• 【子宫内膜肿瘤的侵袭性与金属蛋白酶2和金属蛋白酶2表达的组织抑制剂有关。】 复制标题 收藏 收藏
    DOI:10.1111/j.1525-1438.2006.00717.x 复制DOI
    作者列表:Graesslin O,Cortez A,Uzan C,Birembaut P,Quereux C,Daraï E
    BACKGROUND & AIMS: :Matrix metalloproteinase (MMPs) expression has been linked to gynecological tumor aggressiveness. The objective of this study was to determine MMP-2, MMP-7, and MMP-9 and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 expression in endometrial malignancies and their relation to clinical and histologic parameters. Formalin-fixed, paraffin-embedded tumor samples from 50 patients with endometrial carcinoma treated between 1999 and 2004 were stained with specific monoclonal antibodies. The tumors were grouped according to the FIGO classification. The staining results were compared to histologic and clinical data. Semiquantitative analysis of MMP and TIMP expression showed a significant difference in TIMP-2 expression according to the histologic subtype (P = 0.03) and also a trend towards a difference in MMP-9 expression (P = 0.05). MMP-2 expression increased and TIMP-2 expression fell as the histologic grade increased (P = 0.0007, P < 0.0001, respectively). MMP-2 expression correlated with lymph node metastasis (P = 0.04), while TIMP-2 expression correlated with the depth of myometrial invasion (P = 0.01), vasculolymphatic space involvement (P = 0.02), and lymph node metastasis (P = 0.0003). These results support the involvement of MMPs and TIMPs in endometrial tumor growth and progression. High MMP-2 and low TIMP-2 expression were the most potent markers of endometrial tumors with a high risk of local and distant spread.
    背景与目标: 基质金属蛋白酶(MMPs)的表达与妇科肿瘤的侵袭性有关。这项研究的目的是确定子宫内膜恶性肿瘤中MMP-2,MMP-7和MMP-9以及金属蛋白酶组织抑制剂(TIMP)-1和TIMP-2的表达及其与临床和组织学参数的关系。用特异性单克隆抗体对1999年至2004年间接受治疗的50例子宫内膜癌患者的福尔马林固定,石蜡包埋的肿瘤样品进行染色。根据FIGO分类将肿瘤分组。将染色结果与组织学和临床数据进行比较。 MMP和TIMP表达的半定量分析显示,根据组织学亚型,TIMP-2表达存在显着差异(P = 0.03),并且MMP-9表达也呈现差异的趋势(P = 0.05)。随着组织学分级的升高,MMP-2表达增加而TIMP-2表达下降(分别为P = 0.0007,P <0.0001)。 MMP-2表达与淋巴结转移相关(P = 0.04),而TIMP-2表达与肌层浸润深度(P = 0.01),血管淋巴间隙受累(P = 0.02)和淋巴结转移(P = 0.0003)相关)。这些结果支持MMP和TIMP参与子宫内膜肿瘤的生长和进展。 MMP-2的高表达和TIMP-2的低表达是子宫内膜肿瘤最有效的标志物,具有局部和远处扩散的高风险。
  • 【链霉菌A3(2)中的一种隐秘的I型聚酮化合物合酶(cpk)基因簇。】 复制标题 收藏 收藏
    DOI:10.1007/s00203-006-0176-7 复制DOI
    作者列表:Pawlik K,Kotowska M,Chater KF,Kuczek K,Takano E
    BACKGROUND & AIMS: :The chromosome of Streptomyces coelicolor A3(2), a model organism for the genus Streptomyces, contains a cryptic type I polyketide synthase (PKS) gene cluster which was revealed when the genome was sequenced. The ca. 54-kb cluster contains three large genes, cpkA, cpkB and cpkC, encoding the PKS subunits. In silico analysis showed that the synthase consists of a loading module, five extension modules and a unique reductase as a terminal domain instead of a typical thioesterase. All acyltransferase domains are specific for a malonyl extender, and have a B-type ketoreductase. Tailoring and regulatory genes were also identified within the gene cluster. Surprisingly, some genes show high similarity to primary metabolite genes not commonly identified in any antibiotic biosynthesis cluster. Using western blot analysis with a PKS subunit (CpkC) antibody, CpkC was shown to be expressed in S. coelicolor at transition phase. Disruption of cpkC gave no obvious phenotype.
    背景与目标: :Streptomyces coelicolor A3(2)(Streptomyces属的一种模式生物)的染色体包含一个隐秘的I型聚酮化合物合酶(PKS)基因簇,该基因簇在对基因组进行测序时就显示出来。的ca。 54kb的簇包含三个大基因,编码PKS亚基的cpkA,cpkB和cpkC。在计算机分析中,该合成酶由一个加载模块,五个扩展模块和一个独特的还原酶(而不是典型的硫酯酶)作为末端结构域组成。所有酰基转移酶结构域都对丙二酰增量剂具有特异性,并具有B型酮还原酶。还可以在基因簇中鉴定出剪裁和调节基因。出乎意料的是,一些基因显示出与任何抗生素生物合成簇中未普遍鉴定的初级代谢产物基因高度相似。使用具有PKS亚基(CpkC)抗体的Western印迹分析,显示CpkC在过渡阶段在天蓝色链霉菌中表达。 cpkC的破坏没有明显的表型。
  • 【使用碘-123-N-(2-二乙基氨基乙基)4-碘代苯甲酰胺SPECT可视化眼部黑色素瘤。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Everaert H,Bossuyt A,Flamen P,Mertens J,Franken PR
    BACKGROUND & AIMS: UNLABELLED:Radiolabeled benzamides have recently been introduced for the detection of melanoma. We evaluated the potential clinical applicability of 123I-N-(2-diethylaminoethyl) 4-iodobenzamide ([123I]IDAB) for SPECT imaging of ocular melanoma.

    METHODS:Fourteen patients were studied, 10 with or suspected of malignant ocular melanoma and four with ocular naevi. All patients underwent SPECT imaging of the head and whole-body scintigraphy 4-5 hr after injection of 170 MBq [123I]IDAB.

    RESULTS:A definite tracer hyperfixation was observed in the pathological eye in 9 of 10 (90%) patients with ocular melanoma. The pathological-to-normal eye ratio averaged 1.46 (range 1.07-2.86). The melanoma nature of the scintigraphic lesions was confirmed after enucleation in eight cases and by clinical evolution in two. A false-negative scan was reported in a patient with a small and hypochromic lesion. In patients with ocular naevi, no false-positive scintigrams were documented.

    CONCLUSION:Iodine-123-IDAB scintigraphy may contribute significantly to decide about enucleation in cases where some doubt persists with conventional techniques.

    背景与目标: UNLABELLED :最近已引入放射性标记的苯甲酰胺来检测黑色素瘤。我们评估了123I-N-(2-二乙基氨基乙基)4-碘苯甲酰胺([123I] IDAB)在眼黑色素瘤SPECT成像中的潜在临床应用性。

    方法:14例患者研究发现,有10例疑似恶性眼黑色素瘤或疑似恶性眼黑色素瘤,有4例恶性眼黑色素瘤。所有患者在注射170 MBq [123I] IDAB后4-5小时都进行了头部和全身闪烁显像的SPECT成像。 10例(90%)眼黑色素瘤患者中有9例病理性眼病。病理眼与正常眼的比率平均为1.46(范围为1.07-2.86)。摘除后有8例经临床摘除证实了闪烁体病变的黑色素瘤性质,有2例经临床演变得到了证实。据报道,病灶较小且呈低色病的患者出现假阴性扫描。

    结论:如果对传统方法仍存在疑问,则碘-123-IDAB闪烁显像可能在决定摘除方面有重要作用。

    结论:技术。

  • 【Dlx同源框基因在branch弓近端模式中的作用:Dlx-1,Dlx-2和Dlx-1和-2的突变改变了衍生自第一和第二弓的近端骨骼和软组织结构的形态。】 复制标题 收藏 收藏
    DOI:10.1006/dbio.1997.8556 复制DOI
    作者列表:Qiu M,Bulfone A,Ghattas I,Meneses JJ,Christensen L,Sharpe PT,Presley R,Pedersen RA,Rubenstein JL
    BACKGROUND & AIMS: The Dlx homeobox gene family is expressed in a complex pattern within the embryonic craniofacial ectoderm and ectomesenchyme. A previous study established that Dlx-2 is essential for development of proximal regions of the murine first and second branchial arches. Here we describe the craniofacial phenotype of mice with mutations in Dlx-1 and Dlx-1 and -2. The skeletal and soft tissue analyses of mice with Dlx-1 and Dlx-1 and -2 mutations provide additional evidence that the Dlx genes regulate proximodistal patterning of the branchial arches. This analysis also elucidates distinct and overlapping roles for Dlx-1 and Dlx-2 in craniofacial development. Furthermore, mice lacking both Dlx-1 and -2 have unique abnormalities, including the absence of maxillary molars. Dlx-1 and -2 are expressed in the proximal and distal first and second arches, yet only the proximal regions are abnormal. The nested expression patterns of Dlx-1, -2, -3, -5, and -6 provide evidence for a model that predicts the region-specific requirements for each gene. Finally, the Dlx-2 and Dlx-1 and -2 mutants have ectopic skull components that resemble bones and cartilages found in phylogenetically more primitive vertebrates.

    背景与目标: Dlx同源盒基因家族以复杂的模式在胚胎颅面外胚层和外间质内表达。先前的研究表明,Dlx-2对于鼠的第一和第二分支弓近端区域的发育至关重要。在这里,我们描述了具有Dlx-1和Dlx-1和-2突变的小鼠的颅面表型。具有Dlx-1和Dlx-1和-2突变的小鼠的骨骼和软组织分析提供了其他证据,证明Dlx基因调节branch弓的近现代模式。该分析还阐明了Dlx-1和Dlx-2在颅面发育中的独特作用和重叠作用。此外,缺乏Dlx-1和-2的小鼠具有独特的异常,包括不存在上颌磨牙。 Dlx-1和-2在近端和远端第一和第二弓形中表达,但仅近端区域异常。 Dlx-1,-2,-3,-5和-6的嵌套表达模式为预测每个基因的区域特定要求的模型提供了证据。最后,Dlx-2,Dlx-1和-2突变体具有异位的头骨成分,类似于在系统发育上较原始的脊椎动物中发现的骨骼和软骨。

  • 【疾病机理:2型糖尿病的肝脂肪变性-发病机理和临床意义。】 复制标题 收藏 收藏
    DOI:10.1038/ncpendmet0190 复制DOI
    作者列表:Roden M
    BACKGROUND & AIMS: :Hepatic steatosis is defined by an increased content of hepatocellular lipids (HCLs) and is frequently observed in insulin-resistant states including type 2 diabetes mellitus. A dietary excess of saturated fat contributes significantly to HCL accumulation. Elevated HCL levels mainly account for hepatic insulin resistance, which is probably mediated by partitioning of free fatty acids to the liver (fat overflow) and by an imbalance of adipocytokines (decreased adiponectin and/or increased proinflammatory cytokines). Both free fatty acids and adipocytokines activate inflammatory pathways that include protein kinase C, the transcription factor nuclear factor kappaB, and c-Jun N-terminal kinase 1 and can thereby accelerate the progression of hepatic steatosis to nonalcoholic steatohepatitis and cirrhosis. Proton magnetic resonance spectroscopy has made it possible to quantify HCL concentrations and to detect even small changes in these concentrations in clinical settings. Moderately hypocaloric, fat-reduced diets can decrease HCL levels by approximately 40-80% in parallel with loss of up to 8% of body weight. Treatment with thiazolidinediones (e.g. pioglitazone and rosiglitazone) reduces HCL levels by 30-50% by modulating insulin sensitivity and endocrine function of adipose tissue in type 2 diabetes. Metformin improves hepatic insulin action without affecting HCL levels, whereas insulin infusion for 67 h increases HCL levels by approximately 18%; furthermore, HCL levels positively correlate with the insulin dosage in insulin-treated type 2 diabetes. In conclusion, liver fat is a critical determinant of metabolic fluxes and inflammatory processes, thereby representing an important therapeutic target in insulin resistance and type 2 diabetes mellitus.
    背景与目标: 肝脂肪变性是由肝细胞脂质(HCL)含量增加所定义的,并且经常在包括2型糖尿病在内的胰岛素抵抗状态中观察到。饮食中饱和脂肪过多会大大增加HCL的积累。 HCL水平升高主要是肝脏胰岛素抵抗的原因,这可能是由游离脂肪酸在肝脏中的分配(脂肪溢出)和脂肪细胞因子的失衡(脂联素减少和/或促炎细胞因子增加)介导的。游离脂肪酸和脂肪细胞因子均激活包括蛋白激酶C,转录因子核因子kappaB和c-Jun N端激酶1在内的炎症途径,从而可以加速肝脂肪变性发展为非酒精性脂肪性肝炎和肝硬化。质子磁共振波谱使量化HCL浓度和检测临床环境中这些浓度的微小变化成为可能。适度低热量,低脂肪饮食可将HCL水平降低约40-80%,同时最多可减少8%的体重。噻唑烷二酮类药物(例如吡格列酮和罗格列酮)治疗可通过调节2型糖尿病的胰岛素敏感性和脂肪组织的内分泌功能将HCL水平降低30-50%。二甲双胍在不影响HCL水平的情况下改善了肝胰岛素的作用,而胰岛素输注67 h使HCL水平增加了约18%。此外,在用胰岛素治疗的2型糖尿病中,HCL水平与胰岛素剂量呈正相关。总之,肝脏脂肪是代谢通量和炎症过程的关键决定因素,因此代表了胰岛素抵抗和2型糖尿病的重要治疗靶标。
  • 6 bcl-2 expression in pilomatricoma. 复制标题 收藏 收藏

    【bcl-2在pilomatricoma中的表达。】 复制标题 收藏 收藏
    DOI:10.1097/00000372-199706000-00009 复制DOI
    作者列表:Farrier S,Morgan M
    BACKGROUND & AIMS: Pilomatricoma is a distinctive tumor characterized by a dual population of proliferating basophilic cells and diagnostic shadow cells, believed to arise from the hair matrix. The normal hair matrix undergoes defined cycles of growth (anagen), regression (catagen), and resting (telogen) that are regulated by programmed cell death (apoptosis). bcl-2 is a proto-oncogene that helps to suppress apoptosis in both benign and malignant tumors. In addition, both apoptosis and bel-2 are critical factors in normal hair follicle development. In order to clarify the role of bcl-1, we used immunohistochemical means to study 10 cases of histologically proven pilomatricoma for bcl-2 expression. The study design included both positive and negative controls. All of the pilomatricomas in our series were strongly decorated by bcl-2 immunostaining. Based on our findings of increased bcl-2 staining, we concluded that the faulty suppression of apoptosis contributes to the pathogenesis of pilomatricoma.

    背景与目标: 口唇瘤是一种独特的肿瘤,其特征是增殖的嗜碱性细胞和诊断性影子细胞由双重人群组成,据信这是由毛发基质引起的。正常的毛发基质经历了确定的生长(生长期),消退(生长期)和静止(休止期)周期,这些周期受程序性细胞死亡(细胞凋亡)的调节。 bcl-2是一种原癌基因,有助于抑制良性和恶性肿瘤中的细胞凋亡。此外,凋亡和bel-2都是正常毛囊发育的关键因素。为了阐明bcl-1的作用,我们使用免疫组化方法研究了10例经组织学证实的pilomatricoma的bcl-2表达病例。研究设计包括阳性和阴性对照。 bcl-2免疫染色强烈修饰了我们系列中的所有pilomatricomas。根据bcl-2染色增加的发现,我们得出结论,凋亡的错误抑制是导致毛细血管瘤的发病原因。
  • 【鸡GATA-2和GATA-3的N末端指是独立的序列特异性DNA结合结构域。】 复制标题 收藏 收藏
    DOI:10.1093/emboj/16.10.2874 复制DOI
    作者列表:Pedone PV,Omichinski JG,Nony P,Trainor C,Gronenborn AM,Clore GM,Felsenfeld G
    BACKGROUND & AIMS: The GATA family of vertebrate DNA binding regulatory proteins are expressed in diverse tissues and at different times of development. However, the DNA binding regions of these proteins possess considerable homology and recognize a rather similar range of DNA sequence motifs. DNA binding is mediated through two domains, each containing a zinc finger. Previous results have led to the conclusion that although in some cases the N-terminal finger can contribute to specificity and strength of binding, it does not bind independently, whereas the C-terminal finger is both necessary and sufficient for binding. Here we show that although this is true for the N-terminal finger of GATA-1, those of GATA-2 and GATA-3 are capable of strong independent binding with a preference for the motif GATC. Binding requires the presence of two basic regions located on either side of the N-terminal finger. The absence of one of these near the GATA-1 N-terminal finger probably accounts for its inability to bind. The combination of a single finger and two basic regions is a new variant of a motif that has been previously found in the binding domains of other finger proteins. Our results suggest that the DNA binding properties of the N-terminal finger may help distinguish GATA-2 and GATA-3 from GATA-1 and the other GATA family members in their selective regulatory roles in vivo.

    背景与目标: GATA家族的脊椎动物DNA结合调节蛋白在不同的组织中以及在不同的发育时期表达。但是,这些蛋白质的DNA结合区具有相当的同源性,可以识别相当相似范围的DNA序列基序。 DNA结合是通过两个结构域介导的,每个结构域都包含一个锌指。先前的结果得出的结论是,尽管在某些情况下N末端指可以有助于结合的特异性和强度,但它不能独立地结合,而C末端指对于结合既是必需的又是足够的。在这里,我们表明,尽管对于GATA-1的N端手指来说确实如此,但GATA-2和GATA-3的手指却能够强烈独立地结合,并优先选择基序GATC。结合需要在N末端指形物的两侧都存在两个基本区域。在GATA-1 N端手指附近缺少这些手指之一可能是其无法结合的原因。单个手指和两个基本区域的组合是一个基序的新变体,该变体先前已在其他手指蛋白的结合域中发现。我们的结果表明,N末端手指的DNA结合特性可能有助于区分GATA-2和GATA-3与GATA-1和其他GATA家族成员在体内的选择性调节作用。

  • 【T(2)加权的microMRI和诱发的低髓鞘转基因小鼠的发展过程中视觉系统测量的潜力。】 复制标题 收藏 收藏
    DOI:10.1007/s11064-006-9121-z 复制DOI
    作者列表:Martin M,Reyes SD,Hiltner TD,Givogri MI,Tyszka JM,Fisher R,Campagnoni AT,Fraser SE,Jacobs RE,Readhead C
    BACKGROUND & AIMS: :Our objective was to follow the course of a dysmyelinating disease followed by partial recovery in transgenic mice using non-invasive high-resolution (117 x 117 x 70 microm) magnetic resonance (microMRI) and evoked potential of the visual system (VEP) techniques. We used JOE (for J37 golli overexpressing) transgenic mice engineered to overexpress golli J37, a product of the Golli-mbp gene complex, specifically in oligodendrocytes. Individual JOE transgenics and their unaffected siblings were followed from 21 until 75-days-old using non-invasive in vivo VEPs and 3D T2-weighted microMRI on an 11.7 T scanner, performing what we believe is the first longitudinal study of its kind. The microMRI data indicated clear, global hypomyelination during the period of peak myelination (21-42 days), which was partially corrected at later ages (>60 days) in the JOE mice compared to controls. These microMRI data correlated well with [Campagnoni AT (1995) "Molecular biology of myelination". In: Ransom B, Kettenmann H (eds) Neuroglia--a Treatise. Oxford University Press, London, pp 555-570] myelin staining, [Campagnoni AT, Macklin WB (1988) Cellular and molecular aspects of myelin protein gene-expression. Mol Neurobiol 2:41-89] a transient intention tremor during the peak period of myelination, which abated at later ages, and [Lees MB, Brostoff SW (1984) Proteins in myelin. In: Morell (ed) Myelin. Plenum Press, New York and London, pp 197-224] VEPs which all indicated a significant delay of CNS myelin development and persistent hypomyelination in JOE mice. Overall these non-invasive techniques are capable of spatially resolving the increase in myelination in the normally developing and developmentally delayed mouse brain.
    背景与目标: :我们的目标是通过非侵入性高分辨率(117 x 117 x 70 microm)磁共振(microMRI)和视觉系统诱发电位(VEP)技术来追踪发生髓鞘异常的疾病,然后在转基因小鼠中部分恢复。我们使用经工程改造过表达Golli-mbp基因复合物产物Golli J37(特别是在少突胶质细胞中)的JOE(用于J​​37 golli过表达)转基因小鼠。从21岁到75天大,使用11.7 T扫描仪上的非侵入性体内VEP和3D T2加权显微MRI对个体JOE转基因及其未受影响的兄弟姐妹进行跟踪研究,我们认为这是同类研究中的首次纵向研究。显微MRI数据表明,在峰值髓鞘形成期(21-42天)期间出现了明显的整体性低髓鞘形成,与对照组相比,JOE小鼠在以后的年龄(> 60天)中得到了部分纠正。这些显微MRI数据与[Campagnoni AT(1995)“髓鞘形成的分子生物学”)有很好的相关性。在:Ransom B,Kettenmann H(eds)Neuroglia-专着中。牛津大学出版社,伦敦,第555-570页]髓磷脂染色,[Campagnoni AT,Macklin WB(1988)髓磷脂蛋白基因表达的细胞和分子方面。 [Mol Neurobiol 2:41-89]在髓鞘形成高峰期发生短暂的意向性震颤,此现象在以后的年龄有所减轻,[Lees MB,Brostoff SW(1984)蛋白在髓鞘中。在:莫雷尔(编辑)髓磷脂。 [Plenum Press,纽约和伦敦,第197-224页] VEP均表明JOE小鼠的CNS髓磷脂发育显着延迟和持续性髓鞘减少。总体而言,这些非侵入性技术能够在空间上解决正常发育和发育迟缓的小鼠大脑中髓鞘形成的增加。
  • 【[分子生物学为日常医学病毒学服务。 2.在病毒学诊断中的应用]。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Wattré P
    BACKGROUND & AIMS: :Molecular biology techniques are applied for the diagnosis of meningoencephalitis due to herpesviruses, enteroviruses or polyomaviruses, for the diagnosis of human cytomegalovirus, human parvovirus B19, varicella-zoster virus and rubella virus infections occurring during pregnancy, for the diagnosis and the management of retrovirus infections (HIV and HTLV) and of hepatitis (HBV and HCV), for papillomavirus typing and to detect a link between virus and clinical manifestations (cardiomyopathy or insulinodependent diabetes with coxsackievirus B: Kaposi's sarcoma with HHV 8) or to investigate an environmental contamination with viruses. These new molecular markers which are both qualitative and quantitative represent an important advance in the field of viral diagnosis research, in the monitoring of viral load during the course of infection, in the therapy control of viral disease and in the epidemiology of virus spread. Standardization and automatization are obtained using available commercial reagents and kits.
    背景与目标: :分子生物学技术被用于诊断由疱疹病毒,肠病毒或多瘤病毒引起的脑膜脑炎,用于诊断人巨细胞病毒,人细小病毒B19,水痘-带状疱疹病毒和风疹病毒在怀孕期间发生的感染,用于诊断和管理逆转录病毒感染(HIV和HTLV)和肝炎(H​​BV和HCV),用于乳头瘤病毒分型并检测病毒与临床表现之间的联系(心肌病或胰岛素依赖型糖尿病与柯萨奇病毒B:卡波西氏肉瘤伴HHV 8)或调查环境污染病毒。这些新的定性和定量分子标记代表了病毒诊断研究领域,感染过程中病毒载量的监测,病毒疾病的治疗控制和病毒传播的流行病学的重要进展。使用可用的市售试剂和试剂盒可获得标准化和自动化。
  • 【设计为MMP-3抑制剂的2-silimidinoinoglutaric acid类似物的初步计算机模拟铅系列。】 复制标题 收藏 收藏
