In colorectal cancer (CRC), APC-mediated induction of unregulated cell growth involves post-translational mechanisms that prevent proteasomal degradation of proto-oncogene β-catenin (CTNNB1) and its eventual translocation to the nucleus. However, about 10 percent of colorectal tumors also exhibit increased CTNNB1 mRNA. Here we show in CRC that increased expression of ZNF148, the gene coding for transcription factor ZBP-89, correlated with reduced patient survival. Tissue arrays showed that ZBP-89 protein was overexpressed in the early stages of CRC. Conditional deletion of Zfp148 in a mouse model of Apc-mediated intestinal polyps demonstrated that ZBP-89 was required for polyp formation due to induction of Ctnnb1 gene expression. ChIP and EMSA identified a ZBP-89 binding site in the proximal promoter of CTNNB1. Recipricolly, siRNA-mediated reduction of CTNNB1 expression also decreased ZBP-89 protein. ChIP identified TCF DNA binding sites in the ZNF148 promoter through which Wnt signaling regulates ZNF148 gene expression. Suppression of either ZNF148 or CTNNB1 reduced colony formation in WNT-dependent, but not WNT-independent cell lines. Therefore, the increase in intracellular β–catenin protein initiated by APC mutations is sustained by ZBP-89-mediated feedforward induction of CTNNB1 mRNA.

Background Intestinal metaplasia (IM) is a gastric cancer precursor lesion (GCPL), with the highest risk to progress to gastric cancer (GC). Clinical guidelines recommend gastroscopy every 3 years for extensive IM. Unfortunately, studies on protein biomarkers indicating a transition from IM to GC are lacking. We have recently found that the IFNα-responsive gene Schlafen 4 (Slfn4) present in immune cells correlates with metaplastic changes in Helicobacter-infected mice. Therefore we tested the hypothesis that a human homolog of Slfn4, which is Schlafen 5 (SLFN5) correlates with progression of GCPL to GC. Methods Jurkat T-lymphoid and HL-60 myeloid cell lines were treated with IFNα and SLFN5 mRNA was quantified by qPCR. SLFN5 protein expression in the inflamed gastric mucosa was co-localized to specific immune cell types by immunohistochemistry using CD20, CD2 and MAC2 antibodies. SLFN5 expression was also determined by immunohistochemistry in FFPE samples from individuals with non-atrophic, atrophic gastritis, complete and incomplete IM as well as GC. Results We demonstrated that IFNα treatment of Jurkat and HL-60 cells induced SLFN5 mRNA. SLFN5 protein was expressed mainly by T lymphocytes in inflamed gastric mucosa. The highest level of SLFN5 expression was observed in subjects with IM that progressed to GC. ROC curves demonstrated that combining SLFN5 expression with the histological diagnosis of IM significantly increased the probability of identifying patients that might progress to GC. Conclusion Elevated SLFN5 protein expression in subjects with IM correlated with progression to gastric cancer.

We confirmed the hypothesis that delivery of one infused drug is transiently affected by starting or stopping a second drug infusion in the same line. The magnitude of the changes can be estimated quantitatively. The clinical impact depends on the drugs being co-infused and patient sensitivity, but could be clinically important; the findings have safety implications for infused medication delivery to critically ill or anesthetized children. We recommend minimizing infusion system dead volumes, connecting the most essential infusion(s) to the main fluid pathway as close as possible to the patient, and recognizing the potential for unintended alterations in delivery when multiple drugs co-infuse.

Compared with conventional methods, algorithm-based computer control of carrier and drug flows can improve drug delivery by pump-driven intravenous infusion to better match intent. For norepinephrine infusions, the amount of drug reaching the bloodstream per time appears to be a dominant factor in the hemodynamic response to infusion.