bluuebunny/crossref_metadata_2025_split huggingface dataset:
NKT Cells Coexpressing a GD2-Specific Chimeric Antigen Receptor and IL15 Show Enhanced In Vivo Persistence and Antitumor Activity against Neuroblastoma
Authors: Xu Xin , Huang Wei , Heczey Andras , Liu Daofeng , Guo Linjie , Wood Michael , Jin Jingling , Courtney Amy N. , Liu Bin , Di Pierro Erica J. , Hicks John , Barragan Gabriel A. , Ngai Ho , Chen Yuhui , Savoldo Barbara , Dotti Gianpietro , Metelitsa Leonid S. 
Published: September 2019

Abstract

Purpose:
Vα24-invariant natural killer T cells (NKT) are attractive carriers for chimeric antigen receptors (CAR) due to their inherent antitumor properties and preferential localization to tumor sites. However, limited persistence of CAR-NKTs in tumor-bearing mice is associated with tumor recurrence. Here, we evaluated whether coexpression of the NKT homeostatic cytokine IL15 with a CAR enhances the in vivo persistence and therapeutic efficacy of CAR-NKTs.

Experimental Design:
Human primary NKTs were ex vivo expanded and transduced with CAR constructs containing an optimized GD2-specific single-chain variable fragment and either the CD28 or 4-1BB costimulatory endodomain, each with or without IL15 (GD2.CAR or GD2.CAR.15). Constructs that mediated robust CAR-NKT cell expansion were selected for further functional evaluation in vitro and in xenogeneic mouse models of neuroblastoma.

Results:
Coexpression of IL15 with either costimulatory domain increased CAR-NKT absolute numbers. However, constructs containing 4-1BB induced excessive activation-induced cell death and reduced numeric expansion of NKTs compared with respective CD28-based constructs. Further evaluation of CD28-based GD2.CAR and GD2.CAR.15 showed that coexpression of IL15 led to reduced expression levels of exhaustion markers in NKTs and increased multiround in vitro tumor cell killing. Following transfer into mice bearing neuroblastoma xenografts, GD2.CAR.15 NKTs demonstrated enhanced in vivo persistence, increased localization to tumor sites, and improved tumor control compared with GD2.CAR NKTs. Importantly, GD2.CAR.15 NKTs did not produce significant toxicity as determined by histopathologic analysis.

Conclusions:
Our results informed selection of the CD28-based GD2.CAR.15 construct for clinical testing and led to initiation of a first-in-human CAR-NKT cell clinical trial (NCT03294954).
HER-Family Ligands Promote Acquired Resistance to Trastuzumab in Gastric Cancer
Authors: Sampera Aïda , Sánchez-Martín Francisco Javier , Arpí Oriol , Visa Laura , Iglesias Mar , Menéndez Sílvia , Gaye Élisabeth , Dalmases Alba , Clavé Sergi , Gelabert-Baldrich Mariona , Poulsen Thomas Tuxen , Kragh Michael , Bellosillo Beatriz , Albanell Joan , Rovira Ana , Montagut Clara 
Published: September 2019

Abstract
Despite the clinical benefit of trastuzumab, eventually all HER2-amplified gastric cancer tumors develop drug resistance. We aimed to identify molecular mechanisms of acquired resistance to trastuzumab in gastric cancer by using well-established cell line–based preclinical models, as well as samples from patients with HER2-positive gastric cancer treated with trastuzumab. We studied trastuzumab resistance in NCI-N87 and OE19, two gastric cancer cell lines that overexpress HER2 receptor and are trastuzumab sensitive. Differences at protein, DNA, and RNA levels between the parental and resistant cells were characterized and functional studies were performed. Paired pre- and post-trastuzumab blood and tissue samples from patients with gastric cancer treated with trastuzumab were analyzed. We found that resistant cells were associated with increased activation of MAPK/ERK and PI3K/mTOR pathways driven by SRC activation. Upstream, resistant cells showed increased coexpression of multiple HER-family ligands that allowed for compensatory activation of alternative HER receptors upon HER2 blockade. Simultaneous inhibition of EGFR, HER2, and HER3 by the novel antibody mixture, Pan-HER, effectively reverted trastuzumab resistance in vitro and in vivo. Similarly, an increase in HER-family ligands was observed in serum and tumor from patients with gastric cancer after trastuzumab therapy. We propose that trastuzumab resistance in gastric cancer is mediated by HER-family ligand upregulation that allows a compensatory activation of HER receptors and maintains downstream signaling activation despite trastuzumab therapy. Resistance is reverted by simultaneous inhibition of EGFR, HER2, and HER3, thereby revealing a potential therapeutic strategy to overcome trastuzumab resistance in patients with gastric cancer.
Efficacy of Difluoromethylornithine and Aspirin for Treatment of Adenomas and Aberrant Crypt Foci in Patients with Prior Advanced Colorectal Neoplasms
Authors: Sinicrope Frank A. , Velamala Pruthvi R. , Song Louis M. Wong Kee , Viggiano Thomas R. , Bruining David H. , Rajan Elizabeth , Gostout Christopher J. , Kraichely Robert E. , Buttar Navtej S. , Schroeder Kenneth W. , Kisiel John B. , Larson Mark V. , Sweetser Seth R. , Sedlack Robert R. , Sinicrope Stephen N. , Richmond Ellen , Umar Asad , Della'Zanna Gary , Noaeill Joni S. , Meyers Jeffrey P. , Foster Nathan R. 
Published: September 2019

Abstract
Difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, was shown to act synergistically with a NSAID for chemoprevention of colorectal neoplasia. We determined the efficacy and safety of DFMO plus aspirin for prevention of colorectal adenomas and regression of rectal aberrant crypt foci (ACF) in patients with prior advanced adenomas or cancer. A double-blinded, placebo-controlled trial was performed in 104 subjects (age 46–83) randomized (1:1) to receive daily DFMO (500 mg orally) plus aspirin (325 mg) or matched placebos for one year. All polyps were removed at baseline. Adenoma number (primary endpoint) and rectal ACF (index cluster and total) were evaluated at a one year colonoscopy. ACF were identified by chromoendoscopy. Toxicity was monitored, including audiometry. Eighty-seven subjects were evaluable for adenomas or ACF modulation (n = 62). At one year of treatment, adenomas were detected in 16 (38.1%) subjects in the DFMO plus aspirin arm (n = 42) versus 18 (40.9%) in the placebo arm (n = 44; P = 0.790); advanced adenomas were similar (n = 3/arm). DFMO plus aspirin was associated with a statistically significant reduction in the median number of rectal ACF compared with placebo (P = 0.036). Total rectal ACF burden was also reduced in the treatment versus the placebo arm relative to baseline (74% vs. 45%, P = 0.020). No increase in adverse events, including ototoxicity, was observed in the treatment versus placebo arms. While adenoma recurrence was not significantly reduced by one year of DFMO plus aspirin, the drug combination significantly reduced rectal ACF number consistent with a chemopreventive effect.
A Randomized, Placebo-Controlled, Double-Blind, Dose Escalation, Single Dose, and Steady-State Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers
Authors: Kolesar Jill M. , Andrews Shannon , Green Heather , Havighurst Tom C. , Wollmer Barbara W. , DeShong Katina , Laux Douglas E. , Krontiras Helen , Muccio Donald D. , Kim KyungMann , Grubbs Clinton J. , House Margaret G. , Parnes Howard L. , Heckman-Stoddard Brandy M. , Bailey Howard H. 
Published: September 2019

Abstract
9cUAB30 is a synthetic analogue of 9-cis retinoic acid with chemoprevention activity in cell lines and animal models. The purpose of this phase I placebo-controlled, double-blinded, dose escalation study of 9cUAB30 was to evaluate its safety, pharmacokinetics, and determine a dose for future phase II studies. Participants received a single dose of study drug (placebo or 9cUAB30) on day 1 followed by a 6-day drug-free period and then 28 days of continuous daily dosing starting on day 8. Fifty-three healthy volunteers were enrolled into five dose cohorts (20, 40, 80, 160, and 240 mg). Participants were randomized within each dose level to receive either 9cUAB30 (n = 8) or placebo (n = 2). 9cUAB30 was well tolerated, with no dose limiting toxicities reported and no evidence of persistent elevations in serum triglycerides or cholesterol. Treatment-emergent grade 3 hypertension occurred in 1 of 8 participants at the 20 mg dose level and in 2 of 8 at the 240 mg dose level, all considered unlikely related to study agent; no other grade 3 adverse events were observed. The AUC increased, as expected, between day 1 (single dose) and day 36 (steady state). Pharmacokinetics were linear in dose escalation through 160 mg. 9cUAB30 administered by daily oral dosing has a favorable safety and pharmacokinetic profile. On the basis of the observed safety profile and lack of linearity in pharmacokinetics at doses greater than 160 mg, the recommended phase II dose with the current formulation is 160 mg once daily.
Cross-Cultural Comparisons between the Mughal Tomb Garden of Taj Mahal in Agra (India) and the Dry Landscape Garden of the Ryoan-Ji Zen Monastery in Kyoto (Japan)
Authors: Minnema Lourens 
Published: September 2019

AbstractGardens have always meant a lot to people. Gardens are as much about nature as they are about culture. The extent to which gardens carry and embody both similar and different layers of meaning will be demonstrated by comparing two classical gardens, the Taj Mahal tomb garden of the Mughal rulers in Agra, India, and the Ryoan-ji dry landscape garden of the Zen monks in Kyoto, Japan. Parallels will be drawn by offering a (diachronic) analysis of the historical accumulation of layers of meaning associated with each one of these two gardens, and (synchronic) structural comparisons will be drawn by raising two thematic issues in particular, the inside-outside relationship and the nature-culture relationship. The roles that Islam and Zen Buddhism play in the religious meaning making of these two classical gardens turn out to be strikingly similar, in that they confirm rather than transform other layers of cultural meaning.
Christian Hospitality in the Celebration of ʿId al-Fitr
Authors: Simatupang Florian 
Published: September 2019

Abstract
This article explores the possibility for Christians to discover hospitality and learn reconciliation through Halal bi-halal, a uniquely Indonesian way of observing the Islamic religious festival of ʿId al-Fitri. The exploration will be done in two ways: first, through a broad sacramental lens that will, second, lead to a more particular renewal perspective. The thrust of this presentation is to contend that Christians can experience, and therefore discover, a Christian understanding of hospitality from a non-Christian feast.
Numerical and Wind Tunnel Simulation Studies of the Flow Field and Pollutant Diffusion around a Building under Neutral and Stable Atmospheric Stratifications
Authors: Guo Dong-Peng , Zhao Peng , Yao Ren-Tai , Li Yun-Peng , Hu Ji-Min , Fan Dan 
Published: September 2019

AbstractIn this paper, the k–ε renormalization group (RNG) turbulence model is used to simulate the flow and dispersion of pollutants emitted from a source at the top of a cubic building under neutral and stable atmospheric stratifications, the results of which were compared with corresponding wind tunnel experiment results. When atmosphere stratification is stable, the separation zones on the sides and at the top of a building are relatively smaller than those under neutral conditions, and the effect of the building in the horizontal direction is stronger than that in the vertical direction. The variation in turbulent kinetic energy under stable conditions is significantly lower than that under neutral conditions. The effect of atmospheric stratification on the turbulent kinetic energy becomes gradually more prominent with increased distance. When atmosphere conditions are stable, the vertical distribution of the plume is smaller than that of neutral conditions, but the lateral spread and near-ground concentration are slightly larger than those of neutral conditions, mainly because stable atmospheric stratification suppresses the vertical motions of airflow and increases the horizontal spread of the plume.
Changing Intrasynoptic Type Characteristics and Interannual Frequencies of Circulation Patterns Conducive to Lake-Effect Snowfall
Authors: Suriano Zachary J. 
Published: September 2019

AbstractUsing a temporal synoptic index, synoptic-scale atmospheric patterns suitable for lake-effect snow downwind of Lakes Erie and Ontario are identified and analyzed from 1950 to 2009. In response to prior research noting a trend reversal of snowfall in this region, changes in the inherent meteorological characteristics and winter-season frequencies of lake-effect synoptic weather types are evaluated as possible forcing mechanisms. Four atmospheric patterns are identified during the December–February winter season as lake-effect synoptic types. Changes in inherent meteorological characteristics and winter frequencies of these types are attributed to between 88% and 95% of the observed snowfall changes during the study period. Decreasing air temperatures and surface pressures, increasing boundary layer instability, and changes toward stronger zonal flow are noted for multiple lake-effect synoptic types from 1950 to 1979 as likely forcing mechanisms of observed snowfall increases, on the order of nearly 1.0 cm yr−1 downwind of Lake Ontario per individual synoptic type. Similarly, the significant increases in the winter frequency of multiple lake-effect synoptic types also are attributed to some of the increases in snowfall. From 1980 to 2009, however, the lake-effect synoptic types remained relatively unchanged or decreased in frequency, as did snowfall totals. The results of this study indicate that changes in the synoptic-scale environment are a viable mechanism forcing snowfall trends, in addition to the more commonly considered seasonal temperature and lake-ice considerations, and should be incorporated into future discussions of lake-effect snowfall projections.
On the Efficiency of Baroclinic Eddy Growth and How It Reduces the North Pacific Storm-Track Intensity in Midwinter
Authors: Schemm Sebastian , Rivière Gwendal 
Published: September 2019

Abstract
This study investigates the efficiency of baroclinic eddy growth in an effort to better understand the suppression of the North Pacific storm-track intensity in winter. The efficiency of baroclinic eddy growth depends on the magnitude and orientation of the vertical tilt of the eddy geopotential isolines. The eddy efficiency is maximized if the orientation of the vertical tilt creates an eddy heat flux that aligns with the mean baroclinicity (defined as minus the temperature gradient divided by a stratification parameter) and if the magnitude of the vertical tilt is neither too strong nor too weak. The eddy efficiency is, in contrast to most other eddy measures, independent of the eddy amplitude and thus useful for improving our mechanistic understanding of the effective eddy growth. During the midwinter suppression, the eddy efficiency is reduced north of 40°N over a region upstream of the main storm track, and baroclinic growth is reduced despite a maximum in baroclinicity. Eulerian diagnostics and feature tracking suggest that the reduction in eddy efficiency is due to a stronger poleward tilt with height of eddies entering the Pacific through the northern seeding branch, which results in a more eastward-oriented eddy heat flux and a reduced alignment with the baroclinicity. The stronger poleward tilt with height is constrained by the eddy propagation direction, which is more equatorward when the subtropical jet moves equatorward in winter. In addition, the westward tilt with height is too strong. South of 40°N, the eddy efficiency increases during midwinter but in a region far away from the main storm track.
An Assessment of NASA’s GMAO MERRA-2 Reanalysis Surface Winds
Authors: Carvalho D. 
Published: September 2019

Abstract
The quality of MERRA-2 surface wind fields was assessed by comparing them with 10 years of measurements from a wide range of surface wind observing platforms. This assessment includes a comparison of MERRA-2 global surface wind fields with the ones from its predecessor, MERRA, to assess if GMAO’s latest reanalyses improved the representation of the global surface winds. At the same time, surface wind fields from other modern reanalyses—NCEP-CFSR, ERA-Interim, and JRA-55—were also included in the comparisons to evaluate MERRA-2 global surface wind fields in the context of its contemporary reanalyses. Results show that MERRA-2, CFSR, ERA-Interim, and JRA-55 show similar error metrics while MERRA consistently shows the highest errors. Thus, when compared with wind observations, the accuracy of MERRA-2 surface wind fields represents a clear improvement over its predecessor MERRA and is in line with the other contemporary reanalyses in terms of the representation of global near-surface wind fields. All reanalyses showed a tendency to underestimate ocean surface winds (particularly in the tropics) and, oppositely, to overestimate inland surface winds (except JRA-55, which showed a global tendency to underestimate the wind speeds); to represent the wind direction rotated clockwise in the Northern Hemisphere (positive bias) and anticlockwise in the Southern Hemisphere (negative bias), with the exception of JRA-55; and to show higher errors near the poles and in the ITCZ, particularly in the equatorial western coasts of Central America and Africa. However, MERRA-2 showed substantially lower wind errors in the poles when compared with the other reanalyses.
Dynamics and Thermodynamics of the Mean Transpolar Drift and Ice Thickness in the Arctic Ocean
Authors: Spall Michael A. 
Published: September 2019

Abstract
A theory for the mean ice thickness and the Transpolar Drift in the Arctic Ocean is developed. Asymptotic expansions of the ice momentum and thickness equations are used to derive analytic expressions for the leading-order ice thickness and velocity fields subject to wind stress forcing and heat loss to the atmosphere. The theory is most appropriate for the eastern and central Arctic, but not for the region of the Beaufort Gyre subject to anticyclonic wind stress curl. The scale analysis reveals two distinct regimes: a thin ice regime in the eastern Arctic and a thick ice regime in the western Arctic. In the eastern Arctic, the ice drift is controlled by a balance between wind and ocean drag, while the ice thickness is controlled by heat loss to the atmosphere. In contrast, in the western Arctic, the ice thickness is determined by a balance between wind and internal ice stress, while the drift is indirectly controlled by heat loss to the atmosphere. The southward flow toward Fram Strait is forced by the across-wind gradient in ice thickness. The basic predictions for ice thickness, heat loss, ice volume, and ice export from the theory compare well with an idealized, coupled ocean–ice numerical model over a wide range of parameter space. The theory indicates that increasing atmospheric temperatures or wind speed result in a decrease in maximum ice thickness and ice volume. Increasing temperatures also result in a decrease in heat loss to the atmosphere and ice export through Fram Strait, while increasing winds drive increased heat loss and ice export.
Creating a More Realistic Idealized Supercell Thunderstorm Evolution via Incorporation of Base-State Environmental Variability
Authors: Davenport Casey E. , Ziegler Conrad L. , Biggerstaff Michael I. 
Published: September 2019

Abstract
Convective environments are known to be heterogeneous in both time and space, yet idealized models use fixed base-state environments to simulate storm evolution. Recently, the base-state substitution (BSS) technique was devised to account for environmental variability in a controlled manner while maintaining horizontal homogeneity; BSS involves updating the background environment to reflect a new storm-relative proximity sounding at a prescribed time interval. The study herein sought to assess the ability of BSS to more realistically represent the structure and evolution of an observed supercell thunderstorm in comparison to simulations with fixed base-state environments. An extended dual-Doppler dataset of an intensifying supercell thunderstorm in a varying inflow environment was compared to idealized simulations of the same storm; simulations included those with fixed background environments, as well as a BSS simulation that incorporated environmental variability continuously via tendencies to the base-state variables based on changes in a series of observed soundings. While the simulated supercells were generally more intense than what was measured in the observations, broad trends in reflectivity, vertical velocity, and vertical vorticity were more similar between the observed and BSS-simulated supercell; with a fixed environment, the supercell either shrunk in size and weakened over time, or grew upscale into a larger convective system. Quantitative comparisons examining distributions, areas, and volumes of vertical velocity and vorticity further confirm these differences. Overall, BSS provides a more realistic result, supporting the idea that a series of proximity soundings can sufficiently represent the effects of environmental variability, enhancing accuracy over fixed environments.
High versus standard magnetic resonance image resolution of the cervical spine in patients with axial spondyloarthritis
Authors: Krabbe Simon , Østergaard Mikkel , Sørensen Inge J , Møller Jakob , Jensen Bente , Madsen Ole R , Pedersen Susanne J 
Published: September 2019

Background Sagittal magnetic resonance (MR) images are typically obtained with the same spatial resolution along the entire spine, but cervical vertebrae are smaller and may be harder to assess. Purpose To investigate if high-resolution (high-res) short tau inversion recovery (STIR) and T1-weighted turbo spin echo (T1W) MR imaging (MRI) sequences are superior to standard resolution for detecting inflammatory and structural lesions in the cervical spine of patients with axial spondyloarthritis. Material and Methods Images were obtained in 36 patients. Voxel sizes at high/standard resolution were 1.99/4.33 mm3 (STIR) and 0.89/3.71 mm3 (T1W). High-resolution and standard-resolution images were scored by two readers according to the Canada-Denmark (CANDEN) MRI spine scoring system. Results Higher bone marrow edema scores were obtained at high resolution versus standard resolution (mean 2.1 vs. 1.2, P = 0.040), whereas fat lesion scores (1.8 vs. 1.5, P = 0.27) and new bone formation scores (3.5 vs. 2.8, P = 0.21) were similar. High-resolution MRI did not classify more patients as positive for bone marrow edema, fat, or new bone formation in the cervical spine compared to standard resolution. Using lateral radiographs as reference standard, sensitivity for detecting anterior corner syndesmophytes with both high-resolution and standard-resolution MRI was low (range 7–22%) and sensitivity for detecting ankylosis was low to moderate (20–55%), while specificity was high (≥96%). Conclusion High-resolution MRI allowed identification of more inflammatory lesions in the cervical spine in patients with axial spondyloarthritis when compared to standard resolution, but it did not classify more patients as positive for bone marrow edema. The slightly increased sensitivity at high-resolution MRI seemed to be too modest to have any real clinical importance.