bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defects in the Bcl-2–Regulated Apoptotic Pathway Lead to Preferential Increase of CD25lowFoxp3+ Anergic CD4+ T Cells
Authors: Zhan Yifan , Zhang Yuxia , Gray Daniel , Carrington Emma M. , Bouillet Philippe , Ko Hyun-Ja , O’Reilly Lorraine , Wicks Ian P. , Strasser Andreas , Lew Andrew M. 
Published: July 2011

Abstract
Defects in the Bcl-2–regulated apoptotic pathway inhibit the deletion of self-reactive T cells. What is unresolved, however, is the nature and fate of such self-reactive T cells escaping deletion. In this study, we report that mice with such defects contained increased numbers of CD25lowFoxp3+ cells in the thymus and peripheral lymph tissues. The increased CD25lowFoxp3+ population contained a large fraction of cells bearing self-reactive TCRs, evident from a prominent increase in self-superantigen–specific Foxp3+Vβ5+CD4+ T cells in BALB/c Bim−/− mice compared with control animals. The survival rate of the expanded CD25lowFoxp3+ cells was similar to that of CD25highFoxp3+ CD4 T cells in vitro and in vivo. IL-2R stimulation, but not TCR ligation, upregulated CD25 on CD25lowFoxp3+CD4+ T cells in vitro and in vivo. The expanded CD25lowFoxp3+CD4+ T cells from Bim−/− mice were anergic but also had weaker regulatory function than CD25highFoxp3+ CD4+ T cells from the same mice. Analysis of Bim−/− mice that also lacked Fas showed that the peripheral homeostasis of this expanded population was in part regulated by this death receptor. In conclusion, these results show that self-reactive T cell escapees from thymic deletion in mice defective in the Bcl-2–regulated apoptotic pathway upregulate Foxp3 and become unresponsive upon encountering self-Ag without necessarily gaining potent regulatory function. This clonal functional diversion may help to curtail autoaggressiveness of escaped self-reactive CD4+ T cells and thereby safeguard immunological tolerance.
4-1BB Signaling Synergizes with Programmed Death Ligand 1 Blockade To Augment CD8 T Cell Responses during Chronic Viral Infection
Authors: Vezys Vaiva , Penaloza-MacMaster Pablo , Barber Daniel L. , Ha Sang-Jun , Konieczny Bogumila , Freeman Gordon J. , Mittler Robert S. , Ahmed Rafi 
Published: July 2011

Abstract
Previous studies have identified the inhibitory role that the programmed death 1 (PD-1) pathway plays during chronic infection. Blockade of this pathway results in rescue of viral-specific CD8 T cells, as well as reduction of viral loads in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). We tested the effect of combining PD ligand 1 (PD-L1) blockade with an agonistic regimen that induces 4-1BB costimulation during chronic LCMV infection. There is a boosting effect in the rescue of LCMV-specific CD8 T cell responses after dual treatment with PD-L1 blockade and 4-1BB agonistic Abs when the amount and timing of 4-1BB costimulation are carefully controlled. When PD-L1–blocking Abs are given together with a single low dose of anti–4-1BB agonistic Abs, there is an enhanced and stable expansion of viral-specific CD8 T cells. Conversely, when blocking Abs to PD-L1 are given with a repetitive high dose of anti–4-1BB, there is an initial synergistic expansion of viral-specific CD8 T cells by day 7, followed by dramatic apoptosis by day 14. Viral control paralleled CD8 T cell kinetics after dual treatment. By day 7 posttreatment, viral titers were lower in both of the combined regimens (compared with PD-L1 blockade alone). However, whereas the high dose of anti–4-1BB plus PD-L1 blockade resulted in rebound of viral titers to original levels, the low dose of anti–4-1BB plus PD-L1 blockade resulted in a stable reduction of viral loads. These findings demonstrate the importance of carefully manipulating the balance between activating and inhibitory signals to enhance T cell responses during chronic infection.
Innate Immune Responses in Human Monocyte-Derived Dendritic Cells Are Highly Dependent on the Size and the 5′ Phosphorylation of RNA Molecules
Authors: Jiang Miao , Österlund Pamela , Sarin L. Peter , Poranen Minna M. , Bamford Dennis H. , Guo Deyin , Julkunen Ilkka 
Published: July 2011

