bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomonitoring the Cooked Meat Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine in Hair: Impact of Exposure, Hair Pigmentation, and Cytochrome P450 1A2 Phenotype
Authors: Turesky Robert J. , Liu Lin , Gu Dan , Yonemori Kim M. , White Kami K. , Wilkens Lynne R. , Le Marchand Loïc 
Published: January 2013

Abstract
Background: Hair is a promising tissue to assess exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogen formed in cooked meats. However, an understanding of how dietary exposure to PhIP, cytochrome P450 1A2 activity—a key enzyme involved in PhIP metabolism, and hair pigmentation affect the level of PhIP accrued in hair is required to determine the reliability of the PhIP hair level as a biomarker of exposure to this carcinogen.
Methods: We examined the impact of PhIP exposure, cytochrome P450 1A2 activity, and hair pigmentation on the levels of PhIP accumulated in the hair of volunteers on a 4-week semicontrolled diet of cooked meat containing known quantities of PhIP.
Results: The amount of PhIP in hair increased, on average, 15-fold in light- and dark-haired individuals during consumption of cooked meat. PhIP levels in hair were correlated to PhIP intake (ρ = 0.53; P &lt; 0.001), and the relationship was strengthened when PhIP levels were normalized for the melanin content of hair (ρ = 0.71; P &lt; 0.001). However, PhIP accrual in hair was not correlated to cytochrome P450 1A2 activity, as assessed by the caffeine test, or to the levels of unmetabolized PhIP in urine or to the metabolic ratio of the major urinary metabolite N2-(β-1-glucosiduronyl-2-(hydroxyamino)-1-methyl-6-phenylimidazo[4,5-b]pyridine to unmetabolized PhIP.
Conclusions: The use of the PhIP hair biomarker should take hair pigmentation into account for accurate exposure assessment of PhIP.
Impact: PhIP hair levels can serve as a biomarker in epidemiologic studies investigating the association of heterocyclic aromatic amine (HAA), cooked meat, and cancer risk. Cancer Epidemiol Biomarkers Prev; 22(3); 356–64. ©2013 AACR.
Genetic Profiling Identifies Two Classes of Soft-Tissue Leiomyosarcomas with Distinct Clinical Characteristics
Authors: Italiano Antoine , Lagarde Pauline , Brulard Céline , Terrier Philippe , Laë Marick , Marques Bernard , Ranchere-Vince Dominique , Michels Jean-Jacques , Trassard Martine , Cioffi Angela , Piperno-Neumann Sophie , Chevreau Christine , Blay Jean-Yves , Delcambre Corinne , Isambert Nicolas , Penel Nicolas , Bay Jacques-Olivier , Bonvalot Sylvie , Le Cesne Axel , Coindre Jean-Michel , Chibon Frédéric 
Published: January 2013

Abstract
Purpose: Data about the prognostic factors of soft-tissue leiomyosarcomas and their correlation with molecular profile are limited.
Experimental Design: From 1990 to 2010, 586 adult patients with a primary soft-tissue leiomyosarcoma were included in the French Sarcoma Group (GSF) database after surgery of the primary tumor. Multivariate analyses were conducted by Cox regression model in a backward stepwise procedure. Genetic profiling was conducted for 73 cases.
Results: Median age was 59 years (range, 21–98 years). The median follow-up of patients alive was 46 months. The 5-year metastasis-free survival (MFS) rate was 51% (95% location and grade &gt; I were independent adverse prognostic factors for MFS). The 5-year overall survival (OS) rate was 63% [95% confidence interval (CI), 59–67]. On multivariate analysis, age ≥ 60 years old, tumor size &gt; 5 cm, deep location, and grade &gt; I were independent adverse prognostic factors for OS. Molecular profiling identified specific clusters with activation of different biologic pathways: retroperitoneal leiomyosarcomas are characterized by overexpression of genes involved in muscle differentiation and nonretroperitoneal leiomyosarcomas characterized by overexpression of genes mainly involved in extracellular matrix, wounding, and adhesion pathways. The CINSARC signature but not comparative genomic hybridization (CGH) profiling was predictive of outcome.
Conclusion: Soft-tissue leiomyosarcomas represent a heterogeneous group of tumors with at least two categories, retroperitoneal and extremities leiomyosarcomas, having specific clinical outcome and molecular features. Future clinical trials should consider this heterogeneity for a better stratification of patients. Clin Cancer Res; 19(5); 1190–6. ©2013 AACR.
Modeling Boundary Conditions for Balanced Proliferation in Metastatic Latency
Authors: Taylor Donald P. , Wells Jakob Z. , Savol Andrej , Chennubhotla Chakra , Wells Alan 
Published: January 2013

