bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Meta-analysis of Somatic Mutations from Next Generation Sequencing of 241 Melanomas: A Road Map for the Study of Genes with Potential Clinical Relevance
Authors: Xia Junfeng , Jia Peilin , Hutchinson Katherine E. , Dahlman Kimberly B. , Johnson Douglas , Sosman Jeffrey , Pao William , Zhao Zhongming 
Published: April 2014

Abstract
Next generation sequencing (NGS) has been used to characterize the overall genomic landscape of melanomas. Here, we systematically examined mutations from recently published melanoma NGS data involving 241 paired tumor-normal samples to identify potentially clinically relevant mutations. Melanomas were characterized according to an in-house clinical assay that identifies well-known specific recurrent mutations in five driver genes: BRAF (affecting V600), NRAS (G12, G13, and Q61), KIT (W557, V559, L576, K642, and D816), GNAQ (Q209), and GNA11 (Q209). Tumors with none of these mutations are termed “pan negative.” We then mined the driver mutation-positive and pan-negative melanoma NGS data for mutations in 632 cancer genes that could influence existing or emerging targeted therapies. First, we uncovered several genes whose mutations were more likely associated with BRAF- or NRAS-driven melanomas, including TP53 and COL1A1 with BRAF, and PPP6C, KALRN, PIK3R4, TRPM6, GUCY2C, and PRKAA2 with NRAS. Second, we found that the 69 “pan-negative” melanoma genomes harbored alternate infrequent mutations in the five known driver genes along with many mutations in genes encoding guanine nucleotide binding protein α-subunits. Third, we identified 12 significantly mutated genes in “pan-negative” samples (ALK, STK31, DGKI, RAC1, EPHA4, ADAMTS18, EPHA7, ERBB4, TAF1L, NF1, SYK, and KDR), including five genes (RAC1, ADAMTS18, EPHA7, TAF1L, and NF1) with a recurrent mutation in at least two “pan-negative” tumor samples. This meta-analysis provides a road map for the study of additional potentially actionable genes in both driver mutation-positive and pan-negative melanomas. Mol Cancer Ther; 13(7); 1918–28. ©2014 AACR.
PI3K and Bcl-2 Inhibition Primes Glioblastoma Cells to Apoptosis through Downregulation of Mcl-1 and Phospho-BAD
Authors: Pareja Fresia , Macleod David , Shu Chang , Crary John F. , Canoll Peter D. , Ross Alonzo H. , Siegelin Markus D. 
Published: April 2014

Abstract
Glioblastoma multiforme (GBM) is a highly malignant human brain neoplasm with limited therapeutic options. GBMs display a deregulated apoptotic pathway with high levels of the antiapoptotic Bcl-2 family of proteins and overt activity of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Therefore, combined interference of the PI3K pathway and the Bcl-2 family of proteins is a reasonable therapeutic strategy. ABT-263 (Navitoclax), an orally available small-molecule Bcl-2 inhibitor, and GDC-0941, a PI3K inhibitor, were used to treat established glioblastoma and glioblastoma neurosphere cells, alone or in combination. Although GDC-0941 alone had a modest effect on cell viability, treatment with ABT-263 displayed a marked reduction of cell viability and induction of apoptotic cell death. Moreover, combinatorial therapy using ABT-263 and GDC-0941 showed an enhanced effect, with a further decrease in cellular viability. Furthermore, combination treatment abrogated the ability of stem cell–like glioma cells to form neurospheres. ABT-263 and GDC-0941, in combination, resulted in a consistent and significant increase of Annexin V positive cells and loss of mitochondrial membrane potential compared with either monotherapy. The combination treatment led to enhanced cleavage of both initiator and effector caspases. Mechanistically, GDC-0941 depleted pAKT (Serine 473) levels and suppressed Mcl-1 protein levels, lowering the threshold for the cytotoxic actions of ABT-263. GDC-0941 decreased Mcl-1 in a posttranslational manner and significantly decreased the half-life of Mcl-1 protein. Ectopic expression of human Mcl-1 mitigated apoptotic cell death induced by the drug combination. Furthermore, GDC-0941 modulated the phosphorylation status of BAD, thereby further enhancing ABT-263–mediated cell death.
Implications: Combination therapy with ABT-263 and GDC-0941 has novel therapeutic potential by specifically targeting aberrantly active, deregulated pathways in GBM, overcoming endogenous resistance to apoptosis. Mol Cancer Res; 12(7); 987–1001. ©2014 AACR.
Relationship Between Time in Therapeutic Range and Comparative Treatment Effect of Rivaroxaban and Warfarin: Results From the ROCKET AF Trial
Authors: Piccini Jonathan P. , Hellkamp Anne S. , Lokhnygina Yuliya , Patel Manesh R. , Harrell Frank E. , Singer Daniel E. , Becker Richard C. , Breithardt Günter , Halperin Jonathan L. , Hankey Graeme J. , Berkowitz Scott D. , Nessel Christopher C. , Mahaffey Kenneth W. , Fox Keith A. A. , Califf Robert M. ,   ROCKET AF Investigators
Published: April 2014

