bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I clinical trial of the vaccination for the patients with metastatic melanoma using gp100-derived epitope peptide restricted to HLA-A*2402
Authors: Baba Toshiyuki , Sato-Matsushita Marimo , Kanamoto Akira , Itoh Akihiko , Oyaizu Naoki , Inoue Yusuke , Kawakami Yutaka , Tahara Hideaki 
Published: September 2010

AbstractBackgroundThe tumor associated antigen (TAA) gp100 was one of the first identified and has been used in clinical trials to treat melanoma patients. However, the gp100 epitope peptide restricted to HLA-A*2402 has not been extensively examined clinically due to the ethnic variations. Since it is the most common HLA Class I allele in the Japanese population, we performed a phase I clinical trial of cancer vaccination using the HLA-A*2402 gp100 peptide to treat patients with metastatic melanoma.MethodsThe phase I clinical protocol to test a HLA-A*2402 gp100 peptide-based cancer vaccine was designed to evaluate safety as the primary endpoint and was approved by The University of Tokyo Institutional Review Board. Information related to the immunologic and antitumor responses were also collected as secondary endpoints. Patients that were HLA-A*2402 positive with stage IV melanoma were enrolled according to the criteria set by the protocol and immunized with a vaccine consisting of epitope peptide (VYFFLPDHL, gp100-in4) emulsified with incomplete Freund's adjuvant (IFA) for the total of 4 times with two week intervals. Prior to each vaccination, peripheral blood mononuclear cells (PBMCs) were separated from the blood and stored at -80°C. The stored PBMCs were thawed and examined for the frequency of the peptide specific T lymphocytes by IFN-γ- ELISPOT and MHC-Dextramer assays.ResultsNo related adverse events greater than grade I were observed in the six patients enrolled in this study. No clinical responses were observed in the enrolled patients although vitiligo was observed after the vaccination in two patients. Promotion of peptide specific immune responses was observed in four patients with ELISPOT assay. Furthermore, a significant increase of CD8+gp100-in4+CTLs was observed in all patients using the MHC-Dextramer assay. Cytotoxic T lymphocytes (CTLs) clones specific to gp100-in4 were successfully established from the PBMC of some patients and these CTL clones were capable of lysing the melanoma cell line, 888 mel, which endogenously expresses HLA-restricted gp100-in4.ConclusionOur results suggest this HLA-restricted gp100-in4 peptide vaccination protocol was well-tolerated and can induce antigen-specific T-cell responses in multiple patients. Although no objective anti-tumor effects were observed, the effectiveness of this approach can be enhanced with the appropriate modifications.
A role for the histone deacetylase HDAC4 in the life-cycle of HIV-1-based vectors
Authors: Smith Johanna A , Yeung Jennifer , Kao Gary D , Daniel René 
Published: September 2010

AbstractHIV-1 integration is mediated by the HIV-1 integrase protein, which joins 3'-ends of viral DNA to host cell DNA. To complete the integration process, HIV-1 DNA has to be joined to host cell DNA also at the 5'-ends. This process is called post-integration repair (PIR). Integration and PIR involve a number of cellular co-factors. These proteins exhibit different degrees of involvement in integration and/or PIR. Some are required for efficient integration or PIR. On the other hand, some reduce the efficiency of integration. Finally, some are involved in integration site selection. We have studied the role of the histone deacetylase HDAC4 in these processes. HDAC4 was demonstrated to play a role in both cellular double-strand DNA break repair and transcriptional regulation. We observed that HDAC4 associates with viral DNA in an integrase-dependent manner. Moreover, infection with HIV-1-based vectors induces foci of the HDAC4 protein. The related histone deacetylases, HDAC2 and HDAC6, failed to associate with viral DNA after infection. These data suggest that HDAC4 accumulates at integration sites. Finally, overexpression studies with HDAC4 mutants suggest that HDAC4 may be required for efficient transduction by HIV-1-based vectors in cells that are deficient in other DNA repair proteins. We conclude that HDAC4 is likely involved in PIR.
Comparison of human papillomavirus detection between freshly frozen tissue and paraffin embedded tissue of invasive cervical cancer
Authors: Odida Michael , de Sanjose Silvia , Sandin Sven , Quiros Beatriz , Alemany Laia , Lloveras Belen , Quint Wim , Kleter Bernhard , Alejo Maria , van Doorn Leen-Jan , Weiderpass Elisabete 
Published: September 2010

Abstract

Background
Human Papillomavirus (HPV) detection results comparing paraffin embedded cervical tissue and other cervical specimens have been done with varying degrees of agreement. However, studies comparing freshly frozen specimens and paraffin embedded specimens of invasive cervical carcinomas are lacking. The aim of the study was to compare HPV detection using SPF10 broad-spectrum primers PCR followed by DEIA and genotyping by LiPA25 (version 1) between freshly frozen cervical tissue samples and paraffin embedded blocks of cervical tissue from the same patient. There were 171 pairs of paraffin embedded and freshly frozen samples analyzed from cervical carcinoma cases from Kampala, Uganda.

Results
88.9% (95% CI: 83.2%-93.2%) of paraffin embedded samples were HPV positive compared with 90.1% (95% CI: 84.6%-94.1%) of freshly frozen samples, giving an overall agreement in HPV detection between fresh tissue and paraffin embedded tissue at 86.0% (95% CI: 79.8%-90.8%). Although the proportion of HPV positive cases in freshly frozen tissue was higher than those in paraffin blocks, the difference was not statistically significant (p > 0.05). In both types of tissues, single HPV infections were predominant, with HPV16 accounting for 47% of positive cases. Comparison in the overall agreement, taking into accounts not only positivity in general, but also HPV types, showed a 65% agreement (complete agreement of 59.7%, partial agreement of 5.3%) and complete disagreement of 35.0%. HPV detection in squamous cell carcinomas (SCC) and adenocarcinomas (ADC) was similar in fresh tissue or paraffin blocks (p ≥ 0.05).
p16 immunostaining in samples that had at least one HPV negative results showed that 24 out of 25 cases had an over-expressed pattern.

Conclusions
HPV DNA detection was lower among ADC as compared to SCC. However, such differences were minimized when additional p16 testing was added, suggesting that the technical issues may largely explain the HPV negative cases.
A case-controlled validation study of a blood-based seven-gene biomarker panel for colorectal cancer in Malaysia
Authors: Yip Kok-Thye , Das Prashanta K , Suria David , Lim Chun-Ren , Ng Guey-Hooi , Liew Choong-Chin 
Published: September 2010

AbstractBackgroundColorectal cancer (CRC) screening is key to CRC prevention and mortality reduction, but patient compliance with CRC screening is low. We previously reported a blood-based test for CRC that utilizes a seven-gene panel of biomarkers. The test is currently utilized clinically in North America for CRC risk stratification in the average-risk North American population in order to improve screening compliance and to enhance clinical decision making.MethodsIn this study, conducted in Malaysia, we evaluated the seven-gene biomarker panel validated in a North American population using blood samples collected from local patients. The panel employs quantitative RT-PCR (qRT-PCR) to analyze gene expression of the seven biomarkers (ANXA3, CLEC4D, TNFAIP6, LMNB1, PRRG4, VNN1 and IL2RB) that are differentially expressed in CRC patients as compared with controls. Blood samples from 210 patients (99 CRC and 111 controls) were collected, and total blood RNA was isolated and subjected to quantitative RT-PCR and data analysis.ResultsThe logistic regression analysis of seven-gene panel has an area under the curve (AUC) of 0.76 (95% confidence interval: 0.70 to 0.82), 77% specificity, 61% sensitivity and 70% accuracy, comparable to the data obtained from the North American investigation of the same biomarker panel.ConclusionsOur results independently confirm the results of the study conducted in North America and demonstrate the ability of the seven biomarker panel to discriminate CRC from controls in blood samples drawn from a Malaysian population.
Effects of NOD-like receptors in human B lymphocytes and crosstalk between NOD1/NOD2 and Toll-like receptors
Authors: Petterson Terese , Jendholm Johan , Månsson Anne , Bjartell Anders , Riesbeck Kristian , Cardell Lars-Olaf 
Published: September 2010

ABSTRACTNLRs are recently discovered PRRs detecting substructures of peptidoglycans and triggering innate immunity. NLRs are expressed in several cell types, but the presence in human B lymphocytes is still unknown. This study aimed to investigate expression and function of NLRs in human B lymphocytes. B cells were isolated and analyzed for mRNA and protein expression. The functional responsiveness of NOD1 and NOD2 was investigated upon stimulation with the cognate ligands, with or without stimulation via IgM/IgD/CD40 and/or selected TLR agonists. A differential expression of NLRs was demonstrated in blood-derived and tonsillar B cells, whereas no variations were found among naive, germinal center, or memory B cells. Stimulation with the ligands alone did not induce B cell activation. However, upon concomitant BCR triggering, an increase in proliferation was seen, together with an induction of cell surface markers (CD27, CD69, CD71, CD80, CD86, and CD95) and prolonged survival. Peripheral B cells were activated by NOD1 and NOD2 ligands, whereas tonsil-derived B cells responded solely to NOD1. In contrast, costimulation with CD40L failed to induce activation. Additionally, it was found that NLR ligands could enhance TLR-induced proliferation of B cells. The present study demonstrates expression of functional NLRs in human B cells. We show that NOD1 and NOD2 have the ability to augment the BCR-induced activation independently of physical T cell help. Hence, NLRs represent a new pathway for B cell activation and a potentially important host defense system against bacterial infections.
Basal α-Cell Up-Regulation in Obese Insulin-Resistant Adolescents
Authors: Weiss Ram , D'Adamo Ebe , Santoro Nicola , Hershkop Karen , Caprio Sonia 
Published: September 2010

Context: The aim of this analysis was to evaluate glucagon and c-peptide concentrations in two scenarios: euglycemic hyperinsulinemia and hyperglycemic hyperinsulinemia. We postulated that worsening obesity and insulin resistance will be reflected as an up-regulated (less suppressible) islet secretion profile.
Methods: Eighty-two [34 obese with normal glucose tolerance (NGT), 30 obese with impaired glucose tolerance (IGT), and 18 nonobese with NGT] subjects underwent a euglycemic-hyperinsulinemic clamp (EHC) and a hyperglycemic clamp. C-peptide and glucagon were evaluated at basal and steady-state (SS) conditions.
Results: Basal glucagon was significantly elevated in obese insulin-resistant and obese IGT subjects as was basal c-peptide. SS glucagon and c-peptide levels during the EHC were lower in the lean and obese insulin-sensitive subjects compared with the obese insulin-resistant subjects with NGT or IGT. Fasting glucagon was the only significant determinant (β = 0.66, P &lt; 0.001) of SS glucagon during the EHC (R2 = 0.57). In a longitudinal follow-up of a subsample, those who converted from normal to IGT significantly increased their fasting glucagon concentration in comparison with those who remained with NGT.
Conclusions: Islet up-regulation manifesting as basal elevated glucagon and c-peptide secretion that determines the suppressive effects of hyperinsulinemia appears early in the course of deteriorating glucose tolerance.
Nickel/Lewis Acid-Catalyzed Aryl- and Alkenylcyanation of Unsaturated Bonds
Authors: Yada Akira , Ebata Shiro , Idei Hiroaki , Zhang Di , Nakao Yoshiaki , Hiyama Tamejiro 
Published: September 2010

Abstract
Lewis acid cocatalysts such as organoaluminum and -boron compounds dramatically improve the efficiency of the nickel-catalyzed arylcyanation of alkynes. Electron-rich aryl cyanides, which exhibit poor reactivity in the absence of Lewis acids, smoothly undergo the arylcyanation reaction under the nickel/Lewis acid dual catalysis. Excellent chemoselectivity is observed for aryl cyanides having a chloro or bromo group, which allows a single-step access to a synthetic intermediate of P-3622, a squalene synthetase inhibitor. The scope of the arylcyanation is also expanded to norbornadiene. Alkenylcyanation of alkynes is achieved under the nickel/Lewis acid dual catalysis to give cyano-substituted 1,3-dienes stereoselectively.
Electrochemical Immunosensor for Simultaneous Detection of Dual Cardiac Markers Based on a Poly(Dimethylsiloxane)-Gold Nanoparticles Composite Microfluidic Chip: A Proof of Principle
Authors: Zhou Fang , Lu Min , Wang Wei , Bian Zhi-Ping , Zhang Jian-Rong , Zhu Jun-Jie 
Published: September 2010

BACKGROUND
The emergence of microfluidic immunosensors has provided a promising tool for improving clinical diagnoses. We developed an electrochemical immunoassay for the simultaneous detection of cardiac troponin I (cTnI) and C-reactive protein (CRP), based on microfluidic chips.

METHODS
The quantitative methodology was based on ELISA in poly(dimethylsiloxane)-gold nanoparticle composite microreactors. CdTe and ZnSe quantum dots were bioconjugated with antibodies for sandwich immunoassay. After the CdTe and ZnSe quantum dots were dissolved, Cd2+ and Zn2+ were detected by square-wave anodic stripping voltammetry to enable the quantification of the 2 biomarkers. The 2 biomarkers were measured in 20 human serum samples by using the proposed method and commercially available methods.

RESULTS
This immunosensor allowed simultaneous detection of serum cTnI and CRP. The linear range of this assay was between 0.01 and 50 μg/L and 0.5 and 200 μg/L, with the detection limits of approximately 5 amol and approximately 307 amol in 30-μL samples corresponding to cTnI and CRP, respectively. Slopes close to 1 and the correlation coefficient over 0.99 were obtained for both analytes.

CONCLUSIONS
This strategy demonstrates a proof of principle for the successful integration of microfluidics with electrochemistry that can potentially provide an alternative to protein detection in the clinical laboratory.
Diagnostic Accuracy and User-Friendliness of 5 Point-of-Care D-Dimer Tests for the Exclusion of Deep Vein Thrombosis
Authors: Geersing Geert-Jan , Toll Diane B , Janssen Kristel JM , Oudega Ruud , Blikman Marloes JC , Wijland René , de Vooght Karen MK , Hoes Arno W , Moons Karel GM 
Published: September 2010

BACKGROUNDPoint-of-care D-dimer tests have recently been introduced to enable rapid exclusion of deep venous thrombosis (DVT) without the need to refer a patient for conventional laboratory-based D-dimer testing. Before implementation in practice, however, the diagnostic accuracy of each test should be validated.METHODSWe analyzed data of 577 prospectively identified consecutive primary care patients suspected to have DVT, who underwent 5 point-of-care D-dimer tests—4 quantitative (Vidas®, Pathfast™, Cardiac®, and Triage®) and 1 qualitative (Clearview Simplify®)—and ultrasonography as the reference method. We evaluated the tests for the accuracy of their measurements and submitted a questionnaire to 20 users to assess the user-friendliness of each test.RESULTSAll D-dimer tests showed negative predictive values higher than 98%. Sensitivity was high for all point-of-care tests, with a range of 0.91 (Clearview Simplify) to 0.99 (Vidas). Specificity varied between 0.39 (Pathfast) and 0.64 (Clearview Simplify). The quantitative point-of-care tests showed similar and high discriminative power for DVT, according to calculated areas under the ROC curves (range 0.88–0.89). The quantitative Vidas and Pathfast devices showed limited user-friendliness for primary care, owing to a laborious calibration process and long analyzer warm-up time compared to the Cardiac and Triage. For the qualitative Clearview Simplify assay, no analyzer or calibration was needed, but interpretation of a test result was sometimes difficult because of poor color contrast.CONCLUSIONSPoint-of-care D-dimer assays show good and similar diagnostic accuracy. The quantitative Cardiac and Triage and the qualitative Clearview Simplify D-dimer seem most user-friendly for excluding DVT in the doctor's office.
A Dual-Monoclonal Sandwich ELISA Specific for Hepcidin-25
Authors: Butterfield Anthony M , Luan Peng , Witcher Derrick R , Manetta Joseph , Murphy Anthony T , Wroblewski Victor J , Konrad Robert J 
Published: September 2010

BACKGROUND
Hepcidin, a key regulator of iron metabolism, binds to the iron transporter ferroportin to cause its degradation. In humans, hepcidin deficiency has been linked to hemochromatosis and iron overload, whereas increased concentrations have been reported in anemia of cancer and chronic disease. There is currently an unmet clinical need for a specific immunoassay with a low limit of quantification to measure serum concentrations of hepcidin-25, the active form of the protein.

METHODS
We generated 2 antihepcidin-25 monoclonal antibodies and used them to build a sandwich ELISA. We correlated ELISA results to hepcidin-25 measurements by LC-MS and used ELISA to measure serum hepcidin-25 concentrations in normal individuals, cancer patients, and patients with rheumatoid arthritis.

RESULTS
The sandwich ELISA was highly specific for hepcidin-25, having a limit of quantification of 0.01 μg/L (10 pg/mL). Serum concentrations of hepcidin-25 measured by ELISA correlated with hepcidin-25 concentrations measured by using an independent LC-MS assay (r = 0.98, P &lt; 0.001). Hepcidin-25 concentrations were increased in patients with cancer (median 54.8 μg/L, 25%–75% range 23.2–93.5 μg/L, n = 34) and rheumatoid arthritis (median 10.6 μg/L, 25%–75% range 5.9–18.4 μg/L, n = 76) compared with healthy individuals (median 1.20 μg/L, 25%–75% range 0.42–3.07 μg/L, n = 100).

CONCLUSIONS
The use of 2 monoclonal antibodies in a sandwich ELISA format provides a robust and convenient method for measuring concentrations of the active form of hepcidin. This ELISA should help to improve our understanding of the role of hepcidin in regulating iron metabolism.
Jakob Schlaepfer: A case study in laser innovation and the unexpected
Authors: Huddleston Rob , Whittaker Paul 
Published: September 2010

This report aims to counter some assumptions about the nature of industrial technology by exploring the creative potential of the distancing effect inherent in laser materials processing.
A case study of an industrially based project involving the textile company Jakob Schlaepfer,
based in St Gallen, Switzerland, will provide the research material and underpin the report. The case study presents the development and expansion, by Schlaepfer, of self-customized laser technologies and how different laser processes have come to form an integral part of the design and production
innovation process. Through this historical picture of Schlaepfer's commitment to new technologies and investments that encourage innovation, we aim to offer two propositions that are facilitated by the distance inherent in the creative use of lasers. Firstly, that it is possible to utilize
technologies normally linked with impersonalized standardization in production, to instead create experimental products; and secondly, that technologies normally used to replicate the unexpected and unique capacities of traditional making, can be in-themselves capable of un-programmed unpredictability.
RIA Failure of High Burnup Fuel Rod Irradiated in the Leibstadt Reactor: Out-of-Pile Mechanical Simulation and Comparison with Pulse Reactor Tests
Authors: Grigoriev V. , Jakobsson R. , Schrire D. , Ledergerber G. , Sugiyama T. , Nagase F. , Fuketa T. , Hallstadius L. , Valizadeh S. 
Published: September 2010

Abstract
A high burnup boiling water reactor fuel rod was subjected to reactivity initiation accident (RIA) tests in a research reactor. Two ramp tests were carried out under almost identical irradiation conditions, resulting in cladding failure in a room temperature test, while no failure was observed in a high temperature test. An adjacent segment of the same rod was used for mechanical expansion-due-to-compression (EDC) testing simulating the pellet-cladding mechanical interaction loadings on the cladding during an in-reactor RIA. The EDC tests show the existence of a transition temperature where an abrupt increase in the specimen hoop strain at failure occurs. Additional tests revealed that the transition temperature depends on hydrogen concentration. A possible effect of the rapid heating, which is a specific condition for an in-reactor RIA compared to the static heating in the EDC tests, was verified in the rapid heating/loading tests on unirradiated hydrided Zircaloy, when both loading and heating are performed simultaneously within 50–80 ms. It was shown that strain to failure is dependent on the instantaneous material temperature and is not affected by the pre-heating history. The results show good consistency between the EDC and in-reactor pulse test data. It is concluded that the EDC test can provide valuable information to predict the in-reactor RIA fuel failure.
Texture Evolution of Zircaloy-2 During Beta-Quenching: Effect of Process Variables
Authors: Romero Javier , Preuss Michael , Quinta da Fonseca João , Comstock Robert J. , Dahlbäck Mats , Hallstadius Lars 
Published: September 2010

Abstract
The nuclear industry is interested in developing thermomechanical processes to produce random crystallographic orientation (texture) from cold-rolled Zircaloy-2 sheets used to manufacture boiling water reactor (BWR) channels. Randomized textures are beneficial because they minimize anisotropic irradiation-assisted growth, which in turn reduces bowing and uncontrolled deformation of BWR channels during service. The texture evolution of cold-rolled Zircaloy-2 sheets during the allotropic α→β→α phase transformation was characterized by using synchrotron X-ray diffraction in situ and electron backscatter diffraction. The initial strong rolling texture is weakened only if the α→β→α phase transformation is complete. Plastic deformation and grain growth in the β-phase lead to changes in the β texture and modify the inherited α texture. The global texture evolution is not sensitive to levels of stress that do not cause β plastic deformation. These findings demonstrate that accurate temperature control of the β-quenching process is of utmost importance in order to minimize undesirable irradiation growth of BWR channels during service, and that plastic deformation in the β phase can be employed to modify the inherited α texture. BWR channels with β-quenched textures will exhibit minimum irradiation growth caused by texture.