CXCR4 expression in neuroblastoma primary tumors is associated with clinical presentation of bone and bone marrow metastases

Background/Purpose

The chemokine receptor, CXCR4, has been implicated in the mechanism of tumor cell metastasis to bone and bone marrow. Neuroblastoma, a cancer of children, is well known for its potential to metastasize to these sites. The goal of this study was to investigate whether the degree of expression of CXCR4 on cells from neuroblastoma primary tumors was related to the pattern of metastatic involvement.

Methods

Archived neuroblastoma primary tumor samples and clinical data were collected from 26 patients with newly diagnosed neuroblastoma. Expression of CXCR4 (12g5 antibody) was evaluated on formalin-fixed paraffin-embedded tumor tissues using standard immunohistochemical techniques. Each tumor was graded (grade 1 through 4) based on the proportion of cells that were positive for the 12g5 antibody. Tumor grades for CXCR4 expression were compared with clinical data from each patient.

Results

Higher grades of expression (grade 3 and 4) were found in tumors from patients with high-stage disease (P < .01) and in patients with bone and bone marrow metastases (P ≤ .01). Clinical outcome in patients with tumors highly expressing CXCR4 was significantly worse (P < .01) than in those patients with low-grade CXCR4.

Conclusions

CXCR4 expression in neuroblastoma primary tumors is significantly correlated with the pattern of metastatic spread.     

抗精神病药慢性给药对大鼠海马neuregulin 1与ErbB4表达的影响*

目的:观察抗精神病药慢性给药对大鼠海马内neuregulin 1(神经调节蛋白1,NRG1)与ErbB4蛋白表达的影响。方法:16只Wistar大鼠随机分为4组,分别腹腔注射生理氯化钠溶液、氟哌啶醇(1 mg·kg~(-1))、氯氮平(10 mg·kg~(-1))和利培酮(1 mg·kg~(-1)),qd,连续给药4周。以免疫组织化学方法检测NRG1与ErbB4在海马CA1,CA3和齿状回区的表达。结果:与对照组比较,慢性给予氟哌啶醇、氯氮平或利培酮均显著上调了海马CA3区NRG1与ErbB4的表达。氯氮平还上调了齿状回区NRG1的表达。结论:抗精神病药慢性给药增加大鼠海马NRG1与ErbB4的表达,这种改变可能与抗精神病药治疗效应有关。     

Role of the SLCO1B1 haplotypes on the rifampicin-induced CYP3A activity

Rifampin, a member of the rifamycin class of antibiotics, is well known for its ability to activate the pregnant X receptor and induce drug-metabolizing enzymes and transporters. Available data suggest rifampin entry into hepatocytes is mediated by OATP1B1. Accordingly, it is therefore plausible that modulation of the intracellular concentration of rifampin by OATP1B1 genetic polymorphisms would influence the degree of CYP3A induction. AIM： To study the association between haplotypes of the SLCO1B1 and the rifampicin-mediated inducible CYP3A4 activity. A single-point determination of midazolam plasma concentration method was developed to assess the constitutive and inducible CYP3A4 activity. A pharmacokinetic study of a single dose of 450 mg rifampicin was conducted to evaluate the mechanism of rifampicin-midazolam interaction in different SLCO1B1 genotypic subjects.METHODS： Twenty-three healthy volunteers with different SLCO1B1 haplotypes （7 for SLCO1B1 ＊ 1a/＊ 1a, 7 for SLCO1B1 ＊ 1b/＊ 1b, 7 for SLCO1B1 ＊ 1b / ＊ 15 and 2 for SLCO1B1 ＊ 15/＊ 15） were enrolled in this study. Each was given a single oral dose of 7.5 nag naidazolam on day 0 and day 6. Rifampicin of 450 nag was given from day 1 to day 5. Plasma concentrations of midazolam were measured for up to 8 hours by LC-MS, and its pharmacokinetic parameters were analyzed. Plasma concentrations of a single oral dose of 450 nag rifampicin were measured for up to 12 hours.[第一段]     

