bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intermediate- and Low-Methylation Epigenotypes Do Not Correspond to CpG Island Methylator Phenotype (Low and -Zero) in Colorectal Cancer
Authors: Karpinski Pawel , Walter Michael , Szmida Elzbieta , Ramsey David , Misiak Blazej , Kozlowska Joanna , Bebenek Marek , Grzebieniak Zygmunt , Blin Nikolaus , Laczmanski Lukasz , Sasiadek Maria M. 
Published: November 2012

AbstractBackground: Most recent genome-wide studies on the CpG island methylation in colorectal cancer (CRC) have led to the discovery of at least 3 distinct methylation clusters. However, there remains an uncertainty whether the CRC clusters identified in these studies represent compatible phenotypes.Methods: We carried out comprehensive genome-scale DNA methylation profiling by Illumina Infinium HumanMethylation27 of 21 DNA pools that represent 84 CRC samples divided according to their high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME, respectively) and 70 normal-adjacent colonic tissues. We have also examined the relationship among 3 epigenotypes and chromosomal gains and deletions (assessed by Comparative Genomic Hybridization) in a group of 100 CRC samples.Results: The HME subgroup showed features associated with CpG island methylator phenotype – high (CIMP-high) including methylation of specific CpG sites (CpGs) as well as significantly lower mean number of chromosomal imbalances when compared with other epigenotypes. The IME subgroup displayed the lowest number of methylated CpGs (717 vs. 2,399 and 2,679 in HME and LME, respectively) and highest mean number of chromosomal imbalances when compared with HME (P, 0.001) and LME (P, 0.004). A comparison between the methylation profiles of 3 epigenotypes revealed more similarities between the HME and LME (1,669 methylated CpGs overlapped) than HME and IME (673 methylated CpGs overlapped).Conclusion: Our results provide evidence that IME and LME CRCs show opposite features to those that have been previously attributed to CIMP-low and CIMP-0 CRCs.Impact: These discrepancies should be considered when interpreting the data from a particular epigenotyping method. Cancer Epidemiol Biomarkers Prev; 22(2); 201–8. ©2012 AACR.
Diphtheria Toxin–Epidermal Growth Factor Fusion Protein DAB389EGF for the Treatment of Bladder Cancer
Authors: Yang Xiaoping , Kessler Elizabeth , Su Lih-Jen , Thorburn Andrew , Frankel Arthur E. , Li Yuan , La Rosa Francisco G. , Shen Jingping , Li Chuan-Yuan , Varella-Garcia Marileila , Glodé L. Michael , Flaig Thomas W. 
Published: November 2012

AbstractPurpose: The novel fusion protein, DAB389EGF, is composed of both the catalytic and the translocation domains of diphtheria toxin that are fused to the human EGF, providing a targeting and a toxicity component. We tested DAB389EGF for antitumor activity in both in vitro and in vivo urinary bladder cancer models.Experimental Design: Human bladder cancer lines were treated with DAB389EGF and assessed for growth inhibition and clonogenic suppression. Using 6- to 8-week-old female athymic nude mice implanted orthotopically with HTB9 cells, DAB389EGF was administered intravesically twice weekly for 2 weeks. The response of the luciferase-expressing HTB9 cells was monitored via bioluminescence as the primary endpoint.Results: Treatment response with DAB389EGF was specific and robust, with an IC50 ranging from 0.5 to 15 ng/mL in eight tested bladder cancer cell lines, but greater than 50 ng/mL in the EGF receptor (EGFR)-negative H520 control cell line. Simulating short-duration intravesical therapy used clinically, a 2-hour treatment exposure of DAB389EGF (10 ng/mL) produced clonogenic suppression in three selected bladder cancer cell lines. In vivo, luciferase activity was suppressed in five of six mice treated with DAB389EGF [70 μL (1 ng/μL) per mouse], as compared with only one of six mice treated with a control diphtheria toxin (DT) fusion protein. Histologic assessment of tumor clearance correlated with the bioluminescent changes observed with DAB389EGF treatment. Immunocompetent mice treated with intravesical DAB389EGF did not show any nonspecific systemic toxicity.Conclusions: The intravesical delivery of targeted toxin fusion proteins is a novel treatment approach for non–muscle-invasive urinary bladder cancer. With appropriate targeting, the treatments are effective and well-tolerated in vivo. Clin Cancer Res; 19(1); 148–57. ©2012 AACR.
Contribution of HIF-1α in 4E-BP1 Gene Expression
Authors: Azar Rania , Lasfargues Charline , Bousquet Corinne , Pyronnet Stéphane 
Published: November 2012

