bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of a CSF-induced proliferating subpopulation of human peripheral blood monocytes by surface marker expression and cytokine production
Authors: Finnin Maribel , Hamilton John A , Moss Suzanne T
Published: January 2018

The phenotype of a subpopulation(s) of human monocytes which has been shown to proliferate in vitro in response to macrophage colony-stimulating factor (M-CSF or CSF-1) and granulocyte-macrophage CSF (GM-CSF) is as yet unknown. To identify this proliferating subpopulation(s) we demonstrated first that DNA synthesis was occurring under culture conditions suitable for flow cytometric evaluation. Flow cytometric analysis of surface antigen expression identified that after 5 days of culture the proliferating subpopulation of monocytes expressed CD14, CD13, CD33, CD11b, CD11c, CD87, HLA-DR, CD45RO, and did not express CD86, CD34, CD80, CD4, CD16, and CD56. In addition, these proliferating monocytes (representing approximately 5% of total monocytes) were shown to produce the proinflammatory cytokines interleukin-6 and tumor necrosis factor α in response to lipopolysaccharide stimulation. Further characterization and subsequent isolation of this subpopulation of monocytes may provide new and important information necessary to understand inflammatory diseases such as rheumatoid arthritis, where local proliferation at the site of inflammation may be a key factor contributing to the chronicity of the disease. J. Leukoc. Biol. 66: 953–960; 1999.
Synergistic action of pro-inflammatory agents: cellular and molecular aspects
Authors: Paludan Søren R
Published: January 2018

Generation of an inflammatory response is a complex process involving multiple factors acting in parallel and in concert. Viruses, parasites, and bacteria, particularly lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, act cooperatively with the cytokine interferon (IFN)-γ to induce many of the genes involved in inflammation. In addition, these components synergistically induce secretion of tumor necrosis factor α (TNF-α), which also synergizes strongly with IFN-γ. The molecular mechanisms underlying the synergistic gene induction discussed in this review involve cooperative activation of transcription factors. IFN-γ-activated signal transducer and activator of transcription 1 and interferon regulatory factor-1 function synergistically with nuclear factor κB activated by LPS and TNF-α. In addition, cross-talk between the signal transduction pathways upstream of the activation of the transcription factors contributes to generation of the synergistic action. Cooperative activity of proinflammatory agents profoundly influences the immune response to infections and the efficiency of cellular clearance mechanisms. J. Leukoc. Biol. 67: 18–25; 2000.
CD40-CD40 ligand
Authors: van Kooten Cees , Banchereau Jacques
Published: January 2018

CD40 is a cell surface receptor that belongs to the tumor necrosis factor-R (TNF-R) family, and that was first identified and functionally characterized on B lymphocytes. Its critical role in T cell-dependent humoral immune responses was demonstrated by patients with the hyper-IgM syndrome, as well as by gene targeting in mice. However, in recent years it has become clear that CD40 is expressed much more broadly, including expression on monocytes, dendritic cells, endothelial cells, and epithelial cells. In addition, the CD40-ligand (CD40-L/CD154), a member of the TNF family, is also expressed more widely than activated CD4+ T cells only. Therefore it is now thought that CD40-CD40-L interactions play a more general role in immune regulation. Collectively these studies have culminated in pre-clinical and clinical studies that are in progress. This article reviews recent developments in this field of research, with main emphasis on (1) structure and expression of CD40 and its ligand; (2) CD40 signal transduction; (3) in vitro function of CD40 on different cell types; and (4) in vivo functions of CD40/CD40-L interactions. J. Leukoc. Biol. 67: 2–17; 2000.
Antimicrobial effects of α-MSH peptides
Authors: Cutuli Mariagrazia , Cristiani Silvia , Lipton James M , Catania Anna
Published: January 2018

The presence of the ancient antiinflammatory peptide α-melanocyte-stimulating hormone [α-MSH (1–13), SYSMEHFRWGKPV] in barrier organs such as gut and skin suggests a role in the nonspecific (innate) host defense. α-MSH and and its carboxy-terminal tripeptide (11–13, KPV) were determined to have antimicrobial influences against two major and representative pathogens: Staphylococcus aureus and Candida albicans. α-MSH peptides significantly inhibited S. aureus colony formation and reversed the enhancing effect of urokinase on colony formation. Antimicrobial effects occurred over a broad range of concentrations including the physiological (picomolar) range. Small concentrations of α-MSH peptides likewise reduced viability and germ tube formation of the yeast C. albicans. Antimicrobial influences of α-MSH peptides could be mediated by their capacity to increase cellular cAMP. Indeed, this messenger was significantly augmented in peptide-treated yeast and the potent adenylyl cyclase inhibitor dideoxyadenosine (ddAdo) partly reversed the killing activity of α-MSH peptides. Reduced killing of pathogens is a detrimental consequence of therapy with anti-inflammatory drugs. Because α-MSH has potent anti-inflammatory effects we determined influences of α-MSH on C. albicans and S. aureus killing by human neutrophils. α-MSH peptides did not reduce killing but rather enhanced it, likely as a consequence of the direct antimicrobial activity. α-MSH peptides that combine antipyretic, antiinflammatory, and antimicrobial effects could be useful in treatment of disorders in which infection and inflammation coexist. J. Leukoc. Biol. 67:233–239; 2000.
Phorbol myristate acetate induces neutrophil NADPH-oxidase activity by two separate signal transduction pathways: dependent or independent of phosphatidylinositol 3-kinase
Authors: Karlsson Anna , Nixon Jennifer B , McPhail Linda C
Published: January 2018

The neutrophil NADPH-oxidase can be activated by protein kinase C (PKC) agonists such as phorbol myristate acetate (PMA), resulting in superoxide anion release. This superoxide release is independent of phosphatidylinositol 3-kinase (PI 3-kinase) because the inhibitor wortmannin does not affect the response. In this study, PMA is shown to also induce a wortmannin-sensitive NADPH-oxidase activation, however, not resulting in release of superoxide but in intracellular production of the radical. This indicates that two pools of NADPH-oxidase, one localized in the plasma membrane and the other in the granule membranes, are separately regulated and the signal transduction pathways leading to activation of these pools differ regarding involvement of PI 3-kinase. Activation of both pools was dependent on ERK/MAPK kinase (MEK) activity and protein phosphatase 1 and/or 2A. As the two oxidase responses were differently affected by the inhibitor Gö-6850, different PKC isozymes are suggested to take part in the two signal transduction pathways. J. Leukoc. Biol. 67: 396–404; 2000.
Phosphatidylinositol 3-kinase and mTOR mediate lipopolysaccharide-stimulated nitric oxide production in macrophages via interferon-β
Authors: Weinstein Steven L , Finn Alexander J , Davé Shaival H , Meng Fanying , Lowell Clifford A , Sanghera Jasbinder S , DeFranco Anthony L
Published: January 2018

Bacterial lipopolysaccharide (LPS) elicits responses by macrophages that help the body repel infections. Recent evidence indicates that phosphatidylinositol 3-kinase (PI 3-kinase) may mediate some of these responses. Here, we show that exposing macrophages to LPS rapidly increased membrane-associated PI 3-kinase activity and also elevated p70 S6 kinase activity. Inhibitors of PI 3-kinase or the mammalian target of rapamycin (mTOR) fully blocked p70 S6 kinase activation, implying that this kinase is controlled by PI 3-kinase and mTOR. These inhibitors also substantially reduced LPS-induced nitric oxide (NO) production. This inhibition was, in part, attributable to impaired LPS-stimulated secretion of interferon-β, an autocrine co-factor for NO production. However, the addition of exogenous interferon-β did not fully restore NO production, indicating that the NO response was being inhibited by another mechanism as well. Together, these data suggest that PI 3-kinase, mTOR, and possibly p70 S6 kinase mediate LPS-induced NO production by regulating the secretion of interferon-β and by a second undefined mechanism. J. Leukoc. Biol. 67: 405–414; 2000.
The β-thromboglobulins and platelet factor 4: blood platelet-derived CXC chemokines with divergent roles in early neutrophil regulation
Authors: Brandt Ernst , Petersen Frank , Ludwig Andreas , Ehlert Jan E , Bock Lothar , Flad Hans-D
Published: January 2018

The recruitment of neutrophil granulocytes to sites of tissue injury is one of the earliest events during host defense. Several chemotactic cytokines belonging to the CXC subfamily of chemokines are thought to be implicated in this kind of response. Especially those CXC chemokines that are stored in blood platelets and become immediately released upon activation are likely to dominate neutrophil-dependent host defense at the onset of inflammation. The major platelet-derived CXC chemokines are the β-thromboglobulins and platelet factor 4 (PF-4), which are both released into the blood at micromolar concentrations. The availability as well as the functional activity of these mediators appear to be subject to tight control by diverse regulatory mechanisms. These include proteolytic processing of chemokine precursors, oligomer formation, and the differential usage of neutrophil-expressed receptors. Herein we review our work on early neutrophil regulation by PF-4, the β-thromboglobulin neutrophil-activating peptide 2 (NAP-2) and its major precursor connective tissue-activating peptide III (CTAP-III). We moreover propose a model to assess the contribution by either of these chemokines to coordinated recruitment and activation of neutrophils in response to acute tissue injury. J. Leukoc. Biol. 67: 471–478; 2000.
Activation of cAMP-dependent protein kinase is necessary for actin rearrangements in human neutrophils during phagocytosis
Authors: Ydrenius Liselotte , Majeed Meytham , Rasmusson Birgitta J , Stendahl Olle , Särndahl Eva
Published: January 2018

We have investigated the role of cAMP and cAMP-dependent protein kinase (cAPK) in neutrophil phagocytosis. Inhibition of cAPK with H-89 reduced complement- and IgG-dependent phagocytosis to 83 and 46%, respectively. Fluorescence intensity measurements of phalloidin-stained actin in neutrophils showed a reduced amount of filamentous actin (F-actin) in pseudopods and around the phagosome in cells treated with H-89 or cAMP-elevating agents (forskolin and rolipram). The amount of phosphotyrosine-containing proteins was also reduced in pseudopods and around the phagosome. Taken together, the data show that cAMP/cAPK regulates F-actin reorganization during receptor-mediated phagocytosis, particularly triggered by IgG-FcR interaction. Our results support the hypothesis that active subcortical reorganization of F-actin is a prerequisite for FcR-mediated phagocytosis, but is less important during CR3-mediated ingestion. J. Leukoc. Biol. 67: 520–528; 2000.
Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism
Authors: Yasui Kozo , Agematsu Kazunaga , Shinozaki Koji , Hokibara Sho , Nagumo Haruo , Nakazawa Takayuki , Komiyama Atsushi
Published: January 2018

