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Proliferation is an important characteristic of life, and many signaling pathways participate in this complicated process. The MAPK/Erk pathway is a classic pathway in cell proliferation. In this study, expression levels of key factors in the MAPK/Erk pathway were measured to assess the proliferation level among normal skin, physiological scar, and keloid tissue. Thirty patients were selected randomly from the Department of Plastic Surgery at Peking Union Medical College Hospital from January 2019 to December 2020. Histological appearance and fiber tissue content were observed by Hematoxylin and eosin staining and Masson staining. Expression levels of key factors in the MAPK/Erk pathway (ATF2, c-Jun, c-Myc, p38 and STAT1) and relative proteins (HIF-1α and PCNA) in tissues were detected by immunohistochemistry and analyzed as the percentage of positively stained cells in both the tissue epidermis and dermis. Western blot was used for quantitative analysis of the above factors. In results, keloid tissue showed a significantly higher fiber and less cell content. In the immunohistochemical result, higher expression of key factors was observed in the epidermis than in the dermal layer, and the expression of all factors was increased remarkably in keloid tissue. In western blot analysis, all factors (except STAT1) showed higher expression in keloid tissue. In our former research, keloid showed similar apoptosis level as physiological scar and normal skin. On combining our former conclusion and results in this study, an imbalance condition between the high proliferation level and normal apoptosis level may lead to the growth characteristics of keloid. [ABSTRACT FROM AUTHOR]

There is increasing evidence concerning the occurrence of malignant lymphoma among people suffering from Mikulicz disease, also termed benign lymphoepithelial lesion (BLEL) and immunoglobulin G4-associated disease. However, the underlying molecular mechanism of the malignant transformation remains unclear. The present study aimed to investigate the gene expression profile between BLEL and malignant lymphoepithelial lesion (MLEL) conditions using tissue microarray analysis, to identify genes and pathways which may be associated with the risk of malignant transformation. Comparing gene expression profiles between BLEL tissues (n=13) and MLEL (n=14), a total of 1,002 differentially expressed genes (DEGs) were identified including 364 downregulated and 638 upregulated DEGs in BLEL. The downregulated DEGs in BLEL were frequently associated with immune-based functions, immune cell differentiation, proliferation and survival, and metabolic functions, whereas the upregulated DEGs were primarily associated with organ, gland and tissue developmental processes. The B cell receptor signaling pathway, the transcription factor p65 signaling pathway, low affinity immunoglobulin γ Fc region receptor II-mediated phagocytosis, the high affinity immunoglobulin e receptor subunit γ signaling pathway and Epstein-Barr virus infection, and pathways in cancer, were the pathways associated with the downregulated DEGs. The upregulated DEGs were associated with three pathways, including glutathione metabolism, salivary secretion and mineral absorption pathways. These results suggested that the identified signaling pathways and their associated genes may be crucial for understanding the molecular mechanisms underlying malignant transformation from BLEL, and they may be considered to be markers for predicting malignancy among the BLEL group. [ABSTRACT FROM AUTHOR]

Androgen signalling through the androgen receptor (AR) is essential for prostate tumorigenesis. However, androgen signalling pathways also interact with other growth factor-mediated signalling pathways to regulate the prostatic cell cycle, differentiation, apoptosis and proliferation in the initiation and progression of prostate cancer. Insulin-like growth factor 1 (IGF1) is one of the most prominent growth factors in prostate tumorigenesis. Clinical and experimental evidence has demonstrated that IGF1 signalling supports both androgen-dependent and androgen-independent prostate tumorigenesis, suggesting that improved understanding of the interactions between the IGF1 and androgen axes might aid the development of new therapeutic strategies. Available data have shown a dynamic role of androgen-AR signalling in the activation of IGF1-signalling pathways by augmenting transcription of the IGF1 receptor in prostatic basal epithelial cells and by increasing IGF1 secretion through the suppression of IGF-binding protein 3 expression in prostatic stromal cells. In turn, IGF1 stimulates Wnt-β-catenin signalling in prostatic basal progenitors to promote prostatic oncogenic transformation and prostate cancer development. These findings highlight the cooperative, autocrine and paracrine interactions that underlie the oncogenic effects of androgens and IGF1 and open up new opportunities for therapeutic targeting., (© 2024. Springer Nature Limited.)

Androgens and androgen receptor (AR) mediated signaling pathways are essential for prostate development, morphogenesis, growth, and regeneration. Early tissue recombination experiments showed that AR-deficient urogenital sinus mesenchyme combined with intact urogenital sinus epithelium failed to develop into a prostate, demonstrating a stem cell niche for mesenchymal AR in prostatic development. Androgen signaling remains critical for prostate maturation and growth during postnatal stages. Importantly, most primary prostate cancer (PCa) cells express the AR, and aberrant activation of AR directly promotes PCa development, growth, and progression. Therefore, androgen deprivation therapy (ADT) targeting the AR in PCa cells is the main treatment for advanced PCa. However, it eventually fails, leading to the development of castration-resistant PCa, an incurable disease. Given these clinical challenges, the oncogenic AR action needs to be reevaluated for developing new and effective therapies. Recently, an essential niche role of stromal AR was identified in regulating prostate development and tumorigenesis. Here, we summarize the latest discoveries of stromal AR niches and their interactions with prostatic epithelia. In combination with emerging clinical and experimental evidence, we specifically discuss several important and long-term unanswered questions regarding tumor niche roles of stromal AR and highlight future therapeutic strategies by co-targeting epithelial and stromal AR for treating advanced PCa., (© 2024. The Author(s).)

Apoptosis is a form of programmed cell death that occurs in multicellular organisms. Fibroblasts are the main cellular ingredients in keloid tissue, which has a relatively low apoptosis level. A natural metabolite of estradiol, 2-Methoxyestradiol (2ME2) exerts a pro-apoptotic effect on tumor cells. In this study, the expression levels of key factors in the apoptosis pathway and the expression level of the proliferating cell nuclear antigen (PCNA) were measured to assess the levels of apoptosis and proliferation in both normal skin fibroblasts and keloid fibroblasts. Twelve samples were obtained from 12 patients: 6 keloid patients and 6 non-keloid patients. All 12 of the patients were randomly selected from the Department of Plastic Surgery at Peking Union Medical College Hospital from June 2016 to December 2016. After cell culture, fibroblasts were divided into the following 6 groups: normal skin fibroblasts (S); keloid fibroblasts (K); keloid fibroblasts treated with 2ME2 (2ME2); keloid fibroblasts treated with DMSO (DMSO); keloid fibroblasts treated with the caspase inhibitor Ac-DEVD-CHO (IN); and keloid fibroblasts treated with both Ac-DEVD-CHO and 2ME2 (IN+2ME2). Fibroblasts at up to passage 3 were used for analysis. Cell activity was measured by the cell counting kit-8. TUNEL staining was used to observe the cell apoptotic morphology. The key apoptosis factors (caspase-3, caspase-8, caspase-9, Bcl-2, Bax, and cytochrome-c) and PCNA expression levels were detected by immunofluorescence analysis and Western blotting. A certain concentration of 2ME2 was also used in group S to evaluate the toxicity. Compared with that in the other groups, 2ME2 significantly inhibited cell activity and led to apoptotic appearance of fibroblasts. In protein analysis, 2ME2 remarkably increased the expression of apoptosis factors and decreased the PCNA expression. Apoptosis levels were reduced by both the caspase inhibitor and 2ME2; thus indicating that the pro-apoptosis effect of 2ME2 was achieved through a caspase-dependent mechanism in keloid fibroblasts. Toxicity assessment showed that 2ME2 had a very low influence on normal skin fibroblasts. 2ME2, considered to be a new promising type of chemotherapy drug, exerts a pro-apoptosis effect by regulating the caspase family and an anti-proliferation effect towards keloid fibroblasts, and it presents low toxicity towards normal fibroblasts in vitro ., Competing Interests: None.

Aim: To reveal the cytokines involved in idiopathic orbital inflammatory disease (IOID) and the relationship between Th17 cells, IgE and IOID pathogenesis., Methods: Whole blood samples were processed immediately after collection and serological IgG4, IgG, and IgE antibodies were tested using ELISA. IOID and orbital cavernous hemangioma (CH) tissue samples underwent Bio-Plex multiplex cytokine detection. Hematoxylin-Eosin (HE) staining of all paraffin samples suggested the histological features of IOIDs, and expressions of IgG4 and IL-17A in affected tissues were detected by immunohistochemistry., Results: Among 40 IOID plasma samples, 52.5% (21/40) were positive for IgG4 and 25% (10/40) were positive for IgE. Overlapped IgG4 or IgE positive samples accounted for 22.5% (9/40). Therefore, IOID samples were separated into three groups. The IgE+/IgG4+ group had a relevantly lower level of pro-inflammatory cytokine expression. IL-4 (Th2 cell related), IL-10 and TGF-β1 (Treg cell immunity related) were elevated in all three groups. Some of the Th17 cell related cytokines ( i.e. IL-17A/F, IL-25, IL-23, and IL-33) displayed higher expression levels in the IgE-/IgG4- group compared to the other two groups., Conclusion: We discovered an IgG4-IgE co-positive group as well as Th17 cell immune involvement in IgG4-IgE co-negative subgtroup in IOID for the first time. The pathogenesis of IOID could differ from different subgroups according to the IgG4 and IgE detection. Therefore, we recommend that, Treatment stratagy should be made according to the clinical assessment of IgG4-IgE and Th17 profile detection.

Apoptosis is a process of programmed cell death that occurs in multicellular organisms. The mitochondrial pathway plays a paramount role in apoptosis. In this study, the expression levels of key factors in the mitochondrial pathway and the cell proliferation factor (PCNA) were measured to evaluate the level of apoptosis and proliferation in keloid scars, physiological scars and normal skin tissue. Thirty samples were taken from 30 patients: 10 keloid patients, 10 physiological scar patients and 10 patients without obvious scarring. All 30 patients were selected randomly from the Department of Plastic Surgery at Peking Union Medical College Hospital from June 2016 to December 2016. Hematoxylin and eosin staining and Masson staining were used to observe the differences in histology and fiber tissue content. Mitochondrial pathway factors (caspase-3, caspase-8, caspase-9, Bcl-2, Bax, cytochrome-c) and PCNA expression levels were detected by immunohistochemistry and were analyzed as the percentage of positively stained cells in the epidermis and dermis. Relative protein expression levels were measured by western blotting. Compared with physiological scars and normal skin tissue, keloid tissue had an increase in fiber number and decrease in cell content. In our immunohistochemical and western blot analyses, all tissue types showed similar expression levels of the mitochondrial pathway factors. However, the percentage of PCNA-positive cells and the relative protein expression level of PCNA were significantly higher in keloid tissue. Keloid has a similar apoptosis level as physiological scars and normal skin but has a higher expression of PCNA, indicating that keloid scars have high levels of proliferation and normal apoptosis., Competing Interests: None.