Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.     

新型四腔水箱在腹外科腔镜电凝线清洗消毒中的应用研究

摘要〓目的〓研究四腔水箱在腹外科腔镜电凝线擦拭法清洗消毒中的应用效果。方法〓通过目测法和ATP生物荧光法,对本研究的四腔水箱用于腹外科腔镜电凝线的清洗效果进行评价。结果〓传统治疗碗清洗的206件腔镜电凝线清洗质量合格率为86.4%,四腔水箱清洗的206件腹腔镜电凝线清洗质量合格率为94.6%,差异有统计学意义（P＜0.01）。用四腔水箱清洗腔镜电凝线擦拭过程中的护理人员满意度较高。结论〓四腔水箱可提高腹外科腔镜电凝线清洗质量和护理人员满意度。     

Dying is the Most Grown-Up Thing We Ever Do: But Do Health Care Professionals Prevent Us from Taking It Seriously?

This paper takes a somewhat slant perspective on flourishing and care in the context of suffering, death and dying, arguing that care in this context consists principally of ‘acts of work and courage that enable flourishing’. Starting with the perception that individuals, society and health care professionals have become dulled to death and the process of dying in Western advanced health systems, it suggests that for flourishing to occur, both of these aspects of life need to be faced more directly. The last days of life need to be ‘undulled’. Reflections upon the experiences of the author as carer and daughter in the face of her mother’s experience of death are used as basis for making suggestions about how care systems and professionals might better assist people in dealing with ‘the most grown up thing’ humans ever do, which is to die.     

基于剂量组学预测肺癌患者放射性肺炎发生的研究

目的 探讨剂量组学在预测肺癌根治性放疗患者放射性肺炎发生中的应用潜能。方法 回顾性收集行根治性放疗的314例肺癌患者的临床资料、放疗剂量文件、定位及随访CT图像,根据临床资料及影像学随访资料对放射性肺炎进行分级,提取全肺的剂量组学特征,构建机器学习模型。应用1000次自助抽样法（bootstrap）的最小绝对值收敛和选择算子嵌套逻辑回归（LASSO‐LR）及1000次bootstrap的赤池信息量准则（AIC）向后法筛选与放射性肺炎相关的剂量组学特征,随机按照7∶3划分为训练集及验证集,应用逻辑回归建立预测模型,并应用ROC曲线及校正曲线评价模型的性能。结果 共提取120个剂量组学特征,经LASSO‐LR降维筛选得到12个特征进入“特征池”,再经过AIC向后法筛选,最终筛选出6个剂量组学特征进行模型构建,训练集AUC为0.77（95%CI为0.65~0.87）,独立验证集AUC为0.72（95%CI为0.64~0.81）。结论 利用剂量组学建立的预测模型具有预测放射性肺炎发生的潜力,但仍需继续纳入多中心数据及前瞻性数据进一步挖掘剂量组学的应用潜能。     

Patient-Reported Quality of Life Before and After Chemoradiation for Intact Pancreas Cancer: A Prospective Registry Study

PurposeOur purpose was to determine the effect of chemoradiotherapy (CRT) on patient-reported quality of life (QOL) for patients with intact pancreas cancer.Methods and MaterialsWe reviewed a prospective QOL registry for patients with intact, clinically localized pancreatic ductal adenocarcinoma treated with CRT between June 2015 and November 2018. QOL was assessed pre-CRT (immediately before CRT, after neoadjuvant chemotherapy) and at the completion of CRT with the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) and its component parts: FACT-General (FACT-G) and hepatobiliary cancer subscore (HCS). A minimally important difference from pre-CRT was defined as ≥ 6, 5, and 8 points for FACT-G, HCS, and FACT-Hep, respectively.ResultsOf 157 patients who underwent CRT, 100 completed both pre- and post-CRT surveys and were included in the primary analysis. Median age at diagnosis was 65 years (range, 23-90). National Comprehensive Cancer Network resectability status was resectable (3%), borderline resectable (40%), or locally advanced (57%). Folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) (75%) or gemcitabine and nab-paclitaxel (42%) were given for a median of 6 cycles (range, 0-42) before CRT. Radiation therapy techniques included 3-dimensional conformal (22%), intensity modulated photon (55%), and intensity modulated proton (23%) radiation therapy to a median dose of 50 Gy (range, 36-62.5). Concurrent chemotherapy was most commonly capecitabine (82%). Sixty-three patients (63%) had surgery after CRT. The mean decline in FACT-G, HCS subscale, and FACT-Hep from pre- to post-CRT was 3.5 (standard deviation [SD], 13.7), 1.7 (SD 7.8), and 5.2 (SD 19.4), respectively. Each of these changes were statistically significant, but did not meet the minimally important difference threshold. Pancreatic head tumor location was associated with decline in FACT-Hep. Nausea was the toxicity with the greatest increase from pre- to post-CRT by both physician-assessment and patient-reported QOL.ConclusionsFor patients with intact pancreatic adenocarcinoma, modern CRT is well tolerated with minimal decline in QOL during treatment.     

Nanomedicines: From Bench to Bedside and Beyond

Advancing nanomedicines from concept to clinic requires integration of new science with traditional pharmaceutical development. The medical and commercial success of nanomedicines is greatly facilitated when those charged with developing nanomedicines are cognizant of the unique opportunities and technical challenges that these products present. These individuals must also be knowledgeable about the processes of clinical and product development, including regulatory considerations, to maximize the odds for successful product registration. This article outlines these topics with a goal to accelerate the combination of academic innovation with collaborative industrial scientists who understand pharmaceutical development and regulatory approval requirements—only together can they realize the full potential of nanomedicines for patients.