Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous malignancy. Advances in transcriptomic and genetic profiling have significantly enhanced our understanding of the disease's intrinsic pathogenesis, uncovering numerous potential therapeutic targets. However, the impact of tumor-infiltrating Regulatory T cells (Tregs) on the prognosis of DLBCL remains controversial. Here, we developed a Treg-associated gene signature by integrating single-cell and bulk transcriptome data to predict the prognosis of DLBCL patients receiving standard immunochemotherapy. In total, 227 Tregs feature genes were identified, six of which were selected for constructing a prognostic signature. DLBCL patients possessing high-risk scores had significantly poorer survival outcomes than those who possess low-risk scores in NCICCR and validation cohorts. Mutations in PIM1, MYD88, DTX1, CARD11, CD79B, ETV6, BCL6, and CDKN2A were predominantly observed in the high-risk group, whereas alterations in TNFRSF14 and DNMT3A were more frequently detected in the low-risk group. Immune infiltration analysis revealed that the high-risk group exhibited an immunosuppressive microenvironment, whereas the low-risk group showed a higher abundance of non-cellular components in the tumor microenvironment (TME). Finally, the Treg features TNFRSF25 and SELL can effectively predict long-term responses to Axicabtagene Ciloleucel (Axi-cel) treatment. In summary, our study developed a prognostic signature consisting of six Treg feature genes by integrating single-cell and bulk transcriptomics to predict clinical outcomes in DLBCL patients. The risk signature was significantly associated with immunological characteristics.

Owing to the complex anatomical structure and biomechanics, the current standard palliative treatments for cervical spinal metastases are associated with a high risk of recurrence and complications. Stereotactic body radiotherapy (SBRT) can provide radical dose to tumors while protecting normal organs to the maximum extent. However, the efficacy and safety of SBRT for cervical spinal metastases is not well characterized. Data from 71 patients with cervical spine metastases who were treated with SBRT using CyberKnife between 2006 and 2021 were obtained from our prospectively maintained database. Primary endpoint was pain response at 12 weeks following SBRT completion; secondary endpoints included local control (LC), overall survival (OS), and adverse events. Standard-risk patients were planned to receive 30 Gy (range 21-36) with median fractions of 3 (range 1-3) and high-risk patients 35 Gy (range 24-50) with median fractions of 5 (range 4-5) according to the spinal cord and esophagus dose constraints. The median follow-up time was 17.07 months (range 3.1-118.9). After 12 weeks of SBRT completion, 54 (98.2%) of 55 patients with baseline pain achieved pain response and 46 (83.6%) achieved complete pain response. LC rates were 93.1% and 90% at 1 year and 2 year, respectively. The 1-year and 2-year OS rates were 66.2% and 37.4%, respectively. Eight patients experienced grades 1-4 adverse events (six vertebral compression fracture [VCF], five of them had VCF before SBRT; and two hemiparesis). No grade 5 adverse events were observed. Therefore, risk-adapted SBRT for cervical spine metastases achieved high pain control and LC rates with acceptable adverse events.

The role of N6-methyladenosine (m6A) modification in tumor microenvironment has rarely been explored in follicular lymphoma (FL). To examine the role of m6A modification in biological behavior, especially the immune landscape of FL, we utilized the Gene Expression Omnibus database to determine the expression signatures of m6A-regulators by unsupervised clustering, and then condense into a risk score, which was validated in an external cohort from the Tianjin Medical University Cancer Institute and Hospital. Finally, 16 m6A-regulators in 351 FL patients were evaluated and two m6A clusters were identified, characterized by differences in prognosis and biological behaviors. The m6A score was further developed based on 20-genes to quantify the m6A-regulator expression signature in each patient with FL. The low m6A score was associated with inferior prognosis of patients, with a median survival time of 8.84 (95% confidence interval [CI]: 7.251-10.429) years, which was remarkably shorter than that of patients with high m6A scores (15.73 years, 95% CI: 11.729-19.731; p<0.0001). Genes like TNFRSF14, CREBBP, and CARD11 were shown to be more often mutated in the low m6A group. This group was enriched with immune/inflammatory response but along with the abundant infiltration of exhausted T cells and the upregulated PD-1 and PD-L1 expression. Finally, we verified the m6A score could predict the response to anti-PD-L1 antibodies in an immunotherapy cohort. To conclude, the m6A score recognizes a section of FL patients harboring an exhausted tumor microenvironment and may help guide more effective immunotherapy strategies for patients with FL.

