Intrahepatic cholangiocarcinoma is a malignant tumor with an extremely poor prognosis， and its pathogenesis is complex and remains unclear. In recent years， more and more studies have focused on the role of bile-gut axis in the development and progression of intrahepatic cholangiocarcinoma. Bile-gut axis refers to the complex interaction between bile and gut microbiota， including bile salt metabolism， dynamic changes of microbiota， inflammatory response， and immune system regulation. This article elaborates on the potential mechanisms of bile-gut axis in intrahepatic cholangiocarcinoma， especially gut microbiota dysbiosis， abnormal bile salt metabolism， chronic inflammatory response， and immune system interaction， this article aims to provide new perspectives and possible therapeutic targets for future research and promote the early diagnosis and effective treatment of intrahepatic cholangiocarcinoma.

Objective To investigate the protective effect of lipoic acid-niacin(N2L)on blue light-induced retinal in-jury in mice by regulating the nuclear factor-E2-related factor 2(Nrf2)signaling pathway.Methods Forty-eight male C57BL/6 mice were selected and randomly divided into a wild-type group(+)and an Nrf2 knockout group(-).Each group was further randomly subdivided into four parallel subgroups,with six mice in each.These subgroups were designat-ed as Con+,BL+,N2L+,NS+,Con-,BL-,N2L-,and NS-for corresponding treatments.Electroretinography(ERG)was performed to assess retinal function.TUNEL staining was used to detect photoreceptor cell apoptosis in the mouse retinal tissue.Western blot analysis was conducted to measure the expression levels of heme oxygenase-1(HO-1),B-cell lymphoma-2(Bcl-2),and Bcl-2-associated X proteins(Bax)in the mouse retinal tissue.Results Compared with those in the Con+group,the amplitudes of the ERG b-wave and the second peak(OS2)of mouse oscillatory potentials(OPs)in BL+,NS+,BL-,N2L-,and NS-groups were decreased significantly under medium-and high-intensity stim-ulating light(all P＜0.05).The cell apoptosis rate and the expression level of Bax proteins in BL+,NS+,BL-,N2L-,and NS-groups were significantly higher than those in the Con+group(all P＜0.05).Compared with those in the BL+group,the amplitudes of the ERG b-wave and OS2 of OPs were increased significantly under medium-and high-intensity stimulating light in N2L+and Con-groups(all P＜0.05).N2L+and Con-groups had a significantly lower cell apopto-sis rate than the BL+group(P＜0.05).BL-and NS-groups had a significantly higher cell apoptosis rate and significant-ly lower Bax levels than the BL+group(all P＜0.05).Compared with those in the N2L+group,the amplitudes of the ERG b-wave and OS2 of OPs were reduced significantly under medium-and high-intensity stimulating light in NS+,BL-,N2L-,and NS-groups(all P＜0.05).The cell apoptosis rate and Bax levels in NS+,BL-,N2L-,and NS-groups were significantly higher than those in the N2L+group(all P＜0.05).The Bax level in the Con-group was significantly lower than that in the N2L+group(P＜0.05).Compared with those in the NS+group,the amplitudes of the ERG b-wave and OS2 of OPs were increased significantly under medium-and high-intensity stimulating light in the Con-group(all P＜0.05).The cell apoptosis rate and Bax levels in the Con-group were significantly lower than those in the NS+group(P＜0.05).Compared with those in the Con-group,the amplitudes of the ERG b-wave and OS2 of OPs were decreased significantly under medium-and high-intensity stimulating light in BL-,N2L-,and NS-groups(all P＜0.05).BL-,N2L-,and NS-groups had a significantly higher cell apoptosis rate and Bax levels than the Con-group(all P＜0.05).HO-1 and Bcl-2 levels in BL+,N2L+,and NS+groups were significantly higher than those in the Con+group(all P＜0.05).Compared with those in the BL+group,HO-1 and Bcl-2 levels were increased significantly in the N2L+group and decreased significantly in Con-,BL-,N2L-,and NS-groups(all P＜0.05).HO-1 and Bcl-2 levels in NS+,Con-,BL-,N2L-,and NS-groups were significantly lower than those in the N2L+group(all P＜0.05).Con-,BL-,N2L-,and NS-groups showed significantly lower HO-1 and Bcl-2 levels than the NS+group(all P＜0.05).The N2L-group had significantly higher HO-1 and Bcl-2 levels than the Con-group(both P＜0.05).Conclusion N2L may antag-onize blue light-induced retinal damage in mice by activating the Nrf2 signaling pathway.

Cholangiocarcinoma,as a malignant tumor with strong invasiveness and poor prognosis,has a complex metastasis mechanism,and urgently needs in-depth research.Circulating tumor cells(CTC),as the key cell type for tumor cells to shed from the primary site and enter the bloodstream,have significant research significance.In recent years,studies have found that the invasive pseudopodia of CTC play a significant role in the migration and invasion of tumor cells.Among them,in terms of signal transduction pathways,the Rho family GTPases(RhoA,Rac1,Cdc42)work in coordination to regulate the contractility of the pseudofoot,the branching polymerization and orientation of actin,and the phosphoinositide3-kinase/protein kinase B(PI3K/AKT)pathway promotes the assembly of actin and cross-communicates with the Rho family by activating AKT.At the molecular mechanism level,long non-coding RNAs regulate the expression of pseudopolypod-related genes by adsorbing miRNAs and other means.Matrix metalloproteinase(MMP)degrades the extracellular matrix(ECM)to form an invasion positive feedback.In terms of the microenvironment,cancer-associated fibroblast(CAF)and the cytokines such as transforming growth factor-β(TGF-β)secreted by macrophages,epidermal growth factor(EGF),and interleukin-6(IL-6)activate pseudopodia to form signal transduction pathways.ECM hardness and fiber arrangement affect the extension direction of pseudopodia through mechanical force conduction.This article conducted a comprehensive analysis of the biological characteristics of CTC,the formation mechanism of invasive pseudopodia in cholangiocarcinoma,the metastatic features of cholangiocarcinoma cells and their clinical significance,as well as the role of CTC in the metastatic process of cholangiocarcinoma,in order to summarize the existing research results,explore potential therapeutic targets and future research directions,and provide new ideas for the clinical treatment of cholangiocarcinoma.

Objective To investigate the protective effect of lipoic acid-niacin(N2L)on blue light-induced retinal in-jury in mice by regulating the nuclear factor-E2-related factor 2(Nrf2)signaling pathway.Methods Forty-eight male C57BL/6 mice were selected and randomly divided into a wild-type group(+)and an Nrf2 knockout group(-).Each group was further randomly subdivided into four parallel subgroups,with six mice in each.These subgroups were designat-ed as Con+,BL+,N2L+,NS+,Con-,BL-,N2L-,and NS-for corresponding treatments.Electroretinography(ERG)was performed to assess retinal function.TUNEL staining was used to detect photoreceptor cell apoptosis in the mouse retinal tissue.Western blot analysis was conducted to measure the expression levels of heme oxygenase-1(HO-1),B-cell lymphoma-2(Bcl-2),and Bcl-2-associated X proteins(Bax)in the mouse retinal tissue.Results Compared with those in the Con+group,the amplitudes of the ERG b-wave and the second peak(OS2)of mouse oscillatory potentials(OPs)in BL+,NS+,BL-,N2L-,and NS-groups were decreased significantly under medium-and high-intensity stim-ulating light(all P＜0.05).The cell apoptosis rate and the expression level of Bax proteins in BL+,NS+,BL-,N2L-,and NS-groups were significantly higher than those in the Con+group(all P＜0.05).Compared with those in the BL+group,the amplitudes of the ERG b-wave and OS2 of OPs were increased significantly under medium-and high-intensity stimulating light in N2L+and Con-groups(all P＜0.05).N2L+and Con-groups had a significantly lower cell apopto-sis rate than the BL+group(P＜0.05).BL-and NS-groups had a significantly higher cell apoptosis rate and significant-ly lower Bax levels than the BL+group(all P＜0.05).Compared with those in the N2L+group,the