Abstract
Purpose: Nearly half of cancer metastases become clinically evident five or more years after primary tumor treatment; thus, metastatic cells survived without emerging for extended periods. This dormancy has been explained by at least two countervailing scenarios: cellular quiescence and balanced proliferation; these entail dichotomous mechanistic etiologies. To examine the boundary parameters for balanced proliferation, we conducted in silico modeling.
Experimental Design: To illuminate the balanced proliferation hypothesis, we explored the specific boundary probabilities under which proliferating micrometastases would remain dormant. A two-state Markov chain Monte Carlo model simulated micrometastatic proliferation and death according to stochastic survival probabilities. We varied these probabilities across 100 simulated patients each with 1,000 metastatic deposits and documented whether the micrometastases exceeded one million cells, died out, or remained dormant (survived 1,218 generations).
Results: The simulations revealed a narrow survival probability window (49.7–50.8%) that allowed for dormancy across a range of starting cell numbers, and even then for only a small fraction of micrometastases. The majority of micrometastases died out quickly even at survival probabilities that led to rapid emergence of a subset of micrometastases. Within dormant metastases, cell populations depended sensitively on small survival probability increments.
Conclusions: Metastatic dormancy as explained solely by balanced proliferation is bounded by very tight survival probabilities. Considering the far larger survival variability thought to attend fluxing microenvironments, it is more probable that these micrometastatic nodules undergo at least periods of quiescence rather than exclusively being controlled by balanced proliferation. Clin Cancer Res; 19(5); 1063–70. ©2013 AACR.
Bioactive Grape Proanthocyanidins Enhance Immune Reactivity in UV-Irradiated Skin through Functional Activation of Dendritic Cells in Mice
Authors: Vaid Mudit , Singh Tripti , Prasad Ram , Elmets Craig A. , Xu Hui , Katiyar Santosh K. 
Published: January 2013

AbstractUltraviolet (UV) radiation-induced immunosuppression has been implicated in skin carcinogenesis. Grape seed proanthocyanidins (GSPs) have anti-skin carcinogenic effects in mice and GSPs-fed mice exhibit a reduction in UV-induced suppression of allergic contact hypersensitivity (CHS), a prototypic T-cell–mediated response. Here, we report that dietary GSPs did not inhibit UVB-induced suppression of CHS in xeroderma pigmentosum complementation group A (XPA)-deficient mice, which lack nucleotide excision repair mechanisms. GSPs enhanced repair of UVB-induced DNA damage (cyclobutane pyrimidine dimers) in wild-type, but not XPA-deficient, dendritic cells (DC). Co-culture of CD4+ T cells with DCs from UVB-irradiated wild-type mice resulted in suppression of T-cell proliferation and secretion of T-helper (TH) 1-type cytokines that was ameliorated when the DCs were obtained from GSP-fed mice, whereas DCs obtained from GSP-fed XPA-KO mice failed to restore T-cell proliferation. In adoptive transfer experiments, donor DCs were positively selected from the draining lymph nodes of UVB-exposed donor mice that were sensitized to 2,4,-dinitrofluorobenzene were transferred into naïve recipient mice and the CHS response assessed. Naïve recipients that received DCs from UVB-exposed wild-type donors that had been fed GSPs exhibited a full CHS response, whereas no significant CHS was observed in mice that received DCs from XPA-KO mice fed GSPs. These results suggest that GSPs prevent UVB-induced immunosuppression through DNA repair–dependent functional activation of dendritic cells in mice. Cancer Prev Res; 6(3); 242–52. ©2013 AACR.
Effects of argatroban, danaparoid, and fondaparinux on trombin generation in heparin-induced thrombocytopenia
Authors: Combe Marion , Piot Michèle , Chapelle Céline , Akrour Majid , Tardy Bernard , Tardy-Poncet Brigitte 
Published: January 2013

