Potential effect of chloroquine and propranolol combination to treat colorectal and triple-negative breast cancers.

Drug repositioning explores the reuse of non-cancer drugs to treat tumors. In this work, we evaluated the effect of the combination of chloroquine and propranolol on colorectal and triple-negative breast cancers. Using as in vitro models the colorectal cancer cell lines HCT116, HT29, and CT26, and as triple-negative breast cancer models the 4T1, M-406, and MDA-MB-231 cell lines, we evaluated the effect of the drugs combination on the viability, apoptosis, clonogenicity, and cellular migratory capacity. To explore the in vivo effects of the combination on tumor growth and metastasis development we employed graft models in BALB/c, nude, and CBi mice. In vitro studies showed that combined treatment decreased cell viability in a dose-dependent manner and increased apoptosis. Also, we demonstrated that these drugs act synergically and that it affects clonogenicity and migration. In vivo studies indicated that this drug combination was effective on colorectal models but only partially on breast cancer. These results contributed to the search for new and safe treatments for colorectal and triple-negative carcinomas.

Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment.

Drug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tumor types, available treatments are generally associated to severe side effects. In our work, we explored the effect of combining metformin and propranolol, two repositioned drugs, in both tumor types. We demonstrate that treatment affects viability, epithelial-mesenchymal transition and migratory potential of CRC cells as we described before for TNBC. We show that combined treatment affects different steps leading to metastasis in TNBC. Moreover, combined treatment is also effective preventing the development of 5-FU resistant CRC. Our data suggest that combination of metformin and propranolol could be useful as a putative adjuvant treatment for both TNBC and CRC and an alternative for chemo-resistant CRC, providing a low-cost alternative therapy without associated toxicity.

Grafted nanocellulose and alkaline nanoparticles for the strengthening and deacidification of cellulosic artworks.

HYPOTHESIS: Strongly degraded cellulosic artworks usually need deacidification and consolidation. Alkaline nanoparticles are known to be effective in neutralizing the acidity, while cellulose nanocrystals have the potential to be used as compatible and effective strengthening agents. EXPERIMENTS: We have grafted cellulose nanocrystals with oleic acid using a 1'1-carbonyldiimidazole-mediated procedure, to increase their dispersibility in organic solvents, and synthesized Ca(OH)2 or CaCO3 nanoparticles via a solvothermal process. Grafted nanocellulose and alkaline nanoparticles were used to prepare ethanol-based "hybrids". Prior to the application, the physico-chemical properties of nanocellulose dispersions and "hybrids" were studied by rheology and small-angle X-ray scattering. FINDINGS: Cellulose nanocrystals were effectively grafted and stably dispersed in ethanol. It was shown that the use of ethanol as a dispersing medium, and the addition of alkaline nanoparticles act in a synergistic way, increasing the interactions between grafted cellulose nanocrystals, leading to the formation of clusters. These dispersions are thixotropic, a behavior particularly appealing to conservation purposes, since they can be applied in the liquid state, or, when a more confined application is required, they can be applied in a gel-like state. As a result of the application, an improvement in the mechanical properties of paper and an increase of pH were obtained.

Acetabular fractures: Is it possible to regain the same patient's related quality of life before trauma?

INTRODUCTION: acetabular fractures are difficult to treat with often an unsatisfactory results for patients. The aim of this study is to investigate about the health-related quality-of-life outcome of patients with a traumatic acetabular fracture, as recorded at least 24 months after their surgery. METHODS: a cohort of patients underwent a dedicated acetabular surgical reconstruction for a pelvic trauma between November 2011 and May 2016, were enrolled to investigate, at least two years after injury, their midterm quality of life; SF-36 and LiSat-11 were used. RESULTS: 35 patients were enrolled but only 28 patients were revisited, 20 males (714%) and 8 females (286%) with a mean age of 43 years (19-73). The most common cause was motor vehicle accident (655%). Lower score after trauma are reported in both tests, SF-36 and LiSat 11, for all items. DISCUSSION: comparing the SF-36 score in the Italian normative sample with our SF-36 score before the trauma there is no statistically significant difference (p = 0.1661) underlining how the patients before the trauma were healthy and in good health. Both scores, SF-36 and LiSat-11, before and after trauma are statistically different with respectively p = 0,0002 and p = 0,049 which proves the lower quality of life after trauma in comparison to their life before trauma. CONCLUSIONS: Although the treatment protocols of acetabular fractures have greatly improved over the years, these continue to have disabling consequences that hardly allow to recover a good quality of life two years after the trauma.

