Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? - A preclinical assessment in vitro and in vivo

BACKGROUND: Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors such as bortezomib. METHODS AND RESULTS: In this study, we assessed several combined treatment modalities in vitro and in vivo. By cell-based functional analyses, in a 3D in ovo and an orthotopic mouse model, we demonstrated sensitizing effects of bortezomib combined with cisplatin, radiation and peptide receptor radionuclide therapy (PRRT). By gene expression profiling and western blot, we explored the underlying mechanisms, which resulted in an impaired DNA damage repair. Therapy-induced DNA damage triggered extrinsic proapoptotic signaling as well as the induction of cell cycle arrest, leading to a decreased vital tumor volume and altered tissue composition shown by magnetic resonance imaging and F-18-FDG-PET in vivo, however with no significant additional benefit related to PRRT alone. CONCLUSIONS: We demonstrated that bortezomib has short-term sensitizing effects when combined with DNA damaging therapy by interfering with DNA repair in vitro and in ovo. Nevertheless, due to high tumor heterogeneity after PRRT in long-term observations, we were not able to prove a therapeutic advantage of bortezomib-combined PRRT in an in vivo mouse model

Dark Energy and Gravity

I review the problem of dark energy focusing on the cosmological constant as the candidate and discuss its implications for the nature of gravity. Part 1 briefly overviews the currently popular `concordance cosmology' and summarises the evidence for dark energy. It also provides the observational and theoretical arguments in favour of the cosmological constant as the candidate and emphasises why no other approach really solves the conceptual problems usually attributed to the cosmological constant. Part 2 describes some of the approaches to understand the nature of the cosmological constant and attempts to extract the key ingredients which must be present in any viable solution. I argue that (i)the cosmological constant problem cannot be satisfactorily solved until gravitational action is made invariant under the shift of the matter lagrangian by a constant and (ii) this cannot happen if the metric is the dynamical variable. Hence the cosmological constant problem essentially has to do with our (mis)understanding of the nature of gravity. Part 3 discusses an alternative perspective on gravity in which the action is explicitly invariant under the above transformation. Extremizing this action leads to an equation determining the background geometry which gives Einstein's theory at the lowest order with Lanczos-Lovelock type corrections. (Condensed abstract).Comment: Invited Review for a special Gen.Rel.Grav. issue on Dark Energy, edited by G.F.R.Ellis, R.Maartens and H.Nicolai; revtex; 22 pages; 2 figure

Value Functions and Transversality Conditions for Infinite-Horizon Optimal Control Problems

This paper investigates the relationship between the maximum principle with an infinite horizon and dynamic programming and sheds new light upon the role of the transversality condition at infinity as necessary and sufficient conditions for optimality with or without convexity assumptions. We first derive the nonsmooth maximum principle and the adjoint inclusion for the value function as necessary conditions for optimality that exhibit the relationship between the maximum principle and dynamic programming. We then present sufficiency theorems that are consistent with the strengthened maximum principle, employing the adjoint inequalities for the Hamiltonian and the value function. Synthesizing these results, necessary and sufficient conditions for optimality are provided for the convex case. In particular, the role of the transversality conditions at infinity is clarified

A Braneworld Dark Energy Model with Induced Gravity and the Gauss-Bonnet Effect

We construct a holographic dark energy model with a non-minimally coupled scalar field on the brane where Gauss-Bonnet and Induced Gravity effects are taken into account. This model provides a wide parameter space with several interesting cosmological implications. Especially, the equation of state parameter of the model crosses the phantom divide line and it is possible to realize bouncing solutions in this setup.Comment: 20 pages, 3 eps figures, to appear in IJT

An Observational Overview of Solar Flares

We present an overview of solar flares and associated phenomena, drawing upon a wide range of observational data primarily from the RHESSI era. Following an introductory discussion and overview of the status of observational capabilities, the article is split into topical sections which deal with different areas of flare phenomena (footpoints and ribbons, coronal sources, relationship to coronal mass ejections) and their interconnections. We also discuss flare soft X-ray spectroscopy and the energetics of the process. The emphasis is to describe the observations from multiple points of view, while bearing in mind the models that link them to each other and to theory. The present theoretical and observational understanding of solar flares is far from complete, so we conclude with a brief discussion of models, and a list of missing but important observations.Comment: This is an article for a monograph on the physics of solar flares, inspired by RHESSI observations. The individual articles are to appear in Space Science Reviews (2011

Brain-based classification of youth with anxiety disorders: transdiagnostic examinations within the ENIGMA-Anxiety database using machine learning

Neuroanatomical findings on youth anxiety disorders are notoriously difficult to replicate, small in effect size and have limited clinical relevance. These concerns have prompted a paradigm shift toward highly powered (that is, big data) individual-level inferences, which are data driven, transdiagnostic and neurobiologically informed. Here we built and validated supervised neuroanatomical machine learning models for individual-level inferences, using a case–control design and the largest known neuroimaging database on youth anxiety disorders: the ENIGMA-Anxiety Consortium (N = 3,343; age = 10–25 years; global sites = 32). Modest, yet robust, brain-based classifications were achieved for specific anxiety disorders (panic disorder), but also transdiagnostically for all anxiety disorders when patients were subgrouped according to their sex, medication status and symptom severity (area under the receiver operating characteristic curve, 0.59–0.63). Classifications were driven by neuroanatomical features (cortical thickness, cortical surface area and subcortical volumes) in fronto-striato-limbic and temporoparietal regions. This benchmark study within a large, heterogeneous and multisite sample of youth with anxiety disorders reveals that only modest classification performances can be realistically achieved with machine learning using neuroanatomical data.NWORubicon 019.201SG.022Advanced Behavioural Research MethodsHealth and Well-bein

Composition-function relationships during IL-1-induced cartilage degradation and recovery

SummaryObjectiveTo examine the relationships between biochemical composition and mechanical properties of articular cartilage explants during interleukin-1 (IL-1)-induced degradation and post-exposure recovery.DesignBovine articular cartilage explants were cultured for up to 32 days with or without 20ng/mL IL-1. The dynamic shear modulus |G*dyn| and equilibrium and dynamic unconfined compression moduli (Eequil and |E*dyn|) were measured at intervals throughout the culture period. In a subsequent recovery study, explants were cultured for 4 days with or without 20ng/mL IL-1 and for an additional 16 days in control media. The dynamic moduli |E*dyn| and |G*dyn| were measured at intervals during degeneration and recovery. Conditioned media and explant digests were assayed for sulfated glycosaminoglycans (sGAG) and collagen content.ResultsContinuous IL-1 stimulation triggered progressive decreases in Eequil, |E*dyn|, and |G*dyn| concomitant with the sequential release of sGAG and collagen from the explants. Brief IL-1 exposure resulted in a short release of sGAG but not collagen, followed by a gradual and incomplete repopulation of sGAG. The temporary sGAG depletion was associated with decreases in both |E*dyn| and |G*dyn| which also recovered after removal of IL-1. During IL-1-induced degradation and post-exposure recovery, explant mechanical properties correlated well with tissue sGAG concentration.ConclusionsAs previously shown for developing cartilages and engineered cartilage constructs, cytokine-induced changes in sGAG concentration (i.e., fixed charge density) are coincident with changes in compressive and shear properties of articular cartilage. Further, recovery of cartilage mechanical properties can be achieved by relief from proinflammatory stimuli and subsequent restoration of tissue sGAG concentration