Bisphenol A replacement chemicals,BPF and BPS,induce protumorigenic changes in human mammary gland organoid morphology and proteome

Environmental chemicals such as bisphenol A (BPA) are thought to contribute to carcinogenesis through their endocrine-disrupting properties. Due to accumulating evidence about negative human health effects, BPA is being phased out, but in parallel, exposures to replacement chemicals such as bisphenol S (BPS) and bisphenol F (BPF) are increasing. Little is known about their biologic effects, but because of their high degree of chemical relatedness, they may have overlapping as well as distinct actions as compared with BPA. We investigated this theory using a nonmalignant, human breast tissue-derived organoid system and two end points: morphologic and proteomic alterations. At low-nanomolar doses, replacement chemicals—particularly BPS—disrupted normal mammary organoid architecture and led to an increased branching phenotype. Treatment with the various bisphenols (vs. 17-β-estradiol or a vehicle control) produced distinct proteomic changes. For example, BPS up-regulated Cdc42-interacting protein 4, which supports the formation of invadopodia and a mesenchymal phenotype. In summary, this study used a highly physiologically relevant organoid system to provide evidence that replacement bisphenols have protumorigenic effects on the mammary gland at morphologic and proteomic levels, highlighting the importance of studies to evaluate the potential harmful effects of structurally related environmental chemicals.

Bisphenols, of which the most prevalent is bisphenol A (BPA), are environmental chemicals that are used as plasticizers in a variety of goods, including plastic bottles, children''s toys, eyeglass lenses, food containers, and some types of thermal paper (e.g., cash register receipts). They leach from these products, contaminating humans (and animals) either directly or indirectly via other environmental media, such as household dust. Thus, in most adults, BPA is detected in serum, tissues, and urine (1, 2). Children (ages 6 to 11) have the highest concentrations of urinary BPA (3, 4). This chemical has structural similarities to estrogen (17-β-estradiol [E2]) and as a result, weakly mimics its activity (5). Hormones and growth factors play an important role in controlling prenatal mammary gland development and later on, the morphologic and functional alterations that occur during puberty, pregnancy, and eventually, menopause. Due to this plasticity, the mammary gland is particularly susceptible to the actions of endocrine-disrupting chemicals (EDCs), such as BPA (6–8). In vivo and in vitro studies have consistently shown that exposures to BPA at crucial developmental stages impair mammary gland development and increase neoplastic transformation (9–12). Treating rats with BPA results in mammary epithelial hyperplasia and enhances proliferation (13), common features of precancerous lesions. Additionally, BPA induces cell cycle progression and increases proliferation of human breast cancer cells in vitro via the up-regulated expression of estrogen-dependent genes (14).Based on these and other data, BPA has been removed from many commercial products. Most commonly, this chemical of concern is replaced by bisphenol S (BPS) and bisphenol F (BPF) compounds that share close structural similarities with BPA. However, little is known about their endocrine effects and more broadly, their biological activities. Marketing a product as “BPA free” suggests to the consumer that a product is safer, but research shows that replacement bisphenols have adverse effects similar to, or even greater than, BPA. For example, studies in zebrafish, rodents, and human cell culture models show that BPS and BPF have endocrine-disrupting activities. In zebrafish, despite species-specific differences in estrogen receptor (ER) affinity and specificity, BPF and BPS have estrogenic activities similar to BPA (15–17). In rats, exposure to BPF induces uterine growth, which suggests estrogenic effects (18). BPA, BPF, and BPS promote estrogen-dependent cell cycle progression, proliferation, and migration of human MCF-7 breast cancer cells along with epigenetic changes (19, 20). BPS exposure of pregnant and lactating mice limits milk production, suggesting alterations in mammary gland composition (21). In addition to estrogen signaling, BPF affects other endocrine pathways; in rats, oral administration of this compound alters thyroid hormone levels (22).Current research on bisphenol actions is mainly focused on endocrine effects. It is less well understood whether these chemicals have additional protumorigenic effects independent of their endocrine-disrupting activity. Moreover, tumor development is a multistep process involving heterogeneous cell types and numerous factors, including the potential roles of a variety of environmental chemicals (23, 24). Recapitulating this complexity in an experimental setup is challenging. In this context, tissue organoids are valuable models for understanding the early steps of carcinogenesis. They can be derived from nonmalignant primary tissues ex vivo. When grown for short periods of time in vitro, they maintain many of the genetic and epigenetic features of their normal cognates. Also, organoids have the added advantage of consisting of multiple cell types that are representative of the complexity of the tissue from which they are derived (25, 26).In this study, we exploited the strengths of the human mammary gland organoid culture system to understand the impact of the BPA replacements, BPF and BPS. Organoids established from nonmalignant human mammary gland tissues were exposed to one of the bisphenols, E2, or the vehicle control. The results showed that BPA replacements, in particular BPS, disrupted organoid architecture, enhanced branching, and caused compound-specific proteomic alterations—effects that were mostly E2 independent. Together, these observations suggested that the mammary gland effects of BPA substitutes should be equally or more concerning than those of the compound they are replacing.     

