BACKGROUND & AIMS: CD4+ anti-tumor T cells reactive with rat adenocarcinoma 13762 kill tumor in vitro and cause regression of tumor in vivo. The role of various host immune cells in CD4+ T-cell-mediated tumor elimination in vivo was investigated by adoptive transfer of anti-tumor T cell clones to recipients that were selectively depleted of individual immune cell types. By these means, macrophages and NK cells were found to be required for tumor killing. Depletion of host CD4+ T cells, CD8+ T cells, or neutrophils was without effect on tumor elimination by anti-tumor T cells. An essential role for antigen receptor-negative NK cells is likely dependent upon secretion of IFN-gamma from NK cells since treatment of tumor recipients with anti-IFN-gamma antibody prior to adoptive transfer and tumor challenge abrogated T cell killing, resulting in progressive tumor growth. Viability of adenocarcinoma 13762 or anti-tumor T cells was unaffected by treatment with either IFN-gamma or anti-IFN-gamma antibody in vitro, but cell surface MHC class II expression was induced in tumor cells by exposure to IFN-gamma. In addition, tumor cells were isolated from tumor-bearing animals by absorption using anti-MHC class II antibody, demonstrating that 13762 tumor expresses cell surface MHC class II antigens in situ. However, if hosts were depleted of NK cells before tumor challenge, MHC class II+ tumor was not recovered. Collectively these results suggest that adenocarcinoma 13762 is eliminated by MHC class II-restricted CD4+ T cells by direct tumor killing.

背景与目标： 与大鼠腺癌反应的CD4 + 抗肿瘤T细胞13762在体外杀伤肿瘤并在体内引起肿瘤的消退。通过将抗肿瘤T细胞克隆过继转移到选择性耗尽个体免疫细胞类型的受体，研究了各种宿主免疫细胞在体内CD4 T细胞介导的肿瘤消除中的作用。通过这些方法，发现巨噬细胞和NK细胞是杀死肿瘤所必需的。宿主CD4 T细胞，CD8 T细胞或中性粒细胞的耗竭对抗肿瘤T细胞消除肿瘤没有影响。抗原受体阴性NK细胞的重要作用可能取决于NK细胞中IFN-γ 的分泌，因为在过继转移和肿瘤挑战之前用抗IFN-γ 抗体治疗肿瘤接受者消除了T细胞杀伤，导致进行性肿瘤生长。腺癌13762或抗肿瘤T细胞的活力在体外不受IFN-γ 或抗IFN-γ 抗体治疗的影响，但细胞表面mhcii类表达通过暴露于IFN-γ 在肿瘤细胞中诱导。此外，通过使用抗MHC II类抗体吸收从荷瘤动物中分离肿瘤细胞，证明13762肿瘤原位表达细胞表面MHC II类抗原。但是，如果宿主在肿瘤激发之前耗尽了NK细胞，则MHC II类肿瘤将无法恢复。这些结果共同表明，通过直接杀伤肿瘤，MHC II类限制性CD4 T细胞消除了腺癌13762。

BACKGROUND & AIMS: :We have previously reported that a targeted anti-caries DNA vaccine, pGJA-P, induced accelerated and increased antibody responses compared with a non-targeted anti-caries DNA vaccine. Recently, pGJA-P/VAX, a new targeted anti-caries DNA vaccine for human trials, was constructed by replacing the pCI vector used in the construction of pGJA-P with pVAX1, the only vector authorized by the US Food and Drug Administration in clinical trials. Here, we report on our exploration of the kinetics of the antibody responses generated following pGJA-P/VAX immunization and the persistence of pGJA-P/VAX at both the inoculation site and the draining lymph nodes. Intranasal vaccination of mice with pGJA-P/VAX induced strong antibody responses that lasted for more than 6 months. Furthermore, pGJA-P/VAX could still be detected at both the inoculation site and the draining cervical lymph nodes 6 months after immunization. Thus, the persistent immune responses are likely due to the DNA depot in the host, which acts as a booster immunization.

