Kev Siv Cov Ncauj Cov Ncauj Lus Pom Zoo Module Cov qhab nia hauv lub raum Hloov Ua Ib Lub Hom Phiaj Ntsuas Ntawm Allograft Inflammation

Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com

Arya Zarinsefat 1*, Jose M. Arreola Guerra2, Tara Sigdel 1, Izabella Damm1, Reuben Sarwal 1, Chitranon Chan-on1, Gyula Szabo3, Jorge L. Aguilar-Frasco4, Xicohtencatl Ixtlapale-Carmon

Carlos Salinas-Ramos 4, Leonardo Ramirez-Martinez 4, Claudio Ramirez 4, Mario Vilatoba4, Luis E. Morales Buenrostro4, Josefifina M. Alberu5 thiab Minnie M. Sarwal 1

Department of Surgery, University of California, San Francisco, CA, Tebchaws Asmeskas,

2 Department of Internal Medicine, Centenario Tsev Kho Mob Miguel Hidalgo, Aguascalientes, Mexico,

3 Department of Pathology, University of California, San Francisco, CA, Tebchaws Asmeskas,

4 Instituto Nacional de Ciencias Medicas y Nutricio´n Salvador Zubira´n, Mexico City, Mexico,

5 Department of Medicine, Tecnologico de Monterrey, Escuela de Medicina thiab Ciencias de la Salud, Mexico City, Mexico

Lub raum hloov mus ntev(KT) allograft cov txiaj ntsig tsis tau txhim kho raws li qhov xav tau txawm tias muaj kev nkag siab zoo dua ntawm kev tsis lees paub thiab txhim kho kev tiv thaiv kab mob. Kev ua haujlwm yav dhau los tau lees paub qhov qhab nia tsis lees paub, cov ntaub so ntswg tsis pom zoo module (tCRM), ntsuas los ntawm kev ntsuas kev ua kom pom tseeb ntawm 11 cov noob los ntawm formalin-taw paraffin-embedded (FFPE) biopsy specimens, uas tso cai rau kom muaj nuj nqis, tsis muaj kev ntsuam xyuas ntawm lub cev. raug mob. Peb tau thov tCRM hauv qhov kev sim yav tom ntej ntawm 124 KT cov neeg tau txais, thiab qhov sib txawv ntawm qhov kev ntsuam xyuas los ntawm tCRM thiab histology nyeem los ntawm 2 tus kws kho mob ywj pheej ntawm cov txheej txheem thiab ua rau biopsies tom qab hloov pauv. Plaub 10- hli shaves los ntawm FFPE biopsy specimens tau siv rau RNA extraction thiab amplification los ntawm qPCR ntawm 11 tCRM noob, los ntawm cov qhab nia tCRM raug xam. Kev kuaj mob biopsy ntawm kev tsis lees paub mob hnyav (AR) lossis ciam teb tsis lees txais (BL) tau suav tias muaj qhov mob tshwm sim, thaum lub cev nqaij daim tawv ruaj khov tsis muaj qhov mob. Ntawm 77 biopsies uas tau nyeem los ntawm ob tus kws kho mob, tag nrho ntawm 4 0 qhov tsis sib xws hauv kev kuaj mob tau tshwm sim. Qhov nruab nrab tCRM cov qhab nia rau AR, BL, thiab kev kuaj mob ruaj khov yog 4.87, 1.85, thiab 1.27, raws li, nrog qhov sib txawv tseem ceeb ntawm txhua pawg histologic (Kruskal-Wallis, p < 0.0{="" {34}}01).="" muaj="" qhov="" sib="" txawv="" tseem="" ceeb="" hauv="" tcrm="" cov="" qhab="" nia="" nruab="" nrab="" ntawm="" cov="" kws="" kho="" mob="" ob="" qho="" tib="" si="" nrhiav="" kev="" mob="" vs.="" kev="" tsis="" pom="" zoo="" (p="0.003)," thiab="" ob="" qho="" tib="" si="" nrhiav="" kev="" mob="" vs.="" ob="" qho="" tib="" si="" nrhiav="" tsis="" muaj="" mob="" (p=""><0.001), nrog="" rau="" tag="" nrho="" qhov="" tseem="" ceeb="" ntawm="" txhua="" qhov="" qhab="" nia="" (="" kruskal-wallis,="" p=""><0.001). tus="" qauv="" logistic="" regression="" kwv="" yees="" kev="" mob="" qog="" noj="" ntshav="" siv="" ntau="" yam="" kev="" kho="" mob="" sib="" txawv="" thiab="" tcrm="" tau="" qhia="" txog="" tcrm="" tus="" qhab="" nia="" raws="" li="" qhov="" tseem="" ceeb="" ntawm="" kev="" kwv="" yees="" ntawm="" kev="" mob="" qog="" noj="" ntshav="" (los="" yog:="" 1.90,="" 95="" feem="" pua="" ​​​​ci:="" 1.40–2.68,="" p="">< 0.0001).="" qhov="" tseeb,="" muaj="" nuj="" nqis,="" thiab="" tsis="" muaj="" kev="" ntsuam="" xyuas="" ntawm="" kev="" tsis="" lees="" paub="" cov="" qauv="" kuaj="" mob="" yog="" qhov="" tseem="" ceeb.="" muab="" qhov="" kev="" kuaj="" mob="" tsis="" sib="" xws="" ntawm="" cov="" kws="" kho="" mob="" ntawm="" tib="" cov="" qauv,="" cov="" tib="" neeg="" tuaj="" yeem="" siv="" qhov="" qhab="" nia="" tcrm="" raws="" li="" kev="" sib="" khi="" hauv="" cov="" xwm="" txheej="" tsis="" meej.="" peb="" npaj="" siab="" tias="" tcrm="" tus="" qhab="" nia="" ntau="" tuaj="" yeem="" muab="" qhov="" tsis="" txaus="" ntseeg="" ntawm="" kev="" ua="" txhaum="" cai="" ntawm="" kev="" ua="" txhaum="" cai,="" thiab="" nws="" qhov="" kev="" ntsuam="" xyuas="" sai="" los="" ntawm="" pcr="" ntawm="" ffpe="" shaving="" tuaj="" yeem="" dhau="" los="" ua="" qhov="" tseem="" ceeb="" los="" pab="" txhawb="" kev="" txiav="" txim="" siab="" kho="" mob="" thiab="" kev="" tiv="" thaiv="" kab="">

