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https://www.readbyqxmd.com/read/28324114/novel-25-kb-deletion-of-mertk-causes-retinitis-pigmentosa-with-severe-progression
#1
Daniel R Evans, Jane S Green, Gordon J Johnson, Jeremy Schwartzentruber, Jacek Majewski, Chandree L Beaulieu, Wen Qin, Christian R Marshall, Tara A Paton, Nicole M Roslin, Andrew D Paterson, Somayyeh Fahiminiya, Justin French, Kym M Boycott, Michael O Woods
Purpose: Retinitis pigmentosa (RP) describes a complex group of inherited retinal dystrophies with almost 300 reported genes and loci. We investigated the genetic etiology of autosomal recessive RP (arRP) in a large kindred with 5 affected family members, who reside on the island of Newfoundland, Canada. Methods: Genetic linkage analysis was performed on 12 family members (Infinium HumanOmni2.5-8 BeadChip). Whole exome sequencing analysis (Illumina HiSeq) was performed on one affected individual...
March 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28272423/small-molecule-inhibitors-block-gas6-inducible-tam-activation-and-tumorigenicity
#2
Stanley G Kimani, Sushil Kumar, Nitu Bansal, Kamalendra Singh, Vladyslav Kholodovych, Thomas Comollo, Youyi Peng, Sergei V Kotenko, Stefan G Sarafianos, Joseph R Bertino, William J Welsh, Raymond B Birge
TAM receptors (Tyro-3, Axl, and Mertk) are a family of three homologous type I receptor tyrosine kinases that are implicated in several human malignancies. Overexpression of TAMs and their major ligand Growth arrest-specific factor 6 (Gas6) is associated with more aggressive staging of cancers, poorer predicted patient survival, acquired drug resistance and metastasis. Here we describe small molecule inhibitors (RU-301 and RU-302) that target the extracellular domain of Axl at the interface of the Ig-1 ectodomain of Axl and the Lg-1 of Gas6...
March 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28270700/growth-arrest-specific-6-enhances-the-suppressive-function-of-cd4-cd25-regulatory-t-cells-mainly-through-axl-receptor
#3
Guang-Ju Zhao, Jia-Yi Zheng, Jia-Lan Bian, Long-Wang Chen, Ning Dong, Yan Yu, Guang-Liang Hong, Arvine Chandoo, Yong-Ming Yao, Zhong-Qiu Lu
Background. Growth arrest-specific (Gas) 6 is one of the endogenous ligands of TAM receptors (Tyro3, Axl, and Mertk), and its role as an immune modulator has been recently emphasized. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) are essential for the active suppression of autoimmunity. The present study was designed to investigate whether Tregs express TAM receptors and the potential role of Gas6-TAM signal in regulating the suppressive function of Tregs. Methods. The protein and mRNA levels of TAM receptors were determined by using Western blot, immunofluorescence, flow cytometry, and RT-PCR...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28263720/simvastatin-down-regulates-differential-genetic-profiles-produced-by-organochlorine-mixtures-in-primary-breast-cell-hmec
#4
Javier Rivero, Luis Alberto Henríquez-Hernández, Luis D Boada, Jose Pestano, Octavio P Luzardo, María Camacho, Manuel Zumbado, Pilar F Valerón
Women all over the world are exposed to an unavoidable contamination by organochlorine pesticides and other chemical pollutants. Many of them are considered as xenoestrogens and have been associated with the development and progression of breast cancer. We have demonstrated that the most prevalent pesticide mixtures found in healthy women and in women diagnosed with breast cancer modulates the gene expression in human epithelial mammary cells. Statins are well-known cholesterol-depleting agents acting as inhibitors of cholesterol synthesis...
March 2, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28258690/tam-receptor-tyrosine-kinases-as-emerging-targets-of-innate-immune-checkpoint-blockade-for-cancer-therapy
#5
REVIEW
Yemsratch T Akalu, Carla V Rothlin, Sourav Ghosh
Cancer immunotherapy utilizing T-cell checkpoint inhibitors has shown tremendous clinical success. Yet, this mode of treatment is effective in only a subset of patients. Unresponsive patients tend to have non-T-cell-inflamed tumors that lack markers associated with the activation of adaptive anti-tumor immune responses. Notably, elimination of cancer cells by T cells is critically dependent on the optimal activity of innate immune cells. Therefore, identifying new targets that regulate innate immune cell function and promote the engagement of adaptive tumoricidal responses is likely to lead to the development of improved therapies against cancer...
March 2017: Immunological Reviews
https://www.readbyqxmd.com/read/28258107/non-antibiotic-macrolides-restore-airway-macrophage-phagocytic-function-with-potential-anti-inflammatory-effects-in-chronic-lung-diseases
#6
Sandra J Hodge, Hai Tran, Rhys Hamon, Eugene Roscioli, Greg Hodge, Hubertus Jersmann, Miranda Ween, Paul N Reynolds, Arthur Yeung, Jennifer Treiberg, Sibylle Wilbert
We reported defective efferocytosis associated with cigarette smoking and/or airway inflammation in chronic lung diseases including COPD, severe asthma and childhood bronchiectasis. We also showed defects in phagocytosis of non-typeable H. influenzae (NTHi), a common colonizer of the lower airway in these diseases. These defects could be substantially overcome with low-dose Azithromycin; however, chronic usage may induce bacterial resistance. We investigated two novel macrolides, GS-459755 (2'-desoxy-9-(S)-erythromycylamine) and GS-560660 (Azithromycin-based 2'-desoxy molecule) with significantly diminished antibiotic activity against S...
March 3, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28257233/three-unique-interstitial-macrophages-in-the-murine-lung-at-steady-state
#7
Sophie L Gibbings, Stacey M Thomas, Shaikh M Atif, Alexandra L McCubbrey, A Nicole Desch, Thomas Danhorn, Sonia M Leach, Donna L Bratton, Peter M Henson, William J Janssen, Claudia V Jakubzick
RATIONALE: The current paradigm in macrophage biology is that some tissues mainly contain macrophages from embryonic origin such as microglia in the brain, while other tissues contain postnatal-derived macrophages, such as the gut. However, in the lung and in other organs such as the skin, there are both embryonic and postnatal-derived macrophages. OBJECTIVES: In this study, we demonstrate in the steady-state lung that the mononuclear phagocyte system is comprised of three newly identified interstitial macrophages (IMs), alveolar macrophages (AMs), dendritic cells (DCs) and few extravascular monocytes...
March 3, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28246391/rescue-of-the-mertk-phagocytic-defect-in-a-human-ipsc-disease-model-using-translational-read-through-inducing-drugs
#8
Conor M Ramsden, Britta Nommiste, Amelia R Lane, Amanda-Jayne F Carr, Michael B Powner, Matthew J K Smart, Li Li Chen, Manickam N Muthiah, Andrew R Webster, Anthony T Moore, Michael E Cheetham, Lyndon da Cruz, Peter J Coffey
Inherited retinal dystrophies are an important cause of blindness, for which currently there are no effective treatments. In order to study this heterogeneous group of diseases, adequate disease models are required in order to better understand pathology and to test potential therapies. Induced pluripotent stem cells offer a new way to recapitulate patient specific diseases in vitro, providing an almost limitless amount of material to study. We used fibroblast-derived induced pluripotent stem cells to generate retinal pigment epithelium (RPE) from an individual suffering from retinitis pigmentosa associated with biallelic variants in MERTK...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28210098/mertk-gene-expression-and-photoreceptor-outer-segment-phagocytosis-by-cultured-rat-bone-marrow-mesenchymal-stem-cells
#9
Rong-Mei Peng, Jing Hong, Ying Jin, Yu-Zhao Sun, Yi-Qian Sun, Pei Zhang
BACKGROUND: Bone marrow mesenchymal stem cells (BM-MSCs) are multipotential stem cells that have been used for a broad spectrum of indications. Several investigations have used BM-MSCs to promote photoreceptor survival and suggested that BM-MSCs are a potential source of cell replacement therapy for some forms of retinal degeneration. PURPOSE: To investigate the expression of the MER proto-oncogene, tyrosine kinase (Mertk), involved in the disruption of RPE phagocytosis and the onset of autosomal recessive retinitis pigmentosa in rat BM-MSCs and to compare phagocytosis of the photoreceptor outer segment (POS) by BM-MSCs and RPE cells in vitro...
2017: Molecular Vision
https://www.readbyqxmd.com/read/28184013/phosphatidylserine-sensing-by-tam-receptors-regulates-akt-dependent-chemoresistance-and-pd-l1-expression
#10
Canan Kasikara, Sushil Kumar, Stanley Kimani, Wen-I Tsou, Ke Geng, Viralkumar Davra, Ganapathy Sriram, Connor Devoe, Khanh-Quynh Nguyen, Anita Antes, Allen Krantz, Grzegorz Rymarczyk, Andrzej Wilczynski, Cyril Empig, Bruce D Freimark, Michael Gray, Kyle Schlunegger, Jeff Hutchins, Sergei V Kotenko, Raymond B Birge
Tyro3, Axl and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases (RTKs) that bind vitamin K-dependent endogenous ligands, Protein S (ProS) and Growth arrest specific factor 6 (Gas6), and act as bridging molecules to promote phosphatidylserine (PS)-mediated clearance of apoptotic cells (efferocytosis). TAM receptors are overexpressed in a vast array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo- and radio-resistance to targeted therapeutics, but also have been implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment (TME) that can suppress host anti-tumor immunity...
February 9, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28181551/whole-exome-sequencing-using-ion-proton-system-enables-reliable-genetic-diagnosis-of-inherited-retinal-dystrophies
#11
Marina Riera, Rafael Navarro, Sheila Ruiz-Nogales, Pilar Méndez, Anniken Burés-Jelstrup, Borja Corcóstegui, Esther Pomares
Inherited retinal dystrophies (IRD) comprise a wide group of clinically and genetically complex diseases that progressively affect the retina. Over recent years, the development of next-generation sequencing (NGS) methods has transformed our ability to diagnose heterogeneous diseases. In this work, we have evaluated the implementation of whole exome sequencing (WES) for the molecular diagnosis of IRD. Using Ion Proton(TM) system, we simultaneously analyzed 212 genes that are responsible for more than 25 syndromic and non-syndromic IRD...
February 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28145605/the-tam-receptor-tyro3-regulates-myelination-in-the-central-nervous-system
#12
Rainer Akkermann, Andrea Aprico, Ashwyn A Perera, Helena Bujalka, Alistair E Cole, Junhua Xiao, Judith Field, Trevor J Kilpatrick, Michele D Binder
Myelin is an essential component of the mammalian nervous system, facilitating rapid conduction of electrical impulses by axons, as well as providing trophic support to neurons. Within the central nervous system, the oligodendrocyte is the specialized neural cell responsible for producing myelin by a process that is thought to be regulated by both activity dependent and independent mechanisms but in incompletely understood ways. We have previously identified that the protein Gas6, a ligand for a family of tyrosine kinase receptors known as the TAM (Tyro3, Axl, and Mertk) receptors, directly increases oligodendrocyte induced myelination in vitro...
February 1, 2017: Glia
https://www.readbyqxmd.com/read/28144780/inhibition-of-neutrophil-elastase-contributes-to-attenuation-of-lipopolysaccharide-induced-acute-lung-injury-during-neutropenia-recovery-in-mice
#13
Jong Min Lee, Chang Dong Yeo, Hwa Young Lee, Chin Kook Rhee, In Kyoung Kim, Dong Gun Lee, Sang Haak Lee, Jin Woo Kim
PURPOSE: Patients in whom neutropenia recovery is complicated by pneumonia have an increased risk of acute lung injury (ALI) and detrimental outcomes. The aim of the present study was to investigate whether inhibition of neutrophil elastase (NE) is effective in lipopolysaccharide (LPS)-induced ALI during neutropenia recovery in a murine model, and whether it upregulates the activation of the MerTK signaling pathway. METHODS: Cyclophosphamide was given to mice to induce neutropenia...
January 31, 2017: Journal of Anesthesia
https://www.readbyqxmd.com/read/28127639/increased-mer-and-axl-receptor-tyrosine-kinase-expression-on-glomeruli-in-lupus-nephritis
#14
Shanshan Li, Qianyu Guo, Huaqun Zhu, Zhanguo Li, Yin Su, Bao Dong
Mer and Axl receptor tyrosine kinases (MerTK and AxlTK) play important roles in the clearance of apoptotic cells and the inhibition of inflammatory responses. Previous studies demonstrated that they might participate in glomerular injury in mice model. This study aimed to elucidate the expression of MerTK and AxlTK on glomeruli and analyze their clinical significance in lupus nephritis (LN) patients. Twenty-nine LN and 10 primary nephrotic syndrome (NS) patients were recruited. The expression of MerTK and AxlTK on glomeruli was measured by immunohistochemistry...
