Umhlaza wepancreatic yenye yezona thumba zibulalayo kwihlabathi liphela kwaye azinalo ulwazi oluchanekileyo ngesifo. Ke ngoko, kufuneka imodeli yokuqikelela echanekileyo ukuze kuchongwe izigulane ezisengozini enkulu yomhlaza wepancreatic ukuze kulungiswe unyango kwaye kuphuculwe ulwazi oluchanekileyo ngesifo sabo.
Sifumene idatha ye-RNAseq ye-Cancer Genome Atlas (TCGA) pancreatic adenocarcinoma (PAAD) kwi-database ye-UCSC Xena, safumanisa ii-lncRNAs ezinxulumene ne-immune-related (irlncRNAs) ngohlalutyo lokuhambelana, saza safumanisa umahluko phakathi kwe-TCGA kunye nezicubu eziqhelekileyo ze-pancreatic adenocarcinoma. I-DEirlncRNA) evela kwi-TCGA kunye ne-genotype tissue expression (GTEx) yezicubu ze-pancreatic. Uhlalutyo olongezelelweyo lwe-univariate kunye ne-lasso regression lwenziwe ukwakha iimodeli ze-prognostic signature. Emva koko sibale indawo engaphantsi kwe-curve saza safumanisa ixabiso elifanelekileyo lokuchonga izigulane ezine-pancreatic adenocarcinoma enomngcipheko ophezulu nophantsi. Ukuthelekisa iimpawu zeklinikhi, ukungena kwe-immune cell, i-immunosuppressive microenvironment, kunye nokumelana ne-chemotherapy kwizigulane ezinomhlaza we-pancreatic onomngcipheko ophezulu nophantsi.
Sichonge izibini ze-DEirlncRNA ezingama-20 saza sahlanganisa izigulane ngokwexabiso elifanelekileyo lokunqunyulwa. Sibonise ukuba imodeli yethu yomqondiso wokuxela kwangaphambili inomsebenzi obalulekileyo ekuqikeleleni ikamva lezigulane ezine-PAAD. I-AUC ye-ROC curve yi-0.905 kwingxelo-mbono yonyaka omnye, i-0.942 kwingxelo-mbono yonyaka emi-2, kunye ne-0.966 kwingxelo-mbono yonyaka emi-3. Izigulane ezisengozini enkulu zazinamazinga aphantsi okusinda kunye neempawu zeklinikhi ezimbi kakhulu. Sikwabonise ukuba izigulane ezisengozini enkulu zicinezelwe yi-immunotherapy kwaye zinokuchasana ne-immunotherapy. Uvavanyo lwamayeza okulwa nomhlaza anjenge-paclitaxel, sorafenib, kunye ne-erlotinib ngokusekelwe kwizixhobo zokuqikelela zokubala lunokufaneleka kwizigulane ezisengozini enkulu ezine-PAAD.
Ngokubanzi, uphando lwethu luseke imodeli entsha yomngcipheko wokuxela kwangaphambili ngokusekelwe kwi-irlncRNA edibeneyo, ebonise ixabiso elithembisayo lokuxela kwangaphambili kwizigulane ezinomhlaza wepancreatic. Imodeli yethu yomngcipheko wokuxela kwangaphambili inokunceda ukwahlula izigulane ezine-PAAD ezifanelekileyo kunyango lwezonyango.
Umhlaza wePancreatic sisimila esibi esinomlinganiselo ophantsi wokusinda iminyaka emihlanu kunye nomgangatho ophezulu. Ngexesha lokuxilongwa, uninzi lwezigulane sele zikwinqanaba eliphezulu. Kwimeko yobhubhane we-COVID-19, oogqirha kunye nabongikazi baphantsi koxinzelelo olukhulu xa benyanga izigulane ezinomhlaza wepancreatic, kwaye iintsapho zezigulane nazo zijongene noxinzelelo oluninzi xa zenza izigqibo zonyango [1, 2]. Nangona kwenziwe inkqubela phambili enkulu kunyango lwe-DOADs, olufana nonyango lwe-neoadjuvant, ukususwa kotyando, unyango lwe-radiation, i-chemotherapy, unyango lwe-molecular olujoliswe kuyo, kunye ne-immune checkpoint inhibitors (ICIs), malunga ne-9% kuphela yezigulane ezisinda kwiminyaka emihlanu emva kokuxilongwa [3]. ], 4]. Ngenxa yokuba iimpawu zokuqala ze-pancreatic adenocarcinoma aziqhelekanga, izigulane zihlala zifunyaniswa zine-metastases kwinqanaba eliphezulu [5]. Ke ngoko, kwisigulana esithile, unyango olupheleleyo oluzimeleyo kufuneka lulinganise izibonelelo kunye nokungalungi kwazo zonke iindlela zonyango, kungekuphela nje ukwandisa ukusinda, kodwa nokuphucula umgangatho wobomi [6]. Ke ngoko, imodeli yokuqikelela esebenzayo iyimfuneko ukuvavanya ngokuchanekileyo ukubikezela kwesigulana [7]. Ngoko ke, unyango olufanelekileyo lunokukhethwa ukuze kulinganiswe ukusinda kunye nomgangatho wobomi bezigulane ezine-PAAD.
