ABSTRACT
Olive leaves are a rich source of polyphenols with healthful properties and represent one of the most abundant waste products of olive oil production. The aims of this study were to explore the phenolic composition of olive leaves from the three main Tuscan cultivars (Leccino, Moraiolo and Frantoio) collected in Siena and Grosseto provinces and to investigate the possible use of these compounds as varietal and geographic origin markers. Discriminant factorial analysis (DFA) was used for distinguishing between different cultivars and locations. Apigenin and caffeoyl-secologanoside showed significant differences between cultivars. DFA showed that ligstroside, apigenin and luteolin have the most influence in determining the differences between sites, whereas total polyphenols, olacein and hydroxytyrosol acetate allowed for separation between leaves from the same province. The results of the present study indicate that concentrations of phenolic compounds, measured through high-resolution mass spectrometry, can be used as a marker for both the cultivar and of geographical origin of olive leaves, and possibly of olive-related products, as well as across small geographic scales (less than 50 km distance between sites).
Subject(s)
Olea , Phenols , Plant Leaves , Olea/chemistry , Olea/classification , Plant Leaves/chemistry , Phenols/analysis , Phenols/chemistry , Italy , Polyphenols/analysis , Polyphenols/chemistry , Biomarkers , Geography , Plant Extracts/chemistryABSTRACT
HYPOTHESIS: The development of gels capable to adapt and act at the interface of rough surfaces is a central topic in modern science for Cultural Heritage preservation. To overcome the limitations of solvents or polymer solutions, commonly used in the restoration practice, poly(vinyl alcohol) (PVA) "twin-chain" polymer networks (TC-PNs) have been recently proposed. The properties of this new class of gels, that are the most performing gels available for Cultural Heritage preservation, are mostly unexplored. This paper investigates how chemical modifications affect gels' structure and their rheological behavior, producing new gelled systems with enhanced and tunable properties for challenging applications, not restricted to Cultural Heritage preservation. EXPERIMENTS: In this study, the PVA-TC-PNs structural and functional properties were changed by functionalization with sebacic acid into a new class of TC-PNs. Functionalization affects the porosity and nanostructure of the network, changing its uptake/release of fluids and favoring the uptake of organic solvents with various polarity, a crucial feature to boost the versatility of TC-PNs in practical applications. FINDINGS: The functionalized gels exhibited unprecedented performances during the cleaning of contemporary paintings from the Peggy Gugghenheim collection (Venice), whose restoration with traditional solvents and swabs would be difficult to avoid possible disfigurements to the painted layers. These results candidate the functionalized TC-PNs as a new, highly promising class of gels in art preservation.
ABSTRACT
The UN 2030 Agenda for Sustainable Development established the goal of cutting the use of pesticides in the EU by 50% by 2030. However, a ban on pesticides could seriously affect the productivity of agriculture, resulting in severe issues due to global hunger and food deficiency. Controlled release (CR) of bioactive chemicals could play a valid alternative in this context. To this aim, two biodegradable polymers, namely sodium alginate (AL) and sodium carboxymethylcellulose (CMC), were employed to obtain crosslinked hydrogel beads for the encapsulation and CR of glycoalkaloids extracted from tomato and potato leaves to be used as biocompatible disinfectants for agricultural soils. The physico-chemical characterization of the controlled-release systems was carried out by means of Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy, Scanning Electron Microscopy (SEM), thermogravimetry (TGA), differential scanning calorimetry (DSC) (FWI > 80%) and drying kinetics. The plant extracts and the encapsulation efficiency (~84%) were, respectively, characterized and evaluated by High-performance Liquid Chromatography-Mass Spectrometry (HPLC-MS). Finally, preliminary microbiological tests were conducted to test the efficacy of the most promising systems as biocidal formulations both in the lab and on a model soil, and interesting results were obtained in the reduction of bacterial and fungal load, which could lead to sustainable perspectives in the field.
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Soluplus is an amphiphilic graft copolymer intensively studied as a micellar solubilizer for drugs. An extensive characterization of the nanostructure of its colloidal aggregates is still lacking. Here, we provide insights into the polymer's self-assembly in water, and we assess its use as an encapsulating agent for fragrances. The self-assembly properties of Soluplus aqueous solutions were studied over a wide concentration range (1-70% w/w) by means of small-angle neutron scattering (SANS), differential scanning calorimetry, NMR, and rheometry. SANS analyses revealed the presence of polymeric micelles with a fuzzy surface interacting via a 2-Yukawa potential, up to 15% w/w polymer. Increasing the polymer concentration up to 55% w/w led to tightly packed micelles described according to the Teubner-Strey model. The ability of Soluplus to encapsulate seven perfume molecules, 2-phenyl ethanol, l-carvone, linalool, florhydral, ß-citronellol, α-pinene, and R-limonene, was then examined. We showed that the fragrance's octanol/water partition coefficient (logâ¯Kow), widely used to characterize the solubilization capacity, is not sufficient to characterize such systems and the presence of specific functional groups or molecular conformation needs to be considered. In fact, the combination of SANS, NMR, confocal laser scanning microscopy, and confocal Raman microscopy showed that the perfumes, interacting with different regions of the polymer aggregates, are able to tune the systems' structures resulting in micelles, matrix-type capsules, core-shell capsules, or oil-in-water emulsions.
Subject(s)
Perfume , Micelles , Polyethylene Glycols/chemistry , Polyvinyls , Prospective Studies , Water/chemistryABSTRACT
HYPOTHESIS: Preparation of suspensions of nanoparticles (>1 wt%) coated with a polyelectrolyte multilayers is a challenging task because of the risk of flocculation when a polyelectrolyte is added to a suspension of oppositely charged nanoparticles. This situation can be avoided if the charge density of the polymers and particles is controlled during mixing so as to separate mixing and adsorption events. EXPERIMENTS: The cationic polyethylenimine (PEI) and the anionic carboxymethylcellulose (CMC) were used as weak polyelectrolytes. Polyelectrolyte multilayers build-up was conducted by reducing the charge of one of the components during the addition of the next component. Charge density was controlled by tuning pH. Analysis of the suspension of coated nanoparticles was done by means of dynamic light scattering, electrophoresis and small angle x-ray scattering measurements, while quartz crystal microbalance was used to study the build-up process on flat silica surfaces. FINDINGS: Charge density, controlled through pH, can be used as a tool to avoid flocculation during layer-by-layer deposition of polyelectrolytes on 20 nm silica particles at high concentration (â¼40 wt%). When added to silica at pH 3, PEI did not induce flocculation. Adsorption was triggered by raising the pH to 11, pH at which CMC could be added. The pH was then lowered to 3. The process was repeated, and up to five polyelectrolyte layers were deposited on concentrated silica nanoparticles while inducing minimal aggregation.
Subject(s)
Nanoparticles , Silicon Dioxide , Electrolytes/chemistry , Hydrogen-Ion Concentration , Nanoparticles/chemistry , Polyelectrolytes/chemistry , SuspensionsABSTRACT
HYPOTHESIS: Nanostructured fluids (NSFs) based on water, organic solvents and surfactants are a valid alternative to the use of neat unconfined organic solvents for polymer coatings removal in art conservation. The physico-chemical processes underpinning their cleaning effectiveness in terms of swelling/dewetting of polymer films were identified as key in this context. The role of surfactants on polymers' dewetting was considered to be mainly restricted to the lowering of interfacial tensions. However, recent experiments evidenced that surfactants have an important role in swelling polymer films. EXPERIMENTS: Five different amphiphiles were selected, namely: sodium dodecylsulfate, dimethyldodecyl amine oxide, hexaoxyethylene decyl ether (C9-11E6), pentadecaoxyethylene dodecyl ether (C12E15), and methyoxypentadecaoxyethylene dodecanoate (C11COE15CH3). They were combined with a carefully selected organic solvents' mixture (1-butanol/butanone/dimethyl carbonate) to formulate new NSFs, differing for the surfactant only, and used to perform cleaning tests on surfaces coated with Paraloid B72® and Primal AC33®. Here for the first time, polymer swelling induced by surfactants was quantified and correlated with the glass transition temperature of the two polymers by differential scanning calorimetry, before and after the exposure to the fluids. Confocal laser scanning microscopy and small-angle X-ray scattering provided additional insights on the interaction mechanism. FINDINGS: Nonionics were proven more efficient than zwitterionic/ionic amphiphiles in the polymer swelling, and, overall, methyoxy pentadecaoxyethylene dodecanoate resulted the most effective among the selected surfactants. A direct relation between the effect of surfactants on the polymers' glass transition temperature and cleaning capacity was established. This finding, fundamental to understand the interaction mechanism between NSFs and polymer coatings or paint layers, is key to achieve a selective, effective and complete removal of polymer coatings, as recently shown in the removal of vandalism and over-paintings from street art.
ABSTRACT
Cultural Heritage is a crucial socioeconomic resource; yet, recurring degradation processes endanger its preservation. Serendipitous approaches in restoration practice need to be replaced by systematically addressing conservation issues through the development of advanced materials for the preservation of the artifacts. In the last few decades, materials and colloid science have provided valid solutions to counteract degradation, and we report here the main highlights in the formulation and application of materials and methodologies for the cleaning, protection and consolidation of works of art. Several types of artifacts are addressed, from murals to canvas paintings, metal objects, and paper artworks, comprising both classic and modern/contemporary art. Systems, such as nanoparticles, gels, nanostructured cleaning fluids, composites, and other functional materials, are reviewed. Future perspectives are also commented, outlining open issues and trends in this challenging and exciting field.
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HYPOTHESIS: The removal of over-paintings or graffiti is a priority for conservators and restorers. This operation is complex, especially when over-paintings lay on painted surfaces that must be preserved, as in the case of vandalism on street art, where the layers are usually chemically similar. Traditional methodologies often do not provide satisfactory results and pose health and eco-compatibility concerns. An alternative methodological approach based on an environmentally friendly nanostructured fluid loaded in a retentive hydrogel is here proposed. EXPERIMENTS: Six paints (based on vinyl, acrylic and alkyd polymers) were selected and studied by means of attenuated total reflection - Fourier transform infrared spectroscopy. The phase behavior of four alkyl carbonates (green, low-toxicity organic solvents) and a biodegradable nonionic surfactant in water was investigated with Small angle X-ray scattering (SAXS) in order to formulate a novel nanostructured cleaning system. The developed system, which also includes 2-butanol and an alkyl glycoside hydrotrope, was loaded in highly retentive hydrogels and tested in the selective removal of over-paintings from laboratory mockups and from real pieces of street art. FINDINGS: The selective and controlled removal of modern paints from substrates with similar chemical composition has been achieved using a specifically tailored NSF embedded in a retentive hydrogel. The proposed methodology and cleaning system provided excellent cleaning results, representing a new tool for the conservation of contemporary and, in particular, street art.
ABSTRACT
The use of nanostructured fluids (NSFs), that is, micellar solutions and microemulsions, in art conservation is often associated with cleaning purposes as the removal of polymeric coatings and/or soil from artistic surfaces. In both cases, the use of NSFs grants significant improvements over the use of traditional cleaning techniques that employ neat unconfined organic solvents, water, or aqueous solutions. The study of the nature and properties of surfactants present in NSF formulations is important to boost the effectiveness of these systems in applicative contexts and in the search of innovative and highly performing amphiphiles. This work reports on the methoxy-pentadeca(oxyethylene) dodecanoate (MPD) surfactant in two different NSFs, whose utilization in conservation of cultural heritage is new. Its effectiveness is compared to the conventional nonionic amphiphiles used in conservation practice, as pentadeca(oxyethylene) dodecyl ether, for the cleaning of poly(ethyl methacrylate/methyl acrylate) 70:30, p(EMA/MA), and artificially soiled surfaces. The mechanism, through which NSFs interact with polymeric coatings or soiled surfaces, was investigated by confocal laser scanning microscopy, fluorescence correlation spectroscopy, photographic observation, contact angle, surface tension measurements, and small-angle X-ray scattering. The results highlighted the superior MPD's performance, both in inducing polymer removal and in detaching the soil from coated surfaces. At the microscale, the cleaning involves dewetting-like processes, where the polymer or the soil oily phase is detached from the surface and coalesce into separated droplets. This can be accounted by considering the different surface tensions and the different adsorption mechanisms of MPD with respect to ordinary nonionic surfactants (likely due to the methyl capping of the polar head chain and to the presence of the ester group between the hydrophilic and hydrophobic parts of the MPD surfactant molecule), showing how a tiny change in the surfactant architecture can lead to important differences in the cleaning capacity. Overall, this paper provides a detailed description of the mechanism and the kinetics involved in the NSFs cleaning process, opening new perspectives on simple formulations that are able to target at a specific substance to be removed. This is of utmost importance in the conservation of irreplaceable works of art.
