bluuebunny/crossref_metadata_2025_split huggingface dataset:
Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells
Authors: Fiskus Warren , Sharma Sunil , Qi Jun , Valenta John A. , Schaub Leasha J. , Shah Bhavin , Peth Karissa , Portier Bryce P. , Rodriguez Melissa , Devaraj Santhana G.T. , Zhan Ming , Sheng Jianting , Iyer Swaminathan P. , Bradner James E. , Bhalla Kapil N. 
Published: January 2014

Abstract
The bromodomain and extra-terminal (BET) protein family members, including BRD4, bind to acetylated lysines on histones and regulate the expression of important oncogenes, for example, c-MYC and BCL2. Here, we demonstrate the sensitizing effects of the histone hyperacetylation-inducing pan–histone deacetylase (HDAC) inhibitor panobinostat on human acute myelogenous leukemia (AML) blast progenitor cells (BPC) to the BET protein antagonist JQ1. Treatment with JQ1, but not its inactive enantiomer (R-JQ1), was highly lethal against AML BPCs expressing mutant NPM1c+ with or without coexpression of FLT3-ITD or AML expressing mixed lineage leukemia fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of c-MYC and BCL2 and reduced their levels in the AML cells. Cotreatment with JQ1 and the HDAC inhibitor panobinostat synergistically induced apoptosis of the AML BPCs, but not of normal CD34+ hematopoietic progenitor cells. This was associated with greater attenuation of c-MYC and BCL2, while increasing p21, BIM, and cleaved PARP levels in the AML BPCs. Cotreatment with JQ1 and panobinostat significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (P &lt; 0.01). These findings highlight cotreatment with a BRD4 antagonist and an HDAC inhibitor as a potentially efficacious therapy of AML. Mol Cancer Ther; 13(5); 1142–54. ©2014 AACR.
Targeting Microtubules by Natural Agents for Cancer Therapy
Authors: Mukhtar Eiman , Adhami Vaqar Mustafa , Mukhtar Hasan 
Published: January 2014

Abstract
Natural compounds that target microtubules and disrupt the normal function of the mitotic spindle have proven to be one of the best classes of cancer chemotherapeutic drugs available in clinics to date. There is increasing evidence showing that even minor alteration of microtubule dynamics can engage the spindle checkpoint, arresting cell-cycle progression at mitosis and subsequently leading to cell death. Our improved understanding of tumor biology and our continued appreciation for what the microtubule targeting agents (MTAs) can do have helped pave the way for a new era in the treatment of cancer. The effectiveness of these agents for cancer therapy has been impaired, however, by various side effects and drug resistance. Several new MTAs have shown potent activity against the proliferation of various cancer cells, including resistance to the existing MTAs. Sustained investigation of the mechanisms of action of MTAs, development and discovery of new drugs, and exploring new treatment strategies that reduce side effects and circumvent drug resistance could provide more effective therapeutic options for patients with cancer. This review focuses on the successful cancer chemotherapy from natural compounds in clinical settings and the challenges that may abort their usefulness. Mol Cancer Ther; 13(2); 275–84. ©2014 AACR.
Functional Heterogeneity of PAX5 Chimeras Reveals Insight for Leukemia Development
Authors: Fortschegger Klaus , Anderl Stefanie , Denk Dagmar , Strehl Sabine 
Published: January 2014

Abstract
PAX5, a transcription factor pivotal for B-cell commitment and maintenance, is one of the most frequent targets of somatic mutations in B-cell precursor acute lymphoblastic leukemia. A number of PAX5 rearrangements result in the expression of in-frame fusion genes encoding chimeric proteins, which at the N-terminus consistently retain the PAX5 DNA-binding paired domain fused to the C-terminal domains of a markedly heterogeneous group of fusion partners. PAX5 fusion proteins are thought to function as aberrant transcription factors, which antagonize wild-type PAX5 activity. To gain mechanistic insight into the role of PAX5 fusion proteins in leukemogenesis, the biochemical and functional properties of uncharacterized fusions: PAX5–DACH1, PAX5–DACH2, PAX5–ETV6, PAX5–HIPK1, and PAX5–POM121 were ascertained. Independent of the subcellular distribution of the wild-type partner proteins, ectopic expression of all PAX5 fusion proteins showed a predominant nuclear localization, and by chromatin immunoprecipitation all of the chimeric proteins exhibited binding to endogenous PAX5 target sequences. Furthermore, consistent with the presence of potential oligomerization motifs provided by the partner proteins, the self-interaction capability of several fusion proteins was confirmed. Remarkably, a subset of the PAX5 fusion proteins conferred CD79A promoter activity; however, in contrast with wild-type PAX5, the fusion proteins were unable to induce Cd79a transcription in a murine plasmacytoma cell line. These data show that leukemia-associated PAX5 fusion proteins share some dominating characteristics such as nuclear localization and DNA binding but also show distinctive features.
Implications: This comparative study of multiple PAX5 fusion proteins demonstrates both common and unique properties, which likely dictate their function and impact on leukemia development. Mol Cancer Res; 12(4); 595–606. ©2014 AACR.
Rapid Induction of Apoptosis by PI3K Inhibitors Is Dependent upon Their Transient Inhibition of RAS–ERK Signaling
Authors: Will Marie , Qin Alice Can Ran , Toy Weiyi , Yao Zhan , Rodrik-Outmezguine Vanessa , Schneider Claudia , Huang Xiaodong , Monian Prashant , Jiang Xuejun , de Stanchina Elisa , Baselga José , Liu Ningshu , Chandarlapaty Sarat , Rosen Neal 
Published: January 2014

