bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Adaptor Molecule Signaling Lymphocytic Activation Molecule-Associated Protein (SAP) Regulates IFN-γ and IL-4 Production in Vα14 Transgenic NKT Cells via Effects on GATA-3 and T-bet Expression
Authors: Cen Osman , Ueda Aki , Guzman Laura , Jain Jimmy , Bassiri Hamid , Nichols Kim E. , Stein Paul L. 
Published: April 2014

Abstract
NKT cells comprise a rare regulatory T cell population of limited TCR diversity, with most cells using a Vα14Jα18 TCR. These cells exhibit a critical dependence on the signaling adapter molecule, signaling lymphocytic activation molecule-associated protein (SAP), for their ontogeny, an aspect not seen in conventional αβ T cells. Prior studies demonstrate that SAP enhances TCR-induced activation of NF-κB in CD4+ T cells. Because NF-κB is required for NKT cell development, SAP might promote the ontogeny of this lineage by signaling to NF-κB. In this study, we demonstrate that forced expression of the NF-κB target gene, Bcl-xL, or inhibitory NF-κB kinase β, a catalytic subunit of the IκB kinase complex essential for NF-κB activation, fails to restore NKT cell development in sap−/− mice, suggesting that SAP mediates NKT cell development independently of NF-κB. To examine the role of SAP in NKT cell function, we generated NKT cells in sap−/− mice by expressing a transgene encoding the Vα14Jα18 component of the invariant TCR. These cells bound α-galactosylceramide-loaded CD1d tetramers, but exhibited a very immature CD24+NK1.1− phenotype. Although sap−/− tetramer-reactive cells proliferated in response to TCR activation, they did not produce appreciable levels of IL-4 or IFN-γ. The reduction in cytokine production correlated with the near absence of GATA-3 and T-bet, key transcription factors regulating cytokine expression and maturation of NKT cells. Ectopic expression of GATA-3 partially restored IL-4 production by the NKT cells. Collectively, these data suggest that by promoting GATA-3 and T-bet expression, SAP exerts control over NKT cell development and mature NKT cell cytokine production.
TLR9-Dependent Activation of Dendritic Cells by DNA from Leishmania major Favors Th1 Cell Development and the Resolution of Lesions
Authors: Hkima Abou Fakher Faihaa , Rachinel Nicolas , Klimczak Martine , Louis Jacques , Doyen Noëlle 
Published: April 2014

Abstract
In its vertebrate host, Leishmania encounters cells that express TLRs. Using genetically resistant C57BL/6 mice deficient in either TLR2, 4, or 9, we show in this study that only TLR9-deficient mice are more susceptible to infection with Leishmania major. TLR9-deficient mice resolved their lesions and controlled parasites growth with much lower efficiency than wild-type C57BL/6 mice. The absence of TLR9 also transiently inhibited the development of curative Th1 response. In an attempt to analyze the possible basis for such aberrant response in TLR9−/− mice, we have studied the importance of TLR9 for the activation of dendritic cells (DCs) by L. major. Results show that DCs in the draining lymph nodes are activated following infection with L. major. Furthermore, bone marrow-derived DCs as well as DCs freshly isolated from the spleen of C57BL/6 mice can be activated by either heat-killed or live L. major in vitro. In sharp contrast, L. major failed to activate DCs from TLR9−/− mice. Noteworthily, activation of DCs was abolished either following treatment of the parasites with DNase or after acidification of the endosomal compartment of DCs by chloroquine, pinpointing the DNA of L. major as the possible ligand of TLR9 leading to the activation of DCs. Results showed that DNA purified from L. major was indeed capable of activating DCs in a strictly TLR9-dependent manner. Moreover we showed that the L. major DNA-induced TLR9 signaling in DCs condition these cells to promote IFN-γ production by CD4+ T cells.
Increased IL-15 Production Is Associated with Higher Susceptibility of Memory CD4 T Cells to Simian Immunodeficiency Virus during Acute Infection
Authors: Eberly Matthew D. , Kader Muhamuda , Hassan Wail , Rogers Kenneth A. , Zhou Jianzhong , Mueller Yvonne M. , Mattapallil Mary J. , Piatak Michael , Lifson Jeffrey D. , Katsikis Peter D. , Roederer Mario , Villinger Francois , Mattapallil Joseph J. 
Published: April 2014

