bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depletion of eosinophils in mice through the use of antibodies specific for C-C chemokine receptor 3 (CCR3)
Authors: Grimaldi J Christopher , Yu Nai-Xuan , Grunig Gabrielle , Seymour Brian W P , Cottrez Françoise , Robinson Douglas S , Hosken Nancy , Ferlin Walter G , Wu Xiaoyan , Soto Hortensia , O'Garra Anne , Howard Maureen C , Coffman Robert L 
Published: January 2018

Abstract
We have generated rat monoclonal antibodies specific for the mouse eotaxin receptor, C-C chemokine receptor 3 (CCR3). Several anti-CCR3 mAbs proved to be useful for in vivo depletion of CCR3-expressing cells and immunofluorescent staining. In vivo CCR3 mAbs of the IgG2b isotype substantially depleted blood eosinophil levels in Nippostrongyus brasiliensis-infected mice. Repeated anti-CCR3 mAb treatment in these mice significantly reduced tissue eosinophilia in the lung tissue and bronchoalveolar lavage fluid. Flow cytometry revealed that mCCR3 was expressed on eosinophils but not on stem cells, dendritic cells, or cells from the thymus, lymph node, or spleen of normal mice. Unlike human Th2 cells, mouse Th2 cells did not express detectable levels of CCR3 nor did they give a measurable response to eotaxin. None of the mAbs were antagonists or agonists of CCR3 calcium mobilization. To our knowledge, the antibodies described here are the first mAbs reported to be specific for mouse eosinophils and to be readily applicable for the detection, isolation, and in vivo depletion of eosinophils. J. Leukoc. Biol. 65: 846–853; 1999.
Immunization with dendritic cells breaks immunodominance in CTL responses against minor histocompatibility and synthetic peptide antigens
Authors: Grufman Per , Sandberg Johan K , Wolpert Elisabeth Z , Kärre Klas 
Published: January 2018

Abstract
We have examined the mechanisms involved in immunodominance in two different experimental models: the cytotoxic T lymphocyte (CTL) response in B6 mice against minor histocompatibility antigens of BALB.B mice, and the response of B6 mice against a mixture of five synthetic peptides corresponding to well-defined immunogenic epitopes. The CTL responses in these models focus on a few dominant epitopes, whereas no or only weak responses can be detected against other subdominant epitopes. Neither of these immunodominance phenomena can be explained by insufficient presentation of subdominant epitopes in the presence of the dominant ones. Immunodominance could also be demonstrated in an in vitro system, in which B6 splenocytes primed with BALB.B could interfere with the CTL response against subdominant antigens. This interference was dependent on CD8+ T cells and on the simultaneous presentation of dominant and subdominant antigens on the same antigen-presenting cell, suggesting T cell competition around the antigen-presenting cell as a potential explanation. The immunodominance in both systems could be broken by immunization with dendritic cells (from BALB.B or from B6 loaded with peptides). This procedure allowed detection of CTL responses against both dominant and previously subdominant antigens. J. Leukoc. Biol. 66: 268–271; 1999.
Migration of Langerhans cells and dermal dendritic cells in skin organ cultures: augmentation by TNF-α and IL-1 β
Authors: Stoitzner Patrizia , Zanella Monica , Ortner Ulrike , Lukas Michael , Tagwerker Andrea , Janke Katrin , Lutz Manfred B , Schuler Gerold , Echtenacher Bernd , Ryffel Bernhard , Koch Franz , Romani Nikolaus 
Published: January 2018

Abstract
Migration from sites of antigen encounter to lymphoid organs is essential to the strong immunogenic function of dendritic cells (DC). In the skin, migration proceeds through dermal lymphatic vessels and is regulated in an incompletely understood way by inflammatory mediators. We studied the effects of tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) in mouse skin organ cultures by direct enumeration of migrating DC and by immunohistochemistry. (1) Neutralizing antibodies to TNF-α and IL-1β inhibited migration of DC, also in human skin explants (TNF-α). (2) TNF-α at low concentrations (50 U/mL) and IL-1β (50–3000 U/mL) augmented migration to about 150% of spontaneous migration. (3) High concentrations of TNF-α (5000 U/mL) inhibited migration by approximately 50%. (4) DC migration from skin explants of TNF-α/lymphotoxin-α double-deficient mice and TNF-receptor type 1 and 2 double knock-out mice was not impaired. (5) TNF-α effects were neutralized by anti-IL-1β, and vice versa. We conclude that in normal animals both TNF-α and IL-1 β are required for DC migration to occur. In the complete absence of one cytokine (TNF-α), however, backup mechanisms step in. J. Leukoc. Biol. 66: 462–470; 1999.
Monochloramine enhances Fas (APO-1/CD95)-induced apoptosis in Jurkat T cells
Authors: Ogino Tetsuya , Ma Yuxiang , Than Tin Aung , Omori Masako , Okada Shigeru 
Published: January 2018

Abstract
Monochloramine derivatives are physiological oxidants produced by activated neutrophils. We report the effects of chemically prepared monochloramine (NH2Cl) on Fas-induced apoptosis in Jurkat T cells. When the cells were pretreated with NH2Cl (20–70 μM), subsequent addition of apoptosis-inducing anti-Fas antibody resulted in a synergistic enhancement of apoptosis. Treatment of NH2Cl (50–70 μM) alone resulted in a slight but definite apoptosis. Caspase activities, as measured by DEVD and IETD cleavage activities, were also elevated synergistically by NH2Cl + anti-Fas antibody stimulation. Moreover, a broad caspase inhibitor, Z-VAD-fmk, almost completely inhibited the apoptosis induced by NH2Cl and/or anti-Fas antibody. Fas expression on the Jurkat cell surface was not affected by the NH2Cl treatment. After 3 h of NH2Cl treatment, when the apoptosis was beginning to increase, the cells showed cytochrome c release from mitochondria, proteolytic activation of caspase 9, and poly (ADP-ribose) polymerase cleavage, regardless of Fas stimulation. Z-VAD-fmk almost completely inhibited this poly (ADP-ribose) polymerase cleavage, but not cytochrome c release. By contrast, Fas stimulation alone resulted in neither cytochrome c release nor caspase 9 activation at 3 h, and the increase in the DEVD cleavage activity and apoptosis became evident at later time points. These results suggested that NH2Cl enhanced Fas-induced apoptosis through the cytochrome c release and caspase 9 activation at the early stage of apoptosis. Chloramines derived from acute inflammation may modify immune reactions, such as cell-mediated cytotoxicity and some autoimmune diseases, by the enhancement of Fas-induced apoptosis. J. Leukoc. Biol. 67: 46–52; 2000.
Cloning and expression of bovine p47-phoxand p67-phox: comparison with the human and murine homologs
Authors: Bunger Peggy L , Swain Steve D , Clements Mark K , Siemsen Daniel W , Davis Angela R , Gauss Katherine A , Quinn Mark T 
Published: January 2018

Abstract
Neutrophils play an essential role in bovine cellular host defense, and compromised leukocyte function has been linked to the development of respiratory and mucosal infections. During the host defense process, neutrophils migrate into infected tissues where they become activated, resulting in the assembly of neutrophil membrane and cytosolic proteins to form a superoxide anion-generating complex known as the NADPH oxidase. Two of the essential cytosolic components of the NADPH oxidase are p47-phox and p67-phox. Currently, only the human and murine homologs of these proteins have been sequenced. Because of the important role neutrophils play in bovine host defense, we carried out studies to clone, sequence, and express bovine p47-phox and p67-phox. Using polymerase chain reaction (PCR) cloning techniques and a bovine bone marrow cDNA library, we have cloned both of these bovine NADPH oxidase cytosolic components. Comparison of the bovine sequences with those of the human and murine homologs showed that they were highly conserved, but also revealed important information regarding key structural features of p47-phox and p67-phox, including location of putative phosphorylation sites. Functional expression of bovine p47-phox and p67-phox showed that these proteins could substitute for the human proteins in reconstituting NADPH oxidase activity in a cell-free assay system, again demonstrating the high degree of conservation between human and bovine homologs. This study greatly contributes to our understanding of the potential structural/functional regions of p47-phox and p67-phox as well as providing information that can be used to study the role of neutrophils in bovine inflammatory diseases. J. Leukoc. Biol. 67: 63–72; 2000.
Interleukin-16
Authors: Cruikshank William W , Kornfeld Hardy , Center David M 
Published: January 2018

Abstract
Interleukin 16 (IL-16) was initially described in 1982 as the first T cell chemoattractant. Through interaction with CD4, IL-16 has now been characterized as a chemoattractant for a variety of CD4+ immune cells. Recent in vivo studies have more fully characterized IL-16 as an immunom odulatory cytokine that contributes to the regulatory process of CD4+ cell recruitment and activation at sites of inflammation in association with asthma and several autoimmune diseases. Since its cloning in 1994, IL-16 structure and function have been studied extensively. This review addresses the current data regarding IL-16 protein and gene structure; the expanding list of cells capable of generating IL-16; the direct interaction of IL-16 with its receptor, CD4; and the functional bioactivities of IL-16 as they relate to inflammation and HIV-1 infection. In addition, potential therapeutic modalities for IL-16 relating to inflammation and immune reconstitution in HIV-1 infection are also discussed. J. Leukoc. Biol. 67: 757–766; 2000.
A synthetic pathway for the production of 2-hydroxyisovaleric acid in Escherichia coli
Authors: Cheong Seokjung , Clomburg James M , Gonzalez Ramon 
Published: January 2018

Abstract
Synthetic biology, encompassing the design and construction of novel artificial biological pathways and organisms and the redesign of existing natural biological systems, is rapidly expanding the number of applications for which biological systems can play an integral role. In the context of chemical production, the combination of synthetic biology and metabolic engineering approaches continues to unlock the ability to biologically produce novel and complex molecules from a variety of feedstocks. Here, we utilize a synthetic approach to design and build a pathway to produce 2-hydroxyisovaleric acid in Escherichia coli and demonstrate how pathway design can be supplemented with metabolic engineering approaches to improve pathway performance from various carbon sources. Drawing inspiration from the native pathway for the synthesis of the 5-carbon amino acid l-valine, we exploit the decarboxylative condensation of two molecules of pyruvate, with subsequent reduction and dehydration reactions enabling the synthesis of 2-hydroxyisovaleric acid. Key to our approach was the utilization of an acetolactate synthase which minimized kinetic and regulatory constraints to ensure sufficient flux entering the pathway. Critical host modifications enabling maximum product synthesis from either glycerol or glucose were then examined, with the varying degree of reduction of these carbons sources playing a major role in the required host background. Through these engineering efforts, the designed pathway produced 6.2 g/L 2-hydroxyisovaleric acid from glycerol at 58% of maximum theoretical yield and 7.8 g/L 2-hydroxyisovaleric acid from glucose at 73% of maximum theoretical yield. These results demonstrate how the combination of synthetic biology and metabolic engineering approaches can facilitate bio-based chemical production.
Threshold for the destabilisation of the ion-temperature-gradient mode in magnetically confined toroidal plasmas
Authors: Zocco A. , Xanthopoulos P. , Doerk H. , Connor J. W. , Helander P. 
Published: January 2018

The threshold for the resonant destabilisation of ion-temperature-gradient (ITG) driven instabilities that render the modes ubiquitous in both tokamaks and stellarators is investigated. We discover remarkably similar results for both confinement concepts if care is taken in the analysis of the effect of the global shear ${\hat{s}}$. We revisit, analytically and by means of gyrokinetic simulations, accepted tokamak results and discover inadequacies of some aspects of their theoretical interpretation. In particular, for standard tokamak configurations, we find that global shear effects on the critical gradient cannot be attributed to the wave–particle resonance destabilising mechanism of Hahm & Tang (Phys. Plasmas, vol. 1, 1989, pp. 1185–1192), but are consistent with a stabilising contribution predicted by Biglari et al. (Phys. Plasmas, vol. 1, 1989, pp. 109–118). Extensive analytical and numerical investigations show that virtually no previous tokamak theoretical predictions capture the temperature dependence of the mode frequency at marginality, thus leading to incorrect instability thresholds. In the asymptotic limit ${\hat{s}}\unicode[STIX]{x1D704}\ll 1$, where $\unicode[STIX]{x1D704}$ is the rotational transform, and such a threshold should be solely determined by the resonant toroidal branch of the ITG mode, we discover a family of unstable solutions below the previously known threshold of instability. This is true for a tokamak case described by a local ${\hat{s}}-\unicode[STIX]{x1D6FC}$ local equilibrium, and for the stellarator Wendelstein 7-X, where these unstable solutions are present even for configurations with a small trapped-particle population. We conjecture they are of the Floquet type and derive their properties from the Fourier analysis of toroidal drift modes of Connor & Taylor (Phys. Fluids, vol. 30, 1987, pp. 3180–3185), and to Hill’s theory of the motion of the lunar perigee (Acta Math., vol. 8, 1886, pp. 1–36). The temperature dependence of the newly determined threshold is given for both confinement concepts. In the first case, the new temperature-gradient threshold is found to be rather insensitive to the temperature ratio $T_{i}/T_{e}$, at least for $T_{i}/T_{e}\lesssim 1$, and to be a growing function of the density gradient scale for $T_{i}/T_{e}\gtrsim 1$. For Wendelstein 7-X, the new critical temperature gradient is a growing function of the temperature ratio. The importance of these findings for the assessment of turbulence in stellarators and low-shear tokamak configurations is discussed.
OP11 Structural Uncertainty In Economic Modelling For Smoking Cessation
Authors: Pennington Becky , Filby Alex , Taylor Matthew , Owen Lesley 
Published: January 2018

INTRODUCTION:Guidance for developing economic models recommend that model structure is carefully considered, and assumptions varied in sensitivity analysis (1). Models in smoking cessation have typically used cohort-level approaches, although recently discrete event simulations (DESs) have been developed (2). DESs allow additional flexibility such as modelling changing risk over time, and recurrent events. Our aim was to explore the impact of varying model structure and assumptions on the cost-effectiveness of smoking cessation programs.METHODS:We built a cohort state-transition model which related mortality to smoking status and considered the prevalence (based on smoking status) of five comorbidities associated with smoking, each of which has an associated cost and quality of life decrement. We additionally built a patient-level DES, using the Discretely Integrated Condition Event framework (3). The DES used the same data as the cohort model, except considering incidence for comorbidities rather than prevalence. We considered a population of smokers aged 16 years old and an intervention costing GBP827 on which 27 percent of people quit, compared with no treatment. We produced results using the two models for comparable scenarios, and ran additional scenarios considering different assumptions.RESULTS:In the cohort model, the incremental cost-effectiveness ratio (ICER) for intervention versus no treatment was GBP4,000/quality-adjusted life year (QALY). In the DES, modelling mortality linked to smoker status produced an ICER of GBP1,000/QALY and modelling mortality linked to comorbidities produced an ICER of GBP6,000/QALY. In the DES with mortality linked to comorbidities, varying the relative risk of comorbidities with time since quitting gave an ICER of GBP3,000/QALY. Including relapse increased the ICER to GBP21,000/QALY.CONCLUSIONS:The ICER for the smoking cessation program changes when model assumptions are varied, although the choice of DES versus cohort model appears to make a relatively small difference. Inclusion of relapse substantially changes the ICER, demonstrating the importance of long-term effects in economic models.
OP15 The Incremental Cost Of Delirium Following Aortic Valve Replacement
Authors: Clancy Seth , Potter Brian , Green Phil 
Published: January 2018

