bluuebunny/crossref_metadata_2025_split huggingface dataset:
Network-Based Approaches to Understand the Roles of miR-200 and Other microRNAs in Cancer
Authors: Bracken Cameron P. , Khew-Goodall Yeesim , Goodall Gregory J. 
Published: June 2015

Abstract
microRNAs (miRNA) are well suited to the task of regulating gene expression networks, because any given miRNA has the capacity to target dozens, if not hundreds, of genes. The simultaneous targeting of multiple genes within a pathway may enable miRNAs to more strongly regulate the pathway, or to achieve more subtle control through the targeting of distinct subnetworks of genes. Therefore, as our capacity to discover miRNA targets en masse increases, so must our consideration of the complex networks in which these genes participate. We highlight recent studies in which the comprehensive identification of targets has been used to elucidate miRNA-regulated gene networks in cancer, focusing especially upon miRNAs such as members of the miR-200 family that regulate epithelial–mesenchymal transition (EMT), a reversible phenotypic switch whereby epithelial cells take on the more invasive properties of their mesenchymal counterparts. These studies have expanded our understanding of the roles of miRNAs in EMT, which were already known to form important regulatory loops with key transcription factors to regulate the epithelial or mesenchymal properties of cells. Cancer Res; 75(13); 2594–9. ©2015 AACR.
A Systematic Approach to Defining the microRNA Landscape in Metastasis
Authors: Mudduluru Giridhar , Abba Mohammed , Batliner Jasmin , Patil Nitin , Scharp Maike , Lunavat Taral R. , Leupold Jörg Hendrik , Oleksiuk Olga , Juraeva Dilafruz , Thiele Wilko , Rothley Melanie , Benner Axel , Ben-Neriah Yinon , Sleeman Jonathan , Allgayer Heike 
Published: June 2015

Abstract
The microRNA (miRNA) landscape changes during the progression of cancer. We defined a metastasis-associated miRNA landscape using a systematic approach. We profiled and validated miRNA and mRNA expression in a unique series of human colorectal metastasis tissues together with their matched primary tumors and corresponding normal tissues. We identified an exclusive miRNA signature that is differentially expressed in metastases. Three of these miRNAs were identified as key drivers of an EMT-regulating network acting though a number of novel targets. These targets include SIAH1, SETD2, ZEB2, and especially FOXN3, which we demonstrated for the first time as a direct transcriptional suppressor of N-cadherin. The modulation of N-cadherin expression had significant impact on migration, invasion, and metastasis in two different in vivo models. The significant deregulation of the miRNAs defining the network was confirmed in an independent patient set as well as in a database of diverse malignancies derived from more than 6,000 patients. Our data define a novel metastasis-orchestrating network based on systematic hypothesis generation from metastasis tissues. Cancer Res; 75(15); 3010–9. ©2015 AACR.
Co-occurring Genomic Alterations Define Major Subsets of KRAS-Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities
Authors: Skoulidis Ferdinandos , Byers Lauren A. , Diao Lixia , Papadimitrakopoulou Vassiliki A. , Tong Pan , Izzo Julie , Behrens Carmen , Kadara Humam , Parra Edwin R. , Canales Jaime Rodriguez , Zhang Jianjun , Giri Uma , Gudikote Jayanthi , Cortez Maria A. , Yang Chao , Fan Youhong , Peyton Michael , Girard Luc , Coombes Kevin R. , Toniatti Carlo , Heffernan Timothy P. , Choi Murim , Frampton Garrett M. , Miller Vincent , Weinstein John N. , Herbst Roy S. , Wong Kwok-Kin , Zhang Jianhua , Sharma Padmanee , Mills Gordon B. , Hong Waun K. , Minna John D. , Allison James P. , Futreal Andrew , Wang Jing , Wistuba Ignacio I. , Heymach John V. 
Published: June 2015