Background

Time in therapeutic range (
TTR
) is a standard quality measure of the use of warfarin. We assessed the relative effects of rivaroxaban versus warfarin at the level of trial center
TTR
(c
TTR
) since such analysis preserves randomized comparisons.

Methods and Results

TTR
was calculated using the Rosendaal method, without exclusion of international normalized ratio (
INR
) values performed during warfarin initiation. Measurements during warfarin interruptions >7 days were excluded.
INR
s were performed via standardized finger‐stick point‐of‐care devices at least every 4 weeks. The primary efficacy endpoint (stroke or non‐central nervous system embolism) was examined by quartiles of c
TTR
and by c
TTR
as a continuous function. Centers with the highest c
TTR
s by quartile had lower‐risk patients as reflected by lower
CHADS
2
scores (
P
<0.0001) and a lower prevalence of prior stroke or transient ischemic attack (
P
<0.0001). Sites with higher c
TTR
were predominantly from North America and Western Europe. The treatment effect of rivaroxaban versus warfarin on the primary endpoint was consistent across a wide range of c
TTR
s (
P
value for interaction=0.71). The hazard of major and non‐major clinically relevant bleeding increased with c
TTR
(
P
for interaction=0.001), however, the estimated reduction by rivaroxaban compared with warfarin in the hazard of intracranial hemorrhage was preserved across a wide range of threshold c
TTR
values.

Conclusions

The treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of c
TTR
.
Narrowing Sex Differences in Lipoprotein Cholesterol Subclasses Following Mid‐Life: The Very Large Database of Lipids (VLDL‐10B)
Authors: Swiger Kristopher J. , Martin Seth S. , Blaha Michael J. , Toth Peter P. , Nasir Khurram , Michos Erin D. , Gerstenblith Gary , Blumenthal Roger S. , Jones Steven R. 
Published: April 2014

Background
Women have less risk of atherosclerotic cardiovascular disease compared with men up until midlife (ages 50 to 60), after which the gap begins to narrow post menopause. We hypothesized that the average lipid profile of women undergoes unfavorable changes compared with men after midlife.

Methods and Results

We examined lipids by sex and age in the Very Large Database of Lipids 10B (
VLDL 10B
) study. The analysis included 1 350 908 unique consecutive patients clinically referred for lipoprotein testing by density gradient ultracentrifugation from 2009 to 2011. Ratio variables were created for density subclasses of
LDL
‐C,
HDL
‐C, and
VLDL
‐C (
LLDR
,
LHDR
,
LVDR
, respectively). Men showed higher median
LDL
‐C values than women for ages 20 to 59, with the greatest difference in their 30s: 146 mg/dL in men versus 130 mg/dL in women. In contrast, women consistently had higher values after midlife (age 60), for example ages 70 to 79: 129 mg/dL in women versus 112 mg/dL in men. After age 50, women had higher
LDL
‐C each decade, for example 14% higher from their 30s to 50s, while HDL‐C concentrations did not differ. Women had more buoyant LDL‐C and HDL‐C (lower LLDR and LHDR) than men at all ages but the gap closed in higher age groups. In contrast, women had a generally denser VLDL‐C (higher LVDR) leading into midlife, with the gap progressively closing in higher age groups, approximating that of men in their 60s and 70s.

