Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling

Balanced expression of proteases and their inhibitors is one prerequisite of tissue homeostasis. Metastatic spread of tumor cells through the organism depends on proteolytic activity and is the death determinant for cancer patients. Paradoxically, increased expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural inhibitor of several endometalloproteinases, including matrix metalloproteinases and a disintegrin and metalloproteinase-10 (ADAM-10), in cancer patients is negatively correlated with their survival, although TIMP-1 itself inhibits invasion of some tumor cells. Here, we show that elevated stromal expression of TIMP-1 promotes liver metastasis in two independent tumor models by inducing the hepatocyte growth factor (HGF) signaling pathway and expression of several metastasis-associated genes, including HGF and HGF-activating proteases, in the liver. We also found in an in vitro assay that suppression of ADAM-10 is in principle able to prevent shedding of cMet, which may be one explanation for the increase of cell-associated HGF receptor cMet in livers with elevated TIMP-1. Similar TIMP-1-associated changes in gene expression were detected in livers of patients with metastatic colorectal cancer. The newly identified role of TIMP-1 to create a prometastatic niche may also explain the TIMP-1 paradoxon.     

家兔动脉成形术后血管内膜增殖与普伐他汀联合阿司匹林的干预效应

目的:观察普伐他汀、阿司匹林联用对家兔颈动脉血管成形术后内膜增殖进展的影响及其作用机制。方法:实验于2002-03/12在北京中医药大学教育部中医内科学重点学科实验室完成。雄性日本大耳白兔30只,体质量1.8～2.0kg,动物适应性喂养1周后随机数字表法分为正常对照组(n=9)、假手术组(n=6)、模型组(n=9)、治疗组(n=6)。模型组和治疗组动物氯胺酮、速眠新混合肌注麻醉,沿气管正中切开皮肤,剥离颈总动脉,给予电刺激。术后第2天开始饲喂高脂饲料(胆固醇:0.7%,猪油:3%,普通饲料96.3%);正常对照组无任何干预措施;假手术组仅剥离颈总动脉,不做电刺激,喂高脂饲料;动物连续喂养8周后超声评价颈总动脉,根据B超选择颈总动脉有斑块或血流明显改变者作颈总动脉球囊扩张术。正常对照组、模型组、假手术组喂普通饲料,治疗组喂普伐他汀与阿司匹林含药饲料(普伐他汀5.046mg/kg,阿司匹林2.268g/kg),4周后测血脂和C-反应蛋白浓度、血清一氧化氮及转化生长因子β水平,观察颈动脉组织病理形态学改变,半定量分析增生内膜中胶原含量的变化,免疫组织化学方法分析增生内膜中巨噬细胞和平滑肌细胞阳性百分率。结果:纳入大耳白兔30只,正常对照组中途死亡1只,死因为牙齿畸型影响进食;模型组1只因电刺激8周时超声评价颈动脉未形成斑块及血流无明显改变而剔出实验,进入分析28只。与模型组比,普伐他汀与阿司匹林联用4周后,治疗组胆固醇及三酰甘油水平明显下降[(4.12±2.30),(0.74±0.17)mmol/L;(0.47±0.27),(0.39±0.14)mmol/L;P<0.05],血清C-反应蛋白水平和转化生长因子β水平均降低[(0.86±0.27),(0.57±0.30)mg/L;(3.45±0.77),(3.23±0.34)ng/L;P<0.05],一氧化氮水平升高[(41.79±35.78),(90.14±32.54)mmol/L;P<0.05],动脉内膜增殖程度明显减轻,管腔狭窄率降低,内中膜厚度及内中膜面积比降低[(71.91±14.90)%,(47.20±18.74)%;(0.41±0.17),(0.26±0.04)mm;1.66±0.63,0.78±0.34;P均<0.05],动脉内膜胶原含量减少(30.92±10.05,21.93±5.81,P<0.01),动脉内膜巨噬细胞阳性百分率降低[(13.94±4.91)%,(7.29±7.28)%,P<0.05],平滑肌细胞含量无明显差异(38.37±5.67,35.79±10.68,P>0.05)。结论:普伐他汀与阿司匹林联用具有抑制内膜增生和减少新生内膜胶原含量的作用,其机制与两药抑制炎症反应、保护内皮功能及抑制细胞外基质生成等有关。     

巢式逆转录-聚合酶链反应扩增人骨形成蛋白2全长cDNA及其真核表达载体的构建

目的:利用巢式逆转录-聚合酶链反应扩增的方法,从肌肉组织中扩增人骨形成蛋白2全长cDNA并构建真核表达载体系统。方法:实验于2003-10/2005-10在苏州大学基因工程教研室和北京大学第三医院骨科实验室完成。提取成人肌肉组织内的总RNA,设计内外两对引物以巢式逆转录-聚合酶链反应扩增方法分两次扩增出人骨形成蛋白2全长1188bp基因,经T-A克隆装入pUCM-T质粒载体内,测序验证后,将克隆质粒以Hind Ⅲ和Xba Ⅰ双酶切后与pcDNA3.0载体相连接,构建真核表达载体系统。结果:利用巢式逆转录-聚合酶链反应扩增方法能从成人肌肉组织内扩增出1188bp的人骨形成蛋白2全长cDNA基因,其测序结果显示与Genebank报道序列完全相符。将扩增序列双酶切后与pcDNA3.0载体相连接,经电泳验证,能构建人骨形成蛋白2全长基因的真核表达系统。结论:巢式逆转录-聚合酶链反应扩增方法能从成人肌肉组织内扩增出人骨形成蛋白2全长cDNA基因,并克隆构建真核表达载体系统,为下一步基因组织工程人工骨实验奠定基础。     

抗癌药物的研究:4-氯苯氧乙酰胺衍生物的合成

Since compounds Ⅲ and Ⅳ possess retinoid-like action and analogues of Ⅰ inhibit some cancer cells ,seventeen derivatives of chlorophenoxy acetamide were synthesized.Of the seven compounds screened ,two exhibit cytostatic activity(1 and　2).Mass spectra showeda　special expulsion of SO2 and CO from the sulfonamide compounds,Nuclear magnetic resonancesplitting patterns of these compounds also showed interesting features.     

Beyond “patient-provider race matching.” Black midwives clarify a vision for race-concordant care to achieve equity in Black perinatal health: A commentary on “Do Black birthing persons prefer a Black health care provider during birth? Race concordance in birth”

Racial concordance has been identified as a potential strategy to improve the perinatal health of Black women and birthing people by mitigating implicit bias and improving mutual trust, healthy communication, and satisfaction. In a recent article published in BIRTH: Issues in Perinatal Care, Bogdan-Lovis et al. surveyed 200 Black women to determine whether they possessed a race and gender practitioner preference for their birth practitioner and examined whether race and gender concordance was associated with greater birth satisfaction and perceived respect, trust, practitioner competence, empathy, and use of inclusive communication. In this commentary, written by a group of Black midwives, we respond to the study and offer a vision for race-concordant care that encompasses cultural safety provided in a community-based setting.