bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longterm Effect of Delaying Combination Therapy with Tumor Necrosis Factor Inhibitor in Patients with Aggressive Early Rheumatoid Arthritis: 10-year Efficacy and Safety of Adalimumab from the Randomized Controlled PREMIER Trial with Open-label Extension
Authors: Keystone Edward C. , Breedveld Ferdinand C. , van der Heijde Désirée , Landewé Robert , Florentinus Stefan , Arulmani Udayasankar , Liu Shufang , Kupper Hartmut , Kavanaugh Arthur 
Published: November 2013

Objective.To evaluate the longterm safety of adalimumab administered with or without methotrexate (MTX) and compare the efficacy of combination therapy initialization to adalimumab or MTX monotherapy initialization during the open-label extension (OLE) of the PREMIER trial (ClinicalTrials.govIdentifier:NCT00195663).Methods.Patients with early rheumatoid arthritis (RA) were randomized to receive blinded adalimumab + MTX, adalimumab alone, or MTX alone for 2 years. Following the double-blinded period, patients enrolling in the OLE were given adalimumab for up to 8 additional years, beginning as monotherapy; investigators could add MTX at their discretion. Results for clinical, functional, and radiographic progression were collected for up to 10 years of treatment.Results.During the PREMIER OLE, 250/497 patients (50.3%) completed the trial without new safety signals arising. Similar proportions of patients discontinued the trial early, although lack of efficacy was reported less often for patients initially randomized to the adalimumab + MTX arm (9.3%; 21.2%, and 23.7% for adalimumab and MTX monotherapies, respectively). Clinical and functional disease control was maintained throughout the trial. Patients initially randomized to adalimumab + MTX displayed better outcomes, particularly in prevention of radiographic progression (modified total Sharp score change = 4.0, 8.8, 11.0 at Year 10 for the initial adalimumab + MTX, adalimumab, and MTX arms, respectively).Conclusion.Intensive therapy with adalimumab + MTX combination in patients with early RA has longterm benefits compared to patients initiating with 2-year adalimumab or MTX monotherapy that persists up to 10 years following adalimumab OLE. No new safety findings were observed following longterm adalimumab treatment.
Item Response Theory, Computerized Adaptive Testing, and PROMIS: Assessment of Physical Function
Authors: Fries James F. , Witter James , Rose Matthias , Cella David , Khanna Dinesh , Morgan-DeWitt Esi 
Published: November 2013

Objective.Patient-reported outcome (PRO) questionnaires record health information directly from research participants because observers may not accurately represent the patient perspective. Patient-reported Outcomes Measurement Information System (PROMIS) is a US National Institutes of Health cooperative group charged with bringing PRO to a new level of precision and standardization across diseases by item development and use of item response theory (IRT).Methods.With IRT methods, improved items are calibrated on an underlying concept to form an item bank for a “domain” such as physical function (PF). The most informative items can be combined to construct efficient “instruments” such as 10-item or 20-item PF static forms. Each item is calibrated on the basis of the probability that a given person will respond at a given level, and the ability of the item to discriminate people from one another. Tailored forms may cover any desired level of the domain being measured. Computerized adaptive testing (CAT) selects the best items to sharpen the estimate of a person’s functional ability, based on prior responses to earlier questions. PROMIS item banks have been improved with experience from several thousand items, and are calibrated on over 21,000 respondents.Results.In areas tested to date, PROMIS PF instruments are superior or equal to Health Assessment Questionnaire and Medical Outcome Study Short Form-36 Survey legacy instruments in clarity, translatability, patient importance, reliability, and sensitivity to change.Conclusion.Precise measures, such as PROMIS, efficiently incorporate patient self-report of health into research, potentially reducing research cost by lowering sample size requirements. The advent of routine IRT applications has the potential to transform PRO measurement.
Methodologies for Semiquantitative Evaluation of Hip Osteoarthritis by Magnetic Resonance Imaging: Approaches Based on the Whole Organ and Focused on Active Lesions
Authors: Jaremko Jacob L. , Lambert Robert G.W. , Zubler Veronika , Weber Ulrich , Loeuille Damien , Roemer Frank W. , Cibere Jolanda , Pianta Marcus , Gracey David , Conaghan Philip , Ostergaard Mikkel , Maksymowych Walter P. 
Published: November 2013