Conclusion
The narrowing sex differential in cardiovascular disease risk after midlife is mirrored by a higher total atherogenic lipoprotein cholesterol burden in women and a closer approximation of the less favorable density phenotype characteristic of men.
Consistency of Estimated Global Water Cycle Variations over the Satellite Era
Authors: Robertson F. R. , Bosilovich M. G. , Roberts J. B. , Reichle R. H. , Adler R. , Ricciardulli L. , Berg W. , Huffman G. J. 
Published: April 2014

Abstract
Motivated by the question of whether recent interannual to decadal climate variability and a possible “climate shift” may have affected the global water balance, we examine precipitation minus evaporation (P – E) variability integrated over the global oceans and global land for the period 1979–2010 from three points of view—remotely sensed retrievals and syntheses over the oceans, reanalysis vertically integrated moisture flux convergence (VMFC) over land, and land surface models (LSMs) forced with observations-based precipitation, radiation, and near-surface meteorology.
Over land, reanalysis VMFC and P − evapotranspiration (ET) from observationally forced LSMs agree on interannual variations (e.g., El Niño/La Niña events); however, reanalyses exhibit upward VMFC trends 3–4 times larger than P − ET trends of the LSMs. Experiments with other reanalyses using reduced observations show that upward VMFC trends in the full reanalyses are due largely to observing system changes interacting with assimilation model physics. The much smaller P − ET trend in the LSMs appears due to changes in frequency and amplitude of warm events after the 1997/98 El Niño, a result consistent with coolness in the eastern tropical Pacific sea surface temperature (SST) after that date.
When integrated over the global oceans, E and especially P variations show consistent signals of El Niño/La Niña events. However, at scales longer than interannual there is considerable uncertainty especially in E. This results from differences among datasets in near-surface atmospheric specific humidity and wind speed used in bulk aerodynamic retrievals. The P variations, all relying substantially on passive microwave retrievals over ocean, also have uncertainties in decadal variability, but to a smaller degree.
Enhanced 2-h–8-day Oscillations Associated with Tropical Instability Waves
Authors: Jing Zhao , Wu Lixin , Wu Dexing , Qiu Bo 
Published: April 2014

Abstract
The westward South Equatorial Current (SEC) and eastward Equatorial Undercurrent (EUC) is a marginally stable current system due to the strong vertical shear. The existence of wavelike motions may locally reduce the Richardson number enough to trigger instabilities. Here, velocity measurements from the Tropical Atmosphere Ocean (TAO) array are used to examine the variability of oscillations within 0.125–12 cycles per day (cpd). It is found that the 0.125–12-cpd oscillations become more energetic in the presence of strong tropical instability waves (TIWs). The enhancement of shear variance is most pronounced around the EUC core (115 m), while prominent elevation of kinetic energy occurs around 85 m, where the EUC shear is strongest. Particularly, the energetic 0.125–12-cpd oscillations during strong TIW seasons do not cycle on a daily basis and are more evident during the southward phase of TIWs. The enhanced 0.125–12-cpd oscillations during strong TIW seasons can be ascribed neither to the changing background stratification nor to the vertical migration of EUC core at the corresponding time scales. Its strength is tightly correlated with the EUC shear and, to a lesser extent, the TIW shear. A partial correlation analysis suggests that the correlation to the TIW shear is mainly due to the association between EUC and TIW shear. The strength of the 0.125–12-cpd oscillations does not follow the variation of surface wind speed and wind curl, implying that they are not directly generated by surface wind forcing.
Radar Climatology of Tornadic and Nontornadic Vortices in High-Shear, Low-CAPE Environments in the Mid-Atlantic and Southeastern United States
Authors: Davis Jason M. , Parker Matthew D. 
Published: April 2014

