Large language models perform well on static medical examinations, yet clinical diagnosis often requires iterative evidence gathering under uncertainty. Building on prior interactive evaluation efforts, we introduce an OSCE-inspired standardized patient simulator and a controlled, reproducible benchmark for active diagnostic inquiry. Across 468 cases and 15 models in our protocol, we observe that multi-turn evidence seeking reduces diagnostic accuracy by 12.75

BACKGROUND: Long non-coding RNA (lncRNA) DLEU1 has been implicated in tumorigenesis, yet its mechanistic role in gastric cancer (GC) remains elusive. METHODS: We investigated the epigenetic regulation and oncogenic function of DLEU1 in GC through chromatin immunoprecipitation, RNA-protein interaction assays, and functional analyses in organoids and xenograft models. The molecular mechanisms underlying DLEU1-mediated DNA repair and metabolic adaptation were elucidated using western blotting, quantitative RT-PCR, and luciferase reporter assays. RESULTS: DLEU1 was significantly upregulated in GC, driven by H3K27 acetylation and H3K4 methylation. Mechanistically, DLEU1 promoted DNA repair by facilitating ASCC2 nuclear translocation and its interaction with ALKBH3, thereby stabilizing E2F1 mRNA. In turn, E2F1 directly activated G6PD transcription, leading to enhanced NADPH production, redox homeostasis, and glucose metabolism. Functionally, co-targeting DLEU1 and ASCC2 synergized with G6PD inhibition, significantly impairing GC cells viability and tumor growth. CONCLUSION: Our findings establish DLEU1 as a key oncogenic lncRNA in GC, orchestrating DNA repair, redox balance, and metabolic adaptation via the ASCC2-ALKBH3-E2F1-G6PD axis. Targeting this pathway may provide a promising therapeutic strategy for overcome GC chemoresistance.

Gastric cancer (GC) continues to pose a major global health burden for which chemotherapy remains a first-line treatment. However, the efficacy of chemotherapy is often compromised by the development of chemoresistance, the underlying mechanisms of which remain elusive. Here, by profiling nascent RNA-binding proteins (nRBPs) and chromatin-binding proteins (chrBPs) in GC organoids, we identified RNA-binding motif protein 15 (RBM15) as a chromatin-associated nRBP (chr-nRBP) that is upregulated in GC cells and promotes tumour growth and chemoresistance. Mechanistically, RBM15 contains a microtubule-associated protein 1A/1B-light chain 3 (LC3)-interacting region (LIR) motif, which is directed to the lysosome through autophagy, and impaired nucleophagy leads to its accumulation in tumours. Accumulated RBM15 recruits ubiquitin-specific peptidase 10 (USP10) to the nucleus, where it deubiquitinates and stabilizes nuclear factor erythroid 2-related factor 2 (NRF2), thereby decreasing its proteasome-mediated degradation. This RBM15-USP10-NRF2 axis drives resistance to cisplatin and 5-fluorouracil (5-FU) both in vitro and in vivo. Disruption of this pathway sensitizes GC cells to chemotherapy and suppresses tumour growth. Collectively, our findings suggest that RBM15 is both a predictive biomarker and a therapeutic target for overcoming chemotherapy resistance in GC cells.

Thyroid-associated ophthalmopathy (TAO), a vision-threatening and disfiguring autoimmune orbital disorder, remains a therapeutic challenge due to the lack of therapies with orbital specificity, sustained efficacy, and minimal side effects. Herein, we present G4F7-CRISPR, a fluoropolymer-based CRISPR-Cas9 delivery platform engineered for localized and efficient disruption of thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor 1 receptor (IGF1R), two key mediators of TAO pathogenesis. G4F7-CRISPR achieved high insertion/deletion frequencies in primary orbital fibroblasts (Tshr: 37.2%; Igf1r: 42.8%) and mature adipocytes (Tshr: 22.4%; Igf1r: 24.3%), and maintained robust editing efficiency in orbital adipose tissue of TAO mouse models (Tshr: 30.7%; Igf1r: 32.4%). In both TAO mouse models and 3D human orbital organoids, dual-gene editing of Tshr and Igf1r via G4F7-CRISPR significantly suppressed orbital adipogenesis, inflammation, and fibrosis, demonstrating superior therapeutic efficacy over either single-gene approaches. Comprehensive off-target analyses in both TAO mouse models and orbital organoids revealed minimal off-target activity. Furthermore, G4F7-CRISPR exhibited excellent short- and long-term ocular and systemic safety in TAO mouse models. Notably, it outperformed teprotumumab-the FDA-approved therapy for TAO-in both therapeutic efficacy and safety, highlighting its potential clinical advantages. Collectively, these findings highlight the translational promise of G4F7-CRISPR as a safe, precise, and clinically viable gene therapy for TAO.

Background: Nasal microbiota is a key factor in the development of chronic rhinosinusitis (CRS). Its influence on orbital autoimmune diseases remains unknown. This study aims to investigate the influence of CRS-related nasal dysbiosis on extraocular muscle (EOM) microbiota in patients with or without idiopathic orbital myositis (IOM).Methods: Sixteen subjects were recruited, including 4 cases in each study group [IOM(+) CRS(+) group, IOM(–) CRS(+) group, IOM(+) CRS(–) group, IOM(–) CRS(–) group]. The EOM tissues and corresponding incision tissues were sampled and processed with metagenomic next-generation sequencing (mNGS). The nasal swaps from middle meatus were collected and analyzed with 16s rRNA sequencing. The sequencing data were calculated with Shannon index for microbial diversity, principal component analysis for microbial abundance and linear discriminant analysis effect size for dominant species.Results: A total of 42 species of bacteria, 3 species of fungi and no virus were detected. Both microbial diversity and microbial abundance differed between the EOM and incision samples in IOM(–) CRS(+) and IOM(–) CRS(–) subjects, with Staphylococcus predominant in the EOM samples and Micrococcus luteus predominant in the incision samples. The microbiota also differed between EOM and swap samples in the IOM(–)CRS(+) subjects, and the most distinguishable species in the swab samples was Cutibacterium acnes. Further analysis of the swab samples confirmed nasal dysbiosis in the CRS(+) subjects with Staphylococcus haemolyticus representating as the dominant species. The microbiota of EOM samples differed between the IOM(–)CRS(+) and IOM(–)CRS(–) subjects, resulting into preponderance of Cutibacterium acnes in the IOM(–)CRS(+) subjects. Small discrepancies of EOM microbiota were detected between the IOM(+)CRS(+) and IOM(+)CRS(–) subjects, but data analysis showed no statistical significance. The above findings demonstrate an alteration of EOM microbiota in CRS patients, providing evidence that nasal dysbiosis may play a role in regulating microbial communities in EOM.Conclusions: This study provided a reference spectrum of EOM microbiota in IOM patients and offered insights into the nasal microbiota’s influence on orbital autoimmune conditions.(Trial registration: Chinese Clinical Trial Registry, ChiCTR2100047731. Registered 24 June 2021 - Retrospectively registered, https://www.chictr.org.cn/showproj.aspx?proj=127896)

Mechanical stress generated by breast motion can trigger inflammatory responses, contributing to capsular contracture around implants. Current strategies relying on antioxidant-loaded systems to scavenge ROS face challenges due to rapid activity attenuation, limiting long-term efficacy. This study designed a self-regenerating antioxidant breast implant fixation device using electrospun polyvinylidene fluoride (PVDF) membranes enhanced with barium titanate (BaTiO3) nanoparticles to improve piezoelectricity. An antioxidant polydopamine (PDA) coating was applied to provide renewable antioxidant capacity. Under mechanical stimulation, the built-in piezoelectric output from the BaTiO3/PVDF membrane, generates local electrical cues that promote interfacial electron transfer. These electrons are proposed to convert oxidized quinone moieties in PDA back into reduced catechol/polyphenol groups, enabling regeneration of antioxidant activity. The membrane maintained over 80% scavenging efficiency after 10 oxidative cycles, demonstrating excellent long-term stability. In vitro, ultrasound-stimulated membranes inhibited fibroblast proliferation and migration, sustained ROS clearance for up to 72 h, and induced macrophage polarization toward the anti-inflammatory M2 phenotype. In a co-culture fibrosis model, collagen-associated markers decreased markedly, with hydroxyproline content maintained at a low level (0.985 mu g/104 cells). In vivo subcutaneous implantation in mice showed effective suppression of collagen deposition and inflammation over 30 days, while maintaining normal skin thickness. Collectively, this electroactive membrane offers a self-regenerating solution to potentially mitigate capsular contracture via mechanoelectrochemical synergy, serve as a proof-of-concept strategy for clinical application.

Background This case presents a rare form of thyroid-associated ophthalmopathy with idiopathic choroidal folds, unlinked to optic neuropathy—an unusual finding in thyroid-related eye disease. Instead, bilateral nuclear cataracts and lens dislocation were identified as the primary causes of vision loss, emphasizing the importance of considering multiple, less common contributors in such cases. The decision to begin with cataract surgery exemplifies a tailored, effective approach to multifactorial vision loss, offering insights for cases with overlapping ocular issues. Given recent associations between COVID-19 vaccination and ocular symptoms like choroidal folds and scleritis, posterior scleritis was considered a possible explanation. This underscores the need for further investigation into atypical presentations of thyroid-associated eye disease. Case presentation: A 54-year-old male developed bilateral vision loss and choroidal folds one year following COVID-19 vaccination. Initially diagnosed with thyroid-associated ophthalmopathy, he underwent an adequate course of steroid pulse therapy with no visual improvement. Further assessment revealed bilateral cataracts and lens dislocation. Computed tomography identified mild extraocular muscle thickening but no orbital apex crowding, ruling out compressive optic neuropathy. Lens surgery subsequently restored his vision and normalized his visual fields. However, two months postoperatively, he experienced recurrent blurred vision and restricted movement in the right eye. Magnetic resonance imaging confirmed extraocular muscle enlargement, leading to a diagnosis of compressive optic neuropathy, and tocilizumab therapy was initiated. Following treatment, the patient demonstrated improved vision, reduced muscle thickness, and enhanced motility. Conclusions This case suggests that initial choroidal folds may be due to a combination of vaccine-related side effects and elevated orbital pressure, underscoring the potential for COVID-19 vaccination to cause atypical ocular symptoms.

FAK has emerged as a promising therapeutic target for cancer treatment due to its role in tumor survival, metastasis, and invasion. Herein, we report the rational design, synthesis, and comprehensive evaluation of a novel FAK inhibitor, compound A8. Our structure-activity relationship (SAR) studies identified A8 as a potent FAK inhibitor, with an FAK-IC50 value of 0.87 nM, superior to VS6063 (1.49 nM). In vitro studies demonstrated that A8 significantly suppressed tumor cell viability, cancer stem cell activity, and cell migration in A549 and SKOV-3 cell lines. Mechanistic insights were provided by surface plasmon resonance (SPR) analysis, revealing high-affinity binding of A8 to FAK with a Kd value of 15 μM. Radiolabeling studies with [18F]A8 highlighted favorable tumor uptake and retention in S180 tumor-bearing mice. Notably, A8 efficiently penetrated the blood-brain barrier, with brain uptake values reaching 2.63 ± 0.63 %ID/g at 15 min and 1.62 ± 0.77 %ID/g at 120 min. In vivo antitumor efficacy trials in A549 and SKOV-3 tumor models confirmed A8's robust activity, with tumor inhibition rates of 59.15 % and 57.9 %, respectively, surpassing VS6063 and standard chemotherapeutics. Combination therapy with paclitaxel further enhanced A8's antitumor effects in SKOV-3 models. Acute toxicity studies indicated that A8 was well-tolerated up to 2000 mg/kg in mice, with no observed acute toxicity. Molecular docking and dynamics simulations substantiated the stable binding of A8 to the FAK protein. Collectively, our findings underscore the potential of compound A8 as a lead candidate for FAK-targeted cancer therapeutics, warranting further preclinical and clinical investigations.

