bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decreased variation of inflammatory markers in gestational diabetes
Authors: Pöyhönen‐Alho Maritta , Ebeling P. , Saarinen A. , Kaaja R. 
Published: January 2011

AbstractBackgroundGestational diabetes is a prediabetic state. Sub‐clinical inflammation may play a role in the transition from gestational diabetes to type 2 diabetes; the role of the autonomic nervous system as a mediating system has been raised. We aimed to study the association of the sympathetic nervous system and sub‐clinical inflammation in women with gestational diabetes.MethodsWe studied 41 Caucasian women with gestational diabetes and 22 healthy pregnant and 14 non‐pregnant controls. We assayed plasma noradrenaline, insulin, C‐reactive protein, interleukin‐6, insulin growth factor‐1, serum amyloid A, steroid hormone‐binding globulin, α‐1 acid glycoprotein and cortisol at 2400, 0400 and 0700 h.ResultsNo differences existed in the concentrations of inflammatory markers between gestational diabetes and normal pregnancy but women with gestational diabetes showed loss of variation in C‐reactive protein and serum amyloid A. Levels of hormone‐binding globulin were lower in hypertensive compared with normotensive women with gestational diabetes at all time points and lowest at midnight when α‐1 acid glycoprotein levels were higher in hypertensive women.ConclusionsGestational diabetes is associated with loss of natural variation of C‐reactive protein and serum amyloid A, suggesting altered modulation of inflammation. Hypertension in gestational diabetes seems not to be associated with higher levels of inflammatory markers other than α‐1 acid glycoprotein. Copyright © 2011 John Wiley & Sons, Ltd.
PI3Kγ deficiency delays the onset of experimental autoimmune encephalomyelitis and ameliorates its clinical outcome
Authors: Berod Luciana , Heinemann Christina , Heink Sylvia , Escher Angelika , Stadelmann Christine , Drube Sebastian , Wetzker Reinhard , Norgauer Johannes , Kamradt Thomas 
Published: January 2011

AbstractPI3Ks control signal transduction triggered by growth factors and G‐protein‐coupled receptors and regulate an array of biological processes, including cellular proliferation, differentiation, survival and migration. Herein, we investigated the role of PI3Kγ in the pathogenesis of EAE. We show that, in the absence of PI3Kγ expression, clinical signs of EAE were delayed and mitigated. PI3Kγ‐deficient myelin oligodendrocyte glycoprotein (MOG)35–55‐specific CD4+ T cells appeared later in the secondary lymphoid organs and in the CNS than their WT counterparts. Transfer of WT CD4+ cells into PI3Kγ−/− mice prior to MOG35–55 immunisation restored EAE severity to WT levels, supporting the relevance of PI3Kγ expression in Th cells for the pathogenesis of EAE; however, PI3Kγ was dispensable for Th1 and Th17 differentiation, thus excluding an altered expression of these pathogenetically relevant cytokines as the cause for ameliorated EAE in PI3Kγ−/− mice. These findings demonstrate that PI3Kγ contributes to the development of autoimmune CNS inflammation.
1,25‐Dihydroxyvitamin D3 acts directly on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelitis
Authors: Mayne Christopher G. , Spanier Justin A. , Relland Lance M. , Williams Calvin B. , Hayes Colleen E. 
Published: January 2011

AbstractMultiple sclerosis (MS) is an incurable autoimmune neurodegenerative disease. Environmental factors may be key to MS prevention and treatment. MS prevalence and severity decrease with increasing sunlight exposure and vitamin D3 supplies, supporting our hypothesis that the sunlight‐dependent hormone, 1,25‐dihydroxyvitamin D3 (1,25‐(OH)2D3), inhibits autoimmune T‐cell responses in MS. Moreover, 1,25‐(OH)2D3 inhibits and reverses experimental autoimmune encephalomyelitis (EAE), an MS model. Here, we investigated whether 1,25‐(OH)2D3 inhibits EAE via the vitamin D receptor (VDR) in T lymphocytes. Using bone marrow chimeric mice with a disrupted VDR only in radio‐sensitive hematopoietic cells or radio‐resistant non‐hematopoietic cells, we found that hematopoietic cell VDR function was necessary for 1,25‐(OH)2D3 to inhibit EAE. Furthermore, conditional targeting experiments showed that VDR function in T cells was necessary. Neither 1,25‐(OH)2D3 nor T‐cell‐specific VDR targeting influenced CD4+Foxp3+ T‐cell proportions in the periphery or the CNS in these studies. These data support a model wherein 1,25‐(OH)2D3 acts directly on pathogenic CD4+ T cells to inhibit EAE.
CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity
Authors: Mayer Christian T. , Floess Stefan , Baru Abdul Mannan , Lahl Katharina , Huehn Jochen , Sparwasser Tim 
Published: January 2011