This study was designed to determine whether theophylline would augment granulocyte apoptosis via a mechanism of adenosine A2A receptor antagonism. A selective adenosine A2 receptor agonist (CGS-21680, 1 μM) exhibited the most efficient potency for decreasing neutrophil apoptosis for 16 h from 63 ± 5 to 19 ± 4% (P < 0.001); it exerted poor and adverse effects on eosinophil survival. A selective protein kinase A inhibitor KT-5720 (10 μM) reversed the capacity of dibu-tyryl cAMP but not CGS-21680 to induce an inhibitory effect on neutrophil apoptosis, suggesting that occupancy of adenosine A2 receptors inhibit neutrophil apoptosis by a cAMP-independent mechanism. Theophylline derivatives show the following pattern of potency for inducing neutrophil apoptosis competing with CGS-21680: 8-phenyltheophylline = 8-p-sulfophenyltheophylline > theophylline ≫ enprofylline. This pattern is consistent with the affinity established for A2A receptors. Theophylline demonstrated an additive effect to that of anti-Fas antibody (CH11, 1 μg/mL) in inducing neutrophil apoptosis, but not to that of adenosine deaminase or KF-17837 (a selective A2 receptor antagonist; 1 μM), suggesting conflicting effects on the receptor antagonism. These findings suggest that theophylline has an immunomodulatory action on neutrophil apoptosis via a mechanism of A2A antagonism. J. Leukoc. Biol. 67:529–535; 2000.
Chymase is a potent chemoattractant for human monocytes and neutrophils
Authors: Tani Kenji , Ogushi Fumitaka , Kido Hiroshi , Kawano Tetsuya , Kunori Yuichi , Kamimura Takashi , Cui Ping , Sone Saburo
Published: January 2018

Chymase is a major chymotrypsin-like serine protease expressed in the secretory granules of mast cells in many mammalian species. In this study, we revealed the chemotactic activity of chymase for human mononuclear cells and neutrophils with a 48-well microchemotaxis chamber technique. Human chymase showed the potent chemotactic activity for monocytes and neutrophils dose-dependently in a concentration range from 0.1 to 10 μg/mL, corresponding to about 4–400 μM. The activity was as potent as that of N-formyl-methionyl-leucyl-phenylalanine. Chymase also stimulated cell migration of lymphocytes and purified T cells, but checkerboard analysis revealed that the effect was chemokinetic rather than chemotactic. Inhibition of chymase activities with chymase inhibitors, such as antileukoprotease and Bowman-Birk soybean trypsin inhibitor, significantly inhibited the chemotactic activity of chymase, suggesting that the proteolytic activity of chymase participates in the chemotactic activity. Our results suggest that mast cell chymase acts as a chemoattractant, and may play a role in the accumulation of inflammatory cells in development of the chronic inflammatory responses of allergic and nonallergic diseases. J. Leukoc. Biol. 67: 585–589; 2000.
Definition of human blood monocytes
Authors: Ziegler-Heitbrock H W L
Published: January 2018

At the Definition of Human Blood Monocytes conference held in Munich, Germany in October 1999, experts met to discuss data on the characterization of monocytes in health and disease. Emphasis was on how to best define these cells, on which subpopulations can be identified, and on how the monocytes can best be distinguished from other cells such as natural killer cells, granulocytes, and dendritic cell precursors. J. Leukoc. Biol. 67: 603–606; 2000.
Insights into the role of γδ T lymphocytes in the immunopathogenic response to thermal injury
Authors: Schwacha Martin G , Ayala Alfred , Chaudry Irshad H
Published: January 2018

Studies have shown that cell-mediated immunity is markedly suppressed after thermal injury. T lymphocyte dysfunction and macrophage hyperactivity have been implicated as causative factors. Previous studies have primarily examined the effects of thermal injury on αβ T lymphocytes; however, the role of γδ T lymphocytes in the immune response after thermal injury is unclear. Therefore, wild-type mice and mice lacking the TCR δ gene (TCR δ−/−) were subjected to a third-degree scald burn and cell-mediated immune responses assessed at 7 days post-injury. TCR δ−/−mice had 75% mortality after burn injury compared with 25% mortality in the wild-type group. Plasma interluekin-6 (IL-6) levels were significantly elevated at 2, 4, and 18 h post-injury, whereas no difference was observed in tumor necrosis factor α (TNF-α) and prostaglandin E2 (PGE2) plasma levels. Plasma levels of these inflammatory mediators were similar in wild-type and TCR δ−/-_ mice post-injury. Splenic macrophage PGE2, IL-6, TNF-α, and IL-10 production was significantly increased in wild-type mice at 7 days post-injury, whereas macrophages from injured TCR δ−/− mice had a significantly attenuated capacity to produce IL-6 and TNF-α. In contrast, the increased release of PGE2 and IL-10 by macrophages post-injury was not reduced in TCR δ−/− mice. These results implicate a dual role for γδ T lymphocytes in the immunopathogenic response to burn injury: (1) they contribute to survival from the insult; and (2) they mediate the induction of a pro-inflammatory macrophage phenotype at 7 days post-injury. Thus, γδ T lymphocytes, in part through the modulation of macrophage activity, appear to contribute to the immune dysfunction after thermal injury. J. Leukoc. Biol. 67: 644–650; 2000.
Scavenger receptor-mediated delivery of muramyl dipeptide activates antitumor efficacy of macrophages by enhanced secretion of tumor-suppressive cytokines
Authors: Srividya S , Roy Rajendra P , Basu Sandip K , Mukhopadhyay Amitabha
Published: January 2018

