Blood-based Biomarkers Research Articles

Exploratory Analyses of Circulating Neoplastic-Immune Hybrid Cells as Prognostic Biomarkers in Advanced Intrahepatic Cholangiocarcinoma.

Existing clinical biomarkers do not reliably predict treatment response or disease progression in patients with advanced intrahepatic cholangiocarcinoma (ICC). Circulating neoplastic-immune hybrid cells (CHCs) have great promise as a blood-based biomarker for patients with advanced ICC. Peripheral blood specimens were longitudinally collected from patients with advanced ICC enrolled in the HELIX-1 phase II clinical trial (NCT04251715). CHCs were identified by co-expression of pan-cytokeratin (CK) and CD45, and levels were correlated to patient clinical disease course. Unsupervised machine learning was then performed to extract their morphological features to compare them across disease courses. Five patients were included in this study, with a median of nine specimens collected per patient. A median of 13.5 CHCs per 50,000 peripheral blood mononuclear cells were identified at baseline, and levels decreased to zero following the initiation of treatment in all patients. Counts remained undetectable in three patients who demonstrated end-of-trial clinical treatment response and conversely increased in two patients with evidence of therapeutic resistance. In the post-trial surveillance period, interval counts increased prior to or at the time of clinical progression in three patients and remain undetectable in one patient with continued long-term disease stability. Using our machine learning platform, treatment-resistant CHCs exhibited upregulation of CK and downregulation of CD45 relative to treatment-responsive CHCs. CHCs represent a promising blood-based biomarker to supplement traditional radiographic and biochemical measures.

Impact of Molecular Profiling on Therapy Management in Breast Cancer.

Breast cancer (BC) remains the most prevalent cancer among women and the leading cause of cancer-related mortality worldwide. The heterogeneity of BC in terms of histopathological features, genetic polymorphisms, and response to therapies necessitates a personalized approach to treatment. This review focuses on the impact of molecular profiling on therapy management in breast cancer, emphasizing recent advancements in next-generation sequencing (NGS) and liquid biopsies. These technologies enable the identification of specific molecular subtypes and the detection of blood-based biomarkers such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and tumor-educated platelets (TEPs). The integration of molecular profiling with traditional clinical and pathological data allows for more tailored and effective treatment strategies, improving patient outcomes. This review also discusses the current challenges and prospects of implementing personalized cancer therapy, highlighting the potential of molecular profiling to revolutionize BC management through more precise prognostic and therapeutic interventions.

Evidence for Altered White Matter Organization After Mild Traumatic Brain Injury: A Scoping Review on the Use of Diffusion Magnetic Resonance Imaging and Blood-Based Biomarkers to Investigate Acute Pathology and Relationship to Persistent Post-Concussion Symptoms.

Mild traumatic brain injury (mTBI) is the most common form of traumatic brain injury. Post-concussive symptoms typically resolve after a few weeks although up to 20% of people experience these symptoms for >3 months, termed persistent post-concussive symptoms (PPCS). Subtle white matter (WM) microstructural damage is thought to underlie neurological and cognitive deficits experienced post-mTBI. Evidence suggests that diffusion magnetic resonance imaging (dMRI) and blood-based biomarkers could be used as surrogate markers of WM organization. We conducted a scoping review according to PRISMA-ScR guidelines, aiming to collate evidence for the use of dMRI and/or blood-based biomarkers of WM organization, in mTBI and PPCS, and document relationships between WM biomarkers and symptoms. We focused specifically on biomarkers of axonal or myelin integrity post-mTBI. Biomarkers excluded from this review therefore included the following: astroglial, perivascular, endothelial, and inflammatory markers. A literature search performed across four databases, EMBASE, Scopus, Google Scholar, and ProQuest, identified 100 records: 68 analyzed dMRI, 28 assessed blood-based biomarkers, and 4 used both. Blood biomarker studies commonly assessed axonal cytoskeleton proteins (i.e., tau); dMRI studies assessed measures of WM organization (i.e., fractional anisotropy). Significant biomarker alterations were frequently associated with heightened symptom burden and prolonged recovery time post-injury. These data suggest that dMRI and blood-based biomarkers may be useful proxies of WM organization, although few studies assessed these complementary measures in parallel, and the relationship between modalities remains unclear. Further studies are warranted to assess the benefit of a combined biomarker approach in evaluating alterations to WM organization after mTBI.

Innovations in Early Lung Cancer Detection: Tracing the Evolution and Advancements in Screening.

Lung cancer mortality rates, particularly non-small cell lung cancer (NSCLC), continue to present a significant global health challenge, and the adoption of lung cancer screening remains limited, often influenced by inequities in access to healthcare. Despite clinical evidence demonstrating the efficacy of annual screening with low-dose computed tomography (LDCT) and recommendations from medical organizations including the U.S. Preventive Services Task Force (USPSTF), the national lung cancer screening uptake remains around 5% among eligible individuals. Advancements in the clinical management of NSCLC have recently become more personalized with the implementation of blood-based biomarker testing. Extensive research into tumor-derived cell-free DNA (cfDNA) through fragmentation offers a novel method for improving early lung cancer detection. This review assesses the screening landscape, explores obstacles to lung cancer screening, and discusses how a plasma whole genome fragmentome test (pWGFrag-Lung) can improve lung cancer screening participation and adherence.

Higher serum uric acid as a risk factor for frailty in older adults: A nationwide population-based study.

Uric acid (UA), the terminal breakdown product of purine metabolism, possesses contradictory roles, functioning both as an inflammatory mediator and as an antioxidant. Its clinical relevance, particularly in geriatric populations, remains a topic of ongoing debate. Aiming to elucidate whether circulating UA is detrimental or beneficial to human health, we investigate the association between serum UA concentrations and the frailty index-a comprehensive measure of biological aging in a nationally representative cohort of community-dwelling older adults. We conducted a population-based, cross-sectional study utilizing data from the Korea National Health and Nutrition Examination Survey. The sample included 4268 participants aged 65years and above. A deficit accumulation frailty index (FI) was constructed using 38 items that assess physical, cognitive, psychological, and social domains. Based on the FI, participants were categorized into non-frail (FI≤0.15), pre-frail (0.15<FI≤0.25), or frail (FI>0.25). Serum UA levels were quantified through a colorimetric enzymatic assay. After controlling for confounders such as age, sex, socioeconomic status (including income and education level), lifestyle factors (smoking status), and medical history (hypertension, diabetes, dyslipidemia, stroke, cardiovascular diseases), and body mass index, serum UA levels were observed to be significantly higher in frail participants compared with their non-frail counterparts (P<0.001). Furthermore, serum UA concentrations demonstrated a positive correlation with the FI (P<0.001), and the odds ratio for frailty per 1mg/dL increase in serum UA was 1.22 (P<0.001). Additionally, older adults in the highest quartile of UA levels exhibited a significantly higher FI and 1.66-fold increased odds of frailty compared with those in the lowest quartile (P=0.011 and P=0.005, respectively). These findings suggest that elevated circulating UA levels may act as a pro-aging factor rather than an anti-aging one in older adults, highlighting its potential role in accelerating biological aging. The data further support the utility of serum UA as a potential blood-based biomarker for frailty in this demographic, contributing to the expanding evidence on its significance in geriatric health assessments.

Blood-based biomarkers of neuronal and glial injury in active major neuropsychiatric systemic lupus erythematosus.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a poorly understood and heterogeneous manifestation of SLE. Common major NPSLE syndromes include strokes, seizures, myelitis, and aseptic meningitis. Easily obtainable biomarkers are needed to assist in early diagnosis and improve outcomes for NPSLE. A frequent end-result of major syndromes is neuronal or glial injury. Blood-based neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) have been utilized as markers for monitoring disease activity and/or severity in other neurodegenerative and neuroinflammatory diseases; however, they have not been evaluated in active major NPSLE. This was a case-control study. We enrolled patients aged 12-60 years with active major NPSLE, SLE without active major NPSLE, and healthy controls. Active NPSLE was defined as being <6months from last new or worsening neuropsychiatric symptom. Demographics, clinical data, and serum or plasma biosamples were collected. Thirteen patients with active major NPSLE, 13age/sex/kidney function matched SLE controls without active major NPSLE, and 13age/sex matched healthy controls (mean ages 26.8, 27.3, 26.6years) were included. 92% of each group were female. Major syndromes included stroke (5), autonomic disorder (3), demyelinating disease (2), aseptic meningitis (2), sensorimotor polyneuropathy (2), cranial neuropathy (1), seizures (1), and myelopathy (2). Mean (standard deviation) blood NfL and GFAP were 3.6 pg/ml (2.0) and 50.4 pg/ml (15.0), respectively, for the healthy controls. Compared to healthy controls, SLE without active major NPSLE had mean blood NfL and GFAP levels 1.3pg/ml (p = .42) and 1.2pg/ml higher (p = .53), respectively. Blood NfL was on average 17.9 pg/ml higher (95% CI: 9.2, 34.5; p < .001) and blood GFAP was on average 3.2pg/ml higher (95% CI: 1.9, 5.5; p < .001) for cases of active major NPSLE compared to SLE without active major NPSLE. In a subset of 6 patients sampled at multiple time points, blood NfL and GFAP decreased after immunotherapy. Blood NfL and GFAP levels are elevated in persons with SLE with active major NPSLE compared to disease matched controls and may lower after immunotherapy initiation. Larger and longitudinal studies are needed to ascertain their utility in a clinical setting.

Biomarkers and Endophenotypes of Post-traumatic Headaches.

To review existing literature on biomarkers for post-traumatic headache (PTH). Preclinical models and clinical findings have started to elucidate the biology that underlies PTH. Traumatic brain injury results in ionic flux, glutamatergic surge, and activation of the trigeminal cervical complex resulting in the release of pain neuropeptides. These neuropeptides, including calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP), play a key role in the pathophysiology of migraine and other primary headache disorders. Only two studies were identified that evaluated CGRP levels in PTH. Neither study found a consistent relationship between CGRP levels and PTH. One study did discover that nerve growth factor (NGF) was elevated in subjects with PTH. There is no conclusive evidence for reliable blood-based biomarkers for PTH. Limitations in assays, collection technique, and time since injury must be taken into account. There are multiple ideal candidates that have yet to be explored.

Blood Transcriptomic and Inflammatory Protein Biomarkers Associated with Imminent Pulmonary Exacerbation Risk in Cystic Fibrosis.

The factors that lead to poor pulmonary exacerbation (PEx) outcomes in individuals with cystic fibrosis (CF) are still being investigated; however, delayed diagnosis and treatment are likely contributory. Identifying individuals at imminent risk of PEx could enable closer monitoring and/or earlier initiation of therapies to improve outcomes. The goal of this study was to develop blood-based biomarkers that associate with imminent PEx risk in CF individuals. We examined the whole blood transcriptome and 55 inflammatory proteins from plasma and serum on 72 blood samples from 53 CF individuals. Biomarker candidate genes and proteins were selected from 14 CF individuals with paired stable and PEx visits (Cohort 1). The biomarker candidates were then estimated and tested to classify CF individuals who would experience a PEx within 4-months of a stable clinic visit or not (Cohort 2). A 16-gene panel and 9-protein panel were identified that could distinguish paired stable and PEx visits (AUC = 0.83 ± SE 0.28 and AUC = 0.92 ± SE 0.18, respectively). These two panels also demonstrated strong performance in classifying CF individuals who would experience a PEx within 4 months of a clinically stable visit or not (16-gene panel: AUC = 0.88; 9-protein panel: AUC = 0.83). In comparison, serum calprotectin and clinical variables (i.e. sex, ppFEV1, and the number of IV antibiotics in the preceding year) had AUCs of 0.75 and 0.71, respectively. Blood-based mRNA and protein biomarkers demonstrated strong performance in classifying CF individuals at risk of imminent PEx. If the findings from this study can be validated, there is the potential to use blood biomarkers to enable more personalized disease activity monitoring in CF.

Effect of adalimumab treatment on inflammatory and hematological parameters in patients with Hidradenitis suppurativa

Objective Hidradenitis suppurativa (HS), a chronic inflammatory disease that typically manifests after puberty, is characterised by painful nodules, abscesses, draining sinus tracts, and scars in areas rich in apocrine glands such as the axillary and inguinal regions. In recent years, blood-based biomarkers such as the Neutrophil/Lymphocyte Ratio (NLR), Platelet/Lymphocyte Ratio (PLR), Monocyte/Lymphocyte Ratio (MLR), Mean Platelet Volume (MPV), Systemic Immune-Inflammation Index (SII) and Pan-Immune-Inflammation Value (PIV) have been used as significant indicators of systemic inflammation. While there are few studies evaluating these biomarkers in HS, the response of these markers to treatment has only been assessed in one study to date. Our study aims to investigate the effect of adalimumab treatment on blood-based systemic inflammation biomarkers in HS, where inflammation plays a significant role. Methods The study included 42 adult patients who received adalimumab treatment at our dermatology and venereology clinic between January 2020 and January 2023. Medical records for complete blood count results of the patients were retrospectively reviewed. All systemic inflammation-based biomarkers were calculated from the absolute values of the complete blood count. The SII was calculated with the following formula: (neutrophil count × platelet count/lymphocyte count). The PIV was calculated as follows: (neutrophil count × platelet count × monocyte count/lymphocyte count). Values before the treatment and at the 12th week of treatment were compared. Results When the changes in the inflammatory parameters of the patients were examined, it was found that NLR (2.13 ± 0.87 vs 2.26 ± 1.12), PLR (111.01 ± 39.89 vs 99.43 ± 35.34), MLR (0.27 ± 0.11 vs 0.28 ± 0.12), MPV (9.59 ± 0.71 vs 9.70 ± 0.79), SII (680.79 ± 330.18 vs 687.89 ± 442.66), and PIV (552.02 ± 330.71 vs 605.05 ± 415.96) values did not change statistically significantly after treatment (p > 0.05). While there was a significant decrease in platelet count compared to before treatment, no statistically significant difference was found in the other evaluated blood cells. Conclusion Adalimumab treatment has not had a significant effect on systemic inflammation markers in HS, an inflammatory disease. More studies are needed to evaluate the effect of adalimumab on these markers in HS.

Addressing ovarian cancer research gaps in under-resourced settings using individual initiatives: The OVANORDEST pilot project in Morocco.

183 Background: In Morocco, ovarian cancer (OC) is a neglected women’s cancer. To bridge this gap, early-career cancer researchers might develop and engage in individual initiatives to enhance research outcomes. In this perspective, I recently launched the OVANORDEST project as an individual initiative. This plan outlines a three-step strategy designed to promote OC research, highlighting specific milestones. This abstract presents the findings from the initial feasibility study, which focuses on real-world evidence, implementing inexpensive precision medicine approaches, supporting women in oncology, and enhancing meta-research. Methods: Initially, a bibliometric study was conducted to find research gaps in the field of OC in Morocco. A 16-year real-world retrospective study was conducted at the Hassan II Oncology Center (October 2005-June 2020). To implement precision medicine approaches, quality evidence on several potentially inexpensive blood-based biomarkers such as Pan-Immune Inflammation-Value (PIIV) were explored using a PROSPERO-registered umbrella systematic review and then investigated in an original cohort. Cox regression analyses were applied to identify the effects of different biomarkers on survival outcomes. Meta-research was developed by publishing two special thematic issues and one edited book on OC biomarkers. The project also included a mentorship program designed to empower women oncologists. Results: A total of 258 patients with OC were included. Most patients had advanced FIGO stages at diagnosis. The median overall survival (OS) for the entire cohort was 32 months, with a median progression-free survival (PFS) of 14.6 months. CA-125 positivity, advanced disease stage, and presence of residual disease after surgery were prognostic factors that adversely affected survival. In the multivariable analysis after adjustment for the FIGO stage, high PIIV was an independent predictive factor of OS (HR= 1.83; 95% CI: 1.18-2.84, p=0.007). Two specialized thematic issues were published alongside a book dedicated to ovarian cancer biomarkers. Additionally, careers of a group of women oncologists were boosted and a local patient advocacy group was supported in adopting supportive strategies for patients. Conclusions: Engaging early-career cancer researchers through individual initiatives in under-resourced settings may considerably improve research outcomes. In this context, I propose that sharing this experience, which has been successfully applied in Morocco, could empower health systems and facilitate the generation of research outputs in low- and middle-income countries.

The candidate novel markers PIV and PILE score to predict survival outcomes and therapeutic response in patients with primary central nervous system lymphoma.

24 Background: Recent studies highlighted the predictive value of easily measurable blood-based biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), the platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII). Recently, a novel comprehensive marker that represents the pan-immune-inflammation value (PIV) has been proposed as a more reliable predictor of clinical outcomes. We aimed to investigate the prognostic significance of PIV and PILE score (a score based on PIV, lactate dehydrogenase (LDH), and Eastern Cooperative Oncology Group Performance Status (ECOG PS)), in patients with PCNSL. Methods: A total of 109 patients were enrolled. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. The PILE score was calculated with the sum of individual values (for PIV &lt; median = 0, ≥ median = 1; for LDH ≤ upper limit of normal (ULN) = 0, &gt; ULN = 1; for ECOG PS &lt; 2 = 0, ≥ 2 = 1). The Kaplan–Meier method and Cox hazards regression models were used for survival analyses. The relationship between PIV, PILE, and therapeutic response was examined. Results: Pretreatment high PIV was confirmed to be an independent significant factor for overall survival (OS) in univariate (HR 3.990, 95%CI 1.778-8.954, p &lt; 0.001) and multivariate (HR 3.047, 95%CI 1.175-7.897, p = 0.022) analyses. Baseline PIV was also associated with worse progression-free survival (PFS). Regarding OS, PIV showed a better predictive performance than other widely used systemic inflammation parameters. Significantly shorter OS and PFS were observed in the high PILE group (median OS: 25.60, 95% CI 15.60-NR vs. NR months, 95% CI 26.10-NR, p = 0.008; median PFS: 26.13, 95% CI 23.30-NR vs. 7.13 months, 95% CI 4.87-NR, p &lt; 0.001). High PILE was associated with primary resistance to therapy (high PILE group: 21/42 patients, 50.00%; low PILE group: 5/45 patients, 11.11%; p &lt; 0.001). A significantly lower response rate to initial treatment was found in patients in the high PILE group (23/42, 54.76%) as compared to patients in the low PILE group (7/45, 15.56%; p &lt; 0.001). PILE was independently associated with therapeutic response to initial treatment (OR 0.17, 95% CI 0.05–0.46; p &lt; 0.001). Conclusions: High PIV and high PILE were correlated with worse clinical outcomes in PCNSL patients, indicating that PIV and PILE might be a powerful predictor of prognosis and a potential predictive indicator for treatment response in PCNSL.

Advancing the early detection of canine cognitive dysfunction syndrome with machine learning-enhanced blood-based biomarkers.

Up to half of the senior dogs suffer from canine cognitive dysfunction syndrome (CCDS), the diagnosis method relies on subjective questionnaires such as canine cognitive dysfunction rating (CCDR) scores. Therefore, the necessity of objective diagnosis is emerging. Here, we developed blood-based biomarkers for CCDS early detection. Blood samples from dogs with CCDR scores above 25 were analyzed, and the biomarkers retinol-binding protein 4 (RBP4), C-X-C-motif chemokine ligand 10 (CXCL10), and NADPH oxidase 4 (NOX4) were validated against neurodegenerative models. Lower biomarker levels were correlated with higher CCDR scores, indicating cognitive decline. Machine-learning analysis revealed the highest predictive accuracy when analyzing the combination of RBP4 and NOX4 using the support vector machine algorithm and confirmed potential diagnostic biomarkers. These results suggest that blood-based biomarkers can notably improve CCDS early detection and treatment, with implications for neurodegenerative disease management in both animals and humans.

Plasma-derived exosomal long noncoding RNAs of pancreatic cancer patients as novel blood-based biomarkers of disease

BackgroundPancreatic cancer (PaCa) is one of the most intractable and fatal malignancies and is associated with the dysregulation of long noncoding RNAs (lncRNAs), which are a large class of noncoding RNAs larger than 200 nt that act as competing endogenous RNAs or sponges for miRNAs to induce tumour biological behaviours. However, their clinical value in treating pancreatic cancer has been poorly explained, but they are essential for improving the prognosis of PaCa patients.MethodsWe analysed the plasma-derived exosomal lncRNA profiles of PaCa patients by using whole-transcriptome sequencing analysis and identified significantly differentially expressed lncRNAs, including LINC01268, LINC02802, AC124854.1, and AL132657.1. In the current study, the expression levels of four plasma-derived exosomal lncRNAs in PaCa plasma were validated via quantitative real-time polymerase chain reaction (qRT‒PCR). The relationship between the expression of the four lncRNAs and the clinicopathological features of patients with PaCa was also evaluated.ResultsWe demonstrated that exosomal LINC01268, LINC02802, AC124854.1 and AL132657.1 were highly expressed in PaCa plasma compared with those in normal controls; moreover, they were positively correlated with the serum expression of carbohydrate antigen 19–9 (CA19-9). The receiver operating characteristic curves (AUCs) of the four lncRNAs were 0.8421, 0.6544, 0.7190, and 0.6321, and the AUC value of the combination of the four exosomal lncRNAs increased to 0.8476, with a sensitivity of 0.72 and specificity of 0.89. These results suggested that the plasma-derived exosomal genes LINC01268, LINC02802, AC124854.1, and AL132657.1 may be novel diagnostic markers for PaCa.ConclusionsOur research demonstrated that the plasma-derived exosomal lncRNAs of PaCa patients are novel blood-based biomarkers of disease.

Cerebral ischemia biomarkers: Their roles in early diagnosis and prognosis with potential clinical applications

Cerebral ischemia, caused by a disruption in blood supply to the brain, remains a significant cause of morbidity and mortality worldwide. Identifying reliable biomarkers for the early diagnosis and prognosis of cerebral ischemia is crucial for timely intervention and improved patient outcomes. This review aims to provide a comprehensive overview of the current knowledge on cerebral ischemia biomarkers, focusing on their potential role in early detection and prediction of clinical outcomes. Specifically, we discuss the current advances in the field of cerebral ischemia biomarkers, which serve as essential tools for early diagnosis and monitoring of ischemic stroke. We examine several promising biomarkers, including omics data, genetic (FOXF2 and ATP5H), physiological and neuroinflammatory biomarkers, neuroimaging markers, blood-based biomarkers (proteins, microRNAs, and metabolites), and newer modalities such as exosomes, microvesicles, and cell-free deoxyribonucleic acid (cfDNA). In addition, we highlight the challenges and future directions in translating these biomarkers into clinical practice. Standardization and reproducibility, methodological limitations, and cost and accessibility are critical challenges in the translation of biomarkers into clinical practice. Addressing these challenges requires multi-stakeholder collaborations and coordinated efforts to establish standardized protocols, improve analytical methods, and develop cost-effective biomarker assays. The use of point-of-care testing devices or miniaturized lab-on-a-chip technologies can reduce costs and improve accessibility, particularly in low-resource settings. Furthermore, collaborations between academia, industry, and regulatory agencies can facilitate the translation of biomarkers by addressing regulatory and reimbursement hurdles that affect the affordability and availability of these tests.

Fracture-Related Infection Blood-Based Biomarkers: Diagnostic Strategies

Fracture-related infections are significant postoperative complications that carry substantial patient burden and additional healthcare costs. Despite their impact on outcome, early diagnosis of these infections remains challenging due to current available tests lacking acceptable diagnostic parameters. This review compiles existing information on blood-based biomarkers that have been evaluated as early diagnostic tools and highlights the challenges in their reliability. To begin to overcome these challenges new avenues of biomarker discovery utilizing “omics” technologies and novel analytical methods are being investigated in recent years. It appears that, despite their complexity, these newer approaches may be the future in biomarker discovery for fracture-related infection diagnosis.

Real-world performance of plasma p-tau181 in a heterogeneous memory clinic cohort.

In light of clinical trials and disease-modifying therapies, an early identification of patients at-risk of developing Alzheimer's disease (AD) is crucial. Blood-based biomarkers have shown promising results regarding the in vivo detection of the earliest neuropathological changes in AD. Herein, we investigated the ability of plasma p-tau181 to act as a prescreening marker for amyloid positivity in a heterogeneous memory clinic-based cohort. In this retrospective cross-sectional study, we included a total of 115 patients along the clinical AD continuum (mild cognitive impairment [MCI] due to AD, n = 62, probable AD dementia, n = 53). Based on their biomarker status, they were stratified into an amyloid-positive (Aβ+, n = 88) or amyloid-negative cohort (Aβ-, n = 27). Plasma and CSF p-tau181 concentrations were quantified using an ultrasensitive single-molecule array (SIMOA©). Furthermore, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared using DeLong's test for correlated AUC curves. The median (interquartile range [IQR]) concentration of plasma p-tau181 was significantly higher in Aβ+ patients (3.6 pg/mL [2.5-4.6]), compared with Aβ- patients (1.7 pg/mL [1.2-1.9], p < 0.001). Regarding the distinction between Aβ+ and Aβ- patients and the prediction of amyloid positivity, a high diagnostic accuracy for plasma p-tau181 with an AUC of 0.89 (95% CI = 0.82-0.95) was calculated. Adding the risk factors, age and APOE4, to the model did not significantly improve its performance. Our findings demonstrate that plasma p-tau181 could be a noninvasive and feasible prescreening marker for amyloid positivity in a heterogeneous clinical AD cohort and therefore help in identifying those who would benefit from more invasive assessment of amyloid pathology.

Blood-Based microRNA Biomarker Signature of Early-Stage Pancreatic Ductal Adenocarcinoma With Lead-Time Trajectory in Prediagnostic Samples

Blood-Based microRNA Biomarker Signature of Early-Stage Pancreatic Ductal Adenocarcinoma With Lead-Time Trajectory in Prediagnostic Samples

Plasma C-terminal agrin fragment concentrations across adulthood: Reference values and associations with skeletal muscle health.

Increasing interest surrounds the utility of blood-based biomarkers for diagnosing sarcopenia. C-terminal agrin fragment (CAF), a marker of neuromuscular junction stability, is amongst the most promising candidates; however, a dearth of reference data impedes the incorporation of its use in public health settings. This study aimed to establish reference values for plasma CAF concentrations across adulthood in a large, well-characterized cohort of healthy adults; and comprehensively examine the association between plasma CAF levels and skeletal muscle health. One thousand people aged between 18 and 87years took part in this study (mean age=50.4years; 51% females). Body composition and muscle strength were examined using DXA and hand dynamometry. Plasma CAF concentrations were measured, in duplicate, using commercially available ELISA kits. Sarcopenia and individual sarcopenia signatures [low skeletal muscle index (SMI) only/low grip strength only] were classified using the EWGSOP2 algorithm. Detailed reference CAF values, according to sex and age, are presented. A significant but modest age-related increase in plasma CAF concentration was observed (P=0.018). Across adulthood, CAF concentrations were negatively associated with grip strength and SMI (both P<0.001). In people ≥50years old, CAF concentrations were 22.6% higher in those with sarcopenia (P<0.001), 11.3% higher in those with low SMI (P=0.006) and 9.6% higher in those with low grip strength (P=0.0034), compared with controls. People in the highest CAF concentration quartile, had 3.25 greater odds for sarcopenia (95% CI=1.41-7.49, P=0.005), 2.76 greater odds for low SMI (95% CI=1.24-5.22, P=0.012), and 2.56 greater odds for low grip strength (95% CI=1.07-5.57, P=0.037), compared with those in the lowest quartile. People with a CAF Z-score ≥2 had 9.52 greater odds for sarcopenia (95% CI=3.01-30.05, P<0.001) compared with a Z-score <1. Plasma CAF concentration had an acceptable level of diagnostic accuracy for sarcopenia (AUC=0.772, 95% CI=0.733-0.807, P<0.001). The reference values presented herein may guide the clinical interpretation of circulating CAF and help identify people at risk of poor skeletal muscle outcomes for inclusion in therapeutic interventions. Our findings add clarity to existing data, demonstrating a robust relationship between circulating CAF and skeletal muscle integrity in the largest adult cohort to date, and support the use of CAF as an accessible, cost-effective screening tool for sarcopenia. However, further research into the prognostic utility of plasma CAF, and the establishment of normative data from other populations, are urgently needed if routine CAF screening is to be embedded into public healthcare settings.

Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid

PurposeValproic acid or valproate is an effective antiepileptic drug; however, embryonic exposure to valproate can result in a teratogenic disorder referred to as fetal valproate syndrome (OMIM #609442). Currently there are no diagnostic biomarkers for the condition. This study aims to define an episignature biomarker for teratogenic antenatal exposure to valproate. MethodsDNA extracted from peripheral blood of individuals with teratogenic antenatal exposure to valproate was processed using DNA methylation microarrays. Subsequently, methylation profiling and construction of support vector machine classifiers were performed in R. ResultsGenomic DNA methylation analysis was applied, and a distinct DNA methylation profile was identified in the majority of affected individuals. This profile was used to develop a diagnostic episignature classifier. The valproate exposure episignature exhibited high sensitivity and specificity relative to a large reference data set of unaffected controls and individuals with a wide spectrum of syndromic disorders with episignatures. Gene set enrichment analysis demonstrated an enrichment for terms associated with cell adhesion, including significant overrepresentation of the cadherin superfamily. ConclusionThis study provides evidence of a robust peripheral blood-based diagnostic epigenetic biomarker for a prenatal teratogenic disorder.

Prophylactic IL-23 blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy

BackgroundImmune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood...