BACKGROUND AND OBJECTIVES

Acute kidney injury (AKI) is a common complication of critical illness that often leads to increased mortality and morbidity. Biomarkers detect AKI earlier, providing a window of opportunity for timely intervention. Of the recent biomarkers in literature, the cell cycle arrest biomarkers tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7) were found to be superior in predicting AKI. Our study aimed to evaluate the diagnostic performance of urine TIMP-2/IGFBP-7 in its ability to predict AKI and major adverse kidney events within 30 days (MAKE30) among high-risk patients for AKI. MAKE30 is a composite outcome comprised of all-cause mortality, use of renal replacement therapy (RRT), or persistent renal dysfunction at hospital discharge truncated at 30 days.

We conducted a prospective, cross-sectional study which included 135 adult, non-COVID ICU patients. Baseline urine TIMP-2/IGFBP-7 results were used to dichotomize the population into low risk (< 0.3 ng/mL) or high risk (≥ 0.3 ng/mL) for AKI. Participants were then observed for 30 days and monitored for MAKE30 outcomes. ROC curves were created to calculate the sensitivity, specificity, NPV, PPV, and the AUC of the 0.3 ng/mL cut-off to predict the AKI and MAKE30.

Urine TIMP-2/IGFBP-7 cutoff of 0.3 ng/mL predicted AKI with a sensitivity of 82.4%, specificity of 79.2%, PPV of 57.1%, NPV of 93% and AUC of 0.81. MAKE30 was detected with a sensitivity of 62.8%, specificity of 76.1%, PPV of 55.1%, NPV of 81.4% and AUC of 0.69. Elevated levels of urine TIMP-2/IGFBP-7 were found to be associated with AKI (p <0.01), MAKE30 (p <0.01) and all of its subcomponents. Survival or discharge after 30 days were found to be associated with lower urine TIMP-2/IGFBP-7 levels (p <0.01).

Urine TIMP-2/IGFBP-7, at its current cutoff at 0.3 ng/mL, can predict the likelihood of developing AKI and major adverse kidney events among high-risk patients for AKI. It can serve as a useful adjunct to existing methods, such as serum creatinine, in the early diagnosis and prognosis of acute kidney injury and expanding the therapeutic window to prevent disease progression and improve outcomes.

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.
Child ; Female ; Humans ; Pregnancy ; Body Height ; Human Growth Hormone/therapeutic use* ; Hyperplasia ; Insulin-Like Growth Factor Binding Protein 3 ; Insulin-Like Growth Factor I ; Prospective Studies ; Pituitary Gland/pathology* ; Recombinant Proteins/therapeutic use*

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.
Child ; Humans ; Growth Hormone/metabolism* ; Insulin-Like Growth Factor I/metabolism* ; Insulin-Like Peptides ; Insulin-Like Growth Factor Binding Protein 3 ; Human Growth Hormone/metabolism* ; Dwarfism, Pituitary/diagnosis*

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.
Humans ; Insulin-Like Growth Factor Binding Protein 3/metabolism* ; Culture Media, Conditioned/pharmacology* ; Cachexia/pathology* ; Gastrointestinal Neoplasms ; Somatomedins/metabolism* ; Insulins/metabolism* ; Lipids

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.
Autism Spectrum Disorder ; Autistic Disorder ; Child ; Child, Preschool ; Female ; Humans ; Insulin-Like Growth Factor Binding Protein 3 ; Insulin-Like Growth Factor I ; Male

With the rapid dissemination of information in modern society, Chinese residents pay more attention to the scientific concept of childcare, which makes the child prevention and health care industry develop rapidly. The law of children's growth and development is extremely complex, so it is necessary to detect different biomarkers according to different growth and development evaluation angles. Human growth hormone(hGH), insulin-like growth factor-1(IGF-1), insulin-like growth factor binding protein-3(IGFBP-3), thyroid hormone, sex hormone, anti-müllerian hormone(AMH) and 25-hydroxy vitamin D(25-OH VD) are common biomarkers to monitor children's growth and development. This article aims to explain the concept and characteristics of common biomarkers of growth and development, summarize the detection methods of common biomarkers of growth and development evaluation developed in recent years, and provide a reference for children's prevention and health care to select appropriate detection biomarkers.
Anti-Mullerian Hormone/metabolism* ; Biomarkers ; Child ; Growth and Development ; Human Growth Hormone/metabolism* ; Humans ; Insulin-Like Growth Factor Binding Protein 3 ; Insulin-Like Growth Factor I/metabolism* ; Thyroid Hormones ; Vitamin D

This study aimed to explore the consistency of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) by detecting peripheral whole blood and venous serum among children. As a cross-sectional study, children who were aged 0-14 as well as received physical examinations in the Child Healthcare Department of the Children's Hospital of Nanjing Medical University during January 2022 to April 2022 were enrolled in this study. Meanwhile, both of peripheral whole blood and venous serum samples were collected, and the levels of IGF-1 and IGFBP-3 were assayed individually via chemiluminescence immunoassay (CLIA). Additionally, linear regression equation was used to analyze the correlation of results between two categories of samples, while Inter-class Correlation Coefficient (ICC) was used to evaluate the consistency of test results among two types of samples. The change trends of IGF-1 and IGFBP-3 with age were analyzed at the same time. A total of 203 valid matched samples were collected, including 117 boys and 86 girls. Peripheral whole blood was well correlated with serum IGF-1 (r=0.986, P<0.001) and IGFBP-3 (r=0.974, P<0.001), and the linear regression equation is shown as follows: (IGF-1) _{venous serum} =1.047×(IGF-1) _{peripheral whole blood}-6.840; (IGFBP-3) _{venous serum}=0.924×(IGFBP-3) _{peripheral whole blood}+0.396. The correlation and consistency were still persisted after being stratified by sex and age. ICC of IGF-1 and IGFBP-3 were 0.983 and 0.967, respectively which provided an excellent strength of agreement. The levels of IGF-1 or IGFBP-3 in boys' and girls' peripheral whole blood and serum showed significant statistical differences among various age groups (all P<0.001), and also increased significantly with age (all P _trend<0.001). In conclusion, the results of IGF-1 and IGFBP-3 in peripheral whole blood and venous serum had positive comparability that could be mutually recognized. The detection of IGF-1 and IGFBP-3 in peripheral whole blood had great potential for young age children by providing guidance for nutritional intervention, growth and development assessment.
Male ; Female ; Child ; Humans ; Insulin-Like Growth Factor I/metabolism* ; Insulin-Like Growth Factor Binding Protein 3 ; Cross-Sectional Studies ; Linear Models

