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Papers by Benjamin Fisher

Research paper thumbnail of Effects of beta-estradiol and bisphenol A on heat shock protein levels and localization in the mouse uterus are antagonized by the antiestrogen ICI 182,780

Toxicological sciences : an official journal of the Society of Toxicology, 2001

Bisphenol A (BPA) exhibits many estrogen-like effects in the rodent uterus, but not all of these ... more Bisphenol A (BPA) exhibits many estrogen-like effects in the rodent uterus, but not all of these can be attenuated by antiestrogens. This suggests the involvement of alternate pathways of BPA action that do not involve the estrogen receptor (ER). An examination of the in vivo effects of BPA on uterine gene expression and protein levels should contribute to an understanding of its mechanism of action. In this study we examined the dose-related effects of BPA on levels of a suite of heat shock proteins (hsps) and on the localization of hsp90alpha, a chaperone of the ER, in uteri of ovariectomized B6C3F1 mice and compared these effects with those of beta-estradiol (E2). The antiestrogen ICI 182,780 (ICI) was co-administered with BPA or E2 in order to examine the potential role of the ER. BPA, although less potent than E2, increased hsp90alpha and grp94 to similar levels, but was much less effective than E2 in increasing levels of hsp72. Treatment with 100 mg BPA/kg/day or 2 microg E2/k...

Research paper thumbnail of Bisphenol A-induced increase in uterine weight and alterations in uterine morphology in ovariectomized B6C3F1 mice: role of the estrogen receptor

Toxicological sciences : an official journal of the Society of Toxicology, 2000

The ability of the environmental xenoestrogen bisphenol A (BPA) to increase uterine wet weight in... more The ability of the environmental xenoestrogen bisphenol A (BPA) to increase uterine wet weight in the rodent remains controversial, and few studies have previously examined the effects of BPA on uterine morphology. Furthermore, it is not known whether BPA-induced uterotrophic effects are, similarly to beta-estradiol (E(2)), mediated through the estrogen receptor (ER). In this study, we compared the effects of BPA on uterine wet weight and morphology to those of E(2) in the B6C3F1 ovariectomized mouse. To examine whether these effects were mediated through the ER, the antiestrogen ICI 182, 780 (ICI) was co-administered with BPA or E(2). We report that subcutaneous administration of BPA at doses between 0.8 and 8 mg/day over 4 days significantly increased mean uterine wet weights above those of vehicle (corn oil)-treated mice. The uterine weight data suggest that BPA acts as a partial agonist with an EC(50) of 0.72 mg/day compared to 19.4 ng/day for E(2). BPA (2 mg/day) and E(2) (40 n...

Research paper thumbnail of Relationship between stress protein induction in rat kidney by mercuric chloride and nephrotoxicity

Toxicology and Applied Pharmacology, 1992

Adverse environmental stimuli increase the synthesis of a class of proteins referred to as stress... more Adverse environmental stimuli increase the synthesis of a class of proteins referred to as stress proteins. The effect of mercuric chloride, a model nephrotoxin, on protein synthesis in male rat kidney has been evaluated. Renal slices from exposed rats were incubated with [35S]methionine for 1 hr and subjected to SDS-PAGE, after which 35S-labeled proteins were detected by autoradiography. Enhanced de novo synthesis of 70- and 90-kDa relative molecular mass (M(r)) proteins were detected 2 hr after exposure to 1 mg Hg/kg, with maximum activity occurring at 4-8 hr. By 16 hr postinjection, synthesis of these two proteins had decreased. Dose-related increases in synthesis of these proteins, and of a 110-kDa protein, were observed 4 hr after i.v. injection of 0.25, 0.5, and 1.0 mg Hg/kg, with concomitant inhibition of synthesis of proteins of M(r) 38 and 68 kDa. At a dose of 1 mg/kg, kidney proximal tubules exhibited progressive degenerative changes from 4 to 24 hr. A functional deficit, decreased uptake of [para-3H]aminohippurate into renal slices, was not observed until 16 hr after i.v. injection of 1 mg/kg. No significant histopathologic changes were observed in kidneys 4 hr after treatment with 0.25 or 0.5 mg Hg/kg, iv. No changes in liver protein synthesis were apparent until 16-24 hr, where an increase in the 70- and 90-kDa proteins was observed. A concomitant increase in plasma sorbitol dehydrogenase activity occurred at 16-24 hr; however, there was no histopathological evidence of liver injury. The 72-kDa inducible member of the 70-kDa stress protein family and the 88-kDa member of the 90-kDa protein family were detected by immunoblotting techniques using monoclonal antibodies. The data demonstrate that Hg induces alterations in the expression of renal gene products in vivo as evidenced by enhanced stress protein synthesis and inhibition of synthesis of constitutive proteins. These changes in renal protein synthesis preceded overt renal injury, occurring in the early stages of nephropathy. Altered patterns of stress protein synthesis appeared to be target organ specific. The data suggest that altered protein synthesis patterns may serve as biomarkers of renal injury.

Research paper thumbnail of Metals and Stress Proteins

Handbook of Experimental Pharmacology, 1995

ABSTRACT Prokaryotic and eukaryotic cells respond to physical and chemical stressors or stress by... more ABSTRACT Prokaryotic and eukaryotic cells respond to physical and chemical stressors or stress by increasing the transcription of specific genes that encode for a small class of proteins termed heat shock proteins (hsps). This response is believed to represent a transient reprogramming of gene expression and biological activity which serves to protect sensitive cellular components from irreversible damage and assists in the rapid recovery after the stress is removed or ceases. The changes in gene expression associated with this response following exposure to a stimulus are rapid, and result in both increased de novo synthesis and accumulation of stress proteins. Originally termed the heat shock response because of the induction of these proteins following hyperthermia (RItossa 1962), the signaling mechanism involved in its initiation is sensitive to a variety of physical and chemical insults, including metals (NOver 1991). Because the response can be initiated by a variety of stressors it is generically referred to as the “stress response.” In this review, for convention and to avoid confusion, we have adopted the use of the term “stress proteins” when referring to classic hsps and other stress proteins. Therefore, the hsps will be considered as a subset of the stress proteins, and reference to hsps will be used only when deemed necessary, e.g., when referring to specific references and studies describing specific hsps.

