bluuebunny/crossref_metadata_2025_split huggingface dataset:
Periconal arterial anastomotic circle and posterior lumbosacral watershed zone of the spinal cord
Authors: Gailloud Philippe , Gregg Lydia , Galan Peter , Becker Daniel , Pardo Carlos 
Published: October 2014

BackgroundThe existence of spinal cord watershed territories was suggested in the 1950s. Segmental infarcts within the junctional territories of adjacent radiculomedullary contributors and isolated spinal gray matter ischemia constitute two well-recognized types of watershed injury. This report describes the existence of another watershed territory related to the particular configuration of the spinal vasculature in the region of the conus medullaris.MethodsThe anatomical bases underlying the concept of a posterior lumbosacral watershed zone are demonstrated with angiographic images obtained in a 16-year-old child. The clinical importance of this watershed zone is illustrated with MRI and angiographic data of three patients with a conus medullaris infarction.ResultsIn all three cases of spinal ischemia an intersegmental artery providing a significant radiculomedullary contribution for the lower cord was compromised by a compressive mechanism responsible for decreased spinal cord perfusion (diaphragmatic crus syndrome in two cases, disk herniation in one). The ischemic injury, located at the junction of the anterior and posterior spinal artery territories along the dorsal aspect of the conus medullaris, was consistent with a watershed mechanism. This zone is at risk because of the caudocranial direction of flow within the most caudal segment of the posterior spinal arterial network which, from a functional standpoint, depends on the anterior spinal artery.ConclusionsThe posterior thoracolumbar watershed zone of the spinal cord represents an area at increased risk of ischemic injury, particularly in the context of partial flow impairment related to arterial compression mechanisms.
Stratigraphic continuity and fragmentary sedimentation: the success of cyclostratigraphy as part of integrated stratigraphy
Authors: Hilgen Frederik J. , Hinnov Linda A. , Abdul Aziz Hayfaa , Abels Hemmo A. , Batenburg Sietske , Bosmans Joyce H. C. , de Boer Bas , Hüsing Silja K. , Kuiper Klaudia F. , Lourens Lucas J. , Rivera Tiffany , Tuenter Erik , Van de Wal Roderik S. W. , Wotzlaw Jörn-Frederik , Zeeden Christian 
Published: October 2014

Abstract

The Milankovitch theory of climate change is widely accepted, but the registration of the climate changes in the stratigraphic record and their use in building high-resolution astronomically tuned timescales has been disputed due to the complex and fragmentary nature of the stratigraphic record. However, results of time series analysis and consistency with independent magnetobiostratigraphic and/or radio-isotopic age models show that Milankovitch cycles are recorded not only in deep marine and lacustrine successions, but also in ice cores and speleothems, and in eolian and fluvial successions. Integrated stratigraphic studies further provide evidence for continuous sedimentation at Milankovitch time scales (10
4
years up to 10
6
years). This combined approach also shows that strict application of statistical confidence limits in spectral analysis to verify astronomical forcing in climate proxy records is not fully justified and may lead to false negatives. This is in contrast to recent claims that failure to apply strict statistical standards can lead to false positives in the search for periodic signals. Finally, and contrary to the argument that changes in insolation are too small to effect significant climate change, seasonal insolation variations resulting from orbital extremes can be significant (20% and more) and, as shown by climate modelling, generate large climate changes that can be expected to leave a marked imprint in the stratigraphic record. The tuning of long and continuous cyclic successions now underlies the standard geological time scale for much of the Cenozoic and also for extended intervals of the Mesozoic. Such successions have to be taken into account to fully comprehend the (cyclic) nature of the stratigraphic record.
Characterizing and identifying structural domains at rifted continental margins: application to the Bay of Biscay margins and its Western Pyrenean fossil remnants
Authors: Tugend J. , Manatschal G. , Kusznir N. J. , Masini E. 
Published: October 2014

Abstract
We use the Bay of Biscay and Western Pyrenees as a natural laboratory to develop and apply an approach to characterize and identify distinctive rifted margin domains in offshore and onshore settings. The Bay of Biscay and Western Pyrenees offer access to seismically imaged, drilled and exposed parts of one and the same hyperextended rift system. Offshore, we use gravity inversion and flexural backstripping techniques combined with seismic interpretation to provide estimates of accommodation space, crustal thickness and lithosphere thinning. Onshore, we focus on key outcrops of the former rift domain to describe the nature of sediment and basement rocks, and of their interface. This qualitative and quantitative characterization provides diagnostic elements for the identification of five distinct structural domains at magma-poor rifted margins and their fossil analogues (proximal, necking, hyperthinned, exhumed mantle and oceanic domains). This new approach can be used to reconcile offshore and onshore observations, and to aid interpretation when only local observations are available. Onshore remnants can be placed in an offshore rifted-margin context, enabling the prediction of first-order crustal architecture. For the interpretation of offshore seismic reflection sections, geological insights into rift structures and basement nature can be suggested based on onshore analogies.

