{"id":1595,"date":"2023-02-22T19:54:21","date_gmt":"2023-02-22T19:54:21","guid":{"rendered":"https:\/\/scivetim.eu\/?page_id=1595"},"modified":"2023-03-03T15:13:03","modified_gmt":"2023-03-03T15:13:03","slug":"apoptoza","status":"publish","type":"page","link":"https:\/\/proboostnow.eu\/en_us\/apoptoza\/","title":{"rendered":"Apopt\u00f3za"},"content":{"rendered":"<div class=\"banner has-hover\" id=\"banner-1954694969\">\n          <div class=\"banner-inner fill\">\n        <div class=\"banner-bg fill\" >\n            <img loading=\"lazy\" decoding=\"async\" width=\"730\" height=\"486\" src=\"https:\/\/proboostnow.eu\/wp-content\/uploads\/2023\/02\/Apoptoza.jpg\" class=\"bg attachment-large size-large\" alt=\"\" \/>                                    \n                    <\/div>\n\t\t\n        <div class=\"banner-layers container\">\n            <div class=\"fill banner-link\"><\/div>            \n\n   <div id=\"text-box-1550639829\" class=\"text-box banner-layer x50 md-x50 lg-x50 y70 md-y70 lg-y70 res-text\">\n                                <div class=\"text-box-content text dark\">\n              \n              <div class=\"text-inner text-center\">\n                  \n\n<h3><b>Thymic Protein A stimuluje apopt\u00f3zu aberantn\u00edch bun\u011bk<\/b><\/h3>\n<p>\u00a0<\/p>\n\n              <\/div>\n           <\/div>\n                            \n<style>\n#text-box-1550639829 {\n  width: 60%;\n}\n#text-box-1550639829 .text-box-content {\n  font-size: 100%;\n}\n<\/style>\n    <\/div>\n \n\n        <\/div>\n      <\/div>\n\n            \n<style>\n#banner-1954694969 {\n  padding-top: 56.25%;\n}\n<\/style>\n  <\/div>\n\n\n\t<div id=\"gap-634417358\" class=\"gap-element clearfix\" style=\"display:block; height:auto;\">\n\t\t\n<style>\n#gap-634417358 {\n  padding-top: 30px;\n}\n<\/style>\n\t<\/div>\n\t\n\n\t<div id=\"gap-1697396645\" class=\"gap-element clearfix\" style=\"display:block; height:auto;\">\n\t\t\n<style>\n#gap-1697396645 {\n  padding-top: 30px;\n}\n<\/style>\n\t<\/div>\n\t\n\n\t<div id=\"gap-583012148\" class=\"gap-element clearfix\" style=\"display:block; height:auto;\">\n\t\t\n<style>\n#gap-583012148 {\n  padding-top: 30px;\n}\n<\/style>\n\t<\/div>\n\t\n\n\t<div id=\"text-1644049184\" class=\"text\">\n\t\t\n\n<p>Thymic Protein A stimuluje proces indukovan\u00e9 bun\u011b\u010dn\u00e9 smrti, apopt\u00f3zy bun\u011bk, kter\u00e9 jsou lymfopoetick\u00e9ho p\u016fvodu, tedy nap\u0159\u00edklad b\u00edl\u00fdch krvinek typu T lymfocyt\u016f, pokud jsou malign\u011b zm\u011bn\u011bn\u00e9 nebo napaden\u00e9 virovou infekc\u00ed. P\u0159\u00edkladem takov\u00fdch infekc\u00ed je virov\u00e1 imunodeficience ko\u010dek, felinn\u00ed leuk\u00e9mie a dal\u0161\u00ed.