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https://www.readbyqxmd.com/read/29050517/the-safety-and-efficacy-of-dabrafenib-and-trametinib-for-the-treatment-of-melanoma
#1
Sarah Knispel, Lisa Zimmer, Theodora Kanaki, Selma Ugurel, Dirk Schadendorf, Elisabeth Livingstone
The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment. Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings...
October 20, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/29050218/braf-mek-inhibitors-promote-cd47-expression-that-is-reversible-by-erk-inhibition-in-melanoma
#2
Fen Liu, Chen Chen Jiang, Xu Guang Yan, Hsin-Yi Tseng, Chun Yan Wang, Yuan Yuan Zhang, Hamed Yari, Ting La, Margaret Farrelly, Su Tang Guo, Rick F Thorne, Lei Jin, Qi Wang, Xu Dong Zhang
The expression of CD47 on the cancer cell surface transmits "don't eat me" signalling that not only inhibits phagocytosis of cancer cells by phagocytes but also impairs anti-cancer T cell responses. Here we report that oncogenic activation of ERK plays an important role in transcriptional activation of CD47 through nuclear respiratory factor 1 (NRF-1) in melanoma cells. Treatment with BRAF/MEK inhibitors upregulated CD47 in cultured melanoma cells and fresh melanoma isolates. Similarly, melanoma cells selected for resistance to the BRAF inhibitor vemurafenib expressed higher levels of CD47...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29050198/mtorc1-autophagy-regulated-mertk-in-mutant-brafv600-melanoma-with-acquired-resistance-to-braf-inhibition
#3
Gongda Xue, Reto Kohler, Fengyuan Tang, Debby Hynx, Yuhua Wang, Francesca Orso, Vincent Prêtre, Reto Ritschard, Petra Hirschmann, Peter Cron, Tim Roloff, Reinhard Dummer, Mario Mandalà, Sandrine Bichet, Christel Genoud, Alexandra G Meyer, Manuele G Muraro, Giulio C Spagnoli, Daniela Taverna, Curzio Rüegg, Taha Merghoub, Daniela Massi, Huifang Tang, Mitchell P Levesque, Stephan Dirnhofer, Alfred Zippelius, Brian A Hemmings, Andreas Wicki
BRAF inhibitors (BRAFi) and the combination therapy of BRAF and MEK inhibitors (MEKi) were recently approved for therapy of metastatic melanomas harbouring the oncogenic BRAFV600 mutation. Although these therapies have shown pronounced therapeutic efficacy, the limited durability of the response indicates an acquired drug resistance that still remains mechanistically poorly understood at the molecular level. We conducted transcriptome gene profiling in BRAFi-treated melanoma cells and identified that Mer tyrosine kinase (MerTK) is specifically upregulated...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29048617/mek-inhibitor-pd98059-promotes-breast-cancer-cell-migration-by-inducing-%C3%AE-catenin-nuclear-accumulation
#4
Ying Zhao, Chao-Chao Ge, Jun Wang, Xiao-Xiao Wu, Xiao-Min Li, Wei Li, Sha-Sha Wang, Tong Liu, Jiu-Zhou Hou, Hua Sun, Dong Fang, Song-Qiang Xie
Abnormal activation of the RAF/MEK/ERK signaling pathway has been observed in breast cancer. Thus, a number of MEK inhibitors have been designed as one treatment option for breast cancer. Although some studies have found that these MEK inhibitors inhibit the growth of a variety of human cancer cells, some trials have shown that the use of MEK inhibitors as a treatment for breast cancer does not adequately improve survival for unknown reasons. In the present study, MEK inhibitor PD98059 was used to evaluate its anticancer effects on human breast cancer MCF-7 and MDA-MB-231 cells and to explore the possible mechanism of action...
September 13, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29048431/hspb1-facilitates-erk-mediated-phosphorylation-and-degradation-of-bim-to-attenuate-endoplasmic-reticulum-stress-induced-apoptosis
#5
Donna Kennedy, Katarzyna Mnich, Deepu Oommen, Reka Chakravarthy, Leonardo Almeida-Souza, Michiel Krols, Svetlana Saveljeva, Karen Doyle, Sanjeev Gupta, Vincent Timmerman, Sophie Janssens, Adrienne M Gorman, Afshin Samali
BIM, a pro-apoptotic BH3-only protein, is a key regulator of the intrinsic (or mitochondrial) apoptosis pathway. Here, we show that BIM induction by endoplasmic reticulum (ER) stress is suppressed in rat PC12 cells overexpressing heat shock protein B1 (HSPB1 or HSP27) and that this is due to enhanced proteasomal degradation of BIM. HSPB1 and BIM form a complex that immunoprecipitates with p-ERK1/2. We found that HSPB1-mediated proteasomal degradation of BIM is dependent on MEK-ERK signaling. Other studies have shown that several missense mutations in HSPB1 cause the peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease, which is associated with nerve degeneration...
August 31, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29046298/identification-of-dual-mechanisms-mediating-5-hydroxytryptamine-receptor-1f-induced-mitochondrial-biogenesis
#6
Whitney S Gibbs, Sara M Garrett, Craig C Beeson, Rick G Schnellmann
Our laboratory recently made the novel observation that 5-hydroxytryptamine 1F (5-HT1F) receptor activation induces mitochondrial biogenesis (MB), the production of new, functional mitochondria, in vitro and vivo. We sought to determine the mechanism linking the 5-HT1F receptor to MB in renal proximal tubule cells. Using LY344864, a selective 5-HT1F receptor agonist, we determined that the 5-HT1F receptor is coupled to Gαi/o and induces MB through Gβγ dependent activation of Akt, endothelial nitric oxide (eNOS), cyclic guanosine-monophosphate (cGMP), protein kinase G (PKG) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)...
October 18, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29045061/suppression-of-mapk-signaling-in-braf-activated-pten-deficient-melanoma-by-blocking-%C3%AE-catenin-signaling-in-cancer-associated-fibroblasts
#7
Linli Zhou, Kun Yang, Spencer Dunaway, Zalfa Abdel-Malek, Thomas Andl, Ana Luisa Kadekaro, Yuhang Zhang
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment have been associated with formation of a dynamic and optimized niche for tumor cells to grow and evade cell death induced by therapeutic agents. We recently reported that ablation of β-catenin expression in stromal fibroblasts and CAFs disrupted their biological activities in in vitro studies and in an in vivo B16F10 mouse melanoma model. Here, we show that the development of a BRAF-activated PTEN-deficient mouse melanoma was significantly suppressed in vivo after blocking β-catenin signaling in CAFs...
October 17, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29043551/magi-1-expression-is-decreased-in-several-types-of-human-t-cell-leukemia-cell-lines-including-adult-t-cell-leukemia
#8
Takashi Kozakai, Masahiko Takahashi, Masaya Higuchi, Toshifumi Hara, Kousuke Saito, Yuetsu Tanaka, Masayoshi Masuko, Jun Takizawa, Hirohito Sone, Masahiro Fujii
Membrane-associated guanylate kinase with inverted orientation protein 1 (MAGI-1) is a cytoplasmic scaffold protein that interacts with various signaling molecules; it negatively controls the cell growth of various types of cells and positively controls cell-cell interaction. In T cells, MAGI-1 has been shown to inhibit Akt activity through its interaction with PTEN and MEK1. In this study we found that MAGI-1 expression is decreased in multiple (9 out of 15) human T-cell leukemia cell lines, including adult T-cell leukemia (ATL), T-cell acute lymphoblastic leukemia and chronic T-cell lymphocytic leukemia...
October 17, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/29042989/microrna-22-may-promote-apoptosis-and-inhibit-the-proliferation-of-hypertrophic-scar-fibroblasts-by-regulating-the-mitogen-activated-protein-kinase-kinase-extracellular-signal-regulated-kinase-p21-pathway
#9
Shihua Dong, Yanfeng Sun
Hypertrophic scarring (HS) is a common skin disorder that occurs during the wound healing process, and the pathogenesis of HS remains unclear. Increasing evidence indicated that specific microRNAs (miRs) may be involved in the onset and progression of HS. In the present study, the association between miR-22 and HS was investigated. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to examine the expression of miR-22 in 30 HS and matched normal skin tissues. In addition, human hypertrophic scar fibroblasts (HSFBs) were cultured and transfected with miR-22 mimics, and MTT and Annexin V apoptosis assays were performed to investigate the role of miR-22 in the proliferation and apoptosis of the human HSFBs...
October 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29040023/dramatic-clinical-and-radiographic-response-to-braf-inhibition-in-a-patient-with-progressive-disseminated-optic-pathway-glioma-refractory-to-mek-inhibition
#10
Abhishek Bavle, Jeremy Jones, Frank Y Lin, Amy Malphrus, Adekunle Adesina, Jack Su
While clinical and radiographic responses to agents targeting the mitogen-activated protein kinases (MAPK) pathway have been repor-ted in pediatric low-grade gliomas (LGG), early phase trials indicate refractoriness to these medications in some of these patients. We report a patient with disseminated LGG with the BRAFV600E mutation, which was refractory to selumetinib, a MEK inhibitor, but subsequently showed immediate clinical and radiographic response to dabrafenib, a BRAF inhibitor, with sustained effect for 9 months prior to clinical progression...
