MicroRNAs (miRNAs) from the gene cluster miR-143-145 are diminished in cells of colorectal tumor origin when compared with normal colon epithelia. Until now, no report has addressed the coordinate ...action of these miRNAs in colorectal cancer (CRC). In this study, we performed a comprehensive molecular and functional analysis of the miRNA cluster regulatory network. First, we evaluated proliferation, migration, anchorage-independent growth and chemoresistance in the colon tumor cell lines after miR-143 and miR-145 restoration. Then, we assessed the contribution of single genes targeted by miR-143 and miR-145 by reinforcing their expression and checking functional recovery. Restoring miR-143 and miR-145 in colon cancer cells decreases proliferation, migration and chemoresistance. We identified cluster of differentiation 44 (CD44), Kruppel-like factor 5 (KLF5), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) as proteins targeted by miR-143 and miR-145. Their re-expression can partially revert a decrease in transformation properties caused by the overexpression of miR-143 and miR-145. In addition, we determined a set of mRNAs that are diminished after reinforcing miR-143 and miR-145 expression. The whole transcriptome analysis ascertained that downregulated transcripts are enriched in predicted target genes in a statistically significant manner. A number of additional genes, whose expression decreases as a direct or indirect consequence of miR-143 and miR-145, reveals a complex regulatory network that affects cell signaling pathways involved in transformation. In conclusion, we identified a coordinated program of gene repression by miR-143 and miR-145, in CRC, where either of the two miRNAs share a target transcript, or where the target transcripts share a common signaling pathway. Major mediators of the oncosuppression by miR-143 and miR-145 are genes belonging to the growth factor receptor-mitogen-activated protein kinase network and to the p53 signaling pathway.
Advanced, metastatic melanomas frequently grow in subcutaneous tissues and portend a poor prognosis. Though subcutaneous tissues are largely composed of adipocytes, the mechanisms by which adipocytes ...influence melanoma are poorly understood. Using
and
models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. Additionally, adipocytes directly transfer lipids to melanoma cells, which alters tumor cell metabolism. Adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface. Among the six FATP/SLC27A family members, melanomas significantly overexpress FATP1/SLC27A1. Melanocyte-specific FATP1 expression cooperates with BRAF
in transgenic zebrafish to accelerate melanoma development, an effect that is similarly seen in mouse xenograft studies. Pharmacologic blockade of FATPs with the small-molecule inhibitor Lipofermata abrogates lipid transport into melanoma cells and reduces melanoma growth and invasion. These data demonstrate that stromal adipocytes can drive melanoma progression through FATP lipid transporters and represent a new target aimed at interrupting adipocyte-melanoma cross-talk.
We demonstrate that stromal adipocytes are donors of lipids that mediate melanoma progression. Adipocyte-derived lipids are taken up by FATP proteins that are aberrantly expressed in melanoma. Inhibition of FATPs decreases melanoma lipid uptake, invasion, and growth. We provide a mechanism for how stromal adipocytes drive tumor progression and demonstrate a novel microenvironmental therapeutic target.
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An integrated approach to the geomechanical characterization of coastal sea cliffs was applied at Mt. Pucci (Gargano promontory, Southern Italy) by performing field-based geomechanical investigations ...and remote geostructural investigations via a terrestrial laser scanner (TLS). The consistency of the integrated techniques allowed to achieve a comprehensive and affordable characterization of the main joint sets on the sea cliff slope. The observed joint sets were considered to evaluate the proneness of the slope to rock failures by attributing safety factor (SF) values to the topple- and wedge-prone rock blocks under three combined or independent triggering conditions: (a) hydrostatic water pressures within the joints, (b) seismic action, and (c) strength reduction due to weathering of the joint surfaces. The combined action of weathering and water pressures within the joints was also considered, resulting in a significant decrease in the stability. Furthermore, remote survey analyses via InfraRed Thermography (IRT) and Ground Based Synthetic Aperture Radar Interferometry (GBInSAR) were performed to evaluate the role of the surveyed joint sets in inducing instabilities in the Mt. Pucci sea cliff. The results from the remote surveys: (i) GBInSAR monitoring revealed permanent displacements coupled to cyclic daily displacements, these last ones detected in certain sectors of the cliff wall; (ii) the thermal images allowed us to identify anomalies that correspond well to the main joints and to the slope material released due to recent collapses.
