Sarcomas are difficult to treat and the therapy, even when effective, is associated with long-term and life-threatening side effects. In addition, the treatment regimens for many sarcomas, including ...Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma, are relatively unchanged over the past two decades, indicating a critical lack of progress. Although differentiation-based therapies are used for the treatment of some cancers, the application of this approach to sarcomas has proven challenging. Here, using a CRISPR-mediated gene knockout approach, we show that Inhibitor of DNA Binding 2 (ID2) is a critical regulator of developmental-related genes and tumor growth in vitro and in vivo in Ewing sarcoma tumors. We also identified that homoharringtonine, which is an inhibitor of protein translation and FDA-approved for the treatment of leukemia, decreases the level of the ID2 protein and significantly reduces tumor growth and prolongs mouse survival in an Ewing sarcoma xenograft model. Furthermore, in addition to targeting ID2, homoharringtonine also reduces the protein levels of ID1 and ID3, which are additional members of the ID family of proteins with well-described roles in tumorigenesis, in multiple types of cancer. Overall, these results provide insight into developmental regulation in Ewing sarcoma tumors and identify a novel, therapeutic approach to target the ID family of proteins using an FDA-approved drug.
The addition of molecularly targeted therapies to current chemotherapy regimens may improve acute lymphoblastic leukemia (ALL) outcomes and reduce acute and late toxicities. Checkpoint kinase 1 ...(CHK1) orchestrates cell cycle checkpoint control in the setting of DNA damage. CHK1 is expressed in both T- and B-ALL and represents a promising therapeutic target. Herein, we show that prexasertib, a targeted CHK1 inhibitor, exhibits significant single-agent efficacy
in vivo
using ALL patient-derived xenograft (PDX) models and synergizes
in vitro
with a nucleoside analog. These results support further clinical testing of prexasertib in ALL.
Rapid automatized naming (RAN) is strongly related to literacy gains in developing readers, reading disabilities, and reading ability in children and adults. Because successful RAN performance ...depends on the close coordination of a number of abilities, it is unclear what specific skills drive this RAN-reading relationship. The current study used concurrent recordings of young adult participants' vocalizations and eye movements during the RAN task to assess how individual variation in RAN performance depends on the coordination of visual and vocal processes. Results showed that fast RAN times are facilitated by having the eyes 1 or more items ahead of the current vocalization, as long as the eyes do not get so far ahead of the voice as to require a regressive eye movement to an earlier item. These data suggest that optimizing RAN performance is a problem of scheduling eye movements and vocalization given memory constraints and the efficiency of encoding and articulatory control. Both RAN completion time (conventionally used to indicate RAN performance) and eye-voice relations predicted some aspects of participants' eye movements on a separate sentence reading task. However, eye-voice relations predicted additional features of first-pass reading that were not predicted by RAN completion time. This shows that measurement of eye-voice patterns can identify important aspects of individual variation in reading that are not identified by the standard measure of RAN performance. We argue that RAN performance predicts reading ability because both tasks entail challenges of scheduling cognitive and linguistic processes that operate simultaneously on multiple linguistic inputs.
A non-local formulation of classical continuum mechanics theory known as peridynamics is used to study fracture initiation and growth from a wellbore penetrating the subsurface within the context of ...propellant-based stimulation. The principal objectives of this work are to analyze the influence of loading conditions on the resulting fracture pattern, to investigate the effect of in-situ stress anisotropy on fracture propagation, and to assess the suitability of peridynamics for modeling complex fracture formation.
It is shown that the loading rate significantly influences the number and extent of fractures initiated from a borehole. Results show that low loading rates produce fewer but longer fractures, whereas high loading rates produce numerous shorter fractures around the borehole. The numerical method is able to predict fracture growth patterns over a wide range of loading and stress conditions. Our results also show that fracture growth is attenuated with increasing in-situ confining stress, and, in the case of confining stress anisotropy, fracture extensions are largest in the direction perpendicular to the minimum compressive stress. Since the results are in broad qualitative agreement with experimental and numerical studies found in the literature, suggesting that peridynamics can be a powerful tool in the study of complex fracture network formation.
•Peridynamics is used to study propellant-based well stimulation.•Low loading rates produce fewer but longer fractures.•High loading rates produce numerous shorter fractures.•Fracture growth is attenuated with increasing in-situ confining stress.•Fracture extensions are largest in the direction perpendicular to the minimum compressive stress.
The limited delivery of chemotherapy agents to cancer cells and the nonspecific action of these agents are significant challenges in oncology. We have previously developed a customizable drug ...delivery and activation system in which a nucleic acid functionalized gold nanoparticle (Au-NP) delivers a drug that is selectively activated within a cancer cell by the presence of an mRNA unique to the cancer cell. The amount of drug released from sequestration to the Au-NP is determined by both the presence and the abundance of the cancer cell specific mRNA in a cell. We have now developed this technology for the potent, but difficult to deliver, topoisomerase I inhibitor SN-38. Herein, we demonstrate both the efficient delivery and selective release of SN-38 from gold nanoparticles in Ewing sarcoma cells with resulting efficacy in vitro and in vivo. These results provide further preclinical validation for this novel cancer therapy and may be extendable to other cancers that exhibit sensitivity to topoisomerase I inhibitors.
