A Novel Molecular Marker That Predicts Metastasis of Papillary and
SCI论文摘要中常用的表达方法
SCI论文摘要中常用的表达方法要写好摘要，需要建立一个适合自己需要的句型库（选择的词汇来源于SCI高被引用论文）引言部分（1）回顾研究背景，常用词汇有review, summarize, present, outline, describe等（2）说明写作目的，常用词汇有purpose, attempt, aim等，另外还可以用动词不定式充当目的壮语老表达（3）介绍论文的重点内容或研究范围，常用词汇有study, present, include, focus, emphasize, emphasis, attention等方法部分（1）介绍研究或试验过程，常用词汇有test study, investigate, examine,experiment, discuss, consider, analyze, analysis等（2）说明研究或试验方法，常用词汇有measure, estimate, calculate等（3）介绍应用、用途，常用词汇有use, apply, application等结果部分（1）展示研究结果，常用词汇有show, result, present等（2）介绍结论，常用词汇有summary, introduce,conclude等讨论部分（1）陈述论文的论点和作者的观点，常用词汇有suggest, repot, present, expect, describe 等（2）说明论证，常用词汇有support, provide, indicate, identify, find, demonstrate, confirm, clarify等（3）推荐和建议，常用词汇有suggest,suggestion, recommend, recommendation, propose,necessity,necessary,expect等。
摘要引言部分案例词汇review•Author(s): ROBINSON, TE; BERRIDGE, KC•Title:THE NEURAL BASIS OF DRUG CRA VING - AN INCENTIVE-SENSITIZATION THEORY OF ADDICTION•Source: BRAIN RESEARCH REVIEWS, 18 (3): 247-291 SEP-DEC 1993 《脑研究评论》荷兰SCI被引用1774We review evidence for this view of addiction and discuss its implications for understanding the psychology and neurobiology of addiction.回顾研究背景SCI高被引摘要引言部分案例词汇summarizeAuthor(s): Barnett, RM; Carone, CD; 被引用1571Title: Particles and field .1. Review of particle physicsSource: PHYSICAL REVIEW D, 54 (1): 1-+ Part 1 JUL 1 1996:《物理学评论，D辑》美国引言部分回顾研究背景常用词汇summarizeAbstract: This biennial review summarizes much of Particle Physics. Using data from previous editions, plus 1900 new measurements from 700 papers, we list, evaluate, and average measuredproperties of gauge bosons, leptons, quarks, mesons, and baryons. We also summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors, probability, and statistics. A booklet is available containing the Summary Tables and abbreviated versions of some of the other sections of this full Review.SCI摘要引言部分案例attentionSCI摘要方法部分案例considerSCI高被引摘要引言部分案例词汇outline轮廓概要•Author(s): TIERNEY, L SCI引用728次•Title:MARKOV-CHAINS FOR EXPLORING POSTERIOR DISTRIBUTIONS 引言部分回顾研究背景，常用词汇outline•Source: ANNALS OF STATISTICS, 22 (4): 1701-1728 DEC 1994•《统计学纪事》美国•Abstract: Several Markov chain methods are available for sampling from a posterior distribution. Two important examples are the Gibbs sampler and the Metropolis algorithm.In addition, several strategies are available for constructing hybrid algorithms. This paper outlines some of the basic methods and strategies and discusses some related theoretical and practical issues. On the theoretical side, results from the theory of general state space Markov chains can be used to obtain convergence rates, laws of large numbers and central limit theorems for estimates obtained from Markov chain methods. These theoretical results can be used to guide the construction of more efficient algorithms. For the practical use of Markov chain methods, standard simulation methodology provides several Variance reduction techniques and also gives guidance on the choice of sample size and allocation.SCI高被引摘要引言部分案例回顾研究背景presentAuthor(s): L YNCH, M; MILLIGAN, BG SC I被引用661Title: ANAL YSIS OF POPULATION GENETIC-STRUCTURE WITH RAPD MARKERS Source: MOLECULAR ECOLOGY, 3 (2): 91-99 APR 1994《分子生态学》英国Abstract: Recent advances in the application of the polymerase chain reaction make it possible to score individuals at a large number of loci. The RAPD (random amplified polymorphic DNA) method is one such technique that has attracted widespread interest.The analysis of population structure with RAPD data is hampered by the lack of complete genotypic information resulting from dominance, since this enhances the sampling variance associated with single loci as well as induces bias in parameter estimation. We present estimators for several population-genetic parameters (gene and genotype frequencies, within- and between-population heterozygosities, degree of inbreeding and population subdivision, and degree of individual relatedness) along with expressions for their sampling variances. Although completely unbiased estimators do not appear to be possible with RAPDs, several steps are suggested that will insure that the bias in parameter estimates is negligible. To achieve the same degree of statistical power, on the order of 2 to 10 times more individuals need to be sampled per locus when dominant markers are relied upon, as compared to codominant (RFLP, isozyme) markers. Moreover, to avoid bias in parameter estimation, the marker alleles for most of these loci should be in relatively low frequency. Due to the need for pruning loci with low-frequency null alleles, more loci also need to be sampled with RAPDs than with more conventional markers, and sole problems of bias cannot be completely eliminated.SCI高被引摘要引言部分案例词汇describe•Author(s): CLONINGER, CR; SVRAKIC, DM; PRZYBECK, TR•Title: A PSYCHOBIOLOGICAL MODEL OF TEMPERAMENT AND CHARACTER•Source: ARCHIVES OF GENERAL PSYCHIATRY, 50 (12): 975-990 DEC 1993《普通精神病学纪要》美国•引言部分回顾研究背景，常用词汇describe 被引用926•Abstract: In this study, we describe a psychobiological model of the structure and development of personality that accounts for dimensions of both temperament and character. Previous research has confirmed four dimensions of temperament: novelty seeking, harm avoidance, reward dependence, and persistence, which are independently heritable, manifest early in life, and involve preconceptual biases in perceptual memory and habit formation. For the first time, we describe three dimensions of character that mature in adulthood and influence personal and social effectiveness by insight learning about self-concepts.Self-concepts vary according to the extent to which a person identifies the self as (1) an autonomous individual, (2) an integral part of humanity, and (3) an integral part of the universe as a whole. Each aspect of self-concept corresponds to one of three character dimensions called self-directedness, cooperativeness, and self-transcendence, respectively. We also describe the conceptual background and development of a self-report measure of these dimensions, the Temperament and Character Inventory. Data on 300 individuals from the general population support the reliability and structure of these seven personality dimensions. We discuss the implications for studies of information processing, inheritance, development, diagnosis, and treatment.摘要引言部分案例•（2）说明写作目的，常用词汇有purpose, attempt, aimSCI高被引摘要引言部分案例attempt说明写作目的•Author(s): Donoho, DL; Johnstone, IM•Title: Adapting to unknown smoothness via wavelet shrinkage•Source: JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION, 90 (432): 1200-1224 DEC 1995 《美国统计学会志》被引用429次•Abstract: We attempt to recover a function of unknown smoothness from noisy sampled data. We introduce a procedure, SureShrink, that suppresses noise by thresholding the empirical wavelet coefficients. The thresholding is adaptive: A threshold level is assigned to each dyadic resolution level by the principle of minimizing the Stein unbiased estimate of risk (Sure) for threshold estimates. The computational effort of the overall procedure is order N.log(N) as a function of the sample size N. SureShrink is smoothness adaptive: If the unknown function contains jumps, then the reconstruction (essentially) does also; if the unknown function has a smooth piece, then the reconstruction is (essentially) as smooth as the mother wavelet will allow. The procedure is in a sense optimally smoothness adaptive: It is near minimax simultaneously over a whole interval of the Besov scale; the size of this interval depends on the choice of mother wavelet. We know from a previous paper by the authors that traditional smoothing methods-kernels, splines, and orthogonal series estimates-even with optimal choices of the smoothing parameter, would be unable to perform in a near-minimax way over many spaces in the Besov scale.Examples of SureShrink are given. The advantages of the method are particularly evident when the underlying function has jump discontinuities on a smooth backgroundSCI高被引摘要引言部分案例To investigate说明写作目的•Author(s): OLTV AI, ZN; MILLIMAN, CL; KORSMEYER, SJ•Title: BCL-2 HETERODIMERIZES IN-VIVO WITH A CONSERVED HOMOLOG, BAX, THAT ACCELERATES PROGRAMMED CELL-DEATH•Source: CELL, 74 (4): 609-619 AUG 27 1993 被引用3233•Abstract: Bcl-2 protein is able to repress a number of apoptotic death programs. To investigate the mechanism of Bcl-2's effect, we examined whether Bcl-2 interacted with other proteins. We identified an associated 21 kd protein partner, Bax, that has extensive amino acid homology with Bcl-2, focused within highly conserved domains I and II. Bax is encoded by six exons and demonstrates a complex pattern of alternative RNA splicing that predicts a 21 kd membrane (alpha) and two forms of cytosolic protein (beta and gamma). Bax homodimerizes and forms heterodimers with Bcl-2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of Bcl-2. These data suggest a model in which the ratio of Bcl-2 to Bax determines survival or death following an apoptotic stimulus.SCI高被引摘要引言部分案例purposes说明写作目的•Author(s): ROGERS, FJ; IGLESIAS, CA•Title: RADIATIVE ATOMIC ROSSELAND MEAN OPACITY TABLES•Source: ASTROPHYSICAL JOURNAL SUPPLEMENT SERIES, 79 (2): 507-568 APR 1992 《天体物理学杂志增刊》美国SCI被引用512•Abstract: For more than two decades the astrophysics community has depended on opacity tables produced at Los Alamos. In the present work we offer new radiative Rosseland mean opacity tables calculated with the OPAL code developed independently at LLNL. We give extensive results for the recent Anders-Grevesse mixture which allow accurate interpolation in temperature, density, hydrogen mass fraction, as well as metal mass fraction. The tables are organized differently from previous work. Instead of rows and columns of constant temperature and density, we use temperature and follow tracks of constant R, where R = density/(temperature)3. The range of R and temperature are such as to cover typical stellar conditions from the interior through the envelope and the hotter atmospheres. Cool atmospheres are not considered since photoabsorption by molecules is neglected. Only radiative processes are taken into account so that electron conduction is not included. For comparison purposes we present some opacity tables for the Ross-Aller and Cox-Tabor metal abundances. Although in many regions the OPAL opacities are similar to previous work, large differences are reported.For example, factors of 2-3 opacity enhancements are found in stellar envelop conditions.SCI高被引摘要引言部分案例aim说明写作目的•Author(s):EDV ARDSSON, B; ANDERSEN, J; GUSTAFSSON, B; LAMBERT, DL;NISSEN, PE; TOMKIN, J•Title:THE CHEMICAL EVOLUTION OF THE GALACTIC DISK .1. ANALYSISAND RESULTS•Source: ASTRONOMY AND ASTROPHYSICS, 275 (1): 101-152 AUG 1993 《天文学与天体物理学》被引用934•Abstract:With the aim to provide observational constraints on the evolution of the galactic disk, we have derived abundances of 0, Na, Mg, Al, Si, Ca, Ti, Fe, Ni, Y, Zr, Ba and Nd, as well as individual photometric ages, for 189 nearby field F and G disk dwarfs.The galactic orbital properties of all stars have been derived from accurate kinematic data, enabling estimates to be made of the distances from the galactic center of the star s‘ birthplaces. 结构式摘要•Our extensive high resolution, high S/N, spectroscopic observations of carefully selected northern and southern stars provide accurate equivalent widths of up to 86 unblended absorption lines per star between 5000 and 9000 angstrom. The abundance analysis was made with greatly improved theoretical LTE model atmospheres. Through the inclusion of a great number of iron-peak element absorption lines the model fluxes reproduce the observed UV and visual fluxes with good accuracy. A new theoretical calibration of T(eff) as a function of Stromgren b - y for solar-type dwarfs has been established. The new models and T(eff) scale are shown to yield good agreement between photometric and spectroscopic measurements of effective temperatures and surface gravities, but the photometrically derived very high overall metallicities for the most metal rich stars are not supported by the spectroscopic analysis of weak spectral lines.