Liver transplantation (LT) has become a standard treatment for end-stage liver diseases, and graft injury is intricately associated with poor prognosis. Granzyme B (GZMB) plays a vital role in natural killer (NK) cell biology, but whether NK-derived GZMB affects graft injury remains elusive. Through the analysis of single-cell RNA-sequencing data obtained from human LT grafts and the isolation of lymphocytes from mouse livers following ischemia-reperfusion injury (IRI), we demonstrated that 2NK cells with high expression of GZMB are enriched in patients and mice. Both systemically and liver-targeted depletion of NK cells led to a notable reduction in GZMB⁺ cell infiltration, subsequently resulting in diminished graft injury. Notably, the reconstitution of Il2rg ^-/- Rag2 ^-/- mice with purified Gzmb-KO NK cells demonstrated superior outcomes compared to those with wild-type NK cells. Crucially, global knockout of GZMB and pharmacological inhibition exhibited remarkable improvements in liver function in both mouse IRI and rat LT models. Moreover, a phosphorylated derivative of FDA-approved vidarabine was identified as an effective inhibitor of mouse GZMB activity by molecular dynamics, which could provide a potential avenue for therapeutic intervention. Therefore, targeting NK cell-derived GZMB during the LT process suggests potential therapeutic strategies to improve post-transplant outcomes.

Objective:To explore the expression of family with sequence similarity 83 member A (FAM83A) in colorectal cancer, and the effect of FAM83A knockdown on the proliferation of colorectal cancer cells and the related mechanism.Methods:The expression of FAM83A in the tissues of 102 patients with colorectal cancer and its adjacent tissues was detected by immunohistochemistry. HCT116 cells were divided into experimental group and control group. The experimental group cells were transfected with FAM83A-siRNA plasmid, and the control group cells were transfected with MOCK-siRNA plasmid. The mRNA content of FAM83A in each group was detected by fluorescence quantitative PCR. The expressions of FAM83A, P13K, p-AKT and p-mTOR in each group were detected by Western blot. CCK8 assay and clonogenesis assay were used to detect cell proliferation.Results:The positive rate of FAM83A in colorectal cancer patients was 88.23% (90 cases /102 cases), and the expression rate of FAM83A in paracancer tissues was 10.78% (11 cases /102 cases). The expression rate of Fam83a in colorectal cancer tissues was significantly higher than that in paracancer tissues, with statistical significance ( P<0.001). After siRNA transfection, the mRNA expression levels of FAM83A in HCT116 cells of the experimental group and control group were 1.23±0.20 and 0.43±0.12, respectively, and the protein expression levels of FAM83A were 1.19±0.11 and 0.23±0.08, respectively. The expression levels of P13K were 1.21±0.17 and 0.28±0.09, the expression levels of p-AKT were 1.35±0.23 and 0.57±0.18, and the expression levels of p-mTOR were 1.48±0.20 and 1.05±0.14. The expression of P13K, p-Akt and p-mTOR was down-regulated (all P<0.05). The absorbance of HCT116 cells in the experimental group and the control group was 1.09±0.22 and 2.21±0.27, respectively. The cloning rate of HCT116 cells in the experimental group and the control group was 21.6%±2.4% and 62.7%±4.1%, respectively. The proliferation ability of HCT116 cells in the experimental group decreased significantly ( P<0.05) . Conclusions:The expression of FAM83A is significantly increased in colorectal cancer tissues, which may be related to the malignant degree of colorectal cancer. FAM83A affects the proliferation of colorectal cancer cells through the P13K/AKT/mTOR signaling pathway.