SummaryThere is no in vitro data on the comparison of the effects of danaparoid, argatroban and fondaparinux on thrombin generation in patients with heparin-induced thrombocytopenia. It was the study objective to compare the in vitro anticoagulant potential of argatroban, danaparoid and fondaparinux using a thrombin generation assay TGA on a mixture of control platelet-rich plasma (PRP) and HIT patient platelet-poor plasma (PPP). The plasma of seven patients with a clear HIT diagnosed at our institution was selected. Mixtures of donor PRP and patient PPP were incubated with unfractionated heparin 0.2 U.mL-1, argatroban at 600 ng.mL-1, argatroban at 400 ng.mL-1, danaparoid at 0.65 IU.mL-1 and fondaparinux at 1 [uni03BC]g.mL-1. Thrombin generation was assessed by calibrated thrombinography. The percentage of inhibition of the endogenous thrombin potential observed with argatroban at 600 ng.mL-1 was statistically significantly higher compared with those observed with fondaparinux (median: 53.6% vs. 3.9%; p = 0.031) but not compared with argatroban at 400 ng.mL-1 and danaparoid. The percentage of inhibition of the thrombin peak observed with argatroban at 600 ng.mL-1 was statistically significantly higher compared with those observed with danaparoid (median: 71.2 vs. 56.8; p = 0.031) and fondaparinux (mean: 71.2 vs. 30; p = 0.031) but not with argatroban at 400 ng.mL-1. In conclusion, the in vitro effect of argatroban and danaparoid on thrombin generation seems to corroborate the results of clinical studies of these drugs in the treatment of HIT in term of efficiency. Fondaparinux showed a very small effect on thrombin generation evaluated by calibrated thrombinography.
Endosomal NADPH-oxidase is critical for induction of the tissue factor gene in monocytes and endothelial cells
Authors: Prinz Nadine , Clemens Natascha , Canisius Antje , Lackner Karl 
Published: January 2013

SummaryAntiphospholipid antibodies (aPL) have been shown to induce tissue factor (TF) expression in monocytes and endothelial cells. However, the underlying signal transduction has been more or less elusive in the past. We have recently shown that aPL enter the lysosomal route in monocytes and dendritic cells, and subsequently activate endosomal NADPH-oxidase (NOX). The generation of superoxide which is dismutated to hydrogen peroxide upregulates the intracellular toll like receptors (TLR) 7 and 8, and leads to robust production of inflammatory cytokines. Here we show that induction of TF by aPL follows the same signaling pathway. Inhibition of endosomal NOX by the anion channel blocker niflumic acid or capture of superoxide by the radical scavenger N-acetylcysteine blocks TF induction by aPL. Furthermore, monocytes from mice deficient in NOX2 do not increase TF surface expression in response to aPL, while cells from mice deficient in glutathione peroxidase- 1 (GPx-1) show an increased response. Unexpectedly, also induction of TF by tumour necrosis factor (TNF)⍺ and lipopolysaccharide (LPS) was strongly dependent on the activation of endosomal NOX. While TNF⍺ apparently depends almost fully on endosomal NOX, signalling of LPS is only partially dependent on this pathway. These data provide further insight into the well-known role of reactive oxygen species in the induction of TF expression and suggest that endosomal signalling may represent a central coordinating point in this process.
RAD001-mediated STAT3 upregulation and megakaryocytic differentiation
Authors: Su Yu-Chieh , Li Szu-Chin , Peng Hsuan-Yu , Ho Yang-Hui , Chen Li-Jung , Liao Hui-Fen 
Published: January 2013

SummaryRAD001 is currently used as an immunosuppressant and anticancer drug. Megakaryocyte (MK) differentiation includes development from pluripotent stem cells to proliferation and differentiation toward MK formation and platelet maturation. Our preliminary assay showed that RAD001 might stimulate MK differentiation; however, the exact regulatory mechanisms needed to be elucidated. By the ex vivo assay, RAD001 induced MK differentiation in human haematopoietic stem cells, with both the stimulation of CFU-GM colony formation and CD61 surface marker expression. Then, BALB/c mice were orally administrated with or without agrylin and/or RAD001 for 15 days. The platelet count and bone marrow CFU-MK colony formation were eliminated by agrylin, but unchanged in RAD001 and RAD001 plus agrylin mice. An ex vivo assay of bone marrow-derived stem cells demonstrated that RAD001 increased the number of CFU-MK colonies. The MK count in bone section indicated the decreased effect by agrylin and then recovered by RAD001. The level of plasma thrombopoietin was also enhanced in RAD001-treated mice. The effect of RAD001 on human leukaemic K562 and HEL cells showed the growth inhibition and MK differentiation activities; including morphological observation, CD41 and CD61 expression, and platelet factor 4 secretion. In RAD001-treated HEL cells, p-STAT3 expression, STAT3 translocation, and STAT3-DNA binding activity were up-regulated. Furthermore, STAT3 siRNA decreased the p-STAT3 and CD61 expression, as well as the CD61 fluorescence intensity, indicating that STAT3 may be critical in RAD001-mediated MK differentiation. Conclusion, the present study demonstrated that RAD001 might have the capacity to induce MK differentiation through the up-regulation of STAT3 signalling.
Depolarization of Mitochondria in Endothelial Cells Promotes Cerebral Artery Vasodilation by Activation of Nitric Oxide Synthase
Authors: Katakam Prasad V.G. , Wappler Edina A. , Katz Paige S. , Rutkai Ibolya , Institoris Adam , Domoki Ferenc , Gáspár Tamás , Grovenburg Samuel M. , Snipes James A. , Busija David W. 
Published: January 2013

Objective—
Mitochondrial depolarization after ATP-sensitive potassium channel activation has been shown to induce cerebral vasodilation by the generation of calcium sparks in smooth muscle. It is unclear, however, whether mitochondrial depolarization in endothelial cells is capable of promoting vasodilation by releasing vasoactive factors. Therefore, we studied the effect of endothelial mitochondrial depolarization by mitochondrial ATP-sensitive potassium channel activators, BMS-191095 (BMS) and diazoxide, on endothelium-dependent vasodilation.

Approach and Results—

Diameter studies in isolated rat cerebral arteries showed BMS- and diazoxide-induced vasodilations that were diminished by endothelial denudation. Mitochondrial depolarization-induced vasodilation was reduced by inhibition of mitochondrial ATP-sensitive potassium channels, phosphoinositide-3 kinase, or nitric oxide synthase. Scavenging of reactive oxygen species, however, diminished vasodilation induced by diazoxide, but not by BMS. Fluorescence studies in cultured rat brain microvascular endothelial cells showed that BMS elicited mitochondrial depolarization and enhanced nitric oxide production; diazoxide exhibited largely similar effects, but unlike BMS, increased mitochondrial reactive oxygen species production. Measurements of intracellular calcium ([Ca
2+
]
i
) in cultured rat brain microvascular endothelial cells and arteries showed that both diazoxide and BMS increased endothelial [Ca
2+
]
i
. Western blot analyses revealed increased phosphorylation of protein kinase B and endothelial nitric oxide synthase (eNOS) by BMS and diazoxide. Increased phosphorylation of eNOS by diazoxide was abolished by phosphoinositide-3 kinase inhibition. Electron spin resonance spectroscopy confirmed vascular nitric oxide generation in response to diazoxide and BMS.

