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Ding Jingnuo, Zhao Weifeng, Sashen Cututtuka masu Yaduwa, Asibitin Farko na Jami'ar Suzhou, Birnin Suzhou, Lardin Jiangsu, 215000 Tel.ciwace-ciwace na tsarin narkewar abinci tare da tsawon shekaru 5 gabaɗaya na 14.1%.Yawancin marasa lafiya da ke da HCC ana bincikar su a matakin ci gaba, don haka gwajin farko yana da mahimmanci don rage mace-mace daga HCC.Baya ga alamomin ganowa da aka saba amfani da su kamar maganin alpha-fetoprotein (AFP), lectin-reactive alpha-fetoprotein (AFP-L3), da kuma prothrombin mara kyau (rashi na bitamin K II, PIVKA-II), dabarun biopsy ruwa. An nuna yana da ƙimar bincike a cikin gano HCC.Idan aka kwatanta da hanyoyin ɓarna, biopsy na ruwa zai iya gano ƙwayoyin ƙwayoyin cuta masu yawo.Dabarun biopsy na ruwa suna gano ƙwayoyin tumor da ke zagayawa, DNA na ƙari, zagayawa RNA, da exosomes kuma ana amfani da su don tantancewa da wuri, ganewar asali, da kima na HCC.Wannan labarin yana nazarin ilimin halitta da aikace-aikace na dabaru daban-daban na biopsy na ruwa don keɓe masu alamar halittu waɗanda za su iya zama zaɓuɓɓukan da za a iya amfani da su don tantancewar farko na HCC don haɓaka fara tantance ƙungiyoyin HCC masu haɗari.Mahimman kalmomi: fasaha na biopsy na ruwa, ciwon daji na hepatocellular, ƙungiyar haɗari mai girma.
Ciwon hanta (HCC) cuta ce da ta zama ruwan dare gama gari na sashin narkewar abinci, matsayi na shida a cikin sabbin cututtukan ciwace-ciwacen daji a cikin maza da mata.1 A duk duniya, ciwon daji na hanta shine abu na uku da ke haifar da mutuwar ciwon daji bayan huhu da kansar launin fata, wanda ke da kashi 8.3% na mutuwar ciwon daji daga duk wani mummunan neoplasms.1 Hasashen HCC yana da alaƙa da alaƙa da matakin da aka gano.Babban dalilan rashin rayuwa a cikin HCC sune metastases na intrahepatic, portal venous tumor thrombi, da kuma metastases mai nisa da ke hana resection, kuma yawancin waɗannan halayen sun riga sun kasance a cikin marasa lafiya a lokacin ganewar asali.
Dangane da jagororin bincike da jiyya, manyan abubuwan haɗari don haɓaka HCC sune cirrhosis na hanta, ƙwayar cutar hanta ta B (HBV) ko kamuwa da cutar hanta ta C (HCV), cututtukan hanta mai barasa, da cututtukan hanta maras giya (NAFLD). ).2 Bugu da ƙari, abubuwan haɗari ga HCC sun haɗa da cin abinci mai gurɓataccen aflatoxin, schistosomiasis, wasu abubuwan da ke haifar da cirrhosis, tarihin iyali na ciwon hanta, ciwon sukari, kiba, shan taba, da kuma raunin hanta da miyagun ƙwayoyi ya haifar.Ƙungiyoyin 35- da 45 masu haɗari masu haɗari ya kamata a duba lafiyarsu akai-akai.Binciken farko shine muhimmin dabarun jiyya da wuri don inganta rayuwar marasa lafiya gaba ɗaya tare da HCC.
Ana ba da shawarar alamomin halitta kamar AFP, AFP-L3 da PIVKA-II don fara gwajin HCC3,4.Dabarun biopsy na ruwa sun nuna sakamako masu ban sha'awa a farkon ganewar asali da kimantawar jiyya.5,6 An sami gagarumin ci gaba a cikin biopsy na ruwa na HCC, wanda zai iya samun mafi girman hankali da ƙayyadaddun bayanai fiye da yadda ake amfani da su kamar AFP (Table 1).
AFP ita ce alamar da aka yi amfani da ita sosai a cikin HCC kuma a halin yanzu ita ce mafi cikakkun bayanai na biomarker wanda aka fi amfani dashi don tantancewa da wuri, ganewar asali, da kimanta cutar.Ana ɗaukar matakin da aka ɗauka na AFP a matsayin haɗari ga ci gaban HCC.7,8 Ƙididdigar gano ƙananan ƙwayar hepatocellular carcinoma (sHCC) yana karuwa tare da haɓakar duban dan tayi da kuma ƙididdiga, kuma an gano AFP ba ta da mahimmanci ga gano hHCC a cikin aikin asibiti.Dangane da binciken da aka yi na baya-bayan nan na cibiyar sadarwa9, an sami tabbataccen AFP a cikin 46% (616/1338) na shari'o'in HCC da 23.4% (150/641) na shari'o'in sHCC.Bugu da ƙari, an haɓaka matakan AFP a cikin marasa lafiya da cututtukan hanta na yau da kullum da cirrhosis.10 Don haka, AFP yana da iyakataccen tasirin nunawa ga sHCC.11 Bisa ga ka'idodin Ayyukan Clinical na Asiya-Pacific don Ciwon Hanta, ba a ba da shawarar yin amfani da AFP ba. mafi girman ƙimar bincike a cikin HCC.13 Idan aka kwatanta da biopsy na nama, biopsy na ruwa da farko yana gano metabolites masu alaƙa da ƙari a cikin ruwan jiki (jini, yau, ruwa mai ɗaci, ruwan cerebrospinal, ko fitsari) kuma ba shi da haɗari ga kyallen takarda.14 Bugu da ƙari, biopsies na ruwa na iya nuna munanan sifofin da ba a cikin ƙwayar ƙwayar cuta ta farko.15 Har yanzu ba a yi gwajin ƙwayar ruwa ba a cikin aikin asibiti don kowane nau'in ciwace-ciwacen daji, amma yuwuwar gano cutar kansa a cikin ciwon daji yana jan hankalin masana ilimin oncologists.16 Ruwan ƙwayoyin ruwa na iya gano ƙwayoyin tumor da ke yawo (CTCs), DNA ɗin tumor da ke zagayawa (cDNA), RNA kyauta (ecRNA), da exosomes.A cikin wannan labarin, za mu tattauna halaye, matsayi, da aikace-aikace na dabaru daban-daban na biopsy na ruwa a farkon tantance ƙungiyoyin HCC masu haɗari.
Extracellular DNA (cfDNA) a cikin samfuran jini daga mutane masu lafiya an fara bayyana su a cikin 1948 ta Mandel et al.17 cfDNA guntuwar DNA ce marar tantanin halitta kusan 160-180 bp tsayi, wanda ya samo asali daga ƙwayoyin lymphocytes da ƙwayoyin myeloid.ctDNA wani yanki ne na musamman na DNA na mutant wanda ƙwayoyin tumor suka fitar a cikin jini na gefe, wanda ke wakiltar bayanan kwayoyin halitta na ƙwayoyin tumo bayan wasu matakai na pathophysiological, ciki har da necrosis, apoptosis, da excretion.Adadin ctDNA a cikin jimlar cfDNA ya bambanta da ko'ina tare da nau'in ƙari, kuma an ba da rahoton ɓangarorin cDNA yawanci ƙasa da 167 bp tsayi.18 Binciken Underhill ya nuna cewa gaɓoɓin cfDNA gabaɗaya sun fi cfDNA na yau da kullun.19 Idan aka kwatanta da daidaikun mutane masu lafiya, jimlar tsawon gutsuttsuran cfDNA a cikin jinin masu cutar kansa ya fi guntu, don haka za a iya amfani da cfDNA azaman mai nuna alamar gwajin ƙwayar cuta da wuri.Haɓaka wasu ɓangarori na tsayin guntun cfDNA na iya inganta gano cDNA da ke da alaƙa da ciwace-ciwacen ƙwayoyin cuta marasa ƙarfi.Nazarin ya nuna cewa ana samun ctDNA a cikin sama da 75% na ci gaba na pancreatic, hanji, mafitsara, gastrointestinal, hanta, ovarian, nono, melanoma, da kansa da kuma wuyansa.20,21 Duk da haka, adadin ctDNA a cikin jini ya dogara da wurin da ciwon daji yake.22 A cikin binciken Bettegoud, an gano marasa lafiya masu launin launi, nono, hanta, huhu, da ciwon gurguwar prostate suna da matakan cDNA mafi girma a cikin jininsu fiye da sauran ciwon daji.Sabanin haka, a cikin marasa lafiya da ciwon daji na baka, ciwon daji na pancreatic, ciwon ciki, da glioma, ƙaddamar da cDNA a cikin jini ya ragu.ashirin da daya
Saboda ctDNA ya ƙunshi maye gurbi iri ɗaya kamar ƙwayoyin ƙwayar cuta na farko, ana iya amfani da cDNA don gano takamaiman maye gurbi da canje-canje na epigenetic, gami da methylation, hydroxymethylation, bambance-bambancen nucleotide guda ɗaya, da bambance-bambancen kwafin lamba.ashirin da uku
DNA methylation shine ɗayan sauye-sauye na epigenetic na yau da kullun wanda ke haifar da danniya.Idan aka kwatanta da sel na al'ada, akwai bambance-bambance a cikin babban matakin methylation na kwayar cutar kwayar cutar tumo, musamman a cikin methylation na kwayoyin cutar ciwon tumo, wanda za'a iya ganowa a farkon mataki, yana nuna cewa canje-canje a cikin DNA methylation na iya zama alamar farko. gano cutar tumorigenesis.Ƙwayoyin ƙwayoyin cuta na Tumor da ke da alaƙa da HCC za a iya kunna su ta hanyar methylation mai talla, ta haka yana ƙarfafa tumorigenesis.24 DNA methylation shine alamar da ta dace don farkon ganewar ciwon daji saboda ƙayyadaddun nama, ganowa, da yancin kai na shekaru.Bugu da ƙari, DNA methylation ya fi kowa idan aka kwatanta da maye gurbi na somatic saboda akwai ƙarin yankuna masu niyya da wuraren CpG da yawa da aka canza a kowane yanki na kwayoyin halittar da aka yi niyya.25 Baya ga shafukan CpG da yawa, babban adadin loci hypermethylated mai zaman kansa a cikin ctDNA an gano su a cikin DBX2, THY1, MT1M, INK4A, VIM, FBLN1, da RGS10.26 Xu et al.Kwatanta samfuran cfDNA daga marasa lafiya 1098 HCC da 835 masu sarrafa lafiya sune kwayoyin halittar da ke da alaƙa da HCC an samo su da ƙarfi sosai tare da daidaitattun sa hannu na cDNA methylation na plasma.25 Bisa ga binciken dakin gwaje-gwaje, an samar da samfurin tsinkaya wanda ke dauke da alamun methylation na 10 tare da hankali da kuma ƙayyadaddun 85.7% da 94.3%, bi da bi, kuma waɗannan alamomin sun kasance suna da alaƙa da ƙwayar ƙwayar cuta, matakin ƙwayar cuta, da kuma mayar da martani ga magani.Waɗannan sakamakon sun nuna cewa yin amfani da alamun methylation na cDNA yana riƙe da babban alkawari a cikin ganewar asali, saka idanu, da tsinkaye na HCC.A cikin samfurin methylation wanda ya ƙunshi nau'o'in kwayoyin halittar methylated aberrantly guda uku (APC, COX2, RASSF1A) da kuma miRNA guda ɗaya (miR203) wanda Lu et al27 ya gabatar, ƙwarewa da ƙayyadaddun ƙirar 27 don bincikar HBV masu alaƙa da HCC sun kasance daidai.80%.Bugu da ƙari, samfurin zai iya gano 75% na marasa lafiya na HCC marasa lafiya tare da matakin AFP na 20 ng/mL.Halin halittar dangin Ras mai alaƙa da furotin 1A (RASSF1A) shine babban jerin DNA mai maimaitawa a cikin kwayoyin halittar ɗan adam.Araujo et al.Ƙaddamar da cewa hypermethylation na RASSF1A mai gabatarwa na iya zama mai ƙima mai mahimmanci don tantancewar farko na HCC da yuwuwar manufa ta kwayoyin halitta don maganin epigenetic.28 A cikin binciken daya, an samo maganin RASSF1A mai haɓaka hypermethylation a cikin 73.3% na marasa lafiya tare da HCC.29 Dogon tsaka-tsaki na nucleotide 1 (LINE-1) wani matsakanci ne mai aiki sosai.An samo Hypomethylation na LINE-1 a cikin DNA na 66.7% na samfurori na HCC kuma an hade shi tare da sake dawowa da wuri da rashin lafiya bayan raɗaɗi.29 Hypermethylation tsari ne na gama gari wanda ke taka muhimmiyar rawa wajen haɓaka hanta cirrhosis da HCC.30 Sabanin haka, hydroxymethylation shine tsarin demethylation wanda ke haifar da sake kunnawa da kuma bayyanawa, da kuma gano samfurin 5-hydroxymethylcytosine (5-hmC) a cikin wannan tsari za'a iya amfani dashi don gano ƙwayar cuta.Methylation da hydroxymethylation na cDNA suna hade da tumorigenesis kuma yana iya taimakawa wajen fara gwajin HCC.A cikin nazarin batutuwa na 2554, an samo 31 genom-fadi 5-hmCs a cikin samfurori na cfDNA, kuma an gano kwayoyin 32 ta hanyar kwatanta jerin 5-hmC a cikin marasa lafiya na HCC da ƙungiyoyi masu haɗari irin su wadanda ke da cututtuka na kullum.Hanyoyin bincike na cututtukan hanta.da kuma cirrhosis.Wannan samfurin ya zarce na AFP wajen bambance HCC daga ƙwayoyin da ba ƙari ba.