INTRODUCTION:Postoperative delirium has been associated with poorer long term survival in Transcatheter aortic valve replacement (TAVR) and Surgival aortic valve replacement (SAVR) patients. However, its effect on hospitalization costs and length of stay in these populations has not been formally assessed.METHODS:Using the Medicare Provider Analysis and Review File, we retrospectively analyzed elderly (80 years of age and older) Medicare patients receiving TAVR and SAVR in the United States during the 2015 fiscal year. ICD-9-CM codes were used to identify postoperative delirium diagnoses. The incremental hospital resource consumption, measured as hospital cost and length of stay, was estimated for patients with postoperative delirium during their TAVR or SAVR index hospitalization. Multivariate regression models were used for the adjusted cost estimates controlling for patient demographics, comorbidities, and complications.RESULTS:A total of 21,088 claims were available for analysis (12,114 TAVR and 8,974 SAVR). The mean age of the TAVR group was older compared to the SAVR group (87 versus 84; p < .001) and TAVR patients presented with a higher comorbidity burden (Charlson Index score 3.0 versus 2.1; p < .0001). TAVR patients experiencing postoperative delirium during the index hospitalization was 1.6 percent compared to 3.6 percent of surgical patients (p < .0001). For the overall cohort, the regression adjusted incremental cost of postoperative delirium was (USD15,592; p < .0001). Patients experiencing delirium also had significantly longer hospital length of stay (4.16 days; p < .0001). When stratified by treatment approach, the adjusted incremental cost was USD13,862 for TAVR (p < .0001) and USD16,656 for SAVR (p < .0001).CONCLUSIONS:While infrequent, postoperative delirium significantly increased hospital cost and length of stay following transcatheter or surgical aortic valve replacement (AVR). Despite a significantly higher comorbidity burden, TAVR was associated with lower postoperative delirium rates compared to SAVR. Moreover, post-TAVR delirium may be associated with less resource consumption than post-SAVR delirium. Future studies should seek to determine whether general anesthesia avoidance in appropriately selected transfemoral TAVR patients can further decrease rates of delirium.
OP25 Evidence Gathering Across Key Stakeholders Involved In Early Health Technology Assessment
Authors: Manetti Stefania , Burns Richéal , Turchetti Giuseppe 
Published: January 2018

INTRODUCTION:The adoption and reimbursement of a new or novel medical device frequently occurs after an economic evaluation of the innovation. One important factor for reimbursement rejections by the English National Institute for Health and and Care Excellence (NICE) Medical Technologies Evaluation Programme (MTEP) appears to be the little or no attention to early assessment (1). The aim of this study is to achieve a more in-depth and comprehensive understanding of the value of early Health Technology Assessment (HTA) for new medical devices.METHODS:This study employs a mixed methods research strategy. Our informant interviews involved two types of key stakeholders: health economists in academia and professionals in medical devices firms with a professional role in research and development or market access departments. Our qualitative analysis focused on two samples from six universities (five in the United Kingdom, UK, and one in Italy) and six small to medium-sized enterprises (five in the UK, and one in Italy). Insights from field work interviews helped to design our complementary quantitative analysis.RESULTS:During thematic analysis, barriers to adoption of early HTA emerged across three domains. First, educational barriers (that is, what HTA/early HTA is and how to conduct it) influenced the foundation for the reimbursement strategy. Second, interviewees highlighted the presence of intrinsic barriers (for example, resources for translational and early preclinical research, reliability and reproducibility, evidence, and dissemination of sensitive information) within existing practices and knowledge. Third, several research gaps (that is, medical device classification, standardization of methods, guidelines for developers, and alignment of stakeholders perspectives) were identified. Finally, academics adopted early HTA to assess different aspects of a medical device early in development; however, developers were focused on the assessment of investment and safety/usability factors, especially for in-house evaluations.CONCLUSIONS:If decision makers expect developers to produce better quality evidence and society aims to optimize resources that is, not investing in non-cost-effective technologies, then the incorporation of a more robust analytical framework including a societal perspective is necessary to understand how early HTA can be embedded into all aspects of the development process.