Factors Influencing Growth and Differentiation of Normal and Transformed Human Mammary Epithelial Cells in Culture
George E. Milo, Bruce C. Casto, Charles F. Shuler in Transformation of Human Epithelial Cells: Molecular and Oncogenetic Mechanisms, 2017
Some of our cell lines which have been transformed in vitro to immortality and tumorigenicity have been examined for their expression of differentiation markers, including intermediate filaments, mucins, the extracellular matrix protein fibronectin, and a newly isolated gene designated NB-1 (see below) (Figures 2 and 3). The immortalized cell lines 184A1 and 184B5 maintain some expression of keratins 5 and 14, but Northern blot analysis shows that the level of keratin 5 mRNA is decreased in 184B5, and even further decreased in 184A1, while expression of keratin 18 mRNA is increased relative to normal HMEC. These lines also differ from the normal cells in their barely detectable levels of vimentin mRNA. 184B5 expresses the luminal PEM antigens, including one epitope, recognized by the antibody HMFG-2, which is found in tumor cells (data not shown). The tumorigenic transformants A1N4-TH and B5KTu have very low levels of keratin 5 and increased levels of keratin 18 mRNA. While B5KTu remains vimentin negative, the A1N4-TH cells show reexpression of vimentin. We have not been able to detect keratin 19 mRNA in any of these lines. These results suggest that the transformed cells, particularly 184B5, have a phenotype which is closer to the luminal phenotype than that seen in the normal HMEC, but do not fully resemble breast tumor cells.
Systemic inflammation is associated with circulating cell death released keratin 18 fragments in colorectal cancer
Published in OncoImmunology, 2020
Päivi Sirniö, Juha P. Väyrynen, Shivaprakash J. Mutt, Karl-Heinz Herzig, Jaroslaw Walkowiak, Kai Klintrup, Jyrki Mäkelä, Tuomo J. Karttunen, Markus J. Mäkinen, Anne Tuomisto
Necrotic cell death may stimulate systemic inflammation, and high extent of tumor necrosis has been associated with increased serum IL6 and CRP levels in CRC.10 Keratins such as keratin 18 (KRT18) are intracellular structural proteins, which are released from dead cells and can be used as serum biomarkers of cell death. KRT18 is widely expressed by a variety of single-layered epithelial cells, including gastrointestinal tract epithelium, hepatocytes, and CRC cells.11,12 During apoptotic cell death, caspase-cleaved KRT18 fragments (aKRT18) are released, whereas full-length KRT18 (nKRT18) is released during necrosis.13,14 Different forms of KRT18 are measured by specific enzyme-linked immunosorbent assays (ELISAs) using antibodies M30 and M65. The M30 antibody detects aKRT18, whereas the M65 antibody binds both aKRT18 and nKRT18, thus detecting total KRT18 (tKRT18).15
Biomarkers of drug-induced liver injury: progress and utility in research, medicine, and regulation
Published in Expert Review of Molecular Diagnostics, 2018
Mitchell R. McGill, Hartmut Jaeschke
Like HMGB1, keratin 18 (K18) can be measured in circulation in two forms. K18 is a structural protein, part of the cytoskeleton. During apoptosis, caspases cleave K18 to reveal a novel epitope that is recognized by an antibody called M30 [89]. Both total and caspase-cleaved K18 are elevated in circulation of APAP overdose patients [71], though total is far higher in both APAP overdose and other DILI [73] indicating that the major mode of cell death is oncotic necrosis. Importantly, total K18 is one of the best prognostic biomarkers identified so far for both prediction of later injury in early-presenting APAP overdose patients [72] and for patient death/survival in DILI [73], though the results are still modest. Interestingly, plasma levels of total K18 and the ratio of cleaved-to-total K18 are also predictive of early stage mortality in alcoholic hepatitis [90].
Performance of the paracetamol-aminotransferase multiplication product in risk stratification after paracetamol (acetaminophen) poisoning: a systematic review and meta-analysis
Published in Clinical Toxicology, 2023
Chun En Yau, Haoyang Chen, Bryant Po-Yuen Lim, Mingwei Ng, R. Ponampalam, Daniel Yan Zheng Lim, Yip Han Chin, Andrew Fu Wah Ho
Newer risk stratification tools which measure the formation of reactive metabolites have emerged with increasing research into the molecular mechanisms of drug induced liver injury. These mechanistic biomarkers such as microRNA-122 and keratin-18 are slated to be more unique and applicable to the individual patient [22–24]. However, these biomarker assays are currently not routinely available in most emergency departments or medical centres. Predictors of hepatotoxicity in paracetamol overdose patients using commonly measured biochemical values are needed. One such predictor is the product of the serum paracetamol concentration and aminotransferase activity (AT), using the activity of alanine aminotransferase (ALT) or aspartate transferase (AST), whichever is higher [18]. Lower limit cut-off value paracetamol × aminotransferase = 1500 mg/L × IU/L proposed by Sivilotti et al. [25] and upper limit cut-off value paracetamol × aminotransferase = 10,000 mg/L × IU/L by Wong et al. [26] are the limits investigated by existing studies.
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