bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined Therapy of AXL and HDAC Inhibition Reverses Mesenchymal Transition in Diffuse Intrinsic Pontine Glioma
Authors: Meel Michaël H. , de Gooijer Mark C. , Metselaar Dennis S. , Sewing A. Charlotte P. , Zwaan Kenn , Waranecki Piotr , Breur Marjolein , Buil Levi C.M. , Lagerweij Tonny , Wedekind Laurine E. , Twisk Jos W.R. , Koster Jan , Hashizume Rintaro , Raabe Eric H. , Montero Carcaboso Ángel , Bugiani Marianna , Phoenix Timothy N. , van Tellingen Olaf , van Vuurden Dannis G. , Kaspers Gertjan J.L. , Hulleman Esther 
Published: March 2020

Abstract

Purpose:
Diffuse intrinsic pontine glioma (DIPG) is an incurable type of pediatric brain cancer, which in the majority of cases is driven by mutations in genes encoding histone 3 (H3K27M). We here determined the preclinical therapeutic potential of combined AXL and HDAC inhibition in these tumors to reverse their mesenchymal, therapy-resistant, phenotype.

Experimental Design:
We used public databases and patient-derived DIPG cells to identify putative drivers of the mesenchymal transition in these tumors. Patient-derived neurospheres, xenografts, and allografts were used to determine the therapeutic potential of combined AXL/HDAC inhibition for the treatment of DIPG.

Results:
We identified AXL as a therapeutic target and regulator of the mesenchymal transition in DIPG. Combined AXL and HDAC inhibition had a synergistic and selective antitumor effect on H3K27M DIPG cells. Treatment of DIPG cells with the AXL inhibitor BGB324 and the HDAC inhibitor panobinostat resulted in a decreased expression of mesenchymal and stem cell genes. Moreover, this combination treatment decreased expression of DNA damage repair genes in DIPG cells, strongly sensitizing them to radiation. Pharmacokinetic studies showed that BGB324, like panobinostat, crosses the blood–brain barrier. Consequently, treatment of patient-derived DIPG xenograft and murine DIPG allograft-bearing mice with BGB324 and panobinostat resulted in a synergistic antitumor effect and prolonged survival.

Conclusions:
Combined inhibition of AXL and HDACs in DIPG cells results in a synergistic antitumor effect by reversing their mesenchymal, stem cell-like, therapy-resistant phenotype. As such, this treatment combination may serve as part of a future multimodal therapeutic strategy for DIPG.
Therapeutic and Prophylactic Antitumor Activity of an Oral Inhibitor of Fucosylation in Spontaneous Mammary Cancers
Authors: Disis Mary L. , Corulli Lauren R. , Gad Ekram A. , Koehnlein Marlese R. , Cecil Denise L. , Senter Peter D. , Gardai Shyra J. , Okeley Nicole M. 
Published: March 2020

Abstract

2-fluorofucose (2FF) inhibits protein and cellular fucosylation. Afucosylation of IgG antibodies enhances antibody-dependent cell-mediated cytotoxicity by modulating antibody affinity for FcγRIIIa, which can impact secondary T-cell activation. Immune responses toward most common solid tumors are dominated by a humoral immune response rather than the presence of tumor-infiltrating cytotoxic T cells. IgG antibodies directed against numerous tumor-associated proteins are found in the sera of both patients with breast cancer and transgenic mice bearing mammary cancer. We questioned whether 2FF would have antitumor activity in two genetically distinct transgenic models; TgMMTV-neu (luminal B) and C3(1)-Tag (basal) mammary cancer. 2FF treatment significantly improved overall survival. The TgMMTV-neu doubled survival time compared with controls [P &lt; 0.0001; HR, 7.04; 95% confidence interval (CI), 3.31–15.0], and survival was significantly improved in C3(1)-Tag (P = 0.0013; HR, 3.36; 95% CI, 1.58–7.14). 2FF treated mice, not controls, developed delayed-type hypersensitivity and T-cell responses specific for syngeneic tumor lysates (P &lt; 0.0001). Serum IgG from 2FF-treated mice enhanced tumor lysis more efficiently than control sera (P = 0.004). Administration of 2FF for prophylaxis, at two different doses, significantly delayed tumor onset in both TgMMTV-neu; 20 mmol/L (P = 0.0004; HR, 3.55; 95% CI, 1.60–7.88) and 50 mmol/L (P = 0.0002; HR: 3.89; 95% CI, 1.71–8.86) and C3(1)-Tag; 20 mmol/L (P = 0.0020; HR, 2.51; 95% CI, 1.22–5.18), and 50 mmol/L (P = 0.0012; HR, 3.36; 95% CI, 1.57–7.18). Mammary cancer was prevented in 33% of TgMMTV-neu and 26% of C3(1)-Tag. 2FF has potent antitumor effects in mammary cancer models. The agent shows preclinical efficacy for both cancer treatment and prevention.
Impact of Clinical Characteristics and Statins on Coronary Plaque Progression by Serial Computed Tomography Angiography
Authors: Smit Jeff M. , van Rosendael Alexander R. , El Mahdiui Mohammed , Neglia Danilo , Knuuti Juhani , Saraste Antti , Buechel Ronny R. , Teresinska Anna , Pizzi Maria N. , Roque Albert , Poddighe Rosa , Mertens Bart J. , Caselli Chiara , Rocchiccioli Silvia , Parodi Oberdan , Pelosi Gualtiero , Scholte Arthur J. 
Published: March 2020

