Fluid transfer and vein thickness distribution in high and low temperature hydrothermal systems at shallow crustal level in southern Tuscany (Italy)

Geometric analysis of vein systems hosted in upper crustal rocks and developed in high and low temperature hydrothermal systems is presented. The high temperature hydrothermal system consists of tourmaline-rich veins hosted within the contact aureole of the upper Miocene Porto Azzurro pluton in the eastern Elba Island. The low temperature hydrothermal system consists of calcite-rich veins hosted within the Oligocene sandstones of the Tuscan Nappe, exposed along the coast in southern Tuscany. Vein thickness distribution is here used as proxy for inferring some hydraulic properties (transmissivity) of the fluid circulation at the time of veins’ formation. We derive estimations of average thickness of veins by using the observed distributions. In the case of power law thickness distributions, the lower the scaling exponent of the distribution the higher the overall transmissivity. Indeed, power law distributions characterized by high scaling exponents have transmissivity three order of magnitude lower than negative exponential thickness distribution. Simple observations of vein thickness may thus provides some clues on the transmissivity in hydrothermal systems

Magnetic nanoparticles in the central nervous system: Targeting principles, applications and safety issues

One of the most challenging goals in pharmacological research is overcoming the Blood Brain Barrier (BBB) to deliver drugs to the Central Nervous System (CNS). The use of physical means, such as steady and alternating magnetic fields to drive nanocarriers with proper magnetic characteristics may prove to be a useful strategy. The present review aims at providing an up-to-date picture of the applications of magnetic-driven nanotheranostics agents to the CNS. Although well consolidated on physical ground, some of the techniques described herein are still under investigation on in vitro or in silico models, while others have already entered in—or are close to—clinical validation. The review provides a concise overview of the physical principles underlying the behavior of magnetic nanoparticles (MNPs) interacting with an external magnetic field. Thereafter we describe the physiological pathways by which a substance can reach the brain from the bloodstream and then we focus on those MNP applications that aim at a nondestructive crossing of the BBB such as static magnetic fields to facilitate the passage of drugs and alternating magnetic fields to increment BBB permeability by magnetic heating. In conclusion, we briefly cite the most notable biomedical applications of MNPs and some relevant remarks about their safety and potential toxicity

L-Carnitine Functionalization to Increase Skeletal Muscle Tropism of PLGA Nanoparticles

Muscular dystrophies are a group of rare genetic pathologies, encompassing a variety of clinical phenotypes and mechanisms of disease. Several compounds have been proposed to treat compromised muscles, but it is known that pharmacokinetics and pharmacodynamics problems could occur. To solve these issues, it has been suggested that nanocarriers could be used to allow controlled and targeted drug release. Therefore, the aim of this study was to prepare actively targeted poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) for the treatment of muscular pathologies. By taking advantage of the high affinity for carnitine of skeletal muscle cells due to the expression of Na+-coupled carnitine transporter (OCTN), NPs have been actively targeted via association to an amphiphilic derivative of L-carnitine. Furthermore, pentamidine, an old drug repurposed for its positive effects on myotonic dystrophy type I, was incorporated into NPs. We obtained monodispersed targeted NPs, with a mean diameter of about 100 nm and a negative zeta potential. To assess the targeting ability of the NPs, cell uptake studies were performed on C2C12 myoblasts and myotubes using confocal and transmission electron microscopy. The results showed an increased uptake of carnitine-functionalized NPs compared to nontargeted carriers in myotubes, which was probably due to the interaction with OCTN receptors occurring in large amounts in these differentiated muscle cells

Mitochondrial Features of Mouse Myoblasts Are Finely Tuned by Low Doses of Ozone: The Evidence In Vitro

The mild oxidative stress induced by low doses of gaseous ozone (O3) activates the antioxidant cell response through the nuclear factor erythroid 2-related factor 2 (Nrf2), thus inducing beneficial effects without cell damage. Mitochondria are sensitive to mild oxidative stress and represent a susceptible O3 target. In this in vitro study, we investigated the mitochondrial response to low O3 doses in the immortalized, non-tumoral muscle C2C12 cells; a multimodal approach including fluorescence microscopy, transmission electron microscopy and biochemistry was used. Results demonstrated that mitochondrial features are finely tuned by low O3 doses. The O3 concentration of 10 μg maintained normal levels of mitochondria-associated Nrf2, promoted the mitochondrial increase of size and cristae extension, reduced cellular reactive oxygen species (ROS) and prevented cell death. Conversely, in 20 μg O3-treated cells, where the association of Nrf2 with the mitochondria drastically dropped, mitochondria underwent more significant swelling, and ROS and cell death increased. This study, therefore, adds original evidence for the involvement of Nrf2 in the dose-dependent response to low O3 concentrations not only as an Antioxidant Response Elements (ARE) gene activator but also as a regulatory/protective factor of mitochondrial function

TINITALY/01: a new Triangular Irregular Network of Italy

A new Digital Elevation Model (DEM) of the natural landforms of Italy is presented. A methodology is discussed to build a DEM over wide areas where elevation data from non-homogeneous (in density and accuracy) input sources are available. The input elevation data include contour lines and spot heights derived from the Italian Regional topographic maps, satellite-based global positioning system points, ground based and radar altimetry data. Owing to the great heterogeneity of the input data density, the DEM format that better preserves the original accuracy is a Triangular Irregular Network (TIN). A Delaunay-based TIN structure is improved by using the DEST algorithm that enhances input data by evaluating inferred break-lines. Accordingly to this approach, biased distributions in slopes and elevations are absent. To prevent discontinuities at the boundary between regions characterized by data with different resolution a cubic Hermite blending weight S-shaped function is adopted. The TIN of Italy consists of 1.39×109 triangles. The average triangle area ranges from 12 to about 13000 m2 accordingly to different morphologies and different sources. About 50% of the model has a local average triangle area <500 m2. The vertical accuracy of the obtained DEM is evaluated by more than 200000 sparse control points. The overall Root Mean Square Error (RMSE) is less than 3.5 m. The obtained national-scale DEM constitutes an useful support to carry out accurate geomorphological and geological investigations over large areas. The problem of choosing the best step size in deriving a grid from a TIN is then discussed and a method to quantify the loss of vertical information is presented as a function of the grid step. Some examples of DEM application are outlined. Under request, an high resolution stereo image database of the whole Italian territory (derived from the presented DEM) is available to browse via internet

Pancreatic ductal adenocarcinoma cell lines display a plastic ability to bi‑directionally convert into cancer stem cells

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed when metastatic events have occurred. Cancer stem cells (CSCs) play an important role in tumor initiation, metastasis, chemoresistance and relapse. A growing number of studies have suggested that CSCs exist in a dynamic equilibrium with more differentiated cancer cells via a bi‑directional regeneration that is dependent on the environmental stimuli. In this investigation, we obtain, by using a selective medium, PDAC CSCs from five out of nine PDAC cell lines, endowed with different tumorsphere‑forming ability. PDAC CSCs were generally more resistant to the action of five anticancer drugs than parental cell lines and were characterized by an increased expression of EpCAM and CD44v6, typical stem cell surface markers, and a decreased expression of E‑cadherin, the main marker of the epithelial state. PDAC CSCs were able to re‑differentiate into parental cells once cultured in parental growth condition, as demonstrated by re‑acquisition of the epithelial morphology, the decreased expression levels of EpCAM and CD44v6 and the increased sensitivity to anticancer drugs. Finally, PDAC CSCs injected into nude mice developed a larger subcutaneous tumor mass and showed a higher metastatic activity compared to parental cells. The present study demonstrates the ability to obtain CSCs from several PDAC cell lines and that these cells are differentially resistant to various anticancer agents. This variability renders them a model of great importance to deeply understand pancreatic adenocarcinoma biology, to discover new biomarkers and to screen new therapeutic compounds

Theranostic Role of (32)P-ATP as Radiopharmaceutical for the Induction of Massive Cell Death within Avascular Tumor Core

Drug inaccessibility to vast areas of the tumor parenchyma is amongst the major hurdles for conventional therapies. Treatment efficacy rapidly decreases with distance from vessels and most of the tumor cells survive therapy. Also, between subsequent cycles of treatment, spared cancer cells replace those killed near the vessels, improving their access to nutrients, boosting their proliferation rate, and thus enabling tumor repopulation. Because of their property of "acting at a distance," radioisotopes are believed to overcome the physical barrier of vascular inaccessibility. Methods: A novel molecular imaging tool called Cerenkov Luminescence Imaging (CLI) was employed for the detection of Cerenkov radiation emitted by beta particles, allowing in vivo tracking of beta-emitters. More precisely we investigated using a xenograft model of colon carcinoma the potential use of 32P-ATP as a novel theranostic radiopharmaceutical for tracing tumor lesions while simultaneously hampering their growth. Results: Our analyses demonstrated that 32P-ATP injected into tumor-bearing mice reaches tumor lesions and persists for days and weeks within the tumor parenchyma. Also, the high-penetrating beta particles of 32P-ATP exert a "cross-fire" effect that induces massive cell death throughout the entire tumor parenchyma including core regions. Conclusion: Our findings suggest 32P-ATP treatment as a potential approach to complement conventional therapies that fail to reach the tumor core and to prevent tumor repopulation