amplitudes of the ERG b-wave and OS2 of OPs were reduced significantly under medium-and high-intensity stimulating light in NS+,BL-,N2L-,and NS-groups(all P＜0.05).The cell apoptosis rate and Bax levels in NS+,BL-,N2L-,and NS-groups were significantly higher than those in the N2L+group(all P＜0.05).The Bax level in the Con-group was significantly lower than that in the N2L+group(P＜0.05).Compared with those in the NS+group,the amplitudes of the ERG b-wave and OS2 of OPs were increased significantly under medium-and high-intensity stimulating light in the Con-group(all P＜0.05).The cell apoptosis rate and Bax levels in the Con-group were significantly lower than those in the NS+group(P＜0.05).Compared with those in the Con-group,the amplitudes of the ERG b-wave and OS2 of OPs were decreased significantly under medium-and high-intensity stimulating light in BL-,N2L-,and NS-groups(all P＜0.05).BL-,N2L-,and NS-groups had a significantly higher cell apoptosis rate and Bax levels than the Con-group(all P＜0.05).HO-1 and Bcl-2 levels in BL+,N2L+,and NS+groups were significantly higher than those in the Con+group(all P＜0.05).Compared with those in the BL+group,HO-1 and Bcl-2 levels were increased significantly in the N2L+group and decreased significantly in Con-,BL-,N2L-,and NS-groups(all P＜0.05).HO-1 and Bcl-2 levels in NS+,Con-,BL-,N2L-,and NS-groups were significantly lower than those in the N2L+group(all P＜0.05).Con-,BL-,N2L-,and NS-groups showed significantly lower HO-1 and Bcl-2 levels than the NS+group(all P＜0.05).The N2L-group had significantly higher HO-1 and Bcl-2 levels than the Con-group(both P＜0.05).Conclusion N2L may antag-onize blue light-induced retinal damage in mice by activating the Nrf2 signaling pathway.

Cholangiocarcinoma,as a malignant tumor with strong invasiveness and poor prognosis,has a complex metastasis mechanism,and urgently needs in-depth research.Circulating tumor cells(CTC),as the key cell type for tumor cells to shed from the primary site and enter the bloodstream,have significant research significance.In recent years,studies have found that the invasive pseudopodia of CTC play a significant role in the migration and invasion of tumor cells.Among them,in terms of signal transduction pathways,the Rho family GTPases(RhoA,Rac1,Cdc42)work in coordination to regulate the contractility of the pseudofoot,the branching polymerization and orientation of actin,and the phosphoinositide3-kinase/protein kinase B(PI3K/AKT)pathway promotes the assembly of actin and cross-communicates with the Rho family by activating AKT.At the molecular mechanism level,long non-coding RNAs regulate the expression of pseudopolypod-related genes by adsorbing miRNAs and other means.Matrix metalloproteinase(MMP)degrades the extracellular matrix(ECM)to form an invasion positive feedback.In terms of the microenvironment,cancer-associated fibroblast(CAF)and the cytokines such as transforming growth factor-β(TGF-β)secreted by macrophages,epidermal growth factor(EGF),and interleukin-6(IL-6)activate pseudopodia to form signal transduction pathways.ECM hardness and fiber arrangement affect the extension direction of pseudopodia through mechanical force conduction.This article conducted a comprehensive analysis of the biological characteristics of CTC,the formation mechanism of invasive pseudopodia in cholangiocarcinoma,the metastatic features of cholangiocarcinoma cells and their clinical significance,as well as the role of CTC in the metastatic process of cholangiocarcinoma,in order to summarize the existing research results,explore potential therapeutic targets and future research directions,and provide new ideas for the clinical treatment of cholangiocarcinoma.

Objective To evaluate the clinical efficacy of 125I seeds implantation combined with transcatheter arterial infusion(TAI)in treating advanced pancreatic carcinoma(PC).Methods By using envelope sealing method,76 patients who met enrollment criteria were divided into observation group and control group.Finally,a total of 67 patients were enrolled in this study.The observation group had 31 patients and the patients received 125I seeds implantation combined with TAI therapy,and the control group had 36 patients and the patients received TAI therapy.After 3 courses of treatment,the clinical efficacy,pain score,incidence of obstructive jaundice(OJ),and survival time were compared between the two groups.Results In the observation group and the control group,the objective response rate(ORR)was 48.4％and 25.0％respectively,and the difference was statistically significant(P＜0.05);the disease control rate(DCR)was 83.9％and 66.7％respectively,and the difference was not statistically significant(P＞0.05).In both groups,the postoperative one-month and 3-month pain scores were decreased obviously when compared with the preoperative values(P＜0.05),but the reduction of pain score in the observation group was more obvious than that in the control group(P＜0.05).In the observation group and the control group,the pain relief rates were 23.06％and 13.4％respectively,and the difference was statistically significant(P=0.0252);the incidences of OJ were 19.4％and 50.0％respectively,and the difference was statistically significant(P＜0.05);the median survival time was 7.9 months and 5.1 months respectively,and the difference was statistically significant(P＜0.05).In both groups,the postoperative one-month and 3-month CA199 levels were decreased,and the difference was statistically significant(P＜0.05).No statistically significant difference in the incidences of adverse reactions such as nausea,vomiting,diarrhea and leukopenia existed between the two groups(P＞0.05).Conclusion 125I seeds implantation combined with TAI therapy can effectively relieve cancer pain,prolong survival time in patients with advanced PC,and it is clinically safe.Therefore,this therapy is worthy of clinical promotion.

AIM: To investigate the preventive effect and optimal drug dose of lipoic acid-niacin(N2L)against blue light-induced retinal damage in SD rats, and to explore its possible protective mechanism.METHODS: A total of 36 specific pathogen free-grade male SD rats of 150-200 g were selected and randomly divided into normal control group, blue light injury group, N2L low-dose group(1.0 mg/kg), N2L medium-dose group(2.5 mg/kg), N2L high-dose group(5.0 mg/kg), and physiological saline group, with 6 rats in each group. The normal control group was reared in a 12 h dark and light cycle, and the rest of the groups received 9 h of daily light exposure, 3 h of blue light irradiation with a wavelength of 455 nm and an intensity of 3000±50 lx, and 12 h of darkness to establish the injury model, and were exposed to light exposure for 14 d. For 14 consecutive durations, a 1 mL dose of the corresponding drug was injected intraperitoneally. The rats were reared for another 5 d with a regular 12 h light-dark cycle and were examined by electroretinography. Specimens were prepared by over anesthesia, HE staining, and the thickness of the outer nuclear layer was observed under a optical microscope; superoxide dismutases(SOD)activity was detected by CheKineTM SOD Activity Assay Kit; and the retinal Caspase-3, quinone oxidoreductase 1(NQO1), glutathione S transferase(GST), Bcl-2, and Bax protein expression in rat retina were detected by Western blot.RESULTS: The amplitude of b-wave in dark-vision ERG 3.0 and 10.0(cd·s)/m2 stimulated light, b-wave in bright-vision ERG 3.0(cd·s)/m2 stimulated light, and the amplitude of the 2nd wave peak of oscillatory potential were significantly lower in blue light injury group than that in the normal control group(all P<0.01), while the amplitude was significantly higher in the N2L medium-dose group than in the blue light injury group(all P<0.05), and was not statistically different from that of the normal control group; the thickness of the retina in the blue light injury group was decreased in the ONL compared with that of the normal control group(P<0.001), while in the N2L medium dose group, it was thicker than that of the blue light injury group(P<0.001), and there was no statistically significant difference from the normal control group; SOD activity was significantly higher in the N2L medium-dose group than in the remaining 5 groups(P<0.05); the expression of Caspase-3, Bax, and NQO1 in the blue light injury group was higher than that of the normal control group(all P<0.01), and expression of Bax and Caspase-3 was significantly lower in the N2L medium-dose group compared with the blue light injury group(all P<0.001), whereas GST, NQO1 and Bcl-2 were significantly increased(all P<0.01).CONCLUSION:A concentration of 2.5 mg/kg N2L can effectively antagonize the damaging effect of blue light on the retina of SD rats, and it is expected to be a preventive and curative drug for it.

In recent years, traditional Chinese medicine (TCM) has made great progress in the prevention and treatment of cancer. It has gradually revealed its characteristics and advantages in clinical practice, including alleviating clinical symptoms, prolonging survival time, decreasing the adverse effects of chemotherapy, and improving living quality. However, clinical TCM treatment of cancer lacks systematic theoretical guidance, because ancient TCM has not formed a recognized theoretical system of cognitive cancer, and there still are different opinions on the pathogenesis of cancer. Due to the complexity of cancer, the essence of cancer pathogenesis has not been described accurately by using common pathogenic factors, such as pathogenic wind, cold, dampness, summer heat, dryness, and fire. Ancient and modern TCM physicians have a similar understanding that the occurrence of cancer is related to toxin. In the 1990s, the thought of cancerous toxin was first proposed by Prof Zhou Zhongying, a TCM master based on more than 60 years of clinical practice, who used “pandemic Qi (Li-Qi) is a specific pathogenic factor of epidemic disease” in Wenyi Lun (Treatise on Pestilence) for references. The pathogenesis theory of cancerous toxin was gradually established under the guidance of the thought of cancerous toxin. It holds that the cancerous toxin, a special pathogenic factor of cancer, is the key pathogenesis of the occurrence of malignant tumors. According to the pathogenesis theory of cancerous toxin, the basic pathogenesis of malignant tumors is the accumulation of pathogenic factors and cancerous toxin, and the deficiency of the vital Qi (Zheng-Qi). Therefore, the treatment principle involves eliminating pathogenic factors, resolving cancerous toxin, and supporting the vital Qi. The anticancer detoxification methods and the classification of Chinese medicinal herbs with anticancer detoxification effects were put forward. System theory has much in common with the concepts in the theory system of TCM, such as the universal relation theory, asking for a concrete analysis of concrete conditions, the humanism thought, and so on. This article aims to describe, review, and analyze the pathogenesis theory of cancerous toxin based on system theory for clinical practices.

Objective:To establish a predictive model for myocardial contusion (MC) in patients with rib fractures and evaluate its clinical application value.Methods:A retrospective case-control study was conducted to analyze the clinical data of 370 patients with rib fractures admitted to the Affiliated Jiangsu Shengze Hospital of Nanjing Medical University from January 2017 to December 2019, including 257 males and 113 females, aged 18-95 years [(56.5±14.0)years]. All the patients underwent electrocardiogram examination and myocardial biomarker test within 24 hours on admission, of whom 159 were diagnosed with MC, and 211 with non-MC (NMC). The 370 patients were divided into a training set of 264 patients (106 with MC, 158 with NMC) and a validation set of 106 patients (53 with MC, 53 with NMC) at a ratio of 7∶3 through the completely randomized method. In the training set, the MC group and NMC group were compared in terms of their demographic characteristics, vital signs on admission, types of rib fractures, number of rib fractures, locations of rib fractures, associated thoracic injuries, trauma scores, and laboratory indices. Variables of positive correlation with MC in patients with rib fractures were screened by Spearman correlation analysis, followed by univariate binary Logistic regression analysis for these variables to determine the risk factors for MC in patients with rib fractures. LASSO regression analysis and multivariate Logistic regression analysis were applied to identify the independent risk factors for MC in patients with rib fractures, and the regression equation was constructed. A nomogram prediction model was plotted based on the regression equation with R software. The receiver operating characteristic (ROC) curve was plotted to evaluate the model′s discriminability. Hosmer-Lemeshow (H-L) goodness-of-fit test and calibration curves of 1000 repeated samplings by the Bootstrap method were used to evaluate the calibration of the model. The decision curve analysis (DCA) and clinical impact curve analysis (CIC) were plotted to evaluate its clinical efficacy. A risk scoring was performed according to the assigned β coefficient of independent risk factors. Accordingly, the 370 selected patients with rib fractures were divided into low-risk subgroup of 202 patients, moderate-risk subgroup of 108 patients, high-risk subgroup of 50 patients, and extremely high-risk subgroup of 10 patients. The incidence of MC and in-hospital mortality were compared among different subgroups so as to further verify the clinical application value of the predictive model.Results:In the training set, there were significant differences between the MC group and NMC group in bilateral rib fractures, flail chest, number of rib fractures, upper chest proximal sternum segment, upper chest anterolateral segment, upper chest proximal spinal segment, middle chest anterolateral segment, middle chest proximal spinal segment, lower chest anterolateral segment, pneumothorax, mediastinal emphysema, hemothorax, sternal fractures, chest abbreviated injury scale (c-AIS), injury severity score (ISS), new injury severity score (NISS), white blood cell counts, hemoglobin, hematocrit, total cholesterol, low density lipoprotein, albumin, aspartate aminotransferase, alanine aminotransferase, and blood urea nitrogen ( P<0.05 or 0.01). Spearman correlation analysis showed that the bilateral rib fractures, flail chest, number of rib fractures, upper chest proximal sternum segment, upper chest anterolateral segment, upper chest proximal spinal segment, middle chest anterolateral segment, middle chest proximal spinal segment, lower chest anterolateral segment, pneumothorax, hemothorax, sternal fractures, c-AIS, ISS, NISS, white blood cell count, aspartate aminotransferase and blood urea nitrogen were positively correlated with MC ( P<0.05 or 0.01). Univariate binary Logistic regression analysis verified that the above variables with positive correlation were significantly correlated with MC in patients with rib fractures ( P<0.05 or 0.01). The 4 predictor variables screened by LASSO regression analysis were the upper chest anterolateral segment, middle chest proximal spinal segment, pneumothorax, and sternal fractures. Multivariate Logistic regression analysis confirmed that the aforementioned 4 predictor variables were independent risk factors for MC in patients with rib fractures ( P<0.05 or 0.01). The regression equation of the training set was established based on the above independent risk factors: P=e x/(1+e x), with the x=1.57×"upper chest anterolateral segment"+0.73×"middle chest proximal spinal segment"+1.36×"pneumothorax"+2.16×"sternal fractures"-1.10. In the predictive model for MC in patients with rib fractures established based on the equation, the area under the ROC curve (AUC) was 0.77 (95% CI 0.72, 0.83) and 0.77 (95% CI 0.71, 0.82) in the training set and validation set. The H-L goodness-of-fit test showed χ2=2.77, P=0.429 in the training set, and χ2=1.33, P=0.515 in the validation set, indicating that there was no significant difference between the predicted probability and the actual probability of the model ( P>0.05). The calibration curves showed that the bias-corrected curves of the training set and validation set were in good consistency with the actual curves and were both close to the ideal curves. The DCA of the training set and the validation set showed that within the threshold probability range of 0.2-0.8, the predictive model could obtain good net clinical benefits. The CIC of the training set and the validation set indicated that when the threshold probability was >0.4, the population identified as high-risk MC patients by the predictive model highly matched the actual MC patients. Risk scoring of subgroups found that the incidence of MC and in-hospital mortality among the patients with rib fractures were 80.0% and 6.0% in the high-risk subgroup and 90.0% and 20.0% in the extremely high-risk subgroup, significantly higher than those in the low-risk subgroup (24.8%, 1.0%) and the moderate-risk subgroup (55.6%, 1.9%) ( P<0.05). Conclusions:The predictive model for MC in patients with rib fractures constructed based on the upper chest anterolateral segment, middle chest proximal spinal segment, pneumothorax, and sternal fractures has good predictive efficacy and clinical application value.