Ductular reaction （DR） refers to the adaptive pathological changes that occur after hepatobiliary injury， and it is essentially a repair response involving the proliferation， fibrosis， and inflammation of biliary epithelial cell （BEC）. With the understanding of the biological function of BEC， the potential value of DR in disease prognosis and treatment has gradually become a research hotspot. This article systematically reviews the molecular mechanism of DR， its potential as a therapeutic target， and future development directions， as well as novel therapies suggested by targeting these molecular mechanisms， in order to provide a new direction for overcoming current bottlenecks in the treatment of bile duct diseases.

Based on the theoretical framework of "grease-turbidity-heat toxin"， this paper elucidates the patholo-gical evolution pattern underlying the alternation between active and remission phases of inflammatory bowel disease （IBD）. It is proposed that the active phase of IBD represents a progressive and explosive process characterized by internal accumulation of grease turbidity， constraint transforming into heat， and exuberant heat generating toxin. During the remission phase， the pathogenic process manifests as subsidence of heat toxin， depletion of qi and yin， latent retention of residual turbidity， and a state of coexistence between deficiency of healthy qi and lingering pathogenic factors. Accordingly， a staged therapeutic strategy with dynamic intervention and targeted modulation has been established. During the active phase， treatment follows the sequential principle of unblocking， clearing， and resolving pathogenic factors. In the early stage， the therapeutic approach focuses on regulating qi movement， fortifying the spleen， and resolving turbidity， using Tongxie Essential Formula （痛泻要方） and Shenling Baizhu Powder （参苓白术散） to regulate qi and fortify spleen. In the middle stage， the strategy emphasizes clearing heat， eliminating dampness， and dispersing pathogenic accumulation through downward and outward pathways， and Gegen Qinlian Decoction （葛根芩连汤） combined with Banxia Xiexin Decoction （半夏泻心汤） is used to clear and resolve damp-heat. In the late stage， treatment aims to resolve toxin， restrain sore， cool blood， and stabilize collaterals， using Baitouweng Decoction （白头翁汤）， Shaoyao Decoction （芍药汤）， and Xijiao Dihuang Decoction （犀角地黄汤） to eliminate toxins and cool blood. During the remission phase， the principle of reinforcing， consolidating， and penetrating is adopted to restore internal balance and clear the source， using Sishen Pills （四神丸） and Sijunzi Decoction （四君子汤） to reinforce healthy qi and venting pathogens.

Based on the theory of Zi Wu Liu Zhu （子午流注， the ebb and flow of midnight and midday） and the clinical characteristics of diarrhea-predominant irritable bowel syndrome （IBS-D） that its symptoms mainly occur during chou （丑） period （01：00—03：00）， mao （卯） period （5：00—7：00）， and si （巳） period （9：00—11：00）， this paper proposes a temporal pathogenesis chain of "liver constraint during chou period， intestinal stagnation during mao period， and spleen deficiency during si period". Within this chain， liver constraint serves as the initiating factor， and intestinal stagnation manifests as the branch， while spleen deficiency constitutes the root of the disease. Accordingly， a chronotherapeutic principle of "soothing the liver， regulating the intestines， and fortifying the spleen" is proposed， establishing a corresponding time-based syndrome differentiation and treatment system. During chou period， the treatment should focus on soothing the liver to relieve constraint and calming the mind to tranquilize the spirit， thereby blocking the mechanism of liver constraint overacting on the spleen. During mao period， the focus is regulating qi to resolve dampness and harmonizing the intestine to alleviate the branch symptoms of morning abdominal pain and diarrhea. During si period， the suggested method is fortifying the spleen and supplementing qi to drain dampness and stop diarrhea， thereby restoring the pivot of spleen-stomach transportation and transformation. These methods are complemented by strategies to optimize medication compliance， thereby providing a new chronotherapeutic approach for clinical diagnosis and treatment of IBS-D.

Based on the theoretical framework of "grease-turbidity-heat toxin"， this paper elucidates the patholo-gical evolution pattern underlying the alternation between active and remission phases of inflammatory bowel disease （IBD）. It is proposed that the active phase of IBD represents a progressive and explosive process characterized by internal accumulation of grease turbidity， constraint transforming into heat， and exuberant heat generating toxin. During the remission phase， the pathogenic process manifests as subsidence of heat toxin， depletion of qi and yin， latent retention of residual turbidity， and a state of coexistence between deficiency of healthy qi and lingering pathogenic factors. Accordingly， a staged therapeutic strategy with dynamic intervention and targeted modulation has been established. During the active phase， treatment follows the sequential principle of unblocking， clearing， and resolving pathogenic factors. In the early stage， the therapeutic approach focuses on regulating qi movement， fortifying the spleen， and resolving turbidity， using Tongxie Essential Formula （痛泻要方） and Shenling Baizhu Powder （参苓白术散） to regulate qi and fortify spleen. In the middle stage， the strategy emphasizes clearing heat， eliminating dampness， and dispersing pathogenic accumulation through downward and outward pathways， and Gegen Qinlian Decoction （葛根芩连汤） combined with Banxia Xiexin Decoction （半夏泻心汤） is used to clear and resolve damp-heat. In the late stage， treatment aims to resolve toxin， restrain sore， cool blood， and stabilize collaterals， using Baitouweng Decoction （白头翁汤）， Shaoyao Decoction （芍药汤）， and Xijiao Dihuang Decoction （犀角地黄汤） to eliminate toxins and cool blood. During the remission phase， the principle of reinforcing， consolidating， and penetrating is adopted to restore internal balance and clear the source， using Sishen Pills （四神丸） and Sijunzi Decoction （四君子汤） to reinforce healthy qi and venting pathogens.

Objective To construct a decision support education program for the family members of patients with advanced cancer and to investigate its application effects,so as to improve understanding and acceptance of hospice care for family members of advanced cancer patients.Methods Using the Ottawa Decision Support Framework as a theoretical guide,the program was initially drafted based on a literature review,qualitative interview and expert consultation.From September 2023 to January 2024,a convenience sampling method was used to select patients' families in a tertiary-level hospital in Tianjin as the research subjects,and they were randomly divided into an experimental group and a control group.The experimental group received the decision support education program in addition to routine care,while the control group received routine care.Family members' knowledge about hospice,the scores on the Death Attitude Profile Scale,and their willingness to choose hospice care were compared before and after the interventions.Results The program finally included 4 first-level items,15 second-level items,and 59 third-level items.During the program implementation phase,4 cases withdrew from the study,resulting in 46 cases in the experimental group and 47 cases in the control group.After intervention,the experimental group had higher scores on hospice knowledge and positive attitude towards death than the control group,while scores on negative attitude towards death were lower(P＜0.05);their willingness to choose hospice care for themselves and for the patients was higher than that of the control group(P＜0.05).Conclusion The hospice care decision support education program is scientific,feasible and practical,which can improve the knowledge of hospice care of the family members,improve their attitude towards death,and ultimately improve their willingness to choose hospice care.

Objective To construct a decision support education program for the family members of patients with advanced cancer and to investigate its application effects,so as to improve understanding and acceptance of hospice care for family members of advanced cancer patients.Methods Using the Ottawa Decision Support Framework as a theoretical guide,the program was initially drafted based on a literature review,qualitative interview and expert consultation.From September 2023 to January 2024,a convenience sampling method was used to select patients' families in a tertiary-level hospital in Tianjin as the research subjects,and they were randomly divided into an experimental group and a control group.The experimental group received the decision support education program in addition to routine care,while the control group received routine care.Family members' knowledge about hospice,the scores on the Death Attitude Profile Scale,and their willingness to choose hospice care were compared before and after the interventions.Results The program finally included 4 first-level items,15 second-level items,and 59 third-level items.During the program implementation phase,4 cases withdrew from the study,resulting in 46 cases in the experimental group and 47 cases in the control group.After intervention,the experimental group had higher scores on hospice knowledge and positive attitude towards death than the control group,while scores on negative attitude towards death were lower(P＜0.05);their willingness to choose hospice care for themselves and for the patients was higher than that of the control group(P＜0.05).Conclusion The hospice care decision support education program is scientific,feasible and practical,which can improve the knowledge of hospice care of the family members,improve their attitude towards death,and ultimately improve their willingness to choose hospice care.

Hepatocellular carcinoma(HCC)is one of the most common tumor types and remains a major clinical challenge.Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC.However,few mitophagy inhibitors have been approved for clinical use in humans.Pyrimethamine(Pyr)is used to treat infections caused by protozoan parasites.Recent studies have reported that Pyr may be beneficial in the treatment of various tumors.However,its mechanism of action is still not clearly defined.Here,we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis.Mechanistically,Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells.In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29(SNAP29)-vesicle-associated membrane protein 8(VAMP8)interaction.Moreover,Pyr acted synergistically with sorafenib(Sora)to induce apoptosis and inhibit HCC proliferation in vitro and in vivo.Pyr enhances the sensitivity of HCC cells to Sora,a common chemotherapeutic,by inhibiting mitophagy.Thus,these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor.Notably,Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

Objective To explore the clinical characteristics and genetic mechanisms of patients with Mucolipidosis Ⅲα/β caused by GNPTAB gene mutations.Methods A retrospective analysis was conducted on the clinical data and genetic tests of a confirmed case of Mucolipidosis Ⅲα/β.Various protein prediction tools were used to generate protein models of the wild type and mutant GNPTAB proteins,and computational biology tools were employed to elucidate the differences in protein structure and function between the wild type and mutant variants.Results The patient in this case mainly presented with joint deformities and short stature.Genetic sequencing revealed compound heterozygous mutations in the GNPTAB gene,c.2715+1G＞A and c.1582T＞C;the missense mutation c.1582T＞C has not been reported in the literature.By constructing and analyzing three-dimensional models of the mutants,it was found that the c.2715+1G＞A mutation alters the overall structure of the protein,leading to the loss of protein function,while the c.1582T＞C mutation affects the interaction between the subunit of N-acetylglucosamine-1-phosphate transferase and its ligand.Conclusions This case of MLⅢα/β results from a mutation in the GNPTAB gene,including a missense mutation c.1582T＞C that has not been previ-ously reported,which expands the spectrum of pathogenic mutations of this gene.Through computational analysis of the protein variants resulting from the GNPTAB gene mutation,the understanding of their structure-function relationship has been elaborated,revealing the molecular mechanisms behind the onset of ML Ⅲα/β disease.

Objective To explore the clinical characteristics and genetic mechanisms of patients with Mucolipidosis Ⅲα/β caused by GNPTAB gene mutations.Methods A retrospective analysis was conducted on the clinical data and genetic tests of a confirmed case of Mucolipidosis Ⅲα/β.Various protein prediction tools were used to generate protein models of the wild type and mutant GNPTAB proteins,and computational biology tools were employed to elucidate the differences in protein structure and function between the wild type and mutant variants.Results The patient in this case mainly presented with joint deformities and short stature.Genetic sequencing revealed compound heterozygous mutations in the GNPTAB gene,c.2715+1G＞A and c.1582T＞C;the missense mutation c.1582T＞C has not been reported in the literature.By constructing and analyzing three-dimensional models of the mutants,it was found that the c.2715+1G＞A mutation alters the overall structure of the protein,leading to the loss of protein function,while the c.1582T＞C mutation affects the interaction between the subunit of N-acetylglucosamine-1-phosphate transferase and its ligand.Conclusions This case of MLⅢα/β results from a mutation in the GNPTAB gene,including a missense mutation c.1582T＞C that has not been previ-ously reported,which expands the spectrum of pathogenic mutations of this gene.Through computational analysis of the protein variants resulting from the GNPTAB gene mutation,the understanding of their structure-function relationship has been elaborated,revealing the molecular mechanisms behind the onset of ML Ⅲα/β disease.

Objective:To compare the efficacy and safety of standard treatment with or without adjuvant chemotherapy in patients with highly malignant non-metastatic prostate cancer.Methods:In this prospective non-randomized controlled study, consecutive non-metastatic prostate cancer patients with pathologically proven Gleason score of 9-10 or Gleason score of 5 admitted to Peking University First Hospital were enrolled. Four to six cycles of chemotherapy using docetaxel ± carboplatin regimen were added or not after standard radical therapy. The primary end point was 5-year event-free survival (EFS), and the secondary end points were distant metastasis-free survival (MFS), overall survival (OS), and treatment-related adverse events. The survival curve was drawn by Kaplan-Meier method. The differences between two groups were analyzed by log-rank test.Results:A total of 176 patients were consecutively enrolled from November 2019 to January 2022 of which 138 patients received only standard radical therapy (control group), and 38 patients received adjuvant chemotherapy after standard radical therapy (chemotherapy group). The median follow-up time was 13.4 (2.0-34.0) months. All patients survived. The 30-month EFS rates in the chemotherapy and control groups were 100% and 85.6%, respectively ( P=0.064). There were no events in the chemotherapy group, while there were 12 cases of events in the control group, including 6 cases of biochemical recurrence and 6 cases of imaging progression. The 30-month MFS rates in two groups were 100% and 91.9%, respectively ( P=0.205). After the 1 vs. 2 propensity score matching, the EFS and MFS rates in two groups were 100% vs. 85.7% ( P=0.056), and 100% vs. 92.2% ( P=0.209), respectively. The incidence rates of grade 2 and above urinary toxicity in the chemotherapy and control groups were 2.6% and 7.2% ( P=0.354), respectively. The incidence rates of grade 2 and above rectal toxicity were 5.3% and 5.1% ( P=0.711), respectively. Grade 3 and above chemotherapy-related toxicity in the chemotherapy group were leukopenia (31.6%), thrombocytopenia (2.6%) and alopecia (13.2%). Conclusion:The addition of adjuvant chemotherapy after standard radical therapy tends to improve the overall EFS of patients with highly malignant prostate cancer, and the adverse effects are tolerable, which should be confirmed by long-term follow-up results.