bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma Carotenoid- and Retinol-Weighted Multi-SNP Scores and Risk of Breast Cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium
Authors: Hendrickson Sara J. , Lindström Sara , Eliassen A. Heather , Rosner Bernard A. , Chen Constance , Barrdahl Myrto , Brinton Louise , Buring Julie , Canzian Federico , Chanock Stephen , Clavel-Chapelon Françoise , Figueroa Jonine D. , Gapstur Susan M. , Garcia-Closas Montserrat , Gaudet Mia M. , Haiman Christopher A. , Hazra Aditi , Henderson Brian , Hoover Robert , Hüsing Anika , Johansson Mattias , Kaaks Rudolf , Khaw Kay-Tee , Kolonel Laurence N. , Le Marchand Loic , Lissowska Jolanta , Lund Eiliv , McCullough Marjorie L. , Peplonska Beata , Riboli Elio , Sacerdote Carlotta , Sánchez María-José , Tjønneland Anne , Trichopoulos Dimitrios , van Gils Carla H. , Yeager Meredith , Kraft Peter , Hunter David J. , Ziegler Regina G. , Willett Walter C. 
Published: March 2013

Abstract
Background: Dietary and circulating carotenoids have been inversely associated with breast cancer risk, but observed associations may be due to confounding. Single-nucleotide polymorphisms (SNPs) in β-carotene 15,15′-monooxygenase 1 (BCMO1), a gene encoding the enzyme involved in the first step of synthesizing vitamin A from dietary carotenoids, have been associated with circulating carotenoid concentrations and may serve as unconfounded surrogates for those biomarkers. We determined associations between variants in BCMO1 and breast cancer risk in a large cohort consortium.
Methods: We used unconditional logistic regression to test four SNPs in BCMO1 for associations with breast cancer risk in 9,226 cases and 10,420 controls from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also tested weighted multi-SNP scores composed of the two SNPs with strong, confirmed associations with circulating carotenoid concentrations.
Results: Neither the individual SNPs nor the weighted multi-SNP scores were associated with breast cancer risk [OR (95% confidence interval) comparing extreme quintiles of weighted multi-SNP scores = 1.04 (0.94–1.16) for β-carotene, 1.08 (0.98–1.20) for α-carotene, 1.04 (0.94–1.16) for β-cryptoxanthin, 0.95 (0.87–1.05) for lutein/zeaxanthin, and 0.92 (0.83–1.02) for retinol]. Furthermore, no associations were observed when stratifying by estrogen receptor status, but power was limited.
Conclusions: Our results do not support an association between SNPs associated with circulating carotenoid concentrations and breast cancer risk.
Impact: Future studies will need additional genetic surrogates and/or sample sizes at least three times larger to contribute evidence of a causal link between carotenoids and breast cancer. Cancer Epidemiol Biomarkers Prev; 22(5); 927–36. ©2013 AACR.
U.S. Food and Drug Administration Approval: Vismodegib for Recurrent, Locally Advanced, or Metastatic Basal Cell Carcinoma
Authors: Axelson Michael , Liu Ke , Jiang Xiaoping , He Kun , Wang Jian , Zhao Hong , Kufrin Dubravka , Palmby Todd , Dong Zedong , Russell Anne Marie , Miksinski Sarah , Keegan Patricia , Pazdur Richard 
Published: March 2013

AbstractThe data and regulatory considerations leading to the U.S. Food and Drug Administration (FDA) January 30, 2012 approval of Erivedge (vismodegib) capsules for the treatment of patients with recurrent, locally advanced, or metastatic basal cell carcinoma (BCC) are described. The FDA's approval decision was based primarily on the results observed in a single-arm, parallel cohort, international trial of vismodegib, administered orally at 150 mg daily until disease progression, in patients with pathologically confirmed, recurrent, locally advanced basal cell carcinoma (laBCC) or metastatic basal cell carcinoma (mBCC). An independent review committee confirmed an overall response rate (ORR) of 30.3% [95% confidence interval (CI): 15.6–48.2] in 33 patients with mBCC and an ORR of 42.9% (95% CI: 30.5–56.0) in 63 patients with laBCC; median response durations were 7.6 months and 7.6 months for patients with mBCC and laBCC, respectively. The most common adverse reactions were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, cough, arthralgias, vomiting, headache, ageusia, insomnia, and upper respiratory tract infection. Animal toxicology studies confirmed that vismodegib is a potent teratogenic agent. Approval was based on durable objective tumor responses supported by knowledge of the pathologic role of Hedgehog signaling in BCC and acceptable toxicity in a population without effective alternative therapies. Clin Cancer Res; 19(9); 2289–93. ©2013 AACR.
Characteristics of Lung Cancers Harboring NRAS Mutations
Authors: Ohashi Kadoaki , Sequist Lecia V. , Arcila Maria E. , Lovly Christine M. , Chen Xi , Rudin Charles M. , Moran Teresa , Camidge David Ross , Vnencak-Jones Cindy L. , Berry Lynne , Pan Yumei , Sasaki Hidefumi , Engelman Jeffrey A. , Garon Edward B. , Dubinett Steven M. , Franklin Wilbur A. , Riely Gregory J. , Sos Martin L. , Kris Mark G. , Dias-Santagata Dora , Ladanyi Marc , Bunn Paul A. , Pao William 
Published: March 2013

Abstract
Purpose: We sought to determine the frequency and clinical characteristics of patients with lung cancer harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS-mutant lung cancer cells.
Experimental Design: We reviewed clinical data from patients whose lung cancers were identified at six institutions or reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) to harbor NRAS mutations. Six NRAS-mutant cell lines were screened for sensitivity against inhibitors of multiple kinases (i.e., EGFR, ALK, MET, IGF-1R, BRAF, PI3K, and MEK).
Results: Among 4,562 patients with lung cancers tested, NRAS mutations were present in 30 (0.7%; 95% confidence interval, 0.45%–0.94%); 28 of these had no other driver mutations. 83% had adenocarcinoma histology with no significant differences in gender. While 95% of patients were former or current smokers, smoking-related G:C&gt;T:A transversions were significantly less frequent in NRAS-mutated lung tumors than KRAS-mutant non–small cell lung cancer [NSCLC; NRAS: 13% (4/30), KRAS: 66% (1772/2733), P &lt; 0.00000001]. Five of 6 NRAS-mutant cell lines were sensitive to the MEK inhibitors, selumetinib and trametinib, but not to other inhibitors tested.
Conclusion: NRAS mutations define a distinct subset of lung cancers (∼1%) with potential sensitivity to MEK inhibitors. Although NRAS mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking. Clin Cancer Res; 19(9); 2584–91. ©2013 AACR.
Urinary TMPRSS2:ERG and PCA3 in an Active Surveillance Cohort: Results from a Baseline Analysis in the Canary Prostate Active Surveillance Study
Authors: Lin Daniel W. , Newcomb Lisa F. , Brown Elissa C. , Brooks James D. , Carroll Peter R. , Feng Ziding , Gleave Martin E. , Lance Raymond S. , Sanda Martin G. , Thompson Ian M. , Wei John T. , Nelson Peter S. ,   for the Canary Prostate Active Surveillance Study Investigators
Published: March 2013

Abstract
Purpose: Active surveillance is used to manage low-risk prostate cancer. Both PCA3 and TMPRSS2:ERG are promising biomarkers that may be associated with aggressive disease. This study examines the correlation of these biomarkers with higher cancer volume and grade determined at the time of biopsy in an active surveillance cohort.
Experimental Design: Urine was collected after digital rectal examination prospectively as part of the multi-institutional Canary Prostate Active Surveillance Study (PASS). PCA3 and TMPRSS2:ERG levels were analyzed in urine collected at study entry. Biomarker scores were correlated to clinical and pathologic variables.
Results: In 387 men, both PCA3 and TMPRSS2:ERG scores were significantly associated with higher volume disease. For a negative repeat biopsy, and 1% to 10%, 11% to 33%, 34% or more positive cores, median PCA3, and TMPRSS2:ERG scores increased incrementally (P &lt; 0.005). Both PCA3 and TMPRSS2:ERG scores were also significantly associated with the presence of high-grade disease. For a negative repeat biopsy, Gleason 6 and Gleason ≥7 cancers, the median PCA3, and TMPRSS2:ERG scores also increased incrementally (P = 0.02 and P = 0.001, respectively). Using the marker scores as continuous variables, the ORs for a biopsy in which cancer was detected versus a negative repeat biopsy (ref) on modeling was 1.41 (95% CI: 1.07–1.85), P = 0.01 for PCA3 and 1.28 (95% CI: 1.10–1.49), P = 0.001 for TMPRSS2:ERG.
Conclusions: For men on active surveillance, both PCA3 and TMPRSS2:ERG seem to stratify the risk of having aggressive cancer as defined by tumor volume or Gleason score. Clin Cancer Res; 19(9); 2442–50. ©2013 AACR.
Combined Na
+
/Ca
2+
Exchanger and L-Type Calcium Channel Block as a Potential Strategy to Suppress Arrhythmias and Maintain Ventricular Function
Authors: Bourgonje Vincent J.A. , Vos Marc A. , Ozdemir Semir , Doisne Nicolas , Acsai Karoly , Varro Andras , Sztojkov-Ivanov Anita , Zupko Istvan , Rauch Erik , Kattner Lars , Bito Virginie , Houtman Marien , van der Nagel Roel , Beekman Jet D. , van Veen Toon A.B. , Sipido Karin R. , Antoons Gudrun 
Published: March 2013

