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https://www.readbyqxmd.com/read/29781323/targeting-the-b-cell-receptor-pathway-a-review-of-current-and-future-therapies-for-non-hodgkin-s-lymphoma
#1
Thomas D Rodgers, Patrick M Reagan
The B-cell receptor (BCR) pathway is a crucial aspect of mature lymphocytes and is maintained in B-cell neoplasms. Many small module inhibitors targeting kinases within the BCR pathway are approved, with others in development, offering alternative treatment options to standard chemoimmunotherapy. Areas Covered: This review covers both approved inhibitors and investigational inhibitors of spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), and phosphoinositide-3-kinase (PI3K) in the treatment of B-cell lymphomas...
May 20, 2018: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/29777684/repositioning-of-anti-cancer-drug-candidate-azd7762-to-an-anti-allergic-drug-suppressing-ige-mediated-mast-cells-and-allergic-responses-via-the-inhibition-of-lyn-and-fyn
#2
Young Hwan Park, Do Kyun Kim, Hyun Woo Kim, Hyuk Soon Kim, Dajeong Lee, Min Bum Lee, Keun Young Min, Jimo Koo, Su Jeong Kim, Changhee Kang, Young Mi Kim, Hyung Sik Kim, Wahn Soo Choi
Mast cells are critical effector cells in IgE-mediated allergic responses. The aim of this study was to investigate the anti-allergic effects of 3-[(aminocarbonyl)amino]-5-(3-fluorophenyl)-N-(3S)-3-piperidinyl-2-thiophenecarboxamide (AZD7762) in vitro and in vivo. AZD7762 inhibited the antigen-stimulated degranulation from RBL-2H3 (IC50 , ∼ 27.9 nM) and BMMCs (IC50 , ∼ 99.3 nM) in a dose-dependent manner. AZD7762 also inhibited the production of TNF-α and IL-4. As the mechanism of its action, AZD7762 inhibited the activation of Syk and its downstream signaling proteins, such as Linker of activated T cells (LAT), phospholipase (PL) Cγ1, Akt, and mitogen-activated protein (MAP) kinases (Erk1 / 2, p38, and JNK) in mast cells...
May 16, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29765083/adeno-associated-virus-vector-mediated-interleukin-10-induction-prevents-vascular-inflammation-in-a-murine-model-of-kawasaki-disease
#3
Jun Nakamura, Sachiko Watanabe, Hiroaki Kimura, Motoi Kobayashi, Tadayoshi Karasawa, Ryo Kamata, Fumitake Usui-Kawanishi, Ai Sadatomo, Hiroaki Mizukami, Noriko Nagi-Miura, Naohito Ohno, Tadashi Kasahara, Seiji Minota, Masafumi Takahashi
Kawasaki disease (KD), which is the leading cause of pediatric heart disease, is characterized by coronary vasculitis and subsequent aneurysm formation. Although intravenous immunoglobulin therapy is effective for reducing aneurysm formation, a certain number of patients are resistant to this therapy. Because interleukin-10 (IL-10) was identified as a negative regulator of cardiac inflammation in a murine model of KD induced by Candida albicans water-soluble fraction (CAWS), we investigated the effect of IL-10 supplementation in CAWS-induced vasculitis...
May 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29763550/selective-inhibition-of-the-myeloid-src-family-kinase-fgr-potently-suppresses-aml-cell-growth-in-vitro-and-in-vivo
#4
Mark C Weir, Sherry T Shu, Ravi K Patel, Sabine Hellwig, Li Chen, Li Tan, Nathanael S Gray, Thomas E Smithgall
Acute myelogenous leukemia (AML) is the most common hematologic malignancy in adults, and is often associated with constitutive tyrosine kinase signaling. These pathways involve the non-receptor tyrosine kinases Fes, Syk and the three Src-family kinases expressed in myeloid cells (Fgr, Hck, and Lyn). In this study, we report remarkable anti-AML efficacy of an N-phenylbenzamide kinase inhibitor, TL02-59. This compound potently suppressed the proliferation of bone marrow samples from twenty of twenty-six AML patients, with a striking correlation between inhibitor sensitivity and expression levels of the myeloid Src family kinases Fgr, Hck, and Lyn...
