Advanced intraocular retinoblastoma: evolving criteria for group E disease.

With evolving criteria for classifying intraocular retinoblastoma (RB) from International Intraocular Retinoblastoma Classification (IIRC, 2005) to International Classification of Retinoblastoma (ICRB, 2006), there have been changes in the inclusion criteria for groups E eyes that have not been widely recognized. This brief review highlights issues with the current classification systems (ICRB and IIRC) and layouts a theoretical framework arguing for merging of 2 existing classifications into 1 and subdividing the expanded group E RB, thereby preserving the possibility to reanalyze existing published data.

Recent progress in retinoblastoma: Pathogenesis, presentation, diagnosis and management.

Retinoblastoma, the primary ocular malignancy in pediatric patients, poses a substantial threat to mortality without prompt and effective management. The prognosis for survival and preservation of visual acuity hinges upon the disease severity at the time of initial diagnosis. Notably, retinoblastoma has played a crucial role in unraveling the genetic foundations of oncogenesis. The process of tumorigenesis commonly begins with the occurrence of biallelic mutation in the RB1 tumor suppressor gene, which is then followed by a cascade of genetic and epigenetic alterations that correspond to the clinical stage and pathological features of the tumor. The RB1 gene, recognized as a tumor suppressor, encodes the retinoblastoma protein, which plays a vital role in governing cellular replication through interactions with E2F transcription factors and chromatin remodeling proteins. The diagnosis and treatment of retinoblastoma necessitate consideration of numerous factors, including disease staging, germline mutation status, family psychosocial factors, and the resources available within the institution. This review has systematically compiled and categorized the latest developments in the diagnosis and treatment of retinoblastoma which enhanced the quality of care for this pediatric malignancy.

EHMT2 promotes tumorigenesis in GNAQ/11-mutant uveal melanoma via ARHGAP29-mediated RhoA pathway.

Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma (UM). Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular functions. In search of genetic vulnerability for UM, we found that inhibition of euchromatic histone lysine methyltransferase 2 (EHMT2) expression or activity significantly reduced the proliferation and migration capacity of cancer cells. Notably, elevated expression of EHMT2 had been validated in UM samples. Furthermore, Kaplan-Meier survival analysis indicated high EHMT2 protein level was related to poor recurrence-free survival and a more advanced T stage. Chromatin immunoprecipitation sequencing analysis and the following mechanistic investigation showed that ARHGAP29 was a downstream target of EHMT2. Its transcription was suppressed by EHMT2 in a methyltransferase-dependent pattern in GNAQ/11-mutant UM cells, leading to elevated RhoA activity. Rescuing constitutively active RhoA in UM cells lacking EHMT2 restored oncogenic phenotypes. Simultaneously blocking EHMT2 and GNAQ/11 signaling in vitro and in vivo showed a synergistic effect on UM growth, suggesting the driver role of these two key molecules. In summary, our study shows evidence for an epigenetic program of EHMT2 regulation that influences UM progression and indicates inhibiting EHMT2 and MEK/ERK simultaneously as a therapeutic strategy in GNAQ/11-mutant UM.

High-risk histopathologic features in local advanced conjunctival melanoma.

PURPOSE: To identify high-risk histopathologic and molecular features of local recurrence, nodal metastasis, distant metastasis (DM) and disease-specific death (DSD) in conjunctival melanoma (CoM). METHODS: Ninety patients with pathologically diagnosed CoM between 2008 and 2023 were enrolled. Immunohistochemistry staining of BRAFV600E , NRASQ61R , CD117, PD-1 and PD-L1 was performed in 65 and 45 patients, respectively. Cox regression and Kaplan-Meier survival analysis were conducted to identify risk factors for local recurrence, nodal metastasis, DM and DSD. RESULTS: Pathologically, ulceration (hazard ratio [HR]: 3.170; 95% CI: 1.312-7.659; p = 0.01) and regression (HR: 3.196; 95% CI: 1.094-9.335; p = 0.034) were risk factors for DM. Tumour thickness ≥ 4 mm (HR: 4.889; 95% CI: 1.846-12.946; p = 0.001) and regression (HR: 4.011; 95% CI: 1.464-10.991; p = 0.007) were risk factors for DSD. For patients with tumour thickness < 4 mm, the presence of ulceration indicated a higher risk of nodal metastasis (log-rank p = 0.0011), DM (log-rank p = 0.00051) and DSD (log-rank p = 0.02). Patients with regression (+)/tumour-infiltrating lymphocytes (TILs) (+) had a higher risk for DM (log-rank p = 0.011) and DSD (log-rank p = 0.0032). Molecularly, the positive rate of BRAFV600E , NRASQ61R , CD117, PD-1 and PD-L1 was 40.00% (26/65), 43.08% (28/65), 70.77% (46/65), 46.67% (21/45) and 28.89% (13/45), respectively. Positive BRAFV600E was identified as an independent risk factor for DM (HR: 2.533; 95% CI: 1.046-6.136, p = 0.039). The expression level of BRAFV600E was positively correlated with vascular invasion (p = 0.01), as well as the expression levels of PD-1 (p = 0.038) and PD-L1 (p = 0.049). CONCLUSIONS: Tumour thickness ≥ 4 mm, ulceration, the coexistence of regression and TILs, and positive BRAFV600E were risk factors for poor prognosis of CoM patients. Besides, expression level of BRAFV600E was positively correlated with the expression levels of PD-1 and PD-L1.

Genetic landscape and prognosis of conjunctival melanoma in Chinese patients.

AIMS: Conjunctival melanoma (CoM) is a rare but highly lethal ocular melanoma and there is limited understanding of its genetic background. To update the genetic landscape of CoM, whole-exome sequencing (WES) and targeted next-generation sequencing (NGS) were performed. METHODS: Among 30 patients who were diagnosed and treated at Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, from January 2018 to January 2023, WES was performed on 16 patients, while targeted NGS was conducted on 14 patients. Samples were analysed to identify the mutated genes, and the potential predictive factors for progression-free survival were evaluated. Furthermore, the expression of the mutated gene was detected and validated in a 30-patient cohort by immunofluorescence. RESULTS: Mutations were verified in classic genes, such as BRAF (n=9), NRAS (n=5) and NF1 (n=6). Mutated FAT4 and BRAF were associated with an increased risk for the progression of CoM. Moreover, decreased expression of FAT4 was detected in CoM patients with a worse prognosis. CONCLUSIONS: The molecular landscape of CoM in Chinese patients was updated with new findings. A relatively high frequency of mutated FAT4 was determined in Chinese CoM patients, and decreased expression of FAT4 was found in patients with worse prognoses. In addition, both BRAF mutations and FAT4 mutations could serve as predictive factors for CoM patients.

The insular cortex is not insular in thyroid eye disease: neuroimaging revelations of central-peripheral system interaction.

BACKGROUND: Thyroid eye disease (TED) is highly correlated with dysregulated immunoendocrine status. The insular cortex was found to regulate peripheral inflammation and immunomodulation in mice. This study aimed to explore whether the insular cortex in patients with TED played a modulatory role including the aberrant brain functional alteration and its association with immunoendocrine status. METHODS: This study included 34 active patients (AP), 30 inactive patients (IP) with TED, and 45 healthy controls (HC) matched for age, sex, and educational level. Comprehensive clinical details (especially immunoendocrine markers) and resting-state functional magnetic resonance imaging data were collected from each participant. The amplitude of low-frequency fluctuation (ALFF) was used to probe the aberrant alterations of local neural activity. The seed-based functional connectivity (FC) analysis was used to explore the relationship between the insular cortex and each voxel throughout the whole brain. The correlation analysis was conducted to assess the association between insular neurobiomarkers and immunoendocrine parameters. RESULTS: When compared with the IP and HC groups, the AP group displayed significantly higher ALFF values in the right insular cortex (INS.R) and lower FC values between the INS.R and the bilateral cerebellum. None of the neurobiomarkers differed between the IP and HC groups. Besides, correlations between insular neurobiomarkers and immunoendocrine markers (free thyroxine, the proportion of T cells, and natural killer cells) were identified in both AP and IP groups. CONCLUSIONS: This study was novel in reporting that the dysregulation of the insular cortex activity in TED was associated with abnormal peripheral immunoendocrine status. The insular cortex might play a key role in central-peripheral system interaction in TED. Further research is crucial to enhance our understanding of the central-peripheral system interaction mechanisms involved in autoimmune diseases.

