Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism

Gemcitabine (GEM, 2′,2′-difluorodeoxycytidine) is currently used in advanced pancreatic adenocarcinoma, with a response rate of < 20%. The purpose of our work was to improve GEM activity by addition of cannabinoids. Here, we show that GEM induces both cannabinoid receptor-1 (CB1) and cannabinoid receptor-2 (CB2) receptors by an NF-κB-dependent mechanism and that its association with cannabinoids synergistically inhibits pancreatic adenocarcinoma cell growth and increases reactive oxygen species (ROS) induced by single treatments. The antiproliferative synergism is prevented by the radical scavenger N-acetyl--cysteine and by the specific NF-κB inhibitor BAY 11-7085, demonstrating that the induction of ROS by GEM/cannabinoids and of NF-κB by GEM is required for this effect. In addition, we report that neither apoptotic nor cytostatic mechanisms are responsible for the synergistic cell growth inhibition, which is strictly associated with the enhancement of endoplasmic reticulum stress and autophagic cell death. Noteworthy, the antiproliferative synergism is stronger in GEM-resistant pancreatic cancer cell lines compared with GEM-sensitive pancreatic cancer cell lines. The combined treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects. These findings support a key role of the ROS-dependent activation of an autophagic program in the synergistic growth inhibition induced by GEM/cannabinoid combination in human pancreatic cancer cells

Evaluating susceptibility of karst dolines (sinkholes) for collapse in Sango, Tennessee, USA

Dolines or sinkholes are earth depressions that develop in soluble rocks complexes such as limestone, dolomite, gypsum, anhydrite, and halite; dolines appear in a variety of shapes from nearly circular to complex structures with highly curved perimeters. The occurrence of dolines in the studied karst area is not random; they are the results of geomorphic, hydrologic and chemical processes that have caused partial subsidence, even total collapse of the land surface, when voids and caves are present in the bedrock and the regolith arch overbridging these voids is unstable. In the study area, the majority of collapses occur in the regolith (bedrock cover) that bridges voids in the bedrock. Because these collapsing dolines can damage property and cause even the loss of lives, there is a need to develop methods for evaluating karst hazards; such methods can be used by planners and practitioners for urban and economic development, especially in regions with a growing population. The purpose of this project is threefold: 1) to develop a karst feature database, 2) to investigate critical indicators associated with doline collapse, and 3) to design a doline susceptibility model for potential doline collapse based on external morphometric data. The study revealed the presence of short range spatial dependence in the distribution of the dolines’ morphometric parameters such as circularity, geographic orientation of the main doline axes and the length-to-width doline ratios; therefore, geostatistics can be used to spatially evaluate the susceptibility of the karst area for doline collapse using the probability of occurrence of these critical parameters. The partial susceptibility estimates were combined into final spatial probabilities enabling the identification of areas where undetected dolines may cause significant hazards

Interplay between n-3 and n-6 long-chain polyunsaturated fatty acids and the endocannabinoid system in brain protection and repair.

The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFA) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA) have shown beneficial effects on learning and memory, neuroinflammatory processes and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-archidonoylglycerol (2-AG) are the most widely studied endocannabinoids, and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair

DInSAR measurements of ground deformation by sinkholes, mining subsidence, and landslides, Ebro River, Spain

Differential Interferometric Synthetic Aperture Radar (DInSAR) has been applied to detect and measure ground deformation in a stretch of the Ebro River valley (Spain) excavated in salt-bearing evaporites. The capability of the Small Baseline Subset (SBAS) DInSAR technique to detect ground displacement is analyzed comparing the DInSAR results with the available geomorphological information. The deformation map derived from 27 European Remote Sensing (ERS) satellite images covering more than five years provides sub-centimeter displacement measurements in zones coinciding with known active sinkholes and landslides. Moreover the map provides the first account of mining subsidence in the area. The measured deformation rates reach 1.68 cm/y for the sinkholes, 0.80 cm/y for the landslides and 1.45 cm/y for the area affected by mining subsidence. The SBAS DInSAR technique provided deformation measurements in a small proportion (5-10%) of the known active sinkholes and landslides. This limitation is mainly due to the lack of coherence in agricultural areas, the spatial resolution of the deformation map (pixel size of 90 m), and the parallelism between the ERS satellite line of sight and the linear escarpment on which most of the landslides occur. Despite this, the interferometric technique provides valuable data that complement traditional geomorphological studies including the quantification of the deformation phenomena, the identification of mining subsidence otherwise only recognizable by geodetic methods, and the detection of creep deformation which might correspond to premonitory indicators of catastrophic sinkholes and landslides capable of causing the loss of lives. Detailed DInSAR studies combined with field data would be required to improve the analysis of each deformation area. Copyright (C) 2009 John Wiley & Sons, Ltd. RI Castaneda, Carmen/E-7588-201

The Outstanding Terraced Landscape of the Cinque Terre Coastal Slopes (Eastern Liguria)

Due to a century-old agricultural practice, the coastal landscape of Cinque Terre (eastern Liguria, north-western Italy) has been almost completely modified by slope terracing via reworking of millions of cubic metres of debris cover and the construction of thousands of kilometres of dry stone walls. Given their geomorphological-environmental value, as well as scenic and historical significance, the Cinque Terre represent one of the most outstanding examples of human integration with the natural landscape within the Mediterranean region, and have been recognised since 1997 as a World Heritage Site by UNESCO and included since 1999 within a National Park. Following the abandonment of farming over the last half a century, the terraced slopes have been progressively affected by crumbling of the dry stone walls and mass movements. As dramatically evidenced by the effects of the major rainstorm of October 2011, the Cinque Terre are currently at very high geomorphological risk and thus mitigation measures and conservation policies are urgently needed