bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioavailable Insulin-like Growth Factor-I Inversely Related to Weight Gain in Postmenopausal Women Regardless of Exogenous Estrogen
Authors: Jung Su Yon , Hursting Stephen D. , Guindani Michele , Vitolins Mara Z. , Paskett Electra , Chang Shine 
Published: December 2013

Abstract
Background: Weight gain, insulin-like growth factor-I (IGF-I) levels, and excess exogenous steroid hormone use are putative cancer risk factors, yet their interconnected pathways have not been fully characterized. This cross-sectional study investigated the relationship between plasma IGF-I levels and weight gain according to body mass index (BMI), leptin levels, and exogenous estrogen use among postmenopausal women.
Methods: This study included 794 postmenopausal women who enrolled in an ancillary study of the Women's Health Initiative Observational Study between February 1995 and July 1998. The relationship between IGF-I levels and weight gain was analyzed using ordinal logistic regression. We used the molar ratio of IGF-I to IGF binding protein-3 (IGF-I/IGFBP-3) or circulating IGF-I levels adjusting for IGFBP-3 as a proxy of bioavailable IGF-I. The plasma concentrations were expressed as quartiles.
Results: Among the obese group, women in the third quartile (Q3) of IGF-I and highest quartile of IGF-I/IGFBP-3 were less likely to gain weight (&gt;3% from baseline) than were women in the first quartiles (Q1). Among the normal-weight group, women in Q2 and Q3 of IGF-I/IGFBP-3 were 70% less likely than those in Q1 to gain weight. Among current estrogen users, Q3 of IGF-I/IGFBP-3 had 0.5 times the odds of gaining weight than Q1.
Conclusions: Bioavailable IGF-I levels were inversely related to weight gain overall.
Impact: Although weight gain was not consistent with increases in IGF-I levels among postmenopausal women in this report, avoidance of weight gain as a strategy to reduce cancer risk may be recommended. Cancer Epidemiol Biomarkers Prev; 23(3); 534–44. ©2013 AACR.
Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt
Authors: Qian Zunlei , Li Min , Wang Rui , Xiao Qianqian , Wang Jing , Li Mingying , He Dacheng , Xiao Xueyuan 
Published: December 2013

Abstract
CABYR is a calcium-binding tyrosine phosphorylation–regulated protein that was identified as a novel cancer testis antigen in lung cancer in our previous study. However, the role of CABYR as a driver of disease progression or as a chemosensitizer is poorly understood. This study sought to investigate the relationship between the expression levels of CABYR-a/b, which are the two predominant isoforms of the five isoform proteins encoded by CABYR, and chemosensitivity in non–small cell lung cancer cells. We found that the short hairpin RNA–mediated knockdown of CABYR-a/b significantly inhibited the proliferation of NCI-H460 and A549 cells and resulted in the attenuation of Akt phosphorylation, which is constitutively active in lung cancer cells. The silencing of CABYR-a/b expression notably impacted the downstream components of the Akt pathways: decreasing the phospho-GSK-3β (Ser9) levels and increasing the expression of the p53 and p27 proteins. Furthermore, CABYR-a/b knockdown led to a significant increase in chemosensitivity in response to chemotherapeutic drugs and drug-induced apoptosis, both in vitro and in vivo. Conversely, the transient transfection of CABYR-a/b–depleted cells with constitutively active Akt partially restored the resistance to cisplatin and paclitaxel and significantly decreased the activation of GSK-3β and cleaved PARP. Taken together, our results suggest that the inhibition of CABYR-a/b is a novel method to improve the apoptotic response and chemosensitivity in lung cancer and that this cancer testis antigen is an attractive target for lung cancer drug development.
Implications: Suppression of CABYR-a/b expression increases chemosensitivity of lung cancer cells by inhibiting Akt activity. Mol Cancer Res; 12(3); 335–47. ©2013 AACR.
MEK-Dependent Negative Feedback Underlies BCR–ABL-Mediated Oncogene Addiction
Authors: Asmussen Jennifer , Lasater Elisabeth A. , Tajon Cheryl , Oses-Prieto Juan , Jun Young-wook , Taylor Barry S. , Burlingame Alma , Craik Charles S. , Shah Neil P. 
Published: December 2013

