人类原发性膝关节骨性关节炎病变滑膜全基因组表达与分析
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摘要
研究背景
原发性膝关节骨性关节炎(KOA)又称特发性膝关节骨性关节炎,是老年人常见的一种退行性关节疾病。流行病学调查显示,国内该病的发病率为5%,而60岁以上者更是高达15-20﹪。随着世界人口老龄化,本病的发生率在全球范围内呈现逐年上升趋势,研究该病的病因、发病机制,并有效的进行预防和治疗已成为全球骨科学界的重要课题。
一般认为,KOA的发病与年龄、性别、肥胖、遗传、激素、运动、创伤、职业等多种因素密切相关。其发病是在力学和生物学因素共同作用下导致软骨细胞、细胞外基质及软骨下骨三者降解和合成的正常偶联失衡的结果,基本特征是关节软骨破坏或变性产生的关节病变。临床上以膝关节疼痛、僵硬、活动受限、活动时可有摩擦响声为特征,病变累及骨、关节软骨、滑膜及关节周围支持结构。早期表现为关节疼痛,中期出现退变性膝内翻或膝外翻,晚期全关节间隙消失,伴屈曲畸形。
KOA的诊断通常是依靠临床表现和放射线检查。然而,在KOA的早期并不能通过放射线检查发现关节软骨的变化,因为在放射线检查能够发现软骨有改变之前,软骨一定在分子代谢和超微结构上发生了非常显著的变化。
滑膜是关节滑动体系中的重要组成部分,其中有大量的血液供应和丰富的神经供应,滑膜的分泌、吸收和营养供应是关节软骨维持正常代谢和功能的前提。研究发现,在KOA中,病变关节滑膜细胞凋亡远较正常组增强。
此前的众多对KOA发病机制的研究多以关节软骨为对象,而本项研究在全球范围内首次应用全基因组表达谱芯片技术对人类正常膝关节滑膜及原发性KOA病变滑膜进行了研究与分析。
研究目的
尽管在最近十年来作出了很多努力,但是,原发性KOA的主要发病机制仍然不十分明了,而且没有针对的治疗办法。因此本项研究,目的在于通过人类原发性KOA病变滑膜全基因组基因谱的表达以鉴定与本病相关的全部差异表达基因,根据基因功能的改变情况,探讨其与本病发生的内在联系,并研究潜在的治疗目标。为原发性KOA的基因治疗打下坚实的基础。
与此同时,对部分差异基因进行复孔的实时定量PCR验证,目的是进一步验证所获得的差异基因在原发性KOA病理过程中的意义。
研究方法
1、本次共对16例膝关节滑膜样本进行了实验研究,其中,原发性KOA病人12例,根据纳入标准及排除标准选择。实验用滑膜全部于膝关节镜手术和人工膝关节置换术中获得。并根据Kellgren和Laurence放射学分级标准将每4个病人的滑膜样本分为一组,分为轻(A3)、中(A4)、重(A5)三组;将4例健康人的膝关节滑膜样本分为B1组。
2、RNA样品制备
(1).两相分离
(2).RNA沉淀
(3).RNA清洗
(4).重新溶解RNA沉淀
(5).RNA质量检测
3、aRNA样品标记和合成
(1).cDNA合成
(2).cDNA第二链合成
(3).aRNA合成
(4).aRNA纯化
(5).aa-UTP aRNA间接标记
(6).质量控制
4、芯片预杂交
5、杂交
6、洗片
7、结果扫描,数据读取
8、合成的cDNA用于实时定量PCR
9、进行Realtime PCR反应
研究结果
我们对所有16例实验样本分别进行了全基因组芯片分析,在每张芯片上所拥有的40000个点上, 16例样本所共同拥有的31080个基因得到表达,而每个样本中又会含有少量与其它样本不同的基因。
按照预先的分组,在31080个共有基因范围内,对每个组内每个对应基因运算其均量,将每组样本转变为一个个体(即A3、A4、A5、B1四组),进行组间比较。
首先,我们将病变组(A3、A4、A5三组)分别与健康组(B1)进行比较,找出三组中共同的差异表达基因。
通过本次实验,在31080个共有基因范围内,鉴定出很多差异表达的基因,而具有统计学意义的差异基因共73个,其中:2倍上调的基因46个,4倍上调的基因10个,8倍上调的基因5个;2倍下调的基因27个,4倍下调的基因3个,8倍下调的基因1个。包括我们十分期待的合成代谢和分解代谢矩阵基因功能调节的变化。尤其重要的是氧化防御基因的下调节,过氧化物歧化酶2和3,和谷胱甘肽过氧化物酶3尤其突出。这表明在骨性关节炎细胞和矩阵的连续氧化应激是一个主要的潜在发病机理。与细胞表型稳定性相关的基因,在原发性KOA的关节滑膜中显著减少,说明它的出现受到抑制,是加速关节退化的另一因素。
第二,病变组组间比较:试图通过比较找到轻、中、重度KOA滑膜中基因表达的差异,然而我们发现,这73个差异基因,在病变组间的表达没有显著差异。
根据科学实验结果可以重现的原则,对任意选定的5个差异基因进行了复孔的PCR实时定量检测,通过三次的重复实验,我们发现,三次的结果惊人的一致,经统计学处理,全部是:P<0.001,有显著性差异,进一步证实了膝关节滑膜组织中的差异基因在原发性KOA发生过程中的关键作用。
结论
1、膝关节滑膜中的差异表达基因是原发性膝关节骨性关节炎发生与发展的重要原因。
2、原发性膝关节骨性关节炎发生与发展的差异基因及其功能不因病情轻重的变化而变化。
3、参与合成代谢的相关基因功能下调与参与分解代谢的相关基因功能上调加速了膝关节滑膜的退化,进而加速了全膝关节的退变进程。
4、与免疫相关基因功能的上调使位于滑膜中的吞噬细胞过度活跃,导致破坏与修复的平衡代谢被打破,进而使膝关节滑膜、软骨等结构遭受破坏。
5、与信息传递相关基因功能的下调使膝关节滑膜代谢的协调性被打破而出现代谢紊乱,进而导致膝关节代谢紊乱。
6、多基因联合作用导致了原发性膝关节骨性关节炎的发生与发展。
background
Primary osteoarthritis of the knee (KOA) also known as idiopathic osteoarthritis of the knee, and osteoarthritis (OA) is the most common degenerative joint disease in the aged people all over the world. In a previous epidemioIogical study, prevalence of KOA reachs 5%,and it increased to 15-20﹪in the aged people older than 65 years. With the ageing of the population, the prevalence show an upward trend year by year; the etiology, pathogenesy, and effective prevention and treatment of KOA have become an important global subject in orthopaedicics.
Generally,the prevalence of primary osteoarthritis of the knee are closely related with age, sex, obesity, genetics, hormones, sports, trauma and occupation.Both mechanical and biological factors lead to normal coupling imbalance of degradation and synthesis in the cartilage cells,extracellular matrix and subchondral bone, articular cartilage damage or degeneration initate the articular pathological changes in the osteoarthritis of the knee. The knee pain, stiffness, limitation of activity and friction noise accompanying the activities are mainly clinical characteristics , and osteoarthritis is one of the most common disabling conditions, affecting many parts of the joint, including bone, synovium, ligaments, and articular carilage.The knee pain, Varus knee or valgus knee, joint space disappeared with flexion deformity will appear gradually in mild and moderate and severe late-stage OA.
Diagnosis of OA commonly depends on clinical and radiographic findings. However, changes in cartilage associated with the early stage of OA cannot be detected using radiographs, because significant cartilage degeneration must occur before radiographic findings show alterations of the appearance of cartilage.
Synovium is an important part of Synovial joint sliding system with large number of the rich blood supply and nerve supply; the secretion of synovial, absorption and nutrition supply to maintain normal articular cartilage metabolism and function. Study indicates that the synovial cell apoptosis severely increases in osteoarthritis synovium of the knee joint of humans than normal synovium of the knee joint.
In the pathogenetic study, much attention has been focused on developing assays for cartilage molecules in the primary osteoarthritis of the knee joint of humans,but this is the first report of the use of whole genome expression profiles chip technology to analyse normal synovium of the knee joint of humans and primary osteoarthritis synovium of the knee joint of patients.
