bluuebunny/crossref_metadata_2025_split huggingface dataset:
Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor–Sensitive and -Resistant Chronic Myeloid Leukemia
Authors: Ben-Batalla Isabel , Erdmann Robert , Jørgensen Heather , Mitchell Rebecca , Ernst Thomas , von Amsberg Gunhild , Schafhausen Philippe , Velthaus Janna L. , Rankin Stephen , Clark Richard E. , Koschmieder Steffen , Schultze Alexander , Mitra Subir , Vandenberghe Peter , Brümmendorf Tim H. , Carmeliet Peter , Hochhaus Andreas , Pantel Klaus , Bokemeyer Carsten , Helgason G. Vignir , Holyoake Tessa L. , Loges Sonja 
Published: November 2016

Abstract
Purpose: BCR-ABL kinase inhibitors are employed successfully for chronic myeloid leukemia (CML) treatment. However, resistant disease and persistence of BCR-ABL1–independent leukemia stem and progenitor cells (LSPC) remain clinical challenges. The receptor tyrosine kinase Axl can mediate survival and therapy resistance of different cancer cells. We investigated the therapeutic potential of Axl inhibition in CML.
Experimental Design: We used primary cells from patients with CML and TKI-sensitive and -resistant BCR-ABL1+ CML cell lines and a novel ponatinib-resistant cell line KCL-22 PonR. We analyzed the effects of genetic and pharmacologic Axl blockade by the small-molecule Axl inhibitor BGB324 in vitro and in vivo. In BCR-ABL1–unmutated cells, we also investigated BGB324 in combination with imatinib.
Results: We demonstrate overexpression of Axl receptor tyrosine kinase in primary cells of patients with CML compared with healthy individuals and a further increase of Axl expression in BCR-ABL TKI-resistant patients. We show that Axl blockage decreased growth of BCR-ABL TKI-sensitive CML cells including CD34+ cells and exerts additive effects with imatinib via inhibition of Stat5 activation. BGB324 also inhibits BCR-ABL TKI-resistant cells, including T315I-mutated and ponatinib-resistant primary cells. BGB324 exerted therapeutic effects in BCR-ABL1 T315I-mutated and ponatinib-resistant preclinical mouse models. Notably, BGB324 does not inhibit BCR-ABL1 and consequently inhibits CML independent of BCR-ABL1 mutational status.
Conclusions: Our data show that Axl inhibition has therapeutic potential in BCR-ABL TKI-sensitive as well as -resistant CML and support the need for clinical trials. Clin Cancer Res; 23(9); 2289–300. ©2016 AACR.
Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis
Authors: Reaves Denise K. , Hoadley Katherine A. , Fagan-Solis Katerina D. , Jima Dereje D. , Bereman Michael , Thorpe Lynnelle , Hicks Jyla , McDonald David , Troester Melissa A. , Perou Charles M. , Fleming Jodie M. 
Published: November 2016

Abstract
Lipolysis-stimulated lipoprotein receptor (LSR) has been found in the plasma membrane and is believed to function in lipoprotein endocytosis and tight junctions. Given the impact of cellular metabolism and junction signaling pathways on tumor phenotypes and patient outcome, it is important to understand how LSR cellular localization mediates its functions. We conducted localization studies, evaluated DNA binding, and examined the effects of nuclear LSR in cells, xenografts, and clinical specimens. We found LSR within the membrane, cytoplasm, and the nucleus of breast cancer cells representing multiple intrinsic subtypes. Chromatin immunoprecipitation (ChIP) showed direct binding of LSR to DNA, and sequence analysis identified putative functional motifs and post-translational modifications of the LSR protein. While neither overexpression of transcript variants, nor pharmacologic manipulation of post-translational modification significantly altered localization, inhibition of nuclear export enhanced nuclear localization, suggesting a mechanism for nuclear retention. Coimmunoprecipitation and proximal ligation assays indicated LSR–pericentrin interactions, presenting potential mechanisms for nuclear-localized LSR. The clinical significance of LSR was evaluated using data from over 1,100 primary breast tumors, which showed high LSR levels in basal-like tumors and tumors from African-Americans. In tumors histosections, nuclear localization was significantly associated with poor outcomes. Finally, in vivo xenograft studies revealed that basal-like breast cancer cells that overexpress LSR exhibited both membrane and nuclear localization, and developed tumors with 100% penetrance, while control cells lacking LSR developed no tumors. These results show that nuclear LSR alters gene expression and may promote aggressive cancer phenotypes.
Implications: LSR functions in the promotion of aggressive breast cancer phenotypes and poor patient outcome via differential subcellular localization to alter cell signaling, bioenergetics, and gene expression. Mol Cancer Res; 15(2); 165–78. ©2016 AACR.
Clinical Outcomes of Posterior Versus Anterior Circulation Infarction With Low National Institutes of Health Stroke Scale Scores
Authors: Kim Joon-Tae , Park Man-Seok , Choi Kang-Ho , Kim Beom Joon , Han Moon-Ku , Park Tai Hwan , Park Sang-Soon , Lee Kyung Bok , Lee Byung-Chul , Yu Kyung-Ho , Oh Mi Sun , Cha Jae Kwan , Kim Dae-Hyun , Nah Hyun-Wook , Lee Jun , Lee Soo Joo , Ko Youngchai , Kim Jae Guk , Park Jong-Moo , Kang Kyusik , Cho Yong-Jin , Hong Keun-Sik , Choi Jay Chol , Kim Dong-Eog , Ryu Wi-Sun , Shin Dong-Ick , Yeo Min-Ju , Kim Wook-Joo , Lee Juneyoung , Lee Ji Sung , Bae Hee-Joon , Saver Jeffrey L. , Cho Ki-Hyun 
Published: November 2016

Background and Purpose—
We compared baseline characteristics and outcomes at 3 months between patients with minor anterior circulation infarction (ACI) versus minor posterior circulation infarction (PCI), including the influence of large vessel disease on outcomes.

Methods—
This study is an analysis of a prospective multicenter registry database in South Korea. Eligibility criteria were patients with ischemic stroke admitted within 7 days of stroke onset, lesions in either anterior or posterior circulation, and National Institutes of Health Stroke Scale score of ≤4 at baseline. Patients were divided into 4 groups for further analysis: minor ACI with and without internal carotid artery/middle cerebral artery large vessel disease and minor PCI with and without vertebrobasilar large vessel disease.

Results—

A total of 7178 patients (65.2±12.6 years) were analyzed in this study, and 2233 patients (31.1%) had disability (modified Rankin Scale score 2–6) at 3 months. Disability was 32.3% in minor PCI and 30.3% in minor ACI (
P
=0.07), and death was 1.3% and 1.5%, respectively (
P
=0.82). In a multivariable logistic regression analysis, minor PCI was significantly associated with disability at 3 months when compared with minor ACI (odds ratio, 1.23; 95% confidence interval, 1.09–1.37;
P
<0.001). In pairwise comparisons, minor PCI with vertebrobasilar large vessel disease was independently associated with disability at 3 months, compared with the other 3 groups.

Conclusions—
Our study showed that minor PCI exhibited more frequent disability at 3 months than minor ACI. Especially, the presence of vertebrobasilar large vessel disease in minor PCI had a substantially higher risk of disability. Our results suggest that minor PCI with vertebrobasilar large vessel disease could require more meticulous care and are important targets for further study.
COOLIST (Cooling for Ischemic Stroke Trial)
Authors: Geurts Marjolein , Petersson Jesper , Brizzi Marco , Olsson-Hau Stefan , Luijckx Gert-Jan , Algra Ale , Dippel Diederik W.J. , Kappelle L. Jaap , van der Worp H. Bart 
Published: November 2016

Background and Purpose—
Animal studies suggest that cooling improves outcome after ischemic stroke. We assessed the feasibility and safety of surface cooling to different target temperatures in awake patients with acute ischemic stroke.

Methods—
A multicenter, randomized, open, phase II, clinical trial, comparing standard treatment with surface cooling to 34.0°C, 34.5°C, or 35.0°C in awake patients with acute ischemic stroke and an National Institutes of Health Stroke Scale score of ≥6, initiated within 4.5 hours after symptom onset and maintained for 24 hours. The primary outcome was feasibility, defined as the proportion of patients who had successfully completed the assigned treatment. Safety was a secondary outcome.

Results—

Inclusion was terminated after 22 patients because of slow recruitment. Five patients were randomized to 34.0°C, 6 to 34.5°C, 5 to 35.0°C (cooling was initiated in 4), and 6 to standard care. No (0%), 1 (17%), and 3 (75%) patients, respectively, completed the assigned treatment (
P
=0.03). No (0%), 2 (33%), and 4 (100%) patients reached the target temperature (
P
=0.01). Pneumonia occurred in 8 cooled patients but not in controls (absolute risk increase, 53%; 95% confidence interval, 28–79%;
P
=0.002).

Conclusions—
In awake patients with acute ischemic stroke, surface cooling is feasible to 35.0°C, but not to 34.5°C and 34.0°C. Cooling is associated with an increased risk of pneumonia.

Clinical Trial Registration—

URL:
http://www.trialregister.nl
. Unique identifier: NTR2616.
Door-to-Imaging Time for Acute Stroke Patients Is Adversely Affected by Emergency Department Crowding
Authors: Reznek Martin A. , Murray Evangelia , Youngren Marguerite N. , Durham Natassia T. , Michael Sean S. 
Published: November 2016

Background and Purpose—
National guidelines call for door-to-imaging time (DIT) within 25 minutes for suspected acute stroke patients. Studies examining factors that affect DIT have focused primarily on stroke-specific care processes and patient-specific factors. We hypothesized that emergency department (ED) crowding is associated with longer DIT.

Methods—
We conducted a retrospective investigation of 1 year of consecutive patients in our prospective Code Stroke registry, which included all ED stroke team activations. The registry and electronic health records were abstracted for 27 potential predictors of DIT, including patient, stroke care process, and ED operational factors. We fit a multivariate logistic regression model and calculated odds ratios and 95% confidence intervals. Second, we constructed a random forest recursive partitioning model to cross-validate our findings and explore the proportional importance of each category of predictor. Our primary outcome was the binary variable of DIT within the 25-minute goal.

Results—
A total of 463 patients met inclusion criteria. In the regression model, ED occupancy rate emerged as a predictor of DIT, with odds ratio of 0.83 (95% confidence interval, 0.75–0.91) of DIT within 25 minutes per 10% absolute increase in ED occupancy rate. The secondary analysis estimated that ED operational factors accounted for nearly 14% of the algorithm’s prediction of DIT.

Conclusions—
ED crowding is associated with reduced odds of meeting DIT goals for acute stroke. In addition to improving stroke-specific processes of care, efforts to reduce ED overcrowding should be considered central to optimizing the timeliness of acute stroke care.
Le rôle du kafīl (garant) dans la gouvernance locale selon les contrats d’affermage fiscal à Tripoli au XVIIe–XVIIIe siècle
Authors: Winter Stefan 
Published: November 2016

This article explores the legal institution of kafāla/kefalet (bondsmanship; surety) and its role in shaping local communal government in Syria in the Ottoman period. Drawing on the shar‘īya court registers of Tripoli (in addition to those of Sayda and Antioch as well as the Başbakanlık archives), it shows how iltizām tax-farming contracts in the 18th century increasingly required a pecuniary guarantee for their discharge to be posted by a third party, an act specific to Ḥanafī jurisprudence but not practised uniformly throughout the region. Whereas in some places the kafāla amounted to little more than a pledge of mutual accountability, or was imposed on a community against its will, it could also be used by foreign merchants or local notables to secure the rights to a given district’s commercial produce in advance. By “investing” in revenue collection concessions, the article concludes, both the southern Lebanese Shihābī emirs and the Maronite village population used the kafāla to acquire a direct financial and ultimately political stake in the rural hinterland of Tripoli, before dispensing once more with the idea of mutual or corporative responsibility once all of the province’s tax farms passed under complete Shihābī control in 1763. Cet article traite de l'institution juridique de kafāla / kefalet (cautionnement) et de son rôle dans la gouvernance communautaire locale en Syrie à l’époque ottomane. S'appuyant sur les registres de tribunal shar‘īya de Tripoli (en plus de ceux de Sayda et d'Antioche, ainsi que sur des documents d’archives Başbakanlık), il tâche à montrer comment les contrats de ferme fiscale iltizām du XVIIIe siècle exigèrent de plus en plus qu’une tierce personne se porte garant pour leur acquittement, un acte spécifique à l’école de jurisprudence ḥanafī mais pas appliqué de façon uniforme à travers la région. Alors que la kafāla ne constitua guère plus qu’une promesse de responsabilité collective dans certains cas, ou qu’elle fut imposée à une communauté particulière contre son gré dans d’autres, elle pouvait également servir à des marchands étrangers ou à des notables locaux pour s’assurer les droits sur la production agricole d’un certain district à l’avance. En « investissant » dans de contrats de perception d’impôt d’autrui, cet article propose en conclusion, les émirs Shihābī du Liban-Sud tout comme la population villageoise maronite ont pu utiliser la kafāla pour acquérir une participation financière directe ainsi qu’un droit de regard politique sur l’hinterland rural de Tripoli, avant d’abandonner de nouveau le principe de responsabilité mutuelle ou corporative une fois que toutes les fermes fiscales de la province furent passé sous le contrôle complet des Shihābī en 1763.
Body size, resident status, handedness and claw originality in Uca rosea (Tweedie, 1937) male fights
Authors: Tina Fahmida Wazed , Jaroensutasinee Mullica , Jaroensutasinee Krisanadej 
Published: November 2016