We showed that muramyl dipeptide (MDP) conjugated to maleylated bovine serum albumin (MBSA) was internalized by macrophages (M) through scavenger receptor (SCR)-mediated endocytosis, which leads to 50-fold higher cytotoxic activity against non-M tumor cells compared with that elicited by free MDP-treated M. The enhanced cytotoxic effect of MBSA-MDP was found to be a result of higher secretion of interleukin (IL)-1, IL-6, tumor necrosis factor α (TNF-α), and nitric oxide (NO) because the addition of antibodies directed against IL-1, IL-6, or TNF-α in combination with M cultures totally abrogated the tumoricidal activity of MBSA-MDP. It is interesting to note that MBSA-MDP triggers the secretion of IL-12, whereas IL-10, a M suppressor cytokine, could be detected only on free MDP treatment. The cytotoxic activity of MBSA-MDP was inhibited by indomethacin, indicating a regulatory role for prostaglandin E2 (PGE2). Efficient SCR-mediated intracellular delivery of MDP leading to elimination of cancer cells suggests the immunotherapeutic potential of this approach for treatment of neoplasia. J. Leukoc. Biol. 67: 683–690; 2000.
Differential chemokine receptor expression and function in human monocyte subpopulations
Authors: Weber Christian , Belge Kai-Uwe , von Hundelshausen Philipp , Draude Georg , Steppich Birgit , Mack Mathias , Frankenberger Marion , Weber Kim S C , Ziegler-Heitbrock H W Löms
Published: January 2018

The subset of human blood monocytes expressing low levels of CD14 and high levels of CD16 (CD14+CD16+) exhibits features resembling mature tissue macrophages and can be expanded in inflammatory conditions. We analyzed expression of CC chemokine receptors (CCR) in CD14+CD16+ versus CD14++ monocytes, which may be crucial for specific trafficking. Multicolor flow cytometric analysis of whole peripheral blood revealed that, as opposed to CD14++ monocytes, the CD14+CD16+ subset lacked surface expression of monocyte chemotactic protein-1 (MCP-1) receptor CCR2, however, it showed significantly higher surface expression of the macrophage inflammatory protein 1α (MIP-1α)/RANTES receptor CCR5. This was paralleled by differences in mRNA expression in the subsets, as shown by reverse transcriptase-polymerase chain reaction using sorted cells. In comparison to CD14++ monocytes, CD14+CD16+ cells expressed lower CCR2 but higher CCR5 transcript levels, whereas CCR1 levels were equivalent. Flow cytometric analysis of isolated human monocytes recovered after transendothelial chemotaxis assays revealed that the percentage of CD14+CD16+ cells was dramatically reduced in the fraction migrating toward MCP-1 compared with the fraction that did not migrate or the input, showing that polarized CCR2 expression was accompanied by a differential chemotactic responsiveness. Moreover, CD11b surface expression was preferentially up-regulated by MCP-1 in CD14++ cells but by MIP-1α in CD14+CD16+ monocytes, confirming the functional relevance of distinct CCR expression. The characteristics of CD14+CD16+ cells may reflect preactivation by cytokines and determine their predilective localization during specific inflammatory conditions or susceptibility to infection. J. Leukoc. Biol. 67: 699–704; 2000.
Positive regulation of human T cell activation by Gi2 proteins and interleukin-8
Authors: Lippert Eric , Jacques Yannick , Hermouet Sylvie
Published: January 2018

We investigated whether pertussis toxin (PT)-sensitive heterotrimeric Gi proteins (Gi1, Gi2, Gi3) are involved in the regulation of TCR-induced activation of human T cells. First, Gi proteins were inactivated by PT: pretreatment with PT of purified blood T lymphocytes before CD3 cross-linking inhibited cell proliferation (-71.1 ± 22.0%, P < 0.001), production of interleukin-2 (IL-2; -47.3 ± 12.6%, P = 0.008), and expression of CD25 (-24.6 ± 11.7%, P < 0.001) and CD69 (-25.7 ± 9.0%, P < 0.001). Then, to identify which of the three Gi was involved, Gi1, Gi2, and Gi3 proteins were specifically inactivated by stably transfecting dominant-negative mutated forms of their α subunit in Jurkat cells. After activation, IL-2 production and CD69 expression were inhibited only in cells expressing inactive Gi2. We then studied the effects of interleukin-8 (IL-8), a CXC-chemokine with receptors coupled to Gi2 and produced in an autocrine fashion by activated T cells. Although its effects varied among donors, exogenous IL-8 stimulated proliferation and CD25 expression (up to, respectively, 200 and 77%) of PB T lymphocytes in response to CD3 activation, in a PT-sensitive manner. IL-8 also stimulated IL-2 production (by up to 42%) and CD69 expression, although weakly (+27%). Anti-human IL-8 antibody inhibited proliferation (-43%) and CD25 up-regulation (-45%) of activated T lymphocytes. In summary, several major responses of human T lymphocytes to TCR-mediated activation are regulated by Gi2 proteins, which for this function can be activated by IL-8 in an autocrine manner.
Toll receptors: an expanding role in our understanding of human disease
Authors: Schuster James M , Nelson Peter S
Published: January 2018

Toll receptor proteins in Drosophila are involved in establishing the dorsal-ventral axis in embryogenesis as well as participating in the innate immune response to invading pathogens. The basic mediators of this response show striking similarities in plants, insects, and vertebrates. The cytoplasmic signaling cascade is exemplified by the human interleukin-1 receptor complex (IL-1R), resulting in transcriptional activation of effector proteins through nuclear factor-κB (NF-κB). Six mammalian/human Toll-like receptors (TLR) have been described to date. The TLRs share the IL-1R cytoplasmic signaling cascade but are distinguished by their extracellular leucine-rich repeat (LRR) structure. The LRR superfamily comprises a diverse group of proteins, including a cohort involved in transmembrane signaling. Two of the human TLRs (TLR2, TLR4) have been shown to be involved in the innate response to bacterial pathogens and appear to provide a link between the innate and adaptive immune response. A better understanding of this response may provide improved therapeutic modalities in the treatment of bacterial and fungal sepsis, which continues to be a significant source of morbidity and mortality worldwide. In addition, similar to Drosophila, Toll receptors and related proteins in the LRR superfamily may also be involved in human development, as well as in noninfectious human disease. J. Leukoc. Biol. 67: 767–773; 2000.
Oral feeding of an immunodominant MHC donor-derived synthetic class I peptide prolongs graft survival of heterotopic cardiac allografts in a high-responder rat strain combination
Authors: Zavazava Nicholas , Fändrich Fred , Zhu Xiaofeng , Freese Anja , Behrens Dirk , Yoo-Ott Kyoung-Ae
Published: January 2018

The efficacy of two synthetic major histocompatibility complex (MHC)-derived DA (RT1.Aa) 25-mer peptides (residues 56–80 and 96–120) to modulate alloreactivity was tested in Lewis (RT1.A1) responder animals. The DA peptide 56–80, but not peptide 96–120, induced delayedtype hypersensitivity (DTH). DTH was significantly reduced by oral feeding of peptide 56–80, P = 0.004. In addition, oral feeding of this peptide in combination with a short course of cyclosporin A (CsA) prolonged graft survival of 60% of heterotope transplanted DA cardiac allografts in Lewis recipient rats. Long-term survivors developed low levels of allo-antibodies against donor tissue as compared to rejecting animals and increased levels of interleukin-4 (IL-4) within the allograft. Similarly, IL-4-secreting splenocytes were identified by flow cytometry in these animals, indicating a Th2-type cytokine pattern. However, graft survival was particularly limited to cardiac allografts because donor-type skin grafts were acutely rejected in tolerant animals. It is interesting that residue alignment of peptide 56–80 to the motif of the RT1.A1 molecule showed a preferred class I motif within this sequence, suggesting indirect presentation of this peptide to recipient T cells. Thus, peptide 56–80 appears to represent a dominant epitope that can be exploited for establishing tolerance in this transplantation strain combination. J. Leukoc. Biol. 67: 793–800; 2000.
Characterization of activated lymphocyte-tumor cell adhesion
Authors: Neeson Paul J , Thurlow Peter J , Jamieson Gary P
Published: January 2018

This study demonstrates the variable expression of ICAM-1 and leukocyte function antigen-3 (LFA-3) on four tumor cell lines (COLO526, K562, Daudi, and HT-29). In addition, phorbol ester (PMA) activation of lymphocytes modulated LFA-1 from a uniform to a clustered surface distribution; whereas after treatment with high levels of Mg2+ ions, the unique epitope for high-affinity LFA-1 was identified using clone Mab24. Using a flow cytometric adhesion assay it was demonstrated that PMA-activated lymphocytes formed conjugates with COLO526 and Daudi, and that these conjugates were inhibited by anti-CD2 with varying inhibition by LFA-1 clones MHM24 and 25.3.1. When lymphocytes were induced to express the high-affinity form of LFA-1, conjugates were identified with COLO526, K562, and Daudi and these conjugates were sensitive to the presence of both CD2 and LFA-1 antibodies. Further studies using confocal microscopy confirmed significant adhesion between peripheral blood lymphocytes pre-treated with either PMA or high levels of Mg2+ and the adherent cell line COLO526. In conclusion, this unique study has demonstrated for the first time the important role of the active form of LFA-1 on the lymphocyte cell surface for conjugate formation with an ICAM-1-expressing tumor cell; also, two pathways of cell signaling were identified for conjugate formation to occur. J. Leukoc. Biol. 67: 847–855; 2000.
Improved portal vein venoplasty with an autogenous patch in pediatric living donor liver transplantation
Authors: Feng Mingxuan , Wan Ping , Qiu Bijun , Zhou Tao , Luo Yi , Gu Lihong , Chi Jiachang , Zhong Chengpeng , Lu Yefeng , Zhang Jianjun , Xia Qiang
Published: January 2018

A stenotic or hypoplastic portal vein (PV) represents a challenge for PV reconstruction in pediatric living donor liver transplantation (LDLT). Several PV venoplastic techniques have been developed. However, we still seek improved venoplastic techniques with better efficacy and compatibility. From June 2016 to July 2017, 271 LDLT procedures were performed at the Department of Liver Surgery, Renji Hospital. A total of 16 consecutive children with stenotic and sclerotic PVs underwent a novel technique—the autogenous PV patch plastic technique. Vessel patches were procured from the left branch (LB), or the bifurcation of the right branch and LB of the PV in the native liver. Then, the PVs were enlarged by suturing the patches along the longitudinal axis from the confluence of the PV and coronary vein (CV). In this series, 15/16 achieved good intraoperational PV flow, and 1 showed low PV flow but was treated with stent placement. Within a median follow‐up of 11 months (1‐18 months), 15 patients were alive and had normal graft function, whereas 1 child died from lung infection 1 month after transplantation. No PV complications were detected. In conclusion, the autogenous patch venoplasty technique using the PV‐CV confluence is simple and safe. This novel venoplastic reconstruction technique could serve as a surgical option to achieve satisfactory outcomes, especially those with stenotic PV (<4.5 mm) and dilated CV (>3.0 mm). Liver Transplantation 2018 AASLD.
Computational Tools for the Identification and Interpretation of Sequence Motifs in Immunopeptidomes
Authors: Alvarez Bruno , Barra Carolina , Nielsen Morten , Andreatta Massimo
Published: January 2018

Recent advances in proteomics and mass‐spectrometry have widely expanded the detectable peptide repertoire presented by major histocompatibility complex (MHC) molecules on the cell surface, collectively known as the immunopeptidome. Finely characterizing the immunopeptidome brings about important basic insights into the mechanisms of antigen presentation, but can also reveal promising targets for vaccine development and cancer immunotherapy. This report describes a number of practical and efficient approaches to analyze immunopeptidomics data, discussing the identification of meaningful sequence motifs in various scenarios and considering current limitations. Guidelines are provided for the filtering of false hits and contaminants, and to address the problem of motif deconvolution in cell lines expressing multiple MHC alleles, both for the MHC class I and class II systems. Finally, it is demonstrated how machine learning can be readily employed by non‐expert users to generate accurate prediction models directly from mass‐spectrometry eluted ligand data sets.
Discussion of “The power of monitoring: how to make the most of a contaminated multivariate sample”
Authors: Perrotta Domenico , Torti Francesca
Published: January 2018

We contribute to the discussion of an article where Andrea Cerioli, Marco Riani, Anthony Atkinson and Aldo Corbellini review the advantages of analyzing multivariate data by monitoring how the estimated model parameters change as the estimation parameters vary. The focus is on robust methods and their sensitivity to the nominal efficiency and breakdown point. In congratulating with the authors for the clear and stimulating exposition, we contribute to its discussion with an overview of what we experienced in applying the monitoring in our application domain.
Facilitating adherence to endocrine therapy in breast cancer: stability and predictive power of treatment expectations in a 2-year prospective study
Authors: Pan Yiqi , Heisig Sarah R. , von Blanckenburg Pia , Albert Ute-Susann , Hadji Peyman , Rief Winfried , Nestoriuc Yvonne
Published: January 2018

Purpose

To identify modifiable factors predictive of long-term adherence to adjuvant endocrine therapy (AET).

Methods

As part of a 2-year cohort study in primary care (n = 116), we investigated whether initial treatment expectations predict adherence at 24 months after controlling for demographic, medical, and psychosocial variables. Treatment expectations were measured as necessity–concern beliefs, expected side-effect severity, and expected coping with side effects. Their stability over time and differences of trajectories between the adherent and nonadherent group were examined.

Results

Nonadherence at 24 months was 14.7% (n = 17). Side-effect severity at 3 months [OR 0.25, 95% CI (0.08, 0.81), p = 0.02] and necessity–concern beliefs [OR 2.03, 95% CI (1.11, 3.72), p = 0.02] were the sole predictors of adherence. Necessity–concern beliefs remained stable over 2 years, whereas expected side-effect severity (p = 0.01, η
p
2
 = 0.07) and expected coping with side effects became less optimistic over time (p < 0.001, η
p
2
 = 0.19), the latter particularly among nonadherers (p < 0.01, η
p
2
 = 0.10).

Conclusions

Patients’ initial necessity–concern beliefs about the AET and early severity of side effects affect long-term adherence. Expecting poor management of side effects may also facilitate nonadherence. We suggest that discussing benefits, addressing concerns of AET, and providing side-effect coping strategies could constitute a feasible and promising option to improve adherence in clinical practice.
Risk factors for nasal bleeding in patients undergoing transnasal gastrointestinal endoscopy
Authors: Mieda Mitsuyo , Miyashita Hiroshi , Osawa Hiroyuki , Hirasawa Tomosuke , Makino Nobuko , Toma Sachiko , Tomiyama Takeshi , Miura Yoshimasa , Lefor Alan K. , Yamamoto Hironori
Published: January 2018

Transnasal endoscopy is widely used in screening for upper gastrointestinal lesions because of less associated pain. Nasal bleeding is the most severe adverse effect, but specific risk factors have not been identified. The aim of this study is to identify risk factors for nasal bleeding during transnasal endoscopy. Nasal bleeding occurred in 160/3035 (5.3%) of patients undergoing transnasal endoscopy as part of health checkups. Patient data were retrospectively evaluated including anthropometric, medical, and life‐style parameters with multiple logistic regression analysis. Multiple logistic regression revealed that nasal bleeding was significantly associated with age in decades [odds ratio/10 years 0.78, 95% confidence interval (CI) 0.63–0.97, p = 0.027], female gender (2.15, 95% CI 1.48–3.12, p < 0.001), a history of previous upper gastrointestinal endoscopy (0.55, 95% CI 0.36–0.82, p = 0.004), and chronic/allergic rhinitis (0.60, 95% CI 0.36–0.98, p = 0.043). Other factors including the use of antiplatelet and/or anticoagulant drugs were not significantly associated with nasal bleeding. Female and young patients are significantly associated with an increased risk of bleeding from transnasal endoscopy, but antiplatelet and/or anticoagulant medications and a history of chronic/allergic rhinitis may not be associated.
Eating Money: Corruption and its categorical ‘Other’ in the leaky Indian state
Authors: MATHUR NAYANIKA
Published: January 2018

