Disease Biomarkers Research Articles

Distinctive Pattern of Metal Deposition in Neurologic Wilson Disease: Insights From 7T Susceptibility-Weighted Imaging.

Noninvasive and accurate biomarkers of neurologic Wilson disease (NWD), a rare inherited disorder, could reduce diagnostic error or delay. Excessive subcortical metal deposition seen on susceptibility imaging has suggested a characteristic pattern in NWD. With submillimeter spatial resolution and increased contrast, 7T susceptibility-weighted imaging (SWI) may enable better visualization of metal deposition in NWD. In this study, we sought to identify a distinctive metal deposition pattern in NWD using 7T SWI and investigate its diagnostic value and underlying pathophysiologic mechanism. Patients with WD, healthy participants with monoallelic ATP7B variant(s) on a single chromosome, and health controls (HCs) were recruited. NWD and non-NWD (nNWD) were defined according to the presence or absence of neurologic symptoms during investigation. Patients with other diseases with comparable clinical or imaging manifestations, including early-onset Parkinson disease (EOPD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and neurodegeneration with brain iron accumulation (NBIA), were additionally recruited and assessed for exploratory comparative analysis. All participants underwent 7T T1, T2, and high-resolution SWI scanning. Quantitative susceptibility mapping and principal component analysis were performed to illustrate metal distribution. We identified a linear signal intensity change consisting of a hyperintense strip at the lateral border of the globus pallidus in patients with NWD. We termed this feature "hyperintense globus pallidus rim sign." This feature was detected in 38 of 41 patients with NWD and was negative in all 31 nNWD patients, 15 patients with EOPD, 30 patients with MSA, 15 patients with PSP, and 12 patients with NBIA; 22 monoallelic ATP7B variant carriers; and 41 HC. Its sensitivity to differentiate between NWD and HC was 92.7%, and specificity was 100%. Severity of the hyperintense globus pallidus rim sign measured by a semiquantitative scale was positively correlated with neurologic severity (ρ = 0.682, 95% CI 0.467-0.821, p < 0.001). Patients with NWD showed increased susceptibility in the lenticular nucleus with high regional weights in the lateral globus pallidus and medial putamen. The hyperintense globus pallidus rim sign showed high sensitivity and excellent specificity for diagnosis and differential diagnosis of NWD. It is related to a special metal deposition pattern in the lenticular nucleus in NWD and can be considered as a novel neuroimaging biomarker of NWD. The study provides Class II evidence that the hyperintense globus pallidus rim sign on 7T SWI MRI can accurately diagnose neurologic WD.

Predicting Driving Cessation Among Cognitively Normal Older Drivers: The Role of Alzheimer Disease Biomarkers and Clinical Assessments.

With the aging US population and increasing incidence of Alzheimer disease (AD), understanding factors contributing to driving cessation among older adults is crucial for clinicians. Driving is integral for maintaining independence and functional mobility, but the risk factors for driving cessation, particularly in the context of normal aging and preclinical AD, are not well understood. We studied a well-characterized community cohort to examine factors associated with driving cessation. This prospective, longitudinal observation study enrolled participants from the Knight Alzheimer Disease Research Center and The DRIVES Project. Participants were enrolled if they were aged 65 years or older, drove weekly, and were cognitively normal (Clinical Dementia Rating [CDR] = 0) at baseline. Participants underwent annual clinical, neurologic, and neuropsychological assessments, including β-amyloid PET imaging and CSF (Aβ42, total tau [t-Tau], and phosphorylated tau [p-Tau]) collection every 2-3 years. The primary outcome was time from baseline visit to driving cessation, accounting for death as a competing risk. The cumulative incidence function of driving cessation was estimated for each biomarker. The Fine and Gray subdistribution hazard model was used to examine the association between time to driving cessation and biomarkers adjusting for clinical and demographic covariates. Among the 283 participants included in this study, there was a mean follow-up of 5.62 years. Driving cessation (8%) was associated with older age, female sex, progression to symptomatic AD (CDR ≥0.5), and poorer performance on a preclinical Alzheimer cognitive composite (PACC) score. Aβ PET imaging did not independently predict driving cessation, whereas CSF biomarkers, specifically t-Tau/Aβ42 (hazard ratio [HR] 2.82, 95% CI 1.23-6.44, p = 0.014) and p-Tau/Aβ42 (HR 2.91, 95% CI 1.28-6.59, p = 0.012) ratios, were independent predictors in the simple model adjusting for age, education, and sex. However, in the full model, progression to cognitive impairment based on the CDR and PACC score across each model was associated with a higher risk of driving cessation, whereas AD biomarkers were not statistically significant. Female sex, CDR progression, and neuropsychological measures of cognitive functioning obtained in the clinic were strongly associated with future driving cessation. The results emphasize the need for early planning and conversations about driving retirement in the context of cognitive decline and the immense value of clinical measures in determining functional outcomes.

Blood Pressure Variability and Plasma Biomarkers of Neuronal Injury and Alzheimer's Disease: A Clinic-Based Study of Patients with Diseases Along the Heart-Brain Axis.

Higher blood pressure variability (BPV) predisposes to cognitive decline. To investigate underlying mechanisms, we measured 24-h ambulatory BPV, nocturnal dipping and orthostatic hypotension in 518 participants with vascular cognitive impairment, carotid occlusive disease, heart failure, or reference participants. We determined cross-sectional associations between BPV indices and plasma biomarkers of neuronal injury (neurofilament light chain) and Alzheimer's disease (phosphorylated-tau-181 and Aβ42/Aβ40). None of the BPV indices were significantly associated with any of the biomarkers. Hence, in patients with diseases along the heart-brain axis, we found no evidence for an association between BPV and selected markers of neuronal injury or Alzheimer's disease.

Ellipsoid Zone Reflectivity: Exploring its Potential as a Novel Non-Invasive Biomarker for Assessing Mitochondrial Function

ABSTRACT The ellipsoid zone (EZ) on macular optical coherence tomography (OCT) scans exhibits high intensity due to a high density of light-scattering mitochondria, making its reflectivity a potential marker for mitochondrial function. Here, we developed a reliable analysis tool for extracting relative EZ reflectivity and explore its potential as a biomarker in various diseases. We analysed OCT scans of patients with optic neuritis (ON), primary progressive optic neuropathy (PPON), chronic progressive external ophthalmoplegia (CPEO), dominant optic atrophy (DOA), and healthy controls. EZ reflectivity (normalised to the retina pigment epithelium (RPE) and outer nuclear layer (ONL)) was evaluated. Reliability was assessed using intraclass correlation coefficients (ICC), and group differences were analysed through multivariable linear regression, adjusting for relevant confounders. In total, 12 controls, 23 ON patients, 7 CPEO patients, 13 DOA patients, and 13 PPON patients were included. EZ/RPE20% and EZ/ONL ratios demonstrated good test–retest reliability with ICCs of 0.76 (p < .001) and 0.63 (p = .013), respectively. Multivariable regression analysis revealed that median EZ/RPE20% and EZ/ONL ratios were lower in CPEO (r = -0.12, p = .036, and r = -0.59, p = .011), DOA (r = -0.16, p = .049, and r = -0.55, p = .082), PPON (r = -0.17, p = .014, and r = -0.57, p = .037), and ON (r = -0.11, p = .013, and r = -0.42, p = .006) compared to controls, respectively. These data show that EZ reflectivity can be reliably determined from OCT scans and appears to be reduced in neuroinflammatory and mitochondrial disorders. Further validation in larger prospective cohorts is warranted, but our findings suggest that EZ reflectivity might serve as a non-invasive in-vivo biomarker for mitochondrial health.

Associations between regional blood-brain barrier permeability, aging, and Alzheimer's disease biomarkers in cognitively normal older adults.

Increased blood-brain barrier permeability (BBBp) has been hypothesized as a feature of aging that may lead to the development of Alzheimer's disease (AD). We sought to identify the brain regions most vulnerable to greater BBBp during aging and examine their regional relationship with neuroimaging biomarkers of AD. We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify Ktrans values, as a measure of BBBp, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)- PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBp than YA. In OA, Ktrans values were compared based on sex, Aβ positivity status, and APOE4 carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between Ktrans and AD biomarkers. OA showed greater BBBp than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in Ktrans values based on sex or Aβ positivity, but OA who were APOE4 carriers had significantly higher Ktrans values. There was no direct relationship between averaged Ktrans and global Aβ pathology, but there was a trend for an Ab status by tau interaction on Ktrans in this region. SCCA showed increased Ktrans was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between Ktrans and FTP SUVR. Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBp in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aβ.

Growth/differentiation factor 15 (GDF15) expression in the heart after myocardial infarction and cardioprotective effect of pre-ischemic rGDF15 administration

Growth/differentiation factor-15 (GDF15) is considered an unfavourable prognostic biomarker for cardiovascular disease in clinical data, while experimental studies suggest it has cardioprotective potential. This study focuses on the direct cardiac effects of GDF15 during ischemia–reperfusion injury in Wistar male rats, employing concentrations relevant to patients at high cardiovascular risk. Initially, we examined circulating levels and heart tissue expression of GDF15 in rats subjected to ischemia–reperfusion and sham operations in vivo. We then evaluated the cardiac effects of GDF15 both in vivo and ex vivo, administering recombinant GDF15 either before 30 min of ischemia (preconditioning) or at the onset of reperfusion (postconditioning). We compared infarct size and cardiac contractile recovery between control and rGDF15-treated rats. Contrary to our expectations, ischemia–reperfusion did not increase GDF15 plasma levels compared to sham-operated rats. However, cardiac protein and mRNA expression increased in the infarcted zone of the ischemic heart after 24 h of reperfusion. Notably, preconditioning with rGDF15 had a cardioprotective effect, reducing infarct size both in vivo (65 ± 5% in control vs. 42 ± 6% in rGDF15 groups) and ex vivo (60 ± 4% in control vs. 45 ± 4% in rGDF15 groups), while enhancing cardiac contractile recovery ex vivo. However, postconditioning with rGDF15 did not alter infarct size or the recovery of contractile parameters in vivo or ex vivo. These novel findings reveal that the short-term exogenous administration of rGDF15 before ischemia, at physiologically relevant levels, protects the heart against ischemia–reperfusion injury in both in vivo and ex vivo settings. The ex vivo results indicate that rGDF15 operates independently of the inflammatory, endocrine and nervous systems, suggesting direct and potent cardioprotective properties against ischemia–reperfusion injury.

Cognitive reserve, cortisol, and Alzheimer's disease biomarkers: A memory clinic study.

Cognitive reserve might mitigate the risk of Alzheimer's dementia among memory clinic patients. No study has examined the potential modifying role of stress on this relation. We examined cross-sectional associations of the cognitive reserve index (CRI; education, occupational complexity, physical and leisure activities, and social health) with cognitive performance and AD-related biomarkers among 113 memory clinic patients. The longitudinal association between CRI and cognition over a 3-year follow-up was assessed. We examined whether associations were influenced by perceived stress and five measures of diurnal salivary cortisol. Higher CRI scores were associated with better cognition. Adjusting for cortisol measures reduced the beneficial association of CRI on cognition. A higher CRI score was associated with better working memory in individuals with higher (favorable) cortisol AM/PM ratio, but not among individuals with low cortisol AM/PM ratio. No association was found between CRI and AD-related biomarkers. Physiological stress reduces the neurocognitive benefits of cognitive reserve among memory clinic patients. Physiological stress may reduce the neurocognitive benefits accrued from cognitively stimulating and enriching life experiences (cognitive reserve [CR]) in memory clinic patients. Cortisol awakening response modified the relation between CR and P-tau181, a marker of Alzheimer's disease (AD). Effective stress management techniques for AD and related dementia prevention are warranted.

Brain age gap estimation using attention-based ResNet method for Alzheimer’s disease detection

This study investigates the correlation between brain age and chronological age in healthy individuals using brain MRI images, aiming to identify potential biomarkers for neurodegenerative diseases like Alzheimer's. To achieve this, a novel attention-based ResNet method, 3D-Attention-Resent-SVR, is proposed to accurately estimate brain age and distinguish between Cognitively Normal (CN) and Alzheimer’s disease (AD) individuals by computing the brain age gap (BAG). Unlike conventional methods, which often rely on single datasets, our approach addresses potential biases by employing four datasets for training and testing. The results, based on a combined dataset from four public sources comprising 3844 data points, demonstrate the model's efficacy with a mean absolute error (MAE) of 2.05 for brain age gap estimation. Moreover, the model's generalizability is showcased by training on three datasets and testing on a separate one, yielding a remarkable MAE of 2.4. Furthermore, leveraging BAG as the sole biomarker, our method achieves an accuracy of 92% and an AUC of 0.87 in Alzheimer's disease detection on the ADNI dataset. These findings underscore the potential of our approach in assisting with early detection and disease monitoring, emphasizing the strong correlation between BAG and AD.

Urinary complement biomarkers in immune-mediated kidney diseases.

The complement system, an important part of the innate system, is known to play a central role in many immune mediated kidney diseases. All parts of the complement system including the classical, alternative, and mannose-binding lectin pathways have been implicated in complement-mediated kidney injury. Although complement components are thought to be mainly synthesized in the liver and activated in the circulation, emerging data suggest that complement is synthesized and activated inside the kidney leading to direct injury. Urinary complement biomarkers are likely a better reflection of inflammation within the kidneys as compared to traditional serum complement biomarkers which may be influenced by systemic inflammation. In addition, urinary complement biomarkers have the advantage of being non-invasive and easily accessible. With the rise of therapies targeting the complement pathways, there is a critical need to better understand the role of complement in kidney diseases and to develop reliable and non-invasive biomarkers to assess disease activity, predict treatment response and guide therapeutic interventions. In this review, we summarized the current knowledge on urinary complement biomarkers of kidney diseases due to immune complex deposition (lupus nephritis, primary membranous nephropathy, IgA nephropathy) and due to activation of the alternative pathway (C3 glomerulopathy, thrombotic microangiography, ANCA-associated vasculitis). We also address the limitations of current research and propose future directions for the discovery of urinary complement biomarkers.

An interactive atlas of genomic, proteomic, and metabolomic biomarkers promotes the potential of proteins to predict complex diseases

Multiomics analyses have identified multiple potential biomarkers of the incidence and prevalence of complex diseases. However, it is not known which type of biomarker is optimal for clinical purposes. Here, we make a systematic comparison of 90 million genetic variants, 1453 proteins, and 325 metabolites from 500,000 individuals with complex diseases from the UK Biobank. A machine learning pipeline consisting of data cleaning, data imputation, feature selection, and model training using cross-validation and comparison of the results on holdout test sets showed that proteins were most predictive, followed by metabolites, and genetic variants. Only five proteins per disease resulted in median (min–max) areas under the receiver operating characteristic curves for incidence of 0.79 (0.65–0.86) and 0.84 (0.70–0.91) for prevalence. In summary, our work suggests the potential of predicting complex diseases based on a limited number of proteins. We provide an interactive atlas (macd.shinyapps.io/ShinyApp/) to find genomic, proteomic, or metabolomic biomarkers for different complex diseases.

Temporal composition of the cervicovaginal microbiome associates with hrHPV infection outcomes in a longitudinal study

BackgroundPersistent infections with high-risk human papillomavirus (hrHPV) can cause cervical squamous intraepithelial lesions (SIL) that may progress to cancer. The cervicovaginal microbiome (CVM) correlates with SIL, but the temporal composition of the CVM after hrHPV infections has not been fully clarified.MethodsTo determine the association between the CVM composition and infection outcome, we applied high-resolution microbiome profiling using the circular probe-based RNA sequencing technology on a longitudinal cohort of cervical smears obtained from 141 hrHPV DNA-positive women with normal cytology at first visit, of whom 51 were diagnosed by cytology with SIL six months later.ResultsHere we show that women with a microbial community characterized by low diversity and high Lactobacillus crispatus abundance at both visits exhibit low risk to SIL development, while women with a microbial community characterized by high diversity and Lactobacillus depletion at first visit have a higher risk of developing SIL. At the level of individual species, we observed that a high abundance for Gardnerella vaginalis and Atopobium vaginae at both visits associate with SIL outcomes. These species together with Dialister micraerophilus showed a moderate discriminatory power for hrHPV infection progression.ConclusionsOur results suggest that the CVM can potentially be used as a biomarker for cervical disease and SIL development after hrHPV infection diagnosis with implications on cervical cancer prevention strategies and treatment of SIL.

Nanoenzyme Hydrogel Film-Based Portable Point-of-Care Testing Platform for Double-Signal Visual Detection of PSA.

The development of the Point-of-Care Testing (POCT) platform that combines convenience and cost-effectiveness is crucial for enabling the visual detection of disease biomarkers. In this work, a POCT platform for the sensitive in situ detection of prostate specific antigen (PSA) with dual-signal output was constructed by functionalizing the Eppendorf (EP) tube. This was achieved through the modification of aptamer hairpin probes (AHPs) on the lid of the EP tube and the assembly of a nanoenzyme hydrogel film on its inner wall. The target could trigger the release of Ag+ by AHP and subsequently activate Ag+-dependent DNAzyme (Ag-DNAzyme). This would initiate the cleavage of the DNA-Au/Pt NP hydrogel network, leading to the release of Au/Pt NPs. The released Au/Pt NPs exhibit both peroxidase (POD)-like and catalase (CAT)-like activity to produce a colorimetric response and induce liquid flow under pressure. Therefore, the target can be measured visually and quantitatively through colorimetric analysis and the measurement of total dissolved solids (TDS) using a pressure-triggered liquid flow device integrated into the platform. The designed platform is distinguished by its simplicity, specificity, cost-effectiveness, and remarkable sensitivity. It allows for the visual detection of PSA within concentration ranges of 0.5-100 ng/L (colorimetric) and 3-100 ng/L (TDS reading), boasting detection limits as low as 0.15 ng/L (colorimetric) and 0.57 ng/L (TDS reading). The strategy of target-triggered nanoenzyme release significantly enhances sensitivity and provides a guiding approach for visual biomarker detection.

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.

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.

A compact breath breathalyzer for identifying the non-alcoholic fatty liver disease biomarker

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease worldwide. Currently, its diagnosis relies primarily on imaging and histological examinations, which are invasive and prone to misdiagnosis in the early stage. To address these limitations, detection and analysis of volatile organic compounds (VOCs) in human breath can be a rapid and non-invasive screening method for NAFLD. In this study, a compact breath breathalyzer was developed, utilizing a miniaturized gas chromatography chip with the STM32 microcontroller as the main control chip to manage airflow, temperature, and receive terminal signals from the photoionization detector. In the experiment, a gas mixture comprising five VOCs (pentane, acetone, toluene, octane, and decane) was selected as the simulated typical disease biomarkers in human breath to investigate the breathalyzer's performance and optimize testing conditions for multi-polar and wide-boiling-range breath samples. Results show that the breathalyzer can detect low-boiling components (< 100°C) such as the isoprene and acetone, with a detection limit less than 50 ppb which are two commonly biomarkers of NAFLD. Furthermore, breath samples were collected from 35 non-diseased individuals, and NAFLD early-stage patient samples were simulated by increasing the isoprene concentration by 10 ppb. Convolutional neural network (CNN) were used to identify the VOC signatures in gas chromatograms with predictive accuracy of 85% for the classification model. Therefore, the compact breath breathalyzer has potential application in the rapid and early screening of NAFLD.

A comprehensive analysis of minimally differentially methylated regions common to pediatric and adult solid tumors

Cancer is the second most common cause of death in children aged 1–14 years in the United States, with 11,000 new cases and 1200 deaths annually. Pediatric cancers typically have lower mutational burden compared to adult-onset cancers, however, the epigenomes in pediatric cancer are highly altered, with widespread DNA methylation changes. The rarity of pediatric cancers poses a significant challenge to developing cancer-type specific biomarkers for diagnosis, prognosis, or treatment monitoring. In the current study, we explored the potential of a DNA methylation profile common across various pediatric cancers. To do this, we conducted whole genome bisulfite sequencing (WGBS) on 31 recurrent pediatric tumor tissues, 13 normal tissues, and 20 plasma cell-free (cf)DNA samples, representing 11 different pediatric cancer types. We defined minimal focal regions that were differentially methylated across samples in the multiple cancer types which we termed minimally differentially methylated regions (mDMRs). These methylation changes were also observed in 506 pediatric and 5691 adult cancer samples accessed from publicly available databases, and in 44 pediatric cancer samples we analyzed using a targeted hybridization probe capture assay. Finally, we found that these methylation changes were detectable in cfDNA and could serve as potential cfDNA methylation biomarkers for early detection or minimal residual disease.

MicroRNAs as Key Regulators in RA and SLE: Insights into Biological Functions.

MicroRNAs (miRNAs) are non-coding RNA molecules that bind to mRNAs to regulate gene expression. Since changes in miRNA expression levels have been found in a variety of autoimmune illnesses, miRNAs are important in autoimmune diseases. MiRNAs serve not only as pathogenic factors and biomarkers for autoimmune diseases but also as important targets for disease therapeutics. Although miRNA-based treatments are still in the research stage, in-depth investigations into the biological functions of miRNAs have significantly enhanced our understanding of their mechanisms in autoimmune diseases. The purpose of this review is to summarize the biological functions of miRNAs, their roles in rheumatoid arthritis and systemic lupus erythematosus, therapeutic strategies, and challenges.

Contrastive Brain Network Learning via Hierarchical Signed Graph Pooling Model.

Recently, brain networks have been widely adopted to study brain dynamics, brain development, and brain diseases. Graph representation learning techniques on brain functional networks can facilitate the discovery of novel biomarkers for clinical phenotypes and neurodegenerative diseases. However, current graph learning techniques have several issues on brain network mining. First, most current graph learning models are designed for unsigned graph, which hinders the analysis of many signed network data (e.g., brain functional networks). Meanwhile, the insufficiency of brain network data limits the model performance on clinical phenotypes' predictions. Moreover, few of the current graph learning models are interpretable, which may not be capable of providing biological insights for model outcomes. Here, we propose an interpretable hierarchical signed graph representation learning (HSGPL) model to extract graph-level representations from brain functional networks, which can be used for different prediction tasks. To further improve the model performance, we also propose a new strategy to augment functional brain network data for contrastive learning. We evaluate this framework on different classification and regression tasks using data from human connectome project (HCP) and open access series of imaging studies (OASIS). Our results from extensive experiments demonstrate the superiority of the proposed model compared with several state-of-the-art techniques. In addition, we use graph saliency maps, derived from these prediction tasks, to demonstrate detection and interpretation of phenotypic biomarkers.

Yet more evidence that non-aqueous myelin lipids can be directly imaged with ultrashort echo time (UTE) MRI on a clinical 3T scanner: a lyophilized red blood cell membrane lipid study

Direct imaging of semi-solid lipids, such as myelin, is of great interest as a noninvasive biomarker of neurodegenerative diseases. Yet, the short T2 relaxation times of semi-solid lipid protons hamper direct detection through conventional magnetic resonance imaging (MRI) pulse sequences. In this study, we examined whether a three-dimensional ultrashort echo time (3D UTE) sequence can directly acquire signals from membrane lipids. Membrane lipids from red blood cells (RBC) were collected from commercially available blood as a general model of the myelin lipid bilayer and subjected to D2O exchange and freeze-drying for complete water removal. Sufficiently high MR signals were detected with the 3D UTE sequence, which showed an ultrashort T2* of ∼77–271 µs and a short T1 of ∼189 ms for semi-solid RBC membrane lipids. These measurements can guide designing UTE-based sequences for direct in vivo imaging of membrane lipids.

C-reactive protein/lymphocyte ratio as a prognostic biomarker in acute pancreatitis: A cross-sectional study assessing disease severity.

The C-reactive protein/lymphocyte ratio (CLR) is a prognostic biomarker of various diseases. However, its significance in acute pancreatitis (AP) remains unknown. The main aim of this study was to investigate the association between the CLR and disease severity in patients with AP. This cross-sectional study included 476 AP patients (mild acute pancreatitis (MAP), n =176; moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP), n=300). The primary exposure of interest was the baseline CLR. The primary outcome was the incidence of moderate to severe AP. Multivariate logistic regression and restricted cubic spline analyses were performed to evaluate the association between the CLR and the incidence of moderate to severe AP. Receiver operating characteristic (ROC) analysis was conducted to assess the predictive efficacy, sensitivity, and specificity of CLR in predicting the incidence of moderate to severe AP. The mean age of the patients was 44±13.2 years, and 76.5% were male. The distribution of CLR was 31.6 (interquartile range, 4.5, 101.7). Moderate to severe AP occurred in 300 cases (63.0%). After multiple adjustments, CLR was independently associated with the incidence of moderate to severe AP (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.03, 1.05; P< 0.001). A nonlinear relationship was found between CLR and the incidence of moderate to severe AP, with a threshold of approximately 45. The effect size and CI below and above the threshold value were 1.061 (1.033-1.089) and 1.014 (0.997-1.031), respectively. The area under the curve (AUC) for CLR was 87.577% (95% CI: 84.443% ~ 90.710%) with an optimal cut-off value of 30.835, resulting in a sensitivity of 73.7% and a specificity of 88.6%. There was a nonlinear relationship with a saturation effect between the CLR and the incidence of moderate to severe AP. The CLR measured within 24 h of admission may serve as a promising biomarker for predicting the emergence of moderate to severe AP, thereby providing a more scientifically grounded basis for preventing such cases. Nonetheless, further research is warranted to validate and strengthen these findings.