Roscoe L Warner

University of Michigan | U-M · Medical School

Serum activities of alanine- and aspartate- aminotransferases (ALT and AST) are considered the “gold standard” biomarkers of hepatocyte injury in clinical practice and drug development. However, due to expression of ALT and AST in myocytes, the diagnosis of hepatocellular injury in patients with underlying muscle diseases, including drug-induced mu...

Objective Improved biomarkers of current disease activity and prediction of relapse are needed in antineutrophil cytoplasmic antibody–associated vasculitis (AAV). For clinical relevance, biomarkers must perform well longitudinally in patients on treatment and in patients with nonsevere flares. Methods Twenty-two proteins were measured in 347 serum...

Early diagnosis of drug-induced liver injury (DILI) continues to be a major hurdle during drug development and post marketing. The objective of this study was to evaluate the diagnostic performance of promising biomarkers of liver injury—glutamate dehydrogenase (GLDH), cytokeratin-18 (K18), caspase-cleaved K18 (ccK18), osteopontin (OPN), macrophage...

Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. Since ALT and AST lack liver specificity, the diagnosis of the onset of hepatocellular injury in patients with underlying muscle impairments is severely limited. Thus, we evaluated the potential...

Patient: Female, 44-year-old Final Diagnosis: Acute liver failure Symptoms: APAP overdose Medication: Acetaminophen Clinical Procedure: — Specialty: Molecular Biology Objective Unusual clinical course Background Acetaminophen overdose is the most common cause of acute liver failure. Nevertheless, new biomarker approaches enabling early prediction...

Objective We evaluated potential circulating biomarkers of disease activity in giant cell arteritis (GCA), Takayasu’s arteritis (TAK), polyarteritis nodosa (PAN), and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss). Methods A panel of 22 serum proteins was tested in patients enrolled in the Vasculitis Clinical Research Consorti...

Objective: To investigate serum IL-6 (sIL-6) levels during active disease, complete remission (CR), and relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and to explore the association of changes in sIL-6 with clinical outcomes. Methods: sIL-6 levels were measured at baseline and longitudinally over 18 months, in...

Background The deregulated overproduction of interleukin (IL)−6 has been implicated in several inflammatory and antibody-mediated autoimmune diseases. Objectives To investigate serum IL-6 levels (sIL-6) during active disease, remission, and relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and to explore the associ...

Objectives To evaluate circulating cytokine profiles in patients with ANCA‐associated vasculitis (AAV), classified by ANCA specificity (proteinase 3 (PR3)‐ANCA versus myeloperoxidase (MPO)‐ANCA) or by clinical diagnosis (granulomatosis with polyangiitis (GPA) versus microscopic polyangiitis (MPA)). Methods A panel of 29 cytokines was tested in 186...

To assess the potential of individual bile acids (IBA) and their profiles as mechanistic biomarkers of liver injury for humans in real world situations, we interrogated samples collected under minimum controlled conditions (ie subjects were not fasted). Total bile acids (TBA) have been considered to be biomarkers of liver injury for decades, and mo...

Influence of ethnicity in liver impaired subjects. (TIF)

Principal component analysis: Three groups of bile acids. (TIF)

Performance of the quality control standards in the LC/MS/MS quantitative assay for nine IBA. (DOCX)

IBA in liver impaired subjects. (TIF)

Reference ranges for serum IBAs in healthy populations. (DOCX)

General information for healthy subjects. (XLSX)

General information for subjects with hepatic injury. (XLSX)

Background Evidence supporting the classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) based on ANCA type is accumulating.¹ Objectives To evaluate serum cytokine profiles in patients with AAV classified by ANCA specificity (proteinase 3 (PR3)-ANCA versus myeloperoxidase (MPO)-ANCA) or by clinical diagnosis (...

MicroRNAs (miRNAs) released into the peripheral circulation upon cellular injury have shown a promise as a new class of tissue-specific biomarkers. We were first to demonstrate that next-generation sequencing analysis of serum from human subjects with acetaminophen-induced liver injury revealed a specific signature of circulating miRNAs. We consequ...

