Cardiovascular hardware simulator and artificial aorta-generated central blood pressure waveform database according to various vascular ages for cardiovascular health monitoring applications.

This study presents a database of central blood pressure waveforms according to cardiovascular health conditions, to supplement the lack of clinical data in cardiovascular health research, constructed by a cardiovascular simulator. Blood pressure (BP) is the most frequently measured biomarker, and in addition to systolic and diastolic pressure, its waveform represents the various conditions of cardiovascular health. A BP waveform is formed by overlapping the forward and reflected waves, which are affected by the pulse wave velocity (PWV). The increase in vascular stiffness with aging increases PWV, and the PWV-age distribution curve is called vascular age. For cardiovascular health research, extensive data of central BP waveform is essential, but the clinical data published so far are insufficient and imbalanced in quantity and quality. This study reproduces the central BP waveform using a cardiovascular hardware simulator and artificial aortas, which mimic the physiological structure and properties of the human. The simulator can adjust cardiovascular health conditions to the same level as humans, such as heart rate of 40-100 BPM, stroke volume of 40-100 mL, and peripheral resistance of 12 steps. Also, 6 artificial aortas with vascular ages in the 20-70 were fabricated to reproduce the increase in vascular stiffness due to aging. Vascular age calculated from measured stiffness of artificial aorta and central BP waveform showed an error of less than 3 years from the clinical value. Through this, a total of 636 waveforms were created to construct a central BP waveform database according to controlled various cardiovascular health conditions.

A novel metformin derivative, HL010183, inhibits proliferation and invasion of triple-negative breast cancer cells.

Mounting evidence suggests that metformin (N,N-dimethylbiguanide), a widely prescribed drug for the treatment of type II diabetes, exerts an anti-tumor effect on several cancers including breast cancer. Breast cancer has been estimated as one of the most commonly diagnosed types of cancer among women. In particular, triple-negative breast cancers are associated with poor prognosis and metastatic growth. In the present study, we synthesized a novel metformin derivative 5 (HL010183) and metformin salts, 9a, 9b, and 9c (metformin gamma-aminobutyric acid (GABA) salt, metformin pregabalin salt and metformin gabapentin salt), which exerted more potent inhibitory effects on the proliferation and invasiveness of Hs578T triple-negative breast carcinoma cells than metformin. Importantly, 5 showed approximately 100-fold more potent effects compared to metformin. In a triple-negative breast cancer xenograft model, 5 showed a comparable degree of inhibitory effect on in vivo tumor growth at the 100mg/kg dose to that of metformin at 500 mg/kg. Our results clearly demonstrate that 5 exerts a potent anti-tumor effect both in vitro and in vivo, paving the way for a strategy for treatment of triple-negative breast cancer.

A randomized placebo-controlled, dose-finding study of oral LB80380 in HBeAg-positive patients with chronic hepatitis B.

BACKGROUND: LB80380 is potent antiviral agent against hepatitis B virus (HBV) in vitro and in the woodchuck model. It has an excellent preclinical safety profile including lower potential for renal toxicity than adefovir. It is effective against both wild-type and YMDD mutant HBV. LB80380 is converted to its parent drug, LB80331, after oral absorption, and further metabolized to its active form, LB80317. AIMS/METHODS: This randomized placebo-controlled Phase I/II clinical study of LB80380 was conducted to assess the safety, antiviral activity and pharmacokinetics of its parent drug LB80331 and its active form LB80317 in 29 Asian adults with chronic hepatitis B positive for hepatitis B e antigen in four escalating dose groups (30, 60, 120 and 240 mg once per day) for 4 weeks with a 12-week follow-up period. RESULTS: The mean maximum HBV DNA reduction was 3.05, 4.20, 3.67 and 3.68 log10 copies/ml for 30, 60, 120 and 240 mg per day, respectively. Viral dynamic analysis suggested a high degree of inhibition of HBV replication at doses of 60 mg or higher per day. LB80380 was well tolerated at all dose groups, and no dose-related clinical or laboratory adverse event was reported. CONCLUSION: LB80380 is shown to be a potent and safe antiviral agent for HBV. Marked HBV DNA suppression was observed in all dose groups. The HBV DNA suppression was approximately constant at doses of 60 mg and higher over the 28-day dosing period. The dose response of LB80380 will be evaluated further in large clinical studies.

Dendritic oligoguanidines as intracellular translocators.

A series of polyguanidylated dendritic structures that can be used as molecular translocators have been designed and synthesized based on nonpeptide units. The dendritic oligoguanidines conjugated with fluorescein or with a green fluorescent protein (GFP) mutant as cargos were isolated and characterized. Quantification and time-course analyses of the cellular uptake of the conjugates using HeLa S3 and human cervical carcinoma cells reveal that the polyguanidylated dendrimers have comparable translocation efficiency to the Tat(49-57) peptide. Furthermore, the deconvolution microscopy image analysis shows that they are located inside the cells. These results clearly show that nonlinear, branched dendritic oligoguanidines are capable of translocation through the cell membrane. This work also demonstrates the potential of these nonpeptidic dendritic oligoguanidines as carriers for intracellular delivery of small molecule drugs, bioactive peptides, and proteins.

Characterization of a novel cyclin-dependent kinase 1 inhibitor, BMI-1026.

Cyclin-dependent kinases (Cdks) have been attractive targets for the development of anticancer therapeutic agents. In an effort to generate a new class of anti-Cdk inhibitors, we synthesized aryl aminopyrimidines and examined the effect of these compounds in both in vitro kinase assays and cultured cells. Two of these compounds, BMI-1026 and BMI-1042, induced a strong cell cycle alteration with potent inhibitory activities against cyclin-dependent kinases, collectively known as Cdks. Characterization of BMI-1026 revealed that it imposes a potent G(2)-M arrest and mild G(1)-S and S arrests. In vitro biochemical analyses and in vivo time-lapse microscopy studies revealed that it induces a mitotic catastrophe and precocious mitotic exit even in the presence of nocodazole. These defects appeared to lead to apoptotic cell death in tumorigenic cell lines. Consistent with the induction of mitotic defects and apoptosis, BMI-1026 imposed a selective sensitivity to proliferating versus differentiating or growth-arrested mouse keratinocytes. These data suggest that BMI-1026 could be developed as a potential anti-Cdk1 chemotherapeutic agent.