bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacologic responses of the mouse urinary bladder
Authors: Canda A. , Chapple Christopher , Chess-Williams Russ 
Published: February 2009

Abstract
The aim of the study was to determine pathways involved in contraction and relaxation of the mouse urinary bladder. Mouse bladder strips were set up in gassed Krebs-bicarbonate solution and responses to various drugs and electrical field stimulation were obtained. Isoprenaline (b-receptor agonist) caused a 63% inhibition of carbachol precontracted detrusor (EC50=2nM). Carbachol caused contraction (EC50=0.3µM), responses were antagonised more potently by 4-DAMP (M3-antagonist) than methoctramine (M2-antagonist). Electrical field stimulation caused contraction, which was inhibited by atropine (60%) and less by guanethidine and α,β-methylene-ATP. The neurogenic responses were not potentiated by inhibition of nitric oxide synthase. Presence of an intact urothelium significantly depressed responses to carbachol (p=0.02) and addition of indomethacin and L-NNA to remove prostaglandin and nitric oxide production respectively did not prevent the inhibitory effect of the urothelium. In conclusion, b-receptor agonists cause relaxation and muscarinic agonists cause contraction via the M3-receptor. Acetylcholine is the main neurotransmitter causing contraction while nitric oxide has a minor role. The mouse and human urothelium are similar in releasing a factor that inhibits contraction of the detrusor muscle which is unidentified but is not nitric oxide or a prostaglandin. Therefore, the mouse may be used as a model to study the lower urinary tract.
Inflation of diagnostic tests in hypertensive young adults: a need for diagnostic guideline?
Authors: Kirkpantur Alper , Arici Mustafa , Altun Bulent , Turgan Cetin 
Published: February 2009

Abstract
The cause of hypertension in young adults (age:18–29 years) is mostly a primary condition although secondary causes are frequent in this population. Clinical files of 100 patients were reviewed to evaluate the use of diagnostic tests after completion of diagnostic work-up for hypertension. Seventy-nine patients had primary hypertension while 21 patients had secondary hypertension. Renal imaging studies, serum levels of aldosterone and plasma renin activity, and screening tests for pheochromocytoma were more likely to be performed in patients younger than 24 years, in female patients and in patients without familial history of hypertension in primary hypertensive patients (p<0.05). Renal imaging studies and screening tests for pheochromocytoma were done more frequently in patients with Stage 2 hypertension (p<0,05). Among secondary hypertensives, renal imaging studies and renal biopsy were more ordered in patients younger than 24 years, in female patients, in patients with Stage 2 hypertension and in patients without family history for hypertension (p<0.05). Mean body mass index was higher in patients with primary hypertension than patients with secondary hypertension (p<0.05). Seventy patients (70%) had undergone several screening interventions with negative results. In conclusion, a simple, stepwise diagnostic evaluation would greatly benefit the management of young hypertensives.
Highly Variable Immune-Response Proteins (185/333) from the Sea Urchin,Strongylocentrotus purpuratus: Proteomic Analysis Identifies Diversity within and between Individuals
Authors: Dheilly Nolwenn M. , Nair Sham V. , Smith L. Courtney , Raftos David A. 
Published: February 2009

Abstract185/333 genes and transcripts from the purple sea urchin, Strongylocentrotus purpuratus, predict high levels of amino acid diversity within the encoded proteins. Based on their expression patterns, 185/333 proteins appear to be involved in immune responses. In the present study, one- and two-dimensional Western blots show that 185/333 proteins exhibit high levels of molecular diversity within and between individual sea urchins. The molecular masses of 185/333-positive bands or spots range from 30 to 250 kDa with a broad array of isoelectric points. The observed molecular masses are higher than those predicted from mRNAs, suggesting that 185/333 proteins form strong associations with other molecules or with each other. Some sea urchins expressed &gt;200 distinct 185/333 proteins, and each animal had a unique suite of the proteins that differed from all other individuals. When sea urchins were challenged in vivo with pathogen-associated molecular patterns (PAMPs; bacterial LPS and peptidoglycan), the expression of 185/333 proteins increased. More importantly, different suites of 185/333 proteins were expressed in response to different PAMPs. This suggests that the expression of 185/333 proteins can be tailored toward different PAMPs in a form of pathogen-specific immune response.
Cyclical Expression of EBV Latent Membrane Protein 1 in EBV-Transformed B Cells Underpins Heterogeneity of Epitope Presentation and CD8+ T Cell Recognition
Authors: Brooks Jill M. , Lee Steven P. , Leese Alison M. , Thomas Wendy A. , Rowe Martin , Rickinson Alan B. 
Published: February 2009