FBXO38 deficiency promotes lysosome-dependent STING degradation and inhibits cGAS-STING pathway activation.

F-box only protein 38 (FBXO38) is a member of the F-box family that mediates the ubiquitination and proteasome degradation of programmed death 1 (PD-1), and thus has important effects on T cell-related immunity. While its powerful role in adaptive immunity has attracted much attention, its regulatory roles in innate immune pathways remain unknown. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an important innate immune pathway that regulates type I interferons. STING protein is the core component of this pathway. In this study, we identified that FBXO38 deficiency enhanced tumor proliferation and reduced tumor CD8+ T cells infiltration. Loss of FBXO38 resulted in reduced STING protein levels in vitro and in vivo, further leading to preventing cGAS-STING pathway activation, and decreased downstream product IFNA1 and CCL5. The mechanism of reduced STING protein was associated with lysosome-mediated degradation rather than proteasomal function. Our results demonstrate a critical role for FBXO38 in the cGAS-STING pathway.

Whole-orbit radiomics: machine learning-based multi- and fused- region radiomics signatures for intravenous glucocorticoid response prediction in thyroid eye disease.

BACKGROUND: Radiomics analysis of orbital magnetic resonance imaging (MRI) shows preliminary potential for intravenous glucocorticoid (IVGC) response prediction of thyroid eye disease (TED). The current region of interest segmentation contains only a single organ as extraocular muscles (EOMs). It would be of great value to consider all orbital soft tissues and construct a better prediction model. METHODS: In this retrospective study, we enrolled 127 patients with TED that received 4·5 g IVGC therapy and had complete follow-up examinations. Pre-treatment orbital T2-weighted imaging (T2WI) was acquired for all subjects. Using multi-organ segmentation (MOS) strategy, we contoured the EOMs, lacrimal gland (LG), orbital fat (OF), and optic nerve (ON), respectively. By fused-organ segmentation (FOS), we contoured the aforementioned structures as a cohesive unit. Whole-orbit radiomics (WOR) models consisting of a multi-regional radiomics (MRR) model and a fused-regional radiomics (FRR) model were further constructed using six machine learning (ML) algorithms. RESULTS: The support vector machine (SVM) classifier had the best performance on the MRR model (AUC = 0·961). The MRR model outperformed the single-regional radiomics (SRR) models (highest AUC = 0·766, XGBoost on EOMs, or LR on OF) and conventional semiquantitative imaging model (highest AUC = 0·760, NaiveBayes). The application of different ML algorithms for the comparison between the MRR model and the FRR model (highest AUC = 0·916, LR) led to different conclusions. CONCLUSIONS: The WOR models achieved a satisfactory result in IVGC response prediction of TED. It would be beneficial to include more orbital structures and implement ML algorithms while constructing radiomics models. The selection of separate or overall segmentation of orbital soft tissues has not yet attained its final optimal result.

Mental health disparities between physicians and nurses: Analyzing the impact of occupational stress and work environment fitness using random forest algorithm.

BACKGROUND: The impact of occupational stress and work environment fitness on mental health disparities between physicians and nurses are not well understood. This study aims to identify and rank key determinants of mental health in physicians and nurses in China and compare the differences in their impact on mental health between physicians and nurses. METHODS: A large cross-sectional survey with multistage cluster sampling was conducted. The survey included the Self-Rating Anxiety Scale (SAS Scale), the Center for Epidemiologic Studies Depression Scale (CES-D Scale), the Maslach Burnout Inventory-General Survey (MBI-GS) and the Person-Environment (PE) Fit. We applied a principled, machine learning-based variable selection algorithm, using random forests, to identify and rank the determinants of the mental health in physicians and nurses. RESULTS: In our study, we analyzed a sample of 9964 healthcare workers, and 2729 (27 %) were physicians. The prevalence of anxiety and depressive disorders among physicians and nurses was 31.0 % and 53.3 %, 30.8 % and 47.9 %, respectively. Among physicians with anxiety disorder, we observed a higher likelihood of cynicism, emotional exhaustion, reduced personal accomplishment, and poor organization fitness, job fitness, group fitness, and supervisor fitness, in order of importance. When comparing the effects on depressive disorder in physicians, group fitness and supervisor fitness did not have significant impacts. For nurses, emotional exhaustion had a more significant effect on depressive disorder compared to cynicism. Supervisor fitness did not have a significant impact on anxiety disorder in nurses. LIMITATIONS: Cross-sectional design, self-reporting screening scales. CONCLUSIONS: Compared to individual and hospital characteristics, the primary factors influencing mental health disorders are occupational burnout and the compatibility of the work environment. Additionally, the key determinants of depressive and anxiety disorders among doctors and nurses exhibit slight variations. Employing machine learning methods proves beneficial for identifying determinants of mental health disorders among physicians and nurses in China. These findings could help improve policymaking aimed at addressing the mental well-being of healthcare professionals.

