bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined MEK and PI3K Inhibition in a Mouse Model of Pancreatic Cancer
Authors: Alagesan Brinda , Contino Gianmarco , Guimaraes Alexander R. , Corcoran Ryan B. , Deshpande Vikram , Wojtkiewicz Gregory R. , Hezel Aram F. , Wong Kwok-Kin , Loda Massimo , Weissleder Ralph , Benes Cyril , Engelman Jeffrey A. , Bardeesy Nabeel 
Published: October 2014

Abstract
Purpose: Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being used in clinical trials for patients with PDAC, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMM).
Experimental Design: We performed high-throughput screening of &gt;500 human cancer cell lines (including 46 PDAC lines), for sensitivity to 50 clinically relevant compounds, including MEK and PI3K inhibitors. We tested the top hit in the screen, the MEK1/2 inhibitor, AZD6244, for efficacy alone or in combination with the PI3K inhibitors, BKM120 or GDC-0941, in a KrasG12D-driven GEMM that recapitulates the histopathogenesis of human PDAC.
Results: In vitro screens revealed that PDAC cell lines are relatively resistant to single-agent therapies. The response profile to the MEK1/2 inhibitor, AZD6244, was an outlier, showing the highest selective efficacy in PDAC. Although MEK inhibition alone was mainly cytostatic, apoptosis was induced when combined with PI3K inhibitors (BKM120 or GDC-0941). When tested in a PDAC GEMM and compared with the single agents or vehicle controls, the combination delayed tumor formation in the setting of prevention and extended survival when used to treat advanced tumors, although no durable responses were observed.
Conclusions: Our studies point to important contributions of MEK and PI3K signaling to PDAC pathogenesis and suggest that dual targeting of these pathways may provide benefit in some patients with PDAC. Clin Cancer Res; 21(2); 396–404. ©2014 AACR.
Effects of BRCA1- and BRCA2-Related Mutations on Ovarian and Breast Cancer Survival: A Meta-analysis
Authors: Zhong Qian , Peng Hong-Ling , Zhao Xia , Zhang Lin , Hwang Wei-Ting 
Published: October 2014

Abstract
Purpose: To estimate the effects of BRCA1 and BRCA2 mutations on ovarian cancer and breast cancer survival.
Experimental Design: We searched PubMed and EMBASE for studies that evaluated the associations between BRCA mutations and ovarian or breast cancer survival. Meta-analysis was conducted to generate combined HRs with 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS).
Results: From 1,201 unique citations, we identified 27 articles that compared prognosis between BRCA mutation carriers and noncarriers in patients with ovarian or breast cancer. Fourteen studies examined ovarian cancer survival and 13 studies examined breast cancer survival. For ovarian cancer, meta-analysis demonstrated that both BRCA1 and BRCA2 mutation carriers had better OS (HR, 0.76; 95% CI, 0.70–0.83 for BRCA1 mutation carriers; HR, 0.58; 95% CI, 0.50–0.66 for BRCA2 mutation carriers) and PFS (HR, 0.65; 95% CI, 0.52–0.81 for BRCA1 mutation carriers; HR, 0.61; 95% CI, 0.47–0.80 for BRCA2 mutation carriers) than noncarriers, regardless of tumor stage, grade, or histologic subtype. Among patients with breast cancer, BRCA1 mutation carriers had worse OS (HR, 1.50; 95% CI, 1.11–2.04) than noncarriers but were not significantly different from noncarriers in PFS. BRCA2 mutation was not associated with breast cancer prognosis.
Conclusions: Our analyses suggest that BRCA mutations are robust predictors of outcomes in both ovarian and breast cancers and these mutations should be taken into account when devising appropriate therapeutic strategies. Clin Cancer Res; 21(1); 211–20. ©2014 AACR.
Utilization of the Eμ-Myc Mouse to Model Heterogeneity of Therapeutic Response
Authors: Rempel Rachel E. , Jiang Xiaolei , Fullerton Paul , Tan Tuan Zea , Ye Jieru , Lau Jieying Amelia , Mori Seiichi , Chi Jen-Tsan , Nevins Joseph R. , Friedman Daphne R. 
Published: October 2014

