bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics, Metabolism, and Excretion of the Antiviral Drug Arbidol in Humans
Authors: Deng Pan , Zhong Dafang , Yu Kate , Zhang Yifan , Wang Ting , Chen Xiaoyan 
Published: January 2013

ABSTRACT

Arbidol is a broad-spectrum antiviral drug that is used clinically to treat influenza. In this study, the pharmacokinetics, metabolism, and excretion of arbidol were investigated in healthy male Chinese volunteers after a single oral administration of 200 mg of arbidol hydrochloride. A total of 33 arbidol metabolites were identified in human plasma, urine, and feces. The principal biotransformation pathways included sulfoxidation, dimethylamine
N
-demethylation, glucuronidation, and sulfate conjugation. The major drug-related component in the plasma was sulfinylarbidol (M6-1), followed by unmetabolized arbidol,
N
-demethylsulfinylarbidol (M5), and sulfonylarbidol (M8). The exposures of M5, M6-1, and M8, as determined by the metabolite-to-parent area under the plasma concentration-time curve from 0 to
t
(AUC

0-
t

) ratio, were 0.9 ± 0.3, 11.5 ± 3.6, and 0.5 ± 0.2, respectively. In human urine, glucuronide and sulfate conjugates were detected as the major metabolites, accounting for 6.3% of the dose excreted within 0 to 96 h after drug administration. The fecal specimens mainly contained the unchanged arbidol, accounting for 32.4% of the dose. Microsomal incubation experiments demonstrated that the liver and intestines were the major organs that metabolize arbidol in humans. CYP3A4 was the major isoform involved in arbidol metabolism, whereas the other P450s and flavin-containing monooxygenases (FMOs) played minor roles. These results indicated possible drug interactions between arbidol and CYP3A4 inhibitors and inducers. Further investigations are needed to understand the importance of M6-1 in the efficacy and safety of arbidol, because of its high plasma exposure and long elimination half-life (25.0 h).
Evaluation of the Effect of a Supratherapeutic Dose of Intravenous Ceftaroline Fosamil on the Corrected QT Interval
Authors: Riccobene Todd A. , Rekeda Ludmyla , Rank Douglas , Llorens Lily 
Published: January 2013

ABSTRACT
A randomized, double-blind, placebo-controlled, 3-period crossover study was conducted in 54 healthy adults to assess the effect of ceftaroline fosamil on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using an individual correction formula (QTcIb), was determined predose and at 1, 1.25, 1.5, 2, 4, 8, 12, and 24.5 h after intravenous dosing with a supratherapeutic dose (1,500 mg) of ceftaroline fosamil, 400 mg moxifloxacin (positive control), and placebo. The pharmacokinetic profile of ceftaroline was also evaluated. At each time point following ceftaroline fosamil administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from predose baseline in QTcIb (ΔΔQTcIb) was below 10 ms (maximum, 3.4 ms at 1.5 h after dosing), indicating an absence of clinically meaningful QTc increase. The lower limit of the 90% CI of ΔΔQTcIb for moxifloxacin versus placebo was greater than 5 ms at 5 time points (maximum, 12.8 ms at 1 h after dosing), demonstrating assay sensitivity. There was no apparent correlation between ceftaroline plasma concentrations and ΔΔQTcIb. The supratherapeutic dose of ceftaroline fosamil (1,500 mg) resulted in substantially greater systemic exposure to ceftaroline than previously observed with standard therapeutic doses. Ceftaroline fosamil was well tolerated after a single 1,500-mg intravenous dose, and no clinically meaningful abnormalities in laboratory values or vital signs were observed.
EGFR status in oral squamous cell carcinoma: comparing immunohistochemistry, FISH and CISH detection in a case series study
Authors: Bernardes Vanessa Fátima , Gleber-Netto Frederico Omar , Sousa Sílvia Ferreira de , Rocha Rafael Malagoli , Aguiar Maria Cássia Ferreira de 
Published: January 2013

