Insulin-like Growth Factor Binding Protein Research Articles

Ad Libitum Drinking Does Not Modify Renal Oxidative Stress or Inflammation During Simulated Occupational Heat Stress

Prolonged heat exposure increases acute kidney injury (AKI) risk likely due to renal oxidative stress and inflammation. However, the effect of occupational heat stress (OHS) and the modifying role of hydration on renal oxidative stress and inflammation is unknown. This study tested the hypothesis that compared to fluid restriction ad libitum drinking consistent with OHS recommendations will attenuate renal oxidative stress and inflammation during simulated OHS. In a randomized, crossover design, 13 healthy adults (5 women) completed two 2 h OHS simulations consisting of of 8 circuits of treadmill walking (10 min) and rowing (5 min) at an oxygen uptake of 1.2 L/min in a wet bulb globe temperature of 33.1±0.2°C. In the drinking trial (Drink), subjects were provided 237 mL of a non-caloric sport drink (Gatorade Zero) every 15 min and drank ad libitum. In the fluid restriction trial (NoDrink), no fluid was provided. Rectal temperature and body weight were recorded. Urine and blood samples were collected pre-, post- and 1 h post- exposure. Inflammatory (monocyte chemotactic protein-1, MCP-1) and oxidative stress (thioredoxin 1, TRX-1) markers were measured in urine and serum, and fractional excretion (FE) was calculated. AKI risk was quantified as the product of urine insulin-like growth factor-binding protein 7 and urine tissue inhibitor of metalloproteinase 2 ([IGFBP7•TIMP-2]). Data are presented as mean ± SD. Peak rectal temperature was not different between trials (Drink: 38.5±0.4°C, NoDrink: 38.6±0.4°C, p=0.346). Percent changes in body weight were lower in Drink (1.3±0.8% vs. 2.8±0.9%, p<0.001). FETRX-1 was elevated at post- (0.50±0.00%) compared to pre- (0.36±0.00%, p=0.011) and 1 h post- (0.29±0.13%, p=0.011). FEMCP-1 was elevated at post- (1.25±0.18%) compared to pre- (1.02±0.17%, p=0.006) but not 1 h post- (1.27±0.03%, p>0.999). FETRX-1 and FEMCP-1 did not change significantly between trials (trial x time: p³0.622). [IGFBP7•TIMP-2] was higher at 1 h post- (17.5±1.0 (ng/mL)2/1000) compared to pre- (0.2±0.1 (ng/mL)2/1000, p<0.001) and post- (1.1±0.4 (ng/mL)2/1000, p<0.001) but did not differ between trials (trial x time: p=0.556). Peak changes in [IGFBP7•TIMP-2] were not significantly correlated with peak changes in FETRX-1 (r=0.126, p=0.557) or FEMCP-1 (r=0.292, p=0.166) and were correlated with peak changes in serum MCP-1 (r=0.714, p<0.001) but not serum TRX-1 (r=0.227, p=0.286). Two hours of simulated OHS increased renal inflammation (FEMCP-1), oxidative stress (FETRX-1), and AKI risk ([IGFBP7•TIMP-2]), while ad libitum drinking did not modify FEMCP-1, FETRX-1, or [IGFBP7•TIMP-2]. Lack of correlations between peak changes in [IGFBP7•TIMP-2] and FEMCP-1, FETRX-1, or serum TRX-1, but the strong positive correlation with peak serum MCP-1 suggests a role for systemic inflammation in OHS induced AKI risk. NCT05458843 Funding: R01OH011528. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Violation of Allowable Work Intensity does not Augment Acute Kidney Injury Risk During Simulated Occupational Heat Stress