Percentages of mapped sequencing reads across all liver impairments and T2DM. List of all miRNAs and its presence in serum in percent. (DOCX)

Individual miRNA signatures. List of significantly altered miRNAs detected for all liver impairments and T2DM. (DOCX)

List of small RNA like new predicted miRNAs. List of small RNA like sequences that passed our criteria to be potential novel miRNAs. (DOCX)

List of miRNAs detected across all subjects. Complete circulating miRNAs detected in the serum of all subjects. (DOCX)

Patient characteristics and clinical chemistry data. The table lists all subject including metadata and clinical chemistry paramenters. (DOCX)

List of the most abundant miRNA isoforms detected. The list consist of miRNAs that show differences in the predominantly observed miRNA the conditions. (DOCX)

Significantly altered small RNA like miRNAs. List of small RNA like sequences that passed our criteria to be potential novel miRNAs and are altered upon liver disease and T2DM. (DOCX)

Identified pathways with individual signatures. The table shows all pathways identified with the individual miRNA signatures. (XLSX)

Introduction: Drug-induced liver injury (DILI) is a major cause of attrition of drug candidates during the clinical phase as well as after marker introduction. A main reason is that DILI is difficult to be captured in due time by the classical clinical chemistry bat- tery in view of its limited specificity and sensitivity. Over recent years, microR...

Drug-induced liver-injury (DILI) is recognized as a major reason for withdrawal of drugs from the market. Since the conventional testing paradigm fails to detect about 40% of potentially hepatotoxic compounds, there is an urgent need for mechanistic biomarkers of liver injury applicable in clinical trials. Recently, cell free, serum circulating mic...

The oncofetal antigen - immature laminin receptor protein (OFA/iLRP) has been linked to metastatic tumor spread for several years. The present study, in which two highly-specific, high-affinity OFA/iLRP-reactive mouse monoclonal antibodies were examined for ability to suppress tumor cell growth and metastatic spread in the A20 B-cell leukemia model...

Small vessel vasculitis is a life threatening condition and patients typically present with renal and pulmonary injury. Disease pathogenesis is associated with neutrophil accumulation, activation, and oxidative damage; the latter being driven in large part by myeloperoxidase (MPO) which generates hypochlorous acid (HOCl) among other oxidants. MPO h...

Drug-induced liver-injury (DILI) is a leading cause of acute liver failure and the major reason for withdrawal of drugs from the market. Preclinical evaluation of drug candidates has failed to detect about 40% of potentially hepatotoxic compounds in humans. At the onset of liver injury in humans, currently used biomarkers have difficulty differenti...

Abbreviations: CNU, cutaneous neurovascular unit; DT, double transgenic; EGFRI, EGFR inhibitor; ErbB, avian erythroblastosis oncogene B; KC, keratinocyte; qRT-PCR, quantitative real-time reverse-transcriptase–PCR; ST, single transgenic; WT, wild type

A series of murine monoclonal antibodies were generated using recombinant oncofetal antigen - immature laminin receptor protein (OFA/iLRP) as the immunogen. Several of the antibodies detected the 37kD OFA/iLRP but did not recognize the structurally related 67kD mature laminin receptor protein (LRP), as determined by western blot analysis. Additiona...

Serum creatinine functions as a poor surrogate marker of renal allograft dysfunction and long-term graft survival. By measuring multiple proteins simultaneously in the serum of transplant patients, we can identify unique protein signatures of graft dysfunction. We utilized training and validation cohorts composed of healthy and volunteer subjects,...

Renal disease is epidemic in the United States with approximately 8 × 10(6) people having chronic kidney disease. Renal biopsies are widely used to provide essential diagnostic information to physicians. However, the risk of bleeding complications possibly leading to life-threatening situations results in the contra-indication of biopsy in certain...

Hepatotoxicity remains a major challenge in drug development. While alanine aminotransferase (ALT) remains the gold standard biomarker of liver injury, the availability of alternative biomarker strategies to better predict the potential for severe drug induced liver injury (DILI) is essential. In this study we evaluated the utility of glutamate deh...

Objective: To identify circulating proteins that distinguish between active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and remission in a manner complementary to markers of systemic inflammation. Methods: Twenty-eight serum proteins representing diverse aspects of the biology of AAV were measured before and 6 months...

Prenatal environmental exposures play a critical role in determining late-life chronic disease susceptibility. However, the mechanisms linking the in utero environment and disease development in the offspring are poorly understood. Recent investigations have confirmed a central pathogenic role of T cell chemokine receptors, particularly C-C chemoki...

PADMA 28 is a multi-component herbal mixture formulated according to an ancient Tibetan recipe. PADMA 28 is known to stimulate collagen production and reduced levels of collagen-degrading matrix metalloproteinases (MMPs). The goal of the present study was to determine whether topical treatment of rat skin with PADMA 28 would improve skin structure/...

