Search Results (40)

Background/Objectives: Eph receptor A5 (EphA5) is a receptor tyrosine kinase that is implicated in multiple malignancies, although its role in endometrial cancer (EC) remains unclear. The aim of this study was to investigate the clinicopathological significance of EphA5 expression in EC and explore its association with proliferative and metabolic markers. Methods: We retrospectively analyzed 75 EC tissue samples from treatment-naïve patients by using immunohistochemistry and H-score quantification. Associations between EphA5 expression and clinicopathological parameters were assessed through logistic regression analysis. Kaplan–Meier analysis was used to evaluate survival outcomes. Correlation analysis, stratified according to cancer stage, was used to explore biomarker interactions. Results: High EphA5 expression levels were significantly associated with elevated Ki-67 expression (adjusted odds ratio (aOR): 1.08 per 1-point H-score increase, p = 0.024) and decreased pAMPK expression (aOR: 0.89 per 1-point H-score increase, p = 0.024), indicating its involvement in proliferative and metabolic pathways. Paradoxically, patients with high EphA5 levels had significantly better overall survival probabilities (H-score > 105, log-rank p = 0.007). Stage-specific analyses suggested that EphA5 levels correlated with proliferation in early-stage disease and epithelial–mesenchymal transition in advanced stages. Conclusions: EphA5 may act as a context-dependent biomarker in EC. Despite its positive correlation with proliferation and negative association with metabolic stress signaling, high EphA5 expression levels were predictive of a favorable prognosis. Full article

Background and Clinical Significance: Brenner tumors are rare epithelial tumors that can occur in both males and females. They consist of ovarian transition cells surrounded by dense fibrous tissue and can be classified as benign, borderline, or malignant. While most commonly found in the ovary, extraovarian Brenner tumors (EOBTs) have been reported in the uterus, vagina, broad ligament, and omentum. Case Presentation: A 71-year-old postmenopausal woman presented with a polypous formation on the upper third of the posterior vaginal wall, which was found at a routine health check. Macroscopically, the lesion appeared as a solid, polypoid mass with a yellowish-gray cut surface, measuring approximately 25 × 20 mm. Histological examination revealed a polypoid formation covered by stratified squamous epithelium, with a dense fibrous stroma (Van Gieson [VG]+) and tubular structures lined by clear epithelial cells. Parenchymal cells showed low proliferative activity, with Ki-67 expression in less than 5% of cells, also Cytokeratin (CK) 7/+/p63:/+/ CK AE1/AE3: /+/ Estrogen Receptor (ER): /+/ and Progesterone Receptor (PR)/−/; CK20/-/; p53/−/, Wilms’ Tumor (WT)-1/−/; Prostate-Specific Acid Phosphatase (PSAP)/−/. The final diagnosis was an extraovarian Brenner tumor. The patient was monitored for two months post-excision, with no signs of recurrence. Conclusions: EOBTs are extremely rarely seen and vaginal involvement is far less common. Due to their rarity, these tumors may be confused with other benign or malignant vaginal lesions. In order to differentiate EOBTs from other neoplasms, histological analysis is crucial due to their characteristic transitional-type epithelium and large fibrous stroma. Further studies are required to understand the origin and clinical behavior of EOBTs. Long-term monitoring should be performed to look for any recurrence or malignant change, even though benign Brenner tumors usually have a good prognosis. Awareness of EOBTs and their possible locations is essential for accurate diagnosis and appropriate management. Full article

Background: Pancreatic adenocarcinoma (PAAD) is an aggressive subtype of pancreatic cancer that is estimated to have a 5-year overall survival rate of only 13%. Most patients present with advanced disease with unpredictable outcomes. The identification of prognostic biomarkers is important to accurately stratify these patients. Methods: We investigated the molecular and survival-related role of ENHO in PAAD by analyzing TGCA mRNA and miRNA data. Survival analysis was conducted using TIMER2.0, “survival”, and “survminer”. Gene set enrichment analysis was conducted using enrichr, while miRNA-mRNA interactions were identified using “multiMiR”. Immune infiltration was assessed using CIBERSORT ABS and ImmuCellAI. Results: We observed that ENHO was strikingly downregulated in PAAD tissues (p = 3.68 × 10⁻⁶⁸), and patients with higher ENHO levels enjoyed significantly better overall survival (HR = 0.597; 95% CI: 0.419–0.852; p < 0.01). Pathway analysis showed that genes co-upregulated with ENHO were enriched for insulin secretion and ion channel activity, whereas those co-downregulated were related to epithelial–mesenchymal transition and extracellular matrix remodeling. Higher ENHO also tracked with increased CD8⁺ T-cell infiltration and correlated positively with PDCD1 and LAG3 but negatively with B7-H3, CD70, and NT5E. Conclusions: Our results point to a protective role for ENHO in pancreatic adenocarcinoma. Full article

