bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences in levels of physical activity between White and South Asian populations within a healthcare setting: impact of measurement type in a cross-sectional study
Authors: Yates Thomas , Henson Joe , Edwardson Charlotte , Bodicoat Danielle H , Davies Melanie J , Khunti Kamlesh 
Published: July 2015

ObjectiveWe investigate differences between White and South Asian (SA) populations in levels of objectively measured and self-reported physical activity.DesignCross-sectional study.SettingLeicestershire, UK, 2010–2011.ParticipantsBaseline data were pooled from two diabetes prevention trials that recruited a total of 4282 participants from primary care with a high risk score for type 2 diabetes. For this study, 2843 White (age=64±8, female=37%) and 243 SA (age=58±9, female=34%) participants had complete physical activity data and were included in the analysis.Outcome measuresModerate-intensity to vigorous-intensity physical activity (MVPA) and walking activity were measured using the International Physical Activity Questionnaire (IPAQ), and a combination of piezoelectric pedometer (NL-800) and accelerometer (Actigraph GT3X) were used to objectively measure physical activity.ResultsCompared to White participants, SA participants self-reported less MVPA (30 vs 51 min/day; p<0.001) and walking activity (11 vs 17 min/day; P=0.001). However, there was no difference in objectively measured ambulatory activity (5992 steps/day vs 6157 steps/day; p=0.75) or in time spent in MVPA (18.0 vs 21.5 min/day; p=0.23). Results were largely unaffected when adjusted for age, sex and social deprivation. Compared to accelerometer data, White participants overestimated their time in MVPA by 51 min/day and SA participants by 21 min/day.ConclusionsSA and White groups undertook similar levels of physical activity when measured objectively despite self-reported estimates being around 40% lower in the SA group. This emphasises the limitations of comparing self-reported lifestyle measures across different populations and ethnic groups.Trial registration numberReports baseline data from:Walking Away from Type 2 Diabetes(ISRCTN31392913) andLet's Prevent Diabetes(NCT00677937).
Under-reporting of maternal and perinatal adverse events in New Zealand
Authors: Farquhar Cynthia , Armstrong Sarah , Kim Boa , Masson Vicki , Sadler Lynn 
Published: July 2015

ObjectivesTo determine the proportion of maternal and perinatal mortality and morbidity cases, identified by the Perinatal and Maternal Mortality Review Committee (PMMRC), that are also reported within the annual serious adverse events (SAEs) reports published by the Health Quality and Safety Commission (HQSC).SettingNationally collated data from the PMMRC and HQSC, New Zealand.ParticipantsAnalysis of maternal and perinatal mortality and morbidity data 2009–2012.InterventionsEvery SAE report published by the HQSC from 2009 to 2012 was scrutinised for maternal and perinatal cases using the case history provided by district health boards (DHB). Further detail of each case was requested from each DHB to establish whether they had been identified as maternal or perinatal mortalities or morbidities by the PMMRC.Primary outcome measureThe proportion of maternal and perinatal mortality and morbidity cases identified by HQSC SAE reports, compared with PMMRC reporting.Results58 maternal and perinatal SAEs were identified from the SAE reports 2009–2012. Of these, 50 fit under the PMMRC reporting definitions, all of which were also reported by the PMMRC. In the same time frame, the PMMRC captured 536 potentially avoidable maternal and perinatal mortalities and morbidities that fitted the HQSC SAE definition. Fewer than 9% of maternal and perinatal SAEs are captured by the HQSC SAE reporting process.ConclusionsThe rate of maternal and perinatal adverse event reporting to the HQSC is low and not improving annually, compared with PMMRC reporting of eligible events. This is of concern as these events may not be adequately reviewed locally, and because the SAE report is considered a measure of quality by the DHBs and the HQSC. Currently, the reporting of SAEs to the HQSC cannot be considered a reliable way to monitor or improve the quality of maternity services provided in New Zealand.
Ready, steady, go! What do histopathology trainees think they need from training to enable them to develop autonomy in surgical pathology reporting?
Authors: Finall A , Allery L 
Published: July 2015

AimsThis is a qualitative study of the perceived learning needs of trainees for graded responsibility in histopathological training in the UK.MethodsA focus group with trainees and interviews with consultants was carried out. Participants were asked ‗What do you perceive are the learning needs of histopathology trainees to develop skills for safe and confident independent reporting in surgical histopathology?‘ Data was analysed using open coding content analysis for items relating to training content and structure.ResultsTrainees and consultants perceived a need for a case load of around 100 specimens per week with a continuously variable case mix. It was thought necessary to be the principal presenter of cases at multidisciplinary team meetings. There was a perceived need for adequate amounts of supervision by consultants using double-headed microscopes and sufficient time to develop skills in microscopic visual perception through detailed feature discussion, not necessarily related to specific diagnoses. Being able to write clear histopathology reports, developing the ability to recognise normal histology and to be aware of diagnostic pitfalls were also thought to be important.ConclusionsOur findings may inform efficacious implementation of graded responsibility in histopathology departments and be used as a sound basis for further research.
Silencing Egr1 Attenuates Radiation-Induced Apoptosis in Normal Tissues while Killing Cancer Cells and Delaying Tumor Growth
Authors: Zhao Diana Yi , Jacobs Keith M. , Hallahan Dennis E. , Thotala Dinesh 
Published: July 2015

Abstract
Normal tissue toxicity reduces the therapeutic index of radiotherapy and decreases the quality of life for cancer survivors. Apoptosis is a key element of the radiation response in normal tissues like the hippocampus and small intestine, resulting in neurocognitive disorders and intestinal malabsorption. The Early Growth Response 1 (Egr1) transcription factor mediates radiation-induced apoptosis by activating the transcription of proapoptosis genes in response to ionizing radiation (IR). Therefore, we hypothesized that the genetic abrogation of Egr1 and the pharmacologic inhibition of its transcriptional activity could attenuate radiation-induced apoptosis in normal tissues. We demonstrated that Egr1-null mice had less apoptosis in the hippocampus and intestine following irradiation as compared with their wild-type littermates. A similar result was achieved using Mithramycin A (MMA) to prevent binding of Egr1 to target promoters in the mouse intestine. Abolishing Egr1 expression using shRNA dampened apoptosis and enhanced the clonogenic survival of irradiated HT22 hippocampal neuronal cells and IEC6 intestinal epithelial cells. Mechanistically, these events involved an abrogation of p53 induction by IR and an increase in the ratio of Bcl-2/Bax expression. In contrast, targeted silencing of Egr1 in two cancer cell lines (GL261 glioma cells and HCT116 colorectal cancer cells) was not radioprotective, since it reduced their growth while also sensitizing them to radiation-induced death. Further, Egr1 depletion delayed the growth of heterotopically implanted GL261 and HCT116 tumors. These results support the potential of silencing Egr1 in order to minimize the normal tissue complications associated with radiotherapy while enhancing tumor control. Mol Cancer Ther; 14(10); 2343–52. ©2015 AACR.
Polymorphisms in Genes Involved in EGFR Turnover Are Predictive for Cetuximab Efficacy in Colorectal Cancer
Authors: Stintzing Sebastian , Zhang Wu , Heinemann Volker , Neureiter Daniel , Kemmerling Ralf , Kirchner Thomas , Jung Andreas , Folwaczny Matthias , Yang Dongyun , Ning Yan , Sebio Ana , Stremitzer Stefan , Sunakawa Yu , Matsusaka Satoshi , Yamauchi Shinichi , Loupakis Fotios , Cremolini Chiara , Falcone Alfredo , Lenz Heinz-Josef 
Published: July 2015

Abstract
Transmembrane receptors, such as the EGFR, are regulated by their turnover, which is dependent on the ubiquitin-proteasome system. We tested in two independent study cohorts whether SNPs in genes involved in EGFR turnover predict clinical outcome in cetuximab-treated metastatic colorectal cancer (mCRC) patients. The following SNPs involved in EGFR degradation were analyzed in a screening cohort of 108 patients treated with cetuximab in the chemorefractory setting: c-CBL (rs7105971; rs4938637; rs4938638; rs251837), EPS15 (rs17567; rs7308; rs1065754), NAE1 (rs363169; rs363170; rs363172), SH3KBP1 (rs7051590; rs5955820; rs1017874; rs11795873), SGIP1 (rs604737; rs6570808; rs7526812), UBE2M (rs895364; rs895374), and UBE2L3 (rs5754216). SNPs showing an association with response or survival were analyzed in BRAF and RAS wild-type samples from the FIRE-3 study. One hundred and fifty-three FOLFIRI plus cetuximab-treated patients served as validation set, and 168 patients of the FOLFIRI plus bevacizumab arm served as controls. EGFR FISH was done in 138 samples to test whether significant SNPs were associated with EGFR expression. UBE2M rs895374 was significantly associated with progression-free survival (log-rank P = 0.005; HR, 0.60) within cetuximab-treated patients. No association with bevacizumab-treated patients (n = 168) could be established (P = 0.56; HR, 0.90). rs895374 genotype did not affect EGFR FISH measurements. EGFR recycling is an interesting mechanism of secondary resistance to cetuximab in mCRC. This is the first report suggesting that germline polymorphisms in the degradation process predict efficacy of cetuximab in patients with mCRC. Genes involved in EGFR turnover may be new targets in the treatment of mCRC. Mol Cancer Ther; 14(10); 2374–81. ©2015 AACR.
Assessment of the In Vivo Activity of PI3K and MEK Inhibitors in Genetically Defined Models of Colorectal Cancer
Authors: Raja Meera , Zverev Matt , Seipel Katja , Williams Geraint T. , Clarke Alan R. , Shaw Paul H.S. 
Published: July 2015

Abstract
The objective of tailoring medicines for cancer patients according to the molecular profile of their disease holds great promise for the improvement of cancer therapy. Nevertheless, this approach has been limited, in part, due to the lack of predictive and informative preclinical studies. Herein, we describe an assessment of the therapeutic potential of targeting PI3K/mTOR and MAPK signaling in genetically defined mouse models of colorectal cancer mirroring disease subtypes targeted for novel therapy in the FOCUS4 trial. Our studies demonstrate that dual PI3K/mTOR inhibition is highly effective in invasive adenocarcinoma models characterized by combinatorial mutations in Apc and Pten; Apc and Kras; and Apc, Pten and Kras. MEK inhibition was effective in the combinatorial Apc and Kras setting, but had no impact in either Apc Pten mutants or in Apc Pten Kras triple mutants. Furthermore, we describe the importance of scheduling for combination studies and show that although no additional benefit is gained in Apc Pten mice, combination of PI3K/mTOR and MAPK inhibition leads to an additive benefit in survival in Apc Kras mice and a synergistic increase in survival in Apc Pten Kras mice. This is the first study using robust colorectal cancer genetically engineered mouse models to support the validity of PI3K/mTOR and MEK inhibitors as tailored therapies for colorectal cancer and highlight the potential importance of drug scheduling in the clinic. Mol Cancer Ther; 14(10); 2175–86. ©2015 AACR.
Intrapulmonary Delivery of CpG Microparticles Eliminates Lung Tumors
Authors: Sato Takashi , Shimosato Takeshi , Ueda Atsuhisa , Ishigatsubo Yoshiaki , Klinman Dennis M. 
Published: July 2015

Abstract
CpG oligonucleotides (ODN) stimulate the innate immune system by triggering cells that express TLR9. The resulting response promotes tumor regression, an effect optimized by delivery of CpG ODN to the tumor site. This work examines the effect of instilling CpG ODN adsorbed onto polyketal microparticles (CpG-MP) into the lungs of mice with non–small cell lung cancer. Intrapulmonary delivery of CpG-MP improved ODN uptake and retention at the tumor site, thereby inducing a stronger Th1 response than systemically administered or unadsorbed CpG ODN. CpG-MP reversed the immunosuppression that characterized the tumor microenvironment by (i) decreasing the number of immunosuppressive Tregs and M2 macrophages while (ii) increasing the number of tumoricidal CD8+ T cells and M1 macrophages. These effects promoted tumor regression and culminated in 82% permanent survival of mice with otherwise fatal Lewis lung cancer. Mol Cancer Ther; 14(10); 2198–205. ©2015 AACR.
Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097
Authors: Weisberg Ellen , Halilovic Ensar , Cooke Vesselina G. , Nonami Atsushi , Ren Tao , Sanda Takaomi , Simkin Irene , Yuan Jing , Antonakos Brandon , Barys Louise , Ito Moriko , Stone Richard , Galinsky Ilene , Cowens Kristen , Nelson Erik , Sattler Martin , Jeay Sebastien , Wuerthner Jens U. , McDonough Sean M. , Wiesmann Marion , Griffin James D. 
Published: July 2015

Abstract
The tumor suppressor p53 is a key regulator of apoptosis and functions upstream in the apoptotic cascade by both indirectly and directly regulating Bcl-2 family proteins. In cells expressing wild-type (WT) p53, the HDM2 protein binds to p53 and blocks its activity. Inhibition of HDM2:p53 interaction activates p53 and causes apoptosis or cell-cycle arrest. Here, we investigated the ability of the novel HDM2 inhibitor CGM097 to potently and selectively kill WT p53-expressing AML cells. The antileukemic effects of CGM097 were studied using cell-based proliferation assays (human AML cell lines, primary AML patient cells, and normal bone marrow samples), apoptosis, and cell-cycle assays, ELISA, immunoblotting, and an AML patient–derived in vivo mouse model. CGM097 potently and selectively inhibited the proliferation of human AML cell lines and the majority of primary AML cells expressing WT p53, but not mutant p53, in a target-specific manner. Several patient samples that harbored mutant p53 were comparatively unresponsive to CGM097. Synergy was observed when CGM097 was combined with FLT3 inhibition against oncogenic FLT3-expressing cells cultured both in the absence as well as the presence of cytoprotective stromal-secreted cytokines, as well as when combined with MEK inhibition in cells with activated MAPK signaling. Finally, CGM097 was effective in reducing leukemia burden in vivo. These data suggest that CGM097 is a promising treatment for AML characterized as harboring WT p53 as a single agent, as well as in combination with other therapies targeting oncogene-activated pathways that drive AML. Mol Cancer Ther; 14(10); 2249–59. ©2015 AACR.
Serum Mimecan Is Associated With Arterial Stiffness in Hypertensive Patients
Authors: Gu Xiaosong , Zhao Liangping , Zhu Jing , Gu Haibo , Li Hui , Wang Luchen , Xu Weiting , Chen Jianchang 
Published: July 2015

Background
Mimecan plays an important role in endothelial and vascular smooth muscle cell integrity and may be involved the pathology of arterial stiffness. However, the role of mimecan in arterial stiffness in patients with hypertension is not well defined.

Methods and Results

A total of 116 hypertension patients and 54 healthy controls were enrolled in the investigation. Hypertensive patients were divided into 2 groups: the with arterial stiffness group (brachial‐ankle pulse wave velocity [ba
PWV
] ≥1400 cm/s; n=83) and the without arterial stiffness group (ba
PWV
<1400 cm/s; n=33). A noninvasive measure of vascular stiffness was performed using pulse wave velocity (
PWV
) measurement of ba
PWV
. Hypertensive patients had higher ba
PWV
, mimecan, and endothelin 1 (
ET
‐1) than healthy controls. The arterial stiffness group had higher mimecan and endothelin 1 (
ET
‐1) and lower ankle‐brachial pressure index (
ABI
) than those without stiffness. In hypertensive patients, mimecan was inversely correlated with
ABI
(
P
<0.05) and positively correlated with ba
PWV
,
ET
‐1, and total cholesterol. On multivariable logistic regression analysis, diastolic blood pressure, mimecan,
ET
‐1, and creatinine were independent predictors of arterial stiffness in hypertensive patients (
P
<0.05).

Conclusions

Mimecan levels are higher in hypertensive patients than in healthy controls. Increased plasma mimecan levels are independently associated with increased arterial stiffness as assessed by ba
PWV
.
Long-Term Blood–Brain Barrier Permeability Changes in Binswanger Disease
Authors: Huisa Branko N. , Caprihan Arvind , Thompson Jeffrey , Prestopnik Jillian , Qualls Clifford R. , Rosenberg Gary A. 
Published: July 2015

Background and Purpose—
The blood–brain barrier (BBB) is disrupted in small vessel disease patients with lacunes and white matter hyperintensities (WMHs). The relationship of WMHs and regional BBB permeability changes has not been studied. We hypothesized that BBB disruption occurs in normal appearing WM and regions near the WMHs. To test the hypothesis, we repeated BBB permeability measurements in patients with extensive WMHs related to Binswanger disease.

Methods—

We selected a subset of 22 Binswanger disease subjects from a well-characterized larger prospective vascular cognitive impairment cohort. We used 16 age-matched controls for comparison. The abnormal WM permeability (WMP) was measured twice for several years using dynamic contrast–enhanced magnetic resonance imaging. WMP maps were constructed from voxels above a predetermined threshold. Scans from first and second visits were coregistered. WM was divided into 3 regions: normal appearing WM, WMH ring, and WMH core. The ring was defined as 2 mm on each side of the WMH border. WMP was calculated in each of the 3 specific regions. We used paired
t
test, ANOVA, and Fisher exact test to compare individual changes.

Results—

WMP was significantly higher in subjects than in controls (
P
<0.001). There was no correlation between WMH load and WMP. High permeability regions had minimal overlap between first and second scans. Nine percent of WMP was within the WMHs, 49% within the normal appearing WM, and 52% within the WMH ring (
P
<0.001; ANOVA).

