Mixed occupational and iatrogenic allergic contact dermatitis in a hairdresser.

Allergic contact dermatitis (ACD) is a common occupational disease. Hairdressers and beauticians are at increased risk of occupational chronic hand eczema. We present a case of mixed occupational, non-occupational and iatrogenic ACD in a hairdresser which illustrates that delayed diagnosis can result in high morbidity, and unnecessary treatment and cost. A hairdresser with chronic hand and facial eczema failed medical management with topical steroids and dupilumab. Patch testing revealed contact allergy to multiple occupational exposures, home exposures and topical medicaments.

Transforming activity and therapeutic targeting of C-terminal-binding protein 2 in Apc-mutated neoplasia.

Overexpression of the transcriptional coregulators C-terminal binding proteins 1 and 2 (CtBP1 and 2) occurs in many human solid tumors and is associated with poor prognosis. CtBP modulates oncogenic gene expression programs and is an emerging drug target, but its oncogenic role is unclear. Consistent with this oncogenic potential, exogenous CtBP2 transformed primary mouse and human cells to anchorage independence similarly to mutant H-Ras. To investigate CtBP's contribution to in vivo tumorigenesis, Apcmin/+ mice, which succumb to massive intestinal polyposis, were bred to Ctbp2+/- mice. CtBP interacts with adenomatous polyposis coli (APC) protein, and is stabilized in both APC-mutated human colon cancers and Apcmin/+ intestinal polyps. Ctbp2 heterozygosity increased the median survival of Apcmin/+ mice from 21 to 48 weeks, and reduced polyp formation by 90%, with Ctbp2+/- polyps exhibiting reduced levels of ß-catenin and its oncogenic transcriptional target, cyclin D1. CtBP's potential as a therapeutic target was studied by treating Apcmin/+ mice with the CtBP small-molecule inhibitors 4-methylthio-2-oxobutyric acid and 2-hydroxy-imino phenylpyruvic acid, both of which reduced polyposis by more than half compared with vehicle treatment. Phenocopying Ctbp2 deletion, both Ctbp inhibitors caused substantial decreases in the protein level of Ctbp2, as well its oncogenic partner ß-catenin, and the effects of the inhibitors on CtBP and ß-catenin levels could be modeled in an APC-mutated human colon cancer cell line. CtBP2 is thus a druggable transforming oncoprotein critical for the evolution of neoplasia driven by Apc mutation.

Unraveling the role of proteases in cancer.

Investigators have been studying the expression and activity of proteases in the final steps of tumor progression, invasion and metastasis, for the past 30 years. Recent studies, however, indicate that proteases are involved earlier in progression, e.g., in tumor growth both at the primary and metastatic sites. Extracellular proteases may co-operatively influence matrix degradation and tumor cell invasion through proteolytic cascades, with individual proteases having distinct roles in tumor growth, invasion, migration and angiogenesis. In this review, we use cathepsin B as an example to examine the involvement of proteases in tumor progression and metastasis. We discuss the effect of interactions among tumor cells, stromal cells, and the extracellular matrix on the regulation of protease expression. Further elucidation of the role of proteases in cancer will allow us to design more effective inhibitors and novel protease-based drugs for clinical use.

Tumor cell membrane cathepsin B.

The lysosomal cysteine peptidase cathepsin B was found to be associated with plasma membrane/endosomal fractions of murine B16 amelanotic melanoma cells. Confocal microscopy with three dimensional image analysis indicated that cathepsin B was associated with the external basal cell surface, which would be consistent with its proposed role in degradation of extracellular matrix proteins. We purified and partially characterized cathepsin B from homogenates of murine liver and B16 amelanotic melanoma cells and from lysosomal and membrane/endosomal fractions of the B16 tumor cells. By SDS-PAGE under reducing conditions, the purified cathepsin B from the tumor homogenates was resolved as a single protein band of Mr 31000, corresponding to the single chain form of cathepsin B. In contrast, cathepsin B from liver homogenates was resolved as two bands of Mr 31000 and 24000, corresponding to the single chain and the heavy chain of the double chain form, respectively. The tumor cathepsin B consisted of four isozymes with pIs of 5.64, 5.33, 5.2 and 5.1, whereas the liver cathepsin B consisted of five isozymes with pIs of 5.64, 5.5, 5.45, 5.35 and 5.3. The additional acidic isoforms of cathepsin B in the B16 tumor probably reflect altered glycosylation in tumors. The commonality of isoforms in the B16 plasma membrane/endosomal and lysosomal fractions suggests that retrograde trafficking of cathepsin B from the lysosome to the endosome and its exocytotic release result in the association of cathepsin B with the tumor cell membrane.