Mendelian randomization provides evidence for a causal effect of serum insulin-like growth factor family concentration on risk of atrial fibrillation

BACKGROUND Atrial fibrillation(AF)is one of the most common persistent arrhythmias among adult cardiovascular diseases.It is important to identify potential risk factors for AF.Members of the insulin-like growth factor(IGF)family exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases,and previous population-based studies indicate associations between IGF family members and AF.However,the causal effects of IGF family members in AF have not been evaluated.assess genetic relationships between IGF family members and AF.METHODS MR was performed based on genome-wide association study(GWAS)datasets,and concentration levels of 14 IGF family members were retrieved.An initial MR analysis was conducted to identify single nucleotide polymorphisms potentially associated with IGF serum concentrations.A GWAS meta-analysis including 60620 AF cases and 970216 control participants of European ancestry was then conducted to identify AF causal effects.Two-sample MR packages were used to perform MR analysis in R.MR-Egger,weighted median(WM),and inverse va-riance weighted(IVW)methods were used.RESULTS Core Tip:Due to the high prevalence of atrial fibrillation(AF),and adverse outcomes related to it,it is important to identify risk factors associated with development of the condition.Insulin-like growth factor(IGF)family members exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases,and previous population-based studies indicate associations between IGF family members and AF.However,the causal effects of IGF family members in AF have not been evaluated.The results of the current study provide novel insights on the pathogenesis of AF,and implic-ations of serum IGF family member concentrations when assessing the risk of AF.The study generated evidence on the potential roles of developmental pathological effects in the pathogenesis of AF.Further observational and experimental studies are critically needed.

Interplay between micro RNA-17-5p, insulin-like growth factor-Ⅱ through binding protein-3 in hepatocellular carcinoma

AIM: To investigate the effect of microR NA on insulinlike growth factor binding protein-3(IGFBP-3) and hence on insulin-like growth factor-Ⅱ(IGF-Ⅱ) bioavailability in hepatocellular carcinoma(HCC).METHODS: Bioinformatic analysis was performed using microrna.org, DIANA lab and Segal lab softwares. Total RNA was extracted from 23 HCC and 10 healthy liver tissues using mir Vana mi RNA Isolation Kit. microR NA-17-5p(miR-17-5p) expression was mimicked and antagonized in Hu H-7 cell lines using Hi Per Fect Transfection Reagent, then total RNA was extracted using Biozol reagent then reverse transcribed into cD NA followed by quantification of mi R-17-5p and IGFBP-3 expression using Taq Man real-time quantitative PCR. Luciferase reporter assay was performed to validate the binding of miR-17-5p to the 3'UTR of IGFBP-3. Free IGF-Ⅱ protein was measured in transfected Hu H-7 cells using IGF-Ⅱ ELISA kit. RESULTS: Bioinformatic analysis revealed IGFBP-3 as a potential target for miR-17-5p. Screening of miR-17-5p and IGFBP-3 revealed a moderate negative correlation in HCC patients, where mi R-17-5p was extensively underexpressed in HCC tissues(P = 0.0012), while IGFBP-3 showed significant upregulation in the same set of patients(P = 0.0041) compared to healthy donors. Forcing mi R-17-5p expression in Hu H-7 cell lines showed a significant downregulation of IGFBP-3 mR NA expression(P = 0.0267) and a significant increase in free IGF-Ⅱ protein(P = 0.0339) compared to mock untransfected cells using unpaired t-test. Luciferase assay validated IGFBP-3 as a direct target of mi R-17-5p; luciferase activity was inhibited by 27.5% in cells co-transfected with miR-17-5p mimics and the construct harboring the wild-type binding region 2 of IGFBP-3 compared to cells transfected with this construct alone(P = 0.0474).CONCLUSION: These data suggest that regulating IGF-Ⅱ bioavailability and hence HCC progression can be achieved through targeting IGFBP-3 via manipulating the expression of miR NAs.

