Discovery of Novel and Potent Stearoyl Coenzyme A Desaturase 1 (SCD1) Inhibitors as Anticancer Agents.

A lead compound A was identified previously as an stearoyl coenzyme A desaturase (SCD) inhibitor during research on potential treatments for obesity. This compound showed high SCD1 binding affinity, but a poor pharmacokinetic (PK) profile and limited chemical accessibility, making it suboptimal for use in anticancer research. To identify potent SCD1 inhibitors with more promising PK profiles, we newly designed a series of 'non-spiro' 4, 4-disubstituted piperidine derivatives based on molecular modeling studies. As a result, we discovered compound 1a, which retained moderate SCD1 binding affinity. Optimization around 1a was accelerated by analyzing Hansch-Fujita and Hammett constants to obtain 4-phenyl-4-(trifluoromethyl)piperidine derivative 1n. Fine-tuning of the azole moiety of 1n led to compound 1o (T-3764518), which retained nanomolar affinity and exhibited an excellent PK profile. Reflecting the good potency and PK profile, orally administrated compound 1o showed significant pharmacodynamic (PD) marker reduction (at 0.3mg/kg, bid) in HCT116 mouse xenograft model and tumor growth suppression (at 1mg/kg, bid) in 786-O mouse xenograft model. In conclusion, we identified a new series of SCD1 inhibitors, represented by compound 1o, which represents a promising new chemical tool suitable for the study of SCD1 biology as well as the potential development of novel anticancer therapies.

Estimation of mortality and morbidity risk of radical cystectomy using POSSUM and the Portsmouth predictor equation.

INTRODUCTION: The Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity (POSSUM) and the Portsmouth predictor equation (P-POSSUM) are simple scoring systems used to estimate the risk of complications and death postoperatively. We investigated the use of these scores to predict the postoperative risk in patients undergoing radical cystectomy (RC). MATERIAL AND METHODS: In this retrospective study, we enrolled 280 patients who underwent RC for invasive bladder cancer between January 2003 and December 2011. Morbidity and mortality were predicted using the POSSUM and P-POSSUM equations. We further assessed the ability of the POSSUM and P-POSSUM to predict the mortality and morbidity risk in RC patients with a Clavien-Dindo classification of surgical complications of grade II or higher. RESULTS: The observed morbidity and mortality rates were 58.9% (165 patients) and 1.8% (5 patients), respectively. Predicted morbidity using POSSUM was 49.2% (138 patients) compared to the 58.9% (165 patients) observed (P <0.0001). Compared to the observed death rate of 1.8% (5 patients), predicted mortality using POSSUM and P-POSSUM was 12.1% (34 patients) and 3.9% (11 patients), respectively (P <0.0001 and P = 0.205). The mortality risk estimated by P-POSSUM was not significantly different from the observed mortality rate. CONCLUSIONS: The results of this study supported the efficacy of POSSUM combined with P-POSSUM to predict morbidity and mortality in patients undergoing RC. Further prospective studies are needed to better determine the usefulness of POSSUM and P-POSSUM for a comparative audit in urological patients undergoing RC.

New angiotensin II type 1 receptor blocker olmesartan improves portal hypertension in patients with cirrhosis.

AIM: To evaluate the effect of the new oral angiotensin II type 1 receptor blocker olmesartan on portal hemodynamics in patients with cirrhosis. METHODS: From January 2005 to March 2006, 18 cirrhosis patients treated with endoscopic band ligation for primary esophageal variceal bleeding were included in the present study. Hepatic venous pressure gradient (HVPG) of the patients was >/=12 mmHg at baseline measurement. The patients were given 10 mg olmesartan orally once daily for 2 weeks. Eighteen cirrhosis patients with esophageal variceal bleeding who did not receive any antihypertensive agents were included in the study as control. On day 14, HVPG, blood pressure, heart rate, and parameters of hepatic and renal function were examined after the treatment. Responders were defined as those with HVPG reduction of >20% versus baseline. RESULTS: Olmesartan significantly reduced HVPG by -16.8 +/- 22.0% (P = 0.031) and mean arterial pressure by -13.1 +/- 10.8% (P = 0.0041). Six of 18 (33.3%) patients in the olmesartan group showed >20% reduction of HVPG from baseline values. None of the patients treated with olmesartan had any complications. CONCLUSION: Olmesartan reduces portal pressure and may be safe and highly effective in the treatment of portal hypertension.

Risk factors of delay in restoration of hepatic reserve capacity and local recurrence after radiofrequency ablation therapy for hepatocellular carcinoma (HCC).

BACKGROUND: : Effects of radiofrequency ablation (RFA) on hepatic reserve capacity have not been evaluated thoroughly thus far. The aim of our study is to evaluate the factors that influence to hepatic reserve capacity and local recurrence after RFA. PATIENTS AND METHODS: : We studied a total of 243 patients (310 nodules). The study parameters included rates of local recurrence after undergoing RFA as well as factors for delaying recovery of post-RFA albumin levels (age, gender, the presence and absence of anti-HCV antibody, platelet count, GPT level, prothrombin time (PT), Child-Pugh grade, pre-RFA albumin level, alpha-fetoprotein (AFP) level, the number of nodules, tumor size in diameter, hepatic blood control and the coagulation volume after undergoing RFA. RESULTS: : Rates of local recurrence were 6.5%, 10.4% and 12.0% at 1, 2 and 3 years after undergoing RFA, respectively. In the hepatic reserve capacity studies, it took 1.9 and 5.8 months for 50% and 80% of cases, respectively, to restore serum albumin levels to pre-treatment levels after undergoing RFA. There were significant differences in the time of delay in restoration of serum albumin levels with regard to two factors: patients' age >/=60 years (p=0.0351) and tumor size over 3.5cm in diameter (p<0.001). CONCLUSION: : We cosidered that RFA is a safe and efficacious modality, but thorough attention was necessary for such patients with tumor size over 3.5cm in diameter before undergoing RFA, especially in elderly patients.

Myocardial perfusion during transient slow-flow in the patient with old vein graft intervention: assessment by serial measurement of pressure-derived fractional flow reserve and thermodilution-derived coronary flow reserve.

A patient with distal slow-flow after stenting in the old vein graft intervention was reported. This case is a first in whom guidewire-based serial measurement of pressure-derived fractional flow reserve (FFR(myo)) and thermodilution-based coronary flow reserve (CFR(thermo)) clearly demonstrated the serial change of microvascular circulation. During slow-flow, CFR(thermo) remained in low value despite significant improvement of FFR(myo) from 0.61 to 0.90. After thrombus aspiration and nicorandil injection, coronary flow reestablished immediately. CFR(thermo) improved significantly from 1.3 during slow-flow to 3.6 after restoration of flow.