bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular epidemiology of genitalChlamydia trachomatisinfection in Shenzhen, China
Authors: Zhang Juan-Juan , Zhao Guang-Lu , Wang Feng , Hong Fu-Chang , Luo Zhen-Zhou , Lan Li-Na , Zhang Chun-Lai , Peng Yi , Liu Xiao-Li , Feng Tie-Jian , Chen Xiang-Sheng 
Published: January 2012

ObjectiveTo investigate molecular epidemiology ofChlamydia trachomatisinfection among patients recruited from different clinic settings in Shenzhen, China.MethodsA total of 2534 patients from the sexually transmitted disease (STD) clinics, obstetrics and gynaecology (OBGYN) clinics and genitourinary medicine (GUM) clinics in 34 hospitals participated in the study. TheC trachomatisinfection was determined using COBAS Amplicor system. DNA extracted inC trachomatis-positive samples was amplified using a nested PCR based onompA gene and then genotyped using a microsphere suspension array.ResultsThe overall prevalence of genitalC trachomatisinfection was 17.7%. The prevalence in patients at STD or GUM clinics was significantly higher than that in patients at OBGYN clinics. Being male (adjusted OR (AOR) 2.5, 95% CI 1.8 to 3.4), having no consistent use of a condom with casual partners in the past 3 months (AOR 1.7, 95% CI 1.1 to 2.8) and having any STD symptoms (AOR 3.3, 95% CI 2.0 to 5.4) were independently associated withC trachomatisinfection. Eight genotypes were identified. The most prevalent genotypes were F (22.3%), E (22.0%) and D/Da (12.7%). Other genotypes were G/Ga (8.0%), J (7.3%), K (2.7%), H (2.7%) and I/Ia (0.4%). Eighty-two samples (18.3%) were infected with multiple genotypes. Genotype D/Da among patients from GUM clinics was more common than those from STD or OBGYN clinics. Infections with genotypes G and F were statistically associated with abnormal vaginal discharge (p=0.001) and being married (p=0.014), respectively. Infection with multiple genotypes was more common among patients with a higher income (p=0.011).ConclusionA substantial prevalence of genitalC trachomatisinfection in Shenzhen suggests the importance of detection and treatment of the infection in high-risk groups.
Tpx2 Controls Spindle Integrity, Genome Stability, and Tumor Development
Authors: Aguirre-Portolés Cristina , Bird Alexander W. , Hyman Anthony , Cañamero Marta , Pérez de Castro Ignacio , Malumbres Marcos 
Published: January 2012

Abstract
Tpx2 is a microtubule-associated protein that activates the cell-cycle kinase Aurora A and regulates the mitotic spindle. Overexpression of Tpx2 is associated with the development of different human tumors and strongly correlates with chromosomal instability. By analyzing a conditional null mutation in the mouse Tpx2 gene, we show here that Tpx2 expression is essential for spindle function and chromosome segregation in the mouse embryo. Conditional genetic ablation of Tpx2 in primary cultures resulted in deficient microtubule nucleation from DNA and aberrant spindles during prometaphase. These cells eventually exited from mitosis without chromosome segregation. In addition, Tpx2 haploinsufficiency led to the accumulation of aneuploidies in vivo and increased susceptibility to spontaneous lymphomas and lung tumors. Together, our findings indicate that Tpx2 is essential for maintaining genomic stability through its role in spindle regulation. Subtle changes in Tpx2 expression may favor tumor development in vivo. Cancer Res; 72(6); 1518–28. ©2012 AACR.
KrasG12D and p53 Mutation Cause Primary Intrahepatic Cholangiocarcinoma
Authors: O'Dell Michael R. , Li Huang Jing , Whitney-Miller Christa L. , Deshpande Vikram , Rothberg Paul , Grose Valerie , Rossi Randall M. , Zhu Andrew X. , Land Hartmut , Bardeesy Nabeel , Hezel Aram F. 
Published: January 2012

Abstract
Intrahepatic cholangiocarcinoma (IHCC) is a primary cancer of the liver with an increasing incidence and poor prognosis. Preclinical studies of the etiology and treatment of this disease are hampered by the relatively small number of available IHCC cell lines or genetically faithful animal models. Here we report the development of a genetically engineered mouse model of IHCC that incorporates two of the most common mutations in human IHCC, activating mutations of Kras (KrasG12D) and deletion of p53. Tissue-specific activation of KrasG12D alone resulted in the development of invasive IHCC with low penetrance and long latency. Latency was shortened by combining KrasG12D activation with heterozygous or homozygous deletion of p53 (mean survival of 56 weeks vs. 19 weeks, respectively), which also resulted in widespread local and distant metastasis. Serial analysis showed that the murine models closely recapitulated the multistage histopathologic progression of the human disease, including the development of stroma-rich tumors and the premalignant biliary lesions, intraductal papillary biliary neoplasms (IPBN), and Von Meyenburg complexes (VMC; also known as biliary hamartomas). These findings establish a new genetically and histopathologically faithful model of IHCC and lend experimental support to the hypothesis that IPBN and VMC are precursors to invasive cancers. Cancer Res; 72(6); 1557–67. ©2012 AACR.
Rehabilitation for Oncogene Addiction: Role of Immunity in Cellular Sobriety
Authors: Bajor David L. , Vonderheide Robert H. 
Published: January 2012

Abstract
Clinical responses to oncogene inhibitors result from direct effects on cell-intrinsic growth signals and disruption of downstream messages that produce a protumor immunosuppressive microenvironment. Combining oncogene-targeted and immunomodulatory therapies may result in synergistic effects, producing increased response rates and longer periods of tumor control than can be achieved with either class alone. Clin Cancer Res; 18(5); 1192–4. ©2012 AACR.
Cadherin-11, a Marker of the Mesenchymal Phenotype, Regulates Glioblastoma Cell Migration and Survival In Vivo
Authors: Kaur Harpreet , Phillips-Mason Polly J. , Burden-Gulley Susan M. , Kerstetter-Fogle Amber E. , Basilion James P. , Sloan Andrew E. , Brady-Kalnay Susann M. 
Published: January 2012

Abstract
Glioblastoma multiforme (GBM) is the most malignant and lethal form of astrocytoma. The GBM patient survival time of approximately 1 year necessitates the identification of novel molecular targets and more effective therapeutics. Cadherin-11, a calcium-dependent cell–cell adhesion molecule and mesenchymal marker, plays a role in both normal tissue development and in cancer cell migration. The functional significance of cadherin-11 in GBM has not been investigated. Here, we show that cadherin-11 is expressed in human GBM tumors and human glioma stem-like cells by immunohistochemical labeling. In addition, we show that cadherin-11 is expressed in human glioma cell lines by immunoblotting. Short hairpin RNA–mediated knockdown of cadherin-11 expression in human glioma cell lines results in decreased migration and growth factor–independent cell survival in vitro. More importantly, knockdown of cadherin-11 inhibits glioma cell survival in heterotopic and orthotopic mouse xenograft models. Together, our results show the functional significance of cadherin-11 expression in GBM and provide evidence for a novel role of cadherin-11 in promoting glioma cell survival in an in vivo environment. Thus, our studies suggest cadherin-11 is a viable molecular target for therapeutic intervention in GBM. Mol Cancer Res; 10(3); 293–304. ©2012 AACR.
Antiatherosclerotic Effect of an Antibody That Binds to Extracellular Matrix Glycosaminoglycans
Authors: Soto Yosdel , Acosta Emilio , Delgado Livan , Pérez Arlenis , Falcón Viviana , Bécquer María A. , Fraga Ángela , Brito Víctor , Álvarez Irene , Griñán Tania , Fernández-Marrero Yuniel , López-Requena Alejandro , Noa Miriam , Fernández Eduardo , Vázquez Ana María 
Published: January 2012

Objective—
Subendothelial retention of proatherogenic lipoproteins by proteoglycans is critical in atherosclerosis. The aim of this study was to characterize the recognition and antiatherogenic properties of a chimeric monoclonal antibody (mAb) that reacts with sulfated molecules.