•Author(s): PAYNE, MC; TETER, MP; ALLAN, DC; ARIAS, TA; JOANNOPOULOS, JD•Title:ITERA TIVE MINIMIZATION TECHNIQUES FOR ABINITIO TOTAL-ENERGY CALCULATIONS - MOLECULAR-DYNAMICS AND CONJUGA TE GRADIENTS•Source: REVIEWS OF MODERN PHYSICS, 64 (4): 1045-1097 OCT 1992 《现代物理学评论》美国American Physical Society SCI被引用2654 •Abstract: This article describes recent technical developments that have made the total-energy pseudopotential the most powerful ab initio quantum-mechanical modeling method presently available. In addition to presenting technical details of the pseudopotential method, the article aims to heighten awareness of the capabilities of the method in order to stimulate its application to as wide a range of problems in as many scientific disciplines as possible.SCI高被引摘要引言部分案例includes介绍论文的重点内容或研究范围•Author(s):MARCHESINI, G; WEBBER, BR; ABBIENDI, G; KNOWLES, IG;SEYMOUR, MH; STANCO, L•Title: HERWIG 5.1 - A MONTE-CARLO EVENT GENERA TOR FOR SIMULATING HADRON EMISSION REACTIONS WITH INTERFERING GLUONS SCI被引用955次•Source: COMPUTER PHYSICS COMMUNICATIONS, 67 (3): 465-508 JAN 1992:《计算机物理学通讯》荷兰Elsevier•Abstract: HERWIG is a general-purpose particle-physics event generator, which includes the simulation of hard lepton-lepton, lepton-hadron and hadron-hadron scattering and soft hadron-hadron collisions in one package. It uses the parton-shower approach for initial-state and final-state QCD radiation, including colour coherence effects and azimuthal correlations both within and between jets. This article includes a brief review of the physics underlying HERWIG, followed by a description of the program itself. This includes details of the input and control parameters used by the program, and the output data provided by it. Sample output from a typical simulation is given and annotated.SCI高被引摘要引言部分案例presents介绍论文的重点内容或研究范围•Author(s): IDSO, KE; IDSO, SB•Title: PLANT-RESPONSES TO ATMOSPHERIC CO2 ENRICHMENT IN THE FACE OF ENVIRONMENTAL CONSTRAINTS - A REVIEW OF THE PAST 10 YEARS RESEARCH•Source: AGRICULTURAL AND FOREST METEOROLOGY, 69 (3-4): 153-203 JUL 1994 《农业和林业气象学》荷兰Elsevier 被引用225•Abstract:This paper presents a detailed analysis of several hundred plant carbon exchange rate (CER) and dry weight (DW) responses to atmospheric CO2 enrichment determined over the past 10 years. It demonstrates that the percentage increase in plant growth produced by raising the air's CO2 content is generally not reduced by less than optimal levels of light, water or soil nutrients, nor by high temperatures, salinity or gaseous air pollution. More often than not, in fact, the data show the relative growth-enhancing effects of atmospheric CO2 enrichment to be greatest when resource limitations and environmental stresses are most severe.SCI高被引摘要引言部分案例介绍论文的重点内容或研究范围emphasizing •Author(s): BESAG, J; GREEN, P; HIGDON, D; MENGERSEN, K•Title: BAYESIAN COMPUTATION AND STOCHASTIC-SYSTEMS•Source: STATISTICAL SCIENCE, 10 (1): 3-41 FEB 1995《统计科学》美国•SCI被引用296次•Abstract: Markov chain Monte Carlo (MCMC) methods have been used extensively in statistical physics over the last 40 years, in spatial statistics for the past 20 and in Bayesian image analysis over the last decade. In the last five years, MCMC has been introduced into significance testing, general Bayesian inference and maximum likelihood estimation. This paper presents basic methodology of MCMC, emphasizing the Bayesian paradigm, conditional probability and the intimate relationship with Markov random fields in spatial statistics.Hastings algorithms are discussed, including Gibbs, Metropolis and some other variations. Pairwise difference priors are described and are used subsequently in three Bayesian applications, in each of which there is a pronounced spatial or temporal aspect to the modeling. The examples involve logistic regression in the presence of unobserved covariates and ordinal factors; the analysis of agricultural field experiments, with adjustment for fertility gradients; and processing oflow-resolution medical images obtained by a gamma camera. Additional methodological issues arise in each of these applications and in the Appendices. The paper lays particular emphasis on the calculation of posterior probabilities and concurs with others in its view that MCMC facilitates a fundamental breakthrough in applied Bayesian modeling.SCI高被引摘要引言部分案例介绍论文的重点内容或研究范围focuses •Author(s): HUNT, KJ; SBARBARO, D; ZBIKOWSKI, R; GAWTHROP, PJ•Title: NEURAL NETWORKS FOR CONTROL-SYSTEMS - A SURVEY•Source: AUTOMA TICA, 28 (6): 1083-1112 NOV 1992《自动学》荷兰Elsevier•SCI被引用427次•Abstract:This paper focuses on the promise of artificial neural networks in the realm of modelling, identification and control of nonlinear systems. The basic ideas and techniques of artificial neural networks are presented in language and notation familiar to control engineers. Applications of a variety of neural network architectures in control are surveyed. We explore the links between the fields of control science and neural networks in a unified presentation and identify key areas for future research.SCI高被引摘要引言部分案例介绍论文的重点内容或研究范围focus•Author(s): Stuiver, M; Reimer, PJ; Bard, E; Beck, JW;•Title: INTCAL98 radiocarbon age calibration, 24,000-0 cal BP•Source: RADIOCARBON, 40 (3): 1041-1083 1998《放射性碳》美国SCI被引用2131次•Abstract: The focus of this paper is the conversion of radiocarbon ages to calibrated (cal) ages for the interval 24,000-0 cal BP (Before Present, 0 cal BP = AD 1950), based upon a sample set of dendrochronologically dated tree rings, uranium-thorium dated corals, and varve-counted marine sediment. The C-14 age-cal age information, produced by many laboratories, is converted to Delta(14)C profiles and calibration curves, for the atmosphere as well as the oceans. We discuss offsets in measured C-14 ages and the errors therein, regional C-14 age differences, tree-coral C-14 age comparisons and the time dependence of marine reservoir ages, and evaluate decadal vs. single-year C-14 results. Changes in oceanic deepwater circulation, especially for the 16,000-11,000 cal sp interval, are reflected in the Delta(14)C values of INTCAL98.SCI高被引摘要引言部分案例介绍论文的重点内容或研究范围emphasis •Author(s): LEBRETON, JD; BURNHAM, KP; CLOBERT, J; ANDERSON, DR•Title: MODELING SURVIV AL AND TESTING BIOLOGICAL HYPOTHESES USING MARKED ANIMALS - A UNIFIED APPROACH WITH CASE-STUDIES •Source: ECOLOGICAL MONOGRAPHS, 62 (1): 67-118 MAR 1992•《生态学论丛》美国•Abstract: The understanding of the dynamics of animal populations and of related ecological and evolutionary issues frequently depends on a direct analysis of life history parameters. For instance, examination of trade-offs between reproduction and survival usually rely on individually marked animals, for which the exact time of death is most often unknown, because marked individuals cannot be followed closely through time.Thus, the quantitative analysis of survival studies and experiments must be based oncapture-recapture (or resighting) models which consider, besides the parameters of primary interest, recapture or resighting rates that are nuisance parameters. 结构式摘要•T his paper synthesizes, using a common framework, these recent developments together with new ones, with an emphasis on flexibility in modeling, model selection, and the analysis of multiple data sets. The effects on survival and capture rates of time, age, and categorical variables characterizing the individuals (e.g., sex) can be considered, as well as interactions between such effects. This "analysis of variance" philosophy emphasizes the structure of the survival and capture process rather than the technical characteristics of any particular model. The flexible array of models encompassed in this synthesis uses a common notation. As a result of the great level of flexibility and relevance achieved, the focus is changed from fitting a particular model to model building and model selection.SCI摘要方法部分案例•方法部分•（1）介绍研究或试验过程，常用词汇有test，study, investigate, examine,experiment, discuss, consider, analyze, analysis等•（2）说明研究或试验方法，常用词汇有measure, estimate, calculate等•（3）介绍应用、用途，常用词汇有use, apply, application等SCI高被引摘要方法部分案例discusses介绍研究或试验过程•Author(s): LIANG, KY; ZEGER, SL; QAQISH, B•Title: MULTIV ARIATE REGRESSION-ANAL YSES FOR CATEGORICAL-DATA •Source:JOURNAL OF THE ROY AL STA TISTICAL SOCIETY SERIES B-METHODOLOGICAL, 54 (1): 3-40 1992《皇家统计学会志，B辑：统计方法论》•SCI被引用298•Abstract: It is common to observe a vector of discrete and/or continuous responses in scientific problems where the objective is to characterize the dependence of each response on explanatory variables and to account for the association between the outcomes. The response vector can comprise repeated observations on one variable, as in longitudinal studies or genetic studies of families, or can include observations for different variables.This paper discusses a class of models for the marginal expectations of each response and for pairwise associations. The marginal models are contrasted with log-linear models.Two generalized estimating equation approaches are compared for parameter estimation.The first focuses on the regression parameters; the second simultaneously estimates the regression and association parameters. The robustness and efficiency of each is discussed.The methods are illustrated with analyses of two data sets from public health research SCI高被引摘要方法部分案例介绍研究或试验过程examines•Author(s): Huo, QS; Margolese, DI; Stucky, GD•Title: Surfactant control of phases in the synthesis of mesoporous silica-based materials •Source: CHEMISTRY OF MATERIALS, 8 (5): 1147-1160 MAY 1996•SCI被引用643次《材料的化学性质》美国•Abstract: The low-temperature formation of liquid-crystal-like arrays made up of molecular complexes formed between molecular inorganic species and amphiphilic organic molecules is a convenient approach for the synthesis of mesostructure materials.This paper examines how the molecular shapes of covalent organosilanes, quaternary ammonium surfactants, and mixed surfactants in various reaction conditions can be used to synthesize silica-based mesophase configurations, MCM-41 (2d hexagonal, p6m), MCM-48 (cubic Ia3d), MCM-50 (lamellar), SBA-1 (cubic Pm3n), SBA-2 (3d hexagonal P6(3)/mmc), and SBA-3(hexagonal p6m from acidic synthesis media). The structural function of surfactants in mesophase formation can to a first approximation be related to that of classical surfactants in water or other solvents with parallel roles for organic additives. The effective surfactant ion pair packing parameter, g = V/alpha(0)l, remains a useful molecular structure-directing index to characterize the geometry of the mesophase products, and phase transitions may be viewed as a variation of g in the liquid-crystal-Like solid phase. Solvent and cosolvent structure direction can be effectively used by varying polarity, hydrophobic/hydrophilic properties and functionalizing the surfactant molecule, for example with hydroxy group or variable charge. Surfactants and synthesis conditions can be chosen and controlled to obtain predicted silica-based mesophase products. A room-temperature synthesis of the bicontinuous cubic phase, MCM-48, is presented. A low-temperature (100 degrees C) and low-pH (7-10) treatment approach that can be used to give MCM-41 with high-quality, large pores (up to 60 Angstrom), and pore volumes as large as 1.6 cm(3)/g is described.Estimates 介绍研究或试验过程SCI高被引摘要方法部分案例•Author(s): KESSLER, RC; MCGONAGLE, KA; ZHAO, SY; NELSON, CB; HUGHES, M; ESHLEMAN, S; WITTCHEN, HU; KENDLER, KS•Title:LIFETIME AND 12-MONTH PREV ALENCE OF DSM-III-R PSYCHIATRIC-DISORDERS IN THE UNITED-STA TES - RESULTS FROM THE NATIONAL-COMORBIDITY-SURVEY•Source: ARCHIVES OF GENERAL PSYCHIATRY, 51 (1): 8-19 JAN 1994•《普通精神病学纪要》美国SCI被引用4350次•Abstract: Background: This study presents estimates of lifetime and 12-month prevalence of 14 DSM-III-R psychiatric disorders from the National Comorbidity Survey, the first survey to administer a structured psychiatric interview to a national probability sample in the United States.Methods: The DSM-III-R psychiatric disorders among persons aged 15 to 54 years in the noninstitutionalized civilian population of the United States were assessed with data collected by lay interviewers using a revised version of the Composite International Diagnostic Interview. Results: Nearly 50% of respondents reported at least one lifetime disorder, and close to 30% reported at least one 12-month disorder. The most common disorders were major depressive episode, alcohol dependence, social phobia, and simple phobia. More than half of all lifetime disorders occurred in the 14% of the population who had a history of three or more comorbid disorders. These highly comorbid people also included the vast majority of people with severe disorders.Less than 40% of those with a lifetime disorder had ever received professional treatment,and less than 20% of those with a recent disorder had been in treatment during the past 12 months. Consistent with previous risk factor research, it was found that women had elevated rates of affective disorders and anxiety disorders, that men had elevated rates of substance use disorders and antisocial personality disorder, and that most disorders declined with age and with higher socioeconomic status. Conclusions: The prevalence of psychiatric disorders is greater than previously thought to be the case. Furthermore, this morbidity is more highly concentrated than previously recognized in roughly one sixth of the population who have a history of three or more comorbid disorders. This suggests that the causes and consequences of high comorbidity should be the focus of research attention. The majority of people with psychiatric disorders fail to obtain professional treatment. Even among people with a lifetime history of three or more comorbid disorders, the proportion who ever obtain specialty sector mental health treatment is less than 50%.These results argue for the importance of more outreach and more research on barriers to professional help-seekingSCI高被引摘要方法部分案例说明研究或试验方法measure•Author(s): Schlegel, DJ; Finkbeiner, DP; Davis, M•Title:Maps of dust infrared emission for use in estimation of reddening and cosmic microwave background radiation foregrounds•Source: ASTROPHYSICAL JOURNAL, 500 (2): 525-553 Part 1 JUN 20 1998 SCI 被引用2972 次《天体物理学杂志》美国•The primary use of these maps is likely to be as a new estimator of Galactic extinction. To calibrate our maps, we assume a standard reddening law and use the colors of elliptical galaxies to measure the reddening per unit flux density of 100 mu m emission. We find consistent calibration using the B-R color distribution of a sample of the 106 brightest cluster ellipticals, as well as a sample of 384 ellipticals with B-V and Mg line strength measurements. For the latter sample, we use the correlation of intrinsic B-V versus Mg, index to tighten the power of the test greatly. We demonstrate that the new maps are twice as accurate as the older Burstein-Heiles reddening estimates in regions of low and moderate reddening. The maps are expected to be significantly more accurate in regions of high reddening. These dust maps will also be useful for estimating millimeter emission that contaminates cosmic microwave background radiation experiments and for estimating soft X-ray absorption. We describe how to access our maps readily for general use.SCI高被引摘要结果部分案例application介绍应用、用途•Author(s): MALLAT, S; ZHONG, S•Title: CHARACTERIZATION OF SIGNALS FROM MULTISCALE EDGES•Source: IEEE TRANSACTIONS ON PATTERN ANALYSIS AND MACHINE INTELLIGENCE, 14 (7): 710-732 JUL 1992•SCI被引用508次《IEEE模式分析与机器智能汇刊》美国•Abstract: A multiscale Canny edge detection is equivalent to finding the local maxima ofa wavelet transform. We study the properties of multiscale edges through the wavelet。