Ukungafumani mpendulo ifanelekileyo ye-PAAD ikakhulu kungenxa yokunganyamezelani namayeza e-chemotherapy. Kwiminyaka yakutshanje, izithinteli zokujonga amajoni omzimba ziye zasetyenziswa kakhulu kunyango lwee-tumor eziqinileyo [8]. Nangona kunjalo, ukusetyenziswa kwe-ICIs kumhlaza we-pancreatic akufane kuphumelele [9]. Ke ngoko, kubalulekile ukuchonga izigulana ezinokungenelwa kunyango lwe-ICI.
I-RNA ende engabhalisiyo ikhowudi (i-lncRNA) luhlobo lwe-RNA engabhalisiyo ikhowudi ene-transcripts ezingaphezu kwama-200 nucleotides. Ii-LncRNA zisasazeke kakhulu kwaye zenza malunga ne-80% ye-transcriptome yomntu [10]. Umsebenzi omninzi ubonise ukuba iimodeli zokuxela kwangaphambili ezisekelwe kwi-lncRNA zinokuqikelela ngokufanelekileyo ukuxela kwangaphambili kwesigulane [11, 12]. Umzekelo, ii-lncRNA ezili-18 ezinxulumene ne-autophagy zichongiwe ukuvelisa iimpawu zokuxela kwangaphambili kumhlaza webele [13]. Ezinye ii-lncRNA ezintandathu ezinxulumene nomzimba zisetyenzisiwe ukumisela iimpawu zokuxela kwangaphambili ze-glioma [14].
Kwi-pancreatic cancer, ezinye izifundo ziye zaseka iisignatures ezisekelwe kwi-lncRNA ukuqikelela i-prognosis yesigulane. Isignature ye-3-lncRNA yasekwa kwi-pancreatic adenocarcinoma enendawo engaphantsi kwe-ROC curve (AUC) eyi-0.742 kuphela kunye nokusinda okupheleleyo (OS) kweminyaka emi-3 [15]. Ukongeza, amaxabiso okubonakaliswa kwe-lncRNA ayahluka phakathi kwee-genomes ezahlukeneyo, iifomathi zedatha ezahlukeneyo, kunye nezigulana ezahlukeneyo, kwaye ukusebenza kwemodeli yokuqikelela akuzinzanga. Ke ngoko, sisebenzisa i-algorithm entsha yokumodela, ukudibanisa kunye nokuphindaphinda, ukuvelisa iisignatures ze-lncRNA (irlncRNA) ezinxulumene nokuzikhusela ukwenza imodeli yokuqikelela echanekileyo nezinzileyo [8].
Idatha ye-RNAseq eqhelekileyo (FPKM) kunye nomhlaza we-pancreatic weklinikhi i-TCGA kunye nedatha ye-genotype tissue expression (GTEx) ifunyenwe kwisiseko sedatha se-UCSC XENA (https://xenabrowser.net/datapages/). Iifayile ze-GTF zifunyenwe kwisiseko sedatha se-Ensembl (http://asia.ensembl.org) kwaye zasetyenziselwa ukukhupha iiprofayili ze-lncRNA expression kwi-RNAseq. Sikhuphele ii-genes ezinxulumene ne-immunity kwisiseko sedatha se-ImmPort (http://www.immport.org) kwaye sachonga ii-lncRNAs ezinxulumene ne-immunity (irlncRNAs) sisebenzisa uhlalutyo lwe-correlation (p < 0.001, r > 0.4). Ukuchongwa kwee-irlncRNAs ezichazwe ngokwahlukileyo (DEirlncRNAs) ngokunqumla ii-irlncRNAs kunye nee-lncRNAs ezichazwe ngokwahlukileyo ezifunyenwe kwisiseko sedatha se-GEPIA2 (http://gepia2.cancer-pku.cn/#index) kwi-TCGA-PAAD cohort (|logFC| > 1 kunye ne-FDR) <0.05).
Le ndlela sele ixeliwe ngaphambili [8]. Ngokukodwa, sakha i-X ukuze sithathe indawo ye-lncRNA A kunye ne-lncRNA B ezidibeneyo. Xa ixabiso lokubonakaliswa kwe-lncRNA A liphezulu kunexabiso lokubonakaliswa kwe-lncRNA B, u-X uchazwa njengo-1, kungenjalo u-X uchazwa njengo-0. Ke ngoko, singafumana i-matrix engu-0 okanye - 1. I-axis ethe nkqo ye-matrix imele isampuli nganye, kwaye i-axis ethe tye imele isibini ngasinye se-DEirlncRNA esinexabiso elingu-0 okanye eli-1.
Uhlalutyo lokubuyela umva olulandelelwa yiLasso regression lusetyenzisiwe ukuhlola ii-prognostic DEirlncRNA pairs. Uhlalutyo lokubuyela umva lwe-lasso lusebenzise ukuqinisekiswa okuphindwe kalishumi okuphindaphindwayo amaxesha ali-1000 (p < 0.05), kunye ne-1000 random stimuli ngokubaleka. Xa i-frequency ye-DEirlncRNA pairs nganye idlule amaxesha ali-100 kwi-1000 cycles, ii-DEirlncRNA pairs zakhethwa ukwakha imodeli yomngcipheko wokuxela. Emva koko sisebenzise i-AUC curve ukufumana ixabiso elifanelekileyo lokunquma ukwahlula izigulane ze-PAAD kumaqela anomngcipheko ophezulu nophantsi. Ixabiso le-AUC lemodeli nganye nalo labalwa kwaye ladweliswa njenge-curve. Ukuba i-curve ifikelela kwinqanaba eliphezulu elibonisa ixabiso eliphezulu le-AUC, inkqubo yokubala iyayeka kwaye imodeli ithathwa njengoyena mntu ubalaseleyo. Kwakhiwa iimodeli ze-ROC curve zeminyaka eli-1, eli-3 neli-5. Uhlalutyo lokubuyela umva oluqhelekileyo nolune-multivariate lwasetyenziswa ukuhlola ukusebenza okuzimeleyo kokuxela kwangaphambili kwemodeli yomngcipheko wokuxela.
Sebenzisa izixhobo ezisixhenxe ukufunda amazinga okungena kweeseli zomzimba, kuquka i-XCELL, i-TIMER, i-QUANTISEQ, i-MCPCOUNTER, i-EPIC, i-CIBERSORT-ABS, kunye ne-CIBERSORT. Idatha yokungena kweeseli zomzimba ikhutshelwe kwi-database ye-TIMER2 (http://timer.comp-genomics.org/#tab-5817-3). Umahluko kumxholo weeseli ezingena emzimbeni phakathi kwamaqela anobungozi obuphezulu nabuphantsi kwimodeli eyakhiweyo uhlalutywe kusetyenziswa uvavanyo lwe-Wilcoxon signed-rank, iziphumo ziboniswe kwigrafu yesikwere. Uhlalutyo lwe-Spearman correlation lwenziwe ukuhlalutya ubudlelwane phakathi kwamaxabiso amanqaku omngcipheko kunye neeseli ezingena emzimbeni. I-coefficient yokuhambelana ephumayo iboniswa njenge-lollipop. Umlinganiselo wokubaluleka ubekwe kwi-p < 0.05. Inkqubo yenziwe kusetyenziswa iphakheji ye-R ggplot2. Ukuhlola ubudlelwane phakathi kwemodeli kunye namanqanaba okubonakaliswa kwezakhi zofuzo anxulumene nesantya sokungena kweeseli zomzimba, senze iphakheji ye-ggstatsplot kunye ne-violin plot visualization.
Ukuvavanya iipateni zonyango lwezonyango lomhlaza we-pancreatic, sibale i-IC50 yamayeza e-chemotherapy asetyenziswa rhoqo kwiqela le-TCGA-PAAD. Umahluko kwi-half inhibitory concentrations (IC50) phakathi kwamaqela anobungozi obuphezulu naphantsi uthelekiswe kusetyenziswa uvavanyo lwe-Wilcoxon signed-rank, kwaye iziphumo ziboniswa njengeebhokisi ezenziwe kusetyenziswa i-pRPhetic kunye ne-ggplot2 kwi-R. Zonke iindlela zihambelana nezikhokelo kunye nemigangatho efanelekileyo.
Indlela esiqhuba ngayo uphando lwethu iboniswe kuMfanekiso 1. Sisebenzisa uhlalutyo lolwalamano phakathi kwee-lncRNA kunye neejini ezinxulumene nokuzikhusela komzimba, sikhethe ii-irlncRNA ezingama-724 ezine-p < 0.01 kunye ne-r > 0.4. Siphinde sahlalutya ii-lncRNA ezivezwe ngokwahlukileyo ze-GEPIA2 (Umfanekiso 2A). Ii-irlncRNA ezingama-223 zizonke zavezwa ngokwahlukileyo phakathi kwe-pancreatic adenocarcinoma kunye nezicubu ze-pancreatic eziqhelekileyo (|logFC| > 1, FDR < 0.05), ezibizwa ngokuba zii-DEirlncRNAs.
Ukwakhiwa kweemodeli zomngcipheko oqikelelweyo. (A) Iploti yevolcano yee-lncRNA ezichazwe ngokwahlukileyo. (B) Ukusasazwa kwee-lasso coefficients kwiipaya ze-DEirlncRNA ezingama-20. (C) Umahluko ongephi wokwahluka kokusasazwa kwe-LASSO coefficient. (D) Iploti yehlathi ebonisa uhlalutyo lokubuyela umva olungafaniyo lweepaya ze-DEirlncRNA ezingama-20.
Emva koko sakhe i-matrix engu-0 okanye e-1 ngokuhlanganisa ii-DEirlncRNA ezingama-223. Kwachongwa ii-DEirlncRNA ezipheleleyo ezili-13,687. Emva kohlalutyo lwe-univariate kunye ne-lasso regression, ii-DEirlncRNA ezi-20 ekugqibeleni zavavanywa ukwakha imodeli yomngcipheko wokuxela kwangaphambili (Umfanekiso 2B-D). Ngokusekelwe kwiziphumo zeLasso kunye nohlalutyo lwe-multiple regression, sibale amanqaku omngcipheko kwisigulana ngasinye kwi-TCGA-PAAD cohort (Itheyibhile 1). Ngokusekelwe kwiziphumo zohlalutyo lwe-lasso regression, sibale amanqaku omngcipheko kwisigulana ngasinye kwi-TCGA-PAAD cohort. I-AUC ye-ROC curve yayiyi-0.905 kwi-1-year risk model prediction, i-0.942 kwi-2-year prediction, kunye ne-0.966 kwi-3-year prediction (Umfanekiso 3A-B). Sibeke ixabiso elifanelekileyo le-cutoff le-3.105, sahlulahlula izigulane ze-TCGA-PAAD zibe ngamaqela anomngcipheko ophezulu naphantsi, saza sadweba iziphumo zokusinda kunye nokusasazwa kwamanqaku omngcipheko kwisigulana ngasinye (Umfanekiso 3C-E). Uhlalutyo lukaKaplan-Meier lubonise ukuba ukusinda kwezigulane ze-PAAD kwiqela elinomngcipheko ophezulu kwakuphantsi kakhulu kunoko kwezigulane kwiqela elinomngcipheko omncinci (p < 0.001) (Umfanekiso 3F).
Ukuqinisekiswa kweemodeli zomngcipheko wokuxela kwangaphambili. (A) I-ROC yemodeli yomngcipheko wokuxela kwangaphambili. (B) Iimodeli zomngcipheko wokuxela kwangaphambili we-ROC weminyaka eli-1, eli-2, kunye neli-3. (C) I-ROC yemodeli yomngcipheko wokuxela kwangaphambili. Ibonisa indawo efanelekileyo yokuphela. (DE) Ukusasazwa kwesimo sokusinda (D) kunye namanqaku omngcipheko (E). (F) Uhlalutyo lukaKaplan-Meier lwezigulane ze-PAAD kumaqela anomngcipheko ophezulu nophantsi.
Siphinde savavanya umahluko kumanqaku omngcipheko ngokweempawu zeklinikhi. Iploti yomcu (Umfanekiso 4A) ibonisa ulwalamano olupheleleyo phakathi kweempawu zeklinikhi kunye namanqaku omngcipheko. Ngokukodwa, izigulane ezindala zazinamanqaku omngcipheko aphezulu (Umfanekiso 4B). Ukongeza, izigulane ezinesigaba sesi-2 zazinamanqaku omngcipheko aphezulu kunezigulane ezinesigaba soku-1 (Umfanekiso 4C). Ngokuphathelele inqanaba lethumba kwizigulane ze-PAAD, izigulane zebanga lesi-3 zazinamanqaku omngcipheko aphezulu kunezigulane zebanga loku-1 kunye nelesi-2 (Umfanekiso 4D). Siqhubekile nokwenza uhlalutyo lokubuyela umva lwe-univariate kunye ne-multivariate kwaye sabonisa ukuba amanqaku omngcipheko (p < 0.001) kunye nobudala (p = 0.045) yayizizinto ezizimeleyo zokuxela kwangaphambili kwizigulane ezine-PAAD (Umfanekiso 5A-B). I-ROC curve ibonise ukuba amanqaku omngcipheko aphezulu kunezinye iimpawu zeklinikhi ekuqikeleleni ukusinda kweminyaka eyi-1, 2, kunye ne-3 yezigulane ezine-PAAD (Umfanekiso 5C-E).
Iimpawu zeklinikhi zeemodeli zomngcipheko wokuxela kwangaphambili. I-Histogram (A) ibonisa (B) ubudala, (C) inqanaba le-tumor, (D) inqanaba le-tumor, amanqaku omngcipheko, kunye nesini sezigulane kwi-TCGA-PAAD cohort. **p < 0.01
Uhlalutyo oluzimeleyo lokuqikelela iimodeli zomngcipheko wokuxela kwangaphambili. (AB) Uhlalutyo lokubuyela umva lwe-Univariate (A) kunye ne-multivariate (B) lweemodeli zomngcipheko wokuxela kwangaphambili kunye neempawu zeklinikhi. (CE) I-ROC yeminyaka eyi-1, 2, kunye ne-3 yeemodeli zomngcipheko wokuxela kwangaphambili kunye neempawu zeklinikhi.
Ngoko ke, sihlolisise ulwalamano phakathi kwexesha kunye namanqaku omngcipheko. Sifumanise ukuba amanqaku omngcipheko kwizigulane ze-PAAD adibene ngokuchaseneyo neeseli ze-CD8+ T kunye neeseli ze-NK (Umfanekiso 6A), nto leyo ebonisa ukusebenza okucinezelweyo komzimba kwiqela elinomngcipheko ophezulu. Sikwavavanyile umahluko ekungeneni kweeseli zomzimba phakathi kwamaqela anomngcipheko ophezulu kunye nalawo aphantsi kwaye safumana iziphumo ezifanayo (Umfanekiso 7). Bekukho ukungena okuncinci kweeseli ze-CD8+ T kunye neeseli ze-NK kwiqela elinomngcipheko ophezulu. Kwiminyaka yakutshanje, i-immune checkpoint inhibitors (ICIs) zisetyenziswe kakhulu kunyango lwee-tumor eziqinileyo. Nangona kunjalo, ukusetyenziswa kwe-ICIs kumhlaza we-pancreatic akukaze kuphumelele. Ke ngoko, sivavanye ukubonakaliswa kwezakhi zofuzo zokujonga umzimba kumaqela anomngcipheko ophezulu kunye nalawo aphantsi. Sifumanise ukuba i-CTLA-4 kunye ne-CD161 (KLRB1) zazigqithisile kwiqela elinomngcipheko ophantsi (Umfanekiso 6B-G), nto leyo ebonisa ukuba izigulane ze-PAAD kwiqela elinomngcipheko ophantsi zinokuba novelwano kwi-ICI.
