Chemistry

Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma

T.J. , S.J. , R.M. , C.B. , N.S. , S.B. , A.S. , S.C. , M.D. , W.E.


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Purpose. This international, multicenter, single-arm trial assessed efficacy and safety of intralesional rose bengal (PV-10) in 80 patients with refractory cutaneous or subcutaneous metastatic melanoma. Methods. Sixty-two stage III and 18 stage IV melanoma patients with disease refractory to a median of six prior interventions received intralesional PV-10 into up to 20 cutaneous and subcutaneous lesions up to four times over a 16-week period and were followed for 52 weeks. Objectives were to determine best overall response rate in injected target lesions and uninjected bystander lesions, assess durability of response, and characterize adverse events. Results. For target lesions, the best overall response rate was 51%, and the complete response rate was 26%. Median time to response was 1.9 months, and median duration of response was 4.0 months, with 8% of patients having no evidence of disease after 52 weeks. Response was dependent on untreated disease burden, with complete response achieved in 50% of patients receiving PV-10 to all of their disease. Response of target lesions correlated with bystander lesion regression and the occurrence of locoregional blistering. Adverse events were predominantly mild to moderate and locoregional to the treatment site, with no treatment-associated grade 4 or 5 adverse events. Conclusions. Intralesional PV-10 yielded durable local control with high rates of complete response. Toxicity was confined predominantly to the injection site. Cutaneous bystander tumor regression is consistent with an immunologic response secondary to ablation. This intralesional approach for local disease control could be complementary to current and investigational treatments for melanoma.John F. Thompson, Sanjiv S. Agarwala, B. Mark Smithers, Merrick I. Ross, Charles R. Scoggins, Brendon J. Coventry, Susan J. Neuhaus, David R. Minor, Jamie M. Singer, and Eric A. Wachte

Effect of laser shock peening on the high temperature oxidation resistance of titanium

P.Berger , M.Kanjer , M.Lavisse , M.Optasanu , M.Gorny , M.Peyre , M.Herbst , M.Heintz , M.Geoffroy , M.Montesin , M.Marco


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The effect of laser shock peening on the high temperature oxidation resistance of commercial pure titanium at high temperature was studied in long-time exposure under dry air. A reduction of the gain mass by a factor 4 was found for laser-shock peened samples compared to untreated titanium, which supports the interest of laser-shock treatment for the improvement of high temperature resistance. Short-durations oxidation experiments, devoted to investigate the influence of the LSP treatment on the first stages of the oxidation process, were also carried out by TGA. Several techniques as scanning electron microsco-py, hardness and roughness measurements, X-ray diffraction and X-ray photoelectron spectrometry, micro-Raman spectroscopy, nuclear reaction analysis and electron backscattered diffraction were used to characterize the sample after laser treatment and oxidations. The formation of a continuous nitrogen-rich layer between the oxide layer and the -case area in LSP samples appears to be the key factor to explain the reduction of oxygen diffusion, and thus the improvement of the oxidation resistance of laser shocked titanium. Moreover, the grain-texture of LSP samples after oxidation can also explain the improvement of the high temperature oxidation resistance after long times exposures.

Leptin and Leptin Receptor Expression in Asthma

B.A , P.E , P.M , G.M , L.Guardia, , G.S , C.G , M.Chanez,P , G.D , V.I


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Background: The adipokine leptin is a potential new mediator\ud for bronchial epithelial homeostasis. Asthma is a chronic\ud inflammatory disease characterized by airway remodeling that\ud might affect disease chronicity and severity. TGF-b is a tissue\ud growth factor the dysregulation of which is associated with\ud airway remodeling.\ud Objective: We sought to determine whether a bronchial\ud epithelial dysfunction of the leptin/leptin receptor pathway\ud contributes to asthma pathogenesis and severity.\ud Methods: We investigated in vitro the presence of leptin/leptin\ud receptor on human bronchial epithelial cells. Then we studied\ud the effect of TGF-b and fluticasone propionate on leptin\ud receptor expression. Finally, the role of leptin on TGF-b release\ud and cell proliferation was analyzed. Ex vivo we investigated the\ud presence of leptin/leptin receptor in the epithelium of bronchial\ud biopsy specimens from subjects with asthma of various\ud severities and from healthy volunteers, and some features of\ud airway remodeling, such as reticular basement membrane\ud (RBM) thickness and TGF-b expression in the epithelium, were\ud assessed.\ud Results: In vitro bronchial epithelial cells express leptin/leptin\ud receptor. TGF-b decreased and fluticasone propionate increased\ud leptin receptor expression, and leptin decreased the spontaneous\ud release of TGF-b and increased cell proliferation. Ex vivo the\ud bronchial epithelium of subjects with mild, uncontrolled,\ud untreated asthma showed a decrease expression of leptin and its\ud receptor and an increased RBM thickness and TGF-b\ud expression when compared with values seen in healthy\ud volunteers. Furthermore, severe asthma was associated with a\ud reduced expression of leptin and its receptor and an increased\ud RBM thickness with unaltered TGF-b expression.\ud Conclusions: Decreased expression of leptin/leptin receptor\ud characterizes severe asthma and is associated with airway\ud remodeling features

Role of the Ubiquitinproteasome System in Brain Ischemia: Friend or Foe?

D.Carlos , C.Margarida , S.Ivan , C.Michele , C.Lorella


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The ubiquitin–proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review.The work in the authors laboratory is funded by Fundação para a Ciencia e Tecnologia, COMPETE (Programa Operacional Factores de Competitividade), QREN and FEDER (Fundo Europeu de Desenvolvimento Regional) (PTDC/SAU-NMC/120144/2010, PTDC/NEUNMC/ 0198/2012 and PEst-C/SAU/LA0001/2011)

Copper and iron based thin film nanocomposites prepared by radio-frequency sputtering. part ii: elaboration and characterization of oxide/oxide thin film nanocomposites using controlled ex-situ oxidation process

L.Presmanes , P.Tailhades , A.Barnabe , A.Chapelle


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CuO/CuFe2O4 thin films were obtained on glass substrate by ex situ oxidation in air at 450 C for 12 h from various starting metal/oxide nanocomposites by radio-frequency sputtering technique. The structure and microstructure of the films were examined using grazing incidence X-ray diffraction, Raman spectroscopy, scanning and transmission electron microscopies, X-ray photoelectron spectroscopy, and electron probe microanalysis. These studies reveal that a self-organized bi-layered microstructure with CuO and CuFe2O4 was systematically obtained. Due to the porosity of the upper layer formed during annealing, an increase in total thickness of the film was observed and is directly correlated to the oxidation of the metallic copper content initially present in the as-deposited sample. A self-organization in two stacked layers CuO/CuFe2O4 with various void fractions ranging from 0 to 41 % can be obtained by controlling the as-deposited elaboration step described in the part I of this paper. The highest porosities were observed for films deposited at low argon pressure and low target-to-substrate distance. Due to their specific self-organization in p-and n-type layers associated with their high porosity, such structured films exhibited the best electrical sensitivity to CO2 gas sensing. The obtained results demonstrated the importance of microstructure control to improve the response of sensing layers.
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