Abstract
Recognition of viral genetic material takes place via several different receptor systems, such as retinoic acid-inducible gene I-like receptors and TLRs 3, 7, 8, and 9. At present, systematic comparison of the ability of different types of RNAs to induce innate immune responses in human immune cells has been limited. In this study, we generated bacteriophage ϕ6 and influenza A virus-specific ssRNA and dsRNA molecules ranging from 58 to 2956 nt. In human monocyte-derived dendritic cells (moDCs), short dsRNAs efficiently upregulated the expression of IFN (IFN-α, IFN-β, and IFN–λ1) and proinflammatory (TNF-α, IL-6, IL-12, and CXCL10) cytokine genes. These genes were also induced by ssRNA molecules, but size-specific differences were not as pronounced as with dsRNA molecules. Dephosphorylation of short ssRNA and dsRNA molecules led to a dramatic reduction in their ability to stimulate innate immune responses. Such a difference was not detected for long ssRNAs. RNA-induced cytokine responses correlated well with IFN regulatory factor 3 phosphorylation, suggesting that IFN regulatory factor 3 plays a major role in both ssRNA- and dsRNA-activated responses in human moDCs. We also found that IFN gene expression was efficiently stimulated following recognition of short dsRNAs by retinoic acid-inducible gene I and TLR3 in human embryonic kidney 293 cells, whereas ssRNA-induced responses were less dependent on the size of the RNA molecule. Our data suggest that human moDCs are extremely sensitive in recognizing foreign RNA, and the responses depend on RNA size, form (ssRNA versus dsRNA), and the level of 5′ phosphorylation.
Soluble Proteins Induce Strong CD8+ T Cell and Antibody Responses through Electrostatic Association with Simple Cationic or Anionic Lipopeptides That Target TLR2
Authors: Chua Brendon Y. , Pejoski David , Turner Stephen J. , Zeng Weiguang , Jackson David C. 
Published: July 2011

Abstract
The low immunogenicity exhibited by most soluble proteins is generally due to the absence of molecular signatures that are recognized by the immune system as dangerous. In this study, we show that electrostatic binding of synthetic branched cationic or anionic lipopeptides that contain the TLR-2 agonist Pam2Cys markedly enhance a protein’s immunogenicity. Binding of a charged lipopeptide to oppositely charged protein Ags resulted in the formation of stable complexes and occurs at physiologic pH and salt concentrations. The induction of cell-mediated responses is dependent on the electrostatic binding of lipopeptide to the protein, with no CD8+ T cells being elicited when protein and lipopeptide possessed the same electrical charge. The CD8+ T cells elicited after vaccination with lipopeptide–protein Ag complexes produced proinflammatory cytokines, exhibited in vivo lytic activity, and protected mice from challenge with an infectious chimeric influenza virus containing a single OVA epitope as part of the influenza neuraminidase protein. Induction of a CD8+ T cell response correlated with the ability of lipopeptide to facilitate Ag uptake by DCs followed by trafficking of Ag-bearing cells into draining lymph nodes. Oppositely charged but not similarly charged lipopeptides were more effective in DC uptake and trafficking. Very high protein-specific Ab titers were also achieved by vaccination with complexes composed of oppositely charged lipopeptide and protein, whereas vaccination with similarly charged constituents resulted in significant but lower Ab titers. Regardless of whether similarly or oppositely charged lipopeptides were used in the induction of Ab, vaccination generated dominant IgG1 isotype Abs rather than IgG2a.
Anti-CD3 Therapy Promotes Tolerance by Selectively Depleting Pathogenic Cells while Preserving Regulatory T Cells
Authors: Penaranda Cristina , Tang Qizhi , Bluestone Jeffrey A. 
Published: July 2011