We recently demonstrated that violation of the National Institute of Occupational Safety and Health (NIOSH) heat stress recommendations by exceeding the allowable wet bulb globe temperature (WBGT) for a given moderate work intensity and work:rest ratio augmented acute kidney injury (AKI) risk. However, the role of work intensity (at a fixed work:rest ratio) on AKI risk during NIOSH compliant and non-compliant scenarios remains largely unknown. This study tested the hypothesis that violating the NIOSH recommendations by exceeding the allowable work intensity at a given WBGT and fixed work:rest ratio would augment AKI risk. Twelve healthy adults completed two NIOSH recommendation compliant trials and one noncompliant trial consisting of a 4 h exposure to a fixed WBGT and work intensity. Work-rest ratio was fixed at 30 min of walking and 30 min of rest each hour. Work intensity (i.e., Hprod) was prescribed as a function of WBGT— 412±51 W (27.3±0.3°C; high intensity compliant [Chigh]), 290±75 W (31.6±0.2°C; low intensity compliant [Clow]), and 410±61 W (31.7±0.2°C; high intensity noncompliant [NChigh]). All subjects were provided 237 mL of sport drink every 15 min and drank ad libitum. TC is presented as peak across the 4 h exposure. Urine samples were collected preexposure, and immediately and 1 h postexposure. Urinary inflammatory (monocyte chemotactic protein-1 [MCP-1]), oxidative stress (thioredoxin 1 [TRX-1]), and AKI risk (the product of insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase 2 [IGFBP7·TIMP-2]) biomarkers were measured and normalized to urine flow rate. Urinary biomarkers were log transformed before statistical analysis and data are presented as mean ± SD. Peak Tc was higher during the NChigh trial (38.3±0.4°C) compared to the compliant trials (Chigh: 38.0±0.3°C; Clow: 37.8±0.4°C; p≤0.0095). Body weight change from pre- to postexposure did not differ between trials (p=0.7817). MCP-1 increased from pre- to immediately postexposure in all trials (p≤0.0031) but was not different between trials (p=0.1354). TRX-1 increased from pre- to immediately postexposure in all trials (p≤0.0085) but was not different between trials (p=0.6372). [IGFBP7·TIMP-2] increased from pre- to immediately postexposure in all trials (p=0.0454) but the increase was not different between trials (Chigh: -1.7±2.6 LOG [ng/mL2]/1000; Clow: -1.6±2.4 LOG [ng/mL2]/1000; NChigh:-1.2±2.3 LOG [ng/mL2]/1000; p=0.2076). Simulated occupational heat stress elevates AKI risk, likely due to both inflammation and oxidative stress. Violating the NIOSH recommendations by exceeding either the allowable WBGT (i.e., NChigh versus Chigh) or work intensity (i.e., NChigh versus Clow) resulted in a modest elevation in peak Tc but did not modify AKI risk and/or the urinary inflammatory and oxidative stress responses. RCT: NCT04767347; Supported By: R01OH011528. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Biphasic Kinetics of IGF-I and IGFBP-3 in Response to Military Field Training in Brazilian Air Force Recruits.

Insulin-like growth factor type I (IGF-I) has gained considerable notoriety in military training, primarily because it is responsible for energy deficits and sensitive to an inadequate protein intake, which are situations that are commonly experienced in specific military operations. Therefore, this study aimed to assess the kinetics of IGF-I and insulin-like growth factor binding protein type 3 (IGFBP-3) in a 4-day military field training exercise. The sample comprised 12 male soldiers (21.71 ± 1.64 years). Changes were assessed at 3 times: time 1-basal (control week); time 2-after specific military field training; and time 3-1 week after the specific training (control week). Changes in body composition and serum levels of IGF-I and IGFBP-3 were observed. The main finding of this study was it verified the biphasic kinetics of both IGF-I and IGFBP-3 at the 3 times observed, that is, a significant drop from time 1 (basal-IGF-I: 189 ng/mL and IGFBP-3: 4.71 mg/L) to time 2 (immediately after military training-IGF-I: 162 ng/mL and IGFBP-3: 4.08 mg/L) and a subsequent recovery of these markers, with a significant increase from time 2 (immediately after military training) to time 3 (a week after military training-IGF-I: 199 ng/mL and IGFBP-3: 4.96 mg/L). It can be concluded that IGF-I and IGFBP-3 levels respond quickly to the stimuli caused by military training, especially after specific field training. However, the same markers quickly return to their basal values after this type of training finishes, simply by following the daily routine of the battalion in the control weeks, with no specific intervention being necessary.

Plasma ALS and Gal-3BP differentiate early from advanced liver fibrosis in MASLD patients

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is estimated to affect 30% of the world’s population, and its prevalence is increasing in line with obesity. Liver fibrosis is closely related to mortality, making it the most important clinical parameter for MASLD. It is currently assessed by liver biopsy – an invasive procedure that has some limitations. There is thus an urgent need for a reliable non-invasive means to diagnose earlier MASLD stages.MethodsA discovery study was performed on 158 plasma samples from histologically-characterised MASLD patients using mass spectrometry (MS)-based quantitative proteomics. Differentially abundant proteins were selected for verification by ELISA in the same cohort. They were subsequently validated in an independent MASLD cohort (n = 200).ResultsFrom the 72 proteins differentially abundant between patients with early (F0-2) and advanced fibrosis (F3-4), we selected Insulin-like growth factor-binding protein complex acid labile subunit (ALS) and Galectin-3-binding protein (Gal-3BP) for further study. In our validation cohort, AUROCs with 95% CIs of 0.744 [0.673 – 0.816] and 0.735 [0.661 – 0.81] were obtained for ALS and Gal-3BP, respectively. Combining ALS and Gal-3BP improved the assessment of advanced liver fibrosis, giving an AUROC of 0.796 [0.731. 0.862]. The {ALS; Gal-3BP} model surpassed classic fibrosis panels in predicting advanced liver fibrosis.ConclusionsFurther investigations with complementary cohorts will be needed to confirm the usefulness of ALS and Gal-3BP individually and in combination with other biomarkers for diagnosis of liver fibrosis. With the availability of ELISA assays, these findings could be rapidly clinically translated, providing direct benefits for patients.Graphical

Plasma IGFBP-3 and IGFBP-5 levels are decreased during acute manic episodes in bipolar disorder patients.

Introduction: Bipolar disorder (BD) is a recurrent and disabling psychiatric disorder related to low-grade peripheral inflammation and altered levels of the members of the insulin-like growth factor (IGF) family. The aim of this study was to evaluate the plasma levels of IGF-2, insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, IGFBP-5, IGFBP-7, and inflammatory markers such as tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1β (MIP-1β). Methods: We used the Young Mania Rating Scale (YMRS) to determine the severity of the symptomatology, while proteins were measured by enzyme-linked immunosorbent assay (ELISA). We included 20 patients with BD who suffered a manic episode and 20 controls. Some BD patients (n = 10) were evaluated after a period (17 ± 8days) of pharmacological treatment. Results: No statistical difference was found in IGF-2, IGFBP-1, IGFBP-7, TNF-α, and MIP-1β levels. However, IGFBP-3 and IGFBP-5 levels were found to be statistically decreased in BD patients. Conversely, the MCP-1 level was significantly increased in BD patients, but their levels were normalized after treatment. Intriguingly, only IGFBP-1 levels were significantly decreased after treatment. No significant correlation was found between the YMRS and any of the proteins studied either before or after treatment or between IGF proteins and inflammatory markers. Discussion: To some extent, IGFBP-3 and IGFBP-5 might be further explored as potential indicators of treatment responsiveness or diagnosis biomarkers in BD.

Key mRNAs and lncRNAs of pituitary that affect the reproduction of FecB + + small tail han sheep

BackgroundThe pituitary directly regulates the reproductive process through follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Transcriptomic research on the pituitaries of ewes with different FecB (fecundity Booroola) genotypes has shown that some key genes and lncRNAs play an important role in pituitary function and sheep fecundity. Our previous study found that ewes with FecB + + genotypes (without FecB mutation) still had individuals with more than one offspring per birth. It is hoped to analyze this phenomenon from the perspective of the pituitary transcriptome.ResultsThe 12 Small Tail Han Sheep were equally divided into polytocous sheep in the follicular phase (PF), polytocous sheep in the luteal phase (PL), monotocous sheep in the follicular phase (MF), and monotocous sheep in the luteal phase (ML). Pituitary tissues were collected after estrus synchronous treatment for transcriptomic analysis. A total of 384 differentially expressed genes (DEGs) (182 in PF vs. MF and 202 in PL vs. ML) and 844 differentially expressed lncRNAs (DELs) (427 in PF vs. MF and 417 in PL vs. ML) were obtained from the polytocous-monotocous comparison groups in the two phases. Functional enrichment analysis showed that the DEGs in the two phases were enriched in signaling pathways known to play an important role in sheep fecundity, such as calcium ion binding and cAMP signaling pathways. A total of 1322 target relationship pairs (551 pairs in PF vs. MF and 771 pairs in PL vs. ML) were obtained for the target genes prediction of DELs, of which 29 DEL-DEG target relationship pairs (nine pairs in PF vs. MF and twenty pairs in PL vs. ML). In addition, the competing endogenous RNA (ceRNA) networks were constructed to explore the regulatory relationships of DEGs, and some important regulatory relationship pairs were obtained.ConclusionAccording to the analysis results, we hypothesized that the pituitary first receives steroid hormone signals from the ovary and uterus and that VAV3 (Vav Guanine Nucleotide Exchange Factor 3), GABRG1 (Gamma-Aminobutyric Acid A Receptor, Gamma 1), and FNDC1 (Fibronectin Type III Domain Containing 1) played an important role in this process. Subsequently, the reproductive process was regulated by gonadotropins, and IGFBP1 (Insulin-like Growth Factor Binding Protein 1) was directly involved in this process, ultimately affecting litter size. In addition, TGIF1 (Transforming Growth Factor-Beta-Induced Factor 1) and TMEFF2 (Transmembrane Protein With EGF Like And Two Follistatin Like Domains 2) compensated for the effect of the FecB mutation and function by acting on TGF-β/SMAD signaling pathway, an important pathway for sheep reproduction. These results provided a reference for understanding the mechanism of multiple births in Small Tail Han Sheep without FecB mutation.

Role of the Insulin-like Growth Factor System in Neurodegenerative Disease.

