Mel-18 has been implicated in several processes in tumor progression, in which the Akt pathway is involved as an important key molecular event. However, the function of Mel-18 in human cancers has not been fully established yet. Here, we examined the effect of Mel-18 on tumor angiogenesis in human breast cancer, and found that Mel-18 was a novel regulator of HIF-1a. Mel-18 negatively regulated the HIF-1a expression and its target gene VEGF transcription during both normoxia and hypoxia. We demonstrated that Mel-18 regulated the HIF-1a expression and activity via the PI3K/Akt pathway. Loss of Mel-18 downregulated Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression, consequently activating the PI3K/Akt/MDM2 pathway, and leading to an increase of HIF-1a protein level. Mel-18 modulated the HIF-1a transcriptional activity via regulating the cytoplasmic retention of FOXO3a, a downstream effector of Akt, and recruitment of HIF-1a/CBP complex to the VEGF promoter. Furthermore, our data shows that Mel-18 blocked tumor angiogenesis both in vitro and in vivo. Mel-18 overexpression inhibited in vitro tube formation in human umbilical endothelial cells (HUVECs). Xenografts in NOD/SCID mice derived from stably Mel-18 knocked down MCF7 human breast cancer cells showed increased tumor volume, microvessel density, and phospho-Akt and HIF-1a expression levels. In conclusion, our findings provide that Mel-18 is a novel regulator of tumor angiogenesis through regulating HIF-1a and its target VEGF expressions mediated by the PTEN/PI3K/Akt pathway, suggesting a new tumor-suppressive role of Mel-18 in human breast cancer.

A numerical study was conducted to investigate combustion and emission characteristics in a high-speed direct-injection engine with a common-rail injection system under various operating conditions. In order to analyse the combustion characteristics, several models were used in this study. They were the renormalization group k-e model, the hybrid Kelvin-Helmholtz (wave) and the Rayleigh-Taylor model, the shell auto-ignition model, and the laminar and turbulent characteristic timescale combustion model. The prediction of exhaust emissions was conducted using nitrogen oxide NO x formation with an extended Zel'dovich mechanism and Hiroyasu soot formation with the Nagle-Strickland-Constable oxidation model respectively. Experimental combustion and emission characteristics were compared with calculated results under various operating conditions, such as injection timing, injection pressure, fuel mass, and engine speed. The calculated results show similar patterns to the experimental results in the cylinder pressure and the rate of heat release. In the emissions characteristics, NO x emission decreased as injection timing was retarded and the NO x and soot amounts increased with the increase in the injected fuel mass. The calculated soot trends for various injection timings showed different patterns from the experimental trends as the injection timing were retarded.

In this study, experimental and numerical investigations were performed to analyse the spray characteristics of dimethyl ether (DME) fuel in a common-rail fuel injection system. In order to analyse the DME fuel spray, overall spray characteristics such as the spray tip penetration, the spray evolution process, and the droplet size distribution were investigated by an application of the hybrid break-up model combined with primary and secondary break-up phenomena. The spray development process and spray tip penetration were measured experimentally from injected DME spray images obtained using a visualization system, while the microscopic characteristics were experimentally measured by a phase Doppler particle analyser system. Calculations based on hybrid break-up models were validated against the experimental results, and the associated break-up constants were optimized after the validation. Based on the optimized break-up constant, the calculated results under various experimental conditions were compared with measured results such as the spray development, the spray tip penetration, the Sauter mean diameter (SMD), and the SMD distribution.

