CN109295200B - 高线性能量传递射线辐射的生物学检测标志物及其应用 - Google Patents
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Abstract
本发明公开了高线性能量传递射线辐射的生物学检测标志物及其应用，本发明分析筛选出了12个高LET特异性敏感的生物学检测标志物Retnlb、S100a8、Csf3r、Slc4a1、Tubb1、Clec4d、Il1b、Apol11b、Alas2、Coro1a、Ahsp、Rsad2。该12个特异性基因组合对低LET射线无反应，但接受高LET射线照射后，该基因组合出现转录水平的显著高调，基于该特征性生物学转录水平改变，可用来鉴别不同线性能量传递射线类型。本发明该12个基因标志物也可用于检测或辅助检测高线性能量传递射线引发的肺部辐射损伤。
Description
技术领域
本发明属辐射生物学射线类型检测方法，涉及重离子射线或其他高线性能量传递(high-linear energy transfer，high-LET)射线的生物学检测标志物及其应用。
背景技术
炎症反应是急性、亚急性辐射损伤的常见应激性病理改变。炎症反应主要继发于电离辐射诱导组织细胞损坏、死亡，导致致炎因子(pro-inflammatory factors)的大量生成与释放。急性炎症临床上常表现为红、肿、热、痛、机能掩藏等变化，同时常伴有发热、白细胞增多等全身反应。不同于皮肤或表浅组织，放射性肺损伤通常在炎症早期并无明显临床症状；包括胸片、CT、血常规、肺功能测试等在内的辅助检查也通常表现为阴性。在炎症反应的中晚期才逐渐表现出刺激性、干性咳嗽、伴气急、心悸和胸痛，低热或高热等体征。该阶段通常以接受射线暴露后12周(3个月左右)开始最为显著，临床上通常容易合并细菌性感染引起的感染性肺炎。高电离剂量暴露后的放射性肺部炎症如未得到有效控制，可导致肺部间质性肺纤维化、弥漫性多器官炎症，严重者可导致呼吸衰歇甚至死亡。
原子弹爆炸时间持续仅十几秒钟，特点是具有强大的瞬时杀伤力。核武器的杀伤破坏因素有热辐射(光辐射)、冲击波、早期核辐射、核电磁脉冲、核放射性沾染等5种类型。前四种是在核爆炸最初的十几秒产生的瞬时杀伤破坏因素。放射性沾染可以持续几个月，几年或更长的时间。广岛上的原子弹随着爆炸的结束，前4种直接的危害结束。因此，放射性沾染成为决定核爆之后人类能否安全居住的唯一因素。核爆炸后，蘑菇状烟云中含有大量放射性灰尘，当烟云随风扩散时，放射性烟尘因重力作用，或者随着“黑雨”逐渐降落到地面或其他物体上，形成一个很大的放射性沾染区。
核爆炸产生的“放射性灰尘”主要包含是α射线、β射线和γ射线。也就是说，是高线性能力射线与低线性能量射线的混合射线。这种携带混合射线的放射性烟尘可以通过呼吸道进入肺组织，造成辐射诱导的肺损伤。由于机体对不同类型线性能量传递射线的应激反应有所不同，即相同剂量的高LET射线比低LET射线引起的不可修复细胞损伤或变异更大，人员受到慢性高LET射线暴露后可罹患各种呼吸系统、免疫、肿瘤、造血组织相关疾病。在发生核辐射事故及各类型放射事故后，迅速确认暴露射线种类并检测受辐射剂量是指导后续预防与救治的关键措施之一。
发明内容
本发明提供一种在肺部辐射伤炎症早期就能对高LET射线暴露后射线类型进行检测的方法。本方法可在暴露后3周左右根据基因标志物的mRNA水平准确鉴别高LET射线。
本发明的目的之一在于提供一种检测或辅助检测高线性能量传递射线辐射标志物及其应用。
本发明的另一目的在于提供一种检测或辅助检测高线性能量传递射线辐射的产品。
本发明的再一目的在于提供一种检测或辅助检测高线性能量传递射线辐射引发的肺损伤的产品。
本发明所采取的技术方案是：
12个基因中的至少一种作为检测或辅助检测高线性能量传递射线辐射标志物的应用，所述12个基因为Retnlb、S100a8、Csf3r、Slc4a1、Tubb1、Clec4d、Il1b、Apol11b、Alas2、Coro1a、Ahsp和Rsad2。
定量检测12个基因中至少一种基因的试剂在制备检测或辅助检测高线性能量传递射线辐射的制剂中的应用，所述12个基因为Retnlb、S100a8、Csf3r、Slc4a1、Tubb1、Clec4d、Il1b、Apol11b、Alas2、Coro1a、Ahsp和Rsad2。
进一步的，所述定量检测12个基因中至少一种基因的试剂为定量检测12个基因中至少一种基因的引物或/和探针。
进一步的，所述定量检测12个基因中至少一种基因的引物为：
Retnlb：
Retnlb-F：ATGAAGCCTACACTGTGTTTCC
Retnlb-R：CTGCCAGAAGACGTGACACT
S100a8:
S100a8-F：AAATCACCATGCCCTCTACAAG
S100a8-R：CCCACTTTTATCACCATCGCAA
Csf3r:
Csf3r-F：TGCACCCTGACTGGAGTTAC
Csf3r-R：TGAAATCTCGATGTGTCCACAG
Slc4a1:
Slc4a1-F：AGATCCCAGATCGAGACAGC
Slc4a1-R：GCTCCACATAGACCTGACCG
Tubb1:
Tubb1-F：CTGGGAGGTGATCGGGGAA
Tubb1-R：GCACATACTTCTTACCGTAGGCT
Clec4d:
Clec4d-F：ACCCGACATCCCCAACTGAT
Clec4d-R：CTCTCGTCCAGCGTAAAAAGT
Il1b:
Il1b-F：GAAATGCCACCTTTTGACAGTG
Il1b-R：TGGATGCTCTCATCAGGACAG
Apol11b:
Apol11b-F：AAAAGTCATTGATAACGCCACGG
Apol11b-R：CCTCGCTTGACAACTCTACTG
Alas2:
Alas2-F：GCAGCTATGTTGCTACGGTC
Alas2-R：GATGGGGCAGCGTCCAATAC
Coro1a:
Coro1a-F：TGGCTCTGATCTGTGAGGC
Coro1a-R：TCTTGTCTACTCGTCCAGTCTTG
Ahsp:
Ahsp-F：GGATCTCATTTCCGCAGGATTG
Ahsp-R：CTGCTGCCTGTAATAGTTGATGT
Rsad2:
Rsad2-F：AGCATTAGGGTGGCTAGATCC
Rsad2-R：CTGAGTGCTGTTCCCATCTTC。
定量检测12个基因中至少一种基因的试剂在制备检测或辅助检测高线性能量传递射线辐射引发的肺损伤的药剂中的应用，所述12个基因为Retnlb、S100a8、Csf3r、Slc4a1、Tubb1、Clec4d、Il1b、Apol11b、Alas2、Coro1a、Ahsp和Rsad2。
进一步的，所述定量检测12个基因中至少一种基因的试剂为定量检测12个基因中至少一种基因的引物或/和探针。
进一步的，所述肺损伤为炎症损伤。
进一步的，所述高线性能量传递射线包括重离子射线、α粒子射线、快中子、负π介子、氦、碳、氮、氧、氖。
一种检测或辅助检测高线性能量传递射线辐射的产品，该产品中含有定量检测12个基因中至少一种基因的试剂为定量检测12个基因中至少一种基因的引物或/和探针；所述12个基因为Retnlb、S100a8、Csf3r、Slc4a1、Tubb1、Clec4d、Il1b、Apol11b、Alas2、Coro1a、Ahsp和Rsad2。
一种检测或辅助检测高线性能量传递射线辐射引发的肺损伤的产品，该产品中含有定量检测12个基因中至少一种基因的试剂为定量检测12个基因中至少一种基因的引物或/和探针；所述12个基因为Retnlb、S100a8、Csf3r、Slc4a1、Tubb1、Clec4d、Il1b、Apol11b、Alas2、Coro1a、Ahsp和Rsad2。
进一步的，上述所述产品包括试剂盒或芯片。
本发明的有益效果是：
(1)本发明利用小鼠接受不同LET射线全肺照射后3周的全基因组转录组学分析筛选出12个高LET特异性敏感的生物学检测标志物：Retnlb(Resistin-Like Beta)、S100a8(S100Calcium Binding Protein A8)、Csf3r(Colony Stimulating Factor 3Receptor)、Slc4a1(Solute Carrier Family 4Member 1)、Tubb1(Tubulin Beta 1Class VI)、Clec4d(C-Type Lectin Domain Family 4Member D)、Il1b(Interleukin 1Beta)、Apol11b(Apolipoprotein L1)、Alas2(5'-Aminolevulinate Synthase 2)、Coro1a(Coronin 1A)、Ahsp(Alpha Hemoglobin Stabilizing Protein)、Rsad2(Radical S-AdenosylMethionine Domain Containing 2)。该12个特异性基因组合对低LET射线无反应，但接受高LET射线照射后，该基因组合出现转录水平的显著高调，基于该特征性生物学转录水平改变，可用来鉴别不同线性能量传递射线类型。
(2)本发明12个基因标志物可用于检测或辅助检测高线性能量传递(high-linearenergy transfer，high-LET)射线引发的肺部辐射损伤(早期炎症阶段)。
