New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at ...submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.
Opportunistic modification of the tumour microenvironment by cancer cells enhances tumour expansion and consequently eliminates tumour suppressor components. We studied the effect of fibroblasts on ...the circadian rhythm of growth and protein expression in colon cancer HCT116 cells and found diminished oscillation in the proliferation of HCT116 cells co-cultured with naive fibroblasts, compared with those co-cultured with tumour-associated fibroblasts (TAFs) or those cultured alone, suggesting that TAFs may have lost or gained factors that regulate circadian phenotypes. Based on the fibroblast paracrine factor analysis, we tested IL6, which diminished HCT116 cell growth oscillation, inhibited early phase cell proliferation, increased early phase expression of the differentiation markers CEA and CDX2, and decreased early phase ERK5 phosphorylation. In conclusion, our data demonstrate how the cancer education of naive fibroblasts influences the circadian parameters of neighbouring cancer cells and highlights a putative role for IL6 as a novel candidate for preoperative treatments.
We have recently identified 1,8-naphthyridin-2(1H)-one-3-carboxamide as a new scaffold very suitable for the development of new CB2 receptor potent and selective ligands. In this paper we describe a ...number of additional derivatives in which the same central scaffold has been variously functionalized in position 1 or 6. All new compounds showed high selectivity and affinity in the nanomolar range for the CB2 receptor. Furthermore, we found that their functional activity is controlled by the presence of the substituents at position C-6 of the naphthyridine scaffold. In fact, the introduction of substituents in this position determined a functionality switch from agonist to antagonists/inverse agonists. Finally, docking studies showed that the difference between the pharmacology of these ligands may be in the ability/inability to block the Toggle Switch W6.48(258) (χ1 g+ → trans) transition.
Background and Aim: Contrast harmonic endoscopic ultrasound (CH‐EUS) was recently introduced to clinical practice; its reproducibility among endosonographers is unknown. Our aim was to assess the ...interobserver agreement (IA) in CH‐EUS.
Methods: Fifteen endosonographers (eight experienced and seven non‐experienced) from 11 Italian EUS centers evaluated 80 video‐cases (40 solid pancreatic lesions, 20 pancreatic cystic lesions and 20 submucosal lesions) of CH‐EUS, according to the degree of enhancement, the pattern of distribution and the washout of the contrast agent. IA within each group and between the two groups of observers was assessed with the Fleiss kappa statistic.
Results: Overall IA was moderate for the uptake and fair for the pattern of distribution and the washout. In solid pancreatic lesions, IA was moderate for the uptake and fair for the pattern and the washout. In cystic pancreatic lesions, IA was uniformly moderate for the assessment of uptake, slight for the pattern and fair for the washout. In submucosal tumors, IA was substantial for the uptake, slight for the pattern and fair for the washout. Non‐experienced endosonographers demonstrated, in most cases, comparable IA with the experienced ones.
Conclusions: Interobserver agreement among endosonographers for CH EUS was satisfactory. In particular, overall IA varied from slight to substantial, being fair in the majority of cases. Inherent structural features of the lesions, as well as technical differences between the variables assessed, could have accounted for the fluctuation of the results. Outcomes of IA were reproducible between experienced and non‐experienced endosonographers.
Abstract The aim of this study was to characterize the main features and the usage-induced degradation of the Genius file after four severely curved root canal instrumentations and to compare their ...properties to the Reciproc files. Brand new and ex vivo used files were analysed by scanning electron microscopy (SEM) with energy-dispersive X-ray spectrometry (EDS), differential scanning calorimetry (DSC), X-ray diffraction (XRD), optical metallography, and nano-indentation to disclose their morphological, chemical, mechanical, thermal, and phase composition features. Nano-indentation data were statistically analysed using the Student's t test for normal distribution or the Kolmogorov-Smirnov test for not-normal distributions. SEM analysis showed the presence of micro-cracks near the tip on both files after ex vivo usage test. EDS analysis confirmed that both files are manufactured from an almost equiatomic NiTi alloy. DSC analysis revealed that the transition temperature of the Genius is below 20℃, while that of the Reciproc is above 20℃. XRD analysis of Genius files identified cubic B2 austenite with minor peaks of residual monoclinic B19 martensite, while the contemporaneous presence of martensite, austenite and hexagonal R-phase was observed in the Reciproc files. Significant differences in nanohardness and modulus of elasticity (P<.05) were observed in both Genius and Reciproc files before and after use. The collected results showed that both instruments can be safely used as single-use files.
