bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sierra de Guadarrama (Madrid, Spain): bridging the gap between geology and architecture
Authors: García-Rodriguez Manuel , García-Rodriguez Miguel , Gomez-Heras Miguel 
Published: March 2015

Abstract
The knowledge that societies have of their geological environment and of the materials used in their heritage is of great importance for the sustainable use and conservation of traditional natural stone architecture. Similar weathering mechanisms occur in natural environments and the built environment and, in both cases, weathering may endanger both natural and built heritage. The Sierra de Guadarrama (Spanish Central System) is a privileged area in which natural and built heritage coexist. This paper describes an area of particular monumental and geological interest on the northern slopes of the Sierra de Guadarrama; its main aim is to propose an itinerary for members of the public, presented as a route through the area around Segovia, in which architecture/cultural heritage and an Earth sciences approach are brought together with an educational purpose. To this end, some connections are established between weathering forms in natural and built environments, as well as between the lithological characteristics of the rocks used in construction of ancient monuments in the area and the distribution of stresses and loads of walls.
Early Cretaceous Obernkirchen and Bentheim Sandstones from Germany used as dimension stone in the Netherlands: geology, physical properties, architectural use and comparative weathering
Authors: Dubelaar C. Wim , Nijland Timo G. 
Published: March 2015

Abstract
The Netherlands, with only scarce occurrences of outcropping or shallow buried natural stone, has over centuries imported huge quantities of Early Cretaceous Bentheim Sandstone and Obernkirchen Sandstone from Germany. The present paper provides an overview of their distribution and properties relevant to their use as building stone, and their mutual differences and comparative weathering. Evidence in Dutch architecture for the onset of quarrying of the Bentheim Sandstone is presented, and an overview is given of the use of Bentheim Sandstone and Obernkirchen Sandstone in the Netherlands and Belgium.
Characterization of particulate matter in attic and settled dusts collected from two buildings in Budapest, Hungary
Authors: Baricza Á. , Bajnóczi B. , Tóth M. , Káldos R. , Szabó Cs. 
Published: March 2015

Abstract
We have investigated two buildings covered with Zsolnay glazed architectural ceramics in Budapest (Hungary), one located in the densely built-up area of the city centre with a high traffic rate and one in a city quarter with moderate traffic and more open space. A black crust layer, containing a large amount of artificial particulate matter with different size and chemical composition, was observed on the ceramic material of both buildings, whereas weathered glaze was detected only on the ceramics of the building situated in the city centre. In this paper, our goal is to reveal the role of the particulate matter in the degradation of architectural ceramics. For this reason the attic dust and settled dust from the roofs of the studied buildings were collected. In the attic dust, besides the natural particles of geological origin, three types of artificial particles typically with spherical shape (spherules) were also distinguished: aluminosilicate (two subtypes), carbonaceous, and iron-rich fly-ash. The appearance of gypsum crystallites around the particulate matter in association with all spherule types suggests that the particulate matter greatly contributes to the degradation process.
Comparison between petrophysical properties, durability and use of two limestones of the Paris region
Authors: Vázquez Patricia , Menéndez Beatriz , Denecker Mélanie F. C. , Thomachot-Schneider Celine 
Published: March 2015

Abstract
Most buildings of architectural heritage in Paris and its surroundings are built with Lutetian limestone. Several historic buildings of the ‘Vexin Normand’ region show Lutetian limestone in the upper parts of their walls, while the lower parts are built with a chalk known as ‘Pierre de Vernon’. The ‘Pierre de Vernon’ appears up to the first metre, although in exceptional cases it can reach the middle height of a building. Commonly, chalks exhibit low durability due to their high porosity. However, ‘Pierre de Vernon’ is supposed to have greater durability than other chalks because of its historic use for basement construction.
The objective of this research was to understand the use of the ‘Pierre de Vernon’ in the lower part of the constructions. A petrophysical characterization of Vernon chalk and Lutetian limestone was carried out, focusing mainly on the differences in porosity and water uptake. Salt crystallization tests were done to contrast their response to decay. Colour and roughness measurements and scanning electron microscope observations were performed.
Results show that the different porous networks of these two limestones lead to a high contrast in their hydric properties and responses to decay, and the use of Vernon chalk in the lower sections of buildings has been found to be appropriate.
Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens
Authors: Karjalainen Katja , Jaalouk Diana E. , Bueso-Ramos Carlos , Bover Laura , Sun Yan , Kuniyasu Akihiko , Driessen Wouter H.P. , Cardó-Vila Marina , Rietz Cecilia , Zurita Amado J. , O'Brien Susan , Kantarjian Hagop M. , Cortes Jorge E. , Calin George A. , Koivunen Erkki , Arap Wadih , Pasqualini Renata 
Published: March 2015

