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Surya P Lamichhane,1 Neha Arya,1,2 Nirdesh Ojha,3 Esther Kohler,1 V Prasad Shastri1,2,41Institute for Macromolecular Chemistry, University of Freiburg, Freiburg, 2Helmholtz Virtual Institute on “Multifunctional Biomaterials for Medicine”, 3Laboratory for Process Technology, Department of Microsystems Engineering, University of Freiburg, Freiburg, 4Centre for Biological Signaling Studies (BIOSS), University of Freiburg, Freiburg, GermanyAbstract: The efficient delivery of chemotherapeutics to the tumor via nanoparticle (NP)-based delivery systems remains a significant challenge. This is compounded by the fact that the tumor is highly dynamic and complex environment composed of a plurality of cell types and extracellular matrix. Since glycosaminoglycan (GAG) production is altered in many diseases (or pathologies), NPs bearing GAG moieties on the surface may confer some unique advantages in interrogating the tumor microenvironment. In order to explore this premise, in the study reported here poly-lactide-co-glycolide (PLGA) NPs in the range of 100–150 nm bearing various proteoglycans were synthesized by a single-step nanoprecipitation and characterized. The surface functionalization of the NPs with GAG moieties was verified using zeta potential measurements and X-ray photoelectron spectroscopy. To establish these GAG-bearing NPs as carriers of therapeutics, cellular toxicity assays were undertaken in lung epithelial adenocarcinoma (A549) cells, human pulmonary microvascular endothelial cells (HPMEC), and renal proximal tubular epithelial cells. In general NPs were well tolerated over a wide concentration range (100–600 µg/mL) by all cell types and were taken up to appreciable extents without any adverse cell response in A549 cells and HPMEC. Further, GAG-functionalized PLGA NPs were taken up to different extents in A459 cells and HPMEC. In both cell systems, the uptake of heparin-modified NPs was diminished by 50%–65% in comparison to that of unmodified PLGA. Interestingly, the uptake of chondroitin sulfate NPs was the highest in both cell systems with 40%–60% higher uptake when compared with that of PLGA, and this represented an almost twofold difference over heparin-modified NPs. These findings suggest that GAG modification can be explored as means of changing the uptake behavior of PLGA NPs and these NP systems have potential in cancer therapy.Keywords: tumor microenvironment, nanocarriers, proteoglycans, polysaccharides, passive targeting

The Lower Cretaceous Upper Mannville Formation in West- Central Alberta has been intensively penetrated by wells targeting deeper reservoirs during the last decades. Production and well log data in this area suggest that significant volumes of gas are still present in both conventional and tight reservoirs of this formation. The Upper Mannville reservoirs in West-Central Alberta consist of fluvial sandstones filling incised valleys. The valley infills are made up of arkosic sandstones with a complex mineralogy. The matrix of these sandstones is made up of various amounts of quartz, feldspars, clay minerals and rock fragments. They were subjected to a complex diagenetic history and the resulting paragenesis influenced the present reservoir properties. Consequently, heterogeneities in the petrophysical properties result in significant exploration risks and production issues. We present in this paper results of a diagenetic study, performed within a well constrained stratigraphic framework, that aims at understanding the impact of mineralogy and diagenesis on reservoir quality evolution. Seventy one core samples from eight wells were collected to perform a petrographic analysis, and to propose a paragenetic sequence. Four main diagenetic events were identified that occurred during burial: – clay coating around