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Qiang Zuo, Jing Liu, Liping Huang, Yifei Qin, Teresa Hawley, Claire Seo, Glenn Merlino, Yanlin Yu
Multiple genetic mutations within melanoma not only cause lesion-specific responses to targeted therapy but also alter the molecular route of resistance to that therapy. Inactivation of PTEN occurs in up to 30% of melanomas, frequently with a concurrent activating BRAF mutation. PTEN loss regulates both acquired and intrinsic drug resistance. Here we show that AXL/AKT axis mediated-resistance to BRAF inhibitor (BRAFi) depends upon PTEN status in melanoma. Hyperactivation of both ERK and AKT pathways was associated with BRAFi resistance in melanoma with wildtype PTEN...
March 19, 2018: Oncogene
Martha Kim, Ho-Kyung Choung, Kyoung Min Lee, Sohee Oh, Seok Hwan Kim
PURPOSE: To delineate longitudinal changes in the optic nerve head (ONH) and peripapillary structure during myopia progression in childhood using spectral-domain (SD) OCT and to explore the factors associated with myopic ONH and peripapillary changes. DESIGN: Prospective cohort study. PARTICIPANTS: Twenty-three healthy children with myopia (46 eyes). METHODS: The participants underwent fundus photography, SD OCT, and axial length (AXL) measurements every 6 months for 2 years...
March 14, 2018: Ophthalmology
Delphine Lumbroso, Soaad Soboh, Avi Maimon, Sagie Schif-Zuck, Amiram Ariel, Tal Burstyn-Cohen
The complete resolution of inflammation requires the uptake of apoptotic polymorphonuclear cells (PMN) by local macrophages (efferocytosis) and the consequent reprogramming of the engulfing phagocytes to reparative and pro-resolving phenotypes. The tyrosine kinase receptors TYRO3, AXL, and MERTK (collectively named TAM) are fundamental mediators in regulating inflammatory responses and efferocytosis. Protein S (PROS1) is a ligand for all TAM receptors that mediates various aspects of their activity. However, the involvement of PROS1 in the resolution of inflammation is incompletely understood...
2018: Frontiers in Immunology
Hirokazu Sadahiro, Kyung-Don Kang, Justin T Gibson, Mutsuko Minata, Hai Yu, Junfeng Shi, Rishi Raj Chhipa, Zhihong Chen, Songjia Lu, Yannick Simoni, Takuya Furuta, Hemragul Sabit, Suojun Zhang, Soniya Bastola, Shinobu Yamaguchi, Heba Allah Alsheikh, Svetlana Komarova, Jun Wang, Sung-Hak Kim, Dolores Hambardzumyan, Xinghua Lu, Evan W Newell, Biplab Dasgupta, Mitsutoshi Nakada, Ly James Lee, Louis B Nabors, Lyse A Norian, Ichiro Nakano
Glioblastoma (GBM) is a lethal disease with no effective therapies available. We previously observed upregulation of the TAM (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL in mesenchymal GBM and showed that knockdown of AXL induced apoptosis of mesenchymal, but not proneural, glioma sphere cultures (GSC). In this study, we report that BGB324, a novel small molecule inhibitor of AXL, prolongs the survival of immunocompromised mice bearing GSC-derived mesenchymal GBM-like tumors. We show that protein S (PROS1), a known ligand of other TAM receptors, was secreted by tumor-associated macrophages/microglia and subsequently physically associated with and activated AXL in mesenchymal GSC...
March 12, 2018: Cancer Research
Xiaomei Wang, Anna Malawista, Feng Qian, Christine Ramsey, Heather G Allore, Ruth R Montgomery
The multifactorial immune deterioration in aging--termed "inflamm-aging"--is comprised of a state of low-grade, chronic inflammation and complex dysregulation of responses to immune stimulation. The TAM family (Tyro 3, Axl, and Mer) of receptor tyrosine kinases are negative regulators of Toll like receptor-mediated immune responses that broadly inhibit cytokine receptor cascades to inhibit inflammation. Here we demonstrate elevated expression of TAM receptors in monocytes of older adults, and an age-dependent difference in signaling mediator AKT resulting in dysregulated responses to signaling though Mer...
February 9, 2018: Oncotarget
Bridget Shafit-Zagardo, Ross C Gruber, Juwen C DuBois
Tyro3, Axl, and Mertk, referred to as the TAM family of receptor tyrosine kinases, are instrumental in maintaining cell survival and homeostasis in mammals. TAM receptors interact with multiple signaling molecules to regulate cell migration, survival, phagocytosis and clearance of metabolic products and cell debris called efferocytosis. The TAMs also function as rheostats to reduce the expression of proinflammatory molecules and prevent autoimmunity. All three TAM receptors are activated in a concentration-dependent manner by the vitamin K-dependent growth arrest-specific protein 6 (Gas6)...
March 4, 2018: Pharmacology & Therapeutics
Fang Zhong, Haibing Chen, Yifan Xie, Evren U Azeloglu, Chengguo Wei, Weijia Zhang, Zhengzhe Li, Peter Y Chuang, Belinda Jim, Hong Li, Firas Elmastour, Jalish M Riyad, Thomas Weber, Hongyu Chen, Yongjun Wang, Aihua Zhang, Weiping Jia, Kyung Lee, John C He
Background Diabetic nephropathy (DN) is a leading cause of ESRD in the United States, but the molecular mechanisms mediating the early stages of DN are unclear. Methods To assess global changes that occur in early diabetic kidneys and to identify proteins potentially involved in pathogenic pathways in DN progression, we performed proteomic analysis of diabetic and nondiabetic rat glomeruli. Protein S (PS) among the highly upregulated proteins in the diabetic glomeruli. PS exerts multiple biologic effects through the Tyro3, Axl, and Mer (TAM) receptors...
March 6, 2018: Journal of the American Society of Nephrology: JASN
Claudia M Gorcea, John Burthem, Eleni Tholouli
Acute myeloid leukemia (AML) is a heterogeneous disease with cure rates of only 30-40% in patients <60 years old. Cytogenetic and molecular markers have improved our understanding of the different prognostic entities in AML. FLT3 mutations are present in 30-40% of AML cases, conferring a poor prognosis with reduced survival. AXL activates FLT3, impacting adversely on outcome. Both FLT3 and AXL constitute promising molecular targets. ASP2215 (gilteritinib) is a novel, dual FLT3/AXL inhibitor with promising early phase trial data (NCT02014558)...
March 2, 2018: Future Oncology
Jang Hwan Cho, Atsushi Okuma, Dalal Al-Rubaye, Ejaj Intisar, Richard P Junghans, Wilson W Wong
Axl is a tyrosine kinase receptor that is commonly overexpressed in many cancers. As such, Axl represents an attractive therapeutic target. The transfer of engineered T cell expressing chimeric antigen receptor (CAR) is an exciting cancer therapeutic approach that shows high efficacy against cancers in clinical trials, especially for B cell malignancies. Furthermore, recently developed synthetic Notch (synNotch) receptor has demonstrated potential in enhancing the specificity of CAR T cell therapy and delivering therapeutic payloads to tumors in an antigen-dependent manner...
March 1, 2018: Scientific Reports
Yingying Shen, Xiguang Chen, Jun He, Duanfang Liao, Xuyu Zu
Overexpression and activation of Axl receptor tyrosine kinase have been widely accepted to promote cell proliferation, chemotherapy resistance, invasion, and metastasis in several human cancers, such as lung, breast, and pancreatic cancers. Axl, a member of the TAM (Tyro3, Axl, Mer) family, and its inhibitors can specifically break the kinase signaling nodes, allowing advanced patients to regain drug sensitivity with improved therapeutic efficacy. Therefore, the research on Axl is promising and it is worthy of further investigations...
February 26, 2018: Life Sciences
Cai Yi, Dong Wang, Wei Fan, Kwok-Leung Tsui, Jianhui Lin
Railway axle bearings are one of the most important components used in vehicles and their failures probably result in unexpected accidents and economic losses. To realize a condition monitoring and fault diagnosis scheme of railway axle bearings, three dimensionless steadiness indexes in a time domain, a frequency domain, and a shape domain are respectively proposed to measure the steady states of bearing vibration signals. Firstly, vibration data collected from some designed experiments are pre-processed by using ensemble empirical mode decomposition (EEMD)...
February 27, 2018: Sensors
Nizar M Tannir, Sumanta K Pal, Michael B Atkins
The management of advanced clear-cell renal cell carcinoma has steadily improved over the past decade with the introduction of antiangiogenic and targeted therapies. Recently, three new therapies have been approved for use as second-line options that further advance the treatment armamentarium: nivolumab, a monoclonal antibody targeting the programmed cell death receptor; cabozantinib, a small-molecule tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR), MET, and AXL; and lenvatinib, a small-molecule TKI of VEGF and fibroblast growth factor receptors that is used in combination with everolimus, an inhibitor of the mechanistic target of rapamycin...
February 27, 2018: Oncologist
Fariba Mollarasouli, Verónica Serafín, Susana Campuzano, Paloma Yáñez-Sedeño, José M Pingarrón, Karim Asadpour-Zeynali
A new label-free electrochemical immunosensor is constructed for the selective and sensitive determination of the clinically relevant biomarker receptor tyrosine kinase (AXL) in human serum. The disposable immunosensing platform is prepared by immobilization of the specific anti-AXL antibody onto amine functionalized graphene quantum dots (fGQDs)-modified screen-printed carbon electrodes (SPCEs). The affinity reactions were monitored by measuring the decrease in the differential pulse voltammetric (DPV) response of the redox probe Fe(CN)6 3-/4- ...
