bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors
Authors: Ortiz-Cuaran Sandra , Scheffler Matthias , Plenker Dennis , Dahmen llona , Scheel Andreas H. , Fernandez-Cuesta Lynnette , Meder Lydia , Lovly Christine M. , Persigehl Thorsten , Merkelbach-Bruse Sabine , Bos Marc , Michels Sebastian , Fischer Rieke , Albus Kerstin , König Katharina , Schildhaus Hans-Ulrich , Fassunke Jana , Ihle Michaela A. , Pasternack Helen , Heydt Carina , Becker Christian , Altmüller Janine , Ji Hongbin , Müller Christian , Florin Alexandra , Heuckmann Johannes M. , Nuernberg Peter , Ansén Sascha , Heukamp Lukas C. , Berg Johannes , Pao William , Peifer Martin , Buettner Reinhard , Wolf Jürgen , Thomas Roman K. , Sos Martin L. 
Published: June 2016

Abstract
Purpose: To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686).
Experimental Design: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models.
Results: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRASG12S mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS.
Conclusions: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies. Clin Cancer Res; 22(19); 4837–47. ©2016 AACR.
Cross-Stratification and Differential Risk by Breast Cancer Index and Recurrence Score in Women with Hormone Receptor–Positive Lymph Node–Negative Early-Stage Breast Cancer
Authors: Sestak Ivana , Zhang Yi , Schroeder Brock E. , Schnabel Catherine A. , Dowsett Mitch , Cuzick Jack , Sgroi Dennis 
Published: June 2016

Abstract
Purpose: Previous results from the TransATAC study demonstrated that both the Breast Cancer Index (BCI) and the OncotypeDX Recurrence Score (RS) added significant prognostic information to clinicopathologic factors over a 10-year period. Here, we examined cross-stratification between BCI and RS to directly compare their prognostic accuracy at the individual patient level.
Experimental Design: A total of 665 patients with hormone receptor–positive (HR+) and lymph node–negative disease were included in this retrospective analysis. BCI and RS risk groups were determined using predefined clinical cut-off points. Kaplan–Meier estimates of 10-year risk of distant recurrence (DR) and log-rank tests were used to examine cross-stratification between BCI and RS.
Results: As previously reported, both RS and BCI were significantly prognostic in years 0 to 10. BCI provided significant additional prognostic information to the Clinical Treatment Score (CTS) plus RS (ΔLR-χ2 = 11.09; P &lt; 0.001), whereas no additional prognostic information was provided by RS to CTS plus BCI (ΔLR-χ2 = 2.22; P = 0.1). Restratification by BCI of the low and intermediate RS risk groups led to subgroups with significantly different DR rates (P &lt; 0.001 and P = 0.003, respectively). In contrast, restratified subgroups created by RS of BCI risk groups did not differ significantly.
Conclusions: In this retrospective analysis, BCI demonstrated increased prognostic accuracy versus RS. Notably, BCI identified subsets of RS low and RS intermediate risk patients with significant and clinically relevant rates of DR. These results indicate that additional subsets of women with HR+, lymph node–negative breast cancer identified by BCI may be suitable candidates for adjuvant chemotherapy or extended endocrine therapy. Clin Cancer Res; 22(20); 5043–8. ©2016 AACR.
See related commentary by Brufsky and Davidson, p. 4963
The Prevalence and Significance of the Early Repolarization Pattern in Sudden Arrhythmic Death Syndrome Families
Authors: Mellor Greg , Nelson Christopher P. , Robb Claire , Raju Hariharan , Wijeyeratne Yanushi , Hengstenberg Christian , Reinhard Wibke , Papadakis Michael , Sharma Sanjay , Samani Nilesh J. , Behr Elijah R. 
Published: June 2016

Background—
The early repolarization (ER) pattern is associated with sudden death and has been shown to be heritable. Its significance when identified in families affected by sudden arrhythmic death syndrome (SADS) remains unclear.

Methods and Results—
We analyzed 12-lead ECGs of 401 first-degree relatives of individuals who had died from SADS. The prevalence of ER patterns was compared with family-clustered controls. ER was more common in SADS family members than in controls (21% versus 8%; odds ratio: 5.14; 95% confidence interval, 3.37–7.84) independent of the presence of a familial cardiac diagnosis. Both ascending and horizontal ER patterns were more common. In addition, ER was investigated for associations with findings from ajmaline provocation (n=332), exercise ECG (n=304), and signal-averaged ECG (n=118) when performed. ER was associated with a trend toward late depolarization, in general was suppressed with exercise and was unaffected by ajmaline. Inferior and horizontal patterns were, however, more likely to persist during exercise. Augmentation of ER with ajmaline was rare.

Conclusions—
The ER pattern is more common in SADS family members than controls adjusted in particular for relatedness. The increased prevalence is irrespective of ER subtype and the presence of other inherited arrhythmia syndromes. ER may therefore represent an underlying heritable arrhythmia syndrome or risk factor for sudden death in the context of other cardiac pathology. The differing response of ER subtypes to exercise and ajmaline provocation suggests underlying mechanisms of both abnormal repolarization and depolarization.
Dynamic Feedback of Aerosol Effects on the East Asian Summer Monsoon
Authors: Chen Jen-Ping , Chen I-Jen , Tsai I-Chun 
Published: June 2016

Abstract
The influence of present-day anthropogenic aerosols on the summer monsoon over the East Asia region was simulated using the Community Earth System Model coupled with a slab ocean model. The simulations revealed significant radiative forcing from anthropogenic aerosols and associated changes in clouds over East Asia and the northwestern Pacific; however, their spatial patterns differed from the exhibited surface temperature and precipitation responses. Two major dynamic feedback mechanisms were identified to explain such discrepancies. The wind–evaporation–sea surface temperature (WES) feedback, triggered by an initial cooling over the midlatitude sea surface, induced an equatorward expansion of ocean cooling through strengthened trade winds. The sea surface cooling excited a meridional wave pattern similar to the Pacific–Japan teleconnection pattern. Although the aerosol effect generally caused weakening in summer monsoon strength and regional precipitation over East Asia, precipitation increases were seen over the locations of the midlatitude mei-yu front and around the tropics. These precipitation increases are primarily associated with the WES feedback and teleconnection patterns. The aerosol effect also reached the upper troposphere, causing an equatorward shift of the jet stream over East Asia and the northwestern Pacific, indicating a much broader scale of teleconnection.
Hurricane GPROF: An Optimized Ocean Microwave Rainfall Retrieval for Tropical Cyclones
Authors: Brown Paula J. , Kummerow Christian D. , Randel David L. 
Published: June 2016

AbstractThe Goddard profiling algorithm (GPROF) is an operational passive microwave retrieval that uses a Bayesian scheme to estimate rainfall. GPROF 2014 retrieves rainfall and hydrometeor vertical profile information based upon a database of profiles constructed to be simultaneously consistent with Tropical Rainfall Measuring Mission (TRMM) precipitation radar (PR) and TRMM Microwave Imager (TMI) observations. A small number of tropical cyclones are in the current database constructed from one year of TRMM data, resulting in the retrieval performing relatively poorly for these systems, particularly for the highest rain rates. To address this deficiency, a new database focusing specifically on hurricanes but consisting of 9 years of TRMM data is created. The new database and retrieval procedure for TMI and GMI is called Hurricane GPROF. An initial assessment of seven tropical cyclones shows that Hurricane GPROF provides a better estimate of hurricane rain rates than GPROF 2014. Hurricane GPROF rain-rate errors relative to the PR are reduced by 20% compared to GPROF, with improvements in the lowest and highest rain rates especially. Vertical profile retrievals for four hydrometeors are also enhanced, as error is reduced by 30% compared to the GPROF retrieval, relative to PR estimates. When compared to the full database of tropical cyclones, Hurricane GPROF improves the RMSE and MAE of rain-rate estimates over those from GPROF by about 22% and 27%, respectively. Similar improvements are also seen in the overall rain-rate bias for hurricanes in the database, which is reduced from 0.20 to −0.06 mm h−1.
Ensemble–Variational Integrated Localized Data Assimilation
Authors: Auligné Thomas , Ménétrier Benjamin , Lorenc Andrew C. , Buehner Mark 
Published: June 2016

AbstractHybrid variational–ensemble data assimilation (hybrid DA) is widely used in research and operational systems, and it is considered the current state of the art for the initialization of numerical weather prediction models. However, hybrid DA requires a separate ensemble DA to estimate the uncertainty in the deterministic variational DA, which can be suboptimal both technically and scientifically. A new framework called the ensemble–variational integrated localized (EVIL) data assimilation addresses this inconvenience by updating the ensemble analyses using information from the variational deterministic system. The goal of EVIL is to encompass and generalize existing ensemble Kalman filter methods in a variational framework. Particular attention is devoted to the affordability and efficiency of the algorithm in preparation for operational applications.
A Reformulation of Tropical Cyclone Potential Intensity Theory Incorporating Energy Production along a Radial Trajectory
Authors: Kowaleski Alex M. , Evans Jenni L. 
Published: June 2016

AbstractA modified formula for calculating tropical cyclone (TC) potential intensity (PI) from a balance between energy production and frictional dissipation in the TC surface layer is developed. This modified formula accounts for energy production and frictional dissipation at multiple radii (and therefore at multiple wind speeds) along the TC inflow trajectory. The PI maximum wind speed values VMAX are calculated using this expanded formula for four canonical radial profiles of wind speed. These results are compared to PI VMAX values calculated using the standard assumption that all energy production and frictional dissipation relevant to maximum intensity occurs at the radius of maximum winds (RMW).The new PI formulation developed here results in PI VMAX values substantially higher than the standard PI VMAX for all four of the radial wind speed profiles examined; the difference is explained by the increase in the outer radial limit of energy production. This increase holds true even if outflow temperature increases with increasing radius, although the VMAX increases with increasing outer radius are somewhat more modest in this case. The extended PI formula yields VMAX values 3–17 m s−1 higher than the standard PI VMAX value when calculated with outer energy production–dissipation limits of 2.0–2.5 RMW, although it yields potentially unrealistic values when calculated with larger outer limits (e.g., 6 RMW). These results are presented as a potential explanation for why individual TCs can exceed their standard PI VMAX values in terms of the storm thermodynamics.
Is centralisation the right way to go? The case of internal security policy reforms in Switzerland in the light of community policing
Authors: Jacot-Descombes Caroline , Niklaus Julien 
Published: June 2016

Looking from the angle of the allocation of tasks between cantons and municipalities in Switzerland, this article analyses how security reforms tend to concentrate police institutions at the cantonal level and eliminate local police in order to improve efficiency. As the shift to centralisation is being implemented through consensus-building, cities claim to be special cases and succeed in conserving their local police. The analysis focuses on two cantonal reforms through qualitative data. The results show that institutional changes have led to three main arrangements after reform: the centralisation of police (the municipalities buy the services of the cantonal police); regionalisation (several municipalities implement their policing activities together); and decentralisation (the city conserves its local police). In regard to which arrangement produces the best impact, an evaluation of the perception of actors (citizens and police) shows that the police’s work and the feeling of security are better in a decentralised setting. Points for practitioners Political issues are at the centre of reforms that aim for a new distribution of responsibilities between levels of public authorities in the Swiss security sector. They can strongly influence the new arrangements introduced by reform. Even if cantonal decision-makers have solid arguments to centralise a task, the power of municipalities is stronger. This leads to an asymmetric federalism, where cities can maintain their police and municipalities have to buy cantonal police services. As the decentralised option is better evaluated by citizens and the police, centralisation reforms are difficult to implement where there is a tradition of local police.
The effects of wind velocity and building geometry on air change efficiency in light shafts: Case studies
Authors: Padilla-Marcos Miguel Ángel , Feijó-Muñoz Jesús , Meiss Alberto 
Published: June 2016

The evaluation of the air quality in light shafts requires a specific study of its air renewal ability due to building shape, dimensions and other external conditions. This research has studied the capacity of light shafts to provide natural ventilation through the air change efficiency concept. A methodology based on the limitation of the computational urban domain is used to adapt the indoor air change efficiency index for outdoor environments. Numerical simulations were performed using CFD and a model that was experimentally validated. The aim is to evaluate the effect of the centreline building width and light shaft dimensions in the air change quality within several wind climates. Results would provide a numerically proven tool for designers, summarised in some design-based strategies in order to select which one improves the air change quality. The results indicate that the light shaft dimension perpendicular to the wind direction has a negligible effect on efficiency. For the range of wind velocities studied (0.75–9.00 m/s), the efficiency decreases at higher velocities, up to −7.41% with respect to the mean. For variations in the wind velocity and the centreline building width, a mean variation of ± 18.77% in the efficiency is obtained. Practical applications: The present methodology defines a proceeding to numerically evaluate the air change efficiency in light shafts inside different dimensional cases of buildings within several urban wind conditions.
Pharmacokinetic considerations in the treatment of hypertension in risperidone-medicated patients – thinking of clinically relevant CYP2D6 interactions
Authors: Paulzen Michael , Haen Ekkehard , Gründer Gerhard , Lammertz Sarah E , Stegmann Benedikt , Schruers Koen RJ , Walther Sebastian , Schoretsanitis Georgios 
Published: June 2016

Background: Treatment of arterial hypertension in patients with severe mental illnesses often results in polypharmacy, potentially leading to drug-drug interactions. The objective of the study was to analyse the in vivo inhibitory potential of two antihypertensive drugs, amlodipine and metoprolol on CYP2D6 catalysed 9-hydroxylation of risperidone (RIS). Methods: A therapeutic drug monitoring database with plasma concentrations of RIS and 9-hydroxyrisperidone (9-OH-RIS) of 1584 patients was analysed. Three groups were considered; a group of patients receiving RIS without a potentially cytochrome influencing co-medication (control group, R0, n=852), a group co-medicated with amlodipine (RA, n=27) and a group, co-medicated with metoprolol (RM, n=41). Plasma concentrations, concentration-to-dose ratios (C/Ds) of RIS, 9-OH-RIS and the active moiety (AM), as well as the metabolic ratios were computed and compared using the Kruskal-Wallis test, the Mann-Whitney U test and the Jonckheere-Terpstra test to determine the means and different patterns of distribution of plasma concentrations as well as the concentration-to-dose ratios. Results: The median daily dosage of RIS did not differ between the groups ( p=0.708). No differences were found in median plasma concentrations of RIS, 9-OH-RIS and AM. However, concentration-to-dose ratios for RIS, 9-OH-RIS and AM were significantly higher in the amlodipine group ( p=0.025, p=0.048 and p=0.005). In the metoprolol group, the concentration-to-dose ratio for RIS was significantly higher than in the control group ( p=0.017), while the C/D for 9-OH-RIS and AM was not. Conclusions and limitations: Our data show a potential pharmacokinetic interaction, most likely via CYP3A4 between amlodipine and RIS, reflected in significantly different C/Ds for RIS, 9-OH-RIS and AM. Although the interaction did not result in significantly higher plasma levels, changes in C/Ds and their distribution with regard to the median concentrations were observed.
Pain modulation is affected differently in medication-overuse headache and chronic myofascial pain – A multimodal MRI study
Authors: Michels Lars , Christidi Foteini , Steiger Vivian R , Sándor Peter S , Gantenbein Andreas R , Landmann Gunther , Schreglmann Sebastian R , Kollias Spyros , Riederer Franz 
Published: June 2016