Enhanced glycolysis and lactate accumulation are shared features of human cancers. Lactylation is a lactate-derived posttranslational modification. So far, the impact of lactylation on resistance to osimertinib (a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)) in patients with lung adenocarcinoma (LUAD) remains indistinct. Here, we performed 4D label-free proteomics analysis of LUAD tissues from advanced-stage EGFR-mutant patients treated with surgery with or without neoadjuvant osimertinib to reveal a global lactylation profile and explore the role and molecular mechanism of protein lactylation in resistance to osimertinib. Through scanning the lactylated proteome, we discovered that α-Enolase 1 (ENO1), which acts as a key glycolytic enzyme, underwent lactylation at lysine 89 (K89) in LUAD tissues. The levels of ENO1 lactylation were notably attenuated in LUAD tissues after effective osimertinib treatment and were notably elevated in osimertinib-resistant LUAD cells. We found that monocarboxylate transporters (MCTs) facilitated lactate uptake into LUAD cells for ENO1 lactylation primarily through a p300/CREB-binding protein C (CBP)-dependent mechanism. ENO1 facilitated metabolic reprogramming and lactate production and interacted with several key metabolic enzymes, such as pyruvate kinase M1 (PKM1), pyruvate kinase M2 (PKM2), lactate dehydrogenase B (LDHB), and malate dehydrogenase 2 (MDH2), thus forming a tumor-derived lactate/ENO1 lactylation feedback loop, eventually contributing to osimertinib resistance in LUAD. In the in vivo orthotopic xenograft osimertinib-resistant models, targeted suppression of the tumor-derived lactate/ENO1 lactylation feedback loop effectively ameliorated resistance to osimertinib. Collectively, our findings provide the basis for targeting lactate/lactate-associated signaling to combat resistance to osimertinib.

Ulcerative colitis (UC) is believed to be triggered by a dysregulated inflammatory response to the intestinal microbiota. Acyloxyacyl hydrolase (AOAH) is a unique host lipase that inactivates Gram-negative bacterial lipopolysaccharides (LPS). After finding that AOAH produced in the intestine decreases stimulatory LPS levels in colon contents, we used the dextran sodium sulfate (DSS) model to test the enzyme's ability to prevent colitis in mice. We found that AOAH played a protective role by decreasing colonic inflammation, tissue injury, and barrier permeability. Increasing or decreasing intestinal LPS abundance exacerbated or alleviated colitis, respectively, suggesting that AOAH prevents colitis by reducing stimulatory intestinal LPS levels. AOAH also mitigated colitis-associated colorectal cancer. This highly conserved enzyme may exert its protective effects by preventing LPS-induced injury to the epithelial cell mitochondria that are important for restoring the mucosal epithelial barrier after injury. By decreasing intestinal levels of stimulatory LPS, AOAH prevents colitis and colorectal cancer.

Cripto-1, a glycoprotein and key member of the epidermal growth factor-Cripto-1-FRL-1-Cryptic family, has garnered significant attention in cancer research due to its dual roles in embryonic development and tumor progression. The central role of Cripto-1 in regulating signaling pathways that govern cell behavior positions it as a promising target for enhancing diagnostic precision and therapeutic efficacy in cancer management. This mini-review explores the role of Cripto-1 in cancer biology, focusing on its involvement in key oncogenic pathways such as cell proliferation, migration, angiogenesis, and the maintenance of cancer stem cells (CSCs). Cripto-1 supports CSC self-renewal and contributes to treatment resistance. The review also examines recent advances in Cripto-1-targeted therapy, including monoclonal antibodies, small molecule inhibitors, and early-phase clinical trials, highlighting their therapeutic efficacy and safety profile. By synthesizing these findings, this review offers a comprehensive understanding of Cripto-1’s clinical relevance and provides new insights into its potential to improve diagnostic accuracy and therapeutic outcomes in cancer management.

