Background/Aims: Lenvatinib resistance remains a critical barrier in advanced hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood. Methods: Integrated transcriptomics of lenvatinib-resistant patient tumors and an acquired-resistance murine model identified a novel macrophage subpopulation. Functional validation employed CRISPR-SAM screening, conditioned medium (CM) assays, subcutaneous/orthotopic xenografts, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). Mechanistic studies included ChIP-qPCR, co-immunoprecipitation, and pharmacologic targeting. Clinical relevance was assessed in a retrospective cohort. Results: Resistant HCC exhibited significant enrichment of a COLEC12high TAM subset , which correlated with poor survival and treatment response. These TAMs secreted neuregulin-1 (NRG1) , activating HER2/HER3-AKT signaling in tumor cells to drive cancer stemness and lenvatinib resistance. Mechanistically, in TAMs COLEC12 sequestered STAT1 in the cytoplasm, preventing its phosphorylation, and thereby derepressing STAT3-mediated NRG1 transcription. Depletion of NRG1 reversed the stemness phenotypes and resensitized tumors to lenvatinib both in vitro and in vivo. Clinically, high NRG1 expression predicted an inferior lenvatinib response and shorter survival. Crucially, the bispecific anti-HER2/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models. Conclusions Our work establishes the COLEC12high TAM/NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC.

Objective To investigate the effect and mechanism of nodakenin(Nod)in neuropathic pain(NP).Methods Differential expression genes in the primary somatsensory cortex(S1)of NP data and overlapping genes between the dataset and mitochondrial data were screened and analyzed.Overlapping gene interaction networks were overlapped and core genes were screened.A total of 27 mice were randomly divided into the sham operation group,the model group and the drug administration group(9 mice/group).The chronic compression injury model of sciatic nerve was constructed in the model group and the drug administration group.Nod 10 mg/kg was intraperitoneally injected into the drug administration group for 1 week.Changes of pain behavior and motor ability in mice were detected.HE staining and Nissl staining were used to detect effects of nerve injury and inflammation on brain tissue of S1 region of mice.The expression levels of interleukin-1β,early gene(c-Fos),panthenol-cytochrome c reductase complex III subunit(Uqcrq)and ubiquinone oxidoreductase subunit(Nduf)b5 in S1 brain region were analyzed by Western blot assay.Molecular docking was used to study the target of Nod.PC12 cells were divided into the control group,the IL-1β group(1 μmol/L IL-1β treatment)and the IL-1β+Nod group(1 μmol/L IL-1β+1 μmol/L Nod treatment),and mitochondrial membrane potential was detected in each group.Results In the NP dataset GSE180627,S1 brain region contained 293 differentially expressed genes,and the mitochondrial data contained 1 082 genes.There were 34 overlapping genes,and genes related to oxidative phosphorylation and electron transport chain were enriched.The protein interaction network showed that core genes included electron transport chain related proteins Ndufb5,Uqcrq,Ndufs8,Ndufa7,Ndufa3,Cox6b1 and Mrps33.Compared with the model group,the mechanical foot shrinkage threshold,thermal foot shrinkage reflex latency and rod rotation residence time of mice were increased in the drug administration group,the number of inflammatory infiltrating cells in S1 tissue and the number of Nislet bodies in neurons,expression levels of c-Fos and IL-1β in neurons were decreased,and expression levels of Uqcrq and Ndufb5 were increased(P＜0.05).Molecular docking showed that Nod could bind Uqcrq and Ndufb5.Compared with the IL-1β group,the fluorescence signal of mitochondrial membrane potential was enhanced in the IL-1β+Nod group(P＜0.05).Conclusion Nodakenin can improve pain behavior in mice,and its mechanism involves ameliorating mitochondrial damage in S1.

