The heterogeneous immune microenvironment in breast cancer is affected by hypoxia-related genes

The immune system constitutes an important first-line defence against malignant transformation. However, cancer mediated immunosuppression inactivates the mechanisms of host immune surveillance. Cancer cells shut down anti-cancer immunity through direct cell–cell interactions with leukocytes and through soluble factors, establishing an immunosuppressive environment for unimpeded cancer growth. The composition of the immunosuppressive microenvironment in breast tumours is not well documented. To address this question, selected immunosuppressive factors were analyzed in tumour specimens from 33 breast cancer patients after surgery. The mRNA expression of selected genes was quantified in fresh tumour samples. Tumour infiltrating leukocytes were characterized by flow cytometry to identify regulatory T cells, myeloid derived suppressor cells, and type 2 macrophages. Statistical analysis revealed several interesting correlations between the studied parameters and clinical features. Overall, a surprisingly high degree of heterogeneity in the composition of the immunosuppressive environment was found across all breast cancer samples which adds to the complexity of this disease. The influence of the hypoxia inducible factors (HIFs) on the immune microenvironment was also addressed. The level of HIFs correlated with hormone receptor status and the expression of several immunosuppressive molecules. Targeting HIFs might not only sensitize breast tumours for radiation and chemotherapies but also interfere with cancer immunosuppression.     

p53突变在三阴性乳腺癌转移中的作用及机制

三阴性[雌激素（estrogen receptor,ER）、孕激素受体（progesterone receptor,PR）与人表皮生长因子受体-2（human epidermal growth factor receptor 2,HER-2）均为阴性]乳腺癌（triple negative breast cancer,TNBC）是一个具有特殊生物学行为及临床特征的乳腺癌亚型,而转移是其发病和致死的最主要原因。最近的研究表明,在TNBC中,高频率的p53突变能使p63转录活性丧失,此外,Shar p1作为p53突变/p63调节的主要基因之一,它抑制乳腺癌转移的功能亦丧失,而Shar p1之所以能抑制TNBC的浸润性转移,是因为Sharp1是促进缺氧诱导因子（hypoxia-inducible factor,HIF）降解以及减弱HIF诱导癌细胞恶变的重要因子,从而促进TNBC的转移。所以本文通过在中国知网、Pubmed和Highw ire上检索并研究近100篇文献的基础上,就p53突变通过p63/Shar p1/HIF信号通路促进TNBC转移的作用及机制做一综述。     

Development of astrocytes in the vertebrate eye

Astrocytes represent the earliest glial population in the embryonic optic nerve, contributing critically to retinal angiogenesis and formation of brain‐retinal‐barrier. Despite of many developmental and clinical implications of astrocytes, answers to some of the most fundamental questions of this unique type of glial cells remain elusive. This review provides an overview of the current knowledge about the origination, proliferation, and differentiation of astrocytes, their journey from the optic nerve toward the neuroretina, and their involvement in physiological and pathological development of the visual system. Developmental Dynamics 243:1501–1510, 2014. © 2014 Wiley Periodicals, Inc.     

大鼠股骨骨折合并脑外伤时HIF-1α及Cbfα1的血清表达及意义

目的探讨大鼠股骨骨折合并脑外伤时低氧诱导因子-1α(HIF-1α)及核心结合因子α1(Cbfα1)在血清中的表达及意义。方法选用70只3月龄健康SD大鼠,随机分为假手术组(A组),股骨骨折组(B组),脑外伤组(C组)和骨折合并脑外伤组(D组),分别进行造模。造模术后24 h取C、D组脑组织行苏木素-伊红染色判断脑外伤程度。1 d、3 d、1周、2周、3周、4周、5周通过酶联免疫吸附法(ELISA)检测各组HIF-1α及Cbfα1的血清表达。结果 B、C、D组内不同时间段HIF-1α及Cbfα1表达比较,差异有显著性(P0.05);同一时间段B、C、D组表达均明显高于A组,D组高于B、C两组,差异均有显著性(P0.05)。结论 HIF-1α及Cbfα1在大鼠骨折和脑外伤后均有较明显的表达,在骨折合并脑外伤后表达更加突出,这可能是造成脑外伤后加速骨折愈合的重要因素之一。     

Melatonin attenuated retinal neovascularization and neuroglial dysfunction by inhibition of HIF‐1α‐VEGF pathway in oxygen‐induced retinopathy mice

Retinopathy of prematurity (ROP) is a retinopathy characterized by retinal neovascularization (RNV) occurring in preterm infants treated with high concentrations of oxygen and may lead to blindness in severe cases. Currently, anti‐VEGF therapy is a major treatment for ROP, but it is costly and may cause serious complications. The previous study has demonstrated that melatonin exerted neuroprotective effect against retinal ganglion cell death induced by hypoxia in neonatal rats. However, whether melatonin is anti‐angiogenic and neuroglial protective in the progression of ROP remains unknown. Thus, this study was to investigate the effect of melatonin on RNV and neuroglia in the retina of oxygen‐induced retinopathy (OIR) mice. The results showed a reduction in retinal vascular leakage in OIR mice after melatonin treatment. Besides, the size of retinal neovascular and avascular areas, the number of preretinal neovascular cell nuclei, and the number of proliferative vascular endothelial cells within the neovascular area were significantly decreased in mice treated with melatonin. After oxygen‐induced injury, the density of astrocytes was decreased, accompanied by morphologic and functional changes of astrocytes. Besides, retinal microglia were also activated. Meanwhile, the levels of inflammatory factors were elevated. However, these pathologic processes were all hindered by melatonin treatment. Furthermore, HIF‐1α‐VEGF pathway was activated in the retina of OIR mice, yet was suppressed in melatonin‐treated OIR mice retinas. In conclusion, melatonin prevented pathologic neovascularization, protected neuroglial cells, and exerts anti‐inflammation effect via inhibition of HIF‐1α‐VEGF pathway in OIR retinas, suggesting that melatonin could be a promising therapeutic agent for ROP.