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https://www.readbyqxmd.com/read/28634209/genetic-evidence-that-%C3%AE-arrestins-are-dispensable-for-the-initiation-of-%C3%AE-2-adrenergic-receptor-signaling-to-erk
#1
Morgan O'Hayre, Kelsie Eichel, Silvia Avino, Xuefeng Zhao, Dana J Steffen, Xiaodong Feng, Kouki Kawakami, Junken Aoki, Karen Messer, Roger Sunahara, Asuka Inoue, Mark von Zastrow, J Silvio Gutkind
The β2-adrenergic receptor (β2AR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that β-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of β-arrestin 1 (β-arr1) and β-arr2 in β2AR internalization, trafficking, and signaling to ERK. We found that only β-arr2 was essential for β2AR internalization...
June 20, 2017: Science Signaling
https://www.readbyqxmd.com/read/28634084/drug-delivery-to-melanoma-brain-metastases-can-current-challenges-lead-to-new-opportunities
#2
Gautham Gampa, Shruthi Vaidhyanathan, Jann N Sarkaria, William F Elmquist
Melanoma has a high propensity to metastasize to the brain, and patients with melanoma brain metastases (MBM) have an extremely poor prognosis. The recent approval of several molecularly-targeted agents (e.g., BRAF, MEK inhibitors) and biologics (anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies) has brought new hope to patients suffering from this formerly untreatable and lethal disease. Importantly, there have been recent reports of success in some clinical studies examining the efficacy of both targeted agents and immunotherapies that show similar response rates in both brain metastases and extracranial disease...
June 17, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28633868/daidzein-stimulates-osteogenesis-facilitating-proliferation-differentiation-and-antiapoptosis-in-human-osteoblast-like-mg-63-cells-via-estrogen-receptor-dependent-mek-erk-and-pi3k-akt-activation
#3
Xin Jin, Jing Sun, Bo Yu, Yue Wang, Wei Jia Sun, Jing Yang, Su Hui Huang, Wen Li Xie
Daidzein, a natural soy isoflavone, has a structure similar to estradiol and exhibiting bone-sparing effects against osteoporosis. However, the molecular mechanisms of osteogenesis remain unclear. We hypothesized that daidzein stimulates osteogenesis through estrogen receptor (ER)-dependent signal pathways. To test this hypothesis, we investigated the effects of daidzein compared with 17β-estradiol on proliferation, differentiation, and cisplatin-induced apoptosis in human osteoblast-like MG-63 cells containing 2 ER isoforms...
June 2017: Nutrition Research
https://www.readbyqxmd.com/read/28633598/metabolism-of-inhaled-methylethylketone-in-rats
#4
Frédéric Cosnier, Stéphane Grossmann, Hervé Nunge, Céline Brochard, Samuel Muller, Anne-Marie Lambert-Xolin, Sylvie Sebillaud, Benoît Rieger, Aurélie Thomas, Marie-Josèphe Décret, Manuella Burgart, Laurent Gaté, Benoît Cossec, Pierre Campo
Methylethylketone (MEK) is widely used in industry, often in combination with other compounds. Although nontoxic, it can make other chemicals harmful. This study investigates the fate of MEK in rat blood, brain and urine as well as its hepatic metabolism following inhalation over 1 month (at 20, 200 or 1400 ppm). MEK did not significantly accumulate in the organism: blood concentrations were similar after six-hour or 1-month inhalation periods, and brain concentrations only increased slightly after 1 month's exposure...
February 28, 2017: Drug and Chemical Toxicology
https://www.readbyqxmd.com/read/28632938/mek-inhibitors-induce-akt-activation-and-drug-resistance-by-suppressing-negative-feedback-erk-mediated-her2-phosphorylation-at-thr701
#5
Chia-Hung Chen, Te-Chun Hsia, Ming-Hsin Yeh, Tsung-Wei Chen, Yun-Ju Chen, Jung-Tsu Chen, Ya-Ling Wei, Chih-Yen Tu, Wei-Chien Huang
Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2-positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase-dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event...
June 20, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28631187/serine-peptidase-inhibitor-kazal-type-1-spink1-as-novel-downstream-effector-of-the-cadherin-17-%C3%AE-catenin-axis-in-hepatocellular-carcinoma
#6
Felix H Shek, Ruibang Luo, Brian Y H Lam, Wing Kin Sung, Tak-Wah Lam, John M Luk, Ming Sum Leung, Kin Tak Chan, Hector K Wang, Chung Man Chan, Ronnie T Poon, Nikki P Lee
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Previously, we reported that cadherin-17 (CDH17) and its related CDH17/β-catenin axis may be responsible for inducing HCC in a subset of patients exhibiting CDH17 over-expression. Here we aimed at obtaining a better understanding of the CDH17-related HCC biology and to obtain further indications for the design of targeted therapies in CDH17 over-expressing HCC patients. RESULTS: We found that SPINK1 acts as a downstream effector of the CDH17/β-catenin axis in HCC...
June 19, 2017: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/28630054/slc45a2-a-melanoma-antigen-with-high-tumor-selectivity-and-reduced-potential-for-autoimmune-toxicity
#7
Jungsun Park, Amjad H Talukder, Seonah Lim, Kwanghee Kim, Ke Pan, Brenda Melendez, Sherille D Bradley, Kyle Jackson, Jahan S Khalili, Junmei Wang, Caitlin Creasy, Bih-Fang Pan, Scott E Woodman, Chantale Bernatchez, David Hawke, Patrick Hwu, Kyung-Mi Lee, Jason Roszik, Gregory Lizee, Cassian Yee
Cytotoxic T lymphocyte (CTL)-based immunotherapies have had remarkable success at generating objective clinical responses in patients with advanced metastatic melanoma.  Although the melanocyte differentiation antigens (MDAs) MART-1, PMEL, and tyrosinase were among the first melanoma tumor-associated antigens identified and targeted with immunotherapy, expression within normal melanocytes of the eye and inner ear can elicit serious autoimmune side effects, thus limiting their clinical potential as CTL targets...
June 19, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28629514/erythropoietin-mediated-regulation-of-central-respiratory-command
#8
Tommy Seaborn, Céline Caravagna
Erythropoietin (Epo) is a cytokine expressed throughout the body, including in the central nervous system where it can act as a breathing modulator in the central respiratory network. In vitro, Epo allows maintaining the activity of respiratory neurons during acute hypoxia, resulting in inhibition of the hypoxia-induced rhythm depression. In vivo, Epo action on the central respiratory command results in enhancement of the acute hypoxic ventilatory response, allowing a better oxygenation of the body by improvement of gases exchanges in the lungs...
2017: Vitamins and Hormones
https://www.readbyqxmd.com/read/28629184/determination-of-structural-requirements-of-n-substituted-tetrahydro-%C3%AE-carboline-imidazolium-salt-derivatives-using-in-silico-approaches-for-designing-mek-1-inhibitors
#9
Jingwei Liang, Mingyang Wang, Xinyang Li, Xin He, Chong Cao, Fanhao Meng
Novel N-substituted tetrahydro-β-carboline imidazolium salt derivatives proved to have potent antitumor activity in past research. The Topomer CoMFA and CoMSIA function in Sybyl-X 2.0 software was applied for the identification of important features of N-substituted tetrahydro-β-carboline-imidazolium salt derivative moieties. In the case of Topomer CoMFA, all the compounds were split into two fragments which were used to generate a 3D invariant representation, the statistical results of the Topomer CoMFA model: q² value of 0...
June 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28628649/insights-into-the-binding-mode-of-mek-type-iii-inhibitors-a-step-towards-discovering-and-designing-allosteric-kinase-inhibitors-across-the-human-kinome
#10
Zheng Zhao, Lei Xie, Philip E Bourne
Protein kinases are critical drug targets for treating a large variety of human diseases. Type-III kinase inhibitors have attracted increasing attention as highly selective therapeutics. Thus, understanding the binding mechanism of existing type-III kinase inhibitors provides useful insights into designing new type-III kinase inhibitors. In this work, we have systematically studied the binding mode of MEK-targeted type-III inhibitors using structural systems pharmacology and molecular dynamics simulation. Our studies provide detailed sequence, structure, interaction-fingerprint, pharmacophore and binding-site information on the binding characteristics of MEK type-III kinase inhibitors...
2017: PloS One
https://www.readbyqxmd.com/read/28627617/sorafenib-controls-the-epithelial%C3%A2-mesenchymal-transition-of-ovarian-cancer-cells-via-egf-and-the-cd44%C3%A2-ha-signaling-pathway-in-a-cell-type%C3%A2-dependent-manner
#11
Ga Bin Park, Hyun-Suk Ko, Daejin Kim
Cluster of differentiation (CD) 44 and epidermal growth factor (EGF) are closely involved in cellular migration and have been used as stem cell markers. Although the hyaluronan (HA)‑binding CD44 is responsible for enhanced cellular motility, the mechanism underlying its actions in various cell types and clinical conditions have yet to be elucidated. In the present study, the multikinase inhibitor sorafenib was used to investigate the diverse effects of EGF stimulation on epithelial‑mesenchymal transition (EMT) in ovarian cancer cells using immunoblotting and reverse transcription‑polymerase chain reaction...
June 14, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28626027/selective-activation-of-epidermal-growth-factor-receptor-in-renal-proximal-tubule-induces-tubulointerstitial-fibrosis
#12
Jessica M Overstreet, Yinqiu Wang, Xin Wang, Aolei Niu, Leslie S Gewin, Bing Yao, Raymond C Harris, Ming-Zhi Zhang
Epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis of diabetic nephropathy and renal fibrosis; however, the causative role of sustained EGFR activation is unclear. Here, we generated a novel kidney fibrotic mouse model of persistent EGFR activation by selectively expressing the EGFR ligand, human heparin-binding EGF-like growth factor (HB-EGF), in renal proximal tubule epithelium. Human HB-EGF expression increased tyrosine kinase phosphorylation of EGFR and the subsequent activation of downstream signaling pathways, including ERK and AKT, as well as the profibrotic TGF-β1/SMAD pathway...
June 16, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28623774/discrepancy-in-braf-status-among-patients-with-metastatic-malignant-melanoma-a-meta-analysis
#13
REVIEW
Antonis Valachis, Gustav J Ullenhag
The incidence of malignant melanoma is growing rapidly. Approximately half of the cases are BRAF mutated, making treatment with kinase inhibitors a (MEK and BRAF inhibitors) preferred choice in the advanced setting. The vast majority of these patients will benefit from the treatment. It is therefore of vital importance that the BRAF analysis is reliable and reflects the true nature of the tumour. Intraindividual tumour BRAF heterogeneity may exist, and changes of BRAF status over time might occur. We reviewed the literature by searching the PubMed database and 630 potentially relevant studies were identified...
June 14, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28622298/tgf%C3%AE-pathway-limits-dedifferentiation-following-wnt-and-mapk-pathway-activation-to-suppress-intestinal-tumourigenesis
#14
Patrizia Cammareri, David F Vincent, Michael C Hodder, Rachel A Ridgway, Claudio Murgia, Max Nobis, Andrew D Campbell, Julia Varga, David J Huels, Chithra Subramani, Katie L H Prescott, Colin Nixon, Ann Hedley, Simon T Barry, Florian R Greten, Gareth J Inman, Owen J Sansom
Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis...
June 16, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28622036/molecular-targeted-drugs-and-treatment-of-colorectal-cancer-recent-progress-and-future-perspectives
#15
Fang Geng, Zheng Wang, Hang Yin, Junxian Yu, Bangwei Cao
Nowadays, colorectal cancer is the fourth most common type of tumor all over the world. When diagnosed, ∼50%-60% of tumors have metastasized, thus resulting in a grim prognosis. Chemotherapy is regarded as standard treatment for patients with colorectal cancer, however, limitations of chemotherapy cannot be ignored, such as low selectivity, insufficient concentrations in tumor tissues, and systemic toxicity. Recently, six targeted drugs have been approved by the U.S. Food and Drug Administration (FDA) for treatment of metastatic colorectal cancer (mCRC), including bevacizumab, aflibercept, regorafenib, cetuximab, and panitumumab...
June 2017: Cancer Biotherapy & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28621502/amniotic-membrane-stimulates-cell-migration-by-modulating-transforming-growth-factor-%C3%AE-signaling
#16
Catalina Ruiz-Cañada, Ángel Bernabé-García, Sergio Liarte, Carmen Luisa Insausti, Diego Angosto, José María Moraleda, Gregorio Castellanos, Francisco José Nicolás
Keratinocyte migration is a mandatory aspect of wound-healing. We have previously shown that Amniotic Membrane (AM) applied to chronic wounds assists healing through a process resulting in overexpression of c-Jun at the wound's leading edge. Also, we have demonstrated that amniotic membrane modifies the genetic program induced by TGF-ß in chronic wounds. In this paper, we used a scratch assay of Mv1Lu and HaCaT cells to examine the influence of AM application on the underlying signaling during scratch closure...
June 16, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/28620810/c-jun-integrates-signals-from-both-mek-erk-and-mkk-jnk-pathways-upon-vaccinia-virus-infection
#17
Flávia G G Leite, Alice A Torres, Leonardo C De Oliveira, André F P Da Cruz, Jamária A P Soares-Martins, Anna C T C Pereira, Giliane S Trindade, Jonatas S Abrahão, Erna G Kroon, Paulo C P Ferreira, Cláudio A Bonjardim
Usurpation of the host's signalling pathways is a common strategy employed by viruses to promote their successful replication. Here we show that infection with the orthopoxvirus vaccinia virus (VACV) leads to sustained stimulation of c-Jun activity during the entire infective cycle. This stimulation is temporally regulated through MEK/ERK or MKK/JNK pathways, i.e. during the early/mid phase (1 to 6 hpi) and in the late phase (9 to 24 hpi) of the infective cycle, respectively. As a transcriptional regulator, upon infection with VACV, c-Jun is translocated from the cytoplasm to the nucleus, where it binds to the AP-1 DNA sequence found at the promoter region of its target genes...
June 15, 2017: Archives of Virology
https://www.readbyqxmd.com/read/28620782/role-of-key-genetic-mutations-on-increasing-migration-of-brain-cancer-cells-through-confinement
#18
Loan Bui, Sayem H Bhuiyan, Alissa Hendrick, Cheng-Jen Chuong, Young-Tae Kim
Uncontrolled invasive cancer cell migration is among the major challenges for the treatment and management of brain cancer. Although the genetic profiles of brain cancer cells have been well characterized, the relationship between the genetic mutations and the cells' mobility has not been clearly understood. In this study, using microfluidic devices that provide a wide range of physical confinements from 20 × 5 μm(2) to 3 × 5 μm(2) in cross sections, we studied the effect of physical confinement on the migratory capacity of cell lines with different types of mutations...
September 2017: Biomedical Microdevices
https://www.readbyqxmd.com/read/28620126/impact-of-phosphoinositide-3-kinase-and-vitamin-d3-nuclear-receptor-single-nucleotide-polymorphisms-on-the-outcome-of-malignant-melanoma-patients
#19
Francesca Morgese, Davide Soldato, Silvia Pagliaretta, Riccardo Giampieri, Donatella Brancorsini, Mariangela Torniai, Silvia Rinaldi, Agnese Savini, Azzurra Onofri, Marina Scarpelli, Rossana Berardi
BACKGROUND: Several studies associating single nucleotide polymorphisms (SNPs) frequencies with tumors outcome have been conducted, nevertheless malignant melanoma literature data are inconclusive.Therefore we evaluate the impact of different genotypes for phosphoinositide-3-kinase (PI3K) and vitamin D3 nuclear receptor (VDR) SNPs on melanoma patients' outcome. MATERIALS AND METHODS: Genomic DNA of 88 patients was extracted from blood and tumor samples. SNPs were determined by PCR using TaqMan assays...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28619758/co-targeting-of-mek-and-pdgfr-stat3-pathways-to-treat-pancreaticductal-adenocarcinoma
#20
Nisebita Sahu, Emily Chan, Felix Chu, Thinh Pham, Hartmut Koeppen, William Forrest, Mark Merchant, Jeff Settleman
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human diseases and remains largely refractory to available drug treatments.  Insufficient targeting of the known oncogenic drivers and activation of compensatory feedback loops and inability to prevent metastatic spread contribute to poor prognosis for this disease. The KRAS-driven MEK pathway is mutationally activated in most pancreatic cancers and is an important target for therapeutics. Using a 2-dimensional monolayer culture system as well as 3-dimensional spheroid culture system, we conducted a screen of a large panel of anti-cancer agents, and found that MEK inhibitors were most effective in targeting PDAC spheroids in comparison to monolayer cultures...
June 15, 2017: Molecular Cancer Therapeutics
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