背景与目标： : 我们以前曾报道过，与非靶向抗龋DNA疫苗相比，靶向抗龋DNA疫苗pGJA-P诱导了加速和增加的抗体反应。最近，pGJA-P/VAX是一种用于人体试验的新型靶向抗龋齿DNA疫苗，通过用pVAX1代替用于构建pGJA-P的pCI载体，这是美国食品药品监督管理局在临床试验中唯一授权的载体。在这里，我们报告了我们对pGJA-P/VAX预防接种后产生的抗体反应的动力学以及pGJA-P/VAX在接种部位和引流淋巴结的持久性的探索。用pGJA-P/VAX对小鼠进行鼻内疫苗接种可诱导持续6个月以上的强烈抗体反应。此外预防接种后6个月，在接种部位和引流颈淋巴结中仍可检测到pGJA-P/VAX。因此，持续的免疫反应可能是由于宿主中的DNA储存库而起加强预防接种作用。

BACKGROUND & AIMS: OBJECTIVE:To determine the degree of correlation between Farr and ELISA methods of detecting anti-dsDNA antibodies in patients with systemic lupus erythematosus (SLE), and their association with measures of disease activity. METHODS:Anti-dsDNA antibodies were assayed using the Farr and ELISA methods in patients followed between January 1, 2000, and December 31, 2002. Statistical correlations between Farr and ELISA were determined. Relationships between the 2 assays and measures of disease activity [SLE Disease Activity Index 2000 (SLEDAI-2K-DNA), renal, central nervous system (CNS), and vasculitis] were determined for the same clinic visit. RESULTS:550 patients with 2940 clinic visits met the inclusion criteria. Correlation between Farr and ELISA levels was 0.46 using the first visit for each patient. When the Farr was abnormal, the ELISA was equally likely to be normal or abnormal. Abnormal Farr results were associated with higher SLEDAI-2K scores than normal Farr results (6.2 vs 4.3, respectively; p < 0.0001). There was less of a distinction with ELISA results (5.9 vs 4.8; p = 0.04). Farr levels were significantly associated with the presence of renal disease and vasculitis, while ELISA levels were not. Neither Farr nor ELISA results correlated with the presence of active CNS involvement. CONCLUSION:Farr and ELISA techniques for the detection of anti-dsDNA antibodies in patients with SLE are poorly correlated. The Farr is superior to the ELISA in correlating with measures of global disease activity, as well as renal and vasculitis involvement. The Farr technique should continue to be used in clinical practice. The ELISA adds no additional information.

背景与目标：

BACKGROUND & AIMS: :Human immunodeficiency virus (HIV) binds to cells via an interaction between CD4 and the virus envelope glycoprotein, gp120. Previous studies have localized the high affinity binding site for gp120 to the first domain of CD4, and monoclonal antibodies (mAbs) reactive with this region compete with gp120 binding and thereby block virus infectivity and syncytium formation. Despite a detailed understanding of the binding of gp120 to CD4, little is known of subsequent events leading to membrane fusion and virus entry. We describe two new mAbs reactive with the third domain of CD4 that inhibit steps subsequent to virus binding critical for HIV infectivity and cell fusion. Binding of recombinant gp120 or virus to CD4 is not inhibited by these antibodies, whereas infection and syncytium formation by a number of HIV isolates are blocked. These findings demonstrate that in addition to virus binding, CD4 may have an active role in membrane fusion.

背景与目标： : 人类免疫缺陷病毒 (HIV) 通过CD4与病毒包膜糖蛋白gp120之间的相互作用与细胞结合。先前的研究已将gp120的高亲和力结合位点定位于CD4的第一个结构域，与该区域反应性的单克隆抗体 (mab) 与gp120的结合竞争，从而阻止病毒的感染性和合胞体的形成。尽管对gp120与CD4的结合有详细的了解，但对导致膜融合和病毒进入的后续事件知之甚少。我们描述了两种与CD4的第三结构域反应的新mab，它们抑制了对HIV感染性和细胞融合至关重要的病毒结合之后的步骤。重组gp120或病毒与CD4的结合不受这些抗体的抑制，而许多HIV分离株的感染和合胞体形成被阻断。这些发现表明，除了病毒结合外，CD4可能在膜融合中起积极作用。

BACKGROUND & AIMS: Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular levels of heme and hemeproteins; certain of the latter, i.e. cytochrome P450s, generate pro-inflammatory products from endogenous substrates. Two HO isozymes, the products of distinct genes, have been described; HO-1 is the inducible one, whereas HO-2 is believed to be constitutively expressed. We studied the inducing effects of several metal compounds [CoCl2, SnCl2, ZnCl2, heme, and cobalt protoporphyrin (CoPP)] on HO-1 mRNA content and enzyme activity in cultures of rabbit corneal epithelial (RCE) cells; these metal compounds are known to induce HO in other tissues. Additionally, we studied HO-1 expression in an experimental model of ocular inflammation produced in rabbit corneas by extended contact lens wear, and the relation of HO expression to the induced inflammatory process. SnCl2 added to RCE cells in vitro produced marked time- and concentration-dependent increases in HO-1 mRNA and HO-1 enzyme activity; CoCl2, ZnCl2, and CoPP were inducers of HO as well, though to a lesser degree than SnCl2. Corneas treated for 6 days with contact lenses impregnated with SnCl2 displayed substantially less corneal inflammation, swelling, and new vessel invasion than did controls; attenuation of ocular inflammation was paralleled by SnCl2-induced increases in HO mRNA and HO activity in corneal epithelial cells from treated eyes. It is suggested that amelioration of the inflammatory response produced by extended contact lens wear is due, in part, to the induction of high levels of HO-1 activity by SnCl2, which results in diminished production of pro-inflammatory mediators generated through heme-dependent metabolic processes. Regulation of HO activity in this manner may have clinical applications.

背景与目标： 血红素加氧酶 (HO) 通过将血红素分解为胆汁色素，下调血红素和血红素的细胞水平; 某些后者，即细胞色素p450，从内源性底物产生促炎产物。已经描述了两个HO同工酶，即不同基因的产物; HO-1是可诱导的，而HO-2被认为是组成型表达的。我们研究了几种金属化合物 [CoCl2，SnCl2，ZnCl2，血红素和钴原卟啉 (CoPP)] 对兔角膜上皮 (RCE) 细胞培养物中HO-1 mRNA含量和酶活性的诱导作用; 这些金属化合物已知会在其他组织中诱导HO。此外，我们研究了通过长时间戴隐形眼镜在兔角膜中产生的眼部炎症的实验模型中的HO-1表达，以及HO表达与诱导的炎症过程的关系。体外添加到RCE细胞中的SnCl2会导致HO-1 mRNA和HO-1酶活性随时间和浓度的显着增加; CoCl2，ZnCl2和CoPP也是HO的诱导剂，尽管程度低于SnCl2。与对照组相比，用SnCl2浸渍的隐形眼镜治疗6天的角膜表现出明显更少的角膜炎症，肿胀和新血管浸润; 眼部炎症的减弱与治疗眼角膜上皮细胞中HO mRNA和HO活性的SnCl2-induced增加平行。建议延长隐形眼镜佩戴产生的炎症反应的改善部分是由于SnCl2诱导了高水平的HO-1活性，从而导致通过血红素产生的促炎症介质的产生减少依赖代谢过程。以这种方式调节HO活性可能具有临床应用。

BACKGROUND & AIMS: :Peroxisome proliferator-activated receptors (PPARs) are expressed on vascular tissue. To investigate the direct vasoprotective effects of PPARgamma and PPARalpha ligands, pioglitazone (3 mg/kg/day) and bezafibrate (10 mg/kg/day) were given by gavage to streptozotocin-induced diabetic rats for 4 weeks. Streptozotocin (65 mg/kg, i.p.) significantly increased NADPH oxidase, vascular call adhesion molecule-1 (VCAM-1), and osteopontin mRNA levels in the aorta, as determined by reverse transcription (RT)-polymerase chain reaction (PCR). Immunohistochemical analysis revealed that the expression of osteopontin protein was also enhanced in the streptozotocin-injected rat aorta. Pioglitazone or bezafibrate attenuated the streptozotocin-induced increase in the expression of NADPH oxidase and VCAM-1 mRNA. The enhanced expression of osteopontin gene and protein induced by streptozotocin was suppressed by pioglitazone, whereas treatment with bezafibrate had no effect on the expression of osteopontin. We also demonstrated that pioglitazone or bezafibrate prevented the streptozotocin-induced increase in angiotensin converting enzyme (ACE) gene and protein content, by the means of RT-PCR and Western blotting. On the other hand, the treatment of pioglitazone or bezafibrate in the present study did not affect glucose tolerance, serum insulin or lipid level in streptozotocin-induced diabetic rats. These results suggest that the direct anti-oxidant and anti-inflammatory effects of PPARs ligands in the aorta of streptozotocin-induced diabetic rats were not likely to have been mediated by the normalization of glucose or lipid metabolism, but instead these salutary effects appear to have been associated with the inhibition of the expression of ACE. In addition, pioglitazone appeared to be more effective on the suppression of osteopontin expression compared with bezafibrate.

背景与目标： : 过氧化物酶体增殖物激活受体 (ppar) 在血管组织上表达。为研究PPARgamma和PPARalpha配体的直接血管保护作用，将吡格列酮 (3 mg/kg/天) 和苯扎贝特 (10 mg/kg/天) 灌胃给链脲佐菌素诱导的糖尿病大鼠4周。通过逆转录 (RT)-聚合酶链反应 (PCR) 测定，链脲佐菌素 (65 mg/kg，i.p.) 显着增加主动脉中的NADPH氧化酶，血管呼叫粘附分子-1 (VCAM-1) 和骨桥蛋白mRNA水平。免疫组织化学分析显示，在注射链脲佐菌素的大鼠主动脉中，骨桥蛋白的表达也得到了增强。吡格列酮或苯扎贝特减弱了链脲佐菌素诱导的NADPH氧化酶和VCAM-1 mRNA表达的增加。吡格列酮抑制了链脲佐菌素诱导的骨桥蛋白基因和蛋白的增强表达，而苯扎贝特治疗对骨桥蛋白的表达没有影响。我们还证明，吡格列酮或苯扎贝特通过rt-pcr和Western印迹阻止了链脲佐菌素诱导的血管紧张素转化酶 (ACE) 基因和蛋白质含量的增加。另一方面，本研究中吡格列酮或苯扎贝特的治疗不会影响链脲佐菌素诱导的糖尿病大鼠的葡萄糖耐量，血清胰岛素或脂质水平。这些结果表明，链脲佐菌素诱导的糖尿病大鼠主动脉中ppar配体的直接抗氧化和抗炎作用不太可能由葡萄糖或脂质代谢的正常化介导。但是，这些有益的作用似乎与抑制ACE的表达有关。此外，与苯扎贝特相比，吡格列酮似乎对抑制骨桥蛋白表达更有效。

BACKGROUND & AIMS: :Silent information regulator 2 (Sir2) enzymes or sirtuins are a family of NAD(+)-dependent protein N(ε)-acetyl-lysine (AcK) deacetylases. Sirtuins are also evolutionarily conserved proteins that are present in all kingdoms of life ranging from bacteria to humans. Interestingly, it was recently found that the sirtuins found in various human parasites (especially the Plasmodium, Trypanosoma, and Leishmania species) were pro-survival for the parasites under various conditions. Therefore, these parasitic sirtuins have emerged as novel anti-parasitic therapeutic targets. This article reviews the currently available structural, biochemical, pharmacological, and medicinal chemistry studies on these enzymes, and discusses the perspectives of selectively targeting the parasitic sirtuins as a novel therapeutic strategy for the human parasitic diseases.

背景与目标： : 沉默信息调节因子2 (Sir2) 酶或sirtuins是NAD () 依赖性蛋白N(ε)-乙酰赖氨酸 (AcK) 脱乙酰基酶的家族。Sirtuins也是进化上保守的蛋白质，存在于从细菌到人类的所有生命王国中。有趣的是，最近发现在各种人类寄生虫 (尤其是疟原虫，锥虫和利什曼原虫) 中发现的sirtuins在各种条件下都是寄生虫的生存。因此，这些寄生sirtuins已成为新的抗寄生虫治疗靶标。本文回顾了目前对这些酶的结构，生化，药理和药物化学研究，并讨论了选择性靶向寄生虫sirtuins作为人类寄生虫病新治疗策略的观点。

BACKGROUND & AIMS: BACKGROUND:This study explored the combined impact of depression and inflammation on memory functioning among Mexican-American adults and elders. METHODS:Data were analyzed from 381 participants of the Health and Aging Brain study among Latino Elders (HABLE). Fasting serum samples were collected and assayed in duplicate using electrochemiluminesce on the SECTOR Imager 2400A from Meso Scale Discovery. Positive DepE (depression endophenotype) was codified as any score >1 on a five-point scale based on the GDS-30. Inflammation was determined by TNFα levels and categorized by tertiles (1st, 2nd, 3rd). WMS-III LMI and LMII as well as CERAD were utilized as measures of memory. ANOVAs examined group differences between positive DepE and inflammation tertiles with neuropsychological scale scores as outcome variables. Logistic regressions were used to examine level of inflammation and DepE positive status on the risk for MCI. RESULTS:Positive DepE as well as higher inflammation were both independently found to be associated with lower memory scores. Among DepE positive, those who were high in inflammation (3rd tertile) were found to perform significantly worse on WMS-III LM I (F = 4.75, p = 0.003), WMS-III LM II (F = 8.18, p < 0.001), and CERAD List Learning (F = 17.37, p < 0.001) when compared to those low on inflammation (1st tertile). The combination of DepE positive and highest tertile of inflammation was associated with increased risk for MCI diagnosis (OR = 6.06; 95% CI = 3.9-11.2, p < 0.001). CONCLUSION:Presence of elevated inflammation and positive DepE scores increased risk for worse memory among Mexican-American older adults. Additionally, the combination of DepE and high inflammation was associated with increased risk for MCI diagnosis. This work suggests that depression and inflammation are independently associated with worse memory among Mexican-American adults and elders; however, the combination of both increases risk for poorer memory beyond either alone.

背景与目标：

BACKGROUND & AIMS: PURPOSE:The present study was aimed to evaluate the retinoprotective effects of Moringa oleifera (MO) in Streptozotocin-induced diabetic rats. METHODS:The study was continued for 24 weeks and evaluated for inflammatory (tumor necrosis factor [TNF]-α and interleukin [IL]-1β, angiogenic (vascular endothelial growth factor [VEGF] and protein kinase C [PKC]-β) and antioxidant (Glutathione, Superoxide dismutase, and Catalase) parameters. Retinal leakage was checked by Fluorescein angiography (FA) and fundus photographs were evaluated for retinal vessel caliber (arteriolar and venular). Transmission electron microscopy was done to determine basement membrane (BM) thickness. RESULTS:The results of the present study showed potential hypoglycemic and retinal antioxidant effects of MO. In the present study, a significant rise in the expression of retinal inflammatory (TNF-α and IL-1β) and angiogenic (VEGF and PKC-β) parameters was observed in diabetic retinae as compared to normal retinae. However, MO-treated retinae showed marked inhibition in the expression of inflammatory and angiogenic parameters. Further, in the present study, diabetic retinae showed dilated retinal vessels as compared to normal. However, MO-treated retinae showed marked prevention in the dilatation of retinal vessels. Fluorescein angiograms obtained from diabetic retinae showed leaky and diffused retinal vasculature. On the other hand, MO-treated retinae showed intact retinal vasculature. Further, results of the transmission electron microscopy study showed thickened capillary BM in the diabetic retina as compared to normal retinae. However, treatment with MO prevented thickening of capillary BM. CONCLUSION:Our result suggests that MO may be useful in preventing diabetes induced retinal dysfunction.