Objective: To evaluate the consistency of mass spectrometry (MS) and chemiluminescence immunoassay (CLIA) in detecting serum insulin-like growth factor-1 (IGF-1) and IGF-1 standard deviation score (SDS). Methods: This cross-sectional parallel control study prospectively collected the serum samples of 115 children with short stature disorders who were admitted in the Department of Endocrinology, Beijing Children's Hospital, Capital Medical University from February 2020 to December 2021. The serum IGF-1 level was detected by CLIA and MS, and converted to SDS for consistency analysis. Pearson analysis was used to analyze the correlation between the 2 methods, and Deming regression equation was established. Bland-Altman diagram and weighted Kappa coefficient were used to evaluate the consistency of the 2 methods. Results: There were 46 boys (40.0%) and 69 girls (60.0%), aged (8±3) years. Among the 115 cases, 37 were Turner syndrome, 59 were small for gestational age (SGA) at term, 1 was growth hormone deficiency (GHD) and 18 were other diseases. Pearson correlation analysis showed a preferable correlation between IGF-1 measured by the 2 detection methods (r=0.94, P<0.01), and IGF-1 SDS was also significantly correlated (r=0.92, P<0.01). Bland-Altman analysis showed that the consistency of serum IGF-1 levels detected by the 2 methods was poor, and the mean difference between CLIA and MS was 33.38 μg/L. The result detected by CLIA was significantly higher than that by MS, with SDS of 43.51 μg/L (95%CI -51.89-118.7 μg/L). After converting the results to SDS and removing 3 outliers (including 1 GHD patient), the weighted Kappa showed acceptable consistency (κ=0.68). Conclusion: In clinical application, after converting to IGF-1 SDS, IGF-1 detected by MS and CLIA can be used for cross-reference, but too high or too low levels should be cautious about.
Body Height ; Child ; Cross-Sectional Studies ; Female ; Growth Disorders/diagnosis* ; Human Growth Hormone ; Humans ; Insulin-Like Growth Factor Binding Protein 3 ; Insulin-Like Growth Factor I/metabolism* ; Insulins ; Male

OBJECTIVE: To study the cytokine patterns in patients with rheumatoid arthritis (RA) and healthy individuals and identify candidate serum biomarkers for clinical diagnosis of RA. METHODS: This study was conducted among 59 patients diagnosed with RA in our hospital from 2015 to 2019 with 46 age- and gender-matched healthy subjects who received regular physical examinations in our hospital as the control group. Serological autoimmune profiles of 5 RA patients and 5 healthy control subjects were obtained from human cytokine microarrays. We selected 4 differentially expressed cytokines (LIMPII, ROBO3, Periostin and IGFBP-4) and 2 soluble cytokine receptors of interest (2B4 and Tie-2) and examined their serum levels using enzyme-linked immunosorbent assay in 54 RA patients and 41 healthy control subjects. Spearman correlation test was performed to assess the correlation of serum cytokine and soluble receptor expression levels with the clinical features including rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), disease activity score (DAS28) and health assessment questionnaire (HAQ). Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic capability of these cytokines. RESULTS: We identified 6 dysregulated cytokines and soluble receptors (2B4, LIMPII, Tie-2, ROBO3, periostin and IGFBP-4) in RA patients (P < 0.01). The serum levels of LIMPII, ROBO3 and periostin were significantly correlated with the disease activity indicators including RF (P < 0.001), CRP (P < 0.001), DAS28 (P < 0.001) and HAQ (P < 0.001) in RA patients. Among the 6 candidate cytokines, 2B4 showed the largest area under the curve (AUC) of 0.861 for RA diagnosis (P < 0.001), followed then by LIMPII, ROBO3, periostin, Tie-2 and IGFBP-4. CONCLUSION Serum levels of LIMPII, ROBO3 and periostin can be indicative of the disease activity of RA, and serum 2B4, LIMPII, periostin, ROBO3, IGFBP-4 and Tie-2 levels may serve as biomarkers for the diagnosis of RA.
Arthritis, Rheumatoid/diagnosis* ; Biomarkers ; C-Reactive Protein ; Cytokines ; Humans ; Insulin-Like Growth Factor Binding Protein 4 ; Protein Array Analysis ; Receptors, Cell Surface

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.
Activins ; Anoxia ; Apoptosis ; Biological Processes ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Survival ; Culture Media, Conditioned ; Fibroblasts ; Gene Ontology ; Genome ; HeLa Cells ; Humans ; Insulin-Like Growth Factor Binding Protein 3 ; Membrane Potential, Mitochondrial ; Mesenchymal Stromal Cells ; Tissue Inhibitor of Metalloproteinase-2 ; Uterine Cervical Neoplasms