bluuebunny/crossref_metadata_2025_split huggingface dataset:
PARP1 Trapping and DNA Replication Stress Enhance Radiosensitization with Combined WEE1 and PARP Inhibitors
Authors: Parsels Leslie A. , Karnak David , Parsels Joshua D. , Zhang Qiang , Vélez-Padilla Jonathan , Reichert Zachery R. , Wahl Daniel R. , Maybaum Jonathan , O'Connor Mark J. , Lawrence Theodore S. , Morgan Meredith A. 
Published: November 2017

AbstractKRAS mutations in non–small cell lung cancer (NSCLC) cause increased levels of DNA damage and replication stress, suggesting that inhibition of the DNA damage response (DDR) is a promising strategy for radiosensitization of NSCLC. This study investigates the ability of a WEE1 inhibitor (AZD1775) and a PARP inhibitor (olaparib) to radiosensitize KRAS-mutant NSCLC cells and tumors. In addition to inhibiting the DDR, these small-molecule inhibitors of WEE1 and PARP induce DNA replication stress via nucleotide exhaustion and PARP trapping, respectively. As monotherapy, AZD1775 or olaparib alone modestly radiosensitized a panel of KRAS-mutant NSCLC lines. The combination of agents, however, significantly increased radiosensitization. Furthermore, AZD1775-mediated radiosensitization was rescued by nucleotide repletion, suggesting a mechanism involving AZD1775-mediated replication stress. In contrast, radiosensitization by the combination of AZD1775 and olaparib was not rescued by nucleosides. Whereas both veliparib, a PARP inhibitor that does not efficiently trap PARP1 to chromatin, and PARP1 depletion radiosensitized NSCLC cells as effectively as olaparib, which does efficiently trap PARP, only olaparib potentiated AZD1775-mediated radiosensitization. Taken together, these mechanistic data demonstrate that although nucleotide depletion is sufficient for radiosensitization by WEE1 inhibition alone, and inhibition of PARP catalytic activity is sufficient for radiosensitization by olaparib alone, PARP1 trapping is required for enhanced radiosensitization by the combination of WEE1 and PARP inhibitors.Implications: This study highlights DNA replication stress caused by nucleotide depletion and PARP1 trapping as an important mechanism of radiosensitization in KRAS-mutant tumors and supports further development of DNA replication as a therapeutic target. Mol Cancer Res; 16(2); 222–32. ©2017 AACR.
Adipose-Derived VEGF–mTOR Signaling Promotes Endometrial Hyperplasia and Cancer: Implications for Obese Women
Authors: Sahoo Subhransu S. , Lombard Janine M. , Ius Yvette , O'Sullivan Rachel , Wood Lisa G. , Nahar Pravin , Jaaback Kenneth , Tanwar Pradeep S. 
Published: November 2017

Abstract
Obesity is responsible for increased morbidity and mortality in endometrial cancer. Despite the positive correlation of body mass index (BMI) or obesity in endometrial carcinogenesis, the contribution of adipose tissue to the pathogenesis of endometrial hyperplasia and cancer is unclear. This study clarifies the role of adipocytes in the pathogenesis of endometrial cancer by demonstrating that adipocyte-conditioned medium (ACM) increases proliferation, migration, and survival of endometrial cancer cells compared with preadipocyte-conditioned medium (PACM). Comparative cytokine array analysis of ACM and PACM reveal upregulation of a group of cytokines belonging to the VEGF signaling pathway in ACM. VEGF protein expression is upregulated in visceral adipose tissue (VAT) in obese patients, which is correlated with increased tumor growth in an in vivo xenograft model. The increased tumor size is mechanistically associated with the activation of the PI3K/AKT/mTOR pathway, a downstream target of VEGF signaling, and its suppression decreased the growth-promoting effects of VAT on endometrial cancer cells. Similar to the human model systems, pathologic changes in endometrial cells in a hyperphagic obese mouse model are associated with increased body weight and hyperactive mTOR signaling. Analysis of human tissue specimens depicts increased in tumor vasculature and VEGF-mTOR activity in obese endometrial cancer patients compared with nonobese patients. Collectively, these results provide evidence that VEGF-mTOR signaling drives endometrial cell growth leading to hyperplasia and cancer.
Implications: Adipocyte-derived VEGF–mTOR signaling may be an attractive therapeutic target against endometrial cancer in obese women. Mol Cancer Res; 16(2); 309–21. ©2017 AACR.
Targeted Next-Generation Sequencing for Detecting MLL Gene Fusions in Leukemia
Authors: Afrin Sadia , Zhang Christine R.C. , Meyer Claus , Stinson Caedyn L. , Pham Thy , Bruxner Timothy J.C. , Venn Nicola C. , Trahair Toby N. , Sutton Rosemary , Marschalek Rolf , Fink J. Lynn , Moore Andrew S. 
Published: November 2017

