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PubMed2004

Quantitative determination of expression of the prostate cancer protein alpha-methylacyl-CoA racemase using automated quantitative analysis (AQUA): a novel paradigm for automated and continuous biomarker measurements.

Despite years of discovery and attempts at validation, few molecular biomarkers achieve acceptance in the clinical setting. Tissue-based markers evaluated by immunohistochemistry suffer from a high degree of inter- and intraobserver variability. One recent advance in this field that promises to automate this process is the development of AQUA, a molecular-based method of quantitative assessment of protein expression. This system integrates a set of algorithms that allows for the rapid, automated, continuous, and quantitative analysis of tissue samples, including the separation of tumor from stromal elements and the subcellular localization of signals. This study uses the AQUA system to assess a recently described prostate cancer biomarker, alpha-methylacyl-CoA-racemase (AMACR), and to determine the effectiveness of the quantitative measurement of this marker as a means for making the diagnosis of prostate cancer. Using a prostate cancer progression tissue microarray containing a wide range of prostate tissues, AQUA was directly compared to standard immunohistochemical evaluation for AMACR protein expression using the p504s monoclonal antibody. Both methods produced similar results showing AMACR protein expression to be strongest in the clinically localized prostate cancer, followed by the metastatic tumor samples. Benign prostate tissue was categorized as negative for most tissue samples by immunohistochemistry. However, AMACR was detectable using the AQUA system at low levels using the standard 1:25 dilution but also at 1:250 dilution, which is not detectable by light microscopy. The AQUA system was also able to discriminate foamy gland prostate cancers, which are known to have a lower AMACR expression than typical acinar prostate cancers, from benign prostate tissue samples. Finally, a receiver-operating-characteristic curve was plotted to determine the specificity of the AMACR AQUA Z-score (normalized AQUA score) to predict that a given tissue microarray sample contains cancer. The area under the curve was calculated at 0.90 (P < 0.00001; 95% CI, 0.84 to 0.95). At an AMACR AQUA Z-score score of -0.3, 91% of the 70 samples classified as prostate cancer were correctly categorized without the intervention of a pathologist reviewing the tissue microarray slide. In conclusion, the AQUA system provides a continuous measurement of AMACR on a wide range of prostate tissue samples. In the future, the AMACR AQUA Z-score may be useful in the automated screening and evaluation of prostate tissue biomarkers.

Biomarkers, Tumor↗
PubMed2026

Plasma proteomics: considerations for preanalytical variability; a systematic review with narrative synthesis.

BACKGROUND: The plasma proteome (PP) is a dynamic system subject to pathology-associated changes and a focus for novel disease biomarker discovery. Disease-related PP research assumes protein concentrations in test specimens accurately reflect the in&#xa0;vivo milieu. However, measures to maintain the physicochemical integrity of the proteome before assay are often rudimentary, poorly described, or lacking standardisation in published studies. Contrastingly, in laboratory medicine, there is an expectation that errors in the so-called "preanalytical phase" (PAP) that impact patient results are understood, monitored, and mitigated against, while also being well described in research publications. There is therefore scope for good practice from laboratory medicine to inform PP research workflows. This review considers factors in the PAP which may impact the validity of PP results. CONTENT: A systematic review was conducted per PRISMA guidelines, limited to English-language peer-reviewed studies (2014-2024). Candidate studies were imported, screened, and managed using Covidence systematic review software. SUMMARY: 15 eligible studies were reviewed, covering many relevant processes. 11 studies reported statistically significant differences in PP due to factors in the PAP. Temperature and time-to-processing were the most commonly reported factors affecting the PP, with significant effects reported in 8 studies. OUTLOOK: PAP variability can significantly affect results in PP studies. Careful consideration of the effect of each stage of the PAP is needed when working with the PP. In multicenter studies, pre-defined and research question-specific sample processing workflows are essential for reducing PAP variability, which helps ensure the validity of PP studies.

Humans↗
PubMed2026

Effects of GLP-1 Receptor Agonists and Dual GIP/GLP-1 Receptor Agonists on Inflammatory and Metabolic Biomarkers in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists improve cardiovascular outcomes in type 2 diabetes mellitus (T2DM), but their effects on inflammatory and oxidative biomarkers are not fully defined. MATERIALS AND METHODS: We searched PubMed, Ovid MEDLINE, Scopus, Web of Science and the Cochrane Library from inception to 19 February 2026 for randomised controlled trials (RCTs) in adults with T2DM comparing a GLP-1RA or dual GIP/GLP-1 agonist with placebo or active therapy, and reporting C-reactive protein (CRP or high-sensitivity CRP [hs-CRP]), interleukin-6 (IL-6), tumour necrosis factor-&#x3b1; (TNF-&#x3b1;), monocyte chemoattractant protein-1 (MCP-1), malondialdehyde (MDA) or adiponectin. Random-effects meta-analyses were conducted using standardised mean differences (SMDs). RESULTS: Forty-one RCTs were included. GLP-1RAs significantly reduced CRP/hs-CRP (27 studies, 1991 participants; SMD -0.37, 95% CI -0.59 to -0.14) and MDA (3 studies, 272 participants; SMD -0.98, 95% CI -1.65 to -0.30), and increased adiponectin (16 studies, 1327 participants; SMD 0.30, 95% CI 0.13 to 0.46). Pooled effects on IL-6 (17 studies, 1068 participants; SMD -0.14, 95% CI -0.37 to 0.10), TNF-&#x3b1; (16 studies, 1164 participants; SMD -0.25, 95% CI -0.61 to 0.12) and MCP-1 (7 studies, 450 participants; SMD -0.27, 95% CI -0.58 to 0.03) were not statistically significant, although MCP-1 decreased in sensitivity analyses. Across biomarkers, heterogeneity was moderate to high. Two tirzepatide RCTs (562 participants) showed a significant reduction in IL-6 (SMD -0.28, 95% CI -0.47 to -0.09) and a non-significant trend towards lower CRP/hs-CRP. CONCLUSIONS: In adults with T2DM, incretin-based therapies consistently lower CRP/hs-CRP, reduce oxidative stress (MDA) and increase adiponectin, while effects on IL-6 and TNF-&#x3b1; are more variable. These data support a selective anti-inflammatory and metabolic regulatory profile of GLP-1-based therapy, but heterogeneity and limited data for some biomarkers warrant cautious interpretation and further mechanistic studies. TRIAL REGISTRATION: PROSPERO number: CRD420261321430.

Humans↗
PubMedDate not supplied

Inflammation at a glance: erythrocyte adhesiveness/aggregation test to reveal the presence of inflammation in people with atherothrombosis.

The erythrocyte adhesiveness/aggregation test is a new biomarker to detect low-grade inflammation in patients with atherothrombosis. In a group of 30 individuals with an acute ischemic event, the variability of EAAT during a follow-up period was similar to those obtained for other commonly used markers of the acute phase response, suggesting the potential clinical use of this novel marker.

Aged↗
PubMed2026

Pretreatment EBV-DNA/TLG-Based Risk Stratification Is Associated With Survival Outcomes in Nonmetastatic Nasopharyngeal Carcinoma: An Exploratory Study.