BackgroundNeuroimaging studies revealed structural and functional changes in medication-overuse headache (MOH), but it remains unclear whether similar changes could be observed in other chronic pain disorders.MethodsIn this cross-sectional study, we investigated functional connectivity (FC) with resting-state functional magnetic resonance imaging (fMRI) and white matter integrity using diffusion tensor imaging (DTI) to measure fractional anisotropy (FA) and mean diffusivity (MD) in patients with MOH ( N = 12) relative to two control groups: patients with chronic myofascial pain (MYO; N = 11) and healthy controls (CN; N = 16).ResultsIn a data-driven approach we found hypoconnectivity in the fronto-parietal attention network in both pain groups relative to CN (i.e. MOH < CN and MYO < CN). In contrast, hyperconnectivity in the saliency network (SN) was detected only in MOH, which correlated with FA in the insula. In a seed-based analysis we investigated FC between the periaqueductal grey (PAG) and all other brain regions. In addition to overlapping hyperconnectivity seen in patient groups (relative to CN), MOH had a distinct connectivity pattern with lower FC to parieto-occipital regions and higher FC to orbitofrontal regions compared to controls. FA and MD abnormalities were mostly observed in MOH, involving the insula.ConclusionsHyperconnectivity within the SN along with associated white matter changes therein suggest a particular role of this network in MOH. In addition, abnormal connectivity between the PAG and other pain modulatory (frontal) regions in MOH are consistent with dysfunctional central pain control.
Relationship between serum levels of VIP, but not of CGRP, and cranial autonomic parasympathetic symptoms: A study in chronic migraine patients
Authors: Riesco N , Cernuda-Morollón E , Martínez-Camblor P , Pérez-Alvarez AI , Verano L , García-Cabo C , Serrano-Pertierra E , Pascual J 
Published: June 2016

Background Cranial autonomic parasympathetic symptoms (CAPS) appear in at least half of migraine patients theoretically as a result of the release of peptides by the trigemino-vascular system (TVS). Cranial pain pathways become sensitised by repeated episodes of TVS activation, leading to migraine chronification. Objective The objective of this article is to correlate the presence of CAPS with serum levels of vasoactive intestinal peptides (VIP) and calcitonin gene-related peptide (CGRP). Patients and methods Patients with chronic migraine (CM) were asked about the presence – during migraine attacks – of five CAPS, which were scored from 0 to 10 by using a quantitative scale. Serum VIP and CGRP levels were determined by ELISA. Results We interviewed 87 CM patients (82 females; mean age 44.7 ± 10.6 years). Seventeen had no CAPS, while 70 reported at least one CAPS. VIP levels ranged from 20.8 to 668.2 pg/ml (mean 154.5 ± 123.2). There was a significant positive correlation between scores in the CAPS scale and VIP levels (Spearman correlation coefficient = 0.227; p = 0.035). VIP levels were significantly higher in CM patients by at least one point in the scale vs those with 0 points ( p = 0.002). Analysing symptoms individually, VIP levels were numerically higher in those patients with symptoms, though they were significantly higher only in those patients with lacrimation vs those without it ( p = 0.013). There was no significant correlation between CGRP levels and the score in the CAPS scale. Conclusions Serum VIP, but not CGRP, levels seem to reflect the rate of activation of the parasympathetic arm of the TVS in migraine.
Fabrication and evaluation of electrohydrodynamic jet 3D printed polycaprolactone/chitosan cell carriers using human embryonic stem cell-derived fibroblasts
Authors: Wu Yang , Sriram Gopu , Fawzy Amr S , Fuh Jerry YH , Rosa Vinicius , Cao Tong , Wong Yoke San 
Published: June 2016

Biological function of adherent cells depends on the cell–cell and cell–matrix interactions in three-dimensional space. To understand the behavior of cells in 3D environment and their interactions with neighboring cells and matrix requires 3D culture systems. Here, we present a novel 3D cell carrier scaffold that provides an environment for routine 3D cell growth in vitro. We have developed thin, mechanically stable electrohydrodynamic jet (E-jet) 3D printed polycaprolactone and polycaprolactone/Chitosan macroporous scaffolds with precise fiber orientation for basic 3D cell culture application. We have evaluated the application of this technology by growing human embryonic stem cell-derived fibroblasts within these 3D scaffolds. Assessment of cell viability and proliferation of cells seeded on polycaprolactone and polycaprolactone/Chitosan 3D-scaffolds show that the human embryonic stem cell-derived fibroblasts could adhere and proliferate on the scaffolds over time. Further, using confocal microscopy we demonstrate the ability to use fluorescence-labelled cells that could be microscopically monitored in real-time. Hence, these 3D printed polycaprolactone and polycaprolactone/Chitosan scaffolds could be used as a cell carrier for in vitro 3D cell culture-, bioreactor- and tissue engineering-related applications in the future.