Introduction Home blood pressure monitoring (HBPM) is a useful tool to identify hypertension and to decide whether a patient's blood pressure (BP) is controlled. The use of automatized oscillometric BP measurement devices has become increasingly popular with help of information technology and internet of things to the devices. However, applying HBPM to daily clinical practices is still challenging, because most patients with hypertension are in age groups not familiar to digital devices and internet and high BP criteria using average home BP values are often useless in outpatient clinics without easily accessible average BP calculation tools. Therefore, we developed a simple and straightforward method to interpret HBPM through counts of BP ≥135/85 mmHg. Methods We simulated 400 cases of HBPM using a random number generator function in statistical software. The simulated average home systolic BP (SBP) and its standard deviation (SD) were 125±15 mmHg and 12±5 mmHg and the number of HBP readings was 24 times. The simulated diastolic BP (DBP) was randomly selected to 50–75% of the SBP. The validation of the binary interpretation method was conducted using actual HBPM data from 386 subjects in a rural area of South Korea. Receiver operating characteristics curve analysis was conducted, and linear regression and logarithmic models were fitted between the numbers of home BP ≥135/85 mmHg and mean BP. Hypertension was defined with average home BP ≥135/85 mmHg. Results In the simulated cohort, hypertension was presented in 197 cases (49.3%). The C-index of the numbers of BP readings ≥135/85 mmHg was 0.994 (95% confidence interval [CI] 0.990–0.998), and ≥12 of 24 BP readings ≥135/85 mmHg showed a sensitivity of 95.4%, a specificity of 95.1% and an accuracy of 95.3% for the diagnosis of hypertension. In validation cohort, the numbers of home BP measurements varied from 8 to 81 times. The validation cohort similarly showed that the C-index of the ratio between the number of high BP readings (≥135/85 mmHg) to the number of BP measurements (R-NHBP/NBP) was 0.985 (95% CI, 0.976–0.994) and the best accuracy was shown at R-NHBP/NBP of ≥0.45. R-NHBP/NBP of ≥0.5 showed a sensitivity of 0.957, a specificity of 0.907 and an accuracy of 0.927. The accuracy of the R-NHBP/NBP of ≥0.5 decreased as SD and the range of SBP increased, whereas it did not change with the number of measurements (Figure 1). R-NHBP/NBP <0.2 predicted normotension and R-NHBP/NBP >0.8 predicted hypertension in 95% confidence. Mean widths of the 95 prediction intervals for the average SBP and DBP were 18.2 mmHg and 12.6 mmHg, respectively (Figure 2). Conclusion Counting the number of BP ≥135/85 mmHg can provide accurate assessments for the BP levels. R-NHBP/NBP of ≥0.5 is a simple and accurate marker of high BP in HBPM, and R-NHBP/NBP could be a useful tool to assess BP levels in patients practicing HBPM. FUNDunding Acknowledgement Type of funding sources: None. Figure 1 Figure 2

Chronic stable diabetic patients (n = 6) were compared with healthy control subjects (n = 5) after acute oral intake of 50 mEq of potassium chloride (KCl) to investigate for possible derangements of homeostatic responses for acute term (3 hrs) to acute potassium load. Plasma renin activity (PRA), plasma aldosterone (PA), and transtubular potassium concentration gradient (TTKG) known as a useful semiquantative index of distal nephron potassium secretion were measured. All the baseline parameters were comparable between diabetic and non-diabetic subjects except for significantly reduced creatinine clearance in diabetics (mean +/- SEM, 105 +/- 4 vs. 85 +/- 5 ml/min, p < 0.05). Following acute oral KCl load, the peak increases of serum potassium changes from basal levels were noted at 2 hours in both groups, but were higher in diabetic subjects (mean +/- SEM, 0.42 +/- 0.06 vs. 0.62 +/- 0.09 mEq/L). Also, 4 out of 6 diabetic subjects but none of the control subjects at 2 hours after oral KCl load became hyperkalemic ( > 5.0 mEq/L). PRA did not show any significant changes, whereas PA was increased simultaneously with increments in serum potassium in both groups, with blunted increases in the diabetics. However, TTKG was increased prominently in control subjects (8.18 from 4.98), but only slightly in diabetic subjects (4.55 from 4.18), with statistical difference between the two groups (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)