Search Results (525)

Understanding hormonal and molecular changes during the transition from preterm to near-term gestation is essential for investigating how pregnancy complications impact fetal heart development and contribute to long-term cardiovascular risks for offspring. This study examines these cardiac changes in fetal sheep, focusing on the changes between 116 days (preterm) and 140 days (near term) of gestation (dG, term = 150) using Western blotting, LC-MS/MS, and histological techniques. We observed a strong correlation between cortisol and T₃ (Triiodothyronine) in heart tissue in near-term fetuses, highlighting the role of glucocorticoid signalling in fetal heart maturation. Protein expression patterns in the heart revealed a decrease in multiple glucocorticoid receptor isoforms (GRα-A, GR-P, GR-A, GRα-D2, and GRα-D3), alongside a decrease in IGF-1R (a marker of cardiac proliferative capacity) and p-FOXO1(Thr24) but an increase in PCNA (a marker of DNA replication), indicating a shift towards cardiomyocyte maturation from preterm to near term. The increased expression of proteins regulating mitochondrial biogenesis and OXPHOS complex 4 reflects the known transition from glycolysis to oxidative phosphorylation, essential for meeting the energy demands of the postnatal heart. We also found altered glucose transporter expression, with increased pIRS-1(ser789) and GLUT-4 but decreased GLUT-1 expression, suggesting improved insulin responsiveness as the heart approaches term. Notably, the reduced protein abundance of SIRT-1 and SERCA2, along with increased phosphorylation of cardiac Troponin I(Ser23/24), indicates adaptations for more energy-efficient contraction in the near-term heart. In conclusion, these findings show the complex interplay of hormonal, metabolic, and growth changes that regulate fetal heart development, providing new insights into heart development that are crucial for understanding pathological conditions at birth and throughout life. Full article

Background/Objectives: Kenny–Caffey syndrome 2 (KCS2) is a rare cause of hypoparathyroidism, inherited in an autosomal dominant mode, resulting from pathogenic variants of the FAM111A gene, which is implicated in intracellular pathways regulating parathormone (PTH) synthesis and skeletal and parathyroid gland development. Methods: The case of a boy is reported, presenting with the characteristic and newly identified clinical, biochemical, radiological, and genetic abnormalities of KCS2. Results: The proband had noticeable dysmorphic features, and the closure of the anterior fontanel was delayed until the age of 4 years. Biochemical evaluation at several ages revealed persistent hypocalcemia, high normal phosphorous, and inappropriately low normal PTH. To exclude other causes of short stature, the diagnostic approach revealed low levels of IGF-1, and on CNS MRI, small pituitary gland and empty sella. Nocturnal levels of growth hormone were normal. MRI also revealed bilateral symmetrical microphthalmia and torturous optic nerves. Skeletal survey was compatible with cortical thickening and medullary stenosis of the long bones. Genomic data analysis revealed a well-known pathogenic variant of the FAM111A gene (c.1706G>A, p. R569H), which is linked with KCS2 or nanophthalmos. Conclusions: KCS2, although a rare disease, should be included in the differential diagnosis of hypoparathyroidism and short stature. Understanding the association of pathogenic variants with KCS2 phenotypic variability will allow the advancement of clinical genetics and personalized long-term follow-up and will offer insights into the role of the FAM111A gene in the disease pathogenesis and normal embryogenesis of implicated tissues and organs. Full article

Despite the increasing number of placenta accreta spectrum (PAS) cases in recent years, its impact on neonatal outcomes and respiratory morbidity, as well as the underlying pathogenetic mechanism, has not yet been extensively studied. Moreover, no study has yet demonstrated the effectiveness of antenatal corticosteroid therapy (CT) for the prevention of respiratory distress syndrome (RDS) in newborns of mothers with PAS at the molecular level. In this regard, microRNA (miRNA) profiling by small RNA deep sequencing and quantitative real-time PCR was performed on 160 blood plasma samples from preterm infants (gestational age: 33–36 weeks) and their mothers who had been diagnosed with or without PAS depending on the timing of the antenatal RDS prophylaxis. A significant increase in hsa-miR-199a-3p and hsa-miR-382-5p levels was observed in the blood plasma of the newborns from mothers with PAS compared to the control group. A clear trend toward the normalization of hsa-miR-199a-3p and hsa-miR-382-5p levels in the neonatal blood plasma of the PAS groups was observed when CT was administered within 14 days before delivery, but not beyond 14 days. Direct correlations were found among the hsa-miR-382-5p level in neonatal blood plasma and the hsa-miR-199a-3p level in the same sample (r = 0.49; p < 0.001), the oxygen requirements in the NICU (r = 0.41; p = 0.001), the duration of the NICU stay (r = 0.31; p = 0.019), and the severity of the newborn’s condition based on the NEOMOD scale (r = 0.36; p = 0.005). Logistic regression models based on the maternal plasma levels of hsa-miR-199a-3p and hsa-miR-382-5p predicted the need for cardiotonic therapy, invasive mechanical ventilation, or high-frequency oscillatory ventilation in newborns during the early neonatal period, with a sensitivity of 95–100%. According to the literary data, these miRNAs regulate fetal organogenesis via IGF-1, the formation of proper lung tissue architecture, surfactant synthesis in alveolar cells, and vascular tone. Full article

Immune checkpoint blockade (ICB), radiotherapy, chemotherapy and surgery are currently used as therapeutic strategies against melanoma, lung, bladder and renal cancers, but their efficacy is limited. Thus, I need to predict treatment response and resistance to address this challenge. In this study, I analyzed 350 lung cancer, 320 melanoma, 215 bladder cancer, 139 head and neck cancer and 151 renal carcinoma patients treated with ICB to identify tumor mutations associated with response and resistance to treatment. I identified several tumor mutations linked with a difference in survival outcomes following ICB. In lung cancer, missense mutations in ABL1, ASXL1, EPHA3, EPHA5, ERBB4, MET, MRE11A, MSH2, NOTCH1, PAK7, PAX5, PGR, ZFHX3, PIK3C3 and REL genes were indicative of favorable responses to ICB. Conversely, mutations in TGFBR2, ARID5B, CDKN2C, HIST1H3I, RICTOR, SMAD2, SMAD4 and TP53 genes were associated with shorter overall survival post-ICB treatment. In melanoma, mutations in FBXW7, CDK12, CREBBP, CTNNB1, NOTCH1 and RB1 genes predict resistance to ICB, whereas missense mutations in FAM46C and RHOA genes are associated with extended overall survival. In bladder cancer, mutations in HRAS genes predict resistance to ICB, whereas missense mutations in ERBB2, GNAS, ATM, CDKN2A and LATS1 genes, as well as nonsense mutations in NCOR1 and TP53 genes, are associated with extended overall survival. In head and neck cancer, mutations in genes like PIK3CA and KRAS correlated with longer survival, while mutations in genes like TERT and TP53 were linked to shorter survival. In renal carcinoma, mutations such as EPHA5, MGA, PIK3R1, PMS1, TSC1 and VHL were linked to prolonged overall survival, while others, including total splice mutations and mutations in B2M, BCOR, JUN, FH, IGF1R and MYCN genes were associated with shorter overall survival following ICB. Then, I developed predictive survival models by machine learning that correctly forecasted cancer patient survival following ICB within an error between 5 and 8 months based on their distinct tumor mutational attributes. In conclusion, this study advocates for personalized immunotherapy approaches in cancer patients. Full article

(1) Background: N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPDQ), as a newly discovered environmental toxin, has been found more frequently in our living conditions. The literature reports that damage to the reproductive and cardiovascular system is associated with exposure to 6PPDQ. However, the relationship between 6PPDQ and cancer still requires more investigation. This research aims to investigate the association between 6PPDQ and prostate cancer. (2) Methods and Results: Based on the data retrieved from the Pharmmapper, CTD, SEA, SwissTargetPrediction, GeneCard, and OMIM databases, we summarized 239 potential targets utilizing the Venn tool. Through the STRING network database and Cytoscape software, we constructed a PPI network and confirmed ten core targets, including IGF1R, PIK3R1, PTPN11, EGFR, SRC, GRB2, JAK2, SOS1, KDR, and IRS1. We identified the potential pathways through which 6PPDQ acts on these core targets using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Ultimately, through molecular docking methods, 6PPDQ binds closely with these ten core targets. These findings indicate that 6PPDQ may influence the proteins related to prostate cancer and may be linked to prostate cancer via several known signaling pathways. (3) Conclusions: This article employs innovative network toxicology to elucidate the prostate carcinogenic effects of 6PPDQ through its modulation of specific vital genes and signaling pathways, thereby establishing a foundational platform for future investigations into the impact of 6PPDQ on prostate cancer and potentially other tumors. Full article

The objective of this study was to evaluate the effects of dietary addition of lactic acid and glutamine, and their interactions, on growth performance, nutrient digestibility, digestive enzyme activity, intestinal barrier functions, microflora, and expressions of intestinal development-related genes of weaning piglets. Ninety-six 24-day-old weaning piglets (Duroc × Landrace × Yorkshire, weaned at 21 ± 1 d and fed the basal diet for a 3 d adaptation period) with initial body weight of 7.24 ± 0.09 kg were randomly assigned to one of four dietary treatments with six replicates per treatment and four pigs per replicate in a 2 × 2 factorial treatment arrangements: (1) CON (a 2-period basal diet; control), (2) LS (supplemented with 2% lactic acid), (3) GS (supplemented with 1% glutamine), and (4) LGS (supplemented with 2% lactic acid and 1% glutamine). The study lasted for 28 d. On days 25–28, fresh fecal samples were collected to evaluate apparent total tract digestibility (ATTD) of nutrients. After 28 d, one weaning pig per pen was euthanized, and physiological samples obtained. Results showed that the supplementation of lactic acid improved the ADFI of the pigs (p < 0.05), while the pigs fed the glutamine diet had a greater ADFI and higher G/F (p < 0.05), and there were significant interactive effects between lactic acid and glutamine on the ADFI and G/F of the pigs (p < 0.05). The ATTD of CP and ash for pigs fed with lactic acid was significantly enhanced, and pigs fed the glutamine diet had greater ATTD of CP and ash (p < 0.05), while there were significant interactive effects between lactic acid and glutamine on the ATTD of CP and ash of the pigs (p < 0.05). Pigs fed with lactic acid exhibited greater activity of α-amylase and lipase (p < 0.05); moreover, the activity of lipase in the pigs showed a significant interactive effect between lactic acid and glutamine (p < 0.05). There was a greater villus height and villus height to crypt depth ratio in pigs fed with lactic acid (p < 0.05), and the villus height to crypt depth ratio of pigs fed with glutamine was greater (p < 0.05). There were greater GLUT2, IGF-1, TGF-β2, OCLN, and ZO-1 mRNA levels in pigs fed with lactic acid (p < 0.05), and the supplementation of glutamine increased SGLT1, GLUT2, PepT1, IGF-1, IGF-1R, TGFβ-2, GLP-2, and OCLN mRNA levels (p < 0.05), Additionally, expressions of SGLT1, GLUT2, PepT1, IGF-1, IGF-1R, TGFβ-2, GLP-2, CLDN-2, OCLN, and ZO-1 mRNA levels of pigs showed a positive interactive effect between lactic acid and glutamine (p < 0.05). Supplementation of lactic acid significantly increased the populations of Bifidobacterium in cecal digesta, Lactobacillus in colonic digesta, and the content of butyric acid in colonic digesta (p < 0.05). In addition, there were significant interactive effects between lactic acid and glutamine on populations of Bifidobacterium in cecal digesta, Lactobacillus in colonic digesta, and the content of acetic acid, butyric acid, and total VFAs in cecal digesta of the pigs (p < 0.05). Collectively, the current results indicate that dietary supplementation with lactic acid and glutamine had a positive synergistic effect on weaning pigs, which could improve growth performance through promoting the development of the small intestine, increasing digestive and barrier function, and regulating the balance of microflora in pigs, and which might be a potential feeding additive ensemble to enhance the health and growth of weaning piglets in the post-antibiotic era. Full article

