• 【结直肠腺癌和其他大肠疾病中的雌激素受体。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Sciascia C,Olivero G,Comandone A,Festa T,Fiori MG,Enrichens F
    BACKGROUND & AIMS: :Seventy-two patients with tumor and ten with non-neoplastic colon disease were studied for the presence of estrogen receptors (ER) by three different methods. Only seven specimens (six primary adenocarcinomas and one recurrent cancer) had an ER concentration above 3 fm/mg of cytosolic protein, with no sex, age and tumor stage correlation. Our results suggest that the large bowel does not contain a cytosolic receptor for estradiol.
    背景与目标: : 通过三种不同的方法研究了72例肿瘤患者和10例非肿瘤性结肠疾病的雌激素受体 (ER) 的存在。只有7个标本 (6个原发性腺癌和1个复发性癌症) 的ER浓度高于3 fm/mg的胞质蛋白,没有性别,年龄和肿瘤分期的相关性。我们的结果表明,大肠不含雌二醇的胞质受体。
  • 【胃癌中pRb2/p130,VEGF,EZH2,p53,p16(INK4A),p27(KIP1),p21(WAF1) Ki-67表达模式的免疫组织化学分析。】 复制标题 收藏 收藏
    DOI:10.1002/jcp.20833 复制DOI
    作者列表:Mattioli E,Vogiatzi P,Sun A,Abbadessa G,Angeloni G,D'Ugo D,Trani D,Gaughan JP,Vecchio FM,Cevenini G,Persiani R,Giordano A,Claudio PP
    BACKGROUND & AIMS: :Although the considerable progress against gastric cancer, it remains a complex lethal disease defined by peculiar histological and molecular features. The purpose of the present study was to investigate pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expressions, and analyze their possible correlations with clinicopathological factors. The expression patterns were examined by immunohistochemistry in 47 patients, 27 evaluated of intestinal-type, and 20 of diffuse-type, with a mean follow up of 56 months and by Western blot in AGS, N87, KATO-III, and YCC-2, -3, -16 gastric cell lines. Overall, stomach cancer showed EZH2 correlated with high levels of p53, Ki-67, and cytoplasmic pRb2/p130 (P < 0.05, and P < 0.01, respectively). Increased expression of EZH2 was found in the intestinal-type and correlated with the risk of distant metastasis (P < 0.05 and P < 0.01, respectively), demonstrating that this protein may have a prognostic value in this type of cancer. Interestingly, a strong inverse correlation was observed between p27(KIP1) expression levels and the risk of advanced disease and metastasis (P < 0.05), and a positive correlation between the expression levels of p21(WAF1) and low-grade (G1) gastric tumors (P < 0.05), confirming the traditionally accepted role for these tumor-suppressor genes in gastric cancer. Finally, a direct correlation was found between the expression levels of nuclear pRb2/p130 and low-grade (G1) gastric tumors that was statistically significant (P < 0.05). Altogether, these data may help shed some additional light on the pathogenetic mechanisms related to the two main gastric cancer histotypes and their invasive potentials.
    背景与目标: : 尽管在抗胃癌方面取得了长足的进步,但它仍然是一种由特殊的组织学和分子特征定义的复杂致死疾病。本研究的目的是调查pRb2/p130,VEGF,EZH2,p53,p16(INK4A),p27(KIP1),p21(WAF1),Ki-67表达,并分析其与临床病理因素的可能相关性。通过免疫组织化学检查了47例患者的表达模式,其中27例被评估为肠型,20例被评估为弥漫型,平均随访56个月,并通过Western blot在AGS,N87,KATO-III和YCC-2中进行了检测,-3,-16胃细胞系。总体而言,胃癌显示EZH2与高水平的p53,Ki-67和细胞质pRb2/p130相关 (分别为P <0.05和P <0.01)。在肠型中发现EZH2的表达增加,并且与远处转移的风险相关 (分别为P <0.05和P <0.01),表明该蛋白可能在此类癌症中具有预后价值。有趣的是,p27(KIP1) 表达水平与晚期疾病和转移风险之间存在很强的负相关 (P <0.05),而p21(WAF1) 表达水平与低度 (G1) 胃肿瘤之间存在正相关 (P <0.05),证实了这些肿瘤抑制基因在胃癌中的传统作用。最后,发现核pRb2/p130的表达水平与低级别 (G1) 胃肿瘤之间存在直接相关性,具有统计学意义 (P <0.05)。总之,这些数据可能有助于进一步阐明与两种主要胃癌组织类型及其侵袭潜力有关的致病机制。
  • 【葡萄膜炎患者肝素表面修饰人工晶状体与常规聚甲基丙烯酸甲酯人工晶状体的回顾性分析。】 复制标题 收藏 收藏
    DOI:10.1007/BF02583275 复制DOI
    作者列表:Lardenoye CW,van der Lelij A,Berendschot TT,Rothova A
    BACKGROUND & AIMS: BACKGROUND:Several studies described the benefits of the heparin-surface-modified intraocular tens (HSM IOL) with regard to the reduced inflammation in routine extracapsular cataract extractions. However, limited information is available about the advantages of the HSM IOL in patients with an intraocular inflammation. AIM:To assess the eventual benefits of the HSM IOL compared to the regular polymethylmethacrylate intraocular lens (PMMA IOL) in patients with uveitis. METHODS:A retrospective study of 43 patients with uveitis of various origins who underwent an extracapsular cataract extraction (24 with HSM, 19 with PMMA IOL). The activity of intraocular inflammation, visual acuity, eventual complications, and medications were examined. Standardized follow-up dates were used (before surgery, one and fourteen days, five and eleven months after surgery.) RESULTS:No difference in the inflammatory, activity was noted between HSM and PMMA groups; neither at short term clinical evaluation, nor at five months after surgery. Despite a slightly better visual acuity in the HSM group before surgery, no long term differences were observed. After surgery the increase in visual acuity was similar for both groups, as well as the frequency of cystoid macular oedema (CMO) and synechiae. Fewer patients in HSM group required Nd:YAG posterior capsulotomy, but the difference was not significant. CONCLUSION:No clinical advantage was found when the HSM IOL was compared with the regular PMMA IOL in 43 patients with uveitis.
