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Among the various scanning techniques, spot and raster scanning are the most frequently adopted. Raster scanning turns off the beam only when each isoenergy slice irradiation is completed. This feature intrinsically solves the leakage dose and frequent beam-switching problems encountered during spot scanning. However, to shorten the delivery time of raster scanning, a sophisticated dose control strategy is required to guarantee dose distribution. In this study, a real-time compensation method with raster scanning for synchrotron systems was designed. It is characterized by a small spot-spacing planning strategy and real-time subtraction of the transient number of particles delivered between two planning-spot positions from the planned number of particles of the subsequent raster point. The efficacy of the compensation method was demonstrated by performing accurate raster scanning simulations with an in-house simulation code and accurate final dose evaluations with a commercial treatment planning system. Given the similar dose evaluation criteria under a practical high scanning speed, compared with the spot scanning method, the total delivery time of the compensated raster scanning method was significantly shortened by 53.3% in the case of irradiating a cubical target and by 28.8% in a pelvic case. Therefore, it can be concluded that real-time compensated raster scanning with a fast scanning configuration can significantly shorten the delivery time compared to that of spot scanning. It is important to reduce the pressure on patients caused by prolonged immobilization and to improve patient throughput capacity at particle therapy centers.

Circular RNA (CircRNA) is a newly identified special class of non-coding RNA (ncRNA) that plays an important regulatory role in the progression of certain diseases. Herein, our results indicate that CircMEG3 is downregulated expression and negatively correlated with the expression of telomerase-related gene Cbf5 in human liver cancer. Moreover, CircMEG3 inhibits the growth of human liver cancer stem cells in vivo and in vitro. CircMEG3 inhibits the expression of m6A methyltransferase METTL3 dependent on HULC. Moreover, CircMEG3 inhibits the expression of Cbf5, a component of telomere synthetase H/ACA ribonucleoprotein (RNP; catalyst RNA pseudouracil modification) through METTL3 dependent on HULC. Thereby, CircMEG3 inhibits telomerase activity and shortens telomere lifespan dependent on HULC and Cbf5 in human liver cancer stem cell. Strikingly, increased Cbf5 abrogates the ability of CircMEG3 to inhibit malignant differentiation of human liver cancer stem cells. In summary, these observations provide important basic information for finding effective liver cancer therapeutic targets., Graphical Abstract, CircRNA plays an important regulatory role in the progression of cancer. CircMEG3 inhibits telomerase activity and shortens telomere lifespan dependent on HULC and Cbf5 in human liver cancer stem cells. It provides important basic information for finding effective liver cancer therapeutic targets.

miR-155 is associated with the promotion of tumorigenesis. Herein, we indicate that abnormal miR-155 was negatively correlated with the expression of P21WAF1/Cip1. Our results suggest that miR-155 alters the transcriptome and inhibits the expression of H3F3A in liver cancer cells. Therefore, miR-155 inhibits the methylation modification of histone H3 on the 27th lysine. Notably, on the one hand, miR-155-dependent CTCF loops cause the CDK2 interacting with cyclin E in liver cancer cells; on the other hand, miR-155 promotes the phosphorylation modification of CDK2 by inhibiting H3F3A. Subsequently, miR-155 competitively blocks the binding of RNA polymerase II (RNA Pol II) to the P21WAF1/CIP1 promoter by increasing the phosphorylation of CDK2, inhibiting the transcription and translation of P21WAF1/CIP1. Strikingly, excessive P21WAF1/CIP1 abolishes the cancerous function of miR-155. In conclusion, miR-155 can play a positive role in the development of liver cancer and influence a series of gene expression through epigenetic regulation., Graphical Abstract, miR-155 promotes the phosphorylation modification of CDK2 and inhibits P21WAF1/CIP1 by inhibiting H3F3A. Therefore, miR-155 can play a positive role in the development of liver cancer and influence a series of gene expression through epigenetic regulation.

MicroRNA24-2 (miR24-2) is associated with human tumorigenesis; however, its molecular mechanisms are poorly understood. Herein, our findings demonstrate that miR24-2 promotes the proliferation ability in vitro and the tumorigenic ability in vivo in human liver cancer stem cells (hLCSCs). Mechanically, the miR24-2 targets for 3′ UTR (2,627–2,648) of protein arginine methyltransferase 7 (PRMT7) inhibit the translational ability of prmt7 gene. Moreover, miR24-2 inhibits the di-/tri-methylation of histone H4 arginine 3 by reducing PRMT7 and then promotes the expression of Nanog via long noncoding RNA HULC. Notably, miR24-2 inhibits histone deacetylase HDAC3 through miR675, which promotes the acetylation of histone H4 at lysine 16. Subsequently, miR24-2 enhances the interaction between LC3 and ATG4 dependent on PI3K and triggers cellular autophagy. Strikingly, miR24-2 inhibits the degradation of pyruvate kinase M1 via autophagosome-P62 in hLCSCs. Furthermore, miR24-2 enhances the activity of Src by promoting the binding of PKM1 to the Src promoter regions in hLCSCs. In particular, our results also indicate that src gene determines the oncogenic functions of miR24-2. These results provided a valuable theoretical basis for the discovery of liver cancer therapeutic targets and diagnosis markers based on miR24-2.

miR675 is highly expressed in several human tumor tissues and positively regulates cell progression. Herein, we demonstrate that miR675 promotes malignant transformation of human mesenchymal stem cells. Mechanistically, we reveal that miR675 enhances the expression of the polyubiquitin-binding protein p62. Intriguingly, P62 competes with SETD2 to bind histone H3 and then significantly reduces SETD2-binding capacity to substrate histone H3, triggering drastically the reduction of three methylation on histone H3 36th lysine (H3K36me3). Thereby, the H3K36me3-hMSH6-SKP2 triplex complex is significantly decreased. Notably, the ternary complex’s occupancy capacity on chromosome is absolutely reduced, preventing it from DNA damage repair. By virtue of the reductive degradation ability of SKP2 for aging histone H3.3 bound to mismatch DNA, the aging histone H3.3 repair is delayed. Therefore, the mismatch DNA escapes from repair, triggering the abnormal expression of several cell cycle-related genes and causing the malignant transformation of mesenchymal stem cells. These observations strongly suggest understanding the novel functions of miR675 will help in the development of novel therapeutic approaches in a broad range of cancer types. Keywords: miR675, human mesenchymal stem cell, malignant transformation, P62

Additional file 1: Figure S1. Generation of transgenic mouse lines and morphological features of CRH neurons in the BST and CeA. Figure S2. The novel EYFP-labeled CRH neurons identification and high-resolution images showing diverse morphologies of CRH neurons throughout the brains of CRH-IRES-Cre;Ai32 mice. Figure S3. Expression specificity and dendritic analysis in the mPFC of CRH-IRES-Cre;Ai32 mice. Figure S4. The somatic locations and examples of the reconstructions of somata and dendritic varicosities of reconstructed neurons in the PaAp and Pe and immunofluorescent staining identification of EYFP-labeled CRH neuron and the dendritic varicosities in the CRH-IRES-Cre;Ai32 mice. Table S1. Parameters of somatic volume, total dendritic length, and the number of dendritic branches of the reconstructed neurons in several brain regions. Table S2. Abbreviation for brain regions.