Methods and Results—

chP3R99 mAb recognized sulfated glycosaminoglycans, mainly chondroitin sulfate (CS), by ELISA. This mAb blocked ≈70% of low-density lipoprotein (LDL)–CS association and ≈80% of LDL oxidation in vitro, and when intravenously injected to Sprague-Dawley rats (n=6, 1 mg/animal), it inhibited LDL (4 mg/kg intraperitoneally, 1 hour later) retention and oxidation in the artery wall. Moreover, subcutaneous immunization of New Zealand White rabbits (n=19) with chP3R99 mAb (100 μg, 3 doses at weekly intervals) prevented Lipofundin-induced atherosclerosis (2 mL/kg, 8 days) with a 22-fold reduction in the intima-media ratio (
P
<0.01). Histopathologic and ultrastructural studies showed no intimal alterations or slight thickening, with preserved junctions between endothelial cells and scarce collagen fibers and glycosaminoglycans. In addition, immunization with chP3R99 mAb suppressed macrophage infiltration in aorta and preserved redox status. The atheroprotective effect was associated with the induction of anti-CS antibodies in chP3R99-immunized rabbits, capable of blocking CS-LDL binding and LDL oxidation.

Conclusion—
These results support the use of anti-sulfated glycosaminoglycan antibody–based immunotherapy as a potential tool to prevent atherosclerosis.
Identification of Galectin-1 and Galectin-3 as Novel Partners for Von Willebrand Factor
Authors: Saint-Lu Nathalie , Oortwijn Beatrijs D. , Pegon Julie N. , Odouard Soline , Christophe Olivier D. , de Groot Philip G. , Denis Cécile V. , Lenting Peter J. 
Published: January 2012

Objective—
Although von Willebrand factor (VWF) is a heavily glycosylated protein, its potential to associate with glycan-binding proteins is poorly investigated. Here, we explored its interaction with the glycan-binding proteins galectin-1 and galectin-3.

Methods and Results—

Immunofluorescence analysis using Duolink proximity ligation assays revealed that VWF colocalizes with galectin-1 and galectin-3 in endothelial cells, both before and after stimulation of endothelial cells. Moreover, galectin-1 was found along the typical VWF bundles that are released by endothelial cells. Galectin-1 and galectin-3 could be coprecipitated with VWF from plasma in immunoprecipitation assays, whereas plasma levels of galectin-1 and galectin-3 were significantly reduced in VWF-deficient mice. Binding studies using purified proteins confirmed that VWF could directly interact with both galectins, predominantly via its
N
-linked glycans. In search of the physiological relevance of the VWF-galectin interaction, we found that inhibition of galectins in in vitro perfusion assays was associated with increased VWF-platelet string formation, a phenomenon that was reproduced in galectin-1/galectin-3 double-deficient mice. These mice were also characterized by a more rapid formation of initial thrombi following ferric chloride–induced injury.

Conclusion—
We have identified galectin-1 and galectin-3 as novel partners for VWF, and these proteins may modulate VWF-mediated thrombus formation.
Anti-Inflammatory Effects of Nicotinic Acid in Human Monocytes Are Mediated by GPR109A Dependent Mechanisms
Authors: Digby Janet E. , Martinez Fernando , Jefferson Andrew , Ruparelia Neil , Chai Joshua , Wamil Malgorzata , Greaves David R. , Choudhury Robin P. 
Published: January 2012

Objective—
Nicotinic acid (NA) treatment has been associated with benefits in atherosclerosis that are usually attributed to effects on plasma lipoproteins. The NA receptor GPR109A is expressed in monocytes and macrophages, suggesting a possible additional role for NA in modulating function of these immune cells. We hypothesize that NA has the potential to act directly on monocytes to alter mediators of inflammation that may contribute to its antiatherogenic effects in vivo.

Methods and Results—

In human monocytes activated by Toll-like receptor (TLR)-4 agonist lipopolysaccharide, NA reduced secretion of proinflammatory mediators: TNF-α (by 49.2±4.5%); interleukin-6 (by 56.2±2.8%), and monocyte chemoattractant protein-1 (by 43.2±3.1%) (
P
<0.01). In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-α (by 48.6±7.1%), interleukin-6 (by 60.9±1.6%), and monocyte chemoattractant protein-1 (by 59.3±5.3%) (
P
<0.01; n=7). Knockdown of GPR109A by siRNA resulted in a loss of this anti-inflammatory effect in THP-1 monocytes. However, inhibition of prostaglandin D
2
receptor by MK0524 or COX2 by NS398 did not alter the anti-inflammatory effects of NA observed in activated human monocytes. Preincubation of THP-1 monocytes with NA 0.1 mmol/L reduced phosphorylated IKKβ by 42±2% (
P
<0.001) IKB-α by 54±14% (
P
<0.01). Accumulation of nuclear p65 NF-κB in response to lipopolysaccharide treatment was also profoundly inhibited, by 89±1.3% (n=4;
P
<0.01). NA potently inhibited monocyte adhesion to activated HUVEC, and VCAM, mediated by the integrin, very late antigen 4. Monocyte chemotaxis was also significantly reduced (by 45.7±1.2%;
P
<0.001).

Conclusion—
NA displays a range of effects that are lipoprotein-independent and potentially antiatherogenic. These effects are mediated by GPR109A and are independent of prostaglandin pathways. They suggest a rationale for treatment with NA that is not dependent on levels of plasma cholesterol and possible applications beyond the treatment of dyslipidemia.
FGF19 Signaling Cascade Suppresses
APOA
Gene Expression
Authors: Chennamsetty Indumathi , Claudel Thierry , Kostner Karam M. , Trauner Michael , Kostner Gert M. 
Published: January 2012

Objective—
Lipoprotein(a) is a highly atherogenic lipoprotein, whose metabolism is poorly understood. Currently no safe drugs exists that lower elevated plasma lipoprotein(a) concentrations. We therefore focused on molecular mechanisms that influence apolipoprotein(a) (APOA) biosynthesis.

Methods and Results—

Transgenic human
APOA
mice (tg-
APO
mice) were injected with 1 mg/kg of recombinant human fibroblast growth factor 19 (FGF19). This led to a significant reduction of plasma APOA and hepatic expression of
APOA
. Incubation of primary hepatocytes of tg-
APOA
mice with FGF19 induced ERK1/2 phosphorylation and, in turn, downregulated APOA expression. Repression of APOA by FGF19 was abrogated by specific ERK1/2 phosphorylation inhibitors. The FGF19 effect on APOA was attenuated by transfection of primary hepatocytes with siRNA against the FGF19 receptor 4 (FGFR4). Using promoter reporter assays, mutation analysis, gel shift, and chromatin immune-precipitation assays, an Ets-1 binding element was identified at –1630/–1615bp region in the human
APOA
promoter. This element functions as an Elk-1 binding site that mediates repression of
APOA
transcription by FGF19.

Conclusion—

These findings provide mechanistic insights into the transcriptional regulation of human
APOA
by FGF19. Further studies in the human system are required to substantiate our findings and to design therapeutics for hyper lipoprotein(a).
Site-Specific MicroRNA-92a Regulation of Krüppel-Like Factors 4 and 2 in Atherosusceptible Endothelium
Authors: Fang Yun , Davies Peter F. 
Published: January 2012

Objective—
Endothelial transcription factors Krüppel-like factor 4 (KLF4) and KLF2 are implicated in protection against atherogenesis. Steady-state microRNA (miR) regulation of KLFs in vivo is accessible by screening region-specific endothelial miRs and their targets.

Methods and Results—
A subset of differentially expressed endothelial miRs was identified in atherosusceptible versus protected regions of normal swine aorta. In silico analyses predicted highly conserved binding sites in the 3′-untranslated region (3′UTR) of KLF4 for 5 miRs of the subset (miR-26a, -26b, -29a, -92a, and -103) and a single binding site for a miR-92a complex in the 3′UTR of KLF2. Of these, only miR-92a knockdown and knock-in resulted in responses of KLF4 and KLF2 expression in human arterial endothelial cells. Dual luciferase reporter assays demonstrated functional interactions of miR-92a with full-length 3′UTR sequences of both KLFs and with the specific binding elements therein. Two evolutionarily conserved miR-92a sites in KLF4 3′UTR and 1 site in KLF2 3′UTR were functionally validated. Knockdown of miR-92a in vitro resulted in partial rescue from cytokine-induced proinflammatory marker expression (monocyte chemotactic protein 1, vascular cell adhesion molecule-1, E-selectin, and endothelial nitric oxide synthase) that was attributable to enhanced KLF4 expression. Leukocyte-human arterial endothelial cell adhesion experiments supported this conclusion. In swine aortic arch endothelium, a site of atherosusceptibility where miR-92a expression was elevated, both KLFs were expressed at low levels relative to protected thoracic aorta.

Conclusion—
miR-92a coregulates KLF4 and KLF2 expression in arterial endothelium and contributes to phenotype heterogeneity associated with regional atherosusceptibility and protection in vivo.
Sympathetic Nervous System Regulates Bone Marrow–Derived Cell Egress Through Endothelial Nitric Oxide Synthase Activation
Authors: Récalde Alice , Richart Adèle , Guérin Coralie , Cochain Clément , Zouggari Yasmine , Yin Kiave Ho Wang , Vilar José , Drouet Isabelle , Lévy Bernard , Varoquaux Odile , Silvestre Jean-Sébastien 
Published: January 2012

Objective—
Catecholamines have been shown to control bone marrow (BM)–derived cell egress, yet the cellular and molecular mechanisms involved in this effect and their subsequent participation to postischemic vessel growth are poorly understood.

Methods and Results—

Tyrosine hydroxylase mRNA levels, as well as dopamine (DA) and norepinephrine (NE) contents, were increased in the ischemic BM of mice with right femoral artery ligation. Angiographic score, capillary density, and arteriole number were markedly increased by treatments with DA (IP, 50 mg/kg, 5 days) or NE (IP, 2.5 mg/kg, 5 days). Using chimeric mice lethally irradiated and transplanted with BM-derived cells from green fluorescent protein mice, we showed that DA and NE enhanced by 70% (
P
<0.01) and 62% (
P
<0.001), respectively, the number of green fluorescent protein–positive BM-derived cells in ischemic tissue and promoted their ability to differentiate into cells with endothelial and inflammatory phenotypes. Similarly, both DA and NE increased the in vitro differentiation of cultured BM-derived cells into cells with endothelial phenotype. This increase was blunted by the nitric oxide synthase inhibitor
N
ω
-nitro-
l
-arginine methyl ester. DA and NE also upregulated the number of CD45-positive cells in blood 3 days after ischemia and that of macrophages in ischemic tissue 21 days after ischemia. Of interest, DA and NE increased BM endothelial nitric oxide synthase (eNOS) mRNA levels and were unable to promote BM-derived cell mobilization in chimeric eNOS-deficient mice lethally irradiated and transplanted with BM-derived cells from wild-type animals. Furthermore, administration of a β2 adrenergic agonist (clenbuterol, IP, 2 mg/kg, 5 days) and that of a dopaminergic D1/D5 receptor agonist (SKF-38393, IP, 2.5 mg/kg, 5 days) also enhanced BM-derived cell mobilization and subsequently postischemic vessel growth.

