Objective:To investigate the effects of carnosine on lipopolysaccharide(LPS)-induced inflammasome activation and pyroptosis in microglia,and to clarify its mechanism.Methods:Activation model of microglia was established by LPS(10 ng/ml).CCK-8 assay was used to detect cell activity of microglia treated with different concentrations of carnosine(0.2,1,5,20,50 mmol/L)for 6 h,and the cell activity of microglia pretreated with different concentrations of carnosine for 0.5 h and then stimulated with LPS for 6 h,to screen a suitable concentration.Then microglia were divided into control group,carnosine group(5 mmol/L),LPS group,and LPS+carnosine group:cell morphological changes in each group were observed under an inverted phase contrast microscope;levels of IL-1β,TNF-α and IL-6 in microglial culture medium were measured by ELISA;propidium iodide(PI)staining was used to detect py-roptotic cells;immunofluorescence was used to observe protein expression of Nod-like receptor protein 3(NLRP3).Results:Com-pared with control group,cell viability of microglia in LPS group was significantly decreased(P<0.01),the shape of microglia was mostly"amoeboid",levels of IL-1β,TNF-α and IL-6 in microglial culture medium were significantly increased(P<0.01),the posi-tive rate of PI and the number of NLRP3 positive cells were significantly increased(P<0.01).Compared with LPS group,cell viability of microglia in LPS+carnosine group was significantly increased(P<0.01),the number of"amoeboid"microglia was decreased,levels of IL-1β,TNF-α in microglial culture medium were significantly decreased(P<0.01),and the level of IL-6 was decreased(P<0.05),the positive rate of PI and the number of NLRP3 positive cells were both significantly decreased(P<0.01).Conclusion:Carnosine can inhibit LPS-induced microglia activation and inflammasome activation,thereby inhibiting cell pyroptosis and the release of inflammato-ry factors.

[This corrects the article DOI: 10.1016/j.apsb.2022.07.023.].

As a promising modality for cancer therapy, photodynamic therapy (PDT) still acquired limited success in clinical nowadays due to the extremely serious hypoxia and immunosuppression tumor microenvironment. To ameliorate such a situation, we rationally designed and prepared cascade two-stage re-oxygenation and immune re-sensitization BSA-MHI148@SRF nanoparticles via hydrophilic and hydrophobic self-assembly strategy by using near-infrared photodynamic dye MHI148 chemically modified bovine serum albumin (BSA-MHI148) and multi-kinase inhibitor Sorafenib (SRF) as a novel tumor oxygen and immune microenvironment regulation drug. Benefiting from the accumulation of SRF in tumors, BSA-MHI148@SRF nanoparticles dramatically enhanced the PDT efficacy by promoting cascade two-stage tumor re-oxygenation mechanisms: (i) SRF decreased tumor oxygen consumption via inhibiting mitochondria respiratory. (ii) SRF increased the oxygen supply via inducing tumor vessel normalization. Meanwhile, the immunosuppression micro-environment was also obviously reversed by two-stage immune re-sensitization as follows: (i) Enhanced immunogenic cell death (ICD) production amplified by BSA-MHI148@SRF induced reactive oxygen species (ROS) generation enhanced T cell infiltration and improve its tumor cell killing ability. (ii) BSA-MHI148@SRF amplified tumor vessel normalization by VEGF inhibition also obviously reversed the tumor immune-suppression microenvironment. Finally, the growth of solid tumors was significantly depressed by such well-designed BSA-MHI148@SRF nanoparticles, which could be potential for clinical cancer therapy.

