• 【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后的4-5小时内均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)。摘除八例后,经临床证实有两个病例证实了闪烁体病变的黑色素瘤性质。据报道,病灶较小且呈低色病的患者出现假阴性扫描。

    结论:如果对传统方法仍然存在疑问,则碘-123-IDAB闪烁显像可能会在很大程度上决定摘除术的发生。

    结论:技术。

  • 【脊髓小脑性共济失调类型3和6的灰色和白色物质减少的解离:基于体素的形态学研究。】 复制标题 收藏 收藏
    DOI:10.1016/j.neulet.2006.09.007 复制DOI
    作者列表:Lukas C,Schöls L,Bellenberg B,Rüb U,Przuntek H,Schmid G,Köster O,Suchan B
    BACKGROUND & AIMS: :The aim of this study was to examine the different patterns of cerebellar and/or brainstem atrophy in spinocerebellar ataxia (SCA) type 3 and 6. Eighteen patients (SCA3 n=9, SCA6 n=9) and 15 healthy volunteers were studied. Voxel-based morphometry (VBM) was applied to segmented grey matter (GM) and white matter (WM) of high-resolution T1-weighted brain volumes of each group. We found reduction of grey matter in the pons as well as in the vermis in SCA3 as compared to control subjects. In SCA6 significant grey matter loss was found in hemispheric lobules bilaterally as well as in the vermis. White matter analysis revealed significant changes in SCA3, especially in the pons, in the white matter surrounding the dentate nucleus (DN) and in the cerebellar peduncles, whereas no significant white matter reduction was found in SCA6 patients. Our results demonstrate different patterns of grey and white matter affection detected by magnetic resonance imaging (MRI) in SCA3 and SCA6 patients, confirming the pathological concept of cortical cerebellar atrophy in SCA6. In contrast, SCA3 represents a form of ponto-cerebellar atrophy with predominant affection of pontine nuclei and fibre tracts.
    背景与目标: :本研究的目的是检查3型和6型脊髓小脑共济失调(SCA)的小脑和/或脑干萎缩的不同模式。研究了18例患者(SCA3 n = 9,SCA6 n = 9)和15名健康志愿者。将基于体素的形态计量学(VBM)应用于每组高分辨率T1加权脑体积的分段灰质(GM)和白质(WM)。我们发现与对照组相比,SCA3的脑桥和s中的灰质减少。在SCA6中,在双侧的半球小叶以及在mis骨中都发现了明显的灰质损失。白质分析显示,SCA3的显着变化,尤其是在脑桥,齿状核(DN)周围的白质和小脑梗的脑桥中,特别是在脑桥中,而在SCA6患者中未发现显着的白质减少。我们的结果表明,在SCA3和SCA6患者中通过磁共振成像(MRI)检测到不同的灰白色和白色物质影响模式,证实了SCA6皮质小脑萎缩的病理学概念。相反,SCA3代表了一种桥脑小脑萎缩的形式,主要影响桥脑核和纤维束。
  • 【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。

  • 【疾病机制: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,这可能是由于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/或促炎性细胞因子增加)引起的。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。
  • 5 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,据信它们是由毛发基质引起的。正常的头发基质会经历特定的生长(生长期),消退(退化期)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。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。
  • 【糖尿病患者的高血压治疗不足。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:
    BACKGROUND & AIMS: -2
    背景与目标: -2
  • 【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)和诱发视觉系统(VEP)技术追踪转基因小鼠的运动异常,然后部分恢复。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)Proteins in髓磷脂。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。
  • 【肝细胞癌患者中识别野生型p53衍生表位的CD8 T淋巴细胞频率增加与表位缺失肿瘤变体的存在相关。】 复制标题 收藏 收藏
