bluuebunny/crossref_metadata_2025 huggingface dataset:
Roles, identity, and security: foreign policy contestation in monarchical Kuwait
Authors: Yom Sean
Published: October 2019

The 2011–2012 Arab Spring posed an existential threat to the Gulf Cooperation Council’s six monarchies. A major response was the 2012 GCC Internal Security Pact, an innovative project to enhance cross-border repression of domestic opposition and thus bolster collective security. Yet despite its historic weakness, ongoing domestic unrest, and initial enthusiasm for the agreement, Kuwait’s monarchy did not ultimately ratify the accord. Building on theories of foreign policy roles and identity, this article presents an ideational explanation for this puzzle. The Security Pact failed because it sparked identity contestation. For many Kuwaitis, the prospect of the Sabah monarchy imposing this scheme for greater repression was incompatible with the regime’s historical role of tolerating domestic pluralism and protecting Kuwait from foreign pressures. This role conception of a tolerant protector flowed from historical understandings and collective memory and was cognitively tied to a national self-conception of “Kuwaiti-ness.” The mobilizational scope and symbolic power of this popular opposition convinced the regime to acquiesce, despite possessing the strategic incentive and resources to impose the treaty by force. The Kuwaiti case therefore exemplifies how domestic contestation over regime identities and roles can constrain foreign policy behavior, even in authoritarian states facing severe crises of insecurity.
Financial barriers in accessing medical care for peripheral artery disease are associated with delay of presentation and adverse health status outcomes in the United States
Authors: Jelani Qurat-ul-ain , Jhamnani Sunny , Spatz Erica S , Spertus John , Smolderen Kim G , Wang Jingyan , Desai Nihar R , Jones Philip , Gosch Kensey , Shah Samit , Attaran Robert , Mena-Hurtado Carlos
Published: October 2019

Patient-reported difficulties in affording health care and their association with health status outcomes in peripheral artery disease (PAD) have never been studied. We sought to determine whether financial barriers affected PAD symptoms at presentation, treatment patterns, and patient-reported health status in the year following presentation. A total of 797 United States (US) patients with PAD were identified from the Patient-centered Outcomes Related to TReatment Practices in Peripheral Arterial Disease: Investigating Trajectories (PORTRAIT) study, a prospective, multicenter registry of patients presenting to vascular specialty clinics with PAD. Financial barriers were defined as a composite of no insurance and underinsurance. Disease-specific health status was measured by Peripheral Artery Questionnaire (PAQ) and general health-related quality of life was measured by EuroQol 5 (EQ5D) dimensions at presentation and at 3, 6, and 12 months of follow-up. Among 797 US patients, 21% ( n = 165) of patients reported financial barriers. Patients with financial barriers presented at an earlier age (64 ± 9.5 vs 70 ± 9.4 years), with longer duration of symptoms (59% vs 49%) (all p ⩽ 0.05), were more depressed and had higher levels of perceived stress and anxiety. After multivariable adjustment, health status was worse at presentation in patients with financial barriers (PAQ: –7.0 [–10.7, –3.4]; p < 0.001 and EQ5D: –9.2 [–12.74, –5.8]; p < 0.001) as well as through 12 months of follow-up (PAQ: –8.4 [–13.0, –3.8]; p < 0.001 and EQ5D: –9.7 [–13.2, –6.2]; p < 0.001). In conclusion, financial barriers are associated with later presentation as well as poorer health status at presentation and at 12 months. ClinicalTrials.gov Identifier: NCT01419080
A new vertical dynamic model for railway vehicle with passenger-train-track coupling vibration
Authors: Yu Yuewei , Zhao Leilei , Zhou Changcheng
Published: October 2019

In order to further reveal the vertical random vibration characteristics of railway vehicles, using the system engineering method, taking the passenger, the train system, and the track system (ballast track) as a unified whole, a passenger-train-track vertical coupling dynamic model is established, and the vibration differential equations of the model are derived. In the model, passengers are regarded as a single-degree-of-freedom system attached to the bottom of the carriage, the train system is represented as a 10-degree-of-freedom multi-rigid body model, the track system is regarded as the infinite long Euler beam model with three layers of continuous elastic point support, and the Hertz nonlinear elastic contact theory is applied to the wheel and rail coupling relationship. Based on this, the time-domain numerical solution of the passenger-train-track vertical coupling dynamic model is given by using Newmark- β implicit integration algorithm, and the correctness of the model is verified by the real vehicle test. This study can provide some theoretical basis for the design of railway vehicles and provide fundamentals for the coordinated control and system optimization of railway vehicle ride comfort.
High-frequency wall heat flux measurement during wall impingement of a diffusion flame
Authors: Moussou Julien , Pilla Guillaume , Sotton Julien , Bellenoue Marc , Rabeau Fabien
Published: October 2019

The efficiency of internal combustion engines is limited by heat losses to the wall of the combustion chamber. A precise characterization of wall heat flux is therefore needed to optimize engine parameters. However, the existing measurements of wall heat fluxes have significant limitations; time resolution is often higher than the timescales of the physical phenomena of flame–wall interaction. Furthermore, few studies have investigated diesel flame conditions (as opposed to propagation flames). In this study, the heat flux generated by a diffusion flame impinging on a wall was measured with thin-junction thermocouple, with a time resolution of the whole acquisition chain better than 0.1 ms. The effects of variations in ambient gas temperature, injection pressure and injector–wall distance were investigated. Diesel spray impingement on the wall is shown to cause strong gas–wall thermal exchange, with convection coefficients of 6–12 kW/m2/K. Those results suggest the necessity of close-wall aerodynamic measurements to link macroscopic characteristics of the spray (injection pressure, impingement geometry) to turbulence values.
Trading Liberties for Security: Groupthink, Gender, and 9/11 Effects on U.S. Appellate Decision-Making
Authors: Reid Rebecca , Schorpp Susanne , Johnson Susan W.
Published: October 2019

