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https://www.readbyqxmd.com/read/27903457/glass-forming-ability-of-compounds-in-marketed-amorphous-drug-products
#1
Nicole Wyttenbach, Martin Kuentz
This note is about the glass-forming ability (GFA) of drugs marketed as amorphous solid dispersions or as pure amorphous compounds. A thermoanalytical method was complemented with an in silico study, which made use of molecular properties that were identified earlier as being relevant for GFA. Thus, molar volume together with effective numbers of torsional bonds and hydrogen bonding were used to map drugs that are as amorphous products on the market either as solid dispersion of without co-processed carrier as amorphous drug in a solid dosage form...
November 27, 2016: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/27900869/-evaluation-of-five-years-of-treatment-of-erdheim-chester-disease-with-anakinra-case-report-and-overview-of-literature
#2
Zdeněk Adam, Hana Petrášová, Zdeněk Řehák, Renata Koukalová, Marta Krejčí, Luděk Pour, Eva Vetešníková, Aleš Čermák, Sabina Ševčíková, Petr Szturz, Zdeněk Král, Jiří Mayer
: Erdheim-Chester disease is a histiocytic neoplasm of diseases from the group of non-Langerhans-cell histiocytoses, formed by infiltrates of foamy histiocytes. These pathological histiocytes produce pro-inflammatory cytokines. Therefore Erdheim-Chester disease is called inflammatory histiocytary neoplasm. The disease is accompanied by clinical symptoms of systemic inflammatory response, i.e. B symptoms. Imaging examinations detect typical osteosclerotic changes affecting diaphyses and metaphyses of the lower long bones and fibrotic changes which affect the aorta wall and the vessels leading from it...
2016: Vnitr̆ní Lékar̆ství
https://www.readbyqxmd.com/read/27895032/molecular-pathways-receptor-ectodomain-shedding-in-treatment-resistance-and-monitoring-of-cancer
#3
Miles A Miller, Ryan J Sullivan, Douglas A Lauffenburger
Proteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently over-expressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL-6R; the Notch receptors; type-I and -III TGF-β receptors; receptor tyrosine kinases (RTKs) such as HER2, HER4, and VEGFR2; and in particular, MET and TAM-family RTKs AXL and Mer (MerTK)...
November 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27889325/-langerhans-cell-histiocytosis-and-erdheim-chester-disease-a-continuity
#4
S Parreau, J Haroche, I Pommepuy, J F Emile, J C Bourras, F Archambeaud
INTRODUCTION: Erdheim-Chester disease and langerhans cell histiocytosis are two rare diseases separate on clinical, radiological and histological aspects. However, several cases involving both entities have been described. OBSERVATION: A 70-year-old man had a central diabetes insipidus, xanthelasmas, retroperitoneal fibrosis and osteosclerosis of the legs suggestive of Erdheim-Chester disease. Bone biopsy showed langerhans cell histiocytosis CD1a positive with the presence of BRAF V600E mutation...
November 23, 2016: La Revue de Médecine Interne
https://www.readbyqxmd.com/read/27883956/efficacy-of-braf-inhibitors-in-asian-metastatic-melanoma-patients-potential-implications-of-genomic-sequencing-in-braf-mutated-melanoma
#5
Hee Kyung Kim, Sunyoung Lee, Kyung Kim, Mi Hwa Heo, Hansang Lee, Jinhyun Cho, Nayoung K D Kim, Woongyang Park, Su Jin Lee, Jung Han Kim, Kee-Taek Jang, Sang-Hee Choi, Jeeyun Lee
BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib are currently the standard treatment for metastatic melanoma with BRAF V600 mutations. However, given the rarity of noncutaneous melanoma, including acral and mucosal subtypes, the efficacy of BRAF inhibitors for this subset of patients has not been extensively investigated. Acquired resistance generally appears 6 to 8 months after treatment with a BRAF inhibitor, and the mechanism of resistance is not well established. METHODS: We examined treatment outcomes for patients diagnosed with metastatic melanoma and treated with BRAF inhibitors at Samsung Medical Center between April 2013 and December 2015...
November 21, 2016: Translational Oncology
https://www.readbyqxmd.com/read/27873735/long-term-survival-of-a-patient-with-metastatic-melanoma-treated-with-nivolumab-and-vemurafenib-with-the-development-of-vitiligo
#6
Takeshi Fukumoto, Susumu Fujiwara, Masanobu Sakaguchi, Masahiro Oka, Naomi Kiyota, Yasuo Ejima, Koichi Nakajima, Chikako Nishigori
No abstract text is available yet for this article.
November 21, 2016: European Journal of Dermatology: EJD
https://www.readbyqxmd.com/read/27870838/a-computationally-engineered-ras-rheostat-reveals-ras-erk-signaling-dynamics
#7
John C Rose, Po-Ssu Huang, Nathan D Camp, Jordan Ye, Andrew M Leidal, Inna Goreshnik, Bridget M Trevillian, Miles S Dickinson, Daniel Cunningham-Bryant, Jayanta Debnath, David Baker, Alejandro Wolf-Yadlin, Dustin J Maly
Synthetic protein switches controlled with user-defined inputs are powerful tools for studying and controlling dynamic cellular processes. To date, these approaches have relied primarily on intermolecular regulation. Here we report a computationally guided framework for engineering intramolecular regulation of protein function. We utilize this framework to develop chemically inducible activator of RAS (CIAR), a single-component RAS rheostat that directly activates endogenous RAS in response to a small molecule...
November 21, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27861609/exploring-molecular-mechanisms-of-paradoxical-activation-in-the-braf-kinase-dimers-atomistic-simulations-of-conformational-dynamics-and-modeling-of-allosteric-communication-networks-and-signaling-pathways
#8
Amanda Tse, Gennady M Verkhivker
The recent studies have revealed that most BRAF inhibitors can paradoxically induce kinase activation by promoting dimerization and enzyme transactivation. Despite rapidly growing number of structural and functional studies about the BRAF dimer complexes, the molecular basis of paradoxical activation phenomenon is poorly understood and remains largely hypothetical. In this work, we have explored the relationships between inhibitor binding, protein dynamics and allosteric signaling in the BRAF dimers using a network-centric approach...
2016: PloS One
https://www.readbyqxmd.com/read/27861332/systemic-vasculitis-associated-with-vemurafenib-treatment-case-report-and-literature-review
#9
Adrien Mirouse, Léa Savey, Fanny Domont, Cloé Comarmond, Stéphane Barete, Emmanuelle Plaisier, Philippe Rouvier, Patrice Cacoub, David Saadoun
RATIONALE: Vemurafenib, an inhibitor of mutated B-rapidly accelerated fibrosarcoma, is frequently used in the treatment of melanoma and Erdheim-Chester disease (ECD) patients. Inflammatory adverse effects have been increasingly reported after vemurafenib treatment. PATIENT CONCERNS AND DIAGNOSE: We report 6 cases of vemurafenib-associated vasculitis, of whom a personal case of a 75-year-old man with history of ECD who developed purpura and rapidly progressive pauci-immune glomerulonephritis during treatment with vemurafenib...
November 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27861317/development-and-validation-of-a-simultaneous-quantification-method-of-fourteen-tyrosine-kinase-inhibitors-in-human-plasma-using-lc-ms-ms
#10
Huu-Hien Huynh, Claire Pressiat, Hélène Sauvageon, Isabelle Madelaine, Patricia Maslanka, Céleste Lebbé, Catherine Thieblemont, Lauriane Goldwirt, Samia Mourah
BACKGROUND: A sensitive LC-MS/MS method for the analysis in a small volume of plasma of 14 tyrosine kinase inhibitors (TKIs) currently used (imatinib, dasatinib, ibrutinib, ponatinib, trametinib, sunitinib, cobimetinib, dabrafenib, erlotinib, lapatinib, nilotinib, bosutinib, sorafenib, and vemurafenib) has been developed and validated. This multi-analyte LC-MS/MS assay is of interest for anticancer drug combination therapy. METHODS: After a simple protein precipitation of plasma samples, the chromatographic separation was performed using a UPLC system coupled with MS/MS in a positive ionization mode...