Research paper thumbnail of Latex-associated allergies and anaphylactic reactions

Clinical Immunology and Immunopathology, 1992

The recent reports of severe anaphylactic reactions and several fatalities caused by contact with... more The recent reports of severe anaphylactic reactions and several fatalities caused by contact with latex-containing products raised concerns in the medical community. Although hypersensitivity to natural rubber has been widely reported in the literature, the prevalence and severity of reactions have rapidly increased in the last few years. Latex proteins, constituents of natural latex, appear to be responsible for the sensitization. Many investigators, including our laboratory, are focused on the identification of proteins in raw latex and latex products, specifically those responsible for the elicitation of allergic responses. This paper summarizes available information on the mechanism and epidemiology of latex sensitivity and reviews research efforts toward the identification of the antigen(s) responsible for the reactions. The questions of proper diagnosis and testing, heightening awareness, and prevention of reactions are also addressed.

Research paper thumbnail of Effects of b-Estradiol and Bisphenol A on Heat Shock Protein Levels and Localization in the Mouse Uterus Are Antagonized by the Antiestrogen ICI 182,780

Bisphenol A (BPA) exhibits many estrogen-like effects in the rodent uterus, but not all of these ... more Bisphenol A (BPA) exhibits many estrogen-like effects in the rodent uterus, but not all of these can be attenuated by antiestro- gens. This suggests the involvement of alternate pathways of BPA action that do not involve the estrogen receptor (ER). An exami- nation of the in vivo effects of BPA on uterine gene expression and protein levels should contribute to

Research paper thumbnail of Stress Protein Synthesis Induced in Rat Liver by Cadmium Precedes Hepatotoxicity

Toxicology and Applied Pharmacology, 1993

A diverse array of chemical and physical stressors increases the synthesis of a class of proteins... more A diverse array of chemical and physical stressors increases the synthesis of a class of proteins referred to as heat shock proteins (hsp) or stress proteins. We are investigating the potential of using altered protein synthesis patterns, including the enhanced synthesis of stress proteins, as biomarkers of exposure and cellular injury. The purpose of the present study was to evaluate the effect of a model hepatotoxicant, cadmium (Cd(II)), on stress protein synthesis in male rat liver. To assess target tissue specificity, stress protein synthesis was also studied in kidney. Liver and kidney slices from exposed rats were incubated with [35S]methionine for 1.5 hr, subjected to one-dimensional SDS-PAGE, and 35S-labeled proteins were analyzed by autoradiography. Enhanced de novo synthesis of 70-, 90-, and 110-kilodalton (kDa) relative molecular mass (M(r)) proteins was detected 2 hr after exposure to 2 mg Cd/kg, with maximum activity occurring at 2-4 hr. By 8-16 hr postinjection, synthesis of these proteins had decreased. Synthesis of a 68-kDa protein present in control liver was inhibited 2 hr after exposure with synthesis restored at 16-24 hr. Dose-related increases in synthesis of the three stress proteins were observed 4 hr after iv injection of 1.0 and 2.0 mg Cd/kg, with concomitant inhibition of synthesis of the 68-kDa protein. Mild single cell necrosis of hepatocytes was observed 8 hr after injection of 2 mg Cd/kg which progressed to mild multifocal necrotic foci at 16 hr. No lesions were evident at lower dosages. Increases in plasma sorbitol dehydrogenase activity, a clinical indicator of hepatic injury, was not apparent until 8 hr after exposure. A functional deficit, decreased hepatic microsomal N-demethylase activity, was not observed until 16 hr after iv injection of 2 mg/kg. No changes in kidney de novo stress protein synthesis were observed. No evidence of renal injury was apparent, as evaluated by histopathology, uptake of [para-3H]aminohippurate into renal slices, and blood urea nitrogen values. The 70-kDa stress protein induced early after Cd treatment was identified with a monoclonal antibody as the 72-kDa-inducible hsp. The 90-kDa protein induced by Cd reacted negatively with three monoclonal antibodies to hsp90 and was subsequently identified as a glucose regulated protein (grp94). The data demonstrate that Cd induces alterations in the expression of hepatic gene products in vivo as evidenced by enhanced stress protein synthesis and inhibition of synthesis of constitutive proteins.(ABSTRACT TRUNCATED AT 400 WORDS)

Research paper thumbnail of Stress protein synthesis induced by cadmium-cysteine in rat kidney

Toxicology, 1993

Biomarkers are important tools which enable toxicologists to reliably predict and detect exposure... more Biomarkers are important tools which enable toxicologists to reliably predict and detect exposures to xenobiotics and resultant cell injury, ultimately improving risk assessments. Since the de novo synthesis of stress proteins can be detected early after exposure to some agents, analysis of toxicant-induced changes in gene expression, i.e. alterations in patterns of protein synthesis, may be useful to develop as biomarkers of exposure and toxicity. We are utilizing various xenobiotics as tools to study stress protein synthesis in target organs in order to evaluate the target tissue-specificity of this response. Previous data from this laboratory have demonstrated that induction of stress proteins in rat liver, but not kidney, after acute exposure to CdCl2 precedes hepatoxicity. Since kidney is a target tissue after chronic Cd exposure, it was of interest to examine stress protein synthesis in this tissue. However, dose-limiting hepatotoxicity precluded this evaluation. Cd complexed with molecules such as cysteine (cys) or metallothionein has been used in acute dosing regimens as a tool in order to study the nephrotoxicity of Cd. Therefore, this study was undertaken in order to evaluate Cd-induced stress protein synthesis in an important tissue known to be injured after chronic exposure, i.e. kidney. Specific objectives included comparing stress protein synthesis in rat kidney and liver after acute exposure to Cd-cys and CdCl2, determining the Cd threshold concentration for renal stress protein synthesis and assessing the relationship between stress protein synthesis and nephropathy. Male rats were exposed to equivalent doses of Cd as CdCl2 or Cd-cysteine (molar ratio Cd:cys = 1:15). Kidney Cd concentrations increased 5-fold after i.v. injection of Cd-cys compared to CdCl2, mimicking Cd distribution following chronic exposure. After exposure to Cd, tissue slices were incubated with 35S-methionine. Slices were subsequently homogenized and centrifuged, and the 16,000 g supernatants were subjected to SDS-polyacrylamide gel electrophoresis. Proteins which had incorporated 35S-methionine were detected by autoradiography. De novo synthesis of 70, 90 and 110 kDa proteins was enhanced in liver, but not in kidney, 4 h after injection of 2 mg Cd/kg as CdCl2. In contrast, dose-related increases in synthesis of these proteins were observed in kidney 4 h after injection of 1 and 2mg Cd/kg as Cd-cys, but not at lower dosages. In addition, synthesis of a 68 kDa kidney protein was inhibited at 2 mg Cd/kg as Cd-cys. The threshold for Cd-induced stress protein synthesis was shown to be between 4 and 8 micrograms Cd/g tissue.(ABSTRACT TRUNCATED AT 400 WORDS)

Research paper thumbnail of Mercury Induces Regional and Cell-Specific Stress Protein Expression in Rat Kidney

Toxicological Sciences, 2000

Cells respond to physiologic stress by enhancing the expression of specific stress proteins. Heat... more Cells respond to physiologic stress by enhancing the expression of specific stress proteins. Heat-shock proteins (hsps) and glucoseregulated proteins (grps) are members of a large superfamily of proteins collectively referred to as stress proteins. This particular stress-protein response has evolved as a cellular strategy to protect, repair, and chaperone other essential cellular proteins. The objective of this study was to evaluate the differential expression of four hsps in the renal cortex and medulla during experimental nephrotoxic injury using HgCl 2 . Male Sprague-Dawley rats received single injections of HgCl 2 (0.25, 0.5, or 1 mg Hg/kg, iv). At 4, 8, 16, or 24 h after exposure, kidneys were removed and processed for histopathologic, immunoblot, and immunohistochemical analyses. Nephrosis was characterized as minimal or mild (cytoplasmic condensation, tubular epithelial degeneration, single cell necrosis) at the lower exposures, and progressed to moderate or severe (nuclear pyknosis, necrotic foci, sloughing of the epithelial casts into tubular lumens) at the highest exposures. Western blots of renal proteins were probed with monoclonal antibodies specific for 4 hsps. In whole kidney, Hg(II) induced a time-and dose-related accumulation of hsp72 and grp94. Accumulation of hsp72 was predominantly localized in the cortex and not medulla, while grp94 accumulated primarily in the medulla but not cortex. The high, constitutive expression of hsp73 did not change as a result of Hg(II) exposure, and it was equally localized in cortex and medulla. Hsp90 was not detected in kidneys of control or Hg-treated rats. Since hsp72 has been shown involved in cellular repair and recovery, and since Hg(II) damage occurs primarily in cortex, we investigated the cell-specific expression of this hsp. Hsp72 accumulated primarily in undamaged distal convoluted tubule epithelia, with less accumulation in undamaged proximal convoluted-tubule epithelia. These results demonstrate that expression of specific stress proteins in rat kidney exhibits regional heterogeneity in response to Hg(II) exposure, and a positive correlation exists between accumulation of some stress proteins and acute renal cell injury. While the role of accumulation of hsps and other stress proteins in vivo prior to or concurrent with nephrotoxicity remains to be completely understood, these stress proteins may be part of a cellular defense response to nephrotoxicants. Conversely, renal tubular epithelial cells that do not or are unable to express stress proteins, such as hsp72, may be more susceptible to nephrotoxicity.

Research paper thumbnail of An Expeditious Synthesis of the MDM2–p53 Inhibitor AM-8553

Journal of the American Chemical Society, 2012

The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yie... more The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yield of the initial synthesis. A second generation synthesis is described that features a Noyori dynamic kinetic resolution, a highly diastereoselective allylation, and a novel oxazoline-assisted piperidinone forming reaction to provide AM-8553 in 35.6% yield and 11 steps.

Research paper thumbnail of Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3

Journal of Medicinal Chemistry, 2014

We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activi... more We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.

Research paper thumbnail of Citrullination of autoantigens: Upstream of TNFα in the pathogenesis of rheumatoid arthritis

Research paper thumbnail of Mercury, cadmium, and arsenite enhance heat shock protein synthesis in chick embryos prior to embryotoxicity

Birth Defects Research Part B: Developmental and Reproductive Toxicology, 2003

Cells respond to adverse environmental stimuli by enhancing the expression of specific genes, the... more Cells respond to adverse environmental stimuli by enhancing the expression of specific genes, the products of which include a suite of proteins known as heat shock proteins (hsps), a response often attributed to cellular protection. In this study, we characterized alterations in hsp expression in chick embryos (Hamburger-Hamilton stage 17, 72 h) exposed in ovo to arsenite (As), mercury (Hg), and cadmium (Cd), known developmental toxicants. Embryos were incubated for 2 h following exposure to 3, 10, 30, or 100 nmol metal, or for 2, 4, 12, or 24 h following treatment with 10 nmol metal. An enhanced de novo synthesis of 24-, 70-, and 90-kD, 70- and 90-kD, and 70-kD proteins was observed with As, Hg, and Cd treatments, respectively. These responses were transient; apparent rates of protein synthesis were maximal 2-4 h after exposure and returned to control rates by 24 h. Actinomycin D experiments demonstrated that arsenite-induced expression of these proteins is transcriptionally regulated. Immunoblotting experiments identified the 24-, 70-, and 90-kD proteins as the heat shock proteins hsp24, hsp70, and hsp90, respectively. Exposure duration-related abnormalities were noted in the neural tube with all metals and in the ganglia and somites with Cd and As. Retina, allantois, and limb defects were specific to Cd-treated embryos, and branchial arch defects were specific to As-treated embryos. The data support metal-induced developmental abnormalities, which are preceded by synthesis of stress proteins.

Research paper thumbnail of Heat-induced alterations in embryonic cytoskeletal and stress proteins precede somite malformations in rat embryos

Teratogenesis, Carcinogenesis, and Mutagenesis, 1996

Previous work from this laboratory has demonstrated that heat exposure on gestation day 10 (GDlO)... more Previous work from this laboratory has demonstrated that heat exposure on gestation day 10 (GDlO) resulted in disrupted somite development 24 hr after exposure and subsequent thoracic skeletal malformations in neonates. The purpose of the present study was to examine the effects of in vitro heat shock on de novo protein synthesis and on cytoskeletal protein levels in developing rat embryos. Explanted GDlO embryos were exposed to temperatures of 4242.5"C for 15 min. At various times postexposure (0-27 hr), embryos were labeled with 35S-methionine and processed for sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) separation. Transient enhanced de novo synthesis of 70and 90-kD proteins was observed 1-8 hr after exposure. The 70-kD protein was identified as a eukaryotic stress protein and the presence of this protein was detected between 2 and 27 hr posttreatment. Western blot analysis was used to detect quantitative changes in total actin (microfilaments), tubulin (microtubules), and vimentin (intermediate filaments). Immediately following exposure, a reduction of total vimentin to minimal detectable levels was observed in heat-treated embryos. Levels of total vimentin remained depressed for more than 2 hr and gradually returned to control levels 4-8 hr postexposure. No change in total actin or tubulin was detected in treated embryos. The data demonstrate that heat-induced alterations in proteins comprising intermediate filaments occur concomitantly with the induction of stress proteins and precede aberrant somite morphology. These alterations in embryonic proteins may help elucidate the mechanism(s) by which skeletal malformations are produced.

Research paper thumbnail of Induction of hsp72 in heat-treated rat embryos: A tissue-specific response

Teratology, 1995

Previous studies have demonstrated that heat exposure on gestation day 10 (GD10) resulted in disr... more Previous studies have demonstrated that heat exposure on gestation day 10 (GD10) resulted in disrupted somite development in rat embryos 24 hr after exposure and in thoracic skeletal malformations in neonatal rats examined 3 days postpartum. The production of abnormal somites was correlated with the location of skeletal elements that developed from the affected somites. Heat has also been shown to induce changes in genetic expression whereby new proteins are synthesized and the expression of constituent proteins may be repressed. In the present study, heat-induced alterations in protein synthesis during rat organogenesis that may be associated with previously observed malformation was investigated.

Research paper thumbnail of Explaining Incomplete Contracts as the Result of Contract-Reading Costs

Advances in Economic Analysis & Policy, 2000

Much real-world contracting involves adding finding new clauses to add to a basic agreement, clau... more Much real-world contracting involves adding finding new clauses to add to a basic agreement, clauses which may or may not increase the welfare of both parties. The parties must decide which complications to propose, how closely to examine the other side's proposals, and whether to accept them. This suggests a reason why contracts are incomplete in the sense of lacking Pareto-improving clauses: contract-reading costs matter as much as contract-writing costs. Fine print that is cheap to write can be expensive to read carefully enough to understand the value to the reader, and especially to verify the absence of clauses artfully written to benefit the writer at the reader's expense. As a result, complicated clauses may be rejected outright even if they really do benefit both parties, and this will deter proposing such clauses in the first place.

Research paper thumbnail of Antibodies to citrullinated α-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase

Arthritis & Rheumatism, 2008

Objective. To map the antibody response to human citrullinated ␣-enolase, a candidate autoantigen... more Objective. To map the antibody response to human citrullinated ␣-enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine crossreactivity with bacterial enolase.

Research paper thumbnail of Quantitative power Doppler ultrasound measures of peripheral joint synovitis in poor prognosis early rheumatoid arthritis predict radiographic progression

Rheumatology (Oxford, England), Jan 27, 2015

To assess the value of quantitative vascular imaging by power Doppler US (PDUS) as a tool that ca... more To assess the value of quantitative vascular imaging by power Doppler US (PDUS) as a tool that can be used to stratify patient risk of joint damage in early seropositive RA while still biologic naive but on synthetic DMARD treatment. Eighty-five patients with seropositive RA of <3 years duration had clinical, laboratory and imaging assessments at 0 and 12 months. Imaging assessments consisted of radiographs of the hands and feet, two-dimensional (2D) high-frequency and PDUS imaging of 10 MCP joints that were scored for erosions and vascularity and three-dimensional (3D) PDUS of MCP joints and wrists that were scored for vascularity. Severe deterioration on radiographs and ultrasonography was seen in 45 and 28% of patients, respectively. The 3D power Doppler volume and 2D vascularity scores were the most useful US predictors of deterioration. These variables were modelled in two equations that estimate structural damage over 12 months. The equations had a sensitivity of 63.2% and ...

Research paper thumbnail of IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs

Proceedings of the National Academy of Sciences of the United States of America, Jan 18, 2015

The series of events leading to tertiary lymphoid organ (TLO) formation in mucosal organs followi... more The series of events leading to tertiary lymphoid organ (TLO) formation in mucosal organs following tissue damage remain unclear. Using a virus-induced model of autoantibody formation in the salivary glands of adult mice, we demonstrate that IL-22 provides a mechanistic link between mucosal infection, B-cell recruitment, and humoral autoimmunity. IL-22 receptor engagement is necessary and sufficient to promote differential expression of chemokine (C-X-C motif) ligand 12 and chemokine (C-X-C motif) ligand 13 in epithelial and fibroblastic stromal cells that, in turn, is pivotal for B-cell recruitment and organization of the TLOs. Accordingly, genetic and therapeutic blockade of IL-22 impairs and reverses TLO formation and autoantibody production. Our work highlights a critical role for IL-22 in TLO-induced pathology and provides a rationale for the use of IL-22-blocking agents in B-cell-mediated autoimmune conditions.

Research paper thumbnail of A review of salivary gland histopathology in primary Sjögren's syndrome with a focus on its potential as a clinical trials biomarker

Annals of the rheumatic diseases, 2015

Salivary gland changes, characterised by a focal lymphocytic sialadenitits, play an important rol... more Salivary gland changes, characterised by a focal lymphocytic sialadenitits, play an important role in the diagnosis of primary Sjögren's syndrome (PSS) and were first described over 40 years ago. Recent evidence suggests that minor salivary gland biopsy may also provide information useful for prognostication and stratification, yet difficulties may arise in the histopathological interpretation and scoring, and evidence exists that reporting is variable. With the increasing number of actual and proposed clinical trials in PSS, we review the evidence that might support the role of histopathology as a biomarker for stratification and response to therapy and highlight areas where further validation work is required.

