Molecular biomarkers of dysphagia targeted exercise induced neuroplasticity: A review of mechanistic processes and preliminary data on detraining effects.

While molecular adaptations accompanying neuroplasticity during physical exercises are well-established, little is known about adaptations during dysphagia-targeted exercises. This research article has two primary purposes. First, we aim to review the existing literature on the intersection between resistance (strength) training, molecular markers of neuroplasticity, and dysphagia rehabilitation. Specifically, we discuss the molecular mechanisms of two potential molecular markers: brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) in exercise-induced neuroplasticity. Second, we present preliminary data on the effects of two weeks of detraining on circulating serum BDNF, IGF-1 levels, and expiratory muscle strength. This subset is a part of our more extensive studies related to dysphagia-targeted resistance exercise and neuroplasticity. Five young adult males underwent four weeks of expiratory muscle strength training, followed by two weeks of detraining. We measured expiratory strength, circulating levels of BDNF, and IGF-1 at post-training and detraining conditions. Our results show that expiratory muscle strength, serum BDNF, and IGF-1 levels decreased after detraining; however, this effect was statistically significant only for serum BDNF levels. Oropharyngeal and upper airway musculature involved in swallowing undergoes similar adaptation patterns to skeletal muscles during physical exercise. To fully comprehend the mechanisms underlying the potential neuroplastic benefits of targeted exercise on swallowing functions, mechanistic studies (models) investigating neuroplasticity induced by exercises addressing dysphagia are critical. Such models would ensure that interventions effectively and efficiently achieve neuroplastic benefits and improve patient outcomes, ultimately advancing our understanding of dysphagia-targeted exercise-induced neuroplasticity.

Insulin-like growth factor (IGF) levels in pre-treatment plasma identifying breast cancer: A case control study.

Background: Diabetes (primarily type 2) is linked to a higher risk of breast cancer. Insulin-like growth factor (IGF) is one of the most important factors that affects mitosis and thus inhibits apoptosis. The purpose of this study was to compare the pre-treatment insulin-like growth factor (IGF) levels in breast cancer against normal population. Methods: In this case-control study, 60 patients with breast cancer and 60 healthy controls were enrolled in 2017 and 2018 at Tehran's Shahid-Modarres Hospital. In this study, the blood sugar of the patients was examined before entering the study, and the age of the patients was also within the age limit of 18 to 70 years. They were studied to determine the relationship between insulin-like growth factor (ELISA method) and breast cancer. Results: Both groups have similar IGF-1 levels (Ctrl and Case) (P= 0.188). But, IGF-2 levels were significantly higher in breast cancer patients (373.4 vs. 317.3 ng/ml), (P=0.0001). Conclusion: According to our study, IGF-2 may serve as a prognostic biomarker and potential therapeutic target for breast cancer. However, further investigation is needed to validate this claim.

Unveiling the role of IGF1R in autism spectrum disorder: a multi-omics approach to decipher common pathogenic mechanisms in the IGF signaling pathway.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition marked by impairments in social interaction, communication, and repetitive behaviors. Emerging evidence suggests that the insulin-like growth factor (IGF) signaling pathway plays a critical role in ASD pathogenesis; however, the precise pathogenic mechanisms remain elusive. This study utilizes multi-omics approaches to investigate the pathogenic mechanisms of ASD susceptibility genes within the IGF pathway. Whole-exome sequencing (WES) revealed a significant enrichment of rare variants in key IGF signaling components, particularly the IGF receptor 1 (IGF1R), in a cohort of Chinese Han individuals diagnosed with ASD, as well as in ASD patients from the SFARI SPARK WES database. Subsequent single-cell RNA sequencing (scRNA-seq) of cortical tissues from children with ASD demonstrated elevated expression of IGF receptors in parvalbumin (PV) interneurons, suggesting a substantial impact on their development. Notably, IGF1R appears to mediate the effects of IGF2R on these neurons. Additionally, transcriptomic analysis of brain organoids derived from ASD patients indicated a significant association between IGF1R and ASD. Protein-protein interaction (PPI) and gene regulatory network (GRN) analyses further identified ASD susceptibility genes that interact with and regulate IGF1R expression. In conclusion, IGF1R emerges as a central node within the IGF signaling pathway, representing a potential common pathogenic mechanism and therapeutic target for ASD. These findings highlight the need for further investigation into the modulation of this pathway as a strategy for ASD intervention.

Genome-wide association study for growth traits with 1066 individuals in largemouth bass (Micropterus salmoides).

The largemouth bass is a native species of North America that was first introduced to mainland China in the 1980s. In recent years, it has been extensively farmed in China due to its high meat quality and broad adaptability. In this study, we collected growth trait data from 1,066 largemouth bass individuals across two populations. We generated an average of approximately 7× sequencing coverage for these fish using Illumina sequencers. From the samples, we identified 2,695,687 SNPs and retained 1,809,116 SNPs for further analysis after filtering. To estimate the number of genome-wide effective SNPs, we performed LD pruning with PLINK software and identified 77,935 SNPs. Our GWAS revealed 15 SNPs associated with six growth traits. We identified a total of 24 genes related to growth, with three genes-igf1, myf5, and myf6-directly associated with skeletal muscle development and growth, located near the leading SNP on chromosome 23. Other candidate genes are involved in the development of tissues and organs or other physiological processes. These findings provide a valuable set of SNPs and genes that could be useful for genetic breeding programs aimed at enhancing growth in largemouth bass.

Causal relationship between gut microbiota and insulin-like growth factor 1: a bidirectional two-sample Mendelian randomization study.

Background: The causal relationship between gut microbiota and insulin-like growth factor 1 (IGF-1) remains unclear. The purpose of this study was to explore the causal relationship between gut microbiota and IGF-1 in men and women. Methods: Single-nucleotide polymorphisms (SNPs) related to gut microbiota were derived from pooled statistics from large genome-wide association studies (GWASs) published by the MiBioGen consortium. Pooled data for IGF-1 were obtained from a large published GWAS. We conducted Mendelian randomization (MR) analysis, primarily using the inverse variance weighted (IVW) method. Additionally, we performed sensitivity analyses to enhance the robustness of our results, focusing on assessing heterogeneity and pleiotropy. Results: In forward MR analysis, 11 bacterial taxa were found to have a causal effect on IGF-1 in men; 14 bacterial taxa were found to have a causal effect on IGF-1 in women (IVW, all P < 0.05). After false discovery rate (FDR) correction, all bacterial traits failed to pass the FDR correction. In reverse MR analysis, IGF-1 had a causal effect on nine bacterial taxa in men and two bacterial taxa in women respectively (IVW, all P < 0.05). After FDR correction, the causal effect of IGF-1 on order Actinomycetales (PFDR = 0.049) remains in men. The robustness of the IVW results was further confirmed after heterogeneity and pleiotropy analysis. Conclusion: Our study demonstrates a bidirectional causal link between the gut microbiota and IGF-1, in both men and women.

Maternal-fetal interfaces transcriptome changes associated with placental insufficiency and a novel gene therapy intervention.

The etiology of fetal growth restriction (FGR) is multifactorial, although many cases involve placental insufficiency. Placental insufficiency is associated with inadequate trophoblast invasion resulting in high resistance to blood flow, decreased availability of nutrients, and increased hypoxia. We have developed a non-viral, polymer-based nanoparticle that facilitates delivery and transient gene expression of human insulin-like 1 growth factor (hIGF1) in trophoblast for the treatment of placenta insufficiency and FGR. Using the established guinea pig maternal nutrient restriction (MNR) model of placental insufficiency, the aim of the study was to identify novel pathways in the sub-placenta/decidua that provide insight into the underlying mechanism driving placental insufficiency, and may be corrected with hIGF1 nanoparticle treatment. Pregnant guinea pigs underwent ultrasound-guided sham or hIGF1 nanoparticle treatment at mid-pregnancy, and sub-placenta/decidua tissue was collected 5 days later. Transcriptome analysis was performed using RNA Sequencing on the Illumina platform. The MNR sub-placenta/decidua demonstrated fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion and downregulation of genelists involved in the regulation of cell migration. hIGF1 nanoparticle treatment resulted in marked changes to transporter activity in the MNR + hIGF1 sub-placenta/decidua when compared to sham MNR. Under normal growth conditions however, hIGF1 nanoparticle treatment decreased genelists enriched for kinase signaling pathways and increased genelists enriched for proteolysis indicative of homeostasis. Overall, this study identified changes to the sub-placenta/decidua transcriptome that likely result in inadequate trophoblast invasion and increases our understanding of pathways that hIGF1 nanoparticle treatment acts on in order to restore or maintain appropriate placenta function.

Release kinetics of growth factors loaded into ß-TCP ceramics in an in vitro model.

Introduction: ß-TCP ceramics are bone replacement materials that have recently been tested as a drug delivery system that can potentially be applied to endogenous substances like growth factors found in blood platelets to facilitate positive attributes. Methods: In this work, we used flow chamber loading to load ß-TCP dowels with blood suspensions of platelet-rich plasma (PRP), platelet-poor plasma (PPP), or buffy coat (BC) character. PRP and BC platelet counts were adjusted to the same level by dilution. Concentrations of TGF-ß1, PDGF-AB, and IGF-1 from dowel-surrounding culture medium were subsequently determined using ELISA over 5 days. The influence of alginate was additionally tested to modify the release. Results: Concentrations of TGF-ß1 and PDGF-AB increased and conclusively showed a release from platelets in PRP and BC compared to PPP. The alginate coating reduced the PDGF-AB release but did not reduce TGF-ß1 and instead even increased TGF-ß1 in the BC samples. IGF-1 concentrations were highest in PPP, suggesting circulating levels rather than platelet release as the driving factor. Alginate samples tended to have lower IGF-1 concentrations, but the difference was not shown to be significant. Discussion: The release of growth factors from different blood suspensions was successfully demonstrated for ß-TCP as a drug delivery system with release patterns that correspond to PRP activation after Ca2+-triggered activation. The release pattern was partially modified by alginate coating.

Lactation affects postweaning metabolic profiles, but not follicle size in multiparous sows.

Young sows mobilise body reserves to support milk production during lactation, resulting in a negative energy balance (NEB). This NEB affects the development of follicles and oocytes that give rise to the next litter. Decreased IGF1 levels due to a NEB are thought to play a role in this process. As this has hardly been studied in multiparous sows, the current study focused on relations between lactation BW loss (%), metabolic hormones, and follicle development in multiparous sows at Day 0 and Day 4 after weaning. A total of 31 sows of parity 4.7 ± 2.5 were killed at either Day 0 or Day 4 after weaning. Average BW loss during lactation was 3.3 ± 4.5%, while average backfat loss was 4.1 ± 0.3 mm. The metabolic profile confirmed the metabolic impact of lactation as both non-esterified fatty acid (NEFA), and creatinine levels were higher at Day 0 than that at Day 4. Conversely, serum levels of IGF1 and growth differentiation factor 15 levels were lower on Day 0 than on Day 4. A higher BW loss (%) was related to higher NEFA levels on Day 0, but not on Day 4. IGF1 concentrations in serum and follicle fluid were similar at Day 0 and Day 4 and were not related to follicle size on these days. In conclusion, although lactation affected postweaning metabolic profiles in these multiparous sows, follicle size was not related to these profiles, probably due to the relatively mild BW loss of these sows. IGF1 concentrations were less affected by lactation and did not seem to limit follicle development, as it does in sows experiencing high weight loss.

Distinguishing genetic alterations versus (epi)mutations in Silver-Russell syndrome and focus on the IGF1R gene.

