Design,synthesis and biological evaluation of novel 2,3-indolinedione derivatives against mantle cell lymphoma

2,3-Indolinedione derivatives have been identified as a novel class of promising agents for cancer treatment. In this study, eighteen 2,3-indolinedione derivatives were designed and synthesized, and their anticancer activities against mantle cell lymphoma (MCL) cells were evaluated. Most of them exhibited significant antiproliferative activity against the tested cell lines, and compound K5 was the most potent (MCL cellular IC₅₀ = 0.4–0.7 μM). Further, compound K5 could induce cell apoptosis and cell cycle arrest in G2/M phase. Additionally, the results of drug-likeness analysis demonstrated that these novel 2,3-indolinedione derivatives could have potential as novel treatment strategies for MCL.     

Ki-67 as a prognostic marker in mantle cell lymphoma��consensus guidelines of the pathology panel of the European MCL Network

Mantle cell lymphoma (MCL) has a heterogeneous clinical course and is mainly an aggressive B cell non-Hodgkin lymphoma; however, there are some indolent cases The Ki-67 index, defined by the percentage of Ki-67-positive lymphoma cells on histopathological slides, has been shown to be a very powerful prognostic biomarker. The pathology panel of the European MCL Network evaluated methods to assess the Ki-67 index including stringent counting, digital image analysis, and estimation by eyeballing. Counting of 2 × 500 lymphoma cells is the gold standard to assess the Ki-67 index since this value has been shown to predict survival in prospective randomized trials of the European MCL Network. Estimation by eyeballing and digital image analysis showed a poor concordance with the gold standard (concordance correlation coefficients [CCC] between 0.29 and 0.61 for eyeballing and CCC of 0.24 and 0.37 for two methods of digital image analysis, respectively). Counting a reduced number of lymphoma cells (2 × 100 cells) showed high interobserver agreement (CCC = 0.74). Pitfalls of the Ki-67 index are discussed and guidelines and recommendations for assessing the Ki-67 index in MCL are given.     

Discovery of pyrazolopyrimidine derivatives as potent BTK inhibitors with effective anticancer activity in MCL

Bruton’s tyrosine kinase (BTK) is a key regulator of B-cell receptor (BCR) signaling pathway and takes effect in the regulation of B-cell activation, survival, proliferation and differentiation. It has been proved that BTK is commonly overexpressed in mantle cell lymphoma (MCL), which makes it a focus of targeted therapy for MCL. Our studies yielded a novel series of pyrazolopyrimidine derivatives capable of potent inhibition of BTK. Notably, 12a showed higher selectivity against BTK and exhibited robust antiproliferative effects in both mantle cell lymphoma cell lines and primary patient tumor cells. Low micromolar doses of 12a induced strong cell apoptosis in Jeko-1 and Z138 cells.     

Immune checkpoint blockade and its combination therapy with small-molecule inhibitors for cancer treatment

Initially understood for its physiological maintenance of self-tolerance, the immune checkpoint molecule has recently been recognized as a promising anti-cancer target. There has been considerable interest in the biology and the action mechanism of the immune checkpoint therapy, and their incorporation with other therapeutic regimens. Recently the small-molecule inhibitor (SMI) has been identified as an attractive combination partner for immune checkpoint inhibitors (ICIs) and is becoming a novel direction for the field of combination drug design. In this review, we provide a systematic discussion of the biology and function of major immune checkpoint molecules, and their interactions with corresponding targeting agents. With both preclinical studies and clinical trials, we especially highlight the ICI + SMI combination, with its recent advances as well as its application challenges.     

皱纹盘鲍外套膜、鳃和足粘液细胞的类型与分布

以阿新兰和过碘酸雪夫氏反应(AB．PAS)染色法显微观察皱纹盘鲍(1taliotis discus hannai)的外套膜、鳃和足的粘液细胞。根据所显示颜色的不同,可将粘液细胞分为Ⅰ～Ⅳ4种类型：分别呈红色、蓝色、紫红色和蓝紫色。外套触手和外套膜上皮的粘液细胞以Ⅱ型为主,Ⅳ型较少,密度不均,多为近圆形细胞,大型和小型细胞均有分布。鳃轴和鳃叶上皮的粘液细胞密度较大,以Ⅱ型和Ⅰ型为主,Ⅲ型和Ⅳ型较少,形态有杯形、近圆形或棒状等,多为中型及小型细胞。足的上皮粘液细胞较少,均为Ⅱ型,但局部上皮的细胞含有许多棕色颗粒。     

