The trillions of commensal microorganisms living in the gut lumen profoundly influence the physiology and pathophysiology of the liver through a unique gut-liver axis. Disruptions in the gut microbial communities, arising from environmental and genetic factors, can lead to altered microbial metabolism, impaired intestinal barrier and translocation of microbial components to the liver. These alterations collaboratively contribute to the pathogenesis of liver disease, and their continuous impact throughout the disease course plays a critical role in hepatocarcinogenesis. Persistent inflammatory responses, metabolic rearrangements and suppressed immunosurveillance induced by microbial products underlie the pro-carcinogenic mechanisms of gut microbiota. Meanwhile, intrahepatic microbiota derived from the gut also emerges as a novel player in the development and progression of liver cancer. In this review, we first discuss the causes of gut dysbiosis in liver disease, and then specify the pivotal role of gut microbiota in the malignant progression from chronic liver diseases to hepatobiliary cancers. We also delve into the cellular and molecular interactions between microbes and liver cancer microenvironment, aiming to decipher the underlying mechanism for the malignant transition processes. At last, we summarize the current progress in the clinical implications of gut microbiota for liver cancer, shedding light on microbiota-based strategies for liver cancer prevention, diagnosis and therapy.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

The trillions of commensal microorganisms living in the gut lumen profoundly influence the physiology and pathophysiology of the liver through a unique gut-liver axis. Disruptions in the gut microbial communities, arising from environmental and genetic factors, can lead to altered microbial metabolism, impaired intestinal barrier and translocation of microbial components to the liver. These alterations collaboratively contribute to the pathogenesis of liver disease, and their continuous impact throughout the disease course plays a critical role in hepatocarcinogenesis. Persistent inflammatory responses, metabolic rearrangements and suppressed immunosurveillance induced by microbial products underlie the pro-carcinogenic mechanisms of gut microbiota. Meanwhile, intrahepatic microbiota derived from the gut also emerges as a novel player in the development and progression of liver cancer. In this review, we first discuss the causes of gut dysbiosis in liver disease, and then specify the pivotal role of gut microbiota in the malignant progression from chronic liver diseases to hepatobiliary cancers. We also delve into the cellular and molecular interactions between microbes and liver cancer microenvironment, aiming to decipher the underlying mechanism for the malignant transition processes. At last, we summarize the current progress in the clinical implications of gut microbiota for liver cancer, shedding light on microbiota-based strategies for liver cancer prevention, diagnosis and therapy.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

BACKGROUND:Early exercise treatment is the main prevention way for traumatic joint contracture and is also a research focus.Swimming may be a potential intervention for joint contracture due to the special physical properties of water. OBJECTIVE:To explore the effects of swimming on the development of joint contracture in a rat model and study its mechanisms. METHODS:Twenty-four Sprague-Dawley rats were randomly divided into a blank control group(n=8)and a joint contracture group(n=16).After the surgical operation of knee joint contracture rat models,the joint contracture group was randomly subdivided into a surgical control group(n=8)and a swimming treatment group(n=8).Swimming started in the swimming treatment group in the second week after surgery and lasted for a total of 5 weeks.At the 6th week after surgery,the body mass,knee joint range of motion,and quadriceps diameter were tested,and the diameter/body mass index was calculated.Hematoxylin-eosin staining was performed to detect the pathological changes in the knee joint capsule and quadriceps muscle,and Masson staining was used to observe fibrotic changes in the knee joint capsule.Furthermore,the protein expression of transforming growth factor β1 and type I collagen in the knee joint capsule was quantified by immunohistochemical assay and western blot was performed to detect the protein expression of MuRF1 in the quadriceps femoris. RESULTS AND CONCLUSION:Compared with the blank control group,the knee range of motion decreased in the surgical control and swimming treatment groups(P<0.01),and knee extension deficit and arthrogenic extension deficit were significantly increased(P<0.01),the diameter of the quadriceps muscle was decreased(P<0.01),the joint capsule showed significant fibrosis,the quadriceps muscle was atrophied,and the diameter/body mass index was decreased(P<0.01).Compared with the surgical control group,the swimming treatment group showed a significant increase in knee joint range of motion and quadriceps diameter(P<0.01),and significant improvement in joint capsule fibrosis and quadriceps atrophy.Compared with the blank control group,collagen fiber content and expression of transforming growth factor β1 and type I collagen were increased in the joint capsule of rats in both the surgical control group and the swimming treatment group(P<0.01).Compared with the surgical control group,collagen fiber content and expression of transforming growth factor β1 and type I collagen protein in the joint capsule were decreased in the swimming treatment group.Compared with the blank control group,the expression of MuRF1 protein in the quadriceps muscle of rats in the surgical control group and the swimming treatment group was increased(P<0.05).Compared with the surgical control group,the expression of MuRF1 protein in the quadriceps muscle of rats in the swimming treatment group was decreased(P<0.05).To conclude,early swimming intervention reduces transforming growth factor β1 and type I collagen expression in the joint capsule of traumatic joint contracture rats,decreases MuRF1 expression in the quadriceps muscle,and increases joint range of motion and quadriceps diameter,thereby inhibiting the development of joint contracture.

The trillions of commensal microorganisms living in the gut lumen profoundly influence the physiology and pathophysiology of the liver through a unique gut-liver axis. Disruptions in the gut microbial communities, arising from environmental and genetic factors, can lead to altered microbial metabolism, impaired intestinal barrier and translocation of microbial components to the liver. These alterations collaboratively contribute to the pathogenesis of liver disease, and their continuous impact throughout the disease course plays a critical role in hepatocarcinogenesis. Persistent inflammatory responses, metabolic rearrangements and suppressed immunosurveillance induced by microbial products underlie the pro-carcinogenic mechanisms of gut microbiota. Meanwhile, intrahepatic microbiota derived from the gut also emerges as a novel player in the development and progression of liver cancer. In this review, we first discuss the causes of gut dysbiosis in liver disease, and then specify the pivotal role of gut microbiota in the malignant progression from chronic liver diseases to hepatobiliary cancers. We also delve into the cellular and molecular interactions between microbes and liver cancer microenvironment, aiming to decipher the underlying mechanism for the malignant transition processes. At last, we summarize the current progress in the clinical implications of gut microbiota for liver cancer, shedding light on microbiota-based strategies for liver cancer prevention, diagnosis and therapy.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

Objective:To explore the journey map of patients with chronic constipation during fecal microbiota transplantation.Methods:This study adopted phenomenological methods. From October to December 2023, purposive sampling was used to select chronic constipation follow-up patients who underwent fecal microbiota transplantation at the Intestinal Microecology Center of Shanghai Tenth People's Hospital as respondents for semi-structured interviews. Colaizzi 7-step analysis method and NVivo 11.0 software were used for data analysis.Results:A total of 15 interviewees were interviewed. During fecal microbiota transplantation, the journey map of constipation patients included stages, mood changes, touchpoints, themes, emotional experiences and opportunities. The patient's experience and needs were summarized into three themes and ten sub-themes, including pre-transplant adaptation disorders to new environments (unfamiliarity and confusion-admission coordination disorders, anxiety and expectations-diverse complex emotions, puzzle and helplessness-asymmetric doctor and patient information), effectiveness-related psychological and social experiences in transplantation (attention and expectations-longing for positive efficacy, perception of benefits and risk avoidance, shame and inferiority-treatment stigmatization experience, questioning and despair-unrealized expectations, treatment resistance-sensitive economic burden), post-transplant transition dilemmas (inaccessible medical services-lack of continuous treatment and nursing, disease recurrence troubles) .Conclusions:This study visualizes the experiences and needs of constipation patients during microbiota transplantation through a patient journey map and identifies multidimensional issues and needs of patients. Clinical medical and nursing staff should pay attention to the needs of patients at different stages of the treatment process when formulating intervention programs to improve the quality of fecal microbiota transplantation nursing.

Objective To explore the dilemmas faced by surrogate decision-makers of severe stroke patients in treatment decision-making,and to provide a basis for developing decision support strategies.Methods From April to December 2023,through phenomenological qualitative research with 16 surrogate decision-makers with severe stroke patients from ICU of the department of neurology in a tertiary hospital in Jing'an District,Shanghai.semi-structured in-depth interviews were used to examine the perceptions of decision-making on surrogate.Data were analyzed via Braun's style of thematic analysis.Results 4 themes and 10 sub-themes were identified.Theme 1:negative emotional dilemmas(urgent decision-making leads to anxiety,fear,and unknown stroke trajectory increases the sense of uncertainty).Theme 2:supportive environment dilemmas(lack of information support delays decision-making;lack of family support increases decision-making stress;insufficient economic support increases the burden of decision-making).Theme 3:the dilemma of weighing the pros and cons(difficult trade-offs between risk and reward,tough decisions between reality and ethics,conflicting choices of life and dignity).Theme 4:preference management dilemmas(practical difficulties in adhering to patient preferences,impediments to decision-making due to unknown patient preferences).Conclusion Surrogate decision-makers of severe stroke patients face multiple decision-making dilemmas.Healthcare professionals should provide emotional support in multiple ways and comprehensive support to reduce the decision-making dilemmas experienced by surrogate decision-makers,as well as implement death education for surrogate decision-makers and promote advance care planning to reduce their decision-making stress.