bluuebunny/crossref_metadata_2025_split huggingface dataset:
CT perfusion and angiographic assessment of pial collateral reperfusion in acute ischemic stroke: the CAPRI study
Authors: Consoli Arturo , Andersson Tommy , Holmberg Ake , Verganti Luca , Saletti Andrea , Vallone Stefano , Zini Andrea , Cerase Alfonso , Romano Daniele , Bracco Sandra , Lorenzano Svetlana , Fainardi Enrico , Mangiafico Salvatore 
Published: January 2016

BackgroundThe purpose of this study was to evaluate the correlation between a novel angiographic score for collaterals and CT perfusion (CTP) parameters in patients undergoing endovascular treatment for acute ischemic stroke (AIS).Methods103 patients (mean age 66.7±12.7; 48.5% men) with AIS in the anterior circulation territory, imaged with non-contrast CT, CT angiography, and CTP, admitted within 8 h from symptom onset and treated with any endovascular approach, were retrospectively included in the study. Clinical, neuroradiological data, and all time intervals were collected. Careggi Collateral Score (CCS) was used for angiographic assessment of collaterals and the Alberta Stroke Program Early CT Score (ASPECTS) for semiquantitative analysis of CTP maps. Two centralized core laboratories separately reviewed angiographic data, whereas CT findings were evaluated by an expert neuroradiologist. Univariate and multivariate analysis were performed considering CCS both as an ordinal and a dichotomous variable.Results37/103 patients (35.9%) received intravenous tissue plasminogen activator. Median (IQR) ASPECTS was 9 (6–10) for admission CT, 9 (5–10) for cerebral blood volume (CBV) maps, 3 (2–3) for mean transit time maps, 3 (2–4), for cerebral blood flow maps, and 5 (3–7) for CTP mismatch. Univariate analysis showed a significant correlation between CCS and ASPECTS for all CTP parameters. Multivariate analysis confirmed an independent association only between CCS and CBV (p=0.020 when CCS was considered as a dichotomous variable, p=0.026 with ordinal CCS).ConclusionsA correlation between angiographic assessment of the collateral circulation and CTP seems to be present, suggesting that CCS may provide an indirect evaluation of the infarct core volume to consider for patient selection in AIS.
Plesiosaurian fossils from Baltic glacial erratics: evidence of Early Jurassic marine amniotes from the southwestern margin of Fennoscandia
Authors: Sachs Sven , Hornung Jahn J. , Lierl Hans-Jürgen , Kear Benjamin P. 
Published: January 2016

Abstract

Early Jurassic plesiosaurian fossils are rare in the Scandinavian region, with a few isolated bones and teeth known from Bornholm, and anecdotal finds from East Greenland. The only other identifiable specimens derive from Toarcian-aged (based on ammonites) erratics deposited during Late Pleistocene glacial advances near the town of Ahrensburg, NE of Hamburg in northern Germany. The geographical source of these transported clasts is debated, but reconstructed ice-flow directions and lithofacies comparisons implicate either the offshore Baltic Sea between the Island of Bornholm and Mecklenburg–Vorpommern (Germany) or, less probably, south of the Danish Archipelago (Mecklenburg Bay). These regions collectively bordered the Fennoscandian landmass and adjacent Ringkøbing-Fyn Island in the late Early Jurassic, and were dominated by near-shore marine deltaic to basinal settings. The Ahrensburg plesiosaurian remains include postcranial elements reminiscent of both the microcleidid
Seeleyosaurus
and the rhomaelosaurid
Meyerasaurus
. These occur alongside other classic ‘Germanic province’ marine amniotes, such as the teleosaurid crocodyliform
Steneosaurus
and ichthyosaurian
Stenopterygius
cf.
quadriscissus
: thus, advocating faunal continuity between Scandinavia and southern Germany during the Toarcian, and a less pronounced marine reptile faunal provinciality than previously assumed.
New insights into the Kawah Ijen hydrothermal system from geophysical data
Authors: Caudron Corentin , Mauri Guillaume , Williams-Jones Glyn , Lecocq Thomas , Syahbana Devy Kamil , De Plaen Raphael , Peiffer Loic , Bernard Alain , Saracco Ginette 
Published: January 2016

