Ntu Ⅰ Kev Qhia Txog Tus Kheej Thiab Kev Ua Haujlwm Ntawm Kev Tiv Thaiv Kab Mob Ntshav Qab Zib Cov Kab Mob Ntshav Qab Zib Kos Npe Rau Peb Cov Kab Mob Urologic
May 06, 2023
Abstract
Kev ntseeg siab biomarkers yog xav tau kom paub txog cov neeg mob qog noj ntshav urological uas muaj feem pheej hmoo rov tshwm sim dua. Nyob rau hauv txoj kev tshawb no, peb tau tsim ib qho tshiab tiv thaiv kab mob ntsig txog cov noob caj noob ces kos npe rau ib txhij kwv yees rov tshwm sim rau peb tus kab mob urological. Peb tau sau 14 qhov kev tshaj tawm cov noob caj noob ces suav nrog zais zis, prostate, thiab mob raum. Tag nrho ntawm 2,700 tus qauv tau muab cais rau hauv cov txheej txheem kev cob qhia (n=1,622) thiab validation set (n=1,078). 25 lub cev tiv thaiv kab mob ntsig txog cov noob caj noob ces kos npe suav nrog 41 cov noob tshwj xeeb tau tsim los ntawm qhov tsawg kawg nkaus shrinkage thiab xaiv tus neeg teb xov tooj regression tsom xam thiab Cox regression qauv. Cov kos npe stratified cov neeg mob mus rau hauv cov pab pawg siab thiab tsis tshua muaj kev pheej hmoo nrog qhov sib txawv ntawm kev rov qab tsis muaj sia nyob hauv cov txheej txheem meta-kev cob qhia thiab nws cov subpopulations, thiab yog ib qho kev ywj pheej prognostic yam ntawm cov qog nqaij hlav urological. Qhov kev kos npe no tau pom tias muaj peev xwm muaj peev xwm nyob rau hauv meta-validation thiab ntau yam ywj pheej validation cohorts. Cov tshuaj tiv thaiv kab mob thiab cov kab mob inflammatory, chemotaxis, thiab cytokine kev ua tau zoo nrog cov noob muaj feem cuam tshuam rau kev kos npe. Ib qho kev nkag siab ntau dua ntawm M1 macrophages tau pom nyob rau hauv pab pawg muaj kev pheej hmoo siab piv rau cov pab pawg tsawg. Hauv kev xaus, peb kos npe yog ib qho kev cog lus biomarker rau kev kwv yees rov qab tsis muaj sia nyob hauv cov neeg mob uas mob qog noj ntshav urological.
Ntsiab lus
Mob qog noj ntshav urological; Biomarkers; Immune-related gene khub; Kev muaj sia nyob tsis muaj sia; Prognostic biomarker;Cistanche cov txiaj ntsig.
Nyem qhov no kom tau txais cov ntaub ntawv ntxiv txogDab tsi yog qhov cuam tshuam ntawm Cistanche
Taw qhia
Mob qog noj ntshav zais zis, mob qog nqaij hlav prostate, thiab mob raum mob qog noj ntshav yog cov qog loj hauv cov zis, thiab ze li 2.4 lab tus neeg mob tshiab tau kuaj pom txhua xyoo [1]. Kev ua ntej ntawm cov phiaj xwm kev kho mob thiab kev kho neoadjuvant tau ua kom muaj sia nyob ntev ntawm cov neeg mob [2-4]. Txawm li cas los xij, ntau tus neeg mob raug kev txom nyem txawm tias tom qab ua tiav kev phais [5-7], thiab lawv cov kev kwv yees tseem tsis zoo. Ib tug txhim khu kev qha prognostic biomarker uas tuaj yeem txheeb xyuas cov neeg mob uas muaj kev pheej hmoo siab dua rau kev rov qab los thiab xaiv cov neeg mob uas muaj cov lus teb rau kev kho mob yuav muaj txiaj ntsig zoo rau kev tswj cov qog noj ntshav urological.
