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Previous in vitro studies have identified a nuclear isoform of Cathepsin L. The aim of this study was to examine if nuclear Cathepsin L exists in vivo and examine its association with clinical, pathological and patient outcome data. Cellular localization (nuclear and cytoplasmic) and expression levels v of Cathespin L in 186 colorectal cancer cases using immunohistochemistry. The molecular weight and activity of nuclear and cytoplasmic Cathepsin L in vivo and in vitro were assessed by Western blotting and ELISA, respectively. Epithelial nuclear staining percentage (p 5 0.04) and intensity (p 5 0.006) increased with advancing tumor stage, whereas stromal cytoplasmic staining decreased (p 5 0.02). Using multivariate statistical analysis, survival was inversely associated with staining intensity in the epithelial cytoplasm (p 5 0.01) and stromal nuclei (p 5 0.007). In different colorectal cell lines and in vivo tumors, pro-and active Cathepsin L isoforms were present in both the cytoplasm and nuclear samples, with pro-Cathepsin L at 50 kDa and active Cathepsin L at 25 kDa. Purified nuclear and cytoplasmic fractions from cell lines and tumors showed active Cathepsin L activity. The identification of nuclear Cathepsin L may play an important prognostic role in colorectal disease progression and patient outcome. Moreover, these findings suggest that altering active nuclear Cathepsin L may significantly influence disease progression. ' UICCKey words: colorectal cancer; cathepsin L; disease progression; survival Colorectal cancer is one of the most common cancers in the Western World. Tumor invasion and metastasis are major causes of treatment failure 1 and this multi-step process involves penetration of host extracellular matrix (ECM) by cancer cells, which invade the host stroma and enter the circulation. The outcome of metastasis is dependent on the interaction between the intrinsic properties of the tumor cells and various host factors, and this balance may vary from patient to patient. 2,3 The ability of tumor cells to invade tissues and metastasize is thought to involve an increased expression and activity of proteases including cathepsins. 4,5 Tumor spread is also correlated with increased levels of these activated enzymes. 6 The cysteine protease, Cathepsin L, is thought to participate in tumor cell invasion, although its exact role remains unknown. 7 The Cathepsin L gene is activated by a variety of growth factors and oncogenes. 8 It is initially synthesized as a 334-amino acid precursor containing a 17-amino acid N-terminal signal peptide followed by a 96-amino acid propeptide. 9-11 Pro-Cathepsin L is an inactive precursor and is processed to a single chain form of mature Cathepsin L, which can be further cleaved to the two-chain forms, linked to a light-chain by disulfide bonds. 12,13 Pro-and active forms of Cathepsin L differ in size depending on the species, tissue and cell line investigated. Colorectal cancers have been profiled based on the levels of different cysteine proteases including Cathepsin L. 1...

The high prevalence of celiac disease in patients with autoimmune hypothyroidism, compared to the general population, has been well documented but screening for celiac disease is not recommended as yet in otherwise asymptomatic hypothyroid patients. In recent years the high prevalence of undiagnosed celiac disease in the general population, largely as a result of the many atypical manifestations of the disease, has become apparent. We report the case of a 58-year-old woman with autoimmune hypothyroidism who was initially suspected of having celiac disease on the basis of apparent resistance to levothyroxine therapy, and who had no other clinical or laboratory clues to suggest the diagnosis. Cases of undiagnosed celiac disease causing levothyroxine malabsorbtion have previously been described, but all previous cases had other obvious manifestations of the disease. We believe that this atypical presentation of celiac disease warrants further attention, and that the diagnosis of celiac disease should always be considered in patients requiring higher than expected doses of thyroid hormone replacement, even in patients with normal bowel habit, and no other apparent manifestations of the disease.

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