Abstract
Human aggressive B-cell non-Hodgkin lymphomas (NHL) encompass the continuum between Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL), and display considerable clinical and biologic heterogeneity, most notably related to therapy response. We previously showed that lymphomas arising in the Eμ-Myc transgenic mouse are heterogeneous, mirroring genomic differences between Burkitt lymphoma and DLBCL. Given clinical heterogeneity in NHL and the need to develop strategies to match therapeutics with discrete forms of disease, we investigated the extent to which genomic variation in the Eμ-Myc model predicts response to therapy. We used genomic analyses to classify Eμ-Myc lymphomas, link Eμ-Myc lymphomas with NHL subtypes, and identify lymphomas with predicted resistance to conventional and NF-κB–targeted therapies. Experimental evaluation of these predictions links genomic profiles with distinct outcomes to conventional and targeted therapies in the Eμ-Myc model, and establishes a framework to test novel targeted therapies or combination therapies in specific genomically defined lymphoma subgroups. In turn, this will rationally inform the design of new treatment options for aggressive human NHL. Mol Cancer Ther; 13(12); 3219–29. ©2014 AACR.
Inhibition of HSP90 by AT13387 Delays the Emergence of Resistance to BRAF Inhibitors and Overcomes Resistance to Dual BRAF and MEK Inhibition in Melanoma Models
Authors: Smyth Tomoko , Paraiso Kim H.T. , Hearn Keisha , Rodriguez-Lopez Ana M. , Munck Joanne M. , Haarberg H. Eirik , Sondak Vernon K. , Thompson Neil T. , Azab Mohammad , Lyons John F. , Smalley Keiran S.M. , Wallis Nicola G. 
Published: October 2014

Abstract
Emergence of clinical resistance to BRAF inhibitors, alone or in combination with MEK inhibitors, limits clinical responses in melanoma. Inhibiting HSP90 offers an approach to simultaneously interfere with multiple resistance mechanisms. Using the HSP90 inhibitor AT13387, which is currently in clinical trials, we investigated the potential of HSP90 inhibition to overcome or delay the emergence of resistance to these kinase inhibitors in melanoma models. In vitro, treating vemurafenib-sensitive cells (A375 or SK-MEL-28) with a combination of AT13387 and vemurafenib prevented colony growth under conditions in which vemurafenib treatment alone generated resistant colonies. In vivo, when AT13387 was combined with vemurafenib in a SK-MEL-28, vemurafenib-sensitive model, no regrowth of tumors was observed over 5 months, although 2 of 7 tumors in the vemurafenib monotherapy group relapsed in this time. Together, these data suggest that the combination of these agents can delay the emergence of resistance. Cell lines with acquired vemurafenib resistance, derived from these models (A375R and SK-MEL-28R) were also sensitive to HSP90 inhibitor treatment; key clients were depleted, apoptosis was induced, and growth in 3D culture was inhibited. Similar effects were observed in cell lines with acquired resistance to both BRAF and MEK inhibitors (SK-MEL-28RR, WM164RR, and 1205LuRR). These data suggest that treatment with an HSP90 inhibitor, such as AT13387, is a potential approach for combating resistance to BRAF and MEK inhibition in melanoma. Moreover, frontline combination of these agents with an HSP90 inhibitor could delay the emergence of resistance, providing a strong rationale for clinical investigation of such combinations in BRAF-mutated melanoma. Mol Cancer Ther; 13(12); 2793–804. ©2014 AACR.
Indeterminate Pulmonary Nodules: Risk for Having or for Developing Lung Cancer?
Authors: Massion Pierre P. , Walker Ronald C. 
Published: October 2014

AbstractThis perspective discusses the report by Pinsky and colleagues, which addresses whether noncalcified pulmonary nodules identified on CT screening carry short- and long-term risk for lung cancer. We are facing challenges related to distinguishing a large majority of benign nodules from malignant ones and among those a majority of aggressive from indolent cancers. Key questions in determining individual probabilities of disease, given their history, findings on CT, and upcoming biomarkers of risk, remain most challenging. Reducing the false positives associated with current low-dose computed tomography practices and identification of individuals who need therapy and at what time during tumor surveillance could reduce costs and morbidities associated with unnecessary interventions. Cancer Prev Res; 7(12); 1173–8. ©2014 AACR.
What Inequality means for Children
Authors: Woodhead Martin , Dornan Paul , Murray Helen 
Published: October 2014

