Intestinal hormones and growth factors： Effects on the small intestine

There are various hormones and growth factors which may modify the intestinal absorption of nutrients, and which might thereby be useful in a therapeutic setting, such as in persons with short bowel syndrome. In part I, we focus first on insulin-like growth factors, epidermal and transferring growth factors, thyroid hormones and glucocorticosteroids. Part Ⅱ will detail the effects of glucagon-like peptide （GLP）-2 on intestinal absorption and adaptation, and the potential for an additive effect of GLP2 plus steroids.     

上皮生长因子家族在老年人肠型胃癌发生中的变化

目的　探讨上皮生长因子（ＥＧＦ）家族在老年人胃癌发生中的作用。　方法　采用免疫组化ＬＳＡＢ法观察ＥＧＦ、转化生长因子－α（ＴＧＦ－α）、上皮生长因子受体（ＥＧＦＲ）在老年人肠型胃癌发生不同阶段的表达情况。　结果　ＥＧＦ在正常组织无表达,在胃癌表达最高（７０．８％ ）。ＴＧＦ－α、ＥＧＦＲ在不典型增生组织的表达（分别为７２．２％ 及８３．３％ ）最高;ＴＧＦ－α／ＥＧＦ＋ ＥＧＦＲ共同表达亦以不典型增生组织为最高。ＴＧＦ－α、ＥＧＦＲ在癌周正常组织的表达（分别为５５．６％ 及６１．１％ ）明显高于非癌正常组织（Ｐ＜ ０．０１）;且ＥＧＦ与胃癌的淋巴结转移、浆膜外侵呈正相关（Ｐ＜ ０．０５）。ＥＧＦ家族阳性胃癌粘膜的增殖细胞核抗原（ＰＣＮＡ）标记指数明显高于阴性组（Ｐ＜ ０．０１）,共同表达ＴＧＦ－α／ＥＧＦ＋ＥＧＦＲ胃粘膜的ＰＣＮＡ标记指数也明显高于单独表达ＥＧＦ、ＴＧＦ－α或ＥＧＦＲ组（Ｐ＜ ０．０５）。　结论　ＴＧＦ－α、ＥＧＦＲ与胃癌发生的早期事件关系密切,二者共同表达是癌前病变有意义的标志。ＥＧＦ与进展期癌有关,是判断预后的指标     

大肠癌组织中表皮生长因子及受体的检测

本文应用免疫组化ABC法检测52例大肠癌和18例正常结肠组织中表皮生长因子（EGF）和表皮生长因子受体（EGF－R）的表达状况。正常组织中EGF阳性率22．2％，EGF－R阳性率16．7％，大肠癌EGF阳性率67．3％，EGF－R阳性率61．5％，二者均明显高于正常对照组织，（P＜0．05）。EGF和EGF－R阳性率与患者年龄，性别及肿瘤部位无明显相关，但随着肿瘤浸润度的加深，EGF与EGF－R的阳性率逐渐增高，有淋巴结转移者二者阳性率高于淋转阴性者，特别是EGF与EGF－R双阳者中有82．6％为进展期大肠癌，另发现低分化大肠癌中EGF和EGF－R阳性率明显低于中高分化癌。本文结果提示：部分大肠癌存在EGF或EGF－R的过度表达；EGF与EGF－R的过度表达与肿瘤润度及淋巴转移有关，其检测可作为诊断肿瘤恶性程度的一项辅助指标，部分正常大肠粘膜组织中也有少量EGF或EGF－R表达。     

2型糖尿病肾病患者肾组织中血管内皮细胞生长因子及其受体的变化

目的了解血管内皮细胞生长因子(VEGF)及其受体(VEGF-R)在2型糖尿病肾病患者肾组织中的变化及其与糖尿病肾病(DN)临床与病理表现之间的关系.方法以正常肾组织为对照,采用特异性抗体和免疫组织化学染色方法,对30例DN患者肾组织中VEGF和VEGF-R的分布及其强度变化进行了观察,并结合临床及肾脏病理进行了分析.结果DN患者肾小球VEGF和VEGF-R无论在分布上,还是在强度变化上与正常人相比均有明显差异.DN患者肾小球VEGF和VEGF-R表达增加与患者蛋白尿(83.3%vs33.3%,P＜0.01)、糖尿病视网膜病变(66.7%vs16.7%,P＜0.01)关系密切,而与高血压,糖化血红蛋白水平之间无明显相关性.DN患者肾小球VEGF和VEGF-R表达增加还与肾小球内皮细胞损伤所致的一些组织形态学改变,如K-W结节(72.2%vs16.7%,P＜0.05)、肾小球内皮细胞增生(66.7%vs33.3%,P＜0.05)及微血管瘤形成(61.6%vs25.0%,P＜0.05)的发生显著相关.结论DN患者肾组织中VEGF及VEGF-R2的表达增加与DN患者的蛋白尿形成、糖尿病视网膜病变和内皮细胞损伤所致的形态学改变关系密切.VEGF介导了DN患者肾小球内皮细胞损伤和功能紊乱的发生.     

Human cancers converge at the HIF-2α oncogenic axis

Cancer development is a multistep process, driven by a series of genetic and environmental alterations, that endows cells with a set of hallmark traits required for tumorigenesis. It is broadly accepted that growth signal autonomy, the first hallmark of malignancies, can be acquired through multiple genetic mutations that activate an array of complex, cancer-specific growth circuits [Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70; Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789–799]. The superfluous nature of these pathways is thought to severely limit therapeutic approaches targeting tumor proliferation, and it has been suggested that this strategy be abandoned in favor of inhibiting more systemic hallmarks, including angiogenesis (Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: Mechanisms of anti-tumor activity. Nat Rev Cancer 8:579–591; Stommel JM, et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287–290; Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727–739; Kaiser J (2008) Cancer genetics: A detailed genetic portrait of the deadliest human cancers. Science 321:1280–1281]. Here, we report the unexpected observation that genetically diverse cancers converge at a common and obligatory growth axis instigated by HIF-2α, an element of the oxygen-sensing machinery. Inhibition of HIF-2α prevents the in vivo growth and tumorigenesis of highly aggressive glioblastoma, colorectal, and non–small-cell lung carcinomas and the in vitro autonomous proliferation of several others, regardless of their mutational status and tissue of origin. The concomitant deactivation of select receptor tyrosine kinases, including the EGFR and IGF1R, as well as downstream ERK/Akt signaling, suggests that HIF-2α exerts its proliferative effects by endorsing these major pathways. Consistently, silencing these receptors phenocopies the loss of HIF-2α oncogenic activity, abrogating the serum-independent growth of human cancer cells in culture. Based on these data, we propose an alternative to the predominant view that cancers exploit independent autonomous growth pathways and reveal HIF-2α as a potentially universal culprit in promoting the persistent proliferation of neoplastic cells.     

肝细胞生长因子激活调节机制的研究进展

肝细胞生长因子(hepatocyte growth factor,HGF)又称离散因子,最初是作为促大鼠肝细胞有丝分裂原而被发现的[1].最初分泌的HGF是无活性的,需激活变成它的活化形式才能发挥其生物学作用;尽管肝细胞生长因子激活因子(hepatocyte growth factor activator,HGFA)能够激活前HGF且在血浆中的浓度较高,但其在体内复杂微环境中的作用及其调节机制尚不完全清楚.     

动脉硬化闭塞症与血管新生

随着人们生活水平逐渐提高 ,动脉硬化闭塞症发病率相应升高 ,此类患者相当痛苦 ,但到目前为止没有理想的治疗方法。新近提出的治疗性血管新生为此类患者提供了美好前景。血管新生是指从原有血管床处以发芽方式内皮细胞和平滑肌细胞增生从而形成新的血管。可为患者提供一个治疗性“生物旁路”。 VEGF、FGF、HGF等能通过很多因素调节 ,其中低氧是很重要因素 ,从而促进血管新生起到治疗作用。这已经在动物及临床前期实验得以证实     

