A biomarker panel for acute graft-versus-host disease

No validated biomarkers exist for acute graft-versus-host disease (GVHD). We screened plasma with antibody microarrays for 120 proteins in a discovery set of 42 patients who underwent transplantation that revealed 8 potential biomarkers for diagnostic of GVHD. We then measured by enzyme-linked immunosorbent assay (ELISA) the levels of these biomarkers in samples from 424 patients who underwent transplantation randomly divided into training (n = 282) and validation (n = 142) sets. Logistic regression analysis of these 8 proteins determined a composite biomarker panel of 4 proteins (interleukin-2-receptor-alpha, tumor-necrosis-factor-receptor-1, interleukin-8, and hepatocyte growth factor) that optimally discriminated patients with and without GVHD. The area under the receiver operating characteristic curve distinguishing these 2 groups in the training set was 0.91 (95% confidence interval, 0.87-0.94) and 0.86 (95% confidence interval, 0.79-0.92) in the validation set. In patients with GVHD, Cox regression analysis revealed that the biomarker panel predicted survival independently of GVHD severity. A panel of 4 biomarkers can confirm the diagnosis of GVHD in patients at onset of clinical symptoms of GVHD and provide prognostic information independent of GVHD severity.     

A biomarker panel for peripheral arterial disease

AbstractPeripheral arterial disease (PAD) is common, but often not diagnosed. A biomarker index would be useful to raise suspicion of PAD, so as to trigger appropriate vascular testing and management. The study comprised 540 individuals: 197 individuals with both coronary artery disease and peripheral arterial disease (CAD + PAD); 81 with CAD only; and 262 with no hemodynamically significant disease (NHSD) of the coronary or peripheral arteries. Multiple linear regression was performed to generate a biomarker panel score that could predict ankle-brachial index (ABI). Logistic regression was used to investigate the relationship between disease status and the panel score as well as other risk factors (e.g. age, diabetes status, smoking status). ROC analysis was performed to test the prediction power of the biomarker panel score. Among the plasma markers tested, beta 2 microglobulin (beta2M) and cystatin C had the highest correlation with ABI, and higher than any of the conventional risk factors of age, smoking status, and diabetes status. A biomarker panel score derived from beta2M, cystatin C, hsCRP, and glucose had an increased association with PAD status (OR = 12.4, 95% confidence interval (CI) 6.6-23.5 for highest vs lowest quartile), which was still significant after adjusting for known risk factors (OR = 7.3, 95% CI 3.6-14.9 for highest vs lowest quartile). In conclusion, after taking into account the traditional risk factors for PAD, a biomarker panel comprising beta2M, cystatin C, hsCRP, and glucose adds useful information to assess the risk of disease.     

Klotho: a novel biomarker for cancer

Background

The Klotho gene was originally identified as an anti-aging gene in 1997. Recent studies have demonstrated aberrant expression of Klotho in a number of cancers, including breast cancer, lung cancer, hepatocellular carcinoma (HCC), and so on.

Methods

A literature search focusing on dysregulation of Klotho and its possible mechanisms in cancer was performed.

Results and conclusions

Downregulation of Klotho was found in several cancers, such as pancreatic cancer, HCC, and other tumors. Epigenetic modulation, such as promoter methylation and histone deacetylation, also contributed to the dysregulation of Klotho in cancers. Downregulation of Klotho resulted in promoted proliferation and reduced apoptosis of cancer cells. The relevant mechanisms include the fibroblast growth factor signaling, the insulin-like growth factor 1 receptor pathway, and the Wnt/β-catenin signaling pathway. Furthermore, the Klotho protein hopefully provides new insights into cancer target treatment.

     

Developmental plasticity of CNS microglia

Microglia arise from CD45(+) bone marrow precursors that colonize the fetal brain and play a key role in central nervous system inflammatory conditions. We report that parenchymal microglia are uncommitted myeloid progenitors of immature dendritic cells and macrophages by several criteria, including surface expression of "empty" class II MHC protein and their cysteine protease (cathepsin) profile. Microglia express receptors for stem cell factor and can be skewed toward more dendritic cell or macrophage-like profiles in response to the lineage growth factors granulocyte/macrophage colony-stimulating factor or macrophage colony-stimulating factor. Thus, in contrast to other organs, where terminally differentiated populations of resident dendritic cells and/or macrophages outnumber colonizing precursors, the majority of microglia within the brain remain in an undifferentiated state.     

Stable reliability diagrams for probabilistic classifiers

A probability forecast or probabilistic classifier is reliable or calibrated if the predicted probabilities are matched by ex post observed frequencies, as examined visually in reliability diagrams. The classical binning and counting approach to plotting reliability diagrams has been hampered by a lack of stability under unavoidable, ad hoc implementation decisions. Here, we introduce the CORP approach, which generates provably statistically consistent, optimally binned, and reproducible reliability diagrams in an automated way. CORP is based on nonparametric isotonic regression and implemented via the pool-adjacent-violators (PAV) algorithm—essentially, the CORP reliability diagram shows the graph of the PAV-(re)calibrated forecast probabilities. The CORP approach allows for uncertainty quantification via either resampling techniques or asymptotic theory, furnishes a numerical measure of miscalibration, and provides a CORP-based Brier-score decomposition that generalizes to any proper scoring rule. We anticipate that judicious uses of the PAV algorithm yield improved tools for diagnostics and inference for a very wide range of statistical and machine learning methods.

Calibration or reliability is a key requirement on any probability forecast or probabilistic classifier. In a nutshell, a probabilistic classifier assigns a predictive probability to a binary event. The classifier is calibrated or reliable if, when looking back at a series of extant forecasts, the conditional event frequencies match the predictive probabilities. For example, if we consider all cases with a predictive probability of about 0.80, the observed event frequency ought to be about 0.80 as well. While for many decades, researchers and practitioners have been checking calibration in myriads of applications (1, 2), the topic is subject to a surge of interest in machine learning (3), spurred by the recent recognition that “modern neural networks are uncalibrated, unlike those from a decade ago” (4).     

Butyrylcholinesterase: biomarker for exposure to organophosphorus insecticides

Butyrylcholinesterase (BuChE) is routinely measured to assess exposure to or effects of organophosphorus insecticides (OP). As a biomarker, it can be used to clarify the relation between exposure to OP and health impairment. The interpretation of BuChE inhibition data, particularly of small changes in enzymatic activity, sometimes presents significant complexities. These complexities are presented in this short communication and the factors that influence the degree of BuChE inhibition are discussed. Despite the complexities of their interpretation, BuChE measurements remain a mainstay for the fast initial screening of exposure to OP; thus, they are a useful tool in the protection of humans, domestic animals and wildlife from overexposure to these toxic agents.     

Adiponectin as a novel biomarker for liver fibrosis

Adiponectin is known to play primary roles in the regulation of systemic glucose homeostasis and lipid metabolism. Interestingly, emerging evidence indicates beneficial effects of adiponectin on liver fibrosis; however, the exact mechanisms of this action remain unclear. Herein, we aimed to summarize the recent findings regarding the role of adiponectin in liver fibrogenesis and update the current comprehensive knowledge regarding usefulness of adiponectin-based treatments in liver fibrosis. Adiponectin has been demonstrated to have an anti-fibrotic action in the liver by blocking the activation of hepatic stellate cellmediated adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptoralpha pathways, which in turn diminish the expression of pro-fibrotic genes. In addition, hyperadiponectinemia was noted in patients with various chronic liver diseases(CLDs)-related liver fibrosis. An increase in circulating adiponectin levels was also found to be associated with the development of liver fibrosis, indicating a role of adiponectin as a non-invasive biomarker for predicting the progression of liver fibrosis. It is therefore reasonable to speculate that adiponectin may be developed as a new therapeutic candidate for the treatment of liver fibrosis. Nonetheless, future observations are still necessary to fully elucidate the extent of the effects of adiponectin onliver fibrotic outcomes, in order to modify adiponectin as an anti-fibrotic therapy that would speed up fibrosis reversal in patients with CLD.     

Serum calprotectin as a biomarker for Crohn's disease

Background and aimsIn Crohn's disease, correlation between clinical assessment and disease activity at tissue level is weak. Our aim was to evaluate the value of serum calprotectin as a biomarker for Crohn's disease.MethodsThe STORI trial patients (n = 115) were studied at baseline, in clinical remission before infliximab withdrawal, or at the time of relapse after infliximab withdrawal. Forty healthy controls were also studied. Serum calprotectin level was measured by ELISA. Data were analyzed through correlation analyses, Kaplan Meier curves and Cox model, using available Crohn's Disease Activity Index (CDAI), Crohn's Disease Endoscopic Index of Severity (CDEIS), fecal calprotectin and C-reactive protein levels (hsCRP).ResultsMedian serum calprotectin was 8892 ng/mL (range: 410–125,000 ng/mL) in Crohn disease patients as compared with 1318 ng/mL (range: 215.8–3770 ng/mL) in controls (P < 0.0001). Serum calprotectin was significantly higher for active disease (median = 19,584 ng/mL) than for inactive disease (median = 8353 ng/mL) (P < 0.0001). Serum calprotectin correlated with hsCRP (r = 0.4092, P < 0.0001) and CDAI (r = 0.4442, P < 0.0001), but not with CDEIS, on the contrary to fecal calprotectin (r = 0.6458, 0.5515, 0.2577 with P < 0.0001, P < 0.0001, P = 0.019 respectively). In multivariate analysis, serum calprotectin used as a discrete variable (threshold: 5675 ng/ml), appeared complementary to hsCRP (> 5 mg/l) and fecal calprotectin (> 250 μg/g) to predict relapse after infliximab withdrawal (P = 0.0173, 0.0024 and 0.0002; HR: 3.191, 3.561 and 4.120).ConclusionsAs a CD biomarker, serum calprotectin has a similar profile as hsCRP. It is also complementary to fecal calprotectin and hsCRP for prediction of relapse after infliximab withdrawal.     

C-reactive protein as a biomarker for urological cancers

Systemic inflammation has been linked with the progression of cancer, and, in patients with urological cancers, the presence of a systemic inflammatory response is thought to be indicative of poor prognosis. C-reactive protein (CRP) is an acute-phase reactant, the levels of which can be objectively measured using standardized reliable assays, and a useful marker of systemic inflammation. CRP levels have been shown to predict survival in patients with urological cancers, including renal cell carcinoma, upper urinary tract and bladder cancers, and prostate cancer, and the incorporation of CRP into prognostic models for urological cancers improves the models' predictive accuracy. Furthermore, the kinetics of CRP release and the analysis of dynamic changes in CRP concentrations over time, could predict tumor aggressiveness and potential treatment efficacy. For instance, in long-term survivors of testicular cancer, CRP is associated with the risk of late complications, such as cardiovascular disease, and with the development of second non-germ-cell cancer. CRP could, therefore, be an important biomarker for urological cancers.     

小胶质细胞在脑缺血中的作用

小胶质细胞在脑缺血后炎症中起着重要作用.大量研究表明,小胶质细胞是高度可塑的细胞,可应对不同微环境信呈现不同的表型和功能.小胶质细胞可极化为经典激活的促炎性M1型或替代激活的抗炎性M2型,在缺血性损伤中起着不同的作用.抑制M1而刺激M2有可能成为缺血性卒中治疗的一个新途径.     

MYL2 as a potential predictive biomarker for rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a common malignant soft tissue sarcoma, which is the third most common soft tissue sarcoma after malignant fibrohistoma and liposarcoma. The discovery of potential postbiomarkers could lead to early and more effective treatment measures to reduce the mortality of RMS. The discovery of biomarker is expected to be the direction of targeted therapy, providing a new direction for the precise treatment of RMS.Gene Expression Omnibus database was used to download the tow gene profiles, {"type":"entrez-geo","attrs":{"text":"GSE28511","term_id":"28511"}}GSE28511 and {"type":"entrez-geo","attrs":{"text":"GSE135517","term_id":"135517"}}GSE135517. GEO2R was applied to identify differently expressed genes (DEGs) between RMS and normal group. Database for Annotation, Visualization and Integrated Discovery and Metascape can perform the enrichment analysis for the DEGs. Protein-protein interaction network was constructed, and the hub genes was identified by the Cytoscape. Expression and overall survival analysis of hub genes were performed.A total of 15 common DEGs were screened between RMS and normal tissues. The enrichment analysis here showed that the DEGs mainly enriched in the muscle filament sliding, myofibril, protein complex, sarcomere, myosin complex, nuclear chromosome, and tight junction. The 6 hub genes (DNA Topoisomerase II Alpha, Insulin Like Growth Factor 2, HIST1H4C, Cardiomyopathy Associated 5, Myosin Light Chain 2 [MYL2], Myosin Heavy Chain 2) were identified. Compared with the normal tissues, MYL2 were down-regulated in the RMS tissues. RMS patients with low expression level of MYL2 had poorer overall survival times than those with high expression levels (P < .05).In summary, lower expression of MYL2 was 1 prediction for poor prognosis of RMS. MYL2 is hope to be the target of therapy, which leads to more effective treatment and reduces the mortality rate of RMS.     

Strategies for biomarker research: experimental and methodological design

The meaning of the term biomarker is discussed, a model believed to be of some use in thinking about biomarkers of age and of aging is presented, and some suggestions about pertinent research strategy and tactics are provided.     

Mathematical and statistical strategies for biomarker research of aging

The continuing revolution in personal computers has placed computing power rivaling that of some computational laboratories on the desktops of many investigators. Contained in this article are some suggestions for taking advantage of this enhanced computing power in analyzing data in which an investigator does not have control over his sample. Sample reuse methods, called the jackknife and the bootstrap, are discussed, along with possible applications of time-series methods. Some suggestions for getting help from mathematical scientists are also included.     

Subregional neuroanatomical change as a biomarker for Alzheimer's disease

Regions of the temporal and parietal lobes are particularly damaged in Alzheimer''s disease (AD), and this leads to a predictable pattern of brain atrophy. In vivo quantification of subregional atrophy, such as changes in cortical thickness or structure volume, could lead to improved diagnosis and better assessment of the neuroprotective effects of a therapy. Toward this end, we have developed a fast and robust method for accurately quantifying cerebral structural changes in several cortical and subcortical regions using serial MRI scans. In 169 healthy controls, 299 subjects with mild cognitive impairment (MCI), and 129 subjects with AD, we measured rates of subregional cerebral volume change for each cohort and performed power calculations to identify regions that would provide the most sensitive outcome measures in clinical trials of disease-modifying agents. Consistent with regional specificity of AD, temporal-lobe cortical regions showed the greatest disease-related changes and significantly outperformed any of the clinical or cognitive measures examined for both AD and MCI. Global measures of change in brain structure, including whole-brain and ventricular volumes, were also elevated in AD and MCI, but were less salient when compared to changes in normal subjects. Therefore, these biomarkers are less powerful for quantifying disease-modifying effects of compounds that target AD pathology. The findings indicate that regional temporal lobe cortical changes would have great utility as outcome measures in clinical trials and may also have utility in clinical practice for aiding early diagnosis of neurodegenerative disease.