Abstract
Mixed lineage leukemia (MLL) gene rearrangements characterize approximately 70% of infant and 10% of adult and therapy-related leukemia. Conventional clinical diagnostics, including cytogenetics and fluorescence in situ hybridization (FISH) fail to detect MLL translocation partner genes (TPG) in many patients. Long-distance inverse (LDI)-PCR, the “gold standard” technique that is used to characterize MLL breakpoints, is laborious and requires a large input of genomic DNA (gDNA). To overcome the limitations of current techniques, a targeted next-generation sequencing (NGS) approach that requires low RNA input was tested. Anchored multiplex PCR-based enrichment (AMP-E) was used to rapidly identify a broad range of MLL fusions in patient specimens. Libraries generated using Archer FusionPlex Heme and Myeloid panels were sequenced using the Illumina platform. Diagnostic specimens (n = 39) from pediatric leukemia patients were tested with AMP-E and validated by LDI-PCR. In concordance with LDI-PCR, the AMP-E method successfully identified TPGs without prior knowledge. AMP-E identified 10 different MLL fusions in the 39 samples. Only two specimens were discordant; AMP-E successfully identified a MLL-MLLT1 fusion where LDI-PCR had failed to determine the breakpoint, whereas a MLL-MLLT3 fusion was not detected by AMP-E due to low expression of the fusion transcript. Sensitivity assays demonstrated that AMP-E can detect MLL-AFF1 in MV4-11 cell dilutions of 10−7 and transcripts down to 0.005 copies/ng.
Implications: This study demonstrates a NGS methodology with improved sensitivity compared with current diagnostic methods for MLL-rearranged leukemia. Furthermore, this assay rapidly and reliably identifies MLL partner genes and patient-specific fusion sequences that could be used for monitoring minimal residual disease. Mol Cancer Res; 16(2); 279–85. ©2017 AACR.
CD137 (4-1BB) Costimulation Modifies DNA Methylation in CD8+ T Cell–Relevant Genes
Authors: Aznar M. Angela , Labiano Sara , Diaz-Lagares Angel , Molina Carmen , Garasa Saray , Azpilikueta Arantza , Etxeberria Iñaki , Sanchez-Paulete Alfonso R. , Korman Alan J. , Esteller Manel , Sandoval Juan , Melero Ignacio 
Published: November 2017

AbstractCD137 (4-1BB) costimulation imprints long-term changes that instruct the ultimate behavior of T cells that have previously experienced CD137 ligation. Epigenetic changes could provide a suitable mechanism for these long-term consequences. Genome-wide DNA methylation arrays were carried out on human peripheral blood CD8+ T lymphocytes stimulated with agonist monoclonal antibody to CD137, including urelumab, which is in phase I/II clinical trials for cancer immunotherapy. Several genes showed consistent methylation patterns in response to CD137 costimulation, which were confirmed by pyrosequencing in a series of healthy donors. CD96, HHLA2, CCR5, CXCR5, and CCL5 were among the immune-related genes regulated by differential DNA methylation, leading to changes in mRNA and protein expression. These genes are also differentially methylated in naïve versus antigen-experienced CD8+ T cells. The transcription factor TCF1 and the microRNA miR-21 were regulated by DNA methylation upon CD137 costimulation. Such gene-expression regulatory factors can, in turn, broaden the effects of DNA methylation by controlling expression of their target genes. Overall, chromatin remodeling is postulated to leave CD137-costimulated T lymphocytes poised to differentially respond upon subsequent antigen recognition. Accordingly, CD137 connects costimulation during priming to genome-wide DNA methylation and chromatin reprogramming. Cancer Immunol Res; 6(1); 69–78. ©2017 AACR.
Atrial Substrate and Triggers of Paroxysmal Atrial Fibrillation in Patients With Obstructive Sleep Apnea
Authors: Anter Elad , Di Biase Luigi , Contreras-Valdes Fernando M. , Gianni Carola , Mohanty Sanghamitra , Tschabrunn Cory M. , Viles-Gonzalez Juan F. , Leshem Eran , Buxton Alfred E. , Kulbak Guy , Halaby Rim N. , Zimetbaum Peter J. , Waks Jonathan W. , Thomas Robert J. , Natale Andrea , Josephson Mark E. 
Published: November 2017

Background
Obstructive sleep apnea (OSA) is associated with atrial remodeling, atrial fibrillation (AF), and increased incidence of arrhythmia recurrence after pulmonary vein (PV) isolation. We aimed to characterize the atrial substrate, including AF triggers in patients with paroxysmal AF and OSA.

Methods and Results

In 86 patients with paroxysmal AF (43 with ≥moderate OSA [apnea–hypopnea index ≥15] and 43 without OSA [apnea–hypopnea index <5]), right atrial and left atrial voltage distribution, conduction velocities, and electrogram characteristics were analyzed during atrial pacing. AF triggers were examined before and after PV isolation and targeted for ablation. Patients with OSA had lower atrial voltage amplitude (right atrial,
P
=0.0005; left atrial,
P
=0.0001), slower conduction velocities (right atrial,
P
=0.02; left atrial,
P
=0.0002), and higher prevalence of electrogram fractionation (
P
=0.0001). The areas of atrial abnormality were consistent among patients, most commonly involving the left atrial septum (32/43; 74.4%). At baseline, the PVs were the most frequent triggers for AF in both groups; however, after PV isolation patients with OSA had increased incidence of additional extra-PV triggers (41.8% versus 11.6%;
P
=0.003). The 1-year arrhythmia-free survival was similar between patients with and without OSA (83.7% and 81.4%, respectively;
P
=0.59). In comparison, control patients with paroxysmal AF and OSA who underwent PV isolation alone without ablation on extra-PV triggers had increased risk of arrhythmia recurrence (83.7% versus 64.0%;
P
=0.003).

Conclusions
OSA is associated with structural and functional atrial remodeling and increased incidence of extra-PV triggers. Elimination of these triggers resulted in improved arrhythmia-free survival.
The Rise of the Sage in Greek and Jewish Antiquity
Authors: Uusimäki Elisa 
Published: November 2017

AbstractThis article explores the emergence of the sage as an exemplar in Greek and Jewish antiquity. Greek philosophical writings and Jewish literary accounts are analysed, the latter including texts written in both Hebrew and Greek. The Greek and Jewish sources are compared in order to highlight (dis)similarities between them. It will be argued that the conception of the sage as an idealized figure and object of emulation originates from the classical Greek world, but it becomes integrated into the Jewish discourse on wisdom and good life in the later Hellenistic period. In spite of this shared element, the portrayals of the sage vary regarding the amount of concreteness and the discursive strategies in which his exemplarity is constructed.
Impacts of the Boreal Spring Indo-Pacific Warm Pool Hadley Circulation on Tropical Cyclone Activity over the Western North Pacific
Authors: Guo Yi-Peng , Tan Zhe-Min 
Published: November 2017

AbstractThis study investigated the impacts of the interannual variability in the boreal spring regional Hadley circulation over the Indo-Pacific warm pool (IPWP) on the tropical cyclone (TC) activity over the western North Pacific (WNP). The principal modes of the interannual variability in the IPWP Hadley circulation were calculated using empirical orthogonal function (EOF) analysis. The leading mode (EOF-1) features cross-equatorial southerly wind anomalies over the Indian Ocean and Maritime Continent and has an evident impact on WNP TC activity during summer. In the summer following a positive phase of the EOF-1, a cyclonic circulation anomaly, with upward motion, positive relative vorticity anomalies, and weak sea level pressure, dominates the WNP, and this favors increased TC genesis. However, large positive vertical wind shear anomalies over the South China Sea and Philippine Sea inhibit the TC intensification. A positive wind–sea surface temperature (SST)–precipitation feedback was found to facilitate the ability of the signal of the EOF-1 to persist until the summer. The westerly wind anomalies converge around 10°N over the WNP, thus increasing precipitation, and this increased precipitation enhances the westerly wind anomalies via a Gill-type response. The strengthened westerly wind anomalies increase total wind speeds, which in turn cool the SST in the Bay of Bengal and the South China Sea, and warm the SST in the eastern WNP, increasing the zonal SST gradient. Consequently, this increased zonal SST gradient further enhances the westerly wind anomalies, strengthens the monsoon trough, and increases the WNP precipitation further. Therefore, the WNP precipitation anomalies are sustained into the summer.
Mapping the Energy Cascade in the North Atlantic Ocean: The Coarse-Graining Approach
Authors: Aluie Hussein , Hecht Matthew , Vallis Geoffrey K. 
Published: November 2017

AbstractA coarse-graining framework is implemented to analyze nonlinear processes, measure energy transfer rates, and map out the energy pathways from simulated global ocean data. Traditional tools to measure the energy cascade from turbulence theory, such as spectral flux or spectral transfer, rely on the assumption of statistical homogeneity or at least a large separation between the scales of motion and the scales of statistical inhomogeneity. The coarse-graining framework allows for probing the fully nonlinear dynamics simultaneously in scale and in space and is not restricted by those assumptions. This paper describes how the framework can be applied to ocean flows. Energy transfer between scales is not unique because of a gauge freedom. Here, it is argued that a Galilean-invariant subfilter-scale (SFS) flux is a suitable quantity to properly measure energy scale transfer in the ocean. It is shown that the SFS definition can yield answers that are qualitatively different from traditional measures that conflate spatial transport with the scale transfer of energy. The paper presents geographic maps of the energy scale transfer that are both local in space and allow quasi-spectral, or scale-by-scale, dynamics to be diagnosed. Utilizing a strongly eddying simulation of flow in the North Atlantic Ocean, it is found that an upscale energy transfer does not hold everywhere. Indeed certain regions near the Gulf Stream and in the Equatorial Countercurrent have a marked downscale transfer. Nevertheless, on average an upscale transfer is a reasonable mean description of the extratropical energy scale transfer over regions of O(103) km in size.
Bridging Public Health and Education: Results of a School-Based Physical Activity Program to Increase Student Fitness
Authors: Barrett-Williams Shannon L. , Franks Padra , Kay Christi , Meyer Adria , Cornett Kelly , Mosier Brian 
Published: November 2017

Objective: Power Up for 30 (PU30) is a schoolwide intervention that encourages schools to provide an additional 30 minutes of physical activity during the school day, beyond physical education. The objective of this study was to evaluate the impact of PU30 on Georgia public elementary schools and their students. Methods: A total of 719 of 1320 public elementary schools in Georgia that were sent a baseline survey about school physical activity during October 2013 to September 2014 completed the survey, 160 of which were asked to complete a second survey. In the interim (March to June 2015), half (80) of these schools implemented the PU30 program. The interim surveys, which were completed during March to June 2015, assessed opportunities for student physical activity and staff member professional development focused on student physical activity. Results: Compared with schools that had not implemented the program, more schools using the PU30 program reported offering before- and after-school physical activity programs. Forty-four of 78 (57%) PU30 schools compared with 20 of 53 (38%) non-PU30 schools offered before-school physical activity programs. Likewise, more PU30 schools than non-PU30 schools offered after-school physical activity programs (35% vs 16%), and a greater proportion of students at PU30 schools compared with non-PU30 schools met fitness benchmarks: recess 5 days per week (91% [288 of 323] vs 80% [273 of 341]), offering ≥11 minutes per day of classroom-based physical activity (39% [53 of 136] vs 25% [47 of 189] for kindergarten through second grade; 20% [37 of 187] vs 6% [9 of 152] for grades 3 through 5), and receiving physical activity–related professional development time (42% [136 of 323] vs 14% [48 of 341]). Conclusions: The surveys provided a statewide picture of the physical activity opportunities offered to students and staff members in Georgia elementary schools and demonstrated the effective use of a comprehensive, multicomponent program to offer more school-based physical activity opportunities and to improve student fitness.
Fitness, Sleep-Disordered Breathing, Symptoms of Depression, and Cognition in Inactive Overweight Children: Mediation Models
Authors: Stojek Monika M. K. , Montoya Amanda K. , Drescher Christopher F. , Newberry Andrew , Sultan Zain , Williams Celestine F. , Pollock Norman K. , Davis Catherine L. 
Published: November 2017

Objectives: We used mediation models to examine the mechanisms underlying the relationships among physical fitness, sleep-disordered breathing (SDB), symptoms of depression, and cognitive functioning. Methods: We conducted a cross-sectional secondary analysis of the cohorts involved in the 2003-2006 project PLAY (a trial of the effects of aerobic exercise on health and cognition) and the 2008-2011 SMART study (a trial of the effects of exercise on cognition). A total of 397 inactive overweight children aged 7-11 received a fitness test, standardized cognitive test (Cognitive Assessment System, yielding Planning, Attention, Simultaneous, Successive, and Full Scale scores), and depression questionnaire. Parents completed a Pediatric Sleep Questionnaire. We used bootstrapped mediation analyses to test whether SDB mediated the relationship between fitness and depression and whether SDB and depression mediated the relationship between fitness and cognition. Results: Fitness was negatively associated with depression ( B = –0.041; 95% CI, –0.06 to –0.02) and SDB ( B = –0.005; 95% CI, –0.01 to –0.001). SDB was positively associated with depression ( B = 0.99; 95% CI, 0.32 to 1.67) after controlling for fitness. The relationship between fitness and depression was mediated by SDB (indirect effect = –0.005; 95% CI, –0.01 to –0.0004). The relationship between fitness and the attention component of cognition was independently mediated by SDB (indirect effect = 0.058; 95% CI, 0.004 to 0.13) and depression (indirect effect = –0.071; 95% CI, –0.01 to –0.17). Conclusions: SDB mediates the relationship between fitness and depression, and SDB and depression separately mediate the relationship between fitness and the attention component of cognition.
Relative cerebral blood volume is associated with collateral status and infarct growth in stroke patients in SWIFT PRIME
Authors: Arenillas Juan F , Cortijo Elisa , García-Bermejo Pablo , Levy Elad I , Jahan Reza , Liebeskind David , Goyal Mayank , Saver Jeffrey L , Albers Gregory W 
Published: November 2017

We aimed to evaluate how predefined candidate cerebral perfusion parameters correlate with collateral circulation status and to assess their capacity to predict infarct growth in patients with acute ischemic stroke (AIS) eligible for endovascular therapy. Patients enrolled in the SWIFT PRIME trial with baseline computed tomography perfusion (CTP) scans were included. RAPID software was used to calculate mean relative cerebral blood volume (rCBV) in hypoperfused regions, and hypoperfusion index ratio (HIR). Blind assessments of collaterals were performed using CT angiography in the whole sample and cerebral angiogram in the endovascular group. Reperfusion was assessed on 27-h CTP; infarct volume was assessed on 27-h magnetic resonance imaging/CT scans. Logistic and rank linear regression models were conducted. We included 158 patients. High rCBV ( p = 0.03) and low HIR ( p = 0.03) were associated with good collaterals. A positive association was found between rCBV and better collateral grades on cerebral angiography ( p = 0.01). Baseline and 27-h follow-up CTP were available for 115 patients, of whom 74 (64%) achieved successful reperfusion. Lower rCBV predicted a higher infarct growth in successfully reperfused patients ( p = 0.038) and in the endovascular treatment group ( p = 0.049). Finally, rCBV and HIR may serve as markers of collateral circulation in AIS patients prior to endovascular therapy. Clinical Trial Registration: Unique identifier: NCT0165746.
Radial vs coccygeal artery Doppler blood pressure measurement in conscious cats
Authors: Zeugswetter Florian K , Tichy Alexander , Weber Katharina 
Published: November 2017

Objectives The aims of the study were to compare the results of systolic blood pressure (SBP) measurements at the radial and coccygeal artery by Doppler ultrasonography and to assess the impact of gender, age, body weight, body condition score (BCS) and stress score on disagreements. Methods Eighty cats were included in this prospective, block randomised crossover trial. Blood pressure measurements were performed at home, during hospitalisation or in a local animal shelter by a single trained observer according to the latest ISFM consensus guidelines. Statistical analysis included Spearman’s correlation and ANOVA. Results Measurement or site order had no effect on blood pressure measurements ( P = 0.157, P = 0.965). Correlation of radial and coccygeal SBP was moderate (rsp = 0.519, P <0.001) and measurements at the tail were by mean 18.7 ± 37 mmHg higher. The differences between the measuring sites were neither correlated with age (rsp = 0.044, P = 0.710) nor with body weight (rsp = 0.122, P = 0.337). A significant effect of BCS ( P = 0.016), but not gender ( P = 0.246) or stress score ( P = 0.424) was identified. Of the 25 cats with a coccygeal SBP ⩾170 mmHg, 14 (56%) were categorised as mildly hypertensive or normotensive when measurements were performed at the forelimb. Conclusions and relevance Choice of the measuring site, coccygeal vs radial artery, has a significant impact on Doppler ultrasonographic SBP results. In many cats, these discrepancies are huge and would certainly affect treatment decisions. Possible explanations include cone-shaped tails, especially in obese cats, leading to distal gapping or slippage of cylindrical cuffs and peripheral pulse pressure amplification. Further studies are urgently needed to clarify whether the discordances are artefacts or have a pathological background.