The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in the pathophysiology of neurodegenerative disease. This review focusses on Alzheimer's disease and Parkinson's disease, the two most common neurodegenerative disorders that are increasing in prevalence globally in relation to the aging population and the increasing prevalence of obesity and type 2 diabetes. Rodent models used in the study of the molecular pathways involved in neurodegeneration are described. However, currently, no animal model fully replicates these diseases. Mice with triple mutations in APP, PSEN and MAPT show promise as models for the testing of novel Alzheimer's therapies. While a causal relationship is not proven, the fact that age, obesity and T2D are risk factors in both strengthens the case for the involvement of the IGF system in these disorders. The IGF system is an attractive target for new approaches to management; however, there are gaps in our understanding that first need to be addressed. These include a focus beyond IGF-I on other members of the IGF system, including IGF-II, IGF-binding proteins and the type 2 IGF receptor.

Placental IGFBP1 levels during early pregnancy and the risk of insulin resistance and gestational diabetes

Reduced insulin sensitivity (insulin resistance) is a hallmark of normal physiology in late pregnancy and also underlies gestational diabetes mellitus (GDM). We conducted transcriptomic profiling of 434 human placentas and identified a positive association between insulin-like growth factor binding protein 1 gene (IGFBP1) expression in the placenta and insulin sensitivity at ~26 weeks gestation. Circulating IGFBP1 protein levels rose over the course of pregnancy and declined postpartum, which, together with high gene expression levels in our placenta samples, suggests a placental or decidual source. Higher circulating IGFBP1 levels were associated with greater insulin sensitivity (lesser insulin resistance) at ~26 weeks gestation in the same cohort and in two additional pregnancy cohorts. In addition, low circulating IGFBP1 levels in early pregnancy predicted subsequent GDM diagnosis in two cohorts of pregnant women. These results implicate IGFBP1 in the glycemic physiology of pregnancy and suggest a role for placental IGFBP1 deficiency in GDM pathogenesis.

Selecting potential biomarkers of plasma proteins in mares with endometritis.

Endometritis is a common condition in mares that causes significant economic loss. Lacking obvious clinical signs, the clinical diagnosis of endometritis in mares relies on case-by-case clinical examinations, which can be particularly inefficient in large-scale farms. Therefore, the identification of potential biomarkers can serve as a non-invasive and efficient screening technique for endometritis in mares. To compare the blood proteome between fertile mares and mares with endometritis to identify biomarkers potentially associated with the development of endometritis and validate their predictive potential. Observational and experimental study. Differentially expressed proteins were identified via Data Independent Acquisition (DIA) proteomic profiling in a screening cohort composed of eight healthy mares and eight mares with endometritis. Subsequently, enzyme-linked immunosorbent assay was employed that included a validation cohort of 40 healthy mares and 40 mares with endometritis to verify the accuracy and sensitivity of the identified proteins, thereby establishing a diagnostic threshold. In the screening cohort, 12 proteins were significantly differentially expressed between endometritis mares and healthy controls (p < 0.05, outside the 1/1.2 to 1.2-fold). In the validation experiment, all six screened proteins were assessed with area under the curve (AUC) >0.8. The samples displayed certain levels of individual heterogeneity, and the number of samples analysed was limited. Additionally, the identified biomarkers were primarily associated with generalised inflammation, which potentially limited their specificity for endometritis. Levels of plasma proteins are sensitive indicators of equine endometritis and potential tools for endometritis screening. In plasma, fetuin B, von Willebrand factor, vitamin K-dependent protein C, insulin-like growth factor binding protein 3, interleukin 1 receptor accessory protein, and type II cell cytoskeleton showed great predictive ability, with fetuin B being the best predictor (AUC = 0.93, 95% CI: 0.89-0.98), which performs better when combined with all six detected proteins (AUC = 1, 95% CI: 0.99-1.00).

The Importance of Lung Ultrasound and IGFBP7 (Insulin-like Growth Factor Binding Protein 7) Assessment in Diagnosing Patients with Heart Failure.

