Cancer Stem Cells and Circulatory Tumor Cells Promote Breast Cancer Metastasis

Breast cancer (BC) is a highly metastatic, pathological cancer that significantly affects women worldwide. The mortality rate of BC is related to its heterogeneity, aggressive phenotype, and metastasis. Recent studies have highlighted that the tumor microenvironment (TME) is critical for the interplay between metastasis mediators in BC. BC stem cells, tumor-derived exosomes, circulatory tumor cells (CTCs), and signaling pathways dynamically remodel the TME and promote metastasis. This review examines the cellular and molecular mechanisms governing the epithelial to mesenchymal transition (EMT) that facilitate metastasis. This review also discusses the role of cancer stem cells (CSCs), tumor-derived exosomes, and CTs in promoting BC metastasis. Furthermore, the review emphasizes major signaling pathways that mediate metastasis in BC. Finally, the interplay among CSCs, exosomes, and CTCs in mediating metastasis have been highlighted. Therefore, understanding the molecular cues that mediate the association of CSCs, exosomes, and CTCs in TME helps to optimize systemic therapy to target metastatic BC.     

The bioavailability of ingested 26Al-labelled aluminium and aluminium compounds in the rat

The fractional uptake of ingested aluminium and aluminium compounds (aluminium citrate, aluminium nitrate, aluminium chloride, aluminium sulphate, aluminium hydroxide, aluminium oxide, aluminium metal, powdered aluminium pot electrolyte, acidic sodium aluminium phosphate (SALP), basic sodium aluminium phosphate (Kasal), sodium aluminium silicate and FD&C red 40 aluminium lake) from the gastro-intestinal tract of adult female rats was measured. This was determined by comparing retained body burden of ²⁶Al at seven days post-admistration of an i.v. injection of ²⁶Al-labelled aluminium citrate with that retained following the gastric admistration of ²⁶Al-labelled test compounds as either solutions or suspended solid. The calculated percentage uptake of ²⁶Al for all the aluminium solutions was similar: aluminium citrate 0.08%, aluminium chloride 0.05%, aluminium nitrate 0.05% and aluminium sulphate 0.21%. The uptake of ²⁶Al administered as insoluble particulates was lower: 0.03% for aluminium hydroxide; 0.02% for aluminium oxide; 0.04% for powdered pot electrolyte; 0.12% for sodium aluminium silicate; and 0.09% for FD&C red 40 aluminium lake. For aluminium metal, SALP and Kasal the amount of ²⁶Al present in the rats was insufficient to determine uptake and was less than 0.03%. The results produced for aluminium citrate, aluminium hydroxide and aluminium sulphate are close to those published for man.     

Immunogenicity and protective efficacy of adenoviral and subunit RSV vaccines based on stabilized prefusion F protein in pre-clinical models

Respiratory Syncytial Virus (RSV) remains a leading cause of severe respiratory disease for which no licensed vaccine is available. We have previously described the derivation of an RSV Fusion protein (F) stabilized in its prefusion conformation (preF) as vaccine immunogen and demonstrated superior immunogenicity in naive mice of preF versus wild type RSV F protein, both as protein and when expressed from an Ad26 vaccine vector. Here we address the question if there are qualitative differences between the two vaccine platforms for induction of protective immunity. In naïve mice, both Ad26.RSV.preF and preF protein induced humoral responses, whereas cellular responses were only elicited by Ad26.RSV.preF. In RSV pre-exposed mice, a single dose of either vaccine induced cellular responses and strong humoral responses. Ad26-induced RSV-specific cellular immune responses were detected systemically and locally in the lungs. Both vaccines showed protective efficacy in the cotton rat model, but Ad26.RSV.preF conferred protection at lower virus neutralizing titers in comparison to RSV preF protein. Factors that may contribute to the protective capacity of Ad26.RSV.preF elicited immunity are the induced IgG2a antibodies that are able to engage Fcγ receptors mediating Antibody Dependent Cellular Cytotoxicity (ADCC), and the induction of systemic and lung resident RSV specific CD8 + T cells. These data demonstrate qualitative improvement of immune responses elicited by an adenoviral vector based vaccine encoding the RSV preF antigen compared to the subunit vaccine in small animal models which may inform RSV vaccine development.     

Cross-species comparison of the metabolism and excretion of selexipag

1. The metabolism of the prostacyclin receptor agonist selexipag (NS-304; ACT-293987) and its active metabolite MRE-269 (ACT-333679) has been investigated in liver microsomes and hepatocytes of rats, dogs, and monkeys. MRE-269 formation is the main pathway of selexipag metabolism, irrespective of species. Some interspecies differences were evident for both compounds in terms of both metabolic turnover and metabolic profiles. The metabolism of MRE-269 was slower than that of selexipag in all three species.

2. The metabolism of selexipag was also studied in bile-duct-cannulated rats and dogs after a single oral and intravenous dose of [¹⁴C]selexipag. MRE-269 acyl glucuronide was found in both rat and dog bile. Internal acyl migration reactions of MRE-269 glucuronide were identified in an experiment with the synthetic standard MRE-6001.

3. MRE-269 was the major component in the faeces of rats and dogs. In ex vivo study using rat and dog faeces, selexipag hydrolysis to MRE-269 by the intestinal microflora is considered to be a contributory factor in rats and dogs.

4. A taurine conjugate of MRE-269 was identified in rat bile sample. Overall, selexipag was eliminated via multiple routes in animals, including hydrolysis, oxidative metabolism, conjugation, intestinal deconjugation, and gut flora metabolism.     

海沙瑞林对慢性心力衰竭大鼠心交感神经重构的影响*

目的：探讨海沙瑞林对慢性心力衰竭（ CHF）大鼠心交感神经重构的影响。 方法： SD大鼠随机分为对照 组（ Control 组）、假手术组（ Sham组）、心力衰竭组（ HF组）和海沙瑞林干预组（ HF+Hx 组），应用冠状动脉结 扎法制作CHF大鼠模型，HF+Hx 组大鼠连续4 周尾静脉注射海沙瑞林 100 μg·kg-1·d-1，其他3 组注射等量的生 理盐水。超声心动图测量左心室功能；H-E 染色及Masson 染色观察各组大鼠心肌病理结构变化；免疫组织化学和 免疫印迹检测脑钠肽（ BNP）、神经生长因子（ NGF）、酪氨酸羟化酶（TH）和生长相关蛋白43（ GAP43）表达。 结果：海沙瑞林干预升高CHF大鼠左室射血分数，改善左心室功能，减轻HF组心肌损伤结构病理改变，降低心 肌细胞内BNP 表达，增加NGF、TH和GAP43 表达，差异均具有统计学意义。 结论：CHF大鼠存在心交感神经重构， 海沙瑞林通过改变心交感神经重构， 改善心功能和CHF的预后可能是其实现心保护的机制之一。