Whether combining pretreatment plasma Epstein-Barr virus DNA (EBV-DNA) with 18F-FDG PET/CT-derived total lesion glycolysis (TLG) improves prognostic stratification in nonmetastatic nasopharyngeal carcinoma (NPC) is unclear, particularly in nonendemic populations. We retrospectively analyzed 86 eligible nonmetastatic NPC patients treated with definitive radiotherapy (2010-2024) at a single nonendemic-region institution. EBV-DNA (prespecified cutoff 3500 copies/mL) and TLG (cutoff 200, ROC-derived within this cohort) were dichotomized. Both were available in 59/86 patients (68.6%), who differed from the rest in nodal and overall stage and in RT technique. Baseline PET/CT was in-house in 57 of 86 patients, and a robustness analysis in that subgroup is reported. Given limited events (13 PFS, 9 OS), Cox analyses are exploratory and were supplemented with penalized regression and bootstrap validation. At a median follow-up of 75.5&#x2009;months, 5-year PFS and OS for the whole cohort (n&#x2009;=&#x2009;86) were 81.1% and 85.9%. The EBV-DNAhigh/TLGhigh subgroup remained associated with inferior PFS after adjustment in an exploratory model (adjusted HR&#x2009;=&#x2009;3.97, 95% CI: 1.32-11.93) and, in a single-variable model, with inferior OS (HR&#x2009;=&#x2009;4.13, 95% CI: 1.10-15.52). Discrimination was comparable to the individual-biomarker model for PFS and lower for OS. Five-year PFS fell monotonically across the four risk groups in the complete-case cohort (n&#x2009;=&#x2009;59; 89.7%-58.3%). OS differed across groups (log-rank p&#x2009;=&#x2009;0.044) but was not strictly monotonic, with wide, overlapping confidence intervals. This two-biomarker model is hypothesis-generating and needs prospective, multicenter validation before any consideration of risk-adapted treatment.

Epstein&#x2013;Barr virus DNA↗
PubMed2026

Epigenetic and Transcriptional Regulatory Networks Underlying Psoriasis Pathogenesis.

Psoriasis is a chronic, immune-mediated dermatologic disorder characterized by the hyperproliferation of keratinocytes and dysregulated immune signaling. Although genome-wide association studies have identified susceptibility loci, the multifactorial nature of the disease underlines the importance of nongenetic regulatory mechanisms. Among these epigenetic modifications are those that critically link genetic predisposition with environmental stimuli. This review offers an in-depth overview of the current insights into the role of epigenetic regulation in the pathophysiology of psoriasis. Key mechanisms, including aberrant DNA methylation, histone post-translational modifications (eg, H3K27ac, H3K4me3), and dysregulated noncoding RNAs, are discussed in the context of inflammatory signaling and immune cell function. This review also explores how environmental factors such as UV radiation and air pollution induce the epigenetic reprogramming that perpetuates the proinflammatory state. Furthermore, it highlights the translational potential of targeting epigenetic regulators and epigenome-editing technologies, including clustered regularly interspaced short palindromic repeats (CRISPR) fusion systems, as precision therapeutic strategies. In parallel, advances in single-cell epigenomics, spatial transcriptomics, and the profiling of circulating biomarkers offer novel diagnostic tools. Despite advances, challenges persist, including the limited predictive value of preclinical models and variable epigenetic profiles. Positioning epigenetics as the bridge between genetic risk, environmental triggers, and therapeutic advances, this review presents a framework for precision medicine in psoriasis.

Humans↗
PubMed2006

Age- and tissue-dependent metallothionein and cytosolic metal distribution in a native Mediterranean fish, Mullus barbatus, from the Eastern Adriatic Sea.

The levels of metallothionein (MT), a biomarker of metal exposure, and of cytosolic metals (Zn, Cu, Cd), known as MT inducers, were investigated as variables of age (1 to 8 years) and tissue mass (liver, kidney, brain) of red mullet (Mullus barbatus). Within the age from 1 to 8 years the most significant increase is evident for cytosolic Cd in liver (43-fold) and in kidney (5-fold). MT and essential metals are constant with age or slightly increased. Over the growth period, statistically significant MT and metal increase is evident only between 1 and 6-8 years old specimens, while for Cd in liver and kidney cytosol significant increase already exists at 4 years old specimens. Metal distribution in all tissues follows the order: Zn>Cu>Cd, with even 500-800 times lower Cd levels than essential metal levels. Consequently, MTs follow the levels of essential metals, Zn and Cu, indicating MT involvement in homeostasis of essential metals. In contrast to kidney and brain, hepatic MT levels are not age-dependent. Inclusion of hepatic MT measurements and the associated cytosolic metals will be useful in the assessment of long-term metal effects in demersal fish M. barbatus.

Aging↗
PubMed2006

Association of the VEGF gene polymorphism with diabetic retinopathy in type 2 diabetes patients.

BACKGROUND: Diabetic microvascular complications are the major causes of morbidity and early mortality in diabetes. Vascular endothelial growth factor (VEGF) is a potent multifunctional cytokine which plays a key role in the pathogenesis of diabetic microvascular complications. We examined the possible association of the VEGF gene polymorphisms with diabetic nephropathy and retinopathy in type 2 diabetes patients. METHODS: Genotyping of the VEGF gene insertion/deletion (I/D) and +405 polymorphisms was done by the polymerase chain reaction (PCR) and restriction fragment length polymorphism methods. A total of 426 patients with type 2 diabetes and 493 healthy subjects were genotyped. The frequency of VEGF alleles and genotype distribution were compared in diabetic and control groups. RESULTS: The distribution of the VEGF DD genotype was significantly different in patients with diabetic retinopathy compared with healthy controls, entire diabetic group and patients with no complications (44 vs. 23, 30 and 21%, respectively; P < 0.01). Such differences were not observed in the diabetic nephropathy group. The odds ratio for the D allele was 2.27 (95% CI 1.59-3.25). The multivariate logistic regression analysis revealed that the D allele of the VEGF gene I/D polymorphism was an independent risk factor of retinopathy (P < 0.001). The VEGF +405 genotype was not associated with diabetic complications in type 2 diabetes patients. CONCLUSION: Our study suggests that the I/D polymorphism in the promoter region of the VEGF gene is associated with retinopathy but not nephropathy in type 2 diabetes patients. The multivariate logistic regression analysis showed that the D allele of the VEGF polymorphism is an independent risk factor of diabetic retinopathy after controlling for other clinical variables.

Alleles↗
PubMed2005

Serum markers of collagen metabolism: construction workers compared to sedentary workers.

BACKGROUND: Evaluation of causal relations between physical load and musculoskeletal disorders is hampered by the lack of knowledge as to the biological relevance of different loading parameters and the large variability between individuals. As indicators of molecular changes in the extracellular matrices of structures of the musculoskeletal system, biomarkers of collagen metabolism may provide important information on biological effects of physical load. The carboxyterminal propeptide of type I collagen (PICP) is a serum marker of synthesis and the carboxyterminal telopeptide region of type I collagen (CTx) reflects degradation of type I collagen. AIMS: To explore the feasibility of biomarkers of type I collagen metabolism as measures of the effects of physical load at tissue level. METHODS: Serum concentrations of PICP and CTx were assessed in a group of male construction workers involved in heavy manual materials handling (n = 47) and in a group of male sedentary workers (n = 49). RESULTS: Serum concentrations of both PICP and CTx seemed to be related to heavy physical work. The ratio PICP/CTx, illustrative of the effective metabolic changes, did not differ between the two groups. CONCLUSIONS: The higher turnover rate but similar effective synthesis may be indicative of an increased type I collagen content in the connective tissues as a result of adaptive remodelling in response to years of exposure to physical load. Further validation of these biomarkers is required with respect to dose-response relations and temporal associations between exposure to back load and biomarker concentrations.

Adult↗
PubMed1998

Insulin-like growth factor binding protein-1 as a marker of the metabolic syndrome--a study in borderline hypertension.

AIM: To evaluate insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-1 (IGFBP-1) in borderline hypertension (BHT) in relation to plasma lipoprotein and insulin levels, anthropometric variables and 24-h ambulatory blood pressure (BP). Seventy-five BHT men diastolic BP (DBP) 85-94 mmHg) and 75 age-matched normotensive controls (NT, DBP < or = 80 mmHg) were recruited from a population-based screening program. RESULTS: There was no difference in IGF-I or IGFBP-1 between BHT and NT men. However, subjects with insulin resistance (IR) had decreased levels of IGF-1 (145 +/- 36 vs 153 +/- 28 microg/L, p < 0.05) and IGFBP-1 (41 +/- 15 vs 52 +/- 20 microg/L, p < 0.01) compared to those without IR. IGF-I correlated inversely to BP levels in the BHT group (r = -0.24 to -0.28, p < 0.05). IGFBP-1 correlated inversely with BMI, lipoprotein and insulin levels (r = -0.29 to -0.48, p < 0.01), independent of IR. CONCLUSION: While there are no differences between BHT and NT men in IGF-I and IGFBP-1, both are significantly decreased in IR subjects. IGFBP-1 exhibits a close correlation to metabolic factors. Decreased IGFBP-1 could thus be suggested as a variable marking the "metabolic syndrome" of hypertension.

Adult↗
PubMed2005

Statistical total correlation spectroscopy: an exploratory approach for latent biomarker identification from metabolic 1H NMR data sets.

We describe here the implementation of the statistical total correlation spectroscopy (STOCSY) analysis method for aiding the identification of potential biomarker molecules in metabonomic studies based on NMR spectroscopic data. STOCSY takes advantage of the multicollinearity of the intensity variables in a set of spectra (in this case 1H NMR spectra) to generate a pseudo-two-dimensional NMR spectrum that displays the correlation among the intensities of the various peaks across the whole sample. This method is not limited to the usual connectivities that are deducible from more standard two-dimensional NMR spectroscopic methods, such as TOCSY. Moreover, two or more molecules involved in the same pathway can also present high intermolecular correlations because of biological covariance or can even be anticorrelated. This combination of STOCSY with supervised pattern recognition and particularly orthogonal projection on latent structure-discriminant analysis (O-PLS-DA) offers a new powerful framework for analysis of metabonomic data. In a first step O-PLS-DA extracts the part of NMR spectra related to discrimination. This information is then cross-combined with the STOCSY results to help identify the molecules responsible for the metabolic variation. To illustrate the applicability of the method, it has been applied to 1H NMR spectra of urine from a metabonomic study of a model of insulin resistance based on the administration of a carbohydrate diet to three different mice strains (C57BL/6Oxjr, BALB/cOxjr, and 129S6/SvEvOxjr) in which a series of metabolites of biological importance can be conclusively assigned and identified by use of the STOCSY approach.

Amines↗
PubMed2006

Poor correlation between 6beta-hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity.

AIMS: A non-invasive proposed method for measuring CYP3A activity is the urinary 6beta-hydroxycortisol:cortisol ratio. This ratio has been used as an indicator of CYP3A induction and inhibition, with mixed results. This investigation evaluated the relationship between a validated, biomarker, intravenous midazolam clearance and the urinary cortisol ratio under constitutive conditions and with the influence of a moderate CYP3A inhibitor. METHODS: This was a sequential, cross-over study design. Intravenous midazolam 0.025 mg kg(-1) was administered to 10 male and 10 female subjects once every 14 days for 4 months. Fluvoxamine 150 mg day(-1) was given to all subjects during the last two visits. Total body clearance of midazolam and urinary 6beta-hydroxycortisol:cortisol molar ratio were used as biomarkers of hepatic CYP3A activity. RESULTS: No significant correlations were found between these two markers (r(2) < 0.5, P > 0.05). Larger interindividual and intra-individual variability in CYP3A activity was observed in 6beta-hydroxycortisol:cortisol ratios compared with midazolam clearances. With fluvoxamine therapy, midazolam clearance values decreased approximately 1.5-fold and cortisol ratios decreased approximately 1.9-fold. CONCLUSIONS: The high intra-individual variability of the urinary cortisol ratio, compared with midazolam, makes this a suboptimal CYP3A phenotyping tool.

