Fluid pressure drops during stimulation of segmented faults in deep geothermal reservoirs

Acknowledgements The Institut Cartogràfic i Geològic de Catalunya is acknowledged for their support in our investigation of Geothermal resources. G. Piris was supported by an AGAUR grant of the Industrial Doctorate programme 2016-DI-031. EGR acknowledges the support of the Beatriu de Pinós programme of the Government of Catalonia’s Secretariat for Universities and Research of the Department of Economy and Knowledge (2016 BP 00208). The authors would like to thank three anonymous reviewers and the editors Dr. Carola Meller and Prof. Olaf Kolditz for their helpful comments that improved this manuscript.Peer reviewedPublisher PD

3DHIP-calculator-A new tool to stochastically assess deep geothermal potential using the heat-in-place method from voxel-based 3D geological models

The assessment of the deep geothermal potential is an essential task during the early phases of any geothermal project. The well-known "Heat-In-Place" volumetric method is the most widely used technique to estimate the available stored heat and the recoverable heat fraction of deep geothermal reservoirs at the regional scale. Different commercial and open-source software packages have been used to date to estimate these parameters. However, these tools are either not freely available, can only consider the entire reservoir volume or a specific part as a single-voxel model, or are restricted to certain geographical areas. The 3DHIP-Calculator tool presented in this contribution is an open-source software designed for the assessment of the deep geothermal potential at the regional scale using the volumetric method based on a stochastic approach. The tool estimates the Heat-In-Place and recoverable thermal energy using 3D geological and 3D thermal voxel models as input data. The 3DHIP-Calculator includes an easy-to-use graphical user interface (GUI) for visualizing and exporting the results to files for further postprocessing, including GIS-based map generation. The use and functionalities of the 3DHIP-Calculator are demonstrated through a case study of the Reus-Valls sedimentary basin (NE, Spain)

Outcompeting p53-Mutant Cells in the Normal Esophagus by Redox Manipulation.

As humans age, normal tissues, such as the esophageal epithelium, become a patchwork of mutant clones. Some mutations are under positive selection, conferring a competitive advantage over wild-type cells. We speculated that altering the selective pressure on mutant cell populations may cause them to expand or contract. We tested this hypothesis by examining the effect of oxidative stress from low-dose ionizing radiation (LDIR) on wild-type and p53 mutant cells in the transgenic mouse esophagus. We found that LDIR drives wild-type cells to stop proliferating and differentiate. p53 mutant cells are insensitive to LDIR and outcompete wild-type cells following exposure. Remarkably, combining antioxidant treatment and LDIR reverses this effect, promoting wild-type cell proliferation and p53 mutant differentiation, reducing the p53 mutant population. Thus, p53-mutant cells can be depleted from the normal esophagus by redox manipulation, showing that external interventions may be used to alter the mutational landscape of an aging tissue

Contribution of isotopic research techniques to characterize highmountain-Mediterranean karst aquifers: The Port del Comte (Eastern Pyrenees) aquifer.

Water resources in high mountain karst aquifers are usually characterized by high rainfall, recharge and discharge that leads to the sustainability of the downstream ecosystems. Nevertheless, these hydrological systems are vulnerable to the global change impact. The mean transit time (MTT) is a key parameter to describe the behavior of these hydrologic systems and also to assess their vulnerability. This work is focused on estimating MTT by using water stable isotopes in the framework of high-mountain karst systems with a very thick unsaturated zone (USZ). To this end, it is adapted to alpine zones an existing methodology that combines in a row a semi-distributed rainfall-runoff model used to estimate recharge time series, and a lumped-parameter model to obtain through a convolution integral. The methodology has been applied to the Port del Comte Massif (PCM) hydrological system (Southeastern Pyrenees, NE Spain), a karst aquifer system with an overlying1000 m thick USZ. Six catchment areas corresponding to most important springs of the system are considered. The obtained results show that hydrologically the behavior of the system can be described by an exponential flow model (EM), with MTT ranging between 1.9 and 2.9 years. These values are shorter than those obtained by considering a constant recharge rate along time, which is the easiest and most applied aquifer recharge hypothesis when estimating through lumped-parameter models. This methodology can be useful to improve the characterization and understanding of other high mountain karst aquifers with an overlying thick USZ that are common in many alpine zones elsewhere the globe