Does groupthink affect court deference to the government in times of heightened security concerns? We argue that male judges serving in homogeneous panels in federal appellate courts modified their behavior post-9/11, but that the presence of a female on the panel mitigated these effects. Using data on the U.S. Court of Appeals from 1978 to 2008 in search-and-seizure cases, we argue that women can safeguard against groupthink effects that otherwise trend toward a more deferential, less rights-oriented approach in times of heightened security. Our findings suggest women mitigate their male colleagues’ shift toward more deferential decisions by affecting panel outcomes that are more consistent with peacetime decisions. These results suggest the important role women exert in collegial panels beyond direct voting patterns. In times of heightened security concerns, panel diversity can avoid groupthink that might stand in the judiciary’s way of providing an effective check on executive and legislative power.
Trauma-Focused Cognitive Behavioral Therapy With a 6-Year-Old Boy
Authors: Jørgensen Irene Marcela , Cantio Cathriona , Elklit Ask
Published: October 2019

A considerable minority of children are exposed to prolonged periods of repeated or multiple interpersonal traumas at an early age, yet few interventions exist for this vulnerable population. This current case study presents manualized trauma-focused cognitive behavioral therapy (TF-CBT) with a 6-year-old boy who had been exposed to multiple traumatic events. The boy presented with symptoms of post-traumatic stress disorder (PTSD), depression, attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), specific phobia, reactive attachment disorder, and psychosocial malfunction in several domains. After TF-CBT was implemented, he no longer met the criteria of PTSD, depression, ADHD, and specific phobia. He also improved in several domains of psychosocial function. In addition, the mother reported a better quality of the parent–child relationship, and they both demonstrated a better understanding of trauma reactions and how to apply new coping and problem-solving skills. Finally, the young boy showed improvements in academic performance, social interactions, and general emotional and behavioral functioning. This case study adds to the growing literature, highlighting the utility of using TF-CBT to successfully treat symptoms of PTSD and associated psychopathology in young children with a history of complex trauma.
When Monogenic Isn’t Monogenic—Unravelling the Oligogenic Architecture of the Developmental and Epileptic Encephalopathies
Authors: Scheffer Ingrid E. , Liao Jianxiang
Published: October 2019

[Box: see text]
Reframing Integration for Mixed Methods Research
Authors: Lynam Timothy , Damayanti Rita , Rialine Titaley Christiana , Suharno Nugroho , Bradley Mark , Krentel Alison
Published: October 2019

We suggest and illustrate from our experiences of integration in a public health context in Indonesia, a reframing of integration for mixed methods research that focuses on context, outcomes, objects, and integrative mechanisms. Through describing the tools and conceptualizations that helped us integrate, we argue for expanding the scope of integration to include social process methods (which we describe) and for rethinking the desired outcomes of integration. The article contributes to the field of mixed methods research by proposing: (a) a new framing of integration that supports greater precision as well as an expanded scope over what and how integration could be implemented, (b) a set of theoretical and conceptual models to support integration, and (c) a new and fully integrated data collection instrument.
The other Europe? Scandinavian intellectuals and the fragility of democracy in the wake of World War II
Authors: Strang Johan
Published: October 2019

It is often argued that the Scandinavian post-war period was marked by a democratic optimism that contrasts with the deep concerns for the inherent dangers of popular sovereignty and the thorough moral reconsideration that took place on the European continent in the wake of World War II. This article seeks to balance this view by exploring what Scandinavian intellectuals believed had caused the collapse of democracy in Europe in the 1930s and what they saw as the main threats to democracy in the emerging post-war societies. Focusing on the fears of socialist planning, concerns about the position of individual rights and freedoms in modern societies, and the anxieties concerning the secular total state, the article suggests that the Scandinavian post-war democratic settlement was indeed built around a different set of ideas from those evident in many other places in Europe, but that it was no less informed by recent historical experiences or concerns for the fragility of democracy.
Write to return: The memoir of Hovhannes Cherishian and the restoration of the Armenian hearth
Authors: Lessersohn Nora
Published: October 2019

In this essay, I will analyze the memoir of Hovhannes Cherishian (1886–1967), an Ottoman Armenian shoemaker and genocide survivor from what is now southern Turkey, as an attempt to “restore the ruined ancestral [Armenian] hearth” and render “part of the lost legacy of [his] forebears” back unto “the possession of the Armenian community.” By analyzing examples of transcultural memories from Cherishian’s text, I will highlight the ways in which Cherishian uses his memoir to restore (and thus return to) a complex, multicultural, pre-genocide Ottoman Armenian existence. I will first locate Cherishian’s memoir in nostalgia and memory studies as a way to draw out his role as an author. I will then explore aspects of Cherishian’s text that reveal that which he lost to the genocide—and thus that which he restores through his memoir. In conclusion, I will discuss briefly the importance of memory sources for writing Ottoman and Armenian history.
The transcultural Ottoman table
Authors: Roden Claudia
Published: October 2019

Claudia Roden writes about the Egypt she grew up in – a mixed cosmopolitan world with long-established communities of Armenians, Greeks, Italians, Syrians and Lebanese, as well as French and British expatriates. Roden was born in Cairo in the Jewish community that was itself a mosaic of people who had come from all over the Ottoman Empire. Roden recounts her experiences of collecting recipes from communities who were leaving Egypt after the Suez crisis in 1956 and her nostalgia and determination to preserve a culture that disappeared, and which had few written recipes. This led her to research the cooking of Middle Eastern countries and becoming interested in the cultural and historical background of the food. She focuses on the sophisticated cuisine that developed in ex-Ottoman countries, and Lebanon in particular, emphasizing the importance of transcultural exchanges and memories around the table.
She Came from Kasaba
Authors: Hakim-Dowek Leslie
Published: October 2019

As in Marianne Hirsch’s (2008) notion of ‘devoir de memoire’, this poem-piece, from a new series, uses the role of creation and imagination to strive to ‘re-activate and re-embody’ distant family/historical transcultural spaces and memories within the perspective of a dispersed history of a Middle-Eastern minority, the Sephardi/Jewish community. There is little awareness that Sephardi/Jewish communities were an integral part of the Middle East and North Africa for many centuries before they were driven out of their homes in the second half of the twentieth century. Using a multi-modal approach combining photography and poetry, this photo-poem series has for focus my female lineage. This piece evokes in particular the memory of my grandmother, encapsulating many points in history where persecution and displacement occurred across many social, political and linguistic borders.
Kurdish music in Turkey
Authors: Alan Suna
Published: October 2019

Musician and journalist Suna Alan gives an account of some of the songs she performs and loves. These are mainly Kurdish music. Suna describes the Dengbej tradition to which much of the music belongs. However, her summary of some songs, and excerpts from the lyrics, also draws on music by Sephardi Jews and the Armenians, other cultural groups who lived, like the Kurds, under the Ottoman Empire. The lyrics and Suna’s contextualization of them in terms of the history they tell and from which they emerge reveal the oppression and suffering of these transcultural groups under the Ottoman Empire, but also their fight against injustice. The music remembers their loves as well as their losses.
Heat-shock protein 90α in plasma reflects severity of fatigue in patients with Crohn’s disease
Authors: Grimstad Tore , Kvivik Ingeborg , Kvaløy Jan Terje , Aabakken Lars , Omdal Roald
Published: October 2019

Heat-shock proteins (HSPs) are evolutionarily conserved proteins with important cellular homeostasis functions during harmful conditions, including inflammation. Some HSPs are secreted extracellularly and act on distant cells by down-regulating inflammation and increasing cellular stress defence mechanisms. HSP90α has been postulated to signal fatigue in chronic inflammation. We investigated whether HSP90α is associated with fatigue in patients with Crohn’s disease. Fifty-three patients with newly diagnosed Crohn’s disease were included in a cross-sectional study. Data on demographics and disease distribution were obtained. Fatigue was measured by the fatigue visual analogue scale (fVAS). Disease activity was assessed by the Simple Endoscopic Score for Crohn’s disease and Harvey Bradshaw Index. C-reactive protein, faecal calprotectin and HSP90α were also measured. The median fVAS score was 52 mm, indicating significant fatigue. HSP90α scores correlated significantly with fVAS ( r =  0.31, P =  0.03). In a multivariate regression model, HSP90α was the only significant contributor to fVAS scores (β = 0.31, P =  0.03). When patients were dichotomised into groups with high and low HSP90α concentrations, significantly higher fVAS scores were demonstrated in the group with high HSP90α ( M =  62.4, confidence interval 53.0–71.8 vs. 43.3, 31.6–55.0; P =  0.01). Thus, HSP90α may contribute to fatigue generation and/or modulation in patients with Crohn’s disease.
WS PRO 160 I 120 mg (a combination of sabal and urtica extract) in patients with LUTS related to BPH
Authors: Kirschner-Hermanns Ruth , Funk Petra , Leistner Nadine
Published: October 2019

Introduction:

Lower urinary tract symptoms (LUTS) caused by prostatic enlargement are a common impairing condition in men aged 50 years and older. In the management of LUTS related to benign prostatic hyperplasia (BPH), medication, particularly by α-adrenoceptor antagonists, 5α-reductase inhibitors, and phytopharmaceuticals, is considered the first-line therapy. Despite their popularity, a number of adverse effects on the cardiovascular or cognitive systems have been reported for some of the synthetic drugs. One of the promising herbal preparations for the treatment of patients suffering from LUTS related to BPH is WS PRO 160 I 120 mg, a combination of sabal fruit extract and urtica root extract.

Methods:

This review of the literature summarizes clinical evidence for WS PRO 160 I 120 mg derived from four randomized placebo- or reference-controlled double-blind clinical trials including men aged 50 years and older. In all trials, symptomatic improvement was evaluated by the International Prostate Symptom Score (I-PSS) total score.

Results:

Treatment effects of WS PRO 160 I 120 mg were shown to be superior over placebo and comparable with the 5α-reductase inhibitor finasteride or the α1-adrenoceptor antagonist tamsulosin with more favorable tolerability and safety profiles as compared with the reference drugs.

