bluuebunny/crossref_metadata_2025_split huggingface dataset:
Size evolution of micropyrite from diagenesis to low-grade metamorphism
Authors: Cárdenes Víctor , Merinero Raúl , López-Mungira Aurora , Rubio-Ordoñez Álvaro , Pitcairn Iain K. , Cnudde Veerle 
Published: March 2018

Abstract
Size distribution and evolution of framboidal and euhedral microscopic crystals of pyrite (micropyrites, MPy) have been used for the last thirty years to deduce palaeo-redox conditions. The analysis of the MPy distributions can give valuable information about these palaeo-redox conditions. However, other information can also be retrieved from this type of analysis. In this work, we propose that the formation of new populations of MPy is a proxy of the transition from the anchizone to the epizone. High-resolution X-ray tomography (micro-CT) was used to determine the size distributions of MPy hosted in pelitic rocks subjected to different grades of low temperature metamorphism. These data were filtered and statistically analysed, which allowed us to find a statistical representative size distribution of the MPy present in the samples. The metamorphic grade was determined using the Kübler Index in combination with petrological and scanning electron microscopy (SEM) examination. The results show a relationship between metamorphic grade and MPy size distributions, and that new populations of MPy formed due to the effects of metamorphism. This new methodology for MPy size distribution has different potential applications in some fields of Earth sciences, such as palaeoenvironment reconstruction, ore mining or metamorphic petrology.
Combinatorial Effects of VEGFR Kinase Inhibitor Axitinib and Oncolytic Virotherapy in Mouse and Human Glioblastoma Stem-Like Cell Models
Authors: Saha Dipongkor , Wakimoto Hiroaki , Peters Cole W. , Antoszczyk Slawomir J. , Rabkin Samuel D. , Martuza Robert L. 
Published: March 2018

Abstract
Purpose: Glioblastoma (GBM), a fatal brain cancer, contains a subpopulation of GBM stem-like cells (GSCs) that contribute to resistance to current therapy. Angiogenesis also plays a key role in GBM progression. Therefore, we developed a strategy to target the complex GBM microenvironment, including GSCs and tumor vasculature.
Experimental Design: We evaluated the cytotoxic effects of VEFGR tyrosine kinase inhibitor (TKI) axitinib in vitro and then tested antitumor efficacy of axitinib in combination with oncolytic herpes simplex virus (oHSV) expressing antiangiogenic cytokine murine IL12 (G47Δ-mIL12) in two orthotopic GSC-derived GBM models: patient-derived recurrent MGG123 GSCs, forming vascular xenografts in immunodeficient mice; and mouse 005 GSCs, forming syngeneic tumors in immunocompetent mice.
Results: GSCs form endothelial-like tubes and were sensitive to axitinib. G47Δ-mIL12 significantly improved survival, as did axitinib, while dual combinations further extended survival significantly compared with single therapies alone in both models. In MGG123 tumors, axitinib was effective only at high doses (50 mg/kg), alone and in combination with G47Δ-mIL12, and this was associated with greatly decreased vascularity, increased macrophage infiltration, extensive tumor necrosis, and PDGFR/ERK pathway inhibition. In the mouse 005 model, antiglioma activity, after single and combination therapy, was only observed in immunocompetent mice and not the T-cell–deficient athymic mice. Interestingly, immune checkpoint inhibition did not improve efficacy.
Conclusions: Systemic TKI (axitinib) beneficially combines with G47Δ-mIL12 to enhance antitumor efficacy in both immunodeficient and immunocompetent orthotopic GBM models. Our results support further investigation of TKIs in combination with oHSV for GBM treatment. Clin Cancer Res; 24(14); 3409–22. ©2018 AACR.
Hyperpolarized [1-13C]-Pyruvate Magnetic Resonance Spectroscopic Imaging of Prostate Cancer In Vivo Predicts Efficacy of Targeting the Warburg Effect
Authors: Scroggins Bradley T. , Matsuo Masayuki , White Ayla O. , Saito Keita , Munasinghe Jeeva P. , Sourbier Carole , Yamamoto Kazutoshi , Diaz Vivian , Takakusagi Yoichi , Ichikawa Kazuhiro , Mitchell James B. , Krishna Murali C. , Citrin Deborah E. 
Published: March 2018

