Publications by authors named "Stewart Bryant"

20 Publications

  • Page 1 of 1

Stemless Total Shoulder Arthroplasty With Orthobiologic Augmentation.

Arthrosc Tech 2021 Feb 30;10(2):e531-e538. Epub 2021 Jan 30.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Total shoulder arthroplasty (TSA) has evolved over the years and is used for a variety of indications, with arthritis being the most common. Stemless TSA is a unique bone-preserving design that can eliminate rotational malalignment. Additionally, recent literature has found utility in the use of biological mesh and a platelet-rich plasma injection to improve healing. The purpose of this article is to outline the process of TSA using a stemless system and how to incorporate the use of amnion matrix and platelet-rich plasma into the surgical technique.
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http://dx.doi.org/10.1016/j.eats.2020.10.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917302PMC
February 2021

Mini-Open Achilles Repair With a Flat Braided Suture in a Low-Profile Configuration.

Arthrosc Tech 2021 Feb 16;10(2):e451-e455. Epub 2021 Jan 16.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Achilles repair has evolved over the past 30 years, from large open procedures with high complication rates to shorter, less-invasive procedures with better outcomes. Percutaneous repair has comparable failure rates with open repairs, fewer complications, and faster recovery. However, percutaneous Achilles repairs risk sural nerve injury. A mini-open repair fuses the gap between percutaneous and open procedures, and this approach has the potential to mitigate nerve injury while maintaining the increased efficiency in procedure time and patient recovery. The purpose of this Technical Note and accompanying video is to outline the repair of the Achilles tendon using a mini open repair using a low-profile flat braided suture.
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http://dx.doi.org/10.1016/j.eats.2020.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917089PMC
February 2021

Distal Clavicle Excision for Acromioclavicular Joint Osteoarthritis Using a Fluoroscopic Kirschner Wire Guide.

Arthrosc Tech 2021 Feb 16;10(2):e359-e365. Epub 2021 Jan 16.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Pathology of the acromioclavicular joint is common and often resistant to conservative treatment, requiring distal clavicle excision for definitive relief. First described as an open technique by Mumford and Gurd in 1941, distal clavicle excision has evolved greatly, with arthroscopic techniques currently predominating. No significant difference has been found in patient satisfaction or rate of complication between the techniques in a recent meta-analysis. Indeed, open excisions are still performed at a high rate, owing to the difficulty in technique and visualization with arthroscopic methods. One major critique of arthroscopic distal clavicle excision is difficulty safeguarding against under- and overexcision of the distal clavicle due to the lack of depth perception and visual reference points of the arthroscopic perspective. This Technical Note and accompanying video describe an indirect subacromial arthroscopic distal clavicle excision using a fluoroscopic Kirschner wire guide placed at the proximal border prior to resection to serve as a visual and mechanical reference to overexcision.
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http://dx.doi.org/10.1016/j.eats.2020.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917026PMC
February 2021

Combined Coracoclavicular and Acromioclavicular Joint Reconstruction with Allograft Using a Cerclage Tensioning System.

Arthrosc Tech 2021 Feb 16;10(2):e317-e323. Epub 2021 Jan 16.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Acromioclavicular joint separations are common shoulder injuries, yet standard treatment practices vary. Popular surgical techniques include reconstruction using allografts or neighboring ligaments as well as repair using screws and sutures. This Technical Note and accompanying video describe both an acromioclavicular and coracoclavicular joint reconstruction using an allograft to replace native acromioclavicular ligament along with an AC joint reduction using a Suture Cerclage System to precisely control reduction and restore anatomic alignment.
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http://dx.doi.org/10.1016/j.eats.2020.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917031PMC
February 2021

The effect of using activity workstations on heart rate variability during complex cognitive tasks.

J Am Coll Health 2020 Jul 16:1-8. Epub 2020 Jul 16.

Department of Psychology, Clemson University, Clemson, South Carolina, USA.

The purpose of the current study was to examine the effects of using an activity workstation on the physiological stress response as measured by heart rate variability while completing cognitively demanding tasks. Eleven college students (6 females; age: 19.4 ± 0.9 years) participated in the study. The participants completed three psychologically stressful cognitive tasks while seated at a traditional desk and while using an activity workstation. Heart rate variability was recorded and analyzed with power spectrum density and time-domain analysis. Using activity workstations while completing stressful cognitive tasks did not negatively affect task performance. There was; however, a reduction in low frequency heart rate variability but no change in cardiac sympathovagal balance. The results indicate that using activity workstations while completing difficult tasks reduces sympathetic reactivity to stress in college students. This suggests that using activity workstations could provide a coping mechanism for stress.
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http://dx.doi.org/10.1080/07448481.2020.1782919DOI Listing
July 2020

Single-Institution Experience With Component Separation for Ventral Hernia Repair: A Retrospective Review.