<\/p>\n<p>Krom\u011b laboratorn\u00edch experiment\u016f byly provedeny i klinick\u00e9 studie, kter\u00e9 indukci apopt\u00f3zy thymov\u00fdm proteinem A jednozna\u010dn\u011b prok\u00e1zaly.\u00a0<\/p>\n\t\t\n<style>\n#text-1644049184 {\n  color: rgb(0,0,0);\n}\n#text-1644049184 > * {\n  color: rgb(0,0,0);\n}\n<\/style>\n\t<\/div>\n\t\n\t<div id=\"gap-877961458\" class=\"gap-element clearfix\" style=\"display:block; height:auto;\">\n\t\t\n<style>\n#gap-877961458 {\n  padding-top: 30px;\n}\n<\/style>\n\t<\/div>\n\t\n\n\t<div id=\"text-2558215823\" class=\"text\">\n\t\t\n\n<p class=\"western\"><span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\">Thymic protein A (TPA) je schopen iniciovat apopt\u00f3zu v n\u011bkter\u00fdch bun\u011b\u010dn\u00fdch populac\u00edch, zejm\u00e9na ur\u010dit\u00fdch typ\u016f krevn\u00edch bun\u011bk. Bylo zji\u0161t\u011bno, \u017ee TPA selektivn\u011b zp\u016fsobuje bun\u011b\u010dnou smrt nebo zastaven\u00ed r\u016fstu tk\u00e1n\u011b u aberantn\u00edch T-bun\u011bk, jako jsou lymfomov\u00e9 bu\u0148ky, lymfocyty, kter\u00e9 nesou virus HIV a leukemick\u00e9 bu\u0148ky. I kdy\u017e TPA je schopen stimulovat imunitn\u00ed odpov\u011b\u010f, kter\u00e1 by teoreticky mohla c\u00edlit na malign\u00ed bu\u0148ky bylo zji\u0161t\u011bno, \u017ee TPA\u00a0 selektivn\u011b zp\u016fsobuje bun\u011b\u010dnou smrt aberantn\u00edch T-lymfocyt\u016f v nep\u0159\u00edtomnosti jak\u00e9koli imunitn\u00ed reakce, co\u017e bylo prok\u00e1z\u00e1no experimenty in vitro.<\/span><\/span><\/span> <span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\">TPA je tedy mo\u017en\u00e9 pou\u017e\u00edt k l\u00e9\u010db\u011b poruch charakterizovan\u00fdch produkc\u00ed, v\u00fdvojem nebo aktivitou aberantn\u00edch T-bun\u011bk, proto\u017ee funguje mechanismem nez\u00e1visl\u00fdm na stimulaci imunitn\u00ed odpov\u011bdi. Nab\u00edz\u00ed se tedy mo\u017enost terapie u jedinc\u016f s oslabenou imunitou, v p\u0159\u00edpadech, kdy nelze o\u010dek\u00e1vat, \u017ee by l\u00e9\u010dba spol\u00e9haj\u00edc\u00ed na stimulaci imunitn\u00ed odpov\u011bdi fungovala uspokojiv\u011b. Nap\u0159\u00edklad se zvl\u00e1\u0161t\u011b dob\u0159e hod\u00ed k l\u00e9\u010db\u011b pacient\u016f s poruchou imunity, jako je HIV, a k l\u00e9\u010db\u011b jedinc\u016f, kte\u0159\u00ed sou\u010dasn\u011b dost\u00e1vaj\u00ed imunosupresivn\u00ed l\u00e9ky. Pod\u00e1v\u00e1n\u00ed TPA m\u016f\u017ee tedy b\u00fdt u\u017eite\u010dn\u00e9 p\u0159i l\u00e9\u010db\u011b poruch, jak\u00fdmi jsou r\u016fzn\u00e9 T-bun\u011b\u010dn\u00e9 lymfomy, jako je mycosis fungoides, T-bun\u011b\u010dn\u00e9 leuk\u00e9mie a n\u011bkter\u00e9 virov\u00e9 infekce, jako je HIV, kdy jsou infikov\u00e1ny T-lymfocyty.<\/span><\/span><\/span> <span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\">TPA inhibuje bun\u011b\u010dn\u00fd r\u016fst v kultu\u0159e lymfomov\u00fdch bun\u011bk zp\u016fsobem z\u00e1visl\u00fdm na d\u00e1vce, jak bylo prok\u00e1z\u00e1no experimenty s inkorporac\u00ed 3H-thymidinu. Bylo tak\u00e9 prok\u00e1z\u00e1no, \u017ee zvy\u0161uje m\u00edru bun\u011b\u010dn\u00e9 smrti mezi lymfocyty infikovan\u00fdmi virem HIV. V takov\u00fdch bu\u0148k\u00e1ch TPA tak\u00e9 zpomalil produkci viru. Krom\u011b toho, kdy\u017e byly bu\u0148ky lidsk\u00e9 myelomonocyt\u00e1rn\u00ed leukemick\u00e9 bun\u011b\u010dn\u00e9 linie K562 o\u0161et\u0159eny TPA, zv\u00fd\u0161ila se \u00farove\u0148 apopt\u00f3zy v t\u00e9to bun\u011b\u010dn\u00e9 kultu\u0159e v\u00edce ne\u017e dvojn\u00e1sobn\u011b oproti kontrole. Pro srovn\u00e1n\u00ed, TPA nevykazoval \u017e\u00e1dn\u00fd \u00fa\u010dinek na rychlost r\u016fstu bun\u011bk nelymfoidn\u00ed malign\u00ed bun\u011b\u010dn\u00e9 linie, co\u017e dokazuje, \u017ee \u00fa\u010dinek na lymfomov\u00e9 bu\u0148ky nen\u00ed obecn\u00fdm cytotoxick\u00fdm \u00fa\u010dinkem, ani jej nelze p\u0159ipsat syst\u00e9mov\u00e9 imunitn\u00ed reakci vyvolan\u00e9 TPA.<\/span><\/span><\/span><span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\"> Byl tak\u00e9 testov\u00e1n \u00fa\u010dinek TPA na ko\u017en\u00ed T-bun\u011b\u010dn\u00fd lymfom (CTCL), za pou\u017eit\u00ed my\u0161\u00edho xenograftov\u00e9ho modelu popsan\u00e9ho T. S. Burgerem a kol., v Experimental Dermatology, sv. 13, 406-12 (2004). Ko\u017en\u00ed T-bun\u011b\u010dn\u00e9 lymfomy (CTCL) jsou skupinou lymfoproliferativn\u00edch poruch postihuj\u00edc\u00edch k\u016f\u017ei. Nejb\u011b\u017en\u011bj\u0161\u00ed formou je mycosis fungoides (MF), p\u0159i kter\u00e9 doch\u00e1z\u00ed k malign\u00edmu r\u016fstu T-bun\u011bk ve form\u011b skvrn a pozd\u011bji n\u00e1dor\u016f na k\u016f\u017ei. Id. Burger, et al., popisuje zp\u016fsob r\u016fstu lidsk\u00fdch MF n\u00e1dor\u016f u nah\u00fdch my\u0161\u00ed s deficitem imunity a ukazuje, \u017ee malign\u00ed bu\u0148ky se \u0161\u00ed\u0159\u00ed do lymfatick\u00fdch uzlin, krevn\u00edho \u0159e\u010di\u0161t\u011b a dal\u0161\u00edch org\u00e1n\u016f. Pomoc\u00ed tohoto modelov\u00e9ho syst\u00e9mu se nyn\u00ed uk\u00e1zalo, \u017ee TPA dramaticky zpomaluje r\u016fst n\u00e1doru CTCL. \u00da\u010dinek se stal z\u0159ejm\u00fdm v \u0159\u00e1du dn\u016f po pod\u00e1n\u00ed d\u00e1vky TPA a \u00fa\u010dinek jedn\u00e9 d\u00e1vky p\u0159etrv\u00e1val po dobu alespo\u0148 dvou t\u00fddn\u016f b\u011bhem f\u00e1ze rychl\u00e9ho r\u016fstu modelov\u00e9ho n\u00e1doru.<\/span><\/span><\/span>\u00a0<span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\">Tato data nazna\u010duj\u00ed, \u017ee malign\u00ed bu\u0148ky a virem infikovan\u00e9 bu\u0148ky lymfoidn\u00edho nebo myeloidn\u00edho p\u016fvodu jsou indukov\u00e1ny TPA k zah\u00e1jen\u00ed apopt\u00f3zy a \u017ee tohoto \u00fa\u010dinku lze dos\u00e1hnout in vivo i in vitro. Tato biologick\u00e1 aktivita TPA m\u016f\u017ee b\u00fdt u\u017eite\u010dn\u011b aplikov\u00e1na na l\u00e9\u010dbu r\u016fzn\u00fdch poruch, kter\u00e9 jsou charakterizov\u00e1ny aberantn\u00edmi T-bu\u0148kami nebo jin\u00fdmi aberantn\u00edmi bu\u0148kami hematopoetick\u00e9ho p\u016fvodu. Mezi takov\u00e9 poruchy pat\u0159\u00ed r\u016fzn\u00e9 lymfomy zahrnuj\u00edc\u00ed T-bu\u0148ky, v\u010detn\u011b T-bun\u011b\u010dn\u00e9ho lymfomu dosp\u011bl\u00fdch, prekurzorov\u00e9ho T-bun\u011b\u010dn\u00e9ho lymfoblastick\u00e9ho lymfomu, extranod\u00e1ln\u00edho p\u0159irozen\u00e9ho killer T-bun\u011b\u010dn\u00e9ho lymfomu, enteropatick\u00e9ho lymfomu typu T-bun\u011bk, hepatosplenick\u00e9ho T-bun\u011b\u010dn\u00e9ho lymfomu, subkut\u00e1nn\u00ed panikulitidy jako T-bun\u011b\u010dn\u00fd lymfom, mycosis fungoides nebo ko\u017en\u00ed T-bun\u011b\u010dn\u00fd lymfom (CTCL), Sezaryho syndrom (leukemick\u00e1 f\u00e1ze CTCL), anaplastick\u00fd velkobun\u011b\u010dn\u00fd lymfom, perifern\u00ed T-bun\u011b\u010dn\u00fd lymfom a angioimunoblastick\u00fd T-bun\u011b\u010dn\u00fd lymfom. Dal\u0161\u00ed poruchy l\u00e9\u010diteln\u00e9 popsan\u00fdm zp\u016fsobem zahrnuj\u00ed ur\u010dit\u00e9 leuk\u00e9mie, jako je d\u011btsk\u00e1 leuk\u00e9mie p\u016fvodem z T-bun\u011bk, leuk\u00e9mie dosp\u011bl\u00fdch T-bun\u011bk, lymfocyt\u00e1rn\u00ed leuk\u00e9mie, chronick\u00e1 leuk\u00e9mie T-bun\u011bk, myeloidn\u00ed leuk\u00e9mie a erytroidn\u00ed leuk\u00e9mie. Tyto poruchy tak\u00e9 zahrnuj\u00ed ty virov\u00e9 stavy, kdy jsou infikov\u00e1ny lymfocyty nap\u0159\u00edklad infekce HIV. TPA m\u016f\u017ee prosp\u00edvat subjekt\u016fm infikovan\u00fdm HIV tak\u00e9 jin\u00fdmi zp\u016fsoby, kv\u016fli sv\u00fdm imunostimula\u010dn\u00edm \u00fa\u010dink\u016fm a podpo\u0159e hematopo\u00e9zy, ale t\u00e9\u017e nab\u00edz\u00ed mo\u017enost indukce apopt\u00f3zy aberantn\u00edch T-bun\u011bk a t\u00edm sn\u00ed\u017een\u00ed virov\u00e9 z\u00e1t\u011b\u017ee u pacient\u016f s HIV.<\/span><\/span><\/span> <span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\">Lymfomov\u00e9 bu\u0148ky byly inkubov\u00e1ny po dobu 48 hodin v p\u0159\u00edtomnosti TPA v n\u011bkolika r\u016fzn\u00fdch koncentrac\u00edch. Bu\u0148ky byly pot\u00e9 o\u0161et\u0159eny 3H-thymidinem pro m\u011b\u0159en\u00ed bun\u011b\u010dn\u00e9 proliferace. P\u0159i ka\u017ed\u00e9 koncentraci TPA inhiboval bun\u011b\u010dn\u00fd r\u016fst. Jako kontrola pro stanoven\u00ed, zda \u00fa\u010dinek byl obecnou cytotoxicitou, byla nelymfoidn\u00ed malign\u00ed bun\u011b\u010dn\u00e1 linie tak\u00e9 o\u0161et\u0159ena TPA a v tomto p\u0159\u00edpad\u011b nedo\u0161lo\u00a0 k ovlivn\u011bn\u00ed rychlosti r\u016fstu.