Browsing by Subject "Biochemical markers"
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Item A Biomarker Characterizing Neurodevelopment with applications in Autism(Nature Publishing Group, 2018-01-12) Wu, Di; José, Jorge V.; Nurnberger, John I., Jr.; Torres, Elizabeth B.; Medicine, School of MedicineDespite great advances in neuroscience and genetic studies, our understanding of neurodevelopmental disorders is still quite limited. An important reason is not having objective psychiatric clinical tests. Here we propose a quantitative neurodevelopment assessment by studying natural movement outputs. Movement is central to behaviors: It involves complex coordination, temporal alterations, and precise dynamic controls. We carefully analyzed the continuous movement output data, collected with high definition electromagnetic sensors at millisecond time scales. We unraveled new metrics containing striking physiological information that was unseen neither by using traditional motion assessments nor by naked eye observations. Our putative biomarker leads to precise individualized classifications. It illustrates clear differences between Autism Spectrum Disorder (ASD) subjects from mature typical developing (TD) individuals. It provides an ASD complementary quantitative classification, which closely agrees with the clinicaly assessed functioning levels in the spectrum. It also illustrates TD potential age-related neurodevelopmental trajectories. Applying our movement biomarker to the parents of the ASD individuals studied in the cohort also shows a novel potential familial signature ASD tie. This paper proposes a putative behavioral biomarker to characterize the level of neurodevelopment with high predicting power, as illustrated in ASD subjects as an example.Item Biomarker Discovery in Early Stage Breast Cancer Using Proteomics Technologies(2009-06-24T12:49:22Z) Qi, Guihong; Wang, MuItem Chemotherapy, estrogen, and cognition : neuroimaging and genetic variation(2014-02-25) Conroy, Susan Kim; McDonald, Brenna C.; Saykin, Andrew J.; Chambers, R. Andrew; Miller, Kathy (Kathy D.); Yoder, Karmen K.The time course and biological mechanisms by which breast cancer (BC) and/or alterations in estrogen status lead to cognitive and brain changes remain unclear. The studies presented here use neuroimaging, cognitive testing, genetics, and biomarkers to investigate how post-chemotherapy interval (PCI), chemotherapy-induced amenorrhea (CIA), and genetic variation in the estrogen pathway affect the brain. Chapter 1 examines the association of post-chemotherapy interval (PCI) with gray matter density (GMD) and working memory-related brain activation in BC survivors (mean PCI 6.4, range 3-10 years). PCI was positively associated with GMD and activation in the right frontal lobe, and GMD in this region was correlated with global neuropsychological function. In regions where BC survivors showed decreased GMD compared to controls, this was inversely related to oxidative DNA damage and learning and memory scores. This is the first study to show neural effects of PCI and relate DNA damage to brain alterations in BC survivors. Chapter 2 demonstrates prospectively, in an independent cohort, decreased combined magnitudes of brain activation and deactivation from pre-to post-chemotherapy in patients undergoing CIA compared to both postmenopausal BC patients undergoing chemotherapy and healthy controls. CIA’s change in activity magnitude was strongly correlated with change in processing speed, suggesting this activity increase reflects effective cognitive compensation. These results demonstrate that the pattern of change in brain activity from pre- to post-chemotherapy varies according to pre-treatment menopausal status. Chapter 3 presents the effects of variation in ESR1, the gene that codes for estrogen receptor-α, on brain structure in healthy older adults. ESR1 variation was associated with hippocampus and amygdala volumes, particularly in females. Single nucleotide polymorphism (SNP) rs9340799 influenced cortical GMD and thickness differentially by gender. Apolipoprotein E (APOE)-ε4 carrier status modulated the effect of SNP rs2234693 on amygdala volumes in women. This study showed that genetic variation in estrogen relates to brain morphology in ways that differ by sex, brain region and APOE-ε4 carrier status. The three studies presented here explore the interplay of BC, estrogen, and cognition, showing that PCI, CIA, and ESR1 genotype influence brain phenotypes. Cognitive correlates of neuroimaging findings indicate potential clinical significance of these results.Item Derivation of endothelial colony forming cells from human cord blood and embryonic stem cells(2013) Meador, J. Luke; Kapur, Ruben; Yoder, Mervin