Umdlavuza we-pancreatic ungenye yezimila ezibulalayo kakhulu emhlabeni ezinezibikezelo ezimbi. Ngakho-ke, kudingeka imodeli yokubikezela enembile ukuze kutholakale iziguli ezisengozini enkulu yomdlavuza we-pancreatic ukuze kulungiswe ukwelashwa futhi kuthuthukiswe izibikezelo zalezi ziguli.
Sithole idatha ye-Cancer Genome Atlas (TCGA) pancreatic adenocarcinoma (PAAD) RNAseq kusuka kusizindalwazi se-UCSC Xena, sathola ama-lncRNA ahlobene nokuzivikela komzimba (i-irlncRNAs) ngokuhlaziywa kokuxhumana, futhi sathola umehluko phakathi kwe-TCGA nezicubu ezivamile ze-pancreatic adenocarcinoma. I-DEirlncRNA) evela ku-TCGA kanye ne-genotype tissue expression (GTEx) yezicubu ze-pancreatic. Kwenziwe ukuhlaziywa okwengeziwe kwe-univariate kanye ne-lasso regression ukwakha amamodeli wesiginesha sokubikezela. Sabe sesibala indawo engaphansi kwejika futhi sanquma inani elifanele lokunquma iziguli ezine-pancreatic adenocarcinoma enengozi ephezulu nephansi. Ukuze siqhathanise izici zezokwelapha, ukungena kwamangqamuzana omzimba, i-immunosuppressive microenvironment, kanye nokumelana ne-chemotherapy ezigulini ezinomdlavuza we-pancreatic onengozi ephezulu nephansi.
Sithole amabhangqa angu-20 e-DEirlncRNA futhi sahlanganisa iziguli ngokwenani elifanele lokuqeda. Sibonise ukuthi imodeli yethu yesiginesha yokubikezela inamandla amakhulu ekubikezeleni ukubikezela kweziguli ezine-PAAD. I-AUC yejika le-ROC ingu-0.905 yesibikezelo sonyaka owodwa, u-0.942 wesibikezelo seminyaka emi-2, kanye no-0.966 wesibikezelo seminyaka emi-3. Iziguli ezisengozini enkulu zazinamazinga aphansi okusinda kanye nezici zezokwelapha ezimbi kakhulu. Siphinde sabonisa ukuthi iziguli ezisengozini enkulu zicindezelwe amasosha omzimba futhi zingase zibe nokumelana ne-immunotherapy. Ukuhlolwa kwemithi yokulwa nomdlavuza njenge-paclitaxel, i-sorafenib, kanye ne-erlotinib ngokusekelwe kumathuluzi okubikezela okubala kungafaneleka ezigulini ezisengozini enkulu ezine-PAAD.
Sekukonke, ucwaningo lwethu lusungule imodeli entsha yobungozi bokubikezela esekelwe ku-irlncRNA ebhangqiwe, ebonise inani elithembisayo lokubikezela ezigulini ezinomdlavuza we-pancreatic. Imodeli yethu yobungozi bokubikezela ingasiza ukuhlukanisa iziguli ezine-PAAD ezifanele ukwelashwa.
Umdlavuza we-pancreatic uyisifo esibi esinezinga eliphansi lokusinda iminyaka emihlanu kanye nezinga eliphezulu. Ngesikhathi sokuxilongwa, iziguli eziningi sezivele zisesigabeni esithuthukile. Ngokomongo wobhubhane lwe-COVID-19, odokotela nabahlengikazi bangaphansi kwengcindezi enkulu lapho belapha iziguli ezinomdlavuza we-pancreatic, futhi imindeni yeziguli nayo ibhekene nezingcindezi eziningi lapho yenza izinqumo zokwelashwa [1, 2]. Nakuba kuye kwenziwa intuthuko enkulu ekwelapheni ama-DOAD, njengokwelashwa kwe-neoadjuvant, ukuhlinzwa, ukwelashwa ngemisebe, i-chemotherapy, ukwelashwa ngama-molecule okuqondisiwe, kanye nama-immune checkpoint inhibitors (ICIs), cishe ama-9% eziguli kuphela aphila eminyakeni emihlanu ngemva kokuxilongwa [3]. ], 4]. Ngenxa yokuthi izimpawu zokuqala ze-pancreatic adenocarcinoma azivamile, iziguli zivame ukuxilongwa ngokuthi zine-metastases esigabeni esithuthukile [5]. Ngakho-ke, esigulini esithile, ukwelashwa okuphelele komuntu ngamunye kumele kulinganise izinzuzo kanye nokungalungi kwazo zonke izinketho zokwelashwa, hhayi nje ukwandisa isikhathi sokuphila, kodwa futhi nokuthuthukisa ikhwalithi yokuphila [6]. Ngakho-ke, imodeli yokubikezela ephumelelayo iyadingeka ukuze kuhlolwe ngokunembile ukubikezela kwesiguli [7]. Ngakho-ke, ukwelashwa okufanele kungakhethwa ukuze kulinganiswe ukusinda kanye nekhwalithi yokuphila kweziguli ezine-PAAD.
