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https://www.readbyqxmd.com/read/28626216/therapeutic-effects-of-csf1r-blocking-antibodies-in-multiple-myeloma
#1
Q Wang, Y Lu, R Li, Y Jiang, Y Zheng, J Qian, E Bi, C Zhang, J Hou, S Wang, Q Yi
Our previous studies showed that macrophages (MФs), especially myeloma-associated MФs (MAMs) induce chemoresistance in human myeloma. Here we explored the potential of targeting MФs, by using colony-stimulating factor 1 receptor (CSF1R)-blocking mAbs, to treat myeloma. Our results showed that CSF1R blockade specifically inhibited the differentiation, proliferation and survival of murine M2 MФs and MAMs, and repolarized MAMs towards M1-like MФs in vitro. CSF1R blockade alone inhibited myeloma growth in vivo, by partially depleting MAMs, polarizing MAMs to the M1 phenotype, and inducing a tumor-specific cytotoxic CD4(+) T cell response...
June 19, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28570130/an-integrative-computational-approach-to-evaluate-genetic-markers-for-chronic-lymphocytic-leukemia
#2
Yu Zheng, Xiaoyang Li, Lydia C Manor, Hongbao Cao, Qiusheng Chen
Recent studies reported hundreds of genes linked to chronic lymphocytic leukemia (CLL). However, many of these candidate genes were lack of replication and results were not always consistent. Here, we proposed a computational workflow to curate and evaluate CLL-related genes. The method integrates large-scale literature knowledge data, gene expression data, and related pathways/network information for quantitative marker evaluation. Pathway Enrichment, Sub-Network Enrichment, and Gene-Gene Interaction analysis were conducted to study the pathogenic profile of the candidate genes, with four metrics proposed and validated for each gene...
June 1, 2017: Journal of Computational Biology: a Journal of Computational Molecular Cell Biology
https://www.readbyqxmd.com/read/28566469/visceral-adipose-tissue-activated-macrophage-content-and-inflammatory-adipokine-secretion-is-higher-in-pre-eclampsia-than-in-healthy-pregnancy
#3
Shahzya Huda, FIona Jordan, JAck Bray, Gillian Love, Reba Payne, Naveed Sattar, Dilys J Freeman
Obesity increases preeclampsia risk. Adipose tissue inflammation may contribute to the clinical syndrome of pre-eclampsia. We compared adipose tissue macrophage infiltration and release of pro-inflammatory adipokines in pre-eclampsia and healthy pregnancy. Subcutaneous and visceral adipose tissue biopsies were collected from healthy (n=13) and preeclampsia (n=13) mothers. Basal and lipopolysaccharide stimulated adipocyte TNFα, IL-6, CCL-2 and CRP release was measured. Adipose tissue cell densities of activated (cfms(+)) and total (CD68(+)) macrophages were determined...
May 31, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28539419/microglia-are-irrelevant-for-neuronal-degeneration-and-axon-regeneration-after-acute-injury
#4
Alexander M Hilla, Heike Diekmann, Dietmar Fischer
The role of microglia in de- and regenerative processes after damage of the nervous system still remains ambiguous, partially due to the paucity of appropriate investigative methods. Here, we show that treatment with the pharmacological colony stimulating factor 1 receptor inhibitor PLX5622 specifically eliminated microglia in murine retinae and optic nerves. Interestingly, time course and extent of retinal ganglion cell (RGC) degeneration after optic nerve crush remained unaffected upon microglia depletion, although remnants of pre-labeled apoptotic RGCs were not cleared from the retina in these animals...
May 24, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28449811/effects-of-polymorphisms-identified-in-genome-wide-association-studies-of-never-smoking-females-on-the-prognosis-of-non-small-cell-lung-cancer
#5
Seung Soo Yoo, Hyo-Gyoung Kang, Jin Eun Choi, Sook Kyung Do, Won Kee Lee, Sun Ha Choi, So Yeon Lee, Shin Yup Lee, Jaehee Lee, Seung Ick Cha, Chang Ho Kim, Yangki Seok, Eungbae Lee, Moon Soo Kim, Jong Mog Lee, Hyun-Ju Cho, In-Jae Oh, Young-Chul Kim, Sukki Cho, Sanghoon Jheon, Chi Young Jung, Mi-Hyun Kim, Min Ki Lee, Jae Yong Park
A number of genome-wide association studies have reported several variants that influence the risk of lung cancer in never-smoking females. We evaluated the impact of these variants on survival outcome in never-smoking females with non-small cell lung cancer (NSCLC). In total, 510 never-smoking females with NSCLC who underwent curative surgery were enrolled. Eleven variants associated with lung cancer susceptibility in never-smoking females were genotyped and their associations with survival outcome were analyzed...
April 2017: Cancer Genetics
https://www.readbyqxmd.com/read/28427424/microglial-depletion-alters-the-brain-neuroimmune-response-to-acute-binge-ethanol-withdrawal
#6
T Jordan Walter, Fulton T Crews
BACKGROUND: Recent studies have implicated microglia-the resident immune cells of the brain-in the pathophysiology of alcoholism. Indeed, post-mortem alcoholic brains show increased microglial markers and increased immune gene expression; however, the effects of ethanol on microglial functioning and how this impacts the brain remain unclear. In this present study, we investigate the effects of acute binge ethanol on microglia and how microglial depletion changes the brain neuroimmune response to acute binge ethanol withdrawal...
April 20, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28408464/targetable-kinase-gene-fusions-in-high-risk-b-all-a-study-from-the-children-s-oncology-group
#7
Shalini C Reshmi, Richard C Harvey, Kathryn G Roberts, Eileen Stonerock, Amy Smith, Heather Jenkins, I-Ming Chen, Marc Valentine, Yu Liu, Yongjin Li, Ying Shao, John Easton, Debbie Payne-Turner, Zhaohui Gu, Thai Hoa Tran, Jonathan V Nguyen, Meenakshi Devidas, Yunfeng Dai, Nyla A Heerema, Andrew J Carroll, Elizabeth A Raetz, Michael J Borowitz, Brent L Wood, Anne L Angiolillo, Michael J Burke, Wanda L Salzer, Patrick A Zweidler-McKay, Karen R Rabin, William L Carroll, Jinghui Zhang, Mignon L Loh, Charles G Mullighan, Cheryl L Willman, Julie M Gastier-Foster, Stephen P Hunger
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed childhood B-ALL patients with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of which were excluded from additional analysis because of the presence of BCR-ABL1 (n=46) or ETV6-RUNX1 (n=11)...
April 13, 2017: Blood
https://www.readbyqxmd.com/read/28405620/microglia-mediate-postoperative-hippocampal-inflammation-and-cognitive-decline-in-mice
#8
Xiaomei Feng, Martin Valdearcos, Yosuke Uchida, David Lutrin, Mervyn Maze, Suneil K Koliwad
Surgery can induce cognitive decline, a risk that increases with advancing age. In rodents, postoperative cognitive decline (POCD) is associated with the inflammatory activation of hippocampal microglia. To examine the role of microglia in POCD, we inhibited the colony-stimulating factor 1 receptor (CSF1R) in adult mice, effectively depleting CNS microglia. Surgical trauma (tibial fracture) reduced the ability of mice to remember a conditioned response learned preoperatively, a deficit more pronounced and persistent in mice with diet-induced obesity (DIO)...
April 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28383543/autozygosity-reveals-recessive-mutations-and-novel-mechanisms-in-dominant-genes-implications-in-variant-interpretation
#9
Dorota Monies, Sateesh Maddirevula, Wesam Kurdi, Mohammed H Alanazy, Hisham Alkhalidi, Mohammed Al-Owain, Raashda A Sulaiman, Eissa Faqeih, Ewa Goljan, Niema Ibrahim, Firdous Abdulwahab, Mais Hashem, Mohamed Abouelhoda, Ranad Shaheen, Stefan T Arold, Fowzan S Alkuraya
PURPOSE: The purpose of this study is to describe recessive alleles in strictly dominant genes. Identifying recessive mutations in genes for which only dominant disease or risk alleles have been reported can expand our understanding of the medical relevance of these genes both phenotypically and mechanistically. The Saudi population is enriched for autozygosity, which enhances the homozygous occurrence of alleles, including pathogenic alleles in genes that have been associated only with a dominant inheritance pattern...
April 6, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28377059/design-synthesis-and-optimization-of-bis-amide-derivatives-as-csf1r-inhibitors
#10
Sreekanth A Ramachandran, Pradeep S Jadhavar, Sandeep K Miglani, Manvendra P Singh, Deepak P Kalane, Anil K Agarwal, Balaji D Sathe, Kakoli Mukherjee, Ashu Gupta, Srijan Haldar, Mohd Raja, Siddhartha Singh, Son M Pham, Sarvajit Chakravarty, Kevin Quinn, Sebastian Belmar, Ivan E Alfaro, Christopher Higgs, Sebastian Bernales, Francisco J Herrera, Roopa Rai
Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors...
March 24, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28373688/microglial-recruitment-of-il-1%C3%AE-producing-monocytes-to-brain-endothelium-causes-stress-induced-anxiety
#11
D B McKim, M D Weber, A Niraula, C M Sawicki, X Liu, B L Jarrett, K Ramirez-Chan, Y Wang, R M Roeth, A D Sucaldito, C G Sobol, N Quan, J F Sheridan, J P Godbout
Psychosocial stress contributes to the development of anxiety and depression. Recent clinical studies have reported increased inflammatory leukocytes in circulation of individuals with stress-related psychiatric disorders. Parallel to this, our work in mice shows that social stress causes release of inflammatory monocytes into circulation. In addition, social stress caused the development of prolonged anxiety that was dependent on inflammatory monocytes in the brain. Therefore, we hypothesize that chronic stress drives the production of inflammatory monocytes that are actively recruited to the brain by microglia, and these monocytes augment neuroinflammatory signaling and prolong anxiety...
April 4, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28370718/m2-like-macrophage-polarization-in-high-lactic-acid-producing-head-and-neck-cancer
#12
Toshimitsu Ohashi, Mitsuhiro Aoki, Hiroyuki Tomita, Takashi Akazawa, Katsuya Sato, Bunya Kuze, Keisuke Mizuta, Akira Hara, Hitoshi Nagaoka, Norimitsu Inoue, Yatsuji Ito
Reprogramming of glucose metabolism in tumor cells is referred to as the Warburg effect and results in increased lactic acid secretion into the tumor microenvironment. We have previously shown that lactic acid has important roles as a pro-inflammatory and immunosuppressive mediator and promotes tumor progression. In this study, we examined the relationship between the lactic acid concentration and expression of LDHA and GLUT1, which are related to the Warburg effect, in human head and neck squamous cell carcinoma (HNSCC)...
April 1, 2017: Cancer Science
https://www.readbyqxmd.com/read/28334938/clinical-and-genetic-characterization-of-leukoencephalopathies-in-adults
#13
David S Lynch, Anderson Rodrigues Brandão de Paiva, Wei Jia Zhang, Enrico Bugiardini, Fernando Freua, Leandro Tavares Lucato, Lucia Inês Macedo-Souza, Rahul Lakshmanan, Justin A Kinsella, Aine Merwick, Alexander M Rossor, Nin Bajaj, Brian Herron, Paul McMonagle, Patrick J Morrison, Deborah Hughes, Alan Pittman, Matilde Laurà, Mary M Reilly, Jason D Warren, Catherine J Mummery, Jonathan M Schott, Matthew Adams, Nick C Fox, Elaine Murphy, Indran Davagnanam, Fernando Kok, Jeremy Chataway, Henry Houlden
Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all...
March 2, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28319612/colony-stimulating-factor-1-receptor-is-a-central-component-of-the-foreign-body-response-to-biomaterial-implants-in-rodents-and-non-human%C3%A2-primates
#14
Joshua C Doloff, Omid Veiseh, Arturo J Vegas, Hok Hei Tam, Shady Farah, Minglin Ma, Jie Li, Andrew Bader, Alan Chiu, Atieh Sadraei, Stephanie Aresta-Dasilva, Marissa Griffin, Siddharth Jhunjhunwala, Matthew Webber, Sean Siebert, Katherine Tang, Michael Chen, Erin Langan, Nimit Dholokia, Raj Thakrar, Meirigeng Qi, Jose Oberholzer, Dale L Greiner, Robert Langer, Daniel G Anderson
Host recognition and immune-mediated foreign body response to biomaterials can compromise the performance of implanted medical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate and adaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophages are indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13, lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knockout and CXCL13 neutralization...
June 2017: Nature Materials
https://www.readbyqxmd.com/read/28286294/specific-suppression-of-microgliosis-cannot-circumvent-the-severe-neuropathology-in-peroxisomal-%C3%AE-oxidation-deficient-mice
#15
L Beckers, S Stroobants, S Verheijden, B West, R D'Hooge, M Baes
An important hallmark of various neurodegenerative disorders is the proliferation and activation of microglial cells, the resident immune cells of the central nervous system (CNS). Mice that lack multifunctional protein-2 (MFP2), the key enzyme in peroxisomal β-oxidation, develop excessive microgliosis that positively correlates with behavioral deficits whereas no neuronal loss occurs. However, the precise contribution of neuroinflammation to the fatal neuropathology of MFP2 deficiency remains largely unknown...
March 7, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28273719/depletion-of-microglia-exacerbates-postischemic-inflammation-and-brain-injury
#16
Wei-Na Jin, Samuel Xiang-Yu Shi, Zhiguo Li, Minshu Li, Kristofer Wood, Rayna J Gonzales, Qiang Liu
Brain ischemia elicits microglial activation and microglia survival depend on signaling through colony-stimulating factor 1 receptor (CSF1R). Although depletion of microglia has been linked to worse stroke outcomes, it remains unclear to what extent and by what mechanisms activated microglia influence ischemia-induced inflammation and injury in the brain. Using a mouse model of transient focal cerebral ischemia and reperfusion, we demonstrated that depletion of microglia via administration of the dual CSF1R/c-Kit inhibitor PLX3397 exacerbates neurodeficits and brain infarction...
June 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28273455/a-bach2-cebp-gene-regulatory-network-for-the-commitment-of-multipotent-hematopoietic-progenitors
#17
Ari Itoh-Nakadai, Mitsuyo Matsumoto, Hiroki Kato, Junichi Sasaki, Yukihiro Uehara, Yuki Sato, Risa Ebina-Shibuya, Mizuho Morooka, Ryo Funayama, Keiko Nakayama, Kyoko Ochiai, Akihiko Muto, Kazuhiko Igarashi
Hematopoietic stem cell and multipotent progenitor (MPP) commitment can be tuned in response to an infection so that their differentiation is biased toward myeloid cells. Here, we find that Bach2, which inhibits myeloid differentiation in common lymphoid progenitors, represses a cohort of myeloid genes and activates those linked to lymphoid function. Bach2 repressed both Cebpb and its target Csf1r, encoding C/EBPβ and macrophage colony-stimulating factor receptor (M-CSFr), respectively, whereas C/EBPβ repressed Bach2 and activated Csf1r...
March 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28272478/erythro-myeloid-progenitors-can-differentiate-from-endothelial-cells-and-modulate-embryonic-vascular-remodeling
#18
Bahar Kasaai, Vincenza Caolo, Hanna M Peacock, Stephanie Lehoux, Elisa Gomez-Perdiguero, Aernout Luttun, Elizabeth A V Jones
Erythro-myeloid progenitors (EMPs) were recently described to arise from the yolk sac endothelium, just prior to vascular remodeling, and are the source of adult/post-natal tissue resident macrophages. Questions remain, however, concerning whether EMPs differentiate directly from the endothelium or merely pass through. We provide the first evidence in vivo that EMPs can emerge directly from endothelial cells (ECs) and demonstrate a role for these cells in vascular development. We find that EMPs express most EC markers but late EMPs and EMP-derived cells do not take up acetylated low-density lipoprotein (AcLDL), as ECs do...
March 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28251674/microglial-repopulation-resolves-inflammation-and-promotes-brain-recovery-after-injury
#19
Rachel A Rice, Jason Pham, Rafael J Lee, Allison R Najafi, Brian L West, Kim N Green
Microglia mediate chronic neuroinflammation following central nervous system (CNS) disease or injury, and in doing so, damage the local brain environment by impairing recovery and contributing to disease processes. Microglia are critically dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R) and can be eliminated via administration of CSF1R inhibitors. Resolving chronic neuroinflammation represents a universal goal for CNS disorders, but long-term microglial elimination may not be amenable to clinical use...
June 2017: Glia
https://www.readbyqxmd.com/read/28236968/regulation-of-embryonic-and-postnatal-development-by-the-csf-1-receptor
#20
REVIEW
Violeta Chitu, E Richard Stanley
Macrophages are found in all tissues and regulate tissue morphogenesis during development through trophic and scavenger functions. The colony stimulating factor-1 (CSF-1) receptor (CSF-1R) is the major regulator of tissue macrophage development and maintenance. In combination with receptor activator of nuclear factor κB (RANK), the CSF-1R also regulates the differentiation of the bone-resorbing osteoclast and controls bone remodeling during embryonic and early postnatal development. CSF-1R-regulated macrophages play trophic and remodeling roles in development...
2017: Current Topics in Developmental Biology
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