Although immunotherapy has made a breakthrough in the treatment of cancer,the emergence of drug resistance has limited be-nefits in most patients,and reversing immunotherapy resistance remains a hotly debated and unresolved issue.The tumor microenviron-ment(TME)comprises a large number of T lymphocytes.During the biological processes of proliferation,activation,and the effect of tumor-infiltrating lymphocytes(TILs),TILs face severe local metabolic stress,resulting in metabolic reprogramming to meet the markedly increased energy demand and biosynthesis requirements.This process of adaptive changes in the metabolic pattern is closely related to the pheno-type and function of TILs,affecting immunotherapy efficacy and mediating immunotherapy resistance.In recent years,with the study of TIL metabolism and the search for specific metabolic regulatory points,targeting the TIL metabolic pathway could restore the tumor-killing func-tion and reverse immunotherapy resistance.This review explores the relationship between the metabolic reprogramming of TILs and im-mune resistance,and provides a new strategy for reversing immune resistance.

Traditional antibody drug conjugates(ADC)combine monoclonal antibodies with cytotoxic drugs to accurately strike cancer cells,but there are still many shortcomings in stability,targeting,efficacy,and safety.Novel ADC,such as bi-specific,site-specific,dual-payload,and pro-drug type ADC,can be optimized by simultaneously binding 2 different antigens or epitopes,selecting more stable linkers,coupling with specific amino acid sites of antibodies,carrying different drug payloads,and adopting prodrug strategies,while retaining the characteristics of traditional ADC.Significantly improving the stability,targeting,efficacy and safety of drugs can better meet the needs of clinical treatment.Novel ADC will play a more important role in cancer treatment in the future.Discussing the progress of novel ADC in cancer treatment and analyzing their advantages and challenges can provide theoretical support for the development of anti-cancer strategies and provide directions for drug research and development.

In this study, a single base editing system was used to edit the FecB and GDF9 gene to achieve a targeted site mutation from A to G and from C to T in Ouler Tibetan sheep fibroblasts, and to test its editing efficiency. Firstly, we designed and synthesized sgRNA sequences targeting FecB and GDF9 genes of Ouler Tibetan sheep, followed by connection to epi-ABEmax and epi-BE4max plasmids to construct vectors and electrotransfer into Ouler Tibetan sheep fibroblasts. Finally, Sanger sequencing was performed to identify the target point mutation of FecB and GDF9 genes positive cells. T-A cloning was used to estimate the editing efficiency of the single base editing system. We obtained gRNA targeting FecB and GDF9 genes and constructed the vector aiming at mutating single base of FecB and GDF9 genes in Ouler Tibetan sheep. The editing efficiency for the target site of FecB gene was 39.13%, whereas the editing efficiency for the target sites (G260, G721 and G1184) of GDF9 gene were 10.52%, 26.67% and 8.00%, respectively. Achieving single base mutation in FecB and GDF9 genes may facilitate improving the reproduction traits of Ouler Tibetan sheep with multifetal lambs.
Animals ; Sheep/genetics* ; Gene Editing ; Tibet ; Mutation ; Phenotype ; Mutagenesis, Site-Directed

Objective:To compare the differences in the prevalence of mild micro-hepatic encephalopathy (MHE) among patients with cirrhosis by using the psychometric hepatic encephalopathy score (PHES) and the Stroop smartphone application (Encephal App) test.Methods:This prospective, multi-center, real-world study was initiated by the National Clinical Medical Research Center for Infectious Diseases and the Portal Hypertension Alliance and registered with International ClinicalTrials.gov (NCT05140837). 354 cases of cirrhosis were enrolled in 19 hospitals across the country. PHES (including digital connection tests A and B, digital symbol tests, trajectory drawing tests, and serial management tests) and the Stroop test were conducted in all of them. PHES was differentiated using standard diagnostic criteria established by the two studies in China and South Korea. The Stroop test was evaluated based on the criteria of the research and development team. The impact of different diagnostic standards or methods on the incidence of MHE in patients with cirrhosis was analyzed. Data between groups were differentiated using the t-test, Mann-Whitney U test, and χ2 test. A kappa test was used to compare the consistency between groups. Results:After PHES, the prevalence of MHE among 354 cases of cirrhosis was 78.53% and 15.25%, respectively, based on Chinese research standards and Korean research normal value standards. However, the prevalence of MHE was 56.78% based on the Stroop test, and the differences in pairwise comparisons among the three groups were statistically significant (kappa = -0.064, P < 0.001). Stratified analysis revealed that the MHE prevalence in three groups of patients with Child-Pugh classes A, B, and C was 74.14%, 83.33%, and 88.24%, respectively, according to the normal value standards of Chinese researchers, while the MHE prevalence rates in three groups of patients with Child-Pugh classes A, B, and C were 8.29%, 23.53%, and 38.24%, respectively, according to the normal value standards of Korean researchers. Furthermore, the prevalence rates of MHE in the three groups of patients with Child-Pugh grades A, B, and C were 52.68%, 58.82%, and 73.53%, respectively, according to the Stroop test standard. However, among the results of each diagnostic standard, the prevalence of MHE showed an increasing trend with an increasing Child-Pugh grade. Further comparison demonstrated that the scores obtained by the number connection test A and the number symbol test were consistent according to the normal value standards of the two studies in China and South Korea ( Z = -0.982, -1.702; P = 0.326, 0.089), while the other three sub-tests had significant differences ( P < 0.001). Conclusion:The prevalence rate of MHE in the cirrhotic population is high, but the prevalence of MHE obtained by using different diagnostic criteria or methods varies greatly. Therefore, in line with the current changes in demographics and disease spectrum, it is necessary to enroll a larger sample size of a healthy population as a control. Moreover, the establishment of more reliable diagnostic scoring criteria will serve as a basis for obtaining accurate MHE incidence and formulating diagnosis and treatment strategies in cirrhotic populations.

Objective To explore the effect of radon released from water on the indoor radon activity concentration in groundwater supplies.Methods Two groundwater supplies in a city were chosen.Radon concentrations in three kinds of water samples were determined by using a continuous radon monitor with air-water exchanger,including source water,finished water and tap water.The solid track detector was used to analyze the indoor radon concentration in water supplies.Results The concentrations of radon in source water,finished water and tap water were (7.59 ± 1.36),(3.56 ±0.86),(3.68 ±0.81)Bq/L and (12.19 ±0.57),(7.87 ± 1.12),(9.50 t 1.12) Bq/L,respectively.The concentration of radon was the highest in source water and at less varying level in finished water and tap water.Aeration and filtration tank process significantly decreased radon activity in water.Radon concentrations in aeration and filtration rooms were 4 218 Bq/m3 and 1 937 Bq/m3,respectively,which exceeded the limit in work place (1 000 Bq/m3).Conclusions Aeration and filtration workplaces for groundwater supplies were found to contain elevated radon concentrations in air,which was released from groundwater.Radon issues in groundwater supplies in China should be paid more attention.

Objective To explore the signaling pathway of apoptosis induced by Paclitaxel (PTX) in leukemia cells and the chemosensitizing effect of adding short hairpin RNA(shRNA) on PTX,which targets the silencer of death domains(SODD).Methods After being treated with PTX,the expressions of SODD,B-cell lymphoma/leukemia-2 (Bcl-2),nuclear factor kappa B (NF-κB) and Caspase-3 proteins in Jurkat cells were determined by Western blot ;the shRNA-SODD vectors were constructed and transfected into Jurkat cells by electroporation,and then G418 was used to select the stable tranfected cell line expressing the shRNA-SODD recombinant plasmids.The incidence of cell apoptosis induced by PTX was determined by flow cytometry labeled with propidium iodide.Results During the process of inducing apoptosis of Jurkat cells,PTX could significantly down-regulate the expressions of SODD and Bcl-2 proteins,degrade Caspase-3 and activate NF-κB.The apoptotic sensibility of Jurkat cells transfected with shRNA-SODD to PTX was significantly increased compared with the control group,and the difference was statistically significant (F =10.35,P ＜ 0.05).Conclusions PTX can effectively induce apoptosis of Jurkat cells.Perhaps,SODD/Bcl-2 represents a specific apoptotic signaling pathway of PTX in leukemia cells and this apoptotic signaling pathway is Caspase-3-dependent,in which the function of NF-κB is to modulate the correlative apoptotic factors.Inhibiting the expression of SODD through transfecting shRNA-SODD vectors can significantly increase the apoptotic sensibility of leukemia cells to PTX.

Objective To investigate distribution and antimicrobial resistance among nosocomial pathogens from 13 teaching hospitals in China in 2009. Methods Non-repetitive pathogens from nosocomial BSI, HAP and IAI were collected and sent to the central lab for MIC determination by agar dilution method.WHONET5.6 software was used to analyze the data. Results A total of 2 502 clinical isolates were collected. The top three pathogens of BSI were Escherichia coli [27. 1% (285/1 052 )] , coagulase-negutive staphylococcus [12. 6% ( 133/1 052)] and Klebsiella pneumoniae [10. 8% ( 114/1 052)]. The top three pathogens of HAP were Acinetobacter baumannii [28. 8% (226/785)], Pseudomonas aeruginosa [16. 1% (126/785)] and Klebsiella pneumoniae [14.6% (115/785 )] . The top three pathogens of IAI were Escherichia coli[31.0% ( 206/665 )], Klebsiella pneumonia [11.3% ( 75/665 )] and Enterococcus faecium [10. 8% (72/665)]. Against Escherichia coil and Klebsiella spp. , the antimicrobial agents with higher than 80% susceptibility rate included imipenem and meropenem (98. 1%-100% ), tigecycline (95.3%-100% ), piperacillin-tazobactam ( 88.6% -97. 1% ) and amikacin ( 88. 3% -92. 5% ). Against Enterobacter spp. , Citrobacter spp. and Serratia spp. , the susceptibility rates of tigecycline were 93.5% -100% whereas the value of imipenem and meropenem were 92.9% -100%. Other antimicrobial agents with high activity included amikacin ( 85.2% -96. 7% ), pipcracillin-tazobactam ( 82.4% -96.4% ), cefepime ( 79. 6% -96. 7% ) and cefoperazonc-sulbactam (78. 7%-90. 0% ). Polymyxin B showed the highest susceptibility rateagainst Pseudomonas aeruginosa ( 100% ), followed by amikacin ( 81.9% ) and piperacillin-tazobactam (80.1% ). Polymyxin B also showed the highest susceptibility rate against Acinetobacter baumannii (98. 8% ), followed by tigecycline (90. 1% ) and minocycline (72. 0% ). The incidence of carbapenemresistant Acinetobacter baumannii was 60. 1%. The MRSA rate was 60. 2% and the MRSCoN rate was 84. 2%. All Staphylococcus strains were susceptible to tigecycline, vancomycin, teicoplanin and linezolid except for one isolate of Staphylococcus haemolysis with intermediate to teicoplanin. Two Enterococcus faecalis isolates which were intermediate to linezolid and one Enterococcus faecium isolate which was resistant to vancomycin and teicoplanin was found in this surveillance, while the MICs of tigecycline against these three isolates were 0. 032-0. 064 μg/ml. Conclusions Tigecycline, carbapenems, piperacillin-tazobactam,amikacin and cefepime remain relatively high activity against nosocomial Enterobacteriaceae. Pseudomonas aeruginosa exhibite high susceptibility to polymyxin B, while Acinetobacter baumanni shows high susceptibility to polymyxin B and tigecycline. Tigecycline, vancomycin, teicoplanin and linezolid remain high activity against nosocomial gram-positive cocci.

Objective To observe the efficacy of autologous hematopoietic stem cell transplantation (auto-AHSCT) in treatment of malignant hemopathy. Methods A retrospective study was accomplished on the auto-AHSCT in the treatment of 28 patients with malignant hemopathy from Oct 1994 to May 2009. The median age of the patients was 30 (16-45) years. Among the 28 patients,19 cases were acute myelocytic leukemia (AML),4 cases were acute lymphoblastic leukemia (ALL) and 5 cases were malignant lymphoma (ML). Mobilization of peripheral blood stem cell was recieved by giving granulocyte colony-stimulating factor (G-CSF) 5-10 μg/kg. The patients were pretreated with melphalan (140-160 mg/m2),cyclophosphamide (120 mg/kg) and arabinosylcytosin (2 g/m2). Results Transplant-related side effects was less and the hematologic recovery of most patients(26 cases) was quite rapid. The days to stable neutrophil count of 0.5×109/L and platelet count of 20×109/L were 12(8-38) d and 14(9-128) d,respectively. The median followup duration was 36(7-68) months. 19 cases (68 %) achieved disease-free survival(DFS) and 9 cases (32 %)died in three years. Of the 9 death patients,7 cases (25 %) died of recurrence and 2 cases (7 %) died of posttransplant complications. Conclusion AHSCT is a safe and effective therapy method for malignant hemopathy.

Objective To inwst the antagonistic effect of thrombopoietin on adriamycin induced myocardium injury in rats and explore the mechanism.Methods 32 Wistar rats were randomized into four groups(n=8):Control group,ADM group,ADM+TPOL group and ADM+TPOH group.All agents were given by intraperitoneal injection.The control group was given saline.While the other three groups were given adriamycin at the dosage of20mg/kg.TPO group were injected TPO at the dosages of 10μg/kg or 30μg/kg three times on alternale days.ELISA was used to detect the concentration of CK-MB and cTnI in the serum of rats.The change of cardiocyte ultrastructure was observed by the electron microscope,and pathological change Was observed by immunohistochemistry staining.The expression level of 8- hydroxy-2'-deoxyguanosin(8-OHdG)produced by DNA oxidative damage in myocard tissue were detected.IPP6.0 software was used to detect IOD and calculate the 8-OHdG index.Results The energy of CK-MB and cTNI of TPO group was obviously lower than that in ADM group(P<0.01).The ultragtrueture of cardiocyte in the ADM group Wag damaged more severely than that in TPO group.Pathological Score,IOD and 8-OHdG index of TPO groups were lower than ADM group(P<0.05).These indexes had no significant statistics difference between ADM+TPOL group and ADM+TPOH group.Conclusions TPO can provide heart protection by antagonizing oxidative damage of myocardial cell induced by edriamycin.

Objective To evaluate the efficacy and toxicity for the protocol of low-dose harringtonine and cytarabine(HA regimen)in combination with granulocyte colony-stimulating factor(G-CSF)in elderly patients with acute myelogenous leukemia(AML).Methods Thirty-five AML patients were treated with HAG including low-dose chieved PR.The overall response rate was 83%.5 of 35(14%)was non-remiasion.Two patients died in the duration of treatment.The main complication of chemotherapy is myelosuppresion.Conclusion Low-dose HA regimen in combination with G-CSF is effective and safe in elderly patients with AML.