Morphofunctional transformations during the morphogenesis of the thyroid gland of the offspring of Wistar rats after intrauterine exposure to dexamethasone

Background. In recent years, the prevalence of thyroid pathologies of various origins among children in the world has reached a significantly high level. The use of glucocorticoids during pregnancy remains a debatable issue in obstetrics today, as they can both positively and negatively affect the processes of organ morphogenesis and be the cause of pathological conditions in the postnatal period. Objective: to establish the features of morphofunctional transformations during the morphogenesis of the thyroid gland of the offspring of rats at an early age in normal and after intrauterine action of dexamethasone. Methods. 108 thyroid glands of rats of 3 experimental groups were microscopically examined using histological and immunohistochemical methods, followed by statistical processing of the obtained results. Results. Against the background of high levels of total follicular thyrocytes per 1 day of life in animals that received prenatal dexamethasone, cytoplasmic expression of TgAb was expressed, which correlated with the indicators of nuclear and cytoplasmic Fox-1 expression. From the 7th to the 11th day, a decrease in the total number of thyrocytes per unit area was observed due to the accumulation of colloid in the follicles, an increase in Fox-1 cytoplasmic expression and a decrease in nuclear expression, against the background of increased proliferative activity. By day 21, Fox-1 cytoplasmic and nuclear expression were almost identical. There was a decrease in the intensity of TgAb expression in the cytoplasm of thyrocytes and its expression in the colloid, a decrease in the number of Ki-67 positive thyrocytes per conditional unit area compared with the previous observation period. Conclusion. It was found that prenatal exposure of dexamethasone causes the offspring accelerate the development of morphological structures of the thyroid gland, but functionally they are in a state of stress of both the synthesizing apparatus and the process of hormone excretion, which is expressed in the imbalance of immunohistochemical expression of Fox-1 and TgAb. Such thyrocytes with signs of disturbances in synthetic activity desquamate into the lumen of the follicles, while on the 11th day we compensatory increase in the proliferative activity of the thyroid epithelium.

STEAP3 promotes cancer cell proliferation by facilitating nuclear trafficking of EGFR to enhance RAC1-ERK-STAT3 signaling in hepatocellular carcinoma

STEAP3 (Six-transmembrane epithelial antigen of the prostate 3, TSAP6, dudulin-2) has been reported to be involved in tumor progression in human malignancies. Nevertheless, how it participates in the progression of human cancers, especially HCC, is still unknown. In the present study, we found that STEAP3 was aberrantly overexpressed in the nuclei of HCC cells. In a large cohort of clinical HCC tissues, high expression level of nuclear STEAP3 was positively associated with tumor differentiation and poor prognosis (p < 0.001), and it was an independent prognostic factor for HCC patients. In HCC cell lines, nuclear expression of STEAP3 significantly promoted HCC cells proliferation by promoting stemness phenotype and cell cycle progression via RAC1-ERK-STAT3 and RAC1-JNK-STAT6 signaling axes. Through upregulating the expression and nuclear trafficking of EGFR, STEAP3 participated in regulating EGFR-mediated STAT3 transactivity in a manner of positive feedback. In summary, our findings support that nuclear expression of STEAP3 plays a critical oncogenic role in the progression of HCC via modulation on EGFR and intracellular signaling, and it could be a candidate for prognostic marker and therapeutic target in HCC.