外周血microRNA-126检测在结直肠癌诊断中的意义
外周血microRNA-126检测在结直肠癌诊断中的意义宋红群【摘要】目的探讨外周血microRNA-126对结直肠癌的诊断意义及其与临床病理特征的相关性.方法收集我院住院的46例CRC患者作为观察组,并选取同期60例正常体检者作为对照组.采用逆转录实时荧光定量聚合酶链反应(RT-PCR)方法检测miRNA-126的表达量,分析miRNA-126与年龄、性别、肿瘤位置、分化程度、淋巴结转移、器官侵犯等临床病理特征的关系.采用ROC分析的方法研究外周血清miRNA-126相对表达量对结肠癌的诊断意义.结果观察组患者血清中的miRNA-126的相对表达量明显低于正常对照组(P＜0.05).其表达与分化程度、器官侵犯相关.受试者工作特征曲线(receiver operating characteristic curve,ROC曲线)分析显示,miRNA-126指标的曲线下面积为0.742,可作为一种辅助诊断标准.结论外周血miRNA-126在结肠癌患者中的表达明显降低,对结直肠癌的诊断具有一定的临床意义.【期刊名称】《内蒙古医学杂志》【年(卷),期】2017(049)005【总页数】4页(P513-515,封2)【关键词】miRNA-126;结直肠癌;ROC曲线【作者】宋红群【作者单位】安钢职工总医院,河南安阳 462000【正文语种】中文【中图分类】R735.37最新癌症研究报告显示，2012年全球癌症患病病例及死亡病例均有所增加，新增癌症患者近一半出现在亚洲，而中国新增癌症患者高居第一位[1]。
肺癌、结直肠癌(colorectal cancer，CRC)、前列腺癌及乳腺癌仍然是癌症死亡最常见原因，超过总体癌症死亡率的一半。
作为世界范围内高发病率及死亡率的结直肠癌，严重威胁着人类的健康。
结直肠癌的发病能够早期发现，其发病率和死亡率将会得到改善。
尽管目前的筛查手段如结肠镜检查、粪便潜血检测等多样化，但CRC的早期诊断仍较困难。
Elevated DLL4 expression is correlated with VEGF and predicts poor prognosis of nasopharyngeal ca
ORIGINAL PAPERElevated DLL4expression is correlated with VEGF and predicts poor prognosis of nasopharyngeal carcinomaJia-Xing Zhang •Man-Bo Cai •Xiao-Pai Wang •Li-Ping Duan •Qiong Shao •Zhu-Ting Tong •Ding-Zhun Liao •Yang-Yang Li •Ma-Yan Huang •Yi-Xin Zeng •Jian-Yong ShaoReceived:24September 2012/Accepted:26September 2012/Published online:30December 2012ÓSpringer Science+Business Media New York 2012Abstract Delta-like ligand 4(DLL4),one of the transmembranous Notch ligands,is upregulated at the site of tumor growth,particularly during tumor angiogenesis.Expression pattern of DLL4in nasopharyngeal carcinoma (NPC)and the clinical and prognostic significance remain unclear.In this study,immunohistochemical analysis (IHC)was used to examine the protein level of DLL4in NPC tissues from two independent cohorts.In the testing cohort (311cases),we applied the X-tile program software able to assess the optimal cutoff points for biomarkers in order to accurately classify patients according to clinical outcome.In the validation cohort (113cases),the cutoff score derived from X-title analysis was investigated to determine the association of DLL4expression with disease-specific survival (DFS).Our results showed that high expression of DLL4was observed in 134of 313(42.8%)in the testing cohort and 58of 113(43.6%)in the validation cohort.High expression of DLL4independently predicted poorer disease-specific survival,as evidenced by univariate and multivariate analysis (P \0.05).Moreover,DLL4expres-sion was significantly elevated in distant NPC metastases relative to primary NPC tumors (P =0.001).Importantly,we found a significant positive relationship between DLL4and vascular endothelial growth factor (VEGF)(P \0.001).Patients with dual elevated DLL4and VEGF expression displayed a significant overall survival disadvantage com-pared to those with dual low expression (P \0.05).These findings provide evidence that high expression of DLL4serves as an independent predictor of poor prognosis in NPC patients.Keywords DLL4ÁNasopharyngeal carcinoma ÁImmunohistochemistry ÁPrognosisBackgroundNasopharyngeal carcinoma (NPC),which exhibits a high prevalence in southern China and Southeastern Asia,dis-plays the highest rate of metastasis compared with other head and neck cancers [1–4].The majority of NPC patients exhibit regional lymph node (LN)or distant organ metas-tases at the time of diagnosis [5–7].However,the molec-ular mechanisms underlying NPC development and progression remain poorly understood.Thus,a substantial amount of research on NPC has focused on the discoveryJia-Xing Zhang,Man-Bo Cai and Xiao-Pai Wang:These authors made equal contributions and are joint first authors.J.-X.Zhang ÁY.-X.Zeng ÁJ.-Y.Shao (&)State Key Laboratory of Oncology in South China,Sun Yat-sen University Cancer Center,Guangzhou 510060,China e-mail:shaojy@J.-X.Zhang ÁX.-P.Wang ÁQ.Shao ÁY.-Y.Li ÁJ.-Y.Shao Department of Molecular Diagnostics,Sun Yat-sen University Cancer Center,Guangzhou 510060,ChinaM.-B.Cai ÁY.-X.ZengDepartment of Experiment Research,Sun Yat-sen University Cancer Center,Guangzhou 510060,ChinaL.-P.DuanInstitute of Scientific and Technical Information of China (ISTIC),100038Beijing,ChinaZ.-T.TongDepartment of Radiotherapy,The First Affiliated Hospital,An Hui Medical University,Hefei,ChinaD.-Z.Liao ÁM.-Y.HuangDepartment of Pathology,Sun Yat-sen University Cancer Center,Guangzhou 510060,ChinaMed Oncol (2013)30:390DOI 10.1007/s12032-012-0390-xof promising molecular and genetic alterations responsible for the invasive potential and clinical progression of this malignancy[8–11].However,current investigation and identification of novel molecular biomarkers in NPC that provide reliable prognostic value is limited.Thus,in this study,we aimed to identify an additional novel molecular marker able to not only predict the clinical prognosis but also provide optimal therapeutic targeting to benefit NPC patients.Angiogenesis is an essential step for tumor growth and progression and plays a vital role in tumor invasion and metastasis[12].One signaling pathway that may contribute to this process is the Notch signaling pathway[13,14].The mammalian Notch family consists of four receptors,Notch 1–4,andfive ligands,Jagged1and2,and Delta-like ligand 1,3,and4(DLL1,-3,-4).DLL4,a ligand for Notch receptors1,3,and4,is upregulated by vascular endothelial growth factor(VEGF)and hypoxia,and its activation triggers a negative feedback that restrains the excessive VEGF-effects of vascular sprouting and angiogenesis[15–19].Overall,DLL4functions as a negative regulator of tumor angiogenesis by reducing the number of blood ves-sels;yet surprisingly,it enhances the vasculature structure and function within a tumor by inducing larger vessels, thereby increasing vessel perfusion and tumor oxygenation, resulting in increased tumor growth and progression in vivo [20–22].Recently,DLL4has been shown to mediate tumor resistance to bevacizumab in vivo[23].Activation of the Notch/DLL4signaling pathway has previously been described in several human malignancies and has been linked to poor patient prognosis[22,24–30].Recently reported immunohistochemistry(IHC)studies have dem-onstrated that DLL4protein expression is not restricted to endothelial cells,but is widespread in neoplastic as well as in reactive tissues[22,24,29].Moreover,in breast and colon cancers,DLL4was also reported to possess a posi-tively associated expression level with VEGF and hypoxia markers[28,31].However,the characterization and clin-ical significance of DLL4protein expression in NPC has not been fully elucidated.We have previously reported that elevated expression of VEGF protein is a strong independent predictor of survival in advanced NPC[32].However,by now,no study was conducted to explore the expression pattern of DLL4in NPC.In this study,wefirst constructed two independent NPC tissue sample cohorts from two institutions.Based on our previous work,we intend to analyze the expression level of NPC as well as its relationship regarding NPC patients’prognosis.In the testing cohort(311cases),we applied the X-tile program software able to assess the optimal cutoff points for biomarkers in order to accurately classify patients according to clinical outcome.In the validation cohort(113cases),the cutoff score derived from X-title analysis was investigated to determine the associa-tion of DLL4expression with disease-specific survival (DFS).As far as we concerned,our study is thefirst research to elucidate the expression pattern of DLL4in NPC.Our work demonstrated that DLL4-associated VEGF high expression could potentially serve as a molecular target for NPC therapy.Materials and methodsPatients and tissue microarrayFor this retrospective study,formalin-fixed,paraffin-embedded specimens of NPC were collected between1997 and2000from Sun Yan-Sun University Cancer Center (SYSUCC)(Guangzhou,China).Of the311patients,were 235male and76female,with a median age of47years (range,16–78years).The disease stages for all patients were classified according to the1992NPC staging system of China[33]:2patients were stage I,54patients were stage II,164patients were stage III,and91patients were stage IV.Statistical analysis showed that the agreement rate was72%.Besides,we collected31paired archival tissue samples of liver/pulmonary metastases from NPC cases between January2009and December2009in SYSUCC.All NPC were obtained prior to treatment with standard curative radiotherapy with or without chemo-therapy.The average duration of follow-up in this cohort was63months(median,68months;range,1–120months).In parallel,we assessed another randomly selected, independent validation cohort of133NPC patients between March2003and February2004from the Department of Pathology of Hunan Provincial Cancer Hospital(Changsha,China).This cohort included97males and36females,with a median age of47years(rang from 15to82years):20patients were stage II,68were stage III, and45were stage IV.The average duration of follow-up in this cohort was41months(median,41months;range 6–79months).All of the clinical materials were obtained from patients who provided informed consent in accordance with insti-tutional review board standards and guidelines.Paraffin-embedded specimens from the previously constructed tissue microarray(TMA)and procedures for the TMA construction were reported previously[32]. Immunohistochemistry(IHC)IHC analysis was performed to examine DLL4and VEGF expression in NPC tumor tissue.Primary antibodies against DLL4(1:300dilution,Abcam,USA)and VEGF(1:200Page2of10Med Oncol(2013)30:390dilution,Santa Cruz,USA)were used in this study.The staining protocol utilized in this study was described pre-viously[32].The IHC results were evaluated and scored independently by two pathologists with no prior knowledge of the clinicopathological outcomes of the patients.Semi-quantitative estimates were achieved using a composite score comprised of the sum of the staining intensity values and the relative abundance of positive cells.The intensities were graded as0(negative),1(weakly positive),2(mod-erately positive),and3(strongly positive).The abundance of positive cells was graded from0to4(0\5%positive cells;1,5–25%;2,26–50%;3,51–75%;4,76–100%).Immunoblot analysisCells were harvested and lysed with RIPA buffer(Upstate, USA).Equal amounts of denatured proteins were separated by SDS-PAGE and then transferred electrophoretically to PVDF membranes(Amersham,UK)for immunoblot analysis.The antibody used for immunoblot analysis against DLL4was(1:500dilution,Abcam,USA)an anti-GAPDH antibody(1:3000dilution,Santa Cruz,USA)and was used as the loading control.All protein bands were detected using an enhanced chemiluminescent(ECL) Western blot kit(Amersham,UK).Selection of cutoff point scoreWe applied X-tile plots to assess DLL4expression levels and to optimize the cutoff points based on patient survival outcomes.X-title plots provide a single,global assessment of dividing a population into low-and high-level marker expression in every possible way.X-title data were pre-sented in a right triangular grid where each point represents a different cut-point.The intensity of the color of each cutoff point represents the strength of the association.The X-title software allows the user to move a cursor across the grid and provide an‘‘on-the-fly’’histogram of the resulting population subsets along with an associated Kaplan–Meier curve.The X-title software provides a method of dividing a single cohort into training and validation subsets for P value estimation.In addition,the software can perform standard Monte Carlo simulations(e.g.,cross-validation)to produce corrected P values to assess statistical significance of data assessed by multiple cut-points.The X-tile program divided the testing cohorts(311cases)randomly into a matched training and validation set as a method for selecting optimal cut-points,respectively[34].Statistical significance was assessed using the cutoff score derived from the testing cohort and a separate validation set using a standard log-rank method,with P values obtained from a statistical table.The X-tile plots allowed for the determi-nation of an optimal cutoff value while correcting for the use of minimum P statistics by Miller–Siegmund P value correction[35].Clinical outcome assessmentThe two cohorts of patients in this RCT were all followed up in accordance with a strict protocol.After completion of therapy,patients were observed at3-month intervals during thefirst3years and at6-month intervals thereafter.For deceased patients,we classified the underlying cause of death according to data available on the death certificate. Local relapse was defined as recurrence of NPC confirmed by biopsy,and distant metastasis was defined as evidence of distant metastasis by chest X-ray/computed tomography, abdominal ultrasound,and bone scan.Statistical analysisFor survival analysis,the optimal cutoff point for DLL4 expression was obtained using X-tile software version3.6.1 (Yale University School of Medicine,New Haven,CT, USA).The statistical significance of the