Tuberculosis (TB) is an ancient infectious disease. Before the availability of effective drug therapy, it had high morbidity and mortality. In the past 100 years, the discovery of revolutionary anti-TB drugs such as streptomycin, isoniazid, pyrazinamide, ethambutol and rifampicin, along with drug combination treatment, has greatly improved TB control globally. As anti-TB drugs were widely used, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis emerged due to acquired genetic mutations, and this now presents a major problem for effective treatment. Genes associated with drug resistance have been identified, including katG mutations in isoniazid resistance, rpoB mutations in rifampin resistance, pncA mutations in pyrazinamide resistance, and gyrA mutations in quinolone resistance. The major mechanisms of drug resistance include loss of enzyme activity in prodrug activation, drug target alteration, overexpression of drug target, and overexpression of the efflux pump. During the disease process, Mycobacterium tuberculosis may reside in different microenvironments where it is expose to acidic pH, low oxygen, reactive oxygen species and anti-TB drugs, which can facilitate the development of non-replicating persisters and promote bacterial survival. The mechanisms of persister formation may include toxin-antitoxin (TA) modules, DNA protection and repair, protein degradation such as trans-translation, efflux, and altered metabolism. In recent years, the use of new anti-TB drugs, repurposed drugs, and their drug combinations has greatly improved treatment outcomes in patients with both drug-susceptible TB and MDR/XDR-TB. The importance of developing more effective drugs targeting persisters of Mycobacterium tuberculosis is emphasized. In addition, host-directed therapeutics using both conventional drugs and herbal medicines for more effective TB treatment should also be explored. In this article, we review historical aspects of the research on anti-TB drugs and discuss the current understanding and treatments of drug resistant and persistent tuberculosis to inform future therapeutic development.
Humans ; Pyrazinamide/therapeutic use* ; Isoniazid/therapeutic use* ; Antitubercular Agents/therapeutic use* ; Tuberculosis, Multidrug-Resistant/microbiology* ; Mycobacterium tuberculosis/genetics* ; Tuberculosis/drug therapy* ; Rifampin/therapeutic use* ; Mutation ; Drug Resistance, Multiple, Bacterial/genetics*

OBJECTIVES: To study the correlation of intestinal dominant flora with hyperuricemia, and to explore influencing factors of hyperuricemia. METHODS: Data of gut dominant microbiota were collected from subjects who underwent health check-up in Shulan (Hangzhou) Hospital from January 2018 to April 2020. Subjects with high uric acid and normal uric acid were matched by propensity score matching method according to age, gender and body mass index (BMI). This resulted in 178 pairs as hyperuricemia group and control group. The gut dominant microbiota between hyperuricemia and normal control group were compared. Pearson or Spearman correlation coefficient method was used to analyze the correlation between blood uric acid and intestinal dominant flora. Univariate and multivariate logistic regression were used to analyze the influencing factors of hyperuricemia. RESULTS: The abundance of Atopobium, Lactobacillus, Bacteroides, Enterococcus, Clostridium leptum, Fusobacterium prausnitzii, Bifidobacterium, Clostridium butyricum and the ratio of Bifidobacterium to Enterobacter (B/E) in the hyperuricemia group were significantly lower than those in the control group (all P<0.01). The correlation analysis showed that serum uric acid were negatively correlated with the abundance of Atopobium (r=－0.224, P<0.01), Bacteroides (r=－0.116, P<0.05), Clostridium leptum (r=－0.196, P<0.01), Fusobacterium prausnitzii (r=－0.244, P<0.01), Bifidobacterium (r=－0.237, P<0.01), Eubacterium rectale (r=－0.125, P<0.05), Clostridium butyricum (r=－0.176, P<0.01) and B/E value (r=－0.127, P<0.05). Multivariate logistic regression analysis showed that glutamyl transpeptidase was an independent risk factor for hyperuricemia (OR=1.007, 95%CI: 1.002-1.012, P<0.05), and the Atopobium was an independent protective factor for hyperuricemia (OR=0.714, 95%CI: 0.605-0.842, P<0.01). CONCLUSIONS There are alterations in abundance of gut dominant microbiota in patients with hyperuricemia, and Atopobium abundance appears as a protective factor for hyperuricemia.
Humans ; Uric Acid ; Hyperuricemia ; Body Mass Index ; Risk Factors ; Microbiota

Objective:To compare the efficacy and safety of a new type of plastic biliary stent modified based on the pigtail nasobiliary duct and the common plastic biliary stent for hilar cholangiocarcinoma.Methods:Data of a total of 38 patients with obstructive jaundice caused by hilar cholangiocarcinoma who received endoscopic retrograde cholangiopancreatography (ERCP) palliative treatment at the Endoscopy Center, General Hospital of Northern Theater Command from June 2018 to December 2020 were collected, including 20 cases using the new type of plastic biliary stent (the new stent group), and 18 cases using the common plastic stent (the common stent group). Patients were followed up to May 30, 2021. The procedure time, hospital stay, postoperative biliary infection incidence, the bilirubin decrease, and the patency time of the stents in the two groups were compared.Results:The procedure time was 19.85±1.07 minutes in the new stent group and 22.00±3.38 minutes in the common stent group, respectively, showing no significant difference between them ( t=1.26, P=0.607). The lengths of hospital stay of the two groups were 11.45±2.39 days and 11.33±3.51 days, respectively, showing no significant difference between them ( t=-0.52, P=0.938). The median margins of total bilirubin reduction in the two groups were 122.85 μmol/L and 96.25 μmol/L, respectively, with significant difference ( Z=-2.03, P=0.042). The incidence of long-term cholangitis of the new stent group was significantly lower than that of the common stent group [10.0% (2/20) VS 44.4% (8/18), P=0.027]. The patency time of the new stent group was significantly longer than that of the common stent group (109.45±32.67 days VS 82.11±20.95 days) with significant difference ( t=2.23, P=0.032). Conclusion:In the palliative treatment of hilar bile duct obstruction, the new plastic bile duct stent modified based on pigtail type can reduce the incidence of long-term cholangitis and prolong the patency of bile duct stent compared with the common stent group.

Objective: Comparing the benefit of Abidor, lopinavir/ritonavir and recombinant interferon α-2b triple combination antiviral therapy and lopinavir/ritonavir and interferon dual combination antiviral therapy to hospitalized novel coronavirus pneumonia 2019 in Zhejiang province. Methods: A multi-center prospective study was carried out to compare the effect of triple combination antiviral therapy with dual combination antiviral therapy in 15 medical institutions of Zhejiang Province. All patients were treated with recombinant interferon α-2b (5 million U, 2 times/d) aerosol inhalation. 196 patients were treated with abidol (200 mg, 3 times/d) + lopinavir / ritonavir (2 tablets, 1 time/12 h) as the triple combination antiviral treatment group. 41 patients were treated with lopinavir / ritonavir (2 tablets, 1 time/12 h) as the dual combination antiviral treatment group. The patients who received triple combination antiviral therapy were divided into three groups: within 48 hours, 3-5 days and > 5 days after the symptom onset. To explore the therapeutic effects of triple combination antiviral drugs and dual combination antiviral drugs, as well as triple combination antiviral drugs with different antiviral initiate time. SPSS17.0 software was used to analyze the data. Results: The time of virus nucleic acid turning negative was (12.2 ± 4.7) days in the triple combination antiviral drug group, which was shorter than that in the dual combination antiviral drug group [(15.0 ± 5.0) days] (t = 6.159, P < 0.01 ). The length of hospital stay [12 (9, 17) d] in the triple combination antiviral drug group was also shorter than that in the dual combination antiviral drug group [15 (10, 18) d] (H = 2.073, P < 0.05). Comparing the antiviral treatment which was started within 48 hours, 3-5 days and > 5 days after the symptom onset of triple combination antiviral drug group, the time from the symptom onset to the negative of viral shedding was 13 (10,16.8), 17 (13,22) and 21 (18-24) days respectively (Z = 32.983, P < 0.01), and the time from antiviral therapy to the negative of viral shedding was (11.8±3.9) , (13.5±5.1) and (11.2±4.3) d. The differences among the three groups were statistically significant (Z=32.983 and 6.722, P<0.01 or<0.05). Conclusions The triple combination antiviral therapy of Abidor, Lopinavir/Litonavir and recombinant interferon α-2b showed shorter viral shedding time and hospitalization time compared with the dual combination antiviral therapy. The earlier the time to initiate triple antiviral treatment, the shorter the time of virus shedding.

Surgical minimally invasive techniques such as image intervention, laparoscopy, endoscopy, and assisted medical robotics have become the mainstream of minimally invasive surgery (MIS). However, the vague concept, diverse misunderstanding, and the lack of standards have led to a lot of malpractice in current MIS. Based on the analysis of the clinical situation and the domestic and foreign literatures, the authors have put forward the theory of comprehensive minimally invasive surgery (CMIS), and established the concepts of minimally invasive prevention, minimally invasive diagnosis and minimally invasive follow-up in the view of hepatobiliary surgery. The authors have proposed "three-All" principles of all personnel, all aspects and all processes, and established a comprehensive four-level criteria of outcomes, complications, time and costs for CMIS, in an attempt to provide feasible and practical concepts and standards for MIS from a clinical practice and theoretical level, with a view to standardizing minimally invasive procedures and solving the problem of MIS.

Purpose To assess right ventricular function and synchronous acute response in patients with chronic cardiac failure after cardiac resynchronization therapy (CRT) using equilibrium radionuclide angiography (ERNA).Materials and Methods Twenty-four chronic cardiac failure patients who accepted CRT were included (CRT group) and twenty healthy participants were also selected as the control group.ERNA was performed before and within 48 h after pacemaker implantation to calculate both right ventricular ejection fraction (RVEF) and RV dyssynchrony.RV dyssynchrony was defined as the standard right ventricular phase shift and right ventricular phase standard deviation (RVPS and RVPSD).Results The postoperative RVEF,RVPS and RVPSD in CRT group were significantly improved (P＜0.05).Fifteen patients (62.5％) were classified as acute responders,based on a reduction of at least 15％ in LV end-systolic volume immediately after CRT.The baseline RVEF in responders was higher than that in nonresponders (P＜0.05),while the RVPS and RVPSD were lower (P＜0.05).The postoperative RVPS and RVPSD decreased (P＜0.05),and the RVEF increased (P＜0.05) in both responders and nonresponders after pacemaker implantation,indicating that the right ventricular function and dyssynchrony in CRT group were both improved.Conclusion This study showed a significant improvement in RV ventricular systolic function and synchrony immediately after CRT.ERNA allows assessment of changes in RVEF and RV dyssynchrony before and after CRT implantation.

Objective:To explore the prognostic value of CysC and NT‐proBNP in patients with non‐ST elevation a‐cute coronary syndrome (NSTE‐ACS) .Methods :A total of 166 NSTE‐ACS patients hospitalized in our hospital from Jan 2012 to Dec 2012 were selected .They were followed up for 12 months ,then general data ,levels of CysC , NT‐proBNP ,hsCRP and cTnI etc .and incidence rate of MACE were recorded and measured .According to MACE occurrence during follow‐up or not ,156 cases were divided into non‐MACE group (n=137) and MACE group (n=19) ,risk factors for MACE in NSTE‐ACS patients were analyzed ,receiver operator characteristic curve (ROC) was performed ,and the optimal cutoffs of related indexes predicting MACE occurrence in these patients were analyzed . Results :Compared with non‐MACE group ,there were significant rise in age [ (60.26 ± 10.45) years vs .(64.16 ± 11.21) years] ,levels of CysC [ (1.02 ± 0.11) mg/L vs .(1.15 ± 0.12) mg/L] ,NT‐proBNP [ (251.97 ± 89.65) pg/ml vs .(347.93 ± 107.29) pg/ml] ,hsCRP [ (14.69 ± 3.53) mg/L vs .(17.13 ± 3.68) mg/L] and cTnI [ (0.36 ± 0.46) ng/ml vs .(0.90 ± 0.88) ng/ml] in MACE group ,P<0.05 or <0.01. Multi‐factor regression analysis indica‐ted that CysC ,NT‐proBNP and cTnI levels were independent predictors for MACE in NSTE‐ACS patients ( P<0.05 or <0.01) .ROC curves of CysC ,NT‐proBNP ,cTnI and hsCRP judging prognosis were drawn , only AUC of CysC and NT‐proBNP curves were >0.7 [CysC:0.784 ,95% CI:0.687~0.881 ;NT‐proBNP:0.753 ,95% CI :0.639~0.867] , and it′s analysis indicated that CysC=1.07 mg/L and NT‐proBNP=279.60 pg/ml were their optimal cutoff predicting MACE .Kaplan‐Meier survival curves with above two cutoffs as risk stratification cutoff indicated that survival time of high risk group was significantly shorter than that of low risk group (P<0.05) .Conclusion:Serum CysC and NT‐proBNP levels are independent predictors assessing prognosis in NSTE‐ACS patients .

Objective To investigate the features and clinical value of endoscopic ultrasonography and colonoscopy for appendix mucocele. Methods The patients with mucocele of appendix who were diagnosed by endoscopic ultrasonography and colonoscopy in three hospitals all underwent surgery from January 2008 to March 2015. Appendix mucocele in these patients was confirmed by postoperative pathology and clinical data were retrospectively analyzed. Results A total of 22 patients with appendix mucocele were analyzed retrospectively. The average size of intralumen mucocele was 1. 84±1. 42 cm (0. 6-4. 5 cm) . The colonscopic finding of appendiceal mucocele showed submucosal protuberance at the appendiceal orifice with smooth surface. The appendiceal orifice was found at the edge of appendiceal mucocele. Endoscopic ultrasonogrphy showed low echo with smooth cyst wall in 8 patients, mixed equal echo and low echo in 14 cases. Appendicectomy was performed in 11 patients and resection of ileocecum in 11 others. Conclusion Endoscopic ultrasonography and colonoscopy are valuable for diagnosis and treatment in appendiceal mucocele.