    背景与目标:
  • 【骨髓嵌合体小鼠肿瘤浸润基质细胞的制备及功能分析。】 复制标题 收藏 收藏
    DOI:10.1111/j.1348-0421.2006.tb03830.x 复制DOI
    作者列表:Ishigaki H,Yamamoto Y,Ishida H,Kajino K,Itoh Y,Fujiyama Y,Ogasawara K
    BACKGROUND & AIMS: :Tumor-infiltrating stroma cells (TISC) as well as tumors themselves are thought to be involved in tumor-related immunosuppression, which is one of the critical mechanisms of tumor escape from immune surveillance. However, preparation of TISC is difficult because of the small proportion of TISC in established tumors. Thus, the cells thought to be involved in tumor-related immunosuppression are generally prepared from spleens or draining lymph nodes in tumor-bearing mice. In this study, we developed a method for directly preparing TISC from established tumors in order to analyze their function. Using green fluorescent protein (GFP) transgenic (Tg) mice and C57BL/6 mice transplanted with bone marrow (BM) cells of GFPTg mice, we detected three subpopulations of TISC: one is compatible with immature myeloid cells (ImC) derived from BM and the two other subpopulations, CD11b(+) cells and CD11b(-) cells, do not originate from BM. The TISC including these subpopulations but not each subpopulation independently after culturing with tumors in the presence of GM-CSF could suppress T cell proliferation induced by anti-CD3. In our system, tumors did not inhibit T cell responses directly, but unknown factors from tumors affected immunosuppression by TISC.
    背景与目标: : 肿瘤浸润的基质细胞 (TISC) 以及肿瘤本身被认为与肿瘤相关的免疫抑制有关,这是肿瘤逃避免疫监视的关键机制之一。然而,由于TISC在已建立的肿瘤中的比例较小,因此很难制备TISC。因此,被认为与肿瘤相关的免疫抑制有关的细胞通常是从荷瘤小鼠的脾脏或引流淋巴结中制备的。在这项研究中,我们开发了一种从已建立的肿瘤中直接制备TISC的方法,以分析其功能。使用绿色荧光蛋白 (GFP) 转基因 (Tg) 小鼠和C57BL/6小鼠移植了GFPTg小鼠的骨髓 (BM) 细胞,我们检测到了TISC的三个亚群: 一个与BM衍生的未成熟髓样细胞 (ImC) 相容,另外两个亚群,CD11b(+) 细胞和CD11b(-) 细胞不起源于BM。在gm-csf存在下用肿瘤培养后,包括这些亚群但不是每个亚群的TISC可以抑制anti-CD3诱导的T细胞增殖。在我们的系统中,肿瘤没有直接抑制T细胞反应,但是肿瘤的未知因素会影响TISC的免疫抑制。
  • 【改良摆锤器具的生物力学-力系统的理论考虑和体外分析。】 复制标题 收藏 收藏
    DOI:10.1093/ejo/cjl028 复制DOI
    作者列表:Kinzinger GS,Diedrich PR
    BACKGROUND & AIMS: :The aim of this study was to analyse the acting forces and moments induced by a special orthodontic appliance, the Pendulum K, for molar distalization in the transverse and sagittal planes. The purpose-designed test set-up (artificial maxilla with anchorage unit and two electrothermodynamic molars, an electronic measuring unit, a unit with force-moment sensor, an analogue/digital converter, and a data read-out unit) allowed simulation of in vivo conditions on the one hand and precise determination of the force systems on the other. The appliances investigated were three specimens of the Pendulum K. In vitro measurement of the resulting force systems revealed that the forces and moments in the transverse and sagittal planes remained almost constant over a 3 mm measuring increment when the distal screw was continuously activated (10 activations/mm). Without reactivation of the incorporated distal screw, however, a marked decline in the force systems was recorded. The Pendulum K allows translatory distalization of the upper molars and thus dental arch expansion, dispensing with the need for permanent teeth to be extracted, subject to a corresponding indication. This is achieved by continuous adjustment of an incorporated distal screw and by specific pre-activations of the Pendulum springs.