短蛸外套膜和足粘液细胞的类型及分布

采用阿新兰与过碘酸雪夫氏反应(AB-PAS)染色法对短蛸(Octopusocellatus)外套膜和足各部位粘液细胞进行分类及分析。将粘液细胞分为Ⅰ~Ⅳ4种类型:分别呈红色、蓝色、紫红色和蓝紫色。胴体部背面和腹面的外套膜外表皮均有4种粘液细胞,以Ⅲ型和Ⅳ型粘液细胞为主,背面粘液细胞密度较小,腹面的密度较大。腕上皮皱褶处粘液细胞密度较大,其他大部分区域粘液细胞密度较小,以Ⅱ型为主,另有少量Ⅲ型和Ⅳ型粘液细胞;吸盘外上皮含有大量的粘液细胞,也以Ⅱ型为主。漏斗内外上皮粘液细胞密度较大,基部以Ⅱ型为主,其他部位则以Ⅲ型为主。通过对各部位粘液细胞的分类和比较,可以看出粘液细胞的分布和类型与其所在部位执行的功能有密切的联系。     

Direct innervation of the mantle edge gland by neurosecretory axons in Helisoma duryi (Mollusca: Pulmonata)

Summary The mantle edge gland of Helisoma duryi is innervated by neurosecretory axons from the pallial nerves. Synaptoid contacts occur between axons and gland cells, and there is ultrastructural evidence for the release of neurosecretory material. The mantle edge gland contributes to the deposition of periostracum during shell formation, and direct neurosecretory innervation may control shell growth and regeneration.Supported by a National Research Council of Canada Grant (A-4673) and Negotiated Grant D-61     

紫贻贝长期暴露于亚致死剂量的林丹和阿特拉津下的组织学反应

为开发快速、敏感的生物标记物以监测海洋贝类生物中是否存在农药,我们检测了双壳动物紫贻贝长期暴露在亚致死剂量的丙体六氯环乙烷(林丹,γ-HCH)和2-氯4-乙胺基-6异丙胺基-1,3,5-三氮苯(阿特拉津)下的组织学变化。紫贻贝容易积累环境中的杀虫剂,因此,本研究旨在阐明农药的生物积累与组织病理学效应之间的关系。利用GC/MSD分析法定期对贻贝和水样中的林丹与阿特拉津含量进行测定。将贻贝在实验室中培养21天,以使其代谢适应于带有水质控制的封闭式不间断流动系统。随后,30只贝暴露于亚致死剂量的林丹(0.9 mg/L)或阿特拉津(3.583 mg/L)溶液中56天。实验期间,控制重要的参数,比如温度和盐度分别控制在18℃和34‰。在处理28天和56天后取样,检测组织学损坏及吸收的农药量。暴露的紫贻贝每克干重分别能聚集约304.8-372.0μg/g林丹和83.3-137.4μg/g阿特拉津。组织学改变高度集中在鳃的上皮和外套膜组织;上皮与相邻的组织形成分离状态。组织病理学结果显示,抗性机制的激活使紫贻贝能在亚致死压力下存活。组织病理效应范围从浸润反应到以血淋巴细胞出现间质细胞反应为特征。因此,在农药聚集部位的组织学和超微结构的改变是敏感的,并与农药的生物积累具有正相关关系,说明这些改变可能作为农药暴露的生物标记物。     

TEM immunocytochemistry of a 48 kDa MW organic matrix phosphoprotein produced in the mantle epithelial cells of the Eastern oyster (Crassostrea virginica)

Immunohistochemical TEM of Eastern oyster (Crassostrea virginica) mantle epithelial cells using a polyclonal antibody to a gel purified 48 kDa MW oyster shell phosphoprotein revealed that it is phosphorylated in the Golgi, packaged into secretory vesicles and subsequently exocytosed across the apical membrane of specialized cells. These phosphoprotein producing cells are concentrated along the mantle side facing the shell, in the region of the outer mantle lobe. A layer of calcium enriched immuno-reactive mucous is associated with the apical microvilli of these cells. The 48 kDa phosphoprotein forms a component of the fibrous organic matrix and appears to be involved in calcium supply thus enabling crystal growth at the mineralization front.