Histology and histopathology最新文献

Introduction: For the last three decades, bariatric/metabolic surgeries have highlighted the relevance of certain gastrointestinal hormones in controlling and regulating glucose metabolism. The incretins have been a significant focus in developing therapies against Type 2 Diabetes Mellitus (T2DM). Glucagon-like peptide-1 (GLP-1) has been a primary focus in this field, leading to the development of analogues with high therapeutic potential and efficiency, such as semaglutide. However, recently another incretin, glucose-dependent insulinotropic polypeptide (GIP), has become a key target in T2DM drug development due to its complex pleiotropic effects, which include modulating insulin/glucagon secretion, acting on adipose tissue, and regulating appetite. The description of GIP properties as dual can be ambiguous, as this may refer either to its capacity to regulate both insulin and glucagon or to its distinct actions at the central versus peripheral level. Connecting this multifaceted activity was the rationale for developing combined GIP/GLP-1 analogues, like tirzepatide, and has culminated in triple-receptor agonists such as retratutide, which also engages the glucagon receptor (LY3437943). These multi-agonists potentially enhance the therapeutic potential of GLP-1 analogues.

Commentaries: This review covers GIP physiology, its role within the context of T2DM, and the properties of GIP analogues, which represent a new line of drugs against T2DM. This field includes not only GIP analogues, since some are dual or triple agonists that also target GLP-1. We aim to elucidate the future perspectives offered by the use of these drugs.

Microglia are innate immune cells in the central nervous system (CNS) and play critical roles in proper brain development and function. During postnatal development, microglia have a highly plastic morphology and change rapidly in response to the temporal brain environment. However, their dynamics and phenotypes during this period are still not fully elucidated. Here, we systematically elucidated microglial density and morphological changes during postnatal development as well as in pathological obese conditions. Our results demonstrated a spatiotemporal distribution of microglia in different brain regions associated with gradually increased microglial complexity during postnatal development. Moreover, microglia become reactive in most brain regions of obese mice, but their morphological diversity has a region-specific manner, with an obvious alteration in the hypothalamus. Overall, our data emphasized the morphological dynamics of microglia following developing time windows and provided the basic information for future investigations.

Background: Smad Ubiquitination Regulatory Factor-1 (SMURF1) is implicated in promoting gastric cancer progression by enhancing cell proliferation, migration, and invasion. This study aims to elucidate how SMURF1 drives gastric cancer aggressiveness, with a focus on its interaction with Glutathione S-transferase mu 2 (GSTM2).

Methods: Bioinformatics analysis identified dysregulated SMURF1 and GSTM2 expression in stomach adenocarcinoma (STAD). The relation between GSTM2 and SMURF1 was predicted using Unibrowser. Functional assays, including cell counting kit-8, wound healing, and Transwell invasion, were conducted on gastric cancer cells to explore the effects of GSTM2 and/or SMURF1. The ubiquitination level of GSTM2 was measured using western blot and immunoprecipitation. In vivo tumorigenicity was assessed in a xenograft mouse model, alongside analysis of tumor growth and molecular markers of epithelial-mesenchymal transition (EMT).

Results: SMURF1 was highly expressed and the GSTM2 level was significantly downregulated in STAD. GSTM2 silencing activated the viability, migration, and invasion of gastric cancer cells, and these cell functions were inhibited by GSTM2 overexpression, which was reversed by SMURF1 overexpression. SMURF1 was predicted to be an E3 ubiquitin ligase for GSTM2. SMURF1 overexpression or Cyclohexanecarboxamide (CHX) addition suppressed GSTM2 levels in gastric cancer cells. Silencing of SMURF1 restrained GSTM2 ubiquitination. In vivo, GSTM2 overexpression suppressed tumor growth and EMT markers, such as Vimentin, while elevating E-cadherin, which was offset by SMURF1 upregulation.

Conclusion: This study reveals a novel oncogenic axis, where SMURF1 promotes gastric cancer progression by targeting GSTM2 for degradation. Inhibiting SMURF1 stabilizes GSTM2, leading to reduced cell proliferation, migration, and invasion both in vitro and in vivo.