Abstract
Purpose: To evaluate the potential of hyperpolarized [1-13C]-pyruvate magnetic resonance spectroscopic imaging (MRSI) of prostate cancer as a predictive biomarker for targeting the Warburg effect.
Experimental Design: Two human prostate cancer cell lines (DU145 and PC3) were grown as xenografts. The conversion of pyruvate to lactate in xenografts was measured with hyperpolarized [1-13C]-pyruvate MRSI after systemic delivery of [1-13C] pyruvic acid. Steady-state metabolomic analysis of xenograft tumors was performed with mass spectrometry and steady-state lactate concentrations were measured with proton (1H) MRS. Perfusion and oxygenation of xenografts were measured with electron paramagnetic resonance (EPR) imaging with OX063. Tumor growth was assessed after lactate dehydrogenase (LDH) inhibition with FX-11 (42 μg/mouse/day for 5 days × 2 weekly cycles). Lactate production, pyruvate uptake, extracellular acidification rates, and oxygen consumption of the prostate cancer cell lines were analyzed in vitro. LDH activity was assessed in tumor homogenates.
Results: DU145 tumors demonstrated an enhanced conversion of pyruvate to lactate with hyperpolarized [1-13C]-pyruvate MRSI compared with PC3 and a corresponding greater sensitivity to LDH inhibition. No difference was observed between PC3 and DU145 xenografts in steady-state measures of pyruvate fermentation, oxygenation, or perfusion. The two cell lines exhibited similar sensitivity to FX-11 in vitro. LDH activity correlated to FX-11 sensitivity.
Conclusions: Hyperpolarized [1-13C]-pyruvate MRSI of prostate cancer predicts efficacy of targeting the Warburg effect. Clin Cancer Res; 24(13); 3137–48. ©2018 AACR.
Associations between Pre-Admission Risk Scores and Two-Year Clinical Outcomes in Ischemic Stroke or Transient Ischemic Attack Patients with Non-Valvular Atrial Fibrillation
Authors: Tokunaga Keisuke , Yamagami Hiroshi , Koga Masatoshi , Todo Kenichi , Kimura Kazumi , Itabashi Ryo , Terasaki Tadashi , Shiokawa Yoshiaki , Kamiyama Kenji , Takizawa Shunya , Okuda Satoshi , Okada Yasushi , Kameda Tomoaki , Nagakane Yoshinari , Hasegawa Yasuhiro , Shibuya Satoshi , Ito Yasuhiro , Matsuoka Hideki , Takamatsu Kazuhiro , Nishiyama Kazutoshi , Kario Kazuomi , Yagita Yoshiki , Kitazono Takanari , Kinoshita Naoto , Takasugi Junji , Okata Takuya , Yoshimura Sohei , Sato Shoichiro , Arihiro Shoji , Toyoda Kazunori ,   SAMURAI Study Investigators
Published: March 2018