Uhlalutyo lokuhambelana kwemodeli yomngcipheko wokuxela kwangaphambili kunye nokungena kweeseli zomzimba. (A) Ulwalamano phakathi kwemodeli yomngcipheko wokuxela kwangaphambili kunye nokungena kweeseli zomzimba. (BG) Ibonisa ukubonakaliswa kwezakhi zofuzo kumaqela asemngciphekweni ophezulu nophantsi. (HK) Amaxabiso e-IC50 kumayeza athile okulwa nomhlaza kumaqela asemngciphekweni ophezulu nophantsi. *p < 0.05, **p < 0.01, ns = ayibalulekanga
Siphinde savavanya unxibelelwano phakathi kwamanqaku omngcipheko kunye neearhente ze-chemotherapy eziqhelekileyo kwiqela le-TCGA-PAAD. Sikhangele amayeza asetyenziswa rhoqo okulwa nomhlaza kumhlaza wepancreatic saza sahlalutya umahluko kwiixabiso zawo ze-IC50 phakathi kwamaqela anomngcipheko ophezulu naphantsi. Iziphumo zibonise ukuba ixabiso le-IC50 le-AZD.2281 (olaparib) laliphezulu kwiqela elinomngcipheko ophezulu, nto leyo ebonisa ukuba izigulane ze-PAAD kwiqela elinomngcipheko ophezulu zinokunganyamezeli unyango lwe-AZD.2281 (Umfanekiso 6H). Ukongeza, ixabiso le-IC50 le-paclitaxel, i-sorafenib, kunye ne-erlotinib laliphantsi kwiqela elinomngcipheko ophezulu (Umfanekiso 6I-K). Siphinde safumanisa amayeza angama-34 okulwa nomhlaza anamaxabiso aphezulu e-IC50 kwiqela elinomngcipheko ophezulu kunye namayeza angama-34 okulwa nomhlaza anamaxabiso aphantsi e-IC50 kwiqela elinomngcipheko ophezulu (Itheyibhile 2).
Akunakuphikiswa ukuba ii-lncRNA, ii-mRNA, kunye nee-miRNA zikho ngokubanzi kwaye zidlala indima ebalulekileyo ekuphuhlisweni komhlaza. Kukho ubungqina obaneleyo obuxhasa indima ebalulekileyo ye-mRNA okanye i-miRNA ekuqikeleleni ukusinda ngokubanzi kwiintlobo ezahlukeneyo zomhlaza. Ngokungathandabuzekiyo, iimodeli ezininzi zomngcipheko wokuxela kwangaphambili nazo zisekelwe kwi-lncRNAs. Umzekelo, uLuo et al. Izifundo zibonise ukuba i-LINC01094 idlala indima ebalulekileyo ekwandeni kwe-PC kunye nokusasazeka kwe-metastasis, kwaye ukubonakaliswa okuphezulu kwe-LINC01094 kubonisa ukusinda okungalunganga kwezigulane zomhlaza we-pancreatic [16]. Uphononongo oluvezwe nguLin et al. Izifundo zibonise ukuba ukunciphisa i-lncRNA FLVCR1-AS1 kunxulunyaniswa nokubikezela okungalunganga kwizigulane zomhlaza we-pancreatic [17]. Nangona kunjalo, ii-lncRNA ezinxulumene nokuzikhusela azixoxwa kangako malunga nokuqikelela ukusinda ngokubanzi kwezigulane zomhlaza. Kutshanje, umsebenzi omninzi ugxile ekwakheni iimodeli zomngcipheko wokuxela kwangaphambili ukusinda kwezigulane zomhlaza kwaye ngaloo ndlela ulungise iindlela zonyango [18, 19, 20]. Kukho ukuqondwa okukhulayo kwendima ebalulekileyo yokungena kwe-immune ekuqaliseni umhlaza, ukuqhubela phambili, kunye nokuphendula kunyango olufana ne-chemotherapy. Izifundo ezininzi ziqinisekisile ukuba iiseli ze-immune ezingenela i-tumor zidlala indima ebalulekileyo ekuphenduleni kwi-cytotoxic chemotherapy [21, 22, 23]. Indawo encinci ye-immune immune microenvironment yinto ebalulekileyo ekusindeni kwezigulane ze-tumor [24, 25]. I-immunotherapy, ingakumbi unyango lwe-ICI, isetyenziswa kakhulu kunyango lwee-tumor eziqinileyo [26]. Ii-genes ezinxulumene ne-immune zisetyenziswa kakhulu ukwakha iimodeli zomngcipheko wokuxela kwangaphambili. Umzekelo, uSu et al. Imodeli yomngcipheko wokuxela kwangaphambili onxulumene ne-immune isekelwe kwii-genes ze-protein-coding ukuxela kwangaphambili izigulane zomhlaza we-ovari [27]. Ii-genes ezingabhalisiyo njenge-lncRNAs nazo zifanelekile ekwakheni iimodeli zomngcipheko wokuxela kwangaphambili [28, 29, 30]. ULuo et al bavavanye ii-lncRNA ezine ezinxulumene ne-immune kwaye bakhe imodeli yokuxela kwangaphambili yomngcipheko womhlaza wesibeleko [31]. UKhan et al. Kuchongwe iikopi ezingama-32 ezichazwe ngokwahlukeneyo, kwaye ngokusekelwe koku, kwasekwa imodeli yokuqikelela enekopi ezi-5 ezibalulekileyo, eyacetyiswa njengesixhobo esicetyiswayo kakhulu sokuqikelela ukwaliwa okukhawulezileyo okuqinisekisiweyo yi-biopsy emva kokufakelwa kwezintso [32].
Uninzi lwezi modeli zisekelwe kumanqanaba okubonakaliswa kwezakhi zofuzo, nokuba zii-genes ze-protein-coding okanye ii-genes ezingezizo ze-coding. Nangona kunjalo, i-gene efanayo inokuba namaxabiso okubonakaliswa ahlukeneyo kwii-genomes ezahlukeneyo, iifomathi zedatha nakwizigulane ezahlukeneyo, nto leyo ekhokelela kuqikelelo olungaqinisekanga kwiimodeli zokuqikelela. Kolu phononongo, sakhe imodeli efanelekileyo ngeepere ezimbini ze-lncRNA, ngaphandle kwamaxabiso okubonakaliswa achanekileyo.
Kolu phononongo, sichonge i-irlncRNA okokuqala ngohlalutyo lokuhambelana kunye ne-immune-related genes. Sihlolisise ii-DEirlncRNA ezingama-223 ngokudityaniswa ngee-lncRNA ezichazwe ngokwahlukileyo. Okwesibini, sakhe i-matrix ye-0-okanye-1 esekelwe kwindlela yokudibanisa i-DEirlncRNA epapashiweyo [31]. Emva koko senze uhlalutyo lwe-univariate kunye ne-lasso regression ukuchonga ii-prognostic DEirlncRNA pairs kunye nokwakha imodeli yomngcipheko oqikelelweyo. Sihlalutye ngakumbi unxibelelwano phakathi kwamanqaku omngcipheko kunye neempawu zeklinikhi kwizigulane ezine-PAAD. Sifumanise ukuba imodeli yethu yomngcipheko oqikelelweyo, njengento ezimeleyo yokuqikelela kwizigulane ze-PAAD, inokwahlula ngokufanelekileyo izigulane ezikumgangatho ophezulu kwizigulane ezikumgangatho ophantsi kunye nezigulane ezikumgangatho ophezulu kwizigulane ezikumgangatho ophantsi. Ukongeza, amaxabiso e-AUC e-ROC curve yemodeli yomngcipheko wokuqikelela yayiyi-0.905 kwi-forecast yonyaka o-1, i-0.942 kwi-forecast yonyaka o-2, kunye ne-0.966 kwi-forecast yonyaka o-3.
Abaphandi baxele ukuba izigulane ezine-CD8+ T cell infiltration ephezulu zazinovelwano ngakumbi kunyango lwe-ICI [33]. Ukwanda komxholo weeseli ze-cytotoxic, iiseli ze-CD56 NK, iiseli ze-NK kunye neeseli ze-CD8+ T kwi-tumor immune microenvironment kunokuba sesinye sezizathu zesiphumo soxinzelelo lwe-tumor [34]. Izifundo zangaphambili zibonise ukuba amanqanaba aphezulu e-CD4(+) T kunye ne-CD8(+) T ezifaka i-tumor zazinxulunyaniswa kakhulu nokusinda ixesha elide [35]. Ukungena kakubi kweeseli ze-CD8 T, umthwalo ophantsi we-neoantigen, kunye ne-tumor microenvironment ecinezela kakhulu i-immunosuppressive kukhokelela ekungaphendulini kunyango lwe-ICI [36]. Sifumanise ukuba amanqaku omngcipheko anxulumene kakubi neeseli ze-CD8+ T kunye neeseli ze-NK, nto leyo ebonisa ukuba izigulane ezine-CD8+ T kunye neeseli ze-NK zisenokungafaneleki kunyango lwe-ICI kwaye zinomngcipheko ombi.
