The interactions of phenytoin and its binding site in DI‐S6 segment of Na+ channel voltage‐gated peptide by NMR spectroscopy and molecular modeling study

Abstract: Nuclear magnetic resonance (NMR) spectra of a model peptide (BL‐DIS6), in the presence of anticonvulsant diphenyl drug, phenytoin (DPH), were measured to obtain the interactions between the selected drug and the model peptide. BL‐DIS6's sequence corresponds to the S6 segment in domain I of rat brain type IIA Na⁺‐channel. NMR studies have demonstrated that the magnitude of the chemical shifts of amide‐ and α‐protons can be used as a measurement of the complex stability and binding site of the peptide. Our NMR results propose a 3₁₀‐helical structure for BL‐DIS6, and suggest a binding cavity for DPH that involves the hydrophobic particles of residues Ans‐7, Leu‐8, Val‐11, and Val‐12. Furthermore, molecular modeling was performed to provide a possible complex conformation that the phenyl portion of DPH is accommodated in the proximity of the C‐terminal residues Ala‐11 and Val‐12, and simultaneously the heterocyclic amine ring of DPH is perching at the residue Asn‐7 periphery and stabilizing the phenyl portion deep insertion into the peptide.     

少见纵隔占位病变螺旋CT表现及其优势解剖分布

目的:探讨少见纵隔占位病变的螺旋CT表现特征及其病理基础,以提高临床认识及诊治水平。方法:回顾性分析经临床病理证实的原发性少见纵隔占位病变的螺旋CT表现,观察和评价肿块内部结构、密度分布、边缘特征、强化特征等CT表现特点及其优势解剖分布。结果:32例少见纵隔肿块中良性22例(68.75%,22/32),恶性10例(10/32,31.25%)。22例良性肿块中密度均匀12例(12/22,54.54%),形态规则16例(16/22,72.72%),边界清楚14例(14/22,63.64%),低密度15例(15/22,68.18%)。10例恶性肿块中密度不均匀7例(7/10,70%),形态不规则8例(8/10,80%),边界不清楚6例(6/10,60%),中等密度6例(6/10,60%)。32例肿块中位于上纵隔12例,前纵隔16例,中纵隔9例,后纵隔11例。良性肿块常累及一个解剖分区(15/22,68.18%),恶性多累及二个区以上(6/10,60%)。结论:不同的少见纵隔肿块具有不同特征CT表现及其好发部位,这与其解剖来源和其组织成分不同有关。     

Comparison of intensity-modulated radiotherapy with the 5-field technique,helical tomotherapy and volumetric modulated arc therapy for localized prostate cancer

The outcomes of three methods of intensity-modulated radiation therapy (IMRT) for localized prostate cancer were evaluated. Between 2010 and 2018, 308 D’Amico intermediate- or high-risk patients were treated with 2.2 Gy daily fractions to a total dose of 74.8 Gy in combination with hormonal therapy. Overall, 165 patients were treated with 5-field IMRT using a sliding window technique, 66 were then treated with helical tomotherapy and 77 were treated with volumetric modulated arc therapy (VMAT). The median age of patients was 71 years. The median follow-up period was 75 months. Five-year overall survival (OS) and biochemical or clinical failure-free survival (FFS) rates were 95.5 and 91.6% in the 5-field IMRT group, 95.1 and 90.3% in the tomotherapy group and 93.0 and 88.6% in the VMAT group, respectively, with no significant differences among the three groups. The 5-year cumulative incidence of late grade ≥2 genitourinary and gastrointestinal toxicities were 7.3 and 6.2%, respectively, for all patients. Late grade ≥2 gastrointestinal toxicities were less frequent in patients undergoing VMAT (0%) than in patients undergoing 5-field IMRT (7.3%) and those undergoing tomotherapy (11%) (P = 0.025), and this finding appeared to be correlated with the better rectal DVH parameters in patients undergoing VMAT. Other toxicities did not differ significantly among the three groups, although bladder dose-volume parameters were slightly worse in the tomotherapy group than in the other groups. Despite differences in the IMRT delivery methods, X-ray energies and daily registration methods, all modalities may be used as IMRT for localized prostate cancer.     

左乳癌保乳术后瘤床同步推量sIMRT与HT剂量学研究

目的 探讨左乳癌保乳术后瘤床同步推量静态调强放疗(sIMRT)与螺旋断层放疗(HT)两种放疗技术的剂量学特点.方法 选取左乳癌保乳术后银夹标记瘤床的患者23例,采用医科达Monac05.11计划系统设计sIMRT计划、安科锐TomoTherapy计划系统设计HT计划,处方剂量PGTV:5750cGy/25F、PTV:5...     

