[Left Atrial Strain Independently and Incrementally Predicts High Risk Thromboembolic Findings Over CHA2DS2-VASc Score and BNP].

BACKGROUND: Left atrial longitudinal strain(LAs) is a novel and useful parameter of LA function and reflecting thromboembolic risk. CHA2DS2-VASc score and brain natriuretic protein (BNP) are also used for risk stratifica- tion. However, little is known about the impact of LAs on stroke risk stratification over these parameters. In this study, we aimed to examine whether LAs has independent and incremental risk stratification over them. METHODS: We studied 97 consecutive patients (age: 66 ± 12, 70 males) who underwent transesophageal echocardi- ography for evaluation of left atrial appendage (LAA) thrombus with persistent or paroxysmal atrial fibrillation. We assessed whether patients had spontaneous echo contrast (SEC) or not. Patients with LAA thrombus or sponta- neous echo contrast (SEC) were defined as high risk. LAs was assessed by averaging the segments measured in the 4- and 2-chamber views by transthoracic echocardiography. RESULTS: Among the 97 patients, 51(53%) patients had sinus rhythm and 36 were with SEC. Although LAs (21.0 ?9.0%), CHA2DS2-VASc score (2.7± 1.7) and BNP were mutually associated, only LAs and CHA2DS2-VASc score were independent predictors of high thromboembolic risk but BNP not. In nested logistic regression model anal- yses, predictive ability of a model with CHA2DS2-VASc score was improved by the addition of BNP (p =0.004) and further by adding LAs (p =0.027). CONCLUSION: LAs predicts independently and incrementally LAA thrombus or SEC over CHA2DS2-VASc score and BNP, suggesting that LAs serves as a functional predictor for future thromboembolism. [Original].

A novel compound, NK150460, exhibits selective antitumor activity against breast cancer cell lines through activation of aryl hydrocarbon receptor.

Antiestrogen agents are commonly used to treat patients with estrogen receptor (ER)-positive breast cancer. Tamoxifen has been the mainstay of endocrine treatment for patients with early and advanced breast cancer for many years. Following tamoxifen treatment failure, however, there are still limited options for subsequent hormonal therapy. We discovered a novel compound, NK150460, that inhibits 17ß-estradiol (E2)-dependent transcription without affecting binding of E2 to ER. Against our expectations, NK150460 inhibited growth of not only most ER-positive, but also some ER-negative breast cancer cell lines, while never inhibiting growth of non-breast cancer cell lines. Cell-based screening using a random shRNA library, identified aryl hydrocarbon receptor nuclear translocator (ARNT) as a key gene involved in NK150460's antitumor mechanism. siRNAs against not only ARNT but also its counterpart aryl hydrocarbon receptor (AhR) and their target protein, CYP1A1, dramatically abrogated NK150460's growth-inhibitory activity. This suggests that the molecular cascade of AhR/ARNT plays an essential role in NK150460's antitumor mechanism. Expression of ERα was decreased by NK150460 treatment, and this was inhibited by an AhR antagonist. Unlike two other AhR agonists now undergoing clinical developmental stage, NK150460 did not induce histone H2AX phosphorylation or p53 expression, suggesting that it did not induce a DNA damage response in treated cells. Cell lines expressing epithelial markers were more sensitive to NK150460 than mesenchymal marker-expressing cells. These data indicate that NK150460 is a novel AhR agonist with selective antitumor activity against breast cancer cell lines, and its features differ from those of the other two AhR agonists.

Cytotoxicity of lissoclibadins and lissoclinotoxins, isolated from a tropical ascidian Lissoclinum cf. badium, against human solid-tumor-derived cell lines.

The in vitro growth inhibitory activity of lissoclibadins and lissoclinotoxins isolated from the tropical ascidian Lissoclinum cf. badium against nine human cancer cell lines was examined to evaluate their potential anticancer efficacy. Lissoclibadins 1 (1) and 2 (2), and lissoclinotoxin F (4) showed the strongest activity of the six compounds tested, which were more potent than the anticancer drug cisplatin. Compound 1 has a trimeric structure, and compounds 2 and 4 are structural isomers possessing dimeric structures connected by disulfide and sulfide bonds of trans- and cis-orientations, respectively. Lissoclibadin 3 (3), a dimeric compound connected by two sulfide bonds, and two monomeric compounds (5, 6) were less active than 1, 2, and 4. Lissoclibadin 2 (2) was the most interesting compound possessing potent inhibitory activity against colon (DLD-1 and HCT116), breast (MDA-MB-231), renal (ACHN), and non-small-cell lung (NCI-H460) cancer cell lines and showing no toxicity following a 50 mg/kg single treatment to mice, and preferable stability in rat plasma.