Many plant viruses trigger abnormal differentiation and development of host cells, causing distinct symptoms. Here, in a single-cell RNA sequence analysis, we find transcriptional heterogeneity between cells from rice leaf sheaths that are infected with rice black streaked dwarf virus (RBSDV) and from those that are virus-free. Using 106 973 cells, we construct a single-cell transcriptome atlas with 12 cell types and find that parenchyma and vascular parenchyma cells are the two major cell types affected by RBSDV. Notably, in RBSDV-infected plants, virus-induced tumours are observed to proliferate and show to differentiate from vascular parenchyma cells in a pseudotime analysis. During the differentiation of RBSDV-induced tumour cells, genes that involved in such processes as nucleosome assembly and chromatin remodeling are upregulated, and those involved in photosynthesis and energy metabolism are downregulated. A gene module of DGP1-GLK1-LHCBs that functions in regulating chloroplast development is repressed in the process of tumour cell formation. Moreover, a jasmonate-inducible pathogenesis-related gene, JiPR10, is expressed specifically in RBSDV-induced tumour cells and endows host resistance to RBSDV by inhibiting the proliferation and expansion of tumours. Our cell-type-specific atlas for plant responses to viral infection provides a valuable resource for further study of virus-induced abnormal development of host plants.

In the original publication [...].

To compare the narrowest diameter of the bony nasolacrimal canal (BNLC) in a Chinese population with and without primary acquired nasolacrimal duct obstruction (PANDO). Eighty-one patients with PANDO and forty-two non-PANDO patients underwent computed tomography (CT) covering the full length of their nasolacrimal canals. The narrowest transverse diameters of the BNLC were measured in axial CT images. The narrowest BNLC diameter was significantly shorter in PANDO patients than non-PANDO patients (4.20 ± 0.87 mm vs. 4.95 ± 0.82 mm, p < 0.001), especially in patients aged 40 years and older (4.20 ± 0.84 mm vs. 5.11 ± 0.83 mm, p < 0.001). When males and females were analyzed separately, the differences between PANDO patients and controls remained significant (4.32 ± 0.82 mm vs. 5.70 ± 0.64 mm, p < 0.001, male; 4.18 ± 0.88 mm vs. 4.74 ± 0.75 mm, p < 0.001, female). Generally, in the Chinese population, males have a larger minimum transverse diameter compared to females (5.70 ± 0.64 mm vs. 4.74 ± 0.75 mm, p < 0.001). Furthermore, the narrowest transverse diameter of the BNLC remarkably increased with age (r = 0.432, p < 0.0001). BNLC stenosis may be an important etiological factor for PANDO in the Chinese population.

