232 research outputs found
The Broad Stroke of Hsp90 Inhibitors: Painting over the RAF Inhibitor Paradox.
The novel Hsp90 inhibitor XL888 is undergoing clinical investigation for use in conjunction with the rapidly accelerated fibrosarcoma (RAF) kinase inhibitor vemurafenib to treat unresectable melanoma. The addition of XL888 to current regimens may serve an additional purpose by blocking the RAF inhibitor paradox. Such activity could reduce adverse events in patients and provide a biomarker for the successful inhibition of Hsp90 target proteins
Is there an alternative explanation to post-MI emergence of mitral regurgitation; a CMR-LGE observational study
Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas
FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K-mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox-breaking RAF inhibitor (PLX8394) has been designed. Here, we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenibresistant BRAF splice variant-expressing tumors and reduced splice variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test the efficacy of therapeutic agents. © 2017 American Association for Cancer Research
Characteristics and outcomes of trauma patients with ICU lengths of stay 30 days and greater: a seven-year retrospective study
Mitral regurgitation recovery and atrial reverse remodeling following pulmonary vein isolation procedure in patients with atrial fibrillation: a proof of concept cardiac MRI study
Can increasing the number of excitations (NEX) in late gadolinium enhancement (LGE) imaging prove beneficial in patients who can not hold their breath for the duration of the scan time?
Correction to: Microbial communities associated with distance- and density-dependent seedling mortality in a tropical rainforest (Plant Ecology, (2020), 221, 1, (41-54), 10.1007/s11258-019-00989-y)
© 2020, Springer Nature B.V. The article entitled âMicrobial communities associated with distance- and density-dependent seedling mortality in a tropical rainforestâ, which is part of the special issue on âApplying microbial communities to improve restoration and conservation outcomesâ was published prematurely in Volume 221, Issue 1, January 2020
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