Increased serum galectin-3 levels is an unfavorable prognostic factor in epithelial ovarian cancer

With galectin-3 playing an important role in inflammatory responses, elevated galectin-3 levels have been shown in patients with autoimmune diseases. However, there are limited data regarding galectin-3 expression in patients with autoinflammatory diseases such as adult-onset Still's disease (AOSD). This study aimed to investigate the extracellular galectin-3 expression and examine its association with activity parameters and disease outcome in AOSD patients. Plasma levels of galectin-3 and inflammasome downstream cytokines including interleukin (IL)-1β and IL-18 were determined by ELISA in 42 active AOSD patients and 20 healthy controls (HC). The protein levels of galectin-3 and cytokines were determined using immunoblotting. Plasma levels of galectin-3 and inflammasome downstream cytokines including IL-1β and IL-18 were significantly higher in AOSD patients (median 5.02ng/ml, interquartile range [IQR] 3.12-7.88ng/ml; 3.42pg/ml, IQR 1.48-6.70pg/ml; and 5758pg/ml, IQR 859-11,895pg/ml, respectively) compared with HC (1.86ng/ml, IQR 1.09-2.89ng/ml; 0.99pg/ml, IQR 0.62-1.35pg/ml; and 129pg/ml, IQR 71-155pg/ml, respectively, all p < 0.001). Plasma galectin-3 levels were positively correlated with clinical activity scores, inflammatory parameters values, and the levels of IL-1β and IL-18 in AOSD patients. AOSD patients with systemic pattern had significantly higher galectin-3 levels (median 6.08ng/ml, IQR 4.01-9.54ng/ml) compared with those with chronic articular pattern (3.56ng/ml, IQR 3.04-4.98ng/ml, p < 0.05). After 6-month therapy, galectin-3 levels significantly declined, paralleling the decreases in clinical activity scores and plasma levels of IL-1β and IL-18. Elevated galectin-3 levels and their positive correlation with disease activity scores, inflammatory parameter, and inflammasome downstream cytokines suggest the involvement of galectin-3 in AOSD pathogenesis.Key Points• We revealed for the first time the association of plasma galectin-3 levels with AOSD activity parameters.• We explored the link between galectin-3 levels and NLRP3-inflammasome downstream cytokines in AOSD disease.

Transmembrane 4 L6 family member 1 (TM4SF1) and discoidin domain receptor 1 (DDR1) are expressed in numerous types of cancer, but their expression in epithelial ovarian cancer and the association between their expression and patient prognosis are unclear. The present study aimed to explore the expression of TM4SF1 and DDR1 and their relationship with prognosis in epithelial ovarian cancer. Firstly, the Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) platforms were used to compare the expression levels of TM4SF1 and DDR1 in ovarian cancer and normal ovarian tissue, and Kaplan-Meier plotter was used to analyze the association between gene expression and patient prognosis. The proteins interacting with TM4SF1 and DDR1 were analyzed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and enrichment analysis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways was conducted for the interacting proteins. Furthermore, immunohistochemical staining was performed to detect the expression of TM4SF1 and DDR1 protein in epithelial ovarian cancer tissue and to analyze the association between expression and prognosis. The Oncomine and GEPIA analyses showed that the expression levels of TM4SF1 and DDR1 were significantly higher in epithelial ovarian cancer than in normal ovarian tissue, and the analysis of clinical samples revealed that TM4SF1 and DDR1 were coexpressed in some cases. STRING analysis indicated that the TM4SF1 and DDR1 proteins interact with each other. The overall survival and progression-free survival of patients whose epithelial ovarian cancer coexpressed TM4SF1 and DDR1 were significantly shorter than those of patients lacking TM4SF1 and DDR1 coexpression. Multivariate analysis indicated that TM4SF1 and DDR1 protein coexpression was an independent prognostic factor. In summary, TM4SF1 and DDR1 proteins were coexpressed in some epithelial ovarian cancer tissues and appear to be adverse prognostic factors for epithelial ovarian cancer. In addition, TM4SF1 and DDR1 may have an interactive or mutual regulatory mechanism.

Introduction: This study aimed to evaluate the diagnostic and prognostic value of soluble intercellular adhesion molecule-1 (sICAM-1) and galectin-3 in patients with type 2 diabetes mellitus (T2D) diagnosed with coronavirus disease 2019 (COVID-19). Participants and Method: This prospective observational study included 45 adult patients (≥18 years) with T2D and confirmed COVID-19 who were followed in the Infectious Diseases and Clinical Microbiology departments between May and June 2022. The control group consisted of 45 healthy volunteers without chronic illness who were presented to the internal medicine outpatient clinic. In addition to routine laboratory biomarkers assessed at hospital admission, the serum levels of sICAM-1 and galectin-3 were measured via ELISA kits. Results: The median age of the patients was 66 years (range: 41–77), and 23 (51.1%) were male. Hypertension was the most common comorbidity in addition to diabetes. Compared with those in the control group, the serum levels of both galectin-3 and sICAM-1 were significantly elevated in patients with COVID-19 and T2D (p < 0.001). However, there was no significant difference in galectin-3 or sICAM-1 levels between survivors and nonsurvivors (p = 0.240 and p = 0.266, respectively). Conclusion: Galectin-3 and sICAM-1 demonstrated stronger diagnostic utility than conventional biomarkers in T2D patients with COVID-19. The elevated levels of these markers may reflect the underlying systemic inflammation observed in diabetic patients with COVID-19. The strong correlation between galectin-3 and sICAM-1 suggests a potential link in their inflammatory regulation, although causality cannot be inferred.

CAMP responsive element binding protein 5 (CREB5) has crucial roles in regulating cell growth, proliferation, differentiation and cell cycle regulation. CREB5 has been identified to be overexpressed in several types of human cancer. However, the expression characteristics of CREB5 in epithelial ovarian cancer remains unknown, and its potential clinical prognostic significance has not yet been elucidated. In the present study, quantitative polymerase chain reaction (qPCR) and western blot analysis were performed to detect CREB5 mRNA and protein expression levels in 10 fresh tissue and cell lines epithelial ovarian cancer. Furthermore, CREB5 expression was analyzed using immunohistochemical analysis in 125 clinicopathologically characterized ovarian cancers: Stage I+II (n=31), stage III (n=70), stage IV (n=24). The patient survival rate was evaluated using Kaplan-Meier analysis. CREB5 was significantly overexpressed at both the mRNA and protein levels in epithelial ovarian cancer cells. There was a significant positive correlation between high CREB5 expression and increasing the International Federation of Gynecology and Obstetrics (FIGO) stage and pelvic lymph node metastasis (P<0.05). Patients with high CREB5 expression had a shorter overall survival, whereas patients with low CREB5 expression had longer survival. In addition, patients with high CREB5 expression had shorter relapse-free survival whereas patients with low CREB5 expression had longer relapse-free survival. Univariate logistic regression analysis and stepwise multivariate analysis all revealed that the FIGO stage and high CREB5 expression were significant risk factors for epithelial ovarian cancer (P<0.001), which suggested that CREB5 upregulation may be associated with a poor prognosis; therefore, it may be an independent prognostic indicator of epithelial ovarian cancer and may serve as a tumor-aggressive gene.

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) recently reported a reduction in the average overall mortality among ovarian cancer patients screened with an annual sequential, multimodal strategy that tracked biomarker CA125 over time, where increasing serum CA125 levels prompted ultrasound. However, multiple cases were documented wherein serum CA125 levels were rising, but ultrasound screens were normal, thus delaying surgical intervention. A significant factor which could contribute to false negatives is that many aggressive ovarian cancers are believed to arise from epithelial cells on the fimbriae of the fallopian tubes, which are not readily imaged. Moreover, because only a fraction of metastatic tumors may reach a sonographically-detectable size before they metastasize, annual screening with ultrasound may fail to detect a large fraction of early-stage ovarian cancers. The ability to detect ovarian carcinomas before they metastasize is critical and future efforts towards improving screening should focus on identifying unique features specific to aggressive, early-stage tumors, as well as improving imaging sensitivity to allow for detection of tubal lesions. Implementation of a three-stage multimodal screening strategy in which a third modality is employed in cases where the first-line blood-based assay is positive and the second-line ultrasound exam is negative may also prove fruitful in detecting early-stage cases missed by ultrasound.

The aim of this study was to evaluate the risk factors for invasive primary epithelial ovarian cancer among Japanese women. In 1990-1994, 45,748 women aged 40-69 years were enrolled in the Japan Public Health Center-based Prospective Study cohort. Only 86 epithelial ovarian cancer cases were diagnosed during follow-up through 2008, reflecting the low ovarian cancer incidence rates in Japan. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) according to the exposure of interest. The median age at epithelial ovarian cancer diagnosis was 59 years, with a median follow-up before diagnosis of 7.6 years. There were no statistically significant associations for age at menarche or first birth, breastfeeding, use of exogenous hormones, menopausal status at cohort enrollment, height, body mass index, smoking status, second-hand smoke, alcohol consumption, physical activity and family history of cancer in a first-degree relative. The linear decrease in HR associated with each additional birth was 0.75 (95% CI 0.56-0.99). Among women who usually slept >7 h per day, an HR of 0.4 (95% CI 0.2-0.9) emerged compared to those who slept <6 h. This study did not confirm risk factors for epithelial ovarian cancer among Japanese women that have been reported in studies carried out elsewhere. Usual sleep duration of >7 h per day was inversely associated with epithelial ovarian cancer risk, which is a novel finding that needs to be confirmed in other studies.

Purpose: To investigate the ferritin distribution in epithelial ovarian cancer patients according to the FIGO stage in the prognosis of epithelial ovarian cancer. Method: All ovarian cancer patients were divided into two groups according their FIGO stage. Benign ovarian tumor patients were analyzed as the control. Serum ferritin, serum iron, and other related medical index were detected by automatic instruments for all patients. In addition, ferritin heavy chain (FHC) and ferritin light chain (FLC) proteins were detected by immunohistochemical staining in 60 epithelial ovarian cancer (EOC) patients and 30 benign ovarian tumor (BOT) patients, which were diagnosed in our department between 2011 and 2016. Results: The serum ferritin concentration was significantly higher in the EOC group than in the BOT group (172.56 ± 99.39 ng/mL vs 78.18 ± 43.06 ng/mL; p μmol/L vs 14.92 ± 6.36 μmol/L; p p p p p p p > 0.05). Conclusion: Patients showed an overexpression of ferritin and a downregulation of serum iron correlated with the prognosis of epithelial ovarian cancer, which may be a new target for diagnosis and treatment of epithelial ovarian cancer.

Chronic coronary syndrome (CCS) and atrial fibrillation (AF) are prevalent cardiovascular conditions between whom there is a dual relationship, with significant morbidity and mortality. Recent studies have highlighted the roles of galectin-3 and pentraxin-3 as potential biomarkers in coronary atherosclerosis, yet their specific interactions and implications in patients with CCS and AF remain underexplored. This proof-of-concept study aimed to evaluate the levels of galectin-3 and pentraxin-3 in a cohort of patients with CCS and AF. A total of 131 patients diagnosed with CCS or/and AF were stratified based on coronary stenosis severity (significant, S-CCS and nonsignificant, N-CCS coronary lesions) and arrhythmia burden. Blood samples were collected to measure serum levels of galectin-3 and pentraxin-3 using enzyme-linked immunosorbent assay (ELISA) techniques. Clinical data, including demographic information, comorbidities, medication use, and biological markers of systemic inflammation, were recorded. The galectin-3 value was more than double in patients with S-CCS compared with those with N-CCS (17.39 ± 4.459 ng/mL versus 7.49 ± 2.732 ng/mL, p < 0.001). Atrial fibrillation was not associated with statistically significant variations in galectin-3 values, neither overall nor separately in the group of S-CCS or N-CCS. However, pentraxin-3 values were similar in S-CCS compared with those with N-CCS (2839.18 ± 1521.639 pg/mL versus 2564.07 ± 1299.055 pg/mL, p = 0.417). These values were lower in patients with sinus rhythm, with a mean of 2469.91 ± 1253.782 pg/mL, and steadily increased in those with paroxysmal, persistent, and permanent AF, for whom they reached a mean of 3162.87 ± 1893.068 pg/mL. Elevated levels of galectin-3 appear to correlate with coronary stenosis severity and may inform future strategies for risk stratification, patients' selection for invasive coronarography or therapeutic targeting in CCS.

Objective. Ovarian cancer is the deadliest gynecologic malignancy worldwide. Ultrasound is the most useful non-invasive test for preoperative diagnosis of ovarian cancer. In this study, by leveraging multiple ultrasound images from the same patient to generate personalized, informative statistical radiomic features, we aimed to develop improved ultrasound image-based prognostic models for ovarian cancer. Approach. A total of 2057 ultrasound images from 514 ovarian cancer patients, including 355 patients with epithelial ovarian cancer, from two hospitals in China were collected for this study. The models were constructed using our recently developed Frequency Appearance in Multiple Univariate pre-Screening feature selection algorithm and Cox proportional hazards model. Main results. The models showed high predictive performance for overall survival (OS) and recurrence-free survival (RFS) in both epithelial and nonepithelial ovarian cancer, with concordance indices ranging from 0.773 to 0.794. Radiomic scores predicted 2 year OS and RFS risk groups with significant survival differences (log-rank test, P < 1.0 × 10−4 for both validation cohorts). OS and RFS hazard ratios between low- and high-risk groups were 15.994 and 30.692 (internal cohort) and 19.339 and 19.760 (external cohort), respectively. The improved performance of these newly developed prognostic models was mainly attributed to the use of multiple preoperative ultrasound images from the same patient to generate statistical radiomic features, rather than simply using the largest tumor region of interest among them. The models also revealed that the roundness of tumor lesion shape was positively correlated with prognosis for ovarian cancer. Significance. The newly developed prognostic models based on statistical radiomic features from ultrasound images were highly predictive of the risk of cancer-related death and possible recurrence not only for patients with epithelial ovarian cancer but also for those with nonepithelial ovarian cancer. They thereby provide reliable, non-invasive markers for individualized prognosis evaluation and clinical decision-making for patients with ovarian cancer.

