Homogenization in magnetic-shape-memory polymer composites

Magnetic-shape-memory materials (e.g. specific NiMnGa alloys) react with a large change of shape to the presence of an external magnetic field. As an alternative for the difficult to manifacture single crystal of these alloys we study composite materials in which small magnetic-shape-memory particles are embedded in a polymer matrix. The macroscopic properties of the composite depend strongly on the geometry of the microstructure and on the characteristics of the particles and the polymer. We present a variational model based on micromagnetism and elasticity, and derive via homogenization an effective macroscopic model under the assumption that the microstructure is periodic. We then study numerically the resulting cell problem, and discuss the effect of the microstructure on the macroscopic material behavior. Our results may be used to optimize the shape of the particles and the microstructure.Comment: 17 pages, 4 figure

Phenotypic variations and chemosensitivity in small cell lung cancer

Many complex properties of cancer cells are effectively under selection within the in vivo microenvironment or following therapeutic insult. This critical combination of instability and shifting selection drives the heterogeneity of tumour cell populations in terms of many critical features. Small cell lung cancer (SCLC) is an aggressive, rapidly metastasizing neoplasm with an ability to develop resistance against chemotherapeutic agents. New SCLC therapeutic strategies are urgently needed that contain spreading disease without further compromising tumour chemosensitivity. Variants for attachment to tissue culture plastic of the NCI-H69 cell line, which grows in suspension but generates low frequency appearance of adhesion variants, were enriched, without prejudice for any specific extracellular matrix directed advantage, and then allowed for any proliferation/survival advantage in vitro to impact on the evolution of variation. Two sub-lines were generated representing two stages in variant enrichment. The developed SCLC model, which encompasses elements of variation and heterogeneity, provides opportunities to link in vitro behaviour of SCLC with in vivo characteristics with particular reference to the challenges faced in the management of SCLC such as the accrual of drug resistance. The variant model was characterized using microscopy, flow cytometry and microarray analysis, revealing variation in adherence and morphology impacting on SCLC behaviour, proliferative rate and polysialylation of the neural cell adhesion molecule. The microarray analysis has also revealed new cancer biomarkers that can be explored in clinic studies. This unique SCLC model was used to gain insights into links with chemoresistance. The studies revealed that the variant selection did not result in expansion of a drug resistant clone. Moreover, evidence of clonal evolution/selection was uncovered together with the finding of the absence of CSCs, even in enriched variants, as defined by the classical side population phenotype. The defined PSA expression patterns of the variants allowed for screening of carbohydrates-based agents for polysialylation knock-down.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Modelling avalanches in martensites

Solids subject to continuous changes of temperature or mechanical load often exhibit discontinuous avalanche-like responses. For instance, avalanche dynamics have been observed during plastic deformation, fracture, domain switching in ferroic materials or martensitic transformations. The statistical analysis of avalanches reveals a very complex scenario with a distinctive lack of characteristic scales. Much effort has been devoted in the last decades to understand the origin and ubiquity of scale-free behaviour in solids and many other systems. This chapter reviews some efforts to understand the characteristics of avalanches in martensites through mathematical modelling.Comment: Chapter in the book "Avalanches in Functional Materials and Geophysics", edited by E. K. H. Salje, A. Saxena, and A. Planes. The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-319-45612-6_

Integrated Proteomic Analysis of Human Cancer Cells and Plasma from Tumor Bearing Mice for Ovarian Cancer Biomarker Discovery

Background: The complexity of the human plasma proteome represents a substantial challenge for biomarker discovery. Proteomic analysis of genetically engineered mouse models of cancer and isolated cancer cells and cell lines provide alternative methods for identification of potential cancer markers that would be detectable in human blood using sensitive assays. The goal of this work is to evaluate the utility of an integrative strategy using these two approaches for biomarker discovery. Methodology/Principal Findings: We investigated a strategy that combined quantitative plasma proteomics of an ovarian cancer mouse model with analysis of proteins secreted or shed by human ovarian cancer cells. Of 106 plasma proteins identified with increased levels in tumor bearing mice, 58 were also secreted or shed from ovarian cancer cells. The remainder consisted primarily of host-response proteins. Of 25 proteins identified in the study that were assayed, 8 mostly secreted proteins common to mouse plasma and human cancer cells were significantly upregulated in a set of plasmas from ovarian cancer patients. Five of the eight proteins were confirmed to be upregulated in a second independent set of ovarian cancer plasmas, including in early stage disease. Conclusions/Significance: Integrated proteomic analysis of cancer mouse models and human cancer cell populations provides an effective approach to identify potential circulating protein biomarkers

Plasma Proteome Profiles Associated with Inflammation, Angiogenesis, and Cancer

Tumor development is accompanied by a complex host systemic response, which includes inflammatory and angiogenic reactions. Both tumor-derived and systemic response proteins are detected in plasma from cancer patients. However, given their non-specific nature, systemic response proteins can confound the detection or diagnosis of neoplasia. Here, we have applied an in-depth quantitative proteomic approach to analyze plasma protein changes in mouse models of subacute irritant-driven inflammation, autoreactive inflammation, and matrix associated angiogenesis and compared results to previously described findings from mouse models of polyoma middle T-driven breast cancer and Pdx1-Cre KrasG12D Ink4a/Arf lox/lox -induced pancreatic cancer. Among the confounding models, approximately 1/3 of all quantified plasma proteins exhibited a significant change in abundance compared to control mice. Of the proteins that changed in abundance, the majority were unique to each model. Altered proteins included those involved in acute phase response, inflammation, extracellular matrix remodeling, angiogenesis, and TGFβ signaling. Comparison of changes in plasma proteins between the confounder models and the two cancer models revealed proteins that were restricted to the cancer-bearing mice, reflecting the known biology of these tumors. This approach provides a basis for distinguishing between protein changes in plasma that are cancer-related and those that are part of a non-specific host response

Impact of Protein Stability, Cellular Localization, and Abundance on Proteomic Detection of Tumor-Derived Proteins in Plasma

Tumor-derived, circulating proteins are potentially useful as biomarkers for detection of cancer, for monitoring of disease progression, regression and recurrence, and for assessment of therapeutic response. Here we interrogated how a protein's stability, cellular localization, and abundance affect its observability in blood by mass-spectrometry-based proteomics techniques. We performed proteomic profiling on tumors and plasma from two different xenograft mouse models. A statistical analysis of this data revealed protein properties indicative of the detection level in plasma. Though 20% of the proteins identified in plasma were tumor-derived, only 5% of the proteins observed in the tumor tissue were found in plasma. Both intracellular and extracellular tumor proteins were observed in plasma; however, after normalizing for tumor abundance, extracellular proteins were seven times more likely to be detected. Although proteins that were more abundant in the tumor were also more likely to be observed in plasma, the relationship was nonlinear: Doubling the spectral count increased detection rate by only 50%. Many secreted proteins, even those with relatively low spectral count, were observed in plasma, but few low abundance intracellular proteins were observed. Proteins predicted to be stable by dipeptide composition were significantly more likely to be identified in plasma than less stable proteins. The number of tryptic peptides in a protein was not significantly related to the chance of a protein being observed in plasma. Quantitative comparison of large versus small tumors revealed that the abundance of proteins in plasma as measured by spectral count was associated with the tumor size, but the relationship was not one-to-one; a 3-fold decrease in tumor size resulted in a 16-fold decrease in protein abundance in plasma. This study provides quantitative support for a tumor-derived marker prioritization strategy that favors secreted and stable proteins over all but the most abundant intracellular proteins

UCHL1 Is a Potential Molecular Indicator and Therapeutic Target for Neuroendocrine Carcinomas

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies

ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression

Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3FAX-Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics