Objective To assess the current status and outcomes of living donor liver transplantation (LDLT) in patients with unresectable colorectal cancer liver metastases (CRLM). Methods Two reviewers independently conducted a systematic search of Medline (via PubMed), the Cochrane Library, and ClinicalTrials.gov in accordance with preferred reporting items for systematic reviews guidelines. English-language publications reporting LDLT for unresectable CRLM were identified; study characteristics and recipient outcomes were extracted. Results Twelve studies were retrieved, six completed studies enrolling 55 patients and six ongoing trials. Selected patients appeared to derive benefit from LDLT. Reported overall survival was 100% at 1 year and 100%, 71.4% at 3 years. The 1-year progression-free survival was 85.7% and 75.1%, and 3-year progression-free survival was 68.6% and 53.7%. Conclusions Prospective data on LDLT for unresectable CRLM remain scarce. The approach is still investigational and warrants validation through prospective clinical trials.

OBJECTIVE To investigate a dynamic monitoring of drug consumption （DMDC） model based on the seasonal Mann-Kendall trend test， aiming to provide scientific evidence for the efficient and macroscopic monitoring of drug use. METHODS A monitoring list of key outpatient drugs was established based on the top 20% of drugs ranked by sales volume in the outpatient pharmacy in October 2024. A DMDC model based on the Mann-Kendall trend test was constructed using the monthly usage data of key outpatient drugs from November 2021 to October 2024， aiming to eliminate the impact of seasonal fluctuations and analyze the temporal trends in drug consumption. Taking mucolytic expectorants， triazole derivatives for dermatophytosis， and single-agent hydroxymethylglutaryl coenzyme A （HMG-CoA） reductase inhibitors as examples， the monitoring effectiveness of the DMDC model was demonstrated， and its performance was compared with that achieved by the traditional sequential growth rate ranking method. RESULTS A total of 215 drug varieties were included in the monitoring list， and DMDC models were successfully established for all of them. Among these， 119 showed a significant increasing trend （P＜0.05， S′＞0）. The model successfully monitored the monthly consumption of mucolytic expectorants， triazole derivatives for dermatophytosis， and single- agent HMG-CoA reductase inhibitors. The precision and recall rates of the DMDC model for identifying abnormal drug use were 60.7% and 85.0%， respectively， both significantly higher than those of the sequential growth rate ranking method （8.3% and 15.0%， respectively） （χ2＝20.114， P＜0.001； χ2＝19.600， P＜0.001）. CONCLUSIONS DMDC model based on the seasonal Mann-Kendall trend test can effectively identify long-term trends in drug consumption， eliminate seasonal interference， enhance monitoring accuracy and management efficiency， and is suitable for the dynamic monitoring of drug consumption.

ObjectiveTo investigate the therapeutic effect of sitravatinib on carbon tetrachloride （CCl₄）-induced liver fibrosis in mice. MethodsA total of 30 male C57BL/6J mice， aged 8 weeks， were randomly divided into control group， CCl₄ model group， and low- （5 mg/kg）， middle- （10 mg/kg）， and high-dose （20 mg/kg） sitravatinib groups. All mice except those in the control group were given intraperitoneal injection of CCl₄ for 4 consecutive weeks to induce liver fibrosis， and since the first day of modeling， the mice in the low-， middle-， and high-dose sitravatinib groups were given sitravatinib at the corresponding dose by gavage every day. The serum levels of total cholesterol （TC）， triglyceride （TG）， and alanine aminotransferase （ALT） were measured for the mice in each group； hepatic hydroxyproline content was measured； HE staining， Masson staining， and Sirius Red staining were used to observe liver histopathological changes； quantitative real-time PCR and Western blot were used to measure the mRNA and protein expression levels of α-smooth muscle actin （α-SMA） and collagen type I alpha 1 （Col1a1） in liver tissue. The therapeutic effect of sitravatinib was assessed based on the above results. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the control group， the model group had significant increases in the levels of TC， TG， and ALT （all P<0.05）， and there were no significant differences in the levels of TC， TG， and ALT between the model group and the low-， middle-， and high-dose sitravatinib groups （all P>0.05）. Hepatic hydroxyproline content decreased after sitravatinib intervention， with a significant difference between the middle-/high-dose sitravatinib groups and the CCl₄ model group （both P<0.05）. Histopathological staining showed that the sitravatinib treatment groups had a reduction in collagen deposition， along with thinning and fragmentation of fibrous septa， and in the high-dose sitravatinib group， 4 mice had a fibrosis stage of S0—S1 and 2 mice had a fibrosis stage of S2—S3， suggesting a certain degree of alleviation of liver fibrosis degree compared with the CCl₄ model group （mainly S3—S4）. The measurement of related molecules showed that sitravatinib downregulated the mRNA and protein expression levels of α-SMA and Col1a1 （all P<0.05）. ConclusionSitravatinib can effectively alleviate CCl₄-induced liver fibrosis in mice， possibly by inhibiting hepatic stellate cell activation and collagen synthesis.

ObjectiveTo investigate the potential mechanism of Huatan Sanjie Formula （化痰散结方， HSF） in the treatment of triple negative breast cancer （TNBC） based on the integrinβ1/focal adhesion kinase/yes-associated protein （integrinβ1/FAK/YAP） mechanotransduction signaling pathway. MethodsFifty BALB/c mice were randomly assigned to a model group， doxorubicin group， low-， medium-， and high-dose HSF groups， with 10 mice per group. An orthotopic TNBC transplantation model was established in all mice using syngeneic implantation of 4T1 cells. After successful modeling， mice in the model group received intragastric administration of normal saline 0.2 ml each day. Mice in the low-， medium-， and high-dose HSF groups received HSF by gavage at doses of 5.99， 11.97， and 23.94 g/（kg·d）， respectively. The doxorubicin group received intraperitoneal injections of doxorubicin （1.5 mg/kg） once every two days. All treatments lasted for 30 days. After the final administration， mice were sacrificed， and tumor weight and volume were measured. Hematoxylin-eosin （HE）， Masson's trichrome， and Sirius Red staining were performed to evaluate histopathological changes and collagen fiber deposition in tumor tissues. TUNEL staining was used to assess apoptosis. The Young's modulus of tumor tissues was measured using atomic force microscopy （AFM）. The nuclear-cytoplasmic localization of YAP was determined by immunofluorescence staining. Protein expression levels of integrinβ1， focal adhesion kinase （FAK）， YAP， and phosphorylated focal adhesion kinase （p-FAK） were detected by Western Blotting. The mRNA expression levels of integrinβ1， FAK， and YAP were assessed by quantitative real-time polymerase chain reaction （qRT-PCR）. Pearson correlation analysis was performed to evaluate the relationships among tumor tissue Young's modulus， apoptosis rate， and the expression levels of proteins related to the integrinβ1/FAK/YAP signaling pathway. ResultsCompared to the model group， tumor weight was significantly reduced in the doxorubicin group and the medium- and high-dose HSF groups， while tumor volume significantly decreased in the doxorubicin group and the high-dose HSF group （P＜0.01）. Tumor weight in the high-dose HSF group was significantly lower than that in the low-dose group， and tumor volume was significantly smaller than that in both the low- and medium-dose groups （P＜0.05）. Marked improvements in histopathological morphology were observed in the medium- and high-dose HSF groups and the doxorubicin group， while the proportion of collagen fiber deposition and the nuclear-to-cytoplasmic ratio of YAP were significantly reduced （P＜0.01）. Compared to the model group， all three HSF groups and the doxorubicin group exhibited significantly increased apoptosis rates， decreased Young's modulus， and reduced mRNA expression levels of integrinβ1， and YAP （P＜0.05 or P＜0.01）. Furthermore， protein expression levels of integrinβ1， p-FAK， and YAP in the high-dose HSF group were significantly lower than those in the model group （P＜0.05 or P＜0.01）. Pearson correlation analysis demonstrated a significant negative correlation between tumor tissue Young's modulus and apoptosis rate （r =-0.93， P＜0.01）. In contrast， the protein expression levels of integrinβ1， p-FAK， and YAP were positively correlated with Young's modulus （r=0.88， 0.97， and 0.98， respectively； P＜0.05） and negatively correlated with apoptosis rate （r=-0.93，-0.97， and -0.93， respectively； P＜0.05）. ConclusionHSF can significantly inhibit tumor growth in TNBC model mice. Its antitumor effect may be associated with reducing tumor tissue stiffness through suppression of the integrinβ1/FAK/YAP mechanotransduction signaling pathway.

Background/Aims: Regorafenib is recommended by guidelines and trials as a sequential second-line therapy following progression on first-line sorafenib or lenvatinib in hepatocellular carcinoma (HCC). However, efficacy is limited, highlighting the urgent need to screen suitable patients and develop sensitization strategies. Methods: Acquired sorafenib- or lenvatinib-resistant (SR or LR) HCC cell lines and organoids were established. Genome-wide CRISPR library screen was performed in SR or LR cell strains to identify synthetic lethal targets of regorafenib. RNA-seq and FITC-regorafenib efflux assay were used to elucidate ERBB3-driven downstream signaling. Preclinical mouse models of cell line- and patient-derived xenografts and clinical cohorts of HCC patients were employed to validate the efficacy of ERBB3-guided patient stratification. Results: Screening with CRISPR library, we showed that inhibition of ERBB3 was synthetic lethal with regorafenib in SR or LR cell strains and organoids. Mechanistically, SR or LR triggered feedback activation of ERBB3 signaling and mediated regorafenib efflux via ERBB3-HIF1A-ABCB1 cascade pathway, limiting sensitivity to regorafenib. Moreover, ERBB3-low tumors following SR or LR exhibited significant sensitivity to regorafenib, suggesting its potential as a predictive biomarker to screen optimal candidates for sequential therapy. Seribantumab, an ERBB3-targeting monoclonal antibody, inhibited ERBB3-HIF1A-ABCB1 cascade, and its combination with regorafenib exerted marked synergistic anti-tumor effects on ERBB3-high tumors resistant to sorafenib or lenvatinib both in vitro and in vivo. Conclusions This study revealed that ERBB3 was a key resistance factor driving limited efficacy to sequential regorafenib, but also an effective therapeutic target whose inhibition enhanced regorafenib sensitivity after SR or LR.

ObjectiveTo establish and evaluate a hyperuricemia （HUA） mouse model with the damp-turbidity internal accumulation syndrome. MethodsThirty-six C57BL/6J mice were randomly divided into control group， chemically induced model group （Model）， and model combined with high-fat and fatigue group （Model+HF）. Twenty-four uricase gene knockout （UOX^-/-） mice were randomly divided into UOX^-/- group and UOX^-/-+HF group， with 12 mice in each group. The Model group and the Model+HF group established the HUA model by intragastric administration of potassium oxyazinate combined with adenine. The Model+HF group and the UOX^-/-+HF group adopted a high-fat diet combined with weight-bearing exhaustive swimming to establish the HUA model with the damp-turbidity internal accumulation syndrome. On day 1， 7， 14， 21， and 28 after modeling， the damp-turbidity internal accumulation syndrome score of each group was evaluated. On day 1 and day 28， a weight-bearing swimming exhaustion test was performed， and the exhaustive swimming time was recorded. On day 28， liver and kidney indexes were calculated， and hematoxylin-eosin （HE） staining was used to observe histopathological changes in liver and kidney tissues. Serum levels of uric acid （UA）， xanthine dehydrogenase （XDH）， xanthine oxidase （XOD） and urea nitrogen （BUN） were detected through biochemical assays. ELISA was used to detect serum levels of tumor necrosis factor-α （TNF-α） and interleukin-1β （IL-1β）. Immunohistochemistry was used to detect the protein expression of organic anion transporter 1 （OAT1） and glucose transporter 9 （GLUT9） in renal tissues. Quantitative real-time PCR （qRT-PCR） was used to detect the mRNA expressions of adenosine triphosphate binding transporter G2 （ABCG2）， hypoxia-inducible factor-1α （HIF-1α）， urate anion transporter 1 （URAT1）， and GLUT9 in renal tissues. ResultsOn day 14 of modeling， the damp-turbidity internal accumulation syndrome scores of mice in the Model+HF group and the UOX^-/-+HF group were elevated compared with the control group（P＜0.05）； on day 28， the scores significantly increased， and the exhaustive swimming time was shortened （P＜0.01）， indicating successful establishment of the damp-turbidity internal accumulation syndrome model. Compared with the control group， all other groups exhibited increased kidney index， serum levels of UA， XDH， XOD， BUN， TNF-α， and IL-1β， elevated renal mRNA expression of HIF-1α， URAT1， OAT1， and GLUT9， and decreased renal ABCG2 mRNA expression （P＜0.01 or P＜0.05）. Significant pathological damage in the kidney was observed in the Model+HF group and the UOX^-/-+HF group compared to the Model group and the UOX^-/- group， with decreased serum UA and increased BUN and TNF-α levels （P＜0.05 or P＜0.01）， as well as increased expression of OAT1 and GLUT9 in the renal tissue. ConclusionBoth chemical induction and gene knockout， combined with a high-fat diet and weight-bearing exhaustive swimming， can successfully establish mouse models of HUA with damp-turbidity internal accumulation syndrome. Chemical induction is simple to operate and cost-effective， suitable for short-term drug screening， while UOX gene knockout induces spontaneous elevation of serum uric acid levels without drug administration， which may better mimick human metabolic characteristics.

ObjectiveTo establish and evaluate a hyperuricemia （HUA） mouse model with the damp-turbidity internal accumulation syndrome. MethodsThirty-six C57BL/6J mice were randomly divided into control group， chemically induced model group （Model）， and model combined with high-fat and fatigue group （Model+HF）. Twenty-four uricase gene knockout （UOX^-/-） mice were randomly divided into UOX^-/- group and UOX^-/-+HF group， with 12 mice in each group. The Model group and the Model+HF group established the HUA model by intragastric administration of potassium oxyazinate combined with adenine. The Model+HF group and the UOX^-/-+HF group adopted a high-fat diet combined with weight-bearing exhaustive swimming to establish the HUA model with the damp-turbidity internal accumulation syndrome. On day 1， 7， 14， 21， and 28 after modeling， the damp-turbidity internal accumulation syndrome score of each group was evaluated. On day 1 and day 28， a weight-bearing swimming exhaustion test was performed， and the exhaustive swimming time was recorded. On day 28， liver and kidney indexes were calculated， and hematoxylin-eosin （HE） staining was used to observe histopathological changes in liver and kidney tissues. Serum levels of uric acid （UA）， xanthine dehydrogenase （XDH）， xanthine oxidase （XOD） and urea nitrogen （BUN） were detected through biochemical assays. ELISA was used to detect serum levels of tumor necrosis factor-α （TNF-α） and interleukin-1β （IL-1β）. Immunohistochemistry was used to detect the protein expression of organic anion transporter 1 （OAT1） and glucose transporter 9 （GLUT9） in renal tissues. Quantitative real-time PCR （qRT-PCR） was used to detect the mRNA expressions of adenosine triphosphate binding transporter G2 （ABCG2）， hypoxia-inducible factor-1α （HIF-1α）， urate anion transporter 1 （URAT1）， and GLUT9 in renal tissues. ResultsOn day 14 of modeling， the damp-turbidity internal accumulation syndrome scores of mice in the Model+HF group and the UOX^-/-+HF group were elevated compared with the control group（P＜0.05）； on day 28， the scores significantly increased， and the exhaustive swimming time was shortened （P＜0.01）， indicating successful establishment of the damp-turbidity internal accumulation syndrome model. Compared with the control group， all other groups exhibited increased kidney index， serum levels of UA， XDH， XOD， BUN， TNF-α， and IL-1β， elevated renal mRNA expression of HIF-1α， URAT1， OAT1， and GLUT9， and decreased renal ABCG2 mRNA expression （P＜0.01 or P＜0.05）. Significant pathological damage in the kidney was observed in the Model+HF group and the UOX^-/-+HF group compared to the Model group and the UOX^-/- group， with decreased serum UA and increased BUN and TNF-α levels （P＜0.05 or P＜0.01）， as well as increased expression of OAT1 and GLUT9 in the renal tissue. ConclusionBoth chemical induction and gene knockout， combined with a high-fat diet and weight-bearing exhaustive swimming， can successfully establish mouse models of HUA with damp-turbidity internal accumulation syndrome. Chemical induction is simple to operate and cost-effective， suitable for short-term drug screening， while UOX gene knockout induces spontaneous elevation of serum uric acid levels without drug administration， which may better mimick human metabolic characteristics.

This article introduces the discipline characteristics of the foot and ankle surgery, the development of foot and ankle surgery in the United States, and its specialist physician straining system. The findings are summarized as follows: ①close connection with the standardized residency and the orthopedic specialist training programs; ②clear training objectives and a unified, standardized curriculum, with specialist competency training objectives established in the residency training stage; ③stable financial support for training specialists; and ④ a professional qualification certification system to ensure the quality of physicians. These measures can serve as a reference for developing a training system for foot and ankle surgeons in China and promoting the high-quality development of the discipline.

Objective:To investigate the current status of standardized residency training (SRT) teaching activities at Zhongshan Hospital affiliated to Fudan University, and to explore optimization strategies.Methods:We collected behavioral data from the SRT course selection platform and resident questionnaire survey data throughout 2024. Descriptive analysis, chi-square test, Mann-Whitney U test, and multivariable logistic regression analysis were performed. Results:A total of 170 teaching sessions were conducted in 2024, with interactive practice-based sessions accounting for 42.35% and lecture-based sessions accounting for 47.06%. According to 536 questionnaires, residents' overall satisfaction with teaching activities scored 87.83 points (high satisfaction, ≥85 points; moderate satisfaction, <85 points). The proportion of high satisfaction with interactive practice-based sessions was significantly higher than that with lecture-based sessions (82.81% vs. 75.46%, P=0.034). The enrollment for weekday evening courses filled up significantly faster than that for weekday daytime courses [4 (2, 6) seconds vs. 12 (8, 15) seconds, P<0.001]. Interactive practice-based sessions [odds ratio ( OR)=1.6, 95% CI=1.1-2.3, P=0.018] and weekday evening sessions ( OR=1.4, 95% CI=1.0-2.0, P=0.048) significantly improved resident satisfaction. Conclusions:Optimizing course formats and scheduling can enhance the quality of SRT teaching activities.

Objective:This study aims to evaluate the efficacy of levosimendan in elderly patients with acute heart failure across varying levels of renal function, utilizing real-world data.Methods:We conducted a retrospective cohort study involving 699 elderly patients with acute heart failure who were hospitalized at the Second Xiangya Hospital of Central South University and received positive inotropic drugs between January 2015 and December 2022.The median age of the participants was 71 years(interquartile range, 66 to 77), with 61.9% being male.Among these patients, 171 received non-levosimendan positive inotropic drugs(non-levosimendan group), while 528 were treated with levosimendan(levosimendan group).Baseline clinical data collected during hospitalization were analyzed.The primary outcomes assessed included the reduction in N-terminal pro-brain natriuretic peptide(NT-proBNP)levels following treatment, as well as mortality rates within 30 days and one year.Secondary outcomes encompassed the length of hospital stay and in-hospital mortality.Patients were categorized based on their estimated glomerular filtration rate(eGFR)prior to treatment, with groups defined as those with eGFR≥60 ml·min -1·1.73(m -1) 2 and those with eGFR between 15 and <60 ml·min -1·1.73(m -1) 2.The impact of levosimendan treatment on heart failure improvement and clinical prognosis was analyzed using a double robust method, which accounted for patients with varying levels of renal function. Results:In comparison to the non-levosimendan group, a significantly higher proportion of patients in the levosimendan group exhibited decreased NT-proBNP levels(31.0% vs.47.0%, P<0.001).However, there were no significant differences regarding the length of hospital stay, in-hospital mortality, or mortality rates at 30 days and 1 year(all P>0.05).After applying the double robust method for adjustment, levosimendan was shown to significantly reduce NT-proBNP levels( OR=1.553, 95% CI: 1.225-1.972, P<0.001), although it did not result in a significant improvement in 30-day or 1-year mortality rates.In patients with an eGFR of 15-<60 ml·min -1·1.73(m -1) 2, levosimendan significantly reduced NT-proBNP levels( OR=1.797, 95% CI: 1.308-2.481, P<0.001)and decreased 30-day mortality( HR=0.536, 95% CI: 0.292-0.986, P=0.045).Similarly, in patients with eGFR ≥60 ml·min -1·1.73(m -1) 2, levosimendan significantly reduced NT-proBNP levels( OR=1.965, 95% CI: 1.325-2.933, P<0.001), but did not improve 30-day mortality.Across varying levels of renal function, levosimendan had no significant effect on 1-year mortality. Conclusions:Levosimendan can significantly enhance cardiac function in elderly patients experiencing acute heart failure, irrespective of varying levels of renal function.Notably, greater benefits regarding short-term mortality were observed in patients with an eGFR of 15-<60 ml·min -1·1.73(m -1) 2.