    背景与目标: : 这项研究的目的是分析由特殊的正畸矫治器摆K引起的作用力和力矩,以在横向和矢状平面中使磨牙远侧。目的设计的测试装置 (带有锚固单元和两个电热磨牙的人造上颌骨,一个电子测量单元,一个带力-力矩传感器的单元,一个模拟/数字转换器,和数据读出单元) 一方面可以模拟体内条件,另一方面可以精确确定力系统。所研究的器具是摆锤K的三个样本。所得力系统的体外测量表明,当远端螺钉连续激活 (10个激活/mm) 时,在3毫米测量增量内,横向和矢状平面中的力和力矩几乎保持恒定。但是,如果不重新激活合并的远端螺钉,则记录到力系统明显下降。摆锤K允许上磨牙的平移远端化,从而使牙弓扩张,从而无需拔出恒牙,但要有相应的指示。这是通过连续调节结合的远端螺钉和通过摆簧的特定预激活来实现的。
  • 【热休克蛋白-90 (HSP90) 在多发性骨髓瘤中的表达及HSP90抑制剂 (17-AAG) 的作用分析。】 复制标题 收藏 收藏
    DOI:10.1080/10428190500472123 复制DOI
    作者列表:Duus J,Bahar HI,Venkataraman G,Ozpuyan F,Izban KF,Al-Masri H,Maududi T,Toor A,Alkan S
    BACKGROUND & AIMS: :Heat shock protein 90 (HSP90) is required for structural folding and maintenance of conformational integrity of various proteins, including several associated with cellular signaling. Recent studies utilizing 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, demonstrated an antitumor effect in solid tumors. To test whether HSP90 could be targeted in multiple myeloma (MM) patients, we first investigated expression of HSP90 by immunofluorescence and flow cytometric analysis in a myeloma cell line (U266) and primary myeloma cells. Following demonstration of HSP90 expression in myeloma cells, archival samples of 32 MM patients were analysed by immunoperoxidase staining. Myeloma cells in all patients showed strong cytoplasmic expression of HSP90 in all samples and 55% also demonstrated concurrent nuclear immunopositivity. Treatment of U266 and primary MM cells with 17AAG resulted in significantly increased apoptosis compared to untreated control cells. Analysis of anti-apoptotic BCL2 family proteins and akt in MM cells incubated with 17-AAG revealed down-regulation of BCL-2, BCL-XL, MCL-1 and akt. Furthermore, although a low concentration of bortezomib resulted in no cell death, a combination of 17AAG and bortezomib treatment revealed a synergistic apoptotic effect on the U266 cell line. These data suggest that targeted inhibition of HSP90 may prove to be a valid and innovative strategy for the development of future therapeutic options for MM patients.
    背景与目标: : 热休克蛋白90 (HSP90) 是各种蛋白质的结构折叠和构象完整性维持所必需的,包括与细胞信号传导相关的几种。利用HSP90抑制剂17-allylamino-17-demethoxygeldanamycin (17-AAG) 的最新研究表明,在实体瘤中具有抗肿瘤作用。为了测试HSP90是否可以靶向多发性骨髓瘤 (MM) 患者,我们首先通过免疫荧光和流式细胞仪分析研究了HSP90在骨髓瘤细胞系 (U266) 和原发性骨髓瘤细胞中的表达。在证明骨髓瘤细胞中HSP90表达后,通过免疫过氧化物酶染色分析了32 MM患者的档案样本。所有患者的骨髓瘤细胞在所有样品中均显示出HSP90的强细胞质表达,并且55% 还显示出同时的核免疫阳性。与未处理的对照细胞相比,用17AAG处理U266和原代MM细胞可显着增加细胞凋亡。对与17-aag孵育的MM细胞中抗凋亡BCL2家族蛋白和akt的分析表明,BCL-2,BCL-XL,MCL-1和akt下调。此外,尽管低浓度的硼替佐米不会导致细胞死亡,但17AAG和硼替佐米的组合治疗显示出对U266细胞系的协同凋亡作用。这些数据表明,靶向抑制HSP90可能被证明是开发MM患者未来治疗选择的有效且创新的策略。
  • 【健康干预的优先级设置: 多标准决策分析的必要性。】 复制标题 收藏 收藏
    DOI:10.1186/1478-7547-4-14 复制DOI
    作者列表:Baltussen R,Niessen L
    BACKGROUND & AIMS: :Priority setting of health interventions is often ad-hoc and resources are not used to an optimal extent. Underlying problem is that multiple criteria play a role and decisions are complex. Interventions may be chosen to maximize general population health, to reduce health inequalities of disadvantaged or vulnerable groups, ad/or to respond to life-threatening situations, all with respect to practical and budgetary constraints. This is the type of problem that policy makers are typically bad at solving rationally, unaided. They tend to use heuristic or intuitive approaches to simplify complexity, and in the process, important information is ignored. Next, policy makers