Objective:To explore the value of deep learning (DL) models based on conventional MRI in differentiating orbital solitary fibrous tumors (SFT) from schwannomas.Methods:This was a case-control study. A retrospective analysis was conducted on patients with pathologically confirmed orbital SFT and schwannoma admitted to Eye & ENT Hospital, Fudan University (institution 1) from December 2014 to January 2022 and Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine (institution 2) from July 2015 to May 2022. A total of 140 patients were included, with 104 patients from institution 1 comprising the training cohort for building DL models and 36 patients from institution 2 comprising the external validation cohort for assessing model performance. Based on the preoperative cross-sectional fat-suppressed T 2WI and contrast-enhanced T 1WI (ceT 1WI), tumor contours were outlined on all tumor-containing slices. Six diagnostic models were constructed using residual networks (ResNet) and split-attention residual networks (ResNeSt) with 18 layers (ResNet-18 and ResNeSt-18), based solely on individual T 2WI and ceT 1WI, as well as a combination of both. A radiology resident and an attending radiologist independently reviewed conventional MRI images to determine the tumor type. The performance of the DL models and radiologists in differentiating orbital SFT from schwannoma in the external validation cohort was evaluated using receiver operating characteristic curves, and the areas under the curves (AUC) were compared using the DeLong test. Results:In the external validation cohort, the AUC (95% CI) of the ResNet-18 models based on T 2WI, ceT 1WI, and their combination were 0.861 (0.719-1), 0.896 (0.774-1), and 0.885 (0.755-1), respectively, while the AUC (95% CI) of the ResNeSt-18 models were 0.889 (0.748-1), 0.872 (0.726-1), and 0.910 (0.801-1), respectively. Among these, the ResNeSt-18 model based on the combined sequences achieved the best performance in differentiating the two tumors. The AUC (95% CI) for the individual interpretation of the radiology resident and attending radiologist were 0.729 (0.571-0.887) and 0.771 (0.618-0.923), respectively. The AUC of the ResNeSt-18 model based on the combined sequences was statistically significantly higher than those of the resident and attending radiologist ( Z=1.96, P=0.049; Z=2.00, P=0.045). Conclusion:The ResNeSt-18 model based on conventional MRI can effectively differentiate orbital SFT from schwannoma, demonstrating better performance than those of the radiology resident and the attending radiologist.

High intensity ultraviolet radiation exists in special military operation environments such as oceans,plateaus,polar regions and deserts,which is a leading contributor to eye damage and can lead to luminous keratitis,dry eyes,pterygium,cataract and macular degeneration.Ultraviolet radiation can cause acute and chronic injury to eyes by inducing DNA damage,oxidative stress and inflammatory reaction.The commonly used clinical drugs have played a role in relieving symptoms and promoting the repair of ocular tissues,but there are still limitations.The research on targeted therapeutic drugs,proteins and their derived peptides,vitamins and their coenzymes,as well as natural active ingredients of animals and plants has provided new ideas for the development of more effective drugs that can protect eyes from ultraviolet and for medical support to China's army in special environments.Based on the literature currently available,this paper reviews the eye injury caused by ultraviolet radiation and therapeutic drugs in terms of types of eye diseases,injury mechanisms,treatment strategies and drug development.

Objective To investigate the effect and mechanism of nodakenin(Nod)in neuropathic pain(NP).Methods Differential expression genes in the primary somatsensory cortex(S1)of NP data and overlapping genes between the dataset and mitochondrial data were screened and analyzed.Overlapping gene interaction networks were overlapped and core genes were screened.A total of 27 mice were randomly divided into the sham operation group,the model group and the drug administration group(9 mice/group).The chronic compression injury model of sciatic nerve was constructed in the model group and the drug administration group.Nod 10 mg/kg was intraperitoneally injected into the drug administration group for 1 week.Changes of pain behavior and motor ability in mice were detected.HE staining and Nissl staining were used to detect effects of nerve injury and inflammation on brain tissue of S1 region of mice.The expression levels of interleukin-1β,early gene(c-Fos),panthenol-cytochrome c reductase complex III subunit(Uqcrq)and ubiquinone oxidoreductase subunit(Nduf)b5 in S1 brain region were analyzed by Western blot assay.Molecular docking was used to study the target of Nod.PC12 cells were divided into the control group,the IL-1β group(1 μmol/L IL-1β treatment)and the IL-1β+Nod group(1 μmol/L IL-1β+1 μmol/L Nod treatment),and mitochondrial membrane potential was detected in each group.Results In the NP dataset GSE180627,S1 brain region contained 293 differentially expressed genes,and the mitochondrial data contained 1 082 genes.There were 34 overlapping genes,and genes related to oxidative phosphorylation and electron transport chain were enriched.The protein interaction network showed that core genes included electron transport chain related proteins Ndufb5,Uqcrq,Ndufs8,Ndufa7,Ndufa3,Cox6b1 and Mrps33.Compared with the model group,the mechanical foot shrinkage threshold,thermal foot shrinkage reflex latency and rod rotation residence time of mice were increased in the drug administration group,the number of inflammatory infiltrating cells in S1 tissue and the number of Nislet bodies in neurons,expression levels of c-Fos and IL-1β in neurons were decreased,and expression levels of Uqcrq and Ndufb5 were increased(P＜0.05).Molecular docking showed that Nod could bind Uqcrq and Ndufb5.Compared with the IL-1β group,the fluorescence signal of mitochondrial membrane potential was enhanced in the IL-1β+Nod group(P＜0.05).Conclusion Nodakenin can improve pain behavior in mice,and its mechanism involves ameliorating mitochondrial damage in S1.

Objective:To explore the value of deep learning (DL) models based on conventional MRI in differentiating orbital solitary fibrous tumors (SFT) from schwannomas.Methods:This was a case-control study. A retrospective analysis was conducted on patients with pathologically confirmed orbital SFT and schwannoma admitted to Eye & ENT Hospital, Fudan University (institution 1) from December 2014 to January 2022 and Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine (institution 2) from July 2015 to May 2022. A total of 140 patients were included, with 104 patients from institution 1 comprising the training cohort for building DL models and 36 patients from institution 2 comprising the external validation cohort for assessing model performance. Based on the preoperative cross-sectional fat-suppressed T 2WI and contrast-enhanced T 1WI (ceT 1WI), tumor contours were outlined on all tumor-containing slices. Six diagnostic models were constructed using residual networks (ResNet) and split-attention residual networks (ResNeSt) with 18 layers (ResNet-18 and ResNeSt-18), based solely on individual T 2WI and ceT 1WI, as well as a combination of both. A radiology resident and an attending radiologist independently reviewed conventional MRI images to determine the tumor type. The performance of the DL models and radiologists in differentiating orbital SFT from schwannoma in the external validation cohort was evaluated using receiver operating characteristic curves, and the areas under the curves (AUC) were compared using the DeLong test. Results:In the external validation cohort, the AUC (95% CI) of the ResNet-18 models based on T 2WI, ceT 1WI, and their combination were 0.861 (0.719-1), 0.896 (0.774-1), and 0.885 (0.755-1), respectively, while the AUC (95% CI) of the ResNeSt-18 models were 0.889 (0.748-1), 0.872 (0.726-1), and 0.910 (0.801-1), respectively. Among these, the ResNeSt-18 model based on the combined sequences achieved the best performance in differentiating the two tumors. The AUC (95% CI) for the individual interpretation of the radiology resident and attending radiologist were 0.729 (0.571-0.887) and 0.771 (0.618-0.923), respectively. The AUC of the ResNeSt-18 model based on the combined sequences was statistically significantly higher than those of the resident and attending radiologist ( Z=1.96, P=0.049; Z=2.00, P=0.045). Conclusion:The ResNeSt-18 model based on conventional MRI can effectively differentiate orbital SFT from schwannoma, demonstrating better performance than those of the radiology resident and the attending radiologist.