Serum measurements of testosterone, insulin-like growth factor 1, and insulin-like growth factor binding protein-3 in the diagnosis of prostate cancer among Korean men

Aim： To investigate the relationships of serum testosterone, insulin-like growth factor （IGF）- 1 and IGF-binding protein （IGFBP）-3 levels with prostate cancer risk and also with known prognostic parameters of prostate cancer in Korean men who received radical retropubic prostatectomy （RRP） for clinically-localized prostate cancer. Methods： Serum levels of total testosterone, free testosterone, IGF-1 and IGFBP-3 were determined in 592 patients who subsequently received prostate biopsy. Results were compared between patients who eventually received RRP for prostate cancer （n = 159） and those who were not diagnosed with prostate cancer from biopsy （control group, n = 433）. Among the prostate cancer only patients, serum hormonal levels obtained were analyzed in relation to serum prostate specific antigen （PSA）, pathological T stage and pathological Gleason score. Results： Prostate cancer patients and the control group demon- strated no significant differences regarding serum levels of total testosterone, free testosterone, IGF-I and IGFBP-3 across the different age groups. Among the cancer only patients, no significant associations were observed for serum levels of total testosterone, free testosterone, IGF-1 and IGFBP-3 levels with pathological T stage, pathological Oleason score and preoperative PSA. Conclusion： Our data indicate that simple quantifications of serum testosterone and IGF-1 along with IGFBP-3 levels might not provide useful clinical information in the diagnosis of clinically localized prostate cancer in Korean men. Also, our results suggest that serum levels of testosterone, IGF-1 and IGFBP-3 might not be significantly associated with known prognostic factors of clinically localized prostate cancer in Korean men. （Asian J Androl 2008 Mar; 10： 207-213）

Circulating insulin-like growth factor-binding protein 3 as prognostic biomarker in liver cirrhosis

AIM: To investigate the prognostic significance of insulin-like growth factor-binding protein 3(IGFBP-3) in patients with cirrhosis.METHODS: Prospective study that included two cohorts: outpatients with stable cirrhosis(n = 138) and patients hospitalized for acute decompensation(n = 189). Development of complications, mortality or liver transplantation was assessed by periodical phone calls and during outpatient visits. The cohort of stable cirrhosis also underwent clinical and laboratory evaluation yearly(2013 and 2014) in predefined study visits. In patients with stable cirrhosis, IGFBP-3 levels were measured at baseline(2012) and at second re-evaluation(2014). In hospitalized subjects, IGFBP-3 levels were measured in serum samples collected in the first and in the third day after admission and stored at-80 ℃. IGFBP-3 levels were measured by immunochemiluminescence.RESULTS: IGFBP-3 levels were lower in hospitalized patients as compared to outpatients(0.94 mcg/mL vs 1.69 mcg/m L, P < 0.001) and increased after liver transplantation(3.81 mcg/m L vs 1.33 mcg/mL, P = 0.008). During the follow-up of the stable cohort, 17 patients died and 11 received liver transplantation. Bivariate analysis showed that death or transplant was associated with lower IGFBP-3 levels(1.44 mcg/mL vs 1.74 mcg/m L, P = 0.027). The Kaplan-Meier transplant-free survival probability was 88.6% in patients with IGFBP-3 ≥ 1.67 mcg/mL and 72.1% for those with IGFBP3 < 1.67 mcg/mL(P = 0.015). In the hospitalized cohort, 30-d mortality was 24.3% and was independently associated with creatinine, INR, SpO_2/FiO_2 ratio and IGFBP-3 levels in the logistic regression. The 90-d transplant-free survival probability was 80.4% in patients with IGFBP-3 ≥ 0.86 mcg/mL and 56.1% for those with IGFBP3 < 0.86 mcg/mL(P < 0.001). CONCLUSION: Lower IGFBP-3 levels were associated with worse outcomes in patients with cirrhosis, and might represent a promising prognostic tool that can be incorporated in clinical practice.

Insulin-like growth factor-binding protein-3 inhibits IGF-1-induced proliferation of human hepatocellular carcinoma cells

OBJECTIVE Basic fibroblast growth factor(b FGF)and platelet-derived growth factor(PDGF)produced by hepatocellular carcinoma(HCC)cells are responsible for the cell growth.Accumulating evidence shows that insulin-like growth factor-binding protein-3(IGFBP-3)suppresses HCC cell proliferation in both IGF-dependent and independent manners.The present study is to investigate whether treatment with exogenous IGFBP-3 inhibits bF GF and PDGF production and the cell proliferation of HCC cells.METHODS Cell Counting Kit 8 assay were designed to detect HCC cell proliferation,transcription factor early growth response-1(EGR1)involving in IGFBP-3 regulation of b FGF and PDGF were detected by RT-PCR and Western blot assays.Western blot assay was adopted to detect the IGFBP-3 regulating insulin-like growth factor 1 receptor(IGF-1R)signaling pathway.RESULTS The present study demonstrates that IGFBP-3 suppressed IGF-1-induced b FGF and PDGF expression while it does not affect their expression in the absence of IGF-1.To delineate the underlying mechanism,Western-blot and RT-PCR assays confirmed that the transcription factor early growth response protein 1(EGR1)is involved in IGFBP-3 regulation of b FGF and PDGF.IGFBP-3 inhibition of type 1 insulin-like growth factor receptor(IGF1R),ERK and AKT activation is IGF-1-dependent.Furthermore,transient transfection with constitutively activated AKT or MEK partially blocks the IGFBP-3 inhibition of EGR1,b FGF and PDGF expression.CONCLUSION In conclusion,these findings suggest that IGFBP-3suppresses transcription of EGR1 and its target genes b FGF and PDGF through inhibiting IGF-1-dependent ERK and AKT activation.It demonstrates the importance of IGFBP-3 in the regulation of HCC cell proliferation,suggesting that IGFBP-3 could be a target for the treatment of HCC.

Changes of insulin-like growth factor-Ⅱ and insulin-like growth factor binding protein-3 in cerebrospinal fluid of children with tuberculous meningitis

BACKGROUND： Recent studies have found that insulin-like growth factors （IGFs） and insulin-like growth factor binding protein-3 （IGFBP-3） have stronger neurotrophic and neuroprotective effects. But whether their levels in cerebrospinal fluid could be used as an auxiliary indicator in differentially diagnosing tuberculous meningitis and viral encephalitis is not yet clear. OBJECTIVE： To explore the changes of insulin-like growth factor-Ⅱ （IGF-Ⅱ ） and IGFBP-3 in cerebrospinal fluid （CSF） of children with tuberculous meningitis and the significance of the changes. DESIGN： A non-randomized concurrent controlled study. SETTING： Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College. PARTICIPANTS： Thirty children with tuberculous meningitis （14 males and 16 females） were selected from the Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College from January 2005 to December 2006. Tuberculous meningitis was diagnosed according to their clinical manifestations, the history of close contact with tuberculosis, typical cerebrospinal fluid changes of tuberculous meningitis, positive tuberculosis antibody and effective antituberculosis treatment. There were 30 children （13 males and 17 females） with viral encephalitis, and viral encephalitis was diagnosed according to epidemiological history, clinical manifestations, conventional and biochemical changes of cerebrospinal fluid, and negative bacteriology judgment. Meanwhile, 30 children （13 males and 17 females） without infectious and central nervous system disease were selected as the control group. Informed consent was obtained from the parents of all the enrolled children. METHODS： ①The lumbar puncture operation was implemented immediately to obtain cerebrospinal fluid （3 mL）. The contents of IGF-Ⅱ and IGFBP-3 were detected with immunoradiometric assay. The concentrations of glucose and protein in cerebrospinal fluid were determined with a dry-chemical method. The number of white blood cells was counted by Fushi Method. ②The Pearson correlation analysis was used to analyze the correlation of the contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. MAIN OUTCOME MEASURES： The contents of IGF- Ⅱ and IGFBP-3 in cerebrospinal fluid, and their correlation with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. RESULTS： ①Contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid： The contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid in the tuberculous meningitis group were significantly higher than those in the encephalitis virus group and control group （P 〈 0.05）. There was no significant difference in the contents of IGF- Ⅱ and IGFBP-3 in cerebrospinal fluid between the viral encephalitis group and control group （P 〉 0.05）. ②Correlation： The IGF- Ⅱ and IGFBP-3 contents in cerebrospinal fluid were positively correlated with the protein concentration in cerebrospinal fluid （r =0.821, 0.855, P 〈 0.01）, but negatively with the glucose （r =0.742, - 0.605, P 〈 0.01）. CONCLUSION- ①IGFs and IGVBPs are involved in the pathophysiological process of tuberculous meningitis, as well as the glucose and protein metabolism in cerebrospinal fluid. ②The IGF-Ⅱ and IGFBP-3 contents in cerebrospinal fluid can be used as the auxiliary indicators to differentially diagnose tuberculous meningitis and viral enceohalitis.

Effects of Exogenous Growth Hormone on Growth Hormone-Insulin-Like Growth Factor Axis of Human Gastric Cancer Cell

Aim: To study effects of recombinant human growth hormone (rhGH) on growth hormone-insulin-like growth factor axis (GH-IGFs) of human gastric cancer cell in vivo in order to reveal part mechanism of growth effects of rhGH on gastric cancer. Methods: Nude mice were randomly divided into control group, cisplatin (DDP) group, rhGH group and DDP + rhGH group after human gastric cancer xenograft model of node mice was successfully founded and drugs were used for 6 days. We investigated volume of tumor, inhibitory rate of tumor and cell cycle by slide gauge and flow cytometry. In addition, We also respectively investigated insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) of blood serum of nude mice, IGF-ImRNA, insulin-like growth factor-I receptor (IGF-IR) mRNA and IGFBP-3 mRNA of xenograft of nude mice by enzyme linked immunosorbent assay (ELISA) and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on the first day of completing use of drugs later. Results: Tumor grew obviously slowly and tumor inhibitory rate obviously rose in DDP group and DDP + rhGH group compared with control group and rhGH group (p p p < 0.05). Expressions of IGF-I mRNA and IGF-IR mRNA were not obviously different in all groups. But expression of IGFBP-3 mRNA obviously increased in rhGH group, DDP group and DDP + rhGH group compared with control group;meanwhile, expression of IGFBP-3 mRNA also obviously increased in DDP + rhGH group compared with control group, DDP group and rhGH group. Conclusion: Our results indicated rhGH in short-time use did not improve proliferation of human gastric cancer cells and its mechanism was possible that rhGH in short-time use raised simultaneously IGF-I and IGFBP-3 of blood serum and increased IGFBP-3 mRNA, but degraded ratio of IGF-I and IGFBP-3 of blood serum in human gastric cancer cells.

IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling

Background:Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia.In addition to systemic immune/inflammatory effects in response to tumor progression,tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss.However,the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood.Methods:The yki-gut tumors were induced in fruit flies.Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3(IGFBP-3)treated cells.Immunoblotting was used to display phenotypes of tumor cells and adipocytes.Quantitative polymerase chain reaction(qPCR)analysis was carried out to examine the gene expression levels such as Acc1,Acly,and Fasn et al.Results:In this study,it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes.IGFBP-3,which is highly expressed in cachectic tumor cells,antagonized insulin/IGF-like signaling(IIS)and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes.Conditioned medium from cachectic tumor cells,such as Capan-1 and C26 cells,contained excessive IGFBP-3 that potently induced lipolysis in adipocytes.Notably,neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes.Furthermore,cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS,ensuring their escape from IGFBP-3-associated growth suppression.Finally,cachectic tumor-derived ImpL2,the IGFBP-3 homolog,also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila.Most importantly,IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients,especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients.Conclusion:Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.

Aqueous extract of Protaetia brevitarsis larvae increases mTOR-mediated growth rate in zebrafish larvae

Objective:To evaluate the effects of an aqueous extract of Protaetia brevitarsis(AEPB)on the growth of zebrafish and preosteoblast MC3T3-E1 cells.Methods:The effects of AEPB on the linear growth and the expression of growth-related genes in zebrafish and MC3T3-E1 cells were assessed using various molecular techniques.Furthermore,the involvement of the mammalian target of rapamycin(mTOR)pathway in AEPB-induced growth was investigated by employing the mTOR inhibitor rapamycin.Results:AEPB administration led to a significant and dose-dependent increase in zebrafish larvae growth over time.Additionally,AEPB treatment upregulated the expression of growth hormone-1(GH-1),insulin-like growth factor-1(IGF-1),growth hormone receptor-1(GHR-1),and cholecystokinin-a(CCKA)in zebrafish.Similarly,AEPB stimulated the expression and release of IGF-1 and accelerated mTOR expression in MC3T3-E1 cells.In addition,rapamycin hindered AEPB-induced linear growth in zebrafish larvae and suppressed the expression of growth-promoting genes by inhibiting mTOR activation.Conclusions:AEPB shows growth-promoting effects by upregulating growth-related genes and activating the mTOR signaling pathway.Further investigations are warranted to elucidate its mechanisms of action and explore its potential application in the development of growth-enhancing supplements for various purposes.

2～7岁小于胎龄儿血Ghrelin、胰岛素样生长因子-1和胰岛素样生长因子结合蛋白-3的水平及其意义

目的:探讨Ghrelin与生长激素-胰岛素样生长因子(GH-IGF)轴的关系,以及对小于胎龄儿(SGA)生后生长发育的影响。方法:选择新生儿期足月小于胎龄、现年龄为2～7岁儿童30例作为SGA组,根据有无追赶生长(CUG)分为SGA-CUG组(19例)和SGA-无CUG组(11例);足月适于胎龄(AGA)的2～7岁矮小儿童20例作为AGA矮小组;同时选择足月适于胎龄的2～7岁正常身高儿童19例作为对照组。计算体质量的标准差计分(SDS)、身高SDS、72h摄入热卡,检测空腹血Ghrelin、胰岛素样生长因子-1(IGF-1)、胰岛素样生长因子结合蛋白-3(IGFBP-3)和血糖水平并做相关性分析。结果:SGA-CUG组和SGA-无CUG组血浆Ghrelin水平(mg.L-1)(0.371±0.093和0.446±0.076)均高于AGA矮小组及对照组(0.263±0.174和0.245±0.080)(均P<0.05),SGA-无CUG组升高最为显著,SGA-CUG组与SGA-无CUG组比较差异无统计学意义(P>0.05),矮小组与对照组比较差异无统计学意义(P>0.05)。IGF-1和IGFBP-3水平(mg.L-1)在SGA-无CUG组(123.882±46.275和33.310±8.836)和AGA矮小组(171.83±65.77和42.150±13.515)明显低于SGA-CUG组(380.037±137.548和147.389±46.430)和对照组(354.121±95.023和145.058±30.706)(均P<0.05)。SGA-CUG组和对照组相关分析显示Ghrelin与摄入热量、体质量SDS、IGF-1和IGFBP-3均呈负相关关系(SGA-CUG组r=-0.628,P<0.01;r=-0.658,P<0.05;r=-0.854,P<0.000 1;r=-0.685,P<0.001;对照组r=-0.808,P<0.000 1;r=-0.664,P<0.001;r=-0.771,P<0.000 1;r=-0.502,P<0.05);与年龄、身高SDS及血糖无明显相关关系(SGA-CUG组r=0.255,r=-0.218,r=-0.135,均P>0.05;对照组r=0.203,r=-0.328,r=-0.228,均P>0.05)。结论:Ghrelin与GH-IGF轴之间相互作用,共同调控生长发育。SGA可能存在不同程度的Ghrelin抵抗及GH-IGF轴损害,且生后持续存在。

Effects of insulin-like growth factor binding protein-related protein 1 in mice with hepatic fibrosis induced by thioacetamide

Background Insulin-like growth factor binding protein-related protein 1 （IGFBPrP1） can activate hepatic stellate cells and increase extracellular matrix （ECM） in vitro. However, the effects of IGFBPrP1 in mice with hepatic fibrosis, and the mechanisms of these effects, are currently unknown. We aim to address these issues in this study. Methods Intraperitoneal injection of thioacetamide （TAA） is a classic method for establishing a mouse model of hepatic fibrosis. Using this model, we administered anti-IGFBPrP1 antibody, again via intraperitoneal injection. The morphological changes of liver fibrosis were observed with both HE and Masson stainning. The immunohistochemical assays and Western blotting were used to measure changes in IGFBPrP1, a-smooth muscle actin （a-SMA） and ECM in liver tissues, and the expression of transforming growth factor-β1 （TGF-β1） and Smad3. Data were statistically analyzed using one-way analysis of variance （ANOVA）, the SNK-q test for inter-group differences. Results The Masson staining analysis showed that compared with normal control group, content of collagen fiber in TAA5w group was significantly increased （P 〈0.01）, and it was significantly decreased in TAA5w/alGFBPrP1 group compared with in TAA5w group （P 〈0.01）. The expression of hepatic IGFBPrP1, a-SMA, TGF-β1, Smad3, collagen 1 and fibronectin （FN） was significantly up-regulated in the TAA5w group （P 〈0.01）. Anti-IGFBPrP1 treatment reversed these changes （P 〈0.01）. Conclusions IGFBPrP1 plays an important role in the development of hepatic fibrosis. Anti-IGFBPrP1 prevents fibrosis in mice by suppressing the activation of hepatic stellate cells, inhibiting the synthesis of major components of the ECM （namely, collagen I and FN）. The mechanism for this suppression of fibrosis is associated with the TGF-β1/Smad3 signaling pathways.

Expression of albumin, IGF-1, IGFBP-3 in tumor tissues and adjacent non-tumor tissues of hepatocellular carcinoma patients with cirrhosis

AIM： To explore the expression of albumin （ALB）, insulinlike growth factor （IGF）-I, and insulin-like growth factor binding protein （IGFBP）-3 in tumor tissues and adjacent non-tumor tissues of hepatocellular carcinoma （HCC） patients with cirrhosis.METHODS： Twenty-four HCC patients with cirrhosis who underwent hepatectomy were studied. ALB mRNA, IGF-1 mRNA, and IGFBP-3 mRNA in liver tissues （including tumor tissues and adjacent non-tumor tissues） were detected by reverse transcriptase-polymerase chain reaction（RT-PCR）. Liver Ki67 immunohistochemistry staining was studied. At the same time, 12 patients with cholelithiasis or liver angioma who underwent operation were segregated as normal control.RESULTS： In HCC patients with cirrhosis, hepatic ALB mRNA, IGF-1 mRNA, and IGFBP-3 mRNA of tumor tissues or adjacent non-tumor tissues were lower than the normal liver tissues, while in tumor tissues, hepatic ALB mRNA and IGFBP-3 mRNA were lower, hepatic IGF-1 mRNA was higher than in adjacent non-tumor tissues. Liver Ki67 labeling index （Ki67 LI） in tumor tissues or adjacent nontumor tissues were higher than that in the normal liver tissues, while in tumor tissues it was higher than that in adjacent non-tumor tissues.CONCLUSION： Imbalance of IGF-1 and IGFBP-3 may play a role in hepatocarcinogenesis and tumor development of liver cirrhosis patients.

沙颍河铅污染对儿童GH-IGF-1轴和体格发育的影响

目的：探讨沙颍河铅污染现状及其对儿童生长激素-胰岛素样生长因子-1（ GH-IGF-1）轴和体格发育的影响。方法：随机选择淮河沙颍河流域S县两个村庄作为调查点（依距河岸距离远近分别定为对照区和污染区）；原子吸收分光光度法检测河水和调查点饮用水及土壤中的铅含量。整群抽取两村庄小学8～13岁在校学生作为研究对象，伏安极谱法测定儿童血清铅含量；ELISA法检测儿童血清胰岛素样生长因子-1（ IGF-1）、胰岛素样生长因子结合蛋白3（IGFBP3）、生长激素（GH）和生长激素结合蛋白（GHBP）水平；电子体重计、身高坐高计、皮褶厚度计及Gulick卷尺分别测量体重、身高、皮褶厚度和胸围。结果：河水3个采样断面铅浓度均超过国家地表水水质标准Ⅴ级。污染区饮用水及土壤铅含量均高于对照区（ t＝2．663和2．300，P＜0．05）。污染区儿童血清铅含量高于对照区儿童（t＝3．227，P＝0．002）。污染区男孩身高、体重、皮褶厚度、胸围与对照区比较差异均无统计学意义（P均＞0．05）。两区女孩身高、体重和胸围差异均无统计学意义（P均＞0．05），但污染区女孩皮褶厚度高于对照区（t＝3．036，P＝0．003）。结论：沙颍河流域的饮用水中铅含量明显升高，污染区儿童血清GH-IGF-1轴相关因子水平受到影响。

Possible roles of insulin, IGF-1 and IGFBPs in initiation and progression of colorectal cancer

AIM: To investigate the roles of serum insulin, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding proteins (IGFBPs) in the initiation and progression of colorectal cancer.

