Browsing by Subject "biomarker"
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Item Open Access A Clinician's Perspective on Biomarkers.(Focus (American Psychiatric Publishing), 2018-04-27) Rush, A John; Ibrahim, Hicham MPsychiatrists and mental health professionals regularly perform various clinical tasks (e.g., detection, differential diagnosis, prognostication, treatment selection and implementation). How well they perform each of these tasks has a direct impact on patient outcomes. Measurement-based care has brought greater precision to these tasks and has improved outcomes. This article provides an overview of the types of biomeasures and biomarkers, the clinical uses of biomarkers, and the challenges in their development and clinical use. Although still in their infancy, biomarkers hold the promise of bringing even greater precision and even better outcomes in mental health. Biomeasures that could become biomarkers include genetic, proteomic, metabolomic, and immunologic measures, as well as physiological, functional, and brain structural measures. Mechanistic markers reflect and are based on the specific pathobiological processes that are involved in the development of a clinically defined condition. Some clinically relevant biomarkers may rely on this mechanistic understanding while others may not. Clinical biomarkers serve three broadly defined goals. Diagnostic markers define what is wrong. Prognostic markers define what will happen in the natural course of the condition, although they may also predict the course of illness during treatment. Theranostic markers address issues pertinent to treatment by defining whether, when, whom, and how to treat. Other biomarkers may be used to monitor the overall effect of treatment regardless of the therapeutic effects or to monitor the specific therapeutic effects of the intervention on the disorder itself. Biomarkers can also be used to estimate susceptibility/risk of developing the condition or the biological consequences of having had the disorder.Item Open Access DNA methylation age is associated with mortality in a longitudinal Danish twin study.(Aging Cell, 2016-02) Christiansen, Lene; Lenart, Adam; Tan, Qihua; Vaupel, James W; Aviv, Abraham; McGue, Matt; Christensen, KaareAn epigenetic profile defining the DNA methylation age (DNAm age) of an individual has been suggested to be a biomarker of aging, and thus possibly providing a tool for assessment of health and mortality. In this study, we estimated the DNAm age of 378 Danish twins, age 30-82 years, and furthermore included a 10-year longitudinal study of the 86 oldest-old twins (mean age of 86.1 at follow-up), which subsequently were followed for mortality for 8 years. We found that the DNAm age is highly correlated with chronological age across all age groups (r = 0.97), but that the rate of change of DNAm age decreases with age. The results may in part be explained by selective mortality of those with a high DNAm age. This hypothesis was supported by a classical survival analysis showing a 35% (4-77%) increased mortality risk for each 5-year increase in the DNAm age vs. chronological age. Furthermore, the intrapair twin analysis revealed a more-than-double mortality risk for the DNAm oldest twin compared to the co-twin and a 'dose-response pattern' with the odds of dying first increasing 3.2 (1.05-10.1) times per 5-year DNAm age difference within twin pairs, thus showing a stronger association of DNAm age with mortality in the oldest-old when controlling for familial factors. In conclusion, our results support that DNAm age qualifies as a biomarker of aging.Item Open Access Editorial: Bioinformatics Tools (and Web Server) for Cancer Biomarker Development.(Frontiers in oncology, 2020-01) Xie, Longxiang; Wang, Liuyang; Zhu, Wan; Zhao, Jing; Guo, XiangqianItem Open Access Functional connectivity predicts the dispositional use of expressive suppression but not cognitive reappraisal.(Brain and behavior, 2020-02) Burr, Daisy A; d'Arbeloff, Tracy; Elliott, Maxwell L; Knodt, Annchen R; Brigidi, Bartholomew D; Hariri, Ahmad RINTRODUCTION:Previous research has identified specific brain regions associated with regulating emotion using common strategies such as expressive suppression and cognitive reappraisal. However, most research focuses on a priori regions and directs participants how to regulate, which may not reflect how people naturally regulate outside the laboratory. METHOD:Here, we used a data-driven approach to investigate how individual differences in distributed intrinsic functional brain connectivity predict emotion regulation tendency outside the laboratory. Specifically, we used connectome-based predictive modeling to extract functional connections in the brain significantly related to the dispositional use of suppression and reappraisal. These edges were then used in a predictive model and cross-validated in novel participants to identify a neural signature that reflects individual differences in the tendency to suppress and reappraise emotion. RESULTS:We found a significant neural signature for the dispositional use of suppression, but not reappraisal. Within this whole-brain signature, the intrinsic connectivity of the default mode network was most informative of suppression tendency. In addition, the predictive performance of this model was significant in males, but not females. CONCLUSION:These findings help inform how whole-brain networks of functional connectivity characterize how people tend to regulate emotion outside the laboratory.Item Open Access Genetic polymorphisms of PAI-1 and PAR-1 are associated with acute normal tissue toxicity in Chinese rectal cancer patients treated with pelvic radiotherapy.(OncoTargets and therapy, 2015-01) Zhang, Hui; Wang, Mengyun; Shi, Tingyan; Shen, Lijun; Zhu, Ji; Sun, Menghong; Deng, Yun; Liang, Liping; Li, Guichao; Wu, Yongxin; Fan, Ming; Wei, Qingyi; Zhang, ZhenPlasminogen activator inhibitor type 1 (PAI-1) and protease-activated receptor-1 (PAR-1) are crucial mediators of the intestinal microenvironment and are involved in radiation-induced acute and chronic injury. To evaluate whether genetic polymorphisms of PAI-1 and PAR-1 were predictors of radiation-induced injury in patients with rectal cancer, we retrospectively evaluated 356 rectal cancer patients who had received pelvic radiotherapy and analyzed the association of genetic polymorphisms of PAI-1 and PAR-1 with acute toxicities after radiotherapy. Acute adverse events were scored, including dermatitis, fecal incontinence (anal toxicity), hematological toxicity, diarrhea, and vomiting. The patients were grouped into grade ≥2 and grade 0-1 toxicity groups to analyze the acute toxicities. Genotyping of six single nucleotide polymorphisms (SNPs) of PAI-1 and PAR-1 was performed using TaqMan assays. A logistic regression model was used to estimate the odds ratios and 95% confidence intervals. Of the 356 individuals, 264 (72.5%) had grade ≥2 total toxicities; within this group, there were 65 (18.3%) individuals who reached grade ≥3 toxicities. There were 19.5% (69/354) and 36.9% (130/352) patients that developed grade ≥2 toxicities for diarrhea and fecal incontinence, respectively. The variant genotype GG of rs1050955 in PAI-1 was found to be negatively associated with the risk of diarrhea and incontinence (P<0.05), whereas the AG and GG genotypes of rs2227631 in PAI-1 were associated with an increased risk of incontinence. The CT genotype of PAR-1 rs32934 was associated with an increased risk of total toxicity compared with the CC allele. Our results demonstrated that SNPs in the PAI-1 and PAR-1 genes were associated with acute injury in rectal cancer patients treated with pelvic irradiation. These SNPs may be useful biomarkers for predicting acute radiotoxicity in patients with rectal cancer if validated in future studies.Item Open Access Immediate Post-operative Enterocyte Injury, as Determined by Increased Circulating Intestinal Fatty Acid Binding Protein, Is Associated With Subsequent Development of Necrotizing Enterocolitis After Infant Cardiothoracic Surgery.(Frontiers in pediatrics, 2020-01) Watson, John D; Urban, Tracy T; Tong, Suhong S; Zenge, Jeanne; Khailova, Ludmilla; Wischmeyer, Paul E; Davidson, Jesse AObjectives: 1 Measure serial serum intestinal fatty acid binding protein levels in infants undergoing cardiac surgery with cardiopulmonary bypass to evaluate for evidence of early post-operative enterocyte injury. 2 Determine the association between immediate post-operative circulating intestinal fatty acid binding protein levels and subsequent development of necrotizing enterocolitis. Design: Observational cohort study. Intestinal fatty acid binding protein was measured pre-operatively, at rewarming, and at 6 and 24 h post-operatively. Percent of goal enteral kilocalories on post-operative day 5 and episodes of necrotizing enterocolitis were determined. Multivariable analysis assessed for factors independently associated with clinical feeding outcomes and suspected/definite necrotizing enterocolitis. Setting: Quaternary free-standing children's hospital pediatric cardiac intensive care unit. Patients: 103 infants <120 days of age undergoing cardiothoracic surgery with cardiopulmonary bypass. Interventions: None. Results: Median pre-operative intestinal fatty acid binding protein level was 3.93 ng/ml (range 0.24-51.32). Intestinal fatty acid binding protein levels rose significantly at rewarming (6.35 ng/ml; range 0.54-56.97; p = 0.008), continued to rise slightly by 6 h (6.57 ng/ml; range 0.75-112.04; p = 0.016), then decreased by 24 h (2.79 ng/ml; range 0.03-81.74; p < 0.0001). Sixteen subjects (15.7%) developed modified Bell criteria Stage 1 necrotizing enterocolitis and 9 subjects (8.8%) developed Stage 2 necrotizing enterocolitis. Infants who developed necrotizing enterocolitis demonstrated a significantly higher distribution of intestinal fatty acid binding protein levels at both 6 h (p = 0.005) and 24 h (p = 0.005) post-operatively. On multivariable analysis, intestinal fatty acid binding protein was not associated with percentage of goal enteral kilocalories delivered on post-operative day 5. Higher intestinal fatty acid binding protein was independently associated with subsequent development of suspected/definite necrotizing enterocolitis (4% increase in odds of developing necrotizing enterocolitis for each unit increase in intestinal fatty acid binding protein; p = 0.0015). Conclusions: Intestinal fatty acid binding protein levels rise following infant cardiopulmonary bypass, indicating early post-operative enterocyte injury. Intestinal fatty acid binding protein was not associated with percent of goal enteral nutrition achieved on post-operative day 5, likely due to protocolized feeding advancement based on clinically observable factors. Higher intestinal fatty acid binding protein at 6 h post-operatively was independently associated with subsequent development of necrotizing enterocolitis and may help identify patients at risk for this important complication.Item Open Access Mitochondrial Toxicity.(Toxicol Sci, 2018-01-11) Meyer, Joel N; Hartman, Jessica H; Mello, Danielle FRecent decades have seen a rapid increase in reported toxic effects of drugs and pollutants on mitochondria. Researchers have also documented many genetic differences leading to mitochondrial diseases, currently reported to affect ∼1 person in 4,300, creating a large number of potential gene-environment interactions in mitochondrial toxicity. We briefly review this history, and then highlight cutting-edge areas of mitochondrial research including the role of mitochondrial reactive oxygen species in signaling; increased understanding of fundamental biological processes involved in mitochondrial homeostasis (DNA maintenance and mutagenesis, mitochondrial stress response pathways, fusion and fission, autophagy and biogenesis, and exocytosis); systemic effects resulting from mitochondrial stresses in specific cell types; mitochondrial involvement in immune function; the growing evidence of long-term effects of mitochondrial toxicity; mitochondrial-epigenetic cross-talk; and newer approaches to test chemicals for mitochondrial toxicity. We also discuss the potential importance of hormetic effects of mitochondrial stressors. Finally, we comment on future areas of research we consider critical for mitochondrial toxicology, including increased integration of clinical, experimental laboratory, and epidemiological (human and wildlife) studies; improved understanding of biomarkers in the human population; and incorporation of other factors that affect mitochondria, such as diet, exercise, age, and nonchemical stressors.Item Open Access Plasma acylcarnitines as metabolic signatures of declining health-related quality of life measure in community-dwelling older adults: a combined cross-sectional and longitudinal pilot study.(The journals of gerontology. Series A, Biological sciences and medical sciences, 2022-05-23) Ng, Ted Kheng Siang; Wee, Hai Ning; Ching, Jianhong; Kovalik, Jean-Paul; Chan, Angelique W; Matchar, David BruceBackground
Health-related quality of life (HRQoL) measures are predictors of adverse health outcomes in older adults. Studies have demonstrated cross-sectional associations between HRQoL measures and blood-based biochemical markers. Acylcarnitines (ACs) are a class of metabolites generated in the mitochondria and are predictive of multiple geriatric syndromes. Changes in ACs reflect alterations in central carbon metabolic pathways. However, the prospective relationship between plasma acylcarnitines and declining HRQoL has not been examined. This study aimed to investigate both cross-sectional and longitudinal associations of baseline ACs with baseline and declining EuroQol-5 Dimension/ EuroQol Visual Analogue Scale (EQ-5D/ EQ-VAS) in community-dwelling older adults.Methods
120 community-dwelling older adults with EQ-5D/ EQ-VAS measurements at baseline and follow-up were included. We quantified ACs at baseline using targeted plasma metabolomics profiling. Multivariate regressions were performed to examine cross-sectional and longitudinal associations between the measures.Results
Cross-sectionally, ACs showed no significant associations with either EQ-5D index or EQ-VAS scores. Longitudinally, multiple baseline short-chain ACs were significantly and inversely associated with declining EQ-5D index score, explaining up to 8.5% of variance in the decline.Conclusions
Within a cohort of community-dwelling older adults who had high HRQoL at baseline, we showed that short-chain acylcarnitines are independent predictors of declining HRQoL. These findings reveal a novel association between central carbon metabolic pathways and declining HRQoL. Notably, dysregulation in mitochondrial central carbon metabolism could be detected prior to clinically important decline in HRQoL, providing the first evidence of objective biomarkers as novel predictors to monitor HRQoL in non-pharmacological interventions and epidemiology.Item Open Access Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma.(Int J Cancer, 2015-10-01) Wen, Yang; Han, Jing; Chen, Jianguo; Dong, Jing; Xia, Yongxiang; Liu, Jibin; Jiang, Yue; Dai, Juncheng; Lu, Jianhua; Jin, Guangfu; Han, Jiali; Wei, Qingyi; Shen, Hongbing; Sun, Beicheng; Hu, ZhibinThe early detection of hepatocellular carcinoma (HCC) presents a challenge because of the lack of specific biomarkers. Serum/plasma microRNAs (miRNAs) can discriminate HCC patients from controls. We aimed to identify and evaluate HCC-associated plasma miRNAs originating from the liver as early biomarkers for detecting HCC. In this multicenter three-phase study, we first performed screening using both plasma (HCC before and after liver transplantation or liver hepatectomy) and tissue samples (HCC, para-carcinoma and cirrhotic tissues). Then, we evaluated the diagnostic potential of the miRNAs in two case-control studies (training and validation sets). Finally, we used two prospective cohorts to test the potential of the identified miRNAs for the early detection of HCC. During the screening phase, we identified ten miRNAs, eight of which (miR-20a-5p, miR-25-3p, miR-30a-5p, miR-92a-3p, miR-132-3p, miR-185-5p, miR-320a and miR-324-3p) were significantly overexpressed in the HBV-positive HCC patients compared with the HBV-positive cancer-free controls in both the training and validation sets, with a sensitivity of 0.866 and specificity of 0.646. Furthermore, we assessed the potential for early HCC detection of these eight newly identified miRNAs and three previously reported miRNAs (miR-192-5p, miR-21-5p and miR-375) in two prospective cohorts. Our meta-analysis revealed that four miRNAs (miR-20a-5p, miR-320a, miR-324-3p and miR-375) could be used as preclinical biomarkers (pmeta < 0.05) for HCC. The expression profile of the eight-miRNA panel can be used to discriminate HCC patients from cancer-free controls, and the four-miRNA panel (alone or combined with AFP) could be a blood-based early detection biomarker for HCC screening.Item Open Access Treatment-related biomarkers in pulmonary hypertension.(Am J Respir Cell Mol Biol, 2015-06) Swaminathan, Aparna C; Dusek, Alex C; McMahon, Tim JSignificant advances in the treatment of pulmonary arterial hypertension (PAH) over the last two decades have led to the introduction of multiple classes of oral therapy, but the disease remains devastating for many patients. Disease progression, in spite of oral monotherapy, is a major problem, and alternative therapy, such as infusion of prostacyclins, is cumbersome and carries considerable potential morbidity. Use of combination oral therapy, including drugs from both the endothelin receptor antagonist and phosphodiesterase-5 inhibitor classes, has increased, and there is some evidence to support this approach. Given the multiple options now available in pulmonary hypertension (PH) therapy, biomarkers to guide treatment decisions could be helpful. Here, we review the evidence for and against the clinical use of molecular biomarkers relevant to PH pathogenesis, emphasizing assayable markers that may also inform more rational selection of agents that influence pathways targeted by treatment. We emphasize the interactive nature of changes in mediators and messengers, such as endothelin-1, prostacyclin, brain natriuretic peptide (which has demonstrated biomarker utility), nitric oxide derivatives, and cyclic guanosine monophosphate, which play important roles in processes central to progression of PAH, such as vascular remodeling, vasoconstriction, and maladaptive right ventricular changes, and are relevant to its therapy. Accordingly, we propose that the identification and use of a molecular biomarker panel that assays these molecules in parallel and serially might, if validated, better inform unique patient phenotypes, prognosis, and the rational selection and titration of combination oral and other therapy in individual patients with PH/PAH.