Abstract
Purpose: The IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma.
Experimental Design and Results: First, we show that the IL11R protein is expressed in a variety of human leukemia– and lymphoma–derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand–receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile.
Conclusions: These results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases. Clin Cancer Res; 21(13); 3041–51. ©2015 AACR.
The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models
Authors: Schuller Alwin G. , Barry Evan R. , Jones Rhys D.O. , Henry Ryan E. , Frigault Melanie M. , Beran Garry , Linsenmayer David , Hattersley Maureen , Smith Aaron , Wilson Joanne , Cairo Stefano , Déas Olivier , Nicolle Delphine , Adam Ammar , Zinda Michael , Reimer Corinne , Fawell Stephen E. , Clark Edwin A. , D'Cruz Celina M. 
Published: March 2015

Abstract
Purpose: Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with nonlocalized disease. The HGF receptor MET plays a central role in PRCC and aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 occurring in the majority of cases. The development of effective therapies in PRCC has been hampered in part by a lack of available preclinical models. We determined the pharmacodynamic and antitumor response of the selective MET inhibitor AZD6094 in two PRCC patient-derived xenograft (PDX) models.
Experimental Design: Two PRCC PDX models were identified and MET mutation status and copy number determined. Pharmacodynamic and antitumor activity of AZD6094 was tested using a dose response up to 25 mg/kg daily, representing clinically achievable exposures, and compared with the activity of the RCC standard-of-care sunitinib (in RCC43b) or the multikinase inhibitor crizotinib (in RCC47).
Results: AZD6094 treatment resulted in tumor regressions, whereas sunitinib or crizotinib resulted in unsustained growth inhibition. Pharmacodynamic analysis of tumors revealed that AZD6094 could robustly suppress pMET and the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes, including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a dose- and time-dependent induction of cleaved PARP, a marker of cell death.
Conclusions: Data presented provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication. Clin Cancer Res; 21(12); 2811–9. ©2015 AACR.
Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing
Authors: Parry Marina , Rose-Zerilli Matthew J.J. , Ljungström Viktor , Gibson Jane , Wang Jun , Walewska Renata , Parker Helen , Parker Anton , Davis Zadie , Gardiner Anne , McIver-Brown Neil , Kalpadakis Christina , Xochelli Aliki , Anagnostopoulos Achilles , Fazi Claudia , Gonzalez de Castro David , Dearden Claire , Pratt Guy , Rosenquist Richard , Ashton-Key Margaret , Forconi Francesco , Collins Andrew , Ghia Paolo , Matutes Estella , Pangalis Gerassimos , Stamatopoulos Kostas , Oscier David , Strefford Jonathan C. 
Published: March 2015

Abstract
Purpose: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies.
Experimental Design: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL.
Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02–4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05–4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08–5.2; P = 0.03).
Conclusions: We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively. Clin Cancer Res; 21(18); 4174–83. ©2015 AACR.
Immune Recovery after Allogeneic Hematopoietic Stem Cell Transplantation Following Flu-TBI versus TLI-ATG Conditioning
Authors: Hannon Muriel , Beguin Yves , Ehx Grégory , Servais Sophie , Seidel Laurence , Graux Carlos , Maertens Johan , Kerre Tessa , Daulne Coline , de Bock Muriel , Fillet Marianne , Ory Aurélie , Willems Evelyne , Gothot André , Humblet-Baron Stéphanie , Baron Frédéric 
Published: March 2015

