bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of LRIG1 Locus Increases Risk of Early and Late Relapse of Stage I/II Breast Cancer
Authors: Thompson Patricia A. , Ljuslinder Ingrid , Tsavachidis Spyros , Brewster Abenaa , Sahin Aysegul , Hedman Håkan , Henriksson Roger , Bondy Melissa L. , Melin Beatrice S. 
Published: May 2014

Abstract
Gains and losses at chromosome 3p12-21 are common in breast tumors and associated with patient outcomes. We hypothesized that the LRIG1 gene at 3p14.1, whose product functions in ErbB-family member degradation, is a critical tumor modifier at this locus. We analyzed 971 stage I/II breast tumors using Affymetrix Oncoscan molecular inversion probe arrays that include 12 probes located within LRIG1. Copy number results were validated against gene expression data available in the public database. By partitioning the LRIG1 probes nearest exon 12/13, we confirm a breakpoint in the gene and show that gains and losses in the subregions differ by tumor and patient characteristics including race/ethnicity. In analyses adjusted for known prognostic factors, loss of LRIG1 was independently associated with risk of any relapse (HR, 1.90; 95% CI, 1.32–2.73), relapse ≥ 5 years (HR, 2.39; 95% CI, 1.31–4.36), and death (HR, 1.55; 95% CI, 1.11–2.16). Analyses of copy number across chromosome 3, as well as expression data from pooled, publicly available datasets, corroborated the hypothesis of an elevated and persistent risk among cases with loss of or low LRIG1. We concluded that loss/low expression of LRIG1 is an independent risk factor for breast cancer metastasis and death in stage I/II patients. Increased hazard in patients with loss/low LRIG1 persists years after diagnosis, suggesting that LRIG1 is acting as a critical suppressor of tumor metastasis and is an early clinical indicator of risk for late recurrences in otherwise low-risk patients. Cancer Res; 74(11); 2928–35. ©2014 AACR.
CBP-93872 Inhibits NBS1-Mediated ATR Activation, Abrogating Maintenance of the DNA Double-Strand Break–Specific G2 Checkpoint
Authors: Hirokawa Takahisa , Shiotani Bunsyo , Shimada Midori , Murata Kazuhiro , Johmura Yoshikazu , Haruta Mayumi , Tahara Hidetoshi , Takeyama Hiromitsu , Nakanishi Makoto 
Published: May 2014

Abstract
CBP-93872 was previously identified as a G2 checkpoint inhibitor using a cell-based high-throughput screening system. However, its molecular actions as well as cellular targets are largely unknown. Here, we uncovered the molecular mechanisms underlying abrogation of the G2 checkpoint by CBP-93872. CBP-93872 specifically abrogates the DNA double-stranded break (DSB)–induced G2 checkpoint through inhibiting maintenance but not initiation of G2 arrest because of specific inhibition of DSB-dependent ATR activation. Hence, ATR-dependent phosphorylation of Nbs1 and replication protein A 2 upon DSB was strongly suppressed in the presence of CBP-93872. CBP-93872 did not seem to inhibit DNA-end resection, but did inhibit Nbs1-dependent and ssDNA-induced ATR activation in vitro in a dose-dependent manner. Taken together, our results suggest that CBP-93872 is an inhibitor of maintenance of the DSB-specific G2 checkpoint and thus might be a strong candidate as the basis for a drug that specifically sensitizes p53-mutated cancer cells to DSB-inducing DNA damage therapy. Cancer Res; 74(14); 3880–9. ©2014 AACR.
Hyperpolarized [1-13C] Glutamate: A Metabolic Imaging Biomarker of IDH1 Mutational Status in Glioma
Authors: Chaumeil Myriam M. , Larson Peder E.Z. , Woods Sarah M. , Cai Larry , Eriksson Pia , Robinson Aaron E. , Lupo Janine M. , Vigneron Daniel B. , Nelson Sarah J. , Pieper Russell O. , Phillips Joanna J. , Ronen Sabrina M. 
Published: May 2014