BACKGROUND:Studies have shown that there are significant differences in the geometric morphology of the distal femur of different races and genders,and there are more short female patients in southern China,so the phenomenon of overhanging or insufficient coverage of imported knee prostheses often occurs during surgery. OBJECTIVE:To investigate the characteristics of distal femur bones in southern Chinese women and compare them with imported joint prostheses by simulating the three-dimensional reconstruction of the distal femur bone and matching the femoral side after osteotomy with common imported joint prostheses. METHODS:From January to December 2021,120 female volunteers underwent a CT scan of knee joints.The images were imported into Mimics 20.0 software in Dicom format for three-dimensional reconstruction and then imported into Magic 22.0 software to simulate osteotomy by posterior cruciate ligament preserved total knee arthroplasty and to conduct a matching study with a normal imported joint prosthesis. RESULTS AND CONCLUSION:(1)The functional anteroposterior dimension(fAP)of the distal femur and Persona matched prosthesis had a total overhang rate of 25%(30/120).The fAP≤47 mm group had an overhang than the other groups(P<0.05).The poor coverage rate of Triathlon prosthesis was 12.5%(15/120),and poor coverage was more likely in fAP>53 mm group than in fAP≤53 mm group(P<0.05).(2)The total poor coverage rate of femoral intercondylar width matching with Triathlon prosthesis was 27.5%(33/120).Therefore,the poor coverage rate of bone surface in the central region of the distal femur was more likely in the fAP≤47 mm group than in other groups(P<0.05).The overhang rate of Journey II was 21.6%(26/120),and the overhang rate was higher in the fAP>53 mm group than in the fAP≤53 mm group(P<0.05).(3)Journey II CR prosthesis had the largest difference with the length of the anterior mediolateral diameter of the femur,which was easy to hang out on the anterolateral side of the femoral prosthesis.The Persona CR prosthesis has the largest difference with the length of the posterior mediolateral diameter of the femur,which is easy to be poorly covered in the posterior medial part of the prosthesis.It is recommended to increase the femoral prosthesis with reduced mediolateral diameter in the fAP≤47 mm group and add wider and narrower sizes than the conventional size of intercondylar width,and optimize the anterolateral angular arc design of the femoral prosthesis to improve the matching of posterior cruciate ligament reserved knee prosthesis.

BACKGROUND:Prosthesis restricted selection,soft tissue release,patellar trajectory recovery,and bone defect reconstruction were need to be optimized in total knee arthroplasty for moderate and severe valgus knee.The medial parapatellar approach has disadvantages in the treatment of valgus knee,such as aggravating the medial soft tissue relaxation.In recent years,it has been found that the lateral parapatellar approach has advantages in the treatment of valgus knee,such as exposure and release. OBJECTIVE:To observe the efficacy of the lateral and medial parapatellar approach in total knee arthroplasty for moderate and severe valgus knee,and to explore a more suitable surgical approach for moderate and severe valgus knee. METHODS:Totally 56 patients with moderate and severe valgus knee underwent total knee arthroplasty and would take turns performing surgery through the medial and lateral parapatellar approach according to the order of admission.The lateral group(n=28)underwent total knee arthroplasty through lateral parapatellar approach,and the medial group(n=28)through medial parapatellar approach.Posterior stablized knee prosthesis was used in all patients.The restricted types of prosthesis,thickness of polyethylene,operation time,amount of blood loss,femoro-tibia angle,patellar tilt angle,range of motion,Hospital for Special Surgery score,Western Ontario and McMaster Universities Arthritis Index(WOMAC)score,and complications were collected as observation indexes for statistical analysis. RESULTS AND CONCLUSION:(1)The utilization rate of condyle-restricted prosthesis in the lateral group was significantly lower than that in the medial group.The average thickness of polyethylene liner was lower,and the operation time was shorter in the lateral group compared with the medial group.There were significant differences between the two groups(P<0.05),and there was no significant difference in the amount of surgical bleeding.(2)56 patients were followed up for an average of 2-5 years.There were no signs of prosthesis loosening or bone resorption in all patients.The average patellar tilt angle and femoral tibial angle of the lateral group were lower than those of the medial group,and the average Hospital for Special Surgery score and WOMAC score of the lateral group were higher than those of the medial group,with significant differences(P<0.05).There was no significant difference in the range of motion of the knees between the two groups.(3)Incision fat liquefaction and calf intermuscular venous thrombosis occurred in one case in each group.No infection,poor incision healing,incisional hematoma,prosthesis dislocation,iatrogenic nerve injury,ectopic ossification,or periprosthesis fracture occurred during follow-up.(4)In conclusion,the treatment of moderate and severe valgus knee by lateral parapatellar approach can better protect the tension of the medial soft tissue of the knee,use less condylar restrictive prostheses,and have a more friendly patellar trajectory and higher postoperative function score.

