Dataset Information

Omics data integration analysis identified new biological insights into chronic antibody mediated rejection (CAMR).

ABSTRACT: INTRODUCTION: Chronic antibody-mediated rejection (CAMR) is currently the leading cause of long-term allograft loss, affecting approximately 50-60% of renal transplant recipients after a decade. Although in the last years many studies have performed to define clinical/histological characteristics and to identify the leading causes and triggers of this condition, at the moment, the complete biological machinery associated with this complex complication has been only partially defined. METHODS: We performed mass-spectrometry-based serum proteomics of 19 patients with CAMR and 26 kidney transplant recipients without any functional alteration (CTR). The results were compared with a previously obtained transcriptomic profile of peripheral blood mononuclear cells (PBMC) isolated from 10 CAMR and 8 CTR. The biological elements identified by the statistical analysis were then validated through ELISA in all patients. RESULTS: Proteomics demonstrated that 18 proteins were able to discriminate CAMR from CTR (p<0.01): five proteins resulted more abundant (CHI3L1, LYZ, PRSS2, CPQ, IGLV3-32) while 13 were less abundant (SERPINA5, SERPING1, KNG1, CAMP, VNN1, BTD, WDR1, PON3, AHNAK2, MELTF, CA1, CD44, CUL1) in CAMR compared with CTR patients. The innovative bioinformatic analysis (SVM, PLS-DA) applied to transcriptomic data revealed that 6 genes were down-regulated, and 33 genes were up-regulated in CAMR compared with CTR patients (p<0.01). Notably, only 2 biological elements resulted significantly deregulated in both omics analyses: chitinase-3-like protein 1 (CHI3L1) and plasma protease inhibitor C1 (SERPING1). CHI3L1 was up-regulated in CAMR in both transcriptomics and proteomics, while SERPING1 was up-regulated in CAMR in transcriptomics, but down-regulated in proteomics. ELISA validated the omics data and ROC curve indicated that CHI3L1 had good discrimination power between CAMR and CTR. CONCLUSIONS: The results of the multi-omics analysis confirmed the evident systemic immunological perturbation of patients with CAMR and identified CHI3L1 as a new potential biomarker and therapeutic target for this important clinical complication.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

SUBMITTER: Martina Bartolucci

LAB HEAD: Andrea Petretto

PROVIDER: PXD057746 | Pride | 2025-05-07

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	20241111_124906_Zaza_CT_DSA_DirectDIA_plus.sne	Other
	Bruschi_1222_10_KN68114_CT_DSA_78.raw	Raw
	Bruschi_1222_11_TMG44115_CT_DSA_79.raw	Raw
	Bruschi_1222_12_FS56115_CT_DSA_80.raw	Raw
	Bruschi_1222_13_AA45115_CT_DSA_81.raw	Raw

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Omics data integration analysis identified new biological insights into chronic antibody-mediated rejection (CAMR).

Bruschi Maurizio M Granata Simona S Leone Francesca F Barberio Laura L Candiano Giovanni G Pontrelli Paola P Petretto Andrea A Bartolucci Martina M Spinelli Sonia S Gesualdo Loreto L Zaza Gianluigi G

Journal of translational medicine 20250220 1

<h4>Background</h4>In the last two decades, many studies based on omics technologies have contributed to defining the clinical, immunological, and histological fingerprints of chronic antibody-mediated rejection (CAMR), the leading cause of long-term kidney allograft failure. However, the full biological machinery underlying CAMR has only been partially defined, likely due to the fact thatsingle-omics technologies capture only specific aspects of the biological system and fail to provide a compr ...[more]

PMID: 39979925

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Project description:Background: Liver transplantation (LT) for Hepatocellular carcinoma (HCC) can be offered to patients beyond Milan criteria. However, there are currently no molecular markers that can be used on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to identify proteins on HCC explant predictive of recurrence post-transplant, thereby guiding surveillance strategies and identifying patients beyond Milan criteria who would fare well following LT. Methods: LT recipients who had been transplanted at the University Health Network for HCC beyond Milan criteria in the context of Hepatitis B cirrhosis were identified. Snap-frozen samples from the dominant tumors of recurrent (N=7) and non-recurrent (N=4) patients were analyzed using LC-MS/MS on a Q-Exactive Plus mass spectrometer to delineate a distinctive proteomic signature. These tumors were also profiled by a Human Gene 2.0 ST microarray platform to identify a transcriptomic signature predictive of recurrence and analyzed with R packages. STRING database was used to characterize the implicated pathways. Kaplan-Meier estimator was used to generate a combined proteomic/transcriptomic signature predictive of HCC recurrence in patients with HCC beyond Milan criteria at time of LT. Significantly predictive proteins were verified and internally validated by immunoblotting or immunohistochemistry. Results: A total of 79 proteins and 636 genes were significantly differentially expressed in recurrent HCC, compared to non-recurrent (p<0.05). Among these, LGALS3, LGALS3BP, HAL, THBS1, and BLMH, were significantly increased in recurrent HCC at the protein and gene expression level. In turn, ALDH1A1 protein and gene expression were significantly decreased in recurrent HCC. Univariate survival analysis depicted ALDH1A1 (HR=0.084, 95%CI 0.01-0.68, p=0.02), LGALS3BP (HR=7.14, 95%CI 1.20-42.96, p=0.03), and LGALS3 (HR=2.89, 95%CI 1.01-8.3, p=0.049) as the key dysregulated proteins and genes in the patients with HCC recurrence versus those with non-recurrence by both proteomic and transcriptomic analysis. Decreased ALDH1A1 and significantly increased LGALS3 protein expression in recurrent HCC was verified by immunoblotting. Increased LGALS3BP protein expression in recurrent HCC was orthogonally verified and validated by immunohistochemistry in 30 independent HCC samples. Conclusion: Protein and gene expression of the cancer stem cell marker ALDH1A1 was protective against cancer recurrence in patients transplanted for HCC beyond Milan criteria. Conversely, increased expression of LGALS3 and LGALS3BP on explant was significantly predictive of post-transplant recurrence. These findings were internally validated, suggesting potential utility in identifying patients with HCC beyond Milan who would clearly benefit from transplant with limited recurrence risk and guiding post-transplant surveillance.

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