This article studies corruption in India through an ethnographic elaboration of practices that are colloquially discussed as the ‘eating of money’ (paisa khana) in northern India. It examines both the discourse and practice of eating money in the specific context of the implementation of the National Rural Employment Guarantee Act, 2005 (NREGA). The article works through two central paradoxes that emerge in the study of corruption and the state. The first paradox relates to the corruption–transparency dyad. The ethnography presented shows clearly that the difficulties in the implementation of NREGA arose directly out of the transparency requirements of the statute, which were impeding the traditional eating of money. Instead of corruption being the villain it turns out that, in this particular context, it was its categorical Other—transparency—that was to blame. The second and related paradox emerges from an ethnographic examination of the processes and things through which development performance, corruption, and transparency are established and adjudged in the contemporary Indian state. Corrupt state practices and transparent state functioning are authoritatively proclaimed through an assessment of evidence—material proof in the form of paper—that is constructed by the Indian state itself. The push for transparency in India at the moment is not only leading to an excessive focus on the production of these paper truths but, more dangerously, is also deflecting attention away from what is described as the ‘real’ (asli) life of welfare programmes. Ultimately, this article contends that we need to eschew treating corruption as an explanatory trope for the failure of development in India. Instead of devising ever-more punitive auditing regimes to stem the leakages of the Indian state, this work suggests that we need a clearer understanding of what the state really is; how—and through which material substances—it functions and demonstrates evidence of its accomplishments.
Pīrs and Politics in Punjab, 1937–2013
Authors: MALIK ADEEL , MALIK TAHIR
Published: January 2018

This article provides a first systematic mapping of politically influential shrines across Pakistani Punjab by identifying shrine-related families that have directly participated in elections since 1937. One of the earliest entrants in the politics of pre-partition Punjab, shrine elites (pīrs) have shown remarkable persistence in electoral politics post independence. We find striking long-run continuities in the initial configuration of religion, land, and politics fostered during colonial rule and embodied in political shrines. Exploring possible mechanisms of this persistence, we emphasize the role of shifting political alliances, repeated military interventions, marital ties among shrine elites, and preservation of political brokerage. Defined by their privileged ‘origins and associations’ and organized as a group with a strong sense of solidarity around protecting common interests, the pīrs are a key component of Punjab's power elite, the study of which is central to understanding the genesis and persistence of elites and institutions.
OP08 National Institute for Health Research Health Technology Assessment Programme Research Funding And United Kingdom Burden Of Disease
Authors: Chinnery Fay , Bashevoy Gemma , Blatch-Jones Amanda , Douet Lisa , Puddicombe Sarah , Raftery James
Published: January 2018

INTRODUCTION:

This study compared the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme portfolio of research with the united Kingdom (UK) burden of disease, as measured by Disability-Adjusted Life Years (DALYs).

METHODS:

Design: Cross-sectional study.

Setting: The HTA Programme cohort included all funded applications (n = 363) received by the HTA Programme during the period 1 April 2011 to 31 March 2016. The sample contained primary research and evidence syntheses, all purely methodological studies were excluded since these are not comparable to the other study types.

Main Outcome Measure: Proportion of spend for each of the twenty-one Health Research Classification System (HRCS) health categories were compared with burden of disease in the UK calculated using 2015 DALY data from the Institute for Health Metrics and Evaluation (IHME) Global Health Data Exchange (GHDx).

RESULTS:

The funded HTA Programme projects totalled about GBP397million research spend, which broadly reflected the UK DALY burden. Overall, there was less than 5 percent difference between the actual and predicted programme spend based on the burden of disease in the UK in most instances (seventeen out of the twenty-one HRCS Health Categories).

The largest categories of apportioned spend were Cancer (accounting for 12.1 percent of portfolio), and Mental Health (11.8 percent of portfolio) which particularly reflected the 9.8 percent burden of disease to the UK. Most notable deviations from DALY, where spend was lower than disease burden, were in the Cancer, Cardiovascular and Musculoskeletal categories; which may reflect the importance of other, notably charity, funding.

CONCLUSIONS:

The HTA Programme spend broadly aligns with burden of disease as measured using DALYs. Discrepancies were expected owing to the programme remit and its approach to commissioning research to address market failure particularly in areas that are not already well supported by research charities or industry. Regular review of DALY data during research prioritisation and commissioning allows the HTA Programme to identify and address shortfalls in disease areas and to balance its portfolio.
OP51 Thrombectomy In France: A National Use Of European Network for Health Technology Assessment (EUnetHTA) Joint Assessment
Authors: Lhuillier-Nkandjeu Huguette , Morin-Surroca Michèle
Published: January 2018

INTRODUCTION:

Mechanical thrombectomy (MT) is used in patients with acute ischaemic stroke due to occlusion of a proximal cerebral artery. Over the years endovascular techniques have been used to re-canalise blocked vessels, but are not currently reimbursed by National Health Insurance in France.