Abstract
Acute SIV infection is characterized by explosive infection of memory CD4 T cells in peripheral and mucosal tissues. Interestingly, relatively few memory CD4 T cells are infected until as late as days 7–8 after challenge. However, by day 10 postinfection, most of the memory CD4 T cells are infected and carry viral DNA. The rapidity with which infection expands within 2–3 days to encompass virtually the entire memory CD4 T cell compartment suggests significant alterations in the susceptibility of memory CD4 T cells to infection during this period. The mechanism(s) underlying this increased permissiveness to infection is not known. In this study, we show that IL-15 secretion significantly correlates with the up-regulated expression of CD4 on memory CD4 T cells that is associated with increased permissiveness to SIV infection. Activation and proliferation of memory CD8, but not memory CD4 T cells, preceded the amplification of viral infection. Although memory CD4 T cells did not express normal activation markers, they displayed a significant up-regulation in the density of CD4 but not CCR5 expression between days 7 and 10 postinfection that correlated with increased plasma IL-15 levels and infection in these cells. Culture of purified CD4 T cells with IL-15 and/or SIV was associated with a significant increase in the expression of CD4 and infection of these sorted cells. Our results demonstrate that IL-15 contributes to the increased susceptibility of memory CD4 T cells to SIV during the early phase of acute SIV infection.
Human Circulating CD4+CD25highFoxp3+ Regulatory T Cells Kill Autologous CD8+ but Not CD4+ Responder Cells by Fas-Mediated Apoptosis
Authors: Strauss Laura , Bergmann Christoph , Whiteside Theresa L. 
Published: April 2014

Abstract
Mechanisms utilized by human regulatory T cells (Treg) for elimination of effector cells may vary. We investigated the possibility that the mechanism of Treg suppression depends on Fas/FasL-mediated apoptosis of responder cells (RC). CD4+CD25highFoxp3+ Treg and autologous CD4+CD25− and CD8+CD25− subsets of RC were isolated from blood of 25 cancer patients and 15 normal controls and cocultured in the presence of OKT3 and IL-2 (150 or 1000 IU/ml). Suppression of RC proliferation was measured in CFSE assays. RC and Treg apoptosis was monitored by 7-aminoactinomycin D staining in flow-based cytotoxicity assays. Treg from all subjects expressed CD95+, but only Treg from cancer patients expressed CD95L. These Treg, when activated via TCR plus IL-2, up-regulated CD95 and CD95L expression (p &lt; 0.001) and suppressed CD8+ RC proliferation (p &lt; 0.001) by inducing Fas-mediated apoptosis. However, Treg cocultured with CD4+ RC suppressed proliferation independently of Fas/FasL. In cocultures, Treg were found to be resistant to apoptosis in the presence of 1000 IU/ml IL-2, but at lower IL-2 concentrations (150 IU/ml) they became susceptible to RC-induced death. Thus, Treg and RC can reciprocally regulate Treg survival, depending on IL-2 concentrations present in cocultures. This divergent IL-2-dependent resistance or sensitivity of Treg and RC to apoptosis is amplified in patients with cancer.
A Signaling Polypeptide Derived from an Innate Immune Adaptor Molecule Can Be Harnessed as a New Class of Vaccine Adjuvant
Authors: Kobiyama Kouji , Takeshita Fumihiko , Ishii Ken J. , Koyama Shohei , Aoshi Taiki , Akira Shizuo , Sakaue-Sawano Asako , Miyawaki Atsushi , Yamanaka Yuko , Hirano Hisashi , Suzuki Koichi , Okuda Kenji 
Published: April 2014

Abstract
Modulation of intracellular signaling using cell-permeable polypeptides is a promising technology for future clinical applications. To develop a novel approach to activate innate immune signaling by synthetic polypeptides, we characterized several different polypeptides derived from the caspase recruitment domain (CARD) of IFN-β promoter stimulator 1, each of which localizes to a different subcellular compartment. Of particular interest was, N′-CARD, which consisted of the nuclear localization signal of histone H2B and the IFN-β promoter stimulator 1CARD and which localized to the nucleus. This polypeptide led to a strong production of type I IFNs and molecular and genetic analyses showed that nuclear DNA helicase II is critically involved in this response. N′-CARD polypeptide fused to a protein transduction domain (N′-CARD-PTD) readily transmigrated from the outside to the inside of the cell and triggered innate immune signaling. Administration of N′-CARD-PTD polypeptide elicited production of type I IFNs, maturation of bone marrow-derived dendritic cells, and promotion of vaccine immunogenicity by enhancing Ag-specific Th1-type immune responses, thereby protecting mice from lethal influenza infection and from outgrowth of transplanted tumors in vivo. Thus, our results indicate that the N′-CARD-PTD polypeptide belongs to a new class of vaccine adjuvant that directly triggers intracellular signal transduction by a distinct mechanism from those engaged by conventional vaccine adjuvants, such as TLR ligands.
β-Defensin-2 Promotes Resistance against Infection with P. aeruginosa
Authors: Wu Minhao , McClellan Sharon A. , Barrett Ronald P. , Hazlett Linda D. 
Published: April 2014

