bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between β-Lactamase-Encoding
bla
OXA-51
Variants and DiversiLab Rep-PCR-Based Typing of Acinetobacter baumannii Isolates
Authors: Zander Esther , Nemec Alexandr , Seifert Harald , Higgins Paul G. 
Published: March 2012

ABSTRACT

This study investigated the correlation between
bla
OXA-51
variants and
Acinetobacter baumannii
worldwide clonal lineages 1 to 8 (WW1 to -8). The
bla
OXA-51-like
genes of 102
A. baumannii
isolates were sequenced. Using DiversiLab repetitive-sequence-based PCR (rep-PCR) typing, 92 of these isolates had previously been assigned to WW1 to -8 and 10 were unclustered. Clustering of DNA sequences was performed using the neighbor-joining method and the Jukes-Cantor phylogenetic correction.
bla
OXA-51
variants were in good correlation with DiversiLab-defined clonal lineages. Sequence-based typing of
bla
OXA-51
variants has the potential to be applied for epidemiologic characterization of
A. baumannii
and to identify worldwide clonal lineages 1 to 8.
Standardized One-Step Real-Time Reverse Transcription-PCR Assay for Universal Detection and Quantification of Hepatitis Delta Virus from Clinical Samples in the Presence of a Heterologous Internal-Control RNA
Authors: Scholtes Caroline , Icard Vinca , Amiri Majid , Chevallier-Queyron Philippe , Trabaud Mary-Anne , Ramière Christophe , Zoulim Fabien , André Patrice , Dény Paul 
Published: March 2012

ABSTRACT

As for other chronic viral diseases, quantification of hepatitis delta virus (HDV) loads may be useful for patient management. We describe a one-step quantitative reverse transcription-PCR assay that is reliable and automatable and meets the regulatory authorities' standards for accurate quantification of the major HDV genotypes. It includes an internal control and uses
in vitro
-transcribed RNAs as standards. Its linearity range is 500 to 1.7 × 10
11
copies/ml, its sensitivity is around 150 copies/ml, its repeatability is around 15%, and its reproducibility is below 0.25 log
10
copies/ml.
Modified Vaccinia Virus Ankara-Based Vaccine Vectors Induce Apoptosis in Dendritic Cells Draining from the Skin via both the Extrinsic and Intrinsic Caspase Pathways, Preventing Efficient Antigen Presentation
Authors: Guzman E. , Cubillos-Zapata C. , Cottingham M. G. , Gilbert S. C. , Prentice H. , Charleston B. , Hope J. C. 
Published: March 2012

ABSTRACTDendritic cells (DC) are potent antigen-presenting cells and central to the induction of immune responses following infection or vaccination. The collection of DC migrating from peripheral tissues by cannulation of the afferent lymphatic vessels provides DC which can be used directlyex vivowithout extensivein vitromanipulations. We have previously used bovine migrating DC to show that recombinant human adenovirus 5 vectors efficiently transduce afferent lymph migrating DEC-205+CD11c+CD8−DC (ALDC). We have also shown that recombinant modified vaccinia virus Ankara (MVA) infects ALDCin vitro, causing downregulation of costimulatory molecules, apoptosis, and cell death. We now show that in the bovine system, modified vaccinia virus Ankara-induced apoptosis in DC draining from the skin occurs soon after virus binding via the caspase 8 pathway and is not associated with viral gene expression. We also show that after virus entry, the caspase 9 pathway cascade is initiated. The magnitude of T cell responses to mycobacterial antigen 85A (Ag85A) expressed by recombinant MVA-infected ALDC is increased by blocking caspase-induced apoptosis. Apoptotic bodies generated by recombinant MVA (rMVA)-Ag85A-infected ALDC and containing Ag85A were phagocytosed by noninfected migrating ALDC expressing SIRPα via actin-dependent phagocytosis, and these ALDC in turn presented antigen. However, the addition of fresh ALDC to MVA-infected cultures did not improve on the magnitude of the T cell responses; in contrast, these noninfected DC showed downregulation of major histocompatibility complex class II (MHC-II), CD40, CD80, and CD86. We also observed that MVA-infected ALDC promoted migration of DEC-205+SIRPα+CD21+DC as well as CD4+and CD8+T cells independently of caspase activation. Thesein vitrostudies show that induction of apoptosis in DC by MVA vectors is detrimental to the subsequent induction of T cell responses.
The Magnitude of Dengue Virus NS1 Protein Secretion Is Strain Dependent and Does Not Correlate with Severe Pathologies in the Mouse Infection Model
Authors: Watanabe Satoru , Tan Kah Hin , Rathore Abhay P. S. , Rozen-Gagnon Kathryn , Shuai Wang , Ruedl Christiane , Vasudevan Subhash G. 
Published: March 2012

ABSTRACTThere are conflicting data on the relationship between the level of secreted NS1 (sNS1), viremia, and disease severity upon dengue virus (DENV) infection in the clinical setting, and therefore, we examined this relationship in the widely accepted AG129 mouse model. Because of the failure of a routinely used NS1 detection kit to detect sNS1 of the mouse-adapted DENV2 strain, we screened 15 previously undescribed NS1 monoclonal antibodies and developed a robust capture enzyme-linked immunosorbent assay (ELISA) with detection sensitivity at the low nanogram level (0.2 ng/ml) using recombinant baculovirus-expressed sNS1 as well as sNS1 that was immunoaffinity purified from the various DENV2 strains employed in this study. Using this test, we demonstrated that increased viremia paralleled severe pathologies; however, sNS1 level did not correlate with viremia or severity. Furthermore, among the DENV2 strains that were tested, the level of NS1 secretion did not correspond to virus replication ratein vitro, at the cellular level. Together, our data indicate that the magnitude of NS1 secretion appears to be strain dependent and does not correlate with viral virulence in the AG129 mouse model.
Systems Biology of Tumor Dormancy: Linking Biology and Mathematics on Multiple Scales to Improve Cancer Therapy
Authors: Enderling Heiko , Hahnfeldt Philip , Hlatky Lynn , Almog Nava 
Published: March 2012

Abstract
For many decades, it has been appreciated that tumor progression is not monotonic, and development of a cancer cell does not equate to inevitable cancer presentation in the clinic. Tumor progression is challenged by numerous intrinsic and extrinsic bottlenecks that can hold the tumor in dormant stages for prolonged periods. Given the complex, multiscale nature of these bottlenecks, the Center of Cancer Systems Biology organized a workshop on critical issues of systems biology of tumor dormancy. The program for the meeting this past July, chaired by N. Almog and H. Enderling, included discussions and interactive breakout sessions on regulation of tumor dormancy by angiogenesis, tumor–immune system interactions, cancer stem cell kinetics, and cell signaling pathways. Three important conclusions emerged from the meeting. The first was the urgent need to differentiate between tumor cell and tumor population dormancy of the primary tumor and metastatic deposits, the second was the continued need for interdisciplinary dialogs, and the third was the need to bring cross-scale mechanistic thinking to the field to achieve a more robust understanding of tumor dormancy and its clinical implications. Cancer Res; 72(9); 2172–5. ©2012 AACR.
Hepatocyte–Stellate Cell Cross-Talk in the Liver Engenders a Permissive Inflammatory Microenvironment That Drives Progression in Hepatocellular Carcinoma
Authors: Coulouarn Cédric , Corlu Anne , Glaise Denise , Guénon Isabelle , Thorgeirsson Snorri S. , Clément Bruno 
Published: March 2012

Abstract
Many solid malignant tumors arise on a background of inflamed and/or fibrotic tissues, features that are found in more than 80% hepatocellular carcinomas (HCC). Activated hepatic stellate cells (HSC) play a critical role in fibrogenesis associated with HCC onset and progression, yet their functional impact on hepatocyte fate remains largely unexplored. Here, we used a coculture model to investigate the cross-talk between hepatocytes (human hepatoma cells) and activated human HSCs. Unsupervised genome-wide expression profiling showed that hepatocyte–HSC cross-talk is bidirectional and results in the deregulation of functionally relevant gene networks. Notably, coculturing increased the expression of proinflammatory cytokines and modified the phenotype of hepatocytes toward motile cells. Hepatocyte–HSC cross-talk also generated a permissive proangiogenic microenvironment, particularly by inducing VEGFA and matrix metalloproteinase (MMP)9 expression in HSCs. An integrative genomic analysis revealed that the expression of genes associated with hepatocyte–HSC cross-talk correlated with HCC progression in mice and was predictive of a poor prognosis and metastasis propensity in human HCCs. Interestingly, the effects of cross-talk on migration and angiogenesis were reversed by the histone deacetylase inhibitor trichostatin A. Our findings, therefore, indicate that the cross-talk between hepatoma cells and activated HSCs is an important feature of HCC progression, which may be targeted by epigenetic modulation. Cancer Res; 72(10); 2533–42. ©2012 AACR.
Hypoxia-Inducible Factor-2α Activation Promotes Colorectal Cancer Progression by Dysregulating Iron Homeostasis
Authors: Xue Xiang , Taylor Matthew , Anderson Erik , Hao Cathy , Qu Aijuan , Greenson Joel K. , Zimmermann Ellen M. , Gonzalez Frank J. , Shah Yatrik M. 
Published: March 2012

Abstract
Hypoxia-inducible factor (HIF), a key modulator of the transcriptional response to hypoxia, is increased in colon cancer. However, the role of HIF in colon carcinogenesis in vivo remains unclear. In this study, we found that intestinal epithelium-specific disruption of the von Hippel–Lindau tumor suppressor protein (VHL) resulted in constitutive HIF signaling, and increased HIF expression augmented colon tumorigenesis in the Apcmin/+ intestinal tumor model. Intestine-specific disruption of Vhl increased colon tumor multiplicity and progression from adenomas to carcinomas. These effects were ameliorated in mice with double disruption of Vhl and HIF-2α. Activation of HIF signaling resulted in increased cell survival in normal colon tissue; however, tumor apoptosis was not affected. Interestingly, a robust activation of cyclin D1 was observed in tumors of Apcmin/+ mice in which HIF-2α was activated in the intestine. Consistent with this result, bromodeoxyuridine incorporation indicated that cellular proliferation was increased in colon tumors following HIF activation. Further analysis showed that dysregulation of the intestinal iron absorption transporter divalent metal transporter-1 (DMT-1) was a critical event in HIF-2α–mediated colon carcinogenesis. These data provide a mechanistic basis for the widely reported link between iron accumulation and colon cancer risk. Together, our findings show that a chronic increase in HIF-2α in the colon initiates protumorigenic signaling, which may have important implications in developing preventive and therapeutic strategies for colon cancer. Cancer Res; 72(9); 2285–93. ©2012 AACR.
Biomarker Discovery, Development, and Implementation in France: A Report from the French National Cancer Institute and Cooperative Groups
Authors: Andre Fabrice , Nowak Frederique , Arnedos Monica , Lacroix Ludovic , Viens Patrice , Calvo Fabien 
Published: March 2012

Abstract
Biomarkers are increasingly changing the medical practice in oncology. One of the major challenges in the field of personalized medicine or biologically adapted therapies is to ensure a rapid and extensive implementation of emerging biomarkers as soon as proof of their medical usefulness is obtained. A special program has been developed in France to facilitate the assessment and use of biomarkers. The French National Cancer Institute has set up a total of 28 laboratories in public hospitals to perform biomarker testing for clinical use. This program is enabling all patients who present with cancer to receive free testing for biomarkers, such as K-Ras, epidermal growth factor receptor, c-Kit, and Braf mutations. Funding for these laboratories comes from the French Ministry of Health. The future of these laboratories includes the development of DNA arrays and multiplex technologies for clinical use. Toward that end, the French National Cancer Institute is financing several large clinical trials that several large clinical trials are currently evaluating the feasibility and medical utility of DNA arrays and next-generation sequencing in the context of academic centers. The programs are being run by cooperative groups. Clin Cancer Res; 18(6); 1555–60. ©2012 AACR.
Development and Use of Integral Assays in Clinical Trials
Authors: Schilsky Richard L. , Doroshow James H. , LeBlanc Michael , Conley Barbara A. 
Published: March 2012

Abstract
Clinical trials that include integral biomarkers to determine eligibility, assign treatment, or assess outcome must employ robust assays to measure the molecular analyte of interest. The decision to develop a biomarker assay into a test suitable for use in humans should be driven by clinical need, that is, there should be a clear clinical purpose for undertaking the test development. Supporting in vitro or in vivo research on the ability of the marker to distinguish subgroups of patients with a given characteristic is necessary. The magnitude of the difference in treatment effect expected with use of the marker should be sufficient to support differential treatment prescription for marker-positive and -negative patients. Analytical and clinical validation of the marker assay should be completed before the clinical trial is initiated to ensure that the assay is stable enough for clinical use throughout the trial. Clinical use of the assay requires that it be performed in a Clinical Laboratory Improvement Amendments–accredited laboratory, and the need to apply for an Investigational Device Exemption from the U.S. Food and Drug Administration should be considered. In this article we elaborate on the steps required to get a biomarker assay ready for use as an integral component of a clinical trial and give an example of the use of an integral assay in a phase III trial. Clin Cancer Res; 18(6); 1540–6. ©2012 AACR.
Impact of Preanalytic Factors on the Design and Application of Integral Biomarkers for Directing Patient Therapy
Authors: Hewitt Stephen M. , Badve Sunil S. , True Lawrence D. 
Published: March 2012

AbstractMolecular assays have been routinely applied to improve diagnosis for the last 25 years. Assays that guide therapy have a similar history; however, their evolution has lacked the focus on analytic integrity that is required for the molecularly targeted therapies of today. New molecularly targeted agents require assays of greater precision/quantitation to predict the likelihood of response, i.e., to identify patients whose tumors will respond, while at the same time excluding and protecting those patients whose tumors will not respond or in whom treatment will cause unacceptable toxicity. The handling of tissue has followed a fit-for-purpose approach focused on appropriateness for diagnostic needs, which is less rigorous than the demands of new molecular assays that interrogate DNA, RNA, and proteins in a quantitative, multiplex manner. There is a new appreciation of the importance and fragility of tissue specimens as the source of analytes to direct therapy. By applying a total test paradigm and defining and measuring sources of variability in specimens, we can develop a set of specifications that can be incorporated into the clinical-care environment to ensure that a specimen is appropriate for analysis and will return a true result. Clin Cancer Res; 18(6); 1524–30. ©2012 AACR.
Lessons Learned from the Investigational Device Exemption Review of Children's Oncology Group Trial AAML1031
Authors: Meshinchi Soheil , Hunger Stephen P. , Aplenc Richard , Adamson Peter C. , Jessup J. Milburn 
Published: March 2012

Abstract
The U.S. Food and Drug Administration is now exerting its regulatory authority over the use of molecular diagnostics and related assays for medical decision making in clinical trials, by performing pre–Investigational Device Exemption reviews in all phases of clinical trials. In this review, we assess the analytical performance of the assay for the diagnostic, and consider how that performance affects the diagnostic and the patient and their risks and benefits from treatment. We also discuss the process involved in the first review of a new Children's Oncology Group phase III trial in acute myelogenous leukemia. The lessons learned and recommendations for how to prepare for and incorporate this new level of regulatory review into the protocol development process are presented. Clin Cancer Res; 18(6); 1547–54. ©2012 AACR.
IDH Mutation and Neuroglial Developmental Features Define Clinically Distinct Subclasses of Lower Grade Diffuse Astrocytic Glioma
Authors: Gorovets Daniel , Kannan Kasthuri , Shen Ronglai , Kastenhuber Edward R. , Islamdoust Nasrin , Campos Carl , Pentsova Elena , Heguy Adriana , Jhanwar Suresh C. , Mellinghoff Ingo K. , Chan Timothy A. , Huse Jason T. 
Published: March 2012

Abstract
Purpose: Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma [World Health Organization (WHO) IV], its most malignant subtype, lower grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notable clinical heterogeneity. Accordingly, we sought to identify and characterize clinically relevant molecular subclasses of lower grade diffuse astrocytic gliomas.
Experimental Design: We conducted multidimensional molecular profiling, including global transcriptional analysis, on 101 lower grade diffuse astrocytic gliomas collected at our own institution and validated our findings using publically available gene expression and copy number data from large independent patient cohorts.
Results: We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, platelet—derived growth factor receptor (PDGFR)A overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone. This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors.
Conclusion: We have elucidated molecularly distinct subclasses of lower grade diffuse astrocytic glioma that dictate clinical behavior and show fundamental associations with both IDH mutational status and neuroglial developmental stage. Clin Cancer Res; 18(9); 2490–501. ©2012 AACR.
Spleen Cells from Young but Not Old Immunized Mice Eradicate Large Established Cancers
Authors: Schreiber Karin , Arina Ainhoa , Engels Boris , Spiotto Michael T. , Sidney John , Sette Alessandro , Karrison Theodore G. , Weichselbaum Ralph R. , Rowley Donald A. , Schreiber Hans 
Published: March 2012

AbstractPurpose: Solid tumors that have grown two weeks or longer in mice and have diameters larger than 1 cm are histologically indistinguishable from autochthonous human cancers. When experimental tumors reach this clinically relevant size, they are usually refractory to most immunotherapies but may be destroyed by adoptive T-cell transfer. However, TCR-transgenic T cells and/or tumor cells overexpressing antigens are frequently used in these experiments. Here we studied the requirements for destroying clinical size, unmanipulated 8101 tumors by adoptive cell therapy.Experimental Design: 8101 arose in an old mouse after chronic exposure to UV light. A cancer line was established, which was never serially transplanted. The immunodominant CD8+ T cell-recognized antigen of this tumor is caused by a somatic tumor–specific mutation in the RNA helicase p68. 8101 tumors were treated with spleen cells from young naive, or young and old immunized mice to ascertain the characteristics of immune cells that lead to rejection.Results: Here we show that the mutant p68 peptide has an exceptionally high affinity to the presenting MHC class I molecule Kb and that spleen cells from immunized young syngeneic mice adoptively transferred to Rag−/− or cancer-suppressed euthymic mice eradicate 8101 tumors larger than 1 cm in average diameter and established for several weeks. Spleen cells from naive young mice or from old and boosted (reimmunized) mice were ineffective.Conclusions: Relapse-free destruction of large and long-established tumors expressing a genuine very high-affinity tumor-specific antigen can be achieved by using adoptive transfer of lymphocytes from immunized young individuals. Clin Cancer Res; 18(9); 2526–33. ©2012 AACR.
An Image-Based Model of Atrial Muscular Architecture
Authors: Zhao Jichao , Butters Timothy D. , Zhang Henggui , Pullan Andrew J. , LeGrice Ian J. , Sands Gregory B. , Smaill Bruce H. 
Published: March 2012

Background—
Computer models that capture key features of the heterogeneous myofiber architecture of right and left atria and interatrial septum provide a means of investigating the mechanisms responsible for atrial arrhythmia. The data necessary to implement such models have not previously been available. The aims of this study were to characterize surface geometry and myofiber architecture throughout the atrial chambers and to investigate the effects of this structure on atrial activation.

Methods and Results—

Atrial surface geometry and myofiber orientations were reconstructed in 3D at 50×50×50-μm
3
resolution from serial images acquired throughout the sheep atrial chambers. Myofiber orientations were determined by Eigen-analysis of the structure tensor. These data have been incorporated into an anatomic model that provides the first quantitative representation of myofiber architecture throughout the atrial chambers. By simulating activation on this 3D structure, we have confirmed the roles of specialized myofiber tracts such as the crista terminalis, pectinate muscles, and the Bachman bundle on the spread of activation from the sinus node. We also demonstrate how the complex myocyte arrangement in the posterior left atrium contributes to activation time dispersion adjacent to the pulmonary veins and increased vulnerability to rhythm disturbance generated by ectopic stimuli originating in the pulmonary vein sleeves.

Conclusions—
We have developed a structurally detailed, image-based model of atrial anatomy that provides deeper understanding of the role that myocyte architecture plays in normal and abnormal atrial electric function.