IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling / 中华医学杂志(英文版)

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.

Diagnostic significance and considerations of growth hormone stimulation testing and insulin-like growth factor 1 in growth hormone deficiency / 中国当代儿科杂志

The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis is an essential component of the hypothalamic-pituitary growth hormone axis and plays a crucial role in childhood growth and development. Disruptions and abnormalities in the GH/IGF-1 signaling pathway and its pathways typically manifest as short stature in children. Children with short stature often undergo GH stimulation testing and IGF-1 level measurements to differentiate growth hormone deficiency (GHD) from other causes of growth delay. This article aims to analyze and elucidate the values of GH stimulation testing and IGF-1 measurement, providing reference for the diagnosis of GHD in children.

Therapeutic effect of recombinant human growth hormone on children with growth hormone deficiency and different pituitary developmental conditions: a prospective study / 中国当代儿科杂志

OBJECTIVES@#To investigate the therapeutic effect of recombinant human growth hormone (rhGH) on children with growth hormone deficiency (GHD) and different pituitary developmental conditions.@*METHODS@#A prospective study was performed on 90 children with GHD who were admitted to Xuchang Maternity and Child Health Hospital from June 2020 to December 2021. According to pituitary height on the median sagittal plane, they were divided into three groups: pituitary dysplasia group (n=45), normal pituitary group (n=31), and enlarged pituitary growth group (n=14). The changes in body height, growth velocity, height standard deviation score and serum levels of insulin-like growth factor binding protein-3 (IGFBP-3) and insulin-like growth factor-1 (IGF-1) were examined after treatment in the above three groups, and the differences of the above indices before and after treatment were compared among the three groups.@*RESULTS@#After treatment, all three groups had significant increases in body height, growth velocity, height standard deviation score, and the serum levels of IGFBP-3 and IGF-1 (P<0.05). Compared with the normal pituitary group, the pituitary dysplasia group and the enlarged pituitary growth group had significantly higher values in terms of the differences in body height, growth velocity, height standard deviation score, IGF-1, and IGFBP-3 before and after treatment (P<0.05). There was no significant difference in the incidence rate of adverse reactions among the three groups (P>0.05).@*CONCLUSIONS@#In GHD children with different pituitary developmental conditions, rhGH can promote bone growth and increase body height, especially in children with pituitary dysplasia and pituitary hyperplasia, with good safety.

Serum levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in children with autism spectrum disorder / 中国当代儿科杂志

OBJECTIVES@#To study the serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) in children with autism spectrum disorder (ASD) and their association with the core symptoms of ASD.@*METHODS@#A total of 150 ASD children aged 2-7 years (ASD group) and 165 healthy children matched for age and sex (control group) who were recruited at the outpatient service of Chongqing Health Center for Women and Children were enrolled as subjects. Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS) were used to evaluate the core symptoms of the ASD children. Chemiluminescence was used to measure the serum levels of IGF-1 and IGFBP-3 in both groups.@*RESULTS@#The ASD group had a significantly lower serum level of IGF-1 than the control group (P<0.05). The children with severe ASD had significantly lower serum levels of IGF-1 and IGFBP-3 than those with mild-to-moderate ASD (P<0.001). For the children aged 2-3 years, the ASD group had a significantly lower serum level of IGF-1 than the control group (P<0.05). Boys had a significantly lower serum level of IGF-1 than girls in both ASD and control groups (P<0.05). The serum levels of IGF-1 and IGFBP-3 were negatively correlated with the total score of CARS (r=-0.32 and -0.40 respectively, P<0.001).@*CONCLUSIONS@#The reduction in serum IGF-1 level in early childhood may be associated with the development of ASD, and the serum levels of IGF-1 and IGFBP-3 are associated with the core symptoms of ASD children.

Enhanced Anti-Cancer Effects of Conditioned Medium from Hypoxic Human Umbilical Cord–Derived Mesenchymal Stem Cells

BACKGROUND AND OBJECTIVES: There have been contradictory reports on the pro-cancer or anti-cancer effects of mesenchymal stem cells. In this study, we investigated whether conditioned medium (CM) from hypoxic human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) (H-CM) showed enhanced anti-cancer effects compared with CM from normoxic hUC-MSCs (N-CM). METHODS AND RESULTS: Compared with N-CM, H-CM not only strongly reduced cell viability and increased apoptosis of human cervical cancer cells (HeLa cells), but also increased caspase-3/7 activity, decreased mitochondrial membrane potential (MMP), and induced cell cycle arrest. In contrast, cell viability, apoptosis, MMP, and cell cycle of human dermal fibroblast (hDFs) were not significantly changed by either CM whereas caspase-3/7 activity was decreased by H-CM. Protein antibody array showed that activin A, Beta IG-H3, TIMP-2, RET, and IGFBP-3 were upregulated in H-CM compared with N-CM. Intracellular proteins that were upregulated by H-CM in HeLa cells were represented by apoptosis and cell cycle arrest terms of biological processes of Gene Ontology (GO), and by cell cycle of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. In hDFs, negative regulation of apoptosis in biological process of GO and PI3K-Akt signaling pathway of KEGG pathways were represented. CONCLUSIONS: H-CM showed enhanced anti-cancer effects on HeLa cells but did not influence cell viability or apoptosis of hDFs and these different effects were supported by profiling of secretory proteins in both kinds of CM and intracellular signaling of HeLa cells and hDFs.

Up-regulation of IGF Binding Protein-3 Inhibits Colonic Inflammatory Response

BACKGROUND: The aggravating factors still remained unclear in inflammatory bowel disease (IBD). Despite many different therapeutic approaches, many patients do not respond to the therapy. The anti-inflammatory effect of insulin-like growth factor-binding protein-3 (IGFBP-3) was suggested because of its capability of nuclear factor-κB (NF-κB) signaling inhibition. Therefore, we hypothesized that the up-regulation of IGFBP-3 would inhibit an inflammatory process. METHODS: Lipopolysaccharides (LPS) treated intestinal epithelial cell 6 (IEC-6) and dextran sodium sulfate (DSS) induced colitis mice were used as colitis models. Exogenous IGFBP-3 expression was accomplished using the adenoviral vector system expressing IGFBP-3 (Ad/IGFBP-3). The inflammatory responses and relevant cellular responses in IEC-6 cells influenced by IGFBP-3 expression were evaluated by western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and reactive oxygen species (ROS) measurement. The severity of colitis was evaluated with the colon tissues of DSS-induced mouse model. RESULTS: We found that the IGFBP-3 expression reduced the production of inflammatory cytokines (cyclooxygenase-2, interleukin-1β, tumor necrosis factor-α) and ROS formation. IGFBP-3 expression also induced cell viability and inhibited NF-κB activation. In line with this data, the severity of DSS-induced mouse colitis was greatly ameliorated by the treatment of IGFBP-3 expressing adenoviral particles characterized with less weight loss and preserved colon length compared with the mice treated with DSS alone. The histopathology of the colon showed the reducing signs of colitis in Ad/IGFBP-3 treated DSS-mice group. CONCLUSION: Therefore, our data suggest that Ad/IGFBP-3 up-regulation reduces colonic inflammatory response as a novel therapeutic protocol for IBD.

Factors affecting height velocity in normal prepubertal children

PURPOSE: To analyze the effects of clinical and laboratory factors, including insulin-like growth factor (IGF) levels, on the height velocity of normal prepubertal children. METHODS: Ninety-five healthy prepubertal children (33 boys, 62 girls) were enrolled. The mean chronological age was 6.3±1.4 years, with a height standard deviation score (SDS) of -0.88±0.70. IGF-1, IGF binding protein-3 (IGFBP-3), SDS for anthropometric measurements, and changes in SDS for anthropometric measurements were analyzed for 1 year, and their associations with 1-year height velocity were investigated. RESULTS: The group of children with a 1-year height velocity of ≥6 cm were chronologically younger than the group with a 1-year height velocity of < 6 cm (5.9±1.3 years vs. 6.7±1.3 years, P=0.004), with a lesser increase of SDS for body mass index (BMI) over 1 year (-0.18±0.68 vs. 0.13±0.53, P=0.014). There were no differences between the 2 groups in IGF-1 SDS and IGFBP-3 SDS. Multiple linear regression showed that baseline chronological age (r=0.243, P=0.026) and height SDS (r=0.236, P=0.030) were positively associated with IGF-1 SDS. Binomial logistic regression showed that an older chronologic age at referral (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.47–0.99) and an increase of BMI SDS over 1 year (OR, 0.41; 95% CI, 0.18–0.89) were associated with a decreased growth possibility of an above-average height velocity (≥6 cm/yr). CONCLUSIONS: Height velocity of normal prepubertal children is affected by an increase of BMI SDS and chronological age. Prepubertal IGF-1 SDS reflects height SDS at the time of measurement but is not associated with subsequent height velocity.

Protective Effects of cis-2-Dodecenoic Acid in an Experimental Mouse Model of Vaginal Candidiasis / 生物医学与环境科学（英文）

OBJECTIVE@#To evaluate the efficacy of cis-2-dodecenoic acid (BDSF) in the treatment and prevention of vaginal candidiasis in vivo.@*METHODS@#The activities of different concentrations of BDSF against the virulence factors of Candida albicans (C. albicans) were determined in vitro. An experimental mouse model of Candida vaginitis was treated with 250 μmol/L BDSF. Treatment efficiency was evaluated in accordance with vaginal fungal burden and inflammation symptoms.@*RESULTS@#In vitro experiments indicated that BDSF attenuated the adhesion and damage of C. albicans to epithelial cells by decreasing phospholipase secretion and blocking filament formation. Treatment with 30 μmol/L BDSF reduced the adhesion and damage of C. albicans to epithelial cells by 36.9% and 42.3%, respectively. Treatment with 200 μmol/L BDSF completely inhibited phospholipase activity. In vivo mouse experiments demonstrated that BDSF could effectively eliminate vaginal infection and relieve inflammatory symptoms. Four days of treatment with 250 μmol/L BDSF reduced vaginal fungal loads by 6-fold and depressed inflammation. Moreover, BDSF treatment decreased the expression levels of the inflammatory chemokine-associated genes MCP-1 and IGFBP3 by 2.5- and 2-fold, respectively.@*CONCLUSION@#BDSF is a novel alternative drug that can efficiently control vaginal candidiasis by inhibiting the virulence factors of C. albicans.

Effects of aerobic exercise plus diet control on serum levels of total IGF-1 and IGF-1 binding protein-3 in female obese youths and adolescents / 中国应用生理学杂志

OBJECTIVE@#To investigate the effects of 4-week moderate aerobic exercise plus diet control on serum levels of total insulin-like growth factor 1(IGF-1) and IGF-1 binding protein-3 (IGFBP-3) as well as IGF-1 activity (reflected by molar ratio of IGF-1/IGFBP-3) in female obese adolescents and youths, and their possible role on fat loss, and improvement of glucose and lipid metabolism.@*METHODS@#Nine female obese youths (age:18~19 y) and 30 female obese adolescents (age:14~16 y) were recruited and undertook 4-week aerobic exercise such as swimming and jogging (6 days/week, twice a day, 2 h/time with 5 min rest per 30 min exercise) with gradual increase of intensity from low (heart rate immediately post-exercise of 1st week:100~120 beats/min) to moderate (heart rate immediately post-exercise of 2-4 weeks:120~140 beats/min) level, combined with a diet intervention (total daily energy intake of 1 400 or 1 600 kcal according to basal metabolism rate) in Shanghai Dianfeng weight loss enclosed camp. Nine normal weight young women and 9 female children matched at age and nationality were recruited as the normal control. Before and after the experimental period, anthropometric index (body weight, body mass index(BMI) and waist circumference), glucose and lipid metabolism parameters including fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride (TG); total cholesterol (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL), and serum levels of total IGF-1 and IGFBP-3 were measured, and IGF-1 activity was calculated in the obese and normal control female adolescents.@*RESULTS@#①Compared with normal control, the serum levels of total IGF-1 and IGFBP-3 were decreased in the female obese youths and adolescents, and IGF-1 activity was reduced only in the obese female adolescents. ②The serum level of IGFBP-3 was down-regulated and IGF-1 activity was up-regulated while no change of serum total IGF-1 was induced by 4-week moderate aerobic exercise plus diet control, accompanied with significant decreases of body weight, BMI and waist circumference as well as improvement of glucose and lipid metabolism in the female obese youths and adolescents. Except for a positive association between the increased IGF-1 activity and the decreased waist circumference was found in the female obese youths by Pearson's correlation analysis, there was no relation of the decreased IGFBP-3, the increased IGF-1 activity with the improvements of anthropometric index and glucose and lipid metabolism in female obese youths and adolescents.@*CONCLUSIONS@#The serum level of IGFBP-3 was down-regulated and the IGF-1 activity was up-regulated by 4-week moderate aerobic exercise plus diet control in female obese youths and adolescents. The increase of IGF-1 activity might be associated with the exercise-plus-diet-induced decrease of waist circumstance in female obese youths.

Changes in Serum Concentrations of Insulin-like Growth Factor Binding Protein-3 after General Anesthesia Using Propofol or Isoflurane / 이화의대지

OBJECTIVES: The insulin-like growth factor binding proteins (IGFBP) regulate the bioavailability and bioactivity of insulin-like growth factor. We aimed to evaluate whether the IGFBP-3 level undergo major changes during perioperative periods according to the different kind of anesthetic agents. METHODS: Eighteen adults scheduled for elective total abdominal hysterectomy were enrolled. The patients were randomly assigned to have either propofol or isoflurane for maintenance of general anesthesia. A venous sample was taken for analysis of IGFBP-3 at the following time points: before induction, at the time of peritoneal closure, 1 hour after extubation at recovery room, and 2 and 5 postoperative days. The samples were analyzed by enzyme linked immunosolvent assay. RESULTS: Demographic data were similar between groups. In the both groups, the IGFBP-3 concentration decreased after anesthesia induction, reaching a nadir at the time of peritoneal closure without a significant difference between groups. In analysis between groups, the IGFBP-3 concentration in the isoflurane group on the postoperative 5th day was recovered to preoperative value and significantly higher than that in the propofol group (P < 0.05). CONCLUSION: This is the first study to show that the anesthetics used for general anesthesia affect the IGFBP-3 level during perioperative periods. The decrease of IGFBP-3 level following anesthesia induction in the isoflurane group was recovered to preoperative value, whereas that observed in the propofol group was not recovered on the postoperative 5th day. Further study is needed to establish the definitive effect of general anesthetics on IGFBP-3 and provide a comprehensive interpretation.

Effect of growth hormone treatment on children with idiopathic short stature and idiopathic growth hormone deficiency

PURPOSE: There are inconsistencies in the results reported in a small number of previous studies into growth hormone (GH) treatment in Korean children with idiopathic short stature (ISS) and idiopathic growth hormone deficiency (IGHD). Thus, the authors retrospectively compared the effects of GH in ISS and IGHD. METHODS: From the medical records of 26 ISS and 30 IGHD children, auxological and biochemical changes including chronologic age (CA), bone age (BA), height standard deviation score (HT-SDS), predicted adult height (PAH), midparental height (MPH), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) were compared. RESULTS: Before treatment, IGHD group had younger BA, lower BA/CA ratio, and lower IGF-1 level than those in the ISS group. During GH treatment, the levels of IGF-1 and IGFBP-3 were not different. Although annual BA increment was higher in IGHD group, and annual PAH-SDS increment was higher in ISS group, annual HT-SDS increments were not different. Both HT-SDS and PAH-SDS in the ISS group increased significantly until the end of the second year, and then those were not significantly different from MPH-SDS. In the IGHD group, the HT-SDS showed a significant increase till the end of the second year, and the PAH-SDS was not significantly changed at each year, but both HT-SDS and PAH-SDS were not significantly different from MPH-SDS at the end of the third year. CONCLUSION: During GH treatment, both HT-SDS and PAH-SDS approached the genetic target range of MPH-SDS after 2 years in ISS children and 3 years in IGHD children.

Effects of maternal folate deficiency on the methylation of insulin-like growth factor system in the offspring rats / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the effects of maternal folate deficiency on fetal growth and development and the methylation profiles of insulin-like growth factor system in the offspring rats.</p><p><b>METHODS</b>Twenty-two Sprague-Dawley female rats were randomly assigned to two groups: a folate deficient group (n=12) and a control group (n=10). They were fed with folate deficient and normal diet respectively. Dams were mated after 2 weeks of feeding. Eight female rats from each group were pregnant. On the 20th day of gestation, the fetuses were delivered by caesarean section. Thirty-two fetal rats from each group were randomly selected and the body length and weight were measured. Eight fetal rats from each group were randomly selected and ELISA was used to measure the level of folate content, IGF-1 and IGFBP-3 in the fetal brain and liver. Three fetal rats from each group were randomly selected and methylated DNA immunoprecipitation sequencing (MeDIP-Seq) was used to detect the methylation level of insulin-like growth factor system in the fetal brain and liver. ELISA was used to measure the level of IGF-1 and IGFBP-3 in the maternal serum from both groups.</p><p><b>RESULTS</b>The mean fetal length and weight were lower in the folate deficient group than in the control group (P<0.05). The levels of IGF-1 and IGFBP-3 in the maternal serum, as well as folate content and IGFBP-3 in the fetal brain and liver were significantly lower in the folate deficient group than in the control group (P<0.05). The methylation levels of IGF-1R, IGF-2R, IGFBP-2, IGFBP-5, IGFBP-6 and IGFBP-7 in the fetal brain were higher in the folate deficient group than in the control group (P<0.05). The methylation levels of IGF-1R, IGF-2R, IGFBP-3 and IGFBP-5 in the fetal liver were higher in the folate deficient group than in the control group. The methylation of IGF-2 gene showed a significant reduction in the folate deficient group (P<0.05).</p><p><b>CONCLUSIONS</b>Maternal folate deficiency may cause retardation of growth and development of the offspring, which is possibly associated with the changes of methylation profiles of insulin-like growth factors.</p>

