This article describes the results of experiments examining the competition between the polymer diffusion rate and the crosslinking rate in low‐glass‐transition‐temperature, epoxy‐containing latex films in the presence of a diamine. We examined films formed from donor‐ and acceptor‐labeled poly(butyl acrylate‐co‐methyl methacrylate‐co‐glycidyl methacrylate) copolymer latex and studied the influence of several parameters on the growth rate of gel content and the rate of polymer diffusion. These factors include the molecular weight of the latex polymer, the presence or absence of a diamine crosslinking agent, and the cure protocol. The results were compared to the predictions of a recent theory of the competition between crosslinking and polymer diffusion across interfaces. In the initially formed films, polymer diffusion occurs more rapidly than the chemical reaction rate. Therefore, these films fall into the fast‐diffusion category of this model. In our system (unlike in the model), the latex polymer has a broad distribution of molecular weights and a distribution of diffusivities. The shortest chains contribute to the early time diffusion that we measure. At later stages of our experiment, slower diffusing species contribute to the signal that we measure. The diffusion time decreases substantially, and we observe a crossover to a regime in which the chemical reaction dominates. The increases in chain branching and gel formation bring polymer diffusion to a halt. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 4098–4116, 2002
A thermoplastic olefin blend consisting of isotactic polypropylene (PP) and an ethylene-butene copolymer (EBR) impact modifier (25 wt % EBR) was subjected to a short, high-shear pulse within the flow channel of a pressure-driven microextruder following low-shear channel filling from a reservoir of the melt. The resulting morphology was examined by laser scanning confocal fluorescence microscopy (LSCFM), with contrast provided by a fluorescent tracer in the EBR minor phase. Shear experiments were performed under isothermal conditions with a known wall shear stress for a specified duration, providing a well-defined thermal and flow history. Low-shear channel filling produces small droplets across the central region of the channel and large droplets, consistent with steady-state shear, in the regions near the channel walls. After cooling the molten blend to a crystallization temperature of 153°C, a brief interval (5 s ϳ 1/2000 of the quiescent crystallization time) of high shear (wall shear stress: 0.1 MPa) induces rapid, highly oriented crystallization and a stratified morphology. Ex situ LSCFM reveals a "skin" at the channel walls (ϳ70 m) in which greatly elongated fiberlike droplets, oriented along the flow direction, are embedded in highly oriented crystalline PP. Further from the walls but directly beside the skin layers are surprising zones in which EBR domains show no deformation or orientation. Several zones of intermediate deformation and orientation at an angle to the flow direction are located closer to the center of the channel. At the center of the channel, EBR droplets are spherical, as expected for channel flow. The various strata are explained by the interplay of droplet deformation, breakup, and coalescence with the shear-induced crystallization kinetics of the matrix.