Abstract
The clinical experience with BCR–ABL tyrosine kinase inhibitors (TKI) for the treatment of chronic myelogenous leukemia (CML) provides compelling evidence for oncogene addiction. Yet, the molecular basis of oncogene addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR–ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR–ABL-mediated addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR–ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR–ABL-mediated oncogene addiction is facilitated by persistent high levels of MAP–ERK kinase (MEK)-dependent negative feedback.
Significance: We found that BCR–ABL can confer addiction in vitro by rewiring myeloid GF-R signaling through establishment of MEK-dependent negative feedback. Our findings predict that deeper, more durable responses to targeted agents across a range of malignancies may be facilitated by maintaining negative feedback concurrently with oncoprotein inhibition. Cancer Discov; 4(2); 200–15. ©2013 AACR.
This article is highlighted in the In This Issue feature, p. 131
Genetic Characteristics of Children and Adolescents With Long-QT Syndrome Diagnosed by School-Based Electrocardiographic Screening Programs
Authors: Yoshinaga Masao , Kucho Yu , Sarantuya Jav , Ninomiya Yumiko , Horigome Hitoshi , Ushinohama Hiroya , Shimizu Wataru , Horie Minoru 
Published: December 2013

Background—
A school-based electrocardiographic screening program has been developed in Japan. However, few data are available on the genetic characteristics of pediatric patients with long-QT syndrome who were diagnosed by this program.

Methods and Results—

A total of 117 unrelated probands aged ≤18 years were the subjects who were referred to our centers for genetic testing. Of these, 69 subjects diagnosed by the program formed the screened group. A total of 48 subjects were included in the clinical group and were diagnosed with long-QT syndrome–related symptoms, familial study, or by chance. Mutations were classified as radical, of high probability of pathogenicity, or of uncertain significance. Two subjects in the clinical group died. Genotypes were identified in 50 (72%) and 23 (48%) of subjects in the screened and clinical groups, respectively. Of the
KCNQ1
or
KCNH2
mutations, 31 of 33 (94%) in the screened group and 14 of 15 (93%) in the clinical group were radical and of high probability of pathogenicity. Prevalence of symptoms before (9/69 versus 31/48;
P
<0.0001) and after (12/69 versus 17/48;
P
=0.03) diagnosis was significantly lower in the screened group when compared with that in the clinical group although the QTc values, family history of long-QT syndrome, sudden death, and follow-up periods were not different between the groups.

Conclusions—
These data suggest that the screening program may be effective for early diagnosis of long-QT syndrome that may allow intervention before symptoms. In addition, screened patients should have follow-up equivalent to clinically identified patients.
Reentrant Ventricular Tachycardia Originating From the Periaortic Region in the Absence of Overt Structural Heart Disease
Authors: Nagashima Koichi , Tedrow Usha B. , Koplan Bruce A. , Michaud Gregory F. , John Roy M. , Epstein Laurence M. , Tokuda Michifumi , Inada Keiichi , Reichlin Tobias R. , Ng Justin P. , Barbhaiya Chirag R. , Nof Eyal , Tadros Thomas M. , Stevenson William G. 
Published: December 2013

Background—
In the absence of overt structural heart disease, most left ventricular outflow tract ventricular tachycardias (VTs) have a focal origin and are benign. We hypothesized that multiple morphologies (MMs) of inducible left ventricular outflow tract VT may indicate a scar-related VT that can mimic idiopathic VT.

Methods and Results—

Of 54 consecutive patients referred for ablation of sustained outflow tract VT without overt structural heart disease, 24 had left ventricular outflow tract VT, 10 had MM VT, and 14 had a single VT (SM). The MM group were older (70.3±4.3 versus 53.9±15.9 years;
P
=0.004), had more hypertension (100% versus 29%;
P
=0.0006), and had longer PR intervals and QRS durations compared with the SM group. In contrast to the SM group, the MM group VTs had features consistent with reentry, including induction by programmed stimulation without isoproterenol, entrainment in some, and abnormal electrograms in the periaortic area. Periaortic region voltages suggested scar in the MM group, but not in the SM group. MRI in 2 MM patients was consistent with scar, but not in 10 SM patients. Longer radiofrequency applications were required in the MM group than in the SM group. At a median follow-up of 9.7 (3.0–32.0) months, recurrences tended to be more frequent in the MM group than in the SM group (70% versus 22%;
P
=0.07).

Conclusions—
VTs from small regions of periaortic scar can mimic idiopathic VT but are suggested by multiple VT morphologies and are more difficult to ablate. Whether these patients are at greater risk, as feared for other scar-related VTs, warrants further study.
Long-Term Mortality Associated With Left Ventricular Dysfunction in Mitral Regurgitation Due to Flail Leaflets
Authors: Tribouilloy Christophe , Rusinaru Dan , Grigioni Francesco , Michelena Hector I. , Vanoverschelde Jean-Louis , Avierinos Jean-François , Barbieri Andrea , Pislaru Sorin V. , Russo Antonio , Pasquet Agnès , Théron Alexis , Szymanski Catherine , Lévy Franck , Enriquez-Sarano Maurice 
Published: December 2013

Background—
Ejection fraction (EF) as a marker of left ventricular (LV) dysfunction and the appropriate thresholds for diagnosing severe or mild/moderate LV dysfunction in mitral regurgitation are doubted and poorly followed in clinical practice. We aimed at assessing the role of EF in a large registry of organic mitral regurgitation to objectively establish thresholds for various degrees of LV dysfunction and to analyze whether mitral surgery remains beneficial in those subsets of patients.

Methods and Results—
We investigated the relation between EF and mortality in 1875 patients with mitral regurgitation due to flail leaflets in sinus rhythm (65±13 years; median EF, 66% [60%–71%]) enrolled in the Mitral Regurgitation International Database (MIDA) registry. With EF <60%, mortality after diagnosis increased precipitously under medical management (adjusted hazard ratio [HR], 1.59 [1.19–2.12]) and during the entire follow-up (adjusted HR, 1.51 [1.22–1.87]). Severe LV dysfunction, if defined by EF <30%, would affect a minuscule number of patients (0.3%). Conversely, EF <45% was more frequent (2.9%) and was associated with considerable mortality under medical management (adjusted HR, 2.43 [1.50–3.95]) and during the entire follow-up (adjusted HR, 2.46 [1.67–3.61]). The group with EF of 45% to 60% represented a large proportion of patients (23%), exhibited rarely overt symptoms, and had higher mortality compared with EF >60%. Above 60%, no EF threshold further determined survival. The benefit of surgery remained considerable in the groups with EF <45% (adjusted HR, 0.28 [0.17–0.56]) and with EF of 45% to 60% (adjusted HR, 0.34 [0.21–0.64]).

Conclusions—
EF is valuable in defining presence and severity of LV dysfunction in organic mitral regurgitation. Patients with EF <45% have severe LV dysfunction, catastrophic outcome under medical management, and should not be denied surgery. Although there is no survival gain with EF ranges >60%, with EF dropping <60%, mortality increases precipitously and prompt surgical referral is critical to outcome.
Assessment of Myocardial Infarction and Postinfarction Scar Remodeling With an Elastin-Specific Magnetic Resonance Agent
Authors: Wildgruber Moritz , Bielicki Isabella , Aichler Michaela , Kosanke Katja , Feuchtinger Annette , Settles Marcus , Onthank David C. , Cesati Richard R. , Robinson Simon P. , Huber Armin M. , Rummeny Ernst J. , Walch Axel K. , Botnar René M. 
Published: December 2013

Background—
To prospectively evaluate an elastin-specific MR contrast agent (ESMA) for in vivo targeting of elastic fibers in myocardial infarction (MI) and postinfarction scar remodeling.

Methods and Results—

MI was induced in C57BL/6J mice (n=40) by permanent ligation of the left anterior descending coronary artery. MRI was performed at 7 and 21 days after MI. The merits of gadolinium-based ESMA (Gd-ESMA) were compared with gadopentetic acid (Gd-DTPA) for infarct size determination, contrast-to-noise ratio (CNR), and enhancement kinetics. Specific binding in vivo was evaluated by blocking the molecular target using nonparamagnetic lanthanum-ESMA. In vivo imaging results were confirmed by postmortem triphenyltetrazolium chloride staining, elastica van Gieson staining, and Western blotting. Delayed enhancement MRI revealed prolonged enhancement of Gd-ESMA in the postischemic scar compared with Gd-DTPA. Infarct size measurements showed good agreement between Gd-ESMA and Gd-DTPA and were confirmed by ex vivo triphenyltetrazolium chloride staining. Preinjection of the blocking lanthanum-ESMA resulted in significantly lower CNR of Gd-ESMA at the infarct site (
P
=0.0019). Although no significant differences in CNR were observed between delayed enhancement imaging and Gd-DTPA between days 7 and 21 (1.8± versus 3.8;
P
=ns), Gd-ESMA showed markedly higher CNR on day 21 after MI (14.1 versus 4.9;
P
=0.0032), which correlated with increased synthesis of tropoelastin detected by Western blot analysis and histology. Higher CNR values for Gd-ESMA further correlated with improved ejection fraction of the mice on day 21 after MI.

Conclusions—
Gd-ESMA enables targeting of elastin within the infarct scar in a mouse model of MI. The imaging properties of Gd-ESMA allow quantification of intrascar elastin content in vivo and thereby provide potential for noninvasive characterization of postinfarction scar remodeling.
The effect of serum matrix and gender on cortisol measurement by commonly used immunoassays
Authors: Dodd AJ , Ducroq DH , Neale SM , Wise MP , Mitchem KL , Armston A , Barth JH , El-Farhan N , Rees DA , Evans C 
Published: December 2013

Background Considerable intermethod bias has been observed between cortisol immunoassays, with some also displaying a gender difference. Cortisol immunoassay performance is affected by serum matrix effects such as changes in steroid binding proteins and presence of interfering steroids which can be altered in various clinical settings. This study investigates cortisol immunoassay bias in pregnancy, renal failure and intensive care patients. Methods Serum remaining after routine analysis from pregnant patients, patients on the intensive care unit and patients with renal failure were obtained prior to disposal and used to create 20 anonymous samples per group. A male and female serum pool was prepared and spiked with cortisol. Samples were aliquoted and distributed to four hospitals for cortisol analysis by immunoassays from four different manufacturers. Cortisol was also measured by an isotope dilution-gas chromatography–mass spectrometry method for comparison of assay bias. Results Differences in cortisol immunoassay bias were observed across the different patient groups. A negative bias compared to pooled serum samples was observed for pregnancy serum, whilst a more positive bias was seen in renal failure and intensive care patients. Variation in bias was greatest in renal failure with the Roche E170 the most affected and the Abbott architect the least (interquartile ranges 44% and 14%, respectively). Conclusions Cortisol immunoassay bias may be affected by gender and differences in serum matrix from patients with various clinical conditions. Users of cortisol assays should be aware of differing matrix effects on their assay and the relevance of these for the interpretation of clinical results.
Comparison of frovatriptan plus dexketoprofen (25 mg or 37.5 mg) with frovatriptan alone in the treatment of migraine attacks with or without aura: A randomized study
Authors: Tullo Vincenzo , Valguarnera Fabio , Barbanti Piero , Cortelli Pietro , Sette Giuliano , Allais Gianni , d’Onofrio Florindo , Curone Marcella , Zava Dario , Pezzola Deborha , Benedetto Chiara , Frediani Fabio , Bussone Gennaro 
Published: December 2013

Background Drugs for migraine attacks include triptans and NSAIDs; their combination could provide greater symptom relief. Methods A total of 314 subjects with history of migraine, with or without aura, were randomized to frovatriptan 2.5 mg alone (Frova), frovatriptan 2.5 mg + dexketoprofen 25 mg (FroDex25) or frovatriptan 2.5 mg + dexketoprofen 37.5 mg (FroDex37.5) and treated at least one migraine attack. This was a multicenter, randomized, double-blind, parallel-group study. The primary end point was the proportion of pain free (PF) at two hours. Secondary end points were PF at one and four hours, pain relief (PR) at one, two, four hours, sustained PF (SPF) at 24 and 48 hours, recurrence at 48 hours, resolution of nausea, photophobia and phonophobia at two and four hours, the use of rescue medication and the judgment of the treatment. Results The results were assessed in the full analysis set (FAS) population, which included all subjects randomized and treated for whom at least one post-dose intensity of headache was recorded. The proportions of subjects PF at two hours (primary end point) were 29% (27/93) with Frova compared with 51% (48/95 FroDex25 and 46/91 FroDex37.5) with each combination therapies ( p < 0.05). Proportions of SPF at 24 hours were 24% (22/93) for Frova, 43% (41/95) for FroDex25 ( p < 0.001) and 42% (38/91) for FroDex37.5 ( p < 0.05). SPF at 48 hours was 23% (21/93) with Frova, 36% (34/95) with FroDex25 and 33% (30/91) with FroDex37.5 ( p = NS). Recurrence was similar for Frova (22%, 6/27), FroDex25 (29%, 14/48) and FroDex37.5 (28%, 13/46) ( p = NS), meaning a lack of improvement with the combination therapy. Statistical adjustment for multiple comparisons was not performed. No statistically significant differences were reported in the occurrence of total and drug-related adverse events. FroDex25 and FroDex37.5 showed a similar efficacy both for primary and secondary end points. There did not seem to be a dose response curve for the addition of dexketoprofen. Conclusion FroDex improved initial efficacy at two hours compared to Frova whilst maintaining efficacy at 48 hours in this study. Tolerability profiles were comparable. Intrinsic pharmacokinetic properties of the two single drugs contribute to this improved efficacy profile.
Analysis of the Validity Scales in the Trauma Symptom Checklist for Children
Authors: Butcher Fredrick , Kretschmar Jeff M. , Lin Yingge , Flannery Daniel J. , Singer Mark I. 
Published: December 2013