Abstract

The magmatic–hydrothermal system of Kawah Ijen volcano is one of the most exotic on Earth, featuring the largest acidic lake on the planet, a hyper-acidic river and a passively degassing silicic dome. While previous studies have mostly described this unique system from a geochemical perspective, to date there has been no comprehensive geophysical investigation of the system. In our study, we surveyed the lake using a thermocouple, a thermal camera, an echo sounder and CO
2
sensors. Furthermore, we gained insights into the hydrogeological structures by combining self-potential surveys with ground and water temperatures. Our results show that the hydrothermal system is self-sealed within the upper edifice and releases pressurized gas only through the active crater. We also show that the extensive hydrological system is formed by not one but three aquifers: a south aquifer that seems to be completely isolated, a west aquifer that sustains the acidic upper springs, and an east aquifer that is the main source of fresh water for the lake. In contrast with previous research, we emphasize the heterogeneity of the acidic lake, illustrated by intense subaqueous degassing. These findings provide new insights into this unique, hazardous hydrothermal system, which may eventually improve the existing monitoring system.
Notch4 Signaling Induces a Mesenchymal–Epithelial–like Transition in Melanoma Cells to Suppress Malignant Behaviors
Authors: Bonyadi Rad Ehsan , Hammerlindl Heinz , Wels Christian , Popper Ulrich , Ravindran Menon Dinoop , Breiteneder Heimo , Kitzwoegerer Melitta , Hafner Christine , Herlyn Meenhard , Bergler Helmut , Schaider Helmut 
Published: January 2016

Abstract
The effects of Notch signaling are context-dependent and both oncogenic and tumor-suppressive functions have been described. Notch signaling in melanoma is considered oncogenic, but clinical trials testing Notch inhibition in this malignancy have not proved successful. Here, we report that expression of the constitutively active intracellular domain of Notch4 (N4ICD) in melanoma cells triggered a switch from a mesenchymal-like parental phenotype to an epithelial-like phenotype. The epithelial-like morphology was accompanied by strongly reduced invasive, migratory, and proliferative properties concomitant with the downregulation of epithelial–mesenchymal transition markers Snail2 (SNAI2), Twist1, vimentin (VIM), and MMP2 and the reexpression of E-cadherin (CDH1). The N4ICD-induced phenotypic switch also resulted in significantly reduced tumor growth in vivo. Immunohistochemical analysis of primary human melanomas and cutaneous metastases revealed a significant correlation between Notch4 and E-cadherin expression. Mechanistically, we demonstrate that N4ICD induced the expression of the transcription factors Hey1 and Hey2, which bound directly to the promoter regions of Snail2 and Twist1 and repressed gene transcription, as determined by EMSA and luciferase assays. Taken together, our findings indicate a role for Notch4 as a tumor suppressor in melanoma, uncovering a potential explanation for the poor clinical efficacy of Notch inhibitors observed in this setting. Cancer Res; 76(7); 1690–7. ©2016 AACR.
Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function
Authors: Wang Weihuan , Zimmerman Grant , Huang Xiaoran , Yu Shuiliang , Myers Jay , Wang Yiwei , Moreton Stephen , Nthale Joseph , Awadallah Amad , Beck Rose , Xin Wei , Wald David , Huang Alex Y. , Zhou Lan 
Published: January 2016

