Incidence, clinical features, and survival outcomes of primary malignant lacrimal gland tumors: A population-based analysis.

BACKGROUND: Studies on the epidemiological information and prognosis of primary malignant lacrimal gland tumors (MLGTs) are rare for its low occurrence. The goal of our research was to investigate the epidemiological characteristics and survival outcomes of patients with MLGTs. METHODS: Incidence and demographic information of patients with MLGTs were collected from the Surveillance, Epidemiology, and End Results (SEER) database. To identify independent prognostic factors for disease-specific survival (DSS) and overall survival (OS), univariate and multivariate Cox regression analysis were performed. RESULTS: The overall incidence of primary MLGTs from 1975 to 2020 was 0.413/1,000,000 (according to the 2000 American standard population), with a steadily increasing incidence over years. A total of 964 patients with primary MLGTs were diagnosed, with an average age of 59.3 years. Of these, 53.2% were aged ≥60 years, 57.4% were female, and 77.1% were whites. Multivariate Cox regression analysis demonstrated that year of diagnosis, age, sex, histological type, SEER stage, surgery, and chemotherapy were independent prognostic factors of DSS or OS. CONCLUSIONS: Although primary MLGT is rare, its incidence has steadily increased in the past 46 years, and surgery was related to a better prognosis.

Research progress on the immune microenvironment and immunotherapy in gastric cancer.

The tumor microenvironment, particularly the immune microenvironment, plays an indispensable role in the malignant progression and metastasis of gastric cancer (GC). As our understanding of the GC microenvironment continues to evolve, we are gaining deeper insights into the biological mechanisms at the single-cell level. This, in turn, has offered fresh perspectives on GC therapy. Encouragingly, there are various monotherapy and combination therapies in use, such as immune checkpoint inhibitors, adoptive cell transfer therapy, chimeric antigen receptor T cell therapy, antibody-drug conjugates, and cancer vaccines. In this paper, we review the current research progress regarding the GC microenvironment and summarize promising immunotherapy research and targeted therapies.

Single-cell sequencing in primary intraocular tumors: understanding heterogeneity, the microenvironment, and drug resistance.

Retinoblastoma (RB) and uveal melanoma (UM) are the most common primary intraocular tumors in children and adults, respectively. Despite continued increases in the likelihood of salvaging the eyeball due to advancements in local tumor control, prognosis remains poor once metastasis has occurred. Traditional sequencing technology obtains averaged information from pooled clusters of diverse cells. In contrast, single-cell sequencing (SCS) allows for investigations of tumor biology at the resolution of the individual cell, providing insights into tumor heterogeneity, microenvironmental properties, and cellular genomic mutations. SCS is a powerful tool that can help identify new biomarkers for diagnosis and targeted therapy, which may in turn greatly improve tumor management. In this review, we focus on the application of SCS for evaluating heterogeneity, microenvironmental characteristics, and drug resistance in patients with RB and UM.

Epidemiology and survival outcomes of patients with orbital region non-cutaneous squamous cell carcinoma: a population-based analysis.

Background: Non-cutaneous squamous cell carcinoma (ncSCC) of the orbital region is very rare. Thus, its epidemiological characteristics and prognosis are poorly understood. The aim of the study was to assess the epidemiological characteristics and survival outcomes of ncSCC of the orbital region. Methods: Incidence and demographic data on ncSCC of the orbital region were extracted from the Surveillance, Epidemiology, and End Results (SEER) database and analyzed. The chi-square test was used to calculate the differences between groups. Univariate and multivariate Cox regression analyses were performed to determine the independent prognostic factors for disease-specific survival (DSS) and overall survival (OS). Results: The overall incidence of ncSCC in the orbital region from 1975 to 2019 was 0.68/1,000,000, and the incidence showed an increasing trend during this period. A total of 1,265 patients with ncSCC of the orbital region (mean age, 65.3 years) were identified in the SEER database. Of these, 65.1% were aged ≥60 years, 87.4% were White, and 73.5% were male. The conjunctiva (74.5%) was the most common primary site, followed by the orbit (12.1%), lacrimal apparatus (10.8%), and overlapping lesion of the eye and adnexa (2.7%). Multivariate Cox regression analysis revealed that age, primary site, SEER summary stage, and surgery were independent prognostic factors for DSS, whereas age, sex, marital status, primary site, SEER summary stage, and surgery were independent prognostic factors for OS. Conclusions: The incidence of ncSCC in the orbital region has increased over the past 40 years. It usually affects White people, men, and people aged ≥60 years, and its most common site is the conjunctiva. Orbital SCC has worse survival outcomes than SCC of other sites in the orbital region. Surgery is the independent protective treatment for ncSCC of the orbital region.

Research progress and application of artificial intelligence in thyroid associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is a complicated orbitopathy related to dysthyroid, which severely destroys the facial appearance and life quality without medical interference. The diagnosis and management of thyroid-associated ophthalmopathy are extremely intricate, as the number of professional ophthalmologists is limited and inadequate compared with the number of patients. Nowadays, medical applications based on artificial intelligence (AI) algorithms have been developed, which have proved effective in screening many chronic eye diseases. The advanced characteristics of automated artificial intelligence devices, such as rapidity, portability, and multi-platform compatibility, have led to significant progress in the early diagnosis and elaborate evaluation of these diseases in clinic. This study aimed to provide an overview of recent artificial intelligence applications in clinical diagnosis, activity and severity grading, and prediction of therapeutic outcomes in thyroid-associated ophthalmopathy. It also discussed the current challenges and future prospects of the development of artificial intelligence applications in treating thyroid-associated ophthalmopathy.

The next bastion to be conquered in immunotherapy: microsatellite stable colorectal cancer.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and its incidence continues to rise, particularly in developing countries. The advent of immune checkpoint inhibitors (ICIs) has represented a significant advancement in CRC treatment. Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) serves as a biomarker for immunotherapy, with dMMR/MSI-H CRC exhibiting significantly better response rates to immunotherapy compared to proficient mismatch repair (pMMR)or microsatellite stable (MSS) CRC. While some progress has been made in the treatment of pMMR/MSS CRC in recent years, it remains a challenging issue in clinical practice. The tumor microenvironment (TME) plays a crucial role not only in the development and progression of CRC but also in determining the response to immunotherapy. Understanding the characteristics of the TME in pMMR/MSS CRC could offer new insights to enhance the efficacy of immunotherapy. In this review, we provide an overview of the current research progress on the TME characteristics and advancements in immunotherapy for pMMR/MSS CRC.

Potential Therapeutic Activity of Berberine in Thyroid-Associated Ophthalmopathy: Inhibitory Effects on Tissue Remodeling in Orbital Fibroblasts.

Purpose: Berberine (BBR), an alkaloid produced by a traditional Chinese plant, was recently attributed multiple effects on lipometabolism, inflammation, and fibrosis. Thyroid-associated ophthalmopathy (TAO) is highly associated with these pathologic changes. Thus, we aimed to examine the potential therapeutic effect of BBR in an in vitro model of TAO. Methods: Orbital fibroblasts (OFs) obtained from control donors (n = 6) or patients with TAO (n = 6) were cultured. The CCK-8 assay was conducted for assessing the optimal concentration range. Oil Red O staining, Western blotting, and quantitative RT-PCR (qRT-PCR) were conducted to assess adipogenesis in OFs. RNA sequencing (RNA-seq) was used to screen the key pathways of the antiadipogenic effect mediated by BBR. Along with incremental concentrations of BBR, IL-1ß-induced expression of proinflammatory molecules was determined by ELISA and qRT-PCR. In addition, TGF-ß-induced hyaluronan (HA) production and fibrosis were evaluated by ELISA, qRT-PCR, and Western blotting. Results: TAO-OFs, but not control fibroblasts (CON-OFs), were readily differentiated into adipocytes with the commercial medium. Intracellular lipid accumulation was dose-dependently decreased by BBR, and adipogenic markers were also downregulated. Moreover, the PPARγ and AMPK pathways were screened out by RNA-seq and their downstream effectors were suppressed by BBR. Besides, BBR attenuated IL-1ß-induced expression of proinflammatory molecules in both TAO-OFs and CON-OFs by blocking nuclear factor-κB signaling. BBR's inhibitory effect on TGF-ß-mediated tissue remodeling was also confirmed in OFs. Conclusions: These findings demonstrate BBR has outstanding capabilities of controlling adipogenesis, inflammation, HA production, and fibrosis in OFs, highlighting its potential therapeutic role in TAO management.

Effect of miR-184 and miR-205 on the tumorigenesis of conjunctival mucosa associated lymphoid tissue lymphoma through regulating RasL10B and TNFAIP8.

AIM: To explore the effect of miR-184 and miR-205 on the proliferation and metastasis of conjunctival mucosa associated lymphoid tissue (MALT) lymphoma. METHODS: Tissue of tumor and adjacent normal control from 5 patients with conjunctival MALT was included. RPMI8226 cell line was selected to verify the effect of miRNAs in B cells. The function of microRNA on the RPMI8226 cell apoptosis, migration and invasion was evaluated by apoptosis assay and Transwell assay. The mRNA and protein expression were examined by quantitative RT-PCR and Western blotting. The effect of microRNA on regulation of downstream gene expression was evaluated by luciferase report assay. RESULTS: A decreased level of miR-184 and miR-205 was observed in MALT lymphoma tissue. Exogenous miR-184 and miR-205 analogues promoted apoptosis, and inhibited the survival, migration, and invasion of RPMI8226 cells. miR-184 and miR-205 inhibitor reversed the process. The RNA and protein level of RasL10B and TNFAIP8 were downregulated in MALT lymphoma tissue. The exogenous of miR-184 and miR-205 promoted the expression of RasL10B and TNFAIP8. Meanwhile, inhibition of miR-184 and miR-205 repressed the expression of target gene, RasL10B and TNFAIP8. CONCLUSION: miR-184 and miR-205 suppresses the tumorigenesis of conjunctival MALT lymphoma through regulating RasL10B and TNFAIP8.

A Novel Competing Endogenous RNA Network Associated With the Pathogenesis of Graves' Ophthalmopathy.

Background: Growing evidence has recently revealed the characteristics of long noncoding (lncRNA)/circular RNA (circRNA)-microRNA (miRNA)-mRNA networks in numerous human diseases. However, a scientific lncRNA/circRNA-miRNA-mRNA network related to Graves' ophthalmopathy (GO) remains lacking. Materials and methods: The expression levels of RNAs in GO patients were measured through high-throughput sequencing technology, and the results were proven by quantitative real-time PCR (qPCR). We constructed a protein-protein interaction (PPI) network using the Search Tool for the Retrieval of Interacting Genes (STRING) database and identified hub genes by the Cytoscape plug-in CytoHubba. Then, the miRNAs related to differentially expressed lncRNAs/circRNAs and mRNAs were predicted through seed sequence matching analysis. Correlation coefficient analysis was performed on the interesting RNAs to construct a novel competing endogenous RNA (ceRNA) network. Results: In total, 361 mRNAs, 355 circRNAs, and 242 lncRNAs were differentially expressed in GO patients compared with control patients, 166 pairs were identified, and ceRNA networks were constructed. The qPCR results showed that 4 mRNAs (THBS2, CHRM3, CXCL1, FPR2) and 2 lncRNAs (LINC01820:13, ENST00000499452) were differentially expressed between the GO patients and control patients. Conclusion: An innovative lncRNA/circRNA-miRNA-mRNA ceRNA network between GO patients and control patients was constructed, and two important ceRNA pathways were identified, the LINC01820:13-hsa-miR-27b-3p-FPR2 ceRNA pathway and the ENST00000499452-hsa-miR-27a-3p-CXCL1 pathway, which probably affect the autoimmune response and inflammation in GO patients.

Identification of differentially expressed long non-coding RNAs and mRNAs in orbital adipose/connective tissue of thyroid-associated ophthalmopathy.