On August 16th, 2018, a Mw 5.1 earthquake struck the Molise region (central Italy), inducing 84 earthquake-triggered landslides that predominantly involved soil covers of clayey materials and flysch ...on gently dipping slopes. To quantify the spatiotemporal landslide activity in the months immediately after the earthquake, a differential SAR interferometry (DInSAR) analysis was performed for a time span from 2 years before to one year after the earthquake, recognising both first-time and reactivated landslides. The results showed a clear increase in landslide activity following the low-magnitude earthquake with respect to the activities recorded in the same months of the previous years. Several coherent landslides (earth slides and earth flows) were observed following seasonally recurrent rainfall events. Such increases were observed for both reactivated and first-time landslides, showing decreases in inactive periods and activity over longer periods. Furthermore, the spatial density distribution of the landslides was investigated in the postseismic time interval along transects perpendicular and parallel to the direction of the tectonic element responsible for the seismic event. An asymmetrical distribution was deduced parallel to the fault strike with a higher number of landslides located inside the compressional sector according to a strike-slip faulting mechanism.
To evaluate genetic, demographic and clinical features in patients with cryopyrin-associated periodic syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and ...predictive disease severity markers.
A web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included.
136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss.
Patients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions.
Current energy drivers are pushing research in power generation materials towards improved efficiency and improved environmental impact. In the context of new generation ultra-supercritical (USC) ...power plant, this is represented by increased efficiency, service temperature reaching 750°C, pressures in the range of 35–37.5MPa and associated carbon capture technology. Ni base alloys are primary candidate materials for long term high temperature applications such as boilers. The transition from their current applications, which have required lower exposure times and milder corrosive environments, requires the investigation of their microstructural evolution as a function of thermo-mechanical treatment and simulated service conditions, coupled with modelling activities that are able to forecast such microstructural changes. The lack of widespread microstructural data in this context for most nickel base alloys makes this type of investigation necessary and novel. Alloy INCONEL 617 is one of the Ni-base candidate materials. The microstructures of four specimens of this material crept at temperatures in the 650–750°C range for up to 20,000h have been characterised and quantified. Grain structure, precipitate type and location, precipitate volume fraction, size and inter-particle spacing have been determined. The data obtained are used both as input for and validation of a microstructurally-based CDM model for forecasting creep properties.
While most primary tumors can be effectively treated, therapeutics fail to efficiently eliminate metastases. Metastases arise from cancer cells that leave the primary tumor and seed distant sites. ...Recent studies have shown that cancer cells disseminate early during tumor progression and can remain dormant for years before they resume growth. In these metastatic organs, cancer cells reside in microenvironments where they interact with other cells, but also with the extracellular matrix (ECM). The ECM was long considered to be an inert, non-cellular component of tissues, providing their architecture. However, in recent years, a growing body of evidence has shown that the ECM is a key driver of cancer progression, and it can exert effects on tumor cells, regulating their metastatic fate. ECM remodeling and degradation is required for the early steps of the metastatic cascade: invasion, tumor intravasation, and extravasation. Similarly, ECM molecules have been shown to be important for metastatic outgrowth. However, the role of ECM molecules on tumor dormancy and their contribution to the dormancy-supportive niches is not well understood. In this perspective article, we will summarize the current knowledge of ECM and its role in tumor metastasis and dormancy. We will discuss how a better understanding of the individual components of the ECM niche and their roles mediating the dormant state of disseminated tumor cells (DTCs) will advance the development of new therapies to target dormant cells and prevent metastasis outgrowth.