Abstract
More than half of T-cell acute lymphoblastic leukemia (T-ALL) patients harbor gain-of-function mutations in the intracellular domain of Notch1. Diffuse infiltration of the bone marrow commonly occurs in T-ALL and relapsed B-cell acute lymphoblastic leukemia patients, and is associated with worse prognosis. However, the mechanism of leukemia outgrowth in the marrow and the resulting biologic impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular and molecular abnormalities in leukemia marrow stroma responsible for the suppression of normal hematopoiesis using a T-ALL mouse model and human T-ALL xenografts. We found that actively proliferating leukemia cells inhibited normal hematopoietic stem and progenitor cell (HSPC) proliferation and homing to the perivascular region. In addition, leukemia development was accompanied by the suppression of the endosteum-lining osteoblast population. We further demonstrated that aberrant Notch activation in the stroma plays an important role in negatively regulating the expression of CXLC12 on osteoblasts and their differentiation. Notch blockade reversed attenuated HSPC cycling, leukemia-associated abnormal blood lineage distribution, and thrombocytopenia as well as recovered osteoblast and HSPC abundance and improved the hematopoietic-supportive functions of osteoblasts. Finally, we confirmed that reduced osteoblast frequency and enhanced Notch signaling were also features of the marrow stroma of human ALL tissues. Collectively, our findings suggest that therapeutically targeting the leukemia-infiltrated hematopoietic niche may restore HSPC homeostasis and improve the outcome of ALL patients. Cancer Res; 76(6); 1641–52. ©2016 AACR.
Divergence of Antiangiogenic Activity and Hepatotoxicity of Different Stereoisomers of Itraconazole
Authors: Shim Joong Sup , Li Ruo-Jing , Bumpus Namandje N. , Head Sarah A. , Kumar Pasunooti Kalyan , Yang Eun Ju , Lv Junfang , Shi Wei , Liu Jun O. 
Published: January 2016

Abstract
Purpose: Itraconazole is a triazole antifungal drug that has recently been found to inhibit angiogenesis. Itraconazole is a relatively well-tolerated drug but shows hepatotoxicity in a small subset of patients. Itraconazole contains three chiral centers and the commercial itraconazole is composed of four cis-stereoisomers (named IT-A, IT-B, IT-C, and IT-D). We sought to determine whether the stereoisomers of itraconazole might differ in their antiangiogenic activity and hepatotoxicity.
Experimental Design: We assessed in vitro antiangiogenic activity of itraconazole and each stereoisomer using human umbilical vein endothelial cell (HUVEC) proliferation and tube formation assays. We also determined their hepatotoxicity using primary human hepatocytes in vitro and a mouse model in vivo. Mouse Matrigel plug and tumor xenograft models were used to evaluate in vivo antiangiogenic and antitumor activities of the stereoisomers.
Results: Of the four stereoisomers contained in commercial itraconazole, we found that IT-A (2S,4R,2′R) and IT-C (2S,4R,2′S) were more potent for inhibition of angiogenesis than IT-B (2R,4S,2′R) and IT-D (2R,4S,2′S). Interestingly, IT-A and IT-B were more hepatotoxic than IT-C and IT-D. In mouse models, IT-C showed more potent antiangiogenic/antitumor activity with lower hepatotoxicity compared with itraconazole and IT-A.
Conclusions: These results demonstrate the segregation of influence of stereochemistry at different positions of itraconazole on its antiangiogenic activity and hepatotoxicity, with the 2 and 4 positions affecting the former and the 2′ position affecting the latter. They also suggest that IT-C may be superior to the racemic mixture of itraconazole as an anticancer drug candidate due to its lower hepatotoxicity and improved antiangiogenic activity. Clin Cancer Res; 22(11); 2709–20. ©2016 AACR.
Phase I Study of Veliparib (ABT-888) Combined with Cisplatin and Vinorelbine in Advanced Triple-Negative Breast Cancer and/orBRCAMutation–Associated Breast Cancer
Authors: Rodler Eve T. , Kurland Brenda F. , Griffin Melissa , Gralow Julie R. , Porter Peggy , Yeh Rosa F. , Gadi Vijayakrishna K. , Guenthoer Jamie , Beumer Jan H. , Korde Larissa , Strychor Sandra , Kiesel Brian F. , Linden Hannah M. , Thompson John A. , Swisher Elizabeth , Chai Xiaoyu , Shepherd Stacie , Giranda Vincent , Specht Jennifer M. 
Published: January 2016