    DOI:10.1021/ci0601362 复制DOI
    作者列表:Amin EA,Welsh WJ
    BACKGROUND & AIMS: :Matrix metalloproteinases (MMPs) have been the subject of intense research because of their roles in tumor metastasis and in the rise and spread of degenerative diseases such as osteo- and rheumatoid arthritis. A preliminary class of 140 druglike, small-molecule matrix metalloproteinase-3 inhibitors, intended as starting scaffolds for optimization and synthesis, has been designed in silico using a series of highly predictive three-dimensional quantitative structure-activity relationship models, including comparative molecular field analysis and comparative molecular similarity indices analysis, with docking and scoring. Thalidomide was chosen as the skeleton on which to base the new lead series, as it moderately inhibits MMP-3, is antiangiogenic, and lends itself easily to structural modifications. Most of the new compounds demonstrate medium to high predicted biological activity and good bioavailability as estimated by the octanol-water partition coefficient ClogP. Compound 102 in particular exhibits extremely favorable predicted activity against MMP-3; is moderately bioavailable; satisfies Lipinski's Rule of Five; and shows promise for further optimization, synthesis, and experimental evaluation as a potential adjunct anticancer or antirheumatic therapeutic.
    背景与目标: :基质金属蛋白酶(MMP)由于其在肿瘤转移中以及在变性疾病(例如骨和类风湿性关节炎)的发生和扩散中的作用而受到了广泛的研究。使用一系列高度预测的三维定量结构-活性关系模型,包括比较分子场,在计算机上设计了初步的140种药物样小分子基质金属蛋白酶3抑制剂,旨在作为优化和合成的起始支架。分析和比较分子相似性指数分析,以及对接和评分。选择沙利度胺作为新铅系列的基础,因为它能适度抑制MMP-3,具有抗血管生成作用,并易于进行结构修饰。正如辛醇-水分配系数ClogP所估计的那样,大多数新化合物都具有中等至较高的预测生物活性和良好的生物利用度。特别地,化合物102对MMP-3表现出非常有利的预测活性。具有中等生物利用度;满足Lipinski的五法则;并有望进一步优化,合成和进行实验评估,作为潜在的辅助抗癌药或抗风湿药。
  • 【小鼠第6号染色体上自然杀手基因复合物的2-Mb YAC重叠群和物理图谱。】 复制标题 收藏 收藏
    DOI:10.1006/geno.1997.4721 复制DOI
    作者列表:Brown MG,Fulmek S,Matsumoto K,Cho R,Lyons PA,Levy ER,Scalzo AA,Yokoyama WM
    BACKGROUND & AIMS: :We have constructed a physical map of a > 2-Mb region on mouse chromosome 6 that contains the natural killer gene complex (NKC). The map comprises a contig of 14 overlapping yeast artificial chromosomes onto which we positioned 25 NKC markers. NKC genetically linked genes encode > 17 proteins that directly control innate NK cell-mediated tumor lysis and disease resistance. Herein we show that Nkrp1 genes are clustered in a region flanked by A2m and Cd69 genes and that most Ly49 genes are clustered in a distal region -1 Mb distant. Importantly, syntenic intervals of mouse chromosome 6 and human chromosome 12p that include the NKC are conserved. NKC species conservation suggests that the human NKC may contain orthologues for the mouse viral disease resistance genes, Cmv1 and Rmp1. The high-resolution NKC map will facilitate investigation of NKC gene regulation and identification of phenotypically defined gene products that confer NK cell defense against viral pathogens.
    背景与目标: :我们在小鼠染色体6上构建了一个大于2-Mb区域的物理图,其中包含自然杀伤基因复合体(NKC)。该图包括14个重叠的酵母人工染色体的重叠群,我们在其上定位了25个NKC标记。 NKC遗传连锁基因编码> 17种蛋白质,这些蛋白质直接控制先天NK细胞介导的肿瘤溶解和疾病抵抗力。在本文中,我们显示Nkrp1基因聚集在A2m和Cd69基因侧翼的区域中,而大多数Ly49基因聚集在距离-1 Mb远的区域中。重要的是,保留了包含NKC的小鼠6号染色体和人类12p号染色体的同音间隔。 NKC物种保守性表明,人NKC可能含有小鼠病毒疾病抗性基因Cmv1和Rmp1的直向同源物。高分辨率的NKC图谱将有助于NKC基因调控的研究和表型定义的基因产物的鉴定,这些产物赋予NK细胞防御病毒病原体的能力。
  • 【人类Achaete-Scute同源物2(ASCL2,HASH2)映射到11p15.5染色体,与IGF2接近,并在绒毛外滋养细胞中表达。】 复制标题 收藏 收藏
    DOI:10.1093/hmg/6.6.859 复制DOI
    作者列表:Alders M,Hodges M,Hadjantonakis AK,Postmus J,van Wijk I,Bliek J,de Meulemeester M,Westerveld A,Guillemot F,Oudejans C,Little P,Mannens M
    BACKGROUND & AIMS: Here we describe the cloning of the human Achaete Scute Homologue 2 (HASH2) gene, officially designated ASCL2 (Achaete Scute complex like 2), a homologue of the Drosophila Achaete and Scute genes. In mouse, this gene is imprinted and maps to chromosome 7. We mapped the human homologue close to IGF2 and H19 at 11p15.5, the human region syntenic with mouse chromosome 7, indicating that this imprinted region is highly conserved in mouse and man. HASH2 is expressed in the extravillus trophoblasts of the developing placenta only. The lack of HASH2 expression in non-malignant hydatidiform (androgenetic) moles indicates that HASH2 is also imprinted in man.

