Confirmatory diagnosis of childhood tuberculosis (TB) remains a challenge mainly due to its dependence on sputum samples and the paucibacillary nature of the disease. Thus, only ~ 30% of suspected cases in children are diagnosed and the need for minimally invasive, non-sputum-based biomarkers remains unmet. Understanding host molecular changes by measuring blood-based transcriptomic markers has shown promise as a diagnostic tool for TB. However, the implication of sex contributing to disease heterogeneity and therefore diagnosis remains to be understood. Using publicly available gene expression data (GSE39939, GSE39940; n = 370), we report a sex-specific RNA biomarker signature that could improve the diagnosis of TB disease in children. We found four gene biomarker signatures for male (SLAMF8, GBP2, WARS, and FCGR1C) and female pediatric patients (GBP6, CELSR3, ALDH1A1, and GBP4) from Kenya, South Africa, and Malawi. Both signatures achieved a sensitivity of 85% and a specificity of 70%, which approaches the WHO-recommended target product profile for a triage test. Our gene signatures outperform most other gene signatures reported previously for childhood TB diagnosis.

Mesothelioma is an aggressive cancer, strongly associated with prior exposure to asbestos. Commonly, tumors are detected at late stages of the disease. Detection at early stages might be meaningful, because therapies might be more effective when the tumor burden is relatively low and the tumor has not spread to distant sites. Circulating biomarkers in blood might be a promising tool to improve the early detection of mesothelioma, but for screening in asymptomatic subjects, candidate biomarkers need to be validated in appropriate studies. This study was conducted to assess the performance of biomarkers in liquid biopsies to detect mesothelioma at early stages. Over a period of 10 years, 2769 volunteers formerly exposed to asbestos were annually examined and liquid biopsies were collected. A follow-up was completed 17 months after the last blood collection. The article provides a detailed overview of our lessons learned and experiences of conducting a prospective, longitudinal, multicenter study. The existing cohort of individuals at risk is highly suitable for the validation of blood-based biomarkers for the early detection of mesothelioma as well as lung cancer.

We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases.
Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aβ)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer\'s disease/mild cognitive impairment (AD/MCI), Parkinson\'s disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD).
GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ42/40 .
GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

UNASSIGNED: Current prognostic blood-based biomarkers for pancreatic adenocarcinoma (PDAC) are limited. Recently, promoter hypermethylation of SFRP1 (phSFRP1) has been linked to poor prognosis in patients with gemcitabine-treated stage IV PDAC. This study explores the effects of phSFRP1 in patients with lower stage PDAC.
UNASSIGNED: Based on a bisulfite treatment process, the promoter region of the SFRP1 gene was analyzed with methylation-specific PCR. Kaplan-Meier curves, log-rank tests, and generalized linear regression analysis were used to assess restricted mean survival time survival at 12 and 24 months.
UNASSIGNED: The study included 211 patients with stage I-II PDAC. The median overall survival of patients with phSFRP1 was 13.1 months, compared to 19.6 months in patients with unmethylated SFRP1 (umSFRP1). In adjusted analysis, phSFRP1 was associated with a loss of 1.15 months (95%CI -2.11, -0.20) and 2.71 months (95%CI -2.71, -0.45) of life at 12 and 24 months, respectively. There was no significant effect of phSFRP1 on disease-free or progression-free survival. In stage I-II PDAC, patients with phSFRP1 have worse prognoses than patients with umSFRP1.
UNASSIGNED: Results could indicate that the poor prognosis may be caused by reduced benefit from adjuvant chemotherapy. SFRP1 may help guide the clinician and be a possible target for epigenetically modifying drugs.

BACKGROUND: Pancreatic ductal adenocarcinoma remains one of the major causes of cancer-related mortality globally. Unfortunately, current prognostic biomarkers are limited, and no predictive biomarkers exist. This study examined promoter hypermethylation of secreted frizzled-related protein 1 (phSFRP1) in cfDNA as a prognostic biomarker and predictor of treatment effect in patients with metastatic FOLFIRINOX-treated PDAC and locally advanced PDAC.
METHODS: We performed methylation-specific PCR of the SFRP1 genes\' promoter region, based on bisulfite treatment. Survival was assessed as time-to-event data using the pseudo-observation method and analyzed with Kaplan-Meier curves and generalized linear regressions.
RESULTS: The study included 52 patients with FOLFIRINOX-treated metastatic PDAC. Patients with unmethylated (um) SFRP1 (n = 29) had a longer median overall survival (15.7 months) than those with phSFRP1 (6.8 months). In crude regression, phSFRP1 was associated with an increased risk of death of 36.9% (95% CI 12.0%-61.7%) and 19.8% (95% CI 1.9-37.6) at 12 and 24-months, respectively. In supplementary regression analysis, interaction terms between SFRP1 methylation status and treatment were significant, indicating reduced benefit of chemotherapy. Forty-four patients with locally advanced PDAC were included. phSFRP1 was associated with an increased risk of death at 24-months CONCLUSIONS: This indicates that phSFRP1 is a clinically useful prognostic biomarker in metastatic PDAC and possibly in locally advanced PDAC. Together with existing literature, results could indicate the value of cfDNA-measured phSFRP1 as a predictive biomarker of standard palliative chemotherapy in patients with metastatic PDAC. This could facilitate personalized treatment of patients with metastatic PDAC.

Blood-based biomarkers are promising tools for the diagnosis of Alzheimer disease (AD) at prodromal stages (mild cognitive impairment [MCI]) and are hoped to be implemented as screening tools for patients with cognitive complaints. In this work, we evaluated the potential of peripheral neurological biomarkers to predict progression to AD dementia and the relation between blood and cerebrospinal fluid (CSF) AD markers in MCI patients referred from a general neurological department.
A group of 106 MCI patients followed at the Neurology Department of Coimbra University Hospital was included. Data regarding baseline neuropsychological evaluation, CSF levels of amyloid β 42 (Aβ42), Aβ40, total tau (t-Tau), and phosphorylated tau 181 (p-Tau181) were available for all the patients. Aβ42, Aβ40, t-Tau, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) levels were determined in baseline stored serum and plasma samples by commercial SiMoA (Single Molecule Array) assays. Progression from MCI to AD dementia was assessed at follow-up (mean = 5.8 ± 3.4 years).
At baseline, blood markers NfL, GFAP, and p-Tau181 were significantly increased in patients who progressed to AD at follow-up (p < 0.001). In contrast, plasma Aβ42/40 ratio and t-Tau showed no significant differences between groups. NfL, GFAP, and p-Tau181 demonstrated good diagnostic accuracy to identify progression to AD dementia (area under the curve [AUC] = 0.81, 0.80, and 0.76, respectively), which improved when combined (AUC = 0.89). GFAP and p-Tau181 were correlated with CSF Aβ42. Association of p-Tau181 with NfL was mediated by GFAP, with a significant indirect association of 88% of the total effect.
Our findings highlight the potential of combining blood-based GFAP, NfL, and p-Tau181 to be applied as a prognostic tool in MCI.

Neuroinflammation constitutes a pathological hallmark of Alzheimer\'s disease (AD). Still, it remains unresolved if peripheral inflammatory markers can be utilized for research purposes similar to blood-based beta-amyloid and neurodegeneration measures. We investigated experimental inflammation markers in serum and analyzed interrelations towards AD pathology features in a cohort with a focus on at-risk stages of AD.
Data of 74 healthy controls (HC), 99 subjective cognitive decline (SCD), 75 mild cognitive impairment (MCI), 23 AD relatives, and 38 AD subjects were obtained from the DELCODE cohort. A panel of 20 serum biomarkers was determined using immunoassays. Analyses were adjusted for age, sex, APOE status, and body mass index and included correlations between serum and CSF marker levels and AD biomarker levels. Group-wise comparisons were based on screening diagnosis and routine AD biomarker-based schematics. Structural imaging data were combined into composite scores representing Braak stage regions and related to serum biomarker levels. The Preclinical Alzheimer\'s Cognitive Composite (PACC5) score was used to test for associations between the biomarkers and cognitive performance.
Each experimental marker displayed an individual profile of interrelations to AD biomarkers, imaging, or cognition features. Serum-soluble AXL (sAXL), IL-6, and YKL-40 showed the most striking associations. Soluble AXL was significantly elevated in AD subjects with pathological CSF beta-amyloid/tau profile and negatively related to structural imaging and cognitive function. Serum IL-6 was negatively correlated to structural measures of Braak regions, without associations to corresponding IL-6 CSF levels or other AD features. Serum YKL-40 correlated most consistently to CSF AD biomarker profiles and showed the strongest negative relations to structure, but none to cognitive outcomes.
Serum sAXL, IL-6, and YKL-40 relate to different AD features, including the degree of neuropathology and cognitive functioning. This may suggest that peripheral blood signatures correspond to specific stages of the disease. As serum markers did not reflect the corresponding CSF protein levels, our data highlight the need to interpret serum inflammatory markers depending on the respective protein\'s specific biology and cellular origin. These marker-specific differences will have to be considered to further define and interpret blood-based inflammatory profiles for AD research.

We recently derived and validated a serum-based microRNA risk score (miR-score) which predicted colorectal cancer (CRC) occurrence with very high accuracy within 14 years of follow-up in a large population-based cohort. Here, we aimed to assess and compare the distribution of the miR-score among participants of screening colonoscopy at various stages of colorectal carcinogenesis. MicroRNAs (miRNAs) were profiled by quantitative-real-time-polymerase-chain-reaction in the serum samples of screening colonoscopy participants with CRC (n = 52), advanced colorectal adenoma (AA, n = 100), non-advanced colorectal adenoma (NAA, n = 88), and participants free of colorectal neoplasms (n = 173). The mean values of the miR-score were compared between groups by the Mann-Whitney U test. The associations of the miR-score with risk for colorectal neoplasms were evaluated using logistic regression analyses. MicroRNA risk scores were significantly higher among participants with AA than among those with NAA (p = 0.027) and those with CRC (p = 0.014), whereas no statistically significant difference was seen between those with NAA and those with no colorectal neoplasms (p = 0.127). When comparing adjacent groups, miR-scores were inversely associated with CRC versus AA and positively associated with AA versus NAA [odds ratio (OR), 0.37 (95% confidence interval (CI), 0.16-0.86) and OR, 2.22 (95% CI, 1.06-4.64) for the top versus bottom tertiles, respectively]. Our results are consistent with the hypothesis that a high miR-score may be indicative of an increased CRC risk by an increased tendency of progression from non-advanced to advanced colorectal neoplasms, along with a change of the miR-patterns after CRC manifestation.

Multicancer early detection panels have recently become available to patients with a provider\'s prescription and an out-of-pocket fee. Beyond theoretical modeling, little is known about how these assays will impact primary care practices despite a high likelihood that primary care providers (PCPs) will be ordering these tests with some frequency. In particular, there are concerns about patient counseling, costs, frequency of testing, patient anxiety, and subsequent testing for a positive result. This review aims to appraise the current literature and provide a framework that PCPs can use to discuss these tests with patients and streamline their ordering, interpretation, and overall use into everyday practice.

No reliable predictive blood-based biomarkers are available for determining survival from pancreatic adenocarcinoma (PDAC). This combined discovery and validation study examines promoter hypermethylation (ph) of secreted frizzled-related protein 1 (SFRP1) in plasma-derived cell-free DNA as an independent prognostic marker for survival and Gemcitabine effectiveness in patients with stage IV PDAC. We conducted methylation-specific polymerase chain reaction analysis of the promoter region of the SFRP1 gene, based on bisulfite treatment. Survival was analyzed with Kaplan-Meier curves, log-rank test, and Cox regression. The discovery cohort included 40 patients, 25 receiving Gem. Gem-treated patients with phSFRP1 had a shorter median overall survival (mOS) (4.4 months) than unmethylated patients (11.6 months). Adjusted Cox-regression yielded a hazard rate (HR) of 3.48 (1.39-8.70). The validation cohort included 58 Gem-treated patients. Patients with phSFRP1 had a shorter mOS (3.2 months) than unmethylated patients (6.3 months). Adjusted Cox regression yielded an HR of 3.53 (1.85-6.74). In both cohorts, phSFRP1 was associated with poorer survival in Gem-treated patients. This may indicate that tumors with phSFRP1 are more aggressive and less sensitive to Gem treatment. This knowledge may facilitate tailored treatment of patients with stage IV PDAC. Further studies are planned to examine phSFRP1 in more intensive chemotherapy regimens.