Concurrent gemcitabine and cisplatin combined with 3D conformal radiotherapy for stage III non-small cell lung cancer

Objective： To study the toxicities and efficacy of concurrent gemcitabine plus cisplatin combined with three-dimensional conformal radiotherapy for stage Ⅲ non-small cell lung cancer （NSCLC）. Methods： Thirty-six patients with pathologically diagnosed NSCLC received radiotherapy and concurrent chemotherapy. There were 22 patients with stage Ilia and 14 patients with IIIb. Radiotherapy was given a total of 60-70 Gy in conventional fractionation. Chemotherapy included gemcitabine （600 mg/m^2） and cisplatin （20 mg/m^2）, once per week. Results： Thirty-two patients received a total dose of 60-72 Gy. Two patients received 56 Gy and another two patients received 58 Gy. Thirty-four patients received 4-6 weeks of chemotherapy, while two patients received only 2 weeks of chemotherapy. The overall response rate （CR ＋ PR）, complete response rate （CR）, partially response rate （PR） were 83.3% （30/36）, 11.1% （4/36） and 72.2% （26/36） respectively. The median follow-up duration was 18.4 months. The 1- and 2-year overall survival rates were 77.8% （28/36） and 55.6% （20/36）, respectively. Conclusion： Concurrent gemcitabine and cisplatin combined with three-dimensional conformal radiotherapy for stage III non-small cell lung cancer is effective and well tolerated. Lone-term results need further study.     

消囊汤治疗卵巢囊肿32例临床研究

目的：研究中药消囊汤对卵巢囊肿的影响。方法：将62例卵巢囊肿妇女随机分为消囊汤组及桂枝茯苓胶囊组,两组分别于月经后用自拟消囊汤和中成药桂枝茯苓胶囊治疗,进行临床效果观察和治疗前后B超检测。结果：用药2～6个月,随访半年,消囊汤和桂枝茯苓胶囊治疗卵巢囊肿均有效果（P〈0．05）,但两组总有效率有显著性差异（P〈0．05）,前者疗效率明显优于后者。结论：消囊汤治疗卵巢囊肿有显著疗效,且有扶正祛邪作用。     

髓内钉与钢板治疗肱骨干骨折临床疗效的比较研究

目的:回顾性分析比较交锁髓内钉与加压钢板治疗肱骨干骨折的疗效.方法:手术治疗135例肱骨干骨折,其中肱骨加压钢板内固定59例,交锁髓内钉固定76例,比较两种方法的手术时间、住院时间、术中出血量等疗效指标和术后并发症发生情况以及功能恢复情况.结果:髓内钉组术中出血量平均为125ml,少于钢板组的212ml,差异有统计学意义(P＜0.05),而在手术时间及住院时间方面,两者之间差异没有统计学意义(P＞0.05).髓内钉内固定组1例发生骨不连,钢板组有4例出现骨不连接.桡神经损伤钢板与髓内钉分别为7例、2例,血管损伤分别为1例、0例,骨折畸形愈合两组各1例,肩功能功能障碍分别为3例、6例,所有病例未发生骨感染.术后长期随访,髓内钉组的优良率为89.5%,钢板组为88.1%,两者差异有统计学意义(P＜0.05).结论:与钢板相比,髓内钉具有术中出血量少,桡神经损伤发生率低等优点,应作为肱骨骨折的首选治疗方法.     

激光针灸镇痛效应与穴区肥大细胞功能的关系

目的:观察低强度复合和单激光照射急性佐剂性关节炎大鼠"足三里"穴的镇痛效应及其与肥大细胞脱颗粒效应的关系.方法:采用清洁级SD大鼠66只,随机分为空白组、模型组、假照射组、10.6μm激光组、650 nm激光组和复合激光组,治疗时除空白、模型组外各组照射"足三里"穴30 min.除了空白组,其他5组通过左踝关节腔内注射完全弗式佐剂0.05 mL建立急性佐剂性关节炎模型.采用辐射热缩爪反射的方法,以大鼠缩爪反射的潜伏期为观察指标,比较各组的镇痛效果;通过穴位组织切片和甲苯胺蓝染色,离体对照激光照射前后穴位处局部肥大细胞脱颗粒率的变化.结果:激光照射后,650 nm激光组和复合激光组的痛阈显著高于模型组和假照射组(P＜0.01),650 nm激光组与复合激光组的肥大细胞脱颗粒率也显著高于模型组和假照射组(P＜0.001).10.6μm激光组的痛阈和肥大细胞脱颗粒率与模型组、假照射组比无显著差异.肥大细胞脱颗粒率与缩爪潜伏期的线性相关系数为0.737(P＜0.001).结论:低强度复合650 nm+10.6μm激光和单650 nm激光照射急性佐剂性关节炎大鼠"足三里"穴有显著镇痛效应;穴区中的肥大细胞脱颗粒率与镇痛效应呈正相关,在激光针灸镇痛效应的产生过程中起着重要作用.     