Supplementary material:

Sensitivity of backstripping results to flexural rigidity is available at
http://www.geolsoc.org.uk/SUP18778
.
Distinct Luminal-Type Mammary Carcinomas Arise from Orthotopic Trp53-Null Mammary Transplantation of Juvenile versus Adult Mice
Authors: Nguyen David H. , Ouyang Haoxu , Mao Jian-Hua , Hlatky Lynn , Barcellos-Hoff Mary Helen 
Published: October 2014

Abstract
Age and physiologic status, such as menopause, are risk factors for breast cancer. Less clear is what factors influence the diversity of breast cancer. In this study, we investigated the effect of host age on the distribution of tumor subtypes in mouse mammary chimera consisting of wild-type hosts and Trp53 nullizygous epithelium, which undergoes a high rate of neoplastic transformation. Wild-type mammary glands cleared of endogenous epithelium at 3 weeks of age were subsequently transplanted during puberty (5 weeks) or at maturation (10 weeks) with syngeneic Trp53-null mammary tissue fragments and monitored for one year. Tumors arose sooner from adult hosts (AH) compared with juvenile hosts (JH). However, compared with AH tumors, JH tumors grew several times faster, were more perfused, exhibited a two-fold higher mitotic index, and were more highly positive for insulin-like growth factor receptor phosphorylation. Most tumors in each setting were estrogen receptor (ER)-positive (80% JH vs. 70% AH), but JH tumors were significantly more ER-immunoreactive (P = 0.0001) than AH tumors. A differential expression signature (JvA) of juvenile versus adult tumors revealed a luminal transcriptional program. Centroids of the human homologs of JvA genes showed that JH tumors were more like luminal A tumors and AH tumors were more like luminal B tumors. Hierarchical clustering with the JvA human ortholog gene list segregated luminal A and luminal B breast cancers across datasets. These data support the notion that age-associated host physiology greatly influences the intrinsic subtype of breast cancer. Cancer Res; 74(23); 7149–58. ©2014 AACR.
Suppression of Deacetylase SIRT1 Mediates Tumor-Suppressive NOTCH Response and Offers a Novel Treatment Option in Metastatic Ewing Sarcoma
Authors: Ban Jozef , Aryee Dave N.T. , Fourtouna Argyro , van der Ent Wietske , Kauer Max , Niedan Stephan , Machado Isidro , Rodriguez-Galindo Carlos , Tirado Oscar M. , Schwentner Raphaela , Picci Piero , Flanagan Adrienne M. , Berg Verena , Strauss Sandra J. , Scotlandi Katia , Lawlor Elizabeth R. , Snaar-Jagalska Ewa , Llombart-Bosch Antonio , Kovar Heinrich 
Published: October 2014

Abstract
The developmental receptor NOTCH plays an important role in various human cancers as a consequence of oncogenic mutations. Here we describe a novel mechanism of NOTCH-induced tumor suppression involving modulation of the deacetylase SIRT1, providing a rationale for the use of SIRT1 inhibitors to treat cancers where this mechanism is inactivated because of SIRT1 overexpression. In Ewing sarcoma cells, NOTCH signaling is abrogated by the driver oncogene EWS-FLI1. Restoration of NOTCH signaling caused growth arrest due to activation of the NOTCH effector HEY1, directly suppressing SIRT1 and thereby activating p53. This mechanism of tumor suppression was validated in Ewing sarcoma cells, B-cell tumors, and human keratinocytes where NOTCH dysregulation has been implicated pathogenically. Notably, the SIRT1/2 inhibitor Tenovin-6 killed Ewing sarcoma cells in vitro and prohibited tumor growth and spread in an established xenograft model in zebrafish. Using immunohistochemistry to analyze primary tissue specimens, we found that high SIRT1 expression was associated with Ewing sarcoma metastasis and poor prognosis. Our findings suggest a mechanistic rationale for the use of SIRT1 inhibitors being developed to treat metastatic disease in patients with Ewing sarcoma. Cancer Res; 74(22); 6578–88. ©2014 AACR.
Alcohol Consumption in Relation to Plasma Sex Hormones, Prolactin, and Sex Hormone–Binding Globulin in Premenopausal Women
Authors: Hirko Kelly A. , Spiegelman Donna , Willett Walter C. , Hankinson Susan E. , Eliassen A. Heather 
Published: October 2014

