Synthesis of novel steroidal agonists,partial agonists,and antagonists for the glucocorticoid receptor

Adverse effects of glucocorticoids could be limited by developing new compounds that selectively modulate anti-inflammatory activity of the glucocorticoid receptor (GR). We have synthesized a novel series of steroidal GR ligands, including potent agonists, partial agonists and antagonists with a wide range of effects on inhibiting secretion of interleukin-6. Some of these new ligands were designed to directly impact conformational stability of helix-12, in the GR ligand-binding domain (LBD). These compounds modulated GR activity and glucocorticoid-induced gene expression in a manner that was inversely correlated to the degree of inflammatory response. In contrast, compounds designed to directly modulate LBD epitopes outside helix-12, led to dissociated levels of GR-mediated gene expression and inflammatory response. Therefore, these new series of compounds and their derivatives will be useful to dissect the ligand-dependent features of GR signaling specificity.     

Purging putative siblings from population genetic data sets: a cautionary view

Interest has surged recently in removing siblings from population genetic data sets before conducting downstream analyses. However, even if the pedigree is inferred correctly, this has the potential to do more harm than good. We used computer simulations and empirical samples of coho salmon to evaluate strategies for adjusting samples to account for family structure. We compared performance in full samples and sibling‐reduced samples of estimators of allele frequency (), population differentiation () and effective population size (). Results: (i) unless simulated samples included large family groups together with a component of unrelated individuals, removing siblings generally reduced precision of and ; (ii) based on the linkage disequilibrium method was largely unbiased using full random samples but became increasingly upwardly biased under aggressive purging of siblings. Under nonrandom sampling (some families over‐represented), using full samples was downwardly biased; removing just the right ‘Goldilocks’ fraction of siblings could produce an unbiased estimate, but this sweet spot varied widely among scenarios; (iii) weighting individuals based on the inferred pedigree (to produce a best linear unbiased estimator, BLUE) maximized precision of when the inferred pedigree was correct but performed poorly when the pedigree was wrong; (iv) a variant of sibling removal that leaves intact small sibling groups appears to be more robust to errors in inferences about family structure. Our results illustrate the complex challenges posed by presence of family structure, suggest that no single optimal solution exists and argue for caution in adjusting population genetic data sets for the presence of putative siblings without fully understanding the consequences.     

Establishment and characterization of a cell line from the head kidney of golden pompano Trachinotus ovatus and its application in toxicology and virus susceptibility

A cell line derived from the head kidney of golden pompano Trachinotus ovatus (TOHK) was established and characterized in this study. The TOHK cells grew most rapidly at 28° C and the optimum foetal bovine serum concentration in L‐15 medium was 10%. The TOHK cells have a diploid chromosome number of 2N = 54. The transfection efficiency of TOHK cells was 7·5% at the 15th passage and 72% at the 40th passage. The transfection efficiency in TOHK cells was high, so these cells are suitable for foreign gene expression. The cytotoxic effects of heavy metals and extracellular products from Vibrio anguillarum and Vibrio alginolyticus were demonstrated in TOHK cells, so this TOHK cell line could also be applied in environmental monitoring of heavy metals and pathogenic bacteria. TOHK cell line showed high virus susceptibility, such as grouper nervous necrosis virus (GNNV) and Singapore grouper iridovirus (SGIV). Then, TOHK cell line could be used for the study of viral pathogenesis and the development of antiviral strategies.     

TNF‐α has both stimulatory and inhibitory effects on mouse monocyte‐derived osteoclastogenesis

Phenotypically different osteoclasts may be generated from different subsets of precursors. To what extent the formation of these osteoclasts is influenced or mediated by the inflammatory cytokine TNF‐α, is unknown and was investigated in this study. The osteoclast precursors early blasts (CD31^hiLy‐6C^?), myeloid blasts (CD31⁺Ly‐6C⁺), and monocytes (CD31^?Ly‐6C^hi) were sorted from mouse bone marrow using flow cytometry and cultured with M‐CSF and RANKL, with or without TNF‐α. Surprisingly, TNF‐α prevented the differentiation of TRAcP⁺ osteoclasts generated from monocytes on plastic; an effect not seen with early blasts and myeloid blasts. This inhibitory effect could not be prevented by other cytokines such as IL‐1β or IL‐6. When monocytes were pre‐cultured with M‐CSF and RANKL followed by exposure to TNF‐α, a stimulatory effect was found. TNF‐α also stimulated monocytes’ osteoclastogenesis when the cells were seeded on bone. Gene expression analysis showed that when TNF‐α was added to monocytes cultured on plastic, RANK, NFATc1, and TRAcP were significantly down‐regulated while TNF‐αR1 and TNF‐αR2 were up‐regulated. FACS analysis showed a decreased uptake of fluorescently labeled RANKL in monocyte cultures in the presence of TNF‐α, indicating an altered ratio of bound‐RANK/unbound‐RANK. Our findings suggest a diverse role of TNF‐α on monocytes’ osteoclastogenesis: it affects the RANK‐signaling pathway therefore inhibits osteoclastogenesis when added at the onset of monocyte culturing. This can be prevented when monocytes were pre‐cultured with M‐CSF and RANKL, which ensures the binding of RANKL to RANK. This could be a mechanism to prevent unfavorable monocyte‐derived osteoclast formation away from the bone.

     

MDSCs在恶性肿瘤中的生物学作用及其研究进展

髓源抑制性细胞(myeloid-derived suppressor cells,MDSCs)是一群以骨髓祖细胞和未分化成熟的粒细胞、树突状细胞、巨噬细胞为代表的异质髓细胞,表达的抗原标志多样且不同于成熟髓细胞。当机体处于癌症、炎症、感染等状态时,MDSCs首先从骨髓被募集到外周并在外周被活化,一系列肿瘤来源的慢性炎症相关的因子是介导MDSCs的募集和活化的关键。MDSCs有多种方法抑制机体的获得性和天然抗肿瘤免疫,来帮助肿瘤细胞逃避机体的免疫监视和攻击,促进肿瘤发展。近年来,越来越多的研究者开始关注MDSCs与恶性肿瘤的相关性而且靶向MDSCs的肿瘤免疫治疗也见于报道。本文旨在对MDSCs在恶性肿瘤中的生物学作用及研究进展作一简要综述。     

卵巢囊性颗粒细胞瘤的临床病理学特征、诊断及鉴别诊断

目的:探讨卵巢囊性颗粒细胞瘤的临床病理学特征、诊断和鉴别诊断要点。方法:复习1例卵巢囊性颗粒细胞瘤患者的临床资料、肿物的大体以及镜下病理组织学特征、免疫组化染色特征。结果:患者左侧单房囊性颗粒细胞瘤,大小为14.6 cm×18.9 cm×9.8 cm,囊壁厚薄不均一;镜下可见内壁由颗粒细胞组成,细胞层数不一,可见典型的Call-Exner小体;免疫组化染色可见α-inhibin,Vimentin,CD99均阳性。结论:卵巢囊性颗粒细胞瘤可依据镜下发现不典型增生的颗粒细胞、典型的Call-Exner小体和核沟等特征性的组织形态学作出诊断。     

超声弹性成像与超声造影对肝肿瘤的诊断效果对比

目的:分析超声弹性成像与超声造影对肝肿瘤的诊断效果。方法:收集我院2015年3月至2016年3月收治的肝肿瘤患者76例,术前均行超声弹性成像和超声造影检查,比较超声弹性成像和超声造影与病理诊断(黄金标准)的结果。结果:超声弹性成像与病理检查结果比较无统计学差异(P0.05);超声造影与病理检查结果无统计学差异(P0.05);超声弹性成像和超声造影的敏感性、特异性、准确性无统计学差异(P0.05)。结论:超声弹性成像、超声造影对肝肿瘤诊断中均有重要价值,建议二者联合检测,提高肝肿瘤检出准确率。     

Obesity and melanoma: could fat be fueling malignancy?

Over the last decade, it has become increasingly clear that adipose tissue, and particularly adipocytes, contributes to tumor progression. Obesity, an ever‐increasing worldwide phenomenon, exacerbates this effect. The influence of obesity on melanoma remains poorly studied, although recent data do underline an association between the two diseases in both humans and murine models. Herein, we review the impact of obesity on melanoma incidence and progression and discuss the underlying mechanisms known to be involved. Adipose tissue favors the proliferation and aggressiveness of melanoma cells through a direct dialog, mediated by soluble factors and by exosomes, and through remodeling of the tumor microenvironment. This knowledge could, in the future, help to design new personalized therapeutic options for obese melanoma patients.