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https://www.readbyqxmd.com/read/29222171/tankyrase-inhibition-enhances-the-anti-proliferative-effect-of-pi3k-and-egfr-inhibition-mutually-affecting-%C3%AE-catenin-and-akt-signaling-in-colorectal-cancer
#1
Nina T Solberg, Jo Waaler, Kaja Lund, Line Mygland, Petter A Olsen, Stefan Krauss
Over-activation of the WNT/β-catenin signaling axis is a common denominator in colorectal cancer (CRC). Currently there is no available WNT inhibitor in clinical practice. Although tankyrase inhibitors have been proposed as promising candidates there are many CRC models that do not respond positively to tankyrase inhibition in vitro and in vivo. Therefore, a combinatorial therapeutic approach combining a tankyrase inhibitor (G007-LK) with PI3K (BKM120) and EGFR (Erlotinib) inhibitors in CRC was investigated...
December 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29219946/c1206-a-novel-curcumin-derivative-potently-inhibits-hsp90-and-human-chronic-myeloid-leukemia-cells-in-vitro
#2
Ying-Juan Fan, Yi-Xiang Zhou, Lian-Ru Zhang, Qiao-Fa Lin, Ping-Zhang Gao, Fang Cai, Li-Ping Zhu, Bi Liu, Jian-Hua Xu
4-(4-Pyridinyl methylene) curcumin (C1206) is a new derivative of curcumin that is more active than curcumin in inhibition of heat shock protein 90 (Hsp90) and antitumor action. In this study we investigated the relationship between C1206-induced inhibition of Hsp90 and its anti-leukemic effects. The fluorescence quenching experiments showed that C1206 seemed to bind the middle dimerization domain of Hsp90. The interaction between C1206 and Hsp90 was driven mainly by electrostatic interaction. In in vitro enzyme activity assay, C1206 dose-dependently inhibited Hsp90 ATPase activity with an IC50 value of 4...
December 7, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29216787/mek-inhibitors-under-development-for-treatment-of-non-small-cell-lung-cancer
#3
Chul Kim, Giuseppe Giaccone
The mitogen-activated protein kinase (MAPK) pathway is intimately implicated in the molecular pathogenesis of non-small-cell lung cancer (NSCLC). Aberrant MAPK signaling resulting from the upstream activating mutations converges on mitogen-activated protein kinase kinase 1/2 (MEK1/2), making MEK inhibition an attractive strategy for the treatment of NSCLC. Several MEK inhibitors have demonstrated anticancer activity in patients with NSCLC. Areas covered: In this article, we discuss the biological rationale for the use of MEK inhibitors and summarize the clinical experience with MEK1/2 inhibitors for the treatment of NSCLC, from initial phase I studies to phase II/III studies, both as monotherapy or in combination with other anticancer agents...
December 7, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29215783/polymer-film-dewetting-by-water-surfactant-good-solvent-mixtures-a-mechanistic-insight-and-its-implications-for-the-conservation-of-cultural-heritage
#4
Michele Baglioni, Costanza Montis, David Chelazzi, Rodorico Giorgi, Debora Berti, Piero Baglioni
Aqueous nanostructured fluids (NSFs) have been proposed in the recent past to remove polymer coatings from the surfaces of works of art; this process usually involves film dewetting. Here we report on a major advancement in the study of NSFs cleaning mechanisms using several complementary techniques that are employed to get a mechanistic insight on the interaction of a methacrylic/acrylic copolymer (Paraloid B72®) film laid on glass surfaces and several NSFs, based on two different solvents, i.e. propylene carbonate (PC) and 2-butanone (MEK), and two different surfactants, i...
December 7, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/29215399/hemorrhage-of-liver-and-bone-metastases-as-a-result-of-rapid-response-to-dual-braf-mek-inhibition-in-metastatic-melanoma-a-case-report
#5
Tine Loyson, Emilie Werbrouck, Kevin Punie, Lawrence Bonne, Vincent Vandecaveye, Oliver Bechter
Combination therapy using a BRAF and MEK inhibitor significantly improves both progression-free and overall survival in patients with BRAF V600-mutated stage IV melanoma. Dual MAPK inhibition achieves an objective response in the majority of patients. We present a case of a woman with BRAF V600E-mutated malignant melanoma and rapidly progressing liver, bone, and lymph node metastases. The patient commenced dabrafenib and trametinib with clinical and biochemical signs of response after 2 days. On day 3 she developed grade 3 liver hemorrhage, which was successfully embolized...