Abstract
Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event, and are associated with epigenetically driven modulations of metabolism. Of particular interest is the recently uncovered relationship between the IDH1 mutation and decreased activity of the branched-chain amino acid transaminase 1 (BCAT1) enzyme. Noninvasive imaging methods that can assess BCAT1 activity could therefore improve detection of mutant IDH1 tumors and aid in developing and monitoring new targeted therapies. BCAT1 catalyzes the transamination of branched-chain amino acids while converting α-ketoglutarate (α-KG) to glutamate. Our goal was to use 13C magnetic resonance spectroscopy to probe the conversion of hyperpolarized [1-13C] α-KG to hyperpolarized [1-13C] glutamate as a readout of BCAT1 activity. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized [1-13C] α-KG, hyperpolarized [1-13C] glutamate production was detected both in cells and in vivo, and the level of hyperpolarized [1-13C] glutamate was significantly lower in mutant IDH1 cells and tumors compared with their IDH1-wild-type counterparts. Importantly however, in our cells the observed drop in hyperpolarized [1-13C] glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized [1-13C] glutamate could thus inform on multiple mutant IDH1-associated metabolic events that mediate reduced glutamate production. Cancer Res; 74(16); 4247–57. ©2014 AACR.
Squamous Cell Carcinoma of the Oral Tongue in Young Non-Smokers Is Genomically Similar to Tumors in Older Smokers
Authors: Pickering Curtis R. , Zhang Jiexin , Neskey David M. , Zhao Mei , Jasser Samar A. , Wang Jiping , Ward Alexandra , Tsai C. Jillian , Ortega Alves Marcus V. , Zhou Jane H. , Drummond Jennifer , El-Naggar Adel K. , Gibbs Richard , Weinstein John N. , Wheeler David A. , Wang Jing , Frederick Mitchell J. , Myers Jeffrey N. 
Published: May 2014

AbstractPurpose: Epidemiologic studies have identified an increasing incidence of squamous cell carcinoma of the oral tongue (SCCOT) in younger patients.Experimental Design: DNA isolated from tongue tumors of young (&lt;45 years, non-smokers) and old (&gt;45 years) patients at was subjected to whole-exome sequencing and copy-number analysis. These data were compared with data from similar patients in the TCGA (The Cancer Genome Atlas) project.Results: In this study, we found that gene-specific mutation and copy-number alteration frequencies were similar between young and old patients with SCCOT in two independent cohorts. Likewise, the types of base changes observed in the young cohort were similar to those in the old cohort even though they differed in smoking history. TCGA data also demonstrate that the genomic effects of smoking are tumor site–specific, and we find that smoking has only a minor impact on the types of mutations observed in SCCOT.Conclusions: Overall, tumors from young patients with SCCOT appear genomically similar to those of older patients with SCCOT, and the cause for the increasing incidence of young SCCOT remains unknown. These data indicate that the functional impact of smoking on carcinogenesis in SCCOT is still poorly understood. Clin Cancer Res; 20(14); 3842–8. ©2014 AACR.
Skin Autofluorescence Associates With Vascular Calcification in Chronic Kidney Disease
Authors: Wang Angela Yee-Moon , Wong Chun-Kwok , Yau Yat-Yin , Wong Sharon , Chan Iris Hiu-Shuen , Lam Christopher Wai-Kei 
Published: May 2014

Objective—
This study aims to evaluate the relationship between tissue advanced glycation end products, as reflected by skin autofluorescence, and vascular calcification in chronic kidney disease.

Approach and Results—

Three hundred patients with stage 3 to 5 chronic kidney disease underwent multislice computed tomography to estimate total coronary artery calcium score (CACS) and had tissue advanced glycation end product assessed using a skin autofluorescence reader. Intact parathyroid hormone (
P
<0.001) displaced estimated glomerular filtration rate as third most significant factor associated with skin autofluorescence after age (
P
<0.001) and diabetes mellitus (
P
<0.001) in multiple regression analysis. On univariate multinomial logistic regression analysis, every 1-U increase in skin autofluorescence was associated with a 7.43-fold (95% confidence intervals, 3.59–15.37;
P
<0.001) increased odds of having CACS ≥400 compared with those with zero CACS. Skin autofluorescence retained significance in predicting CACS ≥400 (odds ratio, 3.63; 95% confidence intervals, 1.44–9.18;
P
=0.006) when adjusting for age, sex, serum calcium, phosphate, albumin, C-reactive protein, lipids, blood pressure, estimated glomerular filtration rate, and intact parathyroid hormone but marginally lost significance when additionally adjusting for diabetes mellitus (odds ratio, 2.23; 95% confidence intervals, 0.81–6.14;
P
=0.1). Combination of diabetes mellitus and higher intact parathyroid hormone was associated with greater skin autofluorescence and CACS versus those without diabetes mellitus and having lower intact parathyroid hormone.

