bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sorafenib Is an Inhibitor of UGT1A1 but Is Metabolized by UGT1A9: Implications of Genetic Variants on Pharmacokinetics and Hyperbilirubinemia
Authors: Peer Cody J. , Sissung Tristan M. , Kim AeRang , Jain Lokesh , Woo Sukyung , Gardner Erin R. , Kirkland C. Tyler , Troutman Sarah M. , English Bevin C. , Richardson Emily D. , Federspiel Joel , Venzon David , Dahut William , Kohn Elise , Kummar Shivaani , Yarchoan Robert , Giaccone Giuseppe , Widemann Brigitte , Figg William D. 
Published: February 2012

Abstract
Purpose: Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)5/6/7 repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration.
Experimental Design: Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype.
Results: Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC50 = 18 μmol/L; Ki = 11.7 μmol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C&gt;T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R2 = 0.38 and R2 = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C&gt;T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure.
Conclusions: This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib. Clin Cancer Res; 18(7); 2099–107. ©2012 AACR.
Sphingosine-1-Phosphate Receptor 3 Promotes Neointimal Hyperplasia in Mouse Iliac-Femoral Arteries
Authors: Shimizu Takuya , De Wispelaere Allison , Winkler Martin , D'Souza Travis , Caylor Jacob , Chen Lihua , Dastvan Frank , Deou Jessie , Cho Aesim , Larena-Avellaneda Axel , Reidy Michael , Daum Guenter 
Published: February 2012

Objective—
The objective of this study was to define a role for sphingosine-1-phosphate receptor 3 (S1PR3) in intimal hyperplasia.

Methods and Results—
A denudation model of the iliac-femoral artery in wild-type and S1PR3-null mice was used to define a role for S1PR3 in the arterial injury response because we found in humans and mice that expression of S1PR3 was higher in these arteries compared with carotid arteries. At 28 days after surgery, wild-type arteries formed significantly larger lesions than S1PR3-null arteries. Bromodeoxyuridine labeling experiments demonstrated that on injury, wild-type arteries exhibited higher medial as well as intimal proliferation than S1PR3-null arteries. Because S1PR3 expression in vitro was low, we expressed S1PR3 in S1PR3-null smooth muscle cells (SMCs) using retroviral-mediated gene transfer to study the effects of S1PR3 on cell functions and signaling. SMCs expressing S1PR3, but not vector-transfected controls, responded to sphingosine-1-phosphate stimulation with activation of Rac, Erk, and Akt. SMCs expressing S1PR3 also migrated more.

Conclusion—
In humans and mice, S1PR3 expression was higher in iliac-femoral arteries compared with carotid arteries. S1PR3 promoted neointimal hyperplasia on denudation of iliac-femoral arteries in mice, likely by stimulating cell migration and proliferation through activation of signaling pathways involving Erk, Akt, and Rac.
Comparison of Exercise Treadmill Testing With Cardiac Computed Tomography Angiography Among Patients Presenting to the Emergency Room With Chest Pain
Authors: Blankstein Ron , Ahmed Waleed , Bamberg Fabian , Rogers Ian S. , Schlett Christopher Lothar , Nasir Khurram , Fontes Joao , Tawakol Ahmed , Brady Thomas J. , Nagurney John T. , Hoffmann Udo , Truong Quynh A. 
Published: February 2012

Background—
The aims of our study were to (1) examine how data from exercise treadmill testing (ETT) can identify patients who have coronary plaque or stenosis, using CT angiography (CTA) as the reference standard, and (2) identify patient characteristics that may be used in selecting ETT versus CTA.

Methods and Results—
The Rule Out Myocardial Infarction Using Computer-Assisted Tomography (ROMICAT) trial was an observational cohort study of acute chest pain patients presenting to the emergency department with normal initial troponin and a nonischemic ECG. Univariate and multivariable analyses were performed to assess the relationship of baseline clinical data and ETT parameters with coronary plaque and stenosis on CTA. Of the 220 patients who had ETT (mean age, 51 years; 63% men), 21 (10%) had positive results. A positive ETT had a sensitivity of 30% and specificity of 93% to detect >50% stenosis. The sensitivity increased to 83% after excluding uninterpretable segments and evaluating the ability to detect a >70% stenosis. Predictors of plaque included older age, male sex, diabetes, hypertension, hyperlipidemia, lower functional capacity, and a lower Duke Treadmill Score. Both a positive ETT and a low Duke Treadmill Score were significant univariate and multivariable predictors of stenosis >50% on CTA Whereas the prevalence of stenosis by CTA was greater among patients with more risk factors, coronary stenosis was not present among men <40 years old or women <50 years old or individuals who achieved at least 13 metabolic equivalents on ETT.

Conclusions—
Among low- to intermediate-risk patients with acute chest pain, a positive ETT has a limited sensitivity but high specificity for the detection of >50% stenosis by CTA. Although patients with a high number of clinical risk factors are more likely to have obstructive coronary artery disease, those who are young or who would be expected to have a very high exercise capacity are unlikely to have coronary stenosis and therefore may benefit from initial ETT testing instead of CTA.
Regulatory Role of Dendritic Cells in Postinfarction Healing and Left Ventricular Remodeling
Authors: Anzai Atsushi , Anzai Toshihisa , Nagai Shigenori , Maekawa Yuichiro , Naito Kotaro , Kaneko Hidehiro , Sugano Yasuo , Takahashi Toshiyuki , Abe Hitoshi , Mochizuki Satsuki , Sano Motoaki , Yoshikawa Tsutomu , Okada Yasunori , Koyasu Shigeo , Ogawa Satoshi , Fukuda Keiichi 
Published: February 2012

Background—
Inflammation and immune responses are integral components in the healing process after myocardial infarction. We previously reported dendritic cell (DC) infiltration in the infarcted heart; however, the precise contribution of DC in postinfarction healing is unclear.

Methods and Results—

Bone marrow cells from CD11c-diphtheria toxin receptor/green fluorescent protein transgenic mice were transplanted into lethally irradiated wild-type recipient mice. After reconstitution of bone marrow–derived cells, the recipient mice were treated with either diphtheria toxin (DC ablation) or vehicle (control), and myocardial infarction was created by left coronary ligation. CD11c
+
green fluorescent protein–positive DCs expressing CD11b and major histocompatibility complex class II were recruited into the heart, peaking on day 7 after myocardial infarction in the control group. Mice with DC ablation for 7 days showed deteriorated left ventricular function and remodeling. The DC-ablated group demonstrated enhanced and sustained expression of inflammatory cytokines such as interleukin-1β, interleukin-18, and tumor necrosis factor-α, prolonged extracellular matrix degradation associated with a high level of matrix metalloproteinase-9 activity, and diminished expression level of interleukin-10 and endothelial cell proliferation after myocardial infarction compared with the control group. In vivo analyses revealed that DC-ablated infarcts had enhanced monocyte/macrophage recruitment. Among these cells, marked infiltration of proinflammatory Ly6C
high
monocytes and F4/80
+
CD206
−
M1 macrophages and, conversely, impaired recruitment of anti-inflammatory Ly6C
low
monocytes and F4/80
+
CD206
+
M2 macrophages in the infarcted myocardium were identified in the DC-ablated group compared with the control group.

Conclusions—
These results suggest that the DC is a potent immunoprotective regulator during the postinfarction healing process via its control of monocyte/macrophage homeostasis.
Prognostic Values of Clockwise and Counterclockwise Rotation for Cardiovascular Mortality in Japanese Subjects
Authors: Nakamura Yasuyuki , Okamura Tomonori , Higashiyama Aya , Watanabe Makoto , Kadota Aya , Ohkubo Takayoshi , Miura Katsuyuki , Kasagi Fumiyoshi , Kodama Kazunori , Okayama Akira , Ueshima Hirotsugu ,   for the NIPPON DATA80 Research Group
Published: February 2012

Background—
Although clockwise rotation and counterclockwise rotation are distinct findings of the ECG, their prognostic significance is rarely studied.

Methods and Results—

We studied prognostic values of clockwise and counterclockwise rotation on total, cardiovascular disease (CVD), and subtype mortality using the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980–2004 (NIPPON DATA80) database with a 24-year follow-up. At baseline in 1980, data were collected on study participants aged ≥30 years from randomly selected areas in Japan. We followed 9067 participants (44% men; mean age, 51 years). During the 24-year follow-up, mortality was as follows: 2581 total, 887 CVD, 179 coronary heart disease, 173 heart failure, and 411 stroke. The multivariate-adjusted hazard ratio (HR) with the use of the Cox model including biochemical and other ECG variables revealed that clockwise rotation was significantly positively associated with heart failure in men and women combined (HR=1.79; 95% confidence interval [CI], 1.13–2.83;
P
=0.013), CVD in men and in men and women combined (HR=1.49; 95% CI, 1.12–1.98;
P
=0.007 in men; HR=1.28; 95% CI, 1.02–1.59;
P
=0.030 in combined), and total mortality in men and in men and women combined (HR=1.19; 95% CI, 1.00–1.49;
P
=0.0496 in men; HR=1.15; 95% CI, 1.00–1.32;
P
=0.045 in combined). Counterclockwise rotation was significantly inversely associated stroke in men and women combined (HR=0.77; 95% CI, 0.62–0.96;
P
=0.017), CVD in men and in men and women combined (HR=0.74; 95% CI, 0.59–0.94;
P
=0.011 in men; HR=0.81; 95% CI, 0.70–0.94;
P
=0.006 in combined), and total mortality in women (HR=0.87; 95% CI, 0.77–0.98;
P
=0.023).

Conclusions—
We found a significant positive association of clockwise rotation and a significant inverse association of counterclockwise rotation with CVD mortality in men and in men and women combined, independent of confounding factors including other ECG changes.
Naturalistic Validation of an On-Road Driving Test of Older Drivers
Authors: Ott Brian R. , Papandonatos George D. , Davis Jennifer D. , Barco Peggy P. 
Published: February 2012

Objective: The objective was to compare a standardized road test to naturalistic driving by older people who may have cognitive impairment to define improvements that could potentially enhance the validity of road testing in this population. Background: Road testing has been widely adapted as a tool to assess driving competence of older people who may be at risk for unsafe driving because of dementia; however, the validity of this approach has not been rigorously evaluated. Method: For 2 weeks, 80 older drivers (38 healthy elders and 42 with cognitive impairment) who passed a standardized road test were video recorded in their own vehicles. Using a standardized rating scale, 4 hr of video was rated by a driving instructor. The authors examine weighting of individual road test items to form global impressions and to compare road test and naturalistic driving using factor analyses of these two assessments. Results: The road test score was unidimensional, reflecting a major factor related to awareness of signage and traffic behavior. Naturalistic driving reflected two factors related to lane keeping as well as traffic behavior. Conclusion: Maintenance of proper lane is an important dimension of driving safety that appears to be relatively underemphasized during the highly supervised procedures of the standardized road test. Application: Road testing in this population could be improved by standardized designs that emphasize lane keeping and that include self-directed driving. Additional information should be sought from observers in the community as well as crash evidence when advising older drivers who may be cognitively impaired.
Late Weichselian varve archives re-explored to assess proglacial sedimentary chronologies using the principles of tree-ring analysis
Authors: Helama Samuli , Hyttinen Outi , Salonen Veli-Pekka 
Published: February 2012