<b><i>Background:</i></b> We aimed to clarify associations between pre-admission risk scores (CHADS<sub>2</sub>, CHA<sub>2</sub>DS<sub>2</sub>-VASc, and HAS-BLED) and 2-year clinical outcomes in ischemic stroke or transient ischemic attack (TIA) patients with non-valvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry. <b><i>Methods:</i></b> From 18 Japanese stroke centers, ischemic stroke or TIA patients with NVAF hospitalized within 7 days after onset were enrolled. Outcome measures were defined as death/disability (modified Rankin Scale score ≥3) at 2 years, 2-year mortality, and ischemic or hemorrhagic events within 2 years. <b><i>Results:</i></b> A total of 1,192 patients with NVAF (527 women; mean age, 78 ± 10 years), including 1,141 ischemic stroke and 51 TIA, were analyzed. Rates of death/disability, mortality, and ischemic or hemorrhagic events increased significantly with increasing pre-admission CHADS<sub>2</sub> (<i>p</i> for trend &#x3c;0.001 for death/disability and mortality, <i>p</i> for trend = 0.024 for events), CHA<sub>2</sub>DS<sub>2</sub>-VASc (<i>p</i> for trend &#x3c;0.001 for all), and HAS-BLED (<i>p</i> for trend = 0.004 for death/disability, <i>p</i> for trend &#x3c;0.001 for mortality, <i>p</i> for trend = 0.024 for events) scores. Pre-admission CHADS<sub>2</sub> (OR per 1 point, 1.52; 95% CI 1.35–1.71; <i>p</i> &#x3c;0.001 for death/disability; hazard ratio (HR) per 1 point, 1.23; 95% CI 1.12–1.35; <i>p</i> &#x3c;0.001 for mortality; HR per 1 point, 1.14; 95% CI 1.02–1.26; <i>p</i> = 0.016 for events), CHA<sub>2</sub>DS<sub>2</sub>-VASc (1.55, 1.41–1.72, <i>p</i> &#x3c; 0.001; 1.21, 1.12–1.30, <i>p</i> &#x3c; 0.001; 1.17, 1.07–1.27, <i>p</i> &#x3c; 0.001; respectively), and HAS-BLED (1.33, 1.17–1.52, <i>p</i> &#x3c; 0.001; 1.23, 1.10–1.38, <i>p </i>&#x3c; 0.001; 1.18, 1.05–1.34, <i>p</i> = 0.008; respectively) scores were independently associated with all outcome measures. <b><i>Conclusions:</i></b> In ischemic stroke or TIA patients with NVAF, all pre-admission risk scores were independently associated with death/disability at 2 years and 2-year mortality, as well as ischemic or hemorrhagic events within 2 years.
Transcatheter Closure of Patent Foramen Ovale versus Medical Therapy after Cryptogenic Stroke: A Meta-Analysis of Randomized Controlled Trials
Authors: Darmoch Fahed , Al-Khadra Yasser , Soud Mohamad , Fanari Zaher , Alraies M. Chadi 
Published: March 2018

<b><i>Background:</i></b> Patent foramen ovale (PFO) with atrial septal aneurysm is suggested as an important potential source for cryptogenic strokes. Percutaneous PFO closure to reduce the recurrence of stroke compared to medical therapy has been intensely debated. The aim of this study is to assess whether PFO closure in patients with cryptogenic stroke is safe and effective compared with medical therapy. <b><i>Method:</i></b> A search of PubMed, Medline, and Cochrane Central Register from January 2000 through September 2017 for randomized controlled trails (RCT), which compared PFO closure to medical therapy in patients with cryptogenic stroke was conducted. We used the items “PFO or patent foramen ovale”, “paradoxical embolism”, “PFO closure” and “stroke”. Data were pooled for the primary outcome measure using the random-effects model as pooled rate ratio (RR). The primary outcome was reduction in recurrent strokes. <b><i>Result:</i></b> Among 282 studies, 5 were selected. Our analysis included 3,440 patients (mean age 45 years, 55% men, mean follow-up 2.9 years), 1,829 in the PFO closure group and 1,611 in the medical therapy group. The I<sup>2</sup> heterogeneity test was found to be 48%. A random effects model combining the results of the included studies demonstrated a statistically significant risk reduction in risk of recurrent stroke in the PFO closure group when compared with medical therapy (RR 0.42; 95% CI 0.20–0.91, <i>p</i> = 0.03). <b><i>Conclusion:</i></b> Pooled data from 5 large RCTs showed that PFO closure in patients with cryptogenic stroke is safe and effective intervention for prevention of stroke recurrence compared with medical therapy.
Levels of Endocan, Angiopoietin-2, and Hypoxia-Inducible Factor-1a in Patients with Autosomal Dominant Polycystic Kidney Disease and Different Levels of Renal Function
Authors: Raptis Vassilios , Bakogiannis Constantinos , Loutradis Charalampos , Boutou Afroditi K. , Lampropoulou Ioanna , Intzevidou Elena , Sioulis Athanasios , Balaskas Elias , Sarafidis Pantelis A. 
Published: March 2018