Abstract
The molecular underpinnings that drive the heterogeneity of KRAS-mutant lung adenocarcinoma are poorly characterized. We performed an integrative analysis of genomic, transcriptomic, and proteomic data from early-stage and chemorefractory lung adenocarcinoma and identified three robust subsets of KRAS-mutant lung adenocarcinoma dominated, respectively, by co-occurring genetic events in STK11/LKB1 (the KL subgroup), TP53 (KP), and CDKN2A/B inactivation coupled with low expression of the NKX2-1 (TTF1) transcription factor (KC). We further revealed biologically and therapeutically relevant differences between the subgroups. KC tumors frequently exhibited mucinous histology and suppressed mTORC1 signaling. KL tumors had high rates of KEAP1 mutational inactivation and expressed lower levels of immune markers, including PD-L1. KP tumors demonstrated higher levels of somatic mutations, inflammatory markers, immune checkpoint effector molecules, and improved relapse-free survival. Differences in drug sensitivity patterns were also observed; notably, KL cells showed increased vulnerability to HSP90-inhibitor therapy. This work provides evidence that co-occurring genomic alterations identify subgroups of KRAS-mutant lung adenocarcinoma with distinct biology and therapeutic vulnerabilities.
Significance: Co-occurring genetic alterations in STK11/LKB1, TP53, and CDKN2A/B—the latter coupled with low TTF1 expression—define three major subgroups of KRAS-mutant lung adenocarcinoma with distinct biology, patterns of immune-system engagement, and therapeutic vulnerabilities. Cancer Discov; 5(8); 860–77. ©2015 AACR.
This article is highlighted in the In This Issue feature, p. 783
Deficiency of Superoxide Dismutase Impairs Protein C Activation and Enhances Susceptibility to Experimental Thrombosis
Authors: Dayal Sanjana , Gu Sean X. , Hutchins Ryan D. , Wilson Katina M. , Wang Yi , Fu Xiaoyun , Lentz Steven R. 
Published: June 2015

Objective—
Clinical evidence suggests an association between oxidative stress and vascular disease, and in vitro studies have demonstrated that reactive oxygen species can have prothrombotic effects on vascular and blood cells. It remains unclear, however, whether elevated levels of reactive oxygen species accelerate susceptibility to experimental thrombosis in vivo.

Approach and Results—

Using a murine model with genetic deficiency in superoxide dismutase-1 (SOD1), we measured susceptibility to carotid artery thrombosis in response to photochemical injury. We found that SOD1-deficient (
Sod1
−/−
) mice formed stable arterial occlusions significantly faster than wild-type (

Sod1
+/+

) mice (
P
<0.05).
Sod1
−/−
mice also developed significantly larger venous thrombi than

Sod1
+/+

mice after inferior vena cava ligation (
P
<0.05). Activation of protein C by thrombin in lung was diminished in
Sod1
−/−
mice (
P
<0.05 versus
Sod1
+/+
mice), and generation of activated protein C in response to infusion of thrombin in vivo was decreased in
Sod1
−/−
mice (
P
<0.05 versus

Sod1
+/+

mice). SOD1 deficiency had no effect on the expression of thrombomodulin, endothelial protein C receptor, or tissue factor in lung or levels of protein C in plasma. Exposure of human thrombomodulin to superoxide in vitro caused oxidation of multiple methionine residues, including critical methionine 388, and a 40% decrease in thrombomodulin-dependent activation of protein C (
P
<0.05). SOD and catalase protected against superoxide-induced methionine oxidation and restored protein C activation in vitro (
P
<0.05).

Conclusions—
SOD prevents thrombomodulin methionine oxidation, promotes protein C activation, and protects against arterial and venous thrombosis in mice.
Predictive Factors for Rebleeding After Aneurysmal Subarachnoid Hemorrhage
Authors: van Donkelaar Carlina E. , Bakker Nicolaas A. , Veeger Nic J.G.M. , Uyttenboogaart Maarten , Metzemaekers Jan D.M. , Luijckx Gert-Jan , Groen Rob J.M. , van Dijk J. Marc C. 
Published: June 2015

Background and Purpose—
Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating type of stroke associated with high morbidity and mortality. One of the most feared complications is an early rebleeding before aneurysm repair. Predictors for such an often fatal rebleeding are largely unknown. We therefore aimed to determine predictors for an early rebleeding after aSAH in relation with time after ictus.

Methods—
This observational prospective cohort study included all consecutive patients admitted with aSAH between January 1998 and December 2014 (n=1337) at our University Neurovascular Center. Clinical predictors for rebleeding ≤24 hours were identified using multivariable Cox regression analyses. Kaplan–Meier analyses were applied to evaluate the time of rebleeding ≤72 hours after aSAH.

Results—

A modified Fisher grade of 3 to 4 was a predictor for an in-hospital rebleeding ≤24 hours after ictus (adjusted hazard ratio, 4.4; 95% confidence interval, 2.1–10.6;
P
<0.001). The numbers needed to treat to prevent 1 rebleeding ≤24 hours was calculated 15 (95% confidence interval, 10–25). Also, the initiation of external cerebrospinal fluid-drainage (adjusted hazard ratio, 1.9; 95% confidence interval, 1.4–2.5;
P
<0.001) was independently associated with a rebleeding ≤24 hours. Cumulative in-hospital rebleeding rates were 5.8% ≤24 hours, and 1.2% in the time frame 24–72 hours after ictus.

Conclusions—
In our opinion, timing of treatment of aSAH patients, especially those with an modified Fisher grade of 3 or 4 in a good clinical condition, should be reconsidered. These aSAH patients might be regarded a medical emergency, requiring aneurysm repair as soon as possible. In this respect, our findings should provoke the debate on timing of aneurysm repair, especially in patients considered to be at high risk for rebleeding.
The Madden–Julian Oscillation and Boreal Winter Forecast Skill: An Analysis of NCEP CFSv2 Reforecasts
Authors: Jones Charles , Hazra Abheera , Carvalho Leila M. V. 
Published: June 2015

Abstract
The Madden–Julian oscillation (MJO) is the main mode of tropical intraseasonal variations and bridges weather and climate. Because the MJO has a slow eastward propagation and longer time scale relative to synoptic variability, significant interest exists in exploring the predictability of the MJO and its influence on extended-range weather forecasts (i.e., 2–4-week lead times). This study investigates the impact of the MJO on the forecast skill in Northern Hemisphere extratropics during boreal winter. Several 45-day forecasts of geopotential height (500 hPa) from NCEP Climate Forecast System version 2 (CFSv2) reforecasts are used (1 November–31 March 1999–2010). The variability of the MJO expressed as different amplitudes, durations, and recurrence (i.e., primary and successive events) and their influence on forecast skill is analyzed and compared against inactive periods (i.e., null cases). In general, forecast skill during enhanced MJO convection over the western Pacific is systematically higher than in inactive days. When the enhanced MJO convection is over the Maritime Continent, forecasts are lower than in null cases, suggesting potential model deficiencies in accurately forecasting the eastward propagation of the MJO over that region and the associated extratropical response. In contrast, forecasts are more skillful than null cases when the enhanced convection is over the western Pacific and during long, intense, and successive MJO events. These results underscore the importance of the MJO as a potential source of predictability on 2–4-week lead times.
Routes to Dissipation under Different Dynamical Conditions
Authors: Brüggemann Nils , Eden Carsten 
Published: June 2015

AbstractIn this study, it is investigated how ageostrophic dynamics generate an energy flux toward smaller scales. Numerical simulations of baroclinic instability are used with varying dynamical conditions ranging from quasigeostrophic balance to ageostrophic flows. It turns out that dissipation at smaller scales by viscous friction is much more efficient if the flow is dominated by ageostrophic dynamics than in quasigeostrophic conditions. In the presence of ageostrophic dynamics, an energy flux toward smaller scales is observed while energy is transferred toward larger scales for quasigeostrophic dynamics. Decomposing the velocity field into its rotational and divergent components shows that only the divergent velocity component, which becomes stronger for ageostrophic flows, features a downscale flux. Variation of the dynamical conditions from ageostrophic dynamics to quasigeostrophic balanced flows shows that the forward energy flux and therefore the small-scale dissipation decreases as soon as the horizontal divergent velocity component decreases. A functional relationship between the small-scale dissipation and the local Richardson number is estimated. This functional relationship is used to obtain a global estimate of the small-scale dissipation of 0.31 ± 0.23 TW from a high-resolution realistic global ocean model. This emphasizes that an ageostrophic direct route to dissipation might be of importance in the ocean energy cycle.
Mesoscale Thermodynamic Influences on Convection Initiation near a Surface Dryline in a Convection-Permitting Ensemble
Authors: Trier Stanley B. , Romine Glen S. , Ahijevych David A. , Trapp Robert J. , Schumacher Russ S. , Coniglio Michael C. , Stensrud David J. 
Published: June 2015

Abstract
In this study, the authors examine initiation of severe convection along a daytime surface dryline in a 10-member ensemble of convection-permitting simulations. Results indicate that the minimum buoyancy Bmin of PBL air parcels must be small (Bmin &gt; −0.5°C) for successful deep convection initiation (CI) to occur along the dryline. Comparing different ensemble members reveals that CAPE magnitudes (allowing for entrainment) and the width of the zone of negligible Bmin extending eastward from the dryline act together to influence CI. Since PBL updrafts that initiate along the dryline move rapidly northeast in the vertically sheared flow as they grow into the free troposphere, a wider zone of negligible Bmin helps ensure adequate time for incipient storms to mature, which, itself, is hastened by larger CAPE.
Local Bmin budget calculations and trajectory analysis are used to quantify physical processes responsible for the reduction of negative buoyancy prior to CI. Here, the grid-resolved forcing and forcing from temperature and moisture tendencies in the PBL scheme (arising from surface fluxes) contribute about equally in ensemble composites. However, greater spatial variability in grid-resolved forcing focuses the location of the greatest net forcing along the dryline. The grid-resolved forcing is influenced by a thermally direct vertical circulation, where time-averaged ascent at the east edge of the dryline results in locally deeper moisture and cooler conditions near the PBL top. Horizontal temperature advection spreads the cooler air eastward above higher equivalent potential temperature air at source levels of convecting air parcels, resulting in a wider zone of negligible Bmin that facilitates sustained CI.
Effects of Greenhouse Gas Mitigation on Drought Impacts in the United States
Authors: Boehlert Brent , Fitzgerald Ellen , Neumann James E. , Strzepek Kenneth M. , Martinich Jeremy 
Published: June 2015

Abstract
The authors present a method for analyzing the economic benefits to the United States resulting from changes in drought frequency and severity due to global greenhouse gas (GHG) mitigation. The method begins by constructing reduced-form models of the effect of drought on agriculture and reservoir recreation in the contiguous United States. These relationships are then applied to drought projections based on two climate stabilization scenarios and two twenty-first-century time periods. Drought indices are sector specific and include both the standardized precipitation index and the Palmer drought severity index. It is found that the modeled regional effects of drought on each sector are negative, almost always statistically significant, and often large in magnitude. These results confirm that drought has been an important driver of historical reductions in economic activity in these sectors. Comparing a reference climate scenario to two GHG mitigation scenarios in 2050 and 2100, the authors find that, for the agricultural sector, mitigation reduces both drought incidence and damages through its effects on temperature and precipitation, despite regional differences in the sign and magnitude of effects under certain model scenarios. The current annual damages of drought across all sectors have been estimated at $6–$8 billion (U.S. dollars), but this analysis shows that average annual benefits of GHG mitigation to the U.S. agricultural sector alone reach $980 million by 2050 and upward of $2.2 billion by 2100. Benefits to reservoir recreation depend on reservoir location and data availability. Economic benefits of GHG mitigation are highest in the southwestern United States, where drought frequency is projected to increase most dramatically in the absence of GHG mitigation policies.
A drive through cellular therapy for CLL in 2015: allogeneic cell transplantation and CARs
Authors: Mato Anthony , Porter David L. 
Published: June 2015

Abstract
Over the past decade the development of safer reduced-intensity conditioning regimens, expanded donor pools, advances in supportive care, and prevention/management of graft-versus-host disease have expanded stem cell transplantation (SCT) availability for chronic lymphocytic leukemia (CLL) patients. However, there are now increasingly active treatment options available for CLL patients with favorable toxicity profiles and convenient administration schedules. This raises the critical issue of whether or not attainment of cure remains a necessary goal. It is now less clear that treatment with curative intention and with significant toxicity is required for long-term survival in CLL. In addition, the demonstrated safety and activity of genetically modified chimeric antigen receptor (CAR) T cells present the opportunity of harnessing the power of the immune system to kill CLL cells without the need for SCT. We attempt to define the role of SCT in the era of targeted therapies and discuss questions that remain to be answered. Furthermore, we highlight the potential for exciting new cellular therapy using genetically modified anti-CD19 CAR T cells and discuss its potential to alter treatment paradigms for CLL.
Recurrent CDKN1B (p27) mutations in hairy cell leukemia
Authors: Dietrich Sascha , Hüllein Jennifer , Lee Stanley Chun-Wei , Hutter Barbara , Gonzalez David , Jayne Sandrine , Dyer Martin J. S. , Oleś Małgorzata , Else Monica , Liu Xiyang , Słabicki Mikołaj , Wu Bian , Troussard Xavier , Dürig Jan , Andrulis Mindaugas , Dearden Claire , von Kalle Christof , Granzow Martin , Jauch Anna , Fröhling Stefan , Huber Wolfgang , Meggendorfer Manja , Haferlach Torsten , Ho Anthony D. , Richter Daniela , Brors Benedikt , Glimm Hanno , Matutes Estella , Abdel Wahab Omar , Zenz Thorsten 
Published: June 2015