Abstract
The eukaryotic translation initiation factor 4E (eIF4E) is necessary for the translation of capped mRNAs into proteins. Cap-dependent mRNA translation can be however inhibited by the eIF4E-binding protein 1 (4E-BP1). The hypophosphorylated forms of 4E-BP1 indeed sequester eIF4E and thus block translation initiation and consequent protein synthesis. Different reports indicate that, in addition to hypophosphorylation, 4E-BP1 function can be also regulated at the level of protein expression. This is the case in contact-inhibited cells or in cells exposed to hypoxia. The molecular mechanisms responsible for 4E-BP1 protein accumulation in these conditions remain however unknown. In the present study, we found that 4E-BP1 gene promoter contains a hypoxia-responsive element (HRE) that mediates 4E-BP1 gene upregulation via the hypoxia-inducible factor-1 alpha (HIF-1α) transcription factor. Gene reporter assays then revealed that the presence of such HRE in the promoter of 4E-BP1 gene is involved in 4E-BP1 accumulation in contact-inhibited cells and in cells exposed to hypoxia. We also reveal that the TGF-β–dependent transcription factor SMAD4 cooperates with HIF-1α to fully activate 4E-BP1 gene transcription under hypoxia. These data therefore suggest that HIF-1α contributes to 4E-BP1 gene expression under different conditions. Mol Cancer Res; 11(1); 54–61. ©2012 AACR.
Targeted Inactivation of HDAC2 Restores p16INK4a Activity and Exerts Antitumor Effects on Human Gastric Cancer
Authors: Kim Jeong Kyu , Noh Ji Heon , Eun Jung Woo , Jung Kwang Hwa , Bae Hyun Jin , Shen Qingyu , Kim Min Gyu , Chang Young Gyoon , Kim Seung-Jin , Park Won Sang , Lee Jung Young , Borlak Jürgen , Nam Suk Woo 
Published: November 2012

Abstract
Aberrant regulation of histone deacetylase 2 (HDAC2) was reported for gastric cancers. However, responsive cancer genes in disease onset and progression are less understood. HDAC2 expression was studied by quantitative RT-PCR and Western blotting. The functional consequences of HDAC2 knockdown on cell-cycle regulation, programmed cell death, and gene target identification was investigated by flow cytometry, Western blotting, electron microscopy, anchorage-independent colony formation, and cell migration assay and by whole-genome microarray. Therapeutic efficacy of HDAC2 knockdown was determined in nude mice with small hairpin expressing human gastric cancer cells. Epigenetic regulation of p16INK4a was studied by methylation-specific PCR and chromatin-IP to evidence HDAC2 or acetylated-histone-H4 binding at gene specific promoter sequences. HDAC2 gene and protein expression was significantly upregulated in different histopathologic grades of human gastric cancers and cancer cell lines. HDAC2 inactivation significantly reduced cell motility, cell invasion, clonal expansion, and tumor growth. HDAC2 knockdown-induced G1–S cell cycle arrest and restored activity of p16INK4a and the proapoptotic factors. This treatment caused PARP cleavage and hypophosphorylation of the Rb-protein, repressed cyclinD1, CDK4, and Bcl-2 expression and induced autophagic phenotype, that is, LC3B-II conversion. Some gastric tumors and cancer cells displayed p16INK4a promoter hypermethylation but treatment with 5-aza-deoxycitidine restored activity. With others the methylation status was unchanged. Here, chromatin-IP evidenced HDAC2 binding. Nonetheless, expression of p16INK4a was restored by HDAC2 knockdown with notable histone-H4-acetylation, as determined by chromatin-IP. Thus, p16INK4a is regulated by HDAC2. HDAC2 is a bona fide target for novel molecular therapies in gastric cancers. Mol Cancer Res; 11(1); 62–73. ©2012 AACR.
Analysing responses to aspirin and clopidogrel by measuring platelet thrombus formation under arterial flow conditions
Authors: Hosokawa Kazuya , Ohnishi Tomoko , Sameshima Hisayo , Miura Naoki , Ito Takashi , Koide Takehiko , Maruyama Ikuro 
Published: November 2012