冬凌草甲素衍生物的制备和评价

目的 为研究冬凌草甲素的构效关系,对冬凌草甲素进行结构修饰,合成其衍生物,并评价其细胞毒活性.方法 经常规提取分离得到冬凌草甲素(Ⅰ);通过氧化和酰基化,制备冬凌草甲素衍生物,所获产物采用NMR和MS确证结构;采用MTT法观察衍生物的细胞毒活性.结果 制备了6个冬凌草甲素的衍生物,分别为14-乙酰基冬凌草甲素(Ⅱ)、1,14-二乙酰基冬凌草甲素(Ⅲ)、14一对甲苯磺酰基冬凌草甲素(Ⅳ)、1-氧代冬凌草甲素(Ⅴ),14-乙酰基-1-氧代冬凌草甲素(Ⅵ)、14-对甲苯磺酰基-1-氧代冬凌草甲素(Ⅶ),其中化合物Ⅳ、Ⅵ、Ⅶ为3个新化合物.初步药理实验表明部分衍生物细胞毒活性高于冬凌草甲素.结论 首次评价了1-氧代冬凌草甲素衍生物的细胞毒活性,其活性高于冬凌草甲素.     

RRLC-UV法同时测定丹参中酚酸类成分的含量

目的:建立RRLC-UV法同时测定丹参药材中9种酚酸的含量.方法:以3,4-二羟基苯乙酸为内标,采用Agilent Zorbax Eclipse Plus C_(18)(2.1 mm×50 mm,1.8μm)色谱柱,以乙腈-0.1%甲酸溶液为流动相梯度洗脱,流速0.3 mL·min~(-1),检测波长质量286 nm.结果:这9种成分在测定质量浓度范围内与色谱峰面积线性关系良好,相关系数不低于0.999 5.仪器精密度和方法精密度RSD均小于2.4%,9种成分平均回收率在96.7%～102.6%,RSD均小于3.1%(n=3).结论:该方法简便、快速,结果准确,重复性好,适用于丹参药材的质量控制.     

辣椒碱-羟丙基-β-环糊精包合物制备鉴定及 热力学稳定性研究

目的:制备及鉴定辣椒碱-HP-β-CD包合物,并考察辣椒碱和HP-β-CD之间的包合摩尔比及包合过程的热力学常数.方法:采用饱和水溶液法制备辣椒碱-HP-β-CD包合物,以差示扫描量热法(DSC)、X射线衍射法(XRD)和红外光谱法(IR)对包合物进行鉴定,通过表观溶解度法考察包合物中主客分子之间的包合摩尔比及包合过程的热力学常数.结果:25,35,45℃下辣椒碱和HP-β-CD能形成1:1摩尔比包合物,相溶解度图呈A_L型.结论:辣椒碱-羟丙基-β-环糊精包合物能显著增大药物的溶解度.     

Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN

High-fidelity replication of the large RNA genome of coronaviruses (CoVs) is mediated by a 3′-to-5′ exoribonuclease (ExoN) in nonstructural protein 14 (nsp14), which excises nucleotides including antiviral drugs misincorporated by the low-fidelity viral RNA-dependent RNA polymerase (RdRp) and has also been implicated in viral RNA recombination and resistance to innate immunity. Here, we determined a 1.6-Å resolution crystal structure of severe acute respiratory syndrome CoV 2 (SARS-CoV-2) ExoN in complex with its essential cofactor, nsp10. The structure shows a highly basic and concave surface flanking the active site, comprising several Lys residues of nsp14 and the N-terminal amino group of nsp10. Modeling suggests that this basic patch binds to the template strand of double-stranded RNA substrates to position the 3′ end of the nascent strand in the ExoN active site, which is corroborated by mutational and computational analyses. We also show that the ExoN activity can rescue a stalled RNA primer poisoned with sofosbuvir and allow RdRp to continue its extension in the presence of the chain-terminating drug, biochemically recapitulating proofreading in SARS-CoV-2 replication. Molecular dynamics simulations further show remarkable flexibility of multidomain nsp14 and suggest that nsp10 stabilizes ExoN for substrate RNA binding to support its exonuclease activity. Our high-resolution structure of the SARS-CoV-2 ExoN–nsp10 complex serves as a platform for future development of anticoronaviral drugs or strategies to attenuate the viral virulence.