Identification of Natural and Anthropogenic Geochemical Processes Determining the Groundwater Quality in Port del Comte High Mountain Karst Aquifer (SE, Pyrenees)

The Port del Comte Massif (SE, Pyrenees) contains one of the most important vulnerable and strategic karst aquifers for supplying freshwater to the city of Barcelona (Spain). It is a fragile system, whose possible environmental impact is highly conditioned by land use. To improve the hydrogeological knowledge of the system, between September 2013 and October 2015, a detailed fieldwork was carried out for the revision of the geological model, the inventory of water points, and the in situ physico-chemical characterization on major elements and isotopes of up to a total of 43 springs, as well as precipitation water. This paper focuses on the characterization of the geochemical processes that allow explanation of the observed chemical variability of groundwater drained by the pristine aquifer system to determine the origin of salinity. The results show that the main process is the dissolution of calcite and dolomite, followed by gypsum and halite, and a minor cation exchange-like process. Sulfur and oxygen isotopes from dissolved sulfate in the studied springs point out a geogenic origin related to the dissolution of gypsum from Triassic and Tertiary materials, and that the contribution from anthropogenic sources, like fertilizers, is lower. Nitrate in groundwater is not an important issue, with a few localized cases related with agricultural activities. The multidisciplinary approach has allowed the development of a consistent hydrogeological conceptual model of the functioning of the aquifer system, which can be replicated in other places to understand the geogenic character of the hydrogeochemistry

Prediction of TERTp-mutation status in IDH-wildtype high-grade gliomas using pre-treatment dynamic 18FFET PET radiomics

PURPOSE To evaluate radiomic features extracted from standard static images (20-40~min p.i.), early summation images (5-15~min p.i.), and dynamic 18FFET PET images for the prediction of TERTp-mutation status in patients with IDH-wildtype high-grade glioma. METHODS A total of 159 patients (median age 60.2~years, range 19-82~years) with newly diagnosed IDH-wildtype diffuse astrocytic glioma (WHO grade III or IV) and dynamic 18FFET PET prior to surgical intervention were enrolled and divided into a training (n = 112) and a testing cohort (n = 47) randomly. First-order, shape, and texture radiomic features were extracted from standard static (20-40~min summation images; TBR20-40), early static (5-15~min summation images; TBR5-15), and dynamic (time-to-peak; TTP) images, respectively. Recursive feature elimination was used for feature selection by 10-fold cross-validation in the training cohort after normalization, and logistic regression models were generated using the radiomic features extracted from each image to differentiate TERTp-mutation status. The areas under the ROC curve (AUC), accuracy, sensitivity, specificity, and positive and negative predictive value were calculated to illustrate diagnostic power in both the training and testing cohort. RESULTS The TTP model comprised nine selected features and achieved highest predictability of TERTp-mutation with an AUC of 0.82 (95{\%} confidence interval 0.71-0.92) and sensitivity of 92.1{\%} in the independent testing cohort. Weak predictive capability was obtained in the TBR5-15 model, with an AUC of 0.61 (95{\%} CI 0.42-0.80) in the testing cohort, while no predictive power was observed in the TBR20-40 model. CONCLUSIONS Radiomics based on TTP images extracted from dynamic 18FFET PET can predict the TERTp-mutation status of IDH-wildtype diffuse astrocytic high-grade gliomas with high accuracy preoperatively