(3)本发明公开的12个辐射敏感基因组合对低LET射线(如X射线)辐射无反应，但接受高LET射线辐射后，上述敏感基因组合出现转录水平的明显高调。根据该12个特异性X射线敏感基因(Retnlb、S100a8、Csf3r、Slc4a1、Tubb1、Clec4d、Il1b、Apol11b、Alas2、Coro1a、Ahsp、Rsad2)转录水平差异表达倍数的平均值，即可确定是否为高LET射线暴露。
附图说明
图1：C57BL/6小鼠接受重离子射线12.5Gy照射后3周相比空白对照组(0Gy)，肺组织全基因组转录水平分析后分别获得剂量依赖的上调基因子集，进行火山图差异基因分析。
图2：重离子射线照射组火山图获得差异基因进行KEGG信号通路富集分析，提示与细胞因子-细胞因子受体相互作用、趋化因子信号通路、甲型流感、系统性红斑狼疮、造血细胞谱系、利什曼病、类风湿关节炎、p53信号通路、金黄色葡萄球菌感染，朊病毒等等生物学过程具有高度相关性。
图3：C57BL/6小鼠接受重离子射线12.5Gy(即生物学等效剂量20GyE)或X线20Gy照射后3周，肺组织全基因组转录水平分析后分别获得剂量依赖的上调基因子集，进行火山图差异基因分析。
图4：重离子射线相对空白对照高调差异基因子集(图1)、重离子射线相对X线高调差异基因子集(图3)经维恩图分析获得67个差异表达基因热图。该基因子集在重离子射线照射后3周呈上调表达，但在X线照射后呈稍上调表达或无明显变化。
图5：筛选获得12个特异性敏感基因的热图。该基因组合可以有效提示正常肺组织受到X线或低LET射线辐射时无显著的表达差异，但在重离子射线照射时具有显著的上调表达。
图6：qRT-PCR检测本发明12个特异性敏感基因在受到X射线或重离子射线照射后3周基因表达差异倍数(log2fold change)。该特异性基因组合在重离子射线照射后显著上调表达，在X线照射后无明显改变。
图7：本发明12个特异性敏感基因在空白对照组、X射线照射组、重离子射线照射组的平均值(log2相对表达值)。重离子射线照射后的基因表达量均值显著高于空白对照(P<0.01)与X线照射组(P<0.05)。
具体实施方式
下面结合具体实施例对本发明作进一步的说明。
实施例1
方法：
1.动物实验照射及分组：采用8-10周龄C57BL/6雌性小鼠，SPF级饲养，饲养条件为，温度(23±1)℃，相对湿度55％±5％，压力差≤10Pa，每日光照12h，自由摄食饮水。
2.照射前经异氟烷诱导麻醉后，转移至专用小鼠胸部照射装置并妥善固定。分别采用X线、重离子(碳离子)射线进行全肺野照射，引发肺损伤炎症(早期炎症阶段)。
3.照射及分组包括空白对照组(0Gy)、重离子射线单次12.5Gy照射组、X射线单次20Gy照射组。
4.照射后第3周提取新鲜肺组织、经总RNA抽提试剂(Trizol)处理后采用RNeasyMini试剂盒分离提取总RNA。为了避免DNA污染，用DNase I处理RNA。纯化的RNA在45.0μl无核酸酶的水中洗脱，并-20.0℃储存。使用NanoDrop ND-1000分光光度计评估RNA浓度和纯度。使用2100Bioanalyzer和相应的RNA Nano Chip测定RNA样品的完整性和纯度。基于全基因组基因表达阵列对样品进行分析。使用自带软件包生成表达矩阵并进行数据注释和汇总。在后续统计运算中，对数据进行log2转换以说明基因的表达上升或者下降。为分析不同时间点辐射与基因表达趋势关系，采用R语言软件包进行聚类分析，包括主成分分析，层次聚类，K均值聚类和自组织映射来识别剂量相关基因表达。
结果：
图1为C57BL/6小鼠接受重离子射线12.5Gy照射后3周相比空白对照组(0Gy)，肺组织全基因组转录水平分析后分别获得剂量依赖的上调表达基因子集，并进行差异基因分析的火山图。其中受重离子射线12.5Gy照射后上调表达倍数大于1.5倍的基因有131个，下调表达倍数大于1.5倍的有11个。
图2为对重离子照射组火山图获得差异表达的基因进行KEGG信号通路富集分析，提示与细胞因子-细胞因子受体相互作用、趋化因子信号通路、甲型流感、系统性红斑狼疮、造血细胞谱系、利什曼病、类风湿关节炎、p53信号通路、金黄色葡萄球菌感染，朊病毒等等生物学过程具有高度相关性。
图3为C57BL/6小鼠接受重离子剂量12.5Gy(即生物学等效剂量20GyE)、X射线剂量20Gy照射后3周，肺组织全基因组转录水平分析后分别获得剂量依赖的上调基因子集，并进行了火山图差异表达基因分析。从图中可以看出，其中重离子射线辐射组相对X射线辐射组上调表达倍数大于1.2倍的基因有84个，下调表达倍数大于1.2倍的有82个。