Abstract“Suppressor T cells” were historically defined within the CD8+ T‐cell compartment and recent studies have highlighted several naturally occurring CD8+Foxp3− Treg populations. However, the relevance of CD8+Foxp3+ T cells, which represent a minor population in both thymi and secondary lymphoid organs of nonmanipulated mice, remains unclear. We here demonstrate that de novo Foxp3 induction in peripheral CD8+Foxp3− T cells is counter‐regulated by DC‐mediated co‐stimulation via CD80/CD86. CD8+Foxp3+ T cells fail to develop in TCR‐transgenic mice with Rag1−/− background, similar to classical CD4+Foxp3+ Tregs. Notably, both naturally occurring and induced CD8+Foxp3+ T cells express bona fide Treg markers including CD25, GITR, CTLA4 and CD103, and show defective IFN‐γ production upon restimulation when compared with their CD8+Foxp3− counterparts. However, utilizing DEREG transgenic mice for the isolation of Foxp3+ cells by eGFP reporter expression, we demonstrate that induced CD8+Foxp3+ T cells similar to activated CD8+Foxp3− T cells only mildly suppress T‐cell proliferation and IFN‐γ production. We therefore categorize CD8+Foxp3+ T cells as a tightly controlled population sharing certain developmental and phenotypic properties with classical CD4+Foxp3+ Tregs, but lacking potent suppressive activity.
IL‐22 in antifungal immunity
Authors: Zelante Teresa , Iannitti Rossana , De Luca Antonella , Romani Luigina 
Published: January 2011

AbstractDeciphering cellular and molecular mechanisms that maintain host immune homeostasis with fungi and the breakdown of this homeostatic tolerance during fungal infections disease is a challenge in medical mycology. In fact, the virulence of fungi may be determined by the interaction between fungi and the host immune status and its classification as a commensal microorganism or a pathogen may shift depending on the balance. In addition to the central role of the IL‐12/IFN‐γ‐dependent Th1 responses in cell‐mediated immune protection against fungi, Th17 cells provide protection and inflammation at mucosal surfaces, and Tregs fine‐tune immune responses to prevent damage to the host. Recent evidence indicates that IL‐22‐producing cells, employing primitive antifungal effector mechanisms, contribute to antifungal resistance at mucosal surfaces under conditions of defective adaptive immunity. The fact that IL‐22 production is driven by commensals points to the need of an integrated, systems biology approach to improve our understanding of the inherent and intimate mechanisms underlying multilevel host–fungus interactions.
Co‐stimulation by dendritic cells maintains the peripheral pool of Tregs
Authors: Garbi Natalio , Hämmerling Günter J. 
Published: January 2011

AbstractMany aspects of an immune response are regulated by dendritic cells (DCs). DCs play key proinflammatory roles by sensing microbial invaders and promoting the activation of innate immune cells such as NK cells. In addition, DCs are required for the initiation and maintenance of adaptive T‐cell responses against invading pathogens. Moreover, DCs also fulfill important anti‐inflammatory functions: they induce peripheral T‐cell tolerance by silencing self‐reactive T cells and supporting the homeostasis of regulatory T cells (Tregs). A study in this issue of the European Journal of Immunology reveals that CD80/CD86 expression on DCs contributes to the maintenance of the peripheral pool of Tregs. This Commentary discusses current findings on this topic, focusing on the role of DCs in the homeostatic control of Tregs and myeloid cells, and the potential consequences for T‐cell activation.
Antiprion drugs 6‐aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy
Authors: Barbezier Nicolas , Chartier Aymeric , Bidet Yannick , Buttstedt Anja , Voisset Cécile , Galons Hervé , Blondel Marc , Schwarz Elisabeth , Simonelig Martine 
Published: January 2011

AbstractOculopharyngeal muscular dystrophy (OPMD) is an adult‐onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Insoluble nuclear inclusions form in diseased muscles. We have generated a Drosophila model of OPMD that recapitulates the features of the disorder. Here, we show that the antiprion drugs 6‐aminophenanthridine (6AP) and guanabenz acetate (GA), which prevent formation of amyloid fibers by prion proteins in cell models, alleviate OPMD phenotypes in Drosophila, including muscle degeneration and nuclear inclusion formation. The large ribosomal RNA and its activity in protein folding were recently identified as a specific cellular target of 6AP and GA. We show that deletions of the ribosomal DNA locus reduce OPMD phenotypes and act synergistically with sub‐effective doses of 6AP. In a complementary approach, we demonstrate that ribosomal RNA accelerates in vitro fibril formation of PABPN1 N‐terminal domain. These results reveal the conserved role of ribosomal RNA in different protein aggregation disorders and identify 6AP and GA as general anti‐aggregation molecules.
GSK3β negatively regulates oligodendrocyte differentiation and myelination in vivo
Authors: Azim Kasum , Butt Arthur M. 
Published: January 2011

AbstractGlycogen synthase kinase 3β (GSK3β) is an essential integrating molecule for multiple proliferation and differentiation signals that regulate cell fate. Here, we have examined the effects of inhibiting GSK3β on the development of oligodendrocytes (OLs) from their oligodendrocyte precursors (OP) in vivo by injection into the lateral ventricle of postnatal mice and ex vivo in organotypic cultures of isolated intact rodent optic nerve. Our results show that a range of GSK3β inhibitors (ARA‐014418, lithium, indirubin, and L803‐mt) increase OPs and OLs and promote myelination. Inhibition of GSK3β stimulates OP proliferation and is prosurvival and antiapoptotic. The effects of GSK3β inhibition in OPs is via the canonical Wnt signaling pathway by stimulating nuclear translocation of β‐catenin. However, direct comparison of the effects of Wnt3a and GSK3β inhibition in optic nerves shows that they have opposing actions on OLs, whereby GSK3β inhibition strikingly increases OL differentiation, whereas Wnt3a inhibits OL differentiation. Notably, GSK3β inhibition overrides the negative effects of Wnt3a on OLs, indicating novel GSK3β signaling mechanisms that negatively regulate OL differentiation. We identify that two mechanisms of GSK3β inhibition are to stimulate cAMP response element binding (CREB) and decrease Notch1 signaling, which positively and negatively regulate OL differentiation and myelination, respectively. A key finding is that GSK3β inhibition has equivalent effects in the adult and stimulates the regeneration of OLs and remyelination following chemically induced demyelination. This study identifies GSK3β as a profound negative regulator of OL differentiation that contributes to inefficient regeneration of OLs and myelin repair in demyelination. © 2011 Wiley‐Liss, Inc.
Suppressed microglial E prostanoid receptor 1 signaling selectively reduces tumor necrosis factor alpha and interleukin 6 secretion from toll‐like receptor 3 activation
Authors: Li Xianwu , Cudaback Eiron , Keene C. Dirk , Breyer Richard M. , Montine Thomas J. 
Published: January 2011

AbstractActivation of innate immunity via toll‐like receptors (TLRs) is associated with neurodegenerative diseases, and some effectors, like tumor necrosis factor alpha (TNFα) and interleukin 6 (IL‐6), directly contribute to neurodegeneration. We tested the hypothesis that prostaglandin (PG) E2 receptor subtype 1 (EP1) was necessary for the induction of microglial cytokines following the activation of innate immunity. Primary murine microglia had cytokine secretion by activators of TLR3 > TLR9 > TLR4 > TLR2. TLR3 activation induced early expression of cyclooxygenase 2 (COX2) and delayed expression of membranous PGE synthase and secretion of PGE2. Nonselective and COX2‐selective inhibitors blocked TLR3 induction of TNFα and IL‐6. Moreover, of the nine of twenty cytokines and chemokines induced by TLR3 activation, only TNFα and IL‐6 were significantly dependent on EP1 signaling as determined using microglia from mice homozygous deficient for EP1 gene or wild‐type microglia coincubated with an EP1 antagonist. These results were confirmed by blocking intracellular Ca2+ release with 2‐aminoethoxy‐diphenyl borate or Xestospongin C, inhibitors of IP3 receptors. Our results show that suppression of microglial EP1 signaling achieves much of the desired effect of COX inhibitors by selectively blocking TLR3‐induced microglial secretion of two major effectors of paracrine neuron damage. In combination with the ability of EP1 suppression to ameliorate excitotoxicity, these data point to blockade of EP1 as an attractive candidate therapeutic for neurodegenerative diseases. © 2011 Wiley‐Liss, Inc.
Expression of LPP3 in Bergmann glia is required for proper cerebellar sphingosine‐1‐phosphate metabolism/signaling and development
Authors: López‐Juárez Alejandro , Morales‐Lázaro Sara , Sánchez‐Sánchez Roberto , Sunkara Manjula , Lomelí Hilda , Velasco Iván , Morris Andrew J. , Escalante‐Alcalde Diana 
Published: January 2011