The aim was to assess the efficacy and safety of MT in combination with intravenous tissue plasminogen activator (IV t-PA), or as an alternative to it, in adults with an acute ischaemic stroke who are not eligible for thrombolysis or in whom thrombolysis has failed; to support the reimbursement decision by National Health Insurance.

METHODS:

Within the scope of The European Network for Health Technology Assessment (EUnetHTA), a rapid assessment of “Endovascular therapy using devices for acute ischaemic stroke” was jointly produced with Haute Autorité de santé (HAS) as a reviewer.

RESULTS:

The EUnetHTA report provided a systematic review based on eight randomized controlled trials (RCT) for effectiveness and all available published data for safety.

To produce its assessment, HAS has adapted the EUnetHTA report by:

1.

Updating the systematic literature review including the latest published trials

2.

Retaining the subgroup analysis of the five most recent trials considered more relevant in the EUnetHTA report for the assessment of effectiveness

3.

Analysing specifically the different endovascular interventions studied in the five RCTs

4.

Taking into account contributions from stakeholders.

CONCLUSIONS:

This horizontal collaboration among European HTA doers has facilitated and shortened the assessment of the clinical benefit of this technology, confirming the relevance of EUnetHTA cooperation.

This clinical assessment of thrombectomy is to be completed by the evaluation of its organizational impact in the management of acute ischemic stroke.
OP67 Cost-Effectiveness of Human Papillomavirus-based Primary Cervical Screening In Ireland
Authors: O'Neill Michelle , Murphy Linda , Harrington Patricia , Sroczynski Gaby , Ryan Mairin
Published: January 2018

INTRODUCTION:

The cost-effectiveness of Human papillomavirus (HPV)-based primary cervical screening in the Irish healthcare setting is assessed using a decision-analysis approach to inform a decision around changes to the national screening program. Current practices comprises primary screening with liquid-based cytology (LBC) followed by HPV triage, at 3-yearly intervals for ages 25 to 45 years and 5-yearly until age 60 years.

METHODS:

This study assessed changing the primary screening test from LBC to HPV testing, in both an unvaccinated and a vaccinated (against HPV 16/18) cohort. It considered extending the screening interval (to 5-yearly for all), the upper age limit (from 60 to 65 years) and different test sequences (four possible tests were included: HPV, LBC, partial genotyping for HPV16 or HPV 18 and the molecular biomarker p16INK4a/Ki67). A Markov-model for HPV-infection and cervical cancer was developed based on a German cervical screening model (1). The perspective of the healthcare system was adopted and a 5 percent discount rate used.

RESULTS:

Strategies using HPV as the primary screening test are more effective than LBC-based strategies. The optimal strategy, at a willingness-to-pay threshold of EUR45,000 per quality-adjusted life year (QALY), for the unvaccinated cohort was HPV-based primary screening with a LBC triage test, at five-yearly intervals from age 25 to 60 years. This strategy is cost saving compared with current practice and cost effective when compared to no screening, with an Incremental cost-effectiveness ratio (ICER) of EUR18,164 per QALY. The optimal strategy for the vaccinated cohort was also HPV primary screening with a LBC triage test, at five-yearly intervals from age 25 to 60 years. While more effective and cost saving compared with current practice, it would not be considered cost effective compared with no screening (ICER of EUR58,745/QALY).

CONCLUSIONS:

Based on our analyses, HPV-based cervical screening is more effective and cost saving compared with LBC-based screening for both vaccinated and unvaccinated cohorts in an Irish setting.
OP71 Evidence-Based Searching For Health Technology Assessment – Keeping Up-to-Date With Summarized Research In Information Retrieval (SuRe Info)
Authors: Isojarvi Jaana , Glanville Julie , Chalon Patrice , Kaunelis David , Lefebvre Carol , Wright Kath
Published: January 2018

INTRODUCTION:

Increasing numbers of research papers about information retrieval for Health Technology Assessments (HTA), systematic reviews and other evidence syntheses are being published. It is time-consuming for information specialists to keep up-to-date with the latest developments in the field. To help searchers with this challenge, the Interest Group on Information Retrieval (IRG) of Health Technology Assessment International (HTAi) has compiled the best available research evidence on information retrieval aspects into an open-access web resource: Summarized Research in Information Retrieval for HTA (SuRe Info). The resource can be accessed at http://www.sure-info.org

METHODS:

The Sure Info team run topic-specific search strategies in selected relevant databases to identify information retrieval methods publications that fulfil the SuRe Info inclusion criteria. Eligible publications receive a structured abstract containing a brief critical appraisal. Key messages for search practice based on the appraisals and accepted best practice are summarized into topic-specific chapters.

RESULTS:

SuRe Info currently offers fourteen chapters, with more in development. SuRe Info chapters fall into two categories: (i) chapters about general search methods that are used across all types of research, such as how to develop search strategies and the availability and use of search filters, and (ii) chapters summarizing the methods to use when searching for specific aspects of HTA (as defined in the European Network for HTA (EUnetHTA) HTA Core Model®), including searching for evidence on clinical effectiveness and safety, and identifying economic evaluations. References at the end of each chapter are linked to appraisals of publications that have been used to develop each chapter. Links to the full-text of the publications are provided when freely available. The SuRe Info chapters are reviewed every six months and updated if new evidence is identified or if resources change.

CONCLUSIONS:

SuRe Info is a unique resource, identifying and summarizing current best research evidence on information retrieval aspects for HTA. It supports the timely uptake of potential efficiencies arising from new evidence that may be incorporated into the evidence identification processes of HTA organizations.