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https://www.readbyqxmd.com/read/29156606/synthesis-and-in-vitro-cytotoxicity-of-the-4-halogenoanilino-6-bromoquinazolines-and-their-6-4-fluorophenyl-substituted-derivatives-as-potential-inhibitors-of-epidermal-growth-factor-receptor-tyrosine-kinase
#1
Malose Jack Mphahlele, Hugues K Paumo, Yee Siew Choong
Series of the 2-unsubstituted and 2-(4-chlorophenyl)-substituted 4-anilino-6-bromoquinazolines and their 6-(4-fluorophenyl)-substituted derivatives were evaluated for in vitro cytotoxicity against MCF-7 and HeLa cells. The 2-unsubstituted 4-anilino-6-bromoquinazolines lacked activity, whereas most of their 2-(4-chlorophenyl) substituted derivatives were found to exhibit significant cytotoxicity and selectivity against HeLa cells. Replacement of bromine with 4-fluorophenyl group for the 2-unsubstituted 4-anilinoquinazolines resulted in superior activity against HeLa cells compared to Gefitinib...
November 20, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/29155093/histone-acetylation-of-oligodendrocytes-protects-against-white-matter-injury-induced-by-inflammation-and-hypoxia-ischemia-through-activation-of-bdnf-trkb-signaling-pathway-in-neonatal-rats
#2
Jichong Huang, Li Zhang, Yi Qu, Yan Zhou, Jianghu Zhu, Yafei Li, Tingting Zhu, Fengyan Zhao, Jun Tang, Dezhi Mu
The major pathological damage in encephalopathy of prematurity is white matter injury (WMI). Perinatal hypoxic-ischemia (HI) and inflammation are two major risk factors in the development of WMI. To study the cellular and molecular mechanisms of WMI, we set up a WMI model using lipopolysaccharide-sensitized HI injury in 2-day postnatal rats. Immunofluorescence staining was used to measure the expression of acetylated histone H3 (AH3) in oligodendrocytes, the target cells of WMI; the oligodendrocyte protein markers, NG2, O4, MBP, PLP, and MAG, were detected at different developmental stages...
November 16, 2017: Brain Research
https://www.readbyqxmd.com/read/29155039/perinatal-nicotine-exposure-increases-obesity-susceptibility-by-peripheral-leptin-resistance-in-adult-female-rat-offspring
#3
Wan-Xia Zhang, Yin-Ping Li, Jie Fan, Hui-Jian Chen, Gai-Ling Li, Yan-Qiong Ouyang, You-E Yan
Maternal nicotine (NIC) exposure causes overweight, hyperleptinemia and metabolic disorders in adult offspring. Our study aims to explore the underlying mechanism of perinatal NIC exposure increases obesity susceptibility in adult female rat offspring. In our model, we found that adult NIC-exposed females presented higher body weight and subcutaneous and visceral fat mass, as well as larger adipocytes, while no change was found in food intake. Serum profile showed a higher serum glucose, insulin and leptin levels in NIC-exposed females...
November 15, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29154817/cancer-stem-cell-like-population-is-preferentially-suppressed-by-egfr-tkis-in-egfr-mutated-pc-9-tumor-models
#4
Fan Yang, Yang Li, Bin Liu, Jiacong You, Qinghua Zhou
AIMS: Although the epidermal growth factor receptor (EGFR) and Wnt/β-catenin signaling systems synergistically regulate many essential developmental and regenerative processes in lung cancer, the mechanisms of their crosstalk remain poorly defined. Our study aimed to investigate an interaction between EGFR and the β-catenin signal. RESULTS: In this study, we described a potent activation of β-catenin by EGFR, which is dependent of the PtdIns3K/AKT pathway. We found EGF activated β-catenin signaling via phosphorylation of EGFR and AKT in EGFR-mutated PC-9 lung cancer cells...
November 14, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/29154500/structure-activity-studies-of-peptidomimetics-based-on-kinase-inhibitory-region-of-suppressors-of-cytokine-signaling-1
#5
Sara La Manna, Laura Lopez-Sanz, Marilisa Leone, Paola Brandi, Pasqualina Liana Scognamiglio, Giancarlo Morelli, Ettore Novellino, Carmen Gomez-Guerrero, Daniela Marasco
Suppressors of Cytokine Signaling (SOCS) proteins are negative regulators of JAK proteins that are receptor-associated tyrosine kinases, which play key roles in the phosphorylation and subsequent activation of several transcription factors named STATs. Unlike the other SOCS proteins, SOCS1 and 3 show, in the N-terminal portion, a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Drug discovery processes of compounds based on KIR sequence demonstrated promising in functional in vitro and in inflammatory animal models and we recently developed a peptidomimetic called PS5, as lead compound...
November 20, 2017: Biopolymers
https://www.readbyqxmd.com/read/29154090/proliferative-and-metastatic-roles-for-phospholipase-d-in-mouse-models-of-cancer
#6
REVIEW
Eric Roth, Michael A Frohman
Phospholipase D (PLD) activity has been proposed to facilitate multiple steps in cancer progression including growth, metabolism, angiogenesis, and mobility. The canonical enzymes PLD1 and PLD2 enact their diverse effects through hydrolyzing the membrane lipid phosphatidylcholine to generate the second messenger and signaling lipid phosphatidic acid (PA). However, the widespread expression of PLD1 and PLD2 in normal tissues and the additional distinct enzymatic mechanisms through which PA can be generated have produced uncertainty regarding the optimal settings in which PLD inhibition might ameliorate cancer...
November 14, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/29152592/revisiting-the-igf-1r-as-a-breast-cancer-target
#7
Roudy Chiminch Ekyalongo, Douglas Yee
The type I insulin-like growth factor-1 receptor is a well-described target in breast cancer and multiple clinical trials examining insulin-like growth factor-1 receptor have been completed. Unfortunately, monoclonal antibodies and tyrosine kinase inhibitors targeting insulin-like growth factor-1 receptor failed in phase III breast clinical trials for several reasons. First, insulin-like growth factor-1 receptor antibody therapy resulted in hyperglycemia and metabolic syndrome most likely due to disruption of insulin-like growth factor-1 homeostasis and subsequent growth hormone elevation...
2017: NPJ Precis Oncol
https://www.readbyqxmd.com/read/29152075/a-novel-multikinase-inhibitor-r8-exhibits-potent-inhibition-on-cancer-cells-through-both-apoptosis-and-autophagic-cell-death
#8
Yuqiong Xie, Chunchun Li, Yali Huang, Zhenyu Jia, Jiang Cao
Chemotherapy is an important treatment for cancer patients, especially for those with unresectable lesions. Targeted therapy of cancer by specific inhibition of aberrant tyrosine kinase activities in cancer cells with chemically synthesized tyrosine kinase inhibitors (TKIs), shows better responses while less side effects than traditional chemotherapeutic drugs. It is common that cancer cells often exhibit deregulation of several tyrosine kinases simultaneously, multikinase TKIs (MKIs) therefore have greater advantages over single-target TKIs...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29151955/continuation-of-tyrosine-kinase-inhibitor-is-associated-with-survival-benefit-in-nsclc-patients-with-exon-19-deletion-after-solitary-progression
#9
Feifei Na, Jie Zhang, Lei Deng, Xiaojuan Zhou, Lin Zhou, Bingwen Zou, Min Yu, Yanying Li, Jianxin Xue, Yongmei Liu
INTRODUCTION: The benefit and selection criteria of continuing tyrosine kinase inhibitor (TKI) after secondary resistance in non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutation remain largely unknown. This study was designed to investigate the role and predictive factors of TKI continuation in patients with solitary progression. METHODS: We retrospectively analyzed NSCLCs treated with first generation of TKI from June 2009 to October 2014 in our cancer center...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/29151930/overexpression-of-ptk6-predicts-poor-prognosis-in-bladder-cancer-patients
#10
Xue-Lian Xu, Yun-Lin Ye, Zhi-Ming Wu, Qiu-Ming He, Lei Tan, Kang-Hua Xiao, Rui-Yan Wu, Yan Yu, Jia Mai, Zhi-Ling Li, Xiao-Dan Peng, Yun Huang, Xuan Li, Hai-Liang Zhang, Xiao-Feng Zhu, Zi-Ke Qin
Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase and works as an oncogene in various cancers. Recently, PTK6 has been used as a therapeutic target for breast cancer patients in a clinical study. However, the prognostic value of PTK6 in bladder cancer (BC) remains vague. Therefore, we retrieved 3 independent investigations of Oncomine database and found that PTK6 is highly expressed in BC tissues compared with corresponding normal controls. Similar results were also observed in clinical specimens at both mRNA and protein levels...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/29151702/extraordinary-response-of-metastatic-pancreatic-cancer-to-apatinib-after-failed-chemotherapy-a-case-report-and-literature-review
#11
Cheng-Ming Li, Zhi-Chao Liu, You-Ting Bao, Xin-Dong Sun, Lin-Lin Wang
Chemotherapy has limited efficacy in the treatment of advanced and metastatic pancreatic cancer (PC), and has serious side effects. The development of novel effective agents, especially targeted therapy, is essential for patients with PC. We present a 58-year-old Chinese woman initially diagnosed with locally advanced PC. As the disease progressed to Stage IV, the patient was unable to tolerate chemotherapy after the fourth-line treatment. She was then treated with apatinib, a novel and highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 and achieved a progression-free-survival of 7 mo...