Aims: The aim of this study was to evaluate the ideal timing of PORT in the management of completely resected (R0) Stage IIIA-N2 NSCLC.Patients and Methods: Between January 2008 and December 2015, patients with known histologies of pathologic Stage IIIA-N2 NSCLC who underwent R0 resection and received PORT concurrent with or prior to two sequential cycles of chemotherapy ("early PORT") or with PORT administered after two cycles of chemotherapy ("late PORT") at multiple hospitals. The primary endpoint was OS; secondary end points included pattern of the first failure, LRRFS, and DMFS. Kaplan-Meier OS, LRRFS, and DMFS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS, LRRFS, and DMFS.Results: Of 112 included patients, 41 (36.6%) and 71 (63.4%) patients received early PORT and late PORT, respectively. The median OS, LRRFS, and DMFS were longer for those who received early PORT than for those who received late PORT at the median follow-up of 29.6 months (all p < 0.05). Uni- and multi-variate analyses showed that number of POCT cycles and the combination schedule of PORT and POCT were independent prognostic factors for OS, LRRFS, and DMFS.Conclusions: Early PORT is associated with improved outcomes in pathologic Stage IIIA-N2 R0 NSCLC patients.

Purpose To investigate how necroptosisis, i.e. programmed necrosis, is involved in MODS, and to examine whether Nec-1, a specific necroptosis inhibitor, ameliorates multiorgan injury in MODS. Experimental Design A model of MODS was established in six-week old SD rats using fracture trauma followed by hemorrhage. Control animals received sham surgery. Cell death form and necrosome formation were measured by fluorescence-activated cell sorting and western blotting. MODS rats were randomly assigned to receive Nec-1 or saline with pretreatment and once daily. The first end-point was 72 hours survival. Organ injury and dysfunction, inflammatory cytokine levels, and necroptotic execution protein expression were also recorded. Results Organ injury and dysfunction were significantly more severe in the MODS group than the sham group (all p<0.01). Furthermore, MODS-induced liver, lung and kidney tissue injury was characterized by necroptosis rather than apoptosis, and accompanied by necrosome formation. Compared to MODS group, Nec-1 administration significantly improved 72 hours survival (p<0.01). Nec-1 administration significantly reduced necroptosis-induced liver, lung and kidney injury and dysfunction, inhibited inflammatory cytokines production, inhibited release of necroptotic execution proteins such as high-mobility group box 1 and mixed-lineage kinase domain-like protein pseudokinase in MODS rats (all p<0.01). Conclusions These results suggest that necroptosis is involved the pathology of MODS. Further, a necroptotic inhibitor Nec-1 may be considered as an adjunct treatment for MODS.

While the mechanisms underlying apoptosis and autophagy have been well characterized over recent decades, another regulated cell death event, necroptosis, remains poorly understood. Elucidating the signaling networks involved in the regulation of necroptosis may allow this form of regulated cell death to be exploited for diagnosis and treatment of cancer, and will contribute to the understanding of the complex tumor microenvironment. In this review, we have summarized the mechanisms and regulation of necroptosis, the converging and diverging features of necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy, as well as attempts to exploit this newly gained knowledge to provide therapeutics for cancer.

