Are Wnt/β-Catenin and PI3K/AKT/mTORC1 Distinct Pathways in Colorectal Cancer?

Wnt/β-catenin and phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin complex 1 (PI3K/AKT/mTORC1) pathways both are critically involved in colorectal cancer (CRC) development, although they are implicated in the modulation of distinct oncogenic mechanisms. In homeostatic and pathologic conditions, these pathways show a fine regulation based mainly on feedback mechanisms, and are connected at multiple levels involving both upstream and downstream common effectors. The ability of the Wnt/β-catenin and PI3K/AKT/mTORC1 pathways to reciprocally control themselves represents one of the main resistance mechanisms to selective inhibitors in CRC, leading to the hypothesis that in specific settings, particularly in cancer driven by genetic alterations in Wnt/β-catenin signaling, the relationship between Wnt/β-catenin and PI3K/AKT/mTORC1 pathways could be so close that they should be considered as a unique therapeutic target. This review provides an update on the Wnt/β-catenin and PI3K/AKT/mTORC1 pathway interconnections in CRC, describing the main molecular players and the potential implications of combined inhibitors as an approach for CRC chemoprevention and treatment

Molecular determination of epidermal growth factor receptor in normal and neoplastic colorectal mucosa

The epidermal growth factor receptor (EGFr) is considered a major target for treatment of colorectal cancer (CRC). We found a mean EGFr content significantly lower but more activated in colonic neoplastic tissue than in paired normal mucosa. Phosphorylated (pY1068) EGFr detection in CRC may be a better tool than EGFr detection to select patients for targeted therapies

From the dual function lead AP2238 to AP2469, a multi-target-directed ligand for the treatment of Alzheimer\u2019s disease

The development of drugs with different pharmacological properties appears to be an innovative therapeutic approach for Alzheimer\u2019s disease. In this article, we describe a simple structural modification of AP2238, a first dual function lead, in particular the introduction of the catechol moiety performed in order to search for multi-target ligands. The new compound AP2469 retains antiacetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme (BACE)1 activities compared to the reference, and is also able to inhibit Ab42 self aggregation, Ab42 oligomer-binding to cell membrane and subsequently reactive oxygen species formation in both neuronal and microglial cells. The ability of AP2469 to interfere with Ab42 oligomer-binding to neuron and microglial cell membrane gives this molecule both neuroprotective and antiinflammatory properties. These findings, together with its strong chain-breaking antioxidant performance, make AP2469 a potential drug able to modify the course of the diseas

Effects of seagrasses and algae of the Caulerpa family on hydrodynamics and particle-trapping rates

The widespread decline of seagrass beds within the Mediterranean often results in the replacement of seagrasses by opportunistic green algae of the Caulerpa family. Because Caulerpa beds have a different height, stiffness and density compared to seagrasses, these changes in habitat type modify the interaction of the seafloor with hydrodynamics, influencing key processes such as sediment resuspension and particle trapping. Here, we compare the effects on hydrodynamics and particle trapping of Caulerpa taxifolia, C. racemosa, and C. prolifera with the Mediterranean seagrasses Cymodocea nodosa and Posidonia oceanica. All macrophyte canopies reduced near-bed volumetric flow rates compared to bare sediment, vertical profiles of turbulent kinetic energy revealed peak values around the top of the canopies, and maximum values of Reynolds stress increased by a factor of between 1.4 (C. nodosa) and 324.1 (P. oceanica) when vegetation was present. All canopies enhanced particle retention rates compared to bare sediment. The experimental C. prolifera canopy was the most effective at particle retention (m2 habitat); however, C. racemosa had the largest particle retention capacity per structure surface area. Hence, in terms of enhancing particle trapping and reducing hydrodynamic forces at the sediment surface, Caulerpa beds provided a similar or enhanced function compared to P.oceanica and C. nodosa. However, strong seasonality in the leaf area index of C. racemosa and C. taxifolia within the Mediterranean, combined with a weak rhizome structure, suggests that sediments maybe unprotected during winter storms, when most erosion occurs. Hence, replacement of seagrass beds with Caulerpa is likely to have a major influence on annual sediment dynamics at ecosystem scales.This research was funded by the European Network of Excellence ‘‘Marine Biodiversity and Ecosystem Function’’ (MarBEF); FP6, EC contract no. 505446 and a grant from the Fundacio ´n BBVA. EPM was supported by a European Union Marie Curie host fellowship for transfer of knowledge, MTKD-CT-2004-509254, the Spanish national project EVAMARIA (CTM2005-00395/MAR) and the regional government of Andalusia project FUNDIV(P07-RNM-2516)

Stakeholders’ attitudes about the transplantations of the mediterranean seagrass posidonia oceanica as a habitat restoration measure after anthropogenic impacts: A q methodology approach

Anthropogenic impacts on Posidonia oceanica meadows have led to a decline of this ecosystem throughout the Mediterranean. Transplantations have often been prescribed as a compensation measure to mitigate the impacts caused by coastal maritime works. Here a Q methodology approach was used to investigate the stakeholders’ attitudes in four case studies of P. oceanica transplants realized in Italian waters. Twenty-two respondents were asked to score 37 statements, and the resultant Q-sorting was analyzed via an inverse PCA using the KADE software. Four discourses, corresponding to the significant axes in the factorial analysis were identified: science and conservation (F1), oriented at a rigorous scientific approach; engineering and industry (F2), oriented at the economic development; environmentalism and participation (F3), oriented at the conservation of seagrass meadows; and transplantation-oriented (F4), oriented at the realization of transplants as compensation measures. The main conflicts and agreements between discourses are assessed and discussed, based on the analysis of the distinguishing statements that contributed to consensus or disagreement among discourses. The benefits of the Q methodology in the identification and mediation of conflicts in the four case studies are discussed, and its potential as a powerful aid in the development of a good environmental governance is acknowledged

Il coralligeno toscano: distribuzione, struttura dei popolamenti e monitoraggio mediante utilizzo di differenti indici di qualit\ue0 ecologica.

Coralligenous reefs are one of the main habitat of the Mediterranean Sea for distribution, biodiversity and role in the carbon cycle. Distribution and ecological quality of coralligenous reefs must be assessed under the Marine Strategy Framework Directive. The present work aimed at assess the distribution of coralligenous reefs in Tuscany waters, describing their structure and evaluating their ecological quality through different ecological quality indices. In Tuscany waters, coralligenous reefs are distributed on rocky cliffs between 25-30 m and 50-60 m of depth. The ecological quality resulted always sufficient with values of the indices higher on the islands than on the continental coasts

Sensitivity of snow models to the accuracy of meteorological forcings in mountain environments

Snow models are usually evaluated at sites providing high-quality meteorological data, so that the uncertainty in the meteorological input data can be neglected when assessing model performances. However, high-quality input data are rarely available in mountain areas and, in practical applications, the meteorological forcing used to drive snow models is typically derived from spatial interpolation of the available in situ data or from reanalyses, whose accuracy can be considerably lower. In order to fully characterize the performances of a snow model, the model sensitivity to errors in the input data should be quantified. In this study we test the ability of six snow models to reproduce snow water equivalent, snow density and snow depth when they are forced by meteorological input data with gradually lower accuracy. The SNOWPACK, GEOTOP, HTESSEL, UTOPIA, SMASH and S3M snow models are forced, first, with high-quality measurements performed at the experimental site of Torgnon, located at 2160ma.s.l. in the Italian Alps (control run). Then, the models are forced by data at gradually lower temporal and/or spatial resolution, obtained by (i) sampling the original Torgnon 30 min time series at 3, 6, and 12 h, (ii) spatially interpolating neighbouring in situ station measurements and (iii) extracting information from GLDAS, ERA5 and ERA-Interim reanalyses at the grid point closest to the Torgnon site. Since the selected models are characterized by different degrees of complexity, from highly sophisticated multi-layer snow models to simple, empirical, single-layer snow schemes, we also discuss the results of these experiments in relation to the model complexity. The results show that, when forced by accurate 30 min resolution weather station data, the single-layer, intermediatecomplexity snow models HTESSEL and UTOPIA provide similar skills to the more sophisticated multi-layer model SNOWPACK, and these three models show better agreement with observations and more robust performances over different seasons compared to the lower-complexity models SMASH and S3M. All models forced by 3-hourly data provide similar skills to the control run, while the use of 6- A nd 12-hourly temporal resolution forcings may lead to a reduction in model performances if the incoming shortwave radiation is not properly represented. The SMASH model generally shows low sensitivity to the temporal degradation of the input data. Spatially interpolated data from neighbouring stations and reanalyses are found to be adequate forcings, provided that temperature and precipitation variables are not affected by large biases over the considered period. However, a simple bias-adjustment technique applied to ERA-Interim temperatures allowed all models to achieve similar performances to the control run. Regardless of their complexity, all models show weaknesses in the representation of the snow density

Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer

The Notch signaling pathway drives proliferation, differentiation, apoptosis, cell fate, and maintenance of stem cells in several tissues. Aberrant activation of Notch signaling has been described in several tumours and in gastric cancer (GC), activated Notch1 has been associated with de-differentiation of lineage-committed stomach cells into stem progenitors and GC progression. However, the specific role of the Notch1 ligand (DLL1) in GC has not yet been elucidated. To assess the role of DLL1 in GC cancer, the expression of Notch1 and its ligands DLL1 and Jagged1, was analyzed in 8 gastric cancer cell lines (KATOIII, SNU601, SNU719, AGS, SNU16, MKN1, MKN45, TMK1). DLL1 expression was absent in KATOIII, SNU601, SNU719 and AGS. The lack of DLL1 expression in these cells was associated with promoter hypermethylation and 5-aza-2’deoxycitidine caused up-regulation of DLL1. The increase in DLL1 expression was associated with activation of Notch1 signalling, with an increase in cleaved Notch1 intracellular domain (NICD) and Hes1, and down-regulation in Hath1. Concordantly, Notch1 signalling was activated with the overexpression of DLL1. Moreover, Notch1 signalling together with DLL1 methylation were evaluated in samples from 52 GC patients and 21 healthy control as well as in INS-GAS mice infected with H. pylori and randomly treated with eradication therapy. In GC patients, we found a correlation between DLL1 and Hes1 expression, while DLL1 methylation and Hath1 expression were associated with the diffuse and mixed type of gastric cancer. Finally, none of the samples from INS-GAS mice infected with H. pylori, a model of intestinal-type gastric tumorigenesis, showed promoter methylation of DLL1. This study shows that Notch1 activity in gastric cancer is controlled by the epigenetic silencing of the ligand DLL1, and that Notch1 inhibition is associated with the diffuse type of gastric cancer

Marine Invasion in the Mediterranean Sea: The Role of Abiotic Factors When There Is No Biological Resistance

The tropical red alga Womersleyella setacea (Rhodomelaceae, Rhodophyta) is causing increasing concern in the Mediterranean Sea because of its invasive behavior. After its introduction it has colonized most Mediterranean areas, but the mechanism underlying its acclimatization and invasion process remains unknown. To understand this process, we decided i) to assess in situ the seasonal biomass and phenological patterns of populations inhabiting the Mediterranean Sea in relation to the main environmental factors, and ii) to experimentally determine if the tolerance of W. setacea to different light and temperature conditions can explain its colonization success, as well as its bathymetric distribution range. The bathymetric distribution, biomass, and phenology of W. setacea were studied at two localities, and related to irradiance and temperature values recorded in situ. Laboratory experiments were set up to study survival, growth and reproduction under contrasting light and temperature conditions in the short, mid, and long term.Results showed that, in the studied area, the bathymetric distribution of W. setacea is restricted to a depth belt between 25 and 40 m deep, reaching maximum biomass values (126 g dw m−2) at 30 m depth. In concordance, although in the short term W. setacea survived and grew in a large range of environmental conditions, its life requirements for the mid and long term were dim light levels and low temperatures. Biomass of Womersleyella setacea did not show any clear seasonal pattern, though minimum values were reported in spring. Reproductive structures were always absent. Bearing in mind that no herbivores feed on Womersleyella setacea and that its thermal preferences are more characteristic of temperate than of tropical seaweeds, low light (50 µmol photon m−2 s−1) and low temperature (12°C) levels are critical for W. setacea survival and growth, thus probably determining its spread and bathymetric distribution across the Mediterranean Sea

Ultrasound Stimulation of Piezoelectric Nanocomposite Hydrogels Boosts Chondrogenic Differentiation in Vitro, in Both a Normal and Inflammatory Milieu

The use of piezoelectric nanomaterials combined with ultrasound stimulation is emerging as a promising approach for wirelessly triggering the regeneration of different tissue types. However, it has never been explored for boosting chondrogenesis. Furthermore, the ultrasound stimulation parameters used are often not adequately controlled. In this study, we show that adipose-tissue-derived mesenchymal stromal cells embedded in a nanocomposite hydrogel containing piezoelectric barium titanate nanoparticles and graphene oxide nanoflakes and stimulated with ultrasound waves with precisely controlled parameters (1 MHz and 250 mW/cm2, for 5 min once every 2 days for 10 days) dramatically boost chondrogenic cell commitment in vitro. Moreover, fibrotic and catabolic factors are strongly down-modulated: proteomic analyses reveal that such stimulation influences biological processes involved in cytoskeleton and extracellular matrix organization, collagen fibril organization, and metabolic processes. The optimal stimulation regimen also has a considerable anti-inflammatory effect and keeps its ability to boost chondrogenesis in vitro, even in an inflammatory milieu. An analytical model to predict the voltage generated by piezoelectric nanoparticles invested by ultrasound waves is proposed, together with a computational tool that takes into consideration nanoparticle clustering within the cell vacuoles and predicts the electric field streamline distribution in the cell cytoplasm. The proposed nanocomposite hydrogel shows good injectability and adhesion to the cartilage tissue ex vivo, as well as excellent biocompatibility in vivo, according to ISO 10993. Future perspectives will involve preclinical testing of this paradigm for cartilage regeneration