Abstract
Background: Alcohol consumption is a consistent risk factor for breast cancer, and evidence suggests premenopausal plasma hormones are associated with breast cancer.
Methods: Plasma concentrations of estradiol, estrone, estrone sulfate, testosterone, androstenedione, progesterone, prolactin, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and sex hormone–binding globulin (SHBG) were measured in samples collected in 1996–99. Average alcohol intake was calculated from semiquantitative food frequency questionnaires collected in 1995 and 1999. We used generalized linear models to calculate geometric mean hormone concentrations across alcohol categories and the percentage difference for the highest versus lowest category.
Results: Comparing women who consumed &gt;20 g/d with nondrinkers, levels were 25.7% higher for luteal estrone (geometric mean, 106 vs. 84.5 pg/mL; Ptrend = 0.001), 27.2% higher for luteal estradiol (182 vs. 143 pg/mL; Ptrend = 0.006), and 16.8% higher for SHBG (85.6 vs. 73.3 nmol/L; Ptrend = 0.03); concentrations of free testosterone were 17.9% lower (0.16 vs. 0.20 ng/dL; Ptrend = 0.002). Women consuming &gt;10 g/d compared with nondrinkers had 26.5% higher concentrations of follicular estrone sulfate (950 vs. 751 pg/mL; Ptrend = 0.04). We did not observe significant associations between alcohol and the other sex hormones evaluated. Significant positive associations were observed with beer intake, but not other alcohol types, for DHEA (Pinteraction = 0.003) and androstenedione (Pinteraction = 0.006).
Conclusion: Alcohol consumption was significantly positively associated with plasma luteal estrogen concentrations, but not with androgen levels, nor estrone or estradiol measured in the follicular phase.
Impact: Differences in premenopausal estrogen levels may contribute to the association between alcohol and breast cancer. Cancer Epidemiol Biomarkers Prev; 23(12); 2943–53. ©2014 AACR.
NK Cell Genotype and Phenotype at Diagnosis of Acute Lymphoblastic Leukemia Correlate with Postinduction Residual Disease
Authors: Sullivan Erin M. , Jeha Sima , Kang Guolian , Cheng Cheng , Rooney Barbara , Holladay Martha , Bari Rafijul , Schell Sarah , Tuggle MaCal , Pui Ching-Hon , Leung Wing 
Published: October 2014

Abstract
Purpose: Not all natural killer (NK) cells are equally cytotoxic against leukemia because of differences in receptor gene content and surface expression. We correlated NK cell genotype and phenotype at diagnosis of childhood acute lymphoblastic leukemia (ALL) with minimal residual disease (MRD) after induction chemotherapy.
Experimental Design: The NK cells and leukemia blasts of 244 patients were analyzed at diagnosis by killer-cell immunoglobulin-like receptor (KIR) typing and immunophenotyping. The results were correlated statistically with postinduction MRD status.
Results: The odds of being MRD positive in patients with KIR telomeric (Tel)-A/B genotype were 2.85 times the odds in those with Tel-A/A genotype (P = 0.035). MRD-positive patients were more likely to have KIR2DL5A (P = 0.006) and expressed less activating receptor NKp46 and FASL on their NK cells (P = 0.0074 and P = 0.029, respectively). The odds of being MRD positive increased by 2.01-fold for every percentage increase in NK cells expressing KIR2DL1 in the presence of HLA-C2 ligand (P = 0.034). The quantity of granzyme B inhibitor PI-9 in the leukemia blasts was greater in patients who were MRD positive (P = 0.038). Collectively, five NK cell–related factors (Tel-B–associated KIR2DL5A, NKp46, FASL, granzyme B, and PI-9) are strongly associated with MRD positivity at the end of induction with 100% sensitivity and 80% specificity.
Conclusions: Our data support the hypothesis that NK cells with a strong effector phenotype in the setting of decreased leukemia resistance are associated with better leukemia control. Clin Cancer Res; 20(23); 5986–94. ©2014 AACR.
WHSC1 Promotes Oncogenesis through Regulation of NIMA-Related Kinase-7 in Squamous Cell Carcinoma of the Head and Neck
Authors: Saloura Vassiliki , Cho Hyun-Soo , Kiyotani Kazuma , Alachkar Houda , Zuo Zhixiang , Nakakido Makoto , Tsunoda Tatsuhiko , Seiwert Tanguy , Lingen Mark , Licht Jonathan , Nakamura Yusuke , Hamamoto Ryuji 
Published: October 2014