Objective:To investigate the correlation between three-dimensional histogram analysis of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI)and Gleason score(GS)in prostate cancer(Pca)from two hospital, and its diagnostic efficacy for discriminating low-grade from high-grade Pca.Methods:A total of 102 pathologically confirmed Pca patients in the First Affiliated Hospital of Zhejiang Chinese Medical University and Hangzhou Traditional Chinese Medical Hospital(TCM Hospital)Affiliated to Zhejiang Chinese Medical University from January 2017 to October 2020 were retrospectively analyzed.The quantitative parameters of Pca, including transport constant(K trans), rate constant(K ep), percent volume of the extravascular extracellular space(V e)and fraction of the Intraplasmic contrast volume(V p), were obtained by manually layer by layer delineating of interested regions of all lesions on the original DCE-MRI imaging.Then the three-dimensional histogram analysis of the above parameters were performed to obtain the minimum, maximum, median, mean, area, 10 thpercentile, 25 thpercentile, 75 thpercentile and 90 thpercentile.The correlations between quantitative parameters and GS, and diagnostic efficiencies were analyzed. Results:102 Pca patients were divided into low-grade prostate cancer group(GS≤3+ 4)(n=44)and high-grade Pca group(GS≥4+ 3)(n=58). There were no statistically significant differences in age and location of lesions between the two groups( P>0.05), but there were statistically significant differences in Gleason score, PSA level and lesion diameter between the two groups( U=0.000, 730.000, 711.000, all P<0.05). The median, mean, 10 thpercentile, 25 thpercentile, 75 thpercentile, 90 thpercentile derived from K trans, and K ep(median, mean, 10%, 25%, 75%, 90%)together with maximum of K transand mean for V e were positively correlated with GS( r=0.405 to 0.583, P<0.05), in which mean of K transhad the highest positive correlation( r=0.583, P=0.000). The histogram parameters derived from V pwere negatively correlated with GS( r=-0.301 to 0.341, P<0.05). The area under ROC of 75th percentile derived from K transwas the highest(0.832). When the cut-off value of 75 thpercentile derived from K transwas ≥0.680/min, its Youden index, sensitivity, and specificity were 0.594, 0.776, 0.818, respectively. Conclusions:The three-dimensional histogram of DCE-MRI quantitative parameters has correlation with GS in Pca patients, can be used to discriminate low-grade from high-grade Pca.

Parenteral nutrition-associated liver disease (PNALD) is a liver dysfunction caused by various risk factors presented in patients receiving total parenteral nutrition (TPN). Omega-6 rich Intralipid® and omega-3 rich Omegaven® are two intravenous lipid emulsions used in TPN. TPN could affect the hepatic expression of genes in anti-oxidative stress, but it's unknown whether TPN affects genes in drug metabolism. In this study, either Intralipid®- or Omegaven®-based TPN was administered to mice and the expression of a cohort of genes involved in anti-oxidative stress or drug metabolism was analyzed, glutathione (GSH) levels were measured, and protein levels for two key drug metabolism genes were determined. Overall, the expression of most genes was downregulated by Intralipid®-based TPN ( and ). Omegaven® showed similar results as Intralipid® except for preserving the expression of and and increasing . Total GSH levels were decreased by Intralipid®, but increased by Omegaven®. CYP3A11 protein levels were increased by Omegaven®. In conclusion, TPN reduced the expression of many genes involved in anti-oxidative stress and drug metabolism in mice. However, Omegaven® preserved expression of , suggesting another beneficial effect of Omegaven® in protecting liver functions.

Primary central nervous system lymphoma (PCNSL) is a type of highly invasive non-Hodgkin lymphoma. With a growing number of organ transplantation and immunosuppressant therapy, the incidence of PCNSL has been growing rapidly in recent years, which is attributed to the increased incidence of HIV/AIDS, a prominent risk factor for developing PCNSL. The rising rate of PCNSL incidence is the highest among the intracranial tumors. In the past 20 years, dozens of clinical trials related to PCNSL have been registered, but adequate therapeutics are still challenging. Currently, the chemotherapy regimens based on high-dose methotrexate and whole-brain radiotherapy are the two main therapeutic options; however, the toxicity associated with those is the main problem that challenges medical researchers. Novel agents and therapeutic strategies have been developed in recent years. In the current review, we describe advances in the treatment of PCNSL and discuss novel therapeutic approaches currently in development, such as the use of rituximab, disruption of the blood-brain barrier, and state-of-the-art radiotherapy.
Blood-Brain Barrier ; Central Nervous System* ; Drug Therapy ; Incidence ; Lymphoma* ; Lymphoma, Non-Hodgkin ; Methotrexate ; Organ Transplantation ; Radiotherapy ; Risk Factors ; Rituximab ; Transplants

Objective To investigate the effects and mechanisms of receptor-interacting serine-threonine kinase 3 (RIP3) in the formation of cholestatic hepatic injury.Methods The experimental study was conducted.(1) Processing and viability of hepatic stellate cell line HSC-T6:HSC-T6 cells were transfected by RIP3-siRNA and NC-siRNA,respectively.The viabilities of un-transfected,RIP3-siRNA-transfected and NC-siRNA-transfected HSC-T6 cells were respectively measured by cell-counting kit-8 (CCK-8).HSC-T6 cells were treated by 100 μmol/L Glycochenodeoxycholic acid (GCDCA) at 0,2,4,8 and 12 hours,and then were extracted and stored,12-hour cell viability was measured by CCK-8.RIP3 that was treated by 100 μmol/L GCDCA knocked down HSC-T6 cells to establishment RIP3 knockdown HSC-T6 cells (RIP3-KD cells).RIP3-KD cells were cultured for 12 hours,and cell viability was measured.(2) Mice model of bile duct ligation (BDL):40 adult mice were randomly divided into 8 groups,5 mice in each group.Sham group:bravery manager was only separated,without ligation,and bloods of inferior vena cava and liver tissues were extracted at 7 days postoperatively.The BDL-1,-3,-5,-7,-14,-21 and-28 d groups:bloods of inferior vena cava and liver tissues were extracted at 1,3,5,7,14,21 and 28 days postoperatively,respectively.(3) The relative expressions of RIP3,α-SMA and TNF-αmRNA in the cells and liver tissues were detected by quantitative real-time polymerase chain reaction (RT-PCR).(4) The relative expressions of RIP3,α-SMA and TNF-α proteins were detected by Western blot.Measurement data with normal distribution were represented as-x±s.The ANOVA was used for data analysis in different time gradient.Comparisons among groups were analyzed using the ANOVA.Pairwise comparison was done by the t test.Results (1) The HSC-T6 cells viability and expressions of RIP3,α-SMA,TNF-α mRNA and proteins:results of CCK8 test showed that 12-hour viabilities of GCDCA-treated HSC-T6 cells,GCDCA-treated RIP3-KD cells,HSC-T6 cells and RIP3-KD cells were 61.3％ ±0.3％ and 83.2％ ±0.4％ and 98.4％ ±0.7％ and 97.4％ ±0.7％ respectively,showing statistically significant differences in the viabilities among them (F =115.200,P＜ 0.05),and showing no statistically significant difference in the viabilities between HSC-T6 cells and RIP3-KD cells (t =1.283,P＞ 0.05).There were statistically significant differences in the viabilities between HSC-T6 cells and GCDCA-treated HSC-T6 cells or GCDCA-treated RIP3-KD cells (t =17.910,6.604,P＜ 0.05) and between GCDCA-treated HSC-T6 cells and GCDCA-treated RIP3-KD cells (t=7.186,P＜0.05).Results of RT-PCR test showed relative expressions of RIP3 mRNA in un-transfected,RIP3-siRNA-transfected and NC-siRNA-transfected HSC-T6 cells were respectively 0.012 1±0.001 3,0.011 2±0.003 1 and 0.002 8±0.000 5,with a statistically significant difference (F =20.410,P ＜ 0.05).There was no statistically significant difference in relative expressions of RIP3 mRNA between un-transfected and NC-siRNA-transfected HSC-T6 cells (t =0.483,P ＞0.05).The relative expression of RIP3 mRNA in RIP3-siRNA-transfected HSC-T6 cells was significant different from that in un-transfected and NC-siRNA-transfected HSC-T6 cells (t =11.760,4.586,P＜0.05).The relative expressions of RIP3 mRNA,α-SMA mRNA and TNF-α mRNA in GCDCA-treated HSC-T6 cells at 0,2,4,8 and 12 hours were 0.012 1±0.001 3,0.011 2±0.003 1,0.021 2±0.002 2,0.027 8±0.002 1,0.029 8±0.002 3 and 0.571±0.012,0.611±0.024,0.691±0.021,0.711±0.021,0.752±0.031 and 0.873±0.022,0.912± 0.024,1.015±0.031,1.210±0.042,1.471±0.041,respectively,showing an increased trend over time and statistically significant differences (F=70.720,30.050,166.700,P＜0.05).The relative expressions of RIP3 mRNA in HSC-T6 cells and GCDCA-treated HSC-T6 cells were 0.012 1±0.001 3 and 0.029 8±0.002 3,with a statistically significant difference (t=13.970,P＜0.05).Results of Western blot showed that relative expressions of RIP3 protein in un-transfected,RIP3-siRNA-transfected and NC-siRNA-transfected HSC-T6 cells were respectively 0.054 ± 0.012,0.013 ± 0.008 and 0.052± 0.021,with a statistically significant difference (F =7.410,P＜0.05).There was no statistically significant difference in relative expressions of RIP3 protein between un-transfected and NC-siRNA-transfected HSC-T6 cells (t =0.143,P ＞ 0.05),and statistically significant differences were found in relative expressions of RIP3 protein between RIP3-siRNA-transfected HSC-T6 cells and un-transfected or NC-siRNA-transfected HSC-T6 cells (t =4.924,3.006,P＜0.05).The relative expressions of RIP3,α-SMA and TNF-oα proteins in GCDCA-treated HSC-T6 cells at 0,2,4,8 and 12 hours were 0.045±0.024,0.047±0.034,0.062±0.025,0.121±0.015,0.154±0.034 and 0.064±0.031,0.072±0.017,0.097±0.035,0.078±0.031,0.254±0.051 and 0.078±0.025,0.094±0.037,0.129±0.041,0.198±0.011,0.324±0.061,respectively,showing an increased trend over time and statistically significant differences (F =9.658,15.810,20.090,P＜0.05).The relative expressions of RIP3 protein in HSC-T6 cells and GCDCA-treated HSC-T6 cells at 12 hours were 0.045±0.024 and 0.154±0.034,with a statistically significant difference (t =4.536,P＜0.05).(2) Expressions of RIP3,α-SMA and TNF-α mRNA in hepatic tissues of mice in each group:the results of RT-PCR showed that relative expressions of RIP3 mRNA,α-SMA mRNA and TNF-α mRNA in the Sham,BDL-1 d,BDL-3 d,BDL-5 d,BDL-7 d,BDL-14 d,BDL-21 d,BDL-28 d groups were 0.047 3±0.003 1,0.041 2±0.007 8-0.339 7±0.017 1 and 2.948±0.612,2.654± 1.032-8.387±0.910 and 0.563±0.078,0.610±0.113-1.078± 0.289,respectively,with statistically significant differences (F =25.180,27.820,7.425,P＜0.05).The results of western blot showed that relative expressions of RIP3,α-SMA and TNF-α proteins in Sham,BDL-1 d,BDL-3 d,BDL-5 d,BDL-7 d,BDL-14 d,BDL-21 d,BDL-28 d groups were 0.245±0.011,0.228±0.023-1.018±0.052 and 0.424±0.057,0.392±0.041-0.985±0.081 and 0.551 ±0.052,0.588±0.087-0.962±0.074,respectively,with statistically significant differences (F=19.160,94.410,22.750,P＜0.05).Conclusion Cholestasis promotes hepatic injury and fibrosis by inducing TNF-α pathway activation and upregulation RIP3.

Background and purpose:As one of the most fatal malignant tumors in China, the morbidity and mortality of lung cancer remain high. Early diagnosis and normative treatment is the key to improve the prognosis of lung cancer. The aim of this study was to explore the practice of early lung cancer screening with low-dose spiral computed tomography (CT) based on the current situation in community health service, with integration of superior resources of med-ical institutions at all levels in Shanghai.Methods:From Aug. 2013 to Aug. 2014, we screened high-risk population in selected communities of Minhang District, Shanghai, for early diagnosis of lung cancer with low-dose spiral CT combined with multidisciplinary comprehensive treatment models including minimally invasive surgery, exploring the medical service network covering prevention, diagnosis, treatment, rehabilitation and follow-up.Results:Screening population is 11 332 (male 7 144, female 4 188); Twenty-nine cases with pathological diagnosis of malignant tumor, including 27 cases of pri-mary lung cancer, 1 case of lung metastasis, 1 case of breast cancer. The morbidity of primary lung cancer is 238.26×10-5. There were 22 cases of Stage 0-Ⅰ lung cancer accounting for 81.48% of all diagnosed primary lung cancer.Conclusion:Based on community health service, screening with low-dose spiral CT could improve the early diagnosis rate of lung can-cer with feasibility and validity, which could be applicable in qualified eligible medical center and community in China.

Objective To do screening acute lymphoblastic leukemia patients scFv antibody single chain variable region to cre-ate conditions for the expression and obtain further specificity of antibody fragments.Methods In this study,patients with newly diagnosed acute lymphoblastic leukemia serum as coating antigen using phage display technology,screening phage an-tibody specificity from the semi-synthetic human phage antibody libraries,the first to target the immune antigen-coated tab-let,phage library was added,so that with the target antigen-specific binding phage antibody was immobilized on plates immu-nization,could not be specifically bound phages were rinsed.The eluted specific binding phage,E.coli infection.Could get the specific antibody gene containing phagemid.Results After three “adsorption-elution-amplification”screening process,got stronger leukemia patient antigen-specific phage antibody variable region fragment and identification.Conclusion Got better strain affinity antibody fragments,to create the conditions for the next fragment expression,identification and clinical appli-cation.

Objective To explore the feasibility of low-dose chemotherapy (LDCT) combined with tyrosine kinase inhibitor (TKI) (LDCT+TKI regimen) as the first-line induction regimen for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+-ALL).Methods The efficacies and adverse effects of various induction regimens in 61 newly diagnosed patients with Ph+ ALL were retrospectively analyzed.Results The complete remission (CR) rate of the first induction therapy was 73.8 ％ (45/61) for all 61 cases,and that of the second induction therapy was 86.7 ％ (13/15) for non-remission (NR) patients after the first induction.The total CR rate for two-course induction was 95.1％ (58/61).Treatment related mortality happened in one case (1.6 ％) after the first induction therapy.The response rates between conventional-dose chemotherapy (CDCT)±TKI group and LDCT±TKI group were not statistically different [without TKI,65.5 ％ (19/29) vs 60.0 ％(3/5),P =0.812;with TKI,90.5 ％ (19/21) vs 100.0 ％ (6/6),P =0.432].The response rate of LDCT+TKI group was not statistically different from that of CDCT alone group (P =0.089).The introduction of TKI to LDCT and CDCT could improve the response rate (CDCT+TKI group,P =0.041;LDCT+TKI group,P =0.087).The total response rate of the induction therapy with TKI was significantly higher than that without TKI [92.6 ％ (25/27) vs 64.7 ％ (22/34),P =0.01].The response rate of the TKI-based second induction therapy for non-CR cases after the first induction therapy without TKI was significantly higher than that after the first induction therapy with TKI [100.0 ％ (8/8) vs 33.3 ％ (1/3),P =0.011].There were no significant differences in the efficacies of the first induction therapy between various genetic subgroups (all P ＞ 0.05),and the introduction of TKI to the treatment of various genetic subgroups could improve the efficacies to a certain extent without statistical significance (all P ＞ 0.05).The incidences of treatment related infections and bleeding due to the first induction therapy in all patients were 50.8 ％ (31/61) and 4.9 ％ (3/61),respectively.Compared with LDCT±TKI group,the overall incidences of treatment related infections and bleeding in CDCT±TKI group were higher,but there were no statistical significances [infection,56.0 ％ (28/50) vs 27.3 ％ (3/11),P =0.084;bleeding,6.0 ％ (5/30) vs 0 (0/1 1),P =0.405].The incidence of treatment related infections in LDCT+TKI group was significantly lower than that in CDCT+TKI group [0 (0/6) vs 71.4 ％ (15/21),P =0.002] or that in CDCT alone group [0 (0/6) vs 44.8 ％ (13/29),P =0.039].The incidence of bleeding in LDCT+TKI group was not statistically different from that in CDCT+TKI group or that in CDCT alone group (all P ＞ 0.05).Conclusion LDCT+TKI regimen as the first-line induction regimen in Ph+-ALL is deserved to be investigated further.