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In addition, FGF2 upregulated ONECUT2 expression through the FGFR1/ERK/ELK1 pathway, which formed an FGF2-FGFR1-ONECUT2 positive feedback loop. Knockdown of ONECUT2 inhibited FGF2-induced HCC metastasis. Furthermore, the combination of FGFR1 inhibitor PD173074 with ACLY inhibitor ETC-1002 markedly suppressed ONECUT2-mediated HCC metastasis. In summary, ONECUT2 was a potential prognostic biomarker in HCC and targeting this oncogenic signaling pathway may provide an efficient therapeutic strategy against HCC metastasis.The microrchidia (MORC) family of proteins is a highly conserved nuclear protein superfamily, whose members contain common domain structures (GHKL-ATPase, CW-type zinc finger and coiled-coil domain) yet exhibit diverse biological functions. Despite the advancing research in previous decades, much of which focuses on their role as epigenetic regulators and in chromatin remodeling, relatively little is known about the role of MORCs in tumorigenesis and pathogenesis. MORCs were first identified as epigenetic regulators and chromatin remodelers in germ cell development. Currently, MORCs are regarded as disease genes that are involved in various human disorders and oncogenes in cancer progression and are expected to be the important biomarkers for diagnosis and treatment. A new paradigm of expanded MORC family function has raised questions regarding the regulation of MORCs and their biological role at the subcellular level. Here, we systematically review the progress of researching MORC members with respect to their domain architectures, diverse biological functions, and distribution characteristics and discuss the emerging roles of the aberrant expression or mutation of MORC family members in human disorders and cancer development. Furthermore, the illustration of related mechanisms of the MORC family has made MORCs promising targets for developing diagnostic tools and therapeutic treatments for human diseases, including cancers.Our society is experiencing more stress than ever before, leading to both negative psychiatric and physical outcomes. Chronic stress is linked to negative long-term health consequences, raising the possibility that stress is related to accelerated aging. In this study, we examine whether resilience factors affect stress-associated biological age acceleration. Recently developed "epigenetic clocks" such as GrimAge have shown utility in predicting biological age and mortality. Here, we assessed the impact of cumulative stress, stress physiology, and resilience on accelerated aging in a community sample (N = 444). Cumulative stress was associated with accelerated GrimAge (P = 0.0388) and stress-related physiologic measures of adrenal sensitivity (Cortisol/ACTH ratio) and insulin resistance (HOMA). After controlling for demographic and behavioral factors, HOMA correlated with accelerated GrimAge (P = 0.0186). Remarkably, psychological resilience factors of emotion regulation and self-control moderated these relationships. Emotion regulation moderated the association between stress and aging (P = 8.82e-4) such that with worse emotion regulation, there was greater stress-related age acceleration, while stronger emotion regulation prevented any significant effect of stress on GrimAge. Self-control moderated the relationship between stress and insulin resistance (P = 0.00732), with high self-control blunting this relationship. In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge Acceleration even while accounting for demographic, physiologic, and behavioral covariates. These results demonstrate that cumulative stress is associated with epigenetic aging in a healthy population, and these associations are modified by biobehavioral resilience factors.Spinal cord ischemia-reperfusion injury (SCIRI) is a serious trauma that can lead to loss of sensory and motor function. Ferroptosis is a new form of regulatory cell death characterized by iron-dependent accumulation of lipid peroxides. Ferroptosis has been studied in various diseases; however, the exact function and molecular mechanism of ferroptosis in SCIRI remain unknown. In this study, we demonstrated that ferroptosis is involved in the pathological mechanism of SCIRI. Inhibition of ferroptosis could promote the recovery of motor function in mice after SCIRI. In addition, we found that ubiquitin-specific protease 11 (USP11) was significantly upregulated in neuronal cells after hypoxia-reoxygenation and in the spinal cord in mice with I/R injury. Knockdown of USP11 in vitro and KO of USP11 in vivo (USP11-/Y) significantly decreased neuronal cell ferroptosis. In mice, this promotes functional recovery after SCIRI. In contrast, in vitro, USP11 overexpression leads to classic ferroptosis events. Overexpression of USP11 in mice resulted in increased ferroptosis and poor functional recovery after SCIRI. Interestingly, upregulating the expression of USP11 also appeared to increase the production of autophagosomes and to cause substantial autophagic flux, a potential mechanism through which USP11 may enhance ferroptosis. The decreased autophagy markedly weakened the ferroptosis mediated by USP11 and autophagy induction had a synergistic effect with USP11. Importantly, USP11 promotes autophagy activation by stabilizing Beclin 1, thereby leading to ferroptosis. In conclusion, this study shows that ferroptosis is closely associated with SCIRI, and that USP11 plays a key role in regulating ferroptosis and additionally identifies USP11-mediated autophagy-dependent ferroptosis as a promising target for the treatment of SCIRI.In TNF signaling, ubiquitination of RIP1 functions as an early cell-death checkpoint, which prevents the spatial transition of the signaling complex from complex-I to death-inducing complex-II. Here, we report that ankyrin repeat domain 13a (ANKRD13a) acts as a novel component of complex-II to set a higher signal threshold for the cytotoxic potential of TNF. ANKRD13a deficiency is sufficient to turn the response to TNF from survival to death by promoting the formation of complex-II without affecting NF-κB activation. ANKRD13a binds to ubiquitinated-RIP1 via its UIM, and subsequently limits the association of FADD and caspase-8 with RIP1. Moreover, high ANKRD13a expression is inversely correlated with apoptotic phenotypes in ovarian cancer tissues and is associated with poor prognosis. Our work identifies ANKRD13a as a novel gatekeeper of the early cell-death checkpoint, which may function as part of an escape mechanism from cell death in some cancers.PD-1/PD-L1 inhibitors have shown clinical benefit in lung adenocarcinoma (LUAD). However, the immunotherapy strategy is less effective in patients with EGFR-activating mutations (EGFR MT). Studies showed that besides low expression of PD-L1, the absence of TILs and distinct expression profile of immune checkpoint molecules might be associated with low response of the patient subset. In this study, we first compared CD8A, GZMB and PRF1 mRNA levels in different LUAD subtypes harboring different driver mutations by dataset analyses and investigated the association between 15 well-defined B7-CD28 family members and driver mutations. The results showed that the decreases in the density and function of CD8+ TILs, CD274 (PD-L1 gene), and CD86 and increases in VTCN1 (B7-H4 gene) and HHLA2 were associated with LUAD with EGFR-activating mutations. Immunohistochemical staining studies further supported that PD-L1 was downregulated and B7-H4 was upregulated in the subtype. see more Furthermore, PD-L1 expression was positively associated with levels of CD8A and granzyme B, while B7-H4 expression was negatively associated with granzyme B levels. In lung cancer cell lines, EGFR-activating mutations effectively upregulated B7-H4 and downregulated PD-L1. MEK/ERK-pathway activation upregulated B7-H4, and PI3K/Akt activation upregulated PD-L1. EGFR 19Del mutation was associated with inhibition of CD8+ T-cell function, while knocking down B7-H4 could reverse the inhibition, and further showed tumor-growth inhibition and longer survival in vivo. Taken together, this study shed light on that B7-H4 might be an alternative immune-checkpoint molecule and a potential therapeutic target for LUAD with EGFR MT.Gastric amphicrine carcinoma, in which endocrine and epithelial cell features are present within the same cells, is often confused with gastric mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). In this study, we performed high-resolution copy number (CN) profiling and whole exome sequencing (WES) of formalin-fixed and paraffin-embedded (FFPE) tissues from eight gastric amphicrine carcinomas and compared the molecular features with those of the adenocarcinoma and neuroendocrine carcinoma (NEC) components of eight gastric MiNENs. The most frequent high-level CN variant was a gain of 20q13.12-20q13.2, which was found in five gastric amphicrine carcinomas. Amplifications of MYT1, NTSR1, and ZBTB46 located in this region were demonstrated by qPCR and immunohistochemistry. The CN characteristics of gastric amphicrine carcinomas were different from those of MiNENs in hierarchical clustering analysis, suggesting that amphicrine carcinoma is a separate entity from MiNEN. Moreover, the CN level of C5 (complement C5) was higher in amphicrine carcinoma than in both the adenocarcinoma and the NEC component of MiNENs, suggesting that amphicrine carcinomas might benefit more from C5 inhibitors than MiNENs. WES showed frequent somatic mutations of TP53 (37.5%, 3/8) and APC (25.0%, 2/8) in amphicrine carcinoma. There were no specific mutation characteristics to distinguish amphicrine carcinoma from MiNEN. An integrated KEGG pathway analysis showed that the estrogen signaling pathway was enriched in amphicrine carcinomas, which might be associated with the high morbidity of male patients. In summary, our study revealed the unique CN and mutation characteristics of gastric amphicrine carcinoma and differentiated these characteristics from those of MiNENs. These data provide a foundation for further studies on the development and progression of amphicrine carcinoma.Triple-negative breast cancer (TNBC) with high tumour-infiltrating lymphocytes (TILs) has been associated with a promising prognosis. To better understand the prognostic value of immune cell subtypes in TNBC, we characterised TILs and the interaction between tumour cells and immune cell subtypes. A total of 145 breast cancer tissues were stained by multiplex immunofluorescence (mIF), including panel 1 (PD-L1, PD-1, CD3, CD8, CD68 and CK) and panel 2 (Foxp3, Granzyme B, CD45RO, CD3, CD8 and CK). Phenotypes were analysed and quantified by pathologists using InForm software. We found that in the ER-negative (ER less then 1% and HER2-negative) group and the ER/PR-low positive (ER 1-9% and HER2-negative) group, 11.2% and 7.1% of patients were PD-L1+ by the tumour cell score, 29.0% and 28.6% were PD-L1+ by the modified immune cell score and 30.8% and 32.1% were PD-L1+ by the combined positive score. We combined ER-negative and ER/PR-low positive cases for the survival analysis since a 10% cut-off is often used in biomarkers in TNBC.