Early detection of ovarian cancer using group biomarkers

One reason that ovarian cancer is such a deadly disease is because it is not usually diagnosed until it has reached an advanced stage. In this study, we developed a novel algorithm for group biomarkers identification using gene expression data. Group biomarkers consist of coregulated genes across normal and different stage diseased tissues. Unlike prior sets of biomarkers identified by statistical methods, genes in group biomarkers are potentially involved in pathways related to different types of cancer development. They may serve as an alternative to the traditional single biomarkers or combination of biomarkers used for the diagnosis of early-stage and/or recurrent ovarian cancer. We extracted group biomarkers by applying biclustering algorithms that we recently developed on the gene expression data of over 400 normal, cancerous, and diseased tissues. We identified several groups of coregulated genes that encode for secreted proteins and exhibit expression levels in ovarian cancer that are at least 2-fold (in log2 scale) higher than in normal ovary and nonovarian tissues. In particular, three candidate group biomarkers exhibited a conserved biological pattern that may be used for early detection or recurrence of ovarian cancer with specificity greater than 99% and sensitivity equal to 100%. We validated these group biomarkers using publicly available gene expression data sets downloaded from a NIH Web site (http://www.ncbi.nlm.nih.gov/geo). Statistical analysis showed that our methodology identified an optimum combination of genes that have the highest effect on the diagnosis of the disease compared with several computational techniques that we tested. Our study also suggests that single or group biomarkers correlate with the stage of the disease.     

The role of vascular endothelial growth factor in the kidney in health and disease

Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen, angiogenic factor and enhancer of vascular permeability. Expressed in the epithelial cells of the developing glomerulus and tubular epithelium, VEGF plays an important role in the development and maintenance of the early vasculature of the kidney. Here, we review the available literature regarding the expression and function of VEGF both in the developing and healthy adult kidney. Furthermore, we highlight how VEGF expression is altered in the diseased kidney and how this modulated expression may impact on and reflect underlying functional changes occurring during the disease process. As discussed, many controversial issues remain, particularly concerning the role of VEGF in the diseased kidney. That VEGF has been proposed as a potential future therapeutic target for the management of some renal diseases requires first that the precise role of VEGF in the normal kidney and various renal pathologies be further and more clearly defined.     

Prognostic value of angiographic indices of coronary artery disease from the Coronary Artery Surgery Study (CASS).

The Coronary Artery Surgery Study, CASS, enrolled 24,959 patients between August 1975 and June 1979 who were studied angiographically for suspected coronary artery disease. This paper compares the prognostic value for survival without early elective surgery of eight different indices of the extent of coronary artery disease: the number of diseased vessels, two indices using the number of proximal arterial segments diseased, two empirically generated indices from the CASS data, and the published indices of Friesinger, Gensini, and the National Heart and Chest Hospital, London. All had considerable prognostic information. Typically 80% of the prognostic information in one index was also contained in another. Our analysis shows that good prediction from angiographic data results from a combination of left ventricular function and arteriographic extent of disease. Prognosis may reasonably be obtained from three simple indices: the number of vessels diseased, the number of proximal arterial segments diseased, and a left ventricular wall motion score. These three indices account for an estimated 84% of the prognostic information available. 6-yr survival varies between 93 and 16% depending upon the values of these three indices.     

Essential role for the C5a receptor in regulating the effector phase of synovial infiltration and joint destruction in experimental arthritis

A characteristic feature of rheumatoid arthritis is the abundance of inflammatory cells in the diseased joint. Two major components of this infiltrate are neutrophils in the synovial fluid and macrophages in the synovial tissue. These cells produce cytokines including tumor necrosis factor alpha and other proinflammatory mediators that likely drive the disease through its effector phases. To investigate what mechanisms underlie the recruitment of these cells into the synovial fluid and tissue, we performed expression analyses of chemoattractant receptors in a related family that includes the anaphylatoxin receptors and the formyl-MetLeuPhe receptor. We then examined the effect of targeted disruption of two abundantly expressed chemoattractant receptors, the receptors for C3a and C5a, on arthritogenesis in a mouse model of disease. We report that genetic ablation of C5a receptor expression completely protects mice from arthritis.     

Reduction in glucocorticoid receptors in renal biopsies of patients with lupus nephritis

OBJECTIVES: The first-line treatment for lupus nephritis is the administration of glucocorticoids (GC) that mediate their effects via the glucocorticoid receptor (GR). The aim of this study was to investigate the expression of GR protein in the cortical area of renal parenchyma of normal and diseased renal biopsies from treated and untreated patients. DESIGN AND METHODS: The immunohistochemical EnVision/HRP technique was performed on renal tissue to detect GR protein. Statistical analysis was performed by SAS (2001). RESULTS: The antigen was mainly detected in glomerular podocytes and in tubules. The number of GR-positive podocytes of the controls was significantly higher than in the untreated patients, which was accordingly higher than in patients who were under medication. CONCLUSIONS: The lower number of GR-positive cells in the diseased kidney compared to controls is possibly linked to tissue-specific GC resistance, whereas the decreased GR expression in podocytes of treated compared to untreated patients may be due to a down-regulation effect after GCs' administration.     

NT-proBNP对心脏介入治疗的临床价值

[目的]观察冠心病患者血浆氨基末端B型利钠肽前体（NT-proBNP）对血管病变数目及程度的预测价值,探讨血浆NT-proBNP在介入治疗前和治疗后一年的浓度变化情况,并评估患者预后。[方法]选取经冠状动脉造影证实的冠心病患者467例,按血管狭窄程度将患者分为轻度、中度、重度或闭塞组,依据支架植入情况分为单支、双支、左主干或三支病变组,抽取其静脉血,采用电化学发光免疫分析法,通过Spearman等级相关分析研究血浆NT-proBNP与血管狭窄程度及病变支数的关系。同时将所有植入支架的患者随访一年,分别检测支架术前、术后24 h、6个月及一年的血浆NT-proBNP浓度,用方差分析比较不同时间血浆NT-proBNP水平的变化情况。[结果]Spearman等级相关分析显示血浆NT-proBNP水平与血管病变支数显著相关（ P ＜0．05）,与病变狭窄程度亦相关（ P ＜0．01）。支架术后患者6个月血浆Log NT-proBNP浓度[（1．99＆#177;0．53） pg/mL]及一年的浓度值[（1．95＆#177;0．50） pg/mL]分别与术前[（2．41＆#177;0．50） pg/mL]相比显著降低（ P ＜0．05）。[结论]血浆NT-proBNP可能是预测冠心病患者血管病变数目、严重程度,及监测患者预后的新型生化标记物,可以指导临床医生更好地把握介入治疗的指征。     

Reconstructing visual manifestations of disease from archaeological human remains

This paper reports on a study that aims to fill a niche within scientific illustration by developing a method whereby evidence of disease and trauma in archaeological human remains can be translated into a meaningful visual reconstruction of a diseased or physically impaired individual in life. A case study is presented, which involved reconstructing the rhino-maxillary effects of leprosy in an adult male. It is suggested that such reconstruction illustrations could have an important role in communicating ideas both to specialists and particularly to non-specialists, and may also be valuable as research tools in their own right.     

Differential gene expression in renal-cell cancer

Renal-cell carcinoma (RCC) is an important cause of morbidity and mortality, and its incidence has been increasing. Malignant transformation is thought to be associated with changes in the expression of several genes, and this alteration in gene expression is believed to be critical to the development of the malignant phenotype. In this study, the expression of about 60,000 genes/expressed sequence tags in clear-cell RCC, normal kidney, and a set of diseased nonmalignant kidneys was determined with the use of the Affymetrix microarray technique, and differences in gene expression were analyzed. Many genes were found to be differentially expressed in these two sample sets. The genes that were expressed greater than four times more in RCC, those expressed only in RCC, and those expressed greater than two times more in RCC and also expressed in a limited number of other tissues were analyzed for their expression in a variety of other normal and diseased tissues. Some of the genes identified were overexpressed only in RCC among the tissues examined, and some were overexpressed in several other malignant tissues in addition to RCC. Other genes were overexpressed in RCC compared with normal kidney but were also overexpressed in diseased nonmalignant kidney or a variety of other normal tissues. All of the RCC samples could be clustered together, separate from the normal and diseased kidney samples, with the use of the Eisen clustering technique and a set of 50 genes. The observed changes in gene expression in RCC should help further the understanding of the biology of RCC and may be useful in diagnosis, treatment, and imaging.     

Computational strategies unravel and trace how liver disease changes hepatic drug disposition

Liver disease changes the disposition properties of drugs, complicating drug therapy management. We present normal and "diseased" versions of an abstract, agent-oriented In Silico Livers (ISLs), and validate their mechanisms against disposition data from perfused normal and diseased rat livers. Dynamic tracing features enabled spatiotemporal tracing of differences in dispositional events for diltiazem and sucrose across five levels, including interactions with representations of lobular microarchitectural features, cells, and intracellular factors that sequester and metabolize. Differences in attributes map to measures of histopathology. We measured disease-causing differences in local, intralobular ISL effects, obtaining until now unavailable views of how and where hepatic drug disposition may differ in normal and diseased rat livers from diltiazem's perspective. Exploration of disposition in less and more advanced stages of disease is feasible. The approach and technology represent an important step toward unraveling the complex changes from normal to disease states and their influences on drug disposition.     

不同类型冠心病患者肿瘤坏死因子和白细胞介素-8的表达水平及其临床意义

目的探讨不同类型冠心病患者肿瘤坏死因子-α(TNF-α)和白细胞介素-8(IL-8)的表达水平及其临床意义。方法选择经冠脉造影确诊的冠心病患者176例,将其分为稳定型心绞痛(SAP)组48例、不稳定型心绞痛(UAP)组85例和急性心肌梗死(AMI)组43例,另选50例健康成人为对照组,检测研究对象的血常规、肝肾功能、血糖、血脂、TNF-α及IL-8等,所有冠心病患者经冠脉造影检查后明确冠状动脉病变支数和冠脉Gensini积分情况,比较各组TNF-α和IL-8水平,并分析其与冠心病患者病情程度和冠状动脉的病变程度。结果冠心病三组中TNF-α和IL-8水平均明显高于对照组(P<0.01),UAP组中TNF-α和IL-8水平明显高于SAP组(P<0.01),AMI组中TNF-α和IL-8水平明显高于UAP组(P<0.01),在冠心病患者中双支病变组TNF-α和IL-8水平明显高于单支病变组(P<0.01),而多支病变组TNF-α和IL-8水平也显著高于双支病变组(P<0.01),Gensini积分越高,TNF-α和IL-8水平也越高(P<0.01),TNF-α和IL-8水平与冠脉Gensini积分呈正相关(r分别为0.694、0.669,P<0.01),且IL-8和TNF-α之间呈正相关关系。结论冠心病患者TNF-α和IL-8水平明显增高,两者之间有密切相关,临床上检测TNF-α和IL-8可预测冠心病患者病情严重程度和冠状动脉的病变程度。     

MMP-26、TIMP-4和MMP-9在弥漫大B细胞淋巴瘤中的表达及意义

本研究旨在检测弥漫大B细胞淋巴瘤（diffuse large B cell lymphoma,DLBCL）中基质金属蛋白酶-26（MMP-26）、金属蛋白酶组织抑制蛋白4（TIMP-4）及基质金属蛋白酶-9（MMP-9）的表达,探讨其与DLBCL发生及进展的关系.采用免疫组织化学SABC法检测了95例DLBCL患者淋巴瘤组织中MMP-26、TIMP-4和MMP-9的表达,并分析它们与DLBCL临床病理指标的关系.结果表明,与淋巴结反应性增生（20例）相比较,不同类型的DLBCL高表达MMP-26、TIMP-4、MMP-9.MMP-26表达阳性率与免疫分型有关（P＜0.05）,生发中心型（GCB）中MMP-26的表达低于non-GCB中MMP-26表达,而与临床分期、年龄、性别、疾病部位无关（P＞0.05）;MMP-9表达阳性率与临床分期有关,Ⅲ期、Ⅳ期患者MMP-9蛋白的表达阳性率明显高于Ⅰ、Ⅱ期患者（P＜0.05）,而与免疫分型、年龄、性别、结外病变无关（P＞0.05）;TIMP-4的表达与免疫分型、临床分期、年龄、性别、结外病变均无相关性关（P＞0.05）.DLBCL病理组织中MMP-26与TIMP-4表达无相关性,与MMP-9蛋白的表达呈正相关（r=0.486,P＜0.05）.结论：MMP-26、MMP-9协同表达于DLBCL,MMP-26可能参与DLBCL的发展及侵袭性,MMP-26的表达与DLBCL病理亚型有关,MMP-26可能作为DLBCL分型的参考指标,并有助于对DLBCL恶性程度及预后的预测,其本身有可能成为一个潜在的治疗靶点.     

Towards the application of proteomics in renal disease diagnosis

Proteomics is widely envisioned as playing a significant role in the translation of genomics to clinically useful applications, especially in the areas of diagnostics and prognostics. In the diagnosis and treatment of kidney disease, a major priority is the identification of disease-associated biomarkers. Proteomics, with its high-throughput and unbiased approach to the analysis of variations in protein expression patterns (actual phenotypic expression of genetic variation), promises to be the most suitable platform for biomarker discovery. Combining such classic analytical techniques as two-dimensional gel electrophoresis with more sophisticated techniques, such as MS, has enabled considerable progress to be made in cataloguing and quantifying proteins present in urine and various kidney tissue compartments in both normal and diseased physiological states. Despite these accomplishments, there remain a number of important challenges that will need to be addressed in order to pave the way for the universal acceptance of proteomics as a clinically relevant diagnostic tool. We discuss issues related to three such critical developmental tasks as follows: (i) completely defining the proteome in the various biological compartments (e.g. tissues, serum and urine) in both health and disease, which presents a major challenge given the dynamic range and complexity of such proteomes; (ii) achieving the routine ability to accurately and reproducibly quantify proteomic expression profiles; and (iii) developing diagnostic platforms that are readily applicable and technically feasible for use in the clinical setting that depend on the fruits of the preceding two tasks to profile multiple disease biomarkers.     

超声二维应变成像评价冠心病患者颈动脉弹性功能

目的：应用二维应变成像技术评价冠心病患者的颈动脉血管弹性.方法：选取拟诊冠心病人院行冠状动脉造影检查的住院患者206例,根据冠状动脉造影结果将其分为单支病变组63例、多支病变组113例及非冠心病组30例.分别应用M型超声技术及二维应变成像技术对受试者行颈动脉超声检查,记录测量结果,对数据进行统计分析和处理.结果：①冠状动脉多支病变组收缩期峰值整体圆周应变（Circumferential strain,CS）及收缩早期整体CS小于单支病变组和非冠心病组（P＜0.01）,收缩晚期整体圆周应变率（Circumferential strain rate,CSr）及僵硬度系数β2大于单支病变组和非冠心病组（P＜0.01）,单支病变组收缩期峰值整体CS及收缩早期整体CSr小于非冠心病组（P＜0.01）,收缩晚期整体CSr及β2大于非冠心病组（P＜0.01）;②收缩期峰值整体CS、收缩早期整体CSr、收缩晚期整体CSr、β2的ROC曲线下面积分别为86.9％、82.7％、80.3％、91.4％,对冠心病均有较高的诊断价值（P＜0.001）;③经判别分析所得判别函数：Y=0.817β2＋0.500IMT-0.185斑块（1或者0）,对冠心病的诊断敏感性为78.4％,特异性为93.3％,总判别准确率为80.6％.结论：冠心病患者颈动脉弹性改变早于形态学改变且与冠脉严重程度相关,颈动脉弹性指标CS及CSr有可能成为评价冠心病的参考指标.     

Differential gene expression in uterine leiomyoma

Uterine leiomyomas are the most common tumor of the genitourinary system in women and are a major cause of morbidity. The molecular causes of the disease remain unclear. In this study, we examined gene expression in leiomyomas and normal myometrium. RNA was prepared and gene expression determined with the use of Affymetrix GeneChip U_95 arrays containing approximately 12,000 known genes and 48,000 expression sequence tags. Several genes were found to be differentially expressed in these two sample sets, and these genes were analyzed for their expression in a variety of other normal and diseased tissues. Four genes--doublecortin, calpain 6, interleukin-17B, and proteolipid protein 1--were found to be overexpressed in leiomyomas compared with normal myometrium and eighteen other tissues. Sets of genes were identified whose expression could be used to cluster samples with leiomyomas or normal myometrium with the use of Eisen Cluster software. We conclude that differences in gene expression can be detected between leiomyomas and normal myometrium and that these changes in gene expression may yield clues to the pathophysiology of this common tumor.     

-374T/A polymorphism of the RAGE gene promoter in relation to severity of coronary atherosclerosis

BACKGROUND: We have recently reported that homozygosity for the minor A-allele of RAGE (receptor for advanced glycation end products) -374T/A polymorphism may exert a protective effect toward the development of angiographic coronary artery disease (CAD). Here we focused on the putative involvement of this functional RAGE polymorphism on the severity of coronary atherosclerosis as assessed by angiography. METHODS: In a total of 234 consecutive Caucasian patients with angiographically proven CAD, the severity of coronary atherosclerosis was assessed by the number of diseased vessels (greater than 50% stenosis). Genotyping for the -374T/A variant was performed by means of PCR-RFLPs. RESULTS: The mean number of diseased vessels was significantly lower in patients with the AA genotype (1.47+/-0.68) than in those with the AT or TT genotype (1.88+/-0.82, p=0.029). After confounding variables were controlled for, the number of diseased vessels remained significantly different in the AA genotype carriers from that in the AT or TT carriers (p=0.041, ANCOVA). CONCLUSIONS: Our data suggest that the RAGE -374T/A polymorphism is one of the likely candidate determinants for the genetic variance of disease phenotype in coronary atherosclerosis.