AbstractPurpose: Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation–associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine.Experimental Design: A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. IHC and gene-expression profiling were evaluated as potential predictors of response.Results: Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg twice daily. The MTD of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival [PFS; 10 of 14 (71%) vs. 8 of 27 (30%), mid-P = 0.01]. Median PFS for all 50 patients was 5.5 months (95% confidence interval, 4.1–6.7).Conclusions: Veliparib at 300 mg twice daily combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib's contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation–associated breast cancer. Clin Cancer Res; 22(12); 2855–64. ©2016 AACR.
A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity
Authors: Mysore Veena S. , Szablowski Jerzy , Dervan Peter B. , Frost Patrick J. 
Published: January 2016

Abstract
Multiple myeloma is incurable and invariably becomes resistant to chemotherapy. Although the mechanisms remain unclear, hypoxic conditions in the bone marrow have been implicated in contributing to multiple myeloma progression, angiogenesis, and resistance to chemotherapy. These effects occur via adaptive cellular responses mediated by hypoxia-inducible transcription factors (HIF), and targeting HIFs can have anticancer effects in both solid and hematologic malignancies. Here, it was found that in most myeloma cell lines tested, HIF1α, but not HIF2α expression was oxygen dependent, and this could be explained by the differential expression of the regulatory prolyl hydroxylase isoforms. The anti–multiple myeloma effects of a sequence-specific DNA-binding pyrrole-imidazole (Py-Im) polyamide (HIF-PA), which disrupts the HIF heterodimer from binding to its cognate DNA sequences, were also investigated. HIF-PA is cell permeable, localizes to the nuclei, and binds specific regions of DNA with an affinity comparable with that of HIFs. Most of the multiple myeloma cells were resistant to hypoxia-mediated apoptosis, and HIF-PA treatment could overcome this resistance in vitro. Using xenograft models, it was determined that HIF-PA significantly decreased tumor volume and increased hypoxic and apoptotic regions within solid tumor nodules and the growth of myeloma cells engrafted in the bone marrow. This provides a rationale for targeting the adaptive cellular hypoxic response of the O2-dependent activation of HIFα using polyamides.
Implications: Py-Im polyamides target and disrupt the adaptive hypoxic responses in multiple myeloma cells that may have clinical significance as a therapeutic strategy to treat myeloma engrafted in the bone marrow microenvironment. Mol Cancer Res; 14(3); 253–66. ©2016 AACR.
Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin
Authors: Dickinson Sally E. , Janda Jaroslav , Criswell Jane , Blohm-Mangone Karen , Olson Erik R. , Liu Zhonglin , Barber Christy , Petricoin Emanuel F. , Calvert Valerie S. , Einspahr Janine , Dickinson Jesse E. , Stratton Steven P. , Curiel-Lewandrowski Clara , Saboda Kathylynn , Hu Chengcheng , Bode Ann M. , Dong Zigang , Alberts David S. , Timothy Bowden G. 
Published: January 2016

AbstractThe PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced nonmelanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared with those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here, we explored the use of topical rapamycin as a chemopreventive agent in the context of solar-simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared with controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared with vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC. Cancer Prev Res; 9(3); 215–24. ©2016 AACR.
Serum Magnesium and the Risk of Death From Coronary Heart Disease and Sudden Cardiac Death
Authors: Kieboom Brenda C. T. , Niemeijer Maartje N. , Leening Maarten J. G. , van den Berg Marten E. , Franco Oscar H. , Deckers Jaap W. , Hofman Albert , Zietse Robert , Stricker Bruno H. , Hoorn Ewout J. 
Published: January 2016

Background

Low serum magnesium has been implicated in cardiovascular mortality, but results are conflicting and the pathway is unclear. We studied the association of serum magnesium with coronary heart disease (
CHD
) mortality and sudden cardiac death (
SCD
) within the prospective population‐based Rotterdam Study, with adjudicated end points and long‐term follow‐up.

