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An almost beat-by-beat re-viewing and re-reading of the temptation scene in Trevor Nunn’s 1989 National Theatre production of Othello registered a need to query whether the director’s decision to cast a (black) opera singer rather than a (Shakespearean) actor in the demanding role of Othello had been misguided. This view presupposes that theatrical exigency – the development of a dramatic action and on-stage situation – would be highlighted over the contingency of performative politics, however vital contemporary attention to cultural matters of “inauthenticity” and “political correctness” may be regarded.

UnlabelledPharmacologic and global gene deletion studies demonstrate that cyclooxygenase-2 (PTGS2/COX-2) plays a critical role in DMBA/TPA-induced skin tumor induction. Although many cell types in the tumor microenvironment express COX-2, the cell types in which COX-2 expression is required for tumor promotion are not clearly established. Here, cell type-specific Cox-2 gene deletion reveals a vital role for skin epithelial cell COX-2 expression in DMBA/TPA tumor induction. In contrast, myeloid Cox-2 gene deletion has no effect on DMBA/TPA tumorigenesis. The infrequent, small tumors that develop on mice with an epithelial cell-specific Cox-2 gene deletion have decreased proliferation and increased cell differentiation properties. Blood vessel density is reduced in tumors with an epithelial cell-specific Cox-2 gene deletion, compared with littermate control tumors, suggesting a reciprocal relationship in tumor progression between COX-2-expressing tumor epithelial cells and microenvironment endothelial cells. Lipidomics analysis of skin and tumors from DMBA/TPA-treated mice suggests that the prostaglandins PGE2 and PGF2α are likely candidates for the epithelial cell COX-2-dependent eicosanoids that mediate tumor progression. This study both illustrates the value of cell type-specific gene deletions in understanding the cellular roles of signal-generating pathways in complex microenvironments and emphasizes the benefit of a systems-based lipidomic analysis approach to identify candidate lipid mediators of biologic responses.ImplicationsCox-2 gene deletion demonstrates that intrinsic COX-2 expression in initiated keratinocytes is a principal driver of skin carcinogenesis; lipidomic analysis identifies likely prostanoid effectors.

In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2(flox/flox) mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2(flox/flox);K14Cre(+) mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2(flox/flox);K14Cre(+) papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2(flox/flox); LysMCre(+) myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer.

Rural kitchens of solid-fuel burning households constitute the microenvironment responsible for the majority of human exposures to health-damaging air pollutants, particularly respirable particles and carbon monoxide. Portable nephelometers facilitate cheaper, more precise, time-resolved characterization of particles in rural homes than are attainable by gravitational methods alone. However, field performance of nephelometers must contend with aerosols that are highly variable in terms of chemical content, size, and relative humidity. Previous field validations of nephelometer performance in residential settings explore relatively low particle concentrations, with the vast majority of 24-hour average gravitational PM2.5 concentrations falling below 40 μg/m3. We investigate relationships between 24-hour gravitational particle measurements and nephelometric data logged by the personalDataRAM in highly polluted rural Chinese kitchens, where gravitationally determined 24-hour average respirable particle concentrations were as high as 700 μg/m3. We find that where relative humidity remained below 95%, nephelometric response was strongly linear despite complex mixtures of aerosols and variable ambient conditions. Where 95% relative humidity was exceeded for even a brief duration, nephelometrically determined 24-hour mean particle concentrations were nonsystematically distorted relative to gravitational data, and neither concurrent relative humidity measurements nor use of robust statistical measures of central tendency offered means of correction. This nonsystematic distortion is particularly problematic for rural exposure assessment studies, which emphasize upper quantiles of timeresolved particle measurements within 24-hour samples. Precise, accurate interpretation of nephelometrically resolved short-term particle concentrations requires calibration based on short-term gravitational sampling.

Rural kitchens of solid-fuel burning households constitute the microenvironment responsible for the majority of human exposures to health-damaging air pollutants, particularly respirable particles and carbon monoxide. Portable nephelometers facilitate cheaper, more precise, time-resolved characterization of particles in rural homes than are attainable by gravitational methods alone. However, field performance of nephelometers must contend with aerosols that are highly variable in terms of chemical content, size, and relative humidity. Our investigation of relationships between 24-hour optical and gravitational particle measurements in rural Chinese kitchens depicts that where relative humidity remained below 95%, nephelometric response was strongly linear despite complex mixtures of aerosols. Where 95% relative humidity was exceeded for even a brief duration, nephelometric data were nonsystematically distorted, and neither concurrent relative humidity measurements nor use of robust statistical measures of central tendency offered means of correction. This nonsystematic distortion is particularly problematic for rural exposure assessment studies, which emphasize upper quantiles of timeresolved particle measurements both within and between samples. Precise, accurate interpretation of optically resolved short-term particle concentrations requires short-term gravitational sampling concurrent with optical methods.

BackgroundProstate cancer (PCa) is the leading cancer related death in America. Gleason grading is currently the predominant method for prediction, with only few biomarkers available. More biomarkers, especially as they relate to cancer progression are desirable.MethodsThe abundance of several important proteins in prostate tissue was compared between wild-type mouse dorsal prostate and well-differentiated transgenic adenocarcinoma mouse prostate (TRAMP) mouse dorsal prostates, and between wild-type mouse dorsal prostate and poorly-differentiated TRAMP mouse tumor tissue. 2DIGE method in conjunction with MALDI-ToF and Western blots was used to determine differential expression.ResultsIn TRAMP dorsal prostates with well-differentiated adenocarcinoma, there were few significant changes in the protein abundances compared to wild-type dorsal prostates, with the exception of increases in proliferating cell nuclear antigen (PCNA) and beta tubulin, two proteins implicated in cell proliferation, and a more than 2-fold increase in Hsp60, a protein involved in the suppression of apoptosis. In the poorly-differentiated tumors, the changes in protein abundance were substantial. While some of those changes could be related to the disappearance of stromal tissue or the appearance of epithelial tissue, other changes in protein abundance were more significant to the cancer development itself. Most notable was the overall decrease in calcium homeostasis proteins with a 10-fold decrease in calreticulin and Hsp70 and a 40-fold decrease in creatine kinase bb in the cancerous tissue.ConclusionsProteomics of TRAMP mice provide an excellent method to observe changes in protein abundance, revealing changes in pathways during cancer progression.

IKK (I[kappa]B kinase) [alpha] is essential for embryonic skin development in mice. Mice deficient in IKK[alpha] display markedly hyperplasic epidermis that lacks terminal differentiation, and they die because of this severely impaired skin. However, the function of IKK[alpha] in human skin diseases remains largely unknown. To shed light on the role of IKK[alpha] in human skin diseases, we examined IKK[alpha] expression and Ikk[alpha] mutations in human squamous cell carcinomas (SCCs). We found a marked reduction in IKK[alpha] expression in poorly differentiated human SCCs and identified Ikk[alpha] mutations in exon 15 of Ikk[alpha] in eight of nine human SCCs, implying that IKK[alpha] is involved in development of this human skin cancer. Furthermore, in a chemical carcinogen-induced skin carcinogenesis setting, mice overexpressing human IKK[alpha] in the epidermis under the control of a truncated Ioricrin promoter developed significantly fewer SCCs and metastases than did wild-type mice. The IKK[alpha] transgene altered the skin microenvironment conditions, leading to elevated terminal differentiation in the epidermis, reduced mitogenic activity in the epidermis, and decreased angiogenic activity in the skin stroma. Thus, overexpression of IKK[alpha] in the epidermis antagonized chemical carcinogen-induced mitogenic and angiogenic activities, repressing tumor progression and metastases. angiogenesis | mitogenesis | skin carcinogenesis | differentiation | tumor progression

Diminished apoptosis, a critical event in tumorigenesis, is linked to down-regulated 15-lipoxygenase-1 (15-LOX-1) expression in colorectal cancer cells. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which is the primary product of 15-LOX-1 metabolism of linoleic acid, restores apoptosis. Nonsteroidal antiinflammatory drugs (NSAIDs) transcriptionally up-regulate 15-LOX-1 expression to induce apoptosis. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for linoleic and arachidonic acid metabolites. PPAR-[delta] promotes colonic tumorigenesis. NSAIDs suppress PPAR-[delta] activity in colon cancer cells. The mechanistic relationship between 15-LOX-1 and PPAR-[delta] was previously unknown. Our current study shows that (i) 13-S-HODE binds to PPAR-[delta], decreases PPAR-[delta] activation, and down-regulates PPAR-[delta] expression in colorectal cancer cells; (ii) the induction of 15-LOX-1 expression is a critical step in NSAID down-regulation of PPAR-[delta] and the resultant induction of apoptosis; and (iii) PPAR-[delta] is an important signaling receptor for 13-S-HODE-induced apoptosis. The in vivo relevance of these mechanistic findings was demonstrated in our tumorigenesis studies in nude mouse xenograft models. Our findings indicate that the down-regulation of PPAR-[delta] by 15-LOX-1 through 13-S-HODE is an apoptotic signaling pathway that is activated by NSAIDs.

Previous studies demonstrated a requirement for arachidonic acid metabolites in tumor development in mouse skin. The goal of this study was to determine whether the arachidonate content of epidermal phospholipids could be altered by increasing dietary levels of linoleate and whether specific metabolites of linoleate and arachidonate have dissimilar biological effects. In a series of tumor studies in which the quantity of dietary linoleate was incrementally increased, a slight reduction in phospholipid levels of arachidonate was observed that correlated with an increased phospholipid level of linoleate and a suppression in tumor yield. A comparison of the arachidonate lipoxygenase metabolite 12-hydroxyeicosatetraenoic acid (12-HETE) with the 13-hydroxyoctadecadienoic acid (13-HODE) lipoxygenase metabolite of linoleate revealed that 12-HETE has biological activities that mimic the phorbol ester tumor promoters, whereas 13-HODE has antithetical effects. Specifically, 12(S)-HETE enhanced the activation of protein kinase C by phorbol esters, mimicked phorbol ester-induced adhesion of keratinocytes to fibronectin and mimicked phorbol ester repression of expression of a differentiation-related gene, keratin-1. 13-HODE blocked 12-HETE-induced cell adhesion and prevented 12-HETE-induced suppression of keratin-1 expression. Overall, these studies suggest that arachidonate and linoleate have opposing functions in the epidermis, particularly with regard to events involved in tumor development. J. Nutr. 126: 1099S-1104S, 1996. INDEXING KEY WORDS: arachidonate, linoleate, tumor promotion, mouse, lipoxygenase