Conclusions—
Increased BBB permeability in normal appearing WM and close to the WMH borders supports a relationship between BBB disruption and the development of WMHs.
Interhemispheric Asymmetry of Warming in an Eddy-Permitting Coupled Sector Model
Authors: Hutchinson David K. , England Matthew H. , M. Hogg Andrew , Snow Kate 
Published: July 2015

Abstract
Climate model projections and observations show a faster rate of warming in the Northern Hemisphere (NH) than the Southern Hemisphere (SH). This asymmetry is partly due to faster rates of warming over the land than the ocean, and partly due to the ocean circulation redistributing heat toward the NH. This study examines the interhemispheric warming asymmetry in an intermediate complexity coupled climate model with eddy-permitting (0.25°) ocean resolution, and results are compared with a similar model with coarse (1°) ocean resolution. The models use a pole-to-pole 60° wide sector domain in the ocean and a 120° wide sector in the atmosphere, with Atlantic-like bathymetry and a simple land model. There is a larger high-latitude ocean temperature asymmetry in the 0.25° model compared with the 1° model, both in equilibrated control runs and in response to greenhouse warming. The larger warming asymmetry is caused by greater melting of NH sea ice in the 0.25° model, associated with faster, less viscous boundary currents transporting heat northward. The SH sea ice and heat transport response is relatively insensitive to the resolution change, since the eddy heat transport differences between the models are small compared with the mean flow heat transport. When a wind shift and intensification is applied in these warming scenarios, the warming asymmetry is further enhanced, with greater upwelling of cool water in the Southern Ocean and enhanced warming in the NH. Surface air temperatures show a substantial but lesser degree of high-latitude warming asymmetry, reflecting the sea surface warming patterns over the ocean but warming more symmetrically over the land regions.
Characterization of the Simulated Regional Snow Albedo Feedback Using a Regional Climate Model over Complex Terrain
Authors: Letcher Theodore W. , Minder Justin R. 
Published: July 2015

Abstract
Midlatitude mountain regions are particularly sensitive to climate change because of an active snow albedo feedback (SAF). Here, the SAF is characterized and quantified over the complex terrain of the Colorado Headwaters region using high-resolution regional climate model simulations. A pair of 7-yr control and pseudo-global warming simulations is used to study the regional climate response to a large-scale thermodynamic climate perturbation. Warming is strongly enhanced in regions of snow loss by as much as 5°C. Linear feedback analysis is used to quantify the strength of the SAF within the Headwaters region. The strength of the SAF reaches a maximum value of 4 W m−2 K−1 during April when snow loss coincides with strong incoming solar radiation. Simulations using 4- and 12-km horizontal grid spacing show good agreement in the strength and timing of the SAF, whereas a 36-km simulation shows discrepancies that are tied to differences in snow accumulation and ablation caused by smoother terrain. Energy budget analysis shows that transport by atmospheric circulations acts as a negative feedback to regional warming, damping the effects of the SAF. On the mesoscale, the SAF nonlocally enhances warming in locations with no snow, and enhances snowmelt in locations that do not experience snow cover change. The methods presented here can be used generally to quantify the role of the SAF in simulated regional climate change, illuminating the causes of differences in climate warming between models and regions.
Impact of Environmental Heterogeneity on the Dynamics of a Dissipating Supercell Thunderstorm
Authors: Davenport Casey E. , Parker Matthew D. 
Published: July 2015

Abstract
On 9 June 2009, the Second Verification of the Origins of Rotation in Tornadoes Experiment (VORTEX2) sampled a supercell as it traversed through an increasingly stable environment with decreasing bulk shear and storm-relative helicity. To investigate the impacts of the observed environmental heterogeneity on storm morphology, a series of idealized simulations were conducted. Utilizing the base-state substitution modeling technique, the separate effects of the changing wind profile and the increasingly stable boundary layer were evaluated. The varying base-state environment in each experiment elevated the mean source region of updraft parcels. These elevated parcels were drier (with less instability), and more negatively impacted by entrainment. Thus, as the updraft ingested a larger fraction of elevated parcels, its buoyancy was depleted, leading to demise. Unsurprisingly, the increasingly stable low-level environment played a dominant role in this process; however, wind profile modifications also elevated the mean source region of updraft parcels, which independently impacted storm strength and morphology. Changes to the storm’s internal dynamical processes were assessed using the diagnostic pressure equation. The evolution in total vertical acceleration was primarily related to changes in accelerations that were connected to updraft rotation, as well as shifts in buoyancy. The dynamical accelerations weakened and became maximized at a different altitude, resulting in an increasingly elevated updraft parcel source region. Overall, this study finds that a shifting updraft parcel source region can significantly impact storm maintenance; importantly, such a shift can result from changes in environmental temperature, moisture, or wind profiles.