bluuebunny/crossref_metadata_2025_split huggingface dataset:
Collagen type II is recognized by a pathogenic antibody through germline encoded structures
Authors: Böiers Ulrika , Lanig Harald , Sehnert Bettina , Holmdahl Rikard , Burkhardt Harald 
Published: September 2008

AbstractCollagen type II (CII) is a cartilage‐specific target of pathologic humoral autoimmune responses in rheumatoid arthritis as well as in the collagen‐induced arthritis model. The aim of the present study is to investigate the critical amino acid residues conferring CII epitope specificity of the prototypic arthritogenic murine mAb CIIC1. A homology model of the CIIC1 single‐chain antibody fragment (CIIC1scFv) in complex with its triple helical epitope was established. In silico predictions based on extensive molecular dynamics simulations were experimentally tested by the recombinant expression and functional analysis of CIIC1scFv containing alanine replacements allowing the identification of crucial CII‐binding sites in the CDR2 and CDR3 regions of both heavy and light chains. Since the conversion of the CIIC1scFv sequence into the respective germline at all 13 somatically mutated positions did not affect its CII binding, our data indicate that potentially harmful cartilage‐specific humoral autoimmunity could be germline encoded. The molecular modeling further demonstrates that the rigid collagen triple helix restricts the likelihood of molecular interactions with the CDR regions of the antibody considerably compared with globular antigens. These sterical constraints provide an explanation as to why somatic mutations in the arthritogenic autoantibody have no obvious impact on CII recognition.
The capacity of the TNF family members 4‐1BBL, OX40L, CD70, GITRL, CD30L and LIGHT to costimulate human T cells
Authors: Kober Johanna , Leitner Judith , Klauser Christoph , Woitek Ramona , Majdic Otto , Stöckl Johannes , Herndler‐Brandstetter Dietmar , Grubeck‐Loebenstein Beatrix , Reipert Birgit M. , Pickl Winfried F. , Pfistershammer Katharina , Steinberger Peter 
Published: September 2008

AbstractActivating signals generated by members of the tumour necrosis factor receptor superfamily upon interaction with their cognate ligands play important roles in T‐cell responses. Members of the tumour necrosis factor family namely 4‐1BBL, OX40L, CD70, GITRL, LIGHT and CD30L have been described to function as costimulatory molecules by binding such receptors on T cells. Using our recently described system of T‐cell stimulator cells we have performed the first study where all these molecules have been assessed and compared regarding their capacity to costimulate proliferation and cytokine production of human T cells. 4‐1BBL, which we found to be the most potent molecule in this group, was able to mediate sustained activation and proliferation of human T cells. OX40L and CD70 were also strong inducers of T‐cell proliferation, whereas the costimulatory capacity of human GITRL was significantly lower. Importantly CD30L and LIGHT consistently failed to act costimulatory on human T cells, and we therefore suggest that these molecules might be functionally distinct from the costimulatory members of this family.
Freeze‐and‐thaw‐disrupted tumour cells impair the responsiveness of DC to TLR stimulation
Authors: Tirapu Iñigo , Lewis Amy , Kreutz Martin , McLinden Hayley , Diebold Sandra S. 
Published: September 2008

AbstractCancer immunotherapy aims at inducing immune responses against tumour‐associated antigens that mediate the eradication of tumour cells. For successful vaccination against antigens expressed by the tumour, the immune system has to be provided with sufficient amounts of these antigens in connection with strong immunostimulatory signals such as toll‐like receptor (TLR) ligands. Tumour cells represent a convenient source of relevant tumour‐associated antigens but can have suppressive properties. In this study, we explored how different forms of tumour cell material influence the activation of dendritic cells (DC), which play a crucial role in the induction of anti‐tumour immune responses. We show that freeze‐and‐thaw‐disrupted tumour cells inhibit DC activation in response to TLR stimulation, a phenomenon that is only partially seen with non‐disrupted control cells. This suppression of DC stimulation is independent of tumour cell‐ and species‐specific factors. We tested the hypothesis that phosphatidylserine on cells with disrupted membrane integrity mediates inhibition of TLR‐induced DC activation. Our experimental evidence indicates that phosphatidylserine is not involved in the inhibition of TLR‐mediated DC activation by freeze‐and‐thaw‐disrupted cells. The inhibitory activity associated with disrupted tumour cells could explain why such preparations are less effective tumour vaccines than apoptotic tumour cells.
Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy
Authors: Mueller Katja , Schweier Oliver , Pircher Hanspeter 
Published: September 2008

AbstractWe determined the efficacy of in vitro expanded P14 TCR transgenic CD8 T cells to mediate tumor cell elimination and to protect against viral infection in mice. Contrary to previous studies, an adoptive transfer model without lymphodepletion, vaccination or cytokine treatment was used. Antigen‐activated P14 T cells cultured in IL‐2‐containing medium for 7 days (P14IL‐2) exhibited potent effector cell functions in vitro but did not confer protection against melanoma growth or viral infection. In contrast, P14 T cells cultured in IL‐15 (P14IL‐15) were highly effective in vivo although they displayed only moderate effector functions in vitro. Therapeutic efficacy correlated with the survival of the transferred T cells in the recipients: P14IL‐2 cells disappeared rapidly whereas P14IL‐15 cells persisted for prolonged time. Decreasing the IL‐2 concentration in the culture media improved in vivo survival and efficacy but also lowered the cell yield of the cultures. Finally, we could extend the findings with monoclonal P14 T cells to polyclonal CD8 T cells. Thus, in vitro expansion of antigen‐specific CD8 T cells in IL‐15 allowed the generation of substantial numbers of T cells without inducing terminally differentiated effector cells that turned out to be unfavorable in the transfer model examined here.
Effector CD8+ T cells activated in vitro confer immediate and long‐term tumor protection in vivo
Authors: Perret Rachel , Ronchese Franca 
Published: September 2008

AbstractWe studied the ability of CD8+ T cells activated in vitro to mediate tumor protection after transfer into adoptive hosts. TCR transgenic CD8+ T cells were activated in culture with DC and specific peptide antigen, and briefly expanded in IL‐2 containing medium. Cultured cells acquired a CD44hiCD62Llo phenotype, and following in vivo transfer they preferentially homed to non‐lymphoid tissues and spleen. In vivo, their numbers declined between day 0 and day 20, and then remained relatively stable from day 20 to day 90. Over time, many of the injected cells re‐expressed CD62L, and acquired the ability to localize to secondary lymphoid organs. Transferred T cells underwent low‐level proliferation, expressed IL‐7Rα and IL‐15Rβ, were cytotoxic in vivo, and retained the ability to produce IL‐2, IFN‐γ and TNF‐α upon ex vivo restimulation. In addition, transferred T cells conferred a high degree of tumor protection, which was greatest immediately after injection, and remained significant even when tumor was given 90 days after T‐cell transfer. We conclude that in vitro generated effector T cells can mediate immediate and long‐term tumor protection, and develop into long‐lived memory T‐cell populations in vivo.
DNA polymerase η is a limiting factor for A:T mutations in Ig genes and contributes to antibody affinity maturation
Authors: Masuda Keiji , Ouchida Rika , Yokoi Masayuki , Hanaoka Fumio , Azuma Takachika , Wang Ji‐Yang 
Published: September 2008

AbstractDNA polymerase η (POLH) is required for the generation of A:T mutations during the somatic hypermutation of Ig genes in germinal center B cells. It remains unclear, however, whether POLH is a limiting factor for A:T mutations and how the absence of POLH might affect antibody affinity maturation. We found that the heterozygous Polh+/− mice exhibited a significant reduction in the frequency of A:T mutations in Ig genes, with each type of base substitutions at a level intermediate between the Polh+/+ and Polh−/− mice. These observations suggest that Polh is haplo‐insufficient for the induction of A:T mutations in Ig genes. Intriguingly, there was also a reduction of C to T and G to A transitions in Polh+/− mice as compared with WT mice. Polh−/− mice produced decreased serum titers of high‐affinity antibodies against a T‐dependent antigen, which was associated with a significant reduction in the number of plasma cells secreting high‐affinity antibodies. Analysis of the V region revealed that aa substitutions caused by A:T mutations were greatly reduced in Polh−/− mice. These results demonstrate that POLH is a limiting factor for A:T mutations and contributes to the efficient diversification of Ig genes and affinity maturation of antibodies.
Pulmonary stromal cells induce the generation of regulatory DC attenuating T‐cell‐mediated lung inflammation
Authors: Li Qian , Guo Zhenhong , Xu Xiongfei , Xia Sheng , Cao Xuetao 
Published: September 2008

AbstractThe tissue microenvironment may affect the development and function of immune cells such as DC. Whether and how the pulmonary stromal microenvironment can affect the development and function of lung DC need to be investigated. Regulatory DC (DCreg) can regulate T‐cell response. We wondered whether such regulatory DC exist in the lung and what is the effect of the pulmonary stromal microenvironment on the generation of DCreg. Here we demonstrate that murine pulmonary stromal cells can drive immature DC, which are regarded as being widely distributed in the lung, to proliferate and differentiate into a distinct subset of DCreg, which express high levels of CD11b but low levels of MHC class II (I‐A), CD11c, secrete high amounts of IL‐10, NO and prostaglandin E2 (PGE2) and suppress T‐cell proliferation. The natural counterpart of DCreg in the lung with similar phenotype and regulatory function has been identified. Pulmonary stroma‐derived TGF‐β is responsible for the differentiation of immature DC to DCreg, and DCreg‐derived PGE2 contributes to their suppression of T‐cell proliferation. Moreover, DCreg can induce the generation of CD4+CD25+Foxp3+ Treg. Importantly, infusion with DCreg attenuates T‐cell‐mediated eosinophilic airway inflammation in vivo. Therefore, the pulmonary microenvironment may drive the generation of DCreg, thus contributing to the maintenance of immune homoeostasis and the control of inflammation in the lung.
Reduction of cPLA2α overexpression: An efficient anti‐inflammatory therapy for collagen‐induced arthritis
Authors: Raichel Lior , Berger Slava , Hadad Nurit , Kachko Leonid , Karter Maria , Szaingurten‐Solodkin Irit , Williams Richard O. , Feldmann Marc , Levy Rachel 
Published: September 2008

AbstractCytosolic phospholipase A2α (cPLA2) plays an important role in the development of several inflammatory diseases. The aim of the present study is to determine whether inhibition of cPLA2 expression, using specific antisense oligonucleotides against cPLA2 (antisense), is efficient in reducing inflammation after its development. Two mouse models of inflammation were included in the study: thioglicolate peritonitis and collagen‐induced arthritis (CIA). The antisense was found to be specific and efficient in inhibiting cPLA2 expression and NADPH oxidase activity ex vivo in peritoneal phagocytes. Immunoblotting and immunohistochemistry analysis showed a significant elevation in cPLA2 expression in the inflamed joints of collagen‐induced arthritis mice localized in cell infiltrate, chondrocytes and the surrounding skin and skeletal muscle. Similarly, the cPLA2 metabolite, leukotriene B4, accumulated in the peritoneal cavity of mice with peritonitis. Inhibition of elevated cPLA2 expression after development of inflammation by intravenous administration of antisense resulted in a dramatic reduction in inflammation and a significant reduction in neutrophils recruitment to the site of inflammation in both mouse models of inflammation. Our results demonstrate the critical role of cPLA2 for the duration of inflammation and suggest that inhibition of cPLA2 expression by antisense oligonucleotides may serve as an efficient treatment of inflammatory diseases.
Seismic performance of a 3D full‐scale high‐ductile steel–concrete composite moment‐resisting frame—Part II: Test results and analytical validation
Authors: Braconi A. , Bursi O. S. , Fabbrocino G. , Salvatore W. , Taucer F. , Tremblay R. 
Published: September 2008

AbstractThis paper presents the results of a multi‐level pseudo‐dynamic seismic test program that was performed to assess the performance of a full‐scale three‐bay, two‐storey steel–concrete composite moment‐resisting frame built with partially encased composite columns and partial‐strength beam‐to‐column joints. The system was designed to develop a ductile response in the joint components of beam‐to‐column joints including flexural yielding of beam end plates and shear yielding of the column web panel zone. The ground motion producing the damageability limit state interstorey drift caused minor damage while the ultimate limit state ground motion level entailed column web panel yielding, connection yielding and plastic hinging at the column base connections. The earthquake level chosen to approach the collapse limit state induced more damage and was accompanied by further column web panel yielding, connection yielding and inelastic phenomena at column base connections without local buckling. During the final quasi‐static cyclic test with stepwise increasing displacement–amplitudes up to an interstorey drift angle of 4.6%, the behaviour was ductile although cracking of beam‐to‐end‐plate welds was observed. Correlations with numerical simulations taking into account the inelastic cyclic response of beam‐to‐column and column base joints are also presented in the paper together. Inelastic static pushover and time history analysis procedures are used to estimate the structural behaviour and overstrength factors of the structural system under study. Copyright © 2008 John Wiley & Sons, Ltd.
Vascular risk and depression in the Hispanic Established Population for the Epidemiologic Study of the Elderly (EPESE)
Authors: Zimmerman Jennifer A. , Mast Benjamin T. , Miles Toni , Markides Kyriakos S. 
Published: September 2008