AbstractThe effects of selective phosphoinositide 3-kinase (PI3K) and AKT inhibitors were compared in human tumor cell lines in which the pathway is dysregulated. Both caused inhibition of AKT, relief of feedback inhibition of receptor tyrosine kinases, and growth arrest. However, only the PI3K inhibitors caused rapid induction of cell death. In seeking a mechanism for this phenomenon, we found that PI3K inhibition, but not AKT inhibition, causes rapid inhibition of wild-type RAS and of RAF–MEK–ERK signaling. Inhibition of RAS–ERK signaling is transient, rebounding a few hours after drug addition, and is required for rapid induction of apoptosis. Combined MEK and AKT inhibition also promotes cell death, and in murine models of HER2+ cancer, either pulsatile PI3K inhibition or combined MEK and AKT inhibition causes tumor regression. We conclude that PI3K is upstream of RAS and AKT and that pulsatile inhibition of both pathways is sufficient for effective antitumor activity.Significance: We show that the RAS–ERK pathway is a key downstream effector pathway of oncogenic PI3K. Coordinate downregulation of AKT and ERK is necessary for induction of apoptosis and antitumor activity and can be accomplished with pulsatile dosing, which will likely decrease toxicity and allow administration of therapeutic doses. Cancer Discov; 4(3); 334–47. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 259
Multilocus Genetic Risk Score Associates With Ischemic Stroke in Case–Control and Prospective Cohort Studies
Authors: Malik Rainer , Bevan Steve , Nalls Michael A. , Holliday Elizabeth G. , Devan William J. , Cheng Yu-Ching , Ibrahim-Verbaas Carla A. , Verhaaren Benjamin F.J. , Bis Joshua C. , Joon Aron Y. , de Stefano Anita L. , Fornage Myriam , Psaty Bruce M. , Ikram M. Arfan , Launer Lenore J. , van Duijn Cornelia M. , Sharma Pankaj , Mitchell Braxton D. , Rosand Jonathan , Meschia James F. , Levi Christopher , Rothwell Peter M. , Sudlow Cathie , Markus Hugh S. , Seshadri Sudha , Dichgans Martin 
Published: January 2014

Background and Purpose—
Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.

Methods—
Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.

Results—
A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case–control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.

Conclusions—
A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.
Predicting Stroke Through Genetic Risk Functions
Authors: Ibrahim-Verbaas Carla A. , Fornage Myriam , Bis Joshua C. , Choi Seung Hoan , Psaty Bruce M. , Meigs James B. , Rao Madhu , Nalls Mike , Fontes Joao D. , O’Donnell Christopher J. , Kathiresan Sekar , Ehret Georg B. , Fox Caroline S. , Malik Rainer , Dichgans Martin , Schmidt Helena , Lahti Jari , Heckbert Susan R. , Lumley Thomas , Rice Kenneth , Rotter Jerome I. , Taylor Kent D. , Folsom Aaron R. , Boerwinkle Eric , Rosamond Wayne D. , Shahar Eyal , Gottesman Rebecca F. , Koudstaal Peter J. , Amin Najaf , Wieberdink Renske G. , Dehghan Abbas , Hofman Albert , Uitterlinden André G. , DeStefano Anita L. , Debette Stephanie , Xue Luting , Beiser Alexa , Wolf Philip A. , DeCarli Charles , Ikram M. Arfan , Seshadri Sudha , Mosley Thomas H. , Longstreth W.T. , van Duijn Cornelia M. , Launer Lenore J. 
Published: January 2014

Background and Purpose—
Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

Methods—
The study includes 4 population-based cohorts with 2047 first incident strokes from 22 720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case–control study of ischemic stroke.

Results—

In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016,
P
=2.3×10
−6
; ischemic stroke: Δjoint area under the curve=0.021,
P
=3.7×10
−7
), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (
P
<10
−4
).