Objective.As a wider variety of therapeutic options for osteoarthritis (OA) becomes available, there is an increasing need to objectively evaluate disease severity on magnetic resonance imaging (MRI). This is more technically challenging at the hip than at the knee, and as a result, few systematic scoring systems exist. The OMERACT (Outcome Measures in Rheumatology) filter of truth, discrimination, and feasibility can be used to validate image-based scoring systems. Our objective was (1) to review the imaging features relevant to the assessment of severity and progression of hip OA; and (2) to review currently used methods to grade these features in existing hip OA scoring systems.Methods.A systematic literature review was conducted. MEDLINE keyword search was performed for features of arthropathy (such as hip + bone marrow edema or lesion, synovitis, cyst, effusion, cartilage, etc.) and scoring system (hip + OA + MRI + score or grade), with a secondary manual search for additional references in the retrieved publications.Results.Findings relevant to the severity of hip OA include imaging markers associated with inflammation (bone marrow lesion, synovitis, effusion), structural damage (cartilage loss, osteophytes, subchondral cysts, labral tears), and predisposing geometric factors (hip dysplasia, femoral-acetabular impingement). Two approaches to the semiquantitative assessment of hip OA are represented by Hip OA MRI Scoring System (HOAMS), a comprehensive whole organ assessment of nearly all findings, and the Hip Inflammation MRI Scoring System (HIMRISS), which selectively scores only active lesions (bone marrow lesion, synovitis/effusion). Validation is presently confined to limited assessment of reliability.Conclusion.Two methods for semiquantitative assessment of hip OA on MRI have been described and validation according to the OMERACT Filter is limited to evaluation of reliability.
Preliminary Validation of 2 Magnetic Resonance Image Scoring Systems for Osteoarthritis of the Hip According to the OMERACT Filter
Authors: Maksymowych Walter P. , Cibere Jolanda , Loeuille Damien , Weber Ulrich , Zubler Veronika , Roemer Frank W. , Jaremko Jacob L. , Sayre Eric C. , Lambert Robert G.W. 
Published: November 2013

Objective.Development of a validated magnetic resonance image (MRI) scoring system is essential in hip OA because radiographs are insensitive to change. We assessed the feasibility and reliability of 2 previously developed scoring methods: (1) the Hip Inflammation MRI Scoring System (HIMRISS) and (2) the Hip Osteoarthritis MRI Scoring System (HOAMS).Methods.Six readers (3 radiologists, 3 rheumatologists) participated in 2 reading exercises. In Reading Exercise 1, MRI of the hip of 20 subjects were read at a single time point followed by further standardization of methodology. In Reading Exercise 2, MRI of the hip of 18 subjects from a randomized controlled trial, assessed at 2 timepoints, and 27 subjects from a cross-sectional study were read for HIMRISS and HOAMS bone marrow lesions (BML) and synovitis. Reliability was assessed using intraclass correlation coefficient (ICC) and kappa statistics.Results.Both methods were considered feasible. For Reading 1, HIMRISS ICC were 0.52, 0.61, 0.70, and 0.58 for femoral BML, acetabular BML, effusion, and total scores, respectively; and for HOAMS, summed BML and synovitis ICC were 0.52 and 0.46, respectively. For Reading 2, HIMRISS and HOAMS ICC for BML and synovitis-effusion improved substantially. Interobserver reliability for change scores was 0.81 and 0.71 for HIMRISS femoral and HOAMS summed BML, respectively. Responsiveness and discrimination was moderate to high for synovitis-effusion. Significant associations were noted between BML or synovitis scores and Western Ontario and McMaster Universities Osteoarthritis Index pain scores for baseline values (p ≤ 0.001).Conclusion.The BML and synovitis-effusion components of both HIMRISS and HOAMS scoring systems are feasible and reliable, and should be validated further.
Fascin Confers Resistance to Listeria Infection in Dendritic Cells
Authors: Matsumura Fumio , Yamakita Yoshihiko , Starovoytov Val , Yamashiro Shigeko 
Published: November 2013