<\/span><\/span><\/span> <span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\">Lymfocyty infikovan\u00e9 virem HIV byly inkubov\u00e1ny s TPA v r\u016fzn\u00fdch d\u00e1vk\u00e1ch. Bun\u011b\u010dn\u00e1 smrt nastala p\u0159i ka\u017ed\u00e9 testovan\u00e9 koncentraci a rozsah byl z\u00e1visl\u00fd na d\u00e1vce. Nav\u00edc koncentrace TPA korelovala se sn\u00ed\u017eenou produkc\u00ed viru.<\/span><\/span><\/span> <span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\">Lidsk\u00e1 myelomonocyt\u00e1rn\u00ed leukemick\u00e1 bun\u011b\u010dn\u00e1 linie K562 byla inkubov\u00e1na s TPA. Rychlost apopt\u00f3zy se zv\u00fd\u0161ila v\u00edce ne\u017e dvojn\u00e1sobn\u011b oproti rychlosti v kontroln\u00ed kultu\u0159e.<\/span><\/span><\/span> <span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\">Modelov\u00e9 n\u00e1dory ko\u017en\u00edho T-bun\u011b\u010dn\u00e9ho lymfomu (CTCL) byly zalo\u017eeny u my\u0161\u00ed metodou popsanou v T. S. Burger, et al., Stanoven\u00ed my\u0161\u00edho xenograftov\u00e9ho modelu pro mycosis fungoides, Experimental Dermatology, 13, 406-412 (2004). P\u0159ibli\u017en\u011b 14 dn\u00ed po implantaci n\u00e1dorov\u00fdch bun\u011bk byly my\u0161i o\u0161et\u0159eny TPA. Objem n\u00e1doru v mm3 byl vyhodnocen podle Burgera, et al., jako Velikost = d\u00e9lka x (\u0161\u00ed\u0159ka) 2 x 0,5. V pr\u016fb\u011bhu experimentu se rychlost r\u016fstu n\u00e1doru prudce zv\u00fd\u0161ila u nel\u00e9\u010den\u00fdch my\u0161\u00ed, zat\u00edmco jedin\u00e1 d\u00e1vka TPAv\u00fdznamn\u011b potla\u010dila rychlost r\u016fstu n\u00e1doru u l\u00e9\u010den\u00fdch zv\u00ed\u0159at. Objem n\u00e1doru byl v\u00edce ne\u017e dvakr\u00e1t v\u011bt\u0161\u00ed u nel\u00e9\u010den\u00fdch my\u0161\u00ed ne\u017e u l\u00e9\u010den\u00fdch my\u0161\u00ed. Siln\u00fd \u00fa\u010dinek z jedn\u00e9 d\u00e1vky p\u0159etrv\u00e1val mini\u00edm\u00e1ln\u011b 19 dn\u00ed po jedin\u00e9m o\u0161et\u0159en\u00ed. \u00da\u010dinek TPA je z\u00e1visl\u00fd na d\u00e1vce.<\/span><\/span><\/span> <span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\">\u0160est t\u00fddn\u016f star\u00e9 nah\u00e9 my\u0161i NMRI byly z\u00edsk\u00e1ny od Harlan Winkelmann, Borchen, N\u011bmecko, a byly chov\u00e1ny v individu\u00e1ln\u00edch ventilovan\u00fdch klec\u00edch, potrava a voda ad libitum. CTCL n\u00e1dorov\u00e1 tk\u00e1\u0148 byla implantov\u00e1na v anestezii do boku zv\u00ed\u0159at a velikost n\u00e1doru byla monitorov\u00e1na dvakr\u00e1t t\u00fddn\u011b za pou\u017eit\u00ed metod popsan\u00fdch v Experimental Dermatology, 13, 406-412 (2004). Skupiny po 10 zv\u00ed\u0159atech byly pou\u017eity pro l\u00e9\u010debnou a kontroln\u00ed skupinu.