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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
Takuya Konno, Takeshi Miura, Andrea M Harriott, Naomi Mezaki, Emily S Edwards, Rosa Rademakers, Owen A Ross, James F Meschia, Takeshi Ikeuchi, Zbigniew 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...
March 6, 2018: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
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 is significantly less potent against structurally related epidermal growth factor receptor (EGFR) and other kinases...
March 2, 2018: Journal of Medicinal Chemistry
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
Justyna Sosna, Stephan Philipp, Ricardo Albay, Jorge Mauricio Reyes-Ruiz, David Baglietto-Vargas, Frank M LaFerla, Charles G Glabe
BACKGROUND: Besides the two main classical features of amyloid beta aggregation and tau-containing neurofibrillary tangle deposition, neuroinflammation plays an important yet unclear role in the pathophysiology of Alzheimer's disease (AD). Microglia are believed to be key mediators of neuroinflammation during AD and responsible for the regulation of brain homeostasis by balancing neurotoxicity and neuroprotective events. We have previously reported evidence that neuritic plaques are derived from dead neurons that have accumulated intraneuronal amyloid and further recruit Iba1-positive cells, which play a role in either neuronal demise or neuritic plaque maturation or both...
March 1, 2018: Molecular Neurodegeneration
Elizabeth E Blue, Joshua C Bis, Michael O Dorschner, Debby W Tsuang, Sandra M Barral, Gary Beecham, Jennifer E Below, William S Bush, Mariusz Butkiewicz, Carlos Cruchaga, Anita DeStefano, Lindsay A Farrer, Alison Goate, Jonathan Haines, Jim Jaworski, Gyungah Jun, Brian Kunkle, Amanda Kuzma, Jenny J Lee, Kathryn L Lunetta, Yiyi Ma, Eden Martin, Adam Naj, Alejandro Q Nato, Patrick Navas, Hiep Nguyen, Christiane Reitz, Dolly Reyes, William Salerno, Gerard D Schellenberg, Sudha Seshadri, Harkirat Sohi, Timothy A Thornton, Otto Valadares, Cornelia van Duijn, Badri N Vardarajan, Li-San Wang, Eric Boerwinkle, Josée Dupuis, Margaret A Pericak-Vance, Richard Mayeux, Ellen M Wijsman
BACKGROUND/AIMS: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. METHODS: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study...
February 27, 2018: Dementia and Geriatric Cognitive Disorders
Sofia P Rebelo, Catarina Pinto, Tatiana R Martins, Nathalie Harrer, Marta F Estrada, Pablo Loza-Alvarez, José Cabeçadas, Paula M Alves, Emilio J Gualda, Wolfgang Sommergruber, Catarina Brito
The tumour microenvironment (TME) shapes disease progression and influences therapeutic response. Most aggressive solid tumours have high levels of myeloid cell infiltration, namely tumour associated macrophages (TAM). Recapitulation of the interaction between the different cellular players of the TME, along with the extracellular matrix (ECM), is critical for understanding the mechanisms underlying disease progression. This particularly holds true for prediction of therapeutic response(s) to standard therapies and interrogation of efficacy of TME-targeting agents...
May 2018: Biomaterials
Krista J Spiller, Clark R Restrepo, Tahiyana Khan, Myrna A Dominique, Terry C Fang, Rebecca G Canter, Christopher J Roberts, Kelly R Miller, Richard M Ransohoff, John Q Trojanowski, Virginia M-Y Lee
Though motor neurons selectively degenerate in amyotrophic lateral sclerosis, other cell types are likely involved in this disease. We recently generated rNLS8 mice in which human TDP-43 (hTDP-43) pathology could be reversibly induced in neurons and expected that microglia would contribute to neurodegeneration. However, only subtle microglial changes were detected during disease in the spinal cord, despite progressive motor neuron loss; microglia still reacted to inflammatory triggers in these mice. Notably, after hTDP-43 expression was suppressed, microglia dramatically proliferated and changed their morphology and gene expression profiles...
February 20, 2018: Nature Neuroscience
Xiangjiang Lin, Guolu Meng, Xing Liu, Tengfei Yu, Chuanfeng Bai, Xiaobin Fei, Shengze Deng, Jizong Zhao, Shulin Ren, Junting Zhang, Zhen Wu, Shuo Wang, Jianguo Zhang, Liwei Zhang
OBJECTIVES: To understand the development of Sporadic cerebral cavernous malformations (SCCM) comprehensively, we analyzed gene expression profiles in SCCMs by the gene microarray. METHODS: The total number of the specimens collected in our study was 14, 7 of which were SCCMs, and the others were controls that were obtained from normal brain vessels. The total RNA was extracted and hybridized with Oligonucleotide array containing 21522 genes. The analysis of Gene Ontology (GO) items and molecular pathways was performed based on the GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases...
February 14, 2018: World Neurosurgery
Ailing Liu, Minhui Chen, Rashmi Kumar, Maja Stefanovic-Racic, Robert M O'Doherty, Ying Ding, Willi Jahnen-Dechent, Lisa Borghesi
Obesity, a prevalent condition in adults and children, impairs bone marrow (BM) function. However, the underlying mechanisms are unclear. Here, we show that obese mice exhibit poor emergency immune responses in a toll-like receptor 4 (TLR4)-dependent manner. Canonical myeloid genes (Csf1r, Spi1, Runx1) are enhanced, and lymphoid genes (Flt3, Tcf3, Ebf1) are reduced. Using adoptive transfer and mixed BM chimera approaches we demonstrate that myeloid>lymphoid bias arises after 6 weeks of high-fat diet and depends on precursor cell-autonomous TLR4...
February 16, 2018: Nature Communications
Nicolau Beckmann, Elisa Giorgetti, Anna Neuhaus, Stefan Zurbruegg, Nathalie Accart, Paul Smith, Julien Perdoux, Ludovic Perrot, Mark Nash, Sandrine Desrayaud, Peter Wipfli, Wilfried Frieauff, Derya R Shimshek
Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system (CNS). While multiple effective immunomodulatory therapies for MS exist today, they lack the scope of promoting CNS repair, in particular remyelination. Microglia play a pivotal role in regulating myelination processes, and the colony-stimulating factor 1 (CSF-1) pathway is a key regulator for microglia differentiation and survival. Here, we investigated the effects of the CSF-1 receptor kinase inhibitor, BLZ945, on central myelination processes in the 5-week murine cuprizone model by non-invasive and longitudinal magnetic resonance imaging (MRI) and histology...
February 15, 2018: Acta Neuropathologica Communications
Jesus Cosin-Roger, Marianne R Spalinger, Pedro A Ruiz, Claudia Stanzel, Anne Terhalle, Lutz Wolfram, Hassan Melhem, Kirstin Atrott, Silvia Lang, Isabelle Frey-Wagner, Michael Fried, Michael Scharl, Martin Hausmann, Gerhard Rogler
Gp96 is an endoplasmic reticulum chaperone for multiple protein substrates. Its lack in intestinal macrophages of Crohn's disease (CD) patients is correlated with loss of tolerance against the host gut flora. Gp96 has been stablished to be an essential chaperone for Toll-like receptors (TLRs). We studied the impact of gp96-knockdown on TLR-function in macrophages. TLR2 and TLR4 expression was only decreased but not abolished when gp96 was knocked-down in cell lines, whereas in a monocyte/macrophage specific knock-out mouse model (LysMCre) TLR4 was abolished, while TLR2 was still present...
2018: PloS One
Yongjiang Zheng, Jiguang Bao, Qiyi Zhao, Tianshou Zhou, Xiaoqiang Sun
The emergence of drug resistance is often an inevitable obstacle that limits the long-term effectiveness of clinical cancer chemotherapeutics. Although various forms of cancer cell-intrinsic mechanisms of drug resistance have been experimentally revealed, the role and the underlying mechanism of tumor microenvironment in driving the development of acquired drug resistance remain elusive, which significantly impedes effective clinical cancer treatment. Recent experimental studies have revealed a macrophage-mediated drug resistance mechanism in which the tumor microenvironment undergoes adaptation in response to macrophage-targeted colony-stimulating factor-1 receptor (CSF1R) inhibition therapy in gliomas...
February 13, 2018: Molecular Cancer Therapeutics
Rita A Costa, Deborah M Power
Skin wound healing has been widely studied in mammalian models but the information on teleost cutaneous healing is sparse and frequently considered in the context of viral or bacterial infections or parasitic infestations in aquaculture. In the present study a detailed time course (0 h, 6 h, 1, 2, 3 and 4 days) coupled to morphology and gene expression analysis revealed rapid regeneration of skin without scarring in a marine teleost after a superficial wound caused by the loss of a large area of scales. The integrity of the integument, as assessed by quantification of extracellular matrix (ECM) gene transcripts (fn1a, colIα1, colVα2, colXα1, ogn1, ogn2, crtac1a, cyr61, pcna, krt2 and mmp9) was restored within 2 days...