Background
Progression of coronary artery disease using serial coronary computed tomography angiography (CTA) is of clinical interest. Our primary aim was to prospectively assess the impact of clinical characteristics and statin use on quantitatively assessed coronary plaque progression in a low-risk study population during long-term follow-up.

Methods
Patients who previously underwent coronary CTA for suspected coronary artery disease were prospectively included to undergo follow-up coronary CTA. The primary end point was coronary artery disease progression, defined as the absolute annual increase in total, calcified, and noncalcified plaque volume by quantitative CTA analysis.

Results

In total, 202 patients underwent serial coronary CTA with a mean interscan period of 6.2±1.4 years. On a per-plaque basis, increasing age (β=0.070;
P
=0.058) and hypertension (β=1.380;
P
=0.075) were nonsignificantly associated with annual total plaque progression. Male sex (β=1.676;
P
=0.009), diabetes mellitus (β=1.725;
P
=0.012), and statin use (β=1.498;
P
=0.046) showed an independent association with annual progression of calcified plaque. While hypertension (β=2.259;
P
=0.015) was an independent determinant of noncalcified plaque progression, statin use (β=−2.178;
P
=0.050) was borderline significantly associated with a reduced progression of noncalcified plaque.

Conclusions
Statin use was associated with an increased progression of calcified coronary plaque and a reduced progression of noncalcified coronary plaque, potentially reflecting calcification of the noncalcified plaque component. Whereas hypertension was the only modifiable risk factor predictive of noncalcified plaque progression, diabetes mellitus mainly led to an increase in calcified plaque. These findings could yield the need for intensified preventive treatment of patients with diabetes mellitus and hypertension to slow and stabilize coronary artery disease progression and improve clinical outcome.
Randomized Comparison of Everolimus- and Zotarolimus-Eluting Coronary Stents With Biolimus-Eluting Stents in All-Comer Patients
Authors: Youn Young Jin , Lee Jun-Won , Ahn Sung Gyun , Lee Seung-Hwan , Yoon Junghan , Park Keum Soo , Lee Jin Bae , Yoo Sang-Yong , Lim Do-Sun , Cho Jang Hyun , Choi Cheol Ung , Jeong Myung Ho , Han Kyoo-Rok , Cha Kwang Soo , Lee Sung Yun , Choi Hyun-Hee , Choi Jae Woong , Hyon Min Su , Kim Moo-Hyun 
Published: March 2020

Background:
There is limited data comparing the Xience everolimus-eluting stent (EES) and the Resolute zotarolimus-eluting stent (ZES) with the BioMatrix biolimus-eluting stent (BES).

Methods:
This open-label, randomized, noninferiority trial enrolled all-comer patients to be randomly treated with either BES, EES, or ZES in a 1:1:1 ratio in 15 centers across South Korea. The primary end point was a device-oriented composite outcome consisting of cardiac death, target-vessel myocardial infarction, and clinically indicated target lesion revascularization at 24 months. The BES was compared with the EES and the ZES by intention-to-treat analyses with a noninferiority margin of 3.8%, respectively.