Influence of The -202 A/C insulin-like growth factor-binding protein-3 promoter polymorphism on individual variation in height in Korean girls

PURPOSE: The most common single nucleotide polymorphism in the IGFBP3 promoter region occurs at position -202. This polymorphic variation occurs frequently and may influence growth hormone responsiveness and somatic growth. However, the effects of IGFBP3 promoter polymorphism on growth in children are unknown. METHODS: Restriction fragment length polymorphism-based genotyping of the -202 single nucleotide polymorphism was performed in 146 Korean girls aged between 15 and 16 years, who were selected randomly from the Seoul School Health Promotion Center. The participants were divided into 3 groups (tall, medium, and short) according to the height percentile established from normal reference values for Korean children. The serum levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were then compared according to genotype. RESULTS: The genotype distribution in the participants was 79 AA (54.1%), 60 AC (41.1%), and 7 CC (4.8%). The C allele frequency at the -202 IGFBP3 position was 25.4% in this group. The mean serum IGFBP-3 concentration in girls with the AA genotype was higher than that in girls with the AC genotype in the medium (P=0.047) and short (P=0.035) groups, respectively. There was no difference in the IGF-I to IGFBP-3 molar ratio between the AA and AC genotype groups (P=0.161). CONCLUSION: In conclusion, the -202 polymorphism in the IGFBP3 promoter region is assumed to affect the serum concentration of IGFBP-3 in children as well as in adults. However, it is unclear whether this affects physical development according to the concentration of IGFBP-3.

Short hairpin RNA targeting insulin-like growth factor binding protein-3 restores the bioavailability of insulin-like growth factor-1 in diabetic rats

ABSTRACT Purpose To investigate whether intracavernosal injection of short hairpin RNA for IGFBP-3 could improve erectile function in streptozotocin-induced diabetic rats. Materials and methods After 12 weeks of IGFBP-3 short hairpin RNA injection treatment, intracavernous pressure responses to electrical stimulation of cavernous nerves were evaluated. The expression of IGFBP-3 and IGF-1 at mRNA and protein levels were detected by quantitative real-time PCR analysis and Western blot, respectively. The concentration of cavernous cyclic guanosine monophosphate was detected by enzyme-linked immunosorbent assay. Results At 12 weeks after intracavernous administration of IGFBP-3 shRNA, the cavernosal pressure was significantly increased in response to the cavernous nerves stimulation compared to the diabetic group (P<0.05). Cavernous IGFBP-3 expression at both mRNA and protein levels was significantly inhibited. At the same time, cavernous IGF-1 expression was significantly increased in the IGFBP-3 shRNA treatment group compared to the diabetic group (P<0.01). Cavernous cyclic guanosine monophosphate concentration was significantly increased in the IGFBP-3 shRNA treatment group compared to the diabetic group (P<0.01). Conclusions Gene transfer of IGFBP-3 shRNA could improve erectile function via the restoration of cavernous IGF-1 bioavailability and an increase of cavernous cGMP concentration in the pathogenesis of erectile dysfunction in streptozotocin-induced diabetic rats.

Long-term efficacy of recombinant human growth hormone therapy in short-statured patients with Noonan syndrome

PURPOSE: Noonan syndrome (NS) is characterized by short stature, heart anomalies, developmental delays, dysmorphic features, cryptorchidism, and coagulation defects. Several studies reported the short-term effects of recombinant human growth hormone (rhGH) treatment on the improvement of height. This study was performed to evaluate the long-term efficacy of rhGH in children with NS in Korea. METHODS: This study included 15 prepubertal NS children who received rhGH subcutaneously at a dose of 50-75 µg/kg/day for 6 days a week for at least >3 years. Preand posttreatment data, such as height, weight, bone age, insulin-like growth factor 1 (IGF-1), and IGF binding protein 3 (IGFBP-3) levels, were collected every 6 months. RESULTS: Chronologic age and bone age at the start of treatment were 7.97±1.81 and 5.09±2.12 years, respectively. Height standard deviation score (SDS) was increased from -2.64±0.64 to -1.54±1.24 years after 3 years (P<0.001). Serum IGF-1 SDS levels were elevated from -1.28±1.03 to -0.10±0.94 (P<0.001). Height SDS was more increased in subjects without PTPN11 mutations compared to those with mutations after 3 years (P=0.012). However, the other parameters, including bone age, IGF-1 SDS, and IGFBP-3 SDS, were not significantly different between patients with and without PTPN11 mutations. CONCLUSION: Although this study included a relatively small number of patients, long-term rhGH therapy in NS patients was safe and effective at improving height, growth velocity, and serum IGF-1 levels, in accordance with previous studies. However, the meticulous monitoring of potential adverse events is still needed because of high dose of rhGH and preexisting hyperactivity of RAS-MAPK pathway. Patients with PTPN11 mutations demonstrated a decreased response to rhGH therapy compared to those without mutations.

The Serum Level of Insulin Growth Factor-1 and Insulin Growth Factor Binding Protein-3 in Children with Henoch-Schönlein Purpura

PURPOSE: We investigated whether serum levels of insulin growth factor-1 (IGF-1) and insulin growth factor binding protein-3 (IGFBP-3) are valuable in predicting clinical outcomes or are correlated with other laboratory findings in children with Henoch-Schönlein purpura (HSP). METHODS: We examined 27 children who were consecutively admitted to our hospital with HSP between January 2011 and February 2012. Blood tests (C-reactive protein, white blood cell count, platelet count, erythrocyte sedimentation rate, albumin, immunoglobulin A, complement C3, antineutrophil cytoplasmic antibody, IGF-1, IGFBP-3) and urine tests were performed upon admission. IGF-1 and IGFBP-3 were resampled in the recovery phase. Controls included 473 children whose IGF-1 and IGFBP-3 were sampled for evaluating their growth, at the outpatient department of pediatric endocrinology in our hospital. IGF-1 and IGFBP-3 were compared between the HSP children and controls, and between the acute and recovery phases in HSP children. The ability of these values to predict clinical outcomes including renal involvement was analyzed using bivariate logistic regression analysis (BLRA). RESULTS: IGF-1 and IGFBP-3 were not different between the HSP children and controls (148.7±117.6 vs. 69.2±96.9, P=0.290: 3465.9±1290.9 vs. 3597.2±1,127.6, P=0.560, respectively). There was no significant difference in IGF-1 or IGFBP-3 between acute and recovery phases. Based on the BLRA, no variable, including IGF-1 and IGFBP-3, could predict clinical outcomes including the presence of nephritis. CONCLUSION: We concluded that IGF-1 and IGFBP-3 do not predict clinical outcomes of HSP, including renal involvement, in this study.

Efficacy of different doses of recombinant human growth hormone in the treatment of short stature in children born small for gestational age / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the efficacy and safety of different doses of recombinant human growth hormone (rhGH) in the treatment of short stature in children born small for gestational age (SGA).</p><p><b>METHODS</b>A total of 37 children with short stature born SGA were enrolled, and based on the dose of rhGH treatment, they were divided into low-dose rhGH group (0.1-0.15 IU/kg daily) and high-dose rhGH group (0.16-0.2 IU/kg daily). The changes in height standard deviation score (ΔHtSDS), height velocity (HV), serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3), and fasting blood glucose at 3, 6, 9, 12, and 24 months after treatment were compared between the two groups.</p><p><b>RESULTS</b>ΔHtSDS and HV both increased after the treatment with high- and low-dose rhGH, but ΔHtSDS and HV in the high-dose rhGH group were significantly higher than in the low-dose rhGH group 9, 12 and 24 months after treatment (P<0.05). Both high- and low-dose rhGH treatment increased serum levels of IGF-1 and IGFBP-3. Serum levels of IGF-1 and IGFBP-3 were positively correlated with HtSDS in both groups. One child each in the high- and low-dose rhGH groups experienced transient slight increase in fasting blood glucose (6.1 mmol/L). There were no cases of abnormal thyroid function.</p><p><b>CONCLUSIONS</b>rhGH has good efficacy in the treatment of short stature in children born SGA, with few adverse events, and high-dose rhGH has some advantages over low-dose rhGH.</p>