Evidence for carbon cycling in a large freshwater lake in the Balkans over the last 0.5 million years using the isotopic composition of bulk organic matter

In the DEEP core from the Lake Ohrid ICDP drilling project, the carbon isotope composition of bulk organic matter (δ13CTOC) over the last 516 ka shows a negative correlation with total organic carbon (TOC) and total inorganic carbon (TIC). This relationship is marked by periods of lower δ13CTOC values corresponding to higher TIC and TOC. Along with TOC/TN, the correlation between δ13CTOC and δ13CTIC suggests that most of the organic matter in the core is from aquatic primary production within the lake. The combination of TOC, TIC, and δ13CTOC is able to disentangle long-term glacial/interglacial cycles and, to a lesser extent, millennial scale climate variability. Over the longer term, δ13CTOC shows modest variability, indicating that the δ13C of the dissolved inorganic carbon (DIC) pool is stabilised by the supply of karst spring water characterised by δ13CDIC influenced by the bedrock δ13C value, and the long residence time of the lake water and well mixed upper water column promoting equilibration with atmospheric CO2. However, comparison between arboreal pollen (AP%), TIC and TOC data indicates that the δ13CTOC signal is modulated by the leaching of soil CO2 through runoff and spring discharge, changes in primary productivity, and recycling of organic matter within the lake, all affecting δ13CDIC. Exceptionally low δ13CTOC during some interglacial periods (e.g. MIS7 and MIS9) possibly indicate rapid intensification of organic matter recycling and/or increasing stratification and enhanced methanogenesis, even if the latter process is not supported by the sedimentological data

The transcriptional profile of adipose-derived stromal cells (ASC) mirrors the whitening of adipose tissue with age

Multipotent stem cells persist within the stromal vascular fraction (SVF) of adipose tissue during adulthood. These cells, commonly referred to as adipose-derived stromal cells (ASC), have been extensively investigated over the past years as a promising therapeutic tool based on their regenerative and immunomodulatory properties. However, how ASC might mirror the age-related alteration of the fat they reside in remains unclear. Herein, we show that inguinal adipose tissue in mice turns from brown/beige- to white-like with age and resident ASC readily mirror these changes both at mRNA and microRNA transcriptional level. Mechanistically, our data suggest that these brown/age-related changes in ASC transcription rely on changes in the activity of E2F1 and NFkB transcription factors

Interrupting the nitrosative stress fuels tumor-specific cytotoxic T lymphocytes in pancreatic cancer

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors owing to its robust desmoplasia, low immunogenicity, and recruitment of cancer-conditioned, immunoregulatory myeloid cells. These features strongly limit the success of immunotherapy as a single agent, thereby suggesting the need for the development of a multitargeted approach. The goal is to foster T lymphocyte infiltration within the tumor landscape and neutralize cancer-triggered immune suppression, to enhance the therapeutic effectiveness of immune-based treatments, such as anticancer adoptive cell therapy (ACT). METHODS: We examined the contribution of immunosuppressive myeloid cells expressing arginase 1 and nitric oxide synthase 2 in building up a reactive nitrogen species (RNS)-dependent chemical barrier and shaping the PDAC immune landscape. We examined the impact of pharmacological RNS interference on overcoming the recruitment and immunosuppressive activity of tumor-expanded myeloid cells, which render pancreatic cancers resistant to immunotherapy. RESULTS: PDAC progression is marked by a stepwise infiltration of myeloid cells, which enforces a highly immunosuppressive microenvironment through the uncontrolled metabolism of L-arginine by arginase 1 and inducible nitric oxide synthase activity, resulting in the production of large amounts of reactive oxygen and nitrogen species. The extensive accumulation of myeloid suppressing cells and nitrated tyrosines (nitrotyrosine, N-Ty) establishes an RNS-dependent chemical barrier that impairs tumor infiltration by T lymphocytes and restricts the efficacy of adoptive immunotherapy. A pharmacological treatment with AT38 ([3-(aminocarbonyl)furoxan-4-yl]methyl salicylate) reprograms the tumor microenvironment from protumoral to antitumoral, which supports T lymphocyte entrance within the tumor core and aids the efficacy of ACT with telomerase-specific cytotoxic T lymphocytes. CONCLUSIONS: Tumor microenvironment reprogramming by ablating aberrant RNS production bypasses the current limits of immunotherapy in PDAC by overcoming immune resistance