    DOI:10.1002/ijc.22251 复制DOI
    作者列表:Cicinnati VR,Zhang X,Yu Z,Ferencik S,Schmitz KJ,Dworacki G,Kaczmarek E,Oldhafer K,Frilling A,Baba HA,Schmid KW,Grosse-Wilde H,Broelsch CE,DeLeo AB,Gerken G,Beckebaum S
    BACKGROUND & AIMS: :Wild-type (WT) sequence p53 peptides are attractive candidates for broadly applicable cancer vaccines. The aim of this study was to evaluate the potential of a WT p53-based immunotherapeutic approach for patients with hepatocellular carcinoma (HCC). Circulating CD8+ T cells specific for WT p53(149-157) and WT p53(264-272) HLA-A*0201 restricted epitopes were directly identified in the peripheral blood by the use of peptide/HLA-A2.1 tetramers in 24 HCC patients. Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay. Tumor immunophenotyping was performed to evaluate the p53 status, the expression of major histocompatibility complex (MHC) and costimulatory molecules in freshly isolated tumor cells. HCC patients exhibited significantly higher frequencies of WT p53-specific memory CD8+ T cells and stronger WT p53-specific CTL activity, when compared with healthy controls. Increased frequencies of p53-specific CD8+ T cells and their activity correlated with selective HLA-A2 allele loss and reduced costimulatory molecule expression of tumor cells. Moreover, augmented numbers of p53-specific T cells coincided with high MHC class II expression in tumor cells but were inversely related to the T status of the tumor node metastasis staging system. Our results indicate the existence of natural immunosurveillance and tumor immune evasion, involving a T cell response against WT p53 tumor antigen in patients with HCC. These findings may have important implications for the future development of cancer vaccines.
    背景与目标: :野生型(WT)序列p53肽是广泛应用的癌症疫苗的诱人候选物。这项研究的目的是评估肝细胞癌(HCC)患者基于WT p53的免疫治疗方法的潜力。通过在24 HCC中使用肽/HLA-A2.1四聚体直接在外周血中鉴定出对WT p53(149-157)和WT p53(264-272)HLA-A * 0201限制性表位具有特异性的循环CD8 T细胞耐心。 WT p53肽特异性刺激后的细胞毒性T淋巴细胞(CTL)活性通过使用实时定量聚合酶链反应测定的颗粒酶B和干扰素-γmRNA转录分析来评估。进行肿瘤免疫表型分析以评估新鲜分离的肿瘤细胞中p53的状态,主要组织相容性复合体(MHC)的表达和共刺激分子。与健康对照相比,HCC患者表现出明显更高的WT p53特异性记忆CD8 T细胞频率和更强的WT p53特异性CTL活性。 p53特异性CD8 T细胞的频率增加及其活性与选择性HLA-A2等位基因缺失和肿瘤细胞共刺激分子表达降低有关。此外,p53特异性T细胞数量的增加与肿瘤细胞中II类MHC的高表达相吻合,但与肿瘤淋巴结转移分期系统的T状态呈负相关。我们的结果表明,在肝癌患者中存在自然免疫监视和肿瘤免疫逃避,涉及针对WT p53肿瘤抗原的T细胞应答。这些发现可能对癌症疫苗的未来发展具有重要意义。
  • 【[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。
  • 【I型K13角蛋白在小鼠皮肤乳头状瘤进展中的早期表达。】 复制标题 收藏 收藏
    DOI:10.1093/carcin/11.11.1995 复制DOI
    作者列表:Gimenez-Conti I,Aldaz CM,Bianchi AB,Roop DR,Slaga TJ,Conti CJ