Objective: To investigate the effect of DNA methylation of laminin α3 (LAMA3) on the prognosis of platinum-resistant epithelial ovarian cancer (EOC) and its possible mechanism. Methods: (1) The relationship between DNA methylation of LAMA3 and platinum resistance in EOC was evaluated by bioinformatics. (2) A total of 67 EOC patients treated at Guangxi Medical University Cancer Hospital from January 2000 to December 2012 were selected to detect the levels of LAMA3 DNA methylation in EOC tissues using pyrophosphate sequencing technology to explore its diagnostic efficacy for platinum resistance and prognosis in EOC patients. Furthermore, its impact on chemotherapy efficacy and prognosis of platinum resistant EOC patients were also analyzed. Results: (1) Ten proteins highly interacting with LAMA3 were screened from the Gene Interaction Retrieval Platform (STRING) database, including laminin β (LAMB) 3, laminin γ (LAMC) 3, integrin α (ITGA) 6, intestine protein β4 (ITGB4), ITGA3, LAMC1,LAMB2, dystrophin associated glycoprotein 1 (DAG1), LAMB1 and cytochrome P450c17α (COL17A1) protein; kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that LAMA3 and its related interacting proteins participate in the regulation of malignant tumor occurrence and development through signaling pathways such as apoptosis, cell cycle, DNA damage response, epithelial mesenchymal transition (EMT), androgen receptor (AR), estrogen receptor (ER), phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt), RAS/mitogen activated protein kinase (MAPK), receptor tyrosine kinase (RTK), tuberous sclerosis protein complex (TSC)/mammalian target of rapamycin (mTOR), and their expression levels were related to the sensitivity of chemotherapy drugs such as cisplatin in EOC. (2) Our clinical data analysis found that the LAMA3 DNA methylation level in EOC tissue of the platinum-sensitive group (35 cases) was 71% (25/35), which was higher than 69% (22/32) in the platinum-resistant group (32 cases), with statistically insignificant difference (χ2=0.057, P=0.811). The area under the curve (AUC) of LAMA3 DNA methylation level for assessing platinum resistance in EOC was 0.601, and the AUC for predicting EOC patient prognosis was 0.686. The chemotherapy efficacy of EOC patients with high methylation of LAMA3 DNA was worse than that of patients with low methylation, 50% (12/24) vs 15/15, with statistically significant difference (χ2=10.833, P=0.001). The level of LAMA3 DNA methylation had a significant impact on the progression free survival and overall survival of EOC patients (both P<0.05). Conclusion: The level of LAMA3 DNA methylation has certain diagnostic and predictive value for platinum resistance and prognosis in EOC patients, which may be closely related to the regulatory mechanism, platinum resistance and prognosis of EOC.

Downregulation of KAI1 Metastasis Suppressor Protein Is Associated with a Dismal Prognosis in Epithelial Ovarian Cancer

Ovarian cancer is influenced by reproductive factors, with a reduced risk of epithelial ovarian cancer in parous women. Nonepithelial ovarian cancer frequently affects young women and often precedes or occurs during the childbearing years. However, the impact of reproductive factors on ovarian cancer survival remains unclear: in epithelial ovarian cancer, data are conflicting, and subtype-specific associations have not been examined, and in nonepithelial ovarian cancer, it has not been studied. Using Swedish registers, we evaluated associations between women's reproductive history and cancer-specific mortality by subtype of epithelial and nonepithelial ovarian cancer in 3791 women born 1953 and later, diagnosed from 1990 to 2018. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated using Cox-proportional hazard models. Parity was associated with a 78% decreased risk of cause-specific mortality in 243 women with germ cell tumors (GCTs) (parous vs nulliparous, adjusted for age at diagnosis: HR: 0.22 [95% CI 0.07-0.62]), with a decreased risk with increasing number of births (per birth: HR: 0.60 [95% CI 0.38-0.95]). We found no evidence of associations between parity and cause-specific mortality among the 334 patients with sex-cord stromal tumors, nor among the 3214 patients with epithelial ovarian cancer; neither overall, nor by subtype. In conclusion, in our large, population-based study, parity was associated with a clearly better prognosis in GCTs but not in the other ovarian cancer subtypes. Future research on how hormone exposure impacts GCT development may lead to a better understanding of mechanisms affecting survival.

