CN116966185A - 特拉匹韦在制备malt1抑制剂、抗malt1依赖性肿瘤的药物中的应用及抗肿瘤药物 - Google Patents
特拉匹韦在制备malt1抑制剂、抗malt1依赖性肿瘤的药物中的应用及抗肿瘤药物 Download PDFInfo
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- CN116966185A CN116966185A CN202311114942.8A CN202311114942A CN116966185A CN 116966185 A CN116966185 A CN 116966185A CN 202311114942 A CN202311114942 A CN 202311114942A CN 116966185 A CN116966185 A CN 116966185A
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及特拉匹韦在制备MALT1抑制剂、抗MALT1依赖性肿瘤的药物中的应用及抗肿瘤药物。本发明人在离体细胞药物筛选过程中,偶然发现特拉匹韦具有抑制MALT1作用,而抑制MALT1具有抑制弥漫性大B细胞淋巴瘤和MALT淋巴瘤作用,因此,特拉匹韦具有抗弥漫大B细胞淋巴瘤和MALT淋巴瘤作用,可扩大其适应症范围。
Description
技术领域
本发明涉及特拉匹韦在制备MALT1抑制剂、抗MALT1依赖性肿瘤的药物中的应用及抗肿瘤药物,属于生物医药领域。
背景技术
弥漫性大B细胞淋巴瘤(Diffuse large B cell lymphoma,DLBCL)是非霍奇金(non-Hodgkin lymphoma,NHL)淋巴瘤最常见的类型,约占30-40%。DLBCL是一组大细胞、侵袭性的恶性淋巴瘤。根据基因表达谱,DLBCL分成三种分子亚型:生发中心B细胞型(Germinal center B cell like DLBCL,GCB-DLBCL)、活化B细胞型(Activated B celllike DLBCL,ABC-DLBCL)和原发纵膈B细胞型(Primary mediastinal B cell lymphoma,PMBL)。其中ABC-DLBCL的恶性程度最高,对现有化学疗法有强的耐药性。因此,寻找有效治疗ABC-DLBCL的药物和治疗方法是临床上急需解决的问题。
结外黏膜相关组织边缘区淋巴瘤(mucosa associated lymphoid tissue,MALT淋巴瘤)系发生在淋巴结边缘带的淋巴瘤,MALT1((Mucosa Associated Lymphoid TissueLymphoma Translocation Gene 1,黏膜相关淋巴瘤易位基因1)首先在MALT淋巴瘤组织中发现,其结构包含N端的死亡域(death domain,DD),C端的一个Ig样结构域和一个与caspase家族蛋白同源的结构域,该区域可催化特定精氨酸蛋白的裂解被定义为paracaspase,且是人体唯一的paracaspase。MALT1在NF-κB信号转导和激活中起重要作用,一方面MALT1作为支架蛋白,与CARD家族成员[CARD9、CARD10(也称CARMA3)、CARD11(也称为CARMA1)及CARD14(也称为CARMA2)]以及BCL10形成CARD-BCL10-MALT1(CBM)复合物促进NF-κB信号通路激活;另一方面其蛋白水解酶作用,可裂解NF-κB抑制分子A20、CYLD等继而激活NF-κB信号通路,其表达异常与淋巴瘤和自身免疫性疾病等疾病密切相关。