Conclusions:

The results suggest WS PRO 160 I 120 mg to be considered as a valid alternative in the treatment of patients with early BPH, especially with view to sexual function and a good quality of life, especially in long-term use.
A comparative analysis of underground and bus transit networks through graph theory
Authors: Mussone Lorenzo , Notari Roberto
Published: October 2019

The aim of this paper is to study the topographical features of a transportation infrastructure through graph theory. First, we construct a planar, connected, and simple graph for each considered infrastructure; then, we compute some normalized indices associated to the graph, namely largest eigenvalue, gap, a Betti number, and codimension. The set of indices proposed in this paper is new for this application. These indices are computed from either the adjacency matrix or the edge ideal of the graph, and so they depend on the overall topology of the graph itself; furthermore, since the normalized indices are scale-free, they allow us a more effective comparison between different transportation infrastructures. Two scenarios are considered in order to understand advantages and limits of the proposed approach: the first scenario concerns a set of underground networks of certain large cities in the world, whereas the second one concerns a set of bus transit networks of several medium-sized cities in Italy. Indices calculated for both scenarios show two types of results. First, they show that the proposed indices are able to estimate the different topologies of the considered networks: networks with the same number of vertices and of edges but not with the same graph have different indices. Second, they show that the values of the indices in the two scenarios not only belong to the same curve separately but fit well also into the same curve: the transportation networks, no matter whether underground or bus transit, seem to be controlled by similar mechanisms.
Now I cuss less about ICUS
Authors: Lindsley R. Coleman
Published: October 2019

In this issue of Blood, Malcovati et al show that somatic mutations can identify patients with unexplained cytopenias who have, or are at a high risk of developing, myeloid malignancies. This study provides clear evidence that supports integration of gene-panel sequencing into routine clinical evaluation of unexplained cytopenias.1
Generation of polyclonal plasmablasts from peripheral blood B cells: a normal counterpart of malignant plasmablasts
Authors: Tarte Karin , De Vos John , Thykjaer Thomas , Zhan Fenghuang , Fiol Geneviève , Costes Valérie , Rème Thierry , Legouffe Eric , Rossi Jean-François , Shaughnessy John , Ørntoft Torben F. , Klein Bernard
Published: October 2019

A new way to identify tumor-specific genes is to compare gene expression profiles between malignant cells and their autologous normal counterparts. In patients with multiple myeloma, a major plasma cell disorder, normal plasma cells are not easily attainable in vivo. We report here that in vitro differentiation of peripheral blood B lymphocytes, purified from healthy donors and from patients with multiple myeloma, makes it possible to obtain a homogeneous population of normal plasmablastic cells. These cells were identified by their morphology, phenotype, production of polyclonal immunoglobulins, and expression of major transcription factors involved in B-cell differentiation. Oligonucleotide microarray analysis shows that these polyclonal plasmablastic cells have a gene expression pattern close to that of normal bone marrow–derived plasma cells. Detailed analysis of genes statistically differentially expressed between normal and tumor plasma cells allows the identification of myeloma-specific genes, including oncogenes and genes coding for tumor antigens. These data should help to disclose the molecular mechanisms of myeloma pathogenesis and to define new therapeutic targets in this still fatal malignancy. In addition, the comparison of gene expression between plasmablastic cells and B cells provides a new and powerful tool to identify genes specifically involved in normal plasma cell differentiation.
Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo
Authors: McQuibban G. Angus , Gong Jiang-Hong , Wong Julie P. , Wallace John L. , Clark-Lewis Ian , Overall Christopher M.
Published: October 2019

Monocyte chemoattractant protein (MCP)–3 is inactivated upon cleavage by the matrix metalloproteinase (MMP) gelatinase A (MMP-2). We investigated the susceptibility to proteolytic processing of the 4 human MCPs by 8 recombinant MMPs to determine whether MCP-3 is an isolated example or represents a general susceptibility of chemokines to proteolytic inactivation by these important inflammatory proteases. In addition to MMP-2, MCP-3 is efficiently cleaved by membrane type 1 (MT1)–MMP, the cellular activator of MMP-2, and by collagenase-1 and collagenase-3 (MMP-1, MMP-13) and stromelysin-1 (MMP-3). Specificity was shown by absence of cleavage by matrilysin (MMP-7) and the leukocytic MMPs neutrophil collagenase (MMP-8) and gelatinase B (MMP-9). The closely related chemokines MCP-1, MCP-2, and MCP-4 were not cleaved by MMP-2 or MT1-MMP, but were cleaved by MMP-1 and MMP-3 with varying efficiency. MCPs were typically cleaved between residues 4 and 5, but MCP-4 was further processed at Val7-Pro8. Synthetic MCP analogs corresponding to the MMP-cleaved forms bound CC chemokine receptor (CCR)–2 and CCR-3, but lacked chemoattractant activity in pre-B cells transfected with CCR-2 and CCR-3 or in THP-1 monocytic cells, a transformed leukemic cell line. Moreover, the truncated products of MCP-2 and MCP-4, like MCP-3, were potent antagonists of their cognate CC chemokine receptors in transwell cell migration assays in vitro. When they were injected 24 hours after the initiation of carrageenan-induced inflammation in rat paws, their in vivo antagonist activities were revealed by a greater than 66% reduction in inflammatory edema progression after 12 hours. We propose that MMPs have an important role in modulating inflammatory and immune responses by processing chemokines in wound healing and in disease.
Efficacious immunomodulatory activity of the chemokine stromal cell–derived factor 1 (SDF-1): local secretion of SDF-1 at the tumor site serves as T-cell chemoattractant and mediates T-cell–dependent antitumor responses
Authors: Dunussi-Joannopoulos Kyriaki , Zuberek Krystyna , Runyon Kathlene , Hawley Robert G. , Wong Anthony , Erickson Jamie , Herrmann Steve , Leonard John P.
Published: October 2019

