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Astrocytes contribute in critical ways to the pathophysiology of epilepsy not only through trophic support but also through the regulation of neuronal excitability by modulating glutamate, γ‐aminobutyric acid (GABA), adenosine triphosphate (ATP), and adenosine levels. Calponin‐3 is an actin‐binding protein that is enriched in the brain. We have previously reported that increased calponin‐3 expression is correlated with epileptic seizures. In the present study, we revealed that in the hippocampus of epileptic mice models, increased calponin‐3 protein expression was correlated with the expression of the astrocytic marker glial fibrillary acidic protein (GFAP). Calponin‐3 overexpression in the hippocampus significantly increased susceptibility to epileptic seizures, whereas calponin‐3 downregulation was associated with reduced spontaneous recurrent seizures in mice. Furthermore, changes in calponin‐3 levels corresponded to astrocyte activation in both mice and cultured human astrocytes and were associated with changes in the protein levels of adenosine kinase (ADK) and equilibrative nucleoside transporter 1 (ENT1), which are two key regulators of adenosine metabolism that have been shown to play critical roles in epileptogenesis. Collectively, our findings suggest that calponin‐3 may regulate astrocyte‐mediated adenosine metabolism and could represent a potential therapeutic target for epilepsy. Increased calponin‐3 expression correlates with astrocyte activation in epileptic mice, modulating adenosine metabolism regulators ADK and ENT1. Calponin‐3 overexpression increased susceptibility to epileptic seizures, while its downregulation reduces spontaneous recurrent seizures, identifying it as a potential therapeutic target for epilepsy.

Background Premature ovarian insufficiency (POI) is a condition defined as women developing menopause before 40 years old. These patients display low ovarian reserve at young age and difficulties to conceive even with assisted reproductive technology. The pathogenesis of ovarian insufficiency is not fully understood. Genetic factors may underlie most of the cases. Actin cytoskeleton plays a pivotal role in ovarian folliculogenesis. Calponin 2 encoded by the Cnn2 gene is an actin associated protein that regulates motility and mechanical signaling related cellular functions. Results The present study compared breeding of age-matched calponin 2 knockout ( Cnn2 -KO) and wild type (WT) mice and found that Cnn2- KO mothers had significantly smaller litter sizes. Ovaries from 4 weeks old Cnn2- KO mice showed significantly lower numbers of total ovarian follicles than WT control with the presence of multi-oocyte follicles. Cnn2- KO mice also showed age-progressive earlier depletion of ovarian follicles. Cnn2 expression is detected in the cumulus cells of the ovarian follicles of WT mice and colocalizes with actin stress fiber, tropomyosin and myosin II in primary cultures of cumulus cells. Conclusions The findings demonstrate that the loss of calponin 2 impairs ovarian folliculogenesis with premature depletion of ovarian follicles. The role of calponin 2 in ovarian granulosa cells suggests a molecular target for further investigations on the pathogenesis of POI and for therapeutic development.

Abstract Introduction/Objective Phyllodes tumor (PT), a biphasic fibroepithelial tumor typically found in the breast, is an exceedingly rare finding outside the mammary gland, with only about 160 cases reported to date. We describe a rare case of PT arising from anogenital mammary-like glands (AGMLG). Methods/Case Report A 68-year-old woman presented with a small perianal mass that was incidentally detected during hemorrhoidectomy procedure. It appeared as a pedunculated olive-sized mass on the perianal skin. A papillectomy was performed, and upon sectioning, a solid-cystic lesion measuring 2.0 x 1.4 x 0.9 cm was observed. Microscopic examination revealed a biphasic pattern comprising of glandular epithelium and a stromal component, with a predominance of the latter and together they formed leaf-like slits. These spaces were lined by a bilayered epithelium consisting of secretory (apocrine)-type cells and myoepithelial cells resembling mammary glandular epithelia. Focal clusters of benign glands, morphologically consistent with AGMLGs, were identified at the periphery of the tumor. Immunohistochemically, epithelial components reacted positively for GATA3, mammoglobin, CK7, estrogen receptor and progesterone receptor, while the myoepithelial cells were highlighted by calponin and p63. The AGMLGs in the periphery also stained for GATA3, estrogen receptor and progesterone receptor. The mitotic rate was low (1 to 2 per 50 high-power fields), without atypical mitoses. The lesion was diagnosed as a benign PT. Results (if a Case Study enter NA) NA Conclusion The current case highlights the importance of recognizing PT when it occurs at extra-mammary locations. The entity merits greater attention not only for its malignant potential but also due to the mystery surrounding its origin and the histogenetic link to breast tissue.

At present, clinical outcomes of pancreatic cancer patients are still poor. New therapeutic targets for pancreatic cancer are urgently needed. Previous studies have indicated that Microtubule Associated Monooxygenase, Calponin and LIM Domain Containing 2 (MICAL2) is highly expressed in many tumors and promotes tumor progression. However, the role played by MICAL2 in pancreatic cancer remains unclear. Based on gene expression and clinical information from multiple datasets, we used comprehensive bioinformatics analysis in combination with tissue microarray to explore the function and clinical value of MICAL2. The results showed that MICAL2 was highly expressed in pancreatic cancer tissue and exhibited potential diagnostic capability. High expression of MICAL2 was also associated with poor prognosis and acted as an independent prognostic factor. MICAL2, mainly expressed in fibroblasts of pancreatic cancer, was closely related to metastasis and immune-related features, such as epithelial-mesenchymal transformation, extracellular cell matrix degradation, and inflammatory response. Furthermore, higher MICAL2 expression in pancreatic cancer was also associated with an increase in cancer-associated fibroblasts as well as M2 macrophage infiltration, and a reduction in CD8 + T cell infiltration, thereby facilitating the formation of an immunosuppressive microenvironment. Our results helped elucidate the clinical value and function in metastasis and immunity of MICAL2 in pancreatic cancer. These findings provided potential clinical strategies for diagnosis, targeted therapy combination immunotherapy, and prognosis in patients with pancreatic cancer.

Smooth muscle cell (SMC) contraction and vascular tone are modulated by phosphorylation and multiple modifications of the thick filament, and thin filament regulation of SMC contraction has been reported to involve extracellular regulated kinase (ERK). Previous studies in ferrets suggest that the actin‐binding protein, calponin 1 (CNN1), acts as a scaffold linking protein kinase C (PKC), Raf, MEK and ERK, promoting PKC‐dependent ERK activation. To gain further insight into this function of CNN1 in ERK activation and the regulation of SMC contractility in mice, we generated a novel Calponin 1 knockout mouse (Cnn1 KO) by a single base substitution in an intronic CArG box that preferentially abolishes expression of CNN1 in vascular SMCs. Using this new Cnn1 KO mouse, we show that ablation of CNN1 has two effects, depending on the cytosolic free calcium level: (1) in the presence of elevated intracellular calcium caused by agonist stimulation, Cnn1 KO mice display a reduced amplitude of stress and stiffness but an increase in agonist‐induced ERK activation; and (2) during intracellular calcium depletion, in the presence of an agonist, Cnn1 KO mice exhibit increased duration of SM tone maintenance. Together, these results suggest that CNN1 plays an important and complex modulatory role in SMC contractile tone amplitude and maintenance.

Benign prostatic hyperplasia (BPH) includes epithelial, stromal and mixed hyperplasia, but their specific contributions to voiding symptoms and prostate volume (PV) are unknown. Here, we examined relationships of symptoms and PV with stromal and epithelial markers in patients undergoing laser enucleation for BPH. Tissues were obtained from holmium or thulium laser enucleation of the prostate (n = 146 patients). Expressions of the smooth muscle marker calponin-1 (CNN1) and the glandular-epithelial cell marker keratin-19 (KRT19) were assessed by RT-PCR and Western blot, and analyzed for correlation with international prostate symptom score (IPSS), maximum urinary flow rate (Qmax), and PV. The ratio of CNN1/KRT19 mRNA correlated positively with Qmax (r = 0.3809, p = 0.0263), and by trend negatively with IPSS (r = -0.2161, p = 0.0944). Accordingly, the IPSS increased with keratin protein expression (r = 0.4244, p = 0.0307), while the Qmax tended to correlate negatively with keratin expression (r = -0.2058, p = 0.4999). PV correlated negatively with CNN1 mRNA expression (r = -0.205, p = 0.0405). The inverse correlation of CNN1 with PV persisted in patients without catheterization (r = -0.2568, p = 0.0457), but was lacking in catheterized patients after separated analyses. Voiding symptoms in patients undergoing laser enucleation for BPH aggravate with increasing keratin content. Symptoms in patients needing surgery for BPH depend rather on glandular-epithelial hyperplasia, but not on stromal hyperplasia, what might explain why these patients are refractory to treatment with α1-blockers.

Branching microtubule nucleation is a key mechanism for mitotic and meiotic spindle assembly and requires the hetero-octameric augmin complex. Augmin recruits the major microtubule nucleator, the γ-tubulin ring complex, to pre-existing microtubules to direct the formation of new microtubules in a defined orientation. Although recent structural work has provided key insights into the structural organization of augmin, molecular details of its interaction with microtubules remain elusive. Here, we identify the minimal conserved microtubule-binding unit of augmin across species and demonstrate that stable microtubule anchoring is predominantly mediated via the calponin homology (CH) domain in Dgt6/HAUS6. Comparative sequence and functional analyses in vitro and in vivo reveal a highly conserved functional role of the HAUS6 CH domain in microtubule binding. Using cryo-electron microscopy and molecular dynamics simulations in combination with AlphaFold structure predictions, we show that the D. melanogaster Dgt6/HAUS6 CH domain binds microtubules at the inter-protofilament groove between two adjacent β-tubulin subunits and thereby orients augmin on microtubules. Altogether, our findings reveal how augmin binds microtubules to pre-determine the branching angle during microtubule nucleation and facilitate the rapid assembly of complex microtubule networks. Augmin is essential for microtubule nucleation during cell division. This study reveals how the conserved calponin homology domain of the augmin subunit HAUS6 binds to microtubules to orient augmin for microtubule branching.

Background: Emerging evidence has suggested a pro-oncogenic role of calponin 1 (CNN1) in the initiation of a variety of cancers. Despite this, CNN1 remains unknown in terms of its effects and mechanisms on angiogenesis, prognosis, and immunology in cancer. Materials and Methods: The expression of CNN1 was extracted and analyzed using the TIMER, UALCAN, and GEPIA databases. Meanwhile, we analyzed the diagnostic value of CNN1 by using PrognoScan and Kaplan–Meier plots. To elucidate the value of CNN1 in immunotherapy, we used the TIMER 2.0 database, TISIDB database, and Sangerbox database. Gene set enrichment analysis (GSEA) was used to analyze the expression pattern and bio-progression of CNN1 and the vascular endothelium growth factor (VEGF) in cancer. The expressions of CNN1 and VEGF in gastric cancer were confirmed using immunohistochemistry. We used Cox regression analysis to investigate the association between pathological characteristics, clinical prognosis, and CNN1 and VEGF expressions in patients with gastric cancer. Results: CNN1 expression was higher in normal tissues than it was in tumor tissues of most types of cancers. However, the expression level rebounds during the development of tumors. High levels of CNN1 indicate a poor prognosis for 11 tumors, which include stomach adenocarcinoma (STAD). There is a relationship between CNN1 and tumor-infiltrating lymphocytes (TILs), and the marker genes NRP1 and TNFRSF14 of TILs are significantly related to CNN1 expression in gastric cancers. The GSEA results confirmed the lower expression of CNN1 in tumors when compared to normal tissues. However, CNN1 again showed an increasing trend during tumor development. In addition, the results also suggest that CNN1 is involved in angiogenesis. The immunohistochemistry results validated the GSEA result (take gastric cancer as an example). Cox analysis suggested that high CNN1 expression and high VEGF expression are closely associated with poor clinical prognosis. Conclusion: Our study has shown that CNN1 expression is aberrantly elevated in various cancers and positively correlates with angiogenesis and the immune checkpoint, contributing to cancer progression and poor prognosis. These results suggest that CNN1 could serve as a promising candidate for pan-cancer immunotherapy.

Abstract Introduction/Objective Chondroid syringoma (CS) is an uncommon, benign mixed tumor originating from the sweat gland. Its incidence rate is extremely low, estimated to be less than 0.01%. CS predominantly affects adult males and shows a preference for the head and neck region. Typically, the size of the lesion is smaller than 1.0 cm, and it presents as a solitary, painless, subcutaneous nodule that is soft to firm, non-ulcerative, and gradually progressive. Histologically, CS is characterized by a neoplasm composed of epithelial and myoepithelial cells, which are surrounded by a myxomatous, pseudochondromatous, or hyaline stroma containing mucous secretions. Although atypia is rare in CS, there is a potential for it to undergo malignant transformation. Methods/Case Report A 49-year-old man presented with a slowly growing mass on the medial canthus that had been present for 6 months. Examination revealed a tender, mobile nodule measuring 1.1 cm. An MRI of the head confirmed a subcutaneous lesion without involvement of deeper structures. Excisional biopsy of the lesion suggested adnexal carcinoma with involvement of the margins. The patient underwent Mohs surgery.Histopathology revealed localized basaloid epithelial proliferation forming solid sheets, trabecular, ductal structures with, chondroid myxoid stroma. Immunohistochemically, the tumor cells of solid sheets and trabeculae were positive for CK5/6, P63, and Vimentin, whereas the cells were focally positive for S100, Calponin, alpha Actin, and SOX10. Also, ductal epithelial cells were highlighted with CK7, Cam5.2, EMA, and CEA. Ki-67 showed 1–5% reactivity. A few satellite nodules with infiltrative margins were seen. The atypical features, including cell atypia and a focal infiltrating border, suggest atypical chondroid syringoma. This tumor is considered a low-grade lesion, and no unequivocal evidence of malignancy has been identified. Results (if a Case Study enter NA) NA Conclusion Awareness of chondroid syringoma as a rare cause of eyelid lesions is important because although it is a benign neoplasm, incomplete excision can lead to recurrence or malignant transformation. Chondroid syringoma rarely exhibits atypia but can convert to the malignant spectrum. When malignant, it has a significant potential for recurrence, metastasis, and even death. Due to the tumor's rarity, making an accurate preoperative diagnosis can be challenging. Therefore, the possibility of chondroid syringoma should be kept in mind when dealing with a gradually progressive, soft to firm subcutaneous swelling.

Endothelial cells play an important role in maintenance of the vascular system and the repair after injury. Under proinflammatory conditions, endothelial cells can acquire a mesenchymal phenotype by a process named endothelial-to-mesenchymal transition (EndMT), which affects the functional properties of endothelial cells. Here, we investigated the epigenetic control of EndMT. We show that the histone demethylase JMJD2B is induced by EndMT-promoting, proinflammatory, and hypoxic conditions. Silencing of JMJD2B reduced TGF-β2-induced expression of mesenchymal genes, prevented the alterations in endothelial morphology and impaired endothelial barrier function. Endothelial-specific deletion of JMJD2B in vivo confirmed a reduction of EndMT after myocardial infarction. EndMT did not affect global H3K9me3 levels but induced a site-specific reduction of repressive H3K9me3 marks at promoters of mesenchymal genes, such as Calponin (CNN1), and genes involved in TGF-β signaling, such as AKT Serine/Threonine Kinase 3 (AKT3) and Sulfatase 1 (SULF1). Silencing of JMJD2B prevented the EndMT-induced reduction of H3K9me3 marks at these promotors and further repressed these EndMT-related genes. Our study reveals that endothelial identity and function is critically controlled by the histone demethylase JMJD2B, which is induced by EndMT-promoting, proinflammatory, and hypoxic conditions, and supports the acquirement of a mesenchymal phenotype.