Co-targeting the IGF system and HIF-1 inhibits migration and invasion by (triple-negative) breast cancer cells

BACKGROUND: Metastatic triple-negative breast cancer is mostly incurable, due to lack of suitable drug targets. The insulin-like growth factor (IGF) system could provide such a target, and IGF-1 receptor (IGF-1R)-directed agents are already available, but seem unable to control all the complexities of the system, including crosstalk with hypoxia-inducible pathways. METHODS: Migration of triple-negative MDA-231 breast cancer cells and its modulation by IGFs, the IGF-1R inhibitor NVP-AEW541 and the IGF-2-sequestering monoclonal antibody MAB292 were assessed by the scratch wound healing and Boyden chamber assays; the effect of topotecan (inhibiting hypoxia-inducible factor-1 (HIF-1)) under hypoxia was also evaluated. Constitutive as well as drug-modulated levels of components of the IGF and HIF-1 pathways were evaluated by western blotting and qPCR. RESULTS: IGF-induced migration of MDA-231 cells was not abrogated by the IGF-1R inhibitor NVP-AEW541, whereas IGF-2 sequestration by MAB292 significantly reduced cell migration. Under hypoxia, topotecan was also effective, likely by reducing HIF-1-induced IGF-2 release. Simultaneous targeting of IGF-1R and IGF-2 or HIF-1 completely abolished cell migration. CONCLUSIONS: IR activation may account for the failure of NVP-AEW541 to suppress MDA-231 cell migration. Ligand-targeting compounds, or co-inhibition of the IGF and HIF-1 systems, may prevent activation of compensatory signalling, thereby providing a valuable addition to IGF-1R inhibitor-based therapies

Automobile shredder residues in Italy: characterization and valorization opportunities

At the moment Automobile Shredder Residue (ASR) is usually landfilled worldwide, but European draft Directive 2000/53/CE forces the development of alternative solutions, stating the 95%-wt recovery of an End of Life Vehicle (ELV) weight to be fulfilled by 2015. This work describes two industrial tests, each involving 250-300 t of ELVs, in which different pre-shredding operations were performed. The produced ASR materials underwent an extended characterization and some post-shredding processes, consisting of dimensional, magnetic, electrostatic and densimetric separation phases, were tested on laboratory scale, having as main purpose the enhancement of ASR recovery/recycling and the minimization of the landfilled fraction. The gathered results show that accurate depollution and dismantling operations are mandatory to obtain a high quality ASR material which may be recycled/recovered and partially landfilled according to the actual European Union regulations, with particular concern for Lower Heating Value (LHV), heavy metals content and Dissolved Organic Carbon (DOC) as critical parameters. Moreover post-shredding technical solutions foreseeing minimum economic and engineering efforts, therefore realizable in common European ELVs shredding plants, may lead to multi-purposed (material recovery and thermal valorization) opportunities for ASR reuse/recovery

Novel Ethylene=Norbornene Copolymers as Nonreleasing Antioxidants for Food-Contact Polyolefinic Materials

An efficient procedure for the copolymerization of ethylene (E) with a novel norbornenic comonomer (NArOH) bearing a stabilizing moiety analogous to commercial antioxidant 2,6-di-tert-butyl-4-methylphenol (BHT) is successfully developed. This study is aimed at: i) tuning the concentration of the stabilizing function along the polymer chain, and ii) preparing \u201cnonreleasing\u201d polymeric additives specifically destined to protect commercial low-density polyethylene (LDPE). Films obtained from blends of the novel E=NArOH copolymers with an antioxidant-free LDPE matrix are characterized by superior thermal, thermo-oxidative, and photostability when compared not only with neat LDPE films but also with films stabilized by the commercial BHT additive. Specific migration tests conducted in order to investigate the nonreleasing character of the novel macromolecular additives confirm the reduced risk of migration, from the films into food simulants, of unreacted comonomer or degradation products bearing the antioxidant moiety

Tomographic Representation of Minisuperspace Quantum Cosmology and Noether Symmetries

The probability representation, in which cosmological quantum states are described by a standard positive probability distribution, is constructed for minisuperspace models selected by Noether symmetries. In such a case, the tomographic probability distribution provides the classical evolution for the models and can be considered an approach to select "observable" universes. Some specific examples, derived from Extended Theories of Gravity, are worked out. We discuss also how to connect tomograms, symmetries and cosmological parameters.Comment: 15 page

