BACKGROUND & AIMS: PURPOSE:Panax notoginseng is a commonly used Chinese herb. Although a few studies have found that notoginseng shows anti-tumor effects, the effect of this herb on colorectal cancer cells has not been investigated. 5-Fluorouracil (5-FU) is a chemotherapeutic agent for the treatment of colorectal cancer that interferes with the growth of cancer cells. However, this compound has serious side effects at high doses. In this study, using HCT-116 human colorectal cancer cell line, we investigated the possible synergistic anti-cancer effects between notoginseng flower extract (NGF) and 5-FU on colon cancer cells. METHODS:The anti-proliferation activity of these modes of treatment was evaluated by MTS cell proliferation assay. Apoptotic effects were analyzed by using Hoechst 33258 staining and Annexin-V/PI staining assays. The anti-proliferation effects of four major single compounds from NGF, ginsenosides Rb1, Rb3, Rc and Rg3 were also analyzed. RESULTS:Both 5-FU and NGF inhibited proliferation of HCT-116 cells. With increasing doses of 5-FU, the anti-proliferation effect was slowly increased. The combined usage of 5-FU 5 microM and NGF 0.25 mg/ml, significantly increased the anti-proliferation effect (59.4 +/- 3.3%) compared with using the two medicines separately (5-FU 5 microM, 31.1 +/- 0.4%; NGF 0.25 mg/ml, 25.3 +/- 3.6%). Apoptotic analysis showed that at this concentration, 5-FU did not exert an apoptotic effect, while apoptotic cells induced by NGF were observed, suggesting that the anti-proliferation target(s) of NGF may be different from that of 5-FU, which is known to inhibit thymidilate synthase. CONCLUSIONS:This study demonstrates that NGF can enhance the anti-proliferation effect of 5-FU on HCT-116 human colorectal cancer cells and may decrease the dosage of 5-FU needed for colorectal cancer treatment.

背景与目标：

BACKGROUND & AIMS: There is evidence that neutrophil functions such as chemotaxis and oxygen radical formation are disturbed in rheumatoid arthritis (RA). Medication might also influence these functions. Cyclic formation and depolymerisation of actin microfilaments is crucial in cell motility, but this phenomenon has not been studied in RA. The aim of this study was to investigate basal and dynamic (formyl-methionyl-leucyl-phenylalanine (fMLP)-induced) neutrophil actin polymerisation in ten RA patients (a) during therapy with non-steroidal anti-inflammatory drugs (NSAIDS) and (b) after stopping NSAIDS> The results were compared with those of ten age-matched controls. Basal F-actin content in RA patients with NSAIDS was significantly lower than in RA patients without NSAIDS and controls35.5 (25.0-49.0), 50.5 (27.0-75.0) and 52.5 (32.0-85.0), respectively. Conversely, upon stimulation with fMLP, the actin polymerisation curve of RA patients with NSAIDS was higher than for RA patients without NSAIDS and controls. These results suggest that, in RA, the effects orf NSAIDS on neutrophil functions might be related to changes in the actin polymerisation-depolymerisation cycle.

背景与目标： 有证据表明，类风湿性关节炎 (RA) 的中性粒细胞功能 (例如趋化性和氧自由基形成) 受到干扰。药物也可能影响这些功能。肌动蛋白微丝的循环形成和解聚对细胞运动至关重要，但尚未在RA中研究这种现象。这项研究的目的是研究10名RA患者 (a) 在非甾体类抗炎药 (nsaid) 治疗期间的基础和动态 (甲酰基-甲硫氨酸-亮氨酸-苯丙氨酸 (fMLP) 诱导的) 中性粒细胞肌动蛋白聚合反应 (a) 和 (b) 停止nsaid后的结果进行比较有十个年龄匹配的对照。患有NSAIDS的RA患者的基础F-肌动蛋白含量显着低于没有NSAIDS和对照组的RA患者35.5 (25.0-49.0)，50.5 (27.0-75.0) 和52.5 (32.0-85.0)。相反，用fMLP刺激后，患有NSAIDS的RA患者的肌动蛋白聚合曲线高于没有NSAIDS的RA患者和对照组。这些结果表明，在RA中，orf nsaid对中性粒细胞功能的影响可能与肌动蛋白聚合-解聚周期的变化有关。

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: :Insulin resistance affecting skeletal muscle metabolism is present in the prehypertensive state. The aim of our study was to test the hypothesis that blood pressure value is related to skeletal muscle composition, measured by (31)P magnetic resonance (MR) spectroscopy, and to insulin sensitivity in the offspring of hypertensive parents (OH) and healthy controls. Study groups consisted of 10 healthy young lean OH with normal glucose tolerance, confirmed with oral glucose tolerance test, and 13 controls matched for age, sex, and body mass index. Insulin action was estimated as glucose disposal (M), glucose metabolic clearance rate (MCR), and insulin sensitivity index (M/I) during a 10-hour hyperinsulinemic euglycemic clamp. The sum of immunoreactive insulin values from the oral glucose tolerance test was calculated. (31)P MR spectroscopy was performed on a whole-body MR scanner (Siemens Vision, Erlangen, Germany) operating at 1.5 T and equipped with actively shielded gradient coils. There were no differences in common metabolic and anthropometric parameters between OH and controls except for the blood pressure, which was in the range of normal to high-normal level in OH. Mean blood pressure was significantly higher in OH (95.73 +/- 4.39 vs 83.76 +/- 3.95 mm Hg; P < .001). Trend toward insulin resistance was registered in OH with significantly lower M/I (0.74 +/- 0.47 vs 1.42 +/- 0.65 mg x kg(-1) x min(-1) x mIU(-1) x L(-1); P < .05). There were no significant differences in total serum magnesium (sMg) levels between OH and controls, although a positive correlation exists between sMg and insulin sensitivity expressed as M (r = 0.63, P < .01), MCR (r = 0.54, P < .01), and M/I (r = 0.51, P < .05). No differences in signal intensities of phosphocreatine (PCr), phosphomonoesters, phosphodiesters, inorganic phosphates (Pi), adenosine triphosphates (Patp and betaATP), and calculated concentrations of intracellular ionized magnesium (Mgi) and H(+) ions between the groups were detected. Systolic blood pressure correlates positively with PCr/Patp (r = 0.43, P < .05), Pi/Patp (r = 0.413, P < .05), and Pi/betaATP (r = 0.48, P < .05). Diastolic blood pressure correlates positively only with the ratio Pi/betaATP (r = 0.42, P < .05). The sum of immunoreactive insulin values correlates with PCr/betaATP (r = 0.53, P < .01) and with Pi/betaATP (r = 0.6, P < .01). In conclusion, increase in blood pressure and insulin resistance were confirmed in offspring of OH. Insulin sensitivity is related to sMg and the elevation of blood pressure is associated with the activation of energy metabolism in skeletal muscle. The relationship between muscle energetic characteristics and markers of insulin resistance suggests that the alteration of energy metabolism may be present in early stages of metabolic syndrome.

背景与目标： : 影响骨骼肌代谢的胰岛素抵抗在高血压前期存在。我们研究的目的是检验以下假设: 血压值与通过 (31)P磁共振 (MR) 光谱法测量的骨骼肌组成以及高血压父母 (OH) 和健康的后代的胰岛素敏感性有关对照。研究组由10个健康的年轻lean OH组成，葡萄糖耐量正常，经口服葡萄糖耐量试验证实，以及13个年龄，性别和体重指数相匹配的对照。在10小时的高胰岛素血症正常血糖钳夹中，胰岛素的作用估计为葡萄糖处置 (M)，葡萄糖代谢清除率 (MCR) 和胰岛素敏感性指数 (M/I)。计算了口服葡萄糖耐量试验的免疫反应性胰岛素值之和。(31) 在操作于1.5 T并配备有主动屏蔽梯度线圈的全身MR扫描仪 (Siemens Vision，Erlangen，德国) 上进行P MR光谱。OH和对照组之间的常见代谢和人体测量参数没有差异，但血压在OH的正常至正常水平范围内。OH中的平均血压显着更高 (95.73/- 4.39 vs 83.76/-3.95毫米Hg; P <.001)。在OH中记录了胰岛素抵抗的趋势，M/I显著降低 (0.74 +/- 0.47 vs 1.42 +/- 0.65 mg × kg(-1) × min(-1) × mIU(-1) × L(-1); P <.05)。血清总镁 (sMg) 水平与对照组无显著差异，但sMg与胰岛素敏感性呈正相关，表现为M (r = 0.63，P <.01)，MCR (r = 0.54，P <.01)。和M/I (r = 0.51，P <.05)。检测到磷酸肌酸 (PCr)，磷酸单酯，磷酸二酯，无机磷酸盐 (Pi)，三磷酸腺苷 (Patp和 βatp) 的信号强度以及计算的细胞内离子镁 (Mgi) 和H () 离子浓度之间的差异。收缩压与PCr/Patp (r = 0.43，P <.05) 、Pi/Patp (r = 0.413，P <.05) 和Pi/betaATP (r = 0.48，P <.05) 呈正相关。舒张压仅与Pi/βatp比值正相关 (r = 0.42，P <.05)。免疫反应性胰岛素值的总和与PCr/betaATP (r = 0.53，P <.01) 和Pi/betaATP (r = 0.6，P <.01) 相关。总之，在OH的后代中证实了血压升高和胰岛素抵抗。胰岛素敏感性与sMg有关，血压升高与骨骼肌能量代谢的激活有关。肌肉能量特征与胰岛素抵抗标志物之间的关系表明，能量代谢的改变可能存在于代谢综合征的早期阶段。

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: 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: :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: PURPOSE:The issue of unidentified volume expansion is well recognized as a cause for resistance to antihypertensive therapy. The aim of study is to identify contribution of negative fluid balance to hypertension control and impact on endothelial and cardiac functions among primary hypertensive patients who do not have kidney failure. MATERIALS AND METHODS:This is a prospective interventional study with one-year follow-up. Preceded by volume status measurements were performed by a body composition monitor (BCM), the patients were put on ambulatory blood pressure monitoring for 24 hours. Then, echocardiographic assessments and flow-mediated dilation (FMD) and carotid intima-media thickness (CIMT) measurements were completed. Patients in one of the two groups were kept negative hydrated during trial with diuretic treatment. RESULTS:At the end of one-year follow-up, patients in negative hydrated group were found to have significantly lower CIMT, left ventricle mass index, left ventricular end-diastolic diameter, mean systolic and diastolic BP, non-dipper patient ratio, and higher FMD. In negatively hydrated group, target organ damage significantly reduced during trial. CONCLUSIONS:The significance of negative hydration status with respect to blood pressure control, endothelial and cardiac functions within primary hypertensive patients who do not suffer from kidney failure has been demonstrated.

背景与目标：

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。