Objective
Despite many research efforts in recent decades, the major pathogenetic mechanisms of primary osteoarthritis of the knee, including gene alterations occurring during osteoarthritis cartilage degeneration, are poorly understood, and there is no disease-modifying treatment approach. This study was therefore initiated in order to identify all differentially expressed disease-related genes using global analyses of gene expression in primary OA synovium of the knee joint of humans, according to the changes in gene function,and identify potential therapeutic targets to found solid foundation for gene therapy .
Some differential expression genes were performed real time quantitative polymerase chain reaction in order to further identify the differential expression genes obtained in primary OA synovium of the knee joint of humans and to find the significance in the process of disease.
Methods
1.According to addition and exclusion standards, 12 patients with OA were performed , and OA synovium of the knee joint of humans was obtained at the time of arthroscopic surgery and total knee replacement.According to Kellgren and Laurence radiology classification standards 4 patients became a group, then mild(A3)and moderate(A4)and severe late-stage OA groups(A5)appeared. In addition,4 normal synovium of the knee joint samples became B1 group.
2.RNA sample preparation
(1)two-dimensional separation
(2)RNA praecipitatum
(3)RNA emundation
(4)again dissolve RNA praecipitatum
(5)RNA mass detection
3.aRNA sample symbol and synthesis
(1)cDNA synthesis
(2)second-strand of cDNA synthesis
(3)aRNA synthesis
(4)aRNA depuration
(5)aa-UTP aRNA indirect labelling
(6)quality control
4.chip prehybridization
5.Hybridisation
6.chip emundation
7.result scanning, data reading
8.synthetical cDNA were used to real time quantitative polymerase chain reaction
9.performing real time quantitative polymerase chain reaction
Results
All the 16 samples were performed the genome-wide analysis of chips, among the 16 samples, the 39,202 genes were expressed in evrey sample, and each sample contained a small amount of different genes compared with other samples.
According to the foregoing groups, the 39,202 genes within each group were corresponding calculated the mean, each group was considered as a entirety (A3, A4, A5, B1 four groups), comparing among the four groups. First, we performed a comparison between the disease groups(A3、A4、A5 three groups)and the mormal groups(B1 group)to identify differential expression genes among the three groups in common.
In this experiment, among the 39,202 genes, many differential expression genes were identified, and 73 genes showed statistical significance, of which: 46 genes were up-regulation 2-fold, 10 genes were up-regulation 4-fold, 5 genes were up-regulation 8-fold; 27 genes were down-regulation 2-fold, 3 genes were down-regulation 4-fold, 1 genes were down-regulation 8-fold , very much look forward to including anabolism and catabolism matrix gene function change. Particularly important oxidative defense gene were down-regulation,superoxide dismutase 2 and 3,and glutathione peroxidase 3 particularly conspicuous. This showed that successive oxidative stress of osteoarthritis in the cells and the matrix was a major potential pathogenesis.The genes related cellular phenotypic stability significant decreased in primary OA synovium of the knee joint of humans,that indicated those genes were restrained.It is another factor of accelerating degradation of the joint.
Second,we performed comparison among the three disease groups to identify differential expression genes in mild and moderate and severe late-stage primary OA synovium of the knee joint of patients,but the results showed 73 differential expression genes have not significant deviation in the disease groups.
According to the results of scientific experiments to be reproduceed, 5 differential expression genes were optional selected to perform real time quantitative polymerase chain reaction, through three times repetitive experiments , we miraculously observed the same results of the experiments.Through the statistical treatment, P values less than 0.01 were considered significant to further confirmed differential expression genes in OA synovium of the knee joint of patients played an important role in the process of primary OA.
Conclusion
1.Differential expression genes in primary OA synovium of the knee joint is the root causes in the development process of primary OA.
2.Differential expression genes in primary OA synovium of the knee joint and the function of those genes have no changes following the changes of the development process .
3.Both the genes related in anabolism were down-regulation and the genes related in catabolism were up-regulation accelerate the degeneration of synovial knee, thereby speeding up the entire process of degeneration of the knee.
4.Phagocytic cell in OA synovium become overacfivity because the genes related immunization were up-regulation, breaking the balance of destruction and renovation, then the knee synovium, cartilage and other structures destroyed gradually.
5. Coordination of the synovium of the knee joint metabolism was broken because the the genes related information transfer were down-regulation, thus leading to metabolic disorder of the knee.
6.Many genes unite to initiate the Occurrence and development of primary OA of the knee, it also confirmed organization aging theory from another side.