Methods and Results

Nine‐thousand eight‐hundred and twenty participants (mean age 65.1 years, 56.8% female) were included with a median follow‐up of 8.7 years. We used multivariable Cox proportional hazard models and found that a 0.1 mmol/L increase in serum magnesium level was associated with a lower risk for
CHD
mortality (hazard ratio: 0.82, 95%
CI
0.70–0.96). Furthermore, we divided serum magnesium in quartiles, with the second and third quartile combined as reference group (0.81–0.88 mmol/L). Low serum magnesium (≤0.80 mmol/L) was associated with an increased risk of
CHD
mortality (N=431, hazard ratio: 1.36, 95%
CI
1.09–1.69) and
SCD
(N=217, hazard ratio: 1.54, 95%
CI
1.12–2.11). Low serum magnesium was associated with accelerated subclinical atherosclerosis (expressed as increased carotid intima‐media thickness: +0.013 mm, 95%
CI
0.005–0.020) and increased
QT
‐interval, mainly through an effect on heart rate (
RR
‐interval: −7.1 ms, 95%
CI
−13.5 to −0.8). Additional adjustments for carotid intima‐media thickness and heart rate did not change the associations with
CHD
mortality and
SCD
.

Conclusions

Low serum magnesium is associated with an increased risk of
CHD
mortality and
SCD
. Although low magnesium was associated with both carotid intima‐media thickness and heart rate, this did not explain the relationship between serum magnesium and
CHD
mortality or
SCD
. Future studies should focus on why magnesium associates with
CHD
mortality and
SCD
and whether intervention reduces these risks.
Human-Driven Atmospheric Deposition of N and P Controls on the East Mediterranean Marine Ecosystem
Authors: Christodoulaki S. , Petihakis G. , Mihalopoulos N. , Tsiaras K. , Triantafyllou G. , Kanakidou M. 
Published: January 2016

Abstract
The historical and future impacts of atmospheric deposition of inorganic nitrogen (N) and phosphorus (P) on the marine ecosystem in the east Mediterranean Sea are investigated by using a 1D coupled physical– biogeochemical model, set up for the Cretan Sea as a representative area of the basin. For the present-day simulation (2010), the model is forced by observations of atmospheric deposition fluxes at Crete, while for the hindcast (1860) and forecast (2030) simulations, the changes in atmospheric deposition calculated by global chemistry–transport models are applied to the present-day observed fluxes. The impact of the atmospheric deposition on the fluxes of carbon in the food chain is calculated together with the contribution of human activities to these impacts. The results show that total phytoplanktonic biomass increased by 16% over the past 1.5 centuries. Small fractional changes in carbon fluxes and planktonic biomasses are predicted for the near future. Simulations show that atmospheric deposition of N and P may be the main mechanism responsible for the anomalous N:P ratio observed in the Mediterranean Sea.
Langmuir Turbulence Parameterization in Tropical Cyclone Conditions
Authors: Reichl Brandon G. , Wang Dong , Hara Tetsu , Ginis Isaac , Kukulka Tobias 
Published: January 2016

AbstractThe Stokes drift of surface waves significantly modifies the upper-ocean turbulence because of the Craik–Leibovich vortex force (Langmuir turbulence). Under tropical cyclones the contribution of the surface waves varies significantly depending on complex wind and wave conditions. Therefore, turbulence closure models used in ocean models need to explicitly include the sea state–dependent impacts of the Langmuir turbulence. In this study, the K-profile parameterization (KPP) first-moment turbulence closure model is modified to include the explicit Langmuir turbulence effect, and its performance is tested against equivalent large-eddy simulation (LES) experiments under tropical cyclone conditions. First, the KPP model is retuned to reproduce LES results without Langmuir turbulence to eliminate implicit Langmuir turbulence effects included in the standard KPP model. Next, the Lagrangian currents are used in place of the Eulerian currents in the KPP equations that calculate the bulk Richardson number and the vertical turbulent momentum flux. Finally, an enhancement to the turbulent mixing is introduced as a function of the nondimensional turbulent Langmuir number. The retuned KPP, with the Lagrangian currents replacing the Eulerian currents and the turbulent mixing enhanced, significantly improves prediction of upper-ocean temperature and currents compared to the standard (unmodified) KPP model under tropical cyclones and shows improvements over the standard KPP at constant moderate winds (10 m s−1).