Activated lymphocytes proliferate, secrete cytokines, and can make antibodies. Normally activated B and T cells meet the bioenergetic demand for these processes by up-regulating aerobic glycolysis. In contrast, several lines of evidence suggest that pathogenic lymphocytes in autoimmune diseases like lupus meet ATP demands through oxidative phosphor...

Utilizing a custom antibody‐microarray we have identified unique expression patterns in the serum of kidney transplant patients with biopsy‐proven acute tubular necrosis (ATN) versus healthy transplant patients. Levels of Activin A, Fas Ligand, Fcγ RII, IL‐1α, IFN γ, MCP‐1, MCP‐2, MIP‐1α, MIP‐1β f z VEGF, BLC/BCA‐1, GM‐CSF, IP‐10 and IL‐1 RI were s...

With the development of a 108 protein antibody microarray, we have identified unique expression patterns in the serum of patients with biopsy‐proven acute cellular rejection versus healthy transplant patients. Levels of Gro‐α, IL‐1 RI, IL‐3, IL‐12, IP‐10, Fc‐γ RIIB, MCP‐3 and TGF‐α were significantly increased (p<0.05) in rejecting patients, relati...

Previous in vitro work characterized the protease Q8009 isolated from the venom of the Australian brown snake Pseudonaja textilis textilis with Factor Xa-like activity and hemostatic properties. The purpose of the work described here characterizes the in vivo hemostatic properties in a rat model of parenchymatous organ injury. The key parameters of...

Healing of superficial skin wounds depends on the proliferation and migration of keratinocytes at the wound margin. When human epidermal keratinocytes were incubated on polymerized type I collagen, they rapidly attached and spread. The cells underwent a proliferative response and, over the subsequent 6-day period, covered the collagen surface with...

Nephrogenic systemic fibrosis is a clinical syndrome linked with exposure in renal failure patients to gadolinium-based contrast agents (GBCAs) during magnetic resonance imaging. Recently, we demonstrated that GBCA exposure led to increased matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in human skin...

Hairless rats were topically treated with a combination of 10% curcumin and 3% ginger extract (or with each agent alone) for a 21-day period. Following this, the rats were treated topically with Temovate (corticosteroid) for an additional 15 days. At the end of the treatment period, superficial abrasion wounds were induced in the treated skin. Abra...

Recent studies have shown that ginger extract and curcumin work synergistically to promote wound healing in Temovate‐treated rats. With this in mind, the current study focused on the effects of combined ginger and curcumin on organ cultured human skin and primary dermal fibroblasts. Dermal fibroblasts were treated for a 72‐hour period with a range...

Topical treatment of hairless rats with curcumin and a ginger extract led to increased collagen production and decreased expression of MMP‐9 in treated skin. Rats were pre‐treated topically (21 days) with the botanical preparation followed by a combination of botanicals and Temovate (corticosteroid) for an additional 15 days. Superficial abrasion w...

Aprotinin has been used widely in surgery as an anti-bleeding agent but is associated with a number of side effects. We report that textilinin-1, a serine protease inhibitor from Pseudonaja textilis venom with sequence relatedness to aprotinin, is a potent but reversible plasmin inhibitor and has a narrower range of protease inhibition compared to...

Nephrogenic systemic fibrosis (NSF) is a clinical syndrome linked with exposure in renal failure patients to gadolinium-based magnetic resonance imaging contrast agents (GBCAs). The pathogenesis of the disease is largely unknown. The present study addresses potential pathophysiological mechanisms. Here, we have examined human skin in organ culture...

Connective tissue damage and angiogenesis are both important features of tumour growth and invasion. Here, we show that endothelial cells maintained on a three-dimensional lattice of intact polymerised collagen formed a monolayer of cells with a cobblestone morphology. When the collagen was exposed to organ culture fluid from human basal cell tumou...

Current interest in novel compounds with dermal repair potential has led to the development of a rapid and accurate assay to screen large numbers of samples for newly synthesized tropoelastin in the dermis of natural and photo aged skin. Herein we report the development of a competitive enzyme‐linked immunosorbent assay (ELISA) for rodent tropoelas...

Primary human dermal fibroblasts in monolayer culture exhibit a cytotoxic response to hydrogen peroxide at concentrations greater than 25μM. When pretreated with gingerol enriched Ginger (Zingiber officinale) extract for 72 hours, fibroblasts have an increased capability to cope with peroxide induced injury and cytoxicity. Intact skin was organ cul...

