Reappraisal of psoriasis pathogenesis: the role of TEAD4 expression in keratinocytes.

BACKGROUND: Psoriasis is an immune-mediated inflammatory skin disorder with a multifaceted pathogenesis. Immune dysregulation and immune cell dysfunction are among the mechanisms involved. TEA domain family member 4 (TEAD4) is suggested to play a role in psoriasis development. TEAD4 expression in keratinocytes may have a chemotactic effect and could disturb the function of FOXP3-positive T lymphocytes. This study aimed to evaluate the expressions of TEAD4 and FOXP3 in lesional, nonlesional psoriatic, and healthy skin and assess the clinical impact of their expression. METHODS: This case-control study included 32 cases with psoriasis vulgaris and 32 control groups. Hematoxylin and eosin-stained slides were examined to evaluate the histopathological findings. Moreover, other sections were immunohistochemically stained with FOXP3 and TEAD4. RESULTS: FOXP3 was expressed in inflammatory cells in 56.5, 37.5, and 12.5% of lesional, nonlesional, and healthy skin, whereas it was entirely negative in the keratinocytes. TEAD4 was expressed in keratinocytes in 93.7 and 46.9% of lesional and nonlesional skin, while negative in healthy skin. Significant differences were observed between their lesional, nonlesional, and healthy skin expressions. Furthermore, FOXP3 expression in lesional skin was significantly associated with early onset (P = 0.016), low PASI score (P = 0.002), mild psoriasis (P = 0.007), and axial affection (P = 0.022), while TEAD4 expression was associated with progressive course (P = 0.032), high PASI score (P = 0.002), severe psoriasis (P = 0.001), severe inflammation (P = 0.001), and progressive course (P = 0.017). CONCLUSION: TEAD4 expression was higher in lesional than nonlesional skin and absent in healthy skin, suggesting a role in psoriasis development. TEAD4 expression was also associated with severe and progressive psoriasis. This may be mediated by the downregulation of FOXP3 and dysfunction of Treg cells. TEAD4 could serve as a promising therapeutic target in psoriasis.

The Role of Galectin3, Tubulinß, and Maspin in Promoting Tumor Budding in Colorectal Carcinoma and Their Clinical Implications.

Colorectal cancer (CRC) is a leading cause of death worldwide. Despite the advances in surgical and therapeutic management, tumor metastases and poor prognosis are still major problems. Tumor budding is a relevant prognostic factor in CRC, and it can predict tumor metastasis. Galectin3 is responsible for the development and progression of many cancers through the regulation of cell-cell/cell-matrix interactions and tumor cell invasion. Tubulin is a microtubule protein, and maspin is a serine protease inhibitor; both induce tumor cell invasion through the stimulation of epithelial-mesenchymal transition. This study aims to evaluate the relationship between the expression of galecin3, tubulinß, and maspin in CRC and clinicopathological features, including tumor budding, their prognostic roles, and clinical implications using immunohistochemistry. Galectin3, tubulinß, and maspin were detected in tumor cells in 95%, 65%, and 87.5% of cases and in stromal cells in 28.8%, 40%, and 0% of cases. High expression of galectin3 and tubulinß expression either in tumor cells or stroma was significantly associated with aggressive tumor features such as lymph node metastasis, lymphovascular invasion, tumor budding, and advanced tumor stage. The nucleocytoplasmic expression of maspin in tumor cells showed a significant association with deeper tumor invasion, lymph node metastasis, tumor budding, and advanced tumor stage. Significant associations were found between high galectin3 tumor cell expression and nucleocytoplasmic maspin and shorter survival. High expression of galectin3, tubulinß, and nucleocytoplasmic maspin were significantly associated with aggressive tumor features such as tumor invasion, metastasis, high tumor budding, and short survival in CRC. They could be used as biomarkers for tumor budding and tumor aggressiveness in CRC and may be considered for future target therapy.

Evaluation of ARK5 and SIRT3 expression in renal cell carcinoma and their clinical significance.

BACKGROUND: Globally Renal Cell Carcinoma (RCC) represents 3% of malignant tumours in adults and 1.78% in Egypt. AMPK-related protein kinase 5 (ARK5) is mainly associated with a hypoxic microenvironment which is a feature of the major RCC subtypes. Additionally, it displays decreased mitochondrial respiration. SIRT3 is a mitochondrial deacetylase that modifies multiple mitochondrial proteins. MATERIAL AND METHODS: Fifty eight cases of RCC, and 30 non-neoplastic cases (of End-Stage Kidney Disease (ESKD) were subjected to immunohistochemistry by ARK5 and SIRT3. The results of IHC were correlated together and correlated with the available clinicopathologic and survival data. RESULTS: Although no significant difference was detected between RCC and ESKD groups regarding ARK5 expression, there was a significant association with RCC regarding H-score and nucleocytoplasmic expression (both P = 0.001). Also, SIRT3 was highly expressed in RCC in comparison to the ESKD group (H-score: P = 0.001). There were significant associations between nucleocytoplasmic ARK5 expression and higher tumour grade, low apoptotic and high mitotic indices, tumour extent, advanced tumour stage, and impaired response of tumours to chemotherapeutic drugs (P = 0.039, P = 0.001, P = 0.027, P = 0.011, P = 0.009, and P = 0.014 respectively). Moreover, the H score of ARK5 expression showed significant associations with tumour grade, apoptotic and mitotic indices, tumour extension, tumour stage, and response to therapy (P = 0.01, 0.035, 0.001, 0.004. 0.003 and 0.013). Regarding SIRT3 expression, it showed significant associations with apoptotic and mitotic indices, tumour extent, tumour stage and response to therapy (P = 0.022, 0.02, 0.042, 0.039 and 0.027). Interestingly, there was a highly significant correlation between the expression of ARK5 and SIRT3 (P = 0.009). Univariate survival analysis revealed a significant association between short survival duration and both nucleocytoplasmic expression of ARK5 and positive SIRT3 expression (P = 0.014 and 0.035). CONCLUSION: ARK5 and SIRT3 are overexpressed in RCC and associated with parameters of poor prognosis as well as short survival. Both seem to influence response to therapy in RCC. So, they could be new targets for therapy that may improve tumour response and patients' survival. There is a postulated relationship that needs more extensive investigation.

Can ß-catenin, Tenascin and Fascin be potential biomarkers for personalized therapy in Gastric carcinoma?

Gastric carcinoma (GC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death. Studying the molecular profile of GC is essential for developing targeted therapies. ß-catenin, Tenascin, and Fascin expression are among the molecular abnormalities that are claimed to cause GC progression and chemoresistance. Therefore, they could be used as potential therapeutic targets. This study aimed to evaluate ß-catenin, Tenascin, and Fascin expression and their possible roles as prognostic and predictive biomarkers in GC using immunohistochemistry. This retrospective study included 84 GC cases. Tissue microarrays were constructed, followed by ß-catenin, Tenascin, and Fascin immunostaining. Their expression was assessed and compared with clinicopathological parameters and survival data. The study results revealed that ß-catenin nucleocytoplasmic expression, positive Tenascin, and Fascin expressions were detected in 86.9%, 70%, and 59.5% of cases, respectively. Their expression was significantly associated with poor prognostic parameters, such as deeper tumor invasion, lymph node metastasis, advanced pathological stage, vascular invasion, positive omental nodules, poor response to chemotherapy, and short overall survival. Hence, nucleocytoplasmic ß-catenin expression together with Tenascin and Fascin positivity can be potential prognostic and predictive markers, and they can be used as therapeutic targets for GC.

Predictive Factors of Positive Circumferential and Longitudinal Margins in Early T3 Colorectal Cancer Resection.

BACKGROUND: Malignant involvement of circumferential resection margin (CRM) and longitudinal resection margin (LRM) after surgical resection of colorectal cancer (CRC) are associated with higher rates of recurrence and development of distant metastasis. This can influence the overall patient's prognosis. The aim of the current study was to identify pathological factors as predictors for the involvement of resection margins in early T3 CRC. Patients and Methods. Fifty patients radiologically diagnosed to have cT3a/b (CRC) were included in the study. After resection, the pathological examination was performed to identify patients with positive CRM and/or LRM. Relations between the different pathological parameters and the CMR and LRM involvements were assessed. RESULTS: Positive CRM was present in 17 cases (34%), while positive LRM was found in 6 cases (12%). The involvement of both margins was significantly associated with rectal tumors and tumors with infiltrative gross appearance, grade III, deeper invasion, and positive lymph node metastases. Also, there was a significant association between both margins' positivity and other pathological parameters as signet ring carcinoma, tumor budding, perineural and vascular invasion, high microvessel density (MVD), and sinusoidal vascular pattern, while the presence of necrosis and infiltrative advancing tumor front was significantly associated with CRM involvement only. The depth of tumor invasion and signet ring carcinoma were identified as independent predictor factors for positive CRM and LRM, respectively. CONCLUSION: Preoperative identification of these pathological parameters can be a guide to tailor the management plan accordingly.

Evaluation of topoisomerase II, ki-67, and P53 expression in non-muscle-invasive urothelial carcinoma and their clinical significance.

BACKGROUND: Transurethral resection of tumor is the main treatment of non-muscle-invasive urothelial carcinoma, but it is associated with high rate of recurrence and/or progression and this arouses the need for adjuvant therapy. Topoisomerase II (Top II), KI-67, and P53 are proliferation and cell cycle regulation markers that may predict tumor response to therapy. AIM: This study aimed to assess Top II, KI-67, and P53 expression and their effect on clinical outcome and response to therapy of non-muscle-invasive urothelial carcinoma. MATERIALS AND METHODS: Fifty cases of non-muscle invasive urothelial carcinoma were collected; Top II, KI-67, and P53 expression was evaluated. Patients received treatment then tumor recurrence was correlated with the expression of previous markers. RESULTS: There was a significant association between high Top II score, P53, and KI-67 and high tumor grade (P = 0.0001, 0.001, and 0.0001), submucosal infiltration (P = 0.0001 and 0.01), and recurrence (P = 0.01, 0.001, and 0.001). CONCLUSION: Top II, P53, and KI-67 may predict tumor response to therapy and the clinical outcome in non-muscle-invasive urothelial carcinoma.

Diagnostic value of smoothelin and vimentin in differentiating muscularis propria from muscularis mucosa of bladder carcinoma.

BACKGROUND: Determination of the extent of involvement or pathological staging is one of the requirements for adequate evaluation of bladder cancer specimens. Therefore, the differentiation between MP and MM is essential for proper treatment and avoiding over or under staging. AIM: The present study aimed at evaluation of diagnostic value of smoothelin and vimentin expression both singly and in combination for differentiation between MM and MP. METHODS: This study was carried out on 59 cystectomy specimens of primary bladder carcinoma and eleven cystoscopic biopsies for non-neoplastic bladder lesions (cystitis). RESULTS: Histologically, MM was identified clearly in 40 cases and MP was identified in all 70 examined cases. The cases were immunostained for smoothelin and vimentin. Intensity of smoothelin expression showed significant difference (P = 0.001) between MM and MP with 97.5% sensitivity and 95% specificity and the percentage of smoothelin expression was significantly higher in MP compared to MM (P = 0.001) with 95.7% sensitivity and 85% specificity (using 65% as cut-off point). Vimentin was negative in MP and showed positive expression in 32 cases (80%) of MM with a statistical significant difference (P = 0.001) providing 80% sensitivity and 100% specificity. Combined moderate to strong smoothelin and negative vimentin offered 100% sensitivity and 100% specificity towards the identification of MP. CONCLUSIONS: Differentiation of MM from MP can be made based on histopathological criteria, which are unfortunately overlapping in many cases. Moderate to strong smoothelin expression with negative vimentin could be very helpful procedure in difficult and overlapping cases with a high diagnostic validity.

ß-catenin and SKP2 proteins as predictors of grade and stage of non-muscle invasive urothelial bladder carcinoma.

BACKGROUND: To evaluate the expression of beta-catenin (ß-catenin) and SKP2 proteins in superficial bladder cancer cases and their correlation with tumor grade and stage. METHODS: After institutional review board approval, we retrospectively evaluated the expression of ß-catenin and SKP2 proteins in tissue specimens from patients with non-muscle invasive bladder cancer (NMIBC) and compared their results with a cohort of chronic nonspecific cystitis's. Then we and explored these markers association with tumor grade and stage. RESULTS: A total of 40 patients were retrospectively identified, 50% was NMIBC and the rest were chronic nonspecific cystitis. ß-catenin was expressed in 18 (90%) patients of the NMIBC group in comparison to 14 (70%) of the control group with (P=0.1), while SKP2 protein was only expressed in NMIBC groups (P=0.03). A statistically significant correlation was identified between nucleocytoplasmic localization of ß-catenin and SKP2 with tumor grade, stage. CONCLUSIONS: ß-catenin and SKP2 expression are providing promising results for differentiating higher grade and stage non muscle invasive bladder cancers.

Immunohistochemical analysis of the role and relationship between Notch-1 and Oct-4 expression in urinary bladder carcinoma.

Most tumors contain a minor population of cancer stem cells that are responsible for tumor heterogeneity, resistance to therapy and recurrence. Oct-4 is a transcription factor responsible for self-renewal of stem cells, whereas the Notch family of receptors and ligands may play a pivotal role in the regulation of stem cell maintenance and differentiation. This study aimed at an evaluation of Oct-4 and Notch-1 expression in both carcinoma and stromal cells of 83 cases of primary bladder carcinoma and to study the relationship between them. Notch-1 was expressed in carcinoma and stromal cells of all malignant cases, where expression in both cell types was correlated with parameters indicating differentiation, such as low grade (p < 0.05) and less proliferation (p < 0.05). However, Notch-1 expression in stromal cells was associated with nodal metastasis (p = 0.016) and advanced stage (p = 0.030). 56.6 and 75.9% of carcinoma and stromal cells of malignant cases showed Oct-4 expression, respectively. Oct-4 expression in carcinoma cells or stromal cells was associated with aggressive features of bladder carcinoma, such as poor differentiation (p = 0.001), high proliferation (p < 0.001, 0.030), and liability for recurrence (p = 0.010, p < 0.001). There was an inverse relationship between Notch-1 and Oct-4 expression in carcinoma cells (p = 0.002), but stromal expression of Notch-1 was found to be associated with a nuclear pattern of Oct-4 expression in carcinoma cells (p = 0.030). Oct-4 as a stem cell marker is expressed in carcinoma cells and in stromal cells of bladder carcinoma, where they may cooperate in the progression of bladder carcinoma by acquiring aggressive features, such as a liability for recurrence and dissemination. Notch-1 is also expressed in both carcinoma cells and stromal cells of bladder carcinoma. Although they could share in enhancing differentiation, stromal expression of Notch-1 may have a bad impact, possibly through up-regulation of the active nuclear form of Oct-4 in carcinoma cells.