Inhibition of Sphingolipid Synthesis as a Phenotype-Modifying Therapy in Cystic Fibrosis

Cystic Fibrosis (CF) is an inherited disease associated with a variety of mutations affecting the CFTR gene. A deletion of phenylalanine 508 (F508) affects more than 70% of patients and results in unfolded proteins accumulation, originating a proteinopathy responsible for inflammation, impaired trafficking, altered metabolism, cholesterol and lipids accumulation, impaired autophagy at the cellular level. Lung inflammation has been extensively related to the accumulation of the lipotoxin ceramide. We recently proved that inhibition of ceramide synthesis by Myriocin reduces inflammation and ameliorates the defence response against pathogens infection, which is downregulated in CF. Here, we aim at demonstrating the mechanisms of Myriocin therapeutic effects in Cystic Fibrosis broncho-epithelial cells

Worldline approach to noncommutative field theory

The study of the heat-trace expansion in noncommutative field theory has shown the existence of Moyal nonlocal Seeley-DeWitt coefficients which are related to the UV/IR mixing and manifest, in some cases, the non-renormalizability of the theory. We show that these models can be studied in a worldline approach implemented in phase space and arrive to a master formula for the $n$-point contribution to the heat-trace expansion. This formulation could be useful in understanding some open problems in this area, as the heat-trace expansion for the noncommutative torus or the introduction of renormalizing terms in the action, as well as for generalizations to other nonlocal operators.Comment: 19 pages, version

Quantum theories of (p,q)-forms

We describe quantum theories for massless (p,q)-forms living on Kaehler spaces. In particular we consider four different types of quantum theories: two types involve gauge symmetries and two types are simpler theories without gauge invariances. The latter can be seen as building blocks of the former. Their equations of motion can be obtained in a natural way by first-quantizing a spinning particle with a U(2)-extended supersymmetry on the worldline. The particle system contains four supersymmetric charges, represented quantum mechanically by the Dolbeault operators and their hermitian conjugates. After studying how the (p,q)-form field theories emerge from the particle system, we investigate their one loop effective actions, identify corresponding heat kernel coefficients, and derive exact duality relations. The dualities are seen to include mismatches related to topological indices and analytic torsions, which are computed as Tr(-1)^F and Tr[(-1)^F F] in the first quantized supersymmetric nonlinear sigma model for a suitable fermion number operator F.Comment: 44 pages, 2 figures, a reference adde

Sphingolipid synthesis inhibition by myriocin administration enhances lipid consumption and ameliorates lipid response to myocardial ischemia reperfusion injury

Myocardial infarct requires prompt thrombolytic therapy or primary percutaneous coronary intervention to limit the extent of necrosis, but reperfusion creates additional damage. Along with reperfusion, a maladaptive remodeling phase might occur and it is often associated with inflammation, oxidative stress, as well as a reduced ability to recover metabolism homeostasis. Infarcted individuals can exhibit reduced lipid turnover and their accumulation in cardiomyocytes, which is linked to a deregulation of peroxisome proliferator activated receptors (PPARs), controlling fatty acids metabolism, energy production, and the anti-inflammatory response. We previously demonstrated that Myriocin can be effectively used as post-conditioning therapeutic to limit ischemia/reperfusion-induced inflammation, oxidative stress, and infarct size, in a murine model. In this follow-up study, we demonstrate that Myriocin has a critical regulatory role in cardiac remodeling and energy production, by up-regulating the transcriptional factor EB, PPARs nuclear receptors and genes involved in fatty acids metabolism, such as VLDL receptor, Fatp1, CD36, Fabp3, Cpts, and mitochondrial FA dehydrogenases. The overall effects are represented by an increased \u3b2-oxidation, together with an improved electron transport chain and energy production. The potent immunomodulatory and metabolism regulatory effects of Myriocin elicit the molecule as a promising pharmacological tool for post-conditioning therapy of myocardial ischemia/reperfusion injury

Local Unit Invariance, Back-Reacting Tractors and the Cosmological Constant Problem

When physics is expressed in a way that is independent of local choices of unit systems, Riemannian geometry is replaced by conformal geometry. Moreover masses become geometric, appearing as Weyl weights of tractors (conformal multiplets of fields necessary to keep local unit invariance manifest). The relationship between these weights and masses is through the scalar curvature. As a consequence mass terms are spacetime dependent for off-shell gravitational backgrounds, but happily constant for physical, Einstein manifolds. Unfortunately this introduces a naturalness problem because the scalar curvature is proportional to the cosmological constant. By writing down tractor stress tensors (multiplets built from the standard stress tensor and its first and second derivatives), we show how back-reaction solves this naturalness problem. We also show that classical back-reaction generates an interesting potential for scalar fields. We speculate that a proper description of how physical systems couple to scale, could improve our understanding of naturalness problems caused by the disparity between the particle physics and observed, cosmological constants. We further give some ideas how an ambient description of tractor calculus could lead to a Ricci-flat/CFT correspondence which generalizes the AdS side of Maldacena's duality to a Ricci-flat space of one higher dimension.Comment: 20 pages, 2 figure