阿奇霉素4"-取代亚苄肼基甲酸酯衍生物的合成和抗菌活性

以阿奇霉素11,12-环硼酸酯为原料,设计并合成了18个阿奇霉素4'-取代亚苄肼基甲酸酯及4'-取代亚苄肼基甲酸酯-11,12-环碳酸酯衍生物。体外抗菌活性试验结果表明,所得化合物对受试革兰阳性菌如金黄色葡萄球菌、表皮葡萄球菌、白色葡萄球菌和肺炎双球菌抗菌活性良好,部分化合物对丙型链球菌、革兰阴性菌如鲍氏志贺氏菌和普通变形杆菌也有较强的抗菌活性。     

Modeling of human dermal absorption of octamethylcyclotetrasiloxane (D(4)) and decamethylcyclopentasiloxane (D(5)).

In this study, data for human dermal absorption of octamethylcyclotetrasiloxane, D(4), and decamethylcyclopentasiloxane, D(5), through axilla skin in vivo are interpreted using pharmacokinetic models of dermal absorption by adding the dermal exposure route to inhalation physiologically based pharmacokinetics models developed previously. The compartmental model describing dermal absorption of these compounds included volatilization of the applied chemical from the skin surface, diffusion of absorbed chemical back to the skin surface and evaporation of this chemical from the skin surface after the applied dose had cleared from the application site, uptake from the skin compartment into blood, and a storage compartment within the skin. Data from exposures in volunteers (i.e., D(4) and D(5) concentrations in exhaled air and plasma) were used to estimate model parameters. In volunteers exposed to either D(4) or D(5), the maximum concentration of chemical in exhaled air reached a maximum at or prior to 1 h following administration of the test chemical. Based on model calculations, the percent of applied dose of D(4) that was absorbed into systemic circulation for men and women was 0.12 and 0.30%, respectively; for D(5) about 0.05% of the applied dose was absorbed for both men and women. For both D(4) and D(5), model calculations indicate that more than 83% of the chemical that reached systemic circulation was eliminated by exhalation within 24 h. These whole-body pharmacokinetic models for dermal absorption of two semi-volatile compounds provide a valuable tool for understanding factors controlling their dermal absorption through axilla skin and for applying results from these studies in consumer product risk assessments.     

Protective effects of Passiflora alata extract pretreatment on carbon tetrachloride induced oxidative damage in rats.

The leaf extract of Passiflora alata Dryander (P. alata) has been demonstrated to possess antioxidant activity in vitro. The aim of this study was to investigate the effects of P. alata leaf extract pretreatment on carbon tetrachloride-treated rats. Male Wistar rats were randomly allocated into four groups: group 1 (control - vehicle), group 2 and 3 (P. alata extract - 1 and 5mg/kg, respectively) and group 4 (trolox - 0.18mg/kg). Rats received daily pretreatment by oral gavage for 30 days followed by a single dose of CCl(4) (3ml/kg i.p. in vegetable oil) on the 30th day and were killed after 6h. The pretreatment with the P. alata extract provided significant protection to liver, evidenced by lower degree of necrosis, decreased lipid peroxidation (TBARS) and higher catalase and superoxide dismutase activities. Additionally, pretreated-rats with P. alata (5mg/kg) showed significantly decreased cardiac TBARS levels. Our results indicate that a low oral dose of P. alata leaf extract has both hepato and cardioprotective effects on rats treated with CCl(4).     

大黄橐吾的化学成分

大黄橐吾(Ligularia duciformis)为菊科橐吾属植物，据报道有治疗支气管炎、咳嗽等功效。为寻找其生物活性成分，对其根和根茎的85%乙醇提取物进行了溶剂萃取和硅胶、Sephadex LH-20柱色谱分离。从乙酸乙酯部位得到6个化合物，经理化性质和波谱数据分析，鉴定为咖啡酸-(3-甲氧基-4-羟基)苯丙酯(I)，6β,8β-双羟基雅槛蓝-7(11)-烯-12,8α-内酯(II)，6β,8α-双羟基雅槛蓝-7(11)-烯-12,8β-内酯(III)，6β-羟基雅槛蓝-7(11)-烯-12,8α内酯(IV)，豆甾醇(V)，胡萝卜苷(VI)。化合物I为新化合物，化合物II～V为首次从该植物中分得。化合物的止咳作用正在评价中。     

