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: :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。

BACKGROUND & AIMS: :Menyanthes trifoliata L. is used in Swedish traditional medicine for the treatment of inflammatory diseases of the kidney, e.g. glomerulonephritis. Earlier studies have shown that MtL increases glomerular filtration rate after renal reperfusion ischemia. This activity was suggested to be PAF-inhibitory since MtL also inhibited PAF-induced exocytosis in vitro on human neutrophils (IC(50) = 0.16 mg/ml). The present study further characterizes the anti-inflammatory properties of a rhizome decoction of this plant. MtL inhibited carrageenan-induced rat paw edema (ID(50) ≈ 1.7 g/kg p.o.) and ethyl phenylpropiolate-induced rat ear edema (32% at 2.0 g/kg p.o.) in a dose-dependent manner. Further studies revealed that MtL inhibited both fMLP-induced exocytosis (IC(50) = 0.16 mg/ml) and elastase activity (IC(50) = 0.16 mg/ml). According to these results it is likely that the activity shown in the PAF-test is at least partly due to an inhibition of elastase. MtL showed only minor hemolytic properties at the concentrations used in the PAF- and fMLP-tests, suggesting that the cells in these tests are undamaged. The decoction also inhibited the biosynthesis of LTB(4) (IC(50) ≈ 0.73 mg/ml) and prostaglandins (IC(50) = 0.37 mg/ml) in vitro in a concentration-dependent way. However, at concentrations where the decoction is active in the LTB(4)-test, it also possesses hemolytic properties.

背景与目标： : Menyanthes trifoliata L.在瑞典传统医学中用于治疗肾脏的炎症性疾病，例如肾小球肾炎。较早的研究表明，MtL会增加肾脏再灌注缺血后的肾小球滤过率。该活性被认为是PAF抑制的，因为MtL还抑制了PAF诱导的人嗜中性粒细胞的胞吐作用 (IC(50) = 0.16 mg/ml)。本研究进一步表征了该植物根茎汤的抗炎特性。MtL以剂量依赖性方式抑制角叉菜胶诱导的大鼠爪子水肿 (ID(50) ≈ 1.7g/kg p.o.) 和苯基丙醇酸乙酯诱导的大鼠耳水肿 (32% 2.0g/kg p.o.)。进一步的研究表明，MtL抑制fMLP诱导的胞吐作用 (IC(50) = 0.16 mg/ml) 和弹性蛋白酶活性 (IC(50) = 0.16 mg/ml)。根据这些结果，PAF测试中显示的活性可能至少部分归因于弹性蛋白酶的抑制。在PAF和fMLP测试中使用的浓度下，MtL仅显示出较小的溶血特性，这表明这些测试中的细胞未受损。该汤剂还以浓度依赖性方式抑制体外LTB(4) (IC(50) ≈ 0.73 mg/ml) 和前列腺素 (IC(50) = 0.37 mg/ml) 的生物合成。然而，在汤在LTB(4)-测试中具有活性的浓度下，它也具有溶血特性。

BACKGROUND & AIMS: :Anti-inflammatory and peroxisome proliferator-activated receptors (PPARs) transactivational effects of nine compounds (1 - 9) from the roots of Sophora flavescens were evaluated using NF-κB-luciferase, reverse transcriptase polymerase chain reaction, peroxisome proliferator response element (PPRE)-luciferase, and GAL-4-PPAR chimera assays. Compounds 4 and 8 significantly inhibited TNFα-induced NF-κB transcriptional activity in HepG2 cells in a dose-dependent manner, with IC₅₀ values of 4.0 and 4.4 μM, respectively. Furthermore, the transcriptional inhibitory function of these compounds was confirmed by a decrease in cyclooxgenase 2 and inducible nitric oxide synthase gene expression levels in HepG2 cells. Compounds 1, 3, 5, 6, 8, and 9 significantly activated the transcription of PPARs in a dose-dependent manner, with EC₅₀ values ranging from 1.1 to 13.0 μM. Compounds 1, 3, 5, 6, 8, and 9 exhibited dose-dependent PPARα transactivational activity, with EC₅₀ values in a range of 0.9 - 16.0 μM. Compounds 1, 3, 8, and 9 also significantly upregulated PPARγ activity in a dose-dependent manner, with EC₅₀ values of 10.5, 6.6, 15.7, and 1.6 μM, whereas compounds 1, 8, and 9 demonstrated transactivational PPARβ(δ) effects with EC₅₀ values of 11.4, 10.3, and 1.5 μM, respectively. These results provide a scientific rationale for the use of the roots of S. flavescens and warrant further studies to develop new agents for the prevention and treatment of inflammatory and metabolic diseases.

背景与目标： : 使用NF-κ b-荧光素酶，逆转录酶聚合酶链反应，过氧化物酶体增殖物反应元件 (PPRE)-荧光素酶评估了苦参根中的9种化合物 (1  -  9) 的抗炎和过氧化物酶增殖物激活受体 (ppar) 反式激活作用。GAL-4-PPAR嵌合体分析。化合物4和8以剂量依赖的方式显着抑制了tnf α 诱导的HepG2细胞中的NF-κ b转录活性，其ic of值分别为4.0和4.4  μ m。此外，这些化合物的转录抑制功能被HepG2细胞中环氧合酶2和诱导型一氧化氮合酶基因表达水平的降低所证实。化合物1、3、5、6、8和9以剂量依赖性方式显着激活ppar的转录，其值范围为1.1至13.0  μ m。化合物1、3、5、6、8和9表现出剂量依赖性ppar α 反式激活活性，其值在0.9  -  16.0  μ m的范围内。化合物1、3、8和9也以剂量依赖的方式显着上调ppar γ 活性，其e of value为10.5、6.6、15.7和1.6  μ m，而化合物1、8和9表现出反式激活ppar β(δ) 效应，其e of value为11.4、10.3，和1.5  μ m，分别。这些结果为使用S. flavescens的根提供了科学依据，并需要进一步研究以开发用于预防和治疗炎症和代谢疾病的新药物。

BACKGROUND & AIMS: :Selected plants documented as medicinal in an ethnobotanical study with the Nahua of the Sierra de Zongolica (Veracruz, Mexico) were evaluated for anti-inflammatory and antibacterial activity. One of the potential sides of action of anti-inflammatory drugs is the transcription factor NF-κB. This factor is essential for the immune, inflammatory, and acute phase responses. We therefore tested extracts from a total of 28 plants used by the Nahua Indians for their potential effect on the activation of the transcription factor NF-κB. The leaves of Tithonia diversifolia (Hemsl.) A. Gray (Asteraceae) was the only extract which showed inhibitory activity. Nonspecific DNA binding activities were not noticably influenced. Phytochemical studies to isolate the active principle and further biochemical studies in order to better understand the mode of action of this NF-κB inhibitor have been initiated. Five plants showed noteworthy antibacterial activity against some pathogenic (Staphylococcus aureus ATCC 25933 and Yersinia enterocolitica 03) and nonpathogenic (E. coli DSM 1077, Micrococcus luteus DSM 348) microorganism: Acacia cornigera, Cuscuta tinctoria, Ludwigia octovalvis, Lysiloma divaricata, and Tithonia diversifolia.

背景与目标： : 在一项民族植物学研究中与Sierra de Zongolica (墨西哥韦拉克鲁斯) 的Nahua进行了记录为药用植物的抗炎和抗菌活性评估。抗炎药物的潜在作用方面之一是转录因子NF-κ b。该因素对于免疫，炎症和急性期反应至关重要。因此，我们测试了纳华印第安人使用的总共28种植物的提取物对转录因子NF-κ b激活的潜在影响。Tithonia diversifolia (Hemsl.) A.Gray (菊科) 是唯一具有抑制活性的提取物。非特异性DNA结合活性没有受到明显影响。分离活性原理的植物化学研究和进一步的生化研究已经开始，以便更好地了解这种NF-κ b抑制剂的作用方式。五种植物对某些致病性 (金黄色葡萄球菌ATCC 25933和小肠结肠炎耶尔森氏菌03) 和非致病性 (大肠杆菌DSM 1077，微球菌DSM 348) 微生物具有显着的抗菌活性: 金相相思，刺槐，octovalvis，Lysiloma divaricata和Tithonia diversifolia。

BACKGROUND & AIMS: :Since there are no systematic studies available on the effects of anti-microtubule agents on ciliated protozoa, we screened a wide variety of such compounds for their effects on the growth of Paramecium tetraurelia cell cultures. Compounds tested include agents of widely different chemical composition and with reported effects on widely different cell types. We can differentiate between different drug effects: (a) Rotenone is the only agent without any recognisable effect, (b) Another group of compounds (including colchicine) requires very high concentrations, as compared to higher animal cells, i.e., rather close to a cytotoxic level; this group also includes tubulozole (unexpectedly without any difference between the cis- and the trans-stereoisomer). (c) A third group of drugs inhibits cell culture growth without any lethal effects (benzimidazoles, nocodazole, parbendazole; the [anti-]fungal antibiotic, griseofulvin; the herbicide, trifluralin). (d) Finally a group of agents are active in a concentration range also reported for plants (the herbicide, APM) or for higher animal cells (including the microtubule stabiliser, taxol) or for both (vinblastine, vincristine, triethyl lead), although they are cytotoxic at higher concentrations (like compounds of group [b]). Therefore, in particular compounds of group (c) and possibly of group (d) might be considered further on for a more detailed analysis of a possibly genuine anti-microtubular effect in Paramecium cells. Of particular interest may be nocodazole, parbendazole and trifluralin, since they can inhibit cell culture growth (over 24 h tested) in relatively low concentrations (comparable to other cell types) without any impairment of cell viability.

背景与目标： : 由于尚无关于抗微管剂对纤毛原生动物的影响的系统研究，因此我们筛选了各种此类化合物对草履虫四重草细胞培养物生长的影响。测试的化合物包括化学成分广泛不同的试剂，据报道对细胞类型广泛不同的影响。我们可以区分不同的药物作用 :( a) 鱼藤酮是唯一没有任何可识别作用的药物，(b) 与较高的动物细胞相比，另一组化合物 (包括秋水仙碱) 需要非常高的浓度，即相当接近细胞毒性水平; 该组还包括小管 (出乎意料的是，顺式和反式立体异构体之间没有任何区别)。(c) 第三组药物抑制细胞培养物的生长，而没有任何致死作用 (苯并咪唑，诺考达唑，帕苯达唑; [抗] 真菌抗生素灰黄霉素; 除草剂，氟拉林)。(d) 最后，一组试剂在植物 (除草剂，APM) 或高等动物细胞 (包括微管稳定剂，紫杉醇) 或两者 (长春碱，长春新碱，三乙基铅) 的浓度范围内具有活性，尽管它们在较高浓度下具有细胞毒性 (如 [b] 组的化合物)。因此，特别是可以进一步考虑 (c) 组和 (d) 组的化合物，以更详细地分析草履虫细胞中可能真正的抗微管作用。特别令人感兴趣的可能是诺考达唑，帕苯达唑和三氟拉林，因为它们可以在相对较低的浓度 (与其他细胞类型相当) 下抑制细胞培养物生长 (测试超过24小时)，而不会损害细胞活力。

BACKGROUND & AIMS: :In this study, we investigated the anti-inflammatory effects and mechanisms of Hizikia fusiformis (HF) extracts in lipopolysaccharide (LPS)-induced RAW 264.7 cells. We extracted HF using solvent and sub-critical water techniques. In results, HF extracts inhibited nitric oxide (NO) production in cell-free and LPS-stimulated RAW 264.7 cells. HF210 (extract prepared with sub critical water at 210oC) was most effective. The HF210 extract dose-dependently inhibited inducible nitric oxide synthase expression (iNOS) and nuclear factor kappa (NF-B) p65 translocation from cytosol to the nucleus. Furthermore, HF210 extract dose-dependently inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), Jun N-terminal kinase (JNK), and signal transducers and activators of transcription (STAT)-1in LPS-induced RAW 264.7 cells. Thus, our results suggest that anti-inflammatory effects of HF210 extract showed a noticeable distinction by regulation of multiple signaling pathways in LPS-induced RAW 264.7 cells.

背景与目标： : 在这项研究中，我们研究了梭状冬青 (HF) 提取物在脂多糖 (LPS) 诱导的原始264.7细胞中的抗炎作用和机制。我们使用溶剂和亚临界水技术提取HF。结果，HF提取物抑制无细胞和LPS刺激的原始264.7细胞中一氧化氮 (NO) 的产生。HF210 (在210oC下用亚临界水制备的提取物) 最有效。HF210提取物剂量依赖性地抑制诱导型一氧化氮合酶 (iNOS) 表达和核因子 κ (NF-B) p65从细胞质到细胞核的转运。此外，HF210提取物在LPS诱导的原始264.7细胞中剂量依赖性地抑制p38丝裂原活化蛋白激酶 (p38mapk) 、6月N端激酶 (JNK) 和信号转导子和转录激活子 (STAT)-1的磷酸化。因此，我们的结果表明，HF210提取物的抗炎作用通过调节LPS诱导的原始264.7细胞中的多种信号通路显示出明显的区别。

BACKGROUND & AIMS: We analysed 112 idiopathic inflammatory myopathy (IIM) sera for the presence of anti-Ro, anti-La and anti-histidyl-tRNA synthetase (Jo-1) autoantibodies, and subsequently mapped B cell epitopes on the Ro52 protein recognized by anti-Ro52+ IIM sera. Sera were characterized by immunoblotting, ELISA and RNA precipitation. Both anti-Ro60 and anti-La activity was found in 4% of IIM sera. Anti-Ro52 antibodies were present in 20% of IIM sera. However, in anti-Jo-1+ IIM sera (21%), the frequency of the anti-Ro52 antibodies was found to be much higher (58%). No cross-reactivity between anti-Ro52 and anti-Jo-1 antibodies could be detected in these sera. To learn more about the nature of anti-Ro52 antibodies occurring in IIM sera, we analysed the major epitopes of the Ro52 protein targeted by anti-Ro52+ IIM sera by immunoprecipitation of in vitro translated Ro52 deletion mutants. The major epitope was mapped in the region bordered by amino acids 126 and 252. This part of the protein includes a long alpha-helical region which contains two potential coiled-coil domains as well as a leucine zipper motif. Although no difference in Ro52 epitope recognition between anti-Jo-1+ and anti-Jo-1- IIM sera could be observed, our results suggest that the autoimmune response against Ro52 and Jo-1 in IIM patients is coupled.

背景与目标： 我们分析了112个特发性炎症性肌病 (IIM) 血清中存在抗Ro，抗La和抗组氨酸-tRNA合成酶 (Jo-1) 自身抗体，随后将b细胞表位绘制在anti-Ro52 IIM血清识别的Ro52蛋白上。通过免疫印迹，ELISA和RNA沉淀对血清进行表征。在4% 的IIM血清中发现了anti-Ro60和抗La活性。Anti-Ro52抗体存在于IIM血清的20% 中。然而，在anti-Jo-1 + IIM血清 (21%) 中，发现anti-Ro52抗体的频率要高得多 (58%)。在这些血清中未检测到anti-Ro52和anti-Jo-1抗体之间的交叉反应。为了更多地了解IIM血清中anti-Ro52抗体的性质，我们通过体外翻译的Ro52缺失突变体的免疫沉淀分析了anti-Ro52 IIM血清靶向的Ro52蛋白的主要表位。主要表位被定位在与氨基酸126和252接壤的区域中。蛋白质的这一部分包括一个长的 α 螺旋区域，该区域包含两个潜在的卷曲螺旋结构域以及亮氨酸拉链基序。尽管在anti-Jo-1和anti-Jo-1- IIM血清之间没有观察到Ro52表位识别的差异，但我们的结果表明IIM患者针对Ro52和Jo-1的自身免疫反应是偶联的。

BACKGROUND & AIMS: The growth and vascularization of many tumours has been reported to be associated with the overexpression of the potent mitogenic and angiogenic polypeptide basic fibroblast growth factor (beta-FGF). Consequently, it has been proposed that inhibition of beta-FGF action would prevent the growth of beta-FGF-dependent tumours. In this study, cell culture assays were established to assess the ability of mouse monoclonal DG-2 anti-beta-FGF antibodies to inhibit the mitogenic action of beta-FGF in vitro. Following in vitro characterisation, the monoclonal DG-2 antibodies were used to evaluate the role of beta-FGF in promoting the vascularization and growth of rat chondrosarcoma tumours. The effect the monoclonal anti-B-FGF antibodies had on tumour vascularization and growth in vivo were monitored using a 99m Technetium (99mTc)-labelled red blood cell procedure. The characterization studies confirmed that the DG-2 monoclonal antibody recognised beta-FGF and inhibited its mitogenic action on mouse Balb/c cells and bovine endothelial cells in vitro. When examined in vivo, intralesional administration of mouse monoclonal DG-2 antibody significantly inhibited rat chondrosarcoma growth and vascularization. However when the monoclonal DG-2 antibody was administered intraperitoneally or intravenously no attenuation of rat chondrosarcoma tumour vascularization or growth was observed. This report has confirmed the potential effectiveness of anti-beta-FGF antibodies in the regulation of tumour growth. It has also demonstrated that further studies on the pharmacokinetics of administered antibodies and their mode of delivery are required so that the effectiveness of such anti-growth factor immunotherapy can be assured.

背景与目标： 据报道，许多肿瘤的生长和血管化与有效的有丝分裂和血管生成多肽碱性成纤维细胞生长因子 (β-FGF) 的过表达有关。因此，已经提出抑制 β-FGF作用将阻止 β-FGF依赖性肿瘤的生长。在这项研究中，建立了细胞培养试验以评估小鼠单克隆DG-2抗 β-FGF抗体在体外抑制 β-FGF的促有丝分裂作用的能力。在体外表征之后，使用单克隆DG-2抗体来评估 β-FGF在促进大鼠软骨肉瘤肿瘤的血管化和生长中的作用。使用99m tech (99mTc) 标记的红细胞程序监测单克隆抗B-FGF抗体对体内肿瘤血管化和生长的影响。表征研究证实，DG-2单克隆抗体在体外识别 β-FGF并抑制其对小鼠Balb/c细胞和牛内皮细胞的促有丝分裂作用。当在体内检查时，小鼠单克隆DG-2抗体的病灶内给药可显着抑制大鼠软骨肉瘤的生长和血管形成。然而，当腹膜内或静脉内施用单克隆DG-2抗体时，未观察到大鼠软骨肉瘤肿瘤血管化或生长的减弱。该报告证实了抗 β-FGF抗体在调节肿瘤生长中的潜在有效性。还表明，需要对所给药抗体的药代动力学及其传递方式进行进一步研究，以便可以确保这种抗生长因子免疫疗法的有效性。

BACKGROUND & AIMS: :In 29 patients undergoing percutaneous coronary intervention (PCI), we obtained blood samples at baseline, 10 minutes after standard weight-based abciximab (n=15) or double-bolus eptifibatide (n=14) and 5 minutes after unfractionated heparin (UFH; 70 U/kg bolus). The median percent inhibition was significantly higher in the eptifibatide group compared with the abciximab group both before (96.5% [94-100] vs. 85% [77-89.5] [adenosine diphosphate; ADP]; 89.5% [84-95] vs. 59% [37.5-76.5] [thrombin receptor agonist peptide; TRAP], p<0.001 for both) and after UFH (95% [93-100] vs. 79% [68.8-87.5] [ADP]; 82% [77-93] vs. 51% [34.5-71.3] [TRAP], p<0.001 for both). Addition of UFH significantly reduced platelet inhibition in the abciximab group (85% [77-89.5] vs. 79% [68.8-87.5] [ADP]; 59% [37.5-76.5] vs. 51% [34.5-71.3] [TRAP], p<0.05 for both) but not in the eptifibatide group (96.5% [94-100] vs. 95% [93-100] [ADP]; 89.5% [84-95] vs. 82% [77-93] [TRAP], p=ns for both). Eptifibatide achieved superior platelet inhibition before but especially after UFH compared with abciximab.

背景与目标： : 在29例接受经皮冠状动脉介入治疗 (PCI) 的患者中，我们在基线，基于标准体重的阿昔单抗 (n = 15) 或双推注eptifibatide (n = 14) 后10分钟和普通肝素 (UFH; 70 U/kg推注) 后5分钟获得了血液样本。与阿昔单抗组相比，依替巴肽组的中位抑制百分比均显着更高 (96.5% [94-100] vs. 85% [77-89.5] [二磷酸腺苷; ADP]; 89.5% [84-95] vs. 59% [37.5-76.5] [凝血酶受体激动剂肽; TRAP]，p<0.001) 和UFH之后 (95% [93-100] 对79% [68.8-87.5] [ADP]; 82% [77-93] 对51% [34.5-71.3] [TRAP]，p<0.001)。添加UFH可显着降低阿昔单抗组的血小板抑制作用 (85% [77-89.5] vs. 79% [68.8-87.5] [ADP]; 59% [37.5-76.5] vs. 51% [34.5-71.3] [TRAP]，p<0.05)，但在依替巴肽组中没有 (96.5% [94-100] 对95% [93-100] [ADP]; 89.5% [84-95] 对82% [77-93] [TRAP]，p = ns)。与阿昔单抗相比，依替非巴肽在UFH之前 (尤其是在UFH之后) 获得了更好的血小板抑制作用。

BACKGROUND & AIMS: :A series of cell lines, which differed in their expression of class I (H-2K) or II (I-A) major histocompatibility complex (MHC) antigens, was derived from a line of C3H/He (H-2k) mouse embryo fibroblasts transformed by the v-Ki-ras oncogene. These were prepared by fluorescence-activated cell sorting of cells stained for these antigens either without interferon (IFN) treatment or after induction of antigen expression by either IFN-alpha beta or IFN-gamma, selecting for low or high staining. Cells selected for low (undetectable) constitutive H-2Kk expression were still strongly inducible by either IFN; cells selected for high constitutive expression were induced by IFN to express still higher levels. In all cell lines induction of H-2Kk with one IFN type was paralleled by induction with the other. Expression of H-2Kk appeared largely independent of H-2Dk; in lines which were selected for low H-2Kk expression (constitutive or induced), H-2Dk expression was not much reduced, and lines selected for high H-2Kk expression showed only modest augmentation of H-2Dk. Varying inducibility of I-Ak by IFN-gamma was not closely paralleled by H-2K inducibility by either IFN-alpha beta or -gamma, with again only weak correlation of high and low expression of H2-Kk and I-Ak. On the other hand, expression of I-Ak seemed to be correlated with I-Ek. None of these variable effects could be attributed to differing sensitivity to IFN-alpha beta or -gamma since all the lines showed about the same sensitivity to the anti-viral effects of IFN.

背景与目标： : 一系列细胞系，其I类 (H-2K) 或II类 (i-a) 主要组织相容性复合物 (MHC) 抗原的表达不同，源自由v-Ki-ras癌基因转化的C3H/He (H-2k) 小鼠胚胎成纤维细胞。这些是通过荧光激活的细胞分选针对这些抗原染色的细胞而制备的，无需干扰素 (IFN) 处理或在通过IFN-α β 或IFN-γ 诱导抗原表达后，选择低或高染色。被选择用于低 (不可检测) 组成型H-2Kk表达的细胞仍然被IFN强烈诱导; 被选择用于高组成型表达的细胞被IFN诱导以表达更高的水平。在所有细胞系中，具有一种IFN类型的H-2Kk的诱导与另一种类型的诱导平行。H-2Kk的表达似乎在很大程度上独立于H-2Dk; 在被选择用于低H-2Kk表达 (组成型或诱导型) 的品系中，H-2Dk表达没有减少太多，而被选择用于高H-2Kk表达的品系仅显示出适度的H-2Dk增加。IFN-γ 对I-Ak的诱导性变化与IFN-α β 或-γ 的H-2K诱导性并不紧密平行，H2-Kk和I-Ak的高表达和低表达也仅弱相关。另一方面，i-ak的表达似乎与i-ek相关。这些可变效应都不能归因于对IFN-alpha β 或-γ 的敏感性不同，因为所有品系对IFN的抗病毒效应均表现出相同的敏感性。

BACKGROUND & AIMS: BACKGROUND:Recent studies show that patients with multiple nonsteroidal anti-inflammatory drug (NSAID) intolerance are frequently characterized by autoreactivity; this can be detected by autologous serum skin test (ASST). OBJECTIVE:To assess whether the autologous plasma skin test (APST), a test that was recently shown to be more sensitive than ASST, may be usefully employed as a predictive test for multiple NSAID intolerance in patients with a history of single NSAID intolerance. METHODS:Thirty otherwise normal adults with a history of acute urticaria following the ingestion of one single NSAID underwent an APST before being challenged with a COX-1-inhibiting NSAID other than the offending drug. RESULTS:Sixteen patients experienced urticaria following the ingestion of the alternative NSAID and were therefore classified as multiple NSAID reactors; all 16 (100%) scored positive on APST. In contrast only 3/14 patients finally classified as single NSAID reactors were positive on APST (p < 0.001). The positive and negative predictive value of APST for multiple NSAID intolerance were 86 and 100%, respectively. CONCLUSION:In patients with a history of acute urticaria induced by a single NSAID APST can be usefully employed to detect patients that are prone to react to NSAID other than the original offending one.