AbstractBioactive lipids serve as intracellular and extracellular mediators in cell signaling in normal and pathological conditions. Here we describe that an important regulator of some of these lipids, the lipid phosphate phosphatase‐3 (LPP3), is abundantly expressed in specific plasma membrane domains of Bergmann glia (BG), a specialized type of astrocyte with key roles in cerebellum development and physiology. Mice selectively lacking expression of LPP3/Ppap2b in the nervous system are viable and fertile but exhibit defects in postnatal cerebellum development and modifications in the cytoarchitecture and arrangement of BG with a mild non‐progressive motor coordination defect. Lipid and gene profiling studies in combination with pharmacological treatments suggest that most of these effects are associated with alterations in sphingosine‐1‐phosphate (S1P) metabolism and signaling. Altogether our data indicate that LPP3 participates in several aspects of neuron‐glia communication required for proper cerebellum development. © 2011 Wiley‐Liss, Inc.
Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7
Authors: Oosterhuis Koen , Öhlschläger Peter , van den Berg Joost H. , Toebes Mireille , Gomez Raquel , Schumacher Ton N. , Haanen John B. 
Published: January 2011

AbstractTo allow vaccination irrespective of HLA type, DNA vaccines encoding full‐length antigens are required. However, here, we demonstrate that the immunogenicity of DNA vaccines encoding the full‐length human papillomavirus (HPV) type 16 E7 and E6 proteins is highly reduced compared to vaccines encoding only the immunodominant epitope. Furthermore, the low remaining immunogenicity is essentially lost for both E7 and E6 when a nononcogenic “gene‐shuffled” variant is utilized. To address these issues, we tested whether alterations in transgene design can restore the immunogenicity of full‐length and gene‐shuffled DNA vaccines. Remarkably, genetic fusion of E7 with tetanus toxin fragment C (TTFC) resulted in a dramatic increase in immunogenicity both for the full‐length and the gene‐shuffled version of E7. Moreover, the TTFC fusion vaccines were more immunogenic than a vaccine encoding a fusion of E7 and mycobacterial heat shock protein‐70, which has recently been tested in a clinical trial. Interestingly, vaccination with these TTFC fusion vaccines also resulted in extremely persistent T‐cell responses. The E7‐specific CD8+ T cells induced by TTFC fusion vaccines were functional in terms of IFN‐γ production, formation of immunological memory, in vivo cytolytic activity and tumor eradication. Finally, we show that genetic fusion with TTFC also improves the immunogenicity of a gene‐shuffled E6 DNA vaccine. These data demonstrate that genetic fusion with tetanus toxin fragment C can dramatically improve the immunogenicity of full‐length and gene‐shuffled DNA vaccines. The DNA fusion vaccines developed here will be evaluated for the treatment of HPV‐positive carcinomas in future studies.
IGFBP‐4 activates the Wnt/beta‐catenin signaling pathway and induces M‐CAM expression in human renal cell carcinoma
Authors: Ueno Koji , Hirata Hiroshi , Majid Shahana , Tabatabai Z. Laura , Hinoda Yuji , Dahiya Rajvir 
Published: January 2011

AbstractThe Wnt/β‐catenin signaling pathway is inactivated by Wnt antagonists in most cancers and IGFBP‐4 is an antagonist of the Wnt/ β‐catenin signaling pathway. However, the function of IGFBP‐4 is not currently understood in renal cell carcinoma (RCC). We initially found that the expression of IGFBP‐4 was significantly lower in primary RCC and higher in metastatic RCC compared to normal human kidney tissues. To assess the function of IGFBP4, we established IGFBP4 transfectants (primary renal cancer cell line) and performed functional analyses including Tcf reporter assays, cell viability, invasive capability, mortality, and in vivo tumor growth. Interestingly IGFBP‐4 transfectants promoted cell growth (in vitro and in vivo), invasion, and motility in primary renal cancer. Tcf transcriptional activity was significantly increased in IGFBP‐4 transfectants compared to mock cells and β‐catenin expression was increased. Also the β‐catenin downstream effector, MT1‐MMP showed increased expression in IGFBP4 transfectants. Additionally IGFBP4 induced the expression of M‐CAM, a marker of tumor progression. In order to assess the role of IGFBP4 in metastatic renal cancer, IGFBP‐4 mRNA in a metastatic renal cancer cell lines (ACHN) was knocked‐down using a siRNA technique. The cell growth and motility was decreased in si‐IGFBP4 transfected ACHN cells compared to cells transfected with control siRNA. Tcf activity in ACHN cells was also decreased with si‐IGFBP‐4 transfection. This is a first report documenting that IGFBP‐4 expression in RCC activates cell growth, metastasis, Wnt/beta‐catenin signaling and may be involved in RCC metastasis.
Molecular markers of endometrial carcinoma detected in uterine aspirates
Authors: Colas Eva , Perez Cristina , Cabrera Silvia , Pedrola Nuria , Monge Marta , Castellvi Josep , Eyzaguirre Fernando , Gregorio Jesus , Ruiz Anna , Llaurado Marta , Rigau Marina , Garcia Marta , Ertekin Tugçe , Montes Melania , Lopez‐Lopez Rafael , Carreras Ramon , Xercavins Jordi , Ortega Alicia , Maes Tamara , Rosell Elisabet , Doll Andreas , Abal Miguel , Reventos Jaume , Gil‐Moreno Antonio 
Published: January 2011

AbstractEndometrial cancer (EC) is the most frequent of the invasive tumors of the female genital tract. Although usually detected in its initial stages, a 20% of the patients present with advanced disease. To date, no characterized molecular marker has been validated for the diagnosis of EC. In addition, new methods for prognosis and classification of EC are needed to combat this deadly disease. We thus aimed to identify new molecular markers of EC and to evaluate their validity on endometrial aspirates. Gene expression screening on 52 carcinoma samples and series of real‐time quantitative PCR validation on 19 paired carcinomas and normal tissue samples and on 50 carcinoma and noncarcinoma uterine aspirates were performed to identify and validate potential biomarkers of EC. Candidate markers were further confirmed at the protein level by immunohistochemistry and Western blot. We identified ACAA1, AP1M2, CGN, DDR1, EPS8L2, FASTKD1, GMIP, IKBKE, P2RX4, P4HB, PHKG2, PPFIBP2, PPP1R16A, RASSF7, RNF183, SIRT6, TJP3, EFEMP2, SOCS2 and DCN as differentially expressed in ECs. Furthermore, the differential expression of these biomarkers in primary endometrial tumors is correlated to their expression level in corresponding uterine fluid samples. Finally, these biomarkers significantly identified EC with area under the receiver‐operating‐characteristic values ranging from 0.74 to 0.95 in uterine aspirates. Interestingly, analogous values were found among initial stages. We present the discovery of molecular biomarkers of EC and describe their utility in uterine aspirates. These findings represent the basis for the development of a highly sensitive and specific minimally invasive method for screening ECs.
Expression of p‐JAK2 predicts clinical outcome and is a potential molecular target of acute myelogenous leukemia
Authors: Ikezoe Takayuki , Kojima Shinsuke , Furihata Mutsuo , Yang Jing , Nishioka Chie , Takeuchi Asako , Isaka Mayuka , Koeffler H. Phillip , Yokoyama Akihito 
Published: January 2011

AbstractOur study determined if Janus kinase 2 (JAK2) was activated in acute myelogenous leukemia (AML; n = 77, excluding acute promyelocytic leukemia) by immunohistochemistry (IHC) using a phosphor‐specific antibody against JAK2. p‐JAK2 was detectable in all cases, although its levels varied between patient samples (high levels, n = 31; low levels, n = 46). The quantification of levels of p‐JAK2 by IHC was well correlated with that assessed by Western blot analyses and fluorescence‐activated cell sorting (FACS). Levels of p‐JAK2 were directly correlated with high white blood cell count (52.3 × 103/L in patients with high p‐JAK2 vs. 28.3 × 103/L in patients with low p‐JAK2, p < 0.01) and were inversely correlated with complete remission rates (45% in patients with high p‐JAK2 vs. 78% in patients with low p‐JAK2, p < 0.003). In addition, multivariate analysis confirmed that high levels of p‐JAK2 remained a significant factor for overall survival (hazard ratio = 2.213; 95% confidence interval, 1.212–4.041, p = 0.023). Moreover, we found that AZ960, a novel and specific inhibitor of the JAK2 kinase, potently inhibited the clonogenic growth and induced apoptosis of freshly isolated AML cells from patients in association with cleavage of caspase 3 and downregulation of anti‐apoptotic Bcl‐xL proteins. Taken together, JAK2 may be a promising molecular target for treatment of AML.