bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lorlatinib Treatment Elicits Multiple On- and Off-Target Mechanisms of Resistance in ALK-Driven Cancer
Authors: Redaelli Sara , Ceccon Monica , Zappa Marina , Sharma Geeta G. , Mastini Cristina , Mauri Mario , Nigoghossian Marion , Massimino Luca , Cordani Nicoletta , Farina Francesca , Piazza Rocco , Gambacorti-Passerini Carlo , Mologni Luca 
Published: October 2018

Abstract

Targeted therapy changed the standard of care in ALK-dependent tumors. However, resistance remains a major challenge. Lorlatinib is a third-generation ALK inhibitor that inhibits most ALK mutants resistant to current ALK inhibitors. In this study, we utilize lorlatinib-resistant anaplastic large cell lymphoma (ALCL), non–small cell lung cancer (NSCLC), and neuroblastoma cell lines in vitro and in vivo to investigate the acquisition of resistance and its underlying mechanisms. ALCL cells acquired compound ALK mutations G1202R/G1269A and C1156F/L1198F in vitro at high drug concentrations. ALCL xenografts selected in vivo showed recurrent N1178H (5/10 mice) and G1269A (4/10 mice) mutations. Interestingly, intracellular localization of NPM/ALKN1178H skewed toward the cytoplasm in human cells, possibly mimicking overexpression. RNA sequencing of resistant cells showed significant alteration of PI3K/AKT and RAS/MAPK pathways. Functional validation by small-molecule inhibitors confirmed the involvement of these pathways in resistance to lorlatinib. NSCLC cells exposed in vitro to lorlatinib acquired hyperactivation of EGFR, which was blocked by erlotinib to restore sensitivity to lorlatinib. In neuroblastoma, whole-exome sequencing and proteomic profiling of lorlatinib-resistant cells revealed a truncating NF1 mutation and hyperactivation of EGFR and ErbB4. These data provide an extensive characterization of resistance mechanisms that may arise in different ALK-positive cancers following lorlatinib treatment.

Significance:
High-throughput genomic, transcriptomic, and proteomic profiling reveals various mechanisms by which multiple tumor types acquire resistance to the third-generation ALK inhibitor lorlatinib.
Regulation of eIF4F Translation Initiation Complex by the Peptidyl Prolyl Isomerase FKBP7 in Taxane-resistant Prostate Cancer
Authors: Garrido Marine F. , Martin Nicolas J.-P. , Bertrand Matthieu , Gaudin Catherine , Commo Frédéric , El Kalaany Nassif , Al Nakouzi Nader , Fazli Ladan , Del Nery Elaine , Camonis Jacques , Perez Franck , Lerondel Stéphanie , Le Pape Alain , Compagno Daniel , Gleave Martin , Loriot Yohann , Désaubry Laurent , Vagner Stéphan , Fizazi Karim , Chauchereau Anne 
Published: October 2018

AbstractPurpose:Targeted therapies that use the signaling pathways involved in prostate cancer are required to overcome chemoresistance and improve treatment outcomes for men. Molecular chaperones play a key role in the regulation of protein homeostasis and are potential targets for overcoming chemoresistance.Experimental Design: We established 4 chemoresistant prostate cancer cell lines and used image-based high-content siRNA functional screening, based on gene-expression signature, to explore mechanisms of chemoresistance and identify new potential targets with potential roles in taxane resistance. The functional role of a new target was assessed by in vitro and in vivo silencing, and mass spectrometry analysis was used to identify its downstream effectors.Results:We identified FKBP7, a prolyl-peptidyl isomerase overexpressed in docetaxel-resistant and in cabazitaxel-resistant prostate cancer cells. This is the first study to characterize the function of human FKBP7 and explore its role in cancer. We discovered that FKBP7 was upregulated in human prostate cancers and its expression correlated with the recurrence observed in patients receiving docetaxel. FKBP7 silencing showed that FKBP7 is required to maintain the growth of chemoresistant cell lines and chemoresistant tumors in mice. Mass spectrometry analysis revealed that FKBP7 interacts with eIF4G, a component of the eIF4F translation initiation complex, to mediate the survival of chemoresistant cells. Using small-molecule inhibitors of eIF4A, the RNA helicase component of eIF4F, we were able to kill docetaxel- and cabazitaxel-resistant cells.Conclusions:Targeting FKBP7 or the eIF4G-containing eIF4F translation initiation complex could be novel therapeutic strategies to eradicate taxane-resistant prostate cancer cells.
Clinically Relevant and Minimally Invasive Tumor Surveillance of Pediatric Diffuse Midline Gliomas Using Patient-Derived Liquid Biopsy
Authors: Panditharatna Eshini , Kilburn Lindsay B. , Aboian Mariam S. , Kambhampati Madhuri , Gordish-Dressman Heather , Magge Suresh N. , Gupta Nalin , Myseros John S. , Hwang Eugene I. , Kline Cassie , Crawford John R. , Warren Katherine E. , Cha Soonmee , Liang Winnie S. , Berens Michael E. , Packer Roger J. , Resnick Adam C. , Prados Michael , Mueller Sabine , Nazarian Javad 
Published: October 2018

Abstract

Purpose:
Pediatric diffuse midline glioma (DMG) are highly malignant tumors with poor clinical outcomes. Over 70% of patients with DMG harbor the histone 3 p.K27M (H3K27M) mutation, which correlates with a poorer clinical outcome, and is also used as a criterion for enrollment in clinical trials. Because complete surgical resection of DMG is not an option, biopsy at presentation is feasible, but rebiopsy at time of progression is rare. While imaging and clinical-based disease monitoring is the standard of care, molecular-based longitudinal characterization of these tumors is almost nonexistent. To overcome these hurdles, we examined whether liquid biopsy allows measurement of disease response to precision therapy.

Experimental Design:
We established a sensitive and specific methodology that detects major driver mutations associated with pediatric DMGs using droplet digital PCR (n = 48 subjects, n = 110 specimens). Quantification of circulating tumor DNA (ctDNA) for H3K27M was used for longitudinal assessment of disease response compared with centrally reviewed MRI data.

Results:
H3K27M was identified in cerebrospinal fluid (CSF) and plasma in 88% of patients with DMG, with CSF being the most enriched for ctDNA. We demonstrated the feasibility of multiplexing for detection of H3K27M, and additional driver mutations in patient's tumor and matched CSF, maximizing the utility of a single source of liquid biome. A significant decrease in H3K27M plasma ctDNA agreed with MRI assessment of tumor response to radiotherapy in 83% (10/12) of patients.

Conclusions:
Our liquid biopsy approach provides a molecularly based tool for tumor characterization, and is the first to indicate clinical utility of ctDNA for longitudinal surveillance of DMGs.
Regional Variation in Fundamental Frequency of American English Vowels
Authors: Jacewicz Ewa , Fox Robert Allen 
Published: October 2018

Abstract
We examined whether the fundamental frequency (f0) of vowels is influenced by regional variation, aiming to (1) establish how the relationship between vowel height and f0 (“intrinsic f0”) is utilized in regional vowel systems and (2) determine whether regional varieties differ in their implementation of the effects of phonetic context on f0 variations. An extended set of acoustic measures explored f0 in vowels in isolated tokens (experiment 1) and in connected speech (experiment 2) from 36 women representing 3 different varieties of American English. Regional differences were found in f0 shape in isolated tokens, in the magnitude of intrinsic f0 difference between high and low vowels, in the nature of f0 contours in stressed vowels, and in the completion of f0 contours in the context of coda voicing. Regional varieties utilize f0 control in vowels in different ways, including regional f0 ranges and variation in f0 shape.
Antiplatelet Therapy in Primary Spontaneous and Oral Anticoagulation–Associated Intracerebral Hemorrhage
Authors: Sprügel Maximilian I. , Kuramatsu Joji B. , Gerner Stefan T. , Sembill Jochen A. , Beuscher Vanessa D. , Hagen Manuel , Roeder Sebastian S. , Lücking Hannes , Struffert Tobias , Dörfler Arnd , Schwab Stefan , Huttner Hagen B. 
Published: October 2018

Background and Purpose—
This study determined the influence of concomitant antiplatelet therapy (APT) on hematoma characteristics and outcome in primary spontaneous intracerebral hemorrhage (ICH), vitamin K antagonist (VKA)- and non–VKA oral anticoagulant-associated ICH.

Methods—
Data of retrospective cohort studies and a prospective single-center study were pooled. Functional outcome, mortality, and radiological characteristics were defined as primary and secondary outcomes. Propensity score matching and logistic regression analyses were performed to determine the association between single or dual APT and hematoma volume.

Results—

A total of 3580 patients with ICH were screened, of whom 3545 with information on APT were analyzed. Three hundred forty-six (32.4%) patients in primary spontaneous ICH, 260 (11.4%) in VKA-ICH, and 30 (16.0%) in non–VKA oral anticoagulant-associated ICH were on APT, and these patients had more severe comorbidities. After propensity score matching VKA-ICH patients on APT presented with less favorable functional outcome (modified Rankin Scale score, 0–3; APT, 48/202 [23.8%] versus no APT, 187/587 [31.9%];
P
=0.030) and higher mortality (APT, 103/202 [51.0%] versus no APT, 237/587 [40.4%];
P
=0.009), whereas no significant differences were present in primary spontaneous ICH and non–VKA oral anticoagulant-associated ICH. In VKA-ICH, hematoma volume was significantly larger in patients with APT (21.9 [7.4–61.4] versus 15.7 [5.7–44.5] mL;
P
=0.005). Multivariable regression analysis revealed an association of APT and larger ICH volumes (odds ratio, 1.80 [1.20–2.70];
P
=0.005), which was more pronounced in dual APT and supratherapeutically anticoagulated patients.

Conclusions—
APT does not affect ICH characteristics and outcome in primary spontaneous ICH patients; however, it is associated with larger ICH volume and worse functional outcome in VKA-ICH, presumably by additive antihemostatic effects. Combination of anticoagulation and APT should, therefore, be diligently evaluated and restricted to the shortest possible time frame.
Oxidized Low-Density Lipoprotein to High-Density Lipoprotein Ratio Predicts Recurrent Stroke in Minor Stroke or Transient Ischemic Attack
Authors: Wang Anxin , Li Shiyu , Zhang Nan , Dai Liye , Zuo Yingting , Wang Yilong , Meng Xia , Wang Yongjun 
Published: October 2018

Background and Purpose—
Oxidized low-density lipoprotein (oxLDL) level is thought to be associated with recurrent stroke. We aimed to investigate the association between oxLDL to high-density lipoprotein (HDL) ratio and recurrent stroke in patients with minor stroke or transient ischemic attack.

Methods—
The study included 3019 patients with minor ischemic stroke or high-risk transient ischemic attack from the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events). Baseline oxLDL and HDL levels were measured. The primary outcome was any stroke within 90 days. The secondary outcomes included any stroke within 1 year and ischemic stroke and combined vascular events within 90 days and 1 year. The association between oxLDL/HDL and recurrent stroke was analyzed by using Cox proportional hazards.

Results—

Patients in the highest oxLDL/HDL quartile had a higher risk of recurrent stroke within 90 days (hazards ratio, 1.50; 95% CI, 1.08–2.08) compared with the lowest quartile after adjusting relevant confounding factors (
P
=0.02). Similar results were found for secondary outcomes (
P
<0.05 for all). There were no significant interaction between oxLDL/HDL and use of statins agents.

Conclusions—
Higher serum oxLDL/HDL level in minor stroke or transient ischemic attack was associated with increased risk of recurrent stroke in 90 days and 1 year. OxLDL/HDL may act as a powerful indicator of recurrent stroke in patients with minor stroke or transient ischemic attack.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00979589.
Induced Hypertension in Preventing Cerebral Infarction in Delayed Cerebral Ischemia After Subarachnoid Hemorrhage
Authors: Haegens N. Marlou , Gathier Celine S. , Horn Janneke , Coert Bert A. , Verbaan Dagmar , van den Bergh Walter M. 
Published: October 2018

Background and Purpose—
Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage. If clinical signs of DCI occur, induced hypertension is a plausible but unproven therapeutic intervention. There is clinical equipoise if the use of hypertension induction is useful or not with the consequence that this strategy is irregularly used. We explored the effect of blood pressure augmentation in preventing cerebral infarction in patients with clinical signs of DCI.

Methods—
We performed a retrospective observational study, totaling 1647 patients with aneurysmal subarachnoid hemorrhage admitted at 3 academic hospitals in the Netherlands between 2006 and 2015. To study the primary outcome DCI related cerebral infarcts, we only included patients with no cerebral infarct at the time of onset of clinical signs of DCI. Cox regression was used to test the association between induced hypertension after onset of clinical signs of DCI and the occurrence of DCI related cerebral infarcts. Logistic regression was used to relate hypertension induction with poor outcome after 3 months, defined as a modified Rankin score >3. Results were adjusted for treatment center and baseline characteristics.

Results—
Clinical signs of DCI occurred in 479 (29%) patients of whom 300 without cerebral infarction on computed tomography scan at that time. Of these 300 patients, 201 (67%) were treated with hypertension induction and 99 were not. Of the patients treated with hypertension induction, 41 (20%) developed a DCI related cerebral infarct compared with 33 (33%) with no induced hypertension: adjusted hazard ratio, 0.59; 95% CI, 0.35 to 0.99. Hypertension induction also prevented poor outcome: adjusted odds ratio, 0.27; 95% CI, 0.14 to 0.55.

Conclusions—
Hypertension induction seems an effective strategy for preventing DCI related cerebral infarcts if not already present at the time of onset of clinical signs of DCI. This may lead to a reduction in poor clinical outcome.
C-Reactive Protein, Plasma Amyloid-β Levels, and Their Interaction With Magnetic Resonance Imaging Markers
Authors: Hilal Saima , Ikram M. Arfan , Verbeek Marcel M. , Franco Oscar H. , Stoops Erik , Vanderstichele Hugo , Niessen Wiro J. , Vernooij Meike W. 
Published: October 2018

Background and Purpose—
Inflammation is involved in the pathogenesis of large artery atherosclerosis, ischemic stroke, and Alzheimer dementia. However, the role of inflammation in cerebral small vessel disease and neurodegeneration remains poorly understood. We hypothesize that CRP (C-reactive protein) is associated with brain structural changes and may interact with amyloid to produce vascular and degenerative damage. We examined the association of CRP levels with imaging markers of cerebral small vessel disease and neurodegeneration. Furthermore, we studied the association of CRP with plasma Aβ (amyloid-β) levels and their joint effects with imaging markers.

Methods—
We included 2814 persons (mean age, 56.9 years; 44.8% women) from the Rotterdam Study with complete data on CRP and 1.5 T brain magnetic resonance imaging scans. Aβ levels were measured in a subsample (n=736). Markers of cerebral small vessel disease included lacunes, white matter hyperintensities, microbleeds, and enlarged perivascular spaces. Neurodegeneration was assessed by smaller volumes of gray matter, white matter, and hippocampus. Plasma levels of Aβ1–38, Aβ1–40, and Aβ1–42 were assessed using ELISA.

Results—

Higher CRP levels were associated with larger white matter hyperintensities volume (β=0.07; 95% CI, 0.00–0.13), increasing lacunar (rate ratios, 1.61; 95% CI, 1.19–2.19), enlarged perivascular spaces (rate ratios, 1.01; 95% CI, 1.00–1.03), and deep/infratentorial microbleeds (rate ratios, 1.30; 95% CI, 1.00–1.69) counts. People with high CRP levels had small gray matter volume. We also found significant interaction between CRP and Aβ such that among persons in higher tertiles of Aβ1–42, a strong association was observed between CRP and lacunar (
P
interaction, 0.004), enlarged perivascular spaces (
P
interaction, 0.002), and microbleed counts (
P
interaction, <0.001). Similarly, among persons in higher tertile of Aβ1–38, a strong association was observed between CRP and microbleed counts (
P
interaction, 0.004).

Conclusions—
Higher CRP levels were associated with subclinical markers of cerebral small vessel disease and neurodegeneration. This effect was augmented by an interaction between CRP and Aβ levels. Future longitudinal studies focusing on joint effects of CRP and Aβ on progression of magnetic resonance imaging markers and cognitive decline are warranted.
PETROL FİYATLARI VE İSTİHDAM İLİŞKİSİ: G7 ÜLKELERİ ÖRNEKLEMİNDE PANEL VERİ ANALİZİ
Authors: SARAÇ Şenay , YAĞLIKARA Aykut 
Published: October 2018

Bu
çalışmanın amacı petrol fiyatları ile istihdam arasındaki ilişkiyi her biri net
petrol ithalatçısı olan G7 ülkeleri örnekleminde panel veri analiz yöntemiyle
incelemektir. Bu kapsamda 1986-2014 dönemine ait yıllık ham petrol fiyatları ve
istihdam verileri kullanılarak gerçekleştirilen analizde söz konusu ülkeler
için petrol fiyatları ile istihdam oranları arasında eşbütünleşme ve
nedensellik ilişkisinin varlığı tespit edilmiştir.

Günümüz
koşullarında sanayi üretiminin en önemli girdisi enerji tüketiminden
kaynaklanan maliyetler olup petrol fiyatları bu maliyetlerin ortaya konmasında
önemli bir gösterge niteliği taşımaktadır. Bu nedenle petrol fiyatları ile
makroekonomik değişkenler arasındaki ilişki birçok çalışmada ele alınmıştır.&nbsp;
DÖNÜŞTÜRÜCÜ LİDERLİĞİN İÇ GİRİŞİMCİLİK DAVRANIŞINA ETKİSİ: BOLU İLİNDE BİR ARAŞTIRMA
Authors: BÜYÜKYILMAZ Ozan , KAYIŞ Musa 
Published: October 2018

Bu çalışmada dönüştürücü
liderlik ile iç girişimcilik arasındaki ilişki incelenmektedir. Çalışmanın
amacı, dönüştürücü liderlik uygulamalarının çalışanların iç girişimcilik
davranışları üzerindeki etkisini belirleyebilmektir. Çalışmada dönüştürücü
liderliğin dört boyutunun (idealleştirerek etkileme, ilham verme, entelektüel
teşvik ve bireysel ilgi) iç girişimcilik davranışlarını (risk alma,
yenilikçilik, proaktiflik, özerklik ve bireysel ağ genişletme) etkileme
derecesi araştırılmaktadır. Bu amaç için Bolu ilinde faaliyet gösteren dört
farklı işletmedeki 313 çalışan üzerinde bir araştırma gerçekleştirilmiştir.
Araştırmada kullanılan veriler anket yöntemi kullanılarak elde edilmiştir.
Hipotezler ise regresyon analizi ile test edilmiştir. Çalışmanın sonucunda,
dönüştürücü liderliğin idealleştirerek etkileme, entelektüel teşvik ve bireysel
ilgi boyutlarının farklı iş girişimcilik boyutlarını olumlu yönde etkilediği
belirlenmiştir. Buna karşılık dönüştürücü liderliğin ilham verme boyutunun iç
girişimcilik davranışları üzerinde bir etkisi bulunamamıştır.
Demonstration with Special TCI-15 Datasets of Potential Impacts of New-Generation Satellite Atmospheric Motion Vectors on Navy Regional and Global Models
Authors: Elsberry Russell L. , Hendricks Eric A. , Velden Christopher S. , Bell Michael M. , Peng Melinda , Casas Eleanor , Zhao Qingyun 
Published: October 2018

Abstract
A dynamic initialization assimilation scheme is demonstrated utilizing rapid-scan atmospheric motion vectors (AMVs) at 15-min intervals to simulate the real-time capability that now exists from the new generation of geostationary meteorological satellites. The impacts of these AMVs are validated with special Tropical Cyclone Intensity Experiment (TCI-15) datasets during 1200–1800 UTC 4 October leading up to a NASA WB-57 eyewall crossing of Hurricane Joaquin. Incorporating the AMV fields in the Spline Analysis at Mesoscale Utilizing Radar and Aircraft Instrumentation (SAMURAI) COAMPS Dynamic Initialization (SCDI) means there are 30 and 90 time steps on the 15- and 5-km grids, respectively, during which the mass fields are adjusted to these AMV-based wind increments during each 15-min assimilation period. The SCDI analysis of the three-dimensional vortex structure of Joaquin at 1800 UTC 4 October closely replicates the vortex tilt analyzed from the High-Definition Sounding System (HDSS) dropwindsondes. Vertical wind shears based on the AMVs at 15-min intervals are well correlated with the extreme rapid decay, an interruption of that rapid decay, and the subsequent period of constant intensity of Joaquin. Utilizing the SCDI analysis as the initial conditions for two versions of the COAMPS-TC model results in an accurate 72-h prediction of the interruption of the rapid decay and the period of constant intensity. Upscaling a similar SCDI analysis based on the 15-min interval AMVs provides a more realistic intensity and structure of Tropical Storm Joaquin for the initial conditions of the Navy Global Environmental Model (NAVGEM) than the synthetic TC vortex used operationally. This demonstration for a single 6-h period of AMVs indicates the potential for substantial impacts when an end-to-end cycling version is developed.
Associations of Diabetes-Related Distress and Depressive Symptoms With Glycemic Control in Korean Americans With Type 2 Diabetes
Authors: Jeong Mihyun , Reifsnider Elizabeth 
Published: October 2018

Purpose The purpose of this study was to investigate the associations of diabetes-related distress and depressive symptoms with glycemic control in Korean Americans (KAs) with type 2 diabetes mellitus (T2DM). Methods The cross-sectional, correlational descriptive study explored glycemic control in KA. A total of 119 KA adults with T2DM were recruited from Korean communities in Arizona between July and November 2016. Data were collected by a finger-stick glucose test for A1C, the Diabetes Distress Scale for diabetes-related distress, the Center for Epidemiological Studies Depression for depressive symptoms, and sociodemographics. Height and weight were measured to calculate body mass index. Descriptive statistics, bivariate correlation, and multiple linear regression analyses were performed. Results The total score for diabetes-related distress was positively associated with A1C in both unadjusted and adjusted models, while depressive symptoms were not associated with glycemic control regardless of analysis methods. In the further analysis of the 4 subscales of diabetes-related distress, only regimen-related distress was a significant predictor of poor glycemic control after adjusting for covariates. Emotional burden was not associated with glycemic control, even though there was a weak but significant correlation between emotional burden and glycemic control. Conclusions Diabetes-related distress and depressive symptoms should be recognized as different psychological aspects in T2DM, and individual-centered approaches should be used for diabetes self-management education and support. In addition, diabetes-focused psychological interventions and culturally tailored diabetes self-management programs should be included in comprehensive education and support for KAs with T2D to achieve good glycemic control.