Objective:To investigate the value of gadoxetate disodium-enhanced MRI combined with T 1 mapping in preoperative prediction of cytokeratin 19 (CK19) and glypican-3 (GPC3) positive dual-phenotype hepatocellular carcinoma (DPHCC). Methods:This case-control study included retrospectively enrolled patients with pathologically confirmed HCC from Central People′s Hospital of Zhanjiang (training set, n=85; December 2020 to July 2022) and the Second Affiliated Hospital, School of Medicine, South China University of Technology (test set, n=35; April 2023 to April 2024). Patients were categorized into CK19 and GPC3 positive DPHCC group (training set=19, test set=11) and non-DPHCC group (training set=66, test set=24) based on postoperative immunohistochemical staining. All patients received preoperative MRI scans, including gadoxetate disodium-enhanced imaging and T 1 mapping. Clinical data were collected, qualitative MRI features were evaluated, and quantitative parameters were measured, including signal intensity, T 1 values, apparent diffusion coefficient (ADC), tumor-to-liver ADC ratio (rADC), tumor-to-liver signal intensity ratio, and T 1 relaxation time reduction rate (ΔT 1%). Statistical comparisons between groups were performed using independent t-tests, Mann-Whitney U tests, or χ2 tests. Multivariate logistic regression identified independent predictors of CK19 and GPC3 positive DPHCC, and a combined model was constructed. Predictive performance was evaluated using area under the receiver operating characteristic curve (AUC), with DeLong test comparing model performance. Results:Significant intergroup differences were observed in alpha-fetoprotein (AFP), total bilirubin, direct bilirubin, DWI target sign, rADC, hepatobiliary-phase T 1 (T 1HBP), and ΔT 1% ( P<0.05). Multivariate analysis identified AFP>20 ng/ml ( OR=5.835, 95% CI 1.019-33.397, P=0.048), DWI target sign ( OR=13.408, 95% CI 2.216-81.131, P=0.005), and ΔT1%≤31% ( OR=14.429, 95% CI 2.166-96.125, P=0.006) as independent predictors of DPHCC. The AUC values of the aforementioned three independent predictors and the combined model for predicting DPHCC were 0.641 (95% CI 0.530-0.742), 0.679 (95% CI 0.569-0.777), 0.740 (95% CI 0.634-0.829), and 0.886 (95% CI 0.799-0.945) in the training set, and 0.568 (95% CI 0.390-0.743), 0.669 (95% CI 0.490-0.818), 0.689 (95% CI 0.511-0.843), and 0.824 (95% CI 0.658-0.931) in the test set, respectively. The DeLong test results showed that in the training set, the diagnostic performance of the combined model was superior to those of the three individual features ( Z=3.68, P<0.001; Z=3.15, P=0.002; Z=3.15, P=0.002). In the test cohort, the combined model demonstrated better diagnostic performance than AFP>20 ng/ml and ΔT 1%≤31% ( Z=2.15, P=0.032; Z=2.12, P=0.034), while no statistically significant difference was observed compared with the DWI target sign ( Z=1.77, P=0.076). Conclusion:The integrated model incorporating clinical data, gadoxetate disodium-enhanced MRI, and T 1 mapping parameters effectively predicts CK19 and GPC3 positive DPHCC.

Objective:To investigate the value of gadoxetate disodium-enhanced MRI combined with T 1 mapping in preoperative prediction of cytokeratin 19 (CK19) and glypican-3 (GPC3) positive dual-phenotype hepatocellular carcinoma (DPHCC). Methods:This case-control study included retrospectively enrolled patients with pathologically confirmed HCC from Central People′s Hospital of Zhanjiang (training set, n=85; December 2020 to July 2022) and the Second Affiliated Hospital, School of Medicine, South China University of Technology (test set, n=35; April 2023 to April 2024). Patients were categorized into CK19 and GPC3 positive DPHCC group (training set=19, test set=11) and non-DPHCC group (training set=66, test set=24) based on postoperative immunohistochemical staining. All patients received preoperative MRI scans, including gadoxetate disodium-enhanced imaging and T 1 mapping. Clinical data were collected, qualitative MRI features were evaluated, and quantitative parameters were measured, including signal intensity, T 1 values, apparent diffusion coefficient (ADC), tumor-to-liver ADC ratio (rADC), tumor-to-liver signal intensity ratio, and T 1 relaxation time reduction rate (ΔT 1%). Statistical comparisons between groups were performed using independent t-tests, Mann-Whitney U tests, or χ2 tests. Multivariate logistic regression identified independent predictors of CK19 and GPC3 positive DPHCC, and a combined model was constructed. Predictive performance was evaluated using area under the receiver operating characteristic curve (AUC), with DeLong test comparing model performance. Results:Significant intergroup differences were observed in alpha-fetoprotein (AFP), total bilirubin, direct bilirubin, DWI target sign, rADC, hepatobiliary-phase T 1 (T 1HBP), and ΔT 1% ( P<0.05). Multivariate analysis identified AFP>20 ng/ml ( OR=5.835, 95% CI 1.019-33.397, P=0.048), DWI target sign ( OR=13.408, 95% CI 2.216-81.131, P=0.005), and ΔT1%≤31% ( OR=14.429, 95% CI 2.166-96.125, P=0.006) as independent predictors of DPHCC. The AUC values of the aforementioned three independent predictors and the combined model for predicting DPHCC were 0.641 (95% CI 0.530-0.742), 0.679 (95% CI 0.569-0.777), 0.740 (95% CI 0.634-0.829), and 0.886 (95% CI 0.799-0.945) in the training set, and 0.568 (95% CI 0.390-0.743), 0.669 (95% CI 0.490-0.818), 0.689 (95% CI 0.511-0.843), and 0.824 (95% CI 0.658-0.931) in the test set, respectively. The DeLong test results showed that in the training set, the diagnostic performance of the combined model was superior to those of the three individual features ( Z=3.68, P<0.001; Z=3.15, P=0.002; Z=3.15, P=0.002). In the test cohort, the combined model demonstrated better diagnostic performance than AFP>20 ng/ml and ΔT 1%≤31% ( Z=2.15, P=0.032; Z=2.12, P=0.034), while no statistically significant difference was observed compared with the DWI target sign ( Z=1.77, P=0.076). Conclusion:The integrated model incorporating clinical data, gadoxetate disodium-enhanced MRI, and T 1 mapping parameters effectively predicts CK19 and GPC3 positive DPHCC.

AIM:To explore the efficacy of lenvatinib(Len)in enhancing the therapeutic effects of immune checkpoint inhibitor for hepatocellular carcinoma(HCC)and to delve into its immunomodulatory mechanisms within the tumor microenvironment.METHODS:The effects of various concentrations of Len on the migration of human umbilical vein endothelial cells(HUVECs)and the secretion of CXC chemokine ligand 10(CXCL10)were investigated,and the mechanism by which Len modulates CXCL10 secretion was validated.An orthotopic HCC model was established,and the mice bearing tumors were randomly allocated into 4 groups:PBS group,BMS-202(PD-1/PD-L1 inhibitor)group,Len group,and Len/BMS-202 group.The progression of the orthotopic liver tumors was monitored with small animal in vivo im-aging techniques.On the 13th day after the treatment,mice were sacrificed and tumor tissues were harvested for analysis.Immunofluorescence was employed to identify apoptosis,vascular architecture,and hypoxic status within the tumor tis-sue.The expression levels of proliferation marker Ki67,transforming growth factor-β(TGF-β),and the infiltration de-grees of CD4+T cells and CD8+T cells in the tumor tissue were monitored with immunohistochemistry.The secretion of im-mune factors interferon-γ(IFN-γ),CXCL10 and TGF-α in the mouse serum was quantified with ELISA.Above all data were followed by statistical analysis.RESULTS:(1)Len could facilitate endothelial cell migration within a specific range and potentiated the response of tumor cells to IFN-γ by blocking fibroblast growth factor receptor(FGFR),thereby increasing the secretion of CXCL10 from the tumor cells.(2)Compared with PBS group,tumor growth was slower in all treatment groups,with Len/BMS-202 group showing the most significant inhibition of tumor growth in tumor-bearing mice(P<0.05).(3)Compared with PBS group and monotherapy groups,Len/BMS-202 significantly promoted tumor tissue apoptosis and inhibited tumor cell proliferation(P<0.05).(4)Compared with PBS group and BMS-202 group,both Len group and Len/BMS-202 group manifested a substantial enhancement in pericytes coverage rate(P<0.01),concomitantly showing a marked improvement in hypoxic conditions(P<0.01).(5)Compared with PBS group and monotherapy groups,Len/BMS-202 group showed a significant increase in the infiltration of CD4+T cells and CD8+T cells within the tumor(P<0.01),along with a marked decrease in the expression of TGF-β(P<0.01).(6)Compared with PBS group,all treatment groups collectively induced varying degrees of secretion of IFN-γ,CXCL10 and TGF-α in mouse serum(P<0.05),with Len/BMS-202 group demonstrating the most pronounced effects(P<0.01).CONCLUSION:Lenvatinib may augment the therapeutic efficacy of BMS-202 in HCC by facilitating tumor vascular normalization,alleviating hypoxic conditions,and enhancing the secretion of CXCL10,thereby synergistically activating the tumor immune microenvironment.

BACKGROUND:Intervertebral disc degeneration is an important cause of low back pain.At present,there are many modeling methods for disc degeneration in China and abroad,but there is not a model for low back pain due to disc degeneration. OBJECTIVE:To compare the effect of mechanical puncture combined with tumor necrosis factor α and complete Freund's adjuvant with a conventional disc mechanical puncture alone. METHODS:A total of 18 male adult Sprague-Dawley rats were randomly divided into 3 groups,with 6 animals in each group.No treatment was given in the blank group.Animal models of intervertebral disc degeneration were made in the L4-5 segments of rats in the control using conventional mechanical puncture.In the experimental group,on the basis of mechanical puncture,tumor necrosis factor α+complete Freund's adjuvant was injected into the L4-5 intervertebral discs using a microinjector to establish a model of disc degeneration induced by mechanical puncture combined with inflammatory factors.Four weeks after surgery,the pain threshold of rats was measured by the hot plate method for assessing the perception of heat injury in rats with intervertebral disc degeneration.MRI examination was performed to observe the disc degeneration in each group.ELISA was used to detect the levels of serum tumor necrosis factor α,interleukin 1β,interleukin 6 and prostaglandin E2.Hematoxylin-eosin and Safranin O-fast green staining were used to observe the morphological changes of the disc. RESULTS AND CONCLUSION:In terms of pain,the behavioral pain threshold of the experimental group was continuously decreased,and the levels of serum inflammatory factors were significantly higher compared with the control group.In terms of morphology,the MRI results showed that the L4-5 nucleus pulposus signal completely disappeared in the experimental group.Histopathological results showed that in the control group,the nucleus pulposus was intact,more notochord cells were visible,and some fiber rings were ruptured,while in the experimental group,there are fewer notochord cells and the structure of the nucleus pulposus and fibrous ring is disturbed,with the boundary disappearing.To conclude,mechanical puncture combined with tumor necrosis factor alpha and complete Freund's adjuvant can successfully establish a discogenic low back pain model in rats.This operation is simple and economical to achieve obvious disc degeneration and low back pain,with greatly shortened molding cycle.This model can be used as a reference for studying discogenic low back pain models.

Based on the data of a national sampling survey, this paper described and analyzed the understanding, attitude, behavior, and their differences and influencing factors of Chinese medical researchers on ethical review of biomedical research involving human subject. The survey found that researchers with master’s degree or below, working in scientific research institutes or universities, no overseas experience, living in the central region and not serving as committee members have relatively poor acquaintance of "ethical review" ; researchers with the characteristics of male, the younger age, living in the western region, knowing less about "ethical review" , agree more with the view that "ethical review consumes too much time and energy" ; researchers who serve as members of the ethics committee are more likely to participate in scientific research projects that have not passed the ethical review process. Therefore, recommendations are put forward: comprehensively popularizing the training of ethical review, focusing on strengthening the vulnerable groups and regions, strictly implementing ethical review laws and regulations, and strengthening evaluation and supervision, so as to improve the service quality and efficiency of ethical review in multiple directions.

Based on the data of a national sampling survey, this paper described and analyzed the understanding, attitude, behavior, and their differences and influencing factors of Chinese medical researchers on ethical review of biomedical research involving human subject. The survey found that researchers with master’s degree or below, working in scientific research institutes or universities, no overseas experience, living in the central region and not serving as committee members have relatively poor acquaintance of "ethical review" ; researchers with the characteristics of male, the younger age, living in the western region, knowing less about "ethical review" , agree more with the view that "ethical review consumes too much time and energy" ; researchers who serve as members of the ethics committee are more likely to participate in scientific research projects that have not passed the ethical review process. Therefore, recommendations are put forward: comprehensively popularizing the training of ethical review, focusing on strengthening the vulnerable groups and regions, strictly implementing ethical review laws and regulations, and strengthening evaluation and supervision, so as to improve the service quality and efficiency of ethical review in multiple directions.

Aggregation-induced emission (AIE) refers to an uncommon phenomenon that some fluorogens are weakly emissive in solution but become intensely florescent in aggregated state. Fluorogens with the characteristics of AIE are called AIEgens. Traditional dyes often suffer from a common photophysical phenomenon named aggregation-caused quenching (ACQ). As an anti-ACQ phenomenon, AIE shows great potential in biomedical applications. In this paper, the flurescence mechanism and characteristics of AIE are summarized, and the recent advances of aggregation-induced emission in tumor diagnosis and therapy is reviewed.

Objective To explore the CT dominant phase and optimal classification model in differenting clear cell renal cell carcinoma (ccRCC) from fat‐poor angiomyolipoma (fpAML) through quantitative multiple‐phase CT radiomic features analysis. Methods Clinical and imaging data of 195 cases pathologically confirmed ccRCC (n=131) and fpAML (n=64) were retrospectively studied. All the patients underwent non‐contrast enhanced CT scans and dynamic multi‐phase (corticomedullary phase, medullary phase and excretion phase) contrast‐enhanced CT scans. Regions of interest (ROIs) were manually delineated based on the selected image slices with the maximal diameter of the lesion using ITK‐SNAP software, followed by the acquisition of candidate CT radiomic feature sets from each phase with statistically significant differences by using Mann‐Whitney U test. Then, using the synthetic minority oversampling technique (SMOTE), 232 classification models which are composed of 29 different feature selection algorithms (top 10 features were chosen by the backward elimination method) and 8 different classifiers were constructed. Employing the 5‐fold cross‐validation method, the performance of each classification models for each phase was evaluated using accuracy (ACC), sensitivity (SEN), specificity (SPE) and area under receiver operating characteristic curve (AUC), to acquire dominant CT phases and the optimal classification models for distingushing ccRCC and fpAML, along with the key imaging radiomic features. Results In this study, the mean maximal diameter of ccRCC and fpAML lesions were (3.9±1.4) cm, and (3.5±1.7) cm, respectively, and there was no statistically significant difference in the size of the tumor between two groups (P>0.05). From 102 initial imaging feature sets, the total number of candidate imaging feature sets (P<0.05) were:non‐enhanced phase (n=26), corticomedullary phase (n=71), medullary phase (n=68), excretion phase (n=62). Among the 232 classification models through different combination of classifiers and feature selectors, the amount of classification models which achieved the maximum of AUC value (AUCmax) from different CT phases were: non‐enhanced phase (n=106, 45.7%), corticomedullary phase (n=94, 40.5%), medullary phase (n=23, 9.9%), excretion phase (n=9, 3.9%). Imaging features from non‐enhanced phase and corticomedullary phase yielded higher performance compared with medullary phase and excretion phase, with the corresponding optimal prediction models were SVM‐fisher_score (AUC: 0.897, ACC: 83%, SEN: 84%, SPE:80%) and Logistic Regression‐RFS (AUC: 0.891, ACC: 83%, SEN: 81%, SPE: 89%), respectively. Conclusions The quantitative imaging features from non‐enhanced and corticomedullary phase have better performance among proposed classification models than that from medullary phase and excretion phase. Furthermore, it is feasible to acquire proper combination of feature selection and classifiers to achieve high performance in identifying ccRCC and fpAML.

Objective To explore the construction method and physicochemical properties of disulfide?bonded hyaluronic acid?functionalized sodium?meter probe for hepatocellular carcinoma, and its biological evaluation in vitro and feasibility of MRI. Methods Synthesis of hyaluronic acid?disulfide?bonded?poly ε?caprolactone (HA?SS?PCL) by disulfide?bonded alkynyl?terminated polycaprolacton (alkyne?SS?PCL) and azido?terminated hyaluronic acid (HA?N3) by clicking chemical reaction, then doxorubicin (DOX) and superparamagnetic iron oxide (SPIO) were encapsulated in HA?SS?PCL core by dialysis method.HA?SS?PCL@DOX/SPIO was prepared and its particle size,DOX and SPIO loading rate were measured. With PBS as control group, the safety of HA?SS?PCL on human hepatocellular carcinoma cells HepG2 and normal liver cells LO2 was evaluated by the methylthiazolyl tetrazolium (MTT) assay, and the cytotoxicity of HA?PCL@DOX/SPIO and HA?SS?PCL@DOX/SPIO on human hepatocellular carcinoma cells HepG2 was evaluated. Immunofluorescence and flow cytometry were used to observe the expression of CD44 receptor on the surface of HepG2 cells in HA?PCL@DOX/SPIO and HA?SS?PCL@DOX/SPIO groups. Through in vitro MRI, PBS was used as the control group to observe the changes of T2 signal intensity of HA?PCL@DOX/SPIO and HA?SS?PCL@DOX/SPIO groups when SPIO concentration was 10, 20, 40, 80 μg / ml. One way ANOVA test and t test were used. Results HA?SS?PCL@DOX / SPIO sodium?meter probes were successfully constructed. The particle size of HA?SS?PCL@DOX/SPIO was (126.9±6.3) nm,and they were spherical with uniform size. The loading rates of DOX and SPIO were 61.4% and 58.7%. MTT assay showed that the survival rate of HepG2 and LO2 cells was more than 80% even at 500 μg/ml of HA?SS?PCL, 66.6% in HA?PCL@DOX/SPIO group and 55.2% in HA?SS?PCL@DOX/SPIO group. Immunofluorescence and flow cytometry showed that HA?PCL@DOX/SPIO and HA?SS?PCL@DOX/SPIO groups all have strong fluorescence, and the latter has stronger fluorescence intensity the former fluorescence intensity was 139.70±8.52,less than the latter 245.06±13.21. In vitro MRI showed that the T2 signal intensity of HA?PCL@DOX/SPIO and HA?SS?PCL@DOX/SPIO was significantly lower than that of the control group (F values were 613.591 and 569.234,P=0.000), the latter decline rate was more significant. Conclusion The disulfide?bonded hyaluronic acid?functionalized sodium?meter probe for hepatocellular carcinoma has excellent physicochemical properties, good targeting and MRI functions on human hepatoma cell HepG2 at the cellular level in vitro.

Objective To preliminarily explore the anti?cancer efficiency of disulfide?bonded hyaluronic acid?functionalized targeted sodium?meter probe for hepatocellular carcinoma and the feasibility of MRI. Methods Twenty?one nude mice models of subcutaneous liver cancer transplantation were randomly divided into saline, hyaluronic acid?poly ε?caprolactone@ doxorubicin/superparamagnetic iron oxide (HA?PCL@DOX/SPIO) and HA?disulfide?bonded?PCL@DOX/SPIO (HA?SS?PCL@DOX/SPIO) groups, with 7 mice in each group. The experimental groups were injected with micelles at a dose of Fe 5 mg/kg through the tail vein, and the control group was injected with the same amount of saline via the tail vein. MRI was performed before and after injection (2 h, 4 h, 8 h). The T2 value of the region of interest (tumor) was measured and its decline rate was calculated. Twenty?one nude mice models of orthotopic liver cancer transplantation were randomly divided into saline group,HA?PCL@DOX/SPIO and HA?SS?PCL@DOX/SPIO groups, with 7 mice in each group. The experimental groups were injected with micelles at a dose of DOX 2 mg/kg through the tail vein by three consecutive times a day apart, and the control group was injected with the same amount of saline through the tail vein. Continuous observation for 15 days to calculate tumor inhibition rate. One way ANOVA test was used. Results The T2 value of HA?SS?PCL@DOX/SPIO group decreased significantly after 2, 4 and 8 hours (P<0.05) than initial time, which was distinct compared with HA?PCL@DOX/SPIO group. The growth rate of tumor in HA?SS?PCL@DOX/SPIO and HA?PCL@DOX/SPIO groups was significantly lower than that in the control group (F=21.513,P<0.05). The former had the most obvious inhibitory effect on orthotopic liver cancer (47.7% and 28.2%). Conclusion Disulfide?bonded hyaluronic acid?functionalized targeted sodium?meter probe for hepatocellular carcinoma(HA?SS?PCL@DOX/SPIO) has high anti?cancer efficiency and imaging function at the animal level in vivo, and can be used to monitor the early therapeutic effect of tumor at the molecular imaging level.