图4为将图1中重离子射线组相对空白对照组上调表达的差异基因子集、图3中重离子射线辐射组相对X射线辐射组上调表达的差异基因子集经维恩图分析获得67个上调表达基因的热图。该67个基因子集在重离子射线照射后3周呈上调表达，但在X射线照射后没有上调表达或上调表达不明显，即该67个基因为重离子射线特异性敏感基因。
本发明对上述67个基因作进一步的分析、研究和筛选，最后确定了12个靶基因，即Retnlb、S100a8、Csf3r、Slc4a1、Tubb1、Clec4d、Il1b、Apol11b、Alas2、Coro1a、Ahsp和Rsad2这12个基因。图5为本发明方法基于分别对不同射线照射后小鼠肺组织基因表达水平进行热图分析，该12个基因表达量在重离子射线辐射后3周时间点显著上调表达；而不因X射线辐射发生显著的上调表达。说明本发明12个基因组合可以有效提示正常肺组织受到X线或低LET射线辐射时无显著的表达差异，但在重离子射线照射时具有显著的上调表达。
对上述确定的12个基因进一步进行qRT-PCR检测，测定该12个基因分别在各组(空白照组、20GyX射线组、12.5Gy重离子射线组)肺组织中的表达水平。检测结果如图6所示，从中可以看出，本发明12个基因在X射线、重离子射线照射后的基因表达值的差异，在重离子射线辐射组明显上调表达，而在X射线中，该12个基因未发生显著的上调表达。图7为进一步对图6中各组12个基因差异表达倍数平均值的统计学分析，其中显示，在X射线、重离子射线照射后的基因表达差异倍数平均值，重离子射线组与空白对照组、重离子射线组与X线组表达差异均具有统计学意义(P<0.01，P<0.05)。
上述行qRT-PCR检测本发明12个基因的引物分别为：
Retnlb：
Retnlb-F：ATGAAGCCTACACTGTGTTTCC(SEQ ID NO:1)
Retnlb-R：CTGCCAGAAGACGTGACACT(SEQ ID NO:2)
S100a8:
S100a8-F：AAATCACCATGCCCTCTACAAG(SEQ ID NO:3)
S100a8-R：CCCACTTTTATCACCATCGCAA(SEQ ID NO:4)
Csf3r:
Csf3r-F：TGCACCCTGACTGGAGTTAC(SEQ ID NO:5)
Csf3r-R：TGAAATCTCGATGTGTCCACAG(SEQ ID NO:6)
Slc4a1:
Slc4a1-F：AGATCCCAGATCGAGACAGC(SEQ ID NO:7)
Slc4a1-R：GCTCCACATAGACCTGACCG(SEQ ID NO:8)
Tubb1:
Tubb1-F：CTGGGAGGTGATCGGGGAA(SEQ ID NO:9)
Tubb1-R：GCACATACTTCTTACCGTAGGCT(SEQ ID NO:10)
Clec4d:
Clec4d-F：ACCCGACATCCCCAACTGAT(SEQ ID NO:11)
Clec4d-R：CTCTCGTCCAGCGTAAAAAGT(SEQ ID NO:12)
Il1b:
Il1b-F：GAAATGCCACCTTTTGACAGTG(SEQ ID NO:13)
Il1b-R：TGGATGCTCTCATCAGGACAG(SEQ ID NO:14)
Apol11b:
Apol11b-F：AAAAGTCATTGATAACGCCACGG(SEQ ID NO:15)
Apol11b-R：CCTCGCTTGACAACTCTACTG(SEQ ID NO:16)
Alas2:
Alas2-F：GCAGCTATGTTGCTACGGTC(SEQ ID NO:17)
Alas2-R：GATGGGGCAGCGTCCAATAC(SEQ ID NO:18)
Coro1a:
Coro1a-F：TGGCTCTGATCTGTGAGGC(SEQ ID NO:19)
Coro1a-R：TCTTGTCTACTCGTCCAGTCTTG(SEQ ID NO:20)
Ahsp:
Ahsp-F：GGATCTCATTTCCGCAGGATTG(SEQ ID NO:21)
Ahsp-R：CTGCTGCCTGTAATAGTTGATGT(SEQ ID NO:22)
Rsad2:
Rsad2-F：AGCATTAGGGTGGCTAGATCC(SEQ ID NO:23)
Rsad2-R：CTGAGTGCTGTTCCCATCTTC(SEQ ID NO:24)。