I-CD161 luphawu lweeseli zokubulala zendalo (NK). Iiseli ze-T eziguqulwe yi-CD8+CD161+ CAR zilawula ukusebenza kakuhle kwe-antitumor kwi-HER2+ pancreatic ductal adenocarcinoma xenograft models [37]. Izithinteli zokujonga i-immune zijolise kwi-cytotoxic T lymphocyte associated protein 4 (CTLA-4) kunye ne-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathways kwaye zinamandla amakhulu kwiindawo ezininzi. Ukubonakaliswa kwe-CTLA-4 kunye ne-CD161 (KLRB1) kuphantsi kumaqela anomngcipheko ophezulu, nto leyo ebonisa ukuba izigulane ezineenqaku ezinomngcipheko ophezulu zisenokungafaneleki kunyango lwe-ICI. [38]
Ukuze sifumane iindlela zonyango ezifanelekileyo kwizigulana ezisengozini enkulu, sihlalutye amayeza ahlukeneyo okulwa nomhlaza saza safumanisa ukuba i-paclitaxel, i-sorafenib, kunye ne-erlotinib, ezisetyenziswa kakhulu kwizigulana ezine-PAAD, zinokufaneleka kwizigulana ezisengozini enkulu ezine-PAAD. [33]. UZhang nabanye bafumanise ukuba utshintsho kwindlela yokusabela komonakalo we-DNA (DDR) lunokubangela ukuba izigulane ezinomhlaza we-prostate zingabi nathemba [39]. Uvavanyo lwe-Pancreatic Cancer Olaparib Ongoing (POLO) lubonise ukuba unyango lokugcina nge-olaparib luhlala ixesha elide ngaphandle kokusinda xa kuthelekiswa ne-placebo emva kwe-chemotherapy ye-platinum esekelwe kumgca wokuqala kwizigulana ezine-pancreatic ductal adenocarcinoma kunye ne-germline BRCA1/2 mutations [40]. Oku kunika ithemba elikhulu lokuba iziphumo zonyango ziya kuphucuka kakhulu kweli qela lincinci lezigulana. Kolu phononongo, ixabiso le-IC50 le-AZD.2281 (olaparib) laliphezulu kwiqela elisengozini enkulu, nto leyo ebonisa ukuba izigulana ze-PAAD kwiqela elisengozini enkulu zinokunganyamezelani nonyango nge-AZD.2281.
Iimodeli zokuqikelela kolu phononongo zivelisa iziphumo ezilungileyo zokuqikelela, kodwa zisekelwe kuqikelelo lohlalutyo. Indlela yokuqinisekisa ezi ziphumo ngedatha yeklinikhi ngumbuzo obalulekileyo. I-Endoscopic fine needle aspiration ultrasonography (EUS-FNA) iye yaba yindlela ebalulekileyo yokuxilonga izilonda zepancreatic eziqinileyo nezingaphandle kwepancreatic ezinobuntununtunu be-85% kunye nokucaciswa kwe-98% [41]. Ukufika kweenaliti ze-EUS fine-needle biopsy (EUS-FNB) ikakhulu kusekelwe kwiingenelo ezibonwayo kune-FNA, ezinje ngokuchaneka okuphezulu kokuxilonga, ukufumana iisampulu ezigcina ulwakhiwo lwe-histological, kwaye ngaloo ndlela zivelise izicubu zomzimba ezibaluleke kakhulu kwiimvavanyo ezithile zokuxilonga. idayi ekhethekileyo [42]. Uphononongo olucwangcisiweyo lweencwadi luqinisekisile ukuba iinaliti ze-FNB (ingakumbi i-22G) zibonisa ukusebenza kakuhle kakhulu ekuqokeleleni izicubu kwi-pancreatic mass [43]. Ngokwezonyango, linani elincinci kuphela lezigulana ezifanelekileyo utyando olukhulu, kwaye uninzi lwezigulana lunee-tumor ezingasebenziyo ngexesha lokuxilongwa kokuqala. Kwimisebenzi yeklinikhi, lincinci kuphela inani lezigulana elifanelekileyo utyando olukhulu kuba uninzi lwezigulana lunee-tumor ezingasebenziyo ngexesha lokuxilongwa kokuqala. Emva kokuqinisekiswa kwe-pathological yi-EUS-FNB kunye nezinye iindlela, unyango oluqhelekileyo olungelulo utyando olufana ne-chemotherapy ludla ngokukhethwa. Inkqubo yethu yophando elandelayo kukuvavanya imodeli yokuxela kwangaphambili yale sifundo kwii-cohorts zotyando kunye nezingelulo utyando ngokusebenzisa uhlalutyo olujonga emva.
Ngokubanzi, uphando lwethu luseke imodeli entsha yomngcipheko wokuxela kwangaphambili ngokusekelwe kwi-irlncRNA edibeneyo, ebonise ixabiso elithembisayo lokuxela kwangaphambili kwizigulane ezinomhlaza wepancreatic. Imodeli yethu yomngcipheko wokuxela kwangaphambili inokunceda ukwahlula izigulane ezine-PAAD ezifanelekileyo kunyango lwezonyango.
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Ixesha lokuthumela: Sep-22-2023