阻塞性腺样体和扁桃体肥大与胰岛素样生长因子系统

阻塞性腺样体和扁桃体肥大可能引起儿童生长发育异常,其病理生理机制尚不明确。本文就血清胰岛素样生长因子-1(insulin-likegrowthfactorI,IGF-1)/胰岛素样生长因子结合蛋白-3(insulin-likegrowthfactor-bindingprotein3,IGFBP-3)概况及其在阻塞性腺样体和扁桃体肥大患儿生长激素分泌异常诊断和疗效判断方面的意义进行综述。

左向右分流型先天性心脏病合并心力衰竭患儿血清IGF-1和IGFBP-3的变化及意义

目的探讨左向右分流型先天性心脏病(先心病)合并心力衰竭(心衰)患儿血清胰岛素样生长因子-1(IGF-1)和胰岛素样生长因子结合蛋白-3(IGFBP-3)的变化及意义。方法 20例健康儿童(对照组),20例无心脏基础疾病的心衰患儿(心衰组),20例无心衰的左向右分流型先心病患儿(先心组),30例伴心衰的左向右分流型先心病患儿(先心+心衰组)作为研究对象。对不同组别的血清IGF-1及IGFBP-3进行比较;并对先心+心衰组患儿按心功能Ⅱ、Ⅲ、Ⅳ级分为3个亚组,对其血清IGF-1、IGFBP-3及cTnI水平进行比较及相关性分析。结果先心组血清IGF-1及IGFBP-3水平下降,与对照组比较差异有统计学意义(P<0.01)。先心+心衰组血清IGF-1水平明显下降,与对照组及先心组比较差异有统计学意义(分别P<0.01,P<0.05)。心衰组血清IGF-1及IGFBP-3水平明显增高,与其他各组比较差异有统计学意义(P<0.01)。先心+心衰组患儿按心功能分级比较的各亚组间随心功能下降血清IGF-1水平依次降低(P<0.01),且该组患儿血清IGF-1、IGFBP-3水平与血清cTnI水平呈负相关(分别r=-0.692、-0.530,P<0.05)。结论血清IGF-1水平可作为左向右分流型先心病病情评估的客观指标及合并心衰的危险因素,这也为该类患儿使用外源性IGF-1治疗心衰提供了临床依据。

IGF-I与IGFBP-3在结直肠癌患者血清中表达的临床意义

目的 探讨血清中胰岛素样生长因子 I（IGF-I）、胰岛素样生长因子结合蛋白-3 （IGFBP-3）的表达与结直肠癌发生发展的关系.方法 病例对照研究.选取2014年7月至2016年3月就诊于辽宁省人民医院的113例结直肠癌患者作为结直肠癌（CRC）组,良性对照（N-CRC）组为同期37例结直肠良性病患者,健康对照（normal control,NC）组为同期76名健康体检者.对CRC组进行了有/无淋巴转移（M-CRC/NM-CRC）分亚组和TNM分期.通过化学发光法检测血清中IGF-I、IGFBP-3含量并计算其比值.两组间采用SNK检验,不同组间比较采用单因素方差分析（one-way ANOVA）.结果 在IGF-I浓度方面,NC、N-CRC、CRC组间呈小幅递减趋势,M-CRC与NM-CRC组间比较差异无统计学意义（F=0.343,P=0.559）,T4期低于T1＋T2期、T3期（F=6.279,P=0.003）.IGFBP-3浓度方面,CRC组（3.13 ±1.57）μg/ml与N-CRC组（3.42 ±1.32）μg/ml比较差异无统计学意义（F=3.04,P=0.09）,但CRC组显著低于NC组（4.62 ±1.10）μg/ml（F=10.88,P=0.001）,M-CRC亚组高于NM-CRC亚组（F=4.44,P〈0.05）.IGF-I/IGFBP-3比值方面,CRC组为48.85 ±29.14显著高于N-CRC 组（42.38 ±12.58）（F=5.05,P=0.02）和NC 组（42.46 ±16.24）（F=5.68,P=0.02）.IGF-I ROC曲线下面积（AUC）为0.63（95% CI 0.56~0.70）,诊断价值较低,以102.5作为IGF-I诊断临界值时灵敏度为85.8%,特异度为40.7%;IGFBP-3 ROC 曲线下面积（AUC）为0.72 （95%CI 0.64~0.78）,诊断价值中等,以3.33作为IGFBP-3诊断临界值时灵敏度为78.8%,特异度为62.8%.结论 IGF-I和IGFBP-3在结直肠癌患者血清中均呈低表达,同时与淋巴结转移、TNM分期相关.

