End-stage liver disease (ESLD) covers the end-stage of acute and chronic liver diseases, mainly involving decompensated cirrhosis, various types of liver failure, and advanced liver cancer. Hepatocyte transplantation has shown promise in treating ESLD, but its clinical application is hampered by the shortage of donor hepatocytes. Cell therapy, an emerging effective treatment for ESLD, faces the same limitation due to scarce hepatocyte availability. Hepatocyte-like cells (HLCs), which are terminally differentiated cells, can be induced from both stem cells and somatic cells. As HLCs exhibit the morphology and function of primary hepatocytes, they offer a promising supplementary source of hepatocytes for cell therapy. First, we provide a background for the differentiation and maturation of primary hepatocytes. Subsequently, based on the current insights into the molecular pathways that regulate hepatocyte differentiation in vivo, we describe a strategy for establishing HLC derived from either stem cells or somatic cells. The key characteristics of these HLCs are also detailed. Furthermore, HLC offers therapeutic potential for liver failure, and HLC-based liver organoids and bioartificial liver systems have demonstrated the ability to provide liver functions, offering an innovative approach to treating various types of ESLD. Despite their promise, challenges such as efficiency in differentiation and functional maturation need to be addressed to improve the clinical application of HLCs. This review discusses these advancements and outlines the therapeutic potential and current challenges of HLC therapy for ESLD.

Objective:To investigate the effects of repetitive transcranial magnetic stimulation(rTMS) on learning memory and abnormal Aβ deposition in cerebral amyloid angiopathy(CAA) model mice, and further to investigate whether the mechanism involves the transport function of glymphatic system.Methods:Eight-month-old SPF grade Tg-SWDI mice were randomly divided into the CAA group and the rTMS group according to the random number table method with 7 in each group.Seven wild-type mice of the same genetic background and age served as the control group. The mice in rTMS group received two weeks of high-frequency rTMS intervention, and the mice in CAA group and control group were only restrained without rTMS intervention.Learning and memory functions were evaluated using the Morris water maze test.Amyloid-beta deposition, glymphatic system clearance, and aquaporin-4(AQP4) polarization were assessed using immunofluorescence, and AQP4 expression levels were measured by Western blot.Statistical analysis of the data was conducted using SPSS 25.0 and GraphPad Prism 9.5 softwares.Repeated-measures ANOVA was used for data on escape latency, and one-way ANOVA was used for comparisons between multiple groups for other data.Results:(1)In the novel object recognition test, there were statistically significant differences in recognition indices among the three groups of mice ( F=22.59, P<0.05). Compared with the control group, the mice in the CAA group showed a significant decrease in the new object recognition index ( P<0.05).Compared with the CAA group, the mice in the rTMS group showed a significant increase in the new object recognition index ( P<0.05).(2)In the Y-maze, there were statistical differences in the spontaneous alternation rates among the three groups ( F=5.00, P<0.05). Compared with the control group, the spontaneous alternation rate in the CAA group was significantly lower ( P<0.05).And compared with the CAA group, the spontaneous alternation rate in the rTMS group was significantly higher ( P<0.05).(3)In the Morris water maze test, there were significant interactions in escape latency among the three groups ( F=4.05, P=0.02), significant main effects of time ( F=713.22, P<0.01), and significant main effects of group ( F=421.55, P<0.01). There was no significant statistical difference in swimming speed among the three groups ( F=0.19, P>0.05), while the difference of the number of entries into the inner zone and the proportion of time spent were statistically significant( F=71.67, 294.14, both P<0.05).Compared with the control group, the CAA group mice significantly decreased in the number of entries into the inner zone and the proportion of time spent in the middle zone (both P<0.01).(4)Compared with the CAA group, the rTMS group significantly increased in the number of entries into the inner zone and the proportion of time spent in the middle zone (both P<0.01).The result of immunofluorescence test showed that there was a statistically significant difference in the levels of Aβ in the cerebral vessels among the three groups( F=385.76, P<0.01).The levels of Aβ in the cerebral vessels of the CAA group (62.00±2.65) were significantly higher than those in the control group (9.00±1.00, P<0.01).The levels in the rTMS group (51.33±3.21) were significantly lower than those in the CAA group (62.00±2.65, P<0.01). Using the residual fluorescence tracer levels of the control group as a baseline, there were statistically significant differences in the tracer intensities in the corpus callosum and cerebral cortex( F=258.97, 46.44, both P<0.05), the tracer intensities in the corpus callosum (3.57±0.21) and cerebral cortex (4.96±0.79) of the CAA group mice were significantly higher than those in the rTMS group (1.45±0.14, 1.78±0.47, P<0.01). The polarization of AQP4 in the cerebral cortex of rTMS group (0.51±0.07) was significantly higher than that in the CAA group (0.30±0.02, P<0.01). Conclusion:rTMS can alleviate learning memory and abnormal Aβ deposition in CAA model mice by modulating AQP4 polarisation and promoting transport function of glymphatic system.

Objective:To investigate the effects of repetitive transcranial magnetic stimulation(rTMS) on learning memory and abnormal Aβ deposition in cerebral amyloid angiopathy(CAA) model mice, and further to investigate whether the mechanism involves the transport function of glymphatic system.Methods:Eight-month-old SPF grade Tg-SWDI mice were randomly divided into the CAA group and the rTMS group according to the random number table method with 7 in each group.Seven wild-type mice of the same genetic background and age served as the control group. The mice in rTMS group received two weeks of high-frequency rTMS intervention, and the mice in CAA group and control group were only restrained without rTMS intervention.Learning and memory functions were evaluated using the Morris water maze test.Amyloid-beta deposition, glymphatic system clearance, and aquaporin-4(AQP4) polarization were assessed using immunofluorescence, and AQP4 expression levels were measured by Western blot.Statistical analysis of the data was conducted using SPSS 25.0 and GraphPad Prism 9.5 softwares.Repeated-measures ANOVA was used for data on escape latency, and one-way ANOVA was used for comparisons between multiple groups for other data.Results:(1)In the novel object recognition test, there were statistically significant differences in recognition indices among the three groups of mice ( F=22.59, P<0.05). Compared with the control group, the mice in the CAA group showed a significant decrease in the new object recognition index ( P<0.05).Compared with the CAA group, the mice in the rTMS group showed a significant increase in the new object recognition index ( P<0.05).(2)In the Y-maze, there were statistical differences in the spontaneous alternation rates among the three groups ( F=5.00, P<0.05). Compared with the control group, the spontaneous alternation rate in the CAA group was significantly lower ( P<0.05).And compared with the CAA group, the spontaneous alternation rate in the rTMS group was significantly higher ( P<0.05).(3)In the Morris water maze test, there were significant interactions in escape latency among the three groups ( F=4.05, P=0.02), significant main effects of time ( F=713.22, P<0.01), and significant main effects of group ( F=421.55, P<0.01). There was no significant statistical difference in swimming speed among the three groups ( F=0.19, P>0.05), while the difference of the number of entries into the inner zone and the proportion of time spent were statistically significant( F=71.67, 294.14, both P<0.05).Compared with the control group, the CAA group mice significantly decreased in the number of entries into the inner zone and the proportion of time spent in the middle zone (both P<0.01).(4)Compared with the CAA group, the rTMS group significantly increased in the number of entries into the inner zone and the proportion of time spent in the middle zone (both P<0.01).The result of immunofluorescence test showed that there was a statistically significant difference in the levels of Aβ in the cerebral vessels among the three groups( F=385.76, P<0.01).The levels of Aβ in the cerebral vessels of the CAA group (62.00±2.65) were significantly higher than those in the control group (9.00±1.00, P<0.01).The levels in the rTMS group (51.33±3.21) were significantly lower than those in the CAA group (62.00±2.65, P<0.01). Using the residual fluorescence tracer levels of the control group as a baseline, there were statistically significant differences in the tracer intensities in the corpus callosum and cerebral cortex( F=258.97, 46.44, both P<0.05), the tracer intensities in the corpus callosum (3.57±0.21) and cerebral cortex (4.96±0.79) of the CAA group mice were significantly higher than those in the rTMS group (1.45±0.14, 1.78±0.47, P<0.01). The polarization of AQP4 in the cerebral cortex of rTMS group (0.51±0.07) was significantly higher than that in the CAA group (0.30±0.02, P<0.01). Conclusion:rTMS can alleviate learning memory and abnormal Aβ deposition in CAA model mice by modulating AQP4 polarisation and promoting transport function of glymphatic system.

Objective To explore the objective facial appearance characteristics of patients with coronary heart disease(CHD).Methods From April 7,2019 to December 1,2022,313 patients with CHD were recruited from Dongzhimen Hospital,Beijing University of Chinese Medicine,Dongfang Hospital,Beijing University of Chinese Medicine,and the First Affiliated Hospital of Hunan University of Chinese Medicine,together with 293 healthy controls.Standardized facial images were obtained using the tongue-face diagnostic instrument.The face was divided into six regions:the forehead,left cheek,right cheek,nose,lips,and chin.Nine color parameters were extracted from each region,including red(R),green(G),blue(B),hue(H),saturation(S),value(V),lightness(L),red-green axis(a),and yellow-blue axis(b).Comparisons between groups were performed.Results Compared with the healthy group,in the forehead region,values of R,S,V,a,and b were higher in the coronary heart disease group,whereas B was lower(P<0.05);in the left cheek,nose,and chin regions,R,G,B,V,and L decreased,whereas S,a,and b increased(P<0.05);in the right cheek region,R,G,B,H,V,and L decreased,while S,a,and b increased(P<0.05);in the lips region,R,G,B,H,V,L,and a decreased,whereas S and b increased(P<0.05).Conclusion Compared with healthy individuals,patients with CHD present with a darker,more saturated facial complexion with reduced brightness,overall manifesting as"dark red complexion"and"dense but not bright color,"suggesting the pathogenesis of qi and blood circulation stagnation and internal blood stasis retention.The objective expression of facial features may have greater application value in syndrome differentiation and auxiliary diagnosis in traditional Chinese medicine.

Objective To explore the objective facial appearance characteristics of patients with coronary heart disease(CHD).Methods From April 7,2019 to December 1,2022,313 patients with CHD were recruited from Dongzhimen Hospital,Beijing University of Chinese Medicine,Dongfang Hospital,Beijing University of Chinese Medicine,and the First Affiliated Hospital of Hunan University of Chinese Medicine,together with 293 healthy controls.Standardized facial images were obtained using the tongue-face diagnostic instrument.The face was divided into six regions:the forehead,left cheek,right cheek,nose,lips,and chin.Nine color parameters were extracted from each region,including red(R),green(G),blue(B),hue(H),saturation(S),value(V),lightness(L),red-green axis(a),and yellow-blue axis(b).Comparisons between groups were performed.Results Compared with the healthy group,in the forehead region,values of R,S,V,a,and b were higher in the coronary heart disease group,whereas B was lower(P<0.05);in the left cheek,nose,and chin regions,R,G,B,V,and L decreased,whereas S,a,and b increased(P<0.05);in the right cheek region,R,G,B,H,V,and L decreased,while S,a,and b increased(P<0.05);in the lips region,R,G,B,H,V,L,and a decreased,whereas S and b increased(P<0.05).Conclusion Compared with healthy individuals,patients with CHD present with a darker,more saturated facial complexion with reduced brightness,overall manifesting as"dark red complexion"and"dense but not bright color,"suggesting the pathogenesis of qi and blood circulation stagnation and internal blood stasis retention.The objective expression of facial features may have greater application value in syndrome differentiation and auxiliary diagnosis in traditional Chinese medicine.

Background and objective Pembrolizumab(PEM)has been shown to be effective in clinical trials for the treatment of advanced non-small cell lung cancer(NSCLC),but clinical trials were based on cohorts of patients selected on specific criteria,and whether the findings are consistent with real-world patients is debatable.The aim of this study is to evaluate the efficacy and safety of PEM in the treatment of advanced NSCLC based on real-world data.Methods A retro-spective collection of real-world data from patients with advanced NSCLC receiving PEM was conducted.Propensity score matching was used to eliminate inter-group differences and assess the efficacy and safety of PEM compared to chemotherapy.Results Among 450 matched patients,the incidence rates of any-grade adverse events were 79.87％in the PEM group and86.71％inthe chemotherapy group,while the incidence rates of grade＞3 adverse events were 4.03％and 7.31％,respectively.The objective response rates were 48.63％for PEM and 36.00％for chemotherapy(P=0.011).The median progression-free survival was 15.5 months for PEM and 8.8 months for chemotherapy(P＜0.001),and the median overall survival was not reached for PEM and 26.2 months for chemotherapy(P＜0.001).Conclusion PEM treatment for advanced NSCLC demonstrates favorable survival outcomes and acceptable safety in real-world clinical practice.

Objective:To examine the occurrence of complications in elderly patients who have undergone radical surgery for colorectal cancer.Additionally, this study aims to identify the various risk factors associated with these complications.Methods:This study included elderly patients with colorectal cancer who underwent radical surgery at Beijing Hospital between January 2013 and December 2020.These patients were divided into two groups based on their age.In this study, we examined a total of 906 patients who underwent surgery, with 695 patients under the age of 80 and 211 patients aged 80 and above.We classified postoperative complications into two categories: medical and surgical complications.Our analysis compared comorbidities, clinicopathological factors, perioperative variables, and postoperative morbidity and mortality between the two age groups.We utilized both univariate and multivariate analyses to identify any potential risk factors for postoperative morbidity.Results:When comparing patients under 80 years old to those aged 80 or older, it was found that the latter group had a lower body mass index, worse ASA scores, and more comorbidities.Additionally, the proportion of elderly patients with right colon cancer, pT3-4, and pN+ disease was higher compared to those under 80 years old.Furthermore, the elderly patients aged 80 or older had a lower rate of laparoscopic surgery compared to those under 80 years old.The study found that elderly patients aged 80 years and older had significantly shorter operation times compared to those younger than 80 years[(191.0±70.6)min vs.(214.0±83.3)min, t=3.642, P<0.001]. However, the overall complication rate was higher in the elderly group(32.7%)than in the younger group(22.6%)( χ2=8.839, P=0.004). Upon further analysis, it was found that medical complications increased significantly(20.9% vs.7.5%, χ2=30.547, P<0.001), whereas the rate of surgical complications did not show any statistical difference(15.6% vs.16.4%, χ2=0.069, P=0.832). The mortality rate during the perioperative period was found to be significantly higher in elderly patients aged 80 years and above compared to those below 80 years(1.9% vs.0.3%, χ2=6.316, P=0.029). Further analysis revealed that age was an independent risk factor for medical complications( HR=2.822, 95% CI: 1.804-4.414, P<0.001). Laparoscopic surgery has been shown to significantly decrease surgical complications( HR=0.475, 95% CI: 0.317-0.711, P=0.001). However, if the operation time exceeds 200 minutes, there is a significant increase in surgical complications( HR=1.942, 95% CI: 1.278-2.888, P=0.002). Conclusions:The incidence of postoperative medical complications in very elderly patients with colorectal cancer who undergo radical surgery has risen, although the rate of surgical complications has remained steady.Radical surgery for elderly patients with colorectal cancer is both safe and feasible, but it is important to prioritize the prevention and management of medical complications.

Objective:To evaluate a surgical approach for partial resection of the tenth rib through a retroperitoneal approach for the exposure of Crawford type IV thoracoabdominal aortic aneurysm and complex abdominal aortic aneurysm from 2014 to 2019.Methods:A retrospective analysis was conducted on clinical data and follow-up results of 7 patients who underwent treatment for Crawford type IV thoracoabdominal aortic aneurysm and complex abdominal aortic aneurysm through partial resection of the tenth rib via a retroperitoneal approach.Results:One case (14.3%) had associated Marfan syndrome, and 5 cases (71.4%) underwent left renal artery reconstruction. None of the patients experienced severe complications such as cardiopulmonary complications or renal failure postoperatively, and there was no statistically significant difference in serum creatinine levels between preoperative and postoperative stages during hospitalization ( P=0.205). Follow-up examinations showed no long-term vascular stenosis. Conclusions:Partial resection of the tenth rib through a retroperitoneal approach can avoid incisions of the pleura and diaphragm. It allows for the exposure of the aorta below the diaphragm and has the ability to treat aortic diseases below the diaphragm with smaller incisions and lower complication risks.

Objective:To investigate the effect of LRRK2G2019S mutation on activation of microglia after iron deprivation and its mechanism.Methods:(1) Microglia were differentiated from human induced pluripotent stem cells (IPSC) with the help of hematopoietic progenitor cells (HPC) and identified by immunofluorescent staining, and α-synuclein (α-syn) A53T mutant protein was obtained by protein purification technology. (2) Microglia were divided into control group, α-syn group, α-syn+ deferoxamine (DFO) group; phosphate buffer solution (PBS), 1 μmol/L purified α-syn A53T mutant protein, 1 μmol/L purified α-syn A53T mutant protein+30 mmol/L DFO were given respectively for 24 h. Fe 2+ concentration was detected by colorimetry, Rab35 protein expression was detected by Western blotting, intracellular reactive oxygen species (ROS) level was detected by flow cytometry, and interleukin-6 ( IL-6), tumor necrosis factor-α ( TNF-α) and transforming growth factor-β ( TGF-β) mRNA expressions were detected by real time-PCR (RT-PCR); microglia culture supernatant (MCS) in the 3 groups were transfered to SH-SY5Y cells, and SH-SY5Y cell apoptosis was detected by flow cytometry. (3) Bidirectional DNA sequencing was used to detect leucine rich repeat kinase 2 ( LRRK2) gene mutations in microglia treated with 1 μmol/L purified α-syn A53T mutant protein. Microglia were divided into control group, α-syn group and α-syn+GSK3357679A group, and treated with corresponding drugs for 24 h, respectively (LRRK2 inhibitor GSK3357679A concentration: 10 nmol/L), and LRRK2 protein expression was detected by Western blotting; microglia were divided into control group, α-syn group, α-syn+GSK3357679A, and α-syn+GSK3357679A+DFO group, and treated with corresponding drugs for 24 h, Rab35 protein expression was detected by Western blotting, intracellular ROS level was detected by flow cytometry, and IL-6, TNF-α and TGF-β mRNA expressions were detected by RT-PCR. (4) Microglia were divided into control group, α-syn group, α-syn+rapamycin (RAPA) group, and treated with corresponding drugs for 24 h (concentration of autophagy inducer RAPA: 50 nmol/L); protein expressions of Rab35, P62 and microtubule-associated protein light chain 3 II (LC3II) were detected by Western blotting; intracellular ROS level was detected by flow cytometry, and IL-6, TNF-α and TGF-β mRNA expressions were detected by RT-PCR. (5) Microglia were divided into control group, α-syn group, and α-syn+Rab35 group, and treated with corresponding drugs for 24 h (concentration of Rab35 overexpressed plasmids: 1 μg/mL); Rab35, P62, and LC3II protein expressions were detected by Western blotting; ROS level was detected by flow cytometry, and IL-6, TNF-α and TGF-β mRNA expressions were detected by RT-PCR. Results:(1) Immunofluorescent staining showed negative neuronal nuclei (NeuN) expression and positive ionized calcium-binding adapter molecule 1 (Iba1) expression in microglia, and high LRRK2 expression; PcDNA3.1-SNCA-A53T expression plasmid was constructed and α-syn A53T mutant protein was purified. (2) The Fe 2+ concentration in α-syn group was significantly higher than that in control group, and the Fe 2+ concentration in α-syn+DFO group was significantly lower than that in α-syn group ( P<0.05); the Rab35 protein and TGF-β mRNA expressions in control group, α-syn group and α-syn+DFO group were decreased successively, while the IL-6 and TNF-α mRNA expressions were increased successively, with significant differences ( P<0.05); ROS level and SH-SY5Y cell apoptosis rate in control group, α-syn group, α-syn+DFO group were increased successively. (3) Bidirectional DNA sequencing showed that the LRRK2G2019S mutation in microglia was the most obvious after α-syn A53T mutant protein stimulation; compared with the control group, the α-syn group had significantly increased LRRK2 protein expression, while the α-syn+GSK3357679A group had significantly decreased LRRK2 protein expression compared with α-syn group ( P<0.05); compared with the control group, the α-syn group had significantly decreased Rab35 protein and TGF-β mRNA expressions, and statistically increased IL-6 and TNF-α mRNA expressions ( P<0.05); compared with α-syn group, the α-syn+GSK3357679A group had significantly increased Rab35 protein and TGF-β mRNA expressions, and statistically decreased IL-6 and TNF-α mRNA expressions ( P<0.05); compared with α-syn+GSK3357679A group, α-syn+GSK3357679A+DFO group had significantly increased IL-6 and TNF-α mRNA expressions, and significantly decreased Rab35 protein and TGF-β mRNA expressions ( P<0.05). The α-syn group had higher ROS level than the control group, the α-syn+GSK3357679A group had lower ROS level than the α-syn group, and the α-syn+GSK3357679A+DFO group had higher ROS level than the α-syn+GSK3357679A group. (4) Compared with the control group, the α-syn group had significantly decreased Rab35 and LC3II protein, and TGF-β mRNA expressions, and significantly increased P62 protein, IL-6 and TNF-α mRNA expressions ( P<0.05); compared with α-syn group, the α-syn+RAPA group had significantly increased Rab35 and LC3II protein, and TGF-β mRNA expressions, and significantly decreased P62 protein, and IL-6 and TNF-α mRNA expressions ( P<0.05); the α-syn group had higher ROS level than the control group and α-syn+RAPA group. (5) Compared with the control group, the α-syn group had significantly decreased Rab35 and LC3II protein, and TGF-β mRNA expressions, and statistically increased P62 protein, and IL-6 and TNF-α mRNA expressions ( P<0.05); compared with the α-syn group, the α-syn+Rab35 group had significantly increased Rab35 and LC3II protein, and TGF-β mRNA expressions, and significantly decreased P62 protein, and IL-6 and TNF-α mRNA expressions ( P<0.05). The α-syn group had higher ROS level than the control group and α-syn+Rab35 group. Conclusion:LRRK2G2019S can induce neuroinflammation by inhibiting Rab35-related autophagy under iron deprivation, and Rab35 is expected to be a key factor in intervening neuroinflammation.

Objective:To translate and revise the distress tolerance scale (DTS) and evaluate its psychometric properties in Chinese college student, and to conduct cross-cultural comparisons.Methods:A total of 1 125 college students were measured by the DTS, the 9-item patient health questionnaire-9(PHQ-9), the generalized anxiety disorder-7 (GAD-7) and the type D personality scale-14(DS14). In addition, 433 college student were retested by DTS after 3 weeks.SPSS 26.0 and AMOS 20.0 softwares were used for reliability and validity analysis.Results:(1)The Chinese revised DTS contained 13 items(DTS-13), the items' discrimination was good with the discrimination indices all above 0.4( r=0.402-0.760, all P<0.001). (2)DTS-13 showed a good structural validity with four factors: tolerance, absorption, appraisal and regulation.The confirmatory factor analysis showed a good model fit( χ2/ df=4.751, RMR=0.042, RMSEA=0.058, GFI=0.963, AGFI=0.941, NFI=0.958, CFI=0.966). (3)The criterion correlations of DTS-13 with negative emotions of DS14, depression of PHQ-9 and anxiety of GAD-7 were -0.509, -0.392 and -0.403, respectively.(4)The internal consistency reliability, split-half reliability and test-retest reliability of DTS-13 were 0.895, 0.846 and 0.788.The internal consistency reliabilities of four factors ranged from 0.717 to 0.782 and the retest reliabilities ranged from 0.548 to 0.923.(5)The distress tolerance score of Chinese college students was (3.20±0.71), which was lower than that of American youth ( t=-4.977, P<0.001) and Spanish college students ( t=-13.024, P<0.001). Male students had higher distress tolerance than female students ( t=3.317, P<0.001). Conclusion:The revised DTS-13 retains a four-factor structure and has good psychometric properties.It is suitable for evaluating the capacity of individuals to experience and withstand negative psychological states, and can be used for cross-cultural comparison.