Gene-expression kos npe tau raug txheeb xyuas rau kev ciaj sia stratification ntawm zais zis [8, 9], prostate cancer [10, 11], thiab mob raum [12, 13]. Txawm li cas los xij, feem ntau cov biomarkers tsis tau muab txhais los rau kev kho mob vim yog qhov ua tau zoo tshaj ntawm cov ntaub ntawv qhia kev cob qhia lossis tsis muaj kev lees paub txaus [14]. Lub caij nyoog los txhim kho kev ntseeg tau ntau dua kev tshawb fawb biomarkers tau raug coj los ntawm cov ntaub ntawv loj loj ntawm pej xeem cov noob qhia cov ntaub ntawv [15, 16]. Txawm li cas los xij, nws yog ib qho nyuaj rau kev sib koom ua ke cov ntaub ntawv los ntawm ntau lub platform. Cov txheej txheem ib txwm ua rau nws nyuaj rau normalize cov ntaub ntawv sib txawv, muab cov kev tsis ncaj ncees thiab kev lom neeg ntawm ntau lub platform [17, 18]. Cov txheej txheem tshiab raws li qhov txheeb ze ntawm cov qib qhia cov noob tau siv los tshem tawm qhov yuav tsum tau ua rau cov ntaub ntawv ua ntej, thiab tau txais txiaj ntsig zoo hauv ntau daim ntawv thov [19–21].
Cov pov thawj ntxiv tau qhia tias cov qog tiv thaiv kab mob microenvironment muaj feem cuam tshuam nrog kev tsim thiab kev loj hlob ntawm peb lub ntsiab urologic hlav [22–24]. Lub cev tiv thaiv kab mob molecules, xws li programmed cell tuag 1 (PD-1), PD-1 ligand 1 (PD-L1), thiab cytotoxic T-lymphocyte txuam antigen 4 (CTLA{10}}) , tau ua kom pom qhov zoo tshaj plaws, cov lus teb ruaj khov hauv zais zis [25, 26], mob qog nqaij hlav prostate [27, 28] thiab mob raum [29, 30]. Cov biomarkers muaj feem xyuam rau cov qog tiv thaiv kab mob microenvironment yog li muaj peev xwm ua cov cim cim ntawm cov qog nqaij hlav urological.
Raws li paub zoo, mob qog noj ntshav, mob qog nqaij hlav prostate, thiab mob raum mob qog noj ntshav muaj feem cuam tshuam nrog anatomically thiab tshwm sim los ntawm kev thuam zoo sib xws uas txhawb nqa qog nqaij hlav [31–33]. Yog li ntawd, peb tau tsim nyob rau hauv txoj kev tshawb no ib tug kos npe raws li kev tiv thaiv kab mob gene khub (IRGPs) ib txhij kwv yees qhov rov tshwm sim ntawm zais zis, mob cancer prostate, thiab mob raum.
Cistanche tubulosa
Cov ntaub ntawv thiab cov txheej txheem
1. Kawm tsim thiab cov ntaub ntawv
Peb tau txheeb xyuas tag nrho 14 gene qhia profiles nyob rau hauv peb lub qog urological ntawm lub zais zis, prostate, thiab mob raum, nrog rau xya microarray datasets thiab xya RNA-Seq datasets (Ntxiv daim duab 1). Cov lej nkag, cov platforms, thiab cov qauv piv txwv ntawm cov noob qhia cov ntaub ntawv no tau qhia hauv Cov Lus Ntxiv 1. RNA-Seq cov ntaub ntawv raug rub tawm los ntawm UCSC Xena thiab International Cancer Genome Consortium (ICGC). Cov ntaub ntawv Microarray tau rub tawm los ntawm Gene Expression Omnibus (GEO). Cohorts los ntawm Cancer Genome Atlas (TCGA) tau siv los ua cov txheej txheem kev cob qhia, thiab lwm cov ntaub ntawv tau siv los ua cov txheej txheem siv tau. Tsuas yog cov neeg mob uas muaj cov ntaub ntawv muaj sia nyob tiav tau suav nrog. Peb kuj tsis suav nrog cov neeg mob uas tau txais kev kho hluav taws xob, kev kho neoadjuvant, thiab kev kho cov tshuaj molecular hauv txhua pawg kev cob qhia ywj pheej. Hauv tag nrho, 2,700 tus neeg mob tau suav nrog hauv peb txoj kev tshawb fawb. Peb qhov project tau pom zoo los ntawm Chongqing Medical University's Ethical Review Committee.
2. Gene qhia cov ntaub ntawv ua
Cov ntaub ntawv uas muaj nyob rau hauv pej xeem los ntawm GEO tau ua thawj zaug uas siv cov normalizeBetweenArrays muaj nuj nqi raws li siv nyob rau hauv lub pob 'limma' thiab tom qab ntawd tau ntxiv log-hloov. Txoj hauv kev zoo li qub tsis tau siv hauv TCGA thiab ICGC pawg.
3. Kev txheeb xyuas cov IRGPs tshwj xeeb rau kev kwv yees kwv yees
Peb rub tawm cov tshuaj tiv thaiv kab mob (IRGs) los ntawm ImmPort cov ntaub ntawv nkag mus rau 3/3/2021. 2,483 tshwj xeeb IRGs, tsim 17 pawg, suav nrog cytokines, cytokine receptors, antigen ua, kev nthuav qhia, interleukins, ntuj killer cell cytotoxicity, TGFb, thiab TNF tsev neeg. Tsuas yog IRGs ntsuas los ntawm txhua lub platform nrog qhov nruab nrab qhov sib txawv tsis sib xws > 0.5 hauv txhua qhov kev cob qhia ywj pheej raug xaiv. Cov qhab nia rau txhua IRGP tau tsim los ntawm kev sib piv sib piv ntawm cov qib qhia cov noob hauv qee cov qauv ntawm cov ntaub ntawv. Tus qhab nia IRGPs tau txhais tias yog 1 yog tias qib qhia ntawm IRG 1 loj dua IRG 2; txwv tsis pub, tus qhab nia IRGPs tau teeb tsa li 0 [34]. Tom qab tshem IRGPs nrog cov txiaj ntsig tas li hauv ib tus neeg cov ntaub ntawv, cov IRGPs ntxiv tau txheeb xyuas ntxiv.
4. Kev tsim kho ntawm lub cev tiv thaiv kab mob ntsig txog gene khub index (IRGPI) rau kev kwv yees kwv yees
Prognostic IRGPs raug xaiv raws li cov kauj ruam hauv qab no. Ua ntej, qhov kev kwv yees muaj peev xwm ntawm txhua tus IRGP los kwv yees cov neeg mob rov qab tsis muaj sia nyob (RFS) tau soj ntsuam los ntawm kev siv Cox regression qauv hauv cov ntaub ntawv qhia kev qhia, thiab IRGPs nrog p-tus nqi < 0.05 raug xaiv los ua thawj tus neeg sib tw cov cim. Qhov thib ob, qhov tsawg kawg nkaus qhov txo qis thiab kev xaiv tus neeg teb xov tooj (LASSO) tau siv los lim tawm qee cov ntaub ntawv IRGPs tsawg dua. Qhov ntsuas qhov ntsuas tau txiav txim siab los ntawm qhov xav tau kev ua yuam kev dav dav kwv yees los ntawm 10-fold cross-validation. Txhawm rau txhim kho qhov muaj zog, peb tau muab faib ua cov ntaub ntawv qhia meta tag nrho rau hauv kev cob qhia tshiab thiab kev sim cov ntaub ntawv nrog qhov sib piv 2: 1 thiab rov ua dua qhov sib faib random 30 zaug kom ruaj khov rau IRGPs txheej txheem xaiv. Tus qauv LASSO tau siv rau 30 qhov kev cob qhia, thiab cov IRGPs uas muaj zaus> 15 raug xaiv. Thaum kawg, tus qauv Cox regression multivariate tau siv los tsim IRGPs-raws li kev kwv yees qauv thiab tsim IRGPI rau tag nrho cov qauv. Cov neeg mob tau muab faib ua pawg tsawg thiab muaj kev pheej hmoo siab tiv thaiv kab mob siv qhov nruab nrab IRGPI tus nqi.
Cistanche extract
5. Kev ntsuam xyuas thiab kev lees paub ntawm IRGPI
The prognostic value of the IRGPI was evaluated in the meta-training and independent training sets and was further verified in the meta-validation and multiple independent validation sets. The log-rank test and time-dependent receiver operating characteristic (ROC) curves were adopted to assess the prognostic accuracy of the IRGPI. We combined IRGPI with clinical factors of age, gender, and tumor stage in multivariate Cox analyses. Age (>60) tau hloov mus ua 1, thiab hnub nyoog (<60) was transformed into 0. Stages III and IV were transformed into 1, and stage I and II were transformed into 0.
6. Profileing ntawm infiltrating lub cev tiv thaiv kab mob
CIBERSORT qhia txog kev tiv thaiv kab mob hauv lub cev los ntawm kev siv cov qog nqaij hlav gene qhia profiles [35]. Nws inferred tus txheeb ze proportions ntawm 22 hom infiltrating lub cev tiv thaiv kab mob raws li cov reference gene expression values (LM22) [35]. Hauv txoj kev tshawb no, qhov feem ntawm 22 infiltrating lub cev tiv thaiv kab mob tau txiav txim los ntawm kev siv R pob 'CIBERSORT'. Daim ntawv tso cai tau teeb tsa ntawm 1,000, thiab cov teeb meem nrog CIBERSORT tso zis p-value < 0.05 raug xaiv rau kev tshuaj xyuas ntxiv. Wilcoxon rank sum test tau siv los sib piv qhov sib txawv ntawm cov kab mob hauv lub cev tiv thaiv kab mob ntawm pawg IRGPI siab thiab qis.
7. Gene ontology (GO) tsom xam
R pob 'clusterProfiler' tau siv los ua GO enrichment tsom xam ntawm cov noob muaj feem xyuam rau IRGPI hauv pawg meta-kev cob qhia. BenjaminiHochberg-adjusted p-value < 0.05 (tus nqi nrhiav tsis tseeb, FDR) tau siv los ua qhov pib los txiav txim qhov tseem ceeb.
8. Kev tsim kho thiab kev ntsuam xyuas ntawm nomogram
Lub npe nomogram tau tsim los tsim kom muaj ntau txoj hauv kev rau RFS qhov kev twv ua ntej hauv meta-training cohort raws li IRGPI thiab cov xwm txheej kho mob, uas tau txheeb xyuas ntxiv hauv cov meta-validation cohorts. Ib qho taw qhia tau suav rau txhua yam, thiab tag nrho cov ntsiab lus ntawm txhua yam tau txais rau kev kwv yees ntawm RFS tus nqi ntawm 1, 3, 5, thiab 10 xyoo. Cov phiaj xwm calibration tau raug kos los ntsuas qhov kev ntseeg tau ntawm nomogram.
Standardized Cistanche
9. Kev txheeb cais
Cov pob R 'kev ciaj sia', 'glmnet', 'sure miner', 'timeROC', 'rms', 'CIBERSORT', thiab 'clusterProfiler' tau siv los tsim cov qauv Cox regression, LASSO qauv, Kaplan-Meier nkhaus, sijhawm -dependent ROC nkhaus, nomogram, kev tiv thaiv kab mob ntawm tes suav nrog thiab GO tsom xam. Kev sib koom ua ke ntawm IRGPI cov qhab nia nrog RFS tau txheeb xyuas los ntawm kev ntsuas ntsuas qib. Tus qauv Cox regression tau txais yuav los ua ib qho kev ntsuam xyuas ntau yam ntawm lub koom haum ntawm IRGPI nrog RFS. Qhov ob sab p-tus nqi < 0.05 tau suav tias yog qhov tseem ceeb rau txhua qhov kev xeem. Txhua qhov kev txheeb xyuas txheeb cais tau ua los ntawm R (version 4.0.2).
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Biao Xie 1, Kangjie Li 1, Hong Zhang 1, Guichuan Lai 1, Dapeng Li 2, Xiaoni Zhong 1.
1. Department of Biostatistics, Tsev Kawm Ntawv Kev Noj Qab Haus Huv thiab Kev Tswj Xyuas, Chongqing Medical University, Chongqing, Suav
2. Lub Tsev Kho Mob Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, Suav