Ann Plast Surg 2018 06;80(6S Suppl 6):S343-S347

Purpose: In this study, we reviewed our institution's experience using component separation for repair of ventral hernias.

Methods: This was a retrospective review of all component separations for ventral hernia between July 2009 and December 2015. Recorded data included body mass index (BMI), preoperative albumin, smoking history, comorbidities, additional procedures, length of surgery, hospitalization, recurrence, and postoperative complications.

Results: One hundred ninety-six component separations were performed in the study period. The average patient age was 56 years, and 65.3% of patients were female. The average BMI was 32.6 kg/m; preoperative albumin was 3.59; 18.4% were current smokers; 28.1% were diabetic; and 14.3% had heart disease. Postoperative complications developed in 16.8% of patients. Recurrence developed in 8.7% of patients. Patients who developed a postoperative complication had a higher BMI (P = 0.025) and lower albumin (P = 0.047) compared with patients who did not develop complications. Current smokers were more likely to develop complications (P = 0.008). More than one third of patients had additional procedures at the time of the ventral hernia repair. The addition of a plastic surgery procedure was not associated with an increased risk of developing a complication (P = 0.25). Patients who developed complications had a significantly longer hospital course (P < 0.001) but no difference in total operative time (P = 0.975). Increased number of comorbidities did not statistically correlate with an increased complication rate (P = 0.65) or length of hospital stay (P = 0.43).

Conclusions: We identified risk factors that increase the likelihood of postoperative complications and length of hospital stay. In addition, this study suggests that more comorbidities and additional procedures at the time of the hernia repair may not have as large of impact on complication risk as previously thought.
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http://dx.doi.org/10.1097/SAP.0000000000001349DOI Listing
June 2018

Decreasing Sedentary Behavior: Effects on Academic Performance, Meta-Cognition, and Sleep.

Front Neurosci 2017 9;11:219. Epub 2017 May 9.

Department of Psychology, Clemson UniversityClemson, SC, USA.

There is growing interest in using activity workstations as a method of increasing light physical activity in normally sedentary environments. The current study ( = 117) compared the effects of studying in college students while slowly pedaling a stationary bike with a desktop with studying at traditional desks across 10 weeks in an academic semester. The students were assigned to study either on the stationary bike or at a traditional desk located in the campus library for a minimum of 2 h a week. During the 10 weeks, the students studied for tests or worked on other required academic activities while working at their assigned desk. In addition, the participants completed a pre survey, weekly surveys, and a post survey. We found that although students studying at the traditional desks reported more ease of studying and more effective studying than those using the stationary bikes, the two groups performed equally well on tests in an introductory psychology course. Moreover, the students using the traditional desks reported a decrease in sleep quality later in the semester while those using the activity workstation reported stable levels of sleep quality. The current results indicate that activity workstations could be implemented in university settings to encourage light physical activity without negatively affecting academic performance while providing possible long-term health and well-being benefits. Furthermore, the results suggests that activity workstations could be a means of combating sedentary behavior in environments where individuals are expected to sit either while waiting (e.g., doctor's waiting rooms, airports) or when completing a necessary task (e.g., the workplace, educational settings).
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http://dx.doi.org/10.3389/fnins.2017.00219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422426PMC
May 2017

4-Methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate.

J Med Chem 2017 06 25;60(11):4559-4572. Epub 2017 May 25.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00408DOI Listing
June 2017

Implications of Social Support as a Self-Control Resource.

Front Behav Neurosci 2016 28;10:228. Epub 2016 Nov 28.

Department of Psychology, Clemson University Clemson, SC, USA.

Self-control is an intricate component of decision making and effectively managing day-to-day life. Failing to maintain adequate self-control can have negative effects on many desired goals and social experiences. As such, understanding how different facets of the human experience may affect self-control is an important undertaking. One area that is yet unclear is the possible relationships between social support and self-control. Research suggests that social support can be an effective resource in reducing stress and promoting health and well-being. Research has also indicated that stress can be a limiting factor on self-control. In contrast, few studies have focused on social support as a potential resource for self-control. The goal of this mini-review article is to explore the intersections between self-control and social support and encourage integration of these two relatively independent areas of research. This review will help provide a broader understanding of self-control resources and how we can better understand the relationships between social well-being and our ability to monitor and utilize our capacity to maintain self-control.
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http://dx.doi.org/10.3389/fnbeh.2016.00228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124711PMC
November 2016

Carbohydrate malabsorption mechanism for tumor formation in rats treated with the SGLT2 inhibitor canagliflozin.

