IGF-1R Research Articles

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HomeCirculation ResearchVol. 131, No. 3In this Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn this Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published21 Jul 2022https://doi.org/10.1161/RES.0000000000000562Circulation Research. 2022;131:185Flavin Containing Monooxygenase 2 Prevents Cardiac Fibrosis via CYP2J3-SMURF2 Axis (p 189)FMO2 prevents heart fibrosis after injury, report Ni et al.Download figureDownload PowerPointEven if a patient survives a myocardial infarction (MI), the resulting fibrosis may impair heart function to such an extent the patient ultimately succumbs to heart failure. With the aim of informing fibrosis prevention and treatment strategies, Ni and colleagues searched for genes involved in the process. They performed a transcriptome analysis of heart tissue from rats that had or had not been subjected to MI and found that the gene for flavin-containing monooxygenase 2 (FMO2) was dramatically down-regulated in the MI hearts. Similarly, decreased FMO2 expression was observed in mouse, monkey and human heart tissue after MI. Suppression of FMO2 expression in the hearts of live rats prompted increased myocardial fibrosis and reduced heart function, while ramping up cardiac FMO2 expression immediately after MI reduced scarring and improved function in rodent and monkey hearts compared with controls. The team went on to determine the mechanism of FMO2’s anti-fibrotic effect, showing it interacted with the cytochrome CYP2J3 and disrupted SMAD signaling, which ultimately suppressed fibrotic genes. They also showed that such fibrotic genes could be suppressed in human cardiac scar fibroblasts by boosting FMO2–a strategy that could potentially be adapted clinically to reduce the risk of heart failure.SIRPα Mediates IGF1 Receptor in Cardiomyopathy-Induced by Chronic Kidney Disease (p 207)In chronic kidney disease, SIRPα impairs insulin signaling in the heart, say Thomas et al.Download figureDownload PowerPointCardiomyopathy is a common complication of chronic kidney disease (CKD), but what leads to the heart damage is not fully understood. CKD can exacerbate or induce high blood pressure, which in turn can damage the heart. However, signs of cardiomyopathy can occur at early stages of CKD when blood pressure might still be relatively normal. Thomas and colleagues suspected that signal regulatory protein α (SIRPα) might be an alternative trigger. Levels of SIRPα are elevated in the skeletal muscles of CKD model mice where the protein disrupts insulin signaling and causes muscle atrophy. Sure enough, the team’s new work shows SIRPα causes similar problems in the heart. SIRPα levels were elevated in the hearts of CKD mice and were correlated with impaired insulin/IGF1 receptor signaling, myocardial dysfunction and fibrosis. Furthermore, suppression of SIRPα in these CKD mice prevented myocardial fibrosis and improved heart function. Using biochemical analyses, the team revealed that SIRPα exerts its effect through direct interaction with, and inhibition of, the IGF1 receptor. Together the results suggest that SIRPα could be not only a marker of insulin resistance and cardiomyopathy in CKD, but also a clinical target for treating or preventing this heart damage.Mitochondrial H2S Regulates BCAA Catabolism in Heart Failure (p 222)Li et al suggest a link between hydrogen sulfide production and animo acid metabolism in heart failure.Download figureDownload PowerPointWhile hydrogen sulfide (H2S) is poisonous to humans if inhaled, evidence suggests in its endogenously produced form it protects the heart from myocardial infarction, arrhythmia and other heart-damaging conditions. One of the cellular H2S-producing enzymes is 3-mercaptopyruvate sulfurtransferase (3-MST) and, after a heart injury, mice lacking this enzyme have exacerbated cardiac dysfunction and severe exercise intolerance compared with control animals. To understand how 3-MST might protect the heart, Li and colleagues performed a metabolomic screen in mice with and without 3-MST and found those lacking the enzyme had defects in their catabolism of the branched-chain amino acids (BCAAs) leucine, isoleucine and valine. Importantly, pharmacologically reducing the levels of these BCAAs attenuated the effects of injury in the hearts of 3-MST-lacking mice and control animals. It is not clear how 3-MST regulates BCAA catabolism, but the team’s finding that heart tissue from patients with end-stage heart failure has unusually low levels of 3-MST, suggests it would be worthwhile examining BCAA catabolism in such tissue too. If the results hold true, then modulation of 3-MST, or indeed BCAAs or H2S, could be investigated as potential treatment strategies. Previous Back to top Next FiguresReferencesRelatedDetails July 22, 2022Vol 131, Issue 3 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000562 Originally publishedJuly 21, 2022 PDF download Advertisement

Integrated DNA Copy Number and Expression Profiling Identifies IGF1R as a Prognostic Biomarker in Pediatric Osteosarcoma.

Osteosarcoma is a primary malignant bone tumor arising from bone-forming mesenchymal cells in children and adolescents. Despite efforts to understand the biology of the disease and identify novel therapeutics, the survival of osteosarcoma patients remains dismal. We have concurrently profiled the copy number and gene expression of 226 osteosarcoma samples as part of the Strategic Partnering to Evaluate Cancer Signatures (SPECS) initiative. Our results demonstrate the heterogeneous landscape of osteosarcoma in younger populations by showing the presence of genome-wide copy number abnormalities occurring both recurrently among samples and in a high frequency. Insulin growth factor receptor 1 (IGF1R) is a receptor tyrosine kinase which binds IGF1 and IGF2 to activate downstream pathways involved in cell apoptosis and proliferation. We identify prevalent amplification of IGF1R corresponding with increased gene expression in patients with poor survival outcomes. Our results substantiate previously tenuously associated copy number abnormalities identified in smaller datasets (13q34+, 20p13+, 4q35-, 20q13.33-), and indicate the significance of high fibroblast growth factor receptor 2 (FGFR2) expression in distinguishing patients with poor prognosis. FGFR2 is involved in cellular proliferation processes such as division, growth and angiogenesis. In summary, our findings demonstrate the prognostic significance of several genes associated with osteosarcoma pathogenesis.

Uwhangchungsimwon Inhibits Oxygen Glucose Deprivation/Re-Oxygenation-Induced Cell Death through Neuronal VEGF and IGF-1 Receptor Signaling and Synaptic Remodeling in Cortical Neurons.

Uwhangchungsimwon (UCW), a multi-component herbal product, has long been used to treat vascular diseases such as headache, dizziness, high blood pressure, and stroke. Though the prophylactic actions of UCW are well known, insufficient experimental evidence exists on its effectiveness against stroke. Here, we investigated the mechanism underlying the efficacy of UCW in oxygen glucose deprivation/re-oxygenation (OGD/R)-injury to the primary cortical neurons using an in vitro ischemia model. Neurons secrete vascular endothelial growth factor (VEGF), which acts as a neurotrophic factor in response to an ischemic injury. VEGF modulates neuroprotection and axonal outgrowth by activating the VEGF receptors and plays a critical role in vascular diseases. In this study, cortical neurons were pretreated with UCW (2, 10, and 50 µg/mL) for 48 h, incubated in oxygen-glucose-deprived conditions for 2 h, and further reoxygenated for 24 h. UCW effectively protected neurons from OGD/R-induced degeneration and cell death. Moreover, the role of UCW in sustaining protection against OGD/R injury is associated with activation of VEGF-VEGFR and insulin-like growth factor 1 receptor expression. Therefore, UCW is a potential herbal supplement for the prevention of hypoxic-ischemic neuronal injury as it may occur after stroke.

Preclinical Evaluation of a New Format of 68Ga- and 111In-Labeled Affibody Molecule ZIGF-1R:4551 for the Visualization of IGF-1R Expression in Malignant Tumors Using PET and SPECT

The Insulin-like growth factor-1 receptor (IGF-1R) is a molecular target for several monoclonal antibodies undergoing clinical evaluation as anticancer therapeutics. The non-invasive detection of IGF-1R expression in tumors might enable stratification of patients for specific treatment and improve the outcome of both clinical trials and routine treatment. The affibody molecule ZIGF-1R:4551 binds specifically to IGF-1R with subnanomolar affinity. The goal of this study was to evaluate the 68Ga and 111In-labeled affibody construct NODAGA-(HE)3-ZIGF-1R:4551 for the imaging of IGF-1R expression, using PET and SPECT. The labeling was efficient and provided stable coupling of both radionuclides. The two imaging probes, [68Ga]Ga-NODAGA-(HE)3-ZIGF-1R:4551 and [111In]In-NODAGA-(HE)3-ZIGF-1R:4551, demonstrated specific binding to IGF-1R-expressing human cancer cell lines in vitro and to IGF-1R-expressing xenografts in mice. Preclinical PET and SPECT/CT imaging demonstrated visualization of IGF-1R-expressing xenografts already one hour after injection. The tumor-to-blood ratios at 3 h after injection were 7.8 ± 0.2 and 8.0 ± 0.6 for [68Ga]Ga-NODAGA-(HE)3-ZIGF-1R:4551 and [111In]In-NODAGA-(HE)3-ZIGF-1R:4551, respectively. In conclusion, a molecular design of the ZIGF-1R:4551 affibody molecule, including placement of a (HE)3-tag on the N-terminus and site-specific coupling of a NODAGA chelator on the C-terminus, provides a tracer with improved imaging properties for visualization of IGF-1R in malignant tumors, using PET and SPECT.

Insulin-Like Growth Factor 1 Attenuates the Pro-Inflammatory Phenotype of Neutrophils in Myocardial Infarction.

Acute myocardial infarction (MI) induces an extensive sterile inflammation, which is dominated in the early phase by invading neutrophils and monocytes/macrophages. The inflammatory response after MI critically affects infarct healing and cardiac remodeling. Therefore, modulation of cardiac inflammation may improve outcome post MI. Insulin-like growth factor 1 (IGF1) treatment reduces infarct size and improves cardiac function after MI via IGF1 receptor mediated signaling in myeloid cells. Our study aimed to investigate the effect of IGF1 on neutrophil phenotype both in vitro and in vivo after MI. We show that IGF1 induces an anti-inflammatory phenotype in bone marrow derived neutrophils. On the molecular and functional level IGF1 treated neutrophils were indistinguishable from those induced by IL4. Surprisingly, insulin, even though it is highly similar to IGF1 did not create anti-inflammatory neutrophils. Notably, the IGF1 effect was independent of the canonical Ras/Raf/ERK or PI3K/AKT pathway, but depended on activation of the JAK2/STAT6 pathway, which was not activated by insulin treatment. Single cell sequencing analysis 3 days after MI also showed that 3 day IGF1 treatment caused a downregulation of pro-inflammatory genes and upstream regulators in most neutrophil and many macrophage cell clusters whereas anti-inflammatory genes and upstream regulators were upregulated. Thus, IGF1 acts like an anti-inflammatory cytokine on myeloid cells in vitro and attenuates the pro-inflammatory phenotype of neutrophils and macrophages in vivo after MI. IGF1 treatment might therefore represent an effective immune modulatory therapy to improve the outcome after MI.

Vitexin and Isovitexin Act through Inhibition of Insulin Receptor to Promote Longevity and Fitness in Caenorhabditis elegans

Vitexin and isovitexin are natural plant nutraceuticals for human health and longevity. This research investigates the underlying mechanisms of vitexin and isovitexin on aging and health. The vital role of DAF-2/insulin-like growth factor-1 receptor (IGFR) is illustrated in the insulin/insulin-like growth signaling pathway (IIS) modulated by vitexin and isovitexin. In vitro, in vivo models and molecular docking methods are performed to explore the antiaging mechanism of vitexin and isovitexin. Vitexin and isovitexin (50 and 100µM) extended the lifespan of Caenorhabditis elegans. The declines of pharyngeal pumping and body bending rates, and the increase of intestinal lipofuscin accumulation, three markers of aging, are postponed by these compounds. They inhibit IIS pathway in a daf-16-dependent manner, subsequently increasing the expressions of DAF-16 downstream protein and gene in nematodes. Molecular docking studies demonstrate that these compounds mightinhibit insulin signal by binding to the crucial amino acid residue ARG1003 in the pocket of IGFR. Western blot indicates that IGFR, PI3K, and AKT kinase expressions in senescent cells are decreased after vitexin and isovitexin treatment. Vitexin and isovitexin may inhibit IIS pathway by occupying adenosine-triphosphate binding site pocket of IGFR, subsequently decreasing IGFR expression, thereby promoting longevity and fitness.

Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor.

The ability of drugs and therapeutic antibodies to reach central nervous system (CNS) targets is greatly diminished by the blood–brain barrier (BBB). Receptor-mediated transcytosis (RMT), which is responsible for the transport of natural protein ligands across the BBB, was identified as a way to increase drug delivery to the brain. In this study, we characterized IGF1R5, which is a single-domain antibody (sdAb) that binds to insulin-like growth factor-1 receptor (IGF1R) at the BBB, as a ligand that triggers RMT and could deliver cargo molecules that otherwise do not cross the BBB. Surface plasmon resonance binding analyses demonstrated the species cross-reactivity of IGF1R5 toward IGF1R from multiple species. To overcome the short serum half-life of sdAbs, we fused IGF1R5 to the human (hFc) or mouse Fc domain (mFc). IGF1R5 in both N- and C-terminal mFc fusion showed enhanced transmigration across a rat BBB model (SV-ARBEC) in vitro. Increased levels of hFc-IGF1R5 in the cerebrospinal fluid and vessel-depleted brain parenchyma fractions further confirmed the ability of IGF1R5 to cross the BBB in vivo. We next tested whether this carrier was able to ferry a pharmacologically active payload across the BBB by measuring the hypothermic and analgesic properties of neurotensin and galanin, respectively. The fusion of IGF1R5-hFc to neurotensin induced a dose-dependent reduction in the core temperature. The reversal of hyperalgesia by galanin that was chemically linked to IGF1R5-mFc was demonstrated using the Hargreaves model of inflammatory pain. Taken together, our results provided a proof of concept that appropriate antibodies, such as IGF1R5 against IGF1R, are suitable as RMT carriers for the delivery of therapeutic cargos for CNS applications.

Research Note: Expression of IGF-1 and IGF-1 receptor proteins in skeletal muscle fiber types in chickens with hepatic fibrosis

We investigated the expression of insulin-like growth factor 1 (IGF-1) and IGF-1 type 1 receptor (IGF-1R) in skeletal muscle fiber types in chickens with hepatic fibrosis induced by bile duct ligation (BDL). Eleven hens, approximately 104 weeks old, were randomly assigned to BDL (n = 4) and sham surgery (SHAM; n = 7) groups. In BDL hens, histopathology revealed marked bile duct proliferation and liver fibrosis. The cross-sectional area (CSA) of myofibers from both the pectoralis (PCT) muscles significantly decreased in the BDL group compared with the SHAM group (P < 0.01). In contrast, the CSA of myofibers from the femorotibialis lateralis (FTL) muscle did not decrease in the BDL group. Type I fibers were large, round, and hypertrophic. Elongated type IIA and IIB fibers were also present. For IGF-1 immunostaining, the immunoreaction intensity was higher in the PCT in the BDL group than the SHAM group. Within the BDL group, type I fibers from FTL had a stronger immunoreaction intensity than the type II fibers. For IGF-1R immunostaining, the intensity of the immunoreactions was similar within the PCT in the BDL group compared with the SHAM group. For FTL, type I fibers had stronger reactions to IGF-1R than type II fibers in the BDL group. These results suggest that type I fibers express both IGF-1 and IGF-1R and become hypertrophic in chickens with hepatic fibrosis.

Initiation of muscle protein synthesis was unrelated to simultaneously upregulated local production of IGF-1 by amino acids in non-proliferating L6 muscle cells.

BackgroundIGF-1 is considered an important regulator of muscle protein synthesis. However, its role in stimulation of muscle protein synthesis by amino acids (AA) is not clear, despite pronounced alterations in IGF-1 mRNA expression and signaling in muscle tissues by feeding. This study evaluates the role of locally produced IGF-1 and IGF-1 signaling when skeletal muscle protein synthesis is activated by increased amino acid availability in confluent, non-proliferating cells.MethodsL6 skeletal muscle cells were subjected to amino acid starvation (24 h, 0.14 mM) followed by 18 h amino acid refeeding in Low AA (0.28 mM) or High AA concentrations (9 mM). Protein synthesis rates were estimated by L-[U-14C]-phenylalanine incorporation into cellular proteins. IGF-1 and IGF-1 receptor mRNA expression were quantified by real time PCR. SiRNA knockdown, antibodies and chemical inhibitors were used to attenuate muscle IGF-1 production and signaling.ResultsHigh AA concentrations (9mM) increased IGF-1 mRNA expression (+ 30%, p<0.05) and increased L-[U-14C]-phenylalanine incorporation compared to Low AA in confluent, non-proliferating muscle cells. Blocking IGF-1 signaling by chemical inhibitors reduced IGF-1 mRNA upregulation (~50%, p< 0.01), without decrease of protein synthesis. SiRNA knockdown of IGF-1 reduced protein synthesis, mainly explained by reduced cell proliferation. High AA or IGF-1 inhibitors did not change IGF-1 receptor mRNA expressions.ConclusionAmino acids increased IGF-1 mRNA expression and stimulated muscle protein synthesis. However, simultaneous upregulation of IGF-1 mRNA did not relate to increased protein synthesis by amino acids. The results indicate that increased IGF-1 mRNA expression is rather a covariate to amino acid initiation of protein synthesis in non-proliferating muscle cells; effects that may be related to unrecognized metabolic activities, such as transport of amino acids.

The polymorphism of insulin-like growth factor-1 receptor (IGF-1R) gene in meat-type Lambs in Turkey: I. Effect on growth traits and body measurements

As an important tyrosine kinase activator, insulin-like growth factor-1 receptor (IGF-1R) is activated by IGF-1 and IGF-2 and is a cell surface protein that functionally regulates cell growth and proliferation. This study was conducted to investigate the association between the previously determined single nucleotide polymorphism (SNP; g 0.195C > T) in the IGF-1R gene with growth and skeletal development traits of meat-type lambs. Different sheep breeds and their crosses were involved in the study, and data were collected from a total of 159 lambs (62 males and 97 females). The selected region in IGF-1R was analyzed using PCR-RFLP and the SNP g 0.195C > T substitution was detected. Subsequently, three genotypes were determined for this genetic variation: AA (0.197), AB (0.493), and BB (0.310). The associations between the identified genotypes and growth traits were evaluated for the period from birth to PS (pre-slaughter). Statistical analysis showed that IGF-1R genotypes had a significant effect on birth weight (P < 0.01) and daily weight gain on day 90- PS (P < 0.05). Similarly, the effects of genotype on body measurements, withers height and back height were significant (P < 0.05). In ultrasound measurements, longissimus dorsi (LD) muscle depth, skin thickness, and fat thickness were not significant. The data obtained in this study show that the variation of IGF-1R gene has a significant effect on the growth characteristics of lambs. Therefore, the use of this gene as a genetic marker in the production of lambs for slaughter may lead to more profitable production.

Insulin-like growth factor 1 receptor mediates photoreceptor neuroprotection

Insulin-like growth factor I (IGF-1) is a neurotrophic factor and is the ligand for insulin-like growth factor 1 receptor (IGF-1R). Reduced expression of IGF-1 has been reported to cause deafness, mental retardation, postnatal growth failure, and microcephaly. IGF-1R is expressed in the retina and photoreceptor neurons; however, its functional role is not known. Global IGF-1 KO mice have age-related vision loss. We determined that conditional deletion of IGF-1R in photoreceptors and pan-retinal cells produces age-related visual function loss and retinal degeneration. Retinal pigment epithelial cell-secreted IGF-1 may be a source for IGF-1R activation in the retina. Altered retinal, fatty acid, and phosphoinositide metabolism are observed in photoreceptor and retinal cells lacking IGF-1R. Our results suggest that the IGF-1R pathway is indispensable for photoreceptor survival, and activation of IGF-1R may be an essential element of photoreceptor and retinal neuroprotection.

Fluconazole Is Neuroprotective via Interactions with the IGF-1 Receptor

There is a continuing unmet medical need to develop neuroprotective strategies to treat neurodegenerative disorders. To address this need, we screened over 2000 compounds for potential neuroprotective activity in a model of oxidative stress and found that numerous antifungal agents were neuroprotective. Of the identified compounds, fluconazole was further characterized. Fluconazole was able to prevent neurite retraction and cell death in in vitro and in vivo models of toxicity. Fluconazole protected neurons in a concentration-dependent manner and exhibited efficacy against several toxic agents, including 3-nitropropionic acid, N-methyl D-aspartate, 6-hydroxydopamine, and the HIV proteins Tat and gp120. In vivo studies indicated that systemically administered fluconazole was neuroprotective in animals treated with 3-nitropropionic acid and prevented gp120-mediated neuronal loss. In addition to neuroprotection, fluconazole also induced proliferation of neural progenitor cells in vitro and in vivo. Fluconazole mediates these effects through upregulation and signaling via the insulin growth factor-1 receptor which results in decreased cAMP production and increased phosphorylation of Akt. Blockade of the insulin growth factor-1 receptor signaling with the selective inhibitor AG1024 abrogated the effects of fluconazole. Our studies suggest that fluconazole may be an attractive candidate for treatment of neurodegenerative diseases due to its protective properties against several categories of neuronal insults and its ability to spur neural progenitor cell proliferation.

Bimodal regulation of axonal transport by the GDNF-RET signalling axis in healthy and diseased motor neurons

Deficits in axonal transport are one of the earliest pathological outcomes in several models of amyotrophic lateral sclerosis (ALS), including SOD1G93A mice. Evidence suggests that rescuing these deficits prevents disease progression, stops denervation, and extends survival. Kinase inhibitors have been previously identified as transport enhancers, and are being investigated as potential therapies for ALS. For example, inhibitors of p38 mitogen-activated protein kinase and insulin growth factor receptor 1 have been shown to rescue axonal transport deficits in vivo in symptomatic SOD1G93A mice. In this work, we investigated the impact of RET, the tyrosine kinase receptor for glial cell line-derived neurotrophic factor (GDNF), as a modifier of axonal transport. We identified the fundamental interplay between RET signalling and axonal transport in both wild-type and SOD1G93A motor neurons in vitro. We demonstrated that blockade of RET signalling using pharmacological inhibitors and genetic knockdown enhances signalling endosome transport in wild-type motor neurons and uncovered a divergence in the response of primary motor neurons to GDNF compared with cell lines. Finally, we showed that inhibition of the GDNF-RET signalling axis rescues in vivo transport deficits in early symptomatic SOD1G93A mice, promoting RET as a potential therapeutic target in the treatment of ALS.

Update on thyroid eye disease: Regional variations in prevalence, diagnosis, and management.

Thyroid eye disease (TED) is a rare disease that can lead to decreased quality of life, permanent disfigurement, and vision loss. Clinically, TED presents with exophthalmos, periorbital edema, extraocular muscle dysfunction, and eyelid retraction, and can lead to vision-threatening complications such as exposure to keratopathy and dysthyroid optic neuropathy (DON). Over the last several years, significant advancements have been made in the understanding of its pathophysiology as well as optimal management. Ethnic variations in the prevalence, clinical presentation, and risk of vision-threatening complications of TED are summarized, and risk factors associated with TED are discussed. Additionally, significant advances have been made in the management of TED. The management of TED traditionally included anti-inflammatory medications, orbital radiation therapy, orbital surgical decompression, and biologic therapies. Most recently, targeted therapies such as teprotumumab, an insulin-like growth factor-1 receptor antagonist, have been studied in the context of TED, with promising initial data. In this review, updates in the understanding and management of TED are presented with a focus on the international variations in presentation and management.

Survival-related indicators ALOX12B and SPRR1A are associated with DNA damage repair and tumor microenvironment status in HPV 16-negative head and neck squamous cell carcinoma patients

ObjectivesTo investigate prognostic-related gene signature based on DNA damage repair and tumor microenvironment statue in human papillomavirus 16 negative (HPV16-) head and neck squamous cell carcinoma (HNSCC).MethodsFor the RNA-sequence matrix in HPV16- HNSCC in the Cancer Genome Atlas (TCGA) cohort, the DNA damage response (DDR) and tumor microenvironment (TM) status of each patient sample was estimated by using the ssGSEA algorithm. Through bioinformatics analysis in DDR_high/TM_high (n = 311) and DDR_high/TM_low (n = 53) groups, a survival-related gene signature was selected in the TCGA cohort. Two independent external validation cohorts (GSE65858 (n = 210) and GSE41613 (n = 97)) with HPV16- HNSCC patients validated the gene signature. Correlations among the clinical-related hub differentially expressed genes (DEGs) and infiltrated immunocytes were explored with the TIMER2.0 server. Drug screening based on hub DEGs was performed using the CellMiner and GSCALite databases. The loss-of-function studies were used to evaluate the effect of screened survival-related gene on the motility of HPV- HNSCC cells in vitro.ResultsA high DDR level (P = 0.025) and low TM score (P = 0.012) were independent risk factors for HPV16- HNSCC. Downregulated expression of ALOX12B or SPRR1A was associated with poor survival rate and advanced cancer stages. The pathway enrichment analysis showed the DDR_high/TM_low samples were enriched in glycosphingolipid biosynthesis-lacto and neolacto series, glutathione metabolism, platinum drug resistance, and ferroptosis pathways, while the DDR_high/TM_low samples were enriched in Th17 cell differentiation, Neutrophil extracellular trap formation, PD − L1 expression and PD − 1 checkpoint pathway in cancer. Notably, the expression of ALOX12B and SPRR1A were negatively correlated with cancer-associated fibroblasts (CAFs) infiltration and CAFs downstream effectors. Sensitivity to specific chemotherapy regimens can be derived from gene expressions. In addition, ALOX12B and SPRR1A expression was associated with the mRNA expression of insulin like growth factor 1 receptor (IGF1R), AKT serine/threonine kinase 1 (AKT1), mammalian target of rapamycin (MTOR), and eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) in HPV negative HNSCC. Down-regulation of ALOX12B promoted HPV- HNSCC cells migration and invasion in vitro.ConclusionsALOX12B and SPRR1A served as a gene signature for overall survival in HPV16- HNSCC patients, and correlated with the amount of infiltrated CAFs. The specific drug pattern was determined by the gene signature.

Treating Thyroid Associated Ophthalmopathy in Pediatric Patients.

Thyroid associated ophthalmopathy (TAO) is a common extra-thyroid clinical manifestation of Graves’ disease. It is an inflammatory disease of the eye and orbital tissues. Up to one-third of pediatric Graves’ disease patients could be diagnosed with TAO. The symptoms can be variable with remissions and exacerbations of pediatric Graves’ disease, which has negative effects on the quality of life in children. Teprotumumab is a fully human IgG1κ type monoclonal antibody targeting insulin-like growth factor-1 receptor (IGF-1R), and was approved for the treatment of TAO as a “breakthrough therapy” by the FDA in 2020. Nevertheless, the safety and effectiveness have not been established in pediatric patients. IGF-1R plays an important role in human development, which raises concerns of developmental toxicity. As presented in the pharmacology review report, juvenile monkeys were tested in two separate repeated-dose toxicity studies and no NOAEL was identified. Teprotumumab affected the growth, thymus, spleen and decreased the bone growth. Younger animals seemed to be more sensitive to the effects on normal growth and normal thymus. Hearing impairment posed additional risk to the potential pediatric use, especially for school-age children. Considering the nature of the target, Teprotumumab should not be used empirically in children. More efforts would be made for the further development of teprotumumab for pediatric use.

Analysis on the Efficacy of Bronchial Artery Chemoembolization Combined with 125I Seed Implantation in the Therapy of Advanced Non-Small-Cell Lung Cancer Based on the Medical Database.

Objective To investigate the use and the efficacy of bronchial artery chemoembolization combined with 125I seed implantation in advanced non-small-cell lung cancer (NSCLC) therapy based on the medical database. Methods A total of 102 patients with advanced NSCLC were randomly divided into two groups. The control group was treated with 125I seed implantation, and the observation group was treated with bronchial artery chemoembolization (BACE) combined with 125I seed implantation based on medical database. The clinical efficacy, carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), glycan antigen 125 (CA125), peripheral blood CD3+, CD8+, CD4+/CD8+ T cells, insulin-like growth factor type 1 receptor (IGF-1R), S100 calcium-binding protein A2 (S100A2), long-term efficacy (time to disease progression, six-month survival rate, and one-year survival rate), and safety were then analyzed. Result The disease remission rate in the observation group was 62.75%, which was higher than that in the control group (41.18%). After 1 month and 3 months of treatment, the levels of serum CYFRA21-1, CEA, CA125, and IGF-1R were lower, while serum S100A2 was higher in the observation group than in the control group (P < 0.05). For safety assessment, we found that the incidences of neutropenia, thrombocytopenia, and gastrointestinal reactions had no statistical differences between two groups. The time to disease progression in the observation group was 129.85 d longer than that in the control group, 89.74 d, and the six-month survival rate and 1-year survival rate were higher in the observation group relative to the control group. Conclusion Medical database-based BACE combined with 125I seed implantation in the therapy of advanced NSCLC patients has definite efficacy with certain safety, which can enhance antitumor effect and prolong survival rate in advanced NSCLC patients.

Induced Pluripotent Stem-cells Inhibit Experimental Bleomycin-induced Pulmonary Fibrosis through Regulation of the Insulin-like Growth Factor Signaling.

Idiopathic pulmonary fibrosis (IPF) is among the illnesses with a high mortality rate, yet no specific cause has been identified; as a result, successful treatment has not been achieved. Among the novel approaches for treating such hard-to-cure diseases are induced pluripotent stem cells (IPSCs). Some studies have shown these cells' potential in treating IPF. Therefore, we aimed to investigate the impact of IPSCs on insulin-like growth factor (Igf) signaling as a major contributor to IPF pathogenesis. C57BL/6 mice were intratracheally instilled with Bleomycin (BLM) or phosphate-buffered saline; the next day, half of the bleomycin group received IPSCs through tail vein injection. Hydroxyproline assay and histologic examinations have been performed to assess lung fibrosis. The gene expression was evaluated using specific primers for Igf-1, Igf-2, and insulin receptor substrate 1 (Irs-1) genes and SYBR green qPCR master mix. The data have been analyzed using the 2-ΔΔCT method. The mice that received Bleomycin showed histological characteristics of the fibrotic lung injury, which was significantly ameliorated after treatment with IPSCs comparable to the control group. Furthermore, gene expression analyses revealed that in the BLM group, Igf1, Igf2, and Irs1 genes were significantly upregulated, which were returned to near-normal levels after treatment with IPSCs. IPSCs could modulate the bleomycin-induced upregulation of Igf1, Igf2, and Irs1 genes. This finding reveals a new aspect of the therapeutic impact of the IPSCs on IPF, which could be translated into other fibrotic disorders.