We tested the effects of body size, resident status, handedness, and claw originality onUca rosea(Tweedie, 1937) male fights. We observed 67 pairs of combats between residents and intruders, recorded fighting duration and winner identity (resident/intruder, larger/smaller), identified handedness (right/left claw) and claw types (original/regenerated claw), and measured carapace width and major claw length. Larger/smaller males were determined based on major claw length instead of carapace width. Results showed that (1) body size and resident status jointly and (2) body size, resident status, handedness and claw types together, affected fighting success. Residents won more combats than intruders regardless of handedness. Original clawed residents won more combats than regenerated clawed intruders. Fighting duration was longer in same claw type (original-original and regenerated-regenerated) combats than in different claw type combats. Carapace width was more strongly correlated with original claw length than with regenerated claw length.
An Acoustic Tomography Technique for Concurrently Observing the Structure of the Atmosphere and Water Bodies
Authors: Finn Anthony , Rogers Kevin 
Published: November 2016

AbstractThe opacity of water to radio waves means there are few, if any, techniques for remotely sensing it and the atmosphere concurrently. However, both these media are transparent to low-frequency sound (<300 Hz), which makes it possible to contemplate systems that take advantage of the natural integration along acoustic paths of signals propagating through both media. This paper proposes—and examines with theoretical analysis—a method that exploits the harmonics generated by the natural signature of a propeller-driven aircraft as it overflies an array of surface and underwater sensors. Correspondence of the projected and observed narrowband acoustic signals, which are monitored synchronously on board the aircraft and by both sensor sets, allows the exact travel time of detected rays to be related to a linear model of the constituent terms of sound speed. These observations may then be inverted using tomography to determine the inhomogeneous structures of both regions. As the signature of the aircraft comprises a series of harmonics between 50 Hz and 1 kHz, the horizontal detection limits of such a system may be up to a few hundred meters, depending on the depth of the sensors, roughness of the water surface, errors due to refraction, and magnitude of the sound field generated by the source aircraft. The approach would permit temperature, wind, and current velocity profiles to be observed both above and below the water’s surface.
The Probability Anomaly Correlation and Calibration of Probabilistic Forecasts
Authors: van den Dool Huug , Becker Emily , Chen Li-Chuan , Zhang Qin 
Published: November 2016

Abstract
An ordinary regression of predicted versus observed probabilities is presented as a direct and simple procedure for minimizing the Brier score (BS) and improving the attributes diagram. The main example applies to seasonal prediction of extratropical sea surface temperature by a global coupled numerical model. In connection with this calibration procedure, the probability anomaly correlation (PAC) is developed. This emphasizes the exact analogy of PAC and minimizing BS to the widely used anomaly correlation (AC) and minimizing mean squared error in physical units.
Efficacy and Safety of Percutaneous Coronary Intervention for Elderly Patients in the Second-Generation Drug-Eluting Stent Era: The SHINANO Registry
Authors: Miura Takashi , Miyashita Yusuke , Motoki Hirohiko , Kobayashi Hideki , Kobayashi Masanori , Nakajima Hiroyuki , Kimura Hikaru , Akanuma Hiroshi , Mawatari Eiichiro , Sato Toshio , Hotta Shoji , Kamiyoshi Yuichi , Maruyama Takuya , Watanabe Noboru , Eisawa Takayuki , Aso Shinichi , Hashizume Naoto , Ebisawa Soichiro , Ikeda Uichi 
Published: November 2016

Background: We evaluated the 1-year outcomes of percutaneous coronary intervention (PCI) for elderly patients (aged ≥ 80 years) in the second-generation drug-eluting stent (DES) era. Methods and Results: Between August 2012 and July 2013, 1923 consecutive patients (mean age, 71 ± 11 years; ≥80 years, 23%; men, 77%) who underwent 2250 elective/urgent PCI procedures were enrolled in the Shinshu Prospective Multicenter Analysis for Elderly Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention registry. The primary end point was major adverse cardiovascular events (MACEs; cardiovascular death, myocardial infarction, and stroke) at 1 year. The 1-year incidence of MACEs, cardiac death, and stroke was significantly higher in elderly patients than in nonelderly patients (12.4% vs 5.3%, P < .0001; 7.8% vs 2.2%, P < .0001; and 2.8% vs 1.3%, P = .033, respectively). However, no significant difference in elective PCI procedures was detected. In elderly patients, the incidence of cardiac death and target lesion revascularization was significantly lower for DES than for non-DES (2.7% vs 10.5%, P = .0001 and 4.1% vs 8.6%, P = .029, respectively). Conclusion: Although elderly patients had a significantly poorer prognosis than younger patients, the adverse events rate was comparable in those patients who underwent elective PCI in the second-generation DES era.
Social and emotional education with Australian Year 7 and 8 middle school students: A pilot study
Authors: Midford Richard , Cahill Helen , Geng Gretchen , Leckning Bernard , Robinson Gary , Te Ava Aue 
Published: November 2016

Objective: This pilot study sought to better understand what can be achieved by an evidence-based classroom social and emotional education programme. Design and Methods: A 10-lesson, classroom-based programme that taught about emotional literacy, personal strengths, coping and problem-solving strategies, stress management, emotional regulation and support seeking was provided to 56 students in Years 7 (13 years) and 8 (14 years) in an Australian middle school. Teachers were trained to deliver the programme, with participatory modelling of each activity. Before and after delivery of the programme, students were surveyed for their social and emotional wellbeing using the Kessler 10 (K10) instrument for non-specific psychological distress; the ‘Internal Assets’, ‘School Resources’ and ‘Cooperation and Communication’ questions from the Resilience and Youth Development Module (RYDM) of the California Healthy Kids Survey (CHKS); and questions developed for this study on class connectedness and social and emotional skills. Subsequent to programme completion, focus groups were conducted with teachers and participating students to gauge programme fidelity, utility and engagement. Results: There was an improvement in psychological distress that approached significance ( t = 2, df = 42, p = .053), although the symptomatic score remained in the range indicative of medium-level distress. Cooperation and communication improved significantly ( t = −2.34, df = 42, p = .024) as did class connectedness ( t = −2.46, df = 43, p = .018). There was no change in individual resilience factors, school protective factors, or social and emotional skills. The focus groups were generally positive about the programme, but indicated fidelity was compromised, mainly because the lesson periods were too short. Conclusion: While this small-scale pilot study has a number of limitations, it does indicate the need to improve the psychological wellbeing of middle school students. The findings also provide evidence that brief social and emotional education programmes can have some positive effects.
Choline Protects Against Intestinal Failure–Associated Liver Disease in Parenteral Nutrition–Fed Immature Rats
Authors: Zhu Jie , Lu Ting , Chen Fei , Yan Junkai , Chen Fan , Zhang Qiaosen , Wang Jifan , Yan Weihui , Yu Tingxi , Tang Qingya , Cai Wei 
Published: November 2016

AbstractBackground: Deficiency of choline, a required nutrient, is related to intestinal failure–associated liver disease (IFALD). Therefore, we aimed to investigate the effects of choline supplementation on IFALD and the underlying mechanisms. Methods: Male Sprague‐Dawley rats (4 weeks old) were fed AIN‐93G chow and administered intravenous 0.9% saline (control), parenteral nutrition (PN), or PN plus intravenous choline (600 mg/kg) for 7 days. We evaluated body weight, hepatic histology, biochemical indicators, triglycerides, oxidative status, methylation levels of peroxisomal proliferator‐activated receptor alpha (PPARα) gene promoter, expression of PPARα and carnitine palmitoyltransferase 1 (CPT1), and levels of choline metabolites. Results: The PN + choline group exhibited improved body weight compared with the PN group. PN impaired hepatic function, increased hepatic triglycerides, induced dyslipidemia, enhanced reactive oxygen species and malondialdehyde, and reduced total antioxidant capacity. The PN group had higher pathologic scores than the control group. These results were prevented by choline administration. Compared with the control group, PN increased PPARα promoter methylation and hepatic betaine concentration, reduced hepatic choline and phosphatidylcholine (PC) levels, decreased plasma choline and betaine concentrations, and downregulated PPARα and CPT1 mRNA and protein expression. Choline supplementation elevated hepatic choline and PC levels and enhanced plasma choline, betaine, and PC concentrations but reduced hepatic betaine level, reversed PPARα promoter hypermethylation, and upregulated PPARα and CPT1 mRNA and protein expression in PN‐fed rats, compared with rats receiving PN alone. Conclusion: Choline addition to PN may prevent IFALD by reducing oxidative stress, enhancing hepatic fat export, and promoting fatty acid catabolism in immature rats receiving PN.