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https://www.readbyqxmd.com/read/28078079/looking-forward-to-new-targeted-treatments-for-chronic-spontaneous-urticaria
#1
REVIEW
Emek Kocatürk, Marcus Maurer, Martin Metz, Clive Grattan
The introduction of omalizumab to the management of chronic spontaneous urticaria (CSU) has markedly improved the therapeutic possibilities for both, patients and physicians dealing with this disabling disease. But there is still a hard core of patients who do not tolerate or benefit from existing therapies and who require effective treatment. Novel approaches include the use of currently available drugs off-licence, investigational drugs currently undergoing clinical trials and exploring the potential for therapies directed at pathophysiological targets in CSU...
2017: Clinical and Translational Allergy
https://www.readbyqxmd.com/read/28073159/polymeric-immunoglobulin-receptor-promotes-tumor-growth-in-hepatocellular-carcinoma
#2
Xihua Yue, Jing Ai, Yang Xu, Yi Chen, Min Huang, Xinying Yang, Bo Hu, Haotian Zhang, Changxi He, Xinrong Yang, Weiguo Tang, Xia Peng, Liwei Dong, Hongyang Wang, Jia Fan, Jian Ding, Meiyu Geng
: Deregulation of the immune system is believed to contribute to cancer malignancy, which has led to recent therapeutic breakthroughs facilitating antitumor immunity. In a malignant setting, immunoglobulin receptors, which are fundamental components of the human immune system, fulfill paradoxical roles in cancer pathogenesis. This study describes a previously unrecognized pro-oncogenic function of polymeric immunoglobulin receptor (pIgR) in the promotion of cell transformation and proliferation...
January 10, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28064214/hsp90-promotes-burkitt-lymphoma-cell-survival-by-maintaining-tonic-b-cell-receptor-signaling
#3
Roland Walter, Kuan-Ting Pan, Carmen Doebele, Federico Comoglio, Katarzyna Tomska, Hanibal Bohnenberger, Ryan M Young, Laura Jacobs, Ulrich Keller, Halvard Bönig, Michael Engelke, Andreas Rosenwald, Henning Urlaub, Louis M Staudt, Hubert Serve, Thorsten Zenz, Thomas Oellerich
Burkitt lymphoma (BL) is an aggressive B cell neoplasm that is currently treated by intensive chemotherapy in combination with anti-CD20 antibodies. Due to their toxicity, current treatment regimens are often not suitable for elderly patients or for patients in developing countries where BL is endemic. Targeted therapies for BL are therefore needed. In this study, we performed a compound screen in 17 BL cell lines to identify small molecule inhibitors affecting cell survival. We found that inhibitors of heat shock protein 90 (HSP90) induced apoptosis in BL cells in vitro at concentrations that did not affect normal B cells...
November 15, 2016: Blood
https://www.readbyqxmd.com/read/28054556/phosphorylation-impact-on-spleen-tyrosine-kinase-conformation-by-surface-enhanced-raman-spectroscopy
#4
Maximilien Cottat, Ryohei Yasukuni, Yo Homma, Nathalie Lidgi-Guigui, Nadine Varin-Blank, Marc Lamy de la Chapelle, Christine Le Roy
Spleen Tyrosine Kinase (Syk) plays a crucial role in immune cell signalling and its altered expression or activation are involved in several cancers. Syk activity relies on its phosphorylation status and its multiple phosphorylation sites predict several Syk conformations. In this report, we characterized Syk structural changes according to its phosphorylation/activation status by Surface Enhanced Raman Spectroscopy (SERS). Unphosphorylated/inactive and phosphorylated/active Syk forms were produced into two expression systems with different phosphorylation capability...
January 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28049078/elevated-total-plasma-adiponectin-is-stable-over-time-in-young-women-with-bulimia-nervosa
#5
M Syk, M Ramklint, R Fredriksson, L Ekselius, J L Cunningham
BACKGROUND: Bulimia nervosa (BN) is characterized by dysregulated eating behaviour and present data suggest adipokines may regulate food intake. We investigated a possible association between BN and adipokine levels and hypothesized that plasma (P)-adiponectin would be elevated and P-leptin and P-leptin-adiponectin-ratio would be reduced in women with BN. METHODS: The study was designed as a cross-sectional study with a longitudinal arm for patients with BN. Plasma-adiponectin and leptin was measured in 148 female patients seeking psychiatric ambulatory care and 45 female controls...
December 29, 2016: European Psychiatry: the Journal of the Association of European Psychiatrists
https://www.readbyqxmd.com/read/28017324/the-pattern-recognition-receptor-mincle-is-essential-for-maintaining-the-m1-macrophage-phenotype-in-acute-renal-inflammation
#6
Lin L Lv, Patrick Ming-Kuen Tang, Chun J Li, Yong K You, Jinhong Li, Xiao-Ru Huang, Jun Ni, Min Feng, Bi C Liu, Hui-Yao Lan
Mincle (macrophage-inducible C-type lectin, Clec4e) is a transmembrane pattern recognition receptor involving the innate immunity, but its role in kidney disease is still unexplored. In the obstructed kidney of the unilateral ureteral obstruction model of renal injury, Mincle was specifically detected in the infiltrating M1 macrophages (CD68(+)iNOS(+) cells) on day one but was rapidly reduced following reduction of M1 macrophages during the progression of kidney injury. Interestingly, Mincle-expressing macrophages were progressively increased in the cisplatin-induced acute kidney injury model, where iNOS expression was detected in the CD68(+) cells following Mincle induction...
December 22, 2016: Kidney International
https://www.readbyqxmd.com/read/28011996/the-kinase-inhibitors-r406-and-gs-9973-impair-t-cell-functions-and-macrophage-mediated-anti-tumor-activity-of-rituximab-in-chronic-lymphocytic-leukemia-patients
#7
Ana Colado, María Belén Almejún, Enrique Podaza, Denise Risnik, Carmen Stanganelli, Esteban Enrique Elías, Patricia Dos Santos, Irma Slavutsky, Horacio Fernández Grecco, María Cabrejo, Raimundo Fernando Bezares, Mirta Giordano, Romina Gamberale, Mercedes Borge
Small molecules targeting kinases involved in B cell receptor signaling are showing encouraging clinical activity in chronic lymphocytic leukemia (CLL) patients. Fostamatinib (R406) and entospletinib (GS-9973) are ATP-competitive inhibitors designed to target spleen tyrosine kinase (Syk) that have shown clinical activity with acceptable toxicity in trials with CLL patients. Preclinical studies with these inhibitors in CLL have focused on their effect in patient-derived leukemic B cells. In this work we show that clinically relevant doses of R406 and GS-9973 impaired the activation and proliferation of T cells from CLL patients...
December 23, 2016: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28011673/distinct-patterns-of-b-cell-receptor-signaling-in-non-hodgkins-lymphomas-identified-by-single-cell-profiling
#8
June H Myklebust, Joshua Brody, Holbrook E Kohrt, Arne Kolstad, Debra K Czerwinski, Sébastien Wälchli, Michael R Green, Gunhild Trøen, Knut Liestøl, Klaus Beiske, Roch Houot, Jan Delabie, Ash A Alizadeh, Jonathan M Irish, Ronald Levy
Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkins' lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phospho-specific flow cytometry to obtain signaling profiles of malignant B cells from 95 patients representing 4 types of NHL, revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large B-cell lymphoma patients had high basal phosphorylation levels of most of the measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels...
December 23, 2016: Blood
https://www.readbyqxmd.com/read/28001095/antileukemic-effects-of-midostaurin-in-acute-myeloid-leukemia-the-possible-importance-of-multikinase-inhibition-in-leukemic-as-well-as-nonleukemic-stromal-cells
#9
Tor Henrik Tvedt, Ina Nepstad, Øystein Bruserud
Midostaurin is a multikinase inhibitor that inhibits receptor tyrosine kinases (Flt3, CD117/c-kit, platelet-derived growth factor receptor, vascular endothelial growth factor receptor 2) as well as non-receptor tyrosine kinases (Frg, Src, Syk, Protein kinase C). Combination of midostaurin with conventional intensive chemotherapy followed by one year maintenance monotherapy was recently reported to improve the survival of acute myeloid leukemia (AML) patients with Flt3 mutations. Areas covered: Relevant publications were identified through literature searches in the PubMed database...
December 28, 2016: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/27998003/vitamin-d-contributes-to-mast-cell-stabilization
#10
Zhi-Qiang Liu, Xiao-Xi Li, Shu-Qi Qiu, Yong Yu, Mao-Gang Li, Li-Tao Yang, Lin-Jing Li, Shuai Wang, Peng-Yuan Zheng, Zhi-Gang Liu, Ping-Chang Yang
BACKGROUND AND AIMS: Mast cells are the major effector cells in allergic disorders and many other informatory disorders. The mechanism of mast cell stabilization is not fully understood. Cumulative reports indicate that vitamin D (VitD) contributes to the homeostasis in the body. This study tests a hypothesis that VitD is required in the maintenance of the stability of mast cells. METHODS: The stability of mast cell lines, HMC1 cells, RBL-2H3 cells, p815 cells and mouse bone marrow-derived mast cells (BMMC) was tested in the presence or absence of VitD3...
December 20, 2016: Allergy
https://www.readbyqxmd.com/read/27994755/carboxamide-spleen-tyrosine-kinase-syk-inhibitors-leveraging-ground-state-interactions-to-accelerate-optimization
#11
J Michael Ellis, Michael D Altman, Brandon Cash, Andrew M Haidle, Rachel L Kubiak, Matthew L Maddess, Youwei Yan, Alan B Northrup
Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27974454/the-systemic-lupus-erythematosus-associated-single-nucleotide-polymorphism-rs1143678-in-integrin-%C3%AE-m-cytoplasmic-tail-generates-a-14-3-3%C3%AE-binding-site-that-is-proinflammatory
#12
Li-Teng Ong, Hui-Foon Tan, Chen Feng, Jing Qu, Shuzk-Cheng Loh, Surajit Bhattacharyya, Suet-Mien Tan
The leukocyte integrin αMβ2 (CR3 or Mac-1) has both proinflammatory and immune regulatory functions. Genome-wide association studies have identified several ITGAM (αM subunit) single nucleotide polymorphisms that are associated with systemic lupus erythematosus. The single nucleotide polymorphism rs1143678 substitutes Pro(1146) for Ser in the integrin αM cytoplasmic tail. A detailed functional characterization of this substitution is lacking. Using transfected human cell lines, reconstituted mouse bone marrow neutrophils, and bone marrow-derived macrophages (BMDMs), we showed that P1146S (PS) substitution promoted integrin αMβ2-mediated adhesion, spreading, and migration of cells on iC3b and fibrinogen...
December 14, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27966556/mv140-a-sublingual-polyvalent-bacterial-preparation-to-treat-recurrent-urinary-tract-infections-licenses-human-dendritic-cells-for-generating-th1-th17-and-il-10-responses-via-syk-and-myd88
#13
C Benito-Villalvilla, C Cirauqui, C M Diez-Rivero, M Casanovas, J L Subiza, O Palomares
Recurrent urinary tract infections (RUTIs) are one of the most common bacterial infectious diseases, especially in women. Antibiotics remain the mainstay of treatment, but their overuse is associated with antibiotic-resistant infections and deleterious effects in the microbiota. Therefore, alternative approaches are fully demanded. Sublingual immunization with MV140 (Uromune), a polyvalent bacterial preparation (PBP) of whole heat-inactivated bacteria, demonstrated clinical efficacy for the treatment of RUTIs, but the involved immunological mechanisms remain unknown...
December 14, 2016: Mucosal Immunology
https://www.readbyqxmd.com/read/27935477/regulation-of-b-cell-fate-by-chronic-activity-of-the-ige-b-cell-receptor
#14
Zhiyong Yang, Marcus J Robinson, Xiangjun Chen, Geoffrey A Smith, Jack Taunton, Wanli Liu, Christopher D C Allen
IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE(+) B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE(+) germinal center (GC) B cell but variably increased PC responses...
December 9, 2016: ELife
https://www.readbyqxmd.com/read/27933161/parallel-reductions-of-ige-and-exhaled-nitric-oxide-after-optimized-anti-inflammatory-asthma-treatment
#15
Jörgen Syk, Andrei Malinovschi, Magnus P Borres, Anna-Lena Undén, Anna Andreasson, Mats Lekander, Kjell Alving
Immunoglobulin E (IgE) is crucial for the development of airway inflammation in atopic asthma, and inhibition of IgE using monoclonal antibodies is now part of asthma therapy. However, the impact of ordinary anti-inflammatory treatment on IgE is unclear. The aim of this study was to investigate if optimization of treatment with inhaled corticosteroid (ICS) and leukotriene-receptor antagonist (LTRA) according to symptoms or exhaled nitric oxide (FENO) levels over a one-year period affects IgE concentrations...
June 2016: Immunity, Inflammation and Disease
https://www.readbyqxmd.com/read/27926862/vav-proteins-are-key-regulators-of-card9-signaling-for-innate-antifungal-immunity
#16
Susanne Roth, Hanna Bergmann, Martin Jaeger, Assa Yeroslaviz, Konstantin Neumann, Paul-Albert Koenig, Clarissa Prazeres da Costa, Lesley Vanes, Vinod Kumar, Melissa Johnson, Mauricio Menacho-Márquez, Bianca Habermann, Victor L Tybulewicz, Mihai Netea, Xosé R Bustelo, Jürgen Ruland
Fungal infections are major causes of morbidity and mortality, especially in immunocompromised individuals. The innate immune system senses fungal pathogens through Syk-coupled C-type lectin receptors (CLRs), which signal through the conserved immune adaptor Card9. Although Card9 is essential for antifungal defense, the mechanisms that couple CLR-proximal events to Card9 control are not well defined. Here, we identify Vav proteins as key activators of the Card9 pathway. Vav1, Vav2, and Vav3 cooperate downstream of Dectin-1, Dectin-2, and Mincle to engage Card9 for NF-κB control and proinflammatory gene transcription...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27919819/patterns-of-constitutively-phosphorylated-kinases-in-b-cells-are-associated-with-disease-severity-in-common-variable-immunodeficiency
#17
Eli Taraldsrud, Pål Aukrust, Silje Jørgensen, Ole Christian Lingjærde, Johanna Olweus, June H Myklebust, Børre Fevang
Patients with common variable immunodeficiency (CVID) constitute a clinically and immunologically heterogeneous group characterized by B-cell dysfunction with hypogammaglobulinemia and defective immunoglobulin class switch of unknown etiology. Current classification systems are insufficient to achieve precise disease management. Characterization of signaling pathways essential for B-cell differentiation and class switch could provide new means to stratify patients. We evaluated constitutive and induced signaling by phospho-specific flow cytometry in 26 CVID patients and 18 healthy blood donors...
December 3, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/27917838/overcoming-a-hemihedral-twinning-problem-in-tetrahydrofolate-dependent-o-demethylase-crystals-by-the-microseeding-method
#18
Ayaka Harada, Yukari Sato, Naofumi Kamimura, Nagarajan Venugopalan, Eiji Masai, Toshiya Senda
A tetrahydrofolate-dependent O-demethylase, LigM, from Sphingobium sp. SYK-6 was crystallized by the hanging-drop vapour-diffusion method. However, the obtained P3121 or P3221 crystals, which diffracted to 2.5-3.3 Å resolution, were hemihedrally twinned. To overcome the twinning problem, microseeding using P3121/P3221 crystals as microseeds was performed with optimization of the reservoir conditions. As a result, another crystal form was obtained. The newly obtained crystal diffracted to 2.5-3.0 Å resolution and belonged to space group P21212, with unit-cell parameters a = 102...
December 1, 2016: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/27906453/syk-inhibition-blocks-airway-constriction-and-protects-from-th2-induced-airway-inflammation-and-remodeling-in-mice
#19
Christoph Tabeling, Julia Herbert, Andreas C Hocke, David Lamb, Lutz Wollin, Klaus Erb, Ekaterina Boiarina, Hesam Movassagh, Jörg Scheffel, Jan M Doehn, Stefan Hippenstiel, Marcus Maurer, Abdelilah S Gounni, Wolfgang M Kuebler, Norbert Suttorp, Martin Witzenrath
BACKGROUND: Spleen tyrosine kinase (Syk) is an intracellular non-receptor tyrosine kinase, which has been implicated as central immune modulator promoting allergic airway inflammation. Syk inhibition has been proposed as a new therapeutic approach in asthma. However, the direct effects of Syk inhibition on airway constriction independent of allergen sensitization remain elusive. METHODS: Spectral confocal microscopy of human and murine lung tissue was performed to localize Syk expression...
December 1, 2016: Allergy
https://www.readbyqxmd.com/read/27902465/gene-and-microrna-modulation-upon-trabectedin-treatment-in-a-human-intrahepatic-cholangiocarcinoma-paired-patient-derived-xenograft-and-cell-line
#20
Caterina Peraldo Neia, Giuliana Cavalloni, Giovanna Chiorino, Paola Ostano, Massimo Aglietta, Francesco Leone
Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy with limited therapeutic options. Trabectedin has a high antitumor activity in preclinical models of biliary tract carcinoma (BTC), being a promising alternative treatment. Here, we studied the effect of trabectedin at transcriptomic level on an ICC patient derived xenograft (PDX) and on the derived cell line, MT-CHC01. Further, putative targets of trabectedin were explored in the in vitro model. In vitro, trabectedin inhibited genes involved in protein modification, neurogenesis, migration, and motility; it induced the expression of genes involved in keratinization, tissues development, and apoptotic processes...
November 24, 2016: Oncotarget
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