Background—

L-type calcium channel (LTCC) and Na
+
/Ca
2+
exchanger (NCX) have been implicated in repolarization-dependent arrhythmias, but also modulate calcium and contractility. Although LTCC inhibition is negative inotropic, NCX inhibition has the opposite effect. Combined block may, therefore, offer an advantage for hemodynamics and antiarrhythmic efficiency, particularly in diseased hearts. In a model of proarrhythmia, the dog with chronic atrioventricular block, we investigated whether combined inhibition of NCX and LTCC with SEA-0400 is effective against dofetilide-induced torsade de pointes arrhythmias (TdP), while maintaining calcium homeostasis and hemodynamics.

Methods and Results—
Left ventricular pressure (LVP) and ECG were monitored during infusion of SEA-0400 and verapamil in anesthetized dogs. Different doses were tested against dofetilide-induced TdP in chronic atrioventricular block dogs. In ventricular myocytes, effects of SEA-0400 were tested on action potentials, calcium transients, and early afterdepolarizations. In cardiomyocytes, SEA-0400 (1 μmol/L) blocked 66±3% of outward NCX, 50±2% of inward NCX, and 33±9% of LTCC current. SEA-0400 had no effect on systolic calcium, but slowed relaxation, despite action potential shortening, and increased diastolic calcium. SEA-0400 stabilized dofetilide-induced lability of repolarization and suppressed early afterdepolarizations. In vivo, SEA-0400 (0.4 and 0.8 mg/kg) had no effect on left ventricular pressure and suppressed dofetilide-induced TdPs dose dependently. Verapamil (0.3 mg/kg) also inhibited TdP, but caused a 15±8% drop of left ventricular pressure. A lower dose of verapamil without effects on left ventricular pressure (0.06 mg/kg) was not antiarrhythmic.

Conclusions—
In chronic atrioventricular block dogs, SEA-0400 treatment is effective against TdP. Unlike specific inhibition of LTCC, combined NCX and LTCC inhibition has no negative effects on cardiac hemodynamics.
Impaired Assembly and Post-translational Regulation of 26S Proteasome in Human End-Stage Heart Failure
Authors: Day Sharlene M. , Divald Andras , Wang Ping , Davis Frank , Bartolone Sarah , Jones Richard , Powell Saul R. 
Published: March 2013

Background—
This study examined the hypothesis that 26S proteasome dysfunction in human end-stage heart failure is associated with decreased docking of the 19S regulatory particle to the 20S proteasome. Previous studies have demonstrated that 26S proteasome activity is diminished in human end-stage heart failure associated with oxidation of the 19S regulatory particle Rpt5 subunit. Docking of the 19S regulatory particle to the 20S proteasome requires functional Rpt subunit ATPase activity and phosphorylation of the α-type subunits.

Methods and Results—

An enriched proteasome fraction was prepared from 7 human nonfailing and 10 failing heart explants. Native gel electrophoresis assessed docking of 19S to 20S proteasome revealing 3 proteasome populations (20S, 26S, and 30S proteasomes). In failing hearts, 30S proteasomes were significantly lower (
P
=0.048) by 37% suggesting diminished docking. Mass spectrometry–based phosphopeptide analysis demonstrated that the relative ratio of phosphorylated:non phosphorylated α7 subunit (serine
250
) of the 20S proteasome was significantly less (
P
=0.011) by almost 80% in failing hearts. Rpt ATPase activity was determined in the enriched fraction and after immunoprecipitation with an Rpt6 antibody. ATPase activity (ρmol PO
4
/μg protein per hour) of the total fraction was lowered from 291±97 to 194±27 and in the immunoprecipitated fraction from 42±12 to 3±2 (
P
=0.005) in failing hearts.

