Regenerating Islet-Derived 3-alpha is a Prognostic Biomarker for Gastrointestinal Chronic Graft-Versus-Host Disease

Prognostic biomarkers used to identify likelihood of disease progression have not been identified for chronic graft-versus-host disease (cGVHD), the leading cause of late non-relapse mortality (NRM) in survivors of allogenic hematopoietic cell transplantation. Gastrointestinal cGVHD (GI-cGVHD) has been particularly challenging to classify. Here, we analyzed three proteomics markers [Regenerating-islet-derived-3-alpha (Reg3α), C-X-C-motif-ligand (CXCL9) and Stimulation-2 (ST2)] in two independent cohorts of patients with cGVHD totaling 289 patients. Plasma concentrations of Reg3α were significantly increased in patients with GI-cGVHD compared to those without (p=0.0012, p=0.01 respectively), CXCL9 and ST2 were not. Patients with high Reg3α (≥72ng/mL) vs. low Reg3α had higher NRM (23% vs. 11%, p=0.015). Since Reg3α has been identified as a lower GI-tract marker in acute GVHD, we correlated Reg3α with lower acute-like GI-cGVHD vs. classical fibrotic-like esophageal manifestations and found Reg3a did not differ between the subtypes. No difference was observed between upper and lower subtypes. Patients with extremely high Reg3α (≥180 ng/mL) had higher GI-scores but not higher lower-GI-scores. In multivariate Cox regression model, patients with high Reg3α were 1.9 times more likely to die without relapse. Our findings demonstrate the utility of Reg3α as a prognostic marker for GI-cGVHD. These data warrant prospective biomarker validation studies.

Human disease biomarkers: challenges, advances, and trends in their validation

Biomarkers are important tools in the medical field, once they allow better prediction, characterization, and treatment of diseases. In this scenario, it is essential that biomarkers are highly accurate. Thus, biomarker validation is an essential part of ensuring the effectiveness of a biomarker. Validation of biomarkers is the process by which biomarkers are evaluated for accuracy and consistency, as well as their ability to inform the condition of health or disease. Although, there is no unique measure that can be used to determine the validity for all biomarkers, there are general criteria that all biomarkers must meet to be useful. In this work, we review the definition of biomarkers and discuss the validity components. We then critically discuss the main methods used to validate biomarkers and consider some examples of biomarkers of the diseases which most killer in the world (cardiovascular diseases, cancer, and viral infections), highlighting the potential biochemical pathways of these biomarkers in the biological system. In addition, we also comment on the omic strategies used in the biomarker discovery process and conclude with information about perspectives in biomarker validation through imaging techniques.

Metabolomics Meets Nutritional Epidemiology: Harnessing the Potential in Metabolomics Data

Traditionally, nutritional epidemiology is the study of the relationship between diet and health and disease in humans at the population level. Commonly, the exposure of interest is food intake. In recent years, nutritional epidemiology has moved from a “black box” approach to a systems approach where genomics, metabolomics and proteomics are providing novel insights into the interplay between diet and health. In this context, metabolomics is emerging as a key tool in nutritional epidemiology. The present review explores the use of metabolomics in nutritional epidemiology. In particular, it examines the role that food-intake biomarkers play in addressing the limitations of self-reported dietary intake data and the potential of using metabolite measurements in assessing the impact of diet on metabolic pathways and physiological processes. However, for full realisation of the potential of metabolomics in nutritional epidemiology, key challenges such as robust biomarker validation and novel methods for new metabolite identification need to be addressed. The synergy between traditional epidemiologic approaches and metabolomics will facilitate the translation of nutritional epidemiologic evidence to effective precision nutrition.

Abstract P46: Baseline Characteristics of Patients With Cerebral Cavernous Angiomas With Symptomatic Hemorrhage in a Multisite Trial Readiness Study

Background: Patients with cerebral cavernous angiomas with symptomatic hemorrhage (CASH) have high risk of disability from recurrent bleeding. Candidate medications to prevent rebleeding in CASH lesions will require multisite clinical trials with standardized data collection. Objective: To report the prevalence and baseline cohort features in CASH patients and establish a research network infrastructure for trials. Methods: This prospective observational cohort study includes adults with radiologically verified CASH lesion within 1-year of consent. Exclusions include prior or planned surgical intervention, spinal location, or prior brain irradiation. Six sites enrolled patients into the screening and clinical assessment portion of the study starting July 2018. Patients also had the option to participate in the follow up biomarker validation at 4 sites. Baseline demographics, clinical and imaging information, and outcomes (mRS, PROMIS-29, NIHSS, and EuroQol-5D) were collected. Biomarker imaging included dynamic contrast enhanced quantitative perfusion (DCEQP) and quantitative susceptibility mapping (QSM) that correlated with symptomatic bleeding. Descriptive statistics were performed and one-sample t-test was used to compare whether mean T-scores for PROMIS-29 domains differed significantly from a reference population. Results: As of May 2020, 849 CASH patients were screened of whom 110 (13%) were eligible and enrolled; 73 also enrolled into the biomarker validation study. Average age at enrollment was 46±16 years at a mean of 4.4 months after symptom onset; 53% were female, 41% were familial, and 43% of CASH lesions were brainstem location. At enrollment, 90% of the cohort had independent functional outcome (mRS ≤ 2 and NIHSS <5). Perceived health problems affecting QoL were reported in >30% (EuroQol-5D). CASH cases had significantly worse anxiety but better depression and social satisfaction scores compared to a general population (all P<0.01). Baseline DCEQP and QSM measures did not differ significantly across sites. Conclusion: We demonstrate feasibility of multisite recruitment of CASH patients and report prevalence of baseline features that will aid in design of clinical trials and inclusion of appropriate outcome measures.

Lack of antibodies against seasonal coronavirus OC43 nucleocapsid protein identifies patients at risk of critical COVID-19

Most COVID-19 patients experience a mild disease; a minority suffers from critical disease. We report about a biomarker validation study regarding 296 patients with confirmed SARS-CoV-2 infections from four tertiary care referral centers in Germany and France. Patients with critical disease had significantly less anti-HCoV OC43 nucleocapsid protein antibodies compared to other COVID-19 patients (p=0.007). In multivariate analysis, OC43 negative inpatients had an increased risk of critical disease, higher than the risk by increased age or BMI, and lower than the risk by male sex. A risk stratification based on sex and OC43 serostatus was derived from this analysis. Our results indicate that prior infections with seasonal human coronaviruses can protect against a severe course of COVID-19. Anti-OC43 antibodies should be measured for COVID-19 inpatients and considered as part of the risk assessment. We expect individuals tested negative for anti-OC43 antibodies to particularly benefit from vaccination, especially with other risk factors prevailing.