<\/span><\/span><\/span> <span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\">Zv\u00ed\u0159ata v l\u00e9\u010debn\u00e9 skupin\u011b byla o\u0161et\u0159ena 100 ul injekcemi rekonstituovan\u00e9ho roztoku TPA; zv\u00ed\u0159at\u016fm kontroln\u00ed skupiny bylo injikov\u00e1no 100 ul z\u0159ed\u011bn\u00e9ho fyziologick\u00e9ho roztoku. L\u00e9\u010dba byla pod\u00e1v\u00e1na denn\u011b n\u00e1sledovn\u011b: 13.-17. prosince 2004; 20.-24. prosince 2004; 27.-31. prosince 2004; a 3.-5. ledna 2005. Zv\u00ed\u0159ata byla utracena 6. ledna 2005.<\/span><\/span><\/span> <span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\">Kdy\u017e l\u00e9\u010dba za\u010dala, objem n\u00e1doru byl p\u0159ibli\u017en\u011b 80 mm3. L\u00e9\u010dba podstatn\u011b zpomalila r\u016fst n\u00e1doru. Kdy\u017e byla zv\u00ed\u0159ata usmrcena, objem n\u00e1doru byl t\u00e9m\u011b\u0159 t\u0159ikr\u00e1t v\u011bt\u0161\u00ed u nel\u00e9\u010den\u00fdch (kontroln\u00edch) zv\u00ed\u0159at ve srovn\u00e1n\u00ed s l\u00e9\u010den\u00fdmi zv\u00ed\u0159aty. L\u00e9\u010dba TPA neovlivnila rychlost r\u016fstu l\u00e9\u010den\u00fdch zv\u00ed\u0159at.<\/span><\/span><\/span> <span style=\"color: #777777;\"><span style=\"font-family: Liberation Serif, serif;\"><span style=\"font-size: medium;\">Tk\u00e1\u0148 z n\u00e1dor\u016f byla obarvena hematoxylinem a eosinem pro histologick\u00e9 vy\u0161et\u0159en\u00ed. N\u00e1dorov\u00e1 tk\u00e1\u0148 z l\u00e9\u010den\u00fdch zv\u00ed\u0159at vykazovala m\u00edrn\u00e9 zv\u00fd\u0161en\u00ed koagula\u010dn\u00ed nekr\u00f3zy a m\u00edrn\u00e9 zv\u00fd\u0161en\u00ed angiogeneze ve srovn\u00e1n\u00ed s kontrolami.\u00a0<\/span><\/span><\/span><\/p>\n<p>zdroj: https:\/\/patents.google.com\/patent\/US7776818B2\/en?oq=us7776818<\/p>\n\t\t\n<style>\n#text-2558215823 {\n  color: rgb(0,0,0);\n}\n#text-2558215823 > * {\n  color: rgb(0,0,0);\n}\n<\/style>\n\t<\/div>\n\t\n\t<div id=\"gap-780335211\" class=\"gap-element clearfix\" style=\"display:block; height:auto;\">\n\t\t\n<style>\n#gap-780335211 {\n  padding-top: 30px;\n}\n<\/style>\n\t<\/div>\n\t\n\n\t<div id=\"gap-1693026539\" class=\"gap-element clearfix\" style=\"display:block; height:auto;\">\n\t\t\n<style>\n#gap-1693026539 {\n  padding-top: 30px;\n}\n<\/style>\n\t<\/div>\n\t\n\n\t<div id=\"gap-858518897\" class=\"gap-element clearfix\" style=\"display:block; height:auto;\">\n\t\t\n<style>\n#gap-858518897 {\n  padding-top: 30px;\n}\n<\/style>\n\t<\/div>\n\t\n\n\t<div id=\"gap-640146892\" class=\"gap-element clearfix\" style=\"display:block; 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