Biomarker Research最新文献

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease that often affects the kidneys, causing lupus nephritis. Diagnosis of this affection currently relies on kidney biopsy, an invasive and complex procedure. This study explores the diagnostic value of biomarkers based in the urobiome - the microbial community of the urinary tract - in patients with renal SLE.

Methods: This study enrolled 585 female subjects including Healthy controls, non-renal and renal SLE patients. The taxonomic and functional differences of the urobiome in patients with SLE, as well as in the metabolites of interest, were identified by 16S rRNA profiling with PICRUSt functional inference and nuclear magnetic resonance (NMR). The accuracy of the identified biomarkers was tested by building random forest (RF) classification models. Furthermore, the results were validated in an independent cohort composed by 30 controls, 30 non-renal and 30 renal SLE patients.

Results: Bacterial gene-based biomarkers with an AUC value of 0.7 ± 0.07 and 0.67 ± 0.07 to distinguish renal from non-renal SLE cases were identified. These biomarkers were validated in a validation cohort using quantitative PCR (qPCR), demonstrating their robust diagnostic performance. Furthermore, our analysis uncovered significant urobiome dysbiosis and distinct bacterial functional profile in both groups of SLE patients, with notable differences in amino acid metabolism pathways, particularly those involving valine and leucine, which were assessed by NMR-based urinary metabolite quantification.

Conclusions: Some bacterial genes have been identified in the urobiome of SLE patients that allow differentiation between those with renal and non-renal lupus. These findings offer valuable insight into the association between the urobiome and SLE presentation, and lay the foundation for developing novel diagnostic tools that overcome the limitations of current methods, thereby improving patient care.

The standard of care for the follow-up of kidney allograft recipients combines non-invasive but non-specific biomarkers and kidney biopsies for the gold standard histology-based diagnosis, limited by the sampling bias, haemorrhagic risk, and low cost-effectiveness. We hypothesized that a targeted epigenetic analysis of cell-free DNA (cfDNA) would combine non-invasiveness and specificity for the diagnosis of kidney allograft rejection. We developed an in silico pipeline to identify 9 specific methylation signatures of epithelial or endothelial cell types in glomerular and tubular kidney compartments. Methylation-specific digital Polymerase Chain Reaction (dPCR) were designed and validated for these markers and combined in a 10-plex dPCR. In a retrospective cohort of 170 plasma cfDNA from adult kidney transplant recipients, we evaluated the diagnostic properties of our biomarkers for predicting rejection, evaluated on solid biopsy according to Banff 2022 classification. Combining the dedicated biomarkers with standard-of-care blood tests (donor-specific antibody (DSA), estimated glomerular filtration rate (eGFR)) produced a prediction model with an Area under the Curve (AUC) for biopsy-proven kidney transplant rejection vs. no rejection greater than with DSA and eGFR alone (AUC = of 0.884 vs. 0.776, p = 0.0005). In an alternative model for the prediction of any graft lesion of Banff classification vs. pristine biopsies (all Banff score = 0) epigenetic kidney biomarkers outperformed DSA (AUC = 0.754 vs. 0.596, p = 0.004). Thus, epigenetic signatures derived from the combination of kidney cell type specific methylation marker of cfDNA constitute a promising non-invasive diagnostic and theragnostic tool for kidney transplant patients.

A subset of patients still develops hepatocellular carcinoma (HCC) even after eradication of the hepatitis-C virus (HCV) by anti-HCV treatment. We conducted a genome-wide association study (GWAS) to identify host genetic factors associated with HCC development following HCV eradication in Japan. In this GWAS (n = 517), the discovery cohort included 118 patients without HCC and 67 who developed HCC following HCV eradication with interferon-based therapy. A genome-wide scan for HCC-associated variants was conducted. An independent cohort of 274 patients without HCC and 58 patients with post-eradication HCC was used for replication. The effects of candidate gene variants were assessed clinically and through in vitro cellular assays. The GWAS identified significant variants associated with HCC development following HCV eradication, including rs4778350, located near the long non-coding RNA Prader-Willi non-protein coding RNA 4 (PWRN4) on chromosome 15. In the combined analysis, rs4778350 remained significantly associated with HCC, showing a high odds ratio of 5.86 (95% CI, 3.63-9.44). The frequency of the A allele in rs4778350 differs across ethnic populations. Multivariate analysis revealed that female sex, high platelet count, and higher serum albumin levels were associated with reduced HCC risk, while fibrosis stage F4 and the AA genotype of rs4778350 were linked to increased risk. The AA genotype of rs4778350 enhanced PWRN4 expression, promoting cell proliferation, migration, and invasion. These findings suggest a role for PWRN4 in hepatocarcinogenesis through its association with rs4778350 in patients achieving HCV eradication.

The evolution of targeted protein degradation (TPD) has been significantly propelled by the advent of proteolysis-targeting chimeras (PROTACs), which utilize heterobifunctional molecules to facilitate the ubiquitination-mediated degradation of previously "undruggable" proteins. Mouse double minute 2 (MDM2), which is often overexpressed in various diseases and plays a crucial role in regulating key pathways like p53, emerges as an exemplary candidate for therapeutic exploitation within the TPD realm, serving both as an intrinsic E3 ligase and as a direct protein of interest (POI). By harnessing MDM2's inherent E3 ligase activity, PROTACs have been designed to efficiently degrade specific POIs, achieving substantial success in both in vitro and in vivo studies. Alternatively, PROTACs have been developed to directly target MDM2 itself, offering new approaches for therapeutic intervention. Recent research has yielded valuable strategies for optimizing MDM2-harnessing and MDM2-targeted PROTAC designs, concentrating on warhead selection of POI, linker length and composition optimization, and the choice among various E3 ligases and their corresponding recruiters. These advancements not only broaden the scope of PROTAC technologies but also expedite the development of MDM2-based therapies, inspiring approaches for disease treatment.

Complex crosstalk occurs between protein and nucleic acid modifications, with lactylation, an emerging post-translational modification (PTM), being implicated in tumor progression. However, the mechanisms mediating the crosstalk between lactylation and RNA modifications and their roles in disease pathogenesis remain largely unresolved. In this review, we summarize current advances in the regulatory interactions between lactylation and RNA modifications, explore their functional implications in cancer biology, and discuss the therapeutic potential of targeting these modifications individually or in combination. This work aims to provide a comprehensive overview of their mechanistic involvement in cancer and to inform novel strategies for precision-targeted therapy.

The androgen receptor signaling inhibitor enzalutamide (Enz) is one the primary therapeutic drugs for advanced prostate cancer (PCa). Nevertheless, most of patients ultimately develop resistance to Enz. Through an integrated analysis of CRISPR genome-wide and kinome-wide screens, coupled with observations of elevated expression levels in Enz-resistant cell lines and PCa tumor tissues, our study identified RPS6KC1 as a novel essential gene implicated in Enz resistance. Mechanistically, our research indicates that the Warburg effect induces H3K18 lactylation, which regulates the expression of RPS6KC1 via the transcription factor P65. Elevated expression of RPS6KC1 was found to recruit PRDX3 to the mitochondria, thereby mitigating ferroptosis. These findings suggest that the H3K18la/NF-κB/RPS6KC1/PRDX3 axis is important for the development of resistance to Enz. Our results suggest that the combination of Enz with targeted RPS6KC1 inhibition or a ferroptosis inducer may represent a promising therapeutic strategy to overcome Enz resistance.

Background: There is no established standard treatment for acute myeloid leukemia (AML) patients with FLT3 wild-type relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Multi-kinase inhibitor sorafenib has been widely explored in the treatment of AML patients with FLT3 internal tandem duplication (FLT3-ITD) mutations. Some studies have revealed that the addition of sorafenib to standard chemotherapy could improve outcomes in newly diagnosed AML regardless of FLT3 status. However, the application of sorafenib in FLT3 wild-type AML patients experiencing relapse after allo-HSCT remains minimally investigated.

Methods: We retrospectively compared the effects of conventional treatment combined with or without sorafenib on the outcomes of these patients. The study mainly focused on the treatment response of salvage therapy and survival.

Results: Sixty-two AML patients with FLT3 wild-type who relapsed after allo-HSCT were enrolled in this study, including 38 with sorafenib and 24 without sorafenib. Fifty patients received 68 doses of donor lymphocyte infusion (DLI). The rate of composite complete remission was 65.8% in the sorafenib group, compared with 29.2% in the non-sorafenib group (P = 0.005). With a median follow-up of 13.2 months (IQR, 3.2-43.5) after relapse, the 2-year overall survival (OS) was 47.4% (95%CI, 33.9%-66.2%) and 16.7% (6.8%-40.8%) in the sorafenib and non-sorafenib groups (P = 0.006). The 2-year event-free survival (EFS) was 44.7% (31.4%-63.7%) and 16.7% (6.8%-40.8%) in the two groups (P = 0.012). Multivariable analysis revealed that salvage therapy including sorafenib was the protective factor for longer OS and EFS (HR = 0.395, 95% CI: 0.209-0.746, P = 0.004; HR = 0.406, 95% CI: 0.218-0.754, P = 0.004). The incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were similar between the two groups (P = 0.806, P = 0.908).

Conclusion: Our results suggest that salvage therapy including sorafenib and DLI is associated with improved outcomes for AML patients with FLT3 wild-type relapsing after allo-HSCT.

Background: Coronary artery disease (CAD) remains a leading cause of mortality in developed nations. While previous genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) linked to CAD, their impact on disease progression requires trans-omics validation.

Methods: This study merges whole genome SNP analysis and metabolomic profiling to distinguish CAD patients from high-risk and healthy individuals. A cross-sectional study was conducted, enrolling participants from the Northeastern Taiwan Community Medicine Research Cohort, which spans the period between August 2013 and November 2020. A total of 781 participants were included in the study and categorized into three groups: control (n = 271), high-risk (n = 363), and CAD (n = 147) groups, following a stratification protocol. The study integrated K-clustering of metabolomics and SNP datasets. Subsequently, a machine-learning (ML)-assisted prediction model was developed specifically for CAD identification.

Results: Four significant findings emerged. Firstly, plasma levels of phospholipids decline from healthy controls to high-risk individuals and then decline further among CAD patients. This indicates that plasma phospholipids have potential as biomarkers and implies that they have a role in CAD progression. Secondly, five genes are linked to lipidomic alterations via their top-ranking among CAD-associated SNPs. Thirdly, a specific LPCAT1 haplotype is associated with CAD using a trans-omics approach. Lastly, an ML-assisted trans-omics prediction model for CAD was developed, which achieves an area under the curve of 0.917, with LPCAT1 among the 16 top-ranked predictive features.

Conclusion: This study highlights the usefulness of a multi-omics signature when discriminating CAD patients and suggests that abnormalities in phospholipid metabolism are influenced by LPCAT1 genetic variants. Our findings underscore the potential of multi-omics approaches to our understanding and identification of critical factors in CAD development.

Trial registration number and date of registration: ClinicalTrials.gov Identifier: NCT04839796; Aug 2013.