Conclusions—

Pharmacological depolarization of endothelial mitochondria promotes activation of eNOS by dual pathways involving increased [Ca
2+
]
i
as well as by phosphoinositide-3 kinase-protein kinase B–induced eNOS phosphorylation. Both mitochondrial reactive oxygen species–dependent and –independent mechanisms mediate activation of eNOS by endothelial mitochondrial depolarization.
Fenofibrate Inhibits Endothelin-1 Expression by Peroxisome Proliferator–Activated Receptor α–Dependent and Independent Mechanisms in Human Endothelial Cells
Authors: Glineur Corine , Gross Barbara , Neve Bernadette , Rommens Corinne , Chew Gerard T. , Martin-Nizard Françoise , Rodríguez-Pascual Fernando , Lamas Santiago , Watts Gerald F. , Staels Bart 
Published: January 2013

Objective—
Dyslipidemia contributes to endothelial dysfunction in type 2 diabetes mellitus. Fenofibrate (FF), a ligand of the peroxisome proliferator–activated receptor-α (PPARα), has beneficial effects on microvascular complications. FF may act on the endothelium by regulating vasoactive factors, including endothelin-1 (ET-1). In vitro, FF decreases ET-1 expression in human microvascular endothelial cells. We investigated the molecular mechanisms involved in the effect of FF treatment on plasma levels of ET-1 in type 2 diabetes mellitus patients.

Methods and Results—

FF impaired the capacity of transforming growth factor-β to induce
ET-1
gene expression. PPARα activation by FF increased expression of the transcriptional repressor Krüppel-like factor 11 and its binding to the
ET-1
gene promoter. Knockdown of Krüppel-like factor 11 expression potentiated basal and transforming growth factor-β–stimulated ET-1 expression, suggesting that Krüppel-like factor 11 downregulates ET-1 expression. FF, in a PPARα-independent manner, and insulin enhanced glycogen synthase kinase-3β phosphorylation thus reducing glycogen synthase kinase-3 activity that contributes to the FF-mediated reduction of
ET-1
gene expression. In type 2 diabetes mellitus, improvement of flow-mediated dilatation of the brachial artery by FF was associated with a decrease in plasma ET-1.

Conclusion—
FF decreases ET-1 expression by a PPARα-dependent mechanism, via transcriptional induction of the Krüppel-like factor 11 repressor and by PPARα-independent actions via inhibition of glycogen synthase kinase-3 activity.
Predictors for Recurrent Primary Intracerebral Hemorrhage
Authors: Huhtakangas Juha , Löppönen Pekka , Tetri Sami , Juvela Seppo , Saloheimo Pertti , Bode Michaela K. , Hillbom Matti 
Published: January 2013

Background and Purpose—
Underlying comorbidities, previous strokes, and medication may increase the risk for primary intracerebral hemorrhage (PICH) and its recurrence. The aim of this study was to determine the independent predictors for recurrent PICH.

Methods—
We identified 961 subjects with first-ever PICH from 1993 to 2008 among the population of Northern Ostrobothnia, Finland. Hospital and death records were reviewed and data on drug use were obtained from the national register of prescribed medicines. Kaplan–Meier survival curves and Cox proportional hazards models were used to demonstrate predictors for recurrence of PICH.

Results—

Total follow-up time of the 961 patients was 3481 person-years. During the follow-up time, 58 subjects had altogether 68 recurrent PICHs. The annual average incidence of first recurrence was 1.67%. Cumulative 5- and 10-year incidence rates were 9.6% and 14.2%, respectively. In univariable analysis, history of ischemic stroke, diabetes mellitus, and aspirin use were associated with a higher recurrence rate. In multivariable analysis, only previous ischemic stroke (adjusted hazard ratio, 2.22; 95% confidence interval, 1.22–4.05;
P
=0.009) independently predicted PICH recurrence. Diabetes mellitus tended to increase (adjusted hazard ratio, 2.38; 95% confidence interval, 0.98–5.80;
P
=0.056), whereas treated hypertension tended to decrease (0.45, 0.20–1.01;
P
=0.054) the risk for fatal recurrent PICH.