Ntsiab lus:hloov raum, mob tsis kam lees, biomarkers, transcriptomics, formalin-taw paraffin-embedded (FFPE), graft o

Cistanche tubulosa tiv thaiv kab mob raum, nyem qhov no kom tau txais cov qauv

Taw qhia

Hloov pauv raum(KT) tseem yog qhov kev kho mob zoo tshaj plaws rau cov neeg mob uas muaj kab mob hauv lub raum kawg, nrog txo qis kev tuag piv rau cov neeg mob tos thiab txhim kho txoj sia nyob ntawm ntau pawg neeg pej xeem (1-3). Txawm tias muaj kev txhim kho tseem ceeb hauv ib xyoosraumallograft ciaj sia taus (4), tus nqi ntawm cov kab mob graft poob tom qab thawj xyoo tom qab hloov pauv tseem muaj ntau. Qhov no tau pom txawm tias muaj kev nkag siab zoo dua ntawm allograft tsis lees paub, nrog rau kev tshwm sim ntawm kev txhim kho kev tiv thaiv kab mob. Cov kev faib tawm tam sim no ntawm kev tsis lees paub histological raug kev txom nyem los ntawm kev ua piv txwv yuam kev thiab tsis muaj peev xwm txheeb xyuas qhov tseeb ntawm lub nra hnyav hauv allograft, ib qho tseem ceeb kwv yees ntawm kev ua haujlwm ntev ntev thiab kev ciaj sia (5-9). Qhov tseem ceeb, cov kev tshawb fawb ua ntej tau pom tias kev sib raug zoo ntawm tus kws kho mob ntawm Banff-graded raum allograft pathology muaj qhov sib txawv ntawm qhov kev txhais ntawm biopsy (10, 11).

Kev ua haujlwm dhau los hauv peb lub chaw kuaj xyuas tag nrho-genome microarray cov ntaub ntawv los ntawm 1,030raum, plawv, ntsws, thiab siab allograft biopsies txheeb xyuas ahom tshuaj tiv thaiv kab mobe teb module (CRM) ntawm 11 cov noob uas txhais cov kev tsis lees paub mob hnyav (AR) hla ntau yam allografts (12–14) thiab tau raug lees paub tom qabraumallograft biopsies (15, 16). Thaum cov ntaub ntawv no tau pom tias muaj peev xwm siv tau los ntawm kev siv lub hom phiaj ntsuas xws li CRM tus qhab nia los pab hauv kev kuaj mob biopsy, cov no yog cov kev txheeb xyuas rov qab ntawm cov ntaub so ntswg yav dhau los. Tsis tas li ntawd, tsis muaj kev sib piv ntawm ntau qhov dig muag pathology nyeem ntawm tib lub biopsy, lossis lub peev xwm ntawm CRM tus qhab nia los siv los ua lub hom phiaj tiebreaker lossis cov ntaub ntawv txuas ntxiv los pab rau kev tuaj txog ntawm kev kuaj mob zoo dua.

Hauv qhov kev tshuaj ntsuam no, peb tau saib ntawm serialraumbiopsies uas tau txais los ua ib feem ntawm kev sim tshuaj hauv KT. Peb siv peb cov txheej txheem uas ntsuas cov noob qhia ntawm 11 CRM noob los ntawm RNA cais los ntawm plaub 10-micron shaves tawm ntawm formalin-taw paraffin-embedded (FFPE) thaiv nrog histologically lees paub phenotypes ntawm AR, borderline rejection (BL), thiab ruaj khov kho. Peb xa mus rau qhov qhab nia no raws li cov ntaub so ntswg CRM (tCRM) tau muab daim ntawv thov ntawm CRM cov qhab nia rau cov ntaub so ntswg biopsy (15, 16). Tom qab ntawd peb piv cov kev kuaj mob los ntawm 2 tus kws kho qhov muag tsis pom kev thiab muab piv rau tCRM tus qhab nia rau txhua qhov kev kuaj ntshav. Peb xav tias qhov qhab nia tCRM tuaj yeem siv los ua cov ntaub ntawv taw qhia los pab hauv kev kuaj mob biopsy, thiab tejzaum nws yog lub hom phiaj tiebreaker thaum muaj kev tsis sib haum xeeb ntawm cov kws kho mob.

cistanche txiaj ntsig: anti-inflammatory

Txoj kev

Patient Enrollment and Study Design

Cov neeg mob thiab cov qauv raug sau ua ib feem ntawm TITRATE (Testing Immunosuppression Threshold in Renal Allografts To Extend eGFR) kev sim tshuaj. Nws cov txheej txheem tuaj yeem sab laj rau ntawm ClinicalTrials.gov portal (Identifier: NCT02581436). Luv luv, qhov no yog qhov kev cia siab, qhov muag tsis pom, tswj kev sim tshuaj ntsuam xyuas ntawm 124 KT cov neeg tau txais kev pabcuam uas tau muab rau ob hom kev ua haujlwm txhawm rau txhawm rau ntsuas qhov ua tau zoo thiab kev nyab xeeb ntawm kev tshawb pom raws sijhawm ntawm AR, glomerular filtration rate (GFR), thiab fibrosis indices. nyob rau hauv raws tu qauv biopsies ntawm 12 lub hlis tom qab KT. Kev soj ntsuam ntawm lub raum ua haujlwm tau ua raws li GFR thiab graft biopsies ua raws li txoj cai ntawm 3 thiab 12 lub hlis tom qab KT thiab yog vim li cas. Induction immunosuppression (IS) tau muab tso rau raws li kev pheej hmoo ntawm kev tiv thaiv kab mob nrog Basiliximab (tsis tshua muaj kev pheej hmoo), anti-thymocyte globulin (muaj kev pheej hmoo siab), lossis tsis muaj kev kho induction hauv cov neeg mob uas sib koom ob haplotypes. Kev saib xyuas yog ua raws li tacrolimus, mycophenolate, thiab prednisone.

Txoj kev tshawb no tam sim no yog ib qho kev soj ntsuam ntxiv rau tCRM noob (15) hauv txhua qhov muaj KT biopsies. Rau peb txoj kev tshawb fawb, tom qab tsis suav hnub xoom biopsies, tag nrho ntawm 136 biopsies tau muaj nrog kev sib tw biopsy histology, uas txhua tus tau txhais los ntawm tus kws kho mob ntawm National Institute of Medical Sciences hauv Mexico. Ntawm no 136 biopsies, 77 kuj raug xa mus rau UCSF, kom muaj qhov muag tsis pom kev nyeem ntawv rau kev ntsuam xyuas ntxiv ntawm kev sib raug zoo ntawm tus kws kho mob. Biopsies tau txhais raws li cov txheej txheem Banff tsis ntev los no thaum lub sijhawm kawm (17). Txhua daim ntawv ntawm graft AR (mob cellular lossis antibody-mediated) tau muab tso ua ke rau hauv ib pawg AR. Rau UCSF-nyeem biopsies, ntau cov ntaub ntawv kuaj mob histopathologic muaj, suav nrog hom tshuaj tiv thaiv kab mob sib kis (ABMR), thiab T-cell mediated rejection (TCMR) hom.

Tag nrho RNA Extraction

Peb tau ua raws li cov txheej txheem luam tawm yav dhau los rau kev rho tawm ntawm RNA los ntawm FFPE cov ntaub so ntswg (18). Raws li peb cov kev paub dhau los, peb siv 4 × 10 mm-thick seem kom rho tawm tag nrho RNA los ntawm FFPE cov qauv nrog PureLink FFPE Tag Nrho RNA Isolation nws (Thermo Fisher Scientific, Foster City, CA). RNA cov ntaub ntawv zoo tau soj ntsuam los ntawm 260/280 nqus teeb liab piv thiab tus lej RIN.

cDNA Synthesis thiab Gene Expression Quantification siv qPCR

Tag nrho ntawm 50 ng RNA tau thim rov qab mus rau hauv cov DNA sib ntxiv (cDNA) siv SuperScript VILO (Invitrogen, Thermo Fisher Scientific, Foster City, CA) thiab tom qab ntawd nthuav tawm hauv lub hom phiaj tshwj xeeb ua kom muaj zog rau tag nrho 11 genes siv TaqMan PreAmp Master Mix thiab TaqMan Primers thiab Probes (Thermo Fisher Scientific, Foster City, CA) rau tag nrho ntawm 18 amplification cycles. qPCR cov tshuaj tiv thaiv tau ua nyob rau hauv Fluidigm BioMark FD system (Fluidigm, South San Francisco, CA) siv 18S gene housekeeping gene thiab Human XpressRef Universal Total RNA (Qiagen, Valencia, CA) raws li kev siv RNA rau 40 cycles. Cov ntaub ntawv nti tau raug tshuaj xyuas thawj zaug rau kev tswj xyuas zoo siv BioMark Analysis Software Version 2.0 (Fluidigm, South San Francisco, CA) thiab cov txiaj ntsig Ct raug xa tawm mus rau hauv daim ntawv nthuav qhia. Normalization ntawm cov ntaub ntawv tau ua nyob rau hauv ob kauj ruam. Ct qhov tseem ceeb ntawm cov noob caj noob ces ib txwm ua rau Ct tus nqi ntawm 18S rau txhua tus noob kom tau txais cov txiaj ntsig dCt. dCt qhov tseem ceeb ntawm txhua tus qauv tau normalized tiv thaiv dCt qhov tseem ceeb ntawm cov qauv siv tau kom tau txais ddCt qhov tseem ceeb uas tau siv los xam cov kev hloov pauv (RQ) qhov tseem ceeb rau txhua tus noob hauv txhua tus qauv. Tus qhab nia tCRM tau suav los ntawm kev noj cov geometric txhais tau tias ntawm 11 CRM noob rau txhua tus qauv, raws li tau piav qhia yav dhau los (12).

Kev txheeb cais

Tag nrho cov ntaub ntawv raug xa mus rau R version 3.6.2 (R Foundation, Vienna, Austria) rau kev tshuaj xyuas tom ntej. Cov neeg mob cov pej xeem (Table 1) tau qhia raws li tCRM cov qhab nia siab dua lossis tsawg dua 2.2, peb tau txiav txim siab yav dhau los nrog kev pom zoo AUROC rau kwv yees AR (15). Kev ntsuam xyuas txheeb cais tau ua nrog Tub Kawm Ntawv t-test rau qhov sib txawv tsis tu ncua thiab chi-square xeem rau categorical variables. Bubble thiab bar cov phiaj xwm ntawm tCRM cov qhab nia rau txhua pab pawg kuaj mob pathologic tau tsim siv pob ggplot2. Qhov sib txawv tseem ceeb ntawm txhua pawg pathologic thiab qhov sib txawv sib txawv ntawm txhua pab pawg tau txiav txim siab los ntawm Kruskal-Wallis test. Unsupervised hierarchical clustering siv cov pab pawg pathologic sib txawv thiab tCRM cov noob tau ua, nrog rau cov duab tshav kub tom qab uas tau siv lub pob heatmap. Peb suav hais tias tCRM cov qhab nia siab dua 2.2 kom muaj kev kuaj mob molecular ntawm kev tsis lees paub. Peb tau txheeb xyuas qhov kev kuaj mob biopsy yog qhov zoo rau kev mob yog tias qhov kev kuaj mob pathologic yog AR lossis BL thiab tsis zoo rau kev mob yog tias qhov kev kuaj mob ruaj khov. Peb mam li tsim ib qho kev pom zoo sib txawv ntawm cov kws kho mob, qhov twg ob qho tib si hais tias muaj mob tshwm sim, ob leeg hais tias tsis muaj mob, lossis lawv tsis pom zoo yog tias muaj qhov mob tshwm sim. Cov phiaj xwm bar thiab cov phiaj xwm kub rau tCRM cov qhab nia ntawm qhov kev pom zoo sib txawv tau raug tsim raws li tau piav qhia saum toj no.

Peb suav tus qauv logistic regression los kwv yees qhov tshwm sim binary ntawm o ntawm biopsy. Peb muab cov neeg tau txais kev pab hnub nyoog, lub cev qhov ntsuas qhov ntsuas (BMI), qeeb graft muaj nuj nqi (DGF), poj niam txiv neej, induction regimen, nyob tus neeg pub nyiaj, tus txiv neej pub rau poj niam, yav dhau los KT, pre-KT lim ntshav, thiab tCRM tus qhab nia raws li kev kwv yees sib txawv hauv tus qauv.

Peb tau txais txhua tus neeg mob delta GFR, xam raws li qhov hloov pauv ntawm lawv lub sijhawm ntawm kev kuaj ntshav GFR los ntawm lawv qhov kawg GFR ntawm ob xyoos tom qab KT. Peb siv Pearson correlation coefficient los sib piv cov delta GFR rau tus neeg mob tus qhab nia tCRM uas tau txais los ntawm kev kuaj ntshav. Qhov no tau rov ua dua tom qab tsis suav cov qhab nia tCRM tsawg dua 2. Peb tau siv cov qib siab tshaj plaws pub dawb tshwj xeeb cov tshuaj tiv thaiv kab mob (DSA) uas tau ntsuas los ntawm cov phooj ywg cytometry rau txhua tus neeg mob, sawv cev raws li qhov txhais tau tias FL fluorescence siv (MFI), los ua kev sib raug zoo rau tCRM cov qhab nia thiab xam qhov cuam tshuam Pearson correlation coefficient. Qhov kev sib raug zoo no kuj tau nthuav tawm hauv daim phiaj xwm txheej. Rau kev txheeb xyuas cov qhab nia serial, peb npaj cov neeg mob nrog cov qhab nia tCRM los ntawm hnub tom qab hloov pauv, tsom mus rau plaub tus neeg mob uas tau kuaj pom thawj zaug ntawm AR, tau kho, thiab tom qab ntawd ua raws li kev kuaj ntshav tom qab. Ob tus neeg mob ntxiv uas tau nce tCRM cov qhab nia uas tau nyeem raws li muaj kev kuaj mob ruaj khov, tab sis tom qab ntawd tsim qhov kev kuaj mob tshiab ntawm AR ntawm lawv cov kev soj ntsuam kuaj mob kuj tau npaj. Kev tsim qauv kev kawm thiab kev tshuaj xyuas tom qab tau muab sau tseg ntxiv rau hauv daim duab duab (Daim duab 1).

TSEEM CEEB

Lub raum Allograft Biopsy Tshawb Pom los ntawm Ob Tus Neeg Tsis Txaus Siab, dig muag Pathologists

Cov neeg mob cov pej xeem thiab cov kev hloov pauv ntawm qhov kev txaus siab tsis pom qhov sib txawv loj ntawm cov neeg mob uas muaj tCRM cov qhab nia siab dua lossis tsawg dua 2.2, tshwj tsis yog rau cov hnub nyoog pub dawb siab dua hauv cov neeg mob uas tau qhab nia tCRM siab tom qab hloov pauv biopsies (Table 1). Tag nrho ntawm 77 biopsies tau nyeem los ntawm ob lub chaw, nrog tus kws kho mob 1 (Mexico) kuaj pom 16 AR, 21 BL, thiab 40 qhov kev kuaj mob ruaj khov, thaum tus kws kho mob 2 (UCSF) kuaj pom 10 AR, 39 BL, thiab 28 qhov kev kuaj mob ruaj khov (Table 2) . Muaj tag nrho ntawm 40 qhov kev kuaj mob tsis sib haum ntawm cov kws kho mob, nrog rau feem ntau ntawm cov kev tsis sib haum no los ntawm qhov sib txawv hauv BL qeb.

Tissue Common Rejection Module raws li Tiebreaker Kev Sib Cais Sib Txawv Ntawm Pathology Diagnoses

Peb tom qab ntawd saib lub peev xwm ntawm tCRM cov qhab nia rau kev ntxub ntxaug ntawm kev kuaj mob rau ib tus kws kho mob ib leeg (siv biopsies nyeem ntawm UCSF, muab tias peb muaj cov ntaub ntawv qhia txog keeb kwm yav dhau los). Thaum saib cov qhab nia tCRM los ntawm kev kuaj mob histologic, peb pom qhov sib cais meej nrog cov qhab nia tCRM siab dua hauv cov neeg mob nrog AR piv rau BL / ruaj khov, thiab nrog cov qhab nia ntau dua> 2.2 hauv AR cov neeg mob (Daim duab 2A). Qhov nruab nrab tCRM cov qhab nia thiab qhov sib txawv ntawm qhov sib txawv (IQR) rau AR, BL, thiab kev kuaj mob ruaj khov yog 4.87 (IQR: 2.44– 6.99), 1.85 (IQR: 1.21–2.48), thiab 1.27 (IQR: 0.96– 2.14), ib. Tsis tas li ntawd, muaj qhov sib txawv tseem ceeb ntawm txhua pawg histologic (p < 0.001),="" nrog="" rau="" qhov="" sib="" txawv="" tseem="" ceeb="" ntawm="" ar="" vs.="" bl="" thiab="" ar="" vs.="" ruaj="" khov="" khub="" sib="" piv="" (daim="" duab="" 2b).="" qhov="" no="" qhia="" txog="" kev="" sib="" raug="" zoo="" ntawm="" tcrm="" cov="" qhab="" nia="" nrog="" banff-qib="">

