bluuebunny/crossref_metadata_2025_split huggingface dataset:
The production of reactive oxygen species in peripheral blood neutrophils is modulated by airway mucous
Authors: Babusyte Agne , Jeroch Jolanta , Stakauskas Rimantas , Sakalauskas Raimundas 
Published: February 2009

Abstract
Neutrophils are a major source of reactive oxygen species (ROS). The role of airway mucous on ROS production is unknown. The aim of our study was to investigate the direct influence of bronchoalveolar lavage fluid (BALF) and induced sputum (IS) alone or in combination with chemical/biological stimulus on ROS production in peripheral blood neutrophils during chronic obstructive pulmonary disease (COPD). Neutrophils were isolated from peripheral blood of 47 patients with moderate COPD and 14 healthy individuals (HI). BALF/RPMI (1:1) or IS/RPMI (1:1) from COPD patients were used to stimulate neutrophils alone or in combination with phorbolmyristate- acetate (PMA) (0.1–30 nM) or Staphylococcus aureus bacteria (0.7–500 bact/neutrophil). Relative generation of ROS was measured flow cytometrically. BALF/RPMI and in combination with relatively low PMA or all bacteria concentrations stimulated ROS; while, combination with relatively high PMA concentrations suppressed ROS in of COPD patients and HI. IS/RPMI and its combination with PMA inhibited ROS generation in both groups; whereas, IS stimulated or had a tendency to stimulate ROS production with relatively high bacteria concentrations. In conclusion, BALF and IS directly or in combination with chemical/biological factors modulated ROS production. This effect was stronger in neutrophils from COPD patients and depended on chemical/biological stimulus intensity.
Blood pressure increase detected by ambulatory monitoring correlates with hypoxemia reflecting sleep apnea severity
Authors: Grešová Soňa , Tomori Zoltán , Kurpas Martin , Marossy Alexander , Vrbenská Adela , Kundrík Martin , Donič Viliam 
Published: February 2009

Abstract
Ambulatory blood pressure monitoring and parallel polysomnographic study were performed in 116 adult males divided into 6 groups. Thirty blood-pressure (BP) and polysomnographic variables were measured to test their usefulness for screening for both arterial hypertension and sleep apnea-hypopnea syndrome (SAHS). The development of severe breathing disorders and hypoxemia during sleep was attributed to SAHS, when compared with measurements in healthy controls and in patients with arterial hypertension. Such disorders manifested as an increased apnea-hypopnea index, apnea index, duration of arterial oxygen saturation of less than 85%, and decrease of average arterial oxygen saturation that correlated with nocturnal average diastolic BP (p=0.0049, p=0.0027, p=0.049 and p=0.0457, respectively). These respiratory disorders resulted in various nocturnal, rather than diurnal, and diastolic and systolic BP variables. The acute antihypertensive effect of continuous positive airway pressure therapy for SAHS significantly reduced the episodes of apnea and hypopnea and the secondary component of hypertension caused by excessive sympathetic stimulation. For the SAHS-induced, dose-dependent component of hypertension that responded to continuous positive airway pressure, the following variables, in decreasing significance, were useful: nocturnal average systolic and diastolic BP and 24-hour average systolic and diastolic BP, as well as percent time elevation and mean blood pressure load. The monitoring of these variables could contribute to early diagnostic and prognostic stratification of complications and adequate therapy of the secondary component of hypertension caused by SAHS.
Results after radical surgical treatment for advanced carcinoma of hypopharynx
Authors: Hasdemir Oğuz , Çöl Cavit , Büyükaşık Oktay , Akçayöz Nihat 
Published: February 2009

Abstract
The aim of the study was to investigate patients with hypopharyngeal cancer. And this study focuses on a case series with hypopharynx cancer and cervical oesophageal cancer invading the hypopharynx. There were 13 cases over a period of 8 years, treated with pharyngo-laryngo-esophagectomy (PLE) and cervical lymph node dissection. In 10 of the patients, reconstruction was done with gastric pull-up (GP). In 3 of the 10 patients gastric reconstruction was added to aid in pyloric drainage (2 pyloromyotomy and 1 pyloroplasty) but the remaining 7 patients did not receive such procedures. The reconstruction of the digestive system after PLE is still a matter of debate. GP method is the most frequently preferred method for reconstruction. We believe that a more important problem than gastric drainage is the reflux of the gastric content and pyloric drainage which will not have a positive effect for solving this clinical situation. But we need bigger series for analyze of this specific condition.
CDK2 Phosphorylation of Smad2 Disrupts TGF-β Transcriptional Regulation in Resistant Primary Bone Marrow Myeloma Cells
Authors: Baughn Linda B. , Di Liberto Maurizio , Niesvizky Ruben , Cho Hearn J. , Jayabalan David , Lane Joseph , Liu Fang , Chen-Kiang Selina 
Published: February 2009

Abstract
Resistance to growth suppression by TGF-β1 is common in cancer; however, mutations in this pathway are rare in hematopoietic malignancies. In multiple myeloma, a fatal cancer of plasma cells, malignant cells accumulate in the TGF-β-rich bone marrow due to loss of both cell cycle and apoptotic controls. Herein we show that TGF-β activates Smad2 but fails to induce cell cycle arrest or apoptosis in primary bone marrow myeloma and human myeloma cell lines due to its inability to activate G1 cyclin-dependent kinase (CDK) inhibitors (p15INK4b, p21CIP1/WAF1, p27KIP1, p57KIP2) or to repress c-myc and Bcl-2 transcription. Correlating with aberrant activation of CDKs, CDK-dependent phosphorylation of Smad2 on Thr8 (pT8), a modification linked to impaired Smad activity, is elevated in primary bone marrow myeloma cells, even in asymptomatic monoclonal gammopathy of undetermined significance. Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2. Our findings provide the first direct evidence that pT8 Smad2 couples dysregulation of CDK2 to TGF-β resistance in primary cancer cells, and they suggest that disruption of Smad2 function by CDK2 phosphorylation acts as a mechanism for TGF-β resistance in multiple myeloma.
A Defect in Marco Expression Contributes to Systemic Lupus Erythematosus Development via Failure to Clear Apoptotic Cells
Authors: Rogers Nicola Jane , Lees Mark Jeffrey , Gabriel Luisa , Maniati Eleni , Rose Sarah Jane , Potter Paul Keith , Morley Bernard John 
Published: February 2009

Abstract
Systemic lupus erythematosus is a multisystem autoimmune disease characterized by the production of numerous antinuclear autoantibodies and inflammatory mediators. The BXSB mouse strain is an excellent model of the disease. Previous work has determined a number of important disease susceptibility intervals that have been isolated in separate congenic strains. Here, we have combined expression data from those strains with functional analyses to demonstrate that reduced expression of the innate scavenger receptor Marco (macrophage receptor with collagenous structure) is a primary event in BXSB mice, that reduced mRNA expression is mirrored at the protein level, and that this results in a significant alteration in function. We have confirmed a role for Marco in the clearance of apoptotic cells and a generalized defect in both endocytosis and phagocytosis. The failure to clear apoptotic cells has previously been linked to the development of systemic lupus erythematosus. However, the use of congenic mice with limited phenotypes in this study has enabled us to propose that in the case of Marco at least, disease results from the production of anti-dsDNA Abs.
IgE Influences the Number and Function of Mature Mast Cells, but Not Progenitor Recruitment in Allergic Pulmonary Inflammation
Authors: Mathias Clinton B. , Freyschmidt Eva-Jasmin , Caplan Benjamin , Jones Tatiana , Poddighe Dimitri , Xing Wei , Harrison Krista L. , Gurish Michael F. , Oettgen Hans C. 
Published: February 2009

Abstract
Studies performed using cultured cells indicate that IgE functions not only to trigger degranulation of mast cells following allergen exposure, but also to enhance their survival. Such an influence of IgE on mast cell homeostasis during allergic responses in vivo has not been established. In this study, we show that inhalation of Aspergillus fumigatus extract in mice induced a dramatic rise in IgE accompanied by an increase in airway mast cells. These had an activated phenotype with high levels of FcεRI. Plasma mast cell protease-1 was also increased, indicating an elevated systemic mast cell load. In addition, enhanced levels of IL-5 and eosinophils were observed in the airway. Both mast cell expansion and activation were markedly attenuated in IgE−/− animals that are incapable of producing IgE in response to A. fumigatus. The recruitment of eosinophils to the airways was also reduced in IgE−/− mice. Analyses of potential cellular targets of IgE revealed that IgE Abs are not required for the induction of mast cell progenitors in response to allergen, but rather act by sustaining the survival of mature mast cells. Our results identify an important role for IgE Abs in promoting mast cell expansion during allergic responses in vivo.
Human Basophils Express the Glycosylphosphatidylinositol-Anchored Low-Affinity IgG Receptor FcγRIIIB (CD16B)
Authors: Meknache Nihad , Jönsson Friederike , Laurent Jérôme , Guinnepain Marie-Thérèse , Daëron Marc 
Published: February 2009

AbstractBasophils express not only high-affinity IgE receptors, but also low-affinity IgG receptors. Which, among these receptors, are expressed by human basophils is poorly known. Low-affinity IgG receptors comprise CD32 (FcγRIIA, FcγRIIB, and FcγRIIC) and CD16 (FcγRIIIA and FcγRIIIB). FcγRIIA, FcγRIIC, and FcγRIIIA are activating receptors, FcγRIIB are inhibitory receptors, FcγRIIIB are GPI-anchored receptors whose function is poorly understood. Basophils were reported to express FcγRII, but not FcγRIII. We aimed at further identifying basophil IgG receptors. Basophils from normal donors and from patients suffering from an allergic skin disease (atopic dermatitis), allergic respiratory diseases (allergic rhinitis and asthma), or a nonallergic skin disease (chronic urticaria) were examined. We found that normal basophils contain FcγRIII transcripts and express FcγRIIIB, but not FcγRIIIA, which were detected on 24–81% basophils from normal donors and on 12–100% basophils from patients. Noticeably, the proportion of FcγRIIIB+ basophils was significantly lower in atopic dermatitis patients than in other subjects. This decreased FcγRIII expression was not correlated with an activated phenotype of basophils in atopic dermatitis patients, although FcγRIIIB expression was down-regulated upon basophil activation by anti-IgE. Our results challenge the two dogmas 1) that basophils do not express FcγRIII and 2) that FcγRIIIB is exclusively expressed by neutrophils. They suggest that a proportion of basophils may be lost during enrichment procedures in which FcγRIII+ cells are discarded by negative sorting using anti-CD16 Abs. They unravel an unexpected complexity of IgG receptors susceptible to modulate basophil activation. They identify a novel systemic alteration in atopic dermatitis.
Herpesvirus Seropositivity in Childhood Associates with Decreased Monocyte-Induced NK Cell IFN-γ Production
Authors: Saghafian-Hedengren Shanie , Sundström Yvonne , Sohlberg Ebba , Nilsson Caroline , Linde Annika , Troye-Blomberg Marita , Berg Louise , Sverremark-Ekström Eva 
Published: February 2009

AbstractEBV infection is inversely associated with IgE sensitization in children, and this association is further enhanced by CMV coinfection. In mice, herpesvirus latency causes systemic innate activation and protection from bacterial coinfection, implying the importance of herpesviruses in skewing immune responses during latent infection. Early control of viral infections depends on IFN-γ release by NK cells, which generally requires the presence of accessory cells. We investigated IFN-γ production by NK cells in PBMCs from children seropositive (SP) for EBV alone, for both EBV and CMV, or seronegative for both viruses. The ability of classical (CD14++CD16−) and proinflammatory (CD14+CD16+) monocytes to induce autologous NK cell IFN-γ was studied by coculture experiments with enriched CD3−CD56+ cells. Transwell experiments were used to evaluate how monocytes interact with NK cells to induce IFN-γ synthesis. SP children had a significantly reduced proportion of IFN-γ+ NK cells and cognate intracellular IFN-γ levels, which was more pronounced in CMV-coinfected subjects. Also, resting PBMCs of SP children displayed lower proportions of proinflammatory monocytes. IFN-γ production by NK cells was dependent on interactions with monocytes, with the proinflammatory subset inducing the highest IFN-γ. Finally, SP children had markedly lower levels of plasma IFN-γ, concurrent with in vitro findings. Herpesvirus infections could be one contributing factor for maturation toward balanced Th1-Th2 responses. Our data indicate that early infection by herpesviruses may affect NK cell and monocyte interactions and thereby also influence the development of allergies.
Evolution of Lipopolysaccharide (LPS) Recognition and Signaling: Fish TLR4 Does Not Recognize LPS and Negatively Regulates NF-κB Activation
Authors: Sepulcre María P. , Alcaraz-Pérez Francisca , López-Muñoz Azucena , Roca Francisco J. , Meseguer José , Cayuela María L. , Mulero Victoriano 
Published: February 2009

Abstract
It has long been established that lower vertebrates, most notably fish and amphibians, are resistant to the toxic effect of LPS. Furthermore, the lack of a TLR4 ortholog in some fish species and the lack of the essential costimulatory molecules for LPS activation via TLR4 (i.e., myeloid differentiation protein 2 (MD-2) and CD14) in all the fish genomes and expressed sequence tag databases available led us to hypothesize that the mechanism of LPS recognition in fish may be different from that of mammals. To shed light on the role of fish TLRs in LPS recognition, a dual-luciferase reporter assay to study NF-κB activation in whole zebrafish embryos was developed and three different bony fish models were studied: 1) the gilthead seabream (Sparus aurata, Perciformes), an immunological-tractable teleost model in which the presence of a TLR4 ortholog is unknown; 2) the spotted green pufferfish (Tetraodon nigroviridis, Tetraodontiformes), which lacks a TLR4 ortholog; and 3) the zebrafish (Danio rerio, Cypriniformes), which possesses two TLR4 orthologs. Our results show that LPS signaled via a TLR4- and MyD88-independent manner in fish, and, surprisingly, that the zebrafish TLR4 orthologs negatively regulated the MyD88-dependent signaling pathway. We think that the identification of TLR4 as a negative regulator of TLR signaling in the zebrafish, together with the absence of this receptor in most fish species, explains the resistance of fish to endotoxic shock and supports the idea that the TLR4 receptor complex for LPS recognition arose after the divergence of fish and tetrapods.
Innate Immunity Mediated by MyD88 Signal Is Not Essential for Induction of Lipopolysaccharide-Specific B Cell Responses but Is Indispensable for Protection against Salmonella enterica serovar Typhimurium infection
Authors: Ko Hyun-Jeong , Yang Jin-Young , Shim Doo-Hee , Yang Hyungjun , Park Sung-Moo , Curtiss Roy , Kweon Mi-Na 
Published: February 2009

Abstract
Salmonella organisms are Gram negative and facultative anaerobic bacteria that cause typhoid fever in humans. In this study, we evaluated LPS-specific adaptive immunity in innate immune-deficient mice after oral administration of attenuated Salmonella enterica serovar Typhimurium (S. Typhimurium) strains. Of interest, identical levels of LPS-specific IgG and IgA Abs were elicited in the systemic (i.e., serum and spleen) and mucosal (i.e., fecal extract and small intestine) compartments of wild-type, TLR4−/−, and MyD88−/− mice following oral vaccination with recombinant attenuated S. Typhimurium (RASV). Depletion of CD4+ T cells during RASV vaccination completely abrogated the generation of LPS-specific Abs in MyD88−/− mice. In addition, mRNA expression levels of a B cell-activating factor of the TNF family were significantly increased in the spleens of MyD88−/− mice after oral administration, implying that T cell-independent B cell switching might be also enhanced in the MyD88 signal-deficient condition. Of most interest, orally vaccinated MyD88−/− mice that possessed high levels of LPS-specific IgG and IgA, which had a neutralizing effect against Salmonella, died earlier than nonvaccinated wild-type mice following lethal oral challenge with virulent Salmonella species. These results suggest that innate immunity mediated by MyD88 signal is dispensable for induction of LPS-specific Ab responses following oral administration of attenuated Salmonella strains but indispensable for efficient protection.
Human B Cell Responses to TLR Ligands Are Differentially Modulated by Myeloid and Plasmacytoid Dendritic Cells
Authors: Douagi Iyadh , Gujer Cornelia , Sundling Christopher , Adams William C. , Smed-Sörensen Anna , Seder Robert A. , Karlsson Hedestam Gunilla B. , Loré Karin 
Published: February 2009

Abstract
Selected TLR ligands are under evaluation as vaccine adjuvants and are known to activate dendritic cells (DCs) and B cells to affect vaccine-induced Ab responses. However, the relative contribution of the two main human DC subsets, myeloid (MDCs) and plasmacytoid (PDCs), in supporting B cell responses to TLR ligands remains poorly understood. We found that PDCs but not MDCs markedly enhanced B cell proliferation in response to TLR7/8-L, an imidazoquinoline derivative, and to a lesser extent to TLR9 ligands (CpG ODN classes A, B, and C). PDCs strongly enhanced TLR7/8-L-induced proliferation of both memory and naive B cells but were only able to support memory cells to differentiate to CD27high plasmablasts. In response to TLR7/8 stimulation, PDCs mediated the up-regulation of transcription factors B lymphocyte-induced maturation protein 1 and X-box binding protein 1 and enhanced differentiation of B cells into IgM-, IgG-, and IgA-producing cells. Type I IFN produced to high levels by PDCs was the principal mediator of the effects on TLR7/8 stimulation. Although MDCs expressed higher levels of the known B cell growth factors IL-6, IL-10, and B cell-activating factor in response to TLR7/8 stimulation, they were unable to enhance B cell responses in this system. These data help decipher the different roles of PDCs and MDCs for modulating human B cell responses and can contribute to selection of specific TLR ligands as vaccine adjuvants.
Ignition of p53 Bomb Sensitizes Tumor Cells to Granzyme K-Mediated Cytolysis
Authors: Hua Guoqiang , Wang Shuo , Zhong Chao , Xue Peng , Fan Zusen 
Published: February 2009

