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https://www.readbyqxmd.com/read/28103611/phase-ii-randomised-discontinuation-trial-of-the-met-vegf-receptor-inhibitor-cabozantinib-in-metastatic-melanoma
#1
Adil Daud, Harriet M Kluger, Razelle Kurzrock, Frauke Schimmoller, Aaron L Weitzman, Thomas A Samuel, Ali H Moussa, Michael S Gordon, Geoffrey I Shapiro
BACKGROUND: A phase II randomised discontinuation trial assessed cabozantinib (XL184), an orally bioavailable inhibitor of tyrosine kinases including VEGF receptors, MET, and AXL, in a cohort of patients with metastatic melanoma. METHODS: Patients received cabozantinib 100 mg daily during a 12-week lead-in. Patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumours (RECIST) at week 12 were randomised to cabozantinib or placebo. Primary endpoints were objective response rate (ORR) at week 12 and postrandomisation progression-free survival (PFS)...
January 19, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28103031/-watching-the-dark-state-in-ultrafast-nonadiabatic-photoisomerization-process-of-a-light-driven-molecular-rotary-motor
#2
Xiaojuan Pang, Xueyan Cui, Deping Hu, Chenwei Jiang, Di Zhao, Zhenggang Lan, Fu-Li Li
Photoisomerization dynamics of a light-driven molecular rotary motor, 9-(2-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-ylidene)-9H-fluorene, is investigated with trajectory surface-hopping dynamics at the semi-empirical OM2/MRCI level. The rapid population decay of the S1 excited state for the M isomer is observed, with two different decay timescales (500 fs and 1.0 ps). By weighting the contributions of fast and slow decay trajectories, the averaged lifetime of the S1 excited state is about 710 fs. The calculated quantum yield of the M-to-P photoisomerization of this molecular rotary motor is about 59...
January 19, 2017: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/28100259/antitumor-activity-of-mir-34a-in-peritoneal-mesothelioma-relies-on-c-met-and-axl-inhibition-persistent-activation-of-erk-and-akt-signaling-as-a-possible-cytoprotective-mechanism
#3
Rihan El Bezawy, Michelandrea De Cesare, Marzia Pennati, Marcello Deraco, Paolo Gandellini, Valentina Zuco, Nadia Zaffaroni
BACKGROUND: The value of microRNAs (miRNAs) as novel targets for cancer therapy is now widely recognized. However, no information is currently available on the expression/functional role of miRNAs in diffuse malignant peritoneal mesothelioma (DMPM), a rapidly lethal disease, poorly responsive to conventional treatments, for which the development of new therapeutic strategies is urgently needed. Here, we evaluated the expression and biological effects of miR-34a-one of the most widely deregulated miRNAs in cancer and for which a lipid-formulated mimic is already clinically available-in a large cohort of DMPM clinical samples and a unique collection of in house-developed preclinical models, with the aim to assess the potential of a miR-34a-based approach for disease treatment...
January 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28099856/screening-bioactives-reveals-nanchangmycin-as-a-broad-spectrum-antiviral-active-against-zika-virus
#4
Keiko Rausch, Brent A Hackett, Nathan L Weinbren, Sophia M Reeder, Yoel Sadovsky, Christopher A Hunter, David C Schultz, Carolyn B Coyne, Sara Cherry
Zika virus is an emerging arthropod-borne flavivirus for which there are no vaccines or specific therapeutics. We screened a library of 2,000 bioactive compounds for their ability to block Zika virus infection in three distinct cell types with two different strains of Zika virus. Using a microscopy-based assay, we validated 38 drugs that inhibited Zika virus infection, including FDA-approved nucleoside analogs. Cells expressing high levels of the attachment factor AXL can be protected from infection with receptor tyrosine kinase inhibitors, while placental-derived cells that lack AXL expression are insensitive to this inhibition...
January 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/28096186/translation-reprogramming-is-an-evolutionarily-conserved-driver-of-phenotypic-plasticity-and-therapeutic-resistance-in-melanoma
#5
Paola Falletta, Luis Sanchez-Del-Campo, Jagat Chauhan, Maike Effern, Amy Kenyon, Christopher J Kershaw, Robert Siddaway, Richard Lisle, Rasmus Freter, Matthew J Daniels, Xin Lu, Thomas Tüting, Mark Middleton, Francesca M Buffa, Anne E Willis, Graham Pavitt, Ze'ev A Ronai, Tatjana Sauka-Spengler, Michael Hölzel, Colin R Goding
The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance. However, how MITF is suppressed in vivo and how MITF-low cells in tumors escape senescence are poorly understood...
January 17, 2017: Genes & Development
https://www.readbyqxmd.com/read/28094183/discovering-novel-7-azaindole-based-series-as-potent-axl-kinase-inhibitors
#6
Clémence Feneyrolles, Léa Guiet, Mathilde Singer, Nathalie Van Hijfte, Bénédicte Daydé-Cazals, Bénédicte Fauvel, Gwénaël Chevé, Abdelaziz Yasri
AXL is a receptor tyrosine kinase that plays a key role in tumor growth and proliferation. The scientific community has validated AXL as therapeutic target in the treatment of cancers for several years now, and several AXL inhibitors have been developed but none of them are approved. In this context, we started to design new kinase inhibitors targeting AXL from the 7-azaindole scaffold well known to interact with the ATP binding site of the kinase. Focused screening and chemical diversification around 7-azaindole scaffold were developed, based on modeling studies and medicinal chemistry rational, leading to the discovery of a new family of hits with potent inhibitory activity against AXL...
January 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28081529/zika-virus-induced-microcephaly-and-its-possible-molecular-mechanism
#7
Md Imam Faizan, Mohd Abdullah, Sher Ali, Irshad H Naqvi, Anwar Ahmed, Shama Parveen
Zika virus is an arthropod-borne re-emerging pathogen associated with the global pandemic of 2015-2016. The devastating effect of Zika viral infection is reflected by its neurological manifestations such as microcephaly in newborns. This scenario evoked our interest to uncover the neurotropic localization, multiplication of the virus, and the mechanism of microcephaly. The present report provides an overview of a possible molecular mechanism of Zika virus-induced microcephaly based on recent publications. Transplacental transmission of Zika viral infection from mother to foetus during the first trimester of pregnancy results in propagation of the virus in human neural progenitor cells (hNPCs), where entry is facilitated by the receptor (AXL protein) leading to the alteration of signalling and immune pathways in host cells...
January 13, 2017: Intervirology
https://www.readbyqxmd.com/read/28076778/axl-mediates-zika-virus-entry-in-human-glial-cells-and-modulates-innate-immune-responses
#8
Laurent Meertens, Athena Labeau, Ophelie Dejarnac, Sara Cipriani, Laura Sinigaglia, Lucie Bonnet-Madin, Tifenn Le Charpentier, Mohamed Lamine Hafirassou, Alessia Zamborlini, Van-Mai Cao-Lormeau, Muriel Coulpier, Dorothée Missé, Nolwenn Jouvenet, Ray Tabibiazar, Pierre Gressens, Olivier Schwartz, Ali Amara
ZIKA virus (ZIKV) is an emerging pathogen responsible for neurological disorders and congenital microcephaly. However, the molecular basis for ZIKV neurotropism remains poorly understood. Here, we show that Axl is expressed in human microglia and astrocytes in the developing brain and that it mediates ZIKV infection of glial cells. Axl-mediated ZIKV entry requires the Axl ligand Gas6, which bridges ZIKV particles to glial cells. Following binding, ZIKV is internalized through clathrin-mediated endocytosis and traffics to Rab5+ endosomes to establish productive infection...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28072762/giving-axl-the-axe-targeting-axl-in-human-malignancy
#9
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...