Conclusions—
Previous ischemic stroke independent of confounding factors may increase the risk for PICH recurrence.
Impact of Early Blood Pressure Variability on Stroke Outcomes After Thrombolysis
Authors: Endo Kaoru , Kario Kazuomi , Koga Masatoshi , Nakagawara Jyoji , Shiokawa Yoshiaki , Yamagami Hiroshi , Furui Eisuke , Kimura Kazumi , Hasegawa Yasuhiro , Okada Yasushi , Okuda Satoshi , Namekawa Michito , Miyagi Tetsuya , Osaki Masato , Minematsu Kazuo , Toyoda Kazunori 
Published: January 2013

Background and Purpose—
The present study determines associations between early blood pressure (BP) variability and stroke outcomes after intravenous thrombolysis.

Methods—
In 527 stroke patients receiving intravenous alteplase (0.6 mg/kg), BP was measured 8 times within the first 25 hours. BP variability was determined as ΔBP (maximum-minimum), standard deviation (SD), coefficient of variation, and successive variation.

Results—

The systolic BP course was lower among patients with modified Rankin Scale (mRS) 0 to 1 than those without (
P
<0.001). Most of systolic BP variability profiles were significantly associated with outcomes. Adjusted odds ratios (95% confidence interval) per 10 mm Hg (or 10% for coefficient of variation) on symptomatic intracerebral hemorrhage were as follows: ΔBP, 1.33 (1.08–1.66); SD, 2.52 (1.26–5.12); coefficient of variation, 3.15 (1.12–8.84); and successive variation, 1.82 (1.04–3.10). The respective values were 0.88 (0.77–0.99), 0.73 (0.48–1.09), 0.77 (0.43–1.34), and 0.76 (0.56–1.03) for 3-month mRS 0 to 1; and 1.40 (1.14–1.75), 2.85 (1.47–5.65), 4.67 (1.78–12.6), and 1.99 (1.20–3.25) for death. Initial BP values before thrombolysis were not associated with any outcomes.

Conclusions—
Early systolic BP variability was positively associated with symptomatic intracerebral hemorrhage and death after intravenous thrombolysis.
A Tree-Ring-Based Reconstruction of Delaware River Basin Streamflow Using Hierarchical Bayesian Regression
Authors: Devineni Naresh , Lall Upmanu , Pederson Neil , Cook Edward 
Published: January 2013

AbstractA hierarchical Bayesian regression model is presented for reconstructing the average summer streamflow at five gauges in the Delaware River basin using eight regional tree-ring chronologies. The model provides estimates of the posterior probability distribution of each reconstructed streamflow series considering parameter uncertainty. The vectors of regression coefficients are modeled as draws from a common multivariate normal distribution with unknown parameters estimated as part of the analysis. This leads to a multilevel structure. The covariance structure of the streamflow residuals across sites is explicitly modeled. The resulting partial pooling of information across multiple stations leads to a reduction in parameter uncertainty. The effect of no pooling and full pooling of station information, as end points of the method, is explored. The no-pooling model considers independent estimation of the regression coefficients for each streamflow gauge with respect to each tree-ring chronology. The full-pooling model considers that the same regression coefficients apply across all streamflow sites for a particular tree-ring chronology. The cross-site correlation of residuals is modeled in all cases. Performance on metrics typically used by tree-ring reconstruction experts, such as reduction of error, coefficient of efficiency, and coverage rates under credible intervals is comparable to, or better, for the partial-pooling model relative to the no-pooling model, and streamflow estimation uncertainty is reduced. Long record simulations from reconstructions are used to develop estimates of the probability of duration and severity of droughts in the region. Analysis of monotonic trends in the reconstructed drought events do not reject the null hypothesis of no trend at the 90% significance over 1754–2000.