Metabolic changes in rats after intragastric administration of MGCD0103 (Mocetinostat), a HDAC class I inhibitor

MGCD0103, an isotype-selective HDACi, has been clinically evaluated for the treatment of hematologic malignancies and advanced solid tumors, alone and in combination with standard-of-care agents. In this study, we developed a serum metabolomic method based on gas chromatography-mass spectrometry (GC-MS) to evaluate the effect of intragastric administration of MGCD0103 on rats. The MGCD0103 group rats were given 20, 40, 80 mg/kg of MGCD0103 by intragastric administration each day for 7 days. Pattern recognition analysis, including both principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) revealed that intragastric administration of MGCD0103 induced metabolic perturbations. As compared to the control group, the levels of L-alanine, L-isoleucine, and L-leucine of MGCD0103 group decreased. The results indicate that metabolomic methods based on GC-MS may be useful to elucidate side effect of MGCD0103 through the exploration of biomarkers (L-alanine, L-isoleucine, and L-leucine). According to the pathological changes of liver at difference dosage, MGCD0103 is hepatotoxic and its toxity is dose-dependent.     

Immunolocalization of membrane-type 1 MMP in human rheumatoid synovium tissues

Membrane-type 1 matrix metalloproteinase (MT1-MMP, also known as MMP14), the best characterized membrane-anchored MMP, is an important matrix-degrading proteinase that could digest a broad spectrum of extracellular matrix proteins and accelerate angiogenesis. We have previously reported that some MMPs involved in the angiogenesis and the pannus formation within the joint, leading to the erosion of articular cartilage and bone in the pathological process of rheumatoid arthritis (RA). In the present study, we used immunohistochemistry assay and con-focal scanning technique to study the detailed immunolocalization of MT1-MMP in human RA synovium tissues as well as the infiltrating immune cell subsets. Our results showed that the positive MT1-MMP immunostaining could be found in synoviocytes, vascular endothelial cells, infiltrating macrophages and monocytes in RA synovium tissues, while weak or negative immunostaining could be found in infiltrating T cells, B cells and NK cells, respectively. Moreover, the Ki-67⁺ highly proliferating synoviocytes also showed higher MT1-MMP expression in RA synoviocytes. Thus, the aberrant expression of MT1-MMP in RA synoviocytes as well as infiltrating immune cells may contribute to the proliferation of the synoviocytes, and the angiogenesis and the pannus formation in RA pathological progression.     

~(99)Tc~m-MIBI显像在非霍奇金淋巴瘤化疗疗效评价中的价值

目的探讨99Tcm-MIBI显像在非霍奇金淋巴瘤疗效评价及提示预后方面的临床价值。方法对20例非霍奇金淋巴瘤病人于化疗前后分别行99Tcm-MIBI早期(10 min)与延迟(120 min)双时相显像,计算每例病人早期摄取率(EUR)、延迟期摄取率(DUR)及洗脱率(WR%)并进行比较。对99Tcm-MIBI显像结果进行疗效评价。平均随访时间34个月。结果 8例病人化疗后99Tcm-MIBI显像阴性,达完全缓解(CR)。12例病人化疗后99Tcm-MIBI显像阳性,其中4例达部分缓解(PR),2例处于稳定(SD)状态,6例进展(PD)。将病人分为化疗有效组(CR+PR)12例,疗效不佳组(SD+PD)8例。20例病人化疗后DUR明显低于化疗前(1.2±0.7∶2.9±1.2,P0.05)。化疗有效组与疗效不佳组相比,前者化疗前的DUR值高于后者(2.9±1.2∶1.5±0.9,P0.05),WR%低于后者(21.9±2.4∶42.7±5.6,P0.05),而前者化疗后的DUR值低于后者(1.0±0.2∶2.0±0.3,P0.05)。结论 99Tcm-MIBI作为一种功能性显像,有助于预测、评价非霍奇金淋巴瘤病人的疗效及预后。     

Current states of endogenous stem cells in adult spinal cord

New neurons are continuously generated throughout life in the subgranular zone in the dentate gyrus of the mammalian hippocampus and in the subventricular zone of the lateral ventricles. With the aid of new methodologies, significant progress has been made in the characterization of endogenous stem cells (ependymal cells) and their development in the adult spinal cord. Recent studies have shed light on essential extrinsic and intrinsic molecular mechanisms that govern sequential steps of neurogenesis in the adult spinal cord. This review discusses the occurrence, origin, and specific makers of ependymal cells; the factors regulating neurogenesis of multipotent ependymal cells; and the implications of ependymal cells in the repair of spinal cord injuries. © 2014 Wiley Periodicals, Inc.     

Posterior compensatory network in cognitively intact elders with hippocampal atrophy

Functional compensation in late life is poorly understood but may be vital to understanding long‐term cognitive trajectories. To study this we first established an empirically derived threshold to distinguish hippocampal atrophy in those with Mild Cognitive Impairment (MCI n = 34) from those with proficient cognition (PRO n = 22), using data from a population‐based cohort. Next, to identify compensatory networks we compared cortical activity patterns during a graded spatial working memory (SWM) task in only cognitively proficient individuals, either with (PRO_ATR) or without hippocampal atrophy (PRO_NIL). Multivariate Partial Least Squares analyses revealed that these groups engaged spatially distinct SWM‐related networks. In those with hippocampal atrophy and under conditions of basic‐SWM demand, expression of a posterior compensatory network (PCN) comprised calcarine and posterior parietal cortex strongly correlated with superior SWM performance (r = −0.96). In these individuals, basic level SWM response times were faster and no less accurate than in those with no hippocampal atrophy. Cognitively proficient older individuals with hippocampal atrophy may, therefore, uniquely engage posterior brain areas when performing simple spatial working memory tasks. © 2014 Wiley Periodicals, Inc.     

迷走神经递质P物质对人类肝癌细胞侵袭转移能力的影响及其分子机制

目的探讨迷走神经递质P物质对肝癌细胞侵袭转移能力的影响及其相关分子机制。方法实时荧光定量PCR及琼脂糖凝胶电泳检测并分析两种人肝癌细胞株Hep G2和SMMC-7721中神经肽-1(NK-1)受体表达;Cell Titer Blue检测不同浓度P物质(0、100、250、500 nmol/L)在不同时间点(0、24、48、72、96、120 h)对肝癌细胞增殖能力的影响;肝癌细胞均经不同浓度的(0 nmol/L,对照组;100 nmol/L,实验组)P物质处理48 h,Transwell实验检测细胞迁移和侵袭功能,Western blot检测细胞中上皮-间质转化蛋白质标志表达变化,实时荧光定量PCR及Western blot检测NK-1受体表达变化。结果 Hep G2和SMMC-7721两种人肝癌细胞中均有NK-1受体表达;不同浓度P物质(0、100、250、500 nmol/L)在96 h内不影响两种细胞的增殖能力(P>0.05),而在120 h 250 nmol/L和500 nmol/L P物质可抑制两种细胞增殖(P<0.05);100 nmol/L P物质明显促进两种细胞迁移和侵袭能力(P<0.05);与对照组相比,实验组细胞NK-1受体表达明显上调(P<0.05),同时,细胞中上皮-间质转化蛋白质标志E-Cadherin表达下调,N-Cadherin和Slug表达上调(P<0.05)。结论迷走神经递质P物质与人肝癌细胞中表达的NK-1受体相互作用并使其表达上调,促进细胞发生上皮-间质转化,进而提高其侵袭转移能力。