The sonic effect: Aurality and digital networks in Exurbia

This essay examines the problem of medial specificity in music and sound art, giving particular attention to Seth Kim-Cohen’s call for a non-cochlear sound art based on the notion of “expansion” that has been decisive in visual arts discourses. I argue that Kim-Cohen’s non-cochlear intervention in In the Blink of an Ear might be productively pressured towards the concept of a “sonic effect” that acknowledges the material-discursive particularity of sound without recourse to the phenomenological claims of authenticity that Kim-Cohen correctly abhors. In service of this argument, the essay extensively discusses a sound and media artwork – Exurbia, created by myself and William Brent – that leverages the metaphorics of sound against existing understandings of specific forms of network communication. I argue that the conceptual and material dimensions of the project stridulate in a hum of recursive vectors for considering the constitution and consequences of networked aural interaction. Exurbia can thus be parsed in terms of medial specificity precisely because its digital aural materials are themselves discursive

Long-term prognosis of patients with pediatric pheochromocytoma

A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4%NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.publishersversionPeer reviewe

Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

<p>Abstract</p> <p>Background</p> <p>Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance <it>in vitro </it>occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7_DOX-2), epirubicin (MCF-7_EPI), paclitaxel (MCF-7_TAX-2), or docetaxel (MCF-7_TXT). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters.</p> <p>Results</p> <p>In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance.</p> <p>Conclusion</p> <p>This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of resistance cannot be attributed solely to changes in drug accumulation or the activity of drug transporters. The identities of these additional drug-transporter-independent mechanisms are discussed, including their likely clinical relevance.</p