Background/Objectives: RNA-binding motif protein 3 (RBM3) is a cold-shock protein associated with a favorable prognosis in various malignancies. However, its role in epithelial ovarian cancer (OC) remains unclear. This study aimed to evaluate the prognostic significance of RBM3 expression in OC and its association with clinicopathological features. Methods: We retrospectively analyzed 183 cases of OC. Tissue microarrays were constructed using paired 2 mm tumor cores, and RBM3 expression was assessed by immunohistochemistry. Nuclear staining was semi-quantitatively scored based on intensity and proportion, generating a nuclear score (NS). Cases were classified as high (NS > 1) or low (NS ≤ 1) expression. Associations with clinicopathological parameters and survival outcomes were analyzed using chi-square tests, Kaplan–Meier survival curves, and Cox regression models. Results: High RBM3 expression was observed in 51.4% of cases and was significantly associated with favorable histologic subtypes (mucinous, endometrioid, clear cell), early International Federation of Gynecology and Obstetrics (FIGO) stage, and the absence of distant metastasis. Subgroup survival analyses stratified by histologic subtype revealed no significant differences in survival outcomes. RBM3 expression was correlated with prolonged disease-free and overall survival, although it did not retain significance in multivariate analysis. Conclusions: RBM3 expression is strongly associated with favorable pathological features in epithelial ovarian cancer. Although not an independent prognostic marker, RBM3 may serve as a complementary biomarker for risk stratification and prognosis in clinical practice. Full article

Sex steroid hormones and systemic iron metabolism are emerging as modulators of colorectal cancer (CRC) development and progression. However, information linking systemic factors to tumor characteristics and epithelial–mesenchymal transition (EMT) is limited, particularly in a sex-specific context. We measured serum levels of sex hormones [testosterone, estradiol, progesterone, Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), Carcinoembryonic antigen (CEA)] and iron-related biomarkers (iron, transferrin, ferritin, % transferrin saturation, ceruloplasmin, and the ceruloplasmin/transferrin ratio) in 82 CRC patients and 31 healthy controls. EMT-related proteins [mediator of ErbB2-driven cell motility 1 (MEMO1), E-cadherin, fibronectin, vimentin, and vinculin] were quantified by Western blotting in tumor and adjacent normal mucosa. Non-parametric tests and Spearman correlations were applied, stratified by sex and corrected for age and anemia where appropriate. Progesterone levels were significantly lower in male CRC patients (median 0.17 ng/mL vs. 0.20 ng/mL, p = 0.04) and higher in female patients (0.17 ng/mL vs. 0.10 ng/mL, p = 0.0077) compared with controls. The iron-related biomarkers indicated a pattern of iron deficiency, including in non-anemic patients, with reduced % transferrin saturation (p < 0.01) and an elevated ceruloplasmin/transferrin ratio (p = 0.02). Correlations were found between iron status, tumor stage, and hormonal levels. Progesterone correlated with EMT protein expression in healthy mucosa (e.g., fibronectin in females: ρ = 0.567, p = 0.014; vimentin in males: ρ = −0.446, p = 0.007), but not in tumor tissue. In the healthy mucosa of male patients, ceruloplasmin/transferrin correlated with MEMO1 (ρ = 0.419, p = 0.04), vinculin (ρ = 0.299, p = 0.041), and vimentin (ρ = 0.394, p = 0.07); transferrin levels inversely correlated with MEMO1 expression (ρ = −0.392, p = 0.032), and vimentin showed a positive correlation with serum iron (ρ = 0.350, p = 0.043). Furthermore, fibronectin expression inversely correlated with iron in the sole tumor tissue of female patients (ρ = −0.366, p = 0.040). These findings support the role of sex hormones and iron metabolism in CRC biology, suggesting that EMT might be accompanied by altered iron uptake and redox remodeling, which can enhance cellular motility and the metastatic potential. Full article