Background: In daily practice, there are problems with adequately diagnosing the cause of dyspnea in patients with heart failure with preserved and mildly reduced ejection fractions (HFpEF and HFmrEF). This study aimed to assess the usefulness of lung ultrasound in diagnosing HFpEF and HFmrEF and determine its correlation with IGFBP7 (insulin-like growth factor binding protein 7), NTproBNP (N-terminal pro-B-type natriuretic peptide), and echocardiographic markers. Methods: The research was conducted on 143 patients hospitalized between 2018 and 2020, admitted due to dyspnea, and diagnosed with HFpEF and HFmrEF. Venous blood was collected from all participants to obtain basic biochemical parameters, NTproBNP, and IGFBP7. Moreover, all participants underwent echocardiography and transthoracic lung ultrasound. Two years after hospitalization a follow-up telephone visit was performed. Results: The number of B-lines in the LUS ≥ 16 was determined with a sensitivity of-73% and specificity of-62%, indicating exacerbation of heart failure symptoms on admission. The number of B-lines ≥ 14 on admission was determined as a cut-off point, indicating an increased risk of death during the 2-year follow-up period. The factors that significantly impacted mortality in the study patient population were age and the difference between the number of B-lines on ultrasound at admission and at hospital discharge. IGFBP7 levels had no significant effect on the duration of hospitalization, risk of rehospitalization, or mortality during follow-up. Conclusions: Lung ultrasonography provides additional diagnostic value in patients with HFpEF or HFmrEF and exacerbation of heart failure symptoms. The number of B-lines ≥ 14 may indicate an increased risk of death.

Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer

BackgroundMost primary Triple Negative Breast Cancers (TNBCs) show amplification of the Epidermal Growth Factor Receptor (EGFR) gene, leading to increased protein expression. However, unlike other EGFR-driven cancers, targeting this receptor in TNBC yields inconsistent therapeutic responses.MethodsTo elucidate the underlying mechanisms of this variability, we employ cellular barcoding and single-cell transcriptomics to reconstruct the subclonal dynamics of EGFR-amplified TNBC cells in response to afatinib, a tyrosine kinase inhibitor (TKI) that irreversibly inhibits EGFR.ResultsIntegrated lineage tracing analysis revealed a rare pre-existing subpopulation of cells with distinct biological signature, including elevated expression levels of Insulin-Like Growth Factor Binding Protein 2 (IGFBP2). We show that IGFBP2 overexpression is sufficient to render TNBC cells tolerant to afatinib treatment by activating the compensatory insulin-like growth factor I receptor (IGF1-R) signalling pathway. Finally, based on reconstructed mechanisms of resistance, we employ deep learning techniques to predict the afatinib sensitivity of TNBC cells. ConclusionsOur strategy proved effective in reconstructing the complex signalling network driving EGFR-targeted therapy resistance, offering new insights for the development of individualized treatment strategies in TNBC.

Yak IGFBP3 promotes hepatocyte proliferation through PI3K-Akt signaling pathway

IGFBP3 (Insulin-like growth factor binding protein 3) constitutes a crucial constituent of the insulin-like growth factor (IGF), which are intimately associated with the organism's growth and development processes. Despite its significance, the precise function of IGFBP3 in yak liver development remains largely unexplored. In the present study, we systematically examined the expression profile of IGFBP3 in the liver tissues of yaks across various growth stages, elucidated its influence on the activity of yak hepatocytes, and probed its effects on murine liver development. A comparative analysis revealed that the expression of IGFBP3 was significantly higher in the liver tissue of 5-year-old yaks compared to their 15-month-old and 1-day-old counterparts (P < 0.01). To further validate its biological function, pET-28a-BgIGFBP3 prokaryotic expression vector was constructed. Upon exposing yak hepatocytes to varying concentrations of Bos grunniens (Bg) IGFBP3 protein, we observed augmented cellular activities and elevated colony formation rates. Moreover, our investigation revealed the upregulation of key genes within the PI3K-Akt signaling pathway, including ERBB2, IRS1, PIK3R1, AKT1, RAF1, MAP2K2, and MAPK3, in both yak hepatocyte cultures and murine models. These findings collectively indicate that BgIGFBP3 promotes the proliferation of yak hepatocytes and enhances murine liver development by modulating the PI3K-Akt signaling pathway. The functional relevance of BgIGFBP3 was substantiated through in vivo and in vitro experiments, thereby underscoring its potential as a regulatory factor in liver development processes.

The insulin-like growth factor binding protein-microfibrillar associated protein-sterol regulatory element binding protein axis regulates fibroblast-myofibroblast transition and cardiac fibrosis.

Excessive fibrogenesis is associated with adverse cardiac remodelling and heart failure. The myofibroblast, primarily derived from resident fibroblast, is the effector cell type in cardiac fibrosis. Megakaryocytic leukaemia 1 (MKL1) is considered the master regulator of fibroblast-myofibroblast transition (FMyT). The underlying transcriptional mechanism is not completely understood. Our goal was to identify novel transcriptional targets of MKL1 that might regulate FMyT and contribute to cardiac fibrosis. RNA sequencing (RNA-seq) performed in primary cardiac fibroblasts identified insulin-like growth factor binding protein 5 (IGFBP5) as one of the genes most significantly up-regulated by constitutively active (CA) MKL1 over-expression. IGFBP5 expression was detected in heart failure tissues using RT-qPCR and western blots. Once activated, IGFBP5 translocated to the nucleus to elicit a pro-FMyT transcriptional programme. Consistently, IGFBP5 knockdown blocked FMyT in vitro and dampened cardiac fibrosis in mice. Of interest, IGFBP5 interacted with nuclear factor of activated T-cell 4 (NFAT4) to stimulate the transcription of microfibril-associated protein 5 (MFAP5). MFAP5 contributed to FMyT and cardiac fibrosis by enabling sterol response element binding protein 2 (SREBP2)-dependent cholesterol synthesis. Our data unveil a previously unrecognized transcriptional cascade, initiated by IGFBP5, that promotes FMyT and cardiac fibrosis. Screening for small-molecule compounds that target this axis could yield potential therapeutics against adverse cardiac remodelling.

