Liver regenerative medicine can use functional liver cells to repair or replace damaged liver tissue and it is expected to be rapidly developed as an alternative treatment to liver transplantation. However, regenerative medicine requires cells with stable proliferation ability and liver cell characteristics. Liver organoids are derived from adult stem cells or pluripotent stem cells. They can be proliferated in large quantities and cultured for a long time in vitro, meanwhile maintain genetic stability, and simulate the structural and functional characteristics of organs in the body, providing a new strategy for liver regeneration. This article reviews liver organoids and their research progress in liver regenerative medicine, and discusses their application potential and existing limitations.

Interleukin-17(IL-17)is an important pro-inflammatory cytokine that bridges innate and adaptive immunity,promoting protective immunity against pathogens,but also driving inflamma-tory pathology during infection and autoimmunity.IL-17 has important protective roles in a variety of bacterial zoonoses,but also promotes the development of inflammatory diseases in various organ tissues and is associated with autoimmune diseases induced by bacterial infections.Recent studies have shown that IL-17-secreting CD4+tissue-resident T memory cells play a key role in sustaining adaptive immunity to bacterial infections,and vaccine design strategies targeting IL-17 responses exhibit apparent advantages in improving vaccine efficacy.In this regard,this paper reviews the bio-logical functions of IL-17 and its roles in major bacterial zoonoses and related mechanisms,with the aim of providing a reference for the development of safe and effective IL-17-based immunother-apies.

This study was performed to investigate the effects of Arbutin(Ar)on oxidative stress,apoptosis level and inflammatory response of H9c2 cardiomyocytes induced by lipopolysaccharide(LPS).H9c2 cardiomyocytes were randomly divided into blank control group,lipopolysaccharide group(LPS),LPS+Ar(25 μmol/L)group,LPS+Ar(50 μmol/L)group,LPS+Ar(100 μmol/L)group and Ar(50 μmol/L)group.CCK-8 was used to detect the cell viability of H9c2 cardiomyocytes after LPS treatment and Ar treatment;DCFH-DA fluorescence labeling was used to detect the ROS levels of H9c2 cardiomyocytes;flow cytometry was applied to detect cell apoptosis rate;Western blot was used to detect the expression of apoptosis-related proteins(Caspase-3)and inflammatory proteins(IL-1β and TNF-α).Data showed that compared with the LPS group,the cell viabilities were recovered after Ar treatment.The level of oxidative stress markers(ROS),apoptosis rate,and inflammatory factor levels(IL-1β and TNF-α)in the LPS+Ar groups were significantly reduced compared with the LPS group(P<0.05).In conclusion,Ar can alleviate the damage,apoptosis,oxidative stress and inflammatory response of LPS-induced H9c2 cardiomyocytes.

Objective:To explore the effect of different HER2 expression levels and gene amplification on the efficacy of immunotherapy in metastatic urothelial carcinoma (UC).Methods:The clinical data of 77 patients with metastatic UC who received immunotherapy from June 2017 to April 2021 after failure to the previous chemotherapy were analyzed retrospectively, including 49 males and 28 females with the median age of 62 years. The primary tumors located in bladder in 28 cases (36.4%), renal pelvis in 25 cases (32.5%) and ureter in 24 cases (31.2%). The common metastatic sites included: lymph nodes (n = 45, 58.4%), lung (n = 40, 51.9%), bone (n = 20, 26.0%) and liver (n = 16, 20.8%). 27 patients with bladder UC received surgery on the primary tumors including radical cystectomy (n = 18), partial cystectomy (n = 4) and transurethral resection (n = 5). 43 patients with renal pelvis or ureteral UC received surgery on the primary tumors including radical nephroureterectomy (n = 38), local resection (n = 3) and palliative resection (n = 2). Postoperative intravesical chemotherapy was performed in 15 cases, adjuvant radiotherapy was performed in 6 cases. 3 patients who emerged postoperative bladder recurrence received local radiotherapy. 7 patients received radiotherapy and 1 case received microwave ablation to their metastatic sites. All patients had received first-line chemotherapy and 30 patients (40.0%) had received at least second-line treatment including 70 cases (90.9%) with platinum containing chemotherapy. All 77 patients received anti-PD-1 treatment. 38 patients received sequential regimen after failed to the anti-PD-1 therapy, including antibody-drug conjugate (n = 17), chemotherapy (n = 18) and chemotherapy combined with anti-angiogenesis drugs (n = 12). Immunohistochemical (IHC) staining was used to detect the expression level of HER2 protein in the tumor tissues (74 cases from primary tumors and 3 cases from metastatic tumors) obtained from the initial diagnosis. For patients with HER2 IHC (+ + ), the copy number (CN) of HER2 gene was detected by next-generation sequencing (NGS). HER2 copy number amplification [CN (+ )] was defined as CN ≥ 4, and HER2 copy number non-amplification [CN(-)] was defined as CN < 4. HER2 IHC (0) was defined as HER2 negative, IHC (+ ) or IHC (+ + ) / CN (-)was defined as HER2 low expression, while IHC (+ + ) / CN(+ ) and IHC (+ + + ) were defined as HER2 high expression. Chi-square test or Fisher exact test were used to evaluate the correlation between HER2 expression and objective response rate (ORR) after anti-PD-1 treatment. Kaplan-Meier method and log-rank test were used to compare the differences of median progression free survival (PFS) and overall survival (OS) under different HER2 expression status.Results:All the 77 patients received a median of 11 (range: 2 - 45) doses of anti-PD-1 treatment with a median duration of treatment of 6.4 (range: 1.5 - 47.8) months and the ORR was 33.8% (26/77). The median follow-up time was 30.9 months. The overall median PFS time was 5.8 (95% CI: 3.0 - 8.6) months and the median OS time was 23.6 (95% CI: 8.5 - 38.7) months. HER2 IHC tests were performed in 77 patients. HER2 IHC levels of (0), (+ ), (+ + ) and (+ + + ) were found in 33 (42.9%), 19 (24.7%), 20 (26.0%) and 5 (6.5%) patients, respectively. HER2 copy number was detected in 20 patients with IHC (+ + ), while 1 CN(+ ) and 19 CN(-) were found. The ORR of HER2 negative, low expression and high expression patients were 42.4% (14/33) vs. 31.6% (12/38) vs. 0 (0/6) ( P = 0.08), respectively. The median PFS of the three groups were 11.0 months, 3.7 months and 1.8 months, respectively, with significant differences in overall and pairwise comparison( P=0.001). The median OS of patients with HER2 negative and low expression after anti-PD-1 treatment were 23.6 months and 22.7 months, respectively, while the median OS of patients with HER2 high expression had not been reached, with no significant difference in the overall comparison ( P=0.623). Conclusions:For patients with metastatic UC received anti-PD-1 treatment, the PFS of patients with high HER2 expression was significantly worse than that of patients with low or negative HER2 expression. HER2 expression may have potential value in predicting the efficacy of immunotherapy for metastatic UC who failed the previous chemotherapy, which needs further research.

Compared with normal tissue, interstitial extracellular pH of tumor cells is acidic. The reverse transmembrane pH gradient around tumor cells is closely related to its uncontrolled progression, angiogenesis and metastasis. Changes in urinary pH have an impact on the occurrence, progression and treatment of bladder cancer by regulating the microenvironment of bladder cancer cells. Relevant studies have shown that urinary pH value is an important factor in predicting the final clinical efficacy of bladder cancer patients combined with alkalization agents, which helps to reflect the acid-base balance and immune defense system in the body. Continuous monitoring of urinary pH can provide guidance and decision-making for the prognosis of bladder cancer patients.

OBJECTIVE：To investigate the risk factors for the recurrence of ischemic stroke after secondary prevention ，and to observe the effect of glutathione on 4-HNE. METHODS ：Totally 97 patients with ischemic stroke relapse within one year were treated from Oct. 2017 to Oct. 2019 in 3 hospitals as the Second Affiliated Hospital of Shandong First Medical University due to cerebral thrombosis or cerebral embolism as observation group ，and 97 non-recurrence patients in the same period were paired as control group. The patients in the observation group were randomly divided into conventional treatment group （49 cases）and drug intervention group （48 cases）. The patients in conventional treatment group received routine treatment such as cerebral blood flow recanalization， improving circulation ， controlling blood pressure ， maintaining blood glucose ， treating hyperlipidemia and arrhythmia during hospitalization. Drug intervention group was additionally given Glutathione for injection 1.8 g intragastrically ， once a day ，on the basis of conventional treatment group. 4-HNE concentrations in plasma were determined at admission and 14 days after treatment ，the genetic type of ALDH2 and type of TAST were determined at admission. Multiple liner regression was used to analyze the factors associated with 4-HNE increasing ； conditional Logistic analysis was used to identify independent risk factors resulting to ischem ic stroke recurrence after secondary prevention. RESULTS ：The plasma concentration of 4-HNE at admission and the percentage of arte ry atherosclerosis patients in observation group were significantly higher than control group（P＜0.05）. The distribution of each ALDH2 genotype in 2 groups complied with Hardy-Weinberg genetic equilibrium （P＞ 0.05）. The proportion of patients carrying ALDH2*2 allele in observation group （50.50％）was significantly higher than control group（36.08％）（P＜0.05）. ALDH2*2 allele [ B＝2.33，95％CI（1.35，5.50），P＝0.03] and artery atherosclerosis [ B＝1.90，95％CI （1.29，3.74），P＝0.04] were significantly associated with the elevation of plasma concentration of 4-HNE；artery atherosclerosis [OR＝ 2.93，95％CI（1.84，4.67），P＜0.01]，stroke family history [OR ＝1.50，95％CI（1.18，1.90），P＝0.04]，elevated plasma concentration of 4-HNE [OR ＝1.34，95％CI（1.11，1.62），P＝0.04] were regarded as independent risk factors associating with ischemic stroke recurrence after secondary prevention. After intervention ，plasma concentration of 4-HNE in drug intervention group and conventional treatment group was significantly lower than before intervention （P＜0.05）；there was no statistical significance between 2 groups（P＞0.05）. CONCLUSIONS ：Stroke family history ，artery atherosclerosis and the elevation plasma concentration of 4-HNE are independent risk factors associating with ischemic stroke recurrence after secondary prevention. Although drug intervention can reduce the elevated plasma concentration of 4-HNE，the effect of additional use of glutathione is not more significant than that of conventional treatment.

