Effectiveness of Reinduction and/or Dose Escalation of Ustekinumab in Crohn’s Disease: A Systematic Review and Meta-analysis

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Comparative functional and pharmacological characterization of Sandoz proposed biosimilar adalimumab (GP2017): rationale for extrapolation across indications

Background: Biosimilars are approved biologics that match reference medicine in quality, safety, and efficacy. The development of Sandoz proposed biosimilar adalimumab (SPBA; GP2017) involved a target-directed, iterative state-of-the-art quality-by-design development program. Here, we describe the functional and pharmacological characterization of SPBA and its proposed mechanism of action in immune-mediated inflammatory diseases.

Methods: Sensitive in vitro binding and functional characterization studies, and nonclinical evaluations (pharmacokinetics, pharmacodynamics, and safety/toxicology) were performed as part of a stepwise approach to confirm the biosimilarity of SPBA with reference adalimumab.

Results: Matching values were reported for SPBA and reference adalimumab in binding assays involving tumor necrosis factor (TNF)-α, complement 1q and human immune effector cell Fcγ receptor subtypes in cell-based bioassays for Fc receptor function (complement- and antibody-dependent cytotoxicity), and in apoptosis inhibition. Furthermore, SPBA and reference adalimumab were equivalent in terms of membrane TNF binding and induction of reverse signaling. Pharmacokinetics of SPBA and reference adalimumab were comparable in rabbits, and the two biologics were equally effective in a human TNF transgenic mouse model of polyarthritis.

Conclusion: SPBA matches reference adalimumab with regards to target binding, functional, pharmacokinetic, and pharmacodynamic properties at the nonclinical level supporting its approval in all indications of the reference adalimumab.     

色甘酸钠对子宫内膜异位症大鼠肥大细胞功能的调节作用

目的探讨色甘酸钠干预对子宫内膜异位症大鼠肥大细胞的影响及相关机制。方法取健康雌性未孕SD大鼠36只, 采用自体子宫内膜移植法建立大鼠腹壁子宫内膜异位症模型, 2周后根据每天腹腔注射不同剂量色甘酸钠将大鼠分为4组:大剂量组(色甘酸钠20 mg/kg)、小剂量组(色甘酸钠10 mg/kg)、阴性对照组(仅注射生理盐水)、空白对照组(模型不作任何处理)。两周后处死大鼠, 并收集血液和病灶组织标本, 测量各组子宫内膜异位症病灶的大小, 并对病灶组织进行苏木素—伊红(HE)染色观察组织形态及角蛋白和波形蛋白免疫组织化学染色以鉴定造模是否成功。用甲苯胺蓝染色法检测各组病灶肥大细胞总数及其脱颗粒肥大细胞数、酶联免疫吸附试验测定血清肿瘤坏死因子α(TNF-α)水平、酶免疫分析法测定血清雌二醇水平、免疫组织化学染色法检测子宫内膜异位症病灶肥大细胞中类胰蛋白酶、神经生长因子的表达水平。结果大剂量组活化的肥大细胞数少于阴性对照组( P < 0.05), 脱颗粒肥大细胞数/肥大细胞总数比值大剂量组小于阴性对照组和空白对照组(均 P < 0.05)。同时, 该组血清TNF-α水平、病灶类胰蛋白酶表达均小于阴性对照组和空白对照组(均 P < 0.05);但经色甘酸钠治疗后子宫内膜异位症病灶神经生长因子表达差异并无统计学意义(均 P>0.05)。 结论色甘酸钠可能通过稳定肥大细胞抑制其脱颗粒, 减少TNF-α、类胰蛋白酶的释放, 改善子宫内膜异位症。     

核因子-κB激活在大鼠冠状动脉微栓塞后的心肌组织中的作用及机制

目的 探讨核因子-κB(NF-κB)激活在冠状动脉微栓塞(CME)后心肌组织中的作用及机制.方法 清洁级雄性SD大鼠88只,其中64只经左心窜内注射自体微血栓、同时短暂夹闭主动脉建立大鼠CME模型后,随机分为未治疗组及二硫代氨基甲酸吡咯烷(PDTC)干预组,分别于术后1、3、7、14 d处死;余24只为假手术组.电泳迁移率改变分析(EMSA)检测不同时间点心肌组织NF-κB DNA结合活性,Western blot测定肿瘤坏死因子α(TNFα)、白细胞介素-6(IL-6)及细胞间黏附分子-1(ICAM-1)的表达水平,实时聚合酶链式反应检测TNFα、IL-6及ICAM-1 mRNA 表达含量.结果 NF-κB DNA结合活性在CME后1 d增高,3 d时达到高峰;7 d时明显降低,14 d时与假手术组无显著性差异.CME组在不同观察时间点心肌TNFα、IL-6、ICAM-1蛋白及基因的表达较假手术组均明显增强(P＜0.05).NF-κB DNA结合活性与TNFα、IL-6、ICAM-13种细胞因子的mRNA表达水平均呈显著正相关(分别是r=0.72,P＜0.05;r=0.94,P＜0.01;r=0.62,P＜0.05).NF-κB特异性抑制剂PDTC干预显著抑制CME后心肌中TNFα、IL-6及ICAM-1蛋白及mRNA的表达(P均＜0.05),同时也改善心功能.结论 CME后NF-κB激活促使炎性因子TNFα、IL-6、ICAM-1在基因及蛋白水平明显上调,是诱导CME心肌炎症反应、心功能减低的重要早期事件.     

