EPHA2, EPHA4, and EPHA6 Expression in Uveal Melanomas: Searching for the Culprits of Neoplasia.

Uveal melanomas (UMs) comprise the most common primary intraocular malignancies in adults, with the eye representing the second most common site for melanoma, following the skin. Prognosis remains poor, with approximately half of the cases presenting with metastatic disease at the time of diagnosis. Erythropoietin-producing human hepatocellular receptors (EPHs) comprise the largest known family of tyrosine receptors, in which, along with their ligands, ephrins, play an important role in a plethora of processes in human physiology, and are implicated in key steps of carcinogenesis. In the present study, EPHA2, EPHA4, and EPHA6 immunohistochemical expressions were investigated in UM tissues and further correlated to a multitude of clinicopathological parameters, including disease stage and patients' overall survival (OS). High levels of EPHA2 expression were significantly associated with increased tumor vertical thickness (p = 0.03) and the presence of intrascleral involvement (p = 0.05), whereas high EPHA6 nuclear expression was associated with older age at diagnosis (p = 0.03) and absence of retinal detachment (p = 0.05). In a multivariate survival analysis, increased EPHA4 expression was associated with shortened OS along with the presence of metastasis (p < 0.001) and monosomy 3 (p = 0.02). In a separate model, the concurrent overexpression of at least two of the investigated EPHs (HR = 14.7, p = 0.03) also proved to be an independent poor prognostic factor. In conclusion, our results implicate these specific members of the EPHA group as potential biomarkers for disease prognosis as well as possible targets for the development of novel therapeutic interventions.

EPHA2, EPHA4, and EPHA7 Expression in Triple-Negative Breast Cancer.

Ongoing research continues to elucidate the complex role of ephrin receptors (EPHs) and their ligands (ephrins) in breast cancer pathogenesis, with their varying expression patterns implied to have an important impact on patients' outcome. The current study aims to investigate the clinical significance of EPHA2, EPHA4, and EPHA7 expression in triple-negative breast cancer (TNBC) cases. EPHA2, EPHA4, and EPHA7 protein expression was assessed immunohistochemically on formalin-fixed and paraffin-embedded (FFPE) TNBC tissue sections from 52 TNBC patients and correlated with key clinicopathologic parameters and patients' survival data (overall survival (OS); disease-free survival (DFS)). EPHA2, EPHA4, and EPHA7 expression was further examined in TNBC cell lines. EPHA2 overexpression was observed in 26 (50%) of the TNBC cases, who exhibited a shorter OS and DFS than their low-expression counterparts, with EPHA2 representing an independent prognostic factor for OS and DFS (p = 0.0041 and p = 0.0232, respectively). EPHA4 overexpression was associated with lymph node metastasis in TNBC patients (p = 0.0546). Alterations in EPHA2, EPHA4, and EPHA7 expression levels were also noted in the examined TNBC cell lines. Our study stresses that EPHA2 expression constitutes a potential prognostic factor for TNBC patients. Given the limited treatment options and poorer outcome that accompany the TNBC subtype, EPHA2 could also pose as a target for novel, more personalized, and effective therapeutic approaches for those patients.

High Pregnane X Receptor (PXR) Expression Is Correlated with Poor Prognosis in Invasive Breast Carcinoma.

Pregnane X Receptor (PXR) is involved in human cancer, either by directly affecting carcinogenesis or by inducing drug-drug interactions and chemotherapy resistance. The clinical significance of PXR expression in invasive breast carcinoma was evaluated in the present study. PXR protein expression was assessed immunohistochemically on formalin fixed paraffin-embedded breast invasive carcinoma tissue sections, obtained from 148 patients, and was correlated with clinicopathological parameters, molecular phenotypes, tumor cells' proliferative capacity, and overall disease-free patients' survival. Additionally, the expression of PXR was examined on human breast carcinoma cell lines of different histological grade, hormonal status, and metastatic potential. PXR positivity was noted in 79 (53.4%) and high PXR expression in 48 (32.4%), out of 148 breast carcinoma cases. High PXR expression was positively associated with nuclear grade (p = 0.0112) and histological grade of differentiation (p = 0.0305), as well as with tumor cells' proliferative capacity (p = 0.0051), and negatively with luminal A subtype (p = 0.0295). Associations between high PXR expression, estrogen, and progesterone receptor negative status were also recorded (p = 0.0314 and p = 0.0208, respectively). High PXR expression was associated with shorter overall patients' survival times (log-rank test, p = 0.0009). In multivariate analysis, high PXR expression was identified as an independent prognostic factor of overall patients' survival (Cox-regression analysis, p = 0.0082). PXR expression alterations were also noted in breast cancer cell lines of different hormonal status. The present data supported evidence that PXR was related to a more aggressive invasive breast carcinoma phenotype, being a strong and independent poor prognosticator.

The Clinical Impact of the EPH/Ephrin System in Cancer: Unwinding the Thread.

Erythropoietin-producing human hepatocellular receptors (EPHs) compose the largest known subfamily of receptor tyrosine kinases (RTKs). They bind and interact with the EPH family receptor interacting proteins (ephrins). EPHs/ephrins are implicated in a variety of physiological processes, as well as in cancer pathogenesis. With neoplastic disease remaining a leading cause of death world-wide, the development of novel biomarkers aiding in the field of diagnosis, prognosis, and disease monitoring is of utmost importance. A multitude of studies have proven the association between the expression of members of the EPH/ephrin system and various clinicopathological parameters, including disease stage, tumor histologic grade, and patients' overall survival. Besides their utilization in timely disease detection and assessment of outcome, EPHs/ephrins could also represent possible novel therapeutic targets. The aim of the current review of the literature was to present the existing data regarding the association between EPH/ephrin system expression and the clinical characteristics of malignant tumors.

Impact of Deserosalization on Small Bowel Anastomosis Healing in Swine: A Pilot Study.

BACKGROUND: Healing is related to gastrointestinal anastomotic leak, which is a severe and common complication. This study aimed to investigate the feasibility and the impact of deserosalization on healing of jejuno-jejunal anastomoses in an animal model. MATERIALS AND METHODS: Seven swine underwent three types of side-to-side jejuno-jejunal anastomosis twice and survived seven days. Three different types of jejuno-jejunal side-to-side anastomoses were performed twice at 20-cm distance from each other in each animal: no serosa removal, one-sided, and two-sided serosa removal, respectively. Bursting pressure, tissue hydroxyproline concentration, and pathology scores were evaluated. RESULTS: Hydroxyproline tissue concentration was a mean±standard deviation of 0.37±0.09, 0.38±0.08, and 0.30±0.05 nmoI/ml respectively (p<0.05). Bursting pressure was a mean±standard deviation of 59.02±8.60, 73.20±11.09, and 100.01±7.49 mmHg, respectively (p<0.001). The histopathological assessment did not find any statistically significant differences. CONCLUSION: Deserosalization in jejuno-jejunal anastomosis was technically feasible and seemed to improve mechanical strength and collagen deposition in this experimental porcine model. Further investigation is warranted.

Elevated Hu-Antigen Receptor (HuR) Expression is Associated with Tumor Aggressiveness and Poor Prognosis but not with COX-2 Expression in Invasive Breast Carcinoma Patients.

Hu-antigen R (HuR), a RNA-binding protein, is considered to play a crucial role in tumor development and progression by stabilizing or regulating a group of cellular mRNAs of cancer-related genes, such as cyclooxygenase-2 (COX-2). The present study aimed to evaluate the clinical significance of HuR and COX-2 expression in invasive breast carcinoma. HuR and COX-2 protein expression was assessed immunohistochemically on paraffin-embedded breast cancer tissue sections obtained from 121 patients and was statistically analyzed with clinicopathological parameters, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), as well as with tumor cells' proliferative capacity and overall and disease-free patients' survival. High HuR expression was positively associated with larger tumor size and advanced disease stage (p = 0.0234 and p = 0.0361, respectively), being more frequently observed in ER negative cases (p = 0.0208). High COX-2 expression was negatively associated with histological (p < 0.0001) and nuclear (p = 0.0033) grade and tumor cells' proliferative rate (p = 0.0015), being more frequently observed in luminal-A compared to other molecular subtypes (p = 0.0221). High HuR expression was associated with poor overall and disease-free patients' survival at both univariate (log-rank test, p = 0.0092 and p = 0.0004, respectively) and multivariate (Cox-regression analysis, p = 0.0223 and p = 0.0004, respectively) level. On the other hand, high COX-2 expression was associated with favorable overall and disease-free patients' survival merely at univariate level (log-rank test, p = 0.0389 and p = 0.0154, respectively). HuR expression was not associated with COX-2 expression (Spearman R = 0.1489, p = 0.1032). The present data support evidence that HuR is associated with tumor aggressiveness and poor prognosis in breast carcinoma, reinforcing its potential as promising therapeutic target in this type of neoplasia.

