Vijay Modur

The Brain Injury Biomarker VLP-1 Is Increased in the Cerebrospinal Fluid of Alzheimer Disease Patients

BACKGROUND Definitive diagnosis of Alzheimer disease (AD) can be made only by histopathological examination of brain tissue, prompting the search for premortem disease biomarkers. We sought to determine if the novel brain injury biomarker, visinin-like protein 1 (VLP-1), is altered in the CSF of AD patients compared with controls, and to compare its values to the other well-studied CSF biomarkers 42-amino acid amyloid-beta peptide (Abeta(1-42)), total Tau (tTau), and hyperphosphorylated Tau (pTau). METHODS Using ELISA, we measured concentrations of Abeta(1-42), tTau, pTau, and VLP-1 in CSF samples from 33 AD patients and 24 controls. We compared the diagnostic performance of these biomarkers using ROC curves. RESULTS CSF VLP-1 concentrations were significantly higher in AD patients [median (interquartile range) 365 (166) ng/L] compared with controls [244 (142.5) ng/L]. Although the diagnostic performance of VLP-1 alone was comparable to that of Abeta, tTau, or pTau alone, the combination of the 4 biomarkers demonstrated better performance than each individually. VLP-1 concentrations were higher in AD subjects with APOE epsilon4/epsilon4 genotype [599 (240) ng/L] compared with epsilon3/epsilon4 [376 (127) ng/L] and epsilon3/epsilon3 [280 (115.5) ng/L] genotypes. Furthermore, VLP-1 values demonstrated a high degree of correlation with pTau (r = 0.809) and tTau (r = 0.635) but not Abeta(1-42) (r = -0.233). VLP-1 was the only biomarker that correlated with MMSE score (r = -0.384, P = 0.030). CONCLUSIONS These results suggest that neuronal injury markers such as VLP-1 may have utility as biomarkers for AD.

Enrichment of Genes in the Aortic Intima That Are Associated With Stratified Epithelium Implications of Underlying Biomechanical and Barrier Properties of the Arterial Intima

Background—Arteries and veins are exposed to different pressures and are easily distinguished by morphology. Although several recent studies have focused on differential gene expression between the arterial and venous endothelium, the molecular distinctions that give rise to the dramatic structural distinctions between arteries and veins, such as in the organization of the intima, are not known. Methods and Results—We used high-density oligonucleotide arrays to analyze the transcriptional profile of the mouse aorta and inferior vena cava (IVC), not restricting our analysis to the endothelium, to identify genes whose expression was enriched in aorta over other tissues and the IVC. By quantitative reverse transcription–polymerase chain reaction analysis, these genes have been shown to be highly expressed in the mouse aorta and were either expressed at low levels or were undetectable in the murine IVC. By immunofluorescence analysis of human tissue, we determined that a subset of these aorta-enriched proteins exhibited a primarily intima-restricted expression. Intimal expression of at least a subset of these genes, plakoglobin, galectin 7, sciellin, and SPRR3, was also detected in other types of arteries but not in veins. Furthermore, SPRR3 expression in the intima was primarily associated with atheromas. The proteins identified are functionally related in that they are known to also be enriched in stratified epithelia, where they play an important role in stress-bearing and barrier properties. Conclusions—Vascular expression of these genes has not been reported previously. Our observations suggest that they may play a significant role in the mechanisms by which large arteries may adapt to biomechanical stress.

Biomarkers of tissue injury

Biomarkers of tissue injury have evolved empirically over the last 50-100 years. With the advent of immunoassays and discovery tools such as RNA expression and proteomics, more systematic approaches to the discovery of biomarkers can be expected in the future. This review discusses the evolution of biomarkers of muscle, liver, heart and brain injury and illustrates that a modern discovery tool, such as mRNA profiling, would have predicted the biomarkers for cardiac injury (heart attacks) that actually evolved over 50 years by empiric approaches. We also discuss how novel biomarkers for brain injury were identified using RNA expression approaches. It is our prediction that there will be a growth in the number of valuable biomarkers for identifying cell and organ injury in the next 5-10 years.

Are Companion Diagnostics Useful

We define a companion diagnostics (CDx)5 test as any diagnostic tool that guides the selection of patient treatment. In the US, these tests include diagnostics cleared by the Food and Drug Administration (FDA), as well as laboratory-developed tests (LDTs) run in CLIA-accredited laboratories. The answer to the titles question is obviously in the affirmative. We discuss the growing need to improve, accelerate, and standardize oncology CDx that benefit patients. Recent advances in our understanding of the mutational landscape of cancers have led to the rapid development of targeted therapies for pathogenomic targets. At the same time, advances in next-generation sequencing (NGS) have revealed the complexity of heterogeneous cancers. With the fast pace of change occurring in clinical oncology, flexible approaches to CDx development are needed while test accuracy is maintained for delivering precision medicine to patients. The remarkable efficacies of new targeted therapies have recently changed the paradigm for oncology to one of matching the right patient with the right therapy (1). This approach requires robust laboratory testing of patient samples. FDA-cleared tests exist for a limited number of markers (Table 1). In contrast, LDTs developed in CLIA-certified laboratories are used for >2000 genetic tests (2). LDTs are currently used in oncology for patient care and in clinical trials, which are now evaluating >500 agents targeting >100 genomic alterations. View this table: Table 1. Select list of CDx used for selection of targeted therapies.a The recent success in the development of 2 targeted therapies, crizotinib and vemurafenib, exemplifies the CDx process in which the FDA has co-cleared a diagnostic test (3, 4). The development of the CDx included analytical validation and elements of quality systems (good manufacturing practice, design control, personnel, software, instrumentation, and other parameters) as critical components of the regulatory package. The tests were used to recruit patients to pivotal phase II trials for the presence of the mutation/gene fusion. The …