背景与目标：

BACKGROUND & AIMS: :Auto-anti-idiotypic mechanisms can regulate the protective immune response against Schistosoma mansoni. Anti-idiotypic responses were stimulated by immunization of mice either with nonspecifically induced lymphoblasts, produced with Con A, or with Ag-induced lymphoblasts bearing specific idiotypic receptors. The effect of the induced anti-idiotypic response upon clonotypic cellular reactivity was assessed in vitro through the suppression of antigen-mediated blast transformation by cloned T cells and in vivo by suppression of resistance to S. mansoni and delayed-type hypersensitivity responses against specific Ag. Differential regulation of humoral immune responses was studied at the levels of specific epitopic recognition, the expression of specific Id, and the production of anti-idiotypic responses directed against mAb bearing specific Id. Anti-idiotypic sensitization resulted in variable (10 to 90%) suppression of the immune response to discrete antigenic epitopes, the expression of specific idiotypic phenotypes, and anti-idiotypic, antiparatopic responses against T cell clonotypes and antibody idiotypic phenotypes. In vitro admixture and in vivo challenge studies resulted in consonant differential suppression. Thus idiotypic regulation can mold the fine specificities of the protective immune response to S. mansoni at the clonal level and may provide an approach to optimize the expression and assessment of resistance.

背景与目标： : 自身抗独特型机制可以调节曼氏血吸虫的保护性免疫反应。通过用Con A产生的非特异性诱导的淋巴母细胞或带有特定独特型受体的Ag诱导的淋巴母细胞免疫小鼠来刺激抗独特型反应。诱导的抗独特型反应对克隆型细胞反应性的影响在体外通过克隆的T细胞抑制抗原介导的胚转化进行评估，并在体内通过抑制对曼氏杆菌的抗性和对特异性Ag的延迟型超敏反应进行评估。在特定的表位识别，特定Id的表达以及针对带有特定Id的mAb的抗独特型反应的产生的水平上研究了体液免疫反应的差异调节。抗独特型致敏作用导致对离散抗原表位的免疫应答、特定独特型表型的表达以及针对T细胞克隆型和抗体独特型表型的抗独特型、抗独特型应答的可变 (10至90%) 抑制。体外混合和体内激发研究导致辅音差异抑制。因此，独特型调节可以在克隆水平上塑造对曼氏杆菌的保护性免疫反应的精细特异性，并可能提供一种优化表达和评估抗性的方法。

BACKGROUND & AIMS: :Treatment for multiple myeloma (MM) has significantly advanced in the last decade with the introduction of proteasome inhibitors and immunomodulatory therapies. Unfortunately, MM continues to cause significant morbidity and most patients eventually succumb to the disease. As in other areas of cancer, immunotherapy in MM has also evolved and holds promise to deliver long-lasting remissions or even cure. The signaling lymphocyte activation molecules (SLAM) family of surface proteins represents a group of potential targets for immunotherapy in MM as some of the family members are expressed consistently on plasma cells and also on myeloma propagating pre-plasma cells. Here, we review the SLAM family members in detail, describe their tissue distribution, biologic pathways, as well as relevant pre-clinical studies and clinical trials in MM. Our review demonstrates the value of SLAM family receptors as potential targets for anti-myeloma immunotherapies and outlines how immunotherapeutic approaches can be developed.

背景与目标： : 随着蛋白酶体抑制剂和免疫调节疗法的引入，多发性骨髓瘤 (MM) 的治疗在过去十年中有了显着进步。不幸的是，MM继续引起显着的发病率，大多数患者最终屈服于该疾病。与其他癌症领域一样，MM的免疫疗法也在不断发展，并有望提供持久的缓解甚至治愈。表面蛋白的信号淋巴细胞活化分子 (SLAM) 家族代表了MM中免疫疗法的一组潜在靶标，因为某些家族成员在浆细胞和骨髓瘤传播前浆细胞上一致表达。在这里，我们详细回顾了SLAM家族成员，描述了他们的组织分布，生物学途径，以及相关的临床前研究和MM的临床试验。我们的评论证明了SLAM家族受体作为抗骨髓瘤免疫疗法的潜在靶标的价值，并概述了如何开发免疫治疗方法。