Evaluation of Necrosis Avidity and Potential for Rapid Imaging of Necrotic Myocardium of Radioiodinated Hypocrellins

Purpose

Rapid noninvasive delineation of necrotic myocardium in ischemic regions is very critical for risk stratification and clinical decision-making but still challenging. This study aimed to evaluate the necrosis avidity of radioiodinated hypocrellins and its potential for rapidly imaging necrotic myocardium.

Procedures

The aggregation constants of four natural hypocrellins were analyzed by UV/vis spectroscopy. Then, they were radiolabeled with iodine-131 by iodogen oxidation method. Necrosis avidity of iodine-131-labeled hypocrellins was evaluated in rat models with reperfused liver infarction and muscular necrosis by gamma counting, autoradiography, and histopathology. Their pharmacokinetic properties were examined in normal rats. The potential of iodine-131-labeled hypomycin A ([¹³¹I]HD) for early imaging of necrotic myocardium was explored in rat models with reperfused myocardial infarction. Finally, the possible mechanism of necrosis avidity was investigated by in vitro DNA binding and in vivo blocking experiments.

Results

The aggregation constants of four hypocrellins were all much smaller than that of hypericin, a most studied necrosis avid agent. The radiochemical purities of the four radiotracers after purification were all greater than 95 %, and more than 90 % of tracers remained intact after incubation in rat serum for 24 h. Among the four tracers, [¹³¹I]HD exhibited the highest necrotic to viable tissue uptake ratio and the fastest blood clearance. The necrotic myocardium could be clearly visualized 4 h after injection of [¹³¹I]HD by single-photon emission computed tomography/X-ray computed tomography (SPECT/CT). DNA binding studies suggested that HD could bind to DNA through intercalation. Blocking studies demonstrated that uptake of [¹³¹I]HD in necrotic muscle could be significantly blocked by excess unlabeled HD and ethidium bromide with 67 and 60 % decline at 6 h after coinjection, respectively.

Conclusions

[¹³¹I]HD can be used to rapidly visualize necrotic myocardium. The necrosis avidity mechanism of [¹³¹I]HD may be attributed to its binding to the exposed DNA in necrotic tissues.

     

Increasing of FKBP9 can predict poor prognosis in patients with prostate cancer

BackgroundFK506 binding protein 9 (FKBP9) has been reported and identified for a long time, but its relationship with cancer is rarely studied. For example, the role of FK506 binding protein 9 in prostate cancer (PCa) is still unclear. Therefore, we decided to detect the expression level of FKBP9 in PCa and explore its clinical significance.MethodsThe expression level of FKBP9 protein was detected by immunohistochemistry. In addition, it was demonstrated by high-throughput sequencing of mRNA levels in the TCGA (cancer genome atlas) dataset of 499 patients. Kaplan-meier analysis and Cox proportional hazard regression model were used to evaluate the relationship between FKBP9 expression and survival in prostate cancer patients.ResultsThe expression of FKBP9 was localized in the cytoplasm, which in normal prostate tissues was obviously lower than that in PCa tissues (P = 0.001). High expression of FKBP9 was related with lymph node metastasis (P = 0.022) and distant metastasis (P = 0.028). Kaplan-Meier survival analysis revealed that the BCR-free survival of PCa patients with high FKBP9 level was significantly shortened (P=0.041).ConclusionsFKBP9 may be a cancer promoter that enhances PCa progression, and the level of FKBP9 may be used as an independent precursor of PCa patients.     