Objective To investigate the effect and mechanism of necrostatin-1 (Hec-1) on the level of HMGB-1 protein in liver of rats with hemorrhagic-traumatic shock.Methods A number of 96 male SD rats were divided into sham-operated group,dimethyl sulfoxide (DMSO) group and Nec-1 group (n=32in each) by randomized number method.Rat model of hemorrhagic-traumatic shock was made by fracture of femoral bone and tibia bone and exsanguination from femoral vein until 30 mmHg and maintained at 30-40 mmHg for 90 min,then the shed blood was transfused back with Ringer's solution.The rats in shamoperated group were only under anesthesia for separating and ligating blood vessels,without exsanguination to induce hemorrhagic shock and without replenishment with blood.Rats in Nec-1 group were given 1 mg/kg Nec-1 through femoral vein 5 min before replenishment with blood and Ringer' s solution,while the rats in DMSO group were given equal volume of DMSO solution instead.Eight rats in each group were sacrificed separately at 2 h,8 h,16 h and 24 h after replenishment.The serum and liver tissues of rats in each group were collected to detect serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST),and to observe the pathological changes in liver with hematoxylin-eosin (HE) staining.The level of HMGB-1 in serum was detected by using ELISA.The cytoplasm protein and total protein expressions of HMGB-1 were assessed by using western blot analysis.Results Compared with DMSO group,levels of serum ALT at 8 h (P ＜0.05),16 h (P ＜ 0.01) and 24 h (P ＜ 0.01) in Nec-1 group were significantly lower.Level of serum AST in Nec-1 group were lower compared with DMSO group at 8 h (P ＜ 0.01),16 h (P ＜ 0.01) and 24 h (P ＜0.01).Compared with DMSO group,levels of serum HMGB-1 at 8 h (P ＜ 0.05),16 h (P ＜0.01) and 24 h (P ＜ 0.01) in Nec-1 group were significantly lower.Under light microscopy and transmission electron microscope,hepatic lobule destroyed,the blood extravasated,the immunocyte infiltrated and cellular organelle destroyed were found.Compared with DMSO group,the level of HMGB-1 protein in cytoplasm protein in Nec-1 group were significantly decreased at 8 h (P ＜ 0.01),16 h (P ＜0.01) and 24 h (P ＜0.01).The level of HMGB-1 protein in total protein in Nec-1 group were significantly decreased 8 h (P ＜ 0.05) and 24 h (P ＜ 0.05).Conclusions Nec-1 can remarkably protect the liver of rats with hemorrhagic-traumatic shock,decrease the level of HMGB-1,and protect the hepatocyte effectively.

Background Thrombocytopenia is one of the most common laboratory abnormalities encountered in patients with severe sepsis. It has been reported that thrombocytopenia is linked to mortality in patients with severe sepsis. However, the mechanism of thrombocytopenia in sepsis is unknown. We hypothesized that inflammatory cytokines and microRNAs (miRNAs) are not only involved in the pathogenesis of sepsis, but also are correlated with thrombocytopenia. Patients and methods Eligible patients with severe sepsis were prospectively recruited and treated at our hospital between June 2012 and May 2014. The miRNA and protein expression of interleukin (IL)-18 and IL-27 were detected by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The expression of miR-130a and miR-150 was detected by TaqMan real-time polymerase chain reaction. Results Sixty eligible patients were divided into two groups: 28 severe sepsis patients with thrombocytopenia and 32 severe sepsis patients without thrombocytopenia. The results demonstrated that the miRNA expression and plasma concentration of IL-18 in severe sepsis patients with thrombocytopenia were higher than those in severe sepsis patients without thrombocytopenia (P=0.015 and P=0.034, respectively), and miR-130a expression was significantly lower in severe sepsis patients with thrombocytopenia (P<0.003). Conclusion Our data demonstrate that severe sepsis patients with thrombocytopenia have increased plasma and miRNA expression levels of IL-18 and decreased expression of miR-130a, suggesting that IL-18 and miR-130a might be involved in the pathophysiological process of severe sepsis with thrombocytopenia.

Objective: This study was designed to investigate the protecting mechanism of Nec-1 and identify how necroptosis triggers inflammation. Methods: This study used male Sprague-Dawley rats with traumatic hemorrhagic shock (mean blood pressure maintained at about 35 to 40 mmHg for 90 minutes) followed by fluid resuscitation. Rats in the control group received anesthesia and separation and ligation of blood vessels but not traumatic hemorrhagic shock and reperfusion. Rats in the Nec-1 group received 1 mg/kg Nec-1 5 minutes before reperfusion, while rats in the vehicle group received the same amount of solvent (0.5% dimethyl sulfoxide). Eight animals were sacrificed at 2 hours, 8 hours, 16 hours, and 24 hours post-reperfusion in each group. Results: Nec-1 ameliorated liver traumatic hemorrhagic injury, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory cytokines (TNF-alpha and IL-1 beta), and less severe traumatic hemorrhage-associated histopathologic changes. Traumatic hemorrhagic shock induced necroptosis in the liver, as indicated by an increase of RIP3, was inhibited by Nec-1. Furthermore, traumatic hemorrhagic shock increased the expression of damage-associated molecular patterns (DAMPs), whereas Nec-1 treatment decreased the release of DAMPs. Conclusions: The protective role might result from attenuation of proinflammatory responses (TNF-alpha and IL-1 beta) and DAMPs (HMGB-1) in the liver.