correlation between DLL4expression level and patient survival was estimated using the Mantel–Cox log-rank test.Monte Carlo simulations were used to adjust for multiple observations in optimal cutoff point selection.Receiver operating charac-teristic(ROC)curve analysis was conducted to evaluate the predictive value of the parameters.The chi-square test or Fisher’s exact test was employed to evaluate the relation-ship between DLL4expression and clinicopathological variables.The multivariate Cox proportional hazards model was utilized to estimate the hazard ratios and95% confidence intervals for patient outcome.The relationships between the DLL4expression levels and DFS were determined by Kaplan–Meier analysis.Log-rank tests were performed to determine the difference in survival proba-bilities.All P values quoted were two-sided,and P\0.05 was considered a statistically significant.Statistical analy-sis was performed using SPSS16.0software;SPSS,Chi-cago,IL,USA).ResultsDLL4expression patterns in nasopharyngeal cell lines and tissues and X-title analysisWestern blot analysis demonstrated that in primary NPCs, 6/8(75%)of cases exhibited upregulated DLL4expres-sion compared to adjacent non-neoplastic nasopharyngeal tissues(Fig.1a).For DLL4IHC staining,positive staining was observed primarily in the cell membrane and cyto-plasm(Fig.1b,c,d).DLL4exhibited strong IHC stainingMed Oncol(2013)30:390Page3of10in NPC nests,whereas the paired normal epithelium exhibited weak IHC staining.Positive DLL4staining in tumor vessels of NPC and human colon cancer (positive control)was also observed (Fig.1e,f),while no positive signal was observed in vessels adjacent to normal colon mucosa (negative control)(Fig.1g).To assess statistical significance and,therefore,avoid arbitrary cutoff point selection,the X-tile program was employed to determine cutoff scores for DLL4expression.According to the X-tile plots,we divided the testing cohort into low and high populations based on the cutoff point of over four.The optimal cutoff point determined by the testing cohort was applied to the validation cohort,which in turn identified the highly statistically significant cutoff scores (Fig.2).In the testing cohort,high expression of DLL4was observed in 134of 311(43.1%)of NPC cases.The 5-year DSS rates differed substantially and statistically significantly between low-and high-level DLL4expression of NPC patients in the testing cohort (68.0.vs.50.2%,Fig.2a;P =0.009),whereas in the validation cohort,high DLL4expression was observed in 58of 133(43.6%)NPC.The 5-year DSS rates differed substantially andstatistically significantly between low-and high-level DLL4expression of NPC patients in overall cases (65.1vs.34.8%,Fig.2b;P =0.004).DLL4expression and clinical featuresThe correlation between expressions of DLL4in NPC with respect to clinicopathologic features is shown in Table 1.In the testing cohort,we detected a positive association between DLL4expression level and local relapse and distant metastasis.In the validation cohort,we observed a positive relationship between DLL4expression and distant metastasis only.However,we failed to detect a relationship between DLL4and other patient characteristics,including age,gender,tumor stage,node stage,and TNM stage.To evaluate the clinical relevance of our hypothesis that DLL4regulates NPC metastasis,we collected paired archival tissue samples of liver/pulmonary metastases from NPC cases for comparison with primary NPC tissues (n =31).IHC staining demonstrated that the protein levels of DLL4were significantly higher in the distant metastatic lesions than the matched primary lesions (Fig.3a,b).Fig.1DLL4expression in human NPC and normaladjacent epithelium.a Western blot analysis of DLL4expression in representative NPC (T)and non-neoplastic nasopharyngeal mucosal tissue (N).Equal loading of protein was determined by GAPDH.b DLL4showed cytoplasmic overexpression in NPC tumor tissue than normalnasopharyngeal epithelium;c high-level expression of DLL4in a NPC tumor;d low-level expression of DLL4in NPC tumor;e high-level expression of DLL4was observed in the vessel of NPC.f Strong DLL4staining in the vessel of colon cancer.g No DLL4staining in the vessels of normal colon mucosa.The vessels in each image are indicated by the arrowPage 4of 10Med Oncol (2013)30:390DLL4expression and survival analysisTo evaluate the prognostic value between DLL4expression levels and clinicopathologic features,ROC curves were plotted to test patient survival status.ROC curve analysis confirmed the predictive value of DLL4regarding NPC-specific survival in the validation cohort [area under the curve (AUC)=0.612,P =0.026,Fig.4a].When these findings were further investigated in all cases,DLL4was found to be a promising predictor for NPC patient survival status (AUC =0.591,P =0.001,Fig.4b).Univariate analysis and multivariate Cox regression analysisExpression of DLL4was found to be a significant prog-nostic indicator of poor DSS [hazard ratio (HR),2.076;95%confidence interval (CI),1.248–3.452,P =0.005;Table 2]in the validation cohort,as well as in overall case (HR,1.886;95%CI,1.444–2.464;P \0.001;Table 2).Regarding other parameters,node stage and overall stage expression levels were determined to be positive significant prognostic factors for patient survival in both cohorts.After multivariate analysis,the expression level of DLL4was found to be a significant independent prognostic factor for poor DSS (HR,1.821;95%CI,1.081–3.068,P =0.024;Table 2)in the validation cohort,as well as in overall case (HR,1.809;95%CI,1.380–2.370;P \0.001;Table 2).Correlation between the expression of DLL4and VEGF in NPC tissuesOur previous study revealed that VEGF protein levels are strong independent predictors of survival in advanced NPC cases [32].In this study,we further evaluated thepotentialFig.2X-tile plots of the prognostic marker of DLL4in the NPC cohorts.X-tile analysis was carried out on patient data from the training cohort,equally subdivided into training and validation subsets.X-tile plots of training sets are displayed in the left panels ,with matched validation sets in the smaller inset .The plot showed the chi-square log-rank values created when the cohort was divided into two populations.The cut-point highlighted by the red /blue circle in the left panels was demonstrated on a histogram of the entire cohort (middle panels )and a Kaplan–Meier plot (right panels ).P values were defined by using the cut-point derived from a training subset to parse a separate validation subset.a DLL4expression was divided at the optimal cut-point,as defined by the most significant on the plot (with positive staining of DLL4;P =0.009).b The optimal cut-point for DLL4expression determined by X-tile plot of the testing cohort was applied to the validation cohort and reached high statistical signifi-cance (P =0.004)Med Oncol (2013)30:390Page 5of 10correlation between expression of DLL4and VEGF in our NPC cohort.The results demonstrated a positive correla-tion between expression of DLL4and VEGF in NPC (r s =0.404,n =444,P \0.001,Spearman’s correlation analysis,Fig.5a).Similarly,X-title analysis revealed that a score of three was the optimal cutoff point to classifyTable 1DLL4expression in relation to patient characteristics in the testing and validation cohort VariableTesting cohort Validation cohort Low expression (n =177)High expression (n =134)P valueLow expression (n =75)High expression (n =58)P valueAge B 47year 91694426[47year 86650.98931320.113Gender Male 1311045047Female 46300.46425110.064Tumor stage T1?T249434733T3?T4128910.39928250.500Nodal stage N0?N186592317N2?N391750.42552410.866Local relapse Absent 1671186848Present 10160.047*7100.176Distant metastasisAbsent 1601077048Present 17270.008*5100.031*TNM stage I ?II 3421128III ?IV1431130.41863500.724*Statistically significant differenceWHO World Health Organization,TNM tumor–node–metastasis,DLL4delta-like ligand4Fig.3DLL4expression in distant metastatic and primary NPC.a IHC staining of DLL4protein expression levels in primary NPC and in distant metastases from NPC.The ranges of DLL4expression were shown,with prominent staining in metastatic lesions.b Statisticalanalysis (Pair-samples T test)revealed a significant increase in DLL4expression in distant metastases from NPC relative to expression in primary NPC (P =0.001)Page 6of 10Med Oncol (2013)30:390patients as exhibiting high or low VEGF expression in the testing cohort (data not shown).When the patient cohort was stratified according to tumor expression of both VEGF and DLL4in the validation cohort and in overall cases,the 5-year survival rate in NPC patients with DLL4and VEGF dual overexpression was significantly lower comparedtoFig.4ROC curve analysis for different clinical–pathologic features and DLL4expression.a Age (AUC =0.577;P =0.125),gender (AUC =0.538;P =0.451),tumor stage (AUC =0.571;P =0.159),node stage (AUC =0.611;P =0.027),overall stage (AUC =0.649;P =0.003),DLL4expression (AUC =0.612;P =0.026),implied statistical associations with survival in validation cohort.b Age(AUC =0.565;P =0.018),gender (AUC =0.548;P =0.078),tumor stage (AUC =0.558;P =0.035),node stage (AUC =0.557;P =0.039),overall stage (AUC =0.639;P \0.001),DLL4expres-sion (AUC =0.591;P =0.001),implied statistical associations with survival in overall casesTable 2Univariate and multivariate Cox proportional hazards analysis for disease-specific survival in the validation cohort and overall cases VariableValidation cohort (n =133)All patients (n =444)HR95%CIP valueHR95%CIP valueUnivariateAge ([47years vs.B 47years) 1.5140.912–2.5120.109 1.420 1.087–1.8570.010*Gender (male vs.female)1.4110.777–2.5640.258 1.522 1.093–2.1190.013*Tumor stage (T3?T4vs.T1?T2) 1.5140.914–2.5080.107 1.427 1.083–1.8800.012*Nodel stage (N2?N3vs.N0?N1) 2.423 1.260–4.6570.008* 1.564 1.194–2.0480.001*TNM stage (III ?IV vs.I ?II) 2.620 1.048–6.5510.039* 2.460 1.582–3.826\0.001*DLL4expression (high vs.low) 2.076 1.248–3.4520.005* 1.886 1.444–2.464\0.001*MultivariateAge ([47years vs.B 47years) 1.5250.906–2.5680.112 1.437 1.097–1.8840.009*Gender (male vs.female)1.1810.635–2.1990.599 1.400 1.001–1.9570.049*Tumor stage (T3?T4vs.T1?T2) 1.4340.806–2.5530.220 1.1580.816–1.6430.412Nodel stage (N2?N3vs.N0?N1) 2.650 1.070–6.5610.035* 1.3060.933–1.8300.120TNM stage (III ?IV vs.I ?II) 1.0480.281–3.9100.944 1.921 1.066–3.4620.030*DLL4expression (high vs.low) 1.8211.081–3.0680.024*1.8091.380–2.370\0.001**Statistically significant differenceTNM tumor–node–metastasis,HR hazard ratio,CI confidence interval,DLL4delta-like ligand 4Med Oncol (2013)30:390Page 7of 10dual low expression both in the validation cohort (71.2vs.25.4%,P =0.003,Fig.5b)and in the overall cases (73.0vs.40.6%,P \0.001,Fig.5c).DiscussionNPC is associated with a high rate of treatment failure because of local recurrence and distant metastasis [36].Although many aberrantly expressed genes in NPC have been identified recently,novel molecular biomarkers able to not only define tumor spread and metastatic potential,but also aid clinical outcome assessment remained limited.Angiogenesis is an essential step in tumor growth and plays a vital role in cancer invasion and metastasis;thus,angi-ogenesis leads to an inferior survival outcome in NPC cases [37].The connection between tumor growth and angiogenesis has prompted the development of several approaches to limit tumor angiogenesis and thus control tumor growth [38].The validation of these approaches involves a blockade of the VEGF and DLL4/Notch path-way.Our research group has previously identified VEGF proteins as strong independent predictors of survival in advanced nasopharyngeal carcinoma [32].Here,we present the results of large-scale IHC analyses to investigate the expression dynamics and prognostic significance of DLL4expression in two independent populations of NPC patients.In order to assess the prognostic significance ofDLL4and avoid predetermined arbitrary cutoff points,we applied X-tile plots to generate a more objective cutoff point to enable high/low division of DLL4expression in a testing cohort.The DLL4expression level,classified as high or low by the X-title-derived cutoff point,was further validated as an independent prognostic maker for DSS in the validation cohort and in overall cases.Older reports have indicated that DLL4is primarily expressed by endothelial cells.However,recent evidence has demonstrated that DLL4is also widely distributed in tissues other than vessels [22,24,29].In our study,we observed that high expression of DLL4in NPC tumor cell membrane and cytoplasm was a strong and independent predictor of short DSS.In addition,we found that NPC distant metastases more frequently exhibited overexpres-sion of DLL4compared to primary NPC tissues.This confirms that presence of distant metastasis is a crucial pathological finding for advanced-stage NPC and predicts an inferior clinical outcome.Our data suggest that increased expression of DLL4is a vital factor related to the distant metastasis potential of NPC and thus contributes to the poor prognostic phenotype of the patient.We also found that expression of DLL4exhibited a positive rela-tionship with its upstream regulator,VEGF.Moreover,dual elevated expression of DLL4and VEGF was corre-lated with the poorest clinical outcome.These findings,taken together,provide a possible explanation for the fre-quently observed high DLL4expression inmetastasizedFig.5Kaplan–Meier survival curves of NPC stratified by both DLL4and VEGF expression.a Overexpression of VEGF and DLL4was examined in the same NPC case.b Disease-specific survival (DSS)curves of NPC patients in the validation cohort with dual DLL4and VEGFoverexpression;c DSS curves of NPC patients in overall cases with dual DLL4and VEGF overexpressionPage 8of 10Med Oncol (2013)30:390sites compared to primary tumor sites and the correlation with overexpression of VEGF.However,additional markers of hypoxia and angiogenesis are still needed in order to explore their relationship with DLL4and the underlying mechanism involved in NPC tumorigenesis.In light of its critical role in angiogenesis,DLL4could potentially serve as a therapeutic molecular target for tumor control.Previous reports have demonstrated that DLL4blockade reduced tumor growth by disrupting pro-ductive angiogenesis,and the combination therapy of DLL4and VEGF pathway blockade synergistically inhib-ited tumor growth in preclinical models[39–41].DLL4has been identified as a specific drug target for controlling vessel growth in tumors and other pathological conditions. The fact that elevated expression of DLL4in NPC is consistent with the lack of DLL4expression in normal epithelium suggests that strategies targeting DLL4–Notch signaling might selectively affect the aggressive cells within the NPC cancer nest,but not the normal mucosa. NPC is more radiosensitive than other malignant tumors. During a long course of radiotherapy,chronic hypoxia occurs and results in an inverse effect on radiosensitivity [42,43].In vitro,hypoxia induces elevated expression of both VEGF and DLL4,which further promotes formation of a productive and well-differentiated vascular network, thus promoting cancer invasion and progression.In com-bination with previous studies,ourfindings suggest that VEGF-associated DLL4high expression may favor NPC cell survival following radiotherapy and may promote metastasis to distant organs.In summary,ourfindings illustrate that DLL4is an independent prognostic biomarker of overall survival and distant metastasis for NPC patients.DLL4high expression is a potential novel therapeutic molecular target for NPC. Acknowledgments This study was supported in part by National High Technology Research and Development Program of China(863 Program)(2012AA02A501);the China State Key Basic Research Project(2011CB504805).Conflict of interest The authors declare that they have no conflict of interest.References1.Chang ET,Adami HO.The enigmatic epidemiology of naso-pharyngeal carcinoma.Cancer Epidemiol Biomarkers Prev.2006;15:1765–77.2.Wei WI,Sham JS.Nasopharyngeal ncet.2005;365:2041–54.3.Yu MC,Yuan JM.Epidemiology of nasopharyngeal carcinoma.Semin Cancer Biol.2002;12:421–9.4.Farias TP,Dias FL,Lima RA,et al.Prognostic factors and out-come for nasopharyngeal carcinoma.Arch Otolaryngol Head Neck Surg.2003;129:794–9.5.Ahmad A,Stefani S.Distant metastases of nasopharyngeal car-cinoma:a study of256male patients.J Surg Oncol.1986;33: 194–7.6.Petrovich Z,Cox JD,Roswit B,et al.Advanced carcinoma of thenasopharynx.A clinical study of274patients.Radiology.1982;144:905–8.7.Geara FB,Sanguineti G,Tucker SL,et al.Carcinoma of thenasopharynx treated by radiotherapy alone:determinants of dis-tant metastasis and survival.Radiother Oncol.1997;43:53–61.8.Feng BJ,Huang W,Shugart YY,et al.Genome-wide scan forfamilial nasopharyngeal carcinoma reveals evidence of linkage to chromosome4.Nat Genet.2002;31:395–9.9.Bei JX,Li Y,Jia WH,et al.A genome-wide association study ofnasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet.2010;42:599–603.10.Song LB,Li J,Liao WT,et al.The polycomb group protein Bmi-1represses the tumor suppressor PTEN and induces epithelial-mes-enchymal transition in human nasopharyngeal epithelial cells.J Clin Invest.2009;119:3626–36.11.Cheng AL,Huang WG,Chen ZC,et al.Identification of novelnasopharyngeal carcinoma biomarkers by laser capture micro-dissection and proteomic analysis.Clin Cancer Res.2008;14: 435–45.12.Carmeliet P.Mechanisms of angiogenesis and arteriogenesis.NatMed.2000;6:389–95.13.Shawber CJ,Kitajewski J.Notch function in the vasculature:insights from zebrafish,mouse and man.BioEssays.2004;26: 225–34.14.Gridley T.Notch signaling during vascular development.ProcNatl Acad Sci USA.2001;98:5377–8.15.Shutter JR,Scully S,Fan W,et al.Dll4,a novel Notch ligandexpressed in arterial endothelium.Genes Dev.2000;14:1313–8.16.Rao PK,Dorsch M,Chickering T,et al.Isolation and charac-terization of the notch ligand delta4.Exp Cell Res.2000;260: 379–86.17.Patel NS,Li JL,Generali D,et al.Up-regulation of delta-like4ligand in human tumor vasculature and the role of basal expression in endothelial cell function.Cancer Res.2005;65: 8690–7.18.Williams CK,Li JL,Murga M,et al.Up-regulation of the Notchligand Delta-like4inhibits VEGF-induced endothelial cell function.Blood.2006;107:931–9.19.Liu ZJ,Shirakawa T,Li Y,et al.Regulation of Notch1and Dll4by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis.Mol Cell Biol.2003;23:14–25.20.Noguera-Troise I,Daly C,Papadopoulos NJ,et al.Blockade ofDll4inhibits tumour growth by promoting non-productive angi-ogenesis.Nature.2006;444:1032–7.21.Ridgway J,Zhang G,Wu Y,et al.Inhibition of Dll4signallinginhibits tumour growth by deregulating angiogenesis.Nature.2006;444:1083–7.22.Li JL,Sainson RC,Shi W,et al.Delta-like4Notch ligand reg-ulates tumor angiogenesis,improves tumor vascular function,and promotes tumor growth in vivo.Cancer Res.2007;67:11244–53.23.Li JL,Sainson RC,Oon CE,et al.DLL4-Notch signalingmediates tumor resistance to anti-VEGF therapy in vivo.Cancer Res.2011;71:6073–83.24.Martinez JC,Muller MM,Turley H,et al.Nuclear and membraneexpression of the angiogenesis regulator delta-like ligand4 (DLL4)in normal and malignant human tissues.Histopathology.2009;54:598–606.25.Schadler KL,Zweidler-McKay PA,et al.Delta-like ligand4plays a critical role in pericyte/vascular smooth muscle cell for-mation during vasculogenesis and tumor vessel expansion in Ewing’s sarcoma.Clin Cancer Res.2010;16:848–56.Med Oncol(2013)30:390Page9of10。
血浆纤维蛋白原与胃癌相关性的研究进展
·综述·血浆纤维蛋白原与胃癌相关性的研究进展朱阿颖 靖大道 【摘要】 血浆纤维蛋白原（Ｆｉｂ）是一种由肝细胞合成并分泌的，与凝血、抗凝和纤溶系统相关的急性时相蛋白，其在血浆中高表达会导致体内凝血系统失衡。
胃癌是消化道常见的恶性肿瘤，近年来研究发现，Ｆｉｂ的表达水平与胃癌的发生、发展密切相关。
研究表明，与胃良性病变相比较，胃癌患者Ｆｉｂ表达水平显著升高，且与胃癌分期呈正相关。
血浆Ｆｉｂ在评估胃癌预后方面也具有重要意义，其作为胃癌诊断和预后预测指标之一，已成为近年来的研究热点。
【关键词】 血浆纤维蛋白原；胃癌；预后ＤＯＩ：１０．３９６９／ｊ．ｉｓｓｎ．１６７３ ５３４Ｘ．２０２１．０１．００４ 作者单位：２０００８０ 南京医科大学附属上海一院临床医学院 通信作者：靖大道，Ｅｍａｉｌ：ｄａｄａｏｊｉｎｇ＠１２６．ｃｏｍ 胃癌是一种常见的恶性肿瘤，据全球范围统计，其发病率和病死率分别居恶性肿瘤的第５位和第３位［１］。
中国每年约新发４０万例胃癌，发病率居恶性肿瘤的第２位，病死率居第３位［２］。
在１８４７年，血浆纤维蛋白原（Ｆｉｂ）由德国病理学家ＲｕｄｏｌｆＶｉｒｃｈｏｗ最早命名，是凝血过程中的中心蛋白。
近年来研究发现，Ｆｉｂ不仅与凝血、妊娠、糖尿病和高血压等相关，还与多种恶性肿瘤的诊断和预后有一定关系，如胃癌［３］、非小细胞肺癌［４ ５］、肝细胞癌［６］、胰腺癌［７］、喉鳞癌［８］和结直肠癌［９］等［１０ １２］。
有研究表明，术前Ｆｉｂ水平可在一定程度上预测胃癌患者的预后，有望为经手术治疗及化学治疗的患者提供进一步的诊疗方向［１３］。
本文就Ｆｉｂ与胃癌的发生、发展之间的关系作一简要综述。
１ 犉犻犫的结构与功能Ｆｉｂ是相对分子质量为３４００００的可溶性大分子糖蛋白，其半衰期为３～５ｄ，在血浆中的表达水平通常为２．０～４．０ｇ／Ｌ［１４］。
人体中约７５％的Ｆｉｂ存在于血浆中，其余分布在血小板、淋巴液和组织液中。
molecularmarker分子标记
分子标记的特点：
（1）直接以DNA的形式表现，表现稳定 （2）数量多 （3）多态性高 （4）表现为中性，不影响目标性状的表达； （5）许多标记表现为共显性的特点，能区别
纯合体和杂合体。 （6）成本不太高
molecularmarker分子标记
RFLP标记
植物基因组DNA上的 碱基替换、插入、缺失 或重复等，造成某种限 制性内切酶酶切位点的 增加或丧失，从而产生 限制性片断长度多态 性。
分子标记及辅助育种技术
molecularmarker分子标记
分子标记的类型：
第一类是以分子杂交为核心的分子标记技术，包 括RFLP、DNA指纹技术等； 第二类是以PCR为核心的分子标记技术，包括 RAPD、简单序列重复标记SSR、ห้องสมุดไป่ตู้标位STS、 序列特征化扩增区域SCAR等； 第三类是一些新型的分子标记，如：SNP标记、 表达序列标签EST标记等。
利 用
MAS 的 遗 传 基 础 （以
RFLP 为 例）
MM类型的分子标记所代表的目标基 因mol型ecu及larm其arke频r分率子标记
选择的正确率随 重组率的增加而 迅速下降。重组 值越小，其错选 率越低。
如果要求至少选到 一株目标基因型的 概率为P，则必须选 择具有标记基因型 MM的植株至少为：
RAPD引物扩增电泳检测结果
molecularmarker分子标记
RAPD标记的主要特点：
（1）不需DNA探针，引物设计无须知道序列信息； （2）显性遗传（极少数共显性），不能鉴别杂合子
和纯合子； （3）技术简便，不涉及分子杂交和放射性自显影等
技术； （4）样品需要量少，引物价格便宜，成本较低； （5）实验重复性较差，结果可靠性较低。
%96%b0%e5%88%86%e7%b1%bb%e6%80%9d%e8%b7%af%e5%8f%8a%e7%9b%ae%e6%a0%87%e5%88%86%e5%ad%90%e6%a0%87%e8%
文献标志码：A
论文编号：2009-2374
Two Novel Classifications on Molecular Marker Techniques and Proposal of Targeted Molecular Marker Technique
Xiong Faqian1,2,3, Jiang Jing1, Zhong Ruichun1, Han Zhuqiang1, He Liangqiong1, Li Zhong1, Zhuang Weijian4, Tang Ronghua1,3
(1Cash Crops Research Institute, Guangxi Academy of Agricultural Sciences, Nanning 530007; 2College of Life Science, Fujian Agriculture and Forestry University, Fuzhou 350002;
随机 DNA 分子标记（RDMs）基于基因组中随机 多态性位点开发而成，目的基因标记（GTMs）基于基 因与基因之间的多态性开发而成，而功能性分子标记 （FMs）基于功能基因基序（motif）中功能性单核苷酸 多态性（SNP）位点开发而成。RDMs 与 GTMs 的开发 可以不依赖于表型，而基于功能基因基序中单核苷酸 多态性位点开发而来的 FMs 则与表型直接相关 。 [12-15] 目标分子标记技术是一大类新产生的新型分子标记技 术，在随机分子标记技术基础上增加了对 DNA/cDNA
表 1 目标分子标记技术的代表种类
目标分子标记技术类型 分子标记方法的提出原始参考文献
摘 要：简述了应用广泛的几种常用分子标记技术 RFLP、RAPD、SSR、ISSR、AFLP 的优缺点，以及对这
胰岛素样生长因子Ⅱ mRNA结合蛋白—3(IMP3)在妇科肿瘤中的应用
胰岛素样生长因子Ⅱ mRNA结合蛋白—3(IMP3)在妇科肿瘤中的应用聂佳;章丽霞;刘钧【摘要】胰岛素样生长因子Ⅱ mRNA结合蛋白3(insulin-like growth factor Ⅱ mRNA binding protein 3,1MP3或IGF2 BP3或KH-domain containing protein,KOC,又名L523S)是胰岛素样生长因子RNA结合蛋白家族中的一员,主要表达于发育中的胚胎上皮组织、肌肉和胎盘中,但随着组织分化成熟,表达逐渐下降,在成人组织中仅有极微量的表达.近来研究发现,IMP3在多种恶性肿瘤中表达升高,且与其恶性程度、浸润、转移、预后等密切相关,可能是恶性上皮性肿瘤的生物标志物.本文就目前IMP3在妇科肿瘤的研究进展作一综述.【期刊名称】《川北医学院学报》【年(卷),期】2014(029)006【总页数】5页(P635-639)【关键词】IMP3;妇科肿瘤【作者】聂佳;章丽霞;刘钧【作者单位】川北医学院病理教研室;川北医学院法医学系,四川南充637000;川北医学院病理教研室【正文语种】中文【中图分类】R737.3分子标记物是肿瘤诊断的一个重要依据，尤其是免疫组化技术的成熟，将新型分子标记物的发现与研究炙热化。
随着IMP3的发现与克隆，其在基因及蛋白层面的研究成为肿瘤领域的一个热点。
近年来发现IMP3在多种恶性肿瘤中表达，并可能参与判断肿瘤的恶性程度及预后。
目前的研究主要集中在IMP3的表达特异性、作用机制，本文就IMP3在子宫颈癌、卵巢癌、子宫内膜癌等妇科恶性肿瘤中的进展做一归纳，以期为IMP3的后续研究起一个总结指引作用。
1 IMP3结构与功能胰岛素样生长因子Ⅱ mRNA 结合蛋白3(insulin-like growth factor Ⅱ mRNA binding protein 3，IMP3或IGF2BP3或KH-domain containing protein，KOC，又名L523S，)是高度保守VICKZ(Vg1 RBP/Vera，IMP-1，2，3，CRD-BP，KOC，ZBP-1)家族中的一员[1]，1997年克隆出该基因。
小学上册第11次英语第5单元期末试卷
小学上册英语第5单元期末试卷英语试题一、综合题(本题有100小题，每小题1分，共100分.每小题不选、错误，均不给分)1.What is the name of Harry Potter's school?A. HogwartsB. DurmstrangC. BeauxbatonsD. IlvermornyA2.The bear forages for _____ food in the forest.3.ts have a ______ (独特的) appearance. Some pla4.What do you call a person who plays music?A. ArtistB. MusicianC. DancerD. Singer5.What do we call a person who helps sick people?A. TeacherB. NurseC. EngineerD. Chef6.The ______ produces oxygen for us.7.The phase change from gas to liquid is called ______.8.What is the capital of China?A. ShanghaiB. BeijingC. Hong KongD. TaipeiB9.The _______ (The Scientific Method) transformed science and experimentation.10.The flowers are ________ in the vase.11.What do you call the event where people come together to watch a sports game?A. MatchB. GameC. EventD. CompetitionA12.The __________ is a region known for its societal structures.13. _______ (很好). She want14. A ladybug brings ________________ (好运).15.What is the name of the famous ship that brought the Pilgrims to America?A. MayflowerB. Santa MariaC. TitanicD. PintaA16.Which animal is known for building dams?A. BeaverB. OtterC. FoxD. BearA17.What is the main language spoken in Spain?A. EnglishB. SpanishC. FrenchD. GermanB18.Which animal is known for its ability to change colors?A. ChameleonB. OwlC. EagleD. PenguinA19.My brother plays the ____ (keyboard) in a band.20.The ancient Egyptians believed in many ________ gods.21.What do we call a young bear?A. CubB. KidC. PupD. Calf22.How many days are there in a week?A. 5B. 6C. 7D. 8C23.The chemical formula for calcium phosphate is ______.24.What is the smallest planet in our solar system?A. MarsB. VenusC. MercuryD. Earth25. A ____ enjoys basking in the sun on warm days.26.What is the main language spoken in the UK?A. SpanishB. FrenchC. EnglishD. German27.The cake is ___. (round)28. A plant's ______ (生长速度) can be influenced by sunlight.29.What do you call a scientist who studies rocks?A. GeologistB. BiologistC. ChemistD. PhysicistA30.What do we call the outer layer of the Earth?A. CoreB. MantleC. CrustD. Inner coreC31.The __________ (英法百年战争) lasted from 1337 to 1453.32.I help my parents _______ the house.33.We have a picnic in the ________.34.road network) connects different locations. The ____35.The kitten likes to chase its own ______ (尾巴). It is very ______ (搞笑).36.Frogs start as ______ (蝌蚪) before they become adults.37. A ______ is a type of fish that can change color.38.The __________ (文化交流) fosters understanding and cooperation.39.My sister is learning to _______ (动词). 她想要 _______ (动词).40.An exothermic reaction releases ______.41.What do we call the process of keeping food cold?A. RefrigerationB. BoilingC. CookingD. Frying42.What is the name of the sweet food made from sugar and eggs?A. MeringueB. CandyC. CakeD. PieA43. A _______ is a tool that helps to measure the speed of a moving object.44.Rust forms when iron reacts with _______.45.What do we call the study of the mind and behavior?A. SociologyB. PsychologyC. AnthropologyD. PhilosophyB46.We have a ______ (garden) behind our house.47.Which animal is known for its slow movement?A. RabbitB. SlothC. CheetahD. DeerB48.What is the name of the fairy tale with a glass slipper?A. Snow WhiteB. CinderellaC. Sleeping BeautyD. Little Red Riding Hood49.The apple is ______ and juicy. (red)50. A _______ is used to measure the density of a liquid.51.__________ is the capital city of France. (巴黎)52.The ancient __________ (罗马帝国) was known for its architecture.53.ts are known for their ability to produce ______ and attract beneficial insects. (某些植物因其能产生花蜜而著称，吸引有益昆虫。
急性冠脉综合征患者血浆中 NT-proBNP 和hs-CRP联合检测的应用价值
急性冠脉综合征患者血浆中 NT-proBNP 和hs-CRP联合检测的应用价值葛多英;张伦军;朱安有;何娟娟;陶健;李卫鹏【摘要】目的：检测急性冠脉综合征（ACS）患者血浆中氨基末端钠尿肽前体（NT-proBNP）和超敏CRP（hs-CRP）含量水平，以探讨其在ACS诊断及预后评估中的应用价值。
方法将126例ACS患者作为观察组，58例健康体检者作为对照组；用放射免疫分析法和vitros ECi免疫发光法同时检测2组样本血浆中的hs-CRP和NT-proBNP含量水平，并采用t检验比较2组的x珋±s差异有无显著性，对NT-proBNP与hs-CRP水平关系运用Pearson相关性分析。
结果ACS 患者组血浆中的NT-proBNP和hs-CRP含量水平均显著高于对照组（P＜0．01），对NT-proBNP与hs-CRP浓度水平关系运用Pearson相关性分析，结果表明二者呈显著正相关（P＜0．05）。
结论联合检测血浆中的NT-proBNP 和hs-CRP含量水平，对ACS的诊断和预后评估具有较重要的价值。