Ukubikezela okubi kwe-PAAD kungenxa yokumelana nemithi yamakhemikhali. Eminyakeni yamuva nje, ama-immune checkpoint inhibitors asetshenziswe kabanzi ekwelapheni izimila eziqinile [8]. Kodwa-ke, ukusetshenziswa kwama-ICI kumdlavuza we-pancreatic akuvamile ukuphumelela [9]. Ngakho-ke, kubalulekile ukuhlonza iziguli ezingase zizuze ekwelashweni kwe-ICI.
I-RNA ende engabhalisi (i-lncRNA) uhlobo lwe-RNA engabhalisi enemibhalo engaphezulu kwama-nucleotide angu-200. Ama-LncRNA asakazeke kabanzi futhi akha cishe u-80% we-transcriptome yomuntu [10]. Umsebenzi omningi ukhombisile ukuthi amamodeli okubikezela asekelwe ku-lncRNA angabikezela ngempumelelo ukubikezela kwesiguli [11, 12]. Isibonelo, ama-lncRNA angu-18 ahlobene ne-autophagy atholakale ukuthi akhiqize izimpawu zokubikezela kumdlavuza webele [13]. Amanye ama-lncRNA ayisithupha ahlobene nokuzivikela komzimba asetshenziswe ukusungula izici zokubikezela ze-glioma [14].
Kumdlavuza we-pancreatic, ezinye izifundo zithole izimpawu ezisekelwe ku-lncRNA ukubikezela ukubikezela kwesiguli. Isiginesha se-3-lncRNA sasungulwa ku-pancreatic adenocarcinoma enendawo engaphansi kwe-ROC curve (AUC) engu-0.742 kuphela kanye nokusinda okuphelele (OS) kweminyaka emi-3 [15]. Ngaphezu kwalokho, amanani okubonakaliswa kwe-lncRNA ayahlukahluka phakathi kwama-genome ahlukene, amafomethi edatha ahlukene, kanye neziguli ezahlukene, futhi ukusebenza kwemodeli yokubikezela akuzinzile. Ngakho-ke, sisebenzisa i-algorithm entsha yokumodela, ukuhlanganisa kanye nokuphindaphinda, ukukhiqiza izimpawu ze-lncRNA (irlncRNA) ezihlobene nokuzivikela ukuze kudalwe imodeli yokubikezela enembile futhi ezinzile [8].
Idatha ye-RNAseq ejwayelekile (FPKM) kanye nomdlavuza we-pancreatic we-clinical TCGA kanye nedatha ye-genotype tissue expression (GTEx) itholakale kusizindalwazi se-UCSC XENA (https://xenabrowser.net/datapages/). Amafayela e-GTF atholakale kusizindalwazi se-Ensembl (http://asia.ensembl.org) futhi asetshenziswa ukukhipha amaphrofayili okubonakaliswa kwe-lncRNA ku-RNAseq. Silande izakhi zofuzo ezihlobene nokuzivikela komzimba kusuka kusizindalwazi se-ImmPort (http://www.immport.org) futhi sathola ama-lncRNA ahlobene nokuzivikela komzimba (irlncRNAs) sisebenzisa ukuhlaziywa kokuxhumana (p < 0.001, r > 0.4). Ukuhlonza ama-irlncRNA achazwe ngokuhlukile (i-DEirlncRNAs) ngokuwela ama-irlncRNA kanye nama-lncRNA achazwe ngokuhlukile atholakale kusizindalwazi se-GEPIA2 (http://gepia2.cancer-pku.cn/#index) kuqembu le-TCGA-PAAD (|logFC| > 1 kanye ne-FDR) <0.05).
Le ndlela ibikwe ngaphambilini [8]. Ngokuqondile, sakha u-X ukuze sithathe indawo ye-lncRNA A kanye ne-lncRNA B ebhangqiwe. Uma inani lokubonakaliswa kwe-lncRNA A liphakeme kunenani lokubonakaliswa kwe-lncRNA B, u-X uchazwa njengo-1, ngaphandle kwalokho u-X uchazwa njengo-0. Ngakho-ke, singathola i-matrix engu-0 noma - 1. I-axis eqondile ye-matrix imelela isampula ngayinye, kanti i-axis evundlile imelela i-pair ngayinye ye-DEirlncRNA enenani elingu-0 noma elingu-1.
Ukuhlaziywa kokuhlehla kwe-univariate okulandelwe ukuhlehla kwe-Lasso kwasetshenziswa ukuhlola amabhangqa e-DEirlncRNA okubikezela. Ukuhlaziywa kokuhlehla kwe-lasso kusebenzise ukuqinisekiswa okuphindwe kayishumi okuphindaphindiwe izikhathi eziyi-1000 (p < 0.05), kanye nezisusa ezingahleliwe eziyi-1000 ngokugijima ngakunye. Lapho imvamisa yebhangqa ngalinye le-DEirlncRNA idlula izikhathi eziyi-100 emijikelezweni eyi-1000, amabhangqa e-DEirlncRNA akhethwa ukwakha imodeli yengozi yokubikezela. Sabe sesisebenzisa ijika le-AUC ukuthola inani elifanele lokuhlukanisa iziguli ze-PAAD ngamaqembu anengozi ephezulu nephansi. Inani le-AUC lemodeli ngayinye nalo labalwa futhi ladwetshwa njengejika. Uma ijika lifinyelela iphuzu eliphakeme kakhulu elibonisa inani eliphezulu le-AUC, inqubo yokubala iyama futhi imodeli ibhekwa njengeyona engcono kakhulu. Kwakhiwa amamodeli ejika le-ROC leminyaka eyi-1, 3 kanye ne-5. Ukuhlaziywa kokuhlehla kwe-univariate kanye ne-multivariate kwasetshenziswa ukuhlola ukusebenza okuzimele kokubikezela kwemodeli yengozi yokubikezela.
Sebenzisa amathuluzi ayisikhombisa ukuze ufunde amazinga okungena kwamangqamuzana omzimba, okuhlanganisa i-XCELL, i-TIMER, i-QUANTISEQ, i-MCPCOUNTER, i-EPIC, i-CIBERSORT-ABS, kanye ne-CIBERSORT. Idatha yokungena kwamangqamuzana omzimba ilandwe kusukela kusizindalwazi se-TIMER2 (http://timer.comp-genomics.org/#tab-5817-3). Umehluko kokuqukethwe kwamaseli angena emzimbeni phakathi kwamaqembu anobungozi obuphezulu nabuphansi bemodeli eyakhiwe uhlaziywe kusetshenziswa isivivinyo se-Wilcoxon signed-rank, imiphumela iboniswa kugrafu yesikwele. Ukuhlaziywa kokuxhumana kwe-Spearman kwenziwe ukuze kuhlaziywe ubudlelwano phakathi kwamanani e-risk score kanye namaseli angena emzimbeni. I-coefficient yokuxhumana ephumelayo iboniswa njenge-lollipop. Umkhawulo wokubaluleka ubekwe ku-p < 0.05. Inqubo yenziwe kusetshenziswa iphakheji ye-R ggplot2. Ukuze kuhlolwe ubudlelwano phakathi kwamazinga okubonakaliswa kwemodeli kanye ne-gene ahlobene nesilinganiso sokungena kwamangqamuzana omzimba, senze iphakheji ye-ggstatsplot kanye ne-violin plot visualization.
Ukuze sihlole amaphethini okwelashwa komdlavuza we-pancreatic, sibale i-IC50 yemithi yamakhemikhali esetshenziswa kakhulu eqenjini le-TCGA-PAAD. Umehluko ekugxilweni kwesigamu sokuvimbela (IC50) phakathi kwamaqembu asengozini ephezulu naphansi uqhathaniswe kusetshenziswa isivivinyo se-Wilcoxon signed-rank, futhi imiphumela iboniswa njengezithombe ezikhiqizwe kusetshenziswa i-pRPhetic kanye ne-ggplot2 ku-R. Zonke izindlela zihambisana neziqondiso nezindinganiso ezifanele.
Ukuhamba komsebenzi wocwaningo lwethu kuboniswe kuMfanekiso 1. Sisebenzisa ukuhlaziywa kokuhlobana phakathi kwama-lncRNA kanye nezakhi zofuzo ezihlobene nokuzivikela komzimba, sikhethe ama-irlncRNA angu-724 ane-p < 0.01 kanye ne-r > 0.4. Siphinde sahlaziya ama-lncRNA achazwe ngokuhlukile e-GEPIA2 (Isithombe 2A). Ama-irlncRNA angu-223 abonakaliswe ngokuhlukile phakathi kwe-pancreatic adenocarcinoma kanye nezicubu ezivamile ze-pancreatic (|logFC| > 1, FDR < 0.05), aqanjwe ngokuthi ama-DEirlncRNA.
Ukwakhiwa kwamamodeli engozi yokubikezela. (A) Isakhiwo sentaba-mlilo sama-lncRNA achazwe ngokuhlukile. (B) Ukusatshalaliswa kwama-lasso coefficients kuma-20 DEirlncRNA pairs. (C) Ukwehluka okuyingxenye kokusabalala kwe-LASSO coefficient. (D) Isakhiwo sehlathi esibonisa ukuhlaziywa kokuhlehla okulinganayo kwama-20 DEirlncRNA pairs.
Ngokulandelayo sakha i-matrix engu-0 noma engu-1 ngokubhangqa ama-DEirlncRNA angu-223. Kwatholakala amabhangqa angu-13,687 e-DEirlncRNA. Ngemva kokuhlaziywa kokuhlehla kwe-univariate kanye ne-lasso, amabhangqa angu-20 e-DEirlncRNA ekugcineni ahlolwe ukwakha imodeli yobungozi bokubikezela (Isithombe 2B-D). Ngokusekelwe emiphumeleni ye-Lasso kanye nokuhlaziywa kokuhlehla okuningi, sibale amaphuzu obungozi esigulini ngasinye eqenjini le-TCGA-PAAD (Ithebula 1). Ngokusekelwe emiphumeleni yokuhlaziywa kokuhlehla kwe-lasso, sibale amaphuzu obungozi esigulini ngasinye eqenjini le-TCGA-PAAD. I-AUC yejika le-ROC yayingu-0.905 ekubikezelweni kwemodeli yobungozi yonyaka ongu-1, u-0.942 ekubikezelweni kweminyaka engu-2, kanye no-0.966 ekubikezelweni kweminyaka engu-3 (Isithombe 3A-B). Sibeke inani elifanele kakhulu lomkhawulo ongu-3.105, sahlukanisa iziguli zeqembu le-TCGA-PAAD zibe amaqembu anobungozi obukhulu kanye nalawo anobungozi obuphansi, futhi sahlela imiphumela yokusinda kanye nokusatshalaliswa kwamaphuzu obungozi esigulini ngasinye (Isithombe 3C-E). Ukuhlaziywa kukaKaplan-Meier kubonise ukuthi ukusinda kweziguli ze-PAAD eqenjini elinobungozi obukhulu kwakuphansi kakhulu kunokweziguli eqenjini elinobungozi obuphansi (p < 0.001) (Isithombe 3F).
Ukufaneleka kwamamodeli engozi yokubikezela. (A) I-ROC yemodeli yengozi yokubikezela. (B) Amamodeli engozi yokubikezela ye-ROC yeminyaka engu-1, 2, kanye ne-3. (C) I-ROC yemodeli yengozi yokubikezela. Ibonisa iphuzu elifanele kakhulu. (DE) Ukusatshalaliswa kwesimo sokusinda (D) kanye namaphuzu engozi (E). (F) Ukuhlaziywa kukaKaplan-Meier kweziguli ze-PAAD emaqenjini asengozini ephezulu nephansi.
Siphinde sahlola umehluko kumaphuzu engozi ngokwezimpawu zomtholampilo. Isakhiwo somugqa (Isithombe 4A) sibonisa ubudlelwano obuphelele phakathi kwezici zomtholampilo kanye namaphuzu engozi. Ikakhulukazi, iziguli ezindala zazinamaphuzu engozi aphezulu (Isithombe 4B). Ngaphezu kwalokho, iziguli ezinesigaba sesi-2 zazinamaphuzu engozi aphezulu kuneziguli ezinesigaba I (Isithombe 4C). Ngokuphathelene nebanga lesimila ezigulini ze-PAAD, iziguli zebanga lesi-3 zazinamaphuzu engozi aphezulu kuneziguli zebanga loku-1 nelesi-2 (Isithombe 4D). Siqhubekile nokwenza ukuhlaziywa kokuhlehla kwe-univariate kanye ne-multivariate futhi sabonisa ukuthi amaphuzu engozi (p < 0.001) kanye nobudala (p = 0.045) kwakuyizici ezizimele zokubikezela ezigulini ezine-PAAD (Isithombe 5A-B). Ijika le-ROC libonise ukuthi amaphuzu engozi ayephakeme kunezinye izici zomtholampilo ekubikezeleni ukusinda kweminyaka engu-1, 2, kanye nemi-3 kweziguli ezine-PAAD (Isithombe 5C-E).
Izici zezokwelapha zamamodeli engozi yokubikezela. I-Histogram (A) ikhombisa (B) ubudala, (C) isigaba sesimila, (D) izinga lesimila, amaphuzu engozi, kanye nobulili beziguli eqenjini le-TCGA-PAAD. **p < 0.01
Ukuhlaziywa okuzimele kokubikezela kwamamodeli engozi yokubikezela. (AB) Ukuhlaziywa kokuhlehla kwe-Univariate (A) kanye ne-multivariate (B) kwamamodeli engozi yokubikezela kanye nezici zezokwelapha. (CE) I-ROC yeminyaka engu-1-, 2-, kanye ne-3 yamamodeli engozi yokubikezela kanye nezici zezokwelapha.
Ngakho-ke, sihlole ubudlelwano phakathi kwesikhathi namaphuzu engozi. Sithole ukuthi amaphuzu engozi ezigulini ze-PAAD ayehlobene ngokuphambene namaseli e-CD8+ T namaseli e-NK (Isithombe 6A), okubonisa ukusebenza komzimba okucindezelwe eqenjini elisengozini enkulu. Siphinde sahlola umehluko ekungeneni kwamaseli omzimba phakathi kwamaqembu asengozini enkulu naphansi futhi sathola imiphumela efanayo (Isithombe 7). Kwakukhona ukungena okuncane kwamaseli e-CD8+ T namaseli e-NK eqenjini elisengozini enkulu. Eminyakeni yamuva nje, ama-immune checkpoint inhibitors (ICIs) asetshenziswe kabanzi ekwelapheni izimila eziqinile. Kodwa-ke, ukusetshenziswa kwama-ICI kumdlavuza we-pancreatic akuvamile ukuphumelela. Ngakho-ke, sihlole ukubonakaliswa kwezakhi zofuzo zokuhlolwa komzimba emaqenjini asengozini enkulu naphansi. Sithole ukuthi i-CTLA-4 ne-CD161 (KLRB1) zazivezwe ngokweqile eqenjini elisengozini encane (Isithombe 6B-G), okubonisa ukuthi iziguli ze-PAAD eqenjini elisengozini encane zingase zibe nomuzwa we-ICI.