Conclusions—
Tissue advanced glycation end product, as reflected by skin autofluorescence, showed a significant novel association with vascular calcification in chronic kidney disease. These data suggest that increased tissue advanced glycation end product may contribute to vascular calcification in chronic kidney disease and diabetes mellitus and warrant further experimental investigation.
Genome-Scale Methods Converge on Key Mitochondrial Genes for the Survival of Human Cardiomyocytes in Hypoxia
Authors: Edwards Lindsay M. , Sigurdsson Martin I. , Robbins Peter A. , Weale Michael E. , Cavalleri Gianpiero L. , Montgomery Hugh E. , Thiele Ines 
Published: May 2014

Background—
Any reduction in myocardial oxygen delivery relative to its demands can impair cardiac contractile performance. Understanding the mitochondrial metabolic response to hypoxia is key to understanding ischemia tolerance in the myocardium. We used a novel combination of 2 genome-scale methods to study key processes underlying human myocardial hypoxia tolerance. In particular, we hypothesized that computational modeling and evolution would identify similar genes as critical to human myocardial hypoxia tolerance.

Methods and Results—
We analyzed a reconstruction of the cardiac mitochondrial metabolic network using constraint-based methods, under conditions of simulated hypoxia. We used flux balance analysis, random sampling, and principal component analysis to explore feasible steady-state solutions. Hypoxia blunted maximal ATP (−17%) and heme (−75%) synthesis and shrank the feasible solution space. Tricarboxylic acid and urea cycle fluxes were also reduced in hypoxia, but phospholipid synthesis was increased. Using mathematical optimization methods, we identified reactions that would be critical to hypoxia tolerance in the human heart. We used data regarding single-nucleotide polymorphism frequency and distribution in the genomes of Tibetans (whose ancestors have resided in persistent high-altitude hypoxia for several millennia). Six reactions were identified by both methods as being critical to mitochondrial ATP production in hypoxia: phosphofructokinase, phosphoglucokinase, complex II, complex IV, aconitase, and fumarase.

Conclusions—
Mathematical optimization and evolution converged on similar genes as critical to human myocardial hypoxia tolerance. Our approach is unique and completely novel and demonstrates that genome-scale modeling and genomics can be used in tandem to provide new insights into cardiovascular genetics.
Ranolazine Effectively Suppresses Atrial Fibrillation in the Setting of Heart Failure
Authors: Burashnikov Alexander , Di Diego José M. , Barajas-Martínez Hector , Hu Dan , Cordeiro Jonathan M. , Moise N. Sydney , Kornreich Bruce G. , Belardinelli Luiz , Antzelevitch Charles 
Published: May 2014

Background—
There is a critical need for safer and more effective pharmacological management of atrial fibrillation (AF) in the setting of heart failure (HF).

Methods and Results—
This study investigates the electrophysiological, antiarrhythmic, and proarrhythmic effects of a clinically relevant concentration of ranolazine (5 μmol/L) in coronary-perfused right atrial and left ventricular preparations isolated from the hearts of HF dogs. HF was induced by ventricular tachypacing (2–6 weeks at 200–240 beats per minute; n=17). Transmembrane action potentials were recorded using standard microelectrode techniques. In atria, ranolazine slightly prolonged action potential duration but significantly depressed sodium channel current–dependent parameters causing a reduction of maximum rate of rise of the action potential upstroke, a prolongation of the effective refractory period secondary to the development of postrepolarization refractoriness, and an increase in diastolic threshold of excitation and atrial conduction time. Ranolazine did not significantly alter these parameters or promote arrhythmias in the ventricles. Ranolazine produced greater inhibition of peak sodium channel current in atrial cells isolated from HF versus normal dogs. A single premature beat reproducibly induced self-terminating AF in 10 of 17 atria. Ranolazine (5 μmol/L) suppressed induction of AF in 7 of 10 (70%) atria. In the remaining 3 atria, ranolazine reduced frequency and duration of AF.

Conclusions—
Our results demonstrate more potent suppression of AF by ranolazine in the setting of HF than previously demonstrated in nonfailing hearts and absence of ventricular proarrhythmia. The data suggest that ranolazine may be of benefit as an alternative to amiodarone and dofetilide in the management of AF in patients with HF.
Reference Ranges of Blood Flow in the Major Vessels of the Normal Human Fetal Circulation at Term by Phase-Contrast Magnetic Resonance Imaging
Authors: Prsa Milan , Sun Liqun , van Amerom Joshua , Yoo Shi-Joon , Grosse-Wortmann Lars , Jaeggi Edgar , Macgowan Christopher , Seed Mike 
Published: May 2014

Background—
Phase-contrast MRI with metric-optimized gating is a promising new technique for studying the distribution of the fetal circulation. However, mean and reference ranges for blood flow measurements made in the major fetal vessels using this technique are yet to be established.

Methods and Results—

We measured flow in the major vessels of the fetal circulation in 40 late-gestation normal human fetuses using phase-contrast MRI (mean gestational age, 37 [SD=1.1] weeks). Flows were indexed to the fetal weight, which was estimated from the fetal volume calculated by MRI segmentation. The following mean flows (in mL/min per kilogram; ±2SD) were obtained: combined ventricular output, 465 (351, 579); main pulmonary artery, 261 (169, 353); ascending aorta, 191 (121, 261); superior vena cava, 137 (77, 197); ductus arteriosus, 187 (109, 265); descending aorta, 252 (160, 344); pulmonary blood flow, 77 (0, 160); umbilical vein, 134 (62, 206); and foramen ovale, 135 (37, 233). Expressed as percentages of the combined ventricular output, the mean flows±2 SD were as follows: main pulmonary artery, 56 (44, 68); ascending aorta, 41 (29, 53); superior vena cava, 29 (15, 43); ductus arteriosus, 41 (25, 57); descending aorta, 55 (35, 75); pulmonary blood flow, 16 (0, 34); umbilical vein, 29 (11, 47); and foramen ovale, 29 (7, 51). A strong inverse relationship between foramen ovale shunt and pulmonary blood flow was noted (
r
=−0.64;
P
<0.0001).

Conclusions—
Although too small a sample size to provide normal ranges, these results are in keeping with those predicted in humans based on measurements made in fetal lambs using radioactive microspheres and provide preliminary reference ranges for the late-gestation human fetuses. The wide range we found in foramen ovale shunting suggests a degree of variability in the way blood is streamed through the fetal circulation.
Endoglin Deficiency Impairs Stroke Recovery
Authors: Shen Fanxia , Degos Vincent , Chu Pei-Lun , Han Zhenying , Westbroek Erick M. , Choi Eun-Jung , Marchuk Douglas , Kim Helen , Lawton Michael T. , Maze Mervyn , Young William L. , Su Hua 
Published: May 2014

Background and Purpose—
Endoglin deficiency causes hereditary hemorrhagic telangiectasia-1 and impairs myocardial repair. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia-1 are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that endoglin deficiency impairs stroke recovery.

Methods—

Eng
heterozygous (
Eng

+/–

) and wild-type mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Pial collateral vessels were quantified before pMCAO. Infarct/atrophic volume, vascular density, and macrophages were quantified in various days after pMCAO, and behavioral function was assessed using corner and adhesive removal tests on days 3, 15, 30, and 60 after pMCAO. The association between
ENG
207G>A polymorphism and brain arteriovenous malformation rupture and surgery outcome was analyzed using logistic regression analysis in 256 ruptured and 157 unruptured patients.

Results—

After pMCAO,
Eng

+/–

mice showed larger infarct/atrophic volumes at all time points (
P
<0.05) and showed worse behavior performance (
P
<0.05) at 15, 30, and 60 days when compared with wild-type mice.
Eng

+/–

mice had fewer macrophages on day 3 (
P
=0.009) and more macrophages on day 60 (
P
=0.02) in the peri-infarct region. Although
Eng

+/–

and wild-type mice had similar numbers of pial collateral vessels before pMCAO,
Eng

+/–

mice had lower vascular density in the peri-infarct region (
P
=0.05) on day 60 after pMCAO. In humans,
ENG
207A allele has been associated with worse outcomes after arteriovenous malformation rupture or surgery of patients with unruptured arteriovenous malformation.

Conclusions—
Endoglin deficiency impairs brain injury recovery. Reduced angiogenesis, impaired macrophage homing, and delayed inflammation resolution could be the underlying mechanism.
Concurrent 3-D Sonifications Enable the Head-Up Monitoring of Two Interrelated Aircraft Navigation Instruments
Authors: Towers John , Burgess-Limerick Robin , Riek Stephan 
Published: May 2014

Objective: The aim of this study was to enable the head-up monitoring of two interrelated aircraft navigation instruments by developing a 3-D auditory display that encodes this navigation information within two spatially discrete sonifications. Background: Head-up monitoring of aircraft navigation information utilizing 3-D audio displays, particularly involving concurrently presented sonifications, requires additional research. Method: A flight simulator’s head-down waypoint bearing and course deviation instrument readouts were conveyed to participants via a 3-D auditory display. Both readouts were separately represented by a colocated pair of continuous sounds, one fixed and the other varying in pitch, which together encoded the instrument value’s deviation from the norm. Each sound pair’s position in the listening space indicated the left/right parameter of its instrument’s readout. Participants’ accuracy in navigating a predetermined flight plan was evaluated while performing a head-up task involving the detection of visual flares in the out-of-cockpit scene. Results: The auditory display significantly improved aircraft heading and course deviation accuracy, head-up time, and flare detections. Head tracking did not improve performance by providing participants with the ability to orient potentially conflicting sounds, suggesting that the use of integrated localizing cues was successful. Conclusion: A supplementary 3-D auditory display enabled effective head-up monitoring of interrelated navigation information normally attended to through a head-down display. Application: Pilots operating aircraft, such as helicopters and unmanned aerial vehicles, may benefit from a supplementary auditory display because they navigate in two dimensions while performing head-up, out-of-aircraft, visual tasks.
Stress and Anxiety in Women With Gestational Diabetes During Dietary Management
Authors: Hui Amy Leung , Sevenhuysen Gustaaf , Harvey Dexter , Salamon Elizabeth 
Published: May 2014

Purpose To explore the stress and anxiety experiences during dietary management in women with gestational diabetes (GDM). Methods Thirty women with GDM from the Winnipeg area participated in the mixed methods study. Each participant completed a Food Choice Map semistructured interview, a Perceived Stress Scale, a Pregnancy Anxiety Scale, a State-Trait Anxiety Inventory–Trait questionnaire, and a demographic questionnaire. Stress and anxiety experiences were identified from interview transcripts and categorized into themes based on the constant comparative method. Questionnaire scores aided in interpreting the stress and anxiety experience in the qualitative data. Results Three major themes were generated from the interviews: (1) stress related to GDM diagnosis and the perception of a high risk pregnancy; (2) stress over losing control of GDM during the process of dietary management; and (3) anxiety related to the fear of maternal and infant complications. Women on insulin experienced significantly higher levels of perceived stress ( P < .01), and the dietary management stress was more prevalent in women using insulin compared to the ones on diet treatment only (Fisher exact test, P < .01). Unhealthy diet coping strategies occurred with the stress and anxiety. Conclusions Stress and anxiety were associated with different contexts in this study sample. Women who were on insulin experienced significantly higher levels of perceived stress related to dietary management.
Rapid Systematic Review of Repeated Application of the Epley Maneuver for Treating Posterior BPPV
Authors: Reinink Hendrik , Wegner Inge , Stegeman Inge , Grolman Wilko 
Published: May 2014

ObjectiveTo evaluate the effect of repeated application of the Epley maneuver on patient‐reported symptom relief and resolution of nystagmus in patients with posterior benign paroxysmal positional vertigo (p‐BPPV).Data SourcesPubMed, Embase, and the Cochrane Library.MethodsA systematic search was conducted. Studies reporting original study data were included. Relevance and risk of bias (RoB) of the selected articles were assessed. Studies with low relevance, high RoB, or both were excluded. Success percentages and mean values were extracted.ResultsA total of 955 unique studies were retrieved. Fourteen of these satisfied the eligibility criteria. All of the included studies carried a high relevance and a moderate RoB. The majority of studies were 1‐armed trials, in which the Epley was repeated only in case previous attempt(s) had failed. The maneuver was not repeated if it was successful. In 32% to 90% of patients, the first treatment session was successful. Reported cumulative success percentages ranged from 40% to 100% after the second session, 67% to 98% after the third session, 87% to 100% after the fourth session, and 100% in the studies in which patients received 5 sessions. One study evaluating the effect of multiple maneuvers in a single session showed a rise in success percentages from 84% for 1 maneuver to 90% after 2 maneuvers and 92% after 3 maneuvers.ConclusionMultiple studies with moderate RoB show a beneficial effect of multiple sessions of the Epley maneuver in p‐BPPV patients who are not fully cleared of symptoms after the first session.