On the local solvability of the initial-boundary value problem of fiber spinning of the upper convected Maxwell fluid

The fiber spinning process of a viscoelastic liquid modeled by the constitutive theory of the Maxwell fluid is analyzed.The governing equations are given by one- dimensional mass, momentum, and constitutive equations which arise in the slender bodyapproximation by cross-sectional averaging of the two-dimensional axisymmetric Stokes equationswith free boundary. Existence, uniqueness, andregularity results are proved by means of fixed point arguments, energy estimates, and weak/weak* convergence methods.The complexity in this problem lies with the constitutive model of the Maxwell fluid: when both the outflow velocity at the spinneret andthe pulling velocity at take-upare prescribed, a boundary condition can be imposed for only one of the two elastic stress components at the inlet. The absence ofthe second stress boundary condition makes the mathematical analysis of the problem difficult

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

Analysis of fiber spinning for the upper-convected Maxwell fluid

The fiber spinning process of a viscoelastic liquid modeled by the constitutive theory of the Maxwell fluid is analyzed. The governing equations are given by one-dimensional mass, momentum and constitutive equations, which arise in the slender body approximation by cross-sectional averaging of the two-dimensional axisymmetric Stokes equations with free boundary. Existence, uniqueness and regularity results are proved by means of fixed point arguments, energy estimates and weak/weak* convergence methods. The difficulty in this problem lies with the constitutive model of the Maxwell fluid: when both the outflow velocity at the spinneret and the pulling velocity at take up are prescribed, a boundary condition can be imposed for only one of the two elastic stress components at the inlet. The absence of the second stress boundary condition makes the mathematical analysis of the problem hard. © 2011 Elsevier Ltd. All rights reserved

The effect of shear in fiber spinning

We study the equations of isothermal fiber spinning under the assumption that viscous friction in the fiber is balanced by shear stresses. Our discussion gives a rather complete picture of the existence and nonexistence of stationary solutions. The linearization about steady state of the governing equations is analyzed by semigroup methods and shown to have the spectrally determined growth property. Both linear and nonlinear stability of stationary solutions is investigated numerically. © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Defining function of wild-type and three patient-specific TP53 mutations in a zebrafish model of embryonal rhabdomyosarcoma

In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss- or gain-of-function TP53 mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding p53 variant effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53, yet mutations when present are associated with worse prognosis. Employing a kRASG12D-driven ERMS tumor model and tp53 null (tp53-/-) zebrafish, we define wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumorigenesis, where tp53 loss expands tumor initiation from <35% to >97% of animals. Characterizing three patient-specific alleles reveals that TP53C176F partially retains wild-type p53 apoptotic activity that can be exploited, whereas TP53P153Δ and TP53Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53P153Δ unexpectedly also predisposes to hedgehog-expressing medulloblastomas in the kRASG12D-driven ERMS-model

Genomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer

Abstract Subcutaneous patient-derived xenografts (PDXs) are an important tool for childhood cancer research. Here, we describe a resource of 68 early passage PDXs established from 65 pediatric solid tumor patients. Through genomic profiling of paired PDXs and patient tumors (PTs), we observe low mutational similarity in about 30% of the PT/PDX pairs. Clonal analysis in these pairs show an aggressive PT minor subclone seeds the major clone in the PDX. We show evidence that this subclone is more immunogenic and is likely suppressed by immune responses in the PT. These results suggest interplay between intratumoral heterogeneity and antitumor immunity may underlie the genetic disparity between PTs and PDXs. We further show that PDXs generally recapitulate PTs in copy number and transcriptomic profiles. Finally, we report a gene fusion LRPAP1-PDGFRA. In summary, we report a childhood cancer PDX resource and our study highlights the role of immune constraints on tumor evolution