SummaryHigh residual platelet aggregability and circulating platelet-monocyte aggregates in patients administered aspirin and clopidogrel are associated with ischaemic vascular events. To determine the relevance of these factors with residual thrombogenicity, we measured platelet thrombus formation using a microchip-based flow-chamber system in cardiac patients receiving aspirin and/or clopidogrel, and evaluated its correlation with agonist-inducible platelet aggregation and platelet-monocyte aggregates. Platelet thrombus formation was analysed by measuring flow pressure changes due to the occlusion of micro-capillaries and was quantified by calculating AUC10 (area under the flow pressure curve). The growth and stability of platelet thrombi that formed inside microchips at shear rates of 1000, 1500, and 2000 s-1 were markedly reduced in patients receiving aspirin and/or thienopyridine compared to healthy controls (n=33). AUC10 values of aspirin therapy patients (n=20) were significantly lower and higher than those of healthy controls and dual antiplatelet therapy patients (n=19), respectively, and showed relatively good correlations with collagen-induced platelet aggregation and platelet-monocyte aggregates at 1000 and 1500 s-1 (r

s
>0.59, p<0.01). In contrast, AUC10 in dual antiplatelet therapy patients was significantly correlated with ADP-induced platelet aggregation at all examined shear rates (r

s
>0.59, p<0.01), but did not correlate with collagen-induced aggregation. Aspirin monotherapy patients with high residual platelet thrombogenicity also exhibited significant elevations in both collagen-induced platelet aggregation and platelet-monocyte aggregates. Our results, although preliminary, suggest that residual platelet thrombogenicity in aspirin-treated patients is associated with either collagen-induced platelet aggregation or circulating platelet-monocyte aggregates, but it is predominantly dependent on ADP-induced platelet aggregation in patients receiving dual antiplatelet therapy.
Evaluation of the Global Climate Models in the CMIP5 over the Tibetan Plateau
Authors: Su Fengge , Duan Xiaolan , Chen Deliang , Hao Zhenchun , Cuo Lan 
Published: November 2012

Abstract
The performance of 24 GCMs available in the fifth phase of the Coupled Model Intercomparison Project (CMIP5) is evaluated over the eastern Tibetan Plateau (TP) by comparing the model outputs with ground observations for the period 1961–2005. The twenty-first century trends of precipitation and temperature based on the GCMs’ projections over the TP are also analyzed. The results suggest that for temperature most GCMs reasonably capture the climatological patterns and spatial variations of the observed climate. However, the majority of the models have cold biases, with a mean underestimation of 1.1°–2.5°C for the months December–May, and less than 1°C for June–October. For precipitation, the simulations of all models overestimate the observations in climatological annual means by 62.0%–183.0%, and only half of the 24 GCMs are able to reproduce the observed seasonal pattern, which demonstrates a critical need to improve precipitation-related processes in these models. All models produce a warming trend in the twenty-first century under the Representative Concentration Pathway 8.5 (rcp8.5) scenario; in contrast, the rcp2.6 scenario predicts a lower average warming rate for the near term, and a small cooling trend in the long-term period with the decreasing radiative forcing. In the near term, the projected precipitation change is about 3.2% higher than the 1961–2005 annual mean, whereas in the long term the precipitation is projected to increase 6.0% under rcp2.6 and 12.0% under the rcp8.5 scenario. Relative to the 1961–2005 mean, the annual temperature is projected to increase by 1.2°–1.3°C in the short term; the warmings under the rcp2.6 and rcp8.5 scenarios are 1.8° and 4.1°C, respectively, for the long term.
Anticoagulant Use in Real Time
Authors: Srinivasan Divyamani , Watzak Bree 
Published: November 2012

Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE). Each year, VTE affects about 300 000 to 600 000 people in the United States, and death is the first manifestation in one-fourth of this population.1{Beckman, 2010 #79} Moreover, approximately 10% of the US population has genetic factors that increase their risk for developing thrombosis.1 In addition to inherited disorders, factors that contribute to VTE include prolonged immobilization, trauma, surgery, cancer, and critically ill patients.2 Routine assessment and prophylaxis are recommended in these groups to avoid DVT-related complications.2 Anticoagulants are the mainstay of drugs used in DVT/PE prevention and treatment. Despite the availability of evidence-based guidelines for anticoagulant therapy, there is suboptimal implementation of DVT prophylaxis in hospitalized patients.3 All anticoagulants are “high-alert” drugs, and judicious use is mandatory to prevent bleeding complications.4 This review discusses treatment guidelines, monitoring, side effects, and reversal agents available for some anticoagulant drugs approved for VTE. Dissemination of the knowledge via pharmacy education programs significantly improves the adherence to VTE prophylaxis.5 Understanding the clinical aspects of anticoagulant dispensing as presented in this review is hoped to facilitate implementation of the theoretical knowledge as well as evidence-based guidelines in order to maximize patient benefit.
Retrospective Analysis of Estimated Cost Avoidance Following Pharmacist-Provided Medication Therapy Management Services
Authors: Branham Ashley R. , Katz Aaron J. , Moose Joseph S. , Ferreri Stefanie P. , Farley Joel F. , Marciniak Macary W. 
Published: November 2012

Objective: To compare the estimated cost avoidance (ECA) of pharmacist-provided medication therapy management (MTM) services among common disease states encountered in community pharmacy practice. Design: Retrospective analysis. Setting: Nine community pharmacies in North Carolina. Patients: Three hundred and sixty-four patients who are 65 years of age or older, a Medicare Part D beneficiary and a North Carolina resident. Interventions: An MTM pharmacist-provider conducted medication reviews to eligible patients between July 2009 and October 2009. For each encounter, patient interventions, pharmacist recommendations, and ECA were recorded. Main outcome measure: ECA. Results: In 9 pharmacy locations, 634 MTM interventions were documented during the study period. The ECA in a 4-month period yielded approximately $494 000. Comprehensive medication reviews, new prescription counseling and appropriate medication administration, and technique counseling made up nearly two-thirds of interventions. Overall, the probability that an MTM intervention would result in an ECA greater than $0 was .35. Conclusions: Pharmacist-provided MTM effectively reduced costs associated with patient medication use. Such interventions reduced costs in overall health care specifically in the areas of cardiovascular, gastroesophageal reflux disease, pulmonary, and diabetes groups.
Model-based decision rules reduce the risk of molecular relapse after cessation of tyrosine kinase inhibitor therapy in chronic myeloid leukemia
Authors: Horn Matthias , Glauche Ingmar , Müller Martin C. , Hehlmann Rüdiger , Hochhaus Andreas , Loeffler Markus , Roeder Ingo 
Published: November 2012

Abstract
Molecular response to imatinib (IM) in chronic myeloid leukemia (CML) is associated with a biphasic but heterogeneous decline of BCR-ABL transcript levels. We analyzed this interindividual heterogeneity and provide a predictive mathematical model to prognosticate the long-term response and the individual risk of molecular relapse on treatment cessation. The parameters of the model were determined using 7-year follow-up data from a randomized clinical trial and validated by an independent dataset. Our model predicts that a subset of patients (14%) achieve complete leukemia eradication within less than 15 years and could therefore benefit from discontinuation of treatment. Furthermore, the model prognosticates that 31% of the patients will remain in deep molecular remission (MR5.0) after treatment cessation after a fixed period of 2 years in MR5.0, whereas 69% are expected to relapse. As a major result, we propose a predictor that allows to assess the patient-specific risk of molecular relapse on treatment discontinuation and to identify patients for whom cessation of therapy would be an appropriate option. Application of the suggested rule for deciding about the time point of treatment cessation is predicted to result in a significant reduction in rate of molecular relapse.
Investigations into genome diversity of Haemophilus influenzae using whole genome sequencing of clinical isolates and laboratory transformants
Authors: Power Peter M , Bentley Stephen D , Parkhill Julian , Moxon E Richard , Hood Derek W 
Published: November 2012

Abstract

Background

Haemophilus influenzae is an important human commensal pathogen associated with significant levels of disease. High-throughput DNA sequencing was used to investigate differences in genome content within this species.