December 5, 2017: Melanoma Research
https://www.readbyqxmd.com/read/29214089/systemic-treatment-of-metastatic-conjunctival-melanoma
#6
Simão Pinto Torres, Teresa André, Emanuel Gouveia, Lívio Costa, Maria José Passos
Conjunctival melanoma (CM) is an exceptionally rare tumor, with a propensity for local and distant recurrence, with the lungs, skin, liver, and brain being the most common sites of metastasis. Recent progress in systemic treatments, with checkpoint inhibitors and targeted therapies blocking BRAF and MEK, has redefined the standard of care of advanced unresectable and metastatic melanoma. Although most trials did not include patients with conjunctival melanoma, its close molecular and genetic relationship to cutaneous melanoma might suggest a similar response to these novel agents...
2017: Case Reports in Oncological Medicine
https://www.readbyqxmd.com/read/29213099/apparent-diffusion-coefficient-adc-predicts-therapy-response-in-pancreatic-ductal-adenocarcinoma
#7
M Trajkovic-Arsic, I Heid, K Steiger, A Gupta, A Fingerle, C Wörner, N Teichmann, S Sengkwawoh-Lueong, P Wenzel, A J Beer, I Esposito, R Braren, J T Siveke
Recent advances in molecular subtyping of Pancreatic Ductal Adenocarcinoma (PDAC) support individualization of therapeutic strategies in this most aggressive disease. With the emergence of various novel therapeutic strategies and neoadjuvant approaches in this quickly deteriorating disease, robust approaches for fast evaluation of therapy response are urgently needed. To this aim, we designed a preclinical imaging-guided therapy trial where genetically engineered mice harboring endogenous aggressive PDAC were treated with the MEK targeting drug refametinib, which induces rapid and profound tumor regression in this model system...
December 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29212876/egr-1-mediates-leptin-induced-ppar%C3%AE-reduction-and-proliferation-of-pulmonary-artery-smooth-muscle-cells
#8
Xinming Xie, Shaojun Li, Yanting Zhu, Lu Liu, Rui Ke, Jian Wang, Xin Yan, Lan Yang, Li Gao, Weijin Zang, Manxiang Li
Loss of peroxisome proliferator-activated receptor γ (PPARγ) has been found to contribute to pulmonary artery smooth muscle cell (PASMC) proliferation and pulmonary arterial remodeling therefore the development of pulmonary hypertension (PH). Yet, the molecular mechanisms underlying PPARγ reduction in PASMC remain poorly understood. Here, we demonstrated that leptin dose- and time-dependently inducued PPARγ down-regulation and proliferation of primary cultured rat PASMC, this was accompanied with the activation of extracellular regulated kinase1/2 (ERK1/2) signaling pathway and subsequent induction of early growth response-1 (Egr-1) expression...
December 6, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29212029/melk-promotes-melanoma-growth-by-stimulating-the-nf-%C3%AE%C2%BAb-pathway
#9
Radoslav Janostiak, Navin Rauniyar, TuKiet T Lam, Jianhong Ou, Lihua J Zhu, Michael R Green, Narendra Wajapeyee
Melanoma accounts for more than 80% of skin cancer-related deaths, and current therapies provide only short-term benefit to patients. Here, we show in melanoma cells that maternal embryonic leucine zipper kinase (MELK) is transcriptionally upregulated by the MAPK pathway via transcription factor E2F1. MELK knockdown or pharmacological inhibition blocked melanoma growth and enhanced the effectiveness of BRAFV600E inhibitor against melanoma cells. To identify mediators of MELK function, we performed stable isotope labeling with amino acids in cell culture (SILAC) and identified 469 proteins that had downregulated phosphorylation after MELK inhibition...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29212027/melanoma-therapeutic-strategies-that-select-against-resistance-by-exploiting-myc-driven-evolutionary-convergence
#10
Katherine R Singleton, Lorin Crawford, Elizabeth Tsui, Haley E Manchester, Ophelia Maertens, Xiaojing Liu, Maria V Liberti, Anniefer N Magpusao, Elizabeth M Stein, Jennifer P Tingley, Dennie T Frederick, Genevieve M Boland, Keith T Flaherty, Shannon J McCall, Clemens Krepler, Katrin Sproesser, Meenhard Herlyn, Drew J Adams, Jason W Locasale, Karen Cichowski, Sayan Mukherjee, Kris C Wood
Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29210103/myelination-and-mtor
#11
REVIEW
Gianluca Figlia, Daniel Gerber, Ueli Suter
Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is metabolically demanding and, consistent with this notion, mTORC1-a signaling hub coordinating cell metabolism-has been implicated as a key signal for myelination. Here, we will discuss metabolic aspects of myelination, illustrate the main metabolic processes regulated by mTORC1, and review advances on the role of mTORC1 in myelination of the central nervous system and the peripheral nervous system...
December 6, 2017: Glia
https://www.readbyqxmd.com/read/29210065/hdac-inhibitors-restore-braf-inhibitor-sensitivity-by-altering-pi3k-and-survival-signalling-in-a-subset-of-melanoma
#12
Stuart J Gallagher, Dilini Gunatilake, Kimberley A Beaumont, Danae M Sharp, Jessamy C Tiffen, Anja Heinemann, Wolfgang Weninger, Nikolas K Haass, James S Wilmott, Jason Madore, Peter M Ferguson, Helen Rizos, Peter Hersey
Mutations in BRAF activate oncogenic MAPK signalling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non-genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signalling. Here we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment...
December 6, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29209639/enhancer-remodeling-regulates-epigenetic-adaptation-and-resistance-to-mek1-2-inhibition-in-triple-negative-breast-cancer
#13
Samantha M Bevill, Jon S Zawistowski, Gary L Johnson
Kinase inhibitors targeting the mitogen/extracellular signal-regulated kinase kinase (MEK)- extracellular signal related kinase (ERK) signaling pathway have limited durability in inhibiting growth of triple-negative breast cancer. We defined genome wide enhancer remodeling following MEK inhibition capable of driving adaptive gene transcription. Targeting positive elongation factor (P-TEFb) transcriptional regulatory complex members can block enhancer remodeling making the response to MEK-ERK inhibition durable...
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29209553/antidyskinetic-treatment-with-mtep-affects-multiple-molecular-pathways-in-the-parkinsonian-striatum
#14
Jing-Ya Lin, Zhen-Guo Liu, Cheng-Long Xie, Lu Song, Ai-Juan Yan
Parkinson's disease is characterized by dopaminergic neuron loss and dopamine (DA) depletion in the striatum. Standard treatment is still focused on the restoration of dopamine with exogenous L-Dopa, which however causes L-Dopa-induced dyskinesia (LID). Several studies have shown that antagonism of the metabotropic glutamate receptor 5 alleviates LID, but the underlying mechanisms have remained unclear. We set out to determine where this alleviation may depend on restoring the equilibrium between the two main striatofugal pathways...
2017: Parkinson's Disease
https://www.readbyqxmd.com/read/29207597/inhibition-of-miro1-disturbs-mitophagy-and-pancreatic-%C3%AE-cell-function-interfering-insulin-release-via-irs-akt-foxo1-in-diabetes
#15
Lingling Chen, Chunyan Liu, Jianfeng Gao, Zhiwen Xie, Lawrence W C Chan, Damien J Keating, Yibin Yang, Jiazhong Sun, Fuling Zhou, Yongchang Wei, Xiuli Men, Sijun Yang
Mitochondrial function is essential to meet metabolic demand of pancreatic beta cells respond to high nutrient stress. Mitophagy is an essential component to normal pancreatic β-cell function and has been associated with β-cell failure in Type 2 diabetes (T2D). Our previous studies have indicated that mitochondrial Rho (Miro) GTPase-mediated mitochondrial dysfunction under high nutrient stress leads to NOD-like receptor 3 (NLRP3)-dependent proinflammatory responses and subsequent insulin resistance. However, the in vivo mechanism by which Miro1 underlies mitophagy has not been identified...
October 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/29207139/cpne1-silencing-inhibits-the-proliferation-invasion-and-migration-of-human-osteosarcoma-cells
#16
Zhenhuan Jiang, Jiannong Jiang, Bizeng Zhao, Huilin Yang, Yunliang Wang, Shang Guo, Youping Deng, Deyi Lu, Tieliang Ma, Hongwei Wang, Jinzhi Wang
Osteosarcoma (OS) is the most common primary malignancy of the bone affecting children and adolescents. Copine 1 (CPNE1) is a highly conserved calcium-dependent phospholipid-binding protein and may function in regulating signal transduction and membrane trafficking. In the present study, we investigated CPNE1 expression in osteosarcoma tissues and cells, and studied the effects of small interfering RNA (siRNA)-targeting CPNE1 on proliferation, metastasis and chemosensitivity of the osteosarcoma cells. The results demonstrated that CPNE1 was highly expressed in the osteosarcoma tissues and cell lines...
December 4, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29206651/novel-therapeutic-strategies-and-targets-in-advanced-uveal-melanoma
#17
Vivian Chua, Andrew E Aplin
PURPOSE OF REVIEW: Currently, there are no U.S. Food and Drug Administration-approved or effective treatment options for advanced-stage uveal melanoma. In this article, we focus on therapeutic targets in pathways/mechanisms associated with common mutations in uveal melanoma. We review the challenges associated with targeting of these pathways and novel treatment strategies. RECENT FINDINGS: Common mutations that promote uveal melanoma initiation and progression include alterations in G protein subunit alpha q/11 (GNAQ/GNA11) and breast cancer gene 1-associated protein 1 (BAP1)...
December 4, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/29204524/distant-intracranial-failure-in-melanoma-brain-metastases-treated-with-stereotactic-radiosurgery-in-the-era-of-immunotherapy-and-targeted-agents
#18
Sahaja Acharya, Mustafaa Mahmood, Daniel Mullen, Deshan Yang, Christina I Tsien, Jiayi Huang, Stephanie M Perkins, Keith Rich, Michael Chicoine, Eric Leuthardt, Joshua Dowling, Gavin Dunn, Jesse Keller, Clifford G Robinson, Christopher Abraham
Purpose: Stereotactic radiosurgery (SRS) in combination with immunotherapy (IMT) or targeted therapy is increasingly being used in the setting of melanoma brain metastases (MBMs). The synergistic properties of combination therapy are not well understood. We compared the distant intracranial failure rates of intact MBMs treated with SRS, SRS + IMT, and SRS + targeted therapy. Methods and materials: Combination therapy was defined as delivery of SRS within 3 months of IMT (anti-CTLA-4 /anti-PD-1 therapy) or targeted therapy (BRAF/MEK inhibitors)...
October 2017: Advances in Radiation Oncology
https://www.readbyqxmd.com/read/29203859/interleukin-13-receptor-alpha-2-cooperates-with-egfrviii-signaling-to-promote-glioblastoma-multiforme
#19
Jennifer P Newman, Grace Y Wang, Kazuhiko Arima, Shou P Guan, Michael R Waters, Webster K Cavenee, Edward Pan, Edita Aliwarga, Siao T Chong, Catherine Y L Kok, Berwini B Endaya, Amyn A Habib, Tomohisa Horibe, Wai H Ng, Ivy A W Ho, Kam M Hui, Tomasz Kordula, Paula Y P Lam
The interleukin-13 receptor alpha2 (IL-13Rα2) is a cancer-associated receptor overexpressed in human glioblastoma multiforme (GBM). This receptor is undetectable in normal brain which makes it a highly suitable target for diagnostic and therapeutic purposes. However, the pathological role of this receptor in GBM remains to be established. Here we report that IL-13Rα2 alone induces invasiveness of human GBM cells without affecting their proliferation. In contrast, in the presence of the mutant EGFR (EGFRvIII), IL-13Rα2 promotes GBM cell proliferation in vitro and in vivo...
December 4, 2017: Nature Communications
https://www.readbyqxmd.com/read/29200156/sustained-response-to-targeted-therapy-in-a-patient-with-disseminated-anaplastic-pleomorphic-xanthoastrocytoma
#20
Nisreen Amayiri, Maisa Swaidan, Maysa Al-Hussaini, Hadeel Halalsheh, Anwar Al-Nassan, Awni Musharbash, Uri Tabori, Cynthia Hawkins, Eric Bouffet
Pleomorphic xanthoastrocytoma is a rare brain tumor with unique high frequency of BRAF V600E mutation which is plausible for targeted therapy. The anaplastic variant has generally worse prognosis. We present an adolescent patient with a disseminated relapse of anaplastic pleomorphic xanthoastrocytoma following surgery, radiotherapy, and chemotherapy. She had a dramatic and prolonged response to a BRAF inhibitor (Dabrafinib) and later to addition of a MEK inhibitor (Trametinib) on tumor progression. With minimal side effects and a good quality of life, the patient is alive more than 2 years after initiation of targeted therapy...
December 1, 2017: Journal of Pediatric Hematology/oncology
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