Cartilage destruction in juvenile idiopathic arthritis (JIA) is diagnosed, often too late, on basis of clinical evaluation and radiographic imaging. This case–control study investigated serum chondroitin/dermatan sulfate (CS/DS) as a potential biochemical marker of cartilage metabolism, aiming to improve early diagnosis and precision treatment for JIA. We also measured the levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) (using ELISA methods) in JIA patients (n = 55) both before and after treatment (prednisone, sulfasalazine, methotrexate, administered together), and analyzed their relationships with CS/DS levels. Untreated JIA patients [8.26 µg/mL (6.25–9.66)], especially untreated girls [8.57 µg/mL (8.13–9.78)] and patients with a polyarticular form of the disease [7.09 µg/mL (5.63–8.41)], had significantly reduced levels of serum CS/DS compared with the control [14.48 µg/mL (10.23–15.77)]. Therapy resulted in a significant increase in this parameter, but without normalization. We also found significantly lower levels of IGF-1 [66.04 ng/mL (49.45–96.80)] and IGFBP-3 [3.37 ng/mL (2.65–4.88)] in untreated patients compared with the control [96.92 ng/mL (76.04–128.59), 4.84 ng/mL (4.21–7.750), respectively]. Based on receiver operating characteristic (ROC) curve analysis, the blood concentration of CS/DS demonstrated the highest diagnostic power (AUC = 0.947) for JIA among all the tested markers. Untreated patients showed significant correlations between CS/DS and IGF-1 (r = −0.579, p = 0.0000), IGFBP-3 (r = −0.506, p = 0.0001), and C-reactive protein (r = 0.601, p = 0.0005). The observed changes in CS/DS during the course of JIA, influenced by both impairment of the IGF/IGFBP axis and inflammation, indicate the need for continued therapy to protect patients from potential disability. We suggest that CS/DS may be a useful biomarker of disease activity and could be employed to assess treatment efficacy and progress toward remission. Full article

Background: Glioblastoma multiforme is an aggressive malignancy with a dismal 5-year survival rate of 5–10%. Current therapeutic options are limited, due in part to drug exclusion by the blood–brain barrier (BBB). We have previously shown that high-amplitude repetitive transcranial magnetic stimulation (rTMS) in rats allowed the delivery across the BBB of an IGF signaling inhibitor—IGF-Trap. The objective of this study was to assess the therapeutic effect of IGF-Trap when delivered in conjunction with rTMS on the intracerebral growth of glioma. Results: We found that systemic administration of IGF-Trap without rTMS had a minimal effect on the growth of orthotopically injected glioma cells in rats and mice, compared to control animals injected with vehicle only or treated with sham rTMS. In rats treated with a combination of rTMS and IGF-Trap, we observed a growth retardation of C6 tumors for up to 14 days post-tumor cell injection, although tumors eventually progressed. In mice, tumors were detectable in all control groups by 14–17 days post-injection of glioma GL261 cells and progressed rapidly thereafter. In mice treated with rTMS prior to IGF-Trap administration, tumor growth was inhibited or delayed, although the tumors also eventually progressed. Conclusion: The results showed that rTMS could increase the anti-tumor effect of IGF-Trap during the early phases of tumor growth. Further optimization of the rTMS protocol is required to improve survival outcomes. Full article

Background: CI-RM6P has different binding sites with affinities for both M6P and IGF2, plays a role in the regulation of the TGF-β and IGF pathways that is important for controlling cell growth and differentiation. We hypothesize that previously synthesised derivative of M6P could be an alternative candidate for bone tissue regeneration in terms of higher binding affinity, stability in human serum, low cost and temporal delivery. Methods: CH₃-M6P is synthesised based on previously described protocol; mesenchymal origin of isolated DPSCs was assessed by flow cytometry and AR staining prior to alkaline phosphatase (ALP) activity test, qPCR to evaluate differentiation specific marker expression, immunofluoresence, and SEM/EDS to evaluate organic and inorganic matrix formation; and rat aortic ring model to evaluate angiogenic effect of molecule. Results: CH₃-M6P upregulated ALP activity, the expression of the ALP, Col1, RunX2, Mef2C, TGFβ1, TGFβ1R, TGFβ2, and Smad3 genes under osteogenic conditions. The results of immunofluorescence and SEM/EDS studies did not show enhancing effect on matrix formation. As we observed, the induction effect of CH₃-M6P on the expression of angiogenic genes such as SMAD3 and TGFβ1R, even under osteogenic conditions, within the scope of research, we checked the angiogenic effect of the molecule and compared it to VEGF, showing that the CH₃-M6P is really angiogenic. Conclusions: Our findings provide an important clue for the further exploration of the molecule, which can be necessary to enhance the capability of the commonly used osteomedium, possibly leading to the development of bone-forming drugs and has the potential to be a dual-functioning molecule for bone tissue engineering. Full article

Ovarian cancer (OC) remains one of the leading causes of cancer-related mortality among women. Targeting the insulin-like growth factor 1 (IGF-1) signaling pathway has emerged as a promising therapeutic strategy. Linsitinib, an IGF-1 receptor (IGF-1R) inhibitor, has shown potential in disrupting this pathway. Additionally, metformin, commonly used in the treatment of type 2 diabetes, has been studied for its anti-cancer properties due to its ability to inhibit metabolic pathways that intersect with IGF-1 signaling, making it a candidate for combination therapy in cancer treatments. This study explores the anti-cancer effects of linsitinib and metformin on OVCAR3 cells by the suppression of the IGF-1 signaling pathway by siRNA-mediated IGF-1 gene silencing. The goal is to evaluate their efficacy as therapeutic agents and to emphasize the critical role of this pathway in OC cell proliferation. Cellular viability was evaluated by resazurin-based assay, and apoptosis was assessed by flux cytometry. The results of this study indicate that the combination of linsitinib and metformin exhibits an antagonistic effect (obtained by SynergyFinder 2.0 Software), reducing their anti-neoplastic efficacy in OC cell lines. Statistical analyses were performed using ordinary one-way or two-way ANOVA, followed by Tukey’s or Šídák’s multiple comparison tests. While linsitinib shows promise as a therapeutic option for OC, further research is needed to identify agents that could synergize with it to enhance its therapeutic efficacy, like the combination with standard chemotherapy in OC (carboplatin and paclitaxel). Full article

Sarcopenia is a systemic medical disorder characterized by a gradual decline in muscular strength, function, and skeletal muscle mass. Currently, there is no medication specifically approved for the treatment of this condition. Therefore, the identification of new pharmacological targets may offer opportunities for the development of novel therapeutic strategies. The current in silico study investigated the active ingredients and the mode of action of Citri Reticulatae Pericarpium (CRP) in addressing sarcopenia. The active ingredients of CRP and the potential targets of CRP and sarcopenia were determined using various databases. The STRING platform was utilized to construct a protein–protein interaction network, and the key intersecting targets were enriched through the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Molecular docking was used to determine the binding interactions of the active ingredients with the hub targets. The binding affinities obtained from molecular docking were subsequently validated through molecular dynamics simulation analyses. Five active ingredients and 45 key intersecting targets between CRP and sarcopenia were identified. AKT1, IL6, TP53, MMP9, ESR1, NFKB1, MTOR, IGF1R, ALB, and NFE2L2 were identified as the hub targets with the highest degree node in the protein–protein interaction network. The results indicated that the targets were mainly enriched in PIK3-AKT, HIF-1, and longevity-regulating pathways. The active ingredients showed a greater interaction affinity with the hub targets, as indicated by the results of molecular docking and molecular dynamics simulations. Our findings suggest that the active ingredients of Citri Reticulatae Pericarpium, particularly Sitosterol and Hesperetin, have the potential to improve sarcopenia by interacting with AKT1 and MTOR proteins through the PI3K-AKT signaling pathway. Full article

Schistosomiasis is a parasitic disease that poses a serious threat to human health. However, the pathogenic mechanism during the progression of Schistosoma japonicum infection remains unclear. In order to elucidate this mechanism, we used single-cell RNA sequencing (scRNA-seq) to investigate the transcriptome characteristics of the cellular (single-cell) landscape in the livers of mice infected with Schistosoma japonicum, which were divided into three groups: uninfected mice (0 week (w)), infected mice at 6 w post-infection (the acute phase), and infected mice at 10 w post-infection (the chronic phase). A total of 31,847 liver cells were included and clustered into 21 groups. The cells and T-cells had high heterogeneity in the liver during the progression of schistosome infection. The number and intensity of the intercellular interactions significantly increased at 6 w after infection but decreased at 10 w. The inflammatory signaling pathways chemoattractant cytokine ligand (CCL)5-chemokine C-C-motif receptor (CCR)5 between macrophages and T-cells were predominant at 6 w post-infection; the CCL6-CCR2 signaling pathway between macrophages was predominant at 10 w. The CD80 signaling pathway related to T-cell activation was increased at 6 w after infection, and increased expression of its receptor CD28 on the surfaces of CD4⁺ and CD8⁺ T-cells was confirmed by flow cytometry, suggesting an increase in their activation. In addition, scRNA-seq and quantitative reverse transcription polymerase chain reaction (qRT-PCR) confirmed that the intercellular communication between secretory phosphoprotein 1 (SPP1)-cluster of differentiation (CD44), insulin-like growth factor (IGF)-1-IGF1r and visfatin-insulin receptor (Insr) associated with bone metabolism and insulin metabolism was increased and enhanced in the liver at 6 w post-infection. Overall, we provide the comprehensive single-cell transcriptome landscape of the liver in mice during the progression of schistosome infection and delineate the key cellular and molecular events involved in schistosome infection-induced liver injury and fibrosis. The elevated CCL5-CCR5 and CCL6-CCR2 signaling pathways in the liver may be a drug target for liver injury and fibrosis caused by schistosome infection, respectively. Full article