Abelian gauge potentials on cubic lattices

The study of the properties of quantum particles in a periodic potential subject to a magnetic field is an active area of research both in physics and mathematics; it has been and it is still deeply investigated. In this review we discuss how to implement and describe tunable Abelian magnetic fields in a system of ultracold atoms in optical lattices. After discussing two of the main experimental schemes for the physical realization of synthetic gauge potentials in ultracold set-ups, we study cubic lattice tight-binding models with commensurate flux. We finally examine applications of gauge potentials in one-dimensional rings.Comment: To appear on: "Advances in Quantum Mechanics: Contemporary Trends and Open Problems", G. Dell'Antonio and A. Michelangeli eds., Springer-INdAM series 201

Role of the 5-Lipoxygenase–activating Protein (FLAP) in Murine Acute Inflammatory Responses

Leukotrienes are potent inflammatory mediators synthesized from arachidonic acid (AA) predominately by cells of myeloid origin. The synthesis of these lipids is believed to be dependent not only on the expression of the enzyme 5-lipoxygenase (5-LO), which catalyzes the first steps in the synthesis of leukotrienes, but also on expression of a nuclear membrane protein termed the 5-LO–activating protein (FLAP). To study the relationship of these two proteins in mediating the production of leukotrienes in vivo and to determine whether the membrane protein FLAP has additional functions in various inflammatory processes, we have generated a mouse line deficient in this protein. FLAP-deficient mice develop normally and are healthy. However, an array of assays comparing inflammatory reactions in FLAP-deficient mice and in normal controls revealed that FLAP plays a role in a subset of these reactions. Although examination of DTH and IgE-mediated passive anaphylaxis showed no difference between wild-type and FLAP-deficient animals, mice without FLAP possessed a blunted inflammatory response to topical AA and had increased resistance to platelet-activating factor–induced shock compared to controls. Also, edema associated with Zymosan A–induced peritonitis was markedly reduced in animals lacking FLAP. To determine whether these differences relate solely to a deficit in leukotriene production, or whether they reflect an additional role for FLAP in inflammation, we compared the FLAP-deficient mice to 5-LO–deficient animals. Evaluation of mice lacking FLAP and 5-LO indicated that production of leukotrienes during inflammatory responses is dependent upon the availability of FLAP and did not support additional functions for FLAP beyond its role in leukotriene production

The Phenotypic Spectrum of PNKP-Associated Disease and the Absence of Immunodeficiency and Cancer Predisposition in a Dutch Cohort

Background: We aimed to expand the number of currently known pathogenic PNKP mutations, to study the phenotypic spectrum, including radiological characteristics and genotype-phenotype correlations, and to assess whether immunodeficiency and increased cancer risk are part of the DNA repair disorder caused by mutations in the PNKP gene. Methods: We evaluated nine patients with PNKP mutations. A neurological history and examination was obtained. All patients had undergone neuroimaging and genetic testing as part of the prior diagnostic process. Laboratory measurements included potential biomarkers, and, in the context of a DNA repair disorder, we performed a detailed immunologic evaluation, including B cell repertoire analysis. Results: We identified three new mutations in the PNKP gene and confirm the phenotypic spectrum of PNKP-associated disease, ranging from microcephaly, seizures, and developmental delay to ataxia with oculomotor apraxia type 4. Irrespective of the phenotype, alpha-fetoprotein is a biochemical marker and increases with age and progression of the disease. On neuroimaging, (progressive) cerebellar atrophy was a universal feature. No clinical signs of immunodeficiency were present, and immunologic assessment was unremarkable. One patient developed cancer, but this was attributed to a concurrent von HippelLindau mutation. Conclusions: Immunodeficiency and cancer predisposition do not appear to be part of PNKP-associated disease, contrasting many other DNA repair disorders. Furthermore, our study illustrates that the previously described syndromes microcephaly, seizures, and developmental delay, and ataxia with oculomotor apraxia type 4, represent the extremes of an overlapping spectrum of disease. Cerebellar atrophy and elevated serum alpha-fetoprotein levels are early diagnostic findings across the entire phenotypical spectrum