bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined CDK4/6 and Pan-mTOR Inhibition Is Synergistic Against Intrahepatic Cholangiocarcinoma
Authors: Song Xinhua , Liu Xianqiong , Wang Haichuan , Wang Jingxiao , Qiao Yu , Cigliano Antonio , Utpatel Kirsten , Ribback Silvia , Pilo Maria G. , Serra Marina , Gordan John D. , Che Li , Zhang Shanshan , Cossu Antonio , Porcu Alberto , Pascale Rosa M. , Dombrowski Frank , Hu Hongbo , Calvisi Diego F. , Evert Matthias , Chen Xin 
Published: July 2018

Abstract

Purpose:
Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer type, lacking effective therapies and associated with a dismal prognosis. Palbociclib is a selective CDK4/6 inhibitor, which has been shown to suppress cell proliferation in many experimental cancer models. Recently, we demonstrated that pan-mTOR inhibitors, such as MLN0128, effectively induce apoptosis, although have limited efficacy in restraining proliferation of ICC cells. Here, we tested the hypothesis that palbociclib, due to its antproliferative properties in many cancer types, might synergize with MLN0128 to impair ICC growth.

Experimental Design:
Human ICC cell lines and the AKT/YapS127A ICC mouse model were used to test the therapeutic efficacy of palbociclib and MLN0128, either alone or in combination.

Results:
Administration of palbociclib suppressed in vitro ICC cell growth by inhibiting cell-cycle progression. Concomitant administration of palbociclib and MLN0128 led to a pronounced, synergistic growth constraint of ICC cell lines. Furthermore, while treatment with palbociclib or MLN0128 alone resulted in tumor growth reduction in AKT/YapS127A mice, a remarkable tumor regression was achieved when the two drugs were administered simultaneously. Mechanistically, palbociclib was found to potentiate MLN0128 mTOR inhibition activity, whereas MLN0128 prevented the upregulation of cyclin D1 induced by palbociclib treatment.

Conclusions:
Our study indicates the synergistic activity of palbociclib and MLN0128 in inhibiting ICC cell proliferation. Thus, combination of CDK4/6 and mTOR inhibitors might represent a novel, promising, and effective therapeutic approach against human ICC.
See related commentary by Malumbres, p. 6
A Chemosensitivity Study of Colorectal Cancer Using Xenografts of Patient-Derived Tumor-Initiating Cells
Authors: Maekawa Hisatsugu , Miyoshi Hiroyuki , Yamaura Tadayoshi , Itatani Yoshiro , Kawada Kenji , Sakai Yoshiharu , Taketo M. Mark 
Published: July 2018

Abstract
Current genomic and gene expression analyses provide versatile tools to improve cancer chemotherapy. However, it is still difficult to predict whether each patient responds to a particular regimen or not. To predict chemosensitivity in each patient with colorectal cancer, we developed an evaluation method using the primary tumor-initiating cells (TIC, aka cancer stem cells) xenografted in nude mice subcutaneously (patient-derived spheroid xenografts; PDSX). Simultaneously, we also prepared the conventional patient-derived xenografts (PDX) from the same patients' tumors and compared the dosing results with those of PDSXs. We further compared the chemosensitivities of PDSXs with those of 7 patients who had been given regimens such as FOLFOX and FOLFIRI to treat their metastatic lesions. As per the results, the PDSX method provided much more precise and predictable tumor growth with less variance than conventional PDX, although both retained the epithelial characteristics of the primary tumors. Likewise, drug-dosing tests showed essentially the same results in PDXs and PDSXs, with stronger statistical power in PDSXs. Notably, the cancer chemosensitivity in each patient was precisely reflected in that of the PDSX mice along the clinical course until the resistance emerged at the terminal stage. This “paraclinical” xenograft trials using PDSXs may help selection of chemotherapy regimens efficacious for each patient, and, more importantly, avoiding inefficient ones by which the patient can lose precious time and QOL. Furthermore, the PDSX method may be employed for evaluations of off-label uses of cancer chemotherapeutics and compassionate uses of yet-unapproved new drugs in personalized therapies. Mol Cancer Ther; 17(10); 2187–96. ©2018 AACR.
Maternal Folate Intake and Risk of Childhood Brain and Spinal Cord Tumors: A Systematic Review and Meta-Analysis
Authors: Chiavarini Manuela , Naldini Giulia , Fabiani Roberto 
Published: July 2018

