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Factors Influencing Growth and Differentiation of Normal and Transformed Human Mammary Epithelial Cells in Culture
Published in George E. Milo, Bruce C. Casto, Charles F. Shuler, Transformation of Human Epithelial Cells: Molecular and Oncogenetic Mechanisms, 2017
Martha R. Stampfer, Paul Yaswen
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.
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.
The development and hepatotoxicity of acetaminophen: reviewing over a century of progress
Published in Drug Metabolism Reviews, 2020
Mitchell R. McGill, Jack A. Hinson
Currently, two drugs are the focus of clinical investigation. Mangafodipir is a manganese-containing compound that approved in many countries as an imaging contrast agent. The manganese ions dissociate and enter normal tissues, which makes them appear brighter by MRI. It has also been tested as a MnSOD mimetic, due to the presence of manganese. In the latter case, dissociation is undesirable. Calmangafodipir (CMF) was developed to address that. CMF is a mangafodipir derivative in which all but one manganese is replaced by calcium, which prevents release of the single remaining manganese and facilitates its function as an antioxidant. Mangafodipir itself has been shown to be hepatoprotective after APAP overdose and ischemia–reperfusion injury in mice (Bedda et al. 2003; Coriat et al. 2011). Importantly, a recent phase I clinical trial in which CMF treatment was combined with a truncated NAC regimen revealed that addition of CMF modestly decreased the serum liver injury biomarkers keratin 18 and caspase-cleaved keratin 18 in overdose patients with no effect on serious adverse event reporting (Morrison et al. 2019). These data demonstrate that CMF is a safe and potentially efficacious adjunct to NAC.
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