The heterogeneity of cancer cells between primary breast tumors and lymph node (LN) metastases at the initial therapy remains unclear. This study aimed to determine whether intrinsic subtypes of LN metastasis differ from those of primary breast tumors and how much additional information is obtained. Ninety-three breast cancer cases with LN metastasis were enrolled in the study. Immunohistochemistry for ER, PgR, HER2, and Ki-67 was performed for primary breast tumors and the largest LN metastases. The intrinsic subtype was determined as luminal A (ER⁺, PgR⁺, HER2^-, Ki-67 index <20%), luminal B (ER⁺, HER2^-, PgR^- or PgR⁺, and Ki-67 index >20%), luminal B HER2 rich (ER⁺, HER2⁺), HER2 (ER^-, HER2⁺), and triple-negative (ER^-, PgR^-, HER2^-). The discordance ratios for intrinsic subtypes between the primary tumor and LN metastasis were analyzed. The discordance ratios for ER, PgR, HER2, and Ki-67 were 0/93 (0%), 7/93 (7.5%), 2/93 (2.2%), and 10/93 (10.8%), respectively. The discordance ratio for the intrinsic subtype was 9/93 (9.7%). Considering the intrinsic subtype of LN metastasis, the effects of additional chemotherapy and anti-HER2 therapy could be expected in 4/93 (4.3%) and 1/93 (1.1%) patients, respectively. The discordance ratio for the intrinsic subtype between the primary breast tumor and LN metastasis was 9.7%. Considering the intrinsic subtype of LN metastasis, additional medical therapy could be expected to be effective in 5/93 (5.4%) breast cancer cases with LN metastasis. Immunohistochemistry of metastatic LNs may be useful for planning adjuvant therapy when the analysis of the primary site is inconclusive.

Aims: We aimed to analyze CD63, a cell surface protein that has been associated with tumor aggressiveness in several cancers, including breast, colorectal, and lung cancer, as well as melanoma, in prostate cancer.

Methods: CD63 expression was analyzed immunohistochemically in a cohort of primary prostate cancers from 281 patients. The results were correlated with clinico-pathologic parameters, including biochemical recurrence. In addition, CD63 expression in 251 of the 281 patients with prostate cancer was compared with CD63 expression in matched benign tissue samples (490 tissue samples). The analysis was performed automatically using the open-source software QuPath^© and tested for statistical significance. For comparison with the diagnostic markers AMACR and GOLPH2, CD63 was analyzed in an additional cohort of 198 prostate cancers.

Results: CD63 expression was found in 100% of prostate cancer cases and benign tissue spots. Increased CD63 expression was significantly associated with higher tumor stage (pT), tumor grade (ISUP), as well as shorter progression-free survival (PFS). Compared with the CD63 intensity of benign tissue, expression in tumor tissue was higher in >80% of cases. In addition, combining the expression of CD63 and AMACR, positivity reached 97.2%, making CD63 a promising diagnostic biomarker in challenging cases.

Conclusions: CD63 is commonly overexpressed in prostate cancer, and higher levels are associated with earlier biochemical tumor progression; hence, CD63 is a promising diagnostic and prognostic biomarker in primary prostate cancer.

Endometrial cancer is one of the most common gynecological cancers worldwide, and an average of 42,000 women die each year. Chemotherapy, radiotherapy, and surgery are among the treatments available for endometrial cancer. Currently, drugs used for chemotherapy have had limited success in increasing the cure rate. Betulinic acid, a lupane-type triterpene widely found in the plant kingdom, has attracted attention for cancer treatment in recent years due to its ability to inhibit tumor growth and induce cell apoptosis. The aim of this study is to investigate the mTOR pathway-mediated anticancer effects of betulinic acid in human endometrial cancer cells. The effect of betulinic acid on Ishikawa cell viability was determined by the CCK-8 method. Its effect on the expression of genes involved in apoptosis and the mTOR pathway was assessed by real-time PCR. The effect on protein expression in the mTOR pathway was evaluated with immunohistochemistry and western blot, and the effects on apoptosis via Annexin V. Betulinic acid reduced Ishikawa endometrial cancer cell proliferation. Betulinic acid administration caused a significant decrease in Bcl2 (p=0.008) expression and increased caspase-8 (p=0.001) expression in Ishikawa cells. The results of Annexin V supported the idea that betulinic acid administration triggered apoptosis in Ishikawa cells. The mean rate of apoptotic cells in the betulinic acid group was 22±3.23%, while it was 2.31±0.2% in the control group (p=0.02). Betulinic acid caused a significant decrease in the expression of AKT1 (p=0.0001) and a significant increase in the expression of RAPTOR (p=0.00002). Betulinic acid administration also significantly decreased protein expression in the mTOR pathway. The percentage of p-PI3K, p-AKT, and p-mTOR-positive cells in Ishikawa cells was 89.39±5.19%, 74.84%±5.07, and 82.02%±6.14, respectively, in the control group. In the betulinic acid group, these values were 49.12±19.12% (p=0.002), 44.46±7.39% (p<0.001), and 53.70±8.94% (p<0.001), respectively. This study showed that betulinic acid decreased Ishikawa cell proliferation, triggered apoptosis, and decreased mTOR signaling; thus, betulinic acid may be a potential anticancer agent for the treatment of endometrial cancer.

The incidence of Helicobacter pylori (Hp)-naïve gastric neoplasms (HpNGNs) is increasing due to a growing Hp-naïve population and improved recognition. Among these, HpNGNs that predominantly exhibit foveolar-cell differentiation include foveolar-type gastric adenomas (FGA) and fundic gland polyps with dysplasia (FGPD). Traditionally, FGAs have been considered large, whitish, flat lesions (flat-type FGA), primarily associated with syndromic conditions, such as familial adenomatous polyposis (FAP) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), while sporadic cases are rare. This type exhibits a gastric immunophenotype with diverse differentiation, mainly toward foveolar cells, and harbors APC and KRAS mutations in all sporadic and most syndromic cases. A distinct subset of FGAs, termed foveolar-type gastric adenoma with a raspberry-like appearance (FGA-RA), has been identified. It presents as small, reddish polyps with unique macroscopic and microscopic features and only occurs sporadically. FGA-RA often mimics gastric hyperplastic polyps macroscopically and typically exhibits low-grade dysplasia, making biopsy-based diagnosis challenging and leading to its historical underrecognition. It shows pure foveolar differentiation and consistently harbors Krüppel-like factor 4 (KLF4) mutations. FGPD primarily develops sporadically in Hp-naïve individuals with long-term proton pump inhibitor use. A syndromic form, resembling flat-type FGAs, is also associated with FAP and GAPPS. Histologically, FGPD features dysplasia confined to the superficial foveolar epithelium and mucus neck cells overlying fundic gland polyps, with APC mutations detected in approximately 50% of cases. This review explores the clinicopathological and molecular characteristics of HpNGNs with predominant foveolar cell differentiation, emphasizing the need for an updated histological diagnostic framework.

Objective: This study aimed to investigate the role of SLMO2 in regulating mitochondrial function and its interaction with TRIAP1, which inhibited apoptosis in ovarian cancer cells. The findings provided valuable insights into potential therapeutic targets for ovarian cancer.

Methods: Lentiviral infection models were developed using SKOV3 and OVCAR3 ovarian cancer cell lines. Techniques such as flow cytometry, western blotting, immunofluorescence, and transmission electron microscopy were employed to systematically assess the regulatory effects of SLMO2 and TRIAP1 on cell proliferation, apoptosis, mitochondrial function, and autophagy. Additionally, a subcutaneous mouse tumor xenograft model was utilized to further investigate the combined effects of SLMO2 and TRIAP1 on ovarian cancer cells, with the aim of elucidating the specific mechanisms underlying tumor growth and apoptosis.

