Cancer Risks in Parents Who had a Child with a Congenital Malformation

Cancer risk in parents may be related to congenital malformations (CMs) in their children if they share genetic susceptibility or environmental exposure that may be teratogenic and carcinogenic. We conducted a population‐based cohort study based on Danish register data. We identified 795,607 mothers and 781,424 fathers who had all their children between 1977 and 2007 in Denmark. Information on CM was obtained from the Danish Hospital Registry and information on cancer was obtained from the Danish Cancer Registry. Parents were followed from the birth of their first child until the diagnosis of cancer, death, emigration, or December 31, 2007. We used Cox regression models to estimate hazard ratios (HRs) for cancer including cancer in specific organs in mothers and fathers. Overall, 75,701 (9.5%) mothers and 72,724 (9.3%) fathers had at least one child diagnosed with CMs within the first year of life. Neither mothers (HR = 1.04; 95% CI: 0.99–1.04) nor fathers (HR = 1.03; 95% CI: 0.98–1.09) who had a child with a CM had a higher overall risk of cancer. Mothers (HR = 0.76, 95% CI: 0.58–1.00) or fathers (HR = 0.89, 95% CI: 0.66–1.19) who had a child with a chromosomal malformation had a lower overall cancer risk. The findings also showed a higher risk for some specific types of cancer in parents who had children with a CM in the specific system. Some, or perhaps all, of these findings may be due to chance caused by multiple comparisons. We present all results on paper or online to provide clues for further research and to avoid publication bias.     

Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice

Pulmonary hypertension is a significant cause of morbidity and mortality in infants. Historically, there has been significant study of the signaling pathways involved in vascular smooth muscle contraction in PASMC from fetal sheep. While sheep make an excellent model of term pulmonary hypertension, they are very expensive and lack the advantage of genetic manipulation found in mice. Conversely, the inability to isolate PASMC from mice was a significant limitation of that system. Here we described the isolation of primary cultures of mouse PASMC from P7, P14, and P21 mice using a variation of the previously described technique of Marshall et al.²⁶ that was previously used to isolate rat PASMC. These murine PASMC represent a novel tool for the study of signaling pathways in the neonatal period. Briefly, a slurry of 0.5% (w/v) agarose + 0.5% iron particles in M199 media is infused into the pulmonary vascular bed via the right ventricle (RV). The iron particles are 0.2 μM in diameter and cannot pass through the pulmonary capillary bed. Thus, the iron lodges in the small pulmonary arteries (PA). The lungs are inflated with agarose, removed and dissociated. The iron-containing vessels are pulled down with a magnet. After collagenase (80 U/ml) treatment and further dissociation, the vessels are put into a tissue culture dish in M199 media containing 20% fetal bovine serum (FBS), and antibiotics (M199 complete media) to allow cell migration onto the culture dish. This initial plate of cells is a 50-50 mixture of fibroblasts and PASMC. Thus, the pull down procedure is repeated multiple times to achieve a more pure PASMC population and remove any residual iron. Smooth muscle cell identity is confirmed by immunostaining for smooth muscle myosin and desmin.     

Intravital Video Microscopy Measurements of Retinal Blood Flow in Mice

Alterations in retinal blood flow can contribute to, or be a consequence of, ocular disease and visual dysfunction. Therefore, quantitation of altered perfusion can aid research into the mechanisms of retinal pathologies. Intravital video microscopy of fluorescent tracers can be used to measure vascular diameters and bloodstream velocities of the retinal vasculature, specifically the arterioles branching from the central retinal artery and of the venules leading into the central retinal vein. Blood flow rates can be calculated from the diameters and velocities, with the summation of arteriolar flow, and separately venular flow, providing values of total retinal blood flow. This paper and associated video describe the methods for applying this technique to mice, which includes 1) the preparation of the eye for intravital microscopy of the anesthetized animal, 2) the intravenous infusion of fluorescent microspheres to measure bloodstream velocity, 3) the intravenous infusion of a high molecular weight fluorescent dextran, to aid the microscopic visualization of the retinal microvasculature, 4) the use of a digital microscope camera to obtain videos of the perfused retina, and 5) the use of image processing software to analyze the video. The same techniques can be used for measuring retinal blood flow rates in rats.     

用SITSSICH风险评分预测脑梗死rt-PA静脉溶栓后症状性颅内出血风险的临床研究

目的：探索SITSSICH风险评分预测中国急性脑梗死患者rt．PA静脉溶栓（时间窗为4．5h,rt．PA剂量0．9mg／kg体重）治疗后症状性颅内出血（SICH）风险的效果,为使用SITSSICH风险评分指导溶栓治疗积累临床经验。方法：对86名进行rt-PA静脉溶栓（剂量0．9mg／kg体重）的急性脑梗死患者,进行SITSSICH风险评分,并记录总分及风险水平分层结果,按总分0、1、2、3、4、5、6、7、8、≥9分,分为10组,再按风险水平低危、平均、中危、高危分为4组,记录各组患者溶栓后有颅内出血（包括SICH）的比例,各组间进行比较。结果：SITSSICH风险评分0．5分、6分、7分、8分、≥9分各组SICH的比例分别为0．0％、8．3％、10．0％、25％和50．0％,卡方检验得x2=64．38,P〈0．001（线性趋势检验）,提示随着SITSSICH风险评分值的增加SICH的比例也在增加,存在统计学上的差异。SITSSICH风险评分风险水平低危及平均组的SICH比率为0％,中危、高危组的SICH比率分别11．5％,50％,卡方检验得xZ=-59．52,P〈0．001（线性趋势检验）,提示SITSSICH风险水平越高,SICH的比例也越高,存在统计学上的差异。另外,将SITSSICH风险评分风险水平分层和出血类型做spearman等级相关分析,得到spearman相关系数0．422,P〈0．001;说明SITSSICH风险评分风险水平分层和S1CH呈正相关。结论：对于经标准的rt—PA静脉溶栓方案（时间窗为4．5h,rt-PA剂量0．9mg／kg体重）治疗中国急性脑梗死患者,SITSSICH风险评分分值的增加与SICH风险的增加呈正相关,SITSSICH风险评分是一个能够预测rt-PA静脉溶栓后sICH风险的简单易行的实用的I临床工具。     

First evidence of ethylene production by Fusarium mangiferae associated with mango malformation

Malformation is arguably the most crucial disease of mango (Mangifera indica L.) at present. It is receiving great attention not only because of its widespread and destructive nature but also because of its etiology and control is not absolutely understood. Recently, Fusarium mangiferae is found to be associated with mango malformation disease. There are indications that stress ethylene production could be involved in the disease. Here we have shown the first direct evidence of production of ethylene in pure culture of F. mangiferae obtained from mango. The study also revealed that all the isolates dissected from mango acquire morphological features of F. mangiferae showing most similarity to the features of species with accepted standard features. The isolates of F. mangiferae from mango were observed to produce ethylene in significant amounts, ranging from 9.28–13.66 n mol/g dry wt/day. The findings presented here suggest that F. mangiferae could contribute to the malformation of mango by producing ethylene and probably stimulating stress ethylene production in malformed tissue of mango. Ethylene might be produced through 2-oxoglutarate-dependent oxygenase-type ethylene-forming-enzyme (EFE) pathway in Fusarium sp, which needs to be investigated.     

Overcoming resistance to rapalogs in gliomas by combinatory therapies

Glioblastoma is the most common and aggressive brain tumor type, with a mean patient survival of approximately 1 year. Many previous analyses of the glioma kinome have identified key deregulated pathways that converge and activate mammalian target of rapamycin (mTOR). Following the identification and characterization of mTOR-promoting activity in gliomagenesis, data from preclinical studies suggested the targeting of mTOR by rapamycin or its analogs (rapalogs) as a promising therapeutic approach. However, clinical trials with rapalogs have shown very limited efficacy on glioma due to the development of resistance mechanisms. Analysis of rapalog-insensitive glioma cells has revealed increased activity of growth and survival pathways compensating for mTOR inhibition by rapalogs that are suitable for therapeutic intervention. In addition, recently developed mTOR inhibitors show high anti-glioma activity. In this review, we recapitulate the regulation of mTOR signaling and its involvement in gliomagenesis, discuss mechanisms resulting in resistance to rapalogs, and speculate on strategies to overcome resistance. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).     

MiR-3691-5p is upregulated in docosahexaenoic acid-treated vascular endothelial cell and targets serpin family E member 1

Endothelium, the inner cellular lining of blood vessels, has an important role in the regulation of physiological processes and its dysfunction may initiate cardiovascular complications. Previous investigations have revealed that dietary docosahexaenoic acid (DHA) is related to a lower possibility of cardiovascular disease and mortality. Until now, the molecular mechanisms in the biological activities of DHA remain largely unknown. MicroRNAs (miRNAs) play a vital role in regulating gene expression. Thus, we aimed to investigate whether DHA improves the dysfunction via regulating miRNAs. To understand the protective effects of DHA through modulating miR-3691-5p and its target genes for palmitic acid (PAL) induced apoptosis in endothelial cells. The present study demonstrated that DHA upregulated miR-3691-5p expression, and downregulated the expression of its target gene serpin family E member 1 (SERPINE1). MiR-mimics and inhibitors modulation results indicated that miR-3691-5p regulates endothelial apoptosis through activating antiapoptotic response which controlled by the STAT3 signaling pathway. In conclusion, we have shown that PAL-induced apoptosis could be decreased by DHA treatment through miR-3691-5/SERPINE1 pathways.