Conclusions—
These studies suggest that diminished 26S activity in failing human hearts may be related to impaired docking of the 19S to the 20S as a result of decreased Rpt subunit ATPase activity and α7 subunit phosphorylation.
Effects of Exercise on Left Ventricular Systolic and Diastolic Properties in Patients With Heart Failure and a Preserved Ejection Fraction Versus Heart Failure and a Reduced Ejection Fraction
Authors: Zile Michael R. , Kjellstrom Barbro , Bennett Tom , Cho Yong , Baicu Catalin F. , Aaron Mark F. , Abraham William T. , Bourge Robert C. , Kueffer Fred J. 
Published: March 2013

Background—
The purpose of the current study was to define exercise-induced changes in indices of left ventricular (LV) systolic and diastolic properties in patients with chronic heart failure (HF), compare these changes in patients with HF and a reduced ejection fraction (EF) versus HF and a preserved EF, and compare the hemodynamic responses to activities of daily living with symptom-limited upright exercise.

Methods and Results—
Subjects with HF and a preserved EF (n=8) and subjects with HF and a reduced EF (n=5) underwent symptom-limited Naughton protocol treadmill exercise tests. Implantable hemodynamic monitor data and echocardiographic data were obtained before exercise and at peak exercise. Implantable hemodynamic monitor data were obtained during activities of daily living during a 24-hour time period. In patients with HF and a reduced EF, limited exercise time (639±164 seconds) was associated with a marked rise in right ventricular systolic, diastolic, and estimated pulmonary artery diastolic (ePAD) pressures and an increase in LV end diastolic volume (EDV). LV systolic properties, namely EF, end systolic elastance, stroke work, and preload recruitable stroke work, all decreased. The ePAD/EDV ratio increased; to a large extent, this was dependent on an increase in EDV. By contrast, in HF and a preserved EF, limited exercise time (411±128 seconds) and the marked rise in right ventricular systolic, diastolic, and ePAD pressures were associated with no change in LV EDV. LV systolic properties increased or were unchanged; ePAD/EDV ratio increased during exercise, but the increase was independent of a change in EDV. The ranges of right ventricular systolic, diastolic, and ePAD pressures during activities of daily living were higher than the ranges of these values during the exercise stress test.

Conclusions—
Although exercise limitations were similar between HF and a reduced EF and HF and a preserved EF, there were significant differences in exercise-induced changes in LV systolic and diastolic properties. These differences likely reflect the different pathophysiologies of these clinical syndromes of HF.
Threat sensitivity in the San Marcos salamander: effects of predator diet and prey experience
Authors: Epp Kristen J. 
Published: March 2013

Prey must constantly balance foraging and predator avoidance demands. Avoidance response efficiency may be improved when prey match the intensity of their avoidance behaviours to a perceived level of predatory threat (threat sensitivity). Additionally, experience with predators may influence the intensity of avoidance responses. I examined the possibility that experience with predators in the natural habitat would influence threat sensitive avoidance behaviours of an aquatic salamander, Eurycea nana, by comparing the intensity of avoidance responses to predators that had been fed a neutral diet (low-risk) or a diet of conspecifics (high-risk) between laboratory-reared and recently-collected adult salamanders. I found that laboratory-reared salamanders exhibited graded responses to low- and high-risk predators consistent with threat-sensitive predator avoidance. Predator-experienced salamanders (recently-collected), however, responded less intensely to all predators and their responses showed little evidence of threat sensitivity. These less intense responses observed in experienced salamanders may result from mechanisms of adaptive forgetting, which allow prey to respond to environmental variation. I discuss implications of these results for E. nana and other prey as well as highlighting the need for researchers to consider the longer-term experiences of prey used in studies of predation risk.
Sperm storage in the uterium of the insect-parasitic nematode Sphaerularia vespae (Nematoda: Sphaerulariidae)
Authors: Yushin Vladimir V. , Kosaka Hajime 
Published: March 2013