Association of insulin-like growth factor-binding protein-3 with radiotherapy response and prognosis of esophageal squamous cell carcinoma / 癌症

<p><b>BACKGROUND</b>Insulin-like growth factor-binding protein-3 (IGFBP-3) is suggested to predict the radiosensitivity and/or prognosis of patients with esophageal squamous cell carcinoma (ESCC). The present study was designed to investigate the clinical and prognostic effects of IGFBP-3 on ESCC.</p><p><b>METHODS</b>IGFBP-3 was detected by immunohistochemistry in paraffin-embedded tissues from 70 ESCC patients treated with radiotherapy alone and further examined by western blotting analysis in 10 pairs of fresh ESCC tissues and adjacent non-malignant esophageal specimens. Receiver operating characteristic (ROC) analysis was used to determine cut-off scores for tumor positivity and to evaluate patient survival status. The χ(2) test was performed to analyze the association of IGFBP-3 expression with clinical characteristics and radiotherapy response. Associations between prognostic outcomes and IGFBP-3 expression were investigated using Kaplan-Meier analysis and the Cox proportional hazards model.</p><p><b>RESULTS</b>The threshold for IGFBP-3 positivity was set to greater than 65% [area under the ROC curve (AUC)=0.690, P<0.019]. Of the 70 ESCC patient tissues tested, 32 (45.7%) were defined as having high IGFBP-3 expression. The levels of IGFBP-3 protein expression were decreased in 70.0% (7 of 10) of ESCC tissues compared with adjacent non-malignant esophageal tissue. In addition, IGFBP-3 expression was associated with pathologic classification (P<0.05 for T, N, and M categories and clinical stage). Patients with elevated protein level of IGFBP-3 in the tumor had an improved radiotherapy response and prolonged overall survival (P<0.001).</p><p><b>CONCLUSIONS</b>High level of IGFBP-3 expression in ESCC associates with early clinical stages and are predictive for favorable survival of the patients treated with radiotherapy.</p>

Expression of Insulin-like Growth Factor Binding Protein 3 in Acute Myeloid Leukemia and Its Clinical Significance / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To explore the expression of insulin-like growth factor binding protein 3 (IGFBP3) in acute myeloid leukemia and its clinical significance.</p><p><b>METHODS</b>Using GAPDH as internal reference, IGFBP3 gene expression was detected in the bone marrow mononuclear cells of 43 de novo AML patients, 36 patients with complete remission (CR) and 28 cases of controls by using SYBR-Green I real-time quantitative PCR, the differences of gene expression between the three groups were compared.</p><p><b>RESULTS</b>IGFBP3 gene expression level in the de novo group were lower than that in CR group and control group (P < 0.05), but there was no statistically significant difference of IGFBP3 expression level in CR group and control group (P > 0.05).</p><p><b>CONCLUSIONS</b>The IGFBP3 as a tumor suppressor gene may play a role in the pathogenesis of acute myeloid leukemia, its expression level is recovered after complete remission, therefore, IGFBP3 can be used as an indicator of evaluating clinical curative effect.</p>

Insulin-like growth factor (IGF)-I and IGF binding proteins axis in diabetes mellitus

Increasing evidence suggests an important role of the insulin-like growth factor (IGF)-IGF binding protein (IGFBP) axis in the maintenance of normal glucose and lipid metabolism. Significant changes occur in the local IGF-I-IGFBPs environment in response to the diabetic milieu. A significant reduction of serum IGF-I levels was observed in patients with type 1 diabetes mellitus (T1DM). Inversely, considerably increased serum levels of IGF-I and IGFBP-3 levels were detected in individuals with glucose intolerance including T2DM. Recently, several prospective studies indicated that baseline levels of IGF-I and IGFBPs are associated with the development of diabetes. These findings suggest that disturbances in insulin and IGF-I-IGFBP axis can affect the development of glucose intolerance including diabetes.