Type 1 protein tyrosine kinases in breast carcinoma: a review

One of the most studied onco-gene families in breast tumors is the type 1 protein tyrosine kinase family, which consists of EGFR, c-erbB-2, c-erbB-3, and c-erbB-4. Overexpression of c-erbB-2 protein/mRNA in breast carcinomas is consistently associated with poor prognosis, while EGFR overexpression has been confirmed to have a synergistic clinical effect on the c-erbB-2 influence. The expression pattern of c-erbB-4 in breast carcinomas is special. Unlike other type 1 protein tyrosine kinases, expression of c-erbB-4 protein/mRNA is reduced in carcinomas compared with that in normal breast epithelia, and its expression has also been associated with a better clinical outcome, indicating the need for c-erbB-4 analysis when clinical therapeutic application of EGFR and c-erbB-2 anitbodies is considered. In addition, studies of the adaptor proteins in breast carcinomas are highly indicated in order to clarify the mechanisms behind the dysregulated expression of such receptors in breast carcinomas.     

Involvement of Ras/extracellular signal-regulated kinase, but not Akt pathway in risedronate-induced apoptosis of U937 cells and its suppression by cytochalasin B

Although risedronate, a nitrogen containing bisphosphonate (BPs), strongly inhibits bone resorption by enhanced apoptosis of osteoclasts, its mechanism remained unclear. In this study, we investigated the molecular mechanism of risedronate-induced apoptosis of U937 cells, with a focus on extracellular signal-regulated kinase 1/2 (ERK 1/2) and protein kinase B (Akt) pathways, mitochondria-mediated apoptosis, and the effect of disruption of the actin cytoskeleton. Risedronate facilitated the relocation of Ras from membrane to cytosol through inhibited isoprenylation. Accordingly, risedronate suppressed the phosphorylation of ERK 1/2, a downstream survival signaling kinase of Ras, affected the intracellular distribution of Bcl-xL, and induced the mitochondrial membrane depolarization, cytochrome c release, activated caspase cascade and DNA fragmentation. The risedronate-induced apoptosis was effectively suppressed with cyclosporine A plus trifluoperazine, potent inhibitors of mitochondrial membrane permeability transition (MPT). The risedronate-induced apoptosis was independent of Akt, another cAMP-dependent survival signaling kinase. Risedronate facilitated dephosphorylation of Bad at Ser112, an ERK phosphorylation site, but not at Ser136, an Akt phosphorylation site. All of these apoptosis-related changes induced by risedronate were strongly suppressed by cytochalasin B, an inhibitor of actin filament polymerization. These results indicate that risedronate-induced apoptosis in U937 cells involves Ras/ERK, but not Akt signaling pathway, and is dependent on MPT, and that disruption of the actin cytoskeleton inhibits the risedronate-induced apoptosis at its early step.     

4-Aza-2,3-didehydropodophyllotoxins: new lignan with antitumor activity obtained from one-step synthesis

Podophyllotoxin, a natural lignan, is a good inhibitor of tubulin polymerization with antitumoral properties but it is too toxic for therapeutic use. In order to obtain less toxic drugs, several heterolignans have been prepared. We presented the synthesis and preliminary pharmacological properties of 4-aza-2,3-didehydropodophyllotoxins (dihydropyrrole [3,4-b]quinolin-1-ones), a new azalignan series. A straightforward synthesis was described according to a multicomponent reaction in a one-pot procedure. Starting from an aniline, an aromatic aldehyde, and a cyclic B-diketone, many substituted analogues could be prepared. Our lead, the 4-aza-2,3-didehydropodophyllotoxin, is extremely cytotoxic on various tumor cell lines, active in vivo on murine tumors. Like podophyllotoxin, this drug inhibits microtubule assembly without any effect on depolymerization.