May 15, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29746940/nlrp3-inflammasome-is-involved-in-the-recognition-of-paracoccidioides-brasiliensis-by-human-dendritic-cells-and-in-the-induction-of-th17-cells
#5
Lívia Furquim de Castro, Larissa Nara Alegrini Longhi, Munir Regini Paião, Amauri da Silva Justo-Júnior, Marcelo Bispo de Jesus, Maria Heloisa de Souza Lima Blotta, Ronei Luciano Mamoni
OBJECTIVES: To investigate the involvement of NLRP3 in the effector functions of human dendritic cells (DCs) in response to Paracoccidioides brasiliensis yeast cells (Pb) and to evaluate its role in the modulation of the adaptive immune response. METHODS: DCs were differentiated from purified peripheral blood monocytes and analyzed in relation to the participation of TLR-2, dectin-1, and Syk in Pb recognition, as well as, the indirect mechanisms (Reactive Oxygen Species production, endosome acidification, or K+ efflux) involved in NLRP3 inflammasome activation after the stimulus with Pb...
May 7, 2018: Journal of Infection
https://www.readbyqxmd.com/read/29740433/syk-inhibition-induces-apoptosis-in-germinal-center-like-b-cells-by-modulating-the-antiapoptotic-protein-myeloid-cell-leukemia-1-affecting-b-cell-activation-and-antibody-production
#6
Nathalie Roders, Florence Herr, Gorbatchev Ambroise, Olivier Thaunat, Alain Portier, Aimé Vazquez, Antoine Durrbach
B cells play a major role in the antibody-mediated rejection (AMR) of solid organ transplants, a major public health concern. The germinal center (GC) is involved in the generation of donor-specific antibody-producing plasma cells and memory B cells, which are often poorly controlled by current treatments. Myeloid cell leukemia-1 (Mcl-1), an antiapoptotic member of the B-cell lymphoma-2 family, is essential for maintenance of the GC reaction and B-cell differentiation. During chronic AMR (cAMR), tertiary lymphoid structures resembling GCs appear in the rejected organ, suggesting local lymphoid neogenesis...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29739316/a-genome-wide-survey-of-mutations-in-the-jurkat-cell-line
#7
Louis Gioia, Azeem Siddique, Steven R Head, Daniel R Salomon, Andrew I Su
BACKGROUND: The Jurkat cell line has an extensive history as a model of T cell signaling. But at the turn of the 21st century, some expression irregularities were observed, raising doubts about how closely the cell line paralleled normal human T cells. While numerous expression deficiencies have been described in Jurkat, genetic explanations have only been provided for a handful of defects. RESULTS: Here, we report a comprehensive catolog of genomic variation in the Jurkat cell line based on whole-genome sequencing...
May 8, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29728446/tas05567-a-novel-potent-and-selective-spleen-tyrosine-kinase-inhibitor-abrogates-immunoglobulin-mediated-autoimmune-and-allergic-reactions-in-rodent-models
#8
Hiroaki Hayashi, Ryusuke Kaneko, Shunsuke Demizu, Daichi Akasaka, Manabu Tayama, Takafumi Harada, Hiroki Irie, Yoshio Ogino, Naoko Fujino, Eiji Sasaki
Spleen tyrosine kinase (Syk) is involved in regulation of B-cell receptor (BCR) and Fc receptor (FcR) downstream signal pathways. Syk plays an essential role in production of inflammatory mediators and differentiation in various immune cells and is therefore an attractive target for treating inflammatory conditions, such as autoimmune and allergic diseases. We identified TAS05567 as a highly selective Syk inhibitor and evaluated its therapeutic potential in animal models. In vitro biochemical assays were performed with available kinase assay panels...
May 4, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29725603/stimulation-of-dectin-1-and-dectin-2-during-parenteral-immunization-but-not-mincle-induces-secretory-iga-in-intestinal-mucosa
#9
Alina S Dzharullaeva, Amir I Tukhvatulin, Alina S Erokhova, Alina S Bandelyuk, Nikita B Polyakov, Andrey I Solovyev, Natalia A Nikitenko, Dmitry V Shcheblyakov, Boris S Naroditsky, Denis Y Logunov, Alexander L Gintsburg
Induction of a robust and long-lived mucosal immune response during vaccination is critical to achieve protection against numerous pathogens. However, traditional injected vaccines are generally poor inducers of mucosal immunity. One of the effective strategies to improve vaccine efficacy is incorporation of adjuvant molecules that enhance and polarize adaptive immune reactions. Effects of Syk-coupled lectin receptor agonists as adjuvants to induce mucosal immune reactions during parenteral immunization are not fully studied...
2018: Journal of Immunology Research
https://www.readbyqxmd.com/read/29721381/foxo1-promotes-resistance-of-non-hodgkin-lymphomas-to-anti-cd20-based-therapy
#10
Beata Pyrzynska, Michal Dwojak, Abdessamad Zerrouqi, Giulia Morlino, Piotr Zapala, Nina Miazek, Agnieszka Zagozdzon, Kamil Bojarczuk, Malgorzata Bobrowicz, Marta Siernicka, Marcin M Machnicki, Stefania Gobessi, Joanna Barankiewicz, Ewa Lech-Maranda, Dimitar G Efremov, Przemyslaw Juszczynski, Dinis Calado, Jakub Golab, Magdalena Winiarska
Diminished overall survival rate of non-Hodgkin lymphoma (NHL) patients treated with a combination regimen of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has been recently linked to recurrent somatic mutations activating FOXO1. Despite of the clinical relevance of this finding, the molecular mechanism driving resistance to R-CHOP therapy remains largely unknown. Herein, we investigated the potential role of FOXO1 in the therapeutic efficacy of rituximab, the only targeted therapy included in the R-CHOP regimen...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29719615/identification-of-spleen-tyrosine-kinase-as-a-potential-therapeutic-target-for-esophageal-squamous-cell-carcinoma-using-reverse-phase-protein-arrays
#11
Mustafa A Barbhuiya, Manoj K Kashyap, Vinuth N Puttamallesh, Rekha Vijay Kumar, Xinyan Wu, Akhilesh Pandey, Harsha Gowda
The vast majority of esophageal cancers in China, India and Iran are esophageal squamous cell carcinomas (ESCC). A timely diagnosis provides surgical removal as the main therapeutic option for patients with ESCC. Currently, there are no targeted therapies available for ESCC. We carried out reverse phase protein array-based protein expression profiling of seven ESCC-derivedcell lines and a non-neoplastic esophageal epithelial cell line (Het-1A) to identify differentially expressed proteins in ESCC. SYK non-receptortyrosine kinase was overexpressed in six out of seven ESCC cell lines that were used in the study...
April 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29712773/chronic-lymphocytic-leukemia-derived-il-10-suppresses-antitumor-immunity
#12
Sara S Alhakeem, Mary K McKenna, Karine Z Oben, Sunil K Noothi, Jacqueline R Rivas, Gerhard C Hildebrandt, Roger A Fleischman, Vivek M Rangnekar, Natarajan Muthusamy, Subbarao Bondada
Chronic lymphocytic leukemia (CLL) patients progressively develop an immunosuppressive state. CLL patients have more plasma IL-10, an anti-inflammatory cytokine, than healthy controls. In vitro human CLL cells produce IL-10 in response to BCR cross-linking. We used the transgenic Eμ-T cell leukemia oncogene-1 ( TCL1 ) mouse CLL model to study the role of IL-10 in CLL associated immunosuppression. Eμ-TCL mice spontaneously develop CLL because of a B cell-specific expression of the oncogene, TCL1. Eμ- TCL1 mouse CLL cells constitutively produce IL-10, which is further enhanced by BCR cross-linking, CLL-derived IL-10 did not directly affect survival of murine or human CLL cells in vitro...
April 30, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29693767/7-ketocholesterol-impairs-phagocytosis-and-efferocytosis-via-dysregulation-of-phosphatidylinositol-4-5-bisphosphate
#13
Stella M Lu, Gregory D Fairn
The plasma membrane is inhomogeneously organized containing both highly ordered and disordered nanodomains. 7-Ketocholesterol (7KC), an oxysterol formed from the non-enzymatic oxidation of cholesterol, is a potent disruptor of membrane order. Importantly, 7KC is a component of oxidized LDL and accumulates in macrophage and foam cells found in arterial plaques. Using a murine macrophage cell line, J774, we report that both IgG-mediated and phosphatidylserine (PtdSer)-mediated phagocytic pathways are inhibited by the accumulation of 7KC...
April 24, 2018: Traffic
https://www.readbyqxmd.com/read/29689251/deregulated-psgl-1-expression-in-b-cells-and-dendritic-cells-may-be-implicated-in-human-systemic-sclerosis-development
#14
Javier Silván, Rafael González-Tajuelo, Esther Vicente-Rabaneda, Alicia Pérez-Frías, Marina Espartero-Santos, Antonio Muñoz-Cañejas, Elena García-Lorenzo, Carlos Gamallo, Santos Castañeda, Ana Urzainqui
Systemic sclerosis (SSc) is an autoimmune disorder with high morbidity and mortality, difficult early diagnosis and without curative treatment. PSGL-1 is a leukocyte receptor whose deficiency in mice promotes an SSc-like disease. ADAM8, a metalloprotease that cleaves PSGL-1, is implicated in inflammatory processes. Our goal was to evaluate whether PSGL-1 and ADAM8 contribute to the pathogenesis of human SSc. We found that patients with SSc presented increased PSGL-1 expression on monocytes, dendritic cells (DCs) and T cells, and decreased expression of PSGL-1 on B cells...
April 21, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29681901/putting-on-the-brakes-regulatory-kinases-and-phosphatases-maintaining-b-cell-anergy
#15
REVIEW
S Elizabeth Franks, John C Cambier
B cell antigen receptor (BCR) signaling is a tightly regulated process governed by both positive and negative mediators/regulators to ensure appropriate responses to exogenous and autologous antigens. Upon naïve B cell recognition of antigen CD79 [the immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling subunit of the BCR] is phosphorylated and recruits Src and Syk family kinases that then phosphorylate proximal intermediaries linked to downstream activating signaling circuitry. This plasma membrane localized signalosome activates PI3K leading to generation of PIP3 critical for membrane localization and activation of plecktrin homology domain-containing effectors...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29677469/multidomain-control-over-tec-kinase-activation-state-tunes-the-t-cell-response
#16
Amy H Andreotti, Raji E Joseph, James M Conley, Janet Iwasa, Leslie J Berg
Signaling through the T cell antigen receptor (TCR) activates a series of tyrosine kinases. Directly associated with the TCR, the SRC family kinase LCK and the SYK family kinase ZAP-70 are essential for all downstream responses to TCR stimulation. In contrast, the TEC family kinase ITK is not an obligate component of the TCR cascade. Instead, ITK functions as a tuning dial, to translate variations in TCR signal strength into differential programs of gene expression. Recent insights into TEC kinase structure have provided a view into the molecular mechanisms that generate different states of kinase activation...
April 26, 2018: Annual Review of Immunology
https://www.readbyqxmd.com/read/29673901/the-role-of-syk-in-peripheral-t-cells
#17
Jeoung-Eun Park, Sirshendu Majumdar, David D Brand, Edward F Rosloniec, Ae-Kyung Yi, John M Stuart, Andrew H Kang, Linda K Myers
The aim of this study was to understand how Syk affects peripheral T cell function. T cells from Syk-/- chimeric mice and DR1 Sykfl/fl CD4cre conditional mice gave strong CD3-induced Th1, Th2, and Th17 cytokine responses. However, an altered peptide ligand (APL) of human CII (256-276) with two substitutions (F263N, E266D), also called A12, elicited only Th2 cytokine responses from Sykfl/fl T cells but not Sykfl/fl- CD4cre T cells. Western blots revealed a marked increase in the phosphorylation of Syk, JNK and p38 upon A12/DR1 activation in WT or Sykfl/fl T cells but not in Sykfl/fl CD4-cre cells...
April 16, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/29669390/editorial-title-lessons-learned-from-a-failed-clinical-trial
#18
EDITORIAL
E F A Leijten, T R D J Radstake, K A Reedquist
Spleen tyrosine kinase (Syk), through its capacity to promote the pathogenic activation of B lymphocytes, myeloid cells, osteoclasts, and stromal fibroblast-like synoviocytes, has been subject to intense translational and clinical scrutiny as a potential therapeutic target in rheumatoid arthritis (RA) (1). Initial phase II clinical trials with the Syk inhibitor fostamatinib showed promising effectivity in treating RA patients that had displayed inadequate responses to methotrexate (2,3). However, concerns were raised of drug-dependent adverse effects in these studies, and fostamatinib did not improve disease in RA patients failing other biologic agents (4)...
April 18, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29669173/second-generation-syk-inhibitor-entospletinib-ameliorates-fully-established-inflammation-and-bone-destruction-in-the-cherubism-mouse-model
#19
Tetsuya Yoshimoto, Tatsuhide Hayashi, Toshio Kondo, Mizuho Kittaka, Ernst J Reichenberger, Yasuyoshi Ueki
Cherubism is a craniofacial disorder characterized by maxillary and mandibular bone destruction. Gain-of-function mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for the excessive bone resorption caused by fibrous inflammatory lesions. A homozygous knock-in (KI) mouse model for cherubism (Sh3bp2KI/KI ) develops autoinflammation resulting in systemic bone destruction. While administration of the TNF-α blocker etanercept to neonatal Sh3bp2KI/KI mice prevented the disease onset, this therapy was not effective for adult Sh3bp2KI/KI mice or human cherubism patients who already had lesions...
April 18, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29668708/dectin-1-2-induced-autocrine-pge2-signaling-licenses-dendritic-cells-to-prime-th2-responses
#20
Maria M M Kaisar, Manuel Ritter, Carlos Del Fresno, Hulda S Jónasdóttir, Alwin J van der Ham, Leonard R Pelgrom, Gabriele Schramm, Laura E Layland, David Sancho, Clarissa Prazeres da Costa, Martin Giera, Maria Yazdanbakhsh, Bart Everts
The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently-in an autocrine manner-induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2)...
April 18, 2018: PLoS Biology
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