November 7, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29151594/adipocytes-sustain-pancreatic-cancer-progression-through-a-non-canonical-wnt-paracrine-network-inducing-ror2-nuclear-shuttling
#12
C Carbone, G Piro, N Gaianigo, F Ligorio, R Santoro, V Merz, F Simionato, C Zecchetto, G Falco, G Conti, P T Kamga, M Krampera, F Di Nicolantonio, L De Franceschi, A Scarpa, G Tortora, D Melisi
BACKGROUND: Solid epidemiological evidences connect obesity with incidence, stage, and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions. METHODS: We studied the role of factors secreted by two adipogenic model systems from primary human Bone Marrow Stromal Cells (hBMSC) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS),RESULTS:We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPO(CM)) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSC(CM)) from two different healthy donors...
November 20, 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/29151359/osimertinib-in-untreated-egfr-mutated-advanced-non-small-cell-lung-cancer
#13
Jean-Charles Soria, Yuichiro Ohe, Johan Vansteenkiste, Thanyanan Reungwetwattana, Busyamas Chewaskulyong, Ki Hyeong Lee, Arunee Dechaphunkul, Fumio Imamura, Naoyuki Nogami, Takayasu Kurata, Isamu Okamoto, Caicun Zhou, Byoung Chul Cho, Ying Cheng, Eun Kyung Cho, Pei Jye Voon, David Planchard, Wu-Chou Su, Jhanelle E Gray, Siow-Ming Lee, Rachel Hodge, Marcelo Marotti, Yuri Rukazenkov, Suresh S Ramalingam
Background Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Methods In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily)...
November 18, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29150249/accuracy-of-the-cobas-egfr-mutation-assay-in-non-small-cell-lung-cancer-compared-with-three-laboratory-developed-tests
#14
Haruhiko Nakamura, Hirotaka Koizumi, Hiroki Sakai, Hiroyuki Kimura, Tomoyuki Miyazawa, Hideki Marushima, Hisashi Saji, Masayuki Takagi
BACKGROUND: The reliability of the cobas EGFR assay to detect epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) as an in vitro diagnostic test was compared with 3 laboratory-developed tests (LDTs). MATERIALS AND METHODS: After screening for EGFR mutations using formalin-fixed-paraffin-embedded NSCLC tissue sections using the cobas EGFR assay, 151 samples were further tested with 3 LDTs; the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PCR) clamp, PCR invader, and Cycleave assays...
October 28, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/29148078/soluble-tam-receptor-tyrosine-kinases-in-rheumatoid-arthritis-correlation-with-disease-activity-and-bone-destruction
#15
Liling Xu, Fanlei Hu, Huaqun Zhu, Xu Liu, Lianjie Shi, Yun Li, Hua Zhong, Su Yin
The TAM receptor tyrosine kinases (TAM RTK) are a subfamily of receptor tyrosine kinases, the role of which in autoimmune diseases such as systemic lupus erythematosus has been well-explored, while their functions in rheumatoid arthritis (RA) remain largely unknown. In this study, we investigated the role of soluble TAM receptor tyrosine kinases (sAxl/sMer/sTyro3) in the patients with RA. 306 RA patients, 100 osteoarthritis (OA) patients and 120 healthy controls (HCs) were enrolled in this study. The serum concentrations of sAxl/sMer/sTyro3 were measured by ELISA, then the associations between sAxl/sMer/sTyro3 levels and clinical features of RA patients were analyzed...
November 17, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/29146750/trpm7-transient-receptor-potential-melastatin-like-7-channel-kinase-controls-calcium-responses-in-arterial-thrombosis-and-stroke-in-mice
#16
Sanjeev K Gotru, Wenchun Chen, Peter Kraft, Isabelle C Becker, Karen Wolf, Simon Stritt, Susanna Zierler, Heike M Hermanns, Deviyani Rao, Anne-Laure Perraud, Carsten Schmitz, René P Zahedi, Peter J Noy, Michael G Tomlinson, Thomas Dandekar, Masayuki Matsushita, Vladimir Chubanov, Thomas Gudermann, Guido Stoll, Bernhard Nieswandt, Attila Braun
OBJECTIVE: TRPM7 (transient receptor potential melastatin-like 7 channel) is a ubiquitously expressed bifunctional protein comprising a transient receptor potential channel segment linked to a cytosolic α-type serine/threonine protein kinase domain. TRPM7 forms a constitutively active Mg(2+) and Ca(2+) permeable channel, which regulates diverse cellular processes in both healthy and diseased conditions, but the physiological role of TRPM7 kinase remains largely unknown. APPROACH AND RESULTS: Here we show that point mutation in TRPM7 kinase domain deleting the kinase activity in mice (Trpm7(R/R) ) causes a marked signaling defect in platelets...
November 16, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29146618/management-of-adverse-events-associated-with-cabozantinib-therapy-in-renal-cell-carcinoma
#17
REVIEW
Manuela Schmidinger, Romano Danesi
Cabozantinib was recently approved for the treatment of advanced renal cell carcinoma (RCC) after treatment with vascular endothelial growth factor (VEGF)-targeted therapy. Cabozantinib is a multikinase inhibitor targeting VEGF receptor (VEGFR) 2, mesenchymal-epithelial transition receptor, and "anexelekto" receptor tyrosine kinase. A 60-mg daily dose led to improved overall survival and progression-free survival (PFS) versus everolimus in advanced RCC patients as a second- or later-line treatment in the METEOR trial...
November 16, 2017: Oncologist
https://www.readbyqxmd.com/read/29146616/therapeutic-potential-of-afatinib-for-cancers-with-erbb2-her2-transmembrane-domain-mutations-g660d-and-v659e
#18
Hiromasa Yamamoto, Shinichi Toyooka, Takashi Ninomiya, Shigemi Matsumoto, Masashi Kanai, Shuta Tomida, Katsuyuki Kiura, Manabu Muto, Ken Suzawa, Patrice Desmeules, Mark G Kris, Bob T Li, Marc Ladanyi
We previously reported on a family with hereditary lung cancer, in which a germline mutation in the transmembrane domain (G660D) of avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2; human epidermal growth factor receptor 2 [HER2]) seemed to be responsible for the cancer predisposition. Although few data are available on treatment, anti-ERBB2 therapeutic agents may be effective for ERBB2-mutant cancers. The familial lung cancer patient in one of the authors' institutes developed bone metastasis with enlarging lung tumors and was treated with the ERBB2 inhibitor afatinib...
November 16, 2017: Oncologist
https://www.readbyqxmd.com/read/29146401/neratinib-after-trastuzumab-based-adjuvant-therapy-in-her2-positive-breast-cancer-extenet-5-year-analysis-of-a-randomised-double-blind-placebo-controlled-phase-3-trial
#19
Miguel Martin, Frankie A Holmes, Bent Ejlertsen, Suzette Delaloge, Beverly Moy, Hiroji Iwata, Gunter von Minckwitz, Stephen K L Chia, Janine Mansi, Carlos H Barrios, Michael Gnant, Zorica Tomašević, Neelima Denduluri, Robert Šeparović, Erhan Gokmen, Anna Bashford, Manuel Ruiz Borrego, Sung-Bae Kim, Erik Hugger Jakobsen, Audrone Ciceniene, Kenichi Inoue, Friedrich Overkamp, Joan B Heijns, Anne C Armstrong, John S Link, Anil Abraham Joy, Richard Bryce, Alvin Wong, Susan Moran, Bin Yao, Feng Xu, Alan Auerbach, Marc Buyse, Arlene Chan
BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry...
November 13, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29146136/identification-of-highly-potent-btk-and-jak3-dual-inhibitors-with-improved-activity-for-the-treatment-of-b-cell-lymphoma
#20
Yang Ge, Changyuan Wang, Shijie Song, Jiaxin Huang, Zhihao Liu, Yongming Li, Qiang Meng, Jianbin Zhang, Jihong Yao, Kexin Liu, Xiaodong Ma, Xiuli Sun
The BTK and JAK3 receptor tyrosine kinases are two validated and therapeutically amenable targets in the treatment of B-cell lymphomas. Here we report the identification of several classes of pyrimidine derivatives as potent BTK and JAK3 dual inhibitors. Among these molecules, approximately two thirds displayed strong inhibitory capacity at less than 10 nM concentration, and four compounds (7e, 7g, 7m and 7n) could significantly inhibit the phosphorylation of BTK and JAK3 enzymes at concentrations lower than 1 nM...
November 13, 2017: European Journal of Medicinal Chemistry
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