Objective: Little empirical attention has been paid to the validity scales of the Trauma Symptom Checklist for Children (TSCC). The purpose of this study is to examine the prevalence of cases identified by the validity scales and its analytical impact. Methods: The current study compares regression models using data from two community samples ( n = 3,724 and n = 2,245) and two samples of at-risk youth ( n = 1,758 and n = 204). Using Chow tests to compare coefficients, we demonstrate the implications of removing cases identified by the TSCC validity scales. Results: The Underresponse (UND) scale identified 8% of the community sample and 20% of the at-risk sample. Chow tests revealed significant group differences based on the UND scale for all TSCC subscales. Conclusion: The present study demonstrates the analytical impact of the TSCC validity scales and provides statistical evidence for the removal of invalid cases.
New iPSC for old long QT syndrome modeling: Putting the evidence into perspective
Authors: Li Guoliang , Cheng Gong , Wu Jine , Ma Shuting , Sun Chaofeng 
Published: December 2013

Induced pluripotent stem cells (iPS cells or iPSCs) are typically derived by transfection of certain stem cell-associated genes into non-pluripotent cells, such as adult fibroblasts (typically adult somatic cells). Various diseases can be modeled through iPSC technology. The important implication of iPSCs to offer an unprecedented opportunity to recapitulate pathologic human tissue formation in vitro has generated great excitement and interest in the whole biomedical research community. Long QT syndrome (LQTS), an inherited heart disease, is characterized by prolonged QT interval on a surface electrocardiogram. LQTS presents with life-threatening cardiac arrhythmias, which can lead to fainting, syncope, and sudden death. The iPSC-derived cardiomyocytes from LQTS patients offer a potentially unlimited source of materials for biomedical study. They can be used to recapitulate complex physiological phenotypes, probe toxicological testing and drug screening, clarify the novel mechanistic insights and may also rectify gene defects at the cellular and molecular level. Despite the emerging challenges, iPSC technology has been increasingly recognized as a valuable and growing toolkit for modeling LQTS over other various models of human diseases.
Thapsigargin affects presenilin-2 but not presenilin-1 regulation in SK-N-BE cells
Authors: Rivabene Roberto , Visentin Sergio , Piscopo Paola , Nuccio Chiara De , Crestini Alessio , Svetoni Francesca , Rosa Paolo , Confaloni Annamaria 
Published: December 2013

Presenilin-1 (PS1) and presenilin-2 (PS2) are transmembrane proteins widely expressed in the central nervous system, which function as the catalytic subunits of γ-secretase, the enzyme that releases amyloid-β protein (Aβ) from ectodomain cleaved amyloid precursor protein (APP) by intramembrane proteolysis. Mutations in PS1, PS2, and Aβ protein precursor are involved in the etiology of familial Alzheimer’s disease (FAD), while the cause of the sporadic form of AD (SAD) is still not known. However, since similar neuropathological changes have been observed in both FAD and SAD, a common pathway in the etiology of the disease has been suggested. Given that age-related deranged Ca2+ regulation has been hypothesized to play a role in SAD pathogenesis via PS gene regulation and γ-secretase activity, we studied the in vitro regulation of PS1 and PS2 in the human neuron-like SK-N-BE cell line treated with the specific endoplasmic reticulum (ER) calcium ATPase inhibitor Thapsigargin (THG), to introduce intracellular Ca2+ perturbations and mimic the altered Ca2+ homeostasis observed in AD. Our results showed a consistent and significant down-regulation of PS2, while PS1 appeared to be unmodulated. These events were accompanied by oxidative stress and a number of morphological alterations suggestive of the induction of apoptotic machinery. The administration of the antioxidant N-acetylcysteine (NAC) did not revert the THG-induced effects reported, while treatment with the Ca2+-independent ER stressor Brefeldin A did not modulate basal PS1 and PS2 expression. Collectively, these results suggest that Ca2+ fluctuation rather than ER stress and/or oxidative imbalance seems to play an essential role in PS2 regulation and confirm that, despite their strong homology, PS1 and PS2 could play different roles in AD.