Introduction Emerging evidence suggests psoriatic arthritis (PsA) with axial involvement (axPsA) and radiographic axial spondyloarthritis (r-axSpA) may possibly represent distinct disorders, with some differing clinical manifestations, genetic associations, and radiographic findings. Moreover, axPsA and r-axSpA may respond differently to therapies: guselkumab (interleukin [IL]-23p19 subunit inhibitor [i]) and ustekinumab (IL-12/23p40i) demonstrated improvements in axial symptoms in patients with PsA; however, neither risankizumab (IL-23p19i) nor ustekinumab demonstrated efficacy versus placebo in patients with r-axSpA. Current analyses aim to further understand potential molecular distinctions between axPsA and r-axSpA and examine the pharmacodynamic effects of guselkumab in patients with axPsA and those with PsA without axial involvement (non-axPsA). Methods Post hoc analyses utilized biomarker data from blood and serum samples collected from a subset of participants in phase 3 studies of ustekinumab in r-axSpA and guselkumab in PsA (DISCOVER-1 and DISCOVER-2). Participants with axPsA were identified by investigator-verified sacroiliitis (imaging-confirmed) and axial symptoms. HLA mapping, serum cytokine analysis, and whole-blood RNA sequencing were conducted. Results Relative to r-axSpA, patients with axPsA had a lower prevalence of HLA-B27 , HLA-C01 , and HLA-C02 alleles and a higher prevalence of HLA-B13 , HLA-B38 , HLA-B57 , HLA-C06 , and HLA-C12 alleles. Compared with r-axSpA, patients with axPsA had elevated baseline levels of serum IL-17A and IL-17F cytokines, enrichment of IL-17 and IL-10 pathway-associated genes, and neutrophil gene markers. Across axPsA and non-axPsA cohorts, reductions in cytokine levels and normalization of pathway-associated gene expression with guselkumab treatment were comparable. Conclusion The differences in HLA genetic associations, serum cytokines, and enrichment scores support the concept that axPsA and r-axSpA may be distinct disorders. The comparable pharmacodynamic effects of guselkumab on cytokine levels and pathway-associated genes observed in patients with axPsA and non-axPsA are consistent with demonstrated clinical improvements across PsA cohorts. These findings contribute to the understanding of potential genetic and molecular distinctions between axPsA and r-axSpA. Trial Registration ClinicalTrials.gov identifiers, NCT03162796, NCT0315828, NCT02437162, and NCT02438787. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-023-02475-4.
Glioblastomas (GBMs), the most malignant glial tumors, differ from normal glial progenitor cells in many ways, but little is known about the molecular circuitry underlying these differences. We have discovered a novel means by which GBMs become chemo-resistant, based on inhibition of the redox/Fyn/c-Cbl pathway by overexpression of Cool-1(Beta-Pix). The protein c-Cbl, an E3 ubiquitin ligase, is responsible for the ubiquitination and degradation of multiple receptor tyrosine kinases critical for cell division and cell survival. In normal glial progenitor cells of the CNS, exposure to chemotherapy oxidizes cells, leading to sequential activation of Fyn and c-Cbl. However in GBM cells, exposure to BCNU or other chemical pro-oxidants does not lead to c-Cbl activation. Further studies demonstrated that these agents do cause Fyn activation, suggesting that GBMs inhibit c-Cbl phosphorylation leading to decreased degradation of EGFR, accounting for increased EGFR signaling. We next discovered that the decrease in c-Cbl activation via the redox/Fyn/c-Cbl pathway was due to c-Cbl sequestration by Cool-1, which is overexpressed in GBM cells and samples of tumors. We found that oxidant-associated c-Cbl activation can be restored by shRNA-mediated inhibition of Cool-1 expression, leading to restoration of normal c-Cbl-mediated degradation of RTKs (including EGFR). We further found that restoration of Cool-1 activity modulated multiple other hallmarks of GBM, including changes in migration, cell cycle parameters, and altering the cancer stem cell phenotype of our cells. In contrast, Cool-1/c-Cbl complexes were not found in normal brain or normal glial progenitors and Cool-1 knockdown did not reduce progenitor cell division. The translation of these findings into an in vivo intracranial xenograft model of GBM showed that Cool-1 is essential for tumorigenesis and decreasing Cool-1 levels leads to decreased tumor take, decreased tumor growth, and increased survival. In sum, the ability of Cool-1/c-Cbl interactions to modulate a variety of tumor cell properties suggests that these interactions offer an attractive target for modulating GBM growth, particularly due to the absence of Cool-1/c-Cbl complexes in normal brain tissue and to the lack of effects of Cool-1 knockdown on division of normal glial progenitor cells. The activation of c-Cbl activity through pharmacological agents is a potentially viable strategy for the specific eradication of GBM cells. Citation Format: Brett M. Stevens, Christopher J. Folts, Warner Chen, Addie L. Bardin, Mark Noble. Cool-1-mediated inhibition of c-Cbl as a therapuetic target, which modulates multiple critical properties of glioblastomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4106. doi:10.1158/1538-7445.AM2013-4106
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