    背景与目标: 在这里,我们描述了人类Achaete Scute同源物2(HASH2)基因的克隆,该基因正式命名为ASCL2(Achaete Scute复合物类似2),是果蝇Achaete和Scute基因的同源物。在小鼠中,该基因被印迹并定位于7号染色体。我们在11p15.5处绘制了与IGF2和H19接近的人类同源基因,该区域与小鼠7号染色体呈同义关系,表明该印迹区域在小鼠和人类中高度保守。 HASH2仅在发育中的胎盘的绒毛外滋养细胞中表达。非恶性葡萄胎(雄激素性)痣中缺乏HASH2表达,这表明HASH2也被印在人体内。

  • 【吸入类固醇/长效β2激动剂联合产品可使成年哮喘患者的肺功能提高24小时。】 复制标题 收藏 收藏
    DOI:10.1186/1465-9921-7-110 复制DOI
    作者列表:Lötvall J,Langley S,Woodcock A
    BACKGROUND & AIMS: BACKGROUND:The combination of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) is recommended by treatment guidelines for the treatment of persistent asthma. Two such combination products, salmeterol/fluticasone propionate (SFC, Seretide GSK, UK) and formoterol/budesonide (FBC, Symbicort, AstraZeneca, UK) are commercially available. OBJECTIVES:The purpose of these studies was to evaluate and compare the duration of bronchodilation of both combination products up to 24 hours after a single dose. METHODS:Two randomised, double blind, placebo-controlled, crossover studies were performed. Study A was conducted in 33 asthmatic adults receiving 400-1200 mcg of budesonide or equivalent. Serial forced expiratory volume in one second (FEV1) was measured over 24 hours to determine the duration of effect of both SFC (50/100 mcg) and FBC (4.5/160 mcg). Study B was conducted in 75 asthmatic adults receiving 800-1200 mcg of budesonide or equivalent and comprised a 4 week run-in of 400 mcg bd Becotide followed by 4 weeks treatment with either SFC 50/100 mcg bd or FBC 4.5/160 mcg bd taken in a cross-over manner. Serial 24-hour FEV1 was measured after the first dose and the last dose after each 4-weeks treatment period to determine the offset of action of each treatment. RESULTS:In study A, a single inhalation of SFC and FBC produced a sustained bronchodilation at 16 hours with an adjusted mean increase in FEV1 from pre-dose of 0.22 L (95% CI 0.19, 0.35 L) for SFC and 0.25 L (95% CI 0.21, 0.37 L) for FBC, which was significantly greater than placebo for both treatments (-0.05 L; p < 0.001). In study B, the slope of decline in FEV1 from 2-24 hours post dose was -16.0 ml/hr for SFC and -14.2 ml/hr for FBC. The weighted mean AUC over 24 hours was 0.21 Lxmin and 0.22 Lxmin and mean change from pre-dose FEV1 at 12 hours was 0.21 L for SFC and 0.20 L for FBC respectively CONCLUSION:Both SFC and FBC produced a similar sustained bronchodilator effect which was prolonged beyond 12 hours post dose and was clearly measurable at 24 h.
    背景与目标: 摘要背景:吸入性糖皮质激素(ICS)和长效β2-激动剂(LABA)的结合被治疗指南推荐用于持续性哮喘的治疗。两种这样的组合产品,沙美特罗/丙酸氟替卡松(SFC,英国Seretide GSK)和福莫特罗/布地奈德(FBC,Symbicort,阿斯利康,英国)可商购。
    目的:这些研究的目的是评估和比较两种组合产品在单剂给药后直至24小时的支气管扩张持续时间。
    方法:进行了两项随机,双盲,安慰剂对照,交叉研究。研究A在接受400-1200 mcg布地奈德或同等剂量的33位哮喘成人中进行。在24小时内测量一秒钟的连续呼气量(FEV1),以确定SFC(50/100 mcg)和FBC(4.5 / 160 mcg)的作用持续时间。研究B是在75名接受800-1200 mcg布地奈德或同等水平的哮喘成年人中进行的,包括4周400 mcg bd的Becotide磨合,然后用SFC 50/100 mcg bd或FBC 4.5 / 160 mcg bd进行4周治疗以交叉方式拍摄。在每4周治疗期后的第一剂和最后一剂之后,测量连续的24小时FEV1,以确定每种治疗的作用抵消。
    结果:在研究A中,单次吸入SFC和FBC在16小时产生了持续的支气管扩张作用,与SFC和0.25 L(95 FBC的%CI 0.21,0.37 L),均显着高于两种治疗的安慰剂(-0.05 L; p <0.001)。在研究B中,从剂量后2-24小时开始,FEV1的下降斜率对于SFC为-16.0 ml / hr,对于FBC为-14.2 ml / hr。 24小时的加权平均AUC为0.21 Lxmin和0.22 Lxmin,与12小时前剂量前FEV1相比,SFC和FBC的平均变化分别为0.21 L和0.20 L
    结论:SFC和FBC均产生相似的持续支气管扩张药作用,给药后延长至12小时以上,并且在24 h时明显可测量。
  • 【交联的聚(1-乙烯基-2-吡咯烷酮)凝胶对静态细胞培养中细胞生长的影响。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Hong Y,Chirila TV,Fitton JH,Ziegelaar BW,Constable IJ
    BACKGROUND & AIMS: Poly(1-vinyl-2-pyrrolidinone) (PVP) and copolymers of 1-vinyl-2-pyrrolidinone are insoluble in water when crosslinked but they can absorb very large amounts of water to become syringe-injectable hydrogels. Such gels have been investigated recently as potential substitutes for the vitreous humour in the eye. In this study, during the cytotoxic evaluation by sulforhodamine B colorimetric assay of variously crosslinked PVP gels, it was found that many of them showed protective/growth promoting effects on 3T3 mouse fibroblasts in static cultures, a phenomenon encountered previously only with aqueous solutions of a limited number of natural or synthetic polymers. Particularly, the gels crosslinked with diethylene glycol dimethacrylate (DEGDMA) induced a significant enhancement of cell proliferation, especially in serum-free cultures. No correlation between this effect and the essential gel properties (chemical composition, viscoelasticity and equilibrium water content) could be established. The study demonstrated that crosslinked PVP hydrogels showed a serum-like growth promoting effect on an anchorage-dependent cell line, which may be due to physical protection, inability of the insoluble gels to penetrate cell membranes, and their ability to mimic the extracellular matrix.

