Publications by authors named "Sandra Hoffman"

53 Publications

Scoping Review of Postinfectious Sequelae.

Foodborne Pathog Dis 2021 Jul 22:1-15. Epub 2021 Jul 22.

Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona, USA.

Previous economic estimates of infection with and chronic sequelae following infection lack sufficient data to establish the true burden of disease and its chronic sequelae. This scoping review aims to fill this gap by updating existing literature regarding the development of postinfectious sequelae following infection. Literature published between January 1, 2000, and November 6, 2018, in PubMed, EMBASE, and Scopus was searched for a wide range of postinfectious sequelae and economic estimate terms. This scoping review includes summaries from the 108 articles covering 5 main groupings of outcomes (categories are not exclusive) including vision disorders ( = 58), psychological and mental health disorders ( = 27), neurological disorders ( = 17), fetal death and infection ( = 15), and hearing loss ( = 6), as well as a description of other outcomes reported. While the majority of the included studies assessed the incidence of these outcomes postinfection, very few followed participants long-term. These prospective studies are needed to understand the true burden of postinfectious sequelae over the life course, particularly because congenital infection with can lead to severe outcomes for newborns. This scoping review can be used as an important resource for other researchers wishing to conduct future systematic reviews and meta-analyses, as well as for policy makers interested in developing guidance for public and health care partners.
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http://dx.doi.org/10.1089/fpd.2021.0015DOI Listing
July 2021

Association of Self-Administered Nitrous Oxide for Labor Analgesia With Maternal and Neonatal Process and Outcome Measures.

J Obstet Gynecol Neonatal Nurs 2021 03 23;50(2):154-166. Epub 2021 Jan 23.

Objective: To describe patterns of use of self-administered nitrous oxide (NO) during labor and to determine if maternal and neonatal process and outcome measures differ for women who use NO compared to women who do not use NO.

Design: Retrospective, full-census, observational cohort.

Setting: An upper midwestern U.S., urban, 75-bed quaternary perinatal center with more than 5,000 annual births.

Participants: The participants included two groups of women: 400 who used NO during labor and a comparison group of 6,733 who met NO eligibility but did not use NO.

Methods: We used descriptive statistics to examine patterns of use of NO during labor between January 2015 and March 2017. We examined associations of NO with process (length of first and second stages of labor, time from hospital admission to birth, time from birth to hospital discharge, and total length of stay) and outcome measures (shoulder dystocia, instrumentation, vaginal lacerations, Apgar scores at 5 minutes, nursery disposition) using multivariate linear, logistic, and ordinal regression models.

Results: Three percent (12/400) of women who used NO discontinued because of side effects. Among participants with vaginal births who used NO, 17.6% (62/352) used NO as the only form of pain medication during labor. We found no significant differences in maternal and neonatal outcome measures between the two groups. Among the process measures examined, we found a mean 2-hour-longer time from admission to birth and total length of stay in the NO group (p < .05) compared to the non-NO group.

Conclusion: Most participants who used NO (290/352, 82.3%) transitioned to other pain modalities during labor. Maternal and neonatal process and outcome measures were comparable relative to other pain management modalities, with the exception of longer time durations for two measures.
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http://dx.doi.org/10.1016/j.jogn.2020.11.002DOI Listing
March 2021

An intestinal organoid-based platform that recreates susceptibility to T-cell-mediated tissue injury.

Blood 2020 06;135(26):2388-2401

Kimmel Center for Biology and Medicine at the Skirball Institute.

A goal in precision medicine is to use patient-derived material to predict disease course and intervention outcomes. Here, we use mechanistic observations in a preclinical animal model to design an ex vivo platform that recreates genetic susceptibility to T-cell-mediated damage. Intestinal graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis. We further show that cocultured allogeneic T cells kill Atg16L1-mutant intestinal organoids from mice, which was associated with an aberrant epithelial interferon signature. Using this information, we demonstrate that pharmacologically inhibiting necroptosis or interferon signaling protects human organoids derived from individuals harboring a common ATG16L1 variant from allogeneic T-cell attack. Our study provides a roadmap for applying findings in animal models to individualized therapy that targets affected tissues.
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http://dx.doi.org/10.1182/blood.2019004116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317146PMC
June 2020

Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase.

J Med Chem 2019 05 2;62(10):5096-5110. Epub 2019 May 2.

Flexible Discovery Unit , GlaxoSmithKline , 25-27 avenue du Québec , 91951 Les Ulis Cedex , France.

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00318DOI Listing
May 2019

Caspase-8 Collaborates with Caspase-11 to Drive Tissue Damage and Execution of Endotoxic Shock.

Immunity 2018 07;49(1):42-55.e6

Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta GA 30322, USA. Electronic address:

The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro-pyroptotic caspase-11 and gasdermin D. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate shock without any contribution from caspase-8 or caspase-11. Both proteases had to be present to support tumor necrosis factor- and interferon-β-dependent tissue injury first observed in the small intestine and later in spleen and thymus. Caspase-11 enhanced the activation of caspase-8 and extrinsic cell death machinery within the lower small intestine. Neither caspase-8 nor caspase-11 was individually sufficient for shock. Both caspases collaborated to amplify inflammatory signals associated with tissue damage. Therefore, combined pyroptotic and apoptotic signaling mediated endotoxemia independently of RIPK1 kinase activity and RIPK3 function. These observations bring to light the relevance of tissue compartmentalization to disease processes in vivo where cytokines act in parallel to execute diverse cell death pathways.
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http://dx.doi.org/10.1016/j.immuni.2018.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064639PMC
July 2018

Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases.