Research on how a stratified oral epithelium gained the capability to create the hardest hydroxyapatite-based mineralized tissue produced biologically to protect the surfaces of teeth has been ongoing for at least 175 years. Many advances have been made in unraveling some of the key factors that allowed the innermost undifferentiated epithelial cells sitting on a skin-type basement membrane to transform into highly polarized cells capable of forming and controlling the mineralization of the extracellular organic matrix that becomes enamel. Genetic manipulation of mice has proven to be a useful approach for studying specific events in the amelogenesis developmental sequence but there have been pitfalls in interpreting loss of function data caused in part by conflicting literature, technical problems in tissue preservation, and the total amount of time spent on tooth development between different species that have led to equivocal conclusions. This critical review attempts to discuss some of these issues and highlight the challenges of characterizing amelogenesis in gene-targeted mouse models. Full article

Background: B3 lesions of the breast, for which vacuum-assisted biopsy (VABB) represents the standard tissue sampling approach, have different risks of upgrade to malignancy at surgery and/or follow-up. This study aimed to investigate if complete or partial lesion removal during VABB of B3 lesions presenting as microcalcifications influences their subsequent upgrade rate. Methods: For this retrospective single-center study, we retrieved 165 lesions diagnosed as B3 at VABB that presented solely as microcalcifications categorized as Breast Imaging Reporting & Data System (BI-RADS) 4 or 5 at mammography between January 2016 and December 2020. Surgical pathology or at least 3-year follow-up were obtained to determine potential lesion upgrade to malignancy. χ², Fisher’s, and Mantel–Haenszel tests were performed to assess if complete lesion removal influenced upgrade rates overall and among different B3 subtypes. Results: Complete lesion removal was achieved in 99/165 cases (60.0%) and did not differ among B3 subtypes (p = 0.092). The overall upgrade rate was 8.5% (95% confidence interval [CI] 5.1–13.7%, 14/165), without statistically significant differences among B3 subtypes (p = 0.562). Conversely, completely removed lesions (4.0%, 95% CI 1.6–9.9%) had a statistically significant lower upgrade rate compared to partially removed lesions (15.2%, 95% CI 8.4–25.7%, p = 0.019). According to stratified analysis according to B3 subtypes, the odds ratio of upgrade among completely and partially removed flat epithelial atypia (0.13, 95% CI 0.00–1.45) was lower (Mantel-Haenszel test p = 0.016) than those of atypical ductal hyperplasia (0.31, 95% CI 0.02–3.17) and of lobular neoplasia (0.73, 95% CI 0.01–60.62). Conclusions: The upgrade rate of B3 lesions is significantly influenced by complete lesion removal, both overall and among different B3 subtypes. Full article

Hair follicle stem cells, located in the bulge region of the outer root sheath, are multipotent epithelial stem cells capable of differentiating into epidermal, sebaceous gland, and hair shaft cells. Efficient culturing of these cells is crucial for advancements in dermatology, regenerative medicine, and skin model development. This investigation aimed to develop a protocol for isolating enriched bulge-derived epithelial cells from scalp specimens to produce tissue-engineered substitutes. The epithelium, including hair follicles, was separated from the dermis using thermolysin, followed by microdissection of the bulge region. Epithelial stem cells were isolated using enzymatic dissociation to create a single-cell suspension and compared with the direct explant culture and a benchmark method which isolates cells from the epidermis and pilosebaceous units. After 8 days of culture, the enzymatic digestion of microdissected bulges yielded 5.3 times more epithelial cells compared to explant cultures and proliferated faster than the benchmark method. Cells cultured from all methods exhibited comparable morphology and growth rates. The fully stratified epidermis of tissue-engineered skin was similar, indicating comparable differentiation potential. This enzymatic digestion method improved early-stage cell recovery and expansion while maintaining keratinocyte functionality, offering an efficient hair bulge cell-extraction technique for tissue engineering and regenerative medicine applications. Full article

Odontogenic cysts, commonly detected during routine examinations involving head and neck imaging such as orthopantomograms and computed tomography (CT), are classified into two groups: developmental and inflammatory. Radicular cysts, which belong to the inflammatory group, originate from odontogenic epithelium, while dentigerous cysts of developmental origin are observed as a result of peri-coronal expansion of fluid in the dental follicle. The diagnosis and identification of odontogenic cysts rely on clinical, radiographic, and histological evaluations. This study aimed to demonstrate the expression of Dlx-5 and HLX proteins in radicular and dentigerous cysts. A total of 40 radicular and 40 dentigerous cysts were obtained from patients who visited private oral and dental health clinics in Bingöl and Diyarbakır provinces. After undergoing routine histological procedures, the cysts were stained using Masson’s Trichrome and immunohistochemistry techniques. As a result, the epithelium of radicular cysts was found to be keratinized stratified squamous, with hyaline (Rushton) bodies located within the epithelium. Dentigerous cysts, on the other hand, consisted of non-keratinized stratified squamous epithelium, rete ridges with hyperplastic areas, and inflammatory cell infiltrations. The immunoreactivity induced by Dlx-5 in epithelial and connective tissue cells of radicular and dentigerous cysts was found to be stronger than that of HLX. The positive expression of Dlx-5 and HLX proteins in radicular and dentigerous cysts suggests that these proteins may play a potential role in the pathogenesis of these cysts. Furthermore, it was considered that the expression of Dlx-5 and HLX might help reveal the behavioral differences between odontogenic cysts. Full article

In RNA-seq data analysis, condensing the gene count matrix size is pivotal for downstream investigations, particularly pathway analysis. For this purpose, harnessing machine learning attracts increasing interest, while conventional methodologies depend on p-value comparisons. In this study, 20 tissue samples from real-world cervical cancers were subjected to sequencing, followed by the application of the Mclust algorithm to delineate an optimal cluster. By stratifying tumor budding into high and low groups and quantifying the epithelial-to-mesenchymal transition (EMT) score to scrutinize tumor budding, we discerned 24 EMT-related genes, with 5 showing strong associations with cervical cancer prognosis. Our observations elucidate a biological flow wherein EMT, Matrix Metallopep-tidase 2 (MMP2), and extracellular matrix (ECM) degradation are interconnected, ultimately leading to collagen type VI and exacerbating the prognosis of cervical cancer. The present study underscores an alternative method for selecting useful EMT-related genes by employing an appropriate clustering algorithm, thereby avoiding classical methods while unveiling novel insights into cervical cancer etiology and prognosis. Moreover, when comparing high and low tumor budding, collagen type VI emerges as a potential gene marker for the prognosis of cervical cancer. Full article

The transcription factor ΔNp63 plays a pivotal role in maintaining the integrity of stratified epithelial tissues by regulating the expression of distinct target genes involved in lineage specification, cell stemness, cell proliferation and differentiation. Here, we identified the ABC transporter subfamily member ABCC1 as a novel ΔNp63 target gene. We found that in immortalized human keratinocytes and in squamous cell carcinoma (SCC) cells, ∆Np63 induces the expression of ABCC1 by physically occupying a p63-binding site (p63 BS) located in the first intron of the ABCC1 gene locus. In cutaneous SCC and during the activation of the keratinocyte differentiation program, ∆Np63 and ABCC1 levels are positively correlated raising the possibility that ABCC1 might be involved in the regulation of the proliferative/differentiative capabilities of squamous tissue. However, we did not find any gross alteration in the structure and morphology of the epidermis in humanized hABCC1 knock-out mice. Conversely, we found that the genetic ablation of ABCC1 led to a marked reduction in inflammation-mediated proliferation of keratinocytes, suggesting that ABCC1 might be involved in the regulation of keratinocyte proliferation upon inflammatory/proliferative signals. In line with these observations, we found a significant increase in ABCC1 expression in squamous cell carcinomas (SCCs), a tumor type characterized by keratinocyte hyper-proliferation and a pro-inflammatory tumor microenvironment. Collectively, these data uncover ABCC1 as an additional ∆Np63 target gene potentially involved in those skin diseases characterized by dysregulation of proliferation/differentiation balance. Full article

Caudal type homeobox transcription factor 2 (CDX2) is a gastrointestinal cancer biomarker that regulates epithelial development and differentiation. Absence or low levels of CDX2 have been associated with poor prognosis and proposed as a chemotherapy response predictor. Tumour tissue samples from 668 patients with stage I–IV colorectal cancer were stained for CDX2 and stratified into two subgroups according to expression levels. Statistical tests were used to evaluate CDX2’s relationship with survival and chemotherapy response. Of 646 samples successfully stained, 51 (7.9%) had low CDX2 levels, and 595 (92.1%) had high levels. Low CDX2 staining was associated with poor differentiation and the presence of lymphovascular or perineural invasion and was more common in colon and right-sided tumours. Overall survival (p < 0.001) and disease-free survival (p = 0.009) were reduced in patients with low CDX2 expression. Multivariable analysis validated CDX2 as an independent poor prognostic factor after excluding confounding variables. There was no statistically significant improvement in survival with adjuvant chemotherapy in stage II colon cancer (p = 0.11). In the rectal cohort, there was no relationship between CDX2 levels and therapy response. While confirming the prognostic utility of CDX2 in colorectal cancer, our study highlights that larger studies are required to confirm its utility as a predictive chemotherapy biomarker, especially in left-sided and rectal cancers. Full article