Dewetting acrylic polymer films with water/propylene carbonate/surfactant mixtures - implications for cultural heritage conservation.

The removal of hydrophobic polymer films from surfaces is one of the top priorities of modern conservation science. Nanostructured fluids containing water, good solvents for polymers, either immiscible or partially miscible with water, and surfactants have been used in the last decade to achieve controlled removal. The dewetting of the polymer film is often an essential step to achieve efficient removal; however, the role of the surfactant throughout the process is yet to be fully understood. We report on the dewetting of a methacrylate/acrylate copolymer film induced by a ternary mixture of water, propylene carbonate (PC) and C9-11E6, a nonionic alcohol ethoxylate surfactant. The fluid microstructure was characterised through small angle X-ray scattering and the interactions between the film and water, water/PC and water/PC/C9-11E6, were monitored through confocal laser-scanning microscopy (CLSM) and analised both from a thermodynamic and a kinetic point of view. The presence of a surfactant is a prerequisite to induce dewetting of µm-thick films at room temperature, but it is not a thermodynamic driver. The amphiphile lowers the interfacial energy between the phases and favors the loss of adhesion of the polymer on glass, decreasing, in turn, the activation energy barrier, which can be overcome by the thermal fluctuations of polymer film stability, initiating the dewetting process.

Nanostructured fluids from degradable nonionic surfactants for the cleaning of works of art from polymer contaminants.

Nanostructured fluids containing anionic surfactants are among the best performing systems for the cleaning of works of art. Though efficient, their application may result in the formation of a precipitate, due to the combination with divalent cations that might leach out from the artifact. We propose here two new aqueous formulations based on nonionic surfactants, which are non-toxic, readily biodegradable and insensitive to the presence of divalent ions. The cleaning properties of water-nonionic surfactant-2-butanone (MEK) were assessed both on model surfaces and on a XIII century fresco that could not be cleaned using conventional methods. Structural information on nanofluids has been gathered by means of small-angle neutron scattering, dynamic light scattering and nuclear magnetic resonance with diffusion monitoring. Beside the above-mentioned advantages, these formulations turned out to be considerably more efficient in the removal of polymer coatings than those based on anionic surfactants. Our results indicate that the cleaning process most likely consists of two steps: initially, the polymer film is swollen by the MEK dissolved in the continuous domain of the nanofluid; in the second stage, surfactant aggregates come into play by promoting the removal of the polymer film with a detergency-like mechanism. The efficiency can be tuned by the composition and nature of amphiphiles and is promoted by working as close as possible to the cloud point of the formulation, where the second step proceeds at maximum rate.

Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of α-/γ-tocotrienols and γ-tocopherol.

BACKGROUND: The aim of this study was to evaluate the accuracy of combined structural magnetic resonance imaging (MRI) measures and plasma levels of vitamin E forms, including all eight natural vitamin E congeners (four tocopherols and four tocotrienols) and markers of vitamin E oxidative/nitrosative damage, in differentiating individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects. METHODS: Overall, 81 patients with AD, 86 with MCI and 86 CTL individuals were enrolled from the longitudinal multicentre AddNeuroMed study. MRI and plasma vitamin E data were acquired at baseline. MRI scans were analysed using Freesurfer, an automated segmentation scheme which generates regional volume and cortical thickness measures. Orthogonal partial least squares to latent structures (OPLS), a multivariate data analysis technique, was used to analyse MRI and vitamin E measures in relation to AD and MCI diagnosis. RESULTS: The joint evaluation of MRI and plasma vitamin E measures enhanced the accuracy of differentiating individuals with AD and MCI from CTL subjects: 98.2% (sensitivity 98.8%, specificity 97.7%) for AD versus CTL, and 90.7% (sensitivity 91.8%, specificity 89.5%) for MCI versus CTL. This combination of measures also identified 85% of individuals with MCI who converted to clinical AD at follow-up after 1 year. CONCLUSIONS: Plasma levels of tocopherols and tocotrienols together with automated MRI measures can help to differentiate AD and MCI patients from CTL subjects, and to prospectively predict MCI conversion into AD. Our results suggest the potential role of nutritional biomarkers detected in plasma-tocopherols and tocotrienols-as indirect indicators of AD pathology, and the utility of a multimodality approach.

The enhancement of interstitial transport of a doxorubicin-lactosaminated albumin conjugate by imatinib: in rat hepatocellular carcinoma it is not preferentially higher than that in liver and bone marrow.

