OBJECTIVE To investigate the regulatory effect of autophagy on the resistance of human liver cancer cell Huh7 to lenvatinib. METHODS Using human liver cancer cell Huh7 as subject， the lenvatinib-resist cell model （Huh7-LR） was generated by the low-dose gradient method combined with long-term administration. The sensitivity of parental cell Huh7 and drug-resistant cell Huh7-LR to lenvatinib was detected by using CCK-8 assay and flow cytometry. Western blot assay and GFP-mCherry-LC3 plasmid transfection were performed to detect the expression levels of autophagic protein Beclin-1， autophagic adapter protein sequestosome 1 （p62）， microtubule-associated protein 1 light chain 3 （LC3） and autophagic level. Furthermore， an autophagy activation model was constructed by cell starvation， the protein expression of p62 and autophagy level were detected by using Western blot assay and GFP-mCherry-LC3 plasmid transfection， and the effect of autophagy activation on the sensitivity of Huh7-LR cells to lenvatinib was detected by flow cytometry. RESULTS Compared with parental cells， the drug resistance index of Huh7-LR cells was 6.2； protein expression of p62 was increased significantly， while apoptotic rate， protein expression of Beclin-1 and LC3Ⅱ/ LC3Ⅰ ratio were all reduced significantly （P＜0.05 or P＜0.01）； the level of autophagy was decreased to some extent. Autophagy activation could significantly increase the protein expression of p62 in Huh7-LR cells （P＜0.05） and autophagy level， and significantly increase its apoptotic rate （P＜0.05）. CONCLUSIONS Autophagy is involved in lenvatinib resistance， and activating autophagy can reverse the resistance of liver cancer cells to lenvatinib to some extent.

Objective:To investigate the surgical efficacy of split liver transplantation.Methods:Patients who underwent liver transplantation at the Affiliated Hospital of Qingdao University between January 2015 and December 2022 were retrospectively analyzed. They were divided into split liver transplantation group ( n=60) and whole liver transplantation group ( n=765)according to graft types.In the split liver transplantation group, there were 23 males and 37 females, aged (52.5±10.2) years, and the body mass index was (22.4±3.3) kg/m 2. In the whole liver transplantation group, there were 630 males and 135 females, aged (51.2±9.6) years, and body mass index was (24.5±3.7) kg/m 2.The basic data of the two groups were matched 1∶1 using the propensity score matching method. The independent sample t test and χ2 test were used to compare the intraoperative and postoperative recovery of the two groups of donors and recipients. The overall survival rate and the graft survival rate of the two groups were analyzed by Kaplan-Meier method and the cumulative survival rate was compared by the Log-rank test. Results:Fifty-one well-matched pairs of data with similar baseline characteristics were obtained. The ratio of graft mass to recipient body weight in the matched split liver transplantation group was (1.78±0.55)%. Operation time( M(IQR))(10.8(1.5)hours vs. 8.0(1.9)hours, U=6.608, P<0.01) and cold ischaemia time(5.4(1.3)hours vs. 4.6(2.2)hours, U=2.825, P=0.005) were significantly longer in the split liver transplantation group than those in the whole liver transplantation group. Intra-operative anhepatic phase(53.0(15.0)minutes vs. 57.0(24.0)minutes, U=1.048, P=0.295),bleeding volume(1 000(1 400)ml vs. 1 200(1 200)ml, U=0.966, P=0.334) and intraoperative instillation of red blood cells(9.0(6.5)U vs. 11.0(11.0)U, U=1.732, P=0.083) were not significantly different between the two groups. However,the split liver transplantation group showed significantly longer postoperative intensive care unit stay(5.0(3.0)days vs. 4.0(4.0)days, U=2.677, P=0.007) and postoperative hospital stay(30.0(15.0)days vs. 26.0(15.0)days, U=2.237, P=0.025) and significantly higher incidence of postoperative complications(56.8%(29/51) vs. 36.6%(19/51), χ2=3.935, P=0.047) than the whole liver transplantation group. Furthermore,levels of alanine transaminase and aspartate aminotransferase were significantly higher on postoperative days 1,4 and 7 in the split liver transplantation group(all P<0.05) than in the whole liver transplantation group;however,there were no significant differences in these levels on postoperative days 14 and 28. The time to restoration of normal liver function in both groups(12.5(13.7)days vs. 9.0(12.5)days, U=1.607, P=0.108) was not statistically significant. Furthermore,the median follow-up time after surgery was 25.6 months in both groups. In postoperative years 1,2,3 and 5, the graft survival rates were 88.1%,80.8%,77.8% and 66.7% in the whole liver transplantation group and 80.3%,70.3%,67.3% and 60.5% in the split liver transplantation group( P=0.171),respectively. The patient survival rates in post-operative years 1,2,3 and 5 were 88.1%,80.8%,77.8% and 66.7% in the whole liver transplantation group and 80.3%,75.9%,70.3% and 63.3% in the split liver transplantation group,respectively( P=0.252). However,the differences of graft survival rates and patient survival rates between the two groups were not significant. Conclusion:Although it affects the early recovery of patients after liver transplantation,split liver transplantation has no effect on long-term survival rates and demonstrates surgical efficacy similar to that of whole liver transplantation.

Objective:To investigate the surgical efficacy of split liver transplantation.Methods:Patients who underwent liver transplantation at the Affiliated Hospital of Qingdao University between January 2015 and December 2022 were retrospectively analyzed. They were divided into split liver transplantation group ( n=60) and whole liver transplantation group ( n=765)according to graft types.In the split liver transplantation group, there were 23 males and 37 females, aged (52.5±10.2) years, and the body mass index was (22.4±3.3) kg/m 2. In the whole liver transplantation group, there were 630 males and 135 females, aged (51.2±9.6) years, and body mass index was (24.5±3.7) kg/m 2.The basic data of the two groups were matched 1∶1 using the propensity score matching method. The independent sample t test and χ2 test were used to compare the intraoperative and postoperative recovery of the two groups of donors and recipients. The overall survival rate and the graft survival rate of the two groups were analyzed by Kaplan-Meier method and the cumulative survival rate was compared by the Log-rank test. Results:Fifty-one well-matched pairs of data with similar baseline characteristics were obtained. The ratio of graft mass to recipient body weight in the matched split liver transplantation group was (1.78±0.55)%. Operation time( M(IQR))(10.8(1.5)hours vs. 8.0(1.9)hours, U=6.608, P<0.01) and cold ischaemia time(5.4(1.3)hours vs. 4.6(2.2)hours, U=2.825, P=0.005) were significantly longer in the split liver transplantation group than those in the whole liver transplantation group. Intra-operative anhepatic phase(53.0(15.0)minutes vs. 57.0(24.0)minutes, U=1.048, P=0.295),bleeding volume(1 000(1 400)ml vs. 1 200(1 200)ml, U=0.966, P=0.334) and intraoperative instillation of red blood cells(9.0(6.5)U vs. 11.0(11.0)U, U=1.732, P=0.083) were not significantly different between the two groups. However,the split liver transplantation group showed significantly longer postoperative intensive care unit stay(5.0(3.0)days vs. 4.0(4.0)days, U=2.677, P=0.007) and postoperative hospital stay(30.0(15.0)days vs. 26.0(15.0)days, U=2.237, P=0.025) and significantly higher incidence of postoperative complications(56.8%(29/51) vs. 36.6%(19/51), χ2=3.935, P=0.047) than the whole liver transplantation group. Furthermore,levels of alanine transaminase and aspartate aminotransferase were significantly higher on postoperative days 1,4 and 7 in the split liver transplantation group(all P<0.05) than in the whole liver transplantation group;however,there were no significant differences in these levels on postoperative days 14 and 28. The time to restoration of normal liver function in both groups(12.5(13.7)days vs. 9.0(12.5)days, U=1.607, P=0.108) was not statistically significant. Furthermore,the median follow-up time after surgery was 25.6 months in both groups. In postoperative years 1,2,3 and 5, the graft survival rates were 88.1%,80.8%,77.8% and 66.7% in the whole liver transplantation group and 80.3%,70.3%,67.3% and 60.5% in the split liver transplantation group( P=0.171),respectively. The patient survival rates in post-operative years 1,2,3 and 5 were 88.1%,80.8%,77.8% and 66.7% in the whole liver transplantation group and 80.3%,75.9%,70.3% and 63.3% in the split liver transplantation group,respectively( P=0.252). However,the differences of graft survival rates and patient survival rates between the two groups were not significant. Conclusion:Although it affects the early recovery of patients after liver transplantation,split liver transplantation has no effect on long-term survival rates and demonstrates surgical efficacy similar to that of whole liver transplantation.

OBJECTIVE To investigate the mechanism of glucose -6-phosphate dehydrogenase （G6PD）-induced sorafenib - resistance in hepatocarcinoma cell based on phoshorylated 3-kinase/protein kinase B （PI3K/Akt）signaling pathway . METHODS Cell lines including hepatocarcinoma cell Huh 7，sorafenib-resistant cell Huh 7-SR，G6PD overexpressed cell Huh 7-G6PD and its control cell Huh 7-CT，and compounds including G 6PD inhibitor （6-Aminonicotinamide，6AN）and sorafenib were used as objects or intervention drugs in these research . CCK8 assay was applied to evaluate cell viability . The protein levels of G 6PD and the phosphorylation levels of PI 3K/Akt signaling pathway were detected by Western blot . Flow cytometry was utilized to investigate cell apoptosis. RESULTS Compared with Huh 7 cells，the protein level of G 6PD was significantly increased in Huh 7-SR cells （P＜ 0.05）. The combination of 6AN and sorafenib reduced cell viability of Huh 7-SR cells （P＜0.01）. However，compared with Huh 7- CT，increased cell viability and decreased cell apoptosis rate were observed in Huh 7-G6PD cells while cells were treated with sorafenib（P＜0.01）. Mechanistically，the phosphorylation levels of PI 3K and Akt were significantly decreased in Huh 7-SR cells that were treated with 6AN（P＜0.05）. Moreover，under the condition of no drug intervention ，the phosphorylation levels of PI 3K and Akt were significantly elevated in Huh 7-G6PD cells when compared with Huh 7-CT（P＜0.01）. CONCLUSION G6PD could induce sorafenib -resistance in hepatocarcinoma cell by activating PI 3K/Akt signaling pathway .

Molecular glues can specifically induce aggregation between two or more proteins to modulate biological functions. In recent years, molecular glues have been widely used as protein degraders. In addition, however, molecular glues play a variety of vital roles, such as complex stabilization, interactome modulation and transporter inhibition, enabling challenging therapeutic targets to be druggable and offering an exciting novel approach for drug discovery. Since most molecular glues are identified serendipitously, exploration of their systematic discovery and rational design are important. In this review, representative examples of molecular glues with various physiological functions are divided into those mediating homo-dimerization, homo-polymerization and hetero-dimerization according to their aggregation modes, and we attempt to elucidate their mechanisms of action. In particular, we aim to highlight some biochemical techniques typically exploited within these representative studies and classify them in terms of three stages of molecular glue development: starting point, optimization and identification.

As one of the most lethal diseases, pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities. Furthermore, pancreatic cancer escapes early detection during the curable period because early symptoms rarely emerge and specific markers for this disease have not been found. Although combinations of new drugs, multimodal therapies, and adjuvants prolong survival, most patients still relapse after surgery and eventually die. Consequently, the search for more effective treatments for pancreatic cancer is highly relevant and justified. As a newly re-discovered mediator of gasotransmission, hydrogen sulfide (H

Objective To explore the clinical effect of edaravone on acute ischemic cerebrovascular disease ,and to observe its effect on serum C‐reactive protein (CRP) and matrix metalloproteinase‐9(MMP‐9) level .Methods Eighty four patients with acute ischemic cerebral vascular disease who were treated in our hospital during 2012 May to 2013 December were selected and divided in‐to observation group and control group ,with 42 cases in each group .The control group was treated with anti‐platelet ,regulating blood pressure and blood lipid ,reducing intracranial pressure ,improve microcirculation and other comprehensive treatment ;the pa‐tients in observation group were treated with increased dose of edaravone on the basis of the control group .America national institu‐tes of health stroke scale(NIHSS) and activities of daily living scale (ADL) were used to evaluate the neurological function and ac‐tivities of daily living ability of patients before and after the treatment ,the CRP and MMP‐9 level were detected before and after treatment ,and the adverse reaction during the treatment was recorded .Results After one week and two weeks after treatment , there were significant differences between treatment group and control group in the NIHSS score and ADL score (P<0 .05) ,and there were significant differences between treatment group and control group in CRP and MMP‐9 (P<0 .05) .There was no signifi‐cant difference between treatment group and control group in the reoccurrence rate of adverse reaction (7 .14% vs .4 .76% )(P>0 .05) .Conclusion Edaravone could improve the clinical treatment effect of acute ischemic cerebrovascular disease ,and reducing se‐rum CRP and MMP‐9 level mechanism pathway might be involved in the regulation of its pharmacodynamics .

Objective To study the validity of RAND-UCLA (Rand Corporation and University of California at Los Angeles) consensus panel method in developing guidelines of referral indications for low back pain (LBP).Methods Evidence-based clinical guidelines for LBP management at community level and its referral guidelines published since 2001 and other tools were retrieved with varied tools.All clinical guidelines met inclusion criteria were evaluated with clinical studies and evaluation tools (AGREE).An pool of indication items was established based on evidence for developing referral indications for LBP, which were added by RAND-UCLA consensus panel method, and alternative referral indications were selected and clinical guidelines for LBP referral were established.Results A total of 15 copies of clinical guidelines from nine countries or regions were included in it after critical appraisal.Four copies of referral guidelines from two countries were included.Referral indications for LBP were derived directly from the RAND-UCLA consensus panel process, consisting of 44 referral indications for three groups (immediate, urgent and routine referral).Conclusions The RAND-UCLA consensus panel method is a more useful and practical tool in developing clinical guidelines, referral guidelines, which is worthwhile being recommended and spread.

Objective To investigate the prognosis of patients with nasal NK/T cell lymphoma receiving different treatment modalities. Methods From 1990 to 2004, 85 patients with stage ⅠE and ⅡE primary nasal NK/T cell lymphomas were retrospectively studied. Twenty patients received chemotherapy of CHOP regimen alone, 11 patients received radiotherapy only, 6 patients received radiotherapy followed by more than 2 cycles of chemotherapy, and 48 patients received more than 2 cycles of chemotherapy followed by radiotherapy. Survival analysis was performed by the Kaplan-Meier method, the difference between groups was evaluated by the Log-rank test, and the Cox regression model was used for multivariate analysis. Results The 5-year overall survival rate (OS) was 40%. The 5-year OS was 57% and 28% for limited stage ⅠE and extended stage ⅠE(X2 =8. 87, P =0. 003), and 23% for stage ⅡE, which was similar to extended stage ⅠE (X2 =0. 19, P-0. 664). The 5-year OS was 13%, 54% and 47% for chemotherapy alone, radiotherapy followed with or without chemotherapy, and chemotherapy followed by radiotherapy, respectively. The last two groups had better OS than chemotherapy alone (P = 0. 030 and 0.049). The 5-year OS was 58% and 12% for patients achieving complete response (CR) and uncomplete response (X2 = 30.68, P = 0. 000).The CR rate was 56% and 86% for radiotherapy of ≤50 Gy and >50 Gy (X2 =6.11, P=0. 013). The corresponding 5-year relapse-free survival rate was 89% and 84% (X2 =0.36, P=0.551). Of 68 patients receiving initial chemotherapy, the CR rate of those who received ≤2, 3-4 and ≥5 cycles was 0, 20%and 3 3 % , respectively (X2 = 7.65 , P = 0. 022) . For 5 0 patients who received ≥ 3 cycles of initial chemotherapy and 17 patients who received initial radiotherapy of ≥40 Gy, the CR rate was 28% and 88%(χ2= 18. 75, P= 0. 000). In patients with pathological nodular and ulcer type, the CR rates with radiotherapy were higher than with chemotherapy (100%: 38%, χ2 = 7.92, P = 0. 005; and 100%: 11%,χ2 = 14.40, P = 0. 000). Multivariate analysis showed that stage and recent effect were the independent prognostic factors. Conclusions The initial radiotherapy with 50 Gy is appropriate for early stage nasal NK/T cell lymphomas. Combined chemotherapy could be used for extended stage ⅠE and ⅡE, but the outcome of CHOP regimen is poor.

Objective The purpose of this study is to investigate the influence of comprehensive intervention on the family and social functions in patients with schizophrenia. Methods The stratified randomization, controlled experiment was designed for this study. 300 cases were diagnosed as schizophrenia in accordance with the Chinese classification and diagnostic criteria of mental disorder-3 (CCMD-3) diagnosis standard, and they were randomly divided into intervention group and control group. All the cases were followed up for three years after hospital discharge. Comprehensive interventions were only taken in intervention group, but not in control group. All of the cases were e-valuated by family assessment device (FAD) and social disability screening schedule ( SDSS) at the time of pre - therapy, hospital discharge and the end of 1st, 2nd and 3rd year after hospital discharge. Results In the 3rd year after hospital discharge, the scores of PANSS, FAD and SDSS of intervention group were significantly lower than those of control group ( P < 0.05 ). Conclusion Comprehensive intervention can significantly improve the family and social functions in the patients with schizophrenia.