The chemokine stromal cell–derived factor 1 (SDF-1) is essential for perinatal viability, B lymphopoiesis, and bone marrow myelopoiesis, and is a potent monocyte and T-lymphocyte chemoattractant. Interactions of SDF-1 with its receptor CXCR4 have been implicated in CD34+ cell migration and homing. Here it is shown that human SDF-1β (hSDF-1β) alone secreted by hSDF-1β–transduced tumor cells promotes efficacious antitumor responses. The murine C1498 leukemia and B16F1 melanoma models have been studied. For expression of hSDF-1β by tumor cells (SDF-tumor cells), packaging cell lines secreting retroviruses encoding hSDF-1β have been used. The results demonstrate that 50% (B16F1) and 90% (C1498) of naive mice injected with SDF-tumor cells reject their tumors. Prophylactic vaccination of naive mice with irradiated SDF-tumor cells leads to systemic immunity, and therapeutic vaccination leads to cure of established tumors. Mice that previously rejected live SDF-tumor cells are immune to the rejected tumor but susceptible to another tumor and have in vitro tumor-specific cytotoxic T lymphocyte (CTL) activity. SDF-tumor cells are not rejected by immunodeficientscid mice. Immunohistochemistry shows significant infiltration of SDF-1 tumors by T cells, and in vivo T-cell depletion studies indicate that CD4+ T cells are required for SDF-mediated tumor rejection. In conclusion, the present data suggest that SDF-1/CXCR4 interactions have the potential to regulate efficacious antitumor immune responses; exploitation of these interactions may lead to novel therapeutic interventions.
Predictive values of X-chromosome inactivation patterns and clinicohematologic parameters for vascular complications in female patients with essential thrombocythemia
Authors: Shih Lee-Yung , Lin Tung-Liang , Lai Chang-Liang , Dunn Po , Wu Jin-Hou , Wang Po-Nan , Kuo Ming-Chung , Lee Lai-Chu
Published: October 2019

Essential thrombocythemia (ET) is a heterogeneous disorder in which the clonality of hematopoiesis varies. The clinical significance of clonality status in ET remains to be determined. We used the human androgen receptor gene (HUMARA)–polymerase chain reaction assay to investigate X-chromosome inactivation patterns (XCIPs) and their value in predicting vascular complications in 89 female patients with ET. Fifty-four (68.4%) patients had a clonal pattern of XCIP, and 15 (19.0%) had a polyclonal pattern. The remaining 20 patients had either an ambiguous or a homozygous pattern of XCIP and were therefore excluded from further analysis. Patients with clonal XCIPs were older (P = .029) and were at greater risk for thrombosis (P = .007) than were those with polyclonal XCIPs. We did not find a correlation between the occurrence of hemorrhage and XCIP (P = .492). Advanced age was predictive of thrombosis and hemorrhage. Platelet count did not influence the risk for vascular complications. Hypertension was significantly correlated with thrombotic events (P = .002), whereas diabetes mellitus and hypercholesterolemia were of no predictive value. In a multivariate analysis, age was the significant predictor of thrombosis (P = .030); however, XCIPs (P = .083) and hypertension (P = .073) tended to predict thrombosis. Our results suggest that older patients who have clonal XCIPs or hypertension are at increased risk for thrombosis and should be monitored closely for this complication.
Identification of the genes differentially expressed in human dendritic cell subsets by cDNA subtraction and microarray analysis
Authors: Ahn Jung Hoon , Lee Yoon , Jeon ChoonJu , Lee Sang-Jin , Lee Byung-Hak , Choi Kang Duk , Bae Yong-Soo
Published: October 2019

Recent studies on dendritic cell (DC)–associated genes have been performed using monocyte-derived DCs (MoDCs) in different maturation stages. In our approach, to uncover the novel DC-associated genes and their expression profiles among the different DC subsets, we constructed a subtracted DC-cDNA library from CD1a+, CD14+, and CD11c− DCs by subtracting the genes shared with T cells, B cells, and monocytes, and we then screened the libraries with the aid of microarray technique. The genes showing remarkable specificity to DCs in the microarray analysis were selected and confirmed by semiquantitative reverse transcriptase–polymerase chain reaction. Our investigations revealed the following: (1) Genes highly expressed in myeloid DCs are those involved in antigen uptake/processing/presentation, cell metamorphosis, or chemotaxis. (2) Most of the genes previously identified in MoDCs, such as TARC, ferritin L-chain, lysosomal acid lipase, α- and β-tubulin, osteopontin (Eta-1), and others, are not markedly expressed in CD11c− DCs regardless of their maturation status. On the other hand, specific transcription factors and MHC class II molecules, such as interferon regulatory factor-4 (IRF4) and HLA-DR, are similarly expressed in both DC subsets. (3) CD14+ DCs retain unique features of tissue DCs, as evidenced by the gene expression profile of “no CCR7 but more CCR1” and “no TARC but abundant MCP1 and Eta-1.” (4) The genes for immunoglobulin (Ig) superfamily Z39Ig, CD20-like precursor, glycoprotein NMB (GPNMB), transforming growth factorβ (TGF-β)–induced protein (TGFBI), myeloid DAP12-associated lectin (MDL-1), and 6 novel genes are newly identified as being associated with the phenotypic expression of the DC subsets. These identifications provide important molecular information for further functional studies of the DC subsets.
Generalized crystal-storing histiocytosis associated with monoclonal gammopathy: molecular analysis of a disorder with rapid clinical course and review of the literature
Authors: Lebeau Annette , Zeindl-Eberhart Evelyn , Müller Eva-Christina , Müller-Höcker Josef , Jungblut Peter Roman , Emmerich Bertold , Löhrs Udo
Published: October 2019

Crystal-storing histiocytosis (CSH) is a rare event in disorders associated with monoclonal gammopathy. The intracellular crystal formation is almost always accompanied by the expression of κ light chains. However, the exact mechanism for the storage has not been clarified until now. We report a case of generalized CSH in a 73-year-old man who presented with IgA κ paraproteinemia and paraproteinuria. The initially observed CSH in the bone marrow biopsy was associated with the clinical and pathomorphologic features of a monoclonal gammopathy of undetermined significance. The progression of disease could not be affected by steroid therapy and the patient died of septic shock 7 months after detection of CSH. At the time of autopsy there was evidence for multiple myeloma and generalized CSH. Two-dimensional gel electrophoresis of liver tissue combined with immunoblotting revealed the massive storage of heavy chains of α type and light chains of κ type, each in a monoclonal pattern. Analysis of the stored κ light chain by nanoelectrospray-ionization mass spectrometry indicated that it belongs to the variable κI variability subgroup. We identified some unusual amino acid substitutions including Leu59, usually important for hydrophobic interactions within a protein, at a position where it has never been previously described in plasma cell disorders. In conclusion, we present the first case of CSH with molecular identification of the stored κ subgroup and detection of unusual amino acid substitutions. Our results suggest that conformational alterations induced by amino acid exchanges represent a crucial pathogenic factor in CSH.
Role of Toll-like receptor 2 (TLR2) in neutrophil activation: GM-CSF enhances TLR2 expression and TLR2-mediated interleukin 8 responses in neutrophils
Authors: Kurt-Jones Evelyn A. , Mandell Leisa , Whitney Constance , Padgett Alison , Gosselin Kerri , Newburger Peter E. , Finberg Robert W.
Published: October 2019

In vitro studies as well as clinical trials indicate that the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) enhance the ability of neutrophils (polymorphonuclear leukocytes) to eliminate microbial organisms. Toll-like receptor (TLR) proteins, homologs of the Drosophila protein Toll, have been found on the surface of mammalian cells and are important in the responses of macrophages to bacterial, viral, and fungal antigens. TLR4 is critical for the response to lipopolysaccharide (LPS) of gram-negative bacteria, while TLR2 is important for response to gram-positive bacteria, bacterial peptides, and yeast zymosan. We demonstrate that TLR2, but very little TLR4, is present on the surface of human neutrophils. In addition we demonstrate that GM-CSF and G-CSF dramatically up-regulate TLR2 and CD14 surface expression. GM-CSF treatment also up-regulates TLR2 and CD14 mRNA levels in neutrophils. In addition to increasing receptor expression, GM-CSF treatment enhanced the interleukin 8 (IL-8) secretion and superoxide priming responses of neutrophils to stimulation with TLR2 ligands, including zymosan, peptidoglycan, and lipoarabinomannan. The human monocyte response to crude bacterial LPS is composed of a TLR4-specific response to the pure LPS component and a TLR2-dependent response to associated lipopeptides. The removal of TLR2 lipopeptide components from LPS by phenol re-extraction substantially reduced both the IL-8 and superoxide response of the stimulated neutrophils, indicating that, unlike monocytes, the neutrophil response is preferentially directed to TLR2 ligands. Thus, our studies demonstrate that GM-CSF dramatically enhances the functional response of neutrophils to TLR2 ligands, including LPS-associated lipopeptides.
Transplant Donor KIR Genotype Influences the Rate of CMV Reactivation Following T-Replete Stem Cell Transplantation.
Authors: Cook Mark , Briggs David C. , Craddock Charles F. , Mahendra Premini , Milligan Donald , Fegan Christopher , Darbyshire Philip , Lawson Sarah , Boxall Elizabeth , Moss Paul
Published: October 2019

Background

CMV reactivation is the commonest viral complication following allogeneic stem cell transplantation (SCT) and is a direct consequence of immunodeficiency. Natural killer (NK) and T-cells are the primary effector populations that suppress CMV replication. Killer immunoglobulin-like receptors (KIRs) are expressed on the surface of NK cells and T-cell subsets. Inhibitory KIRs have specificity for defined alleles of class I HLA and deliver an inhibitory signal to the cell. Activating KIRs bind weakly to HLA molecules and their true ligands remain unknown. KIR genes are polymorphic. Two broad haplotypes exist which differ in the number of activatory KIR genes that they contain. Haplotype A has 1 activatory KIR gene whereas haplotype B contains additional activatory genes.

Methods

We studied 107 patients undergoing allogeneic SCT at 3 UK Institutions to evaluate the effect of activating KIRs on CMV reactivation. Two thirds received standard myeloablative conditioning with TBI/Cy or Bu/Cy. One third received non-myeloablative conditioning. Recipient/donor CMV sero-status was determined by ELISA. Reactivation was defined as two successive PCR assays detecting >400 copies/ml. KIR genotyping was performed by PCR-SSP.

Results

In CMV seropositive recipients, the CMV reactivation rate was 50% in transplants from sibling donors and 64% in transplants from unrelated or HLA non-identical donors. In sibling transplants where both donor and recipient were CMV seropositive and the donor was homozygous for KIR Haplotype A (group A) the CMV reactivation rate was 65% .In contrast if the donor possessed at least one KIR haplotype B (group B) the reactivation rate was reduced to 27.5% (p=0.014). The protective effect of group B donors was seen only in patients who received a myeloablative non-T-depleted transplant. Here, the reactivation rate was 70.6% (12 from 17) when transplanted from a group A donor compared with 23.8% (5 from 21) when transplanted from a group B donor (p=0.0039). If a group B donor was used no reactivation was seen after 41 days, whereas in transplants from group A donors the risk of reactivation continued until day 100 (figure 1,p=0.018). The donor KIR genotype did not influence CMV reactivation rates in patients who received T-depleted grafts from sibling, unrelated or haploidentical donors.

Conclusion

In T-cell replete sibling donor transplants the use of a donor with multiple activating KIRs significantly reduces the risk of CMV reactivation when both donor and recipient are CMV seropositive. This is the first direct evidence of activating KIRs exerting a controlling effect on CMV in humans.
Stable RNAi-Mediated Knock-Down of P-Glycoprotein by a Transposon-Based Vector System Restores Imatinib Sensitivity.
Authors: Rumpold Holger F. , Wolf Anna M. , Gastl Guenther A. , Gunsilius Eberhard , Wolf Dominik G.F.
Published: October 2019

Overexpression of P-glycoprotein (PgP) is critical for resistance of malignant cells against cytotoxic agents. However, the role of PgP overexpression for the sensitivity of chronic myeloid leukemia (CML) to imatinib remains controversial. We therefore constructed a transposon-based (Sleeping beauty) RNAi system for the stable down-regulation of PgP in imatinib/doxorubicin resistant K562/Dox cell lines. RT-PCR demonstrated the stable integration of the transposon into the genome. Real-time PCR revealed a rapid and almost complete degradation of MDR1 mRNA 72 h after nucleofection. PgP knockdown on protein level was much more efficient in the stable setting as compared to the transient approach. This observation points out to the requirement of stable knockdown approaches for siRNA-mediated downregulation of proteins with long half-life time. The functional impact of stable PgP knock-down was demonstrated by a reduced efflux of rhodamine and doxorubicin. In parallel, MDR1 knockdown cells were re-sensitized to doxorubicin as well as to imatinib-induced cell death. This observation supports the notion that up-regulation of MDR1 in CML might contribute to imatinib resistance in vivo.

In summary we describe a very efficient tool for the stable knock-down of PgP by transposon-mediated siRNA delivery in CML cells and propose that the down-regulation of PgP in CML can restore sensitivity to imatinib.
Donor Activating Kir Genes and Survival after Haplo-Identical Hematopoietic Transplantation.
Authors: Mancusi Antonella , Ruggeri Loredana , McQueen Karina , Perruccio Katia , Aversa Franco , Martelli Massimo F. , Parham Peter , Velardi Andrea
Published: October 2019

Although NK cell alloreactivity impacts beneficially on the outcome of haploidentical transplantation in AML patients, largely through its GvL effect (Ruggeri et al, Science 2002), TRM (~40%, largely due to infections) remains a major problem. In a search for additional donor selection criteria, here we determined the donor KIR genotypes and correlated them with transplantation outcomes in 74 AML recipients. Transplants from donors carrying group A KIR haplotype genes, which mainly encode for inhibitory receptors (and for the activating KIR2DS4 gene) (n=22), were compared with those from donors carrying group B KIR haplotype genes, which encode for additional activating KIRs (KIR2DS1, 2, 3, 5 and KIR3DS1) (n=52). Event-free survival appeared better in AML patients transplanted from donors bearing B haplotype genes (48% vs 23%, p=0.066). As expected, other well established factors of good prognosis, such as NK cell alloreactivity and disease status at transplant, played significant independent roles (H.R.=0.42 donor NK cell alloreactivity present vs absent, 95% C.I.=0.22–0.79, p=0.007; H.R.=0.39 remission vs relapse at transplant, 95% C.I.=0.21–0.72, p=0.003). However, after adjusting for donor-vs-recipient NK cell alloreactivity and transplantation in remission, transplantation from donors carrying group B haplotype KIR genes still tended to emerged as an independent predictor of survival (H.R.=0.56 B haplotype genes present vs absent, 95% C.I.=0.3–1.0, p=0.07). This might have been the consequence of reduced incidence of leukaemia relapse. In an analysis of factors involved in relapse, donor-vs-recipient NK alloreactivity and disease status at transplant were confirmed as strong independent protective factors (H.R.=0.18 donor NK cell alloreactivity present vs absent, 95% C.I.=0.05–0.68, p=0.01; H.R.=0.15 remission vs relapse at transplant, 95% C.I.=0.04–0.58, p=0.006). Transplantation from donors carrying activating group B haplotype KIR genes had no effect on relapse (H.R.=0.59 B haplotype genes present vs absent, 95% C.I.= 0.17–2.05, p>0.1). Strikingly, in analyzing TRM, transplantation from these donors was associated with a markedly reduced TRM (59% vs 30%, p=0.03), and emerged as the only statistically significant protective factor (H.R.=0.46 B haplotype genes present vs absent, 95% C.I.= 0.22–0.97, p=0.04), even when compared with NK cell alloreactivity (H.R.=0.56 donor NK cell alloreactivity present vs absent, 95% C.I.=.026–1.20, p>0.1) and disease status at transplant (H.R.=0.53 remission vs relapse at transplant, 95% C.I.=0.25–1.11, p=0.09). Thus, transplantation from donors carrying activating (group B haplotype) genes could be a new donor selection criterion which might help reduce infectious mortality after haploidentical hematopoietic transplantation.