胰腺癌组织VEGF和MVD表达与CT灌注成像的关系

血管内皮生长因子作为肿瘤血管生成的一种主要调控因子,与微血管密度密切相关．胰腺癌组织的血管内皮生长因子和微血管密度的测定对于判断患者的预后,指导临床治疗和判断疗效等具有重要作用．CT灌注成像可以通过无创伤检查反映胰腺癌的肿瘤血管构成, 在治疗前后提供有价值依据,对胰腺癌的诊治有重要意义．     

Stereotaktische Laserthermoablation bei mesialer Temporallappenepilepsie mit Hippocampussklerose rechts – Patientenentscheidung,Durchführung und Visualisierung von Gedächtnisfunktion

Clinical Epileptology - Wir berichten über einen 30-jährigen Patienten, der mit 21 Jahren an einer fokalen Epilepsie mit epigastrischen Auren und nicht bewusst erlebten...     

免疫磁珠分选骨髓衍生肝干细胞亚群c-Kit+lin-

目的:利用免疫磁性细胞分选系统分离纯化骨髓衍生肝干细胞亚群c-Kit lin-。方法:实验于2006-07/08在南方医科大学实验动物中心完成。6～8周龄的SPF级纯系BALB/C雄性小鼠10只,体质量18～20g。收集小鼠股骨骨髓细胞,利用免疫磁性细胞分选系统,通过两步法分选纯化c-Kit lin-:将获取的lin-细胞悬液8℃条件下1500r/min离心10min,弃上清,按80μL/107加入Buffer重悬细胞。按20μL/107加生物素抗体磁珠,混匀,4℃冰箱孵育15min,按1mL/107加入Buffer洗细胞1次,8℃条件下1500r/min离心10min,弃上清,按500μL/108加入Buffer重悬细胞。Buffer500μL润MS柱,悬液过柱后,Buffer500μL/次洗柱3次,柱子脱离磁场,加1mLBuffer,用配套柱塞推出柱中的c-Kit lin-细胞,收集到c-kit lin-细胞,细胞计数。取2.0×106个细胞分成10等份,流式细胞仪分析c-Kit lin-细胞纯度,计算回收率,评估纯化效率,苔盼兰染色检测纯化前后的细胞活力。计算活细胞的百分率。细胞纯度和细胞回收率的计算:细胞纯度=分离产物中的阳性细胞数/分离细胞的总细胞数×100%,细胞回收率=分离产物中的阳性细胞数/起始标本阳性细胞总数×100%。结果:10只小鼠均进入结果分析。利用免疫磁性细胞分选系统分选出的骨髓衍生肝干细胞亚群c-Kit lin-细胞纯度和回收率分别为(77.98±2.34)%,75.40%,纯化前后细胞活力不受影响。结论:免疫磁性细胞分选系统能有效分选骨髓衍生肝干细胞亚群c-Kit lin-,纯度和回收率高,且不影响细胞活力。     

An exercise programme for community-dwelling, mobility-restricted and chronically ill older adults with structured support by the general practitioner’s practice (HOMEfit)

Programmes containing health-enhancing physical exercise should be evaluated using standards that are just as rigorous as those required for drug development. In contrast to new medicines, exercise programmes are highly complex. This has to be taken into account when designing the research plan. In order to illustrate the development process of a “complex intervention”, we use the example of an exercise programme for community-dwelling, mobility-restricted and chronically ill older adults. Based on a framework for evaluation of complex interventions (Medical Research Council [MRC], UK), a research plan was set up containing the phases: development, feasibility, evaluation, implementation. The development phase resulted in the design of a home-based exercise programme in which the target group is approached and supported via their general practitioner and an exercise therapist. A feasibility study was performed. Three quantitative criteria for feasibility (adoption, safety, continuing participation) were statistically confirmed which permitted the decision to proceed with the research plan. So far, the MRC framework has proved to be valuable for the development of the new programme.     

The brain‐derived neutrophic factor val66met polymorphism and sudden unexpected infant death

Aim: Findings of hypoxia prior to death and involvement of a dysregulation of the serotonergic network in sudden infant death syndrome (SIDS) may indicate that brain‐derived neutrophic factor (BDNF) also is of importance with regard to sudden unexpected infant death. Based on this, the purpose of this study was to investigate the BDNF val66met polymorphism in SIDS cases, cases of infectious death and controls. Methods: The polymorphism was investigated in 163 SIDS cases, 34 cases of infectious death and 121 controls, using real‐time PCR and fluorescence melting curve analysis. Results: There were no differences in val66met genotype distribution between neither the SIDS cases nor the cases of infectious death and controls (p = 0.95 and p = 0.52, respectively). Conclusion: The study indicates that the val66met polymorphism is not important for sudden unexpected infant death. However, several other SNPs in the BDNF gene, as well as in other genes involved in this pathway, including G‐protein, have to be investigated to fully exclude any involvement of BDNF in SIDS.     

Psychological change following 18 months of cochlear implant use.

Consecutive recipients of multichannel cochlear implants participated in preimplant as well as 9-month and 18-month psychological evaluations. Before receiving a cochlear implant, psychological tests indicated that the implant recipients were more depressed, suspicious, socially isolated, lonely, and socially anxious than was the general population. After 18 months of implant use, there was a significant reduction in depression, loneliness, social anxiety, social isolation, and suspiciousness. These changes in psychological state did not correlate with improved performance on audiological measures. The data suggest that although cochlear implants can have a positive effect on the emotional and behavioral status of persons with acquired postlingual profound deafness, the psychological outcome of implants is not simply a function of the audiological benefit assessed with standardized speech-based audiological tests.