June 29, 2018: Analytica Chimica Acta
Gail Otulakowski, Doreen Engelberts, Martin Post, Claire Masterson, Brian P Kavanagh
BACKGROUND: Lower tidal volumes are increasingly used in acute respiratory distress syndrome, but mortality has changed little in the last 20 yr. Therefore, in addition to ventilator settings, it is important to target molecular mediators of injury. Sepsis and other inflammatory states increase circulating concentrations of Gas6, a ligand for the antiinflammatory receptor Axl, and of a soluble decoy form of Axl. We investigated the effects of lung stretch on Axl signaling. METHODS: We used a mouse model of early injury from high tidal volume and assessed the effects of inhibiting Axl on in vivo lung injury (using an antagonist R428, n = 4/group)...
February 23, 2018: Anesthesiology
Tomoki Ogoshi, Daisuke Kotera, Shungo Nishida, Takahiro Kakuta, Tada-Aki Yamagishi, Albert M Brouwer
For a series of neutral [2]rotaxanes consisting of a pillar[5]arene ring and axles possessing two stations separated by flexible spacers of different lengths, the free energies of activation for the ring shuttling between the stations are found to be independent of the spacer length. The constitution of the spacer affects the activation energies: replacement of CH2 groups by repulsive oxygen atoms in the axle increases the barrier. The explanation for the observed length-independence lies in the presence of a barrier for re-forming the stable co-conformation, which makes the ring travel back and forth along the thread in an intermediate state...
February 23, 2018: Chemistry: a European Journal
Ling Dai, Wanhua Wu, Wenting Liang, Wentong Chen, Xingke Yu, Jiecheng Ji, Chao Xiao, Cheng Yang
Mixing γ-cyclodextrin (γ-CD), cucurbit[6]uril (CB[6]) and tetraammonium-bearing axles together led to a spontaneous formation of γ-CD-CB[6]-cowheeled [4]pseudorotaxanes. The well-defined unsymmetrical cavities thus formed enhance the binding affinity towards chiral amines by factors of several hundreds and show remarkably improved chiral discrimination.
February 22, 2018: Chemical Communications: Chem Comm
Samuel H Myers, Carolin Temps, Douglas R Houston, Valerie G Brunton, Asier Unciti-Broceta
Pyrazolopyrimidines with potent antiproliferative properties were developed by an adaptive strategy that applies ligand-based design and phenotypic screening iteratively and is informed by biochemical assays. To drive development toward specific oncopathways, compounds were tested against cancer cells that overexpress, or not, AXL kinase. Identified phenotypic hits were found to inhibit oncotargets AXL, RET, and FLT3. Subsequent optimization generated antiproliferative lead compounds with unique selectivity profiles, including selective AXL inhibitors and a highly potent inhibitor of FLT3...
February 21, 2018: Journal of Medicinal Chemistry
Yen-Lin Chen, Yi-Ting Tsai, Ting-Ting Chao, Yi-No Wu, Meng-Chuan Chen, Ying-Hung Lin, Chun-Hou Liao, Shang-Shing P Chou, Han-Sun Chiang
Purpose: Impotence is one of the major complications occurring in prostate cancer patients after radical prostectomy (RP). Self-repair of the injured nerve has been observed in animal models and in patients after RP. However, the downstream signalling is not well documented. Here, we found that the DAPK/CIP2A complex is involved in GAS6/AXL-related Schwann cell proliferation. Materials and Methods: The 3 groups were a sham group, a 14-day post-bilateral cavernous nerve injury (BCNI) group and a 28-day post-BCNI group...
January 19, 2018: Oncotarget
Shih-Ping Su, Efrat Flashner-Abramson, Shoshana Klein, Mor Gal, Rachel S Lee, Jianmin Wu, Alexander Levitzki, Roger J Daly
The small molecule drug NT157 has demonstrated promising efficacy in pre-clinical models of a number of different cancer types, reflecting activity against both cancer cells and the tumour microenvironment. Two known mechanisms of action are degradation of insulin-receptor substrates (IRS)-1/2, and reduced Stat3 activation, although it is possible that others exist. In order to interrogate the effects of this drug on cell signalling pathways in an unbiased manner, we have undertaken mass spectrometry-based global tyrosine phosphorylation profiling of NT157-treated A375 melanoma cells...
February 12, 2018: Molecular Cancer Therapeutics
Guoan Zhang, Meng Wang, Hongli Zhao, Wen Cui
Axl receptor tyrosine kinase (hereafter Axl) is a member of the tyrosine-protein kinase receptor Tyro3, Axl and proto-oncogene tyrosine-protein kinase Mer family of receptor tyrosine kinases, possessing multiple different functions in normal cells. Axl is overexpressed and activated in numerous different human cancer types, triggering several signaling pathways and enhancing tumor progression. The present review assesses previous studies on the function of Axl in non-small cell lung cancer (NSCLC). Axl is overexpressed in the tumor tissues of a number of patients with NSCLC and is associated with poorer clinical outcomes; it promotes NSCLC tumor growth, invasion/metastasis, drug resistance and the epithelial-mesenchymal transition, thus providing a survival advantage to tumor cells...
March 2018: Oncology Letters
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