strong cytomegalovirus-chicken beta-actin hybrid promoter) rescued about 30% of male mice with lifespan prolongation to at least 6 months, extensive hepatic expression and restoration of significant enzyme activity in liver. In contrast, a vector of the AAV8 serotype driven by the thyroxine-binding globulin promoter led to weaker liver expression and did not rescue arginase-1 deficient mice to any great extent. Since the induced arginase-1 deficient mouse model displays a much more severe phenotype when compared to human arginase-1 deficiency, these studies reveal that it may be feasible with gene therapy strategies to correct the various manifestations of the disorder and they provide optimism for future clinical studies

Teaching an old dog new tricks : activity-on-target interferon to treat T-cell acute lymphoblastic leukemia

Background Type 1 interferon (IFN) has a long history in the treatment of cancer, including hematological malignancies. The anti-cancer effects induced by IFN result from a combination of 1) direct cancer cell growth inhibition by cell cycle arrest, apoptosis, or differentiation and 2) the activation of the immune system involving antigen presentation by Clec9A+ dendritic cells and priming of cytotoxic CD8+ T-cells. However, IFN therapy experienced variable and unpredictable success in the clinic. Its clinical application is severely impeded by a complex pattern of adverse side-effects, due to the multifaceted activity pattern of IFN. Therefore, safe exploitation of the anti-cancer potential of IFN requires strategies to direct their activity to selected target cells, avoiding systemic toxicity. Aims Safe exploitation of the anti-cancer potential of IFN requires strategies to direct their activity to selected target cells, avoiding systemic toxicity. Methods To improve the therapeutic index of IFN, we have developed AcTaferons (Activity-on-Target Interferon), optimized (mutant) immunocytokines. Mutated IFNa2Q124R, with a strongly reduced affinity for its receptor complex, was fused to single domain antibodies targeting cell-specific domains, which selectively restores the AcTaferon (AFN) activity in a cell-type specific manner. As such, CD8-AFN and Clec9A-AFN were generated which selectively target either CD8+ T(-ALL) cells or Clec9A+ dendritic cells. Results Using CD8- and CD8+ mouse T-ALL cell lines, we evaluated the direct and indirect anti-leukemic effects of our novel AFNs, in vitro and in vivo upon transplantation in immunocompromised and immunocompetent syngeneic hosts. A significant reduction in the leukemic burden was observed. These anti-cancer effects of AFN were similar as observed for the wildtype IFN, but in a cell-type specific manner and with drastically reduced adverse side-effects. Monotherapy was even sufficient to completely cure a proportion of leukemic mice, which highlights the strong anti-leukemic power of these optimized immunocytokines. Strinkingly only the direct effect CD8-AFN on in vivo CD8+ T-ALL was synergistic with asparaginase treatment. No synergism was observed between asparaginase and the indirect immune-mediated Clec9A-AFN anti-leukemic effect. Conclusion In conclusion, we have developed novel optimized immunocytokines as an off-the-shelve targeted immunotherapy for T-ALL