AbstractObjectiveAlthough vascular depression has received considerable research attention, relatively little research in this area has focused on minority samples. This study investigated the association between baseline vascular risk factors (VRFs) and risk for elevated depressive symptoms at 2‐year follow‐up in a sample of 964 individuals without significant depressive symptomotology (CES‐D < 12) or cognitive impairment (MMSE≥ 24) at baseline from the Hispanic Established Population for the Epidemiologic Study of the Elderly.MethodsWe examined the associations between self‐reported baseline vascular risk factors (chest pain, heart attack, stroke, hypertension, diabetes, and smoking) and a composite of these risk factors with elevated depressive symptoms (CES‐D ≥ 16) at 2‐year follow‐up.ResultsSeventy‐four (7.7%) of the 964 participants without evidence of depression at baseline demonstrated elevated depressive symptoms (CESD ≥ 16) 2 years later. There was an overall pattern of higher rates of elevated depressive symptoms at 2‐year follow‐up with increasing number of vascular risk factors (0 VRFs = 6.4%, 1 VRF = 5.5%, 2 VRFs = 7.7%, and 3 or more VRFs = 14.7%). After controlling for demographic variables, physical functioning, and other medical conditions, the cumulative vascular risk index was significantly associated with elevated depressive symptoms at 2‐year follow‐up (p < 0.05).ConclusionsOur results suggest vascular conditions may contribute to risk for depression over time among Mexican American elders, and this is relatively independent of other medical conditions. These findings suggest that depression is an additional long‐term complication of these common cardiovascular disorders. Copyright © 2008 John Wiley & Sons, Ltd.
Predictors of response to sertraline in patients with major depression
Authors: Morishita Shigeru , Kinoshita Toshihiko 
Published: September 2008

AbstractObjectiveInvestigation of the characteristics of patients being treated with antidepressants would be useful in determining which patients would most likely benefit from antidepressant. The purpose of this study was to examine the possible predictors of response to sertraline in major depression.MethodA retrospective cohort analysis was carried out among major depression patients. Eighty two patients were identified who were receiving sertraline to treat major depression.ResultsThe cumulative percentage of responders was over 80% after 6 weeks, and the cumulative percentage of responders was over 80% in patients receiving a 75 mg daily dose. Clinical factors, including age, gender, frequency of episodes, and family history were examined as possible predictors of response to sertraline. On Cox proportional hazards analysis, age, and gender were independent predictive factors of improvement with sertraline. The most influential factor was age (ecoef = 1.894), followed by gender (ecoef = 0.542); age over 40 years (χ2 = 5.598, df = 1,p = 0.018) and female gender (χ2 = 7.370, df = 1,p = 0.0066) were significantly associated with improvement.ConclusionsA 6‐week treatment period, a 75 mg daily dose, age over 40 years, and female gender appear to be predictors of response to sertraline in major depression. These factors should guide clinicians in determining the choice of antidepressant. Copyright © 2008 John Wiley & Sons, Ltd.
Hypomethylation of retrotransposable elements correlates with genomic instability in non‐small cell lung cancer
Authors: Daskalos Alexandros , Nikolaidis Georgios , Xinarianos George , Savvari Paraskevi , Cassidy Adrian , Zakopoulou Roubini , Kotsinas Athanasios , Gorgoulis Vassilis , Field John K. , Liloglou Triantafillos 
Published: September 2008