Systemic inflammation in chronic obstructive pulmonary disease and asthma: Similarities and differences

Background and objective:   While recent studies have shown that patients with COPD and patients with asthma exhibit evidence of airway and systemic inflammation, markers of systemic inflammation have not been compared between the two diseases.
Methods:   To evaluate circulating inflammatory markers, blood was sampled from 111 patients with COPD, 75 control subjects and 46 asthmatic patients (some of whom were smokers). Measurements of WCC, serum levels of fibrinogen, high-sensitivity (hs)-CRP, IL-8, IL-6, tumour necrosis factor-α (TNF-α), transforming growth factor (TGF)-β1, tissue inhibitors of metalloproteinase (TIMP)-1, neutrophil elastase and alpha1-antitrypsin (α1-AT) were performed.
Results:   Serum TNF-α, IL-6 and TIMP-1 concentrations were significantly higher in patients with stable COPD and patients with asthma than in control patients. Serum α1-AT levels were significantly higher in COPD patients than in asthmatic patients and control subjects, and serum TGF-β1 levels were higher in asthma patients than in COPD patients. Smoking status had no effect on markers in COPD and asthmatic patients.
Conclusions:   Although COPD and asthma share common markers of systemic inflammation, serum levels of TGF-β1 and α1-AT may reflect differences between the diseases.     

Investigation of osteoclastogenic signalling of the RANKL substitute LIGHT

LIGHT (TNFSF14) is a member of the TNF superfamily and is known to substitute for RANKL to induce osteoclast differentiation. LIGHT binds HVEM and LTβR, but it is not known whether these receptors play a role in osteoclast formation or whether LIGHT acts via RANKL signalling pathways. We found that both RANKL and LIGHT strongly induced phosphorylation of Akt and NFκB but not JNK in mouse osteoclast precursor cells. The addition of an Akt inhibitor showed decreased osteoclast differentiation and resorption mediated by both RANKL and LIGHT. RT-PCR and FACS analysis showed that CD14⁺ human osteoclast precursors expressed HVEM and LTβR; expression levels of HVEM increased in the course of osteoclastogenesis and a decrease in LIGHT expression was associated with an increase in HVEM suggesting that there is a feedback loop related to this receptor. Our findings show that LIGHT is not inhibited by the soluble RANKL receptor OPG and that LIGHT is a potent osteoclastogenesis factor that activates the Akt, NFκB and JNK pathways.     

TNF-alpha −308G>A polymorphism is associated with suicide attempts in major depressive disorder

Background

Despite the substantial role of the cytokine network in depression and suicide, few studies have investigated the role of genetic polymorphisms of pro- and anti-inflammatory cytokines in suicide in major depressive disorder (MDD). The aim of this study was to investigate whether tumor necrosis factor-alpha (TNF-alpha) −308G>A, interferon-gamma (IFN-gamma) +874A>T, and interleukin-10 (IL-10) −1082A>G are associated with increased risk for suicide attempts in MDD.

Methods

Among patients with MDD, 204 patients who had attempted suicide and 97 control patients who had not attempted suicide were recruited. A chi-square test was used to identify a possible risk genotype or allele type for suicide. A subsequent multivariate logistic regression analysis was conducted to investigate the influence of a risk genotype or allele type adjusted for other environmental factors. The lethality of the suicide attempt was also tested between genotype and allele types among suicidal patients with MDD.

Results

The GG genotype of the TNF-alpha −308G>A polymorphism was found to significantly increase risk for suicide attempt (adjusted OR=2.630, 95% CI=1.206 to 5.734). IFN-gamma +874A>T and IL-10 −1082A>G were not associated with risk for suicide. Lethality of the suicide attempt was not associated with any of the three cytokine genotypes or allele types.

Limitations

Limitations include a relatively small sample size and a cross-sectional design.

Conclusions

TNF-alpha −308G>A polymorphism is an independent risk factor for suicide attempts in MDD. Future studies should clarify the neural mechanisms by which the GG genotype of TNF-alpha −308G>A influences suicide in MDD.     

Proteolytic activity of Plasmodium falciparum subtilisin-like protease 3 on parasite profilin,a multifunctional protein

Subtilisin-like proteases of malaria parasite Plasmodium falciparum (PfSUB1, 2 and 3) are expressed at late asexual blood stages. PfSUB1 and 2 are considered important drug targets due to their essentiality for parasite blood stages and role in merozoite egress and invasion of erythrocytes. We have earlier shown the in vitro serine protease activity of PfSUB3 and its localization at asexual blood stages. In this study, we attempted to identify the biological substrate(s) of PfSUB3 and found parasite profilin (PfPRF) as a substrate of the protease. Eukaryotic profilins are multifunctional proteins with primary role in regulation of actin filament assembly. PfPRF possesses biochemical features of eukaryotic profilins and its rodent ortholog is essential in blood stages. Profilin from related apicomplexan parasite Toxoplasma gondii (TgPRF) is known to be involved in parasite motility, host cell invasion, active egress from host cell, immune evasion and virulence in mice. In this study, mature PfSUB3 proteolysed recombinant PfPRF in a dose-dependent manner in in vitro assays. Recombinant PfPRF was assessed for its proinflammatory activity and found to induce high level of TNF-α and low but significant level of IL-12 from mouse bone marrow-derived dendritic cells. Proteolysis of PfPRF by PfSUB3 is suggestive of the probable role of the protease in the processes of motility, virulence and immune evasion.