A database (Italian acronym CEDIT) of earthquake-induced ground failures in Italy is presented, and the related content is analysed. The catalogue collects data regarding landslides, liquefaction, ...ground cracks, surface faulting and ground changes triggered by earthquakes of Mercalli epicentral intensity 8 or greater that occurred in the last millennium in Italy. As of January 2013, the CEDIT database has been available online for public use (http://www.ceri.uniroma1.it/cn/gis.jsp ) and is presently hosted by the website of the Research Centre for Geological Risks (CERI) of the Sapienza University of Rome. Summary statistics of the database content indicate that 14% of the Italian municipalities have experienced at least one earthquake-induced ground failure and that landslides are the most common ground effects (approximately 45%), followed by ground cracks (32%) and liquefaction (18%). The relationships between ground effects and earthquake parameters such as seismic source energy (earthquake magnitude and epicentral intensity), local conditions (site intensity) and source-to-site distances are also analysed. The analysis indicates that liquefaction, surface faulting and ground changes are much more dependent on the earthquake source energy (i.e. magnitude) than landslides and ground cracks. In contrast, the latter effects are triggered at lower site intensities and greater epicentral distances than the other environmental effects.
Mechanical response of rock masses to the periodical fluctuation of surface temperatures is a relevant topic to be focused on for the comprehension of short- to long-term stability of rock slopes ...continuously stressed by slight yet periodical actions. To better understand how preparatory factors can lead rock masses toward failure, thermal and strain monitoring activities are ongoing in a selected quarry wall, where an experimental test-site was implemented on a jointed rock block. The role of pervasive joints in perturbing the heating-cooling process of the rock mass and their related effects was already output by direct and remote monitoring. For these purposes, FDM numerical modelling was focused on the comprehension and simulation of induced mechanical effects due to cyclical thermal forcings over a simplified 2D half-space. Therefore, the role of rock mass joints on both heat propagation and resulting thermo-mechanical effects was analysed, basing on monitoring data, field experiments and numerical modelling. Numerical results output the role of periodic daily, annual and compound thermal input in inducing irreversible deformation along joints under different rock mass jointing configuration, as a function of the intrinsic period of thermal input and joint attitude. Temperature distribution across joints was also analysed as a possible constraining effect for time and space distribution of yielding. A sensitivity analysis of heat propagation conditions was performed in order to infer the role of joint sets on induced thermo-mechanical strains at the rock block scale. A non-negligible influence on surficial as well as deeper portions of the rock mass was observed, highlighting how near-surface temperature fluctuations can drive the long-term evolution of rock block conditions towards failure.
•Thermally induced strains in rock mass were numerically reproduced.•Daily, annual and a composition of temperature variations were modelled.•Thermo-mechanical sensitivity analysis was experimented.•Jointing conditions markedly influence temperature fields.•Temperature fields can control the distribution of rock failures.
•Cellulose nanocrystals (CNC) and PLGA nanoparticles (NPs) were synthesized.•Ternary poly(vinyl alcohol) (PVA) nanocomposites with CNC and PLGA NPs were produced.•CNC are able to increase the PVA ...elongation properties.•The synergic presence of CNC and PLGA produced a nucleation effect.•Stem cells up-take easily the NPs released from PVA bio-nanocomposites.
The formation of a new generation of hybrid bio-nanocomposites is reported: these are intended at modulating the mechanical, thermal and biocompatibility properties of the poly(vinyl alcohol) (PVA) by the combination of cellulose nanocrystals (CNC) and poly (d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) loaded with bovine serum albumin fluorescein isothiocynate conjugate (FITC-BSA). CNC were synthesized from microcrystalline cellulose by hydrolysis, while PLGA nanoparticles were produced by a double emulsion with subsequent solvent evaporation. Firstly, binary bio-nanocomposites with different CNC amounts were developed in order to select the right content of CNC. Next, ternary PVA/CNC/NPs bio-nanocomposites were developed. The addition of CNC increased the elongation properties without compromising the other mechanical responses. Thermal analysis underlined the nucleation effect of the synergic presence of cellulose and nanoparticles. Remarkably, bio-nanocomposite films are suitable to vehiculate biopolymeric nanoparticles to adult bone marrow mesenchymal stem cells successfully, thus representing a new tool for drug delivery strategies.
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