在ABC-DLBCL中,CARD11(也称为CARMA1)、BCL10和MALT1常常活性增强或是处于持续活化的状态,进而引起NF-κB的过度活化以及肿瘤的发生发展。抑制CBM的表达能选择性地杀死ABC-DL BCL细胞,而特异性地抑制MALT1的活性能够抑制ABC-DLBCL细胞生长,促进肿瘤细胞死亡,提示抑制MALT1是治疗ABC-DLBCL的非常具有潜力的药物靶点。研究表明,MALT1抑制剂MI-2和吩噻嗪类衍生物(如Mepazine)可有效抑制ABC-DLBCL细胞增殖。但MI-2现只是工具药,不能用于临床;吩噻嗪类衍生物同时也是多巴胺受体的拮抗剂,具有一定副作用如心脏毒性,限制了其应用。因此,寻找MALT1抑制剂对于靶向治疗恶性肿瘤ABC-DLBCL具有重要意义。
研究报道,MALT1对恶性肿瘤弥漫性大B细胞淋巴瘤,特别是ABC-DLBCL的肿瘤细胞存活非常重要,抑制MALT1能够有效地、选择性地抑制ABC-DLBCL肿瘤细胞生长。因此,抑制MALT1的药物(MALT1抑制剂)能够预防或治疗弥漫性大B细胞淋巴瘤,特别是ABC-DLBCL。
特拉匹韦是一种丙型肝炎病毒(HCV)NS3/4A丝氨酸蛋白酶抑制剂,具有抑制HCV复制而抗病毒作用,但是否具有抑制MALT1作用和抗ABC-DLBCL淋巴瘤作用尚未见报道。
在本发明中,除非另有说明,“特拉匹韦”应理解为“特拉匹韦的化合物或它的半合成衍生物之一或它们的盐(化合物的盐或半合成衍生物的盐)之一或它们的酯(化合物的酯或半合成衍生物的酯)之一或它们的酯盐(化合物的酯的盐或半合成衍生物的酯的盐)之一”或“氘代特拉匹韦”;或特拉匹韦的任何立体异构形式。
发明内容
本申请人首次发现特拉匹韦对MALT1具有抑制作用,特拉匹韦是否具有通过抑制MALT1进而抑制弥漫性大B细胞淋巴瘤和MALT淋巴瘤的作用尚未见报道。
针对现有技术的不足,本发明的目的之一在于提供特拉匹韦在制备MALT1抑制剂中的应用;本发明的目的之二在于提供特拉匹韦在制备预防或治疗MALT1依赖性肿瘤的药物中的应用;本发明的目的之三在于提供一种抗肿瘤药物。
特拉匹韦的结构式如式Ⅰ所示,分子式为:C36H53N7O6。
为了解决上述技术问题,本发明的技术方案如下:
特拉匹韦或其药学上可接受的盐在制备MALT1抑制剂中的应用。
进一步地,所述MALT1抑制剂预防或治疗MALT1依赖性肿瘤。
进一步地,所述MALT1依赖性肿瘤包括但不限于弥漫性大B细胞淋巴瘤和MALT淋巴瘤中的一种或几种。
进一步地,所述弥漫性大B细胞淋巴瘤是活化B细胞型弥漫性大B细胞淋巴瘤。
进一步地,特拉匹韦通过抑制MALT1,进而抑制CARD家族蛋白、BCL10和MALT1组成的CBM复合物,从而发挥预防或治疗作用。
进一步地,所述CARD家族蛋白包括但不限于:CARD9、CARD10、CARD11、CARD14中的一种或几种。
进一步,所述肿瘤细胞包括弥漫性大B细胞淋巴瘤(HBL1,TMD8,OC1-Ly10,andOCI-Ly3)等细胞中一种或几种。
特拉匹韦或其药学上可接受的盐在制备预防或治疗MALT1依赖性肿瘤的药物中的应用。
进一步地,所述MALT1依赖性肿瘤包括弥漫性大B细胞淋巴瘤,进一步地,所述弥漫性大B细胞淋巴瘤是活化B细胞型弥漫性大B细胞淋巴瘤。
可选的,所述药物可以制备成药剂学上可以接受的任意一种剂型。
进一步地,所述药物的剂型包括注射剂、脂质体、凝胶制剂、片剂、胶囊剂、颗粒剂、散剂、口服液、滴丸、喷雾剂等中的一种。
进一步地,所述应用中的给药方式为皮下注射、静脉注射、肌肉注射、口服给药、舌下含服、腹腔注射、脑内注射、皮肤粘膜给药、局部注射或植入的递送装置给药等。
优选地,所述应用中的给药方式为口服给药。
一种抗肿瘤药物,含有活性成分A和活性成分B,所述活性成分A为特拉匹韦和/或其药学上可接受的盐;所述活性成分B包括细胞毒类抗肿瘤药物、表观遗传修饰酶抑制剂、PARP1/2抑制剂、泛素蛋白酶体抑制剂、周期蛋白依赖性激酶抑制剂、免疫检查点抑制剂、抗凋亡蛋白抑制剂、代谢通路抑制剂、抗新生血管生成药物、酪氨酸激酶抑制剂、其他激酶抑制剂中的一种或几种;优选地,所述酪氨酸激酶抑制剂包括EGFR抑制剂、ALK抑制剂、BCR-ABL抑制剂、BTK抑制剂、ErB2/HER2抑制剂、血管内皮生长因子受体抑制剂、多靶点抑制剂中的一种或几种;优选地,所述其他激酶抑制剂包括PI3K、AKT/mTOR通路抑制剂、MAPK信号通路抑制剂中的一种或几种。
进一步地,所述细胞毒类抗肿瘤药物包括影响DNA结构和功能的药物、影响核酸生物合成的药物、干扰转录过程和阻止RNA合成的药物、抑制蛋白质合成与功能的药物中的至少一种。
优选地,所述影响DNA结构和功能的药物包括环磷酰胺、顺铂、卡铂、喜树碱类、伊立替康、拓扑替康、鬼臼毒素衍生物中的至少一种;优选地,影响核酸生物合成的药物包括甲氨蝶呤、5-FU、卡培他滨中的至少一种;优选地,所述干扰转录过程和阻止RNA合成的药物包括多柔比星、表柔比星、吡柔比星、阿柔比星、伊达比星、柔红霉素、米托蒽醌中的至少一种;所述抑制蛋白质合成与功能药物包括紫杉醇。
进一步,表观遗传修饰酶抑制剂包括组蛋白去乙酰化酶抑制剂包括伏立诺他(Vorinostat,SAHA),贝利司他(Belinostat,PXD101),罗米地辛(Romidepsin,FK228,Depsipeptide),帕比司他(Panobinostat,LBH589),吉维司他(Givinostat,ITF2357),莫替司他(Mocetinostat,MGCD0103),恩替司他(Entinostat,MS-275),奎诺司他(Quisinostat,JNJ-26481585),普雷司他(Pracinostat,SB939),阿贝司他(Abexinostat,PCI-24781),瑞考司他(Ricolinostat,ACY-1215),他地那兰(Tacedinaline,CI994),非美诺司他(Fimepinostat,CUDC-907),瑞诺司他(Resminostat),丙戊酸(Valproic acid,VPA),妥西司他(Tucidinostat),西达本胺(Chidamide),度马诺司他(Domatinostat,4SC-202),丙戊酸钠(Valproic acid sodium salt,Sodium valproate)中的一种或几种。
进一步,抗凋亡蛋白抑制剂包括BCL-2抑制剂,所述BCL-2抑制剂包括维奈妥拉(venetoclax)。
优选地,所述酪氨酸激酶抑制剂包括伊马替尼、达沙替尼、尼洛替尼、舒尼替尼、博舒替尼、拉帕替尼、瑞戈非尼、帕唑帕尼和普纳替尼中的至少一种;BTK抑制剂包括依鲁替尼(ibrutinib)、acalabrutinib中的至少一种。
优选地,PI3K、AKT/mTOR通路抑制剂包括idelalisib、copanlisib、坦罗莫司(temsirolimus)、依维莫司(everolimus)中的至少一种。
优选地,MAPK信号通路抑制剂包括B-RAF抑制剂和/或MEK抑制剂,B-RAF抑制剂包括威罗非尼(vemurafenib)、达拉非尼(dabrafenib)中的至少一种,MEK抑制剂包括曲美替尼(trametinib)、考比替尼(cobimetinib)中的至少一种。
优选地,所述肿瘤包括弥漫大B细胞淋巴瘤和/或MALT1淋巴瘤。
进一步地,所述弥漫性大B细胞淋巴瘤包括活化B细胞型弥漫性大B细胞淋巴瘤。
本发明人在离体细胞药物筛选过程中,偶然发现特拉匹韦具有抑制MALT1作用,而抑制MALT1具有抑制弥漫性大B细胞淋巴瘤和MALT淋巴瘤作用,因此,特拉匹韦具有抗弥漫性大B细胞淋巴瘤和MALT淋巴瘤作用,可扩大其适应症范围。
本发明将特拉匹韦用于制备抗肿瘤药物,尤其是抗弥漫大B细胞淋巴瘤和MALT淋巴瘤等肿瘤,效果明显。特拉匹韦联合其他抗肿瘤药物,可增强抗瘤药物的抗肿瘤作用,可增强这些药物的抗肿瘤作用。
下面对本发明做进一步的解释:
申请人研究发现,特拉匹韦具有抑制MALT1活性,特拉匹韦对肿瘤细胞的抑制作用。同时,特拉匹韦联合其他抗肿瘤药物,可增强其他抗肿瘤药物的抗肿瘤作用,而这些作用在MALT1表达或活性高的肿瘤细胞更敏感。联合用药时,特拉匹韦与其他抗肿瘤药物的比例按剂量比为1:(0.001~1000),具体可根据药物对不同肿瘤的敏感性而定。
本发明证实特拉匹韦对MALT1具有抑制作用,可用于制备MALT1抑制剂。
附图说明
图1是实施例1中特拉匹韦对MALT1抑制作用情况图。
图2是实施例2中特拉匹韦对弥漫性大B细胞淋巴瘤细胞(OCL-ly3)的抑制作用曲线(IC50μmol/L,μM)。
具体实施方式
以下将结合实施例来详细说明本发明。需要说明的是,在不冲突的情况下,本发明中的实施例及实施例中的特征可以相互组合。
实施例1
细胞实验:特拉匹韦对MALT1的抑制作用。
实施药品:特拉匹韦购于试剂公司。
SH-SY5Y细胞低氧损伤模型的建立及分组:
SH-SY5Y细胞长至融合度为90%时,传代并种板,用含20%FBS RPMI 1640正常培养基于95%空气、5% CO2、37℃细胞培养箱中培养。待细胞长至融合度为70-80%时,用含1%FBS RPMI 1640正常培养基同步化处理12h,再换无血清无糖RPMI 1640培养基置于1%O2、94%N2、5%CO2细胞培养箱中低氧8h(培养基需将细胞表层覆盖),之后换1%FBS RPMI1640正常培养基于95%空气、5%CO2细胞培养箱中复氧24h。常氧对照组在同步化处理后更换成1%FBS RPMI 1640正常培养基继续培养,每次模型组换液都对常氧组进行换液保持一致性。
MALT1沉默(MALT1siRNA)实验:取出含MALT1 siRNA或Negative Control(NC)siRNA冻干粉(5nmol)(购自广州锐博试剂公司),将冻干粉瞬时离心至EP管底部,加入250μL无菌DEPC水配置成浓度为20μM的siRNA储存液,分装后于-80℃保存。待细胞生长到密度达到60-70%时即可进行细胞转染。将含MALT1 siRNA或NC siRNA的转染复合物(用riboFECTTMCP Buffer及reagent配制)加入含RPMI 1640培养基(含20%FBS)的细胞板中,使转染复合物终浓度为50nM。摇匀,继续常氧培养6h后更换为含20%FBS RPMI 1640正常培养基继续培养12h再进行低氧和/或特拉匹韦药物处理。
MALT1过表达(MALT1-GFP)实验:MALT1-GFP腺病毒(MALT1过表达)试剂、GFP腺病毒(对照)试剂购于上海吉凯基因公司;待细胞板内细胞融合率达60%左右时即可进行转染,用含20%FBS RPMI 1640正常培养基稀释上述腺病毒(MOI=1000,腺病毒滴度为2*1010)后,分别直接加入细胞培养板中,95%空气、5% CO2、37℃的细胞培养箱中继续培养24h再进行低氧及特拉匹韦药物处理。
乳酸脱氢酶(lactate dehydrogenase,LDH)释放率测定
根据市购乳酸脱氢酶试剂盒操作说明书进行测定,按照实验要求设计分组,另设置背景空白对照组、样品最大酶活性组各一组。在样品最大酶活性孔组中加入体积为原培养基1/10的LDH释放试剂,继续培养1小时。每孔吸取120μL上清液,加入到新的96孔板中,每孔分别加入60μL LDH检测工作液,混匀,室温孵育30min(避光),在490nm测定样品吸光度。计算:细胞LDH释放率(%)=(处理样品组吸光度-样品对照组吸光度)/(细胞最大酶活性组吸光度-样品对照组吸光度)×100%实验分组如下:
正常对照组(Control组):常氧调节下培养组;
低氧组(Hypoxia组):无糖条件下低氧(1% O2)8h,复氧24h;
+MALT1 siRNA组:转染MAL T1 siRNA片段后低氧8h,复氧24h;
+Negative Control(NC)siRNA组:阴性对照组,转染NC siRNA片段后低氧8h,复氧24h;
低氧+特拉匹韦组[Hypoxia+Telaprevir10μmol/L(μM)]:低氧时向培基中加入特拉匹韦10μM,再进行低氧处理,即低氧8h,复氧24h。
低氧+特拉匹韦+MALT1沉默组(Hypoxia+Telaprevir+MALT1 siRNA):MALT1siRNA沉默后,进行低氧及特拉匹韦药物处理。
低氧+特拉匹韦+MALT1过表达组(Hypoxia+Telaprevir+MALT1-GFP):转染MALT1-GFP腺病毒后(MALT1过表达),进行低氧及特拉匹韦药物处理。
低氧+特拉匹韦+GFP对照组:(Hypoxia+Telaprevir+GFP):转染GFP腺病毒后(GFP对照),进行低氧及特拉匹韦药物处理。
实验结果:
图1展示了特拉匹韦对低氧(Hypoxia)诱导的SH-SY5Y细胞死亡(LDH释放率)的影响情况,具体地,由图1A可知,低氧(Hypoxia)诱导的SH-SY5Y细胞死亡(LDH释放率增加),但该作用可被MALT1沉默(+MALT1 siRNA)所抑制((LDH释放率降低);参见图1B,特拉匹韦抑制低氧诱导的SH-SY5Y细胞死亡(+telaprevir),MALT1的沉默(+telaprevir+MALT1siRNA)没有更进一步降低细胞死亡;参见图1C,特拉匹韦抑制低氧诱导的SH-SY5Y细胞死亡的作用可被MALT1过表达(+telaprevir+MALT1-GFP)取消(LDH释放率增加);这些结果表明特拉匹韦通过抑制MALT1减少低氧诱导的SH-SY5Y细胞死亡。可见,特拉匹韦对MALT1有抑制作用。数据表示为均数±标准误,n=3-4,*P<0.05,**P<0.01vs Control;#P<0.05,##P<0.01vsHypoxia;&&P<0.01vs+telaprevir。
实施例2
细胞实验:特拉匹韦对弥漫性大B细胞淋巴瘤细胞(活化B细胞型,ABC-DLBCL)的抑制作用实施药品:特拉匹韦购于试剂公司。
肿瘤细胞株:弥漫性大B细胞淋巴瘤活化B细胞型(ABC-DLBCL细胞株,OCI-Ly3)购于细胞库。
细胞培养方法:按常规进行,将以上细胞于1640培养基中培养(含10%胎牛血清,100U/mL青霉素和链霉素),细胞融合生长至90%时,采用胰酶消化,待细胞皱缩变圆,细胞间隙明显后,立即用培养基终止消化,将细胞打散吹匀为单个悬浮状态,分瓶传代,于37℃、含5%CO2的细胞培养箱中培养。后续实验采用对数生长期细胞完成。
药物处理方法:分别用不同浓度的特拉匹韦(比如2.5、5、10、20、40μmol/L)处理上述细胞48小时,设置对照组(含培基和细胞,无药物处理)、实验组(含不同浓度药物的培基和细胞)、溶媒组(含DMSO的培基和细胞,无药物处理)和/或空白组(只含培基,无细胞)、,每组设置4~6个复孔。CCK8检测细胞活力,评价药物对肿瘤细胞生长的抑制作用。
实验结果:
如图2所示,特拉匹韦处理人弥漫性大B细胞淋巴瘤活化B细胞型OCI-Ly3细胞48小时,细胞活力明显降低,具有明显的抑制和杀灭肿瘤细胞作用,并呈现出剂量依赖性(IC50为8.05μmol/L)。