Results: SLMO2 enhanced mitochondrial function by increasing membrane potential and reducing reactive oxygen species (ROS) levels. Furthermore, through its interaction with TRIAP1, SLMO2 inhibited autophagy, which further suppressed apoptosis in ovarian cancer cells and regulated mitochondrial function. In vivo experiments showed decreased ROS levels and reduced expression of autophagy-related proteins, further supporting the roles of SLMO2 and TRIAP1 in the regulation of mitochondrial function.

Conclusions: SLMO2 regulated mitochondrial function and inhibited apoptosis in ovarian cancer cells by interacting with TRIAP1. The combination of SLMO2 and TRIAP1 promoted tumor cell growth and induced oxidative stress, suggesting potential therapeutic targets for ovarian cancer.

Purpose: To investigate the role of ubiquitin-specific protease 7 (USP7) in thyroid cancer (TC) pathogenesis and sorafenib resistance.

Methods: USP7 expression was compared in normal human thyroid cells and TC cells. The TC line with maximal differential USP7 expression was selected for further study. The functional interaction between USP7 and never in mitosis A (NIMA)-related kinase 2 (NEK2)/autophagy-related 5 (ATG5) was elucidated through a Pearson correlation coefficient analysis and co-immunoprecipitation assay. The half-inhibitory concentration (IC50) of sorafenib in resistant follicular thyroid (FTC) cells was determined following USP7 knockdown and ATG5 overexpression. Furthermore, the effects of USP7 knockdown and the autophagy inducer rapamycin (RAPA) on FTC cell function were assessed by colony formation and Transwell assays. The function of USP7 was validated in vivo using a xenograft mouse model, and tumor growth was assessed through gross examination and histopathological staining.

Results: High USP7 expression promoted the proliferation, migration, and invasion of FTC cells and was positively correlated with NEK2 and ATG5 levels. USP7 enhanced NEK2 stability via deubiquitination. Knocking down USP7 downregulated ATG5, and this effect was reversed by NEK2 overexpression. USP7 inhibition reduced the IC₅₀ of sorafenib in FTC cells, which was reversed by ATG5 overexpression. USP7 knockdown attenuated FTC cell proliferation, migration, and invasion while increasing the apoptosis rate, and these effects were reversed by RAPA treatment. Knocking down USP7 suppressed the growth of TC xenografts in vivo, improved tumor tissue differentiation, and reduced the percentage of Ki-67-positive cells.

Conclusion: USP7 promoted the progression of FTC and induced sorafenib resistance by enhancing NEK2/ATG5-mediated autophagy. This study provides novel insights and potential therapeutic strategies for FTC treatment and overcoming drug resistance.

Oncocytic carcinomas of the salivary glands represent a rare and diverse group of malignancies characterised by granular eosinophilic cytoplasm due to abundant mitochondria. This review provides a comprehensive overview of oncocytic salivary gland carcinomas, categorised by their morphological patterns: monophasic, biphasic, and complex. Monophasic entities include oncocytic intraductal carcinoma (OIDC), oncocytic salivary duct carcinoma (OSDC), acinic cell carcinoma (ACC), and secretory carcinoma (SC). These tumours vary significantly in histological architecture, immunohistochemical profiles, and genetic alterations, ranging from TRIM33::RET fusions and BRAF V600E mutations in OIDC to NR4A3 rearrangements in ACC and ETV6::NTRK3 fusions in SC. Biphasic tumours, such as oncocytic epithelial-myoepithelial carcinoma (OEMC) and oncocytic adenocarcinoma not otherwise specified (OANOS), further complicate diagnosis due to dual cellular composition and overlapping features with other neoplasms. Complex-pattern tumours, particularly oncocytic mucoepidermoid carcinoma (OMEC), highlight diagnostic challenges and underscore the need for advanced molecular diagnostics. This article emphasises the critical role of integrated histopathological examination, immunohistochemical staining, and molecular profiling in the accurate classification of these neoplasms. Despite diagnostic advancements, some entities, like OANOS, remain provisional, pending widespread access to transcriptomic tools. Recognising the molecular heterogeneity and clinicopathologic nuances of oncocytic carcinomas is essential for improving diagnostic precision, prognostication, and guiding targeted therapy.