原发性膝关节骨性关节炎(KOA)又称特发性膝关节骨性关节炎,是老年人常见的一种退行性关节疾病。流行病学调查显示,国内该病的发病率为5%,而60岁以上者更是高达15-20﹪。随着世界人口老龄化,本病的发生率在全球范围内呈现逐年上升趋势,研究该病的病因、发病机制,并有效的进行预防和治疗已成为全球骨科学界的重要课题。
一般认为,KOA的发病与年龄、性别、肥胖、遗传、激素、运动、创伤、职业等多种因素密切相关。其发病是在力学和生物学因素共同作用下导致软骨细胞、细胞外基质及软骨下骨三者降解和合成的正常偶联失衡的结果,基本特征是关节软骨破坏或变性产生的关节病变。临床上以膝关节疼痛、僵硬、活动受限、活动时可有摩擦响声为特征,病变累及骨、关节软骨、滑膜及关节周围支持结构。早期表现为关节疼痛,中期出现退变性膝内翻或膝外翻,晚期全关节间隙消失,伴屈曲畸形。
KOA的诊断通常是依靠临床表现和放射线检查。然而,在KOA的早期并不能通过放射线检查发现关节软骨的变化,因为在放射线检查能够发现软骨有改变之前,软骨一定在分子代谢和超微结构上发生了非常显著的变化。
滑膜是关节滑动体系中的重要组成部分,其中有大量的血液供应和丰富的神经供应,滑膜的分泌、吸收和营养供应是关节软骨维持正常代谢和功能的前提。研究发现,在KOA中,病变关节滑膜细胞凋亡远较正常组增强。
此前的众多对KOA发病机制的研究多以关节软骨为对象,而本项研究在全球范围内首次应用全基因组表达谱芯片技术对人类正常膝关节滑膜及原发性KOA病变滑膜进行了研究与分析。
研究目的
尽管在最近十年来作出了很多努力,但是,原发性KOA的主要发病机制仍然不十分明了,而且没有针对的治疗办法。因此本项研究,目的在于通过人类原发性KOA病变滑膜全基因组基因谱的表达以鉴定与本病相关的全部差异表达基因,根据基因功能的改变情况,探讨其与本病发生的内在联系,并研究潜在的治疗目标。为原发性KOA的基因治疗打下坚实的基础。
与此同时,对部分差异基因进行复孔的实时定量PCR验证,目的是进一步验证所获得的差异基因在原发性KOA病理过程中的意义。
研究方法
1、本次共对16例膝关节滑膜样本进行了实验研究,其中,原发性KOA病人12例,根据纳入标准及排除标准选择。实验用滑膜全部于膝关节镜手术和人工膝关节置换术中获得。并根据Kellgren和Laurence放射学分级标准将每4个病人的滑膜样本分为一组,分为轻(A3)、中(A4)、重(A5)三组;将4例健康人的膝关节滑膜样本分为B1组。
2、RNA样品制备
(1).两相分离
(2).RNA沉淀
(3).RNA清洗
(4).重新溶解RNA沉淀
(5).RNA质量检测
3、aRNA样品标记和合成
(1).cDNA合成
(2).cDNA第二链合成
(3).aRNA合成
(4).aRNA纯化
(5).aa-UTP aRNA间接标记
(6).质量控制
4、芯片预杂交
5、杂交
6、洗片
7、结果扫描,数据读取
8、合成的cDNA用于实时定量PCR
9、进行Realtime PCR反应
研究结果
我们对所有16例实验样本分别进行了全基因组芯片分析,在每张芯片上所拥有的40000个点上, 16例样本所共同拥有的31080个基因得到表达,而每个样本中又会含有少量与其它样本不同的基因。
按照预先的分组,在31080个共有基因范围内,对每个组内每个对应基因运算其均量,将每组样本转变为一个个体(即A3、A4、A5、B1四组),进行组间比较。
首先,我们将病变组(A3、A4、A5三组)分别与健康组(B1)进行比较,找出三组中共同的差异表达基因。
通过本次实验,在31080个共有基因范围内,鉴定出很多差异表达的基因,而具有统计学意义的差异基因共73个,其中:2倍上调的基因46个,4倍上调的基因10个,8倍上调的基因5个;2倍下调的基因27个,4倍下调的基因3个,8倍下调的基因1个。包括我们十分期待的合成代谢和分解代谢矩阵基因功能调节的变化。尤其重要的是氧化防御基因的下调节,过氧化物歧化酶2和3,和谷胱甘肽过氧化物酶3尤其突出。这表明在骨性关节炎细胞和矩阵的连续氧化应激是一个主要的潜在发病机理。与细胞表型稳定性相关的基因,在原发性KOA的关节滑膜中显著减少,说明它的出现受到抑制,是加速关节退化的另一因素。
第二,病变组组间比较:试图通过比较找到轻、中、重度KOA滑膜中基因表达的差异,然而我们发现,这73个差异基因,在病变组间的表达没有显著差异。
根据科学实验结果可以重现的原则,对任意选定的5个差异基因进行了复孔的PCR实时定量检测,通过三次的重复实验,我们发现,三次的结果惊人的一致,经统计学处理,全部是:P<0.001,有显著性差异,进一步证实了膝关节滑膜组织中的差异基因在原发性KOA发生过程中的关键作用。
结论
1、膝关节滑膜中的差异表达基因是原发性膝关节骨性关节炎发生与发展的重要原因。
2、原发性膝关节骨性关节炎发生与发展的差异基因及其功能不因病情轻重的变化而变化。
3、参与合成代谢的相关基因功能下调与参与分解代谢的相关基因功能上调加速了膝关节滑膜的退化,进而加速了全膝关节的退变进程。
4、与免疫相关基因功能的上调使位于滑膜中的吞噬细胞过度活跃,导致破坏与修复的平衡代谢被打破,进而使膝关节滑膜、软骨等结构遭受破坏。
5、与信息传递相关基因功能的下调使膝关节滑膜代谢的协调性被打破而出现代谢紊乱,进而导致膝关节代谢紊乱。
6、多基因联合作用导致了原发性膝关节骨性关节炎的发生与发展。
background
Primary osteoarthritis of the knee (KOA) also known as idiopathic osteoarthritis of the knee, and osteoarthritis (OA) is the most common degenerative joint disease in the aged people all over the world. In a previous epidemioIogical study, prevalence of KOA reachs 5%,and it increased to 15-20﹪in the aged people older than 65 years. With the ageing of the population, the prevalence show an upward trend year by year; the etiology, pathogenesy, and effective prevention and treatment of KOA have become an important global subject in orthopaedicics.
Generally,the prevalence of primary osteoarthritis of the knee are closely related with age, sex, obesity, genetics, hormones, sports, trauma and occupation.Both mechanical and biological factors lead to normal coupling imbalance of degradation and synthesis in the cartilage cells,extracellular matrix and subchondral bone, articular cartilage damage or degeneration initate the articular pathological changes in the osteoarthritis of the knee. The knee pain, stiffness, limitation of activity and friction noise accompanying the activities are mainly clinical characteristics , and osteoarthritis is one of the most common disabling conditions, affecting many parts of the joint, including bone, synovium, ligaments, and articular carilage.The knee pain, Varus knee or valgus knee, joint space disappeared with flexion deformity will appear gradually in mild and moderate and severe late-stage OA.
Diagnosis of OA commonly depends on clinical and radiographic findings. However, changes in cartilage associated with the early stage of OA cannot be detected using radiographs, because significant cartilage degeneration must occur before radiographic findings show alterations of the appearance of cartilage.
Synovium is an important part of Synovial joint sliding system with large number of the rich blood supply and nerve supply; the secretion of synovial, absorption and nutrition supply to maintain normal articular cartilage metabolism and function. Study indicates that the synovial cell apoptosis severely increases in osteoarthritis synovium of the knee joint of humans than normal synovium of the knee joint.
In the pathogenetic study, much attention has been focused on developing assays for cartilage molecules in the primary osteoarthritis of the knee joint of humans,but this is the first report of the use of whole genome expression profiles chip technology to analyse normal synovium of the knee joint of humans and primary osteoarthritis synovium of the knee joint of patients.
Objective
Despite many research efforts in recent decades, the major pathogenetic mechanisms of primary osteoarthritis of the knee, including gene alterations occurring during osteoarthritis cartilage degeneration, are poorly understood, and there is no disease-modifying treatment approach. This study was therefore initiated in order to identify all differentially expressed disease-related genes using global analyses of gene expression in primary OA synovium of the knee joint of humans, according to the changes in gene function,and identify potential therapeutic targets to found solid foundation for gene therapy .
