Trends in template/fragment-free protein structure prediction

Predicting the structure of a protein from its amino acid sequence is a long-standing unsolved problem in computational biology. Its solution would be of both fundamental and practical importance as the gap between the number of known sequences and the number of experimentally solved structures widens rapidly. Currently, the most successful approaches are based on fragment/template reassembly. Lacking progress in template-free structure prediction calls for novel ideas and approaches. This article reviews trends in the development of physical and specific knowledge-based energy functions as well as sampling techniques for fragment-free structure prediction. Recent physical- and knowledge-based studies demonstrated that it is possible to sample and predict highly accurate protein structures without borrowing native fragments from known protein structures. These emerging approaches with fully flexible sampling have the potential to move the field forward

Annonaceous acetogenins nanosuspensions stabilized by PCL–PEG block polymer: significantly improved antitumor efficacy

Jingyi Hong,1,* Yanhong Li,1,2,* Yijing Li,1 Yao Xiao,1,2 Haixue Kuang,2 Xiangtao Wang1 1Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 2School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China *These authors contributed equally to this work Abstract: Annonaceous acetogenins (ACGs) have shown superior antitumor activity against a variety of cancer cell lines, but their clinical application has been limited by their poor solubility. In this study, ACGs-nanosuspensions (NSps) were successfully prepared by a precipitation ultrasonic method using monomethoxypoly (ethylene glycol)2000–poly (ε-caprolactone)2000 (mPEG2000–PCL2000) as a stabilizer. The resultant ACGs-NSps had a mean particle size of 123.2 nm, a zeta potential of -20.17 mV, and a high drug payload of 73.68%. ACGs-NSps were quite stable in various physiological solutions, and they exhibited sustained drug release. Compared to free drug, ACGs-NSps exhibited stronger cytotoxicity against 4T1, MCF-7, and HeLa cells. An in vivo real-time biodistribution investigation after labeling with 1,1'-dioctadecyltetramethyl indotricarbocyanine iodide, a noninvasive near-infrared fluorescence probe, demonstrated that ACGs-NSps could effectively accumulate in tumor. An in vivo antitumor activity study in 4T1 tumor-bearing mice revealed that ACGs-NSps achieved much better therapeutic efficacy than the traditional dosage form (oil solution) even at 1/10 of the dose (74.83% vs 45.53%, P<0.05), demonstrating that NSp was a good dosage form for ACGs to treat cancer. Keywords: annonaceous acetogenins, mPEG2000–PCL2000, near–infrared fluorescence, biodistribution, antitumor efficac

A stabilizer-free and organic solvent-free method to prepare 10-hydroxycamptothecin nanocrystals: in vitro and in vivo evaluation

Xiaofeng Yang,1 Yingying Liu,1,2 Yanna Zhao,1 Meihua Han,1 Yifei Guo,1 Haixue Kuang,2 Xiangtao Wang1 1Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 2School of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, People’s Republic of China Abstract: 10-Hydroxycamptothecin (10-HCPT) is a promising anticancer drug with a wide spectrum of antitumor activities. Due to its poor solubility, the carboxylate form that shows high water solubility but minimal anticancer activity and pharmacokinetic defects is used in the marketed 10-HCPT injections, resulting in its limited clinical application. To develop a simple, safe, and highly effective drug delivery system, a modified acid–base microprecipitation combined with a high-pressure homogenization technique was adopted to prepare 10-HCPT nanocrystals. Neither organic solvents nor stabilizers were employed throughout the preparation process. The in vitro and in vivo performances of the resulting10-HCPT nanocrystals were investigated systematically. The nanocrystals were spherical with a small size of ~130 nm, and the actual drug-loading content was as high as 75%. The nanocrystals displayed a sustained release pattern and were proven to have a higher cell uptake and antiproliferative activity than the 10-HCPT injections. The 10-HCPT nanocrystals also showed enhanced drug accumulation in tumors and better anticancer efficacy in 4T1-bearing mice. In summary, the 10-HCPT nanocrystals prepared in this study seem to be a promising delivery system for a new form of 10-HCPT dosages. Keywords: 10-hydroxycamptothecin, drug delivery, poloxamer 188, high drug payload, 4T1 cell

Ethanol ablation of hepatocellular carcinoma Up to 5.0 cm by using a multipronged injection needle with high-dose strategy

PURPOSE: To investigate whether ethanol ablation by using a multipronged needle delivery system (multipronged ethanol ablation) could eradicate hepatocellular carcinoma (HCC) up to 5.0 cm in diameter with a single-session high-dose strategy. MATERIALS AND METHODS: The hospital ethics committee approved the prospective study, and each patient provided written informed consent. One hundred forty-one patients (125 men, 16 women; mean age, 53 years; range, 27-76 years) with 164 primary or recurrent HCC ranging from 1.3 to 5.0 cm in diameter (mean, 2.9 cm +/- 0.9) were treated with high-dose multipronged ethanol ablation. Patients were unsuitable for surgery, declined surgery and radiofrequency ablation, or had tumors located at unfavorable sites. Primary technique effectiveness (PTE) (complete ablation within two sessions), local tumor progression (LTP), and complications after the treatment were observed. Twenty risk factors of local effectiveness and complications were analyzed by means of univariate and multivariate analysis. RESULTS: Mean number of treatment sessions was 1.1. The mean volume of ethanol per tumor was 31 mL (range, 8-68 mL). PTE was achieved in 134 (95%) of 141 patients and was significantly associated with tumor pattern (capsulated vs noncapsulated, P = .018). After a mean follow-up period of 25 months, LTP was observed in 16 (12%) of 134 patients, and in nine (56%) patients, LTP occurred in tumors 3.1-5.0 cm in diameter. Alanine aminotransferase level (P = .023) was the independent risk factor for LTP. Three (2%) of 141 patients had major complications. CONCLUSION: Multipronged ethanol ablation with a high-dose strategy can be used to treat HCC up to 5.0 cm in diameter effectively and safely, often in a single sessio