Maye gurbi a cikin yankuna masu ƙididdigewa na iya haifar da rashin daidaituwa na rubutu, wanda zai iya haifar da canje-canje a cikin jerin furotin da kuma ciwon daji.Bambance-bambancen nucleotide guda ɗaya sune mahimman alamomin genomic don fara gwajin ƙwayar cuta saboda babban amincin nama da babban ƙari da takamaiman nama.Yawancin binciken da suka danganci HCC ta amfani da jerin tsararraki na gaba (NGS) don exome da dukkanin jerin kwayoyin cutar daji na ciwon daji sun gano kwayoyin halittar kwayar halitta na yau da kullun kamar TP53 da CTNNB1, da kuma da yawa ciki har da ARID1A, MLL, IRF2.Sabbin kwayoyin halitta, ATM, CDKN2A, FGF19, PIK3CA, RPS6KA3 da JAK1 suna nuna matsakaicin adadin maye gurbi. Binciken aikin mutant na mutant yana nuna cewa canje-canje a cikin gyare-gyare na chromatin, Wnt / β-catenin da JAK / STAT transduction siginar, hanyar P53-cell cycle, epigenetic modifiers, oxidative stress hanyoyin, PI3K / AKT / MTOR hanya da RAS / RAF / Hanyar MAPK kinase tana taka muhimmiyar rawa a cikin HCC oncogenesis.32,33 A cikin binciken da aka gano maye gurbi mai alaƙa da ƙari, Huang et al ya gano cewa yawancin maye gurbi da ke da alaƙa da ctDNA shine 19.5%, kuma takamaiman shine 90% .34 Bugu da ƙari, marasa lafiya waɗanda suka fuskanci mamayewa na jijiyoyin jini sun fi dacewa su sami maye gurbin ctDNA (P=0.041) da kuma ɗan gajeren rayuwa ba tare da sake dawowa ba (P <0.001). Binciken aikin mutant na mutant yana nuna cewa canje-canje a cikin gyare-gyare na chromatin, Wnt / β-catenin da JAK / STAT transduction siginar, hanyar P53-cell cycle, epigenetic modifiers, oxidative stress hanyoyin, PI3K / AKT / MTOR hanya da RAS / RAF / Hanyar MAPK kinase tana taka muhimmiyar rawa a cikin HCC oncogenesis.32,33 A cikin binciken da aka gano maye gurbi mai alaƙa da ƙari, Huang et al ya gano cewa yawancin maye gurbi da ke da alaƙa da ctDNA shine 19.5%, kuma takamaiman shine 90% .34 Bugu da ƙari, marasa lafiya waɗanda suka fuskanci mamayewa na jijiyoyin jini sun fi dacewa su sami maye gurbin ctDNA (P=0.041) da kuma ɗan gajeren rayuwa ba tare da sake dawowa ba (P <0.001).Binciken aikin mutant gene yana nuna cewa canje-canje a cikin gyare-gyaren chromatin, Wnt / β-catenin da JAK / STAT siginar, hanyar P53 cell cycle, epigenetic modifiers, oxidative stress hanyoyin, PI3K / AKT / MTOR hanya, da kuma RAS / RAF / MAPK kinase hanyar taka. Muhimmiyar rawa a cikin HCC tumorigenesis.32,33 A cikin binciken da ya gano maye gurbi mai alaƙa da ƙari, Huang et al.an gano cewa mitar ctDNA da ke da alaƙa da maye gurbi ya kasance 19.5% kuma ƙayyadaddun shine 90%..34 Кроме того, у пациентов с сосудистой инвазией чаще встречались мутаци цДНК (P=0,041) и берцер .34 Bugu da ƙari, marasa lafiya tare da mamayewar jijiyoyin jini suna da ƙarin maye gurbi na cDNA (P = 0.041) da kuma ɗan gajeren rayuwa marar cuta (P <0.001).Binciken aiki na kwayoyin halitta sun bayyana gyare-gyaren chromatin, Wnt / β-catenin da JAK / STAT siginar, hanyar P53 cell cycle, epigenetic gyare-gyare, hanyar damuwa na oxidative, hanyar PI3K / AKT / MTOR, da RAS / RAF / MAPK Hanyar kinase tana taka muhimmiyar rawa a cikin oncogenesis na HCC. 32,33 在一项检测到肿瘤相关突变的研究中,Huang 等人发现肿瘤相关突变依赖于ctDNA 的频率为19.5%,特异性为90% .34 此外,经历血管侵犯的患者更有可能发生ctDNA突变(P=0.041)和更短的无复发生存期(P<0.001)。 32.33 在 一 一 一 到 相关 相关 到 到 到 到 检测, Huang 等等 发现, Huang 依赖于 依赖于 Cton 的 为 190%, 0.041) 和 更 更 发生 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管 血管短的无复发生存期(P<0.001)。32,33 A cikin binciken da ya gano maye gurbi da ke da alaƙa da ƙari, Huang et al.gano cewa maye gurbi da ke da alaƙa da ƙwayar cuta sun kasance 19.5% dogara ga cDNA tare da ƙayyadaddun 90% 34. Bugu da ƙari, marasa lafiya waɗanda suka sami mamayewar jijiyoyin jini sun fi iya haɓaka cDNA.мутация (P = 0,041) и более короткая безрецидивная выживаемость (P <0,001). maye gurbi (P=0.041) da gajeriyar rayuwa marar cuta (P <0.001).Wani nau'in direban HCC na kowa shine TP53, wanda ke da ƙimar maye gurbin sama da 30%.Nazarin ya nuna cewa yawan maye gurbi na TP53 a cikin ctDNA a cikin jini da fitsari ya tashi daga 5% zuwa 60%.Binciken 35 Johan ya nuna cewa bakan maye gurbi na ctDNA a ƙarshen HCC yana da irin wannan canjin canji zuwa farkon HCC, gami da mai tallata TERT (51%), TP53 (32%), CTNNB1 (17%), PTEN (8%), maye gurbi a cikin AXIN1 ., ARID2, KMT2D da TSC2 (6% kowanne).36 β-catenin (CTNNB1) oncogene yana taka muhimmiyar rawa a cikin hanyar siginar Wnt.CTNNB1 mai haɗin kai na rubutun na iya inganta maganganun kwayoyin halitta, wanda zai iya haifar da yaduwar kwayar halitta, hana apoptosis, da angiogenesis.CTNNB1 kuma na iya yin hulɗa tare da TERT don haifar da canjin hanta.33 Mai tallata TERT akai-akai yana canzawa a wasu ciwace-ciwacen ciwace-ciwace.Canje-canje a cikin TERT, ɗayan farkon canje-canjen kwayoyin halitta a cikin mummunan canji na HCC, na iya haifar da sake kunna telomerase a cikin hanta na cirrhotic kuma yana iya haɓaka haɓakawa da hana tsufa.Maye gurbi a cikin mai gabatarwa na 33-37 TERT an ba da rahoton faruwa a cikin 59-90% na marasa lafiya tare da nodules na hanta mai yaduwa da farkon HCC kuma suna da alaƙa da rayuwa.38
Canjin lambar kwafi (CNA) muhimmin nau'in maye gurbi ne.Bincike ya nuna cewa yaɗuwar da kuma mai da hankali nauyi na CNA sa hannu ne na kwayoyin halitta wanda ke da ikon tsinkayar kutsewar rigakafi da ƙari a wasu nau'ikan ciwon daji.39 Alamar infiltration mai aiki, babban aikin cytolytic, kumburi mai tsanani da alamomin kwayoyin halitta da ke hade da gabatarwar antigen a cikin HCC.Binciken bayanan jeri na nucleotide polymorphisms guda ɗaya a cikin batutuwa 477 ya nuna ƙaramin nauyi akan CNS.Sabanin haka, ciwace-ciwacen chromosomally maras ƙarfi tare da babban nauyin CNA mai girma ya nuna alamun rashin amincewa da rigakafi kuma suna da alaƙa da haɓakawa, gyaran DNA, da rashin aiki na TP53.Xu et al.ya nuna cewa ƙungiyar HCC tana da ƙimar CNA mafi girma fiye da ƙungiyar cututtukan hanta.40 Yin amfani da jerin kwayoyin halitta gaba ɗaya na tantanin halitta guda ɗaya, an gano CNAs suna bayyana da wuri a cikin hepatocarcinogenesis kuma sun kasance da kwanciyar hankali yayin ci gaban ƙari.41 Chung et al.an gano cewa matakan cfDNA sun haɓaka sosai a cikin marasa lafiya na HCC kuma cewa CNAs masu fa'ida a cikin cfDNA sun kasance muhimmiyar alamar tsinkaya mai zaman kanta a cikin marasa lafiya na HCC da aka bi da su tare da sorafenib.42 Marasa lafiya masu nauyin CNA mafi girma sun fi samun ci gaba da cututtuka da mutuwa fiye da waɗanda ke da ƙananan nauyin CNA.Ollerich et al.gano cewa za a iya amfani da ma'aunin rashin zaman lafiya na lambar kwafi (CNI) don tantance CNA a cikin cfDNA na masu ciwon daji.Sun lura cewa marasa lafiya da ke fama da ciwon daji suna da ƙima mafi girma na CNI fiye da ƙungiyar kulawa, wanda ke kimanta amsawar haƙuri ga tsarin chemotherapy da immunotherapy.43 Waɗannan sakamakon suna ba da shawarar cewa CNAs da aka samu a cikin samfuran biopsy na ruwa na iya zama alamun tsinkaya a cikin marasa lafiya da ciwon daji mai ci gaba.HCC akan bangon tsarin jiyya.
A halin yanzu, hanyoyin da ake amfani da su don gano ctDNA za a iya raba su zuwa hanyoyin da aka yi niyya da waɗanda ba a yi niyya ba.A taƙaice, hanyoyin da aka yi niyya kamar dijital polymerase sarkar amsa (dPCR), BEAMing dijital PCR, Amplification Refractory Mutation System-PCR, Capp-Seq da Tam-Seq suna da matuƙar kula da ƙayyadaddun kwayoyin halitta.Hanyoyin da ba a ke so ba kamar tsarin tsarin kwayoyin halitta gabaɗaya da NGS suna ba da cikakkiyar ra'ayi na gabaɗayan yanayin yanayin halitta.44 Idan aka kwatanta da ɓangarorin da aka yi niyya, gabaɗayan jerin kwayoyin halitta na iya gano ba kawai maye gurbi da sakawa ba, har ma da sake tsarawa da bambance-bambancen kwafi.hasashe, da CTC da cfDNA alamomi ne masu kyau waɗanda za a iya amfani da su don saka idanu mai ƙarfi na HCC.45 Bugu da kari, binciken cfDNA na iya zama mafi amfani wajen gano HCC.Yan et al.ya nuna cewa cfDNA a cikin plasma na marasa lafiya tare da HCC ya fi girma fiye da marasa lafiya da fibrosis na hanta da kuma kula da lafiya.Idan aka kwatanta da AFP, ana tsammanin ctDNA zai zama mafi kyawun alamar nunawa don farkon HCC.46 A cikin bincike mai zuwa na biopsies na ruwa guda 47 waɗanda suka gwada cfDNA da furotin a cikin yawan jama'a, an nuna su da tasiri wajen bambanta marasa lafiya tare da HCC daga marasa lafiya ba tare da HCC ba.A cikin bin 331 duban dan tayi na al'ada da marasa lafiya na AFP-marasa kyau, hankali da ƙayyadaddun cfDNA don bincikar HCC sun kasance 100% da 94%, bi da bi, don haka cDNA na iya gano HCC a cikin mutanen asymptomatic HBsAg seropositive.A cikin binciken Yeo48, an sami babban mitar (92.5%) na hypermethylation na mai gabatarwa RASSF1A a cikin marasa lafiya tare da HCC.Bugu da kari, Xu et al.ya ƙirƙiri samfurin bincike don hango ko hasashen HCC ta amfani da kwamiti na takamaiman alamomin methylation tare da ƙayyadaddun ƙayyadaddun ƙayyadaddun yanayin 90.5% da 83.3%, bi da bi.Ƙungiyar ta ba da damar marasa lafiya da HCC su bambanta daga marasa lafiya da wasu cututtuka na hanta, wanda ya fi AFP.Sun kuma gano cewa abubuwan sarrafawa na yau da kullun waɗanda aka gwada tabbatacce na iya samun abubuwan haɗari ga HCC, kamar kamuwa da cutar HBV ko tarihin amfani da barasa.25 Mun ɗauka cewa manyan abubuwan haɗari ga HCC na iya haɓaka hypermethylation na cfDNA, wanda hakan zai ba da gudummawa ga ci gaban HCC, don haka cfDNA na iya taka muhimmiyar rawa wajen tantance ƙungiyoyi masu haɗari.Kai et al.taƙaita cikakken kewayon maye gurbi na ctDNA kuma ya ba da ingantacciyar dabara don tantance nauyin ƙari a cikin marasa lafiya.49 Wannan dabarar na iya gano tumorigenesis mai tsaka-tsaki na watanni 4.6 kafin canza hoton hoto kuma ya nuna kyakkyawan aikin bincike idan aka kwatanta da magungunan biomarkers AFP, AFP-L3, da PIVKA-II.An nuna ƙimar bincike na gwajin cDNA lokacin da ba a samu kimantawar hoto ba, don haka gwajin cDNA yana da daraja a cikin ganewar HCC na farko a cikin ƙungiyoyi masu haɗari.Kwanan nan, masana kimiyya sun yi amfani da fasahar NGS don nazarin alamomi na bambancin kwayoyin halitta (ciki har da 5-hydroxymethylcytosine, 5'-motif, fragmentation, nucleosome trace, HIFI) a cikin 3204 samfurori na asibiti da cfDNA.Samfuran HIFI 50 da aka sake ingantawa tare da jirgin ƙasa mai zaman kansa guda uku, gwaji, da saitin gwaji sun nuna tsayayyen wariya tsakanin mutanen HCC da waɗanda ba HCC ba tare da 95.79% da 95.42% na hankali a cikin takamaiman gwajin HCC da saitin gwaji, bi da bi.Jima'i sun kasance 95.00% da 97.83%, bi da bi.Ƙimar bincike ta hanyar HIFI ya fi na AFP girma a bambance HCC daga cirrhosis.Bugu da ƙari, ana kuma amfani da ctDNA a cikin maganin tiyata.Atsushi et al.ƙaddara matakan ctDNA da aka riga aka yi a cikin marasa lafiya tare da HCC kuma sun gano cewa yawan maimaitawa da kuma yawan ƙwayar ƙwayar cuta a cikin ƙungiyar cDNA mai kyau sun kasance mafi girma fiye da na cDNA mara kyau, kuma matakan cDNA sun kasance masu dangantaka sosai.tare da ci gaban ƙari.51 Kasancewa mai ƙima mai ƙima, ctDNA na iya yin hasashen ikon HCC don mamaye tasoshin.Wang et al.An yi jerin jerin kwayoyin halitta gaba ɗaya na marasa lafiya 46 tare da HCC, kuma bincike mai yawa ya nuna cewa ƙimar kofa na mitar allele na bambancin cDNA don mamayewa cikin microvessels shine 0.83%, hankali 89.7% da takamaiman 80.0%.Halin haɗari mai zaman kanta don mamayewar microvascular a cikin HCC mai daidaitawa, yana ba da shawarar cewa cDNA na iya taimakawa jagorar mafi kyawun magani.A ƙarshe, ctDNA yana da cikakken tasiri a cikin abin da ya faru da ci gaban HCC kuma ana iya amfani dashi don tantancewa da wuri, kimantawar tiyata, da kuma lura da cututtuka.
CTCs ƙwayoyin cuta ne waɗanda aka samo daga ciwace-ciwacen farko ko metastases waɗanda ke yin metastasize zuwa jini.Kwayoyin Tumor suna ɓoye matrix metalloproteinases (MMPs), waɗanda ke rushe membrane na ƙasa, suna barin ƙwayoyin tumo su shiga cikin jini da tasoshin lymph kai tsaye.Koyaya, yawancin CTCs ana kawar dasu da sauri ta anoikis, harin rigakafi, ko damuwa mai ƙarfi.53 Canjin epithelial-mesenchymal (EMT) yana ba da damar CTCs su kasance cikin keɓancewa daga ƙwayar ƙwayar cuta ta farko, mamaye capillaries, da samun ingantaccen rayuwa mai mahimmanci, metastasis, mamayewa, da juriya na ƙwayoyi.Nazarin ya nuna cewa akwai nau'i mai zurfi a cikin nau'in ciwon daji daban-daban a cikin ciwace-ciwacen ƙwayar cuta na farko.Don haka, bincike na CTC zai iya haifar da cikakkiyar fahimtar nau'in ƙwayar ƙwayar cuta.54
Takamaiman alamomi don CTCs masu alaƙa da HCC sun haɗa da glypican-3 (GPC3), asialoglycoprotein receptor (ASGPR), kwayar halitta adhesion cell epithelial (EpCAM) da alamomi masu alaƙa da tantanin halitta irin su CD44, CD90, 55 da ƙwayoyin adhesion na intercellular.1 (ICAM1e).).57 Bayanin GPC3 ya fi kowa a cikin ƙwayoyin tumor HCC tare da tsaka-tsaki da ƙananan bambanci kuma yana inganta ƙaura na waje;Bugu da kari, kasancewar GPC3+ CTCs yana nuna HCC metastatic.58 ASGPR shine furotin transmembrane wanda aka bayyana kawai akan saman hepatocytes kuma an bayyana shi sosai a cikin HCC da aka bambanta.EpCAM yana ɗaya daga cikin sunadaran da ke da alaƙa da membrane don kama CTCs.An gano EpCAM a matsayin alamar farfajiyar sel HCC tare da halaye na sel, 59 wanda ya dace da nau'ikan sifofin asibiti na HCC, kamar mamayewar jijiyoyin jini, an tantance matakan AFP, da ci gaba na ciwon hanta a Asibitin Barcelona (BCLC).60 CTC EMT phenotype yana da haɓaka sosai.Hanyoyin EMT 54 a cikin CTC suna haɓaka metastasis na HCC.Bayyana alamun EMT irin su vimentin, karkatarwa, E-box zinc yat binding (ZEB) 1, ZEB2, katantanwa, slug, da E-cadherin an yi nazari a cikin CTC da aka samu hanta daga marasa lafiya na HCC.58 Tsarin CanPatrol™ wanda Cheng [61] ya ƙirƙira CTCs zuwa ƙananan ƙungiyoyin dabi'a guda uku bisa manyan alamomin da aka bayyana: epithelial phenotype (EpCAM, CK8/18/19), mesenchymal phenotype (vimentin, coiled), da gauraye phenotypes.A cikin marasa lafiya 176, jimillar CTC ta fi AFP wajen bambance HCC daga cutar hanta mara kyau.Ma'aunin AUC na jimlar CTC, AFP, da haɗin CTC da AFP sun kasance 0.774 (95% CI, 0.704-0.834), 0.669 (95% CI, 0.587-0.750), da 0.821 (95% CI, 0.756-0.8) ).), bi da bi.Rarraba CTC dangane da EMT na iya yin hasashen ganewar HCC, sake dawowa da wuri, metastasis, da ɗan gajeren lokaci gabaɗaya.
A halin yanzu, hanyoyin gano CSC sun haɗa da hanyoyin jiki da hanyoyin nazarin halittu.Hanyoyin jiki, sau da yawa ana kiranta haɓakawa bisa ga kaddarorin halittu, galibi sun dogara ne akan kaddarorin jiki na CSC, kamar girman, yawa, caji, motsi da nakasa.Dangane da kaddarorin jiki, akwai hanyoyi daban-daban kamar tsarin tushen tacewa, dielectrophoresis, da dai sauransu. Na ƙarshe, wanda kuma aka sani da haɓaka tushen immunoaffinity, galibi ya dogara ne akan ɗaurin antigen-antibody tunda hanyar tana amfani da ƙwayoyin rigakafi akan takamaiman biomarkers. irin su EpCAM, ASGPR, mai karɓar haɓakar haɓakar haɓakar ɗan adam 2 (HER2), takamaiman antigen prostate (PSA), pancytokeratin ɗan adam (P-CK) da carbamoyl phosphate synthase 1 (CPS1).62 Wani nau'in, wanda ake kira hanyar rashin haɓakawa, yana amfani da sitometry mai gudana don bambance CTCs daga leukocytes dangane da girman makaman nukiliya-zuwa-cytoplasmic da girma.A halin yanzu, gwajin da FDA kawai ta amince don gano CTC shine tsarin Cell-Search™, wanda ke amfani da alamar tantanin halitta na EpCAM. Duk da haka, haɗuwa da tushen CTC ganowa zai iya ƙara yawan ƙimar.54 Cakudawar rigakafin rigakafi da ASGPR da CPS1 sun sami adadin gano CTC na 91% a cikin marasa lafiya na HCC.63 Zhang et al sun yi amfani da CTC-Chip tare da rigakafi ga ASGPR, P -CK da CPS1, da kuma bambanta marasa lafiya na HCC daga waɗanda ke da ciwon hanta mara kyau ko kuma wadanda ba na HCC ba a cikin adadin 100%.64 Nazarin Wang ya gano EpCAM + CTCs a cikin 60% na 42 HCC marasa lafiya kuma ya sami dangantaka mai mahimmanci tsakanin duka biyun. ƙimar da adadin CTCs tare da matakin TNM.65 Guo et al sun gano cewa an haɓaka ƙimar PCR ta CTC a cikin 125/171 (73%) marasa lafiya waɗanda matakin AFP ya kasance <20 ng/mL tare da hankali na 72.5% da ƙayyadaddun 95.0%, idan aka kwatanta da 57.0% da 90.0% na AFP a yanke 20 ng/mL.66 Haɗin AFP da CTC na iya inganta ganowar HCC.45 An yi imanin cewa CTCs suna da fa'ida akan AFP a farkon tantancewar ƙungiyoyi. a babban haɗari ga HCC. Duk da haka, haɗuwa da tushen CTC ganowa zai iya ƙara yawan ƙimar.54 Cakudawar rigakafin rigakafi da ASGPR da CPS1 sun sami adadin gano CTC na 91% a cikin marasa lafiya na HCC.63 Zhang et al sun yi amfani da CTC-Chip tare da rigakafi ga ASGPR, P -CK da CPS1, da kuma bambanta marasa lafiya na HCC daga waɗanda ke da ciwon hanta mara kyau ko kuma wadanda ba na HCC ba a cikin adadin 100%.64 Nazarin Wang ya gano EpCAM + CTCs a cikin 60% na 42 HCC marasa lafiya kuma ya sami dangantaka mai mahimmanci tsakanin duka biyun. ƙimar da adadin CTCs tare da matakin TNM.65 Guo et al sun gano cewa an haɓaka ƙimar PCR ta CTC a cikin 125/171 (73%) marasa lafiya waɗanda matakin AFP ya kasance <20 ng/mL tare da hankali na 72.5% da ƙayyadaddun 95.0%, idan aka kwatanta da 57.0% da 90.0% na AFP a yanke 20 ng/mL.66 Haɗin AFP da CTC na iya inganta ganowar HCC.45 An yi imanin cewa CTCs suna da fa'ida akan AFP a farkon tantancewar ƙungiyoyi. a babban haɗari ga HCC.Duk da haka, haɗe-haɗen gano CTCs na tushen alamar na iya ƙara yawan adadin sakamako mai kyau.54 Cakudawar anti-ASGPR da CPS1 antibodies sun sami adadin gano CTC na 91% a cikin marasa lafiya tare da HCC.63 Zhang et al.ya yi amfani da CTC-Chip tare da ƙwayoyin rigakafi akan ASGPR, P-CK da CPS1, sannan kuma ya bambanta marasa lafiya da HCC daga waɗanda ke da cututtukan hanta mara kyau ko waɗanda ba HCC a cikin adadin 100%.частота и количество ЦОК со стадией TNM.65 Guo и соавторы обнаружили, что показатель ПЦР, полученный из ЦОК, был повышен у 125/171 (73%) пациентов, у которых уровень АФП был <20 нг/мл с чувствительностью 72,5% и специфичность 95,0% по сравнению с 57,0% и 90,0% для АФП при пороговом уровне 20 нг/мл.66 Комбинация АФП и ЦОК может улучшить обнаружение ГЦК.45 Считается, что ЦОК имеют преимущество перед АФП при раннем скрининге групп. mita da adadin CTCs tare da matakin TNM.65 Guo et al sun gano cewa PCR da aka samo daga CTC an haɓaka a cikin 125/171 (73%) marasa lafiya waɗanda ke da matakan AFP <20 ng/mL tare da hankali na 72.5% da ƙayyadaddun ƙayyadaddun. 95.0% idan aka kwatanta da 57.0% da 90.0% na AFP a matakin yankewa na 20 ng/mL.66 Haɗin AFP da CTC na iya inganta gano HCC.45 CTCs ana la'akari da samun fa'ida akan AFP a farkon nunawa. kungiyoyi.tare da babban haɗarin HCC.Koyaya, haɗe-haɗe na tushen alamar alama na CTCs na iya ƙara yawan adadin ingantattun sakamako.54 Cakudawar anti-ASGPR da ƙwayoyin rigakafin CPS1 sun sami ƙimar gano 91% CTC a cikin marasa lafiya tare da HCC.63 Zhang et al.An yi amfani da kwakwalwan CTC tare da ƙwayoyin rigakafi akan ASGPR, P-CK da CPS1 da kuma bambanta marasa lafiya tare da HCC daga cututtukan hanta mara kyau da marasa HCC tare da 100%.Binciken 64 Wang ya gano 60% na EpCAM+ CTCs a cikin marasa lafiya na HCC 42 kuma ya sami muhimmiyar alaƙa tsakanin abin da ya faru da adadin CTC a matakin TNM. 65 Guo 等人发现,在AFP 水平<20 ng/mL 的125/171 (73%) 名患中,CTC 衍生的 PCR值为20 ng/mL 时的特异性为57.0% 和90.0%. 65 Guo 等 人 发现 在 在 在 发现水平 <20 Ng / ML 的 05/171 (73%) 名 ,, CTC截止 截止截止 20NE 截止值 为 为 为 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 的 的 截止 截止 截止 截止 的 的 的 的 的 的 的 的 的 为 57.0% 和 90.0%.65 Guo et al.обнаружили, что у 125/171 (73%) пациентов с уровнем АФП <20 нг/мл показатели ПЦР, полученные с помощью ЦОК, были повышены с чувствительностью 72,5% и специфичностью 95,0%, в то время как АФП на уровне отсечки Специфичность составляла 20 нг/мл. An gano cewa a cikin 125/171 (73%) marasa lafiya tare da matakan AFP <20 ng/mL, ƙimar PCR da aka samo daga CTC sun haɓaka tare da haɓakar 72.5% da ƙayyadaddun 95.0%, yayin da AFP ke cikin takamaiman yankewa. ya kasance 20 ng/ml.ml ya kasance 57.0% da 90.0%.66 Haɗin ORP da CTC yana haɓaka gano HCC.Ana tsammanin CTCs 45 sun fi AFP a farkon tantance yawan mutanen HCC masu haɗari.Don haka, ga ƙungiyoyin HCC masu inganci da haɗarin CTC, gwajin CTC yakamata a haɗa shi akai-akai tare da duban dan tayi da gano AFP.Duk da haka, ana ɗaukar CTCs masu mahimmancin tsinkaya na metastasis na ƙari da sake dawowa, kuma gano CTC ba a ba da shawarar kansa azaman kayan aikin bincike ba.62 Saboda haka, CTC na iya zama mafi kyawun tsinkayar halitta fiye da sauran alamomin da ake amfani da su a halin yanzu. Zhou et al ya gano cewa marasa lafiya tare da adadin EpCAM + CTCs da kuma kwayoyin T masu tsarawa sun nuna haɗari mafi girma na ci gaba da sake dawowa HCC, fiye da wadanda ke da ƙananan lambobi na CTCs, tare da sake dawowa na 66.7% vs 10.3% (P <0.001) .67 An ba da rahoton irin wannan binciken ta hanyar Zhong et al.68 Bugu da ƙari, Qi ya gano cewa 101 na marasa lafiya 112 (90.81%) tare da HCC, ciki har da wadanda ke da cututtuka na farko, suna da kyau ga CTCs kuma an gano ƙananan nodules na HCC bayan 3. zuwa watanni 5 na bibiya. Zhou et al ya gano cewa marasa lafiya tare da adadin EpCAM + CTCs da kuma kwayoyin T masu tsarawa sun nuna haɗari mafi girma na bunkasa sake dawowa HCC fiye da wadanda ke da ƙananan lambobi na CTCs, tare da sake dawowa na 66.7% vs 10.3% (P <0.001) .67 A. An ba da rahoton irin wannan binciken ta hanyar Zhong et al.68 Bugu da ƙari, Qi ya gano cewa 101 daga cikin marasa lafiya 112 (90.81%) tare da HCC, ciki har da wadanda ke da cututtuka na farko, sun kasance masu kyau ga CTCs kuma an gano ƙananan nodules na HCC bayan 3 zuwa Watanni 5 na bibiya. Чжоу и др.обнаружили, что у пациентов с повышенным количеством ЦОК EpCAM+ и регуляторных Т-клеток риск развития рецидива ГЦК был выше, чем у пациентов с низким количеством ЦОК, с коэффициентом рецидивов 66,7% против 10,3% (P <0,001)67. Zhou et al ya gano cewa marasa lafiya tare da EpCAM + CTCs masu girma da kuma kwayoyin T masu tsarawa suna da haɗari mafi girma na sake dawowa HCC fiye da wadanda ke da ƙananan CTCs, tare da yawan maimaitawa na 66.7% vs 10.3% (P <0.001) 67.An gudanar da irin wannan binciken ta hanyar Zhong et al.68. Bugu da ƙari, Qi ya gano cewa 101 daga cikin 112 marasa lafiya (90.81%) tare da HCC, ciki har da wadanda ke da cututtuka na farko, suna da CTCs, kuma an gano ƙananan ƙananan nodules na HCC bayan watanni 3 zuwa 5 na biyo baya. Zhou 等 等 等 等 发现 人 人 发现 较 较 较 较 较 的相比, CTC, CTC 的和 Hcc 的细胞高 的 的风险 的 风险 为 66.7% 和 10.3% (P <0.001). Zhou 等 的 的 人与, CTC, 患者 T 细胞 复发 复发 更, 复发率 Hcc 复发 为更, 复发率 Hcc 复发 为更, 为 Hcc 为 为 为为 Hcy 为 为为 Hcy p <0.001) …………………………………………. Чжоу da др.обнаружили, что пациенты с повышенным количеством ЦОК EpCAM+ и регуляторных Т-клеток имели более высокий риск рецидива ГЦК по сравнению с пациентами с меньшим количеством ЦОК, с частотой рецидивов 66,7% и 10,3% соответственно (P <0,001). Zhou et al.sun gano cewa marasa lafiya tare da haɓakar EpCAM + CTCs da ƙwayoyin T masu tsarawa suna da haɗari mafi girma na sake dawowa HCC idan aka kwatanta da marasa lafiya da ƙananan CTCs, tare da sake dawowa na 66.7% da 10.3%, bi da bi (P <0.001).An ruwaito irin wannan binciken ta hanyar Zhong et al.68 Bugu da ƙari, Qi ya gano cewa 101 na 112 HCC marasa lafiya (90.81%), ciki har da marasa lafiya da farkon cututtuka, suna da sakamako mai kyau na CTC kuma sun sami ƙananan ƙananan nodules na HCC bayan ziyarar 3.Dubawa har zuwa watanni 5.Sun kuma sami CTC a cikin marasa lafiya 12 masu fama da cutar HBV na yau da kullun kuma sun sami ƙananan ciwace-ciwacen HCC a cikin watanni 5 a cikin marasa lafiya 2 na CTC.69 Don haka, ana iya amfani da CTCs don tsinkayar HCC, 70 amma ana iya amfani da su akai-akai azaman masu tsinkayar halittu.
Kamar cfDNA, ana fitar da cfRNA zuwa cikin jini ta tsarin daban-daban.Wadannan kwayoyin halitta a cikin jini na gefe suna wakiltar nama mai ciwon daji na asali.Idan aka kwatanta da alamun da aka gano ta hanyoyin da ba masu cin zarafi ba, cfRNAs sun fi daidaitawa sosai, takamaiman nama, kuma suna da yawa a cikin yanayin waje.An ba da rahoton mahimmanci da ƙimar bincike na miRNAs 71 (miRNAs) a cikin HCC a cikin bincike da yawa.miRNAs RNA ne na ƙarshe waɗanda ba sa coding (ncRNAs) waɗanda ke tsara ayyuka daban-daban na rayuwa ta hanyar hana fassarar RNAs manzo (mRNAs).miRNAs suna cikin jikin apoptotic wanda aka lullube a cikin exosomes, amma kuma suna iya daure su da sunadarai da lipids a cikin jini na gefe kuma ana iya amfani da su don kimanta HCC.microRNAs suna shiga cikin farfadowar hanta, metabolism na lipid, apoptosis, kumburi, da haɓakar HCC.72 Oncogenic miRNAs kamar miR-21, miR-155 da miR-221 sanannu ne a cikin HCC.Musamman, miR-21 yana taka muhimmiyar rawa a cikin haɗin gwiwar collagen a cikin matrix extracellular da fibrosis kuma yana haɓaka hepatocarcinogenesis ta hanyar kunna ƙwayoyin hematopoietic.72,73 Tumor suppressor miRNAs a cikin HCC sun haɗa da miRNA-122, miRNA-29, dangin Let-7, da dangin miRNA-15.Iyalin Let-7 sun ƙunshi miRNAs masu hana ƙari da yawa waɗanda ke nufin dangin RAS.Iyalin miR-15 sun haɗa da miR-15a, miR-15b, miR-16, miR-195, da miR-497, waɗanda ke da ƙarin jeri na wasu mRNAs.Bugu da kari, dogayen RNAs marasa coding (lncRNAs) da RNAs madauwari (cirRNAs) suma suna da mahimmanci don fara tantance HCC.lncRNAs suna wakiltar mafi girman aji na ncRNAs, gami da mRNA-kamar ncRNAs, kuma suna shiga cikin cututtukan cututtukan mutane da yawa.LncRNAs suna taka rawar tsari a cikin microenvironment hanta da cututtukan hanta na yau da kullun.74 CircRNAs suma rukuni ne na ncRNAs tare da ayyuka da yawa a cikin ƙa'idar bayanin kwayoyin halitta.Kwanan nan, an ɗauki cirRNAs azaman kayan aikin bincike don HCC.
Zazzage RNA kyauta yana da kwanciyar hankali na ban mamaki, gami da juriya ga zafin jiki, pH, da RNase, wanda ke sa keɓancewar fnRNA daga jini na gefe ya zama ƙasa da wahala ta amfani da daidaitattun hanyoyin tsarkakewa na RNA.Hanyoyin da aka fi amfani da su sun haɗa da NGS, microarray da RT-qPCR.NGS yana ba da damar auna microRNAs a ko'ina cikin kwayoyin halitta.Duk da haka, wannan hanya yana da tsada kuma ba a daidaita bincike ba.Sabanin haka, RT-qPCR ba shi da tsada, yana haɓaka acid ɗin nucleic da sauri, kuma yana ba da fa'idodi da yawa kamar haɓakar hankali, daidaito mafi girma, faffadan fa'ida mai ƙarfi, da buƙatar samfura kaɗan.Microarrays wata hanya ce da ake amfani da ita don gano miRNA bisa la'akari da ƙayyadaddun ƙayyadaddun ƙayyadaddun miRNAs masu niyya tare da ƙarin binciken DNA, 75 amma nazarin bayanan microarray yana ɗaukar lokaci.
An ba da rahoton zagayawa miR-122 da Let-7 suna da amfani wajen gano farkon matakin HCC a cikin ƙungiyoyi masu haɗari, alamomi a cikin marasa lafiya tare da nodules masu alaƙa da HBV da farkon matakin HCC.76 Kai et al.An gano cewa membobin dangin Let-7 (miR-92, miR-122, miR-125b, miR-143, miR-192, miR-16, miR-126, da miR-199a/b) suna cikin haɗarin kamuwa da cuta na yau da kullun. HCC a cikin marasa lafiya da ciwon hanta.Iyalin Let-7 na iya zama mai tasiri mai tasiri mai mahimmanci don tsinkayar ci gaban HCC a cikin ƙungiyoyi masu haɗari masu haɗari da ke hade da ciwon hanta na kullum C. 77 miR-122 yana da babban ganewar asali a gano farkon HCC a cikin marasa lafiya tare da cirrhosis na hanta.78 Serum da ke zagayawa MiR-107 kuma an kimanta shi a farkon matakan HCC, 79 kuma ya nuna kyakkyawan yuwuwar a cikin yawan jama'a masu haɗari.Zhou et al ya ruwaito cewa rukunin miRNAs (miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a da miR-801) na iya bambanta HCC daga ciwon hanta na B (CHB) da cirrhosis. Hankali ya kasance 79.1% da 75%, kuma takamaiman 76.4% da 91.1%, bi da bi.80 A cikin HCC da ke da alaƙa da HBV, mun gano cewa matakan miR150 sun ragu sosai idan aka kwatanta da waɗanda ke cikin marasa lafiya na HBV na yau da kullun ba tare da HCC ba (hantsi 79.1%, ƙayyadaddun 76.5%).-224 an ɗaukaka shi a cikin HCC idan aka kwatanta da kulawar lafiya, kuma ƙididdigar rukuni ya nuna matakan mafi girma a cikin marasa lafiya tare da HCC da ke hade da HBV.cirrhosis mai alaƙa da hanta da hanta da masu cutar HCC sun gano sirna mai rarraba siRNA wanda ke ƙunshe da siRNA guda bakwai daban-daban waɗanda zasu iya gano HCC a cikin sarrafawa daban-daban;Kewayon AUC a gwajin farko ya fi masu aikin sa kai na AFP kyau.Sun gano cewa miRNA guda huɗu (miR-1972, miR-193a-5p, miR-214-3p, da miR-365a-3p) na iya bambanta marasa lafiya da HCC daga marasa lafiya ba tare da HCC ba.MiRNA guda biyar masu wuce gona da iri (miR-122-5p, miR-125b-5p, miR-885-5p, miR-100-5p, da miR-148a-3p) ana daukar yiwuwar kamuwa da cutar HBV a cikin HCC, cirrhosis, da CHB biomarkers, musamman miR-34a-5p na iya zama alamomin halitta don hanta cirrhosis, 85 kuma yana iya zama masu yuwuwar tantancewar HCC a farkon yawan mutanen da ke da haɗari.Mafi binciken lncRNA a cikin HCC yana aiki sosai a cikin ciwon hanta (HULC).Sauran nazarin sun nuna cewa HULC da ke yawo a cikin marasa lafiya na HCC za a iya amfani da su azaman alamar bincike saboda wannan lncRNA yana da haɓaka sosai a cikin marasa lafiya na HCC idan aka kwatanta da mutane masu lafiya.71,86 Daga cikin sauran lnRNAs, LINC00152 ana ɗaukar mafi kyawun bincike lncRNA saboda babban AUC, azanci da ƙayyadaddun bayanai.86 A cikin binciken daya, maganganun jini na LINC00152 a hankali ya karu daga kulawar lafiya na yau da kullun zuwa marasa lafiya tare da CHB da cirrhosis, kuma a ƙarshe ya kasance mafi girma a cikin HCC.Nazarin maganganun cirsMARCA5 a cikin plasma na marasa lafiya tare da HCC sun nuna ci gaba da raguwa a cikin magana a cikin HCC daga ciwon hanta zuwa cirrhosis da raunuka masu tasowa.87 Nazari na ROC masu lankwasa sun tabbatar da yuwuwar waɗannan circRNAs wajen rarrabe marasa lafiya tare da hanta ko hanta cirrhosis daga waɗanda ke da HCC, musamman waɗanda ke da matakan AFP da ke ƙasa da 200 ng/mL.Bugu da ƙari, Zhu ya yi nazarin RNA na cyclic 13,617 a cikin samfuran plasma daga masu HCC masu alaƙa da HBV kuma ya tabbatar da cewa an bayyana RNA na cyclic 6 daban-daban a cikin HCC da HBV masu dangantaka da cirrhosis, yana nuna cewa cRNA na iya zama da amfani.alamomi don farawa da farko na ƙungiyoyi masu haɗari irin su waɗanda ke hade da cututtukan hanta, marasa lafiya na sclerosis.88
Exosomes ne membrane vesicles 40-160 nm a diamita;vesicles na ciki da yawa suna haɗuwa tare da membrane cell kuma ana fitar da su cikin matrix extracellular.Sun ƙunshi abubuwa da yawa masu aiki, gami da lipids, proteins, RNA da DNA, kuma suna taka muhimmiyar rawa wajen sadarwa tsakanin sel, duka ƙwayoyin HCC da waɗanda ba HCC ba.89,90 Exosomes suna daidaita ci gaban HCC ta hanyar kunna fibroblasts hepatocyte da stelate cell, ƙwayoyin rigakafi, hepatocytes na al'ada, da ƙwayoyin HCC.91 A cikin ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar kuma ta haifar da yawan adadin exosomes wanda aka ɗauka daga kwayoyin cutar ciwon daji zuwa kwayoyin da ba su da girma, wanda hakan ke shiga cikin oncogenesis, lalata, da siginar salula.92 Nazarin ya nuna cewa exosomes na iya canja wurin oncogenes zuwa ga al'ada Kwayoyin a lokacin pathological tafiyar matakai, wanda zai iya zama daya daga cikin hanyoyin da ƙari mamayewa da kuma metastasis.93 Matsayin exosomes a cikin ci gaban ciwon daji na iya zama mai ƙarfi kuma musamman ga nau'in ciwon daji, 89 Exosomes na iya zama cikin ciki ta kusa ko sel masu nisa don daidaita kwayoyin halitta da yawa a cikin sel masu karɓa waɗanda zasu iya shiga cikin ions sadarwar intercellular da hulɗar microenvironment ta salula, suna iya daidaita siginar salula da metabolism.94 Halaye da sauye-sauyen canje-canje na kwayoyin kaya na exosome kai tsaye suna nuna halaye da sauye-sauye na canje-canje na ƙwayoyin tumor mahaifa, 95 wanda kuma shine tushen yin amfani da exosomes a cikin ganewar asali da tsinkayen ciwon daji, da kuma tsinkayar amsawar mutum ga maganin ciwon daji. ..96
Hanyoyin dakin gwaje-gwaje na al'ada don warewa da nazarin exosomes suna da rikitarwa, matakai da yawa, da cin lokaci, gami da ultracentrifugation, tacewa, chromatography girman keɓancewa, tsarkakewar rigakafi, lalatawar Yamma, gwajin immunosorbent mai alaƙa da enzyme (ELISA), PCR, da bincike na kwarara.miniaturized tsarin da lab-on-a-chip dandamali ta amfani da micro/nanotechnology ana samun yadu ɓullo da ga sauri, dace a wurin keɓewar exosomes.Nanoparticle tracking analysis (NTA) hanya ce ta yadu da aka yi amfani da ita don nuna girman da taro na exosomes, gami da hanyoyin kamar magnetic nanoparticles da polyhydroxyalkanoates.Hanyoyin microfluidic da electrochemical kuma na iya gano exosomes cikin sauri a cikin yawan amfanin ƙasa.
Protein Exosomal sune mahimman alamomi don ganewar HCC.A cikin binciken Arbelaiz, matakin 98 RasGAP SH3 daurin furotin (G3BP) da polymeric immunoglobulin receptor (PIGR) ya kasance mai girma sosai a cikin exosomes da aka samo daga HCC, kuma ingantaccen haɗin haɗin sunadarai biyu ya fi na AFP.Yawan nauyin ƙarfe muhimmin abu ne da ke ba da gudummawa ga haɓakar HCC.Tseng ya ruwaito cewa hepcidin na iya taka muhimmiyar rawa wajen jure HCC.99 Exosomes da aka samo daga sera na marasa lafiya na HCC suna da adadi mafi girma mafi girma na bambance-bambancen hepcidin mRNA fiye da takwarorinsu masu lafiya, suna ba da shawarar cewa hepcidin na iya zama maƙasudin binciken halittu na HCC.Sunan 14-3-3ζ a cikin exosomes da 100 HCC ya samar zai iya rage yawan kunnawa T cell, haɓakawa, da bambance-bambancen kuma zai iya haifar da canjin kwayar halitta T zuwa cikin kwayoyin T, wanda ya haifar da raguwar kwayar cutar T.101 Wannan yana goyan bayan binciken da yawa da ke bincika ƙauyen ƙwayar cuta daga sa ido na rigakafi, 102 wanda zai iya ba da gudummawa ga ƙwayar cuta ta HCC.
Baya ga kasancewar ecRNA a cikin jini ko jini, ana iya amfani da exosomes masu wadatar da RNA don matakan da ba su da ƙarfi a cikin ainihin lokacin gwajin ƙwayar cuta kuma don ƙayyade haɓakar ƙwayar cuta da amsawa ga jiyya.Matsayin exosomal miRNA-21 a cikin jinin jini a cikin ƙungiyar HCC ya ninka sau 2.21 sama da na ƙungiyar CHB, kuma a cikin ƙungiyar HCC ya ninka sau 5.57 fiye da na yawan jama'a masu lafiya.A cikin binciken Wang, exosomes sun haɓaka HCC sosai idan aka kwatanta da marasa lafiya na cirrhotic tare da ƙimar AUC na 0.83 (95% CI 0.74-0.93) da 0.94 (95% CI 0.88-1.00).104 Bayanan da aka samu sun bayyana shigar da takamaiman kwayoyin kaya na exosomal a cikin tsarin tsarin oncogenesis da ci gaban HCC.105 Maganin magani na miR-221, miR-103, miR-181c, miR-181a, miR-93 da miR-26a yayi daidai.da metastasis, da matakan miR21 sun fi girma a cikin marasa lafiya na HCC fiye da a cikin kulawar lafiya da kuma a cikin marasa lafiya na CHB.102 LncRNA yana da yuwuwar ƙimar ganowa a cikin HCC.Nazarin ya nuna cewa exosomes da aka samo daga sera na marasa lafiya na HCC suna da matakan da suka fi girma na LINC00161, LINC000635, da lncRNA da aka kunna ta hanyar canza yanayin girma-β fiye da marasa lafiya ba tare da HCC ba, kuma waɗannan lncRNAs suna da dangantaka da matakan TNM da ƙwayar ƙwayar cuta.110 Conigliaro et al.CD90 + exosomes an samo su don bayyana manyan matakan lncRNAH19, wanda ya karu da haɓakar haɓakar haɓakar haɓakar ƙwayar cuta (VEGF) da kuma samar da mai karɓar VEGF-R1, ta haka yana ƙarfafa angiogenesis.93 CircRNAs wani nau'i ne na exosomal ncRNAs - wanda aka bayyana a ƙananan matakai amma barga a cikin nau'in jinsin, circRNAs kuma suna nuna ƙayyadaddun nau'in tantanin halitta, nau'in nama, matakin ci gaba, da aikin tsari.111 circRNAs sune masu gano kwayoyin halitta don farkon kuma mafi ƙarancin cutar kansa.Gwajin asibiti 112 na baya-bayan nan sun nuna cewa keɓancewar miRNA guda ɗaya a cikin tsinkayar HCC bai dace ba.Saboda haka, hadaddun ganowa ta amfani da gwaje-gwaje masu yawa (misali, miR-122 da miR-48a a hade tare da AFP) na iya inganta gano farkon HCC da bambance-bambancen HCC daga cirrhosis.100
Marasa lafiya tare da CHB da hanta cirrhosis sune mafi yawan rukunin haɗari masu haɗari don haɓaka HCC.Ga ƙungiyoyi masu haɗarin gaske, da zarar an sami ci gaba mai ɗorewa na ƙwayoyin cuta, ya kamata a samar da dabarun sa ido mai tsada dangane da haɗarin HCC, kuma tuntuɓar gwajin farko shine mabuɗin don haɓaka ganewar asali da magani na HCC tare da ƙimar ƙimar inganci mai girma2 ..Hanyoyin gwajin farko don ciwon daji suna da iyakoki da yawa: ingantattun hanyoyin tantancewa da wuri ba a samar da su ba don yawancin nau'in ciwon daji, kuma riko da yawanci ba su da yawa.Idan aka kwatanta da hanyoyin gwajin farko na gargajiya, fasahar biopsy na ruwa tana da fa'ida a bayyane: sauƙi na samfur, gano panrac, ingantaccen samfuri mai kyau, da ingantaccen martani ga nau'in ƙari.Idan aka yi la'akari da ingancin hanyoyin da ke da alaƙa da biopsy na ruwa, ba a gwada amfani da su a gwajin HCC akai-akai ba.Duk da ci gaban da aka samu na ingantaccen ganowa a matakin kwayoyin halitta, biopsy na ruwa yana da tsada don gano HCC a cikin majinyata da aka yi niyya, yana iyakance yawan amfani da shi idan aka kwatanta da takamaiman hanyoyin hoto kamar duban dan tayi da kuma hoton maganadisu.113,114 Duk da haka, wani binciken da aka yi a baya ya nuna cewa biopsy na ruwa ya nuna muhimmiyar fa'ida dangane da shekarun rayuwa masu inganci (QALYs).115 Amfanin biopsy na ruwa a farkon carcinoma na ciki da kuma nasopharynx an kuma nuna su.116,117 Ra'ayi na yanzu shine biopsy na ruwa zai iya haɗawa da alamun kwayoyin halitta da kuma tantancewar rediyo a cikin ganowa da gano ciwace-ciwace.117 118
Dangane da wallafe-wallafen na yanzu, fasahar biopsy na ruwa ta nuna matuƙar hankali da ƙayyadaddun ƙayyadaddun gwajin farko na ƙungiyoyi masu haɗari don cutar kansar hanta.Ko da kuwa nau'in biopsy na ruwa, yana iya bambanta HCC daga mutane masu haɗari ba tare da HCC ba, yana nuna mahimmancin tantancewar farko kamar yadda bambance-bambance tsakanin masu haɗari da masu lafiya sun bayyana.ctDNA yana da ɗan gajeren rabin rayuwa kuma ana iya amfani da shi don gano HCC, don haka duk wani canje-canje a cikin cDNA da aka samu na ƙari zai iya ba da tabbataccen shaidar ci gaba na ƙari, musamman ga ƙananan ciwace-ciwace.Babban matakin ctDNA yana nuna haɓakawa da yaduwar cutar kansa kuma alama ce ta farko na ci gaba da sake dawowa.Bugu da ƙari, dangane da sakamakon ctDNA, marasa lafiya na iya samun jiyya na mutum-mutumi da kuma biyo baya.119 takamaiman wuraren methylation na iya zama alama mafi kyau fiye da AFP don gano farkon HCC da nodules na cirrhotic.A cikin lokuta masu rikitarwa na HCC, manyan matakan cDNA suna nuni da mamayewar microvascular da sake dawowa bayan aiki da metastasis.Canje-canje a lambar kwafin suna da alaƙa da rayuwar marasa lafiya tare da HCC.Ana iya ɗauka cewa ƙimar cDNA na iya shiga cikin jiyya na HCC gabaɗaya, kuma cDNA na iya zama alama mai tasiri na daidaitawar warkewa.Alamomi dangane da takamaiman maye gurbi a cikin ctDNA an karɓi su ta jagororin asibiti don hasashen inganci da sa ido kan juriyar ƙwayoyi.Gwajin ctDNA na iya zama kayan aikin biopsy mafi amfani don tantancewa da wuri.CTCs kuma suna taka muhimmiyar rawa a farkon tantance ƙungiyoyin HCC masu haɗari.Alamomi daban-daban na CTC masu alaƙa da HCC suna da mahimmanci musamman a farkon, haɓakawa, da maimaitawar HCC.A matsayin membrane vesicles, exosomes suna shiga cikin sadarwar intercellular, musamman a cikin ƙwayoyin HCC.MicroRNAs masu kewayawa suna da ƙarfi a cikin jini kuma don haka yana iya zama mafi amfani ga farkon gwajin HCC.A hankali, an gano sunadaran exosomal da exosomes masu arzikin RNA, kuma an tabbatar da ingancinsu ga HCC.Abin sha'awa shine, ana iya haɗa nau'o'i daban-daban na HCC tare da maye gurbi daban-daban, don haka za mu iya zaɓar nau'ikan alamomin halitta daban-daban don tantancewa da wuri dangane da nau'o'i daban-daban na HCC.120
Koyaya, dabarun biopsy na ruwa na yanzu suna da tambaya dangane da kwanciyar hankali kuma ba za su iya yin gwajin farko ko sa ido kan HCC ba, amma har yanzu suna iya haɗawa da tantancewar mutum da ganewar asali.121 A matsayin nau'i na biopsy na ruwa, ganowa da hoton ctDNA, CTC, cfRNA da exosome-hade AFP ko PIVKA-II suna da aikace-aikace masu ban sha'awa a farkon ganewar asali da tsinkaye na HCC.Koyaya, ainihin hanyar sakin ctDNA cikin jini ya rage don bayyana shi.Bayyana ainihin kaddarorin nazarin halittu na ctDNA na iya sauƙaƙe amfani da shi azaman alama.Ƙananan adadin ctDNA a cikin wurare dabam dabam da kuma ƙayyadaddun buƙatun kulawa da samfurin ƙalubale ne don aiwatar da asibiti na gano cDNA a cikin HCC.Bugu da kari, maye gurbi na kwayoyin halitta ba su da takamaiman siffofi da ke ba da damar gano ainihin ƙwayoyin cuta na carcinogens.Tunda bambance-bambancen kwayoyin halitta da na somatic suma suna nan a cikin kyallen takarda na yau da kullun, maye gurbin kwayoyin halitta da aka gano ta hanyar biopsy na ruwa na iya zama mai iyakacin amfani a farkon gwajin HCC.122 Ƙayyadaddun ƙayyadaddun maƙasudai masu amfani da kwayoyin halitta masu amfani da kwayoyin halitta waɗanda ke taimakawa bambance cDNA daga DNA marasa ƙari sune batutuwa mafi mahimmanci a cikin amfani da cDNA.rashin amfani na masu hankali da takamaiman alamomi don gano CTCs.Kwayoyin da za a iya amfani da su kawai waɗanda ke da yuwuwar metastatic an samo su, kuma ba a fayyace madaidaicin haɗakar alamomin wadatar CSC ba.Ware CTCs don al'adu da kimanta bayanan martabarsu shima babban aiki ne mai wahala.Saboda matsalolin ganowa, keɓewa da tsarkakewar abubuwan da ke haifar da cutar, har yanzu ba a san takamaiman tsarin kwayoyin halitta ba, kuma binciken da aka yi a baya kan tsarin exosomes da HCC ba a zurfafa ba, da kuma yadda ake ware miRNAs, lncRNAs, da furotin zuwa exosomes. , kuma ba a bayyana ko ɗaukar exosome takamaiman tsari ne na nau'in ba.Amfani da exosomes don ganewar asali da magani na HCC har yanzu yana kan matakin farko.Rashin daidaituwa na hanyoyin biopsy na ruwa, irin su nau'in bututun da ake amfani da su don tattara jini, ƙarar jini, ajiyar samfurin da ganowa, keɓewa da haɓakawa, na iya hana amfani da su a cikin aikin asibiti na yau da kullum saboda bambance-bambance a cikin ayyuka a fadin cibiyoyin kiwon lafiya.Ana ci gaba da bincika ingancin biopsy na ruwa a farkon tantancewa, ganewar asali, kimanta inganci, da hasashen HCC, musamman ga ƙungiyoyi masu haɗari.Fasahar biopsy na ruwa tana da babban yuwuwar kuma ana tsammanin za a yi amfani da shi sosai a cikin aikin asibiti na ciwon hanta a nan gaba.
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