Constitutive stilbene contents of grapevine cluster stems as potential source of resveratrol in wine

Ripe clusters of 8 Vitis vinifera L. varieties (Cabernet franc, Gewürztraminer, Marzemino, Merlot, Moscato, Pinot gris, Sauvignon, Tocai friulano) were analysed to determine the constitutional levels of trans- and cis-resveratrol, ε-viniferin and pterostilbene. Grape stems were extracted by an hydroalcoholic solution, in order to simulate the resveratrol extraction from stems that might occur during alcoholic fermentation, due to the presence of little pieces of stems in the fermenting must. The average stem concentrations of constitutive trans-, cis-resveratrol and ε-viniferin were 142, 0.30, and 70 mu g.g-1 FW, respectively; pterostilbene was not found. Varieties differed significantly in their stilbene content. The percentage of trans-resveratrol extracted from the stems by a hydroalcoholic solution varied from 2.5 % (Gewürztraminer) to 32.9 % (Marzemino), the contribution of the stems to the trans-resveratrol concentration of the hydroalcoholic solution being, on the average, 34 mu g.l-1

Structural analysis of a subduction-related contact in southern Sesia-Lanzo Zone (Austroalpine Domain, Italian Western Alps)

A new foliation trajectory map at 1:10000 scale, represented here with an interpretative structural map, is derived from an original field analysis at 1:5000 scale in the southern Sesia-Lanzo Zone (SLZ). It shows the relative chronology of overprinting foliations, characterised by the mineral assemblages that mark superposed fabrics in each rock type. This map and the associated cross-sections, which synthesise the 3D structural outline of the tectonic contact between the Eclogitic Micaschists Complex (EMC), the Rocca Canavese Thrust Sheets and the Lanzo Ultramafic Complex, allow the correlation of the structural and metamorphic imprints that developed in these crustal and mantle complexes during Alpine subduction. Furthermore, the map and cross-sections allow the immediate perception of the metamorphic environments in which the structural imprints developed in each complex successively under eclogite, blueschist and greenschist facies conditions. The represented structural and metamorphic evolution of the southern end of the SLZ (internal Western Alps) has been inferred based on multiscale structural analysis. The dominant fabrics at the regional scale are two superposed mylonitic foliations that developed under blueschist and greenschist facies conditions, respectively. Metamorphic assemblages underlying the successive fabrics in the different metamorphic complexes allow us to identify contrasting metamorphic evolutions indicating that the tectonic contacts between the EMC, the Rocca Canavese Thrust Sheets and the Lanzo Ultramafic Complex developed under blueschist facies conditions and were successively reactivated during the greenschist facies retrogression

Elicitation and accumulation of stilbene phytoalexins in grapevine berries infected by Botrytis cinerea

At three developmental stages berries of field-grown Castor (interspecific crossing) and Huxelrebe (V. vinifera L. crossing) were in vitro inoculated with two strains of Botrytis cinerea Pers. to investigate the response of berries to fungal infection With respect to the time course of phytoalexin (trans-resveratrol, ε-viniferin and pterostilbene) accumulation and Visual disease symptoms. In infected berries the amounts of ε-viniferin dominated over pterostilbene. The stilbene phytoalexin content decreased during berry development and sugar accumulation. Grape varieties reacted differently to B. cinerea strains with regard to stilbene response and Visual symptoms. Mechanical damage of the berry skin induced uninfected berries to synthesize low amounts of phytoalexins. It can be assumed that after extraction and degradation ε-viniferin of mature berries is a source of resveratrol in wine

The nasal delivery of nanoencapsulated statins – An approach for brain delivery

© 2016 Clementino et al. Purpose: Along with their cholesterol-lowering effect, statins have shown a wide range of pleiotropic effects potentially beneficial to neurodegenerative diseases. However, such effects are extremely elusive via the conventional oral administration. The purpose of the present study was to prepare and characterize the physicochemical properties and the in vivo biodistribution of simvastatin-loaded lecithin/chitosan nanoparticles (SVT-LCNs) suitable for nasal administration in view of an improved delivery of the statins to the brain. Materials and methods: Chitosan, lecithin, and different oil excipients were used to prepare nanocapsules loaded with simvastatin. Particle size distribution, surface charge, structure, simvastatin loading and release, and interaction with mucus of nanoparticles were determined. The nanoparticle nasal toxicity was evaluated in vitro using RPMI 2651 nasal cell lines. Finally, in vivo biodistribution was assessed by gamma scintigraphy via Tc99m labeling of the particles. Results: Among the different types of nanoparticles produced, the SVT-LCN_MaiLab showed the most ideal physicochemical characteristics, with small diameter (200 nm), positive surface charge (+48 mV) and high encapsulation efficiency (EE; 98%). Size distribution was further confirmed by nanoparticle tracking analysis and electron microscopy. The particles showed a relatively fast release of simvastatin in vitro (35.6%±4.2% in 6 hours) in simulated nasal fluid. Blank nanoparticles did not show cytotoxicity, evidencing that the formulation is safe for nasal administration, while cytotoxicity of simvastatin-loaded nanoparticles (IC50) was found to be three times lower than the drug solution (9.92 vs 3.50 μM). In rats, a significantly higher radioactivity was evidenced in the brain after nasal delivery of simvastatin-loaded nanoparticles in comparison to the administration of a similar dose of simvastatin suspension. Conclusion: The SVT-LCNs developed presented some of the most desirable characteristics for mucosal delivery, that is, small particle size, positive surface charge, long-term stability, high EE, and mucoadhesion. In addition, they displayed two exciting features: First was their biodegradability by enzymes present in the mucus layer, such as lysozyme. This indicates a new Trojan-horse strategy which may enhance drug release in the proximity of the nasal mucosa. Second was their ability to enhance the nose-to-brain transport as evidenced by preliminary gamma scintigraphy studies

Small Angle Scattering and Zeta Potential of Liposomes Loaded with Octa(carboranyl)porphyrazine

In this work the physicochemical characterization of liposomes loaded with a newly synthesised carboranyl porphyrazine (H2HECASPz) is described. This molecule represents a potential drug for different anticancer therapies, such as Boron Neutron Capture Therapy, Photodynamic Therapy and Photothermal Therapy. Different loading methods and different lipid mixtures were tested. The corresponding loaded vectors were studied by Small Angle Scattering (SANS and SAXS), light scattering and zeta potential. The combined analysis of structural data at various length scales and the measurement of the surface charge allowed to obtain a detailed characterization of the investigated systems. The mechanisms underlying the onset of differences in relevant physicochemical parameters (size, polydispersity and charge) were also critically discussed

Randomised controlled trial comparing single agent paclitaxel vs epidoxorubicin plus paclitaxel in patients with advanced ovarian cancer in early progression after platinum-based chemotherapy: an Italian Collaborative Study from the ‘Mario Negri’ Institute, Milan, G.O.N.O. (Gruppo Oncologico Nord Ovest) group and I.O.R. (Istituto Oncologico Romagnolo) group

The aim of the study was to evaluate the role of epidoxorubicin plus paclitaxel combination (ET) vs single agent paclitaxel (T), as second-line chemotherapy treatment in advanced ovarian cancer patients in early progression within 12 months after platinum-based chemotherapy. From October 1994 up to June 1999, 234 patients from 34 Italian hospitals were randomised to receive: (A) epidoxorubicin (E) 80 mg m(-2) + paclitaxel (T) 175 mg m(-2) (3 h infusion), every 21 days for 4-6 cycles. (B) Paclitaxel 175 mg m(-2) (3 h infusion) every 21 days for 4-6 cycles. Evaluable for survival analysis were 106 and 106 patients in ET and T arm, respectively. Platinum-based monochemotherapy was the first-line treatment in 43% patients, while polichemotherapy containing anthracyclines was the preferred first-line therapy in 22% patients. The median time from the end of first-line therapy to randomisation was 3 months. Treatment was completed in 87 and 85% of T and ET arm, respectively. Haematological toxicity was significantly more common in ET group (ECOG grade 3-4 neutropenia: 37.4% in ET vs 18.2% in T arm). Neuropathies were similar in both arms (sensory: ECOG grade 2-3: 12.1% in ET vs 14.7% in T arm, motor: 6.1% in ET vs 5.3% in T arm). Objective response was achieved in 37.4% of patients in ET group and in 46.9% of patients in T arm. At a median follow-up of time of 48 months, a total of 180 patients progressed and 163 patients died. Survival analysis showed no difference between ET and T (median time to progression: 6 months for both regimens, median survival: 12 and 14 months for ET and T, respectively; hazard ratio for mortality of ET vs T: 1.17 (95% CI 0.86-1.59; P=0.33). The ET regimen does not seem to be more effective than T in refractory advanced ovarian cancer patients in early progression after platinum-based chemotherapy. Despite an acceptable response rate, the control of disease progression remains poor

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer