Wnt signaling is often constitutively active in colorectal cancer cells. The expression of the intestinal specific transcription factor CDX2 is found to be transiently decreased in invasive cells at the tumor/stroma interface. A recent ChIP-Seq study has indicated that several Wnt signaling-related genes are regulated by CDX2. The aim was to investigate the role of decreased CDX2 level on the expression of APC, AXIN2 and GSK3β in migrating colon cancer cells at the invasive front. CDX2-bound promoter and enhancer regions from APC, AXIN2 and GSK3β were analyzed for gene regulatory activity and the expression pattern of APC and GSK3β at the invasive front was evaluated by immunohistochemical procedures. Transfection of intestinal and non-intestinal cell lines demonstrated that CDX2 activated APC and AXIN2 promoter activities via intestinal cell-specific enhancer elements. Suppressed CDX2 expression was associated with endogenous downregulation of APC and AXIN2 expression in Caco-2 cells but did not affect GSK3β expression. Furthermore, elevated levels of nuclear β-catenin and reduced levels of cytoplasmic APC were correlated to a low CDX2 expression in migrating colon cancer cells in vivo. These results suggest that a low CDX2 level has influence on the Wnt signaling in invasive colon cancer cells possibly promoting cellular migration.

Background: Polypharmacy is most prevalent among the elderly population and in particular among nursing home residents. The frequency of the use of drugs with pharmacogenomics (PGx)-based dosing guidelines for CYP2D6, CYP2C9, CYP2C19 and SLCO1B1 were measured among nursing home residents in the Capital Region of Denmark as well as drug–drug interactions. The aim was to evaluate the potential of applying PGx-test as a supportive tool in medication reviews. Methods: Drug use among nursing home residents during 2017–2018 in the Capital Region of Copenhagen, for drugs with PGx-based dosing guidelines available through the PharmGKB website, were measured. Drug–drug interactions were scored in severity by using drug interaction checkers. Results: The number of residents using drugs with PGx-based actionable dosing guidelines (AG) were 119 out of 141 residents (84.3%). Of these 119 residents, 87 residents used drugs with AG for CYP2C19, 47 residents for CYP2D6, and 42 residents for SLCO1B1. In addition, 30 residents used two drugs with an AG for CYP2C19, and for CYP2D6, it was only seven residents. The most used drugs with AG were clopidogrel (42), pantoprazole (32), simvastatin (30), metoprolol (25), and citalopram (24). The most frequent drug interactions found with warnings were combinations of proton pump inhibitors and clopidogrel underscoring the potential for phenoconversion. Conclusion: this study clearly showed that the majority of the nursing home residents were exposed to drugs or drug combinations for which there exist PGx-based AG. This indeed supports the notion of accessing and accounting for not only drug–gene but also drug–drug–gene interactions as a supplement to medication review.

Background: The cytochrome P450 drug metabolizing enzymes CYP2D6 and CYP2C19 are the major targets for pharmacogenomics (PGx) testing and determining for drug response. Clinical dosing guidelines for specific drug-gene interactions (DGI) are publicly available through PharmGKB. The aim of this register study was to map the use of drugs in Denmark for drugs having actionable dosing guidelines (AG) i.e., dosing recommendations different from standard dosing for CYP2D6 or CYP2C19 DGI in terms of consumption. Methods: The Danish Register of Medicinal Product Statistics was the source to retrieve consumption in Defined Daily Dose (DDD) i.e., the assumed average maintenance dose per day for a drug used for its main indication in adults and number of users (2017 data). Clinical dosing guidelines were available from the PharmGKB website. Results: Forty-nine drugs have guidelines corresponding to 14.5% of total sales in DDD. Twenty-eight drugs have AG corresponding to 375.2 million DDD. Pantoprazole, lansoprazole, omeprazole, clopidogrel, and metoprolol constituted fifty-eight percent of the consumption in DDD of drugs having AG. The consumption of antidepressant drugs, opioids, and antipsychotic drugs were 157.0 million DDD; with 441,850 users, 48.9 million DDD; with 427,765 users, and 23.7 million DDD; with 128,935 users, respectively. Age distributions of consumption of drugs and drug combinations, e.g., for sertraline redeemed either alone or in combination with metoprolol and tramadol, are presented. Conclusion: This exploratory register study clearly showed that a large fraction of the Danish population, especially the elderly, are exposed to drugs or drug combinations for which there exist AG related to PGx of CYP2D6 or CYP2C19.

MicroRNAs are small regulatory RNAs that are deregulated in a wide variety of human cancers, including different types of B-cell lymphoma. Nevertheless, the feasibility of circulating microRNA for early diagnosis of B-cell lymphoma has not been established. To address the possibility of detecting specific circulating microRNAs years before a B-cell lymphoma is diagnosed, we studied the plasma expression of microRNA first in pre-treatment samples from patients with diffuse large B-cell lymphoma and subsequently in repository samples from blood donors who later developed B-cell lymphomas. In addition, we studied the microRNA expression in the diagnostic lymphoma biopsy. The most strongly induced (miR-326) and suppressed (miR-375) plasma microRNA at diagnosis, when compared with healthy blood donors, were also substantially up- or down-regulated in plasma repository samples taken from several months to up to two years before the blood donors were diagnosed with B-cell lymphoma. Importantly, at these time points the donors had no signs of disease and felt healthy enough to donate blood. In conclusion, this first study of plasma microRNA profiles from apparently healthy individuals, taken several years before B-cell lymphoma diagnosis, suggests that plasma microRNA profiles may be predictive of lymphoma development.

World Health Organization guidelines now recommend routine use of viral load testing, where available, for patients receiving antiretroviral treatment (ART). However, its use has not been routinely implemented in many resource-limited settings due to cost, availability and accessibility. Viral load testing is complex, making its application in resource-limited settings challenging. We describe the issues encountered by Médecins Sans Frontières (MSF) when using routine viral load testing in a large HIV programme in sub-Saharan Africa.