Role of polymorphisms of the IGF2 and IGFBP3 genes and risk of gastric carcinoma in China

Background The insulin-like growth factor signaling pathway plays an important role in the modulation of cell growth and proliferation.The aim of this study was to investigate the role of polymorphisms of the insulin-like growth factor 2 （IGF2） and IGF-binding protein 3 （IGFBP3） genes,which encode key proteins of this pathway,as risk factors for gastric carcinoma （GC）.Methods A case-control study including 404 histologically confirmed GC patients and 424 healthy controls of the same ethnicity was conducted to retrospectively investigate the genetic polymorphisms of two genes,IGF2＋820A＞G （rs680） and IGFBP3 A-202C （rs2854744）.Adjusted odds ratios （ORs） and 95％ confidence intervals （C/s） were calculated using Logistic regression.Results The IGF2 genetic variants examined contributed to GC risk individually （OR,1.26; 95％ CI,1.08-1.46）.The genotype frequencies of IGFBP3 A-202C were not significantly different between the cancer cases and controls （P ＞0.05）.Compared to the IGF2 AA genotype,carriers of one variant combined genotype were more pronounced among young subjects （＜60 years）,male subjects,never smokers,and those with a family history of cancer （OR=1.36,95％ CI=1.09-1.72,P ＜0.05; OR=1.61,95％ C/=1.28-2.08,P ＜0.05; OR=1.46,95％ C/=1.11-1.98,P ＜0.05; OR=1.53,95％ C/=0.91-2.6,P ＜0.05; respectively）.Moreover,when the combined effects of the risk genotypes were investigated,significant associations were detected between highrisk genotypes in IGF2 and IGFBP3 （OR,2.47; 95％ CI,1.75-3.49）.Conclusions Our results suggest that polymorphic variants of the IGF2 genes modulate gastric carcinogenesis.Moreover.when the IGF2 and IGFBP3 variants are evaluated toaether,a areater effect on GC risk is observed.

Effects of parenteral nutrition with and without GH on the GH/IGF-1 axis after hepatectomy in hepatocellular carcinoma with liver cirrhosis

Postoperative hepatic insulin-like growth factor-1(IGF-1)production may be severely disturbed in patients with liver cirrhosis.Complex alterations in the GH/IGF-1 axis are thought to play an important role in the protein catabolism that complicates major surgical procedures.The aim of this study was to explore the effects of parenteral nutrition(PN)with and without growth hormone(GH)on the GH/IGF-1 axis after hepatectomy for hepatocellular carcinoma(HCC)with cirrhosis and evaluate the potential roles of recombinant human GH(rhGH)therapy.Twenty-four patients with HCC with cirrhosis who underwent hepatectomy were randomly divided into two groups:a PN group(n=12)and an rhGH+PN group(n=12).Liver function,serum GH,IGF-1 and IGFBP-3 were measured before the operation and at postoperative days(POD)1 and 6.Insulin-like growth factor-1 and IGFBP-3 mRNA in the liver tissue was detected by RT-PCR.The liver Ki67 immunohistochemistry staining was studied.At the same time,12 patients with cholelithiasis or liver hemangioma who underwent operation served as normal control group.On POD 6,serum prealbumin,GH,IGF-1,IGFBP-3,hepatic IGF-1 mRNA,IGFBP-3 mRNA and liver Ki67 LI were higher in the rhGH+PN group than in the PN group.There was no significant difference in the 6-and 12-month tumor-free survival rate and the median tumor-free survival time between the PN group and the rhGH+PN group(P>0.05).These data indicate that rhGH+PN could ameliorate the changes in the GH/IGF-1 axis after hepatectomy for HCC in the setting of cirrhosis.