综上所述，本发明提供了一种针对肺部辐射伤早期炎症阶段的检测标靶，一种基于上述12种特异性基因标志物表达水平改变的检测方法，鉴别出是客体是否受到高线性能量传递(high-linear energy transfer，high-LET)射线的损伤。本发明利用小鼠接受低、高LET射线全肺照射后3周的全基因组转录组学分析筛选出高LET特异性敏感基因组合。该特异性基因组合对低LET射线(如X射线)无明显响应，但接受高LET射线照射后，该基因组合出现转录水平的显著上调表达，基于该特异性生物学转录水平改变，也可用来鉴别不同线性能量传递射线类型。
本发明发现，当高线性能量传递(high-linear energy transfer，high-LET)射线急性暴露后，可以根据小鼠肺组织相关辐射敏感基因转录水平应激性改变而建立一种快速生物学剂量评估手段。该检测方法所包含的基因标志物对高LET射线(如重离子射线、α粒子)具有高度特异的辐射敏感性，对低LET射线(如X射线)无辐射敏感性，因此可以用来鉴别正常组织急性高LET射线辐射暴露，并提供辐射参考剂量。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
SEQUENCE LISTING
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Claims (3)
1.定量检测11个基因表达水平的试剂在制备检测重离子射线辐射引发的肺损伤炎症的制剂中的应用，所述11个基因为Retnlb、S100a8、Csf3r、Slc4a1、Tubb1、Clec4d、Il1b、Apol11b、Alas2、Coro1a和Rsad2，所述肺损伤炎症为早期炎症阶段。
2.根据权利要求1所述的应用，其特征在于，定量检测11个基因表达水平的引物为：
Retnlb：
Retnlb-F：ATGAAGCCTACACTGTGTTTCC
Retnlb-R：CTGCCAGAAGACGTGACACT
S100a8:
S100a8-F：AAATCACCATGCCCTCTACAAG
S100a8-R：CCCACTTTTATCACCATCGCAA
Csf3r:
Csf3r-F：TGCACCCTGACTGGAGTTAC
Csf3r-R：TGAAATCTCGATGTGTCCACAG
Slc4a1:
Slc4a1-F：AGATCCCAGATCGAGACAGC
Slc4a1-R：GCTCCACATAGACCTGACCG
Tubb1:
Tubb1-F：CTGGGAGGTGATCGGGGAA
Tubb1-R：GCACATACTTCTTACCGTAGGCT
Clec4d:
Clec4d-F：ACCCGACATCCCCAACTGAT
Clec4d-R：CTCTCGTCCAGCGTAAAAAGT
Il1b:
Il1b-F：GAAATGCCACCTTTTGACAGTG
Il1b-R：TGGATGCTCTCATCAGGACAG
Apol11b:
Apol11b-F：AAAAGTCATTGATAACGCCACGG
Apol11b-R：CCTCGCTTGACAACTCTACTG
Alas2:
Alas2-F：GCAGCTATGTTGCTACGGTC
Alas2-R：GATGGGGCAGCGTCCAATAC
Coro1a:
Coro1a-F：TGGCTCTGATCTGTGAGGC
Coro1a-R：TCTTGTCTACTCGTCCAGTCTTG
Rsad2:
Rsad2-F：AGCATTAGGGTGGCTAGATCC
Rsad2-R：CTGAGTGCTGTTCCCATCTTC。
3.一种检测重离子射线辐射引发的肺损伤炎症的产品，其特征在于，该产品中含有定量检测11个基因表达水平的引物；所述11个基因为Retnlb、S100a8、Csf3r、Slc4a1、Tubb1、Clec4d、Il1b、Apol11b、Alas2、Coro1a、Ahsp和Rsad2；所述肺损伤炎症为早期炎症阶段；所述定量检测11个基因表达水平的引物为：
Retnlb：
Retnlb-F：ATGAAGCCTACACTGTGTTTCC
Retnlb-R：CTGCCAGAAGACGTGACACT
S100a8:
S100a8-F：AAATCACCATGCCCTCTACAAG
S100a8-R：CCCACTTTTATCACCATCGCAA
Csf3r:
Csf3r-F：TGCACCCTGACTGGAGTTAC
Csf3r-R：TGAAATCTCGATGTGTCCACAG
Slc4a1:
Slc4a1-F：AGATCCCAGATCGAGACAGC
Slc4a1-R：GCTCCACATAGACCTGACCG
Tubb1:
Tubb1-F：CTGGGAGGTGATCGGGGAA
Tubb1-R：GCACATACTTCTTACCGTAGGCT
Clec4d:
Clec4d-F：ACCCGACATCCCCAACTGAT
Clec4d-R：CTCTCGTCCAGCGTAAAAAGT