<b><i>Background:</i></b> Many epidemiological studies have investigated the effect of maternal diet and prenatal multivitamin supplementation on pediatric cancer risk. Childhood brain and spinal cord tumors (CBSCT) have been attributed to different possible risk factors. <b><i>Methods:</i></b> We conducted a systematic review and meta-analysis on maternal folate intake before and during pregnancy and the risk of CBSCT. We systematically reviewed publications obtained by searching the Insitute for Scientific Information Web of Knowledge and PubMed literature databases. We extracted the risk estimate of the highest and the lowest reported categories of intake from each study and conducted a meta-analysis using a random-effects model. <b><i>Results:</i></b> The results of the pooled analysis of all 10 studies, 1 cohort and 9 case-control studies, indicated that maternal folate intake was inversely associated with CBSCT risk (OR 0.77; 95% CI 0.67–0.88, <i>p</i> &#x3c; 0.001; <i>I</i><sup>2</sup> = 51.22%, <i>p</i> = 0.001). Separate analyses on the basis of the source of folate (folic acid supplementation, dietary folate) and in relation to the timing of exposure (before pregnancy, during pregnancy) found that folic acid supplementation was associated with an approximately 23% reduction in ­CBSCT risk (OR 0.77, 95% CI 0.66–0.90, <i>p</i> = 0.001; <i>I</i><sup>2</sup> = 53.18%, <i>p</i> = 0.001) and consumption during pregnancy was associated with an approximately 20% reduction in CBSCT risk (OR 0.80, 95% CI 0.67–0.97, <i>p</i> = 0.020; <i>I</i><sup>2</sup> = 62.48%, <i>p </i>&#x3c; 0·001). <b><i>Conclusions:</i></b> Maternal consumption of folic acid is associated with a reduced risk of CBSCT. Further investigations are necessary to increase the reliability of the results and estimate the relationship between dose-response and the best outcome.
Impacts of Ice Particle Shape and Density Evolution on the Distribution of Orographic Precipitation
Authors: Jensen Anders A. , Harrington Jerry Y. , Morrison Hugh 
Published: July 2018

Abstract
An IMPROVE-2 orographic precipitation case is simulated using the Ice-Spheroids Habit Model with Aspect-Ratio Evolution (ISHMAEL) microphysics. In ISHMAEL, the evolution of ice particle properties such as mass, shape, size, density, and fall speed are predicted. These ice particle properties along with the ice size distributions from ISHMAEL and model-derived spatial distribution of accumulated precipitation are compared to observations. ISHMAEL predicts planar and columnar particles at spatial locations that agree with observations. Sensitivity simulations are used to explore the impact of predicting ice particle shape evolution on orographic cloud properties and precipitation compared to the traditional approach of representing snow and graupel using separate categories with conversion from snow to graupel during riming. High biases in both IWCs aloft and surface precipitation accumulation occur in the Umpqua River valley using separate snow and graupel categories because snow that does not convert to graupel is advected over the Coast Range and precipitates out in the valley. Improvements in IWCs aloft and surface precipitation using ISHMAEL occur from both predicting various vapor-grown habits and predicting the impact of partial riming on ice particle properties. Compared to traditional microphysics schemes, ISHMAEL also produces less spatial variability in accumulated precipitation.
Influence of Turbulent Fluctuations on Cloud Droplet Size Dispersion and Aerosol Indirect Effects
Authors: Chandrakar K. K. , Cantrell W. , Shaw R. A. 
Published: July 2018