    背景与目标: 聚(1-乙烯基-2-吡咯烷酮)(PVP)和1-乙烯基-2-吡咯烷酮的共聚物在交联时不溶于水,但它们可以吸收大量的水,成为可注射注射器的水凝胶。最近已经研究了这种凝胶作为眼睛中玻璃体液的潜在替代物。在这项研究中,通过磺酰罗丹明B比色法对各种交联的PVP凝胶进行细胞毒性评估时,发现它们中的许多在静态培养物中对3T3小鼠成纤维细胞均显示出保护/促生长作用,这种现象以前仅在A的水溶液中会遇到。数量有限的天然或合成聚合物。特别地,用二甘醇二甲基丙烯酸甲酯(DEGDMA)交联的凝胶诱导细胞增殖的显着增强,尤其是在无血清培养物中。在这种作用与基本的凝胶性质(化学组成,粘弹性和平衡水含量)之间没有相关性。该研究表明,交联的PVP水凝胶对锚定依赖性细胞系显示出类似血清的生长促进作用,这可能是由于物理保护,不溶性凝胶无法穿透细胞膜以及它们模仿细胞外基质的能力所致。

  • 【印度斯坦链霉菌JCM 3268中含2-脱氧链胺胺的抗生素的生物合成:2-脱氧鞘氨醇合酶的表征。】 复制标题 收藏 收藏
    DOI:10.1038/ja.2006.51 复制DOI
    作者列表:Hirayama T,Tamegai H,Kudo F,Kojima K,Kakinuma K,Eguchi T
    BACKGROUND & AIMS: :A part of the new biosynthetic gene cluster for 2-deoxystreptamine-containing antibiotics was identified from Streptoalloteichus hindustanus. The alloH gene in the gene cluster was deduced to encode 2-deoxy-scyllo-inosose synthase and the expressed protein AlloH was confirmed to have this enzyme activity. Furthermore, biochemical properties of AlloH were studied.
    背景与目标: :从印度链球菌中鉴定出了一种新的生物合成基因簇,用于含有2-脱氧链胺的抗生素。推导了基因簇中的alloH基因编码2-脱氧-鞘氨醇合酶,并证实表达的蛋白AlloH具有这种酶活性。此外,研究了AlloH的生化特性。

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