January 10, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28054238/protective-effects-of-pterostilbene-against-myocardial-ischemia-reperfusion-injury-in-rats
#10
Miao Wu, Shijuan Lu, Jianghua Zhong, Kang Huang, Saidan Zhang
Pterostilbene (PTB) has been suggested to protect against myocardial ischemia/reperfusion (MI/R) injury. Gas6/Axl signaling has been suggested to play an important role in cell survival. However, the interaction between PTB and Gas6/Axl signaling in MI/R remains unclear. This study aims to evaluate the role of Gas6/Axl signaling in the protective effects of PTB against MI/R injury. In experiment 1, the rats were subjected to 30 min of ischemia, followed by 3, 6, and 12 h of reperfusion, respectively. In experiment 2, the rats were administered intraperitoneally with PTB or vehicle and subjected to MI/R injury...
January 4, 2017: Inflammation
https://www.readbyqxmd.com/read/28051775/annexing-axl-endothelial-cell-infection-by-the-zika-virus
#11
EDITORIAL
Ingrid Fleming
No abstract text is available yet for this article.
November 11, 2016: Circulation Research
https://www.readbyqxmd.com/read/28049839/gas6-is-a-key-homeostatic-immunological-regulator-of-host-commensal-interactions-in-the-oral-mucosa
#12
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/28049763/the-receptor-tyrosine-kinase-axl-mediates-nuclear-translocation-of-the-epidermal-growth-factor-receptor
#13
Toni M Brand, Mari Iida, Kelsey L Corrigan, Cara M Braverman, John P Coan, Bailey G Flanigan, Andrew P Stein, Ravi Salgia, Jana Rolff, Randall J Kimple, Deric L Wheeler
The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance...
January 3, 2017: Science Signaling
https://www.readbyqxmd.com/read/28035396/anticancer-effect-of-luteolin-is-mediated-by-downregulation-of-tam-receptor-tyrosine-kinases-but-not-interleukin-8-in-non-small-cell-lung-cancer-cells
#14
Youn Ju Lee, Taeho Lim, Min Su Han, Sun-Hwa Lee, Suk-Hwan Baek, Hong-Yan Nan, Chuhee Lee
TAM receptor tyrosine kinases (RTKs), Tyro3, Axl and MerTK, transduce diverse signals responsible for cell survival, growth, proliferation and anti-apoptosis. In the present study, we demonstrated the effect of luteolin, a flavonoid with antioxidant, anti-inflammatory and anticancer activities, on the expression and activation of TAM RTKs and the association with its cytotoxicity in non-small cell lung cancer (NSCLC) cells. We observed the cytotoxic effect of luteolin in parental A549 and H460 cells as well as in cisplatin-resistant A549/CisR and H460/CisR cells...
February 2017: Oncology Reports
https://www.readbyqxmd.com/read/28034848/regulated-intramembrane-proteolysis-of-the-axl-receptor-kinase-generates-an-intracellular-domain-that-localizes-in-the-nucleus-of-cancer-cells
#15
Yinzhong Lu, Jun Wan, Zhifeng Yang, Xiling Lei, Qi Niu, Lanxin Jiang, Willemijn M Passtoors, Aiping Zang, Patrick C Fraering, Fang Wu
Deregulation of the TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases (RTKs) has recently been demonstrated to predominately promote survival and chemoresistance of cancer cells. Intramembrane proteolysis mediated by presenilin/γ-secretase is known to regulate the homeostasis of some RTKs. In the present study, we demonstrate that AXL, but not TYRO3 or MERTK, is efficiently and sequentially cleaved by α- and γ-secretases in various types of cancer cell lines. Proteolytic processing of AXL redirected signaling toward a secretase-mediated pathway, away from the classic, well-known, ligand-dependent canonical RTK signaling pathway...
December 29, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28025482/implication-of-the-receptor-tyrosine-kinase-axl-in-head-and-neck-cancer-progression
#16
Anne von Mässenhausen, Johannes Brägelmann, Hannah Billig, Britta Thewes, Angela Queisser, Wenzel Vogel, Glen Kristiansen, Andreas Schröck, Friedrich Bootz, Peter Brossart, Jutta Kirfel, Sven Perner
Head and neck squamous cell carcinoma (HNSCC) remains a clinical challenge and identification of novel therapeutic targets is necessary. The receptor tyrosine kinase AXL has been implicated in several tumor entities and a selective AXL small molecule inhibitor (BGB324) is currently being tested in clinical trials for patients suffering from non-small cell lung cancer or acute myeloid leukemia. Our study investigates AXL expression during HNSCC progression and its use as a potential therapeutic target in HNSCC...
December 22, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28008921/reprogramming-the-immunological-microenvironment-through-radiation-and-targeting-axl
#17
Todd A Aguilera, Marjan Rafat, Laura Castellini, Hussein Shehade, Mihalis S Kariolis, Angela Bik-Yu Hui, Henning Stehr, Rie von Eyben, Dadi Jiang, Lesley G Ellies, Albert C Koong, Maximilian Diehn, Erinn B Rankin, Edward E Graves, Amato J Giaccia
Increasing evidence suggests that ionizing radiation therapy (RT) in combination with checkpoint immunotherapy is highly effective in treating a subset of cancers. To better understand the limited responses to this combination we analysed the genetic, microenvironmental, and immune factors in tumours derived from a transgenic breast cancer model. We identified two tumours with similar growth characteristics but different RT responses primarily due to an antitumour immune response. The combination of RT and checkpoint immunotherapy resulted in cures in the responsive but not the unresponsive tumours...
December 23, 2016: Nature Communications
https://www.readbyqxmd.com/read/28005093/ultrasound-guided-percutaneous-reconstruction-of-the-anterolateral-ligament-surgical-technique-and-case-report
#18
Alan M Hirahara, Wyatt J Andersen
The first noted description of the anterolateral ligament (ALL) is often attributed to Dr. Paul Segond (1879). Segond described a "fibrous, pearly band showing extreme amounts of tension during forced internal rotation" that was responsible for an avulsion at the lateral aspect of the proximal tibia. In 2013, Dr. Steven Claes confirmed the presence of the ALL as the band of tissue detailed by Segond. Recent biomechanical studies have shown that the ALL is a vital stabilizer during internal rotation of the knee...
November 2016: American Journal of Orthopedics
https://www.readbyqxmd.com/read/27997117/engineering-high-affinity-protein-protein-interactions-using-a-high-throughput-microcapillary-array-platform
#19
Sungwon Lim, Bob Chen, Mihalis S Kariolis, Ivan K Dimov, Thomas M Baer, Jennifer R Cochran
Affinity maturation of protein-protein interactions requires iterative rounds of protein library generation and high-throughput screening to identify variants that bind with increased affinity to a target of interest. We recently developed a multipurpose protein engineering platform, termed μSCALE (Microcapillary Single Cell Analysis and Laser Extraction). This technology enables high-throughput screening of libraries of millions of cell-expressing protein variants based on their binding properties or functional activity...
December 20, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27987320/association-between-axl-hippo-transducers-and-survival-outcomes-in-male-breast-cancer
#20
Anna Di Benedetto, Marcella Mottolese, Francesca Sperati, Cristiana Ercolani, Luigi Di Lauro, Laura Pizzuti, Patrizia Vici, Irene Terrenato, Abeer M Shaaban, Matthew P Humphries, Sreekumar Sundara-Rajan, Maddalena Barba, Valerie Speirs, Ruggero De Maria, Marcello Maugeri-Saccà
Male breast cancer (MBC) is an uncommon malignancy. We have previously reported that the expression of the Hippo transducers TAZ/YAP and their target CTGF was associated with inferior survival in MBC patients. Preclinical evidence demonstrated that Axl is a transcriptional target of TAZ/YAP. Thus, we herein assessed AXL expression to further investigate the significance of active TAZ/YAP-driven transcription in MBC. For this study, 255 MBC samples represented in tissue microarrays were screened for AXL expression, and 116 patients were included...
December 17, 2016: Journal of Cellular Physiology
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