CONTEXT: Silver-Russell Syndrome (SRS) is a growth retardation disorder characterized by pre- and post-natal growth failure, relative macrocephaly at birth, prominent forehead, body asymmetry, and feeding difficulties. The main molecular mechanisms are imprinting alterations at multiple loci, though a small number of pathogenic variants have been reported in the SRS genes IGF2-PLAG1-HMGA2 and CDKN1C. However, around 40% of clinically suspected SRS cases do not achieve a molecular diagnosis, highlighting the necessity to uncover the underlying mechanism in unsolved cases. OBJECTIVE: evaluate the frequency of genetic variants in undiagnosed SRS patients (NH-CSS≥4), and investigate whether (epi)genetic patients may be distinguished from genetic patients. METHODS: 132 clinically SRS patients without (epi)genetic deregulations were investigated by Whole Exome (n=15) and Targeted (n=117) Sequencing. Clinical data from our cohort and from an extensive revision of literature were compared. RESULTS: pathogenic variants were identified in 9.1% of this cohort: 3% in IGF2, PLAG1, and HMGA2 genes, while 3% in the IGF1R gene, associated with IGF-1 resistance (IGF1RES), an SRS differential diagnosis. Overall, IGF2-PLAG1-HMGA2 and IGF1R account for 3.6% of SRS with NH-CSS score ≥ 4. A clinical cross-comparison of (epi)genetic versus genetic SRS underlined (epi)genotype-phenotype correlation, highlighted the prevalence of body asymmetry and relative macrocephaly in mosaic (epi)genetic SRS and recurrence of genetic familial cases. Furthermore, overlapping features were evidenced in (epi)genetic SRS and IGF1RES patients. CONCLUSION: Our study explores the frequency of genetic SRS, underscores body asymmetry as distinctive phenotype in (epi)genetic SRS and suggests IGF1R sequencing in SRS diagnostic flow-chart.

Effects of an acute maximal exercise bout on serum insulin-like growth factor-1 in adults with MDD.

Exercise has acute, positive effects on mood and can lead to antidepressant effects over time when repeated regularly. The mechanisms underlying the antidepressant effects of exercise training are not well known, limiting the prescription of exercise training for depression. Serum Insulin-Like Growth Factor-1 (IGF-1) appears dysregulated in those with Major Depressive Disorder (MDD), suggesting MDD could inhibit or alter the IGF-1 response to exercise. In healthy individuals, exercise has been shown to acutely increase serum IGF-1, which may act positively on the dysregulated IGF-1 system in MDD. Therefore, the purpose of this study was to examine the sensitivity of serum IGF-1 levels to an acute maximal exercise bout in adults with MDD and healthy controls. Additionally, clinical and behavioral factors of MDD are likely to affect this system, such as depression severity, antidepressant usage and physical activity habits. Baseline data were used from a larger trial in Germany (SPeED Study) collected from individuals with mild to moderate MDD (n=113) and healthy controls (n=34) that were matched for age, sex, and education. Demographics, depression severity (Hamilton Depression Rating Scale-17), self-reported antidepressant usage, MVPA (International Physical Activity Questionnaire-Short Form), and blood draws before and after a maximal exercise test were collected. Multiple linear regressions were conducted to determine relationships between depression severity, antidepressant usage, and physical activity with peripheral IGF-1 levels following acute exercise. Covariates included demographic factors and IGF-1 pre-exercise (baseline levels). Acute IGF-1 changes occurred similarly in depression (mean ± SD; 11.3 ± 12.9) as well as healthy adults (11.3 ± 20.4: p>0.05). Neither depression severity, antidepressant use, nor regular physical activity were significant predictors of peripheral IGF-1 levels at baseline or following exercise. Individuals with MDD are likely to have favorable exercise-induced IGF-1 changes regardless of clinical and behavioral differences. Acute exercise increases peripheral IGF-1 briefly, and in response to repeated exercise bouts, the IGF-1 system could normalize over time. The normalization of the IGF-1 system might be a possible mechanism underlying mood increases that occur during exercise with exercise training research warranted.