Expression and Clinical Significance of Concomitant FAK/SRC and p-Paxillin in Mobile Tongue Squamous Cell Carcinoma.

BACKGROUND/AIM: The focal adhesion kinase (FAK)/SRC phosphorylation cascade and its downstream target paxillin have been implicated in malignant transformation, tumor growth and progression, together with metastasis. The present study aimed to evaluate the clinical significance of concomitant FAK/SRC and p-paxillin expression in mobile tongue squamous cell carcinoma (SCC). MATERIALS AND METHODS: FAK, SRC and phospho-paxillin expression in 48 mobile tongue SCC tissue samples was assessed immunohistochemically and analyzed with respect to clinicopathological characteristics and patient survival. RESULTS: Concomitant high FAK/SRC expression was significantly associated with high grade of tumor differentiation (p=0.048) and longer disease-free patient survival (log-rank test, p=0.019). High p-paxillin expression was significantly associated with greater depth of invasion (p=0.002), lymph node metastasis (p=0.048) and poorer disease-free patient survival (log-rank test, p=0.021; Cox-regression analysis, p=0.031). CONCLUSION: The present study provides evidence that FAK/SRC and paxillin play a role in the pathophysiological aspects of mobile tongue SCC and could constitute therapeutic targets.

Evaluation of cannabinoid CB1 and CB2 receptors expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients' survival.

Cannabinoid receptors (CB1R and CB2R) constitute essential members of the endocannabinoid system (ECS) which participates in many different functions indispensable to homeostatic regulation in several tissues, exerting also antitumorigenic effects. The present study aimed to assess the clinical significance of CB1R and CB2R protein expression in mobile tongue squamous cell carcinoma (SCC). CB1R and CB2R expression was assessed immunohistochemically on 28 mobile tongue SCC tissue samples and was analyzed in relation with clinicopathological characteristics and overall and disease-free patients' survival. CB1R, CB2R, and concomitant CB1R/CB2R expression was significantly increased in older compared to younger mobile tongue SCC patients (p = 0.0243, p = 0.0079, and p = 0.0366, respectively). Enhanced CB2R and concomitant CB1R/CB2R expression was significantly more frequently observed in female compared to male mobile tongue SCC patients (p = 0.0025 and p = 0.0016, respectively). Elevated CB2R expression was significantly more frequently observed in mobile tongue SCC patients presenting well-defined tumor shape compared to those with diffuse (p = 0.0430). Mobile tongue SCC patients presenting enhanced CB1R, CB2R, or concomitant CB1R/CB2R expression showed significantly longer overall (log-rank test, p = 0.004, p = 0.011, p = 0.018, respectively) and disease-free (log-rank test, p = 0.003, p = 0.007, p = 0.027, respectively) survival times compared to those with low expression. In multivariate analysis, CB1R was identified as an independent prognostic factor for disease-free patients' survival (Cox-regression analysis, p = 0.032). The present study provides evidence that CB1R and CB2R may play a role in the pathophysiological aspects of the mobile tongue SCC and even each molecule may constitute a potential target for the development of novel anti-cancer drugs for this type of malignancy.

Clinical Significance of Hu-Antigen Receptor (HuR) and Cyclooxygenase-2 (COX-2) Expression in Human Malignant and Benign Thyroid Lesions.

Hu-antigen R (HuR) is considered to play a crucial role in tumor formation and growth by binding to mRNAs encoding proteins such as Cyclooxygenase-2 (COX-2) and inducing their expression via mRNA stabilization and/or altered translation. The present study aimed to evaluate the clinical significance of HuR and COX-2 proteins' expression in human benign and malignant thyroid lesions. HuR and COX-2 proteins' expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 98 patients with benign (n = 48) and malignant (n = 50) lesions and was statistically analyzed with clinicopathological parameters, follicular cells' proliferative capacity and recurrence risk rate. Enhanced HuR and COX-2 expression was significantly more frequently observed in malignant compared to benign thyroid lesions (p = 0.0073 and p = 0.0016, respectively), as well as in papillary carcinomas compared to hyperplastic nodules (p = 0.0039 and p = 0.0009, respectively). Positive associations of both HuR and COX-2 expression with follicular cells' proliferation rate were also noted (p = 0.0087 and p = 0.0127, respectively). In malignant thyroid lesions, elevated COX-2 expression was significantly associated with female patients' gender (p = 0.0381) and the presence of lymph node metastases (p = 0.0296). The present data support evidence that both HuR and COX-2 may be involved in the malignant state of thyroid neoplasia and may be utilized in the diagnosis of malignant thyroid tumors.