Tissue Inhibitor Metalloproteinase-2·IGF-Binding Protein 7 for the Prediction of Acute Kidney Injury following Cardiac Surgery

Introduction: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication associated with increased morbidity and mortality. Tissue inhibitor metalloproteinase-2·insulin-like growth factor-binding protein 7 (TIMP-2·IGFBP7) determines tubular stress markers, which may occur prior to tubular damage. Previous studies on the use of TIMP-2·IGFBP7 for the prediction of CSA-AKI showed divergent results. Therefore, this study aimed to explore the predictive value of TIMP-2·IGFBP7 measurements for the early detection of acute kidney injury (AKI) and short-term adverse outcomes after cardiac surgery. Methods: In the prospective cohort study, blood and urine samples were collected 6–12 h after cardiac surgery. Blood samples to monitor serum creatinine levels were additionally extracted from days 1 to 7. AKI was defined based on the KDIGO consensus guidelines. AKI within 7 days following surgery was the primary outcome. The initiation of renal replacement therapy, in intensive care unit mortality, and the combination of both were secondary outcomes. Results: A total of 557 patients were enrolled; 134 (24.06%) of them developed AKI and 33 (5.9%) had moderate or severe AKI. AKI developed more frequently in elderly patients with diabetes or with higher baseline serum creatinine levels. Patients with AKI had higher EuroSCORE II, Cleveland Clinic Score, and simplified renal index (SRI) than those without AKI. Urinary TIMP-2·IGFBP7 was significantly higher in patients with AKI. The area under the curve was 0.66 in predicting all AKI and 0.70 in predicting stages 2 and 3 AKI. The resulting sensitivity and specificity were 44.0% and 83.9%, respectively, for a calculated threshold TIMP-2·IGFBP7 value of 0.265 (ng/mL)2/1,000. The TIMP-2·IGFBP7 values, SRI score, and age were significantly associated with AKI within 7 days postoperatively. A total of 33 patients reached the composite endpoint; the percentage of patients who reached the composite endpoint in the TIMP-2·IGFBP7 of >0.265 (ng/ml)2/1,000 group was significantly higher than that of ≤0.265 (ng/mL)2/1,000 group. Conclusions: Postoperative implementation of TIMP-2·IGFBP7 improved the prediction of CSA-AKI and may aid in identifying patients at risk of short-term adverse outcomes. We identified an ideal calculated cutoff value of 0.265 (ng/mL)2/1,000 for the prediction of CSA-AKI among all AKI patients.

Construction of a risk predictive model of acute kidney injury based on urinary tissue inhibitor of metalloproteinase 2 and insulin-like growth factor-binding protein 7 and its early predictive value in critically ill patients

