Algorithm for J-Integral Measurements by Digital Image Correlation

The work is devoted to the testing of the algorithm for calculating J-integral based on the construction of vector fields by digital image correlation (DIC) method. A comparative analysis of J-integral values calculated using DIC and instrumental data obtained in accordance with ASTM E 1820 "Standard Test Method for Measurement of Fracture Toughness" has made. It is shown that this approach can be used for cases when the standard technique for measuring the J-integral cannot be applied, or the standard technique does not allow achieving the required accuracy for the integral determination in local areas of the loaded material

Combined inhibition of Bcl-2/Bcl-xL and Usp9X/Bag3 overcomes apoptotic resistance in glioblastoma in vitro and in vivo

Despite great efforts taken to advance therapeutic measures for patients with glioblastoma, the clinical prognosis remains grim. The antiapoptotic Bcl-2 family protein Mcl-1 is overexpressed in glioblastoma and represents an important resistance factor to the BH-3 mimetic ABT263. In this study, we show that combined treatment with ABT263 and GX15-070 overcomes apoptotic resistance in established glioblastoma cell lines, glioma stem-like cells and primary cultures. Moreover, this treatment regimen also proves to be advantageous in vivo. On the molecular level, GX15-070 enhanced apoptosis by posttranslational down-regulation of the deubiquitinase, Usp9X, and the chaperone Bag3, leading to a sustained depletion of Mcl-1 protein levels. Moreover, knock-down of Usp9X or Bag3 depleted endogenous Mcl-1 protein levels and in turn enhanced apoptosis induced through Bcl-2/Bcl-xL inhibition. In conclusion, combined treatment with ABT263 and GX15-070 results in a significantly enhanced anti-cancer activity in vitro as well as in vivo in the setting of glioblastoma. Both drugs, ABT263 and GX15-070 have been evaluated in clinical studies which facilitates the translational aspect of taking this combinatorial approach to the clinical setting. Furthermore we present a novel mechanism by which GX15-070 counteracts Mcl-1 expression which may lay a foundation for a novel target in cancer therapy

A Potential Role for the Inhibition of PI3K Signaling in Glioblastoma Therapy

Glioblastoma multiforme (GBM) is the most common primary brain tumor and among the most difficult to treat malignancies per se. In almost 90% of all GBM alterations in the PI3K/Akt/mTOR have been found, making this survival cascade a promising therapeutic target, particular for combination therapy that combines an apoptosis sensitizer, such as a pharmacological inhibitor of PI3K, with an apoptosis inducer, such as radio- or chemotherapy. However, while in vitro data focusing mainly on established cell lines has appeared rather promising, this has not translated well to a clinical setting. In this study, we analyze the effects of the dual kinase inhibitor PI-103, which blocks PI3K and mTOR activity, on three matched pairs of GBM stem cells/differentiated cells. While blocking PI3K-mediated signaling has a profound effect on cellular proliferation, in contrast to data presented on two GBM cell lines (A172 and U87) PI-103 actually counteracts the effect of chemotherapy. While we found no indications for a potential role of the PI3K signaling cascade in differentiation, we saw a clear and strong contribution to cellular motility and, by extension, invasion. While blocking PI3K-mediated signaling concurrently with application of chemotherapy does not appear to be a valid treatment option, pharmacological inhibitors, such as PI-103, nevertheless have an important place in future therapeutic approaches

Why dapsone stops seizures and may stop neutrophils' delivery of VEGF to glioblastoma

Lopez-Gomez et al. recently published remarkable but mechanistically unexplained empirical evidence that the old antibiotic dapsone has antiepileptic activity. We addressed the question "Why should a sulfone antibiotic reduce seizures?". We report here our conclusions based on data from past studies that seizures are associated with elevated interleukin-8 (IL-8) and that dapsone inhibits IL-8 release and function in several different clinical and experimental contexts. Diverse CNS insults cause an increase in CNS IL-8. Thus, the pro-inflammatory environment generated by increase IL-8 leads to a lower seizure threshold. Together this evidence indicates dapsone exerts anti-seizure activity by diminishing IL-8 signalling. Since IL-8 is clearly upregulated in glioblastoma and contributes to the florid angiogenesis of that disease, and since interference with IL-8 function has been shown to inhibit glioblastoma invasion and growth in several experimental models, and dapsone has been repeatedly been shown to clinically inhibit IL-8 function when used to treat human neutrophilic dermatoses, we believe that dapsone thereby reduces seizures by countering IL-8 function and may similarly retard glioblastoma growth by such anti-IL-8 function. © 2012 The Neurosurgical Foundation.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Epidermal to Mesenchymal Transition and Failure of EGFR-Targeted Therapy in Glioblastoma

Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is almost never curable with the current standard treatment consisting of surgical resection, irradiation and temozolomide. The prognosis remains poor despite undisputable advances in the understanding of this tumor’s molecular biology and pathophysiology, which unfortunately has so far failed to translate into a meaningful clinical benefit. Dysregulation and a resulting prominent pathophysiological role of the epidermal growth factor receptor (EGFR) have been identified in several different malignant tumor entities, GBM among them. The EGFR is overexpressed in about 40% of GBM cases, and half of these coexpress a mutant, constitutively activated subtype, EGFRvIII. Unfortunately, recent trials studying with therapeutic approaches targeted against the EGFR and EGFRvIII have failed to meet expectations, with only a minority of patients responding despite evidence of good <em>in vitro</em> and rodent model activity. Having potentially high relevance within this context, epithelial to mesenchymal transition (EMT) is a phenomenon associated with early stages of carcinogenesis, cancer invasion and recurrence. During EMT, epithelial cells lose many of their epithelial characteristics, prominently E-cadherin expression, and acquire properties that are typical for mesenchymal cells such as the expression of vimentin. Epithelial to mesenchymal transition has been specifically demonstrated in GBM. In this review, we summarize the evidence that EMT may precipitate GBM resistance to EGFR-targeted therapy, and may thus be among the principal factors contributing to the clinical failure of targeted therapy against EGFR and EGFRvIII