Abstract
Tornadoes occurring in environments characterized by strong vertical wind shear [0–6-km bulk wind difference ≥35 knots (kt; 1 kt = 0.51 m s−1) (18 m s−1)] but low CAPE (&lt;500 J kg−1) are an important challenge for forecasters, especially in the mid-Atlantic and southeastern United States. In this study, 95 tornadic and 135 nontornadic vortices were tracked in high-shear, low-CAPE (HSLC) environments. Values of azimuthal shear were recorded along the vortex tracks, and operationally relevant radar reflectivity signatures were also manually identified in association with these vortices. Statistically significant differences in azimuthal shear were found between tornadic and nontornadic vortices within 60 km of the radar, particularly near the surface. Although there were significant differences between tornadic and nontornadic vortices from nonsupercells (primarily quasi-linear convective systems), this was not the case for supercellular vortices. Beyond 60 km from the radar, no statistically significant differences were found. Numerous reflectivity signatures were also studied, including hook echoes and weak-echo regions associated with supercell vortices, as well as rear-inflow notches, bowing segments, and forward-inflow notches associated with nonsupercell vortices. These signatures were found to have a high probability of detection close to the radar, but also a high false alarm rate, and were observed much less often &gt;100 km from the radar. Overall, while azimuthal shear and radar reflectivity signatures show the potential for high probability of detection in close proximity to operational radars, high false alarm rates, and short lead times appear to be an unavoidable trade-off in HSLC environments.
The use of aprepitant in a case of refractory nausea and vomiting
Authors: Lowery Lucy , Andrew Inga , Gill Sarah , Lee Mark 
Published: April 2014

Background: This case report describes a patient whose refractory nausea and vomiting significantly improved with the use of aprepitant, a neurokinin receptor antagonist currently only licensed for short-term use in chemotherapy-induced nausea and vomiting. Case presentation: A patient with breast cancer and meningeal metastases had an 18-month history of nausea and vomiting refractory to a number of antiemetics commonly used in palliative care. The nausea and vomiting resolved after receiving two doses of the drug aprepitant. Case management and outcome: Maintenance antiemetic treatment with aprepitant was continued over a 5-month period with no recurrence of nausea and vomiting, and no observed side effects. Conclusions: Aprepitant has a potential role as an antiemetic for refractory symptoms within the palliative-care setting.
MRI Anatomy of the Tibial ACL Attachment and Proximal Epiphysis in a Large Population of Skeletally Immature Knees
Authors: Swami Vimarsha Gopal , Mabee Myles , Hui Catherine , Jaremko Jacob Lester 
Published: April 2014

Background: To aid in performing anatomic physeal-sparing anterior cruciate ligament (ACL) reconstruction, it is important for surgeons to have reference data for the native ACL attachment positions and epiphyseal anatomy in skeletally immature knees. Purpose: To characterize anatomic parameters of the ACL tibial insertion and proximal tibial epiphysis at magnetic resonance imaging (MRI) in a large population of skeletally immature knees. Study Design: Cross-sectional study; Level of evidence, 3. Methods: The ACL tibial attachment site and proximal epiphysis were examined in 570 skeletally immature knees with an intact ACL (age, 6-15 years) using 1.5-T proton density–weighted sagittal MRI; also measured were the tibial anteroposterior diameter; anterior, central, and posterior ACL attachment positions; vertical height of the epiphysis; and maximum oblique epiphyseal depth extending from the ACL tibial attachment center to the tibial tuberosity. Results: In adolescents (11-15 years of age), the center of the ACL’s tibial attachment was 51.5% ± 5.7% of the anteroposterior diameter of the tibia, with no significant differences between sexes or age groups ( P > .05 in all cases). Mean vertical epiphyseal height was 15.9 ± 1.7 mm in the adolescent group, with significant differences between 11-year-olds (15.2 ± 1.5 mm) and 15-year-olds (16.6 ± 1.6 mm), P < .001, and between males (16.6 ± 1.5 mm) and females (14.8 ± 1.4), P < .001. Mean maximum oblique depth was 30.0 ± 5.3 mm, with a significant difference between 11-year-olds (26.7 ± 4.9 mm) and 15-year-olds (32.7 ± 5.1 mm), P < .001, and between males (29.7 ± 6.4 mm) and females (27.8 ± 5.2 mm), P < .001. The maximum oblique depth occurred at a mean angle of ~50°, and this angle did not change with age or sex. There was a significant moderate correlation ( r = 0.39, P < .001) between epiphyseal vertical height and maximum oblique depth. Conclusion: The center of the ACL tibial attachment was consistently near 51% of the anteroposterior diameter, regardless of age or sex. The vertical depth of the tibial epiphysis was ~16 mm in adolescents. Maximum oblique depth from ACL attachment was ~30 mm, occurring at a mean angle ~50° regardless of age or sex. The normative values for tibial ACL attachment and epiphyseal anatomy presented here may be helpful in selecting candidates for surgery and in planning surgical approaches for pediatric ACL reconstruction.
Two Methods of Hemodynamic and Volume Status Assessment in Critically Ill Patients
Authors: Eiferman Daniel S. , Davido H. Tracy , Howard James M. , Gerckens Jennifer , Evans David C. , Cook Charles H. , Stawicki S. P. A. 
Published: April 2014