November 16, 2016: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/27846237/integrated-genomics-identifies-mir-32-mcl-1-pathway-as-a-critical-driver-of-melanomagenesis-implications-for-mir-replacement-and-combination-therapy
#11
Prasun J Mishra, Pravin J Mishra, Glenn Merlino
AIMS: Cutaneous malignant melanoma is among the deadliest human cancers, broadly resistant to most clinical therapies. A majority of patients with BRAFV600E melanomas respond well to inhibitors such as vemurafenib, but all ultimately relapse. Moreover, there are no viable treatment options available for other non-BRAF melanoma subtypes in the clinic. A key to improving treatment options lies in a better understanding of mechanisms underlying melanoma progression, which are complex and heterogeneous...
2016: PloS One
https://www.readbyqxmd.com/read/27842767/drug-hepatotoxicity-newer-agents
#12
REVIEW
Chalermrat Bunchorntavakul, K Rajender Reddy
Idiosyncratic hepatotoxicity is one of the most common reasons for an approved drug being restricted. This article focuses on hepatotoxicity of selected and recently introduced agents, such as, tyrosine kinase inhibitors, monoclonal antibodies, novel oral anticoagulants, newer antiplatelets, antibiotics, anti-diabetics, anti-epileptics, anti-depressants, anti-psychotics and anti-retrovirals. Overall, the incidence of clinically relevant hepatotoxicity from newer agents seems to be lower than that of the older agents...
February 2017: Clinics in Liver Disease
https://www.readbyqxmd.com/read/27835901/mutational-activation-of-braf-confers-sensitivity-to-transforming-growth-factor-beta-inhibitors-in-human-cancer-cells
#13
Lindsay C Spender, G John Ferguson, Sijia Liu, Chao Cui, Maria Romina Girotti, Gary Sibbet, Ellen B Higgs, Morven K Shuttleworth, Tom Hamilton, Paul Lorigan, Michael Weller, David F Vincent, Owen J Sansom, Margaret Frame, Peter Ten Dijke, Richard Marais, Gareth J Inman
Recent data implicate elevated transforming growth factor-β (TGFβ) signalling in BRAF inhibitor drug-resistance mechanisms, but the potential for targeting TGFβ signalling in cases of advanced melanoma has not been investigated. We show that mutant BRAFV600E confers an intrinsic dependence on TGFβ/TGFβ receptor 1 (TGFBR1) signalling for clonogenicity of murine melanocytes. Pharmacological inhibition of the TGFBR1 blocked the clonogenicity of human mutant BRAF melanoma cells through SMAD4-independent inhibition of mitosis, and also inhibited metastasis in xenografted zebrafish...
November 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/27834212/preclinical-efficacy-of-a-raf-inhibitor-that-evades-paradoxical-mapk-pathway-activation-in-protein-kinase-braf-mutant-lung-cancer
#14
Ross A Okimoto, Luping Lin, Victor Olivas, Elton Chan, Evan Markegard, Andrey Rymar, Dana Neel, Xiao Chen, Golzar Hemmati, Gideon Bollag, Trever G Bivona
Oncogenic activation of protein kinase BRAF drives tumor growth by promoting mitogen-activated protein kinase (MAPK) pathway signaling. Because oncogenic mutations in BRAF occur in ∼2-7% of lung adenocarcinoma (LA), BRAF-mutant LA is the most frequent cause of BRAF-mutant cancer mortality worldwide. Whereas most tumor types harbor predominantly the BRAF(V600E)-mutant allele, the spectrum of BRAF mutations in LA includes BRAF(V600E) (∼60% of cases) and non-V600E mutant alleles (∼40% of cases) such as BRAF(G469A) and BRAF(G466V) The presence of BRAF(V600E) in LA has prompted clinical trials testing selective BRAF inhibitors such as vemurafenib in BRAF(V600E)-mutant patients...
November 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27822406/pd-1-inhibition-and-treatment-of-advanced-melanoma-role-of-pembrolizumab
#15
REVIEW
Ali R Jazirehi, Alexandra Lim, Tam Dinh
Remarkable clinical responses have been seen in patients with metastatic melanoma with targeted therapy (BRAFi vemurafenib, MEKi) and with modern immune cell-based approaches such as TCR engineered adoptive cell transfer (ACT) and earlier experiences with high-dose IL-2. The proximal mediators of these immune therapies are tumor-reactive CTL. Various mechanisms of resistance to immune-mediated apoptotic signals have been described, including phenotypic changes, effector cell exhaustion, functional tolerance, deficiencies in Ag processing and presentation, and mutation or down-regulation of antigenic epitopes...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27813079/the-plasma-membrane-ca-2-pump-pmca4b-inhibits-the-migratory-and-metastatic-activity-of-braf-mutant-melanoma-cells
#16
L Hegedus, T Garay, E Molnar, K Varga, A Bilecz, S Torok, R Padanyi, K Paszty, M Wolf, M Grusch, E Kallay, B Dome, W Berger, B Hegedus, A Enyedi
Oncogenic mutations of BRAF lead to constitutive ERK activity that supports melanoma cell growth and survival. While Ca(2+) signaling is a well-known regulator of tumor progression, the crosstalk between Ca(2+) signaling and the Ras-BRAF-MEK-ERK pathway is much less explored. Here we show that in BRAF mutant melanoma cells the abundance of the plasma membrane Ca(2+) ATPase isoform 4b (PMCA4b, ATP2B4) is low at baseline but markedly elevated by treatment with the mutant BRAF specific inhibitor vemurafenib. In line with these findings gene expression microarray data also shows decreased PMCA4b expression in cutaneous melanoma when compared to benign nevi...
November 4, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27797970/molecular-pathways-maintaining-mapk-inhibitor-sensitivity-by-targeting-nonmutational-tolerance
#17
Michael P Smith, Claudia Wellbrock
Targeting hyperactive MAPK signaling has proven to be an effective treatment for a variety of different cancers. Responses to the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitors trametinib and cobimetinib are, however, transient, and complete remission is rarely observed; rather, outgrowth of resistant clones within progressed tumors appears inevitable. These resistant tumors display great heterogeneity, which poses a major challenge to any salvage therapy. Recent focus has, therefore, been on the early dynamics of inhibitor response during tumor regression...
October 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27781490/dabrafenib-in-brafv600-mutated-anaplastic-pleomorphic-xanthoastrocytoma
#18
Nicholas F Brown, Thomas Carter, Paul Mulholland
Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor. Anaplastic features are found in 20-30% of cases of PXA and are associated with poor outcomes. Typical treatment is with gross total resection, followed by radiation therapy and cytotoxic chemotherapy at relapse. BRAFV600 mutations have been identified in 38-60% of patients with PXA. Several case reports and small case series have identified clinical benefit with BRAF inhibition in patients with BRAFV600-mutated PXA. We report the second published case of successful treatment with the BRAF inhibitor dabrafenib in a female patient with relapsed anaplastic PXA with a BRAFV600 mutation, and the first published case of dabrafinib treatment following intolerance to vemurafenib...
October 26, 2016: CNS Oncology
https://www.readbyqxmd.com/read/27776286/inventory-of-oral-anticancer-agents-pharmaceutical-formulation-aspects-with-focus-on-the-solid-dispersion-technique
#19
E Sawicki, J H M Schellens, J H Beijnen, B Nuijen
Dissolution from the pharmaceutical formulation is a prerequisite for complete and consistent absorption of any orally administered drug, including anticancer agents (oncolytics). Poor dissolution of an oncolytic can result in low oral bioavailability, high variability in blood concentrations and with that suboptimal or even failing therapy. This review discusses pharmaceutical formulation aspects and absorption pharmacokinetics of currently licensed orally administered oncolytics. In nearly half of orally dosed oncolytics poor dissolution is likely to play a major role in low and unpredictable absorption...
September 20, 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/27765851/the-braf-inhibitor-vemurafenib-activates-mitochondrial-metabolism-and-inhibits-hyperpolarized-pyruvate-lactate-exchange-in-braf-mutant-human-melanoma-cells
#20
Teresa Delgado-Goni, Maria Falck Miniotis, Slawomir Wantuch, Harold G Parkes, Richard Marais, Paul Workman, Martin O Leach, Mounia Beloueche-Babari
Understanding the impact of BRAF signaling inhibition in human melanoma on key disease mechanisms is important for developing biomarkers of therapeutic response and combination strategies to improve long-term disease control. This work investigates the downstream metabolic consequences of BRAF inhibition with vemurafenib, the molecular and biochemical processes that underpin them, their significance for antineoplastic activity, and potential as noninvasive imaging response biomarkers. (1)H NMR spectroscopy showed that vemurafenib decreases the glycolytic activity of BRAF-mutant (WM266...
December 2016: Molecular Cancer Therapeutics
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