Nutrition, Growth, and Age at Puberty in Heifers.

Puberty onset and age at first calving have a critical impact on livestock production for good reproductive efficiency of the herd and to reduce the duration of the non-productive stage of the growing heifer. Besides genetic factors, sexual maturation is also affected by environmental factors, such as nutrition, which can account for up to 20% of the observed variability. The rate of body weight gain during growth is considered the main variable influencing the age at puberty, dependent on planes of nutrition in growing animals during the prepubertal-to-pregnancy stage. This paper reviews current knowledge concerning nutrition management and attainment of puberty in heifers, considering the relevance of some indicators such as body measurements and hormones strictly linked to the growth and puberty process. Puberty onset is dependent on the acquisition of adequate subcutaneous adipose tissue mass, as it is the main source of the hormone leptin. Until a certain level, body condition score and age at puberty are negatively correlated, but beyond that, for fatter animals, such correlation is gradually lost. Age at puberty in heifers was reported to be negatively related to IGF-1. Future research should be planned considering the need to standardize the experimental animals and conditions.

Estetrol Inhibits the Prostate Cancer Tumor Stimulators FSH and IGF-1.

Background: The co-treatment of androgen deprivation therapy (ADT) for advanced prostate cancer (PCa) with the fetal estrogen estetrol (E4) may further inhibit endocrine PCa tumor stimulators. We previously reported the suppression of follicle-stimulating hormone (FSH), total and free testosterone, and prostate-specific antigen by ADT+E4. Here, we provide more detailed data on FSH suppression by E4 and present new findings on the effect of ADT+E4 on insulin-like growth factor-1 (IGF-1). Methods: A Phase II, double-blind, randomized, placebo-controlled study (the PCombi study) was conducted in advanced PCa patients treated with ADT. The study assessed the effect of E4 co-treatment with LHRH agonist ADT on tumor stimulators, including FSH and IGF-1. Patients starting ADT were randomized 2:1 to receive either 40 mg E4 (n = 41) or placebo (n = 21) for 24 weeks. Non-parametric analyses were performed on the per-protocol population (PP) and individual changes were visualized. Results: The PP included 57 patients (37 ADT+E4; 20 ADT+placebo). ADT+E4 almost completely suppressed FSH in all patients (98% versus 37%; p < 0.0001). IGF-1 levels decreased by 41% with ADT+E4 versus an increase of 10% with ADT+placebo (p < 0.0001). Conclusions: The almost complete suppression of the tumor stimulator FSH using ADT plus E4 observed in all individual patients in this study, along with the augmented suppression of IGF-1 versus an increase by ADT only, may be clinically relevant and suggest the enhanced anti-cancer treatment efficacy of E4 in addition to the previously reported additional suppression of total and free T and PSA.

Evaluation of insulin-like growth factor-1 in apparently healthy infants and prepubertal Egyptian children with different nutritional statuses.

OBJECTIVES: to estimate insulin-like growth factor-1 (IGF-1) levels in apparently healthy infants and prepubertal children and compare results among different nutritional statuses. METHODS: Our cross-sectional work is a sub-study of a screening project for anemia and nutritional status. We included 252 apparently healthy infants and children with a mean age of 3.7 ± 1.3 years (1.1-6.6), with equal gender distribution. Data retrieved included breastfeeding and anthropometric measures. We tested the stored blood samples for IGF-1 levels. The sample size was reached when all kits were consumed. RESULTS: abnormal anthropometric measures were detected in 32.9%, either a single or multiple, and 86.5% were breastfed. Girls had significantly higher serum IGF-1 levels than boys (P: <0.001), which was noticeable in girls with abnormal nutritional status detected with anthropometry. Breastfeeding showed no significant association with IGF-1 levels. No significant difference was observed between IGF-1 levels between children with normal versus those with abnormal growth measures. Children with overweight or obesity had significantly lower IGF-1 than children with other body mass index (BMI) categories. Serum IGF-1 levels correlated positively with arm muscle area Z scores in infants and toddlers and weight and BMI Z scores in children between three and four. Also, IGF-1 correlated positively with the triceps skinfold Z score and arm muscle area Z score between four and five. CONCLUSIONS: Among studied infants and prepubertal children, serum IGF-1 was significantly higher in girls than boys and was considerably lower in children with overweight or obesity. Breastfeeding showed no association with IGF-1 levels.

Predictive value of IGF-1/IGFBP-3 ratio for thyroid nodules in type 2 diabetic mellitus.

Aims: To explore the predictive value of the IGF-1/IGFBP-3 ratio for the presence of thyroid nodules in patients with type 2 diabetes mellitus (T2DM). Methods: This observational study prospectively enrolled patients with T2DM at the Second Hospital of Jilin University between May 2021 and January 2022. Thyroid nodule (TN) status was determined by ultrasonography. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value of the serum IGF-1/IGFBP-3 molar ratio for TNs. Multivariable logistic regression analysis was conducted to identify risk factors for thyroid nodules in patients with T2DM. Results: A total of 122 patients (mean age ± standard deviation: 52.57 ± 11.71 years; 74 males) were enrolled. 37.7% (n=46) of patients did not have TNs, while 62.3% (n=76) had TNs. The duration of diabetes, age, and HDL-C level were significantly higher in the T2DM group with TNs compared to the group without TNs (all P < 0.05). The area under the ROC curve (AUC) for the combination of IGF-1, IGFBP-3, and the serum IGF-1/IGFBP-3 molar ratio in predicting TNs in T2DM patients was 0.619 (P < 0.001). Additionally, multivariable logistic regression analysis revealed that the duration of diabetes, age, fasting plasma glucose (FPG), fasting insulin (FINS), thyroid-stimulating hormone (TSH), IGF-1, and IGFBP-3 levels were independent risk factors for thyroid nodules, while the serum IGF-1/IGFBP-3 molar ratio level was an independent protective factor for thyroid nodules in patients with T2DM (all P < 0.05). Conclusion: The combination of IGF-1, IGFBP-3, and the serum IGF-1/IGFBP-3 molar ratio may have a better predictive value for TNs in T2DM patients than using any single marker alone. The duration of diabetes, age, FPG, FINS, TSH, IGF-1, IGFBP-3, and the serum IGF-1/IGFBP-3 molar ratio levels were independently associated with thyroid nodules in patients with T2DM.

Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity.

Diminished signaling via insulin/insulin-like growth factor-1 (IGF-1) axis is associated with longevity in different model organisms. IGF-1 gene is highly conserved across species, with only few evolutionary changes identified in it. Despite its potential role in regulating lifespan, no coding variants in IGF-1 have been reported in human longevity cohorts to date. This study investigated the whole exome sequencing data from 2,487 individuals in a cohort of Ashkenazi Jewish centenarians, their offspring, and controls without familial longevity to identify functional IGF-1 coding variants. We identified two likely functional coding variants IGF-1:p.Ile91Leu and IGF-1:p.Ala118Thr in our longevity cohort. Notably, a centenarian specific novel variant IGF-1:p.Ile91Leu was located at the binding interface of IGF-1 - IGF-1R, whereas IGF-1:p.Ala118Thr was significantly associated with lower circulating levels of IGF-1. We performed extended all-atom molecular dynamics simulations to evaluate the impact of Ile91Leu on stability, binding dynamics and energetics of IGF-1 bound to IGF-1R. The IGF-1:p.Ile91Leu formed less stable interactions with IGF-1R's critical binding pocket residues and demonstrated lower binding affinity at the extracellular binding site compared to wild-type IGF-1. Our findings suggest that IGF-1:p.Ile91Leu and IGF-1:p.Ala118Thr variants attenuate IGF-1R activity by impairing IGF-1 binding and diminishing the circulatory levels of IGF-1, respectively. Consequently, diminished IGF-1 signaling resulting from these variants may contribute to exceptional longevity in humans.