Results:

Because of slow recruitment and low event rates, this trial was prematurely terminated after enrollment of 1935 (75%) of the intended 2580 patients. Of the 1911 patients randomized to either EES (n=638), BES (n=634), or ZES (n =639), the rate of device-oriented composite outcome was 3.6%, 2.2%, and 3.9%, respectively, at 24 months (BES versus EES: absolute risk difference −1.4% [upper limit of 1-sided 95% CI: −3.2%];
P
for noninferiority
<0.001; BES versus ZES: absolute risk difference −1.7% [upper limit of 1-sided 95% CI: −3.6%];
P
for noninferiority
<0.001).

Conclusions:
The BES was noninferior to either the EES or the ZES in all-comer patients for device-oriented composite outcome at the 24-month follow-up. However, caution is advised regarding interpretation of these results due to the premature termination of this study.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01397175.
Zooming In and Out on One's Life: Autobiographical Representations at Multiple Time Scales
Authors: D'Argembeau Arnaud 
Published: March 2020

Abstract
The ability to decouple from the present environment and explore other times is a central feature of the human mind. Research in cognitive psychology and neuroscience has shown that the personal past and future is represented at multiple timescales and levels of resolution, from broad lifetime periods that span years to short-time slices of experience that span seconds. Here, I review this evidence and propose a theoretical framework for understanding mental time travel as the capacity to flexibly navigate hierarchical layers of autobiographical representations. On this view, past and future thoughts rely on two main systems—event simulation and autobiographical knowledge—that allow us to represent experiential contents that are decoupled from sensory input and to place these on a personal timeline scaffolded from conceptual knowledge of the content and structure of our life. The neural basis of this cognitive architecture is discussed, emphasizing the possible role of the medial pFC in integrating layers of autobiographical representations in the service of mental time travel.
Gallucci's Commentary on Dürer’s 'Four Books on Human Proportion'
Authors: Hutson James 
Published: March 2020

In 1591, Giovanni Paolo Gallucci published his Della simmetria dei corpi humani, an Italian translation of Albrecht Dürer’s Four Books on Human Proportion. While Dürer’s treatise had been translated earlier in the sixteenth-century into French and Latin, it was Gallucci’s Italian translation that endured in popularity as the most cited version of the text in later Baroque treatises, covering topics that were seen as central to arts education, connoisseurship, patronage, and the wider appreciation of the studia humanitatis in general.
The text centres on the relationships between beauty and proportion, macrocosm and microcosm: relationships that were not only essential to the visual arts in the early modern era, but that cut across a range of disciplines – music, physiognomics and humoral readings, astronomy, astrology and cosmology, theology and philosophy, even mnemonics and poetry. In his version of the text, Gallucci expanded the educational potential of the treatise by adding a Preface, a Life of Dürer, and a Fifth Book providing a philosophical framework within which to interpret Dürer’s previous sections.
This translation is the first to make these original contributions by Gallucci accessible to an English-speaking audience. Gallucci’s contributions illuminate the significance of symmetry and proportion in the contemporary education of the early modern era, informing our understanding of the intellectual history of this period, and the development of art theory and criticism. This is a valuable resource to early modern scholars and students alike, especially those specialising in history of art, philosophy, history of science, and poetry.
Broadening of the Cloud Droplet Size Distribution due to Thermal Radiative Cooling: Turbulent Parcel Simulations
Authors: Barekzai Mares , Mayer Bernhard 
Published: March 2020

Abstract
Despite impressive advances in rain forecasts over the past decades, our understanding of rain formation on a microphysical scale is still poor. Droplet growth initially occurs through diffusion and, for sufficiently large radii, through the collision of droplets. However, there is no consensus on the mechanism to bridge the condensation coalescence bottleneck. We extend the analysis of prior methods by including radiatively enhanced diffusional growth (RAD) to a Markovian turbulence parameterization. This addition increases the diffusional growth efficiency by allowing for emission and absorption of thermal radiation. Specifically, we quantify an upper estimate for the radiative effect by focusing on droplets close to the cloud boundary. The strength of this simple model is that it determines growth-rate dependencies on a number of parameters, like updraft speed and the radiative effect, in a deterministic way. Realistic calculations with a cloud-resolving model are sensitive to parameter changes, which may cause completely different cloud realizations and thus it requires considerable computational power to obtain statistically significant results. The simulations suggest that the addition of radiative cooling can lead to a doubling of the droplet size standard deviation. However, the magnitude of the increase depends strongly on the broadening established by turbulence, due to an increase in the maximum droplet size, which accelerates the production of drizzle. Furthermore, the broadening caused by the combination of turbulence and thermal radiation is largest for small updrafts and the impact of radiation increases with time until it becomes dominant for slow synoptic updrafts.
ENSO-Unrelated Variability in Indo–Northwest Pacific Climate: Regional Coupled Ocean–Atmospheric Feedback
Authors: Wang Chuan-Yang , Xie Shang-Ping , Kosaka Yu 
Published: March 2020

AbstractRegional ocean–atmospheric interactions in the summer tropical Indo–northwest Pacific region are investigated using a tropical Pacific Ocean–global atmosphere pacemaker experiment with a coupled ocean–atmospheric model (cPOGA) and a parallel atmosphere model simulation (aPOGA) forced with sea surface temperature (SST) variations from cPOGA. Whereas the ensemble mean features pronounced influences of El Niño–Southern Oscillation (ENSO), the ensemble spread represents internal variability unrelated to ENSO. By comparing the aPOGA and cPOGA, this study examines the effect of the ocean–atmosphere coupling on the ENSO-unrelated variability. In boreal summer, ocean–atmosphere coupling induces local positive feedback to enhance the variance and persistence of the sea level pressure and rainfall variability over the northwest Pacific and likewise induces local negative feedback to suppress the variance and persistence of the sea level pressure and rainfall variability over the north Indian Ocean. Anomalous surface heat fluxes induced by internal atmosphere variability cause SST to change, and SST anomalies feed back onto the atmosphere through atmospheric convection. The local feedback is sensitive to the background winds: positive under the mean easterlies and negative under the mean westerlies. In addition, north Indian Ocean SST anomalies reinforce the low-level anomalous circulation over the northwest Pacific through atmospheric Kelvin waves. This interbasin interaction, along with the local feedback, strengthens both the variance and persistence of atmospheric variability over the northwest Pacific. The response of the regional Indo–northwest Pacific mode to ENSO and influences on the Asian summer monsoon are discussed.
How Significant Was the 1877/78 El Niño?
Authors: Huang Boyin , L’Heureux Michelle , Hu Zeng-Zhen , Yin Xungang , Zhang Huai-Min 
Published: March 2020

AbstractPrevious research has shown that the 1877/78 El Niño resulted in great famine events around the world. However, the strength and statistical significance of this El Niño event have not been fully addressed, largely due to the lack of data. We take a closer look at the data using an ensemble analysis of the Extended Reconstructed Sea Surface Temperature version 5 (ERSSTv5). The ERSSTv5 standard run indicates a strong El Niño event with a peak monthly value of the Niño-3 index of 3.5°C during 1877/78, stronger than those during 1982/83, 1997/98, and 2015/16. However, an analysis of the ERSSTv5 ensemble runs indicates that the strength and significance (uncertainty estimates) depend on the construction of the ensembles. A 1000-member ensemble analysis shows that the ensemble mean Niño-3 index has a much weaker peak of 1.8°C, and its uncertainty is much larger during 1877/78 (2.8°C) than during 1982/83 (0.3°C), 1997/98 (0.2°C), and 2015/16 (0.1°C). Further, the large uncertainty during 1877/78 is associated with selections of a short (1 month) period of raw-data filter and a large (20%) acceptance criterion of empirical orthogonal teleconnection modes in the ERSSTv5 reconstruction. By adjusting these two parameters, the uncertainty during 1877/78 decreases to 0.5°C, while the peak monthly value of the Niño-3 index in the ensemble mean increases to 2.8°C, suggesting a strong and statistically significant 1877/78 El Niño event. The adjustment of those two parameters is validated by masking the modern observations of 1981–2017 to 1861–97. Based on the estimated uncertainties, the differences among the strength of these four major El Niño events are not statistically significant.
The Neutrally Buoyant Sediment Trap: Two Decades of Progress
Authors: Estapa Margaret , Valdes James , Tradd Kaitlyn , Sugar Jackson , Omand Melissa , Buesseler Ken 
Published: March 2020