结论:特拉匹韦具有抑制弥漫性大B细胞淋巴瘤细胞的作用。
上述实施例发现特拉匹韦可抑制肿瘤细胞生长,具有抗肿瘤作用,可用作治疗和预防癌症,为治疗癌症提供了新的药物。
但本发明不局限于上述癌症,故该药同样适用于治疗其他癌症。
上述实施例阐明的内容应当理解为这些实施例仅用于更清楚地说明本发明,而不用于限制本发明的范围,在阅读了本发明之后,本领域技术人员对本发明的各种等价形式的修改均落入本申请所附权利要求所限定的范围。
Claims (10)
1.抗肿瘤药物在制备预防或治疗MALT1依赖性肿瘤的药物中的应用,所述抗肿瘤药物含有活性成分A和活性成分B,其特征在于,所述活性成分A为特拉匹韦和/或其药学上可接受的盐;所述活性成分B 包括细胞毒类抗肿瘤药物、表观遗传修饰酶抑制剂、PARP1/2抑制剂、泛素蛋白酶体抑制剂、周期蛋白依赖性激酶抑制剂、免疫检查点抑制剂、抗凋亡蛋白抑制剂、代谢通路抑制剂、抗新生血管生成药物、酪氨酸激酶抑制剂、其他激酶抑制剂中的一种或几种。
2.根据权利要求1所述的应用,其特征在于,所述MALT1依赖性肿瘤包括弥漫大B细胞淋巴瘤和/或MALT1淋巴瘤。
3.根据权利要求2所述的应用,其特征在于,所述弥漫大 B 细胞淋巴瘤包括活化B细胞型弥漫性大B细胞淋巴瘤。
4.根据权利要求1-3任一项所述的应用,其特征在于,所述细胞毒类抗肿瘤药物包括影响DNA结构和功能的药物、影响核酸生物合成的药物、干扰转录过程和阻止RNA合成的药物、抑制蛋白质合成与功能的药物中的至少一种。
5.根据权利要求4所述的应用,其特征在于,所述影响DNA结构和功能的药物包括环磷酰胺、顺铂、卡铂、喜树碱类、伊立替康、拓扑替康、鬼臼毒素衍生物中的至少一种;优选地,影响核酸生物合成的药物包括甲氨蝶呤、5-FU、卡培他滨中的至少一种;优选地,所述干扰转录过程和阻止RNA合成的药物包括多柔比星、表柔比星、吡柔比星、阿柔比星、伊达比星、柔红霉素、米托蒽醌中的至少一种;所述抑制蛋白质合成与功能药物包括紫杉醇。
6.根据权利要求1-3任一项所述的应用,其特征在于,表观遗传修饰酶抑制剂包括组蛋白去乙酰化酶抑制剂,所述组蛋白去乙酰化酶抑制剂包括伏立诺他、贝利司他、罗米地辛、帕比司他、吉维司他、莫替司他、恩替司他、奎诺司他、普雷司他、阿贝司他、瑞考司他、他地那兰、非美诺司他、瑞诺司他、丙戊酸、妥西司他、西达本胺、度马诺司他、丙戊酸钠中的一种或几种。
7.根据权利要求1-3任一项所述的应用,其特征在于,抗凋亡蛋白抑制剂包括BCL-2抑制剂,BCL-2抑制剂包括维奈妥拉。
8.根据权利要求1-3任一项所述的应用,其特征在于,所述酪氨酸激酶抑制剂包括EGFR抑制剂、ALK抑制剂、BCR-ABL抑制剂、BTK抑制剂、ErB2/HER2抑制剂、血管内皮生长因子受体抑制剂、多靶点抑制剂中的一种或几种。
9.根据权利要求8所述的应用,其特征在于,所述酪氨酸激酶抑制剂包括伊马替尼、达沙替尼、尼洛替尼、舒尼替尼、博舒替尼、拉帕替尼、瑞戈非尼、帕唑帕尼和普纳替尼中的至少一种;优选地,BTK抑制剂为acalabrutinib。
10.根据权利要求1-3任一项所述的应用,其特征在于,所述其他激酶抑制剂包括PI3K、AKT/mTOR通路抑制剂、MAPK信号通路抑制剂中的一种或几种;
优选地,PI3K、AKT/mTOR通路抑制剂包括idelalisib、copanlisib、坦罗莫司、依维莫司的至少一种;MAPK信号通路抑制剂包括B-RAF抑制剂和/或MEK抑制剂,所述B-RAF抑制剂包括威罗非尼、达拉非尼中的至少一种,所述MEK抑制剂包括曲美替尼、考比替尼的至少一种。
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