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Protein Target Quantification Decision Tree
(Hindawi, 2013) Kim, Jong Won; You, Jinsam; Biochemistry and Molecular Biology, School of Medicine
The utility of mass spectrometry-(MS-) based proteomic platforms and their clinical applications have become an emerging field in proteomics in recent years. Owing to its selectivity and sensitivity, MS has become a key technological platform in proteomic research. Using this platform, a large number of potential biomarker candidates for specific diseases have been reported. However, due to lack of validation, none has been approved for use in clinical settings by the Food and Drug Administration (FDA). Successful candidate verification and validation will facilitate the development of potential biomarkers, leading to better strategies for disease diagnostics, prognostics, and treatment. With the recent new developments in mass spectrometers, high sensitivity, high resolution, and high mass accuracy can be achieved. This greatly enhances the capabilities of protein biomarker validation. In this paper, we describe and discuss recent developments and applications of targeted proteomics methods for biomarker validation.
Atopy, Cytokine Production, and Airway Reactivity as Predictors of Pre-School Asthma and Airway Responsiveness
(Wiley, 2014) Sarria, Edgar E.; Mattiello, Rita; Yao, Weiguo; Chakr, Valentina; Tiller, Christina J.; Kisling, Jeffrey; Tabbey, Rebeka; Yu, Zhangsheng; Kaplan, Mark H.; Tepper, Robert S.; Pediatrics, School of Medicine
Background: Childhood asthma is often characterized by recurrent wheezing, airway hyper-reactivity, atopy, and altered immune characteristics; however, our understanding of the development of these relationships from early in life remains unclear. The aim of our study was to evaluate whether atopy, cytokine production by peripheral blood mononuclear cells (PBMCs), and airway responsiveness, assessed in infants and toddlers, are associated with asthma and airway responsiveness at 4-years of age.
Methods: Infants with eczema (N = 116), enrolled prior to wheezing, were assessed at entry (mean age of 10.7 months), at 1-year follow-up (N = 112), and at 4-years of age (N = 94). Total serum IgE, specific IgE to allergens, and cytokines produced by stimulated PBMCs, were assessed at entry and 1-year follow-up. Spirometry was obtained at all 3-visits, while airway reactivity to methacholine was assessed at entry and 1-year follow-up, and bronchodilator (BD) responsiveness, as well as current asthma was assessed at 4-years of age.
Results: We found that pre-school children with asthma had lower spirometry and a greater BD-response. Serum IgE, particularly to egg and/or milk, and altered cytokine production by PBMCs at entry to the study were associated with asthma, lower spirometry, and greater airway responsiveness at 4-years of age. In addition, we found that airway responsiveness, as well as spirometry, tracked from infancy to 4-years of age.
Conclusions: While spirometry and airway responsiveness track longitudinally from early in life, atopy and cytokine production by PBMCs are associated not only with an increased risk of pre-school asthma, but also lower spirometry and increased airway responsiveness.
Erythropoietin: multiple targets, actions, and modifying influences for biological and clinical consideration
(Rockefeller University Press, 2013) Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
Erythropoietin (EPO), a humoral regulator of erythropoiesis and replacement therapy for selected red blood cell disorders in EPO-deficient patients, has been implicated in a wide range of activities on diverse cell, tissue, and organ types. EPO signals via two receptors, one comprising EPO receptor (EPOR) homodimers and the other a heterodimer of EPOR and CD131-the common β chain component of the GM-CSF, interleukin (IL)-3, and IL-5 receptors. Ligation of EPORs triggers various signaling pathways, including the JAK2-STAT5 and MAPK-NF-κB pathways, depending both on the receptor and the target cell type. A new study in this issue reveals a novel EPO-triggered pathway involving a Spi2A serpin-lysosome-cathepsin cascade that is initiated through the homodimeric EPOR complex and is required for the survival of erythroid progenitors. A full understanding of EPO's effects on various cell types and their potential clinical relevance requires more work on the signaling events initiated through both EPORs, the effects of other cytokines and growth factors that modulate EPO's actions, and a comparison of the effects of full-length versus truncated forms of EPO.
Moderate-vigorous physical activity improves long-term clinical outcomes without worsening pain in fibromyalgia
(Wiley, 2013) Kaleth, Anthony S.; Saha, Chandan K.; Jensen, Mark P.; Slaven, James E.; Ang, Dennis C.; Exercise & Kinesiology, School of Health and Human Sciences
Objective: To evaluate the relationship between long-term maintenance of moderate to vigorous physical activity (MVPA) and clinical outcomes in fibromyalgia (FM).
Methods: Patients with FM (n = 170) received individualized exercise prescriptions and completed baseline and followup physical activity assessments using the Community Health Activities Model Program for Seniors questionnaire at weeks 12, 24, and 36. The primary outcome was the change in the Fibromyalgia Impact Questionnaire-Physical Impairment (FIQ-PI) score. The secondary outcomes included improvements in overall well-being (FIQ total score), pain severity ratings, and depression.
Results: Using a threshold increase in MVPA of ≥10 metabolic equivalent hours/week above usual activities, 27 subjects (15.9%) increased and sustained (SUS-PA), 68 (40%) increased but then declined (UNSUS-PA), and 75 (44.1%) did not achieve (LO-PA) this benchmark. Compared to LO-PA subjects, both SUS-PA and UNSUS-PA subjects reported greater improvement in FIQ-PI (P < 0.01) and FIQ total score (P < 0.05). Additionally, the SUS-PA group reported greater improvement in pain severity compared to the LO-PA group (P < 0.05). However, there were no significant group differences between SUS-PA and UNSUS-PA for any primary or secondary outcome measure.
Conclusion: Increased participation in MVPA for at least 12 weeks improved physical function and overall well-being in patients with FM. Although sustained physical activity was not associated with greater clinical benefit compared with unsustained physical activity, these findings also suggest that performing greater volumes of physical activity is not associated with worsening pain in FM. Future research is needed to determine the relationship between sustained MVPA participation and subsequent improvement in patient outcomes.
Differential Activation and Inhibition of RhoA by Fluid Flow Induced Shear Stress in Chondrocytes
(Wiley, 2013) Wan, Qiaoqiao; Kim, Seung Joon; Yokota, Hiroki; Na, Sungsoo; Biomedical Engineering, Purdue School of Engineering and Technology
Physical force environment is a major factor that influences cellular homeostasis and remodelling. It is not well understood, however, as a potential role of force intensities in the induction of cellular mechanotransduction. Using a fluorescence resonance energy transfer-based approach, we asked whether activities of GTPase RhoA in chondrocytes are dependent on intensities of flow-induced shear stress. We hypothesized that RhoA activities can be either elevated or reduced by selecting different levels of shear-stress intensities. The result indicates that C28/I2 chondrocytes have increased RhoA activities in response to high shear stress (10 or 20 dyn/cm(2) ), whereas a decrease in activity was seen with an intermediate shear stress of 5 dyn/cm(2) . No changes were seen under low shear stress (2 dyn/cm(2) ). The observed two-level switch of RhoA activities is closely linked to the shear-stress-induced alterations in actin cytoskeleton and traction forces. In the presence of constitutively active RhoA (RhoA-V14), intermediate shear stress suppressed RhoA activities, while high shear stress failed to activate them. In chondrocytes, expression of various metalloproteinases is, in part, regulated by shear and normal stresses through a network of GTPases. Collectively, the data suggest that intensities of shear stress are critical in differential activation and inhibition of RhoA activities in chondrocytes.