    BACKGROUND & AIMS: :The premalignant evolution of chemically induced mouse skin papillomas is characterized by dysplastic changes, aneuploidy, induction of gamma-glutamyl transpeptidase (GGT), and changes in the expression of keratins, especially differentiation-associated K1. This keratin, which is expressed in normal epidermis and early papillomas, is no longer present in more advanced dysplastic and aneuploid papillomas and in fully invasive carcinomas. More recently, it has been shown that K13, a keratin normally present in internal epithelia but not in epidermis, is aberrantly expressed in epidermal tumors. In the present study, the timing of expression of K13 and its correlation with other markers of premalignant evolution were investigated. Papillomas were induced by SENCAR mice by a single initiating dose of 20 nmol of 7,12-dimethylbenz[a]-anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA) (2 micrograms twice a week). Tumors were randomly harvested at 10, 20 and 35 weeks of promotion. K13 and K1 expression in papillomas was studied using immunoblotting and immunostaining of consecutive sections, as previously described. As expected from previous studies, the distribution of K1 in papillomas collected at 10 weeks of promotion was restricted to differentiated cells and was uniform throughout the section of the papilloma. Conversely, K13 was expressed only as small foci in 10 out of 21 papillomas (48%). Papillomas of 20 weeks were also positive for K1. Staining for K13 was positive in these papillomas with the exception of only one that was essentially negative, presenting only one small positive focus. Some of the papillomas collected at week 35 were negative for K1, but immunostaining with K13 showed uniform staining of suprabasal cells in all the papillomas studied. In all cases, immunohistochemical results were confirmed by immunoblotting with proteins extracted from 7 microns sections from each paraffin block. These results indicate that keratins K1 and K13 are coexpressed in most papillomas from 10 to 35 weeks of promotion. However, analysis of adjacent sections showed that K13 positive areas are topographically located in the K1 negative areas of the papillomas, suggesting a shift in the differentiation program from epidermal to mucosal types of keratinization. Based on these and previous studies from our laboratory, we conclude that K13 is an early marker of papillomas progression, which occurs before gross chromosomal abnormalities are present in the stem line of the tumors, and precedes dysplastic changes and the onset of GGT expression, and is probably concomitant at the individual cell level with loss of K1.
    背景与目标: 化学诱导的小鼠皮肤乳头状瘤的恶变前特征是发育异常改变,非整倍性,γ-谷氨酰转肽酶(GGT)的诱导以及角蛋白表达的变化,特别是分化相关的K1。这种角蛋白在正常表皮和早期乳头状瘤中表达,不再存在于更晚期的发育异常和非整倍性乳头状瘤以及全浸润性癌中。最近,已经显示出正常存在于内部上皮而不是表皮中的角蛋白K13在表皮肿瘤中异常表达。在本研究中,研究了K13的表达时机及其与恶变前其他标志物的相关性。 SENCAR小鼠通过单次起始剂量20 nmol的7,12-二甲基苯并[a]-蒽(DMBA)诱导并用12-O-十四烷酰phorbol-13-乙酸盐(TPA)促进(每周两次,每次2微克)诱导乳头状瘤。在促进的第10、20和35周时随机收集肿瘤。如先前所述,使用免疫印迹和连续切片的免疫染色研究了乳头状瘤中K13和K1的表达。正如先前研究所预期的,在促进10周后收集的乳头状瘤中K1的分布仅限于分化的细胞,并且在整个乳头状瘤切片中是一致的。相反,在21个乳头状瘤中,有10个中的K13仅表达为小灶(48%)。 20周的乳头状瘤也对K1呈阳性。在这些乳头状瘤中,K13染色呈阳性,只有一种基本上呈阴性,只有一个小的阳性焦点。在第35周收集的一些乳头状瘤对K1呈阴性,但用K13进行的免疫染色显示在所有研究的乳头状瘤中均均匀地染色了上基底细胞。在所有情况下,免疫组织化学结果均通过从每个石蜡块的7微米切片中提取的蛋白质进行的免疫印迹证实。这些结果表明,角质蛋白K1和K13在大多数乳头状瘤的生长10至35周内共表达。然而,对相邻切片的分析表明,K13阳性区域在地形上位于乳头状瘤的K1阴性区域,这表明分化程序已从表皮类型向角膜黏膜类型转移。根据我们实验室的这些研究和先前的研究,我们得出结论,K13是乳头状瘤进展的早期标志物,发生在肿瘤的干系中出现明显的染色体异常之前,并在发育异常改变和GGT表达发作之前发生,以及在单个细胞水平可能伴随K1丢失。
  • 【设计为MMP-3抑制剂的2-silyimidinoglutaric 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。已在计算机上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类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。
  • 【缺乏5α-还原酶1型的小鼠中的胎儿死亡是由雌激素过多引起的。】 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1型甾体5α-还原酶的雌性小鼠的窝产仔数减少。纯合缺陷型雌性的平均产仔数为2.7头,而野生型对照为8.0头。在突变动物中,卵子发生,受精,着床和胎盘形态正常。胎儿丢失发生在妊娠10.75至11.0天之间,与胎盘雄激素产生的中期妊娠激增和野生型小鼠蜕膜中5α-还原酶1型表达的诱导相称。在敲除第9天,雄烯二酮和睾丸激素的血浆水平要高2至3倍,而雌二醇水平在整个妊娠早期和中期都长期升高2至3倍。在突变小鼠中施用雌激素受体拮抗剂或芳香酶抑制剂可逆转高死亡率的胎儿死亡,而雌二醇治疗野生型妊娠小鼠会造成胎儿浪费。结果表明,在有缺陷的小鼠中,未能通过5α-还原雄激素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,雌性动物体内雄激素的5α-还原在预防妊娠期雌激素毒性中起着至关重要的作用。
  • 【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,该区域包含自然杀手基因复合体(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。
  • 【大鼠清道夫B类清道夫受体(SRBI)的克隆,鉴定和细胞分布。】 复制标题 收藏 收藏
    DOI:10.1006/bbrc.1997.6646 复制DOI
    作者列表:Mizutani T,Sonoda Y,Minegishi T,Wakabayashi K,Miyamoto K
    BACKGROUND & AIMS: :An immediately inducible gene by gonadotropin was isolated from rat ovaries primed with pregnant mare serum gonadotropin (PMSG) by using a subtraction cloning procedure. Homology analysis revealed that the gene is a rat homologue of scavenger receptor class B-I, which was recently identified as a specific receptor for high density lipoprotein (HDL). The structure of rat SRBI was determined by nucleotide sequence analysis of full-length cDNAs for SRBI. Northern blot analysis revealed that rat SRBI mRNA levels were rapidly and strongly increased within 3 h by the injection of PMSG. In situ hybridization study revealed that SRBI mRNA was strongly induced in theca interna cells of immature rat ovary stimulated with 30 IU of PMSG for 6 h. SRBI mRNA expression was also observed in corpora lutea of the adult rat ovary. These findings indicate that expression of SRBI mRNA is restricted to and induced in the ovarian steroidogenic cell types where cholesterol is used as a substrate for synthesis of steroid hormones. Our data strongly suggest that SRBI may play a significant role in the ovarian steroidogenesis by mediating selective uptake of cholesterol from HDL to ovarian theca interna cells or to corpus luteum.
    背景与目标: :通过减法克隆程序,从用怀孕母马血清促性腺激素(PMSG)引发的大鼠卵巢中分离出由促性腺激素立即诱导的基因。同源性分析显示该基因是清道夫受体B-I类的大鼠同源物,最近被鉴定为高密度脂蛋白(HDL)的特异性受体。通过SRBI全长cDNA的核苷酸序列分析确定大鼠SRBI的结构。 Northern印迹分析表明,通过注射PMSG,大鼠SRBI mRNA水平在3小时内迅速而强烈地增加。原位杂交研究表明,SRBI mRNA在30 IU PMSG刺激6 h的未成熟大鼠卵巢的内膜细胞中被强烈诱导。在成年大鼠卵巢的黄体中也观察到了SRBI mRNA表达。这些发现表明,SRBI mRNA的表达受限于卵巢类固醇生成细胞类型并在其中被诱导,其中胆固醇被用作类固醇激素合成的底物。我们的数据有力地表明,SRBI可能通过介导HDL对胆固醇和卵巢黄体的选择性摄取来介导胆固醇的选择性摄取,从而在卵巢类固醇生成中发挥重要作用。

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