背景与目标：

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVES:Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population. METHODS:Olaratumab was tested at 15 or 20 mg/kg in four phase II studies (in patients with nonsmall cell lung cancer, glioblastoma multiforme, STS, and gastrointestinal stromal tumors) as a single agent or in combination with chemotherapy. PK sampling was performed to measure olaratumab serum levels. PK data were analyzed by nonlinear mixed-effect modeling techniques using NONMEM®. RESULTS:The PKs of olaratumab were best described by a two-compartment PK model with linear clearance (CL). Patient body weight was found to have a significant effect on both CL and central volume of distribution (V 1), whereas tumor size significantly affected CL. A small subset of patients developed treatment-emergent anti-drug antibodies (TE-ADAs); however, TE-ADAs did not have any effect on CL or PK time course of olaratumab. There was no difference in the PKs of olaratumab between patients who received olaratumab as a single agent or in combination with chemotherapy. CONCLUSION:The PKs of olaratumab were best described by a model with linear disposition. Patient body weight and tumor size were found to be significant covariates. The PKs of olaratumab were not affected by immunogenicity or chemotherapeutic agents.

背景与目标：

BACKGROUND & AIMS: :Melatonin improves survival and functional impairment including hemolysis, thrombocytopenia, and hypotension when administered in a prophylactic manner or early after initiation of sepsis or endotoxemia. In the present study, melatonin was given not before first symptoms of systemic inflammation became manifest. Lipopolysaccharide was infused at a rate of 0.5 mg/kg × h to induce systemic inflammation in male Wistar rats. Melatonin (single dose 3 mg/kg × 15 min) was intravenously administered 180 and 270 min after starting of the lipopolysaccharide infusion. Systemic and vital parameters (e.g., systemic blood pressure and breathing rate) as well as blood and plasma parameters (acid-base parameters; electrolytes; parameters of tissue injury such as glucose concentration, lactate concentration, hemolysis, and aminotransferase activities; parameters of thromboelastometry; and platelet count) were determined in regular intervals. Infusion of lipopolysaccharide led to characteristic symptoms of severe systemic inflammation including hypotension, metabolic acidosis and hypoglycemia, electrolyte and hemostatic disturbances, thrombocytopenia, and hemolysis. Melatonin neither decreased mortality nor reduced lipopolysaccharide-dependent changes to vital, blood, and plasma parameters. Even though melatonin may have a beneficial effect in early stages of systemic inflammation, it can hardly be an option in therapy of manifest sepsis or endotoxemia in an intensive care unit.

背景与目标： : 当以预防性方式或在脓毒症或内毒素血症开始后早期给药时，褪黑素可改善生存和功能障碍，包括溶血，血小板减少症和低血压。在本研究中，褪黑激素不是在全身炎症的最初症状出现之前就给予的。以0.5 mg/kg × h的速率输注脂多糖以诱导雄性Wistar大鼠全身炎症。在开始脂多糖输注后180和270分钟静脉内施用褪黑素 (单剂量3 mg/kg × 15分钟)。全身和生命参数 (例如，全身血压和呼吸频率) 以及血液和血浆参数 (酸碱参数; 电解质; 组织损伤参数，例如葡萄糖浓度，乳酸浓度，溶血和氨基转移酶活性; 血栓弹性测定参数; 和血小板计数) 定期确定。输注脂多糖会导致严重全身性炎症的特征性症状，包括低血压，代谢性酸中毒和低血糖，电解质和止血障碍，血小板减少症和溶血。褪黑素既不能降低死亡率，也不能降低脂多糖依赖性的生命，血液和血浆参数变化。尽管褪黑激素在全身性炎症的早期阶段可能具有有益的作用，但在重症监护病房中，褪黑激素很难成为明显败血症或内毒素血症的治疗选择。

BACKGROUND & AIMS: :HMGB1 is a nuclear protein that is released or secreted following trauma or severe cellular stress. Extracellular HMGB1 triggers inflammation and recruits leukocytes to the site of tissue damage. We review recent evidence that the ability of HMGB1 to recruit leukocytes may be entirely due to the formation of a heterocomplex with the homeostatic chemokine CXCL12. The HMGB1-CXCL12 heterocomplex acts on the CXCR4 receptor more potently than CXCL12 alone. Notably, only one of the redox forms of HMGB1, the one where all cysteines are reduced (all-thiol), can bind CXCL12. Both HMGB1 containing a disulfide bond between C23 and C45, which induces chemokine and cytokine release by activating TLR4, and HMGB1 terminally oxidized to contain a cysteine sulfonate are inactive in recruiting leukocytes. Thus, the chemoattractant and cytokine-inducing activities of HMGB1 are separable, and we propose that they appear sequentially during the development of inflammation and its resolution. The HMGB1-CXCL12 heterocomplex constitutes a specific target that may hold promise for the treatment of several pathologies.