螺旋断层调强与固定野调强技术在全乳放疗中的近期临床效果

  目的  研究早期乳腺癌保乳术后应用螺旋断层调强放疗(helical tomotherapy, HT)和固定野调强放疗(fixed-field intensity-modulated radiotherapy, FF-IMRT)的近期疗效和早期临床反应。  方法  2012年9月至2013年3月本院使用HT(HT组)和FF-IMRT(FF-IMRT组)进行保乳术后全乳放疗的早期乳腺癌患者共24例, 每组12例, 术后病理分期0~ⅡB期, 全乳放疗剂量46~50 Gy/23~25次。其中接受化疗者11例(45.8%), 接受内分泌治疗者18例(75%)。对两组靶区及危及器官剂量分布进行评估, 对放疗毒性反应及美容效果进行评价。  结果  与FF-IMRT组相比, HT组的计划靶区(planning target volume, PTV)105%、PTV110%高剂量区减少(P=0.000, P=0.023), 靶区的均匀性和适形度改善(P=0.003, P=0.002)。患侧肺的V₅、V₂₀、Dmean(P=0.002, P=0.001, P=0.000), 双肺的V₅、V₂₀、Dmean(P=0.010, P=0.002, P=0.009)及心脏的V₅、V₂₀(P=0.033, P=0.030)等受量降低。HT组出现Ⅰ、Ⅱ级放射性皮炎者分别有10例(83.3%)、2例(16.7%), FF-IMRT组出现Ⅰ、Ⅱ级放射性皮炎者分别有11例(91.7%)、1例(8.3%); 所有患者均未出现放射性肺炎。HT组患者美容效果为满意者12例(100%), FF-IMRT组美容效果为满意者11例(91.7%)。两组患者的近期不良反应和美容效果评价差异均无统计学意义。  结论  应用HT与FF-IMRT技术进行保乳术后全乳放疗, 可获得满意的近期临床效果, 长期治疗效果还有待进一步随诊观察。     

Structural insights into membrane remodeling by SNX1

The sorting nexin (SNX) family of proteins deform the membrane to generate transport carriers in endosomal pathways. Here, we elucidate how a prototypic member, SNX1, acts in this process. Performing cryoelectron microscopy, we find that SNX1 assembles into a protein lattice that consists of helical rows of SNX1 dimers wrapped around tubular membranes in a crosslinked fashion. We also visualize the details of this structure, which provides a molecular understanding of how various parts of SNX1 contribute to its ability to deform the membrane. Moreover, we have compared the SNX1 structure with a previously elucidated structure of an endosomal coat complex formed by retromer coupled to a SNX, which reveals how the molecular organization of the SNX in this coat complex is affected by retromer. The comparison also suggests insight into intermediary stages of assembly that results in the formation of the retromer-SNX coat complex on the membrane.

Sorting nexins (SNXs) exist as a large family of proteins defined by the presence of a PX (phox homology) domain (1, 2). Members of this family have been found to act as coat proteins in endosomal pathways that include recycling from endosomes to the plasma membrane and retrieval from endosomes to the Golgi complex (3, 4). Defects in these transport processes is associated with various neurologic disorders including Alzheimer’s disease, Parkinson’s disease, and Down’s syndrome (5, 6).Coat proteins assemble into complexes on the membrane to initiate intracellular transport pathways by coupling two main functions: bending the membrane to generate transport carriers and binding to cargoes for their sorting into these carriers (7). Retromer, a trimeric complex consisting of Vps26, Vps29, and Vps35, has been found to couple with different SNXs to form multiple endosomal coat complexes, in which select members of the SNX family act in membrane deformation while retromer acts in cargo recognition (8–17). Recently, a detailed molecular view of this functional cooperation has been achieved by elucidating the structure of a retromer-SNX complex on the membrane (18).Notably, it has been further discovered recently that an endosomal coat complex can be formed with only SNX members. SNX1/2 have been found to heterodimerize with SNX5/6 to form the endosomal SNX–BAR sorting complex for promoting exit 1 (ESCPE-1) complex, in which SNX1/2 are proposed to act in membrane deformation while SNX5/6 act in cargo recognition (19). As such, a key question has become whether SNX that acts in membrane deformation in this type of coat complex would be organized similarly on the membrane, as previously elucidated for SNX in the context of a retromer-SNX complex (18).One of the best characterized mechanisms of membrane deformation involves proteins that possess the BAR (Bin/Amphiphysin/Rvs) domain. This domain has been shown to undergo homodimerization to form a banana-shaped structure, which can impart membrane curvature through a scaffolding mechanism that involves electrostatic interactions between the positive charges lining the concave side of the curved BAR dimer and the negative charges that line the surface of the membrane bilayer. In some cases, the BAR domain can deform the membrane through a second mechanism, which involves the formation of an amphipathic helix that inserts into one leaflet of the membrane bilayer to generate bilayer asymmetry in driving membrane curvature (20, 21).Besides the PX domain, SNX1 also possesses a BAR domain. However, studies have found that its BAR domain is not sufficient in driving membrane deformation. Instead, the PX domain as well as the linker region between the BAR and PX domains are also needed (22, 23). As such, a key goal has been to achieve a better understanding of how the various parts of SNX1 contribute to its ability to deform the membrane.Structural studies, such as those involving crystallography and single-particle electron microscopy (EM), have been advancing a molecular understanding of coat proteins (24), including components of endosomal coats (17, 19, 22, 25–27). Notably, however, these approaches solve protein structures in solution, but the functional form of coat proteins involves their association with the membrane. In this study, we have pursued cryo-EM to reveal how SNX1 is organized on the membrane to explain its ability to deform the membrane. The result advances a molecular understanding of how an endosomal coat that contains only SNXs generates transport carriers. Moreover, by comparing our SNX1 structure to the previously solved retromer-SNX structure (18), we delineate the extent to which the molecular organization of SNX on the membrane is affected by the presence of retromer. This comparison also suggests insight into intermediary stages of coat assembly that form the retromer-SNX complex on the membrane.     

质子点扫描技术与光子Tomotherapy在前列腺癌应用中的剂量学比较

目的:比较前列腺癌质子点扫描技术（SSS-PT）与光子螺旋断层放射治疗（HT）两者之间的剂量学特点,其数据将为临床提供一定的参考。方法:选取12例既往前列腺癌患者作为研究对象,定位后,将CT图像分别传至Raystation和HT计划系统进行放疗计划设计。处方剂量为69 Gy/25 F。比较分析两种放疗计划的靶区适形度指数（CI）、均匀性指数（HI）、靶区和危及器官剂量学参数。结果:靶区的均匀性方面,SSS-PT优于HT（P=0.001）;直肠平均剂量SSS-PT［（21.92±4.00） Gy］低于HT［（31.97±2.60） Gy］（P=0.000）;膀胱平均剂量SSS-PT［（17.62±3.15） Gy］低于HT［（30.52±3.94） Gy］（P=0.000）;对于直肠和膀胱的保护,SSS-PT在低、中剂量区总是优于HT。结论:SSS-PT和HT两种治疗方式在靶区剂量分布均可满足临床需求,在同样靶区覆盖条件下,SSS-PT相较于HT能够更好地保护直肠和膀胱,尤其是在低、中剂量区。     

螺旋断层放疗自适应技术的初步应用

目的：通过比较螺旋断层自适应计划与非自适应计划中危及器官的受照剂量体积,评估应用螺旋断层放疗减少周围正常组织受照体积的临床可行性。方法与材料：收集5例患者治疗过程中每完成5个分次剂量后在螺旋断层治疗机上采集的兆伏级CT（MVCT）图像并勾画肿瘤范围（GTV）并测量GTV的体积,评价GTV的体积变化。完成20个分次照射剂量后应用MVCT图像勾画缩减后的GTV并创建自适应计划,通过比较自适应计划与非自适应计划危及器官的体积剂量直方图（DVH）,评估自适应放疗的剂量学优势。结果：5例应用螺旋断层放疗自适应技术的病人的GTV在完成25个治疗分次后与治疗前比较均有明显的缩小（约为40%～60%）。三例肺癌患者接受20 Gy照射的同侧肺的体积平均减少了8.76%;两例盆腔患者接受40 Gy照射的小肠体积减少了1.48%;接受40 Gy照射的直肠体积减少了8.86%;接受45 Gy照射的膀胱体积减少了7.67%。而应用螺旋断层放疗系统实施自适应放疗技术平均只需要185.4min。结论：应用螺旋断层放疗的自适应技术减少周围正常组织的受照体积在临床上是可行的。     

TQA数据趋势与TomoTherapy输出稳定性的联系

目的:探讨TomoTherapy QualityAssurance（TQA）数据趋势与螺旋断层放疗（Helical Tomotherapy,HT）系统输出的联系。方法:回顾性分析了本院HT系统近3年内TQA各个模块的参数和数据趋势,探讨其与HT系统的静态输出剂量和输出能量（D20/D10）变化的相关性。结果:楔形阶梯静态模块的z轴偏移参数与HT的静态输出剂量的相关性最强（r=0.883,P<0.01）。基本剂量测定模块的出口检测器平整度值对能量变化最敏感（r=0.902）,其次是楔形阶梯静态模块的能量差异（r=0.897）和楔形阶梯螺旋模块的能量差异（r=0.852）,灵敏度分别为2.3×10-4、3.1×10-4和5.7×10-4。结论:TQA有助于用户追踪HT输出剂量和能量变化,及早进行必要的机器维护或剂量校准。     

梗阻性黄疸实施64排螺旋CT诊断分析

目的：对梗阻性黄疸实施64排螺旋CT诊断的应用价值进行分析和探讨。方法选择2012年10月—2014年10月在该院进行治疗的梗阻性黄疸患者80例,对其临床资料进行回顾性分析,患者均行64排螺旋CT扫描和增强扫描,并将扫描结果进行CPR和MPR处理,评价患者的胆管梗阻定位以及定性诊断结果,并将其与手术病理诊断和ERCP结果进行比较。结果80例梗阻性黄疸患者的CT诊断均符合手术病理诊断和ERCP结果;其中有47例患者为良性病变,45例患者为正确诊断;33例患者为恶性病变,30例患者为正确诊断。64排螺旋CT对梗阻性黄疸的定位为100%(90/90),定性准确率为93.8%（75/80）。结论64排螺旋CT的处理功能非常强大,能够对梗阻性黄疸进行准确的定位,且定性准确率高,是一种无创且有效的检查方法。