Introduction: The invasive nature and potential complications associated with pulmonary artery (PA) catheters (PACs) have prompted the pursuit of less invasive monitoring options. Before implementing new hemodynamic monitoring technologies, it is important to determine the interchangeability of these modalities. This study examines monitoring concordance between the PAC and the arterial waveform analysis (AWA) hemodynamic monitoring system. Methods: Critically ill patients undergoing hemodynamic monitoring with PAC were simultaneously equipped with the FloTrac AWA system (both from Edwards Lifesciences, Irvine, California). Data were concomitantly obtained for hemodynamic variables. Bland-Altman methodology was used to assess CO measurement bias and κ coefficent to show discrepancies in intravascular volume. Results: Significant measurement bias was observed in both CO and intravascular volume status between the 2 techniques (mean bias, −1.055 ± 0.263 liter/min, r = 0.481). There was near-complete lack of agreement regarding the need for intravenous volume administration (κ = 0.019) or the need for vasoactive agent administration (κ = 0.015). Conclusions: The lack of concordance between PAC and AWA in critically ill surgical patients undergoing active resuscitation raises doubts regarding the interchangeability and relative accuracy of these modalities in clinical use. Lack of awareness of these limitations can lead to errors in clinical decision making when managing critically ill patients.
Body mass index and cancer screening: Findings from the English Longitudinal Study of Ageing
Authors: Beeken Rebecca J , Wilson Rose , McDonald Laura , Wardle Jane 
Published: April 2014

Objectives Obesity is associated with an increased cancer incidence and mortality and therefore cancer screening is particularly important for obese individuals. However, some US studies find lower screening uptake in this group. This study explored whether rates of breast and colorectal screening in England are lower for obese than healthy weight individuals. Setting Data were from the English Longitudinal Study of Ageing (ELSA). Methods We analysed data from adults who were eligible to have been invited to the UK national screening programmes for breast or colorectal cancer (CRC) in the last five years, and had been given the screening module in Wave 5 of ELSA (N = 1804 for CRC screening, N = 2401 for breast cancer screening). Weight and height were measured by a nurse at Wave 4 (two years earlier). Logistic regression was used to calculate the odds of breast and CRC screening (ever) for participants in higher weight categories (Body Mass Index [BMI] ≥ 25) compared with healthy weight individuals (BMI <25), controlling for socio-demographic variables. Results Of ELSA participants, 63% reported CRC screening, and 92% of the women reported breast cancer screening. Obesity was associated with lower CRC screening, but effects were strongest for class III obesity (BMI ≥40) (45% screened; OR = 0.48, 95% CI = 0.32–0.93, P = .029). There was no association between weight status and breast cancer screening. Conclusion Severe obesity appears to be a deterrent to CRC screening but not breast cancer screening. Targeted interventions may be required to promote CRC screening uptake in this group, which already has a heightened risk as a consequence of weight.
Marketisation and the dual welfare state: Neoliberalism and inequality in Australia
Authors: Spies-Butcher Ben 
Published: April 2014

AbstractAustralian social policy has seen apparently contradictory developments over the period of economic restructuring. Social spending has increased based on a highly redistributive model while inequality has grown. This article explores the relationship between Australia’s experience of economic restructuring and the political dynamics of an emerging ‘dual welfare state’. Importantly, the article argues that Australian reformers did not reject the state per se, nor egalitarianism as an objective. Instead, reform sought to combine greater competition with compensation, generating larger inequalities in market incomes alongside growing social spending. The article explores how Labor combined neoclassical ideas about competition with a commitment to a ‘small state’ version of social democracy. This did moderate inequalities through the period of restructuring, but it also altered the dynamics of political contestation. The article provides two typologies to understand this political dynamic, arguing forms of marketisation opened the door to a political contest over the nature, rather than the extent, of public provision, while the model of targeting reinforced paternalist tendencies inherent in neoliberal reform.