To establish a risk predictive model nomogram of acute kidney injury (AKI) in critically ill patients by combining urinary tissue inhibitor of metalloproteinase 2 (TIMP2) and insulin-like growth factor-binding protein 7 (IGFBP7), and to verify the predictive value of the model. A prospective observational study was conducted. The patients with acute respiratory failure or circulatory disorder admitted to the intensive care unit (ICU) of Northern Jiangsu People's Hospital from November 2017 to April 2020 were enrolled. The patients were enrolled within 24 hours of ICU admission, and their general conditions and relevant laboratory test indicators were collected. At the same time, urine was collected to determine the levels of biomarkers TIMP2 and IGFBP7, and TIMP2×IGFBP7 was calculated. Patients were divided into non-AKI and AKI groups according to whether grade 2 or 3 AKI occurred within 12 hours after enrollment. The general clinical data and urinary TIMP2×IGFBP7 levels of patients between the two groups were compared. The indicators with P < 0.1 in univariate analysis were included in the multivariate Logistic regression analysis to obtain the independent risk factors for grade 2 or 3 AKI within 12 hours in critical patients. An AKI risk predictive model nomogram was established, and the application value of the model was evaluated. A total of 206 patients were finally enrolled, of whom 54 (26.2%) developed grade 2 or 3 AKI within 12 hours of enrollment, and 152 (73.8%) did not. Compared with the non-AKI group, the patients in the AKI group had higher body mass index (BMI), pre-enrollment serum creatinine (SCr), urinary TIMP2×IGFBP7 and proportion of using vasoactive drugs, and additional exposure to AKI (use of nephrotoxic drugs before enrollment) was more common. Multivariate Logistic regression analysis showed that BMI [odds ratio (OR) = 1.23, 95% confidence interval (95%CI) was 1.10-1.37, P = 0.000], pre-enrollment SCr (OR = 1.01, 95%CI was 1.00-1.02, P = 0.042), use of nephrotoxic drugs (OR = 2.84, 95%CI was 1.34-6.03, P = 0.007) and urinary TIMP2×IGFBP7 (OR = 2.19, 95%CI was 1.56-3.08, P = 0.000) was an independent risk factor for the occurrence of grade 2 or 3 AKI in critical patients. An AKI risk predictive model nomogram was constructed based on the independent risk factors of AKI. Bootstrap validation results showed that the model had good discrimination and calibration in internal validation. Receiver operator characteristic curve (ROC curve) analysis showed that the area under the ROC curve (AUC) of urinary TIMP2×IGFBP7 alone in predicting grade 2 or 3 AKI within 12 hours in critical patients was 0.74 (95%CI was 0.66-0.83), the optimal cut-off value was 1.40 (μg/L) 2/1 000 (sensitivity was 66.7%, specificity was 85.0%), and the predictive performance of the model incorporating urinary TIMP2×IGFBP7 was significantly better than that of the model without urinary TIMP2×IGFBP7 [AUC (95%CI): 0.85 (0.79-0.91) vs. 0.77 (0.70-0.84), P = 0.005], net reclassification index (NRI) was 0.29 (95%CI was 0.08-0.50, P = 0.008), integrated discrimination improvement (IDI) was 0.13 (95%CI was 0.07-0.19, P < 0.001). The AKI risk predictive model based on urinary TIMP2×IGFBP7 has high clinical value and is expected to be used to early predict the occurrence of AKI in critically ill patients.

Insulin-like growth factor-1 and insulin-like growth factor binding protein-3 as early predictors of growth, body composition, and neurodevelopment in preterm infants.

To investigate the relationship between insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3) and long-term growth, body composition, and neurodevelopment in preterm infants. Prospective data were collected from ≤32 weeks gestational age infant cohort (N = 50). IGF-1 and IGFBP-3 concentrations were measured at 1 week (early) and 35 weeks (late) post-menstrual age (PMA). Growth, body composition, and neurodevelopment outcomes were measured at 4 and 12 months PMA. Relationships were measured by linear regression analysis. Early IGFBP-3 concentration was positively associated with neurodevelopment at 12 months PMA. Early IGF-1 concentration was positively associated with weight at 4 months PMA, head circumference at 12 months PMA, and body mass index at 12 months PMA. Late IGFBP-3 concentration was positively associated with weight at 4 months PMA. Further investigation of these associations may lead to novel biomarkers and/or treatments to optimize health outcomes in preterm infants.

Ex Vivo Culture of Circulating Tumor Cells in the Cerebral Spinal Fluid from Melanoma Patients to Study Melanoma-Associated Leptomeningeal Disease.

Melanoma-associated leptomeningeal disease (M-LMD) occurs when circulating tumor cells (CTCs) enter into the cerebral spinal fluid (CSF) and colonize the meninges, the membrane layers that protect the brain and the spinal cord. Once established, the prognosis for M-LMD patients is dismal, with overall survival ranging from weeks to months. This is primarily due to a paucity in our understanding of the disease and, as a consequence, the availability of effective treatment options. Defining the underlying biology of M-LMD will significantly improve the ability to adapt available therapies for M-LMD treatment or design novel inhibitors for this universally fatal disease. A major barrier, however, lies in obtaining sufficient quantities of CTCs from the patient-derived CSF (CSF-CTCs) to conduct preclinical experiments, such as molecular characterization, functional analysis, and in vivo efficacy studies. Culturing CSF-CTCs ex vivo has also proven to be challenging. To address this, a novel protocol for the culture of patient-derived M-LMD CSF-CTCs ex vivo and in vivo is developed. The incorporation of conditioned media produced by human meningeal cells (HMCs) is found to be critical to the procedure. Cytokine array analysis reveals that factors produced by HMCs, such as insulin-like growth factor-binding proteins (IGFBPs) and vascular endothelial growth factor-A (VEGF-A), are important in supporting CSF-CTC survival ex vivo. Here, the usefulness of the isolated patient-derived CSF-CTC lines is demonstrated in determining the efficacy of inhibitors that target the insulin-like growth factor (IGF) and mitogen-activated protein kinase (MAPK) signaling pathways. In addition, the ability to intrathecally inoculate these cells in vivo to establish murine models of M-LMD that can be employed for preclinical testing of approved or novel therapies is shown. These tools can help unravel the underlying biology driving CSF-CTC establishment in the meninges and identify novel therapies to reduce the morbidity and mortality associated with M-LMD.

Multiomics plasma effects of switching from triple antiretroviral regimens to dolutegravir plus lamivudine.

The DOLAM trial revealed that switching from triple antiretroviral therapy (three-drug regimen; 3DR) to dolutegravir plus lamivudine (two-drug regimen; 2DR) was virologically non-inferior to continuing 3DR after 48 weeks of follow-up. Weight increased with 2DR relative to 3DR but it did not impact on metabolic parameters. Multiomics plasma profile was performed to gain further insight into whether this therapy switch might affect specific biological pathways. DOLAM (EudraCT 201500027435) is a Phase 4, randomized, open-label, non-inferiority trial in which virologically suppressed persons with HIV treated with 3DR were assigned (1:1) to switch to 2DR or to continue 3DR for 48 weeks. Untargeted proteomics, metabolomics and lipidomics analyses were performed at baseline and at 48 weeks. Univariate and multivariate analyses were performed to identify changes in key molecules between both therapy arms. Switching from 3DR to 2DR showed a multiomic impact on circulating plasma concentration of N-acetylmuramoyl-L-alanine amidase (Q96PD5), insulin-like growth factor-binding protein 3 (A6XND0), alanine and triglyceride (TG) (48:0). Correlation analyses identified an association among the up-regulation of these four molecules in persons treated with 2DR. Untargeted multiomics profiling studies identified molecular changes potentially associated with inflammation immune pathways, and with lipid and glucose metabolism. Although these changes could be associated with potential metabolic or cardiovascular consequences, their clinical significance remains uncertain. Further work is needed to confirm these findings and to assess their long-term clinical consequences.

Biologically Informed Polygenic Scores for Brain Insulin Receptor Network Are Associated with Cardiometabolic Risk Markers and Diabetes in Women.

To investigate associations between variations in the co-expression-based brain insulin receptor polygenic score and cardiometabolic risk factors and diabetes mellitus. This cross-sectional study included 1,573 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Cardiometabolic markers included body composition, waist circumference, circulating lipids, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein 1 and 3 (IGFBP-1 and -3). Glucose and insulin levels were measured during a standardized 2-hour 75 g oral glucose tolerance test and impaired glucose regulation status was defined by the World Health Organization 2019 criteria. Analyzes were adjusted for population stratification, age, smoking, alcohol consumption, socioeconomic status, chronic diseases, birth weight, and leisure-time physical activity. Multinomial logistic regression indicated that one standard deviation increase in hePRS-IR was associated with increased risk of diabetes mellitus in all participants (adjusted relative risk ratio, 1.17; 95% confidence interval, 1.01 to 1.35). In women, higher hePRS-IR was associated with greater waist circumference and higher body fat percentage, levels of glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, insulin, and IGFBP-1 (all P≤0.02). The mePRS-IR was associated with decreased IGF-1 level in women (P=0.02). No associations were detected in men and studied outcomes. hePRS-IR is associated with sex-specific differences in cardiometabolic risk factor profiles including impaired glucose regulation, abnormal metabolic markers, and unfavorable body composition in women.

Abstract 560: IGF1 induces the expression of CYR61 in metastatic prostate cancer

Abstract The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. Interestingly, CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-I (IGF1). High serum levels of IGF1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. The correlation between PCa aggressiveness and circulating levels of CYR61 and IGF1 is poorly studied. Our goal was to assess the contribution of CYR61-IGF1 interaction to PCa cell proliferation. Their combined role may explain a proportion of aggressive PCa. This study was designed to characterize the role of IGF1-induced expression of CYR61 in metastatic PCa cellular models and to determine if this interaction contributes to aggressive tumor properties (e.g., proliferation, migration, tumorsphere formation). Using immunoblotting, we demonstrated that CYR61 is upregulated in the metastatic cell line PC3. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF1 signaling, we assessed the activation of either the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silencing. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not affect the MAPK pathway. In addition, we found that IGF1 induces protein expression of CYR61 in a time-dependent manner, validated by both immunoblotting and confocal microscopy. In conclusion, these data provided evidence that CYR61 expression is induced by IGF1, and its inhibition decreased the capacity of metastatic PCa cells to proliferate, indicating a potential utilization of CYR61 inhibition in the therapy of metastatic PCa. Citation Format: Greisha L. Ortiz Hernandez, Mya Walker, Leanne Woods-Burnham, Rick A. Kittles, Carlos A. Casiano, Susan Neuhausen. IGF1 induces the expression of CYR61 in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 560.