Chem Biol Interact 2014 Sep 14;221:109-18. Epub 2014 Aug 14.

Janssen Research & Development, LLC, 1000 Route 202 South, Raritan, NJ 08869, United States. Electronic address:

Canagliflozin is an SGLT2 inhibitor used for the treatment of type 2 diabetes mellitus. Studies were conducted to investigate the mechanism responsible for renal tubular tumors and pheochromocytomas observed at the high dose in a 2-year carcinogenicity study in rats. At the high dose (100mg/kg) in rats, canagliflozin caused carbohydrate malabsorption evidenced by inhibition of intestinal glucose uptake, decreased intestinal pH and increased urinary calcium excretion. In a 6-month mechanistic study utilization of a glucose-free diet prevented carbohydrate malabsorption and its sequelae, including increased calcium absorption and urinary calcium excretion, and hyperostosis. Cell proliferation in the kidney and adrenal medulla was increased in rats maintained on standard diet and administered canagliflozin (100mg/kg), and in addition an increase in the renal injury biomarker KIM-1 was observed. Increased cell proliferation is considered as a proximal event in carcinogenesis. Effects on cell proliferation, KIM-1 and calcium excretion were inhibited in rats maintained on the glucose-free diet, indicating they are secondary to carbohydrate malabsorption and are not direct effects of canagliflozin.
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http://dx.doi.org/10.1016/j.cbi.2014.08.001DOI Listing
September 2014

Mass or molar? Recommendations for reporting concentrations of therapeutic drugs.

Med J Aust 2013 Apr;198(7):368-9

St Vincent's Hospital, Sydney, NSW, Australia.

A working party (WP) from the Australasian Association of Clinical Biochemists, Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, Royal College of Pathologists of Australasia and Royal Australasian College of Physicians recommends the following: *mass units should be used for reporting therapeutic drug concentrations in Australia and New Zealand; and the litre (L) should be used as the denominator when expressing concentration. Examples of these units are mg/L and μg/L Exceptions to these principles include: *drugs for which there is current uniformity of reporting and supporting information using molar units, notably lithium (mmol/L) and methotrexate (μmol/L); *drugs that are also present as endogenous substances, where the units used routinely should continue to be used. This applies to many substances, including minerals (eg, iron; μmol/L), vitamins (eg, vitamin D; nmol/L) and hormones (eg, thyroxine; pmol/L). *drugs for which the denominator is not a 198 of fluid and there is international uniformity of reporting (eg, thiopurine metabolites; per 109 red blood cells). These recommendations relate to drugs that are used therapeutically, whether measured for therapeutic drug monitoring purposes or for assessment of overdose. Other substances, such as drugs of misuse, heavy metals or environmental toxins, were not considered by the WP and are thus not covered by this document. These recommendations should also be applied to other supporting documentation such as published guidelines, journal articles and websites. The implementation of these recommendations in New Zealand is subject to local confirmation.
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http://dx.doi.org/10.5694/mja12.10366DOI Listing
April 2013

The inhibin B response to the testicular toxicant 1, 3 dinitrobenzene in male rats.

Birth Defects Res B Dev Reprod Toxicol 2013 Feb 24;98(1):29-34. Epub 2013 Jan 24.

Drug Safety Sciences, Janssen Research & Development, LLC Raritan, NJ, USA.

Background: This study was conducted as part of an ILSI-HESI International Life Sciences Institute-Health & Environmental Sciences Institute consortium effort to assess the utility of circulating Inhibin B as an early biomarker of Sertoli cell-specific testicular toxicity in rats. 1, 3-Dinitrobenzene (1,3-DNB) was selected as a testicular toxicant in this study as it is known to target Sertoli cells.

Methods: 1,3-DNB (2 and 6 mg/kg/day) or control (corn oil) was administered orally to male rats for two or five consecutive days. Blood was collected from rats treated for 2 days on days 1 and 2 and from rats treated for 5 days on days 1, 3, and 5. The resulting serum was evaluated for Inhibin B and follicle stimulating hormone. At the end of the treatment periods, the testes were removed, weighed, and examined histopathologically.

Results: Daily administration of 1,3-DNB resulted in decreased testis weight only on day 5 and only at the high dose (6 mg/kg/day). There was a time-dependent increase in incidence and severity of testicular findings characterized by degeneration of the germinal epithelium with loss of pachytene spermatocytes and vacuolization of the Sertoli cells in the seminiferous tubules at the high dose. Inhibin B levels in 1,3-DNB-treated animals were decreased with treatment only on day 5 at the high dose; there were no associated changes in follicle stimulating hormone.