Conclusion—
These results unravel, for the first time, a major role for the sympathetic nervous system in BM-derived cell egress through stromal eNOS activation.
Cardiac Myosin Binding Protein-C Mutations in Families With Hypertrophic Cardiomyopathy
Authors: Page Stephen P. , Kounas Stavros , Syrris Petros , Christiansen Michael , Frank-Hansen Rune , Andersen Paal Skytt , Elliott Perry M. , McKenna William J. 
Published: January 2012

Background—
Small selected cohort studies suggest that mutations in the cardiac myosin binding protein-C (MYBPC3) gene cause late-onset, clinically benign hypertrophic cardiomyopathy (HCM). The aim of this study was to test this hypothesis in a large series of families with HCM associated with MYBPC3 mutations.

Methods and Results—

The initial study population comprised 57 probands with 42 mutations (26 [61.9%] novel) in MYBPC3. Missense mutations (15, 45.6%) were the most frequent, and multiple mutations occurred in 4 (7.0%) probands. Another 110 mutation carriers were identified during familial evaluation; 38 were clinically affected with left ventricular hypertrophy ≥13 mm. Disease penetrance was, therefore, incomplete (56.9% in all mutation carriers, 34.5% in relatives), related to age (38.4% <40 versus 68.6% ≥40 years,
P
<0.001), and was greater in males than females (65.1% versus 48.1%,
P
=0.03). In 9 families (25 individuals) with the R502W mutation, there was marked heterogeneity in age at diagnosis (5 to 80 years), pattern of hypertrophy (11 none, 9 asymmetrical, 3 concentric, 1 apical, 1 eccentric), and prognosis (premature sudden death in 2 individuals compared with survival to advanced age in 6 individuals). During follow up of 7.9+/−4.5 years, in 82 clinically affected individuals the annual risk of sudden death and all cause mortality was 0.46% and 0.93% per year, respectively.

Conclusions—
Disease expression in families with HCM related to MYBPC3 mutations shows marked heterogeneity with incomplete, age-related, and gender specific penetrance. Importantly, complex genetic status is observed and should be considered when mutation analysis and cascade screening is used in the evaluation of at risk family members.
Assessment of Long-Term Effects of Irbesartan on Heart Failure With Preserved Ejection Fraction as Measured by the Minnesota Living With Heart Failure Questionnaire in the Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) Trial
Authors: Rector Thomas S. , Carson Peter E. , Anand Inder S. , McMurray John J. , Zile Michael R. , McKelvie Robert S. , Komajda Michel , Kuskowski Michael , Massie Barry M. ,   for the I-PRESERVE Trial Investigators
Published: January 2012

Background—
The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was used in a large, multinational, randomized, placebo-controlled trial to measure adverse effects of heart failure with preserved ejection fraction (HF-PEF) on patients' lives and the effects of irbesartan.

Methods and Results—

Patients with symptomatic HF-PEF were randomly assigned to irbesartan (up to 300 mg daily) or placebo. The MLHFQ was administered at baseline (n=3605), month 6 (n=3137), month 14 (n=2904), and the end of study (median, 56 months, n=2205). Baseline MLHFQ scores of 43±21 indicated that HF-PEF had a substantial adverse effects. Estimated retest reliability was 0.80. Baseline MLHFQ scores were associated with other measures of the severity of heart failure including symptoms, signs of congestion, cardiac structure, and time to hospitalizations or deaths attributed to heart failure. Slight improvement in shortness of breath or fatigue was associated with significant improvement in MLHFQ scores (−5.9 and −5.0,
P
<0.0001). Compared with placebo, further improvement in MLHFQ scores was not observed with irbesartan after 6 months (mean adjusted difference, 0.4; 95% confidence interval, −0.8 to 1.7), 14 months (0.5; 95% confidence interval, −0.9 to 1.8), or the end of study (2.0; 95% confidence interval, −4.1 to 0.01).

Conclusions—
The MLHFQ scores are a reliable, valid, and sensitive measure of the adverse impact of HF-PEF on patients' lives. Irbesartan did not substantially improve MLHFQ scores during a long period of follow-up.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00095238.