may select interventions for only political motives. This indicates the need for rational and transparent approaches to priority setting. Over the past decades, a number of approaches have been developed, including evidence-based medicine, burden of disease analyses, cost-effectiveness analyses, and equity analyses. However, these approaches concentrate on single criteria only, whereas in reality, policy makers need to make choices taking into account multiple criteria simultaneously. Moreover, they do not cover all criteria that are relevant to policy makers. Therefore, the development of a multi-criteria approach to priority setting is necessary, and this has indeed recently been identified as one of the most important issues in health system research. In other scientific disciplines, multi-criteria decision analysis is well developed, has gained widespread acceptance and is routinely used. This paper presents the main principles of multi-criteria decision analysis. There are only a very few applications to guide resource allocation decisions in health. We call for a shift away from present priority setting tools in health--that tend to focus on single criteria--towards transparent and systematic approaches that take into account all relevant criteria simultaneously.
    背景与目标: : 卫生干预措施的优先级设定通常是临时性的,资源的使用没有达到最佳程度。潜在的问题是,多个标准发挥作用,决策很复杂。可以选择干预措施,以最大程度地提高总体人口健康水平,减少弱势或弱势群体的健康不平等,ad/或应对威胁生命的情况,所有这些都涉及实际和预算方面的限制。这是政策制定者通常不善于理性地、没有帮助地解决的问题。他们倾向于使用启发式或直观的方法来简化复杂性,在此过程中,重要的信息被忽略。接下来,政策制定者可能只出于政治动机选择干预措施。这表明需要合理和透明的方法来确定优先级。在过去的几十年中,已经开发了许多方法,包括循证医学,疾病负担分析,成本效益分析和公平性分析。但是,这些方法仅集中在单个标准上,而实际上,决策者需要同时考虑多个标准来做出选择。此外,它们并未涵盖与决策者相关的所有标准。因此,有必要开发一种多标准方法来确定优先级,并且最近确实已将其确定为卫生系统研究中最重要的问题之一。在其他科学学科中,多准则决策分析得到了很好的发展,得到了广泛的认可,并被常规使用。本文介绍了多准则决策分析的主要原理。只有很少的应用程序来指导健康中的资源分配决策。我们呼吁从目前的卫生优先事项设定工具 (往往侧重于单一标准) 转向透明和系统的方法,同时考虑到所有相关标准。
  • 【在台湾,替加环素与其他抗菌剂对肺炎链球菌,流感嗜血杆菌和卡他莫拉菌的体外活性比较。】 复制标题 收藏 收藏
    DOI:10.1089/mdr.2006.12.130 复制DOI
    作者列表:Lau YJ,Hsueh PR,Liu YC,Shyr JM,Huang WK,Teng LJ,Liu CY,Luh KT
    BACKGROUND & AIMS: :We compared the in vitro activities of tigecycline to those of other agents against 300 nonduplicate isolates of Streptococcus pneumoniae (194 isolates), Haemophilus influenzae (60 isolates), and Moraxella catarrhalis (46 isolates) recovered from patients treated in three major hospitals in Taiwan from August through December, 2003. All of these isolates were inhibited at 0.5 mg/L of tigecycline. For S. pneumoniae isolates, 72% were not susceptible to penicillin (69% intermediate and 3% resistant) and 96% were not susceptible to azithromycin. Among the 178 isolates resistant to azithromycin, 53 isolates (30%) had the M phenotype and 70% had the cMLSB phenotype. The rate of nonsusceptibility to ertapenem, telithromycin, moxifloxacin, and quinupristindalfopristin in S. pneumoniae was 3%, 2%, 1%, and 57%, respectively. For H. influenzae, 36 (60%) were not susceptible to ampicillin, among which 31 possessed beta-lactamase. A high rate (8.3%) of H. influenzae isolates with beta-lactamase-negative and ampicillin-resistant phenotype was found. All H. influenzae isolates were susceptible to azithromycin, but 40% of them were not susceptible to clarithromycin. Ninety-eight percent (44 isolates) of M. catarrhalis possessed beta-lactamase. All three fluoroquinolones tested were highly active (MIC90 < or =0.12 mg/L) against H. influenzae and M. catarrhalis.