February 4, 2018: Molecular Immunology
Xiaoxia Yang, Honglei Ren, Kristofer Wood, Minshu Li, Shenfeng Qiu, Fu-Dong Shi, Cungen Ma, Qiang Liu
The activation of microglia and the various substances they produce have been linked to the pathologic development of Parkinson's disease (PD), but the precise role of microglia in PD remains to be defined. The survival of microglia depends on colony-stimulating factor 1 receptor (CSF1R) signaling, and CSF1R inhibition results in rapid elimination of microglia in the central nervous system. Using a mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment, we showed that the depletion of microglia via the CSF1R inhibitor PLX3397 exacerbated the impairment of locomotor activities and the loss of dopaminergic neurons...
January 22, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
D Lori Wheeler, Alan Sariol, David K Meyerholz, Stanley Perlman
Recent findings have highlighted the role of microglia in orchestrating normal development and refining neural network connectivity in the healthy CNS. Microglia are not only vital cells in maintaining CNS homeostasis, but also respond to injury, infection, and disease by undergoing proliferation and changes in transcription and morphology. A better understanding of the specific role of microglia in responding to viral infection is complicated by the presence of nonmicroglial myeloid cells with potentially overlapping function in the healthy brain and by the rapid infiltration of hematopoietic myeloid cells into the brain in diseased states...
January 29, 2018: Journal of Clinical Investigation
Clare Pridans, Kristin A Sauter, Katharine M Irvine, Gemma M Davis, Lucas Lefevre, Anna Raper, Rocio Rojo, Ajit J Nirmal, Philippa Beard, Michael Cheeseman, David A Hume
Signaling via the colony stimulating factor 1 receptor (CSF1R) controls the survival, differentiation and proliferation of macrophages. Mutations in CSF1, or CSF1R in mice and rats have pleiotropic effects on postnatal somatic growth. We tested the possible application of CSF1-Fc as a therapy for low birth weight (LBW) at term, using a model based upon maternal dexamethasone treatment in rats. Neonatal CSF1-Fc treatment did not alter somatic growth, and did not increase the blood monocyte count. Instead, there was a substantial increase in the size of liver in both control and LBW rats, and the treatment greatly exacerbated the lipid droplet accumulation seen in the dexamethasone LBW model...
December 21, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
Leon P Pradel, Andreas Franke, Carola H Ries
Tumor-associated Mφs display a plastic phenotype that is regulated by the local tumor milieu. Gene expression analysis and functional characterization of Mφs exposed in vitro to individual cytokines aids to delineate the cross-talk between defined cytokines shaping the complex Mφ phenotype. Human monocyte-derived Mφs can be differentiated in vitro with the T helper cell type 2 response cytokines IL-4 and IL-13 or the immunosuppressive IL-10. Notably, only the latter subset undergoes apoptosis when treated with the CSF 1 receptor (CSF1R) blocking antibody emactuzumab...
January 4, 2018: Journal of Leukocyte Biology
Muhammad Baghdadi, Hiraku Endo, Atsushi Takano, Kozo Ishikawa, Yosuke Kameda, Haruka Wada, Yohei Miyagi, Tomoyuki Yokose, Hiroyuki Ito, Haruhiko Nakayama, Yataro Daigo, Nao Suzuki, Ken-Ichiro Seino
Despite recent advances in diagnosis and treatment of lung cancers, the 5-year survival rate remains unsatisfactory, which necessitates the identification of novel factors that associates with disease progression and malignant degree for improving diagnostic and therapeutic strategies. Recent progress in cancer immunology research has unveiled critical roles for colony stimulating factor 1 receptor (CSF1R) in multiple aspects of the tumor microenvironment. CSF1R is expressed on tumor-associated macrophages (TAMs), and mediates important pro-tumorigenic functions...
January 11, 2018: Scientific Reports
Audrey C Knight, Samuel A Brill, Suzanne E Queen, Patrick M Tarwater, Joseph L Mankowski
Chronic microglial activation and associated neuroinflammation are key factors in neurodegenerative diseases including HIV-associated neurocognitive disorders. Colony stimulating factor 1 receptor (CSF1R)-mediated signaling is constitutive in cells of the myeloid lineage, including microglia, promoting cell survival, proliferation, and differentiation. In amyotrophic lateral sclerosis and Alzheimers disease, CSF1R is upregulated. Inhibiting CSF1R signaling in animal models of these diseases improved disease outcomes...
January 8, 2018: Journal of Neuropathology and Experimental Neurology
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