Characterization and regulation of the neonatal growth hormone surge.

High neonatal growth hormone (GH) secretion has been described in several species. However, the neuroendocrine mechanisms behind this surge remain unknown. Thus, the pattern of postnatal GH secretion was investigated in mice and rats. Blood GH levels were very high on postnatal day (P)1 and progressively decreased until near zero by P17 in C57BL/6 mice without sex differences. This pattern was similar to that observed in rats, except that female rats showed higher GH levels on P1 than males. In comparison, follicle-stimulating hormone exhibited higher secretion in females during the first three weeks of life. Hypothalamic Sst mRNA and somatostatin neuroendocrine terminals in the median eminence were higher in P20/P21 mice than in newborns. Knockout mice for GH-releasing hormone (GHRH) receptor showed no GH surge, whereas knockdown mice for the Sst gene displayed increased neonatal GH peak. Leptin deficiency caused only minor effects on early-life GH secretion. GH receptor ablation in neurons or the entire body did not affect neonatal GH secretion, but the subsequent reduction in blood GH levels was attenuated or prevented by these genetic manipulations, respectively. This phenotype was also observed in knockout mice for the insulin-like growth factor-1 (IGF-1) receptor in GHRH neurons. Moreover, glucose-induced hyperglycemia overstimulated GH secretion in neonatal mice. In conclusion, GH surge in the first days of life is not regulated by negative feedback loops. However, neonatal GH secretion requires GHRH receptor, and is modulated by somatostatin and blood glucose levels, suggesting that this surge is controlled by hypothalamic-pituitary communication.

Kinase library screening identifies IGF-1R as an oncogenic vulnerability in intrahepatic cholangiocarcinoma stem-like cells.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer of the peripheral bile ducts and is recognized by the abundance of cancer stem-like cells (CSCs) within the tumor mass. While CSC markers in iCCA are well-defined, the molecular vulnerabilities of this subpopulation remain elusive. METHODS: The 96-well, three dimensional (3D) tumorsphere culture was adapted from a well-established CSC model, validated for CSC markers through gene expression analysis. Kinase library screening was then conducted to reveal potential oncogenic vulnerable pathways. RNA interference was utilized to stably silence the candidate gene in three iCCA cell lines and its impact on iCCA cell proliferation and tumorsphere formation efficiency (TFE) was evaluated. RESULTS: Kinase inhibitor library screening identified the top 50 kinase inhibitors crucial for tumorsphere viability, with 11 inhibitors targeting the IGF-1R/PI3K/AKT axis. Further dose-dependent analysis of the top 'hit' inhibitors confirmed IGF-1R as the candidate molecule. Upon stably silencing of IGF-1R, all three iCCA cell lines exhibited decreased AKT activation, impeded proliferation and reduced TFE, indicating a decline in CSC subpopulations. CONCLUSIONS: IGF-1R plays a critical role in maintaining iCCA-stem like cell populations. GENERAL SIGNIFICANCE: Our data highlight the potential utility of IGF-1R as a prognostic marker of iCCA and a therapeutic target for eliminating its CSC subpopulation.

Nanoparticle-mediated delivery of placental gene therapy via uterine artery catheterization in a pregnant rhesus macaque.

Nanoparticles offer promise as a mechanism to non-invasively deliver targeted placental therapeutics. Our previous studies utilizing intraplacental administration demonstrate efficient nanoparticle uptake into placental trophoblast cells and overexpression of human IGF1 (hIGF1). Nanoparticle-mediated placental overexpression of hIGF1 in small animal models of placental insufficiency and fetal growth restriction improved nutrient transport and restored fetal growth. The objective of this pilot study was to extend these studies to the pregnant nonhuman primate and develop a method for local delivery of nanoparticles to the placenta via maternal blood flow from the uterine artery. Nanoparticles containing hIGF1 plasmid driven by the placenta-specific PLAC1 promoter were delivered to a mid-gestation pregnant rhesus macaque via a catheterization approach that is clinically used for uterine artery embolization. Maternal-fetal interface, fetal and maternal tissues were collected four days post-treatment to evaluate the efficacy of hIGF1 treatment in the placenta. The uterine artery catheterization procedure and nanoparticle treatment was well tolerated by the dam and fetus through the four-day study period following catheterization. Nanoparticles were taken up by the placenta from maternal blood as plasmid-specific hIGF1 expression was detected in multiple regions of the placenta via in situ hybridization and qPCR. The uterine artery catheterization approach enabled successful delivery of nanoparticles to maternal circulation in close proximity to the placenta with no concerns to maternal or fetal health in this short-term feasibility study. In the future, this delivery approach can be used for preclinical evaluation of the long-term safety and efficacy of nanoparticle-mediated placental therapies in a rhesus macaque model.

Prolactin deficiency in the context of other pituitary hormone abnormalities : Special issue: hypoprolactinemia: a neglected endocrine disorder.

Prolactin deficiency is rare. It generally occurs when pituitary disorders, such as large pituitary tumors, pituitary apoplexy, and other conditions associated with sellar mass effect lead to global failure of pituitary function and hypopituitarism. In these situiations, prolactin is commonly the last pituitary hormone affected, after growth hormone and gonadotropins are lost and thyroid-stimulating hormone and adrenocorticotopic hormone secretion is impaired. Prolactin deficiency accompanies several congenital syndromes due to mutations in PROP1 and Pit1/ POU1F and in X-linked IGSF1 deficiency syndrome, and several aqcuired conditions including Sheehan syndrome, IgG4-related hypophysitis, and immune checkpoint-inhibitor-induced hypophysitis. In women, prolactin deficiency prevents lactation following childbirth among other symptoms associated with hypopituitarism. Human prolactin is not available commercially as replacement therapy. However, recombinant human prolactin administered daily to women with hypoprolactinemia and alactogenesis was found to lead to the production of significant milk volume sufficient for lactation.

Serum insulin-like growth factor-1 as a potential prognostic biomarker for heart failure with reduced ejection fraction: a meta-analysis.

Background: Most studies have indicated that peripheral insulin-like growth levels factor-1 (IGF-1) is valuable in diagnosing heart failure, although the results have been inconsistent. To help solve the debate, we performed a meta-analysis to explore the relationship between IGF-1 and heart failure (HF). Methods: We conducted an extensive search across various databases such as Embase, Cochrane Library, Pubmed, Medline, and Web of Science on May 30, 2023. From the extensive pool of studies, we selected 16 relevant articles, encompassing a total of 1,380 cases and 1,153 controls, to conduct a rigorous meta-analysis. Results: The total results indicated that there is an association between lower IGF-1 level and HF. The random-effects model yielded a pooled standardized mean difference (SMD) of -0.598 (95% CI: -1.081 to -0.116, P = 0.015). Further subgroup analysis also showed that IGF-1 levels were associated with HF in the age difference ≥5 years subgroup and body mass index difference >1 subgroup. Additionally, significant association between IGF-1 levels and HF were detected in the "serum" samples and "Europe" subgroups. Importantly, we observed IGF-1 showed significant lower levels in patients with reduced ejection fraction (HFrEF) compared to the controls, not in patients with preserved ejection fraction (HFpEF). The Begg's and Egger's tests revealed no indication of publication bias. Conclusions: Our meta-analysis has provided evidence suggesting a substantial correlation between reduced levels of IGF-1 and the occurrence of HF. Further prospective studies are necessary to ascertain the use of IGF-1 as a reliable biomarker for diagnosing HF, especially for HFrEF. But the diagnosis of HFpEF should be cautious.