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Objective: Distraction osteogenesis (DO) has been widely used to treat bone defects as its effectiveness in bone regeneration. Currently, distraction devices for establishing DO models are mainly developed for rats or large animals. However, a mouse DO model is in great need for in-depth mechanistic investigations using various transgenic mice. The current study reports the development of a reproducible murine DO model. Methods: A mini-titanium lengthener was designed and fabricated. The mini-lengthener was applied on the murine femur with four threaded pins using a designed clamp as the drilling and insertion guide. After transverse osteotomy using a Gigli saw, and after 5 days of latency, DO procedures started at 0.3 mm/day for 10 days, and the consolidation period was left for 28 days. The bone formation was monitored by radiography and histology. Potential effects on animal locomotion during DO were also measured by behavior tests. Results: Separated bone segments maintained good alignment during the entire DO phases. New bone formation was found as early as the end of the distraction phase. Active bone remodeling was found between the separated bone segments at late distraction and early consolidation phases. At the mature consolidation phase, bone remodeling was mainly observed in the contact cortical bone. Mice underwent DO procedure did not have significant impairment in their locomotion. Conclusion: We have successfully developed a murine femoral DO model, which may be used to study the biological processes of DO. We also developed the mini-lengthener and the guide clamp to ensure the standardization and reproducibility of the mouse DO model.The translational potential of this article: Current study reports the development of a murine femoral DO model. A well-established murine DO model will facilitate further investigations of the biological mechanisms of DO in various transgenic and normal mice.

Background & Aims: Exploiting key regulators responsible for hepatocarcinogenesis is of great importance for the prevention and treatment of hepatocellular carcinoma (HCC). However, the key players contributing to hepatocarcinogenesis remain poorly understood. We explored the molecular mechanisms underlying the carcinogenesis and progression of HCC for the development of potential new therapeutic targets. Methods: The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and Genotype-Tissue Expression (GTEx) databases were used to identify genes with enhanced expression in the liver associated with HCC progression. A murine liver-specific Ftcd knockout (Ftcd-LKO) model was generated to investigate the role of formimidoyltransferase cyclodeaminase (FTCD) in HCC. Multi-omics analysis of transcriptomics, metabolomics, and proteomics data were applied to further analyse the molecular effects of FTCD expression on hepatocarcinogenesis. Functional and biochemical studies were performed to determine the significance of loss of FTCD expression and the therapeutic potential of Akt inhibitors in FTCD-deficient cancer cells. Results: FTCD is highly expressed in the liver but significantly downregulated in HCC. Patients with HCC and low levels of FTCD exhibited worse prognosis, and patients with liver cirrhosis and low FTCD levels exhibited a notable higher probability of developing HCC. Hepatocyte-specific knockout of FTCD promoted both chronic diethylnitrosamine-induced and spontaneous hepatocarcinogenesis in mice. Multi-omics analysis showed that loss of FTCD affected fatty acid and cholesterol metabolism in hepatocarcinogenesis. Mechanistically, loss of FTCD upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element–binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis. Conclusions: Taken together, we identified a FTCD-regulated lipid metabolic mechanism involving PPARγ and SREBP2 signaling in hepatocarcinogenesis and provide a rationale for therapeutically targeting of HCC driven by downregulation of FTCD. Impact and implications: Exploiting key molecules responsible for hepatocarcinogenesis is significant for the prevention and treatment of HCC. Herein, we identified formimidoyltransferase cyclodeaminase (FTCD) as the top enhanced gene, which could serve as a predictive and prognostic marker for patients with HCC. We generated and characterised the first Ftcd liver-specific knockout murine model. We found loss of FTCD expression upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element–binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis, and provided a rationale for therapeutic targeting of HCC driven by downregulation of FTCD.

Circular RNAs (circRNA) is a class of non-coding RNAs that can regulate gene translation and function. Here the authors show that a circRNA, circNDUFB2, is downregulated in non-small cell lung cancer tissues, and likely contributes to anti-tumor immunity by regulating both degradation of oncoproteins and induction of innate immunity.