A case of TFE-3-positive non-neoplastic pseudodecidualized endometrium presenting as a cervical mass

Introduction/Objective TFE-3 gene encodes a transcription factor that promotes the expression of genes involved in cell growth and proliferation. Its overactivation can result in oncogenic activity. Although TFE-3 seems to be almost universally expressed in normal tissues, this expression should be at very low levels and strong nuclear expression of TFE-3 is seen almost exclusively in tumors containing or lacking the TFE-3 gene fusion. These include renal cell carcinoma, alveolar soft part sarcomas, epithelioid hemangioendotheliomas, PEComas, granular cell tumour, solid pseudopapillary neoplasm of the pancreas, and ovarian sclerosing stromal tumors. It must be emphasized that only nuclear expression of TFE-3 is of diagnostic value, as non-specific cytoplasmic staining is common. Methods/Case Report A 30-year-old woman with pelvic pain, heavy vaginal bleeding and ureteral stricture on oral contraceptive pill was found to have a cervical mass on exam. Cervical biopsy showed fragments of benign squamous epithelium and polypoid endometrial tissue with atrophic glandular component, stromal pseudodecidualization and abundant mixed inflammation. The stroma was positive for CD10, and negative for P16, desmin, cytokeratin ae1/ae3, CD34, calretinin. There was patchy moderate to strong nuclear staining for TFE-3 (Anti-TFE-3 rabbit monoclonal primary antibody, Cell MarqueTM). No evidence of a neoplastic process was seen, and the overall findings fit with either prolapsed endometrial tissue or endometriosis. TFE-3 by FISH showed no rearrangement of the TFE-3 gene region, ruling out alveolar soft part sarcoma. Results (if a Case Study enter NA) NA Conclusion The Human Protein Atlas, a program mapping all the human proteins in cells and tissues, shows that endometrial stromal and glandular cells can have moderate TFE-3 nuclear expression, using Anti-TFE-3 rabbit polyclonal antibody (Prestige Antibodies ®). In our case, focal strong expression was seen using a monoclonal antibody. In the pathology literature this finding has not been previously reported. Pathologists should be aware of the possibility of strong nuclear expression of TFE-3 in non-neoplastic endometrium to avoid potential misdiagnosis.

A Rare Medullary Carcinoma of Jejunum

Introduction/Objective Medullary carcinoma of jejunum is an extremely rare condition. These tumors account for less than 0.04% of all colorectal cancers and less than 3 cases to date has been reported in the small intestine Methods/Case Report We present a case of 78-year-old woman with a celiac disease and collagenous colitis, chronic diarrhea, chronic anemia and 2.1 cm apple core lesion on mid to distal jejunum on CT leading to partial obstruction. Results (if a Case Study enter NA) Histologically tumor showed invasive carcinoma in a solid growth pattern with pushing border. The tumor cells were uniform, enlarged with prominent nucleoli and brisk mitotic activity. There was prominent inflammatory response within and around the tumor. Immunohistochemical stains were positive for CK7, CDX2 CK19, CKAE1-3 and negative for CD45, CK20, Chromogranin Synaptophysin, PAX-8. MLH1 &PMS2 showed loss of nuclear expression and MSH2 & MSH6 with Intact nuclear expression. Microsatellite instability was High (MSI- H) with instability in two or more microsatellite markers. Diagnosis of medullary carcinoma of jejunum was made. Conclusion Although the clinical manifestations can be consistent with signs of intestinal obstruction, often these rare tumors are discovered incidentally. Conditions such as celiac disease, Crohn’s disease, and other chronic inflammatory illnesses have been linked to contributing risk factors. Imaging and appropriate tumor markers have less role in diagnosis; however, biopsy is needed for definitive diagnosis. Even though the development of these tumors in the small bowel is rare, further enhancement of awareness can aid in the appropriate early detection and appropriate treatment modalities.

Histone Deacetylase (HDAC)−1, −2, −4, and −6 in Uveal Melanomas: Associations with Clinicopathological Parameters and Patients’ Survival

