Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma.

BACKGROUND: Radiotherapy has an ameliorative effect on a wide variety of tumors, but hepatocellular carcinoma (HCC) is insensitive to this treatment. Overactivated mammalian target of rapamycin (mTOR) plays an important part in the resistance of HCC to radiotherapy; thus, mTOR inhibitors have potential as novel radiosensitizers to enhance the efficacy of radiotherapy for HCC. METHODS: A lead compound was found based on pharmacophore modeling and molecular docking, and optimized according to the differences between the ATP-binding pockets of mTOR and PI3K. The radiosensitizing effect of the optimized compound (2a) was confirmed by colony formation assays and DNA double-strand break assays in vitro. The discovery and preclinical characteristics of this compound are described. RESULTS: The key amino acid residues in mTOR were identified, and a precise virtual screening model was constructed. Compound 2a, with a 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine scaffold, exhibited promising potency against mTOR (mTOR IC50=7.1 nmol/L (nM)) with 126-fold selectivity over PI3Kα. Moreover, 2a significantly enhanced the sensitivity of HCC to radiotherapy in vitro in a dose-dependent manner. CONCLUSION: A new class of selective mTOR inhibitors was developed and their radiosensitization effects were confirmed. This study also provides a basis for developing mTOR-specific inhibitors for use as radiosensitizers for HCC radiotherapy.

Plasmakinetic enucleation of the prostate versus transvesical open prostatectomy for benign prostatic hyperplasia >80 mL: 12-month follow-up results of a randomized clinical trial.

OBJECTIVE: To prospectively evaluate perioperative results and 12-month follow-up after plasmakinetic enucleation of the prostate (PKEP) and transvesical open prostatectomy (OP) for benign prostatic hyperplasia (BPH) >80 mL. METHODS: A total of 83 patients with a prostate >80 mL were randomized to either PKEP or OP. Perioperative and postoperative outcome data were obtained during a 12-month follow-up. RESULTS: No statistical differences were observed in the preoperative data. Both groups resulted in a similar and significant postoperative improvement in International Prostate Symptom Score (IPSS), quality of life (QOL), maximum uroflow rate (Qmax), postvoid residual (PVR) urine volume and prostate specific antigen (PSA), but no significant difference was found between the groups at the 12-month follow-up. Compared to OP, operation time (111.2 ± 27.1 minutes vs 109.6 ± 28.2 minutes, P = .708) were not significantly different between the groups, but blood loss was significantly less (10.2 ± 4.5 g/l vs 15.1 ± 4.3 g/l, P <.001), and bladder irrigation (2.4 ± 1.0 days vs 4.3 ± 1.1 days, P <.001), catheterization time (3.3 ± 1.1 days vs 6.2 ± 1.3 days, P <.001), and hospital stay (5.4 ± 1.2 days vs 9.3 ± 1.1 days, P <.001) were significantly shorter in the PKEP group. Effects on erectile function were similar in both groups, but adverse events were less frequent in the PKEP group. CONCLUSION: PKEP can be performed safely and is an equally effective procedure for treatment of large BPH with OP, with minimal complications and faster postoperative recovery. The PKEP helps to reduce the morbidity associated with OP and may become the attractive alternative to OP for patients with large BPH.

[Immunological regulation and treatment of Brucea javanica and Fructus Psoraleae on rats with Pneumocystis carinii pneumonia].

OBJECTIVE: To study the immunological regulation and treatment of Brucea javanica and Fructus Psoraleae, traditional Chinese medicine, on rats with Pneumocystis carinii pneumonia (PCP). METHODS: Rats were injected subcutaneously by dexamethasone. When the rats got Pc infected, they were divided into two groups: rats in one group were treated with the mixture of Brucea javanica and Fructus Psoraleae and another group was used as infected control. Control with normal rats was also established. Observations were made on the number of cysts in lungs and the changes of CD4+ T cells, CD8+ T cells and TNF-alpha in the serum to demonstrate the immunological regulation and killing effect of the medicine on cysts in the infected rats. RESULTS: The body weight of the rats treated with Brucea javanica and Fructus Psoraleae increased considerably than that of immunosuppressed rats and the normal control. The damaged lung got improved and repaired, and a significant cyst reduction was shown in the treated group. The CD4+ T cells, CD8+ T cells and level of TNF-alpha in serum also increased in the treated group significantly. CONCLUSION: The mixture of Brucea javanica and fructus psoraleae plays an immunological regulation on rats with Pneumocystis carinii pneumonia and shows certain killing effect on the cysts.

[Electron microscopical observation on rats with Pneumocystis carinii pneumonia treated with Brucea javanica and Fructus Psoraleae].

Rats with Pneumocystis carinii pneumonia (PCP) were established by hypodermic injection of dexamethasone and treated by Brucea javanica combined with Fructus Psoraleae 2 ml (Brucea javanica 0.12 mg and Fructus Psoraleae 1.0 mg) per rat per day for 7 days or 14 days. The effect of cyst-killing and the pathological change were observed under transmission electron microscope. Lung damage was alleviated or repaired, and a significant reduction of cysts was shown in the treatment group. The results show that a combination of Brucea javanica and Fructus Psoraleae played a significant restraining and killing effect on cysts, and helped repair the impairment of pneumonia.