Abstract
Monoclonal anti-CD3 Abs have been used clinically for two decades to reverse steroid-resistant acute graft rejection. In autoimmune diabetes, short course treatment with FcR-nonbinding (FNB) anti-CD3 mAb in mice with recent onset of diabetes induces long-term disease remission. Induction of tolerogenic regulatory T cells (Tregs) has been implicated to be one of the mechanisms of action by FNB anti-CD3 mAb in these settings. In this study, we examined the effect of FNB anti-CD3 mAb treatment on the homeostasis of naive, effector, and regulatory T cells in vivo. Anti-CD3 treatment induced a transient systemic rise in the percentage but not absolute number of CD4+Foxp3+ Tregs due to selective depletion of CD4+Foxp3− conventional T cells. T cell depletion induced by FNB anti-CD3 mAb was independent of the proapoptotic proteins Fas, caspase-3, and Bim and was not inhibited by overexpression of the anti-apoptotic protein, Bcl-2. Tregs were not preferentially expanded and we found no evidence of conversion of conventional T cells into Tregs, suggesting that the pre-existing Tregs are resistant to anti-CD3–induced cell death. Interestingly, expression of the transcription factor Helios, which is expressed by thymus-derived natural Tregs, was increased in Tregs after FNB anti-CD3 mAb treatment, suggesting that the anti-CD3 treatment can alter, and potentially stabilize, Treg function. Taken together, the results suggest that FNB anti-CD3 therapy promotes tolerance by restoring the balance between pathogenic and regulatory T cells.
NKT Cells Inhibit Antigen-Specific Effector CD8 T Cell Induction to Skin Viral Proteins
Authors: Mattarollo Stephen R. , Yong Michelle , Gosmann Christina , Choyce Allison , Chan Dora , Leggatt Graham R. , Frazer Ian H. 
Published: July 2011

Abstract
We recently demonstrated that CD1d-restricted NKT cells resident in skin can inhibit CD8 T cell-mediated graft rejection of human papillomavirus E7-expressing skin through an IFN-γ–dependent mechanism. In this study, we examined the role of systemically derived NKT cells in regulating the rejection of skin grafts expressing viral proteins. In lymph nodes draining transplanted skin, Ag-specific CD8 T cell proliferation, cytokine production, and cytotoxic activity were impaired by NKT cells. NKT cell suppression was mediated via CD11c+ dendritic cells. Inhibition of CD8 T cell function did not require Foxp3+ regulatory T cells or NKT cell-secreted IFN-γ, IL-10, or IL-17. Thus, following skin grafting or immunization with human papillomavirus-E7 oncoprotein, NKT cells reduce the capacity of draining lymph node-resident APCs to cross-present Ag to CD8 T cell precursors, as evidenced by impaired expansion and differentiation to Ag-specific CD8 T effector cells. Therefore, in the context of viral Ag challenge in the skin, systemic NKT cells limit the capacity for effective priming of adaptive immunity.
Lung Tumor-Associated Dendritic Cell-Derived Amphiregulin Increased Cancer Progression
Authors: Hsu Ya-Ling , Huang Ming-Shyan , Cheng Da-En , Hung Jen-Yu , Yang Chih-Jen , Chou Shah-Hwa , Kuo Po-Lin 
Published: July 2011

Abstract
The interaction of cancer within a microenvironment is an important factor determining cancer development. This study analyzed the soluble factors secreted by tumor-associated dendritic cells (TADCs), which are responsible for increasing lung cancer growth, migration, invasion, and epithelial-to-mesenchymal transition. Addition of amphiregulin, present in large amounts in TADC-conditioned medium (CM), mimicked the inductive effect of TADC-CM on lung cancer progression, supported by the enhancement of cell proliferation, migration, and invasion as well as osteolytic bone metastases phenotypes. In contrast, neutralization of amphiregulin from TADC-CM decreased the advanced malignancy-inductive properties of TADC-CM. Significant upregulation of amphiregulin has been seen in tumor-infiltrating CD11c+ DCs in human lung cancer samples and patients’ sera. The enhancement of amphiregulin in TADCs has also been noted in mice transplanted with lung cancer cells. Induction of lung cancer progression by TADC-derived amphiregulin is associated with increased STAT3 and AKT activation, which subsequently increases the expression of cyclin D, Twist, and Snail. Blocking AKT significantly decreases TADC-CM and amphiregulin-mediated migration by decreasing the upregulation of Snail, whereas inhibition of STAT3 reduced the modulation of TADC-derived amphiregulin on Twist and cyclin D expression, suggesting that cooperation of STAT3 and AKT plays a critical role in TADC-mediated cancer progression. Moreover, mice treated with anti-amphiregulin Abs showed decreased incidence of cancer development and increased survival rates. Our study suggests that inhibition of amphiregulin or amphiregulin-related signaling is an attractive therapeutic target in lung cancer patients.
Interaction with FcγRIIB Is Critical for the Agonistic Activity of Anti-CD40 Monoclonal Antibody
Authors: White Ann L. , Chan H. T. Claude , Roghanian Ali , French Ruth R. , Mockridge C. Ian , Tutt Alison L. , Dixon Sandra V. , Ajona Daniel , Verbeek J. Sjef , Al-Shamkhani Aymen , Cragg Mark S. , Beers Stephen A. , Glennie Martin J. 
Published: July 2011

AbstractA high activatory/inhibitory FcγR binding ratio is critical for the activity of mAb such as rituximab and alemtuzumab that attack cancer cells directly and eliminate them by recruiting immune effectors. Optimal FcγR binding profiles of other anti-cancer mAb, such as immunostimulatory mAb that stimulate or block immune receptors, are less clear. In this study, we analyzed the importance of isotype and FcγR interactions in controlling the agonistic activity of the anti-mouse CD40 mAb 3/23. Mouse IgG1 (m1) and IgG2a (m2a) variants of the parental 3/23 (rat IgG2a) were engineered and used to promote humoral and cellular responses against OVA. The mouse IgG1 3/23 was highly agonistic and outperformed the parental Ab when promoting Ab (10–100-fold) and T cell (OTI and OTII) responses (2- to &gt;10-fold). In contrast, m2a was almost completely inactive. Studies in FcγR knockout mice demonstrated a critical role for the inhibitory FcγRIIB in 3/23 activity, whereas activatory FcγR (FcγRI, -III, and -IV) was dispensable. In vitro experiments established that the stimulatory effect of FcγRIIB was mediated through Ab cross-linking delivered in trans between neighboring cells and did not require intracellular signaling. Intriguingly, activatory FcγR provided effective cross-linking of 3/23 m2a in vitro, suggesting the critical role of FcγRIIB in vivo reflects its cellular distribution and bioavailability as much as its affinity for a particular Ab isotype. In conclusion, we demonstrate an essential cross-linking role for the inhibitory FcγRIIB in anti-CD40 immunostimulatory activity and suggest that isotype will be an important issue when optimizing reagents for clinical use.
Repair of Chromosomal RAG-Mediated DNA Breaks by Mutant RAG Proteins Lacking Phosphatidylinositol 3-Like Kinase Consensus Phosphorylation Sites
Authors: Gapud Eric J. , Lee Baeck-Seung , Mahowald Grace K. , Bassing Craig H. , Sleckman Barry P. 
Published: July 2011

Abstract
Ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunits (DNA-PKcs) are members of the phosphatidylinositol 3-like family of serine/threonine kinases that phosphorylate serines or threonines when positioned adjacent to a glutamine residue (SQ/TQ). Both kinases are activated rapidly by DNA double-strand breaks (DSBs) and regulate the function of proteins involved in DNA damage responses. In developing lymphocytes, DSBs are generated during V(D)J recombination, which is required to assemble the second exon of all Ag receptor genes. This reaction is initiated through a DNA cleavage step by the RAG1 and RAG2 proteins, which together comprise an endonuclease that generates DSBs at the border of two recombining gene segments and their flanking recombination signals. This DNA cleavage step is followed by a joining step, during which pairs of DNA coding and signal ends are ligated to form a coding joint and a signal joint, respectively. ATM and DNA-PKcs are integrally involved in the repair of both signal and coding ends, but the targets of these kinases involved in the repair process have not been fully elucidated. In this regard, the RAG1 and RAG2 proteins, which each have several SQ/TQ motifs, have been implicated in the repair of RAG-mediated DSBs. In this study, we use a previously developed approach for studying chromosomal V(D)J recombination that has been modified to allow for the analysis of RAG1 and RAG2 function. We show that phosphorylation of RAG1 or RAG2 by ATM or DNA-PKcs at SQ/TQ consensus sites is dispensable for the joining step of V(D)J recombination.
Association of peptic ulcer disease and pulmonary disease with risk of periprosthetic fracture after primary total knee arthroplasty
Authors: Singh Jasvinder A. , Lewallen David G. 
Published: July 2011

AbstractObjectiveTo assess the association of specific comorbidities with periprosthetic fractures after primary total knee replacement (TKR).MethodsWe used the prospectively collected data in the Mayo Clinic total joint registry from 1989–2008 on all patients who had undergone primary TKR. The outcome of interest was postoperative periprosthetic fractures during followup. The main predictors of interest were comorbidities grouped from the validated Deyo‐Charlson index. Multivariable‐adjusted Cox regression analyses were adjusted for sex, age, body mass index (BMI), American Society of Anesthesiology (ASA) class, operative diagnosis, and implant fixation. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated.ResultsWe included 17,633 primary TKRs with a mean followup of 6.3 years. The mean age was 68 years, 55% were women, and the mean BMI was 31 kg/m2. There were 188 postoperative periprosthetic fractures on postoperative day 1 or later; 162 fractures (86%) occurred on postoperative day 90 or later. In multivariable analyses that simultaneously adjusted for all comorbidities and other variables (age, sex, BMI, ASA, operative diagnosis, and cement status), the following 2 conditions were significantly associated with an increased hazard of postoperative periprosthetic fractures: peptic ulcer disease (HR 1.87, 95% CI 1.28–2.75; P = 0.0014) and chronic obstructive pulmonary disease (HR 1.62, 95% CI 1.10–2.40; P = 0.02).ConclusionPeptic ulcer disease and chronic obstructive pulmonary disease are associated with a higher risk of periprosthetic fractures after primary TKR. This may be related to the disease or its treatments, which need further study. Identification of specific risk factors may allow for implementation of intervention strategies to reduce this risk.
Changes in cotherapies after initiation of disease‐modifying antirheumatic drug therapy in patients with rheumatoid arthritis
Authors: Kawai Vivian K. , Grijalva Carlos G. , Arbogast Patrick G. , Curtis Jeffrey R. , Solomon Daniel H. , Delzell Elizabeth , Chen Lang , Ouellet‐Hellstrom Rita , Herrinton Lisa , Liu Liyan , Mitchel Edward F. , Stein C. Michael , Griffin Marie R. 
Published: July 2011

