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https://www.readbyqxmd.com/read/29444487/paracrine-fibroblast-growth-factor-initiates-oncogenic-synergy-with-epithelial-fgfr-src-transformation-in-prostate-tumor-progression
#1
Qianjin Li, Lishann Ingram, Sungjin Kim, Zanna Beharry, Jonathan A Cooper, Houjian Cai
Cross talk of stromal-epithelial cells plays an essential role in both normal development and tumor initiation and progression. Fibroblast growth factor (FGF)-FGF receptor (FGFR)-Src kinase axis is one of the major signal transduction pathways to mediate this cross talk. Numerous genomic studies have demonstrated that expression levels of FGFR/Src are deregulated in a variety of cancers including prostate cancer; however, the role that paracrine FGF (from stromal cells) plays in dysregulated expression of epithelial FGFRs/Src and tumor progression in vivo is not well evaluated...
February 11, 2018: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/29443392/spatial-aspects-of-oncogenic-signaling-determine-response-to-combination-therapy-in-slice-explants-from-kras-driven-lung-tumors
#2
Katja Närhi, Ashwini S Nagaraj, Elina Parri, Riku Turkki, Petra W van Duijn, Annabrita Hemmes, Jenni Lahtela, Virva Uotinen, Mikko I Mäyränpää, Kaisa Salmenkivi, Jari Räsänen, Nina Linder, Jan Trapman, Antti Rannikko, Olli Kallioniemi, Taija Af Hällström, Johan Lundin, Wolfgang Sommergruber, Simon Anders, Emmy W Verschuren
A key question in precision medicine is how functional heterogeneity in solid tumors informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signaling and therapy response can be modeled in precision-cut slices from Kras-driven non-small cell lung cancer (NSCLC) of varying histopathologies. Unexpectedly, profiling of in situ tumors demonstrates that signaling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma (ASC), and MAPK activity in adenocarcinoma (AC)...
February 14, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29440662/wdr1-is-a-novel-eya3-substrate-and-its-dephosphorylation-induces-modifications-of-the-cellular-actin-cytoskeleton
#3
Mihaela Mentel, Aura E Ionescu, Ioana Puscalau-Girtu, Martin S Helm, Rodica A Badea, Silvio O Rizzoli, Stefan E Szedlacsek
Eyes absent (EYA) proteins are unusual proteins combining in a single polypeptide chain transactivation, threonine phosphatase, and tyrosine phosphatase activities. They play pivotal roles in organogenesis and are involved in a variety of physiological and pathological processes including innate immunity, DNA damage repair or cancer metastasis. The molecular targets of EYA tyrosine phosphatase activity are still elusive. Therefore, we sought to identify novel EYA substrates and also to obtain further insight into the tyrosine-dephosphorylating role of EYA proteins in various cellular processes...
February 13, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29440449/impact-of-the-anti-cancer-drug-nt157-on-tyrosine-kinase-signalling-networks
#4
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
https://www.readbyqxmd.com/read/29440352/c-src-dependent-and-independent-functions-of-matk-in-osteoclasts-and-osteoblasts
#5
Jung Ha Kim, Kabsun Kim, Inyoung Kim, Semun Seong, Nacksung Kim
The non-receptor tyrosine kinase c-Src participates in bone metabolism by regulating the activities of both the bone-resorbing osteoclasts and bone-forming osteoblasts. In this study, we investigated whether megakaryocyte-associated tyrosine kinase (Matk), a potent inhibitor of c-Src, affects the functions of murine osteoclasts and osteoblasts. Results revealed that the formation of osteoclasts with actin rings was attenuated by Matk overexpression in osteoclast precursor cells but was enhanced by Matk knockdown...
February 12, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29440289/neo212-inhibits-migration-and-invasion-of-glioma-stem-cells
#6
Nagore I Marín-Ramos, Thu Zan Thein, Hee-Yeon Cho, Stephen D Swenson, Weijun Wang, Axel H Schönthal, Thomas C Chen, Florence M Hofman
Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays an important role in tumor progression. The poor prognosis in GBM is associated with a high rate of tumor recurrence, and resistance to the standard of care chemotherapy, temozolomide (TMZ). The novel compound NEO212, a conjugate of TMZ and perillyl alcohol (POH), has proven to be 10 fold more cytotoxic to glioma stem cells (GSCs) than TMZ, and is active against TMZ-resistant tumor cells...
February 13, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29438996/global-identification-of-sumo-substrates-reveals-crosstalk-between-sumoylation-and-phosphorylation-promotes-cell-migration
#7
Ijeoma Uzoma, Jianfei Hu, Eric Cox, Shuli Xia, Jianying Zhou, Hee-Sool Rho, Catherine Guzzo, Corry Paul, Olutobi Ajala, C Rory Goodwin, Junseop Jeong, Cedric Moore, Hui Zhang, Pamela Meluh, Seth Blackshaw, Michael Matunis, Jiang Qian, Heng Zhu
Proteomics studies have revealed that SUMOylation is widely used posttranslational modification (PTM) in eukaryotes. However, how SUMO E1/2/3 complexes use different SUMO isoforms and recognize substrates remains largely unknown.  Using a human proteome microarray-based activity screen, we identified over 2,500 proteins that undergo SUMO E3-dependent SUMOylation.  We next constructed a SUMO isoform- and E3 ligase-dependent enzyme-substrate relationship network. Protein kinases were significantly enriched among SUMOylation substrates, suggesting crosstalk between tyrosine phosphorylation and SUMOylation...
February 8, 2018: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/29438361/a-first-in-human-phase-i-study-to-determine-the-maximum-tolerated-dose-of-the-oral-src-abl-inhibitor-azd0424
#8
Victoria K Woodcock, Sally Clive, Richard H Wilson, Vicky M Coyle, Michael R L Stratford, Lisa K Folkes, Richard Eastell, Claire Barton, Paul Jones, Shamim Kazmi-Stokes, Helen Turner, Sarah Halford, Adrian L Harris, Mark R Middleton
BACKGROUND: Src is involved in cancer invasion and metastasis. AZD0424, an oral inhibitor of Src and ABL1, has shown evidence of anti-tumour activity in pre-clinical studies. METHODS: A phase Ia, dose escalation study was performed to assess the safety of continuous oral dosing with AZD0424 in advanced solid tumours. Secondary objectives included investigation of AZD0424 pharmacokinetics, effect on Src activity using markers of bone turnover, and anti-tumour activity...
February 13, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29437870/cpt2-downregulation-adapts-hcc-to-lipid-rich-environment-and-promotes-carcinogenesis-via-acylcarnitine-accumulation-in-obesity
#9
Naoto Fujiwara, Hayato Nakagawa, Kenichiro Enooku, Yotaro Kudo, Yuki Hayata, Takuma Nakatsuka, Yasuo Tanaka, Ryosuke Tateishi, Yohko Hikiba, Kento Misumi, Mariko Tanaka, Akimasa Hayashi, Junji Shibahara, Masashi Fukayama, Junichi Arita, Kiyoshi Hasegawa, Hadassa Hirschfield, Yujin Hoshida, Yoshihiro Hirata, Motoyuki Otsuka, Keisuke Tateishi, Kazuhiko Koike
OBJECTIVE: Metabolic reprogramming of tumour cells that allows for adaptation to their local environment is a hallmark of cancer. Interestingly, obesity-driven and non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) mouse models commonly exhibit strong steatosis in tumour cells as seen in human steatohepatitic HCC (SH-HCC), which may reflect a characteristic metabolic alteration. DESIGN: Non-tumour and HCC tissues obtained from diethylnitrosamine-injected mice fed either a normal or a high-fat diet (HFD) were subjected to comprehensive metabolome analysis, and the significance of obesity-mediated metabolic alteration in hepatocarcinogenesis was evaluated...
February 6, 2018: Gut
https://www.readbyqxmd.com/read/29435691/common-data-elements-collected-among-universities-for-sport-related-concussion-studies
#10
Jingzhen Yang, Corinne Peek-Asa, James M Noble, James Torner, Paul Schmidt, Martha L Cooper
BACKGROUND: Universities are increasingly implementing programs to effectively respond to and manage sport-related concussions (SRCs). One such effort is to develop common data elements (CDEs) and standardize data collection methods. The objectives of this study were to describe CDEs currently collected by Big Ten and Ivy League universities for SRC studies, and to compare the data collected with the core CDEs recommended by the National Institute of Neurological Disorders and Stroke (NINDS)...
February 12, 2018: Injury Epidemiology
https://www.readbyqxmd.com/read/29435137/activation-of-mapk-signalling-results-in-resistance-to-saracatinib-azd0530-in-ovarian-cancer
#11
Niamh McGivern, Aya El-Helali, Paul Mullan, Iain A McNeish, D Paul Harkin, Richard D Kennedy, Nuala McCabe
SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29434030/src-mediated-phosphorylation-converts-fhl1-from-tumor-suppressor-to-tumor-promoter
#12
Xiang Wang, Xiaofan Wei, Yang Yuan, Qingrui Sun, Jun Zhan, Jing Zhang, Yan Tang, Feng Li, Lihua Ding, Qinong Ye, Hongquan Zhang
FHL1 has been recognized for a long time as a tumor suppressor protein that associates with both the actin cytoskeleton and the transcriptional machinery. We present in this study a paradigm that phosphorylated FHL1 functions as an oncogenic protein by promoting tumor cell proliferation. The cytosolic tyrosine kinase Src interacts with and phosphorylates FHL1 at Y149 and Y272, which switches FHL1 from a tumor suppressor to a cell growth accelerator. Phosphorylated FHL1 translocates into the nucleus, where it binds to the transcription factor BCLAF1 and promotes tumor cell growth...
February 6, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29433983/common-co-activation-of-axl-and-cdcp1-in-egfr-mutation-positive-non-smallcell-lung-cancer-associated-with-poor-prognosis
#13
Niki Karachaliou, Imane Chaib, Andres Felipe Cardona, Jordi Berenguer, Jillian Wilhelmina Paulina Bracht, Jie Yang, Xueting Cai, Zhigang Wang, Chunping Hu, Ana Drozdowskyj, Carles Codony Servat, Jordi Codony Servat, Masaoki Ito, Ilaria Attili, Erika Aldeguer, Ana Gimenez Capitan, July Rodriguez, Leonardo Rojas, Santiago Viteri, Miguel Angel Molina-Vila, Sai-Hong Ignatius Ou, Morihito Okada, Tony S Mok, Trever G Bivona, Mayumi Ono, Jean Cui, Santiago Ramón Y Cajal, Peng Cao, Rafael Rosell
Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo...
February 5, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29432410/angiopoietin-like-4-attenuates-brain-edema-and-neurological-deficits-in-a-mouse-model-of-experimental-intracerebral-hemorrhage
#14
Zhandong Qiu, Jia Yang, Gang Deng, Yu Fang, Dayong Li, Suming Zhang
BACKGROUND Angiopoietin-like 4 (ANGPTL4) is neuroprotective when administered acutely for the treatment of cerebral ischemia. The aim of the present study was to evaluate the preventive effects of ANGPTL4 on the formation of brain edema and to determine whether it promotes the recovery of neurological function following intracerebral hemorrhage (ICH). MATERIAL AND METHODS Recombinant human ANGPTL4 (rhANGPTL4; 40 µg/kg) or a vehicle was administered intraperitoneally 5 min prior to bacterial collagenase-induced ICH in male C57/B6J mice...
February 12, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29431655/fentanyl-induces-rapid-onset-hyperalgesic-priming-type-i-at-peripheral-and-type-ii-at-central-nociceptor-terminals
#15
Dioneia Araldi, Eugen V Khomula, Luiz F Ferrari, Jon D Levine
Systemic fentanyl induces hyperalgesic priming, long-lasting neuroplasticity in nociceptor function characterized by prolongation of inflammatory mediator hyperalgesia. To evaluate priming at both nociceptor terminals, we studied, in male Sprague--Dawley rats, the effect of local administration of agents that reverse Type I (protein translation) or Type II (combination of Src and mitogen-activated protein kinase [MAPK]) priming. While at the central terminal, priming induced by systemic, intradermal or intrathecal fentanyl was reversed by the combination of Src and MAPK inhibitors, at the peripheral terminal it was reversed by the protein translation inhibitor...
February 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29427623/paracrine-signaling-by-vegf-c-promotes-non-small-cell-lung-cancer-cell-metastasis-via-recruitment-of-tumor-associated-macrophages
#16
Yanchao Deng, Yang Yang, Bei Yao, Lei Ma, Qipeng Wu, Zhicheng Yang, Luyong Zhang, Bing Liu
High expression of tumoral vascular endothelial growth factor C (VEGF-C) is correlated with clinical non-small cell lung cancer (NSCLC) metastasis and patient survival. Nevertheless, the comprehensive mechanisms accounting for VEGF-C-mediated cancer progression remain largely unclear. The present study found that VEGF-C expression was upregulated in various NSCLC cell lines. By utilizing transwell migration assay, we found that both recombinant VEGF-C protein and overexpression of VEGF-C in NSCLC cells (A549 and H441 cell lines) could efficiently enhance RAW264...
February 7, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29426960/two-microcephaly-associated-novel-missense-mutations-in-cask-specifically-disrupt-the-cask-neurexin-interaction
#17
Leslie E W LaConte, Vrushali Chavan, Abdallah F Elias, Cynthia Hudson, Corbin Schwanke, Katie Styren, Jonathan Shoof, Fernando Kok, Sarika Srivastava, Konark Mukherjee
Deletion and truncation mutations in the X-linked gene CASK are associated with severe intellectual disability (ID), microcephaly and pontine and cerebellar hypoplasia in girls (MICPCH). The molecular origin of CASK-linked MICPCH is presumed to be due to disruption of the CASK-Tbr-1 interaction. This hypothesis, however, has not been directly tested. Missense variants in CASK are typically asymptomatic in girls. We report three severely affected girls with heterozygous CASK missense mutations (M519T (2), G659D (1)) who exhibit ID, microcephaly, and hindbrain hypoplasia...
February 9, 2018: Human Genetics
https://www.readbyqxmd.com/read/29425698/assessment-of-sleep-quantity-and-sleep-disturbances-during-recovery-from-sports-related-concussion-in-youth-athletes
#18
Donna L Murdaugh, Kim E Ono, Andrew Reisner, Thomas G Burns
OBJECTIVE: To determine the relationship between sleep quantity and sleep disturbances on symptoms and neurocognitive ability at the acute phase (<7 days) and post-sports-related concussion (SRC; >21 days). DESIGN: Prospective inception cohort study SETTING: General community setting of regional middle and high schools. PARTICIPANTS: Sample included 528 youth athletes with SRC and 443 controls ages 10-18. MAIN OUTCOME MEASURES: Athletes completed the Immediate Post-Concussive Assessment and Cognitive Testing (ImPACT) battery...
February 6, 2018: Archives of Physical Medicine and Rehabilitation
https://www.readbyqxmd.com/read/29423065/phosphatase-of-regenerating-liver-3-is-expressed-in-acute-lymphoblastic-leukemia-and-mediates-leukemic-cell-adhesion-migration-and-drug-resistance
#19
Magnus A Hjort, Pegah Abdollahi, Esten N Vandsemb, Mona H Fenstad, Bendik Lund, Tobias S Slørdahl, Magne Børset, Torstein B Rø
Phosphatase of regenerating liver-3 (PRL-3/PTP4A3) is upregulated in multiple cancers, including BCR-ABL1- and ETV6-RUNX-positive acute lymphoblastic leukemia (ALL). With this study, we aim to characterize the biological role of PRL-3 in B cell ALL (B-ALL). Here, we demonstrate that PRL-3 expression at mRNA and protein level was higher in B-ALL cells than in normal cells, as measured by qRT-PCR or flow cytometry. Further, we demonstrate that inhibition of PRL-3 using shRNA or a small molecular inhibitor reduced cell migration towards an SDF-1α gradient in the preB-ALL cell lines Reh and MHH-CALL-4...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29422996/melatonin-regulates-cre-dependent-gene-transcription-underlying-osteoblast-proliferation-by-activating-src-and-pka-in-parallel
#20
Lin Tao, Yue Zhu
Several studies have indicated a relationship between melatonin and idiopathic scoliosis, including our previous work which demonstrated that melatonin can inhibit osteoblast proliferation; however, the mechanism remains unclear. Here, we utilized a MTT assay to show that melatonin significantly reduces osteoblast proliferation in a concentration-and time-dependent manner. Through a combination of techniques, including real-time PCR, MTT assays, immunofluorescence, and luciferase assays, we confirmed that melatonin-induced changes in phosphorylated cAMP response element-binding protein (CREB) reduced transcriptional activity in a melatonin receptor-dependent manner...
2018: American Journal of Translational Research
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