<b><i>Background:</i></b> Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an alternative pathway of renal damage in autosomal dominant polycystic kidney disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. <b><i>Methods:</i></b> The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A; estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m<sup>2</sup>), 26 ADPKD patients with preserved renal function (Group B; eGFR &#x3e;70 mL/min/1.73 m<sup>2</sup>), and 26 age- and sex-matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-inducible factor-1a (HIF-1a) were determined by enzyme-linked immunosorbent assay techniques. <b><i>Results:</i></b> Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/mL), angiopoietin-2 (5,595.43 ± 3,390), and HIF-1a (163.68 ± 37.84 pg/mL) compared to patients in Group B (6.86 ± 0.59 ng/mL, <i>p</i> = 0.017, 3,854.41 ± 3,014.30, <i>p</i> = 0.018, 136.84 ± 42.10 pg/mL, <i>p</i> = 0.019 respectively) or controls (4.83 ± 0.69 ng/mL, 1,069 ± 427.88 pg/mL, 70.20 ± 17.49 pg/mL, <i>p</i> &#x3c; 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (<i>p</i> &#x3c; 0.001) despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with asymmetric dimethylarginine (ADMA; endocan <i>r</i> = 0.908, <i>p</i> &#x3c; 0.001, angiopoietin-2 <i>r</i> = 0.983, <i>p</i> &#x3c; 0.001 and HIF-1a <i>r</i> = 0.998, <i>p</i> &#x3c; 0.001), and only weak or modest correlations with eGFR. <b><i>Conclusions:</i></b> This study suggests that endothelial dysfunction causing microcirculatory changes, linked to angiogenesis and hypoxia, may come early in the course of ADPKD and could be a key regulator of renal injury progression.
Feasibility of “Watch-and-Wait” Management before Repeat Hepatectomy for Colorectal Liver Metastases
Authors: Kishi Yoji , Nara Satoshi , Esaki Minoru , Shimada Kazuaki 
Published: March 2018

<b><i>Background:</i></b> Whether repeat hepatectomy for colorectal liver metastases should be performed after chemotherapy or observation is unclear. <b><i>Methods:</i></b> We selected patients with resectable hepatic recurrence after their first hepatectomies performed between 2000 and 2015. They were classified according to the further treatment: Group A, prompt repeat hepatectomy; Group B, observation; and Group C, ≤6 months of chemotherapy. In Group B/C, patients who later underwent hepatectomy and those who did not due to disease progression were classified as B1/C1 and B2/C2, respectively. Predictors of B2/C2 were evaluated. <b><i>Results:</i></b> Groups A, B, and C consisted of 81, 36, and 17 patients, respectively. Recurrence-free interval was longer in Group A (median months; Group A, 10.3; Group B, 5.7; Group C, 3.5; <i>p</i> &#x3c; 0.01). Group B1/C1 and B2/C2 included 34 and 19 patients, respectively. Five-year survival after recurrence of Group B1/C1 was 56%, which was comparable with Group A (56%, <i>p</i> = 0.77) and better than Group B2/C2 (0%, <i>p</i> &#x3c; 0.01). Multivariate analysis showed synchronous colorectal liver metastases (OR 7.23) and recurrent hepatic tumor number (OR 4.04) were predictors of tumor progression. <b><i>Conclusion:</i></b> Selecting patients optimally either for prompt or delayed repeat hepatectomy following chemotherapy or observation is a feasible strategy.
Telomerase Mediates Lymphocyte Proliferation but Not the Atherosclerosis-Suppressive Potential of Regulatory T-Cells
Authors: Richardson Gavin David , Sage Andrew , Bennaceur Karim , Al Zhrany Nayef , Coelho-Lima Jose , Dookun Emily , Draganova Lilia , Saretzki Gabriele , Breault David T. , Mallat Ziad , Spyridopoulos Ioakim 
Published: March 2018

Objective—
Atherosclerosis is an age-related disease characterized by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence, a potential causative role of telomerase in atherogenesis is critically debated.

Approach and Results—

In this study, we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo. Using primary lymphocytes and myeloid cell cultures, we demonstrate that cultivation under hyperoxic conditions induced oxidative stress resulting in chronic activation of CD4
+
cells and significantly reduced CD4
+
T-cell proliferation. The latter was telomerase dependent because oxidative stress had no effect on the proliferation of primary lymphocytes isolated from telomerase knockout mice. In contrast, myeloid cell proliferation was unaffected by oxidative stress nor reliant on telomerase. Telomerase reverse transcriptase deficiency had no effect on regulatory T-cell (T
reg
) numbers in vivo or suppressive function ex vivo. Adoptive transfer of telomerase reverse transcriptase
–
/–
T
regs
into Rag2
–/–
ApoE
–/–
(recombination activating gene 2/apolipoprotein E) double knockout mice demonstrated that telomerase function was not required for the ability of T
regs
to protect against atherosclerosis. However, telomere length was critical for T
reg
function.

Conclusions—

Telomerase contributes to lymphocyte proliferation but plays no major role in T
reg
function, provided that telomere length is not critically short. We suggest that oxidative stress may contribute to atherosclerosis via suppression of telomerase and acceleration of telomere attrition in T
regs
.
CaMKII (Ca
2+
/Calmodulin-Dependent Kinase II) in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration, and Neointima Formation
Authors: Nguyen Emily K. , Koval Olha M. , Noble Paige , Broadhurst Kim , Allamargot Chantal , Wu Meng , Strack Stefan , Thiel William H. , Grumbach Isabella M. 
Published: March 2018

Objective—
The main objective of this study is to define the mechanisms by which mitochondria control vascular smooth muscle cell (VSMC) migration and impact neointimal hyperplasia.

Approach and Results—

The multifunctional CaMKII (Ca
2+
/calmodulin-dependent kinase II) in the mitochondrial matrix of VSMC drove a feed-forward circuit with the mitochondrial Ca
2+
uniporter (MCU) to promote matrix Ca
2+
influx. MCU was necessary for the activation of mitochondrial CaMKII (mtCaMKII), whereas mtCaMKII phosphorylated MCU at the regulatory site S92 that promotes Ca
2+
entry. mtCaMKII was necessary and sufficient for platelet-derived growth factor–induced mitochondrial Ca
2+
uptake. This effect was dependent on MCU. mtCaMKII and MCU inhibition abrogated VSMC migration and mitochondrial translocation to the leading edge. Overexpression of wild-type MCU, but not MCU S92A, mutant in MCU
−
/−
VSMC rescued migration and mitochondrial mobility. Inhibition of microtubule, but not of actin assembly, blocked mitochondrial mobility. The outer mitochondrial membrane GTPase Miro-1 promotes mitochondrial mobility via microtubule transport but arrests it in subcellular domains of high Ca
2+
concentrations. In Miro-1
−/−
VSMC, mitochondrial mobility and VSMC migration were abolished, and overexpression of mtCaMKII or a CaMKII inhibitory peptide in mitochondria (mtCaMKIIN) had no effect. Consistently, inhibition of mtCaMKII increased and prolonged cytosolic Ca
2+
transients. mtCaMKII inhibition diminished phosphorylation of focal adhesion kinase and myosin light chain, leading to reduced focal adhesion turnover and cytoskeletal remodeling. In a transgenic model of selective mitochondrial CaMKII inhibition in VSMC, neointimal hyperplasia was significantly reduced after vascular injury.