Risk factors for cataract in retinoblastoma management.

AIMS: To investigate the risk factors for cataract following eye-preserving therapies for retinoblastoma. METHODS: This retrospective, single-centre cohort study included patients diagnosed with retinoblastoma receiving eye-preserving therapies between January 2017 and June 2021. Cataract by the end of the follow-up was the main outcome. RESULTS: Cataract was found in 31 of 184 (16.8%) included eyes during a mean follow-up of 27.6 months. The cataract and control groups were similar regarding patients' laterality, sex and disease stage. Eyes in the cataract group were more likely to present with endophytic retinoblastoma (p=0.02) and greater intraocular pressure (p=0.001). Competing risk regression analysis (univariate Fine-Gray model) showed that the growth pattern (p=0.01), intraocular pressure (p=0.01), number of intra-arterial chemotherapy (IAC) cycles (p=0.001), melphalan dose per IAC cycle (p=0.001) and number of intravitreous chemotherapy (IvitC) cycles (p=0.001) were associated with cataract occurrence. Multivariate analysis included higher intraocular pressure (p=0.003), a higher melphalan dose per IAC cycle (p=0.001) and an increasing number of IvitC cycles (p=0.04) as independent risk factors for cataract. CONCLUSIONS: Repeated IAC and/or IvitC with melphalan were the most common eye-preserving therapies that induced cataract formation. The toxic effect of melphalan was an essential factor in cataract development, as indicated by the association of cataract occurrence with the melphalan dose.

Correlating somatic copy number alteration in aqueous humour cfDNA with chemotherapy history, eye salvage and pathological features in retinoblastoma.

BackgroundThis study determined to probe the potential association between somatic copy number alteration (SCNA) in retinoblastoma (RB) aqueous humour (AH) and pathological high-risk factors, clinical features and previous chemotherapy history. METHODS: Single-centre retrospective cohort study from including 58 AH samples collected from 58 patients diagnosed. Among them, 41 samples were collected after enucleation and 17 samples were collected before intravitreal chemotherapy. SCNAs were accessed by conducting shallow whole-genome sequencing in cell-free (cf) DNA of AH. HRs and ORs were applied to measure risk factors. RESULTS: Canonical RB SCNAs including 1q gain (87%), 2p gain (50%), 6p gain (76%), 16q loss (69%) were frequently detected. Non-classical RB SCNAs in AH including 17q gain (53%), 19q loss (43%), 7q gain (35%) were also commonly observed. 19q loss was significantly more common in patients with cT3c or worse stage than others (p=0.034). 2p gain(p=0.001) and 7q gain(p=0.001) were both more common in patients with primary enucleation than those with previous chemotherapy. Interestingly, both 2p gain (HR=1.933, p=0.027) and 7q gain (HR=2.394, p=0.005) might predict enucleation. Correlation analysis with pathological features among enucleated eyes showed that 19q loss can predict a higher risk for both massive choroid invasion (OR=4.909, p=0.038) and postlaminar optic nerve invasion (OR=4.250, p=0.043). DISCUSSION: Sequencing of AH cfDNA in RB can provide sufficient in vivo information. 19q loss was a potential signature of advanced cases clinically and pathologically.Repeated sampling from eyes receiving sequential chemotherapy should be conducted to evaluate fluctuation of SCNA in future study.

Does vitreous haemorrhage and calcification lead to increased risk of enucleation in advanced retinoblastoma?

PURPOSE: To explore whether varying degrees of vitreous haemorrhage (VH) and calcification act as risk factors for enucleation in patients with advanced retinoblastoma (RB). METHODS: Advanced RB was defined by the international classification of RB (Philadelphia version). Basic information for retinoblastoma patients diagnosed as groups D and E in our hospital between January 2017 and June 2022 was reviewed by logistics regression models. Additionally, a correlation analysis was performed, excluding variables with a VIF (variance inflation factor) >10 from the multivariate analysis. RESULTS: A total of 223 eyes diagnosed with RB were included in assessing VH and calcification; of these, 101 (45.3%) eyes experienced VH, and 182 (76.2%) eyes were found to have calcification within the tumour through computed tomography (CT) or B-scan ultrasonography. Ninety-two eyes (41.3%) were enucleated, of which 67 (72.8%) had VH and 68 (73.9%) calcification, both of which were significantly relevant to enucleation (p < 0.001*). Other clinical risk factors, such as corneal edema, anterior chamber haemorrhage, high intraocular pressure during treatment and iris neovascularization, correlated significantly with enucleation (p < 0.001*). Multivariate analysis included IIRC (intraocular international retinoblastoma classification), VH, calcification and high intraocular pressure during treatment as independent risk factors for enucleation. CONCLUSIONS: Despite identifying different potential risk factors for RB, there remains significant controversy concerning which patients require enucleation, and the degree of VH varies. Such eyes need to be evaluated carefully, and management with appropriate adjuvant therapy may improve the outcome of these patients.

Histone lactylation-boosted ALKBH3 potentiates tumor progression and diminished promyelocytic leukemia protein nuclear condensates by m1A demethylation of SP100A.

Albeit N1-Methyladenosine (m1A) RNA modification represents an important regulator of RNA metabolism, the role of m1A modification in carcinogenesis remains enigmatic. Herein, we found that histone lactylation enhances ALKBH3 expression and simultaneously attenuates the formation of tumor-suppressive promyelocytic leukemia protein (PML) condensates by removing the m1A methylation of SP100A, promoting the malignant transformation of cancers. First, ALKBH3 is specifically upregulated in high-risk ocular melanoma due to excessive histone lactylation levels, referring to m1A hypomethylation status. Moreover, the multiomics analysis subsequently identified that SP100A, a core component for PML bodies, serves as a downstream candidate target for ALKBH3. Therapeutically, the silencing of ALKBH3 exhibits efficient therapeutic efficacy in melanoma both in vitro and in vivo, which could be reversed by the depletion of SP100A. Mechanistically, we found that YTHDF1 is responsible for recognition of the m1A methylated SP100A transcript, which increases its RNA stability and translational efficacy. Conclusively, we initially demonstrated that m1A modification is necessary for tumor suppressor gene expression, expanding the current understandings of dynamic m1A function during tumor progression. In addition, our results indicate that lactylation-driven ALKBH3 is essential for the formation of PML nuclear condensates, which bridges our knowledge of m1A modification, metabolic reprogramming, and phase-separation events.

Establishment and Characterization of a TP53-Mutated Eyelid Sebaceous Carcinoma Cell Line.

Purpose: Eyelid sebaceous carcinoma (SeC) is the third most frequent eyelid malignancy worldwide and is relatively prevalent in Asian patients. An eyelid SeC cell line model is necessary for experimental research to explore the etiology and pathogenesis of eyelid SeC. This study established and characterized an eyelid SeC cell line with a TP53 mutation that might be useful for analyzing potential treatment options for eyelid SeC. Methods: The eyelid SeC cell line SHNPH-SeC was obtained from a patient with eyelid SeC at Shanghai Ninth People's Hospital (SHNPH), Shanghai JiaoTong University School of Medicine. Immunofluorescence staining was employed to detect the origination and proliferation activity. Short tandem repeat (STR) profiling was performed for verification. Chromosome analysis was implemented to investigate chromosome aberrations. Whole exome sequencing (WES) was used to discover genomic mutations. Cell proliferation assays were performed to identify sensitivity to mitomycin-C (MMC) and 5-fluorouracil (5-FU). Results: SHNPH-SeC cells were successively subcultured for more than 100 passages and demonstrated rapid proliferation and migration. Karyotype analysis revealed abundant chromosome aberrations, and WES revealed SeC-related mutations in TP53, KMT2C, and ERBB2. An in vivo tumor model was successfully established in NOD/SCID mice. Biomarkers of eyelid SeC, including cytokeratin 5 (CK5), epithelial membrane antigen (EMA), adipophilin, p53, and Ki-67, were detected in SHNPH-SeC cells, original tumors, and xenografts. MMC and 5-FU inhibited the proliferation and migration of SHNPH-SeC cells, and SHNPH-SeC cells presented a greater drug response than non-TP53-mutated SeC cells. Conclusions: The newly established eyelid SeC cell line SHNPH-SeC demonstrates mutation in TP53, the most commonly mutated gene in SeC. It presents SeC properties and malignant characteristics that may facilitate the investigation of cellular behaviors and molecular mechanisms of SeC to explore promising therapeutic strategies.

The Use of rAAV2-RB1-Mediated Gene Therapy in Retinoblastoma.

Purpose: Retinoblastoma (RB) is a life-threatening malignancy that arises from the retina and is activated upon homozygous inactivation of the tumor suppressor RB1. Gene therapy targeting RB1 is an effective strategy to treat RB. However, it is difficult to target the RB1 gene by site-specific repair, with up to 3366 gene mutation sites identified in RB1. Thus, it is necessary to construct a promising and efficacious gene therapeutic strategy for patients with RB. Methods: To recover the function of the RB1 protein, we constructed a recombinant adeno-associated virus 2 (rAAV2) expressing RB1 that can restore RB1 function and significantly inhibit RB progression. To confirm the clinical feasibility of rAAV2-RB1, the RB1 protein was validated in vitro and in vivo after transfection. To further evaluate the clinical efficacy, RB patient-derived xenograft models were established and applied. The biosafety of rAAV2-RB1 was also validated in immunocompetent mice. Results: rAAV2-RB1 was a rAAV2 expressing the RB1 protein, which was validated in vitro and in vivo. In vitro, rAAV2-RB1 was effectively expressed in patient-derived RB cells. In mice, intravitreal administration of rAAV2-RB1 in a population-based patient-derived xenograft trial induced limited tumor growth. Moreover, after transfection of rAAV2-RB1 in immunocompetent mice, rAAV2-RB1 did not replicate and was expressed in other important organs, except retinas, inducing minor local side effects. Conclusions: Our study suggested a promising efficacy gene therapeutic strategy, which might provide a chemotherapy-independent treatment option for RB.

Immune-related visual dysfunction in thyroid eye disease: a combined orbital and brain neuroimaging study.

OBJECTIVES: To investigate the pathological interplay between immunity and the visual processing system (VPS) in thyroid eye disease (TED). METHODS: A total of 24 active patients (AP), 26 inactive patients (IP) of TED, and 27 healthy controls (HCs) were enrolled. Orbital magnetic resonance imaging (MRI) and resting-state functional MRI (rs-fMRI) were conducted for each participant. Multiple MRI parameters of the intraorbital optic nerve (ON) were assessed. The amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) were calculated. Correlation analyses were carried out on the above parameters and clinical characteristics. RESULTS: Visual functioning scores differentiated between the AP and IP groups. The ON subarachnoid space and ON sheath diameter were significantly higher in AP than in IP. Six vision-related brain regions were identified in TED patients compared with HCs, including right calcarine (CAL.R), right cuneus (CUN.R), left postcentral gyrus (PoCG.L), right middle temporal gyrus (MTG.R), left superior frontal gyrus (SFG.L), and left caudate (CAU.L). The brain activity of MTG.R, SFG.L, and CAU.L differentiated between the AP and IP groups. The correlation analysis revealed a close association among the vision-related brain regions, MRI parameters of ON, and clinical characteristics in AP and IP, respectively. CONCLUSIONS: Combined orbital and brain neuroimaging revealed abnormalities of the VPS in TED, which had a close correlation with immune statuses. Vision-related brain regions in TED might be possibly altered by peripheral immunity via a direct or indirect approach. CLINICAL RELEVANCE STATEMENT: The discovery of this study explained the disparity of visual dysfunction in TED patients with different immune statuses. With the uncovered neuroimaging markers, early detection and intervention of visual dysfunction could be achieved and potentially benefit TED patients. KEY POINTS: • Patients with different immune statuses of thyroid eye disease varied in the presentation of visual dysfunction. • The combined orbital and brain neuroimaging study identified six altered vision-related brain regions, which had a significant correlation with the MRI parameters of the intraorbital optic nerve and immunological characteristics. • Peripheral immunity might possibly give rise to alterations in the central nervous system part of the visual processing system via a direct or indirect approach.

Prime editing: current advances and therapeutic opportunities in human diseases.

Gene editing ushers in a new era of disease treatment since many genetic diseases are caused by base-pair mutations in genomic DNA. With the rapid development of genome editing technology, novel editing tools such as base editing and prime editing (PE) have attracted public attention, heralding a great leap forward in this field. PE, in particular, is characterized by no need for double-strand breaks (DSBs) or homology sequence templates with variable application scenarios, including point mutations as well as insertions or deletions. With higher editing efficiency and fewer byproducts than traditional editing tools, PE holds great promise as a therapeutic strategy for human diseases. Subsequently, a growing demand for the standard construction of PE system has spawned numerous easy-to-access internet resources and tools for personalized prime editing guide RNA (pegRNA) design and off-target site prediction. In this review, we mainly introduce the innovation and evolutionary strategy of PE systems and the auxiliary tools for PE design and analysis. Additionally, its application and future potential in the clinical field have been summarized and envisaged.

Predictive model for the progression of inactive thyroid eye disease: a retrospective study.

PURPOSE: This study aimed to develop a model for predicting the progression of inactive thyroid eye disease (TED). METHODS: We retrospectively analyzed 107 patients with inactive TED, who did not receive any TED treatment during the follow-up period of 3-6 months. A multivariable regression analysis was employed to examine the clinical risk factors influencing the progress of TED and a predictive model based on risk factors was established. RESULTS: Seventeen (15.9%) patients had progressed at the last observation. Male (p = 0.024), having smoking history (p = 0.009), compound indicator combined the duration of TED and immunosuppressive treatment history before 3 months (p = 0.026) and more severe diplopia (p = 0.015) were found to be the potential risk factors for progression. Among the subset of patients who exhibited progression, there was a notable escalation in the severity of proptosis (p = 0.021), margin reflex distance-1 (p = 0.031), and clinical activity score (p = 0.011). The multivariable stepwise regression analysis identified positive smoking history as well as untreated and having a duration of TED > 12 months as independent risk factors of TED progression. A predictive model including these risk factors was built, with the AUC (Area Under Curve) score of 0.783. CONCLUSIONS: The predictors of TED progression include smoking history and composite indicators of duration time and treatment history. Our model may provide recommendations for immunosuppressive therapy and prognostic predictions for inactive TED patients preparing for surgery.

Application of Quantitative MRI in Thyroid Eye Disease: Imaging Techniques and Clinical Practices.

Thyroid eye disease (TED) is a complex autoimmune disorder that impairs various orbital structures, leading to cosmetic damage and vision loss. Magnetic resonance imaging (MRI) is a fundamental diagnostic tool utilized in clinical settings of TED, for its accurate demonstration of orbital lesions and indication of disease conditions. The application of quantitative MRI has brought a new prospect to the management and research of TED, offering more detailed information on morphological and functional changes in the orbit. Therefore, many researchers concentrated on the implementation of different quantitative MRI techniques on TED for the exploration of clinical practices. Despite the abundance of studies utilizing quantitative MRI in TED, there remain considerable barriers and disputes on the best exploitation of this tool. This could possibly be attributed to the complexity of TED and the fast development of MRI techniques. It is necessary that clinical and radiological aspects of quantitative MRI in TED be better integrated into comprehensive insights. Hence, this review traces back 30 years of publications regarding quantitative MRI utilized in TED and elucidates this promising application in the facets of imaging techniques and clinical practices. We believe that a deeper understanding of the application of quantitative MRI in TED will enhance the efficacy of the multidisciplinary management of TED. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.