Conclusions—
The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.
Mild Hypothermia After Intravenous Thrombolysis in Patients With Acute Stroke
Authors: Piironen Katja , Tiainen Marjaana , Mustanoja Satu , Kaukonen Kirsi-Maija , Meretoja Atte , Tatlisumak Turgut , Kaste Markku 
Published: January 2014

Background and Purpose—
Hypothermia improves outcome in resuscitated patients and newborns with hypoxic brain injury. We studied the safety and feasibility of mild hypothermia in awake patients with stroke after intravenous thrombolysis.

Methods—
Patients were randomized 1:1 to mild hypothermia (35°C) or to standard stroke unit care within 6 hours of symptom onset. Hypothermia was induced with a surface-cooling device and cold saline infusions. Active cooling was restrained gradually after 12 hours at <35.5°C. The primary outcome measure was the number of patients with <36°C body temperature for >80% of the 12-hour cooling period.

Results—
We included 36 patients with a median of National Institutes of Health Stroke Scale score of 9 one hour after thrombolysis. Fifteen of 18 (83%) patients achieved the primary end point. Sixteen (89%) patients reached <35.5°C in a median time of 10 hours (range, 7–16 hours) from symptom onset, spent 10.5 hours (1–17 hours) in hypothermia, and were back to normothermia in 23 hours (15–29 hours). Few serious adverse events were more common in the hypothermia group. At 3 months, 7 patients (39%) in both groups had good outcome (modified Ranking Scale, 0–2), whereas poor outcome (modified Ranking Scale, 4–6) was twice as common in the normothermia group (44% versus 22%).

Conclusions—
Mild hypothermia with a surface-cooling device in an acute stroke unit is safe and feasible in thrombolyzed, spontaneously breathing patients with stroke, despite the adverse events.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00987922.
The Impact of Plantations on Weather and Climate in Coastal Desert Regions
Authors: Wulfmeyer Volker , Branch Oliver , Warrach-Sagi Kirsten , Bauer Hans-Stefan , Schwitalla Thomas , Becker Klaus 
Published: January 2014

AbstractRecent advances in technology permit the irrigation of dry, coastal areas, avoiding the use of fossil water and conflicts with other land use (e.g., for food production). Consequently, it becomes reasonable to consider large-scale plantations for mitigating increases in atmospheric concentrations by carbon sequestration and to study local modifications of weather and climate. This work investigates the impact of plantations in Oman and the Sonora Desert in Mexico assuming an area of about 100 km × 100 km. For this purpose, an advanced land surface–atmosphere model was adapted to the local changes of land cover and operated on the convection-permitting scale. Explicit simulations of the impact of the plantation on soil–vegetation–atmosphere feedback were performed for a duration of 1 yr. A strong modification of diurnal cycles of variables such as surface fluxes, temperature, and boundary layer depth was found. Over the plantations, the mean temperature decreased as a result of nonlinear changes of the diurnal cycle caused by less warming during the day than cooling during the night. Moreover, the plantations caused an increase in vertical instability and a modification of the horizontal flow leading to the development of convergence zones. During several isolated cases in summer, this process led to convection initiation and precipitation with an enhancement of about 30 mm in both areas, respectively. These convection-permitting simulations lend confidence that an increase in precipitation could be induced at the mesoscale by the introduction of vegetation in desert regions. Furthermore, this effect should be included in a quantitative assessment of climate engineering by afforestation.
A Method to Linearly Evaluate Rainfall Frequency–Intensity Distribution
Authors: Li Jian , Yu Rucong 
Published: January 2014

AbstractThis study presents a method to linearly evaluate the rainfall frequency–intensity distribution, which is an important component of climatological rainfall characteristics. To grasp and represent the key information of the rainfall frequency distribution by intensity, a two-parameter double exponential function is formulated and fitted to the hourly rainfall observation at each station. The values of the two parameters are estimated by transforming the distribution to a linear pattern. The two parameters determine the location and shape of the fitted distribution curve, and they have different modulating effects in different intensity categories, one governing the low-intensity section and the other dominating the intense rainfall. Through analysis of the estimated parameters, essential features of rainfall distribution can be obtained and assessed. The proposed method is applied to analyze the climatology and long-term variation of the late-summer rainfall in China. It is found that topography and monsoon circulation are two major factors controlling the rainfall frequency–intensity distribution. At stations with high surface altitudes and complex orography, the frequency of light rain is extremely high and the number of intense rainfall events is relatively small. In the plain areas of eastern China, especially those influenced by the main monsoon rain belt, heavy rainfall is more frequent. By tracking the displacement of the parameter pairs, the decadal changes in rainfall frequency–intensity distribution can be clearly visualized and evaluated on a plane constructed by the two parameters. The southern flooding and northern drought pattern can be attributed to the changes in light and moderate rainfall, while the intense rainfall exhibits opposite trends.
Utility of SCaMPR Satellite versus Ground-Based Quantitative Precipitation Estimates in Operational Flood Forecasting: The Effects of TRMM Data Ingest
Authors: Lee Haksu , Zhang Yu , Seo Dong-Jun , Kuligowski Robert J. , Kitzmiller David , Corby Robert 
Published: January 2014

