mTORC2 promotes pancreatic cancer progression and parp inhibitor resistance

Pancreatic cancer is one of the most aggressive cancers with a median survival time of less than 5 months,and conventional chemotherapeutics are the main treatment strategy.Poly(ADP-ribose)polymerase(PARP)inhibitors have been recently approved for BRCA1/2-mutant pancreatic cancer,opening a new era for targeted therapy for this disease.However,most pancreatic cancer patients carry wild-type BRCA1/2 with resistance to PARP inhibitors.Here,we reported that mammalian target of rapamycin complex 2(mTORC2)kinase is overexpressed in pancreatic cancer tissues and promotes pancreatic cancer cell growth and invasion.Moreover,we found that knockdown of the mTORC2 obligate subunit Rictor sensitized pancreatic cancer cells to the PARP inhibitor olaparib.Mechanistically,we showed that mTORC2 positively regulates homologous recombination(HR)repair by modulating BRCA1 recruitment to DNA double-strand breaks(DSBs).In addition,we confirmed that combination treatment with the mTORC2 inhibitor PP242 and the PARP inhibitor olaparib synergistically inhibited pancreatic cancer growth in vivo.Thus,this study provides a novel target and strategy for optimizing PARP inhibitor efficiency in pancreatic cancers.

The enhancing effect and promoting mechanisms of the stereoisomeric monoterpene alcohol esters as enhancers for drugs with different physicochemical properties

To explore the structure-activity connections of amphiphilic permeation enhancers containing the length of the hydrophobic chains as well as the properties of the polar head,O-acylgeraniol and O-acylnerol derivatives were synthesized from geraniol/nerol(cis-isomer of geraniol) and pharmaceutical excipient acids in this research. Their promotion of the percutaneous absorption of three drugs as the model, flurbiprofen(FP), isosorbide dinitrate(ISDN) and donepezil(DNP), which were selected based on their physicochemical properties,was tested by in vitro skin penetration and in vivo. Molecular simulation, ATR-FTIR, CLSM and histological observation were implement to evaluate the mode of action of the enhancers.The results indicated that(E)-3,7-dimethyl-2,6-octadien-1-yl tetradecanoate(GER-C14, trans-)achieved the highest enhancement ability for the three drugs;additionally, the in vivo results obtained were in good correlation with the in vitro data. Molecular docking results suggested that enhancers loosen the hydrogen bonds between ceramides, and the results of molecular simulation indicated that GER-C14, NER-C14 could insert into the middle of the lipid bilayer to form an independent phase. According to ATR-FTIR and histological evaluation, the enhancers extracted lipids and influenced the protein region, thereby disturbing the skin array. In addition, CLSM described the dynamic effects of enhancers on lipids between stratum corneum(SC) cells. In conclusion, GER-C14 had a better penetration promotion effect, which broadened our understanding of stereoisomeric penetration enhancers.

传统甲状腺切除术与小切口甲状腺切除术治疗甲状腺结节的临床疗效对比

目的探讨传统甲状腺切除术与小切口甲状腺切除术治疗甲状腺结节的临床疗效。方法选择2017年5月-2019年5月我院收治的行甲状腺切除患者48例,随机分为对照组和观察组,每组24例。对照组行传统甲状腺切除术,观察组行小切口甲状腺切除术,对患者效果进行评估,比较两组患者的手术各项指标。结果观察组护手术持续时间、术中出血量、切口长度、术后引流量及患者住院时间,均短于对照组(P<0.05)。结论与传统甲状腺切除术相比,小切口甲状腺切除术能够明显缩短手术时间,减少并发症事件的发生,具有较高的安全性,提高患者的生活质量,值得推广应用。