AbstractLINE‐1 and Alu elements are non‐LTR retrotransposons, constituting together over 30% of the human genome and they are frequently hypomethylated in human tumors. A relationship between global hypomethylation and genomic instability has been shown, however, there is little evidence to suggest active role for hypomethylation‐mediated reactivation of retroelements in human cancer. In our study, we examined by Pyrosequencing the methylation levels of LINE‐1 and Alu sequences in 48 primary nonsmall cell carcinomas and their paired adjacent tissues. We demonstrate a significant reduction of the methylation levels of both elements (p = 7.7 × 10−14 and 9.6 × 10−7, respectively). The methylation indices of the 2 elements correlated (p = 0.006), suggesting a possible common mechanism for their methylation maintenance. Genomic instability was measured utilizing 11 fluorescent microsatellite markers located on lung cancer hot‐spot regions such as 3p, 5q 9p, 13q and 17p. Hypomethylation of both transposable elements was associated with increased genomic instability (LINE, p = 7.1 × 10−5; Alu, p = 0.008). The reduction of the methylation index of LINE‐1 and Alu following treatment of 3 lung cell lines with 5‐aza‐2′‐deoxycitidine, consistently resulted in increased expression of both elements. Our study demonstrates the strong link between hypomethylation of transposable elements with genomic instability in non‐small cell lung cancer and provides early evidence for a potential active role of these elements in lung neoplasia. As demethylating agents are now entering lung cancer trials, it is imperative to gain a greater insight into the potential reactivation of silent retrotransposons in order to advance for the clinical utilization of epigenetics in cancer therapy. © 2008 Wiley‐Liss, Inc.
How to minimize formation and growth of tumours: Potential benefits of decapod crustaceans for cancer research
Authors: Vogt Günter 
Published: September 2008

AbstractTumours have only rarely been observed in the decapod crustaceans, a large animal group of more than 10,000 species that includes the commercially important and well investigated shrimp, lobsters, crayfish and crabs. Analysis of the literature and information from cancer and diseases data bases revealed a total of 15 incidences, some of them being questionable. Even in the long‐lived species, which can reach life spans of almost 100 years, neoplasias are virtually unknown. The data published so far suggest that the strikingly different frequencies of carcinogenesis between decapods and other well investigated animal groups like mammals, fish, insects and molluscs is based on differences of the metabolic pathways for carcinogens, the immune systems, and the regulation of stem cells. Therefore, representatives of the Decapoda may serve as useful models to study how organisms can successfully prevent or control spontaneously and environmentally induced cell proliferation. A particularly promising candidate for in‐depth investigation of these topics is the marbled crayfish, a rather new clonal lineage that is presently being introduced as a laboratory model in development and epigenetics. © 2008 Wiley‐Liss, Inc.
Dietary fats altered nephrotoxicity profile of methylmercury in rats
Authors: Jin Xiaolei , Lok Eric , Caldwell Don , Mueller Rudi , Kapal Kamla , Liston Virginia , Kubow Stan , Chan Hing Man , Mehta Rekha 
Published: September 2008

AbstractWeanling male Sprague–Dawley rats were administered semi‐purified isocaloric diet containing soy oil (SO), seal oil (SE), docosahexaenoic acid (DHA), fish oil (FO) or lard (LA) for 28 days, and then gavaged with 0, 1 or 3 mg MeHg kg−1body weight per day and fed the same diet for 14 days. Serum and 24 h urine samples were collected on the day of necropsy, and analyzed for markers of kidney function and diseases. Kidney slices were analyzed for para‐amino‐hippurate (PAH) and tetraethylammonium (TEA) uptake, total mercury and MeHg content, and examined for pathological lesions. Total mercury and MeHg contents increased significantly and dose‐dependently in all dietary groups. MeHg significantly increased relative kidney weight in all groups, serum creatinine in all except SO group, serum uric acid in the DHA and LA groups, serum Mg in all except the LA group, and urinary protein in the SO group. MeHg significantly decreased serum urea nitrogen in SE, FO and LA groups, urinary creatinine in the DHA group, PAH uptake in all except the SE group, and TEA uptake in all groups. MeHg caused nephrosis in all dietary groups. MeHg also significantly increased neutrophil counts in all except the SE group, decreased serum albumin and triglyceride in all except the DHA group, and increased serum total cholesterol in all groups, suggesting a nephrotic syndrome‐like outcome. These results confirmed that kidney tubules are major targets of MeHg nephrotoxicity. Treatment with dietary fats did not prevent, but rather altered the profile of, nephrotoxicity of MeHg in rats. Copyright © 2008 John Wiley & Sons, Ltd.