The finding that imatinib enhances the drug transport from bloodstream to neoplastic cells suggested a possible role of this drug as an adjuvant to the chemotherapeutics given in the treatment of solid malignancies.The present experiments aimed to verify whether imatinib can selectively increase the penetration of a doxorubicin-lactosaminated human albumin conjugate (L-HSA-DOXO) in chemically induced rat hepatocellular carcinomas (HCCs). We observed that imatinib increased the uptake of L-HSA-DOXOby HCCs but at the same time caused a similar enhanced penetration of the conjugate in liver and bone marrow. To our knowledge, this is the first demonstration that the enhancing effect of imatinib on interstitial drug transport is not restricted to the tumors, but can be also displayed in normal tissues. This observation casts some doubts about the possibility that the value of anticancer agents with toxic side effects on liver and bone marrow can be improved by imatinib.

Effects of zinc supplementation on antioxidant enzyme activities in healthy old subjects.

A large body of experimental research indicates that oxidative stress contributes to the processes related to aging and age-related diseases. Trace elements, particularly zinc (Zn), are essential components of the endogenous enzymatic antioxidant defenses. The aim of this study was to determine the activity of three main antioxidant enzymes in plasma [i.e. superoxide dismutase (pSOD), catalase (CAT), glutathione peroxidase (GPx)] and of SOD in erythrocyte (eSOD) in a group of 1108 healthy elderly subjects from different European countries. The same enzymatic activities were evaluated in a subgroup of 108 subjects before and after Zn supplementation. We observed that eSOD activity increased with age, whereas plasma Zn decreased. Moreover, we found that women showed higher eSOD activity and lower plasma Zn compared to men. There were no age and gender-related differences in the activities of pSOD, CAT and GPx. After Zn supplementation, the activities of Zn-dependent enzymes (pSOD and eSOD), as well as plasma Zn concentration, were significantly higher than before supplementation. These results were not influenced by age, gender, plasma Zn variations (Delta Zn) and geographic area. These data suggest the potential beneficial effects of Zn supplementation on Zn-dependent antioxidant enzymes in healthy elderly subjects.

Efficacy of doxorubicin coupled to lactosaminated albumin on rat hepatocellular carcinomas evaluated by ultrasound imaging.

BACKGROUND/AIMS: Doxorubicin was conjugated with lactosaminated human albumin, a hepatotropic drug carrier, in order to increase its efficacy in the treatment of hepatocellular carcinoma. In rats bearing hepatocellular carcinomas induced by diethylnitrosamine, lactosaminated human albumin coupled doxorubicin enhanced the drug concentrations in the tumours and lowered those in extrahepatic tissues. The aim of the present study was to investigate the effects of lactosaminated human albumin coupled doxorubicin on the growth of established rat hepatocellular carcinomas induced by diethylnitrosamine. METHODS: Lactosaminated human albumin coupled doxorubicin and the free drug were i.v. administered to rats twice a week for 4 weeks at the single dose of 1 microg/g. Growth of individual tumours was followed through time by ultrasonography. RESULTS: In the control animals injected with saline the mean area of the tracked tumours significantly increased during the whole period of treatment. In the group of rats treated with lactosaminated human albumin coupled doxorubicin the mean area of the followed hepatocellular carcinomas remained practically unchanged. The free drug inhibited tumour growth only in the first period of drug administration. Lactosaminated human albumin coupled doxorubicin also hindered the development of new neoplastic nodules, which was unaffected by the free drug. CONCLUSIONS: The results support lactosaminated human albumin coupled doxorubicin as a promising agent for a systemic chemotherapy of hepatocellular carcinomas to treat noncurable patients.

Antioxidant enzyme activities in healthy old subjects: influence of age, gender and zinc status: results from the Zincage Project.

Enzymatic activities of plasma superoxide dismutase (pSOD), catalase (CAT) and glutathione peroxidase (GPx) and erythrocyte superoxide dismutase (eSOD) were assayed in 981 healthy community dwelling old subjects participating in the Zincage Project. The relationship between antioxidant enzyme activities and, respectively, gender, age and zinc status were assessed. eSOD activity was higher in nonagenarians than in 80 year old subjects. Plasma Zn was lower in nonagenarians compared with younger subjects. The prevalence of Zn deficiency increased with age, with normal Zn levels observed in about 80% of adult subjects and only in 37% of the nonagenarians. Women showed higher eSOD and CAT activities compared to men, whereas plasma Zn was higher in men than in women. There was a positive correlation between eSOD activity and age and a negative correlation between eSOD activity and plasma Zn concentrations. An inverse correlation was also found between plasma Zn concentration and age. Further studies on different aspects of Zn metabolism--intake, plasma concentration, peripheral cell concentration, activity and amount of Zn-dependent enzymes--are warranted.