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Epithelial to mesenchymal transition (EMT) has been hypothesized as a mechanism by which cells change phenotype during carcinogenesis, as well as tumor metastasis. Whether EMT is involved in cancer metastasis has a specific, practical impact on the field of circulating tumor cells (CTCs). Since the generally accepted definition of a CTC includes the expression of epithelial surface markers, such as EpCAM, if a cancer cell loses its epithelial surface markers (which is suggested in EMT), it will not be separated and/or identified as a CTC. We have developed, and previously reported on the use of, a purely negative enrichment technology enriching for CTCs in the blood of squamous cell carcinoma of the head and neck (SCCHN). This methodology does not depend on the expression of surface epithelial markers. Using this technology, our initial data on SCCHN patient blood indicates that the presence of CTCs correlates with worse disease-free survival. Since our enrichment is not dependent on epithelial markers, we have initiated investigation of the presence of mesenchymal markers in these CTC cells to include analysis of: vimentin, epidermal growth factor receptor, N-cadherin, and CD44. With the aid of confocal microscopy, we have demonstrated not only presumed CTCs that express and/or contain: a nucleus, cytokeratins, vimentin, and either EGFR, CD44, or N-cadherin, but also cells that contain all of the aforementioned proteins except cytokeratins, suggesting that the cells have undergone the EMT process. We suggest that our negative depletion enrichment methodology provides a more objective approach in identifying and evaluating CTCs, as opposed to positive selection approaches, as it is not subjective to a selection bias and can be tailored to accommodate a variety of cytoplasmic and surface markers which can be evaluated to identify a multitude of phenotypic patterns within CTCs from individual patients, including so-called EMT as presented here.

Loss of genome-wide methylation is a common feature of cancer, and the degree of hypomethylation has been correlated with genomic instability. Global methylation of repetitive elements possibly arose as a defense mechanism against parasitic DNA elements, including retrotransposons and viral pathogens. Given the alterations of global methylation in both viral infection and cancer, we examined genome-wide methylation levels in head and neck squamous cell carcinoma (HNSCC), a cancer causally associated with human papilloma virus (HPV). We assayed global hypomethylation levels in 26 HNSCC samples, compared with their matched normal adjacent tissue, using Pyrosequencing-based methylation assays for LINE repeats. In addition, we examined cell lines derived from a variety of solid tumors for LINE and SINE (Alu) repeats. The degree of LINE and Alu hypomethylation varied among different cancer cell lines. There was only moderate correlation between LINE and Alu methylation levels, with the range of variation in methylation levels being greater for the LINE elements. LINE hypomethylation was more pronounced in HPV-negative than in HPV-positive tumors. Moreover, genomic instability, as measured by genome-wide loss-of-heterozygosity (LOH) single nucleotide polymorphism (SNP) analysis, was greater in HNSCC samples with more pronounced LINE hypomethylation. Global hypomethylation was variable in HNSCC. Its correlation with both HPV status and degree of LOH as a surrogate for genomic instability may reflect alternative oncogenic pathways in HPV-positive versus HPV-negative tumors.

The identification of tumor suppressor genes has classically depended on their localization within recurrent regions of loss of heterozygosity. According to Knudson's two-hit hypothesis, the remaining allele is lost, either genetically or, more recently identified, through epigenetic events. To date, retrospective analyses have determined promoter methylation as a common alternative alteration in cancer cells to silence cancer-related genes. Here we report an application of restriction landmark genomic scanning that allows for DNA methylation profiling along a region of recurrent loss of heterozygosity at chromosome 6q23-q24. This approach resulted in the identification of a tumor suppressor gene, TCF21, which is frequently lost in human malignancies. We demonstrate that TCF21 is expressed in normal lung airway epithelial cells and aberrantly methylated and silenced in the majority of head and neck squamous cell carcinomas and non-smallcell lung cancers analyzed. TCF21 is known to regulate mesenchymal cell transition into epithelial cells, a property that has been shown to be deficient in carcinomas. We further demonstrate that exogenous expression of TCF21 in cells that have silenced the endogenous TCF21 locus resulted in a reduction of tumor properties in vitro and in vivo.

Epistemologies of situated knowledges, advanced by scholars such as Donna Haraway, Lorraine Code, and Maureen Ford, challenge mainstream epistemology's claim to be the gold standard in determining what counts as knowledge. In this essay, James Lang uses the work of these and other feminist theorists to explicate the notion of situated knowledges and then uses this notion to trouble the legitimacy of employing Kantian‐inspired propositional rationalism to justify all knowledge claims. Lang challenges the notions of the discrete, objective, impartial, interchangeable subject and the static passivity of objects of knowing. He demonstrates the inevitable involvement of the subjective in knowledge construction and justification; he claims that knowledge is necessarily embodied, partial, and situated and, further, that its construction, claiming, and enacting are activities with moral and political ramifications. Finally, Lang shows that re‐visioning contexts of education through lenses of epistemologies of situated knowledges reveals a vastly expanded moral landscape with significant implications for educators, students, and educational theorists.

I discuss potential ethical issues for an educator required by a publicly-funded Ontario (or similar) Roman Catholic School Board employer to teach students such that when they graduate they will be \"discerning believer[s] formed in the Catholic Faith community who celebrate[s] the signs and sacred mystery of God's presence through word, sacrament, prayer, forgiveness, reflection, and moral living\" (1998, p. 5). I contrast the moral responsibilities of a Catholic religious studies educator with the moral responsibilities of a public school educator who is guided by principles of liberalism as characterized, primarily, by some of the works of Will Kymlicka. Ici, j'aborde les questions éthiques possibles auquel un enseignant a dû faire face parce qu'un conseil scolaire catholique de l'Ontario financé par le public (ou équivalent), en tant qu'employeur, lui a demandé d'enseigner aux étudiants de façon à ce que lorsqu'ils obtiendront leur diplôme, ils puissent \"discerner le(s) croyant(s) formé(s) au sein de la foi catholique qui célèbre les signes et le mystère sacré de l'existence de Dieu par les mots, les sacrements, les prières, le pardon, la la pensée et la bonne moralité\" (1998, p. 5). J'oppose ici, les responsabilités morales d'un enseignant dans les études d'un milieu catholique, aux responsabilités morales d'un enseignant d'une école publique qui est, lui, dirigé par les principes de libéralisme comme il est, avant tout, précisé dans certains travaux de Will Kymlicka.

I discuss potential ethical issues for an educator required by a publicly-funded Ontario (or similar) Roman Catholic School Board employer to teach students such that when they graduate they will be \"discerning believer[s] formed in the Catholic Faith community who celebrate[s] the signs and sacred mystery of God's presence through word, sacrament, prayer, forgiveness, reflection, and moral living\" (I 998, p. 5). I contrast the moral responsibilities of a Catholic religious studies educator with the moral responsibilities of a public school educator who is guided by principles of liberalism as characterized, primarily, by some of the works of Will Kymlicka.

Myoferlin, a member of ferlin family of proteins, was first discovered as a candidate gene for muscular dystrophy and cardiomyopathy. Recently, myoferlin was shown to be also expressed in endothelial and cancer cells where it was shown to modulate vascular endothelial growth factor (VEGFR)-2 and epidermal growth factor receptor (EGFR) signaling by enhancing their stability and recycling. Based on these reports, we hypothesized that myoferlin might be regulating IL-6 signaling by modulating IL-6R stabilization and recycling. However, in our immunoprecipitation (IP) experiments, we did not observe myoferlin binding with IL-6R. Instead, we made a novel discovery that in resting cells myoferlin was bound to EHD2 protein and when cells were treated with IL-6, myoferlin dissociated from EHD2 and binds to activated STAT3. Interestingly, myoferlin depletion did not affect STAT3 phosphorylation, but completely blocked STAT3 translocation to nucleus. In addition, inhibition of STAT3 phosphorylation by phosphorylation-defective STAT3 mutants or JAK inhibitor blocked STAT3 binding to myoferlin and nuclear translocation. Myoferlin knockdown significantly decreased IL-6-mediated tumor cell migration, tumorsphere formation and ALDH-positive cancer stem cell population, in vitro . Furthermore, myoferlin knockdown significantly decreased IL-6-meditated tumor growth and tumor metastasis. Based on these results, we have proposed a novel model for the role of myoferlin in chaperoning phosphorylated STAT3 to the nucleus.

CpG islands frequently contain gene promoters or exons 1 and are usually unmethylated in normal cells 1 , 2 , 3 . Methylation of CpG islands is associated with delayed replication, condensed chromatin and inhibition of transcription initiation 4 , 5 , 6 , 7 . The investigation of aberrant CpG-island methylation in human cancer has primarily taken a candidate gene approach, and has focused on less than 15 of the estimated 45,000 CpG islands 8 in the genome. Here we report a global analysis of the methylation status of 1,184 unselected CpG islands in each of 98 primary human tumours using restriction landmark genomic scanning 9 (RLGS). We estimate that an average of 600 CpG islands (range of 0 to 4,500) of the 45,000 in the genome were aberrantly methylated in the tumours, including early stage tumours. We identified patterns of CpG-island methylation that were shared within each tumour type, together with patterns and targets that displayed distinct tumour-type specificity. The expression of many of these genes was reactivated by experimental demethylation in cultured tumour cells. Thus, the methylation of particular subsets of CpG islands may have consequences for specific tumour types.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600,000 new cases diagnosed each year. Understanding the molecular pathways that lead to HNSCC is crucial to identify new targets for anti-cancer drug development. Protein kinase Cε (PKCε) is elevated in HNSCC and regulates the activation of Akt, Stat3, and Rho GTPases. To date, the molecular mechanism of PKCε dysregulation in HNSCC remains to be elucidated. In silico analysis identified three putative microRNA-107 (miR-107) binding sites in the 3'-untranslated region (UTR) of PKCε. An inverse relationship was revealed between miR-107 and PKCε in HNSCC cell lines. Delivery of miR-107 reduced PKCε levels in SCC15, SCC25, and CAL27, three HNSCC cell lines with high PKCε and low miR-107. The activity of a luciferase reporter construct containing the 3'-UTR of PKCε was down-regulated by miR-107 and mutations in the three cognate miR-107 binding sites completely ablated the regulation by miR-107. Treatment with miR-107 significantly blocked cell proliferation, DNA replication, colony formation, and invasion in SCC25 and CAL27 cells. Ectopic expression of miR-resistant PKCε was sufficient to partially rescue the loss-of-function phenotype in miR-107-overexpressing SCC25 cells. Tumor growth in nude mice was retarded by 93 ± 7% in CAL27/miR-107 cells compared to CAL27/miR-control cells. Lastly, human primary HNSCC tumors with elevated PKCε had reduced miR-107 expression. Our results demonstrate that PKCε is directly regulated by miR-107 and moreover, suggest that miR-107 may be a potential anti-cancer therapeutic for HNSCC.

With few exceptions, educators and educational theorists regard indoctrination as the antithesis of acceptable educational practice. Fearing charges of indoctrination, educators want to be clear about the distinctions between teaching and indoctrinating and philosophers of education have responded with hundreds of scholarly articles and books focused on clarifying this troublesome term. Over the course of the past century, their efforts to deliver a compelling normative conceptual tool for educators have produced a massive, fractious, and inconclusive discourse that appears unable to successfully indict those they would label indoctrinators or to explain the apparent harms of indoctrination to the satisfaction of those who claim to have been indoctrinated. In response, this dissertation identifies core, un-interrogated, epistemological assumptions that shape and constrain the dominant conceptions of indoctrination developed in the literature as impediments to better conceptions of indoctrination and the harms it is purported to induce. The epistemology of the dominant discourse on indoctrination (the “EDDI”) is shown to be consistent with “mainstream epistemology” (ME) and its fixed, universalist-reductivist conception of rationality that permeates contemporary understandings of knowledge and teaching. ME is “troubled” through critiques based on feminist epistemologies of situated knowledges (“ESK”). The latter reject ME's universalist, artificially reductive “S knows ‘that p’” rubric—on which the EDDI is predicated—as reliant on idealized notions of a form of detached, impartial rationality available to all universally interchangeable rationally autonomous individuals. Against this narrow, idealized, rationality, ESK present knowledge as constitutive of embodied, particular, situated, knowers. Applied to contexts of education, ESK radically reconfigure the notions of rationality and of acceptable and unacceptable education, under which indoctrination is subsumed, to reveal vastly expanded epistemological/moral responsibilities for those engaged in educational practices. In educational contexts that are understood as inherently moral, ESK are used to suggest revitalized and morally enhanced conceptions of indoctrination that can better account for the dialogical construction of knowledges among situated knowers in contexts of asymmetrical power arrangements.