SIRPα Mediates IGF1 Receptor in Cardiomyopathy Induced by Chronic Kidney Disease.

Chronic kidney disease (CKD) is characterized by increased myocardial mass despite near-normal blood pressure, suggesting the presence of a separate trigger. A potential driver is SIRPα (signal regulatory protein alpha)-a mediator impairing insulin signaling. The objective of this study is to assess the role of circulating SIRPα in CKD-induced adverse cardiac remodeling. SIRPα expression was evaluated in mouse models and patients with CKD. Specifically, mutant, muscle-specific, or cardiac muscle-specific SIRPα KO (knockout) mice were examined after subtotal nephrectomy. Cardiac function was assessed by echocardiography. Metabolic responses were confirmed in cultured muscle cells or cardiomyocytes. We demonstrate that SIRPα regulates myocardial insulin/IGF1R (insulin growth factor-1 receptor) signaling in CKD. First, in the serum of both mice and patients, SIRPα was robustly secreted in response to CKD. Second, cardiac muscle upregulation of SIRPα was associated with impaired insulin/IGF1R signaling, myocardial dysfunction, and fibrosis. However, both global and cardiac muscle-specific SIRPα KO mice displayed improved cardiac function when compared with control mice with CKD. Third, both muscle-specific or cardiac muscle-specific SIRPα KO mice did not significantly activate fetal genes and maintained insulin/IGF1R signaling with suppressed fibrosis despite the presence of CKD. Importantly, SIRPα directly interacted with IGF1R. Next, rSIRPα (recombinant SIRPα) protein was introduced into muscle-specific SIRPα KO mice reestablishing the insulin/IGF1R signaling activity. Additionally, overexpression of SIRPα in myoblasts and cardiomyocytes impaired pAKT (phosphorylation of AKT) and insulin/IGF1R signaling. Furthermore, myotubes and cardiomyocytes, but not adipocytes treated with high glucose or cardiomyocytes treated with uremic toxins, stimulated secretion of SIRPα in culture media, suggesting these cells are the origin of circulating SIRPα in CKD. Both intracellular and extracellular SIRPα exert biologically synergistic effects impairing intracellular myocardial insulin/IGF1R signaling. Myokine SIRPα expression impairs insulin/IGF1R functions in cardiac muscle, affecting cardiometabolic signaling pathways. Circulating SIRPα constitutes an important readout of insulin resistance in CKD-induced cardiomyopathy.

Expression of IGF-1 receptor and GH receptor in hepatic tissue of patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

ObjectiveThe GH and IGF-1 axis is a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) given its lipolytic, anti-inflammatory and anti-fibrotic properties. IGF-1 receptor (IGF-1R) and GH receptor (GHR) expression in adult, human hepatic tissue is not well understood across the spectrum of NAFLD severity. Therefore, we sought to investigate hepatic IGF-1R and GHR expression in subjects with NAFLD utilizing gene expression analysis (GEA) and immunohistochemistry (IHC). DesignGEA (n = 318) and IHC (n = 30) cohorts were identified from the Massachusetts General Hospital NAFLD Tissue Repository. GEA subjects were categorized based on histopathology as normal liver histology (NLH), steatosis only (Steatosis), nonalcoholic steatohepatitis (NASH) without fibrosis (NASH F0), and NASH with fibrosis (NASH F1–4) with GEA by the Nanostring nCounter assay. IHC subjects were matched for age, body mass index (BMI), sex, and diabetic status across three groups (n = 10 each): NLH, Steatosis, and NASH with fibrosis (NASH F1–3). IHC for IGF-1R, IGF-1 and GHR was performed on formalin-fixed, paraffin-embedded hepatic tissue samples. ResultsIGF-1R gene expression did not differ across NAFLD severity while IGF-1 gene expression decreased with increasing NAFLD severity, including when controlled for BMI and age. GHR expression did not differ by severity of NAFLD based on GEA or IHC. ConclusionsIGF-1R and GHR expression levels were not significantly different across NAFLD disease severity. However, expression of IGF-1 was lower with increasing severity of NAFLD. Additional research is needed regarding the contribution of the GH/IGF-1 axis to the pathophysiology of NAFLD and NASH.