Abstract
Corneal infection with Pseudomonas aeruginosa results in corneal perforation in susceptible C57BL/6 (B6) mice, but not in resistant BALB/c mice. To explore the role of two important defensins, murine β-defensin-1 (mBD1) and mBD2, in the ocular immune defense system, their mRNA and protein expression levels were tested by real-time RT-PCR and Western blot, respectively. mRNA, protein, and immunostaining data demonstrated that both mBD1 and mBD2 were constitutively expressed in normal BALB/c and B6 corneas, and they were disparately up-regulated in BALB/c (more) vs B6 (less) corneas after infection. To determine whether either defensin played a role in host resistance, BALB/c mice were treated with either mBD1 or mBD2 small interfering RNA by subconjunctival injection together with topical application. Increased corneal opacity and worsened disease were displayed after knockdown of mBD2 but not of mBD1. mBD2 silencing also increased bacterial counts and polymorphonuclear neutrophil infiltration in BALB/c corneas. Real-time RT-PCR data further demonstrated that mBD2, not mBD1, differentially modulated mRNA expression of proinflammatory cytokines/molecules such as IFN-γ, MIP-2, IL-1β, TNF-α, IL-6, and inducible NO synthase; TLR signaling molecules, including TLR2, TLR4, TLR9, and MyD88; and the transcription factor NF-κB. Additionally, in vivo studies indicated that mBD2 silencing enhanced corneal nitrite levels and NF-κB activation. Collectively, the data provide evidence that mBD2, but not mBD1, is required for host resistance against P. aeruginosa-induced corneal infection.
Dendritic Cell-Based Therapeutic Vaccination against Myeloma: Vaccine Formulation Determines Efficacy against Light Chain Myeloma
Authors: Cohen Sharon , Haimovich Joseph , Hollander Nurit 
Published: April 2014

Abstract
Multiple myeloma is an incurable plasma cell malignancy. Immunotherapy in myeloma patients had limited success to date. We have previously demonstrated that dendritic cells (DCs) pulsed with autologous Ig Id induced Id-reactive CD8+ T cells and protection against a myeloma tumor challenge. In this work, we studied the therapeutic efficacy of chemotherapy combined with different formulations of DC-based vaccines in mice bearing large plasma cell tumors. The comparative study demonstrated that s.c. injection of DCs loaded with Id coupled to keyhole limpet hemocyanin, s.c. injection of DCs loaded with irradiated tumor cells, and intratumoral injection of naive DCs were similarly effective in mediating tumor regression and long-term survival. However, whereas the Id-keyhole limpet hemocyanin-DC vaccine was inefficient against myeloma cells that lost expression of the Ig H chain, intratumoral injection of naive DCs and s.c. injection of DCs loaded with irradiated tumor cells were highly effective against cells producing L chains only. This may be of particular importance for patients with L chain myeloma. Given that T cells respond primarily to peptides derived from H chain CDRs, attempts to treat L chain disease with myeloma protein-pulsed DCs may be futile. Vaccination with tumor cell-loaded DCs may, however, induce an effective antitumor response.
Disruption of CCR5-Dependent Homing of Regulatory T Cells Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer
Authors: Tan Marcus C. B. , Goedegebuure Peter S. , Belt Brian A. , Flaherty Brian , Sankpal Narendra , Gillanders William E. , Eberlein Timothy J. , Hsieh Chyi-Song , Linehan David C. 
Published: April 2014

Abstract
Tumors evade immune destruction by actively inducing immune tolerance through the recruitment of CD4+CD25+Foxp3+ regulatory T cells (Treg). We have previously described increased prevalence of these cells in pancreatic adenocarcinoma, but it remains unclear what mechanisms are involved in recruiting Tregs into the tumor microenvironment. Here, we postulated that chemokines might direct Treg homing to tumor. We show, in both human pancreatic adenocarcinoma and a murine pancreatic tumor model (Pan02), that tumor cells produce increased levels of ligands for the CCR5 chemokine receptor and, reciprocally, that CD4+ Foxp3+ Tregs, compared with CD4+ Foxp3− effector T cells, preferentially express CCR5. When CCR5/CCL5 signaling is disrupted, either by reducing CCL5 production by tumor cells or by systemic administration of a CCR5 inhibitor (N,N-dimethyl-N-{{4-{[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl}amino}}benzyl]-N,N-dimethyl-N- {{{4-{{{[2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptan-8-yl]carbonyl}amino}}benzyl}}}tetrahydro-2H-pyran-4-aminiumchloride; TAK-779), Treg migration to tumors is reduced and tumors are smaller than in control mice. Thus, this study demonstrates the importance of Tregs in immune evasion by tumors, how blockade of Treg migration might inhibit tumor growth, and, specifically in pancreatic adenocarcinoma, the role of CCR5 in the homing of tumor-associated Tregs. Selective targeting of CCR5/CCL5 signaling may represent a novel immunomodulatory strategy for the treatment of cancer.
A Novel Antiangiogenic Effect for Telomerase-Specific Virotherapy through Host Immune System
Authors: Ikeda Yoshihiro , Kojima Toru , Kuroda Shinji , Endo Yoshikatsu , Sakai Ryo , Hioki Masayoshi , Kishimoto Hiroyuki , Uno Futoshi , Kagawa Shunsuke , Watanabe Yuichi , Hashimoto Yuuri , Urata Yasuo , Tanaka Noriaki , Fujiwara Toshiyoshi 
Published: April 2014

Abstract
Soluble factors in the tumor microenvironment may influence the process of angiogenesis; a process essential for the growth and progression of malignant tumors. In this study, we describe a novel antiangiogenic effect of conditional replication-selective adenovirus through the stimulation of host immune reaction. An attenuated adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of E1 genes, could replicate in and cause selective lysis of cancer cells. Mixed lymphocyte-tumor cell culture demonstrated that OBP-301-infected cancer cells stimulated PBMC to produce IFN-γ into the supernatants. When the supernatants were subjected to the assay of in vitro angiogenesis, the tube formation of HUVECs was inhibited more efficiently than recombinant IFN-γ. Moreover, in vivo angiogenic assay using a membrane-diffusion chamber system s.c. transplanted in nu/nu mice showed that tumor cell-induced neovascularization was markedly reduced when the chambers contained the mixed lymphocyte-tumor cell culture supernatants. The growth of s.c. murine colon tumors in syngenic mice was significantly inhibited due to the reduced vascularity by intratumoral injection of OBP-301. The antitumor as well as antiangiogenic effects, however, were less apparent in SCID mice due to the lack of host immune responses. Our data suggest that OBP-301 seems to have antiangiogenic properties through the stimulation of host immune cells to produce endogenous antiangiogenic factors such as IFN-γ.
Metabolic syndrome and cognitive decline: the role of physical activity
Authors: Rinaldi M. , Graffi G. , Rabino Massa E. 
Published: April 2014

Metabolic Syndrome (MetS) is a cluster of conditions, each of which represents a risk factor for cardiovascular disease: central obesity, hyperglycemia, dyslipidemia and hypertension. Any of these conditions and MetS itself have been associated to Alzheimer's Disease and Vascular Dementia. In recent years there is a growing evidence for the role of physical activity in preventing metabolic diseases and cognitive decline. In our research we assessed the prevalence of MetS in a sample of 154 elderly people. Furthermore, we evaluated cognition (with Mini Mental State Examination, MMSE) and the physical activity level in every patient. We found a significant association between MetS, borderline cognitive impairment and sedentary lifestyle.
Rural prevalence of type 2 diabetes mellitus: A cross sectional study
Authors: Rathod Hetal , Darade Sanjay , Chitnis Uday , Bhawalkar Jitendra , Jadhav Sudhir , Banerjee Amitav 
Published: April 2014