Thaum ua haujlwm tsis muaj kev saib xyuas hierarchical pawg ntawm tCRM cov noob, peb pom muaj qhov sib koom ua ke los ntawm kev kuaj mob pathologic (Daim duab 2C). Thaum kuaj xyuas txhua qhov nqaij ntuag ze ze, txawm tias qhov sib koom ua ke los ntawm kev kuaj mob qhia tau tias muaj kev sib txawv hauv cov pab pawg, cov qhab nia tCRM sib raug (xws li xim gradient) feem ntau cuam tshuam nrog kev kuaj mob. Peb pom cov qhab nia siab dua nrog kev kuaj mob uas cuam tshuam txog qib ntawm kev mob ntau dua, qhia txog lub peev xwm ntawm tCRM kom tsis txhob muaj kev ntxub ntxaug thiab ua kom muaj txiaj ntsig ntawm qhov mob hauv allograft yam tsis muaj kev tsis ncaj ncees. Thaum peb siv peb tCRM txiav tawm ntawm 2.2 (molecular kuaj mob ntawm qhov mob), peb pom muaj zog pawg los ntawm kev kuaj mob molecular. Txawm li cas los xij, feem ntau ntawm AR thiab BL pawg ua ke nrog cov noob caj noob ces thiab cov qhab nia siab tCRM, nrog rau qhov tsis sib xws rau feem ntau ntawm cov kab mob histologically-qib ruaj khov.

Tissue Common Rejection Module Kev ntxub ntxaug ntawm hom tshwj xeeb ntawm Graft Rejection

Tom qab ntawd peb saib lub peev xwm ntawm tCRM cov qhab nia kom paub qhov txawv ntawm ntau hom kev tsis lees paub: C4d-positive (n=9) thiab tsis zoo ABMR (n=4), TCMR (n=3) , BL (n=21), thiab ruaj khov (n=40) biopsies. Qhov nruab nrab tCRM cov qhab nia thiab IQR rau C4d zoo ABMR, C4d-negative ABMR, TCMR, BL, thiab kev kuaj mob ruaj khov yog 4.22 (IQR: 3.80-5.98), 3.47 (IQR: 1.71–6.51), 2. {23}} (IQR: 2.58–3.05), 1.91 (IQR: 1.32–2.88), thiab 1.37 (IQR: 0.99–2.00), feem. Tsis tas li ntawd, muaj qhov sib txawv tseem ceeb ntawm txhua pawg histologic (p < 0.001),="" nrog="" rau="" qhov="" sib="" txawv="" tseem="" ceeb="" ntawm="" kev="" sib="" piv="" sib="" piv="" saib="" c4d-positive="" abmr="" vs.="" tcmr,="" c4d-positive="" abmr="" vs.="" bl,="" c4d-positive="" abmr="" vs.="" ,="" tcmr="" vs.="" ruaj="" khov,="" thiab="" bl="" vs.="" cov="" pab="" pawg="" ruaj="" khov="" (daim="" duab="" 3a).="" qhov="" no="" ib="" zaug="" ntxiv="" qhia="" txog="" kev="" sib="" raug="" zoo="" ntawm="" tcrm="" cov="" qhab="" nia="" nrog="" rau="" banff-qib="" pathology="" tshwj="">

Thaum ua haujlwm tsis muaj kev saib xyuas hierarchical pawg ntawm tCRM cov noob, peb pom cov qauv zoo sib xws ntawm kev sib koom ua ke raws li kev mob qog noj ntshav raws li tau piav qhia dhau los (Daim duab 3B). Nrog rau ntau qhov kev kuaj mob tshwj xeeb ntawm C4d-zoo thiab tsis zoo ABMR thiab TCMR, peb pom qhov tseem ceeb tshaj plaws homogenous pawg ntawm ABMR pawg. Raws li yav dhau los, thaum kuaj xyuas txhua qhov kev kuaj mob kom zoo, txawm tias qhov kev sib koom ua ke los ntawm kev kuaj pom muaj qhov sib txawv hauv pawg pawg, cov qhab nia tCRM sib raug (xws li xim xim gradient) feem ntau cuam tshuam nrog kev kuaj mob. Peb pom cov qhab nia siab dua nrog kev kuaj mob uas cuam tshuam txog qib ntawm kev mob ntau dua, qhia txog lub peev xwm ntawm tCRM kom tsis txhob muaj kev ntxub ntxaug thiab ua kom muaj txiaj ntsig ntawm qhov mob hauv allograft yam tsis muaj kev tsis ncaj ncees. Thaum kawg, thawj ceg ntawm peb pawg tsis muaj kev saib xyuas muaj feem ntau ntawm cov qauv uas muaj ib qho kev mob qog noj ntshav, tshwj xeeb tshaj yog cov mob ABMR, TCMR, lossis BL (Daim duab 3B).

Tissue Common Rejection Module Discriminates los ntawm Pathologist Daim Ntawv Pom Zoo / Kev Tsis Pom Zoo

Peb tom qab ntawd saib cov qhab nia tCRM rau kev pom zoo thiab kev tsis pom zoo ntawm cov kws kho mob, uas tau txhais raws li tau piav qhia dhau los. Ntawm 77 tom qab hloov pauv biopsies uas tau nyeem los ntawm ob tus kws kho mob, ob leeg tau hais tias muaj mob hauv 33.8 feem pua, tsis muaj qhov mob hauv 22.1 feem pua, thiab tsis pom zoo thaum muaj qhov mob hauv 44.2 feem pua ​​​​ntawm cov qauv. Thaum kuaj xyuas cov qhab nia tCRM, peb tau sau tseg cov qhab nia nce ntxiv raws li qhov kev pom zoo sib txawv tau nce los ntawm tsis muaj qhov mob, tsis pom zoo, thiab kev pom zoo thaum muaj qhov mob (Daim duab 4A). Muaj qhov sib txawv tseem ceeb hauv tCRM cov qhab nia nruab nrab ntawm cov kws kho mob ob qho tib si pom qhov mob vs. kev tsis pom zoo (p=0.003), thiab ob qho tib si nrhiav qhov mob vs. ob qho tib si nrhiav tsis muaj mob (p <0.001 ),="" nrog="" rau="" tag="" nrho="" qhov="" tseem="" ceeb="" ntawm="" txhua="" qhov="" qhab="" nia="" (p=""><>

Thaum ua haujlwm tsis muaj kev saib xyuas hierarchical pawg ntawm tCRM cov noob, peb pom cov pawg ntawm kev kuaj ntshav biopsy raws li kev pom zoo sib txawv (Daim duab 4B). Peb tuaj yeem pom tau tias pawg ntawm cov noob caj noob siab siab sib haum rau ob tus kws kho mob pom zoo raws li qhov muaj mob, thaum qhov sib txawv, cov noob qes qis sib raug rau ob tus kws kho mob pom zoo tsis muaj qhov mob lossis tsis pom zoo ntawm lawv. Tsis tas li ntawd, peb pom tias qhov sib thooj tCRM cov qhab nia rau txhua qhov kev kuaj mob biopsy nyiam nyiam cov qhab nia siab dua thiab qis dua qhov twg cov kws kho mob pom zoo rau qhov mob lossis tsis muaj qhov mob, raws li. Txawm hais tias qhov kev sib koom ua ke tsis zoo tag nrho, qhov pom meej meej pom.

Tissue Common Rejection Module raws li tus kwv yees ntawm kev tsis lees paub thiab Graft Function saum toj no, peb qhia txog kev siv tshuaj kho mob ntawm tCRM raws li nws hais txog kev kuaj mob kom raug. Txawm hais tias nws daim ntawv thov muaj cuam tshuam txog dab tsi yog ib txwm muaj kev kuaj mob biopsy-pov thawj, peb xav tshawb tCRM kev siv hauv tus qauv rau kev kwv yees kev tsis lees paub / mob. Siv peb qhov sib txawv ntawm qhov sib txawv ntawm qhov mob (AR thiab BL biopsies), peb tau tsim cov qauv logistic regression los kwv yees qhov tshwm sim binary ntawm o ntawm biopsy. Cov kev hloov kho kho mob tau piav qhia yav dhau los (Table 3). Interestingly, tsuas yog ib qho tseem ceeb kwv yees ntawm qhov mob raws li kev kuaj mob los ntawm pathology yog tCRM tus qhab nia (los yog: 1.90, 95 feem pua ​​​​CI: 1.40–2.68, p < 0.{{16="" }}01),="" thaum="" muaj="" ib="" tug="" txiv="" neej="" pub="" dawb="" rau="" tus="" poj="" niam="" tau="" txais="" kev="" tiv="" thaiv="" nrog="" ciam="" teb="" tseem="" ceeb="" (los="" yog:="" 0.27,="" 95="" feem="" pua="" ​​​​ci:="" 0.07–0.98,="" p="">

Peb mam li saib lub peev xwm ntawm tCRM los kwv yees kev hloov mus sij hawm ntev hauv GFR. Peb tau txheeb xyuas qhov delta GFR (los ntawm GFR thaum lub sijhawm kuaj ntshav mus rau qhov kawg GFR) mus rau tus neeg mob tus qhab nia tCRM los ntawm qhov kev kuaj mob biopsy (Pearson correlation coefficient=0.21, p=0.{{6} }25). Peb mam li rov hais dua qhov no tom qab tsis suav nrog tCRM cov qhab nia tsawg dua 2, yog li ntawd peb tsuas yog saib ntawm qhov siab tshaj plaws tCRM qhov tseem ceeb kom pom cov txiaj ntsig ntawm delta GFR, uas ua rau muaj kev sib raug zoo rau 0.32 (p=0). 05). Peb kuj tau saib qhov kev sib raug zoo ntawm txhua tus neeg mob siab tshaj DSA qib nrog lawv cov qhab nia tCRM (Cov duab ntxiv 1), saib seb puas muaj kev sib koom ua ke ntawm DSA qib thiab tCRM cov qhab nia, uas peb tsis pom muaj kev cuam tshuam (Pearson correlation coefficient { {11}}, p=0.99).

Thaum kawg, peb tau saib cov neeg mob uas muaj serial biopsies thiab tCRM cov qhab nia. Serial tCRM cov qhab nia tau npaj rau ib tus neeg mob los ntawm hnub tom qab hloov pauv (Daim duab 4C). Muaj plaub tus neeg mob uas tau kuaj pom thawj zaug ntawm AR thiab tau kho, tom qab ntawd ua raws li kev kuaj ntshav tom qab (Daim duab 4C, kab liab). Peb tau sau tseg tias tag nrho plaub tus neeg mob thawj zaug tau nce qib tCRM, thiab tom qab kev kho mob tau txo qis hauv lawv cov qhab nia, tsuas yog ib tus neeg mob tau kuaj pom AR ntawm qhov thib ob biopsy. Ntawm cov ntawv ceeb toom, ob tus neeg mob uas tau nce tCRM cov qhab nia uas tau nyeem los ntawm tus kws kho mob raws li kev kuaj mob ruaj khov tau tsim muaj kev nce hauv lawv cov qhab nia tCRM thiab kev kuaj mob tshiab ntawm AR ntawm lawv cov kev soj ntsuam kuaj mob (Daim duab 4C, kab xiav).

cistanche tubulosa extract:txhim kho lub raum ua haujlwm

Kev sib tham

Peb xav tias qhov qhab nia tCRM tuaj yeem siv los ua cov ntaub ntawv taw qhia los pab hauv kev kuaj mob biopsy, thiab tejzaum nws yog lub hom phiaj tiebreaker thaum muaj kev tsis sib haum xeeb ntawm cov kws kho mob. Saum toj no peb qhia tau hais tias tus qhab nia tCRM tuaj yeem sib cais ntawm kev kuaj mob. tCRM muaj peev xwm cais tawm ntawm kev sib xyaw ua ke AR vs. BL vs. cov qauv ruaj khov thiab tseem tuaj yeem sib cais ntawm ntau qhov tshwj xeeb AR kev kuaj mob xws li ABMR vs. TCMR thiab ABMR vs. BL, raws li peb tau pom saum toj no. Ib qho kev paub tsis zoo ntawm kev sib koom ua ke / lub hom phiaj xwm txheej ntawm Banff cov txheej txheem yog qhov tsis sib xws tuaj yeem tshwm sim ntawm cov kws kho mob saib ntawm cov qauv biopsy zoo ib yam. Peb tau ua pov thawj saum toj no tias kev tsis pom zoo ntawm cov kws kho mob txog kev mob plab hauv lub raum biopsies yog qhov tshwm sim. Peb qhia tau hais tias thaum muaj kev pom zoo ntawm cov kws kho mob ntawm qhov muaj lossis tsis muaj qhov mob, qhov no yuav ua rau qhov siab tshaj ntawm tCRM. Ib feem ntawm cov nqi hluav taws xob hauv tCRM tus qhab nia tuaj yeem nyob ntawm no, hauv nws lub peev xwm los muab lub hom phiaj kev ntsuas ntawm qhov mob, tab sis kuj tseem ua haujlwm raws li kev sib khi hauv cov xwm txheej uas qhov kev kuaj mob tsis meej, tab sis cov qhab nia tCRM kom meej meej taw qhia ib txoj kev lossis lwm qhov. Piv txwv li, tus kws kho mob nyeem cov kab mob biopsy uas tsis paub meej tias nws yog AR lossis BL, tab sis nrog cov qhab nia tCRM siab heev, tuaj yeem ua tau ntau lub hom phiaj thiab qhov tseeb txog kev kuaj mob ntawm AR.

Tsis tas li ntawd, txoj kev tshawb no qhia tau hais tias tus qhab nia tCRM yuav raug siv los kwv yees cov txiaj ntsig kev kho mob ntev ntev. Txawm hais tias qhov kev sib raug zoo ntawm kev hloov pauv hauv GFR thiab siab dua tCRM cov qhab nia tsis muaj zog, peb tau pom qhov kev sib raug zoo ntawm lawv, nrog rau kev sib raug zoo dua thaum peb lim rau tCRM cov qhab nia siab dua 2, qhia tias cov qhab nia siab dua qhia txog qib siab dua ntawm allograft. kev raug mob uas tuaj yeem kwv yees txo qis kev ua haujlwm ntev ntev (ntau dua delta GFR). Qhov zoo siab, peb tsis pom qhov sib txheeb ntawm cov neeg mob DSA qib thiab tCRM cov qhab nia. Qhov no tej zaum yuav yog vim qhov tseeb tias ntau tus neeg mob nrog DSAs tsis tas yuav mus tsim ABMR, nrog rau kev paub tias DSAs sib txawv tuaj yeem cuam tshuam qhov kev pheej hmoo sib txawv ntawm kev tsim ABMR. Tsis tas li ntawd, los ntawm kev taug qab cov neeg mob nrog serial biopsies thiab tCRM cov qhab nia, peb tau pom tias feem ntau ntawm cov neeg mob uas tau nce tCRM cov qhab nia thiab AR muaj qhov txo qis hauv lawv cov qhab nia, nrog rau kev txhim kho cov kab mob qog nqaij hlav tom qab biopsies (tom qab histology mus los ntawm AR kom ruaj khov. ). Qhov tseem ceeb, muaj 2 qhov xwm txheej uas cov qhab nia tCRM tau nce siab, tab sis qhov kev kuaj mob pathologic tau ruaj khov ntawm biopsy. Ob qho xwm txheej no tau ua rau muaj qhov nce ntxiv tCRM tus qhab nia ntawm qhov kev kuaj ntshav tom qab, nrog rau kev kuaj mob sib xws ntawm AR. Qhov no qhia tau hais tias muaj peev xwm ntawm kev kuaj mob tsis zoo vim yog qhov xwm txheej ntawm kev faib tawm histologic, lossis hais tias qhov kev nthuav qhia siab ntawm tCRM noob uas cuam tshuam nrog kev mob qog noj ntshav, tuaj yeem ua rau pom qhov tseeb pathologic uas yuav ua rau muaj kev kuaj mob ntawm AR. Txawm li cas los xij, qhov no qhia txog kev siv hluav taws xob ntau lub hom phiaj tCRM tus qhab nia hauv kev pab ua qhov kev kuaj mob ntawm AR.