Chronic exposure to airborne particulates is well described as the primary cause of occupational pulmonary injury and increases the risk of asthma, chronic bronchitis, allergic rhinitis and hypersensitivity pneumonitis. Sources of both inorganic and organic particulates are derived of bacterial, fungal, chemical, plant, or animal origin. While inha...

Endothelial cells maintained on a three‐dimensional lattice of intact, polymerized type I collagen formed a monolayer of cells with a cobblestone morphology. When the collagen was exposed to organ culture fluid from human skin (previously characterized and shown to contain a high level of active matrix metalloproteinase‐1 [MMP‐1]), degradation of t...

MDI 301 is a picolinic acid‐substituted ester of retinoic acid (RA) and has been shown to increase epidermal thickness and pro‐collagen synthesis in organ‐cultured human skin. Unlike RA, MDI 301 does not induce expression of pro‐inflammatory cytokines or induce expression of leukocyte adhesion molecules. In the present study topical MDI 301 improve...

Following development of an antibody microarray we undertook a six month study of a single batch of chips to determine the loss of sensitivity over time. Picogram amounts of capture antibodies are spotted onto epoxy‐silane slides using a Piezorray printer. A single printing, of eleven slides containing 30 anti‐rat antibodies was stored at 4°C in a...

Mice on a calorie-restricted (CR) diet (total calories restricted to 70% of ad libitum; AL) for periods of time ranging from 3 to 18 months were examined for response to topical treatment with all-trans retinoic acid (RA). Daily application of a 0.1% solution of RA to the shaved skin of UM-HET3 mice on an AL diet produced a severe irritation that w...

MDI 301 is a picolinic acid-substituted ester of 9-cis retinoic acid. It has been shown in the past that MDI 301 increases epidermal thickness, decreases matrix metalloproteinase (MMP) activity, and increases procollagen synthesis in organ-cultured human skin. Unlike all-trans retinoic acid (RA), MDI 301 does not induce expression of proinflammator...

Hemostatic properties of a factor Xa-like protease (Q8009) from the Australian snake Pseudonaja textilis textilis were determined. In tail-tip transection and dermal incision (hind limb) models, reagents were applied with collagen matrix. Blood was collected on filter paper chads for 12 one-minute intervals or until hemostasis. Determination of blo...

Mice lacking matrix metalloproteinase-3 (MMP-3; stromelysin-1) demonstrated significantly less injury than their normal counterparts following the formation of IgG-containing immune complexes in the alveolar wall or in the wall of the peritoneum. Likewise, mice lacking MMP-3 demonstrated less lung injury following intra-tracheal instillation of the...

The role of interleukin-6 (IL-6) in granulomatous vasculitis is not well understood. To investigate its involvement in this type of vasculitis a model of glucan-induced pulmonary vasculitis employed interleukin-6 deficient (IL-6-/-) mice. Briefly, IL-6-/- mice and C57B/J6 wild type (IL-6+/+) mice were injected intravenously with a suspension of glu...

The use of bacteria as a tool for machining, also known as bio-machining, is a novel material removal process. This study char-acterizes the surface changes and relates the material removal rate to quantified bacterial concentrations resulting from machin-ing of pure polycrystalline Cu using the bacterium Acidithiobacil-lus ferrooxidans. Cu blocks,...

Previous studies have suggested that Interleukin-6 (IL-6) acts as a marker of vasculitis. To determine the role of IL-6 in vasculitis we utilized two models of immune complex induced vascular injury (dermal Arthus and acute pulmonary alveolitis) in IL-6 deficient (IL-6(-/-)) and IL-6 sufficient (IL-6(+/+)) mice. Plasma and bronchoalveolar lavage (B...

Partial hepatectomy triggers hepatocyte proliferation, hepatic matrix remodeling, and hepatocyte apoptosis, all of which are important processes in the regenerating liver. Previous studies have shown an increase in the levels of matrix metalloproteinases gelatinase A (MMP-2) and gelatinase B (MMP-9) after partial hepatectomy. The goal of this study...

Complement-mediated tissue injury in humans occurs upon deposition of immune complexes, such as in autoimmune diseases and acute respiratory distress syndrome. Acute lung inflammatory injury in wild-type and C3-/- mice after deposition of IgG immune complexes was of equivalent intensity and was C5a dependent, but injury was greatly attenuated in Hc...

The objective of this study was to assess matrix metalloproteinase (MMP) and MMP inhibitor expression in the airspace of patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and to determine the prognostic significance of MMP expression in this patient population. Twenty-eight patients with ALI or ARDS were prospectiv...