bluuebunny/crossref_metadata_2025_split huggingface dataset:
Persistence and Dose Escalation of Tumor Necrosis Factor Inhibitors in US Veterans with Rheumatoid Arthritis
Authors: Cannon Grant W. , DuVall Scott L. , Haroldsen Candace L. , Caplan Liron , Curtis Jeffrey R. , Michaud Kaleb , Mikuls Ted R. , Reimold Andreas , Collier David H. , Harrison David J. , Joseph George J. , Sauer Brian C. 
Published: August 2014

Objective.Limited evidence exists comparing the persistence, effectiveness, and costs of biologic therapies for rheumatoid arthritis in clinical practice. Comparative effectiveness studies are needed to understand real-world experience with these agents. We evaluated treatment patterns, costs, and effectiveness of tumor necrosis factor inhibitor (TNFi) agents in patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry.Methods.Observational data from the VARA registry and linked administrative databases were analyzed. Longitudinal data from VARA patients initiating adalimumab (ADA), etanercept (ETN), or infliximab (IFX) from 2003 (the date all agents were available within the Veteran Affairs) to 2010 were analyzed. Outcomes included Disease Activity Score using 28 joints (DAS28), treatment persistence, dose escalation, and direct costs of drugs and drug administration.Results.For 563 eligible patients, baseline DAS28, DAS28 improvements, and persistence on initial treatment were similar across agents. Fewer patients receiving ETN (n = 5/290; 2%) underwent dose escalation than did patients taking ADA (n = 32/204; 16%) or IFX (n = 44/69; 64%). Annual costs for first course of TNFi therapy were lower for injectable ADA ($13,100 US) and ETN ($13,500 US) than for intravenously administered IFX ($16,900 US).Conclusion.Despite similar persistence and clinical disease activity for these TNFi agents, rates of dose escalation were highest with ADA and IFX. Higher overall costs were noted for IFX without increases in effectiveness.
Current Smoking is Associated with Incident Ankylosing Spondylitis — The HUNT Population-based Norwegian Health Study
Authors: Videm Vibeke , Cortes Adrian , Thomas Ranjeny , Brown Matthew A. 
Published: August 2014

Objective.Smoking contributes to progression of ankylosing spondylitis (AS). Because smoking is also a risk factor for incident rheumatoid arthritis (RA) and psoriatic arthritis, our aim was to test whether smoking habits are associated with incident AS.Methods.Using data from the HUNT health study of the entire adult population of Nord-Trøndelag, Norway, participants in HUNT2 (1995–1997) and HUNT3 (2006–2008) were identified who reported a diagnosis of AS in HUNT3 but not in HUNT2 (n = 107). Incident AS cases were compared with AS-unaffected individuals (n = 35,278) in a case-control design. Participants with RA were excluded.Results.Present smoking was significantly associated with incident self-reported AS in logistic regression adjusted for potential confounders (OR 1.99, 95% CI 1.28–3.11, p = 0.002). Previous smoking (OR 1.15, 95% CI 0.66–2.02, p = 0.62) or total pack-years at HUNT2 (OR 1.01, 95% CI 0.99–1.04, p = 0.21) were not significant. The association with present smoking remained significant in various sensitivity analyses: including only cases with high probability of true AS diagnosis (OR 1.82, 95% CI 1.03–3.19, p = 0.04); including only cases with AS reported more than 3–5 years after HUNT2 (OR 2.34, 95% CI 1.09–5.03, p = 0.029), or including only participants genotyped for HLA-B27 (94 cases and 859 controls) adjusting for genotype (OR 1.79, 95% CI 1.04–2.85, p = 0.033). Hypertension was also significantly associated with incident AS (OR from 1.65 to 2.81).Conclusion.In the HUNT population-based study, incident AS was associated with current smoking and hypertension. If verified in further studies, this suggests that smoking should be discouraged in those at a higher AS risk, e.g., with a family history or carrying HLA-B27.
The Ataxia Telangiectasia Mutated and Cyclin D3 Proteins Cooperate To Help Enforce TCRβ and IgH Allelic Exclusion
Authors: Steinel Natalie C. , Fisher Megan R. , Yang-Iott Katherine S. , Bassing Craig H. 
Published: August 2014

Abstract
Coordination of V rearrangements between loci on homologous chromosomes is critical for Ig and TCR allelic exclusion. The Ataxia Telangietasia mutated (ATM) protein kinase promotes DNA repair and activates checkpoints to suppress aberrant Ig and TCR rearrangements. In response to RAG cleavage of Igκ loci, ATM inhibits RAG expression and suppresses further Vκ-to-Jκ rearrangements to enforce Igκ allelic exclusion. Because V recombination between alleles is more strictly regulated for TCRβ and IgH loci, we evaluated the ability of ATM to restrict biallelic expression and V-to-DJ recombination of TCRβ and IgH genes. We detected greater frequencies of lymphocytes with biallelic expression or aberrant V-to-DJ rearrangement of TCRβ or IgH loci in mice lacking ATM. A preassembled DJβ complex that decreases the number of TCRβ rearrangements needed for a productive TCRβ gene further increased frequencies of ATM-deficient cells with biallelic TCRβ expression. IgH and TCRβ proteins drive proliferation of prolymphocytes through cyclin D3 (Ccnd3), which also inhibits VH transcription. We show that inactivation of Ccnd3 leads to increased frequencies of lymphocytes with biallelic expression of IgH or TCRβ genes. We also show that Ccnd3 inactivation cooperates with ATM deficiency to increase the frequencies of cells with biallelic TCRβ or IgH expression while decreasing the frequency of ATM-deficient lymphocytes with aberrant V-to-DJ recombination. Our data demonstrate that core components of the DNA damage response and cell cycle machinery cooperate to help enforce IgH and TCRβ allelic exclusion and indicate that control of V-to-DJ rearrangements between alleles is important to maintain genomic stability.
The Late Endosomal Transporter CD222 Directs the Spatial Distribution and Activity of Lck
Authors: Pfisterer Karin , Forster Florian , Paster Wolfgang , Supper Verena , Ohradanova-Repic Anna , Eckerstorfer Paul , Zwirzitz Alexander , Donner Clemens , Boulegue Cyril , Schiller Herbert B. , Ondrovičová Gabriela , Acuto Oreste , Stockinger Hannes , Leksa Vladimir 
Published: August 2014

Abstract
The spatial and temporal organization of T cell signaling molecules is increasingly accepted as a crucial step in controlling T cell activation. CD222, also known as the cation-independent mannose 6-phosphate/insulin-like growth factor 2 receptor, is the central component of endosomal transport pathways. In this study, we show that CD222 is a key regulator of the early T cell signaling cascade. Knockdown of CD222 hampers the effective progression of TCR-induced signaling and subsequent effector functions, which can be rescued via reconstitution of CD222 expression. We decipher that Lck is retained in the cytosol of CD222-deficient cells, which obstructs the recruitment of Lck to CD45 at the cell surface, resulting in an abundant inhibitory phosphorylation signature on Lck at the steady state. Hence, CD222 specifically controls the balance between active and inactive Lck in resting T cells, which guarantees operative T cell effector functions.
Differences in the Transduction of Canonical Wnt Signals Demarcate Effector and Memory CD8 T Cells with Distinct Recall Proliferation Capacity
Authors: Boudousquié Caroline , Danilo Maxime , Pousse Laurène , Jeevan-Raj Beena , Angelov Georgi S. , Chennupati Vijaykumar , Zehn Dietmar , Held Werner 
Published: August 2014

Abstract
Protection against reinfection is mediated by Ag-specific memory CD8 T cells, which display stem cell–like function. Because canonical Wnt (Wingless/Int1) signals critically regulate renewal versus differentiation of adult stem cells, we evaluated Wnt signal transduction in CD8 T cells during an immune response to acute infection with lymphocytic choriomeningitis virus. Whereas naive CD8 T cells efficiently transduced Wnt signals, at the peak of the primary response to infection only a fraction of effector T cells retained signal transduction and the majority displayed strongly reduced Wnt activity. Reduced Wnt signaling was in part due to the downregulation of Tcf-1, one of the nuclear effectors of the pathway, and coincided with progress toward terminal differentiation. However, the correlation between low and high Wnt levels with short-lived and memory precursor effector cells, respectively, was incomplete. Adoptive transfer studies showed that low and high Wnt signaling did not influence cell survival but that Wnt high effectors yielded memory cells with enhanced proliferative potential and stronger protective capacity. Likewise, following adoptive transfer and rechallenge, memory cells with high Wnt levels displayed increased recall expansion, compared with memory cells with low Wnt signaling, which were preferentially effector-like memory cells, including tissue-resident memory cells. Thus, canonical Wnt signaling identifies CD8 T cells with enhanced proliferative potential in part independent of commonly used cell surface markers to discriminate effector and memory T cell subpopulations. Interventions that maintain Wnt signaling may thus improve the formation of functional CD8 T cell memory during vaccination.
The Expression of Sphingosine-1 Phosphate Receptor-1 in Chronic Lymphocytic Leukemia Cells Is Impaired by Tumor Microenvironmental Signals and Enhanced by Piceatannol and R406
Authors: Borge Mercedes , Remes Lenicov Federico , Nannini Paula R. , de los Ríos Alicandú María M. , Podaza Enrique , Ceballos Ana , Fernández Grecco Horacio , Cabrejo María , Bezares Raimundo F. , Morande Pablo E. , Oppezzo Pablo , Giordano Mirta , Gamberale Romina 
Published: August 2014

Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of clonal B lymphocytes. Proliferation occurs in lymphoid tissues upon interaction of leukemic cells with a supportive microenvironment. Therefore, the mobilization of tissue-resident CLL cells into the circulation is a useful therapeutic strategy to minimize the reservoir of tumor cells within survival niches. Because the exit of normal lymphocytes from lymphoid tissues depends on the presence of sphingosine-1 phosphate (S1P) and the regulated expression of S1P receptor-1 (S1PR1), we investigated whether the expression and function of S1PR1 can be modulated by key microenvironment signals. We found that activation of CLL cells with CXCL12, fibroblast CD40L+, BCR cross-linking, or autologous nurse-like cells reduces their S1PR1 expression and the migratory response toward S1P. Moreover, we found that S1PR1 expression was reduced in the proliferative/activated subset of leukemic cells compared with the quiescent subset from the same patient. Similarly, bone marrow–resident CLL cells expressing high levels of the activation marker CD38 showed a lower expression of S1PR1 compared with CD38low counterparts. Finally, given that treatment with BCR-associated kinase inhibitors induces a transient redistribution of leukemic cells from lymphoid tissues to circulation, we studied the effect of the Syk inhibitors piceatannol and R406 on S1PR1 expression and function. We found that they enhance S1PR1 expression in CLL cells and their migratory response toward S1P. Based on our results, we suggest that the regulated expression of S1PR1 might modulate the egress of the leukemic clone from lymphoid tissues.
Role of TGF-β Signaling in Generation of CD39+CD73+ Myeloid Cells in Tumors
Authors: Ryzhov Sergey V. , Pickup Michael W. , Chytil Anna , Gorska Agnieszka E. , Zhang Qinkun , Owens Philip , Feoktistov Igor , Moses Harold L. , Novitskiy Sergey V. 
Published: August 2014

Abstract
There is growing evidence that generation of adenosine from ATP, which is mediated by the CD39/CD73 enzyme pair, predetermines immunosuppressive and proangiogenic properties of myeloid cells. We have previously shown that the deletion of the TGF-β type II receptor gene (Tgfbr2) expression in myeloid cells is associated with decreased tumor growth, suggesting protumorigenic effect of TGF-β signaling. In this study, we tested the hypothesis that TGF-β drives differentiation of myeloid-derived suppressor cells into protumorigenic terminally differentiated myeloid mononuclear cells (TDMMCs) characterized by high levels of cell-surface CD39/CD73 expression. We found that TDMMCs represent a major cell subpopulation expressing high levels of both CD39 and CD73 in the tumor microenvironment. In tumors isolated from mice with spontaneous tumor formation of mammary gland and conditional deletion of the type II TGF-β receptor in mammary epithelium, an increased level of TGF-β protein was associated with further increase in number of CD39+CD73+ TDMMCs compared with MMTV-PyMT/TGFβRIIWT control tumors with intact TGF-β signaling. Using genetic and pharmacological approaches, we demonstrated that the TGF-β signaling mediates maturation of myeloid-derived suppressor cells into TDMMCs with high levels of cell surface CD39/CD73 expression and adenosine-generating capacity. Disruption of TGF-β signaling in myeloid cells resulted in decreased accumulation of TDMMCs, expressing CD39 and CD73, and was accompanied by increased infiltration of T lymphocytes, reduced density of blood vessels, and diminished progression of both Lewis lung carcinoma and spontaneous mammary carcinomas. We propose that TGF-β signaling can directly induce the generation of CD39+CD73+ TDMMCs, thus contributing to the immunosuppressive, proangiogenic, and tumor-promoting effects of this pleiotropic effector in the tumor microenvironment.
Idiotype-Specific Th Cells Support Oligoclonal Expansion of Anti-dsDNA B Cells in Mice with Lupus
Authors: Aas-Hanssen Kristin , Funderud Ane , Thompson Keith M. , Bogen Bjarne , Munthe Ludvig A. 
Published: August 2014

