Augmenting Design Learning through Computer-Aided Exploration

Much of engineering design courses are taught through the use of standard and simplified textbook problems that typically have a “correct” answer. In helping undergraduate students learn engineering design, it is very important that they explore scenarios that are realistic. A majority of the current educational methods and computer-based tools do not bridge the gap between the textbook problems and the real world and also lack affordances for design exploration. Although computational methods such as Finite Element Analysis (FEA) have this potential, they are hard to use and require the users to spend a significant effort in learning to use them. Also, several instructors have identified significant knowledge gaps between theory and practice in concepts related to structural design and strength of materials when the students reach their senior year. To this end, a problem-based, exploration-focused interface to allow for rapid design exploration within engineering design curricula using an easy-to-use, simplified and constrained version of finite elements for stress analysis and exploration has been developed. This interface makes it possible for users to rapidly explore various design options by incorporating a FEA back end for design exploration. The current approach uses constrained design problems for weight minimization that incorporates elements of structural topology optimization but does not automate it. In addition the tool constrains the solution generation process so that users do not get poor results. Instead, the user is provided with control on decision making for changing the shape through material removal while obtaining good solutions. Using this interface, the decision making and methodology of users in the course of the activities that provide a context of control, challenge and reflection is explored. Using questionnaires, video and verbal protocol analysis assessment is integrated in ways that are important and interesting for learning. The interface demonstrates that computational tools that are transformed for learning purposes can scaffold and augment learning processes in new ways

Chromosomal instability drives metastasis through a cytosolic DNA response

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs

Loss of periostin/OSF-2 in ErbB2/Neu-driven tumors results in androgen receptor-positive molecular apocrine-like tumors with reduced Notch1 activity

INTRODUCTION: Periostin (Postn) is a secreted cell adhesion protein that activates signaling pathways to promote cancer cell survival, angiogenesis, invasion, and metastasis. Interestingly, Postn is frequently overexpressed in numerous human cancers, including breast, lung, colon, pancreatic, and ovarian cancer.METHODS: Using transgenic mice expressing the Neu oncogene in the mammary epithelium crossed into Postn-deficient animals, we have assessed the effect of Postn gene deletion on Neu-driven mammary tumorigenesis.RESULTS: Although Postn is exclusively expressed in the stromal fibroblasts of the mammary gland, Postn deletion does not affect mammary gland outgrowth during development or pregnancy. Furthermore, we find that loss of Postn in the mammary epithelium does not alter breast tumor initiation or growth in mouse mammary tumor virus (MMTV)-Neu expressing mice but results in an apocrine-like tumor phenotype. Surprisingly, we find that tumors derived from Postn-null animals express low levels of Notch protein and Hey1 mRNA but increased expression of androgen receptor (AR) and AR target genes. We show that tumor cells derived from wild-type animals do not proliferate when transplanted in a Postn-null environment but that this growth defect is rescued by the overexpression of active Notch or the AR target gene prolactin-induced protein (PIP/GCDFP-15).CONCLUSIONS: Together our data suggest that loss of Postn in an ErbB2/Neu/HER2 overexpression model results in apocrine-like tumors that activate an AR-dependent pathway. This may have important implications for the treatment of breast cancers involving the therapeutic targeting of periostin or Notch signaling

Autopsy findings of previously described case of diffuse intrinsic pontine glioma-like tumor with EZHIP expression and molecular features of PFA ependymoma

http://deepblue.lib.umich.edu/bitstream/2027.42/173995/1/40478_2021_Article_1215.pd

Metastasis and immune evasion from extracellular cGAMP hydrolysis

Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune stimulatory metabolite whose breakdown products include the immune suppressor, adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wildtype ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part, through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune suppressive pathway