Abstract
Ag-presenting dendritic cells (DCs) must survive bacterial infection to present Ag information to naive T cells. The greater ability of DCs’ host defense is evident from the report that DCs are more resistant to Listeria monocytogenes than macrophages. However, the molecular mechanism of this resistance is unclear. We found that Listeria replicate more slowly in wild-type DCs compared with fascin1 knockout DCs. This finding is significant because fascin1, an actin-bundling protein, is specifically and greatly induced upon maturation of dendritic cells, but not other blood cells, including macrophages and neutrophils. Infection by Listeria makes phagosomes more acidic in wild-type DCs than in fascin1 knockout DCs, suggesting that fascin1 facilitates phagolysosomal fusion for killing of phagocytosed Listeria. We further found that fascin1 binds to LC3, an autophagosome marker, both in vivo and in vitro. Listeria are associated with LC3 to a greater extent in wild-type DCs than in fascin1 knockout DCs, suggesting that fascin1 facilitates autophagy for eradication of cytoplasmic Listeria. Taken together, our results suggest that fascin1 plays critical roles in the survival of DCs during Listeria infection, allowing DCs to function in innate and adaptive immunity.
The Tumor Promoter and NF-κB Modulator Bcl-3 Regulates Splenic B Cell Development
Authors: Zhang Xiaoren , Paun Andrea , Claudio Estefania , Wang Hongshan , Siebenlist Ulrich 
Published: November 2013

Abstract
Bcl-3 is an atypical member of the family of IκB proteins. Unlike the classic members, Bcl-3 functions as a nuclear transcriptional cofactor that may, depending on context, promote or suppress genes via association with p50/NF-κB1 or p52/NF-κB2 homodimers. Bcl-3 is also an oncogene, because it is a partner in recurrent translocations in B cell tumors, resulting in deregulated expression. Bcl-3 functions, however, remain poorly understood. We have investigated the role of Bcl-3 in B cells and discovered a previously unknown involvement in the splenic development of these cells. Loss of Bcl-3 in B cells resulted in significantly more marginal zone (MZ) and fewer follicular (FO) B cells. Conversely, transgenic expression of Bcl-3 in B cells generated fewer MZ and more FO B cells. Both Bcl-3−/− FO and MZ B cells were more responsive to LPS stimulation compared with their wild-type counterparts, including increased proliferation. By contrast, Bcl-3−/− FO B cells were more prone to apoptosis upon BCR stimulation, also limiting their expansion. The data reveal Bcl-3 as a regulator of B cell fate determination, restricting the MZ path and favoring the FO pathway, at least in part, via increased signal-specific survival of the latter, a finding of relevance to its tumorigenic activity.
Caveolin-1 Tyr14 Phosphorylation Induces Interaction with TLR4 in Endothelial Cells and Mediates MyD88-Dependent Signaling and Sepsis-Induced Lung Inflammation
Authors: Jiao Hao , Zhang Yang , Yan Zhibo , Wang Zhen-Guo , Liu Gongjian , Minshall Richard D. , Malik Asrar B. , Hu Guochang 
Published: November 2013

Abstract
Activation of TLR4 by the endotoxin LPS is a critical event in the pathogenesis of Gram-negative sepsis. Caveolin-1, the signaling protein associated with caveolae, is implicated in regulating the lung inflammatory response to LPS; however, the mechanism is not understood. In this study, we investigated the role of caveolin-1 in regulating TLR4 signaling in endothelial cells. We observed that LPS interaction with CD14 in endothelial cells induced Src-dependent caveolin-1 phosphorylation at Tyr14. Using a TLR4-MD2-CD14–transfected HEK-293 cell line and caveolin-1–deficient (cav-1−/−) mouse lung microvascular endothelial cells, we demonstrated that caveolin-1 phosphorylation at Tyr14 following LPS exposure induced caveolin-1 and TLR4 interaction and, thereby, TLR4 activation of MyD88, leading to NF-κB activation and generation of proinflammatory cytokines. Exogenous expression of phosphorylation-deficient Y14F caveolin-1 mutant in cav-1−/− mouse pulmonary vasculature rendered the mice resistant to LPS compared with reintroduction of wild-type caveolin-1. Thus, caveolin-1 Y14 phosphorylation was required for the interaction with TLR4 and activation of TLR4-MyD88 signaling and sepsis-induced lung inflammation. Inhibiting caveolin-1 Tyr14 phosphorylation and resultant inactivation of TLR4 signaling in pulmonary vascular endothelial cells represent a novel strategy for preventing sepsis-induced lung inflammation and injury.
Cutting Edge: The Signals for the Generation of T Cell Memory Are Qualitatively Different Depending on TCR Ligand Strength
Authors: Knudson Karin M. , Hamilton Sara E. , Daniels Mark A. , Jameson Stephen C. , Teixeiro Emma 
Published: November 2013

Abstract
CD8 T cell memory critically contributes to long-term immunity. Both low- and high-affinity TCR signals are able to support the differentiation of memory CD8 T cells. However, it is unclear whether the requirements for memory development change when TCR signal strength is altered. To gain further insight into this question, we used a TCRβ transmembrane domain mutant model that is defective in the generation of memory in response to high-affinity ligands. Surprisingly, lowering TCR signal strength, by stimulation with low-affinity ligands, resulted in normal memory development. Restoration of memory correlated with recovery of TCR-dependent NF-κB signaling. Thus, these data provide novel evidence that the requirements for memory are qualitatively different depending on TCR signal strength.
Differences in the Phenotype, Cytokine Gene Expression Profiles, and In Vivo Alloreactivity of T Cells Mobilized with Plerixafor Compared with G-CSF
Authors: Lundqvist Andreas , Smith Aleah L. , Takahashi Yoshiyuki , Wong Susan , Bahceci Erkut , Cook Lisa , Ramos Catalina , Tawab Abdul , McCoy J. Philip , Read Elizabeth J. , Khuu Hanh M. , Bolan Charles D. , Joo Jungnam , Geller Nancy , Leitman Susan F. , Calandra Gary , Dunbar Cynthia , Kurlander Roger , Childs Richard W. 
Published: November 2013

Abstract
Plerixafor (Mozobil) is a CXCR4 antagonist that rapidly mobilizes CD34+ cells into circulation. Recently, plerixafor has been used as a single agent to mobilize peripheral blood stem cells for allogeneic hematopoietic cell transplantation. Although G-CSF mobilization is known to alter the phenotype and cytokine polarization of transplanted T cells, the effects of plerixafor mobilization on T cells have not been well characterized. In this study, we show that alterations in the T cell phenotype and cytokine gene expression profiles characteristic of G-CSF mobilization do not occur after mobilization with plerixafor. Compared with nonmobilized T cells, plerixafor-mobilized T cells had similar phenotype, mixed lymphocyte reactivity, and Foxp3 gene expression levels in CD4+ T cells, and did not undergo a change in expression levels of 84 genes associated with Th1/Th2/Th3 pathways. In contrast with plerixafor, G-CSF mobilization decreased CD62L expression on both CD4 and CD8+ T cells and altered expression levels of 16 cytokine-associated genes in CD3+ T cells. To assess the clinical relevance of these findings, we explored a murine model of graft-versus-host disease in which transplant recipients received plerixafor or G-CSF mobilized allograft from MHC-matched, minor histocompatibility–mismatched donors; recipients of plerixafor mobilized peripheral blood stem cells had a significantly higher incidence of skin graft-versus-host disease compared with mice receiving G-CSF mobilized transplants (100 versus 50%, respectively, p = 0.02). These preclinical data show plerixafor, in contrast with G-CSF, does not alter the phenotype and cytokine polarization of T cells, which raises the possibility that T cell–mediated immune sequelae of allogeneic transplantation in humans may differ when donor allografts are mobilized with plerixafor compared with G-CSF.
Double Positive Thymocytes Select Mucosal-Associated Invariant T Cells
Authors: Seach Natalie , Guerri Lucia , Le Bourhis Lionel , Mburu Yvonne , Cui Yue , Bessoles Stéphanie , Soudais Claire , Lantz Olivier 
Published: November 2013

Abstract
NKT and mucosal-associated invariant T (MAIT) cells express semi-invariant TCR and restriction by nonclassical MHC class Ib molecules. Despite common features, the respective development of NKT and MAIT subsets is distinct. NKTs proliferate extensively and acquire effector properties prior to thymic export. MAIT cells exit the thymus as naive cells and acquire an effector/memory phenotype in a process requiring both commensal flora and B cells. During thymic development, NKTs are selected by CD1d-expressing cortical thymocytes; however, the hematopoietic cell type responsible for MAIT cell selection remains unresolved. Using reaggregated thymic organ culture and bone marrow chimeras, we demonstrate that positive selection of mouse iVα19 transgenic and Vβ6 transgenic MAIT cell progenitors requires MHC-related 1–expressing CD4+CD8+ double positive thymocytes, whereas thymic B cells, macrophages, and dendritic cell subsets are dispensable. Preincubation of double positive thymocytes with exogenous bacterial ligand increases MHC-related 1 surface expression and enhances mature MAIT cell activation in the in vitro cocultures. The revelation of a common cell type for the selection of both NKT and MAIT subsets raises questions about the mechanisms underlying acquisition of their specific features.
Essential Functions for ID Proteins at Multiple Checkpoints in Invariant NKT Cell Development
Authors: Verykokakis Mihalis , Krishnamoorthy Veena , Iavarone Antonio , Lasorella Anna , Sigvardsson Mikael , Kee Barbara L. 
Published: November 2013

Abstract
Invariant NKT (iNKT) cells display characteristics of both adaptive and innate lymphoid cells (ILCs). Like other ILCs, iNKT cells constitutively express ID proteins, which antagonize the E protein transcription factors that are essential for adaptive lymphocyte development. However, unlike ILCs, ID2 is not essential for thymic iNKT cell development. In this study, we demonstrated that ID2 and ID3 redundantly promoted iNKT cell lineage specification involving the induction of the signature transcription factor PLZF and that ID3 was critical for development of TBET-dependent NKT1 cells. In contrast, both ID2 and ID3 limited iNKT cell numbers by enforcing the postselection checkpoint in conventional thymocytes. Therefore, iNKT cells show both adaptive and innate-like requirements for ID proteins at distinct checkpoints during iNKT cell development.
Coupled IL-2–Dependent Extracellular Feedbacks Govern Two Distinct Consecutive Phases of CD4 T Cell Activation
Authors: Waysbort Nir , Russ Dor , Chain Benjamin M. , Friedman Nir 
Published: November 2013

Abstract
T cells integrate cell-specific Ag receptor signaling with shared signals mediated by secreted cytokines, which often involve regulatory feedback loops. IL-2 signaling, for example, reduces the synthesis of IL-2 and increases the synthesis of IL-2Rα-chain, whereas both genes require TCR signaling for their activation. The ways by which T cells dynamically integrate these private and public signals during activation are not well understood. We combined robotics, multiparameter flow cytometry, and real-time quantitative PCR to analyze T cell activation at high temporal resolution over several days. Two distinct temporal phases of T cell activation were evident. First, Ag-dependent signals activated low IL-2Rα and high IL-2 production, independent of IL-2 signaling. Subsequently, secreted IL-2 acted as a shared resource driving high IL-2Rα expression, reduced IL-2 synthesis, and cell proliferation. This transition was independent of continued TCR signaling. Our data allowed the determination of the parameters of the IL-2–mediated extracellular positive and negative feedback circuits and demonstrated that the two loops are coupled and become activated at a similar level of IL-2 signaling. We propose that temporal separation of private and shared signals allows T cells to first integrate Ag-specific responses and subsequently share information leading to collective decision making.
Two Types of TNF-α Exist in Teleost Fish: Phylogeny, Expression, and Bioactivity Analysis of Type-II TNF-α3 in Rainbow Trout Oncorhynchus mykiss
Authors: Hong Suhee , Li Ronggai , Xu Qiaoqing , Secombes Chris J. , Wang Tiehui 
Published: November 2013

Abstract
TNF-α is a cytokine involved in systemic inflammation and regulation of immune cells. It is produced chiefly by activated macrophages as a membrane or secreted form. In rainbow trout, two TNF-α molecules were described previously. In this article, we report a third TNF-α (TNF-α3) that has only low identities to known trout molecules. Phylogenetic tree and synteny analyses of trout and other fish species suggest that two types (named I and II) of TNF-α exist in teleost fish. The fish type-II TNF-α has a short stalk that may impact on its enzymatic release or restrict it to a membrane-bound form. The constitutive expression of trout TNF-α3 was generally lower than the other two genes in tissues and cell lines, with the exception of the macrophage RTS-11 cell line, in which expression was higher. Expression of all three TNF-α isoforms could be modulated by crude LPS, peptidoglycan, polyinosinic:polycytidylic acid, and rIFN-γ in cell lines and primary macrophages, as well as by bacterial and viral infections. TNF-α3 is the most responsive gene at early time points post-LPS stimulation and can be highly induced by the T cell–stimulant PHA, suggesting it is a particularly important TNF-α isoform. rTNF-α3 produced in CHO cells was bioactive in different cell lines and primary macrophages. In the latter, it induced the expression of proinflammatory cytokines (IL-1β, IL-6, IL-8, IL-17C, and TNF-αs), negative regulators (SOCS1–3, TGF-β1b), antimicrobial peptides (cathelicidin-1 and hepcidin), and the macrophage growth factor IL-34, verifying its key role in the inflammatory cytokine network and macrophage biology of fish.