Micelle formation and growth in salt-free aqueous solutions have been investigated for five cetyltrimethylammonium (CTA) mono- and dichlorobenzoates using small-angle neutron scattering (SANS) and rheological measurements. Manipulation of the chlorine substitution pattern provides an excellent means of tuning micellar morphology and solution properties. Two of the surfactants, CTA 2,6-dichlorobenzoate and CTA 2-chlorobenzoate, form Newtonian aqueous solutions containing roughly spherical micelles below ca. 70 mM. There follows a region with increasing concentration of significant micellar growth to prolate ellipsoids (or rigid, short cylindrical micelles), micellar overlap, and apparent maximum aggregation numbers, 〈n〉's, at ca. 200 and 167 mM (φ = 0.095 and 0.073), respectively. Above these latter concentrations, the SANS Q max values scale as C 1/2, characteristic of an entangled polymer-like micellar network. The three surfactants having chlorine substituents para and/or meta to the counterion's COO- group (namely CTA35ClBz, CTA4ClBz, and CTA34ClBz) form highly viscoelastic aqueous solutions containing entangled wormlike micelles at mM concentrations. For CTA35ClBz, C* is ≤2 mM (φ ≈ 0.001), the micelles have a persistence length of 50 nm, and the solutions are Maxwell fluids at C ≥ 20 mM. The mean micellar contour length, assessed from dynamic rheological measurements analyzed using the formalism of Cates and Granek, reaches a maximum of 10 μm at ca. 15−20 mM. The C-dependences of the network correlation lengths, micellar entanglement lengths, and mean contour lengths, are analyzed to explain the recovery of Newtonian fluid behavior at C ≥ 70 mM.
Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with ‘paradox breaker’ RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein–protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions.
The present study was undertaken to determine in model studies whether currently available acoustic rhinometry instrumentation might be used to analyze the nasal cavity configuration of infants and children. A simple nasal cavity model was constructed using eight Lucite inserts that were placed between standard nosepieces provided by the manufacturer and a 35-cm-long polyvinyl chloride pipe closed at its distal end. To simulate the nasal valve, the inserts were 12 mm in length and had apertures ranging in diameter from 2 to 9 mm. A series of experiments was conducted to evaluate the accuracy with which the acoustic rhinometer measured the size of each insert aperture and the configuration of the model system distal to that aperture. Transmission losses caused errors in the area measurement of the insert aperture and the tube distal to the insert. When the insert aperture was < 6 mm in diameter (0.28 cm2), the aperture area was overestimated by > 10%, whereas the area of the distal tube was underestimated by > 10%. As a result of response lags, the acoustic rhinometer also failed to provide an accurate indication of insert length. Finally, oscillation artifacts caused estimates of the distal pipe area to fluctuate. These three systematic errors are described, and their potential impact on acoustic rhinometry in children is discussed.
Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies. We demonstrate effectiveness of multiple MEKi against diverse BRAF-fusions with novel N-terminal partners, with trametinib being the most potent. However, resistance to MEKi or PLX8394 develops via increased RTK expression causing activation of PI3K/mTOR pathway in BRAF-fusion expressing resistant clones. To circumvent acquired resistance, we show potency of combinatorial targeting with trametinib and everolimus, an mTOR inhibitor (mTORi) against multiple BRAF-fusions. While single-agent mTORi and MEKi PLGG clinical trials are underway, our study provides preclinical rationales for using MEKi and mTORi combinatorial therapy to stave off or prevent emergent drug-resistance in BRAF-fusion driven PLGGs.
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