The spermatheca found in the ‘uterium’ (highly transformed part of parasitic female) of the sphaerularioidid nematode Sphaerularia vespae, an endoparasite of a common Japanese hornet, Vespa simillima, was studied with TEM. The uterium consists of a thick trophic epithelium exposed to the insect haemocoel and a protective cavity which contains the female genital tube and storage cells (fat body). The uterium cavity contains the female reproductive system composed of the usual parts: uterus, oviduct and ovary. The genital pore of the young uterium is an opening of the short narrow uterine tube which joins to the voluminous spermatheca. The spermatheca is a dilated distal part of the uterus, storing numerous tiny spermatozoa. The spermatheca is blocked distally by the oviduct. The spermatozoa are uniform amoeboid cells only 1.4-1.6 μm in size with a highly condensed nucleus about 0.8 μm in size. The transparent sperm cytoplasm contains several mitochondria, small membranous organelles (specific organelles characteristic of nematode spermatozoa), occasional bundles of fibres and centriole-like bodies. The S. vespae spermatozoa are very similar to the spermatozoa stored in the uterus of infective females of another sphaerularioidid nematode, Deladenus sp., and have the main features of sperm found in many other rhabditid nematodes.
Indian Ocean Variability in the CMIP5 Multimodel Ensemble: The Basin Mode
Authors: Du Yan , Xie Shang-Ping , Yang Ya-Li , Zheng Xiao-Tong , Liu Lin , Huang Gang 
Published: March 2013

Abstract
This study evaluates the simulation of the Indian Ocean Basin (IOB) mode and relevant physical processes in models from phase 5 of the Coupled Model Intercomparison Project (CMIP5). Historical runs from 20 CMIP5 models are available for the analysis. They reproduce the IOB mode and its close relationship to El Niño–Southern Oscillation (ENSO). Half of the models capture key IOB processes: a downwelling oceanic Rossby wave in the southern tropical Indian Ocean (TIO) precedes the IOB development in boreal fall and triggers an antisymmetric wind anomaly pattern across the equator in the following spring. The anomalous wind pattern induces a second warming in the north Indian Ocean (NIO) through summer and sustains anticyclonic wind anomalies in the northwest Pacific by radiating a warm tropospheric Kelvin wave. The second warming in the NIO is indicative of ocean–atmosphere interaction in the interior TIO. More than half of the models display a double peak in NIO warming, as observed following El Niño, while the rest show only one winter peak. The intermodel diversity in the characteristics of the IOB mode seems related to the thermocline adjustment in the south TIO to ENSO-induced wind variations. Almost all the models show multidecadal variations in IOB variance, possibly modulated by ENSO.
Objective Detection of Oceanic Eddies and the Agulhas Leakage
Authors: Beron-Vera Francisco J. , Wang Yan , Olascoaga María J. , Goni Gustavo J. , Haller George 
Published: March 2013

Abstract
Mesoscale oceanic eddies are routinely detected from instantaneous velocities derived from satellite altimetry data. While simple to implement, this approach often gives spurious results and hides true material transport. Here it is shown how geodesic transport theory, a recently developed technique from nonlinear dynamical systems, uncovers eddies objectively. Applying this theory to altimetry-derived velocities in the South Atlantic reveals, for the first time, Agulhas rings that preserve their material coherence for several months, while ring candidates yielded by other approaches tend to disperse or leak within weeks. These findings suggest that available velocity-based estimates for the Agulhas leakage, as well as for its impact on ocean circulation and climate, need revision.
Using Frontogenesis to Identify Sting Jets in Extratropical Cyclones
Authors: Schultz David M. , Sienkiewicz Joseph M. 
Published: March 2013

AbstractSting jets, or surface wind maxima at the end of bent-back fronts in Shapiro–Keyser cyclones, are one cause of strong winds in extratropical cyclones. Although previous studies identified the release of conditional symmetric instability as a cause of sting jets, the mechanism to initiate its release remains unidentified. To identify this mechanism, a case study was selected of an intense cyclone over the North Atlantic Ocean during 7–8 December 2005 that possessed a sting jet detected from the NASA Quick Scatterometer (QuikSCAT). A couplet of Petterssen frontogenesis and frontolysis occurred along the bent-back front. The direct circulation associated with the frontogenesis led to ascent within the cyclonically turning portion of the warm conveyor belt, contributing to the comma-cloud head. When the bent-back front became frontolytic, an indirect circulation associated with the frontolysis, in conjunction with alongfront cold advection, led to descent within and on the warm side of the front, bringing higher-momentum air down toward the boundary layer. Sensible heat fluxes from the ocean surface and cold-air advection destabilized the boundary layer, resulting in near-neutral static stability facilitating downward mixing. Thus, descent associated with the frontolysis reaching a near-neutral boundary layer provides a physical mechanism for sting jets, is consistent with previous studies, and synthesizes existing knowledge. Specifically, this couplet of frontogenesis and frontolysis could explain why sting jets occur at the end of the bent-back front and emerge from the cloud head, why sting jets are mesoscale phenomena, and why they only occur within Shapiro–Keyser cyclones. A larger dataset of cases is necessary to test this hypothesis.