The 29.9-kb single-stranded RNA genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the global COVID-19 pandemic, is replicated and transcribed by the viral RNA-dependent RNA polymerase (RdRp, nsp12) (1–3). Unlike the high-fidelity cellular replicative DNA polymerases, viral RdRp enzymes, including the CoV RdRp, do not contain a proofreading exonuclease domain to ensure high fidelity. The resulting higher mutation rate (10⁻⁴ to 10⁻⁶ substitutions per nucleotide per round of replication) is generally thought to promote rapid viral adaptation in response to selective pressure (4–6). However, the lack of proofreading activity in RdRp poses a particular challenge for the replication of CoVs, which feature the largest known RNA virus genomes (27 to 32 kb, up to twice the length as the next-largest nonsegmented RNA viral genomes) (7, 8). It has been reported that SARS-CoV nsp12 is the fastest viral RdRp known but with an error rate more than one order of magnitude higher than the generally admitted error rate of viral RdRps (9), clearly necessitating a unique proofreading mechanism.To mitigate the low fidelity of RdRp, all coronaviruses encode a 3′-to-5′ exoribonuclease (ExoN) in multifunctional nsp14 (10–12), which forms a complex with nsp10 critical for the ExoN activity, and additionally contains a C-terminal guanine N7 methyl transferase (N7-MTase) domain. Mutations of SARS-CoV-2 nsp14 exhibit strong association with increased genome-wide mutation load (13, 14), and genetic inactivation of ExoN in engineered SARS-CoV and murine hepatitis virus (MHV) leads to 15- to 20-fold increases in mutation rates (7, 15, 16). Furthermore, in a mouse model, SARS-CoV with inactivated ExoN shows a mutator phenotype with decreased fitness and lower virulence over serial passage, suggesting a potential strategy for generating a live, impaired-fidelity coronavirus vaccine (17). Alternatively, recent studies show that ExoN inactivation abrogates replication of SARS-CoV-2 and Middle East Respiratory Syndrome CoV (18), hinting at additional functions for ExoN in viral replication. Indeed, ExoN activity has been reported to mediate the extensive viral RNA recombination required for subgenomic messenger RNA (mRNA) synthesis during normal replication of CoVs, including SARS-CoV-2 (19), and it was shown to be required for resistance to the antiviral innate immune response for MHV (20). ExoN inactivation also significantly increases the sensitivity of CoVs to nucleoside analogs that target RdRp, which is consistent with the biochemical activity of ExoN to excise mutagenic or chain-terminating nucleotides misincorporated by RdRp (21–23). These observations combine to suggest that chemical inhibition of ExoN could be an effective antiviral strategy against CoVs. In this study, we determined high-resolution crystal structures of the SARS-CoV-2 ExoN–nsp10 complex and studied its biochemical activities. Furthermore, we used molecular dynamics (MD) simulations to better understand the dynamics of nsp14, nsp10, and their interaction with RNA.     

Identification of Fenton-like active Cu sites by heteroatom modulation of electronic density

Developing heterogeneous catalysts with atomically dispersed active sites is vital to boost peroxymonosulfate (PMS) activation for Fenton-like activity, but how to controllably adjust the electronic configuration of metal centers to further improve the activation kinetics still remains a great challenge. Herein, we report a systematic investigation into heteroatom-doped engineering for tuning the electronic structure of Cu-N₄ sites by integrating electron-deficient boron (B) or electron-rich phosphorus (P) heteroatoms into carbon substrate for PMS activation. The electron-depleted Cu-N₄/C-B is found to exhibit the most active oxidation capacity among the prepared Cu-N₄ single-atom catalysts, which is at the top rankings of the Cu-based catalysts and is superior to most of the state-of-the-art heterogeneous Fenton-like catalysts. Conversely, the electron-enriched Cu-N₄/C-P induces a decrease in PMS activation. Both experimental results and theoretical simulations unravel that the long-range interaction with B atoms decreases the electronic density of Cu active sites and down-shifts the d-band center, and thereby optimizes the adsorption energy for PMS activation. This study provides an approach to finely control the electronic structure of Cu-N₄ sites at the atomic level and is expected to guide the design of smart Fenton-like catalysts.