the grains; – compaction/dissolution of matrix grains; – quartz and feldspars dissolution that initiated smectite-illite transformation and kaolinisation; – carbonate cementation in the remaining pore space. Clay minerals content and carbonate cementation are the main factors that altered the reservoir quality of these sandstones. The Smectite-Illite transformation was initiated after potassium was released in the formation fluids due to K-feldspars dissolution. This transformation proportionally increased with temperature during burial. Carbonate cementation occured during the uplift phase of the basin, intensively plugging the pore space where the clay content is reduced. Additional SEM and XRD analyses allowed characterizing and quantifying more accurately the different mineralogical phases occluding the porous network. The characterization of both mineralogy and petrophysical properties gives useful keys to locate the diagenetic phases laterally and vertically, and to predict the petrophysical properties distribution. La Formation Mannville Supérieur du Crétacé Inférieur d’Ouest-Central Alberta a été intensivement forée les précédentes décennies par des puits visant des réservoirs plus profonds. Cependant, les données de production dans ce secteur suggèrent que des volumes significatifs de gaz soient présents dans les réservoirs tant conventionnels que non conventionnels (“tight reservoirs”) de cette formation. Les réservoirs de la Formation Mannville Supérieur d’Ouest-Central Alberta sont constitués de grès fluviatiles remplissant des vallées incisées. Ces grès présentent une minéralogie complexe, avec des quantités variables de quartz, de feldspaths, de minéraux argileux et des fragments de roche. Ils ont été soumis à une histoire diagénétique complexe et la paragenèse qui en résulte a eu un impact sur leurs propriétés réservoirs. Par conséquent, les hétérogénéités dans les propriétés réservoirs induisent des risques significatifs en termes d’exploration et de production de ces réservoirs. Nous présentons dans cet article les résultats de l’étude diagénétique, effectuée dans un cadre stratigraphique bien contraint, visant à comprendre l’impact de la minéralogie et de la diagenèse sur l’évolution de la qualité des réservoirs. Soixante et onze échantillons prélevés sur huit puits ont permis de réaliser une analyse pétrographique et proposer une séquence paragénétique. Quatre événements diagénétiques principaux ont été identifiés et sont liés à l’enfouissement du bassin : – coating d’argile autour des grains; – compaction/dissolution de grains matriciels; – dissolution partielle des grains de quartz et de feldspaths, qui ont initiés la transformation smectite-illite et kaolinisation; – cimentation carbonatée dans l’espace poreux restant. Les transformations de minéraux argileux et la cimentation carbonatée sont les facteurs principaux qui ont affecté la porosité et la perméabilité de ces grès. La transformation Smectite-Illite a été amorcée après que le potassium issu de la dissolution des feldspaths ait été libéré dans le fluide de formation. Cette transformation augmente proportionnellement avec l’enfouissement et la température. Une intense cimentation carbonatée est survenue pendant la phase de soulèvement du bassin, colmatant de façon très significative l’espace poreux là où la teneur en argile était réduite. Des analyses au Microscope Électronique à Balayage et des analyses de DRX ont permis de caractériser et d’évaluer quantitativement les différentes phases diagénétiques responsables de l’évolution de l’espace poreux. La caractérisation de la minéralogie et de l’évolution des propriétés pétrophysiques des réservoirs apportent des clés utiles pour localiser les différentes phases diagénétiques temporellement et spatialement, afin de prédire la distribution de propriétés pétrophysiques.

This study concerns an approach for dolomite quantification and stoichiometry calculation by using X-ray diffractometry coupled with cell and Rietveld refinements and equipped with a newly substantial database of dolomite composition. A greater accuracy and precision are obtained for quantifying dolomite as well as other mineral phases and calculating dolomite stoichiometry compared to the classical “Lumsden line” and previous methods. The applicability of this approach is verified on dolomite reference material (Eugui) and on Triassic (Upper Muschelkalk-Lettenkohle) carbonates from the French Jura. The approach shown here is applicable to bulk dolostones as well as to specific dolomite cements and was combined with petrographical and isotopic analyses. Upper Muschelkalk dolomites were formed during burial dolomitization under fluids characterized by increased temperature and variable isotopic composition through burial. This is clear from their Ca content in dolomites which gradually approaches an ideal stoichiometry (from 53.16% to 51.19%) through increasing dolomitization. Lettenkohle dolostones consist of near-ideal stoichiometric (51.06%Ca) and well-ordered dolomites associated with anhydrite relicts. They originated through both sabkha and burial dolomitization. This contribution gives an improved method for the characterization of different dolomite types and their distinct traits in sedimentary rocks, which allows a better evaluation of their reservoir potential. Cette étude propose une approche pour la quantification de la dolomite et le calcul de sa stoechiométrie grâce à l’utilisation de la diffraction des rayons X couplée aux affinements de maille et de Rietveld et complétée par de nombreuses données issues de la littérature. Elle permet d’obtenir une meilleure justesse et précision pour la quantification de la dolomite (et des autres phases minérales) ainsi que pour le calcul de sa stoechiométrie par rapport à l’équation de Lumsden et de méthodes antérieures. L’approche proposée est vérifiée grâce à l’analyse d’un échantillon référence de dolomite (Eugui) et appliquée à des roches carbonatées du Trias (Muschelkalk supérieur-Lettenkohle) du Jura français. Elle est combinée à une étude pétrographique et isotopique et peut être appliquée tant aux roches qu’aux ciments dolomitiques. Les dolomies du Muschelkalk supérieur se sont formées au cours d’une dolomitisation d’enfouissement associée à des fluides dont la température augmente et ayant une composition isotopique variable au cours de l’enfouissement. Outre la pétrographie, ceci est également mis en évidence par le pourcentage de Ca calculé dans les dolomites, qui atteint progressivement une stoechiométrie idéale (de 53,16 % à 51,19 %) parallèlement au développement de la dolomitisation. Les dolomites du Lettenkohle montrent une stoechiométrie proche d’une stoechiométrie idéale (51,06 % Ca), sont ordonnées et associées à de l’anhydrite. Leur formation est liée à deux étapes de dolomitisation : de type sabkha et d’enfouissement. Cette étude permet ainsi une meilleure caractérisation des différents types de dolomites dans les roches sédimentaires et par conséquent une meilleure détermination de leur potentiel en tant que réservoir.

Serpentinite-hosting mud volcanoes, located in the Marianna forearc subduction zone, were drilled during IODP Expedition 366. Recovered samples from Asùt Tesoru seamount provide new insights on the generation of organic matter in deep environments. Short-chain alcohols, volatile fatty acids and light hydrocarbons are produced within hyperalkaline pore fluids (pH 12.5) rich in H2. The stable isotope values of those species show heavy δ13C values, suggesting a formation process through Fischer-Tropsch-Type reactions. This close isotopic study brings new constraints on the reaction pathways leading to the formation of not only light hydrocarbons, but also of short-chain organic molecules. These compounds may serve as precursors of building blocks essential to life in deep oceanic settings.

Abstract Background The acquisition of proliferative and invasive phenotypes is considered a hallmark of neoplastic transformation; however, the underlying mechanisms are less well known. Lipid phosphate phosphatase-3 (LPP3) not only catalyzes the dephosphorylation of the bioactive lipid sphingosine-1-phosphate (S1P) to generate sphingosine but also may regulate embryonic development and angiogenesis via the Wnt pathway. The goal of this study was to determine the role of LPP3 in tumor cells. Results We observed increased expression of LPP3 in glioblastoma primary tumors and in U87 and U118 glioblastoma cell lines. We demonstrate that LPP3-knockdown inhibited both U87 and U118 glioblastoma cell proliferation in culture and tumor growth in xenograft assays. Biochemical experiments provided evidence that LPP3-knockdown reduced β-catenin, CYCLIN-D1, and CD133 expression, with a concomitant increase in phosphorylated β-catenin. In a converse experiment, the forced expression of LPP3 in human colon tumor (SW480) cells potentiated tumor growth via increased β-catenin stability and CYCLIN-D1 synthesis. In contrast, elevated expression of LPP3 had no tumorigenic effects on primary cells. Conclusions These results demonstrate for the first time an unexpected role of LPP3 in regulating glioblastoma progression by amplifying β-catenin and CYCLIN-D1 activities.