Abstract
Inactivation of tumor suppressor p53 results in loss of the apoptosis-regulating function of the p53 protein in tumor cells. Restoration of wild-type p53 expression in p53 mutant tumor cells increases tumor susceptibility to CTL-mediated cytolysis. However, the direct role of p53 in regulating tumor sensitivity to NK cell-mediated lysis and the functional relationship between p53 and granzymes in the control of tumor killing are still poorly documented. In this study, we found that p53 can sensitize tumor-killing susceptibility to NK and granzyme K-mediated cytolysis. Granzyme K is constitutively expressed in high levels in NK cells and induces rapid caspase-independent cell death. Granzyme K may exert a critical role in NK cell-mediated tumor clearance. p53 associates with granzyme K and is a physiological substrate of granzyme K. p53 was processed to three cleavage products of p40, p35, and p13 fragments at Lys24 and Lys305. These three cleavage products harbor strong proapoptotic activities that amplify the proapoptotic action of p53 to potentiate tumor-killing sensitivity. Therefore, p53 is as a cytotoxic bomb that can be triggered by granzyme K, leading to potentiating killing efficacy.
Kinetic of RelA Activation Controls Magnitude of TLR-Mediated IL-12p40 Induction
Authors: Bode Konrad A. , Schmitz Frank , Vargas Leonardo , Heeg Klaus , Dalpke Alexander H. 
Published: February 2009

Abstract
IL-12 is a crucial cytokine for dendritic cell-mediated induction of Th 1 cell differentiation. TLR ligands induce IL-12 to differing extents. Stimulation of dendritic cells allowed for the differentiation of three groups of TLRs; potency to induce IL-12 decreased in the order of TLR7/9, TLR3/4, and TLR1/2/6 stimulation. The MAPK, PI3K, and IRF (IFN regulatory factor) signaling pathways could be ruled out to be the cause for the differences in IL-12p40 induction. However, we observed that stimulation of dendritic cells with different TLR ligands resulted in striking differences in the kinetics of NF-κB activation. LPS induced a rapid but short-lived activation of RelA, whereas CpG-DNA stimulation resulted in prolonged RelA activity at the IL-12p40 promoter. Only TLR2 and TLR4 ligands were capable of inducing S536 phosphorylation of RelA, which has been proposed to be responsible for early termination of NF-κB activation. It is suggested that differences in the kinetics of a common TLR signaling module affect the biological response patterns of various TLRs, with IL-12p40 being a gene that needs prolonged NF-κB activation.
Genetically Encoded Förster Resonance Energy Transfer Sensors for the Conformation of the Src Family Kinase Lck
Authors: Paster Wolfgang , Paar Christian , Eckerstorfer Paul , Jakober Andrea , Drbal Karel , Schütz Gerhard J. , Sonnleitner Alois , Stockinger Hannes 
Published: February 2009

Abstract
The current model for regulation of the Src family kinase member Lck postulates a strict correlation between structural condensation of the kinase backbone and catalytic activity. The key regulatory tyrosine 505, when phosphorylated, interacts with the Src homology 2 domain on the same molecule, effectively suppressing tyrosine kinase activity. Dephosphorylation of Tyr505 upon TCR engagement is supposed to lead to unfolding of the kinase structure and enhanced kinase activity. Studies on the conformation-activity relationship of Lck in living cells have not been possible to date because of the lack of tools providing spatiotemporal resolution of conformational changes. We designed a biochemically active, conformation-sensitive Förster resonance energy transfer biosensor of human Lck using the complete kinase backbone. Live cell imaging in Jurkat cells demonstrated that our biosensor performed according to Src family kinase literature. A Tyr505 to Phe mutation opened the structure of the Lck sensor, while changing the autophosphorylation site Tyr394 to Phe condensed the molecule. The tightly packed structure of a high-affinity YEEI tail mutant showed that under steady-state conditions the bulk of Lck molecules exist in a mean conformational configuration. Although T cell activation commenced normally, we could not detect a change in the conformational status of our Lck biosensor during T cell activation. Together with biochemical data we conclude that during T cell activation, Lck is accessible to very subtle regulatory mechanisms without the need for acute changes in Tyr505 and Tyr394 phosphorylation and conformational alterations.