Background: Uveal melanoma (UM) represents the most common primary intraocular malignancy in adults, exerting high metastatic potential and poor prognosis. Histone deacetylases (HDACs) play a key role in carcinogenesis, and HDAC inhibitors (HDACIs) are currently being explored as anti-cancer agents in clinical settings. The aim of this study was to evaluate the clinical significance of HDAC−1, −2, −4, and −6 expression in UM. Methods: HDAC−1, −2, −4, and −6 expression was examined immunohistochemically in 75 UM tissue specimens and was correlated with tumors’ clinicopathological characteristics, the presence of tumor-infiltrating lymphocytes (TILS), as well as with our patients’ overall survival (OS). Results: HDAC−2 was the most frequently expressed isoform (66%), whereas we confirmed in addition to the expected nuclear expression the presence of cytoplasmic expression of class I HDAC isoforms, namely HDAC−1 (33%) and HDAC−2 (9.5%). HDAC−4 and −6 expression was cytoplasmic. HDAC−1 nuclear expression was associated with increased tumor size (p = 0.03), HDAC−6 with higher mitotic index (p = 0.03), and nuclear HDAC−2 with epithelioid cell morphology (p = 0.03) and presence of tumor-infiltrating lymphocytes (p = 0.04). The association with the remaining parameters including Monosomy 3 was not significant. Moreover, the presence as well as the nuclear expression pattern of HDAC−2 were correlated with patients’ improved OS and remained significant in multivariate survival analysis. Conclusions: These findings provide evidence for a potential role of HDACs and especially HDAC−2 in the biological mechanisms governing UM evolution and progression.

SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis

Background Solute carrier family 7 member 11(SLC7A11) is a component of cysteine/glutamate transporter, which plays a key role in tumor growth; however, its underlying effect on radiosensitivity in esophageal squamous cell carcinoma (ESCC) remains unclear. This study aimed to clarify SLC7A11’s expression and correlation with nuclear expression of nuclear factor erythroid-2 (NRF2)-associated radioresistance in ESCC. Methods We included 127 ESCC patients who received radical chemoradiotherapy. Immunohistochemical staining was used to detect SLC7A11 and NRF2 nuclear expression, and the relationship between clinicopathological characteristics and survival rates or therapy response were evaluated. Western blot, dual-reporter assays and Chromatin immunoprecipitation (ChIP)-sequencing were used to analyze their relationship in vitro. Their roles in radioresistance were then investigated through multiple validation steps. Results NRF2 nuclear expression and SLC7A11 expression were overexpressed in ESCC tissues and were positively correlated with one another. NRF2 nuclear expression was significantly associated with tumor length, lymph node metastasis, and TNM stage, while SLC7A11 expression was associated with lymph node metastasis. Patients with high NRF2 nuclear expression and SLC7A11 expression had significantly shorter overall and progression-free survival, and poor treatment response. The multivariate model showed that NRF2 nuclear expression and SLC7A11 expression, sex and tumor location are independent prognostic factors. In vitro analysis confirmed that hyperactivation of NRF2 induced SLC7A11 expression by directly binding to its promoter region, promoting radioresistance, reducing radiotherapy-induced lipid peroxidation levels, PTGS2 expression, and radiotherapy-related ferroptosis morphologic features. Conclusion Our study reveals a connection between high SLC7A11 expression and NRF2 nuclear expression in patients with ESCC that was related to worse survival and poorer therapy outcomes. SLC7A11-mediated ferroptosis inhibition induced NRF2-associated radioresistance, highlighting potential of NRF2/SLC7A11/ferroptosis axis as future therapeutic targets against therapy resistance biomarker.

Evaluation of E-Cadherin and β-Catenin Immunoreactivity for Determining Undifferentiated Cells in Anaplastic Thyroid Carcinoma

