Multiple Biomarkers Research Articles

Associations of tau, Aβ, and brain volume of the Papez circuit with cognition in Alzheimer's disease.

This study aimed to investigate the cross-sectional associations between regional Alzheimer's disease (AD) biomarkers, including tau, β-amyloid (Aβ), and brain volume, within the Papez circuit, and neuropsychological functioning across the preclinical and clinical spectrum of AD. We utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 251 Aβ-positive participants. Participants were categorized into three groups based on the Clinical Dementia Rating (CDR): 73 individuals with preclinical AD (CDR = 0), 114 with prodromal AD (CDR = 0.5), and 64 with clinical AD dementia (CDR ≥ 1). Linear regression analyses, adjusted for age, gender, and education years, were employed to evaluate the associations between five regions of interest (the hippocampus, para-hippocampus, entorhinal cortex, posterior cingulate cortex, and thalamus) and five neuropsychological tests across the three imaging modalities. In the preclinical stage of AD, flortaucipir PET was associated with impaired global cognition and episodic memory (range standardized β = 0.255-0.498, p < 0.05 corrected for multiple comparisons), while florbetapir PET and brain volume were marginally related to global cognition (range standardized β = 0.221-0.231, p < 0.05). In the clinical stages of AD (prodromal and dementia), both increased flortaucipir uptake and decreased brain volume were significantly associated with poorer global neuropsychological and episodic memory performance (range standardized β = 0.222-0.621, p < 0.05, most regions of interest survived correction for multiple comparisions). However, a slight relationship was observed between florbetapir uptake and poorer global cognitive function. The regions most affected by flortaucipir PET were the hippocampus, para-hippocampus, and posterior cingulate cortex. During the clinical stages, the hippocampus and entorhinal cortex exhibited the most significant volumetric changes. Tau PET and brain volume measurements within the Papez circuit are more sensitive indicators of early cognitive deficits in AD than Aβ PET. Furthermore, during the clinical stages of AD, both flortaucipir PET and brain volume of the Papez circuit are closely correlated with cognitive decline. These findings underscore the importance of integrating multiple biomarkers for the comprehensive evaluation of AD pathology and its impact on cognition.

Clinical validation of image-based AI predictive biomarkers for precision neoadjuvant triple-negative breast cancer treatment (PEAR-TNBC).

TPS627 Background: Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancer subtypes, with a 5-year recurrence rate of 30% in patients with localized disease. Pathological Complete Response (pCR) strongly predicts the risk of recurrence and death, which are reduced by approximately 80% in patients who achieve a pCR following neoadjuvant treatment. There are multiple treatment regimens available for TNBC patients in the neoadjuvant setting but no biomarkers to match patients to treatments. Giving ineffective treatment leads to worse outcomes for patients and additional burden on healthcare systems. Pear Bio has developed a functional precision medicine test coupling an organ-on-a-chip with a computer vision (CV) pipeline through which an individual patient’s response to different treatments can be monitored simultaneously ex vivo. Each microtumor’s response is monitored using time-lapse 3D microscopy. A proprietary CV pipeline quantifies the responses (e.g. tumor cell viability, culture size). Lab test responses are correlated to the clinical outcomes of the patients to identify biomarkers with high predictive accuracy. This generates multiple CV-based biomarkers with potential predictive value. PEAR-TNBC (NCT05435352) is a prospective, observational UK-wide trial aimed at assessing the test’s accuracy in predicting pCR in TNBC patients in the neoadjuvant setting. The study recruits patients with early TNBC (N=54) who are willing to undergo an additional core needle biopsy prior to starting neoadjuvant therapy. The assay is run in parallel with the patient’s treatment and the treating oncologist is blind to the results of the Pear Bio test. Methods: The study has 2 cohorts (A and B), each recruiting at least 20 evaluable patients. To be eligible, patients need to have ≥10mm tumor, stage I-III, TNBC, with planned neoadjuvant treatment followed by surgery and be willing to undergo a study-specific core needle biopsy procedure. Cohort B also requires a 40mL blood sample. To be evaluable, eligible patients’ samples must be successfully cultured in the 3D ex vivo assay and they must complete at least 4 cycles of neoadjuvant chemotherapy prior to surgery. Cohort A recruitment began on 05/27/22 and has recruited 20 evaluable patients, through 5 sites. Cohort B accrual will begin upon completion of Cohort A. The primary endpoint is the accuracy of the Pear test in predicting pCR, defined as specificity, with secondary outcomes as sensitivity, and positive and negative predictive values. Novel aspects include a focus on specificity (i.e. accurately predicting patients who will not achieve pCR) combined with the use of Receiver-operating characteristic curves to define optimal cutoffs for the CV biomarkers. Future trials will aim to run the test prior to therapy selection, guiding the choice of regimen to assess the test’s ability to increase pCR rates. Clinical trial information: NCT05435352 .

Multiplexed electrochemical nucleic acid sensor based on visible light-mediated metal-free thiol-yne click reaction for simultaneous detection of different nucleic acid targets

Simultaneous detection of multiple tumor biomarkers with a simple and low-cost assay is crucial for early cancer detection and diagnosis. Herein, we presented a low-cost and simple assay for multiplexed detection of tumor biomarkers using a spatially separated electrodes strategy. The sensor is fabricated based on a metal-free thiol-yne click reaction, which is mediated by visible light, on commercially available indium tin oxide (ITO) electrodes. Four biomarkers, including p53 DNA, Brca2 DNA, K-ras DNA, and MicroRNA-204 RNA, were used as model analytes, and the corresponding oligonucleotide probes were modified on the desired electrode units sequentially with 530 nm irradiation light in the presence of photosensitizer Eosin Y. By this visible light-mediated coupling reaction, oligonucleotide probe densities of up to 9.2 ± 0.7 × 1010 molecules/cm2 were readily obtained on the ITO electrode surface. The proposed multiplexed E-NA sensor could detect four different nucleic acid targets concurrently without crosstalk among adjacent electrodes and was also successfully applied for detecting targets in a 20% fetal calf serum sample. The detection limits for p53 DNA, Brca2 DNA, K-ras DNA, and MicroRNA-204 RNA were 0.72 nM, 0.97 nM, 2.15 nM, and 1.73 nM, respectively. The developed approach not only has a great potential for developing cost-effective biosensors on affordable substrates for nucleic acid target detection, but also be easily extended to detect other targets by modifying the specific oligonucleotide probes anchored on the electrode.

Association of baseline inflammatory biomarkers and clinical outcomes in patients with advanced renal cell carcinoma (aRCC) treated with immune checkpoint inhibitors (ICIs).

4548 Background: Multiple inflammatory biomarkers such as modified Glasgow Prognostic Score (mGPS), neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), and neutrophil to eosinophil ratio (NER) have been identified in RCC. We analyzed those biomarkers in patients with aRCC treated with ICIs to assess the association with treatment outcomes. Methods: A retrospective analysis was conducted on adult patients with aRCC treated with ICIs at Emory Winship Cancer Institute between 2018 and 2023. Clinical benefit (CB) is determined by stable disease, partial response, and complete response. mGPS (combining albumin and CRP), NLR, MLR, PLR, and NER data were collected from the baseline bloodwork. Multivariate and univariate analyses were conducted on PFS, OS, and CB. MVA was built by controlling the age, gender, race, BMI, smoking status, IMDC risk group, clear cell histology, prior treatment, liver metastases, ECOG performance score, and number of distant metastases, which were subject to backward elimination at the significant level of p &lt; 0.2 Results: Our analysis included a total of 401 patients (118:283 F:M, median age: 66). On univariate analysis, high mGPS, NLR, MLR, PLR, and NER were related to inferior CB; hazard ratios (HR) (95% CI, p value) were 3.03 (1.35-6.77, p=0.005), 1.86 (1.14-3.03, p=0.013), 1.83 (1.10-3.02, p=0.019), 2.37 (1.52-3.71, p &lt;.001), 1.93 (1.22-3.05, p=0.005) respectively. On multivariate analysis, NLR, PLR, NER had statistically significant correlation with CB, HR (95% CI) were 1.75 (1.01-3.04, p=0.047), 2.21 (1.33-3.66, p=0.002), 2.07 (1.24-3.47, p=0.006). Conclusions: The results demonstrated that high systemic inflammatory biomarkers may be related to worse clinical outcomes with ICI treatment. Prospective studies are needed for further validation. [Table: see text]

Impact of histone deacetylase inhibition and arimoclomol on heat shock protein expression and disease biomarkers in primary culture models of familial ALS.

Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including motor neuron disease, and amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including the upregulation of heat shock proteins (HSP) to increase chaperoning capacity. Motor neurons have a high threshold for upregulating stress-inducible HSPA1A, but constitutively express high levels of HSPA8. This study compared the expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TAR DNA binding protein 43kDa (TDP-43)G348C, fused in sarcoma (FUS)R521G, or superoxide dismutase I (SOD1)G93A. All variants were poor inducers of Hspa1a, and reduced levels of Hspa8 mRNA and protein, indicating multiple compromises in chaperoning capacity. To promote HSP expression, cultures were treated with the putative HSP coinducer, arimoclomol, andclass I histone deacetylase inhibitors, to promote active chromatin for transcription, and with the combination. Treatments had variable, often different effects on the expression of Hspa1a and Hspa8, depending on the ALS variant expressed, mRNA distribution (somata and dendrites), and biomarker of toxicity measured (histone acetylation, maintaining nuclear TDP-43 and the neuronal Brm/Brg-associated factor chromatin remodeling complex component Brg1, mitochondrial transport, FUS aggregation). Overall, histone deacetylase inhibition alone was effective on more measures than arimoclomol. As in the FUS model, arimoclomol failed to induce HSPA1A or preserve Hspa8 mRNA in the TDP-43 model, despite preserving nuclear TDP-43 and Brg1, indicating neuroprotective properties other than HSP induction. The data speak to the complexity of drug mechanisms against multiple biomarkers of ALS pathogenesis, as well as to the importance of HSPA8 for neuronal proteostasis in both somata and dendrites.

Assessing the impact of imidacloprid, glyphosate, and their mixtures on multiple biomarkers in Corbicula largillierti

Pesticide mixtures are frequently utilized in agriculture, yet their cumulative effects on aquatic organisms remain poorly understood. Aquatic animals can be effective bioindicators and invasive bivalves, owing to their widespread distribution, provide an opportunity to assess these impacts. Glyphosate and imidacloprid, among the most prevalent pesticides globally, are frequently detected in freshwater systems in South America. This study aims to understand the cumulative effects of pesticide mixtures on aquatic organisms, using invasive Corbicula largillierti clams from a natural stream in northwestern Argentina. We conducted 48-hour exposure experiments using two concentrations of imidacloprid (20 and 200 μg L−1 a.i), two concentrations of glyphosate (0.3 and 3 mg L−1 a.i), and two combinations of these pesticides (both at low and high concentrations, respectively), simulating the direct contamination of both pesticides based on their agronomic recipe and observed values in Argentine aquatic environments. Clam metabolism was assessed through the examination of multiple oxidative stress parameters and measuring oxygen consumption rate as a proxy for standard metabolic rate (SMR). Our findings revealed that imidacloprid has a more pronounced effect compared to glyphosate. Imidacloprid significantly decreased clam SMR and cellular levels of reduced glutathione (GSH). However, when both pesticides were present, also cellular glycogen and thiobarbituric acid-reactive substances (TBARS) were affected. Proteins and glutathione S-Transferase (GST) activity were unaffected by either pesticide or their mixture at the assayed concentrations, highlighting the need to test several stress parameters to detect toxicological impacts. Our results indicated additive effects of imidacloprid and glyphosate across all measured parameters. The combination of multiple physiological and cytological biomarkers in invasive bivalves offers significant potential to enhance biomonitoring sensitivity and obtain insights into the origins and cellular mechanisms of chemical impacts. These studies can improve pollution regulatory policies and pesticide management.

Anthocyanins and Type 2 Diabetes: An Update of Human Study and Clinical Trial.

Anthocyanins are phenolic compounds occurring in fruits and vegetables. Evidence from pre-clinical studies indicates their role in glucose level regulation, gut microbiota improvement, and inflammation reduction under diabetic conditions. Therefore, incorporating these research advancements into clinical practice would significantly improve the prevention and management of type 2 diabetes. This narrative review provides a concise overview of 18 findings from recent clinical research published over the last 5 years that investigate the therapeutic effects of dietary anthocyanins on diabetes. Anthocyanin supplementation has been shown to have a regulatory effect on fasting blood glucose levels, glycated hemoglobin, and other diabetes-related indicators. Furthermore, increased anthocyanin dosages had more favorable implications for diabetes treatment. This review provides evidence that an anthocyanin-rich diet can improve diabetes outcomes, especially in at-risk groups. Future research should focus on optimal intervention duration, consider multiple clinical biomarkers, and analyze anthocyanin effects among well-controlled versus poorly controlled groups of patients with diabetes.

Hair product use and urinary biomarker concentrations of non-persistent endocrine disrupting chemicals among reproductive-aged Black women

BackgroundStudies have shown an association between hair product use and adverse health outcomes. Scientists have hypothesized that exposure to endocrine-disrupting chemicals (EDCs) drives these associations, but few studies have directly evaluated associations between hair product use and biomarkers of EDCs. Even more limited are studies of Black women, who frequently use EDC-containing products (e.g., hair relaxers). ObjectiveWe estimated associations between hair product use and EDC biomarker concentrations. MethodsWe leveraged cross-sectional data from the Study of Environment, Lifestyle, and Fibroids, a cohort of females aged 23–34 years who self-identified as Black/African American from the Detroit-metropolitan area (USA; n = 425). On structured questionnaires, participants reported their past 24-h and past 12-month use of hair products, including relaxers/straighteners/perms, styling products, moisturizers, oils, and hair food. We quantified urinary concentrations of 19 phthalate/phthalate alternative metabolites, 7 phenols, and 4 parabens using high performance liquid chromatography isotope dilution tandem mass spectrometry. EDC biomarker concentrations were creatinine-adjusted and natural log-transformed. We used multivariable linear regression to estimate mean percent differences in EDC biomarker concentrations and 95% confidence intervals (CIs) associated with hair product use, adjusting for sociodemographic confounders. ResultsHair product use was associated with greater concentrations of multiple EDC biomarkers. Notably, use of hair products in the previous 24 h (compared with non-use) was associated with 16.2% (95% CI = 0.7%, 35.9%), 35.0% (95% CI = 2.6%, 77.6%), and 32.3% (95% CI = 8.8%, 92.0%) higher concentrations of mono-isobutyl phthalate, methyl paraben, and ethyl paraben, respectively. Use of hair relaxers/straighteners/perms, styling products, moisturizers, oils, and hair food in the past 12 months was also associated with higher concentrations of multiple phthalate, phenol, and paraben biomarkers. ConclusionHair product use was associated with higher biomarker concentrations of multiple phthalates, phenols, and parabens. These findings suggest that hair products are potentially important exposure sources for hormonally-active chemicals among Black women.

Metal exposure and blood lipid biomarkers in early pregnancy: A cross-sectional study

Recognizing the risk factors for dyslipidemia during pregnancy is crucial for safeguarding the health of both the mothers and the offspring. Growing evidence emerged and suggested links between environmental factors, including metals, and alteration in lipid levels or dyslipidemia in general populations. However, knowledge of the associations during pregnancy remains extremely lacking. Herein, we aimed to explore whether elevated metal exposure constitutes a risk factor for dyslipidemia in pregnant women. Based on the Tongji-Shuangliu Birth Cohort (TSBC), a total of 663 pregnant women were recruited and their urinary levels of 17 metals and blood lipid biomarkers in early pregnancy were measured, namely triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). The multivariable linear regression models revealed that exposure to selected metals during early pregnancy was significantly associated with some important biomarkers. In particular, after natural log-transformed for the levels of lipid biomarkers and metals, copper (Cu) exposure was positively associated with HDL-C (β = 0.024, 95% CI: 0.001, 0.046), while zinc (Zn) was associated with TG (β = 0.062, 95% CI: 0.013, 0.110) and selenium with TC (β = 0.028, 95% CI: 0.004, 0.054). Exposure to rubidium (Rb) was positively associated with multiple lipid biomarkers, including HDL-C (β = 0.020, 95% CI: 0.002, 0.037) and LDL-C (β = 0.022, 95% CI: 0.001, 0.042). Mixture exposure analysis further identified significant associations between Cu and HDL-C, Zn and TG, Rb and HDL-C, when multiple metal exposures were considered in the Bayesian kernel machine regression model simultaneously. Our findings showed that exposure to several metals during early pregnancy was associated with an increased prevalence of blood lipid abnormalities in pregnant women. These findings underscore the potential impact of metal combinations on lipid metabolism and increase our understanding of the risk factors associated with abnormal lipid metabolism during pregnancy.

Interplay of clinical biomarkers in allergic asthma diagnosis and severity: A case-control study.

Given asthma's large phenotypic diversity, the study was aimed to use specific biomarkers to characterize Allergic asthma (AA) and its severity. Blood was collected from 42 healthy controls (HCs) and 96 patients with AA. Biomarkers related to blood cell number and function: total leukocyte count (TLCs), neutrophil, lymphocyte, monocyte, eosinophil, basophil, neutrophil-to-lymphocyte ratio (NLR), immunoglobulin E (IgE), tryptase and eosinophilic cationic protein (ECP) as well as remodelling biomarkers (Matrix metalloproteinase (MMP-9), (MMP-16), Fibroblast growth factor (FGF-18) and (FGF-23) and alpha-skeletal muscle actin-1 (ACTa-1) were measured. Significant differences were observed in hematological parameters with higher levels of total leukocytes, eosinophil, and basophil counts in the AA group compared to HCs. The disease group also had significantly higher levels of several serum biomarkers (IgE, TPs, ECP, MMP-9, MMP-16, FGF-18, FGF-23, and ACTa-1) compared to HC. Forced expiratory volume 1 (FEV1) and forced vital capacity (FVC) had a strong negative correlation with ECP, IgE, and ACTa-1. FEV1 was negatively correlated with MMP-16 and tryptase. Patients with AA have higher levels of several biomarkers, such as MMP-9, MMP-16, FGF-18, FGF-23, IgE, tryptase, and ACTa-1. In addition, IgE, tryptase, ACTa-1, and MMP-16 are related to lung function impairment in AA. This indicates that measuring multiple biomarkers may be of value in the future when diagnosing and monitoring AA.

