Ruwhof, C. & van der Laarse, A. Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc. Res. 47, 23–37 (2000).

The yield of synthesis is not great, André says, so it is difficult to predict whether a residue of unreacted epichlorohydrin might be carried over in the final product. Nevertheless, he asks, “Which impurities does the US Pharmacopoeia require testing for? Chlorides, sulfates, sodium and potassium, none of which is toxic at such levels.” He wonders how many manufacturers of this compound are even aware of the potential risk.

Additional clinical trials may divert a significant amount of Company resources and may ultimately be unsuccessful.

Since the completion of the Phase 2a study, pre-clinical toxicology studies have been conducted to support our ongoing clinical programs and regulatory submissions. These studies were performed in compliance with the EMA’s ICH M3 (R2) guidelines by WIL Research, a global contract research organization, at its facility in Holland. The toxicity program for Aramchol included repeat dose studies of up to six months in rats and up to nine months in dogs by oral administration, the intended route of administration in the clinical trials and beyond. The dose level of 1000 mg/kg/day in rats and 1500 mg/kg/day in dogs, which is the maximal feasible dose in both species showed no-observed-adverse-effect-level, or NOAEL. There were no observations noted in the rat study. The findings in the dog study were limited to changes in plasma lipids, including decreases in total blood cholesterol levels, LDL, HDL and phospholipids, and a slight increase in the size of the adrenal glands, which were considered to be an extension of the primary pharmacology of Aramchol and non-toxic effects, and skin scales from week 13 onwards in all Aramchol-treated groups, with a dose-related incidence. After six months this was not accompanied by any microscopic alteration of the skin and therefore considered not toxicologically relevant. Results from the study show that after nine months the presence of scales in all Aramchol-treated groups was accompanied by minor test item-related microscopic findings in the skin: Hyperkeratosis of the epidermis, correlating to the scales, and keratin plugs in the hair follicles (in males at 750/500 and 1500 mg/kg). After a 12-week treatment-free recovery period, fewer scales were noted and microscopically there was partial recovery. As these findings were minor and no clinical symptoms like scratching were noted, these findings were considered not adverse. 

We have never declared or paid any cash dividends on our ordinary shares and do not anticipate paying any cash dividends in the foreseeable future. Payment of cash dividends, if any, in the future will be at the discretion of our Board and will depend on then-existing conditions, including our financial condition, operating results, contractual restrictions, capital requirements, business prospects and other factors our Board may deem relevant.

(b)      Designed such internal control over financial reporting, or caused such internal control over financial reporting to be designed under our supervision, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles;

In the presence of L-NAME, the relaxation observed in response to the β-BA was significantly smaller than under control and β-BA (200 mg/kg) groups (Fig. 5a). Pretreatment of NO synthase inhibitor L-NAME reduced basal NO formation in the rats of the model group, treatment showed better contractile response in aorta compared with the model group, suggesting a higher NO formation in the vessel. eNOS phosphorylation and cell viability were increased by β-BA under OGD treatment in HUVECs (Fig. 5b), and the protective effect of β-BA was attenuated by knockdown of eNOS (Fig. 5b) (P < 0.01). All the aforementioned results indicate that eNOS is essential for β-BA mediated protection of endothelium function.

        In May 2014, the Financial Accounting Standards Board ("FASB") issued Accounting Standards Update ("ASU") 2014-09, "Revenue from Contracts with Customers." The standard, including subsequently issued amendments, replaces most prior revenue recognition guidance in U.S. GAAP and permits the use of either the retrospective or cumulative effect transition method. The standard requires an entity to recognize the amount of revenue to which it expects to be entitled for the transfer of promised goods or services to customers. The standard is effective for annual and interim periods beginning after December 15, 2017. The Company has one contract subject to the new standard, the Merck Agreement, and all performance obligations were completed upon the expiration of the research term in April 2016. See Note 4, "Revenue Recognition." The Company adopted the new standard on January 1, 2018 using the retrospective method. The adoption of ASU 2014-09 did not have a significant impact on the Company’s consolidated financial statements for the periods presented.

Forgot about Godel. Good friends with Einstein. Studied Kant and Husserl, a phenomenologist, believed in God and wrote an ontological proof of God. I never could comprehend one single word of his incompleteness theorem. Not a word.

Pursuant to the terms of the UCSD Agreement, we shall provide our proprietary drug product candidate Aramchol, without cost, to conduct the study as required pursuant to the Protocol and shall provide funds to conduct the ARTISAN Study over the duration of the study.

In this study, we investigated the role of miR-322 in hypoxia-induced cellular responses in rat PASMCs. We provide evidence that HIF-1α, but not HIF-2α, upregulates the transcription of miR-322 and that miR-322 may modulate proliferation and migration of PASMCs via the BMP-Smad pathway.

(a) Schematic diagram of cloned rat putative promoter region of miR-322, stretching from upstream 1000 bp. The position of the putative HRE matching the core sequence (A/G)CGTG is labeled in box, between two functional CACAG elements (P1k). A mutant promoter was constructed with the sequence as shown below (P1k-m). (b) Luciferase reporter assays of miR-322 promoter activity with both wild (pGL4-P1k) and mutant constructs (pGl4-P1k-m) in the presence or absence of CoCl2 (200μM) (left panel); Under these conditions, the protein levels of HIF-1α and HIF-2α were stabilized after CoCl2 treatment in the cells as determined by western blot analysis and normalized to β-actin levels (right panel). (c) miR-322 promoter activity assessed by luciferase reporter assay after CoCl2 treatment was diminished by HIF-1α knockdown. Cells were transduced with shRNA targeting HIF-1α (shHIF-1α) or HIF-2α (shHIF-2α) and miR-322 promoter activity was determined in the luciferase reporter assay after transfection of wild type and mutant constructs and CoCl2 treatment (left panel) as described under Methods; Control (sh-Con) or HIF-1α/-2α shRNA-transfected cells were harvested for protein analysis by western blot to determine knockdown specificity (right panel); *p < 0.05 compared with sh-Con. (d & e) A7r5 cells were transfected with recombinant adenoviruses expressing oxygen-dependent degradation domains (ODDD-wt) or mutated ODDD (ODDD-mut) under normoxic conditions. The influence on the miR-322 promoter reporter activity (d) and the endogenous expression levels (e) of miR-322 were determined by real-time PCR. All the bar plots represent means ± SD. *p < 0.05, **p < 0.01,compared with ODDD-mut. (f) Western blot for HIF-1α and HIF-2α in ODDD–transfected A7r5 cells after 24 hours. β-actin served as loading control. The full-length blots with these antibodies were presented in supplementary Figure S3. All gels have been run simultaneously under the same experimental conditions. (g) HIF-1α dynamic binding on the HRE site (−797 to −793) on the miR-322 promoter. ChIP assays were performed with indicated antibodies in the absence or presence of CoCl2 (left), or transfected with ODDD-wt or ODDD-mut (right) as described under Methods. Representative gel with input lanes showing products after PCR amplification and before immunoprecipitation.