Abstract
Systemic lupus erythematosus (SLE) is marked by a Th cell–dependent B cell hyperresponsiveness, with frequent germinal center reactions and hypergammaglobulinemia. The specificity of Th cells in lupus remains unclear, but B cell Ids have been suggested. A hallmark is the presence of anti-dsDNA, mutated IgG autoantibodies with a preponderance of arginines in CDR3 of the Ig variable H chain (IgVH). B cells can present V region–derived Id peptides on their MHC class II molecules to Id-specific Th cells. We show that Id-specific Th cells support the proliferation of anti-dsDNA Id+ B cells in mice suffering from systemic autoimmune disease with SLE-like features. Mice developed marked clonal expansions of B cells; half of the IgVH sequences were clonally related. Anti-dsDNA B cells made up 40% of B cells in end-stage disease. The B cells expressed mutated IgVH with multiple arginines in CDR3. Hence, Id-driven T cell–B cell collaboration supported the production of classical anti-dsDNA Abs, recapitulating the characteristics of such Abs in SLE. The results support the concept that Id-specific Th cells may trigger the development of SLE and suggest that manipulation of the Id-specific T cell repertoire could play a role in treatment.
Concomitant TLR/RLH Signaling of Radioresistant and Radiosensitive Cells Is Essential for Protection against Vesicular Stomatitis Virus Infection
Authors: Spanier Julia , Lienenklaus Stefan , Paijo Jennifer , Kessler Annett , Borst Katharina , Heindorf Sabrina , Baker Darren P. , Kröger Andrea , Weiss Siegfried , Detje Claudia N. , Staeheli Peter , Kalinke Ulrich 
Published: August 2014

Abstract
Several studies indicated that TLR as well as retinoic acid–inducible gene I–like helicase (RLH) signaling contribute to vesicular stomatitis virus (VSV)–mediated triggering of type I IFN (IFN-I) responses. Nevertheless, TLR-deficient MyD88−/−Trif−/− mice and RLH-deficient caspase activation and recruitment domain adaptor inducing IFN-β (Cardif)−/− mice showed only marginally enhanced susceptibility to lethal VSV i.v. infection. Therefore, we addressed whether concomitant TLR and RLH signaling, or some other additional mechanism, played a role. To this end, we generated MyD88−/−Trif−/−Cardif−/− (MyTrCa−/−) mice that succumbed to low-dose i.v. VSV infection with similar kinetics as IFN-I receptor–deficient mice. Three independent approaches (i.e., analysis of IFN-α/β serum levels, experiments with IFN-β reporter mice, and investigation of local IFN-stimulated gene induction) revealed that MyTrCa−/− mice did not mount IFN-I responses following VSV infection. Of note, treatment with rIFN-α protected the animals, qualifying MyTrCa−/− mice as a model to study the contribution of different immune cell subsets to the production of antiviral IFN-I. Upon adoptive transfer of wild-type plasmacytoid dendritic cells and subsequent VSV infection, MyTrCa−/− mice displayed significantly reduced viral loads in peripheral organs and showed prolonged survival. On the contrary, adoptive transfer of wild-type myeloid dendritic cells did not have such effects. Analysis of bone marrow chimeric mice revealed that TLR and RLH signaling of radioresistant and radiosensitive cells was required for efficient protection. Thus, upon VSV infection, plasmacytoid dendritic cell–derived IFN-I primarily protects peripheral organs, whereas concomitant TLR and RLH signaling of radioresistant stroma cells as well as of radiosensitive immune cells is needed to effectively protect against lethal disease.
The N-Terminal Domain of NLRC5 Confers Transcriptional Activity for MHC Class I and II Gene Expression
Authors: Neerincx Andreas , Jakobshagen Kristin , Utermöhlen Olaf , Büning Hildegard , Steimle Viktor , Kufer Thomas A. 
Published: August 2014

Abstract
Ag presentation to CD4+ and CD8+ T cells depends on MHC class II and MHC class I molecules, respectively. One important regulatory factor of this process is the transcriptional regulation of MHC gene expression. It is well established that MHC class II transcription relies on the NLR protein CIITA. Recently, another NLR protein, NLRC5, was shown to drive MHC class I expression. The molecular mechanisms of the function of NLRC5 however remain largely elusive. In this study, we present a detailed functional study of the domains of NLRC5 revealing that the N-terminal domain of human NLRC5 has intrinsic transcriptional activity. Domain swapping experiments between NLRC5 and CIITA showed that this domain contributes to MHC class I and MHC class II gene expression with a bias for activation of MHC class I promoters. Delivery of this construct by adeno-associated viral vectors upregulated MHC class I and MHC class II expression in human cells and enhanced lysis of melanoma cells by CD8+ cytotoxic T cells in vitro. Taken together, this work provides novel insight into the function of NLRC5 and CIITA in MHC gene regulation.
Representation Stability of Power Sets and Square Free Polynomials
Authors: Ashraf Samia , Azam Haniya , Berceanu Barbu 
Published: August 2014