AbstractThe biological carbon flux from the ocean’s surface into its interior has traditionally been sampled by sediment traps, which physically intercept sinking particulate matter. However, the manner in which a sediment trap interacts with the flow field around it can introduce hydrodynamic biases, motivating the development of neutral, self-ballasting trap designs. Here, the performance of one of these designs, the neutrally buoyant sediment trap (NBST), is described and evaluated. The NBST has been successfully used in a number of scientific studies since a prototype was last described in the literature two decades ago, with extensive modifications in subsequent years. Originated at Woods Hole Oceanographic Institution, the NBST is built around a profiling float and carries cylindrical collection tubes, a feature that distinguishes it from other neutral traps described in the literature. This paper documents changes to the device that have been implemented over the last two decades, including wider trap tubes; Iridium Communications, Inc., satellite communications; and the addition of polyacrylamide gel collectors and optical sedimentation sensors. Information is also provided with the intent of aiding the development of similar devices by other researchers, including the present adaptation of the concept to utilize commercially available profiling float hardware. The performance of NBSTs built around commercial profiling floats is comparable to NBSTs built around customized floats, albeit with some additional operational considerations. Data from recent field studies comparing NBSTs and traditional, surface-tethered sediment traps are used to illustrate the performance of the instrument design. Potential improvements to the design that remain to be incorporated through future work are also outlined.
A Multi-Time-Scale Four-Dimensional Variational Data Assimilation Scheme and Its Application to Simulated Radial Velocity and Reflectivity Data
Authors: Sun Tao , Chen Yaodeng , Sun Juanzhen , Wang Hongli , Chen Haiqin , Wang Yuanbing , Meng Deming 
Published: March 2020

AbstractIn this study, a multi-time-scale four-dimensional variational data assimilation (MTS-4DVar) scheme is developed and applied to the assimilation of radar observations. The MTS-4DVar employs multitime windows with various time lengths in the framework of incremental 4DVar in the Weather Research and Forecasting Data Assimilation (WRFDA). The objective of MTS-4DVar is to enable the 4DVar data assimilation system to extract multiscale information from radar observations, and the algorithm of MTS-4DVar is first discussed in detail. Using a heavy rainfall case, it is shown that the nonlinearity growth of reflectivity is faster than that of radial velocity, suggesting that the time window for assimilating reflectivity in the incremental 4DVar should be shorter than that of radial velocity. A series of single observation tests and observing system simulation experiments (OSSEs) are then presented to examine the physical characteristics and performance of MTS-4DVar. These experiments demonstrate that the MTS-4DVar is capable of combining the larger-scale information from a longer time window and the local-scale features from a shorter time window. With the OSSEs it is shown that the value of the cost function is reduced properly in the minimization of the MTS-4DVar with a combination of longer and shorter time windows. By assimilating the radar radial velocity alone, we found that the MTS-4DVar reduces the analysis and forecast errors and improves the precipitation forecasts in comparison with the normal incremental 4DVar. Additional assimilation of reflectivity further improved the precipitation forecasts, and the results show that the radar reflectivity can also be well assimilated by using MTS-4DVar.
Chronic lymphocytic leukemia focus in the context of a cardiac mass in a pretreated patient: an exceptional incidental finding
Authors: Lolli Ginevra , Broccoli Alessandro , Stefoni Vittorio , Argnani Lisa , Leone Ornella , Cavo Michele , Zinzani Pier Luigi 
Published: March 2020

Background: B-cell chronic lymphocytic leukemia (B-CLL) is a lymphoproliferative disorder consisting of clonal proliferation and accumulation of small, mature, CD5-positive B-lymphocytes in the blood, bone marrow, and lymphoid tissues. Among extranodal localizations, cardiac involvement is extremely rare: to our knowledge, there are no findings reported in the literature of concomitant B-CLL diagnosis in the context of atrial myxoma (so-called collision tumours) and the best strategy to treat these malignancies is unclear. Case report: We report the case of a 67-year-old woman diagnosed with B-CLL and atrial myxoma. Our patient was cardiologically symptomless and the cardiac mass was an incidental finding. The cardiac tumor appeared several years after B-CLL diagnosis. Histologic examination of the cardiac mass, removed in the suspicion of an atrial myxoma, revealed a lymphoid focus of B-CLL. The patient underwent surgery and subsequent systemic therapy for B-CLL. Conclusions: The concomitant presence of B-CLL in the context of an atrial myxoma is extremely rare. The best strategy to treat these cardiac hematologic malignancies is unclear.