Il1b:
Il1b-F：GAAATGCCACCTTTTGACAGTG
Il1b-R：TGGATGCTCTCATCAGGACAG
Apol11b:
Apol11b-F：AAAAGTCATTGATAACGCCACGG
Apol11b-R：CCTCGCTTGACAACTCTACTG
Alas2:
Alas2-F：GCAGCTATGTTGCTACGGTC
Alas2-R：GATGGGGCAGCGTCCAATAC
Coro1a:
Coro1a-F：TGGCTCTGATCTGTGAGGC
Coro1a-R：TCTTGTCTACTCGTCCAGTCTTG
Rsad2:
Rsad2-F：AGCATTAGGGTGGCTAGATCC
Rsad2-R：CTGAGTGCTGTTCCCATCTTC。
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| CN102858991A (zh) * | 2009-10-15 | 2013-01-02 | 克雷桑多生物科技公司 | 生物标志物及炎性疾病活动性的测量和监测方法 |
| CN107801402A (zh) * | 2015-04-06 | 2018-03-13 | 株式会社爱茉莉太平洋 | 用于诊断由微尘引起的皮肤损伤的组合物及包含高良姜素作为有效成分的组合物 |
| EP3299478A1 (en) * | 2016-09-27 | 2018-03-28 | Oncology Venture ApS | Methods for predicting drug responsiveness in cancer patients |
| CN108300780A (zh) * | 2018-02-07 | 2018-07-20 | 北京泱深生物信息技术有限公司 | Tmtc1基因作为一种新的分子标志物 |
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| CN102586243A (zh) * | 2012-03-08 | 2012-07-18 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 一种预防电磁辐射致脑损伤的标志物 |
| US10435747B2 (en) * | 2014-08-19 | 2019-10-08 | Arizona Board Of Regents On Behalf Of Arizona State University | Radiation biodosimetry systems |
| US11613784B2 (en) * | 2016-03-25 | 2023-03-28 | The Trustees Of Columbia University In The City Of New York | Next-generation biomarkers to detect sun damage and predict skin cancer risk |
| CN106636328B (zh) * | 2016-09-27 | 2019-11-01 | 南方医科大学 | 关于工频电磁辐射的微小rna剂量标志物 |
| CN106645740B (zh) * | 2016-09-27 | 2019-02-12 | 南方医科大学 | 关于工频电磁辐射的趋化因子剂量标志物 |
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| CN102858991A (zh) * | 2009-10-15 | 2013-01-02 | 克雷桑多生物科技公司 | 生物标志物及炎性疾病活动性的测量和监测方法 |
| CN107801402A (zh) * | 2015-04-06 | 2018-03-13 | 株式会社爱茉莉太平洋 | 用于诊断由微尘引起的皮肤损伤的组合物及包含高良姜素作为有效成分的组合物 |
| EP3299478A1 (en) * | 2016-09-27 | 2018-03-28 | Oncology Venture ApS | Methods for predicting drug responsiveness in cancer patients |
| CN108300780A (zh) * | 2018-02-07 | 2018-07-20 | 北京泱深生物信息技术有限公司 | Tmtc1基因作为一种新的分子标志物 |
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