ABSTRACT
The removal of hydrophobic polymer coatings from artistic surfaces is a ubiquitous challenge in art restoration. Over the years, nanostructured fluids (NSFs), aqueous surfactant solutions containing a good solvent for the polymer, have been successfully applied in polymer removal interventions; however, the precise role of the surfactant in promoting polymer film dewetting is not fully understood. This contribution addresses the interaction of a NSF of water/propylene carbonate containing a nonionic surfactant with an acrylic polymer film commonly used in art conservation. Combining confocal microscopy and fluorescence correlation spectroscopy, we monitored the penetration of the fluid into the polymer film, defining its compositional changes and following the polymer swelling. The ensemble of results highlights that the surfactant role is twofold: (i) at the polymer-support interface, it promotes the detachment of the polymer film from the underlying support; (ii) inside the polymer film, it accelerates polymer swelling by increasing the chains' mobility.
ABSTRACT
BACKGROUND: Sorafenib is the first targeted agent proven to improve survival of patients with advanced hepatocellular carcinoma (HCC) and it has been used in first line treatments with heterogeneous response across patients. Most of the promising agents evaluated in first-line or second-line phase III trials for HCC failed to improve patient survival. The absence of molecular characterisation, including the identification of pathways driving resistance might be responsible for these disappointing results. METHODS: 2D DIGE and MS analyses were used to reveal proteomic signatures resulting from Notch3 inhibition in HepG2 cells, combined with brivanib treatment. The therapeutic potential of Notch3 inhibition combined with brivanib treatment was also demonstrated in a rat model of HCC and in cell lines derived from different human cancers. RESULTS: Using a proteomic approach, we have shown that Notch3 is strongly involved in brivanib resistance through a p53-dependent regulation of enzymes of the tricarboxylic acid (TCA), both in vitro and in vivo. CONCLUSION: We have demonstrated that regulation of the TCA cycle is a common mechanism in different human cancers, suggesting that Notch3 inhibitors combined with brivanib treatment may represent a strong formulation for the treatment of HCC as well as Notch3-driven cancers.
Subject(s)
Alanine/analogs & derivatives , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Receptor, Notch3/antagonists & inhibitors , Triazines/pharmacology , Alanine/pharmacology , Animals , Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor , Drug Resistance, Neoplasm , Electrophoresis, Polyacrylamide Gel , Gene Knockdown Techniques , Hep G2 Cells , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms, Experimental/drug therapy , Liver Neoplasms, Experimental/genetics , Liver Neoplasms, Experimental/therapy , MCF-7 Cells , Molecular Targeted Therapy , Proteomics , RNA, Small Interfering/administration & dosage , Rats , Rats, Wistar , Receptor, Notch3/deficiency , Receptor, Notch3/genetics , Two-Dimensional Difference Gel ElectrophoresisABSTRACT
Long non-coding RNAs (lncRNAs) are ncRNAs more than 200 nucleotides long that participate to a wide range of biological functions. However, their role in cancer is poorly known. By using an NGS-based approach we analyzed the intragenic and poliA-lncRNAs in hepatocellular carcinoma (HCC) and we assayed the relationships between their deregulated expression and clinical-pathological characteristics. The expression profile of lncRNAs was studied in a discovery series of 28 HCC and matched cirrhosis and was validated in an independent cohort of 32 HCC patients both in tissue and serum. The correlation between lncRNA expression and clinical-pathological variables, EMT markers and putative sponged microRNAs level were investigated. Functional experiments were performed in HCC-derived cell lines to clarify the role of selected lncRNAs in HCC. A panel of deregulated lncRNAs differentiated HCC from cirrhotic tissue. CASC9 and LUCAT1 were up-regulated in a subset of HCC-derived cell lines and in half of HCCs which displayed a lower recurrence after surgery. LUCAT1 and CASC9 silencing increased cell motility and invasion capability in HCC cells and influenced the EMT phenotype. LUCAT1 was demonstrated to directly sponge the onco-miR-181d-5p. Both LUCAT1 and CASC9 were secreted in exosomes, and higher circulating CASC9 levels were associated with tumor size and HCC recurrence after surgery, suggesting its potential usage as putative non-invasive prognostic biomarker of recurrence.
ABSTRACT
The removal of hydrophobic materials from a porous support, such as wax stains on wall paintings, is particularly challenging. In this context, traditional methods display several drawbacks. The limitations of these methods can be overcome by amphiphile-based aqueous nanostructured fluids, such as micellar solutions and microemulsions. In this study, a microemulsion for the removal of wax spots from artistic surfaces was formulated. The nanostructured fluid includes a non-ionic surfactant, i.e., Triton X-100, and two apolar solvents, namely p-xylene and n-nonane. The solvents were selected on the basis of solubility tests of three waxes in several organic solvents. The nanostructured fluid was characterized by means of small-angle X-rays scattering (SAXS) and the information about micelle structure was used to understand the interaction between the microemulsion and the selected waxes. The microemulsion was then tested during the restoration of the frescoes in the Major Chapel of the Santa Croce Basilica in Florence, Italy. After some preliminary tests on fresco mockups reproduced in the laboratory, the nanostructured fluid was successfully used to clean some wax deposits from the real paintings, hardly removable with traditional physico-mechanical methods.
ABSTRACT
The removal of aged varnishes from the surface of easel paintings using the common conservation practice (i.e., by means of organic solvents) often causes pigment leaching, paint loss, and varnish redeposition. Recently, we proposed an innovative cleaning system based on semi-interpenetrated polymer networks (SIPNs), where a covalently cross-linked poly(hydroxyethyl methacrylate), pHEMA, network is interpenetrated by linear chains of poly(vinylpyrrolidone), PVP. This chemical gel, simply loaded with water, was designed to safely remove surface dirt from water-sensitive artifacts. Here, we modified the SIPN to confine complex cleaning fluids, able to remove aged varnishes. These complex fluids are 5-component water-based nanostructured systems, where organic solvents are partially dispersed as nanosized droplets in a continuous aqueous phase, using surfactants. The rheological behavior of the SIPN and the nanostructure of the fluids loaded into the gel were investigated, and the mechanical behavior of the gel was optimized by varying both the cross-linking density and the polymer concentration. Once loaded with the complex fluids, the hydrogels maintained their structural and mechanical features, while the complex fluids showed a decrease in the size of the dispersed solvent droplets. Two challenging case studies have been selected to evaluate the applicability of the SIPN hydrogels loaded with the complex fluids. The first case study concerns the removal of a surface layer composed by an aged brown resinous patina from a wood panel, the second case study concerns the removal of a homogeneous layer of yellowed varnish from a watercolor on paper. The results show that the confinement of complex fluids into gels allowed unprecedented removal of varnishes from artifacts overcoming the limitations of traditional cleaning methods.
ABSTRACT
Aqueous nanostructured fluids (NSFs) have been proposed to remove polymer coatings from the surface of works of art; this process usually involves film dewetting. The NSF cleaning mechanism was studied using several techniques that were employed to obtain mechanistic insight on the interaction of a methacrylic/acrylic copolymer (Paraloid B72) film laid on glass surfaces and several NSFs, based on two solvents and two surfactants. The experimental results provide a detailed picture of the dewetting process. The gyration radius and the reduction of the Tg of Paraloid B72 fully swollen in the two solvents is larger for propylene carbonate than for methyl ethyl ketone, suggesting higher mobility of polymer chains for the former, while a nonionic alcohol ethoxylate surfactant was more effective than sodium dodecylsulfate in favoring the dewetting process. FTIR 2D imaging showed that the dewetting patterns observed on model samples are also present on polymer-coated mortar tiles when exposed to NSFs.
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This corrects the article DOI: 10.1038/srep44685.
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One of the main problems connected to the conservation of street art is the selective removal of overlying undesired graffiti, i.e., drawings and tags. Unfortunately, selective and controlled removal of graffiti and overpaintings from street art is almost unachievable using traditional methodologies. Recently, the use of nanofluids confined in highly retentive pHEMA/PVP semi-interpenetrated polymer networks was proposed. Here, we report on the selective removal of acrylic overpaintings from a layer of acrylic paint on mortar mockups in laboratory tests. The results of the cleaning tests were characterized by visual and photographic observation, optical microscopy, and FT-IR microreflectance investigation. It was shown that this methodology represents a major advancement with respect to the use of nonconfined neat solvents.
ABSTRACT
Complementary and alternative medicine (CAM) is the term used to describe many kinds of products, practices, and systems that are not part of conventional medicine. Cancer patients usually do everything they can to combat the disease, manage its symptoms, and cope with the side effects of treatment. Unfortunately, patients who use CAM underestimate the risk of interaction with cancer therapy or worse they omit conventional therapy thus reducing the possibility of cancer remission. Herein we analyzed the effects of Vidatox 30 CH (venom extracted from the Junceus Rhopalurus scorpion) on hepatocellular carcinoma (HCC), the second leading cause of cancer-related deaths. We found out that Vidatox increases HCC proliferation and invasion whereas it does not seem to interact with sorafenib, the orally active multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma. Our results suggest that the concentration of Vidatox used in the present study has not anti-neoplastic effects and care must be taken in hiring Vidatox in patients with HCC.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/chemically induced , Gene Expression Regulation, Neoplastic , Hepatocytes/drug effects , Liver Neoplasms/chemically induced , Niacinamide/analogs & derivatives , Phenylurea Compounds/pharmacology , Spider Venoms/toxicity , Animals , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Cytokines/genetics , Cytokines/metabolism , Diethylnitrosamine , Hep G2 Cells , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Male , Niacinamide/pharmacology , Rats, Wistar , Scorpions/chemistry , Scorpions/pathogenicity , Scorpions/physiology , Signal Transduction , Sorafenib , Spider Venoms/antagonists & inhibitors , Spider Venoms/isolation & purification , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Vascular Endothelial Growth Factor Receptor-2/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Purpose: The aberrant expression of miR-221 is a hallmark of human cancers, including hepatocellular carcinoma (HCC), and its involvement in drug resistance, together with a proved in vivo efficacy of anti-miR-221 molecules, strengthen its role as an attractive target candidate in the oncologic field. The discovery of biomarkers predicting the response to treatments represents a clinical challenge in the personalized treatment era. This study aimed to investigate the possible role of miR-221 as a circulating biomarker in HCC patients undergoing sorafenib treatment as well as to evaluate its contribution to sorafenib resistance in advanced HCC.Experimental Design: A chemically induced HCC rat model and a xenograft mouse model, together with HCC-derived cell lines were employed to analyze miR-221 modulation by Sorafenib treatment. Data from the functional analysis were validated in tissue samples from surgically resected HCCs. The variation of circulating miR-221 levels in relation to Sorafenib treatment were assayed in the animal models and in two independent cohorts of patients with advanced HCC.Results: MiR-221 over-expression was associated with Sorafenib resistance in two HCC animal models and caspase-3 was identified as its target gene, driving miR-221 anti-apoptotic activity following Sorafenib administration. Lower pre-treatment miR-221 serum levels were found in patients subsequently experiencing response to Sorafenib and an increase of circulating miR-221 at the two months assessment was observed in responder patients.Conclusions: MiR-221 might represent a candidate biomarker of likelihood of response to Sorafenib in HCC patients to be tested in future studies. Caspase-3 modulation by miR-221 participates to Sorafenib resistance. Clin Cancer Res; 23(14); 3953-65. ©2017 AACR.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Caspase 3/genetics , Liver Neoplasms/drug therapy , MicroRNAs/genetics , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Aged , Aged, 80 and over , Animals , Apoptosis/genetics , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice , Middle Aged , Niacinamide/administration & dosage , Niacinamide/adverse effects , Phenylurea Compounds/adverse effects , Sorafenib , Xenograft Model Antitumor AssaysABSTRACT
Hepatocellular carcinoma (HCC) ranks fifth in frequency worldwide amongst all human cancers causing one million deaths annually. Despite many promising treatment options, long-term prognosis remains dismal for the majority of patients who develop recurrence or present with advanced disease. Notch signaling is an evolutionarily conserved pathway crucial for the development and homeostasis of many organs including liver. Herein we showed that aberrant Notch1 is linked to HCC development, tumor recurrence and invasion, which might be mediated, at least in part, through the Notch1-E-Cadherin pathway. Collectively, these findings suggest that targeting Notch1 has important therapeutic value in hepatocellular carcinoma. In this regard, comparative analysis of the secretome of HepG2 and HepG2 Notch1 depleted cells identified novel secreted proteins related to Notch1 expression. Soluble E-Cadherin (sE-Cad) and Thrombospondin-1 (Thbs1) were further validated in human serum as potential biomarkers to predict response to Notch1 inhibitors for a tailored individualized therapy.