Abstract
Background: Recent studies in India indicate rising trends of diabetes even in rural areas. Continuous monitoring of the diabetes situation is required by repeated cross sectional studies in different parts of the country both urban rural to plan control measures. Aim: To estimate the prevalence of Type 2 diabetes in a sample of rural population and explore associations between diabetes and known risk factors. Materials and Methods: A cross sectional study was carried out in 3 villages in the rural field practice area of a medical college in Pune, India. All eligible adults of both genders were included and screened for diabetes by house to house survey. A total of 1000 subjects were examined. Physical examination included measuring height, weight, and waist hip ratio. Blood glucose was estimated using glucometer. Family history of diabetes was also elicited. Data was analysed by descriptive statistics using proportions with 95% confidence intervals. Various associations were explored using using Odds Ratio with 95% confidence intervals as applicable. Results: The prevalence of diabetes mellitus was 9.1% (91/1000; 95% CI 7.4, 11). Most cases of newly detected diabetics were in the age group 36 - 40 years. There was no association between gender and diabetes (OR = 1.38, 95% CI 0.88, 2.17). Overweight status was associated with diabetes: 38.5% (35/91) of diabetics were overweight compared to 18.6% (169/909) of non-diabetics (OR = 2.74, 95% CI 1.69, 4.41). Similarly abnormal waist hip ratio was associated with diabetes: 47.25% (43/91) of diabetics had high waist hip ratio compared with 29.59% (269/909) of non-diabetics (OR = 2.13, 95% CI 1.35, 3.37). Also family history was strongly associated with diabetes: 27.5% (25/91) of diabetics gave positive family history compared with 9.4% (85/909) of non-diabetics (OR = 3.67, 95% CI = 2.13, 6.30). Conclusion: The burden of diabetes was present in the rural population studied. The associated known risk factors were also prevalent and showed strong relationship with diabetes. Diabetes mellitus erstwhile thought to be a disease of urban life appears to be equally prevalent in the rural setting.
Cobalt Protoporphyrin Pretreatment Protects Human Embryonic Stem Cell-Derived Cardiomyocytes From Hypoxia/Reoxygenation Injury In Vitro and Increases Graft Size and Vascularization In Vivo
Authors: Luo Jun , Weaver Matthew S. , Cao Baohong , Dennis James E. , Van Biber Benjamin , Laflamme Michael A. , Allen Margaret D. 
Published: April 2014

Abstract

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) can regenerate infarcted myocardium. However, when implanted into acutely infarcted hearts, few cells survive the first week postimplant. To improve early graft survival, hESC-CMs were pretreated with cobalt protoporphyrin (CoPP), a transcriptional activator of cytoprotective heme oxygenase-1 (HO-1). When hESC-CMs were challenged with an in vitro hypoxia/reoxygenation injury, mimicking cell transplantation into an ischemic site, survival was significantly greater among cells pretreated with CoPP versus phosphate-buffered saline (PBS)-pretreated controls. Compared with PBS-pretreated cells, CoPP-pretreated hESC-CM preparations exhibited higher levels of HO-1 expression, Akt phosphorylation, and vascular endothelial growth factor production, with reduced apoptosis, and a 30% decrease in intracellular reactive oxygen species. For in vivo translation, 1 × 107 hESC-CMs were pretreated ex vivo with CoPP or PBS and then injected intramyocardially into rat hearts immediately following acute infarction (permanent coronary ligation). At 1 week, hESC-CM content, assessed by quantitative polymerase chain reaction for human Alu sequences, was 17-fold higher in hearts receiving CoPP- than PBS-pretreated cells. On histomorphometry, cardiomyocyte graft size was 2.6-fold larger in hearts receiving CoPP- than PBS-pretreated cells, occupying up to 12% of the ventricular area. Vascular density of host-perfused human-derived capillaries was significantly greater in grafts composed of CoPP- than PBS-pretreated cells. Taken together, these experiments demonstrate that ex vivo pretreatment of hESC-CMs with a single dose of CoPP before intramyocardial implantation more than doubled resulting graft size and improved early graft vascularization in acutely infarcted hearts. These findings open the door for delivery of these, or other, stem cells during acute interventional therapy following myocardial infarction or ischemia.
Audit Firm Size, Earnings Management, and Information Asymmetry
Authors: Chen Xiaolin , Kong Dongmin , Wang Yutao 
Published: April 2014

Abstract
Using a sample of 8,788 observations from Chinese listed firms from 2001 to 2009, we investigate the difference in the information content of discretionary accruals between those audited by Top 10 and non-Top 10 accounting firms. We find that discretionary accruals are positively related to the probability of informed trading (PIN) and bid-ask spreads; the larger the discretionary accruals, the higher will be PIN, the level of information asymmetry, and bid-ask spreads. Furthermore, we argue that the significance level of the correlation between discretionary accruals and PIN/bid-ask spreads differs between companies audited by Top 10 and by other firms. The positive relationship between discretionary accruals and PIN/bid-ask spreads is significantly weaker in companies audited by the Top 10. This indicates that the Top 10 firms are better at restraining opportunistic earnings management, and also that the information content of their clients’ discretionary accruals is higher and their information asymmetry lower. Our study contributes to a better understanding of the two types of earnings management through manipulating discretionary accruals; one is based on delivering value-related information and the other arises from opportunism.