BackgroundThe impact of dexmedetomidine (DEX) on postoperative survival outcomes in cancer remains controversial. Our study aimed to investigate the influence of intraoperative DEX administration on postoperative mortality outcomes in colorectal cancer patients.MethodsThis was a retrospective cohort study of adult patients undergoing colorectal cancer surgery in a large academic hospital in southern China between 2011 and 2018. Patients were divided into two groups: the DEX group, in which patients received intravenous DEX during the operation, and the non-DEX group. The primary endpoint was overall death or tumor recurrence, deriving two outcome variables: “all-cause death” and “recurrence or death.” Secondary endpoints included total hospital stay, postoperative hospital stay, and postoperative complications. Multivariable Cox regression and propensity score matching were used to control confounders.ResultsA total of 1,367 adult patients were included, of which 485 pairs were matched. Patients who received intraoperative DEX had a lower all-cause death rate (8.0% vs. 14.2%, P = 0.002) and a lower recurrence or death rate (14.8% vs. 23.1%, P = 0.001). Intraoperative DEX administration was associated with a lower risk of all-cause death postoperatively [adjusted hazard ratio (HR) and 95% confidence interval (CI): 0.74, 0.52–1.07 in overall patients; 0.66, 0.45–0.98 in matched patients] compared with non-DEX. The risk of recurrence or death was lower with a marginal significance (HR and 95% CI: 0.75, 0.56–1.01) in matched patients. The total hospital stay and postoperative hospital stay were lower in patients who used DEX than those who did not use it (β and 95% CI: −0.96 [−1.71, −0.22] and −0.95 [−1.47, −0.43], respectively, in matched patients). Meanwhile, the risk of postoperative complications was not associated with DEX.ConclusionsIn patients undergoing colorectal cancer surgery, intraoperative DEX administration was associated with better postoperative survival.

ObjectivesTransforming growth factor β1 (TGFβ1)-interleukin 11 (IL11) is a newly found critical signaling pathway in fibrotic diseases such as Graves’ orbitopathy (GO). It has now been confirmed that enhanced glycolysis plays a key role in the pathogenesis of GO. However, little is known about the relationship between glycolysis and IL11-mediated fibrosis in GO. This study aimed to identify the relationship between glycolysis and TGFβ1-IL11 signaling pathway and investigate the role of IL11 in glycolysis-facilitated fibrosis in GO.MethodsOrbital connective tissues were collected from GO and control patients. Primary orbital fibroblasts (OFs) were cultured from clinical tissues. Patient-derived xenografts were established via intraorbital transplantation of GO orbital tissue in humanized NCG mice. Protein levels were measured using Capillary Western Immunoassay (WES). Small interfering RNA (siRNA) was used to construct transfected OF strains. Lactate production was measured to assess glycolysis status. Animal models were assessed by T2-weighted magnetic resonance (MR) scan. Immunohistochemistry staining was applied to patients’ orbital connective tissues.ResultsOrbital connective tissues were collected from GO patients. Immunohistochemical (IHC) staining of GO tissues revealed the phenomenon of pyruvate dehydrogenase kinase 2 (PDK2)-enhanced glycolysis and upregulated IL11-IL11Rα pathway. In vitro experiments showed successful induction of fibrosis of patient-derived orbital fat/connective tissues, which could be alleviated by dichloroacetic acid (DCA). MRI images and analysis of hematoxylin and eosin (HE) and Masson-stained section demonstrated enhanced glycolysis in GO, facilitating fibrosis of the orbital tissue. Targeting PDK2 decreased IL11 expression to suppress fibrosis. In vivo experiment confirmed anti-fibrotic effect of inhibition of glycolysis.ConclusionsPDK2-enhanced glycolysis exacerbates fibrosis via IL11-IL11Rα signaling pathway, shedding light on a potential therapeutic role of metabolic modulators such as DCA in GO treatment.

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah -/- mice accumulated more hepatic lipid than did Aoah +/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah -/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah -/- mice also increased hepatic expression of Cd36 and Fabp3 , which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara . Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.

Chatbot-based multimodal AI holds promise for collecting medical histories and diagnosing ophthalmic diseases using textual and imaging data. This study developed and evaluated the ChatGPT-powered Intelligent Ophthalmic Multimodal Interactive Diagnostic System (IOMIDS) to enable patient self-diagnosis and self-triage. IOMIDS included a text model and three multimodal models (text + slit-lamp, text + smartphone, text + slit-lamp + smartphone). The performance was evaluated through a two-stage cross-sectional study across three medical centers involving 10 subspecialties and 50 diseases. Using 15640 data entries, IOMIDS actively collected and analyzed medical history alongside slit-lamp and/or smartphone images. The text + smartphone model showed the highest diagnostic accuracy (internal: 79.6%, external: 81.1%), while other multimodal models underperformed or matched the text model (internal: 69.6%, external: 72.5%). Moreover, triage accuracy was consistent across models. Multimodal approaches enhanced response quality and reduced misinformation. This proof-of-concept study highlights the potential of chatbot-based multimodal AI for self-diagnosis and self-triage. (The clinical trial was registered on June 26, 2023, on ClinicalTrials.gov under the registration number NCT05930444.).