Research paper thumbnail of Effects of beta-estradiol and bisphenol A on heat shock protein levels and localization in the mouse uterus are antagonized by the antiestrogen ICI 182,780

Toxicological sciences : an official journal of the Society of Toxicology, 2001

Bisphenol A (BPA) exhibits many estrogen-like effects in the rodent uterus, but not all of these ... more Bisphenol A (BPA) exhibits many estrogen-like effects in the rodent uterus, but not all of these can be attenuated by antiestrogens. This suggests the involvement of alternate pathways of BPA action that do not involve the estrogen receptor (ER). An examination of the in vivo effects of BPA on uterine gene expression and protein levels should contribute to an understanding of its mechanism of action. In this study we examined the dose-related effects of BPA on levels of a suite of heat shock proteins (hsps) and on the localization of hsp90alpha, a chaperone of the ER, in uteri of ovariectomized B6C3F1 mice and compared these effects with those of beta-estradiol (E2). The antiestrogen ICI 182,780 (ICI) was co-administered with BPA or E2 in order to examine the potential role of the ER. BPA, although less potent than E2, increased hsp90alpha and grp94 to similar levels, but was much less effective than E2 in increasing levels of hsp72. Treatment with 100 mg BPA/kg/day or 2 microg E2/k...

Research paper thumbnail of Bisphenol A-induced increase in uterine weight and alterations in uterine morphology in ovariectomized B6C3F1 mice: role of the estrogen receptor

Toxicological sciences : an official journal of the Society of Toxicology, 2000

The ability of the environmental xenoestrogen bisphenol A (BPA) to increase uterine wet weight in... more The ability of the environmental xenoestrogen bisphenol A (BPA) to increase uterine wet weight in the rodent remains controversial, and few studies have previously examined the effects of BPA on uterine morphology. Furthermore, it is not known whether BPA-induced uterotrophic effects are, similarly to beta-estradiol (E(2)), mediated through the estrogen receptor (ER). In this study, we compared the effects of BPA on uterine wet weight and morphology to those of E(2) in the B6C3F1 ovariectomized mouse. To examine whether these effects were mediated through the ER, the antiestrogen ICI 182, 780 (ICI) was co-administered with BPA or E(2). We report that subcutaneous administration of BPA at doses between 0.8 and 8 mg/day over 4 days significantly increased mean uterine wet weights above those of vehicle (corn oil)-treated mice. The uterine weight data suggest that BPA acts as a partial agonist with an EC(50) of 0.72 mg/day compared to 19.4 ng/day for E(2). BPA (2 mg/day) and E(2) (40 n...

Research paper thumbnail of Relationship between stress protein induction in rat kidney by mercuric chloride and nephrotoxicity

Toxicology and Applied Pharmacology, 1992

Adverse environmental stimuli increase the synthesis of a class of proteins referred to as stress... more Adverse environmental stimuli increase the synthesis of a class of proteins referred to as stress proteins. The effect of mercuric chloride, a model nephrotoxin, on protein synthesis in male rat kidney has been evaluated. Renal slices from exposed rats were incubated with [35S]methionine for 1 hr and subjected to SDS-PAGE, after which 35S-labeled proteins were detected by autoradiography. Enhanced de novo synthesis of 70- and 90-kDa relative molecular mass (M(r)) proteins were detected 2 hr after exposure to 1 mg Hg/kg, with maximum activity occurring at 4-8 hr. By 16 hr postinjection, synthesis of these two proteins had decreased. Dose-related increases in synthesis of these proteins, and of a 110-kDa protein, were observed 4 hr after i.v. injection of 0.25, 0.5, and 1.0 mg Hg/kg, with concomitant inhibition of synthesis of proteins of M(r) 38 and 68 kDa. At a dose of 1 mg/kg, kidney proximal tubules exhibited progressive degenerative changes from 4 to 24 hr. A functional deficit, decreased uptake of [para-3H]aminohippurate into renal slices, was not observed until 16 hr after i.v. injection of 1 mg/kg. No significant histopathologic changes were observed in kidneys 4 hr after treatment with 0.25 or 0.5 mg Hg/kg, iv. No changes in liver protein synthesis were apparent until 16-24 hr, where an increase in the 70- and 90-kDa proteins was observed. A concomitant increase in plasma sorbitol dehydrogenase activity occurred at 16-24 hr; however, there was no histopathological evidence of liver injury. The 72-kDa inducible member of the 70-kDa stress protein family and the 88-kDa member of the 90-kDa protein family were detected by immunoblotting techniques using monoclonal antibodies. The data demonstrate that Hg induces alterations in the expression of renal gene products in vivo as evidenced by enhanced stress protein synthesis and inhibition of synthesis of constitutive proteins. These changes in renal protein synthesis preceded overt renal injury, occurring in the early stages of nephropathy. Altered patterns of stress protein synthesis appeared to be target organ specific. The data suggest that altered protein synthesis patterns may serve as biomarkers of renal injury.

Research paper thumbnail of Metals and Stress Proteins

Handbook of Experimental Pharmacology, 1995

ABSTRACT Prokaryotic and eukaryotic cells respond to physical and chemical stressors or stress by... more ABSTRACT Prokaryotic and eukaryotic cells respond to physical and chemical stressors or stress by increasing the transcription of specific genes that encode for a small class of proteins termed heat shock proteins (hsps). This response is believed to represent a transient reprogramming of gene expression and biological activity which serves to protect sensitive cellular components from irreversible damage and assists in the rapid recovery after the stress is removed or ceases. The changes in gene expression associated with this response following exposure to a stimulus are rapid, and result in both increased de novo synthesis and accumulation of stress proteins. Originally termed the heat shock response because of the induction of these proteins following hyperthermia (RItossa 1962), the signaling mechanism involved in its initiation is sensitive to a variety of physical and chemical insults, including metals (NOver 1991). Because the response can be initiated by a variety of stressors it is generically referred to as the “stress response.” In this review, for convention and to avoid confusion, we have adopted the use of the term “stress proteins” when referring to classic hsps and other stress proteins. Therefore, the hsps will be considered as a subset of the stress proteins, and reference to hsps will be used only when deemed necessary, e.g., when referring to specific references and studies describing specific hsps.

Research paper thumbnail of Latex-associated allergies and anaphylactic reactions

Clinical Immunology and Immunopathology, 1992

The recent reports of severe anaphylactic reactions and several fatalities caused by contact with... more The recent reports of severe anaphylactic reactions and several fatalities caused by contact with latex-containing products raised concerns in the medical community. Although hypersensitivity to natural rubber has been widely reported in the literature, the prevalence and severity of reactions have rapidly increased in the last few years. Latex proteins, constituents of natural latex, appear to be responsible for the sensitization. Many investigators, including our laboratory, are focused on the identification of proteins in raw latex and latex products, specifically those responsible for the elicitation of allergic responses. This paper summarizes available information on the mechanism and epidemiology of latex sensitivity and reviews research efforts toward the identification of the antigen(s) responsible for the reactions. The questions of proper diagnosis and testing, heightening awareness, and prevention of reactions are also addressed.

Research paper thumbnail of Effects of b-Estradiol and Bisphenol A on Heat Shock Protein Levels and Localization in the Mouse Uterus Are Antagonized by the Antiestrogen ICI 182,780

Bisphenol A (BPA) exhibits many estrogen-like effects in the rodent uterus, but not all of these ... more Bisphenol A (BPA) exhibits many estrogen-like effects in the rodent uterus, but not all of these can be attenuated by antiestro- gens. This suggests the involvement of alternate pathways of BPA action that do not involve the estrogen receptor (ER). An exami- nation of the in vivo effects of BPA on uterine gene expression and protein levels should contribute to

Research paper thumbnail of Stress Protein Synthesis Induced in Rat Liver by Cadmium Precedes Hepatotoxicity

Toxicology and Applied Pharmacology, 1993

A diverse array of chemical and physical stressors increases the synthesis of a class of proteins... more A diverse array of chemical and physical stressors increases the synthesis of a class of proteins referred to as heat shock proteins (hsp) or stress proteins. We are investigating the potential of using altered protein synthesis patterns, including the enhanced synthesis of stress proteins, as biomarkers of exposure and cellular injury. The purpose of the present study was to evaluate the effect of a model hepatotoxicant, cadmium (Cd(II)), on stress protein synthesis in male rat liver. To assess target tissue specificity, stress protein synthesis was also studied in kidney. Liver and kidney slices from exposed rats were incubated with [35S]methionine for 1.5 hr, subjected to one-dimensional SDS-PAGE, and 35S-labeled proteins were analyzed by autoradiography. Enhanced de novo synthesis of 70-, 90-, and 110-kilodalton (kDa) relative molecular mass (M(r)) proteins was detected 2 hr after exposure to 2 mg Cd/kg, with maximum activity occurring at 2-4 hr. By 8-16 hr postinjection, synthesis of these proteins had decreased. Synthesis of a 68-kDa protein present in control liver was inhibited 2 hr after exposure with synthesis restored at 16-24 hr. Dose-related increases in synthesis of the three stress proteins were observed 4 hr after iv injection of 1.0 and 2.0 mg Cd/kg, with concomitant inhibition of synthesis of the 68-kDa protein. Mild single cell necrosis of hepatocytes was observed 8 hr after injection of 2 mg Cd/kg which progressed to mild multifocal necrotic foci at 16 hr. No lesions were evident at lower dosages. Increases in plasma sorbitol dehydrogenase activity, a clinical indicator of hepatic injury, was not apparent until 8 hr after exposure. A functional deficit, decreased hepatic microsomal N-demethylase activity, was not observed until 16 hr after iv injection of 2 mg/kg. No changes in kidney de novo stress protein synthesis were observed. No evidence of renal injury was apparent, as evaluated by histopathology, uptake of [para-3H]aminohippurate into renal slices, and blood urea nitrogen values. The 70-kDa stress protein induced early after Cd treatment was identified with a monoclonal antibody as the 72-kDa-inducible hsp. The 90-kDa protein induced by Cd reacted negatively with three monoclonal antibodies to hsp90 and was subsequently identified as a glucose regulated protein (grp94). The data demonstrate that Cd induces alterations in the expression of hepatic gene products in vivo as evidenced by enhanced stress protein synthesis and inhibition of synthesis of constitutive proteins.(ABSTRACT TRUNCATED AT 400 WORDS)

Research paper thumbnail of Stress protein synthesis induced by cadmium-cysteine in rat kidney

Toxicology, 1993

Biomarkers are important tools which enable toxicologists to reliably predict and detect exposure... more Biomarkers are important tools which enable toxicologists to reliably predict and detect exposures to xenobiotics and resultant cell injury, ultimately improving risk assessments. Since the de novo synthesis of stress proteins can be detected early after exposure to some agents, analysis of toxicant-induced changes in gene expression, i.e. alterations in patterns of protein synthesis, may be useful to develop as biomarkers of exposure and toxicity. We are utilizing various xenobiotics as tools to study stress protein synthesis in target organs in order to evaluate the target tissue-specificity of this response. Previous data from this laboratory have demonstrated that induction of stress proteins in rat liver, but not kidney, after acute exposure to CdCl2 precedes hepatoxicity. Since kidney is a target tissue after chronic Cd exposure, it was of interest to examine stress protein synthesis in this tissue. However, dose-limiting hepatotoxicity precluded this evaluation. Cd complexed with molecules such as cysteine (cys) or metallothionein has been used in acute dosing regimens as a tool in order to study the nephrotoxicity of Cd. Therefore, this study was undertaken in order to evaluate Cd-induced stress protein synthesis in an important tissue known to be injured after chronic exposure, i.e. kidney. Specific objectives included comparing stress protein synthesis in rat kidney and liver after acute exposure to Cd-cys and CdCl2, determining the Cd threshold concentration for renal stress protein synthesis and assessing the relationship between stress protein synthesis and nephropathy. Male rats were exposed to equivalent doses of Cd as CdCl2 or Cd-cysteine (molar ratio Cd:cys = 1:15). Kidney Cd concentrations increased 5-fold after i.v. injection of Cd-cys compared to CdCl2, mimicking Cd distribution following chronic exposure. After exposure to Cd, tissue slices were incubated with 35S-methionine. Slices were subsequently homogenized and centrifuged, and the 16,000 g supernatants were subjected to SDS-polyacrylamide gel electrophoresis. Proteins which had incorporated 35S-methionine were detected by autoradiography. De novo synthesis of 70, 90 and 110 kDa proteins was enhanced in liver, but not in kidney, 4 h after injection of 2 mg Cd/kg as CdCl2. In contrast, dose-related increases in synthesis of these proteins were observed in kidney 4 h after injection of 1 and 2mg Cd/kg as Cd-cys, but not at lower dosages. In addition, synthesis of a 68 kDa kidney protein was inhibited at 2 mg Cd/kg as Cd-cys. The threshold for Cd-induced stress protein synthesis was shown to be between 4 and 8 micrograms Cd/g tissue.(ABSTRACT TRUNCATED AT 400 WORDS)