L-type amino acid transporter (LAT) 1 expression in 18F-FET-negative gliomas

BACKGROUND O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) is a highly sensitive PET tracer for glioma imaging, and its uptake is suggested to be driven by an overexpression of the L-type amino-acid transporter 1 (LAT1). However, 30{\%} of low- and 5{\%} of high-grade gliomas do not present enhanced 18F-FET uptake at primary diagnosis ({\textquotedbl}18F-FET-negative gliomas{\textquotedbl}) and the pathophysiologic basis for this phenomenon remains unclear. The aim of this study was to determine the expression of LAT1 in a homogeneous group of newly diagnosed 18F-FET-negative gliomas and to compare them to a matched group of 18F-FET-positive gliomas. Forty newly diagnosed IDH-mutant astrocytomas without 1p/19q codeletion were evaluated (n = 20 18F-FET-negative (tumour-to-background ratio (TBR) 1.6)). LAT1 immunohistochemistry (IHC) was performed using SLC7A5/LAT1 antibody. The percentage of LAT1-positive tumour cells ({\%}) and the staining intensity (range 0-2) were multiplied to an overall score (H-score; range 0-200) and correlated to PET findings as well as progression-free survival (PFS). RESULTS IHC staining of LAT1 expression was positive in both, 18F-FET-positive as well as 18F-FET-negative gliomas. No differences were found between the 18F-FET-negative and 18F-FET-positive group with regard to percentage of LAT1-positive tumour cells, staining intensity or H-score. Interestingly, the LAT1 expression showed a significant negative correlation with the PFS (p = 0.031), whereas no significant correlation was found for TBRmax, neither in the overall group nor in the 18F-FET-positive group only (p = 0.651 and p = 0.140). CONCLUSION Although LAT1 is reported to mediate the uptake of 18F-FET into tumour cells, the levels of LAT1 expression do not correlate with the levels of 18F-FET uptake in IDH-mutant astrocytomas. In particular, the lack of tracer uptake in 18F-FET-negative gliomas cannot be explained by a reduced LAT1 expression. A higher LAT1 expression in IDH-mutant astrocytomas seems to be associated with a short PFS. Further studies regarding mechanisms influencing the uptake of 18F-FET are necessary

PSMA Expression in Glioblastoma as a Basis for Theranostic Approaches: A Retrospective, Correlational Panel Study Including Immunohistochemistry, Clinical Parameters and PET Imaging

Aim: The aim of the current study was to enlighten the evolution of prostate-specific membrane antigen (PSMA) expression in glioblastoma between initial diagnosis and recurrence in order to provide preliminary insight for further clinical investigations into innovative PSMA-directed treatment concepts in neuro-oncology. Methods: Patients who underwent resection for de-novo glioblastoma (GBM) and had a re-resection in case of a recurrent tumor following radiochemotherapy and subsequent chemotherapy were included (n = 16). Histological and immunohistochemical stainings were performed at initial diagnosis and at recurrence (n = 96 tissue specimens). Levels of PSMA expression both in endothelial and non-endothelial cells as well as vascular density (CD34) were quantified via immunohistochemistry and changes between initial diagnosis and recurrence were determined. Immunohistochemical findings were correlated with survival and established clinical parameters. Results: PSMA expression was found to be present in all GBM tissue samples at initial diagnosis as well as in all but one case of recurrent tumor samples. The level of PSMA expression in glioblastoma varied inter-individually both in endothelial and non-endothelial cells. Likewise, the temporal evolution of PSMA expression highly varied in between patients. The level of vascular PSMA expression at recurrence and its change between initial diagnosis and recurrence was associated with post recurrence survival time: Patients with high vascular PSMA expression at recurrence as well as patients with increasing PSMA expression throughout the disease course survived shorter than patients with low vascular PSMA expression or decreasing vascular PSMA expression. There was no significant correlation of PSMA expression with MGMT promoter methylation status or Ki-67 labelling index. Conclusion: PSMA is expressed in glioblastoma both at initial diagnosis and at recurrence. High vascular PSMA expression at recurrence seems to be a negative prognostic marker. Thus, PSMA expression in GBM might present a promising target for theranostic approaches in recurrent glioblastoma. Especially PSMA PET imaging and PSMA-directed radioligand therapy warrant further studies in brain tumor patients

Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer

A single-progenitor model as the unifying paradigm of epidermal and esophageal epithelial maintenance in mice

Abstract: In adult skin epidermis and the epithelium lining the esophagus cells are constantly shed from the tissue surface and replaced by cell division. Tracking genetically labelled cells in transgenic mice has given insight into cell behavior, but conflicting models appear consistent with the results. Here, we use an additional transgenic assay to follow cell division in mouse esophagus and the epidermis at multiple body sites. We find that proliferating cells divide at a similar rate, and place bounds on the distribution cell cycle times. By including these results in a common analytic approach, we show that data from eight lineage tracing experiments is consistent with tissue maintenance by a single population of proliferating cells. The outcome of a given cell division is unpredictable but, on average, the likelihood of producing proliferating and differentiating cells is equal, ensuring cellular homeostasis. These findings are key to understanding squamous epithelial homeostasis and carcinogenesis