Adult↗
PubMed1998

Glutathione S-transferases--biomarkers of cancer risk and chemopreventive response.

The critical role of the glutathione S-transferase (GST) multigene family in cellular protection in combination with the large interindividual variability in the expression of these enzymes has prompted an investigation of their importance in cancer prevention and susceptibility. Previous preclinical and clinical studies from this laboratory have established an association between decreased GST activity and increased risk for colorectal cancer. Based upon the increased incidence of colon malignancies among patients with ulcerative colitis, GST activity has been examined in a mouse model of induced colitis. Significant decreases (50% of controls) in the GST activity of colon tissue were observed during the establishment and progression of colitis. These data suggested that depletion of cellular protection may be an important event in the carcinogenic progression of ulcerative colitis. The ability of the dithiolthione oltipraz to induce GST expression within the murine colon has been demonstrated. Use of chemopreventive regimens to induce phase 2 detoxication enzyme expression represents a promising strategy for the prevention of cancer. Clinical studies revealed that the GST activity of blood lymphocytes from individuals with either a personal or family history of colorectal cancer or a personal history of colon polyps was decreased significantly when compared to that of healthy controls. Phase 1 clinical evaluation of oltipraz has demonstrated its ability to induce GST activity as well as the level of transcripts encoding gamma-glutamylcysteine synthetase (gamma-GCS) and DT-diaphorase in the colon mucosa of individuals at increased risk for colorectal cancer. The observed correlation between the posttreatment response in blood lymphocytes and colon mucosa suggested that blood lymphocytes may be used in future trials as a surrogate biomarker of the responsiveness of colon tissue to chemopreventive regimens.

Animals↗
PubMed2005

Individual variability in esterase activity and CYP1A levels in Chinook salmon (Oncorhynchus tshawytscha) exposed to esfenvalerate and chlorpyrifos.

Acetylcholinesterase (AChE) activity has traditionally been monitored as a biomarker of organophosphate (OP) and/or carbamate exposure. However, AChE activity may not be the most sensitive endpoint for these agrochemicals, because OPs can cause adverse physiological effects at concentrations that do not affect AChE activity. Carboxylesterases are a related family of enzymes that have higher affinity than AChE for some OPs and carbamates and may be more sensitive indicators of environmental exposure to these pesticides. In this study, carboxylesterase and AChE activity, cytochrome P4501A (CYP1A) protein levels, and mortality were measured in individual juvenile Chinook salmon (Oncorhynchus tshawytscha) following exposure to an OP (chlorpyrifos) and a pyrethroid (esfenvalerate). As expected, high doses of chlorpyrifos and esfenvalerate were acutely toxic, with nominal concentrations (100 and 1 microg/l, respectively) causing 100% mortality within 96 h. Exposure to chlorpyrifos at a high dose (7.3 microg/l), but not a low dose (1.2 microg/l), significantly inhibited AChE activity in both brain and muscle tissue (85% and 92% inhibition, respectively), while esfenvalerate exposure had no effect. In contrast, liver carboxylesterase activity was significantly inhibited at both the low and high chlorpyrifos dose exposure (56% and 79% inhibition, respectively), while esfenvalerate exposure still had little effect. The inhibition of carboxylesterase activity at levels of chlorpyrifos that did not affect AChE activity suggests that some salmon carboxylesterase isozymes may be more sensitive than AChE to inhibition by OPs. CYP1A protein levels were approximately 30% suppressed by chlorpyrifos exposure at the high dose, but esfenvalerate had no effect. Three teleost species, Chinook salmon, medaka (Oryzias latipes) and Sacramento splittail (Pogonichthys macrolepidotus), were examined for their ability to hydrolyze a series of pyrethroid surrogate substrates and in all cases hydrolysis activity was undetectable. Together these data suggest that (1) carboxylesterase activity inhibition may be a more sensitive biomarker for OP exposure than AChE activity, (2) neither AChE nor carboxylesterase activity are biomarkers for pyrethroid exposure, (3) CYP1A protein is not a sensitive marker for these agrochemicals and (4) slow hydrolysis rates may be partly responsible for acute pyrethroid toxicity in fish.

Acetylcholinesterase↗
PubMed2004

Assessing the clinical impact of prostate-specific antigen assay variability and nonequimolarity: a simulation study based on the population of the United Kingdom.

BACKGROUND: Prostate-specific antigen (PSA) is the most widely used serum biomarker to differentiate between malignant and benign prostate disease. Assays that measure PSA can be biased and/or nonequimolar and hence report significantly different PSA values for samples with the same nominal amount. This report investigates the effects of biased and nonequimolar assays on the decision to recommend a patient for a prostate biopsy based on age-specific PSA values. METHODS: A simulation model, calibrated to the distribution of PSA values in the United Kingdom, was developed to estimate the effects of bias, nonequimolarity, and analytical imprecision in terms of the rates of men who are recommended to have a biopsy on the basis of their assay-reported PSA values when their true PSA values are below the threshold (false positives) or vice versa (false negatives). RESULTS: False recommendation rates for a calibrated equimolar assay are 0.5-0.9% for analytical imprecision between 5% and 10%. Positive bias leads to significant increases in false positives and significant decreases in false negatives, whereas negative bias has the opposite effect. False-positive rates for nonequimolar assays increase from 0.5% to 13% in the worst-case scenario, whereas false-negative rates are almost always 0%. CONCLUSIONS: Biased and nonequimolar assays can have major detrimental effects on both false-negative and false-positive rates for recommending biopsy. PSA assays should therefore be calibrated to the International Standards and be unbiased and equimolar in response to minimize the likelihood of incorrect clinical decisions, which are potentially detrimental for both patient and healthcare provider.

Aged↗
PubMed2025

Pharmacoproteomics in the development of personalised medicine in Age-related Macular Degeneration (PHARPRO-AMD) study protocol.

INTRODUCTION: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among people over 55 years of age globally, being neovascular AMD (nAMD) its most aggressive form. Its treatment consists of the use of drugs that block vascular endothelial growth factor (anti-VEGF). Proteomics may allow the identification of differentially expressed proteins between responders and non-responders to each anti-VEGF drug. Thus, the objective of Pharmacoproteomics in the development of personalised medicine in Age-related Macular Degeneration (PHARPRO-AMD) is to find new proteomic biomarkers, predictive of response to antiangiogenic treatment in patients with nAMD. METHODS AND ANALYSIS: PHARPRO-AMD is a nationwide, multicentre, prospective, observational study. Treatment-na&#xef;ve patients with nAMD starting anti-VEGF therapy will be enrolled and followed up for 2 years. During this period, clinical variables will be gathered to classify treatment response. In addition, blood, tear and vitreous and aqueous humour samples will be collected and will undergo a ZenoSWATH proteomic analysis. Relevant biomarkers identified and response classification will be used to perform a multivariate logistic regression and construct receiver operating characteristic curves. RESULTS: The study is expected to identify a panel of proteomic biomarkers predictive of anti-VEGF treatment response. Integrating data from invasive and non-invasive biological samples may enhance clinical applicability. Once validated, these biomarkers could support the design of future clinical trials on biomarker-guided therapies, helping to optimise treatment regimens and improve visual outcomes. CONCLUSIONS: The PHARPRO-AMD study aims to provide proof-of-concept for biomarker-guided anti-VEGF therapy in nAMD, potentially improving vision outcomes. A notable limitation is the exclusion of patients with visual acuity above 73 Early Treatment of Diabetic Retinopathy Study letters, a criterion chosen to reduce potential ceiling effects and improve response assessment accuracy. ETHICS AND DISSEMINATION: Approved by the Galician Network of Ethics Committees, with nationwide validity. Anonymised data will be deposited in open-access repositories and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Spanish Clinical Studies Registry (REec) (0033-2024-OBS).

Humans↗