    背景与目标: : 我们比较了替加环素与其他药物对300种非重复肺炎链球菌分离株 (194株),流感嗜血杆菌 (60株) 和卡他莫拉菌 (46株) 的体外活性,这些分离株是从8月到2003年12月在台湾的三家主要医院中康复的。在0.5 mg/L替加环素的浓度下,所有这些分离株均被抑制。对于肺炎链球菌分离株,72% 对青霉素不敏感 (69% 中间体和3% 耐药),96% 对阿奇霉素不敏感。在对阿奇霉素耐药的178株中,53株 (30% 株) 具有M表型,70% 株具有cMLSB表型。肺炎链球菌对厄他培南,泰利霉素,莫西沙星和奎奴普汀的不敏感性分别为3%,2%,1% 和57%。对于流感嗜血杆菌,36 (60%) 对氨苄青霉素不敏感,其中31具有 β-内酰胺酶。发现具有 β-内酰胺酶阴性和氨苄青霉素抗性表型的流感嗜血杆菌分离株率高 (8.3%)。所有流感嗜血杆菌分离株对阿奇霉素敏感,但其中40% 对克拉霉素不敏感。卡他氏杆菌的百分之九十八 (44个分离株) 具有 β-内酰胺酶。测试的所有三种氟喹诺酮类药物对流感嗜血杆菌和卡他氏杆菌具有高度活性 (MIC90 <或 = 0.12 mg/L)。
  • 【雌激素过量引起的缺乏1型5α-还原酶的小鼠的胎儿死亡。】 复制标题 收藏 收藏
    DOI:10.1210/mend.11.7.9933 复制DOI
    作者列表:Mahendroo MS,Cala KM,Landrum DP,Russell DW
    BACKGROUND & AIMS: :Female mice deficient in steroid 5alpha-reductase type 1 have a decreased litter size. The average litter in homozygous deficient females is 2.7 pups vs. 8.0 pups in wild type controls. Oogenesis, fertilization, implantation, and placental morphology appear normal in the mutant animals. Fetal loss occurs between gestation days 10.75 and 11.0 commensurate with a midpregnancy surge in placental androgen production and an induction of 5alpha-reductase type 1 expression in the decidua of wild type mice. Plasma levels of androstenedione and testosterone are 2- to 3-fold higher on gestation day 9, and estradiol levels are chronically elevated by 2- to 3-fold throughout early and midgestation in the knockout mice. Administration of an estrogen receptor antagonist or inhibitors of aromatase reverse the high rate of fetal death in the mutant mice, and estradiol treatment of wild type pregnant mice causes fetal wastage. The results suggest that in the deficient mice, a failure to 5alpha-reduce androgens leads to their conversion to estrogens, which in turn causes fetal death in midgestation. These findings indicate that the 5alpha-reduction of androgens in female animals plays a crucial role in guarding against estrogen toxicity during pregnancy.
    背景与目标: : 缺乏类固醇5α-还原酶1型的雌性小鼠的产仔数减少。纯合缺陷雌性的平均产仔为2.7幼仔,而野生型对照为8.0幼仔。在突变动物中,卵子发生,受精,植入和胎盘形态似乎正常。胎儿损失发生在妊娠10.75和11.0之间,与妊娠中期胎盘雄激素产生激增和野生型小鼠蜕膜中5α-还原酶1型表达的诱导相称。在妊娠第9天,雄烯二酮和睾丸激素的血浆水平高2至3倍,在整个妊娠早期和中期,敲除小鼠的雌二醇水平长期升高2至3倍。施用雌激素受体拮抗剂或芳香化酶抑制剂可逆转突变小鼠的高胎儿死亡率,而雌二醇处理野生型妊娠小鼠会导致胎儿浪费。结果表明,在缺陷小鼠中,未能减少5α-雄激素会导致其转化为雌激素,进而导致妊娠中期胎儿死亡。这些发现表明,雌性动物中雄激素的5α 减少在预防怀孕期间的雌激素毒性中起着至关重要的作用。
  • 【对FOXP3的分析揭示了其作为转录阻遏物的功能所需的多个结构域。】 复制标题 收藏 收藏
    DOI:10.4049/jimmunol.177.5.3133 复制DOI
    作者列表:Lopes JE,Torgerson TR,Schubert LA,Anover SD,Ocheltree EL,Ochs HD,Ziegler SF
    BACKGROUND & AIMS: :Foxp3 has been shown to be both necessary and sufficient for the development and function of naturally arising CD4+ CD25+ regulatory T cells in mice. Mutation of Foxp3 in Scurfy mice and FOXP3 in humans with IPEX results in fatal, early onset autoimmune disease and demonstrates the critical role of FOXP3 in maintaining immune homeostasis. The FOXP3 protein encodes several functional domains, including a C2H2 zinc finger, a leucine zipper, and a winged-helix/forkhead (FKH) domain. We have shown previously that FOXP3 functions as a transcriptional repressor and inhibits activation-induced IL-2 gene transcription. To characterize the role of each predicted functional domain on the in vivo activity of FOXP3, we have evaluated the location of point mutations identified in a large cohort of patients with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) and found them to cluster primarily within the FKH domain and the leucine zipper, but also present within the poorly defined N-terminal portion of the protein. The molecular functions of each of the IPEX-targeted domains were investigated. We show that FOXP3 is constitutively localized to the nucleus and this localization requires sequences at both the amino and C-terminal ends of its FKH domain. Moreover, FOXP3 was found to homodimerize through its leucine zipper. We also identify a novel functional domain within the N-terminal half of FOXP3, which is required for FOXP3-mediated repression of transcription from both a constitutively active and a NF-AT-inducible promoter. Furthermore, we demonstrate that IPEX mutations in these domains correlate with deficiencies in FOXP3 repressor function, corroborating their in vivo relevance.