Conclusions: Changes in serum Inhibin B levels were detected only in association with moderate or severe testicular toxicity as evidenced by histopathology and is therefore considered to be of limited value as a biomarker for Sertoli cell toxicity.
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http://dx.doi.org/10.1002/bdrb.21038DOI Listing
February 2013

Diabetogenic effect of a series of tricyclic delta opioid agonists structurally related to cyproheptadine.

Toxicol Sci 2010 Oct 8;117(2):493-504. Epub 2010 Jul 8.

Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477, USA.

The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic β-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic β-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.
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http://dx.doi.org/10.1093/toxsci/kfq200DOI Listing
October 2010

Predictive toxicogenomics approaches reveal underlying molecular mechanisms of nongenotoxic carcinogenicity.

Mol Carcinog 2006 Dec;45(12):914-33

Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, New Jersey, USA.

Toxicogenomics technology defines toxicity gene expression signatures for early predictions and hypotheses generation for mechanistic studies, which are important approaches for evaluating toxicity of drug candidate compounds. A large gene expression database built using cDNA microarrays and liver samples treated with over one hundred paradigm compounds was mined to determine gene expression signatures for nongenotoxic carcinogens (NGTCs). Data were obtained from male rats treated for 24 h. Training/testing sets of 24 NGTCs and 28 noncarcinogens were used to select genes. A semiexhaustive, nonredundant gene selection algorithm yielded six genes (nuclear transport factor 2, NUTF2; progesterone receptor membrane component 1, Pgrmc1; liver uridine diphosphate glucuronyltransferase, phenobarbital-inducible form, UDPGTr2; metallothionein 1A, MT1A; suppressor of lin-12 homolog, Sel1h; and methionine adenosyltransferase 1, alpha, Mat1a), which identified NGTCs with 88.5% prediction accuracy estimated by cross-validation. This six genes signature set also predicted NGTCs with 84% accuracy when samples were hybridized to commercially available CodeLink oligo-based microarrays. To unveil molecular mechanisms of nongenotoxic carcinogenesis, 125 differentially expressed genes (P<0.01) were selected by Student's t-test. These genes appear biologically relevant, of 71 well-annotated genes from these 125 genes, 62 were overrepresented in five biochemical pathway networks (most linked to cancer), and all of these networks were linked by one gene, c-myc. Gene expression profiling at early time points accurately predicts NGTC potential of compounds, and the same data can be mined effectively for other toxicity signatures. Predictive genes confirm prior work and suggest pathways critical for early stages of carcinogenesis.
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http://dx.doi.org/10.1002/mc.20205DOI Listing
December 2006

Drug-induced oxidative stress in rat liver from a toxicogenomics perspective.

Toxicol Appl Pharmacol 2005 Sep;207(2 Suppl):171-8

Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ 08869, USA.

Macrophage activators (MA), peroxisome proliferators (PP), and oxidative stressors/reactive metabolites (OS/RM) all produce oxidative stress and hepatotoxicity in rats. However, these three classes of hepatotoxicants give three distinct gene transcriptional profiles on cDNA microarrays, an indication that rat hepatocytes respond/adapt quite differently to these three classes of oxidative stressors. The differential gene responses largely reflect differential activation of transcription factors: MA activate Stat-3 and NFkB, PP activate PPARa, and OS/RM activate Nrf2. We have used gene signature profiles for each of these three classes of hepatotoxicants to categorize over 100 paradigm (and 50+ in-house proprietary) compounds as to their oxidative stress potential in rat liver. In addition to a role for microarrays in predictive toxicology, analyses of small subsets of these signature profiles, genes within a specific pathway, or even single genes often provide important insights into possible mechanisms involved in the toxicities of these compounds.
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http://dx.doi.org/10.1016/j.taap.2005.02.031DOI Listing
September 2005

A gene expression signature for oxidant stress/reactive metabolites in rat liver.

Biochem Pharmacol 2004 Dec;68(11):2249-61

Johnson and Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ, USA.

Formation of free radicals and other reactive molecules is responsible for the adverse effects produced by a number of hepatotoxic compounds. cDNA microarray technology was used to compare transcriptional profiles elicited by training and testing sets of 15 oxidant stressors/reactive metabolite treatments to those produced by approximately 85 other paradigm compounds (mostly hepatotoxicants) to determine a shared signature profile for oxidant stress-associated hepatotoxicity. Initially, 100 genes were chosen that responded significantly different to oxidant stressors/reactive metabolites (OS/RM) compared to other samples in the database, then a 25-gene subset was selected by multivariate analysis. Many of the selected genes (e.g., aflatoxin aldehyde reductase, diaphorase, epoxide hydrolase, heme oxgenase and several glutathione transferases) are well-characterized oxidant stress/Nrf-2-responsive genes. Less than 10 other compounds co-cluster with our training and testing set compounds and these are known to generate OS/RMs as part of their mechanisms of toxicity. Using OS/RM signature gene sets, compounds previously associated with macrophage activation formed a distinct cluster separate from OS/RM and other compounds. A 69-gene set was chosen to maximally separate compounds in control, macrophage activator, peroxisome proliferator and OS/RM classes. The ease with which these 'oxidative stressor' classes can be separated indicates a role for microarray technology in early prediction and classification of hepatotoxicants. The ability to rapidly screen the oxidant stress potential of compounds may aid in avoidance of some idiosyncratic drug reactions as well as overtly toxic compounds.
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http://dx.doi.org/10.1016/j.bcp.2004.08.003DOI Listing
December 2004

Inverse gene expression patterns for macrophage activating hepatotoxicants and peroxisome proliferators in rat liver.

Biochem Pharmacol 2004 Jun;67(11):2141-65

Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, NJ, USA.

Macrophage activation contributes to adverse effects produced by a number of hepatotoxic compounds. Transcriptional profiles elicited by two macrophage activators, LPS and zymosan A, were compared to those produced by 100 paradigm compounds (mostly hepatotoxicants) using cDNA microarrays. Several hepatotoxicants previously reported to activate liver macrophages produced transcriptional responses similar to LPS and zymosan, and these were used to construct a gene signature profile for macrophage activators in the liver. Measurement of cytokine mRNAs in the same liver samples by RT-PCR independently confirmed that these compounds are associated with macrophage activation. In addition to expected effects on acute phase proteins and metabolic pathways that are regulated by LPS and inflammation, a strong induction was observed for many endoplasmic reticulum-associated stress/chaperone proteins. Additionally, many genes in our macrophage activator signature profile were well-characterized PPARalpha-induced genes which were repressed by macrophage activators. A shared gene signature profile for peroxisome proliferators was determined using a training set of clofibrate, WY 14643, diethylhexylphthalate, diisononylphthalate, perfluorodecanoic acid, perfluoroheptanoic acid, and perfluorooctanoic acid. The signature profile included macrophage activator-induced genes that were repressed by peroxisome proliferators. NSAIDs comprised an interesting pharmacological class in that some compounds, notably diflunisal, co-clustered with peroxisome proliferators whereas several others co-clustered with macrophage activators, possibly due to endotoxin exposure secondary to their adverse effects on the gastrointestinal system. While much of these data confirmed findings from the literature, the transcriptional patterns detected using this toxicogenomics approach showed relationships between genes and biological pathways requiring complex analysis to be discerned.
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http://dx.doi.org/10.1016/j.bcp.2004.01.029DOI Listing
June 2004

Toward the identification of liver toxicity markers: a proteome study in human cell culture and rats.

Proteomics 2003 Oct;3(10):1835-62

Eurogentec Proteomics, Teltow/Berlin, Germany.

The effects of toxic and nontoxic compound treatments were investigated by high resolution custom developed 2-11 pH gradient NEPHGE (non equilibrium pH gradient electrophoresis) two-dimensional electrophoresis. Two models were compared: (i) in vivo rat and (ii) the human cell line HepG2, to test their suitability in a proteomics based approach to identify a toxicity marker. 163 and 321 proteins were identified from the rat liver and the HepG2 proteome. These represent various isoforms of 113 and 194 different NCBI annotated gene sequences, respectively. Nine compounds were selected to induce proteome variations associated with liver toxicity and metabolism. The rat liver proteome database consists of 78 gels, the HepG2 database of 52 gels. Variant proteins were assessed regarding their usefulness as a toxicity marker by evaluating their treatment specificity against multiple control treatments. Thirteen potential toxicity marker proteins were found in rat liver and eight in HepG2. Catalase and carbamoylphosphate synthetase-1 isoforms were found to be significantly changed after treatment by 4/4 and 3/4 toxic compounds in rat liver, respectively. Aldo-keto-reductase family 1, member C1 was implicated for 3/4 liver cell toxic compounds in HepG2. Our approach was able to differentiate the quality of potential toxicity markers and provided useful information for an ongoing characterization of more compounds in a wider number of toxicity classes.
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http://dx.doi.org/10.1002/pmic.200300552DOI Listing
October 2003