October 17, 2017: Pediatric Hematology and Oncology
https://www.readbyqxmd.com/read/29039603/blockade-of-%C3%AE-7-nicotinic-acetylcholine-receptors-inhibit-nicotine-induced-tumor-growth-and-vimentin-expression-in-non-small-cell-lung-cancer-through-mek-erk-signaling-way
#11
Chun Zhang, Ping Yu, Liang Zhu, Qingnan Zhao, Xiaotong Lu, Shuhong Bo
Nicotine can stimulate the progression of non-small cell lung cancer (NSCLC) through nicotinic acetylcholine receptors (nAChRs). The persistent proliferation of cancer cells is one of the key effects of nicotinic signaling. The present study aimed to clarify the mechanism of nicotine-induced proliferation in NSCLCs at the receptor subtype level. We have previously reported that there are various subtypes of nicotinic receptors expressed in NSCLC cell lines. In the present study, we demonstrated that blocking α7nAChRs agonized by nicotine could suppress the proliferation of H1299 cells in vitro and decrease H1299 tumor xenograft growth in nude mice...
October 2, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29038361/tumor-necrosis-factor-%C3%AE-decreases-aquaporin-3-expression-in-intestinal-epithelial-cells-through-inhibition-of-constitutive-transcription
#12
Michael A Peplowski, Andrew J Vegso, Vadim Iablokov, Michael Dicay, Raza S Zaheer, Bernard Renaux, David Proud, Morley D Hollenberg, Paul L Beck, Wallace K MacNaughton
Inflammatory diseases of the gut are associated with altered electrolyte and water transport, leading to the development of diarrhea. Epithelially expressed aquaporins (AQPs) are downregulated in inflammation, although the mechanisms involved are not known. We hypothesized that AQP3 expression in intestinal epithelial cells is altered in intestinal inflammation and that these changes are driven by tumor necrosis factor (TNF) α Human colonic adenocarcinoma (HT-29) cells were treated with TNFα to investigate signaling mechanisms in vitro...
October 2017: Physiological Reports
https://www.readbyqxmd.com/read/29037868/the-fungal-neurotoxin-penitrem-a-induces-the-production-of-reactive-oxygen-species-in-human-neutrophils-at-submicromolar-concentrations
#13
H F Berntsen, I L Bogen, M B Wigestrand, F Fonnum, S I Walaas, A Moldes-Anaya
Penitrem A is a fungal neurotoxin that recurrently causes intoxication in animals, and occasionally also in humans. We have previously reported that penitrem A induced the production of reactive oxygen species (ROS) in rat cerebellar granule cells, opening for a new mechanism of action for the neurotoxin. The aim of this study was to examine the potential of penitrem A to induce ROS production in isolated human neutrophil granulocytes, and to study possible mechanisms involved. Penitrem A significantly increased the production of ROS in human neutrophils at concentrations as low as 0...
October 13, 2017: Toxicology
https://www.readbyqxmd.com/read/29037608/chemokine-ccl8-and-its-receptor-ccr5-in-the-spinal-cord-are-involved-in-visceral-pain-induced-by-experimental-colitis-in-mice
#14
Ying Lu, Bao-Chun Jiang, De-Li Cao, Lin-Xia Zhao, You-Li Zhang
Visceral hypersensitivity induced by inflammatory bowel disease (IBD) is a clinical challenge since the underlying mechanisms remain elusive. Chemokines and their receptors have been suggested to modulate inflammatory pain and neuropathic pain. However, the exact chemokines involved in visceral pain remain to be determined. Here, we investigated the effects of spinal chemokine CCL8 and its major receptor CCR5 on the development of visceral hyperalgesia. We showed that intracolonic injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice produced significant colonic inflammation and visceral hypersensitivity to colorectal distension...
October 13, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/29035842/derivation-and-characterization-of-integration-free-ipsc-line-isrm-um51-derived-from-six2-positive-renal-cells-isolated-from-urine-of-an-african-male-expressing-the-cyp2d6-4-17-variant-which-confers-intermediate-drug-metabolizing-activity
#15
Martina Bohndorf, Audrey Ncube, Lucas-Sebastian Spitzhorn, Jürgen Enczmann, Wasco Wruck, James Adjaye
SIX2-positive renal cells isolated from urine from a 51year old male of African origin bearing the CYP2D6 *4/*17 variant were reprogrammed by nucleofection of a combination of two episomal-based plasmids omitting pathway (TGFβ, MEK and GSK3β) inhibition. The induced pluripotent stem cells (iPSCs) were characterized by immunocytochemistry, embryoid body formation, DNA-fingerprinting and karyotype analysis. Comparative transcriptome analyses with human embryonic stem cell lines H1 and H9 revealed a Pearson correlation of 0...
October 7, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29032172/lps-enhances-expression-of-cd204-through-the-mapk-erk-pathway-in-murine-bone-marrow-macrophages
#16
Ryota Hashimoto, Ryo Kakigi, Kyoko Nakamura, Seigo Itoh, Hiroyuki Daida, Takao Okada, Youichi Katoh
BACKGROUND AND AIMS: Lipopolysaccharide (LPS) is a main component of the Gram-negative bacterial cell wall and is associated with a greater risk of atherosclerosis development in periodontal disease. LPS has been reported to increase both CD36 and CD204 expression and enhance the uptake of modified low-density lipoprotein (LDL). However, the signaling pathways by which LPS enhances these expression levels and function have not been fully elucidated, although the clarification of these signaling pathways is important for identifying therapeutic targets for atherosclerosis...
October 6, 2017: Atherosclerosis
https://www.readbyqxmd.com/read/29030911/phosphorylated-erk-is-a-potential-prognostic-biomarker-for-sorafenib-response-in-hepatocellular-carcinoma
#17
Yuelong Liang, Jiang Chen, Qingsong Yu, Tong Ji, Bin Zhang, Junjie Xu, Yi Dai, Yangyang Xie, Hui Lin, Xiao Liang, Xiujun Cai
Sorafenib, the only approved drug for hepatocellular carcinoma, acts as a remarkable inhibitor of Raf serine-threonine kinases. However, Sorafenib is expensive, and clinical experience shows that it is not an effective treatment for many patients. Previous study has demonstrated that phosphorylated ERK (pERK) is a key downstream component in the RAF/MEK/ERK signaling pathway. Here, we investigate whether pERK is a useful biomarker for treating HCC with Sorafenib. In vitro cell viability assays showed that the efficacy of Sorafenib was distinctly different according to the level of pERK...
October 13, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/29030545/fructose-1-6-bisphosphate-couples-glycolytic-flux-to-activation-of-ras
#18
Ken Peeters, Frederik Van Leemputte, Baptiste Fischer, Beatriz M Bonini, Hector Quezada, Maksym Tsytlonok, Dorien Haesen, Ward Vanthienen, Nuno Bernardes, Carmen Bravo Gonzalez-Blas, Veerle Janssens, Peter Tompa, Wim Versées, Johan M Thevelein
Yeast and cancer cells share the unusual characteristic of favoring fermentation of sugar over respiration. We now reveal an evolutionary conserved mechanism linking fermentation to activation of Ras, a major regulator of cell proliferation in yeast and mammalian cells, and prime proto-oncogene product. A yeast mutant (tps1∆) with overactive influx of glucose into glycolysis and hyperaccumulation of Fru1,6bisP, shows hyperactivation of Ras, which causes its glucose growth defect by triggering apoptosis. Fru1,6bisP is a potent activator of Ras in permeabilized yeast cells, likely acting through Cdc25...
October 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29029417/anti-tumor-activity-of-anthrax-toxin-variants-that-form-a-functional-translocation-pore-by-intermolecular-complementation
#19
Shihui Liu, Qian Ma, Rasem Fattah, Thomas H Bugge, Stephen H Leppla
Anthrax lethal toxin is a typical A-B type protein toxin secreted by Bacillus anthracis. Lethal factor (LF) is the catalytic A-subunit, a metalloprotease having MEKs as targets. LF relies on the cell-binding B-subunit, protective antigen (PA), to gain entry into the cytosol of target cells. PA binds to cell surface toxin receptors and is activated by furin protease to form an LF-binding-competent oligomer-PA pre-pore, which converts to a functional protein-conductive pore in the acidic endocytic vesicles, allowing translocation of LF into the cytosol...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29026704/therapeutic-inhibitors-against-mutated-braf-and-mek-for-the-treatment-of-metastatic-melanoma
#20
REVIEW
Sunhyo Ryu, Chakyung Youn, Ae Ran Moon, Amanda Howland, Cheryl A Armstrong, Peter I Song
Melanoma is one of the most aggressive cancers in the world and is responsible for the majority of skin cancer deaths. Recent advances in the field of immunotherapy using active, adoptive, and antigen-specific therapeutic approaches, have generated the expectation that these technologies have the potential to improve the treatment of advanced malignancies, including melanoma. Treatment options for metastatic melanoma patients have been dramatically improved by the FDA approval of new therapeutic agents including vemurafenib, dabrafenib, and sorafenib...
September 2017: Chonnam Medical Journal
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