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https://www.readbyqxmd.com/read/29785143/pilot-study-of-the-antifibrotic-effects-of-the-multikinase-inhibitor-pacritinib-in-a-mouse-model-of-liver-fibrosis
#1
Suliman Al-Fayoumi, Taishi Hashiguchi, Yuka Shirakata, John Mascarenhas, Jack W Singer
Background: Fibrotic diseases result from an exuberant response to chronic inflammation. Myelofibrosis is the end result of inflammation in bone, caused by an inflammatory process triggered by production of abnormal myeloid cells driven by mutations affecting the JAK-STAT pathway. Inflammatory cytokine overproduction leads to increased mesenchymal cell proliferation, culminating in fibrosis. Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and the JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion in myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow fibrosis in most patients...
2018: Journal of Experimental Pharmacology
https://www.readbyqxmd.com/read/29780305/comparing-effects-of-transforming-growth-factor-%C3%AE-1-on-microglia-from-rat-and-mouse-transcriptional-profiles-and-potassium-channels
#2
Starlee Lively, Doris Lam, Raymond Wong, Lyanne C Schlichter
The cytokine, transforming growth factor β1 (TGFβ1), is up-regulated after central nervous system (CNS) injuries or diseases involving microglial activation, and it has been proposed as a therapeutic agent for treating neuroinflammation. Microglia can produce and respond to TGFβ1. While rats and mice are commonly used for studying neuroinflammation, very few reports directly compare them. Such studies are important for improving pre-clinical studies and furthering translational progress in developing therapeutic interventions...
2018: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29774106/hematopoietic-restricted-ptpn11e76k-reveals-indolent-mpn-progression-in-mice
#3
Stefan P Tarnawsky, Wen-Mei Yu, Cheng-Kui Qu, Rebecca J Chan, Mervin C Yoder
Juvenile Myelomonocytic Leukemia (JMML) is a pediatric myeloproliferative neoplasm (MPN) that has a poor prognosis. Somatic mutations in Ptpn11 are the most frequent cause of JMML and they commonly occur in utero . Animal models of mutant Ptpn11 have probed the signaling pathways that contribute to JMML. However, existing models may inappropriately exacerbate MPN features by relying on non-hematopoietic-restricted Cre-loxP strains or transplantations into irradiated recipients. In this study we generate hematopoietic-restricted models of Ptpn11E76K-mediated disease using Csf1r-MCM and Flt3Cre...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29769439/csf1r-dependent-myeloid-cells-are-required-for-nk%C3%A2-mediated-control-of-metastasis
#4
Michal Beffinger, Paulino Tallón de Lara, Sònia Tugues, Marijne Vermeer, Yannick Montagnolo, Isabel Ohs, Virginia Cecconi, Giulia Lucchiari, Aron Gagliardi, Nikola Misljencevic, James Sutton, Roman Spörri, Burkhard Becher, Anurag Gupta, Maries van den Broek
Myeloid leukocytes are essentially involved in both tumor progression and control. We show that neo-adjuvant treatment of mice with an inhibitor of CSF1 receptor (CSF1R), a drug that is used to deplete tumor-associated macrophages, unexpectedly promoted metastasis. CSF1R blockade indirectly diminished the number of NK cells due to a paucity of myeloid cells that provide the survival factor IL-15 to NK cells. Reduction of the number of NK cells resulted in increased seeding of metastatic tumor cells to the lungs but did not impact on progression of established metastases...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29760082/a-cytokine-network-involving-il-36%C3%AE-il-23-and-il-22-promotes-antimicrobial-defense-and-recovery-from-intestinal-barrier-damage
#5
Vu L Ngo, Hirohito Abo, Estera Maxim, Akihito Harusato, Duke Geem, Oscar Medina-Contreras, Didier Merlin, Andrew T Gewirtz, Asma Nusrat, Timothy L Denning
The gut epithelium acts to separate host immune cells from unrestricted interactions with the microbiota and other environmental stimuli. In response to epithelial damage or dysfunction, immune cells are activated to produce interleukin (IL)-22, which is involved in repair and protection of barrier surfaces. However, the specific pathways leading to IL-22 and associated antimicrobial peptide (AMP) production in response to intestinal tissue damage remain incompletely understood. Here, we define a critical IL-36/IL-23/IL-22 cytokine network that is instrumental for AMP production and host defense...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29749055/aars2-related-ovarioleukodystrophy-clinical-and-neuroimaging-features-of-three-new-cases
#6
I Taglia, I Di Donato, S Bianchi, A Cerase, L Monti, R Marconi, A Orrico, A Rufa, A Federico, M T Dotti
INTRODUCTION: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), previously known as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmentary orthochromatic leukodystrophy (POLD), is the most frequent non-vascular adult-onset leukoencephalopathy. It is caused by autosomal dominant mutations in CSF1R gene. Recently, also autosomal recessive mutations in AARS2 gene were found to be the cause of an adult-onset leukodystrophy with axonal spheroids...
May 10, 2018: Acta Neurologica Scandinavica
https://www.readbyqxmd.com/read/29719257/csf1r-macrophages-sustain-pancreatic-tumor-growth-through-t-cell-suppression-and-maintenance-of-key-gene-programs-that-define-the-squamous-subtype
#7
Juliana B Candido, Jennifer P Morton, Peter Bailey, Andrew D Campbell, Saadia A Karim, Thomas Jamieson, Laura Lapienyte, Aarthi Gopinathan, William Clark, Ewan J McGhee, Jun Wang, Monica Escorcio-Correia, Raphael Zollinger, Rozita Roshani, Lisa Drew, Loveena Rishi, Rebecca Arkell, T R Jeffry Evans, Colin Nixon, Duncan I Jodrell, Robert W Wilkinson, Andrew V Biankin, Simon T Barry, Frances R Balkwill, Owen J Sansom
Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model...
May 1, 2018: Cell Reports
https://www.readbyqxmd.com/read/29705792/outlook-immunotherapy-in-gastrointestinal-carcinoma-innovative-strategies
#8
Markus Moehler, Katrin Göpfert, Heinz-Josef Lenz
Immune checkpoint inhibitors are emerging as a therapeutic approach for patients with advanced or metastatic gastrointestinal malignancies following the recent Food and Drug Administration and Asian approvals for colorectal, gastric, and hepatocellular carcinoma. As discussed in earlier articles, phase I-II trials demonstrate quite positive clinical activity, particularly in patients with immunogenic cancer subtypes. This outreach paper discusses some of the next innovative immunotherapy strategies under development...
2018: Oncology Research and Treatment
https://www.readbyqxmd.com/read/29700822/genetic-analysis-of-adult-leukoencephalopathy-patients-using-a-custom-designed-gene-panel
#9
M Kunii, H Doi, Y Ishii, C Ohba, K Tanaka, M Tada, R Fukai, S Hashiguchi, H Kishida, N Ueda, Y Kudo, C Kugimoto, T Nakano, N Udaka, S Miyatake, N Miyake, H Saitsu, Y Ito, K Takahashi, H Nakamura, A Tomita-Katsumoto, H Takeuchi, S Koyano, N Matsumoto, F Tanaka
Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom-designed gene panel. We selected 55 leukoencephalopathy-related genes for the gene panel...
April 26, 2018: Clinical Genetics
https://www.readbyqxmd.com/read/29668829/complete-response-to-csf1r-inhibitor-in-a-translocation-variant-of-teno-synovial-giant-cell-tumor-without-genomic-alteration-of-the-csf1-gene
#10
M Brahmi, L Alberti, F Tirode, M Karanian, L Eberst, D Pissaloux, P Cassier, J Y Blay
No abstract text is available yet for this article.
April 14, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29643229/t-cell-induced-csf1-promotes-melanoma-resistance-to-pd1-blockade
#11
Natalie J Neubert, Martina Schmittnaegel, Natacha Bordry, Sina Nassiri, Noémie Wald, Christophe Martignier, Laure Tillé, Krisztian Homicsko, William Damsky, Hélène Maby-El Hajjami, Irina Klaman, Esther Danenberg, Kalliopi Ioannidou, Lana Kandalaft, George Coukos, Sabine Hoves, Carola H Ries, Silvia A Fuertes Marraco, Periklis G Foukas, Michele De Palma, Daniel E Speiser
Colony-stimulating factor 1 (CSF1) is a key regulator of monocyte/macrophage differentiation that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). We show that CSF1 is expressed in human melanoma, and patients with metastatic melanoma have increased CSF1 in blood compared to healthy subjects. In tumors, CSF1 expression correlated with the abundance of CD8+ T cells and CD163+ TAMs. Human melanoma cell lines consistently produced CSF1 after exposure to melanoma-specific CD8+ T cells or T cell-derived cytokines in vitro, reflecting a broadly conserved mechanism of CSF1 induction by activated CD8+ T cells...
April 11, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29593242/the-role-of-csf1r-dependent-macrophages-in-control-of-the-intestinal-stem-cell-niche
#12
Anuj Sehgal, David S Donaldson, Clare Pridans, Kristin A Sauter, David A Hume, Neil A Mabbott
Colony-stimulating factor 1 (CSF1) controls the growth and differentiation of macrophages.CSF1R signaling has been implicated in the maintenance of the intestinal stem cell niche and differentiation of Paneth cells, but evidence of expression of CSF1R within the crypt is equivocal. Here we show that CSF1R-dependent macrophages influence intestinal epithelial differentiation and homeostasis. In the intestinal lamina propria CSF1R mRNA expression is restricted to macrophages which are intimately associated with the crypt epithelium, and is undetectable in Paneth cells...
March 28, 2018: Nature Communications
https://www.readbyqxmd.com/read/29574785/resident-alveolar-macrophages-are-master-regulators-of-arrested-alveolarization-in-experimental-bronchopulmonary-dysplasia
#13
Tatiana V Kalymbetova, Balachandar Selvakumar, José Alberto Rodríguez-Castillo, Miša Gunjak, Christina Malainou, Miriam Ruth Heindl, Alena Moiseenko, Cho-Ming Chao, István Vadász, Konstantin Mayer, Jürgen Lohmeyer, Saverio Bellusci, Eva Böttcher-Friebertshäuser, Werner Seeger, Susanne Herold, Rory E Morty
Trophic functions for macrophages are emerging as key mediators of developmental processes; including bone, vessel, and mammary gland development. Yolk sac-derived macrophages mature in the distal lung shortly after birth. Myeloid-lineage macrophages are recruited to the lung and are activated under pathological conditions. These pathological conditions include bronchopulmonary dysplasia (BPD), a common complication of preterm birth characterized by stunted lung development, where formation of alveoli is blocked...
March 25, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29572360/altered-compensatory-cytokine-signaling-underlies-the-discrepancy-between-flt3-and-flt3l-mice
#14
Vivek Durai, Prachi Bagadia, Carlos G Briseño, Derek J Theisen, Arifumi Iwata, Jesse T Davidson, Marco Gargaro, Daved H Fremont, Theresa L Murphy, Kenneth M Murphy
The receptor Flt3 and its ligand Flt3L are both critical for dendritic cell (DC) development, but DC deficiency is more severe in Flt3l-/- mice than in Flt3-/- mice. This has led to speculation that Flt3L binds to another receptor that also supports DC development. However, we found that Flt3L administration does not generate DCs in Flt3-/- mice, arguing against a second receptor. Instead, Flt3-/- DC progenitors matured in response to macrophage colony-stimulating factor (M-CSF) or stem cell factor, and deletion of Csf1r in Flt3-/- mice further reduced DC development, indicating that these cytokines could compensate for Flt3...
March 23, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29571946/nilotinib-in-locally-advanced-pigmented-villonodular-synovitis-a-multicentre-open-label-single-arm-phase-2-trial
#15
Hans Gelderblom, Claire Cropet, Christine Chevreau, Richard Boyle, Martin Tattersall, Silvia Stacchiotti, Antoine Italiano, Sophie Piperno-Neumann, Axel Le Cesne, Virginia Ferraresi, Nicolas Penel, Florence Duffaud, Philippe Cassier, Maud Toulmonde, Paolo Casali, Sophie Taieb, Séverine Guillemaut, Séverine Metzger, David Pérol, Jean-Yves Blay
BACKGROUND: Pigmented villonodular synovitis (alternatively known as diffuse-type giant cell tumour) is a rare, locally aggressive tumour driven by a specific translocation resulting in the overexpression of colony-stimulating factor 1 (CSF1). CSF1 receptor (CSF1R) inhibitors (ie, tyrosine kinase inhibitors and antibodies) induce a response in patients with pigmented villonodular synovitis. We investigated the safety and efficacy of a CSF1R tyrosine kinase inhibitor, nilotinib, in patients with locally advanced non-resectable pigmented villonodular synovitis...
March 20, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29544907/mendelian-adult-onset-leukodystrophy-genes-in-alzheimer-s-disease-critical-influence-of-csf1r-and-notch3
#16
Celeste Sassi, Michael A Nalls, Perry G Ridge, Jesse R Gibbs, Michelle K Lupton, Claire Troakes, Katie Lunnon, Safa Al-Sarraj, Kristelle S Brown, Christopher Medway, Jenny Lord, James Turton, Jose Bras, Sonja Blumenau, Mareike Thielke, Christa Josties, Dorette Freyer, Annette Dietrich, Monia Hammer, Michael Baier, Ulrich Dirnagl, Kevin Morgan, John F Powell, John S Kauwe, Carlos Cruchaga, Alison M Goate, Andrew B Singleton, Rita Guerreiro, Angela Hodges, John Hardy
Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively...
June 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29514082/periostin-limits-tumor-response-to-vegfa-inhibition
#17
Ioanna Keklikoglou, Ece Kadioglu, Stefan Bissinger, Benoît Langlois, Axel Bellotti, Gertraud Orend, Carola H Ries, Michele De Palma
Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs) under extended vascular-endothelial growth factor A (VEGFA) blockade are dependent on periostin (POSTN), a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA+ stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy...
March 6, 2018: Cell Reports
https://www.readbyqxmd.com/read/29509319/partial-loss-of-function-of-colony-stimulating-factor-1-receptor-in-a-patient-with-white-matter-abnormalities
#18
T Konno, T Miura, A M Harriott, N Mezaki, E S Edwards, R Rademakers, O A Ross, J F Meschia, T Ikeuchi, Z K Wszolek
BACKGROUND AND PURPOSE: Mutations in colony-stimulating factor 1 receptor (CSF1R) cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Patients with ALSP can be misdiagnosed as having acute ischemic stroke due to hyperintensity lesions on diffusion-weighted magnetic resonance imaging. Mutant CSF1R proteins identified in ALSP show a complete loss of autophosphorylation of CSF1R. METHODS: We conducted mutation screening of CSF1R in 123 patients with definite acute ischemic cerebrovascular syndrome and positive family history of stroke...
June 2018: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/29499108/design-synthesis-and-structure-activity-relationship-study-of-2-oxo-3-4-dihydropyrimido-4-5-d-pyrimidines-as-new-colony-stimulating-factor-1-receptor-csf1r-kinase-inhibitors
#19
Qiuju Xun, Zhang Zhang, Jinfeng Luo, Linjiang Tong, Minhao Huang, Zhen Wang, Jian Zou, Yingqiang Liu, Yong Xu, Hua Xie, Zheng-Chao Tu, Xiaoyun Lu, Ke Ding
Colony stimulating factor 1 receptor kinase (CSF1R) is a well validated molecular target for anticancer drug discovery. Herein, we report the design, synthesis, and structure-activity relationship study of 2-oxo-3,4-dihydropyrimido[4,5- d]pyrimidines as new orally bioavailable CSF1R inhibitors. One of the most promising compounds, 3bw, potently inhibits CSF1R kinase with an IC50 value of 3.0 nM, while it is less potent against structurally related epidermal growth factor receptor (EGFR) and other kinases. The kinase inhibition of 3bw was further validated by Western blotting analysis in RAW264...
March 22, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29496785/csf1r-inhibition-prevents-radiation-pulmonary-fibrosis-by-depletion-of-interstitial-macrophages
#20
Lydia Meziani, Michele Mondini, Benoît Petit, Alexandre Boissonnas, Vincent Thomas de Montpreville, Olaf Mercier, Marie-Catherine Vozenin, Eric Deutsch
Radiation-induced lung fibrosis (RIF) is a delayed side-effect of chest radiotherapy, frequently associated with macrophage infiltration.We aimed to characterise the role of pulmonary macrophages in RIF using human lung biopsies from patients receiving radiotherapy for thorax malignancies and a RIF model developed in C57BL/6 mice after 16-Gy thorax irradiation.High numbers of macrophages (both interstitial and alveolar) were detected in clinical and preclinical RIF. In the preclinical model, upregulation of T-helper (Th)2 cytokines was measured, whereas Th1 cytokines were downregulated in RIF tissue lysate...
March 2018: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
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