January 26, 2017: Clinical Rheumatology
https://www.readbyqxmd.com/read/28118606/protein-s-drives-oral-squamous-cell-carcinoma-tumorigenicity-through-regulation-of-axl
#15
Ghada Abboud-Jarrous, Shivam Priya, Avi Maimon, Stuart Fischman, Mayan Cohen-Elisha, Rakefet Czerninski, Tal Burstyn-Cohen
The TAM family of proto-oncogenic receptor protein tyrosine kinases, comprising of TYRO3, AXL, and MERTK, is implicated in many human cancers. Their activation leads to cancer cell proliferation, enhanced migration, invasion, and drug resistance; however how TAMs are activated in cancers is less understood. We previously showed that Protein S (PROS1) is a ligand of the TAM receptors. Here we identify PROS1 as a mediator of Oral Squamous Cell Carcinoma (OSCC) in proliferation, cell survival and migration. We demonstrate that excess PROS1 induces OSCC proliferation and migration...
January 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28075192/loss-of-monocyte-chemoattractant-protein-1-expression-delays-mammary-tumorigenesis-and-reduces-localized-inflammation-in-the-c3-1-sv40tag-triple-negative-breast-cancer-model
#16
Taryn L Cranford, Kandy T Velázquez, Reilly T Enos, Jackie E Bader, Meredith S Carson, Ioulia Chatzistamou, Mitzi Nagarkatti, E Angela Murphy
Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a major modulator in the progression of mammary tumorigenesis, largely due to its ability to recruit macrophages to the tumor microenvironment. Macrophages are key mediators in the connection between inflammation and cancer progression and have been shown to play an important role in tumorigenesis. Thus, MCP-1 may be a potential therapeutic target in inflammatory and difficult-to-treat cancers such as triple negative breast cancer (TNBC). We examined the effect of MCP-1 depletion on mammary tumorigenesis in a model of TNBC...
February 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28072762/giving-axl-the-axe-targeting-axl-in-human-malignancy
#17
REVIEW
Carl M Gay, Kavitha Balaji, Lauren Averett Byers
The receptor tyrosine kinase AXL, activated by a complex interaction between its ligand growth arrest-specific protein 6 and phosphatidylserine, regulates various vital cellular processes, including proliferation, survival, motility, and immunologic response. Although not implicated as an oncogenic driver itself, AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is overexpressed in several haematologic and solid malignancies, including acute myeloid leukaemia, non-small cell lung cancer, gastric and colorectal adenocarcinomas, and breast and prostate cancers...
February 14, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28067670/mertk-receptor-cleavage-promotes-plaque-necrosis-and-defective-resolution-in-atherosclerosis
#18
Bishuang Cai, Edward B Thorp, Amanda C Doran, Brian E Sansbury, Mat J A P Daemen, Bernhard Dorweiler, Matthew Spite, Gabrielle Fredman, Ira Tabas
Atherothrombotic vascular disease is often triggered by a distinct type of atherosclerotic lesion that displays features of impaired inflammation resolution, notably a necrotic core and thinning of a protective fibrous cap that overlies the core. A key cause of plaque necrosis is defective clearance of apoptotic cells, or efferocytosis, by lesional macrophages, but the mechanisms underlying defective efferocytosis and its possible links to impaired resolution in atherosclerosis are incompletely understood. Here, we provide evidence that proteolytic cleavage of the macrophage efferocytosis receptor c-Mer tyrosine kinase (MerTK) reduces efferocytosis and promotes plaque necrosis and defective resolution...
February 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28049839/gas6-is-a-key-homeostatic-immunological-regulator-of-host-commensal-interactions-in-the-oral-mucosa
#19
Maria Nassar, Yaara Tabib, Tal Capucha, Gabriel Mizraji, Tsipora Nir, Meirav Pevsner-Fischer, Gili Zilberman-Schapira, Oded Heyman, Gabriel Nussbaum, Herve Bercovier, Asaf Wilensky, Eran Elinav, Tal Burstyn-Cohen, Avi-Hai Hovav
The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3-AXL-MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28035529/hereditary-retinal-dystrophy
#20
Thomas C Hohman
As our understanding of the genetic basis for inherited retinal disease has expanded, gene therapy has advanced into clinical development. When the gene mutations associated with inherited retinal dystrophies were identified, it became possible to create animal models in which individual gene were altered to match the human mutations. The retina of these animals were then characterized to assess whether the mutated genes produced retinal phenotypes characteristic of disease-affected patients. Following the identification of a subpopulation of patients with the affected gene and the development of techniques for the viral gene transduction of retinal cells, it has become possible to deliver a copy of the normal gene into the retinal sites of the mutated genes...
December 30, 2016: Handbook of Experimental Pharmacology
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