Ukuhlaziywa kobudlelwano bemodeli yobungozi bokubikezela kanye nokungena kwamaseli omzimba. (A) Ubudlelwano phakathi kwemodeli yobungozi bokubikezela kanye nokungena kwamaseli omzimba. (BG) Kubonisa ukuvezwa kwezakhi zofuzo emaqenjini asengozini ephezulu nephansi. (HK) Amanani e-IC50 emithi ethile yokulwa nomdlavuza emaqenjini asengozini ephezulu nephansi. *p < 0.05, **p < 0.01, ns = akubalulekile
Siphinde sahlola ubudlelwano phakathi kwamaphuzu obungozi kanye nama-chemotherapy avamile eqenjini le-TCGA-PAAD. Sifune imithi yokulwa nomdlavuza esetshenziswa kakhulu kumdlavuza we-pancreatic futhi sahlaziya umehluko emananini ayo e-IC50 phakathi kwamaqembu asengozini ephezulu naphansi. Imiphumela ibonise ukuthi inani le-IC50 le-AZD.2281 (olaparib) laliphezulu eqenjini elisengozini ephezulu, okubonisa ukuthi iziguli ze-PAAD eqenjini elisengozini ephezulu zingase zingamelani nokwelashwa kwe-AZD.2281 (Isithombe 6H). Ngaphezu kwalokho, amanani e-IC50 e-paclitaxel, i-sorafenib, kanye ne-erlotinib ayephansi eqenjini elisengozini ephezulu (Isithombe 6I-K). Siphinde sathola imithi yokulwa nomdlavuza engu-34 enamanani aphezulu e-IC50 eqenjini elisengozini ephezulu kanye nemithi yokulwa nomdlavuza engu-34 enamanani aphansi e-IC50 eqenjini elisengozini ephezulu (Ithebula 2).
Akunakuphikwa ukuthi ama-lncRNA, ama-mRNA, nama-miRNA akhona kabanzi futhi adlala indima ebalulekile ekuthuthukisweni komdlavuza. Kunobufakazi obanele obusekela indima ebalulekile ye-mRNA noma i-miRNA ekubikezeleni ukusinda okuphelele ezinhlotsheni eziningana zomdlavuza. Akungabazeki ukuthi amamodeli amaningi obungozi bokubikezela nawo asekelwe kuma-lncRNA. Isibonelo, uLuo et al. Izifundo zikhombisile ukuthi i-LINC01094 idlala indima ebalulekile ekwandeni kwe-PC kanye nokwanda kwe-metastasis, futhi ukuvezwa okuphezulu kwe-LINC01094 kubonisa ukusinda okungekuhle kweziguli zomdlavuza we-pancreatic [16]. Ucwaningo olwethulwe nguLin et al. Izifundo zikhombisile ukuthi ukwehla kwe-lncRNA FLVCR1-AS1 kuhlotshaniswa nokubikezela okungekuhle kweziguli zomdlavuza we-pancreatic [17]. Kodwa-ke, ama-lncRNA ahlobene nokuzivikela komzimba awaxoxwa kangako maqondana nokubikezela ukusinda okuphelele kweziguli zomdlavuza. Muva nje, umsebenzi omningi ugxile ekwakheni amamodeli obungozi bokubikezela ukubikezela ukusinda kweziguli zomdlavuza futhi ngaleyo ndlela kulungiswe izindlela zokwelapha [18, 19, 20]. Kukhona ukuqashelwa okwandayo kwendima ebalulekile yokungena kwamasosha omzimba ekuqaleni komdlavuza, ukuqhubekela phambili, kanye nokusabela ekwelashweni okufana ne-chemotherapy. Izifundo eziningi ziqinisekisile ukuthi amangqamuzana omzimba angena ngesimila adlala indima ebalulekile ekuphenduleni i-cytotoxic chemotherapy [21, 22, 23]. I-tumor immune environment iyisici esibalulekile ekusindeni kweziguli ezinesimila [24, 25]. I-immunotherapy, ikakhulukazi i-ICI therapy, isetshenziswa kabanzi ekwelapheni izimila eziqinile [26]. Izakhi zofuzo ezihlobene nomzimba zisetshenziswa kabanzi ukwakha amamodeli engozi yokubikezela. Isibonelo, uSu et al. Imodeli yengozi yokubikezela ehlobene nomzimba isekelwe kuzakhi zofuzo ezibhala amaprotheni ukubikezela ukubikezela kweziguli ezinomdlavuza wesibeletho [27]. Izakhi zofuzo ezingabhalisi njenge-lncRNA nazo zifanelekile ekwakheni amamodeli engozi yokubikezela [28, 29, 30]. ULuo et al bahlole ama-lncRNA amane ahlobene nomzimba futhi bakha imodeli yokubikezela ingozi yomdlavuza wesibeletho [31]. UKhan et al. Kwatholakala imibhalo engama-32 ebhalwe ngendlela ehlukile, futhi ngokusekelwe kulokhu, kwasungulwa imodeli yokubikezela enemibhalo emi-5 ebalulekile, eyaphakanyiswa njengethuluzi elinconywa kakhulu lokubikezela ukwenqatshwa okubukhali okuqinisekiswe yi-biopsy ngemuva kokufakelwa izinso [32].
Iningi lala mamodeli lisekelwe emazingeni okubonakaliswa kwezakhi zofuzo, kungaba izakhi zofuzo ezibhala amaprotheni noma izakhi zofuzo ezingabhalisi. Kodwa-ke, izakhi zofuzo ezifanayo zingaba namanani ahlukene okubonakaliswa kuma-genome ahlukene, amafomethi edatha kanye nasezigulini ezahlukene, okuholela ekulinganisweni okungazinzile kumamodeli okubikezela. Kulolu cwaningo, sakhe imodeli enengqondo enama-lncRNA amabili, ngaphandle kwamanani aqondile okubonakaliswa.
Kulesi sifundo, sithole i-irlncRNA okokuqala ngokuhlaziywa kokuxhumana ngamajini ahlobene nokuzivikela komzimba. Sihlole ama-DEirlncRNA angu-223 ngokuhlanganisa ama-lncRNA achazwe ngokuhlukile. Okwesibili, sakha i-matrix engu-0-noma-1 esekelwe endleleni yokubhanqa ye-DEirlncRNA eshicilelwe [31]. Sabe sesenza ukuhlaziywa kokuhlehla kwe-univariate kanye ne-lasso ukuze sithole ama-prognostic DEirlncRNA pairs futhi sakhe imodeli yobungozi obubikezelayo. Siphinde sahlaziya ubudlelwano phakathi kwamaphuzu obungozi kanye nezici zemitholampilo ezigulini ezine-PAAD. Sithole ukuthi imodeli yethu yobungozi obubikezelayo, njengesici esizimele sokubikezela ezigulini ze-PAAD, ingahlukanisa ngempumelelo iziguli zezinga eliphezulu ezigulini zezinga eliphansi kanye neziguli zezinga eliphezulu ezigulini zezinga eliphansi. Ngaphezu kwalokho, amanani e-AUC ejika le-ROC lemodeli yobungozi obubikezelayo ayengu-0.905 esibikezelweni sonyaka ongu-1, angu-0.942 esibikezelweni seminyaka engu-2, kanye no-0.966 esibikezelweni seminyaka engu-3.
Abacwaningi babike ukuthi iziguli ezine-CD8+ T cell ephezulu zizizwela kakhulu ekwelashweni kwe-ICI [33]. Ukwanda kokuqukethwe kwamaseli ane-cytotoxic, amaseli e-CD56 NK, amaseli e-NK kanye namaseli e-CD8+ T endaweni encane yomzimba yokuzivikela yesimila kungaba esinye sezizathu zomphumela wokucindezela isimila [34]. Izifundo zangaphambilini zibonise ukuthi amazinga aphezulu e-CD4(+) T kanye ne-CD8(+) T efaka isimila ahlotshaniswa kakhulu nokusinda isikhathi eside [35]. Ukungena kabi kwamaseli e-CD8 T, umthwalo ophansi we-neoantigen, kanye nendawo encane yomzimba yokuvimbela amasosha omzimba kuholela ekuntuleni impendulo ekwelashweni kwe-ICI [36]. Sithole ukuthi amaphuzu obungozi ahlobene kabi namaseli e-CD8+ T kanye namaseli e-NK, okubonisa ukuthi iziguli ezine-CD8+ T cells kanye namaseli e-NK zingase zingafaneleki ukwelashwa kwe-ICI futhi zinesimo esibi kakhulu.
I-CD161 iyisibonakaliso samaseli e-natural killer (NK). Amaseli e-T adluliselwe ku-CD8+CD161+ CAR athuthukisa ukusebenza kahle kwe-in vivo antitumor kumamodeli e-HER2+ pancreatic ductal adenocarcinoma xenograft [37]. Ama-immune checkpoint inhibitors ahlose i-cytotoxic T lymphocyte ahlobene ne-protein 4 (CTLA-4) kanye ne-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) futhi anamandla amakhulu ezindaweni eziningi. Ukuvezwa kwe-CTLA-4 kanye ne-CD161 (KLRB1) kuphansi emaqenjini asengozini enkulu, okubonisa ukuthi iziguli ezinezinga eliphezulu lobungozi zingase zingafaneleki ukwelashwa kwe-ICI. [38]
Ukuze sithole izinketho zokwelapha ezifanele iziguli ezisengozini enkulu, sihlaziye imithi eyahlukahlukene yokulwa nomdlavuza futhi sathola ukuthi i-paclitaxel, i-sorafenib, kanye ne-erlotinib, ezisetshenziswa kabanzi ezigulini ezine-PAAD, zingase zifanele iziguli ezisengozini enkulu ezine-PAAD. [33]. UZhang nabanye bathole ukuthi ukuguqulwa kwanoma iyiphi indlela yokusabela komonakalo we-DNA (DDR) kungaholela ekubikezelweni okubi kweziguli ezinomdlavuza we-prostate [39]. Isivivinyo se-Pancreatic Cancer Olaparib Ongoing (POLO) sibonise ukuthi ukwelashwa kokugcina nge-olaparib kwandisa isikhathi sokusinda okungenalo ukuqhubekela phambili uma kuqhathaniswa ne-placebo ngemuva kwe-chemotherapy esekelwe ku-platinum yokuqala ezigulini ezine-pancreatic ductal adenocarcinoma kanye ne-germline BRCA1/2 mutations [40]. Lokhu kunikeza ithemba elikhulu lokuthi imiphumela yokwelashwa izothuthuka kakhulu kuleli qembu elincane leziguli. Kulolu cwaningo, inani le-IC50 le-AZD.2281 (olaparib) laliphezulu eqenjini elisengozini enkulu, okubonisa ukuthi iziguli ze-PAAD eqenjini elisengozini enkulu zingase zingamelani nokwelashwa nge-AZD.2281.
Amamodeli okubikezela kulolu cwaningo akhiqiza imiphumela emihle yokubikezela, kodwa asekelwe ekubikezeleni kokuhlaziya. Indlela yokuqinisekisa le miphumela ngemininingwane yezokwelapha ngumbuzo obalulekile. I-Endoscopic fine needle aspiration ultrasonography (EUS-FNA) isibe yindlela ebalulekile yokuxilonga izilonda ze-pancreatic eziqinile nezingaphandle kwe-pancreatic ngokuzwela okungu-85% kanye nokucaciswa okungu-98% [41]. Ukufika kwezinaliti ze-EUS fine-needle biopsy (EUS-FNB) kusekelwe kakhulu ezinzuzweni ezibonwayo kune-FNA, njengokunemba okuphezulu kokuxilonga, ukuthola amasampula agcina isakhiwo se-histological, ngaleyo ndlela akhiqize izicubu zomzimba ezibalulekile ekuxilongweni okuthile. i-staining ekhethekile [42]. Ukubuyekezwa okuhlelekile kwezincwadi kuqinisekisile ukuthi izinaliti ze-FNB (ikakhulukazi i-22G) zibonisa ukusebenza kahle kakhulu ekuvuneni izicubu ezivela ezixukwini ze-pancreatic [43]. Ngokwezokwelapha, inani elincane kuphela leziguli elifanelekela ukuhlinzwa okukhulu, futhi iziguli eziningi zinezimila ezingasebenzi ngesikhathi sokuxilongwa kokuqala. Emtholampilo, ingxenye encane kuphela yeziguli efanelekile ukuhlinzwa okukhulu ngoba iziguli eziningi zinezimila ezingasebenzi ngesikhathi sokuxilongwa kokuqala. Ngemva kokuqinisekiswa kwe-pathological yi-EUS-FNB nezinye izindlela, ukwelashwa okujwayelekile okungekona ukuhlinzwa okufana ne-chemotherapy kuvame ukukhethwa. Uhlelo lwethu locwaningo olulandelayo ukuhlola imodeli yokubikezela yalolu cwaningo kuma-cohorts okuhlinzwa kanye nalawo angahlinzwa ngokuhlaziya okubheka emuva.
Sekukonke, ucwaningo lwethu lusungule imodeli entsha yobungozi bokubikezela esekelwe ku-irlncRNA ebhangqiwe, ebonise inani elithembisayo lokubikezela ezigulini ezinomdlavuza we-pancreatic. Imodeli yethu yobungozi bokubikezela ingasiza ukuhlukanisa iziguli ezine-PAAD ezifanele ukwelashwa.
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Isikhathi sokuthunyelwe: Septhemba-22-2023