Research paper thumbnail of Mercury Induces Regional and Cell-Specific Stress Protein Expression in Rat Kidney

Toxicological Sciences, 2000

Cells respond to physiologic stress by enhancing the expression of specific stress proteins. Heat... more Cells respond to physiologic stress by enhancing the expression of specific stress proteins. Heat-shock proteins (hsps) and glucoseregulated proteins (grps) are members of a large superfamily of proteins collectively referred to as stress proteins. This particular stress-protein response has evolved as a cellular strategy to protect, repair, and chaperone other essential cellular proteins. The objective of this study was to evaluate the differential expression of four hsps in the renal cortex and medulla during experimental nephrotoxic injury using HgCl 2 . Male Sprague-Dawley rats received single injections of HgCl 2 (0.25, 0.5, or 1 mg Hg/kg, iv). At 4, 8, 16, or 24 h after exposure, kidneys were removed and processed for histopathologic, immunoblot, and immunohistochemical analyses. Nephrosis was characterized as minimal or mild (cytoplasmic condensation, tubular epithelial degeneration, single cell necrosis) at the lower exposures, and progressed to moderate or severe (nuclear pyknosis, necrotic foci, sloughing of the epithelial casts into tubular lumens) at the highest exposures. Western blots of renal proteins were probed with monoclonal antibodies specific for 4 hsps. In whole kidney, Hg(II) induced a time-and dose-related accumulation of hsp72 and grp94. Accumulation of hsp72 was predominantly localized in the cortex and not medulla, while grp94 accumulated primarily in the medulla but not cortex. The high, constitutive expression of hsp73 did not change as a result of Hg(II) exposure, and it was equally localized in cortex and medulla. Hsp90 was not detected in kidneys of control or Hg-treated rats. Since hsp72 has been shown involved in cellular repair and recovery, and since Hg(II) damage occurs primarily in cortex, we investigated the cell-specific expression of this hsp. Hsp72 accumulated primarily in undamaged distal convoluted tubule epithelia, with less accumulation in undamaged proximal convoluted-tubule epithelia. These results demonstrate that expression of specific stress proteins in rat kidney exhibits regional heterogeneity in response to Hg(II) exposure, and a positive correlation exists between accumulation of some stress proteins and acute renal cell injury. While the role of accumulation of hsps and other stress proteins in vivo prior to or concurrent with nephrotoxicity remains to be completely understood, these stress proteins may be part of a cellular defense response to nephrotoxicants. Conversely, renal tubular epithelial cells that do not or are unable to express stress proteins, such as hsp72, may be more susceptible to nephrotoxicity.

Research paper thumbnail of An Expeditious Synthesis of the MDM2–p53 Inhibitor AM-8553

Journal of the American Chemical Society, 2012

The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yie... more The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yield of the initial synthesis. A second generation synthesis is described that features a Noyori dynamic kinetic resolution, a highly diastereoselective allylation, and a novel oxazoline-assisted piperidinone forming reaction to provide AM-8553 in 35.6% yield and 11 steps.

Research paper thumbnail of Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3

Journal of Medicinal Chemistry, 2014

We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activi... more We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;,3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;:4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.

Research paper thumbnail of Citrullination of autoantigens: Upstream of TNFα in the pathogenesis of rheumatoid arthritis

Research paper thumbnail of Mercury, cadmium, and arsenite enhance heat shock protein synthesis in chick embryos prior to embryotoxicity

Birth Defects Research Part B: Developmental and Reproductive Toxicology, 2003

Cells respond to adverse environmental stimuli by enhancing the expression of specific genes, the... more Cells respond to adverse environmental stimuli by enhancing the expression of specific genes, the products of which include a suite of proteins known as heat shock proteins (hsps), a response often attributed to cellular protection. In this study, we characterized alterations in hsp expression in chick embryos (Hamburger-Hamilton stage 17, 72 h) exposed in ovo to arsenite (As), mercury (Hg), and cadmium (Cd), known developmental toxicants. Embryos were incubated for 2 h following exposure to 3, 10, 30, or 100 nmol metal, or for 2, 4, 12, or 24 h following treatment with 10 nmol metal. An enhanced de novo synthesis of 24-, 70-, and 90-kD, 70- and 90-kD, and 70-kD proteins was observed with As, Hg, and Cd treatments, respectively. These responses were transient; apparent rates of protein synthesis were maximal 2-4 h after exposure and returned to control rates by 24 h. Actinomycin D experiments demonstrated that arsenite-induced expression of these proteins is transcriptionally regulated. Immunoblotting experiments identified the 24-, 70-, and 90-kD proteins as the heat shock proteins hsp24, hsp70, and hsp90, respectively. Exposure duration-related abnormalities were noted in the neural tube with all metals and in the ganglia and somites with Cd and As. Retina, allantois, and limb defects were specific to Cd-treated embryos, and branchial arch defects were specific to As-treated embryos. The data support metal-induced developmental abnormalities, which are preceded by synthesis of stress proteins.