随着靶向药物的不断上市,恶性淋巴瘤的治疗已经取得了长足进展,但仍有40%的患者出现原发耐药或复发而最终死亡[1] ,针对这部分的患者我们还迫切需要寻找新的治疗方法. 近年来,免疫治疗作为一种新的有效治疗手段备受关注,也为复发/难治恶性淋巴瘤患者的治疗提供了新的思路.

Objective To investigate the effect and mechanism of necrostatin-1 (Nec-1) on the expression of hepatic macrophage inflammatory protein-1α( MIP-1α) in hemorrhagic-traumatic shock rats.Methods The model was Sprague-Dawley ( SD) rats suffered hemorrhagic -traumatic shock.A number of 40 male SD rats were divided into model group, DMSO group, Nec-1 group and sham group with 10 rats in each group by randomized digital number method.Rats in sham group were only received anesthesia, separating and ligating blood vessels, without trauma induced hemorrhagic and reperfusion. Rats in model group were received hemorrhagic -traumatic shock without other intervention.Rats in Nec-1 group were received 1mg/kg Nec-1 through femoral vein 5 minutes before reperfusion, while the rats in DMSO group were received the same amount of solvent.The serum and liver tissues of each group were collected 24 hours after reperfusion.Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by automatic biochemistry analyzer.The pathology changes in liver were observed by hematoxylin -eosin ( HE ) staining.The expression of MIP-1αin serum was detected by ELISA.The MIP-1αmRNA in the liver was determined by reverse transcription-polymerase chain reaction ( RT -PCR ) .The protein expressions of MIP -1αwere assessed by Western blotting analysis.Results Compared with model group and DMSO group, there was no different between the expressions of ALT, ATS and MIP-1αin serum (P>0.05).Levels of serum ALT, AST and MIP-1α24 hours after reperfusion in Nec-1 group were significantly decreased compared with model group and DMSO group (P<0.05).Under light microscopy, it was noted that hepatic lobule destroyed, the blood extravasated, and the immunocyte infiltrated.Compared with DMSO group and model group, the expression levels of MIP-1αprotein and MIP-1αmRNA in Nec-1 group were significantly decreased (P<0.05).Conclusion Nec-1 can remarkable protect the liver of rats with hemorrhagic-traumatic shock, decrease the expression of MIP-1αprotein, reduce the infiltration of immunocyte.

Objective: To investigate the protective effect of z-VAD-FMK and Necrostatin-1 on the organs of rats with MODS. Methods: Adult male SD rats were used and rat model was produced by hemorrhagic shock based on injecting LPS. A total of 80 rats were randomly divided into four groups: z-VAD-FMK group; Nec-1 group; z-VAD-FMK+Nec-1 group and model group with 20 rats in each group. And the 72 h mortality was observed. In addition, other 40 rats were randomly divided into five groups: sham group; z-VAD-FMK group; Nec-1 group; z-VAD-FMK+Nec-1 group; model group, with 8 rats in each group. The samples of different groups were collected at 24 h after injecting LPS or normal saline. Serum ALT and AST were detected by automatic biochemistry analyzer. PaO2was detected by blood gas analyzer. And serum TNF-α and IL-1β were detected by ELISA. The pathological changes of liver, lung and intestine were observed by HE staining. Results: After hemorrhagic shock, the expression of ALT, AST, TNF-α and IL-1β significantly increased(P0.01) while the level of PaO2markedly reduced(P0.01). Under light microscopy, hepatic sinus expansion, liver cells degeneration, necrosis, as well as infiltration of abundant inflammatory cells were observed; the structure of alveolar walls were destroyed and the pulmonary interstitial hyperemia and infiltration of abundant inflammatory cells were observed; the structure of intestinal villi were destroyed and the top part of villi cells and crypt cells degeneration, necrosis, as well as infiltration of abundant inflammatory cells were observed. Compared with model group, the up-regulation degree of ALT, AST, TNF-α and IL-1β and the PaO2reduction were smaller in z-VAD-FMK group, Nec-1 group and z-VAD-FMK+Nec-1 group(P0.01). And the changes in z-VAD-FMK+Nec-1 group were the most significant. In addition, the 72 h mortality significantly reduced(P0.05). Conclusion: The z-VAD-FMK, Nec-1 and z-VAD-FMK+Nec-1 can significantly reduce the organ damage of rats with MODS, and combining z-VAD-FMK and Nec-1 can bring marked results.

OBJECTIVE To investigate the effects of necrostatin-1( Nec-1) on the liver of rats with trauma induced hemorrhagic shock. METHODS Trauma induced hemorrhagic shock model was produced by adopting the left femur, tibia fracture and soft tissue injury, bleeding and reperfusion in male Sprague-Dawley (SD) rats. A total of 22 rats were divided into model group and Nec-1 group with 11 rats in each group by randomized digital number method and the 72-hour mortality was observed. In addition, 72 rats were randomly divided into sham group, model group, Nec-1 group with 24 rats in each group. Rats in sham group were only received anesthesia, separating a nd ligating blood vessels, without trauma induced hemorrhagic and reperfusion, and the rats in Nec-1 group were received 1 mg/kg Nec-1 through femoral vein 5 minutes before reperfusion, and the rats in Nec-1 group were received the same amount of solvent. The serum and liver tissues of each group were collected at 2, 4, 8 hours after reperfusion. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by automatic biochemistry analyzer. The pathology changes in liver were observed by hematoxylin-eosin (HE) staining. The mRNA expressions of tumor necrosis factor-α (TNF-α) and interleukin -1β (IL-1β) in the liver were determined by reverse transcription-polymerase chain reaction (RT-PCR). The protein expressions of receptor interaction of protease 1/3( RIP1/RIP3) were also assessed by Western blot analysis. RESULTS Compared to the model group, Nec-1 significantly reduced the 72 hour mortality [18.18% (2/11) vs. 63.64% (7/11), P = 0.040]. Two hours after trauma induced hemorrhagic shock and reperfusion, the expressions of ALT and AST in model group were significantly increased compared with those in sham group. [ ALT (U/L): 110.21 ± 22.32 vs. 80.98 ± 19.94, AST (U/L): 364.29 ± 64.83 vs. 279.76 ± 70.64, both P<0.05], and reached the peak at 8 hours [ALT (U/L): 387.41± 47.11 vs. 82.76 ±22.44, AST ( U/L): 973.35 ±77.51 vs.261.49 ± 52.03, both P <0.01]. Levels of serum ALT and AST in NEc-1 group were significantly decreased compared with model group [ALT (U/L) 4 hours: 144.64 ± 33.79 vs. 213.96 ± 36.21, 8 hours: 159.48 ± 43.57 vs. 387.41>11; AST (U/L): 4 hours: 398.78 ± 59.48 vs. 630.61 ± 59.93, 8 hours: 427.38 ± 80.75 vs. 973.35 ± 77.51, all P < 0.01] Under light microscopy, it was noted that the hepatic sinus expansion, liver cells degeneration, necrosis, as well as infiltration of abundant inflammatory cells were observed. But the pathology changes in hepatic tissues were significantly mitigated in Nec-1 group. Along with the time extension, the mRNA expressions of TNF-α and IL-β and the protein expressions of RIP1 and RIP3 were markedly up-regulated. Compared with model group, difference in the mRNA expressions of TNF-α and IL-β in hepatic tissues in Nec-1 group were statistically significant, and the most obvious difference was at 8 hours [TNF-α mRNA: 1.457 ± 0.081 vs. 2.317 ± 0.062, IL-β mRNA: 0.690 ± 0.087 vs. 1.812 ± 0.112, both P<0.01]. But there was no statistically significant difference in RIP1 and RIP3 between Nec-1 group and model group [RIP1 protein 8 hours: 0.561 ± 0.033 vs. 0.587 ± 0.036, RIP3 protein 8 hours: 0.976 ± 0.040 vs. 1.044 ± 0.115, both P > 0.05]. CONCLUSION Nec-1 may be remarkable protect effect on the liver of rats with trauma induced hemorrhage shock and reperfusion, and the intrinsic mechanisms need further investigation.

Objective To observe the influence of mesenteric lymph on the vascular endothelial cell necroptosis of rats with trauma-hemorrhagic shock( THS). Methods We constructed THS rat models and collected mesenteric lymph from trauma-hemorrhagic shock( T / HS) rats and trauma-sham shock( T / SS) rats. The subcultured human umbilical vein endothelial cells( HUVECs) were divided into 3 groups. T / HS group was cultivated with T / HS mesenteric lymph and T / SS group was cultivated with T / SS mesenteric lymph( all mesenteric lymph were diluted 1∶ 1 with PBS),and the control group was cultivated with the same amount PBS. After being cultured for 3 h,the cell viability was measured by MTT,and receptor interaction protein 1( RIP1) and RIP3 were analyzed by Western blot. The subcultured HUVECs were divided into 6 groups,PBS,Nec-1,solvent DMSO were respectively added into A( D),B( E),C( F) groups,1 hour later,T / HS mesenteric lymph that diluted 1∶ 1 with PBS was added into D,E and F groups. After 3 h incubation,the cell activity and necroptosis was observed. Results The cell viability was lower,and the expression levels of RIP1 and RIP3 were increased in T / HS group as compared with those of the control group and T / SS group( all P 0. 01). The cell viability was higher,and the expression levels of RIP1 and RIP3 were decreased in the E group as compared with those of D and F groups( all P 0. 01),but they were respectively lower and increased as compared with A,B and C groups( all P 0. 01). Conclusion Mesenteric lymph of rats with THS can induce vascular endothelial cell necroptosis,and Nec-1 can inhibit the occurrence of necroptosis partially.

目的:探讨z-VAD-FMK对大鼠肾缺血再灌注损伤的影响及其机制.方法:30只雄性SD大鼠随机分为3组:假手术组、对照组(DMSO组)、给药组(z-VAD-FMK组),每组10只.对照组和给药组大鼠采用切除右肾,夹闭左侧肾动脉45 min后再恢复血流的方法制成肾缺血再灌注模型,于模型完成前15 min尾静脉给药;假手术组只切除右肾.模型成功后24 h收集大鼠血清和肾脏组织;测定血清肌酐(Scr)、尿素氮(BUN);HE染色观察肾组织病理改变;TUNEL检测肾细胞凋亡;ELISA检测TNF-α、IL-10浓度;Western blot检测caspase-3和caspase-8表达.结果:与对照组相比,给药组Scr与BUN水平明显降低(P＜0.01);HE染色可见肾小管上皮细胞脱落、间质水肿、炎细胞浸润明显减少;肾小球和肾小管上皮细胞凋亡指数明显降低(P＜0.01);TNF-α、IL-10表达水平明显降低(P＜0.01);caspase-3和caspase-8表达明显降低(P＜0.01).结论:z-VAD-FMK对大鼠肾缺血再灌注损伤有保护作用,其机制可能与抑制细胞凋亡,减轻炎症损伤有关.

Background The suppressor of cytokine signaling family (SOCS) is an important negative regulator in the JAK-STAT signaling pathway. This study was designed to explore the correlation between SOCS-1, 2 and 3, Hepatitis B Virus (HBV) and interferon (IFN), and the relationship between SOCS and IFN therapeutic efficacy. Methods Four types of mouse models were established. Mice were administered with HBV replicative plasmid pHBV4.1 and IFN inducer Poly IC (Group A), pHBV4.1 (Group B), Poly IC (Group C) and saline (Group D), respectively. Liver tissues were harvested from the mice and SOCS expression was determined. Meanwhile, patients with chronic hepatitis B (CHB) were treated with pegylated interferon α-2b for 24-48 weeks. Liver biopsy was collected and the baseline SOCS expression was determined. Serum assay was performed for efficacy evaluation and correlation analysis. Results In animal studies, the expression level of SOCS-1 and 3 was found in the descending order of B, A, C and D. The difference between Group B and D suggested that HBV could induce SOCS. The difference between Group A and C suggested that HBV could still induce SOCS with up-regulated endogenous IFN. The difference between Group C and D suggested that ploy IC could induce SOCS, while the difference between Group B and A suggested that Poly IC might have a stronger inhibition effect for SOCS. There was no difference in SOCS-2 expression. In clinical studies, eight of twenty-four enrolled patients achieved either complete or partial therapeutic response. The expression of both SOCS-1 and 3 was higher in CHB patients than in normal controls. The baseline HBV-DNA level was positively correlated with SOCS-1 and 3. The age, viral genotype, HBVDNA, SOCS-1 and SOCS-3 were found to be related to IFN efficacy. Conclusion HBV could induce both SOCS-1 and 3 expression regardless of endogenous IFN level. Elevated IFN could directly up-regulate SOCS-1 and 3 expression, but it could also indirectly down-regulate SOCS-1 and 3 expression by inhibiting HBV replication. HBV might play a more important role in the SOCS up-regulation than IFN, a possible reason why patients with high HBV viral load encounter poor efficacy of IFN treatment.

目的 探讨Necrostatin-1(Nec-1)对大鼠肾缺血-再灌注损伤的保护作用及其机制.方法 将90只雄性SD大鼠按随机数字表法分为三组:假手术组、DMSO对照组、Nec-1组,每组30只.DMSO对照组和Nec-1组采用夹闭双侧大鼠肾动脉45 min再恢复血流的方法制成肾缺血-再灌注模型,于模型完成前15 min尾静脉给药.假手术组不夹闭双侧肾动脉.模型制备成功后于再灌注后2、12、24h收集血清及肾组织;检测血清肌酐(Scr)、尿素氮(BUN);HE染色观察肾组织病理改变;酶联免疫吸附试验(ELISA)方法检测肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)浓度;Western blot方法检测受体相互作用蛋白1和3(RIP1、RIP3)的表达.结果 Nec-1组Scr、BUN浓度各时间点均较DMSO对照组明显降低(P＜0.05,P＜0.01);HE染色可见肾小管上皮细胞脱落坏死、间质水肿、炎细胞浸润明显减少;TNF-α、IL-1β浓度亦均降低(P＜0.01,P＜0.05).DMSO对照组及Nec-1组RIP1蛋白和RIP3蛋白表达均较假手术组明显升高(P＜0.01).结论 Nec-1能明显减轻大鼠肾缺血-再灌注损伤,其机制可能与抑制细胞程序性坏死有关.

Objective To establish a model of mouse continuing endotoxemia thrombocytopenia (TCP) induced by lipopolysaccharide (LPS), observe changes of the mean platelet volume (MPV) and thrombopoietin (TPO) in this model. Methods C57/BL mice were randomly divided into four groups, LPS low dose (5 mg/kg) of continue injection (LL-c) group, LPS low dose (5 mg/kg) of single injection (LL) group, LPS high dose (50 mg/kg) of single injection (HL) group and physiological saline injection (control) group. The blood platelet count (PLT) and MPV were detected before injection as the base line. The values of PLT, TPO, MPV and mortality were observed after treatment. Results The value of PLT was significantly lower in LL-c group than that of basic line (P < 0.01), which was continued in the baseline level of about 30%. The PLT levels were lower and then higher in HL and LL groups. The value of MPV was significantly higher in LL-c group than that of basic line (P< 0.01), which was augmentation and then diminution in HL group and LL group. The TPO level of 7-day was significantly higher in LL-c group than that of control group (P< 0.05). The mortality were respectively 5 rats, 0 rat and 14 rats in LL-c group, LL group and HL group. Conclusion The model of continuing endotoxemia TCP can be induced by consecutive low dose LPS intraperitoneal injection.