The Fenton-like process presents one of the most powerful water treatment technologies to tackle persistent organic pollutants resulting from rapid economic development and unsustainable industrial and agricultural expansion (1 –4). The peroxymonosulfate (PMS)-based advanced oxidation process has attracted extensive attention due to its high efficiency at a wide pH range and ease of transport and storage (5 –7). However, the sluggish kinetics of PMS activation during oxidation processes results in prohibitive costs and substantial chemical inputs (8, 9). Therefore, developing efficient catalysts to accelerate the reaction kinetics of PMS is crucial toward efficient catalytic oxidation of recalcitrant organics. Although homogeneous first-row transition metals (Co²⁺, Fe²⁺, Cu²⁺, and Mn²⁺) generally exhibit remarkable capabilities for PMS activation, they also suffer problems such as poor recyclability and accumulation of sludge (10 –12). Comparatively, heterogeneous catalysts [e.g., transition metal oxides (13, 14), supported nanoparticles (NPs) (15, 16), and carbon-based materials (17, 18)] can be readily recovered and regenerated and are recognized as promising candidates for PMS activation. Nevertheless, the heterogeneity of NPs results in lower utilization efficiency of surface atoms (with 81.6% atoms buried and unavailable for 6-nm nickel NPs) and generally slower reaction kinetics than their homogeneous counterparts (19).Single-atom catalysts (SACs) featuring utmost atom-utilization efficiency and tunable electronic structure can break the limitations of heterogeneous catalysts in terms of the kinetics and catalytic activity (20, 21). Thus, SACs show a great potential to address the slow reaction kinetics of PMS for the Fenton-like process via maximizing the number of catalytic sites (22). For instance, a single-site Fe catalyst exhibited much faster reaction kinetics toward the degradation of phenol than the Fe NP catalyst, owing to the maximized atomic utilization (23). In addition, the synergetic effect between the atomic center and pyrrolic N site of supports endowed Co SACs with dual reaction sites and high activity for PMS-based oxidation (24). To further accelerate the reaction kinetics of PMS, various strategies have been developed to improve the intrinsic activity of single atomic sites. By controlling the configurations of single atomic sites, PMS was more favorable for adsorption and activation on the CoN_2 + 2 site than the CoN₄ site (25). Previous work shows that manipulating the electronic structure of single sites plays an essential role in mediating the intrinsic activity (26, 27). It is highly desirable to gain insights into tuning the electronic structure of single-atom sites to achieve superior PMS activation kinetics.Recent studies demonstrate that the electronic structure of isolated metal sites can be directly modulated by altering the coordinated atom species of the metal centers, favorable for expediting catalytic activity (28, 29). Notably, controlling the long-range interactions with suitable functionalities on the substrate of SACs can be a promising approach for tuning the electronic structure of metal centers (30). Indeed, the kinetic activity of single atomic sites was successfully tuned by the introduction of electron-withdrawing oxidized S groups or electron-donating thiophene-like S species into carbon supports of SACs (31). To this end, nonmetallic heteroatoms offer a substantial potential to serve as electron-withdrawing/donating functionalities on the carbon plane by chemical substitution (32, 33). Specifically, boron (B) with a vacant 2p_z orbital conjugating with the carbon π system extracts the electrons, while phosphorus (P) with a readily available lone electron pair and low electronegativity is expected to donate electron in graphene (34, 35). With this strategy, incorporating particular heteroatoms (B/P) into the substrate is a possible route to deplete/enrich the electronic density of metal centers, tuning the electronic structure of single sites to promote PMS activation kinetics.In this work, we designed a versatile strategy to systematically tune the electronic structure of Cu-N₄ sites by integrating specific heteroatoms (B/P) into N-doped carbon substrates of Cu SACs. Subsequently, the effect of the controlled electronic features of Cu centers on facilitating PMS reaction kinetics was explored. Here, the heteroatom modified Cu-N₄ catalysts were first prepared by using a hydrogen-bonding-assisted pyrolysis approach. Synchrotron X-ray adsorption spectroscopy and the projected density of states (PDOS) analysis verified the successful regulation of the electronic configuration of the Cu-N₄ SACs by different heteroatom functionalities. Furthermore, electron paramagnetic resonance and Raman spectra were employed to elucidate the PMS activation mechanism in the Cu-N₄/C-B/PMS system. This study opens an avenue to regulating the electronic structures of single active site of SACs to accelerate PMS activation kinetics for pollutant degradation.     

电子束CT和超声心动图在诊断先天性心脏病中的对照研究

目的 探讨电子束CT(electron beam computed tomography,EBCT)和超声心动图在先天性心脏病(简称先心病)诊断中的价值.方法 32例经临床及经胸超声心动图(transthoracic echocardiography,TTE)诊断为先心病的患者进行EBCT心血管造影检查,与导管法心血管造影检查和手术结果进行对照.结果 32例患者中,EBCT总体诊断符合率87.5%(28/32),TTE诊断符合率78.1%(25/32).EBCT对心外及大血管与房室连接诊断准确率为96.6%(57/59),明显优于TTE的66.1%(39/59).而TTE对心内畸形的诊断准确率为97.7%(43/44),高于EBCT的81.8%(36/44).EBCT与TTE两者结合,可将诊断准确率提高为96.9%(31/32).结论 EBCT对先天性心脏病有重要的诊断价值,尤其对心外及大血管与房室连接关系诊断准确率较高.将EBCT与TTE检查相结合,可大大提高对各种先心病的诊断准确率.