Extracellular matrix remodeling and orbital adipose/connective tissue expansion are two key features of thyroid-associated ophthalmopathy (TAO). Recent studies have indicated the critical role of long non-coding RNAs (lncRNAs) in the pathogenesis of ocular disorders. However, little is known about the roles of lncRNAs in orbital adipose/connective tissue of TAO. In this study, the profiles of lncRNAs and mRNAs in the orbital adipose/connective tissue of TAO were identified by RNA sequencing. A total of 809 differential lncRNAs and 607 differential mRNAs were identified, among which 52 genes were found to be significantly related to the extracellular matrix. Co-expression network analysis suggested that lncRNAs might regulate extracellular matrix remodeling in orbital adipose/connective tissue of TAO. Additionally, the target genes of lncRNAs involved in the lipid metabolism and cytokine-cytokine receptor interaction were also identified. These results may provide potential regulatory mechanisms of lncRNAs in the orbital adipose/connective tissue of TAO.

Clinical Nocardia species: Identification, clinical characteristics, and antimicrobial susceptibility in Shandong, China.

Nocardia is a pathogen responsible for a variety of clinical infections. Here, we aimed to investigate the species distribution, clinical manifestations, and antimicrobial susceptibility of Nocardia species over 3 years in two tertiary general hospitals in China. In this retrospective study, a total of 27 Nocardia species were isolated from 27 individuals between January 2017 and December 2019. Nocardia isolates were identified to species level by mass spectrometry and 16S rRNA PCR sequencing. Clinical data were collected from medical records. Antimicrobial susceptibility was determined by the standard Broth microdilution method. The 27 patients with Nocardia infection included 12 males and 15 females with a mean age of 60.11 years. Among 27 Nocardia isolates, 7 species were identified, with the most common species being Nocardia otitidiscaviarum (40.7%). The antimicrobial susceptibility profiles varied between different Nocardia species. Notably, all Nocardia isolates were linezolid susceptible. The majority of Nocardia isolates were collected from a department of respiratory medicine (55.56%) and sputum specimen (44.44%). Pulmonary region was the most involved body site (70.37%) followed by skin (7.4%) and pleural cavity (7.4%). Most patients with Nocardia infection needed combination antibiotic therapy. Two deaths were reported during the treatment period and 24 patients achieved improvement after antibiotic therapy. The clinical manifestations of Nocardia infection and antimicrobial susceptibility profiles varied with diverse Nocardia species. Thus, the accurate identification of these species is crucial for the diagnosis and the selection of antibiotic treatment.

Transforming growth factor-ß1 suppress pentraxin-3 in human orbital fibroblasts.

PURPOSE: Transforming growth factor-ß (TGF-ß), recognized as a crucial factor in regulating fibrosis and tissue remodeling, plays a role in thyroid-associated ophthalmopathy (TAO). Pentraxin-3 (PTX3), a member of pentraxins, was recently implicated in many autoimmune and fibrotic diseases. Thus, we hypothesize if there is a potential correlation between TGF-ß and PTX3 in orbital fibroblasts (OFs). METHODS: Several strains of OFs obtained from patients with TAO (n = 8) and healthy donors (n = 3) were established as the study model. Recombinant TGF-ß1 was exerted as an intervention and the expression of PTX3 was detected. To uncover the underlying mechanism, specific inhibitors of TGF-ß and siRNA knockdown of Smads were utilized. RESULTS: We found that TGF-ß1 can reduce PTX3 protein expression in OFs. We also demonstrated that this downregulation was mediated at a pretranslational level, and PTX3 mRNA was inhibited in a time- and concentration-dependent manner by TGF-ß1. Interestingly, the basic level of PTX3 and the magnitude of suppression were not significantly different between TAO and control groups. Furthermore, the TGF-ß receptor complex (type I:type II) and the Smad2/3-Smad4-dependent pathway are essential for TGF-mediated PTX3 repression. CONCLUSION: These findings indicated that TGF-ß1 can inhibit PTX3 expression in human OFs, which may participate in inflammation and fibrosis in patients with TAO and provide a potential target for the antifibrotic treatment.

Altered Corneal Nerves in Chinese Thyroid-Associated Ophthalmopathy Patients Observed by In Vivo Confocal Microscopy.

BACKGROUND Thyroid-associated ophthalmopathy (TAO) is a common endocrine autoimmune disease. The present study explored corneal nerve changes in TAO patients. MATERIAL AND METHODS Thirty-eight Chinese TAO patients and 20 healthy individuals were included in the study. Central corneal subbasal nerve density and morphology were evaluated with in vivo laser scanning confocal microscopy and quantified using automated CCmetrics software. RESULTS The values of the central corneal subbasal nerve plexus parameters of both active and inactive TAO patients were significantly decreased compared with those of controls, including corneal nerve fiber density (CNFD) (P<0.001 for both), corneal nerve branch density (CNBD) (P<0.001 for both), corneal nerve fiber length (CNFL) (P<0.001 for both), corneal nerve fiber total branch density (CTBD) (P<0.001 for both), corneal nerve fiber area (CNFA) (P<0.001 for both), corneal nerve fiber width (CNFW) (P=0.046, P=0.027, respectively), and corneal nerve fiber fractal dimension (ACNFrD) (P<0.001 for both). In addition, CNFD and ACNFrD values were significantly lower in the active TAO patients compared with those in the inactive TAO patients (P=0.020, P=0.002, respectively). There were significant correlations between CNFD, CNBD, CNFL, CTBD, CNFA, and ACNFrD and the ocular surface parameters and activity assessment items. CONCLUSIONS Abnormal corneal subbasal nerves were observed in both active and inactive Chinese TAO patients, suggesting that nerve degeneration is associated with the disease. However, the exact underlying mechanisms remain to be elucidated.

CD34- Orbital Fibroblasts From Patients With Thyroid-Associated Ophthalmopathy Modulate TNF-α Expression in CD34+ Fibroblasts and Fibrocytes.

Purpose: Orbital fibroblasts from patients with Graves' disease (GD-OF) express many different cytokines when treated with bovine thyrotropin (bTSH). The present study aimed to determine why TNF-α cannot be induced by bTSH in GD-OF. Methods: Fibrocytes and GD-OFs were cultivated from donors who were patients in a busy academic medical center practice. Real-time PCR, Western blot analysis, reporter gene assays, cell transfections, mRNA stability assays, ELISA, and flow cytometry were performed. Results: We found that bTSH induces TNF-α dramatically in fibrocytes but is undetectable in GD-OF. The induction in fibrocytes is a consequence of increased TNF-α gene promoter activity and is independent of ongoing protein synthesis. It could be attenuated by dexamethasone and the IGF-1 receptor inhibiting antibody, teprotumumab. When separated into pure CD34+ OF and CD34- OF subsets, TNF-α mRNA became highly inducible by bTSH in CD34+ OF but remained undetectable in CD34- OF. Conditioned medium from CD34- OF inhibited induction of TNF-α in fibrocytes. Conclusions: Our data indicate that CD34- OF appear to release a soluble(s) factor that downregulates expression and induction by bTSH of TNF-α in fibrocytes and their derivative CD34+ OF. We proffer that CD34- OF produce an unidentified modulatory factor that attenuates TNF-α expression in GD-OF and may do so in the TAO orbit.

PTX3: A Potential Biomarker in Thyroid Associated Ophthalmopathy.

BACKGROUND: Thyroid associated ophthalmopathy (TAO) is an autoimmune disease, which involves inflammation and tissue remodeling. Pentraxin-3 (PTX3) is a component of innate immune system and recently implicated in autoimmunity. This observation may indicate that PTX3 participates in the inflammatory process of TAO. METHODS: All studies were performed on TAO patients and healthy controls (45: 28 in total). RNA-seq was used to detect differential gene expression of orbital adipose-connective tissue. Quantitative PCR was performed to verify the results. PTX3 protein in orbital adipose-connective tissues was visualized by immunohistochemistry (IHC). PTX3 concentration in serum was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: RNA-seq showed 1.86-log⁡2FC higher PTX3 expression in the orbital adipose-connective tissues from TAO group than controls (FDR = 0.0059). qPCR confirmed the difference (5.59-fold increase, p = 0.0012). The presence of PTX3 protein was demonstrated. Orbital adipose tissue from healthy controls showed weak staining for PTX3 while tissue from TAO group was strongly positive. Serum PTX3 concentration was significantly elevated in patients when compared to the control group (1.9-fold increase; p < 0.0001). CONCLUSIONS: Patients with TAO showed increased presence of PTX3 in orbital tissue and serum, which may suggest a potential relationship of PTX3 and TAO.

