Regulation of RAS oncogenicity by acetylation

Members of the RAS small GTPase family regulate cellular responses to extracellular stimuli by mediating the flux through downstream signal transduction cascades. RAS activity is strongly dependent on its subcellular localization and its nucleotide-binding status, both of which are modulated by posttranslational modification. We have determined that RAS is posttranslationally acetylated on lysine 104. Molecular dynamics simulations suggested that this modification affects the conformational stability of the Switch II domain, which is critical for the ability of RAS to interact with guanine nucleotide exchange factors. Consistent with this model, an acetylation-mimetic mutation in K-RAS4B suppressed guanine nucleotide exchange factor-induced nucleotide exchange and inhibited in vitro transforming activity. These data suggest that lysine acetylation is a negative regulatory modification on RAS. Because mutations in RAS family members are extremely common in cancer, modulation of RAS acetylation may constitute a therapeutic approach.     

Low rate of active treatment of patients with hilar cholangiocarcinoma

Introduction

The results of surgical resection and palliative chemotherapy use in hilar cholangiocarcinoma (HC) have been well publicised but the proportion of patients able to undergo these treatments and the comparative outcomes in a population of patients with HC are less well known.

Methods

Patients with HC were identified by review of all patients undergoing percutaneous cholangiography over a nine-year period (2002–2010) in a tertiary facility. The treatment undertaken and outcomes were recorded.

Results

Overall, 68 patients were identified (37 female) with a median age of 70 years. Forty-five (66%) were treated solely by insertion of a metal stent (median survival 4.73 months) and nine (13%) also received palliative chemotherapy (median survival 13.7 months). Persisting jaundice after stent insertion was noted in 18 of 35 patients (51%) tested within one month of death. Fourteen patients (21%) underwent surgical resection (median survival 20.2 months).

Conclusions

Patients undergoing surgical resection had significantly longer survival than those receiving only a palliative stent but not compared with those also receiving palliative chemotherapy, with short-term follow-up. Only a third of patients, however, receive active treatment (surgery or chemotherapy) and improvements in long-term biliary palliation are needed.     

腹膜外切口单层缝合与常规分层缝合法在化脓性或坏疽性阑尾炎术后疗效比较中的系统评价

目的评价腹膜外切口单层缝合与常规分层缝合法在化脓性或坏疽性阑尾炎术后的临床疗效。方法计算机检索Co-chrane Library、PubMed、Embase、SCI、CNKI、CBM、VIP、WANFANG DATA,纳入腹膜外切口单层缝合与常规分层缝合法在化脓性或坏疽性阑尾炎术后疗效比较的随机对照试验,对纳入研究的方法学质量进行评价,用Cochrane协作网提供的RevMan 5.1软件对数据进行统计分析,并对统计结果进行系统评价。结果共纳入6个随机对照试验,共计1 885例患者。Meta分析结果显示:腹膜外切口单层缝合与常规分层缝合法在手术时间[MD=-17.09,95%CI(-19.32,-14.87)],术后切口感染率[RR=0.06,95%CI(0.03,0.12)],7 d内出院率[RR=1.17,95%CI(1.13,1.22)]方面差异均具有统计学意义,但两者在术后疼痛程度(需应用镇痛药物比率)[RR=1.05,95%CI(0.91,1.20)]方面的差异无统计学意义。结论目前研究表明,与常规分层缝合法相比,腹膜外切口单层缝合法能显著缩短化脓性或坏疽性阑尾炎患者的手术时间,降低术后切口感染率,提高7 d内出院率,但本研究纳入的样本量小且质量不高,因此,有必要开展更多高质量、多中心的随机盲法对照试验进一步予以证实其疗效。     