Acid ceramidase (AC), a key enzyme of sphingolipid metabolism, seems to play an important role in cancer progression. The objective of this study was to explore the expression of AC in ovarian cancer and its impact on prognosis. Expression analysis of AC in n=112 ovarian cancer patients was performed by immunohistochemical analysis of primary paraffin-embedded tumor samples. The results were scored on the basis of the staining intensity and percentage of positive tumor cells, resulting in an immunoreactive score from 0 to 12. These results were correlated to clinical and pathologic characteristics and survival. AC expression correlated significantly only with FIGO stage (0.047). In serous carcinoma, low level of AC was independently associated with reduced progression-free survival and overall survival of 12.0 mo [95% confidence interval (CI), 5.78-18.23] versus 18.1 mo (95% CI, 11.61-24.59; P=0.008) and 35.7 mo (95% CI, 22.24-47.16) versus 58.7 mo (95% CI, 36.48-80.91; P=0.032), respectively. In multivariate analysis, AC presents as an independent prognostic factor for progression-free survival (hazard ratio 1.88; 95% CI, 1.13-3.11; P=0.015). AC is a prognostic factor in epithelial ovarian cancer. Low AC expression can be associated with tumor progression in carcinoma of the ovaries. These results are in contrast to the concept of AC as a promoter for cancer progression. Nevertheless, they are supported by the lately discovered tumor-suppressing function of sphingosine, the enzymatic product of AC.

e15562 Background: Acid ceramidase (AC), a key enzyme of sphingolipid metabolism, plays an important role in cancer progression. Objective of this study was to explore the expression of AC in ovarian cancer and its relationship with prognosis. Methods: The expression of AC in n=119 ovarian cancer patients was determined by immunohistochemistry and correlated to clinical and pathological characteristics as well as survival. Results: Low AC expression was independently associated with reduced progression-free survival of 14 (CI95%: 9.20-18.8) vs. 19.6 (CI95%: 11.1-28.1) months (p=0.004) as well as reduced overall survival of 41.2 (CI95%: 30.7-51.7) months versus 58.1 (CI 95%: 34.6-81.6) months (p=0.096). In multivariate analysis AC presents as independent prognostic factor for PFS (HR 1.70; CI95%: 1.00-2.88, p=0.05) and OS (HR 1.44; CI95%: 0.80-2.62, P=0.23). Conclusions: Acid ceramidase is an independant prognostic factor in epithelial ovarian cancer. Low AC expression is associated with tumour progression in ovarian carcinoma. These results are in contrast to the concept of AC as an promoter for tumor progression, but are supported by the tumour-suppressing and proapoptotic function of the enzymatic product of AC, i.e. sphingosine (SPH) in various cancer types.

Objectives To study the predictive value for coronary artery calcification (CAC) of plasma galectin-3 and brachial-ankle pulse wave velocity (BaPWV) in coronary arteriography (CAG) patients. Methods Patients who received coronary arteriography (CAG) examination were recruited. The level of plasma galectin-3 was measured by the enzyme-linked immunosorbent assay. The arterial stiffness was analyzed by BaPWV and ankle-brachial index (ABI) which were measured using a volume-plethysmographic device. Receiver operating characteristic (ROC) curve was used to analyze the prognostic value of galectin-3 or BaPWV for coronary artery calcification (CAC). Results The level of galectin-3 and BaPWV was significantly higher in CAC patients compared with that in control (p < 0.01). The level of plasma galectin-3 was positively correlated with BaPWV (r = −0.296, p < 0.01) and negatively correlated with ABI (r = −0.296, p < 0.01). ROC curve analysis revealed that galectin-3 ≥5.90 ng/ml was the most powerful predictor for CAC with sensitivity of 85.5% and specificity of 83.5%. The area under the curve (AUC) was 0.916. When the level of BaPWV was more than 1909 m/s, the sensitivity and specificity were 61.8% and 69.6%, respectively, for predicting CAC. The AUC was 0.646. Conclusions The level of plasma galectin-3 increases significantly in CAC patients compared to control, and its level is related to BaPWV and ABI. Galectin-3 and BaPWV can be used to predict CAC, and the diagnosis value (sensitivity and specificity) of galectin-3 for CAC is better than that of BaPWV.