Abstract
Cloud droplet relative dispersion, defined as the standard deviation over the mean cloud droplet size, is of central importance in determining and understanding aerosol indirect effects. In recent work, it was found that cloud droplet size distributions become broader as a result of supersaturation variability and that the sensitivity of this effect is inversely related to cloud droplet number density. The subject is investigated in further detail using an extensive dataset from a laboratory cloud chamber capable of producing steady-state turbulence. An extended stochastic theory is found to successfully describe properties of the droplet size distribution, including an analytical expression for the relative dispersion. The latter is found to depend on the cloud droplet removal time, which in turn increases with the cloud droplet number density. The results show that relative dispersion decreases monotonically with increasing droplet number density, consistent with some recent atmospheric observations. Experiments spanning fast to slow microphysics regimes are reported. The observed dispersion is used to estimate time scales for autoconversion, demonstrating the important role of the turbulence-induced broadening effect on precipitation development. An initial effort is made to extend the stochastic theory to an atmospheric context with a steady updraft, for which autoconversion time is the controlling factor for droplet lifetime. As in the cloud chamber, relative dispersion is found to increase with decreasing cloud droplet number density.
Multitechnique Assessment of the Interannual to Multidecadal Variability in Steric Sea Levels: A Comparative Analysis of Climate Mode Fingerprints
Authors: Pfeffer Julia , Tregoning Paul , Purcell Anthony , Sambridge Malcolm 
Published: July 2018

AbstractBecause of increased emissions of greenhouse gases oceans are warming, causing sea level to rise as the density of seawater falls. Predicting the rates of steric expansion is challenging because of the natural variability of the ocean and because observations are insufficient to adequately cover the ocean basins. Here, we investigate the ability of one ocean reanalysis, two objective analyses, and one combination of satellite geodetic measurements to accommodate data gaps and to reconstruct typical patterns of the steric sea level variability at interannual and multidecadal time scales. Six climate indices are used to identify robust features of the internal variability, using a Least Absolute Shrinkage and Selection Operator (LASSO) regression to select significant predictors of the steric variability. Spatially consistent fingerprints are revealed for all climate indices in the ocean reanalysis dataset, allowing the recovery of most of the steric variability observed in the tropical and North Pacific, as well as large fractions of the Atlantic and Indian Ocean signals. Robust climate mode fingerprints are also identified with high spatial resolution but limited temporal coverage in the geodetic observations. The objective analyses fail to detect many of the patterns expected from climate modes, especially before the Argo era. Climate indices constitute valuable yet underexploited tools to assess the performance of different techniques to reconstruct steric sea levels at interannual and multidecadal scales. Such progress will increase confidence in the historical reconstructions of steric sea levels, which is necessary to improve the closure of regional and global sea level budgets and to validate the predictions of climate models.
Interannual Variation of the Spring and Summer Precipitation over the Three River Source Region in China and the Associated Regimes
Authors: Sun Bo , Wang Huijun 
Published: July 2018

AbstractThis study analyzes the interannual and interdecadal variability of spring and summer precipitation over the Three River Source (TRS) region in China using four datasets. A general consistency is revealed among the four datasets with regard to the interannual and interdecadal variability of TRS precipitation during 1979–2015, demonstrating a confidence of the four datasets in representing the precipitation variability over the TRS region. The TRS spring and summer precipitation shows distinct interannual and interdecadal variability, with an overall increasing trend in the spring precipitation and an interdecadal oscillation in the summer precipitation. The regimes associated with the interannual variability of TRS spring and summer precipitation are further investigated. The interannual variability of TRS spring precipitation is essentially modulated by an anomalous easterly water vapor transport (WVT) branch associated with the leading mode of Eurasian spring circulation. El Niño–Southern Oscillation (ENSO) may affect the interannual variability of TRS spring precipitation by causing southerly WVT anomalies toward the TRS region. The interannual variability of TRS summer precipitation is essentially modulated by an anomalous southwesterly WVT branch over the TRS region, which is mainly associated with a Eurasian wave train connected with the summer North Atlantic Oscillation. A strong East Asian summer monsoon and an El Niño–decaying summer may also contribute to the southwesterly WVT anomalies over the TRS region.
Variability of the Cold Season Climate in Central Asia. Part I: Weather Types and Their Tropical and Extratropical Drivers
Authors: Gerlitz Lars , Steirou Eva , Schneider Christoph , Moron Vincent , Vorogushyn Sergiy , Merz Bruno 
Published: July 2018

AbstractTo understand the atmospheric mechanisms resulting in a pronounced cold season climate variability in central Asia, an objective weather-type classification is conducted, utilizing ak-means-based clustering approach applied to 500-hPa geopotential height (GPH) fields. Eight weather types (WT) are identified and analyzed with regard to characteristic pressure patterns and moisture fluxes over Eurasia and specific near-surface climate conditions over central Asia. To identify remote drivers of the central Asian climate, WT frequencies are analyzed for their relationships with tropical and extratropical teleconnection modes. The results indicate an influence of Northern Hemispheric planetary wave tracks on westerly moisture fluxes with positive anomalies of precipitation associated with the formation of a Rossby trough over central Asia. Particularly the propagation of the east Atlantic–western Russia and the Scandinavian patterns is shown to modulate regional climate conditions. Variations of ENSO are shown to affect the frequency of particular WTs because of the formation of an anticyclonic anomaly over the Indian Ocean and an increase of tropical fluxes of moisture and heat into central Asia during El Niño events. Further a WT internal influence of ENSO is distinctly defined, with enhanced moisture supply during the ENSO warm phase. The analysis of climatic trends shows that 50% of observed temperature changes can be assigned to variations of the WT composition, indicating that most likely changing regional circulation characteristics account for the enhanced warming rates in central Asia. Trends of precipitation sums are likewise shown to be associated with changing WT frequencies, although the WT–precipitation relationships include large uncertainties.
Revisiting the Relationship among Metrics of Tropical Expansion
Authors: Waugh D. W. , Grise K. M. , Seviour W. J. M. , Davis S. M. , Davis N. , Adam O. , Son S.-W. , Simpson I. R. , Staten P. W. , Maycock A. C. , Ummenhofer C. C. , Birner T. , Ming A. 
Published: July 2018

AbstractThere is mounting evidence that the width of the tropics has increased over the last few decades, but there are large differences in reported expansion rates. This is, likely, in part due to the wide variety of metrics that have been used to define the tropical width. Here we perform a systematic investigation into the relationship among nine metrics of the zonal-mean tropical width using preindustrial control and abrupt quadrupling of CO2 simulations from a suite of coupled climate models. It is shown that the latitudes of the edge of the Hadley cell, the midlatitude eddy-driven jet, the edge of the subtropical dry zones, and the Southern Hemisphere subtropical high covary interannually and exhibit similar long-term responses to a quadrupling of CO2. However, metrics based on the outgoing longwave radiation, the position of the subtropical jet, the break in the tropopause, and the Northern Hemisphere subtropical high have very weak covariations with the above metrics and/or respond differently to increases in CO2 and thus are not good indicators of the expansion of the Hadley cell or subtropical dry zone. The differing variability and responses to increases in CO2 among metrics highlights that care is needed when choosing metrics for studies of the width of the tropics and that it is important to make sure the metric used is appropriate for the specific phenomena and impacts being examined.
Marginal Ice Zone Thickness and Extent due to Wave Radiation Stress
Authors: Sutherland Peter , Dumont Dany 
Published: July 2018

AbstractOcean surface wave radiation stress represents the flux of momentum due to the waves. When waves are dissipated or reflected by sea ice, that momentum is absorbed or reflected, resulting in a horizontal forcing that frequently compresses the ice. In this work, wave radiation stress is used to estimate the compressive force applied by waves to the marginal ice zone (MIZ). It is balanced by an ice internal compressive stress based on Mohr–Coulomb granular materials theory. The ice internal stress can be related to ice thickness, allowing this force balance to be used as a model for the estimation of MIZ ice thickness. The model was validated and tested using data collected during two field campaigns in the St. Lawrence estuary in 2016 and 2017. Modeled ice thickness was found to be consistent with the mean measured ice thickness over the conditions available. The range of validity of the model is discussed, and a definition of MIZ extent, based on the relative strength of wind and wave forcing, is proposed.
A Quality Control Procedure Based on Bending Angle Measurement Uncertainty for Radio Occultation Data Assimilation in the Tropical Lower Troposphere
Authors: Liu Hui , Kuo Ying-Hwa , Sokolovskiy Sergey , Zou Xiaolei , Zeng Zhen , Hsiao Ling-Feng , Ruston Benjamin C. 
Published: July 2018

AbstractThe fluctuation of radio occultation (RO) signals in the presence of refractivity irregularities in the moist lower troposphere results in uncertainties of retrieved bending angle and refractivity profiles. In this study the local spectral width (LSW) of RO signals, transformed to impact parameter representation, is used for the characterization of the uncertainty (random error) of retrieved bending angle and refractivity profiles. A large LSW has some correlation with the large mean difference (bias) of retrieved refractivity and bending angle from radiosondes and European Centre for Medium-Range Weather Forecasts analyses based on data from 2008 to 2014. An LSW-based quality control (QC) procedure is developed to eliminate low-quality (large random errors and biases) profiles from data assimilation. The LSW-based QC procedure is tested and evaluated in the assimilation of Constellation Observing System for Meteorology, Ionosphere and Climate RO data using the NCAR Data Assimilation Research Testbed and the Weather Research and Forecasting Model. Preliminary results, based on a 2-week data assimilation cycle, show that the LSW-based QC procedure improves water vapor analyses in the moist lower troposphere.
What Is the Added Value of a Convection-Permitting Model for Forecasting Extreme Rainfall over Tropical East Africa?
Authors: Woodhams Beth J. , Birch Cathryn E. , Marsham John H. , Bain Caroline L. , Roberts Nigel M. , Boyd Douglas F. A. 
Published: July 2018

ABSTRACT
Forecasting convective rainfall in the tropics is a major challenge for numerical weather prediction. The use of convection-permitting (CP) forecast models in the tropics has lagged behind the midlatitudes, despite the great potential of such models in this region. In the scientific literature, there is very little evaluation of CP models in the tropics, especially over an extended time period. This paper evaluates the prediction of convective storms for a period of 2 years in the Met Office operational CP model over East Africa and the global operational forecast model. A novel localized form of the fractions skill score is introduced, which shows variation in model skill across the spatial domain. Overall, the CP model and the global model both outperform a 24-h persistence forecast. The CP model shows greater skill than the global model, in particular on subdaily time scales and for storms over land. Forecasts over Lake Victoria are also improved in the CP model, with an increase in hit rate of up to 20%. Contrary to studies in the midlatitudes, the skill of both models shows a large dependence on the time of day and comparatively little dependence on the forecast lead time within a 48-h forecast. Although these results provide more motivation for forecasters to use the CP model to produce subdaily forecasts with increased detail, there is a clear need for more in situ observations for data assimilation into the models and for verification. A move toward ensemble forecasting could have further benefits.
Is There a “Tipping Point” between Simulated Nontornadic and Tornadic Supercells in VORTEX2 Environments?
Authors: Coffer Brice E. , Parker Matthew D. 
Published: July 2018

Abstract
Previous work has suggested that the lower-tropospheric wind profile may partly determine whether supercells become tornadic. If tornadogenesis within the VORTEX2 composite environments is more sensitive to the lower-tropospheric winds than to either the upper-tropospheric winds or the thermodynamic profile, then systematically varying the lower-tropospheric wind profile might reveal a “tipping point” between nontornadic and tornadic supercells. As a test, simulated supercells are initiated in environments that have been gradually interpolated between the low-level wind profiles of the nontornadic and tornadic VORTEX2 supercell composites while also interchanging the upper-tropospheric winds and thermodynamic profile. Simulated supercells become tornadic when the low-level wind profile incorporates at least 40% of the structure from the tornadic VORTEX2 composite environment. Both the nontornadic and tornadic storms have similar outflow temperatures and availability of surface vertical vorticity near their updrafts. Most distinctly, a robust low-level mesocyclone and updraft immediately overlie the intensifying near-surface circulation in each of the tornadic supercells. The nontornadic supercells have low-level updrafts that are disorganized, with pockets of descent throughout the region where surface vertical vorticity resides. The lower-tropospheric wind profile drives these distinct configurations of the low-level mesocyclone and updraft, regardless of the VORTEX2 composite upper-tropospheric wind profile or thermodynamic profile. This study therefore supports a potentially useful, robust link between the probability of supercell tornadogenesis and the lower-tropospheric wind profile, with tornadogenesis more (less) likely when the orientation of horizontal vorticity in the lowest few hundred meters is streamwise (crosswise).