风湿性心脏病心房颤动患者心房组织肝细胞生长因子结缔组织生长因子与转化生长因子β1基因表达的研究

目的 观察风湿性心脏病心房颤动患者心房组织中肝细胞生长因子(HGF)、结缔组织生长因子(CTGF)、转化生长因子(TGF)-β1基因表达的变化.方法 35例行心脏手术者于术中获取的右心耳(约200 mg)分为3组,风湿性心脏病27例,其中窦性心律者8例,慢性持续性心房颤动者19例(≥16个月),分别列为风湿性心脏病窦性心律组和风湿性心脏病心房颤动组,另先天性心脏病患者8例(均为窦性心律)作为对照组,以β-肌动蛋白为内参照基因,通过实时荧光定量聚合酶链反应(real time PCR)技术,测定各组心房组织中HGF、CTGF、TGF-β1与Ⅰ型和Ⅲ型胶原mRNA的含量,苏木素-伊红(HE)和Massom病理染色观察右心耳组织纤维化程度.结果 与对照组比较,CTGF、TGF-β1、Ⅰ型胶原、Ⅲ型胶原mRNA表达在风湿性心脏病窦性心律组和风湿性心脏病心房颤动组均显著增加(P<0.05),且风湿性心脏病心房颤动组与风湿性心脏病窦性心律组比较也明显增加(P<0.05);HGF在风湿性心脏病窦性心律组较对照组增加,但比较差异无统计学意义,而在风湿性心脏病心房颤动组HGF下降明显,与对照组和风湿性心脏病窦性心律组比较差异均有统计学意义(P<0.05);相关性分析显示风湿性心脏病心房颤动患者心房组织Ⅰ型胶原、Ⅲ型胶原、TGF-β1和CTGF的mRNA表达与左房直径和组织纤维化面积有相关性.结论 风湿性心脏病患者Ⅰ型胶原和Ⅲ型胶原mRNA表达增加,CTGF、TGF-β1mRNA表达上调.具有抗纤维化作用的HGF mRNA表达在心房颤动时下降,可能是使得风湿性心脏病患者心房颤动易于发生和维持的重要原因.     

非小细胞肺癌患者血清血管内皮生长因子、血小板衍生生长因子和表皮生长因子受体测定的临床意义

目的 探讨血清血管内皮生长因子(vascular endothelial growth factor,VEGF)、血小板衍生生长因子(platelet-derived growth factor,PDGF)和表皮生长因子受体(epidermal growth factor receptor,EGFR)测定在非小细胞肺癌(non-small cell lung cancer,NSCLC)诊断和预后判定中的意义.方法 采用双抗体夹心ABC-ELISA法测定31例NSCLC患者及30名健康者血清VEGF、PDGF和EGFR的含量.结果 NSCLC患者血清VEGF、PDGF和EGFR测定值均高于健康对照组(P值均＜0.01).血清VEGF、PDGF和EGFR测定值与NSCLC病理分型无关(P值均＞0.05),与远处转移有关,远处转移组的测定值高于未转移组(P＜0.05～0.01).NSCLC患者血清VEGF与PDGF测定值之间呈显著正相关(r=0.641,P＜0.01),血清VEGF和EGFR测定值呈正相关(r=0.369,P＜0.05).结论 检测血清VEGF、PDGF和EGFR水平对NSCLC的诊断和预后判定具有一定价值.     

Elevated serum concentrations of activated hepatocyte growth factor activator in patients with multiple myeloma

Objectives: Hepatocyte growth factor (HGF) is a potential key factor in multiple myeloma. Conversion of pro‐HGF to its active form is a critical limiting step for its biological effects. We aimed to examine the levels of the most potent activator, the hepatocyte growth factor activator (HGFA), in serum and bone marrow plasma of patients with multiple myeloma. Methods: The activated form of HGFA was measured by an enzyme‐linked immunosorbent assay in serum (n = 49) and bone marrow plasma (n = 16) from multiple myeloma patients, and in serum from healthy controls (n = 24). Results: The median concentrations of activated HGFA in myeloma and control sera were 39.7 (range 6.2–450.0) and 17.6 ng/mL (range 4.8–280.6), respectively. The difference was statistically significant (P = 0.037). The median concentration of activated HGFA in bone marrow plasma was 6.1 ng/mL (range 3.5–30.0). Conclusion: We here show for the first time that the activated form of HGFA is present at high levels in serum and bone marrow of myeloma patients, thus providing a necessary prerequisite for the activation of HGF.     

甲状腺增殖性疾患组织表皮生长因子及其受体的表达

目的　探讨表皮生长因子 (EGF)及其受体 (EGFR)在甲状腺增殖性疾患中的表达及其作用。方法　应用免疫组化ABC染色方法观察 70例甲状腺组织切片EGF及EGFR的表达。结果(1)EGF在正常、肿瘤及非肿瘤组织中几乎均无表达。 (2 )乳头状、滤泡型甲状腺癌及其混合癌EGFR阳性表达高于非癌疾患及正常组织 (P <0 .0 5 ) ,阳性表达程度以强阳性为主。 (3)在正常组织、良性腺瘤、结节性甲状腺肿及桥本病 ,弱或中度的EGFR阳性表达率各组间差异无显著性。正常组织阳性表达率虽高达 83.3 % ,但 2 / 3表达为弱阳性。 (4 )乳头状甲状腺癌以细胞浆表达EGFR占优势 ,滤泡型及混合型甲状腺癌主要为混合着色 ,但与非癌混合着色不同的是多数以胞浆表达占优势 ;良性疾患以混合染色为主 ,但结节性甲状腺肿以膜着色居多。正常组织为浆、膜混合着色。结论　 (1)对EGFR强阳性表达尤其细胞浆为主者应高度疑及甲状腺癌。 (2 )各甲状腺良性疾患均有不同程度EGFR表达 ,虽无统计学意义上的差别 ,却可说明EGFR对于良性肿瘤及非肿瘤增殖性疾患的生成均有不应忽视的作用。     

胃癌患者检测表皮生长因子及受体的意义

目的:探讨表皮生长因子(EGF)及其受体(EGFR)的表达与胃癌发生及胃癌生物学行为的关系。方法:采用免疫组化S-P法对50例胃癌进行研究。结果:EGF和EGFR在早期胃癌中的阳性率均为20％(2/10),在进展期胃癌的阳性率分别为62.5％(25/40)和60％(24/40),进展期胃癌EGF和EGFR的阳性率均显著高于早期胃癌(P<0.05)。有转移组的EGF及EGFR阳性率高于无转移组(P<0.05)。EGF及EGFR的表达与胃癌的组织学类型有关。结论:EGF及EGFR阳性的肿瘤可能具有更强的浸润与转移能力,检测EGF和EGFR有助于判断胃癌预后。     

结直肠腺瘤中IGF-Ⅰ、IGF-ⅠR、IGF-Ⅱ的表达及其意义

[目的]探讨胰岛素样生长因子(insulin-like growth factor,IGF)-Ⅰ、IGF-ⅠR、IGF-Ⅱ在结直肠腺瘤(colorectal adenoma,CRA)中的表达及意义。[方法]入选行电子结肠镜检查并经活检病理确诊的CRA 100例、结直肠癌(colorectal cancer,CRC)30例、炎性息肉30例,另选20例正常结直肠黏膜者作为阴性对照,应用免疫组织化学SP法检测所有入选者IGF-Ⅰ、IGF-IR、IGF-Ⅱ的表达。[结果]阴性对照组IGF-Ⅰ、IGF-ⅠR、IGF-Ⅱ的阳性表达分别为5.0%、10.0%、10.0%,与炎性息肉组(分别为6.7%、10.0%、10.0%)差异无统计学意义(P0.05),CRA组(分别为36.0%、48.0%、44.0%)、CRC组(分别为63.3%、80.0%、73.3%)较阴性对照组、炎性息肉组均呈逐渐增加趋势,差异有统计学意义(P0.01);CRA组IGF-Ⅰ、IGF-ⅠR、IGF-Ⅱ的阳性表达与性别、年龄、数量、部位均无明显关系(P0.05),与腺瘤大小、增生程度、组织学分类差异有统计学意义(P0.01);CRA组IGF-Ⅰ、IGF-ⅠR、IGF-Ⅱ的表达相互间呈正相关(P0.01)。[结论]在正常人群的结直肠黏膜向腺瘤的转化,以及腺瘤的增长和转化过程中,IGFs和IGFs-R轴发挥着极其重要作用,IGF-Ⅰ、IGF-ⅠR、IGF-Ⅱ有可能作为CRA癌变的预测指标,对临床早期诊治具有重要意义。     

结缔组织生长因子在肾间质纤维化中的表达及其意义

目的 :研究结缔组织生长因子 (connectivetissuegrowthfactor,CTGF)在原发性肾小球肾炎小管间质病变中的表达及其与肾间质纤维化之间的关系。　 方法 :选择不同类型原发性肾小球肾炎患者 42例 ,根据小管间质病变分级分为四组 :0级 8例 ,1级 12例 ,2级 12例 ,3级 10例。应用免疫组织化学方法分别观察四组中CTGF、TGF β1、FN和COL Ⅲ的表达 ,并将CTGF表达水平与患者血肌酐 (SCr)和内生肌酐清除率 (Ccr)进行比较。　 结果 :肾小管上皮细胞 (从近端小管到髓质集合管 )是间质中CTGF的主要来源 ,CTGF表达量与肾小管间质病变程度成正比 (P=0 0 0 5 )。此外 ,CTGF与TGF β1、FN和COL Ⅲ的表达量成正相关 (P均 <0 0 5 ) ;与患者Ccr升高水平成正比 (P <0 0 0 5 )。　 结论 :随着慢性肾小管间质病变程度加重 ,CTGF蛋白质分子表达量显著增加 ,它可能在肾间质纤维化形成过程中起重要作用。CTGF作为TGF β1的下游因子 ,可能通过促进细胞外基质 (ECM)如FN和COL Ⅲ等合成增加 ,参与肾间质纤维化发生。     

Serum levels of platelet-derived growth factor-BB and vascular endothelial growth factor as prognostic factors for patients with fulminant hepatic failure

Background and Aims: In animal models for acute liver injury, the administration of some angiogenic factors such as vascular endothelial growth factor (VEGF) and granulocyte‐colony stimulating factor (G‐CSF) are shown to reduce liver injury and improve liver proliferative capacity. The aim of the present study was to assess the role of angiogenic factors in fulminant hepatic failure (FHF). Methods: Serum levels of nine angiogenic factors (angiopoietin‐2, follistatin, G‐CSF, hepatocyte growth factor [HGF], interleukin‐8, leptin, platelet‐derived growth factor [PDGF]‐BB, platelet endothelial cell adhesion molecule‐1 and VEGF) were measured using the Bio‐Plex Protein Array System in 30 patients, 17 of whom were diagnosed with FHF, 13 with acute hepatitis (AH), and 20 controls. Results: Serum levels of PDGF‐BB and VEGF were lower in FHF patients than AH patients and controls (PDGF‐BB; 2050 ± 1572 pg/mL vs 4521 ± 2419 pg/mL vs 8506 ± 5500 pg/mL, VEGF; 39 ± 38 pg/mL vs 144 ± 122 pg/mL vs 205 ± 121 pg/mL). By using univariate logistic regression models, serum levels of PDGF‐BB and VEGF were associated with poor outcomes. Serum PDGF‐BB levels were strongly correlated with serum VEGF levels (r = 0.70). Furthermore, serum PDGF‐BB levels were significantly correlated with platelet counts (r = 0.79), PT activity (r = 0.37) and D.Bil/T.Bil ratio (r = 0.50), while serum VEGF levels were significantly correlated with platelet counts (r = 0.68) and PT activity (r = 0.38). Conclusions: We consider that serum levels of PDGF‐BB and VEGF are worth investigating as biomarkers for predicting outcomes of FHF patients.     

狼疮性肾炎患者血清VEGF、PIGF的表达水平及意义

目的探讨狼疮性肾炎（LN）患者血清血管内皮生长因子（VEGF）、胎盘生长因子（PIGF）的表达水平及意义。方法选择LN患者（LN组）34例、健康体检者（对照组）28例,采用ELISA法检测两组患者血清VEGF、PIGF的水平,同时常规检测ESR、系统性红斑狼疮活动性指数（SLEDAI）评分和补体C3等,并分析血清VEGF、PIGF水平与各指标的关系。结果 LN组患者血清VEGF、PIGF水平明显高于对照组（P均〈0.05）。相关分析显示,LN组血清VEGF、PIGF水平与ESR、SLEDAI评分、24 h尿蛋白定量均呈正相关（rVEGF分别为0.518、0.340、0.029;rPIGF分别为0.381、0.177、0.034,P均〈0.05）;血清PIGF水平与补体C3呈负相关（r=-0.347,P〈0.05）,与肌酐水平呈正相关（r=0.543,P〈0.05）;血清VEGF和PIGF水平亦呈正相关（r=0.305,P〈0.05）。结论 VEGF、PIGF参与了LN的起病和发展,VEGF、PIGF可作为监测系统性红斑狼疮病情和活动度的指标。     

Expression of epidermal growth factor and fibroblast growth factor in human hepatocellular carcinoma: an immunohistochemical study

ABSTRACT— Expression of epidermal growth factor (EGF) and fibroblast growth factor (FGF) was examined in 56 patients with hepatocellular carcinoma (HCC) using an immunohistochemical method. EGF and FGF were expressed on carcinoma cells in 14 (25%) and 23 cases (41%), respectively. In the 23 FGF-positive cases, 11 cases were positive for both acidic and basic FGF, while 18 were positive for acidic FGF, and 16 were positive for basic FGF. In non-cancerous hepatic tissues, FGF was weakly positive in macrophages, hepatocytes and vascular endothelial cells in some cases, while EGF was totally negative. There were no significant correlations between the expression of EGF or FGF on carcinoma cells and the various clinicopathologic factors examined. These data suggest that EGF and FGF are produced by human HCC cells in vivo. The roles of the expression of these growth factors in the development and progression of HCC remain only speculative.