Glaciogenic varves are formed annually in proglacial basins and provide detailed geochronological archives about the dynamics of deglaciation. Varve chronologies are constructed from multiple varve series measured at individual localities. Temporal connection between the series is traditionally achieved by visual comparison of varve-thickness variations. This connection method resembles that of dendrochronological cross-dating. By contrast, dendrochronological correlation proceeds through the routine of statistical (along with visual) comparisons between the tree-ring series, providing quantification of the dating results, their veracity and robustness. Here we demonstrate the advantages and convenience of applying tree-ring statistical methods to varve records, using an extensive varve archive originating from southern Finland. The data series of individual varve-thickness diagrams were metamorphosed by detrending, prewhitening and averaging, that is, by the methods adopted from tree-ring science. Subsequently, it was seen that the series having 80 or more varves have a higher potential to be unambiguously cross-dated than shorter series. The varve-thickness diagrams could be categorized into two types, those having regional chronological importance and those showing only subregional (distance < 20 km) correlativity. The varves of former type ought to be regarded as primary constituents of the geochronology. The varves of latter type have low geochronological validity although they may bear local sedimentological importance. The findings have the potential to modernize the science of varve-based geochronologies.
Valueless Knowledge-Commodities and Financialization
Authors: Teixeira Rodrigo Alves , Rotta Tomas Nielsen 
Published: February 2012

We present a Marxian theory of the capitalist production of knowledge and of financialization as two processes subsumed under the principle of autonomization of capital. Our approach consists of three tasks. The first is to develop the principle of autonomization. The second is to show how financialization can be a misleading term. The third is to develop a new theory of the production and distribution of valueless knowledge-commodities and knowledge-rent. Our Marxian framework demonstrates how the autonomization of capital manifests itself in its two active dimensions: the financial through financialization, and the productive through knowledge-commodities. JEL codes: B51, O33, O34 1
Statistical Evidence of Falling Profits as Cause of Recession
Authors: Tapia Granados José A. 
Published: February 2012

Data on 251 quarters of the U.S. economy show that recessions are preceded by declines in profits. Profits stop growing and start falling four or five quarters before a recession. They strongly recover immediately after the recession. Since investment is to a large extent determined by profitability and investment is a major component of demand, the fall in profits leading to a fall in investment, in turn leading to a fall in demand, seems to be a basic mechanism in the causation of recessions. JEL codes: E01, E11, E32
Reverse D4F, an Apolipoprotein-AI Mimetic Peptide, Inhibits Atherosclerosis in ApoE-null Mice
Authors: Qin Shucun , Kamanna Vaijinath S. , Lai Jack H. , Liu Tianjiao , Ganji Shobha H. , Zhang Linhua , Bachovchin William W. , Kashyap Moti L. 
Published: February 2012

Objective: Synthetic class A amphipathic helical peptide analogs of apolipoprotein-AI (apoAI; with varied phenylalanine residues) are emerging therapeutic approaches under investigation for atherosclerosis. Utilizing retroinverso sequencing, we designed reverse-D4F (Rev-D4F) peptide with 18 d-amino acids containing 4 phenylalanine residues and reverse order that allows the side chain residues to be of exact alignment and superimposable to those of the parent l-amino acid peptide. This study examined the effect of Rev-D4F on atherosclerosis in apolipoprotein E (apoE)-null mice and the underlying mechanisms. Materials/Methods: ApoE-null mice were fed a chow diet and administered water (control), Rev-D4F, or L4F mimetic peptides (0.4 mg/mL, equivalent to 1.6 mg/d) orally in drinking water for 6 weeks. Aortic root atherosclerotic lesion area, lesion macrophage content, and the ability of plasma high-density lipoprotein (HDL) to influence monocyte chemotaxis were measured. Results: Rev-D4F significantly decreased aortic sinus atherosclerotic lesion area and lesion macrophage content without affecting plasma total and HDL-cholesterol levels in apoE-null mice. The HDL from Rev-D4F-treated mice showed enhanced anti-inflammatory monocyte chemotactic activity, while low-density lipoprotein (LDL) exhibited reduced proinflammatory activity. In in vitro studies, Rev-D4F inhibited LDL oxidation, endothelial cell vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemotactic factor 1 (MCP-1) expression, and monocyte adhesion to aortic endothelial cells. Conclusions: The Rev-D4F inhibits atherosclerosis by inhibiting endothelial inflammatory/oxidative events and improving HDL function. The data suggest that Rev-D4F may be an effective apoAI mimetic peptide for further development in preventing atherosclerosis.
Assessing brain connectivity at rest is clinically relevant in early multiple sclerosis
Authors: Faivre Anthony , Rico Audrey , Zaaraoui Wafaa , Crespy Lydie , Reuter Françoise , Wybrecht Delphine , Soulier Elisabeth , Malikova Irina , Confort-Gouny Sylviane , Cozzone Patrick J , Pelletier Jean , Ranjeva Jean-Philippe , Audoin Bertrand 
Published: February 2012

Objective: The present study aims to determine the clinical counterpart of brain resting-state networks reorganization recently evidenced in early multiple sclerosis. Methods: Thirteen patients with early relapsing–remitting multiple sclerosis and 14 matched healthy controls were included in a resting state functional MRI study performed at 3 T. Data were analyzed using group spatial Independent Component Analysis using concatenation approach (FSL 4.1.3) and double regression analyses (SPM5) to extract local and global levels of connectivity inside various resting state networks (RSNs). Differences in global levels of connectivity of each network between patients and controls were assessed using Mann–Whitney U-test. In patients, relationship between clinical data (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite Score – MSFC) and global RSN connectivity were assessed using Spearman rank correlation. Results: Independent component analysis provided eight consistent neuronal networks involved in motor, sensory and cognitive processes. For seven RSNs, the global level of connectivity was significantly increased in patients compared with controls. No significant decrease in RSN connectivity was found in early multiple sclerosis patients. MSFC values were negatively correlated with increased RSN connectivity within the dorsal frontoparietal network ( r = −0.811, p = 0.001), the right ventral frontoparietal network ( r = − 0.587, p = 0.045) and the prefronto-insular network ( r = −0.615, p = 0.033). Conclusions: This study demonstrates that resting state networks reorganization is strongly associated with disability in early multiple sclerosis. These findings suggest that resting state functional MRI may represent a promising surrogate marker of disease burden.
Efficacy and cost-effectiveness of an automated screening algorithm in an inpatient clinical trial
Authors: Beauharnais Catherine C , Larkin Mary E , Zai Adrian H , Boykin Emily C , Luttrell Jennifer , Wexler Deborah J 
Published: February 2012

Introduction Screening and recruitment for clinical trials can be costly and time-consuming. Inpatient trials present additional challenges because enrollment is time sensitive based on length of stay. We hypothesized that using an automated prescreening algorithm to identify eligible subjects would increase screening efficiency and enrollment and be cost-effective compared to manual review of a daily admission list. Methods Using a before-and-after design, we compared time spent screening, number of patients screened, enrollment rate, and cost-effectiveness of each screening method in an inpatient diabetes trial conducted at Massachusetts General Hospital. Manual chart review (CR) involved reviewing a daily list of admitted patients to identify eligible subjects. The automated prescreening (APS) method used an algorithm to generate a daily list of patients with glucose levels ≥ 180 mg/dL, an insulin order, and/or admission diagnosis of diabetes mellitus. The census generated was then manually screened to confirm eligibility and eliminate patients who met our exclusion criteria. We determined rates of screening and enrollment and cost-effectiveness of each method based on study sample size. Results Total screening time (prescreening and screening) decreased from 4 to 2 h, allowing subjects to be approached earlier in the course of the hospital stay. The average number of patients prescreened per day increased from 13 ± 4 to 30 ± 16 (P < 0.0001). Rate of enrollment increased from 0.17 to 0.32 patients per screening day. Developing the computer algorithm added a fixed cost of US$3000 to the study. Based on our screening and enrollment rates, the algorithm was cost-neutral after enrolling 12 patients. Larger sample sizes further favored screening with an algorithm. By contrast, higher recruitment rates favored individual CR. Limitations Because of the before-and-after design of this study, it is possible that unmeasured factors contributed to increased enrollment. Conclusion Using a computer algorithm to identify eligible patients for a clinical trial in the inpatient setting increased the number of patients screened and enrolled, decreased the time required to enroll them, and was less expensive. Upfront investment in developing a computerized algorithm to improve screening may be cost-effective even for relatively small trials, especially when the recruitment rate is expected to be low.