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with relapse being a major obstacle to successful treatment. Our understanding of the mechanisms driving chemotherapy ...resistance and ultimately relapse in leukemia remains incomplete. Herein, we investigate the impact of the tumor microenvironment on leukemia cell drug responses using human plasma-like media (HPLM), designed to mimic physiological conditions more accurately ex vivo . We demonstrate that while most chemotherapeutics maintain an efficacy in HPLM comparable to standard tissue culture media, the thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) exhibit significantly reduced potency and efficacy against both B- and T- leukemia cells in HPLM. By merging our understanding of thiopurines’ mechanism of action with the metabolites supplemented in HPLM compared to standard media, we proposed and subsequently validated the hypothesis that hypoxanthine, a purine derivative, is responsible for conferring resistance to the thiopurines. Importantly, the concentration of hypoxanthine required for resistance is comparable to physiological levels found in vivo , supporting clinical relevance. Our findings demonstrate the utility of a more physiologic media in identifying and characterizing mechanisms by which the microenvironment can enable resistance. Understanding such interactions may inform strategies to overcome drug resistance and improve therapeutic outcomes in pediatric leukemia.
This paper proposes a novel methodology for 3-D simulations of pressure waves propagating in fluid-filled fractures in an elastic body — the so-called Krauklis waves. The problem is governed by an ...approximation to the compressible Navier–Stokes equations for the viscous fluid in the fracture cavity coupled to the elastic-wave equation in the surrounding solid. The solid is assumed to be isotropic linear elastic and the fluid to be Newtonian. The elastic-wave equation is discretized in space with a quadratic Generalized Finite Element Method (GFEM) and in time by Newmark’s method while the Krauklis waves equations are discretized in space by a quadratic standard FEM and in time by the α-method. A monolithic solver is adopted for the coupled problem and is numerically shown to be stable for the adopted approximation spaces. The GFEM is particularly appealing for the discretization of 3-D fractures since it does not require meshes fitting their geometry. Furthermore, analytical asymptotic solutions are used to enrich the GFEM approximation spaces, increasing the accuracy of the method. Mesh adaptivity around the fracture fronts is employed to further decrease the discretization error while controlling the computational time. The methodology is verified with analytical solutions and compared with experimental data. Different fracture geometries are investigated to demonstrate the complex 3-D effects of the physical phenomenon and the robustness of the proposed GFEM methodology.
•Mesh of proposed GFEM does not need to fit the geometry of fluid-filled fractures.•Singular enrichments and mesh adaptivity lead to an efficient and accurate method.•Method is shown to be stable, and is verified and validated.•Several fracture geometries are analyzed attesting the robustness of the method.•3-D effects are shown to be important even for planar rectangular fractures.
This collection celebrates the semicentennial of the publication of Hans Blumenberg's The Legitimacy of the Modern Age. The question that inspired Blumenberg may continue to provoke readers today, ...when challenges to secularism have emerged both in academic discourse and in political life: Can modernity ground its own normativity without appealing to the religious past? Or must we abandon the attempt to seek a rational grounding for modern norms? Is secularism still valid as a political framework and as a cognitive and moral ideal, or is it mistaken to believe in the independence or "self-assertion" of secular modernity?
In this article, we contribute to the longstanding debate among economists regarding the question of “nature or nurture” with respect to economics students’ attitudes toward various allocation ...mechanisms for a scarce resource. While previous research starts the debate by beginning with first-year economics students, we aim to evaluate pre-first-year individuals, i.e., school pupils. Drawing on the seminal works of Haucap, J., & Just, T. (2010). Not guilty? Another look at the nature and nurture of economics students.
,
(2), 239–254 and Frey, B. S., Pommerehne, W. W., & Gygi, B. (1993). Economics indoctrination or selection? Some empirical results.
,
(3), 271–281, we investigate a sample of 697 pupils ranging from the 5th to the 13th grades to determine whether pupils are “born economists” (nature), develop economic thinking (nurture), or both. We find that young individuals start to think differently in early grades and that their thinking and attitudes are shaped differently throughout their school careers, thereby providing support for the effects of both nature and nurture. Our findings show that school time impacts fairness judgments, particularly regarding price mechanisms. Regarding learning or indoctrination, we find that economics-inclined pupils are positively affected by lessons in economics in school, while pupils who are economics-averse draw completely diametric conclusions from economics lessons, thereby exhibiting increased disapproval of price allocation over the course of these classes and increased approval of the first come, first served and governmental action mechanisms. Moreover, we find strong effects of gender and migration background in this context. This study is the first to elucidate the development of economic thinking in 5th–13th grade pupils. Our results are important for economists, educators, and researchers because they can serve as a starting point for subsequent investigations in this under-researched field.
Individual readers vary greatly in the quality of their lexical representations, and consequently in how quickly and efficiently they can access orthographic and lexical knowledge. This variability ...may be explained, at least in part, by individual differences in exposure to printed language, because practice at reading promotes the development of stronger reading skills. In the present eyetracking experiment, we tested the hypothesis that the efficiency of word recognition during reading improves with increases in print exposure, by determining whether the magnitude of the repetition-priming effect is modulated by individual differences in scores on the author recognition test (ART). Lexical repetition of target words was manipulated across pairs of unrelated sentences that were presented on consecutive trials. The magnitude of the repetition effect was modulated by print exposure in early measures of processing, such that the magnitude of the effect was inversely related to scores on the ART. The results showed that low levels of print exposure, and thus lower-quality lexical representations, are associated with high levels of difficulty recognizing words, and thus with the greatest room to benefit from repetition. Furthermore, the interaction between scores on the ART and repetition suggests that print exposure is not simply an index of general reading speed, but rather that higher levels of print exposure are associated with an enhanced ability to access lexical knowledge and recognize words during reading.
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