Objective To introduce and enhance an experimental technique for intraventricular drug delivery via an implantable osmotic pump.Methods Eight-week-old male SD rats were selected and the requisite equipment and reagents were prepared.The osmotic pump was assembled and brought to operational status before conducting the implantation surgery.Following anesthesia,the rats underwent skin preparation and the upper surface of the skull was surgically exposed.A point directly above the ventricle was located using a brain stereotaxic apparatus,and a small hole was drilled at that location with a high-speed cranial drill.The pump body was then implanted subcutaneously in the neck and the needle was inserted into the drilled hole,and secured with dental cement.Once solidified,the needle base was removed,the subcutaneous soft tissue and scalp were sutured in layers,and the animal was returned to its cage for rearing in isolation.Results The osmotic pump was successfully implanted subcutaneously in the rat's neck,the needle was securely fixed to the skull,and the catheter interface remained intact.The rats were sacrificed and the brain tissue was removed.Examination of the extracted brain tissue revealed no significant hematoma around the puncture site or needle tract,and the presence of blue dye in the ventricular and adjacent tissues indicated successful drug delivery to the ventricle.Conclusions The introduction of a brain stereotaxic apparatus to aid localization,coupled with enhancements to the operational procedure,may improve the accuracy and safety of the implantation process resulting in a high success rate for intraventricular drug administration.

OBJECTIVE To stu dy the effects of different processing me thods on the contents of the pharmacodynamic index components in Citrus aurantium and their antioxidant activity. METHODS According to the general principles of 2020 edition of Chinese Pharmacopoeia （volume Ⅳ） and the relevant processing methods in 2015 edition of Processing Specifications of Traditional Chinese Medicine in Zhejiang Province ，the samples of C. aurantium were prepared by steaming with water ，boiling with water ，stir-frying with vinegar ，stir-frying with wine ，stir-frying with bran ，processing with bran and processing with honey. The contents of moisture and ash in different products of C. aurantium were detected. The contents of naringin and neohesperidin in different products of C. aurantium were determined by high performance liquid chromatography. The antioxidant activity of different products was investigated by DPPH and ABTS + radical scavenging experiments and the total reducing power test. RESULTS The contents of moisture ，ash，naringin and neohesperidin were in line with the relevant requirements in 2015 edition of Processing Specifications of Traditional Chinese Medicine in Zhejiang Province . The content of naringin in descending order was as follow ： unprocessed sample ＞sample processed with honey ＞sample processed with bran ＞sample boiled with water ＞sample stir-fried with vinegar＞sample stir-fried with wine ＞sample stir-fried with bran ＞sample steamed with water. The content of neohesperidin in descending order was as follow ：unprocessed sample ＞sample boiled with water ＞sample processed with bran ＞sample processed with honey ＞sample stir-fried with vinegar ＞sample steamed with water ＞sample stir-fried with wine ＞sample stir-fried with bran. The samples after boiling with water ，processing with bran ，and stir-fried with bran had better DPPH radicals scavenging ability （IC50 were 7.49，8.37 and 10.22 mg/mL，respectively）. The samples after boiling with water ，steaming with water ，and processed with bran had better ABTS + radicals scavenging ability （IC50 were 1.76，2.03 and 2.72 mg/mL，respectively）. In addition ， compared with sample stir-fried with wine and processed with 发。E-mail：wanglu1286@163.com honey，unprocessed sample and other processed products of C.aurantium had bet ter total reducing ability. CONCLUSIONS After processing ，the contents of the main pharmacodynamic index components in C. aurantium have been reduced ，but they were also in line with the relevant requirements in 2015 edition of Processing Specifications of Traditional Chinese Medicine in Zhejiang Province . The antioxidant ability of some processed products has been enhanced.