Galectin-1 (Gal-1), a member of the human lectin family, has garnered attention for its association with aggressive behavior in human tumors, prompting research into the development of targeted drugs. This study aims to assess the staining pattern and prognostic significance of Gal-1 immunohistochemical expression in a homogeneous cohort of Western patients with gastric cancer (GC). A total of 149 cases were included and tissue microarrays were constructed. Stromal Gal-1 expression was observed to some extent in most tumors, displaying a cytoplasmic pattern. Cases with stromal Gal-1 overexpression showed significantly more necrosis, lymphovascular invasion, advanced pTNM stages, recurrences, and cancer-related deaths. Epithelial Gal-1 expression was present in 63.8% of the cases, primarily exhibiting a cytoplasmic pattern, and its overexpression was significantly associated with lymphovascular invasion, peritumoral lymphocytic infiltration, and tumor-related death. Kaplan/Meier curves for cancer-specific survival (CSS) revealed a significantly worse prognosis for patients with tumors exhibiting stromal or epithelial Gal-1 overexpression. Furthermore, stromal Gal-1 expression stratified stage III patients into distinct prognostic subgroups. In a multivariable analysis, increased stromal Gal-1 expression emerged as an independent prognostic factor for CSS. These findings underscore the prognostic relevance of Gal-1 and suggest its potential as a target for drug development in Western patients with GC. Full article

The process of epithelial-mesenchymal transition (EMT) involves the phenotypic transformation of cells from epithelial to mesenchymal status. The cells exhibiting EMT contain features of cancer stem cells (CSC), and the dual processes are responsible for progressive cancers. Activation of hypoxia-inducible factors (HIF) is fundamental to the pathogenesis of clear cell renal cell carcinoma (ccRCC), and their role in promoting EMT and CSCs is crucial for ccRCC tumour cell survival, disease progression, and metastatic spread. In this study, we explored the status of HIF genes and their downstream targets, EMT and CSC markers, by immunohistochemistry on in-house accrued ccRCC biopsies and adjacent non-tumorous tissues from patients undergoing partial or radical nephrectomy. In combination, we comprehensively analysed the expression of HIF genes and its downstream EMT and CSC-associated targets relevant to ccRCC by using publicly available datasets, the cancer genome atlas (TCGA) and the clinical proteome tumour analysis consortium (CPTAC). The aim was to search for novel biological prognostic markers that can stratify high-risk patients likely to experience metastatic disease. Using the above two approaches, we report the development of novel gene signatures that may help to identify patients at a high risk of developing metastatic and progressive disease. Full article

Oral mucositis is the most common and severe non-hematological complication associated with cancer radiotherapy, chemotherapy, or their combination. Treatment of oral mucositis focuses on pain management and the use of natural anti-inflammatory, sometimes weakly antiseptic mouth rinses in combination with optimal oral cavity hygiene. To prevent negative effects of rinsing, accurate testing of oral care products is necessary. Due to their ability to mimic realistic in-vivo conditions, 3D models may be an appropriate option in compatibility testing of anti-inflammatory and antiseptically effective mouth rinses. We present a 3D model of oral mucosa based on the cell line TR-146 with a physical barrier, characterized by high transepithelial electrical resistance (TEER) and confirmed cell integrity. Histological characterization of the 3D mucosa model showed a stratified, non-keratinized multilayer of epithelial cells similar to that of human oral mucosa. By means of immuno-staining, tissue-specific expression of cytokeratin 13 and 14 was shown. Incubation of the 3D mucosa model with the rinses had no effects on cell viability, but TEER decreased 24h after incubation in all solutions except ProntOral^®. Analogous to skin models, the established 3D model meets the quality control criteria of OECD guidelines and may therefore be suitable for comparing the cytocompatibility of oral rinses. Full article