Some differential expression genes were performed real time quantitative polymerase chain reaction in order to further identify the differential expression genes obtained in primary OA synovium of the knee joint of humans and to find the significance in the process of disease.
Methods
1.According to addition and exclusion standards, 12 patients with OA were performed , and OA synovium of the knee joint of humans was obtained at the time of arthroscopic surgery and total knee replacement.According to Kellgren and Laurence radiology classification standards 4 patients became a group, then mild(A3)and moderate(A4)and severe late-stage OA groups(A5)appeared. In addition,4 normal synovium of the knee joint samples became B1 group.
2.RNA sample preparation
(1)two-dimensional separation
(2)RNA praecipitatum
(3)RNA emundation
(4)again dissolve RNA praecipitatum
(5)RNA mass detection
3.aRNA sample symbol and synthesis
(1)cDNA synthesis
(2)second-strand of cDNA synthesis
(3)aRNA synthesis
(4)aRNA depuration
(5)aa-UTP aRNA indirect labelling
(6)quality control
4.chip prehybridization
5.Hybridisation
6.chip emundation
7.result scanning, data reading
8.synthetical cDNA were used to real time quantitative polymerase chain reaction
9.performing real time quantitative polymerase chain reaction
Results
All the 16 samples were performed the genome-wide analysis of chips, among the 16 samples, the 39,202 genes were expressed in evrey sample, and each sample contained a small amount of different genes compared with other samples.
According to the foregoing groups, the 39,202 genes within each group were corresponding calculated the mean, each group was considered as a entirety (A3, A4, A5, B1 four groups), comparing among the four groups. First, we performed a comparison between the disease groups(A3、A4、A5 three groups)and the mormal groups(B1 group)to identify differential expression genes among the three groups in common.
In this experiment, among the 39,202 genes, many differential expression genes were identified, and 73 genes showed statistical significance, of which: 46 genes were up-regulation 2-fold, 10 genes were up-regulation 4-fold, 5 genes were up-regulation 8-fold; 27 genes were down-regulation 2-fold, 3 genes were down-regulation 4-fold, 1 genes were down-regulation 8-fold , very much look forward to including anabolism and catabolism matrix gene function change. Particularly important oxidative defense gene were down-regulation,superoxide dismutase 2 and 3,and glutathione peroxidase 3 particularly conspicuous. This showed that successive oxidative stress of osteoarthritis in the cells and the matrix was a major potential pathogenesis.The genes related cellular phenotypic stability significant decreased in primary OA synovium of the knee joint of humans,that indicated those genes were restrained.It is another factor of accelerating degradation of the joint.
Second,we performed comparison among the three disease groups to identify differential expression genes in mild and moderate and severe late-stage primary OA synovium of the knee joint of patients,but the results showed 73 differential expression genes have not significant deviation in the disease groups.
According to the results of scientific experiments to be reproduceed, 5 differential expression genes were optional selected to perform real time quantitative polymerase chain reaction, through three times repetitive experiments , we miraculously observed the same results of the experiments.Through the statistical treatment, P values less than 0.01 were considered significant to further confirmed differential expression genes in OA synovium of the knee joint of patients played an important role in the process of primary OA.
Conclusion
1.Differential expression genes in primary OA synovium of the knee joint is the root causes in the development process of primary OA.
2.Differential expression genes in primary OA synovium of the knee joint and the function of those genes have no changes following the changes of the development process .
3.Both the genes related in anabolism were down-regulation and the genes related in catabolism were up-regulation accelerate the degeneration of synovial knee, thereby speeding up the entire process of degeneration of the knee.
4.Phagocytic cell in OA synovium become overacfivity because the genes related immunization were up-regulation, breaking the balance of destruction and renovation, then the knee synovium, cartilage and other structures destroyed gradually.
5. Coordination of the synovium of the knee joint metabolism was broken because the the genes related information transfer were down-regulation, thus leading to metabolic disorder of the knee.
6.Many genes unite to initiate the Occurrence and development of primary OA of the knee, it also confirmed organization aging theory from another side.
引文
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