Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are important hepatic transporters that mediate the uptake of many clinically important drugs, including statins from the blood into the liver. Reduced transport function of OATP1B1 and OATP1B3 can lead to clinically relevant drug-drug interactions (DDIs). Considering the importance of OATP1B1 and OATP1B3 in hepatic drug disposition, substantial efforts have been given on evaluating OATP1B1/1B3-mediated DDIs in order to avoid unwanted adverse effects of drugs that are OATP substrates due to their altered pharmacokinetics. Growing evidences suggest that the transport function of OATP1B1 and OATP1B3 can be regulated at various levels such as genetic variation, transcriptional and post-translational regulation. The present review summarizes the up to date information on the regulation of OATP1B1 and OATP1B3 transport function at different levels with a focus on potential impact on OATP-mediated DDIs.

CAR-T (chimeric antigen receptor T cells) immunotherapy is effective in many hematological cancers; however, efficacy in solid tumors is disappointing. Doublecortin-like kinase 1 (DCLK1) labels tumor stem cells (TSCs) in genetic mouse models of colorectal cancer (CRC). Here, we describe a novel CAR-T targeting DCLK1 (CBT-511; with our proprietary DCLK1 single-chain antibody variable fragment) as a treatment strategy to eradicate CRC TSCs. The cell surface expression of DCLK1 and cytotoxicity of CBT-511 were assessed in CRC cells (HT29, HCT116, and LoVo). LoVo-derived tumor xenografts in NOD Scid gamma (NSG™) mice were treated with CBT-511 or mock CAR-T cells. Adherent CRC cells express surface DCLK1 (two-dimensional, 2D). A 4.5-fold increase in surface DCLK1 was observed when HT29 cells were grown as spheroids (three-dimensional, 3D). CBT-511 induced cytotoxicity (2D; p < 0.0001), and increased Interferon gamma (IFN-γ) release in CRC cells (2D) compared to mock CAR-T (p < 0.0001). Moreover, an even greater increase in IFN-γ release was observed when cells were grown in 3D. CBT-511 reduced tumor growth by approximately 50 percent compared to mock CAR-T. These data suggest that CRC cells with increased clonogenic capacity express increased surface DCLK1. A DCLK1-targeted CAR-T can induce cytotoxicity in vitro and inhibit xenograft growth in vivo.

The polycomb group protein, BMI1 plays important roles in chromatin modification, stem cell function, DNA damage repair and mitochondrial bioenergetics. Such diverse cellular functions of BMI1 could be, in part, due to post-translational modifications, especially phosphorylation. To date, AKT has been reported as a kinase that by site specific phosphorylation of BMI1 modulates its oncogenic functions. Immunoprecipitation in conjunction with kinase assay and mass spectrometry was used to determine association with and site specific phosphorylation of BMI1 by CK2α. Functional implications of the BMI1/CK2α axis was examined in cancer cells utilizing siRNA and exogenous gene expression followed by biochemical and phenotypic studies. Correlations between expression of CK2α and BMI1 were determined from cell lines and formalin fixed paraffin embedded tissues representing the normal fallopian tube epithelium and high grade serous ovarian cancer samples. Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. In ovarian cancer cell lines, expression of CK2α correlated with the phospho-species, as well as basal BMI1 levels. Preventing phosphorylation of BMI1 at Serine 110 significantly decreased half-life and stability of the protein. Additionally, re-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function. Clinically, compared to normal fallopian tube epithelial tissues, the expression of both BMI1 and CK2α were significantly higher in tumor tissues obtained from high-grade serous ovarian cancer patients. Among tumor samples, the expression of BMI1 and CK2α positively correlated (Spearman coefficient = 0.62, P = 0.0021) with each other. Taken together, our findings establish an important regulatory role of CK2α on BMI1 phosphorylation and stability and implicate the CK2α/BMI1 axis in ovarian cancer.

The American Cancer Society discourages the dual use of electronic cigarettes (ECs) and cigarettes because such use has not resulted in reduced exposures to the harmful effects of smoking. American Indian (AI) people have the highest prevalence of smoking and of EC use in the United States, but very little is known about dual EC and cigarette use in AI communities. In 2016, 375 adult AI in Oklahoma who smoked cigarettes completed a survey about EC use (vaping). We describe vaping patterns, nicotine dependence, and reasons for EC use among the subset of 44 (12%) current dual EC users. To differentiate habitual EC users from occasional or merely curious users, we defined dual use as using ECs on some days or every day in the past 30 days. About one-third of dual users vaped ten or more times daily. About two-thirds used a tank product. Eleven percent used ECs without nicotine and another 9% were unsure of the nicotine content. A minority (40%) enjoyed vaping more than smoking, and most (76%) would smoke first on days they did both. Thirty-one percent vaped within 5 min of waking and another 24% within 30 min. Although the two-item heaviness of use index did not differ significantly between smoking and vaping, the ten-item Penn State Dependence Index (PSDI) suggested greater dependence on smoking than vaping (11.02 vs. 6.42, respectively; p < .0001). The most common reasons for vaping were to reduce smoking (79%), enjoyment of flavors (78%), and ability to vape where smoking is not allowed (73%). Perceptions of less harm to others (69%) or to self were the next most common (65%). Fewer than half used ECs to reduce stress, for affordability, or because others used them. Nearly 20% of dual users used ECs either without nicotine or without knowing if the product contained nicotine. The PSDI indicated greater dependence on smoking than vaping. Reasons for vaping were nearly equal between smoking reduction and enjoying flavors. Understanding patterns of dual use will inform future efforts to address nicotine dependence for AI communities with high prevalence of smoking.

To study the association between knowledge of diseases caused by smoking, perceptions of harm of cigarettes and intention to quit among cigarettes and e-cigarettes users. Methods: Using US Populati...