Wake Forest, NC, United States
Wake Forest, NC, United States

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Svensson-Arvelund J.,Linköping University | Ernerudh J.,Linköping University | Buse E.,Covance | Cline J.M.,Section on Comparative Medicine | And 6 more authors.
Toxicologic Pathology | Year: 2014

During pregnancy, the maternal immune system is challenged by the semiallogeneic fetus, which must be tolerated without compromising fetal or maternal health. This review updates the systemic and local immune changes taking place during human pregnancy, including some examples in rodents. Systemic changes are induced by contact of maternal blood with placental factors and include enhanced innate immunity with increased activation of granulocytes and nonclassical monocytes. Although a bias toward T helper (Th2) and regulatory T cell (Treg) immunity has been associated with healthy pregnancy, the relationship between different circulating Th cell subsets is not straightforward. Instead, these adaptations appear most evidently at the fetal-maternal interface, where for instance Tregs are enriched and promote fetal tolerance. Also innate immune cells, that is, natural killer cells and macrophages, are enriched, constituting the majority of decidual leukocytes. These cells not only contribute to immune regulation but also aid in establishing the placenta by promoting trophoblast recruitment and angiogenesis. Thus, proper interaction between leukocytes and placental trophoblasts is necessary for normal placentation and immune adaptation. Consequently, spontaneous maladaptation or interference of the immune system with toxic substances may be important contributing factors for the development of pregnancy complications such as preeclampsia, preterm labor, and recurrent miscarriages. © 2013 by The Author(s).


PubMed | New York State Psychiatric Institute, Columbia University Medical Center, Section on Comparative Medicine and Columbia University
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2016

We recently reported the radiosynthesis and in vitro evaluation of [


PubMed | The Center for Botanical Lipids and Inflammatory Disease Prevention and Section on Comparative Medicine
Type: | Journal: Physiology & behavior | Year: 2016

Deficiencies in omega-3 (n-3) long chain polyunsaturated fatty acids (LC-PUFAs) and increases in the ratio of omega-6 (n-6) to n-3 LC-PUFAs in brain tissues and blood components have been associated with psychiatric and developmental disorders. Most studies have focused on n-3 LC-PUFA accumulation in the brain from birth until 2years of age, well before the symptomatic onset of such disorders. The current study addresses changes that occur in childhood and adolescence. Postmortem brain (cortical gray matter, inferior temporal lobe; n=50) and liver (n=60) from vervet monkeys fed a uniform diet from birth through young adulthood were collected from archived tissues. Lipids were extracted and fatty acid levels determined. There was a marked reduction in the ratio of n-6 LC-PUFAs, arachidonic acid (ARA) and adrenic acid (ADR), relative to the n-3 LC-PUFA, docosahexaenoic acid (DHA), in temporal cortex lipids from birth to puberty and then a more gradual decrease though adulthood. This decrease in ratio resulted from a 3-fold accumulation of DHA levels while concentrations of ARA remained constant. Early childhood through adolescence appears to be a critical period for DHA accretion in the cortex of vervet monkeys and may represent a vulnerable stage where lack of dietary n-3 LC-PUFAs impacts development in humans.


Melendez G.C.,Section on Cardiology | Manteufel E.J.,Medical College of Wisconsin | Dehlin H.M.,Medical College of Wisconsin | Register T.C.,Section on Comparative Medicine | Levick S.P.,Medical College of Wisconsin
Heart Lung and Circulation | Year: 2015

Background: The sensory nerve neuropeptide substance P (SP) regulates cardiac fibrosis in rodents under pressure overload conditions. Interestingly, SP induces transient increased expression of specific genes in isolated rat cardiac fibroblasts, without resultant changes in cell function. This suggests that SP 'primes' fibroblasts, but does not directly activate them. We investigated whether these unusual findings are specific to rodent fibroblasts or are translatable to a larger animal model more closely related to humans. Methods: We compared the effects of SP on genes associated with extracellular matrix (ECM) regulation, cell-cell adhesion, cell-matrix adhesion and ECM in cardiac fibroblasts isolated from a non-human primate and Sprague-Dawley rats. Results: We found that rodent and non-human primate cardiac fibroblasts showed similar responses in genes that relate to ECM regulation and cell adhesion in response to SP. There were large discrepancies in ECM component genes, however, this did not result in collagen or laminin synthesis in rat or non-human primate fibroblasts in response to SP. Conclusions: This study further supports the notion that SP serves as a 'primer' for fibroblasts rather than initiating direct effects and suggests that rodent fibroblasts are a suitable model for studying gene and functional responses to SP in the absence of human or non-human primate fibroblasts. © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).


Jorgensen M.J.,Section on Comparative Medicine | Aycock S.T.,Animal Resources Program | Clarkson T.B.,Section on Comparative Medicine | Kaplan J.R.,Section on Comparative Medicine
Journal of the American Association for Laboratory Animal Science | Year: 2013

Our goal was to assess a nonhuman primate diet that mimicked the Western-type diet of humans with regard to palatability and the diet's effects on plasma lipid concentrations and other cardiometabolic risk factors. We evaluated male (n = 8) and female (n = 11) African green monkeys (vervets; Chlorocebus aethiops sabaeus) that initially were fed a standard diet. Each cohort then was divided into 2 groups, which received either standard chow or the Western diet. Food consumption and fecal quality were measured weekly. Body weight, waist circumference, and body-mass index were measured every 2 wk. CBC and clinical chemistry analyses were performed at baseline and 4 wk after the diet change. Plasma lipid concentrations, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glucose, insulin, and fructosamine were measured at baseline and at 4, 8, and 12 wk after the diet change. Isoflavones were measured in the male monkeys at 6 wk after diet change, and lipid particle size was measured in the female monkeys at the 12-wk point. Green monkeys readily ate the Western diet and maintained baseline body weight and morphometric measures, with no adverse effects on fecal quality or clinical measures. Total plasma cholesterol was higher in monkeys fed the Western diet compared with standard chow. Isoflavones were higher in male monkeys fed standard chow compared with the Western diet, but lipid particle size did not differ by diet in female monkeys. Our data indicate that the Western diet led to changes in various biomedical risk factors of green monkeys to become similar to those of humans in the United States. Copyright 2013 by the American Association for Laboratory Animal Science.


Jasinska A.J.,University of California at Los Angeles | Lin M.K.,University of California at Los Angeles | Lin M.K.,University of Trier | Service S.,University of California at Los Angeles | And 16 more authors.
Human Molecular Genetics | Year: 2012

Non-human primates provide genetic model systems biologically intermediate between humans and other mammalian model organisms. Populations of Caribbean vervet monkeys (Chlorocebus aethiops sabaeus) are genetically homogeneous and large enough to permit well-powered genetic mapping studies of quantitative traits relevant to human health, including expression quantitative trait loci (eQTL). Previous transcriptome-wide investigation in an extended vervet pedigree identified 29 heritable transcripts for which levels of expression in peripheral blood correlate strongly with expression levels in the brain. Quantitative trait linkage analysis using 261 microsatellite markers identified significant (n 5 8) and suggestive (n 5 4) linkages for 12 of these transcripts, including both cis- and trans-eQTL. Seven transcripts, located on different chromosomes, showed maximum linkage to markers in a single region of vervet chromosome 9; this observation suggests the possibility of a master trans-regulator locus in this region. For one cis-eQTL (at B3GALTL, beta-1,3-glucosyltransferase), we conducted follow-up single nucleotide polymorphism genotyping and fine-scale association analysis in a sample of unrelated Caribbean vervets, localizing this eQTL to a region of <200 kb. These results suggest the value of pedigree and population samples of the Caribbean vervet for linkage and association mapping studies of quantitative traits. The imminent whole genome sequencing of many of these vervet samples will enhance the power of such investigations by providing a comprehensive catalog of genetic variation. © The Author 2012. Published by Oxford University Press.


Fang X.,Wake forest University | Gyabaah K.,Wake forest University | Nickkholgh B.,Wake forest University | Cline J.M.,Section on Comparative Medicine | And 2 more authors.
Prostate | Year: 2015

BACKGROUND The epithelial layer of prostate glands contains several types of cells, including luminal and basal cells. Yet there is paucity of animal models to study the cellular origin of normal or neoplastic development in the prostate to facilitate the treatment of heterogenous prostate diseases by targeting individual cell lineages. METHODS We developed a mouse model that expresses different types of fluorescent proteins (XFPs) specifically in prostatic cells. Using an in vivo stochastic fluorescent protein combinatorial strategy, XFP signals were expressed specifically in prostate of Protein Kinase D1 (PKD1) knock-out, K-RasG12D knock-in, and Phosphatase and tensin homolog (PTEN) and PKD1 double knock-out mice under the control of PB-Cre promoter. RESULTS In vivo XFP signals were observed in prostate of PKD1 knock-out, K-RasG12D knock-in, and PTEN PKD1 double knock-out mice, which developed normal, hyperplastic, and neoplastic prostate, respectively. The patchy expression pattern of XFPs in neoplasia tissue indicated the clonal origin of cancer cells in the prostate. CONCLUSIONS The transgenic mouse models demonstrate combinatorial fluorescent protein expression in normal and cancerous prostatic tissues. This novel prostate-specific fluorescent labeled mouse model, which we named Prorainbow, could be useful in studying benign and malignant pathology of prostate. Prostate 75:988-1000, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.


Morimoto Y.,University of Hawaii at Manoa | Killeen J.,University of Hawaii at Manoa | Killeen J.,Kapiolani Medical Center for Women and Children | Hernandez B.Y.,University of Hawaii at Manoa | And 2 more authors.
European Journal of Cancer Prevention | Year: 2013

It is well established that pregnancies protect against breast cancer; however, the mechanism involved is not completely understood. We investigated the influence of parity on hormonal and proliferation markers in benign tissue from tumor blocks of breast cancer cases. Women with breast cancer were recruited from a case-control study nested within the Multiethnic Cohort study. Tissue microarrays of benign tissue cores were available for 159 participants. Immunostaining for estrogen receptor α (ERα) and ERβ, progesterone receptor, human epidermal growth factor receptor 2 (Her2/neu), Ki-67, and proliferating cell nuclear antigen (PCNA) in epithelial tissue was evaluated by a pathologic expert. We applied logistic regression models to examine marker expression by parity (0, 1-2, and ≥3 live births with adjustment for age at diagnosis and BMI). Of the 159 women, 24 were nulliparous, 63 had one or two live births, and 72 had three or more live births. Inverse associations were observed between parity and expression of ERα (Ptrend=0.02) and PCNA (Ptrend=0.04). Among nulliparous women, 45.5% were ERα positive in contrast to 18.0 and 18.9% of women with one or two and at least three live births, respectively. The respective values for PCNA were 56.5, 44.3, and 31.1%. No associations were detected for ERβ, progesterone receptor, Her2/neu, and Ki-67. The current findings suggest that pregnancies may protect against breast cancer by reducing susceptibility to estrogenic stimuli and proliferative activity as assessed by the expression of ERα and PCNA in breast tissue. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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