背景与目标： : HMGB1是一种核蛋白，在创伤或严重的细胞应激后释放或分泌。细胞外HMGB1触发炎症并将白细胞募集到组织损伤部位。我们回顾了最近的证据，即HMGB1募集白细胞的能力可能完全是由于与稳态趋化因子cxcl12形成了异复合物。HMGB1-CXCL12的异源复合物比单独的CXCL12更有效地作用于CXCR4受体。值得注意的是，只有HMGB1的一种氧化还原形式 (所有半胱氨酸被还原的一种) 可以结合cxcl12。含有C23和C45之间的二硫键的HMGB1和通过激活TLR4诱导趋化因子和细胞因子释放的HMGB1，以及末端氧化为含有半胱氨酸磺酸盐的HMGB1在募集白细胞中均无活性。因此，HMGB1的趋化因子和细胞因子诱导活性是可分离的，我们建议它们在炎症的发展及其消退过程中依次出现。HMGB1-CXCL12的异源复合物构成特定的靶标，可以有望治疗几种病理。

BACKGROUND & AIMS: OBJECTIVES:Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is caused by TNFRSF1A mutations, known to induce intracellular retention of the TNFα receptor 1 (TNFR1) protein, defective TNFα-induced apoptosis, and production of reactive oxygen species. As downregulation of autophagy, the main cellular pathway involved in insoluble aggregate elimination, has been observed to increase the inflammatory response, we investigated whether it plays a role in TRAPS pathogenesis. METHODS:The possible link between TNFRSF1A mutations and inflammation in TRAPS was studied in HEK-293T cells, transfected with expression constructs for wild-type and mutant TNFR1 proteins, and in monocytes derived from patients with TRAPS, by investigating autophagy function, NF-κB activation and interleukin (IL)-1β secretion. RESULTS:We found that autophagy is responsible for clearance of wild-type TNFR1, but when TNFR1 is mutated, the autophagy process is defective, probably accounting for mutant TNFR1 accumulation as well as TRAPS-associated induction of NF-κB activity and excessive IL-1β secretion, leading to chronic inflammation. Autophagy inhibition due to TNFR1 mutant proteins can be reversed, as demonstrated by the effects of the antibiotic geldanamycin, which was found to rescue the membrane localisation of mutant TNFR1 proteins, reduce their accumulation and counteract the increased inflammation by decreasing IL-1β secretion. CONCLUSIONS:Autophagy appears to be an important mechanism in the pathogenesis of TRAPS, an observation that provides a rationale for the most effective therapy in this autoinflammatory disorder. Our findings also suggest that autophagy could be proposed as a novel therapeutic target for TRAPS and possibly other similar diseases.

背景与目标：

BACKGROUND & AIMS: :M-type phospholipase A2 receptor (PLA2R) is the major target antigen in primary membranous nephropathy (PMN). Previous studies have evaluated the diagnostic value of serum anti-PLA2R antibody. However, the correlation of serum anti-PLA2R antibody and glomerular PLA2R deposition, and their association with clinical characteristics need to be further evaluated.A total of 136 patients were involved as inception group because serum anti-PLA2R antibody and glomerular PLA2R antigen were simultaneously measured. We examined serum anti-PLA2R antibody by ELISA and glomerular PLA2R deposition by immunofluorescence assay.Positive serum anti-PLA2R antibody and glomerular PLA2R deposition were seen in 58.8% (80/136) and 95.6% (130/136) patients, respectively (P < .001). Proteinuria, serum total protein, serum albumin, serum creatinine, and estimated glomerular filtration rate (eGFR) had significant differences between patients with serum anti-PLA2R antibody and those without. Serum anti-PLA2R antibody levels were correlated with serum albumin, serum creatinine, eGFR, and proteinuria. Glomerular PLA2R deposition intensities were weakly correlated with proteinuria. Unexpectedly, there was a positive correlation rather than a negative correlation between glomerular PLA2R deposition intensity and eGFR.In conclusion, serum anti-PLA2R antibody is more closely correlated with disease activity and renal function than glomerular PLA2R deposition.

背景与目标： : M型磷脂酶A2受体 (PLA2R) 是原发性膜性肾病 (PMN) 的主要靶抗原。先前的研究已经评估了血清anti-PLA2R抗体的诊断价值。但是，血清anti-PLA2R抗体与肾小球PLA2R沉积的相关性及其与临床特征的相关性有待进一步评估。共有136例患者作为起始组，因为同时测量了血清anti-PLA2R抗体和肾小球PLA2R抗原。ELISA法检测血清anti-PLA2R抗体，免疫荧光法检测肾小球PLA2R沉积，58.8% 例 (80/136例) 和95.6% 例 (130/136例) 血清anti-PLA2R抗体和肾小球PLA2R沉积阳性 (p  < .001)。蛋白尿，血清总蛋白，血清白蛋白，血清肌酐和估计的肾小球滤过率 (eGFR) 在具有血清anti-PLA2R抗体的患者与没有血清白蛋白的患者之间具有显着差异。血清anti-PLA2R抗体水平与血清白蛋白，血清肌酐，eGFR和蛋白尿相关。肾小球PLA2R沉积强度与蛋白尿的相关性较弱。不料，肾小球PLA2R沉积强度与eGFR呈正相关而非负相关，结论血清anti-PLA2R抗体与疾病活动和肾功能的相关性比肾小球PLA2R沉积更密切。

BACKGROUND & AIMS: :Novel treatment strategies for tuberculosis are urgently needed. Many different preclinical models assessing anti-tuberculosis drug activity are available, but it is yet unclear which combination of models is most predictive of clinical treatment efficacy. The aim of this study was to determine the role of our in vitro time kill-kinetics assay as an asset to a predictive preclinical modeling framework assessing anti-tuberculosis drug activity. The concentration- and time-dependent mycobacterial killing capacities of six anti-tuberculosis drugs were determined during exposure as single drugs or in dual, triple and quadruple combinations towards a Mycobacterium tuberculosis Beijing genotype strain and drug resistance was assessed. Streptomycin, rifampicin and isoniazid were most active against fast-growing M. tuberculosis. Isoniazid with rifampicin or high dose ethambutol were the only synergistic drug combinations. The addition of rifampicin or streptomycin to isoniazid prevented isoniazid resistance. In vitro ranking showed agreement with early bactericidal activity in tuberculosis patients for some but not all anti-tuberculosis drugs. The time-kill kinetics assay provides important information on the mycobacterial killing dynamics of anti-tuberculosis drugs during the early phase of drug exposure. As such, this assay is a valuable component of the preclinical modeling framework.

背景与目标： 迫切需要新的结核病治疗策略。有许多不同的评估抗结核药物活性的临床前模型，但尚不清楚哪种模型组合最能预测临床治疗效果。这项研究的目的是确定我们的体外时间杀伤动力学测定法作为评估抗结核药物活性的预测性临床前建模框架的资产的作用。在暴露于结核分枝杆菌北京基因型菌株的过程中，确定了六种抗结核药物的浓度和时间依赖性的分枝杆菌杀伤能力，并评估了耐药性。链霉素，利福平和异烟肼对快速生长的结核分枝杆菌最有效。异烟肼与利福平或高剂量乙胺丁醇是唯一的协同药物组合。在异烟肼中添加利福平或链霉素可防止异烟肼耐药性。体外排名显示，对于某些 (但不是所有) 抗结核药物，结核病患者的早期杀菌活性一致。时间杀伤动力学测定法提供了有关药物暴露早期抗结核药物的分枝杆菌杀伤动力学的重要信息。因此，该测定是临床前建模框架的有价值的组成部分。