The mechanisms underlying this apparently improved immune competence remain to be investigated.
Home Telemetric System for Pulmonary Function Surveillance: A Useful Procedure for Detection of Late-Onset Noninfectious Pulmonary Complications (LONIPC) after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).
Authors: Guihot Amélie , Becquemin Marie-Hélène , Couderc Louis-Jean , Randrianarivelo Odile , Rivaud Elisabeth , Philippe Bruno , Neveu Hélène , Vernant Jean-Paul , Dhedin Nathalie
Published: October 2019

Late-onset noninfectious pulmonary complications (LONIPC) of allogeneic hematopoïetic stem cell transplantation (HSCT) occur in 2 to 25% of recipients. LONIPC include bronchiolitis obliterans (BrOb), which is associated with an obstructive syndrome, bronchiolitis obliterans with organizing pneumonia (BOOP) and interstitial pneumonia (IP), which are associated with a restrictive syndrome on pulmonary function tests. LONIPC have poor prognosis with death from respiratory failure in more than 30% of cases. We evaluated a telemetric system for home pulmonary function surveillance, for early diagnosis and treatment of LONIPC in allogeneic HSCT recipients.

We conducted a prospective study of 35 patients living in Paris area, who survived over 3 months after HSCT (median age 46 years, myeloablative conditioning regimen in 54.2% of patients, HLA-identical sibling donor in 65.7%) between June 2001 and January 2004. Three months after HSCT, patients were delivered a portable spirometer (Spirotel®, M-Elect France), measuring vital capacity, forced expiratory volume per second, and mid expiratory flow 25 to 75 values. Data were transmitted by phone to hospital twice a week. If significant deterioration (>20%) was confirmed by plethysmography, then patients were admitted in Pneumology Department.

Thirteen episodes of spirometric deterioration were detected in 11 patients during a median follow-up period of 18 months (1 to 42). LONIPC was diagnosed on spirometric, CT scan and broncho-alveolar lavage criteria during 8 episodes in 7/35 patients (20%), occurring after a median time of 11 months (6 to 18) after HSCT. One of these 7 patients had previously developed acute graft versus host disease (GVHD) and 5 had current chronic GVHD. LONIPC were BrOb, (n=3), interstitial pneumonia (n=4), or both BrOb and interstitial pneumonia (n=1). Patients were treated with increasing immunosuppressive regimens (prednisone and/or, mycophenolate mofetil, and/or cyclosporine A). Five patients improved and 2 were stabilised. There was no case of long-term oxygen therapy or death from respiratory failure (median follow-up 24 months (12 to 34) from LONIPC diagnosis). Telemetric home monitoring of pulmonary function is a reliable procedure easy-to-use for early diagnosis of LONIPC, which might improve the usual severe prognosis of LONIPC occurring after allogeneic HSCT.
Oral Administration of the Opium Alkaloid Noscapine (NOS) Exhibits Potent Anti-Tumor Activity Against Non-Hodgkin’s Lymphomas and Myeloma Cell Lines In Vitro and In Vivo in SCID-beige Murine Xenograft Models.
Authors: O’Connor Owen , Mastrella J. , Smith E. , Toner L. , Auerbach A. , Leonard J. P.
Published: October 2019

Noscapine is an oral opiate alkaloid with structural similarity to colchicine that induces cell cycle arrest and apoptosis. Its mechanism of action appears similar to vincristine (VCN). In a trypan blue exclusion assay, noscapine exhibits increasing potency with increasing duration of exposure in B- and T-cell lymphomas, and myelomas (MM). For example, following 24 hours of exposure to noscapine, the OPM2 (MM), H9 (TCL) and RL (BCL) lines exhibited an IC50 of approximately 10 to 15 mM. Exposure for up to 96 hours effected IC50 of 30 nM, 700 nM, and 500 nM for the OPM2, H9 and RL lines respectively. Across all cell lines studied, increasing the duration of exposure by only a couple of days resulted in multiple log decreases in IC50. Combining noscapine with doxorubicin and 4-hydroxycyclophosphamide in vitro resulted in at least additive or better cytotoxicity. In vivo, both intraperitoneal and oral doses of noscapine were evaluated on a daily schedule for 14 days (200, 300, 400 and 600 mg/kg). These data demonstrated that the toxicity was much greater when administered by the i.p. route, where 60% of animals died as a result of toxicity in the 600 mg/kg i.p. cohort, while none died from toxicity when given by oral gavage. Preliminary efficacy experiments demonstrated that by day 15, animals treated with 600 and 400 mg/kg noscapine by oral gavage exhibited tumor growth delays that were 30 to 50% of the control tumor volume. Activation of caspase 3 by noscapine demonstrated a linear dose response relationship which was strongly related to duration of drug exposure. Noscapine may represent a new well tolerated oral therapy for the control of lymphoma and myeloma. Antimitotic agents with effects like VCN may be improved with higher area under of the curve of exposure, and thus are well suited for oral administration. Ongoing phase I studies are determining the MTD and DLT associated with noscapine. Phase 2 studies are warranted.