AbstractObjectiveWe hypothesized that initiation of a new disease‐modifying antirheumatic drug (DMARD) for treatment of rheumatoid arthritis (RA) would decrease the use of corticosteroids, nonsteroidal antiinflammatory drugs (NSAIDs), and narcotics.MethodsUsing administrative databases, we assembled 4 retrospective cohorts of RA patients (1998–2005) and identified 5 groups initiating DMARD regimens: methotrexate (MTX) with (new MTX) or without (first MTX) use of other nonbiologic DMARDs in the previous year; new hydroxychloroquine (HCQ) and/or sulfasalazine (SSZ; new HCQ/SSZ) and new leflunomide (new LEF), both with previous use of MTX; and new tumor necrosis factor α (TNFα) antagonists (new anti‐TNF). We compared within‐person differences in any use of cotherapies (≥1 prescription) between the 6 months before and the 6–12 months after DMARD initiation.ResultsAmong 32,476 DMARD initiators, the prevalence of corticosteroid, NSAID, and narcotic use increased by 15%, 5%, and 6%, respectively, in the 6 months before initiation compared to the previous 6 months, suggesting worsening of the disease. In the 6–12 months after initiation for most initiator groups, more patients stopped using corticosteroids and NSAIDs than started, with overall decreases of 8.9% (95% confidence interval [95% CI] 8.4–9.4%) for corticosteroids and 12.9% (95% CI 12.3–13.4%) for NSAIDs. The proportion of narcotic users changed little (overall decrease of 2.5%; 95% CI 1.9–3.0%).ConclusionUse of all 3 cotherapies increased in the 6 months before initiation of new DMARD regimens for RA. Use of corticosteroids and NSAIDs decreased modestly 6–12 months after initiation, but there was only a very small decrease in narcotic use. These differential changes require further study.
Structural and Material Design of Open‐Cell Powder Metallurgical Foams
Authors: Quadbeck Peter , Kümmel Kerstin , Hauser Ralf , Standke Gisela , Adler Jörg , Stephani Günter , Kieback Bernd 
Published: July 2011

AbstractHigh porosity permeable materials have been manufactured on the basis of the highly uniform structure of foamed polyurethane since the 1950 s. This paper shows the development of open cell foams based on all kinds of steels, titanium alloys, and also open‐cell molybdenum foams made by a powder metallurgical replication technique. Such materials show a wide range of physical and mechanical properties, which may be adapted to various requirements. The automotive industry, for example, needs high‐temperature resistant materials with high permeability and good strength for catalytic conversion. For orthopaedic implants, the network‐like metal foams made of titanium, tantalum, or steel exhibit a bone‐like structure. The powder metallurgical replication route represents an economic method to process open‐cell metal foams with a unique combination of properties for a wide range of applications.
Highly Reproducible Surface‐Enhanced Raman Scattering on a Capillarity‐Assisted Gold Nanoparticle Assembly
Authors: Que Ronghui , Shao Mingwang , Zhuo Shujuan , Wen Chunye , Wang Suidong , Lee Shuit‐Tong 
Published: July 2011

AbstractA facile method based on capillarity‐assisted assembly is used to fabricate high‐performance surface‐enhanced Raman scattering (SERS) substrates employing clean Au nanoparticles (NPs). This method is better than micro‐channel way because the former may supply large‐area uniform assembly and overcome the uneven radial distribution. Such densely‐arranged assembly of Au NPs exhibits high reproducibility and large Raman enhancement factors of 3 × 1010, arising from strong electromagnetic field coupling induced by adjacent Au NPs. The spot‐to‐spot SERS signals show that the relative standard deviation (RSD) in the intensity of the main Raman vibration modes (1310, 1361, 1509, 1650 cm−1) of Rhodamine 6G at a concentration of 1 × 10−10 M are consistently less than 20%, demonstrating good spatial uniformity and reproducibility. The SERS signals of sudan dye at a 1 × 10−8 M concentration also shows high reproducibility with a low RSD of <20%. Further, the assembly substrate is stable, retaining excellent uniformity and sensitivity after storage for months. This assembly strategy integrating the advantages of low‐cost production, high sensitivity, and reproducibility would significantly facilitate practical SERS detection.