ObjectivesTo compare the immunohistochemistry (IHC) expression of epidermal growth factor receptor (EGFR) in oral squamous cell carcinomas (OSCC) with the gene amplification evaluated by fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization (CISH) and their association with clinicopathological parameters. Additionally, we tested the sensibility and specificity of CISH in comparison with FISH.DesignCase series studySettingOral surgery and pathology department in a school of dentistry.Participants52 patients with histopathological diagnosis of OSCC.MethodsTumour tissue samples from 52 patients with OSCC were evaluated by IHC, FISH and CISH using tissue microarray technology. Clinicopathological data from all patients were collected.ResultsEGFR+ rates were 53.8% (28/52) by IHC, 5.8% (3/52) by CISH and 15.4% (8/52) by FISH. Amplification detected by CISH and FISH with IHC negative occurred in 3.8% (2/52), and one case (1.9%) showed amplification detected by CISH and FISH and protein overexpression concomitantly. There were 9.6% FISH+ cases with IHC and CISH negative rates and 6/8 (75%) FISH+ and also EGFR+ cases; however, an association between protein expression and gene amplification was not found for both techniques. IHC and FISH rates were not associated with clinicopathological features. CISH+ rates were associated with T3–T4 status. Compared with FISH assay, CISH reached a sensitivity of 37.5% and specificity of 100%.ConclusionsThere is no association between EGFR expression and gene amplification in OSCC when the IHC is driven to external epitopes of the protein. Although CISH demonstrates specificity, technical problems may influence sensibility when compared with FISH.
Dynamic process model for identifying modified data using mobile agents in real time ETL processes
Authors: Mrunalini M. , Kumar T. V. Suresh , Kanth K. Rajani 
Published: January 2013

Usability and accessibility issues are common causes why software fails to meet user requirements. However, requirements engineers still focus on functional requirements and might ignore to also elicit system usability and accessibility requirements. This is a high risk which can lead to project and software failure. Improving the usability and accessibility of a system in a later development stage is costly and time consuming. Targeting these concerns, the workshop envisioned that research must address the proper integration of system usability and accessibility requirements into the requirements engineering process and also must focus on how to manage and control the evaluation of these requirements in a systematic way.
UsARE 2012 provided a platform for discussing issues which are relevant for both fields, the Requirements Engineering (RE) and the Human Computer Interaction (HCI). The workshop aim was to bring\ together people from these two communities (RE and HCI) to explore this integration. Researchers and practitioners were invited to submit contributions including problem statements, technical solutions, experience reports, planned work and vision papers. Envisioned results may help aligning RE and HCI processes in order to overcome open issues in these fields.
ST6Gal-I Protein Expression Is Upregulated in Human Epithelial Tumors and Correlates with Stem Cell Markers in Normal Tissues and Colon Cancer Cell Lines
Authors: Swindall Amanda F. , Londoño-Joshi Angelina I. , Schultz Matthew J. , Fineberg Naomi , Buchsbaum Donald J. , Bellis Susan L. 
Published: January 2013

Abstract
The ST6Gal-I sialyltransferase adds an α2-6–linked sialic acid to the N-glycans of certain receptors. ST6Gal-I mRNA has been reported to be upregulated in human cancer, but a prior lack of antibodies has limited immunochemical analysis of the ST6Gal-I protein. Here, we show upregulated ST6Gal-I protein in several epithelial cancers, including many colon carcinomas. In normal colon, ST6Gal-I localized selectively to the base of crypts, where stem/progenitor cells are found, and the tissue staining patterns were similar to the established stem cell marker ALDH1. Similarly, ST6Gal-I expression was restricted to basal epidermal layers in skin, another stem/progenitor cell compartment. ST6Gal-I was highly expressed in induced pluripotent stem (iPS) cells, with no detectable expression in the fibroblasts from which iPS cells were derived. On the basis of these observations, we investigated further an association of ST6Gal-I with cancer stem cells (CSC). Selection of irinotecan resistance in colon carcinoma cells led to a greater proportion of CSCs compared with parental cells, as measured by the CSC markers CD133 and ALDH1 activity (Aldefluor). These chemoresistant cells exhibited a corresponding upregulation of ST6Gal-I expression. Conversely, short hairpin RNA (shRNA)-mediated attenuation of ST6Gal-I in colon carcinoma cells with elevated endogenous expression decreased the number of CD133/ALDH1-positive cells present in the cell population. Collectively, our results suggest that ST6Gal-I promotes tumorigenesis and may serve as a regulator of the stem cell phenotype in both normal and cancer cell populations. Cancer Res; 73(7); 2368–78. ©2012 AACR.
Inhibition of Protein Kinase CK2 Reduces Cyp24a1 Expression and Enhances 1,25-Dihydroxyvitamin D3 Antitumor Activity in Human Prostate Cancer Cells
Authors: Luo Wei , Yu Wei-Dong , Ma Yingyu , Chernov Mikhail , Trump Donald L. , Johnson Candace S. 
Published: January 2013

Abstract
Vitamin D has broad range of physiological functions and antitumor effects. 24-Hydroxylase, encoded by the CYP24A1 gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D3. Inhibition of CYP24A1 enhances 1,25D3 antitumor activity. To isolate regulators of CYP24A1 expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with CYP24A1 promoter driving luciferase expression to screen a small molecular library for compounds that inhibit CYP24A1 promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz inhibits CYP24A1 promoter activity induced by 1,25D3 in prostate cancer cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz-treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D3-induced CYP24A1 mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D3-mediated target gene expression. Finally, inhibition of CK2 by TBBz or CK2 siRNA significantly enhances 1,25D3-mediated antiproliferative effect in vitro and in vivo in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25D3 and CK2 inhibitor enhances 1,25D3-mediated antitumor effect. Cancer Res; 73(7); 2289–97. ©2013 AACR.
A 12-Gene Set Predicts Survival Benefits from Adjuvant Chemotherapy in Non–Small Cell Lung Cancer Patients
Authors: Tang Hao , Xiao Guanghua , Behrens Carmen , Schiller Joan , Allen Jeffrey , Chow Chi-Wan , Suraokar Milind , Corvalan Alejandro , Mao Jianhua , White Michael A. , Wistuba Ignacio I. , Minna John D. , Xie Yang 
Published: January 2013

Abstract
Purpose: Prospectively identifying who will benefit from adjuvant chemotherapy (ACT) would improve clinical decisions for non–small cell lung cancer (NSCLC) patients. In this study, we aim to develop and validate a functional gene set that predicts the clinical benefits of ACT in NSCLC.
Experimental Design: An 18-hub-gene prognosis signature was developed through a systems biology approach, and its prognostic value was evaluated in six independent cohorts. The 18-hub-gene set was then integrated with genome-wide functional (RNAi) data and genetic aberration data to derive a 12-gene predictive signature for ACT benefits in NSCLC.
Results: Using a cohort of 442 stage I to III NSCLC patients who underwent surgical resection, we identified an 18-hub-gene set that robustly predicted the prognosis of patients with adenocarcinoma in all validation datasets across four microarray platforms. The hub genes, identified through a purely data-driven approach, have significant biological implications in tumor pathogenesis, including NKX2-1, Aurora Kinase A, PRC1, CDKN3, MBIP, and RRM2. The 12-gene predictive signature was successfully validated in two independent datasets (n = 90 and 176). The predicted benefit group showed significant improvement in survival after ACT (UT Lung SPORE data: HR = 0.34, P = 0.017; JBR.10 clinical trial data: HR = 0.36, P = 0.038), whereas the predicted nonbenefit group showed no survival benefit for 2 datasets (HR = 0.80, P = 0.70; HR = 0.91, P = 0.82).
Conclusions: This is the first study to integrate genetic aberration, genome-wide RNAi data, and mRNA expression data to identify a functional gene set that predicts which resectable patients with non–small cell lung cancer will have a survival benefit with ACT. Clin Cancer Res; 19(6); 1577–86. ©2013 AACR.
HER2-Targeted Hybrid Peptide That Blocks HER2 Tyrosine Kinase Disintegrates Cancer Cell Membrane and Inhibits Tumor GrowthIn Vivo
Authors: Kawamoto Megumi , Horibe Tomohisa , Kohno Masayuki , Kawakami Koji 
Published: January 2013

AbstractHER2 is a transmembrane oncoprotein encoded by the HER2/neu gene and is overexpressed in approximately 20% to 30% of breast cancers. We have recently designed a novel class of drug, the hybrid peptide, which is chemically synthesized and is composed of a target-binding peptide and a lytic peptide containing cationic-rich amino acid components that disintegrate the cell membrane, leading to cancer cell death via membrane lysis. In this study, we designed a HER2-binding peptide linked to this novel lytic peptide, which we termed the HER2-lytic hybrid peptide and assessed the cytotoxic activity of this hybrid peptide in vitro and in vivo. The HER2-lytic hybrid peptide showed high cytotoxic activity against all ovarian and breast cancer cell lines, even trastuzumab- and/or lapatinib-resistant cells, but not against normal cells. Competition assays using anti-HER2 antibody and knockdown of this receptor by siRNA confirmed the specificity of the HER2-lytic hybrid peptide. In addition, it was shown that the HER2-lytic hybrid peptide can disintegrate the cancer cell membrane of HER2-overexpressing SK-BR-3 cancer cells in only 5 minutes, but not normal cells, and block HER2 signaling. Intravenous administration of the HER2-lytic peptide in the athymic mouse implanted with BT-474 and MDA-MB-453 cells significantly inhibited tumor progression. The HER2-lytic hybrid peptide was effective even in breast cancer cell lines that are resistant to trastuzumab and/or lapatinib in vitro and in vivo. Therefore, this hybrid peptide may provide a potent treatment option for patients with cancer. Mol Cancer Ther; 12(4); 384–93. ©2013 AACR.
Vascular Endothelial Growth Factor-Angiopoietin Chimera With Improved Properties for Therapeutic Angiogenesis
Authors: Anisimov Andrey , Tvorogov Denis , Alitalo Annamari , Leppänen Veli-Matti , An Yuri , Han Eun Chun , Orsenigo Fabrizio , Gaál Emília Ilona , Holopainen Tanja , Koh Young Jun , Tammela Tuomas , Korpisalo Petra , Keskitalo Salla , Jeltsch Michael , Ylä-Herttuala Seppo , Dejana Elisabetta , Koh Gou Young , Choi Chulhee , Saharinen Pipsa , Alitalo Kari 
Published: January 2013

Background—
There is an unmet need for proangiogenic therapeutic molecules for the treatment of tissue ischemia in cardiovascular diseases. However, major inducers of angiogenesis such as vascular endothelial growth factor (VEGF/VEGF-A) have side effects that limit their therapeutic utility in vivo, especially at high concentrations. Angiopoietin-1 has been considered to be a blood vessel stabilization factor that can inhibit the intrinsic property of VEGF to promote vessel leakiness. In this study, we have designed and tested the angiogenic properties of chimeric molecules consisting of receptor-binding parts of VEGF and angiopoietin-1. We aimed at combining the activities of both factors into 1 molecule for easy delivery and expression in target tissues.

Methods and Results—
The VEGF–angiopoietin-1 (VA1) chimeric protein bound to both VEGF receptor-2 and Tie2 and induced the activation of both receptors. Detailed analysis of VA1 versus VEGF revealed differences in the kinetics of VEGF receptor-2 activation and endocytosis, downstream kinase activation, and VE-cadherin internalization. The delivery of a VA1 transgene into mouse skeletal muscle led to increased blood flow and enhanced angiogenesis. VA1 was also very efficient in rescuing ischemic limb perfusion. However, VA1 induced less plasma protein leakage and myeloid inflammatory cell recruitment than VEGF. Furthermore, angioma-like structures associated with VEGF expression were not observed with VA1.

Conclusions—
The VEGF–angiopoietin-1 chimera is a potent angiogenic factor that triggers a novel mode of VEGF receptor-2 activation, promoting less vessel leakiness, less tissue inflammation, and better perfusion in ischemic muscle than VEGF. These properties of VA1 make it an attractive therapeutic tool.
Digital imaging of micro bivalves
Authors: TURNER JAMES A. 
Published: January 2013

Advancements in digital camera technology, microscope optics and image capture software have allowed researchers to create more detailed and higher quality images than ever before. Digital imaging using light microscopy at high magnifi - cations does, however, have its limitations. Features that may be diagnostic for species identifi cation can often be diffi cult to illustrate using standard imaging techniques alone, and other methods, such as Scanning Electron Microscopy (SEM) and traditional line illustration, may be better suited to the task. The best results are often achieved by using a combination of these methods to create visual taxonomic guides to bivalve species. Drawing from the experiences gained whilst undertaking digital imaging projects, this paper covers current working practices in place at Amgueddfa Cymru - National Museum Wales, providing details of the equipment and techniques in use. Specimen preparation, lighting methods, digital image post-processing and image fi le management are discussed. These topics will detail the methods used for capturing aspects of bivalve morphology of both the shell and the anatomy of specimens 5 mm in size or less in order to produce publication quality images for taxonomic research.
Aerosol Effects on Simulated Storm Electrification and Precipitation in a Two-Moment Bulk Microphysics Model
Authors: Mansell Edward R. , Ziegler Conrad L. 
Published: January 2013

Abstract
The effects of cloud condensation nuclei (CCN) concentrations are found to strongly affect the microphysical and electrical evolution of a numerically simulated small multicell storm. The simulations reproduce the well-known effects of updraft invigoration and delay of precipitation formation as increasing CCN from low to intermediate concentrations causes droplet sizes to decrease. Peak updrafts increased from 16 m s−1 at the lowest CCN to a maximum of 21–22 m s−1 at moderate CCN, where condensation latent heating is maximized. The transition from low to high CCN first maximizes warm-rain production before switching over to the ice process as the dominant precipitation mechanism. Average graupel density stays fairly high and constant at lower CCN, but then drops monotonically at higher CCN concentration, although high CCN also foster the appearance of small regions of larger, high-density graupel with high simulated radar reflectivity.
Graupel production increases monotonically as CCN concentration rises from 50 to about 2000 cm−3. The lightning response is relatively weak until the Hallett–Mossop rime-splintering ice multiplication becomes more active at CCN &gt; 700 cm−3. At very high CCN concentrations (&gt;2000 cm−3), graupel production decreases slowly, but lightning activity drops dramatically when the parameterization of Hallett–Mossop rime-splintering ice multiplication is based on the number of large cloud droplets collected by graupel. Conversely, lightning activity remains steady at extremely high CCN concentration when the Hallett–Mossop parameterization is based simply on the rate of rime mass accumulation. The results lend support to the aerosol hypothesis as applied to lightning production, whereby greater CCN concentration tends to lead to greater lightning activity, but with a large sensitivity to ice multiplication.
Reply to “Comments on ‘Erroneous Model Field Representations in Multiple Pseudoproxy Studies: Corrections and Implications’”*
Authors: Smerdon Jason E. , Kaplan Alexey , Amrhein Daniel E. 
Published: January 2013

Abstract
The commenters confirm the errors identified and discussed in Smerdon et al., which either invalidated or required the reinterpretation of quantitative results from pseudoproxy experiments presented or used in several earlier papers. These errors have a strong influence on the spatial skill assessments of climate field reconstructions (CFRs), despite their small impacts on skill statistics averaged over the Northern Hemisphere. On the basis of spatial performance and contrary to the claim by the commenters, the Regularized Expectation Maximization method using truncated total least squares (RegEM-TTLS) cannot be considered a preferred CFR technique. Moreover, distinctions between CFR methods in the context of the discussion in the original paper are immaterial. Continued investigations using accurately described and faithfully executed pseudoproxy experiments are critical for further evaluation and improvement of CFR methods.
Simulating SST Teleconnections to Africa: What is the State of the Art?
Authors: Rowell David P. 
Published: January 2013

Abstract
This study provides an overview of the state of the art of modeling SST teleconnections to Africa and begins to investigate the sources of error. Data are obtained from the Coupled Model Intercomparison Project (CMIP) archives, phases 3 and 5 (CMIP3 and CMIP5), using the “20C3M” and “historical” coupled model experiments. A systematic approach is adopted, with the scope narrowed to six large-scale regions of sub-Saharan Africa within which seasonal rainfall anomalies are reasonably coherent, along with six SST modes known to affect these regions. No significant nonstationarity of the strength of these 6 × 6 teleconnections is found in observations. The capability of models to represent each teleconnection is then assessed (whereby half the teleconnections have observed SST–rainfall correlations that differ significantly from zero). A few of these teleconnections are found to be relatively easy to model, while a few more pose substantial challenges to models and many others exhibit a wide variety of model skill. Furthermore, some models perform consistently better than others, with the best able to at least adequately simulate 80%–85% of the 36 teleconnections. No improvement is found between CMIP3 and CMIP5. Analysis of atmosphere-only simulations suggests that the coupled model teleconnection errors may arise primarily from errors in their SST climatology and variability, although errors in the atmospheric component of teleconnections also play a role. Last, no straightforward relationship is found between the quality of a model's teleconnection to Africa and its SST or rainfall biases or its resolution. Perhaps not surprisingly, the causes of these errors are complex, and will require considerable further investigation.