Integrated toxicity of secondary, tertiary, wetland effluents on human stem cells triggered by ERα and PPARγ agonists

Residual pollutants in discharged and reused water pose both direct and indirect human exposure. However, health effects caused by whole effluent remain largely unknown due to the lack of human relevant model for toxicity test. Effluents from four secondary wastewater treatment plants (SWTPs), a tertiary wastewater treatment plant (TWTP) and a constructed wetland (CW) were evaluated for the integrated toxicity of the organic extractions. Multiple-endpoint human mesenchymal stem cells (MSCs) assay was used as an in vitro model relevant to human health. The effluents caused cytotoxicity, oxidative stress and genotoxicity in MSCs. The osteogenic and neurogenic differentiation were inhibited and the adipogenic differentiation were stimulated by some of the effluent extractions. The SWTP, TWTP and CW treatments reduced integrated biomarker response (IBR) by 26.3 %, 17.5 % and 33.3 % respectively, where the IBR values of final CW (8.3) and TWTP (8.2) effluents were relatively lower than SWTPs (9.1). Among multiple biomarkers, the inhibition of osteogenesis was the least reduced by wastewater treatment. Besides, ozone disinfection in tertiary treatment increased cytotoxicity and differentiation effects suggesting the generation of toxic products. The mRNA expressions of estrogen receptor alpha (ERα) and peroxisome proliferator-activated receptor gamma (PPARγ) were significantly upregulated by effluents. The inhibitory effects of effluents on neural differentiation were mitigated after antagonizing ERα and PPARγ in the cells. It is suggested that ERα and PPARγ agonists in effluents were largely accountable for the impairment of stem cell differentiation. Besides, the concentrations of n-C29H60, o-cresol, fluorene and phenanthrene in the effluents were significantly correlated with the intergrated stem cell toxicity. The present study provided toxicological evidence for the relation between water contamination and human health, with an insight into the key toxicity drivers. The necessity for deep water treatment and the potential means were suggested for improving water quality.

Associations of sedentary behavior and screen time with biomarkers of inflammation and insulin resistance.

Sedentary behavior (SB) has been linked to risk factors of cardiometabolic disease, with inconsistent findings reported in the literature. We aimed to assess the associations of SB with multiple biomarkers of inflammation and insulin resistance in adults. Domain-specific SB, sitting time and moderate-to-vigorous physical activity (MVPA) were measured in 78 adults (mean ± SD 52.0 ± 10.8 y). Body fat percentage (BF%) was assessed using multi-frequency bioelectrical impedance. A blood draw assessed glucose, insulin, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, and adiponectin. Adiponectin-leptin ratio (ALR), homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) were calculated. Multivariable linear regression analyses, controlling for age, sex, MVPA, and BF%, were used to assess associations. After adjustment for age, sex and MVPA, total SB (7.5 ± 2.5h/day) was positively associated with leptin, insulin, HOMA-IR, HOMA-β (Standardized Beta (β) range 0.21-0.32) and negatively associated with ALR (β = -0.24, p < 0.05 for all). Similarly, total sitting time (7.2 ± 2.9h/day) was associated with TNF-α (β = 0.22) and ALR (β = -0.26). These associations were attenuated to non-significance after adjustment for BF%. Leisure screen time was detrimentally associated with IL-6 (β = 0.24), leptin (β = 0.21), insulin (β = 0.37), HOMA-IR (β = 0.37), and HOMA-β (β = 0.34), independent of age, sex and MVPA (p < 0.05 for all). Only the associations with insulin (β = 0.26), HOMA-IR (β = 0.26), and HOMA-β (β = 0.23) remained significant after further controlling BF% (p < 0.05). Self-reported SB is associated with biomarkers of inflammation and insulin resistance, independent of MVPA, and in some cases BF%.

#3011 Pathophysiological link between renal and cardiovascular disease in patients with type 2 diabetes mellitus: preliminary results from a proteomic study

Abstract Background and Aims Diabetic kidney disease (DKD) affects nearly 40% of people with diabetes and is the leading cause of chronic kidney disease (CKD). A high prevalence of cardiovascular disease (CVD) is known in this population. Indeed, DKD and CVD are often related and lead to worse outcomes in type 2 diabetes mellitus (T2D), i.e. cardiac fibrosis and CV events are frequently described in patients with DKD. However, specific associations and accurate prediction biomarkers for DKD and CVD progression in T2D are still lacking as various proteins may play a multi-mechanistic role. Lipocalin-2 (LCN2) is involved in several pathophysiological processes (inflammation, renal disease and cardiometabolic complications in CKD). Its leukocyte-chemoattractant effect has shown to reduce CVD in experimental models of cardiomyopathy when suppressed. Excess LCN2 in CKD is a determinant of disease progression, but also a potent mediator of cardiac injury in CKD. Insulin-like growth factor binding proteins (IGFBPs) also play an important role in cell homeostasis by regulating cell transcription, migration, and apoptosis. IGFBP-3 down-regulation has demonstrated to be a predictor of rapid renal progression in T2DM. On the other hand, IGFBP-6 increases when GFR drops, being involved in the pathophysiological process of CKD as an apoptosis-inducing protein In this context, a proteomic-based approach would optimise the clinical utility of multiple plasma biomarkers. The aim was to identify proteins associated with DKD, cardiac fibrosis (estimated by the PICP biomarker) and the presence of a new CV event. Method A prospective cohort of 91 T2D patients, with a minimum follow-up of 3 years (mean: 4 years) was analysed. We evaluated the association between rates of change in GFR and PICP during follow-up (fold-change: end/initial) and their interaction with the development of a composite of cardiovascular (CV) events: CV death, stroke, ischaemic heart disease, atrial fibrillation, valvular heart disease and CV-related hospitalisation. In addition, ninety-two proteins were quantified in serum samples using a multiplex proximity extension assay with high-throughput protein detection technology (Olink proteomics, Cardiometabolic panel). Associations between variations in these proteins and changes in PICP and eGFR (all expressed as fold change from baseline) were assessed using linear regression analyses adjusted for their respective baseline values. All analyses were adjusted by multiple testing (Benjamini-Hochberg, FDR = 0.05%) using R software. Results Sixty-eight (74.7%) men and 23 (25.3%) women were included in the analysis. The mean age at baseline was 65.8 years, and the mean follow-up was 4 years (minimum 3 years). Sixteen cardiovascular events were recorded. An inverse association was observed between GFR and PICP (p = 0.003). Interaction analysis showed that this correlation occurred only in patients with incident CV events (p for interaction &amp;lt;0.001) (Fig. 1). By proteomic analysis (Fig. 2) several proteins were found to be significantly related to one of the three parameters studied (change in GFR, change in PICP and change with cardiovascular event), of which 3 proteins presented an overlap for all the parameters analysed: Lipocalin 2 (LCN2) and Insulin-like growth factor binding proteins 3 and 6 (IGFBP3 and IGFBP6). Interestingly, LCN2 and IGFBP6 were more highly expressed in patients with CV events whereas IGFBP3 was downregulated in these patients. Conclusion In patients with DKD, worsening enal function is associated with elevated circulating levels of the collagen synthesis biomarker PICP, particularly in those who developed at least one CV event. The link shown with LCN2, IGFBP-6 and IGFBP-3 shed light on possible multi-mechanistic pathways involved in DKD and narrow the scope towards a common pathway involving an interaction between pro-apoptotic and local inflammatory factors.

#1550 Incident hypertension: immune biomarkers and vascular phenotypes

Abstract Background and Aims Blood pressure (BP) regulation is mediated by cardiac, vascular, endocrine, renal, and immune system interactions. Hence, hypertension may exist as different phenotypic variants, with different clinical features and susceptibility to target organ damage. We aimed to analyse the circulating protein biomarker ‘signature’ of: 1) untreated hypertension; 2) hypertensive phenotypes identified by arterial and blood pressure parameters. Method 61 patients with hypertension, and 61 controls were assessed using 24hr ambulatory BP monitoring; endothelial function, arterial stiffness, carotid intima-media thickness (CIMT), and cardiovascular variability [1]. Circulating protein biomarkers analysed using Olink® Inflammation plasma biomarker panel, reported as NPX (Normalized Protein eXpression), in Log2 scale. Results 34 biomarkers dominated by cytokines and chemokines differed between normotensive and hypertensive subjects (Fig. 1), though failed to meet Bonferroni-adjusted threshold. Inflammatory biomarkers correlated with BP and arterial stiffness, BP variability, and CIMT, but not endothelial function. Associations were concordant across systolic and diastolic BP; TPP1, CCL7, CCL11, and CCL21 positively correlating; IL18R1, and KYNU negatively. These relationships were more pronounced in hypertensive subgroup, 85 biomarkers correlating including CD molecules (CD200R1, CD22, CD58, CD6, CD70) and cytokines (IL-5, IL-11, IL-15, IL-18, IL-32, IL-1RL2, IL-22RA1, IL-5RA). HGF, AGE, and CCL21 showed greatest between group differences and correlated with multiple BP or vascular parameters. Systolic nocturnal dipping demonstrated negative correlation with biomarkers relating to immune cell interactions and cellular adhesion (CTRC, EPHA1, LGALS4, SIT1, SMOC, IL-18 and TNFSF11). Machine learning techniques identified three phenotypes of hypertension, ‘arterially stiffened’, ‘vaso-protected’, and ‘non-dipper’ [1]. Sixteen of the 85 correlating biomarkers also differed between these phenotypic groups: Conclusion Hypertension is linked to alterations in circulating immune biomarkers. Multiple biomarkers correlated with both arterial stiffness and BP parameters. Some biomarkers are only correlated in the hypertensive group. Many also relate to nocturnal dipping, and differed across the hypertension endotypes. HGF is a promising biomarker for BP and arterial function; warranting further validation.

Asian winter monsoon controls marine primary productivity in north Arabian Sea during the Holocene

The Arabian Sea (AS), which is strongly impacted by monsoon winds, is one of the most biologically productive regions. The forcing of Asian monsoons on Holocene productivity remains debated in north AS, an area influenced by summer and winter monsoon. A sediment core from Makran margin was utilized to analyze organic biomarkers and high-resolution bromine intensities, unveiling the forces of biological productivity through the past 8000 years. Alkenone sea surface temperature (SST) records show significant cooling in north AS and augmented SST difference between north and west AS toward the late Holocene, suggesting Asian winter monsoon (AWM) strengthening during the period. The Holocene productivity signals in north AS, indicated by the bromine to rubidium ratio and multiple biomarkers, are responsive to SST changes and thus mainly controlled by the AWM variation, not modulated by Asian summer monsoon (ASM). Millennial-to-centennial-scale variability of marine productivity during the Holocene is closely related to North Atlantic climate oscillations, mainly through atmospheric circulations in winter.

Simultaneous Detection of Multiple Biomarkers by Peptide Nucleic Acids‐Based Triplex Molecular Beacon in a Nanopore

AbstractIn this study, we propose an enhanced nanopore sensing strategy that utilizes a peptide nucleic acid (PNA)‐based triplex molecular beacon sensor to achieve the simultaneous detection of multiple biomarkers with a high degree of sensitivity. The sensor is a triplex switch composed of a triplex‐forming DNA strand and an oligo‐arginine‐tagged PNA strand, serving as the target recognition moiety and signal output element, respectively. Upon target binding to the recognition element of the sensor, the PNA signal output strand is released and a hybrid complex of the target‐DNA recognition strand is formed simultaneously. Due to the positive charges carried by the PNA‐Arg strands, they could be driven through the nanopore under positive electric field, effectively eliminating interferences from co‐existing target‐DNA complexes. This approach enables label‐free, one‐step detection of targets without requiring complex treatments and procedures. Leveraging the modular properties of DNA recognition strand, this method can be applied universally, and here, we successfully demonstrate its application using three SARS‐CoV‐2 related biomarkers.

Clinical Correlations between Serological Markers and Endometrial Cancer.

Background: Endometrial cancer is associated with changes in blood cell counts and with high levels of inflammatory markers, thus reflecting the tumor's impact on various biological processes and suggesting their potential as biomarkers for endometrial cancer diagnosis, prognosis, and treatment response. The neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio in peripheral blood sampled preoperatively from patients have been reported to be independently associated with the prognosis of different types of malignancies. Objectives: This study aimed to compare several blood markers-red blood cells, white blood cells, platelet parameters, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, C-reactive protein, and fibrinogen-in patients with benign or malignant endometrial tumors. Material and methods: Our retrospective study included 670 patients (192 diagnosed with endometrial cancer and 478 with endometrial hyperplasia), and we compared the serological parameters discussed above with those sampled the day before surgery. Results: Analysis of complete blood count indices revealed no significant differences in red blood cell or total white blood cell parameters between the endometrial cancer group and the endometrial hyperplasia group. However, a distinct pattern emerged in the white blood cell differential. The endometrial cancer group showed a statistically significant decrease in lymphocyte count compared with the endometrial hyperplasia group. In contrast, the endometrial cancer group showed significantly higher mean platelet counts and increased mean platelet volume compared with controls. Furthermore, the endometrial cancer group demonstrated a marked inflammatory response, as evidenced by significantly elevated levels of C-reactive protein, fibrinogen, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio compared with the endometrial hyperplasia group. Conclusions: The current research revealed statistically significant differences in multiple serological biomarkers between the two groups. These findings support the initial hypothesis regarding the potential utility of these biomarkers in endometrial cancer diagnosis, prognosis, and treatment response, highlighting the existence of biomarkers affordable for analysis under any health system, regardless of the country's level of development.

Tumor biomarkers for diagnosis, prognosis and targeted therapy.

Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.

A novel method for multiple cardiovascular disease biomarker detection using a SERF-based microfluidic platform

As cardiovascular diseases (CVDs) are the leading cause of death worldwide, it is of great importance to realize a rapid and sensitive diagnosis. Multiple CVD biomarker detection, which holds higher accuracy and speed of early CVD diagnosis, is becoming a promising alternative to single biomarker analysis. Cardiac troponin I (cTnI), C-reactive protein (CRP), brain-type natriuretic peptide (BNP), and heart fatty acid binding protein (H-FABP) are four significant diagnostic biomarkers for CVDs. Among the several methods for biomarker detection, such as optical, magnetic, mechanical, and electrical methods, the magnetic method stands out because of its stability, low toxicity, noninvasive detection, facile manipulation with an external magnetic field, and immunity to the interference of background light. At present, the lack of multiplexing capability, the imprecision of magnetic signal localization, and the agglomeration and non-specific adsorption of magnetic nanoparticles all limit the clinical application of magnetic detection. This paper presented a novel method for multiple CVD biomarker detection using a spin exchange relaxation-free (SERF)-based microfluidic platform. One or more SERF atomic magnetometers were used to scan the remanent field of magnetic labels to detect four CVD biomarkers in 70 min, with a detection limit of 1.88 pg/mL (cTnI), 1.58 pg/mL (CRP), 1.45 pg/mL (BNP), and 1.71 pg/mL (H-FABP). The results showed two-dimensional magnetic fields with a resolution of submillimeter level and a sensitivity of pT level. The measurement technique provides a new magnetic methodology for applications in clinical diagnosis.

One-Year Longitudinal Assessment of Patients With CMT1A Using Quantitative MRI.

Intramuscular fat fraction (FF) assessed using quantitative MRI (qMRI) has emerged as one of the few responsive outcome measures in CMT1A suitable for future clinical trials. This study aimed to identify the relevance of multiple qMRI biomarkers for tracking longitudinal changes in CMT1A and to assess correlations between MRI metrics and clinical parameters. qMRI was performed in CMT1A patients at 2 time points, a year apart, and various metrics were extracted from 3-dimensional volumes of interest at thigh and leg levels. A semiautomated segmentation technique was used, enabling the analysis of central slices and a larger 3D muscle volume. Metrics included proton density (PD), magnetization transfer ratio (MTR), and intramuscular FF. The sciatic and tibial nerves were also assessed. Disease severity was gauged using Charcot Marie Tooth Neurologic Score (CMTNSv2), Charcot Marie Tooth Examination Score, Overall Neuropathy Limitation Scale scores, and Medical Research Council (MRC) muscle strength. Twenty-four patients were included. FF significantly rose in the 3D volume at both thigh (+1.04% ± 2.19%, p = 0.041) and leg (+1.36% ± 1.87%, p = 0.045) levels. The 3D analyses unveiled a length-dependent gradient in FF, ranging from 22.61% ± 10.17% to 26.17% ± 10.79% at the leg level. There was noticeable variance in longitudinal changes between muscles: +3.17% ± 6.86% (p = 0.028) in the tibialis anterior compared with 0.37% ± 4.97% (p = 0.893) in the gastrocnemius medialis. MTR across the entire thigh volume showed a significant decline between the 2 time points -2.75 ± 6.58 (p = 0.049), whereas no significant differences were noted for the 3D muscle volume and PD. No longitudinal changes were observed in any nerve metric. Potent correlations were identified between FF and primary clinical measures: CMTNSv2 (ρ = 0.656; p = 0.001) and MRC in the lower limbs (ρ = -0.877; p < 0.001). Our results further support that qMRI is a promising tool for following up longitudinal changes in CMT1A patients, FF being the paramount MRI metric for both thigh and leg regions. It is crucial to scrutinize the postimaging data extraction methods considering that annual changes are minimal (around +1.5%). Given the varied FF distribution, the existence of a length-dependent gradient, and the differential fatty involution across muscles, 3D volume analysis appeared more suitable than single slice analysis.