Background/Aims: Cholangiocarcinoma (CCA) is a primary malignant neoplasm with an extremely poor prognosis. While combined chemoradiotherapy has been demonstrated to delay CCA progression to a certain extent, the absence of specific molecular biomarkers or targets significantly hinders the diagnosis and treatment of CCA. Methods: Through cross-analysis of proteomics and ADMA modificationomics, we identified DDX1 overexpressed in CCA with elevated R602-ADMA modifications. HPLC-MS/MS identified PRMT1 as the methyltransferase and USP10 as the deubiquitinating enzyme for DDX1. Immunofluorescence and nuclear-cytoplasmic partitioning experiments confirmed DDX1’s nuclear localization. GO and KEGG analyses clarify the biological functions of DDX1 in response to hypoxia. RNA-seq transcriptomics analyzed key pathways influenced by DDX1. A hydrodynamic in situ CCA mouse model was established to validate the chemopreventive effects of the PRMT1-specific inhibitor GSK715 on CCA development. Results: DDX1 promotes CCA progression both in vivo and in vitro and can be inhibited by GSK715. Mechanistically, PRMT1 mediates ADMA modification at position R602 of DDX1. This modification promotes DDX1 nuclear localization by recruiting USP10 to deubiquitinate DDX1, while simultaneously inhibiting PRMT1 degradation. DDX1 promotes the transcription of PRMT1 and USP10 by binding to the mRNA 3’UTR region, establishing a positive feedback regulatory pathway. This mechanism promotes the occurrence and development of CCA and can serve as a target for the inhibitor GSK715 to suppress CCA progression. Conclusions Our study identified DDX1-R602-ADMA modification as a novel ADMA modification in CCA. It further confirmed its pivotal role in CCA progression. Targeting the USP10-PRMT1-DDX1 axis may represent a significant therapeutic approach for CCA.

Flash radiotherapy (FLASH-RT) is an advanced radiotherapy technique known for its ultra-high dose rate (>40 Gy/s) irradiation. Preclinical studies have demonstrated that FLASH-RT is highly effective in reducing radiation damage to normal tissues, while still effectively killing tumors. This wider therapeutic window in terms of dose rate makes FLASH-RT a promising and disruptive technique for the future of radiotherapy. However, the biological mechanisms underlying FLASH-RT are not yet fully understood, and there are multiple technical challenges to be addressed before its clinical application. In this article, we provide a brief overview of the recent research progress in FLASH-RT, covering its biological mechanisms, preclinical studies, and the status and challenges in clinical application, aiming to offer valuable reference and inspiration for the future translation of FLASH-RT into clinical practice.

Objective To make sciatic nerve traction injury models of rabbit , in order to prospectively evaluate possibility and accuracy of diffusion tensor tracking (DTT) in sciatic nerve injures. Methods The right sciatic nerves of 32 New Zealand white rabbits were selected for traction injury , and the left sciatic nerves were the sham operation side. DTI scan was performed before and after the operation on 1st day , 3rd day, and 1 week, 2, 3, 4, 6 and 8th week respectively, and DTT was reconstructed. Then the length of reconstructed fiber tracts and fiber density index were calculated. After the MRI scan , the sciatic nerve was removed to perform pathologic examination at different time points. Results The difference of the length of reconstructed fiber tracts between nerve traction injury and sham operation side was significant at 1 day~2weeks after operation (P<0.05), while the difference was not significant at 3~8 weeks.The fiber density index of nerve traction injury and sham operation side was significantly different at 1 day~8 weeks(P<0.05). 1day after operation, myelin sheath of traction portion was obviously twisting. 3 days after operation , a large amount of myelin sheath broke down. 2 weeks after operation , axon, myelin sheath degeneration and regeneration coexisted at the same time. 8 weeks after operation , nerve fibers regenerated and restored to normal structure. Conclusion The length time curve and density index-time curve of nerve traction injury are consistent with the changes of pathology , which can be used as a supplementary method to evaluate the degeneration and regeneration in nerve injury.

Objective To investigate the correlation between eigenvalues(λ∥ andλ⊥)of sciatic nerve and limb function in a rabbit model of acute nerve traction inj ury for finding the role ofλ∥ andλ⊥ on diagnosis of nerve inj uries.Methods The right sciatic nerves of 32 Newland rabbits were selected to be performed as traction injury,and then left sciatic nerves were treated as control for the sham operation side.MRI DTI scan was performed before and after the operation on 1 day ,3 day,and 1 week,2,3,4,6 and 8 weeks respectively.Theλ∥ andλ⊥ of inj ured sciatic nerves and sham operated nerves were measured,meanwhile functional exami-nations were evaluated,and then analyzing the correlation betweenλ⊥ of inj ured sciatic nerves and the score of inj ured limb function in the periods of 3 days to 8 weeks;finally different portions of sciatic nerve were removed for histological examinations.Results Theλ⊥ of inj ured sciatic nerves in the proximal portion was slightly increased at 3 days and recovered to the normal at 2 weeks.Theλ⊥ of inj ured sciatic nerves in the traction portion and distal portion were slightly raised at 1 day,reached to its maximum value at 3 days,and then decreased gradually after 1 week and dropped to the pre-operation level after 4 weeks.Theλ⊥ of inj ured sciatic nerves in the proximal portions was significantly higher than that of the sham-operated nerves from 1 day to 1 week(F=7.275,P=0.000). Theλ⊥ of inj ured sciatic nerves in the traction portion and distal portion were significantly higher than that of the sham-operated nerves from 1 day to 3 weeks(F=5.851,F=3.794,P=0.001,P=0.000).However,there was no significantly difference between theλ∥ of inj ured nerves in each portion and sham-operated nerves .The negative correlation between theλ⊥ of inj ured sciatic nerves in the distal portion and the score of the nerve function in the injured limb was found (r=-0.938,r=-0.897,P<0.01).Conclu-sion Theλ⊥ of inj ured nerves in the traction portion and distal portion could monitor the process of degeneration and regeneration of sciatic nerve in traction inj ury,while theλ∥ plays no obvious role in diagnosis of nerve inj uries.

BACKGROUND:Magnetic resonance diffusion tensor imaging can display the dispersion changes of peripheral nerve injury and be used to conduct quantitative research, so it has good application prospects in displaying the nerve injury and regeneration. OBJECTIVE:To investigate the possibility of magnetic resonance diffusion tensor imaging of rabbit acute sciatic nerve traction injury, and to figure out the value of diffusion tensor parameters in the diagnosis of peripheral nerve injuries and to reveal the pathologic basis. METHODS:The right hind limb sciatic nerves of 32 New Zealand white rabbits were selected to make the regeneration and repair models, the left hind limb nerves as the sham-operation side. Diffusion tensor imaging examination of sciatic nerves were performed at 1 and 3 days, 1, 2, 3, 4, 6 and 8 weeks after operation with 1.5 T MRI. Fractional anisotropy and apparent diffusion coefficient were measured through diffusion tensor tracing
reconstruction, and then the pathological examination was performed. RESULTS AND CONCLUSION:Diffusion tensor imaging revealed only the proximal nerve, injured nerve as wel as the middle of the distal nerve at 1 day after traction injury. At 1 week, the nerve of distal portion appeared thinner and shorter fiber bundle. At 2-6 weeks after operation, the fiber bundle was increased and thickened. At 8 weeks after operation, the distal nerve fibers had nearly restored to the level before injury. There was significant difference in the fractional anisotropy value of traction portion and distal portions between traction injury and sham-operation group at 1 day-8 weeks after operation (P<0.05). While there was significant difference in the fractional anisotropy value of proximal traction portion between traction injury and sham-operation group 1 day-1 week after operation (P<0.05). There were no significant differences in the apparent diffusion coefficient values between traction injury and sham-operation group at 1 day-8 weeks after operation. Fal of fractional anisotropy value in the early stage of nerve traction injury was the result of myelin sheath broke down and axonal disintegrated;recovery of fractional anisotropy value resulted from myelin sheath proliferated and myelin sheath grew slowly to mature. Diffusion tensor tracing can show the abnormal change of the sciatic nerve with traction injury in rabbit clearly and early, and the measurement of fractional anisotropy value can be used as the sensitive method to monitor the degeneration and regeneration after nerve traction injury.