<b><i>Introduction:</i></b> An immunohistochemical study has occasionally been performed to diagnose anaplastic thyroid carcinoma (ATC). However, antibodies to confirm the undifferentiated nature of ATC have not yet been evaluated. The aim of this study was to evaluate E-cadherin and β-catenin expressions in immunoreactivity to determine undifferentiated carcinoma cells in the diagnosis of ATC. <b><i>Methods:</i></b> We immunohistochemically examined 29 ATCs, 30 poorly differentiated thyroid carcinomas (PDTCs), 22 well-differentiated thyroid carcinomas (WDTCs), and 3 squamous cell carcinomas. Antibodies for thyroid transcription factor-1 (TTF-1), paired-box gene 8 (PAX8), β-catenin, and E-cadherin were used. <b><i>Results:</i></b> All WDTCs tested positive for TTF-1, PAX8, and E-cadherin. The positive rates of TTF-1, PAX8, and E-cadherin were 93.3, 93.3, and 100%, respectively, in PDTCs and 17.2, 51.7, and 10.3%, respectively, in ATCs. WDTC expressed the lateral cell membrane staining for β-catenin and E-cadherin, whereas PDTC showed circumferential cell membranous expression (fishnet pattern). β-catenin cell membrane expression in ATCs is lost or discontinuous. Carcinoma cells with β-catenin nuclear expression without cell membranous expression were scattered in 72.4% of ATCs but were not observed in the other carcinomas. <b><i>Conclusion:</i></b> We propose 3 immunohistochemical findings to determine undifferentiated carcinoma cells in the diagnosis of ATC: (1) β-catenin nuclear expression with no or reduced cell membranous expression, (2) the loss or discontinuous pattern of E-cadherin expression, and (3) the loss of PAX8 nuclear expression.

Prognostic Significance of JMJD3 Expression in Pleural Mesotheliomas

Pleural mesothelioma is a disease associated with asbestos exposure and patients often have poor prognosis. Biomarkers that can stratify tumours more efficiently are much sought after to enable more personalized treatment options and predict prognosis. Jumonji domain-containing protein D3 (JMJD3) has variable expression in a range of tumours. However, there has been much discordance in the immunohistochemical labelling of JMJD3 between cancers at different sites and ambiguity exists regarding its functional significance. Recent evidence suggests that although nuclear expression of JMJD3 has a demethylase role in most cancers, there are also demethylase-independent actions of JMJD3 that need to be explored including its cytoplasmic expression. We analysed JMJD3 labelling in 99 pleural mesothelioma tissues and correlated nuclear and cytoplasmic expression with survival outcomes. We found that low nuclear and high cytoplasmic expression were associated with poor survival outcomes in our cohort (p = 0.014 and p = 0.041, respectively). Additionally, we found that low nuclear expression of JMJD3 was frequent in the sarcomatoid subtype (p < 0.001). Finally, we showed that cytoplasmic labelling is an independent prognostic marker of poor survival. Our cohort only contained a small number of tumours with high cytoplasmic expression of JMJD3, and a larger cohort study may provide clearer stratification.

High expression of DNA damage-inducible transcript 4 (DDIT4) is associated with advanced pathological features in the patients with colorectal cancer

DNA damage-inducible transcript 4 (DDIT4) is induced in various cellular stress conditions. This study was conducted to investigate expression and prognostic significance of DDIT4 protein as a biomarker in the patients with colorectal cancer (CRC). PPI network and KEGG pathway analysis were applied to identify hub genes among obtained differentially expressed genes in CRC tissues from three GEO Series. In clinical, expression of DDIT4 as one of hub genes in three subcellular locations was evaluated in 198 CRC tissues using immunohistochemistry method on tissue microarrays. The association between DDIT4 expression and clinicopathological features as well as survival outcomes were analyzed. Results of bioinformatics analysis indicated 14 hub genes enriched in significant pathways according to KEGG pathways analysis among which DDIT4 was selected to evaluate CRC tissues. Overexpression of nuclear DDIT4 protein was found in CRC tissues compared to adjacent normal tissues (P = 0.003). Furthermore, higher nuclear expression of DDIT4 was found to be significantly associated with the reduced tumor differentiation and advanced TNM stages (all, P = 0.009). No significant association was observed between survival outcomes and nuclear expression of DDIT4 in CRC cases. Our findings indicated higher nuclear expression of DDIT4 was significantly associated with more aggressive tumor behavior and more advanced stage of disease in the patients with CRC.