Introduction:Tocilizumab (TCZ) has been demonstrated to be effective in treating thyroid-associated ophthalmopathy (TAO); however, its efficacy in hormone-resistant dysthyroid optic neuropathy (DON) remains unclear. This study aims to identify baseline and post-treatment indicators that can predict the necessity for surgical intervention following TCZ therapy. Methods:Thirty-one hormone-resistant DON patients treated with TCZ were categorized into surgery (n=15, 7 males, 8 females) and non-surgery (n=16, 8 males, 8 females) groups based on their post-TCZ surgical status. Retrospective comparisons between the two groups were performed using pre- and post-treatment ophthalmic assessments, biomarkers, and orbital magnetic resonance imaging (MRI) scans. The predictive value of identified variables was evaluated through receiver operating characteristic (ROC) curve analysis and logistic regression analysis. Results:The surgery group exhibited a significantly higher baseline thyroid-stimulating hormone receptor antibody (TRAb) (P=0.001) and a positive change in the maximal signal intensity ratio of extraocular muscle to temporalis muscle (SIR(EOM/temporalis)MAX), whereas the non-surgery group demonstrated a negative change (P<0.001). A TRAb cut-off value of ≤5.07 IU/L predicted non-surgery with 93.3% sensitivity and 81.2% specificity, while a SIR(EOM/temporalis)MAX cut-off value of ≤-1.83 had 86.7% sensitivity and 87.5% specificity. The area under the curve was 0.846 for TRAb and 0.863 for SIR(EOM/temporalis)MAX. Multivariate regression confirmed SIR(EOM/temporalis)MAX change (P=0.017) as an independent predictor of surgical intervention. Linear regression revealed a significant correlation between SIR(EOM/temporalis)MAX change and TCZ dosage in the non-surgery group (P=0.005), but not in the surgery group. Discussion:The percentage change in SIR(EOM/temporalis)MAX following TCZ treatment and baseline TRAb can serve as predictors of the necessity for surgical intervention in hormone-resistant DON. These indicators assist in the personalization of TCZ therapy and in the avoidance of unnecessary surgical procedures.

Background Melanoma is a highly aggressive tumor, predominantly found in the skin, recognized as skin cutaneous melanoma (SKCM). Lymph node metastasis is commonly used as the route of metastasis in SKCM, necessitating the discovery of prognostic genes associated with this process for improved prognosis. Methods The prognostic significance of lymph node metastasis in SKCM was assessed through Kaplan-Meier analysis in SEER and TCGA-SKCM datasets. Prognostic genes were identified and a prognostic risk model was constructed Enrichment analysis and immune cell infiltration analysis were also carried out.Moreover, a validation in vitro and in vivo were conducted by CCK8,flow cytometry,transwell and animal study. Results The Kaplan-Meier survival curve revealed that patients with lymph node metastasis had a worse prognosis compared to those without. FCGR3B and PRF1 were screened by TCGA analysis.Additionally, significant differences in nine immune cell types were observed between the two risk groups. Notably, a strong positive association with CD8 T cells and a negative relationship with M2 macrophages were exhibited by PRF1. The validation of our nomogram were conducted in vitro and in vivo, and the results showed the correlations between CD8+ T cell and PRF1. Conclusion In summary, two prognostic genes (FCGR3B and PRF1) were identified, and a prognostic risk model was developed for SKCM. These findings provide a novel approach for the diagnosis and treatment of SKCM.