Research paper thumbnail of Heat-induced alterations in embryonic cytoskeletal and stress proteins precede somite malformations in rat embryos

Teratogenesis, Carcinogenesis, and Mutagenesis, 1996

Previous work from this laboratory has demonstrated that heat exposure on gestation day 10 (GDlO)... more Previous work from this laboratory has demonstrated that heat exposure on gestation day 10 (GDlO) resulted in disrupted somite development 24 hr after exposure and subsequent thoracic skeletal malformations in neonates. The purpose of the present study was to examine the effects of in vitro heat shock on de novo protein synthesis and on cytoskeletal protein levels in developing rat embryos. Explanted GDlO embryos were exposed to temperatures of 4242.5"C for 15 min. At various times postexposure (0-27 hr), embryos were labeled with 35S-methionine and processed for sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) separation. Transient enhanced de novo synthesis of 70and 90-kD proteins was observed 1-8 hr after exposure. The 70-kD protein was identified as a eukaryotic stress protein and the presence of this protein was detected between 2 and 27 hr posttreatment. Western blot analysis was used to detect quantitative changes in total actin (microfilaments), tubulin (microtubules), and vimentin (intermediate filaments). Immediately following exposure, a reduction of total vimentin to minimal detectable levels was observed in heat-treated embryos. Levels of total vimentin remained depressed for more than 2 hr and gradually returned to control levels 4-8 hr postexposure. No change in total actin or tubulin was detected in treated embryos. The data demonstrate that heat-induced alterations in proteins comprising intermediate filaments occur concomitantly with the induction of stress proteins and precede aberrant somite morphology. These alterations in embryonic proteins may help elucidate the mechanism(s) by which skeletal malformations are produced.

Research paper thumbnail of Induction of hsp72 in heat-treated rat embryos: A tissue-specific response

Teratology, 1995

Previous studies have demonstrated that heat exposure on gestation day 10 (GD10) resulted in disr... more Previous studies have demonstrated that heat exposure on gestation day 10 (GD10) resulted in disrupted somite development in rat embryos 24 hr after exposure and in thoracic skeletal malformations in neonatal rats examined 3 days postpartum. The production of abnormal somites was correlated with the location of skeletal elements that developed from the affected somites. Heat has also been shown to induce changes in genetic expression whereby new proteins are synthesized and the expression of constituent proteins may be repressed. In the present study, heat-induced alterations in protein synthesis during rat organogenesis that may be associated with previously observed malformation was investigated.

Research paper thumbnail of Explaining Incomplete Contracts as the Result of Contract-Reading Costs

Advances in Economic Analysis & Policy, 2000

Much real-world contracting involves adding finding new clauses to add to a basic agreement, clau... more Much real-world contracting involves adding finding new clauses to add to a basic agreement, clauses which may or may not increase the welfare of both parties. The parties must decide which complications to propose, how closely to examine the other side's proposals, and whether to accept them. This suggests a reason why contracts are incomplete in the sense of lacking Pareto-improving clauses: contract-reading costs matter as much as contract-writing costs. Fine print that is cheap to write can be expensive to read carefully enough to understand the value to the reader, and especially to verify the absence of clauses artfully written to benefit the writer at the reader's expense. As a result, complicated clauses may be rejected outright even if they really do benefit both parties, and this will deter proposing such clauses in the first place.

Research paper thumbnail of Antibodies to citrullinated α-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase

Arthritis & Rheumatism, 2008

Objective. To map the antibody response to human citrullinated ␣-enolase, a candidate autoantigen... more Objective. To map the antibody response to human citrullinated ␣-enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine crossreactivity with bacterial enolase.

Research paper thumbnail of Quantitative power Doppler ultrasound measures of peripheral joint synovitis in poor prognosis early rheumatoid arthritis predict radiographic progression

Rheumatology (Oxford, England), Jan 27, 2015

To assess the value of quantitative vascular imaging by power Doppler US (PDUS) as a tool that ca... more To assess the value of quantitative vascular imaging by power Doppler US (PDUS) as a tool that can be used to stratify patient risk of joint damage in early seropositive RA while still biologic naive but on synthetic DMARD treatment. Eighty-five patients with seropositive RA of <3 years duration had clinical, laboratory and imaging assessments at 0 and 12 months. Imaging assessments consisted of radiographs of the hands and feet, two-dimensional (2D) high-frequency and PDUS imaging of 10 MCP joints that were scored for erosions and vascularity and three-dimensional (3D) PDUS of MCP joints and wrists that were scored for vascularity. Severe deterioration on radiographs and ultrasonography was seen in 45 and 28% of patients, respectively. The 3D power Doppler volume and 2D vascularity scores were the most useful US predictors of deterioration. These variables were modelled in two equations that estimate structural damage over 12 months. The equations had a sensitivity of 63.2% and ...

Research paper thumbnail of IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs

Proceedings of the National Academy of Sciences of the United States of America, Jan 18, 2015

The series of events leading to tertiary lymphoid organ (TLO) formation in mucosal organs followi... more The series of events leading to tertiary lymphoid organ (TLO) formation in mucosal organs following tissue damage remain unclear. Using a virus-induced model of autoantibody formation in the salivary glands of adult mice, we demonstrate that IL-22 provides a mechanistic link between mucosal infection, B-cell recruitment, and humoral autoimmunity. IL-22 receptor engagement is necessary and sufficient to promote differential expression of chemokine (C-X-C motif) ligand 12 and chemokine (C-X-C motif) ligand 13 in epithelial and fibroblastic stromal cells that, in turn, is pivotal for B-cell recruitment and organization of the TLOs. Accordingly, genetic and therapeutic blockade of IL-22 impairs and reverses TLO formation and autoantibody production. Our work highlights a critical role for IL-22 in TLO-induced pathology and provides a rationale for the use of IL-22-blocking agents in B-cell-mediated autoimmune conditions.

Research paper thumbnail of A review of salivary gland histopathology in primary Sjögren's syndrome with a focus on its potential as a clinical trials biomarker

Annals of the rheumatic diseases, 2015

Salivary gland changes, characterised by a focal lymphocytic sialadenitits, play an important rol... more Salivary gland changes, characterised by a focal lymphocytic sialadenitits, play an important role in the diagnosis of primary Sjögren's syndrome (PSS) and were first described over 40 years ago. Recent evidence suggests that minor salivary gland biopsy may also provide information useful for prognostication and stratification, yet difficulties may arise in the histopathological interpretation and scoring, and evidence exists that reporting is variable. With the increasing number of actual and proposed clinical trials in PSS, we review the evidence that might support the role of histopathology as a biomarker for stratification and response to therapy and highlight areas where further validation work is required.