In the quinolinic acid (QA)-rat model of Huntington's disease (HD), 15 days after QA injection, striatal glutamate, measured by in vivo microdialysis, was unchanged while a significant decrease in ...adenosine occurred. The decrease in adenosine may depend on QA-induced striatal cell loss. Probe perfusion of the adenosine A(2A) receptor antagonist SCH 58261 significantly increased striatal glutamate outflow, suggesting a potential detrimental effect of A(2A) antagonism at later stages of the neurodegenerative process induced by QA.
In the quinolinic acid (QA)-rat model of Huntington's disease (HD), 15 days after QA injection, striatal glutamate, measured by in vivo microdialysis, was unchanged while a significant decrease in ...adenosine occurred. The decrease in adenosine may depend on QA-induced striatal cell loss. Probe perfusion of the adenosine A2A receptor antagonist SCH 58261 significantly increased striatal glutamate outflow, suggesting a potential detrimental effect of A2A antagonism at later stages of the neurodegenerative process induced by QA.
Ce volume s'adresse aux spécialistes de différentes disciplines allant de la littérature, à l’histoire de l’art jusqu’à des formes artistiques plus proches de notre époque comme la photographie et la ...bande dessinée. Le fil rouge qui relie les différentes contributions est non seulement l’intérêt constant que toutes les époques traversées ont porté à cette interaction, mais également le lien entre passé et présent que le couple texte et image parvient à établir (voir par exemple le cas du dessinateur Vincent Vanoli qui, en 2000, réalise une bande dessinée à partir du Décaméron de Boccace). Ce sujet a été choisi parce qu'il traverse plusieurs périodes et plusieurs genres de la culture italienne. Il a donc été intéressant de voir comment chaque époque a abordé cette question. D'un point de vue strictement méthodologique, quatre sont les principaux points forts du volume : 1) le croisement des regards et des approches de spécialistes de divers horizons et formations (littéraires, historiens de l’art, photographes, auteurs de bandes dessinées) ; 2) le choix d’étudier le rapport entre textes et images sur une ample période qui va de Dante à l’époque contemporaine, en passant par le Quattrocento et la Renaissance ; 3) le fait d’avoir considéré le terme image tant d’un point de vue figuratif que littéraire ; 4) l’absence d’un cadre théorique prédéterminé de référence. Les coordinatrices du volume ont en effet privilégié une approche historique laissant aux contributeurs la liberté de s’exprimer sur la base de leurs connaissances. Ce qui ne veut pas dire que l’ouvrage n’ait pas une cohérence intrinsèque, comme le souligne par ailleurs la présentation. L’ouvrage se structure en deux grandes parties (« De Dante à Cellini » ; « Expériences contemporaines »), reliées entre elles par une « Note d’histoire de l’art » consacrée à une œuvre d’Antonello de Messine qui, par ses déviations par rapport à la règle de la perspective, renouvelle la jouissance de l’œuvre d’art et donc la perception que le spectateur a de l’image artistique.
In the quinolinic acid (QA)-rat model of Huntington’s disease (HD), 15 days after QA injection, striatal glutamate, measured by in vivo microdialysis, was unchanged while a significant decrease in ...adenosine occurred. The decrease in adenosine may depend on QA-induced striatal cell loss. Probe perfusion of the adenosine A
2A receptor antagonist SCH 58261 significantly increased striatal glutamate outflow, suggesting a potential detrimental effect of A
2A antagonism at later stages of the neurodegenerative process induced by QA.
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