    背景与目标: : Foxp3已被证明对于小鼠中自然产生的CD4 CD25调节性T细胞的发育和功能既必要又充分。在患有pex的Scurfy小鼠中Foxp3和人类中FOXP3的突变会导致致命的,早发性自身免疫性疾病,并证明了FOXP3在维持免疫稳态中的关键作用。FOXP3蛋白编码几个功能结构域,包括C2H2锌指,亮氨酸拉链和有翼螺旋/叉头 (FKH) 结构域。我们先前已经证明FOXP3作为转录阻遏物起作用并抑制激活诱导的IL-2基因转录。为了表征每个预测的功能域对FOXP3体内活性的作用,我们评估了在免疫失调,多内分泌病,肠病,X连锁综合征 (IPEX),发现它们主要聚集在FKH结构域和亮氨酸拉链内,但也存在于蛋白质定义不明确的N端部分。研究了每个pex靶向域的分子功能。我们证明FOXP3组成性地定位于细胞核,并且这种定位需要在其FKH结构域的氨基和C末端都具有序列。此外,发现FOXP3通过其亮氨酸拉链同向二聚。我们还在FOXP3的N末端一半内鉴定了一个新的功能结构域,这是FOXP3-mediated抑制组成型活性和NF-AT诱导启动子转录所必需的。此外,我们证明了这些域中的IPEX突变与FOXP3阻遏物功能的缺陷相关,从而证实了它们在体内的相关性。
  • 【白种人患者肺肿瘤中HER2基因的突变分析: 突变主要存在于具有细支气管肺泡特征的腺癌中。】 复制标题 收藏 收藏
    DOI:10.1002/ijc.22143 复制DOI
    作者列表:Buttitta F,Barassi F,Fresu G,Felicioni L,Chella A,Paolizzi D,Lattanzio G,Salvatore S,Camplese PP,Rosini S,Iarussi T,Mucilli F,Sacco R,Mezzetti A,Marchetti A
    BACKGROUND & AIMS: :Activating mutations in the tyrosine kinase domain of the HER2 gene have recently been reported in lung adenocarcinomas, mainly in East Asian patients. Our study was devised to evaluate the prevalence and nature of HER2 mutations in lung adenocarcinomas from Caucasian patients. The mutational status of the HER2 gene was evaluated in 403 lung adenocarcinomas by PCR-single strand conformation polymorphism analysis and direct sequencing of Exons 19 and 20. We found HER2 mutations in 9 (2.2%) cases. Seven (78%) of the mutations were in frame duplications/insertions at codons 776-779 (YVMA), the other 2 were base substitutions resulting in aminoacid changes. The hotspot mutation at bases 776-779 was previously found to be the most frequent HER2 mutation in Asiatic patients. The distribution of mutations was significantly different between conventional lung adenocarcinomas (CLAs) and lung adenocarcinomas with bronchioloalveolar features (ABAFs). Seven (6.2%) of 113 ABAFs and 2 (0.7%) of 290 CLA were mutated (p = 0.0025). In addition, the frequency of HER2 mutations was slightly higher in females (4.1%) than in males (1.8%) and in never smokers (3.1%) than in smokers (1.9%), but differences were not statistically significant. This series of tumors was also investigated for EGFR and K-ras mutations. EGFR mutations were observed in 43 (10.7%) cases, and K-ras mutations in 110 (27.3%) cases. EGFR, HER2 and K-ras mutations were found to be mutually exclusive events. The presence of HER2 mutations in a subset of patients with lung adenocarcinoma raise hope to treat these patients with HER2 specific kinase inhibitors.
    背景与目标: : 最近在肺腺癌 (主要是东亚患者) 中报道了HER2基因酪氨酸激酶结构域的激活突变。我们的研究旨在评估白种人肺腺癌中HER2突变的患病率和性质。通过PCR-单链构象多态性分析和外显子19和20的直接测序,评估了403例肺腺癌中HER2基因的突变状态。我们在9 (2.2%) 例病例中发现HER2突变。7 (78%) 个突变在密码子776-779 (YVMA) 的帧重复/插入中,另外2个是导致氨基酸变化的碱基取代。先前发现776-779碱基的热点突变是亚洲患者中最常见的HER2突变。在常规肺腺癌 (cras) 和具有细支气管肺泡特征的肺腺癌 (ABAFs) 之间,突变的分布显着不同。113 ABAFs中的7个 (6.2%) 和290 CLA中的2个 (0.7%) 发生突变 (p = 0.0025)。此外,女性 (4.1%) 的HER2突变频率略高于男性 (1.8%),从不吸烟者 (3.1%) 高于吸烟者 (1.9%),但差异无统计学意义。还研究了这一系列肿瘤的EGFR和K-ras突变。在43 (10.7%) 例中观察到EGFR突变,在110 (27.3%) 例中观察到K-ras突变。发现EGFR,HER2和K-ras突变是相互排斥的事件。在一部分肺腺癌患者中存在HER2突变,这使人们希望用HER2特异性激酶抑制剂治疗这些患者。
  • 【关系质量,激素避孕选择和青少年妇女不使用避孕套的发展关联。】 复制标题 收藏 收藏
    DOI:10.1016/j.jadohealth.2005.12.027 复制DOI
    作者列表:Sayegh MA,Fortenberry JD,Shew M,Orr DP
    BACKGROUND & AIMS: PURPOSE:Consistent condom use is critical to efforts to prevent sexually transmitted infections among adolescents, but condom use may decline as relationships and contraceptive needs change. The purpose of this research is to assess changes in condom non-use longitudinally in the context of changes in relationship quality, coital frequency and hormonal contraceptive choice. METHODS:Participants were women (aged 14-17 years at enrollment) recruited from three urban adolescent medicine clinics. Data were collected at three-month intervals using a face-to-face structured interview. Participants were able to contribute up to 10 interviews, but on average contributed 4.2 interviews over the 27-month period. Independent variables assessed partner-specific relationship quality (five items; scale range 5-25; alpha = .92, e.g., this partner is a very important person to me); and, number of coital events with a specific partner. Additional items assessed experience with oral contraceptive pills (OCP) use and injected depo medroxy-progesterone acetate (DMPA). The outcome variable was number of coital events without condom use during the past three months. Analyses were conducted as a three-level hierarchical linear growth curve model using HLM 6. The Level 1 predictor was time, to test the hypothesis that condom non-use increases over time. Level 2 predictors assessed relationship quality and coital frequency across all partners to assess hypotheses that participants' condom non-use increases over time as a function of relationship quality and coital frequency. Level 3 predictors assessed the participant-level influence of OCP or DMPA experience on time-related changes in condom non-use. RESULTS:A total of 176 women reported 279 sex partners and contributed 478 visits. Both average coital frequency and average condom non-use linearly increased during the 27-month follow-up. At any given follow-up, about 35% reported recent OCP use, and 65% reported DMPA use. HLM analyses showed that condom non-use increased as a function of time (beta = .12; p = .03, Level 1 analysis). Increased condom non-use over time was primarily a function of increased coital frequency (beta = .01; p = .00), although higher levels of relationship quality were associated with increased condom non-use at enrollment (beta = .44; p = .00, Level 2 analysis). The temporal rise in condom non-use significantly increased among DMPA users (beta = .06; p = .00) but not OCP users (Level 3 analysis) (beta = -.04; p = .06). CONCLUSIONS:Developmentally, relationship characteristics and coital frequency appear to have increasing weight in decisions about condom use. Hormonal contraceptive methods are not equivalently associated with the overall temporal decline in condom use. Future research associated with dual contraceptive/condom use should address differential factors associated condom use in combination with different hormonal methods.
    背景与目标:
  • 【人冠状动脉粥样斑块切除术中肝细胞生长因子的免疫组织化学分析: 与转化生长因子 β 亚型的比较。】 复制标题 收藏 收藏
    DOI:10.1007/s004280050050 复制DOI
    作者列表:Ueda H,Imazu M,Hayashi Y,Ono K,Yasui W,Yamakido M
    BACKGROUND & AIMS: The expression and localization of hepatocyte growth factor/scatter factor (HGF/SF) were examined immunohistochemically in 59 human coronary artery lesions retrieved by directional coronary atherectomy and compared with the localization of transforming growth factor beta isoforms (TGF-beta 1, -beta 2, and -beta 3). In 21 of the 59 specimens (35.6%) HGF-like immunoreactivity (HGF-IR) was revealed. The HGF immunopositivity rate of 45% (14/31) in thrombotic tissue was significantly (P < 0.05) higher than the rates of 7.3% (4/55), 7.1% (3/42), and 0% (0/14) in fibrous tissue, neointimal hyperplasia and atheromatous gruel, respectively. Immunoreactivity for HGF was much weaker than that for TGF-beta isoforms in these components except in thrombotic tissue. These cells exhibiting strong HGF-IR were inflammatory cells such as monocytes/macrophages in thrombotic tissue, in tissue lesions adjacent to a thrombus, and outside the capillary walls in a portion of the neovascularized lesions. Smooth muscle cells (SMCs) hardly demonstrated HGF-IR. In contrast, in control coronary arteries obtained at autopsy, the HGF-IR was strongly expressed in SMCs. These findings suggest that HGF produced by macrophages play a part in the process of coronary plaque formation attributable to thrombus in man.

    背景与目标: 通过免疫组织化学检查了通过定向冠状动脉粥样斑块切除术检索的59例人冠状动脉病变中肝细胞生长因子/散射因子 (HGF/SF) 的表达和定位,并将其与转化生长因子 β 亚型 (tgf-β1,-β2和-β3) 的定位进行了比较。在59个标本中的21个 (35.6%) 中,HGF样免疫反应性 (hgf-ir) 被揭示。血栓组织中45% (14/31) 的HGF免疫阳性率显着 (P < 0.05) 高于纤维组织,新内膜增生和动脉粥样硬化稀粥中的7.3% (4/55),7.1% (3/42) 和0% (0/14)。分别。除血栓形成组织外,这些成分中HGF的免疫反应性比TGF-β 同工型的免疫反应性弱得多。这些表现出强hgf-ir的细胞是炎性细胞,例如血栓形成组织中,与血栓相邻的组织病变以及部分新生血管病变的毛细血管壁外部的单核细胞/巨噬细胞。平滑肌细胞 (smc) 几乎不显示HGF-IR。相反,在尸检获得的对照冠状动脉中,hgf-ir在smc中强烈表达。这些发现表明,巨噬细胞产生的HGF在人类血栓形成引起的冠状动脉斑块形成过程中发挥了作用。
  • 【氟化分子作为中枢神经系统中的药物和显像剂。】 复制标题 收藏 收藏
    DOI:10.2174/156802606777951046 复制DOI
    作者列表:Sun S,Adejare A
    BACKGROUND & AIMS: :The strategic use of fluorine substitution in drug discovery and drug development is well documented. The small size and high electronegativity of fluorine are among properties of this element that lend special advantages. Applications in drugs targeted to the central nervous system (CNS) have been particularly fruitful in addition to favorable properties seen in many peripherally acting drugs. Fluorine substitution can be used to solve problems unique to the CNS, such as blood brain barrier (BBB) penetration. Likewise, use of the positron emitting isotope, (18)F, provides a unique tool for non-invasive imaging and diagnoses in the CNS. In this review, fluorine in CNS drugs and drug discovery are discussed.
    背景与目标: : 氟替代在药物发现和药物开发中的战略用途已得到充分证明。氟的小尺寸和高电负性是该元素的特殊优点之一。除了在许多外周作用药物中看到的有利特性外,针对中枢神经系统 (CNS) 的药物中的应用特别富有成效。氟替代可用于解决CNS特有的问题,例如血脑屏障 (BBB) 渗透。同样,使用正电子发射同位素 (18)F为CNS中的非侵入性成像和诊断提供了独特的工具。本文对中枢神经系统药物中的氟和药物发现进行了讨论。
  • 【蛋白质结构-功能关系的生物信息学分析: 白细胞弹性蛋白酶 (ELA2) 错义突变的案例研究。】 复制标题 收藏 收藏
    DOI:10.1002/humu.20407 复制DOI
    作者列表:Thusberg J,Vihinen M
    BACKGROUND & AIMS: :Cyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations.
    背景与目标: : 周期性和先天性中性粒细胞减少症是由人类中性粒细胞弹性蛋白酶 (HNE) 基因 (ELA2) 突变引起的,导致免疫缺陷,其特征是血液中中性粒细胞水平降低或振荡。HNE突变可能会导致酶活性丧失,从而导致免疫系统功能受损。为了了解疾病的结构基础,我们采用了生物信息学的方法,在序列和结构水平上分析了所有已知的HNE错义突变。我们的结果表明,32种不同的突变对HNE的结构和功能具有不同的影响,影响结构紊乱和聚集趋势,保持接触的稳定性和静电特性。大部分突变位于保守的氨基酸,这通常是确定蛋白质结构和功能的关键。大多数引起疾病的HNE错义突变会导致蛋白质的主要结构变化和稳定性丧失。一些突变也会影响功能残基,导致催化活性降低或配体结合改变。我们的分析揭示了HNE中所有已知的错义突变的推定作用,从而阐明了周期性和先天性中性粒细胞减少症的结构基础。我们已经采用并分析了一组30种不同的方法来预测氨基酸取代的影响。我们介绍了这些方法在众多基因,蛋白质和疾病分析中的适用性分析的结果和经验,以揭示蛋白质结构-功能关系和疾病基因型-表型相关性。

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