Understanding how poverty and inequalities impact on children is the major goal of Young Lives, a unique longitudinal, mixed-methods study. Two cohorts totaling 12,000 children are being tracked since 2001, growing-up in Ethiopia, the state of Andhra Pradesh (ap) India, Peru and Vietnam. Earlier versions of this paper were prepared as Young Lives contribution to aunicef/unWomen consultation on the post-2015 Development agenda (www.worldwewant2015.org/inequalities) and published as Woodhead, Dornan and Murray (2013).We summarise Young Lives evidence to date on eight research issues that are central to any child rights agenda:1.How inequalities interact in their impact on children’s development and the vulnerability of the most disadvantaged households.2.The ways inequalities rapidly undermine the development of human potential.3.How gender differences interconnect with other inequalities, but do not always advantage boys in Young Lives countries.4.The links between poverty, early ‘stunting’, and later outcomes, including psycho-social functioning, as well as emerging evidence that some children recover.5.Inequalities that open up during the later years of childhood, linked to transitions around leaving school, working, and anticipating marriage etc.6.Children’s own perceptions of poverty and inequality, as these shape their well-being and long-term prospects.7.Evidence of the growing significance of education, including the ways school systems can increase as well as reduce inequalities.8.The potential of social protection programmes in poverty alleviation.We conclude that since inequalities are multidimensional, so too must be the response. Equitable growth policies, education and health services, underpinned by effective social protection, all have a role to play.
Nomenclature and taxonomy of Telmatoscopus Eaton and Seoda Enderlein; with a discussion of parameral evolution in Paramormiini and Pericomaini (Diptera: Psychodidae, Psychodinae)
Authors: KVIFTE GUNNAR MIKALSEN 
Published: October 2014

Historically, Telmatoscopus Eaton, 1904 has been a nomenclaturally and taxonomically problematic taxon as different authors have used different type species to define their concepts of the genus. Here it is shown that Pericoma advena Eaton, 1893 is the valid type species rather than Pericoma morula Eaton, 1893. Furthermore, the genus Seoda Enderlein, 1935 is revived for the genus comprising Pericoma labeculosa Eaton, 1893, P. morula and their relatives. The differences between Telmatoscopus and Seoda are described in detail based on historical and freshly collected material of the three putative type species. Four new synonymies are proposed: Panimerus havelkai Wagner, 1975 and Telmatoscopus seguyi Vaillant, 1990 are synonymized with Telmatoscopus advena, and Telmatoscopus incanus Nielsen, 1964 and Telmatoscopus vaillanti Withers, 1986 are synonymized with Seoda morula. A potential phylogenetic pattern in the male genital sclerites is discussed in detail. In Telmatoscopus, the jointed appendages of the gonocoxally derived parameral complex are separate small sclerites found near the bases of the distiphallic lobes of the aedeagus. In Seoda, they are fused medially to form a small, moveable triangular or arrow-shaped sclerite. Medial parameral sclerite fusion in Psychodinae is otherwise known to occur only in Pericomaini and the paramormiine genus Psychomasina Ježek, 2004; however, many genera of Paramormiini show an apparently intermediate condition where the parameres are fused in one end to form a V- or U-shaped "furca". It is hypothesized that Paramormiini is paraphyletic with respect to Pericomaini, as suggested in a previous phylogenetic hypothesis based on molecular data.
A Study on the Asymmetric Rapid Intensification of Hurricane Earl (2010) Using the HWRF System
Authors: Chen Hua , Gopalakrishnan Sundararaman G. 
Published: October 2014

Abstract
In this study, the results of a forecast from the operational Hurricane Weather Research and Forecast (HWRF) system for Hurricane Earl (2010) are verified against observations and analyzed to understand the asymmetric rapid intensification of a storm in a sheared environment. The forecast verification shows that HWRF captured well Earl’s observed evolution of intensity, convection asymmetry, wind field asymmetry, and vortex tilt in terms of magnitude and direction in the pre rapid and rapid intensification (RI) stages. Examination of the high-resolution forecast data reveals that the tilt was large at the RI onset and decreased quickly once RI commenced, suggesting that vertical alignment is the result instead of the trigger for RI. The RI onset is associated with the development of upper-level warming in the eye, which results from upper-level storm-relative flow advecting the warm air caused by subsidence warming in the upshear-left region toward the low-level storm center. This scenario does not occur until persistent convective bursts (CB) are concentrated in the downshear-left quadrant. The temperature budget calculation indicates that horizontal advection plays an important role in the development of upper-level warming in the early RI stage. The upper-level warming associated with the asymmetric intensification process occurs by means of the cooperative interaction of the convective-scale subsidence, resulting from CBs in favored regions and the shear-induced mesoscale subsidence. When CBs are concentrated in the downshear-left and upshear-left quadrants, the subsidence warming is maximized upshear and then advected toward the low-level storm center by the storm-relative flow at the upper level. Subsequently, the surface pressure falls and RI occurs.
Regional Simulation of the October and November MJO Events Observed during the CINDY/DYNAMO Field Campaign at Gray Zone Resolution
Authors: Wang Shuguang , Sobel Adam H. , Zhang Fuqing , Sun Y. Qiang , Yue Ying , Zhou Lei 
Published: October 2014

Abstract
This study investigates the October and November MJO events observed during the Cooperative Indian Ocean Experiment on Intraseasonal Variability in the Year 2011 (CINDY)/Dynamics of the MJO (DYNAMO) field campaign through cloud-permitting numerical simulations. The simulations are compared to multiple observational datasets. The control simulation at 9-km horizontal grid spacing captures the slow eastward progression of both the October and November MJO events in surface precipitation, outgoing longwave radiation, zonal wind, humidity, and large-scale vertical motion. The vertical motion shows weak ascent in the leading edge of the MJO envelope, followed by deep ascent during the peak precipitation stage and trailed by a broad second baroclinic mode structure with ascent in the upper troposphere and descent in the lower troposphere. Both the simulation and the observations also show slow northward propagation components and tropical cyclone–like vortices after the passage of the MJO active phase. Comparison with synthesized observations from the northern sounding array shows that the model simulates the passage of the two MJO events over the sounding array region well. Sensitivity experiments to SST indicate that daily SST plays an important role for the November MJO event, but much less so for the October event.
Analysis of the moist static energy (MSE) budget shows that both advection and diabatic processes (i.e., surface fluxes and radiation) contribute to the development of the positive MSE anomaly in the active phase, but their contributions differ by how much they lead the precipitation peak. In comparison to the observational datasets used here, the model simulation may have a stronger surface flux feedback and a weaker radiative feedback. The normalized gross moist stability in the simulations shows an increase from near-zero values to ~0.8 during the active phase, similar to what is found in the observational datasets.
On the Challenges of Tomography Retrievals of a 2D Water Vapor Field Using Ground-Based Microwave Radiometers: An Observation System Simulation Experiment
Authors: Meunier Véronique , Turner David D. , Kollias Pavlos 
Published: October 2014

AbstractTwo-dimensional water vapor fields were retrieved by simulated measurements from multiple ground-based microwave radiometers using a tomographic approach. The goal of this paper was to investigate how the various aspects of the instrument setup (number and spacing of elevation angles and of instruments, number of frequencies, etc.) affected the quality of the retrieved field. This was done for two simulated atmospheric water vapor fields: 1) an exaggerated turbulent boundary layer and 2) a simplified water vapor front. An optimal estimation algorithm was used to obtain the tomographic field from the microwave radiometers and to evaluate the fidelity and information content of this retrieved field.While the retrieval of the simplified front was reasonably successful, the retrieval could not reproduce the details of the turbulent boundary layer field even using up to nine instruments and 25 elevation angles. In addition, the vertical profile of the variability of the water vapor field could not be captured. An additional set of tests was performed using simulated data from a Raman lidar. Even with the detailed lidar measurements, the retrieval did not succeed except when the lidar data were used to define the a priori covariance matrix. This suggests that the main limitation to obtaining fine structures in a retrieved field using tomographic retrievals is the definition of the a priori covariance matrix.
Diagnosis of the Source of GFS Medium-Range Track Errors in Hurricane Sandy (2012)
Authors: Torn Ryan D. , Whitaker Jeffrey S. , Pegion Philip , Hamill Thomas M. , Hakim Gregory J. 
Published: October 2014

Abstract
Medium-range forecasts of Hurricane Sandy’s track were characterized by widely diverging solutions, with some suggesting that Sandy would make landfall over the mid-Atlantic region of the United States, while others forecast the storm to move due east to the north of Bermuda. Here, dynamical processes responsible for the eastward-tracking forecasts are diagnosed using an 80-member ensemble of experimental Global Forecast System (GFS) forecasts initialized five days prior to landfall. Comparing the ensemble members with tracks to the east against those with tracks to the west indicates that the eastern members were characterized by a lower-amplitude upper-tropospheric anticyclone on the poleward side of Sandy during the first 24 h of the forecast, which in turn was associated with a westerly perturbation steering wind. The amplification of this ridge in each set of members was modulated by differences in the advection of potential vorticity (PV) by the irrotational wind associated with Sandy’s secondary circulation and isentropic lift along a warm front that formed on the poleward side of Sandy. The amplitude of the irrotational wind in this region was proportional to the 0-h water vapor mixing ratio, and to a lesser extent the 0-h upper-tropospheric horizontal divergence. These two quantities modulated the vertical profile of grid-scale condensation within the model and subsequent upper-tropospheric divergence. The results from this study suggest that additional observations within regions of large-scale precipitation outside the tropical cyclone (TC) core could benefit TC track forecasts, particularly when the TC is located near an upper-tropospheric PV gradient.
Self-care management among patients with type 2 diabetes in East Jerusalem
Authors: Daoud Nihaya , Osman Amira , Hart Trevor A , Berry Elliott M , Adler Bella 
Published: October 2014

Objective: Little research exists on diabetes self-care management (DSCM) in Arab populations. We examined the contribution of health belief constructs, socioeconomic position (SEP) and clinical factors (glycated haemoglobin [HbA1C] level, type of diabetes treatments, and receiving professional guidance) to DSCM among Arab patients in East Jerusalem with type 2 diabetes. Method: Using a structured questionnaire, we conducted face-to-face interviews with a random sample of 230 patients with type 2 diabetes in a large diabetes clinic. DSCM included engagement in any of the following in the last week: physical activity, consumption of low-fat and low-sugar diet, self-monitoring of blood glucose, medication uptake and foot care. We obtained HbA1C levels from the clinic’s patient registry. We used linear regression to examine the contribution of health beliefs, SEP and clinical factors to explaining DSCM. Results: Adherence to DSCM was low. Most patients (84.8%) were physically inactive, 64.3% did not consume a low-fat or low-sugar diet (46.5%) and 51% did not self-monitor blood glucose. However, medication adherence (95.7%) and foot care were high (77.4%). About 71% of participants had high HbA1C (>7.0%). In the multivariate analysis, total DSCM scores were higher among patients with low financial barriers, high perception of the benefits of DSCM and higher self-efficacy. Patients using oral medication (vs insulin) had significantly lower DSCM scores. Conclusion: Among Arab patients with diabetes, more interventions are needed to encourage DSCM, specifically in areas of lifestyle (diet and physical activity). Patients’ financial barriers, benefits of DSCM and patient self-efficacy should be emphasised.
Perceptual Load in Different Regions of the Visual Scene and Its Relevance for Driving
Authors: Marciano Hadas , Yeshurun Yaffa 
Published: October 2014

Objective: The aim of this study was to better understand the role played by perceptual load, at both central and peripheral regions of the visual scene, in driving safety. Background: Attention is a crucial factor in driving safety, and previous laboratory studies suggest that perceptual load is an important factor determining the efficiency of attentional selectivity. Yet, the effects of perceptual load on driving were never studied systematically. Method: Using a driving simulator, we orthogonally manipulated the load levels at the road (central load) and its sides (peripheral load), while occasionally introducing critical events at one of these regions. Results: Perceptual load affected driving performance at both regions of the visual scene. Critically, the effect was different for central versus peripheral load: Whereas load levels on the road mainly affected driving speed, load levels on its sides mainly affected the ability to detect critical events initiating from the roadsides. Moreover, higher levels of peripheral load impaired performance but mainly with low levels of central load, replicating findings with simple letter stimuli. Conclusion: Perceptual load has a considerable effect on driving, but the nature of this effect depends on the region of the visual scene at which the load is introduced. Application: Given the observed importance of perceptual load, authors of future studies of driving safety should take it into account. Specifically, these findings suggest that our understanding of factors that may be relevant for driving safety would benefit from studying these factors under different levels of load at different regions of the visual scene.