Key Points
Somatic CDKN1B (p27) mutations were identified in 16% (13/81) of HCL patients and coexist with BRAFV600E mutations. CDKN1B is the second most common mutated gene in HCL implicating altered cell cycle regulation and/or senescence in HCL.
CdSe/ZnS Quantum Dots-Labeled Mesenchymal Stem Cells for Targeted Fluorescence Imaging of Pancreas Tissues and Therapy of Type 1 Diabetic Rats
Authors: Liu Haoqi , Tang Wei , Li Chao , Lv Pinlei , Wang Zheng , Liu Yanlei , Zhang Cunlei , Bao Yi , Chen Haiyan , Meng Xiangying , Song Yan , Xia Xiaoling , Pan Fei , Cui Daxiang , Shi Yongquan 
Published: June 2015

Abstract
Mesenchymal stem cells (MSCs) have been used for therapy of type 1 diabetes mellitus. However, the in vivo distribution and therapeutic effects of transplanted MSCs are not clarified well. Herein, we reported that CdSe/ZnS quantum dots-labeled MSCs were prepared for targeted fluorescence imaging and therapy of pancreas tissues in rat models with type 1 diabetes. CdSe/ZnS quantum dots were synthesized, their biocompatibility was evaluated, and then, the appropriate concentration of quantum dots was selected to label MSCs. CdSe/ZnS quantum dots-labeled MSCs were injected into mouse models with type 1 diabetes via tail vessel and then were observed by using the Bruker In-Vivo F PRO system, and the blood glucose levels were monitored for 8 weeks. Results showed that prepared CdSe/ZnS quantum dots owned good biocompatibility. Significant differences existed in distribution of quantum dots-labeled MSCs between normal control rats and diabetic rats (p < 0.05). The ratios of the fluorescence intensity (RFI) analysis showed an accumulation rate of MSCs in the pancreas of rats in the diabetes group, and was about 32 %, while that in the normal control group rats was about 18 %. The blood glucose levels were also monitored for 8 weeks after quantum dots-labeled MSC injection. Statistical differences existed between the blood glucose levels of the diabetic rat control group and MSC-injected diabetic rat group (p < 0.01), and the MSC-injected diabetic rat group displayed lower blood glucose levels. In conclusion, CdSe/ZnS-labeled MSCs can target in vivo pancreas tissues in diabetic rats, and significantly reduce the blood glucose levels in diabetic rats, and own potential application in therapy of diabetic patients in the near future.
A positive fluid balance is an independent prognostic factor in patients with sepsis
Authors: Acheampong Angela , Vincent Jean-Louis 
Published: June 2015

Abstract
Introduction
Intravenous fluid administration is an essential component of sepsis management, but a positive fluid balance has been associated with worse prognosis. We analyzed whether a positive fluid balance and its persistence over time was an independent prognostic factor in septic patients.

Methods
We prospectively studied fluid intake and output for 7 days in 173 consecutive adult patients treated for sepsis in our Department of Intensive Care.

Results
Of the 173 patients, 59 died (34 %). Mean daily fluid intake was higher in non-survivors than in survivors (59 ± 24 ml/kg vs. 48 ± 23 ml/kg, p = 0.03), but output volumes were similar. As a result, the daily fluid balance was more than twice as large in the non-survivors as in the survivors (29 ± 22 vs. 13 ± 19 ml/kg, p <0.001). Persistence of a positive fluid balance over time was associated with increased mortality. Using a multivariable time-dependent Cox model, a positive fluid balance was independently associated with higher mortality (adjusted hazard ratio 1.014 [1.007–1.022] per ml/kg increase, p <0.001).

Conclusions
Persistence of a positive daily fluid balance over time was quite strongly associated with a higher mortality rate in septic patients.