n-3多不饱和脂肪酸对大鼠酒精性脂肪肝炎性反应及肝纤维化的影响

目的探讨n-3多不饱和脂肪酸(n-3PUFA)对大鼠酒精性脂肪肝炎性反应、肝纤维化的影响及机制。方法选择40只雄性SD大鼠,编号后采用随机数字表法分为对照组、模型组、n-3PUFA组、n-3PUFA+内毒素(LPS)组,每组各10只,对照组给予正常饲料及每日生理盐水灌胃,另外3组大鼠采用酒精灌胃的方式建立酒精性脂肪肝模型,n-3PUFA组给予n-3PUFA干预、n-3PUFA+LPS组给予n-3PUFA及Toll样受体4(TLR4)激动剂LPS干预。8周后,处死大鼠取肝和血清标本,观察各组大鼠肝组织病理变化,测定4组大鼠肝脏中TLR4、核因子-κB (NF-KB)、肿瘤坏死因子-α(TNF-α)、单核细胞趋化蛋白-1(MCP-1)和白细胞介素1(IL-1)的表达水平,以及血清中转化生长因子-β1(TGF-β1)、透明质酸(HA)和Ⅳ型胶原(C-Ⅳ)的含量。结果对照组大鼠肝组织结构正常,模型组可见弥漫性肝细胞脂肪变性,n-3PUFA组肝细胞脂肪变性减轻,而n-3PUFA+LPS组肝组织脂肪变性较n-3PUFA组加重。模型组大鼠肝脏中TLR4、NF-κB、TNF-α、MCP-1和IL-1的mRNA表达水平及血清中TGF-β1、HA和C-Ⅳ的含量高于对照组,差异有统计学意义(P<0.05);n-3PUFA组肝脏中TLR4、NF-κB、TNF-α、MCP-1和IL-1的mRNA表达水平及血清中TGF-β1、HA和C-Ⅳ的含量低于模型组,差异有统计学意义(P <0.05);n-3PUFA+LPS组肝脏中TLR4、NF-κB、TNF-α、MCP-1和IL-1的mRNA表达水平及血清中TGF-β1、HA和C-Ⅳ的含量高于n-3PUFA组,差异有统计学意义(P<0.05)。结论 n-3PUFA对大鼠酒精性脂肪肝炎性反应及肝纤维化具有抑制作用,且该作用与TLR4/NF-κB信号通路阻断有关。     

常规MRI纹理分析鉴别WHO Ⅱ级与Ⅲ级胶质瘤的 价值

目的 探讨常规MRI纹理分析在WHO Ⅱ级与Ⅲ级胶质瘤鉴别中的临床价值。方法 回顾性分析经病理证实的40例WHO Ⅱ级和46例WHO Ⅲ级胶 质瘤的常规MRI影像。在MaZda上勾画肿瘤最大层面进行纹理分析,选出与肿瘤级别显著相关的特征纹理参数并统计分析各特征纹理参数的诊断效能。 结果 四种MRI序列（包括T1WI、T2WI、FLAIR、T1WI增强）鉴别WHO Ⅱ级和Ⅲ级胶质瘤的最小误判率为9.30%,出现在T2WI序列中。多元Logistic回归 分析显示,T2WI序列中熵（OR=2.497;P=0.009 ）及游程长非均匀度因子（OR=1.844;P=0.011）与胶质瘤级别独立相关。根据ROC曲线分析结果,以 熵=2.46为阈值鉴别WHO Ⅱ级和Ⅲ级胶质瘤的曲线下面积为0.843,敏感性、特异性分别为0.814、0.767;以游程长非均匀度因子=363.22为阈值鉴别 WHO Ⅱ级和Ⅲ级胶质瘤的曲线下面积为0.808,敏感性、特异性分别为0.794、0.778。结论 常规MRI纹理分析有助于鉴别WHO Ⅱ级与Ⅲ级胶质瘤, T2WI纹理参数中熵及游程长非均匀度因子的鉴别诊断价值最高。     

UNC45A-related osteo-oto-hepato-enteric syndrome in a Chinese neonate

Unexplained diarrhea and cholestasis are common clinical phenotypes in newborns, indicating there is only a little common genetic basis for these conditions. However, it has been reported that defects in the UNC45A gene can lead to osteo-oto-hepato-enteric syndrome. However, to date, only 10 patients with this syndrome have been reported in 2 studies; therefore, there is still a lack of analysis regarding the correlation between disease phenotype and genotype. Trio-whole exome sequencing was conducted using DNA samples from a newborn with congenital diarrhea and cholestasis from a Chinese Han family. The UNC45A variants were verified using Sanger sequencing. In addition, we applied a crystal structure model to analyze the potential hazards associated with the variants. The plasmids were constructed in vitro and transfected into human 293T cells for Western blot (WB) analysis. After the mutant protein was fused with the Green Fluorescent Protein label, intracellular localization was observed using laser confocal microscopy. The gene detection results showed that the UNC45A gene of the newborn examined in the present study harbored the compound heterozygous variants p.Arg819Ter, and p.Leu237Pro; this was confirmed via Sanger sequencing. Analysis of the Leu237Pro crystal structure model suggested that this variant may decrease local structural stability and affect protein function. The Western blot and laser confocal microscopy observation results suggested that the Leu237Pro mutation leads to reduced protein expression, while the Arg819Ter mutation completely inhibits the expression of the protein. The compound heterozygous variants of UNC45A (p.Arg819Ter and p.Leu237Pro) may be pathogenic factors of congenital diarrhea and cholestasis in this neonatal patient. Therefore, UNC45A deficiency should be considered when intractable diarrhea and cholestasis occur in newborns.