ADAR1-dependent miR-3144-3p editing simultaneously induces MSI2 expression and suppresses SLC38A4 expression in liver cancer.

Aberrant adenosine-to-inosine (A-to-I) RNA editing, catalyzed by adenosine deaminase acting on double-stranded RNA (ADAR), has been implicated in various cancers, but the mechanisms by which microRNA (miRNA) editing contributes to cancer development are largely unknown. Our multistage hepatocellular carcinogenesis transcriptome data analyses, together with publicly available data, indicated that ADAR1 was the most profoundly dysregulated gene among RNA-editing enzyme family members in liver cancer. Targeted inactivation of ADAR1 inhibited the in vitro tumorigenesis of liver cancer cells. An integrative computational analyses of RNA-edited hotspots and the known editing frequency of miRNAs suggested that the miRNA miR-3144-3p was edited by ADAR1 during liver cancer progression. Specifically, ADAR1 promoted A-to-I editing of canonical miR-3144-3p to replace the adenosine at Position 3 in the seed region with a guanine (ED_miR-3144-3p(3_A < G)) in liver cancer cells. We then demonstrated that Musashi RNA-binding protein 2 (MSI2) was a specific target of miR-3144-3p and that MSI2 overexpression was due to excessive ADAR1-dependent over-editing of canonical miR-3144-3p in liver cancer. In addition, target prediction analyses and validation experiments identified solute carrier family 38 member 4 (SLC38A4) as a specific gene target of ED_miR-3144-3p(3_A < G). The ectopic expression of both ADAR1 and the ED_miR-3144-3p(3_A < G) mimic enhanced mitotic activities, and ADAR1 suppressed SLC38A4 expression in liver cancer cells. Treatments with mouse-specific ADAR1-, MSI2-siRNA-, or SLC38A4-expressing plasmids suppressed tumorigenesis and tumor growth in a mouse model of spontaneous liver cancer. Our findings suggest that the aberrant regulation of ADAR1 augments oncogenic MSI2 effects by excessively editing canonical miR-3144-3p and that the resultant ED_miR-3144-3p(3_A < G) simultaneously suppresses tumor suppressor SLC38A4 expression, contributing to hepatocellular carcinogenesis.

Miniplate Augmented Tension-Band Wiring for Comminuted Patella Fractures.

The aim of this study was to introduce various applications of miniplate augmented tension-band wiring (TBW) for comminuted patella fractures and to evaluate the clinical outcomes. Comminuted articular patella fractures were managed with anterior cortical miniplate fixation with a TBW technique from January 2014 to January 2016. The primary end point was radiographic union. Secondary end points were complications related to the procedure. Functional outcomes including range of motion were also evaluated. Thirty patients were followed up for a mean of 20 months (range, 12-28) postoperatively. The primary union rate was 96% (29 of 30 patients). Mean time to union was 3.2 months. One patient required additional surgery because of acute postoperative infection. Twenty-five patients recovered a full range of motion relative to the contralateral limb. The mean Bostman score at the last follow-up was 28.6 points (range, 26-30). In conclusion, miniplate augmented TBW is a versatile and useful technique for comminuted patella fracture fixation.

Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers.

BACKGROUND: Pitavastatin is a potent, newly developed 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor for the treatment of hyperlipidemia. We characterized the effects of organic anion transporting polypeptide 1 B 1 (OATP 1 B 1) alleles *1a, *1b, and *15 on the pharmacokinetics of pitavastatin. METHODS: Twenty-four healthy Korean volunteers who had previously participated in a pharmacokinetic study of pitavastatin (single oral dose, 1--8 mg) were further investigated. Subjects were grouped according to OATP 1 B 1 genotype. Dose-normalized area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) values were analyzed, because different dosages were administered to subjects, whereas the pharmacokinetics showed linear characteristics. RESULTS: Dose-normalized pitavastatin AUCs for *1b/*1b (group 1), *1a/*1a or *1a/*1b (group 2), and *1a/*15 or *1b/*15 (group 3) were 38.8+/-13.3, 54.4 +/-12.4, and 68.1+/-6.3 ng.h.mL(-1).mg(-1) (mean+/-SD), respectively, with significant differences between all 3 groups (P=.008) and between subjects carrying and those not carrying the *15 allele (P = .004). Dose-normalized pitavastatin C(max) values were 13.2+/- 3.3, 18.2+/-5.7, and 29.4+/- 9.6 ng.mL(-1).mg(-1) in groups 1, 2, and 3, respectively, and also showed significant differences (P=.003) in a manner similar to that shown by AUC. No significant differences were found between the genotype groups in terms of dose-normalized AUC or C(max) values of pitavastatin lactone. CONCLUSION: OATP 1 B 1 variant haplotypes were found to have a significant effect on the pharmacokinetics of pitavastatin. These results suggest that the *15 allele is associated with decreased pitavastatin uptake from blood into hepatocytes and that OATP 1 B 1 genetic polymorphisms have no effect on the pharmacokinetics of pitavastatin lactone.

New view on the initial development site and radiographic classification system of osteoarthritis of the knee based on radiographic analysis.

INTRODUCTION: Radiographic pathology of severe osteoarthritis of the knee (OAK) such as severe osteophyte at tibial spine (TS), compartment narrowing, marginal osteophyte, and subchondral sclerosis is well known. Kellgren-Lawrence grading system, which is widely used to diagnose OAK, describes narrowing-marginal osteophyte in 4-grades but uses osteophyte at TS only as evidence of OAK without detailed-grading. However, kinematically the knee employs medial TS as an axis while medial and lateral compartments carry the load, suggesting that early OAK would occur sooner at TS than at compartment. Then, Kellgren-Lawrence system may be inadequate to diagnose early-stage OAK manifested as a subtle osteophyte at TS without narrowing-marginal osteophyte. This undiagnosed-OAK will deteriorate becoming a contributing factor in an increasing incidence of OAK. METHODS: This study developed a radiographic OAK-marker based on both osteophyte at TS and compartment narrowing-marginal osteophyte and graded as normal, mild, moderate, and severe. With this marker, both knee radiographs of 1,728 patients with knee pain were analyzed. RESULTS: Among 611 early-stage mild OAK, 562 or 92% started at TS and 49 or 8% at compartment. It suggests the initial development site of OAK, helping develop new site-specific radiographic classification system of OAK accurately to diagnose all severity of OAK at early, intermediate, or late-stage. It showed that Kellgren-Lawrence system missed 92.0% of early-stage mild OAK from diagnosis. CONCLUSIONS: A subtle osteophyte at TS is the earliest radiographic sign of OAK. A new radiographic classification system of OAK was suggested for accurate diagnosis of all OAK in severity and at stage.