Common Immunosuppressive Monotherapy for Graves' Ophthalmopathy: A Meta-Analysis.

BACKGROUND: Several immunosuppressive therapeutic regimens are widely used to treat Graves' ophthalmopathy (GO), including oral glucocorticoids (OGC), intravenous glucocorticoids (IVGC), retrobulbar injections of glucocorticoids (ROGC) and orbital radiotherapy (OR). The priority among these is unknown. This meta-analysis investigated the efficacy and tolerability of the above regimens. METHODS: The PubMed, EMBASE, and Cochrane Library databases and the Chinese Biomedicine Database were searched up to November 18, 2014. Randomized controlled trials (RCTs) comparing monotherapies (OGC, IVGC, ROGC and OR) in patients with moderate-to-severe active GO were selected. The main efficacy measures were the response rate, the standard mean difference (SMD) in the reduction in the clinical activity score (CAS) and the mean difference (MD) in proptosis from baseline to the end of treatment. The main tolerability measure was the risk ratio (RR) for adverse events. The pooled estimates and 95% confidence intervals (95% CIs) were calculated using the RevMan software, version 5.1. RESULTS: Seven published RCTs involving 328 participants were included in the present meta-analysis, including IVGC versus OGC (3 trials), ROGC versus OGC (3 trials) and OR versus OGC (1 trial). IVGC was more effective than OGC in response rate (RR = 1.48, 95% CI = 1.18-1.87) and had an obvious CAS reduction (SMD = 0.69, 95% CI = 0.13-1.25). IVGC caused fewer adverse events than OGC. ROGC and OGC had no statistically significant difference in response rate (RR = 1.16, 95% CI = 0.94-1.42). OR also did not differ significantly compared with OGC (RR = 0.93, 95% CI = 0.54-1.60). ROGC and OR had fewer adverse events, such as weight gain, compared with OGC. CONCLUSIONS: For patients with GO in the moderate-to-severe active phase, current evidence gave priority to IVGC, which had a statistically significant advantage over OGC and caused fewer adverse events. ROGC and OR did not provide greater efficacy than OGC, although better tolerability and fewer adverse events were shown.

[Expressions of lysozyme C and lactoferrin in tears of thyroid-associated ophthalmopathy patients].

OBJECTIVE: To explore the differential expressions of lysozyme C and lactoferrin in tears of thyroid-associated ophthalmopathy (TAO) patients versus healthy subjects by proteomics. METHODS: Tear samples were obtained from patients with active period TAO and age and gender-matched healthy subjects without symptoms of ocular surface. Then they were divided into patient and control groups. Then tear samples of two groups were analyzed. sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of 15% gel was performed to determine the different protein bands in sample groups. And different labeled protein bands were collected for in-gel tryptic digestion. Mass spectrometry was employed to determine the protein components from different protein bands. Then Scaffold search engine was used for analyzing the results of mass spectrometry and identifying specific proteins. RESULTS: Based on mass spectrometric analysis of different protein bands, most proteins were down-regulated or became absent in TAO patients. Both lysozyme C and lactoferrin were up-regulated. Identification of protein relative quantitative ratio (patient/control): lysozyme C: 4.88, lactoferrin: 1.61. CONCLUSIONS: Lysozyme C and lactoferrin are two important effectors of tear function and metabolism. Both are up-regulated in TAO patients' tears. Thus both are probably involved in inflammatory process of TAO and play synergistic roles in the pathogenesis of disease.