AbstractPurpose: A conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) combining total lymphoid irradiation (TLI) plus anti-thymocyte globulin (ATG) has been developed to induce graft-versus-tumor effects without graft-versus-host disease (GVHD).Experimental Design: We compared immune recovery in 53 patients included in a phase II randomized study comparing nonmyeloablative HCT following either fludarabine plus 2 Gy total body irradiation (TBI arm, n = 28) or 8 Gy TLI plus ATG (TLI arm, n = 25).Results: In comparison with TBI patients, TLI patients had a similarly low 6-month incidence of grade II-IV acute GVHD, a lower incidence of moderate/severe chronic GVHD (P = 0.02), a higher incidence of CMV reactivation (P &lt; 0.001), and a higher incidence of relapse (P = 0.01). While recovery of total CD8+ T cells was similar in the two groups, with median CD8+ T-cell counts reaching the normal values 40 to 60 days after allo-HCT, TLI patients had lower percentages of naïve CD8 T cells. Median CD4+ T-cell counts did not reach the lower limit of normal values the first year after allo-HCT in the two groups. Furthermore, CD4+ T-cell counts were significantly lower in TLI than in TBI patients the first 6 months after transplantation. Interestingly, while median absolute regulatory T-cell (Treg) counts were comparable in TBI and TLI patients, Treg/naïve CD4+ T-cell ratios were significantly higher in TLI than in TBI patients the 2 first years after transplantation.Conclusions: Immune recovery differs substantially between these two conditioning regimens, possibly explaining the different clinical outcomes observed (NCT00603954). Clin Cancer Res; 21(14); 3131–9. ©2015 AACR.
MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide
Authors: Erice Oihane , Smith Michael P. , White Rachel , Goicoechea Ibai , Barriuso Jorge , Jones Chris , Margison Geoffrey P. , Acosta Juan C. , Wellbrock Claudia , Arozarena Imanol 
Published: March 2015

Abstract
Melanoma and other solid cancers are frequently resistant to chemotherapies based on DNA alkylating agents such as dacarbazine and temozolomide. As a consequence, clinical responses are generally poor. Such resistance is partly due to the ability of cancer cells to use a variety of DNA repair enzymes to maintain cell viability. Particularly, the expression of MGMT has been linked to temozolomide resistance, but cotargeting MGMT has proven difficult due to dose-limiting toxicities. Here, we show that the MGMT-mediated resistance of cancer cells is profoundly dependent on the DNA repair enzyme PARP. Both in vitro and in vivo, we observe that MGMT-positive cancer cells strongly respond to the combination of temozolomide and PARP inhibitors (PARPi), whereas MGMT-deficient cells do not. In melanoma cells, temozolomide induced an antiproliferative senescent response, which was greatly enhanced by PARPi in MGMT-positive cells. In summary, we provide compelling evidence to suggest that the stratification of patients with cancer upon the MGMT status would enhance the success of combination treatments using temozolomide and PARPi. Mol Cancer Ther; 14(5); 1236–46. ©2015 AACR.
Synthetic Lethal Screens Identify Vulnerabilities in GPCR Signaling and Cytoskeletal Organization in E-Cadherin–Deficient Cells
Authors: Telford Bryony J. , Chen Augustine , Beetham Henry , Frick James , Brew Tom P. , Gould Cathryn M. , Single Andrew , Godwin Tanis , Simpson Kaylene J. , Guilford Parry 
Published: March 2015

Abstract
The CDH1 gene, which encodes the cell-to-cell adhesion protein E-cadherin, is frequently mutated in lobular breast cancer (LBC) and diffuse gastric cancer (DGC). However, because E-cadherin is a tumor suppressor protein and lost from the cancer cell, it is not a conventional drug target. To overcome this, we have taken a synthetic lethal approach to determine whether the loss of E-cadherin creates druggable vulnerabilities. We first conducted a genome-wide siRNA screen of isogenic MCF10A cells with and without CDH1 expression. Gene ontology analysis demonstrated that G-protein–coupled receptor (GPCR) signaling proteins were highly enriched among the synthetic lethal candidates. Diverse families of cytoskeletal proteins were also frequently represented. These broad classes of E-cadherin synthetic lethal hits were validated using both lentiviral-mediated shRNA knockdown and specific antagonists, including the JAK inhibitor LY2784544, Pertussis toxin, and the aurora kinase inhibitors alisertib and danusertib. Next, we conducted a 4,057 known drug screen and time course studies on the CDH1 isogenic MCF10A cell lines and identified additional drug classes with linkages to GPCR signaling and cytoskeletal function that showed evidence of E-cadherin synthetic lethality. These included multiple histone deacetylase inhibitors, including vorinostat and entinostat, PI3K inhibitors, and the tyrosine kinase inhibitors crizotinib and saracatinib. Together, these results demonstrate that E-cadherin loss creates druggable vulnerabilities that have the potential to improve the management of both sporadic and familial LBC and DGC. Mol Cancer Ther; 14(5); 1213–23. ©2015 AACR.
First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway
Authors: Hagel Margit , Miduturu Chandra , Sheets Michael , Rubin Nooreen , Weng Weifan , Stransky Nicolas , Bifulco Neil , Kim Joseph L. , Hodous Brian , Brooijmans Natasja , Shutes Adam , Winter Christopher , Lengauer Christoph , Kohl Nancy E. , Guzi Timothy 
Published: March 2015

Abstract
Aberrant signaling through the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR 4) signaling complex has been shown to cause hepatocellular carcinoma (HCC) in mice and has been implicated to play a similar role in humans. We have developed BLU9931, a potent and irreversible small-molecule inhibitor of FGFR4, as a targeted therapy to treat patients with HCC whose tumors have an activated FGFR4 signaling pathway. BLU9931 is exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19 due to amplification as well as a liver tumor xenograft that overexpresses FGF19 mRNA but lacks FGF19 amplification. Approximately one third of patients with HCC whose tumors express FGF19 together with FGFR4 and its coreceptor klotho β (KLB) could potentially respond to treatment with an FGFR4 inhibitor. These findings are the first demonstration of a therapeutic strategy that targets a subset of patients with HCC.
Significance: This article documents the discovery of BLU9931, a novel irreversible kinase inhibitor that specifically targets FGFR4 while sparing all other FGFR paralogs and demonstrates exquisite kinome selectivity. BLU9931 is efficacious in tumors with an intact FGFR4 signaling pathway that includes FGF19, FGFR4, and KLB. BLU9931 is the first FGFR4-selective molecule for the treatment of patients with HCC with aberrant FGFR4 signaling. Cancer Discov; 5(4); 424–37. ©2015 AACR.
See related commentary by Packer and Pollock, p. 355
This article is highlighted in the In This Issue feature, p. 333
The Impact of Grid and Spectral Nudging on the Variance of the Near-Surface Wind Speed
Authors: Vincent Claire Louise , Hahmann Andrea N. 
Published: March 2015

AbstractGrid and spectral nudging are effective ways of preventing drift from large-scale weather patterns in regional climate models. However, the effect of nudging on the wind speed variance is unclear. In this study, the impact of grid and spectral nudging on near-surface and upper boundary layer wind variance in the Weather Research and Forecasting Model is analyzed. Simulations are run on nested domains with horizontal grid spacing of 15 and 5 km over the Baltic Sea region. For the 15-km domain, 36-h simulations initialized each day are compared with 11-day simulations with either grid or spectral nudging at and above 1150 m above ground level (AGL). Nested 5-km simulations are not nudged directly but inherit boundary conditions from the 15-km experiments. Spatial and temporal spectra show that grid nudging causes smoothing of the wind in the 15-km domain at all wavenumbers, both at 1150 m AGL and near the surface where nudging is not applied directly, while spectral nudging mainly affects longer wavenumbers. Maps of mesoscale variance show spatial smoothing for both grid and spectral nudging, although the effect is less pronounced for spectral nudging. On the inner, 5-km domain, an indirect smoothing impact of nudging is seen up to 200 km inward from the dominant inflow boundary at 1150 m AGL, but there is minimal smoothing from the nudging near the surface, indicating that nudging an outer domain is an appropriate configuration for wind-resource modeling.
An Assessment of Direct Radiative Forcing, Radiative Adjustments, and Radiative Feedbacks in Coupled Ocean–Atmosphere Models
Authors: Chung Eui-Seok , Soden Brian J. 
Published: March 2015

AbstractIn this study, radiative kernels are used to separate direct radiative forcing from radiative adjustments to that forcing to quantify the magnitude and intermodel spread of tropospheric and stratospheric adjustments in coupled ocean–atmosphere climate models. Radiative feedbacks are also quantified and separated from radiative forcing by assuming that feedbacks are a linear response to changes in global-mean surface temperature. The direct radiative forcing due to a quadrupling of CO2 is found to have an intermodel spread of ~3 W m−2. In contrast to previous studies, relatively small estimates of cloud adjustments are obtained, which are both positive and negative. This discrepancy is at least partially attributable to small, but nonnegligible, global-mean surface warming in fixed sea surface temperature experiments, which aliases a surface-driven feedback response into estimates of the adjustments. This study suggests that correcting for the bias induced from this global-mean surface warming offers a more accurate estimate of tropospheric adjustments. It is shown that the regional patterns in the tropospheric adjustments tend to oppose the radiative feedback. This compensation is closely tied to spatial inhomogeneities in the initial rate of surface warming, suggesting that a substantial part of the spatial variation in the estimated tropospheric adjustment is an artifact of the linear regression methodology. Even when assuming that the global-mean estimates of the tropospheric adjustments are valid, neglecting them introduces little uncertainty in estimates of the total forcing, feedback, or effective climate sensitivity relative to the intermodel spread in these values.