Results
Genomic DNA sequence was obtained from 85 strains of H. influenzae and from other related species, selected based on geographical site of isolation, disease association and documented genotypic and phenotypic differences. When compared by Mauve alignment these indicated groupings of H. influenzae that were consistent with previously published analyses; c apsule expressing strains fell into two distinct groups and those of serotype b (Hib) were found in two closely positioned lineages. For 18 Hib strains representing both lineages we found many discrete regions (up to 40% of the total genome) displaying sequence variation when compared to a common reference strain. Evidence that this naturally occurring pattern of inter-strain variation in H. influenzae can be mediated by transformation was obtained through sequencing DNA obtained from a pool of 200 independent transformants of a recipient (strain Rd) using donor DNA from a heterologous Hib strain (Eagan).

Conclusion
Much of the inter-strain variation in genome sequence in H. influenzae is likely the result of inter-strain exchanges of DNA, most plausibly through transformation.
Complex sputum microbial composition in patients with pulmonary tuberculosis
Authors: Cui Zelin , Zhou Yuhua , Li Hong , Zhang Yan , Zhang Shulin , Tang Shenjie , Guo Xiaokui 
Published: November 2012

Abstract

Background
An increasing number of studies have implicated the microbiome in certain diseases, especially chronic diseases. In this study, the bacterial communities in the sputum of pulmonary tuberculosis patients were explored. Total DNA was extracted from sputum samples from 31 pulmonary tuberculosis patients and respiratory secretions of 24 healthy participants. The 16S rRNA V3 hyper-variable regions were amplified using bar-coded primers and pyro-sequenced using Roche 454 FLX.

Results
The results showed that the microbiota in the sputum of pulmonary tuberculosis patients were more diverse than those of healthy participants (p<0.05). The sequences were classified into 24 phyla, all of which were found in pulmonary tuberculosis patients and 17 of which were found in healthy participants. Furthermore, many foreign bacteria, such as Stenotrophomonas, Cupriavidus, Pseudomonas, Thermus, Sphingomonas, Methylobacterium, Diaphorobacter, Comamonas, and Mobilicoccus, were unique to pulmonary tuberculosis patients.

Conclusions
This study concluded that the microbial composition of the respiratory tract of pulmonary tuberculosis patients is more complicated than that of healthy participants, and many foreign bacteria were found in the sputum of pulmonary tuberculosis patients. The roles of these foreign bacteria in the onset or development of pulmonary tuberculosis shoud be considered by clinicians.
Wnt3a induces exosome secretion from primary cultured rat microglia
Authors: Hooper Claudie , Sainz-Fuertes Ricardo , Lynham Steven , Hye Abdul , Killick Richard , Warley Alice , Bolondi Cecilia , Pocock Jennifer , Lovestone Simon 
Published: November 2012

Abstract

Background
Microglia, the immune effector cells of the CNS and the signaling molecule Wnt, both play critical roles in neurodevelopment and neurological disease. Here we describe the inducible release of exosomes from primary cultured rat microglia following treatment with recombinant carrier-free Wnt3a.

Results
Wnt3a was internalised into microglia, being detectable in early endosomes, and secreted in exosomes through a GSK3-independent mechanism. Electron microscopy demonstrated that exosomes were elliptical, electron-dense (100 nm) vesicles that coalesced with time in vitro. In contrast to microglia, primary cortical neurons released exosomes constitutively and the quantity of exosomes released was not altered by Wnt3a treatment. The proteomic profile of the microglial-derived exosomes was characterised using liquid chromatography-tandem mass spectrometry (LC/MS/MS) and the vesicles were found to be associated with proteins involved in cellular architecture, metabolism, protein synthesis and protein degradation including β-actin, glyceraldehyde-3-phosphate dehydrogenase, ribosomal subunits and ubiquitin (45 proteins in total). Unlike lipopolysaccharide, Wnt3a did not induce a neurotoxic, pro-inflammatory phenotype in primary microglia.

Conclusion
These findings reveal a novel mechanism through which Wnt3a signals in microglia resulting in the release of exosomes loaded with proteinaceous cargo.