%Objective To investigate the levels of N-Terminal proB-Type natriuretic peptide ( NT-proBNP) and high-sen-sitivity C-reactive protein (hs-CRP) in plasma of patients with acute coronary syndrome (ACS),and to explore the clinical meanings.Methods 126 ACS patients were set as an observationgroup ,and 58 healthy adults as a control group .Radiation immunity analysis method and vitros ECi immune luminescence detection were applied simultaneously to detect the hs -CRP and the NT-proBNP levels in plasma of t wo sets of samples;x±s of the two groups were calculated respectively by using t test to compare differences .Pearson correlation analysis was conducted to analyze the relationship between the NT -proBNP and hs-CRP levels.Results In comparison with the normalcontrols ,the levels of NT-proBNP and hs-CRP were higher in ACS pa-tients.The difference was significant(P<0.01).The level of NT-proBNP was positively correlated with that of hs-CRP(P<0.05).Conclusion Combined detection of plasma levels of NT-proBNP and hs-CRP is of clinical value for the diagnosis and prognosis of ACS .【期刊名称】《淮海医药》【年(卷),期】2014(000)004【总页数】3页(P323-324,325)【关键词】急性冠脉综合征;氨基末端脑钠肽前体;超敏CRP【作者】葛多英;张伦军;朱安有;何娟娟;陶健;李卫鹏【作者单位】蚌埠医学院第一附属医院检验科，安徽蚌埠 233004;蚌埠医学院第一附属医院核医学科，安徽蚌埠 233004;蚌埠医学院第一附属医院核医学科，安徽蚌埠 233004;蚌埠医学院第一附属医院核医学科，安徽蚌埠 233004;蚌埠医学院第一附属医院核医学科，安徽蚌埠233004;蚌埠医学院第一附属医院核医学科，安徽蚌埠 233004【正文语种】中文【中图分类】R541.4冠心病是一类常见多发的心血管疾病,严重危害着人类健康。
IMP3在原发性消化系统肿瘤中的作用
IMP3在原发性消化系统肿瘤中的作用高园园【摘要】胰岛素样生长因子Ⅱ mRNA结合蛋白3(IMP3)是最新发现的一种mRNA结合蛋白,在正常成年人体内的表达与肿瘤的发生、发展密切相关.在原发性消化系统肿瘤中,IMP3蛋白通过与多种促肿瘤转移因子的mRNA相结合,促进这些因子的表达,从而促进肿瘤的转移.近几年的研究结果表明,在胰腺癌、肝癌、结肠癌等多种肿瘤中IMP3蛋白的表达明显升高,而在良性肿瘤中几乎不表达,因此其可作为多种恶性肿瘤诊断和预后判断的分子标志物.【期刊名称】《医学综述》【年(卷),期】2013(019)017【总页数】3页(P3089-3091)【关键词】胰岛素样生长因子ⅡmRNA结合蛋白3;消化系统;肿瘤【作者】高园园【作者单位】南京医科大学第一附属医院肝脏外科,南京,210029【正文语种】中文【中图分类】R602胰岛素样生长因子Ⅱ mRNA结合蛋白3(insulin-like growth factorⅡ mRNA binding protein 3，IMP3)是一种具有高度保守性的mRNA结合蛋白，在正常的成人体内通常检测不出，但在胚胎期水平较高，对胚胎的发育有一定的促进作用。
病理状态下，IMP3表达与原发性消化道肿瘤、肺癌、肾癌、恶性间皮瘤等相关，并且提示远处癌转移的可能性和不良的预后。
虽然IMP3在肿瘤发展、浸润、转移方面的具体机制不是很明确，但近年来IMP3在临床实践中已经作为一种新肿瘤标志物，用于鉴别肿瘤的良恶性，且对后续治疗和肿瘤的预后有着高度的指导意义，因此其临床应用广受关注。
该文就近年来关于IMP3在原发性消化道肿瘤发生、发展中的作用研究进展予以综述。
1 IMP3的结构、分布和调节机制1.1 IMP3的结构编码 IMP3的基因位于人类第7号染色体短臂第1区第1条带的第2个亚带，同属KOC(K homology domain containing protein overexpressed in cancer)基因，该基因含有250 bp的5'-UTR非编码区、一个1740 bp开放阅读区和一个 2168 bp的 3'-UTR。
心血管疾病患者脑钠肽的表达
心血管疾病患者脑钠肽的表达张勇【摘要】脑钠肽水平的提高与心力衰竭的发展相关.大量临床实践表明,脑肽钠可作心力衰竭、心肌缺血、心脏肥厚、冠状动脉粥样硬化等病症的预后指标,脑钠肽浓度的轻度升高亦可对心血管疾病起到预后作用.%The increasing of brain natriuretic peptide level is related with the development of heart failure.Plenty of clinical practice show that brain natriuretic peptide can be used for heart failure, myocardiai ischemia, cardiac hypertrophy,coronary atherosclerosis and other diseases as the prognostic index, the slightly elevated concentration of brain nattriuretic peptide may also play a prognostic role in the cardiovascular disease.【期刊名称】《中国医药导报》【年(卷),期】2011(008)023【总页数】2页(P14-15)【关键词】脑钠肽;心血管疾病;预后;诊断【作者】张勇【作者单位】广东省深圳市观澜人民医院检验科,广东深圳,518110【正文语种】中文【中图分类】R779.6脑钠肽（brain natriuretic peptide，BNP）为利钠肽家族系神经激素。
BNP对于心血管疾病（如心力衰竭、心室肥厚、高血压、心肌梗死等）有诊断、治疗与判断预后的价值。
BNP的全面研究，将给心血管疾病的诊断与治疗打开新的通路。
1 BNP的生理作用来自于心脏的BNP与利钠肽（ANP），序列与作用强度皆极相似，血浆BNP水平浓度的高低会直接影响血管的舒张，并且对钠有促进作用，可通过利尿对身体的水分进行调节，并可稳定血压，维持体内环境稳定。
如何做好细胞克隆形成
如何做好细胞克隆形成(⼀) 实验⽬的通过细胞在细胞培养板上的克隆形成能⼒来提⽰细胞的增殖能⼒。
(⼆) 实验原理克隆形成是测定细胞增殖能⼒的有效⽅法之⼀。
单个细胞在体外持续6代以上，其后代所组成的细胞群称为克隆。
这时每个克隆含有50个以上的细胞，⼤⼩在0.3-1.0 mm之间，通过计数克隆形成率，可对单个细胞的增殖潜⼒做定量分析，了解细胞的增殖能⼒和独⽴⽣存能⼒。
(三) 实验流程(四) 实验材料⽣物安全柜、荧光显微镜、离⼼机、倒置显微镜、CO2培养箱；完全培养基、胰酶、PBS、结晶紫、4%多聚甲醛(五) 实验步骤1. 准备感染后细胞[如果是克隆形成预实验，直接⽤空细胞进⾏实验] ：将处于对数⽣长期的各实验组细胞胰酶消化，完全培养基重悬，制成细胞悬液，计数。
吸弃培养基PBS清洗加⼊胰酶终⽌消化收集细胞离⼼获取沉淀细胞计数2. 细胞接种：于6孔板培养板中各实验组接种500-1000个细胞/孔[正常增殖速度为1:5-1:10传代，3天长满细胞，可以接种500个细胞，其余增殖缓慢细胞，可以接种800-1000；接种时注意梯度稀释细胞悬液，观察细胞密度，以免因计数不准确导致实验结果偏差] ，每个实验组设3个复孔，培养基为含30%FBS的完全培养基；铺板铺板后摇匀3. 将接种好的细胞摇匀后轻放于培养箱中继续培养，每隔3 天进⾏换液并观察细胞状态，显微镜下观察克隆⼤⼩[3复孔之间克隆⼤⼩应相似] ，待单个克隆⽣长到⼤⼩不超过图⽚视野时可以进⾏拍照；4. 拍完照之后的将6孔板放⼊培养箱中继续培养，待孔中⼤多数单个克隆中细胞数⼤于50为⽌，弃上清，PBS洗涤细胞1次。
铺板后第三天铺板后第六天铺板后第九天5. 每孔加⼊1 mL 4%多聚甲醛[有毒，注意在安全柜中操作] ，4度冰箱固定细胞60min，PBS洗涤细胞1次。
6. 每孔加⼊洁净、⽆杂质结晶紫染液1000 µL，染细胞2min。
7. ddH2O洗涤细胞数次，晾⼲，数码相机拍照整，克隆计数。
LTBP蛋白功能探讨
•综述•LTBP蛋白功能探讨王文娟马海芬*• 764 •浙江临床医学2021年5月第23卷第5期潜在转化生长因子P结合蛋白（LTBP)家族是细胞外 基质（EC M)的重要组成成分，其主要功能与调节原纤蛋白、转化生长因子P(TGF-p )相关，不同种类的LTBP蛋白功能不完全相同，其中LTBP2蛋白功能侧重于原纤蛋白的调节，而LTBP4则集中于TGF-p1的调节，因此所造成的疾病也 有较大不同。
本文主要介绍LTBP家族的分类、结构、功能，并分別介绍LTBP2与LTBP4缺陷所诱发疾病的不同，现综述如下。
1L T B P蛋白的分类、结构与功能ECM是由大分子构成的错综复杂的网络，为细胞的生存 及活动提供适宜的场所，并通过信号转导系统影响细胞的形 状、代谢、功能、迁移、增殖和分化。
TGF-P作为转化生长 因子超家族一员，有多种功能，促进ECM如胶原蛋白、纤粘连蛋白的表达和抑制ECM的降解，对细胞的形态发生、增殖和分化过程起重要作用，有利于胚胎发育和细胞修复。
ITBP家族是ECM的重要组成成分，蛋白分子量介于120-220 kDa11 ITBP蛋白均具有钙结合表皮生长因子（EGF)结构域、8胱氨酸重复单位（8-C yS)结构域，对于8-C yS结构域而言，目前具有同样结构域的蛋白仅为原纤蛋白，相对于原纤蛋内，LTBP蛋白的长度更短且具有较多未知序列，可能与蛋白的延 展性密切相关12L LTBP的功能主要包括:（1 )与原纤蛋A的结合从而调控ECM;(2 )通过与TGF- p的结合影响TGF- p 的激活。
在与原纤蛋白的结合中，目前已知的LTBP蛋闩包括 LTBP1-4四种，四种蛋白的C-段序列均被证实能够与原纤 蛋白_1的N端序列相互作用，与此同时在各种组织中LTBP 蛋白均与原纤蛋白-1共定位，在原纤蛋白1缺失的小鼠中，LTBP蛋白的定位受到影响，除此之外LTBP也能够与其它的 细胞外基质组分如纤维连接蛋白（fibronectin)、Fihulin等结合因此LTBP的部分功能被认为是纤维蛋白与细胞外基 质其余组分的连接蛋A(4],而部分的研究也集中于LTBP与老化、增生、弹性纤维的联系。
血清降钙素原对经皮肾镜碎石术后尿脓毒血症的早期诊断价值
血清降钙素原对经皮肾镜碎石术后尿脓毒血症的早期诊断价值徐灵玲;曾章锐;郭婧澜;常欧;邓青富;刘靳波【摘要】目的：探讨血清降钙素原( PCT)对经皮肾镜碎石术后尿脓毒血症的早期诊断价值。
方法回顾性分析185例因上尿路结石并泌尿道感染行经皮肾镜碎石术患者临床资料。
其中术后并发尿脓毒血症(观察组)94例,术后未并发尿脓毒血症(对照组)91例。
检测两组术前及术后24 h血清PCT、CRP和WBC计数。
受试工作特征曲线( ROC)评价血清PCT对经皮肾镜碎石术后尿脓毒血症的早期诊断价值。
结果两组术前血清PCT、WBC计数比较P均>0.05,CRP比较P<0.05；与术前比较,观察组术后24 h血清PCT水平升高(P<0.05),CRP、WBC计数差异无统计学意义(P均>0.05)。
血清PCT诊断经皮肾镜碎石术后尿脓毒血症的ROC曲线下面积为0.872(95%CI：0.632~0.975)；血清PCT诊断尿脓毒血症的敏感度为90.24%,特异度为82.57%,阳性预测值为81.35%,阴性预测值为88.37%。
结论血清PCT 可作为早期诊断经皮肾镜碎石术后尿脓毒血症的可靠预测指标。
【期刊名称】《山东医药》【年(卷),期】2016(000)004【总页数】2页(P49-50)【关键词】尿脓毒血症;降钙素原;经皮肾镜碎石术;C反应蛋白;白细胞计数【作者】徐灵玲;曾章锐;郭婧澜;常欧;邓青富;刘靳波【作者单位】泸州医学院附属医院，四川泸州646000;泸州医学院附属医院，四川泸州646000;泸州医学院附属医院，四川泸州646000;泸州医学院附属医院，四川泸州646000;泸州医学院附属医院，四川泸州646000;泸州医学院附属医院，四川泸州646000【正文语种】中文【中图分类】R631.2尿源性脓毒血症(尿脓毒血症)是经皮肾镜碎石术的严重并发症之一。
上尿路结石合并泌尿道感染行手术治疗后发生尿脓毒血症是临床上处理棘手的问题，如何尽早诊断尿脓毒血症，并进行早期干预至关重要 [1~3]。
EB病毒DNA及鼻咽癌治疗预后之相关联性
苏彦烨
Outline
? Introduction of nasopharynx
? Introduction of nasopharyngeal carcinoma (NPC)
meat - dimethylnitrosamines)
Normal
NPC
Symptoms and Fra bibliotekigns? Neck mass ? Ear fullness and hearing impairment ? (middle ear effusion) ? Blood tingled sputum ? Nasal obstruction ? Headache ? Diplopia
? This study provide convincing evidence for the use of plasma EBV DNA measurements for the early diagnosis and staging of NPC a well as for monitoring recurrence and metastasis of this tumor
?
Shao JY. et al. Cancer 2004
EBV DNA level and distant metastasis
Conclusion --EBV DNA level was highly related to
distant metastasis Close monitoring EBV DNA level could
尿液中PCA3评分对前列腺癌早期诊断的临床意义
尿液中PCA3评分对前列腺癌早期诊断的临床意义杨帮东;姜行康;齐灿;李海波;刘冉录;杨阔;乔宝民;张志宏;徐勇【摘要】目的:探讨不同尿液中前列腺癌基因3 (PCA3)评分的截断值对可疑前列腺癌患者诊断的应用价值.方法:纳入123例因血清总前列腺特异性抗原(t-PSA)升高和(或)直肠指诊(DRE)异常住院的患者,采集前列腺按摩后的初始尿液标本,使用实时定量PCR检测尿沉渣中PSA及PCA3 mRNA的表达,测定穿刺前尿样PCA3的评分.结合穿刺的病理结果分析不同尿PCA3评分的截断值对诊断前列腺癌的敏感性和特异性(阳性预测和阴性预测).结果:经穿刺病理结果证实前列腺癌32例,前列腺良性增生91例.当取PCA3评分截断值为35时,可避免52.7％(48例)的患者进行不必要的穿刺,8.8％(8例)的患者被漏诊(被漏诊的患者均是低危前列腺癌);当取PCA3评分截断值为50时,可避免72.5％(66例)的患者进行不必要的穿刺,但13.2％(12例)的患者被漏诊,且2例(16.7％)是中高危前列腺癌.结论:检测可疑前列腺癌患者尿液中PCA3评分可减少不必要的穿刺,且取截断值为35时可获得较高的诊断价值.【期刊名称】《天津医科大学学报》【年(卷),期】2013(019)006【总页数】3页(P487-489)【关键词】前列腺癌;前列腺癌基因3;尿前列腺癌基因3评分;穿刺活检【作者】杨帮东;姜行康;齐灿;李海波;刘冉录;杨阔;乔宝民;张志宏;徐勇【作者单位】天津医科大学第二医院泌尿外科,天津市泌尿外科研究所,天津300211;天津医科大学第二医院泌尿外科,天津市泌尿外科研究所,天津300211;天津医科大学第二医院泌尿外科,天津市泌尿外科研究所,天津300211;天津医科大学第二医院泌尿外科,天津市泌尿外科研究所,天津300211;天津医科大学第二医院泌尿外科,天津市泌尿外科研究所,天津300211;天津医科大学第二医院泌尿外科,天津市泌尿外科研究所,天津300211;天津医科大学第二医院泌尿外科,天津市泌尿外科研究所,天津300211;天津医科大学第二医院泌尿外科,天津市泌尿外科研究所,天津300211;天津医科大学第二医院泌尿外科,天津市泌尿外科研究所,天津300211【正文语种】中文【中图分类】R737.25前列腺癌（prostate cancer，PCa）是老年男性泌尿生殖系统中常见的恶性肿瘤之一。
甲胎蛋白的相关认识
甲胎蛋白的相关认识标签：甲胎蛋白；肝细胞癌；慢性乙肝预后；综述甲胎蛋白（alpha fetoprotein，AFP）是在胎儿早期由肝脏合成的一种糖蛋白，早在50多年前Halbrecht等[1]就有关于AFP是胎儿发育早期由肝脏和卵黄囊合成的一种血清糖蛋白的报到。
在临床中常用于诊断肝细胞癌（hepatocellular carcinoma，HCC）及判断慢性乙肝（chronic hepatitis B，CHB）的预后。
随着科学技术的不断进步及临床研究的不断深入，对于AFP的相关认识也在不断发展。
综合临床有关研究认识如下。
1 AFP生成的相关认识AFP是胚胎特异的血清a-球蛋白，分子量68 kpa，基因定位于4号染色体的长臂11～12区，其调控的区域包括有：启动子（promoter），沉寂子（silencer）及增强子（enhancer）[2]。
郭兰生等[3]研究认为AFP是内胚层源性细胞幼稚期的产物，是机体的内胚层源性组织在胚胎形成过程中，由实体细胞早期发育阶段产生并分泌。
也有学者认为AFP可能起源于祖肝细胞和卵圆细胞，他们研究发现AFP常在干细胞肿瘤和肝母细胞瘤表达，通常在肝细胞癌和新生儿时期AFP 可表达出较高水平[4]。
在人出生后3个月开始，随着干细胞表达的下降，血清中AFP的水平也逐渐降低，到出生后的第二年接近于成人水平。
正常成人肝细胞失去合成AFP的能力，故而正常成人血中AFP含量会维持在一个较低的水平。
当肝细胞恶变后，可能是因为肝癌细胞基因启动肝细胞的原始生长因子，机体重新获得合成AFP的能力，在肝癌细胞大量增生的过程中，同时释放出AFP，使血清中AFP的含量也不断地升高[5]。
因此，在正常成人血清中如出现AFP水平升高，则可能是机体生长代谢出现异常的反应。
2 AFP的生理功能2.1 转运功能AFP是由591个氨基酸构成的糖蛋白，属于类白蛋白一族[6]。
相似的物质结构决定其有类似于蛋白质的运输功能，其转运功能表现为可以结合及运送许多有关配体[7]。
趋化素样因子超家族成员5研究进展
趋化素样因子超家族成员5研究进展袁也晴;萧云备;刘振华;张晓威;徐涛;王晓峰【摘要】趋化素样因子超家族(CMTM)是北京大学人类疾病基因研究中心在国际上首次报道的新基因家族,CMTM5是该家族成员,其基因编码产物具有潜在的四次跨膜蛋白结构,是一个新的肿瘤抑制基因.研究表明,CMTM5广泛表达于人类正常组织,在大多数肿瘤细胞系和组织中表达明显下调或不表达,恢复其表达可抑制肿瘤细胞的增殖、黏附和迁移等生物行为.CMTM5抗肿瘤活性的机制尚不明确,可能参与了多个与癌症发生发展密切相关的信号通路.对CMTM5与肿瘤发生发展机制的进一步研究具有重要意义,其有望成为肿瘤基因治疗的新靶标.%CKLF-like MARVEL transmembrane domain containing member (CMTM) is a novel generic family firstly reported by Peking University Center for Human Disease Genomics. CMTM5 belongs to this family and has exhibited tumor-inhibiting activities. It can encode proteins approaching to the transmembrane 4 superfamily (TM4SF). CMTM5 is broadly expressed in normal adult and fetal human tissues, but is undetect-able or down-regulated in most carcinoma cell lines and tissues. Restoration of CMTM5 may inhibit the proliferation , migration, and invasion of carcinoma cells. Although the exact mechanism of its anti-tumor activity remains unclear, CMTM5 may be involved in various signaling pathways governing the occurrence and development of tumors. CMTM5 may be a new target in the gene therapies for tumors, while further studies on CMTM5 and its anti-tumor mechanisms are warranted.【期刊名称】《中国医学科学院学报》【年(卷),期】2012(034)006【总页数】4页(P625-628)【关键词】趋化素样因子超家族成员5;四次跨膜蛋白超家族;肿瘤抑制基因【作者】袁也晴;萧云备;刘振华;张晓威;徐涛;王晓峰【作者单位】北京大学人民医院泌尿外科,北京100044;北京大学人民医院泌尿外科,北京100044;北京大学人民医院泌尿外科,北京100044;北京大学人民医院泌尿外科,北京100044;北京大学人民医院泌尿外科,北京100044;北京大学人民医院泌尿外科,北京100044【正文语种】中文【中图分类】R73-34趋化素样因子超家族 (CKLF-like MARVEL transmembrane domain containing member，CMTM，or chemokine-like factor super family，CKLFSF)是我国在国际上首次报道的新基因家族，由9个基因:趋化素样因子 (chemokine-like factor，CKLF)和 CMTM 1～8组成。
人血清高尔基体蛋白-73与HBV相关肝病的研究的开题报告
人血清高尔基体蛋白-73与HBV相关肝病的研究的开题报告题目：人血清高尔基体蛋白-73与HBV相关肝病的研究背景与意义：HBV相关肝病是一种常见的严重传染病，全球约有2亿人感染HBV病毒，其中大约1000万人死亡。
高尔基体蛋白-73（GP73）是一种在人类肝细胞癌组织中高度表达的糖蛋白，其在诊断和监测肝癌方面具有潜在的临床应用价值。
近年来的研究表明，GP73还可能作为HBV相关肝病的生物标记物。
目的：本研究旨在评估GP73在HBV相关肝病的临床应用价值，确定其与HBV相关肝病的关联关系，并探讨其作为肝癌监测的有效性。
研究内容：1. 收集HBV相关肝病患者的临床资料和生物标本，包括血清和肝组织。
2. 通过ELISA分析，检测血清中GP73的表达水平，并比较HBV相关肝病患者与正常对照组的差异。
3. 对肝组织标本进行免疫组织化学染色，评估GP73的表达和定位情况。
4. 分析GP73与HBV相关肝病的相关性，包括HBV感染的不同程度、肝硬化等因素的影响。
5. 初步探讨GP73作为肝癌监测的有效性。
方法：1. 研究对象：纳入确诊为HBV相关肝病的患者和正常对照组，招募50例。
2. 样本收集与储存：收集血清和肝组织标本，进行规范化处理，并进行冷冻保存。
3. ELISA分析：使用商业ELISA试剂盒检测血清中GP73表达水平，按照试剂盒说明书进行操作。
4. 免疫组织化学染色：将肝组织标本进行石蜡包埋、切片、烘干和染色，识别GP73的表达情况。
5. 数据分析：采用统计学方法比较HBV相关肝病患者和正常对照组中GP73表达水平的差异，并初步探讨GP73在肝癌监测中的应用。
预期结果：本研究的预期结果将包括GP73在HBV相关肝病中的表达及定位情况、GP73与HBV相关肝病的相关性以及GP73作为肝癌监测的初步验证结果。
此研究亦将探讨GP73与HBV相关肝病的潜在机制和应用前景。
参考文献：1. Li H, et al. Serum GP73, a marker for evaluating progression in patients with chronic HBV infections. Braz J Med Biol Res.2017;50(10):e6332.2. Sun Y, et al. Elevated serum GP73 level predicts high risk of incidence of hepatocellular carcinoma in patients with chronic hepatitisB virus infection. BMC Gastroenterol. 2018;18(1):70.3. Zhao WJ, et al. GP73 as a novel biomarker for the detection of hepatocellular carcinoma: a meta-analysis. Medicine. 2016;95(7):e3073.4. Liu X, et al. The clinical significance and potential molecular mechanism of GP73 in HBV-related hepatocellular carcinoma. Medicine. 2017;96(44):e8171.。
- 1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
- 2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
- 3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。
Oncofetal Protein IMP3A Novel Molecular Marker That Predicts Metastasis of Papillary and Chromophobe Renal Cell CarcinomasZhong Jiang,MD1Christine M.Lohse,MS2Peigou G.Chu,MD,PhD3Chin-Lee Wu,MD,PhD4Bruce A.Woda,MD1Kenneth L.Rock,MD1Eugene D.Kwon,MD51Department of Pathology,University of Massachu-setts Medical Center,Worcester,Massachusetts.2Division of Biostatistics,Mayo Clinic,Rochester, Minnesota.3Division of Pathology,City of Hope National Medical Center,Los Angeles,California.4Department of Pathology,Massachusetts Gen-eral Hospital,Boston,Massachusetts.5Department of Urology,Mayo Clinic,Rochester, Minnesota.BACKGROUND.Whether an oncofetal protein,IMP3,can serve as a prognostic biomarker to predict metastasis for patients with localized papillary and chromo-phobe subtypes of renal cell carcinomas(RCCs)was investigated. METHODS.The expression of IMP3in334patients with primary papillary and chromophobe RCC from multiple medical centers was evaluated by immunohis-tochemistry.The317patients with localized papillary and chromophobe RCCs were further evaluated for outcome analyses.RESULTS.IMP3was significantly increased in a subset of localized papillary and chromophobe RCCs that subsequently metastasized.Patients with localized IMP3-positive tumors(n533;10%)were over10times more likely to metasta-size(risk ratio[RR],11.38;95%confidence interval[CI], 5.40-23.96;P<.001) and were nearly twice as likely to die(RR,1.91;95%CI,1.13–3.22;P5.016)com-pared with patients with localized IMP3negative tumors.The5-year metastasis-free and overall survival rates were64%and58%for patients with IMP3-positive localized papillary and chromophobe RCCs compared with98%and85%for patients with IMP3negative tumors,respectively.In multivariable analysis adjust-ing for the TNM stage and nuclear grade,patients with IMP3-positive tumors were still over10times more likely to progress to distant metastasis(RR,13.45; 95%CI,6.00–30.14;P<.001)and were still nearly twice as likely die(RR,1.95; 95%CI,1.15–3.31;P5.013)compared with patients with IMP3-negative tumors. CONCLUSIONS.IMP3is an independent prognostic biomarker that can be used to identify a subgroup of patients with localized papillary and chromophobe RCC who are at high risk for developing distant metastasis.Cancer2008;112:2676–82.Ó2008American Cancer Society.KEYWORDS:IMP3,oncofetal protein,mRNA binding protein,prognostic biomarker, papillary renal cell carcinoma,chromophobe renal cell carcinoma.R enal cell carcinoma(RCC)is the most common type of kidney cancer and accounts for about85%of malignant kidney tumors.1,2The incidence of RCC has been rising steadily.3It is expected that about51,190new cases of kidney cancer will be diag-nosed in the US in2007with approximately12,890mortalities.4 There are several subtypes of RCC according to the Union Inter-national Contre le Cancer(UICC)and the American Joint Commit-tee on Cancer(AJCC)recommendations,5originally proposed at the Heidelberg conference.6Of these,the most common subtypes are clear cell or conventional(70%),papillary(10%-15%)and chromo-phobe(5%)RCC.5These subtypes of RCC not only exhibit distinct cytogenetic abnormalities but also affect patient prognosis differ-ently.7-13Clear-cell RCCs are characterized by loss of genetic mate-rial in the chromosome3p.5Fifty percent of clear-cell RCCs showThe authors thank Karen Dresser(University ofMassachusetts Medical Center)for technicalsupport.Address for reprints:Zhong Jiang,MD,Depart-ment of Pathology,Three Biotech,One InnovationDr.,Worcester,MA01605;Fax:(508)793-6110;E-mail:jiangz@,or Eugene D.Kwon,MD,Department of Urology,Mayo Clinic,200FirstSt.Southwest,Rochester,MN55905;Fax:(507)284-4951;E-mail:kwon.eugene@Received November6,2007;revision receivedDecember11,2007;accepted December17,2007.ª2008American Cancer SocietyDOI10.1002/cncr.23484Published online15April2008in Wiley InterScience(). 2676somatic mutations in the von Hippel-Lindau(VHL) gene and an additional10%to20%of these tumors show inactivation of the VHL gene.5Papillary RCCs are characterized by trisomies(chromosomes3q,7, 12,16,17,and20)and loss of the Y chromosome.5 Chromophobe RCCs are characterized by monosomy of multiple chromosomes(1,2,6,10,13,17,and21) and hypodiploidy.5Localized papillary and chromo-phobe RCCs exhibit favorable prognosis with less fre-quent metastasis relative to clear-cell RCCs.7–14 Consequently,relatively little is known about molec-ular expression profiles associated with metastatic progression of papillary and chromophobe tumors compared with clear-cell RCC,which has been the dominant focus of studies reported in the literature.IMP3is a member of the insulin-like growth fac-tor II(IGF-II)mRNA binding protein(IMP)family that consists of IMP1,IMP2,and IMP3.15IMP family members play an important role in RNA trafficking and stabilization,cell growth,and cell migration dur-ing the early stages of embryogenesis.16The IMP3 gene is located on chromosome7p11.217and is iden-tical to the KOC(KH domain containing protein overexpressed in cancer)protein that was originally cloned from a pancreatic tumor cDNA screen.18 IMP3is expressed in developing epithelia,muscle, and placenta during early stages of human and mouse embryogenesis,but it is expressed at low or undetectable levels in adult tissues.15,16The expres-sion of IMP3/KOC is also found in malignant tumors including pancreas,lung,stomach,and colon can-cers,and soft tissue sarcomas but it is not detected in adjacent benign tissues.15,18–20Moreover,recent studies have demonstrated that IMP3is an important protein for tumor cell proliferation and invasion.21,22 These findings indicate that IMP3is an oncofetal protein that may play a critical role in malignant transformation and tumor progression.Recently,we have found that IMP3oncofetal protein is a new bio-marker for aggressive localized RCC.23In addition,a validation study has confirmed that IMP3is an inde-pendent prognostic marker for the clear cell(conven-tional)subtype of RCCs.24In this validation study, 163of629(25.9%)localized clear-cell RCC speci-mens expressed tumor cell IMP3.Patients with loca-lized clear-cell RCC and positive IMP3expression were nearly5times more likely to progress to distant metastasis compared with patients with IMP3-nega-tive tumors(risk ratio[RR]4.71;P<.001).As the pre-dominance of RCCs are of the clear cell subtype,it is unclear whether IMP3plays an important role to predict metastasis for other relatively rare subtypes, such as papillary and chromophobe RCCs.In the current study we investigated the association of IMP3expression with clinicopathologic features and out-come using a multi-institutional cohort of patients with localized papillary and chromophobe RCC sub-types to evaluate whether IMP3could serve as an in-dependent biomarker to predict tumor progression and metastasis.MATERIALS AND METHODSPatient SelectionBy using the combined resources of the Mayo Clinic, the University of Massachusetts Medical Center (UMMC),Massachusetts General Hospital(MGH), and City of Hope National Medical Center(CHNMC) we identified334patients treated with radical ne-phrectomy or nephron-sparing surgery for papillary or chromophobe RCC.The Mayo Clinic patients (n5246)were treated between1990and1999,while the UMMC(n539),MGH(n538),and CHNMC (n511)patients were treated between1989and 2003.There were254(76%)patients with papillary RCC and80(24%)with chromophobe RCC. Clinicopathologic FeaturesThe clinicopathologic features studied included age, sex,histologic subtype classified according to the UICC,AJCC,and Heidelberg guidelines,5,6tumor size,primary tumor classification,regional lymph node involvement,distant metastases,the TNM stage groupings,and nuclear grade.IMP3Immunohistochemical Staining Immunohistochemical studies were performed by the Department of Pathology at UMMC on5-m m sec-tions of formalin-fixed,paraffin-embedded tissue as previously described.20Antigen retrieval was carried out with0.01mol/L citrate buffer at pH6.0in an 800W microwave oven for15minutes before immu-nostaining.The slides were stained on the Dako Autostainer(Dako,Carpentaria,Calif)using the EnVision(Dako)staining reagents.The sections were first blocked for endogenous protein binding and peroxidase activity with an application of Dual Endo-genous Block(Dako)for10minutes,followed by a buffer wash.The sections were then incubated with a mouse monoclonal antibody specific for IMP3 (L523S,Corixa,Seattle,Wash)at a2.0m g/mL concen-tration for30minutes,followed again by a buffer wash.Sections were then incubated with the Envi-sion plus;Dual Link reagent(a polymer conjugated with goat antimouse-Ig and horseradish peroxidase) for30minutes.The sections were then washed and treated with diaminobenzidine(DAB)and hydrogen peroxide,which reacted with the end product.A ton-IMP3,a Prognostic Marker/Jiang et al.2677ing solution (DAB Enhancer,Dako)was used to enrich the final color.The sections were counter-stained with hematoxylin,dehydrated,and cover-slipped with permanent media.Sections of urothelial carcinoma with known positivity of IMP3were used as positive controls for the L523S mouse monoclonal antibody (MoAb)specific for IMP3/KOC (Corixa)staining.Negative control sections were stained by replacing the primary antibody with nonimmune mouse IgG (Vector,Burlingame,Calif)at 2.0m g/mL.IMP3expression was recorded as negative or positive after visual assessment by a genitourinary pathologist (Z.J.)without knowledge of patient out-come.One slide per case for immunohistochemistry was evaluated.Positive staining of IMP3was defined as dark brown cytoplasmic staining pattern in the tu-mor epithelial cells,which can be easily observed at low-power magnification (340).Scant fine granular background staining of epithelial cells,which cannot be seen at low-power magnification,or no staining at all was considered negative.Statistical MethodsAssociations of IMP3expression with clinicopatho-logic features were evaluated using Wilcoxon rank sum,chi-square,and Fisher exact tests.Kaplan-Meier curves were used to observe the associations of IMP3expression with outcome.The magnitudes of these associations were evaluated using Cox proportional hazards regression models and summarized with RRs and 95%confidence intervals (CI).Statistical analyses were performed using the SAS software package (SAS Institute,Cary,NC).All tests were 2-sided and P -values <.05were considered statistically significant.RESULTSIMP3protein was observed to be expressed within the cytoplasm of both papillary as well as chromo-phobe tumor cells (Fig.1).There were 40(12%)pap-illary or chromophobe RCC tumors with positive IMP3expression and 294(88%)with negative parisons of clinicopathologic fea-tures by IMP3expression are summarized in Table1.FIGURE 1.Immunohistochemical stains for IMP3showing that papillary renal cell carcinoma (RCC)(left)and chromophobe RCC (right)were positive for IMP3.TABLE 1Comparison of Clinicopathologic Features by IMP3Tumor Expression for 334Patients With Papillary and Chromophobe RCCFeatureTumor IMP3expressionP Negative n 5294Positive n 540Age at surgery,y,median [range]65[21–89]63[44–80].883Tumor size,cm,median [range] 4.1[0.3–15.0]5.5[0.7–25.0].090No.(%)Sex.929Women 68(23.1)9(22.5)Men226(76.9)31(77.5)RCC histologic subtype .081Papillary228(77.6)26(65.0)Chromophobe66(22.5)14(35.0)2002Primary tumor classification .008pT1213(72.5)21(52.5)pT249(16.7)7(17.5)pT331(10.5)12(30.0)pT41(0.3)0Regional lymph node involvement .003pNX and pN0289(98.3)37(92.5)pN1and pN25(1.7)5(12.5)Distant metastases at presentation .058pM0289(98.3)37(92.5)pM15(1.7)3(7.5)2002TNM stage groupings .002I 211(71.8)21(52.5)II 48(16.3)6(15.0)III 28(9.5)7(17.5)IV7(2.4)6(15.0)Nuclear grade <.00119(3.1)02176(59.9)12(30.0)3103(35.0)19(47.5)46(2.0)9(22.5)RCC indicates renal cell carcinoma.2678CANCER June 15,2008/Volume 112/Number 12Positive IMP3tumor expression was significantly associated with later tumor stage and higher tumor grade.For example,70%of the IMP3-positive tumors were high-grade(ie,grade3or4)compared with only37%of the IMP3-negative tumors(P<.001).There were17patients with papillary or chromo-phobe RCC who had extrarenal disease at nephrec-tomy,including9with regional lymph node involvement,7with distant metastases,and1with both.(Note that7of the17patients with extrarenal disease had IMP3-positive tumors.)As such,associa-tions of IMP3expression with patient outcome were evaluated using the317patients(240papillary and 77chromophobe)with localized disease at nephrec-tomy(ie,pNX/pN0;pM0;primary tumor classifica-tions of pT1,pT2,or pT3).In this subset there were 284(89.6%)papillary or chromophobe RCC tumors with negative IMP3expression and33(10.4%)with positive IMP3expression.Twenty-eight of the317patients with localized disease progressed to distant metastases at a median of3.1years after nephrectomy(range,0-10).Distant metastasis-free survival rates(SE,number still at risk)at5and10years after nephrectomy were94.1% (1.4%,240)and88.3%(2.3%,98),respectively.There was a significant difference in metastasis-free sur-vival between patients with papillary and chromo-phobe RCC(P5.007;log-rank test).Metastasis-free survival rates(SE,number still at risk)at5and10 years after nephrectomy were96.4%(1.2%,192)and 91.6%(2.2%,79),respectively,for patients with papil-lary RCC compared with86.6%(4.2%,48)and77.3%(6.3%,19),respectively,for patients with chromo-phobe RCC.Patients with localized IMP3-positive tumors were over10times more likely to progress to distant metastasis compared with patients with localized IMP3-negative tumors(RR,11.38;95%CI,5.40–23.96; P<.001;Table2).In fact,15(45.5%)of the33 patients with IMP3-positive tumors progressed com-pared with only13(4.6%)of the284patients with IMP3-negative tumors.Metastasis-free survival rates (SE,number still at risk)at5and10years after ne-phrectomy were63.9%(8.8%,17)and48.6%(9.5%, 12),respectively,for patients with IMP3-positive tumors compared with97.7%(0.9%,223)and93.4% (1.9%,86),respectively,for patients with IMP3-nega-tive tumors(Fig.2).In multivariable analysis adjust-ing for primary tumor classification and nuclear grade,patients with IMP3-positive tumors were still over10times more likely to progress compared with patients with IMP3-negative tumors(RR,13.45;95% CI,6.00–30.14;P<.001;Table2).When stratified by histologic subtype,IMP3expression was univariately and significantly associated with progression to dis-tant metastasis among patients with papillary RCC (RR,9.14;95%CI, 3.39-24.64;P<.001)as well as among patients with chromophobe RCC(RR,11.91; 95%CI, 3.58-39.61;P<.001),although there were too few patients who progressed in these subsets to evaluate these associations in a multivariable setting.At last follow-up103patients had died at a me-dian of 4.5years after nephrectomy(range,0–16). Among the214patients who were still alive at lastTABLE2Associations of IMP3Tumor Expression With Outcome for317Patients With Localized Papillary and Chromophobe RCCUnivariateMetastases-Free survival Overall survivalRisk ratio(95%CI)P Risk ratio(95%CI)PIMP3expressionNegative 1.0(reference) 1.0(reference)Positive11.38(5.40–23.96)<.001 1.91(1.13–3.22).016Multivariable2002Primary tumor classificationpT1 1.0(reference) 1.0(reference)pT2 4.38(1.69–11.36).0020.97(0.55–1.68).900pT310.94(4.18–28.68)<.001 2.28(1.29–4.04).005Nuclear grade1and2 1.0(reference) 1.0(reference)3and4 5.30(1.94–14.49).001 1.38(0.93–2.06).112IMP3expressionNegative 1.0(reference) 1.0(reference)Positive13.45(6.00–30.14)<.001 1.95(1.15–3.31).013RCC indicates renal cell carcinoma;CI,confidence interval.IMP3,a Prognostic Marker/Jiang et al.2679follow-up the median duration of follow-up was 8.8years (range,0–16).Overall survival rates (SE,num-ber still at risk)at 5and 10years after nephrectomy were 82.2%(2.2%,240)and 65.4%(3.1%,98),respec-tively.There was not a statistically significant differ-ence in overall survival between patients with localized papillary and chromophobe RCC (P 5.997;log-rank test).In univariate analyses,patients with localized IMP3-positive tumors were nearly twice as likely to die compared with patients with localized IMP3-neg-ative tumors (RR,1.91;95%CI,1.13-3.22;P 5.016;Table 2).Seventeen (51.5%)of the 33patients with IMP3-positive tumors died compared with 86(30.3%)of the 284patients with IMP3-negative tumors.Over-all survival rates (SE,number still at risk)at 5and 10years after nephrectomy were 57.9%(9.0%,17)and 47.1%(9.2%,12),respectively,for patients with IMP3-positive tumors compared with 85.0%(2.2%,223)and 67.4%(3.3%,86),respectively,for patients with IMP3-negative tumors (Fig.3).In multivariable analysis adjusting for primary tumor classification and nuclear grade,patients with IMP3-positive tumors were still nearly twice as likely to die com-pared with patients with IMP3-negative tumors (RR,1.95;95%CI, 1.15-3.31;P 5.013;Table 2).In fact,IMP3status was still significantly associated with death after adjusting for primary tumor classification,nuclear grade,tumor size,and histologic subtype (RR,1.82;95%CI,1.07-3.12;P 5.029).DISCUSSIONPapillary and chromophobe subtypes of RCC encom-pass relatively understudied forms of malignancy in comparison to clear-cell RCC.In this study we demonstrate that expression of IMP3in papillary and chromophobe RCCs can predict tumor metastasis and provide important prognostic information in patients with localized disease who undergo nephrectomy.Currently,surgical resection of a tumor (nephrec-tomy)is the standard of care for almost all patients with RCC.1,2,25After nephrectomy,patients with met-astatic disease typically receive systemic treatment (eg,immunotherapy),which can be associated with potentially significant toxicity.1,2,25As such,to avoid toxicities associated with systemic treatment,watch-ful waiting is the standard of care for patients lacking overt metastases after radical nephrectomy.1,2,25Recently,3new drugs have been used for treatment of patients with metastatic RCC.Sorafenib and suni-tinib,multikinase receptor inhibitors,can block the signaling cascade of the vascular endothelial growth factor (VEGF)2,3,and R1,as well as platelet-derived growth factor (PDGF)that are critical to angiogen-esis.26–29Temsirolimus inhibits the mammalian tar-get of rapamycin complex 1kinase that regulates protein translation and appears to have very promis-ing activity in nonclear-cell RCCs.30However,these new drugs have only been evaluated in patients with clinically metastatic RCC.For localized RCC,patients at high risk for metastasis should be selected for immediate adjuvant therapy trials,yet themeta-FIGURE 3.Association of IMP3tumor expression with death for 317patients with localized papillary and chromophobe renal cell carcinoma (RCC).Overall survival rates (SE,number still at risk)at 5and 10years after nephrectomy were 57.9%(9.0%,17)and 47.1%(9.2%,12),respectively,for patients with IMP3-positive tumors compared with 85.0%(2.2%,223)and 67.4%(3.3%,86),respectively,for patients with IMP3-negativetumors.FIGURE 2.Association of IMP3tumor expression with progression to dis-tant metastases for 317patients with localized papillary and chromophobe renal cell carcinoma (RCC).Metastasis-free survival rates (SE,number still at risk)at 5and 10years after nephrectomy were 63.9%(8.8%,17)and 48.6%(9.5%,12),respectively,for patients with IMP3-positive tumors com-pared with 97.7%(0.9%,223)and 93.5%(1.9%,86),respectively,for patients with IMP3-negative tumors.2680CANCER June 15,2008/Volume 112/Number 12static potential of localized tumors is often unpre-dictable.The literature clearly supports that histologic subtype influences RCC outcomes,and that conven-tional clear-cell RCC and nonclear-cell RCC(chromo-phobe and papillary)exhibit different propensities for metastatic dissemination.7–14Specifically,patients with localized papillary and chromophobe RCCs tend to experience less aggressive disease spread and, thus,have a markedly better prognosis compared with patients with clear-cell RCC.7–14However,as we report in this study,patients with papillary or chro-mophobe RCCs also develop metastasis,albeit rarely. Furthermore,patients with IMP3-positive tumors show significantly higher risk of developing metasta-sis compared with patients with IMP3-negative tumors.In the current study,45%of patients with IMP3-positive tumors developed metastasis com-pared with only4.6%of patients with IMP3-negative tumors.In addition,IMP3status independently pre-dicted metastatic spread in patients with localized papillary and chromophobe RCC;in multivariable analysis,patients with IMP3-positive papillary or chromophobe RCCs were13times more likely to de-velop subsequent metastases than those with IMP3-negative tumors,even after adjustment for other well-known clinical variables such as tumor stage and grade.Thus,our results strongly suggest that patients with IMP3-positive papillary or chromo-phobe RCC should not be regarded as having indo-lent disease and should be followed up aggressively relative to patients with IMP3-negative tumors.In vitro studies have demonstrated that IMP3,an oncofetal protein,plays a crucial role for tumor prolif-eration and invasion21,22and,therefore,may play a direct role in facilitating RCC metastasis.Interestingly, Yaniv et al31reported that IMP3in Xenopus laevis is required for the migration of cells forming the roof plate of the neural tube and,subsequently,for neural crest migration,which suggested that IMP3is impor-tant for promoting cell migration.These findings could explain why IMP3expression is associated with tumor progression and metastasis.However,further study is required to investigate whether IMP3plays a direct role in the biological behavior of RCC.Our previous and current studies demonstrate that IMP3encompasses an important biomarker for the3most common subtypes of RCC.However,there are some limitations to our current study that war-rant discussion.First,to our knowledge,we are the first group to describe IMP3as a prognostic marker for papillary and chromophobe RCC;as such,our results need to be externally validated by other groups using independent cohorts of patients.Sec-ond,papillary RCC can be divided into2further sub-types(types1and2)based on a combination of histologic as well as cytogenetic features.Specifically, type1papillary RCC tumors tend to be of lower grade and less aggressive,whereas type2papillary RCC tumors are often associated with chromosomal aberrations(ie,9p loss)as well as higher tumor grade,positive N stage and M stage,and poorer patient survival.32–34Because cytogenetic analysis to distinguish type1from type2papillary RCC is not routinely conducted at our institutions,in the cur-rent study we were unable to address whether IMP3 expression differs based on papillary RCC subtype. Thus,future studies will be required to test whether type2papillary RCCs express higher levels of IMP3 than type1papillary RCCs,a finding that would be consistent with the general observation that more aggressive forms of RCC tend to express increased levels of IMP3.Third,the relationship between IMP3 and other prognostic markers(both among clear-cell RCC and among papillary and chromophobe RCC) remains unclear and is currently the focus of future research by our group.In summary,IMP3is an independent prognostic biomarker for patients with localized papillary or chro-mophobe RCC.Although relatively rare,patients with localized papillary and chromophobe RCC can develop metastasis after nephrectomy,and IMP3expression can be used to help identify subgroups of patients with high potential for developing metastasis after sur-gery.IMP3expression may provide important prognos-tic information for patients with papillary and chromophobe RCC,and will assist physicians in select-ing high-risk patients who might benefit from early and tailored systematic therapy after nephrectomy. REFERENCES1.Cohen HT,McGovern FJ.Renal-cell carcinoma[review].NEngl J Med.2005;353:2477–2490.2.Motzer RJ,Bander NH,Nanus DM.Renal-cell carcinoma[see comment][review].N Engl J Med.1996;335:865–875. 3.Chow WH,Devesa SS,Warren JL,Fraumeni JF Jr.Risingincidence of renal cell cancer in the United States[see comment].JAMA.1999;281:1628–1631.4.Jemal A,Siegel R,Ward E,et al.Cancer statistics,2007.CACancer J Clin.2007;57:43–66.5.Storkel S,Eble JN,Adlakha K,et al.Classification of renalcell carcinoma:Workgroup No. 1.Union Internationale Contre le Cancer(UICC)and the American Joint Commit-tee on Cancer(AJCC).Cancer.1997;80:987–989.6.Kovacs G,Akhtar M,Beckwith BJ,et al.The Heidelbergclassification of renal cell tumours[review].J Pathol.1997;183:131–133.7.Amin MB,Amin MB,Tamboli P,et al.Prognostic impact ofhistologic subtyping of adult renal epithelial neoplasms:an experience of405cases[see comment].Am J Surg Pathol.2002;26:281–291.IMP3,a Prognostic Marker/Jiang et al.26818.Amin MB,Corless CL,Renshaw AA,Tickoo SK,Kubus J,Schultz DS.Papillary(chromophil)renal cell carcinoma: histomorphologic characteristics and evaluation of conven-tional pathologic prognostic parameters in62cases[see comment].Am J Surg Pathol.1997;21:621–635.9.Cheville JC,Lohse CM,Zincke H,Weaver AL,Blute ML.Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma.Am J Surg Pathol.2003;27:612–624.u WK,Cheville JC,Blute ML,Weaver AL,Zincke H.Prog-nostic features of pathologic stage T1renal cell carcinoma after radical nephrectomy.Urology.2002;59:532–537.11.Ljungberg B,Alamdari FI,Stenling R,Roos G.Prognosticsignificance of the Heidelberg classification of renal cell carcinoma.Eur Urol.1999;36:565–569.12.Lohse CM,Cheville JC.A review of prognostic pathologicfeatures and algorithms for patients treated surgically for re-nal cell carcinoma[review].Clin Lab Med.2005;25:433–464.13.Moch H,Gasser T,Amin MB,Torhorst J,Sauter G,Mihatsch MJ.Prognostic utility of the recently recom-mended histologic classification and revised TNM staging system of renal cell carcinoma:a Swiss experience with 588tumors.Cancer.2000;89:604–614.14.Beck SD,Patel MI,Snyder ME,et al.Effect of papillary andchromophobe cell type on disease-free survival after ne-phrectomy for renal cell carcinoma.Ann Surg Oncol.2004;11:71–77.15.Nielsen J,Christiansen J,Lykke-Andersen J,Johnsen AH,Wewer UM,Nielsen FC.A family of insulin-like growth fac-tor II mRNA-binding proteins represses translation in late development.Mol Cell Biol.1999;19:1262–1270.16.Mueller-Pillasch F,Pohl B,Wilda M,et al.Expression of thehighly conserved RNA binding protein KOC in embryogen-esis.Mech Dev.1999;88:95–99.17.Monk D,Bentley L,Beechey C,et al.Characterisation ofthe growth regulating gene IMP3,a candidate for Silver-Russell syndrome.J Med Genet.2002;39:575–581.18.Mueller-Pillasch F,Lacher U,Wallrapp C,et al.Cloning of agene highly overexpressed in cancer coding for a novel KH-domain containing protein.Oncogene.1997;14:2729–2733. 19.Wang T,Fan L,Watanabe Y,et al.L523S,an RNA-bindingprotein as a potential therapeutic target for lung cancer.Br J Cancer.2003;88:887–894.20.Yantiss RK,Woda BA,Fanger GR,et al.KOC(K homologydomain containing protein overexpressed in cancer):a novel molecular marker that distinguishes between benign and malignant lesions of the pancreas.Am J Surg Pathol.2005;29:188–195.21.Liao B,Hu Y,Herrick DJ,Brewer G.The RNA-binding pro-tein IMP-3is a translational activator of insulin-like growth factor II leader-3mRNA during proliferation of human K562leukemia cells.J Biol Chem.2005;280:18517–18524. 22.Vikesaa J,Hansen TV,Jonson L,et al.RNA-binding IMPspromote cell adhesion and invadopodia formation.EMBO J.2006;25:1456–1468.23.Jiang Z,Chu PG,Woda BA,et al.Analysis of RNA-bindingprotein IMP3to predict metastasis and prognosis of renal-cell carcinoma:a retrospective ncet Oncol.2006;7: 556–564.24.Hoffmann NE,Sheinin Y,Lohse CM,et al.External valida-tion of IMP3expression as an independent prognostic marker for metastatic progression and death for patients with clear cell renal cell carcinoma.Cancer.2008;112:1471–1479.25.Motzer RJ,Russo P.Systemic therapy for renal cell carci-noma[review].J Urol.2000;163:408–417.26.Escudier B,Eisen T,Stadler WM,et al.Sorafenib inadvanced clear-cell renal-cell carcinoma[see comment].N Engl J Med.2007;356:125–134.27.Motzer RJ,Bukowski RM.Targeted therapy for metastaticrenal cell carcinoma[review].J Clin Oncol.2006;24:5601–5608.28.Motzer RJ,Hutson TE,Tomczak P,et al.Sunitinib versusinterferon alfa in metastatic renal-cell carcinoma[see com-ment].N Engl J Med.2007;356:115–124.29.Motzer RJ,Rini BI,Bukowski RM,et al.Sunitinib inpatients with metastatic renal cell carcinoma[see com-ment].JAMA.2006;295:2516–2524.30.Hudes G,Carducci M,Tomczak P,et al.Temsirolimus,interferon alfa,or both for advanced renal-cell carcinoma.N Engl J Med.2007;356:2271–2281.31.Yaniv K,Fainsod A,Kalcheim C,Yisraeli JK.The RNA-bind-ing protein Vg1RBP is required for cell migration during early neural development.Development.2003;130:5649–5661.32.Delahunt B,Eble JN.Papillary renal cell carcinoma:a clini-copathologic and immunohistochemical study of105 tumors.Mod Pathol.1997;10:537–544.33.Delahunt B,Eble JN,McCredie MR,Bethwaite PB,StewartJH,Bilous AM.Morphologic typing of papillary renal cell carcinoma:comparison of growth kinetics and patient sur-vival in66cases.Hum Pathol.2001;32:590–595.34.Gunawan B,von Heydebreck A,Fritsch T,et al.Cytogeneticand morphologic typing of58papillary renal cell carcino-mas:evidence for a cytogenetic evolution of type2from type1tumors.Cancer Res.2003;63:6200–6205.2682CANCER June15,2008/Volume112/Number12。