C.; Corson, Timothy W.; Meyer, Jason S.Endothelial Colony Forming Cells (ECFCs) are highly proliferative endothelial progenitor cells with clonal proliferative potential and in vivo vessel forming ability. While endothelial cells have been derived from human induced pluripotent stem cells (hiPS) or human embryonic stem cells (hES), they are not highly proliferative and require ectopic expression of a TGFβ inhibitor to restrict plasticity. Neuropilin-1 (NRP-1) has been reported to identify the emergence of endothelial precursor cells from human and mouse ES cells undergoing endothelial differentiation. However, the protocol used in that study was not well defined, used uncharacterized neuronal induction reagents in the culture medium, and failed to fully characterize the endothelial cells derived. We hypothesize that NRP-1 expression is critical for the emergence of stable endothelial cells with ECFC properties from hES cells. We developed a novel serum and feeder free defined endothelial differentiation protocol to induce stable endothelial cells possessing cells with cord blood ECFC-like properties from hES cells. We have shown that Day 12 hES cell-derived endothelial cells express the endothelial markers CD31+ NRP-1+, exhibit high proliferative potential at a single cell level, and display robust in vivo vessel forming ability similar to that of cord blood-derived ECFCs. The efficient production of the ECFCs from hES cells is 6 logs higher with this protocol than any previously published method. These results demonstrate progress towards differentiating ECFC from hES and may provide patients with stable autologous cells capable of repairing injured, dysfunctional, or senescent vasculature if these findings can be repeated with hiPS.Item Dissecting Suicidality Using a Combined Genomic and Clinical Approach(Nature Publishing Group, 2017-01) Niculescu, Alexander B; Le-Niculescu, Helen; Psychiatry, School of MedicineItem Effects of choline kinase activity on phospholipid metabolism and malignant phenotype of prostate cancer cells(2010-10) Bansal, Aditya; DeGrado, Timothy R.; Harris, Robert A. (Robert Allison), 1939-; Bosron, William F.; Klaunig, James E.High choline uptake and increased choline kinase activity have been reported in many cancers. This has motivated the use of choline as a biomarker for tumor imaging. Tumors in general are heterogeneous in nature with respect to oxygen tension. There are regions of hypoxia and normoxia that are expected to have different metabolism but regulation of choline metabolism under hypoxia is poorly understood. It is important to clarify the status of choline metabolism in hypoxic microenvironment as it will have an impact on potential of choline as a cancer biomarker. The primary goal was to determine the status of choline phosphorylation in hypoxic cancer cells and its effect on uptake of choline. This was examined by tracer studies in cancer cells exposed to hypoxia. It was observed that hypoxia universally inhibits choline uptake /phosphorylation in cancer cells. Decreased choline phosphorylation resulted in transient uptake of choline radiotracers in cultured cancer cells and 9L tumors suggesting potential problem in using choline as a biomarker for cancers in hypoxic microenvironment. To investigate the mechanism behind decrease in choline phosphorylation, steady state levels of choline metabolites were measured and choline kinase catalyzed choline phosphorylation step was found to be rate-limiting in PC-3 cells. This suggested that modulation in choline kinase levels can alter choline metabolism in hypoxic cancer cells. Expression and activity assays for choline kinase revealed that choline kinase expression is down-regulated in hypoxia. This regulation involved transcriptional level mediation by HIF1 at the conserved HRE7 site in choline kinase promoter. To further understand the importance of down-regulation of choline kinase in hypoxia, stable prostate cancer cell lines over-expressing choline kinase were generated. Effect of over-expression of choline kinase in hypoxia was evaluated in terms of malignant phenotypes like proliferation rate, anchorage independent growth and invasion potential. Both over-expression of choline kinase and hypoxia had a pronounced effect on malignant phenotypes of prostate cancer cells. Further study showed that increased choline kinase activity and hypoxic tumor microenvironment are important for progression of early-stage, androgen-dependent LNCaP prostate cancer cells but confer little survival advantage in undifferentiated, androgen-independent PC-3 prostate cancer cells.Item Heat shock protein 90, a potential biomarker for type I diabetes: mechanisms of release from pancreatic beta cells(2016-05-23) Ocaña, Gail Jean; Blum, Janice Sherry, 1957-; Kaplan, Mark H.; Serezani, C. Henrique; Sun, JieHeat shock protein (HSP) 90 is a molecular chaperone that regulates diverse cellular processes by facilitating activities of various protein clients. Recent studies have shown serum levels of the alpha cytoplasmic HSP90 isoform are elevated in newly diagnosed type I diabetic patients, thus distinguishing this protein as a potential biomarker for pre-clinical type I diabetes mellitus (TIDM). This phase of disease is known to be associated with various forms of beta cell stress, including endoplasmic reticulum stress, insulitis, and hyperglycemia. Therefore, to test the hypothesis that HSP90 is released by these cells in response to stress, human pancreatic beta cells were subjected to various forms of stress in vitro. Beta cells released HSP90 in response to stimulation with a combination of cytokines that included IL-1β, TNF-α, and IFN-γ, as well as an agonist of toll-like receptor 3. HSP90 release was not found to result from cellular increases in HSP90AA1 gene or HSP90 protein expression levels. Rather, cell stress and ensuing cytotoxicity mediated by c-Jun N-terminal kinase (JNK) appeared to play a role in HSP90 release. Beta cell HSP90 release was attenuated by pre-treatment with tauroursodeoxycholic acid (TUDCA), which has been shown previously to protect beta cells against JNK-mediated, cytokine-induced apoptosis. Experiments here confirmed TUDCA reduced beta cell JNK phosphorylation in response to cytokine stress. Furthermore pharmacological inhibition and siRNA-mediated knockdown of JNK in beta cells also attenuated HSP90 release in response to cytokine stress. Pharmacological inhibition of HSP90 chaperone function exacerbated islet cell stress during the development of TIDM in vivo; however, it did not affect the overall incidence of disease. Together, these data suggest extracellular HSP90 could serve as a biomarker for preclinical TIDM. This knowledge may be clinically relevant in optimizing treatments aimed at restoring beta cell mass. The goal of such treatments would be to halt the progression of at-risk patients to insulin dependence and lifelong TIDM.Item Luminescence-Based MicroRNA Detection Methods(2012-08-27) Cissell, Kyle A.; Deo, Sapna K.; Long, Eric C. (Eric Charles); Simpson, Garth; Mao, ChengdeMicroRNAs (miRNA) are short, 18-24 nucleotide long noncoding RNAs. These small RNAs, which are initially transcribed in the nucleus, are transported into the cell cytoplasm where they regulate protein translation either through direct cleavage of mRNA, or indirect inhibition through binding to mRNA and disrupting the protein translation machinery. Recently, miRNAs have gained much attention due to their implication in numerous diseases and cancers. It has been found that heightened or lowered levels of miRNA in diseased cells vs. healthy cells are linked to disease progression. It is therefore immensely important to be able to detect these small molecules. Current detection methods of Northern blotting, microarrays, and qRT-PCR suffer from drawbacks including low sensitivity, a lack of simplicity, being semi-quantitative in nature, time-consuming, and requiring expensive instruments. This work aims to develop novel miRNA technologies which will address these above problems. Bioluminescent labels are promising alternatives to current methods of miRNA detection. Bioluminescent labels are relatively small, similar in size to fluorescent proteins, and they emit very intense signals upon binding to their substrate. Bioluminescent labels are advantageous to fluorescent labels in that they do not require an external excitation source, rather, the excitation energy is supplied through a biochemical reaction. Therefore, background signal due to excitation is eliminated. They also have the advantage of being produced in large amounts through bacterial expression. Four miRNA detection methods are presented which utilize luminescence-based methods. Three employ Renilla luciferase, a bioluminescent protein, and one is based on fluorescence. The presented methods are capable of detecting miRNA from the picomole (nanomolar) level down to the femtomole (picomolar) level. These methods are rapid, sensitive, simple, and quantitative, can be employed in complex matrices, and do not require expensive instruments. All methods are hybridization-based and do not require amplification steps.Item MOLECULAR PROFILING IN BREAST CANCER AND TOXICOGENOMICS(2011-08-23) Liu, Jiangang; Zhou, Yaoqi; Dunker, A. Keith; Chen, Jake; Uversky, Vladimir N.; Liu, Yunlong; Li, Dan S.This dissertation presents a body of research that attempts to tackle the ‘overfitting’ problem for gene signature and biomarker development in two different aspects (mechanistically and computationally). In achievement of a deeper understanding of cancer molecular mechanisms, this study presents new approaches to derive gene signatures for various biological phenotypes, including breast cancer, in the context of well-defined and mechanistically associated biological pathways. We identified the pattern of gene expression in the cell cycle pathway can indeed serve as a powerful biomarker for breast cancer prognosis. We further built a predictive model for prognosis based on the cell cycle gene signature, and found our model to be more accurate than the Amsterdam 70-gene signature when tested with multiple gene expression datasets generated from several patient populations. Aside from demonstrating the effectiveness of dimensionality reduction, phenotypic dissection, and prognostic or diagnostic prediction, this approach also provides an alternative to the current methodology of identifying gene expression markers that links to biological mechanism. This dissertation also presents the development of a novel feature selection algorithm called Predictive Power Estimate Analysis (PPEA) to computationally tackle on overfitting. The algorithm iteratively apply a two-way bootstrapping procedure to estimate predictive power of each individual gene, and make it possible to construct a predictive model from a much smaller set of genes with the highest predictive power. Using DrugMatrix™ rat liver data, we identified genomic biomarkers of hepatic specific injury for inflammation, cell death, and bile duct hyperplasia. We demonstrated that the signature genes were mechanistically related to the phenotype the signature intended to predict (e.g. 17 out of top 20 genes for inflammation selected by PPEA were members of NF-kB pathway, which is a key pre-inflammatory pathway for a xenobiotic response). The top 4 gene signature for BDH has been further validated by QPCR in a toxicology lab. This is important because our results suggest that the PPEA model not largely deters the over-fitting problem, but also has the capability to elucidate mechanism(s) of drug action and / or of toxicity.Item MRI Measures of Neurodegeneration as Biomarkers of Alzheimer's Disease(2012-03-19) Risacher, Shannon Leigh; Shen, Li; Farlow, Martin R.; Gao, Sujuan; McDonald, Brenna C.; Saykin, Andrew J.; Yoder, Karmen K.Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. Many researchers believe that an effective AD treatment will prevent the development of disease rather than treat the disease after a diagnosis. Therefore, the development of tools to detect AD-related pathology in early stages is an important goal. In this report, MRI-based markers of neurodegeneration are explored as biomarkers of AD. In the first chapter, the sensitivity of cross-sectional MRI biomarkers to neurodegenerative changes is evaluated in AD patients and in patients with a diagnosis of mild cognitive impairment (MCI), a prodromal stage of AD. The results in Chapter 1 suggest that cross-sectional MRI biomarkers effectively measure neurodegeneration in AD and MCI patients and are sensitive to atrophic changes in patients who convert from MCI to AD up to 1 year before clinical conversion. Chapter 2 investigates longitudinal MRI-based measures of neurodegeneration as biomarkers of AD. In Chapter 2a, measures of brain atrophy rate in a cohort of AD and MCI patients are evaluated; whereas in Chapter 2b, these measures are assessed in a pre-MCI stage, namely older adults with cognitive complaints (CC) but no significant deficits. The results from Chapter 2 suggest that dynamic MRI-based measures of neurodegeneration are sensitive biomarkers for measuring progressive atrophy associated with the development of AD. In the final chapter, a novel biomarker for AD, visual contrast sensitivity, was evaluated. The results demonstrated contrast sensitivity impairments in AD and MCI patients, as well as slightly in CC participants. Impaired contrast sensitivity was also shown to be significantly associated with known markers of AD, including cognitive impairments and temporal lobe atrophy on MRI-based measures. The results of Chapter 3 support contrast sensitivity as a potential novel biomarker for AD and suggest that future studies are warranted. Overall, the results of this report support MRI-based measures of neurodegeneration as effective biomarkers for AD, even in early clinical and preclinical disease stages. Future therapeutic trials may consider utilizing these measures to evaluate potential treatment efficacy and mechanism of action, as well as for sample enrichment with patients most likely to rapidly progress towards AD.