Objective:To explore the prognostic value of PD-L1 expression level in patients with metastatic renal cell carcinoma (mRCC).Methods:The clinicopathological and survival data of patients with mRCC in our hospital from Jan 2014 to Apr 2016 were retrospectively analyzed including 46 males and 15 females. The median age of these patients was 56 years(range: 29-75 years), with 41 patients ≤60 years and 20 patients >60 years. The baseline data before the systemic therapy showed 36 patients(59.0%)had 1 metastatic organ and 25 patients (41.0%) had equal or more than 2 organs to be metastasized. Among them, 17 patients(27.9%)had lung metastasis and 54 patients(88.5%)had liver metastasis. Abnormal baseline LDH occurred in 4 patients and 52 patients had normal LDH. Favorite and intermediate risk patients categorized by MSKCC risk stratification accounted for 59.6%(34 patients)and 40.4%(23 patients), respectively. Six patients(9.8%)experienced distant metastasis at initial diagnosis, with 4 of them undergoing primary site resection, and the other 55 patients undergoing radical nephrectomy. PD-L1 expression was detected by the immunohistochemical staining method. PD-L1 staining rate ≥1% detected on the tumor cell membrane was defined as positive expression. The correlation between PD-L1 expression and clinicopathological characteristics were compared. Kaplan-Meier method and log-rank test were used to compare the differences about DFS and OS under different factors. Cox proportional hazards regression model is used for multivariable analysis of survival data.Results:The detailed pathological types of the 61 patients with renal cell carcinoma were classified as 53 clear cell carcinomas, 3 papillary carcinomas, 1 collecting duct carcinoma, 2 translocation renal cell carcinomas and 2 being unclassified. There were 4, 20, 19 and 9 patients categorized as WHO/ISUP nuclear grade 1, 2, 3 and 4, and 26, 12, 20 and 2 patients were categorized as T 1, T 2, T 3 and T 4 stage, respectively. Five patients had regional lymph node metastasis(N+), and the other 56 patients had no regional lymph node metastasis(N-). The numbers of patients categorized as stage Ⅰ, Ⅱ, Ⅲ and Ⅳ diseases according to TNM staging system were 20, 11, 21 and 8, respectively. The total PD-L1 positive rate was 24.6%(15/61). The corresponding PD-L1 expression rate of patients with WHO/ISUP nuclear grade 1-4 were 0(0 patient), 5.0%(1 patient), 31.6%(6 patients)and 44.4%(4 patients), respectively; With the increasing WHO/ISUP nuclear grade, the positive rate of PD-L1 gradually escalated with a linear correlation ( P=0.006). The PD-L1 expression of the normal and abnormal LDH group were 19.2%(10 patients)and 75.0%(3 patients), respectively, with significant difference( P=0.035). Univariate analysis of disease-free survival time(DFS)showed that the prognostic factors include PD-L1( P=0.045), age group( P=0.014), WHO/ISUP nuclear grade( P<0.001), T stage( P=0.015), N stage( P=0.026)and TNM stage( P=0.005). However multivariate analysis only suggested WHO/ISUP nuclear grade as the independent prognostic factors for DFS( HR=1.8, 95% CI 1.1-2.9, P=0.018). Either in univariate or multivariate analysis, PD-L1 was not a prognostic factor for overall survival (OS)of mRCC patients(univariate analysis: P=0.154; multivariate analysis: P=0.902). The independent prognostic factors of OS include WHO/ISUP nuclear grade( HR=3.0, 95% CI 1.1-8.0, P=0.033)and MSKCC risk stratification( HR=5.9, 95% CI 1.2-29.7, P=0.03). Conclusions:This study showed that the higher the WHO/ISUP nuclear grade of patients with mRCC, the higher the positive rate of PD-L1. PD-L1 expression was not the independent prognostic factor for DFS or OS of mRCC.

Objective To explore the effect of goal-directed therapy bundle based on pulse-indicated continuous cardiac output (PiCCO) parameters to the prevention and treatment of acute kidney injury (AKI) in patients after cardiopulmonary bypass cardiac operation. Methods A prospective observational study was conducted. The adult patients with selective cardiopulmonary bypass cardiac operation admitted to the Third People's Hospital of Chengdu from December 2015 to January 2018 were enrolled. All patients were divided into two groups based on informed consent for PiCCO monitor at the time of admission to the intensive care unit (ICU): regular monitoring and treatment group (group A) and goal-directed therapy group based on PiCCO parameters (group B). In group A, the restrictive capacity management strategy was implemented to maintain the mean arterial pressure (MAP) > 65 mmHg (1 mmHg = 0.133 kPa) and the central venous pressure (CVP) between 8 mmHg and 10 mmHg. In group B, volume and hemodynamic status were optimized depending on PiCCO parameters to a goal of cardiac index (CI) > 41.68 mL·s-1·m-2, global end diastolic volume index (GEDVI) > 700 mL/m2 or intrathoracic blood volume index (ITBVI) > 850 mL/m2, extravascular lung water index (EVLWI) < 10 mL/kg, and MAP > 65 mmHg. Then the changes in hemodynamics and different prognosis of the patients in two groups were observed. Risk factors affecting the AKI were analyzed by Logistic regression. Results 171 cases were included, with 68 in group A and 103 in group B. There were no significant differences in gender, age, pre-operative scores by European system for cardiac operative risk evaluation (EuroScore), operation ways, operation time, cardiopulmonary bypass time, intraoperative dominant liquid equilibrium quantity, the use of intra-aortic balloon counterpulsation (IABP) during operation, and serum creatinine (SCr) level at the time of admission to ICU between the two groups. There were no significant differences in CVP within 24 hours after admission to ICU between the two groups. MAP in group B was significantly higher than that in group A at 8 hours and 16 hours after ICU admission (mmHg: 68.9±6.3 vs. 66.7±5.1, 69.0±4.9 vs. 67.0±5.3, both P < 0.05). Sequential organ failure assessment (SOFA) score in group B was significantly lower than that in group A at 24 hours after ICU admission (5.7±2.2 vs. 6.9±2.8, P < 0.05). Dominant liquid equilibrium quantity in group B was significant higher than that in group A at 24 hours after ICU admission (mL/kg: 7.1±6.2 vs. -0.1±8.2, P < 0.01), but there was no significant difference of that between groups at 48 hours and 72 hours after ICU admission. Compared with group A, incidence of combination with AKI during 72 hours after ICU admission was significantly decreased in group B [48.5% vs. 69.1%; odds ratio (OR) =0.422, 95% confidence interval (95%CI) = 0.222-0.802, P < 0.05], and incidence of moderate to severe AKI was also significantly decreased in group B (19.4% vs. 35.3%; OR = 0.442, 95%CI = 0.220-0.887, P < 0.05). There was no significant difference in usage of continuous renal replacement therapy (CRRT) after ICU admission between both groups (group A was 4.4%, group B was 4.9%, P > 0.05). It was shown by correlation analysis that only MAP and CI at 8 hours after ICU admission were significantly negatively correlated with AKI (MAP and AKI: r = -0.697, P = 0.000;CI and AKI: r = -0.664, P = 0.000). It was shown by Logistic regressive analysis that the MAP and CI at 8 hours after ICU admission were independent risk factors that influence the incidence of AKI at 72 hours after ICU admission (MAP:OR = 0.736, 95%CI = 0.636-0.851, P = 0.000; CI: OR = 0.006, 95%CI = 0.001-0.063, P = 0.000). There were no significant differences in the duration of mechanical ventilation, the length of ICU stay, the post-operation complications (except AKI), 7-day and 28-day mortality between the two groups. Conclusions Goal-directed therapy bundle based on PiCCO parameters reduced the incidence of AKI in patients after cardiopulmonary bypass cardiac operation and improved the severity of systemic disease. However, it did not reduce the duration of mechanical ventilation, length of ICU stay, the incidence of complications (except AKI), short-term mortality. The MAP and CI at 8 hours after ICU admission were independent risk factors that influence the incidence of AKI in patients after cardiopulmonary bypass cardiac operation.

Objective To evaluate the clinical efficacy and complications of lattice carbon dioxide laser in the treatment of female mild to moderate stress incontinence.Methods 30 cases of mild to moderate stress urinary incontinence in our hospital from August to October 2017 were reviewed.The average age was (46.5 ±3.5) years old,all married and has been bred,12 patients with mild stress incontinence and 18 patients with moderate stress urinary incontinence.Preoperative preparation including:1h urine cushion test measured leakage of urine,urine flow rate,residual urine,the international consultation on incontinence questionnaire (ICI-Q-SF) score,urine routine examination.Preoperative urine flow rate (31.87 ± 2.42) ml/s,preoperative (1 h) pad test (8.19 ± 2.42) ml,preoperative ICI-Q-SF score (4-8).The power was 12.5 mJ,the efficacy was 25％,and the single treatment was chosen.Urine flow rate,1 h urine pad test,residual urine test,ICI-Q-SF score,and subjective satisfaction were recorded at 1,3,6 months after operation.Results All 30 patients in this group were followed up for more than 6 months.The pad test was (2.14 ± 0.36) ml,(1.02 ± 0.54) ml,(0.80 ± 0.41) ml at 1,3 and 6 months postoperatively,which were significantly different from preoperative pad test (P ＜ 0.01,).The urine flow rate at 1,3,6 months after operation was (30.53 ± 3.15) ml/s,(32.19 ± 2.72) ml/s,(31.23 ± 5.76) ml/s,respectively,and there was no significant difference between the 3 groups (P ＞ 0.05).There was no significant difference between preoperative and postoperative urine flow rate (P ＞ 0.05).The ICI-Q-SF at 1,3,6 months after operation were 3 (1-4),3 (0-4),3 (0-4),which were significantly different from preoperative ICI-Q-SF.Among the 30 patients,3 cases had frequent urination after operation,1 case had frequent urination before operation,and became more severe after operation.The residual urine of 30 patients was negative after operation.All patients had no dysuria and no vaginal bleeding.No signs of urinary incontinence were observed after 6 months follow-up.Conclusions For patients with mild stress urinary incontinence,there is no obvious serious complication in the short term after the laser treatment of dot matrix carbon dioxide laser.The clinical treatment is safe and the leakage of urine can be improved.

Objective To investigate the safety and effectiveness of open radical prostatectomy (ORP) for locally advanced prostate cancer (LAPC).Methods From January 2012 to April 2017,132 cases underwent ORP were included.The mean age was 65.1 years old (ranged 41 to 83 years old),median PSA was 28.9 ng/ml (ranged 1.2 to 319.7 ng/ml) and mean Glcason score was 8.0(ranged 6.0 to 10.0).The number of clinical stage T3aN0,T3bN0,T4N0 and T1 ～4N1 were 92 cases(69.7％),20 cases (15.2％),8 cases (6.1％) and 12 cases (9.0％),respectively.Results The median length of hospital day,mean operative time and median blood loss were 9 d,180 min and 350 ml respectively.The intraoperative complication rate was 3.0％ (4/132),including 2 rectum injury and 2 iliac vessel injury.Pathological tumor stage revealed that ≤ pT2 N0 7 cases (5.3％),pT3a N0 61 cases (46.2％),pT3b N0 38 cases (28.8％),pT4N0 12 cases (9.1％) and pT1～4N1 14 cases (10.6％).The mean Gleason score was 8.0 (ranged 6 tol0).The numbers of patients with perineural invasion,seminal vesicle invasion and positive surgical margin were 81 cases (61.4％),49 cases (37.1％) and 41 cases (31.1％) respectively.The median follow-up duration was 24.1 (ranged 1.8 to 62.2) months.The rate of postoperative complications was 3.0％ (4/132) including 1 urethral stricture,1 wound infection,1 intestinal fistula and 1 lymphatic fistula.The rates of patients with urinary continence 1,3,6 and 12 months after surgery were 30.4％ (38/125)、63.9％ (76/119)、72.6％ (82/112)、89.1％ (90/101).The rates of adjuvant hormonal therapy and radiotherapy were 34.1％ (45/132) and 38.6％ (51/132).One patient (0.8％) died of lung cancer.The rate of biochemical recurrence(BCR) was 25.8％ (34/132).The 5-year BCRfree survival rate was 57.2％ (95％ CI 41.9％ ～ 70.6％).Conclusion The oncological control and functional recovery outcomes of ORP for locally advanced prostate cancer were reliable.