Conclusions—

These findings identify mitochondrial CaMKII as a key regulator of mitochondrial Ca
2+
uptake via MCU, thereby controlling mitochondrial translocation and VSMC migration after vascular injury.
Experimental Right Ventricular Hypertension Induces Regional β1‐Integrin–Mediated Transduction of Hypertrophic and Profibrotic Right and Left Ventricular Signaling
Authors: Sun Mei , Ishii Ryo , Okumura Kenichi , Krauszman Adrienn , Breitling Siegfried , Gomez Olga , Hinek Aleksander , Boo Stellar , Hinz Boris , Connelly Kim A. , Kuebler Wolfgang M. , Friedberg Mark K. 
Published: March 2018

Background

Development of right ventricular (
RV
) hypertension eventually contributes to
RV
and left ventricular (
LV
) myocardial fibrosis and dysfunction. The molecular mechanisms are not fully elucidated.

Methods and Results

Pulmonary artery banding was used to induce
RV
hypertension in rats in vivo. Then, we evaluated cardiac function and regional remodeling 6 weeks after pulmonary artery banding. To further elucidate mechanisms responsible for regional cardiac remodeling, we also mimicked
RV
hypertensive stress by cyclic mechanical stretching applied to confluent cultures of cardiac fibroblasts, isolated from the
RV
free wall, septal hinge points, and
LV
free wall. Echocardiography and catheter evaluation demonstrated that rats in the pulmonary artery banding group developed
RV
hypertension with leftward septal displacement,
LV
compression, and increased
LV
end‐diastolic pressures. Picrosirius red staining indicated that pulmonary artery banding induced marked
RV
fibrosis and dysfunction, with prominent fibrosis and elastin deposition at the septal hinge points but less
LV
fibrosis. These changes were associated with proportionally increased expressions of integrin‐β1 and profibrotic signaling proteins, including phosphorylated Smad2/3 and transforming growth factor‐β1. Moreover, mechanically stretched fibroblasts also expressed significantly increased levels of α‐smooth muscle actin, integrin‐β1, transforming growth factor‐β1, collagen I deposition, and wrinkle formation on gel assays, consistent with myofibroblast transformation. These changes were not observed in parallel cultures of mechanically stretched fibroblasts, preincubated with the integrin inhibitor (
BTT
‐3033).

Conclusions

Experimentally induced
RV
hypertension triggers regional
RV
, hinge‐point, and
LV
integrin β1‐dependent mechanotransduction signaling pathways that eventually trigger myocardial fibrosis via transforming growth factor‐β1 signaling. Reduced
LV
fibrosis and preserved global function, despite geometrical and pressure aberrations, suggest a possible elastin‐mediated protective mechanism at the septal hinge points.
Introduction: Perspectives on Women’s Religious Activities in Early Modern Europe and the Americas
Authors: Lehtsalu Liise , Moran Sarah , Evangelisti Silvia 
Published: March 2018

Abstract
Proposing activity as a useful category of analysis, this special issue considers Catholic and Protestant women in Europe and the Americas in the sixteenth to the eighteenth centuries. We examine women in religious communities, which include both monastic communities as well as confessional communities. A close analysis of the social, economic, and cultural actions of these women religious challenges historiographical assumptions about monastic cloister and domestic space in the early modern period. In fact, we revisit monastic and domestic spaces to reveal them as stages for previously unexamined activity. This cross-denominational and transnational special issue highlights new spheres of women’s religious activity and raises new questions for the study of early modern women’s lives and their capacity to act in early modern society, economy, and culture.