不同呼吸机湿化管道系统在老年机械通气患者中的应用效果对比

目的:探讨不同呼吸机湿化管道系统在老年机械通气患者中的应用效果。方法:选取老年机械通气患者140例,随机分为3组,其中A组(n=43)使用MR410型湿化管道系统,B组(n=47)使用MR730型湿化管道系统,C组(n=50)采用MR 850型一次性双加热式、自动加水加湿湿化管道系统。观察3组湿化效果、并发症发生情况、通气时间及管道护理情况。结果:C组湿化效果适中比例最高,其次为B组,A组最低,3组间差异有统计学意义(P<0.01)。C组无导管痰痂和气道痉挛的发生,A组发生率最高,3组间差异有统计学意义(P<0.01)。C组通气时间、管道总更换次数、呼吸机管道护理时数均低于A、B组,差异有统计学意义(P<0.01)。结论:使用MR850型一次性双加热式、自动加水加湿湿化管道系统湿化效果最好,能降低并发症发生率,缩短通气时间和护理工作量。     

Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease,achalasia and hypertension

Moyamoya disease (MMD) is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory moyamoya collateral vessels. Homozygous mutations in GUCY1A3 have been reported as a cause of MMD and achalasia. Probands (n = 96) from unrelated families underwent sequencing of GUCY1A3. Functional studies were performed to confirm the pathogenicity of identified GUCY1A3 variants. Two affected individuals from the unrelated families were found to have compound heterozygous mutations in GUCY1A3. MM041 was diagnosed with achalasia at 4 years of age, hypertension and MMD at 18 years of age. MM149 was diagnosed with MMD and hypertension at the age of 20 months. Both individuals carry one allele that is predicted to lead to haploinsufficiency and a second allele that is predicted to produce a mutated protein. Biochemical studies of one of these alleles, GUCY1A3 Cys517Tyr, showed that the mutant protein (a subunit of soluble guanylate cyclase) has a significantly blunted signaling response with exposure to nitric oxide (NO). GUCY1A3 missense and haploinsufficiency mutations disrupt NO signaling leading to MMD and hypertension, with or without achalasia.     

Effect of farnesol on a mouse model of systemic candidiasis, determined by use of a DPP3 knockout mutant of Candida albicans

This work extends our previous observation that the fungus Candida albicans secretes micromolar levels of farnesol and that accumulation of farnesol in vitro prevents the yeast-to-mycelium conversion in a quorum-sensing manner. What does farnesol do in vivo? The purpose of this study was to determine the role of farnesol during infection with a well-established mouse model of systemic candidiasis with C. albicans A72 administered by tail vein injection. This question was addressed by altering both endogenous and exogenous farnesol. For endogenous farnesol, we created a knockout mutation in DPP3, the gene encoding a phosphatase which converts farnesyl pyrophosphate to farnesol. This mutant (KWN2) produced six times less farnesol and was ca. 4.2 times less pathogenic than its SN152 parent. The strain with DPP3 reconstituted (KWN4) regained both its farnesol production levels and pathogenicity. These mutants (KWN1 to KWN4) retained their full dimorphic capability. With regard to exogenous farnesol, farnesol was administered either intraperitoneally (i.p.) or orally in the drinking water. Mice receiving C. albicans intravenously and farnesol (20 mM) orally had enhanced mortality (P < 0.03). Similarly, mice (n = 40) injected with 1.0 ml of 20 mM farnesol i.p. had enhanced mortality (P < 0.03), and the onset of mortality was 30 h sooner than for mice which received a control injection without farnesol. The effect of i.p. farnesol was more pronounced (P < 0.04) when mice were inoculated with a sublethal dose of C. albicans. These mice started to die 4 days earlier, and the percent survival on day 6 postinoculation (p.i.) was five times lower than for mice receiving C. albicans with control i.p. injections. In all experiments, mice administered farnesol alone or Tween 80 alone remained normal throughout a 14-day observation period. Finally, beginning at 12 h p.i., higher numbers of C. albicans cells were detected in kidneys from mice receiving i.p. farnesol than in those from mice receiving control i.p. injections. Thus, reduced endogenous farnesol decreased virulence, while providing exogenous farnesol increased virulence. Taken together, these data suggest that farnesol may play a role in disease pathogenesis, either directly or indirectly, and thus may represent a newly identified virulence factor.     

湖北省接受艾滋病HAART患者CD4+T淋巴细胞变化趋势及影响因素

目的 分析湖北省接受艾滋病HAART患者CD4⁺T淋巴细胞变化趋势及影响因素。 方法 筛选2012年1月1日以后接受HAART的成年患者,利用一般线性模型、重复测量方差分析来分析患者的基线、治疗后6、12个月的CD4⁺T淋巴细胞计数情况及影响因素。 结果 1 843例研究对象基线CD4⁺T淋巴细胞计数均值为(218.94±143.96)个/μl,接受HAART后6个月为(334.31±188.62)个/μl,12个月后为(382.79±204.44)个/μl,差异有统计学意义(F=6 856.98,P=0.000)。影响HAART治疗后CD4⁺T淋巴细胞计数上升的主要因素是:性别、开始治疗年龄、WHO临床分期、初始治疗方案、基线CD4⁺T淋巴细胞计数。受性别、基线CD4⁺T淋巴细胞计数、开始治疗年龄、初始治疗方案等影响,治疗后CD4⁺T淋巴细胞计数随时间推移呈线性上升趋势;其中,女性、开始治疗年龄越小、基线CD4⁺T淋巴细胞计数越高、初始治疗方案含二线药物的患者上升较快。受WHO临床分期因素影响,治疗后CD4⁺T淋巴细胞计数随时间推移上升趋势符合二次方曲线方程,WHO临床分期越靠前,上升速度较快。 结论 湖北省艾滋病患者接受HAART后CD4⁺T淋巴细胞计数上升受多种因素影响,建议针对不同的患者及早开展HAART,提高抗病毒治疗的效果和患者生命质量。     

Cross-sectional analysis of the implant-abutment interface

The purpose of this study was to develop a technique to evaluate the implant-abutment gap of an external hexagon implant system as a function of radius. Six implants of 3.75 mm in diameter (Conexao Sistema de Protese Ltda, Sao Paulo, Brazil) and their respective abutments were screw connected and torqued to 20 N cm(-1). The implants were mounted in epoxy assuring an implant long-axis position perpendicular to the vertical axis. Each implant was grounded through its thickness parallel to implant long-axis at six different distance interval. Implant-abutment gap distances were recorded along the implant-abutment region for each section. Individual measurements were related to their radial position through trigonometric inferences. A sixth degree polynomial line fit approach determined radial adaptation patterns for each implant. Micrographs along implant sections showed a approximately 300 mum length implant-abutment engagement region. All implants presented communication between external and internal regions through connection gaps and inaccurate implant-abutment alignment. Average gap distances were not significantly different between implants (P > 0.086). Polynomial lines showed implant-abutment gap values below 10 mum from 0 mum to approximately 250 mum of the implant-abutment engagement region. Gap distances significantly increased from approximately 250 mum to the outer radius of the implant-abutment engagement region. The technique described provided a broader scenario of the implant-abutment gap adaptation compared with previous work concerning implant-abutment gap determination, and should be considered for better understanding mechanical aspects or biological effects of implant-abutment adaptation on peri-implant tissues.     

一种西地那非类似物的合成工艺研究

目的 探讨合成一种西地那非类似物的新方法.方法 设计以WG 001-01-08和五硫化二磷为原料,经过硫化得到目标化合物（一种西地那非类似物）的合成路线,并以收率和杂质为指标考察反应试剂、反应温度、加料顺序对反应的影响.结果 成功制备了目标化合物,收率为90％;较佳反应条件为以4-甲基吡啶为溶剂,120℃反应4h,先加WG001-01-08后加五硫化二磷.结论 新方法收率较高,杂质少,反应条件温和,适合工业化生产.