bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma
Authors: Ryan Russell J.H. , Drier Yotam , Whitton Holly , Cotton M. Joel , Kaur Jasleen , Issner Robbyn , Gillespie Shawn , Epstein Charles B. , Nardi Valentina , Sohani Aliyah R. , Hochberg Ephraim P. , Bernstein Bradley E. 
Published: July 2015

Abstract
B-cell lymphomas frequently contain genomic rearrangements that lead to oncogene activation by heterologous distal regulatory elements. We used a novel approach called “pinpointing enhancer-associated rearrangements by chromatin immunoprecipitation,” or PEAR-ChIP, to simultaneously map enhancer activity and proximal rearrangements in lymphoma cell lines and patient biopsies. This method detects rearrangements involving known cancer genes, including CCND1, BCL2, MYC, PDCD1LG2, NOTCH1, CIITA, and SGK1, as well as novel enhancer duplication events of likely oncogenic significance. We identify lymphoma subtype–specific enhancers in the MYC locus that are silenced in lymphomas with MYC-activating rearrangements and are associated with germline polymorphisms that alter lymphoma risk. We show that BCL6-locus enhancers are acetylated by the BCL6-activating transcription factor MEF2B, and can undergo genomic duplication, or target the MYC promoter for activation in the context of a “pseudo-double-hit” t(3;8)(q27;q24) rearrangement linking the BCL6 and MYC loci. Our work provides novel insights regarding enhancer-driven oncogene activation in lymphoma.
Significance: We demonstrate a novel approach for simultaneous detection of genomic rearrangements and enhancer activity in tumor biopsies. We identify novel mechanisms of enhancer-driven regulation of the oncogenes MYC and BCL6, and show that the BCL6 locus can serve as an enhancer donor in an “enhancer hijacking” translocation. Cancer Discov; 5(10); 1058–71. ©2015 AACR.
See related commentary by Mack et al., p. 1018.
This article is highlighted in the In This Issue feature, p. 1005
An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101
Authors: Doebele Robert C. , Davis Lara E. , Vaishnavi Aria , Le Anh T. , Estrada-Bernal Adriana , Keysar Stephen , Jimeno Antonio , Varella-Garcia Marileila , Aisner Dara L. , Li Yali , Stephens Philip J. , Morosini Deborah , Tuch Brian B. , Fernandes Michele , Nanda Nisha , Low Jennifer A. 
Published: July 2015

Abstract
Oncogenic TRK fusions induce cancer cell proliferation and engage critical cancer-related downstream signaling pathways. These TRK fusions occur rarely, but in a diverse spectrum of tumor histologies. LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors. Preclinical models of LOXO-101 using TRK-fusion–bearing human-derived cancer cell lines demonstrate inhibition of the fusion oncoprotein and cellular proliferation in vitro, and tumor growth in vivo. The tumor of a 41-year-old woman with soft-tissue sarcoma metastatic to the lung was found to harbor an LMNA–NTRK1 gene fusion encoding a functional LMNA–TRKA fusion oncoprotein as determined by an in situ proximity ligation assay. In a phase I study of LOXO-101 (ClinicalTrials.gov no. NCT02122913), this patient's tumors underwent rapid and substantial tumor regression, with an accompanying improvement in pulmonary dyspnea, oxygen saturation, and plasma tumor markers.
Significance: TRK fusions have been deemed putative oncogenic drivers, but their clinical significance remained unclear. A patient with a metastatic soft-tissue sarcoma with an LMNA–NTRK1 fusion had rapid and substantial tumor regression with a novel, highly selective TRK inhibitor, LOXO-101, providing the first clinical evidence of benefit from inhibiting TRK fusions. Cancer Discov; 5(10); 1049–57. ©2015 AACR.
This article is highlighted in the In This Issue feature, p. 1005
Complement Factor H Antibodies from Lung Cancer Patients Induce Complement-Dependent Lysis of Tumor Cells, Suggesting a Novel Immunotherapeutic Strategy
Authors: Campa Michael J. , Gottlin Elizabeth B. , Bushey Ryan T. , Patz Edward F. 
Published: July 2015

Abstract
Characterization of the humoral immune response in selected patients with cancer who uniformly do well may lead to the development of novel therapeutic strategies. We have previously shown an association between patients with early-stage nonmetastatic lung cancer and autoantibodies to complement factor H (CFH). CFH protects normal and tumor cells from destruction by the alternative complement pathway by inactivating C3b, a protein that is essential for formation of a lytic complex on the cell surface. Here, we show that CFH autoantibodies in lung cancer patients recognize a conformationally distinct form of CFH in vitro, are IgG3 subclass, and epitope map to a crucial functional domain of CFH known to interact with C3b. Purified CFH autoantibodies inhibited binding of CFH to A549 lung tumor cells, increased C3b deposition, and caused complement-dependent tumor cell lysis. This work demonstrates that CFH autoantibodies isolated from patients with lung cancer can kill tumor cells in vitro, suggesting that they may perform this function in vivo as well. Development of specific antibodies to the conformationally distinct epitope of CFH may lead to a useful biologic therapy for lung cancer. Cancer Immunol Res; 3(12); 1325–32. ©2015 AACR.
Asymptomatic Brugada Syndrome
Authors: Sieira Juan , Ciconte Giuseppe , Conte Giulio , Chierchia Gian-Battista , de Asmundis Carlo , Baltogiannis Giannis , Di Giovanni Giacomo , Saitoh Yukio , Irfan Ghazala , Casado-Arroyo Rubén , Julià Justo , La Meir Mark , Wellens Francis , Wauters Kristel , Pappaert Gudrun , Brugada Pedro 
Published: July 2015

Background—
Among Brugada syndrome patients, asymptomatic individuals are considered to be at the lowest risk. Nevertheless, arrhythmic events and sudden cardiac death are not negligible. Literature focused on this specific group of patients is sparse. The purpose of this study is to investigate the clinical characteristics, management, and long-term prognosis of asymptomatic Brugada syndrome patients.

Methods and Results—

Patients presenting with spontaneous or drug-induced Brugada type I ECG and no symptoms at our institution were considered eligible. A total of 363 consecutive patients (200 men, 55.1%; mean age, 40.9±17.2 years; 41 [11.3%] with spontaneous type I ECG) were included. Electrophysiological study was performed in 321 (88.4%) patients, and ventricular arrhythmias were induced in 32 (10%) patients. An implantable cardioverter defibrillator was implanted in 61 (16.8%) patients. After a mean follow-up time of 73.2±58.9 months, 9 arrhythmic events occurred, accounting for an annual incidence rate of 0.5%. Event-free survival was 99.0% at 1 year, 96.2% at 5 years, and 95.4% at 10 and 15 years. Univariate analysis identified as risk factors: electrophysiological study inducibility (hazard ratio, 11.4;
P
<0.01), spontaneous type I (hazard ratio, 4.0;
P
=0.04), and previous sinus node dysfunction (hazard ratio, 8.0; 95% confidence interval, 1.0–63.9;
P
=0.05). At the multivariate analysis, only inducibility remained significant (hazard ratio, 9.1;
P
<0.01)

Conclusions—
Arrhythmic events in asymptomatic Brugada syndrome patients are not insignificant. Ventricular arrhythmia inducibility, spontaneous type I ECG, and presence of sinus node dysfunction might be considered as risk factors and used to drive long-term management.
Effects of Wild-Type and Mutant Forms of Atrial Natriuretic Peptide on Atrial Electrophysiology and Arrhythmogenesis
Authors: Hua Rui , MacLeod Sarah L. , Polina Iuliia , Moghtadaei Motahareh , Jansen Hailey J. , Bogachev Oleg , O’Blenes Stacy B. , Sapp John L. , Legare Jean-Francois , Rose Robert A. 
Published: July 2015

Background—
Atrial natriuretic peptide (ANP) is a hormone with numerous beneficial cardiovascular effects. Recently, a mutation in the ANP gene, which results in the generation of a mutant form of ANP (mANP), was identified and shown to cause atrial fibrillation in people. The mechanism(s) through which mANP causes atrial fibrillation is unknown. Our objective was to compare the effects of wild-type ANP and mANP on atrial electrophysiology in mice and humans.

Methods and Results—

Action potentials (APs), L-type Ca
2+
currents (
I
Ca,L
), and Na
+
current were recorded in atrial myocytes from wild-type or natriuretic peptide receptor C knockout (NPR-C
−/−
) mice. In mice, ANP and mANP (10–100 nmol/L) had opposing effects on atrial myocyte AP morphology and
I
Ca,L
. ANP increased AP upstroke velocity (
V
max
), AP duration, and
I
Ca,L
similarly in wild-type and NPR-C
−/−
myocytes. In contrast, mANP decreased
V
max
, AP duration, and
I
Ca,L
, and these effects were completely absent in NPR-C
−/−
myocytes. ANP and mANP also had opposing effects on
I
Ca,L
in human atrial myocytes. In contrast, neither ANP nor mANP had any effect on Na
+
current in mouse atrial myocytes. Optical mapping studies in mice demonstrate that ANP sped electric conduction in the atria, whereas mANP did the opposite and slowed atrial conduction. Atrial pacing in the presence of mANP induced arrhythmias in 62.5% of hearts, whereas treatment with ANP completely prevented the occurrence of arrhythmias.

Conclusions—
These findings provide mechanistic insight into how mANP causes atrial fibrillation and demonstrate that wild-type ANP is antiarrhythmic.
Left Atrial Appendage Occlusion Device and Novel Oral Anticoagulants Versus Warfarin for Stroke Prevention in Nonvalvular Atrial Fibrillation
Authors: Briceno David F. , Villablanca Pedro , Cyrille Nicole , Massera Daniele , Bader Eric , Manheimer Eric , Aagaard Philip , Ferrick Kevin , Gross Jay , Kim Soo Gyum , Krumerman Andrew , Palma Eugen , Guttenplan Nils , Romero Jorge , Fisher John , Garcia Mario , Natale Andrea , Di Biase Luigi 
Published: July 2015

Background—
Nonvalvular atrial fibrillation is the most common arrhythmia. Patients with nonvalvular atrial fibrillation are at increased risk of stroke; therefore, we evaluated the efficacy and safety of different approaches to prevent this major complication.

Methods and Results—

We conducted electronic database searches of phase III randomized controlled trials. The groups were novel oral anticoagulants, Watchman left atrial appendage occlusion device (DEVICE), and warfarin. Efficacy outcomes were stroke or systemic embolism, and all-cause mortality. Safety outcome was major bleeding and procedure-related complications. A subgroup analysis of the elderly population was done. We used random-effects model to compare pooled outcomes and tested for heterogeneity. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for each outcome. Seven randomized controlled trials (n=73 978) were included. There was a significant difference favoring novel oral anticoagulants for systemic embolism (OR, 0.84; 95% CI, 0.72–0.97;
P
=0.01), all-cause mortality (OR, 0.89; 95% CI, 0.84–0.94;
P
<0.001), and safety outcomes (OR, 0.79; 95% CI, 0.65–0.97;
P
=0.026) compared with warfarin. No difference was seen between DEVICE and warfarin for efficacy end points; however, DEVICE had more complications (OR, 1.85; 95% CI, 1.14–3.01;
P
=0.012). In the elderly (6 randomized controlled trials, n=30 699), systemic embolism was favored with novel oral anticoagulants over warfarin (OR, 0.77; 95% CI, 0.68–0.87;
P
≤0.001). No evidence of significant publication bias was found.

Conclusions—
Novel oral anticoagulants is superior to warfarin for stroke prevention in nonvalvular atrial fibrillation. This benefit was also observed in the elderly population. DEVICE is a reasonable noninferior alternative to warfarin for stroke prevention, but cautious use is essential given safety concerns.
Effects of Pravastatin on Human Placenta, Endothelium, and Women With Severe Preeclampsia
Authors: Brownfoot Fiona C. , Tong Stephen , Hannan Natalie J. , Binder Natalie K. , Walker Susan P. , Cannon Ping , Hastie Roxanne , Onda Kenji , Kaitu’u-Lino Tu’uhevaha J. 
Published: July 2015

Abstract—
Preeclampsia is a major pregnancy complication where excess placental release of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin causes maternal endothelial and multisystem organ injury. Clinical trials have commenced examining whether pravastatin can be used to treat preeclampsia. However, the preclinical evidence supporting pravastatin as a treatment is limited to animal models, with almost no studies in human tissues. Therefore, we examined whether pravastatin reduced sFlt-1 and soluble endoglin secretion and decreased endothelial dysfunction in primary human tissues. Pravastatin reduced sFlt-1 secretion from primary endothelial cells, purified cytotrophoblast cells, and placental explants obtained from women with preterm preeclampsia. It increased soluble endoglin secretion from endothelial cells but did not change secretion from placental explants. The regulation of sFlt-1 by pravastatin seemed to be mediated via the 3-hydroxy-3-methylglutaryl-coenzyme A reductase cholesterol synthesis pathway. Pravastatin also reduced markers of endothelial dysfunction, including vascular cell adhesion molecule-1 expression and leukocyte adhesion on endothelial cells and increased endothelial cell migration and invasion. We also treated 4 patients with preterm preeclampsia presenting at <30 weeks of gestation with daily pravastatin. Pravastatin seemed to stabilize blood pressure, proteinuria, and serum uric acid levels. Furthermore, serum sFlt-1 levels decreased. We collected the placentas at delivery and found that pravastatin reduced sFlt-1 secretion. These results indicate that pravastatin reduced sFlt-1 and soluble endoglin production and decreased endothelial dysfunction in primary human tissues. We also present pilot data, suggesting that pravastatin can stabilize clinical and biochemical features of preterm preeclampsia. Our data obtained in human tissues support the concept that pravastatin is a candidate therapeutic for preeclampsia.

Clinical Trial Registration—

URL:
http://www.anzctr.org.au
. Unique identifier: ACTRN12613000268741.
The USArray Transportable Array as a Platform for Weather Observation and Research
Authors: Tytell Jonathan , Vernon Frank , Hedlin Michael , de Groot Hedlin Catherine , Reyes Juan , Busby Bob , Hafner Katrin , Eakins Jennifer 
Published: July 2015

Abstract
The USArray Transportable Array (TA), a component of the National Science Foundation’s EarthScope Initiative, has proven to be a successful model for large-scale real-time monitoring networks. Approximately 400 stations are deployed simultaneously in the continental United States on a nominal Cartesian grid across an area of approximately 2,000,000 km2. Each station was originally designed to operate autonomously as a seismic observing platform capable of recording and transmitting data at 1 and 40 samples per second in real time. The expansion of onboard instrumentation to include surface atmospheric pressure sensors improved the USArray’s real-time capability in monitoring the atmosphere and weather phenomena at the same sample rates. Though not a traditional weather monitoring station, the combination of these seismic and pressure sensors at each TA station can contribute to the observation of surface weather phenomena and has facilitated broader-scale observational applications. Twenty-five TA stations have a Vaisala WXT520 weather station installed in order to create an observational array of “full meteorological” (full-met) stations. Meteorological phenomena have been recorded in high detail, including a data quality comparison between a pair of TA and National Weather Service (NWS) stations, a gust-front passage, rainfall measurements following a squall-line passage, and a near pass of a tornado by one station. Additional products have been constructed from the TA data for visualization and research purposes. The large spatial extent and station configuration of the TA network increases the probability for making high-resolution recordings of data from rare encounters with atmospheric events.
Parameterization of the Spatial Variability of Rain for Large-Scale Models and Remote Sensing
Authors: Lebo Z. J. , Williams C. R. , Feingold G. , Larson V. E. 
Published: July 2015

AbstractThe spatial variability of rain rate R is evaluated by using both radar observations and cloud-resolving model output, focusing on the Tropical Warm Pool–International Cloud Experiment (TWP-ICE) period. In general, the model-predicted rain-rate probability distributions agree well with those estimated from the radar data across a wide range of spatial scales. The spatial variability in R, which is defined according to the standard deviation of R (for R greater than a predefined threshold Rmin) σ(R), is found to vary according to both the average of R over a given footprint μ(R) and the footprint size or averaging scale Δ. There is good agreement between area-averaged model output and radar data at a height of 2.5 km. The model output at the surface is used to construct a scale-dependent parameterization of σ(R) as a function of μ(R) and Δ that can be readily implemented into large-scale numerical models. The variability in both the rainwater mixing ratio qr and R as a function of height is also explored. From the statistical analysis, a scale- and height-dependent formulation for the spatial variability of both qr and R is provided for the analyzed tropical scenario. Last, it is shown how this parameterization can be used to assist in constraining parameters that are often used to describe the surface rain-rate distribution.
Drop Size Distributions and Radar Observations of Convective and Stratiform Rain over the Equatorial Indian and West Pacific Oceans
Authors: Thompson Elizabeth J. , Rutledge Steven A. , Dolan Brenda , Thurai Merhala 
Published: July 2015

Abstract
Two-dimensional video disdrometer (2DVD) data were analyzed from two equatorial Indian (Gan) and west Pacific Ocean (Manus) islands where precipitation is primarily organized by the intertropical convergence zone and the Madden–Julian oscillation (MJO). The 18 (3.5) months of 2DVD data from Manus (Gan) Island show that 1) the two sites have similar drop size distribution (DSD) spectra of liquid water content, median diameter, rain rate R, radar reflectivity z, normalized gamma number concentration Nw, and other integral rain parameters; 2) there is a robust Nw-based separation between convective (C) and stratiform (S) DSDs at both sites that produces consistent separation in other parameter spaces.
The 2DVD data indicate an equatorial, maritime average C/S rainfall accumulation fraction (frequency) of 81/19 (41/59) at these locations. It is hypothesized that convective fraction and frequency estimates are slightly higher than previous radar-based studies, because the ubiquitous weak, shallow convection (&lt;10 mm h−1) characteristic of the tropical warm pool is properly resolved by this high-resolution DSD dataset and identification method. This type of convection accounted for about 30% of all rain events and 15% of total rain volume. These rain statistics were reproduced when newly derived C/S R(z) equations were applied to 2DVD-simulated reflectivity. However, the benefits of using separate C/S R(z) equations are only realizable when C/S partitioning properly classifies each rain type. A single R(z) relationship fit to all 2DVD data yielded accurate total rainfall amounts but overestimated (underestimated) the stratiform (convective) rain fraction by ±10% and overestimated (underestimated) stratiform (convective) rain accumulation by +50% (−15%).
Evaluation of a Regional Climate Modeling Effort for the Western United States Using a Superensemble from Weather@home*
Authors: Li Sihan , Mote Philip W. , Rupp David E. , Vickers Dean , Mera Roberto , Allen Myles 
Published: July 2015

Abstract
Simulations from a regional climate model (RCM) as part of a superensemble experiment were compared with observations of surface meteorological variables over the western United States. The RCM is the Hadley Centre Regional Climate Model, version 3, with improved physics parameterizations (HadRM3P) run at 25-km resolution and nested within the Hadley Centre Atmosphere Model, version 3 (HadAM3P). Overall, the means of seasonal temperature were well represented in the simulations; 95% of grid points were within 2.7°, 2.4°, and 3.6°C of observations in winter, spring, and summer, respectively. The model was too warm over most of the domain in summer except central California and southern Nevada. HadRM3P produced more extreme temperatures than observed. The overall magnitude and spatial pattern of precipitation were well characterized, though HadRM3P exaggerated the orographic enhancement along the coastal mountains, Cascade Range, and Sierra Nevada. HadRM3P produced warm/dry northwest, cool/wet southwest U.S. patterns associated with El Niño. However, there were notable differences, including the locations of the transition from warm (dry) to cool (wet) in the anomaly fields when compared with observations, though there was disagreement among observations. HadRM3P simulated the observed spatial pattern of mean annual temperature more faithfully than any of the RCM–GCM pairings in the North American Regional Climate Change Assessment Program (NARCCAP). Errors in mean annual precipitation from HadRM3P fell within the range of errors of the NARCCAP models. Last, this paper provided examples of the size of an ensemble required to detect changes at the local level and demonstrated the effect of parameter perturbation on regional precipitation.
Cloud Object Analysis of CERES Aqua Observations of Tropical and Subtropical Cloud Regimes: Four-Year Climatology
Authors: Xu Kuan-Man , Wong Takmeng , Dong Shengtao , Chen Feng , Kato Seiji , Taylor Patrick C. 
Published: July 2015

Abstract
Four distinct types of cloud objects—tropical deep convection, boundary layer cumulus, stratocumulus, and overcast stratus—were previously identified from CERES Tropical Rainfall Measuring Mission (TRMM) data. Six additional types of cloud objects—cirrus, cirrocumulus, cirrostratus, altocumulus, transitional altocumulus, and solid altocumulus—are identified from CERES Aqua satellite data in this study. The selection criteria for the 10 cloud object types are based on CERES footprint cloud fraction and cloud-top pressure, as well as cloud optical depth for the high-cloud types. The cloud object is a contiguous region of the earth with a single dominant cloud-system type. The data are analyzed according to cloud object types, sizes, regions, and associated environmental conditions. The frequency of occurrence and probability density functions (PDFs) of selected physical properties are produced for the July 2006–June 2010 period. It is found that deep convective and boundary layer types dominate the total population while the six new types other than cirrostratus do not contribute much in the tropics and subtropics. There are pronounced differences in the size spectrum between the types, with the largest ones being of deep convective type and with stratocumulus and overcast types over the ocean basins off west coasts. The summary PDFs of radiative and cloud physical properties differ greatly among the size categories. For boundary layer cloud types, the differences come primarily from the locations of cloud objects: for example, coasts versus open oceans. They can be explained by considerable variations in large-scale environmental conditions with cloud object size, which will be further qualified in future studies.