Abstract Background Biological role and clinical significance of circular RNAs (circRNAs) remain largely unknown. Herein, we aimed to investigate biological function, molecular mechanism, and clinical significance of a circular RNA FOXM1 (circFOXM1) in non-small cell lung cancer (NSCLC). Methods Expression of circFOXM1 was measured in 48 paired samples of NSCLC by qRT-PCR. Functional roles of circFOXM1 on tumor cells were explored by in vitro and in vivo assays. Transcriptome sequencing was employed to screen the molecules involved in circFOXM1 regulatory network. RNA immunoprecipitation, luciferase analysis, RNA pull-down, and rescue assay were used to investigate potential mechanisms of circFOXM1. Results We found that circFOXM1 was significantly upregulated in NSCLC tissues, and its upregulation was positively correlated with advanced clinical stage and poor prognosis of NSCLC patients. Gain or loss-of-function assay showed that circFOXM1 promoted cell proliferation and cell cycle progression. In vivo assays showed that silencing circFOXM1 inhibited xenograft tumor growth. Mechanically, transcriptome sequencing data indicated that silencing circFOXM1 led to the downregulation of cell cycle-related mRNAs. RNA pull-down and dual-luciferase reporter assay suggested that circFOXM1 could bind to miR-614, and FAM83D was an essential gene involved in the circFOXM1/miR-614 regulatory network. Conclusions circFOXM1promotes NSCLC progression by interacting with miR-614 and thus inactivating the function of miR-614, which will further release the suppression of FAM83D. circFOXM1/miR-614/FAM83D regulatory network may serve as a potential therapeutic target for NSCLC patients.

Musculoskeletal diseases, such as osteoporosis and sarcopenia, are tremendous and growing public health concerns. Considering the intimate functional relationship between muscle and bone throughout development, growth, and aging, muscle provides the primary source of skeletal loading through contraction force. However, significant gaps exist in our knowledge regarding the role of muscle in bone homeostasis and little is known regarding the mechanism through which the central nervous system responds and regulates unloading-induced bone loss. Here, we showed that the basolateral amygdala (BLA) and medial part of the central nucleus (CeM) are anatomically connected with the musculoskeletal system. Unloading-induced bone loss is accompanied by a decrease in serum semaphorin 3A (Sema3A) levels as well as sensory denervation. In vivo fiber photometry recordings indicated that the mechanical signal is integrated by the BLA and CeM within 24 h and subsequently regulates bone remodeling. Moreover, chemogenetic activation of BLACaMKII neurons mitigates severe bone loss caused by mechanical unloading via increased serum levels of Sema3A and sensory innervation. These results indicate that the BLA integrates the mechanosensory signals rapidly and mediates the systemic hormonal secretion of Sema3A to maintain bone homeostasis.

Circular RNAs are known to regulate cancer. Here, the authors show that the circular RNA circTP63 promotes lung squamous cell carcinoma by competing with endogenous RNA to upregulate FOXM1.

Ferroptosis, a unique form of iron-dependent cell death triggered by lipid peroxidation accumulation, holds great promise for cancer therapy. Despite the crucial role of GPX4 in regulating ferroptosis, our understanding of GPX4 protein regulation remains limited. Through FACS-based genome-wide CRISPR screening, we identified MALT1 as a regulator of GPX4 protein. Inhibition of MALT1 expression enhances GPX4 ubiquitination-mediated degradation by up-regulating the E3 ubiquitin ligase RC3H1. Using both rescue assays and functional genetic screening, we demonstrate that pharmacologically targeting MALT1 triggers ferroptosis in liver cancer cells. Moreover, we show that targeting MALT1 synergizes with sorafenib or regorafenib to induce ferroptosis across multiple cancer types. These findings elucidate the modulatory effects of the MALT1-RC3H1 axis on GPX4 stability, revealing a molecular mechanism that could be exploited to induce ferroptosis for cancer therapy. [ABSTRACT FROM AUTHOR]