First order parent formulation for generic gauge field theories

We show how a generic gauge field theory described by a BRST differential can systematically be reformulated as a first order parent system whose spacetime part is determined by the de Rham differential. In the spirit of Vasiliev's unfolded approach, this is done by extending the original space of fields so as to include their derivatives as new independent fields together with associated form fields. Through the inclusion of the antifield dependent part of the BRST differential, the parent formulation can be used both for on and off-shell formulations. For diffeomorphism invariant models, the parent formulation can be reformulated as an AKSZ-type sigma model. Several examples, such as the relativistic particle, parametrized theories, Yang-Mills theory, general relativity and the two dimensional sigma model are worked out in details.Comment: 36 pages, additional sections and minor correction

Galileons as Wess-Zumino Terms

We show that the galileons can be thought of as Wess-Zumino terms for the spontaneous breaking of space-time symmetries. Wess-Zumino terms are terms which are not captured by the coset construction for phenomenological Lagrangians with broken symmetries. Rather they are, in d space-time dimensions, d-form potentials for (d+1)-forms which are non-trivial co-cycles in Lie algebra cohomology of the full symmetry group relative to the unbroken symmetry group. We introduce the galileon algebras and construct the non-trivial (d+1)-form co-cycles, showing that the presence of galileons and multi-galileons in all dimensions is counted by the dimensions of particular Lie algebra cohomology groups. We also discuss the DBI and conformal galileons from this point of view, showing that they are not Wess-Zumino terms, with one exception in each case.Comment: 49 pages. v2 minor changes, version appearing in JHE

Pharmacologically directed strategies in academic anticancer drug discovery based on the European NCI compounds initiative

Background: The European NCI compounds programme, a joint initiative of the EORTC Research Branch, Cancer Research Campaign and the US National Cancer Institute, was initiated in 1993. The objective was to help the NCI in reducing the backlog of in vivo testing of potential anticancer compounds, synthesised in Europe that emerged from the NCI in vitro 60-cell screen. Methods: Over a period of more than twenty years the EORTC—Cancer Research Campaign panel reviewed ~2000 compounds of which 95 were selected for further evaluation. Selected compounds were stepwise developed with clear go/no go decision points using a pharmacologically directed programme. Results: This approach eliminated quickly compounds with unsuitable pharmacological properties. A few compounds went into Phase I clinical evaluation. The lessons learned and many of the principles outlined in the paper can easily be applied to current and future drug discovery and development programmes. Conclusions: Changes in the review panel, restrictions regarding numbers and types of compounds tested in the NCI in vitro screen and the appearance of targeted agents led to the discontinuation of the European NCI programme in 2017 and its transformation into an academic platform of excellence for anticancer drug discovery and development within the EORTC-PAMM group. This group remains open for advice and collaboration with interested parties in the field of cancer pharmacology

Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel

The clinical success of small-molecule vascular disrupting agents (VDAs) depends on their combination with conventional therapies. Scheduling and sequencing remain key issues in the design of VDA–chemotherapy combination treatments. This study examined the antitumour activity of ZD6126, a microtubule destabilising VDA, in combination with paclitaxel (PTX), a microtubule-stabilising cytotoxic drug, and the influence of schedule and sequence on the efficacy of the combination. Nude mice bearing MDA-MB-435 xenografts received weekly cycles of ZD6126 (200 mg kg−1 i.p.) administered at different times before or after PTX (10, 20, and 40 mg kg−1 i.v.). ZD6126 given 2 or 24 h after PTX showed no significant benefit, a result that was attributed to a protective effect of PTX against ZD6126-induced vascular damage and tumour necrosis, a hallmark of VDA activity. Paclitaxel counteracting activity was reduced by distancing drug administrations, and ZD6126 given 72 h after PTX potentiated the VDA's antitumour activity. Schedules with ZD6126 given before PTX improved therapeutic activity, which was paralleled by a VDA-induced increase in cell proliferation in the viable tumour tissue. Paclitaxel given 72 h after ZD6126 yielded the best response (50% tumours regressing). A single treatment with ZD6126 followed by weekly administration of PTX was sufficient to achieve a similar response (57% remissions). These findings show that schedule, sequence and timing are crucial in determining the antitumour efficacy of PTX in combination with ZD6126. Induction of tumour necrosis and increased proliferation in the remaining viable tumour tissue could be exploited as readouts to optimise schedules and maximise therapeutic efficacy