Abstract
Squamous cell carcinoma of the head and neck (SCCHN) is a relatively common malignancy with suboptimal long-term prognosis, thus new treatment strategies are urgently needed. Over the last decade, histone methyltransferases (HMT) have been recognized as promising targets for cancer therapy, but their mechanism of action in most solid tumors, including SCCHN, remains to be elucidated. This study investigated the role of Wolf–Hirschhorn syndrome candidate 1 (WHSC1), an NSD family HMT, in SCCHN. Immunohistochemical analysis of locoregionally advanced SCCHN, dysplastic, and normal epithelial tissue specimens revealed that WHSC1 expression and dimethylation of histone H3 lysine 36 (H3K36me2) were significantly higher in SCCHN tissues than in normal epithelium. Both WHSC1 expression and H3K36me2 levels were significantly correlated with histologic grade. WHSC1 knockdown in multiple SCCHN cell lines resulted in significant growth suppression, induction of apoptosis, and delay of the cell-cycle progression. Immunoblot and immunocytochemical analyses in SCCHN cells demonstrated that WHSC1 induced H3K36me2 and H3K36me3. Microarray expression profile analysis revealed NIMA-related kinase-7 (NEK7) to be a downstream target gene of WHSC1, and chromatin immunoprecipitation (ChIP) assays showed that NEK7 was directly regulated by WHSC1 through H3K36me2. Furthermore, similar to WHSC1, NEK7 knockdown significantly reduced cell-cycle progression, indicating that NEK7 is a key player in the molecular pathway regulated by WHSC1.
Implications: WHSC1 possesses oncogenic functions in SCCHN and represents a potential molecular target for the treatment of SCCHN. Mol Cancer Res; 13(2); 293–304. ©2014 AACR.
Methylation Analysis of the FAM19A4 Gene in Cervical Scrapes Is Highly Efficient in Detecting Cervical Carcinomas and Advanced CIN2/3 Lesions
Authors: De Strooper Lise M.A. , Meijer Chris J.L.M. , Berkhof Johannes , Hesselink Albertus T. , Snijders Peter J.F. , Steenbergen Renske D.M. , Heideman Daniëlle A.M. 
Published: October 2014

Abstract
Primary testing for human papillomavirus (HPV) in cervical screening requires triage to differentiate women with transient infection from those with persistent infection who require more intensive management given their risk for cervical (pre)cancer. In this study, the clinical performance of a novel methylation marker FAM19A4 for the triage of high-risk (hr)HPV-positive women was evaluated. Using a training-validation set approach, we analyzed a FAM19A4 quantitative methylation-specific PCR (qMSP). The training set comprised hrHPV-positive cervical scrapes of 43 women with cervical intraepithelial neoplasia grade 3 or worse (CIN3+) and 135 women with ≤CIN1. The validation set comprised hrHPV-positive cervical scrapes of 52 women with CIN2+, including 33 CIN3+, 19 CIN2, and 166 women with ≤CIN1. The methylation threshold of FAM19A4 qMSP that gave rise to CIN3+ specificity of 70% in the training set was applied in the validation set. This resulted in CIN3+ sensitivity of 75.8% [95% confidence interval (CI), 61.1–90.4] at 67.0% (95% CI, 60.3–73.8) specificity. Next, the validated qMSP was applied to an independent series of hrHPV-positive cervical scrapes of 22 women with cervical cancer, 29 with advanced CIN2/3 [i.e., women with a known preceding hrHPV infection (PHI) lasting ≥5 years as proxy of longer duration of lesion existence], and 19 with early CIN2/3 (i.e., PHI &lt;5 years). All carcinomas (22/22) and advanced CIN2/3 lesions (29/29) were FAM19A4 methylation–positive, compared with 42.1% (8/19; 95% CI, 19.9–64.3) of early CIN2/3 lesions. In conclusion, FAM19A4 is an attractive triage marker for hrHPV-positive women, with a high reassurance for the detection of cervical carcinoma and advanced CIN2/3 lesions. Cancer Prev Res; 7(12); 1251–7. ©2014 AACR.
Ischemic Electrocardiographic Abnormalities and Prognosis in Decompensated Heart Failure
Authors: Greig Douglas , Austin Peter C. , Zhou Limei , Tu Jack V. , Pang Peter S. , Ross Heather J. , Lee Douglas S. 
Published: October 2014

Background—
Identification of coronary ischemia may enable targeted diagnostic and therapeutic strategies for acute heart failure. We determined the risk of 30-day mortality associated with ischemic ECG abnormalities in patients with acute heart failure.

Methods and Results—

Among 8772 patients (53.4% women, median 78 years [Q1, Q3: 68,84]) presenting with acute heart failure to 86 hospital emergency departments in Ontario, Canada, Q-waves, T-wave inversion, or ST-depression were present in 51.8% of subjects. However, presence of ST-depression was the only finding associated with 30-day mortality with adjusted odds ratio 1.24 (95% confidence interval [CI], 1.02–1.50). Using continuous net reclassification improvement, addition of ST-depression to the Emergency Heart failure Mortality Risk Grade model reclassified 16.9% of patients overall, and 29.3% of those with a history of ischemic heart disease (both
P
<0.001). By adding ST-depression to the model, the Emergency Heart failure Mortality Risk Grade was extended to predict 30-day death with high discrimination (
c
-statistic 0.801), with 0.57% mortality rate in the lowest risk decile. Adjusted odds ratios for 30-day mortality were 2.81 (95% CI, 1.48–5.31;
P
=0.002) in quintile 2, 7.41 (95% CI, 4.13–13.30;
P
<0.001) in quintile 3, and 14.47 (95% CI, 8.20–25.54;
P
<0.001) in quintile 4 compared with the lowest risk quintile. When the highest risk quintile was subdivided into 2 equally sized risk strata (deciles 9 and 10), the adjusted odds ratios for 30-day mortality were 27.20 (95% CI, 15.33–48.27;
P
<0.001) in decile 9 and 58.96 (95% CI, 33.54–103.65;
P
<0.001) in highest risk decile 10.

Conclusions—
Presence of ST-depression on the ECG reclassified risk of 30-day mortality in patients with acute heart failure, identifying both high- and low-risk subsets.
Cardiac Remodeling in Response to 1 Year of Intensive Endurance Training
Authors: Arbab-Zadeh Armin , Perhonen Merja , Howden Erin , Peshock Ronald M. , Zhang Rong , Adams-Huet Beverly , Haykowsky Mark J. , Levine Benjamin D. 
Published: October 2014

Background—
It is unclear whether, and to what extent, the striking cardiac morphological manifestations of endurance athletes are a result of exercise training or a genetically determined characteristic of talented athletes. We hypothesized that prolonged and intensive endurance training in previously sedentary healthy young individuals could induce cardiac remodeling similar to that observed cross-sectionally in elite endurance athletes.

Methods and Results—

Twelve previously sedentary subjects (aged 29±6 years; 7 men and 5 women) trained progressively and intensively for 12 months such that they could compete in a marathon. Magnetic resonance images for assessment of right and left ventricular mass and volumes were obtained at baseline and after 3, 6, 9, and 12 months of training. Maximum oxygen uptake (

max) and cardiac output at rest and during exercise (C
2
H
2
rebreathing) were measured at the same time periods. Pulmonary artery catheterization was performed before and after 1 year of training, and pressure-volume and Starling curves were constructed during decreases (lower body negative pressure) and increases (saline infusion) in cardiac volume. Mean

max rose from 40.3±1.6 to 48.7±2.5 mL/kg per minute after 1 year (
P
<0.00001), associated with an increase in both maximal cardiac output and stroke volume. Left and right ventricular mass increased progressively with training duration and intensity and reached levels similar to those observed in elite endurance athletes. In contrast, left ventricular volume did not change significantly until 6 months of training, although right ventricular volume increased progressively from the outset; Starling and pressure-volume curves approached but did not match those of elite athletes.

Conclusions—
One year of prolonged and intensive endurance training leads to cardiac morphological adaptations in previously sedentary young subjects similar to those observed in elite endurance athletes; however, it is not sufficient to achieve similar levels of cardiac compliance and performance. Contrary to conventional thinking, the left ventricle responds to exercise with initial concentric but not eccentric remodeling during the first 6 to 9 months after commencement of endurance training depending on the duration and intensity of exercise. Thereafter, the left ventricle dilates and restores the baseline mass-to-volume ratio. In contrast, the right ventricle responds to endurance training with eccentric remodeling at all levels of training.