Urine Measurements of the Renin-Angiotensin System-Regulated Proteins Predict Death and Graft Loss in Kidney Transplant Recipients Enrolled in a Ramipril versus Placebo Randomized Controlled TrialFarkona, Kotlyar, Burns
et alJ Proteome Res (2025)
Abstract: The renin-angiotensin system (RAS) is involved in kidney fibrosis. We previously identified six RAS-regulated proteins (RHOB, BST1, LYPA1, GLNA, TSP1, and LAMB2) that were increased in the urine of patients with kidney allograft fibrosis, compared to patients without fibrosis. We hypothesized that these urinary RAS-regulated proteins predicted primary outcomes in kidney transplant recipients enrolled in the largest RAS inhibitor randomized controlled trial. Urine excretion of 10 peptides corresponding to the six RAS-regulated proteins was quantified using parallel reaction monitoring mass spectrometry assays (normalized by urine creatinine) in a subset of patients in the trial. Machine learning models predicting outcomes based on urine peptide excretion rates were developed and evaluated. Urine samples (n = 111) from 56 patients were collected at 0, 6, 12, and 24 months. Twenty-four primary outcomes (doubling of serum creatinine, graft loss, or death) occurred in 17 patients. Logistic regression utilizing eight peptides of TSP1, BST1, LAMB2, LYPA1, and RHOB, from the last urine sample prior to outcomes, predicted a graft loss with an AUC of 0.78 (p = 0.00001). A random forest classifier utilizing BST1 and LYPA1 peptides predicted death with an AUC of 0.80 (p = 0.0016). Urine measurements of RAS-regulated proteins may predict outcomes in kidney transplant recipients, although further prospective studies are required.
Finding Potential Drug Targets for Pre-Eclampsia Using Mendelian Randomisation and Colocalisation AnalysisXu, Pan, Wu
et alAm J Reprod Immunol (2025) 93 (3), e70063
Abstract: Pre-eclampsia (PE) is a common complication of pregnancy and there is an urgent need for new drug targets. We performed whole proteome-wide Mendelian randomisation (MR) and colocalisation analyses to identify potential therapeutic targets for PE.A two-sample MR study was conducted using summary-level statistics of 734 plasma proteins retrieved from large genome-proteome-wide association studies. The summary statistics of PE or eclampsia were obtained from the FinnGen consortium. Wald ratio and Inverse variance weighted (IVW) were used to assess the causal association between proteins and PE. Colocalisation analyses were conducted to examine whether the identified proteins and PE shared incidental variants.Genetically predicted circulating levels of 42 proteins were associated with PE risk after Benjamini-Hochberg correction. Nineteen of the gene-predicted proteins showed evidence of increased PE risk (CRELD1, CPA4, AHSG, NFASC, QDPR, NTM, PZP, FAM171B, RTN4R, FLRT2, ADH4, ADM, SPINK5, LGALS4, CKM, SPON2, UROS, CXCL10 and APOBEC3G); 23 proteins reduced the risk of PE (CLIC5, NEO1, SWAP70, KLK8, VWA2, FSTL1, CXCL11, APOB, NPPB, CNTN4, IL12B, ACHE, TCN1, GFRA2, GNMT, HPGDS, DPT, MANBA, SPARCL1, ACE, FUT8, BST1 and ACP1). Bayesian colocalisation indicated that six proteins (VWA2, ACHE, CXCL10, PZP, AHSG and UROS) and PE, which were identified as high evidence of colocalisation with PE.This study provides evidence of the causal association between genetically predicted 42 proteins associated with PE risk, which might be promising drug targets for PE.© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Anti-PD1 based precision induction therapy in unresectable stage III non-small cell lung cancer: a phase II umbrella clinical trialYi, Bian, Wang
et alNat Commun (2025) 16 (1), 1932
Abstract: The efficacy and safety of induction-immunotherapy followed by surgery for unresectable Stage III non-small cell lung cancer (NSCLC) remain challenging. In this open-label, single-center, phase II clinical umbrella trial (ChiCTR2000035367), 100 unresectable Stage III NSCLC patients are enrolled. Patients with PD-L1 expression ≥ 50% but contraindications to anti-angiogenic therapy receive immuno-monotherapy. Patients with PD-L1 expression ≥ 1% and no contraindications to anti-angiogenic therapy receive immunotherapy plus anti-angiogenesis therapy. Patients with PD-L1 expression between 1% and 49%, contraindications to anti-angiogenic therapy, or negative/unknown PD-L1 expression receive chemoimmunotherapy. The primary endpoint is the major pathological response (MPR) rate. Among 47 surgically-treated patients, the MPR rate is 61.7% (95% confidence interval [CI]: 46.4%-75.5%), achieving the prespecified endpoint. For secondary endpoints, the objective response rate for all patients is 54.0% (95% CI: 43.7-64.0). The median event-free survival is 29.9 months (95% CI: 17.0-42.7). Most common adverse event is anemia (49.0%). Exploratory transcriptomic analyses reveal Bone Marrow Stromal Cell Antigen 1 (BST1) as a promising biomarker for response to chemoimmunotherapy. Generally, for unresectable stage III NSCLC patients, anti-PD1 based induction-therapy according to PD-L1 expression and contraindication to antiangiogenic therapy followed by surgery is a feasible option.© 2025. The Author(s).
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