AbstractThe symmetric group 𝓢n acts on the power set 𝓟(n) and also on the set of square free polynomials in n variables. These two related representations are analyzed from the stability point of view. An application is given for the action of the symmetric group on the cohomology of the pure braid group.
Advective and atmospheric forced changes in heat and fresh water content in the Norwegian Sea, 1951–2010
Authors: Mork Kjell Arne , Skagseth Øystein , Ivshin Victor , Ozhigin Vladimir , Hughes Sarah L. , Valdimarsson Héðinn 
Published: August 2014

AbstractClimate variability in the Norwegian Sea was investigated in terms of ocean heat and fresh water contents of Atlantic water above a reference surface, using hydrographic data during spring 1951–2010. The main processes acting on this variability were examined and then quantified. The area‐averaged water mass cooled and freshened, but a deepening of the reference surface resulted in a positive trend in the heat content of 0.3 W m−2. Air‐sea heat fluxes explained about half of the interannual variability in heat content. The effect of the advection of Atlantic and Arctic waters on the variability varied with time, apparently due to large‐scale changes in the ocean circulation. The data are consistent with the explanation that changing wind patterns caused buffering and then release of Arctic water in the Iceland Sea during the late 1960s to early 1970s, and this caused large hydrographic changes in the Norwegian Sea.
Quantifying light absorption by organic carbon in Western North American snow by serial chemical extractions
Authors: Dang Cheng , Hegg Dean A. 
Published: August 2014

AbstractLight‐absorbing particulates (LAPs) in snow, namely black carbon (BC), organic carbon (OC), and iron oxides, can reduce snow albedo and influence regional and global climate. Partitioning light absorption by LAPs to BC and non‐BC (i.e., OC and iron oxides) is important yet difficult due to both technical limitations and the complicated nature of LAPs. In this work, we applied serial chemical extractions on LAP samples acquired from snow samples in western North America to study the light absorption by different types of OC. We also estimated the light absorption due to iron oxides. Based on these chemical analyses, we then compared our estimation of the non‐BC light absorption with that from an optical method. The results suggest that humic‐like substances (sodium hydroxide (NaOH)‐soluble), polar OCs (methanol‐soluble), and iron oxides are responsible for 9%, 4%, and 14% (sample means) of the total light absorption, respectively, in our samples, though it should also be noted that there is great variance in these means. The total light absorption due to non‐BC LAPs estimated by chemical methods is lower than that estimated by optical method by about 10% in all sampling regions. Reasons for this difference are explored.
Potential groundwater age tracer found: Halon‐1301 (CF3Br), as previously identified as CFC‐13 (CF3Cl)
Authors: Beyer Monique , van der Raaij Rob , Morgenstern Uwe , Jackson Bethanna 
Published: August 2014

AbstractGroundwater dating using anthropogenic and natural tracer substances is a powerful tool for understanding groundwater dynamics for improved management of groundwater resources. Due to limitations in individual dating methods, often multiple tracers are used to reduce ambiguities. It is commonly accepted that there is a need for further complementary age tracers, in addition to current ones (e.g., tritium, SF6, and CFCs). We propose a potential new groundwater age tracer, Halon‐1301 (CF3Br), which can easily be determined using gas chromatography with an attached electron capture detector (GC/ECD) developed by Busenberg and Plummer (2008). Its peak was noted by Busenberg and Plummer (2008), but they believed it to be CFC‐13 (CF3Cl) at that time. We performed rigorous tests on gases containing or excluding Halon‐1301 and CFC‐13 and modern water samples and concluded that the two compounds have extremely similar retention times. Additionally, we found that the ECD response of CFC‐13 is far too low to be detected in groundwater or air using standard volumes and sampling techniques. However, the peak areas and concentrations Busenberg and Plummer (2008) reported are in line with what would be expected for Halon‐1301. Thus, we are confident that the peak formerly identified as CFC‐13 is actually Halon‐1301. Busenberg agrees with our findings. We further suggest that Halon‐1301 has potential as a (complementary) age tracer, due to its established atmospheric history, and could hypothetically be used to date groundwater recharged in the 1970s or onward. We discuss known relevant properties, such as solubility and stability of Halon‐1301 in the context of how these effect its potential application as a groundwater age tracer. Some open questions remain concerning how conservative Halon‐1301 is—is it subject to degradation, retardation, and/or local contamination in groundwater. We are confident that Halon‐1301 possesses important tracer relevant properties, but further work is required to fully assess its applicability and reliability as a groundwater age tracer in different groundwater environments.