Growth Factor System Research Articles

Molecular Secrets Revealed: How Diabetes may be Paving the Way for Leukemia.

Type 2 Diabetes Mellitus (T2DM) and leukemia are two major global health concerns, both contributing significantly to morbidity and mortality. Epidemiological evidence demonstrates a strong correlation between T2DM and an increased risk of leukemia, particularly driven by insulin resistance, hyperglycemia, and the resultant metabolic dysregulation. Key shared risk factors, including obesity and chronic inflammation, create a conducive environment for leukemogenesis, intensifying cancer cell proliferation and resistance to standard therapies. Insulin resistance, in particular, triggers oncogenic pathways such as PI3K/AKT and MAPK, exacerbating the aggressive phenotype seen in leukemia patients with T2DM. Additionally, clonal hematopoiesis of indeterminate potential (CHIP) is implicated in the higher leukemia risk observed in diabetic populations, especially among the elderly. Molecular mechanisms like the insulin-like growth factor (IGF) system further highlight the intricate link between these diseases, promoting survival and proliferation of leukemia cells. The coexistence of T2DM in leukemia patients is associated with poorer prognostic outcomes, including increased susceptibility to infections, reduced survival, and greater treatment resistance. Antidiabetic agents, notably metformin and pioglitazone, show promise in enhancing chemotherapy efficacy and improving patient outcomes by targeting metabolic pathways. These results highlight the need for comprehensive treatment approaches that target both metabolic abnormalities and cancer-related mechanisms in patients suffering from both T2DM and leukemia.

VEGF-Virus Interactions: Pathogenic Mechanisms and Therapeutic Applications.

Many types of viruses directly or indirectly target the vascular endothelial growth factor (VEGF) system, which is a central regulator of vasculogenesis and angiogenesis in physiological homeostasis, causing diverse pathologies. Other viruses have been developed into effective therapeutic tools for VEGF modulation in conditions such as cancer and eye diseases. Some viruses may alter the levels of VEGF in the pathogenesis of respiratory syndromes, or they may encode VEGF-like factors, promoting vascular disruption and angiogenesis to enable viruses' systemic spread. Oncogenic viruses may express interactive factors that perturb VEGF's functional levels or downstream signaling, which increases the neovascularization and metastasis of tumors. Furthermore, many viruses are being developed as therapeutic vectors for vascular pathologies in clinical trials. Major examples are those viral vectors that inhibit the role of VEGF in the neovascularization required for cancer progression; this is achieved through the induction of immune responses, by exposing specific peptides that block signaling or by expressing anti-VEGF and anti-VEGF receptor-neutralizing antibodies. Other viruses have been engineered into effective pro- or anti-angiogenesis multitarget vectors for neovascular eye diseases, paving the way for therapies with improved safety and minimal side effects. This article critically reviews the large body of literature on these issues, highlighting those contributions that describe the molecular mechanisms, thus expanding our understanding of the VEGF-virus interactions in disease and therapy. This could facilitate the clinical use of therapeutic virus vectors in precision medicine for the VEGF system.

Characterization of a novel IGFBP-2 transcript in the ovarian granulosa cells of chicken follicles: mRNA expression, function and effect of reproductive hormones and IGF1

Insulin-like growth factor binding protein-2 (IGFBP-2), a binding protein of insulin-like growth factor (IGF) system, regulates the activity of IGFs and also influences cellular function with endogenous activity. In mammals, IGFBP-2 is reported to affect ovarian follicle development and steroidogenesis; however, its role in the chicken ovary is unknown. In this study, we investigated the mRNA expression and function of a novel IGFBP-2 transcript and the effect of reproductive hormones and insulin-like growth factor 1 (IGF1) on its expression in the ovarian granulosa cells of chicken follicles. The mRNA expression of IGFBP-2 was significantly increased in granulosa cells after follicle selection and was higher in hierarchical granulosa cells (Post-GCs) than in pre-hierarchical granulosa cells (Pre-GCs). IGFBP-2 promoted the proliferation and inhibited the apoptosis of both Pre-GCs and Post-GCs, enhanced the mRNA expression of genes involved in progesterone (P4) synthesis in Pre-GCs. However, in Post-GCs, IGFBP-2 inhibited the mRNA expression of these genes and suppressed P4 secretion. The mRNA expression of IGFBP-2 was inhibited by estradiol (E2) and follicle-stimulating hormone (FSH), but enhanced by P4 in Pre-GCs. In Post-GCs, FSH and IGF1 stimulated the mRNA expression of IGFBP-2 synergistically. Knockdown of IGFBP-2 attenuated the stimulatory effect of IGF1 on the mRNA expression of the side chain cleavage enzyme cytochrome P450 family 11 subfamily A member 1 (CYP11A1). These findings indicate that IGFBP-2 is regulated by FSH and IGF1, exerts different functions in Pre-GCs and Post-GCs in regulating IGF1 and plays an important role in chicken follicle development by affecting granulosa cell proliferation and P4 synthesis.

Evolutionary Sequences and Structural Information-driven Reconstruction of New Insulin-like Growth Factor-I Peptide Variants.

Insulin-like growth factor-I (IGF-I) is crucial in controlling cell growth, proliferation, and apoptosis. Its strong link to the development of cancers such as breast, prostate, lung, thyroid, and colorectal has positioned the IGF-1 signalling pathway as a promising target for novel cancer therapies. When activated, the IGF-1 receptor (IGF-1R) binds to IGF-I, playing a central role in promoting tumour cell growth and survival. In this study, we combined evolutionary sequences with structural and functional data of IGF-1 to reconstruct ancestral sequences and design novel IGF-1 peptide variants. The insulin-like growth factor system exhibits a vast sequence diversity, yet it shares a similar structural topology with conserved three pairs of disulfide linkages. Our study reveals that IGF-1 is associated with the IGF system of cell surface receptors through protein-protein interactions. Reconstructed IGF-1 variants show similar structure fold to reported viral IGF-1 competitive antagonists. This new insight guides the design of novel natural IGF-1 mimic peptides. It enhances our understanding of IGF-1's functionality and opens new avenues for the development of therapeutic peptides and small molecules as anticancer agents.

The Insulin-like Growth Factor System and Aging.

There is strong evidence that insulin-like growth factor (IGF) signaling is involved in fundamental aspects of the aging process. However, the extracellular part of the IGF system is complex with various receptors, ligand effectors, high affinity IGF binding proteins, proteinases and endogenous inhibitors that all, along with their biological context, must be considered. The IGF system components are evolutionarily conserved, underscoring the importance of understanding this system in physiology and pathophysiology. This review will briefly describe the different components of the IGF system and then discuss past and current literature regarding the IGFs and aging, with a focus on cellular senescence, model organisms of aging, centenarian genetics, and three age-related diseases - pulmonary fibrosis, Alzheimer's disease, and macular degeneration - in appropriate murine models and in humans. Commonalities in mechanism suggest conditions where IGF system components may be disease drivers and potential targets in promoting healthy aging in humans.

Regression-based rectangular tolerance regions as reference regions in laboratory medicine

Reference ranges are invaluable in laboratory medicine, as these are indispensable tools for the interpretation of laboratory test results. When assessing measurements on a single analyte, univariate reference intervals are required. In many cases, however, measurements on several analytes are needed by medical practitioners to diagnose more complicated conditions such as kidney function or liver function. For such cases, it is recommended to use multivariate reference regions, which account for the cross-correlations among the analytes. Traditionally, multivariate reference regions (MRRs) have been constructed as ellipsoidal regions. The disadvantage of such regions is that they are unable to detect component-wise outlying measurements. Because of this, rectangular reference regions have recently been put forward in the literature. In this study, we develop methodologies to compute rectangular MRRs that incorporate covariate information, which are often necessary in evaluating laboratory test results. We construct the reference region using tolerance-based criteria so that the resulting region possesses the multiple use property. Results show that the proposed regions yield coverage probabilities that are accurate and are robust to the sample size. Finally, we apply the proposed procedures to a real-life example on the computation of an MRR for three components of the insulin-like growth factor system.

Gene deletion of Pregnancy-associated Plasma Protein-A (PAPP-A) improves pathology and cognition in an Alzheimer's disease mouse model

Alzheimer's disease (AD) is a progressive neurodegenerative disease of age with no effective preventative or treatment approaches. Deeper understanding of the mechanisms underlying the accumulation of toxic β-amyloid oligopeptides and the formation of amyloid plaque in AD has the potential to identify new therapeutic targets. Prior research links the insulin-like growth factor (IGF) system to pathologic mechanisms underlying AD. Suppression of local IGF-I receptor (IGFIR) signaling in AD mice has been shown to reduce plaque formation in the brain and delay neurodegeneration and behavioral changes. However, direct inhibitors of IGFIR signaling are not a viable treatment option for AD due to the essentiality of the IGFIR in physiological growth and metabolism. We have previously demonstrated a more selective means to reduce local IGFIR signaling through inhibition of PAPP-A, a novel zinc metalloprotease that regulates local IGF-I bioavailability through cleavage of inhibitory IGF binding proteins. Here we tested if deletion of PAPP-A in a mouse model of AD provides protection against pathology and behavioral changes. We show that compared to AD mice, AD/PAPP-A KO mice had significantly less plaque burden, reduced astrocytic activation, decreased IGF-IR activity, and improved cognition. Human senile AD plaques showed specific immunostaining for PAPP-A. Thus, inhibition of PAPP-A expression or activity may represent a novel treatment strategy for AD.

Circulating proteomic profiles in women with morbid obesity compared to normal-weight women

In this study, we aimed to evaluate circulating proteomic levels in women with morbid obesity (MO) compared to normal-weight (NW) women. Moreover, we have compared the proteomic profile between women with metabolically healthy (MH) MO and those with type 2 diabetes mellitus (T2DM). The study included 66 normal-weight (NW) women and 129 women with MO (54 MH and 75 with T2DM). Blood samples were processed for proteomics, involving protein extraction, quantification, digestion with peptide labelling and Nano (liquid chromatography (LC)-(Orbitrap) coupled to mass/mass spectrometry (MS/MS) analysis. Statistical analyses were performed. We identified 257 proteins. Women with MO showed significantly increased levels of 35 proteins and decreased levels of 45 proteins compared to NW women. Enrichment analysis of metabolic pathways revealed significant findings. Women with MO have an altered proteomic profile compared to normal-weight women, involving proteins significantly related to chylomicron assembly, complement cascade, clotting pathways and the insulin growth factor system. Regarding women with MO and T2DM compared to MHMO women, the proteomic profile shows alterations in mostly the same pathways associated with obesity. These findings confirmed in previous reports can help us better understand the pathophysiology of obesity and associated diseases. SignificanceWomen with morbid obesity (MO) exhibit substantial proteomic alterations compared to normal-weight (NW) women, involving 80 proteins. These alterations are linked to significant metabolic pathways, including chylomicron assembly, complement cascade, clotting pathways and the insulin growth factor system. Additionally, women with MO and type 2 diabetes mellitus (T2DM) compared to metabolically healthy MO women share similar proteomic changes than the first comparison. These findings enhance our understanding of the pathophysiology of obesity and associated diseases, offering potential targets for therapeutic intervention.

Participation of the insulin-like growth factor system in the early maturity in juvenile male European sea bass

It is known that the insulin-like growth factor (Igf) system is involved in gonadal development and, in turn, reproduction in vertebrates. In this study, the circulating levels of Igf-1 and follicle-stimulating hormone (Fsh) were assessed as physiological signals related to gonadal maturation stage in juvenile male European sea bass at 1 year of age. The seasonal profiles of Igf-1 and Fsh were analyzed in non-precocious (NP) and precocious (PR) fish during the early onset of puberty. Subsequently, gonadal expression patterns of the three igf genes and their two receptors, igf-1r and igf-2r, were studied during their first year of life. The analysis was continued to evaluate the mRNA expression profiles of three genes (sox17, scf, nf2) mediating spermatogenesis progression. Collectively, these results demonstrated that PR males have higher circulating levels of Igf-1 as compared to NP fish before and during the putative gonadal development period (PGD). Plasma Fsh levels were significantly higher in PR males as compared to NP fish before the start of the PGD period, although this was followed by a decrease in Fsh levels and a subsequent recovery, coinciding with the reproductive season (February). Results showed that the total variance associated with the appearance of precocity may be explained by the contribution of factors such as body size and plasma levels of Igf-1, Fsh and sex steroids in male sea bass. Expression of igfs was high during stage I, and this was significantly correlated with the expression of genes related to cell cycle progression, including sox17, scf and nf2. Finally, the decreased expression of all these gonadal factors in precocious animals suggests their potential involvement in regulating the proliferative growth of spermatogonia and supporting cells during the early stages of spermatogenesis, thus evoking the onset of puberty in male sea bass.

Gene expression changes in Brodmann’s Area 46 differentiate epidermal growth factor and immune system interactions in schizophrenia and mood disorders

How early in life stress-immune related environmental factors increase risk predisposition to schizophrenia remains unknown. We examined if pro-inflammatory changes perturb the brain epidermal growth factor (EGF) system, a system critical for neurodevelopment and mature CNS functions including synaptic plasticity. We quantified genes from key EGF and immune system pathways for mRNA levels and eight immune proteins in post-mortem dorsolateral prefrontal (DLPFC; Brodmann’s Area (BA) 46) and orbitofrontal (OFC; BA11) cortices from people with schizophrenia, mood disorders and neurotypical controls. In BA46, 64 genes were differentially expressed, predominantly in schizophrenia, where attenuated expression of the MAPK-ERK, NRG1-PI3K-AKT and mTOR cascades indicated reduced EGF system signalling, and similarly diminished immune molecular expression, notably in TLR, TNF and complement pathways, along with low NF-κB1 and elevated IL12RB2 protein levels were noted. There was nominal evidence for altered convergence between ErbB-PI3K-AKT-mTOR and TLR pathways in BA46 in schizophrenia. Comparatively minimal changes were noted in BA11. Overall, distinct pathway gene expression changes may reflect variant pathological processes involving immune and EGF system signalling between schizophrenia and mood disorder, particularly in DLPFC. Further, the abnormal convergence between innate immune signalling and candidate EGF signalling pathways may indicate a pathologically important interaction in the developing brain in response to environmental stressors.

IGF Signaling in the Heart in Health and Disease.

One of the most vital processes of the body is the cardiovascular system's proper operation. Physiological processes in the heart are regulated by the balance of cardioprotective and pathological mechanisms. Theinsulin-like growth factor system (IGF system, IGF signaling pathway) plays a pivotal role in regulating growth and development of various cells and tissues. In myocardium, the IGF system provides cardioprotective effects as well as participates in pathological processes. This review summarizes recent data on the role of IGF signaling in cardioprotection and pathogenesis of various cardiovascular diseases, as well as analyzes severity of these effects in various scenarios.

Palmitic Acid Modulation of the Insulin-Like Growth Factor System in Hypothalamic Astrocytes and Neurons

Introduction: Insulin-like growth factor (IGF)1 and IGF2 have neuroprotective effects, but less is known regarding how other members of the IGF system, including IGF binding proteins (IGFBPs) and the regulatory proteinase pappalysin-1 (PAPP-A) and its endogenous inhibitor stanniocalcin-2 (STC2) participate in this process. Here, we analyzed whether these members of the IGF system are modified in neurons and astrocytes in response to palmitic acid (PA), a fatty acid that induces cell stress when increased centrally. Methods: Primary hypothalamic astrocyte cultures from male and female PND2 rats and the pro-opiomelanocortin (POMC) neuronal cell line, mHypoA-POMC/GFP-2, were treated with PA, IGF1 or both. To analyze the role of STC2 in astrocytes, siRNA assays were employed. Results: In astrocytes of both sexes, PA rapidly increased cell stress factors followed by increased Pappa and Stc2 mRNA levels and then a decrease in Igf1, Igf2, and Igfbp2 expression and cell number. Exogenous IGF1 did not revert these effects. In mHypoA-POMC/GFP-2 neurons, PA reduced cell number and Pomc and Igf1 mRNA levels, and increased Igfbp2 and Stc2, again with no effect of exogenous IGF1. PA increased STC2 expression, but no effects of decreasing its levels by interference assays or exogenous STC2 treatment in astrocytes were found. Conclusions: The response of the IGF system to PA was cell and sex specific, but no protective effects of the IGFs were found. However, the modifications in hypothalamic PAPP-A and STC2 indicate that further studies are required to determine their role in the response to fatty acids and possibly in metabolic control.

Plasma soluble fms-like tyrosine kinase-1, placental growth factor, and vascular endothelial growth factor system gene variants as predictors of survival in heart failure.

Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt-1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF. ELISA assays for sFlt-1, PlGF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt-1 or PlGF levels were genotyped. sFlt-1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All-cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt-1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt-1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt-1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57-16.1; p < 0.001) in PEOPLE, independent of age, NT-proBNP, ischaemic aetiology, diabetic status and beta-blocker therapy. Plasma sFlt-1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF.

A novel role of IGFBP5 in the migration, invasion and spheroids formation induced by IGF-I and insulin in MCF-7 breast cancer cells

PurposeThe insulin-like growth factor (IGF) system includes IGF-I, IGF-II insulin and their membrane receptors. IGF system also includes a family of proteins namely insulin-like growth factor-binding proteins (IGFBPs) composed for six major members (IGFBP-1 to IGFBP6), which capture, transport and prolonging half-life of IGFs. However, it has been described that IGFBPs can also have other functions.MethodsIGFBP5 expression was inhibited by shRNAs, migration was analyzed by scratch-wound assays, invasion assays were performed by the Boyden chamber method, spheroids formation assays were performed on ultra-low attachment surfaces, expression and phosphorylation of proteins were analyzed by Western blot.ResultsIGFBP5 is a repressor of IGF-IR expression, but it is not a repressor of IR in MCF-7 breast cancer cells. In addition, IGFBP5 is a suppressor of migration and MMP-9 secretion induced by IGF-I and insulin, but it does not regulate invasion in MCF-7 cells. IGFBP5 also is a repressor of MCF-7 spheroids formation. However treatment with 340 nM rescues the inhibitory effect of IGFBP in the MCF-7 spheroids formation.ConclusionIGFBP5 regulates IGF-IR expression, migration and MMP-9 secretion induced by IGF-I and/or insulin, and the spheroids formation in MCF-7 breast cancer cells.

Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches.

Dysregulation of the insulin-like growth factor (IGF) system determines the onset of various pathological conditions, including cancer. Accordingly, therapeutic strategies have been developed to block this system in tumor cells, but the results of clinical trials have been disappointing. After decades of research in the field, it is safe to say that one of the major reasons underlying the poor efficacy of anti-IGF-targeting agents is derived from an underestimation of the molecular complexity of this axis. Genetic, transcriptional, post-transcriptional and functional interactors interfere with the activity of canonical components of this axis, supporting the need for combinatorial approaches to effectively block this system. In addition, cancer cells interface with a multiplicity of factors from the extracellular compartment, which strongly affect cell destiny. In this review, we will cover novel extracellular mechanisms contributing to IGF system dysregulation and the implications of such dangerous liaisons for cancer hallmarks and responses to known and new anti-IGF drugs. A deeper understanding of both the intracellular and extracellular microenvironments might provide new impetus to better decipher the complexity of the IGF axis in cancer and provide new clues for designing novel therapeutic approaches.

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.

The Role of Insulin-like Growth Factor (IGF) System in the Corneal Epithelium Homeostasis-From Limbal Epithelial Stem Cells to Therapeutic Applications.

The corneal epithelium, comprising three layers of cells, represents the outermost portion of the eye and functions as a vital protective barrier while concurrently serving as a critical refractive structure. Maintaining its homeostasis involves a complex regenerative process facilitated by the functions of the lacrimal gland, tear film, and corneal nerves. Crucially, limbal epithelial stem cells located in the limbus (transitional zone between the cornea and the conjunctiva) are instrumental for the corneal epithelium integrity by replenishing and renewing cells. Re-epithelialization failure results in persistent defects, often associated with various ocular conditions including diabetic keratopathy. The insulin-like growth factor (IGF) system is a sophisticated network of insulin and other proteins essential for numerous physiological processes. This review examines its role in maintaining the corneal epithelium homeostasis, with a special focus on the interplay with corneal limbal stem cells and the potential therapeutic applications of the system components.

IGFBP-rP1 is a potential therapeutic target in androgenic alopecia.

The available interventions for androgenic alopecia (AGA), the most common type of hair loss worldwide, remain limited. The insulin growth factor (IGF) system may play an important role in the pathogenesis of AGA. However, the exact role of IGF binding protein-related protein 1 (IGFBP-rP1) in hair growth and AGA has not been reported. In this study, we first found periodic variation in IGFBP-rP1 during the hair cycle transition in murine hair follicles (HFs). We further demonstrated that IGFBP-rP1 levels were lower in the serum and scalp HFs of individuals with AGA than in those of healthy controls. Subsequently, we verified that IGFBP-rP1 had no cytotoxicity to human outer root sheath cells (HORSCs) and that IGFBP-rP1 reversed the inhibitory effects of DHT on the migration of HORSCs invitro. Finally, a DHT-induced AGA mouse model was created. The results revealed that the expression of IGFBP-rP1 in murine HFs was downregulated after DHT treatment and that subcutaneous injection of IGFBP-rP1 delayed catagen occurrence and prolonged the anagen phase of HFs in mice with DHT-induced AGA. The present work shows that IGFBP-rP1 is involved in hair cycle transition and exhibits great therapeutic potential for AGA.

Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.

Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P < 1.0 × 10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets.

IGF1R inhibition and PD-1 blockade improve anti-tumor immune response in epithelial ovarian cancer.

The insulin-like growth factor (IGF) system plays a key role in regulating growth and invasiveness in epithelial ovarian cancer (EOC) and is considered a promising therapeutic target. EOC is an immunosuppressive disease, although there are limited data about the involvement of the IGF1R system in the anti-tumor immune response in the EOC microenvironment. In the current study, we hypothesized that IGF 1 receptor (IGF1R) involvement in the maturation of dendritic cells (DC) with the co-inhibition of IGF1R and PD-1 would affect the EOC microenvironment. We found that DC pretreated with IGF1R inhibitor resulted in fewer EOC cells. Moreover, in vivo experiments conducted with an EOC mouse model, with anti-PD-1/IGF1R combined, resulted in lower tumor weight compared to individual treatments. Additionally, anti-PD-1/IGF1R treatment increased DC by 34% compared with AEW-541 and 40% with anti-PD-1. The combined treatment increased CD8+ T-cell levels compared to AEW-541 alone. RNA-seq data analysis indicated that anti-PD-1/IGF1R led to a more potent immune response, as reflected by altered gene expression levels related to anti-tumor immune response, compared with either treatment alone. These findings provide novel evidence that IGF1R axis inhibition combined with PD-1 blockade may be an effective therapeutic strategy for selected EOC patient populations.