Programmed cell death 4 (Pdcd4) is a tumor suppressor, which has been demonstrated to efficiently suppress tumorigenesis. Biochemically, Pdcd4 binds with translation initiation factor 4A and represses protein translation. Beyond its role in tumor suppression, growing evidence suggests that Pdcd4 enhances the chemosensitivity of several anticancer drugs. To date, numerous translational targets of Pdcd4 have been identified. These targets govern important signal transduction pathways, and their attenuation may improve chemosensitivity or overcome drug resistance. This review will discuss the signal transduction pathways regulated by Pdcd4 and the potential mechanisms through which Pdcd4 enhances chemosensitivity or counteracts drug resistance. Full article

RNA-binding proteins (RBPs) play critical roles in regulating post-transcriptional gene expression, managing processes such as mRNA splicing, stability, and translation. In normal intestine, RBPs maintain the tissue homeostasis, but when dysregulated, they can drive colorectal cancer (CRC) development and progression. Understanding the molecular mechanisms behind CRC is vital for developing novel therapeutic strategies, and RBPs are emerging as key players in this area. This review highlights the roles of several RBPs, including LIN28, IGF2BP1–3, Musashi, HuR, and CELF1, in CRC. These RBPs regulate key oncogenes and tumor suppressor genes by influencing mRNA stability and translation. While targeting RBPs poses challenges due to their complex interactions with mRNAs, recent advances in drug discovery have identified small molecule inhibitors that disrupt these interactions. These inhibitors, which target LIN28, IGF2BPs, Musashi, CELF1, and HuR, have shown promising results in preclinical studies. Their ability to modulate RBP activity presents a new therapeutic avenue for treating CRC. In conclusion, RBPs offer significant potential as therapeutic targets in CRC. Although technical challenges remain, ongoing research into the molecular mechanisms of RBPs and the development of selective, potent, and bioavailable inhibitors should lead to more effective treatments and improved outcomes in CRC. Full article

Objectives: Thyroid eye disease (TED) treatment has been recently revolutionized with the approval of teprotumumab, a targeted insulin growth factor 1 receptor (IGF1R) inhibitor. To date, teprotumumab is the only FDA-approved drug for treating TED. In this article, we would like to temper the current enthusiasm around IGF1R inhibitors. Methods: critical review of the literature by independent academic practitioners. Results: several questions should be raised. First, “how an orphan drug has become a blockbuster with annual sales exceeding $1 billion?” Teprotumumab infusions are expensive, costing about USD 45,000 for one infusion and USD 360,000 for eight infusions in a 75 kg patient. Teprotumumab approval was based on two randomized clinical trials investigating active (clinical activity score ≥ 4) TED patients. Despite this, teprotumumab was approved by the FDA for “the treatment of TED” without distinguishing between active and inactive forms. The second question is as follows: “how can a new drug, compared only to a placebo, become the new standard without being compared to historically established gold standard medical or surgical treatments?” Teprotumumab has never been compared to other medical treatments in active TED nor to surgery in chronic TED. Up to 75% of patients may experience proptosis regression after treatment discontinuation. Finally, ototoxicity has emerged as a potentially devastating side effect requiring frequent monitoring. Investigation into the long-term side effects, especially in women of childbearing age, is also warranted. Conclusions: Teprotumumab is undoubtedly a major treatment option in TED. However, before prescribing a drug, practitioners should assess its benefit/risk ratio based on the following: (i) evidence-based medicine; (ii) their empirical experience; (iii) the cost/benefit analysis; (iv) the long-term outcomes and safety profile. Full article