Abstract
CD8+ T cells specific for EBV latent cycle epitopes can be reactivated in vitro by stimulating with the autologous EBV-transformed B lymphoblastoid cell line (LCL). The resultant CD8+ clones kill epitope peptide-loaded targets, but frequently do not kill or show only low levels of lysis of the unmanipulated LCL in 5-h cytotoxicity assays. However, they reproducibly show clear LCL recognition in cytokine (IFN-γ) release assays and inhibit LCL outgrowth in long-term coculture assays. We show that this growth inhibition is not mediated by cytokines, but by slow killing detectable in extended cytotoxicity assays. The paradoxical earlier findings reflect the fact that cytokine assays are more sensitive indicators of Ag-specific recognition in situations in which the target population is heterogeneous at the single-cell level in terms of epitope display. Such heterogeneity exists within LCLs with, at any one time, subpopulations showing large differences in sensitivity to T cell detection. These differences are not cell cycle related, but correlate with differing levels of EBV latent membrane protein (LMP)1 expression at the single-cell level. In this study, LMP1 is not itself a CD8+ T cell target, but its expression enhances Ag-processing capacity and HLA class I expression. We propose that LMP1 levels fluctuate cyclically in individual cells and, over time, all cells within a LCL pass through a LMP1high T cell-detectable phase.
CREB Mediates Prostaglandin F2α-Induced MUC5AC Overexpression
Authors: Chung Wen-Cheng , Ryu Seung-Hee , Sun Hongxia , Zeldin Darryl C. , Koo Ja Seok 
Published: February 2009

Abstract
Mucus secretion is an important protective mechanism for the luminal lining of open tubular organs, but mucin overproduction in the respiratory tract can exacerbate the inflammatory process and cause airway obstruction. Production of MUC5AC, a predominant gel-forming mucin secreted by airway epithelia, can be induced by various inflammatory mediators such as prostaglandins. The two major prostaglandins involved in inflammation are PGE2 and PGF2α. PGE2-induced mucin production has been well studied, but the effect of PGF2α on mucin production remains poorly understood. To elucidate the effect and underlying mechanism of PGF2α on MUC5AC production, we investigated the signal transduction of PGF2α associated with this effect using normal human tracheobronchial epithelial cells. Our results demonstrated that PGF2α induces MUC5AC overproduction via a signaling cascade involving protein kinase C, ERK, p90 ribosomal S6 protein kinase, and CREB. The regulation of PGF2α-induced MUC5AC expression by CREB was further confirmed by cAMP response element-dependent MUC5AC promoter activity and by interaction between CREB and MUC5AC promoter. The abrogation of all downstream signaling activities via suppression of each signaling molecule along the pathway indicates that a single pathway from PGF2α receptor to CREB is responsible for inducing MUC5AC overproduction. As CREB also mediates mucin overproduction induced by PGE2 and other inflammatory mediators, our findings have important clinical implications for the management of airway mucus hypersecretion.
Synergistic Induction of Inflammation by Bacterial Products Lipopolysaccharide and fMLP: An Important Microbial Pathogenic Mechanism
Authors: Chen Ling-Yu , Pan Warren W. , Chen Miao , Li Jain-Dong , Liu Wei , Chen Guoqiang , Huang Shuang , Papadimos Thomas J. , Pan Zhixing K. 
Published: February 2009

Abstract
A wide variety of stimuli have been shown to induce inflammation, but bacteria products/components are considered the major inducers during bacterial infections. We previously demonstrated that bacterial products/components such as LPS, a glycolipid component of the bacterial outer membrane, and formylated peptides (fMLP), a bacterial-derived peptide, induced proinflammatory cytokine gene expression in human peripheral blood monocytes. We now present evidence that mixtures of bacterial products/components LPS and fMLP behave synergistically in the induction of inflammation in vitro and in vivo. Furthermore, our results indicate that the TLR4 and the IKKβ-IκBα signaling pathways are involved in the synergistic induction of inflammatory cytokines. The mechanism of synergistic activation of NF-κB is depended on nuclear translocation of p65 and phosphorylation of p65 at both Ser536 and Ser276 sites. These results demonstrate an important role for bacterial products/components from lysed bacteria in the pathogenesis of infectious diseases. We believe that this synergistic induction of inflammation by bacterial products LPS and fMLP represents an important pathogenic mechanism during bacterial infection, which may suggest novel therapeutic strategies or targets to minimize host injury following bacterial infection.
A Phase I-II Study of α-Galactosylceramide-Pulsed IL-2/GM-CSF-Cultured Peripheral Blood Mononuclear Cells in Patients with Advanced and Recurrent Non-Small Cell Lung Cancer
Authors: Motohashi Shinichiro , Nagato Kaoru , Kunii Naoki , Yamamoto Heizaburo , Yamasaki Kazuki , Okita Kohsuke , Hanaoka Hideki , Shimizu Naomi , Suzuki Makoto , Yoshino Ichiro , Taniguchi Masaru , Fujisawa Takehiko , Nakayama Toshinori 
Published: February 2009

Abstract
To evaluate the safety, immune responses, and antitumor responses after the administration of α-galactosylceramide (αGalCer) KRN7000-pulsed PBMC cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs), a phase I-II study in patients with non-small cell lung cancer was conducted. Patients with advanced non-small cell lung cancer or recurrent lung cancer refractory to the standard therapy were eligible. αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs (1 × 109/m2) were i.v. administered four times. Immune responses were monitored weekly. Twenty-three patients were enrolled in this study and 17 cases (73.9%) completed. No severe adverse event related to the treatment was observed. After the injection of αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs, an increased number of IFN-γ-producing cells in the peripheral blood were detected in 10 patients (58.8%). Five cases remained as stable disease, and the remaining 12 cases were evaluated as progressive disease. The estimated median survival time (MST) of the 17 cases was 18.6 mo (range, 3.8 to 36.3 mo). Ten patients who displayed increased IFN-γ-producing cells (≥2-fold) showed prolonged MST (31.9 mo; range, 14.5 to 36.3 mo) as compared with poor-responder patients (n = 7) MST (9.7 mo; range, 3.8 to 25.0 mo) (log-rank test, p = 0.0015). The administration of αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs was well tolerated and was accompanied by the successful induction of NKT cell-dependent immune responses. The increased IFN-γ-producing cells that result from αGalCer stimulation in PBMCs were significantly associated with prolonged MST. These results are encouraging and warrant further evaluation for survival benefit of this immunotherapy.
LAG-3 Regulates Plasmacytoid Dendritic Cell Homeostasis
Authors: Workman Creg J. , Wang Yao , El Kasmi Karim C. , Pardoll Drew M. , Murray Peter J. , Drake Charles G. , Vignali Dario A. A. 
Published: February 2009

Abstract
Lymphocyte activation gene 3 (LAG-3) is a CD4-related, activation-induced cell surface molecule expressed by various lymphoid cell types and binds to MHC class II with high affinity. We have previously shown that LAG-3 negatively regulates the expansion of activated T cells and T cell homeostasis, and is required for maximal regulatory T cell function. In this study, we demonstrate for the first time that LAG-3 is also expressed on CD11clow/B220+/PDCA-1+ plasmacytoid dendritic cells (pDCs). Lag3 expression, as determined by real time PCR, was ∼10-fold greater in pDCs than in either regulatory T cells or activated T effector cells. Activated pDCs also generate ∼5 times more sLAG-3 than activated T cells. LAG-3-deficient pDCs proliferate and expand more than wild-type pDCs in vivo in response to the TLR9 ligand, CpG. However, the effect of LAG-3 appears to be selective as there was no effect of LAG-3 on the expression of MHC class II, TLR9, and chemokine receptors, or on cytokine production. Lastly, adoptive transfer of either Lag3+/+ or Lag3−/− T cells plus or minus Lag3+/+ or Lag3−/− pDCs defined a role for LAG-3 in controlling pDC homeostasis as well as highlighting the consequences of deregulated Lag3−/− pDCs on T cell homeostasis. This raised the possibility of homeostatic reciprocity between T cells and pDCs. Collectively, our data suggests that LAG-3 plays an important but selective cell intrinsic and cell extrinsic role in pDC biology, and may serve as a key functional marker for their study.
Naive Mouse Macrophages Become Activated following Recognition of L5178Y Lymphoma Cells via Concurrent Ligation of CD40, NKG2D, and CD18 Molecules
Authors: Buhtoiarov Ilia N. , Rakhmilevich Alexander L. , Lanier Lewis L. , Ranheim Erik A. , Sondel Paul M. 
Published: February 2009

Abstract
Under different circumstances, tumors can inhibit or activate macrophage (Mφ) effector functions. We studied the mechanisms of tumor-Mφ interactions leading to Mφ activation. The results show that L5178Y mouse T cell lymphoma cells can prime naive mouse Mφ to subsequent LPS stimulation, resulting in increased NO production and antilymphoma effects in vitro. L5178Y cells, but not naive splenocytes, primed Mφ to ligation of TLR4 but not TLR9. L5178Y-primed Mφ incubated with LPS showed down-regulation of CD40 and up-regulation of NKG2D expression. Although L5178Y T cell lymphoma cells primed naive mouse Mφ, several other mouse and human cells lines failed to prime mouse Mφ. Neither L5178Y-conditioned supernatants nor coculture of Mφ and L5178Y cells in Transwells resulted in priming, indicating that direct L5178Y cell-Mφ contact was needed. Several receptor-ligand pairs are reciprocally expressed on Mφ and L5178Y cell membranes and can be potentially involved in Mφ priming. Of these, the CD40-CD154 pair played the most important role, as blocking the interaction of these molecules substantially reduced in vitro Mφ priming. Furthermore, simultaneous blocking of interactions between CD40-CD154, NKG2D-H60, and CD18-ICAM-1/2 led to complete abrogation of Mφ-mediated NO secretion and complete inhibition of Mφ-mediated tumor cell cytostasis. The priming of Mφ to LPS with L5178Y cells was also observed in vivo. These results suggest that contact with certain tumor cells via CD40, NKG2D, and CD18 molecules on the Mφ may facilitate Mφ-mediated antitumor immune surveillance.
Trypanosoma cruzi Triggers an Early Type I IFN Response In Vivo at the Site of Intradermal Infection
Authors: Chessler Anne-Danielle C. , Unnikrishnan Meera , Bei Amy K. , Daily Johanna P. , Burleigh Barbara A. 
Published: February 2009

Abstract
Early interactions between the protozoan parasite Trypanosoma cruzi and mammalian hosts at primary sites of infection (skin and mucosal membranes) are predicted to be critical determinants of parasite survival and dissemination in the host. To investigate the early host response triggered by three different strains of T. cruzi at a local infection site, changes in host gene expression were monitored in a murine intradermal infection model using Affymetrix oligonucleotide arrays. Robust induction of IFN-stimulated genes was observed in excised skin 24 h postinfection where the level of IFN-stimulated gene induction was parasite strain-dependent, with the least virulent strain triggering a muted IFN response. Infection of mice immunodepleted of IFN-γ-producing cells or infection of IFN-γ-deficient mice had minimal impact on the IFN response generated in T. cruzi-infected mice. In contrast, infection of mice lacking the type I IFN receptor demonstrated that type I IFNs are largely responsible for the IFN response generated at the site of infection. These data highlight type I IFNs as important components of the innate immune response to T. cruzi at the site of inoculation and their role in shaping the early transcriptional response to this pathogen.
TLR2 Engagement on CD8 T Cells Enables Generation of Functional Memory Cells in Response to a Suboptimal TCR Signal
Authors: Mercier Blandine C. , Cottalorda Anne , Coupet Charles-Antoine , Marvel Jacqueline , Bonnefoy-Bérard Nathalie 
Published: February 2009

Abstract
TLR are involved in the detection of microbial infection as well as endogenous ligands that signal tissue and cell damage in mammals. This recognition plays an essential role in innate immune response and the initiation of adaptive immune response. We have previously shown that murine CD8 T cells express TLR2, and that costimulation of Ag-activated CD8 T cells with TLR2 ligands enhances their proliferation, survival, and effector functions. We also demonstrated that TLR2 engagement on CD8 T cells significantly reduces their need for costimulatory signals delivered by APC. We show in this study that TLR2 engagement on CD8 T cells lowers the Ag concentration required for optimal activation, and converts a partial activation into a productive process leading to a significant expansion of cells. Using altered peptide ligands, we demonstrate that TLR2 engagement increases CD8 T cell activation and enables the generation of functional memory cells in response to a low TCR signal. This increased activation is associated with an augmented activation of the PI3K. Taken together, our results demonstrate that TLR2 engagement on CD8 T cells lowers their activation threshold for TCR signal strength and enables efficient memory cell generation in response to a weak TCR signal.
The Role of Hepatic Invariant NKT Cells in Systemic/Local Inflammation and Mortality during Polymicrobial Septic Shock
Authors: Hu Caroline K. , Venet Fabienne , Heffernan David S. , Wang Yvonne L. , Horner Brian , Huang Xin , Chung Chun-Shiang , Gregory Stephen H. , Ayala Alfred 
Published: February 2009

AbstractNKT cells have been described as innate regulatory cells because of their rapid response to conserved glycolipids presented on CD1d via their invariant TCR. However, little is known about the contribution of the hepatic NKT cell to the development of a local and/or systemic immune response to acute septic challenge (cecal ligation and puncture (CLP)). We found not only that mice deficient in invariant NKT cells (Jα18−/−) had a marked attenuation in CLP-induced mortality, but also exhibited an oblation of the systemic inflammatory response (with little effect on splenic/peritoneal immune responsiveness). Flow cytometric data indicated that following CLP, there was a marked decline in the percentage of CD3+α-galactosylceramide CD1d tetramer+ cells in the mouse C57BL/6J and BALB/c liver nonparenchymal cell population. This was associated with the marked activation of these cells (increased expression of CD69 and CD25) as well as a rise in the frequency of NKT cells positive for both Th1 and Th2 intracellular cytokines. In this respect, when mice were pretreated in vivo with anti-CD1d-blocking Ab, we observed not only that this inhibited the systemic rise of IL-6 and IL-10 levels in septic mice and improved overall septic survival, but that the CLP-induced changes in liver macrophage IL-6 and IL-10 expressions were inversely effected by this treatment. Together, these findings suggest that the activation of hepatic invariant NKT cells plays a critical role in regulating the innate immune/systemic inflammatory response and survival in a model of acute septic shock.
Lipopolysaccharide Initiates a Positive Feedback of Epidermal Growth Factor Receptor Signaling by Prostaglandin E2 in Human Biliary Carcinoma Cells
Authors: Finzi Laetitia , Shao Matt X. G. , Paye François , Housset Chantal , Nadel Jay A. 
Published: February 2009

Abstract
Bacterial products (e.g., LPS) are viewed as critical stimuli in inflammation-associated cancer. Cyclooxygenase 2 (COX-2), a major effector of LPS, and EGFR, are key to carcinogenesis, notably in the hepatobiliary tract. In this study, we tested the hypothesis that LPS can initiate an interaction between the epidermal growth factor receptor (EGFR) and COX-2 pathways. We examined the effect of LPS in biliary carcinoma cells that displayed constitutive COX-2 expression and PGE2 production and in normal human biliary epithelial cells in which COX-2/PGE2 expression was virtually absent. LPS induced early phosphorylation of EGFR and ERK1/2 in both types of cells, which reached maximum levels within 30 min (first phase). However, only the carcinoma cells showed a second significant rise in both EGFR and ERK phosphorylation 6 h after exposure to LPS (second phase). Inhibition of COX-2/PGE2 production prevented the second, but not the first, phase of EGFR and ERK1/2 phosphorylation, implicating COX-2/PGE2 in the second phase of phosphorylation. LPS induced COX-2-derived PGE2 production at 4 h, which was before the rise in the second phosphorylation that occurred at 6 h. Exogenous PGE2 also caused EGFR activation via a signaling pathway involving TACE-dependent TGF-α release. Inhibition of the second phase of EGFR phosphorylation with EGFR or COX-2 inhibitor prevented LPS-induced cell invasion in vitro, demonstrating the biological importance of this COX-2 feedback signaling in cancer cells. We conclude that LPS triggers a positive feedback loop involving COX-2/PGE2 in biliary carcinoma cells and that this second phase of EGFR phosphorylation is implicated in cell invasion by LPS.
Human Basophils Secrete IL-3: Evidence of Autocrine Priming for Phenotypic and Functional Responses in Allergic Disease
Authors: Schroeder John T. , Chichester Kristin L. , Bieneman Anja P. 
Published: February 2009

Abstract
Although IL-3 is commonly recognized for its growth factor-like activity, in vitro studies have long demonstrated a unique capacity for this cytokine to also augment the proinflammatory properties and phenotype of human basophils. In particular, basophils secrete mediators that are hallmarks in allergic disease, including vasoactive amines (e.g., histamine), lipid metabolites (e.g., leukotriene C4), and cytokines (e.g., IL-4/IL-13), which are all markedly enhanced with IL-3 pretreatment. This priming phenomenon is observed in response to both IgE-dependent and IgE-independent stimulation. Additionally, IL-3 directly activates basophils for IL-13 secretion and enhanced CD69 expression, two markers that are elevated in allergic subjects. Lymphocytes are commonly thought to be the source of the IL-3 that primes for these basophil responses. However, we demonstrate herein for the first time that basophils themselves rapidly produce IL-3 (within 4 h) in response to IgE-dependent activation. More importantly, our findings definitively show that basophils rapidly bind and utilize the IL-3 they produce, as evidenced by functional and phenotypic activity that is inhibited in the presence of neutralizing anti-IL-3 receptor (CD123) Abs. We predict that autocrine IL-3 activity resulting from low-level IgE/FcεRI cross-linking by specific allergen represents an important mechanism behind the hyperreactive nature of basophils that has long been observed in allergic disease.