Molecular kom muaj nuj nqis ntawm tag nrho cov kab mob inflammatory hauv lub raum allograft yog ib qho tseem ceeb los tsim kom muaj thaum lub sij hawm muaj kev cuam tshuam biopsy (5, 6, 9). Peb txoj kev pab txhawb kev siv cov qauv biopsy uas twb muaj lawm kom ua tau zoo (tag nrho cov sij hawm sim yog 4-6 teev rau qhov kev ntsuam xyuas pom). Thaum cov kev ntsuam xyuas tsis zoo, xws li pub dawb los ntawm cov cell-dawb DNA (dd-cfDNA), tab tom npaj rau kev kuaj mob thaum ntxov ntawm AR (19-23), ib qho tsis zoo ntawm cov kev ntsuam xyuas no yog tias lawv tsis nug ncaj qha rau lub hom phiaj ntawm cov ntaub so ntswg. kev txaus siab, txawm tias dd-cfDNA raug tso tawm los ntawm allograft. Nrog tCRM, cov ntaub so ntswg biopsy uas twb tau txais tuaj yeem ua tiav siv cov ntaub so ntswg tsawg los ntawm cov ntaub so ntswg tshiab lossis cov ntaub ntawv FFPE archived, khaws cia feem ntau ntawm niam txiv FFPE thaiv rau kev tshuaj ntsuam histologic ntxiv.

Peb txoj kev tshawb fawb yog ib feem txwv los ntawm qhov cuam tshuam ntawm tCRM. Biopsies tseem yog tus qauv kub thiab feem ntau tau txais, tso cai rau molecular profiling nrog tCRM, tab sis thaum kawg, kev hloov pauv mus rau qhov tsis muaj kev cuam tshuam ntawm cov ntshav lossis zis yuav yog qhov zoo tshaj plaws rau cov neeg mob. Peb lub chaw kuaj mob tam sim no ua haujlwm ntawm kev siv CRM genes hauv cov zis los pab rau kev kuaj mob ntawm graft rejection (14). Tsis tas li ntawd, thaum txoj kev tshawb no yog qhov kev sim yav tom ntej, daim ntawv thov ntawm tCRM tsis yog siv rau kev txiav txim siab kho mob thiab yog qhov kev tshawb nrhiav kev tshawb nrhiav. Peb txoj haujlwm yav tom ntej yuav tau txais txiaj ntsig los ntawm kev txiav txim siab tus qhab nia tCRM raws li qhov ua tau qhov kawg, lossis qhov ua tau zoo hauv cov qhab nia thaum txiav txim siab txog qhov kawg ntawm kev kuaj mob rau cov qog nqaij hlav. Tsis tas li ntawd, thaum peb cov qauv kev tshawb fawb suav nrog TCMR kev kuaj mob, feem ntau ntawm peb cov qauv muaj rau kev tshuaj xyuas yog cov qauv ABMR. Thaum peb pom tias qhov qhab nia tCRM tau nce siab tsis hais hom AR tam sim no, kev ua haujlwm yav tom ntej yuav tsum tau siv ntau tus qauv hauv txhua pawg ntawm AR hom tshwj xeeb.

Peb tau pom tias qhov qhab nia tCRM muaj peev xwm sib cais ntawm cov kab mob pathologic, siv cov qauv FFPE uas twb muaj lawm. Qhov tseem ceeb, kev hloov pauv muaj nyob ntawm cov kws kho mob sib txawv, uas tau pom nyob rau hauv peb cov ntaub ntawv raws li ob tus kws kho mob dig muag ua kev kuaj mob. Yog li ntawd, peb pom tau hais tias tsis yog tsuas yog tuaj yeem pab tCRM hauv kev kuaj mob pathologic tab sis tshwj xeeb tshaj yog thaum muaj kev tsis pom zoo lossis tsis paub tseeb, qhov qhab nia yuav raug siv kom ncav cuag qhov kawg, muaj zog dua qhov xaus.

cistanche tubulosa txiaj ntsig: kho cov kab mob raum

DATA AVAILABILITY STATEMENT

Cov ntaub ntawv nyoos txhawb cov lus xaus ntawm tsab xov xwm no yuav muab los ntawm cov kws sau ntawv, yam tsis muaj kev tshwj tseg.

ETHIC STATEMENT

Cov kev tshawb fawb uas koom nrog tib neeg tau raug tshuaj xyuas thiab pom zoo los ntawm UCSF IRB. Cov neeg mob/cov neeg tuaj koom tau muab lawv daim ntawv tso cai tso cai los koom rau hauv txoj kev tshawb no.

AUTHOR CONTRIBUTIONS

AZ tau pab txhawb rau kev tsim qauv, kev txheeb xyuas cov ntaub ntawv, kev txhais lus, sau ntawv sau, thiab sau cov ntawv sau. JG tau pab txhawb rau txoj kev kawm tsim, sau cov ntaub ntawv, thiab sau ntawv sau. TS tau pab txhawb rau kev txheeb xyuas cov ntaub ntawv thiab sau ntawv kho. ID pab txhawb rau kev ua qauv. RS, thiab GS pab txhawb rau kev ua qauv. CC pab txhawb rau kev ua qauv thiab tshuaj xyuas. JF, XC, CSR, LM, thiab CR pab txhawb rau cov qauv thiab cov ntaub ntawv sau. MV tau pab txhawb rau cov neeg mob rau npe thiab hloov pauv. LB pab txhawb rau tus neeg mob rau npe. JA tau pab txhawb rau txoj kev tshawb fawb tsim, sau cov ntaub ntawv, thiab kev tshuaj xyuas cov ntawv sau. MS tau pab txhawb rau kev kawm tsim, sau cov ntaub ntawv, kev tshuaj ntsuam xyuas, thiab kev tshuaj xyuas cov ntawv sau. Txhua tus kws sau ntawv tau pab txhawb rau tsab xov xwm thiab pom zoo rau cov ntawv xa tawm.

txhim kho lub raum ua haujlwm cistanche tubulosa

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