J Med Chem 2017 02 10;60(4):1247-1261. Epub 2017 Feb 10.

Centre for Immunobiology, Blizard Institute, Barts, and The London School of Medicine and Dentistry, Queen Mary University of London , E1 2AD London, U.K.

RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01751DOI Listing
February 2017

DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors.

J Med Chem 2016 Mar 23;59(5):2163-78. Epub 2016 Feb 23.

Platform Technology & Science, GlaxoSmithKline , King of Prussia, Pennsylvania 19406, United States.

The recent discovery of the role of receptor interacting protein 1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as a highly promising target for the treatment of multiple inflammatory diseases. We screened RIP1 against GSK's DNA-encoded small-molecule libraries and identified a novel highly potent benzoxazepinone inhibitor series. We demonstrate that this template possesses complete monokinase selectivity for RIP1 plus unique species selectivity for primate versus nonprimate RIP1. We elucidate the conformation of RIP1 bound to this benzoxazepinone inhibitor driving its high kinase selectivity and design specific mutations in murine RIP1 to restore potency to levels similar to primate RIP1. This series differentiates itself from known RIP1 inhibitors in combining high potency and kinase selectivity with good pharmacokinetic profiles in rodents. The favorable developability profile of this benzoxazepinone template, as exemplified by compound 14 (GSK'481), makes it an excellent starting point for further optimization into a RIP1 clinical candidate.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01898DOI Listing
March 2016

High throughput screening identifies ATP-competitive inhibitors of the NLRP1 inflammasome.

Bioorg Med Chem Lett 2015 Jul 19;25(14):2739-43. Epub 2015 May 19.

Pattern Recognition Receptor DPU, GlaxoSmithKline, Collegeville Road, Collegeville, PA 19426, USA.

Nod-like receptors (NLRs) are cytoplasmic pattern recognition receptors that are promising targets for the development of anti-inflammatory therapeutics. Drug discovery efforts targeting NLRs have been hampered by their inherent tendency to form aggregates making protein generation and the development of screening assays very challenging. Herein we report the results of an HTS screen of NLR family member NLRP1 (NLR family, pyrin domain-containing 1) which was achieved through the large scale generation of recombinant GST-His-Thrombin-NLRP1 protein. The screen led to the identification of a diverse set of ATP competitive inhibitors with micromolar potencies. Activity of these hits was confirmed in a FP binding assay, and two homology models were employed to predict the possible binding mode of the leading series and facilitate further lead-optimization. These results highlight a promising strategy for the identification of inhibitors of NLR family members which are rapidly emerging as key drivers of inflammation in human disease.
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http://dx.doi.org/10.1016/j.bmcl.2015.05.032DOI Listing
July 2015

Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis.

ACS Med Chem Lett 2013 Dec 4;4(12):1238-43. Epub 2013 Nov 4.

Pattern Recognition Receptor DPU and Platform Technology & Science, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States.

Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo[2,3-d]pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNFα induced lethal shock.
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http://dx.doi.org/10.1021/ml400382pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027519PMC
December 2013

Generation of realistic HMPAO SPECT images using a subresolution sandwich phantom.

Neuroimage 2013 Nov 9;81:8-14. Epub 2013 May 9.

Department of Nuclear Medicine, University Hospital Southampton, UK.

Unlabelled: Traditional interpretation of rCBF SPECT data is of a qualitative nature and is dependent on the observer's understanding of the normal distribution of the tracer. The use of a normal database in quantitative regional analysis facilitates the detection of functional abnormality in individual and group studies by accounting for inter-subject variability. The ability to simulate realistic images would allow various important areas related to the use of normal databases to be studied. These include the optimisation of the detection of abnormal blood flow and the portability of normal databases between gamma camera systems. To investigate this further we have constructed a hardware phantom and scanned various configurations of radioactive brain patterns and simulated skull configurations.

Methods: A subresolution sandwich phantom was constructed with a simulated skull which was assembled using a high-resolution segmented MR scan printed with a (99m)TcO₄ - mixture and scanned using a double-headed gamma camera with parallel-hole collimators. Various different grey-to-white matter (GM:WM) ratios and aluminium simulated skull configurations were used. A single difference measure between the phantom data and a control database mean image was used for optimisation. The realism of phantom data was assessed using statistical parametric mapping (SPM) and ROI analysis.

Results: Optimisation was achieved with a range of WM:GM ratios from 1.9 to 2.4:1 with various simulated skull configurations.

Conclusion: The ability to simulate realistic HMPAO SPECT scans has been demonstrated using a subresolution sandwich phantom. Further work, involving scanning the optimised phantom on different gamma camera systems and comparison with camera-specific normal databases should further refine the phantom configuration.
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http://dx.doi.org/10.1016/j.neuroimage.2013.05.003DOI Listing
November 2013

The effect of rosiglitazone on bone mass and fragility is reversible and can be attenuated with alendronate.

J Bone Miner Res 2013 Jul;28(7):1653-65

Musculoskeletal Diseases, GlaxoSmithKline, King of Prussia, PA 19406, USA.

Rosiglitazone (RSG) is an antidiabetic drug that has been associated with increased peripheral fractures, primarily in postmenopausal women. In this report, we investigated the underlying mechanisms of RSG-associated bone loss in ovariectomized (OVX) rats and determined whether changes in bone parameters associated with RSG administration are reversible on treatment cessation or preventable by coadministration with an antiresorptive agent. Nine-month-old Sprague-Dawley rats underwent OVX or sham operation. Sham-operated rats received oral vehicle only; OVX animals were randomized to receive vehicle, RSG, alendronate (ALN), or RSG plus ALN for 12 weeks. All treatment started the day after ovariectomy. After the 12-week treatment period, the OVX and RSG groups also underwent an 8-week treatment-free recovery period. Bone densitometry measurements, bone turnover markers, biomechanical testing, and histomorphometric analysis were conducted. Microcomputed tomography was also used to investigate changes in microarchitecture. RSG significantly increased deoxypyridinoline levels compared with OVX. Significant exacerbation of OVX-induced loss of bone mass, strength, and microarchitectural deterioration was observed in RSG-treated OVX animals compared with OVX controls. These effects were observed predominantly at sites rich in trabecular bone, with less pronounced effects in cortical bone. Coadministration of RSG and ALN prevented the bone loss associated with RSG treatment. Following cessation of RSG treatment, effects on bone mass and strength showed evidence of reversal. Thus, treatment of OVX rats with RSG results in loss of bone mass and strength, primarily at sites rich in trabecular bone, mainly due to increased bone resorption. These effects can be prevented by concomitant treatment with ALN and may be reversed following discontinuation of RSG.
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http://dx.doi.org/10.1002/jbmr.1918DOI Listing
July 2013

Antagonists of the calcium receptor. 2. Amino alcohol-based parathyroid hormone secretagogues.

J Med Chem 2009 Nov;52(21):6599-605

Department of Medicinal Chemistry, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.

When administered as a single agent to rats, the previously reported calcium receptor antagonist 3 elicited a sustained elevation of plasma PTH resulting in no increase in overall bone mineral density. The lack of a bone building effect for analogue 3 was attributed to the large volume of distribution (V(dss)(rat) = 11 L/kg), producing a protracted plasma PTH profile. Incorporation of a carboxylic acid functionality into the amino alcohol template led to the identification of 12 with a lower volume of distribution (V(dss)(12) = 1.18 L/kg) and a shorter half-life. The zwitterionic nature of antagonist 12 necessitated the utility of an ester prodrug approach to increase overall permeability. Antagonist 12 elicited a rapid and transient increase in circulating levels of PTH following oral dosing of the ester prodrug 11 in the dog. The magnitude and duration of the increases in plasma levels of PTH would be expected to stimulate new bone formation.
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http://dx.doi.org/10.1021/jm900563eDOI Listing
November 2009

An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation.

Bone 2010 Feb 26;46(2):534-42. Epub 2009 Sep 26.

GlaxoSmithKline, UM 2230, 709 Swedeland Road, King of Prussia, PA 19406-2711, USA.

Daily subcutaneous administration of exogenous parathyroid hormone (PTH) promotes bone formation in patients with osteoporosis. Here we describe two novel, short-acting calcium-sensing receptor antagonists (SB-423562 and its orally bioavailable precursor, SB-423557) that elicit transient PTH release from the parathyroid gland in several preclinical species and in humans. In an ovariectomized rat model of bone loss, daily oral administration of SB-423557 promoted bone formation and improved parameters of bone strength at lumbar spine, proximal tibia and midshaft femur. Chronic administration of SB-423557 did not increase parathyroid cell proliferation in rats. In healthy human volunteers, single doses of intravenous SB-423562 and oral SB-423557 elicited transient elevations of endogenous PTH concentrations in a profile similar to that observed with subcutaneously administered PTH. Both agents were well tolerated in humans. Transient increases in serum calcium, an expected effect of increased parathyroid hormone concentrations, were observed post-dose at the higher doses of SB-423557 studied. These data constitute an early proof of principle in humans and provide the basis for further development of this class of compound as a novel, orally administered bone-forming treatment for osteoporosis.
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http://dx.doi.org/10.1016/j.bone.2009.09.028DOI Listing
February 2010

Genetic polymorphisms of estrogen receptors alpha and beta and the risk of developing prostate cancer.

PLoS One 2009 Aug 5;4(8):e6523. Epub 2009 Aug 5.

Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania; United States of America.

Estrogen may be involved in the development of prostate cancer. The association between genetic polymorphisms of estrogen receptors alpha (ESR1) and beta (ESR2) and prostate cancer risk was examined in a nested case-control study in Washington County, Maryland. Incident prostate cancer cases (n = 269) were matched to one or two controls (n = 440) by age, sex, race, and date of blood donation. Associations between estrogen receptor genotypes or dietary intake and the development of prostate cancer were examined in conditional logistic regression models. Results from this study showed that six single base-pair polymorphisms (SNPs) of ESR1 (rs1801132, rs2077647, rs746432, rs2273206, rs851982, rs2228480) and four SNPs of ESR2 (rs4986938, rs928554, rs8018687, rs number not available for ESR2 5696 bp 3' of STP A>G) were not significantly associated with prostate cancer risk, either by allelic or genotypic frequencies. However, an interactive association with BMI was observed in the relationship between prostate cancer risk and genotypes of ESR2 38 bp 3' of STP G>A (rs4986938) (p = 0.031). An interaction between intake level of phytoestrogen and genotypes of ESR1 Ex1-192G>C (rs746432) and between intake level of phytoestrogen and genotypes of ESR1 Ex8+229G>A (rs2228480) and risk of prostate cancer was observed (p = 0.0009 and p = 0.044, respectively). In conclusion, selected genetic polymorphisms of ESR1 and ESR2, overall, were not associated with prostate cancer risk. However, a variation in risk by BMI and phytoestrogen intake was implicated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006523PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715882PMC
August 2009

Leucocyte cathepsin K affects atherosclerotic lesion composition and bone mineral density in low-density lipoprotein receptor deficient mice.

Cardiovasc Res 2009 Feb 17;81(2):278-85. Epub 2008 Nov 17.

Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research , Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands.

Aims: Cathepsin K (CatK), an established drug target for osteoporosis, has been reported to be upregulated in atherosclerotic lesions. Due to its proteolytic activity, CatK may influence the atherosclerotic lesion composition and stability. In this study, we investigated the potential role of leucocyte CatK in atherosclerotic plaque remodelling.

Methods And Results: To assess the biological role of leucocyte CatK, we used the technique of bone marrow transplantation to selectively disrupt CatK in the haematopoietic system. Total bone marrow progenitor cells from CatK(+/+), CatK(+/-), and CatK(-/-) mice were transplanted into X-ray irradiated low-density lipoprotein receptor knockout (LDLr(-/-)) mice. The selective silencing of leucocyte CatK resulted in phenotypic changes in bone formation with an increased total bone mineral density in the CatK(-/-) chimeras and an effect of gene dosage. The absence of leucocyte CatK resulted in dramatically decreased collagen and increased macrophage content of the atherosclerotic lesions while lesion size was not affected. The atherosclerotic lesions also demonstrated less elastic lamina fragmentation and a significant increase in the apoptotic and necrotic area in plaques of mice transplanted with CatK(-/-) bone marrow.

Conclusion: Leucocyte CatK is an important determinant of atherosclerotic plaque composition, vulnerability, and bone remodelling, rendering CatK an attractive target for pharmaceutical modulation in atherosclerosis and osteoporosis.
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http://dx.doi.org/10.1093/cvr/cvn311DOI Listing
February 2009

The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acids, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity.

Am J Epidemiol 2008 Oct;168(7):831-40

Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland 21205, USA.

Lung cancer cases diagnosed during the period 1975 through 1993 and matched controls were identified in the rosters of Washington County, Maryland residents who had donated blood for a serum bank in 1974 or 1989. Plasma from participants in the 1989 project was assayed for ascorbic acid; serum or plasma was assayed for participants in either project for alpha- and beta-carotene, cryptoxanthin, lutein/zeaxanthin, lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Among the total group of 258 cases and 515 controls, serum/plasma concentrations were significantly lower among cases than controls for cryptoxanthin, beta-carotene, and lutein/zeaxanthin with case-control differences of -25.5, -17.1, and -10.1%, respectively. Modest nonsignificant case-control differences in a protective direction were noted for alpha-carotene and ascorbic acid. There were only trivial differences for lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Findings are reported for males and females and for persons who had never smoked cigarettes, former smokers, and current smokers at baseline. These results and those from previous studies suggest that beta-carotene is a marker for some protective factor(s) against lung cancer; that cryptoxanthin, alpha-carotene, and ascorbic acid need to be investigated further as potentially protective factors or associates of a protective factor; and that lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity are unlikely to be associated with lung cancer risk. Until specific preventive factors are identified, the best protection against lung cancer is still the avoidance of airborne carcinogens, especially tobacco smoke; second best is the consumption of a diet rich in fruits and vegetables.
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http://dx.doi.org/10.1093/aje/kwn328DOI Listing
October 2008

Effects of repeated freeze-thaw cycles on concentrations of cholesterol, micronutrients, and hormones in human plasma and serum.

Am J Epidemiol 2008 Oct;168(7):827-30

Department of Epidemiology, Johns Hopkins School of Public Health, Hagerstown, MD 21742, USA.

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http://dx.doi.org/10.1093/aje/kwn327DOI Listing
October 2008

The Washington County Training Center: an exemplar of public health research in the field.

Am J Epidemiol 2008 Oct;168(7):676-82

Department of Epidemiology, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD, USA.

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http://dx.doi.org/10.1093/aje/kwn270DOI Listing
October 2008

Nonmelanoma skin cancer and risk for subsequent malignancy.

J Natl Cancer Inst 2008 Sep 26;100(17):1215-22. Epub 2008 Aug 26.

Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.

Background: Individuals with a personal history of nonmelanoma skin cancer (NMSC) may have an increased risk of subsequent noncutaneous malignancies. To test this hypothesis, we carried out a community-based, prospective cohort study.

Methods: In the CLUE (Give Us a Clue to Cancer and Heart Disease) II cohort, which was established in Washington County, MD, in 1989, the risk of new malignancies was compared among individuals with (n = 769) and without (n = 18,405) a personal history of NMSC (total n = 19,174) during a 16-year follow-up period. Pathologically confirmed NMSC (and other malignancies) were ascertained from the Washington County Cancer Registry. Cox regression analysis with time-dependent covariates was used to determine the hazard ratios (presented as multivariable-adjusted relative risks [RRs]) and 95% confidence intervals (CIs) of second primary malignancies associated with a previously confirmed NMSC diagnosis. All statistical tests were two-sided.

Results: The crude incidence rate (per 10,000 person-years) of subsequent cancers other than NMSC among participants with a positive personal history of NMSC was 293.5 and with a negative history was 77.8. Compared with persons with no personal history of NMSC, those with such a history had a statistically significantly increased risk of being diagnosed with a subsequent cancer other than NMSC (RR = 1.99, 95% CI = 1.70 to 2.33) after adjusting for age, sex, body mass index, smoking status, and educational level. The association was observed for both basal cell carcinoma (multivariable-adjusted RR = 2.03, 95% CI = 1.70 to 2.42) and squamous cell carcinoma (multivariable-adjusted RR = 1.97, 95% CI = 1.50 to 2.59) of the skin. NMSC was a statistically significantly stronger cancer risk factor in younger age groups than in older age groups (P for interaction = .022).

Conclusions: This community-based, prospective cohort study provides evidence for an association between an NMSC diagnosis and an increased risk of subsequent cancer, even after adjusting for individual-level risk factors.
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http://dx.doi.org/10.1093/jnci/djn260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720713PMC
September 2008

Non-cancer adverse health conditions and perceived health and function among cancer survivors participating in a community-based cohort study in Washington County, Maryland.

J Cancer Surviv 2008 Mar 12;2(1):12-9. Epub 2008 Feb 12.

Prevention and Research Center, Weinberg Center for Women's Health and Medicine, Mercy Medical Center, 227 St. Paul Place, Baltimore, MD 21202, USA.

Introduction: This study was conducted in an ongoing community-based cohort study to examine the prevalence of non-cancer adverse health conditions among cancer survivors and the association of these conditions with self-rated health and functional status.

Methods: Data were analyzed from CLUE II, a community-based cohort study in Washington County, Maryland that began in 1989. Cross-sectional comparisons were made between 1,261 cancer survivors and 1,261 age- and gender-matched individuals without a history of cancer. Information on non-cancer adverse health conditions, self-rated health, and activities of daily living was based on self-report.

Results: Compared to individuals without a history of cancer, cancer survivors were significantly more likely to report a diagnosis of cardiovascular disease (33.8% versus 29.8%; p = 0.009) and endocrine disease (other than diabetes) (17.0% versus 14.3%; p = 0.02). Further, cancer survivors reporting two or more non-cancer adverse health conditions had a greater likelihood of reporting fair or poor self-rated health (odds ratio (OR) 4.11; 95% confidence interval (95% CI) 3.06, 5.54), and difficulty with at least one activity of daily living (OR 6.03; 95% CI 4.01, 9.05) compared to cancer survivors who did not report other adverse health conditions.

Discussions/conclusions: Findings from this cross-sectional data analysis indicate that cancer survivors are at increased risk for non-cancer adverse health conditions, which are associated with poorer self-rated health, more interference with normal activities, and functional limitations.

Implications For Cancer Survivors: Increased attention must be given to the preventive care and treatment of non-cancer adverse health conditions among cancer survivors to decrease non-cancer morbidity and mortality and to maintain and improve quality of life.
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http://dx.doi.org/10.1007/s11764-008-0046-1DOI Listing
March 2008

Systemic activation of the transient receptor potential vanilloid subtype 4 channel causes endothelial failure and circulatory collapse: Part 2.

J Pharmacol Exp Ther 2008 Aug 22;326(2):443-52. Epub 2008 May 22.

Investigative and Cardiac Biology, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, UW2510, King of Prussia, PA 19406, USA.

The transient receptor potential (TRP) vanilloid subtype 4 (V4) is a nonselective cation channel that exhibits polymodal activation and is expressed in the endothelium, where it contributes to intracellular Ca2+ homeostasis and regulation of cell volume. The purpose of the present study was to evaluate the systemic cardiovascular effects of GSK1016790A, a novel TRPV4 activator, and to examine its mechanism of action. In three species (mouse, rat, and dog), the i.v. administration of GSK1016790A induced a dose-dependent reduction in blood pressure, followed by profound circulatory collapse. In contrast, GSK1016790A had no acute cardiovascular effects in the TRPV4-/- null mouse. Hemodynamic analyses in the dog and rat demonstrate a profound reduction in cardiac output. However, GSK1016790A had no effect on rate or contractility in the isolated, buffer-perfused rat heart, and it produced potent endothelial-dependent relaxation of rodent-isolated vascular ring segments that were abolished by nitric-oxide synthase (NOS) inhibition (N-nitro-L-arginine methyl ester; L-NAME), ruthenium red, and endothelial NOS (eNOS) gene deletion. However, the in vivo circulatory collapse was not altered by NOS inhibition (L-NAME) or eNOS gene deletion but was associated with (concentration and time appropriate) profound vascular leakage and tissue hemorrhage in the lung, intestine, and kidney. TRPV4 immunoreactivity was localized in the endothelium and epithelium in the affected organs. GSK1016790A potently induced rapid electrophysiological and morphological changes (retraction/condensation) in cultured endothelial cells. In summary, inappropriate activation of TRPV4 produces acute circulatory collapse associated with endothelial activation/injury and failure of the pulmonary microvascular permeability barrier. It will be important to determine the role of TRPV4 in disorders associated with edema and microvascular congestion.
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http://dx.doi.org/10.1124/jpet.107.134551DOI Listing
August 2008

A community-based study of cigarette smoking behavior in relation to variation in three genes involved in dopamine metabolism: Catechol-O-methyltransferase (COMT), dopamine beta-hydroxylase (DBH) and monoamine oxidase-A (MAO-A).

Prev Med 2008 Jul 1;47(1):116-22. Epub 2008 Apr 1.

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.

Objective: Cigarette smoking behavior may be influenced by catechol-O-methlyltransferase (COMT), dopamine beta-hydroxylase (DBH), and monamine oxidase-A (MAO-A), genes that play roles in dopamine metabolism. The association between common polymorphisms of these genes and smoking behavior was assessed among 10,059 Caucasian volunteers in Washington County, MD in 1989.

Methods: Age-adjusted logistic regression was used to measure the association between variants of these single nucleotide polymorphisms and smoking initiation and persistent smoking.

Results: Overall, no association was seen between each genotype and smoking behavior. However, among younger (<54 years) women, the COMT GG genotype was positively associated with smoking initiation (OR=1.3; 95% CI: 1.0 1.5), and the MAO-A TT genotype was inversely associated with persistent smoking (OR=0.7; 95% CI: 0.4, 1.0). Men who smoked fewer than 10 cigarettes per day were more likely to be persistent smokers if they had the COMT GG (OR=1.7; 95% CI: 1.0, 2.9) or the DBH GG (OR=1.6; 95% CI: 1.0, 2.5) genotypes.

Conclusion: Overall the results of this large community-based study do not provide evidence to support the presence of important associations between variants of COMT, DBH, or MAO-A and smoking initiation or persistent smoking.
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http://dx.doi.org/10.1016/j.ypmed.2008.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577854PMC
July 2008

ACSM clinician profile.

Authors:
Sandra Hoffman

Curr Sports Med Rep 2008 May-Jun;7(3):117

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http://dx.doi.org/10.1097/01.CSMR.0000319707.40922.25DOI Listing
August 2008

Genetic polymorphisms of peroxisome proliferator-activated receptors and the risk of cardiovascular morbidity and mortality in a community-based cohort in washington county, Maryland.

PPAR Res 2008 ;2008:276581

Prevention and Research Center, Weinberg Center for Women's Health and Medicine, Mercy Medical Center, 227 Street Paul Place, 6th Floor, Baltimore, MD 21202, USA.

The primary aim of this study was to examine prospectively the associations between 5 peroxisome proliferator-activated receptor (PPAR) single nucleotide polymorphisms (SNPs) and cardiovascular morbidity and mortality in a community-based cohort study in Washington County, Maryland. Data were analyzed from 9,364 Caucasian men and women participating in CLUE-II. Genotyping on 5 PPAR polymorphisms was conducted using peripheral DNA samples collected in 1989. The followup period was from 1989 to 2003. The results showed that there were no statistically significant associations between the PPAR SNPs and cardiovascular deaths or events. In contrast, statistically significant age-adjusted associations were observed for PPARG rs4684847 with both baseline body mass and blood pressure, and for PPARG rs709158, PPARG rs1175543, and PPARD rs2016520 with baseline cholesterol levels. Future studies should be conducted to confirm these findings and to explore the associations in populations with greater racial and ethnic diversity.
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http://dx.doi.org/10.1155/2008/276581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2233806PMC
July 2011

Single nucleotide polymorphisms in inflammation-related genes and mortality in a community-based cohort in Washington County, Maryland.

Am J Epidemiol 2008 Apr 7;167(7):807-13. Epub 2008 Feb 7.

Prevention and Research Center, Weinberg Center for Women's Health and Medicine, Mercy Medical Center, Baltimore, MD 21202, USA.

The purpose of this study was to examine the associations between single nucleotide polymorphisms (SNPs) in genes controlling inflammatory processes and mortality. Data were analyzed from 9,933 individuals who participated in two large community-based cohort studies conducted in Washington County, Maryland, in 1974 and 1989, designated "CLUE I" and "CLUE II," respectively. DNA from blood collected in 1989 was genotyped for 47 SNPs in 23 inflammation-related genes, including interferon-gamma (IFNgamma), lymphotoxin-alpha (LTalpha), tumor necrosis factor-alpha (TNFalpha), C-reactive protein (CRP), peroxisome proliferator-activated receptor (PPAR), and the human endothelial nitric oxide synthase (eNOS). All participants were followed from 1989 to the date of death or to June 20, 2005. The results showed no observable patterns of association for the SNPs and the all-cause and cause-specific mortality outcomes, although statistically significant associations were observed between at least one mortality outcome and SNPs in eNOS (reference SNP (rs) 1799983), PPARG (rs4684847), CRP (rs2794521), IFNgamma (rs2069705), TNFalpha (rs1799964), and LTalpha (rs2229094). Additionally, three of the four examined CRP SNPs were strongly associated with CRP serum concentration among those with CRP measurements. The authors' findings from this community-based prospective cohort study suggest that the selected SNPs are not associated with overall or cause-specific death, although CRP genotypes may be associated with systemic inflammation.
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http://dx.doi.org/10.1093/aje/kwm378DOI Listing
April 2008

Body mass, polymorphisms in obesity-related genes, and the risk of developing breast cancer among women with benign breast disease.

Cancer Detect Prev 2007 10;31(2):95-101. Epub 2007 Apr 10.

Prevention and Research Center, The Weinberg Center for Women's Health and Medicine, Mercy Medical Center, 227 St. Paul Place, Baltimore, MD 21202, USA.

Background: A cohort study was conducted among post-menopausal women to determine whether genetic polymorphisms in selected obesity-related genes (PPARG, LPL, LEPR, PON1, PON2, TNF-alpha) were associated with the progression of benign breast disease (BBD) to breast cancer and whether the selected polymorphisms modified the association between body mass and breast cancer among women with BBD.

Methods: Among participants in an ongoing cohort study, 994 Caucasian post-menopausal women had a breast biopsy for BBD. Of these women, 61 subsequently developed breast cancer. A short questionnaire was administered at baseline in 1989. Genotypes were determined using DNA extracted from blood collected in 1989.

Results: In this cohort, body mass index (BMI) was positively associated with the risk of developing breast cancer. In contrast, polymorphisms in PON1 (Gln192Arg) and LEPR (IVS2+6920) were associated with a decreased risk of developing invasive breast cancer. No statistically significant associations were observed for polymorphisms in PPARG, PON2, LPL, or TNF and breast cancer risk or for interactions between the polymorphisms and BMI and breast cancer risk.

Conclusions: The findings suggest that specific polymorphisms in the PON1 and LEPR genes may play a role in progression of BBD to breast cancer among post-menopausal Caucasian women.
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http://dx.doi.org/10.1016/j.cdp.2007.02.004DOI Listing
July 2007

Frequencies of single nucleotide polymorphisms in genes regulating inflammatory responses in a community-based population.

BMC Genet 2007 Mar 14;8. Epub 2007 Mar 14.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Background: Allele frequencies reported from public databases or articles are mostly based on small sample sizes. Differences in genotype frequencies by age, race and sex have implications for studies designed to examine genetic susceptibility to disease. In a community-based cohort of 9,960 individuals, we compared the allele frequencies of 49 single nucleotide polymorphisms (SNPs) of genes involved in inflammatory pathways to the frequencies reported on public databases, and examined the genotypes frequencies by age and sex. The genes in which SNPs were analyzed include CCR2, CCR5, COX1, COX2, CRP, CSF1, CSF2, IFNG, IL1A, IL1B, IL2, IL4, IL6, IL8, IL10, IL13, IL18, LTA, MPO, NOS2A, NOS3, PPARD, PPARG, PPARGC1 and TNF.

Results: Mean(SD) age was 53.2(15.5); 98% were Caucasians and 62% were women. Only 1 out of 33 SNPs differed from the SNP500Cancer database in allele frequency by >10% in Caucasians (n = 9,831), whereas 12 SNPs differed by >10% (up to 50%) in African Americans (n = 105). Two out of 15 SNPs differed from the dbSNP database in allele frequencies by >10% in Caucasians, and 5 out of 15 SNPs differed by >10% in African Americans. Age was similar across most genotype groups. Genotype frequencies did not differ by sex except for TNF(rs1799724), IL2(rs2069762), IL10(rs1800890), PPARG(rs1801282), and CRP(rs1800947) with differences of less than 4%.

Conclusion: When estimating the size of samples needed for a study, particularly if a reference sample is used, one should take into consideration the size and ethnicity of the reference sample. Larger sample size is needed for public databases that report allele frequencies in non-Caucasian populations.
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http://dx.doi.org/10.1186/1471-2156-8-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1838428PMC
March 2007

Nonsteroidal anti-inflammatory drugs and the risk of developing breast cancer in a population-based prospective cohort study in Washington County, MD.

Int J Cancer 2007 Jul;121(1):211-15

Prevention and Research Center, Weinberg Center for Women's Health and Medicine, Mercy Medical Center, Baltimore, MD 21202, USA.

The objective of this study was to examine the association between nonsteroidal anti-inflammatory drug (NSAID) use and the development of breast cancer, and to assess whether this association differed by estrogen receptor (ER) subtype. Data were analyzed from 15,651 women participating in CLUE II, a cohort study initiated in 1989 in Washington County, MD. Medication data were collected at baseline in 1989 and in 1996. Incident cases of invasive breast cancer occurring from baseline to March 27, 2006 were identified through linkage of cohort participants with the Washington County Cancer Registry and the Maryland State Cancer Registry. Cox proportional hazards modeling was used to calculate the risk ratios (RR) and 95% confidence intervals (95% CI) for breast cancer associated with medication use. Among women in the CLUE II cohort, 418 invasive breast cancer cases were identified during the follow-up period. The results showed that self-reported use of NSAIDs in both 1989 and in 1996 was associated with a 50% reduction in the risk of developing invasive breast cancer compared with no NSAID use in either 1989 or 1996 (RR = 0.50; 95% CI 0.28, 0.91). The protective association between NSAID use and the risk of developing breast cancer was consistent among ER-positive and ER-negative breast cancers, although only the RR for ER-positive breast cancer was statistically significant. Overall, findings from this study indicate that NSAID use is associated with a decrease in breast cancer risk and that the reduction in risk is similar for ER-positive and ER-negative tumors.
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http://dx.doi.org/10.1002/ijc.22656DOI Listing
July 2007

Meat and dairy consumption and subsequent risk of prostate cancer in a US cohort study.

Cancer Causes Control 2007 Feb;18(1):41-50

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Rm. E 6138, Baltimore, MD 21205, USA.

Objective: To evaluate the association of meat and dairy food consumption with subsequent risk of prostate cancer.

Methods: In 1989, 3,892 men 35+ years old, who participated in CLUE II study of Washington County, MD, completed an abbreviated Block food frequency questionnaire. Intake of meat and dairy related foods was calculated using consumption frequency and portion size. Incident prostate cancer cases (n = 199) were ascertained through October 2004. Cox proportional hazards regression was used to calculate hazard ratios (HR) of total and advanced (SEER states three and four; n = 54) prostate cancer and 95% confidence intervals (CI) adjusted for age, BMI at age 21, and intake of energy, saturated fat, and tomato products.

Results: Intakes of total mean (HR = 0.90, 95% CI 0.60-1.33, comparing highest to lowest tertile) and red meat (HR = 0.87, 95% CI 0.59-1.32) were not statistically significantly associated with prostate cancer. However, processed meat consumption was associated with a non-statistically significant higher risk of total (5+ vs. < or =1 servings/week: HR = 2.24; 95% CI 0.90-5.59) prostate cancer. There was no association across tertiles of dairy or calcium with total prostate cancer, although compared tp < or =1 servings/week consumption of 5+ servings/week of dairy foods was associated with an increased risk of prostate cancer (HR = 1.65, 98% CI 1.02-2.66).

Conclusion: Overall, consumption of processed meat, but not total meat or red meat, was associated with a possible increased risk of total prostate cancer in this prospective study. Higher intake of dairy foods but not calcium was positively associated with prostate cancer. Further investigation into the mechanisms by which processed meat and dairy consumption might increase the risk of prostate cancer is suggested.
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http://dx.doi.org/10.1007/s10552-006-0082-yDOI Listing
February 2007

Alcohol dehydrogenase genetic polymorphisms, low-to-moderate alcohol consumption, and risk of breast cancer.

Alcohol Clin Exp Res 2007 Mar;31(3):467-76

Department of Epidemiology, The Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.

Background: In vitro, human isoenzymes encoded by genes homozygous for the ADH1C*1 or ADH1B*2 alleles metabolize ethanol to acetaldehyde at a faster rate than those homozygous for the ADH1C*2 or ADH1B*1 allele. Because alcohol is a known risk factor for breast cancer, we evaluated the joint association of genetic variants in ADH and alcohol consumption in relation to breast cancer.

Methods: A nested case-control study of 321 cases and matched controls was conducted. Five single nucleotide polymorphisms (SNPs) in the ADH1C and ADH1B genes were genotyped. Logistic regression was used to assess odds ratios (ORs) and 95% confidence limits (CIs) for each SNP. Haplotype analysis of all 5 SNPs was also undertaken.

Results: Among drinkers, the median intake of total alcohol was 13 g/wk (10th-90th percentiles; 4.5-135.9) in cases and 18 g/wk (10th-90th percentiles; 4.5-104.1) in controls. Women who drank alcohol tended to be at an increased risk of developing breast cancer compared with those who did not drink (OR=1.40%, 95% CI 0.97-2.03), particularly those who were premenopausal at the time of breast cancer diagnosis (OR=2.69%, 95% CI: 1.00-7.26). Of the known functional alleles, breast cancer risk was not significantly increased among carriers of at least 1 ADH1C*1 or ADH1B*2 allele, when compared with those homozygous for the genotype at each locus. However, breast cancer risk tended to be lower among women who inherited the G allele at ADH1B IVS1+896A>G (OR=0.62, 95% CI 0.37-1.04). Overall haplotype frequencies were not significantly different between cases and controls.

Conclusions: In this study low levels of alcohol are associated with a modest increase in breast cancer risk that is not altered by known functional allelic variants of the ADH1B and 1C gene. The protective association conferred by the G allele at ADH1B IVS1+896A>G needs further evaluation.
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http://dx.doi.org/10.1111/j.1530-0277.2006.00334.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787101PMC
March 2007
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