Abstract
This study examines the utility of satellite-based quantitative precipitation estimates (QPEs) from the Self-Calibrating Multivariate Precipitation Retrieval (SCaMPR) algorithm for hydrologic prediction. In this work, two sets of SCaMPR QPEs, one without and the other with Tropical Rainfall Measurement Mission (TRMM) version 6 data integrated, were used as input forcing to the lumped National Weather Service hydrologic model to retrospectively generate flow simulations for 10 Texas catchments over 2000–07. The year 2000 was used for the model spinup, 2001–04 for calibration, and 2005–07 for validation. The results were validated using observed streamflow alongside similar simulations obtained using interpolated gauge QPEs with varying gauge network densities, and still others using the operational radar–gauge multisensor product (MAPX). The focus of the evaluation was on the high-flow events. A number of factors that could impact the relative utility of SCaMPR satellite QPE and gauge-only analysis (GMOSAIC) for flood prediction were examined, namely, 1) the incremental impacts of TRMM version 6 data ingest, 2) gauge density, 3) effects of calibration approaches, and 4) basin properties. Results indicate that ground-sensor-based QPEs in a broad sense outperform SCaMPR QPEs, while SCaMPR QPEs are competitive in a minority of catchments. TRMM ingest helped substantially improve the SCaMPR QPE–based simulation results. Change in calibration forcing, that is, calibrating the model using individual QPEs rather than the MAPX (the most accurate QPE), yielded overall improvements to the simulation accuracy but did not change the relative performance of the QPEs.
The Predictability of Rainfall over the Greater Horn of Africa. Part I: Prediction of Seasonal Rainfall
Authors: Nicholson Sharon E. 
Published: January 2014

Abstract
The predictability of each of the three rainy seasons affecting the Horn of Africa is examined using multiple linear regression and cross validation. In contrast to most other empirical forecast models, atmospheric dynamics are emphasized. Two geographical sectors are considered: the summer rainfall region with a single rainfall peak in the boreal summer and an equatorial rainfall region with rainy seasons in both the boreal spring and the boreal autumn. These two seasons are termed the “long rains” and “short rains,” respectively, in much of East Africa. Excellent predictability is noted 5 months in advance for both regions during the boreal autumn season and 2 months in advance for the summer season in the summer rainfall region. There is also excellent predictability for the short rains of the equatorial region 2 months in advance. Two notable findings are that atmospheric variables generally provide higher forecast skill than surface variables, such as sea surface temperatures and sea level pressure, and that ENSO and the Indian Ocean dipole provide less forecast skill than atmospheric variables associated with them. As in other studies, the results show that the spring predictability barrier limits the lead time for the forecasting of spring and summer rainfall.
Eulerian and Lagrangian Correspondence of High-Frequency Radar and Surface Drifter Data: Effects of Radar Resolution and Flow Components
Authors: Rypina I. I. , Kirincich A. R. , Limeburner R. , Udovydchenkov I. A. 
Published: January 2014

AbstractThis study investigated the correspondence between the near-surface drifters from a mass drifter deployment near Martha’s Vineyard, Massachusetts, and the surface current observations from a network of three high-resolution, high-frequency radars to understand the effects of the radar temporal and spatial resolution on the resulting Eulerian current velocities and Lagrangian trajectories and their predictability. The radar-based surface currents were found to be unbiased in direction but biased in magnitude with respect to drifter velocities. The radar systematically underestimated velocities by approximately 2 cm s−1 due to the smoothing effects of spatial and temporal averaging. The radar accuracy, quantified by the domain-averaged rms difference between instantaneous radar and drifter velocities, was found to be about 3.8 cm s−1. A Lagrangian comparison between the real and simulated drifters resulted in the separation distances of roughly 1 km over the course of 10 h, or an equivalent separation speed of approximately 2.8 cm s−1. The effects of the temporal and spatial radar resolution were examined by degrading the radar fields to coarser resolutions, revealing the existence of critical scales (1.5–2 km and 3 h) beyond which the ability of the radar to reproduce drifter trajectories decreased more rapidly. Finally, the importance of the different flow components present during the experiment—mean, tidal, locally wind-driven currents, and the residual velocities—was analyzed, finding that, during the study period, a combination of tidal, locally wind-driven, and mean currents were insufficient to reliably reproduce, with minimal degradation, the trajectories of real drifters. Instead, a minimum combination of the tidal and residual currents was required.