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11	Tolerated illegality and intolerable legality: from legal philosophy to critique Plyley, Kathryn 26 April 2018 (has links) This project uses Michel Foucault’s underdeveloped notion of “tolerated illegality” as a departure point for two converging inquiries. The first analyzes, and then critiques, dominant legal logics and values. This part argues that traditional legal philosophers exhibit a “disagreement without difference,” generally concurring that legal certainty and predictability enhance agency. Subsequently, this section critiques “formal legal” logic by linking it to science envy (specifically the desire for certainty and predictability), and highlighting its agency- limiting effects (e.g. the violence of law en-force-ment). The second part examines multiple dimensions of tolerated illegality, exploring the permutations of this complex socio-legal phenomenon. Here the implications of tolerated illegality are mapped across different domains, ranging from the dispossession of Indigenous peoples of their lands, to the latent ideologies embedded in superhero shows. This section also examines the idea of liberal “tolerance,” as well as the themes of power, domination, politics, bureaucracy, and authority. Ultimately, this project demonstrates that it is illuminating to study legality and (tolerated) illegality in tandem because although analyses of “formal legality” provide helpful analytical texture, the polymorphous and entangled nature of tolerated illegality makes clear just how restricted and artificial strict analyses of legality can be. / Graduate tolerated illegality legality rule of law socio-legal critique Indigenous resurgence power relations toleration superheroes law and film law and television critical legal thought Michel Foucault Lon Fuller Wendy Brown tolerance legal philosophy Antigone The Wire gap studies scientism in law Indigenous dispossession law and order neoliberalism legal certainty and predictability bureaucracy Daredevil
12	Antitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder Sutherland, Mark, Gill, Jason H., Loadman, Paul, Laye, Jonathan P., Sheldrake, Helen M., Illingworth, Nicola A., Alandas, Mohammed N., Cooper, Patricia A., Searcey, M., Pors, Klaus, Shnyder, Steven, Patterson, Laurence H. 01 October 2012 (has links) No / We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor alpha-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in gamma-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers. Animals Antineoplastic agents Biotransformation CHO cells Carcinoma Cell line Tumor Cell survival Cricetinae Cytochrome P-450 CYP1A1 Female Gene expression Humans Indoles Liver Maximum tolerated dose Mice Inbred BALB C Microsomes Pyrroles Tumor burden Urinary bladder neoplasms Xenograft model antitumor assays REF 2014 Metabolism Pharmacokinetics Pharmacology Transitional cell Drug therapy Enzymology Pathology Genetics

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Tolerated illegality and intolerable legality: from legal philosophy to critique

Antitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder